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Multicomponent reactions in the synthesis of nitrogen heterocycles and their application to drug discovery
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Multicomponent reactions in the synthesis of nitrogen heterocycles and their application to drug discovery
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Content
MULTICOMPONENT REACTIONS
IN THE SYNTHESIS OF NITROGEN HETEROCYCLES
AND THEIR APPLICATION TO DRUG DISCOVERY
by
Alexey Butkevich
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
May 2011
Copyright 2011 Alexey Butkevich
ii
Dedication
This work
is gratefully dedicated
to Dr. Viktor V. Sokolov
iii
Acknowledgements
I would like to express my gratitude to Professor Nicos A. Petasis for giving me
an opportunity to work under his guidance. I greatly esteem his support and
encouragement throughout the years of my studies, the freedom I have enjoyed in my
research, as well as his devotion, enthusiasm and positive thinking every time it comes to
science.
I would like to thank my qualification exam and dissertation committee members,
Professor G. K. Surya Prakash, Professor Nouri Neamati, Professor Travis J. Williams
and Professor Thieo Hogen-Esch, for their time, suggestions and helpful discussions.
My heartfelt thanks go to all the past and present members of Petasis group
(trying to put chronologically): Petros Yiannikouros, Fotini Liepouri, Jasim Uddin, Wei
Huang, Kalyan Nagulapalli, Gosia Myslinska, Jeremy Winkler, Charles Arden, Min Zhu,
Kenny Young, Anne-Marie Finaldi, Jamie Jarusiewicz, Dave Rosenberg and Marcos
Sainz – for their help and friendship during the last five years. I must also thank Roppei
Yamada, Shili Xu, Srinivas Odde and all other students and postdocs from Dr. Neamati’s
lab who worked with us on the propiolamide project.
I am thankful to Kristen Aznavour and Tim Stewart for the X-ray analyses of my
samples. I will have nothing but my very best memories of their research advisor,
Professor Robert Bau, for his being always so open and ready to help and his valuable
suggestions.
iv
I am immensely grateful to all the supporting staff of the Loker Hydrocarbon
Research Institute and USC Department of Chemistry. I would specially like to thank
Carole Phillips, Heather Connor, Michele Dea, Jessy May, David Hunter, Danielle Hayes
and Katie McKissick for their hard work and constant support. I acknowledge Professor
Travis J. Williams, Allan Kershaw and Kenny Young for their help with NMR
experiments, Jim Merritt and Phillip Sliwoski for making and repairing our lab glassware,
and Drs. Michael Quinlan and James Ellern for being accessible and helpful through the
entire teaching plight. I am greatly indebted to all the people from Olah-Prakash group
for being there to help (and to have a cup of coffee) every time I had to ask.
To all my friends – they know who they are – I owe you the best of these five
years. In particular, I have been happy to have around my compatriots Mike Zibinsky,
Nadia Fomina, Inessa Bychinskaya, Misha Ryazanov, Anton Shakhmin, Victoria Piunova,
Katya Vaskova, Anna Popova and Vadim Mozhayskiy, all of whom I thank for their kind
support and good time spent together.
Last and most of all, I thank my parents for their incessant patience and
understanding, unyielding support and unconditional love.
v
Table of Contents
Dedication ii
Acknowledgements iii
List of Tables vii
List of Figures viii
Abstract xi
Chapter 1. Introduction. Multicomponent reactions and their role in drug discovery. 1
Chapter 1. References. 9
Chapter 2. Multicomponent synthesis of isoindoline derivatives. 11
2.1 Introduction. Synthetic approaches to isoindoline derivatives based on [4+2]
cycloaddition. 11
2.2 New multicomponent strategy for the synthesis of isoindolines. 29
2.3 Petasis-Diels-Alder reaction with salicylaldehydes. 30
2.3 Petasis-Diels-Alder reaction with heterocyclic aldehydes. 51
2.4 Petasis-Diels-Alder reaction with glyoxylic acid. 57
2.5 Petasis-Diels-Alder reaction with sugars and sugar ketals. 60
2.6 Experimental. 70
2.7 Chapter 2. References. 127
Chapter 3. Synthesis of 2H-chromenes and 1,2-dihydroquinolines from aryl
aldehydes and alkenylboron compounds. Petasis reaction with aliphatic aldehydes. 132
3.1 Introduction. Synthetic approaches to 2H-chromenes and 1,2-dihydroquinolines. 132
3.2 Synthesis of 2H-chromenes by catalytic Petasis reaction. 138
3.3 Synthesis of racemic α-tocopherol analog. 144
3.4 Novel synthesis of 1,2-dihydroquinolines from 2-sulfamidobenzaldehydes and
alkenyl trifluoroborates. 150
3.5 Three-component condensation with simple aromatic and aliphatic aldehydes. 162
3.6 Experimental. 175
3.7 Chapter 3. References. 206
Chapter 4. Synthesis of cytostatic propiolamide pseudodipeptides by Ugi reaction
and investigation into their mechanism of action. 211
4.1 Introduction. Classical Passerini and Ugi reactions. Ugi reaction with unusual
partners. 211
4.2 Discovery of cytotoxic propiolamide pseudodipeptides and resynthesis of the
initial set of 19 compounds. 222
vi
4.3 SAR studies in propiolamide pseudodipeptides. 228
4.4 Synthesis of fluorescent-tagged active compound and reference molecules for
intracellular imaging. 240
4.5 Mechanistic studies 245
4.6 Experimental 262
4.7 Chapter 4. References. 339
Chapter 5. Design and synthesis of human apurinic/apyrimidinic endonuclease type 1
(APE1) inhibitors. 344
5.1 Introduction. Dual function of APE1/Ref-1 and its known inhibitors. 344
5.2 Synthesis of the test compounds targeting Ref-1 redox function. 350
5.3 Synthesis of the test compounds targeting APE1 endonuclease activity. 357
5.4 Experimental 365
5.5 Chapter 5. References. 402
Conclusions 405
Bibliography 407
Appendix: Selected spectra 422
vii
List of Tables
Table 2.1. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-
Diels-Alder reaction: variation of the aldehyde structure................................................. 33
Table 2.2. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-
Diels-Alder reaction: variation of the allylamine structure (N-alkyl-N-allylamines)....... 37
Table 2.3. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-
Diels-Alder reaction: variation of the allylamine structure (N-allylanilines). .................. 39
Table 2.4. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-
Diels-Alder reaction: variation of the allylamine structure (substituted allylamines)...... 40
Table 2.5. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-
Diels-Alder reaction: heterocyclic aldehydes. .................................................................. 54
Table 2.6. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-
Diels-Alder reaction: reactions with glyoxylic acid. ........................................................ 59
Table 2.7. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-
Diels-Alder reaction: reactions with D- and L-arabinose.................................................. 66
Table 2.8. Crystallographic data and structure refinement details for 2.92. .................... 93
Table 3.1. Synthesis of 2H-chromene 3.10 mediated by tertiary amines....................... 144
Table 3.2. Synthesis of 1,2-dihydroquinoline 3.37, optimization of reaction
conditions........................................................................................................................ 153
Table 3.3. Synthesis of 1,2-dihydroquinolines by modified Petasis reaction. ............... 156
Table 3.4. Petasis reaction with aliphatic aldehydes...................................................... 169
Table 3.5. Effect of reaction conditions in the tandem aldol-Petasis reaction. .............. 173
Table 3.6. Crystallographic data and structure refinement details for 3.65. .................. 189
Table 4.1. In vitro cytotoxicity of the compounds 4.10, 4.13, 4.18, 4.14, 4.15
against human ovarian cancer cell lines.......................................................................... 229
viii
List of Figures
Figure 1.1. Mechanistic classification of multicomponent reactions................................. 2
Figure 1.2. Tandem MCR-cycloaddition reaction (Ugi 4CR + Diels-Alder). ................... 3
Figure 1.3. A union of two multicomponent reactions (Petasis 3CR ∩ Grigg 3CR)......... 4
Figure 1.4. Metal-catalyzed multicomponent reactions..................................................... 5
Figure 2.1. Atom numbering in isoindoline, 2H-isoindole, indoline and (1H-)indole. ... 11
Figure 2.2. Some naturally occurring isoindolines and indolines.................................... 13
Figure 2.3. Structural diversity of cytochalasans............................................................. 14
Figure 2.4. Synthetic approaches to hexahydro-1H-isoindoles based on Diels-Alder
reaction.............................................................................................................................. 15
Figure 2.5. Aromatic aldehydes proven unreactive in Petasis-Diels-Alder reaction....... 32
Figure 2.6. Kinetic studies of intramolecular Diels-Alder cyclization of 2.93................ 41
Figure 2.7. ORTEP drawing of 2.92 (50% thermal ellipsoids)........................................ 44
Figure 2.8. Diastereocontrol in Petasis-Diels-Alder reaction of sugars........................... 64
Figure 3.1. Two possible reactant combinations for the synthesis of isoindolines by
tandem Petasis-Diels-Alder reaction............................................................................... 140
Figure 3.2. Natural (2R)-tocopherols and tocotrienols, members of the vitamin E
family. ............................................................................................................................. 145
Figure 3.3. Retrosynthetic approach to the tocopherol analog 3.24. ............................. 146
Figure 3.4. Carbonyl compounds found unreactive in the synthesis of
1,2-dihydroquinolines. .................................................................................................... 158
Figure 3.5. ORTEP drawing of 3.65 (50% thermal ellipsoids)...................................... 159
Figure 4.1. Examples of “convertible” isocyanides....................................................... 221
ix
Figure 4.2. Cytotoxic propiolamides 4.10-4.28 identified in high throughput
screening. ........................................................................................................................ 225
Figure 4.3. Cytotoxic propiolamides 4.10, 4.13, 4.18, 4.14, 4.15 selected for SAR
studies. ............................................................................................................................ 229
Figure 4.4. Analogs of the compound 4.10.................................................................... 230
Figure 4.5. Analogs of the compounds 4.13 and 4.18 and their IC
50
values against
NCI/ADR cells................................................................................................................ 233
Figure 4.6. Loss of cytotoxicity in polar analogs of 4.10 (IC
50
values against
NCI/ADR cells). ............................................................................................................. 234
Figure 4.7. Variation of the amide group in 4.14 analogs (IC
50
values against
NCI/ADR cells). ............................................................................................................. 234
Figure 4.8. Variation of the anilide substitution in 4.14/4.15 analogs (IC
50
values
against OVCAR8 cells)................................................................................................... 235
Figure 4.9. Analogs of the compound 4.14 and their IC
50
values against OVCAR8
cells. ................................................................................................................................ 235
Figure 4.10. Analogs of the compound 4.51 and their IC
50
values against OVCAR8
cells. ................................................................................................................................ 236
Figure 4.11. Analogs of 4.14/4.51 lacking one aryl substituent and their IC
50
values
against OVCAR8 cells.................................................................................................... 238
Figure 4.12. Analogs of 4.13/4.75 lacking one aryl substitutent and their IC
50
values
against OVCAR8 cells.................................................................................................... 238
Figure 4.13. Structures and optical characteristics of the BODIPY fluorescent tag
4.81 and BODIPY FL EDA............................................................................................ 241
Figure 4.14. Subcellular localization of the fluorescent-tagged propiolamide 4.80
and the reference molecules 4.86, 4.87........................................................................... 244
Figure 4.15. Tyrosine kinase erbB1 inhibitors geftinib and canertinib. ........................ 245
Figure 4.16. Relative reaction rates between N-acetyl-L-cysteine and substituted
propiolamides 4.96-4.99. ................................................................................................ 249
x
Figure 4.17. Relative reaction rates between N-acetyl-L-cysteine and substituted
propiolamides 4.96-4.99 (pseudo-zero order kinetics). .................................................. 250
Figure 4.18. Determination of the kinetic equation for the reaction between 4.97
and N-acetyl-L-cysteine.................................................................................................. 251
Figure 4.19. Relative reaction rates between N-acetyl-L-cysteine and substituted
propiolamides 4.99-4.101 (pseudo-zero order kinetics). ................................................ 252
Figure 4.20. Relative reaction rates between N-acetyl-L-cysteine and 4.99 with
different amines (pseudo-zero order kinetics). ............................................................... 255
Figure 5.1. Short patch and long patch variations of base excision repair pathway...... 345
Figure 5.2. APE1/Mg
2+
-catalyzed DNA cleavage at the abasic site.............................. 347
Figure 5.3. Compounds inhibiting endonuclease activity of APE1............................... 350
Figure 5.4. Ref-1 redox and HEY-C2 cells growth inhibition of compound E3330
and its analogs................................................................................................................. 351
Figure 5.5. Acetylenic analogs of E3330....................................................................... 352
Figure 5.6. Dicarboxylic acid APE1 inhibitors and their IC
50
values............................ 358
Figure 5.7. Pyrrolone-based APE1 inhibitors, their IC
50
values and GOLD fitness
scores............................................................................................................................... 360
Figure 5.8. The analogs of compound 5.36.................................................................... 362
Figure 5.9. Keto-enol isomerization of the compound 5.57 under basic conditions. .... 364
xi
Abstract
This dissertation comprises two separate projects, relying on the use of
multicomponent reactions as a common theme. The introduction (Chapter 1) briefly
overviews the utility of multicomponent reactions highlighting their medicinal chemistry
applications. The first part (Chapters 2 and 3) describes the development of new practical
synthetic methodologies for one-step synthesis of nitrogen heterocycles (isoindolines and
dihydroquinolines) using three-component reaction of boronic acids, amines and
aldehydes (Petasis reaction) or its variations. The second part (Chapters 4 and 5) deals
with the applications of multicomponent reactions to the diversity oriented synthesis of
biologically active small molecules.
Chapter 2 reviews the known synthetic approaches to isoindoline derivatives
based on [4+2] cycloadditions and describes the development of our own methodology
based on tandem Petasis-Diels-Alder reaction, focusing on the expansion of the substrate
scope (salicylaldehydes, heterocyclic aldehydes, glyoxylic acid, sugars and sugar ketals)
and diastereoselectivity. Some transformations of the reaction products are also
investigated.
Chapter 3 briefly overviews the known syntheses of 1,2-dihydroquinolines,
discusses a new variation of catalytic version of Petasis reaction (2H-chromene synthesis,
catalyzed by tertiary amines) and development of trifluoroborate-based approach to 1,2-
dihydroquinolines. This methodology is further extended onto the novel trifluoroborate-
xii
based three-component reaction involving 2-sulfamidobenzaldehydes, simple aromatic
and aliphatic aldehydes.
Chapter 4 includes a short review of classical Passerini and Ugi reactions from the
mechanistic point, demonstrating the applicability of these reactions to the diversity-
oriented synthesis of a wide variety of drug-like molecules. An insight is given into
suggested biological mechanism of action of a series of 18 simple propiolamide
pseudodipeptides, prepared in one step by Ugi reaction. Structure-activity relationship
studies in a series of ~50 analogs prepared by Ugi reaction with some post-
multicomponent step modifications are described, and preparation of fluorescent
propiolamide-based tools for the identification of their intracellular targets is outlined.
The reactions of propiolamides with biologically relevant nucleophiles are studied by
NMR methods.
Chapter 5 describes the dual role of APE1/Ref-1 enzyme and briefly overviews a
small number of known small molecule inhibitors. A set of ~20 diverse molecules aimed
at selective targeting either its endonuclease or redox function is prepared using single-
step multicomponent and multistep synthetic approaches.
1
Chapter 1. Introduction. Multicomponent reactions and their
role in drug discovery.
Multicomponent reactions (MCRs) are convergent single-step chemical processes,
in which a specific product is formed from three or more starting materials. The reactants
interact with each other in a sequence of elementary steps according to a certain reaction
pathway, or program.
1
Mechanistically, three types of MCRs can be differentiated:
2,3
1)
type I reactions, in which all reaction substeps are equilibria; 2) type II MCRs, which
differ from type I reactions in that the final step (formation of a final product in the
sequence of subreactions) is irreversible and 3) type III MCRs, which are sequences of
irreversible reactions:
2
A
1
+ A
2
+ ... + A
n
[B] ... [Y] Z
(type I MCR)
... Z
(type II MCR)
... Z
(type III MCR)
A
1
+ A
2
+ ... + A
n
A
1
+ A
2
+ ... + A
n
[B]
[B]
[Y]
[Y]
R
O
+ NH
3
R NH
2
OH + H
+
, -H
2
O
- H
+
, +H
2
O
R
NH
2
+ CN
-
- CN
-
R NH
2
CN
R
1 O
+ R
2
CO
2
H
R
1 OH
R
2
CO
2
-
+ R
3
NC
- R
3
NC
R
1
OH
N
R
3
R
2
CO
2
-
R
1
OH
N
R
3
O
O
R
2
R
1
O
HN
R
3
O
R
2
O
(Strecker reaction)
(Passerini reaction)
SH
S
O
CoA
+
- CoASH
S
O
HO
2
C
S
O
CoA
- CO
2
, - CoASH
S
O O
...
(polyketide synthesis)
Figure 1.1. Mechanistic classification of multicomponent reactions.
Strecker synthesis and Mannich reaction are good examples of the type I MCR,
while isocyanide-based MCRs (Passerini and Ugi reactions) terminate with an
irreversible step (Mumm rearrangement) and therefore belong to type II. Similarly,
MCRs resulting in formation of a heterocyclic system (e.g., Hantzsch reaction) are
considered type II. The three-component reaction (3CR) of amines, organoboron species
and aldehydes, generally referred to as Petasis reaction, which was extensively studied in
our group in its many variations, also belongs to type II group of MCRs. As for type III
reactions, they are presently rare in preparative organic chemistry (though at least some
one-pot syntheses could be classified into this group),
4
but are important for biosynthetic
3
transformations (e.g., synthesis of polyketides from S-acylCoA units by polyketide
syntheses, or RNA polymerase-catalyzed elongation of RNA chain from ribonucleoside
triphosphates).
Generally, type II MCRs are preferred in synthetic organic chemistry, because
due to the presence of an irreversible step the overall reaction equilibrium is shifted in
favor of the product, and, with appropriate selection of substrates, these reactions tend to
yield a single product in high yield and usually under mild conditions.
1
Sometimes, if the
MCR products contain multiple functional groups or unsaturated fragments, they are
capable of intramolecular reactions or cycloadditions, so that the initial MCR product
undergoes further transformation under the reaction conditions. Such reactions have been
referred to as zipper, tandem, cascade or domino transformations, and represent an
efficient way to construct a polycyclic system, as can be illustrated with the following
example of a tandem Ugi-intramolecular Diels-Alder reaction:
5
N
N
N
O
Ph
NC
+
CO
2
H
PhNH
2
+
+
MeOH
60
o
C, 1 h
N
N
N
Ph
N
O NH
Ph
O
- N
2 N
N
Ph
O
NH
Ph
O
48%
Figure 1.2. Tandem MCR-cycloaddition reaction (Ugi 4CR + Diels-Alder).
Another approach to rapidly increase molecular complexity is unification of
several (in examples reported to date, two or three) multicomponent reactions. For
4
example, the union of Petasis 3CR and Ugi 4CR gives a 7CR union reaction. Some
Petasis 3CR-based union MCRs have been developed in our group,
6
for example:
OMe
B(OH)
2
+ BnNH
2
+
O
CO
2
H
+
O
O + N
O
O
PhMe
reflux
24 h
N
N
Bn
O O
MeO O
45%
Petasis 3CR
CO
2
H
NHBn
MeO
+
O
O + N
O
O
Grigg 3CR
- CO
2
Figure 1.3. A union of two multicomponent reactions (Petasis 3CR ∩ Grigg 3CR).
Most of the named multicomponent reactions rely on classic transition metal-free
electrophile-nucleophile interactions, which is an additional advantage for medicinal
chemistry applications, as it eliminates the necessity to remove trace metal impurities
from the products. However, the scope of MCR chemistry can be significantly expanded
with introduction of organometallic intermediates, with the scope of new possibilities
depending on the metal, due to activation of normally unreactive functional groups.
7
For
example, use of only Pd(0) catalysts would allow for activation of double and triple
carbon-carbon bonds towards nucleophilic attack, conversion of aryl and vinyl halides to
C-nucleophilic species, activation of allenes, 1,3-dienes and alkylidenecyclopropanes,
and conversion of allylic compounds (halides, acetates etc.) to electrophilic π-
allylpalladium species. Several examples of transition metal-enabled MCRs
8-10
are shown
in Figure 1.4:
5
I
+ Ph Ph + MeO B(OH)
2
PdCl
2
(5 mol%)
KF, DMF - H
2
O
100
o
C, 2 h
Ph Ph
OMe
93%
PhCHO + MeO NH
2
+ n-Bu
CuCl (30 mol%)
THF, reflux
N
MeO
Ph
n-Bu
48%
O
+ BnNH
2
+ CO
2
Me MeO
2
C
[Rh(CO)
2
Cl]
2
(5 mol%)
DCE, 60
o
C, 1.5 h
N Bn
MeO
2
C
CO
2
Me
89%
Figure 1.4. Metal-catalyzed multicomponent reactions.
Multicomponent reactions have been extensively employed in drug discovery as
valuable tools for both rapid generation of diverse libraries of small molecules and quick
modification of known active compounds with increase in structural complexity.
11
For
example, Ca
2+
channel modulator nifedipine (1.1), its long-acting analog amlodipine (1.2),
both approved drugs,
12
and monastrol
13
(1.3), mitotic kinesin Eg5 inhibitor (used as a
research tool) have all been prepared by one-step three-component condensations:
6
O
CO
2
Et
(2 eq)
+
O
NO
2
+ NH
3
Hantzsch 3CR
N
H
NO
2
CO
2
Et EtO
2
C
1.1
N
3
O
O
CO
2
Et
+
O
Cl
+
NH
2
CO
2
Me
1) Hantzsch 3CR
2) Pd/CaCO
3
N
H
Cl
CO
2
Et MeO
2
C
1.2
O
NH
2
O
CO
2
Et
+
O
OH
+
NH
2
S
H
2
N
Biginelli 3CR
N
H
NH
EtO
2
C
S
1.3
OH
Scheme 1.1.
Multicomponent reactions have found applications in de novo drug discovery, as
well as in process optimization for the synthesis of generic versions of drugs and in
search for novel analogs based on known active compounds. The high activity of
monastrol (1.3) was identified by screening of 16000 member Biginelli 3CR library.
14
In
more recent work,
15
a p38 α MAP kinase inhibitor 1.4 was prepared by unnamed four-
component condensation, based on tandem Knoevenagel condensation-Michael addition
(Scheme 1.2).
7
Br
O
+
O
O
+ AcO
-
NH
4
+
+
CN
CN
4CR
N
O
Br
NH
2
CN
1.4
Scheme 1.2.
A synthetic approach to an antiplatelet agent clopidogrel 1.5 (irreversible inhibitor
of P2Y
12
receptor) has recently been reviewed using the variations of Petasis and Ugi
3CRs,
16
allowing the preparation of the racemic molecule in just two steps from the
appropriate building blocks (Scheme 1.3):
NH
S
+
O
Cl
+
NC
1) Ugi 3CR
2) H
+
N
S
HO
2
C Cl
NH
S
+
B(OH)
2
Cl
+
Petasis 3CR
CO
2
H
O
N
S
HO
2
C Cl
MeOH, H
+
N
S
MeO
2
C Cl
1.5
81%
49%
90%
Scheme 1.3.
A series of oxazole-containing analogs 1.7 of known efficient antimalarial drug
chloroquine (1.6) have recently been prepared by 3CR version of Ugi reaction and
evaluated against chloroquine-resistant K1 strain of P. falciparum with promising
results
17
(Scheme 1.4):
8
N Cl
HN
NEt
2
N Cl
HN
NH
2
n
CN
Bn
O
N
O
Ugi 3CR
N Cl
HN
H
N
n
R
O
N
Bn
N
O
1.6
RCHO
+
+
1.7
Scheme 1.4.
In our group, a particular focus has been made on the practical application of
MCRs, primarily the three-component condensation of boronic acids, amines and
carbonyl compounds (Petasis reaction), to the synthesis of biologically active compounds.
As an example, a concise high-yielding stereoselective synthesis of (+)-cytoxazone 1.8
(unnatural isomer of the cytokine modulator (–)-cytoxazone, 1.9), starting from D-
glyceraldehyde, has been developed
18
(Scheme 1.5):
+
+
H
N
B(OH)
2
MeO
O OH
OH
Petasis 3CR
91%
MeO
OH
N
OH
1) Pd(dba)
2
, dppb
thiosalicylic acid
THF, 60
o
C, 1 h
2) Boc
2
O, Et
3
N
MeOH, 1 h
MeO
OH
HN
OH
Boc
Bu
t
OK (2 eq)
THF, RT
MeO
71%
97%
O
HN
OH
O
1.8
MeO
O
HN
OH
O
1.9
Scheme 1.5.
In continuation of these studies, the development of novel variations of Petasis reaction
and search for applications of this and other MCRs to medicinal chemistry problems are
underway. The present dissertation describes part of this ongoing work.
9
Chapter 1. References.
1
Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
2
Ugi, I. Pure Appl. Chem. 2001, 73, 187.
3
Ugi, I.; Werner, B.; Dömling, A. Molecules 2003, 8, 53.
4
Puri, N.; Hünsch, S.; Sund, C.; Ugi, I.; Chattopadhyaya, J. Tetrahedron 1995, 51, 2991.
5
Akritopoulou-Zanze, I.; Wang, Y.; Zhao, H.; Djuric, S. W. Tetrahedron Lett. 2009, 50,
5773.
6
Douglass, Bradley J. “Synthetic molecular programming and substrate-dependent drug
discovery: from multi-component reactions to cyclic peptides” Ph.D. thesis, University of
Southern California, 2006.
7
Balme, G.; Bouyssi, D.; Monteiro, N. Metal-catalyzed multicomponent reactions. In:
Zhu, J., Bienayme, H. Multicomponent reactions, Wiley-VCH, Weinheim, 2005.
8
Zhang, X.; Larock, R. C. Org. Lett. 2003, 5, 2993.
9
Syeda Huma, H. Z.; Halder, R.; Kalra, S. S.; Das, J.; Iqbal, J. Tetrahedron Lett. 2002,
43, 6485.
10
Wender, P.; Pedersen, T. M.; Scanio, M. J. C. J. Am. Chem. Soc. 2002, 124, 15154.
11
Hulme, C. Applications of multicomponent reactions in drug discovery – lead
generation to process development. In: Zhu, J., Bienayme, H. Multicomponent reactions,
Wiley-VCH, Weinheim, 2005.
12
Christen, D. P. Dihydropyridine calcium channel blockers for hypertension. In:
Johnson, D. S.; Li, J. J. The art of drug synthesis, Wiley Interscience, Hoboken, 2007.
13
Bose, D. S.; Sudharshan, M.; Chavhan, S. W. ARKIVOC 2005, 228.
14
Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.; Mitchison,
T. J. Science, 1999, 286, 971.
15
Serry, A. M.; Luik, S.; Laufer, S.; Abadi, A. H. J. Comb. Chem. 2010, 12, 559.
16
Kalinski, C.; Lemoine, H.; Schmidt, J.; Burdack, C.; Kolb, J.; Umkehrer, M.; Ross, G.
Synthesis 2008, 4007.
10
17
Musonda, C. C.; Little, S.; Yardley, V.; Chibale, K. Bioorg. Med. Chem. Lett. 2007, 17,
4733.
18
Raber, Jeffrey C. “Design and synthesis of novel heterocycles and peptidomimetics
from organoboronic acids, amines and carbonyl compounds” Ph.D. thesis, University of
Southern California, 2002.
11
Chapter 2. Multicomponent synthesis of isoindoline derivatives.
2.1 Introduction. Synthetic approaches to isoindoline derivatives based on
[4+2] cycloaddition.
Isoindoline is a heterobicyclic system, containing a benzene ring fused to the
double bond of 2,5-dihydro-1H-pyrrole. The suffix “-ine” refers to a single saturation,
and unlike the parent unsaturated compound, 2H-isoindole, isoindoline is a perfectly
stable molecule. The unsubstituted isoindoline can be prepared, for example, by reduction
of phthalimide,
1
debenzylation of 2-benzyl derivative
2
or hydrolysis of 2-tosyl
derivative;
3
it is also commercially available.
5
6
7
7a
3a
4
1
NH
3
2
5
6
7
7a
3a
4
1
NH
3
2
5
6
7
7a
3a
4
N
H
2
3
1
5
6
7
7a
3a
4
N
H
2
3
1
Isoindoline 2H-Isoindole Indoline Indole
Figure 2.1. Atom numbering in isoindoline, 2H-isoindole, indoline and (1H-)indole.
While isoindoline derivatives seem to be much less abundant among natural
products than their more common isomers, indolines and indoles (2H-isoindoles are
generally reactive compounds, and the only 2H-isoindole found in nature has a 4,7-
quinone structure),
4
numerous compounds have been isolated from plants, fungi and
animal sources. Recently, two simple isoindolines were isolated from dried bodies of
antlions (larvae of the species in the family Myrmeleontidae, used in traditional Chinese
medicine).
5
Several phytotoxic isoindolinones (among them zinnimidine and porritoxin)
12
were isolated from the culture liquid of fungus Alternaria porri, the causative agent of
black spot disease in leeks and onions.
6
Spiropachysine, a major alkaloid from leaves of
Pachysandra terminalis,
7
contains an isoindolin-1-one fragment spiroannelated to a
steroid-like perhydrocyclopentaphenanthrene core. Multiple erythrinaline alkaloids (for
example, (+)-crystamidine
8
or (+)-erythristemine
9
), isolated from a number of Erythrina
species, contain an indoline fragment with a partially reduced aromatic ring, annelated to
an isoquinoline system. Alkaloids form the plants of the family Berberidaceae (barberries)
often contain isoindolinone or isoquinolinone unit fused to a six-, seven- or even eight-
membered benzo-annelated nitrogen heterocycle, as can be illustrated with examples of
lennoxamine
10
and magallanesine.
11
Staurosporine, a nanomolar-level inhibitor of protein
kinase C,
12
isolated from Streptomyces staurosporeus, contains an isoindolinone motif
fused with two indole fragments. As can be seen from these diverse examples, most of
the natural isoindolines contain a carbonyl group in 1-position.
13
NH
OH
O
N
OH
O
OH
NH
OMe
O
O
N
OMe
O
O
OH
Zinnimidine Porritoxin
NMe
2
H
H N
O
Spiropachysine
O
O
N
O
MeO
(+)-Crystamidine
N
OMe
MeO
MeO
MeO
(+)-Erythristemine
O
O
N
O
OMe
OMe
Lennoxamine
O
O
N
O
O
OMe
OMe
Magallanesine
H
N
N N
O
O
MeO
NHMe
Staurosporine
unnamed isoindolines, isolated
from antlion larvae
Figure 2.2. Some naturally occurring isoindolines and indolines.
Probably best known for their practically useful biological properties isoindoline
derivatives are the mycotoxins of cytochalasan group. Their common structural feature is
a macrocyclic ring annelated to 7-7a bond of the saturated six-membered ring of
isoindolin-1-one; however, many open-chain analogues have been discovered since.
13
The members of cytochalasan family are further classified according to the substituent in
3-position of isoindoline ring: bearing a benzyl group (cytochalasins), 4-methoxybenzyl
group (pyrichalasins), (indol-3-yl)methyl group (chaetoglobosins) or isobutyl group
(aspochalasins).
14
Cytochalasins are potent, cell-permeable inhibitors of actin
14
polymerization; they achieve the inhibition by end-capping the fast growing end of the
actin chain,
15
blocking further monomer addition. This, in turn, results in inability of cell
to produce contractile microfilaments and blocks cytoplasmic division, arresting the cell
cycle in G1-S transition.
16
O HN
O
O
OH
H
OH
Cytochalasin B
HN
O
OH
H
Cytochalasin D
O
OH
AcO
HN
O
H
Cytochalasin G
N
H
O
O
O
OH
H
O
Dihydrocytochalasin B
O
HN
OH
O
δ -lactone
Cytochalasin Z
10
HO
OH
H
HN
OH
O
OH
HN
O
H
Phomacin C
O
OH
HO
Figure 2.3. Structural diversity of cytochalasans.
Synthetic approaches to polysubstituted isoindolines that do not start with
preformed isoindoline, isoindolin-1-one or phthalimide moiety may rely on a single (or
double) C–N bond formation to close the five-membered ring, or, more efficiently, on a
15
cycloaddition reaction with simultaneous formation of two carbon-carbon bonds. Because
of the goal of this chapter, this introduction will focus on [4+2] cycloaddition approach to
hexahydro-1H-isoindoles.
Four alternative retrosynthetic approaches to hexahydro-1H-isoindoles employing
Diels-Alder reaction can be considered:
N + N
N N
N N +
N N + (II)
(I) (III)
(IV)
Figure 2.4. Synthetic approaches to hexahydro-1H-isoindoles based on Diels-Alder
reaction.
From these, all except II rely on an intermolecular reaction. The route I was successfully
applied to a great variety of combinations with activated dienophiles, usually maleimide
derivatives (5,5-difluoro-1,5-dihydro-2H-pyrrol-2-one,
17
several porphyrins
18
and
hexaphyrins
19
were other successful examples). It has been shown that a proper selection
of triene instead of diene allows for performing the cycloaddition step twice, giving the
single diastereoisomer of the resulting polycyclic molecule as a major product (Scheme
2.1).
20
16
+ N
O
O
Ph
PhMe, 25
o
C
N
H
H
O
O
Ph
83%
+ N
O
O
Bu
t
CH
2
Cl
2
, 25
o
C
114 h
48 h
N
H
H
O
O
Bu
t
N
O
O
Bu
t
H
H
H N
H
H
O
O
Bu
t
N
O
O
Bu
t
H
H
H
+
80% (d.r. 96:4)
Scheme 2.1.
In another example, the reaction with a chiral dienophile (derived in several steps from
pyroglutamic acid) also gave a single diastereoisomer of the product (Scheme 2.2).
21
N
O
EtO
2
C
O
Ph
TMSO
OMe
+
PhMe, reflux
48 h
N
MeO
CO
2
Et
O
O
O
H
Ph
53%
Scheme 2.2.
Similar approach was used to prepare (–)-kainic acid, the parent member of a class of
marine natural products (Scheme 2.3).
22
17
N
MeO
2
C
Boc
CO
2
Me
+
TMSO
OMe
CH
2
Cl
2
, RT
15 kbar
N
Boc
CO
2
Me
O
MeO
2
C H
80%
N
H
CO
2
H
CO
2
H
(-)-Kainic acid
Scheme 2.3.
The routes III and IV are much more uncommon; the main reason for this seems
to be the prerequisite of having an appropriately substituted diene incorporating
pyrrolidine ring. However, the following synthesis of granulatimide analogues 2.1
23
relies
on the route III type of transformation.
N
H
H
N
O
O
R
+ NH
O
O
dioxane
170
o
C, 1 h
or MW, 200 W
N
H R
H
N
NH
O
O
O
O
DDQ
N
H R
H
N
NH
O
O
O
O
2.1
Scheme 2.4.
In works of Y. Yamamoto,
24,25
the intermediate 3,4-bis(methylene)pyrrolidines
2.3 (starting materials for route IV as shown on Figure 2.2) were generated by iridium-
catalyzed cyclization of N-allyl-N-propargylamines 2.2. This reaction by itself produces
2,3,4-trisubstituted pyrroles 2.4; however, in the presence of a dienophile the
intermediate dienes are intercepted and form, by further dehydrogenation, 4,5,6,7-
tetrahydro-2H-isoindoles 2.5.
18
N
Bn
Bu CO
2
Me
+ N
O
O
[Ir(cod)Cl]
2
(3 mol%)
AcOH (12 mol%)
toluene, MW
150
o
C, 0.5 h
N N Bn
MeO
2
C Bu
H
H
O
O
Ph
Ph
61%
N
Bu
MeO
2
C
Bn
[Ir]
N N Bn
MeO
2
C Bu
H
H
O
O
Ph
N Bn
MeO
2
C
Bu
15%
[4+2]
- H
2
2.2
2.3
2.4
2.5
Scheme 2.5.
Intramolecular Diels-Alder reaction (route II on Figure 2.2) is preferable to the
approaches listed above for enthropy reasons, but it requires an efficient method to
prepare the starting amine containing both diene and dienophile fragments. The majority
of examples involved furan ring as a diene partner and an electron-poor dienophile, such
as an acrylic or maleic acid amide. These were introduced easiest by acylation of
furfurylamines, either with maleic anhydride
26,27
or using peptide coupling reagents
(Scheme 2.6).
28
19
O
BnHN
R
2
R
1
+
R
4
R
3
CO
2
H
DIC, EtN(i-Pr)
2
DMAP (cat.)
CH
2
Cl
2
RT, 45 min
N
O
R
1
R
2
H
Bn
O
R
3
R
4
60-89%
O
ArHN
R
+ O
O
O
C
6
H
6
RT, 2-7 d
N
O
H
Ar
O
CO
2
H
R
52-77%
R = H or Me
Scheme 2.6.
When substituted maleic anhydrides are used, the pattern of substitution in furan diene
may affect the regioselectivity of the reaction (Scheme 2.7).
29
O
BnHN
+
MeS
O
O
O
C
6
H
6
65
o
C, 24 h
N
O
H
Bn
O
CO
2
H
80%
MeS
O
BnHN
+ O
O
O
C
6
H
6
65
o
C, 24 h
N
O
Bn
O
CO
2
H
92%
Scheme 2.7.
20
Notably, the intermolecular reaction of these dienes (with amino group protected in the
form of amide) with maleic anhydride fails under identical conditions.
30
Instead of the
carbonyl group activating the double bond of the dienophile, manganese and especially
tungsten vinylcarbenes behave as reactive dienophilic partners in this type of
intramolecular Diels-Alder reaction.
31
On the contrary, simple N-allyl-N-furfurylamines 2.6 do not undergo
intermolecular Diels-Alder reaction easily. With unsubstituted allyl, the reaction takes 60
days at ambient temperature or 3 days at 50 °C.
32
The reaction rate may be improved by
using 10% DMSO in water as a solvent and increasing temperature,
33
or by switching to
solvent-free conditions and using microwave irradiation (with 10 mol% In(OTf)
3
catalyst).
34
O
N
R
RT, 60 d or 50
o
C, 3 d
(R = Ar)
10% DMSO in H
2
O
108
o
C, 3 h
(R = Ts)
N
O
H
R
66-85% (R = Ar)
62% (R = Ts)
2.6 2.7
Scheme 2.8.
The Diels-Alder product 2.7 with R = Bn (Scheme 2.8) was found to be unstable,
reverting to the starting material upon attempted isolation.
33
This retro-Diels-Alder was
even more pronounced in case of 2-substituted allyls, making even the detection of the
Diels-Alder product 2.11 in the reaction mixture impossible, while the corresponding
21
acrylamide derivative 2.8 converted into the cycloaddition product 2.9 on heating.
35
An
attempt to reduce the lactam product with LiAlH
4
resulted in retro-Diels-Alder reaction
leading to 2.10:
O
N
Ph
N
O
Ph
O
N
Ph
N
O
Ph
O
O
LiAlH
4
, Et
2
O
reflux, 24 h
2.8 2.9 2.10 2.11
Scheme 2.9.
Furfurylamines, branched in α-position to the nitrogen, generally give mixtures of
diastereomeric Diels-Alder adducts, as can be illustrated with the following example:
36
O
NO
2
+
N
O
H
45% (d.r. 83:17)
H
N
reflux, 7 d
THF
O
2
N
Scheme 2.10.
Some success with running this reaction diastereoselectively and thus gaining
access to chiral hexahydroisoindolines from achiral precursors has been achieved with 8-
aminomenthol derivatives. First, the chiral allylamine 2.12 or furfurylamine 2.13 was
prepared from (–)-8-aminomenthol by alkylation or reductive amination, and the product
was then reacted with a furfural or α, β-unsaturated aldehyde to prepare the hemiaminal
ether, which underwent intramolecular [4+2] cycloaddition
37
(Scheme 2.11).
22
OH
H
N
O
+
O
PhMe
reflux, 80 h N
O
H
H
H
O
H
+
N
O
H
H
H
O
H
96% (d.r. 90:10)
OH
H
N
+
PhMe
reflux, 120 h N
O
H
H
H
+
93% (d.r. 97:3)
O
O
O
H
N
O
H
H
H
O
H
2.12
2.13
Scheme 2.11.
Similarly to reduction of 2.9 to 2.10 shown in Scheme 2.9, more substituted tricyclic
adducts (2.14, 2.15) suffered from spontaneous retro-Diels-Alder reaction on
deprotection (cleavage of aminomenthol auxiliary group):
N
O
H
H
H
O
H
AlH
3
THF, -10
o
C
N
OH
H
H
O
H
N
O
H
H
H
O
H
AlH
3
THF, -10
o
C
N
OH
H
H
O
H
Ph
Ph
Ph
Ph
1) PCC, CH
2
Cl
2
2) KOH
1) PCC, CH
2
Cl
2
2) KOH
O
N
H
Ph
2.14
2.15
Scheme 2.12.
Alternatively, chiral furfurylamines 2.17 could be prepared from aminomenthol-
derived hemiaminal ethers 2.16. Their acylation with acryloyl chlorides gave the amides
2.18, which underwent intramolecular Diels-Alder diastereoselectively
38
(Scheme 2.13).
23
N
O
H
H
Bn N
Ph
O
Li
THF, -90
o
C to -30
o
C
N
O
H
H
Bn
HN
Ph
O
Cl
O
, B
CH
2
Cl
2
, 0
o
C
N
O
H
H
Bn
PhN
O
O
50 - 60
o
C
24 h
N
O
H
H
Bn
N
O
H
O
Ph
95% over 2 steps
2.17
2.18
2.16
Scheme 2.13.
There are but a few reports in the literature about the use of dienes other than
furans in this type of isoindoline synthesis. Interestingly, many of them imply the Diels-
Alder reaction with inverse electron demands. For example, anthracene-9-carboxamides
2.19 bearing an allyl or propargyl substituent at the nitrogen atom were found to cyclize
on heating
39
(Scheme 2.14).
N
H
O
p-xylene
135
o
C, 5 h
HN
O
97%
2.19
Scheme 2.14.
Similarly, allylamides of cinnamic (2.20) and 2-furoic acid (2.21) were reported
to undergo intramolecular Diels-Alder reaction
40
(stereochemistry not specified in the
original paper):
24
HN
O
DMF
140
o
C, 30 h
HN
O
60%
HN
O
DMF
140
o
C, 12 h
HN
O
90%
O
O
2.20
2.21
Scheme 2.15.
1,3-Butadienes (2.22, 2.23) carrying an electron-withdrawing group can also undergo
intramolecular [4+2] cycloaddition with N-allylsulfamide fragment upon heating in
toluene. In this case, formation of a particular diastereoisomer of the product depends on
the nature of electron-withdrawing group, with some combinations of substituents giving
a mixture of diastereoisomers
41
(Scheme 2.16).
N
PhO
2
S
Ph
Ts
PhMe
reflux, 5 d
N PhO
2
S
Ph
Ts
H
91%
N
PhO
2
S
Ph
CN
PhMe
reflux, 5 d
N PhO
2
S
Ph
NC
H
85%
2.22
2.23
Scheme 2.16.
N-Allylated Zincke aldehydes (5-amino-2,4-pentadienals, 2.24), readily available
by aminolysis of pyridinium salts, undergo on heating a pericyclic rearrangement reaction
(6 π-electrocyclization – [1,5]-hydride shift – 6 π-electrocyclic ring opening) yielding N-
allylamides of 2,4-pentadienoic acid. Under the reaction conditions, these compounds
25
furnish the products of intramolecular [4+2]-cycloaddition (Diels-Alder reaction with
inverse electron demands). A variety of polysubstituted 2,3,3a,4,5,7a-hexahydro-1H-
isoindol-1-ones 2.25 were prepared in moderate to good yields using this methodology
42
(Scheme 2.17).
N
H
O
Bn
N
H
H
H
H
O
Bn N
O
Bn
O
H
N
O
H
52% 65% 76%
60%
N
O
H
H
73%
Ph
R
4
N
R
3
O
R
5
R
6
R
1
R
2
o-dichlorobenzene
200 - 220
o
C, w µ
N
R
2
R
1
R
6
R
5
R
4
O
R
3
Mechanism:
N O
R
N
E/Z
O
R
6 π
N
O
R
H
[1,5]
N
O
R
H
6 π
N
O
R
[4+2]
N
O
R
2.24
2.25
Scheme 2.17.
Gold(I)-catalyzed intramolecular [4+2]-cycloaddition of allenedienes 2.26 was
demonstrated to yield 4-methylene-2,3,3a,4,5,7a-hexahydro-1H-isoindoles 2.27
diastereoselectively and in high yields; however, proper selection of the catalyst proved
26
critical to avoid formation of the products of [4+3] and [2+2] cycloadditions
43
(Scheme
2.18).
N
C
Ts
(ArO)
3
PAuCl (10 mol%)
AgSbF
6
(10 mol%)
CH
2
Cl
2
, 0
o
C, 40 min
N
H
H
Ts
97%
Ar = 2,4-di(tert-butyl)phenyl
2.26 2.27
Scheme 2.18.
Enantioselective version of this reaction, with ee’s as high as 92-97% for certain
examples, has also been developed based on the use of extremely hindered chiral
binaphthole-phosphoramidite ligands.
Similarly, Rh(I)-catalyzed intramolecular [4+2] cycloaddition of enedienes 2.28-
2.30 proceeds diastereoselectively (d.r. from 9:1 to >80:1 and yields above 70% were
reported for a series of products),
44
for example:
27
N Ts
[Rh(cod)Cl]
2
(1 mol%)
(RO)
3
P, THF
55
o
C, 50 h
N
H
H
Ts
85%, d.r. > 80:1
R = hexafluoroisopropyl
N
Ts
[Rh(cod)Cl]
2
(1 mol%)
(RO)
3
P, THF
55
o
C, 36 h
N
H
Ts
73%, d.r. > 50:1
H
N Ts
Ph
(Ph
3
P)
3
Rh
+
SbF
6
-
(5 mol%)
PhMe, 80
o
C, 24 h
N
H
H
Ts
83%, d.r.9:1
Ph
2.28
2.29
2.30
Scheme 2.19.
Heck coupling reaction on N-cinnamyl- (2.31) or N-cinnamoylacrylamides (2.33)
at high temperatures proceeds with an interception of the alkylpalladium intermediate
through carbopalladation of the styryl C=C-bond followed by C–H insertion on the
aromatic ring ( σ-bond metathesis), and results in formation of tricycles (2.32, 2.34)
containing hexahydroisoindole fragment, which are structurally identical to the formal
[4+2] cycloaddition products
45,46
(Scheme 2.20).
28
N
Ph
Bn
PhI (1.1 eq)
(n-Bu)
3
N (2 eq)
Pd(OAc)
2
(2 mol%)
PPh
3
(4 mol%)
N
H
H
Bn
60%
O
Ph
DMF, 155
o
C
N
Ph
Bn
(n-Bu)
3
N (2 eq)
Pd(OAc)
2
(2 mol%)
PPh
3
(4 mol%)
N
H
H
Bn
79%
O
Ph
DMF, 155
o
C
O
+
Br
(1.1 eq)
O
O
O
2.31
2.32
2.33
2.34
Scheme 2.20.
As an alternative to the concerted [4+2] synthesis of isoindoline heterocycles,
radical cyclizations have been explored and were found feasible for certain combinations
of reactants and substitution patterns.
47
As stated above, the synthesis of isoindolines following route II (Figure 2.4)
requires an efficient method for preparation of the starting materials. Multicomponent
reactions offer great advantage by providing an easy way to achieve structural diversity,
as can be illustrated with the example reported by K. Paulvannan,
48
who used the Ugi
reaction for the single step multicomponent preparation of 5,7a-epoxy-2,3,3a,4,5,7a-
hexahydro-1H-isoindoles (2.35, 2.36) (Scheme 2.21). Both solution and solid phase
syntheses were attempted. The reaction was found to proceed with good
diastereoselectivity for compounds 2.35, while the presence of a stereocenter in the amine
side chain did not provide sufficient stereocontrol for 2.36:
29
O
O
+BnNH
2
+BnNC +
R
1
R
2
CO
2
H
MeOH
RT, 36 h
N
O
H
NHBn
O
Bn
R
2
R
1
O
89%, d.r. 92:8 (R
1
= CO
2
Et, R
2
= H)
70%, d.r. 92:8 (R
1
= H, R
2
= CO
2
Et)
++BnNC+
R
1
R
2
CO
2
H
MeOH
RT, 36 h
N
O
H
R
2
R
1
O
89%, d.r. 64:36 (R
1
= CO
2
Et, R
2
= H)
75%, d.r.60:40 (R
1
= H, R
2
= CO
2
Et)
Ph
O
O
H
2
N
Ph
O
NHBn
2.35
2.36
Scheme 2.21.
It was our goal to explore a multicomponent approach to polysubstituted
isoindoline derivatives, similar to 2.35 and 2.36, using the three-component Petasis
reaction.
2.2 New multicomponent strategy for the synthesis of isoindolines.
The efficiency of a single step multicomponent approach to the isoindoline core,
demonstrated in numerous examples above, prompted us to investigate the applicability
of the three-component condensation of boronic acids, amines and carbonyl compounds
as a first step of a novel tandem process
49
that would be followed by enthropy-favored
intramolecular [4+2]-cycloaddition. The proposed strategy is outlined in Scheme 2.22.
30
X
B(OH)
2
HN
R
5
R
4
O
R
1
R
2
R
3
R
9
R
10
R
8
R
6
R
7
Petasis 3CR X
R
1
R
2
R
3
R
4
N
R
5
R
6
R
7
R
8
R
9
R
10
[4+2]
X
R
1
R
2
R
3
N
R
10
R
9
R
8
R
7
R
6
R
5
R
4
stereochemistry?
A
1
+ A
2
+ ... + A
n
MCR
B
1
... B
m
C
starting materials
reactive intermediates
final product
General scheme of a tandem multicomponent reaction:
The proposed synthesis of isoindolines:
A
1
A
2
A
3
B
C
Scheme 2.22.
The following studies investigated the stereoselectivity of the cycloaddition step, the
scope of possible reaction partners and the limitations of this methodology.
2.3 Petasis-Diels-Alder reaction with salicylaldehydes.
The three-component reaction of salicylaldehydes, amines and aryl-, heteroaryl-
or alkenylboronic acids was reported by our group in 2001.
50
For most examples, the
yields varied between 60% and 80%. It was also noticed that the structure of an aromatic
aldehyde is critical to the success of the reaction: simple aryl aldehydes do not react, 2-
hydroxybenzaldehydes react easily while 3- or 4-hydroxybenzaldehydes are unreactive,
and more electron-rich 2,3,4-trihydroxy- or 2,4,6-trihydroxybenzaldehyde fail to give any
products of the three-component reaction. Aryl ketones are also unreactive, as was shown
on example of 2'-hydroxyacetophenone.
51
This suggested the coordination-activation
mechanism for the reaction, in which the presence of both iminium and boronate
31
fragments in close proximity to each other was required for the transfer of C-nucleophilic
group (R
4
on Scheme 2.23):
O
OH
R
1
+
R
2
NH
R
3
+ R
4
B(OH)
2
O
R
1
N
R
2
R
3
B
R
4
HO
OH
N
R
2
R
3
R
4
O
B
HO OH
R
1
N
R
2
R
3
R
4
OH
R
1
Scheme 2.23.
The best results were obtained when more reactive electron-rich boronic acids
(such as 4-methoxy-, 3,4-dimethoxybenzoic or furan-2-boronic acids) are used.
Alkenylboronic acids (e.g., 2-phenylvinylboronic acid) react easily, however in this case
other reaction pathways are possible (see Chapter 3). For the implementation of our
isoindoline strategy, the combination of furan-2-boronic acid as a source of internal diene
group, salicylaldehyde as a reactive carbonyl component and a secondary allylamine as a
source of dienophile fragment appeared quite favorable, with the presence of a phenol
functional group in the product allowing further modification, intramolecular reactions
and other diversity-oriented transformations.
Indeed, an attempted reaction between salicylaldehyde (2.42), furan-2-boronic
acid (2.38) and diallylamine (2.39) in ethanol at ambient temperature over 5 d afforded
66% of the target Petasis-Diels-Alder product 2.43 along with some unreacted
salicylaldehyde, while no open form compound 2.44 was detected (the stereochemistry of
2.43 was not proven at this point):
32
+
O
B(OH)
2
+
H
N
EtOH, RT O
OH
N
O
H
OH
5 d
N
O
HO
66%
not detected
2.42
2.38
2.39
2.43 2.44
Scheme 2.24.
In agreement with the earlier observations, simple aromatic aldehydes
(benzaldehyde (2.45), 4-methoxy- (2.46) and 4-nitrobenzaldehyde (2.47)) did not
participate in this reaction even after long reaction times (2 weeks) with heating to 75 °C.
Similarly, 5-bromo-2-methoxybenzaldehyde (2.48), 5-bromo-2-(2-
hydroxyethoxy)benzaldehyde (2.49) and 2-carboxybenzaldehyde (2.50) were all found
unreactive.
X
O O
Br
OMe
O
Br
O OH
O
O
OH
2.45 X = H
2.46 X = OMe
2.47 X = NO
2
2.48
2.49
2.50
Figure 2.5. Aromatic aldehydes proven unreactive in Petasis-Diels-Alder reaction.
Longer reaction times led to no improvement; however, with moderate heating
(70-75 °C) the reaction was complete in 24 h. The excess amount of furan-2-boronic acid
(1.5 eq), known to decompose gradually on heating, did not improve the yield
significantly while somewhat complicated the isolation of pure product during
chromatographic separation. The representative series of the tandem three-component
reaction-cycloaddition products was therefore prepared from several commercially
33
available aldehydes using stoichiometric quantities of the reagents in ethanol (0.4 M) at
70 °C over 24 h:
Table 2.1. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-Diels-
Alder reaction: variation of the aldehyde structure.
Entry Aldehyde
Boronic
acid
Amine Product
Yield,
%
1
O
OH
2.42
O
B(OH)
2
2.38
H
N
2.39
N
O
H
OH
2.43
60
2
O
OH
2.51
O
2
N
O
B(OH)
2
2.38
H
N
2.39
N
O
H
OH
2.52
O
2
N
53
3
O
OH
2.53
Br
O
B(OH)
2
2.38
H
N
2.39
N
O
H
OH
2.54
Br
85
4
O
OH
2.55
MeO
O
B(OH)
2
2.38
H
N
2.39
N
O
H
OH
2.56
MeO
57
34
Table 2.1 (continued)
Entry Aldehyde
Boronic
acid
Amine Product
Yield,
%
5
O
OH
2.57
Bu
t
Bu
t
O
B(OH)
2
2.38
H
N
2.39
N
O
H
OH
2.58
Bu
t
Bu
t
82
6
O
OH
2.59
O
B(OH)
2
2.38
H
N
2.39
N
O
H
OH
2.60
83
7
O
OH
2.53
Br
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
OH
2.62
Br
85
8
O
OH
2.59
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
OH
2.63
89
9
O
OH
2.64
OMe
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
OH
2.65
OMe
84
35
Table 2.1 (continued)
Entry Aldehyde
Boronic
acid
Amine Product
Yield,
%
10
N
O
OH
2.66
HO
HCl
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
N
OH
2.67
HO
81
a
a Sodium acetate (1 eq) was added to the reaction mixture.
The attempts to use 4-(diethylamino)-2-hydroxybenzaldehyde and 2,3-
dihydroxybenzaldehyde as aldehyde components in this reaction resulted in formation of
dark colored mixtures, from which no individual compounds could be isolated.
The reaction with N-alkyl-N-allylamines could also be performed as a one-pot
procedure, without isolation of the intermediate secondary amine, as can be illustrated
with the following preparation of compound 2.63:
Ph
O
+
NH
2
EtOH, RT, 1 h
then
NaBH
4
(0.5 eq)
RT, 3 h
Ph N
H
AcOH to pH = 6
O
OH
2.59
O
B(OH)
2
2.38
70
o
C, 24 h
2.61
2.45
2.68
N
Bn
O
H
OH
2.63
68%
Scheme 2.25.
36
The only reaction product with primary allylamine was the imine 2.69, and
addition of neither protic (p-toluenesulfonic, trifluoroacetic) nor Lewis acids (zinc triflate)
in stoichiometric amounts did not promote the three-component condensation:
+
O
B(OH)
2
+
O
OH
NH
O
H
OH
RT, 3 d
or
70
o
C, 24 h
not detected
2.59 2.38
2.70
EtOH
NH
2
2.68
N
OH
2.69
Scheme 2.26.
A variety of secondary allylamines, easily prepared either by alkylation of
primary amines with corresponding allyl bromides or by reductive amination, was tested
in Petasis-Diels-Alder reaction (Tables 2.2-2.4). N-Allyl-N-tritylamine failed to
participate in the three-component reaction, presumably by steric reasons, and was
recovered from the reaction mixture. The chiral allylamines were of particular interest in
terms of evaluation of diastereoselectivity of the reaction, however, all the observed de’s
were modest (<30%) and no attempts were made to establish the actual relative
configurations of major and minor stereoisomers (the compounds 2.77a and 2.77b could
not be separated on the column).
37
Table 2.2. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-Diels-
Alder reaction: variation of the allylamine structure (N-alkyl-N-allylamines).
Entry Aldehyde
Boronic
acid
Amine Product Yield, %
1
O
OH
2.59
O
B(OH)
2
2.38
H
N
2.71
OMe
N
O
H
OH
OMe
2.72
94
2
O
OH
2.42
O
B(OH)
2
2.38
H
N
2.73
Ph
2.74a
N
Ph
O
H
OH
N
Ph
O
H
OH
2.74b
40
(major),
14
(minor)
3
O
OH
2.59
O
B(OH)
2
2.38
H
N
2.73
Ph
2.75a
N
Ph
O
H
OH
N
Ph
O
H
OH
2.75b
57
(major),
17
(minor)
38
Table 2.2 (continued)
Entry Aldehyde
Boronic
acid
Amine Product Yield, %
4
O
OH
2.59
O
B(OH)
2
2.38
H
N
2.76
CO
2
Me
Ph
N
CO
2
Me
O
H
OH
N
CO
2
Me
O
H
OH
Ph
Ph
2.77a
2.77b
68
N-Allylaniline (2.77) did not react well at 70 °C, and no product was isolated after the
reaction was run at 120 °C in 2-methoxyethanol for 24 h. It was possible to prepare the
compounds 2.78 and 2.80 by running the reaction at 100 °C (solvent n-butanol, 24 h),
however the isolation of pure products required tedious separations and the isolated
yields were twice as low as compared to N-alkyl-N-allylamine reactants. Other solvents
were screened, giving either lower conversions (DMF, 1,4-dioxane, toluene) or no
product formation (acetic acid). Shorter reaction time (14 h) decreased the yield of 2.78
to 24%, while 48 h reaction resulted in complete loss of the product, apparently due to
decomposition. The electron-poor N-allyl-4-nitroaniline 2.81 proved completely
unreactive.
39
Table 2.3. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-Diels-
Alder reaction: variation of the allylamine structure (N-allylanilines).
Entry Aldehyde
Boronic
acid
Amine Product
Yield,
%
1
O
OH
2.59
O
B(OH)
2
2.38
NHPh
2.77
2.78
N
Ph
O
H
OH
38
2
O
OH
2.59
O
B(OH)
2
2.38
H
N
OMe
2.79
N
O
H
OH
OMe
2.80
40
3
O
OH
2.59
O
B(OH)
2
2.38
H
N
NO
2
2.81
N
O
H
OH
NO
2
2.82
—
2-Substituted allylamines were found generally as reactive as unsubstituted, however, the
substitution at 3-position resulted in formation of more complex mixtures and decreased
the yield of cycloadducts significantly:
40
Table 2.4. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-Diels-
Alder reaction: variation of the allylamine structure (substituted allylamines).
Entry Aldehyde
Boronic
acid
Amine Product
Yield,
%
1
O
OH
2.59
O
B(OH)
2
2.38
NHBn
2.83
N
Ph
O
OH
2.84
76
2
O
OH
2.59
O
B(OH)
2
2.38
NHBn
2.85
Br
N
Ph
O
Br
OH
2.86
89
3
O
OH
2.59
O
B(OH)
2
2.38
NHBn
2.87
Ph
N
Ph
O
H
OH
2.88
Ph
35
4
O
OH
2.59
O
B(OH)
2
2.38
NHBn
2.89
N
Ph
O
H
OH
2.90
11
5
O
OH
2.59
O
B(OH)
2
2.38
NHBn
2.91
Ph
N
Ph
O
H
OH
2.92
Ph
83
41
When the reaction with N-allyl-N-(E)-cinnamylamine (2.87) (entry 3, Table 2.4)
was run in ethanol at room temperature, the product of three-component condensation
(2.93) precipitated in good yield:
OH
O
+
O
B(OH)
2
+ Ph NHBn
EtOH
RT, 24 h
OH
N
O
Ph
Bn
2.59
2.38
2.87
2.93
79%
Scheme 2.27.
OH
N
O
Ph
Bn
H
N
Ph
O
H
OH
Ph H
CDCl
3
, 19
o
C
2.93
2.88
C
0
= 0.09 M
Figure 2.6. Kinetic studies of intramolecular Diels-Alder cyclization of 2.93.
This compound underwent spontaneous cyclization to 2.88 in solution; over
prolonged reaction times, yellow discoloration and build-up of unidentified byproducts
42
were observed. The reaction followed zero-order kinetics (Figure 2.6), as expected for an
intramolecular process, with reaction constant k = 5 · 10
-7
mol·L
-1
·s
-1
(0.09 M in CDCl
3
at
19 °C), and was slower in DMSO-d
6
under identical conditions (2 · 10
-7
mol·L
-1
·s
-1
). The
scale-up and isolation of pure 2.88 proved difficult, as even mild heating of the solutions
and attempts to purify the reaction mixture on silica resulted in formation of bright
yellow-orange oil, from which no individual products of decomposition could be isolated,
and loss of significant part of the material. The analytically pure sample of 2.88 was
obtained by chromatography of the reaction mixture on neutral alumina.
The reversibility of intramolecular cycloaddition was proven by equilibrating the
solutions of 2.88 and 2.93 in CDCl
3
at room temperature (25 °C) over 2 week period,
which in both cases resulted in formation of the mixture 2.93:2.88 in 10:90 ratio,
excluding the byproduct(s) not taken into account. An attempt to alkylate the phenol
hydroxyl group yielded the mixture of open (2.94) and cyclic from (2.95) of the alkylated
compound (which were not separated and characterized) in 60:40 ratio after similar
equilibration in CDCl
3
solution. This suggested an important role of intramolecular
hydrogen bond formation between the OH-group of phenol and the amine nitrogen in
facilitation of the intramolecular Diels-Alder reaction:
43
OH
N
O
Ph
Ph
N
Ph
O
H
O
Ph
MeI, Cs
2
CO
3
, DMF
RT, overnight
OMe
N
O
Ph
Ph
H
N
Ph
O
H
OMe
Ph
2.93 2.88
2.94 2.95
10 (2.93) : 90 (2.88)
(CDCl
3
, 25
o
C, 14 d)
60 (2.94) : 40 (2.95)
(CDCl
3
, 25
o
C, 14 d)
Scheme 2.28.
The possibility of stabilization of the Diels-Alder products with the adjacent
phenol ring was further corroborated by the crystal structure of the compound 2.92. The
positions of O2 and N1 atoms suggest the presence of an intramolecular hydrogen bond
in the crystal (Figure 2.7).
44
Figure 2.7. ORTEP drawing of 2.92 (50% thermal ellipsoids).
The structure of 2.92 was also used to unambiguously determine the relative
stereochemistry in the entire series of isoindoline derivatives described above.
Only limited variation of boronic acid partner was attempted because of limited
commercial availability of substituted furan-2-boronic acids. 5-Methylfuran-2-boronic
acid (2.96) afforded the Petasis-Diels-Alder product 2.97 only when the reaction was run
for 3 d at room temperature (by the end of this time the pure product precipitated);
running the reaction at 70 °C resulted in orange-red discoloration of the reaction mixture
and decomposition:
45
+O
B(OH)
2
+
O
OH
RT, 3 d
2.59
2.96
EtOH
NHBn
2.68
N
Bn
O
H
OH
2.97
73%
Scheme 2.29.
The reactions with 5-formylfuran-5-boronic acid underwent quick and visible
decomposition even when run at room temperature. Benzofuran-2-boronic acid reacted
cleanly at room temperature, giving only the three-component reaction product; further
heating of the reaction mixture resulted in formation of bright-orange material, from
which no individual decomposition products could be isolated. The product of the three-
component reaction between 2-phenylvinylboronic acid, 2.59 and 2.61 also decomposed
on heating without intramolecular cyclization. The attempts to use 1-Boc-pyrrole-2-
boronic acid as an intramolecular diene source failed for similar reasons.
Given an ability to easily produce the 1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindoles in a single-step transformation and in practicable yields, further
transformations of these molecules were to be investigated from the diversity standpoint.
An aromatization reaction of the similar heterocycle 2.98 into isoindoline 2.99 was
reported to proceed in good yield on heating its solution in acetic acid with aqueous
hydrobromic acid
52
(Scheme 2.30).
46
N Bn
O
HBr, AcOH
60
o
C, 2 h
N Bn
2.98 2.99
Scheme 2.30.
This system was chosen as the starting conditions for aromatization of the compound
2.63. The first results, however, were not encouraging, as even though the starting
material was consumed completely after 2 h heating at 70 °C, a mixture of products
formed, from which the individual compound 2.100 was isolated in low yield:
N
Bn
O
H
OH
2.63
HBr, AcOH
70
o
C, 2 h
N
O
Bn
OAc
H
H
2.100
23%
Scheme 2.31.
Substitution of HBr with HCl still resulted in formation of mixture, but increased the
yield of 2.100 to 59%; it was therefore suggested that the use of an acid with non-
nucleophilic anion might improve the yield. However, the reaction failed completely with
catalytic amound (5 mol%) of p-toluenesulfonic acid. Gratifyingly, use of
methanesulfonic acid (5 eq) provided the target 2.100 in high yield:
47
N
Bn
O
H
OH
2.63
MsOH (5 eq)
AcOH
70
o
C, 2 h
N
O
Bn
OAc
H
H
2.100
92%
Scheme 2.32.
An attempt to decrease the amount of acid catalyst was not successful: with just 1
eq of MsOH, no 2.100 was formed, as one equivalent of acid was deemed necessary for
the stoichiometric protonation of the amine nitrogen. Intermediate quantities (2 eq) of
MsOH resulted in incomplete conversion and less clean reaction.
The compound 2.62 was similarly converted to the tetracyclic product 2.101:
N
Bn
O
H
OH
2.62
MsOH (5 eq)
AcOH
70
o
C, 2 h
N
O
Bn
OAc
Br
H
H
2.101
90%
Br
Scheme 2.33.
In case of 2.67, however, the cyclization involved the alcohol hydroxyl group
(rather than OH of phenol) acting as a nucleophile, resulting in a different polycyclic
system of 2.102:
48
N
Bn
O
H
N
OH
2.67
MsOH (5 eq)
AcOH
70
o
C, 2 h
2.102
86%
HO
N
OAc
Bn
H
N
O
OH
H
Scheme 2.34.
When trifluoroacetic acid was used as a solvent instead of acetic acid, the
expected aromatized isoindoline 2.103 was formed in 60% yield. Without the addition of
methanesulfonic acid, the trifluoroacetate analogue (2.104) of compound 2.100 was
prepared but could not be isolated in pure state, probably due to easy elimination of
trifluoroacetic acid and/or hydrolysis of trifluoroacetate on silica and subsequent
decomposition with formation of green-colored byproducts. Alternatively, the
aromatization of 2.63 can be run in neat methanesulfonic acid, requiring shorter reaction
time (1 h) and providing 2.103 in slightly improved yield (68%):
N
Bn
O
H
OH
2.63
MsOH (5 eq)
CF
3
CO
2
H
70
o
C, 2 h
or
MsOH
70
o
C, 1 h
60-68%
N
Bn
OH
2.103
N
O
Bn
OCOCF
3
H
H
2.104
Scheme 2.35.
49
The transformation of type 2.63 Æ 2.100 can be explained to proceed via the
acid-catalyzed ring opening of 7-oxabicyclo[2.2.1]hept-2-ene system followed by the
interception of an intermediate allyl cation with an internal nucleophile (OH of phenol or
alcohol), resulting in formation of the compound 2.105 that is then esterified under
reaction conditions with acetic or trifluoroacetic acid to give 2.100 or 2.104, respectively:
N
Bn
OH
H
OH
2.63
H
+
N
Bn
H
HO
OH
- H
+
N
O
Bn
OH
H
H
2.105
RCO
2
H
H
+
cat.
2.100
or
2.104
Scheme 2.36.
Indeed, when the compound 2.63 was treated with methanesulfonic acid in 1,4-dioxane,
2.105 was formed in 72% yield, even though the reaction was much slower in this case.
Alternatively, it was prepared by hydrolysis of 2.100 in nearly quantitative yield:
N
Bn
O
H
OH
2.63
MsOH (5 eq)
1,4-dioxane
70
o
C, 24 h
N
O
Bn
OH
H
H
2.105
72%
K
2
CO
3
(2 eq)
MeCN - MeOH - H
2
O
N
O
Bn
OAc
H
H
2.100
~100%
RT, 1 h
Scheme 2.37.
50
Only trace amounts of the compound 2.105 were detected in the reaction mixture when
this reaction was run in ethanol or water (most of 2.63 remained unchanged after 24 h at
70 °C). The attempts to intercept the allyl cation intermediate in an intermolecular
reaction with a nucleophile (2 eq of 4-methoxythiophenol, 5 eq of MsOH, 1,4-dioxane,
70 °C, 24 h) or to achieve one-pot esterification of 2.105 with stoichiometric amounts of
carboxylic acid (1.1 eq of 4-nitrobenzoic acid, 5 eq of MsOH, 1,4-dioxane, 70 °C, 22 h or
1.1 eq of AcOH, 5 eq of MsOH, 1,4-dioxane, 70 °C, 22 h) were unsuccessful.
Epoxidation of the double bond in 2.63 could not be achieved under a variety of
conditions (mCPBA in CH
2
Cl
2
, 0 °C to RT; H
2
O
2
in AcOH, RT; H
2
O
2
in Ac
2
O, RT).
However, the conditions for successful epoxidation of endic hydrazides
53
have been
reported in the literature, under which peroxyformic acid is the active epoxidating agent.
Running the epoxidation reaction under those conditions afforded the expected exo-
epoxide 2.106 in 68% yield (along with 12% of recovered starting material). All attempts
to rearrange this compound under acidic conditions resulted only in intractable mixtures.
N
Bn
O
H
OH
2.63
H
2
O
2
(50%) (2 eq)
HCO
2
H (98%)
RT, 2 h
N
Bn
O
H
OH
2.106
O
68%
Scheme 2.38.
Some transition metal-catalyzed transformations of the prepared isoindoline derivatives
were also explored. Several attempts at Rh(I)-catalyzed ring opening of 7-
51
oxabicyclo[2.2.1]hept-2-ene system of 2.63 (with 3 mol% of [Rh(cod)Cl]
2
catalyst and 6
mol% of dppf ligand in anhydrous THF at 75 °C in closed vial), as described by
Lautens,
54
were unsuccessful in either intramolecular (with or without stoichiometric
amount of Et
3
N added) or intermolecular (with 5 eq of N-methylaniline) versions. Pd(0)-
catalyzed allylic substitution of acetate in 2.100 proceeded in nearly quantitative yield
and was regioselective, but afforded a mixture of two diastereoisomers of 2.107 in 1:1
ratio:
N
O
Bn
OAc
H
H
2.100
+
N
H
O
(1.5 eq)
Pd(PPh
3
)
4
(5 mol%)
MeCN
70
o
C, 1 h N
O
Bn
N
H
H
2.107
O
99.5%
Scheme 2.39.
2.3 Petasis-Diels-Alder reaction with heterocyclic aldehydes.
Several heterocyclic aldehydes possessing a heteroatom in ortho-position to the
aldehyde group have been reported to participate in the three-component condensation
with amines and boronic acids,
55
however the yields were impracticably low. Earlier in
our group, several successful examples have been identified. 2- and 4-
imidazolecarbaldehydes were reported to react with primary and secondary amines and 2-
52
phenylvinylboronic acid to give the products of three-component condensation in yields
not exceeding 50%,
56
for example:
N
H
N
O
+
Ph
B(OH)
2
+ NNH
PhMe
reflux, 17 h
N
H
N N
N
Ph
39%
N
H
N
O
+
Ph
B(OH)
2
+
PhMe
reflux, 17 h
N
H
N HN Ph
Ph
31%
PhNH
2
Scheme 2.40.
2-Pyridinecarbaldehyde reacted with boronic acids and secondary or primary
amines (with the latter in the presence of anhydrous MgSO
4
or p-toluenesulfonic acid)
affording the three-component reaction products in 15-83% yields
57
(Scheme 2.41).
53
N
O
+ NNH Boc +
S
B(OH)
2
MeCN
reflux, 28 h
N
N
S
N
Boc
57%
N
O
+
Ph
B(OH)
2
+BnNH
2
PhMe, MgSO
4
RT, 2 d
N
HN
Bn
Ph
69%
N
O
+
N NH
2
MeO B(OH)
2
+
TsOH H
2
O (0.5 eq)
RT, 3 h
CH
2
Cl
2
N
HN
74%
OMe
N
Scheme 2.41.
It was therefore of interest to evaluate a variety of heterocyclic aldehydes as possible
partners in tandem Petasis-Diels-Alder reaction. For most of the examples, the conditions
optimized for the reaction with salicylaldehydes were quite satisfactory (Table 2.5);
however, use of acetonitrile as a solvent was mandatory in case of pyridine-type
aldehydes, while for the aldehydes with pyrrole-type nitrogen the results were superior in
ethanol:
Het CHO +
O
B(OH)
2
+
NHBn
EtOH or MeCN
70
o
C, 24 h
N
Bn
Het
H O
Scheme 2.42.
54
Table 2.5. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-Diels-
Alder reaction: heterocyclic aldehydes.
Entry Aldehyde
Boronic
acid
Amine Product
Yield,
%
1
N
H
N
O
2.108
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
N
NH
2.109
85
2
N
H
N
O
2.110
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
N
NH
2.111
37
3
N
H
N
O
2.112
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
N
NH
2.113
71
4
H
N
O
2.114
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
NH
2.115
50
5
2.116
NH O
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
NH
2.117
41
55
Table 2.5 (continued)
Entry Aldehyde
Boronic
acid
Amine Product
Yield,
%
6
H
N
O
2.118
EtO
2
C
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
NH EtO
2
C
2.119
24
7
N
O
2.120
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
N
2.121
63
a
8
N
S
O
2.122
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
S
N
2.123
13
a
a Acetonitrile was used as a solvent.
The requirement for a coordinating group in ortho position to the carbonyl in the
aldehydes molecule suggested that, just as in the case of salicylaldehydes (Scheme 2.23),
the coordination of boronic acid to form the reactive tetracoordinate boronate species (A,
B in Scheme 2.43) is critical for the success of the reaction. This coordination must be
weaker for pyridine-type aldehydes, as more susceptible to hydrolysis pyridinium
complex B is formed, requiring the use of aprotic solvent:
56
O
+
R
2
NH
R
3
+ R
4
B(OH)
2
N
R
2
R
3
N
R
2
R
3
R
4
N
R
2
R
3
R
4
X
NH
R
1
X
N
B
R
4
HO OH
R
1
A
X
N
B
HO
OH
R
1
X
NH R
1
N
X
O
R
1
+
R
2
NH
R
3
+ R
4
B(OH)
2
N
X
R
1
N
R
2
R
3
N
X
N
R
2
R
3
R
4
B
OH
R
1
N
X
N
R
2
R
3
R
4
R
1
B
R
4
HO OH
B
OH
Scheme 2.43.
Several other aldehydes failed to participate in the reaction for various reasons. 4-
(Hydroxymethylidene)-3-methyl-1H-pyrazol-5-one (2.124, tautomeric form of 5-
hydroxy-3-methyl-1H-pyrazole-4-carbaldehyde) was only converted to the 1:1 mixture of
(E/Z)-enamines (2.125), which seemingly failed to react with boronic acid:
N
N
H
O
OH
N
N
H
OH
O
NHBn
2.61
EtOH
RT, 24 h
N
N
H
O
N
Bn
2.124
2.125
Scheme 2.44.
Pyrrole-2-carbaldehyde did not yield any of the three-component reaction product
under a variety of conditions (with or without heating, in ethanol or acetonitrile) due to
extensive self-condensation with formation of purple-red dyes. Further attempts were
then aimed at 5-substituted pyrrole-2-carbaldehydes. Surprisingly, 3,5-dimethylpyrrole-2-
carbaldehyde also did not participate in the reaction, recovering back 73% of the starting
57
aldehyde along with minute amounts of an unidentified blue-green dye. The pyrrole
aldehyde 2.118, containing an electron-withdrawing carbethoxy group, provided the
target tricyclic molecule 2.119 with a pyrrole substituent, albeit in low yield (24%).
Furan-2-carbaldehyde, quinoline-2-carbaldehyde and benzoxazole-2-
carboxaldehyde formed complex mixtures under the reaction conditions, from which no
attempts were made to isolate the products. In accordance with earlier observations made
in our group, 1-methylimidazole-2-carbaldehyde did not yield any products of the three-
component reaction in either protic or aprotic solvents.
2.4 Petasis-Diels-Alder reaction with glyoxylic acid.
Glyoxylic acid has long been reported as one of the best reaction partners in
Petasis reaction.
58,59
More recently, the facile synthesis of racemic α-amino acids, which
are the products of this reaction, has been efficiently used as a key step in novel synthetic
approaches to polysubstituted indoles
60
and γ, δ-unsaturated α-amino acids.
61
The reaction
has also found application in the synthesis of heterocyclic systems, such as 1,4-
benzodiazepin-3-ones,
62
piperazinones and benzopiperazinones.
63
In many cases, the
isolation of the product is facilitated by precipitation of a pure amino acid, as the most
polar component in the reaction mixture, from the reaction medium, eliminating the need
for tedious chromatographic separations or sometimes even crystallization. The reaction
is known to work well with a variety of amines, both primary and secondary, aromatic as
well as aliphatic, and is often successful even with less reactive boronic acids, where
other carbonyl partners would give substantially lower yields or fail to perform. Some of
the known limitations of this type of the three-component reaction are the ability of
58
certain amino acid products to decarboxylate under the reaction conditions and generally
poor results with electron-rich anilines.
64
The very first attempt to prepare Petasis-Diels-Alder product 2.127 from N-allyl-
N-benzylamine, glyoxylic acid monohydrate and furan-2-boronic acid under the
conditions optimized for salicylaldehydes was successful, but it was soon realized that
more complex mixtures generally formed on heating and the yields deteriorated due to
decomposition of amino acids. Indeed, the heating was not important at all for the success
of this reaction, as 2.127 formed in high yield when the reaction mixture was stirred at
room temperature and precipitated from ethanol in 24 h. If, for different combinations of
reactants, no precipitation occurred in that time, pure products would still precipitate over
the period of 2 or 3 days. The optimal conditions for these reactions were identified as
stirring at room temperature (20-25 °C) in ethanol (0.67-1 M) for 3 days followed by
simple filtration of the product. Many of the tricyclic amino acids are well soluble in
water, so washing with a little of cold methanol or methanol-diethyl ether mixture,
followed by pure diethyl ether or ethyl acetate, was preferred. The results are presented in
the Table 2.6.
59
Table 2.6. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-Diels-
Alder reaction: reactions with glyoxylic acid.
Entry Aldehyde
Boronic
acid
Amine Product
Yield,
%
1
HO
2
C CHO H
2
O
2.126
O
B(OH)
2
2.38
NHBn
2.61
N
Bn
O
H
HO
2
C
2.127
82
2
HO
2
C CHO H
2
O
2.126
O
B(OH)
2
2.38
H
N
2.71
OMe
N
O
H
HO
2
C
OMe
2.128
80
3
HO
2
C CHO H
2
O
2.126
O
B(OH)
2
2.38
H
N
2.129
OMe MeO
N
O
H
HO
2
C
OMe
2.130
MeO
77
4
HO
2
C CHO H
2
O
2.126
O
B(OH)
2
2.38
NHPh
2.77
N
Ph
O
H
HO
2
C
2.131
41
5
HO
2
C CHO H
2
O
2.126
O
B(OH)
2
2.96
NHBn
2.61
N
Bn
O
H
HO
2
C
2.132
51
6
HO
2
C CHO H
2
O
2.126
O
B(OH)
2
2.38
NH
2
2.68
HO
2
C N
H
O
2.133
46
60
Table 2.6 (continued)
Entry Aldehyde
Boronic
acid
Amine Product
Yield,
%
7
HO
2
C CHO H
2
O
2.126
O
B(OH)
2
2.38
NHBn
2.134
HO
2
C N
O
Bn
2.135
71
8
HO
2
C CHO H
2
O
2.126
N
B(OH)
2
2.136
Boc
NHBn
2.61
HO
2
C N
N
Bn
Boc
2.137
73
Unsubstituted allylamine (2.68) and N-benzyl-N-homoallylamine (2.134) afforded
only the regular three-component reaction products (entries 6 and 7), which did not
undergo subsequent intramolecular cyclization under the reaction conditions. Similarly,
N-Boc-pyrrole-2-boronic acid (2.136) afforded amino acid 2.137 in good yield but no
Diels-Alder product was obtained.
2.5 Petasis-Diels-Alder reaction with sugars and sugar ketals.
The diastereoselective reaction with glyoxylic acid proved an expedient way to
prepare a variety of racemic 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-3-carboxylic
acids (Table 2.6). These compounds can be considered N-protected analogs of amino acid
proline. L-Proline is the only proteinogenic amino acid with secondary amino group, the
fact that accounts for its conformational rigidity and makes it a crucial component for
maintaining certain structural features in proteins, such as secondary structure turns and
edge strands of β-sheets. L-Proline- and L-hydroxyproline-rich proteins collagen and
61
elastin are the main components of connective tissue in animals, and these amino acids
are important constituents of structural glycoproteins found in plant cell walls. Another
important feature of proline in polypeptide chain is the relatively high population of cis-
configuration of the peptide bond in X-Pro dyads (where X is another amino acid).
Additionally, the process of cis-/trans- isomerization of amides, required for peptide
folding, is kinetically slow for X-Pro, necessitating the action of dedicated prolyl
isomerase enzymes.
65
In laboratory use, L-proline has found widespread recognition as one of the
cheapest organocatalysts, often providing good enantioselectivities in reactions of
carbonyl compounds proceeding via enamine intermediates, such as aldol
66
and nitroso-
aldol condensations.
