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University of Southern California Dissertations and Theses

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Multicomponent reactions of allenyl and alkynyl boron derivatives with amines and aldehydes and their use in the synthesis of novel multifunctional amines and heterocycles

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Multicomponent reactions of allenyl and alkynyl boron derivatives with amines and aldehydes and their use in the synthesis of novel multifunctional amines and heterocycles

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Content MULTICOMPONENT REACTIONS OF ALLENYL AND ALKYNYL BORON
DERIVATIVES WITH AMINES AND ALDEHYDES AND THEIR USE IN THE
SYNTHESIS OF NOVEL MULTIFUNCTIONAL AMINES AND
HETEROCYCLES

by
Fotini Liepouri

A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)

May 2007

Copyright 2007 Fotini Liepouri
ii
Dedication

To my father Alexandros, my brother Yiorgos and all my friends

iii
Acknowledgements
During these last five years at USC along with the journey of pursuing a
Ph.D. degree, I ran into many interesting and helpful people who played different
roles and contributed in unique and variable ways in my professional as well as
personal development. The least I could do is express them my sincere and deep
acknowledgements.
But before everyone else, I would like to express my gratitude to my family
and beloved ones back home. Their support and encouragement not only gave me the
“activation energy” to start this journey but also was part of the “essential fuel” to
continue when I was running out of my “personal resources and motivation”,
something that most chemistry graduate students experience quite often…
Looking back into my early days here, I would deeply like to thank my
advisor Dr. Nicos Petasis for being the first to welcome me here. But most
importantly, I would like to thank him for welcoming me in his research group and
giving me the opportunity to work in a really exciting project for me. His guidance
and supervision was really stimulating and helped me broaden my scientific horizons
in directions I had not imagined in the beginning of that journey. I also appreciate the
discrete supervision which left me a lot of space for personal contribution and
considerable freedom in experimentation, something really important to me.
Furthermore, I would like to express my gratitude to all the members of my
screening and thesis committee for accepting to be there and share their ideas and
iv
thoughts with me. Special thanks to Dr. Surya Prakash who besides being a great
teacher was always available for discussion and guidance.
Also I would like to thank all those different people from the USC chemistry
department who made this work possible. Many thanks to Heather Connor and
Michele Dea from the main office, Carole Phillips and all the LHI staff as well as to
Allan Kershaw, James Merritt and Ross Lewis for their technical support.
Last but not least I would like to thank all the past and present members of
the group for creating a nice working environment and for sharing ideas, frustration
and insight, thus making this process easier and more fun. Thank you all.

v
Table of Contents
Dedication ................................................................................................................. ii
Acknowledgements..................................................................................................iii
List of Tables .........................................................................................................viii
List of Schemes......................................................................................................... x
Abstract ................................................................................................................... xv
CHAPTER 1: Multicomponent reactions- A brief introduction............................... 1
1.1 Multicomponent Reactions (MCRs). General aspects.................................. 1
1.2 The historical development of MCRs ........................................................... 3
Figure 1.1: The history of MCRs in brief ................................................................. 4
1.3 The latest advances. Miscellaneous MCRs................................................. 15
1.4 MCRs in drug development and natural product synthesis ........................ 33
1.5 New directions in MCRs. What’s next?...................................................... 41
1.6 Chapter 1 References .................................................................................. 46
CHAPTER 2: Single-step synthesis of allenyl and propargylic amine
derivatives. Reactivity studies of allenic boron derivatives in a three-
component MCR with amines and carbonyl compounds. ...................................... 55
2.1 Fast assembly of multifunctionalized molecules by a three component
reaction between boronic acids, amines and aldehydes.......................................... 55
2.2 Allenic boronic acid. A potential partner for the Petasis reaction ............... 65
2.3 Results and discussion ................................................................................. 72
2.3.1 Reactivity studies of allenic boronic acid in the Petasis reaction. .......... 72
2.3.1.1 Selective synthesis of propargylic and allenyl α-amino acids .................... 74
2.3.1.2 Mechanistic hypothesis ............................................................................... 78
2.3.1.3 Synthesis of allenic β-amino alcohols......................................................... 82
2.3.2 Reactivity studies of potassium allenyl trifluoroborate salt in the
Petasis reaction........................................................................................................ 90
2.3.2.1 Potassium organotrifluoroborate salts. General aspects.............................. 90
2.3.2.2 Reactivity of potassium allenyl trifluoroborate salt in the α-amino
acid version of the Petasis reaction ......................................................................... 93
2.3.2.3 Mechanistic hypothesis ............................................................................. 100
2.3.2.4 Reactivity of potassium allenyl trifluoroborate salt in the β-amino
alcohol version of the Petasis reaction.................................................................. 102
2.4 Experimental.............................................................................................104
2.4.1 General......................................................................................................104
vi
2.4.2 Synthesis and physical data....................................................................... 105
2.5 Chapter 2 References ................................................................................ 124
CHAPTER 3: Chiral induction in the synthesis of allenyl and propargyl
amines. The effect of chiral amines and α-hydroxy aldehydes in the allenyl
version of the Petasis reaction............................................................................... 132
3.1 Diastereoselectivity in the Petasis reaction............................................... 132
3.1.1 The effect of chiral amines in the Petasis reaction.................................... 133
3.1.2 The effect of chiral a-hydroxy aldehydes in the Petasis reaction.............. 137
3.2 Results and discussion..............................................................................139
3.2.1 Chiral amines in the allenyl/propargyl extention on the Petasis
reaction.................................................................................................................. 139
3.2.2 Chiral α-hydroxyaldehydes in the allenyl/propargyl extention on the
Petasis reaction...................................................................................................... 146
3.3 Experimental.............................................................................................148
3.3.1 General......................................................................................................148
3.3.2 Synthesis and physical data....................................................................... 150
3.4 Chapter 3 References ................................................................................. 166
CHAPTER 4: Substituted allenyl boron derivatives. Synthetic methodology
and reactivity studies in the Petasis reaction......................................................... 167
4.1 Substituted allenyl boron derivatives. Their role and potential in
organic synthesis ................................................................................................... 167
4.2 Results and discussion..............................................................................170
4.2.1 Synthetic attempts towards substituted boron derivatives ........................ 170
4.2.2 Reactivity of novel allenyl boron derivatives in the Petasis reaction ....... 179
4.3 Experimental.............................................................................................189
4.3.1 General......................................................................................................189
4.3.2 Experimental observations........................................................................189
4.3.3 Synthesis and physical data....................................................................... 191
4.4 Chapter 4 References ................................................................................ 209
CHAPTER 5: Studies in Palladium catalyzed three-component annulations
of α- allenyl amine derivatives.............................................................................. 211
5.1 Multicomponent Pd promoted transformations of allenes........................ 211
5.2 Results and discussion..............................................................................219
5.2.1 Pd catalyzed three-component annulations of the allenyl amines with
carbon pronucleophiles. Synthesis of five and seven-membered nitrogen
heterocycles........................................................................................................... 219
5.2.2 Pd catalyzed three-component annulations of the allenyl amines with
nitrogen nucleophiles. Synthesis of piperazines, pyrrolines and aziridines.......... 228
5.3 Experimental.............................................................................................234
vii
5.3.1 General......................................................................................................234
5.3.2 Synthesis and physical data....................................................................... 235
5.4 Chapter 5 References ................................................................................ 253
CHAPTER 6: Reactivity of Methoxy alkynyl boronates in the Petasis
Reaction. One-step synthesis of functionalized propargyl amines. Scope and
limitations.............................................................................................................. 255
6.1 Propargyl amines. General aspects ........................................................... 255
6.1.1 The biological importance of propargyl amines ....................................... 255
6.1.2 Synthetic approaches towards propargyl amines ...................................... 257
6.2 Results and discussion..............................................................................266
6.2.1 An alternative approach to propargyl amines. Reactivity of alkynyl
boron derivatives in the Petasis Reaction.............................................................. 266
6.2.1.1 Synthesis of methoxy alkynyl diisopropyl boronate................................. 267
6.2.1.2 One-step synthesis of propargyl amines by the Petasis Reaction.
Scope and limitations ............................................................................................ 270
6.3 Experimental.............................................................................................275
6.3.1 General......................................................................................................275
6.3.2 Synthesis and physical data....................................................................... 276
6.4 Chapter 6 References ................................................................................ 288
Bibliography.......................................................................................................... 294
Appendix- Selected Spectra .................................................................................. 317

viii
List of Tables
Table 1.1: Examples of palladium catalyzed MCRs................................................. 18
Table 1.2: Examples of nickel and copper catalyzed MCRs. ................................... 20
Table 1.3: Cycloaddition relayed MCRs................................................................... 25
Table 1.4: Examples of sequential-annulations MCRs............................................. 28
Table 1.5: Organocatalytic MCRs............................................................................. 30
Table 1.6: Acid promoted MCRs.............................................................................. 32
Table 2.1: The reactions of allenic boronic acid and boronates................................ 70
Table 2.2: Homopropargylic α-amino acids by the Petasis reaction......................... 77
Table 2.3: Allenic α-amino acids by the Petasis reaction ......................................... 78
Table 2.4: Allenic β-amino alcohols by utilizing primary amines............................ 84
Table 2.5: Allenic β-amino alcohols by utilizing secondary amines ........................ 85
Table 2.6: Potassium allenyl trifluoroborate salt in the α-amino acid version of
the Petasis reaction............................................................................................ 95
Table 2.7: Potassium allenyl trifluoroborate salt in the Petasis reaction ................ 102
Table 3.1: Chiral amines in synthesizing allenyl and homopropargyl α-amino
acids ................................................................................................................ 140
Table 3.2: Chiral amines in synthesizing allenyl and homopropargyl β-amino
alcohols ........................................................................................................... 144
Table 3.3: Chiral α-hydroxy aldehydes in the allenyl version of the Petasis
reaction............................................................................................................ 146
Table 4.1: Reactivity studies of 4.19, 4.23 and 4.24 in combination with 2.104
and 2.109......................................................................................................... 180
Table 4.2: Reactivity studies of 4.19, 4.23 and 4.24 in combination with 2.104
and secondary amines ..................................................................................... 184
Table 4.3: Reactivity studies of 4.19 and/or 4.24 in combination with 2.144
and 2.109......................................................................................................... 188
Table 5.1: Annulation attempts of the allylamine derivatives 5.50 and 5.51.......... 223
Table 5.2: Annulation attempts of the benzyl amine derivatives 5.59, 5.60 and
5.63.................................................................................................................. 228
Table 5.3: Intramolecular cyclization attempts of 2.149 and 5.64.......................... 232
ix
Table 6.1: The major synthetic approaches towards propargyl amines.................. 264
Table 6.2: 3-methoxy-prop-1-ynyl diisopropyl boronate in the Petasis
Reaction .......................................................................................................... 273

x
List of Schemes
Scheme 1.1: The formation of “benzoylazotide” by a four component MCR............ 4
Scheme 1.2: The formation of dihydropyridines by the Hantzsch reaction................ 5
Scheme 1.3: The original Biginelli dihydropyrimidinone condensation .................... 5
Scheme 1.4: The Mannich reaction............................................................................. 6
Scheme 1.5: The synthesis of allyl isocyanide (Lieke, 1859)..................................... 7
Scheme 1.6: General synthesis of isocyanides by dehydration of formylamines
(Ugi, 1958) .......................................................................................................... 8
Scheme 1.7: The classic Passerini reaction (Passerini. 1921)..................................... 8
Scheme 1.8: Suggested mechanism of the Passerini reaction..................................... 9
Scheme 1.9: Synthesis of hydantoins by the Bucherer-Bergs reaction..................... 10
Scheme 1.10: Synthesis of thiazolines by the Asinger reaction................................ 12
Scheme 1.11: The Ugi four component reaction ...................................................... 12
Scheme 1.12: The basic types of the U-4CR scaffolds............................................. 14
Scheme 1.13: The Gewald reaction .......................................................................... 14
Scheme 1.14: The Pauson-Khand reaction ............................................................... 15
Scheme 1.15: Highly stereocontrolled synthesis of β-Lactams by an MCR ............ 21
Scheme 1.16: Synthesis of isochromenes by a bimetallic Pd(II)-Cu(II)
catalyzed MCR.................................................................................................. 22
Scheme 1.17: The use of bimetallic Pd-Ru catalytic system in a MCR ................... 22
Scheme 1.18: A Ru(II) catalyzed three-component reaction approach towards
aryl boronates.................................................................................................... 23
Scheme 1.19: Robinson’s synthesis of tropinone by a double Mannich
reaction.............................................................................................................. 26
Scheme 1.20: Synthesis of Nifepidine by Hantsch (1882) ....................................... 34
Scheme 1.21: Examples of biologically active compounds synthesized by
MCRs ................................................................................................................ 38
Scheme 1.22: Examples of natural products synthesized by MCRs......................... 39
Scheme 1.23: Generation of molecular complexity by an Ugi-Diels Alder-
Allylation-ROM/RCM sequence ...................................................................... 42
xi
Scheme 1.24: The seven component reaction........................................................... 45
Scheme 2.1: The Petasis three-component reaction.................................................. 56
Scheme 2.2: The mechanistic hypothesis of the Petasis reaction ............................. 57
Scheme 2.3: Types of compounds synthesized by the Petasis three-component
reaction.............................................................................................................. 61
Scheme 2.4: Implementation of the Petasis reaction in DOS ................................... 63
Scheme 2.5: Application of the Petasis reaction in target oriented synthesis........... 65
Scheme 2.6: Synthetic methodology for allenic boronic acid derivatives................ 66
Scheme 2.7: The propargylic rearrangement ............................................................ 66
Scheme 2.8: The addition of allenyl and propargyl boronates in unhindered
oxo compounds ................................................................................................. 68
Scheme 2.9: Chelation control during the addition to aldehydes favors
formation of the threo isomer............................................................................ 68
Scheme 2.10: Preparation methods for allenic boronic acid and boronates ............. 72
Scheme 2.11: The preparation of allenic boronic acid.............................................. 74
Scheme 2.12: Synthesis of propargyl and allenyl α-amino acids ............................. 76
Scheme 2.13: Mechanistic hypothesis for the synthesis of propargylic and
allenic α-amino acids ........................................................................................ 79
Scheme 2.14: The addition of ammonia to glyoxylic acid monohydrate with
pH...................................................................................................................... 81
Scheme 2.15: The reaction of hydroxyglycine with allenyl boronic acid................. 82
Scheme 2.16: Synthesis of allenic and homopropargyl β- amino alcohols by
the Petasis reaction............................................................................................ 83
Scheme 2.17: The competing Amadori rearrangement of glycoladehyde with
primary amines.................................................................................................. 88
Scheme 2.18: Synthetic methodologies towards potassium
organotrifluoroborate salts ................................................................................ 90
Scheme 2.19: The synthesis of allenyl potassium organotrifluoroborate salt........... 94
Scheme 2.20: Participation of potassium allenyl trifluoroborate salt in the
Petasis reaction.................................................................................................. 95
Scheme 2.21: Proposed mechanism for 2.178 in the Petasis reaction .................... 100
Scheme 3.1: Methodology towards optically pure α-amino acids.......................... 135
xii
Scheme 3.2: Representative α-hydroxy aldehydes employed in the Petasis
reaction............................................................................................................ 137
Scheme 3.3: The Petasis reaction with chiral α-hydroxyaldehydes........................ 138
Scheme 3.4: Scaffolds obtained by synthetic manipulation of the products........... 139
Scheme 3.5: Chiral amines in synthesizing propargyl and allenyl α-amino
acids ................................................................................................................ 140
Scheme 3.6: Determination of the stereochemical preference by employing
(R)-Phenylglycinol 3.1 in combination with allenyl boronic acid 2.65 and
glyoxylic acids monohydrate 2.104 ................................................................ 143
Scheme 3.7: Oxazolidinone formation originating from 3.60 ................................ 147
Scheme 3.8: Proposed non chelation model of reaction of α-hydroxy
aldehydes in the Petasis reaction towards the anti- β- amino polyol
products........................................................................................................... 148
Scheme 4.1: Novel α and γ-substituted allenyl boron sources for the Petasis
reaction............................................................................................................ 169
Scheme 4.2: The types of scaffolds that can be synthesized by utilizing 4.1
and 4.2 in the Petasis reaction......................................................................... 170
Scheme 4.3: Synthesis of 2-(1-methoxy-propa-1,2-dienyl)-4,4,5,5-
tetramethyl-[1,3,2]dioxaborolane.................................................................... 171
Scheme 4.4: The retrosynthetic path towards boronates of type 4.11 .................... 173
Scheme 4.5: Synthesis of 4.16 ................................................................................ 173
Scheme 4.6: Higher hydrocarbons are the mostly obtained when Grignard
reagents are employed..................................................................................... 174
Scheme 4.7: Synthesis of the allenyl bromide 4.22 ................................................ 175
Scheme 4.8: Synthesis of 4,4,5,5-Tetramethyl-2-octa-1,2-dienyl-
[1,3,2]dioxaborolane 4.19 ............................................................................... 176
Scheme 4.9: Synthesis of 4.23 and 4.24 from 4.19................................................. 177
Scheme 4.10: Synthesis of 4.26 with two alternative pathways ............................. 178
Scheme 4.11: 4.10 does not constitute a reactive boron source for the Petasis
reaction............................................................................................................ 179
Scheme 4.12: Synthesis of novel propargyl and/or allenyl α-amino acids by
employing 4.19, 4.23 and/or 4.24 in the Petasis reaction with 2.104 and
2.109................................................................................................................ 180
Scheme 4.13: Addition of 4.23 to glyoxylic acid monohydrate ............................. 182
xiii
Scheme 4.14: Control in the selective synthesis of allenyl or propargyl α-
amino acids ..................................................................................................... 183
Scheme 4.15: The preformed imine 4.34 is not reactive towards 4.23 or 4.19....... 186
Scheme 4.16: The reaction of p-nitroaniline 2.180 with 2.104 and 4.19................ 186
Scheme 4.17: 4.26 is not reactive in the Petasis reaction........................................ 187
Scheme 4.18: Reactivity studies of 4.19 and 4.24 in synthesizing novel allenyl
β-amino alcohols............................................................................................. 188
Scheme 5.1: The possible adducts from addition of nucleophiles to allenes.......... 213
Scheme 5.2: The mechanisms of additions of nucleophiles to allenes ................... 214
Scheme 5.3: Three-component additions to allenes................................................ 215
Scheme 5.4: The carbopalladation mechanism operates in the three-
component additions to allenes ....................................................................... 216
Scheme 5.5: The ring systems from allenes carrying carbon pronucleophiles
and their precursors......................................................................................... 217
Scheme 5.6: Pd catalyzed annulations of allenyl amine derivatives....................... 218
Scheme 5.7: Palladium catalyzed annulation of the allenyl amine derivatives
5.46.................................................................................................................. 220
Scheme 5.8: Derivatization of 2.151b to 5.50 and 5.51.......................................... 221
Scheme 5.9: Palladium catalyzed cyclizations of 5.50 and 5.51 ............................ 222
Scheme 5.10: Characteristic signals of 5.53a and 5.53c from the
1
H NMR
spectra ............................................................................................................. 223
Scheme 5.11: Derivatization of 2.149b to 5.59, 5.60 and 5.63............................... 225
Scheme 5.12: Synthesis of 5.60 by two different routes......................................... 226
Scheme 5.13: Palladium catalyzed cyclizations of 5.59, 5.60 and 5.63 ................. 226
Scheme 5.14: Palladium catalyzed cyclizations of 2.163 ....................................... 229
Scheme 5.15: The free OH group does not interfere in the Pd catalyzed three-
component cyclizations................................................................................... 231
Scheme 5.16: Synthesis of pyrroline and aziridines by Palladium catalyzed
intamolecular cyclizations of 2.149 and 5.64.................................................. 231
Scheme 6.17: Some biologically active propargyl amines ..................................... 256
Scheme 6.18: two-component-process for synthesizing propargyl amides by
utilizing chiral binapthol octyl boronates........................................................ 267
xiv
Scheme 6.19: Synthesis of alkynyl boronates from alkynyl organometallics ........ 267
Scheme 6.20: Alkynyl boronates from reaction of alkynyldiaminoboranes
with TMS protected diols................................................................................ 268
Scheme 6.21: Decomposition of alkynyl boronates during transesterfication
attempts ........................................................................................................... 268
Scheme 6.22: The synthesis of 3-methoxy-prop-1-ynyl diisopropyl boronate
6.51.................................................................................................................. 269
Scheme 6.23: 3-methoxy-prop-1-ynyl diisopropyl boronate failed to yield the
three-component product when combined with glyoxylic acid
monohydrate or ethyl glyoxalate..................................................................... 271

xv
Abstract
This dissertation presents our efforts in the field of multicomponent reactions
and more specifically in the three-component condensation among amines, carbonyl
compounds and organoboron derivatives. This process is referred as “Petasis
reaction” in the literature. This thesis describes new extensions of the Petasis
reaction to allenyl and alkynyl boron components.
Chapter one is an introduction to the field of multicomponent reactions. A
limited historical review is attempted to the landmarks of this Chemistry which
established the main principles and demonstrated the potential of this chemistry in
many different fields such as basic academic research, synthetic organic chemistry,
medicinal and industrial applications.
Chapter two discusses the general features of the Petasis reaction and all the
research previously conducted concerning the process. Furthermore, our initial
efforts in expanding the process to new boron components such as allenyl boron
derivatives are included. Interesting features for the synthetic potential of the process
were reveled through multiple types of reagents-controlled synthesis for the two
isomeric types of products that can potentially be obtained (homopropargylic versus
allenic scaffolds).
Chapter three discusses the stereoselectivity of the Petasis reaction when
chiral components are used in combination with allenyl boronic acid and potassium
allenyl trifluoroborate salt. The degree of chiral induction of various chiral amines on
xvi
the reaction and the determination of the absolute stereochemical preference are
discussed. Also, results of the use of chiral α-hydroxy aldehydes to control the
diastereoselectivity of the allenyl version of the Petasis reaction are presented.
Chapter four concerns our results in developing methodology towards novel
α and γ monosubstituted allenyl boron analogues and in exploring their role in the
three-component condensation with amines and carbonyl compound. Five novel
analogues were synthesized and used in the Petasis reaction yielding a number of
novel multifunctionalized amine derivatives.
Chapter five deals with the synthetic manipulation of the allenyl adducts
obtained from the Petasis reaction. The reactivity of the allenyl moiety towards
palladium promoted transformations allowed for the synthesis of various
heterocycles.
Chapter six discusses our efforts in synthesizing a novel alkynyl boron analog
and our initial studies of reactivity of this boron source in the Petasis reaction. A
number of propargyl amines were synthesized by those attempts where the scope and
limitations of this version were revealed.