67
The unnatural enantiomer, D-proline, commands significantly
higher prices, while the homologs of proline, D- and L-pipecolic acids, are even more
expensive. The only other easily available analog, L-4-thiazolidinecarboxylic acid (“L-
thiaproline”), is conveniently prepared from L-cysteine, but has the same configuration of
α-carbon as the natural L-proline. A variety of synthetic organocatalysts (one of the most
useful is (S)-(–)-5-(2-pyrrolidinyl)-1H-tetrazole) have been derived from L-proline, while
their D-series analogs are either not commercially available or much less affordable.
Proline-derived reagents for asymmetric synthesis (e.g., SAMP and RAMP, respectively
(S)-(–)- and (R)-(+)-1-amino-2-(methoxymethyl)pyrrolidine, both stereoisomers of
diphenylprolinol and CBS catalysts derived from it) have also been developed.
It was important, therefore, to investigate the possibility of applying our three-
component methodology to the synthesis of proline analogs in both enantiomerically pure
62
forms. Indeed, the Petasis reaction of α-hydroxyaldehydes is known for its
diastereospecificity
68
and has since been applied to the synthesis of enantiopure amino-
polyols, aminosugars, azasugars and saturated nitrogen heterocycles (Scheme 2.45).
63,69
OO
HO Ph
+
Ph
B(OH)
2 + Bn
2
NH
EtOH, RT
Ph
NBn
2
OH
Ph
88%
>99% de, >99% ee
O HO
2
C
HO
OH
OH
OH
+
Ph
B(OH)
2
+
HN
MeOH, RT
24 h Ph
N
OH
OH
OH
OH
CO
2
H
83%
>99% de, >99% ee
D-Glucuronic acid
Scheme 2.45.
In preliminary studies, α-hydroxy substituent was found to facilitate the
intramolecular Diels-Alder reaction significantly. When the reaction between
paraformaldehyde (2.138), furan-2-boronic acid (2.38) and N-allyl-N-benzylamine (2.61)
was allowed to proceed for 24 h at 70 °C, only open form of the three-component
reaction product 2.139 was formed; glycolaldehyde dimer (2.141), however, afforded
only the Diels-Alder product (2.143) in similar yield as a single diastereoisomer:
63
(CH
2
O)
n
+
O
B(OH)
2
+
NHBn
EtOH
70
o
C, 24 h
O
N
Bn
N
Bn
O
H
63% not formed
+
O
B(OH)
2
+
NHBn
EtOH
70
o
C, 24 h
O
N
Bn
N
Bn
O
H
64%
not formed
O
O OH
HO
HO
HO
2.139 2.140
2.142 2.143
2.138
2.38
2.61
2.141
2.38
2.61
(0.5 eq)
Scheme 2.46.
An attempt to prepare the compound 2.140 by running the reaction in water (80
°C, 24 h) resulted in formation of mixture of 2.139 and 2.140 in 2:1 ratio, however pure
2.140 could not be isolated on the column due to reversibility of the Diels-Alder step, a
problem described in the literature.
33
Running the reaction with paraformaldehyde in the
presence of imidazole (1 eq) under identical conditions did not afford any of 2.140 either,
giving only 2.139 in 55% yield.
Six commercially available inexpensive sugars have been screened as potential
precursors to chiral isoindoline derivatives: pentoses (D-arabinose, D-ribose, D-xylose)
and hexoses (D-galactose, D-glucose, D-mannose). From these, it was necessary to select
a pair with different configuration of 2-hydroxy substituent, as this group defines the
future absolute configuration of the tricyclic fragment (Figure 2.8):
64
O
HO
HO
OH
OH
OH
D-glucose (2R-)
O
HO
HO
OH
OH
OH
D-galactose (2R-)
O
HO
HO
HO
OH
OH
D-mannose (2S-)
HO
HO
O
HO
OH
D-arabinose (2S-)
HO OH
O
HO
OH
D-ribose (2R-)
OH
OH
O
HO
OH
D-xylose (2R-)
R
OH
O
R
OH
N
Bn
O
N
HO
H
Bn
O
H
N
HO
H
R
Bn
O
R
Figure 2.8. Diastereocontrol in Petasis-Diels-Alder reaction of sugars.
The reaction was tested under the conditions found optimal for salicylaldehydes
(0.4-0.5 M in ethanol, 70 °C, 24 h). Unfortunately, the cheapest possible starting
materials – hexoses – were found inappropriate for this reaction, forming complex
mixtures of polar products. In the pentose series, the content of the product in the mixture
decreased sharply from D-arabinose to D-ribose and D-xylose, which was typical
behaviour for these sugars in the three-component reaction according to previous
investigations.
64
Use of D-arabinose (2.144) resulted in >50% conversions to Diels-Alder
product 2.145, and the latter was conveniently found to precipitate from the reaction
mixture on cooling (alternatively, the crystallization can be promoted by the removal of
boric acid by-product by repeated evaporation with methanol and finally cooling the
solution of the semi-solid evaporation residue in a small amount of methanol, diluting
65
with diethyl ether if necessary), eliminating the need for chromatographic separation. The
other enantiomer of this sugar, L-arabinose (2.146), is a natural constituent of many plant
polysaccharides and is therefore widely available and even cheaper than D-isomer, which
is not typical for majority of carbohydrates. It afforded the enantiomeric product 2.147 in
similar yield:
HO
HO
O
HO
OH
D-arabinose
+
O
B(OH)
2
+ NHBn
EtOH
70
o
C, 24 h
N
HO
H
Bn
O
H
OH
HO
OH
2.145
OH
OH
O
OH
OH
L-arabinose
+
O
B(OH)
2
+ NHBn
EtOH
70
o
C, 24 h
N
HO
H
Bn
O
H
OH
HO
OH
2.147
55%
48%
2.144
2.146
2.38
2.61
2.38
2.61
Scheme 2.47.
Longer reaction times (48 h) did not improve the yield in this transformation
(52% on example of 2.145). Other solvents were also investigated with the aim to
maximize precipitation of pure Diels-Alder products while retaining by-products in
solution. It was necessary to use alcohols to ensure dissolution of sugars; however, too
polar (and acidic) 2,2,2-trifluoroethanol failed to provide any product from the resulting
66
dark-brown mixture. The product 2.145 did not precipitate from methanol at 0.4 M
concentration, while the use of 1-propanol and 2-propanol resulted in 46% and 26%
isolated yields, respectively, after simple filtration.
The reaction could be extended to other N-allyl-N-benzylamines, substituted in
the aromatic ring, from which the derivatives of 4-methoxy- and 4-bromobenzylamine
were also isolated without the need for chromatographic separation:
Table 2.7. Synthesis of 1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindoles by Petasis-Diels-
Alder reaction: reactions with D- and L-arabinose.
Entry Aldehyde
Boronic
acid
Amine Product
Yield,
%
1
HO
HO
O
HO
OH
D-arabinose
2.144
O
B(OH)
2
2.38
NHBn
2.61
N
HO
H
Bn
O
H
OH
HO
OH
2.145
55
2
OH
OH
O
HO
OH
L-arabinose
2.146
O
B(OH)
2
2.38
NHBn
2.61
N
HO
H
Bn
O
H
OH
HO
OH
2.147
48
3
HO
HO
O
HO
OH
D-arabinose
2.144
O
B(OH)
2
2.38
H
N
2.71
OMe
N
HO
H
O
H
OH
HO
OH
2.148
OMe
63
67
Table 2.7 (continued)
Entry Aldehyde
Boronic
acid
Amine Product
Yield,
%
4
HO
HO
O
HO
OH
D-arabinose
2.144
O
B(OH)
2
2.38
H
N
2.149
Br
N
HO
H
O
H
OH
HO
OH
2.150
Br
52
5
OH
OH
O
HO
OH
L-arabinose
2.146
O
B(OH)
2
2.38
H
N
2.149
Br
N
HO
H
O
H
OH
HO
OH
2.151
Br
60
Sugar ketals retaining 2-hydroxy substituent, such as 3,4-O-isopropylidene-
arabinose (2.152 (D-isomer), 2.155 (L-isomer)), are easily available from arabinose.
70
Prepared in situ without isolation of the pure ketal, they were successfully employed in
Petasis-Diels-Alder reaction; however, longer reaction times (3 d at 70 °C) were required
to attain practically useful yields of the Diels-Alder products:
68
HO
HO
O
HO
OH
D-arabinose
+
OMe
OMe
DMF
TsOH (cat.)
O
OH
OH
O
O
O
B(OH)
2
NHBn
EtOH
70
o
C, 24 h
N
Bn
O
H
H
HO
HO
O
O
HO
HO
O
O
N
O
Bn
+
2.153
11%
2.154
33%
+
OMe
OMe
DMF
TsOH (cat.)
O
OH
OH
O
O
O
B(OH)
2
NHBn
EtOH
70
o
C, 3 d
N
Bn
O
H
H
HO
HO
O
O
HO
HO
O
O
N
O
Bn
+
2.156
44%
2.157
26%
OH
OH
O
HO
OH
L-arabinose
2.144
2.146
2.152
2.155
Scheme 2.48.
The analogs 2.159 and 2.160 were similarly prepared from cyclohexanone
dimethyl ketal (2.158) and D- and L-arabinose, respectively (open chain by-products were
not isolated):
69
HO
HO
O
HO
OH
D-arabinose
+
MeO OMe
N
Bn
O
H
H
HO
HO
O
O
2.159
44%
+
OH
OH
O
HO
OH
L-arabinose
MeO OMe
N
Bn
O
H
H
HO
HO
O
O
2.160
44%
2.158
2.158
2.144
2.146
Scheme 2.49.
Several attempts to prepare a simpler chiral isoindoline derivative by cutting off
the polyhydroxylated chain were not successful. Thus, an attempt of oxidative cleavage
with sodium periodate or sodium periodate-RuCl
3
catalyst followed by reduction with
sodium borohydride did not yield the chiral analog of 2.143. The intermediate aldehyde
2.161 was found to be unstable and it was not possible to isolate it either by itself, or as
2,4-dinitrophenylhydrazone. It was therefore decided to cleave the side chain by Jones’
oxidation, and this reaction did provide the amino acid 2.162, the chiral analog of 2.127,
but the yield was impracticably low (22%). Longer reaction times (an overnight run) did
not result in overoxidation and did not improve the yield:
70
N
HO
H
Bn
O
H
OH
HO
OH
2.145
NaIO
4
(3 eq)
NaHCO
3
(3 eq)
Et
2
O - H
2
O
0-5
o
C
N
Bn
O
H
O
NaBH
4
N
Bn
O
H
HO
2.161
2.143
N
HO
H
Bn
O
H
OH
HO
OH
2.147
CrO
3
(2.2 M)
H
2
SO
4
(2.2 M)
H
2
O - acetone
0
o
C to RT, 1 h
N
HO
2
C
Bn
O
H
2.162
22%
Scheme 2.50.
2.6 Experimental.
All reactions, unless otherwise noted, were run using commercially available
solvents and reagents as received, without additional preparation and purification, in
ordinary laboratory glassware or screw-cap glass vials.
1
H and
13
C NMR spectra were
recorded on Varian Mercury 400, Varian 400-MR (400 MHz) or Varian VNMRS-500
(500 MHz) 2-channel NMR spectrometers, using residual
1
H or
13
C signals of deuterated
solvents as internal standards. CH
3
OH was used as an internal standard for the spectra
obtained in D
2
O.
71
Silica gel (60 Å, 40-63 µm; Sorbent Technologies) was used as a
sorbent for flash column chromatography. Automated flash chromatography was
performed on Isolera One flash purification system (Biotage), default fraction volume –
12 mL.
71
N
O
H
OH
2.43. ( ±)-2-[(3R,3aS,6S,7aR)-2-Allyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-
yl]phenol. In a 2 dram vial equipped with a stirring bar, the mixture of salicylaldehyde
(244 mg, 2 mmol), diallylamine (194 mg, 2 mmol) and furan-2-boronic acid (224 mg, 2
mmol) in anhydrous ethanol (5 mL) was stirred at 70 °C for 24 h. TLC control
(silica/CH
2
Cl
2
-hexane 1:1, stained with basic KMnO
4
): R
f
0.5. The clear solution was
evaporated, and the product was isolated by flash
chromatography (silica, CH
2
Cl
2
-hexane 1:1, changed to
CH
2
Cl
2
-methanol 3:1 after elution of unreacted
salicylaldehyde) as viscous yellow oil. Yield 324 mg
(60%). Running the reaction at room temperature for 5
days yielded 353 mg (66%) of the product.
1
H NMR (CDCl
3
, 400 MHz): δ 11.0-12.7 (br.s, 1H; OH), 7.14-7.20 (m, 1H; H
Ar
), 7.01
(dd, J = 7.5 Hz, 1.9 Hz, 1H; H
Ar
), 6.77-6.85 (m, 2H; H
Ar
), 6.17 (dd, J = 5.8 Hz, 1.6 Hz,
1H; H
c2
), 5.81-5.93 (m, 1H; H
b3
), 5.74 (d, J = 5.8 Hz, 1H; H
c1
), 5.20 (dq, J = 17.2 Hz, 1.3
Hz, 1H; H
b1
), 5.14 (d, J = 10.2 Hz, 1H; H
b2
), 5.02 (dd, J = 4.4 Hz, 1.9 Hz, 1H; H
c3
), 3.98
(s, 1H; H
a
), 3.51 (ddt, J = 13.5 Hz, 5.4 Hz, 1.6 Hz, 1H; H
b4
/H
b5
), 3.46 (dd, J = 8.8 Hz, 6.4
Hz, 1H; H
c8
), 3.16 (dd, J = 13.5 Hz, 7.8 Hz, 1H; H
b4
/H
b5
), 2.28 (dd, J = 11.0 Hz, 8.8 Hz,
1H; H
c7
), 2.15-2.19 (m, 1H; H
c6
), 1.75 (ddd, J = 11.5 Hz, 4.4 Hz, 3.0 Hz, 1H; H
c4
/H
c5
),
1.38 (dd, J = 11.5 Hz, 7.2 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 157.8, 135.1,
N
H
b5
H
b4
H
b3
H
b1
H
b2
H
a
O
H
c2
H
c1
H
c3
H
c4
H
c5
H
c6
H
c7
H
c8
HO
72
135.0, 133.2, 129.1, 128.9, 121.2, 119.2, 118.8, 116.8, 100.0, 79.8, 69.9, 56.7, 56.4, 43.2,
29.1.
N
O
H
OH
O
2
N
2.52. ( ±)-2-[(3R,3aS,6S,7aR)-2-Allyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-yl]-
4-nitrophenol. Prepared similarly to 2.43, TLC control (silica/CH
2
Cl
2
, stained with basic
KMnO
4
): R
f
0.4. The product was isolated by flash chromatography (silica, CH
2
Cl
2
) as
viscous yellow oil. Yield 355 mg (53%).
1
H NMR (CDCl
3
, 400 MHz): δ 13.0-15.0 (br.s,
1H; OH), 8.11 (dd, J = 9.1 Hz, 2.9 Hz, 1H; H
Ar
), 8.00 (d, J = 2.9 Hz, 1H; H
Ar
), 6.86 (d, J
= 9.1 Hz, 1H; H
Ar
), 6.24 (dd, J = 6.2 Hz, 1.7 Hz, 1H; H
c2
), 5.79-5.91 (m, 1H; H
b3
), 5.68
(d, J = 6.2 Hz, 1H; H
c1
), 5.25 (d, J = 17.0 Hz, 1H; H
b1
), 5.19 (d, J = 10.4 Hz, 1H; H
b2
),
5.06 (dd, J = 4.6 Hz, 1.7 Hz, 1H; H
c3
), 4.13 (s, 1H; H
a
), 3.41-3.53 (m, 2H; H
b4
/H
b5
+ H
c8
),
3.25 (dd, J = 12.9 Hz, 7.5 Hz, 1H; H
b4
/H
b5
), 2.37 (dd, J = 10.8 Hz, 9.1 Hz, 1H; H
c7
),
2.12-2.22 (m, 1H; H
c6
), 1.78 (ddd, J = 11.6 Hz, 4.1 Hz, 3.3 Hz, 1H; H
c4
/H
c5
), 1.41 (dd, J
= 11.6 Hz, 7.5 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 165.0, 139.8, 136.0,
133.8, 131.9, 125.3, 125.2, 121.1, 121.9, 117.3, 99.6, 79.9, 69.2, 56.7, 56.3, 43.2, 29.2.
73
N
O
H
OH
Br
2.54. ( ±)-2-[(3R,3aS,6S,7aR)-2-Allyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-yl]-
4-bromophenol. Prepared similarly to 2.43, TLC control (silica/CH
2
Cl
2
, stained with
basic KMnO
4
): R
f
0.7. The product was isolated by flash chromatography (silica, CH
2
Cl
2
-
hexane 1:1 to CH
2
Cl
2
) as viscous yellow oil. Yield 590 mg (85%).
1
H NMR (CDCl
3
, 400
MHz): δ 11.8-12.8 (br.s, 1H; OH), 7.22 (dd, J = 8.7 Hz, 2.5 Hz, 1H; H
Ar
), 7.10 (d, J = 2.5
Hz, 1H; H
Ar
), 6.68 (d, J = 8.7 Hz, 1H; H
Ar
), 6.16 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.72-
5.89 (m, 1H; H
b3
), 5.71 (d, J = 5.8 Hz, 1H; H
c1
), 5.17 (d, J = 17.0 Hz, 1H; H
b1
), 5.11 (d, J
= 10.4 Hz, 1H; H
b2
), 4.99 (dd, J = 4.1 Hz, 1.7 Hz, 1H; H
c3
), 3.90 (s, 1H; H
a
), 3.36-3.48
(m, 2H; H
b4
/H
b5
+ H
c8
), 3.13 (dd, J = 13.3 Hz, 7.9 Hz, 1H; H
b4
/H
b5
), 2.25 (dd, J = 10.8 Hz,
9.1 Hz, 1H; H
c7
), 2.08-2.18 (m, 1H; H
c6
), 1.78 (dt, J = 11.6 Hz, 4.1 Hz, 1H; H
c4
/H
c5
), 1.34
(dd, J = 11.6 Hz, 7.5 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 157.0, 135.3,
134.6, 132.7, 131.6, 131.4, 123.2, 119.1, 118.7, 110.7, 99.7, 79.7, 69.2, 56.6, 56.2, 43.1,
29.0.
74
N
O
H
OH
MeO
2.56. ( ±)-2-[(3R,3aS,6S,7aR)-2-Allyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-yl]-
5-methoxyphenol. Prepared similarly to 2.43, TLC control (silica/CH
2
Cl
2
, stained with
basic KMnO
4
): R
f
0.2. The product was isolated by flash chromatography (twice on silica,
CH
2
Cl
2
-hexane 1:1 to CH
2
Cl
2
to CH
2
Cl
2
-methanol 1:1) as viscous yellow oil. Yield 342
mg (57%).
1
H NMR (CDCl
3
, 400 MHz): δ 11.6-12.9 (br.s, 1H; OH), 6.85 (d, J = 7.9 Hz,
1H; H
Ar
), 6.29-6.37 (m, 2H; H
Ar
), 6.11 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.76-5.89 (m,
1H; H
b3
), 5.73 (d, J = 5.8 Hz, 1H; H
c1
), 5.15 (d, J = 17.0 Hz, 1H; H
b1
), 5.09 (d, J = 10.4
Hz, 1H; H
b2
), 4.95 (dd, J = 4.6 Hz, 1.7 Hz, 1H; H
c3
), 3.89 (s, 1H; H
a
), 3.70 (s, 3H; OMe),
3.46 (dd, J = 13.7 Hz, 5.4 Hz, 1H; H
b4
/H
b5
) 3.39 (dd, J = 8.7 Hz, 6.2 Hz, 1H; H
c8
), 3.08
(dd, J = 13.7 Hz, 7.9 Hz, 1H; H
b4
/H
b5
), 2.20 (dd, J = 10.8 Hz, 8.7 Hz, 1H; H
c7
), 2.08-2.13
(m, 1H; H
c6
), 1.67 (dt, J = 11.6 Hz, 3.7 Hz, 1H; H
c4
/H
c5
), 1.32 (dd, J = 11.6 Hz, 7.9 Hz,
1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 160.2, 158.9, 134.9, 133.1, 129.6, 118.5,
113.3, 105.2, 101.8, 99.9, 79.6, 69.2, 56.5, 56.1, 54.8, 42.8, 29.0.
75
N
O
H
OH
2.58. ( ±)-2-[(3R,3aS,6S,7aR)-2-Allyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-yl]-
4,6-di-tert-butylphenol. Prepared similarly to 2.43. The product precipitated from the
reaction mixture. The mixture was cooled, the crystals filtered off and washed with
methanol-water (1:1). White crystals, yield 627 mg (82%).
1
H NMR (CDCl
3
, 400 MHz):
δ 12.0-12.2 (br.s, 1H; OH), 7.22 (d, J = 2.5 Hz, 1H; H
Ar
), 6.86 (d, J = 2.5 Hz, 1H; H
Ar
),
6.16 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.80-5.92 (m, 1H; H
b3
), 5.75 (d, J = 5.8 Hz, 1H;
H
c1
), 5.16-5.23 (m, 1H; H
b1
), 5.13 (d, J = 10.0 Hz, 1H; H
b2
), 5.03 (dd, J = 4.6 Hz, 1.7 Hz,
1H; H
c3
), 3.90 (s, 1H; H
a
), 3.54 (ddt, J = 13.3 Hz, 5.4 Hz, 1.2 Hz, 1H; H
b4
/H
b5
), 3.42-3.51
(m, 1H; H
c8
), 3.11 (dd, J = 13.3 Hz, 7.9 Hz, 1H; H
b4
/H
b5
), 2.20-2.31 (m, 2H; H
c6
+ H
c7
),
1.75 (ddd, J = 11.2 Hz, 4.1 Hz, 2.9 Hz, 1H; H
c4
/H
c5
), 1.37-1.45 (m, 10H; H
c4
/H
c5
+ Bu
t
),
1.27 (s, 9H; Bu
t
).
13
C NMR (CDCl
3
, 100 MHz): δ 154.5, 140.7, 136.0, 135.9, 134.8,
133.8, 124.0, 123.1, 120.7, 118.6, 100.3, 94.9, 80.0, 70.9, 56.7, 56.1, 43.5, 34.9, 34.2,
31.7, 29.6.
76
N
O
H
OH
2.60. ( ±)-1-[(3R,3aS,6S,7aR)-2-Allyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-yl]-
2-naphthol. Prepared similarly to 2.43. The product precipitated from the reaction
mixture. The mixture was cooled, the crystals filtered off and washed with methanol-
water (1:1). Light tan crystals, yield 530 mg (83%).
1
H NMR (CDCl
3
, 400 MHz): δ 14.2
(s, 1H; OH), 7.66-7.78 (m, 3H; H
Ar
), 7.38-7.46 (m, 1H; H
Ar
), 7.24-7.32 (m, 1H; H
Ar
), 7.07
(d, J = 9.1 Hz, 1H; H
Ar
), 6.07 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.89-6.03 (m, 1H; H
b3
),
5.56 (d, J = 5.8 Hz, 1H; H
c1
), 5.24 (d, J = 17.0 Hz, 1H; H
b1
), 5.16 (d, J = 10.0 Hz, 1H;
H
b2
), 5.10 (dd, J = 4.6 Hz, 1.7 Hz, 1H; H
c3
), 4.82 (s, 1H; H
a
), 3.54-3.64 (m, 2H; H
b4
/H
b5
+
H
c8
), 3.24 (dd, J = 13.3 Hz, 7.9 Hz, 1H; H
b4
/H
b5
), 2.43 (dd, J = 10.8 Hz, 9.1 Hz, 1H; H
c7
),
2.23-2.33 (m, 1H; H
c6
), 1.81 (ddd, J = 11.6 Hz, 4.1 Hz, 2.9 Hz, 1H; H
c4
/H
c5
), 1.41 (dd, J
= 11.6 Hz, 7.9 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 156.9, 135.3, 134.5,
133.0, 132.7, 129.7, 128.6, 128.4, 126.6, 122.6, 121.7, 120.0, 119.3, 110.3, 99.7, 80.0,
66.2, 57.3, 57.0, 43.2, 29.4.
77
N
Ph
O
H
OH
Br
2.62. ( ±)-2-[(3R,3aS,6S,7aR)-2-Benzyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-
yl]-4-bromophenol. The starting material, N-allyl-N-benzylamine (2.61), was prepared
from benzaldehyde and allylamine by reductive amination with NaBH
4
(1.3 eq) in
ethanol. The compound 2.62 was prepared similarly to 2.43. The product precipitated
from the reaction mixture. The mixture was cooled, the crystals filtered off and washed
with cold methanol. White needles, yield 680 mg (85%).
1
H NMR (CDCl
3
, 400 MHz):
12.4 (br.s, 1H; OH), 7.29-7.40 (m, 6H; H
Ar
), 7.25 (d, J = 2.5 Hz, 1H; H
Ar
), 6.82 (d, J =
8.7 Hz, 1H; H
Ar
), 6.24 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.84 (d, J = 5.8 Hz, 1H; H
c1
),
5.07 (dd, J = 4.2 Hz, 1.7 Hz, 1H; H
c3
), 4.12 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 4.03 (s, 1H;
H
a
), 3.55 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.26 (dd, J = 9.1 Hz, 6.2 Hz, 1H; H
c8
), 2.28 (dd, J
= 10.8 Hz, 9.1 Hz, 1H; H
c7
), 2.11-2.20 (m, 1H; H
c6
), 1.75 (dt, J = 11.6 Hz, 3.7 Hz, 1H;
H
c4
/H
c5
), 1.39 (dd, J = 11.6 Hz, 7.5 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz):
157.0, 136.4, 135.5, 134.9, 132.0, 131.8, 129.3, 128.6, 127.8, 123.3, 118.9, 111.1, 99.8,
80.0, 70.3, 58.4, 56.5, 43.4, 29.1.
78
N
Ph
O
H
OH
2.63. ( ±)-1-[(3R,3aS,6S,7aR)-2-Benzyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-
yl]-2-naphthol. Prepared similarly to 2.43. The product precipitated from the reaction
mixture. The mixture was cooled, the crystals filtered off, washed with methanol-water
(1:1) and a little of cold methanol. Off-white crystals, yield 656 mg (89%).
1
H NMR
(CDCl
3
, 400 MHz): δ 14.2 (s, 1H; OH), 7.74-7.88 (m, 3H; H
Ar
), 7.46-7.52 (m, 1H; H
Ar
),
7.28-7.45 (m, 6H; H
Ar
), 7.19 (d, J = 8.7 Hz, 1H; H
Ar
), 6.11 (dd, J = 5.8 Hz, 1.7 Hz, 1H;
H
c2
), 5.65 (d, J = 5.8 Hz, 1H; H
c1
), 5.13 (dd, J = 4.4 Hz, 1.7 Hz, 1H; H
c3
), 4.96 (s, 1H;
H
a
), 4.25 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.62 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.35 (dd, J =
9.1 Hz, 6.6 Hz, 1H; H
c8
), 2.43 (dd, J = 10.8 Hz, 9.1 Hz, 1H; H
c7
), 2.20-2.30 (m, 1H; H
c6
),
1.81 (ddd, J = 11.6 Hz, 4.4 Hz, 3.3 Hz, 1H; H
c4
/H
c5
), 1.40 (dd, J = 11.6 Hz, 7.5 Hz, 1H;
H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 156.7, 136.4, 135.3, 134.6, 132.9, 129.8, 129.5,
128.7, 128.6, 128.4, 127.7, 126.7, 122.6, 121.7, 120.0, 110.3, 99.7, 80.0, 66.9, 59.2, 56.6,
43.3, 29.3.
79
N
Ph
O
H
OH
OMe
2.65. ( ±)-2-[(3R,3aS,6S,7aR)-2-Benzyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-
yl]-6-methoxyphenol. Prepared similarly to 2.43 on 1 mmol scale (in 2.5 mL of ethanol),
TLC control (silica/EtOAc-hexane 1:3, stained with basic KMnO
4
): R
f
0.4. The product
was isolated by flash chromatography (silica, EtOAc-hexane 1:3) as light yellow viscous
oil. Yield 294 mg (84%).
1
H NMR (CDCl
3
, 400 MHz): δ 12.6 (br.s, 1H; OH), 7.26-7.38
(m, 5H; H
Ar
), 6.89 (dd, J = 7.9 Hz, 1.7 Hz, 1H; H
Ar
), 6.83 (t, J = 7.9 Hz, 1H; H
Ar
), 6.75
(dd, J = 7.9 Hz, 1.7 Hz, 1H; H
Ar
), 6.18 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.80 (d, J = 5.8
Hz, 1H; H
c1
), 5.04 (dd, J = 4.2 Hz, 1.7 Hz, 1H; H
c3
), 4.20 (d, J = 12.9 Hz, 1H; H
b1
/H
b2
),
4.11 (s, 1H; H
a
), 3.95 (s, 3H; OMe), 3.54 (d, J = 12.9 Hz, 1H; H
b1
/H
b2
), 3.24 (dd, J = 8.7
Hz, 5.8 Hz, 1H; H
c8
), 2.25 (dd, J = 11.2 Hz, 8.7 Hz, 1H; H
c7
), 2.14-2.22 (m, 1H), 1.72
(ddd, J = 11.6 Hz, 4.2 Hz, 2.9 Hz, 1H; H
c4
/H
c5
), 1.36 (dd, J = 11.6 Hz, 7.5 Hz, 1H;
H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 148.3, 147.2, 136.5, 135.1, 135.0, 129.2, 128.4,
127.5, 121.2, 121.1, 118.8, 110.9, 99.9, 79.8, 70.5, 58.4, 56.4, 55.7, 43.1, 29.1.
80
N
Ph
O
H
N
OH
HO
2.67. ( ±)-4-[(3R,3aS,6S,7aR)-2-Benzyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-
yl]-5-(hydroxymethyl)-2-methylpyridin-3-ol. Prepared similarly to 2.43 from pyridoxal
hydrochloride on a 1 mmol scale (in 2.5 mL of ethanol) with addition of sodium acetate
(82 mg, 1 mmol). TLC control (silica/EtOAc, stained with basic KMnO
4
): R
f
0.3-0.45.
The product was isolated by flash chromatography (silica, EtOAc-hexane 1:3) as
yellowish foam. Recrystallization from diethyl ether-hexane yielded 294 mg (81%) of the
product as white crystals.
1
H NMR (CDCl
3
, 400 MHz): δ 13.1 (s, 1H; OH), 7.92 (s, 1H;
H
d
), 7.23-7.34 (m, 5H; H
Ar
), 6.18 (dd, J = 6.0 Hz, 1.9 Hz, 1H; H
c2
), 5.73 (d, J = 6.0 Hz,
1H; H
c1
), 5.05 (dd, J = 4.4 Hz, 1.9 Hz, 1H; H
c3
), 4.54-4.63 (m, 2H; CH
2
OH), 4.45 (s, 1H;
H
a
), 4.00 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.54 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.30 (dd, J =
9.3 Hz, 6.5 Hz, 1H; H
c8
), 2.49 (s, 3H; CH
3
), 2.40-2.52 (br.s, 1H, CH
2
OH), 2.31 (dd, J =
11.1 Hz, 9.3 Hz, 1H; H
c7
), 2.12-2.20 (m, 1H; H
c6
), 1.73 (ddd, J = 11.6 Hz, 4.4 Hz, 3.2 Hz,
1H; H
c4
/H
c5
), 1.37 (dd, J = 11.6 Hz, 7.4 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz):
δ 152.2, 147.4, 138.3, 135.7, 135.4, 134.2, 132.6, 129.2, 128.3, 127.7, 126.0, 99.1, 79.9,
65.4, 59.7, 58.5, 56.5, 43.5, 28.8, 18.4.
81
N
O
H
OH
OMe
2.72. ( ±)-1-[(3R,3aS,6S,7aR)-2-(4-Methoxybenzyl)-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindol-3-yl]-2-naphthol. The starting amine was prepared from 4-
methoxybenzaldehyde (2.46) and allylamine by reductive amination with NaBH
4
(1.3 eq)
in ethanol. The compound 2.72 was prepared similarly to 2.43. Light yellow foam, yield
749 mg (94%).
1
H NMR (CDCl
3
, 400 MHz): δ 14.1-14.5 (br.s, 1H; OH), 7.74-7.90 (m,
3H; H
Ar
), 7.44-7.52 (m, 1H; H
Ar
), 7.28-7.38 (m, 3H; H
Ar
), 7.18-7.24 (m, 1H; H
Ar
), 6.90 (d,
J = 8.7 Hz, 2H; H
Ar
), 6.07 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.63 (d, J = 5.8 Hz, 1H; H
c1
),
5.10 (dd, J = 4.2 Hz, 1.7 Hz, 1H; H
c3
), 4.95 (s, 1H; H
a
), 4.15 (d, J = 12.5 Hz, 1H;
H
b1
/H
b2
), 3.80 (s, 3H; OMe), 3.55 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.34 (dd, J = 9.1 Hz, 6.6
Hz, 1H; H
c8
), 2.41 (dd, J = 10.8 Hz, 9.1 Hz, 1H; H
c7
), 2.18-2.28 (m, 1H; H
c6
), 1.78 (dt, J
= 11.6 Hz, 3.7 Hz, 1H; H
c4
/H
c5
), 1.37 (dd, J = 11.6 Hz, 7.5 Hz, 1H; H
c4
/H
c5
).
13
C NMR
(CDCl
3
, 100 MHz): δ 159.0, 156.6, 135.1, 134.4, 132.8, 130.6, 129.6, 128.6, 128.35,
128.27, 126.6, 122.5, 121.6, 119.9, 113.7, 110.2, 99.5, 79.8, 66.5, 58.2, 56.3, 55.0, 43.0,
29.1.
82
N
Ph
O
H
OH
N
Ph
O
H
OH
2-{(1S,2R,5S,7S)-3-[(1S)-1-Phenylethyl]-10-oxa-3-azatricyclo[5.2.1.0
1,5
]dec-8-en-2-
yl}phenol (2.74a) and 2-{(1R,2S,5R,7R)-3-[(1S)-1-phenylethyl]-10-oxa-3-
azatricyclo[5.2.1.0
1,5
]dec-8-en-2-yl}phenol (2.74b). Prepared similarly to 2.43 from N-
allyl-N-[(1S)-1-phenylethyl]amine (2.73).
72
TLC control (silica/CH
2
Cl
2
, stained with
basic KMnO
4
): R
f
0.45 (2.74a, major diastereoisomer), R
f
0.3 (2.74b, minor
diastereoisomer). The products were isolated by flash chromatography (silica, CH
2
Cl
2
):
2.74a as viscous yellowish oil (269 mg, yield 40%) and 2.74b as viscous light-pink oil
(90 mg, yield 14%).
2.74a (major):
1
H NMR (CDCl
3
, 400 MHz): δ 12.9 (s, 1H; OH), 7.26-7.40 (m, 5H, H
Ar
),
7.18-7.24 (m, 1H, H
Ar
), 7.08 (dd, J = 7.5 Hz, 1.7 Hz, 1H, H
Ar
), 6.91 (dd, J = 8.3 Hz, 1.2
Hz, 1H, H
Ar
), 6.86 (td, J = 7.5 Hz, 1.2 Hz, 1H, H
Ar
), 6.15 (dd, J = 5.8 Hz, 1.7 Hz, 1H;
H
c2
), 5.69 (d, J = 5.8 Hz, 1H; H
c1
), 4.98 (dd, J = 4.2 Hz, 1.7 Hz, 1H; H
c3
), 4.20 (s, 1H;
H
a
), 3.81 (q, J = 7.0 Hz, 1H; H
b
), 3.18 (dd, J = 7.9 Hz, 5.4 Hz, 1H; H
c8
), 2.11-2.24 (m,
2H; H
c7
+H
c6
), 1.65 (ddd, J = 11.6 Hz, 4.6 Hz, 2.5 Hz, 1H; H
c4
/H
c5
), 1.41 (d, J = 7.0 Hz,
3H; CH
3
), 1.31 (dd, J = 11.6 Hz, 7.5 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ
158.1, 142.0, 135.0, 134.9, 128.65, 128.60, 128.0, 127.6, 127.3, 123.4, 119.4, 117.1,
100.3, 79.7, 68.8, 64.3, 56.4, 42.1, 29.5, 21.9.
2.74b (minor):
1
H NMR (CDCl
3
, 400 MHz): δ 12.1 (s, 1H; OH), 7.29-7.32 (m, 2H, H
Ar
),
7.08-7.22 (m, 4H, H
Ar
), 6.78-6.81 (m, 2H, H
Ar
), 6.68 (td, J = 7.5 Hz, 1.2 Hz, 1H, H
Ar
),
83
6.15 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.66 (d, J = 5.8 Hz, 1H; H
c1
), 5.01 (dd, J = 4.2 Hz,
1.7 Hz, 1H; H
c3
), 4.19 (s, 1H; H
a
), 3.99 (q, J = 7.0 Hz, 1H; H
b
), 3.34 (dd, J = 8.7 Hz, 6.6
Hz, 1H; H
c8
), 2.48 (dd, J = 10.8 Hz, 9.1 Hz, 1H; H
c7
), 2.14-2.23 (m, 1H; H
c6
), 1.75 (ddd,
J = 11.6 Hz, 4.6 Hz, 2.9 Hz, 1H; H
c4
/H
c5
), 1.50 (d, J = 7.0 Hz, 3H; CH
3
), 1.37 (dd, J =
11.6 Hz, 7.5 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 157.5, 141.2, 135.1, 135.0,
128.5, 128.1, 127.8, 127.5, 122.7, 119.1, 116.6, 100.0, 79.7, 77.0, 67.8, 60.4, 53.4, 42.5,
29.7, 15.0.
N
Ph
O
H
OH
N
Ph
O
H
OH
1-{(1S,2R,5S,7S)-3-[(1S)-1-Phenylethyl]-10-oxa-3-azatricyclo[5.2.1.0
1,5
]dec-8-en-2-
yl}-2-naphthol (2.75a) and 1-{(1R,2S,5R,7R)-3-[(1S)-1-phenylethyl]-10-oxa-3-
azatricyclo[5.2.1.0
1,5
]dec-8-en-2-yl}-2-naphthol (2.75b). Prepared similarly to 2.43 on 1
mmol scale (in 2.5 mL of ethanol), TLC control (silica/CH
2
Cl
2
-hexane 1:1, stained with
basic KMnO
4
): R
f
0.55 (2.75a, major diastereoisomer), R
f
0.2 (2.75b, minor
diastereoisomer). The products were isolated by flash chromatography (silica, CHCl
3
-
hexane 1:1 to CHCl
3
): 2.75a as viscous yellow oil (217 mg, yield 57%) and 2.75b as
light-yellow foam (67 mg, yield 17%).
2.75a (major):
1
H NMR (CDCl
3
, 400 MHz): δ 14.7 (s, 1H; OH), 7.77-7.84 (m, 2H, H
Ar
),
7.74 (d, J = 9.3 Hz, 1H, H
Ar
), 7.44-7.50 (m, 1H, H
Ar
), 7.29-7.43 (m, 6H, H
Ar
), 7.17 (d, J =
8.8 Hz, 1H; H
Ar
), 6.04 (dd, J = 6.0 Hz, 1.6 Hz, 1H; H
c2
), 5.47 (d, J = 6.0 Hz, 1H; H
c1
),
84
5.04 (dd, J = 4.4 Hz, 1.6 Hz, 1H; H
c3
), 5.02 (s, 1H; H
a
), 3.85 (q, J = 7.0 Hz, 1H; H
b
), 3.24
(dd, J = 9.1 Hz, 6.7 Hz, 1H; H
c8
), 2.34 (dd, J = 10.8 Hz, 9.3 Hz, 1H; H
c7
), 2.19-2.28 (m,
1H; H
c6
), 1.70 (ddd, J = 11.6 Hz, 4.6 Hz, 2.8 Hz, 1H; H
c4
/H
c5
), 1.38 (d, J = 7.0 Hz, 3H;
CH
3
), 1.31 (dd, J = 11.6 Hz, 7.4 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 157.3,
142.3, 135.2, 134.3, 131.7, 129.5, 128.7, 128.3, 127.6, 127.2, 126.7, 122.5, 121.5, 120.1,
112.6, 99.7, 79.8, 65.9, 65.2, 57.3, 42.2, 29.7, 21.7.
2.75b (minor):
1
H NMR (CDCl
3
, 400 MHz): δ 13.9 (s, 1H; OH), 7.66-7.71 (m, 2H; H
Ar
),
7.62 (d, J = 9.1 Hz, 1H; H
Ar
), 7.32-7.40 (m, 3H; H
Ar
), 7.22-7.27 (m, 1H; H
Ar
), 7.07-7.13
(m, 2H; H
Ar
), 6.99-7.06 (m, 2H; H
Ar
), 6.04 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.47 (d, J =
5.8 Hz, 1H; H
c1
), 5.09 (s, 1H; H
a
), 5.06 (dd, J = 4.4 Hz, 1.7 Hz, 1H; H
c3
), 4.05 (q, J = 7.0
Hz, 1H; H
b
), 3.48 (dd, J = 8.7 Hz, 6.6 Hz, 1H; H
c8
), 2.64 (dd, J = 10.8 Hz, 8.7 Hz, 1H;
H
c7
), 2.24-2.33 (m, 1H; H
c6
), 1.80 (ddd, J = 11.6 Hz, 4.4 Hz, 2.9 Hz, 1H; H
c4
/H
c5
), 1.57
(d, J = 7.0 Hz, 1H; CH
3
), 1.39 (dd, J = 11.6 Hz, 7.5 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
,
100 MHz): δ 156.5, 140.5, 135.2, 134.7, 132.1, 129.4, 128.5, 128.2, 128.0, 127.9, 127.5,
126.4, 122.3, 121.2, 119.8, 112.0, 99.4, 79.9, 63.4, 61.3, 53.8, 42.6, 29.9, 15.4.
N
CO
2
Me
O
H
OH
N
CO
2
Me
O
H
OH
Ph Ph
+
Methyl (2S)-2-[(1R,2S,5R,7R)-2-(2-hydroxy-1-naphthyl)-10-oxa-3-
azatricyclo[5.2.1.0
1,5
]dec-8-en-3-yl]-3-phenylpropanoate (2.77a) and methyl (2S)-2-
85
[(1S,2R,5S,7S)-2-(2-hydroxy-1-naphthyl)-10-oxa-3-azatricyclo[5.2.1.0
1,5
]dec-8-en-3-
yl]-3-phenylpropanoate (2.77b) (not separated). Prepared similarly to 2.43 from methyl
(2S)-2-(allylamino)-3-phenylpropanoate (2.76)
73
on 1 mmol scale (in 2.5 mL of ethanol),
TLC control (silica/CH
2
Cl
2
, stained with basic KMnO
4
): R
f
0.3. The product was isolated
by flash chromatography (silica, CH
2
Cl
2
) as viscous yellow oil, yield 310 mg (68%).
1
H
NMR (CDCl
3
, 400 MHz): δ 12.87 (s, 0.67H), 12.84 (s, 0.33H), 7.71-7.84 (m, 3H), 7.43-
7.49 (m, 1H), 7.30-7.36 (m, 1H), 7.09-7.25 (m, 6H), 6.06-6.10 (m, 1H), 5.53 (d, J = 5.8
Hz, 0.67H), 5.47-5.50 (m, 2×0.33H), 5.20 (s, 0.67H), 5.08-5.11 (m, 1H), 3.90 (dd, J =
10.4 Hz, 4.6 Hz, 0.33H), 3.84 (dd, J = 10.8 Hz, 5.0 Hz, 0.67H), 3.72 (dd, J = 8.3 Hz, 6.6
Hz, 0.33H), 3.65 (dd, J = 8.7 Hz, 7.0 Hz, 0.67H), 3.62 (s, 3×0.67H), 3.40 (s, 3×0.33H),
3.22-3.30 (m, 1H), 3.17 (dd, J = 13.3 Hz, 10.4 Hz, 0.33H), 3.10 (dd, J = 12.9 Hz, 5.0 Hz,
0.67H), 2.74-2.89 (m, 1H), 2.31-2.46 (m, 1H), 1.84-1.91 (m, 1H), 1.41-1.49 (m, 1H).
13
C
NMR (CDCl
3
, 100 MHz): δ 171.0, 170.6, 156.5, 156.4, 136.8, 136.2, 134.91, 134.85,
134.77, 132.34, 132.26, 129.8, 129.7, 128.9, 128.8, 128.6, 128.5, 128.4, 128.33, 128.30,
126.8, 126.71, 126.67, 126.5, 122.6, 121.4, 119.8, 111.5, 111.0, 99.2, 99.0, 79.8, 66.2,
65.9, 63.9, 62.3, 54.9, 53.9, 51.6, 51.5, 42.7, 42.6, 37.2, 34.5, 29.7, 29.5.
N
Ph
O
H
OH
2.78. ( ±)-1-[(3R,3aS,6S,7aR)-2-Phenyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-
yl]-2-naphthol. In a 1 dram vial equipped with a stirring bar, the mixture of 2-hydroxy-1-
86
naphthaldehyde (172 mg, 1 mmol), N-allylaniline (133 mg, 1 mmol) and furan-2-boronic
acid (112 mg, 1 mmol) in 1-butanol (2.5 mL) was stirred at 100 °C for 24 h. TLC control
(silica/CH
2
Cl
2
-hexane 1:1, stained with basic KMnO
4
): R
f
0.5. The solvent was
evaporated, and the product was isolated by flash chromatography (silica, CH
2
Cl
2
-hexane
1:1) as yellowish foam. Yield 135 mg (38%).
1
H NMR (CDCl
3
, 400 MHz): δ 11.3 (s, 1H;
OH), 7.94 (d, J = 8.7 Hz, 1H; H
Ar
), 7.85 (d, J = 7.9 Hz, 1H; H
Ar
), 7.77 (d, J = 8.7 Hz, 1H;
H
Ar
), 7.50-7.57 (m, 1H; H
Ar
), 7.37-7.44 (m, 1H; H
Ar
), 7.17-7.25 (m, 2H; H
Ar
), 7.09 (d, J =
8.7 Hz, 1H; H
Ar
), 6.86-6.97 (m, 3H; H
Ar
), 6.15 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.61 (s,
1H; H
a
), 5.51 (d, J = 5.8 Hz, 1H; H
c1
), 5.14 (dd, J = 4.6 Hz, 1.7 Hz, 1H; H
c3
), 4.23 (dd, J
= 8.7 Hz, 7.5 Hz, 1H; H
c7
/H
c8
), 3.11 (dd, J = 10.4 Hz, 9.1 Hz, 1H; H
c7
/H
c8
), 2.50-2.60 (m,
1H; H
c6
), 1.97 (ddd, J = 11.6 Hz, 4.6 Hz, 2.9 Hz, 1H; H
c4
/H
c5
), 1.52 (dd, J = 11.6 Hz, 7.5
Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 155.9, 148.3, 135.0, 134.9, 131.5,
129.9, 129.2, 128.9, 127.0, 123.1, 122.0, 121.2, 119.8, 116.1, 111.9, 99.1, 80.0, 65.4, 55.6,
41.9, 30.5.
N
O
H
OH
OMe
2.80. ( ±)-1-[(3R,3aS,6S,7aR)-2-(4-Methoxyphenyl)-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindol-3-yl]-2-naphthol. The starting material, N-allyl-p-anisidine (2.79), was
prepared by alkylation on (2-nitrobenzenesulfonyl)-p-anisidine with allyl bromide (1.1 eq
87
in DMF, 1.5 eq K
2
CO
3
, 40-50 °C, 19 h) and deprotection with thiosalicylic acid (2 eq in
DMF, 4 eq K
2
CO
3
, 60-70 °C, 24 h). The compound 2.80 was prepared similarly to 2.78,
TLC control (silica/CH
2
Cl
2
, stained with basic KMnO
4
): R
f
0.6. The product was isolated
by flash chromatography (silica, CH
2
Cl
2
-hexane 1:1), the fractions containing the product
were pooled, and the second column (silica, CH
2
Cl
2
) was run to isolate the pure product
as white foam. Yield 155 mg (40%).
1
H NMR (CDCl
3
, 400 MHz): δ 11.9 (s, 1H; OH),
7.90 (d, J = 8.7 Hz, 1H; H
Ar
), 7.8 (dd, J = 7.9 Hz, 1.2 Hz, 1H; H
Ar
), 7.75 (d, J = 8.7 Hz,
1H; H
Ar
), 7.46-7.53 (m, 1H; H
Ar
), 7.34-7.40 (m, 1H; H
Ar
), 7.08 (d, J = 8.7 Hz, 1H; H
Ar
),
6.82-6.87 (m, 2H; H
Ar
), 6.72-6.78 (m, 2H; H
Ar
), 6.14 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
),
5.50 (d, J = 5.8 Hz, 1H; H
c1
), 5.50 (s, 1H; H
a
), 5.13 (dd, J = 4.6 Hz, 1.7 Hz, 1H; H
c3
),
4.14 (dd, J = 8.7 Hz, 7.0 Hz, 1H; H
c7
/H
c8
), 3.70 (s, 1H; OMe), 3.06 (dd, J = 10.8 Hz, 8.7
Hz, 1H; H
c7
/H
c8
), 2.47-2.56 (m, 1H; H
c6
), 1.94 (ddd, J = 11.6 Hz, 4.6 Hz, 2.5 Hz, 1H;
H
c4
/H
c5
), 1.50 (dd, J = 11.6 Hz, 7.5 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ
156.1, 154.5, 142.0, 135.0, 134.9, 131.6, 129.9, 128.83, 128.78, 126.9, 123.0, 121.9,
119.8, 117.4, 114.5, 111.8, 99.3, 80.0, 65.9, 56.2, 55.4, 42.1, 30.2.
N
Ph
O
OH
2.84. ( ±)-1-[(3R,3aS,6S,7aR)-2-Benzyl-7a-methyl-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindol-3-yl]-2-naphthol. The starting amine (2.83) was prepared by alkylation of
benzylamine with methallyl chloride (1-chloro-2-methyl-2-propene) with catalytic
88
amount of KI added. The compound 2.84 was prepared similarly to 2.43. The product
precipitated from the reaction mixture. The mixture was cooled, the crystals filtered off,
washed with methanol-water (1:1) and a little of cold methanol. White crystals, yield 580
mg (76%).
1
H NMR (CDCl
3
, 400 MHz): δ 14.7 (s, 1H; OH), 7.70-7.79 (m, 3H; H
Ar
),
7.28-7.48 (m, 7H; H
Ar
), 7.13 (d, J = 8.8 Hz, 1H; H
Ar
), 6.12 (dd, J = 6.0 Hz, 1.9 Hz, 1H;
H
c2
), 5.65 (d, J = 6.0 Hz, 1H; H
c1
), 5.07 (dd, J = 4.6 Hz, 1.9 Hz, 1H; H
c3
), 4.94 (s, 1H;
H
a
), 4.28 (d, J = 12.1 Hz, 1H; H
b1
/H
b2
), 3.57 (d, J = 12.1 Hz, 1H; H
b1
/H
b2
), 3.02 (d, J =
9.3 Hz, 1H; H
c7
/H
c8
), 2.71 (d, J = 9.3 Hz, 1H; H
c7
/H
c8
), 2.13 (dd, J = 11.6 Hz, 4.6 Hz, 1H;
H
c4
/H
c5
), 1.07 (s, 3H; CH
3
), 1.04 (d, J = 11.6 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100
MHz): δ 156.2, 136.4, 134.5, 133.5, 132.9, 129.7, 129.6, 128.7, 128.6, 128.4, 127.8,
126.5, 122.6, 122.3, 120.3, 109.2, 101.8, 80.1, 68.4, 63.4, 60.3, 48.3, 39.4, 22.5.
N
Ph
O
Br
OH
2.86. ( ±)-1-[(3R,3aR,6S,7aS)-2-Benzyl-7a-bromo-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindol-3-yl]-2-naphthol. The starting amine (2.85) was prepared by alkylation of
benzylamine with 2,3-dibromopropene. The compound 2.86 was prepared similarly to
2.43. The product precipitated from the reaction mixture. The mixture was cooled, the
crystals filtered off, washed with methanol-water (1:1) and a little of cold methanol.
White crystals, yield 793 mg (89%).
1
H NMR (CDCl
3
, 400 MHz): δ 13.4 (s, 1H; OH),
7.68-7.83 (m, 3H; H
Ar
), 7.23-7.48 (m, 7H; H
Ar
), 7.19 (d, J = 8.8 Hz, 1H; H
Ar
), 6.20 (dd, J
89
= 6.0 Hz, 1.9 Hz, 1H; H
c2
), 5.86 (d, J = 6.0 Hz, 1H; H
c1
), 5.18 (dd, J = 4.6 Hz, 1.9 Hz, 1H;
H
c3
), 4.94 (s, 1H; H
a
), 4.32 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.59 (d, J = 12.5 Hz, 1H;
H
b1
/H
b2
), 3.54 (d, J = 11.1 Hz, 1H; H
c7
/H
c8
), 2.93 (d, J = 11.1 Hz, 1H; H
c7
/H
c8
), 2.55 (dd,
J = 12.5 Hz, 4.6 Hz, 1H; H
c4
/H
c5
), 1.82 (d, J = 12.5 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
,
100 MHz): δ 155.9, 136.3, 135.8, 133.5, 133.0, 130.1, 129.4, 128.8, 128.5, 127.9, 126.7,
122.7, 122.0, 120.3, 108.1, 101.9, 80.6, 67.1, 65.8, 64.5, 59.1, 41.4.
N
Ph
O
H
OH
Ph
2.88. ( ±)-1-[(3R,3aS,6R,7S,7aR)-2-Benzyl-7-phenyl-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindol-3-yl]-2-naphthol. The starting N-allyl-N-cinnamylamine (2.87) was
prepared from cinnamaldehyde and benzylamine by reductive amination (NaBH
4
in
ethanol). The compound 2.88 was prepared similarly to 2.43, TLC control (silica/CH
2
Cl
2
,
stained with basic KMnO
4
): R
f
0.8. The product was isolated by flash chromatography
(twice on neutral alumina, CH
2
Cl
2
-hexane 1:1) as white crystals, yield 315 mg (35%).
The product should not be heated during evaporation of the solvent, and turns yellow
upon redissolving with gradual formation of retro-Diels-Alder compounds (2.93) along
with colored decomposition products.
1
H NMR (CDCl
3
, 400 MHz): δ 14.1 (s, 1H; OH),
7.96 (d, J = 8.8 Hz, 1H; H
Ar
), 7.84-7.91 (m, 2H; H
Ar
), 7.53-7.60 (m, 1H; H
Ar
), 7.20-7.50
(m, 11H; H
Ar
), 7.10-7.15 (m, 2H; H
Ar
), 6.02 (dd, J = 6.0 Hz, 1.4 Hz, 1H; H
c2
), 5.92 (d, J =
90
5.8 Hz, 1H; H
c1
), 5.26 (dd, J = 4.2 Hz, 1.4 Hz, 1H; H
c3
), 5.05 (s, 1H; H
a
), 4.31 (d, J =
12.5 Hz, 1H; H
b1
/H
b2
), 3.68 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.56 (dd, J = 8.3 Hz, 5.6 Hz,
1H; H
c8
), 3.51 (t, J = 4.2 Hz, 1H; H
c4
), 2.58-2.71 (m, 2H; H
c6
+H
c7
).
13
C NMR (CDCl
3
,
100 MHz): δ 156.5, 139.0, 136.2, 136.1, 133.2, 132.9, 129.9, 129.5, 128.7, 128.6, 128.5,
128.1, 127.9, 127.7, 126.8, 126.6, 122.7, 121.6, 119.9, 110.2, 101.1, 84.3, 67.0, 59.0, 56.7,
51.7, 48.8.
N
Ph
O
H
OH
2.90. ( ±)-1-[(3R,3aS,6R,7aR)-2-Benzyl-7,7-dimethyl-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindol-3-yl]-2-naphthol. The starting amine (2.89) was prepared by alkylation of
benzylamine with prenyl bromide (1-bromo-3-methyl-2-butene) in diethyl ether.
Prepared similarly to 2.43, TLC control (silica/CH
2
Cl
2
, stained with basic KMnO
4
): R
f
0.75. The product was isolated by flash chromatography (silica, CH
2
Cl
2
-hexane 1:1 to
CH
2
Cl
2
), the fractions containing the product were pooled, and the second column (silica,
EtOAc-hexane 1:6) was run to isolate the product as viscous yellow oil. Trituration of the
oil with diethyl ether followed by dilution with hexane and cooling gave white crystals,
yield 85 mg (11%).
1
H NMR (CDCl
3
, 400 MHz): δ 13.9 (s, 1H; OH), 7.72-7.86 (m, 3H;
H
Ar
), 7.27-7.49 (m, 7H; H
Ar
), 7.17 (d, J = 8.8 Hz, 1H; H
Ar
), 6.18 (br.d, J = 6.0 Hz, 1H;
H
c2
), 5.67 (d, J = 6.0 Hz, 1H; H
c1
), 4.83 (s, 1H; H
a
), 4.39 (br.s, 1H; H
c3
), 4.20 (d, J = 12.5
91
Hz, 1H; H
b1
/H
b2
), 3.53 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.17 (dd, J = 9.3 Hz, 6.5 Hz, 1H;
H
c8
), 2.50 (dd, J = 11.1 Hz, 9.3 Hz, 1H; H
c7
), 1.92 (dd, J = 11.1 Hz, 6.5 Hz, 1H; H
c6
),
1.25 (s, 3H; CH
3
), 0.86 (s, 3H; CH
3
).
13
C NMR (CDCl
3
, 100 MHz): δ 156.4, 136.6, 135.1,
134.6, 132.9, 129.8, 129.5, 128.7, 128.6, 128.5, 127.7, 126.7, 122.7, 121.7, 119.8, 110.6,
101.1, 88.9, 67.4, 59.1, 54.3, 52.9, 40.0, 26.4, 25.1.
N
Ph
O
H
OH
Ph
2.92. ( ±)-1-[(1S,3R,3aS,6S,7aR)-2-Benzyl-1-phenyl-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindol-3-yl]-2-naphthol. 1-Phenyl-2-propene-3-amine hydrochloride was
prepared from cinnamyl alcohol by Overman rearrangement with 2,2,2-
trichloroacetonitrile followed by hydrolysis
74
and converted to the secondary amine (2.91)
by reductive amination with benzaldehyde (1 eq NaOAc and 1.2 eq NaBH
4
in ethanol).
The compound 2.92 was prepared similarly to 2.43, TLC control (silica/CH
2
Cl
2
-hexane
2:1, stained with basic KMnO
4
): R
f
0.35. The product was isolated by flash
chromatography (silica, CH
2
Cl
2
-hexane 2:1) as yellowish crystals, yield 370 mg (83%).
A single crystal for X-ray diffraction analysis was grown in CH
2
Cl
2
-methanol.
1
H NMR
(CDCl
3
, 400 MHz): δ 14.1 (s, 1H; OH), 7.74-7.78 (m, 2H; H
Ar
), 7.69 (d, J = 8.7 Hz, 1H;
H
Ar
), 7.42-7.55 (m, 5H; H
Ar
), 7.36-7.41 (m, 1H; H
Ar
), 7.29-7.34 (m, 1H; H
Ar
), 7.04-7.16
(m, 4H; H
Ar
), 6.94-6.98 (m, 2H; H
Ar
), 6.06 (dd, J = 5.8 Hz, 1.8 Hz, 1H; H
c2
), 5.61 (d, J =
5.8 Hz, 1H; H
c1
), 5.17 (s, 1H; H
a
), 5.03 (dd, J = 4.6 Hz, 1.7 Hz, 1H; H
c3
), 3.85 (d, J =
92
13.7 Hz, 1H; H
b1
/H
b2
), 3.76 (d, J = 13.7 Hz, 1H; H
b1
/H
b2
), 3.70 (d, J = 10.0 Hz, 1H; H
c8
),
2.27-2.39 (m, 1H; H
c6
), 1.79 (ddd, J = 11.6 Hz, 4.2 Hz, 2.9 Hz, 1H; H
c4
/H
c5
), 1.25 (dd, J
= 11.6 Hz, 7.9 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 170.5, 158.3, 139.8,
132.1, 131.1, 130.8, 129.21, 129.17, 128.8, 128.2, 128.1, 126.8, 126.7, 123.2, 122.8,
116.2, 112.3, 96.0, 71.1, 69.0, 55.6, 55.4, 42.2, 33.0, 21.3.
X-ray crystallography data for 2.92.
X-ray diffraction data were collected on a Bruker SMART APEX CCD
diffractometer with graphite-monochromatic Mo K α radiation ( λ= 0.71073 Å) at 110 K.
The cell parameters for 2.92 were obtained from the least-squares refinement of the spots
(from 60 collected frames) using the SMART program. A hemisphere of the crystal data
was collected up to a resolution of 0.75 Å, and the intensity data were processed using the
Saint Plus program. All calculations for the structure determination were carried out
using the SHELXTL package (version 6.14).
75
Initial atomic position were located by
direct methods using XS, and the structure was refined by the least square methods using
SHELX with 5201 independent reflections within the range of theta 1.77 – 27.57°
(completeness 97.4 %). Absorption corrections were applied by SADABS.
76
Calculated
hydrogen positions were input and refined in a riding manner along with the
corresponding carbons. A summary of the refinement details and resulting factors are
given in Table 2.8.
93
Table 2.8. Crystallographic data and structure refinement details for 2.92.
formula C
31
H
27
NO
2
fw 445.54
T (K) 110 K
λ (Å) 0.71073
crystal system Monoclinic
space group P2(1)/n
a, (Å) / b, (Å) / c, (Å) 8.7127(11) / 16.884(2) / 15.983(2)
α, (deg) / β, (deg) / γ, (deg) 90 / 101.124(2) / 90
V, (Å
3
) 2307.1(5)
Z 4
D
calc
, (Mg/m
3
) 1.283
µ (mm
-1
) 0.079
F(000) 944
crystal size (mm) 0.3 x 0.25 x 0.01
θ range for data collection (deg) 1.77–27.57
index ranges
-9<=h<=11
-21<=k<=21
-20<=l<=16
reflections collected 14134
independent reflections / R
int
5201 / 0.0361
completeness to θ = 27.57° 97.4%
transmission factors min/max ratio: 0.843576
refinement method
Full-matrix least-squares on F
2
data / restraints / parameters 5201 / 0 / 308
GOF on F
2
1.036
R
1
, wR
2
[I>2 σ(I)] 0.0485, 0.1108
R
1
, wR
2
(all data) 0.0715, 0.1201
peak and hole (e.Å
-3
) 0.260, -0.196
94
OH
N
Ph
Ph
O
2.93. ( ±)-1-[{Benzyl[(2E)-3-phenylprop-2-enyl]amino}(2-furyl)methyl]-2-naphthol.
In a 1 dram vial equipped with a stirring bar, the mixture of 2-hydroxy-1-naphthaldehyde
(172 mg, 1 mmol), N-allyl-N-cinnamylamine (223 mg, 1 mmol) and furan-2-boronic acid
(112 mg, 1 mmol) in ethanol (2.5 mL) was stirred at room temperature for 24 h. The
white crystalline precipitate was filtered off and washed with cold methanol. Yield 350
mg (79%).
1
H NMR (CDCl
3
, 400 MHz): δ 12.99 (s, 1H; OH), 7.86 (d, J = 8.7 Hz, 1H;
H
Ar
), 7.78 (d, J = 7.9 Hz, 1H; H
Ar
), 7.75 (d, J = 8.7 Hz, 1H; H
Ar
), 7.41-7.47 (m, 1H; H
Ar
),
7.25-7.41 (m, 11H; H
Ar
), 7.23 (d, J = 8.7 Hz, 1H; H
Ar
), 6.43 (d, J = 2.9 Hz, 1H; H
a3
),
6.27-6.37 (m, 1H; H
d3
), 6.18-6.27 (m, 2H; H
d4
+H
a2
), 5.83 (s, 1H; H
b
), 3.89 (br.d, J = 13.7
Hz, 1H; H
c1/c2
), 3.72 (d, J = 13.7 Hz, 1H; H
c1/c2
), 3.31-3.48 (m, 2H; H
d1
+H
d2
).
13
C NMR
(CDCl
3
, 100 MHz): δ 156.1, 152.3, 142.3, 136.5, 131.9, 129.9, 129.3, 129.0, 128.7, 128.6,
128.5, 127.8, 127.5, 126.7, 126.4, 122.6, 120.7, 119.7, 113.3, 110.7, 109.8, 94.9, 59.1,
54.5, 50.9.
95
N
Ph
O
H
OH
2.97. ( ±)-1-[(3R,3aS,6S,7aR)-2-Benzyl-6-methyl-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindol-3-yl]-2-naphthol. In a 1 dram vial equipped with a stirring bar, the
mixture of 2-hydroxy-1-naphthaldehyde (172 mg, 1 mmol), N-allyl-N-benzylamine (147
mg, 1 mmol) and 5-methylfuran-2-boronic acid (126 mg, 1 mmol) in ethanol (2.5 mL)
was stirred at room temperature for 72 h. The white crystalline precipitate was filtered off
and washed with cold methanol-water (1:1). Yield 280 mg (73%).
1
H NMR (CDCl
3
, 400
MHz): δ 14.1 (s, 1H; OH), 7.83 (d, J = 8.7 Hz, 1H; H
Ar
), 7.77 (d, J = 8.3 Hz, 1H; H
Ar
),
7.72 (d, J = 8.7 Hz, 1H; H
Ar
), 7.42-7.48 (m, 1H; H
Ar
), 7.27-7.40 (m, 6H; H
Ar
), 7.13 (d, J =
9.1 Hz, 1H; H
Ar
), 5.91 (d, J = 5.8 Hz, 1H; H
c2
), 5.59 (d, J = 5.8 Hz, 1H; H
c1
), 4.88 (s, 1H;
H
a
), 4.20 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.57 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.30 (dd, J =
8.7 Hz, 6.2 Hz, 1H; H
c8
), 2.42 (dd, J = 10.8 Hz, 8.7 Hz, 1H; H
c7
), 2.26-2.35 (m, 1H; H
c6
),
1.66 (s, 3H; Me), 1.47 (d, J = 5.4 Hz, 2H; H
c4
+H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ
156.7, 137.8, 136.6, 135.7, 132.9, 129.7, 129.5, 128.65, 128.59, 128.4, 127.7, 126.7,
122.6, 121.9, 120.0, 110.3, 99.3, 88.0, 67.3, 59.3, 56.8, 46.6, 35.9, 19.3.
96
N
O
Ph
OAc
H
H
2.100. ( ±)-(3S,4aR,6aR,13aS)-6-Benzyl-3,4,4a,5,6,6a-
hexahydronaphtho[1',2':4,5]furo[3,2-c]isoindol-3-yl acetate. Methanesulfonic acid
(240 mg, 2.5 mmol, 5 eq) was added to the solution of 2.63 (185 mg, 0.5 mmol) in glacial
acetic acid (2 mL), and the reaction mixture was stirred at 70 °C for 2 h. TLC control
(silica/20% EtOAc in hexane, stained with basic KMnO
4
): R
f
0.55. The reaction mixture
was poured into water (50 mL), solid NaHCO
3
was added in small portions to pH ~ 6,
and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were
dried over Na
2
SO
4
, the filtrate was evaporated and the product was isolated from the
residue by flash chromatography (silica, 10% EtOAc in hexane) as white crystals, yield
189 mg (92%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.88 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 9.1
Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.28-7.45 (m, 7H), 7.20 (d, J = 8.7 Hz, 1H), 5.94-6.03
(m, 2H), 5.58-5.65 (m, 1H), 5.19 (s, 1H), 4.22 (d, J = 14.1 Hz, 1H), 3.57 (d, J = 14.1 Hz,
1H), 2.94 (dd, J = 9.6 Hz, 5.4 Hz, 1H), 2.66-2.75 (m, 2H), 2.25-2.37 (m, 2H), 2.20 (s,
3H).
13
C NMR (CDCl
3
, 100 MHz): δ 170.5, 158.4, 139.8, 132.1, 131.1, 130.8, 129.2,
129.2, 128.8, 128.2, 128.1, 126.8, 126.7, 123.2, 122.8, 116.2, 112.3, 96.0, 71.1, 69.0, 55.6,
55.4, 42.2, 33.0, 21.3.
97
N
O
Ph
OAc
H
H
Br
2.101. ( ±)-(3S,4aS,6aR,11aS)-6-Benzyl-8-bromo-3,4,4a,5,6,6a-
hexahydro[1]benzofuro[3,2-c]isoindol-3-yl acetate. Prepared similarly to 2.100 on 1
mmol scale. The residue was purified by flash chromatography on silica (25 g SiliCycle
cartridge, 25 mL/min, gradient 0% to 20% EtOAc-hexane over 15 CV). White crystals,
yield 394 mg (90%).
1
H NMR (CDCl
3
, 500 MHz): δ 7.36-7.40 (m, 4H), 7.26-7.32 (m,
2H), 7.20 (d, J = 1.9 Hz, 1H), 6.69 (d, J = 6.6 Hz, 1H), 5.92-5.97 (m, 1H), 5.83 (dd, J =
10.0 Hz, 1.9 Hz, 1H), 5.45-5.50 (m, 1H), 4.58 (s, 1H), 3.89 (d, J = 13.8 Hz, 1H), 3.65 (d,
J = 13.8 Hz, 1H), 2.71 (dd, J = 9.4 Hz, 5.4 Hz, 1H), 2.61 (dd, J = 9.4 Hz, 1.7 Hz, 1H),
2.50-2.57 (m, 1H), 2.17-2.24 (m, 1H), 2.07-2.15 (m, 1H), 2.11 (s, 3H).
13
C NMR (CDCl
3
,
125 MHz): δ 170.5, 159.3, 138.6, 132.4, 131.4, 129.6, 128.9, 128.5, 128.2, 127.1, 125.5,
111.8, 111.4, 94.9, 71.0, 68.5, 55.1, 54.0, 42.6, 32.9, 21.3.
98
N
OAc
Ph
H
N
O
OH
H
2.102. ( ±)-(4bR,6aS,8S,10aR)-5-Benzyl-4-hydroxy-3-methyl-4b,6,6a,7,8,12-
hexahydro-5H-pyrido[4',3':4,5]pyrano[3,2-c]isoindol-8-yl acetate. Prepared similarly
to 2.100, TLC control (silica/EtOAc-hexane 1:1, stained with basic KMnO
4
): R
f
0.3. The
residue was purified by flash chromatography on silica (10 g Biotage cartridge, 12
mL/min, gradient 10% to 100% EtOAc-hexane over 15 CV). Viscous colorless oil, yield
175 mg (86%).
1
H NMR (CDCl
3
, 500 MHz): δ 13.18 (br.s, 1H), 7.98 (s, 1H), 7.24-7.33
(m, 5H), 6.18 (dd, J = 5.8 Hz, 1.7 Hz, 1H), 5.73 (d, J = 5.8 Hz, 1H), 5.13 (d, J = 12.7 Hz,
1H), 5.04 (dd, J = 4.4 Hz, 1.7 Hz, 1H), 4.93 (d, J = 12.7 Hz, 1H), 4.33 (s, 1H), 3.98 (d, J
= 12.4 Hz, 1H), 3.63 (d, J = 12.4 Hz, 1H), 3.32 (dd, J = 8.8 Hz, 6.4 Hz, 1H), 2.51 (s, 3H),
2.34 (dd, J = 11.1 Hz, 9.1 Hz, 1H), 2.16-2.23 (m, 1H), 2.02 (s, 3H), 1.74 (ddd, J = 11.6
Hz, 4.4 Hz, 3.3 Hz, 1H), 1.38 (dd, J = 11.6 Hz, 7.7 Hz, 1H).
13
C NMR (CDCl
3
, 125
MHz): δ 170.4, 152.2, 149.1, 140.4, 135.8, 134.9, 134.5, 129.2, 128.4, 127.8, 127.1,
126.7, 99.2, 79.8, 65.9, 61.4, 58.7, 56.8, 43.8, 29.1, 21.0, 19.0.
99
N
Ph
OH
2.103. ( ±)-1-(2-Benzyl-2,3-dihydro-1H-isoindol-1-yl)-2-naphthol. Method A. 2.63 (185
mg, 0.5 mmol) was dissolved in methanesulfonic acid (1 mL) and the mixture was stirred
for 1 h at 70 °C. TLC control (silica/20% EtOAc in hexane): R
f
0.6 (2.63), R
f
0.8 (2.103).
The resulting dark-green solution was worked up as described for 2.100, and the product
was isolated by flash chromatography (silica, 10% EtOAc in hexane) as white crystals,
yield 120 mg (68%).
Method B. The reaction is run on the same scale in trifluoroacetic acid (2 mL) with
addition of methanesulfonic acid (240 mg, 2.5 mmol, 5 eq) at 70 °C for 2 h. Worked up
as described above. The yield of crude product from the column was 140 mg, trituration
with diethyl ether followed by cooling gave 106 mg (60%) of 2.103.
1
H NMR (CDCl
3
, 400 MHz): δ 13.09 (s, 1H; OH), 8.02 (d, J = 8.3 Hz, 1H), 7.86 (d, J =
7.9 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.51-7.57 (m, 1H), 7.31-7.46 (m, 6H), 7.18-7.24 (m,
2H), 7.16 (d, J = 8.7 Hz, 1H), 7.04-7.11 (m, 1H), 6.77 (d, J = 7.5 Hz, 1H), 5.94 (br.s, 1H),
4.33 (d, J = 12.9 Hz, 1H), 4.23 (d, J = 12.9 Hz, 1H), 3.88 (dd, J = 12.9 Hz, 2.9 Hz, 1H),
3.70 (d, J = 12.9 Hz, 1H).
13
C NMR (CDCl
3
, 100 MHz): δ 156.5, 141.0, 137.8, 136.5,
133.5, 129.8, 129.5, 129.0, 128.7, 128.5, 127.8, 127.7, 127.6, 126.8, 123.1, 122.5, 122.1,
121.0, 120.1, 112.6, 68.7, 57.9, 56.5.
100
N
O
Ph
OH
H
H
2.105. ( ±)-(3S,4aR,6aR,13aS)-6-Benzyl-3,4,4a,5,6,6a-
hexahydronaphtho[1',2':4,5]furo[3,2-c]isoindol-3-ol. Method A. Methanesulfonic acid
(240 mg, 2.5 mmol, 5 eq) was added to the solution of 2.63 (185 mg, 0.5 mmol) in 1,4-
dioxane (2 mL), and the reaction mixture was stirred at 70 °C for 24 h. TLC control
(silica/EtOAc-hexane 1:1, stained with basic KMnO
4
): R
f
0.5. After the workup as
described for 2.100, the product was isolated by flash chromatography (silica, 40%
EtOAc in hexane) as off-white flakes, yield 133 mg (72%). The compound is sensitive to
oxidation in air, turning blue-green.
Method B. A solution of K
2
CO
3
(183 mg, 1 mmol) in water (2 mL) was added to the
stirred suspension of 2.100 (206 mg, 0.5 mmol) in methanol (10 mL). Acetonitrile (5 mL)
was added, and the mixture was stirred at room temperature for 1 h. TLC control
(silica/EtOAc-hexane 1:1, stained with vanillin): R
f
0.5 (2.105, orange-brown), R
f
0.85
(2.100, orange-brown). The reaction mixture was poured into water (75 mL), extracted
with EtOAc (3×25 mL), the combined extracts were washed with water (25 mL) and
dried over Na
2
SO
4
. Evaporation of the filtrate gave pure 2.105 in nearly quantitative yield.
1
H NMR (CDCl
3
, 400 MHz): δ 7.88 (br.d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.68
(br.d, J = 8.3 Hz, 1H), 7.39-7.44 (m, 1H), 7.27-7.38 (m, 6H), 7.19 (d, J = 9.1 Hz, 1H),
6.08-6.12 (m, 1H), 5.90 (dd, J = 10.0 Hz, 2.1 Hz, 1H), 5.19 (s, 1H), 4.50-4.56 (m, 1H),
101
4.25 (d, J = 13.7 Hz, 1H), 3.56 (d, J = 13.7 Hz, 1H), 2.93 (dd, J = 9.5 Hz, 5.4 Hz, 1H),
2.61-2.71 (m, 2H), 2.23-2.30 (m, 1H), 2.08-2.20 (m, 1H), 1.94 (br.s, 1H).
13
C NMR
(CDCl
3
, 100 MHz): δ 158.5, 139.9, 135.2, 132.2, 131.1, 129.2, 128.8, 128.3, 128.2, 127.7,
126.8, 126.7, 123.3, 122.8, 116.1, 112.2, 96.4, 71.3, 66.4, 55.7, 55.6, 42.7, 37.4.
N
Ph
O
H
OH
O
2.106. ( ±)-1-[(1S,2R,5R,7S,8S,10S)-3-Benzyl-9,11-dioxa-3-
azatetracyclo[5.3.1.0
1,5
.0
8,10
]undec-2-yl]-2-naphthol. 2.63 (369 mg, 1 mmol) was
dissolved in 98% formic acid (2 mL), and 50 wt.% H
2
O
2
(130 mg, 2 mmol, 2 eq) was
added in one portion. The reaction mixture was stirred for 2 h at room temperature, and
the precipitate began to form. TLC control (silica/EtOAc-hexane 1:1, stained with basic
KMnO
4
): R
f
0.4 (2.106, does not stain), R
f
0.85 (2.63). After the workup as described for
2.100, the product was isolated by flash chromatography (silica, EtOAc-hexane 1:1).
Trituration with diethyl ether gave white crystals, yield 262 mg (68%).
1
H NMR (CDCl
3
,
400 MHz): δ 13.78 (br.s, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.74-7.81 (m, 2H), 7.55-7.60 (m,
1H), 7.28-7.38 (m, 6H), 7.17 (d, J = 9.1 Hz, 1H), 4.95 (s, 1H), 4.65 (d, J = 5.0 Hz, 1H),
4.14 (d, J = 12.2 Hz, 1H), 3.55 (d, J = 12.2 Hz, 1H), 3.11-3.17 (m, 2H), 2.80 (d, J = 3.3
Hz, 1H), 2.41-2.49 (m, 1H), 2.37 (dd, J = 10.8 Hz, 8.7 Hz, 1H), 1.73 (ddd, J = 12.5 Hz,
4.6 Hz, 3.7 Hz, 1H), 1.59 (dd, J = 12.5 Hz, 7.9 Hz, 1H).
13
C NMR (CDCl
3
, 100 MHz): δ
102
156.4, 136.0, 132.6, 130.0, 129.3, 128.5, 127.7, 126.7, 122.8, 121.5, 119.6, 109.9, 95.5,
77.0, 76.7, 65.4, 58.8, 55.1, 49.6, 48.8, 45.4, 31.7.
N
O
Ph
N
H
H
O
2.107. ( ±)-(4aS,6aR,13aS)-6-Benzyl-3-(4-morpholinyl)-3,4,4a,5,6,6a-
hexahydronaphtho[1',2':4,5]furo[3,2-c]isoindole. In a 10 mL microwave vial
containing a stirring bar, the mixture of 2.100 (206 mg, 0.5 mmol), morpholine (65 µL,
65 mg, ~0.75 mmol, 1.5 eq), Pd(PPh
3
)
4
(29 mg, 0.025 mmol, 5 mol%) in anhydrous
acetonitrile (3 mL) was sealed under N
2
atmosphere. The reaction mixture was stirred for
1 h at 70 °C, and its color changed to pink-orange from initially yellow. TLC control
(silica/EtOAc-hexane 1:1, stained with basic KMnO
4
): R
f
0.35 (2.107), R
f
0.85 (2.100).
The product was isolated by flash chromatography on silica (25 g SiliCycle cartridge, 25
mL/min, gradient 10% to 100% EtOAc-hexane over 12 CV). Viscous colorless oil, yield
218 mg (99.5%). Mixture of 2 diastereoisomers in 1:1 ratio.
1
H NMR (CDCl
3
, 500 MHz):
δ 7.77-7.86 (m, 2H), 7.64 (d, J = 8.3 Hz, 0.5H), 7.42-7.47 (m, 0.5H), 7.21-7.40 (m, 6H),
7.13-7.18 (m, 1H), 6.00-6.08 (m, 1H), 5.88-5.96 (m, 1H), 5.13 (s, 0.5H), 4.52 (s, 0.5H),
4.38 (d, J = 12.7 Hz, 0.5H), 4.21 (d, J = 13.5 Hz, 0.5H), 3.70-3.84 (m, 4H), 3.39-3.47 (m,
103
1H), 3.14-3.20 (m, 0.5H), 2.81-2.92 (m, 1.5H), 2.60-2.74 (m, 4H), 2.52-2.58 (m, 0.5H),
2.36 (t, J = 8.8 Hz, 0.5H), 2.19 (q, J = 12.2 Hz, 0.5H), 1.84-2.02 (m, 1.5H).
13
C NMR
(CDCl
3
, 125 MHz): δ 158.5, 157.6, 140.1, 139.1, 133.6, 132.3, 131.8, 131.6, 131.03,
130.99, 129.5, 129.24, 129.19, 128.9, 128.8, 128.6, 128.24, 128.21, 128.1, 127.0, 126.83,
126.76, 126.7, 123.2, 123.1, 122.8, 122.7, 119.4, 116.3, 112.9, 112.2, 97.4, 93.3, 75.3,
70.8, 67.4, 60.3, 59.6, 56.7, 55.9, 55.5, 55.4, 49.5, 49.0, 43.0, 41.0, 28.4, 21.7.
N
Ph
O
H
N
NH
2.109. ( ±)-(3R,3aS,6S,7aR)-2-Benzyl-3-(1H-imidazol-2-yl)-1,2,3,6,7,7a-hexahydro-
3a,6-epoxyisoindole. Prepared similarly to 2.43 on 1 mmol scale (in 2.5 mL of ethanol),
TLC control (silica/EtOAc, stained with basic KMnO
4
): R
f
0.25-0.4. The product was
isolated by flash chromatography (silica, EtOAc), and the yellow residue was triturated
with diethyl ether to give yellowish solid. Yield 250 mg (85%).
1
H NMR (CDCl
3
, 400
MHz): δ 8.5-11.0 (very br.s, 1H, NH), 7.23-7.34 (m, 5H; H
Ar
), 7.09 (s, 2H; H
imidazole
),
6.22 (dd, J = 6.0 Hz, 1.4 Hz, 1H; H
c2
), 5.80 (d, J = 6.0 Hz, 1H; H
c1
), 5.05 (dd, J = 4.6 Hz,
1.4 Hz, 1H; H
c3
), 4.32 (s, 1H; H
a
), 3.97 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.68 (d, J = 12.5
Hz, 1H; H
b1
/H
b2
), 3.32 (dd, J = 8.4 Hz, 7.0 Hz, 1H; H
c8
), 2.35 (dd, J = 10.2 Hz, 8.8 Hz,
1H; H
c7
), 2.03-2.12 (m, 1H; H
c6
), 1.72-1.79 (m, 1H; H
c4
/H
c5
), 1.32 (dd, J = 11.6 Hz, 7.4
Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 148.0, 138.5, 135.4, 134.4, 128.7,
128.3, 127.1, 99.4, 79.9, 63.7, 59.1, 57.8, 42.2, 29.3.