1
CHAPTER 1: Multicomponent reactions- A brief introduction

1.1 Multicomponent Reactions (MCRs). General aspects
Multicomponent reactions (MCRs) constitute one of the most valuable tools
in the preparation of multifunctionalized and structurally diverse drug-like chemical
entities as well as diverse libraries of small molecules. MCRs are convergent
chemical processes in which three or more starting materials are combined in a
single chemical step to form a specific product
1
. In those chemical transformations,
depending on the number of components used, multiple chemical bonds are formed
in one pot while the products usually contain most of the functionality present in the
starting materials.
Systematic mechanistic study for a number of MCRs has revealed three
different types. MCRs of type I are collections of equilibria between all participating
subreactions, including the last step tha forms the product. Type II MCRs differ from
type I at the final step which is irreversible and thus drives the process towards the
desired direction, yielding the product in more efficiently. Type III MCRs constitute
of a sequence of irreversible subreactions that all proceed towards the product.
The outcome of MCRs is highly depended on the nature of the reactants as
well as the reactions conditions (solvent, temperature concentration etc)
2
. In
principle, for an MCR to be feasible and efficient, the compatibility as well as the
2
relative reactivity of all the possible “pairs of reagents” is to be considered during the
planning stages. This is of great importance since these processes constitute a
network of elementary reactions between the different components. Multiple
equilibria coexist from which specific reactive species are formed in situ which then
participate in an irreversible step that drives the reaction to completion, towards one
specific type of product, thus making the process efficient and free of byproducts
3
.
Having in mind those general principles, it’s becoming profound that choosing the
different components is a task of significant complexity, especially when the number
of reagents increases.
MCRs being convergent in nature are very valuable synthetically since they
combine characteristics such as: improved product yields (especially when compared
with the corresponding linear multistep approaches), significantly shorter one pot
synthetic routes, atom economy, access to a large number of products as well as high
exploratory power. Theoretically, the number of possible products increases with the
multiplicity of the reaction (exponential growth) as well as by altering the structural
features of the starting materials. As initially recognized by Ugi during the
development of the four-component process, “starting with 1000 each of the educts
carboxylic acid, amines, aldehydes and isocyanides, 1000
4
products are accessible”.
4

Using this concept, more complex, natural-product like structures, leading to
libraries of up to two million compounds have been generated in a few steps, an
accomplishment that was not feasible by using the classical linear stepwise
3
approaches usually employed in organic synthesis
5
. This last characteristic in
combination with the high degree of functionality present in most of the products are
particularly appreciated in constructing large number of analogues for biological
screening in drug design, as well as in structure-activity relationship studies in
biologically active compounds, thus extending the importance of MCRs to biology,
medicinal chemistry and drug development.
As a result, research in the field of MCRs is and will continue to be very
active. As statistics show, the number of articles published per year in the field
shows an increasing trend in the last two decades
6
since the value and power of these
processes are now being realized and utilized in academia as well as industry. The
intellectual challenge in developing new and efficient MCRs, based on the
knowledge accomplished so far in combination with the increasing need for small,
easily accessible drug-like diverse molecular scaffolds constitute the driving forces
that make this field one of the most promising and fascinating areas of chemistry.

1.2 The historical development of MCRs
The appearance of MCRs dates back to the mid 19
th
century. The first
example reported in 1838 by Laurent and Gerhardt.
7-8
In that, “benzoylazotide” 1.5
was formed from bitter almond oil and ammonia. In chemistry terms, that was a four
component condensation of benzaldehyde with ammonia and hydrogen cyanide to
form an intermediate α-amino cyanide which underwent a consecutive condensation
4
with another benzaldehyde molecule to form a Schiff base (Scheme 1.1)
8Error!
Bookmark not defined.
.

O
NH
3 HCN ++
NH
2
CN
O
N
CN
1.5
1.1
1.2 1.4 1.3 1.1

Scheme 1.1: The formation of “benzoylazotide” by a four component MCR

The historical development of MCRs after this first demonstration is outlined
in Figure 1.1.

Figure 1.1: The history of MCRs in brief

But it was no earlier than 1850 that the chemistry of MCRs officially began
9

with the introduction by Strecker
10
of a new methodology in synthesizing α-amino
acids via the exact same α-amino cyanides formed by aldehydes, ammonia and
hydrogen cyanide followed by a post MCR hydrolysis of the cyanide functionality.
11

The “benzoylazotide” formation reaction, 1838
The Strecker reaction, 1850
The Hantzsch reaction, 1882
The Biginelli reaction, 1891
The Mannich reaction, 1912
The Passerini reaction, 1921
The Ugi reaction, 1959
Miscellaneous MCRs
Organometallic MCRs
5
In 1882 the Hantzsch reaction was introduced
12
and many interesting
heterocycles were formed. This is a four component process among ammonia, an
aldehyde and an acetoacid ester to form various dihydropyridines 1.8 (Scheme 1.2).
13

R
1
O
+
R
2
OR
3
O O
2 + NH
3
N
R
1
R
3
OOC
R
2
COOR
3
R
2
H
1.6 1.7 1.8 1.2

Scheme 1.2: The formation of dihydropyridines by the Hantzsch reaction

Shortly after the discovery of the Hantzsch reaction, the Biginelli
14
three
component reaction emerged in 1893 to yield 3, 4- dihydropyrimidin-2(1H)-ones 7, a
closely related type of medicinally important heterocycles (Scheme 1.3). In this
process an aromatic aldehyde such as benzaldehyde 1.1 condenses with urea 1.10
and acetoacid ester 1.9 in the presence of catalytic amounts of HCl while the product
usually precipitates out upon cooling thus making this method the lead technology
towards these types of pharmaceutically interesting targets or for constructing
libraries of such analogs.
O
+
Me OEt
O O
+
N
NH
EtOOC
Me O
H
1.9 1.11
H
2
N NH
2
O
1.1 1.10

Scheme 1.3: The original Biginelli dihydropyrimidinone condensation

6
The scope of this reaction has been significantly extended by modifications
of the components used, allowing access to a large number of multifunctionalized
dihydropyrimidinone analogues.
15-16
The scaffold resulting from a Biginelli
transformation has been given the acronym DHPM and those types of compounds
constitute a field of very active research due to the interesting biological properties
they exhibit.
17,18,19,20

Reviewing the landmarks of the history of MCRs, the Mannich reaction is the
next stop. Discovered in 1912
21
, this process has been one of the mostly cited and
used reactions in the practice of organic synthesis
22
, especially in the synthesis of
complicated natural products. In origin, the Mannich reaction is a three component
condensation among an enolizable CH-acidic carbonyl compound 1.12, an amine
1.13 and an nonenolizable aldehyde (usually formaldehyde 1.14) to yield a β-
aminocarbonyl compound of type 1.15 (Scheme 1.4).

H
O
+
R
1
O
+
1.12 1.14 1.13
H
R
2
R
3
N
H
R
4
R
1
N
R
4
O
R
2
R
3
1.15

Scheme 1.4: The Mannich reaction
The Mannich reaction as well as all the processes mentioned above were later
grouped under the general term of aminoalkylation reactions since they all involved
the formation of an imine or iminium electrophile intermediate from a reaction
between an amine and a carbonyl component which subsequently reacts with a mild
7
nucleophile (e.g. CN
-
in the Strecker reaction or a carbon nucleophile in the
Hantzsch, Biginelli and Mannich reactions). Other name reactions also belong in this
category of MCRs and this term is also a way to distinguish and monitor the
chronological progress in the field, according to the chemistry knowledge and
findings accumulated over time.
The next generation of MCRs started with the development of the chemistry
of the isocyanides.
23,24,25
Isocyanides a.k.a. isonitriles, are compounds with an
extraordinary functional group. They constitute one of the few classes of organic
compounds with a divalent carbon and their chemical reactions correspond to
conversions of the divalent carbon atom C
II
into the tetravalent C
IV
. The synthetically
most important property of the isocyanides derives directly from the bonding profile
between the nitrogen and the carbon atoms.
6
This is their ability to react with both
nucleophiles (through their π* orbital) and electrophiles (through their π orbital) at
the same position, the carbon atom leading to the so called, α-adduct. The
isocyanide chemistry began in 1859 when the synthesis of the first such compound,
allyl isocyanide 1.18 from allyl iodide and silver cyanide was reported (Scheme
1.5).
26

I
AgCN +
N
C
1.18 1.16 1.17

Scheme 1.5: The synthesis of allyl isocyanide (Lieke, 1859)

8
The classical syntheses of isocyanides were developed in 1867 by Gautier
(AgCN method)
27
and Hoffman.
28
However, their wide synthetic utilization in
chemistry was explored after the most general method for preparation of isocyanides
by dehydration of formylamines 1.19 emerged in 1958
29
(Scheme 1.6). This method
contributed significantly in enriching the availability of isocyanides
30
something that
eventually lead to the development of the “Isocyanide-based MCRs” (IMCRs) which
constitute the most important and versatile class of MCRs.

POCl
3
, py
R
N
C R
N O
H
t-BuOK
1.19 1.20

Scheme 1.6: General synthesis of isocyanides by dehydration of formylamines (Ugi, 1958)

The first IMCR, introduced by Passerini in 1921
31
was developed shortly
after the reactivity of isocyanides was recognized. The Passerini condensation is a
three component reaction between a carboxylic acid 1.22, a carbonyl compound 1.21
and an isocyanide 1.20 that yields α-acyloxycarboxamide scaffolds 1.23 in one pot.
R
4
N
C R
1
R
2
R
3
OH
O O
++ R
3
O
N
R
4
O
R
1
R
2
O
H
1.23 1.20 1.21 1.22

Scheme 1.7: The classic Passerini reaction (Passerini. 1921)

A plausible mechanism has been proposed, based on the experimental data
obtained and on the mechanistic studies performed. It concerns the formation of a
loosely hydrogen-bonded adduct 1.24 from the acid (1.22) and the carbonyl (1.21)
9
component, thus activating both components which subsequently react with the
isocyanide 1.20 to form α-adduct 1.26. The α adduct which is unstable and cannot be
isolated, rearranges in an intramolecular transacylation to the stable α-
acyloxycarboxamide 1.23 (Scheme 1.8).