104
N
Ph
O
H
N
NH
2.111. ( ±)-(3R,3aS,6S,7aR)-2-Benzyl-3-(1H-imidazol-4(5)-yl)-1,2,3,6,7,7a-hexahydro-
3a,6-epoxyisoindole. Prepared similarly to 2.43 on 1 mmol scale (in 2.5 mL of ethanol),
TLC control (silica/EtOAc-methanol 10:1, stained with basic KMnO
4
): R
f
0.4. The
product was isolated by flash chromatography (silica, EtOAc-methanol 10:1), the
fractions containing the products were pooled, evaporated, and the residue was
recrystallized from EtOAc-hexane to give 109 mg (37%) of 2.111 as light-tan crystals.
1
H
NMR (CDCl
3
, 400 MHz): δ 7.73 (d, J = 1.0 Hz, 1H; H
im-2
), 7.23-7.35 (m, 5H; H
Ar
), 7.13
(s, 1H; H
im-4
), 6.23 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.95 (d, J = 5.8 Hz, 1H; H
c1
), 5.05
(dd, J = 4.6 Hz, 1.7 Hz, 1H; H
c3
), 4.12 (s, 1H; H
a
), 3.99 (d, J = 12.9 Hz, 1H; H
b1
/H
b2
),
3.59 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.27 (dd, J = 8.3 Hz, 6.6 Hz, 1H; H
c8
), 2.27 (dd, J =
10.4 Hz, 8.3 Hz, 1H; H
c7
), 2.07-2.16 (m, 1H; H
c6
), 1.75 (ddd, J = 11.6 Hz, 4.6 Hz, 3.3 Hz,
1H; H
c4
/H
c5
), 1.34 (dd, J = 11.6 Hz, 7.5 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz):
δ 138.7, 135.4, 135.1, 135.0, 128.8, 128.2, 127.0, 99.9, 79.8, 62.1, 58.3, 57.4, 42.2, 29.1.
105
N
Ph
O
H
N
NH
2.113. ( ±)-(3R,3aS,6S,7aR)-3-(1H-Benzimidazol-2-yl)-2-benzyl-1,2,3,6,7,7a-
hexahydro-3a,6-epoxyisoindole. The starting aldehyde 2.112 was prepared by periodate
cleavage of 1,2-bis(2-benzimidazolyl)-1,2-ethanediol dihydrochloride
77
(with 1 eq of
NaIO
4
in water). The compound 2.113 was prepared similarly to 2.43. The starting
aldehyde dissolved in the reaction mixture completely over 4 h, and the product
precipitated overnight. The mixture was cooled, the crystals were filtered off and washed
with cold methanol. White crystals, yield 242 mg (71%).
1
H NMR (CDCl
3
, 400 MHz): δ
9.96 (br.s, 1H; NH), 7.79-7.85 (m, 1H; H
Ar
), 7.46-7.52 (m, 1H; H
Ar
), 7.23-7.36 (m, 7H;
H
Ar
), 6.23 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.82 (d, J = 5.8 Hz, 1H; H
c1
), 5.08 (dd, J =
4.6 Hz, 1.7 Hz, 1H; H
c3
), 4.49 (s, 1H; H
a
), 4.02 (d, J = 12.9 Hz, 1H; H
b1
/H
b2
), 3.75 (d, J =
12.9 Hz, 1H; H
b1
/H
b2
), 3.39 (dd, J = 8.3 Hz, 6.6 Hz, 1H; H
c8
), 2.43 (dd, J = 10.4 Hz, 8.7
Hz, 1H; H
c7
), 2.10-2.19 (m, 1H; H
c6
), 1.76-1.83 (m, 1H; H
c4
/H
c5
), 1.36 (dd, J = 11.6 Hz,
7.9 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 154.4, 138.0, 135.6, 134.2, 128.8,
128.4, 127.3, 99.4, 79.9, 64.1, 59.1, 57.9, 42.5, 29.3.
106
N
Ph
O
H
NH
2.115. ( ±)-(3R,3aS,6S,7aR)-2-Benzyl-3-(1H-indol-2-yl)-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindole. The starting aldehyde 2.112 was prepared by reduction of indole-2-
carbonyl chloride
78
with (Ph
3
P)
2
CuBH
4
.
79
The compound 2.115 was prepared similarly to
2.43 on 1 mmol scale (in 2.5 mL of ethanol), TLC control (silica/10% EtOAc in hexane,
stained with basic KMnO
4
): R
f
0.2. The product was isolated by flash chromatography
(silica, 10% EtOAc in hexane), the fractions containing the products were pooled,
evaporated, and the residue was triturated with diethyl ether to give 171 mg (50%) of
2.115 as white crystals.
1
H NMR (CDCl
3
, 400 MHz): δ 8.79 (br.s, 1H; NH), 7.66 (d, J =
7.5 Hz, 1H; H
Ar
), 7.46 (d, J = 7.9 Hz, 1H; H
Ar
), 7.26-7.39 (m, 5H; H
Ar
), 7.21-7.26 (m, 1H;
H
Ar
), 7.14-7.20 (m, 1H; H
Ar
), 6.61 (d, J = 1.7 Hz, 1H; H
Ar
), 6.22 (d, J = 5.8 Hz, 1.7 Hz,
1H; H
c2
), 5.84 (d, J = 5.8 Hz, 1H; H
c1
), 5.07 (dd, J = 4.2 Hz, 1.7 Hz, 1H; H
c3
), 4.26 (s, 1H;
H
a
), 4.04 (d, J = 12.9 Hz, 1H; H
b1
/H
b2
), 3.60 (d, J = 12.9 Hz, 1H; H
b1
/H
b2
), 3.32 (dd, J =
8.3 Hz, 6.2 Hz, 1H; H
c8
), 2.33 (dd, J = 10.8 Hz, 8.7 Hz, 1H; H
c7
), 2.10-2.19 (m, 1H; H
c6
),
1.80 (ddd, J = 11.2 Hz, 4.2 Hz, 3.3 Hz, 1H; H
c4
/H
c5
), 1.37 (dd, J = 11.2 Hz, 7.5 Hz, 1H;
H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 138.6, 138.2, 135.6, 135.3, 135.2, 129.2, 128.9,
128.3, 127.1, 121.4, 120.4, 119.7, 110.9, 100.8, 100.1, 79.9, 63.5, 58.3, 57.1, 42.5, 29.1.
107
N
Ph
O
H
NH
2.117. ( ±)-(3R,3aS,6S,7aR)-2-Benzyl-3-(1H-indol-7-yl)-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindole. Prepared similarly to 2.43 on 1 mmol scale (in 2.5 mL of ethanol), TLC
control (silica/CH
2
Cl
2
-hexane 1:1, stained with basic KMnO
4
): R
f
0.3. The product was
isolated by flash chromatography (silica, CH
2
Cl
2
-hexane 1:1 to CH
2
Cl
2
) as light-yellow
oil. Yield 140 mg (41%).
1
H NMR (CDCl
3
, 400 MHz): δ 9.9 (br.s, 1H; NH), 7.73 (d, J =
7.9 Hz, 1H; H
Ar
), 7.20-7.42 (m, 8H; H
Ar
), 6.67-6.71 (m, 1H; H
Ar
), 6.12 (br.d, J = 5.8 Hz,
1H; H
c2
), 5.55 (d, J = 5.8 Hz, 1H; H
c1
), 5.09 (br.d, J = 4.2 Hz, 1H; H
c3
), 4.30 (s, 1H; H
a
),
4.10 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.56 (d, J = 12.5 Hz, 1H; H
b1
/H
b2
), 3.42 (dd, J = 8.7
Hz, 6.2 Hz, 1H; H
c8
), 2.40 (dd, J = 10.8 Hz, 8.7 Hz, 1H; H
c7
), 2.14-2.23 (m, 1H; H
c6
),
1.84 (dt, J = 11.2 Hz, 3.7 Hz, 1H; H
c4
/H
c5
), 1.39 (dd, J = 11.2 Hz, 7.9 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 138.4, 135.6, 134.72, 134.69, 129.2, 128.6, 128.2, 127.0,
123.8, 122.2, 121.2, 119.8, 119.7, 102.2, 100.5, 79.7, 69.7, 58.5, 57.0, 43.7, 28.9.
108
N
Ph
O
H
NH EtO
2
C
2.119. Ethyl ( ±)-5-[(1S,2R,5S,7S)-3-benzyl-10-oxa-3-azatricyclo[5.2.1.0
1,5
]dec-8-en-2-
yl]-2-methyl-1H-pyrrole-3-carboxylate. The starting aldehyde (2.118) was prepared
according to the literature procedure.
80
The compound 2.119 was prepared similarly to
2.43 on 1 mmol scale (in 2 mL of ethanol), TLC control (silica/5% EtOAc in CH
2
Cl
2
,
stained with basic KMnO
4
): R
f
0.3. The product was isolated by flash chromatography
(silica, 5% EtOAc in CH
2
Cl
2
) as viscous light-brown oil. Yield 90 mg (24%).
1
H NMR
(CDCl
3
, 500 MHz): δ 8.78 (br.s, 1H; NH), 7.30-7.35 (m, 2H), 7.23-7.29 (m, 3H), 6.56 (d,
J = 2.8 Hz, 1H), 6.20 (dd, J = 5.8 Hz, 1.7 Hz, 1H), 5.88 (d, J = 5.8 Hz, 1H), 5.01 (dd, J =
4.4 Hz, 1.7 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.98 (s, 1H), 3.96 (d, J = 13.0 Hz, 1H),
3.54 (d, J = 13.0 Hz, 1H), 3.23 (dd, J = 8.6 Hz, 6.6 Hz, 1H), 2.56 (s, 3H), 2.24 (dd, J =
10.2 Hz, 8.8 Hz, 1H), 2.01-2.08 (m, 1H), 1.70-1.75 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H), 1.31
(dd, J = 11.3 Hz, 7.5 Hz, 1H).
13
C NMR (CDCl
3
, 125 MHz): δ 165.7, 138.6, 135.3, 135.0,
134.3, 128.8, 128.7, 128.2, 127.0, 112.3, 108.1, 99.9, 79.8, 62.7, 59.2, 58.1, 57.1, 42.1,
29.0, 14.5, 13.3.
109
N
Ph
O
H
N
2.121. ( ±)-(3R,3aS,6S,7aR)-2-Benzyl-3-pyridin-2-yl-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindole. Prepared similarly to 2.43 on 1 mmol scale (in 2.5 mL of acetonitrile),
TLC control (silica/EtOAc-hexane 1:1, stained with basic KMnO
4
): R
f
0.4. The product
was isolated by flash chromatography (silica, EtOAc-hexane 1:1) as brown oil. Yield 190
mg (63%).
1
H NMR (CDCl
3
, 400 MHz): δ 8.63-8.67 (m, 1H; H
Ar
), 7.64-7.72 (m, 2H;
H
Ar
), 7.15-7.73 (m, 6H; H
Ar
), 6.15 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.65 (d, J = 5.8 Hz,
1H; H
c1
), 5.02 (dd, J = 4.2 Hz, 1.7 Hz, 1H; H
c3
), 4.18 (s, 1H; H
a
), 3.93 (d, J = 12.9 Hz,
1H; H
b1
/H
b2
), 3.64 (d, J = 12.9 Hz, 1H; H
b1
/H
b2
), 3.35 (dd, J = 8.3 Hz, 6.2 Hz, 1H; H
c8
),
2.34 (dd, J = 10.4 Hz, 8.3 Hz, 1H; H
c7
), 2.11-2.20 (m, 1H; H
c6
), 1.74 (ddd, J = 11.6 Hz,
4.4 Hz, 3.3 Hz, 1H; H
c4
/H
c5
), 1.31 (dd, J = 11.6 Hz, 7.6 Hz, 1H; H
c4
/H
c5
).
13
C NMR
(CDCl
3
, 100 MHz): δ 160.9, 149.3, 138.7, 136.2, 134.8, 134.6, 128.6, 127.8, 126.6, 121.8,
121.6, 100.0, 79.4, 70.7, 58.5, 57.6, 42.1, 28.9.
N
Ph
O
H
S
N
2.123. ( ±)-(3S,3aS,6S,7aR)-2-Benzyl-3-(1,3-thiazol-2-yl)-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindole. Prepared similarly to 2.43 on 1 mmol scale (in 2.5 mL of acetonitrile),
110
TLC control (silica/10% EtOAc in hexane, stained with basic KMnO
4
): R
f
0.2. The
product was isolated by flash chromatography (silica, 10% EtOAc in hexane) as light-
brown oil. Yield 39 mg (13%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.86 (d, J = 3.3 Hz, 1H;
H
Ar
), 7.38-7.42 (m, 2H; H
Ar
), 7.29-7.35 (m, 3H; H
Ar
), 7.22-7.28 (m, 1H; H
Ar
), 6.22 (dd, J
= 5.8 Hz, 1.2 Hz, 1H; H
c2
), 5.76 (d, J = 5.8 Hz, 1H; H
c1
), 5.04 (dd, J = 4.6 Hz, 1.2 Hz, 1H;
H
c3
), 4.47 (s, 1H; H
a
), 4.12 (d, J = 12.9 Hz, 1H; H
b1
/H
b2
), 3.65 (d, J = 12.9 Hz, 1H;
H
b1
/H
b2
), 3.27 (dd, J = 8.3 Hz, 6.6 Hz, 1H; H
c8
), 2.28 (dd, J = 10.4 Hz, 8.7 Hz, 1H; H
c7
),
2.09-2.17 (m, 1H; H
c6
), 1.73 (ddd, J = 11.6 Hz, 4.2, 2.9 Hz, 1H; H
c4
/H
c5
), 1.30 (dd, J =
11.6 Hz, 7.9 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ 175.1, 143.8, 138.6, 135.6,
134.1, 128.6, 128.2, 127.1, 119.4, 99.8, 79.9, 67.0, 58.7, 57.5, 41.6, 29.3.
N
Ph
O
H
HO
2
C
2.127. ( ±)-(3S,3aS,6S,7aR)-2-Benzyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-3-
carboxylic acid. In a 2 dram vial equipped with a stirring bar, the mixture of glyoxylic
acid monohydrate (304 mg, 3.3 mmol, 1.1 eq), N-allyl-N-benzylamine (441 mg, 3 mmol)
and furan-2-boronic acid (336 mg, 3 mmol) in ethanol (4 mL) was stirred at room
temperature for 3 days (precipitation of the product begins after ~3 h). TLC control
(silica/EtOAc-methanol 2:1, stained with basic KMnO
4
): R
f
0.35. The precipitate is
filtered off, washed with cold methanol and diethyl ether. White crystals, yield 670 mg
(82%).
1
H NMR (D
2
O, 400 MHz): δ 7.31-7.41 (m, 5H), 6.38 (dd, J = 5.8 Hz, 2.1 Hz, 1H),
111
6.11 (d, J = 5.8 Hz, 1H), 5.09 (dd, J = 4.6 Hz, 2.1 Hz, 1H), 4.43 (d, J = 12.9 Hz, 1H),
4.23 (d, J = 12.9 Hz, 1H), 4.07 (s, 1H), 3.92 (dd, J = 11.2 Hz, 7.1 Hz, 1H), 2.97 (t, J =
11.2 Hz, 1H), 2.10-2.20 (m, 1H), 1.77 (ddd, J = 12.0 Hz, 4.6 Hz, 2.9 Hz, 1H), 1.42 (dd, J
= 12.0 Hz, 7.9 Hz, 1H).
13
C NMR (D
2
O, 100 MHz): δ 169.0, 137.4, 132.1, 130.6, 130.0,
129.3, 129.1, 96.4, 81.2, 69.0, 58.9, 58.7, 41.9, 29.3.
N
O
H
HO
2
C
OMe
2.128. ( ±)-(3S,3aS,6S,7aR)-2-(4-Methoxybenzyl)-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindole-3-carboxylic acid. Prepared similarly to 2.127 on 2 mmol scale in 3 mL
of ethanol. The precipitate is filtered off, washed with cold methanol, cold EtOAc-
methanol (2:1) and EtOAc-hexane (1:1). White crystals, yield 480 mg (80%).
1
H NMR
(DMSO-d
6
, 400 MHz): δ 7.30-7.36 (m, 2H), 6.88-6.93 (m, 2H), 6.36 (dd, J = 6.0 Hz, 1.5
Hz, 1H), 6.28 (d, J = 6.0 Hz, 1H), 5.01 (dd, J = 4.4 Hz, 1.5 Hz, 1H), 3.89-4.00 (m, 2H),
3.75 (s, 3H), 3.60 (s, 1H), 3.50 (dd, J = 9.5 Hz, 7.3 Hz, 1H), 2.47 (t, J = 9.9 Hz, 1H),
1.91-2.01 (m, 1H), 1.60-1.68 (m, 1H), 1.30 (dd, J = 11.5 Hz, 7.7 Hz, 1H).
13
C NMR
(DMSO-d
6
, 100 MHz): δ 168.1, 159.0, 135.9, 134.2, 131.1, 126.1, 113.6, 96.8, 79.3, 67.3,
57.5, 57.2, 55.0, 41.5, 29.8.
112
N
O
H
HO
2
C
OMe
MeO
2.130. ( ±)-(3S,3aS,6S,7aR)-2-(2,4-Dimethoxybenzyl)-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindole-3-carboxylic acid. The starting amine (2.129) was prepared from 2,4-
methoxybenzaldehyde and allylamine by reductive amination with NaBH
4
(1.3 eq) in
ethanol. The compound 2.130 was prepared similarly to 2.127 on 2 mmol scale in 3 mL
of ethanol. TLC control (silica/40% methanol in EtOAc, stained with basic KMnO
4
): R
f
0.3. The product did not precipitate and was isolated by flash chromatography (silica,
30% to 50% methanol in EtOAc). The fractions containing the product were pooled,
evaporated, and the solid residue was recrystallized from smallest amount of methanol-
EtOAc-hexane added to complete crystallization. Off-white crystals, yield 510 mg (77%).
1
H NMR (DMSO-d
6
, 400 MHz): δ 7.31 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H),
6.52 (dd, J = 8.3 Hz, 2.5 Hz, 1H), 6.38 (dd, J = 5.8 Hz, 1.7 Hz, 1H), 6.30 (d, J = 5.8 Hz,
1H), 5.02 (dd, J = 4.6 Hz, 1.7 Hz, 1H), 4.10 (d, J = 12.9 Hz, 1H), 4.02 (d, J = 12.9 Hz,
1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.73 (s, 1H), 3.65 (dd, J = 10.4 Hz, 7.5 Hz, 1H), 2.59 (t, J
= 10.4 Hz), 1.92-2.01 (m, 1H), 1.63-1.70 (m, 1H), 1.31 (dd, J = 11.6 Hz, 7.9 Hz, 1H).
13
C
NMR (DMSO-d
6
, 100 MHz): δ 166.3, 161.1, 158.6, 136.0, 134.1, 132.7, 112.5, 104.8,
98.3, 96.5, 79.4, 67.7, 57.5, 55.6, 55.2, 52.2, 41.2, 30.4.
113
N
Ph
O
H
HO
2
C
2.131. ( ±)-(3S,3aS,6S,7aR)-2-Phenyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-3-
carboxylic acid. Prepared similarly to 2.127 on 2 mmol scale in 3 mL of ethanol. TLC
control (silica/EtOAc-hexane-acetic acid 45:50:5, stained with basic KMnO
4
): R
f
0.4. The
product was isolated by flash chromatography (silica, EtOAc-hexane-acetic acid 20:75:5).
The fractions containing the product were pooled, evaporated, and the residue was
recrystallized from EtOAc-hexane. Off-white crystals, yield 210 mg (41%), readily
oxidizes in the air.
1
H NMR (CD
3
OD, 400 MHz): δ 7.16-7.22 (m, 2H), 6.67-6.72 (m, 1H),
6.52-6.58 (m, 2H), 6.51 (dd, J = 6.2 Hz, 1.7 Hz, 1H), 6.36 (d, J = 6.2 Hz, 1H), 5.09 (dd, J
= 4.6 Hz, 1.7 Hz, 1H), 4.91 (s, 1H), 4.29 (s, 1H), 3.95 (t, J = 8.3 Hz, 1H), 2.99 (t, J = 8.7
Hz, 1H), 2.41 (ddd, J = 16.2 Hz, 8.7 Hz, 2.5 Hz, 1H), 1.92 (ddd, J = 12.0 Hz, 4.6 Hz, 2.9
Hz, 1H), 1.58 (dd, J = 11.6 Hz, 7.5 Hz, 1H).
13
C NMR (CD
3
OD, 100 MHz): δ 175.3,
148.2, 138.7, 134.1, 130.2, 118.1, 113.1, 98.0, 81.6, 65.1, 54.8, 49.3, 42.1, 32.6, 24.3.
N
O
H
HO
2
C
Ph
2.132. ( ±)-(3S,3aS,6S,7aR)-2-Benzyl-6-methyl-1,2,3,6,7,7a-hexahydro-3a,6-
epoxyisoindole-3-carboxylic acid. Prepared similarly to 2.127 on 2 mmol scale in 3 mL
of ethanol. The precipitate is filtered off, washed with cold EtOAc. White crystals, yield
114
290 mg (51%).
1
H NMR (D
2
O, 400 MHz): δ 7.43-7.55 (m, 5H), 6.40 (d, J = 5.8 Hz, 1H),
6.24 (d, J = 5.8 Hz, 1H), 4.82 (s, 2H), 4.57 (d, J = 12.9 Hz, 1H), 4.33 (d, J = 12.9 Hz, 1H),
4.12 (s, 1H), 4.06 (dd, J = 11.2 Hz, 7.1 Hz, 1H), 3.14 (t, J = 11.6 Hz, 1H), 2.33-2.42 (m,
1H), 1.62-1.73 (m, 5H).
13
C NMR (D
2
O, 100 MHz): δ 169.5, 141.2, 133.3, 131.3, 130.8,
130.0, 129.9, 96.5, 90.8, 70.0, 59.8, 59.5, 45.7, 36.2, 18.5.
HO
2
C N
H
O
2.133. 2-(Allylamino)-2-(2-furyl)acetic acid. Prepared similarly to 2.127 on 2 mmol
scale in 3 mL of ethanol. The resulting suspension was evaporated to dryness, re-
evaporated several times with methanol, the solid residue was refluxed for 5 min with
EtOAc (with small amount of methanol added), cooled down to -78 °C and left overnight
in freezer. The crystals were filtered off and washed with EtOAc. Yield 168 mg (46%).
1
H NMR (CD
3
OD, 400 MHz): δ 7.58-7.60 (m, 1H), 6.61 (d, J = 3.3 Hz, 1H), 6.48 (d, J =
3.3 Hz, 1.7 Hz, 1H), 5.85-5.97 (m, 1H), 5.41-5.49 (m, 2H), 4.94 (br.s, 2H), 4.74 (s, 1H),
3.47-3.57 (m, 2H).
13
C NMR (CD
3
OD, 100 MHz): δ 169.4, 148.0, 145.2, 129.4, 124.0,
113.2, 112.1, 59.4, 49.2.
115
HO
2
C N
O
Ph
2.135. 2-[Benzyl(3-butenyl)amino]-2-(2-furyl)acetic acid. Prepared similarly to 2.127
from N-benzyl-N-homoallylamine (2.134)
81
on 2 mmol scale in 3 mL of ethanol. TLC
control (silica/EtOAc, stained with basic KMnO
4
): R
f
0.4. The product was isolated by
flash chromatography (silica, EtOAc) as viscous yellowish oil, yield 404 mg (71%). The
compound crystallizes slowly (over 1 week) from EtOAc-hexane as white hygroscopic
crystals.
1
H NMR (CD
3
OD, 400 MHz): δ 7.65-7.67 (m, 1H), 7.56-7.62 (m, 2H), 7.40-
7.47 (m, 3H), 6.76 (d, J = 3.3 Hz, 1H), 6.54 (dd, J = 3.3 Hz, 1.7 Hz, 1H), 5.51-5.63 (m,
1H), 5.03-5.11 (m, 2H), 4.52 (d, J = 13.3 Hz, 1H), 4.05 (d, J = 13.3 Hz, 1H), 3.05-3.15
(m, 1H), 2.85-2.94 (m, 1H), 2.35-2.46 (m, 2H).
13
C NMR (CD
3
OD, 100 MHz): δ 169.0,
146.8, 145.7, 134.2, 132.7, 131.7, 130.7, 130.2, 119.0, 115.6, 112.2, 64.7, 57.8, 51.7, 30.0.
HO
2
C N
N
Ph
Boc
2.137. 2-[Allyl(benzyl)amino]-2-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]acetic acid.
Prepared similarly to 2.127 on 1 mmol scale in 2 mL of ethanol. TLC control
(silica/EtOAc-hexane 1:1, stained with basic KMnO
4
): R
f
0.3. The product was isolated
by flash chromatography (silica, EtOAc-hexane 1:1). The fractions containing the
product were pooled, evaporated, and the residue was recrystallized from CH
2
Cl
2
-hexane
116
to give white crystals (270 mg, 73% yield).
1
H NMR (CDCl
3
, 400 MHz): δ 7.20-7.38 (m,
6H), 6.49 (br.s, 1H), 6.14 (t, J = 3.4 Hz, 1H), 5.72-5.87 (m, 1H), 5.19-5.39 (m, 2H), 3.97
(br.s, 2H), 3.48 (br.s, 2H), 1.55 (s, 9H).
13
C NMR (CDCl
3
, 100 MHz): δ 149.6, 132.1,
129.1, 128.8, 128.1, 122.8, 120.7, 116.8, 110.5, 84.7, 63.0, 55.3, 54.2, 27.9.
N
O
Ph
2.139. N-Benzyl-N-(2-furylmethyl)-2-propen-1-amine. Prepared similarly to 2.43 using
paraformaldehyde (60 mg, 2 mmol), TLC control (silica/EtOAc-hexane 1:4, stained with
basic KMnO
4
): R
f
0.8. The product was isolated by flash chromatography on a short
column (silica, EtOAc-hexane 1:4) as colorless oil. Yield 287 mg (63%).
1
H NMR
(CDCl
3
, 400 MHz): δ 7.30-7.41 (m, 5H), 7.22-7.28 (m, 1H), 6.34 (dd, J = 3.3 Hz, 1.7 Hz,
1H), 6.20 (d, J = 3.3 Hz, 1H), 5.86-5.97 (m, 1H), 5.24 (dq, J = 17.4 Hz, 1.7 Hz, 1H), 5.18
(dq, J = 10.4 Hz, 1.7 Hz, 1H), 3.65 (s, 2H), 3.61 (s, 2H), 3.10-3.14 (m, 2H).
13
C NMR
(CDCl
3
, 100 MHz): δ 152.6, 141.9, 139.1, 135.8, 128.9, 128.2, 126.9, 117.7, 110.0, 108.6,
57.3, 56.4, 49.2.
117
N
Ph
OH
H
O
2.143. ( ±)-[(3R,3aS,6S,7aR)-2-Benzyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindol-3-
yl]methanol. Prepared similarly to 2.43 using glycolaldehyde dimer (120 mg, 1 mmol;
equivalent of 2 mmol of monomeric glycolaldehyde), TLC control (silica/EtOAc-hexane
1:1, stained with basic KMnO
4
): R
f
0.35. The product was isolated by flash
chromatography (silica, EtOAc-hexane 1:1) as viscous light yellow oil, yield 331 mg
(64%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.24-7.39 (m, 5H; H
Ar
), 6.58 (d, J = 5.8 Hz, 1H;
H
c1
), 6.31 (dd, J = 5.8 Hz, 1.7 Hz, 1H; H
c2
), 5.00 (dd, J = 4.3 Hz, 1.7 Hz, 1H; H
c3
), 3.98
(d, J = 12.9 Hz, 1H; H
b1
/H
b2
), 3.81 (dd, J = 11.2 Hz, 1.7 Hz, 1H; H
a2
/H
a3
), 3.70 (dd, J =
11.2 Hz, 3.7 Hz, 1H; H
a2
/H
a3
), 3.62 (d, J = 12.9 Hz, 1H; H
b1
/H
b2
), 3.3 (br.s, 1H; OH),
3.21 (dd, J = 8.7 Hz, 7.0 Hz, 1H; H
c8
), 3.01-3.06 (m, 1H; H
a1
), 2.24 (dd, J = 10.8 Hz, 8.7
Hz, 1H; H
c7
), 1.85-1.94 (m, 1H; H
c6
), 1.68 (ddd, J = 11.2 Hz, 4.3 Hz, 3.3 Hz, 1H;
H
c4
/H
c5
), 1.32 (dd, J = 11.2 Hz, 7.5 Hz, 1H; H
c4
/H
c5
).
13
C NMR (CDCl
3
, 100 MHz): δ
138.6, 135.4, 134.9, 128.5, 128.1, 126.9, 98.6, 79.3, 65.1, 59.6, 58.3, 58.0, 42.4, 29.5.
118
N
Ph
O
H
H
HO
OH
HO
OH
2.145. (1R,2S,3R)-1-[(1R,2S,5R,7R)-3-Benzyl-10-oxa-3-azatricyclo[5.2.1.0
1,5
]dec-8-
en-2-yl]butane-1,2,3,4-tetrol. Prepared similarly to 2.43 using D-arabinose (300 mg, 2
mmol). The precipitate is filtered off, washed with cold methanol and a little cold
methanol-water (1:1). White crystals, yield 380 mg (55%).
1
H NMR (DMSO-d
6
, 400
MHz): δ 7.27-7.34 (m, 4H), 7.20-7.26 (m, 1H), 6.59 (d, J = 5.8 Hz, 1H), 6.31 (dd, J = 5.8
Hz, 1.7 Hz, 1H), 5.19 (d, J = 5.4 Hz, 1H), 4.89 (dd, J = 4.2 Hz, 1.7 Hz, 1H), 4.63-4.67 (m,
2H), 4.38-4.45 (m, 2H), 3.90 (t, J = 6.6 Hz, 1H), 3.73 (dd, J = 7.9 Hz, 5.4 Hz, 1H), 3.55-
3.68 (m, 2H), 3.39-3.47 (m, 1H), 3.36 (s, 3H), 3.34 (d, J = 12.9 Hz, 1H), 3.08 (d, J = 6.6
Hz, 1H), 2.93 (t, J = 7.9 Hz, 1H), 1.96 (t, J = 9.6 Hz, 1H), 1.78-1.87 (m, 1H), 1.55 (ddd, J
= 11.2 Hz, 4.2 Hz, 2.5 Hz, 1H), 1.21 (dd, J = 11.2 Hz, 7.5 Hz, 1H).
13
C NMR (DMSO-d
6
,
100 MHz): δ 139.4, 135.1, 135.0, 128.5, 128.1, 126.7, 97.9, 78.1, 71.2, 70.6, 69.7, 67.0,
63.5, 60.5, 59.0, 40.8, 30.4.
119
N
Ph
O
H
H
HO
OH
HO
OH
2.147. (1S,2R,3S)-1-[(1S,2R,5S,7S)-3-Benzyl-10-oxa-3-azatricyclo[5.2.1.0
1,5
]dec-8-en-
2-yl]butane-1,2,3,4-tetrol. Prepared similarly to 2.43 using L-arabinose (300 mg, 2
mmol). The product did not precipitate on cooling. The reaction mixture was diluted with
diethyl ether (35 mL), and the flaky precipitate that formed was filtered off and discarded.
The filtrate was left overnight for crystallization of the product, the crystals were filtered
off and washed with diethyl ether. Yield 330 mg (48%). The
1
H and
13
C NMR spectra
were identical to those of compound 2.145.
N
O
H
H
HO
OH
HO
OH
OMe
2.148. (1R,2S,3R)-1-[(1R,2S,5R,7R)-3-(4-Methoxybenzyl)-10-oxa-3-
azatricyclo[5.2.1.0
1,5
]dec-8-en-2-yl]butane-1,2,3,4-tetrol. Prepared similarly to 2.43
from D-arabinose on 5 mmol scale in 7 mL of ethanol. The reaction mixture was
evaporated to dryness and re-evaporated three times with methanol. The crystalline
residue was recrystallized from methanol-acetone with addition of a small amount of
water. White crystals, yield 1.18 g (63%).
1
H NMR (DMSO-d
6
, 400 MHz): δ 7.22 (d, J =
120
8.3 Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 6.57 (d, J = 5.8 Hz, 1H), 6.31 (dd, J = 5.8 Hz, 1.7
Hz, 1H), 5.33 (d, J = 4.6 Hz, 1H), 4.89 (dd, J = 4.6 Hz, 1.7 Hz, 1H), 4.62-4.69 (m, 2H),
4.43 (t, J = 5.8 Hz, 1H), 4.32 (d, J = 12.5 Hz, 1H), 3.91 (t, J = 6.2 Hz, 1H), 3.72 (s, 3H),
3.68-3.75 (m, 1H), 3.55-3.68 (m, 2H), 3.42-3.47 (m, 1H), 3.40 (s, >4H; OH+H
2
O), 3.28
(d, J = 12.5 Hz, 1H), 3.08 (d, J = 6.2 Hz, 1H), 2.91 (t, J = 7.5 Hz, 1H), 1.95 (t, J = 9.6 Hz,
1H), 1.75-1.85 (m, 1H), 1.54 (ddd, J = 11.2 Hz, 3.7 Hz, 2.5 Hz, 1H), 1.21 (dd, J = 11.2
Hz, 7.5 Hz, 1H).
13
C NMR (DMSO-d
6
, 100 MHz): δ 158.1, 135.3, 134.9, 131.2, 129.7,
113.5, 97.8, 78.2, 71.2, 70.8, 69.5, 67.1, 63.5, 59.8, 58.8, 55.0, 40.8, 30.3.
N
O
H
H
HO
OH
HO
OH
Br
2.150. (1R,2S,3R)-1-[(1R,2S,5R,7R)-3-(4-Bromobenzyl)-10-oxa-3-
azatricyclo[5.2.1.0
1,5
]dec-8-en-2-yl]butane-1,2,3,4-tetrol. The starting amine (2.149)
was prepared from 4-bromobenzaldehyde and allylamine by reductive amination with
NaBH
4
(1.3 eq) in ethanol. The compound 2.150 was prepared similarly to 2.43 from D-
arabinose on 1 mmol scale in 2.5 mL of ethanol. The precipitate is filtered off, washed
with cold methanol and diethyl ether. White crystals, yield 220 mg (52%).
1
H NMR
(DMSO-d
6
, 400 MHz): δ 7.47-7.52 (m, 2H), 7.26-7.31 (m, 2H), 6.59 (d, J = 5.8 Hz, 1H),
6.30 (dd, J = 5.8 Hz, 1.7 Hz, 1H), 5.03 (d, J = 5.4 Hz, 1H), 4.89 (dd, J = 4.2 Hz, 1.7 Hz,
1H), 4.60-4.65 (m, 2H), 4.41 (d, J = 5.8 Hz, 1H), 4.33 (d, J = 13.3 Hz, 1H), 3.87 (t, J =
121
6.6 Hz, 1H), 3.67-3.73 (m, 1H), 3.55-3.67 (m, 2H), 3.40-3.46 (m, 1H), 3.36 (d, J = 13.3
Hz, 1H), 3.07 (d, J = 7.1 Hz, 1H), 2.95 (t, J = 7.5 Hz, 1H), 1.94 (dd, J = 10.4 Hz, 8.3 Hz,
1H), 1.79-1.88 (m, 1H), 1.54 (ddd, J = 11.2 Hz, 4.2 Hz, 2.5 Hz, 1H), 1.21 (dd, J = 11.2
Hz, 7.5 Hz, 1H).
13
C NMR (DMSO-d
6
, 100 MHz): δ 138.8, 135.0, 134.9, 131.0, 130.6,
119.7, 97.8, 78.1, 71.2, 70.5, 69.8, 66.7, 63.5, 59.4, 58.9, 40.8, 30.4.
N
O
H
H
HO
OH
HO
OH
Br
2.151. (1S,2R,3S)-1-[(1S,2R,5S,7S)-3-(4-Bromobenzyl)-10-oxa-3-
azatricyclo[5.2.1.0
1,5
]dec-8-en-2-yl]butane-1,2,3,4-tetrol. Prepared similarly to 2.43
from L-arabinose on 1 mmol scale in 2.5 mL of ethanol. The precipitate is filtered off,
washed with cold methanol and diethyl ether. White crystals, yield 256 mg (60%). The
1
H and
13
C NMR spectra were identical to those of compound 2.150.
N
Ph
O
H
H
HO
HO
O
O
HO
HO
O
O
N
O
Ph
(R)-[(1R,2S,5R,7R)-3-Benzyl-10-oxa-3-azatricyclo[5.2.1.0
1,5
]dec-8-en-2-yl][(4S,5R)-5-
(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (2.153) and (1R,2S)-2-
122
[allyl(ethyl)amino]-2-(2-furyl)-1-[(4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl]-1-ethanol (2.154). D-Arabinose (300 mg, 2 mmol) was suspended in
DMF (4 mL) followed by addition of 2,2-dimethoxypropane (1.25 g, 12 mmol, 6 eq) and
p-toluenesulfonic acid monohydrate (10 mg, 0.053 mmol, ~2.5 mol%), and the mixture
was stirred at room temperature. TLC control (silica/10% methanol in EtOAc, stained
with 2,4-DNPH stain): R
f
0.7 (D-arabinose ketal), R
f
<0.1 (D-arabinose). The precipitate
dissolved in 30 min, and the reaction was complete in 1.5 h. Solid NaOAc (~20 mg) was
added, and the reaction mixture was sonicated for several minutes. The solvent was
completely removed on a rotary evaporator, and the crude D-arabinose ketal (viscous
syrup, 567 mg) was used directly in the next step.
The ketal was redissolved in absolute ethanol (5 mL), and N-allyl-N-benzylamine
(294 mg, 2 mmol) and furan-2-boronic acid (224 mg, 2 mmol) were added to the solution.
The reaction mixture was stirred at 70 °C for 24 h. TLC control (silica/EtOAc-hexane 1:1,
stained with basic KMnO
4
): R
f
0.5 (2.154), R
f
0.15-0.2 (2.153). The products were
isolated by flash chromatography (silica, EtOAc-hexane 1:1 to EtOAc to 10% methanol
in EtOAc).
2.153: Colorless crystals, reprecipitated with diethyl ether from solution in a minimal
volume of CH
2
Cl
2
. Yield 87 mg (11%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.28-7.34 (m,
4H), 7.21-7.27 (m, 1H), 6.72 (d, J = 5.9 Hz, 1H), 6.29 (dd, J = 5.9 Hz, 1.6 Hz, 1H), 4.98
(dd, J = 4.3 Hz, 1.6 Hz, 1H), 4.72 (dd, J = 6.6 Hz, 4.3 Hz, 1H), 4.30-4.36 (m, 1H), 4.22
(d, J = 13.4 Hz, 1H), 3.78-3.88 (m, 3H), 3.52 (d, J = 13.4 Hz, 1H), 3.14-3.20 (m, 1H),
2.97-3.05 (m, 2H), 2.90 (br.t, J = 5.9 Hz, 1H), 2.09-2.16 (m, 1H), 1.91-2.00 (m, 1H), 1.66
123
(ddd, J = 11.3 Hz, 4.0 Hz, 2.7 Hz, 1H), 1.53 (s, 3H), 1.34 (s, 3H), 1.28-1.34 (m, 1H).
13
C
NMR (CDCl
3
, 100 MHz): δ 139.2, 135.2, 134.6, 128.4, 128.3, 127.0, 108.3, 98.3, 79.1,
77.3, 75.4, 69.9, 67.6, 61.3, 60.2, 59.3, 41.6, 30.4, 27.4, 25.0.
2.154: Viscous oil, yield 255 mg (33%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.46-7.48 (m,
1H), 7.28-7.33 (m, 4H), 7.21-7.27 (m, 1H), 6.40 (dd, J = 3.2 Hz, 1.9 Hz, 1H), 6.26 (d, J =
3.2 Hz, 1H), 5.73-5.85 (m, 1H), 5.18-5.25 (m, 1H), 5.11-5.17 (m, 1H), 4.85 (d, J = 7.0 Hz,
1H), 4.18-4.24 (m, 2H), 3.96 (d, J = 9.9 Hz, 1H), 3.88 (d, J = 14.0 Hz, 1H), 3.67-3.77 (m,
2H), 3.30-3.37 (m, 1H), 3.15 (d, J = 14.0 Hz, 1H), 2.75-2.87 (m, 2H), 1.45 (s, 3H), 1.38
(s, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 151.4, 141.9, 139.3, 136.4, 128.6, 128.1, 126.8,
117.2, 110.0, 109.7, 107.8, 77.2, 74.5, 66.9, 61.4, 59.4, 55.2, 54.5, 26.8, 24.8.
N
Ph
O
H
H
HO
HO
O
O
HO
HO
O
O
N
O
Ph
(S)-[(1S,2R,5S,7S)-3-Benzyl-10-oxa-3-azatricyclo[5.2.1.0
1,5
]dec-8-en-2-yl][(4R,5S)-5-
(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (2.156) and (1S,2R)-2-
[allyl(ethyl)amino]-2-(2-furyl)-1-[(4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl]-1-ethanol (2.157). Prepared similarly to 2.153 and 2.154 from L-
arabinose; the three-component condensation was run for 3 d at 70 °C and yielded 170
mg (44%) of 2.156 and 102 mg (26%) of 2.157. The
1
H and
13
C NMR spectra were
identical to those of compounds 2.153 and 2.154.
124
N
Ph
O
H
H
HO
HO
O
O
2.159. (R)-[(1R,2S,5R,7R)-3-Benzyl-10-oxa-3-azatricyclo[5.2.1.0
1,5
]dec-8-en-2-
yl][(2S,3R)-3-(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-2-yl]methanol. Prepared
similarly to 2.153 from D-arabinose, using and cyclohexanone dimethyl ketal (1.73 g, 12
mmol, 6 eq). The three-component condensation was run for 3 d at 70 °C and yielded 190
mg (44%) of 2.159. The non-Diels-Alder product was detected in the reaction mixture
but was not isolated.
1
H NMR (CDCl
3
, 400 MHz): δ 7.32-7.37 (m, 4H), 7.24-7.31 (m,
1H), 6.75 (d, J = 5.7 Hz, 1H), 6.32 (dd, J = 5.7 Hz, 1.6 Hz, 1H), 5.02 (dd, J = 4.1 Hz, 1.6
Hz, 1H), 4.75 (dd, J = 6.7 Hz, 3.2 Hz, 1H), 4.35-4.40 (m, 1H), 4.30 (d, J = 13.7 Hz, 1H),
3.80-3.91 (m, 2H), 3.58 (d, J = 13.7 Hz, 1H), 3.21 (dd, J = 8.6 Hz, 7.3 Hz, 1H), 2.97-3.09
(m, 3H), 2.17 (dd, J = 10.2 Hz, 8.6 Hz, 1H), 1.96-2.05 (m, 1H), 1.35-1.82 (m, 10H), 1.35
(dd, J = 11.5 Hz, 7.3 Hz, 1H).
13
C NMR (CDCl
3
, 100 MHz): δ 139.2, 135.3, 134.6, 128.4,
128.2, 127.0, 108.9, 98.4, 79.1, 76.9, 74.9, 70.1, 67.7, 61.4, 60.4, 59.5, 41.5, 37.1, 34.3,
30.6, 25.1, 24.0, 23.7.
125
N
Ph
O
H
H
HO
HO
O
O
2.160. (S)-[(1S,2R,5S,7S)-3-Benzyl-10-oxa-3-azatricyclo[5.2.1.0
1,5
]dec-8-en-2-
yl][(2R,3S)-3-(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-2-yl]methanol. Prepared
similarly to 2.159 from L-arabinose. Yield 190 mg (44%). The
1
H and
13
C NMR spectra
were identical to those of compound 2.159.
N
Ph
O
H
HO
2
C
2.162. (3S,3aS,6S,7aS)-2-Benzyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-3-
carboxylic acid. A stirred suspension of 2.147 (347 mg, 1 mmol) in acetone (20 mL) was
acidified by addition of 1 M H
2
SO
4
(0.5 mL). The precipitate dissolved quickly. To this
solution, cooled with ice-water bath, 5 mL of Jones’ reagent (2.2 M CrO
3
and 2.2 M
H
2
SO
4
in water) was added quickly dropwise. The reaction mixture was stirred at room
temperature for 1 h and quenched by addition of 2-propanol (3 mL), diluted with water
(10 mL) and neutralized with solid NaHCO
3
. TLC control (a sample of quenched and
neutralized reaction mixture extracted with EtOAc; silica/EtOAc-methanol 4:1, stained
with basic KMnO
4
): R
f
0.1 (2.162), R
f
0.7 (2.147). The resulting suspension was
extracted with EtOAc (4 × 30 mL), and the combined extracts were dried over Na
2
SO
4
.
126
The filtrate was evaporated, and the product was isolated by by flash chromatography
(silica, EtOAc-methanol 2:1) to give 60 mg (22%) of the product. The
1
H and
13
C NMR
spectra were identical to those of compound 2.127.
127
2.7 Chapter 2. References.
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van Goethem, S.; van der Veken, P.; Dubois, V.; Soroka, A.; Lambeir, A. M.; Chen, X.;
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21
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132
Chapter 3. Synthesis of 2H-chromenes and 1,2-
dihydroquinolines from aryl aldehydes and alkenylboron
compounds. Petasis reaction with aliphatic aldehydes.
3.1 Introduction. Synthetic approaches to 2H-chromenes and 1,2-
dihydroquinolines.
Chromenes and chromanes are frequently found among natural compounds, many
of which possess useful biological activity. From the two possible isomers of chromene,
2,2-disubstituted 2H-chromenes are by far prevalent, while the corresponding carbonyl
derivatives, coumarines (2H-chromen-2-ones) and chromones (4H-chromen-4-ones) are
equally widespread. 2H-Chromenes retaining at least one hydrogen in 2-position are
sensitive to oxidation, converting into chromenylium (benzopyrilium) cations, and these
derivatives are also widely occurring in nature. In particular, polyhydroxylated 2-
phenylchromenylium (flavilium) glycosides constitute an important class of plant
pigments (anthocyanins), which are responsible for red, purple and blue colors of
flowering plants. Tocopherols and tocotrienes, the compounds with antioxidant and free
radical-scavenging properties, constitute the vitamin E family.
1
Recently, 3-nitro-2H-
chromene derivative active against Helicobacter pylori was identified (micromolar
inhibitor of H. pylori flavodoxin, an enzyme essential for survival of the bacteria).
2
Several reviews on synthetic approaches to chromenes have been recently
published,
3-5
with the more common strategies illustrated in the Scheme 3.1:
133
O
R
1
R
2
R
PhNEt
2
reflux
O
R
1
R
2
R
R
2
R
1
OH
R
1) mCPBA
2) - H
2
O
OH
R
+
R
1
R
2
O
PhB(OH)
2
AcOH
toluene, ∆
O
O
R
1
R
2
R
HMPA
toluene, ∆
O
OH
R
1
R
2
R
O
R
1
R
2
R
HO
R
3
R
1
or R
2
= EWG
PPh
3
O
OH
R
R
2
R
3
+
R
2
, R
3
= EWG
O
OH
R
+
R
3
= EWG
R
2
R
1
R
3
K
2
CO
3
DMF, ∆
Scheme 3.1.
1,2-Dihydroquinolines can be considered nitrogen analogs of 2H-chromenes. As
in case with 2H-chromenes, 1,2-dihydroquinolines with only one substituent in 2-position,
if 1-position is unsubstituted or alkyl-substituted, are quite sensitive to oxidation, and
they have often been used as intermediates in the synthesis of 2-substituted quinolines.
Under acidic conditions, 1,2-dihydroquinolines disproportionate into quinolines and
1,2,3,4-tetrahydroquinolines.
6
2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline,
commonly abbreviated EEDQ, has found practical use as a peptide-coupling reagent; it is
134
also biologically active (irreversible dopamine receptor antagonist).
7
The majority of
synthetic methods towards 1,2-dihydroquinolines start from quinolines (with or without
activation by alkylation or acylation of the nitrogen) or from 2-aminobenzaldehydes, 2-
aminoacetophenones and their N-protected analogs. Some of these approaches are
illustrated in Schemes 3.2-3.9.
The parent compound, unsubstituted 1,2-dihydroquinoline, was prepared by
reduction of quinoline with lithium aluminium hydride in diethyl ether.
6
2-Alkyl- and 2-
aryl-1,2-dihydroquinolines were formed in the reaction of quinoline with organolithium
or organomagnesium reagents; the products were further stabilized by N-acylation with
alkyl chloroformates.
6,8
Use of chiral diamino ligands in reactions with organolithium
reagents allowed to obtain enantioenriched 1,2-dihydroquinolines.
9
Alternatively, N-ethoxycarbonylquinolinium salts can be coupled with terminal
acetylenes in the presence of copper catalyst and base
10
(Scheme 3.2).
N
ClCO
2
Et
N
OEt O
Cl
-
R
CuI, (i-Pr)
2
NEt
CH
2
Cl
2
, RT
N
OEt O
R
Scheme 3.2.
In our group, similar activation of quinolines was used in a modification of the
three-component reaction with aryl or allyl trifluoroborates, with quinoline acting as an
iminium source
11
(Scheme 3.3).
135
N
+
Cl O
O
+
MeO
BF
3
K
CH
2
Cl
2
RT, 16 h
N
O O OMe
67%
Scheme 3.3.
Gold-catalyzed three-component reaction of quinolines, acetylenedicarboxylate
esters and terminal alkynes also yields 2-alkynyl-1,2-dihydroquinolines
12
(Scheme 3.4).
N
+
CO
2
Me
CO
2
Me
+ R
AuCl
3
(2 mol%)
CH
2
Cl
2
, RT
N
MeO
2
C
CO
2
Me
R
Scheme 3.4.
Von Braun reaction of quinolines (with cyanogen bromide and a nucleophile with
optional base additives such as NaHCO
3
) results in formation of 1-cyano-1,2-
dihydroquinoline products
13
(Scheme 3.5).
N
+ BrCN
MeOH
NaHCO
3
or Et
3
N
N
CN
OMe
Scheme 3.5.
Conversely, the use of acyl chlorides as the activating electrophilic species and
cyanide as a nucleophile (Reissert reaction, first reported in 1905) gives 2-cyano-1,2-
dihydroquinoline derivatives and is one of the oldest methods of functionalization of
136
quinolines.
14
When quinoline N-oxides are acylated instead of quinolines, the
intermediate 1,2-dihydroquinolines eliminate carboxylic acid (Henze modification),
which is a useful synthetic approach to 2-cyanoquinolines (and 2-cyanopyridines).
15
The syntheses of 1,2-dihydroquinolines starting from 2-aminobenzaldehydes and
2-aminoaryl ketones generally rely on Michael and aldol type reactions. Use of 2-
aminobenzaldehydes
16
as starting materials is complicated by their inherent instability,
and N-protected compounds (amides or sulfamides) can be used instead
17,18
(Scheme 3.6).
O
NH
2
R +
R'
NO
2
TA*, PhCO
2
H
4 MS, i-PrOH Å
N
H
R
NO
2
R'
*
TA* - chiral thiourea
organocatalyst
O
NHP
R +
P = ArSO
2
or Cbz
R
1
R
2
O
K
2
CO
3
, CHCl
3
- H
2
O
BnEt
3
N
+
Cl
-
(cat.)
or
B*, NaOAc
4 MS, 1,2-DCE Å
N
R
R
1
*
P
R
2
O
B* - chiral base
Scheme 3.6.
2'-Aminochalcones undergo intramolecular cyclization into 4-chloro-1-formyl-
1,2-dihydroquinolines upon treatment with Vilsmeier reagent.
19
The corresponding
alcohols cyclize on simple heating in xylene,
20
likely via o-quinonemethide imine
intermediates (Scheme 3.7).
137
NH
2
O
Ar
DMF, POCl
3
90
o
C
N
Cl
Ar
O
N
H
OH
R
1
R
p-xylene
reflux, 2.5-7.5 h
N
R
R
1
- H
2
O
N R
1
R
Scheme 3.7.
In a similar approach, the allyl alcohols 3.1, prepared by Morita-Baylis-Hillman
reaction between 2-azidobenzaldehydes and alkenes with an electron-withdrawing group,
are acetylated and the acetates 3.2 are reacted with triethyl phosphite. The products of the
Staudinger reaction (intermediates 3.3) cyclize on heating into 1,2-dihydroquinolines (3.4)
retaining the phosphate group
21
(Scheme 3.8).
O
N
3
R
+
EWG
dioxane, RT
1h to 5d
N
3
R
OH
EWG
Ac
2
O
DMAP
RT, 0.5h
N
3
R
OAc
EWG
P(OEt)
3
0 - 5
o
C
N
R
OAc
EWG
P(OEt)
3
toluene
reflux, 3-48 h
N
R
EWG
3.1 3.2
3.3
3.4
P
O
OEt
OEt
Scheme 3.8.
138
Ring-closing metathesis has also found some use in the synthesis of 1,2-
dihydroquinolines
22,23
(Scheme 3.9).
N
R
P = ArSO
2
, Bn, R'CO
P
R
1
Grubbs' I or II (5 mol%)
CH
2
Cl
2
(0.01 M)
N
R
P
R
1
Scheme 3.9.
3.2 Synthesis of 2H-chromenes by catalytic Petasis reaction.
Earlier in our group, it has been found that the reaction between salicylaldehyde,
trans-2-phenylvinylboronic acid and secondary amines does not always lead to the
expected three-component reaction products, but, depending on the reaction conditions,
often gives a low-polar neutral product with cis-configuration of the double bond,
identified as 2-phenyl-2H-chromene.
24
Following the disclosure of this transformation,
Finn et al. reported this strategy as a useful synthetic approach to a variety of 2H-
chromenes, with the yields generally exceeding 90%, using catalytic quantities of the
secondary amine.
25
For one particular example, they have isolated the intermediate three-
component reaction product 3.5, and successfully converted it to the corresponding
chromene 3.6 on heating with base:
139
OH
O
+
Bu
B(OH)
2
N
H
O
(1 eq)
dioxane
90
o
C, 12 h
OH
N
Bu
O
3.5
80%
+
O Bu
3.6
20%
Bn
2
NH (5 mol%)
dioxane
90
o
C, 12 h
O Bu
3.6
92%
2,6-lutidine
90
o
C, 0.5 h
Scheme 3.10.
The mechanism of the cyclization suggested by the authors in the same paper
implied acid catalysis (protonation of benzylamine nitrogen followed by elimination of
the amine and intramolecular attack of the phenol with allylic rearrangement).
Alkenyl trifluoroborates have been reported to react similarly to boronic acids,
providing 50-90% yields of 2H-chromenes.
26
This reaction, named catalytic Petasis reaction in the literature,
25
drew our
attention during the investigation of the scope of reagents for the three-component
synthesis of isoindolines (see Chapter 2). When the reverse combination of Diels-Alder
reaction partners was used (alkenylboronic acid and secondary furfurylamine), only the
chromene product 3.10 formed in very high yield (Scheme 3.11):
140
O
B(OH)
2
R
O
OH
NHR'
R
N
OH
O
R'
N
R'
OH R
O
B(OH)
2
R
O
OH
NHR'
R''
O
R
N
OH
R'
R''
O
N
R'
OH R
O
R''
O R''
R
not formed
Figure 3.1. Two possible reactant combinations for the synthesis of isoindolines by
tandem Petasis-Diels-Alder reaction.
OH
O
Br
3.7
+
Ph
B(OH)
2
3.8
+
O
NHBn
3.9
EtOH
70
o
C, 24 h
O
Br
3.10
Ph
96%
Scheme 3.11.
As in the case with Petasis-Diels-Alder reaction (Scheme 2.26), the reaction with
primary furfurylamine resulted in only traces of chromene product and mostly in
formation of imine. With secondary amines, the reaction was found to work particularly
well in protic solvents (alcohols and water), and was faster under these conditions (3 h in
water at 80 °C, as estimated by TLC control) than it was reported for original conditions
in 1,4-dioxane (12 h at 90 °C).
25
Both 2-phenylvinylboronic acid (3.8) and the
corresponding trifluoroborate salt (3.11) performed equally well (Scheme 3.12).
141
OH
O
Br
3.7
+
Ph
B(OH)
2
3.8
+
3.12
H
2
O
80
o
C, 3 h
O
Br
3.10
Ph
82%
or
Ph
BF
3
K
3.11
Bn
2
NH
Scheme 3.12.
The cyclization to 2H-chromene in water was apparently incomplete, as upon
isolation during chromatography purification only about 25% of the product was eluted at
once, and the broad purple-colored band developed on silica. When left on solvent-wet
sorbent for 30 min, the color faded and the remaining amount of 3.10 was then eluted.
The yield (82-90%) or reaction time could not be further improved by addition of protic
(Amberlyst 15 resin in H
+
form) or Lewis (Yb(OTf)
3
) acid catalysts, and the addition of
silica gel (3 g/mmol) directly into the reaction mixture did not allow to avoid the
necessity to complete cyclization on silica gel column during chromatography. An
attempt to run the reaction with catalytic quantities of dibenzylamine (10 mol%) in water
was not satisfactory, resulting in low conversion.
Gois at al.
27
have recently published a similar study on Petasis reaction in water.
They could not, however, reproduce our conditions of the reaction with stoichiometric
benzylamine, probably because the cyclization on silica step was omitted, and reported
only 58% yield in this transformation. The use of other secondary amines was
investigated, and the best results were obtained with 1.2 eq diethylamine over 24 h. Less
than stoichiometric quantities of the amine (40 and 20 mol%) were detrimental, and
yields were also lower over shorter reaction times (5 h). Overall, their conditions for the
reaction seem to offer no advantage over ours. No successful reaction of
142
salicilyladehydes with boronic acids and primary amines was reported; however the use
of α-amino acid L-phenylalanine (3.15) as an amine component resulted in formation of
boron-containing complexes (e.g, 3.16) in single diastereomeric form and high yields:
OH
O
3.13
+ PhB(OH)
2
3.14
+
H
2
O
90
o
C, 20 h
O
N
3.16
B
86%; 99% d.e.
Bn
NH
2
CO
2
H
3.15
O
Ph
Bn
O
Scheme 3.13.
Other solvents and amines were also screened briefly with the purpose to evaluate
the possibility of running the catalytic version of the reaction in enantioselective
synthesis of 2H-chromenes. (S)-Diphenylprolinol (3.17) was selected as a chiral
secondary amine. Running the reaction under standard conditions (ethanol, 70 °C, 24 h)
gave racemic 3.10 in 78% yield, while the reaction in anhydrous acetonitrile was much
slower (giving only 11% isolated yield after 24 h at 70 °C) with very little selectivity
observed (10% ee). (R,R)-Pseudoephedrine (3.18) and L-proline (3.19) gave only 2% ee
and similarly low yields of 3.10 under these conditions (Scheme 3.14):
OH
O
Br
3.7
+
Ph
B(OH)
2
3.8
B*, solvent
70
o
C, 24 h
O
Br
3.10
Ph
B*
Yield of
3.10, %
(ee, %)
3.17 (10 mol%)
3.18 (10 mol%)
3.19 (20 mol%)
11(10)
10(2)
6(-2)
3.17 (10 mol%)
78(0)
Solvent
EtOH
MeCN
MeCN
MeCN
N
H
Ph
Ph
OH
3.17
Ph
HO NHMe
3.18
N
H
OH
3.19
O
Scheme 3.14.
143
Surprisingly, it has been found that tertiary amines can also mediate the catalytic
Petasis synthesis of chromenes. This implies reactive intermediate other than iminium,
and the reaction may possibly proceed through α-hydroxyammonium cation 3.20 and o-
quinone methide intermediate 3.21 which, upon addition of an alkenyl nucleophile,
results in formation of zwitterion 3.22. The latter undergoes cyclization either with allylic
rearrangement (path a) or via elimination of tertiary amine and 6 π-electrocyclization of
another o-quinone methide 3.23 (path b):
OH
O
Br
3.7
R
3
N
O
OH
Br
3.20
NR
3
Ph
B(OH)
2
3.8
O
Br
NR
3
Ph
B(OH)
3
O
Br
NR
3
Ph
O
Br
NR
3
Ph
path a
- R
3
N
O
Br
3.10
Ph
O
Br
Ph
or
3.21
- B(OH)
3
3.22
3.22
path b
- R
3
N
3.23
π 6
Scheme 3.15.
This mechanism requires nucleophilic tertiary amine, and its nucleophilicity is expected
to be more important than basicity, as the mechanism does not involve a deprotonation
step per se. Indeed, the results of screening of different amines, presented in the Table 3.1,
demonstrate that nucleophilic tertiary amines are in fact more effective in this
transformation than sterically hindered secondary amines (such as TMP, entry 8), while
144
tetrabutylammonium hydroxide and sodium ethoxide, both relatively strong bases, are
completely ineffective:
Table 3.1. Synthesis of 2H-chromene 3.10 mediated by tertiary amines.
Entry Conditions
a
Yield of 3.10, %
1 Et
3
N (1 eq), EtOH, 24 h 53
2 Et
3
N (2 eq), EtOH, 24 h 61
3 Et
3
N (0.1 eq), EtOH, 24 h traces
4 Et
3
N (1 eq), H
2
O, 48 h 38
5 (i-Pr)
2
NEt (1 eq), EtOH, 24 h 31
6 (i-Pr)
2
NEt (1 eq), EtOH, 7 d 37
7 DABCO (1 eq), EtOH, 7 d 14
8
N
H (1 eq), EtOH, 24 h
traces
9 PhNMe
2
(1 eq), EtOH, 24 h 0
10 Pyridine (1 eq), EtOH, 24 h 0
11 EtONa (1 eq), EtOH, 24 h 0
12 Bu
4
N
+
OH
–
(1 eq), EtOH, 24 h 0
a All reactions were run at 70 °C, concentration – 0.4 M.
3.3 Synthesis of racemic α-tocopherol analog.
As an example of the practical utility of the catalytic Petasis synthesis of 2H-
chromenes, a short approach to tocopherol analogs was devised. The tocopherol family
comprises several 2-R-2-methylchroman-6-ols, where R is a branched aliphatic chain,
and the members of the family differ in number and position of methyl substituents in the
aromatic ring. All natural tocopherols have (2R)- absolute configuration. Together with
145
tocotrienols (analogous compounds with unsaturated R substituent), they belong to the
vitamin E series of compounds, which are powerful natural antioxidants and radical
scavengers (even though the prevalence of this mode of action has been questioned in
recent studies).
28
Due to their high lipophilicity, their high reactivity towards radical
species is particularly important in lipid peroxidation reactions, and they are believed to
play important role in protection of cell membranes.
29
Other biological roles of
tocopherols have been suggested (but not all of them finally confirmed), including their
function as signaling and gene-regulatory molecules.
30,31
The natural members (vitamers)
of the vitamin E family are shown in Figure 3.2.
O
HO
-tocopherol α
β
γ δ
O
HO
-tocopherol
O
HO
-tocopherol
O
HO
-tocopherol
O
HO
-tocotrienol α
β
O
HO
-tocotrienol
γ
O
HO
-tocotrienol δ
O
HO
-tocotrienol
Figure 3.2. Natural (2R)-tocopherols and tocotrienols, members of the vitamin E family.
146
Synthetic tocopherols are commonly available in all-racemic forms, produced on
industrial scale by Friedel-Crafts alkylation of trimethylhydroquinone with the tertiary
allyl alcohol isophytol or primary allyl alcohol phytol in the presence of Lewis acid
catalyst such as ZnCl
2
.
32
The syntheses of individual stereoisomers of tocopherol and its
analogs have also been reported, relying on palladium couplings or other reactions
between the chromane derivative and a suitable side chain component,
33-35
or on
asymmetric reduction of chalcones with pre-installed phytol-derived side chain and
subsequent cyclization.
36
To the best of our knowledge, the catalytic version of Petasis reaction has never
been used for the synthesis of tocopherol analogs. The simplest (±)- α-tocopherol analog
3.24 with a straight side chain lacking a 2-methyl group was selected as a target, allowing
a straightforward convergent synthesis:
O
HO
O
PO
(HO)
2
B
OH
PO
O
OH
HO
3.24
3.25
3.26
3.27 3.28
Figure 3.3. Retrosynthetic approach to the tocopherol analog 3.24.
147
The key intermediate 3.25 can be conveniently prepared by catalytic Petasis
reaction between 1-hexadecenylboronic acid 3.26 and suitably substituted
salicylaldehyde 3.27. The latter can be prepared from inexpensive trimethylhydroquinone
(3.28), the same starting material that is used in the industrial synthesis of all-rac- α-
tocopherol.
The necessity of protection of the hydroxyl group became obvious after the
preliminary experiments, as 2-monosubstituted 6-hydroxy-2H-chromenes were found
very air-sensitive. The starting 2,5-dihydroxy-3,4,6-trimethylbenzaldehyde (3.29) was
prepared by Duff formylation (using slightly optimized literature procedure)
37
(Scheme
3.16).
OH
HO
3.28
(CH
2
)
6
N
4
glycerol, H
3
BO
3
150
o
C, 30 min
OH
HO
3.29
O
52%
Ph
B(OH)
2
3.8
Bn
2
NH (20 mol%)
EtOH, 70
o
C, 24 h
O
HO
3.30
63-68%
Ph
Scheme 3.16.
The resulting 3.30 readily oxidized on silica as well as in crystalline state, turning green,
and could not be isolated in more than 90% purity. The selective protection of 3.29 with
benzyl group was then attempted according to the synthesis of 5-methoxy analog reported
in the literature
38
(Scheme 3.17).
148
OH
HO
3.28
TBSCl,
N
H
N
DMF, RT, 2 h
OTBS
HO
3.31
BnBr (1.2 eq)
K
2
CO
3
, KI (cat.)
DMF, RT, 2 d
OTBS
BnO
3.32
70% over 2 steps
Bu
4
N
+
F
-
THF, RT, 1h
OH
BnO
3.33
(CH
2
O)
n
SnCl
4
, Bu
3
N
PhMe, 90-100
o
C, 2 h
OH
BnO
3.32
12% over 2 steps
O
Scheme 3.17.
However, the final formylation step gave very poor results, making this approach
impractical. Fortunately, a recent report
39
described an easy deprotection of aryl benzyl
ethers bearing 2-carboxamido, 2-formyl, 2-carboalkoxy, 2-carboxy, 2-cyano or 2-nitro
group in 1:1 TFA-toluene mixture, with or without cation-scavenging additive
(thioanisole). This reaction allowed us to prepare the target aldehyde 3.32 in just three
steps from 3.28 (reaction conditions were not optimized):
OH
HO
3.29
O
BnBr (2.2 eq)
K
2
CO
3
, KI (cat.)
DMF, 50
o
C
overnight
OBn
BnO
3.33
O
TFA-toluene (1:1)
RT, 4 h
OH
BnO
3.32
O
59% 81%
Scheme 3.18.
149
Several attempts were made to prepare 3.33 (or directly 3.32) by electrophilic
formylation of 1,4-bis(benzyloxy)-2,3,5-trimethylbenzene under various conditions
(Vilsmeyer reagent, paraformaldehyde + Lewis acid, dichloromethyl methyl ether +
SnCl
4
), but they were unsuccessful and this alternative approach was not further pursued.
1-Hexadecenylboronic acid (3.26) was prepared from catecholborane and
technical (~90%) 1-hexadecyne in 69% yield according to the standard procedure and
was a stable crystalline solid:
13
+
O
BH
O
neat, 0 60
o
C, 1 h
then H
2
O
13
B(OH)
2
3.26
69%
Scheme 3.19.
The condensation step performed with catalytic (20 mol%) benzylamine (70 °C, 0.4 M in
ethanol, 48 h) gave only 20% of the target chromene 3.27 (the rest of the unreacted
aldehyde 3.32 was recovered). Better results were obtained at higher temperatures (110
°C, 0.5 M in n-butanol, 24 h) with 1 eq of benzylamine (57% isolated yield of 3.27,
unreacted 3.32 recovered); however, harsher conditions (180 °C, 0.5 M in diethylene
glycol monoethyl ether, 24 h) resulted in complete decomposition. Addition of an acid
catalyst (Amberlyst 15 resin in H
+
form) did not accelerate the reaction. The deprotection
step, as expected, posed no problems and hydrogenation of the double bond of 2H-
chromene was achieved simultaneously, offering the target 3.24. The hydrogenation had
to be run at 60 °C due to insufficient solubility of 3.27 in ethanol (Scheme 3.20).
150
OH
BnO
3.32
O
+
13
B(OH)
2
3.26
Bn
2
NH (1 eq)
BuOH, 110
o
C, 24 h
O
BnO
3.27
13
H
2
, Pd/C (5%)
EtOH, 60
o
C
overnight
O
HO
3.24
13
80%
57%
Scheme 3.20.
Unlike all-rac- α-tocopherol, which is a viscous air-sensitive oil and is usually
supplied in ester form (acetate, palmitate, succinate or water-soluble tocofersolan, which
is a mixed succinic ester of α-tocopherol and polyethylene glycol) to prevent oxidation,
the analog 3.24 is an air-stable white crystalline solid. Biological activity of this
compound was not evaluated.
3.4 Novel synthesis of 1,2-dihydroquinolines from 2-
sulfamidobenzaldehydes and alkenyl trifluoroborates.
Finn et al. reported
25
that 2-aminobenzaldehyde did not react under the conditions
of catalytic Petasis reaction, and this approach has not been further explored since.
However, the acidity of a sulfanilide proton is very similar to that of phenolic OH (e.g.,
for N-(2-formylphenyl)methanesulfonamide 3.34 and salicylaldehyde the calculated
values of pK
a
are 8.89±0.50 and 8.17±0.10, respectively, at 25 °C).
40
The acidity of
151
salicylaldehyde is further enhanced due to formation of intramolecular hydrogen bond,
and one can expect similar behavior from 2-sulfamidobenzaldehydes.
2-Sulfamidobenzaldehydes, such as 3.34, are easily available
41
and, unlike simple
2-aminobenzaldehydes (which easily undergo self-condensation, requiring preparation
and steam-distillation immediately before use to obtain monomeric derivatives),
42
they
are bench-stable compounds. The compounds 3.34 and the corresponding N-tosylamide
3.35
41
were selected as appropriate starting materials; however, in the initial attempts
(under usual conditions for the three-component condensation) they failed to show any
reactivity (Scheme 3.21).
O
NHMs
+
B(OH)
2
MeO
+
or
Ph
B(OH)
2
BnNHMe
EtOH or MeCN
RT to 70
o
C, 48 h to 5 d
O
NHTs
or
3.34
3.35
Scheme 3.21.
Similarly, the reaction of 3.34 with potassium 2-phenylvinyltrifluoroborate (3.36) failed
to provide any 1,2-dihydroquinoline, while 5-bromosalicylaldehyde 3.7 gave the
corresponding 2H-chromene 3.10 in 92% yield under these conditions:
152
O
OH
3.7
Br
+
Ph
BF
3
K
3.36
Bn
2
NH (1 eq)
Yb(OTf)
3
(10 mol%)
MeCN, 70
o
C, 24 h
O
Br
3.10
Ph
92%
O
NHMs
3.34
+
Ph
BF
3
K
3.36
Bn
2
NH (1 eq)
Yb(OTf)
3
(10 mol%)
MeCN, 70
o
C, 24 h
N
3.37
Ph
Ms
Scheme 3.22.
During the studies of tetracoordinate boronate complexes, Vedejs et al.
43
introduced a procedure allowing an easy generation of highly reactive electrophilic
tricoordinate organoboron species, aryldifluoroboranes (ArBF
2
). For example,
phenyldifluoroborane (PhBF
2
) formed upon treatment of suspension of potassium
phenyltrifluoroborate in acetonitrile with chlorotrimethylsilane, and was identified by its
characteristic signals in
11
B (11.6 ppm) and
19
F (-127.9 ppm) NMR spectra in CD
3
CN.
44
Some organodifluoroboranes have been isolated and fully characterized.
45
Another
activation reagent for trifluoroborates, BF
3
·Et
2
O, was used by Batey et al. for allylation
and crotylation of aldehydes and gave better results for their systems.
46
The general
reaction scheme for the activation of trifluoroborates is presented in Scheme 3.23.
+
RBF
3
K + R
3
SiCl [RBF
2
] +R
3
SiF + KCl
RBF
3
KBF
3
[RBF
2
] +KBF
4
Scheme 3.23.
153
The first of these two reactions can be considered irreversible despite close values
of B–F and Si–F bond energies ( ∆H° 150 kcal/mol and 135 kcal/mol, respectively),
because under appropriate conditions (heating in anhydrous non-polar solvents) inorganic
salt will irreversibly precipitate and fluorosilane will be lost due to its low boiling point
(for example, 16 °C at 1 atm for Me
3
SiF). The situation is much less definite in case of
BF
3
activation. Silicon tetrachloride was successfully used for activation of
trifluoroborates in at least one example (intramolecular cyclization of α, ω-
azidotrifluoroborates).
47
Thus, a brief screening of “fluoride acceptor” additives, along with other Lewis
acids, resulted in identification of suitable conditions for the alkenyl trifluoroborate-based
synthesis of 1,2-dihydroquinolines (Scheme 3.24 and Table 3.2):
O
NHMs
3.34
+
Ph
BF
3
K
3.36
R
3
N, LA
PhMe, 80
o
C, 18 h
N
3.37
Ph
Ms
LA = Lewis acid additive
Scheme 3.24.
Table 3.2. Synthesis of 1,2-dihydroquinoline 3.37, optimization of reaction conditions.
Entry Conditions Yield of 3.37, %
1 TMSCl (1 eq), Et
3
N (2 eq), MeCN 21
a
2 TMSCl (2 eq), Et
3
N (excess) 32
b
3 TMSCl (5 eq), Et
3
N (5 eq) 0
4 TMSCl (2 eq), Et
3
N (2 eq) 59
5 TMSCl (2 eq), Et
3
N (2 eq), 1,4-dioxane 10
c
154
Table 3.2 (continued)
Entry Conditions Yield of 3.37, %
6 TMSCl (2 eq), (i-Pr)
2
NEt (2 eq) 31
7 TMSCl (2 eq), pyridine (excess) 0
d
8 TMSCl (2 eq), DABCO (2 eq) 0
9 TMSCl (2 eq), DBU (2 eq) 0
10 TMSCl (2 eq), PhNMe
2
(2 eq) 0
e
11 TMSCl (2 eq), Et
3
N (2 eq), 4 Å MS 27
12 TBSCl (2 eq), Et
3
N (2 eq) 48
13 TMSOTf (2 eq), Et
3
N (2 eq) 35
14 BF
3
·Et
2
O (2 eq), Et
3
N (2 eq) 44
15 BCl
3
(2 eq), Et
3
N (2 eq), heptane mixture
f
16 AlCl
3
(2 eq), Et
3
N (2 eq) traces
17 ZnBr
2
(2 eq), Et
3
N (2 eq) 0
18 FeCl
3
(2 eq), Et
3
N (2 eq) 0
19 TiCl
4
(2 eq), Et
3
N (2 eq) 0
20 Ti(Oi-Pr)
4
(2 eq), Et
3
N (2 eq) 0
a Reaction was run in acetonitrile. b Et
3
N was used as a solvent. c Reaction was run in 1,4-dioxane.
d Reaction was run in pyridine. e Different product was formed, see discussion below. f 1M BCl
3
in
heptane was used as a reaction medium without addition of toluene.
The best conditions were identified as follows: the reaction was run in 0.4 M
concentration in anhydrous toluene; solid reagents were mixed under nitrogen in an oven-
dried 10 mL microwave tube, the tube was sealed with aluminium cap with a silicon
rubber inlet, injected with anhydrous solvent, amine, and after stirring for 5-10 min,
chlorotrimethylsilane, and stirred in a silicon oil bath preheated to 80 °C for 18 h. Soon
after the heating began, the precipitate of trifluoroborate salt gradually dissolved with
noticeable bubbling due to formation of low-boiling TMSF byproduct. By the end of the
155
reaction time, the mixture was light-brown with fine precipitate of KCl. The appearance
of orange or pink color upon addition of TMSCl was not normal for this reaction and
suggested the presence of nucleophilic impurities, such as water (in wet solvent or
trifluoroborate salt) or secondary amines (see discussion below), and was indicating
potentially lower yields of 1,2-dihydroquinoline product.
An attempt to use N,N-dimethylaniline (Table 3.2, entry 10) as a base resulted in
formation of a diphenylmethane derivative (three-component reaction with N,N-
dimethylaniline acting as a C-nucleophile), which was not purified and fully
characterized. This unusual type of Petasis reaction has been described before
48
for
glyoxylic and α-ketocarboxylic acids as carbonyl components.
Among the additives studied, only the silyl halides (Table 3.2, entries 1-12), silyl
triflates (entry 13), and boron trifluoride etherate (entry 14), but none of other Lewis
acids afforded the desired product, confirming the formation of alkenyl difluoroborate
(according to Scheme 3.23) as an active reaction partner. The proposed reaction
mechanism is therefore essentially identical to the one described in Scheme 3.15 for
typical catalytic Petasis reaction:
156
R
3
N
N
OH
NR
3
N
NR
3
Ph
BF
2
(OH)
N
NR
3
Ph
N
NR
3
Ph
path a
- R
3
N
N Ph
or
path b
- R
3
N
π 6
O
NHMs
3.34
Ph
BF
3
K
3.36
TMSX or BF
3
- TMSF, - KX
or
- KBF
4
Ph
BF
2
Ms
Ms
-BF
2
(OH)
Ms
Ms
N
3.37
Ph
Ms
Ms
Scheme 3.25.
A variety of alkenyl trifluoroborates and 2-sulfamidobenzaldehydes were
converted to 1,2-dihydroquinolines in 30-60% yields (Table 3.3).
Table 3.3. Synthesis of 1,2-dihydroquinolines by modified Petasis reaction.
Entry Aldehyde Trifluoroborate salt Product
Yield,
%
1
O
NHMs
3.34
Ph
BF
3
K
3.36
N
3.37
Ph
Ms
59
157
Table 3.3 (continued)
Entry Aldehyde Trifluoroborate salt Product
Yield,
%
2
O
NHNs
3.38
Ph
BF
3
K
3.36
N
3.39
Ph
Ns
36
a
3
O
NHMs
3.40
Br
Ph
BF
3
K
3.36
N
3.41
Ph
Ms
Br
59
4
O
NHMs
3.42
MeO
MeO
Ph
BF
3
K
3.36
N
3.43
Ph
Ms
MeO
MeO
46
5
O
NHMs
3.44
O
2
N
Ph
BF
3
K
3.36
N
3.45
Ph
Ms
O
2
N
53
6
O
NHMs
3.34
BF
3
K
Cl
3.46
N
3.47
Ms
Cl
48
7
O
NHMs
3.34
BF
3
K
MeO
3.48
N
3.49
Ms
OMe
26
8
O
NHMs
3.34
BF
3
K
F
3
C
3.50
N
3.51
Ms
CF
3
33
9
O
NHMs
3.34
BF
3
K
3.52
N
3.53
Ms
60
158
Table 3.3 (continued)
Entry Aldehyde Trifluoroborate salt Product
Yield,
%
10
O
NHMs
3.40
Br
Bu
BF
3
K
3.54
N
3.55
Bu
Ms
Br
32
11
O
NHMs
3.40
Br
BF
3
K
3.56
N
3.57
Br
18
12
O
NHMs
3.34
BF
3
K
3.58
Ph
— —
13
O
NHMs
3.34
Ph
BF
3
K
3.59
— —
a Ns = 2-nitrophenylsulfonyl.
Unsubstituted vinyltrifluoroborate salt provided 7-bromoquinoline
49
in low yield
as the only isolated product (entry 11), and the attempts to use 1-substituted
vinyltrifluoroborates to prepare 3-substituted 1,2-dihydroquinolines were unsuccessful
(entries 12 and 13).
Some other carbonyl compounds were tested in this reaction and did not yield 1,2-
dihydroquinoline products:
CO
2
Me
NHMs NHMs NHAc
O
O
NHMs
Ph
O
3.60 3.61 3.62 3.63
Figure 3.4. Carbonyl compounds found unreactive in the synthesis of 1,2-
dihydroquinolines.
159
2-(Acetamido)benzaldehyde (3.60) remained inert under the reaction conditions,
which can be explained by much lower acidity of acetanilide NH group when compared
to sulfanilides (calculated pK
a
value is 14.61±0.70 at 25 °C).
40
Methyl N-
mesylanthranilate (3.61) and 2'-sulfamidoaryl ketones, such as 2-
(methanesulfamido)acetophenone (3.62) and 2-(methanesulfamido)benzophenone (3.63),
all failed to provide 1,2-dihydroquinoline derivatives. Instead, 3.62 underwent self-
condensation under the reaction conditions resulting in 4-methylquinoline derivative 3.65
(the structure of the latter confirmed by single crystal X-ray diffraction analysis):
NHMs
O
3.62
+
Ph
BF
3
K
3.36
Et
3
N(2eq)
PhMe, 80
o
C, 18 h
TMSCl (2 eq)
N
3.64
Ph
Ms
not formed
N
MsHN
3.65
70%
Scheme 3.26.
Figure 3.5. ORTEP drawing of 3.65 (50% thermal ellipsoids).
160
Similar TMSCl-mediated Fiedländer synthesis of quinolines has been reported in the
literature.
50
Attempts to further functionalize the double bond of 1,2-dihydroquinoline 3.37
using oxidative Heck coupling reaction with 4-methoxyphenylboronic acid (3.66) were
not successful (conditions tested: 3.66 (1.2 eq), Pd(OAc)
2
(10 mol%), Na
2
CO
3
(2 eq),
DMF, stirring under O
2
atmosphere at 50 °C for 24 h;
51
3.66 (2 eq), Pd(OAc)
2
(2 mol%),
2,9-dimethyl-1,10-phenanthroline (3 mol%), N-methylmorpholine (2 eq), acetonitrile,
stirring under O
2
atmosphere at 50 °C for 24 h
52,53
), resulting only in formation of
oxidative homocoupling product (4,4'-dimethoxybiphenyl). However, 3.37 can be
converted easily and in nearly quantitative yields into quinoline (3.67) and 1,2,3,4-
tetrahydroquinoline (3.68) derivatives (Scheme 3.27).
N
3.37
Ph
Ms
NaOH, EtOH
50
o
C, 12 h
N
3.67
Ph
H
2
, Pd/C (5%)
EtOH, RT, 12 h
N
3.68
Ph
Ms
Scheme 3.27.