R
4
N
C
R
1
R
2 R
3
O
O
+
O
O
H
R
1
R
2
R
3
OH
O
C
R
3
O
O
O
H
R
1
N
R
4
R
2
O
O
H O
N
R
4
R
3
R
1
R
2
R
4
N
O R
3
O
R
2
R
1 H O
1.22 1.21 1.24
1.20
1.26
"a-adduct"
1.23
1.25

Scheme 1.8: Suggested mechanism of the Passerini reaction.

The scope and limitations of the Passerini reaction were explored
32
and
revealed the attractive features of that process which include mild and neutral
reaction conditions, temperatures below or at room temperature, high concentrations
thus minimizing the volume of solvents. The reaction is very general and allows
almost all the possible combinations of starting materials to transform to the
corresponding product. The use of α, β unsaturated ketones as well as extreme cases
of steric hindrance present in the starting materials were only shown to be limiting
10
the scope of the reaction.
8
The α-acyloxycarboxamide scaffold is a frequent motif in
many natural products as well as in pharmacologically active depsipeptides thus
making the Passerini reaction a particularly valuable method by which highly diverse
libraries of these compounds can be constructed fast and screened for biological
activity. Multiple variations of the Passerini reaction have been investigated yielding
a plethora of scaffolds by altering the starting materials or by using bifunctionalized
components that eventually undergo tandem reactions in the course of the reaction
thus resulting in structures with significant complexity in some cases.
8

Even though the Passerini reaction was the first IMCR discovered, an actual
revolution in chemistry, the investigation of the scope of the reaction was delayed
due to the very limited availability of the starting isocyanides and the lack of
synthetic methodologies towards them at that time.
The next highlight in the historical progress of MCRs was the Bucherer-
Bergs reaction (Scheme 1.9), a very efficient method to prepare hydantoins 1.29
which was discovered in 1934.
33-34

R
1
R
2
O
+
KCN (NH
4
)
2
CO
3
+
H
N
NH
O O
R
1
R
2
1.29 1.21 1.27 1.28

Scheme 1.9: Synthesis of hydantoins by the Bucherer-Bergs reaction

This was the first actual four- component process that appeared in the
literature and concerned the condensation between a carbonyl compound, hydrogen
11
cyanide, carbon dioxide and ammonia.
35
In practical terms the reaction is performed
by the use of (NH
4
)
2
CO
3
and KCN (besides the oxo component) which in the course
of the reaction generate in situ the CO
2
and NH
3
units that eventually get
incorporated in the hydantoin skeleton.
In 1938 the first metal catalyzed MCR was discovered by Otto Roelen, the
hydroformylation reaction.
36
In this process an olefin, carbon monoxide and
hydrogen react in the presence of a cobalt catalyst (Co
2
(CO)
a
) to form an aldehyde.
The interest for this reaction is still active and continuous efforts are being made for
optimizing different features by altering the catalyst (rhodium catalysts are also used)
and the reaction conditions.
37
Hydroformylation is one of the most important
industrial processes for the conversion of alkenes to aldehydes and subsequently to
alcohols carboxylic acids as well as a large number of widely used chemicals
(plasticizers, detergents, surfactants as well as chemical intermediates). Interestingly,
more than seven million tons of aldehydes are produced annually by this method
while the hydroformylation of propene provides 75% of the oxo chemicals consumed
in the world.
38

Another metal catalyzed MCR was discovered in 1939 by Reppe,
39-40
the
carbonylation of olefins and acetylenes which also became an important industrial
process. The reaction concerns the addition of CO in olefins and acetylenes in protic
media which eventually leads to carboxylic acid derivatives.
41
It is catalyzed by a
nickel carbonyl catalyst and is used in industry for the bulk production of carboxylic
12
acids.
42
Fifty thousands tons of propionic acid are annually produced by
carbonylation of ethylene while the bulk production of acrylic acid is also based on
that technology.
In 1956 a multicomponent process towards thiazoline scaffolds 1.32 was
introduced by Asinger.
43
Two versions of the reaction have been explored. The first
one is a three-component condensation between an oxo compound, sulfur and
ammonia while the second involves four-components,
44
an oxo compound, an α-halo
oxo compound, sodium hydrogen sulfide and ammonia (Scheme 1.10).
R
1
R
2
O
+
+
NaSH R
3
O
X
R
5
R
4
+ NH
3
S N
R
3
R
5
R
4
R
1
R
2
1.32 X: Halogen 1.21 1.30 1.31 1.2

Scheme 1.10: Synthesis of thiazolines by the Asinger reaction

A major milestone in the field of MCRs was set by Ugi in 1959 by
introducing his four component process.
45
The Ugi reaction came along with his
development of the most general methods for synthesizing isocyanides.
29, 46
In the
Ugi reaction a carbonyl component, an amine, a carboxylic acid and an isocyanide
are combined to form α-acylamido amides 1.34 (Scheme 1.11).
R
4
N
C
R
1
R
2
R
3
OH
O O
++ R
3
N
N
R
4
O
R
1
R
2
O
H
1.34
+ R
5
NH
2
R
5
1.21 1.22 1.20 1.33

Scheme 1.11: The Ugi four component reaction
13

The Ugi reaction is conceptually similar to the Passerini reaction but the
introduction of the fourth component (the amine) adds one more point of diversity
thus making the method by far the most versatile IMCR, something that translates to
a higher number of possible scaffolds that can potentially be synthesized. The
suggested mechanism
47
for the Ugi condensation concerns the formation of an imine
between the amine and the carbonyl component which in the presence of the
carboxylic acid and the isocyanide reacts in a similar fashion as the carbonyl
component in the Passerini reaction, yielding the corresponding α-adduct which then
undergoes a Mumm rearrangement, yielding the final Ugi-type product. The scope of
the Ugi reaction has been explored extensively and it has been shown that all the
possible combinations of starting materials lead to the corresponding product, even
in cases where significant steric hindrance is present. The only limitation in the use
of the acid component being, the ability of the latter to undergo the irreversible
rearrangement that gives the α-acylamido amide scaffold. The skeletons of the
products are determined by their amine and acids components. Twelve types of
carboxylic acid derivatives and four types of amines can be combined to give all the
different types of Ugi products
9
(Scheme 1.12). Also, the use of appropriately
designed bifunctional components can lead to cyclic structures through
intramolecular condensation. Furthermore, the panel of the Ugi-derived products can
be enriched even more by the latest advances in the field which include the
14
combination of different MCRs in synthesizing even more complex molecular
scaffolds (the union concept) as well as various post-MCRs modifications.
3

R
1
N
N
R
6
R
3
R
4
O
R
5
1.35
"Carbonamides"
R
2
R
1
N
N
R
6
R
3
R
4
S
R
5
R
2
1.36
"Thiocarbonamides"
1.37
"Selenoamides"
R
1
N
N
R
6
R
3
R
4
Se
R
5
R
2
R
1
N
N
R
6
R
3
R
4
R
5
R
2
N
R
7
1.38
"Amidines"
N
N
N
N
R
5
N
R
1
R
3
R
4
R
2
1.39
"Tetrazoles"
N
N
R
1
R
3
R
4
X R
5
N
R
7
1.40, X=O "Hydantoine imides"
1.41, X=S "Thiohydantoine imides"
1.42, X=NR8 "Iminoimides"
N
N
R
5
R
2
R
3
O
R
4
OH
R
1
O
1.43
"Hydroxylamino
carbonamides"
N
N
R
5
R
2
R
3
O
R
4
N
R
1
O
R
7
R
6
1.44
"Hydrazine carbonamides"
N
N
R
5
R
2
R
3
O
R
4
R
1
O
R
6
R
1
N
N
R
3
R
4
O
R
5
R
2
R
6
O
1.45
"Acylamides"
1.46
"Diacylamides"

Scheme 1.12: The basic types of the U-4CR scaffolds

The synthesis of polysubstituted thiophenes 1.49 was reported in 1961 by
Gewald
48
from the reaction between a carbonyl compound (aldehydes, ketones or 1,
3 dicarbonyls) with activated nitriles and elemental sulfur in the presence of an
amine base (Scheme 1.13).
49

R
1
R
2
O
R
3
CN
S
8 ++
NEt
3
S
NH
2
R
3
R
2
R
1
1.49 1.48 1.47 1.13

Scheme 1.13: The Gewald reaction
15
One more “name reaction” that belongs among the most well known MCRs
is the Pauson-Khand, which was developed in 1971.
50
The transformation yields
substituted cyclopentanones 1.53 and involves the [2+2+1] cycloaddition reaction
between an alkene, an alkyne and carbon monoxide, in the presence of Co
2
(CO)
8
catalyst (Scheme 1.14). It has formed a wide synthetic application in synthesizing
prostaglandin analogues.
51

++
Co
2
(CO)
8
O
L
S
R
S L
R
CO
1.53 1.50 1.51 1.52

Scheme 1.14: The Pauson-Khand reaction

1.3 The latest advances. Miscellaneous MCRs.
Since the potential of MCRs was realized by the abovementioned historical
development and by the numerous synthetic applications, a plethora of new and
conceptually different reactions were introduced in the literature. To this, major role
played the great advances in catalysis and realizing the role of metals in activating
various organic compounds through different modes of complexation. The field of
developing new MCRs is continuously growing to different directions, based on
various conceptual approaches to the extent that no classification and comprehensive
review is possible for the purpose of this introduction.
16
Even though there is no way to group the latest advances in the field, the very
general term of “metal catalyzed MCRs” can includes all those MCRs for which the
presence of a metal catalyst is essential. Among transition metals, palladium
52
and to
a lesser extend nickel
53
and copper(I) have become very popular for their ability to
catalyze many cascade processes under mild conditions and often with high degree
of chemo-, regio- and stereoselectivities. Representative examples from the recent
literature
54
that involve the use of palladium catalysts in various MCRs are included
in Table 1.1.
The first three entries in Table 1.1 represent domino processes by which
polysubstituted tetrahydrofurans
55
1.57, pyrroles
56
1.61 and α-aminoacid-derived
imidazolines
57
1.62 are obtained respectively. Entry 1 is a Michael-carbopalladation-
cyclization process while entry 2 involves a 1, 3 dipolar cycloaddition-
decarboxylation sequence of the alkyne component to the münchone intermediate
obtained under the reaction conditions. Entry 3 involves münchone intermediates as
well. The presence of CO is essential for those last two reactions even though the
“CO unit” in not necessarily retained at the products (entry 2).
Entry 4 involves a Pd catalyzed four-component coupling between an alkyne
an aryl iodide a hydrazine and carbon monoxide to yield polysubstituted pyrrazoles
58

1.65. The presence of Pd catalyst was proven essential for that MCR which probably
involves a carbonylative Sonogashira coupling followed by the construction of the
heterocyclic core, even though the mechanistic aspects have not been clarified.
17
In entry 5 homopropargylic alcohols 1.68 are synthesized by a Pd catalyzed
three-component reaction between allenes, boronic acids and aldehydes.
59
Boron to
palladium transmetallation followed by the allene insertion leads to the in situ
formation of a reactive allyl palladium species which then reacts with the aldehyde
component and forms the product.
Entries 6 and 7 represent MCRs where a Sonogashira coupling product is
intercepted by an additional component and participates in a tandem process towards
versatile and structurally more complicated scaffolds. Entry 6 represents the MCRs
where interception of the expected Sonogashira product by a domino process
occurs
60
while the product in entry 7 originates from an alternative route where the
Sonogashira product undergoes an isomerization before reacting further.
61
The route
under which every process operates is a consequence of the structural features of the
components used.
Entry 8 is an impressive example of a palladium catalyzed MCR between
aryl iodides, isolated dienes and various nucleophiles such as amines
62
(entry 8) and
carbon nucleophiles. It concerns the formation of an organopalladium intermediate
that undergoes consecutive migrations through hydride eliminations along the carbon
chain to finally give the substitution pattern of 1.77. Remarkably, the indicated
product is selectively obtained even when significantly long carbon chains separate
the two alkene units (up to 10 carbon atoms).

18
Table 1.1: Examples of palladium catalyzed MCRs
Entry Multicomponent transformation
HO
R
2
R
1
CO
2
Et EtO
2
C
R
3
Pd
0
cat.
base
O
R
1
R
2
Ar
CO
2
Et
CO
2
Et
R
3
ArI
+ +
N
R
2
R
1
R
3
R
4
R
5
Cl
O
N
R
1
R
2
R
3
R
4
R
5
Pd
O
N
Cl
R
5
R
1
R
2
(5%)
L
2
CO, EtN
i
Pr
2
+ +
N
R
2
R
1
R
3
Cl
O
NNH
R
3
R
2
R
2
R
1
+ +
CO
5% Pd
2
(dba)
3
10% L
CH
3
CN
2
CO
2
Ph
+ +
1% PdCl
2
(PPh
3
)
2
R
1
H
N
NH
2
ArI
N
N
R
1
Ar
Ph
CO
X
+ +
5% Pd(II)
5% [HPPh(t-Bu)
2
]BF
4

CsF, THF, RT, 24hr
R
1
•
R
2
H
O
X
B(OH)
2
R
2
R
1
OH
R
1
+ +
I
X'H
Ph R
2
-X
Pd(PPh
3
)
2
Cl
2
2eq. MeMgCl
R
1
X'
Ph
R
2
0-95
o
C, 5-21 hr
EWG
+ +
2% Pd(PPh
3
)
2
Cl
2
1% CuI, Et
3
N, THF,
reflux, 64 hr
Ar
2
NH
2
NH
2
Cl
I
Ar
1
OH
NN
Ar
2
Ar
1
EWG
n
Ar-I R
1
R
2
NH
+ +
5% Pd(dba)
2
2 eq. n-Bu
4
NCl,
DMF, 100
o
C, 24hr
Ar
n-1
N
R
1
R
2
1
2
3
4
5
6
7
8
R
1
H
O
+ +
0.25% PdBr
2
35% LiBr, NMP,
1% H
2
SO
4
, 120
o
C,
12hr
R
2
N
H
R
3
O
9 CO
R
2
N R
3
O
COOH R
1
1.57 1.54 1.55 1.56
1.58 1.50 1.59
1.60
1.61
1.58 1.59 1.52 1.62
1.56 1.63 1.64 1.65
1.66 1.67 1.6 1.68
1.69 1.63 1.70 1.71
1.72 1.73 1.74 1.75
1.76 1.56 1.13 1.77
1.6 1.78 1.52 1.79

19
The last entry of table 1.1 involves a palladium catalyzed MCR towards the
synthesis of unnatural α-amino acids 1.79.
63
The presence of 0.25% PdBr
2
and 1%
H
2
SO
4
constitutes a very efficient catalytic system that yields the corresponding α-
amino acids in very satisfactory yields. Extension of the methodology to urea
components results in the formation of hydantoins where enzymatic kinetic
resolution of the racemic products gives access to the corresponding optically pure
scaffolds.
Nickel complexation with unsaturated systems has been widely used in
designing new MCRs.
53
Entries 1 and 2 in Table 1.2 represent such processes.
Complexation of Ni
0
with alkynes and aldehydes
64
(entry 1) or enones
65
(entry 2) in
the presence of an organometallic reagent promotes alkylating coupling among the
three components yielding the corresponding scaffolds 1.82 and 1.85. Based on the
same principals is entry 3 where Ni(0) complexes with allenes and aldehydes and in
the presence of a silane the reductive coupling product 1.89 is formed.
66
If
dialkyzincs are used instead of silanes, the alkylative coupling product is obtained.
The ability of allenes to insert to a M-C bonds has also been used in designing MCR
sequences such as entry 4 in which the initial oxidative addition of the aryl iodide to
the Ni(0) catalyst and the subsequent allene insertion in the presence of
organometallic reagents leads to the corresponding diene coupling products 1.92.
67

20
Table 1.2: Examples of nickel and copper catalyzed MCRs.
Entry Multicomponent transformation

O
R
1
R
2 + +
(R
3
)
2
Zn
R
1
R
2
OH R
3
10% Ni(COD)
2
R
2
R
3
R
1
O
R
4 + +
BuLi/ZnCl
2
5% Ni(COD)
2

10% PPh
3
R
2
R
3
O
R
1
R
4
Bu
H
•
H
R
1
R
2
+ +
R
3
SiH
20% Ni(COD)
2

40% L
Ar
O
-78
o
C-RT, 6hr
R
1
Ar
R
2
OSiR
3
R
1
•
+ +
2.5% NiCl
2
(PPh
3
)
2

1.4 eq. Zn
THF, 50
o
C, 24hr
R
3
-I
R
2
ZrCp
2
Cl
R
1
R
2
R
3
N
R
2
R
1
R
3
R
4
Cl
O
+ +
10% CuI
EtN
i
Pr
2
R
2
N
R
1
R
4
O
R
3
CH
3
CN, RT, 15min
R
2 + +
10% CuI
SO
2
R
1
N
3 R
2
H
N
R
3
R
2
R
3
NSO
2
R
1
R
2
THF, 0
o
C, 1hr
THF, 0
o
C, 1hr
THF, RT, 1-2hr
1
2
3
4
5
6
1.82
1.85
1.92
1.93
1.95
1.6 1.80 1.81
1.83 1.80 1.84
1.86 1.87 1.88 1.89
1.67 1.90 1.91
1.58 1.80 1.59
1.94 1.80 1.13

The ability of Cu(I) to complex with alkynes and activate them is the basis
for the development of Cu(I) catalyzed MCRs. Entries 5 and 6 represent such MCRs.
In entry 5 the in situ formed copper acetyllide attacks the N-acyliminium salt
yielding the propargylamide product 1.93.
68
Further manipulation of those scaffolds
with NaH gives the corresponding oxazoles. Entry 6 is a wide scope MCR for
21
synthesizing amidines 1.95 in which tosyl azide was shown to react with alkynes in a
totally different way compared to the corresponding alkyl azides.
69

Besides using copper as a catalyst, copper organometallics have also been
employed in MCRs and an example is depicted in Scheme 1.15. In this example, a
MCR between dialkylcuprates, α,β unsaturated compounds and various imines yields
cis and trans β-Lactams 1.99 in a totally stereocontrolled manner determined by the
imine component.
70
The method also gives excellent enantioselectivity when chiral
auxiliaries are incorporated on the Michael acceptor.
R
1
O
X
(R
2
)
2
CuLi
COOR
4
N
R
3
++
THF
0
o
C, 3hr
N
O R
3
COOR
4
R
1
R
2
1.99 1.96 1.97 1.98

Scheme 1.15: Highly stereocontrolled synthesis of β-Lactams by an MCR

The use of a bimetallic Pd(II)/Cu(II) catalytic system is also a continuously
evolving direction in the field of MCRs. In this specific example
71
(Scheme 1.16),
the domino process yields isochromene derivatives 1.102. The presence of both
metals was necessary for that transformation but also the structure of the starting
material was of significant importance. The process involves a palladium catalyzed
Sakurai reaction followed by an intramolecular attack to the Cu(II) coordinated
alkyne. In this example, even though the basic concepts on which the construction of
the isochromene skeleton is based have been demonstrated in other metal promoted
MCRs, the complementary role of Pd(II) and Cu(II) in selectively activating the
22
different functional groups is a remarkable example of the control in reactivity
tuning that can be obtained by using metal catalysts.

+
Toluene, RT, 14hr
R
1
O
SiMe
3
5% Pd(OAc)
2
, 20% L
0.5-1.2 eq. CuI
O
R
1
1.102 1.100 1.101

Scheme 1.16: Synthesis of isochromenes by a bimetallic Pd(II)-Cu(II) catalyzed MCR
Bimetallic catalytic systems have also been employed in domino process that
incorporate the ring closing metathesis (RCM) reaction for construction of various
carbocycles. One representative example is depicted in Scheme 1.17.
72

+
N
N
10% Pd(OAc)
2
,
20% PPh
3

2eq. K
2
CO
3
O
O
I
• +
NHSO
2
Ph
N
N
O
O
N
PhO
2
S
5% Grubbs 2
nd

generation cat.
Toluene, 80
o
C, 18hr 1.106 1.103 1.104 1.105

Scheme 1.17: The use of bimetallic Pd-Ru catalytic system in a MCR

A very novel approach towards aryl boronates 1.109 by Ru(II) catalyzed
intermolecular cyclotrimerization of alkynyl boronates, propargyl alcohol derivatives
and a third alkyne is depicted in Scheme 1.18.
73
The design of the process eliminates
the problems related to low chemo- and regioselectivity which is the common
problem that accompanies the intermolecular cyclotrimerization of alkynes. That is
accomplished by using a temporary boron tether between the alkynyl boronate and
23
the propargylic alcohol component. Tandem Suzuki coupling of the resulting
boronates yields diaryl components in the same pot.

+ + R
1
B
PrOi
PrOi
HO
R
2
5% Cp*RuCl(cod)
DCE, RT, 24hr
B
O
PrOi
R
1
R
2
1.109 1.107 1.108 1.80

Scheme 1.18: A Ru(II) catalyzed three-component reaction approach towards aryl boronates.