Secondary amines, commonly used in catalytic Petasis reaction, should not be
used for the synthesis of 1,2-dihydroquinolines as, in addition to the target heterocycle,
they also give the products of the three-component reaction, as illustrated in the following
example:
161
O
NHMs
3.34
+
Ph
BF
3
K
3.36
+Bn
2
NH
3.12
BF
3
Et
2
O (2 eq)
(2 eq)
PhMe, 80
o
C, 18 h
N
3.37
Ph
Ms
+
NHMs
3.69
NBn
2
Ph
30% 26%
Scheme 3.28.
When an aryl trifluoroborate was used instead of alkenyl trifluoroborate, the three-
component condensation product was the only major product in the mixture and could be
isolated in moderate yield:
O
NHMs
3.34
+
BF
3
K
3.70
+
3.71
(2 eq)
PhMe, 80
o
C, 18 h
3.72
55%
MeO
N
H
O
TMSCl (2 eq)
NH
N
OMe
O
Ms
O
NHMs
3.40
+
BF
3
K
3.70
PhMe, 80
o
C, 18 h
3.73
31%
MeO
TMSCl (2 eq)
NH
NBn
2
OMe
Ms
+Bn
2
NH
3.12
(2 eq) Br
Br
Scheme 3.29.
Typical for these three-component reactions with nucleophilic amines was the
appearance of bright orange-red coloration upon addition of the Lewis acid, which
gradually faded with the reaction progress to the final light-brown color of the reaction
mixture. Though no studies on the nature of reaction intermediates has been done, the
162
color may suggest formation of the o-quinoid intermediate 3.74 similar to 3.21 (Scheme
3.15) postulated for the ordinary catalytic Petasis reaction:
O
NHMs
R
1
+ R
2
NH
LA
-H
2
O
NR
2
NMs
R
1
NR
2
NMs
R
1
R
2
BF
2
R
2
NHMs
R
1
NR
2
3.74
Scheme 3.30.
3.5 Three-component condensation with simple aromatic and aliphatic
aldehydes.
Simple aromatic aldehydes that do not bear coordinating groups (hydroxyl,
pyrrole-type NH or pyridine-type N) in o-position and simple aliphatic aldehydes (with
notable exception of formaldehyde) are known to be unreactive under conditions of three-
component Petasis reaction. Several research groups were trying to overcome this
obstacle, with limited success so far. In our group, the first example of successful
coordination-free three-component condensation was achieved by reaction of aminal
(3.75) with 2-phenylvinylboronic acid (3.8) and BF
3
·Et
2
O.
54
It was suggested that the
reactive intermediate in this reaction is benzaldiminium cation (3.77); however, the
necessity to prepare the starting aminal makes this approach inconvenient:
163
Ph
N
N
O
O
+
Ph
B(OH)
2
BF
3
Et
2
O (1.4 eq)
PhMe, 80
o
C, 24 h
Ph
N
O
Ph
3.75
3.76
3.8
Ph
N
O
3.77
Scheme 3.31.
Another successful strategy was the activation of alkenyl trifluoroborates with
chlorotrimethylsilane, as described above for the reaction with sulfamidobenzaldehydes
(Scheme 3.25). Unsubstituted benzaldehyde, thiophene-2-carboxaldehyde, 3- and 4-
pyridinecarboxaldehydes gave the three-component reaction products under these
conditions in yields around 30% (Scheme 3.32).
55
Ar O
+
Ph
BF
3
K
3.36
+
3.71
N
H
O
PhMe, 80
o
C, 18-48 h
TMSCl (1 eq)
Ar
N
O
Ph
S
N
N
Ar =
29-37%
Scheme 3.32.
Reaction of imines with organodifluoroboranes, generated in situ from
trifluoroborate salts and BF
3
·Et
2
O, was explored by Tehrani group. The imines generated
from a 2,2-dichlorinated aliphatic aldehyde were employed to avoid enolization and self-
condensation under reaction conditions (Scheme 3.33).
56
164
R
1
N
R
2
Cl Cl
[RBF
2
]
CH
2
Cl
2
- HFIP (9:1)
R
1
N
R
2
Cl Cl
B
R
F F
R
1
HN
R
2
Cl Cl
R
9-90%
Scheme 3.33.
For N-homoallylimines this reaction proceeded with [3,3]-sigmatropic rearrangement of
iminium intermediates (Scheme 3.34)
57
.
N
Cl Cl
[RBF
2
]
CH
2
Cl
2
, RT
N
Cl Cl
B
R
F F
[3,3]
N
Cl Cl
B
R
F F
N
Cl Cl
F
2
B
R
HN
Cl Cl
R
R =
Ph
R = Ph
16%
( )
()
31%
Scheme 3.34.
Alternatively, the imines were generated from 2-fluoroaziridines (Scheme 3.35)
58
.
N
Ph
Ph
R
F
Ar
BF
3
K
+
BF
3
Et
2
O
CH
2
Cl
2
, RT
N
Ph
Ph
F
R LA
N
F
Ph
Ph
R LA
N
Ph
Ph
R LA
F
N
Ph
Ph
R B
F
Ph
F F
NH
Ph
Ph
R
F
Ph
30-66%
Scheme 3.35.
The reactions on Schemes 3.33-3.35 involve the coordination of
organodifluoroborane to an imine and intramolecular transfer of a C-nucleophilic group
165
in an immonium intermediate that ensued. However, this cannot hold true for the
secondary amine-derived immonium ions of type 3.77, which are believed to be reactive
species in the coordination-free Petasis reactions such as those in Schemes 3.31 and 3.32.
Therefore, the intermolecular transfer of a nucleophilic group must be possible in these
cases, and one should expect this reaction to have a mechanism different from usual
three-component version of this reaction.
Indeed, in the similar reaction reported for perfluoroalkylsilane nucleophiles, the
perfluoroalkyl (R
F
) group is transferred onto an iminium intermediate generated from an
aldehyde or aldimine (Scheme 3.36).
59
R
O
+
R
1
N
R
2
TMS
TMSOTf
CH
2
Cl
2
, 0
o
C RT
R
1
N
R
2
R
TfO
-
R
F
TMS
NaOAc or KF
DMF
R
1
N
R
2
R R
F
R
1
N
R
2
MeOTf
CH
2
Cl
2
, -20
o
C RT
Me
N
R
2
R
1
TfO
-
R
F
TMS
NaOAc or KF
DMF
Me
N
R
2
R
1
R
F
35-92%
34-94%
Scheme 3.36.
Perfluoroalkyl-substituted O-silylhemiaminals have been reported to react with in
situ generated 2-phenylvinyldifluoroboranes through formation of a pair of iminium and
boronate intermediates, and the transfer of the styryl group proceeded in good yields
(Scheme 3.37).
60
166
R
F
OH
OMe
+
HNR
2
1) 4 MS, CH
2
Cl
2
2) TMS-imidazole
THF
Å
R
F
NR
2
OTMS
Ph
BF
2
R
F
NR
2
BF
2
(OTMS)
Ph
R
F
NR
2
Ph
63-78%
Scheme 3.37.
The iminium salt formation from aldehydes, amines (or silylamines) and silyl
halides or triflates has been confirmed by earlier studies. An aromatic aldehyde (3.78)
and TMS-amine (3.79), taken in stoichiometric quantities, react quickly via formation of
O-silylhemiaminal (3.80) giving aminal 3.81, hexamethyldisiloxane byproduct 3.82 and
recovering 0.5 eq of the starting aldehyde.
61
With 2 eq of TMS-amine, the conversion to
aminal 3.81 is complete (Scheme 3.38).
Ar
O
+ TMS NR
2
TMSOTf (cat.)
1 eq 1 eq
Ar OTMS
1 eq
NR
2
Ar NR
2
0.5 eq
NR
2
+TMS
2
O
CCl
4
or CH
2
Cl
2
0.5 eq
+
Ar
O
1 eq
3.78 3.79
3.80 3.81
3.82
3.78
Ar
O
+ TMS NR
2
TMSOTf (cat.)
1 eq 2 eq
CCl
4
or CH
2
Cl
2
3.78 3.79
Ar NR
2
1 eq
NR
2
+TMS
2
O
1 eq
3.81
3.82
Scheme 3.38.
These reactions are also possible with nucleophilic catalysis (TBAF cat.), proceeding at
much slower rate, and this version was used in the preparation of aminals of aliphatic
aldehydes.
In Scheme 3.38, the transformation 3.80 Æ 3.81 is the one proceeding through an
iminium triflate intermediate. These intermediates (3.83) have been isolated and
167
characterized explicitly for aldehydes and ketones (in the latter case, the reaction can be
complicated with formation of enamines and enol silyl ethers).
62
R
1
R
2
O + TMS NR
2
3.79
TMSOTf or TMSCl (1.1 eq)
DMF or HCO
2
Et
R
1
R
2
NR
2
TfO
-
or Cl
-
3.83
Scheme 3.39.
Silylamines 3.79 can be easily prepared from the corresponding primary or
secondary amines and isolated by distillation.
63
In case of primary amines, both mono-
and disilylated derivatives were selectively prepared.
64
Our initial interest in these
compounds as starting materials for Petasis-type reactions was stimulated with
disappointing product yields in the three-component reaction of sulfamidobenzaldehydes
(Scheme 3.29). In the very first attempt, when TMS-morpholine (3.84) was used instead
of morpholine (3.71) in the synthesis of 3.72, the yield improved dramatically:
O
NHMs
3.34
+
BF
3
K
3.70
+
3.84
PhMe, 80
o
C, 18 h
3.72
81%
MeO
N
O
Et
3
N (1 eq)
TMSCl (1 eq)
NH
N
OMe
O
Ms
TMS
Scheme 3.40.
Using BF
3
·Et
2
O (1 eq) instead of TMSCl in this system gave 3.72 in 61% yield.
Further efforts therefore addressed the problem of low-yielding reactions with
simple aromatic aldehydes, but no substantial improvements were made:
168
O
R
+
Ph
BF
3
K
3.36
+
3.84
N
O
TMS
R = H, OMe, NO
2
PhMe, 80
o
C, 18 h
Et
3
N (1 eq)
TMSCl (1 eq)
R
N
Ph
O
3.76 (R = H), 35%
3.85 (R = OMe), 27%
3.86 (R = NO
2
),21%
Scheme 3.41.
It was found that the tertiary amine additive was not necessary for this reaction
and use of only 1 eq of TMSCl increased the yield slightly, but not in the case of
electron-rich benzaldehyde 3.90. However, an attempt to prepare 3.76 taking only TMS-
morpholine (2 eq of 3.84, without any Lewis acid additive) failed, and increasing the
amount of 3.84 to 2 eq with TMSCl additive (1 eq) was also detrimental (27% yield of
3.76):
Ph
O
+
Ph
BF
3
K
3.36
+
3.84
N
O
TMS
PhMe, 80
o
C, 18 h
TMSCl (1 eq)
Ph
N
Ph
O
3.76
47%
3.87
Ph O
+
Ph
BF
3
K
3.36
+
3.88
NMe
2
TMS
PhMe, 80
o
C, 18 h
TMSCl (1 eq)
Ph
NMe
2
Ph
3.89
48%
3.87
+
Ph
BF
3
K
3.36
+
3.88
NMe
2
TMS
PhMe, 80
o
C, 18 h
TMSCl (1 eq)
NMe
2
Ph
3.91
26%
O
MeO
MeO
MeO
MeO
3.90
Scheme 3.42.
169
The goal of the subsequent experiments was to investigate the possibility of
running the coordination-free three-component reaction with aliphatic aldehydes. More
problems were expected, most importantly stemming from enolization and self-
condensation of the aldehydes having at least one α-hydrogen. Surprisingly, it was found
that the yields were comparable to those in the reactions with simple aromatic aldehydes,
and taking an excess (2.2 eq) of aliphatic aldehyde to compensate for condensation losses
improved the yield of products only slightly. The standard conditions were running the
reaction in anhydrous toluene (0.4 M of TMS-amine and trifluoroborate) at 80 °C for 18
h in a sealed (under nitrogen atmosphere) microwave tube. The results of these
experiments are presented in Table 3.4.
Table 3.4. Petasis reaction with aliphatic aldehydes.
Entry Aldehyde
Trifluoroborate
salt
TMS-amine Product
Yield,
%
1
Ph
O
3.92
Ph
BF
3
K
3.36
3.84
N
O
TMS
Ph
3.93
N
Ph
O
22
2
O
3.94
(2.2 eq)
Ph
BF
3
K
3.36
3.84
N
O
TMS
3.95
N
Ph
O
31
a
3
O
3.96
(2.2 eq)
Ph
BF
3
K
3.36
3.84
N
O
TMS
3.97
N
Ph
O
26
170
Table 3.4 (continued)
Entry Aldehyde
Trifluoroborate
salt
TMS-amine Product
Yield,
%
4
O
3.98
(2.2 eq)
Ph
BF
3
K
3.36
3.84
N
O
TMS
3.99
N
Ph
O
24
5
O
3.100
(2.2 eq)
Ph
BF
3
K
3.36
3.84
N
O
TMS
3.101
N
Ph
O
35
6
O
3.102
(2.2 eq)
Ph
BF
3
K
3.36
3.84
N
O
TMS
3.103
N
Ph
O
15
7
F
3
C OH
3.104
OMe
Ph
BF
3
K
3.36
3.84
N
O
TMS
F
3
C
3.105
N
Ph
O
33
b
8
O
3.106
(2.2 eq)
Ph
BF
3
K
3.36
3.84
N
O
TMS
3.107
N
Ph
O
2.5
c
9
O
3.96
(2.2 eq)
BF
3
K
3.108
Ph
3.84
N
O
TMS
3.109
N
O
Ph
77
171
Table 3.4 (continued)
Entry Aldehyde
Trifluoroborate
salt
TMS-amine Product
Yield,
%
10
O
3.94
(2.2 eq)
BF
3
K
3.108
Ph
3.88
NMe
2
TMS
3.110
NMe
2
Ph
54
11
Ph
O
3.111
Ph
(2.2 eq)
BF
3
K
3.108
Ph
3.84
N
O
TMS
Ph
3.112
N
O
Ph Ph
35
a Tandem aldol condensation-Petasis reaction product also formed, see discussion below. b 2 eq of TMSCl
was used. c The product of the three-component reaction was minor in the reaction mixture and was not
fully characterized (see discussion below).
1-(Trimethylsilyl)imidazole, 1-(trimethylsilyl)benzotriazole and
hexamethyldisilazane did not yield products of the three-component condensation.
The reaction with isobutyraldehyde (3.96, entry 3) was used as a standard for
variation of the reaction conditions. Decreasing the amount of 3.96 to 1 eq resulted in
lower isolated yield of 3.97 (21%), and so did the substitution of TMSCl with BF
3
·Et
2
O
(17%) or NbF
5
65
(22%) and running the reaction in anhydrous heptane instead of toluene
(13%). No product was obtained with catalytic quantity of TMSCl (15 mol%).
Primary aliphatic aldehydes (unbranched in α-position) generally underwent aldol
condensation to some extent under the reaction conditions. The products, β-
hydroxyaldehydes (3.113), were also found able to participate in three-component
condensation and gave the products of tandem aldol-Petasis reaction (3.114) as minor
reaction mixture components and in single diastereomeric form (although the relative
configuration was not established). Alternatively – for example, if TMS-amine was added
172
to the reaction mixture after long (5 h) delay, or if trifluoroborate salt (e.g., potassium 2-
bromo-2-phenylvinyltrifluoroborate, potassium vinyltrifluoroborate) failed to participate
– the compounds 3.113 dehydrated under the reaction conditions giving α, β-unsaturated
aldehydes 3.115 as the only reaction products (single isomers, but the geometry of the
double bond was not established). The reactions in Scheme 3.43 are some of the observed
examples of these transformations:
O
3.94
+
Ph
BF
3
K
3.36
TMSCl (1 eq)
PhMe, 80
o
C, 5 h
(2.2 eq)
N O TMS (1 eq)
3.84
80
o
C, 18 h
O
3.94
+
Ph
BF
3
K
3.36
(2.2 eq)
+
3.84
N
O
TMS
TMSCl (1 eq)
PhMe, 80
o
C, 18 h
3.95
N
Ph
O
+
N
Ph
O
OH
OH
O
3.113
O
3.115
aldol
condensation
- H
2
O
Ph
O
31%
3.114
7.5%
(2.2 eq)
+
Ph
BF
3
K
3.36
+
3.84
N
O
TMS
3.116
TMSCl (1 eq)
PhMe, 80
o
C, 18 h
N
Ph
O
Ph
OH
3.117
4.1%
Ph
Scheme 3.43.
173
Table 3.5 illustrates the effects of reaction conditions on the outcome of the aldol-
Petasis reaction:
Table 3.5. Effect of reaction conditions in the tandem aldol-Petasis reaction.
Entry Conditions
a
Yield of 3.95,
%
Yield of 3.114,
%
1
3.94 (1 eq), 3.36 (1 eq), 3.84 (1 eq),
TMSCl (1 eq), 80 °C, 18 h
25 4.3
2
3.94 (2.2 eq), 3.36 (1 eq), 3.84 (1 eq),
TMSCl (1 eq), 80 °C, 18 h
31 7.5
3
3.94 (2.2 eq), 3.36 (1 eq), 3.84 (1 eq),
TMSCl (1 eq), 80 °C, 3 d
25 6.9
4
3.94 (2.2 eq), 3.36 (1 eq), 3.71 (1 eq),
TMSCl (1 eq), 80 °C, 18 h
25 2.6
5
3.94 (2.2 eq), 3.36 (1 eq), 3.84 (1 eq),
TMSCl (1 eq), TMSBt (1 eq), 80 °C, 18 h
32 0
a All reactions were run in anhydrous toluene. b Morpholine (3.71) was dried and freshly distilled over
KOH. c TMSBt = 1-(trimethylsilyl)benzotriazole.
Cyclopropanecarboxaldehyde (3.106; Table 3.3, entry 8) underwent more
complex transformations under reaction conditions: the target compound 3.107 was a
only a minor component of the reaction mixture, while the cyclopropylaldiminium
intermediate 3.118 mostly underwent nucleophilic ring opening (homoallylic
rearrangement) and the resulting enamine 3.119 condensed with the second molecule of
the aldehyde, giving α, β-unsaturated aldehyde 3.120 (single isomer, configuration of the
double bond was not determined) as the major product. The compound 3.120 was water-
soluble and large part of it was lost during extraction workup:
174
O
3.106
(2.2 eq)
+
Ph
BF
3
K
3.36
+
3.84
N
O
TMS
TMSCl (1 eq)
PhMe, 80
o
C, 18 h
3.107
N
Ph
O
2.5%
+
O
N
O
3.120
>26%
N
O
N
O
3.118
HN
O
O
N
N
O
O
-
O NH
enamine aldol
Scheme 3.38
3.119
Scheme 3.44.
Similar rearrangement has been reported in the literature.
66
The reaction with acetylenic trifluoroborate salts was the only reactant
combination giving moderate to high yields for a variety of aldehydes and silylamines
(e.g., Table 3.3, entries 9-11) and was explored in collaboration.
67,68
Importantly, the
aldehyde 3.111 (entry 11) participated well in this reaction even though it failed to react
with 2-phenylvinyltrifluoroborate (3.36). The yields of the reaction with acetylenic
trifluoroborates were only slightly lower when the unprotected amines were used instead
of TMS-amines: for example, the yield of 3.109 (entry 9) was 70% with morpholine
(3.71) used as a staring material versus 77% in the reaction with TMS-morpholine (3.84).
In a control experiment, when taken instead of alkynyl trifluoroborate, terminal alkyne
175
(phenylacetylene) would not add to immonium intermediate under standard reaction
conditions.
3.6 Experimental.
All reactions, unless otherwise noted, were carried in flame dried flasks or oven-
dried microwave tubes under dry nitrogen or argon atmosphere. Anhydrous solvents
were purchased from commercial sources (Sigma-Aldrich, Alfa Aesar, EMD).
1
H and
13
C NMR spectra were recorded on Varian Mercury 400, Varian 400-MR (400 MHz) or
Varian VNMRS-500 (500 MHz) 2-channel NMR spectrometers, using residual
1
H or
13
C
signals of deuterated solvents as internal standards. Silica gel (60 Å, 40-63 µm; Sorbent
Technologies) was used as a sorbent for flash column chromatography.
O
Br
3.10. 6-Bromo-2-phenyl-2H-chromene. Method A. The solution of 5-
bromosalicylaldehyde (201 mg, 1 mmol), 2-phenylvinylboronic acid (148 mg, 1 mmol)
and the appropriate amount of a secondary or tertiary amine in 2.5 mL of absolute ethanol
was prepared in a 2 dram screw-cap glass vial, flushed with dry nitrogen, and stirred at 70
°C for the indicated amount of time. TLC control (silica/CH
2
Cl
2
-hexane 1:1): R
f
0.8. The
reaction mixture was then evaporated to dryness and pure 3.10 was isolated by column
chromatography (silica gel, CH
2
Cl
2
-hexane 1:2) as light yellow oil that gradually
crystallized when refrigerated. The yield depended on the amine used. For reactions with
176
chiral amines, the enantiomer ratio of 3.10 was determined by HPLC using Rainin
instrument equipped with Chiralpak AD column (100% hexane, 1 mL/min; t = 5.47 min,
6.58 min).
Method B. The mixture of either 2-phenylvinylboronic acid (148 mg, 1.0 mmol) or
potassium 2-phenylvinyltrifluoroborate (210 mg, 1.0 mmol) with 5-bromosalicylaldehyde
(201 mg, 1.0 mmol) and dibenzylamine (197 mg, 1.0 mmol) in 2 mL of water was stirred
at 80 °C for 3 h. The reaction mixture was extracted with 3×10 mL CH
2
Cl
2
, dried over
Na
2
SO
4
, filtered and evaporated. The yellow syrupy residue was purified by flash
chromatography (silica gel, CH
2
Cl
2
-hexane 1:5). The product 3.10 (R
f
0.4) was eluted,
then the mixture was left on solvent-wet silica until the purple-colored band faded
completely, and more product was eluted with CH
2
Cl
2
. Total yield was 235 mg (82%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.42-7.58 (m, 5H), 7.30 (dd, J = 8.6 Hz, J = 2.3 Hz, 1H),
7.24 (d, J = 2.3 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.55 (dd, J = 9.9 Hz, J = 1.1 Hz, 1H),
6.00-6.04 (m, 1H), 5.93 (dd, J = 9.9 Hz, J = 3.4 Hz, 1H).
13
C NMR (CDCl
3
, 100 MHz): δ
152.1, 140.1, 131.9, 129.0, 128.7, 128.5, 127.0, 125.9, 123.1, 122.9, 117.7, 113.0, 77.2.
B(OH)
2
3.26. (E)-1-Hexadecenylboronic acid. 1-Hexadecyne (tech., 90%; 2.81 mL, 2.22 g, 10
mmol) and catecholborane (1.1 mL, 1.2 g, 10 mmol) were mixed at 0 °C under argon.
The mixture was let warm to room temperature and stirred for 30 min, and then heated up
to 60 °C and stirred at this temperature for 2 h. Water (25 mL) was then added, and
viscous white oil separated and eventually crystallized. The suspension was stirred for 2 h
177
at room temperature, cooled down in ice-water bath, the precipitate was filtered off,
washed with water (2 × 20 mL) and pentane. Dried in air overnight. White crystals, yield
1.85 g (69%).
1
H NMR (DMSO-d
6
, 400 MHz): δ 7.44 (br.s, 2H), 6.41 (dt, J = 17.4 Hz,
6.4 Hz, 1H), 5.29 (d, J = 17.4 Hz, 1H), 2.00-2.09 (m, 2H), 1.05-1.43 (m, 24H), 0.82-0.88
(m, 3H).
13
C NMR (DMSO-d
6
, 100 MHz): δ 150.4, 35.5, 31.8, 29.55, 29.51, 29.4, 29.2,
29.1, 28.6, 22.6, 14.4.
OH
O
HO
3.29. 2,5-Dihydroxy-3,4,6-trimethylbenzaldehyde. The mixture of boric acid (6.3 g)
and glycerol (27 g) was heated to 170 °C in vacuo (~16 mm Hg) with stirring until all
water was distilled off (~1 h). The resulting solution of glyceroboric acid was cooled
down to 160 °C, and trimethylhydroquinone (2.73 g) was added, followed by
hexamethylenetetramine (3.6 g). As the latter dissolved, the reaction began with bubbling
and the change of color from light yellow to dark yellow-brown. The stirred mixture was
cooled to 110 °C over 15 min, and the mixture of conc. H
2
SO
4
(6 mL) and water (18 mL)
was gradually added. The reaction mixture was then refluxed (bath temperature ~150 °C)
for 30 min, and its color changed to red-brown and the precipitate (golden yellow needles)
began to form. TLC control (silica/EtOAc-hexane 1:3): R
f
0.3. The reaction mixture was
cooled down and left overnight to complete crystallization, the dark red precipitate was
filtered off (product!), and the filtrate was diluted with water to 100 mL and extracted
178
with EtOAc (5 × 20 mL). The combined extracts were dried over Na
2
SO
4
, filtered and
evaporated to give the second crop of the crude product. The combined solids were
redissolved in hot EtOAc, the solution was filtered through a plug of silica gel (3 cm) and
washed with EtOAc (300 mL). The filtrate was evaporated to dryness and recrystallized
from CHCl
3
-hexane (20 mL + 40 mL). Yield 1.67 g of 3.29 (52%, lit. 43-48%), bright-
yellow crystals. The analytical data were identical to reported in literature.
37
OBn
O
BnO
3.33. 2,5-Bis(benzyloxy)-3,4,6-trimethylbenzaldehyde. The mixture of 3.29 (188 mg,
1.04 mmol), benzyl bromide (393 mg, 2.30 mmol, 2.2 eq), K
2
CO
3
(460 mg, 3.33 mmol,
3.2 eq) and KI (10 mg) in DMF (5 mL) was stirred under nitrogen at 50 °C overnight.
TLC control (silica/CH
2
Cl
2
-hexane 1:1): R
f
0.1 (3.29), R
f
0.55 (3.33). The reaction
mixture was poured into 80 mL of water and extracted with CH
2
Cl
2
(4 × 25 mL). The
combined extracts were washed with water (50 mL) and dried over K
2
CO
3
. The dark
brown filtrate was evaporated to dryness, redissolved in a minimal volume of CH
2
Cl
2
and
filtered through a short plug of silica gel (2.5 cm), followed by elution with CH
2
Cl
2
-
hexane (1:1, 100 mL). Evaporation of the filtrate gave pure 3.33 as light tan crystals,
yield 291 mg (81%).
1
H NMR (CDCl
3
, 400 MHz): δ 10.55 (s, 1H), 7.36-7.55 (m, 10H),
4.89 (s, 2H), 4.77 (s, 2H), 3.60 (s, 3H), 2.34 (s, 3H), 2.29 (s, 3H).
13
C NMR (CDCl
3
, 100
179
MHz): δ 192.6, 157.5, 152.2, 138.6, 136.9, 136.1, 131.1, 129.2, 128.55, 128.46, 128.3,
128.0, 127.9, 127.7, 126.3, 77.8, 74.5, 14.0, 13.1, 12.4.
OH
O
BnO
3.32. 2-(Benzyloxy)-5-hydroxy-3,4,6-trimethylbenzaldehyde.
39
The solution of 3.33
(291 mg, 0.81 mmol) in the mixture of trifluoroacetic acid (2.5 mL) and toluene (2.5 mL)
was stirred at room temperature for 4 h. Clear dark-orange solution formed. TLC control
(silica/5% EtOAc in hexane): R
f
0.5. The reaction mixture was poured into 50 mL of sat.
aqueous NaHCO
3
, extracted with EtOAc (3 × 25 mL), and the combined organic layers
were dried over Na
2
SO
4
, filtered and evaporated to dryness. Trituration of the residue
with diethyl ether-pentane gave light-brown crystals of the product. Yield 129 mg (59%).
1
H NMR (CDCl
3
, 400 MHz): δ 12.24 (s, 1H), 10.24 (s, 1H), 7.34-7.50 (m, 5H), 4.71 (s,
2H), 2.51 (s, 3H), 2.30 (s, 3H), 2.17 (s, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 195.0, 158.0,
147.6, 142.0, 137.0, 130.3, 128.6, 128.2, 127.8, 124.1, 116.2, 75.1, 14.2, 11.1, 10.6.
O
BnO
3.27. 6-(Benzyloxy)-5,7,8-trimethyl-2-tetradecyl-2H-chromene. The suspension of
3.32 (135 mg, 0.5 mmol), 3.26 (134 mg, 0.5 mmol) and dibenzylamine (100 mg, ~0.5
mmol) in 1 ml of 1-butanol was prepared in a 1 dram screw-cap glass vial, flushed with
180
dry nitrogen, and stirred at 110
o
C for 24 h. The reaction mixture was evaporated to
dryness. The product was isolated by flash chromatography on silica (elution with
EtOAc-hexane 1:100), followed by unreacted 3.32 (elution with EtOAc-hexane 1:9). The
fractions containing the product were evaporated to dryness, and the solid residue was
recrystallized from ethanol, yielding 135 mg (57%) of crystalline air-sensitive 3.27.
1
H
NMR (CDCl
3
, 400 MHz): δ 7.49-7.54 (m, 2H), 7.40-7.46 (m, 2H), 7.34-7.39 (m, 1H),
6.60 (dd, J = 10.0 Hz, 1.7 Hz, 1H), 5.77 (dd, J = 10.0 Hz, 3.3 Hz, 1H), 4.69-4.77 (m, 3H),
2.27 (s, 3H), 2.25 (s, 3H), 2.16 (s, 3H), 1.77-1.90 (m, 1H), 1.43-1.70 (m, 3H), 1.10-1.42
(m, 22H), 0.92 (t, J = 6.8 Hz, 3H).
13
C NMR (CDCl
3
, 100 MHz,): δ 149.1, 147.6, 137.8,
130.4, 128.5, 127.8, 127.7, 125.4, 123.6, 122.6, 121.7, 119.0, 74.6, 74.1, 34.8, 31.9, 29.7,
29.67, 29.61, 29.4, 25.3, 22.7, 14.1, 13.1, 11.7, 11.5.
O
HO
3.24. 5,7,8-Trimethyl-2-tetradecylchroman-6-ol. Compound 3.27 (96 mg, 0.2 mmol)
was suspended in 10 mL of anhydrous ethanol in a 25 mL round-bottom flask, and 10 mg
of 5% palladium on carbon was added under nitrogen. The reaction mixture was stirred
overnight at 60
o
C under hydrogen (1 atm). Upon cooling, the product precipitated. The
reaction mixture was filtered through short plug of Celite, washed with dichloromethane
(100 mL). The filtrate was evaporated and dried in vacuo to give 62 mg (80%) of pure
3.24 as white crystals. The compound can be recrystallized from methanol.
1
H NMR
181
(CDCl
3
, 400 MHz): δ 4.25 (s, 1H), 3.78-3.88 (m, 1H), 2.61-2.73 (m, 2H), 2.17 (s, 3H),
2.14 (s, 3H), 2.11 (s, 3H), 1.94-2.03 (m, 1H), 1.18-1.80 (m, 27H), 0.90 (t, J = 6.8 Hz, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 147.0, 144.8, 122.3, 120.8, 118.7, 118.3, 74.8, 35.4, 31.9,
29.69, 29.66, 29.6, 29.4, 28.0, 25.6, 23.2, 22.7, 14.1, 12.1, 11.7, 11.2.
N
S
O
O
3.37. 1-(Methylsulfonyl)-2-phenyl-1,2-dihydroquinoline. The mixture of potassium 2-
phenylvinyltrifluoroborate 3.36 (210 mg, 1 mmol), N-(2-
formylphenyl)methanesulfonamide 3.34 (199 mg, 1 mmol; prepared from 2-aminobenzyl
alcohol by literature procedure
41
) and a stirring bar were sealed in a 10 mL glass vial,
which was subsequently flushed with dry nitrogen. Anhydrous toluene (2.5 mL) was
injected followed by triethylamine (280 µL, 203 mg, 2 mmol), and the resulting
suspension was stirred at room temperature for 5 min. Chlorotrimethylsilane (260 µL,
223 mg, 2 mmol) was then added in one portion. The mixture was stirred at 80 °C for 18
h, cooled and diluted with 30 mL of EtOAc and 20 mL of water. The layers were
separated and the aqueous layer was re-extracted with EtOAc (3×20 mL). The combined
organic layers were dried over Na
2
SO
4
, filtered and evaporated. TLC control
(silica/EtOAc-hexane 1:3, stained with vanillin): R
f
0.45 (gray). The product was isolated
by flash chromatography (silica, EtOAc-hexane 1:5) and crystallized upon trituration
with diethyl ether-pentane. White crystals, yield 167 mg (59%).
1
H NMR (CDCl
3
, 400
182
MHz): δ 7.56-7.60 (m, 1H), 7.36-7.40 (m, 1H), 7.21-7.31 (m, 6H), 6.86 (d, J = 9.6 Hz,
1H), 6.34 (dd, J = 9.6 Hz, 5.8 Hz, 1H), 6.04 (d, J = 5.8 Hz, 1H), 2.79 (s, 3H).
13
C NMR
(100 MHz, CDCl
3
): δ 138.1, 132.9, 128.6, 128.4, 127.99, 127.97, 127.24, 127.20, 126.9,
126.7, 126.5, 126.3, 56.9, 37.7.
N
S
O
O
NO
2
3.39. 1-[(2-Nitrophenyl)sulfonyl]-2-phenyl-1,2-dihydroquinoline. The starting
aldehyde (3.38) was prepared from 2-aminobenzyl alcohol by literature procedure.
41
The
compound 3.39 was prepared similarly to 3.37, TLC control (silica/EtOAc-hexane 1:3,
stained with vanillin): R
f
0.3 (gray). The product was isolated by flash chromatography
(silica, EtOAc-hexane 1:3) and crystallized upon trituration with diethyl ether-pentane.
White crystals, yield 140 mg (36%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.68 (d, J = 7.9 Hz,
1H), 7.63 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.33-7.41 (m, 3H), 7.19-7.31 (m,
6H), 7.09 (dd, J = 7.1 Hz, 1.7 Hz, 1H), 6.41 (d, J = 9.6 Hz, 1H), 6.21 (dd, J = 9.6 Hz, 6.0
Hz, 1H), 6.14 (d, J = 6.0 Hz, 1H).
13
C NMR (CDCl
3
, 100 MHz): δ 147.7, 137.4, 133.7,
131.8, 130.8, 130.6, 130.4, 129.0, 128.5, 128.4, 128.1, 128.0, 127.5, 127.3, 127.1, 126.4,
124.9, 123.5, 57.1.
183
N
S
O
O
Br
3.41. 7-Bromo-1-(methylsulfonyl)-2-phenyl-1,2-dihydroquinoline. The starting
aldehyde (3.40) was prepared from 4-bromo-2-fluorobenzaldehyde by literature
method.
69
The compound 3.41 was prepared similarly to 3.37, TLC control
(silica/EtOAc-hexane 1:3, stained with vanillin): R
f
0.3 (gray). The product was isolated
by flash chromatography (silica, EtOAc-hexane 1:3) and crystallized upon trituration
with diethyl ether-pentane. White crystals, yield 213 mg (59%).
1
H NMR (CDCl
3
, 400
MHz): δ 7.75 (s, 1H), 7.25-7.37 (m, 6H), 7.10 (dd, J = 8.1 Hz, 1.2 Hz, 1H), 6.62 (d, J =
9.6 Hz, 1H), 6.36 (ddd, J = 9.6 Hz, J = 5.8 Hz, J = 1.2 Hz, 1H), 6.03 (d, J = 5.8 Hz, 1H),
2.82 (s, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 137.7, 134.1, 129.6, 129.5, 128.6, 128.2,
127.8, 127.6, 127.2, 126.8, 125.5, 121.7, 56.9, 38.2.
N
S
O
O
MeO
MeO
3.43. 6,7-Dimethoxy-1-(methylsulfonyl)-2-phenyl-1,2-dihydroquinoline. The starting
aldehyde (3.42) was prepared from the corresponding 2-aminobenzyl alcohol according
to the literature procedure.
41
The compound 3.43 was prepared similarly to 3.37, TLC
control (silica/EtOAc-hexane 1:3, stained with vanillin): R
f
0.2 (brown). The product was
isolated by flash chromatography (silica, EtOAc-hexane 1:3) and dried in vacuo to give
157 mg of viscous yellowish oil, yield 46%.
1
H NMR (CDCl
3
, 400 MHz): δ 7.28-7.33 (m,
184
2H), 7.14-7.23 (m, 3H), 7.06 (s, 1H), 6.71 (d, J = 9.6 Hz, 1H), 6.65 (s, 1H), 6.14 (dd, J =
9.6 Hz, J = 5.8 Hz, 1H), 5.89 (d, J = 5.8 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.71 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 148.5, 147.4, 138.1, 128.2, 127.8, 127.1, 125.90, 125.87,
124.4, 121.0, 110.9, 108.7, 56.5, 55.8, 37.0.
N
S
O
O
O
2
N
3.45. 1-(Methylsulfonyl)-6-nitro-2-phenyl-1,2-dihydroquinoline. The starting aldehyde
(3.44) was prepared from 2-fluoro-5-nitrobenzaldehyde (with 2 eq methanesulfonamide
and 2 eq NaH in anhydrous DMF). The compound 3.45 was prepared similarly to 3.37,
TLC control (silica/EtOAc-hexane 1:3, stained with vanillin): R
f
0.25 (green). The
product was isolated by flash chromatography (silica, EtOAc-hexane 1:3) and dried in
vacuo to give 175 mg of viscous yellow oil, yield 53%.
1
H NMR (CDCl
3
, 400 MHz): δ
8.10 (d, J = 2.5 Hz, 1H), 8.06 (dd, J = 9.1 Hz, J = 2.5 Hz, 1H), 7.71 (d, J = 9.1 Hz, 1H),
7.24-7.35 (m, 5H), 6.90 (d, J = 9.6 Hz, 1H), 6.46 (dd, J = 9.6 Hz, J = 6.0 Hz, 1H), 6.12 (d,
J = 6.0 Hz, 1H), 2.87 (s, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 145.0, 138.9, 137.4, 129.7,
128.7, 128.5, 128.0, 127.0, 125.6, 124.6, 123.4, 121.8, 57.4, 39.2.
185
N
S
O
O
Cl
3.47. 2-(4-Chlorophenyl)-1-(methylsulfonyl)-1,2-dihydroquinoline. Prepared similarly
to 3.37, TLC control (silica/EtOAc-hexane 1:3, stained with vanillin): R
f
0.35 (gray). The
product was isolated by flash chromatography (silica, EtOAc-hexane 1:3) and
crystallized upon trituration with diethyl ether-pentane. White crystals, yield 154 mg
(48%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.54-7.59 (m, 1H), 7.21-7.33 (m, 7H), 6.87 (d, J =
9.8 Hz, 1H), 6.31 (dd, J = 9.8 Hz, J = 6.0 Hz, 1H), 5.99 (d, J = 6.0 Hz, 1H), 2.79 (s, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 136.6, 133.9, 132.6, 128.9, 128.7, 128.6, 127.9, 127.0,
126.79, 126.75, 126.6, 56.2, 37.8.
N
S
O
O
OMe
3.49. 2-(4-Methoxyphenyl)-1-(methylsulfonyl)-1,2-dihydroquinoline. Prepared
similarly to 3.37, TLC control (silica/EtOAc-hexane 1:3, stained with vanillin): R
f
0.4
(brown). The product was isolated by flash chromatography (silica, EtOAc-hexane 1:9 to
1:5) and crystallized upon trituration with diethyl ether-pentane. White crystals, yield 83
mg (26%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.52-7.56 (m, 1H), 7.20-7.30 (m, 5H), 6.84 (d,
J = 9.6 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H), 6.29 (dd, J = 9.6 Hz, J = 5.8 Hz, 1H), 5.98 (d, J
= 5.8 Hz, 1H), 3.77 (s, 3H), 2.78 (s, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 159.4, 132.9,
129.9, 128.7, 128.6, 128.1, 127.5, 127.0, 126.6, 126.5, 126.1, 113.8, 56.6, 55.2, 37.8.
186
N
S
O
O
CF
3
3.51. 1-(Methylsulfonyl)-2-[4-(trifluoromethyl)phenyl]-1,2-dihydroquinoline.
Prepared similarly to 3.37, TLC control (silica/EtOAc-hexane 1:5, stained with vanillin):
R
f
0.2 (gray). The product was isolated by flash chromatography (silica, EtOAc-hexane
1:4) and crystallized upon drying in vacuo. Trituration with diethyl ether-pentane gives
colorless needles, yield 117 mg (33%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.61 (d, J = 7.5
Hz, 1H), 7.48-7.57 (m, 4H), 7.22-7.31 (m, 3H), 6.90 (d, J = 9.6 Hz, 1H), (dd, J = 9.6 Hz,
J = 6.0 Hz, 1H), 6.08 (d, J = 6.0 Hz, 1H), 2.81 (s, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ
142.3, 132.6, 130.1 (q,
2
J
C,F
= 32 Hz), 129.0, 127.8, 127.6, 127.1, 126.98, 126.91, 126.88,
126.2, 125.4 (q,
3
J
C,F
= 4 Hz), 121.2 (q,
1
J
C,F
= 271 Hz), 56.3, 37.8.
19
F NMR (CDCl
3
,
376 MHz): δ -62.59.
N
S
O
O
3.53. 2-Cyclohex-1-en-1-yl-1-(methylsulfonyl)-1,2-dihydroquinoline. Prepared
similarly to 3.37, TLC control (silica/EtOAc-hexane 1:5, stained with vanillin): R
f
0.4
(gray). The product was isolated by flash chromatography (silica, EtOAc-hexane 1:9) and
dried in vacuo to give 174 mg of viscous colorless oil, yield 60%.
1
H NMR (CDCl
3
, 400
MHz): δ 7.53 (d, J = 7.9 Hz, 1H), 7.09-7.23 (m, 3H), 6.64 (d, J = 9.5 Hz, 1H), 6.00 (dd, J
= 9.5 Hz, J = 5.6 Hz, 1H), 5.53-5.58 (m, 1H), 5.15 (d, J = 5.6 Hz, 1H), 2.09-2.20 (m, 1H),
187
1.74-1.95 (m, 3H), 1.35-1.62 (m, 4H).
13
C NMR (CDCl
3
, 100 MHz): δ 133.8, 133.2,
128.2, 128.1, 127.1, 126.7, 126.4, 126.2, 125.7, 125.4, 59.0, 37.3, 25.1, 24.9, 22.4, 21.9.
N
S
O
O
Br
3.55. 7-Bromo-2-butyl-1-(methylsulfonyl)-1,2-dihydroquinoline. Prepared similarly to
3.37, TLC control (silica/EtOAc-hexane 1:3, stained with vanillin): R
f
0.45 (gray). The
product was isolated by flash chromatography (silica, EtOAc-hexane 1:6 to 1:5) and
dried in vacuo to give 110 mg of viscous colorless oil, yield 32%.
1
H NMR (CDCl
3
, 400
MHz): δ 7.77 (d, J = 1.7 Hz, 1H), 7.33 (dd, J = 8.3 Hz, J = 1.7 Hz, 1H), 7.01 (d, J = 8.3
Hz, 1H), 6.49 (d, J = 9.6 Hz, 1H), 6.11 (dd, J = 9.6 Hz, J = 5.8 Hz, 1H), 4.65-4.73 (m,
1H), 2.66 (s, 3H), 1.17-1.47 (m, 6H), 0.84 (t, J = 7.0 Hz, 1H).
13
C NMR (CDCl
3
, 100
MHz): δ 133.9, 130.2, 130.1, 129.7, 127.6, 127.0, 124.0, 121.2, 55.1, 37.8, 32.7, 27.2,
22.0, 13.9.
N Br
3.57. 7-Bromoquinoline. Prepared similarly to 3.37 using potassium vinyltrifluoroborate.
The product was isolated by flash chromatography (silica, EtOAc-hexane 1:5 to 1:1) and
dried in vacuo to give 37 mg (18%) of colorless oil, which crystallized on cooling to
colorless needles.
1
H NMR (CDCl
3
, 400 MHz): δ 8.88-8.91 (m, 1H), 8.26-8.29 (m, 1H),
188
8.08-8.13 (m, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.59-7.64 (m, 1H), 7.37-7.42 (m, 1H).
13
C
NMR (CDCl
3
, 100 MHz): δ 151.2, 148.7, 135.9, 131.7, 130.1, 129.0, 126.8, 123.5, 121.4.
N
HN
S
O O
3.65. N-[2-(4-methyl-2-quinolinyl)phenyl]methanesulfonamide. The reaction was run
identically to 3.37 using N-(2-acetylphenyl)methanesulfonamide (3.62; prepared from 2'-
aminoacetophenone
41
). TLC control (silica/EtOAc-hexane 1:3, stained with vanillin): R
f
0.25 (yellow). The product was isolated by flash chromatography (silica, EtOAc-hexane
1:3) and crystallized upon trituration with diethyl ether. Bright yellow crystals, yield 108
mg (70%).
1
H NMR (400 MHz, CDCl
3
): δ 13.7 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.91-
7.97 (m, 1H), 7.78 (dd, J = 8.3 Hz, 1.2 Hz, 1H), 7.75 (s, 1H), 7.68-7.73 (m, 1H), 7.53-
7.59 (m, 1H), 7.38-7.44 (m, 1H), 7.18-7.24 (m, 1H), 2.91 (s, 3H), 2.74 (d, J = 0.8 Hz,
3H).
13
C NMR (100 MHz, CDCl
3
): δ 156.2, 146.3, 145.1, 138.6, 130.7, 130.1, 129.0,
128.9, 126.9, 126.5, 124.0, 123.5, 120.1, 119.7, 39.4, 19.1.
X-Ray crystallography data for 3.65.
X-ray diffraction data were collected on a Bruker SMART APEX CCD diffractometer
with graphite-monochromatic Mo K α radiation ( λ= 0.71073 Å) at 110 K. The cell
parameters for 3.65 were obtained from the least-squares refinement of the spots using
the SMART program. A hemisphere of the crystal data was collected up to a resolution of
189
0.75 Å, and the intensity data were processed using the Saint Plus program. All
calculations for the structure determination were carried out using the SHELXTL
package (version 6.14).
70
Initial atomic position were located by direct methods using XS,
and the structure was refined by the least square methods using SHELX with 5201
independent reflections within the range of theta 2.10 – 25.68° (completeness 99.5%).
Absorption corrections were applied by SADABS.
71
Calculated hydrogen positions were
input and refined in a riding manner along with the corresponding carbons. A summary
of the refinement details and resulting factors are given in Table 3.6.
Table 3.6. Crystallographic data and structure refinement details for 3.65.
formula C
17
H
16
N
2
O
2
S
fw 312.39
T (K) 160(2) K
λ (Å) 0.71073
crystal system Monoclinic
space group P2(1)/c
a, (Å) / b, (Å) / c, (Å) 8.995(3) / 8.468(3) / 19.573(6)
α, (deg) / β, (deg) / γ, (deg) 90 / 97.716(5) / 90
V, (Å
3
) 1477.4(7)
Z 4
D
calc
, (Mg/m
3
) 1.395 Mg/m
3
µ (mm
-1
) 0.226
F(000) 652
crystal size (mm) 1.188 x 0.405 x 0.036
θ range for data collection (deg) 2.10–25.68
index ranges -10<=h<=10
reflections collected 7791
independent reflections / R
int
2781 / 0.1104
completeness to θ = 25.68° 99.5 %
refinement method Full-matrix least-squares on F
2
data / restraints / parameters 2781 / 0 / 201
GOF on F
2
1.084
R
1
, wR
2
[I>2 σ(I)] 0.0599, 0.1795
R
1
, wR
2
(all data) 0.0698, 0.1885
peak and hole (e.Å
-3
) 0.791, -0.638
190
N
3.67. 2-Phenylquinoline. The solution of 3.37 (285 mg, 1 mmol) and NaOH (400 mg, 10
mmol) in absolute ethanol (10 mL) was stirred at 50
o
C for 12 h. The reaction mixture
was then poured into water (30 mL), extracted with EtOAc (3 × 20 mL), and the
combined organic extracts were washed with water (25 mL). The organic layer was then
dried over Na
2
SO
4
, filtered and evaporated to give yellowish crystals of the product (205
mg, >99%).
1
H NMR (CDCl
3
, 400 MHz): δ 8.15-8.24 (m, 4H), 7.88 (d, J = 8.3 Hz, 1H),
7.83 (d, J = 8.3 Hz, 1H), 7.71-7.77 (m, 1H), 7.51-7.57 (m, 3H), 7.45-7.50 (m, 1H).
13
C
NMR (CDCl
3
, 100 MHz): δ 157.3, 148.3, 139.7, 136.7, 129.7, 129.6, 129.3, 128.8, 127.5,
127.4, 127.1, 126.2, 119.0.
N
S
O
O
3.68. 1-(Methylsulfonyl)-2-phenyl-1,2,3,4-tetrahydroquinoline. To the solution of 3.37
(285 mg, 1 mmol) in absolute ethanol (10 mL) 5% Pd-C (20 mg) was added under
nitrogen. The reaction mixture was stirred overnight at room temperature under hydrogen
atmosphere (1 atm), filtered through a short plug of silica gel and washed with EtOAc
(200 mL). The filtrate was evaporated and dried in vacuo to yield the product (290 mg,
>99%) as viscous colorless oil.
1
H NMR (CDCl
3
, 400 MHz): δ 7.82 (d, J = 7.9 Hz, 1H),
7.23-7.37 (m, 6H), 7.12-7.20 (m, 2H), 5.61 (t, J = 6.8 Hz, 1H), 2.89 (s, 3H), 2.64-2.81 (m,
191
2H), 2.48-2.57 (m, 1H), 2.05-2.15 (m, 1H).
13
C NMR (CDCl
3
, 100 MHz): δ 141.7, 136.2,
131.4, 128.6, 128.4, 127.0, 126.9, 125.9, 124.5, 123.4, 59.0, 39.0, 31.4, 25.1.
NH
S
O
O
N Ph Ph
Ph
3.69. N-{2-[(E)-1-(Dibenzylamino)-3-phenyl-2-
propenyl]phenyl}methanesulfonamide. The mixture of potassium 2-
phenylvinyltrifluoroborate 3.36 (210 mg, 1 mmol), N-(2-
formylphenyl)methanesulfonamide 3.34 (199 mg, 1 mmol) and dibenzylamine 3.12 (394
mg, 2 mmol) was sealed in a 10 mL glass vial equipped with a stirring bar and flushed
with dry nitrogen. Anhydrous toluene (2.5 mL) was injected and the resulting suspension
was stirred at room temperature for 5 min. Boron trifluoride-diethyl ether complex
(BF
3
·Et
2
O; 250 µL, 281 mg, ~2 mmol) was then added in one portion. The reaction
mixture was heated to 80
o
C, turning bright orange, and was stirred at this temperature for
18 h, cooled and worked up as described above for 3.37. TLC control (silica/EtOAc-
hexane 1:3, stained with vanillin): R
f
0.4 (3.37, gray), R
f
0.6 (3.69, gray). The products
were isolated by flash chromatography (silica, EtOAc-hexane 1:9, changed to 1:5 after
elution of 3.69), yielding 124 mg (26%) of 3.69 and 86 mg (30%) of 3.37.
3.69:
1
H NMR (CDCl
3
, 400 MHz): δ 10.65 (s, 1H), 7.72-7.76 (m, 1H), 7.55 (d, J = 7.5
Hz, 2H), 7.29-7.50 (m, 15H), 7.03-7.13 (m, 1H), 6.60-6.74 (m, 2H), 4.56 (d, J = 8.3 Hz,
1H), 3.90 (d, J = 13.1 Hz, 1H), 3.58 (d, J = 13.1 Hz, 1H), 2.58 (s, 3H).
13
C NMR (CDCl
3
,
192
100 MHz): δ 137.4, 137.2, 136.5, 136.1, 129.62, 129.59, 129.3, 128.86, 128.83, 128.77,
128.3, 127.5, 126.6, 123.9, 123.0, 120.5, 64.6, 54.3, 39.4.
NH
S
O
O
N Ph Ph
OMe Br
3.73. N-{5-Bromo-2-[(dibenzylamino)(4-
methoxyphenyl)methyl]phenyl}methanesulfonamide. The mixture of potassium 4-
methoxyphenyltrifluoroborate 3.70 (216 mg, 1 mmol), N-(5-bromo-2-
formylphenyl)methanesulfonamide 3.34 (278 mg, 1 mmol) and dibenzylamine 3.12 (394
mg, 2 mmol) was sealed in a 10 mL glass vial equipped with a stirring bar and flushed
with dry nitrogen. Anhydrous toluene (2.5 mL) was injected and the resulting suspension
was stirred at room temperature for 5 min. Chlorotrimethylsilane (260 µL, 223 mg, 2
mmol) was then added in one portion. The reaction mixture was heated to 80
o
C, turning
bright orange, and was stirred at this temperature for 18 h, cooled and worked up as
described above for 3.37. TLC control (silica/EtOAc-hexane 1:3, stained with vanillin):
R
f
0.65 (3.73, pink to orange). The product were isolated by flash chromatography (silica,
EtOAc-hexane 1:9 to 1:7), yielding 175 mg (31%) of 3.73.
1
H NMR (CDCl
3
, 400 MHz):
δ 11.06 (s, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.38-7.45 (m, 4H), 7.29-7.37 (m, 8H), 7.11 (dd,
J = 8.3 Hz, 1.8 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.3 Hz, 1H), 4.88 (s, 1H),
3.96 (d, J = 13.3 Hz, 2H), 3.92 (s, 3H), 3.51 (d, J = 13.3 Hz, 2H), 2.67 (s, 3H).
13
C NMR
193
(CDCl
3
, 100 MHz): δ 159.4, 138.7, 136.9, 132.0, 131.2, 129.6, 128.8, 128.0, 127.8, 127.7,
126.4, 122.4, 122.1, 114.2, 66.4, 55.3, 54.1, 39.6.
NH
S
O
O
N
OMe
O
3.72. N-{2-[(4-Methoxyphenyl)(4-morpholinyl)methyl]phenyl}methanesulfonamide.
Prepared similarly to 3.73 using morpholine 3.71 and N-(2-
formylphenyl)methanesulfonamide (3.34). TLC control (silica/CH
2
Cl
2
, stained with
vanillin): R
f
0.2 (3.72, pink), R
f
0.5 (3.34, yellow). The product was isolated by flash
chromatography (silica, CH
2
Cl
2
changed to EtOAc-CH
2
Cl
2
1:1 after elution of the
unreacted 3.34) and dried in vacuo to give 207 mg of viscous colorless oil, yield 55%.
Replacing morpholine with the equivalent amount of N-(trimethylsilyl)morpholine 3.84
increased the yield to 81%.
1
H NMR (CDCl
3
, 400 MHz): δ 11.60 (s, 1H), 7.47 (dd, J =
8.3 Hz, 0.8 Hz, 1H), 7.28-7.34 (m, 2H), 7.13-7.21 (m, 2H), 6.93 (td, J = 7.5 Hz, 0.8 Hz,
1H), 6.80-6.85 (m, 2H), 4.39 (s, 1H), 3.70-3.80 (m, 4H), 3.72 (s, 3H), 2.91 (s, 3H), 2.38-
2.53 (m, 4H).
13
C NMR (CDCl
3
, 100 MHz): δ 159.0, 136.5, 130.5, 130.4, 129.0, 128.4,
127.4, 123.1, 116.6, 114.0, 75.9, 66.6, 55.1, 52.0, 39.2.
194
Ph
N
Ph
O
3.76. 4-[(E)-1,3-Diphenyl-2-propenyl]morpholine. Prepared similarly to 3.73 using N-
(trimethylsilyl)morpholine 3.84 and benzaldehyde. TLC control (silica/5% EtOAc in
CH
2
Cl
2
, stained with vanillin): R
f
0.4 (gray to purple). The product was isolated by flash
chromatography (silica, CH
2
Cl
2
to 5% EtOAc in CH
2
Cl
2
) and dried in vacuo to give 97
mg of viscous colorless oil, yield 35%. Running this reaction in the absence of
triethylamine increased the yield to 47%.
1
H NMR (CDCl
3
, 400 MHz): δ 7.45-7.49 (m,
2H), 7.23-7.43 (m, 8H), 6.63 (d, J = 15.8 Hz, 1H), 6.35 (dd, J = 15.8 Hz, 8.7 Hz, 1H),
3.85 (d, J = 8.7 Hz, 1H), 3.73-3.80 (m, 4H), 2.55-2.67 (m, 2H), 2.41-2.49 (m, 2H).
13
C
NMR (CDCl
3
, 100 MHz): δ 141.5, 136.6, 131.5, 131.3, 128.6, 128.4, 127.9, 127.5, 127.2,
126.3, 74.7, 67.0, 52.1.
N
Ph
O
MeO
3.85. 4-[(E)-1-(4-Methoxyphenyl)-3-phenyl-2-propenyl]morpholine. Prepared
similarly to 3.73 using N-(trimethylsilyl)morpholine 3.84 and 4-methoxybenzaldehyde.
TLC control (silica/5% EtOAc in CH
2
Cl
2
, stained with vanillin): R
f
0.3 (pink to purple).
The product was isolated by flash chromatography (silica, 5% to 10% EtOAc in CH
2
Cl
2
)
and dried in vacuo to give 82 mg of viscous yellow oil, yield 27%.
1
H NMR (CDCl
3
, 400
195
MHz): δ 7.27-7.42 (m, 6H), 7.21-7.26 (m, 1H), 6.89-6.94 (m, 2H), 6.58 (d, J = 15.8 Hz,
1H), 6.32 (dd, J = 15.8 Hz, 8.7 Hz, 1H), 3.82 (s, 3H), 3.78 (d, J = 8.7 Hz, 1H), 3.72-3.76
(m, 4H), 2.51-2.63 (m, 2H), 2.38-2.47 (m, 2H).
13
C NMR (CDCl
3
, 100 MHz): δ 158.7,
136.7, 133.5, 131.5, 131.1, 128.9, 128.4, 127.4, 126.3, 113.9, 74.0, 67.1, 55.1, 52.1.
N
Ph
O
O
2
N
3.86. 4-[(E)-1-(4-Nitrophenyl)-3-phenyl-2-propenyl]morpholine. Prepared similarly to
3.73 using N-(trimethylsilyl)morpholine 3.84 and 4-nitrobenzaldehyde. TLC control
(silica/5% EtOAc in CH
2
Cl
2
, stained with vanillin): R
f
0.5 (brown). The product was
isolated by flash chromatography (silica, EtOAc-CH
2
Cl
2
1:50 to 1:20) and dried in vacuo
to give 68 mg of viscous orange oil, yield 21%.
1
H NMR (CDCl
3
, 400 MHz): δ 8.14-8.23
(m, 2H), 7.60-7.65 (m, 2H), 7.35-7.39 (m, 2H), 7.28-7.34 (m, 2H), 7.22-7.27 (m, 1H),
6.64 (d, J = 15.8 Hz, 1H), 6.19 (dd, J = 15.8 Hz, 9.1 Hz, 1H), 3.95 (d, J = 9.1 Hz, 1H),
3.68-3.78 (m, 4H), 2.53-2.63 (m, 2H), 2.36-2.43 (m, 2H).
13
C NMR (CDCl
3
, 100 MHz):
δ 149.4, 147.1, 136.0, 132.9, 129.4, 128.6, 128.0, 126.4, 123.9, 74.0, 66.9, 51.9.
Ph
NMe
2
Ph
3.89. (E)-N,N-Dimethyl-1,3-diphenyl-2-propen-1-amine. The mixture of potassium 2-
phenylvinyltrifluoroborate 3.36 (210 mg, 1 mmol), benzaldehyde (106 mg, 1 mmol), N-
196
(trimethylsilyl)dimethylamine 3.88 (117 mg, 1 mmol) and a stirring bar were sealed in a
10 mL glass vial, which was subsequently flushed with dry nitrogen. Anhydrous toluene
(2.5 mL) was injected followed by chlorotrimethylsilane (130 µL, 112 mg, 1 mmol). The
mixture was stirred at 80
o
C for 18 h and worked up as described for 3.73. TLC control
(silica/EtOAc-CH
2
Cl
2
2:1, stained with vanillin): R
f
0.25-0.45 (brown). The product was
isolated by flash chromatography (silica, EtOAc-CH
2
Cl
2
2:1) and dried in vacuo to give
brownish oil (114 mg, 48%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.24-7.53 (m, 10H), 6.67 (d,
J = 15.8 Hz, 1H), 6.48 (dd, J = 15.8 Hz, 8.7 Hz, 1H), 3.81 (d, J = 8.7 Hz, 1H), 2.36 (s,
6H).
13
C NMR (CDCl
3
, 100 MHz): δ 142.2, 136.8, 131.8, 131.0, 128.5, 128.4, 127.7,
127.4, 127.1, 126.3, 75.3, 43.8.
NMe
2
Ph
MeO
MeO
3.91. (E)-1-(3,4-Dimethoxyphenyl)-N,N-dimethyl-3-phenyl-2-propen-1-amine.
Prepared similarly to 3.89 using 3,4-dimethoxybenzaldehyde. TLC control
(silica/CH
2
Cl
2
-methanol 100:3, stained with vanillin): R
f
0.3 (bright blue). The product
was isolated by flash chromatography (silica, CH
2
Cl
2
, changed to CH
2
Cl
2
-methanol
100:3 after elution of the unreacted benzaldehyde) and found contaminated with 2-
phenylvinylboronic acid. Re-purified on a short column (silica, 5% Et
3
N in CH
2
Cl
2
) and
dried in vacuo to give yellow oil (77 mg, 26%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.51-7.56
(m, 2H), 7.43-7.48 (m, 2H), 7.34-7.39 (m, 1H), 7.15 (d, J = 1.7 Hz, 1H), 7.07 (dd, J = 8.3
Hz, 1.7 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 15.8 Hz, 1H), 6.53 (dd, J = 15.8
197
Hz, J = 8.7 Hz, 1H), 4.08 (s, 3H), 4.03 (s, 3H), 3.81 (d, J = 8.7 Hz, 1H), 2.42 (s, 6H).
13
C
NMR (CDCl
3
, 100 MHz): δ 149.0, 148.0, 136.8, 135.0, 131.9, 130.7, 128.4, 127.3, 126.2,
119.8, 110.9, 110.3, 75.0, 55.8, 55.7, 43.8.
N
Ph
O
Ph
3.93. 4-[(E)-1-Phenethyl-3-phenyl-2-propenyl]morpholine. Prepared similarly to 3.89
using hydrocinnamaldehyde 3.92 (tech., 90%; 150 mg, ~1 mmol) and N-
(trimethylsilyl)morpholine 3.84. TLC control (silica/EtOAc-hexane 1:3, stained with
basic KMnO
4
): R
f
0.3. The product was isolated by flash chromatography (silica, EtOAc-
hexane 1:3) and dried in vacuo to give light-yellow oil (69 mg, 22%).
1
H NMR (CDCl
3
,
400 MHz): δ 7.22-7.49 (m, 10H), 6.54 (d, J = 15.8 Hz, 1H), 6.23 (dd, J = 15.8 Hz, J = 9.1
Hz, 1H), 3.74-3.84 (m, 4H), 2.95-3.03 (m, 1H), 2.55-2.84 (m, 6H), 2.10-2.20 (m, 1H),
1.84-1.95 (m, 1H).
13
C NMR (CDCl
3
, 100 MHz): δ 142.1, 136.7, 133.3, 129.0, 128.5,
128.4, 128.3, 127.5, 126.3, 125.7, 67.4, 67.2, 50.3, 33.5, 32.4.
N
Ph
O
N
Ph
O
OH
4-[(E)-1-Butyl-3-phenyl-2-propenyl]morpholine (3.95) and (E)-3-(4-morpholinyl)-1-
phenyl-4-propyl-1-nonen-5-ol (3.114). Prepared similarly to 3.89 using valeraldehyde
198
3.94 (103 mg, 1.2 mmol, 1.2 eq) and N-(trimethylsilyl)morpholine 3.84. TLC control
(silica/EtOAc-hexane 1:3, stained with basic KMnO
4
): R
f
0.25 (3.95), R
f
0.35 (3.114).
The products were isolated by flash chromatography (silica, EtOAc-hexane 1:3),
collecting 3.114 (15 mg, 4.3%) and 3.95 (66 mg, 25%) as yellow oils. Running this
reaction with 2.2 eq of aldehyde gives 7.5% of 3.114 and 31% of 3.95.
3.95:
1
H NMR (CDCl
3
, 400 MHz): δ 7.36-7.41 (m, 2H), 7.29-7.35 (m, 2H), 7.21-7.26 (m,
1H), 6.44 (d, J = 15.8 Hz, 1H), 6.10 (dd, J = 15.8 Hz, J = 8.7 Hz, 1H), 3.67-3.78 (m, 4H),
2.81-2.88 (m, 1H), 2.59-2.67 (m, 2H), 2.49-2.57 (m, 2H), 1.68-1.79 (m, 1H), 1.45-1.56
(m, 1H), 1.20-1.40 (m, 4H), 0.86-0.93 (m, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 136.8,
132.7, 129.8, 128.5, 127.3, 126.2, 68.4, 67.2, 50.5, 31.5, 28.4, 22.7, 14.0.
3.114:
1
H NMR (CDCl
3
, 400 MHz): δ 7.43-7.47 (m, 2H), 7.35-7.40 (m, 2H), 7.27-7.33
(m, 1H), 6.56 (d, J = 15.8 Hz, 1H), 6.36 (dd, J = 15.8 Hz, J = 10.0 Hz, 1H), 3.65-3.80 (m,
5H), 3.06 (dd, J = 10.0 Hz, J = 2.5 Hz, 1H), 2.43-2.86 (br.m, 4H), 1.92-2.00 (m, 1H),
1.08-1.68 (m, 12H), 0.90-0.98 (m, 6H).
13
C NMR (CDCl
3
, 100 MHz): δ 136.3, 134.9,
128.7, 127.9, 126.4, 126.1, 73.5, 71.8, 67.0, 52.5, 40.9, 35.7, 30.3, 27.4, 23.0, 20.9, 14.2.
N
Ph
O
3.97. 4-[(E)-1-Isopropyl-3-phenyl-2-propenyl]morpholine. Prepared similarly to 3.89
using isobutyraldehyde 3.96 (158 mg, 2.2 mmol, 2.2 eq) and N-
(trimethylsilyl)morpholine 3.84. TLC control (silica/EtOAc-hexane 1:3, stained with
199
basic KMnO
4
): R
f
0.3. The product was isolated by flash chromatography (silica, EtOAc-
hexane 1:3) and dried in vacuo to give light-yellow oil (63 mg, 26%).
1
H NMR (CDCl
3
,
400 MHz): δ 7.37-7.41 (m, 2H), 7.30-7.35 (m, 2H), 7.21-7.26 (m, 1H), 6.42 (d, J = 16.2
Hz, 1H), 6.08 (dd, J = 16.2 Hz, J = 9.6 Hz, 1H), 3.66-3.76 (m, 4H), 2.56-2.64 (m, 2H),
2.43-2.54 (m, 3H), 1.99 (octet, J = 6.6 Hz, 1H), 0.98 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6
Hz, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 137.0, 133.6, 128.5, 127.9, 127.3, 126.2, 74.4,
67.3, 50.6, 28.0, 20.3, 18.3.
N
Ph
O
3.99. 4-[(E)-1-(1-Ethylpropyl)-3-phenyl-2-propenyl]morpholine. Prepared similarly to
3.89 using 2-ethylbutyraldehyde 3.98 (220 mg, 2.2 mmol, 2.2 eq) and N-
(trimethylsilyl)morpholine 3.84. TLC control (silica/5% EtOAc in hexane, stained with
vanillin): R
f
0.3 (bluish-gray). The product was isolated by flash chromatography (silica,
5% to 10% EtOAc in hexane) and dried in vacuo to give light-yellow oil (66 mg, 24%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.35-7.40 (m, 2H), 7.28-7.35 (m, 2H), 7.20-7.26 (m, 1H),
6.41 (d, J = 15.8 Hz, 1H), 6.06 (dd, J = 15.8 Hz, J = 9.6 Hz, 1H), 3.65-3.75 (m, 4H),
2.69-2.77 (m, 1H), 2.55-2.63 (m, 2H), 2.39-2.48 (m, 2H), 1.58-1.69 (m, 2H), 1.43-1.56
(m, 1H), 1.23-1.35 (m, 1H), 1.10-1.22 (m, 1H), 0.87-0.96 (m, 6H).
13
C NMR (CDCl
3
,
100 MHz): δ 137.0, 133.2, 128.5, 128.3, 127.3, 126.2, 70.3, 67.4, 50.6, 40.7, 29.7, 21.7,
21.6, 11.5, 10.8.
200
N
O
Ph
3.101. 4-[(E)-1-Cyclopentyl-3-phenyl-2-propenyl]morpholine. Prepared similarly to
3.89 using cyclopentanecarbaldehyde 3.100 (216 mg, 2.2 mmol, 2.2 eq) and N-
(trimethylsilyl)morpholine 3.84. TLC control (silica/EtOAc-hexane 1:5, stained with
vanillin): R
f
0.3 (blue). The product was isolated by flash chromatography (silica, EtOAc-
hexane 1:5) and dried in vacuo to give light-yellow oil (95 mg, 35%).
1
H NMR (CDCl
3
,
400 MHz): δ 7.26-7.31 (m, 2H), 7.19-7.25 (m, 2H), 7.10-7.16 (m, 1H), 6.31 (d, J = 16.2
Hz, 1H), 6.04 (dd, J = 16.2 Hz, J = 9.5 Hz, 1H), 3.54-3.66 (m, 4H), 2.54-2.64 (m, 3H),
2.34-2.41 (m, 2H), 2.09 (sextet, J = 7.9 Hz, 1H), 1.62-1.72 (m, 1H), 1.33-1.59 (m, 6H),
1.08-1.20 (m, 1H).
13
C NMR (CDCl
3
, 100 MHz): δ 136.9, 133.0, 128.4, 128.1, 127.2,
126.2, 72.7, 67.3, 50.0, 40.6, 30.1, 29.6, 25.4, 25.2.
N
Ph
O
3.103. 4-[(E)-1-(tert-Butyl)-3-phenyl-2-propenyl]morpholine. Prepared similarly to
3.89 using trimethylacetaldehyde 3.102 (189 mg, 2.2 mmol, 2.2 eq) and N-
(trimethylsilyl)morpholine 3.84. TLC control (silica/EtOAc-hexane-Et
3
N 1:9:0.03,
stained with basic KMnO
4
): R
f
0.55. The product was isolated by flash chromatography
(silica, EtOAc-hexane-Et
3
N 1:9:0.03) and dried in vacuo to give white solid (40 mg,
201
15%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.38-7.43 (m, 2H), 7.31-7.37 (m, 2H), 7.22-7.27
(m, 1H), 6.44 (d, J = 15.8 Hz, 1H), 6.28 (dd, J = 15.8 Hz, J = 9.6 Hz, 1H), 3.64-3.75 (m,
4H), 2.70-2.77 (m, 2H), 2.55 (d, J = 9.6 Hz, 1H), 2.44-2.51 (m, 2H), 0.97 (s, 9H).
13
C
NMR (CDCl
3
, 100 MHz): δ 137.1, 134.0, 128.5, 127.3, 126.3, 126.1, 77.0, 67.6, 52.6,
35.9, 27.4.
F
3
C
N
O
Cl
3.105. 4-[(E)-3-(4-Chlorophenyl)-1-(trifluoromethyl)-2-propenyl]morpholine.
Prepared similarly to 3.89 using trifluoroacetaldehyde methyl hemiacetal 3.104 (130 mg,
1 mmol), N-(trimethylsilyl)morpholine 3.84 and 2 eq of chlorotrimethylsilane. TLC
control (silica/EtOAc-hexane 1:8, stained with vanillin): R
f
0.3 (yellowish). The product
was isolated by flash chromatography (silica, EtOAc-hexane 1:8) and dried in vacuo to
give light yellow oil (100 mg, 33%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.29-7.36 (m, 4H),
6.68 (d, J = 15.8 Hz, 1H), 6.16 (dd, J = 15.8 Hz, J = 8.3 Hz, 1H), 3.68-3.77 (m, 4H), 3.60
(quintet, J = 8.3 Hz, 1H), 2.69-2.81 (m, 4H).
13
C NMR (CDCl
3
, 100 MHz): δ 136.2,
134.1, 128.8, 127.9, 125.6 (quartet, J = 285.6 Hz), 119.2, 68.4 (quartet, J = 27.1 Hz), 67.2,
50.3.
19
F NMR (376 MHz, CDCl
3
): δ -69.59.
202
N
Ph
O
O
N
O
4-[(E)-1-Cyclopropyl-3-phenyl-2-propenyl]morpholine (3.107) and 3-cyclopropyl-2-
[2-(4-morpholinyl)ethyl]-2-propenal (3.120). The mixture of potassium 2-
phenylvinyltrifluoroborate 3.36 (210 mg, 1 mmol), cyclopropanecarbaldehyde 3.106 (154
mg, 2.2 mmol, 2.2 eq), N-(trimethylsilyl)morpholine 3.84 (159 mg, 1 mmol) and a
stirring bar were sealed in a 10 mL glass vial, which was subsequently flushed with dry
nitrogen. Anhydrous toluene (2.5 mL) was injected followed by chlorotrimethylsilane
(130 µL, 112 mg, 1 mmol). The mixture was stirred at 80
o
C for 18 h and worked up as
described for 3.73, using sat. aqueous NaCl instead of water for extraction. TLC control
(silica/5% methanol in EtOAc, stained with basic KMnO
4
): R
f
0.65 (3.107), R
f
0.4
(3.120). The products were isolated by flash chromatography (silica, EtOAc-hexane 1:3
to pure EtOAc, changed to 5% methanol in EtOAc after elution of 3.107), and crude
3.107 and 3.120 were re-purified by preparative TLC (silica/EtOAc) to yield pure 3.107
(6 mg, 2.5%) and 3.120 (41 mg, 20%). The geometry of the double bond in 3.120 was not
established.
3.107:
1
H NMR (CDCl
3
, 400 MHz): δ 7.39 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H),
7.20-7.23 (m, 1H), 6.40 (d, J = 15.8 Hz, 1H), 6.20 (dd, J = 15.8 Hz, J = 8.7 Hz, 1H),
3.70-3.80 (m, 4H), 2.70-2.83 (m, 2H), 2.55-2.65 (m, 2H), 2.00 (t, J = 8.7 Hz, 1H), 0.84-
0.95 (m, 1H), 0.67-0.77 (m, 1H), 0.45-0.55 (m, 1H), 0.35-0.44 (m, 1H), 0.07-0.15 (m,
203
1H).
13
C NMR (CDCl
3
, 100 MHz): δ 136.9, 131.6, 130.6, 128.5, 127.4, 126.3, 74.2, 67.1,
52.0, 13.4, 7.3, 2.2.
3.120:
1
H NMR (CDCl
3
, 400 MHz): δ 9.24 (s, 1H), 5.79 (d, J = 10.8 Hz, 1H), 3.65-3.70
(m, 4H), 2.50-2.56 (m, 2H), 2.43-2.50 (m, 2H), 2.33-2.39 (m, 2H), 1.76-1.86 (m, 1H),
1.05-1.11 (m, 2H), 0.68-0.74 (m, 2H).
13
C NMR (CDCl
3
, 100 MHz): δ 193.7, 161.0,
139.4, 66.9, 57.3, 53.5, 21.4, 12.3, 9.6.
N
O
Ph
3.109. 4-(1-Isopropyl-3-phenyl-2-propynyl)morpholine. Prepared similarly to 3.89
using isobutyraldehyde 3.96 (158 mg, 2.2 mmol, 2.2 eq), N-(trimethylsilyl)morpholine
3.84 (159 mg, 1 mmol) and potassium 2-phenylethynyltrifluoroborate (208 mg, 1 mmol).
TLC control (silica/10% EtOAc in hexane, stained with vanillin): R
f
0.35 (brown-orange).
The product was isolated by flash chromatography (silica, 10% EtOAc in hexane) and
dried in vacuo to give colorless crystals (186 mg, 77%).
1
H NMR (CDCl
3
, 400 MHz): δ
7.46-7.52 (m, 2H), 7.29-7.37 (m, 3H), 3.73-3.85 (m, 4H), 3.06 (d, J = 9.5 Hz, 1H), 2.71-
2.78 (m, 2H), 2.52-2.60 (m, 2H), 1.89-2.02 (m, 1H), 1.17 (d, J = 6.6 Hz, 3H), 1.08 (d, J =
6.6 Hz, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 131.5, 128.1, 127.7, 123.2, 86.6, 86.5, 67.1,
65.0, 49.8, 29.8, 20.2, 19.7.
204
NMe
2
Ph
3.110. N,N-Dimethyl-1-phenyl-1-heptyn-3-amine. Prepared similarly to 3.89 using
valeraldehyde 3.94 (190 mg, 2.2 mmol, 2.2 eq) and potassium 2-
phenylethynyltrifluoroborate (208 mg, 1 mmol). TLC control (silica/20% EtOAc in
hexane, stained with vanillin): R
f
0.2 (brown to gray). The product was isolated by flash
chromatography (silica, EtOAc-hexane 1:5 to EtOAc-hexane-Et
3
N 1:4:0.02) and dried in
vacuo to give yellowish oil (117 mg, 54%).
1
H NMR (CDCl
3
, 400 MHz): δ 7.45-7.50 (m,
2H), 7.30-7.35 (m, 3H), 3.56 (t, J = 7.5 Hz, 1H), 2.37 (s, 6H), 1.68-1.78 (m, 2H), 1.36-
1.62 (m, 4H), 0.94-1.00 (m, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 131.6, 128.1, 127.7,
123.3, 86.8, 85.9, 58.1, 41.3, 33.6, 28.8, 22.4, 14.0.
N
O
Ph
Ph Ph
3.112. 4-(1-Benzhydryl-3-phenyl-2-propynyl)morpholine. Prepared similarly to 3.89
using diphenylacetaldehyde 3.111 (235 mg, 1.2 mmol, 1.2 eq) and potassium 2-
phenylethynyltrifluoroborate (208 mg, 1 mmol). White crystals, yield 130 mg (35%).
1
H
NMR (CDCl
3
, 400 MHz): δ 7.27-7.52 (m, 15H), 4.35-4.42 (m, 2H), 3.69-3.77 (m, 2H),
3.60-3.68 (m, 2H), 2.84-2.91 (m, 2H), 2.67-2.75 (m, 2H).
13
C NMR (CDCl
3
, 100 MHz):
δ 142.6, 141.8, 131.7, 129.0, 128.5, 128.4, 128.3, 128.2, 128.1, 126.7, 126.3, 123.2, 88.4,
85.9, 67.1, 62.2, 54.0, 49.8.
205
N
Ph
O
Ph
OH
Ph
3.117. (E)-4-(4-Morpholinyl)-1,3,6-triphenyl-5-hexen-2-ol. Prepared similarly to 3.89
using phenylacetaldehyde 3.116 (264 mg, 2.2 mmol, 2.2 eq) and N-
(trimethylsilyl)morpholine 3.84. TLC control (silica/EtOAc-hexane 1:3, stained with
vanillin): R
f
0.25 (blue-gray). The product was isolated by flash chromatography (silica,
EtOAc-hexane 1:3) and dried in vacuo to give light yellow oil (17 mg, 4.1%).
1
H NMR
(CDCl
3
, 400 MHz): δ 7.20-7.40 (m, 13H), 7.13-7.18 (d, J = 7.1 Hz, 1H), 6.46 (dd, J =
15.8 Hz, J = 9.6 Hz, 1H), 6.04 (d, J = 15.8 Hz, 1H), 4.62-4.70 (m, 1H), 3.72-3.82 (m, 4H),
3.33-3.39 (m, 1H), 3.01-3.07 (m, 1H), 2.68-2.82 (m, 2H), 2.55-2.67 (m, 2H), 2.49 (dd, J
= 13.7 Hz, J = 7.9 Hz, 1H).
13
C NMR (CDCl
3
, 100 MHz): δ 139.4, 139.1, 136.2, 136.1,
129.6, 129.5, 128.6, 128.1, 128.0, 127.9, 126.8, 126.4, 126.0, 124.5, 75.4, 73.0, 66.8, 52.5,
49.0, 42.0.
206
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61
Aube, B.; Christot, I., Combret, J.-C.; Klein, J.-L. Bull. Soc. Chim. Fr. 1988, 1009.
62
Schroth, W.; Jahn, U.; Ströhl, D. Chem. Ber. 1994, 127, 2013.
63
Brill, W. K.-D.; Nielsen, J.; Caruthers, M. H. J. Am. Chem. Soc. 1991, 113, 3972.
64
Lebedev, A. V.; Lebedeva, A. B.; Sheludyakov, V. D.; Ovcharuk, S. N.; Kovaleva, E.
A.; Ustinova, O. L. Russ. J. Gen. Chem. 2006, 76, 469.
65
Kim, S. S.; Rajagopal, G. Synthesis 2007, 215.
66
van der Maeden, F. P. B.; Steinberg, H.; De Boer, T. J. Rec. Trav. Chim. 1971, 90, 423.
67
Myslinska, Malgorzata. “New organoboron based multicomponent methodologies for
the synthesis of novel heterocycles” Ph.D. thesis, University of Southern California,
2009.
68
Petasis, N. A.; Myslinska, M.; Butkevich, A. N., “One-step three-component reactions
of organotrifluoroborates with carbonyls and amine derivatives,” 237th American
Chemical Society National Meeting, Salt Lake City, UT, March 22-26, 2009, ORGN-
310.
69
Nishiguchi, A.; Ikemoto, T.; Ito, T.; Miura, S.; Tomimatsu, K. Heterocycles 2007, 71,
1183.
210
70
Sheldrick, G. M. SHELXTL, version 6.14; Bruker Analytical X-ray System, Inc.,
Madison, WI, 1997.
71
Blessing, R. H. Acta Crystallogr. 1995, A51, 33.
211
Chapter 4. Synthesis of cytostatic propiolamide
pseudodipeptides by Ugi reaction and investigation into their
mechanism of action.
4.1 Introduction. Classical Passerini and Ugi reactions. Ugi reaction with
unusual partners.
Isocyanide-based multicomponent reactions (MCRs) have played tremendous role
in drug discovery.
1
Their major advantage, the ability to quickly introduce molecular
diversity and generate a large set of drug-like compounds containing amide functionality,
made them especially appreciated in 1990’s, when combinatorial chemistry approaches
were developed and widely accepted in pharmaceutical industry, and the MCRs such as
Ugi four-component condensation (4CC) became a cornerstone in the synthesis of
peptidomimetics and, in their intramolecular versions, heterocycles. The simplicity of the
multicomponent strategy allowed for relatively quick transitions from initial hit
identification (4.1) to optimized molecule (4.2) to clinical candidate (4.3), as can be
illustrated with the following example of development of G-protein coupled β-chemokine
receptor type 5 (CCR5) antagonists (Scheme 4.1)
1
.
212
N
O
R
1
+
R
4
N
Boc
CO
2
H
R
3
+ R
2
NH
2
+ NC
4CC
N
R
1
O
N
R
2
O
N
Boc
R
4
R
3
N
R
1
N
N
R
2
O R
4
O
R
3
N
NH
N
O
O
Ph 6
N
NH
N
O
O
O
O
N
NH
N
O
O
HO
O
HO
2
C
4.1
4.2
4.3
Scheme 4.1.
While a variety of multicomponent reactions employing isocyanide as one of the
components has been described in the literature, most of them are stemming from very
similar Passerini (3CC) or Ugi (4CC) reactions.
Passerini reaction (a three-component condensation of isonitriles, aldehydes or
ketones, and carboxylic acids, described in 1921 by Mario Passerini) was the first
isocyanide-based multicomponent reaction reported in the literature
2
(Scheme 4.2).
NC
N
N
Ph
+
O
+
O
OH
H
N
N
N
Ph
O
O
O
Scheme 4.2.
The reaction begins with the protonation of a carbonyl compound followed by
nucleophilic addition of isonitrile. The carboxylate nucleophile then attacks the
213
intermediate nitrilium ion followed by the acyl group transfer, which is the irreversible
step (Scheme 4.3).
R
1
O
R
2
R
3
O
OH
R
3
O
O
R
1
OH
R
2
R
4
NC
R
1
OH
R
2
N
R
4
R
1
R
2
O
R
1
R
2
O
NR
4
OH
R
3 O
O
NHR
4
R
3
O
Scheme 4.3.
A different mechanism (concerted, trimolecular reaction with five-membered transition
state) has been suggested possible at high concentrations in non-polar solvents.
3
Imines react similarly to carbonyl compounds and do not need to be pre-formed,
and the resulting combination of a primary amine, aldehyde (or ketone), carboxylic acid
and isonitrile interact in Ugi reaction (first reported in 1961 by Ivar Karl Ugi) according
to a similar mechanism. As with Passerini reaction, the final acyl transfer (Mumm
rearrangement) is irreversible (Scheme 4.4).
214
R
1
N
R
2
R
1
O
R
2
+
R
3
NH
2
R
3
R
4
O
OH
R
4
O
O
R
1
NH
R
2
R
5
NC
R
1
NH
R
2
N
R
5
R
1
R
2
O
R
1
R
2
N
NR
5
NH
R
4 O
O
NHR
5
R
4
O
R
3
R
3
R
3
R
3
Scheme 4.4.
As can be expected from an intermolecular process, this reaction gives better results
when run at higher concentrations. The usual recommendation is running Ugi reaction at
1.0 M concentration or above in polar protic solvents (alcohols). 2,2,2-Trifluoroethanol
has been reported to perform particularly well.
4
By themselves, Ugi reaction products represent useful diamide scaffolds that can
be further transformed to heterocycles, for example:
5
R
1
O
N
H
R
2
O
H
N
R
3
R
1
O
N
R
2
O
H
N
R
3
OMe MeO
TFA
CH
2
Cl
2
TFA-TFAA
N
O
NH
R
3
R
1
R
2
Lawesson's
reagent
N
S
NH
R
3
R
1
R
2
R
1
O
N
R
2
O
H
N
R
3
R
2
OMe
4.4
Scheme 4.5.
215
Use of ammonia as an amine component in Ugi reaction was found
disadvantageous, as hemiaminal products (4.4 for the reaction run in methanol) were
formed in this case, necessitating the use of 2,4-dimethoxybenzylamine as a protected
ammonia equivalent and subsequent deprotection.
Another simple way of transformation of Ugi products into heterocycles is
intramolecular C- or N-alkylation or arylation, affording azetidinones,
6
diketopiperazines,
7
benzodiazepines and benzoxazepines,
8
and isoindolones
9
(Scheme
4.6).
O
N
R
3
O
NHR
4
R
2
Cl
N
O R
2
Ph
N
H
O
R
4
N
N
O
O
R
3
R
2
R
4
R
3
= Ph-CH=CH-
O
2
N
F
N
O
R
2
R
3
NHR
4
O
B
B
X
N
O R
3
NHR
4
O
R
O
2
N
n
N
O
2
N
O
R
2
R
3
NHR
4
O
B
B
R
2
= -(CH
2
)
n
-XHR
X = O, NH; n = 0, 2, 3
Scheme 4.6.
The modifications of the Ugi reaction included either formation of cyclic products
by incorporating two or even three of the reaction partners in a single starting material,
resulting in formation of cyclic amides, or by variation of the reaction partners, most
commonly replacing a carboxylic acid with another proton source.
10
Of special interest
(due to their structural similarity to β-lactame antibiotics) are β-lactame products that can
be obtained from β-amino acids and β-ketocarboxylic acids generally in moderate to
good yields. Many tandem reaction combinations have also been studied, such as Ugi-
Diels-Alder,
11
Ugi-Knoevenagel,
12
Ugi-Buchwald-Hartwig
13
or Ugi-Heck
14
reactions,
216
where the product of the multicomponent step underwent further intramolecular
cycloaddition or coupling reaction.
The extension of Ugi methodology to unusual reaction partners allows to
significantly extend the list of possible 4CC reaction products beyond the regular
diamides. The first observations of the use of nucleophiles other than carboxylate were
reported by Ugi himself in 1962
15
(Scheme 4.7).
R
1
O
R
2
+
R
3
NH
R
4
H
+
R
1
N
R
2
R
4
R
3
R
5
NC
N
3
-
R
4
N
R
3
R
1
R
2
N
N
3
R
5
N
N
N
N
R
5 R
1
R
2
N
R
3
R
4
R
5
NC
NCX
-
X = O, S
H
N
R
3
R
1
R
2
N
N
R
5
C
X
R
4
= H
N
H
N
R
3
NR
5
X
R
1
R
2
R
5
NC
HSe
-
R
4
N
R
3
R
1
R
2
N
H
Se
R
5
R
5
NC
S
2
O
3
-
R
4
N
R
3
R
1
R
2
N
S
R
5
SO
3
-
R
4
N
R
3
R
1
R
2
N
H
S
R
5
Scheme 4.7.
More examples have been reported in the publications that followed. For example,
use of thioacids instead of carboxylic acids offers thioamides
16
(Scheme 4.8).
R
1
N
R
2
R
1
O
R
2
+
R
3
NH
2
R
3
R
4
O
SH R
5
NC N
R
1
R
2
S
NHR
5
R
3
O
R
4
,
see Scheme 4.4
Scheme 4.8.
Carbon dioxide in methanol can act as a carboxyl component (an equivalent of
methoxyformic acid) in Ugi reaction, resulting in formation of carbamates.
17
These
products can be then cyclized into hydantoines under basic conditions; however, better
217
results have been obtained on basic cyclization of the corresponding
trichloroacetamides
18
(Scheme 4.9).
R
1
O
+ R
2
NH
2
+ CO
2
+ R
3
NC
MeOH
N
O
NHR
3
R
2
O
MeO
R
1
R
1
O
+ R
2
NH
2
++ R
3
NC
Cl
3
C
O
OH
MeOH
N
O
NHR
3
R
2
O
Cl
3
C
R
1
N
N
R
2
O
R
3
O
R
1
NaOH
EtOH
B
Scheme 4.9.
Another important variation is the Ugi-Smiles reaction, in which an acidic phenol
is taken as a nucleophile (and as a proton source) instead of carboxylic acid. In this
transformation, the final irreversible Mumm rearrangement step is replaced with Smiles
rearrangement, which proceeds through a Meisenheimer-type complex and therefore
requires at least one strong electron-withdrawing group in ortho- or para-position to OH-
group of phenol. Thiophenols give thioamides, similarly to the reaction shown in Scheme
4.8. 2-Hydroxy- and 2-mercaptopyridines (with electron-withdrawing group in 5-position)
and similar heterocycles (pyrimidines, triazoles, benzothiazoles) perform equally well
19-21
(Scheme 4.10).
218
R
1
N
R
2
XH
R
1
NH
R
2
R
4
NC
R
1
NH
R
2
N
R
4
R
1
O
R
2
+
R
3
NH
2
R
3
R
3 R
3
O
2
N
X
O
2
N
R
1
NH
R
2
R
3
NO
2
R
1
R
2
N
NR
4
X
NO
2
N X
R
3
R
1
R
2
NR
4
NHR
4
X
R
3
NO
2
Scheme 4.10.
Lewis acids can be used instead of Brønsted acids to promote the formation of
iminium species in the Ugi reaction. In this case, if anhydrous solvents are used, the
initial iminoester products of the three-component condensation can be isolated, while in
protic solvents the corresponding amides form upon hydrolysis
17,22
(Scheme 4.11).
R
1
O
+ + R
4
NC
R
2
NH
R
3
ROH
BF
3
Et
2
O
R
3
N
R
2
N
OR
R
4
R
1
H
+
, H
2
O
R
3
N
R
2
N
H
O
R
4
R
1
Scheme 4.11.
Just as amines, hydrazines participate in Ugi-type reactions, giving the products
of four- or three-component
23,24
(in case of trisubstituted hydrazines) condensation.
Hydrazones
25
and semicarbazones
26
can be introduced in the reaction instead of the
mixture of an aldehyde and a hydrazine derivative. Further variations, such as the use of
219
non-carboxylate nucleophiles or intramolecular Ugi reaction, have been developed
(Scheme 4.12).
NNH + CH
2
O + NC
HCl, MeOH
NN
H
2
C
O
HN
87%
NNH++ NC
R
1
R
2
O
HN
3
, MeOH
NN
R
1
R
2
N
N
N
N
26-62%
HO
2
C
O
N
H
N
t-BuCN, i-PrOH, 50
o
C
N
NH
O
O
O
NHt-Bu
72%
H
2
N
O
N
H
N R
1
R
2
R
3
O
CO
2
H ++ R
4
NC
MeOH
HN
N
NHR
4
O
O
O
R
3
O
NH
2
R
1
R
2
46-73%
Scheme 4.12.
Classical four-component Ugi reactions with O-alkylhydroxylamines
27
and N-
alkylhydroxylamines
28
have been reported. Recently, a variation of the Ugi reaction with
N-methylhydroxylamine was developed to yield α-ketoamides in moderate to high yields
by elimination of acetic acid from the intermediate Ugi products
29
(Scheme 4.13).
220
R
1
O
+ R
2
NC
MeNHOH HCl
AcOH
MeOH, RT
Me
N
OAc
R
1
O
NHR
2
- AcOH
Me
N
R
1
O
NHR
2
H
+
O
R
1
O
NHR
2
R
1
N
Me O
R
1
N
Me O
N
R
2
R
1
N
Me OH
NR
2
OAc
- MeNH
2
Scheme 4.13.
More examples of atypical Ugi reactions are covered in the comprehensive review.
16
The scope and practicality of the Ugi reaction may be further extended with
development of the methods of selective cleavage of either or both amide bonds, turning
this reaction into a convenient method of preparation of N-monosubstituted α-amino
acids and their protected analogs. Some cleavable carboxylic acid and isocyanide partners
have been introduced, with known limitations. Ugi adducts from α-ketocarboxylic acids
can be hydrolyzed with methanolic KOH yielding N-arylglycines
30
(Scheme 4.14).
Ar
1 O
+
Ar
2
NH
2
+
R
1
CO
2
H
O
+
R
2
NC
MeOH
RT, 2 d
R
1
O
N
O
Ar
2
Ar
1
NHR
2
O KOH, MeOH
RT, 2 h
H
N
Ar
2
CO
2
H
Ar
1
+
R
1
O
O
NHR
2
Scheme 4.14.
1-Cyclohexenyl isocyanide (4.5),
31
2-isocyanophenyl 4-methoxybenzoate (4.6),
32
2-isocyano-2-methylpropyl phenyl carbonate (4.7)
33
and 1-isocyano-2-(2,2-
dimethoxyethyl)benzene (4.8)
34
(Figure 4.1) have been proposed as “convertible”
isonitriles, leaving an amide group of the product cleavable to a carboxylic acid
221
derivative under specific conditions. Other isonitriles, containing a branched alkyl group,
such as 1,1,3,3-tetramethylbutyl isocyanide (4.9, Walborsky reagent)
35
or even tert-butyl
isocyanide
36
in some cases, are capable of protolytic dealkylation leaving a primary
amide group:
NC
O
NC
NC
OMe
OMe
NC
4.5 4.7 4.8 4.9
O
PhO
NC
O
O
OMe
4.6
Figure 4.1. Examples of “convertible” isocyanides.
O
N
MeO
Ph
O
H
N
HCl (1.7%)
THF - H
2
O
RT, overnight
O
N
MeO
Ph
CO
2
H
83%
AcCl (5 eq)
MeOH
55
o
C, 3 h
O
N
MeO
Ph
CO
2
Me
100%
Ph
O
N
Ph
O
H
N
t-BuOK
4 MS, THF
0
o
C, 10 min
O
O
OPh
Å
Ph
O
N
Ph
O
N
O
O
83%
RSH (5 eq)
BuLi (2 eq)
THF
0
o
C, 10 min
Ph
O
N
Ph
O
83%
SR
N
R
O
N
H
O
OMe
OMe
CSA (0.5 eq)
C
6
H
6
, 80
o
C
N
R
O
N
O
96%
Cs
2
CO
3
(1 eq)
DMF - H
2
O
N
R
O
CO
2
H
97%
N
N
NH
2
+
OMe
O
+ NC
ZrCl
4
(10 mol%)
n-BuOH, W, 140
o
C
7 min
µ
HBF
4
(1 eq)
W, 160
o
C
20 min
µ
N
N
N
NH
2
OMe
95%
Scheme 4.15.
222
The major drawback of the Ugi reaction is the lack of efficient realization of its
enantioselective version. The typical approach to prepare chiral α-amino acid derivatives
by Ugi reaction would be to use chiral (for example, sugar-derived) amines and
“convertible” isonitriles in the four-component condensation, isolate the pure major
diastereoisomer and get rid of the sugar and isonitrile auxiliaries by hydrolysis.
37
However, apart from the possible separation difficulties, this method requires several
extra steps and is very atom-inefficient.
4.2 Discovery of cytotoxic propiolamide pseudodipeptides and resynthesis
of the initial set of 19 compounds.
Cytotoxic drugs remain central to the modern antineoplastic chemotherapy,
usually as a part of certain standardized multi-agent treatment regimes (protocols)
developed for a particular kind of cancer. In general, tumor cells fall into three different
categories: 1) terminally differentiated, non-dividing cells; 2) cells that continue to
proliferate (grow and divide); 3) resting cells that are not actively dividing but may be
recruited back into the process of cell division. This cell division process is named cell
cycle and includes four distinct phases: G
1
(gap 1, during which the cell grows and
prepares for DNA synthesis), S (synthesis phase, during which DNA replication takes
place), G
2
(gap 2, the cell continues to grow and prepares for mitosis) and M (mitosis, the
orderly cell division in two, which itself is a complex process including several phases
finished by cytokinesis, physical separation of the two newly formed cells). There are
several checkpoints in the cell cycle, ensuring the readiness of the cell to enter the next
step and especially the integrity of the genetic material.
38
During the G
1
phase, up until
223
certain point, the cell may exit the division cycle and become resting (termed G
0
phase).
The cells that are fully differentiated or have exceeded a certain number of allowed
divisions (so-called Hayflick limit, 40 to 60 for human fetal cells) do not return into the
cell cycle from G
0
phase.
39,40
Cytotoxic agents mostly affect actively dividing cells, and depending on their
mechanism of action they may induce their effects during the particular phase of cell
cycle, or may be cell-cycle-nonspecific. Antimetabolites (e.g., 5-fluorouracil,
methotrexate) and topoisomerase inhibitors (e.g., topotecan, etoposide) are affecting
DNA synthesis and therefore act specifically during S phase. Spindle poisons and mitotic
inhibitors block microtubule assembly (vinca alkaloids) or disassembly (taxanes,
epothilones) and are acting during M phase. Alkylating agents and platinum derivatives
cause DNA crosslinking and are cell-cycle-nonspecific. Newer approaches in anticancer
chemotherapy include developments of targeted therapies: small molecule enzyme
inhibitors (e.g., imatinib) and monoclonal antibodies (e.g., trastuzumab) aiming at known
abnormalities in tumor cell biochemistry.
41
The main problem with cytotoxic drugs is their inherent non-specificity, resulting
in their being toxic to all fast-dividing cells. Pronounced side effects are therefore
associated with this type of therapy, and development of milder agents to limit toxicity
only to cancerous cells based on particular features of their metabolism is always
desirable. Another issue with the cytotoxic agents currently in use is the development of
drug resistance by cancer cells. Several mechanisms are known to interfere with therapy,
the more important being overexpression of drug efflux pumps (e.g., p-glycoprotein,
224
normally removing toxins or xenobiotic metabolites from cells), enhancing DNA repair
mechanisms and increasing intracellular glutathione concentrations (mitigating the effects
of electrophilic alkylating agents).
42,43
During the work performed in the research group of Prof. Nouri Neamati, USC
School of Pharmacy, cell-based high throughput screening of diverse library of 10,000
compounds using MTT assays has been conducted in search of novel anticancer cytotoxic
agents. Two compounds (4.10 and 4.11), containing an electrophilic tertiary propiolamide
fragment, have been identified as potential leads. Using cheminformatics tools, 17 other
tertiary propiolamides 4.12-4.28 with similar structures were found available from
commercial libraries. Additionally, 61 other structurally similar compounds lacking
propiolamide fragment were acquired but found inactive in preliminary tests. For in vitro
and in vivo studies of the 19 initial candidates, aimed at investigation into their activity,
toxicity and mechanism of action, the compounds 4.10-4.28 have been resynthesized on
1-2 mmol scale and purified to >96% active compound content:
225
OMe
N
H
N
O
O
MeO
OMe
N
H
N
O
O
CF
3
OMe
OMe
OMe
N
H
N
O
O
S
N
N
H
N
O
O
N N
N
F
OMe
N
H
N
O
O
S
MeO
OMe
N
H
N
O
O
S
N
H
N
O
O
S
MeO
OMe
O
O
N
H
N
O
O
N
N
H
N
O
O
N N
N
N
H
N
O
O
F
O
OMe
N
H
N
O
O
MeO
OMe
N
H
N
O
O
F
CF
3
N
H
N
O
O
CF
3
S
N
H
N
O
O
N
H
N
O
O
F
O
O
N
H
N
O
O
S
CF
3
N
H
N
O
O
Cl
N
H
N
O
O
S
N
H
N
O
O
F
F
4.10 (54%) 4.11 (93%) 4.12 (86%)
4.13 (60%)
4.14 (55%) 4.15 (70%) 4.16 (25%)
4.17 (86%)
4.18 (54%)
4.19 (80%)
4.20 (7%) 4.21 (60%)
4.22 (67%)
4.23 (82%) 4.24 (92%)
4.25 (56%)
4.26 (61%)
4.27 (66%)
4.28 (69%)
Figure 4.2. Cytotoxic propiolamides 4.10-4.28 identified in high throughput screening.
226
All the compounds were easily prepared by Ugi reaction in methanol or 2,2,2-
trifluoroethanol in yields >50% (with the only exception of compound 4.20, likely due to
losses during isolation and purification):
R
1
O
+ R
2
NH
2
+
OH
O
+ R
3
NC
MeOH or CF
3
CH
2
OH
O
N
R
2
R
1
NHR
3
O
RT, 48 h
Scheme 4.16.
The compounds 4.10-4.28 are bench-stable crystalline solids. The products 4.14,
4.16, 4.28 (derived from 2-substituted anilines), 4.19 (furfurylamine derivative), 4.24 and
4.26 (derived from benzylamines) exist in two rotameric forms on NMR time scale due to
hindered rotation around C(=O)–NR
2
amide bond. All active compounds satisfy
Lipinsky’s rule of five: ≤ 5 hydrogen bond donors, ≤ 10 hydrogen bond acceptors,
molecular weight ≤ 500 g/mol and n-octanol-water partition coefficient (calculated atom-
based values) clogP < 5. Additionally, desirable for good absorption is the value of polar
surface area < 140 Å
2
.
44-47
For the compounds 4.10-4.28 this parameter (as calculated
using Accelrys Discovery Studio suite v.2.0) was less or around 50 Å
2
, except for the
tetrazole derivatives 4.13 (122.06 Å
2
) and 4.18 (129.21 Å
2
). Therefore, these compounds
demonstrate desirable physicochemical properties and are likely to possess good oral
bioavailability, making this type of molecules promising for further experimental
evaluations.
As evidenced in MTT and colony formation assays, the compounds 4.10-4.28
were found to exhibit cytotoxicity at low micromolar concentrations against several
human cancer cell lines. In particular, they all showed cytotoxicity in doxorubicin-
227
resistant NCI/ADR-RES cell line, overexpressing p-glycoproteins and multiple drug
resistance transporters.
48,49
The tetrazoles 4.13 and 4.18 and benzylamine-derived
compounds 4.19, 4.24 and 4.26 were slightly inferior, while all other propiolamides
demonstrated cytotoxic concentrations IC
50
< 1 µM against this cell line. However, the
tetrazole derivatives performed better against other cell lines, in particular 5367 (highly
metastatic bladder cancer, lacking Rb tumor suppressor protein) (IC
50
= 0.7 ± 0.5 µM for
4.13, 0.4 ± 0.1 µM for 4.18) and MDA-MB-435 melanoma (IC
50
= 0.6 ± 0.3 µM for
4.18). The compounds 4.13 and 4.18 have demonstrated favorable pharmacokinetic
profile in mice, consistent with ADMET predictions.
For in vivo studies (nude mouse xenograft model using MDA-MB-435 cells),
compound 4.11 (IC
50
= 6.3 ± 1.1 µM) was selected, administered intraperitoneally in
doses increasing from 10 to 40 mg/kg over 26 days followed by monitoring for additional
17 days. Significant reduction of tumor burden has been demonstrated without any drug-
related death or body weight loss. Histopathological examinations of the organs derived
from at least three mice in the treatment group showed no histological evidence of organ
toxicity.
Mechanistically, the compound 4.13 was shown to induce cell cycle arrest in both
S and G
2
/M phases in MDA-MB-435 cells. Both 4.10 and 4.11 triggered late apoptosis in
MDA-MB-435 cells, and 4.13 was demonstrated to be able to trigger early apoptosis as
well. To understand the mechanisms underlying the cytotoxicity of these compounds, an
investigation of their effects on apoptosis signaling pathways has been undertaken. The
compound 4.10 was positively shown to up-regulate the expression of pro-apoptotic
228
protein p53; activation (by cleavage of full-length pro-enzyme) of caspase-9 was also
detected. Further pathway analysis was then performed using Kinexus™ 628-antibody
microarray, followed by Ingenuity Pathway Analysis (IPA) software processing of the
results. The pathway suggested by IPA was Nrf2-mediated oxidative stress pathway with
increase in formation of reactive oxygen species (peroxide and superoxide). As a
preliminary validation of this pathway, the compounds 4.10, 4.11, 4.13 and even less
active 4.27 (IC
50
> 10 µM) all demonstrated significant increase in mitochondrial
superoxide production in MDA-MB-435 cells at their respective IC
50
. Formation of
reactive oxygen species other than superoxide was not observed, suggesting the
superoxide induction as a unique mechanism for the activity of these compounds.
4.3 SAR studies in propiolamide pseudodipeptides.
For structure-activity relationship (SAR) studies, three series of analogs have
been chosen based on their superior activity against OVCAR3, OVCAR8, HEY and
NCI/ADR-RES human ovarian cancer cell lines: the analogs of compounds 4.10,
4.13/4.18 and 4.14/4.15 (these pairs of compounds from the initial set were structurally
similar):
229
OMe
N
H
N
O
O
MeO
OMe
4.10
N
N
H
N
O
O
N N
N
R
1
4.13 (R
1
= F)
4.18 (R
1
= H)
R
3
N
H
N
O
O
S
R
1
4.14 (R
1
, R
3
= OMe, R
2
= H)
4.15 (R
1
, R
3
= H, R
2
= OMe)
R
2
Figure 4.3. Cytotoxic propiolamides 4.10, 4.13, 4.18, 4.14, 4.15 selected for SAR studies.
Table 4.1. In vitro cytotoxicity of the compounds 4.10, 4.13, 4.18, 4.14, 4.15 against
human ovarian cancer cell lines.
OVCAR3 OVCAR8 HEY NCI/ADR
Compound
IC
50
a
, µM
4.10 9 7.8 1.1 0.9
4.13 1.9 1 0.3 0.2
4.18 0.3 1.1 0.25 0.32
4.14 6 2.5 0.4 0.23
4.15 2.1 1.2 0.35 0.25
a
Cytotoxic concentration (IC
50
) is defined as drug concentration causing a 50% decrease in cell population using MTT
assay.
From the chemical standpoint, the propiolamides 4.10-4.28 are expected to
behave as electrophilic alkylating agents. The reported molecular targets of similar
unsaturated amides are Cys residues in the proteins.
50,51
It was therefore important to
confirm the necessity of presence of an α, β-unsaturated carbonyl fragment for their
cytotoxic activity and exclude non-covalent binding. Seven analogs (4.29-4.35) of the
compound 4.10 bearing different acyl substituents were prepared by Ugi reaction in
methanol (with addition of 1 eq of methanesulfonic acid for the compound 4.35):
230
OMe
N
H
N
O
R
O
MeO
OMe
O
O
O O
Br
O O
Br
O
Br
O
N
O
4.10 4.29 4.30 4.31
4.32 4.33 4.34
4.35
Figure 4.4. Analogs of the compound 4.10.
From these compounds, only the electrophilic α-bromoacetamide 4.32 was found
active (IC
50
~ 7 µM against all four cell lines), though less so than the original 4.10
against HEY and NCI/ADR. The compound 4.35, containing a tertiary amine in α-
position to the propiolamide triple bond, which was reported beneficial for cysteine
deprotonation in the protein target,
50
was also less active (IC
50
= 5 µM against OVCAN8
and HEY and 10.2 µM against NCI/ADR). All other compounds were inactive (IC
50
> 10
µM), including the acrylamide derivative 4.29. The corresponding N-formyl analog
(Figure 4.4, R = H) was found unstable, likely due to intramolecular cyclization onto 3,5-
dimethoxyaniline ring, quickly building up an impurity that was not characterized.
An attempt was made to prepare the vinylsulfonamide analog (4.36) of the
compound 4.10 according to the synthetic plan shown in Scheme 4.17:
231
OMe
NH
2
MeO
+
B(OH)
2
MeO
+
HO
2
C CHO H
2
O
3CC
OMe
HN
MeO
CO
2
H
OMe
NH
2
peptide
coupling
OMe
HN
MeO
OMe
O
H
N
Cl
SO
2
Cl
, B
OMe
N
MeO
OMe
O
H
N S
O O
4.36
Scheme 4.17.
However, it was found that the three-component condensation with 3,5-dimethoxyaniline
results in formation of a C-alkylation and not the expected N-alkylation product which
gives, after coupling with cyclohexylamine and sulfamidation with 2-
chloroethanesulfonyl chloride,
52
the compound 4.39 with quite different topology. This
compound was also tested against NCI/ADR cell line and was found inactive:
232
OMe
NH
2
MeO
+
B(OH)
2
MeO
+
HO
2
CCHO H
2
O
MeCN
RT, overnight
CO
2
H
OMe
MeO
OMe H
2
N
NH
2
(3 eq)
HATU, DMSO
RT, overnight
OMe
MeO
OMe H
2
N
H
N
O
Cl
SO
2
Cl
Et
3
N, CHCl
3
RT, 1.5 h
OMe
MeO
OMe N
H
N
O
S
S
O O
O
O
4.37 4.38
4.39
32% over 3 steps
Scheme 4.18.
The compounds 4.13 and 4.18 were among the most active in the preliminary
tests, so a series of analogs with varying number of the fluorine atoms in the phenyl ring
was synthesized demonstrating, except for the less active 3-substituted analog 4.40,
comparable activities against NCI/ADR cells. The 3-pyridine analog 4.41 had the activity
comparable to 3-fluorophenyl compound 4.40, but was found unstable in solution (likely
do to activation of the propiolamide group to nucleophilic attack by the presence of a
basic site in the molecule). Substitution of tetrazole ring with stereoelectronically similar
carboxylic acid derivatives
53
(esters and amide) was detrimental; surprisingly, bulky tert-
butyl ester 4.47 demonstrated an activity comparable to the initial compound. The
corresponding free carboxylic acid 4.48, prepared by acid hydrolysis of 4.47 (basic
hydrolysis of 4.46 failed) was found completely inactive:
233
N
N
H
N
O
O
N N
N
F
n
F
F
F F
F
F
F F
F F
N
4.18 4.13 4.40 4.41
4.42 4.43 4.44
(0.2 M) µ (0.32 M)µµ (2 M) (2.5 M) µ
(0.52 M) µ (0.32 M) µ (0.45 M) µ
N
R
N
H
N
O
O
N N
N
N
N N
N
O NH
2
O OMe
O O
O OH
4.18
(R = Me)
4.45 4.46
4.47
4.48
(R = H)
(0.32 M) µ (2.5 M) µ (2.2 M) µ
(0.43 M) µ
(>10 M) µ
Figure 4.5. Analogs of the compounds 4.13 and 4.18 and their IC
50
values against
NCI/ADR cells.
A larger batch of the most active of the tetrazole-containing propiolamides,
compound 4.13, was synthesized for in vivo studies in mice, however they had to be
terminated early due to high acute toxicity of this compound, and the tetrazole analogs of
4.13 and 4.18 were not investigated further.
A loss of cytotoxicity in more polar compound 4.48 has also been observed for
4.10 analogs 4.49 and 4.50, in which hydrogen bond-donating groups (phenolic OH) have
been introduced. The yield of Ugi reactions was also much lower for reactions with
hydroxybenzaldehydes:
234
OMe
N
H
N
O
O
MeO
OMe
OMe
N
H
N
O
O
MeO
OH
OMe
N
H
N
O
O
MeO
OMe
OH
4.10 (54%)
4.50 (13%)
4.49 (20%)
(0.9 M) µ
(>10 M) µ
(5.5 M) µ
Figure 4.6. Loss of cytotoxicity in polar analogs of 4.10 (IC
50
values against NCI/ADR
cells).
In the series of analogs of compounds 4.14 and 4.15, some improvement has been
achieved with the substitution of cyclopentylamide with ethyl ester of glycine (compound
4.51, Figure 4.7). As in the previous examples, the presence of more polar groups at the
C-terminus of the Ugi product, or introduction of phenol hydroxyls resulted in lower
activity, however 3-OH analog of 4.15 (compound 4.54, Figure 4.8) remained quite
active:
OMe
N
H
N
O
R
O
S
MeO
4.14
H
N
H
N CO
2
Et
H
N CO
2
H
H
N
N
H
O
N
O
4.51 4.52
4.53
(0.23 M) µ
(0.2 M)µµ (8 M)
Figure 4.7. Variation of the amide group in 4.14 analogs (IC
50
values against NCI/ADR
cells).
235
N
H
N
O
S
RO
N
H
N
O
O
S
MeO
OR
O
CO
2
Et
N
H
N
O
S
MeO
O
OMe
OMe
4.15 (R = Me)
4.54 (R = H)
4.51 (R = Me)
4.55 (R = H)
4.56
(1.2 M) µ
(2.2 M) µ
(0.61 M) µ
(>10 M) µ
(2.2 M) µ
Figure 4.8. Variation of the anilide substitution in 4.14/4.15 analogs (IC
50
values against
OVCAR8 cells).
Further attempts have been made to install different thiol-reactive acyl groups at
the N-terminus of 4.14 and 4.51 analogs. However, as in the case of 4.10 analogs, only
propiolamides (4.61, 4.62) and bromoacetamide (4.58) were found active against
OVCAR8 and NCI/ADR cells, while other known thiol-reactive compounds (e.g.,
maleimide 4.60) were completely ineffective:
OMe
N
H
N
O
R
O
S
MeO
O
4.14
O
4.57
Br
O
4.58
O
N
O
4.59
O
N
O
O
4.60
H
N
O
O
4.61
N
H
O
4.62
O
4.63
O
O
2
N
F
4.64
O
N
N
N
(2.5 M) µ (>10 M) µ
(5.5 M) µ (>10 M) µ
(>10 M) µ
(3.1 M) µ
(1.5 M) µ
(>10 M) µ
(>10 M) µ
Figure 4.9. Analogs of the compound 4.14 and their IC
50
values against OVCAR8 cells.
236
O
O
2
N
4.69
F
O
O
2
N
4.70
Cl
OMe
N
H
N
O
R
O
S
MeO
CO
2
Et
O
4.51
O
4.66
O
4.67
Br
Br
O
4.68
N
O
4.65
(0.61 M) µ
(>10 M) µ
(>10 M) µ
(>10 M) µ
Figure 4.10. Analogs of the compound 4.51 and their IC
50
values against OVCAR8 cells.
From these series, the propiolamides with extended acyl chain (4.61 and 4.62)
were prepared via corresponding N-Boc-Gly or N-Boc- β-Ala Ugi derivatives, followed
by deprotection and HATU coupling with propiolic acid:
NH
2
+
+
NC
OMe
MeO
S
O
BocHN CO
2
H
n
+
MeOH
RT, 24 h
OMe
N
H
N
O
O
S
MeO
BocHN
n
1) TFA, CH
2
Cl
2
RT, 3 h
CO
2
H 2)
HATU, EtN(i-Pr)
2
DMSO
RT, overnight
OMe
N
H
N
O
O
S
MeO
H
N
n
O
4.61 (n = 1)
4.62 (n = 2)
49% over 3 steps
37% over3steps
Scheme 4.19.
237
The compound 4.63 was prepared from 4.14 by copper-catalyzed “click” reaction
with in situ-generated methyl azide
54
(Scheme 4.20).
OMe
N
N
H
O
O
S
MeO
+(MeO)
2
SO
2
+NaN
3
CuSO
4
· 5H
2
O (5 mol%)
Na ascorbate (10 mol%)
DMF - H
2
O (4:1)
RT, overnight
OMe
N
N
H
O
O
S
MeO
N
N
N
4.14
4.63 (52%)
Scheme 4.20.
The compound 4.68 was prepared by addition of pyrrolidine to 4.51:
OMe
N
N
H
O
O
S
MeO
4.51
CO
2
Et
+ NH
MeCN
RT, 3 h
OMe
N
N
H
O
O
S
MeO
4.68 (88%)
CO
2
Et
N
Scheme 4.21.
All other compounds in Figures 4.9 and 4.10 were prepared in a single step four-
component Ugi condensation from the corresponding acids (either commercially
available or prepared according to known literature procedures). The corresponding
amides of 2-bromoacrylic and buta-2,3-dienoic acids
55,56
could not be prepared by means
of Ugi reaction.
238
It was also of interest to evaluate the role of the aryl substituents for the activity of
cytostatic propiolamides. Several derivatives of 4.14/4.51 and 4.13/4.18 have been
prepared:
OMe
N
N
H
O
R
O
S
MeO
4.14 (R = cyclopentyl)
4.51 (R = CH
2
CO
2
Et)
N
N
H
O
S
O
OMe
N
N
H
O
O
MeO
OMe
N
N
H
O
O
MeO
CO
2
Et
OMe
N
NH
2
O
O
MeO
(0.61 M) µ
(2.5 M) µ
4.71
4.72
4.73 4.74
(2.2 M) µ
(0.52 M) µ
(2.2 M) µ
(0.51 M) µ
Figure 4.11. Analogs of 4.14/4.51 lacking one aryl substituent and their IC
50
values
against OVCAR8 cells.
N
N
H
N
O
R
O
N N
N
F
4.13 (R = cyclopentyl)
4.75 (R = CH
2
CO
2
Et)
µ (1 M)
(0.2 M) µ
N
N
H
N
O
O
N N
N
N
N
H
N
O
O
N N
N
CO
2
Et
4.76
µ (10 M)
4.77
µ (>10 M)
Figure 4.12. Analogs of 4.13/4.75 lacking one aryl substitutent and their IC
50
values
against OVCAR8 cells.
239
The compound 4.74 was prepared by simple alkylation of 2,4-dimethoxyaniline
followed by EDC coupling with propiolic acid:
NH
2
OMe
OMe
+
Cl
CONH
2
K
2
CO
3
, KI (cat.)
DMF, 80
o
C, 24 h
HN
OMe
OMe
CONH
2
CO
2
H
EDC HCl
DMAP (10 mol%)
CH
2
Cl
2
0
o
C RT, 1.5 h
N
OMe
OMe
CONH
2
O
4.78 (40%)
4.74 (54%)
Scheme 4.22.
Generally, the analogs of compound 4.14 lacking the thiophene substituent were
no less active than the original compound, and the 4.72 was found more active against
both OVCAR8 and NCI/ADR cell lines. Contrarily, the analogs of 4.13 (and its glycine
ethyl ester analog 4.75) lost their activity when the aryl substitiuent in the phenylglycine
fragment was removed. The compound 4.71, derived from methylamine, also was
comparably active against OVCAR8 and NCI/ADR. The Passerini reaction, initially
attempted to prepare the analog of 4.14 without the 2,4-dimethoxyaryl substituent, gave
only N-cyclopentylpropiolamide 4.79 in 57% yield (Scheme 4.23). This represents a
common problem with atypical product formation in Passerini reactions with strong
carboxylic acids
57
.
240
+
+
NC
S
O
CO
2
H
MeOH
RT, 48 h
O
O
H
N
O
S
not formed
O
N
H
4.79 (57%)
Scheme 4.23.
However, it must be understood that protein target selectivity of the propiolamide
compounds would suffer if the side substituents were removed from the propiolamide
pseudopeptide backbone. Therefore, the best 4.14 analog – compound 4.51 – active
against both OVCAR8 and NCI/ADR was selected among the molecules retaining both
aryl substituents for in vivo studies. The preliminary studies were quite encouraging
demonstrating the reduction of tumor burden without treatment-associated toxicity.
4.4 Synthesis of fluorescent-tagged active compound and reference
molecules for intracellular imaging.
For intracellular imaging, the fluorescent derivative 4.80 based on compound 4.51
with BODIPY
58
fragment linked via short ethylenediamine linker, was prepared. The
commercially available (from Invitrogen, a part of Life Technologies) BODIPY
derivatives bearing the amino or carboxyl group appropriate for tagging by peptide-
coupling reaction are supplied in milligram quantities and are very expensive. The
recently reported symmetric BODIPY derivative 4.81
59
has optical characteristics ( λmax
for absorption and emission and fluorescence quantum yield) very similar to those of the
commonly used amine-tagged green-emitting dye BODIPY FL EDA (4.82):
241
N
B
N
O
H
N
F F
NH
2
N
B
N
F F
N
H
O
NH
2
4.81
4.82
λmax (absorption) = 502 nm
λ max (emission) = 512 nm
BODIPY FL EDA
λmax (absorption) = 508 nm
λmax (emission) = 514 nm
Φ 0.15
Φ 0.22
Figure 4.13. Structures and optical characteristics of the BODIPY fluorescent tag 4.81
and BODIPY FL EDA.
The compound 4.81 is easily available in just two steps from commercial
materials and was prepared with slight optimization of the literature procedure
59
(Scheme
4.24).
N
H
(2 eq)
+
CO
2
Me
O 1) TFA (cat.), CH
2
Cl
2
2) DDQ (1 eq)
3) BF
3
Et
2
O, Et
3
N
N
B
N
F F
4.83
CO
2
Me
H
2
N
NH
2
MeOH
RT, 3 d
N
B
N
O
H
N
F F
NH
2
4.81
54%
64%
Scheme 4.24.
The dye 4.81 was then linked using HATU coupling to the compound 4.52
(carboxylic acid 4.51 derivative) to give the target 4.80. For comparative studies, a
structurally similar inactive analog 4.84, containing an acetamide fragment instead of
242
propiolamide, was prepared by Ugi reaction, hydrolyzed to the carboxylic acid 4.85 and
coupled to the dye giving the inactive dye conjugate 4.86 (Scheme 4.25).
+
+
S
O
CO
2
H R
CN CO
2
Et
NH
2
OMe
MeO
+
MeOH
RT, 24 h
MeO
OMe
N
O
R
H
N
O
CO
2
Et
S
LiOH
THF - H
2
O
RT, 1 h
MeO
OMe
N
O
R
H
N
O
CO
2
H
S
4.51 (R = )
4.84 (R = Me)
CCH
4.52 (R = )
4.85 (R = Me)
CCH
MeO
OMe
N
O
R
H
N
O
CO
2
H
S
4.52 (R = )
4.85 (R = Me)
CCH
+
N
B
N
O
H
N
F F
NH
2
4.81
HATU, EtN(i-Pr)
2
DMSO
RT, 2-2.5 h
N
B
N
F F
O
H
N
N
H
H
N
O
O
N
S
OMe
OMe
R
O
4.80 (R = )
4.86 (R = Me)
CCH
Scheme 4.25.
As a background control, and to exclude any possible specific binding of the dye,
4.81 was acetylated to give the diamide 4.87 which was used as a reference dye with the
polarity similar to conjugated pseudodipeptides 4.80 and 4.86:
243
N
B
N
O
H
N
F F
NH
2
4.81
Ac
2
O, py
CH
2
Cl
2
RT, 30 min
N
B
N
O
H
N
F F
N
H
4.87
O
Scheme 4.26.
To evaluate the subcellular location of the protein targets of cytotoxic
propiolamide pseudodipeptides, the fluorescent imaging studies have been performed in
the laboratory of Prof. Nouri Neamati at the USC School of Pharmacy. Ovarian cancer
cells (OVCAR-8) were treated with 4.80 (fluorescent analog of the best active compound
4.51) or the reference molecules 4.86 (fluorescent analog of inactive acetamide analog
4.84) and 4.87 (blank dye) at 2 µM for 1 h. Cells were then fixed and permeabilized and
treated with nuclear stain DRAQ5. Actin was stained with Alexa Fluor 488-phalloidin.
The results are shown in Figure 4.14. Cells treated with 4.80 demonstrated strong
fluorescent emission from perinuclear space, suggesting high-affinity binding with the
target protein. Only weak emission was observed with non-electrophilic isosteric
molecule 4.86. Reference dye 4.87 demonstrated no emission, which confirmed the
absence of possible binding due to the dye fragment.
244
Figure 4.14. Subcellular localization of the fluorescent-tagged propiolamide 4.80 and the
reference molecules 4.86, 4.87.
Alexa Fluor 488
Phalloidin
DRAQ5 Merged
O
O
HN
OH NH
OH
NMe
2
Me
2
N
O H
2
N
SO
3
-
SO
3
-
NH
2
+
CO
2
-
O
HN
Phalloidin
DRAQ5 Merged 4.87
N
B
N
F F
O
H
N
N
H
O
DRAQ5 Merged 4.80
N
B
N
F F
O
H
N
N
H
O
H
N
O
N
S
OMe
OMe
O
DRAQ5 Merged 4.86
N
B
N
F F
O
H
N
N
H
O
H
N
O
N
S
OMe
OMe
O
245
4.5 Mechanistic studies.
From the point of biochemistry involved, the propiolamide pseudodipeptide
compounds 4.10-4.28 possess a Michael acceptor group and are therefore likely to react
with a sulfhydryl group of a certain protein (or proteins), but their molecular targets are
yet unknown. It is the known fact that the reactivity of acetylenic ketones and similar
electron-deficient alkynes towards biologically relevant nucleophiles drops significantly
in the order: –SH group of Cys > ε–NH
2
group of Lys > –OH group of Ser.
60
This
property of Michael acceptors has been used in development of some drug candidates.
For example, geftinib is a known reversible inhibitor of epidermal growth factor receptor
tyrosine kinase erbB1 (other names EGFR or HER-1 in humans), that binds to its target
through noncovalent interactions. An unpaired Cys residue (C773), located in immediate
proximity to the binding site, allowed for development of an irreversible inhibitor
canertinib, containing an acrylamide fragment
51
(Figure 4.15).
N
N
HN
F
Cl
O N
O
MeO
geftinib
N
N
HN
F
Cl
HN
O
O
N
O
canertinib
Figure 4.15. Tyrosine kinase erbB1 inhibitors geftinib and canertinib.
Several propiolate and propiolamide adducts to protected cysteine derivatives
have been prepared, usually as the mixtures of (E)- and (Z)-isomers of resulting 3-
alkylthioacrylates or 3-alkylthioacrylamides
61
(Scheme 4.27).
246
HS
CO
2
Me
NHCbz
+ Dye O
X
O
Et
3
N, CH
2
Cl
2
Dye O
X
O
S
CO
2
Me
NHCbz
X = O or NH
Dye = Coumarin or Sudan I
Scheme 4.27.
The resulting 3-alkylthioacrylates and 3-alkylthioacrylamides normally do not,
even reversibly, add a second equivalent of thiol under basic conditions.
60
With more
reactive esters the double addition has been observed when tributylphosphine was used as
a catalyst,
62
however the rate of the second addition step was determined to be 10
3
times
slower than the first addition. α, α, α-Trifluoromethyl acetylenic ketones are also capable
of second addition of the thiol.
63
With simple propiolamides, the reaction stops after
single addition and, depending on the solvent and reaction conditions, may yield the
kinetic (Z)-product or thermodynamic mixture of (E)- and (Z)-isomer, usually in favor of
the former. The formation of (Z)-isomer was explained in theoretical studies of this
reaction, which suggested that trans-bending of the acetylene was favored upon initial
addition of anion, resulting in (Z)-anionic intermediate 4.90. It then undergoes quick
protonation in protic solvents (water, alcohols); in aprotic solvents, it isomerizes into
allenic intermediate 4.91, giving rise to the mixture of (E)- and (Z)-products
60
(Scheme
4.28).
247
H
Nu
-
60
o
O
X
Nu
H
X
O
H
+
(fast)
Nu
H H
X
O
isomerization
C
H
Nu
X
O
H
+
Nu
H H
X
O
+
Nu
H
H
O
X
(Z)-
(Z)- (E)-
in protic solvents in aprotic solvents
4.90 4.91
Scheme 4.28.
Propiolic esters have been reported to be more reactive than amides. Their
reaction with protected cysteine derivatives gave, in addition to the Michael addition
product 4.92, the dehydroalanine derivative 4.93 (formed by elimination of enethiolate
intermediate 4.94, which could be intercepted in the presence of electrophilic reagents)
and divinyl sulfide 4.95 (formed from 4.94).
64
OMe
O
HS
CO
2
Et
NHBoc
+
CH
2
Cl
2
, 0
o
C
Et
3
N (cat.)
MeO
O
S
CO
2
Et
NHBoc
H
CO
2
Et
NHBoc
MeO
O
S
S
MeO
2
C
MeO
2
C
4.92
4.93
4.94
4.95
Scheme 4.29.
248
3-Substituted 2-alkynoic amides have been reported to react differently: instead of
a nucleophilic addition of thiol, the oxidative coupling of cysteine –SH groups takes
place, resulting in formation of cystine derivatives
60
(Scheme 4.30).
Bu
NHBn
O
HS
CO
2
Me
NHCbz
+
MeCN
Et
3
N (cat.)
RT, 24 h
BnHN
O
S
Bu
NHCbz
CO
2
Me
S
CO
2
Me
NHCbz
S
MeO
2
C
NHCbz
not formed
major product
Scheme 4.30.
To supply a mechanistic base for our SAR studies of cytostatic propiolamides,
seven simple propiolamides 4.96-4.102 with different substitution patterns have been
prepared:
N
H
O
Bn
N
O
Bn
N
H
O
Ph
4.96
4.97
4.98
N
O
4.99 (X = H)
4.100 (X = OMe)
4.101 (X = CO
2
Me)
4.102 (X = NO
2
)
X
Scheme 4.31.
The kinetics of the thiolate addition to propiolic esters was reported to be rather
complex;
62
however, for Bu
3
P-catalyzed reaction it could be satisfactorily approximated
by an equation –d[RSH]/dt = k[HC ≡CCO
2
R][RSH][Bu
3
P]. Indeed, when the reactants (a
propiolamide, N-acetyl-L-cysteine 4.103 and Et
3
N) were taken in stoichiometric
249
quantities, the function of thiol concentration versus time C(t) could not be approximated
to any simple reaction order:
N
O
R
2
R
1
+
HS
CO
2
H
NHAc
Et
3
N (2 eq)
CDCl
3
, 20
o
C
N
O
R
2
R
1
S
CO
2
H
NHAc
C
0
= 0.2 M
4.96-4.99
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0.2
01 23 4 5 678 9 10 11 12
t, h
C(N-Ac-Cys), M
R1 = Bn, R2 = H
R1 = Bn, R2 = Me
R1 = Ph, R2 = H
R1 = Ph, R2 = Me
Figure 4.16. Relative reaction rates between N-acetyl-L-cysteine and substituted
propiolamides 4.96-4.99.
However, the relative rates of the reaction could be established to fall in the order 4.98
(R
1
= Ph, R
2
= H) > 4.96 (R
1
= Bn, R
2
= H) > 4.99 (R
1
= Ph, R
2
= Me) > 4.97 (R
1
= Bn,
R
2
= Me), indicating that: 1) N-monosubstituted propiolamides are generally more
reactive than N,N-disubstituted and 2) N-arylpropiolamides are more reactive than N-
alkylpropiolamides. Taking an excess of propiolamide (5 eq), the reaction can be forced
into pseudo-zero order on thiol over a large enough interval of thiol concentrations (from
100% down to 20% of C
0
; the compound 4.98 reacts too fast under these conditions):
250
N
O
R
2
R
1
+
HS
CO
2
H
NHAc
Et
3
N (2 eq)
CDCl
3
, 20
o
C
N
O
R
2
R
1
S
CO
2
H
NHAc
C
0
= 0.1 M
4.96-4.99
(5 eq)
Figure 4.17. Relative reaction rates between N-acetyl-L-cysteine and substituted
propiolamides 4.96-4.99 (pseudo-zero order kinetics).
It was established that the reaction has first order on the reactants other than thiol
under these conditions (Figure 4.18), giving the resulting kinetic equation in form
–d[RSH]/dt = k[propiolamide][Et
3
N]:
251
N
O
Bn
+
HS
CO
2
H
NHAc
Et
3
N(2 or 4eq)
CDCl
3
, 20
o
C
N
O
Bn
S
CO
2
H
NHAc
(5 or 10 eq)
4.97 C
0
= 0.1 M
y = -0.0088x + 0.1
y = -0.0186x + 0.1
y = -0.0182x + 0.0912
-0.02
0
0.02
0.04
0.06
0.08
0.1
01 23 4 5 67 89 10 11 12
t, h
C(N-Ac-Cys), M
2 eq Et3N, 5 eq amide
4 eq Et3N, 5 eq amide
2 eq Et3N, 10 eq amide
Linear (2 eq Et3N, 5 eq amide)
Linear (4 eq Et3N, 5 eq amide)
Linear (2 eq Et3N, 10 eq amide)
Figure 4.18. Determination of the kinetic equation for the reaction between 4.97 and N-
acetyl-L-cysteine.
The effect of substituents in the aromatic ring was evaluated on example of
compounds 4.99-4.102: electron-donating group (–OMe) in para-position of the aromatic
ring (compound 4.100) decreased and electron-withdrawing groups (–CO
2
Me, –NO
2
)
increased the reaction rate compared to 4.99 (the compound 4.102 reacted too fast under
these conditions). Interestingly, substitution of N-benzyl with N-(2-picolyl) substituent
decreased the reaction rate nearly twice (not shown):
252
N
O
X
4.99-4.102
(5 eq)
Et
3
N(2eq)
CDCl
3
, 20
o
C
+
HS
CO
2
H
NHAc
C
0
= 0.1 M
N
O
X
S
CO
2
H
NHAc
y = -0.0687x + 0.1
y = -0.016x + 0.1
y = -0.0099x + 0.1
-0.01
0.01
0.03
0.05
0.07
0.09
0 1234 5 6 7 8 9 10 11
t, h
C(N-Ac-Cys), M
X = H
X = MeO
X = CO2Me
Linear (X = CO2Me)
Linear (X = H)
Linear (X = MeO)
Figure 4.19. Relative reaction rates between N-acetyl-L-cysteine and substituted
propiolamides 4.99-4.101 (pseudo-zero order kinetics).
Taken together, the data on Figures 4.17 and 4.19 suggest that the reaction rate of
thiol addition to propiolamides, as expected, increases with the decrease of electron
density on the carbonyl group.
Two mechanisms of nucleophilic addition of thiols can be proposed and may
coexist independently. Simple addition of thiolate nucleophile with subsequent
protonation was displayed in Scheme 4.28. Alternatively, the addition of amine (Et
3
N in
our case, or any other nucleophilic base) may take place first, followed by the attack of
thiolate on an enammonium intermediate, where the corresponding steps must be slow or
fast to satisfy the established kinetic equation:
253
NR
1
R
2
O
+ Et
3
N
slow
fast?
C Et
3
N
O
NR
1
R
2
RSH
RS
fast
NR
1
R
2
O
Et
3
N
RS
Et
3
N
fast
NR
1
R
2
O
RS
C Et
3
N
O
N
H
R
1
if R
2
= H
N
O
Et
3
N
R
1
Et
3
N
fast
NHR
1
O
RS
(or solvent)
RSH
Scheme 4.32.
The possibility of intramolecular proton transfer may account for significantly higher
reaction rates with secondary propiolamides (4.96, 4.98) in aprotic solvents.
To further investigate into the possibility of the reaction to proceed along the
pathway shown in Scheme 4.32, the reaction of propiolamide 4.96 with amines was
studied on NMR scale:
NHBn
O
+ Et
3
N
CHCl
3
, RT
24 h
NHBn
O
Et
3
N
Cl
-
E/Z ratio ~ 4:1
C
NHBn
O
Et
3
N
H
NHBn
O
Et
3
N
CCl
3
-
H
NHBn
O
+ NH
CDCl
3
, RT
24 h
NHBn
O
N
4.96
4.96
NHBn
O
+
N
NH
CDCl
3
, RT
3 days
NHBn
O
N
N
4.96
E/Z ratio ~ 1:3
NHBn
O
+BnNH
2
CDCl
3
, RT
3 days
?
4.96
100% E-isomer
CHCl
3
:CCl
2
Scheme 4.33.
The reaction of 4.96 with Et
3
N proceeded slowly with abstraction of the proton from the
solvent (CHCl
3
or CDCl
3
), resulting in formation of dichlorocarbene and darkening of the
reaction mixture with gradual buildup of byproducts. In H
2
O-MeOH, this reaction gave a
254
mixture of solvolysis products. Pyrrolidine reacted with 4.96 quickly and quantitatively,
with formation only of (E)-isomer of the product. Imidazole reacted similarly, but much
slower, and yielded both (E)- and (Z)-addition products in favor of the latter. Primary
amines (on example of benzylamine) reacted much slower than secondary and slower
than Et
3
N, giving mixtures of the products that were not separated and identified.
The reaction of propiolamide 4.96 with thiols was demonstrated to proceed with
non-nucleophilic bases on at least two examples:
SH
H
2
NOC
NHBoc
+
NHBn
O
DBU (20 mol%)
CDCl
3
, RT
24 h
S
H
2
NOC
NHBoc
O
NHBn
Z/E ratio ~2:1
SH
H
2
NOC
NHBoc
OO
NaH
S
H
2
NOC
NHBoc NHBn
O
RT, overnight
S
H
2
NOC
NHBoc
O
NHBn
4.96 4.104
4.104
Scheme 4.34.
However, DBU was found to react with 4.96 (giving mixtures of unidentified products),
and another non-nucleophilic base, PMP (1,2,2,6,6-pentamethylpiperidine) was selected.
Unlike Et
3
N, PMP did not form any addition products to 4.96 in anhydrous CHCl
3
at RT
over 24 h, but the reaction of 4.99 with N-acetyl-L-cysteine proceeded similarly to Et
3
N-
mediated addition:
255
O
N
Ph
(5 eq)
base (2eq)
CDCl
3
, 21
o
C
S
HO
2
C
NHAc
N
O
Ph
4.99
+
HS
CO
2
H
NHAc
C
0
= 0.1 M
pK
a
(Et
3
N) = 10.59; pK
a
(Imidazole) = 6.89; pK
a
(PMP) = 11.25 at 30 °C
Figure 4.20. Relative reaction rates between N-acetyl-L-cysteine and 4.99 with different
amines (pseudo-zero order kinetics).
Despite the close pK
a
values of Et
3
N and PMP, the reaction with the latter is significantly
slower (as can be seen in comparison with much weaker nucleophilic base, imidazole),
suggesting the importance of the amine as a nucleophile in the thiol addition. Hence, the
pathways depicted in Schemes 4.28 and 4.32 are likely to coexist in the amine-mediated
nucleophilic addition of thiols to propiolamides.
In the protein target of the compounds 4.10-4.28 and their analogs, only the
regular 20 proteinogenic amino acids are likely to be present. From these, only side
256
chains of His (containing an imidazole ring), Lys (primary amino group) and Arg
(guanidine) contain basic groups (another rare possibility would be an –NH
2
group of any
N-terminal amino acid, or N-terminal Pro, which is extremely unusual). These amino
acids (or their analogs and protected derivatives) were tested and indeed were found to be
able to catalyze addition of N-acetyl-L-cysteine to 4.96 under conditions when the side
chain basic group is not protonated, for example for His:
H
2
NOC
SH
NHBoc
+
HO
2
C
N
H
N
NH
2
(20 mol%)
MeOH - H
2
O
H
N
O
Bn
S
H
2
NOC
NHBoc
HO
2
C
N
H
N
BocHN
(20 mol%)
MeOH - H
2
O
no addition product
N
H
N
BocHN
(20 mol%)
MeOH - H
2
O
BnHN
O
N
H
O
Bn
4.96 4.104
H
N
O
Bn
S
H
2
NOC
NHBoc
H
2
NOC
SH
NHBoc
+ N
H
O
Bn
4.96 4.104
H
2
NOC
SH
NHBoc
+ N
H
O
Bn
4.96 4.104
Scheme 4.35.
For imidazole (and similarly for guanidine and primary amines) it was shown that
only free base, and not the imidazolium salt, catalyzed the thiol addition:
257
imidazole (20 mol%)
MeOH - H
2
O
H
2
NOC
SH
NHBoc
+
HO
2
C
SH
NHAc
+
imidazole (20 mol%)
MeOH - H
2
O
no reaction
imidazole (1.2 eq or 2 eq)
CHCl
3
H
2
NOC
SH
NHBoc
+
MeOH - H
2
O
N
H
H
N
MsO
-
(20 mol%)
no reaction
N
H
O
Bn
4.96
4.104
N
H
O
Bn
4.96
N
H
O
Bn
4.96
4.104
4.103
H
N
O
Bn
S
H
2
NOC
NHBoc
H
N
O
Bn
S
HO
2
C
NHAc
Scheme 4.36.
In biologically relevant targets (for example, zinc finger-containing
transcriptional repressors), multiple Cys residues (in contrast to unpaired Cys, as in the
erbB1 example referenced above) may be involved in the protein activity, and the
cytostatic propiolamides might disrupt their function by interacting with more than one –
SH group. It was therefore of interest to investigate the reversibility of thiol additions to
propiolamides and the possibility of thiol-thiol displacement reactions under biologically
relevant conditions.
In accordance to the literature data,
60
double addition of Cys analogs 4.103 or
4.104 was never observed in amine-mediated addition to propiolamides in either protic
(H
2
O-MeOH) or aprotic (CHCl
3
) solvents. Several Cys analog adducts have been
prepared on a preparative scale:
258
HO
2
C
SH
NHAc
+ N
H
O
Bn
4.96
4.103
Et
3
N (2 eq)
CHCl
3
RT, overnight
H
N
O
Bn
S
HO
2
C
NHAc
4.105 (78%)
E/Z ratio ~ 2:3
O
N
Ph
4.99
+
SH
OMe
Et
3
N (2 eq)
CHCl
3
RT, overnight
N
O
Ph
S
MeO
+
N
O
Ph
S
MeO
4.106 (77%)
4.107 (23%)
HS
CO
2
Me
NHBoc
NH
3
- H
2
O, PhMe
RT, overnight
HS
CONH
2
NHBoc
4.104 (>95%)
4.99
imidazole (20 mol%)
MeOH - H
2
O
RT, overnight
N
O
Ph
S
H
2
NOC
NHBoc
4.108 (78%)
E/Z ratio ~ 1:5
mCPBA (1.3 eq)
CH
2
Cl
2
-10
o
C, 10 min
N
O
Ph
S
H
2
NOC
BocHN
4.109 (85%)
O
Scheme 4.37.
No thiol displacement has been noticed under either neutral or basic conditions;
however, in the presence of strong acid both E/Z-isomerization and thiol exchange were
observed, likely through the intermediates shown in Scheme 4.38:
259
+
SH
OMe
CH
3
OH - H
2
O
NaOH
no reaction
+
SH
OMe
H
N
O
Bn
S
MeO
CH
3
OH - H
2
O
HCl
H
N
O
Bn
S
HO
2
C
NHAc
4.105
H
N
O
Bn
S
HO
2
C
NHAc
4.105
E/Z ratio ~ 2:3
H
N
O
Bn
S
HO
2
C
NHAc
E/Z ratio ~ 1:1
+
E/Z ratio ~ 1:1
R
1
S
O
NHR
H
+
R
1
S
OH
NHR
R
2
SH
- H
+
R
1
S
O
NHR
SR
2
H
+
R
1
HS
O
NHR
SR
2
- R
1
SH
O
NHR
SR
2
- H
+
R
2
S
O
NHR
Scheme 4.38.
E/Z-Isomerization of 4.106 also required the presence of strong acid:
O
N
Ph
S
MeO
MsOH (2 eq)
CHCl
3
RT, overnight
O
N
Ph
S
MeO
Z/E ratio ~ 1:5
Et
3
N (2 eq)
CHCl
3
RT, overnight
no isomerization
RT, overnight
CHCl
3
- CH
3
OH
N
H
H
N
MsO
-
(2 eq)
no isomerization
4.106
4.106/4.107
Scheme 4.39.
260
The sulfoxide 4.109, formed by oxidation of N-Boc-cysteamide adduct 4.108, underwent
facile base-catalyzed displacement of thiol:
Et
3
N (2 eq)
CDCl
3
RT, overnight
N
O
Ph
S
H
2
NOC
BocHN O
N
O
S
MeO
+
SH
OMe
(2 eq)
4.109
4.106/4.107
Scheme 4.40.
Two amine adducts (4.110 and 4.111) have also been prepared, but were found to
be resistant against amine displacement with thiols under neutral and basic conditions;
under acidic conditions, only the compound 4.111 yielded the substitution product:
NH +
O
N
Ph
4.99
MeCN
RT, overnight
O
N
Ph
4.110 (84%)
N
N
NH +
O
N
Ph
4.99
MeCN
80
o
C, 4 h
O
N
Ph
4.111 (50%)
N
N
Scheme 4.41.
261
O
N
Ph
4.110
N
Et
3
N (20 mol%)
or
TsOH (20 mol%)
H
2
NOC
SH
NHBoc
+
4.104
no reaction
CHCl
3
or
MeOH - H
2
O
O
N
Ph
4.111
N
N
Et
3
N (1 eq)
or
AcOH (1 eq)
H
2
NOC
SH
NHBoc
+
4.104
no reaction
CHCl
3
or
MeOH - H
2
O
MsOH (1 eq)
CHCl
3
RT, 24 h
S
H
2
NOC
NHBoc
N
O
Ph
+
N
H
H
N
MsO
-
Scheme 4.42.
The inertness of 4.110 towards thiols may explain the lack of activity of the
compound 4.68 as opposed to the highly active parent 4.51. To probe the activity of
cysteine adducts, two N-acetyl-L-cysteine adducts (4.112, 4.113) have been prepared
from active molecules 4.15 and 4.58 and were also found inactive (IC
50
> 10 µM against
OVCAR8 and NCI/ADR cell lines):
OMe
N
H
N
O
S
MeO
O
Br
HO
2
C
SH
NHAc
+
4.103
4.58
Et
3
N (2.5 eq)
CH
2
Cl
2
RT, overnight
OMe
N
H
N
O
S
MeO
O
S
4.113 (99%)
HO
2
C
NHAc
N
H
N
O
S
O
HO
2
C
SH
NHAc
+
4.103
4.15
MeO
Et
3
N (2.5 eq)
CH
2
Cl
2
RT, overnight
N
N
H
O
S
O
4.112 (88%)
MeO
S
HO
2
C
NHAc
Scheme 4.43.
262
4.6 Experimental
All reactions, unless otherwise noted, were carried in flame dried flasks or oven-
dried microwave tubes under dry nitrogen or argon atmosphere. Anhydrous solvents
were purchased from commercial sources (Sigma-Aldrich, Alfa Aesar, EMD). Ugi
reactions were run in 1 or 2 dram vials, flushed with nitrogen and sealed, with magnetic
stirring in reagent grade methanol (TCI) or 2,2,2-trifluoroethanol (Aldrich).
1
H and
13
C
NMR spectra were recorded on Varian Mercury 400, Varian 400-MR (400 MHz) or
Varian VNMRS-500 (500 MHz) 2-channel NMR spectrometers. Chemical shifts are
reported as parts per million ( δ) relative to tetramethylsilane. CF multiplets in
13
C NMR
spectra are interpreted wherever possible. Silica gel (60 Å, 40-63 µm; Sorbent
Technologies) was used as a sorbent for flash column chromatography. Automated flash
chromatography was performed on Isolera One flash purification system (Biotage),
default fraction volume – 12 mL.
General synthetic procedure for the Ugi reaction. The solution of 2 mmol of the
corresponding aniline or benzylamine, 2 mmol of aromatic aldehyde, 2.2 mmol of
propiolic acid and 2.2 mmol of isocyanide in 2 mL of methanol was stirred at room
temperature for 24-48 h (unless otherwise noted). The products that precipitated form the
reaction mixture were filtered off, washed with aqueous methanol (1:1) and recrystallized
from ethyl acetate-hexane (filtering, if necessary, the ethyl acetate solution through a
short plug of silica gel before crystallization). Otherwise, the reaction mixture was
evaporated to dryness and subject to column chromatography in ethyl acetate-hexane.
263
The fractions containing the target compound were evaporated to dryness and the product
was recrystallized from ethyl acetate-hexane.
OMe
N
H
N
O
O
MeO
OMe
4.10. N-[2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl]-N-(3,5-
dimethoxyphenyl)prop-2-ynamide. The Ugi reaction was run on 1 mmol scale in 2 mL
of methanol. Yield 241 mg (54%).
1
H NMR (400 MHz, CDCl
3
): δ 7.07-7.13 (m, 2H),
6.71-6.77 (m, 2H), 6.30-6.45 (m, 3H), 5.86 (s, 1H), 5.53 (br.d, J = 8.3 Hz, 1H), 3.76 (s,
3H), 3.74-3.85 (m, 1H), 3.66 (s, 6H), 2.83 (s, 1H), 1.80-1.96 (m, 2H), 1.51-1.75 (m, 3H),
1.23-1.40 (m, 2H), 0.96-1.17 (m, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 167.7, 160.3,
159.8, 153.5, 140.8, 131.6, 125.8, 113.9, 108.7, 101.3, 80.1, 76.1, 64.8, 55.5, 55.3, 48.8,
32.8, 25.5, 24.8, 24.7.
264
N
H
N
O
O
CF
3
OMe
4.11. N-[2-(Cyclopentylamino)-1-(3-methoxyphenyl)-2-oxoethyl]-N-[3-
(trifluoromethyl)phenyl]prop-2-ynamide. The starting material, cyclopentyl isocyanide,
was prepared according to the literature procedure
65
(bp 80-90 °C/~100 mm Hg). Yield
828 mg (93%).
1
H NMR (400 MHz, CDCl
3
): δ 7.24-7.60 (m, 4H), 7.09 (t, J = 7.9 Hz,
1H), 6.74 (d, J = 7.9 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.58 (s, 1H), 6.06 (s, 1H), 5.88
(br.d, J = 7.1 Hz, 1H), 4.20 (sextet, J = 6.6 Hz, 1H), 3.60 (s, 3H), 2.82 (s, 1H), 1.83-2.02
(m, 2H), 1.47-1.65 (m, 4H), 1.33-1.45 (m, 1H), 1.19-1.31 (m, 1H).
13
C NMR (100 MHz,
CDCl
3
): δ 167.9, 159.5, 153.3, 139.2, 134.7, 134.5, 130.6 (quartet, J = 33.1 Hz), 129.3,
128.9, 128.0 (quartet, J = 3.7 Hz), 125.1 (quartet, J = 3.7 Hz), 123.3 (quartet, J = 273.6
Hz), 122.5, 115.2, 114.9, 81.1, 75.6, 64.1, 55.1, 51.7, 32.7, 32.6, 23.59, 23.57.
19
F NMR
(376 MHz, CDCl
3
): δ -62.72.
265
OMe
OMe
N
H
N
O
O
S
4.12. N-[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl]-N-(3,4-
dimethoxyphenyl)prop-2-ynamide. Yield 706 mg (86%).
1
H NMR (400 MHz, CDCl
3
):
δ 7.19 (dd, J = 4.9 Hz, J = 1.2 Hz, 1H), 6.91 (br.d, J = 3.3 Hz, 1H), 7.19 (dd, J = 4.9 Hz,
J = 3.7 Hz, 1H), 6.60-6.75 (m, 3H), 6.23 (br.d, J = 7.5 Hz, 1H), 6.20 (s, 1H), 4.15 (sextet,
J = 6.6 Hz, 1H), 3.77 (s, 3H), 3.65 (s, 3H), 2.84 (s, 1H), 1.82-1.98 (m, 2H), 1.45-1.63 (m,
4H), 1.28-1.43 (m, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 167.1, 153.5, 148.9, 148.2,
135.0, 131.1, 129.7, 127.8, 126.2, 122.7, 113.0, 109.9, 80.6, 75.8, 59.2, 55.7, 55.5, 51.5,
32.6, 32.5, 23.50, 23.46.
N
N
H
N
O
O
N N
N
F
4.13. N-[2-(Cyclopentylamino)-1-(2-fluorophenyl)-2-oxoethyl]-N-[3-methyl-4-(1H-
tetrazol-1-yl)phenyl]prop-2-ynamide. The starting material, 3-methyl-4-(1H-tetrazol-1-
yl)aniline, was synthesized from commercially available 2-methyl-4-nitroaniline
266
according to the reported procedure.
66
Yield 532 mg (60%).
1
H NMR (400 MHz, CDCl
3
):
δ 8.81 (s, 1H), 7.23-7.60 (m, 3H), 7.10-7.21 (m, 2H), 6.94-7.08 (m, 2H), 6.38 (s, 1H),
6.22 (br.d, J = 7.1 Hz, 1H), 4.26 (sextet, J = 6.6 Hz, 1H), 2.93 (s, 1H), 2.12 (s, 3H), 1.90-
2.07 (m, 2H), 1.43-1.74 (m, 5H), 1.31-1.42 (m, 1H).
13
C NMR (100 MHz, CDCl
3
): 167.4,
160.7 (d, J = 248.5 Hz), 153.0, 142.9, 140.5, 133.9 (d, J = 14.2 Hz), 132.5, 131.2 (d, J =
9.0 Hz), 131.1, 129.5, 125.6, 124.4 (d, J = 2.6 Hz), 120.7 (d, J = 12.9 Hz), 115.4 (d, J =
21.9 Hz), 81.2, 75.6, 70.1, 57.5, 51.8, 32.72, 32.65, 23.6, 17.7.
19
F NMR (376 MHz,
CDCl
3
): δ -115.35.
OMe
N
H
N
O
O
S
MeO
4.14. N-[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl]-N-(2,4-
dimethoxyphenyl)prop-2-ynamide. Yield 453 mg (55%). In CDCl
3
, mixture of two
rotameric forms in 60:40 ratio.
1
H NMR (400 MHz, CDCl
3
):
1
H NMR (400 MHz,
CDCl
3
): δ 7.34 (d, J = 8.7 Hz, 0.6H), 7.12-7.22 (m, 0.6H+0.4H+0.4H), 7.01 (d, J = 3.3
Hz, 0.4H), 6.91 (d, J = 3.3 Hz, 0.6H), 6.86 (dd, J = 5.4 Hz, J = 3.7 Hz, 0.4H), 6.82 (dd, J
= 5.4 Hz, J = 3.7 Hz, 0.6H), 6.53 (d, J = 8.7 Hz, 0.4H), 6.37-6.46 (m, 0.6H+0.6H+0.4H),
6.27 (d, J = 2.5 Hz, 0.6H), 6.22 (dd, J = 8.7 Hz, J = 2.5 Hz, 0.4H), 6.12 (s, 0.4H), 5.99 (s,
0.6H), 4.15-4.27 (m, 0.6H+0.4H), 3.82 (s, 1.2H), 3.78 (s, 1.8H), 3.75 (s, 1.2H), 3.55 (s,
1.8H), 2.74 (s, 0.4H), 2.72 (s, 0.6H), 1.89-2.06 (m, 2×0.6H+2×0.4H), 1.31-1.75 (m,
267
6×0.6H+6×0.4H).
13
C NMR (100 MHz, CDCl
3
): δ 167.5, 167.2, 161.2, 161.0, 157.1,
157.0, 154.7, 154.3, 135.6, 134.5, 132.0, 131.9, 129.7, 129.5, 127.7, 127.5, 126.0, 125.5,
120.9, 120.0, 104.3, 103.9, 99.0, 98.8, 78.4, 78.2, 76.2, 76.1, 60.4, 60.0, 55.7, 55.4, 55.3,
51.6, 51.3, 32.89, 32.86, 32.8, 23.8, 23.8, 23.7.
OMe
N
H
N
O
O
S
4.15. N-[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl]-N-(3-methoxyphenyl)prop-2-
ynamide. Yield 533 mg (70%).
1
H NMR (400 MHz, CDCl
3
): δ 7.23 (d, J = 5.0 Hz, 1H),
7.13 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 3.3 Hz, 1H), 6.72-6.89 (m, 4H), 6.10-6.17 (m, 2H),
4.19 (sextet, J = 6.6 Hz, 1H), 3.68 (s, 3H), 2.84 (s, 1H), 1.86-2.00 (m, 2H), 1.48-1.66 (m,
4H), 1.32-1.45 (m, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 167.0, 159.5, 153.2, 139.8,
135.0, 129.9, 129.1, 128.0, 126.3, 122.2, 115.00, 114.97, 80.7, 75.7, 60.0, 55.2, 51.7, 32.7,
23.6, 23.5.
268
N
H
N
O
O
S
MeO
OMe
4.16. N-[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl]-N-(2,5-
dimethoxyphenyl)prop-2-ynamide. The reaction was run in 2,2,2-trifluoroethanol (2
mL) for 1 h. Yield 207 mg (25%). In CDCl
3
, mixture of two rotameric forms in 50:50
ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.26 (br.d, J = 6.2 Hz, 0.5H), 7.21 (dd, J = 5.0 Hz, J
= 1.0 Hz, 0.5H), 7.18 (dd, J = 5.0 Hz, J = 1.0 Hz, 0.5H), 7.05 (d, J = 2.9 Hz, 0.5H), 7.03
(d, J = 3.3 Hz, 0.5H), 6.94 (d, J = 3.3 Hz, 0.5H), 6.87 (dd, J = 5.4 Hz, J = 3.7 Hz, 0.5H),
6.73-6.86 (m, 4×0.5H), 6.69 (d, J = 9.1 Hz, 0.5H), 6.51 (br.d, J = 7.1 Hz, 0.5H), 6.18 (d,
J = 2.9 Hz, 0.5H), 6.16 (s, 0.5H), 5.89 (s, 0.5H), 4.22 (sextet, J = 7.1 Hz, 0.5H), 4.20
(sextet, J = 7.1 Hz, 0.5H), 3.85 (s, 3×0.5H), 3.74 (s, 3×0.5H), 3.61 (s, 3×0.5H), 3.52 (s,
3×0.5H), 2.73 (s, 0.5H), 2.70 (s, 0.5H), 1.90-2.05 (m, 4×0.5H), 1.32-1.75 (m, 12×0.5H).
13
C NMR (100 MHz, CDCl
3
): δ 167.3, 167.1, 154.2, 153.6, 153.2, 150.4, 150.2, 135.7,
134.6, 129.8, 129.5, 128.3, 127.7, 127.4, 127.2, 126.2, 125.5, 116.4, 116.2, 116.1, 115.8,
112.5, 112.0, 78.3, 78.0, 76.1, 75.9, 60.6, 60.3, 56.2, 55.8, 55.7, 55.6, 51.6, 51.2, 32.8,
32.7, 23.75, 23.71, 23.6.
269
O
O
N
H
N
O
O
4.17. N-[2-(Cyclopentylamino)-2-oxo-1-phenylethyl]-N-(2,3-dihydro-1,4-
benzodioxin-6-yl)prop-2-ynamide. Yield 697 mg (86%).
1
H NMR (400 MHz, CDCl
3
):
δ 7.17-7.25 (m, 3H), 7.10-7.16 (m, 2H), 6.52-6.80 (m, 3H), 5.93 (s, 1H), 5.74 (d, J = 7.5
Hz, 1H), 4.10-4.25 (m, 5H), 2.84 (s, 1H), 1.84-2.00 (m, 2H), 1.46-1.62 (m, 4H), 1.21-
1.41 (m, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 168.0, 153.9, 143.6, 142.8, 133.7, 132.1,
130.1, 128.6, 128.4, 123.8, 119.5, 116.5, 80.5, 76.1, 64.9, 64.1, 63.9, 51.5, 32.72, 32.67,
23.60, 23.57.
N
N
H
N
O
O
N N
N
4.18. N-[2-(Cyclopentylamino)-2-oxo-1-phenylethyl]-N-[3-methyl-4-(1H-tetraazol-1-
yl)phenyl]prop-2-ynamide. Yield 461 mg (54%).
1
H NMR (400 MHz, CDCl
3
): δ 8.81 (s,
1H), 7.13-7.35 (m, 8H), 6.13 (s, 1H), 5.96 (d, J = 6.6 Hz, 1H), 4.22 (sextet, J = 6.6 Hz,
1H), 2.93 (s, 1H), 2.09 (s, 1H), 1.86-2.04 (m, 2H), 1.50-1.68 (m, 4H), 1.25-1.48 (m, 2H).
270
13
C NMR (100 MHz, CDCl
3
): 167.9, 153.1, 142.9, 140.9, 134.4, 133.8, 133.4, 132.5,
130.1, 129.9, 129.0, 128.7, 125.5, 81.2, 75.8, 64.3, 51.7, 32.68, 32.65, 23.58, 23.56, 17.6.
N
H
N
O
O
F
O
4.19. N-[2-(Cyclopentylamino)-1-(2-fluorophenyl)-2-oxoethyl]-N-(2-
furylmethyl)prop-2-ynamide. Yield 586 mg (80%). In CDCl
3
, mixture of two rotameric
forms in 70:30 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.44 (td, J = 7.5 Hz, J = 1.2 Hz,
0.7H), 7.29-7.37 (m, 2×0.3H), 7.22-7.29 (m, 0.7H), 7.13-7.19 (m, 2×0.3H+0.7H), 7.09
(td, J = 7.5 Hz, J = 1.2 Hz, 0.7H), 6.97-7.05 (m, 0.3H), 6.87-6.94 (m, 0.7H), 6.34 (s,
0.3H), 6.17 (dd, J = 2.9 Hz, J = 1.7 Hz, 0.3H), 6.09-6.14 (m, 0.3H+0.7H), 6.07 (s, 0.7H),
6.02 (br.d, J = 7.1 Hz, 0.7H), 5.95 (d, J = 3.3 Hz, 0.3H), 5.85 (d, J = 3.3 Hz, 0.7H), 4.90
(d, J = 17.0 Hz, 0.7H), 4.76 (d, J = 17.0 Hz, 0.7H), 4.61 (d, J = 15.8 Hz, 0.3H), 4.27 (d, J
= 15.8 Hz, 0.3H), 4.19 (sextet, J = 7.1 Hz, 0.3H), 4.13 (sextet, J = 7.1 Hz, 0.7H), 3.26 (s,
0.3H), 3.18 (s, 0.7H), 1.85-1.99 (m, 2×0.3H+2×0.7H), 1.47-1.64 (m, 4×0.3H+4×0.7H),
1.19-1.35 (m, 2×0.3H+2×0.7H).
13
C NMR (100 MHz, CDCl
3
): δ 167.4, 167.2, 161.4 (d, J
= 249.8 Hz), 161.1 (d, J = 249.8 Hz), 156.3, 154.3, 154.2, 149.9, 149.8, 141.9, 141.6,
131.1, 131.0, 130.92, 130.90, 130.6 (d, J = 9.0 Hz), 124.4 (d, J = 2.6 Hz), 124.1 (d, J =
2.6 Hz), 121.3 (d, J = 14.2 Hz), 115.7 (d, J = 20.6 Hz), 115.3 (d, J = 21.9 Hz), 110.6,
271
110.3, 108.7, 108.0, 80.9, 80.0, 75.5, 74.8, 60.4, 55.23, 55.21, 51.5, 51.4, 44.6, 39.4,
32.64, 32.60, 23.6.
19
F NMR (376 MHz, CDCl
3
): -114.62 (0.3F), -114.75 (0.7F).
OMe
N
H
N
O
O
MeO
OMe
4.20. N-[2-(Cyclopentylamino)-1-(4-methoxyphenyl)-2-oxoethyl]-N-(3,5-
dimethoxyphenyl)prop-2-ynamide. Yield 62 mg (7%).
1
H NMR (400 MHz, CDCl
3
): δ
7.04-7.14 (m, 2H), 6.70-6.77 (m, 2H), 6.30-6.45 (m, 3H), 5.86 (s, 1H), 5.53 (br.d, J = 7.1
Hz, 1H), 4.20 (sextet, J = 6.6 Hz, 1H), 3.74 (s, 3H), 3.64 (s, 6H), 2.83 (s, 1H), 1.85-2.02
(m, 2H), 1.47-1.63 (m, 4H), 1.21-1.41 (m, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 168.2,
160.2, 159.7, 153.4, 140.6, 131.5, 125.6, 113.8, 108.7, 101.2, 80.1, 76.1, 64.6, 55.4, 55.2,
51.6, 32.8, 32.7, 23.62, 23.60.
N
H
N
O
O
F
CF
3
4.21. N-[2-(Cyclopentylamino)-1-(4-fluorophenyl)-2-oxoethyl]-N-[3-
(trifluoromethyl)phenyl]prop-2-ynamide. Yield 522 mg (60%).