Another general term under which many MCRs can be classified is the
cycloaddition-based MCRs and those usually employ domino processes one of
which is a classical annulation reaction
74
such as Diels-Alder reaction, 1,3 dipolar
cycloadditionts etc.. Some representative examples whose main purpose is to
demonstrate the various general principles, on which the philosophy of those MCRs
was based, are depicted in Table 1.3. Entry 1 is a Knoevenagel-Diels Alder (inverse
electron demand) sequence which is known as the Tietze MCR
75
and has been used
extensively in constructing various scaffolds. The Tietze reaction involves the initial
formation of a 1-oxo-1,3-butadiene unit by condensation of a dicarbonyl compound
and an aldehyde which in the presence of a dienophile such as various vinyl ethers
undergoes Diels Alder reaction towards oxygen containing heterocycles 1.112. Entry
2 involves an inverse-electron-demand Diels-Alder cycloaddition following the
formation of aniline-derived imines. It is also known as the Grieco 3-CR
76
and
constitutes a fast assembly of substituted tetrahydroquinolines 1.115. Entry 3
represents another domino process
77
where appropriately designed components
24
participate in an aza Diels- Alder-allylation sequence yielding polysubstituted
piperidines 1.118. Also typical Diels Alder cycloadditions can occur in assembling
scaffolds containing both the diene and alkene moieties. Such an example is depicted
in entry 4 where the quinolinic nitrogen gets activated after reaction with acryloyl
chloride and the subsequent iminium salt undergoes a vinylogous allylation.
78
The
coexistence of both alkene and diene in the same molecule and in favorable positions
yields the Diels Alder adduct 1.122 simultaneously and in very good yields. Entry 5
is a three-component process that involves the condensation of two equivalent of
aldehyde with an amide in the presense of an acid catalyst (p-TSA) to form a 1-
acylamino-1, 3 diene which undergoes a subsequent Diels Alder reaction when a
dienophile is present in the same pot, yielding highly substituted cyclohexene 1.124
and cyclohexadiene derivatives.
79

Another type of cycloaddition that has been engaged in a MCR process is the
1, 3 dipolar cycloaddition.
74
The formation of 1, 3 dipoles from the reaction of
glycine with formaldehyde, has been widely used in designing MCR processes that
are relayed with this type of cycloaddition. The resulting 1, 3 dipoles are intercepted
by various dipolarophiles to give a number of highly functionalized scaffolds
1.127.
80
Entry 7 is a somewhat unusual 1, 3 dipolar cycloaddition-relayed MCR. The
addition of isocyanides to activated alkynes leads to the 1, 3 dipolar intermediate
which successfully reacts with aryl aldehydes (example shown), formaldehyde and
quinones
81
to yield substituted furans 1.131 (when aldehydes are used) and
25
iminolactones (for quinones). Also aziridination of olefins, a formal [2+1]
cycloaddition has been utilized in a multicomponent version (entry 8, Table 1.3).
82

Table 1.3: Cycloaddition relayed MCRs.
Entry Multicomponent transformation

+
+
(CH
2
NH
3
+
)
2
(AcO
-
)
2
CH
3
CN, Q
R
1
H
O
1
OO
O O
R
2
OR
3
2
3
4
5
O O
O
R
1
R
2
R
3
O
O
NH
2.
TFA
X
O
+ +
CH
3
CN
RT, 3hr
H
N
H
H
N
NR
1
R
2
B
O O
+ +N R
3
O
O
R
4
O
Toluene
80
o
C, 72hr
N
N
O
O
R
3
NR
1
R
2
R
4
OH
N
N
H
H
O
H
R
1
+ +
Cl
O
SnBu
3
R
1
DCM
0
o
C-RT, 2hr
NMR, (CH
3
CO)
2
O
1.5% p-TSA
80-120
o
C
20-90hr
R
1
O
+ +
NH
2
R
2
O
2
N
O
O
R
3
N R
3
O
O
R
1
COHN
R
2
R
2
6
7
8
O
H
N Ph
Benzene
∆, mol.sieves
+ +
HCHO
Z
Z
O
O
O
N
Ph
O
H
O
Z
Z
O
CHO
NO
2
MeOOC COOMe + +
N C
Cy
Benzene
80
o
C, 3 hr
O
CyHN
MeOOC COOMe
NO
2
Ar
R
1
R
2
Pyridine N-oxide
Pyridine
DCM, 3hr
0
o
C-RT
+ +MnN
O
O N
N
Ts
2
O
N
Ts R
2
R
1
Ts
O
1.6 1.110 1.111 1.112
1.113
1.1 1.114
1.115
1.116 1.117 1.6 1.118
1.119 1.120 1.121 1.122
1.123 1.6 1.117 1.124
O
1.127
1.131
1.135
1.125 1.14 1.126
1.128 1.129 1.130
1.132 1.133 1.134

26

But besides the cycloaddition-relayed MCRs, various MC-stepwise
annulations have been reported in the literature.
83
One of the most famous examples
in the history of organic chemistry is that of tropinone’s 1.139 construction
developed by Robinson in 1917
84
(Scheme 1.19).

This consists of a double Mannich
reaction, the first being intermolecular followed by a second, intramolecular one.

+ + O
O
-
O O
-
O O O
Ca
2+
CH
3
NH
2
1. H
2
O, RT, 50hr
2. HCl
N
O
1.139 1.136 1.137 1.138

Scheme 1.19: Robinson’s synthesis of tropinone by a double Mannich reaction

In most cases, these sequential annulative MCRs are conceptually based on
1,4 Michael additions relayed to various cyclization transformations. Representative
examples are included in Table 1.4. Entry 1 is a five-membered ring construction.
The methodology involves a Michael addition of a nucleophile stabilized by groups
which can later serve as leaving groups, followed by a 2
nd
Michael addition and a
irreversible 1,3 cyclization.
83
Entries 2, 3 and 4 involve sequential cyclization
approaches to six-membered rings. Entry 2 yields substituted pyridines 1.147
through a one-pot three-bond forming annulation of N,N dimethylhydrazone anions,
α,β-unsaturated ketones and acyl cyanides.
85
The elementary reactions involve a
Michael addition, a Claisen condensation and a 1,6 carbonyl addition. Entry 3 is a
representative case of a three component Michael-Michael-1,6 Wittig sequence.
86
In
27
these transformations the reaction conditions play crucial role for the outcome since
the first Michael addition should be complete before the second one.
The intellectual as well as practical challenge of designing an efficient 4C
sequential annulative MCR composed by three different 1,4 Michael additions has
been addressed in a number of literature reports.
83
Careful selection of the reaction
conditions and the starting materials can result in the development of selective
routes, free of the various byproducts that can results from side, undesirable
competitive reactions. Such examples are depicted in entries 4 and 5 in Table 1.4.
Entry 4 is a Michael- Michael- Michael-1,6 Aldol sequence between LiSnBu
3
, two
different α,β-unsaturated ketones and one α,β-unsaturated ester.
87
Entry 5 represents
a general process of a one-pot, four-bond formation via a consecutive ketene
addition, Wittig, Diels-Alder sequence. The extraordinary selectivity of the process
relies on the easily accessible ketenylidene triphenylphosphorane. As a consequence,
all four components are mixed together at the start of the reaction since its
component reacts only after its partner has been formed in the course of the reaction
sequence.
88
Entry 6 is a domino process that involves a Michael addition of the
dicarbonyl compound to the enone followed by reaction of the in situ formed adduct
with a functionalized aliphatic amine yielding polyheterocyclic scaffolds 1.160 or
spirocyclic skeletons when the corresponding anilines are employed as starting
materials.
89

28
Table 1.4: Examples of sequential-annulations MCRs
Entry Multicomponent transformation

+ +
1
2
3
4
5
+ +
+
+
+ +
6
+ +
O
PPh
3
Br
PhS SPh
SPh
THF
-70
o
C, 44 hr
O
SPh
PhS
PPh
2
O
R
1
N
N
R
2
CN
O
O
R
4
R
3
N
R
3
O
R
4
R
2
R
1
THF
1.-78
o
C- RT, 23 hr
2. AcOH, reflux, 4hr
O
-
R
1
O
1. THF, -78
o
C, 3 hr
2. Et
3
B, -78
o
C, 1 hr
3. DMF/
PPh
3
Br
O
R
1
O
LiSnBu
3
O
R
1
1.
COOMe
2.
THF, -70
o
C, 20 hr
O
O
HO
R
1
O
SnBu
3
CC O Ph
2
P R
1
-OH R
2
-CHO
+
COOR
1
R
2
Toluene
120
o
C, 24 hr
N
Bn
O
COOEt
O
R
1
R
2
NH
2
XH
N
Bn
N
COOEt
X
THF, 4 Å MS
R
1
R
2
RT, 24 hr
1.143
1.147
1.150
1.153
1.156
1.160
1.140 1.141 1.142
1.144 1.145 1.146
1.148 1.149
1.140 1.151 1.152
1.149
1.154 1.155 1.114 1.6
1.157 1.158 1.159

The class of organocatalytic MCRs where an organic compound catalyzes the
process is one more direction that has been evolving. Some representative examples
are included in Table 1.5. Entry 1 is a particular example where the catalytic use of a
good nucleophile initiates a cascade reaction where two units of the starting material
are incorporated into the final product 1.162 in a chemo-differentiating fashion.
90

29
The concept of organocatalysis has been applied to a variety of domino processes
such as Aldol/ Knoevenagel/Diels Alder sequences due to the appealing
characteristics of high yield, excellent diastereoselectivity as well as the ability for
asymmetric synthesis with use of readily available chiral α-aminoacids as chiral
catalysts. Also it has been combined with metal catalysis to yield even more
complicated structures. An impressive example of the latter approach is shown in
entry 2 where a proline catalyzed MCR (a Wittig/Knoevenagel/Diels Alder
sequence) is followed by a Cu
I
catalyzed Huisgen cycloaddition to yield a single
diastereomer of ditriazole 1.165 in one pot and in 94% yield.
91
Highly functionalized
oxazolidinones 1.170 in enantiomerically pure form have been synthesized by an
organocatalytic MCR sequence including the coupling of α,β unsaturated aldehydes
with thiols and azodicarboxylates.
92
Thiazolium salts in combination with organic
bases have also been successfully employed in organocatalytic MCRs and very
general synthetic methodologies towards polysubstituted pyrroles 1.174
93
and
imidazoles 1.176
94
have been developed. Amino and diaminosubstituted 1, 3
thiazoles 1.180 have been efficiently obtained by a DBU promoted three-component
reaction between an amidine hydrochloride, an isothiocyanate and an α bromo
ketone.
95
The use of simple organic bases in promoting MCRs sequences has found
numerous applications in constructing various libraries of heterocycles
53
and most of
them involve the initial formation of an imine intermediate which eventually gets
attacked inter- or intramolecularly by different types of nucleophiles (nitrogen or
30
sulfur in most cases). The resulting nucleophilic amine reacts with various
electrophilic components or participates in intramolecular coupling reactions thus
yielding a plethora of heterocyclic scaffolds.
Table 1.5: Organocatalytic MCRs
Entry Multicomponent transformation