1
H NMR (400 MHz,
272
CDCl
3
): δ 7.24-7.54 (m, 4H), 7.09 (dd, J = 8.7 Hz, J = 5.4 Hz, 2H), 6.88 (t, J = 8.7 Hz,
2H), 6.09 (s, 1H), 5.87 (br.s, 1H), 4.21 (sextet, J = 7.1 Hz, 1H), 2.83 (s, 1H), 1.79-2.05
(m, 2H), 1.48-1.68 (m, 4H), 1.35-1.47 (m, 1H), 1.21-1.32 (m, 1H).
13
C NMR (100 MHz,
CDCl
3
): δ 167.9, 162.8 (d, J = 249.8 Hz), 153.4, 138.9, 134.7, 132.1 (d, J = 9.0 Hz),
130.8 (quartet, J = 33.5 Hz), 129.1 (d, J = 2.6 Hz), 129.0, 128.1 (quartet, J = 3.9 Hz),
125.3 (quartet, J = 3.9 Hz), 123.3 (quartet, J = 271.7 Hz), 115.6 (d, J = 20.6 Hz), 81.3,
75.5, 63.3, 51.7, 31.73, 32.71, 23.63, 23.59.
19
F NMR (376 MHz, CDCl
3
): δ -62.80, -
111.77.
N
H
N
O
O
CF
3
S
4.22. N-[2-(Cyclohexylamino)-2-oxo-1-thien-2-ylethyl]-N-[3-
(trifluoromethyl)phenyl]prop-2-ynamide. Yield 579 mg (67%).
1
H NMR (400 MHz,
CDCl
3
): δ 7.46-7.55 (m, 2H), 7.35-7.43 (m, 2H), 7.23 (dd, J = 5.0 Hz, J = 0.8 Hz, 1H),
6.92 (d, J = 3.3 Hz, 1H), 6.85 (dd, J = 5.0 Hz, J = 3.3 Hz, 1H), 6.25 (s, 1H), 6.16 (br.d, J
= 7.1 Hz, 1H), 4.20 (sextet, J = 6.7 Hz, 1H), 2.85 (s, 1H), 1.87-2.03 (m, 2H), 1.50-1.67
(m, 4H), 1.31-1.46 (m, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 167.0, 153.0, 139.1, 134.5,
134.0, 131.9 (quartet, J = 33.5 Hz), 130.1, 129.1, 128.2, 127.4 (quartet, J = 3.9 Hz), 126.6,
125.4 (quartet, J = 3.9 Hz), 123.3 (quartet, J = 273.0 Hz), 81.4, 75.4, 59.3, 51.8, 32.7,
23.63, 23.58.
19
F NMR (376 MHz, CDCl
3
): δ -62.69.
273
N
H
N
O
O
4.23. N-[2-(Cyclopentylamino)-2-oxo-1-phenylethyl]-N-(2-naphthyl)prop-2-ynamide.
Yield 652 mg (82%).
1
H NMR (400 MHz, DMSO-d
6
): δ 8.24 (d, J = 6.6 Hz, 1H), 7.88
(br.s, 1H), 7.74-7.84 (m, 2H), 7.60-7.73 (m, 1H), 7.40-7.50 (m, 2H), 6.99-7.17 (m, 5H),
6.10 (s, 1H), 4.11 (s, 1H), 4.08 (sextet, J = 6.6 Hz, 1H), 1.71-1.90 (m, 2H), 1.38-1.68 (m,
5H), 1.21-1.33 (m, 1H).
13
C NMR (100 MHz, DMSO-d
6
): δ 168.2, 152.8, 136.2, 134.3,
132.2, 131.9, 130.01, 129.96, 128.7, 127.9, 127.4, 127.3, 126.5, 126.2, 83.1, 76.8, 63.6,
50.7, 32.1, 31.8, 23.44, 23.40.
N
H
N
O
O
F
O
O
4.24. N-(1,3-Benzodioxol-5-ylmethyl)-N-[2-(benzylamino)-1-(2-fluorophenyl)-2-
oxoethyl]prop-2-ynamide. Yield 814 mg (92%). In DMSO-d
6
, mixture of two rotameric
forms in 60:40 ratio.
1
H NMR (400 MHz, DMSO-d
6
): δ 8.99 (t, J = 5.8 Hz, 0.4H), 8.85 (t,
J = 5.8 Hz, 0.6H), 7.22-7.38 (m, 6H), 7.18 (td, J = 7.5 Hz, J = 1.2 Hz, 0.4H), 7.11 (td, J =
274
7.5 Hz, J = 1.2 Hz, 0.6H), 6.97-7.03 (m, 0.4H), 6.84-6.91 (m, 0.6H), 6.63 (d, J = 7.9 Hz,
0.6H), 6.57 (d, J = 7.9 Hz, 0.4H), 6.46 (s, 0.4H), 6.42 (d, J = 1.2 Hz, 0.6H), 6.34 (dd, J =
7.9 Hz, J = 1.2 Hz, 0.6H), 6.28 (d, J = 1.2 Hz, 0.4H), 6.25 (s, 0.6H), 6.19 (dd, J = 7.9 Hz,
J = 1.2 Hz, 0.4H), 5.88-5.95 (m, 2×0.6H+2×0.4H), 5.07 (d, J = 17.0 Hz, 0.6H), 4.93 (d, J
= 15.8 Hz, 0.4H), 4.81 (s, 0.4H), 4.62 (s, 0.6H), 4.51 (d, J = 17.0 Hz, 0.6H), 4.26-4.44 (m,
2×0.6H+2×0.4H), 4.15 (d, J = 15.8 Hz, 0.4H).
13
C NMR (100 MHz, DMSO-d
6
): δ 168.6,
161.4 (d, J = 247.2 Hz), 161.2 (d, J = 247.2 Hz), 154.7, 154.6, 151.7, 147.1, 147.0, 146.2,
146.0, 139.3, 139.2, 131.7, 131.56, 131.48, 131.40, 131.37, 131.32, 130.88, 130.86,
130.62, 130.60, 128.8, 128.7, 127.8, 127.7, 127.4, 127.3, 124.9 (d, J = 2.6 Hz), 124.7 (d,
J = 2.6 Hz), 122.9 (d, J = 14.2 Hz), 122.3 (d, J = 14.2 Hz), 120.5, 119.7, 115.6 (d, J =
20.6 Hz), 115.3 (d, J = 20.6 Hz), 108.0, 107.9, 107.7, 106.9, 101.2, 101.1, 84.2, 83.1,
76.7, 75.9, 59.0, 54.5, 50.6, 47.4, 43.0, 42.8.
19
F NMR (376 MHz, DMSO-d
6
): δ -114.70
(0.6F), -115.24 (0.4F).
N
H
N
O
O
S
CF
3
4.25. N-[2-(Benzylamino)-2-oxo-1-thien-2-ylethyl]-N-[3-
(trifluoromethyl)phenyl]prop-2-ynamide. Yield 498 mg (56%).
1
H NMR (400 MHz,
CDCl
3
): δ 7.58 (d, J = 7.5 Hz, 1H), 7.53 (br.d, J = 7.9 Hz, 1H), 7.47 (br.s, 1H), 7.41 (t, J
= 7.9 Hz, 1H), 7.22-7.35 (m, 6H), 6.95 (d, J = 3.3 Hz, 1H), 6.87 (dd, J = 5.0 Hz, J = 3.7
275
Hz, 1H), 6.78 (br.t, J = 5.4 Hz, 1H), 6.33 (s, 1H), 4.42-4.54 (m, 2H), 2.88 (s, 1H).
13
C
NMR (100 MHz, CDCl
3
): δ 127.6, 153.0, 139.1, 137.6, 134.2, 133.9, 130.9 (quartet, J =
33.5 Hz), 130.3, 129.1, 128.5, 128.3, 127.39, 127.35, 127.30, 127.26, 126.6, 125.4
(quartet, J = 3.9 Hz), 123.3 (quartet, J = 273.0 Hz), 81.4, 75.3, 59.6, 43.7.
19
F NMR (376
MHz, CDCl
3
): δ -62.57.
N
H
N
O
O
Cl
4.26. N-(2-Chlorobenzyl)-N-[2-(cyclopentylamino)-2-oxo-1-phenylethyl]prop-2-
ynamide. Yield 482 mg (61%). In CDCl
3
, mixture of two rotameric forms in 80:20 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.05-7.33 (m, 9×0.8H+6×0.2H), 6.97-7.03 (m, 2×0.2H),
6.87-6.92 (m, 0.2H), 6.21 (s, 0.2H), 6.06 (br.d, J = 7.5 Hz, 0.2H), 5.99 (br.d, J = 7.1 Hz,
0.8H), 5.78 (s, 0.8H), 5.14 (d, J = 17.9 Hz, 0.8H), 4.95 (d, J = 17.0 Hz, 0.2H), 4.93 (d, J
= 17.9 Hz, 0.8H), 4.64 (d, J = 17.0 Hz, 0.2H), 4.12-4.28 (m, 0.8H+0.2H), 3.40 (s, 0.2H),
3.04 (s, 0.8H), 1.87-1.99 (m, 2×0.8H+2×0.2H), 1.49-1.65 (m, 4×0.8H+4×0.2H), 1.27-
1.40 (m, 2×0.8H+2×0.2H).
13
C NMR (100 MHz, CDCl
3
): δ 167.6, 167.5, 155.0, 154.4,
134.1, 133.7, 133.5, 131.9, 131.8, 129.4, 129.17, 128.88, 128.71, 128.62, 128.56, 128.02,
127.7, 127.6, 126.3, 126.2, 81.0, 79.6, 75.5, 75.4, 66.0, 62.2, 51.5, 51.4, 48.9, 45.1, 32.6,
32.5, 23.57, 23.54.
276
N
H
N
O
O
S
4.27. N-[2-(Cyclohexylamino)-2-oxo-1-thien-2-ylethyl]-N-phenylprop-2-ynamide.
Yield 487 mg (66%).
1
H NMR (400 MHz, CDCl
3
): δ 7.16-7.35 (m, 6H), 6.97 (d, J = 2.9
Hz, 1H), 6.85-6.91 (m, 1H), 6.24 (s, 1H), 6.15 (br.d, J = 7.9 Hz, 1H), 3.75-3.87 (m, 1H),
2.84 (s, 1H), 1.83-1.99 (m, 2H), 1.53-1.75 (m, 3H), 1.27-1.43 (m, 2H), 1.08-1.25 (m, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 166.6, 153.3, 138.7, 134.9, 130.0, 129.8, 128.8, 128.5,
127.9, 126.2, 80.8, 75.7, 59.7, 48.7, 32.5, 32.4, 25.3, 24.6, 24.5.
N
H
N
O
O
F
F
4.28. N-[2-(Cyclohexylamino)-1-(2-fluorophenyl)-2-oxoethyl]-N-(2-
fluorophenyl)prop-2-ynamide. Yield 548 mg (69%). In CDCl
3
, mixture of two
rotameric forms in 75:25 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.91 (td, J = 7.9 Hz, J =
1.7 Hz, 0.75H), 7.31 (br.t, J = 7.9 Hz, 0.25H), 7.10-7.25 (m, 2×0.75H+2×0.25H), 6.84-
7.09 (m, 3×0.75H+3×0.25H), 6.68-6.82 (m, 2×0.75H+2×0.25H), 6.40-6.47 (m,
0.75H+0.25H), 6.15 (s, 0.25H), 6.09 (br.d, J = 7.9 Hz, 0.75H), 3.70-3.82 (m,
0.75H+0.25H), 2.80 (s, 0.25H), 2.71 (s, 0.75H), 1.49-1.98 (m, 5×0.75H+5×0.25H), 0.94-
277
1.37 (m, 5×0.75H+5×0.25H).
13
C NMR (100 MHz, CDCl
3
): δ 167.2, 165.9, 161.0 (d, J =
249.8 Hz), 160.8 (d, J = 248.5 Hz), 159.2 (d, J = 249.8 Hz), 159.1 (d, J = 251.1 Hz),
153.8, 153.6, 133.2, 131.7, 131.5, 131.2, 130.8, 130.7, 130.65, 130.57, 126.4 (d, J = 11.6
Hz), 126.0 (d, J = 12.9 Hz), 124.1, 124.0 (d, J = 3.9 Hz), 123.4 (d, J = 3.9 Hz), 121.3 (d,
J = 14.2 Hz), 120.1 (d, J = 14.2 Hz), 115.9 (d, J = 20.6 Hz), 115.2 (d, J = 20.6 Hz), 79.9,
79.2, 75.4, 75.1, 58.58, 58.56, 56.67, 56.64, 48.9, 48.4, 32.48, 32.44, 25.33, 25.27, 24.7,
24.6, 24.52, 24.48.
19
F NMR (376 MHz, CDCl
3
): δ -114.95 (0.75F+0.25F), -118.16
(0.25F), -119.47 (0.75F).
N
MeO OMe
O
OMe
N
H
O
4.29. N-[2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl]-N-(3,5-
dimethoxyphenyl)acrylamide. Yield 472 mg (52%).
1
H NMR (400 MHz, DMSO-d
6
): δ
7.94 (d, J = 7.5 Hz, 1H), 6.98-7.03 (m, 2H), 6.68-6.73 (m, 2H), 6.29 (t, J = 2.5 Hz, 1H),
6.15 (dd, J = 16.6 Hz, J = 2.5 Hz, 1H), 6.01 (s, 1H), 5.93 (dd, J = 16.6 Hz, J = 10.4 Hz,
1H), 5.54 (dd, J = 10.4 Hz, J = 2.5 Hz, 1H), 3.65 (s, 3H), 3.58 (br.s, 6H), 1.48-1.80 (m,
5H), 0.91-1.32 (m, 5H).
13
C NMR (100 MHz, DMSO-d
6
): δ 168.7, 164.2, 159.6, 158.5,
140.7, 131.3, 129.2, 127.2, 127.0, 113.1, 109.4, 99.5, 62.9, 55.1, 54.9, 47.8, 32.2, 25.1,
24.6, 24.5.
278
N
MeO OMe
O
OMe
N
H
O
4.30. 2-[Acetyl(3,5-dimethoxyphenyl)amino]-N-cyclohexyl-2-(4-
methoxyphenyl)acetamide. Yield 585 mg (66%).
1
H NMR (400 MHz, DMSO-d
6
): δ
7.87 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.3 Hz, 2H), 6.26 (t, J =
2.1 Hz, 1H), 5.95 (s, 1H), 3.64 (s, 3H), 3.58 (s, 6H), 1.48-1.82 (m, 8H), 0.91-1.32 (m,
5H).
13
C NMR (100 MHz, DMSO-d
6
): δ 169.1, 168.9, 159.6, 158.4, 142.0, 131.2, 127.4,
113.0, 109.1, 99.4, 65.1, 62.6, 55.0, 54.9, 47.8, 32.2, 25.1, 24.6, 24.5, 22.9.
N
MeO OMe
O
OMe
N
H
O
4.31. N-[2-(cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl]-N-(3,5-
dimethoxyphenyl)propanamide. Yield 554 mg (61%).
1
H NMR (400 MHz, DMSO-d
6
):
δ 7.85 (d, J = 7.5 Hz, 1H), 6.97 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.3 Hz, 2H), 6.26 (br.s,
1H), 5.94 (s, 1H), 3.64 (s, 3H), 3.58 (br.s, 6H), 1.89-2.10 (m, 2H), 1.47-1.79 (m, 5H),
0.84-1.33 (m, 8H).
13
C NMR (100 MHz, DMSO-d
6
): δ 172.3, 169.0, 159.6, 158.4, 151.1,
279
141.5, 131.2, 127.4, 113.0, 109.2, 99.4, 62.7, 55.0, 54.9, 47.8, 32.22, 32.18, 27.4, 25.1,
24.6, 24.5, 9.4.
N
MeO OMe
O
OMe
N
H
O
Br
4.32. 2-[(Bromoacetyl)(3,5-dimethoxyphenyl)amino]-N-cyclohexyl-2-(4-
methoxyphenyl)acetamide.
Yield 175 mg (17%).
1
H NMR (400 MHz, CDCl
3
): δ 7.09
(d, J = 8.7 Hz, 2H), 6.85 (br.s, 1H), 6.73 (d, J = 8.7 Hz, 2H), 6.33 (t, J = 2.1 Hz, 1H),
5.89 (br.s, 1H), 5.81 (s, 1H), 5.55 (d, J = 8.3 Hz, 1H), 3.75 (s, 6H), 3.72 (s, 3H), 3.45-
3.85 (m, 3H), 1.78-1.96 (m, 2H), 1.50-1.71 (m, 3H), 1.22-1.40 (m, 2H), 0.96-1.17 (m,
3H).
13
C NMR (100 MHz, CDCl
3
): δ 168.1, 166.7, 160.7, 159.6, 140.9, 131.5, 126.0,
113.8, 108.0, 101.3, 65.6, 55.5, 55.2, 48.7, 32.81, 32.77, 27.9, 25.4, 24.8, 24.7.
N
MeO OMe
O
OMe
N
H
O
Br
4.33. 3-Bromo-N-[2-(cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl]-N-(3,5-
dimethoxyphenyl)propanamide. Yield 530 mg (50%).
1
H NMR (400 MHz, DMSO-d
6
):
280
δ 7.88 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.82-7.10 (br.s, 1H), 6.70 (d, J = 8.7
Hz, 2H), 6.29 (t, J = 2.5 Hz, 1H), 5.96 (s, 1H), 5.80 (br.s, 1H), 3.65 (s, 3H), 3.40-3.74
(m+br.s, 9H), 2.52-2.69 (m, 2H), 1.48-1.78 (m, 5H), 0.90-1.31 (m, 5H).
13
C NMR (100
MHz, DMSO-d
6
): δ 168.9, 168.7, 159.6, 158.5, 140.8, 131.3, 127.0, 113.1, 109.2, 99.7,
94.5, 62.8, 55.1, 54.9, 47.8, 37.3, 32.2, 28.8, 25.1, 24.6, 24.5.
N
MeO OMe
O
OMe
N
H
O
Br
4.34. 4-Bromo-N-[2-(cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl]-N-(3,5-
dimethoxyphenyl)butanamide. Yield 160 mg (15%).
1
H NMR (400 MHz, CDCl
3
): δ
7.06 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.30 (t, J = 2.1 Hz, 1H), 5.84 (s, 1H),
5.58 (d, J = 7.9 Hz, 1H), 3.75-3.84 (m, 1H), 3.73 (s, 3H), 3.65 (br.s, 6H), 3.35-3.45 (m,
2H), 2.21-2.36 (m, 2H), 2.07-2.17 (m, 2H), 1.78-1.95 (m, 2H), 1.50-1.69 (m, 3H), 1.25-
1.38 (m, 2H), 0.94-1.15 (m, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 172.0, 168.7, 160.6,
159.4, 141.7, 131.5, 126.5, 113.6, 108.2, 100.7, 65.0, 55.4, 55.1, 48.6, 33.6, 32.8, 32.6,
28.2, 25.4, 24.8, 24.7.
281
N
MeO OMe
O
OMe
N
H
O
N
O
4.35. N-[2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl]-N-(3,5-
dimethoxyphenyl)-4-morpholin-4-ylbut-2-ynamide. N-Propargylmorpholine was
prepared by literature method
67
and converted to 4-(4-morpholinyl)-2-butynoic acid
according to the procedure reported for 4-(dimethylamino)-2-butynoic acid.
50
The Ugi
reaction was run on 1 mmol scale in the presence of 1 eq of methanesulfonic acid, and the
reaction mixture was neutralized by addition of solid NaHCO
3
prior to isolation of the
product. Yield 103 mg (19%).
1
H NMR (400 MHz, CDCl
3
): δ 7.10 (d, J = 8.3 Hz, 2H),
6.74 (d, J = 8.3 Hz, 2H), 6.38 (br.s, 2H), 6.31 (t, J = 2.2 Hz, 1H), 5.87 (s, 1H), 5.55 (d, J
= 8.3 Hz, 1H), 3.75 (s, 3H), 3.71-3.85 (m, 1H), 3.65 (s, 6H), 3.47-3.55 (m, 4H), 3.23 (s,
2H), 2.00-2.10 (m, 4H), 1.75-1.97 (m, 2H), 1.51-1.70 (m, 3H), 1.26-1.40 (m, 2H), 0.96-
1.17 (m, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 167.8, 160.4, 159.7, 154.1, 141.1, 131.6,
125.9, 113.8, 108.9, 100.9, 88.1, 79.5, 66.5, 64.5, 55.4, 55.2, 51.3, 48.7, 47.1, 32.7, 25.4,
24.74, 24.66.
282
OMe
MeO
OMe N
H
N
O
S
S
O O
O
O
4.39. 2-{4-[Bis(vinylsulfonyl)amino]-2,6-dimethoxyphenyl}-N-cyclohexyl-2-(4-
methoxyphenyl)acetamide. The mixture of 3,5-dimethoxyaniline (306 mg, 2 mmol),
glyoxylic acid monohydrate (202 mg, 2.2 mmol, 1.1 eq) and 4-methoxyphenylboronic
acid (304 mg, 2 mmol) in 5 mL of acetonitrile was stirred overnight at room temperature.
The resulting brown suspension was evaporated to dryness, and the amino acid 4.37 was
isolated by flash column chromatography on silica (EtOAc-methanol-5% aq. NH
3
7:2:1;
R
f
0.28) as light tan crystals (288 mg) and was used in the next step without further
purification.
The mixture of the crude amino acid 4.37, cyclohexylamine (600 mg, 6 mmol)
and HATU (760 mg, 2 mmol) in 3 mL of DMSO was stirred overnight at room
temperature. The reaction mixture was poured into 50 mL of 0.1 N NaOH, extracted with
3×25 mL of ethyl acetate. Combined organic extracts were washed with 50 mL of water
and dried over Na
2
SO
4
. After evaporation of the solvent, the residue was subject to flash
column chromatography on silica (EtOAc; R
f
0.25) to yield ~2:1 mixture of the target
amide 4.38 and N''-cyclohexyl-N,N,N',N'-tetramethylguanidine as brownish foam (637
mg), which was used directly in the next step.
283
The crude amide 4.38 was dissolved in 5 mL of anhydrous CHCl
3
. Triethylamine
(420 µL, 3 mmol) was then added, followed by dropwise addition of 2-
chloroethanesulfonyl chloride (160 µL, 1.5 mmol). The reaction mixture was stirred at
room temperature for 1.5 h, poured into 50 mL of ethyl acetate and washed with 2×30
mL of 1 N HCl, 30 mL of water and 20 mL of brine. The organic layer was dried over
Na
2
SO
4
. The product 4.39 was isolated by flash column chromatography on silica
(EtOAc-hexane 3:2) as white foam. Yield 370 mg (32% over 3 steps).
1
H NMR (400
MHz, CDCl
3
): δ 7.21-7.26 (m, 2H), 7.03 (dd, J = 16.6 Hz, J = 10.0 Hz, 2H), 6.80-6.85
(m, 2H), 6.42 (s, 2H), 6.31 (d, J = 16.6 Hz, 2H), 6.12 (d, J = 10.0 Hz, 2H), 5.38 (br.d,
1H), 5.24 (s, 1H), 3.77 (s, 3H), 3.75 (s, 6H), 1.83-1.92 (m, 1H), 1.72-1.81 (m, 1H), 1.49-
1.65 (m, 3H), 1.26-1.41 (m, 2H), 0.94-1.17 (m, 3H).
13
C NMR (100 MHz, CDCl
3
): δ
171.5, 158.6, 158.0, 135.9, 133.0, 130.6, 130.2, 129.6, 120.2, 114.0, 107.4, 55.9, 55.1,
47.8, 32.9, 32.6, 25.4, 24.6.
N
O
N
H
O
N
N N
N
F
4.40. N-[2-(Cyclopentylamino)-1-(3-fluorophenyl)-2-oxoethyl]-N-[3-methyl-4-(1H-
tetrazol-1-yl)phenyl]prop-2-ynamide. Yield 573 mg (64%).
1
H NMR (400 MHz,
284
CDCl
3
): δ 8.82 (s, 1H), 7.40 (br.s, 1H), 7.16-7.34 (m, 3H), 6.93-7.08 (m, 3H), 6.08 (s,
1H), 5.89 (br.d, 1H), 4.26 (sextet, J = 6.6 Hz, 1H), 2.96 (s, 1H), 2.16 (s, 3H), 1.92-2.10
(m, 2H), 1.53-1.72 (m, 4H), 1.28-1.52 (m, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 167.4,
162.5 (d, J = 246.5 Hz), 153.2, 142.9, 140.7, 135.6 (d, J = 7.5 Hz), 132.2 (d, J = 13.5 Hz),
132.7, 130.4 (d, J = 9.0 Hz), 129.8, 125.8, 117.1 (d, J = 22.6 Hz), 116.2 (d, J = 19.5 Hz),
81.6, 75.6, 63.8, 51.9, 32.8, 23.6, 17.8.
19
F NMR (376 MHz, CDCl
3
): δ -111.21.
N
O
N
H
O
N
N N
N
N
4.41. N-[2-(Cyclopentylamino)-2-oxo-1-pyridin-3-ylethyl]-N-[3-methyl-4-(1H-
tetrazol-1-yl)phenyl]prop-2-ynamide. The Ugi reaction was run on 2 mmol scale in 3
mL of 2,2,2-trifluoroethanol for 1 h. Yield 211 mg (25%).
1
H NMR (400 MHz, DMSO-
d
6
): δ 9.83 (s, 1H), 8.35-8.42 (m, 2H), 8.33 (br.d, 1H), 7.31-7.60 (m, 4H), 7.22 (dd, J =
7.9 Hz, J = 4.6 Hz, 1H), 6.10 (s, 1H), 4.34 (s, 1H), 4.06 (sextet, J = 6.6 Hz, 1H), 3.34 (s,
1H), 2.04 (s, 3H), 1.72-1.89 (m, 2H), 1.37-1.65 (m, 5H), 1.20-1.32 (m, 1H).
13
C NMR
(100 MHz, DMSO-d
6
): δ 167.3, 152.3, 150.9, 149.1, 144.4, 140.2, 133.9, 133.2, 132.3,
130.1, 129.8, 126.1, 123.1, 111.9, 83.8, 76.4, 64.2, 61.3, 59.7, 50.7, 32.0, 31.8, 23.4, 23.3,
17.2.
285
N
O
N
H
O
N
N N
N
F
4.42. N-[2-(Cyclopentylamino)-1-(4-fluorophenyl)-2-oxoethyl]-N-[3-methyl-4-(1H-
tetrazol-1-yl)phenyl]prop-2-ynamide. Yield 480 mg (54%).
1
H NMR (400 MHz,
CDCl
3
): δ 8.80 (s, 1H), 7.33 (br.s, 1H), 7.10-7.24 (m, 3H), 6.94 (t, J = 8.3 Hz), 6.08 (s,
1H), 5.85 (br.d, 1H), 4.21 (sextet, J = 6.6 Hz, 1H), 2.91 (s, 1H), 2.12 (s, 3H), 1.87-2.05
(m, 2H), 1.50-1.67 (m, 4H), 1.35-1.46 (m, 1H), 1.23-1.34 (m, 1H).
13
C NMR (100 MHz,
CDCl
3
): δ 167.9, 162.9 (d, J = 251.1 Hz), 153.3, 143.0, 140.8, 134.5, 134.1, 132.7, 132.2
(d, J = 9.0 Hz), 130.0, 129.2 (d, J = 3.0 Hz), 125.8, 115.9 (d, J = 22.6 Hz), 81.6, 75.7,
63.5, 51.9, 32.9, 32.8, 23.7, 17.9.
19
F NMR (376 MHz, CDCl
3
): δ -111.25.
286
N
O
N
H
O
N
N N
N
F
F
4.43. N-[2-(Cyclopentylamino)-1-(3,4-difluorophenyl)-2-oxoethyl]-N-[3-methyl-4-
(1H-tetrazol-1-yl)phenyl]prop-2-ynamide. Yield 710 mg (76%).
1
H NMR (400 MHz,
CDCl
3
): δ 8.79 (s, 1H), 7.37 (br.s, 1H), 7.16-7.25 (m, 2H), 7.03-7.15 (m, 2H), 6.96-7.01
(m, 1H), 6.00 (s, 1H), 5.85 (br.d, 1H), 4.23 (sextet, J = 6.7 Hz, 1H), 2.93 (s, 1H), 2.16 (s,
3H), 1.91-2.08 (m, 2H), 1.54-1.70 (m, 4H), 1.38-1.50 (m, 1H), 1.27-1.38 (m, 1H).
13
C
NMR (100 MHz, CDCl
3
): δ 167.4, 153.2, 150.2 (dd, J = 254.1 Hz, J = 46.6 Hz), 150.0
(dd, J = 254.1 Hz, J = 46.6 Hz), 143.0, 140.3, 134.3, 134.1, 132.7, 130.3 (t, J = 4.5 Hz),
129.7, 126.5 (t, J = 4.5 Hz), 125.8, 119.2 (dd, J = 12.0 Hz, J = 7.5 Hz), 117.5 (dd, J =
15.0 Hz, J = 3.0 Hz), 81.8, 75.4, 62.9, 51.7, 32.6, 23.6, 17.7.
19
F NMR (376 MHz,
CDCl
3
): δ -135.88 (2F).
287
N
O
N
H
O
N
N N
N
F
F F
F
F
4.44. N-[2-(Cyclopentylamino)-2-oxo-1-(pentafluorophenyl)ethyl]-N-[3-methyl-4-
(1H-tetrazol-1-yl)phenyl]prop-2-ynamide. Yield 604 mg (58%).
1
H NMR (400 MHz,
CDCl
3
): δ 8.92 (s, 1H), 7.60 (br.s, 1H), 7.20-7.40 (m, 2H), 6.64 (br.s, 2H), 4.24 (sextet, J
= 6.6 Hz, 1H), 3.02 (s, 1H), 2.20 (s, 3H), 1.87-2.05 (m, 2H), 1.52-1.70 (m, 4H), 1.33-1.50
(m, 2H).
13
C NMR (100 MHz, CDCl
3
): δ 164.7, 153.0, 146.7, 144.2, 142.9, 140.5, 139.9,
138.6, 136.0, 134.6, 133.6, 133.2, 128.9, 126.1, 108.6, 82.3, 74.9, 53.4, 52.1, 32.5, 32.3,
23.5, 17.8.
19
F NMR (376 MHz, CDCl
3
): δ -137.62 (d, J = 21.2 Hz, 2F), -150.10 (t, J =
21.2 Hz, 1F), -160.29 (t, J = 21.2 Hz, 2F).
N
O
N
H
O
O NH
2
4.45. 4-[[2-(Cyclopentylamino)-2-oxo-1-phenylethyl](propioloyl)amino]benzamide.
Yield 214 mg (28%).
1
H NMR (400 MHz, DMSO-d
6
): δ 8.23 (d, J = 7.1 Hz, 1H), 7.93 (s,
288
1H), 7.64 (d, J = 8.3 Hz, 2H), 7.26-7.45 (m, 3H), 7.05-7.18 (m, 5H), 6.04 (s, 1H), 4.21 (s,
1H), 4.06 (sextet, J = 6.6 Hz, 1H), 1.71-1.88 (m, 2H), 1.36-1.65 (m, 5H), 1.20-1.31 (m,
1H).
13
C NMR (100 MHz, DMSO-d
6
): δ 168.1, 166.9, 152.4, 141.3, 134.1, 133.3, 130.7,
130.0, 128.0, 127.9, 127.2, 83.3, 76.6, 63.4, 50.7, 32.1, 31.8, 23.42, 23.38.
N
O
N
H
O
CO
2
Me
4.46. Methyl 4-[[2-(cyclopentylamino)-2-oxo-1-
phenylethyl](propioloyl)amino]benzoate. Yield 482 mg (60%).
1
H NMR (400 MHz,
CDCl
3
): δ 7.87 (d, J = 8.7 Hz, 2H), 7.18-7.38 (m, 4H), 7.14 (d, J = 7.0 Hz, 2H), 6.10 (s,
1H), 5.69 (br.d, 1H), 4.27 (sextet, J = 6.6 Hz, 1H), 3.90 (s, 3H), 2.83 (s, 1H), 1.90-2.08
(m, 2H), 1.52-1.69 (m, 4H), 1.37-1.48 (m, 1H), 1.25-1.36 (m, 1H).
13
C NMR (100 MHz,
CDCl
3
): δ 167.9, 166.3, 153.2, 142.9, 133.2, 131.0, 130.2, 129.9, 129.7, 128.9, 128.6,
80.9, 75.8, 64.5, 52.2, 51.7, 32.80, 32.75, 23.6.
289
N
O
N
H
O
O O
4.47. tert-Butyl 4-[[2-(cyclopentylamino)-2-oxo-1-
phenylethyl](propioloyl)amino]benzoate. The starting material, tert-butyl 4-
aminobenzoate, was prepared according to the literature procedure.
68
Yield 990 mg
(74%).
1
H NMR (400 MHz, DMSO-d
6
): δ 8.24 (d, J = 6.6 Hz, 1H), 7.67 (d, J = 8.7 Hz,
2H), 7.43 (br.s, 2H), 7.06-7.19 (m, 5H), 6.06 (s, 1H), 4.22 (s, 1H), 4.06 (sextet, J = 6.6
Hz, 1H), 1.72-1.88 (m, 2H), 1.37-1.66 (m, 5H), 1.49 (s, 9H), 1.21-1.32 (m, 1H).
13
C
NMR (100 MHz, DMSO-d
6
): δ 168.0, 164.2, 152.2, 142.7, 134.0, 131.2, 130.5, 130.0,
128.7, 128.0, 83.4, 81.0, 76.5, 63.4, 50.6, 32.0, 31.8, 27.6, 23.40, 23.37.
N
O
N
H
O
CO
2
H
4.48. 4-[[2-(Cyclopentylamino)-2-oxo-1-phenylethyl](propioloyl)amino]benzoic acid.
The ester 4.47 (446 mg, 1 mmol) was dissolved in 10 mL CH
2
Cl
2
and 2 mL (3.1 g, 27
mmol, 27 eq) of trifluoroacetic acid was added. The mixture was stirred at room
temperature for 3.5 h and poured into 50 mL of ethyl acetate and 25 mL of water. The
290
organic phase was washed with 3×25 mL of water, 25 mL of brine and dried over
Na
2
SO
4
. The solvent was evaporated to dryness and the solid residue was recrystallized
from ethyl acetate-hexane. Yield 354 mg (91%).
1
H NMR (400 MHz, DMSO-d
6
): 13.0 (s,
1H), 8.24 (d, J = 7.1 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.05-7.18 (m, 5H), 6.05 (s, 1H),
4.23 (s, 1H), 4.06 (sextet, J = 6.6 Hz, 1H), 1.71-1.88 (m, 2H), 1.35-1.64 (m, 5H), 1.20-
1.32 (m, 1H).
13
C NMR (100 MHz, DMSO-d
6
): 168.0, 166.6, 152.2, 151.1, 142.7, 134.0,
131.1, 130.0, 129.0, 128.0, 127.9, 83.4, 76.5, 63.5, 50.7, 32.1, 31.8, 23.41, 23.38.
N
MeO OMe
O
OMe
N
H
O
OH
4.49. N-[2-(Cyclohexylamino)-1-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl]-N-(3,5-
dimethoxyphenyl)prop-2-ynamide. Yield 190 mg (20%).
1
H NMR (400 MHz, DMSO-
d
6
): δ 8.89 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 6.62-6.73 (m, 1H), 6.35-6.60 (m+br.s, 4H),
6.30 (t, J = 2.1 Hz, 1H), 5.81 (s, 1H), 4.17 (s, 1H), 3.65 (s, 3H), 3.60 (s, 7H), 1.48-1.78
(m, 5H), 0.93-1.32 (m, 5H).
13
C NMR (100 MHz, CDCl
3
): δ 167.9, 159.2, 152.4, 147.1,
145.6, 140.2, 126.4, 121.3, 117.3, 111.2, 109.5, 99.9, 82.5, 76.8, 63.1, 55.3, 55.1, 47.9,
32.2, 25.1, 24.6, 24.5.
291
N
MeO OMe
O
OH
N
H
O
4.50. N-[2-(Cyclohexylamino)-1-(4-hydroxyphenyl)-2-oxoethyl]-N-(3,5-
dimethoxyphenyl)prop-2-ynamide. Recrystallized from acetone-hexane. Yield 110 mg
(13%).
1
H NMR (400 MHz, DMSO-d
6
): δ 9.38 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 6.88 (d,
J = 8.3 Hz, 2H), 6.50 (d, J = 8.3 Hz, 2H), 6.3-6.6 (br.s, 1H), 6.28 (t, J = 2.1 Hz, 1H), 5.84
(s, 1H), 4.16 (s, 1H), 3.59 (s, 6H), 3.50-3.62 (m, 1H), 1.47-1.78 (m, 5H), 0.92-1.33 (m,
5H).
13
C NMR (100 MHz, DMSO-d
6
): δ 168.1, 159.3, 156.8, 152.3, 140.3, 131.3, 124.3,
114.6, 109.6, 99.8, 82.3, 76.8, 63.1, 55.1, 47.9, 32.15, 32.11, 25.1, 24.5, 24.4.
N
O
N
H
O
CO
2
Et
OMe
MeO
S
4.51. Ethyl {[[(2,4-dimethoxyphenyl)(propioloyl)amino](thien-2-
yl)acetyl]amino}acetate. The reaction was run on 3 mmol scale in 3 mL of methanol.
Yield 1.04 g (81%). In CDCl
3
, mixture of two rotameric forms in 60:40 ratio.
1
H NMR
(400 MHz, CDCl
3
): δ 7.85 (t, J = 5.0 Hz, 0.4H), 7.26 (d, J = 8.7 Hz, 0.6H), 7.21 (d, J =
5.0 Hz, 0.6H), 7.18 (d, J = 5.0 Hz, 0.4H), 7.09 (t, J = 5.0 Hz, 0.6H), 7.04 (d, J = 3.3 Hz,
292
0.4H), 6.91 (d, J = 3.3 Hz, 0.6H), 6.84 (d, J = 5.0 Hz, 0.6H), 6.83 (d, J = 5.0 Hz, 0.4H),
6.67 (d, J = 8.7 Hz, 0.4H), 6.42 (t, J = 1.8 Hz, 0.6H), 6.40 (d, J = 2.9 Hz, 0.4H), 6.33 (d, J
= 2.9 Hz, 0.6H), 6.25 (dd, J = 8.7 Hz, J = 2.5 Hz, 0.4H), 6.06 (s, 0.4H), 5.95 (s, 0.6H),
4.08-4.25 (m, 3×0.6H+3×0.4H), 4.05 (d, J = 5.0 Hz, 0.6H), 4.00 (d, J = 5.0 Hz, 0.4H),
3.84 (s, 3×0.4H), 3.78 (s, 3×0.6H), 3.75 (s, 3×0.4H), 3.64 (s, 3×0.6H), 2.75 (s, 0.4H),
2.73 (s, 0.6H), 1.21-1.30 (m, 3×0.6H+3×0.4H).
13
C NMR (100 MHz, CDCl
3
): δ 169.6,
168.3, 168.0, 161.3, 161.1, 157.1, 156.9, 154.7, 154.2, 134.9, 134.3, 132.2, 131.7, 129.8,
129.7, 127.6, 127.5, 126.3, 125.6, 121.1, 120.1, 104.3, 104.0, 98.9, 98.8, 78.7, 78.5, 76.1,
76.0, 69.4, 61.4, 61.3, 61.0, 60.35, 60.31, 55.9, 55.5, 55.4, 41.8, 41.6, 14.1.
N
O
N
H
O
CO
2
H
OMe
MeO
S
4.52. {[[(2,4-Dimethoxyphenyl)(propioloyl)amino](thien-2-yl)acetyl]amino}acetic
acid. The ester 4.51 (430 mg, 1 mmol) was suspended in the mixture of THF (2 mL) and
water (2 mL). Solid LiOH·H
2
O (46 mg, 1.1 mmol, 1.1 eq) was then added to the reaction
mixture. Homogeneous brown solution forms after ~15 min. After 1 h, the reaction
mixture was diluted with 20 mL of water and 15 mL of 2 N HCl. The product was
extracted with 3×25 mL of ethyl acetate, the combined organic extracts were dried over
Na
2
SO
4
, and the product was isolated by flash column chromatography (silica – acetic
acid-ethyl acetate 3:97). Yield 404 mg (~100%). In CDCl
3
, mixture of two rotameric
293
forms in 60:40 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 8.89 (br.s, 0.6H+0.4H), 8.02 (t, J =
5.2 Hz, 0.4H), 7.32 (t, J = 5.2 Hz, 0.6H), 7.26 (d, J = 8.3 Hz, 0.6H), 7.21 (dd, J = 5.2 Hz,
J = 1.2 Hz, 0.6H), 7.18 (dd, J = 5.2 Hz, J = 1.2 Hz, 0.4H), 7.03 (dd, J = 3.5 Hz, J = 1.2
Hz, 0.4H), 6.91 (dd, J = 3.5 Hz, J = 1.2 Hz, 0.6H), 6.80-6.85 (m, 0.6H+0.4H), 6.65 (d, J
= 8.7 Hz, 0.4H), 6.42 (t, J = 2.5 Hz, 0.6H), 6.40 (d, J = 2.5 Hz, 0.4H), 6.33 (d, J = 2.5 Hz,
0.6H), 6.25 (dd, J = 8.7 Hz, J = 2.5 Hz, 0.4H), 6.10 (s, 0.4H), 5.96 (s, 0.6H), 4.25 (dd, J =
18.7 Hz, J = 5.8 Hz, 0.4H), 4.12 (d, J = 5.4 Hz, 2×0.6H), 4.07 (dd, J = 18.7 Hz, J = 5.0
Hz, 0.4H), 3.83 (s, 3×0.4H), 3.78 (3×0.6H), 3.75 (3×0.4H), 3.64 (3×0.6H), 2.80 (s, 0.4H),
2.78 (s, 0.6H).
13
C NMR (100 MHz, CDCl
3
): δ 172.7, 172.6, 169.0, 168.6, 161.4, 161.2,
157.0, 156.8, 155.0, 154.6, 134.4, 134.1, 132.1, 131.8, 130.1, 130.0, 127.8, 127.7, 126.5,
125.7, 120.8, 119.7, 104.5, 104.1, 98.9, 98.8, 79.4, 79.3, 75.8, 75.7, 60.9, 60.6, 56.0, 55.5,
55.44, 55.41, 41.74, 41.68.
N
O
N
H
O
OMe
MeO
S
H
N
O
N
O
4.53. N-(2,4-Dimethoxyphenyl)-N-[2-({2-[(2-morpholin-4-ylethyl)amino]-2-
oxoethyl}amino)-2-oxo-1-thien-2-ylethyl]prop-2-ynamide. The acid 4.52 (402 mg, 1
mmol), 4-(2-aminoethyl)morpholine (130 mg, 1 mmol), HATU (380 mg, 1 mmol) and
175 µL (1 mmol) of ethyldiisopropylamine were mixed in 1 mL of DMSO, and the
reaction mixture was stirred at room temperature for 3 h (control by TLC, silica –
294
methanol-ethyl acetate 1:4). The reaction mixture was poured into 50 mL of 0.1 N NaOH
and extracted with 3×25 mL of ethyl acetate. Combined organic extracts were washed
with 2×30 mL of water, 30 mL of brine, dried over Na
2
SO
4
and evaporated. The product
was isolated by flash column chromatography (silica – methanol-ethyl acetate 1:4). Yield
365 mg (71%). In CDCl
3
, mixture of two rotameric forms in 60:40 ratio.
1
H NMR (400
MHz, CDCl
3
): δ 7.72 (t, J = 5.8 Hz, 0.4H), 7.44 (t, J = 5.8 Hz, 0.6H), 7.17-7.24 (m,
0.6H+2×0.4H), 6.90-7.03 (m, 2×0.6H+2×0.6H), 6.81-6.87 (m, 2×0.6H), 6.34-6.42 (m,
2×0.6H+0.4H), 6.30 (dd, J = 8.7 Hz, J = 2.5 Hz, 0.4H), 5.80 (s, 0.4H), 5.62 (s, 0.6H),
4.12-4.22 (m, 0.6H+0.4H), 3.72-3.78 (m, 6×0.6H+6×0.4H), 3.63-3.69 (m,
4×0.6H+4×0.4H), 3.29-3.45 (m, 2H), 2.79 (s, 0.4H), 2.77 (s, 0.6H), 2.40-2.53 (m,
6×0.6H+6×0.4H).
13
C NMR (100 MHz, CDCl
3
): δ 168.8, 168.6, 168.4, 161.3, 161.1,
156.8, 156.4, 154.8, 154.3, 134.8, 134.4, 131.8, 130.0, 129.7, 127.9, 127.6, 126.5, 125.8,
121.1, 120.5, 104.6, 104.1, 98.9, 79.1, 79.0, 75.9, 75.8, 66.8, 62.6, 62.0, 57.0, 56.9, 55.9,
55.7, 55.4, 53.3, 43.6, 36.2.
N
O
N
H
O
S
OH
4.54. N-[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl]-N-(3-hydroxyphenyl)prop-2-
ynamide. Yield 568 mg (77%).
1
H NMR (400 MHz, DMSO-d
6
): δ 9.49 (s, 1H), 8.18 (d,
J = 6.6 Hz, 1H), 7.37 (dd, J = 5.4 Hz, J = 1.2 Hz, 1H), 6.97 (t, J = 8.3 Hz, 1H), 6.80-6.92
295
(m, 3H), 6.59-6.70 (m, 2H), 6.18 (s, 1H), 4.19 (s, 1H), 4.00 (sextet, J = 6.6 Hz, 1H), 1.69-
1.85 (m, 2H), 1.37-1.66 (m, 5H), 1.23-1.35 (m, 1H).
13
C NMR (100 MHz, DMSO-d
6
): δ
167.4, 156.9, 152.3, 139.2, 135.9, 129.5, 128.6, 127.8, 126.2, 121.5, 117.9, 115.4, 82.9,
76.6, 58.5, 50.8, 32.0, 31.7, 23.5, 23.4.
OH
OMe
NH
2
4.88. 4-Amino-3-methoxyphenol. Solid NaNO
2
(2.66 g, 38.6 mmol, ~1.9 eq) was added
in small portions with stirring to 66 mL of conc. H
2
SO
4
, cooled in dry ice-ethylene glycol
bath. To the resulting solution 1,3-dimethoxybenzene (2.6 mL, ~2.76 g, 20 mmol) was
added dropwise over 20 min, followed by stirring for 15 min at the same temperature.
Clear brown solution formed. The reaction mixture was poured into the mixture of ice
(~600 mL) and urea (6 g, pre-dissolved in water). The resulting dark brown liquid, from
which the crystalline precipitate gradually separates, was stirred for 40 min, the solid
(crude 3-methoxy-4-nitrosophenol
69
) was filtered off, washed with cold water and dried
overnight on filter. It was then redissolved in the mixture of 10% aq. NaOH (50 mL) and
water (25 mL). The solution was heated up to 70-80 °C, and solid Na
2
S
2
O
4
(6.2 g, 35.6
mmol, ~1.8 eq) was added in portions (color changed from orange-brown to violet and
finally to light yellow-brown). The mixture was cooled down in ice-water bath and
neutralized with acetic acid to pH ~ 6. The product precipitates as yellowish-white
needles. The crystals were filtered off, washed with ice-cold water and dried on filter
296
under a flow of N
2
. The compound oxidizes very easily, turning blue-gray. Yield 1.36 g
(49%). The solutions for NMR analysis should be prepared under N
2
atmosphere.
1
H
NMR (CD
3
CN, 400 MHz): δ 6.52 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 2.6 Hz, 1H), 6.21 (dd,
J = 8.4 Hz, J = 2.6 Hz, 1H), 4.4 (br.s, 2H), 3.76 (s, 3H).
13
C NMR (CD
3
CN, 100 MHz): δ
150.3, 148.9, 130.4, 116.0, 107.5, 100.6, 56.0.
OH
MeO
N
O
S
H
N
O
OEt
O
4.55. Ethyl 2-{[2-(4-hydroxy-2-methoxypropioloylanilino)-2-(2-
thienyl)acetyl]amino}acetate. The Ugi reaction was run on 4 mmol scale. The product
was isolated by flash chromatography on silica (40 g Yamazen Universal cartridge, 35
mL/min, gradient 20% to 100% EtOAc in hexane over 10 CV) and recrystallized from
CH
2
Cl
2
-hexane. Yield 1.02 g (61%), light tan crystals. In DMSO-d
6
, mixture of two
rotameric forms in 82:18 ratio.
1
H NMR (DMSO-d
6
, 500 MHz): δ 9.69 (s, 0.18H), 9.56 (s,
0.82H), 8.56 (t, J = 5.8 Hz, 0.82H), 8.37 (t, J = 5.8 Hz, 0.18H), 7.43 (dd, J = 5.0 Hz, J =
1.4 Hz, 0.18H), 7.34 (dd, J = 5.0 Hz, J = 1.4 Hz, 0.82H), 7.32 (d, J = 8.6 Hz, 0.82H),
7.07-7.10 (m, 0.18H), 6.90 (dd, J = 5.0 Hz, J = 3.3 Hz, 0.18H), 6.83-6.86 (m, 0.82H),
6.79 (dd, J = 5.0 Hz, J = 3.6 Hz, 0.82H), 6.61 (d, J = 8.6 Hz, 0.18H), 6.38 (d, J = 2.5 Hz,
0.18H), 6.23 (dd, J = 8.3 Hz, J = 2.5 Hz, 0.82H), 6.13-6.18 (m, 2×0.82H+0.18H), 5.99 (s,
0.18H), 4.04-4.12 (m, 2×0.82H+0.18H), 4.02 (s, 0.82H), 3.89-3.95 (m, 0.82H+2×0.18H),
297
3.80 (dd, J = 17.4 Hz, J = 5.8 Hz, 0.82H), 3.72 (s, 3×0.18H), 3.49 (s, 3×0.82H), 1.19 (t, J
= 7.2 Hz, 3×0.18H), 1.16 (t, J = 7.2 Hz, 3×0.82H).
13
C NMR (DMSO-d
6
, 125 MHz): δ
169.4, 169.3, 168.9, 167.5, 158.9, 158.8, 157.2, 157.0, 153.73, 153.71, 136.2, 131.7,
129.6, 129.4, 127.7, 127.5, 126.1, 125.5, 118.6, 118.4, 106.6, 106.3, 99.3, 99.0, 81.5, 80.6,
76.9, 76.7, 60.5, 60.3, 59.7, 58.4, 55.5, 55.1, 41.02, 40.98, 13.94.
N
O
H
N
O
S
OMe
OMe
MeO
4.56. N-[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl]-N-(3,4,5-
trimethoxyphenyl)prop-2-ynamide. Yield 670 mg (76%).
1
H NMR (400 MHz, CDCl
3
):
δ 7.28-7.33 (m, 1H), 7.01 (br.d, J = 3.3 Hz, 1H), 6.90-6.95 (m, 1H), 6.46 (br.s, 2H), 6.16
(s, 1H), 6.04 (br.d, J = 6.2 Hz, 1H), 4.23 (sextet, J = 6.6 Hz, 1H), 3.84 (s, 3H), 3.74 (s,
6H), 2.92 (s, 1H), 1.91-2.06 (m, 2H), 1.57-1.70 (m, 4H), 1.36-1.49 (m, 2H).
13
C NMR
(100 MHz, CDCl
3
): δ 167.1, 153.3, 152.7, 138.3, 135.2, 134.2, 130.0, 128.1, 126.4, 107.5,
80.6, 75.8, 60.9, 60.1, 56.1, 51.8, 32.7, 23.60, 23.56.
298
N
O
N
H
O
OMe
MeO
S
4.57. N-[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl]-N-(2,4-
dimethoxyphenyl)acrylamide. Yield 443 mg (53%). In CDCl
3
, mixture of two
rotameric forms in 60:40 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.17-7.33 (m,
2×0.6H+2×0.4H), 7.05 (d, J = 2.9 Hz, 0.4H), 6.93 (d, J = 2.9 Hz, 0.6H), 6.90 (t, J = 4.2
Hz, 0.4H), 6.84 (t, J = 4.2 Hz, 0.6H), 6.65 (br.d, 0.6H), 6.55 (d, J = 8.3 Hz, 0.4H), 6.34-
6.50 (m, 2×0.6H+2×0.4H), 6.24-6.33 (m, 0.6H+0.4H), 6.20 (s, 0.4H), 6.13 (s, 0.6H),
5.90-6.04 (m, 0.6H+0.4H), 5.48-5.58 (m, 0.6H+0.4H), 4.19-4.32 (m, 0.6H+0.4H), 3.82 (s,
1.8H), 3.80 (s, 1.2H), 3.79 (s, 1.2H), 3.54 (s, 1.8H), 1.93-2.09 (m, 2×0.6H+2×0.4H),
1.37-1.78 (m, 6×0.6H+6×0.4H).
13
C NMR (100 MHz, CDCl
3
): δ 168.4, 168.1, 167.1,
166.6, 160.9, 160.7, 156.6, 156.5, 136.7, 135.4, 131.7, 131.6, 129.27, 129.25, 128.3,
128.2, 128.0, 127.4, 127.2, 125.8, 125.2, 121.1, 120.5, 104.3, 104.1, 99.0, 98.8, 60.8, 60.3,
55.5, 55.4, 55.2, 51.4, 51.1, 32.94, 32.87, 32.8, 23.8, 23.71, 23.65.
299
N
O
N
H
O
OMe
MeO
S
Br
4.58. 2-[(Bromoacetyl)(2,4-dimethoxyphenyl)amino]-N-cyclopentyl-2-thien-2-
ylacetamide. Yield 520 mg (54%). In CDCl
3
, mixture of two rotameric forms in 70:30
ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.33 (d, J = 8.3 Hz, 0.7H), 7.18 (dd, J = 5.2 Hz, J =
1.2 Hz, 0.3H), 7.15 (dd, J = 5.0 Hz, J = 1.2 Hz, 0.7H), 6.97-7.04 (m, 0.7H), 6.83-6.88 (m,
0.7H+0.3H), 6.78 (dd, J = 5.0 Hz, J = 3.3 Hz, 0.7H), 6.58 (d, J = 8.7 Hz, 0.3H), 6.40-6.50
(m, 2×0.7H+0.3H), 6.21-6.26 (m, 0.7H+0.3H), 6.10 (s, 0.7H), 6.07 (s, 0.3H), 4.15-4.27
(m, 0.7H+0.3H), 3.78 (s, 3×0.3H), 3.77 (s, 3×0.7H), 3.75 (s, 3×0.3H), 3.68 (d, J = 11.6
Hz, 0.7H), 3.66 (d, J = 11.6 Hz, 0.3H), 3.613 (d, J = 11.6 Hz, 0.3H), 3.607 (d, J = 11.6
Hz, 0.7H), 3.51 (s, 2×0.7H+2×0.3H), 1.88-2.06 (m, 2×0.7H+2×0.3H), 1.33-1.75 (m,
6×0.7H+6×0.3H).
13
C NMR (100 MHz, CDCl
3
): δ 167.9, 167.6, 167.4, 161.2, 161.1,
156.3, 156.1, 135.8, 134.5, 131.6, 131.5, 129.5, 127.7, 127.4, 125.9, 125.3, 120.2, 119.8,
104.5, 104.2, 99.1, 98.9, 61.1, 60.0, 55.6, 55.4, 55.2, 51.5, 51.2, 32.9, 32.82, 32.76, 28.2,
27.9, 23.8, 23.72, 23.68.
300
N
O
N
H
O
N
O
OMe
MeO
S
4.59. N-[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl]-N-(2,4-dimethoxyphenyl)-4-
morpholin-4-ylbut-2-ynamide. The Ugi reaction was run on 1 mmol scale in the
presence of 1 eq of methanesulfonic acid, and the reaction mixture was neutralized by
addition of solid NaHCO
3
prior to isolation of the product. Yield 308 mg (60%). In
CDCl
3
, mixture of two rotameric forms in 60:40 ratio.
1
H NMR (400 MHz, CDCl
3
): δ
7.35 (dd, J = 8.3 Hz, J = 0.8 Hz, 0.6H), 7.14-7.20 (m, 0.6H+2×0.4H), 7.00 (d, J = 3.3 Hz,
0.4H), 6.90 (d, J = 3.3 Hz, 0.6H), 6.83-6.87 (m, 0.4H), 6.78-6.83 (m, 0.6H), 6.55 (d, J =
8.7 Hz, 0.4H), 6.39-6.47 (m, 2×0.6H+0.4H), 6.27 (d, J = 2.1 Hz, 0.6H), 6.22 (dd, J = 8.7
Hz, J = 2.1 Hz, 0.4H), 6.12 (s, 0.4H), 6.01 (s, 0.6H), 4.21 (sextet, J = 6.6 Hz, 0.6H+0.4H),
3.83 (s, 3×0.4H), 3.75 (s, 3×0.6H), 3.73 (s, 3×0.4H), 3.53 (s, 3×0.6H), 3.46-3.53 (m,
4×0.6H+4×0.4H), 3.22 (s, 2×0.6H+2×0.4H), 1.88-2.06 (m, 6×0.6H+6×0.4H), 1.31-1.75
(m, 6×0.6H+6×0.4H).
13
C NMR (100 MHz, CDCl
3
): δ 167.7, 167.4, 161.1, 160.9, 157.2,
157.1, 155.3, 154.9, 135.7, 134.6, 132.3, 132.1, 129.6, 129.5, 127.6, 127.4, 126.0, 125.4,
121.2, 120.4, 104.3, 104.0, 99.0, 98.8, 86.5, 86.2, 79.6, 79.5, 66.5, 60.2, 59.7, 55.7, 55.31,
55.25, 51.6, 51.2, 51.1, 51.0, 47.0, 32.92, 32.87, 32.81, 32.77, 23.80, 23.76, 23.7.
301
N
O
N
H
O
OMe
MeO
S
N
O
O
4.60. N-Cyclopentyl-2-{(2,4-dimethoxyphenyl)[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-
yl)acetyl]amino}-2-thien-2-ylacetamide. The starting material, 2-(N-maleimido)acetic
acid, was prepared according to the literature procedure.
70
Yield 428 mg (43%). In
DMSO-d
6
, mixture of two rotameric forms in 80:20 ratio.
1
H NMR (400 MHz, DMSO-
d
6
): δ 8.01 (d, J = 7.1 Hz, 0.8H), 7.91 (d, J = 7.1 Hz, 0.2H), 7.62 (d, J = 8.7 Hz, 0.8H),
7.38 (dd, J = 5.0 Hz, J = 1.2 Hz, 0.2H), 7.30 (dd, J = 4.0 Hz, J = 2.1 Hz, 0.8H), 7.10 (s,
2×0.2H), 7.09 (s, 2×0.8H), 7.01 (dd, J = 4.0 Hz, J = 1.2 Hz, 0.2H), 6.88 (dd, J = 5.0 Hz, J
= 3.3 Hz, 0.2H), 6.74-6.80 (m, 2×0.8H+0.2H), 6.64 (d, J = 2.5 Hz, 0.2H), 6.51 (dd, J =
8.7 Hz, J = 2.5 Hz, 0.8H), 6.37-6.42 (m, 0.8H+0.2H), 6.02 (s, 0.2H), 5.97 (s, 0.8H), 3.90-
4.02 (m, 0.8H+0.2H), 3.88 (s, 2×0.2H), 3.66-3.80 (m, 6×0.2H), 3.71 (s, 3×0.8H), 3.63 (s,
3×0.8H), 3.35 (s, 2×0.8H), 1.32-1.87 (m, 7×0.8H+7×0.2H), 1.17-1.30 (m, 0.8H+0.2H).
13
C NMR (100 MHz, DMSO-d
6
): δ 170.33, 170.28, 168.3, 166.6, 166.0, 160.5, 156.4,
135.6, 134.8, 132.4, 129.2, 129.0, 127.3, 126.2, 125.6, 119.0, 118.5, 104.8, 99.0, 98.7,
59.9, 59.2, 55.9, 55.5, 55.33, 55.26, 50.5, 50.3, 32.2, 32.1, 31.9, 31.6, 23.49, 23.45, 23.40.
302
OMe
N
H
N
O
S
MeO
O
H
N
O
4.61. N-{2-[[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl](2,4-
dimethoxyphenyl)amino]-2-oxoethyl}prop-2-ynamide. The Ugi reaction was run with
N-Boc-Gly (385 mg, 2.2 mmol), 2-thiophenecarboxaldehyde (224 mg, 2 mmol), 2,4-
dimethoxyaniline (306 mg, 2 mmol) and cyclopentyl isocyanide (209 mg, 2.2 mmol) in 3
mL of methanol for 24 h. The reaction mixture was evaporated to dryness and the N-Boc-
amine product (820 mg) was isolated by flash column chromatography (silica – ethyl
acetate-hexane 1:1) as brownish solid. It was then dissolved in CH
2
Cl
2
(10 mL) and
trifluoroacetic acid (4.4 mL, 6.8 g, 60 mmol, 30 eq) was added. The dark brown solution
was stirred at room temperature for 3 h, poured into 50 mL of saturated aqueous NaHCO
3
,
extracted with 3×25 mL of ethyl acetate. Combined organic extracts were dried over
Na
2
SO
4
and evaporated to brown foam (837 mg). The crude amine was dissolved in 2 mL
DMSO, and propiolic acid (140 mg, 2 mmol), HATU (760 mg, 2 mmol) and
ethyldiisopropylamine (350 µL, 2 mmol) were added to the solution, which was then
stirred overnight at room temperature (control by TLC, silica – ethyl acetate-hexane 3:1).
The reaction mixture was poured into 50 mL of 0.1 N NaOH and extracted with 3×25 mL
of ethyl acetate. Combined organic extracts were washed with 50 mL of water, dried over
Na
2
SO
4
and evaporated. The product was isolated by flash column chromatography
(silica – ethyl acetate-hexane 3:1) and recrystallized from ethyl acetate-hexane. Yield 459
303
mg (49% over 3 steps). In DMSO-d
6
, mixture of two rotameric forms in 80:20 ratio.
1
H
NMR (400 MHz, DMSO-d
6
): δ 8.86 (t, J = 5.8 Hz, 0.2H), 8.79 (t, J = 5.8 Hz, 0.8H), 8.08
(d, J = 7.1 Hz, 0.8H), 7.93 (d, J = 7.1 Hz, 0.2H), 7.56 (d, J = 8.7 Hz, 0.8H), 7.38 (d, J =
5.4 Hz, 0.2H), 7.28 (t, J = 3.3 Hz, 0.8H), 7.01 (d, J = 3.7 Hz, 0.2H), 6.88 (dd, J = 5.0 Hz,
J = 3.7 Hz, 0.2H), 6.74-6.79 (m, 2×0.8H), 6.63 (d, J = 8.7 Hz, 0.2H), 6.61 (d, J = 2.5 Hz,
0.2H), 6.47 (d, J = 8.7 Hz, J = 2.9 Hz, 0.8H), 6.37 (d, J = 3.0 Hz, 0.8H), 6.34 (d, J = 3.0
Hz, 0.2H), 6.08 (s, 0.2H), 6.02 (s, 0.8H), 4.16 (s, 0.2H), 4.15 (s, 0.8H), 3.89-4.05 (m,
0.8H+0.2H), 3.81 (s, 3×0.2H), 3.72 (s, 3×0.2H), 3.70 (s, 3×0.8H), 3.57 (s, 3×0.8H), 3.48
(d, J = 6.2 Hz, 0.8H+0.2H), 3.38 (s, 0.8H+0.2H), 1.35-1.87 (m, 7×0.8H+7×0.2H), 1.20-
1.32 (m, 0.8H+0.2H).
13
C NMR (100 MHz, DMSO-d
6
): δ 168.6, 167.8, 160.4, 156.4,
151.72, 151.67, 137.6, 135.9, 132.4, 131.3, 129.0, 128.9, 127.3, 127.2, 125.6, 119.3,
119.0, 105.0, 104.6, 99.0, 98.6, 78.0, 76.2, 59.1, 55.8, 55.4, 55.3, 55.2, 50.6, 50.4, 41.1,
41.0, 32.2, 32.1, 32.0, 31.8, 23.52, 23.46.
OMe
N
H
N
O
S
MeO
O
N
H
O
4.62. N-{3-[[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl](2,4-
dimethoxyphenyl)amino]-3-oxopropyl}prop-2-ynamide. Prepared similarly to 4.61
from N-Boc- β-Ala. After two recrystallizations from ethyl acetate-hexane, yield 355 mg
(37% over 3 steps). In CDCl
3
, mixture of two rotameric forms in 60:40 ratio.
1
H NMR
304
(400 MHz, CDCl
3
): δ 7.25 (d, J = 8.3 Hz, 0.6H), 7.14-7.18 (m, 0.6H+0.4H), 7.12 (br.d,
0.4H), 6.95-7.02 (m, 0.6H+0.4H), 6.92-6.95 (m, 0.4H), 6.78-6.84 (m, 2×0.6H+0.4H),
6.63 (d, J = 8.3 Hz, 0.4H), 6.41 (d, J = 2.5 Hz, 0.6H+0.4H), 6.39 (d, J = 2.5 Hz, 0.6H),
6.28 (d, J = 2.5 Hz, 0.6H), 6.25 (dd, J = 8.4 Hz, J = 2.5 Hz, 0.6H), 5.93 (s, 0.6H), 5.89 (s,
0.4H), 4.22 (sextet, J = 7.1 Hz, 0.6H+0.4H), 3.79 (s, 3×0.4H), 3.76 (s, 3×0.6H), 3.73 (s,
3×0.4H), 3.58 (s, 3×0.6H), 3.47 (quartet, J = 5.8 Hz, 2×0.6H+2×0.4H), 2.781 (s, 0.4H),
2.775 (s, 0.6H), 2.17-2.25 (m, 2×0.6H+2×0.4H), 1.89-2.06 (m, 2×0.6H+2×0.4H), 1.52-
1.72 (m, 4×0.6H+4×0.4H), 1.30-1.47 (m, 2×0.6H+2×0.4H).
13
C NMR (100 MHz, CDCl
3
):
δ 173.2, 172.8, 168.6, 168.3, 161.0, 160.8, 156.0, 155.9, 151.94, 151.91, 136.2, 135.5,
131.4, 131.2, 129.6, 129.3, 127.5, 127.2, 126.1, 125.5, 121.0, 120.3, 105.0, 104.6, 99.2,
99.1, 73.1, 73.0, 62.3, 60.7, 55.7, 55.4, 55.3, 51.5, 51.1, 35.3, 33.6, 33.4, 32.95, 32.85,
32.81, 31.5, 23.8, 23.7, 23.6, 22.6, 14.0.
OMe
N
N
H
O
O
S
MeO
N
N
N
4.63. N-[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl]-N-(2,4-dimethoxyphenyl)-1-
methyl-1H-1,2,3-triazole-4-carboxamide. The compound 4.14 (125 mg, 0.303 mmol),
CuSO
4
·5H
2
O (4 mg, 15.15 µmol, 5 mol%) and sodium ascorbate (6 mg, 30.3 µmol, 10
mol%) were stirred in the mixture of DMF (1 mL) and water (0.25 mL) until yellow
305
suspension formed. Dimethyl sulfate (32 µl, 42 mg, 0.333 mmol, 1.1 eq) followed by
solid NaN
3
(24 mg, 0.364 mmol, 1.2 eq) were then added, and the clear brown solution
was stirred overnight at room temperature (control by TLC, silica – ethyl acetate). The
reaction mixture was poured into 50 mL of 5% aq. NH
3
, extracted with 3×25 mL of ethyl
acetate. The combined extracts were dried over Na
2
SO
4
, and the product was isolated by
flash column chromatography (silica – ethyl acetate) as white foam. Recrystallization
from ethyl acetate-hexane yields 74 mg (52%) of white crystals. In CDCl
3
, mixture of
two rotameric forms in 60:40 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.27-7.35 (m,
2×0.6H), 7.26 (d, J = 5.0 Hz, 0.4H), 7.22 (d, J = 5.0 Hz, 0.6H), 7.12 (d, J = 2.9 Hz, 0.4H),
7.04 (br.s, 2×0.4H), 6.98 (d, J = 2.9 Hz, 0.6H), 6.92 (t, J = 4.4 Hz, 0.4H), 6.86 (t, J = 4.4
Hz, 0.6H), 6.73 (d, J = 7.1 Hz, 0.6H), 6.56 (d, J = 8.7 Hz, 0.4H), 6.45 (dd, J = 8.7 Hz, J =
2.1 Hz, 0.6H), 6.42 (d, J = 2.1 Hz, 0.4H), 6.34 (s, 0.4H), 6.29 (d, J = 2.1 Hz, 0.6H), 6.25
(dd, J = 8.7 Hz, J = 2.1 Hz, 0.4H), 6.19 (s, 0.6H), 4.20-4.32 (m, 0.6H+0.4H), 3.95 (s,
3×0.6H+3×0.4H), 3.82 (s, 3×0.6H), 3.79 (s, 3×0.4H), 3.70 (s, 3×0.4H), 3.49 (s, 3×0.6H),
1.93-2.08 (m, 2×0.6H+2×0.4H), 1.38-1.78 (m, 6×0.6H+6×0.4H).
13
C NMR (100 MHz,
CDCl
3
): δ 168.2, 167.8, 162.3, 161.7, 161.1, 160.9, 157.1, 156.8, 142.6, 136.3, 135.2,
131.61, 131.56, 129.61, 129.56, 127.7, 127.4, 126.5, 125.9, 125.3, 122.0, 121.2, 104.2,
104.1, 99.2, 99.1, 61.2, 61.1, 55.6, 55.4, 55.3, 51.5, 51.2, 36.5, 33.0, 32.9, 32.8, 23.83,
23.77, 23.7.
306
N
O
N
H
O
OMe
MeO
S
F
O
2
N
4.64. N-[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl]-N-(2,4-dimethoxyphenyl)-4-
fluoro-3-nitrobenzamide. Yield 600 mg (57%). In CDCl
3
, mixture of two rotameric
forms in 60:40 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 8.02-8.12 (m, 0.6H+0.4H), 7.59-
7.66 (m, 0.6H+0.4H), 7.32-7.37 (m, 0.6H), 7.27-7.31 (m, 0.4H), 7.18-7.22 (m, 0.6H),
7.11-7.15 (m, 0.4H), 7.02-7.11 (m, 0.6H+0.4H), 6.92-6.97 (m, 0.4H), 6.80-6.91 (m,
2×0.6H+0.4H), 6.68-6.73 (m, 0.4H), 6.27-6.32 (m, 0.6H), 6.18-6.27 (m,
2×0.6H+2×0.4H), 6.05-6.10 (m, 0.6H), 5.96 (br.s, 0.4H), 4.19-4.32 (m, 0.6H+0.4H), 3.69
(s, 3×0.6H+3×0.4H), 3.66 (s, 3×0.4H), 3.48 (s, 3×0.6H), 1.91-2.06 (m, 2×0.6H+2×0.4H),
1.32-1.74 (m, 6×0.6H+6×0.4H).
13
C NMR (100 MHz, CDCl
3
): δ 168.6, 168.3, 168.0,
167.4, 160.9, 160.8, 155.8, 155.4, 136.5, 135.11, 135.07, 135.02, 134.96, 134.9, 133.3,
133.2, 132.9, 131.7, 130.9, 129.65, 129.61, 127.7, 127.5, 126.1, 126.0, 125.9, 125.71,
125.70, 122.4, 121.6, 117.9, 117.8, 117.7, 117.6, 104.7, 104.4, 99.1, 98.7, 94.9, 62.9, 60.7,
55.35, 55.32, 55.1, 51.7, 51.4, 33.0, 32.9, 32.8, 23.74, 23.69, 23.65.
19
F NMR (376 MHz,
CDCl
3
): δ -114.39 (0.4F), -115.09 (0.6F).
307
N
O
N
H
O
CO
2
Et
OMe
MeO
S
4.65. Ethyl {[[but-2-ynoyl(2,4-dimethoxyphenyl)amino](thien-2-
yl)acetyl]amino}acetate. Yield 628 mg (71%). In CDCl
3
, mixture of two rotameric
forms in 60:40 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.97 (t, J = 4.2 Hz, 0.4H), 7.17-7.32
(m, 2×0.6H+2×0.4H), 7.06 (d, J = 3.3 Hz, 0.4H), 6.93 (d, J = 3.3 Hz, 0.4H), 6.82-6.90 (m,
0.6H+0.4H), 6.68 (d, J = 8.7 Hz, 0.4H), 6.41-6.47 (0.6H+0.4H), 6.39 (d, J = 2.5 Hz,
0.6H), 6.27 (dd, J = 8.7 Hz, J = 2.5 Hz, 0.4H), 6.10 (s, 0.4H), 5.86 (s, 0.6H), 4.00-4.31
(m, 4×0.6H+4×0.4H), 3.87 (s, 3×0.4H), 3.82 (s, 3×0.6H), 3.78 (s, 3×0.4H), 3.71 (s,
3×0.6H), 1.73 (s, 3×0.6H+3×0.4H), 1.25-1.34 (m, 3×0.6H+3×0.4H).
13
C NMR (100 MHz,
CDCl
3
): δ 169.7, 169.6, 168.8, 168.2, 160.9, 160.7, 157.0, 156.6, 155.8, 155.2, 135.2,
134.9, 132.3, 131.5, 129.6, 129.4, 127.4, 127.3, 126.2, 125.3, 121.8, 120.6, 104.1, 103.9,
98.8, 98.6, 89.5, 89.3, 73.7, 61.3, 61.2, 60.8, 60.6, 55.8, 55.5, 55.34, 55.30, 41.7, 41.5,
14.0, 3.8.
308
OMe
N
H
N
O
S
MeO
CO
2
Et
O
Br
4.66. Ethyl 2-{[2-{[(E)-3-bromo-2-propenoyl]-2,4-dimethoxyanilino}-2-(2-
thienyl)acetyl]amino}acetate. The starting material, (E)-3-bromo-2-propenoic acid, was
prepared according to the literature procedure.
71
Yield 445 mg (44%) after two
crystallizations (EtOAc/hexane and CHCl
3
). In CDCl
3
, mixture of two rotameric forms in
67:33 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.74 (br.t, J = 5.0 Hz, 0.33H), 7.49-7.56 (m,
1H), 7.12-7.22 (m, 2H+0.33H), 7.04 (d, J = 3.3 Hz, 0.33H), 6.87 (d, J = 3.3 Hz, 0.67H),
6.70-6.86 (m, 1H), 6.68 (d, J = 8.7 Hz, 0.33H), 6.40-6.45 (m, 1H), 6.33-6.35 (m, 0.67H),
6.25-6.32 (m, 1H+0.33H), 6.00 (s, 0.33H), 5.98 (s, 0.67H), 3.98-4.24 (m, 4H), 3.794 (s,
3×0.67H), 3.788 (s, 3×0.33H), 3.77 (s, 3×0.33H), 3.62 (s, 3×0.67H), 1.23-1.29 (m, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 169.7, 168.8, 168.6, 165.2, 164.6, 161.2, 161.0, 156.5,
156.3, 135.7, 134.8, 131.8, 131.6, 129.6, 128.4, 128.3, 127.51, 127.47, 126.2, 125.4,
124.9, 124.7, 120.6, 120.1, 104.6, 104.4, 99.10, 99.06, 61.9, 61.4, 61.3, 60.7, 55.8, 55.50,
55.47, 41.7, 41.6, 14.1.
309
OMe
N
H
N
O
S
MeO
CO
2
Et
O Br
4.67. Ethyl 2-{[2-{[(Z)-3-bromo-2-propenoyl]-2,4-dimethoxyanilino}-2-(2-
thienyl)acetyl]amino}acetate. The starting material, (Z)-3-bromo-2-propenoic acid, was
prepared according to the literature procedure.
71
Yellowish foam, yield 500 mg (49%). In
CDCl
3
, mixture of two rotameric forms in 67:33 ratio.
1
H NMR (400 MHz, CDCl
3
): δ
7.88 (br.t, J = 5.0 Hz, 0.33H), 7.29 (d, J = 8.3 Hz, 0.67H), 7.25 (br.t, J = 5.0 Hz, 0.67H),
7.18-7.22 (m, 1H), 7.08 (d, J = 3.3 Hz, 0.33H), 6.93 (d, J = 6.7 Hz, 0.67H), 6.81-6.87 (m,
1H), 6.65 (d, J = 8.7 Hz, 0.33H), 6.38-6.50 (m, 3H), 6.31 (d, J = 2.5 Hz, 0.67H), 6.25 (dd,
J = 8.7 Hz, J = 2.5 Hz, 0.33H), 6.17 (s, 0.33H), 6.14 (s, 0.67H), 4.00-4.27 (m, 4H), 3.83
(s, 3×0.33H), 3.78 (s, 3×0.67H), 3.76 (s, 3×0.33H), 3.61 (s, 3×0.67H), 1.25-1.32 (m, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 169.6, 168.7, 168.6, 166.0, 165.6, 161.1, 160.9, 156.4,
156.3, 135.4, 134.6, 131.5, 131.1, 129.60, 129.56, 127.4, 127.3, 126.8, 126.1, 125.4,
120.4, 119.6, 115.8, 115.6, 104.4, 104.1, 98.8, 98.7, 61.25, 61.21, 60.8, 59.8, 55.7, 55.34,
55.32, 41.7, 41.6, 14.0.
310
OMe
N
H
N
O
S
MeO
CO
2
Et
O
N
4.68. Ethyl 2-{[2-{2,4-dimethoxy[(E)-3-(1-pyrrolidinyl)-2-propenoyl]anilino}-2-(2-
thienyl)acetyl]amino}acetate. To the stirred solution of 4.51 (424 mg, 1 mmol) in
acetonitrile (2 mL) pyrrolidine (92 µL, 78 mg, 1.1 mmol, 1.1 eq) was added in one
portion. The mixture was stirred at room temperature for 3 h. TLC control (silica/EtOAc,
stained with vanillin): R
f
0.25 (4.68, olive), R
f
0.85 (4.51, black). The reaction mixture
was evaporated to dryness and the product was isolated by flash chromatography on
silica (10 g Biotage cartridge, 12 mL/min, 100% EtOAc over 18 CV) to yield 437 mg
(88%) of 4.68 as yellowish foam. In CDCl
3
, mixture of two rotameric forms in 55:45
ratio.
1
H NMR (400 MHz, CDCl
3
): δ 8.32 (br.t, J = 5.0 Hz, 0.45H), 7.76 (br.t, J = 5.0 Hz,
0.55H), 7.64-7.71 (m, 1H), 7.16 (dd, J = 5.0 Hz, J = 1.1 Hz, 0.55H), 7.10 (dd, J = 5.0 Hz,
J = 1.1 Hz, 0.45H), 7.02-7.06 (m, 0.55H), 6.99-7.02 (m, 0.45H), 6.85-6.88 (m, 0.55H),
6.76-6.82 (m, 1H), 6.65 (d, J = 8.6 Hz, 0.45H), 6.36-6.40 (m, 1H+0.55H), 6.22 (dd, J =
8.6 Hz, J = 2.6 Hz, 0.45H), 6.10 (s, 0.45H), 5.72 (s, 0.55H), 3.98-4.26 (m, 4H), 3.78 (s,
3×0.45H), 3.77 (s, 3×0.55H), 3.73 (s, 3×0.45H), 3.66 (s, 3×0.55H), 3.05 (br.s, 4H), 1.72-
1.85 (m, 4H), 1.21-1.28 (m, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 170.7, 170.3, 170.1,
169.9, 169.5, 160.3, 160.0, 157.0, 156.6, 147.81, 147.79, 137.7, 137.1, 132.4, 131.5,
128.7, 128.6, 126.7, 126.5, 125.8, 124.9, 123.5, 122.3, 104.2, 104.1, 99.0, 98.8, 85.6, 85.3,
61.5, 61.3, 61.0, 55.6, 55.5, 55.33, 55.27, 41.7, 41.5, 25.0, 14.1.
311
N
O
N
H
O
OEt
OMe
MeO
S
O F
NO
2
4.69. Ethyl {[[(2,4-dimethoxyphenyl)(2-fluoro-5-nitrobenzoyl)amino](thien-2-
yl)acetyl]amino}acetate. Yield 750 mg (69%). In CDCl
3
, mixture of two rotameric
forms in 60:40 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 8.33 (dd, J = 5.4 Hz, J = 2.9 Hz,
0.4H), 8.29 (dd, J = 5.4 Hz, J = 2.9 Hz, 0.6H), 8.03-8.12 (m, 0.6H+0.4H), 7.83 (t, J =5.0
Hz, 0.4H), 7.29-7.34 (m, 0.6H), 7.24-7.29 (m, 0.6H+0.4H), 7.15-7.21 (m, 0.6H+0.4H),
7.00-7.05 (m, 0.6H+0.4H), 6.97-7.00 (m, 0.6H+0.4H), 6.93 (dd, J = 5.4 Hz, J = 3.7 Hz,
0.4H), 6.88 (dd, J = 5.4 Hz, J = 3.7 Hz, 0.6H), 6.72 (dd, J = 8.7 Hz, J = 1.7 Hz, 0.4H),
6.25-6.30 (m, 2×0.6H), 6.21 (s, 0.4H), 6.18 (d, J =2.5 Hz, 0.4H), 6.14 (dd, J = 8.7 Hz, J =
2.5 Hz, 0.4H), 6.08 (d, J = 2.5 Hz, 0.6H), 4.15-4.32 (m, 4×0.6H+4×0.4H), 3.76 (s,
3×0.4H), 3.69 (s, 3×0.6H), 3.66 (s, 3×0.4H), 3.60 (s, 3×0.6H), 1.28-1.36 (m,
3×0.6H+3×0.4H).
13
C NMR (100 MHz, CDCl
3
): δ 169.6, 168.2, 165.7, 165.3, 162.8,
162.6, 161.1, 160.9, 160.2, 160.1, 155.7, 143.29, 143.26, 143.22, 143.19, 135.2, 134.4,
131.3, 131.1, 129.9, 127.8, 127.6, 126.5, 126.41, 126.38, 126.3, 126.2, 126.1, 125.99,
125.95, 125.7, 124.7, 124.62, 124.57, 120.5, 120.0, 116.55, 116.51, 116.30, 116.27, 104.3,
104.0, 98.4, 61.8, 61.5, 60.6, 55.4, 55.25, 55.15, 41.8, 41.6, 14.1.
19
F NMR (376 MHz,
CDCl
3
): δ -103.24.
312
N
O
N
H
O
OEt
OMe
MeO
S
O Cl
NO
2
4.70. Ethyl {[[(2,4-dimethoxyphenyl)(2-chloro-5-nitrobenzoyl)amino](thien-2-
yl)acetyl]amino}acetate. Yield 837 mg (74%). In CDCl
3
, mixture of two rotameric
forms in 60:40 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 8.22-8.28 (m, 2×0.4H), 7.91-7.97 (m,
0.6H+0.4H), 7.83 (t, J = 4.6 Hz, 0.4H), 7.29-7.37 (m, 2×0.6H+0.4H), 7.22-7.27 (m,
0.6H+0.4H), 7.12-7.20 (m, 0.6H+0.4H), 6.95 (dd, J = 3.3 Hz, J = 1.2 Hz, 0.6H), 6.89 (dd,
J = 5.0 Hz, J = 3.3 Hz, 0.4H), 6.86 (dd, J = 5.0 Hz, J = 3.3 Hz, 0.6H), 6.74 (d, J = 8.7 Hz,
0.4H), 6.18-6.25 (m, 2×0.6H+0.4H), 6.16 (d, J = 2.5 Hz, 0.4H), 6.07 (d, J = 2.5 Hz,
0.4H), 6.05 (d, J = 2.9 Hz, 0.6H), 4.12-4.30 (m, 4×0.6H+4×0.4H), 3.80 (s, 3×0.4H), 3.65
(s, 3×0.6H), 3.624 (s, 3×0.4H), 3.616 (s, 3×0.6H), 1.25-1.33 (m, 3×0.6H+3×0.4H).
13
C
NMR (100 MHz, CDCl
3
): δ 169.62, 169.58, 168.3, 168.1, 167.1, 166.8, 161.2, 161.0,
155.8, 155.7, 145.44, 145.37, 137.7, 137.1, 135.1, 134.3, 130.9, 130.8, 130.21, 130.16,
130.0, 129.9, 127.8, 127.7, 126.3, 125.7, 124.5, 124.4, 122.7, 120.4, 119.9, 104.2, 104.0,
98.4, 61.5, 60.6, 55.5, 55.3, 55.2, 41.9, 41.7, 14.14, 14.11.
313
N
O
N
H
O
S
4.71. N-[2-(Cyclopentylamino)-2-oxo-1-thien-2-ylethyl]-N-methylprop-2-ynamide.
Prepared according to the general procedure using 40 wt% aqueous solution of
methylamine. Yield 310 mg (53%). In CDCl
3
, mixture of two rotameric forms in 75:25
ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.32-7.38 (m, 0.75H+0.25H), 7.14 (d, J = 3.3 Hz,
0.75H), 7.09 (d, J = 3.7 Hz, 0.25H), 6.97-7.03 (m, 0.75H+0.25H), 6.36 (s, 0.75H), 6.34 (s,
0.25H), 6.29 (br.d, 0.75H), 6.17 (br.d, 0.25H), 4.26 (sextet, J = 7.1 Hz, 0.25H), 4.19
(sextet, J = 6.6 Hz, 0.75H), 3.26 (s, 0.25H), 3.19 (s, 0.75H), 3.14 (s, 3×0.75H), 2.88 (s,
3×0.25H), 1.88-2.05 (m, 2×0.75H+2×0.25H), 1.50-1.70 (m, 4×0.75H+4×0.25H), 1.33-
1.46 (m, 2×0.75H+2×0.25H).
13
C NMR (100 MHz, CDCl
3
): δ 166.9, 166.4, 153.9, 153.5,
136.2, 135.5, 128.9, 128.1, 127.3, 127.2, 126.8, 126.7, 80.3, 75.4, 75.2, 61.5, 55.1, 51.8,
51.5, 33.2, 32.8, 32.7, 29.7, 23.7.
N
O
N
H
O
OMe
MeO
4.72. N-[2-(Cyclopentylamino)-2-oxoethyl]-N-(2,4-dimethoxyphenyl)prop-2-ynamide.
Prepared according to the general procedure using 37 wt% aqueous solution of
formaldehyde. Yield 462 mg (70%). In CDCl
3
, mixture of two rotameric forms in 85:15
ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.20 (br.s, 0.15H), 7.10-7.17 (m, 0.85H), 7.01-7.06
314
(m, 0.15H), 6.78 (br.d, 0.85H), 6.48-6.56 (m, 2×0.85H+2×0.15H), 4.45 (d, J = 16.2 Hz,
0.85H+0.15H), 4.08-4.21 (m, 0.85H+0.15H), 4.05 (d, J = 16.2 Hz, 0.85H+0.15H), 3.88 (s,
3×0.15H), 3.85 (s, 3×0.85H), 3.82 (s, 3×0.85H), 3.80 (s, 3×0.15H), 3.21 (s, 0.15H), 2.77
(s, 0.85H), 1.82-2.04 (m, 2×0.85H+2×0.15H), 1.50-1.72 (m, 4×0.85H+4×0.15H), 1.24-
1.45 (m, 2×0.85H+2×0.15H).
13
C NMR (100 MHz, CDCl
3
): δ 167.1, 161.0, 155.8, 154.7,
129.5, 123.1, 105.9, 105.0, 100.1, 99.6, 78.3, 75.9, 56.1, 56.0, 55.6, 55.5, 53.1, 51.1, 51.0,
32.9, 32.8, 32.7, 23.69, 23.66.
N
O
N
H
O
CO
2
Et
OMe
MeO
4.73. Ethyl ({[(2,4-dimethoxyphenyl)(propioloyl)amino]acetyl}amino)acetate.
Prepared according to the general procedure using 37 wt% aqueous solution of
formaldehyde. Yield 410 mg (59%). In CDCl
3
, mixture of two rotameric forms in 90:10
ratio.
1
H NMR (400 MHz, DMSO-d
6
): δ 8.47 (t, J = 5.1 Hz, 0.1H), 8.38 (t, J = 5.1 Hz,
0.9H), 7.36 (d, J = 8.6 Hz, 0.9H), 7.14 (d, J = 8.6 Hz, 0.1H), 6.62-6.72 (m, 0.9H+0.1H),
6.48-6.59 (m, 0.9H+0.1H), 4.71 (d, J = 16.2 Hz, 0.9H), 4.43 (br.d, 0.1H), 4.13 (s,
0.9H+0.1H), 4.07 (quartet, J = 7.0 Hz, 2×0.9H+2×0.1H), 3.72-3.92 (m, 7×0.9H+7×0.1H),
3.63 (d, J = 16.2 Hz, 0.9H+0.1H), 3.37 (s, 0.9H+0.1H), 1.17 (t, J = 7.0 Hz,
3×0.9H+3×0.1H).
13
C NMR (100 MHz, DMSO-d
6
): δ 169.6, 167.6, 160.5, 155.8, 153.7,
131.2, 122.6, 104.6, 99.1, 81.7, 76.5, 60.4, 55.8, 55.4, 50.0, 40.7, 14.0.
315
OMe MeO
H
N
O
NH
2
4.78. 2-(2,4-Dimethoxyanilino)acetamide. The mixture of 2,4-dimethoxyaniline (3.06 g,
20 mmol), 2-chloroacetamide (1.87 g, 20 mmol), K
2
CO
3
(8.28 g, 60 mmol) and KI (500
mg, 3 mmol) in 50 mL of dry DMF was stirred at 80 °C for 24 h. TLC control
(silica/EtOAc, stained with vanillin): R
f
0.8 (2,4-dimethoxyaniline, yellow), R
f
0.35 (4.78,
orange). The reaction mixture was poured into 300 mL of water and extracted with
EtOAc (4 × 100 mL). The combined extracts were washed with water (3 × 100 mL),
brine and dried over Na
2
SO
4
. The product was isolated by flash chromatography on silica
(50 g Biotage cartridge, 50 mL/min, the starting aniline was first eluted with EtOAc-
CH
2
Cl
2
(1:1), then gradient 0% to 30% methanol in CH
2
Cl
2
over 8 CV). Yield 1.66 g
(40%). White crystals; readily oxidize in the air, especially when wet, turning green.
1
H
NMR (DMSO-d
6
, 400 MHz): δ 7.36 (br.s, 1H), 7.13 (br.s, 1H), 6.50 (d, J = 2.4 Hz, 1H),
6.38 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 6.29 (d, J = 8.4 Hz, 1H), 4.85 (t, J = 5.6 Hz, 1H),
3.78 (s, 3H), 3.66 (s, 3H), 3.56 (d, J = 5.6 Hz, 2H).
13
C NMR (DMSO-d
6
, 100 MHz): δ
172.2, 151.3, 147.3, 131.8, 109.5, 103.9, 99.1, 55.32, 55.27, 46.9.
316
N
O
MeO
NH
2
O
OMe
4.74. N-(2-Amino-2-oxoethyl)-N-(2,4-dimethoxyphenyl)-2-propynamide. Solid 4.78
(1.05 g, 5 mmol) was suspended in anhydrous CH
2
Cl
2
at 0 °C, followed by addition of
DMAP (61 mg, 0.5 mmol, 10 mol%) and propiolic acid (310 µL, ~350 mg, 5 mmol).
EDC·HCl (960 mg, 5 mmol) was then added in one portion. Clear yellow solution formed.
The reaction mixture was removed from ice-water bath and stirred at RT for 1.5 h. TLC
control (after extraction with EtOAc of a sample diluted with aq.HCl; silica/EtOAc,
stained with vanillin): R
f
0.35 (4.78, orange), R
f
0.45 (4.74, pink). The reaction mixture
was poured into 1 N HCl (100 mL), the layers were separated, and the aqueous layer was
re-extracted with EtOAc (25 mL) and CH
2
Cl
2
(25 mL). The combined organic phases
were washed with 1 N HCl (50 mL), water (2 × 50 mL), brine and dried over Na
2
SO
4
.
The product was isolated by flash chromatography on silica (25 g 50 µm Interchim
Puriflash cartridge, 25 mL/min, gradient 0% to 20% methanol in CH
2
Cl
2
over 12 CV).
Recrystallization from EtOAc-hexane gave 712 mg (54%) of 4.74 as light tan crystals. In
DMSO-d
6
, mixture of two rotameric forms in 80:20 ratio.
1
H NMR (DMSO-d
6
, 400
MHz): δ 7.43 (br.s, 0.2H), 7.36 (d, J = 8.4 Hz, 0.8H), 7.36 (br.s, 0.8H), 7.16 (br.s, 0.2H),
7.15 (d, J = 8.4 Hz, 0.2H), 7.06 (br.s, 0.8H), 6.66 (d, J = 2.5 Hz, 0.8H), 6.64 (d, J = 2.5
Hz, 0.2H), 6.55 (dd, J = 8.4 Hz, J = 2.5 Hz, 0.8H), 6.52 (dd, J = 8.4 Hz, J = 2.5 Hz, 0.2H),
4.58 (d, J = 16.4 Hz, 1H), 4.09 (s, 0.8H), 3.81 (s, 3×0.8H), 3.78 (s, 3×0.8H+3×0.2H),
317
3.76 (s, 3×0.2H), 3.53 (d, J = 16.4 Hz, 1H), 3.34 (s, 0.2H).
13
C NMR (DMSO-d
6
, 100
MHz): 169.2, 168.9, 160.4, 159.9, 155.8, 154.8, 153.6, 153.5, 131.1, 130.0, 122.8, 121.2,
104.7, 104.6, 99.13, 99.08, 82.0, 81.5, 76.6, 76.2, 55.8, 55.6, 55.3, 53.4, 50.1.
N
O
N
H
O
CO
2
Et
N
N N
N
F
4.75. Ethyl ({(2-fluorophenyl)[[3-methyl-4-(1H-tetrazol-1-
yl)phenyl](propioloyl)amino]acetyl}amino)acetate. Yield 690 mg (74%).
1
H NMR
(400 MHz, CDCl
3
): δ 8.77 (s, 1H), 7.21-7.45 (m, 3H), 7.11-7.20 (m, 2H), 6.92-7.02 (m,
2H), 6.69 (t, J = 5.0 Hz, 1H), 6.48 (s, 1H), 4.10-4.19 (m, 3H), 3.98 (dd, J = 17.9 Hz, J =
5.0 Hz, 1H), 2.91 (s, 1H), 2.08 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H).
13
C NMR (100 MHz,
CDCl
3
): δ 169.3, 168.1, 160.8 (d, J = 248.5 Hz), 153.0, 142.9, 140.4, 133.9 (d, J = 14.2
Hz), 132.7, 131.6, 131.4 (d, J = 9.0 Hz), 129.4, 125.7, 124.4 (d, J = 3.9 Hz), 120.1 (d, J =
14.2 Hz), 115.4 (d, J = 21.9 Hz), 81.4, 75.5, 61.5, 57.4, 41.6, 17.7, 14.0.
19
F NMR (376
MHz, CDCl
3
): δ -114.93.
318
N
O
N
H
O
N
N N
N
4.76. N-[2-(Cyclopentylamino)-2-oxoethyl]-N-[3-methyl-4-(1H-tetrazol-1-
yl)phenyl]prop-2-ynamide. Prepared according to the general procedure using 37 wt%
aqueous solution of formaldehyde. Yield 645 mg (92%). In CDCl
3
, mixture of two
rotameric forms in 85:15 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 8.91 (s, 0.85H+0.15H),
7.50-7.58 (m, 0.85H+0.15H), 7.44-7.50 (m, 0.85H), 7.39-7.43 (m, 0.15H), 7.30-7.39 (m,
0.85H+0.15H), 6.58 (br.d, 0.15H), 6.51 (d, J = 7.5 Hz, 0.85H), 4.59 (br.s, 2×0.15H), 4.31
(s, 2×0.85H), 4.07-4.23 (m, 0.85H+0.15H), 3.34 (br.s, 0.15H), 3.02 (s, 0.85H), 2.20 (s,
3×0.85H), 2.14 (br.s, 3×0.15H), 1.85-1.97 (m, 2×0.85H+2×0.15H), 1.47-1.67 (m,
4×0.85H+4×0.15H), 1.32-1.43 (m, 2×0.85H+2×0.15H).
13
C NMR (100 MHz, CDCl
3
): δ
166.4, 152.9, 143.6, 143.1, 135.1, 132.4, 131.1, 126.8, 126.6, 81.5, 75.3, 52.4, 51.4, 32.7,
23.6, 17.8.
319
N
O
N
H
O
N
N N
N
CO
2
Et
4.77. Ethyl ({[[3-methyl-4-(1H-tetrazol-1-
yl)phenyl](propioloyl)amino]acetyl}amino)acetate. Yield 432 mg (58%). In DMSO-d
6
,
mixture of two rotameric forms in 70:30 ratio.
1
H NMR (400 MHz, DMSO-d
6
): δ 9.89 (s,
0.7H), 9.85 (s, 0.3H), 8.70 (t, J = 5.8 Hz, 0.3H), 8.57 (t, J = 5.8 Hz, 0.7H), 7.66 (d, J =
2.1 Hz, 0.7H), 7.64 (s, 0.3H), 7.62 (s, 0.7H), 7.57 (dd, J = 8.7 Hz, J = 2.1 Hz, 0.7H), 7.47
(d, J = 2.1 Hz, 0.3H), 7.39 (dd, J = 8.7 Hz, J = 2.1 Hz, 0.3H), 4.73 (s, 0.3H), 4.66 (s,
0.7H), 4.42 (s, 2×0.3H), 4.41 (s, 2×0.7H), 4.05-4.13 (m, 2×0.7H+2×0.3H), 3.91 (d, J =
5.8 Hz, 2×0.3H), 3.86 (d, J = 5.8 Hz, 2×0.7H), 2.16 (s, 3×0.7H), 2.13 (s, 3×0.3H), 1.17 (t,
J = 7.1 Hz, 3×0.7H+3×0.3H).
13
C NMR (100 MHz, DMSO-d
6
): δ 169.6, 169.5, 167.9,
167.4, 153.4, 152.2, 144.6, 143.3, 142.2, 134.4, 134.1, 132.2, 130.7, 129.0, 126.94,
126.87, 126.8, 125.0, 83.7, 83.4, 76.3, 75.8, 60.54, 60.49, 53.7, 50.9, 40.9, 40.7, 17.33,
17.29, 14.0.
320
N
B
N
F F
CO
2
Me
4.83. 4,4-Difluoro-8-(4'-methoxycarbonyl)phenyl-1,3,5,7-tetramethyl-2,6-diethyl-4-
bora-3a,4a-diaza-s-indacene.
59
2,4-Dimethylpyrrole (1.1 mL, 10.7 mmol) and methyl 4-
formylbenzoate (870 mg, 5.3 mmol) were dissolved in 500 mL of CH
2
Cl
2
.
Trifluoroacetic acid (25 µL) was added, and the solution was stirred at room temperature
for 50 min. The reaction mixture gradually turned pink. A suspension of 1.21 g of 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ) in 50 mL of CH
2
Cl
2
was added, the reaction
mixture immediately turning dark purple-red. After stirring for further 50 min,
triethylamine (10 mL; the mixture turned yellow-brown) followed by 10 mL of neat
BF
3
·Et
2
O were added, and the dark red reaction mixture was stirred for 1 h. The reaction
mixture was washed with brine and dried over Na
2
SO
4
. TLC control (silica/CH
2
Cl
2
-
hexane 5:1): R
f
0.5 (4.83, orange with yellow-green fluorescence), the non-fluorescent
impurities appear at R
f
< 0.3 (pink). The product was isolated by flash chromatography
(silica gel, CH
2
Cl
2
-hexane 2:1), the fluorescent fractions were combined and evaporated,
giving ~ 6 g of viscous dark orange oil. This was left in a porcelain evaporating dish for 3
days, leaving behind semi-crystalline residue, which was triturated with 10 mL of hexane,
the crystals were filtered off on a sintered glass funnel and thoroughly washed with water.
Dried in air overnight. Dark red crystals, yield 1.09 g (54%).
1
H NMR (CDCl
3
, 500 MHz):
δ 8.18 (“d”, 2H), 7.41 (“d”, 2H), 5.98 (s, 2H), 3.97 (s, 3H), 2.56 (s, 6H), 1.36 (s, 6H).
13
C
321
NMR (CDCl
3
, 125 MHz): δ 14.4-14.65 (m), 52.2-52.4 (m), 117.4 (d,
1
J
C-F
= 337 Hz,
CFCl
3
), 121.5 (br.s), 128.4, 130.4, 130.9, 131.0 (br.s), 140.0, 140.3, 142.8 (br.s), 156.1,
166.3-166.5 (m).
19
F NMR (CDCl
3
, 470 MHz): δ -146.6 (m, approximately 1:1:1:1 q,
1
J
F-B
= 32 Hz);
11
B NMR (CDCl
3
, relative to external BF
3
·Et
2
O, 0.0 ppm; 160 MHz): δ
0.71 (t,
1
J
B-F
= 32 Hz).
N
B
N
F F
O
H
N
NH
2
4.81. 4,4-Difluoro-8-(4'-(2''-aminoethylcarbamoyl))phenyl-1,3,5,7-tetramethyl-2,6-
diethyl-4-bora-3a,4a-diaza-s-indacene.
59
A solution of 4.83 (305 mg, 0.8 mmol) and
triethylamine (6 mL) in methanol (30 mL) was stirred at room temperature for 3 days.
TLC control (silica/CH
2
Cl
2
-methanol-triethylamine 100:20:1): R
f
0.4. The reaction
mixture was evaporated on rotary evaporator (bath temperature 40-50 °C), and the
remaining Et
3
N was carefully blown out with a stream of nitrogen. The product was
isolated by flash chromatography (twice on silica gel, CH
2
Cl
2
-methanol-triethylamine
100:10:1 to 100:15:1 to 100:20:1) as bright red crystals. Recrystallization from EtOAc-
hexane (with addition of minimal amount of CH
2
Cl
2
to dissolve the solid) gave 208 mg
(64%) of 4.81 as orange crystals.
1
H NMR (CDCl
3
, 500 MHz): δ 7.92-7.95 (m, 2H), 7.31-
7.34 (m, 2H), 7.08 (br.t, J = 5.0 Hz, 1H), 5.96 (s, 2H), 3.52 (q, J = 5.0 Hz, 2H), 2.97 (t, J
322
= 5.0 Hz, 2H), 2.53 (s, 6H), 1.32 (s, 6H).
13
C NMR (CDCl
3
, 125 MHz): δ 166.6, 155.8,
142.9, 140.3, 138.1, 134.9, 130.9, 128.3, 127.8, 121.4, 42.3, 41.1, 14.5, 14.43-14.59 (m).
19
F NMR (CDCl
3
, 470 MHz): δ -146.1 (m, approximately 1:1:1:1 q,
1
J
F-B
= 32 Hz).
N
B
N
F F
O
H
N
N
H
H
N
O
O
N
S
O
OMe
OMe
4.80. N-{2-[(2-{[2-[2,4-Dimethoxy(propioloyl)anilino]-2-(2-
thienyl)acetyl]amino}acetyl)amino]ethylcarbamoyl}phenyl-1,3,5,7-tetramethyl-2,6-
diethyl-4-bora-3a,4a-diaza-s-indacene. 4.81 (82 mg, 0.2 mmol), 4.52 (88 mg, 0.22
mmol) and N-ethyldiisopropylamine (35 µL, ~27 mg, 0.21 mmol) were mixed in DMSO
(1 mL) followed by the addition of HATU (76 mg, 0.2 mmol), and the reaction mixture
was stirred for 2.5 h at room temperature. TLC control (silica/EtOAc-methanol 100:2): R
f
0.3. The resulting dark orange solution was poured into the mixture of EtOAc (50 mL)
and 0.1 N NaOH (30 mL), the organic phase was separated, and the aqueous layer was
re-extracted with EtOAc (30 mL). The combined organic phases were washed with 1 N
HCl (2 × 50 mL), water (50 mL), brine and dried over Na
2
SO
4
. The product was isolated
by flash chromatography (silica gel, EtOAc-methanol 100:2), and the fractions containing
the product were evaporated to give orange solid (84 mg). This was recrystallized from
323
CH
2
Cl
2
-hexane and dried in vacuo to give pure 4.80 as bright-orange crystals, yield 76
mg (48%). Purity >99% by HPLC on YMC-Pack SIL column (5 µm silica, porosity 12
nm, 150×4.6 mm ID), conditions: 20% isopropanol-hexane, 2 mL/min (t = 10.21 min).
MS (ESI): 833.3 (M+K
+
), 1627.3 (2M+K
+
). In CDCl
3
, mixture of two rotameric forms in
62:38 ratio.
1
H NMR (CDCl
3
, 500 MHz): δ 8.04-8.11 (m, 2H), 7.93-8.00 (m, 1H), 7.50-
7.57 (m, 1H), 7.40 (br.t, J = 5.0 Hz, 0.62H), 7.30-7.36 (m, 2H), 7.20-7.24 (m, 1H), 7.09
(d, J = 8.6 Hz, 0.62H), 7.03 (d, J = 8.6 Hz, 0.38H), 6.95-6.98 (m, 0.38H), 6.92-6.94 (m,
0.62H), 6.87 (dd, J = 5.3 Hz, J = 3.6 Hz, 0.38H), 6.84 (dd, J = 5.3 Hz, J = 3.6 Hz, 0.62H),
6.34-6.44 (m, 2H), 5.96 (s, 2H), 5.60 (s, 0.38H), 5.46 (s, 0.62H), 4.35 (dd, J = 16.9 Hz, J
= 7.5 Hz, 0.38H), 4.30 (dd, J = 17.1 Hz, J = 6.9 Hz, 0.62H), 3.83 (s, 3×0.62H), 3.78 (s,
3×0.62H), 3.76 (s, 3×0.38H), 3.71 (s, 3×0.38H), 3.43-3.73 (m, 4H), 2.82 (s, 0.62H), 2.81
(s, 0.38H), 2.54 (s, 6H), 1.34 (s, 6H).
13
C NMR (CDCl
3
, 125 MHz): δ 169.9, 169.6, 168.8,
168.5, 166.7, 166.6, 161.6, 161.4, 156.6, 155.9, 155.7, 155.4, 154.9, 143.0, 140.72,
140.70, 137.88, 137.86, 134.9, 134.8, 134.4, 134.2, 131.5, 131.4, 131.0, 130.3, 129.8,
128.31, 128.26, 128.1, 127.9, 126.7, 126.0, 121.3, 121.2, 121.0, 104.9, 104.5, 99.3, 99.2,
80.3, 80.0, 75.51, 75.48, 64.3, 63.2, 55.95, 55.93, 55.51, 55.48, 43.93, 43.88, 40.54, 40.49,
39.74, 39.71, 14.6, 14.5.
19
F NMR (CD
3
OD, 470 MHz): δ -146.2 (m, approximately
1:1:1:1 q,
1
J
F-B
= 32 Hz).
324
N
B
N
F F
O
H
N
N
H
H
N
O
O
N
S
OMe
OMe
O
4.86. N-{2-[(2-{[2-[2,4-Dimethoxy(acetyl)anilino]-2-(2-
thienyl)acetyl]amino}acetyl)amino]ethylcarbamoyl}phenyl-1,3,5,7-tetramethyl-2,6-
diethyl-4-bora-3a,4a-diaza-s-indacene. The starting material, 4.85, was prepared
similarly to 4.52 (the product crystallized upon evaporation of EtOAc extracts and was
recrystallized from EtOAc-hexane as white crystals, yield 93%) from 4.84 (prepared in
52% according to the general procedure for Ugi reaction). 4.81 (82 mg, 0.2 mmol), 4.85
(85 mg, 0.22 mmol) and N-ethyldiisopropylamine (35 µL, ~27 mg, 0.21 mmol) were
mixed in DMSO (1 mL) followed by the addition of HATU (76 mg, 0.2 mmol). TLC
control (silica/EtOAc-methanol 100:2): R
f
0.25. The reaction mixture was poured into
the mixture of EtOAc (50 mL) and 0.1 N NaOH (30 mL), the organic phase was
separated, and the aqueous layer was re-extracted with EtOAc (30 mL). The combined
organic phases were washed with 1 N HCl (2 × 50 mL), water (50 mL), brine and dried
over Na
2
SO
4
. The product was isolated by flash chromatography (silica gel, EtOAc-
methanol 100:2 to 100:5 to 100:7), and the fractions containing the product were
evaporated to give orange viscous oil. This was re-evaporated several times with CH
2
Cl
2
and dried in vacuo to yield orange solid (148 mg, 94%). Purity 99% by HPLC on YMC-
325
Pack SIL column (5 µm silica, porosity 12 nm, 150×4.6 mm ID), conditions: 20%
isopropanol-hexane, 2 mL/min (t = 8.58 min). In CDCl
3
, mixture of two rotameric forms
in 57:43 ratio.
1
H NMR (CDCl
3
, 500 MHz): δ 8.05-8.16 (m, 3H), 7.56-7.64 (m, 1H),
7.40-7.45 (m, 0.57H), 7.34-7.38 (m, 2×0.43H), 7.30-7.34 (m, 2×0.57H), 7.22-7.24 (m,
0.57H), 7.19-7.22 (m, 0.57H), 7.09-7.12 (m, 0.43H), 7.01 (d, J = 8.6 Hz, 0.57H), 6.89-
6.94 (m, 1H), 6.83-6.88 (m, 1H), 6.47 (d, J = 2.5 Hz, 0.57H), 6.33-6.42 (m, 1.43H), 5.97
(s, 2H), 5.42 (s, 0.43H), 5.28 (s, 0.57H), 4.39 (dd, J = 17.0 Hz, J = 7.5 Hz, 0.43H), 4.32
(dd, J = 17.0 Hz, J = 7.2 Hz, 0.57H), 3.86 (s, 3×0.57H), 3.78 (s, 3×0.57H), 3.76 (s,
3×0.43H), 3.63 (s, 3×0.43H), 3.45-3.73 (m, 2H), 2.54 (s, 6H), 1.808 (s, 3×0.57H), 1.805
(s, 3×0.43H), 1.34 (s, 6H).
13
C NMR (CDCl
3
, 125 MHz): δ 173.5, 173.1, 170.1, 169.8,
169.7, 169.2, 166.53, 166.49, 161.3, 161.0, 155.9, 155.7, 155.1, 143.0, 140.72, 140.67,
137.93, 137.88, 135.8, 135.6, 135.0, 134.9, 131.1, 130.6, 130.5, 130.0, 129.5, 128.3,
128.12, 128.09, 127.6, 126.5, 125.9, 123.0, 122.9, 121.3, 105.3, 104.9, 99.5, 99.4, 65.3,
64.0, 55.9, 55.8, 55.6, 55.5, 43.93, 43.88, 40.4, 39.80, 39.76, 22.5, 22.3, 14.6.
N
B
N
F F
O
H
N
N
H
O
4.87. 4,4-Difluoro-8-(4'-(2''-acetamidoethylcarbamoyl))phenyl-1,3,5,7-tetramethyl-
2,6-diethyl-4-bora-3a,4a-diaza-s-indacene. To the solution of 4.81 (30 mg, 0.073 mmol)
326
in CH
2
Cl
2
(2 mL) was added pyridine (18 µL, 0.219 mmol, 3 eq) and acetic anhydride
(21 µL, 0.219 mmol, 3 eq). In a few minutes, clear solution turned into an orange
suspension. TLC control (silica/5% MeOH in EtOAc): R
f
0.35. After stirring for 30 min,
the reaction mixture was poured into EtOAc (50 mL) and washed with 0.5 N HCl (30
mL), sat. NaHCO
3
(30 mL), brine and dried over Na
2
SO
4
. The crude product after
evaporation was dissolved in a minimal volume of 2,2,2-trifluoroethanol (due to its poor
solubility in common solvents) and purified by flash chromatography (silica gel, 3% to
7% MeOH in EtOAc) to yield 24 mg (73%) of the target dye as pink-orange crystals.
Purity 99% by HPLC on YMC-Pack SIL column (5 µm silica, porosity 12 nm, 150×4.6
mm ID), conditions: 10% isopropanol-hexane, 2 mL/min.
1
H NMR (CD
3
OD, 400 MHz):
δ 7.99-8.03 (m, 2H), 7.45-7.49 (m, 2H), 6.08 (s, 2H), 3.50-3.55 (m, 2H), 3.40-3.45 (m,
2H), 2.49 (s, 6H), 1.96 (s, 3H), 1.41 (s, 3H).
13
C NMR (CD
3
OD, 100 MHz): δ 173.9,
169.6, 157.1, 144.5, 142.4, 139.6, 136.5, 132.3, 129.8, 129.5, 122.5, 41.0, 40.1, 22.7, 14.8,
14.57-14.65 (m).
19
F NMR (CD
3
OD, 470 MHz): δ -147.2 (m, approximately 1:1:1:1 q,
1
J
F-B
= 32 Hz).
OTBS
MeO
N
O
S
H
N
O
OEt
O
4.89. Ethyl 2-{[2-(4-(tert-butyl)dimethylsilyloxy-2-methoxypropioloylanilino)-2-(2-
thienyl)acetyl]amino}acetate. A solution of TBSCl (91 mg, 0.6 mmol) in anhydrous
327
DMF (1 mL) was added to the solution of 4.55 (208 mg, 0.5 mmol) and imidazole (136
mg, 2 mmol) in 3 mL of anhydrous DMF, pre-cooled in dry ice/ethylene glycol bath. The
flask was removed from the bath and the resulting clear yellow solution was stirred at RT
for 2.5 h. The mixture was poured into 75 mL of water and extracted with CH
2
Cl
2
(4 × 25
mL), the combined organic phases were washed with water (4 × 30 mL), brine and dried
over MgSO
4
. The compound was isolated by flash chromatography on silica (25 g
Silicycle cartridge, 25 mL/min, gradient 10% to 100% EtOAc in hexane over 10 CV).
The fractions containing the product were pooled, evaporated and dried in vacuo to yield
196 mg (74%) of 4.89 as off-white foam. In CDCl
3
, mixture of two rotameric forms in
60:40 ratio.
1
H NMR (CDCl
3
, 500 MHz): δ 7.92 (br.t, J = 4.7 Hz, 0.4H), 7.17-7.22 (m,
0.6H+0.4H), 7.14-7.16 (m, 0.4H), 7.10 (br.t, J = 5.0 Hz, 0.6H), 7.01-7.03 (m, 0.4H),
6.89-6.92 (m, 0.6H), 6.79-6.84 (m, 0.6H+0.4H), 6.60 (d, J = 8.3 Hz, 0.4H), 6.34-6.39 (m,
0.6H+0.4H), 6.25 (d, J = 2.2 Hz, 0.6H), 6.19 (dd, J = 8.3 Hz, J = 2.2 Hz, 0.4H), 6.04 (s,
0.4H), 5.96 (s, 0.6H), 3.95-4.27 (m, 4×0.6H+4×0.4H), 3.83 (s, 3×0.4H), 3.61 (s, 3×0.6H),
2.73 (s, 0.4H), 2.70 (s, 0.6H), 1.24-1.30 (m, 3×0.6H+3×0.4H), 0.95 (s, 9×0.6H), 0.93 (s,
9×0.4H), 0.18 (s, 3×0.6H), 0.17 (s, 3×0.6H), 0.15 (s, 6×0.4H).
13
C NMR (CDCl
3
, 125
MHz): δ 169.62, 169.56, 168.4, 168.1, 157.6, 157.5, 157.0, 156.9, 154.6, 154.2, 134.8,
134.3, 132.2, 131.6, 129.83, 129.76, 127.5, 127.4, 126.3, 125.5, 121.6, 120.7, 111.9,
111.7, 104.1, 104.0, 78.7, 78.4, 76.05, 75.95, 61.4, 61.3, 61.2, 60.3, 55.9, 55.4, 41.8, 41.6,
25.59, 25.57, 18.2, 14.10, 14.08, -4.46, -4.48, -4.53.
328
N
H
O
4.96. N-Benzyl-2-propynamide. Benzylamine (2.14 g, 20 mmol) and 4-
(dimethylamino)pyridine (DMAP; 244 mg, 2 mmol, 10 mol%) were dissolved in 50 mL
of anhydrous CH
2
Cl
2
and the solution was cooled in ice-water bath. Propiolic acid (1.4 g,
20 mmol) was then added, followed by dropwise addition of the solution of N,N'-
dicyclohexylcarbodiimide (DCC; 4.12 g, 20 mmol) in 50 mL of anhydrous CH
2
Cl
2
. The
reaction mixture was removed from ice-water bath and stirred at room temperature for 3
h. The resulting suspension was cooled down, the precipitate of N,N'-dicyclohexylurea
was washed with a little of cold CH
2
Cl
2
, the filtrate was washed with 2 N HCl, sat.
aqueous NaHCO
3
, water, brine (50 mL each) and dried over MgSO
4
. The compound was
isolated by flash chromatography on silica (25 g Biotage cartridge, 25 mL/min, gradient
20% to 80% EtOAc in hexane over 12 CV). The fractions containing the product were
evaporated and the solid residue was recrystallized from CH
2
Cl
2
-hexane giving 2.59 g
(81%) of 4.96 as white crystals. In CDCl
3
, mixture of two rotameric forms in 90:10 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.24-7.38 (m, 5H), 6.32 (br.s, 0.9H), 6.11 (br.s, 0.1H),
4.62 (d, J = 6.8 Hz, 2×0.1H), 4.46 (d, J = 5.7 Hz, 2×0.9H), 3.13 (s, 0.1H), 2.79 (s, 0.9H).
13
C NMR (100 MHz, CDCl
3
): δ 152.0, 136.9, 128.84, 128.78, 127.87, 127.81, 127.14,
79.7, 77.1, 73.6, 47.2, 43.8.
329
N
O
4.97. N-Benzyl-N-methyl-2-propynamide. Prepared similarly to 4.96. Viscous
yellowish oil, crystallizes when refrigerated. Yield 67%. In CDCl
3
, mixture of two
rotameric forms in 60:40 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.20-7.38 (m, 5H), 4.77 (s,
2×0.6H), 4.59 (s, 2×0.4H), 3.15 (s, 0.4H), 3.13 (s, 0.6H), 3.10 (s, 3×0.4H), 2.86 (s,
3×0.6H).
13
C NMR (100 MHz, CDCl
3
): δ 153.5, 153.4, 135.8, 135.7, 128.8, 128.6, 128.1,
127.9, 127.6, 127.3, 79.3, 78.9, 75.74, 75.70, 54.6, 49.7, 35.6, 31.7.
N
H
O
4.98. N-Phenyl-2-propynamide. Prepared similarly to 4.96. Yellowish crystals, yield
55%.
1
H NMR (400 MHz, CDCl
3
): δ 7.95 (br.s, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.33 (t, J =
7.8 Hz, 2H), 7.15 (t, J = 7.8 Hz, 1H), 2.92 (s, 1H).
13
C NMR (100 MHz, CDCl
3
): δ 149.8,
136.9, 129.1, 125.2, 120.1, 77.5, 74.2.
N
O
4.99. N-Methyl-N-phenyl-2-propynamide. Prepared similarly to 4.96. White crystals,
yield 61%. In CDCl
3
, mixture of two rotameric forms in 80:20 ratio.
1
H NMR (400 MHz,
CDCl
3
): δ 7.36-7.48 (m, 3H), 7.29-7.34 (m, 2H), 3.62 (s, 0.8H), 3.35 (s, 3×0.8H), 3.31 (s,
330
0.2H), 2.84 (s, 3×0.2H).
13
C NMR (100 MHz, CDCl
3
): δ 152.9, 142.5, 129.2, 129.1,
128.1, 127.2, 127.0, 125.3, 80.0, 79.5, 76.2, 39.5, 36.4.
N
O
OMe
4.100. N-(4-Methoxyphenyl)-N-methyl-2-propynamide. Prepared similarly to 4.96.
Yellowish crystals, yield 72%. In CDCl
3
, mixture of two rotameric forms in 80:20 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.19 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 3.81 (s,
3×0.8H), 3.78 (s, 0.8H), 3.54 (s, 3×0.2H), 3.27 (s, 3×0.8H+0.2H), 2.81 (3×0.2H).
13
C
NMR (100 MHz, CDCl
3
): δ 159.1, 153.2, 135.4, 128.3, 126.6, 114.3, 79.9, 79.5, 76.3,
55.4, 36.6.
N
O
CO
2
Me
4.101. Methyl 4-[methyl(propioloyl)amino]benzoate. Prepared similarly to 4.96. White
crystals, yield 54%. In CDCl
3
, mixture of two rotameric forms in 75:25 ratio.
1
H NMR
(400 MHz, CDCl
3
): δ 8.08 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H), 3.92 (s,
3H+0.25H), 3.63 (s, 3×0.25H), 3.34 (s, 3×0.75H), 2.84 (s, 0.75H).
13
C NMR (100 MHz,
CDCl
3
): δ 166.1, 146.4, 130.6, 129.6, 126.9, 124.6, 79.9, 76.0, 52.3, 36.2.
331
H
N
O
S
HO
2
C
NHAc
4.105. (2R)-2-(Acetylamino)-3-{[(E/Z)-3-(benzylamino)-3-oxo-1-
propenyl]sulfanyl}propanoic acid. N-Acetyl-L-cysteine 4.103 (326 mg, 2 mmol) and
4.96 (318 mg, 2 mmol) were mixed in chloroform (3 mL), triethylamine (560 µL, 4 mmol,
2 eq) was added and the rection mixture was stirred at room temperature overnight. The
resulting clear solution was poured into 50 mL of 1 N HCl, extracted with EtOAc (5 × 25
mL), and the combined organic layers were dried over Na
2
SO
4
. The product was isolated
by flash chromatography (silica gel, 20% MeOH in EtOAc) as white foam. Yield 505 mg
(78%). Mixture of (E)- and (Z)-isomers in 43:57 ratio.
1
H NMR (400 MHz, CD
3
OD): δ
7.53 (d, J = 14.9 Hz, 0.43H), 7.19-7.33 (m, 5H), 6.98 (d, J = 10.0 Hz, 0.57H), 6.05 (d, J =
14.9 Hz, 0.43H), 5.96 (d, J = 10.0 Hz, 0.57H), 5.05 (br.s, 3H), 4.70 (dd, J = 7.9 Hz, J =
4.6 Hz, 0.43H), 4.65 (dd, J = 7.9 Hz, J = 4.6 Hz, 0.57H), 4.41 (s, 2×0.43H), 4.37 (s,
2×0.57H), 3.39 (dd, J = 13.7 Hz, J = 4.6 Hz, 0.43H), 3.23 (dd, J = 13.7 Hz, J = 4.6 Hz,
0.43H), 3.18 (dd, J = 14.1 Hz, J = 7.9 Hz, 0.57H), 3.09 (dd, J = 14.1 Hz, J = 7.9 Hz,
0.57H), 1.98-2.02 (m, 3H).
13
C NMR (100 MHz, CD
3
OD): 173.41, 173.36, 173.2, 172.9,
168.5, 166.9, 146.4, 143.0, 140.0, 139.9, 129.5, 128.6, 128.25, 128.20, 118.3, 116.7, 54.3,
53.3, 44.2, 43.9, 38.4, 34.7, 22.4.
332
N
O
Ph
S
MeO
N
O
Ph
S
MeO
(Z)-3-[(4-Methoxyphenyl)sulfanyl]-N-methyl-N-phenyl-2-propenamide (4.106) and
(E)-3-[(4-methoxyphenyl)sulfanyl]-N-methyl-N-phenyl-2-propenamide (4.107).
Prepared similarly to 4.105 on 3 mmol scale in 3 mL CHCl
3
from 4-methoxythiophenol
and 4.99. The products was isolated by flash chromatography (silica gel, 20% MeOH in
EtOAc) as white foam. TLC control (silica/30% EtOAc in hexane): R
f
0.4 (4.107), R
f
0.55 (4.106), both stained red to gray with vanillin. The products were isolated by flash
chromatography on silica (25 g 15 µm PuriFlash cartridge, 20 mL/min, gradient 5% to
50% EtOAc in hexane over 15 CV) as white viscous oils and crystallized upon
refrigeration.
4.106: Yield 691 mg (77%).
1
H NMR (400 MHz, CDCl
3
): δ 7.38-7.45 (m, 4H), 7.30-7.35
(m, 1H), 7.20-7.25 (m, 2H), 6.85-6.93 (m, 3H), 5.75 (d, J = 9.7 Hz, 1H), 3.80 (s, 3H),
3.38 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 166.1, 159.5, 148.1, 143.6, 133.0, 129.4,
128.2, 127.2, 127.0, 114.5, 112.6, 55.1, 36.7.
4.107: Yield 206 mg (23%).
1
H NMR (400 MHz, CDCl
3
): δ 7.66 (d, J = 14.7 Hz, 1H),
7.31-7.37 (m, 2H), 7.23-7.30 (m, 3H), 7.06-7.10 (m, 2H), 6.76-6.81 (m, 2H), 5.51 (d, J =
14.7 Hz, 1H), 3.79 (s, 3H), 3.31 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 164.5, 160.0,
144.4, 143.3, 134.5, 129.2, 127.13, 127.09, 121.5, 115.8, 114.8, 55.2, 37.0.
333
N
O
S
H
2
NOC
NHBoc
4.108. tert-Butyl (1R)-2-amino-1-({[(E/Z)-3-(benzylamino)-3-oxo-1-
propenyl]sulfanyl}methyl)-2-oxoethylcarbamate. The starting material, N-Boc-L-
cysteamide 4.104, was prepared from commercially available N-Boc-L-cysteine methyl
ester according to the literature procedure
72
in 95% yield. The mixture of 4.104 (400 mg,
1.82 mmol), 4.99 (289 mg, 1.82 mmol) and imidazole (25 mg, 0.36 mmol, 20 mol%) in
methanol (5 mL) and water (5 mL) was stirred overnight at room temperature. It was then
evaporated to dryness and the product was isolated by flash chromatography on silica (25
g 50 µm RediSep Rf Gold cartridge, 25 mL/min, gradient 35% to 100% EtOAc in hexane
over 10 CV, then 100% EtOAc over 5 CV) to give 536 mg (78%) of 4.108 as white foam.
Mixture of (E)- and (Z)-isomers in 20:80 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.57 (d, J
= 15.0 Hz, 0.2H), 7.34-7.40 (m, 2H), 7.26-7.32 (m, 1H), 7.11-7.16 (m, 2H), 6.88 (br.d, J
= 9.7 Hz, 0.8H), 6.64 (br.s, 1H), 6.00 (br.s, 0.2H), 5.93 (br.s, 0.8H), 5.79 (br.d, J = 15.0
Hz, 0.2H), 5.73 (br.d, J = 9.7 Hz, 0.8H), 5.66 (d, J = 7.9 Hz, 1H), 4.27-4.37 (m, 1H), 3.29
(s, 3H), 3.15 (dd, J = 14.1 Hz, J = 5.1 Hz, 1H), 2.95 (dd, J = 14.1 Hz, J = 6.8 Hz, 1H),
1.40 (s, 9H).
13
C NMR (100 MHz, CDCl
3
): δ 172.4, 171.2, 166.3, 155.2, 145.7, 143.5,
129.6, 127.5, 127.3, 127.1, 114.5, 80.3, 60.3, 54.2, 38.1, 36.9, 28.2.
334
N
O
S
H
2
NOC
BocHN
+
N
O
S
H
2
NOC
BocHN
O O
4.109. tert-Butyl (1R)-2-amino-1-({[(E/Z)-3-(methylanilino)-3-oxo-1-
propenyl]sulfinyl}methyl)-2-oxoethylcarbamate.
73
To the solution of 4.108 (379 mg, 1
mmol) in CH
2
Cl
2
(6 mL), cooled to -10 °C in dry ice/ethylene glycol bath, 3-
chloroperoxybenzoic acid (mCPBA, <77% of active compound; 300 mg, ~1.3 eq) was
added in one portion, and the cold mixture was stirred for 10 min. TLC control
(silica/EtOAc, stained with vanillin): R
f
0.25 (4.109, gray-brown), R
f
0.3 (impurity,
yellow-brown), R
f
0.55 (4.108, black). The reaction mixture was quenched with aqueous
NaHSO
3
(control with iodine-starch paper), let warm to room temperature with stirring
and diluted with 10 mL of sat. aqueous NaHCO
3
. The mixture was extracted with CH
2
Cl
2
(3 × 25 mL), the combined organic layers were dried over Na
2
SO
4
, evaporated and the
product was isolated by flash chromatography on silica (25 g 50 µm RediSep Rf Gold
cartridge, 25 mL/min, gradient 0% to 15% methanol in EtOAc over 15 CV) to give 336
mg (85%) of 4.109 as white foam. Mixture of (E)- and (Z)-isomers of 2 diastereomeric
sulfoxides (1:1).
1
H NMR (400 MHz, CDCl
3
): δ 7.32-7.46 (m, 3H), 7.14-7.23 (m, 2H),
6.70 (d, J = 9.9 Hz, 0.5H), 6.65 (d, J = 10.1 Hz, 0.5H), 6.10-6.22 (m, 2H), 5.90-6.07
(br.m, 2H), 4.60-4.75 (br.m, 1H), 3.47-3.68 (m, 2H), 3.28-3.32 (m, 3H), 1.38-1.46 (m,
9H).
13
C NMR (100 MHz, CDCl
3
): δ 172.5, 172.3, 163.6, 163.4, 155.5, 154.9, 153.7,
153.0, 142.5, 142.4, 130.0, 129.9, 128.4, 128.3, 126.8, 126.7, 125.7, 125.5, 80.3, 80.0,
64.3, 60.3, 56.4, 55.3, 50.1, 49.8, 37.5, 37.4, 28.23, 28.17.
335
O
N N
4.110. (E)-N-Methyl-N-phenyl-3-(1-pyrrolidinyl)-2-propenamide. To the stirred
solution of 4.99 (318 mg, 2 mmol) in acetonitrile (1 mL) pyrrolidine (183 µL, 156 mg,
2.2 mmol, 1.1 eq) was added in one portion. The mixture quickly heats up to boiling due
to exothermic reaction; it was then left stirring overnight at room temperature. TLC
control (silica/EtOAc, stained with vanillin): R
f
0.25 (4.110, yellow), R
f
0.85 (4.99,
white). The reaction mixture was evaporated to dryness and the product was isolated by
flash chromatography on silica (10 g Biotage cartridge, 12 mL/min, 100% EtOAc over 20
CV) to yield 388 mg (84%) of 4.110 as yellowish crystals upon trituration with hexane.
1
H NMR (400 MHz, CDCl
3
): δ 7.62 (d, J = 12.6 Hz, 1H), 7.29-7.35 (m, 2H), 7.16-7.23
(m, 3H), 4.29 (d, J = 12.6 Hz, 1H), 3.27 (s, 3H), 3.05 (br.s, 4H), 1.75-1.82 (m, 4H).
13
C
NMR (100 MHz, CDCl
3
): δ 169.0, 146.7, 145.2, 129.0, 127.5, 126.3, 86.5, 48.8, 36.8,
25.1.
O
N N
N
4.111. (E)-3-(1H-Imidazol-1-yl)-N-methyl-N-phenyl-2-propenamide. The solution of
4.99 (318 mg, 2 mmol) and imidazole (150 mg, 2.2 mmol, 1.1 eq) in acetonitrile (2 mL)
was stirred at 80 °C for 4 h. TLC control (silica/5% methanol in CH
2
Cl
2
, stained with
basic KMnO
4
): R
f
0.45 (4.111), R
f
0.8 (4.99). The reaction mixture was evaporated to
336
dryness and crude product was isolated by flash chromatography on silica (25 g Puriflash
cartridge, 25 mL/min, gradient 0% to 15% methanol in CH
2
Cl
2
over 18 CV). The
resulting brownish-yellow oil was repurified by by flash chromatography on silica (24 g
50 µm RediSep Rf Gold cartridge, 35 mL/min, gradient 0% to 15% methanol in CH
2
Cl
2
over 18 CV, fraction volume – 8 mL). Evaporation without heating and recrystallization
from CHCl
3
gave 230 mg (50%) of the product as a mixture of (E)- and (Z)-isomers in
45:55 ratio.
1
H NMR (400 MHz, CDCl
3
): δ 7.90 (d, J = 13.9 Hz, 0.45H), 7.86 (s, 0.55H),
7.66 (s, 0.45H), 7.58 (s, 0.55H), 7.44-7.50 (m, 1H), 7.29-7.42 (m, 2H), 7.21-7.26 (m, 1H),
7.02-7.12 (m, 2H), 6.97 (s, 0.45H), 6.58 (d, J = 10.4 Hz, 0.55H), 5.98 (d, J = 13.9 Hz,
0.45H), 5.39 (d, J = 10.4 Hz, 0.55H), 3.40 (s, 3×0.45H), 3.36 (s, 3×0.55H).
13
C NMR
(100 MHz, CDCl
3
): δ 164.4, 142.82, 142.77, 138.5, 137.4, 134.1, 131.0, 129.8, 129.6,
129.3, 127.7, 127.6, 127.4, 127.0, 126.5, 119.5, 115.9, 109.9, 107.2, 37.2, 36.7.
N
O
N
H
O
S
OMe
S
HO
2
C
NHAc
4.112. (2R)-2-(Acetylamino)-3-({(1E/Z)-3-[[2-(cyclopentylamino)-2-oxo-1-thien-2-
ylethyl](3-methoxyphenyl)amino]-3-oxoprop-1-enyl}thio)propanoic acid. Compound
4.15 (192 mg, 0.5 mmol) and N-acetyl-L-cysteine (90 mg, 0.55 mmol, 1.1 eq) were
dissolved under argon in 5 mL CH
2
Cl
2
. Et
3
N (175 µL, 1.25 mmol, 2.5 eq) was then
injected into the flask and the reaction mixture was stirred overnight at room temperature.
337
The reaction mixture was then diluted with 25 mL of ethyl acetate, 20 mL of water and
acidified with 2N HCl. Aqueous layer was re-extracted with 20 mL of ethyl acetate, the
combined organic layers were washed with 30 mL of water and dried over Na
2
SO
4
. The
product was isolated by flash column chromatography (silica – methanol-ethyl acetate
1:1). Yield 240 mg (88%). The product is a mixture of (E)- and (Z)-isomers in ~9:1 ratio.
1
H NMR (400 MHz, DMSO-d
6
): δ 8.17 (d, J = 7.1 Hz, 0.1H), 8.12 (d, J = 7.1 Hz, 0.9H),
7.81-7.88 (m, 0.1H), 7.76 (br.d, 0.9H), 7.54 (dd, J = 15.0 Hz, J = 3.7 Hz, 0.9H+0.1H),
7.33 (d, J = 5.0 Hz, 0.9H+0.1H), 7.07-7.16 (m, 0.9H), 7.00-7.07 (m, 0.1H), 6.73-6.88 (m,
4×0.9H+4×0.1H), 6.28-6.35 (m, 0.9H+0.1H), 5.46 (d, J = 15.0 Hz, 0.9H), 5.38 (d, J =
10.4 Hz, 0.1H), 4.14-4.25 (m, 0.9H+0.1H), 3.94-4.05 (m, 0.9H+0.1H), 3.63 (s,
3×0.9H+3×0.1H), 3.08-3.22 (m, 0.9H+0.1H), 2.88-3.00 (m, 0.9H+0.1H), 1.81 (s,
3×0.9H+3×0.1H), 1.68-1.85 (m, 2×0.9H+2×0.1H), 1.20-1.65 (m, 6×0.9H+6×0.1H).
13
C
NMR (100 MHz, DMSO-d
6
): δ 172.6, 169.0, 168.3, 163.3, 158.9, 145.4, 145.3, 140.0,
137.3, 129.1, 129.0, 127.4, 126.1, 123.1, 116.3, 114.6, 113.5, 58.4, 55.0, 53.4, 50.7, 35.4,
35.3, 32.1, 32.0, 31.8, 31.7, 30.7, 30.1, 23.51, 23.45, 22.6.
N
O
H
N
O
OMe
MeO
S
S
HO
2
C
NHAc
4.113. (2R)-2-(Acetylamino)-3-({2-[[2-(cyclopentylamino)-2-oxo-1-thien-2-
ylethyl](2,4-dimethoxyphenyl)amino]-2-oxoethyl}thio)propanoic acid. Compound
338
4.58 (241 mg, 0.5 mmol) and N-acetyl-L-cysteine (90 mg, 0.55 mmol, 1.1 eq) were
dissolved under argon in 5 mL CH
2
Cl
2
. Et
3
N (175 µL, 1.25 mmol, 2.5 eq) was then
injected into the flask and the reaction mixture was stirred overnight at room temperature.
The reaction mixture was then diluted with 25 mL of ethyl acetate, 20 mL of water and
acidified with 2N HCl. Aqueous layer was re-extracted with 20 mL of ethyl acetate, the
combined organic layers were washed with 30 mL of water and dried over Na
2
SO
4
. The
product was isolated by flash column chromatography (silica – methanol-ethyl acetate
1:2). Yield 280 mg (99%). In DMSO-d
6
, mixture of two rotameric forms in 75:25 ratio.
1
H NMR (400 MHz, DMSO-d
6
): δ 7.85-8.05 (m, 2×0.75H+0.25H), 7.49 (dd, J = 8.7 Hz,
J = 2.1 Hz, 0.75H), 7.34-7.38 (m, 0.25H), 7.27 (d, J = 4.6 Hz, 0.75H), 7.01 (d, J = 3.3 Hz,
0.25H), 6.84-6.89 (m, 0.25H), 6.73-6.78 (m, 2×0.75+0.25H), 6.65 (d, J = 8.3 Hz, 0.25H),
6.57 (d, J = 2.5 Hz, 0.25H), 6.42 (dt, J = 8.7 Hz, J = 2.1 Hz, 0.75H), 6.32-6.36 (m,
0.75H), 6.30 (dd, J = 8.7 Hz, J = 2.9 Hz, 0.25H), 6.04 (d, J = 7.1 Hz, 0.25H), 5.99 (d, J =
2.1 Hz, 0.75H), 4.14-4.30 (m, 0.75H+0.25H), 3.90-4.06 (m, 0.75H+0.25H), 3.81 (s,
3×0.25H), 3.71 (s, 3×0.25H), 3.69 (s, 3×0.75H), 3.58 (s, 3×0.75H), 2.96-3.07 (m,
2×0.75H+2×0.25H), 2.83-2.95 (m, 0.75H+0.25H), 2.62-2.73 (m, 0.75H+0.25H), 1.79 (s,
3×0.75H), 1.78 (s, 3×0.25H), 1.20-1.83 (m, 8×0.75H+8×0.25H).
13
C NMR (100 MHz,
DMSO-d
6
): δ 169.2, 169.2, 168.9, 168.6, 168.5, 160.2, 156.2, 136.3, 132.42, 132.36,
131.6, 131.0, 128.9, 127.2, 127.1, 126.1, 125.5, 120.5, 119.9, 104.3, 104.2, 98.7, 98.4,
64.2, 63.5, 59.7, 59.3, 55.7, 55.3, 55.2, 52.6, 52.4, 50.6, 50.3, 34.9, 34.7, 34.2, 34.0, 33.9,
32.2, 32.0, 31.8, 30.6, 30.1, 23.5, 23.4, 22.4, 20.71, 20.67, 18.6, 14.0, 13.5.
339
4.7 Chapter 4. References.
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344
Chapter 5. Design and synthesis of human
apurinic/apyrimidinic endonuclease type 1 (APE1) inhibitors.
5.1 Introduction. Dual function of APE1/Ref-1 and its known inhibitors.
Base excision repair (BER) pathway is one of the several known cellular
mechanisms of DNA repair which is responsible for removing small, non-helix-distorting
DNA defects (damaged and unusual bases, abasic sites). Typically, such bases are
removed by a DNA glycosylase, leaving an abasic site, which is then excised by
apurinic/apyrimidinic endonucleases (APE).
1
One-base gap is then filled by DNA
polymerase β, and the integrity of phosphate-deoxyribose backbone is restored by DNA
ligase III (so-called short patch pathway). In alternative, long patch pathway, several
adjacent bases are removed and replaced at a time, which requires a different set of
auxiliary factors: proliferating cellular nuclear antigen (PCNA), replication factor C
(RPC), flap endonuclease (FEN1), and a different ligase (DNA ligase I).
2
In both
variations, the abasic site excision step, performed by APE1 enzyme in mammalian cells,
is indispensable for correction of alkylation or oxidative DNA damage:
345
Figure 5.1. Short patch and long patch variations of base excision repair pathway.
3
The human APE1 enzyme is responsible for >95% of DNA abasic site processing,
and the frequency of base-loss events has been estimated as high as 10
5
per cell per day.
4
The vital importance of this endonuclease is demonstrated by the embryonic lethality of
APE1 mouse knockouts and the lack of viable cell lines completely deficient for APE1,
2
as well as by the fact that the part of the APE1 protein responsible for its endonuclease
activity is highly conserved from bacteria to mammals (it belongs to the ExoIII/Xth
family of endonucleases).
5
Overexpression of APE1, however, is known to cause
resistance to chemotherapy with alkylating agents and radiotherapy of certain human
cancers, as it has been demonstrated for malignant gliomas
6
and osteosarcomas,
7
and is
346
associated with poor prognosis. This makes APE1 a promising therapeutic and
chemopreventive target.
2
Mechanistically, APE1 begins the excision of the abasic site with penetrating the
DNA helix from both the major and minor grooves with its rigid DNA-binding site and
stabilizes an extrahelical conformation for target abasic nucleotides. The arginine R177 is
inserted through the major groove to form a hydrogen bond to the non-target 3'-phosphate
of the abasic site. The target 5'-phosphate is oriented by hydrogen bonding with
asparagines N174 and N212 and histidine H309. The hydrolysis of this phosphate group
proceeds via pentacovalent transition state with hydroxyl group transferred onto
phosphorus center from a water molecule, coordinated to the aspartate D210 through a
hydrogen bond, while on the opposite side the P–O bond cleavage is facilitated by
coordination of Mg
2+
ion. The net result is the hydrolysis of the phosphate ester at the 3'-
position of the intact nucleotide and inversion of the phosphate group, which remains
attached to the 5' carbon of the abasic site
8
(Figure 5.2).
347
O
B
O
P O
O
O
O
OH
HN
H
N
H
2
N O
HO
H
O O
NH
2
O
O O
Mg
2+
O
O
N174
E96
N212
D210
H309
D283
abasic site
O
B
O
P O
O
O
O
OH
HN
H
N
H
2
N O
HO O
NH
2
O
O O
Mg
2+
O
O
N174
E96
N212
D210
H309
D283
abasic site
OH
O
B
O
P
O
O
O O
OH
HN
H
N
H
2
N O
HO O
NH
2
O
O O
Mg
2+
O
O
N174
E96
N212
D210 H309
D283
abasic site
OH
Figure 5.2. APE1/Mg
2+
-catalyzed DNA cleavage at the abasic site.
APE1 protein also possesses a redox function, unique to mammals, and the redox
and DNA repair domains are located separately within the N- and C-terminal regions of
the protein. As a redox regulator (named Ref-1), it is responsible for maintaining the
transcription factors in their active reduced state and, therefore, for changes in gene
expression.
9,10
Of the seven cysteine residues present in human APE1, C65 was identified
as the critical residue required for its redox activity through analysis of single C-to-A
substitutions (APE1-C65A mutant protein was found redox-inactive). Inhibition of this
function may be beneficial in the treatment of melanoma, as many of human melanoma
348
cell lines (in particular c83-2c) were found to overexpress this protein,
11
and some other
types of cancer.
12
Apart from these two basic functions, APE1 was identified as a component of
endoplasmic reticulum-associated SET complex, which is a target of caspase-independent
cell death mechanism mediated by the cytotoxic T-lymphocyte protease granzyme A. It
was shown that APE1 activity in this complex is that of an apoptotic nuclease, targeting
undamaged DNA.
4
Numerous small molecule inhibitors of endonuclease function of APE1 have been
identified to date. The simpliest is methoxyamine (O-methylhydroxylamine), an indirect
inhibitor which reacts with aldehyde groups at the abasic sites, blocking the DNA repair
activity of APE1
2
(Scheme 5.1).
O
B
O
P O
O
O
O
OH
abasic site
MeONH
2
O
B
O
P O
O
O
HO
N
MeO
Scheme 5.1.
Direct inhibitors interrupt the coordination between the abasic fragment of a DNA
strand, APE1 active site and Mg
2+
cation in such a way that makes DNA cleavage
impossible. Some molecular modeling studies have been done, yet the exact binding
mode of these small molecule inhibitors is unknown, as no co-crystal structures have
been resolved. The most active inhibitors reported to date are small polar molecules that
349
do not have many common features, for example NCA (CRT0044876, 7-nitroindole-2-
carboxylic acid),
13
NSC-13755,
14
6-hydroxy-DL-DOPA.
15
Several compounds that have
been identified to possess APE1 inhibitor properties have other known biological targets,
such as lucanthone (topoisomerase II inhibitor),
16
methyl 3,4-dephostatine (tyrosine
phosphatase inhibitor), Reactive Blue 2 dye (purinoreceptor antagonist), mitoxantrone
(topoisomerase II inhibitor, also capable of DNA intercalation) and aurintricarboxylic
acid (potent inhibitor of ribonuclease and topoisomerase II, generally inhibits protein-
nucleic acid interactions).
15
Two widely occurring natural compounds, a flavonoid
myricetin
15
and a stilbene derivative resveratrol,
2
have demonstrated pronounced effects
on APE1 function, inhibiting its endonuclease activity in vitro. The structures of these
compounds are shown in Figure 5.3.
350
N
H
CO
2
H
NO
2
NCA
(3 M) µ
CO
2
H
NO
2
Sb
O
HO
HO
NSC-13755
(4 M) µ
HO
HO
OH
NH
2
CO
2
H
6-hydroxy-DL-DOPA
(10 M) µ
S
O HN
NEt
2
lucanthone
HO
HO N
NO
methyl 3,4-dephostatine
(8.9 M) µ
O
O
HN NH
N
N
N
Cl
H
N
SO
3
Na
NH
2
SO
3
Na
SO
3
Na
Reactive Blue 2
(10 M) µ
O
O
HN
HN
H
N
OH
N
H
OH
OH
OH
mitoxantrone
(2 M) µ
O
CO
2
H
CO
2
H
OH
HO
2
C
HO
aurintricarboxylic acid
(25 M) µ
O
OH
OH
OH
HO
OH O
myricetin
HO
OH
OH
resveratrol
Figure 5.3. Compounds inhibiting endonuclease activity of APE1.
5.2 Synthesis of the test compounds targeting Ref-1 redox function.
Unlike inhibitors of endonuclease activity of APE1, the reports on selective
inhibitors of its redox activity (Ref-1), affecting the regulation of APE1-controlled
transcription factors,
17
are quite rare. A small molecule PNRI-299 was reported to bind
into a hydrophobic pocket of Ref-1 in close proximity to the side chain of C65,
suggesting a possibility of covalent binding of this compound as a Michael acceptor.
18
This binding resulted in selective inhibition of AP-1 (activator protein-1, controlled by
Ref-1) transcription with IC
50
= 20 µM (Scheme 5.2).
351
N
N
N
NC
O
O
O
NHBn O
PNRI-299
R SH
R' SH
R
S
S
R'
N
N
N
NC
O
O
O
NHBn O
S
R
Scheme 5.2.
The compound E3330, a very specific inhibitor of Ref-1 with high binding
affinity, contains a 2,3-dimethoxy-1,4-benzoquinone fragment typical for a compound
from coenzyme Q
10
(ubiquinone) series. The latter is a key component of electron
transport chain, crucial to aerobic cellular respiration in human and animal cells (in plant
cells, 2,3-dimethyl analog – plastoquinone – plays the same role). About 20 analogs of
E3330 have been synthesized and many of them were found to possess comparable or
superior Ref-1 inhibitory activity
19,20
(Figure 5.4).
O
O
MeO
MeO
CO
2
H
E3330
IC
50
10 M
GI
50
35 M
µ
µ
O
O
MeO
MeO
CO
2
H
IC
50
3 M
GI
50
45 M
µ
µ
O
O
MeO
MeO
IC
50
10 M
GI
50
35 M
µ
µ
O
N
H
OH
O
O
Cl
IC
50
1 M
GI
50
8 M
µ
µ
O
N
H
OH
O
O
Br
CO
2
H
IC
50
1 M
GI
50
25 M
µ
µ
OMe
O
O
Br
CO
2
H
IC
50
5 M
GI
50
15 M
µ
µ
Figure 5.4. Ref-1 redox and HEY-C2 cells growth inhibition of compound E3330 and its
analogs.
352
It was noted that apart from the redox-active 1,4-quinone fragment all E3300
analogs contained at least one electron-poor C=C double bond, which can enable these
compounds to react as Michael acceptors with biologically relevant nucleophilic species.
The chemical reactivity of these quinones has not been investigated; however, it is known
that critical for Ref-1 redox activity is the presence of C65 cysteine in the molecule of the
protein, and that this cysteine residue is not surface accessible (i.e., buried inside the
protein, requiring very specific binding or protein conformation change for interaction
with a small molecule).
21
This allowed us to suggest the possibility of covalent binding of
these compounds with the thiol group of C65 in Ref-1.
From our previous experience with propiolamides as cysteine-reactive molecules,
it was suggested that designing a compound structurally similar to E3330, containing a
quinone fragment with attached hydrophobic chain and an electron-deficient triple C ≡C
bond, may provide another Ref-1 redox activity inhibitor. Four molecules were designed
and prepared for this purpose:
O
O
O
O
MeO
MeO
O
O
N O
O
O
MeO
MeO
N O
5.1
5.3
5.2
5.4
Figure 5.5. Acetylenic analogs of E3330.
353
Several hybrid ubiquinones, similar to 5.3 and 5.4 (although devoid of
electrophilic groups), have been prepared before and studied as potential inhibitors of
mitochondrial complex I.
22
The compounds 5.1 and 5.2 were prepared from very inexpensive commercially
available trimethylhydroquinone 5.5. This compound was alkylated to dimethoxy
derivative 5.6 and was then subjected to oxidative iodination under the conditions
reported by Tietze group.
23
However, significant overoxidation of 5.6 to quinones (5.8,
5.9) was observed (Scheme 5.3).
OH
OH
Me
2
SO
4
(3 eq)
OMe
OMe
95%
I
2
(0.2 eq)
H
5
IO
6
(0.4 eq)
H
2
SO
4
(cat.)
AcOH - H
2
O
55
o
C, 15 h
OMe
OMe
43%
I
O
O
O
O
I
++
32%
5.5
K
2
CO
3
acetone
reflux, 24 h
5.6 5.7 5.8 5.9
Scheme 5.3.
The iodinated hydroquinone ether 5.7 was then separated and coupled with 1-
undecyne in Sonogashira reaction to give 5.10. Similar coupling could not be achieved
when attempted between 2-bromo-3,5,6-trimethyl-1,4-benzoquinone and 1-undecyne,
even though Suzuki and Stille couplings have been reported to work with halogenated
quinones.
24
Finally, 5.10 was oxidated with ammonium cerium(IV) nitrate (CAN) to the
target 5.1 (Scheme 5.4).
354
OMe
OMe
I
8
(1.5 eq)
Pd(PPh
3
)
2
Cl
2
(5 mol%)
CuI (10 mol%)
Et
2
NH, 45
o
C, 4 h
OMe
OMe
8
CAN (4.5 eq)
MeCN - H
2
O
RT, 1.5 h
O
O
8
5.7
75%
5.10
53%
5.1
Scheme 5.4.
To prepare 5.2, the compound 5.6 was formylated under Duff conditions,
providing the aldehyde 5.11 in high yield. The reductive amination with 1-decylamine
afforded the secondary amine 5.12, which was coupled with propiolic acid and EDC·HCl
in the presence of DMAP catalyst. The product 5.13 could not be completely separated
from the by-product 5.14, resulting from the nucleophilic addition of the secondary amine
molecule across the triple bond of the propiolamide 5.13. However, the mixture of 5.13
and 5.14 could be oxidized directly, and the target 5.2 was prepared in acceptable yield
(Scheme 5.5).
355
OMe
OMe
(CH
2
)
6
N
4
(1 eq)
TFA, reflux 24 h
OMe
OMe
O
92%
H
2
N
9
NaBH(OAc)
3
(1.5 eq)
1,2-dichloroethane
RT, 24 h
OMe
OMe
H
N
76%
9
CO
2
H (1.2 eq)
EDC HCl (1.2 eq)
DMAP (10 mol%)
MeCN, 0
o
C, 1 h
OMe
OMe
N
9
O
+
N N
O
R R
CAN (4.5 eq)
MeCN - H
2
O
RT, 1 h
O
O
N
9
O
33% over 2 steps
OMe
OMe
OMe
OMe
E/Z = 1:1
.
5.6 5.11 5.12
(R = 1-decyl) 5.13 5.14
5.2
Scheme 5.5.
The compounds 5.3 and 5.4 were synthesized similarly starting from 2,3,4,5-
tetramethoxytoluene 5.17. This compound was prepared from commercially available
2,3-dimethoxy-5-methyl-1,4-benzoquinone (coenzyme Q
0
) 5.15 (Scheme 5.6), which in
turn could be obtained by oxidation of 3,4,5-trimethoxytoluene, available on large scale
(hundreds of grams)
25
.
MeO
MeO
O
O
NaBH
4
(5 eq)
H
2
O - MeOH - Et
2
O
RT, 15 min
MeO
MeO
OH
OH
Me
2
SO
4
(4 eq)
K
2
CO
3
acetone
reflux, 48 h
MeO
MeO
OMe
OMe
86% over 2 steps
5.15 5.16 5.17
Scheme 5.6.
356
For the synthesis of 5.3, the iodination of 5.17 under optimized conditions yielded
the aryl iodide 5.18 in 89% yield without significant overoxidation. It was then coupled
with 1-undecyne, and the alkyne product 5.19 was oxidized with CAN to the target 5.3.
This oxidation proceeded much faster than the transformation 5.10 Æ 5.1 (Scheme 5.7).
I
2
(0.6 eq)
H
5
IO
6
(0.2 eq)
H
2
SO
4
cat.
AcOH - H
2
O
55
o
C, 15 h
MeO
MeO
OMe
OMe
I
89%
Pd(PPh
3
)
2
Cl
2
(5 mol%)
CuI (10 mol%)
Et
2
NH, 50
o
C, 4 h
8
(1.5 eq)
MeO
MeO
OMe
OMe
8
76%
CAN (3 eq)
MeCN - H
2
O
0
o
C, 15 min
MeO
MeO
O
O
8
45%
MeO
MeO
OMe
OMe
5.17 5.18 5.19
5.3
Scheme 5.7.
The compound 5.4 was prepared from 5.17 similarly to the synthesis of 5.2 from 5.6.
However, pure propiolamide 5.22 could be isolated in this case (Scheme 5.8).
357
MeO
MeO
OMe
OMe
(CH
2
)
6
N
4
(1 eq)
TFA
reflux, 2 h
MeO
MeO
OMe
OMe
O
64%
H
2
N
8
NaBH(OAc)
3
(1.5 eq)
1,2-dichloroethane
RT, 48 h
Na
2
SO
4
MeO
MeO
OMe
OMe
H
N
95%
8
CO
2
H (1.2 eq)
EDC HCl (1.2 eq)
DMAP (10 mol%)
MeCN, 0
o
C, 1 h
MeO
MeO
OMe
OMe
N
8
O
83%
CAN (3 eq)
MeCN - H
2
O
0
o
C, 10 min
MeO
MeO
O
O
N
8
O
64%
5.17 5.20 5.21
.
5.22
5.4
Scheme 5.8.
The studies of the activity of compounds of 5.1-5.4 as inhibitors of redox activity
of Ref-1, as well as other redox-active protein targets, are currently ongoing.
5.3 Synthesis of the test compounds targeting APE1 endonuclease activity.
During the work performed in the research group of Prof. Nouri Neamati, USC
School of Pharmacy, based on the 3D pharmacophore model studies, a set of small
molecules, commercially available from small molecule libraries, have been predicted to
possess APE1-inhibitory activity. From 80 compounds selected for screening, 46 (57.5%)
were demonstrated to actually inhibit the APE1 catalytic activity with IC
50
< 100 µM.
26
Some of the most active compounds (IC
50
≤ 5 µM) are shown in Figure 5.6:
358
N
Cl
CO
2
H
CO
2
H
S
S
O
O
CO
2
H
CO
2
H
HO
2
C
N
N
N
N
CO
2
H HO
2
C
S
N
O
CO
2
H
S
N
HO
2
C
O
O
HO
2
C
S
S
O
CO
2
H
5.23
5.24
5.25
5.26
5.27
(4 1 M) ± µ
(4 1 M) ± µ
(4 1 M) ± µ
(3 1 M) ± µ
(5 2 M) ± µ
Figure 5.6. Dicarboxylic acid APE1 inhibitors and their IC
50
values.
These compounds share the common structural feature of being dicarboxylic acids, and
some of them (e.g., 5.25, 5.27 in Figure 5.6) are symmetric. The necessity of the presence
of two negatively ionizable groups can be explained by comparison of a small molecule
inhibitor with abasic DNA fragment, which contains two negatively charged phosphate
groups (with the distance between them 8.07 ± 1 Å) in 3' and 5' positions of the abasic
deoxyribose unit. At least one of these groups may be involved in coordination with Mg
2+
ion, required for the nuclease action of APE1 (see Figure 5.2). The reported co-crystal
structure of an abasic DNA fragment with APE1 and Mn
2+
as Mg
2+
surrogate (1DEW in
the Protein data Bank) suggests the coordination of the metal to 5'-phosphate after the
cleavage. However, there are no available co-crystal structures of APE1 with small
molecule inhibitors. For such co-crystallization attempt, the analog 5.35 of the compound
5.23 containing a heavier halogen atom (Br instead of Cl) was prepared according to
Scheme 5.9 from 1,4-cyclohexadione monoethylene ketal:
359
O
OO
LiHDMS, THF
-78
o
C RT
Br
Cl
O
THF
-78
o
C RT
30 min
O
OO
O
Br
MeONa (cat.)
MeOH, RT
1.5 h
OO
O
Br
RO
2
C
transesterification
with EtOH
during workup
HCl
H
2
O - THF, RT
4 days
O
Br
HO
2
C
O
~100%
5.28
5.29
5.30
5.31
(R = Me)
62% over 2 steps
(R = Et)
16% over 2 steps
5.32
H
2
N CO
2
Me HCl
AcONa (1 eq)
TsOH H
2
O (10 mol%)
N
CO
2
Me
CO
2
Me
Br
+
O
Br
CO
2
Me
O
MeOH
reflux, 48 h
LiOH H
2
O (3 eq)
H
2
O - THF, RT
overnight
N
CO
2
H
CO
2
H
Br
.
.
89%
5.33
10%
5.34
.
98%
5.35
Scheme 5.9.
The ketone 5.28 was α-acylated according to the literature procedure;
27
it was
found convenient not to isolate the intermediate diketone 5.29 but to introduce the crude
5.29 (an impure mixture of diketo- and keto-enol forms by
1
H NMR) into the following
retro-Dieckmann condensation step. The resulting ester underwent facile
transesterification when re-evaporated with ethanol during the reaction workup, and both
methyl (5.30) and ethyl (5.31) esters of the resulting 7-ketoacid were isolated and
characterized separately. The dioxolane protection of the second ketone was then
360
removed by acidic hydrolysis of the mixture of the esters, which proceeded quantitatively.
The pyrrole diester 5.33 was prepared by Paal-Knorr condensation of the 4,7-diketoacid
5.32 with glycine methyl ester, and some of the unreacted starting material was recovered
in the form of the ester 5.34. Finally, the diester 5.33 was hydrolyzed into the target
dicarboxylic acid 5.35 in nearly quantitative yield. A sample of 5.35 was supplied for X-
ray crystallography studies, and samples of 5.33 and 5.35 were sent for evaluation of
their APE1-inhibitory activity.
In a separate screening, a series of non-carboxylate APE1 inhibitors was
discovered based on the previously reported HIV-1 integrase (IN) inhibitors containing 4-
acyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one core.
28-30
The structures of the most potent
pyrrolone APE1 inhibitors (IC
50
< 20 µM), identified in the assay, are shown in Figure
5.7:
N
O
OH
O
MeO
MeO
N
O
OH
O
EtO
N
N
N
O
OH
O
N
HO
OMe
N
O
OH
O
OMe
HO
OEt
5.36
IC
50
19 2 M ± µ
GOLD FS 62.68
IC
50
19 0 M ± µ
GOLD FS 59.83
5.38
IC
50
19 2 M ± µ
GOLD FS 59.92
5.37
IC
50
19 1 M ± µ
GOLD FS 56.58
5.39
N
O
R
1
OH
O
R
3
R
2
4-acyl-3-hydroxy-1,5-
dihydro-2H-pyrrol-2-one
5
1
2
3
4
Figure 5.7. Pyrrolone-based APE1 inhibitors, their IC
50
values and GOLD fitness scores.
361
Just as human APE1, viral HIV-1 IN requires a Mg
2+
cofactor (substitutable for
Mn
2+
in in vitro studies). It was suggested that the inhibitory activity of these and similar
compounds likely stemmed from their ability, as 1,3-diketones, to coordinate a metal ion
in the active center of the enzyme.
31
The compound 5.36 was selected as a starting point
for further modification of the structure. The syntheses of similar 4-acyl-3-hydroxy-1,5-
dihydro-2H-pyrrol-2-ones have been reported using the three-component reaction
between aldehydes, amines and α, γ-diketoesters (the latter are easily obtainable by
condensation of dimethyl or diethyl oxalate with 1 eq of an aryl methyl ketone)
32-34
(Scheme 5.10).
Ar
O
+
MeO
OMe
O
O
MeONa
MeOH - Et
2
O
RT, overnight
Ar
O
CO
2
Me
OH
R
1
O
R
2
NH
2
solvent
RT, overnight
N
O
Ar
OH
O
R
1
R
2
5.40-5.44
5.36, 5.45-5.51
Scheme 5.10.
However, the preparation of 5.36 according to the literature procedure (in
dioxane at room temperature or at 90 °C) required its isolation by column
chromatography. A brief screening of other solvents (ethanol, toluene, DMF, acetic acid,
2,2,2-trifluoroethanol, acetonitrile, pyridine) demonstrated that the reaction proceeded
well in all of these solvents, but it was cleaner and the conversion of diketoester was
complete only in DMF and pyridine. The workup could be further simplified when
DMSO was used instead of DMF, requiring only simple acidic water-EtOAc extraction
followed by recrystallization of the compound, sometimes directly from the organic
362
phase. A short series of 5.36 analogs was prepared using this optimized procedure in
yields around 80%:
N
O
OH
O
MeO
MeO
5.36
83%
N
O
OH
O
MeO
MeO
5.45
66%
N
O
OH
O
MeO
5.46
86%
N
O
OH
O
5.47
81%
N
O
OH
O
MeO
MeO
HO
5.48
81%
N
O
OH
O
MeO
MeO
MsHN
5.49
79%
N
O
OH
O
MsHN
5.50
80%
N
O
OH
O
N
5.51
74%
Figure 5.8. The analogs of compound 5.36.
To evaluate the necessity of the presence of 1,3-diketone moiety for the activity of
the compounds, two analogs of 5.36 were prepared by modification of the 1,3-diketo
fragment:
N
O
OH
O
MeO
MeO
5.36
+ (MeO)
2
SO
2
K
2
CO
3
DMSO
RT, 24 h
N
O
OMe
O
MeO
MeO
5.52
78%
N
O
OH
O
MeO
MeO
5.36
+ N
2
H
4
H
2
O
.
AcOH
reflux, 3.5h
N
O
N
HN
MeO
MeO
5.53
98%
Scheme 5.11.
363
Several heterocyclic analogs of 5.36 retaining the acyl substituent and the 1,3-
diketo fragment have also been prepared to evaluate their inhibitory activity against
APE1 by simple acylation of the parent CH-acidic heterocycles:
MeO
MeO N
N
O OH
O O
MeO
MeO
O
Cl
+ NN
O O
O
pyridine
RT, overnight
5.54
64%
MeO
MeO
O
Cl
+
Ca(OH)
2
dioxane
90-95
o
C, 2.5 h S
N
O
S
MeO
MeO
O
S
N
OH
S
5.55
61%
O
CO
2
Et
+ MeNHNH
2
EtOH
reflux, 1 h
N
H
N
O
MeO
MeO
O
Cl
Ca(OH)
2
, dioxane
reflux, overnight
MeO
MeO
O
N
N
OH
5.56
27%
MeO
MeO
O
Cl
+ N
O
O
LiHMDS, THF
-78
o
C RT
overnight
MeO
MeO
O
N
O
O
5.57
35%
Scheme 5.12.
According to the
1
H NMR data, the compounds 5.54-5.56 (as well as the original
4-acyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, e.g. 5.36) exist in solution exclusively
in the form of enol tautomer. On the contrary, compound 5.57 contained only 5-7% of
364
enolic form in CDCl
3
and acetone-d
6
solutions. Upon addition of base (NaOD in D
2
O) to
its acetone-d
6
solution, the diketo form gradually converted into the enol isomer:
Figure 5.9. Keto-enol isomerization of the compound 5.57 under basic conditions (red –
no base, green – 15 min after addition of NaOD, blue – 4 h after addition of NaOD).