+
1
2
3
4
5
+ +
+ +
+
6
+ +
DABCO
0
o
C
20% L-Pro, EtOH
65
o
C, 3-12 hr
BnN
3
, CuSO
4
, Cu
RT, 15-48 hr
N
S
Br
HO(CH
2
)
2
20%
30% DBU
R
5
NH2, p-TSA
N
S
Br
HO(CH
2
)
2
5-20%
Et
3
N, 35-60
o
C,
R
4
NH
2
24 hr
DBU, DMF
0
o
C- RT
EWG
2
R
1
R
2
O
O
EWG
R
1
R
2
EWG
PPh
3
O
Ar
O
2
NN
O
O O
N N
O
O O
O
O
O
N
N
N
N
N
N
Bn
Bn
N
H
Ph
OTMS
Ph
10%
Toluene, -15
o
C, 30 min,
NaBH
4
, NaOH, aq., 24 hr
R
1
O
R
2
SH
N
N
COOR
ROOC
NO
O
H
N
ROOH
2
C
S
R
1
R
2
R
1
SiX
3
O
R
2
R
4
O
R
3
N
R
5
R
1
R
2
R
3
R
4
+
R
1
O
R
2
N
H
R
3
O SO
2
Tol
N
N
R
4
R
1
R
2
R
3
R
1
NH
2
NH
2
Cl
R
2
NCS
R
3
Br
O
N
S
R
NHR
2
R
3
O
R
1
: Ar or BnS R: Ar when R
1
: Ar
R: NH
2
when R
1
: BnS
1.162
1.165
1.170
1.174
1.176
1.180
1.161 1.21
1.163 1.87
1.164
1.166 1.167 1.168
1.169
1.171 1.172
1.173
1.6 1.175
1.173
1.177 1.178 1.179

Brønsted and Lewis acid-catalyzed processes also play an important role in
MCR-based synthesis of heterocycles. The classical strong acids that have been
31
widely used are: H
2
SO
4
, HCl, TiCl
4
and BF
3
:OEt
2
. Entry 1 in Table 1.6 is a HCl-
catalyzed three-component approach to triazines 1.183, by which a library of 37
analogs was constructed.
96
Highly functionalized α-amino acid esters 1.187 carrying
substituted tetrahydrofuran and tetrahydropyran substituents with multiple chiral
centers were synthesized by a TiCl
4
promoted three-component process between
dihydrofurans, N-tosyl imino esters and silanes.
97
Entry 3 in Table 1.6 is a TMSOTf
catalyzed one-step synthesis of homoallylic ethers 1.89 directly from oxo compounds
by a three component methodology that employs TMS-protected ethers and
allylsilanes as partners.
98
This MCR process is closely related to the classic two-
component Sakurai reaction and as a consequence it’s officially cited as “The silyl
modified Sakurai reaction” (SMS reaction).
Even though the use of classical acids has been proven efficient in many
MCRs, the need for milder and thus more tolerant to functionality conditions lead to
the development of a new generation of acid catalysts. The use of rare earth metal
triflates is superior in many carbon-carbon bond forming reactions as well as Diels-
Alder cyclizations. Also they selectively activate aldimines for nucleophilic attacks
in the presence of aldehydes, thus making them the catalysts of choice for all those
MCRs that fall under the category of “aminoalkylation”. One more advantage is the
fact that no strict anhydrous conditions are needed since the catalysts are active in
the presence of water. Cis aziridines 1.192 originating from aliphatic aldehydes were
successfully synthesized by an MCR process for which the use of catalytic Yb(OTf)
3

32
proved critical.
99
β-Lactams 1.194, among other heterocycles, were also synthesized
more efficiently when the stoichiometric use of Lewis acid was replaced by a
catalytic 10% Yb(OTf)
3
.
100
In entry 6 the catalyst played a major role in the outcome
of the reaction between aldehydes, amines and dihydropyridines. Only the use of
Sc(OTf)
3
or In(OTf)
3
suppressed the competing reduction of the in situ formed
imines by the DHPs thus making the process feasible, which is a modified Grieco
reaction.
101

Table 1.6: Acid promoted MCRs
Entry Multicomponent transformation
+ +
1
2
3
4
5
+ +
+
+
6
+ +
+
+
+
NH
2
X
NH
NHR
1
NCHN R
2
R
3
O
N
N
N
NH
2
R
3
R
2
X
. HCl
HCl, EtOH
RT-80
o
C,
3-24 hr
O
EtO
NTs
O
Et
3
SiNu
TiCl
4
DCM
O
Nu
COOEt
TsHN
+
R
1
R
2
O
TMSOR
3
SiMe
3
10% TMSOTf
CCl
4
, RT
R
1
OR
3
R
1
RCHO Ph
2
CHNH
2
N
2
CHCOOEt
10% Yb(OTf)
3
Hexanes
MS 4A
0-RT, 12 hr
N
CHPh
2
COOEt R
R
1
NH
2
R
3
O
SPy
OTBDMS
H
R
2
10% Yb(OTf)
3
N
O R
1
R
3
R
2
CH
3
NO
2
, RT, 15hr
N
R
2
R
1
OEt
O
O
NH
2
10% Sc(OTf)
3
CH
3
CN
MS 4A
RT, 12 hr
N
NH
COOEt
R
2
R
1
1.183
1.187
1.189
1.192
1.194
1.198
1.181 1.21 1.182
1.184 1.185 1.186
1.21 1.101 1.188
1.6 1.190 1.191
1.33 1.193 1.6
1.195 1.196 1.197

33
1.4 MCRs in drug development and natural product synthesis
Drug development has traditionally been following an iterative cycle of
screening and synthesis involving the manipulation of individual structures. The
feedstock of this collection has accommodated a plethora of structures ranging from
natural products to various low molecular weight scaffolds that were proven active
towards specific biological targets such as proteins, enzymes, receptors etc. The
introduction of high-throughput biological screening which led to the acceleration of
identifying medicinally active targets has contributed to our understanding of the
molecular basis of many biological functions. It has also given us insight about ways
of approaching and regulating various biological functions by synthesizing artificial
molecules that can mimic the physiological function of their natural candidates. Due
to the technological advances in the field, there is a high demand for new and
selective molecules for biological testing and evaluation through fast, practical,
selective, atom economical and environmentally benign methods. MCRs constitute
one of the most valuable and powerful synthetic tools that conceptually satisfy many
of those requirements, even though optimization of the process and selectivity are
issues of significant importance. But definitely MCRs have been proven invaluable
in identifying medicinal candidates through construction of large and highly versatile
compound libraries that usually employ automated procedures applicable both in
solution as well as on solid phase.
34
The potential of applying MCRs for synthesizing medicinally active
molecules was realized in the mid 20
th
century when Nifedipine 1.201, a calcium
channel modulator was synthesized in one step by the Hantzsch reaction in a single
step (Scheme 1.20).
3

O
O O
2
NO
2
CHO
NH
3 ++
N
H
NO
2
EtO
2
C CO
2
Et
"Nifedipine" 1.201
1.199 1.200 1.2

Scheme 1.20: Synthesis of Nifepidine by Hantsch (1882)

Since then, a continuously increasing number of publications have been
demonstrating the role MCRs play in drug design and development. Among the
numerous examples of biologically active compounds synthesized by MCRs are:
enzyme inhibitors, receptor ligands, regulators of protein-protein interactions,
peptide nucleic acid mimics (DNA mimics), ion channel blockers, bioconjugates,
peptidomimetics. Also MCRs have been used for optimization of the process of
already marketed drugs. Characteristic examples are Crixivan (HIV protease
inhibitor), antibiotics of the azidomycin family, substance P inhibitors and various
anesthetics based on the Xylocain structure. A very strict and limited selection of
some of the most characteristic examples of drugs and drug candidates by MCRs are
depicted in Scheme 1.21.
35
Compound 1.202 is an antagonist of the a
1a
adrenoreceptor. The compound
was evaluated among other analogues and showed remarkable subtype selectivity for
a
1a
vs a
1b
and a
1d
(1500-fold), a consequence of the specific substitution pattern.
102

Compound 1.203 is a non-nucleosidic analogue with antiviral activity to Hepatitis B
virus (HBV), potential therapeutic for chronic HBV infection.
103
Compound 1.204 is
an Azinomycin analogue synthesized by the Passerini reaction in a combinatorial
fashion yielding potent analogues with comparable activity to that of the natural
product.
104
Scaffold 1.205, a common motif identified in numerous serine and
cysteine proteases inhibitors is obtained in one pot by the Passerini reaction followed
by an oxidation step.
105
Compound 1.206 is synthesized by a methodology that
involves a Passerini-Dieckman sequence. The scaffold obtained by this sequence
exhibits inhibitory activity towards HIV-1 protease while SAR studies revealed the
best candidates.
106
Compound 1.207 a.k.a. Xylocain is a local anesthetic synthesized
by the Ugi reaction and has been one of the mostly cited examples to demonstrate the
potential of MCRs in drug discovery and process.
107
Based on that methodology a
library of local anesthetics was constructed, many of which are marketed drugs.
Scaffold 1.208 was obtained by a tandem Ugi-PDC oxidation strategy,
108
similar to
the methodology towards scaffold 1.205. The ketoamide moiety is
pharmacologically active since it binds in the active site of cysteine proteases thus
nominating this type of compounds as potential inhibitors. Compound 1.209 belongs
to a family of inhibitors of the hematopoietic protein tyrosine phosphatase and the
36
synthetic strategy was based on an Ugi MCR performed on solid phase.
109