365
Finally, the 2-acylphenol analog of 5.61 was prepared from o-vanillin:
O
OH
OMe
MOMBr, EtN(i-Pr)
2
toluene
RT, overnight
O
OMOM
OMe
5.58
96%
MeO
MeO
Li
-30
o
C RT
OH
MeO
MeO
OMOM
OMe
5.59
63%
MnO
2
CH
2
Cl
2
RT, 3 d
O
MeO
MeO
OMOM
OMe
5.60
85%
HCl
H
2
O - MeOH
RT, 2 h
O
MeO
MeO
OH
OMe
5.61
97%
Scheme 5.13.
The studies of the biological activity of the compounds 5.45-5.57, 5.61 are
currently underway.
5.4 Experimental
All reactions, unless otherwise noted, were run using commercially available
solvents and reagents as received, without additional preparation and purification, in
ordinary laboratory glassware.
1
H and
13
C NMR spectra were recorded on Varian
Mercury 400, Varian 400-MR (400 MHz) or Varian VNMRS-500 (500 MHz) 2-channel
NMR spectrometers, using residual
1
H or
13
C signals of deuterated solvents as internal
standards. Silica gel (60 Å, 40-63 µm; Sorbent Technologies) was used as a sorbent for
flash column chromatography. Automated flash chromatography was performed on
Isolera One flash purification system (Biotage), default fraction volume – 12 mL.
366
OMe
OMe
5.6. 1,4-Dimethoxy-2,3,5-trimethylbenzene.
35
A mixture of trimethylhydroquinone (20
g, 0.132 mol), dimethyl sulfate (38 mL, 49.8 g, 0.395 mol) and K
2
CO
3
(72.6 g, 0.526 mol)
in 200 mL acetone was refluxed for 24 h. The reaction mixture was evaporated on the
rotary evaporator, diluted with water (150 mL) and extracted with ether (3 × 50 mL). The
combined organic phases were dried over MgSO
4
and concentrated. Distillation in vacuo
afforded 22.5 g (95%) of product (bp 85-90 °C / 0.25 mm Hg) as light yellow liquid.
1
H
NMR (CDCl
3
, 400 MHz): δ 6.57 (s, 1H), 3.81 (s, 3H), 3.69 (s, 3H), 2.32 (s, 3H), 2.24 (s,
3H), 2.15 (s, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 153.4, 150.5, 130.5, 127.6, 123.7,
110.2, 60.1, 55.7, 16.2, 12.6, 11.8.
OMe
OMe
I
O
O
O
O
I
1-Iodo-2,5-dimethoxy-3,4,6-trimethylbenzene (5.7), 2,3,5-trimethyl-1,4-
benzoquinone (5.8) and 2-iodo-3,5,6-trimethyl-1,4-benzoquinone (5.9).
23
1,4-
Dimethoxy-2,3,5-trimethylbenzene 5.6 (4.33 g, 24.0 mmol) was dissolved in a mixture of
glacial acetic acid (33 mL), water (10 mL) and conc. H
2
SO
4
(1.2 mL). After the addition
of iodine (1.22 g, 4.8 mmol) and periodic acid (2.19 g, 9.6 mmol) the reaction mixture
was protected from light and stirred at 55 °C for 15 h. The resulting light-orange solution
367
was diluted with water (50 mL) and extracted with ether (2 × 60 + 40 mL). The combined
organic phases were washed with sat. aqueous NaHCO
3
until neutral (no more CO
2
evolves and aqueous phase turns violet), then with 0.1 M Na
2
S
2
O
3
(50 mL) and brine,
dried over MgSO
4
and evaporated. TLC (silica/CH
2
Cl
2
-hexane 1:1, stained with basic
KMnO
4
) shows the colorless spot of 5.7 (R
f
0.45) followed by two spots of quinone
byproducts (R
f
0.4 for 5.9 and 0.3 for 5.8). The products were isolated by flash
chromatography on silica (120 g SiliCycle cartridge, 40 mL/min, gradient 10% to 100%
CH
2
Cl
2
-hexane over 12 CV), yielding after evaporation of the pooled fractions 3.14 g
(43%) of 5.7 (pink light-sensitive solid, refrigerate!), 1.15 g (32%) of 5.8 (yellow solid)
and small amount of 5.9 (orange-yellow crystals).
5.7:
1
H NMR (CDCl
3
, 400 MHz): δ 3.71 (s, 3H), 3.64 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H),
2.17 (s, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 154.0, 152.9, 132.8, 131.1, 128.6, 96.5,
60.28, 60.26, 22.1, 13.9, 12.9.
5.8:
1
H NMR (CDCl
3
, 400 MHz): δ 6.50-6.53 (m, 1H), 1.98-2.01 (m, 6H), 1.96-1.98 (m,
3H).
13
C NMR (CDCl
3
, 100 MHz): δ 187.8, 187.4, 145.2, 140.8, 140.6, 133.0, 15.8, 12.3,
12.0.
5.9:
1
H NMR (CDCl
3
, 400 MHz): δ 2.27 (s, 3H), 2.05-2.08 (m, 3H), 2.01-2.04 (m, 3H).
13
C NMR (CDCl
3
, 100 MHz): δ 182.9, 180.2, 152.0, 140.7, 139.9, 121.4, 22.8, 13.7, 12.5.
368
OMe
OMe
8
5.10. 1,4-Dimethoxy-2,3,5-trimethyl-6-(1-undecynyl)benzene.
23
Under nitrogen
atmosphere, in a flame-dried flask to a stirred solution of 5.7 (612 mg, 2 mmol) in
diethylamine (4 mL), Pd(PPh
3
)
2
Cl
2
(70 mg, 0.1 mmol, 5 mol%) and CuI (40 mg, 0.2
mmol, 10 mol%) were added, followed by 1-undecyne (600 µL, ~3 mmol). The reaction
mixture was heated up to 45 °C (yellow suspension quickly turns dark brown) and stirred
at this temperature for 4 h. Upon cooling, the mixture was diluted with ether (40 mL) and
washed with water (2 × 100 mL). The organic phase was washed with brine, dried over
Na
2
SO
4
, concentrated and thoroughly dried in vacuo to remove diethylamine. TLC
(silica/CH
2
Cl
2
-hexane 1:1, stained with vanillin): R
f
0.3 (olive to blue-green). The residue
was purified by flash chromatography on silica (24 g 30 µm PuriFlash cartridge, 25
mL/min, gradient 5% to 80% CH
2
Cl
2
-hexane over 15 CV). Fractions containing the
product were pooled, evaporated without heating and dried at 0.25 mm Hg. Light-brown
viscous oil, 498 mg (75%).
1
H NMR (400 MHz, CDCl
3
): δ 3.81 (s, 3H), 3.64 (s, 3H),
2.50 (t, J = 7.1 Hz, 2H), 2.34 (s, 3H), 2.19 (s, 3H), 2.16 (s, 3H), 1.60-1.69 (m, 2H), 1.45-
1.55 (m, 2H), 1.23-1.39 (m, 10H), 0.86-0.92 (m, 3H).
13
C NMR (100 MHz, CDCl
3
): δ
155.4, 152.6, 131.0, 130.5, 128.0, 116.1, 97.8, 75.7, 60.3, 60.0, 31.9, 29.5, 29.3, 29.2,
28.94, 28.91, 22.6, 19.8, 14.13, 14.05, 12.8, 12.4.
369
O
O
8
5.1. 2,3,5-Trimethyl-6-(1-undecynyl)-1,4-benzoquinone.
36
5.10 (495 mg, 1.5 mmol)
was dissolved in acetonitrile (30 mL), and the solution of (NH
4
)
2
Ce(NO
3
)
6
(2.47 g, 4.5
mmol) in 30 mL of water was added dropwise over 5 min. The reaction mixture was
stirred for 1 h. TLC (silica/10% EtOAc in hexane, stained with basic KMnO
4
) showed
incomplete oxidation: both the starting material (R
f
0.75) and the product (R
f
0.6, yellow
spot) are present. More (NH
4
)
2
Ce(NO
3
)
6
(1.26 g, 2.3 mmol in 15 mL of water) was added,
at which point the spot of 5.10 disappeared. The reaction mixture was quenched by
addition of water (60 mL), extracted with CH
2
Cl
2
(3 × 60 mL), dried over MgSO
4
and
concentrated to give 381 mg of yellow-orange oil. This was purified by flash
chromatography on silica (24 g 15 µm PuriFlash cartridge, 25 mL/min, gradient 0% to
10% EtOAc in hexane over 15 CV, fraction volume < 8 mL with manual control),
yielding 239 mg (53%) of pure 5.1 as bright yellow oil, crystallizing in the freezer (-30
°C).
1
H NMR (400 MHz, CDCl
3
): δ 2.51 (t, J = 7.1 Hz, 2H), 2.17 (s, 3H), 2.02 (s, 6H),
1.58-1.67 (m, 2H), 1.40-1.49 (m, 2H), 1.20-1.36 (m, 10H), 0.84-0.90 (m, 3H).
13
C NMR
(100 MHz, CDCl
3
): δ 186.8, 183.8, 145.9, 141.1, 140.5, 129.1, 108.3, 74.2, 31.9, 29.4,
29.2, 29.1, 28.9, 28.4, 22.7, 20.2, 14.7, 14.1, 12.50, 12.48.
370
OMe
OMe
O
5.11. 2,5-Dimethoxy-3,4,6-trimethylbenzaldehyde.
35
Trifluoroacetic acid (30 mL, 390
mol) was added to a stirred suspension of hexamethylenetetramine (4 g, 28.8 mmol) in
neat 5.6 (5.2 g, 28.9 mmol), the first ~7 mL was added slowly due to exothermic reaction.
The clear reaction mixture was refluxed for 24 h (bath temperature 140 °C). Upon
cooling, the mixture was poured into 150 mL of water, quenched carefully with 10% aq.
Na
2
CO
3
(150 mL) and then neutralized with more concentrated aq. Na
2
CO
3
. The product
separated as oil and crystallized. It was extracted with CH
2
Cl
2
(2 × 70 + 40 mL), the
combined extracts were dried over MgSO
4
and filtered through a plug of Na
2
SO
4
. The
filtrate was evaporated, redissolved in hexane (this leaves behind some viscous brown oil)
and refiltered through a plug of Na
2
SO
4
. The filtrate was evaporated and the residue was
recrystallized from ethanol-water to give 5.52 g (92%) of 5.11 as yellow solid.
1
H NMR
(CDCl
3
, 400 MHz): δ 10.48 (s, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 2.49 (s, 3H), 2.60 (s, 3H),
2.00 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 192.8, 159.0, 153.4, 138.4, 131.0, 129.0,
126.1, 63.2, 60.2, 13.6, 12.8, 12.0.
371
OMe
OMe
H
N
9
5.12. N-Decyl-N-(2,5-dimethoxy-3,4,6-trimethylbenzyl)amine. The mixture of 5.11
(1.32 g, 6.37 mmol), 1-decylamine (1g, 6.37 mmol) and Na
2
SO
4
(5 g) in 30 mL of dry
1,2-dichloroethane was stirred for 2 h, followed by the addition of NaBH(OAc)
3
(2.03 g,
9.56 mmol). The resulting light-yellow suspension was stirred overnight, poured into
10% aq. K
2
CO
3
(50 mL), extracted with EtOAc (3 × 30 mL), washed with brine and
dried over Na
2
SO
4
. TLC (silica/20% methanol in EtOAc, stained with basic KMnO
4
): R
f
0.4. Evaporated and purified by flash chromatography (silica gel, 10% to 20% methanol
in EtOAc) to yield 1.68 g (76%) of viscous brownish oil, crystallizing in the freezer (-30
°C).
1
H NMR (CDCl
3
, 400 MHz): δ 6.81 (br.s, 1H), 3.96 (s, 2H), 3.69 (s, 3H), 3.62 (s,
3H), 2.69 (t, J = 7.6 Hz, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 2.16 (s, 3H), 1.56-1.66 (m, 2H),
1.17-1.30 (m, 14H), 0.85 (t, J = 6.8 Hz, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 153.5,
153.2, 131.3, 128.6, 128.2, 125.4, 61.1, 60.1, 47.7, 44.2, 31.8, 29.5, 29.24, 29.22, 28.1,
27.0, 22.6, 14.0, 12.8, 12.7, 12.3.
O
O
N
9
O
5.2. N-Decyl-N-[(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methyl]-2-
propynamide. To the solution of 5.12 (1.68 g, 4.81 mmol) and DMAP (0.58 mmol, 10
372
mol%) in anhydrous acetonitrile (20 mL), cooled in ice-water bath, propiolic acid (360
µL, 406 mg, 5.8 mmol) was added quickly dropwise. White suspension formed.
EDC ·HCl (1.11 g, 5.8 mmol) was then added in one portion, and clear solution formed.
The reaction mixture was stirred at 0 °C for 1 h, poured into 1.5 N HCl (75 mL),
extracted with EtOAc (3 × 30 mL), washed with water (30 mL), brine (30 mL) and dried
over Na
2
SO
4
. TLC (silica/EtOAc, stained with basic KMnO
4
): R
f
0.9 (5.13), R
f
< 0.3
(5.12). The intermediate amide 5.13 was isolated by flash chromatography (silica gel,
25% EtOAc in hexane) as viscous yellowish oil (1.58 g) and was used in the oxidation
step without further purification.
The crude 5.13 was oxidized in acetonitrile (60 mL) using the procedure for 5.1
(with 3 + 1.5 eq of CAN over 1 h). TLC (silica/15% EtOAc in hexane, stained with
vanillin): R
f
0.25 (5.13, stained brown), 0.22 (5.2, yellow spot, stained reddish-brown).
Worked up similarly to 5.1 and purified by flash chromatography on silica (80 g 50 µm
SiliCycle cartridge, 35 mL/min, gradient 3% to 30% EtOAc in hexane over 15 CV,
fraction volume 10 mL). The fractions containing pure product were pooled and
evaporated to yield 599 mg bright yellow oil (33% over 2 steps). In CDCl
3
, mixture of
two rotameric forms in 76:24 ratio.
1
H NMR (CDCl
3
, 400 MHz): δ 4.74 (s, 2×0.24H),
4.44 (s, 2×0.76H), 3.48-3.56 (m, 2×0.76H), 3.11-3.17 (m, 2×0.24H), 3.20 (s, 0.24H), 3.07
(s, 0.76H), 2.11 (s, 3×0.76H+3×0.24H), 2.01-2.04 (m, 3×0.24H), 1.98-2.01 (m,
6×0.76H+3×0.24H), 1.54-1.65 (m, 2×0.76H), 1.40-1.50 (m, 2×0.24H), 1.15-1.33 (m,
12H), 0.82-0.89 (m, 3×0.76H+3×0.24H).
13
C NMR (100 MHz, CDCl
3
): δ 187.2, 186.9,
186.8, 186.2, 153.4, 153.3, 144.8, 144.5, 141.1, 141.0, 140.8, 140.4, 137.5, 136.9, 79.4,
373
78.7, 76.2, 75.7, 49.1, 43.9, 43.6, 39.2, 31.8, 29.5, 29.44, 29.41, 29.23, 29.21, 29.15, 28.6,
26.9, 26.8, 26.5, 22.6, 14.0, 12.6, 12.45, 12.41, 12.3.
MeO
MeO
OMe
OMe
5.17. 2,3,4,5-Tetramethoxytoluene.
25
To the stirred solution of NaBH
4
(2.6 g, 68.4
mmol) in water (75 mL) a solution of coenzyme Q
0
(2,3-dimethoxy-5-methyl-1,4-
benzoquinone, 5.15; 2.5 g, 13.7 mmol) in a mixture of ether (35 mL) and methanol (18
mL) was added in thin stream. The red-orange color of the quinone disappeared
immediately. After stirring for 15 min, the mixture was transferred into a separatory
funnel, the ether layer was removed, and the aqueous phase was re-extracted with ether (3
× 50 mL). the combined ether extracts were washed with brine (100 mL) and dried over
MgSO
4
. Evaporation of the solvent yields crude hydroquinone 5.16 as pale-orange oil,
which was used immediately in the next step.
The crude 5.16 was dissolved in deoxygenated acetone (50 mL), followed by
addition of K
2
CO
3
(10 g, 72.5 mmol) and dimethyl sulfate (5 mL, 6.63 g, 52.6 mmol),
and the mixture was refluxed overnight. TLC (silica/15% EtOAc in hexane, stained with
vanillin): R
f
0.45 (brown). The solvent was evaporated and the residue diluted with water
(60 mL) and extracted with EtOAc (4 × 40 mL). The combined extracts were dried over
Na
2
SO
4
, evaporated and the product was isolated by flash chromatography on silica (50 g
Biotage cartridge, 40 mL/min, gradient 3% to 30% EtOAc in hexane over 10 CV) as
374
colorless oil (2.49 g, 86% over 2 steps).
1
H NMR (CDCl
3
, 400 MHz): δ 6.43 (s, 1H), 3.91
(s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 2.21 (s, 3H).
13
C NMR (100 MHz,
CDCl
3
): δ 149.1, 147.0, 145.4, 140.8, 125.8, 108.3, 61.1, 61.0, 60.6, 56.1, 15.8.
MeO
MeO
OMe
OMe
I
5.18. 1-Iodo-2,3,4,5-tetramethoxy-6-methylbenzene. 2,3,4,5-Tetramethoxytoluene 5.17
(1.8 g, 8.5 mmol) was dissolved in a mixture of glacial acetic acid (10 mL), water (3mL)
and conc. H
2
SO
4
(0.4 mL). After the addition of iodine (1.3 g, 5.1 mmol) and periodic
acid (388 mg, 1.7 mmol) the reaction mixture was protected from light and stirred at 50-
55 °C for 15 h. The resulting mixture, containing some solid iodine, was diluted with
water (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases
were washed with sat. aqueous NaHCO
3
until the aqueous layer is neutral (by universal
indicator paper), then with 5% aq. Na
2
S
2
O
3
(30 mL) and brine (30 mL), dried over
Na
2
SO
4
and evaporated. TLC (silica/CH
2
Cl
2
-hexane 1:1, stained with vanillin) shows
complete conversion: R
f
0.45 (5.18, yellowish-brown), R
f
0.25 (5.17, brown). Colorless
light-sensitive oil (turns light-brown, refrigerate!), yield 2.55 g (89%).
1
H NMR (CDCl
3
,
400 MHz): δ 3.91 (s, 3H), 3.89 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 2.36 (s, 3H).
13
C NMR
(100 MHz, CDCl
3
): δ 149.5, 147.8, 147.2, 144.5, 130.4, 92.6, 61.2, 61.1, 60.8, 60.6, 21.4.
375
MeO
MeO
OMe
OMe
8
5.19. 1,2,3,4-Tetramethoxy-5-methyl-6-(1-undecynyl)benzene. Under nitrogen
atmosphere, in a flame-dried flask to a stirred solution of 5.18 (676 mg, 2 mmol) in
diethylamine (4 mL), Pd(PPh
3
)
2
Cl
2
(70 mg, 0.1 mmol, 5 mol%) and CuI (40 mg, 0.2
mmol, 10 mol%) were added, followed by 1-undecyne (600 µL, ~3 mmol). The reaction
mixture was heated up to 50 °C and stirred at this temperature for 4 h (light-brown
solution with flakes of Pd(0) formed). Upon cooling, the mixture was diluted with ether
(50 mL), extracted with 1 N HCl (50 + 25 mL), washed with water (30 mL), brine and
dried over Na
2
SO
4
. TLC (silica/30 % CH
2
Cl
2
in hexane, stained with vanillin): R
f
0.2
(orange to green). Purified by flash chromatography on silica (25 g SiliCycle cartridge,
25 mL/min, gradient 10% to 70% CH
2
Cl
2
-hexane over 17 CV, to 100% CH
2
Cl
2
over 2
CV, and 100% CH
2
Cl
2
over 2 CV). Fractions containing the product were pooled and
evaporated without heating to brownish oil. On freezing at -30
o
C, small amount of dark
brown solid separated. The product was redissolved in hexane, decanted off the solid
impurity and evaporated giving 550 mg of 5.19 (76%).
1
H NMR (CDCl
3
, 400 MHz): δ
3.91 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.77 (s, 3H), 2.49 (t, J = 7.1 Hz, 2H), 2.28 (s, 3H),
1.58-1.67 (m, 2H), 1.43-1.52 (m, 2H), 1.23-1.37 (m, 10H), 0.84-0.91 (m, 3H).
13
C NMR
(100 MHz, CDCl
3
): δ 151.0, 147.7, 147.0, 144.6, 129.2, 113.9, 98.1, 74.7, 61.3, 61.2,
61.0, 60.6, 31.9, 29.5, 29.3, 29.2, 28.91, 28.89, 22.7, 19.8, 14.1, 13.8.
376
MeO
MeO
O
O
8
5.3. 2,3-Dimethoxy-5-methyl-6-(1-undecynyl)-1,4-benzoquinone. To the cold (0-5 °C,
ice-water bath) solution of 5.19 (543 mg, 1.5 mmol) in acetonitrile (30 mL) the solution
of (NH
4
)
2
Ce(NO
3
)
6
(2.47 g, 4.5 mmol) in 30 mL of water was added quickly dropwise.
The reaction mixture was stirred for 15 min at 0-5 °C, TLC control (silica/10% EtOAc in
hexane, stained with basic KMnO
4
): R
f
0.45 (starting material), R
f
0.3 (product). The
reaction mixture was quenched by addition of water (60 mL), extracted with CH
2
Cl
2
(3 ×
60 mL), dried over MgSO
4
and concentrated. The residue was purified by flash
chromatography on silica (25 g SiliCycle cartridge, 25 mL/min, gradient 3% to 20%
EtOAc in hexane over 12 CV, fraction volume < 6 mL with manual control). The
fractions containing pure product were pooled and evaporated without heating yielding
225 mg (45%) of pure 5.3 as dark red-orange oil, crystallizing in the freezer (-30 °C).
1
H
NMR (CDCl
3
, 400 MHz): δ 3.99 (s, 3H), 3.95 (s, 3H), 2.50 (t, J = 7.1 Hz, 2H), 2.13 (s,
3H), 1.55-1.65 (m, 2H), 1.37-1.47 (m, 2H), 1.18-1.35 (m, 10H), 0.82-0.88 (m, 3H).
13
C
NMR (100 MHz, CDCl
3
): δ 183.6, 180.6, 145.5, 144.3, 143.8, 127.6, 109.1, 73.8, 61.3,
61.1, 31.8, 29.4, 29.2, 29.0, 28.8, 28.3, 22.6, 20.1, 14.3, 14.0.
377
MeO
MeO
OMe
OMe
O
5.20. 2,3,4,5-Tetramethoxy-6-methylbenzaldehyde. Trifluoroacetic acid (13 mL, 19.24
g, 169 mmol) was gradually added (exothermic reaction) to a stirred mixture of
hexamethylenetetramine (1.64 g, 11.7 mmol) and 5.17 (2.49 g, 11.7 mmol). The clear
reaction mixture was refluxed for 2 h; TLC control (silica/15% EtOAc in hexane, stained
with 2,4-DNPH): R
f
0.48 (5.17), R
f
0.4 (5.20, stained bright orange). Upon cooling, the
mixture was poured into a solution of Na
2
CO
3
(10 g) in 100 mL of water, extracted with
CH
2
Cl
2
(4 × 40 mL) and the combined extracts were dried over MgSO
4
. The product was
isolated by flash chromatography on silica (50 g Biotage cartridge, 40 mL/min, gradient
3% to 30% EtOAc in hexane over 10 CV) as light-yellowish oil (1.81 g, 64%).
1
H NMR
(CDCl
3
, 400 MHz): δ 10.39 (s, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 3.87 (s, 3H), 3.72 (s, 3H),
2.41 (s, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 191.4, 154.9, 152.3, 147.9, 144.1, 129.6,
123.3, 62.4, 61.2, 61.0, 60.7, 12.2.
MeO
MeO
OMe
OMe
H
N
8
5.21. N-Nonyl-N-(2,3,4,5-tetramethoxy-6-methylbenzyl)amine. The mixture of 5.20
(720 mg, 3 mmol), 1-nonylamine (429 mg, 3 mmol) and Na
2
SO
4
(3 g) in 15 mL of dry
1,2-dichloroethane was stirred for 7 h, followed by the addition of NaBH(OAc)
3
(954 mg,
378
4.5 mmol). The mixture was stirred for 2 days and worked up as described for 5.12. TLC
control (silica/20% methanol in EtOAc, stained with basic KMnO
4
): R
f
0.5. Purified by
flash chromatography (silica gel, 10% to 20% methanol in EtOAc) to yield 1.05 g (95%)
of brownish oil, crystallizing in the freezer (-30 °C).
1
H NMR (CDCl
3
, 400 MHz): δ 6.81
(br.s, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.69 (s, 3H), 2.65 (t, J = 7.5 Hz, 2H),
2.21 (s, 3H), 1.53-1.64 (m, 2H), 1.10-1.27 (m, 12H), 0.73-0.82 (m, 3H).
13
C NMR (100
MHz, CDCl
3
): δ 148.5, 147.8, 147.0, 144.2, 126.5, 122.5, 61.0, 60.81, 60.77, 60.4, 47.9,
43.5, 31.6, 29.3, 29.1, 29.0, 27.8, 26.9, 22.4, 13.9, 11.8.
MeO
MeO
OMe
OMe
N
8
O
5.22. N-Nonyl-N-(2,3,4,5-tetramethoxy-6-methylbenzyl)-2-propynamide. Compound
5.22 was prepared from 5.21 and the reaction was worked up similarly to the synthesis of
the intermediate 5.13. TLC control (silica/25% EtOAc in hexane, stained with vanillin):
R
f
0.4 (brown). The product was isolated by flash chromatography on silica (50 g Biotage
cartridge, 40 mL/min, gradient 5% to 50% EtOAc in hexane over 10 CV) as colorless oil
(1.00 g, 83%). In CDCl
3
, mixture of two rotameric forms in 63:37 ratio.
1
H NMR (CDCl
3
,
400 MHz): δ 4.84 (s, 2×0.37H), 4.69 (s, 2×0.63H), 3.92 (s, 3×0.37H), 3.91 (s, 3×0.63H),
3.87 (s, 3×0.63H), 3.86 (s, 3×0.37H), 3.81 (s, 3×0.37H), 3.80 (s, 3×0.63H), 3.75 (s,
3×0.63H+3×0.37H), 3.23-3.29 (m, 2×0.63H), 3.19 (s, 0.37H), 3.06 (s, 0.63H), 3.05-3.11
(m, 2×0.37H), 2.19 (s, 3×0.37H), 2.10 (s, 3×0.63H), 1.41-1.51 (m, 2×0.63H), 1.29-1.38
379
(m, 2×0.37H), 1.07-1.29 (m, 12H), 0.81-0.88 (m, 3×0.63H+3×0.37H).
13
C NMR (100
MHz, CDCl
3
): δ 153.2, 153.1, 149.3, 147.9, 147.8, 147.2, 146.9, 144.6, 144.4, 127.3,
126.9, 122.4, 121.9, 78.8, 78.1, 76.6, 76.2, 61.3, 61.06, 61.04, 61.01, 60.98, 60.95, 60.7,
60.6, 47.1, 44.6, 43.3, 38.4, 31.77, 31.76, 29.4, 29.2, 29.14, 29.12, 28.5, 26.9, 26.8, 26.7,
22.6, 14.0, 11.8, 11.7.
MeO
MeO
O
O
N
8
O
5.4. N-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methyl]-N-nonyl-
2-propynamide. Compound 5.4 was prepared from 5.22 using the procedure described
for 5.3 (reaction time 10 min). TLC control (silica/30% EtOAc in hexane, stained with
vanillin): R
f
0.5 (starting material, stained brown), R
f
0.3 (product, yellow spot). Isolation
was performed by flash chromatography on silica (50 g Biotage cartridge, 40 mL/min,
gradient 5% to 60% EtOAc in hexane over 12 CV) giving 650 mg of bright orange oil,
impure as seen by
1
H,
13
C NMR data. This was re-purified by flash chromatography on
silica (25 g SiliCycle cartridge, 25 mL/min, gradient 5% to 60% EtOAc in hexane over
10 CV) to yield 595 mg (64%) of 5.4 as bright orange viscous oil (purity 96-97%). In
CDCl
3
, mixture of two rotameric forms in 86:14 ratio.
1
H NMR (CDCl
3
, 400 MHz): δ
4.69 (s, 2×0.14H), 4.36 (s, 2×0.86H), 3.952 (s, 3×0.14H), 3.951 (s, 3×0.14H), 3.947 (s,
3×0.86H), 3.93 (s, 3×0.86H), 3.48-3.55 (m, 2×0.86H), 3.21 (s, 0.14H), 3.08-3.14 (m,
2×0.14H), 3.08 (s, 0.86H), 2.07 (s, 3×0.86H+3×0.14H), 1.51-1.62 (m, 2×0.86H), 1.37-
380
1.47 (m, 2×0.14H), 1.11-1.30 (m, 12H), 0.78-0.85 (m, 3×0.86H+3×0.14H).
13
C NMR
(100 MHz, CDCl
3
): δ 183.9, 183.8, 183.5, 183.1, 153.4, 153.1, 144.4, 144.3, 144.2, 144.1,
143.3, 143.2, 135.8, 135.3, 79.6, 78.8, 76.0, 75.5, 61.08, 61.05, 61.0, 49.2, 43.9, 43.0,
39.0, 31.63, 31.61, 29.3, 29.2, 29.05, 29.03, 29.01, 29.00, 28.5, 26.8, 26.7, 26.4, 22.4,
13.9, 12.3, 12.0.
O
OO
O
Br
5.29. 7-(4-Bromobenzoyl)-1,4-dioxaspiro[4.5]decan-8-one.
27
In a flame-dried flask, a
solution of lithium bis(trimethylsilyl)amide (LiHMDS; 1.0 M in THF, 13 mL, ~13 mmol)
in anhydrous THF (50 mL) was cooled down to -78 °C. 1,4-Cyclohexanedione
mono(ethylene) ketal (2 g, 12.82 mmol) was dissolved in 10 mL of anhydrous THF and
this solution was added dropwise over a period of 30 min. The reaction mixture was then
heated up to RT and stirred for 30 min, followed by cooling to -78 °C and addition of 4-
bromobenzoyl chloride (2.81 g, 12.82 mmol) in anhydrous THF (10 mL) over 5 min. The
reaction mixture was let warm to RT, turning into white suspension, and further stirred
for 30 min at RT. Clear light-yellow solution formed. The mixture was poured into 150
mL of water, acidified with 2 N HCl and extracted with EtOAc (3 × 50 mL). The
combined extracts were washed with brine and dried over Na
2
SO
4
. TLC (silica/30%
EtOAc in hexane, stained with vanillin) showed the intermediate 5.29 as a tailing spot
381
with R
f
0.4, stained light brown. The yellowish semi-solid residue obtained upon
evaporation was used directly in the next step.
OO
O
Br
O
MeO
OO
O
Br
O
EtO
Methyl 3-{2-[3-(4-bromophenyl)-3-oxopropyl]-1,3-dioxolan-2-yl}propanoate (5.30)
and ethyl 3-{2-[3-(4-bromophenyl)-3-oxopropyl]-1,3-dioxolan-2-yl}propanoate
(5.31).
37
The crude 5.21, prepared on 12.82 mmol scale, was dissolved in anhydrous
methanol (50 mL), and sodium methoxide solution (25 wt% in MeOH) was added at RT.
Most of the solid dissolved and brownish-yellow solution formed. The reaction mixture
was diluted with EtOAc (50 mL), acidified with 1N HCl to pH ~ 2 and diluted with water
to 400 mL (total volume), followed by extraction with EtOAc (100 + 50 mL). The
combined organic phases were dried over Na
2
SO
4
, concentrated and re-evaporated with
ethanol (3 × 40 mL) to complete drying (Note: this should not be done as it leads to
significant transesterification!). TLC control (silica/30% EtOAc in hexane, stained with
vanillin): R
f
0.48 (5.31), R
f
0.4 (5.30), both stained purple to gray-brown. Purified by
flash chromatography on silica (120 g SiliCycle cartridge, 40 mL/min, gradient 7% to
60% EtOAc in hexane over 15 CV), collecting pure 5.31 (810 mg, 16%) followed by
5.30 (2.94 g, 62%).
5.30:
1
H NMR (CDCl
3
, 400 MHz): δ 7.76-7.81 (m, 2H), 7.54-7.58 (m, 2H), 3.88-3.93 (m,
4H), 3.64 (s, 3H), 2.95-3.01 (m, 2H), 2.35-2.40 (m, 2H), 2.03-2.08 (m, 2H), 1.98-2.02 (m,
382
2H).
13
C NMR (100 MHz, CDCl
3
): δ 198.4, 173.8, 135.6, 131.7, 129.5, 127.9, 110.0,
65.0, 51.6, 32.8, 32.0, 31.1, 28.5.
5.31:
1
H NMR (CDCl
3
, 400 MHz): δ 7.76-7.81 (m, 2H), 7.54-7.58 (m, 2H), 4.09 (q, J =
7.0 Hz, 2H), 3.87-3.93 (m, 4H), 2.95-3.01 (m, 2H), 2.33-2.39 (m, 2H), 2.03-2.08 (m, 2H),
1.98-2.02 (m, 2H), 1.22 (t, J = 7.0 Hz, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 198.4, 173.3,
135.6, 131.7, 129.5, 127.9, 110.1, 65.0, 60.3, 32.9, 32.0, 31.1, 28.8, 14.1.
O
Br
O
HO
O
5.32. 7-(4-Bromophenyl)-4,7-dioxoheptanoic acid. The esters 5.30 and 5.31 (10 mmol
total) obtained from the previous step were added to the mixture of THF (50 mL) and 3 N
HCl (50 mL). Clear homogeneous solution formed after 2 h. The reaction mixture was
stirred for 4 days. From the resulting clear light-yellow solution THF was evaporated on
a rotary evaporator, and the product precipitated out. Water (50 mL) was added and the
mixture was left in ice-water bath to complete crystallization. The acid was filtered off
and washed with small amount of ice-cold water. After drying in the air, pure 5.32 was
obtained as yellowish crystals (3.15 g, ~100%).
1
H NMR (DMSO-d
6
, 400 MHz): δ 12.11
(s, 1H), 7.87-7.92 (m, 2H), 7.71-7.75 (m, 2H), 3.18-3.24 (m, 2H), 2.79-2.85 (m, 2H),
2.71-2.77 (m, 2H), 2.38-2.44 (m, 2H).
13
C NMR (DMSO-d
6
, 100 MHz): δ 207.7, 197.7,
173.7, 135.3, 131.7, 129.8, 127.2, 36.6, 35.7, 32.0, 27.6.
383
Br
N
CO
2
Me
CO
2
Me
O
Br
MeO
2
C
O
Methyl 3-[5-(4-bromophenyl)-1-(2-methoxy-2-oxoethyl)-1H-pyrrol-2-yl]propanoate
(5.33) and methyl 7-(4-bromophenyl)-4,7-dioxoheptanoate (5.34).
38
The mixture of
the diketoacid 5.32 (1.57 g, 5 mmol), glycine methyl ester hydrochloride (630 mg, 5
mmol), sodium acetate (410 mg, 5 mmol) and p-toluenesulfonic acid monohydrate (95
mg, 0.5 mmol, 10 mol%) in methanol (30 mL) was refluxed for 48 h (bath temperature
100 °C). TLC control (silica/30% EtOAc in hexane, stained with vanillin): R
f
0.5 (5.33,
bright red), R
f
0.3 (5.34, white). The reaction mixture was evaporated, redissolved in
EtOAc, filtered and re-evaporated. Purified by flash chromatography on silica (80 g
SiliCycle cartridge, 35 mL/min, gradient 7% to 70% EtOAc in hexane over 12 CV),
collecting 5.33 (1.685 g) followed by 5.34 (210 mg, 13%). The pyrrole 5.33 was
recrystallized from EtOAc-hexane, yielding 1.473 g (78%) of pure product as white
crystals.
5.33:
1
H NMR (CDCl
3
, 500 MHz): δ 7.48-7.52 (m, 2H), 7.14-7.18 (m, 2H), 6.17 (d, J =
3.6 Hz, 1H), 5.99-6.02 (m, 1H), 4.58 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 2.81-2.86 (m,
2H), 2.71-2.75 (m, 2H).
13
C NMR (CDCl
3
, 125 MHz): δ 173.2, 169.5, 133.7, 133.6,
132.0, 131.7, 130.4, 121.3, 108.8, 106.2, 52.6, 51.8, 45.9, 32.6, 21.8.
5.34:
1
H NMR (CDCl
3
, 500 MHz): δ 7.78-7.81 (m, 2H), 7.54-7.58 (m, 2H), 3.64 (s, 3H),
3.20-3.24 (m, 2H), 2.85-2.89 (m, 2H), 2.81-2.85 (m, 2H), 2.57-2.61 (m, 2H).
13
C NMR
384
(CDCl
3
, 125 MHz): δ 207.3, 197.3, 173.1, 135.2, 131.8, 129.5, 128.2, 51.7, 37.1, 36.0,
32.2, 27.6.
Br
N
CO
2
H
CO
2
H
5.35. 3-[5-(4-Bromophenyl)-1-(carboxymethyl)-1H-pyrrol-2-yl]propanoic acid.
LiOH·H
2
O (331 mg, 7.89 mmol) was dissolved in water (15 mL) and added to the
solution of 5.33 (1 g, 2.63 mmol) in THF (15 mL). Homogeneous mixture formed within
10 min. The reaction was left stirring overnight, filtered through a layer of sand and
washed with water. The filtrate was concentrated on a rotary evaporator (bath
temperature 40 °C) to remove THF and some water. The remaining water solution was
acidified with 2 N HCl and left in refrigerator (0-5 °C) for 2 h. The white crystals of 5.35
were filtered off, washed with cold water (50 mL) and dried in air. Yield 905 mg (98%).
1
H NMR (DMSO-d
6
, 500 MHz): δ 12.8 (br.s., 2H), 7.57-7.61 (m, 2H), 7.19-7.24 (m, 2H),
6.10 (d, J = 3.6 Hz, 1H), 5.91 (br.d, J = 3.6 Hz, 1H), 4.60 (s, 2H), 2.69-2.75 (m, 2H),
2.55- 2.60 (m, 2H).
13
C NMR (DMSO-d
6
, 125 MHz): δ 173.7, 170.6, 134.4, 132.4, 132.2,
131.5, 129.9, 119.9, 108.2, 105.6, 45.7, 32.4, 21.3.
385
MeO
MeO
OH O
CO
2
Me
5.40. Methyl (Z)-4-(3,4-dimethoxyphenyl)-2-hydroxy-4-oxo-2-butenoate.
39
To the
solution of sodium methoxide, prepared by dissolution of sodium (840 mg, 36 mmol) in
anhydrous methanol (or by mixing stock 25 wt% solution of sodium methoxide in
methanol with anhydrous methanol), the solution of 3',4'-dimethoxyacetophenone (5.4 g,
30 mmol) and dimethyl oxalate (3.54 g, 30 mmol) was gradually added. Bright yellow
color appeared, followed by precipitation of the sodium salt of the diketoester. The
reaction mixture was stirred overnight, the solid was filtered off, washed with methanol,
ether and dried on the filter. It was then redissolved in water (300 mL), and acetic acid
was added to the stirred solution to pH ~ 4. The resulting suspension was stirred in ice-
water bath for 1 h, the precipitate was filtered off and washed with cold water and dried
in air over 2 days. Light yellow crystals, yield 6.2 g (78%).
1
H NMR (CDCl
3
, 400 MHz):
δ 15.4 (br.s, 1H), 7.63 (dd, J = 8.5 Hz, J = 2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.03 (s,
1H), 6.92 (d, J = 8.5 Hz, 1H), 3.94 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H).
13
C NMR (100
MHz, CDCl
3
): δ 190.7, 166.7, 162.9, 154.2, 149.3, 128.0, 122.9, 110.4, 109.9, 98.1, 56.1,
56.0, 53.1.
386
MeO
OH O
CO
2
Me
5.41. Methyl (Z)-4-(4-methoxyphenyl)-2-hydroxy-4-oxo-2-butenoate. Prepared
analogously to 5.40 from 4'-methoxyacetophenone in 82% yield. White crystals.
1
H
NMR (DMSO-d
6
, 400 MHz): δ 8.04 (d, J = 9.1 Hz, 2H), 7.07 (d, J = 9.1 Hz, 2H), 7.05 (s,
1H), 3.86 (s, 3H), 3.85 (s, 3H).
13
C NMR (DMSO-d
6
, 100 MHz): δ 190.0, 167.0, 164.1,
162.2, 130.4, 126.9, 114.4, 97.7, 55.6, 52.9.
OH O
CO
2
Me
5.42. Methyl (Z)-4-(4-methoxyphenyl)-2-hydroxy-4-oxo-2-butenoate. Prepared
analogously to 5.40 from acetophenone in 71% yield. White crystals. In DMSO-d
6
,
mixture of two tautomeric forms in 92:8 (ketoenol:diketone) ratio.
1
H NMR (DMSO-d
6
,
400 MHz): δ 8.05 (d, J = 7.5 Hz, 2×0.92H), 7.97 (d, J = 7.5 Hz, 2×0.08H), 7.66-7.72 (m,
0.92H+0.08H), 7.52-7.60 (m, 2×0.92H+2×0.08H), 7.11 (s, 0.92H), 4.62 (s, 2×0.08H),
3.86 (s, 3×0.92H), 3.78 (s, 3×0.08H).
13
C NMR (DMSO-d
6
, 100 MHz): δ 190.2, 168.6,
161.9, 134.2, 134.1, 129.0, 127.8, 98.0, 53.0 (only the signals of the major tautomer are
listed).
387
OH O
CO
2
Me
MsHN
5.43. Methyl (Z)-2-hydroxy-4-{4-[(methylsulfonyl)amino]phenyl}-4-oxo-2-butenoate.
Prepared analogously to 5.40 from 4'-(methylsulfonylamino)acetophenone
40
in 50% yield.
Light yellow crystals.
1
H NMR (DMSO-d
6
, 400 MHz): δ 10.5 (br.s, 1H), 8.06 (d, J = 8.8
Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.07 (s, 1H), 3.85 (s, 3H), 3.15 (s, 3H).
13
C NMR
(DMSO-d
6
, 100 MHz): δ 189.7, 167.6, 162.1, 144.1, 129.9, 128.6, 117.5, 97.8, 53.0, 40.0.
N
OH O
CO
2
Me
5.44. Methyl (Z)-4-(2-pyridyl)-2-hydroxy-4-oxo-2-butenoate. Prepared analogously to
5.40 from 2-acetylpyridine. The crude product was precipitated from the solution of
sodium salt with acetic acid (to pH ~ 6), filtered off and dried in air overnight.
Purification was achieved by fractional crystallization from CH
2
Cl
2
-hexane, adding
increasing amounts of hexane (viscous brown tar that precipitated first was filtered off
through a plug of cotton wool, followed by crystallization of the product, which was
redissolved with heating and addition of more CH
2
Cl
2
). After 4-5 crystallizations, the
pure product precipitates as cream-colored crystals in 31% yield. In DMSO-d
6
, mixture
of two tautomeric forms in 85:15 (ketoenol:diketone) ratio.
1
H NMR (DMSO-d
6
, 500
MHz): δ 8.77-8.80 (m, 0.85H), 8.63-8.65 (m, 0.15H), 8.03-8.15 (m, 2×0.85H+0.15H),
7.98-8.01 (m, 0.15H), 7.71-7.75 (m, 0.85H), 7.67-7.70 (m, 0.15H), 7.42 (s, 0.85H), 4.38
388
(s, 2×0.15H), 3.86 (s, 3×0.85H), 3.76 (s, 3×0.15H).
13
C NMR (DMSO-d
6
, 125 MHz): δ
195.0, 189.0, 186.1, 165.7, 162.2, 160.6, 150.8, 150.5, 149.2, 148.6, 138.2, 138.1, 128.20,
128.16, 122.5, 121.7, 98.9, 53.0, 52.8, 49.1.
MeO
MeO
N
OH
O
O
5.36. 4-(3,4-Dimethoxybenzoyl)-3-hydroxy-1-methyl-5-(4-methylphenyl)-1,5-
dihydro-2H-pyrrol-2-one. The diketoester 5.40 (532 mg, 2 mmol), 4-
methylbenzaldehyde (240 mg, 2 mmol) and 40 wt% aq. methylamine (180 mg, 2.2 mmol)
were dissolved in DMSO (3 mL) and stirred at RT for 24 h. The reaction mixture was
poured into 1 N HCl (75 mL), extracted with EtOAc (4 × 25 mL), washed with brine and
dried over Na
2
SO
4
. The filtrate was concentrated and the residue was recrystallized from
CH
2
Cl
2
-hexane. White crystals, yield 449 mg (61%). The yield of the reaction run on 5
mmol scale was 83%.
1
H NMR (CDCl
3
, 400 MHz): δ 10.8 (br.s, 1H), 7.43 (dd, J = 8.3
Hz, J = 2.1 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.07 (s, 4H), 6.81 (d, J = 8.3 Hz, 1H), 5.42
(s, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 2.84 (s, 3H), 2.27 (s, 3H).
13
C NMR (100 MHz,
CDCl
3
): δ 187.0, 164.7, 153.3, 148.8, 138.7, 131.6, 129.7, 129.4, 127.5, 124.0, 118.8,
111.1, 109.8, 63.9, 56.0, 55.9, 27.9, 21.1.
389
N
O
MeO
MeO
OH
O
5.45. 4-(3,4-Dimethoxybenzoyl)-3-hydroxy-1,5-dimethyl-1,5-dihydro-2H-pyrrol-2-
one. Prepared analogously to 5.36 from 5.40 (532 mg, 2 mmol), acetaldehyde (200 µL,
184 mg, 4.18 mmol) and methylamine (250 µL of 40 wt% aq. solution, ~3 mmol) in 4
mL DMSO. Yellowish crystals, yield 385 mg (66%).
1
H NMR (CDCl
3
, 400 MHz): δ 10.7
(br.s, 1H), 7.47 (dd, J = 8.4 Hz, J = 2.2 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 6.93 (d, J = 8.4
Hz, 1H), 4.57 (q, J = 6.4 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.09 (s, 3H), 1.31 (d, J = 6.4
Hz, 3H).
13
C NMR (100 MHz, CDCl
3
): δ 187.7, 164.0, 157.7, 153.4, 149.1, 129.8, 123.5,
119.1, 111.2, 110.1, 56.1, 56.0, 55.9, 27.5, 17.0.
N
O
MeO
OH
O
5.46. 4-(4-Methoxybenzoyl)-3-hydroxy-1-methyl-5-(4-methylphenyl)-1,5-dihydro-
2H-pyrrol-2-one. Prepared analogously to 5.36 from 5.41, the product precipitates from
DMSO. The reaction mixture was diluted with EtOAc (20 mL), 2 N HCl (10 mL) was
added, shaken well, and hexane (~30 mL) was added until the product precipitates from
organic layer. The biphasic mixture was then let cool in ice-water bath, the crystals were
filtered off, washed with cold water, EtOAc-hexane and hexane. White crystals with
pinkish tinge, yield 580 mg (86%).
1
H NMR (DMSO-d
6
, 500 MHz): δ 11.5 (br.s, 1H),
390
7.69-7.73 (m, 2H), 7.14-7.18 (m, 2H), 7.10-7.13 (m, 2H), 6.94-6.99 (m, 2H), 5.38 (s, 1H),
3.80 (s, 3H), 2.70 (s, 3H), 2.23 (s, 3H).
13
C NMR (DMSO-d
6
, 125 MHz): δ 187.5, 165.0,
162.8, 149.7, 137.4, 133.0, 131.2, 130.4, 129.1, 127.3, 119.9, 113.4, 62.3, 55.4, 27.2, 20.6.
N
O
OH
O
5.47. 4-Benzoyl-3-hydroxy-1-methyl-5-(4-methylphenyl)-1,5-dihydro-2H-pyrrol-2-
one. Prepared analogously to 5.36 from 5.42, the product precipitates from DMSO.
White crystals, yield 495 mg (81%).
1
H NMR (DMSO-d
6
, 600 MHz): δ 11.7 (br.s, 1H),
7.66-7.69 (m, 2H), 7.52-7.56 (m, 1H), 7.41-7.45 (m, 2H), 7.18 (d, J = 7.9 Hz, 2H), 7.13
(d, J = 7.9 Hz, 2H), 5.38 (s, 1H), 2.70 (s, 3H), 2.24 (s, 3H).
13
C NMR (DMSO-d
6
, 150
MHz): δ 188.9, 164.9, 151.1, 137.9, 137.4, 133.0, 132.4, 129.1, 128.6, 128.0, 127.4,
119.3, 62.2, 27.3, 20.6.
MeO
MeO
N
OH
O
HO
O
5.48. 4-(3,4-Dimethoxybenzoyl)-3-hydroxy-5-(4-hydroxyphenyl)-1-methyl-1,5-
dihydro-2H-pyrrol-2-one. Prepared analogously to 5.36 from 5.40 and 4-
hydroxybenzaldehyde. White crystals, yield 600 mg (81%).
1
H NMR (DMSO-d
6
, 500
391
MHz): δ 11.4 (br.s, 1H), 9.43 (s, 1H), 7.43 (dd, J = 8.6 Hz, J = 1.9 Hz, 1H), 7.26 (d, J =
1.9 Hz, 1H), 7.05-7.09 (m, 2H), 7.01 (d, J = 8.6 Hz, 1H), 6.66-6.71 (m, 2H), 5.32 (s, 1H),
3.82 (s, 3H), 3.76 (s, 3H), 2.69 (s, 3H).
13
C NMR (DMSO-d
6
, 125 MHz): δ 187.5, 164.9,
157.2, 152.8, 149.4, 148.1, 130.1, 128.6, 125.8, 124.0, 120.0, 115.3, 111.1, 110.5, 62.2,
55.6, 55.4, 27.1.
MeO
MeO
N
OH
O
MsHN
O
5.49. N-{4-[3-(3,4-Dimethoxybenzoyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-
pyrrol-2-yl]phenyl}methanesulfonamide. Prepared analogously to 5.36 from 5.40 and
4-(methanesulfonamido)benzaldehyde.
41
White crystals, yield 705 mg (79%).
1
H NMR
(DMSO-d
6
, 500 MHz): δ 11.5 (br.s, 1H), 9.78 (s, 1H), 7.45 (dd, J = 8.6 Hz, J = 1.9 Hz,
1H), 7.24-7.28 (m, 3H), 7.11-7.15 (m, 2H), 7.00 (d, J = 8.6 Hz, 1H), 5.39 (s, 1H), 3.82 (s,
3H), 3.76 (s, 3H), 2.97 (s, 3H), 2.71 (s, 3H).
13
C NMR (DMSO-d
6
, 125 MHz): δ 187.4,
165.0, 152.8, 149.7, 148.1, 138.2, 131.1, 130.1, 128.5, 124.0, 119.7, 119.4, 111.1, 110.5,
62.1, 55.6, 55.4, 39.5, 27.3.
392
MsHN
N
OH
O
O
5.50. N-(4-{[4-Hydroxy-1-methyl-2-(4-methylphenyl)-5-oxo-2,5-dihydro-1H-pyrrol-
3-yl]carbonyl}phenyl)methanesulfonamide. Prepared analogously to 5.36 from 5.43.
White crystals, yield 640 mg (80%).
1
H NMR (DMSO-d
6
, 500 MHz): δ 11.6 (br.s, 1H),
10.25 (s, 1H), 7.68-7.72 (m, 2H), 7.19-7.23 (m, 2H), 7.15-7.19 (m, 2H), 7.10-7.14 (m,
2H), 5.37 (s, 1H), 3.08 (s, 3H), 2.69 (s, 3H), 2.23 (s, 3H).
13
C NMR (DMSO-d
6
, 125
MHz): δ 187.6, 165.0, 150.3, 142.5, 137.4, 133.0, 132.4, 130.6, 129.1, 127.4, 119.6,
117.1, 62.2, 39.8, 27.3, 20.6.
N
N
OH
O
O
5.51. 3-Hydroxy-1-methyl-5-(4-methylphenyl)-4-(2-pyridinylcarbonyl)-1,5-dihydro-
2H-pyrrol-2-one. Prepared analogously to 5.36 from 5.44, recrystallized from CH
2
Cl
2
-
hexane. Yellow crystals, yield 458 mg (74%).
1
H NMR (AcOH-d
4
, 500 MHz): δ 11.6
(br.s, 1H), 8.81-8.84 (m, 1H), 8.18-8.24 (m, 2H), 7.82-7.88 (m, 1H), 7.19-7.23 (m, 2H),
7.12-7.16 (m, 2H), 5.32 (s, 1H), 2.85 (s, 3H), 2.29 (s, 3H).
13
C NMR (AcOH-d
4
, 125
MHz): δ 182.4, 167.9, 158.8, 152.1, 146.4, 142.2, 139.1, 134.4, 130.2, 129.7, 128.8,
125.8, 120.1, 64.6, 28.6, 21.2.
393
N
OMe
O
O
MeO
MeO
5.52. 4-(3,4-Dimethoxybenzoyl)-3-methoxy-1-methyl-5-(4-methylphenyl)-1,5-
dihydro-2H-pyrrol-2-one. The mixture of 5.36 (367 mg, 1 mmol), K
2
CO
3
(166 mg, 1.2
mmol) and dimethyl sulfate (105 µL, 139 mg, 1.1 mmol) in DMSO (1 mL) was stirred at
RT for 24 h. The resulting light-yellow suspension was poured into 20 mL of 0.1 N
NaOH and extracted with EtOAc (2 × 30 mL). The combined organic phases were
washed with water (20 mL) and brine (20 mL) and dried over Na
2
SO
4
. TLC control
(silica/80% EtOAc in hexane, stained with vanillin): R
f
0.45 (maroon). Purified by flash
chromatography on silica (25 g SiliCycle cartridge, 25 mL/min, gradient 20% to 100%
EtOAc in hexane over 10 CV), evaporated and dried at 0.25 mm Hg to yield white foam
(297 mg, 78%).
1
H NMR (CDCl
3
, 500 MHz): δ 7.38 (dd, J = 8.3 Hz, J = 1.9 Hz, 1H),
7.31 (d, J = 1.9 Hz, 1H), 7.04-7.11 (m, 4H), 6.85 (d, J = 8.3 Hz, 1H), 5.31 (s, 1H), 3.93 (s,
3H), 3.91 (s, 3H), 3.87 (s, 3H), 2.86 (s, 3H), 2.27 (s, 3H).
13
C NMR (125 MHz, CDCl
3
): δ
189.1, 165.2, 153.6, 149.0, 148.8, 138.4, 131.1, 130.7, 129.5, 127.0, 125.7, 124.8, 110.5,
109.8, 64.1, 59.6, 55.9, 55.8, 27.6, 21.0.
394
N
O
N
HN
MeO
MeO
5.53. 3-(3,4-Dimethoxyphenyl)-5-methyl-4-(4-methylphenyl)-4,5-dihydropyrrolo[3,4-
c]pyrazol-6(2H)-one.
42
The solution of 5.36 (400 mg, 1.09 mmol) and N
2
H
4
·H
2
O (58 µL,
1.2 mmol) in glacial acetic acid (5 mL) was refluxed for 3.5 h. TLC control
(silica/EtOAc): R
f
0.45 (blue fluorescence). Poured into the mixture of sat. aq. NaHCO
3
(30 mL) and EtOAc (20 mL), then gradually diluted with hexane to complete
crystallization, filtered off the yellowish crystals, washed with water and hexane. Yield
387 mg (98%).
1
H NMR (DMSO-d
6
, 600 MHz): δ 14.1 (br.s, 1H), 7.13-7.19 (m, 4H),
7.06-7.10 (m, 1H), 6.88-6.92 (m, 2H), 5.69 (s, 1H), 3.71 (s, 3H), 3.55 (s, 3H), 2.70 (s,
3H), 2.26 (s, 3H).
13
C NMR (DMSO-d
6
, 150 MHz): δ 161.3, 148.6, 137.9, 137.2, 133.7,
129.5, 127.8, 124.7, 121.2, 118.0, 111.8, 109.3, 60.4, 55.4, 55.2, 27.2, 20.6.
MeO
MeO N
N
O OH
O O
5.54. 5-(3,4-Dimethoxybenzoyl)-1,3-dimethylbarbituric acid.
43
Solid 3,4-
dimethoxybenzoyl chloride (2.01 g, 10 mmol) was added portionwise over 10 min to the
solution of 1,3-dimethylbarbituric acid (1.56 g, 10 mmol) in pyridine (6 mL). The
resulting brown suspension was stirred at RT for 1.5 h, at which point it solidified and
was left overnight without stirring. The reaction was quenched by careful addition of the
395
mixture of water (5 mL) and conc. HCl (15 mL) (exothermic), the red-brown suspension
was stirred for 15 min and poured into the mixture of water (75 mL) and EtOAc (25 mL).
After stirring for ~ 30 min, the precipitate was filtered off and redissolved on filter with
multiple portions of boiling EtOAc, leaving behind the small amount of viscous brown
solid. The organic layer was separated, and the aqueous layer was re-extracted with
EtOAc (3 × 25 mL). The combined organic phases were dried over Na
2
SO
4
, concentrated,
and the residue was recrystallized from ethanol (~ 40 mL). Light orange needles, yield
2.05 g (64%). The second crystallization (from EtOAc, cooling down to RT only) yields
1.77 g (55%) of orange-yellow needles.
1
H NMR (DMSO-d
6
, 400 MHz): δ 7.24-7.30 (m,
1H), 7.21 (d, J = 1.5 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 3.84 (s, 3H), 3.75 (s, 3H), 3.19 (s,
6H).
13
C NMR (DMSO-d
6
, 100 MHz): δ 188.6, 152.1, 150.1, 147.4, 126.5, 123.2, 112.6,
110.3, 94.9, 55.59, 55.57, 27.7.
MeO
MeO
O
S
N
OH
S
5.55. 5-(3,4-Dimethoxybenzoyl)-3-methyl-2-thioxo-1,3-thiazolidin-4-one.
44
3-
Methylrhodanine (885 mg, 5 mmol) was mixed with calcium hydroxide (750 mg, 10
mmol) in dioxane (4 mL). The mixture was heated to 90-95 °C and stirred at this
temperature for 2.5 h (yellow-orange color gradually appears). The reaction mixture was
cooled down and poured into 2 N HCl (15 mL), the solid was filtered off, washed with
water and recrystallized from boiling acetic acid (30 mL) with addition of minimal
396
amount of water, left overnight at RT, filtered off and washed with ether and pentane.
Yield 950 mg (61%). For the biological testing, a 300 mg sample was dissolved in 5 mL
DMSO + 20 mL ethanol, heated to boiling and filtered while hot, the filtrate was diluted
with 5-10 mL of ethanol and left to crystallize at RT. From this mixture, 5.55 crystallizes
slowly in yellow-orange needles (recovery ~ 250 mg).
1
H NMR (DMSO-d
6
, 500 MHz): δ
7.29-7.33 (m, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 3.85 (s, 3H), 3.81 (s,
3H), 3.32 (s, 3H).
13
C NMR (DMSO-d
6
, 125 MHz): δ 191.5, 163.8, 151.9, 148.2, 124.4,
122.3, 111.2, 97.4, 55.7, 55.6, 30.8.
MeO
MeO
O
N
N
OH
5.56. 4-(3,4-Dimethoxybenzoyl)-2,5-dimethyl-2,4-dihydro-3H-pyrazol-3-one.
45
To the
solution of 1,3-dimethyl-5-pyrazolone (623 mg, 5.6 mmol; prepared from ethyl
acetoacetate and methylhydrazine),
46
in dioxane (10 mL), calcium hydroxide (1.03 g,
13.9 mmol) and the solution of 3,4-dimethoxybenzoyl chloride (2.01 g, 10 mmol) in
dioxane (5 mL) were added, the latter dropwise over 5 min. The reaction mixture was
refluxed overnight (eventually turning pink), and was quenched by pouring into 2 N HCl
(20 mL). The resulting homogeneous solution was extracted with EtOAc (10 × 30 mL,
until the extracts have only light yellow color), the organic phases were evaporated and
the residue was recrystallized from methanol-water. This leaves behind white crystals
(850 mg), identified by
1
H NMR as 3,4-dimethoxybenzoic acid. From the filtrate, the
target pyrazolone precipitates overnight as white needles (filtered off and washed with
397
cold water). Yield 420 mg (27%).
1
H NMR (CDCl
3
, 500 MHz): δ 11.0 (br.s, 1H), 7.25
(dd, J = 8.4 Hz, J = 1.9 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 3.94
(s, 3H), 3.91 (s, 3H), 3.61 (s, 3H), 2.10 (s, 3H).
13
C NMR (CDCl
3
, 125 MHz): δ 191.7,
160.5, 152.2, 148.8, 146.5, 130.8, 122.3, 110.8, 110.0, 102.1, 56.0, 55.9, 32.5, 15.9.
MeO
MeO
O
N
O
O
5.57. 3-(3,4-Dimethoxybenzoyl)-1-methyl-2,5-pyrrolidinedione. N-Methylsuccinimide
(565 mg, 5 mmol) was dissolved in anhydrous THF (10 mL), the solution was cooled
down to -78 °C, and lithium bis(trimethylsilyl)amide (LiHMDS; 5 mL of 1.0 M solution
in THF, ~5 mmol) was added, resulting in formation of white suspension. The mixture
was let warm to RT, turning yellow, and stirred at this temperature for 15 min, at which
point green discoloration begins to appear. The mixture was cooled down to -78 °C, and
the solution of 3,4-dimethoxybenzoyl chloride (1 g, 5 mmol) in 10 mL of anhydrous THF
was added over 10 min. The clear yellow solution was removed from cold bath and let
warm to RT, turning into yellowish-white suspension. This was stirred overnight at RT,
poured into 100 mL of 0.5 N HCl, extracted with EtOAc (3 × 30 mL), and the combined
extracts were dried over Na
2
SO
4
. TLC control (silica/EtOAc): R
f
0.65 (product), 0.5 (3,4-
dimethoxybenzoic acid), 0.3 (3,4-dimethoxybenzamide). Isolated by flash
chromatography on silica (50 g Biotage cartridge, 40 mL/min, gradient 50% to 100%
EtOAc in hexane over 4 CV, then 100% EtOAc over 6 CV, then 0% to 15% methanol in
398
EtOAc over 5 CV) as yellowish oil, recrystallized from CH
2
Cl
2
-hexane to give 486 mg
(35%) of white crystals. In acetone-d
6
, mixture of two tautomeric forms in 95:5
(ketoimide:enolimide) ratio.
1
H NMR (acetone-d
6
, 500 MHz): δ 7.85 (dd, J = 8.6 Hz, J =
2.0 Hz, 0.95H), 7.63 (d, J = 2.0 Hz, 0.95H), 7.42 (dd, J = 8.6 Hz, J = 2.2 Hz, 0.05H),
7.36 (d, J = 2.2 Hz, 0.05H), 7.13 (d, J = 8.6 Hz, 0.95H), 7.08 (d, J = 8.6 Hz, 0.05H), 5.62
(s, 0.05H), 5.12 (dd, J = 8.8 Hz, J = 3.9 Hz, 0.95H), 3.94 (s, 3H), 3.89 (s, 3H), 3.61 (s,
2×0.05H), (dd, J = 17.7 Hz, J = 3.9 Hz, 0.95H), 3.00 (s, 3×0.05H), 2.95 (dd, J = 17.7 Hz,
J = 8.8 Hz, 0.95H), 2.90 (s, 3×0.95H).
13
C NMR (acetone-d
6
, 125 MHz): 191.7, 160.5,
152.2, 148.8, 146.5, 130.8, 122.3, 110.8, 110.0, 102.1, 56.0, 55.9, 32.5, 15.9 (only the
signals of the major tautomer are listed).
OMOM
OMe
O
5.58. 3-Methoxy-2-(methoxymethoxy)benzaldehyde. To the solution of o-vanillin (1 g,
6.58 mmol) and MOMBr (800 µL, 1.22 g, 9.80 mmol) in toluene (10 mL),
ethyldiisopropylamine (1.5 mL, 1.11 g, 8.63 mmol) was gradually added. Lots of white
crystalline precipitate formed, and the reaction mixture was left stirring overnight at RT.
It was then diluted with EtOAc (50 mL), poured into sat. aq. NH
4
Cl (50 mL), the organic
layer was separated and the aqueous layer re-extracted with EtOAc (2 × 30 mL). The
combined organic phases were washed with sat. aq. NH
4
Cl (50 mL), water (2 × 50 mL),
sat. aq. NaHCO
3
(2 × 50 mL), brine and dried over Na
2
SO
4
. The filtrate was evaporated
and dried under 0.25 mm Hg, yielding 1.24 g (96%) of the product as white crystals.
1
H
399
NMR (CDCl
3
, 500 MHz): δ 10.46 (s, 1H), 7.39-7.44 (m, 1H), 7.12-7.16 (m, 2H), 5.21 (s,
2H), 3.87 (s, 3H), 3.55 (s, 3H).
13
C NMR (CDCl
3
, 125 MHz): δ 190.3, 152.4, 149.3,
130.3, 124.4, 119.2, 117.8, 99.4, 57.8, 56.0.
OMOM
OMe
OH
MeO
MeO
5.59. (3,4-Dimethoxyphenyl)[3-methoxy-2-(methoxymethoxy)phenyl]methanol. 4-
Bromoveratrol (400 µL, 606 mg, 2.79 mmol) was dissolved in 15 mL of anhydrous THF,
cooled down to -78 °C, and n-BuLi (3.7 mL of 1.6 M in hexane, ~5.9 mmol, 2.1 eq) was
gradually added. The reaction mixture was then warmed up to -30 °C and stirred at this
temperature for 1 h. The solution of aldehyde 5.58 (497 mg, 2.54 mmol) in anhydrous
THF (10 mL) was then added, and light orange clear solution formed. TLC control
(silica/EtOAc-hexane 1:1, stained with vanillin): R
f
0.4 (purple). The reaction mixture
was poured into 100 mL of water, extracted with EtOAc (4 × 35 mL), the combined
organic layers were washed with brine and dried over Na
2
SO
4
. Purified by flash
chromatography on silica (40 g Yamazen Universal cartridge, 35 mL/min, gradient 10%
to 100% EtOAc in hexane over 12 CV). Colorless oil, yield 533 mg (63%).
1
H NMR
(CDCl
3
, 500 MHz): δ 6.95-7.01 (m, 2H), 6.86-6.90 (m, 1H), 6.81 (dd, J = 8.3 Hz, J = 1.7
Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.72 (dd, J = 8.0 Hz, J = 1.4 Hz, 1H), 6.14 (d, J = 4.1
Hz, 1H), 5.08 (d, J = 6.0 Hz, 1H), 5.02 (d, J = 6.0 Hz, 1H), 3.814 (s, 3H), 3.810 (s, 3H),
3.79 (s, 3H), 3.66 (d, J = 4.1 Hz, 1H), 3.52 (s, 3H).
13
C NMR (CDCl
3
, 125 MHz): δ 151.6,
400
148.5, 147.7, 143.7, 138.4, 135.5, 124.4, 119.8, 118.4, 111.4, 110.6, 109.6, 98.9, 69.7,
57.3, 55.6, 55.55, 55.53.
OMOM
OMe
O
MeO
MeO
5.60. (3,4-Dimethoxyphenyl)[3-methoxy-2-(methoxymethoxy)phenyl]methanone.
The solution of 5.59 (533 mg, 1.60 mmol) in 30 mL of anhydrous CH
2
Cl
2
was stirred for
3 days with 1 g of activated MnO
2
(<5 µm) powder. TLC control (silica/EtOAc-hexane
1:1, stained with vanillin): R
f
0.45 (red). Filtered through a plug of Celite, evaporated and
isolated the product by flash chromatography on silica (40 g Yamazen Universal
cartridge, 35 mL/min, gradient 10% to 100% EtOAc in hexane over 10 CV). Colorless oil,
slowly solidified to colorless crystals. Yield 450 mg (85%).
1
H NMR (CDCl
3
, 500 MHz):
δ 7.54 (d, J = 1.9 Hz, 1H), 7.28 (dd, J = 8.3 Hz, J = 1.9 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H),
6.99 (dd, J = 8.0 Hz, J = 1.4 Hz, 1H), 6.86 (dd, J = 8.0 Hz, J = 1.4 Hz, 1H), 6.79 (d, J =
8.3 Hz, 1H), 4.95 (s, 2H), 3.870 (s, 3H), 3.866 (s, 3H), 3.83 (s, 3H), 3.18 (s, 3H).
13
C
NMR (CDCl
3
, 125 MHz): δ 194.2, 153.3, 152.2, 148.7, 142.8, 135.1, 130.2, 126.1, 124.1,
120.2, 113.7, 110.6, 109.6, 98.6, 56.9, 55.80, 55.76, 55.7.
401
OH
OMe
O
MeO
MeO
5.61. (3,4-Dimethoxyphenyl)(2-hydroxy-3-methoxyphenyl)methanone. The
benzophenone 5.60 (450 mg, 1.36 mmol) was dissolved with heating in 20 mL of
methanol, and 2 N HCl (10 mL) was added. The solution, which at once turned light
yellow, was stirred at RT for 2 h. TLC control (silica/5% EtOAc in CH
2
Cl
2
, stained with
vanillin): R
f
0.5 (5.61, red), 0.4 (5.60, red). The reaction mixture is evaporated and re-
evaporated to dryness with ethanol (2 × 50 mL). The yellow crystalline residue is purified
on a short column (silica gel, EtOAc-CH
2
Cl
2
-hexane 10:40:50) and recrystallized from
CH
2
Cl
2
-hexane. Light yellow crystals, yield 379 mg (97%).
1
H NMR (CDCl
3
, 500 MHz):
δ 11.97 (s, 1H), 7.31-7.36 (m, 2H), 7.23-7.27 (m, 1H), 7.08 (br.d, J = 8.0 Hz, 1H), 6.92 (d,
J = 8.0 Hz, 1H), 6.83 (t, J = 8.0 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H).
13
C
NMR (CDCl
3
, 125 MHz): δ 199.9, 152.9, 152.7, 148.92, 148.90, 130.4, 124.44, 124.40,
119.7, 117.8, 116.5, 112.0, 109.9, 56.2, 56.1, 56.0.
402
5.5 Chapter 5. References.
1
Myles, G. M.; Sancar, A. Chem. Res. Toxicol. 1989, 2, 197.
2
Fishel, M. L.; Kelley, M. R. Mol. Aspects Med. 2007, 28, 375.
3
Abbotts, R.; Madhusudan, S. Cancer Treat. Rev. 2010, 36, 425.
4
Marenstein, D. R.; Wilson, D. M.; Teebor, G. W. DNA Repair 2004, 3, 527.
5
Tell, G.; Quadrifoglio, F.; Tiribelli, C.; Kelley, M. R. Antioxidants & Redox Signaling
2009, 11, 601.
6
Bobola, M. S.; Emond, M. J.; Blank, A.; Meade, E. H.; Kolstoe, D. D.; Berger, M. S.;
Rostomily, R. C.; Silbergeld, D. L.; Spence, A. M.; Silber, J. R. Clin. Cancer Res. 2004,
10, 7875.
7
Wang, D.; Luo, M.; Kelley, M. R. Mol. Cancer Ther. 2004, 3, 679.
8
Mol, C. D.; Izumi, T.; Mitra, S.; Tainer, J. A. Nature 2000, 403, 451.
9
Evans, A. R.; Limp-Foster, M.; Kelley, M. R. Mut. Res. 2000, 461, 83.
10
Luo, M.; He, H.; Kelley, M. R.; Georgiadis, M. M. Antioxidants & Redox Signaling
2010, 12, 1247.
11
Yang, S.; Meyskens, F. L. Antioxidants & Redox Signaling 2009, 11, 639.
12
Zou, G.-M.; Maitra, A. Mol. Cancer Ther. 2008, 7, 2012.
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Conclusions
1. A simple approach to isoindoline derivative based on tandem Petasis-Diels-Alder
reaction has been proposed, and this transformation was shown to be nearly universal
for all carbonyl compounds that are able to participate in Petasis reaction. The
reaction is diastereoselective and provides enantiopure isoindolines when arabinose-
derived starting aldehydes are used.
2. The use of tertiary amines in catalytic version of Petasis reaction has been
investigated and the methodology was extended to the synthesis of 1,2-
dihydroquinoline derivatives from 2-sulfamidobenzaldehydes. “Coordination-free”
three-component reaction of simple aromatic and aliphatic aldehydes has been
demonstrated possible with N-silylated secondary amines.
3. A series of propiolamide-based pseudodipeptide anticancer small molecules with yet
unidentified protein target has been prepared using Ugi reaction. The best compounds
in the series demonstrated high nanomolar activity against several human ovarian
cancer cell lines in cell cultures and atymic mice without treatment-associated
toxicity. The reactions of propiolamides with biologically relevant sulfur and nitrogen
nucleophiles have been studied. The fluorescent derivatives of the best compound and
its mimics have been prepared for intracellular imaging.
4. Four E3330 analogs targeting the redox function of APE1/Ref-1 enzyme, and a short
series of acylpyrrolone-based compounds aimed to inhibit its endonuclease activity
406
have been prepared. The biological studies of these compounds are currently
underway in our collaborator’s lab at the USC School of Pharmacy.
407
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422
Appendix: Selected spectra
N
O
H
OH
2.43
423
424
N
O
H
OH
Br
2.54
425
N
O
H
OH
2.60
426
N
Ph
O
H
OH
2.63
427
N
Ph
O
H
N
OH
HO
2.67
428
N
Ph
O
H
OH
N
Ph
O
H
OH
2.75a (major isomer)
429
N
Ph
O
H
OH
N
Ph
O
H
OH
2.75b (minor isomer)
430
N
O
H
OH
OMe
2.80
431
N
Ph
O
OH
2.84
432
N
Ph
O
H
OH
Ph
2.88
433
N
Ph
O
H
OH
2.90
434
N
Ph
O
H
OH
Ph
2.92
435
OH
N
Ph
Ph
O
2.93
436
N
Ph
O
H
OH
2.97
437
N
O
Ph
OAc
H
H
2.100
438
N
O
Ph
OAc
H
H
Br
2.101
439
N
OAc
Ph
H
N
O
OH
H
2.102
440
N
Ph
OH
2.103
441
N
O
Ph
OH
H
H
2.105
442
N
Ph
O
H
OH
O
2.106
443
N
O
Ph
N
H
H
O
2.107
444
445
N
Ph
O
H
N
NH
2.109
446
N
Ph
O
H
N
NH
2.113
447
N
Ph
O
H
NH EtO
2
C
2.119
448
N
Ph
O
H
N
2.121
449
N
Ph
O
H
HO
2
C
2.127
450
N
O
H
HO
2
C
OMe
MeO
2.130
451
N
Ph
O
H
HO
2
C
2.131
452
N
O
H
HO
2
C
Ph
2.132
453
HO
2
C N
H
O
2.133
454
HO
2
C N
O
Ph
2.135
455
N
O
Ph
2.139
456
N
Ph
OH
H
O
2.143
457
N
Ph
O
H
H
HO
OH
HO
OH
2.145
458
459
N
Ph
O
H
H
HO
HO
O
O
2.153
460
HO
HO
O
O
N
O
Ph
2.154
461
N
Ph
O
H
H
HO
HO
O
O
2.160
462
O
Br
3.10
463
O
HO
3.24
464
O
BnO
3.27
465
OH
O
BnO
3.32
466
OBn
O
BnO
3.33
467
N
S
O
O
3.37
468
N
S
O
O
MeO
MeO
3.43
469
N
S
O
O
CF
3
3.51
470
N
S
O
O
3.53
471
N
S
O
O
Br
3.55
472
N
HN
S
O O
3.65
473
N
3.67
474
N
S
O
O
3.68
475
NH
S
O
O
N Ph Ph
Ph
3.69
476
NH
S
O
O
N
OMe
O
3.72
477
Ph
N
Ph
O
3.76
478
NMe
2
Ph
MeO
MeO
3.91
479
N
Ph
O
3.95
480
N
Ph
O
3.97
481
F
3
C
N
O
Cl
3.105
482
N
Ph
O
3.107
483
N
O
Ph
3.109
484
N
O
Ph
Ph Ph
3.112
485
N
Ph
O
OH
3.114
486
N
Ph
O
Ph
OH
Ph
3.117
487
O
N
O
3.120
488
OMe
N
H
N
O
O
MeO
OMe
4.10
489
N
H
N
O
O
CF
3
OMe
4.11
490
N N
NH
O
O
N
N
N
F
4.13
491
OMe
N
H
N
O
O
S
MeO
4.14
492
OMe
N
H
N
O
O
S
4.15
493
N
H
N
O
O
F
F
4.28
494
N
MeO OMe
O
OMe
N
H
O
Br
4.32
495
N
MeO OMe
O
OMe
N
H
O
N
O
4.35
496
OMe
MeO
OMe N
H
N
O
S
S
O O
O
O
4.39
497
N
O
HN
O
N
N
N
N
F
F
F
F
F
4.44
498
N
O
N
H
O
O O
4.47
499
N
O
N
H
O
CO
2
H
4.48
500
N
MeO OMe
O
OH
N
H
O
4.50
501
N
O
N
H
O
CO
2
Et
OMe
MeO
S
4.51
502
N
O
N
H
O
OMe
MeO
S
H
N
O
N
O
4.53
503
OH
MeO
N
O
S
H
N
O
CO
2
Et
4.55
504
N
O
N
H
O
OMe
MeO
S
4.57
505
N
O
N
H
O
OMe
MeO
S
N
O
O
4.60
506
OMe
N
H
N
O
S
MeO
O
H
N
O
4.61
507
OMe
N
N
H
O
O
S
MeO
N
N
N
4.63
508
N
O
N
H
O
CO
2
Et
OMe
MeO
S
Cl
NO
2
4.70
509
N
O
N
H
O
S
4.71
510
N
O
N
H
O
OMe
MeO
4.72
511
N
O
MeO
NH
2
O
OMe
4.74
512
N
B
N
F F
O
H
N
N
H
H
N
O
O
N
S
O
OMe
OMe
4.80
513
N
B
N
F F
O
H
N
NH
2
4.81
514
N
B
N
F F
O
H
N
N
H
H
N
O
O
N
S
OMe
OMe
O
4.86
515
N
B
N
F F
O
H
N
N
H
O
4.87
516
N
H
O
4.96
517
N
O
4.97
518
N
O
4.99
519
H
N
O
S
HO
2
C
NHAc
4.105
520
N
O Ph
S MeO
4.106
521
N
O
Ph
S
MeO
4.107
522
N
O
S
H
2
NOC
NHBoc
4.108
523
N
O
S
H
2
NOC
BocHN
+
N
O
S
H
2
NOC
BocHN
O O
4.109
524
O
N N
4.110
525
O
N N
N
4.111
526
N
O
H
N
O
S
S
HO
2
C
NHAc
MeO
OMe
4.113
527
O
O
8
5.1
528
O
O
N
9
O
5.2
529
MeO
MeO
O
O
8
5.3
530
MeO
MeO
O
O
N
8
O
5.4
531
OMe
OMe
8
5.10
532
OMe
OMe
H
N
9
5.12
533
MeO
MeO
OMe
OMe
I
5.18
534
MeO
MeO
OMe
OMe
8
5.19
535
MeO
MeO
OMe
OMe
O
5.20
536
MeO
MeO
OMe
OMe
H
N
8
5.21
537
MeO
MeO
OMe
OMe
N
8
O
5.22
538
OO
O
Br
O
MeO
5.30
539
O
Br
O
HO
O
5.32
540
Br
N
CO
2
Me
CO
2
Me
5.33
541
Br
N
CO
2
H
CO
2
H
5.35
542
MeO
MeO
N
OH
O
O
5.36
543
MeO
MeO
OH O
CO
2
Me
5.40
544
N
OH O
CO
2
Me
5.44
545
N
O
MeO
MeO
OH
O
5.45
546
N
N
OH
O
O
5.51
547
N
OMe
O
O
MeO
MeO
5.52
548
N
O
N
HN
MeO
MeO
5.53
549
MeO
MeO N
N
O OH
O O
5.54
550
MeO
MeO
O
N
N
OH
5.56
551
MeO
MeO
O
N
O
O
5.57
552
OMOM
OMe
O
5.58
553
OMOM
OMe
OH
MeO
MeO
5.59
554
OMOM
OMe
O
MeO
MeO
5.60
555
OH
OMe
O
MeO
MeO
5.61
Abstract (if available)
Abstract
This dissertation comprises two separate projects, relying on the use of multicomponent reactions as a common theme. The introduction (Chapter 1) briefly overviews the utility of multicomponent reactions highlighting their medicinal chemistry applications. The first part (Chapters 2 and 3) describes the development of new practical synthetic methodologies for one-step synthesis of nitrogen heterocycles (isoindolines and dihydroquinolines) using three-component reaction of boronic acids, amines and aldehydes (Petasis reaction) or its variations. The second part (Chapters 4 and 5) deals with the applications of multicomponent reactions to the diversity oriented synthesis of biologically active small molecules.
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University of Southern California Dissertations and Theses
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Asset Metadata
Creator
Butkevich, Alexey
(author)
Core Title
Multicomponent reactions in the synthesis of nitrogen heterocycles and their application to drug discovery
School
College of Letters, Arts and Sciences
Degree
Doctor of Philosophy
Degree Program
Chemistry
Publication Date
02/15/2011
Defense Date
01/31/2011
Publisher
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
APE1,BODIPY,boronic acid,cancer,chromene,diastereoselective,dihydroquinoline,drug discovery,heterocycles,isoindoline,kinetics,medicinal chemistry,multicomponent reaction,nitrogen heterocycles,NMR,OAI-PMH Harvest,organic synthesis,Petasis reaction,propiolamide,pyrroline,Ref-1,tocopherol,trifluoroborate,Ugi reaction
Language
English
Contributor
Electronically uploaded by the author
(provenance)
Advisor
Petasis, Nicos A. (
committee chair
), Neamati, Nouri (
committee member
), Williams, Travis J. (
committee member
)
Creator Email
alexnbt@yandex.ru,butkevic@usc.edu
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-m3658
Unique identifier
UC1284882
Identifier
etd-Butkevich-4146 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-439727 (legacy record id),usctheses-m3658 (legacy record id)
Legacy Identifier
etd-Butkevich-4146.pdf
Dmrecord
439727
Document Type
Dissertation
Rights
Butkevich, Alexey
Type
texts
Source
University of Southern California
(contributing entity),
University of Southern California Dissertations and Theses
(collection)
Repository Name
Libraries, University of Southern California
Repository Location
Los Angeles, California
Repository Email
cisadmin@lib.usc.edu
Tags
APE1
BODIPY
boronic acid
cancer
chromene
diastereoselective
dihydroquinoline
drug discovery
heterocycles
isoindoline
kinetics
medicinal chemistry
multicomponent reaction
nitrogen heterocycles
NMR
organic synthesis
Petasis reaction
propiolamide
pyrroline
Ref-1
tocopherol
trifluoroborate
Ugi reaction