Compound 1.210 is the 18-iteration feedback of applying a genetic algorithm on an
Ugi-derived series of inhibitors of the serine protease thrombin. The method
combines the experimental information from the enzyme assays with an algorithm
that adopts genetic rules of evolution (replication, crossover and mutation). The
feedback is new proposed structures that could be more potent inhibitors than the
ones used in the initial assays.
110
The application of the Ugi reaction in synthesizing
Peptide Nucleic Acid (PNA) monomers is represented by scaffold 1.211 in Scheme
1.21.
111
The method is suitable for incorporation of all the four DNA bases and was
proven unique in yielding various PNAs with unprecedented substitution patterns.
The high generality of the Ugi MCR has made feasible the construction of novel
glycoconjugates. Compound 1.212 is a representative example of this literally
unrestricted class of compounds which can potentially play major role in the
development of lead pharmaceuticals that mediate and regulate cell communication
on membrane surfaces.
112
Compound 1.213 is an analog of the monocyclic β-lactam
family of antibiotics, structurally similar to the natural product Nocardicin A. A
library of 17 related compounds was constructed by the Ugi method.
113
Compound
1.214 was synthesized by applying the Gewald MCR
114
and among other analogues
it showed significant activity through selective allosteric enhancement of the A1
adenosine receptor (A
1
AR) which is known to be implicated in the propagation of
cardiac impulse. Compound 1.215, one of the most potent inhibitors of collagenase-1
37
(a matrix metalloprotease), was identified out of a library of analogues carrying the
thiol diketopiperazine scaffold. SAR studies revealed the substitution patterns with
very good selectivity for collagenase-1 versus collagenase-2.
115
Compound 1.216,
a.k.a. Crixivan is a marketed drug against HIV. It inhibits the HIV protease and this
is an example that demonstrates the role of MCRs in the development of short, more
efficient and less costly processes to drug manufacturing. In particular, the Ugi
reaction was proven invaluable synthetic tool that significantly shortened the
synthetic route yielding a key intermediate fast and efficiently.
116
Compound 1.217 is
an inhibitor of substance P (a neuropeptide isolated from brain cells). A chiral
advanced synthetic intermediate is obtained by a three-component coupling between
boronic acid, chiral amines and oxo compounds (introduced in Chapter 2). The
remarkable fact accompanying this preparation is the high diastereoselection of the
process achieved by a selective precipitation of the desired isomer out of the reaction
mixture.
117
That conveniently constituted the driving force towards the diastereomer
of interest.
38
N
H
N
F
F
N
H
N H
2
N
O
O O
Ph
COOMe
N
H
N
F
Cl
MeCO
2
N
F
F
O
H
N
O
O O
O
OH
C
5
H
13
PGHN N
H
R
2
R
1
O
O
N
H
O
O
O
HO
R
1
N
H
N
R
4
O
O
O
R
3
R
2
Ph
Ph
H
N
N
O
N
H
H
N
HOOC
O
O
Ph
S
H
N
N
O
O O
Ph
HN NH
2
O
OH
O
HO OH
N
OH
HO O
O
OH
OH
N
OH
HO
O
H
N
N
H
CO
2
Me
O
O
CO
2
Me
N
NHPG
HO
2
C
R
2
R
1
Base
O
N
O
N
N O
O
HS
NO
2
OMe
MeO
O
N
H
O
H
N
t-Bu
t-Bu
S
NH
2
O
H
N N
N
N
O N
H
OH
Ph
O
OH
N
O O
CF
3
CF
3
F
H
N
N
H
N
O
1.202 1.203 1.204
1.205
1.206
1.207 "Xylocain"
1.208
1.209 1.210 1.211
1.212
1.213
1.214 1.215
1.216 "Crixivan" 1.217
O
O
NO
2
COOCHPh
2
OH
OMe

Scheme 1.21: Examples of biologically active compounds synthesized by MCRs

Besides the construction of diversity-oriented molecular libraries by MCRs,
those processes have been used in the practice of target-oriented organic synthesis
towards various complex natural products with the first elegant approach of
39
tropinone by Robinson showing the way.
84
Since then, new MCR methodologies
have been developed towards specific families of natural products but also known
MCRs have been incorporated in linear approaches when a key intermediate can be
obtained by such a process. Structures of significant frame complexity, heavily
functionalized have been constructed. Only a few characteristic examples withdrawn
from the literature are mentioned here (Scheme 1.22), mainly due to the biological
importance and the unique molecular architecture of the target natural products.

O
HO
CO
2
H
HO
1.218 "PGE 1"
O
OH
O
OH
HO
H
OH
Cl
OH
O
O
O
H
O
AcO
OH
O
O
H
OMe
HO
O
OAc
1.219 "Spongistatin 1"
O O
OAc
C
10
H
21
1.220
N
H
N
MeO
2
C
OMe
H
1.221 "Hirsutine"
HN
N
N
H
H
N
OH
OH
NH
2
H
2
N
1.222 "(-)-Decarbamoylsaxitoxin"
N
H
N
NH
O CO
2
H
O
H
N
HN
O
O
CO
2
H
O
1.223 "Mutoporin" 1.224 "Ecteinascidin 743"
NH
O
O
S
O
O
Me
OAc
NMe
OMe
HO Me
MeO
HO
H
OH

Scheme 1.22: Examples of natural products synthesized by MCRs

40
For example, the Noyori three-component methodology has been the most
popular synthetic strategy to access trans-1-2-disubstituted cyclopentane systems. By
adopting this method a number of prostagladins were synthesized even in multigram
scale. PGE1 1.218 is a representative example.
118
Inspired by the molecular
architecture and the plethora of natural products carrying various spiro-ether
moieties a new MCR was designed to specifically yield the latter functionality. In
other words, in this case the synthetically challenging substructure of 1.219 urged the
development of a new MCR due to the advantages of MCRs over the linear, stepwise
approaches. In that, a lithiated dithiane reacts with two different epoxides in a three-
component process mediated by a solvent induced Brooks rearrangement. Based on
that approach, an advanced intermediate was constructed for synthesizing various
members of the Spongistatin family. This is a family of highly toxic marine natural
products and Spongistatin 1 1.219 is one of the members synthesized with the
abovementioned methodology.
119
Application of a variation of the method
introduced in entry 3, Table 1.3 was utilized for the lactone 1.220 a pheromone of
the female Culex mosquito.
120
The Tietze reaction has been applied for the synthesis
of the natural product Hirsutene 1.221 and other structurally related analogues of the
indole alkaloids family.
121
A modified, Mannich based intramolecular MCR was
utilized to obtain a bicyclic advanced intermediate towards the synthetically
challenging (-)-Decarbamoylsaxitoxin 1.222, a potent neurotoxin from Spondylus
butleri.
122
The Ugi MCR was incorporated in the synthesis of Mutoporin 1.223 and
41
yielded an acyclic dipeptide which was further synthetically manipulated to the
densely functionalized natural product.
123
Ecteinascidin 743 1.224 a natural product
isolated from the marine tunicate Ecteinascidia turbinate represents a powerful
antitumor agent which has been submitted to clinical trials. For synthesizing that
unique frame two MCRs were of significant importance, a Mannich and an Ugi
reaction. The Mannich reaction served as a tool towards the phenylglycinol moiety
that subsequently participated in the Ugi process to yield the key intermediate for
constructing the skeleton of the natural product.
124

It is clear from all the abovementioned examples which represent a very
limited percentage of the actual applications of MCRs in drug development and in
organic synthesis that the molecular complexity that can be achieved is tremendous.
As a consequence, the fields of target as well as diversity-oriented synthesis through
MCRs are still in their infancy. The knowledge accumulated with time combined
with the art of organic synthesis and the unrestricted chemical imagination has still a
lot to reveal about the potential of those processes.

1.5 New directions in MCRs. What’s next?
A question that naturally comes up regarding MCRs is what’s next in the
field and what is the way to new MCRs? The evolution of MCRs with time has been
dramatic and the progress towards synthetically useful reactions in on going. The
conceptually first MCR, a process of the prebiotic world was the combination of six
42
molecules of HCN
125
to yield the DNA base Adenine but practically speaking, its
synthetic potential is very limited. Instead, highly efficient and diverse methods
dominate the last 150 years of chemistry regarding the MCR field leading to the
impressive condensation of up seven different components
126
in a selective fashion
as well as the creative combination of MCRs with other elementary processes to
reach levels of advanced molecular complexity. Compound 1.228 (Scheme 1.23) is
an impressive demonstration of the latter. It was constructed in one pot by an Ugi
reaction coupled with a Diels Alder, a double amide allylation and a final ring
opening/closing metathesis. In this highly diverse and extremely short sequence 4
rings and 15 new bonds are formed!
127

NH
2
O
Si
Ph
Ph
Ph
N
C
O
CHO
Ph N
H
COOH
O
N
N
O
Ph
H
HO
O
H
N
O
Br
O
H
+
1. Ugi
2. Diels Alder
3. Allylation
4. ROM/RCM
1.228
1.224 1.225
1.226 1.227

Scheme 1.23: Generation of molecular complexity by an Ugi-Diels Alder-Allylation-ROM/RCM
sequence

The discovery of new MCRs
3
often involves the following approaches:
• Random discovery or trial and error approaches. Random discovery
of MCRs usually occurs when the outcome of a known process is different from the
expected. That chemical discrepancy mainly occurs when alternative pathways
43
become competitive or dominating induced by the specific substitution pattern of a
starting material.
• Combinatorial discovery. This systematic approach to new MCRs was
inspired by the random discovery mentioned earlier. In particular in the
combinatorial discovery a large number of starting materials with varying
substitution patterns and functional groups are allowed to react with all the possible
reactions co-existing in the same pot. The complex reaction mixture is analyzed by
HPLC-MS for new products. Besides the new scaffolds discovered the method
indirectly reveals new patterns of reactivity and provides theoretical information
about the kinetically favored pathways among the plethora that could potentially take
place. From such an approach where 10 different starting materials were mixed a
new three-component reaction was discovered between ketones, isocyanides and aryl
hydrazines to 2, 3-dihydrocinnolines.
• Discovery by design. In designing new MCRs knowledge of the
possible elementary bimolecular processes between the different components and the
reactivity of the intermediates in the presence of all the starting materials is of
primary importance. Ideally an efficient MCR should be accompanied by an
irreversible process to yield the desired product which would constitute the driving
force towards the preferred direction.
• Discovery by computational methods. MCR construction guidelines
can be automated by using suitable computational reaction database-searching
44
techniques. Efforts to organize all the basic principles that a new an efficient MCR
should satisfy, along with creating an integrated database of elementary reactions are
the two major pillars under which this approach is based. Such a task requires
comprehensive knowledge of reactivity patterns between various starting materials
but should also consider deviations and alternative pathways attributed to
substitution, stereochemistry, isomerization etc. For that purpose a number of
chemical languages have been developed to encode the various chemical processes
leading to stable products or reactive intermediates in a universal and “in progress”-
integrated way.
3
As a consequence, third partners for novel MCRs can be anticipated
by the program if someone selects the first two components. Also, depending on the
size of the database a number of possible alternative pathways can be predicted,
leading to surprising or unexpected structures. Ugi used the computer program
IGOR2 to propose a new process. The experimental data indeed yielded a novel
product but not the anticipated one. This was a follow up product originating from a
subsequent reaction that the program had not predicted, due to lack of information.
As indicated by the abovementioned example, the computational discovery of MCRs
is still in its infancy but definitely the integration and organization of the chemical
knowledge in such a systematic way will become one of the most powerful tools
towards novel processes and applications.
• The union concept. The combination of known MCRs is one more
direction to new, higher-order MCRs. Two MCRs can be combined if the product or
45
an advanced intermediate of the first is a starting material or intermediate of the
second one. Ideally, no irreversible side reactions should take place between the
components that would consume the starting materials and drive the reaction to non-
desirable routes. The seven component reaction, a union of the Ugi and the Asinger
reactions to synthesize thiazolidines
126
1.234 (Scheme 1.24) is a demonstration of the
union concept “in action”.
CHO
Br
NaSH NH
3
CHO N
C
CO
2
MeOH ++ + +++
N
S
HN
O
O
O
1.234 1.229 1.30 1.2 1.230 1.231 1.232 1.233

Scheme 1.24: The seven component reaction
Taking into consideration all the different directions regarding the discovery
of new MCRs someone can safely conclude that the main objective for the field is
the expansion of the pool and diversity of those processes. In other words, the target
is to discover new and alternative ways of transforming the pool of the readily
available chemicals to a plethora of different moieties or substructures in the course
of the various MCRs.

46
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117. Pye, P.J.; Rossen, K.; Weissman, S.A.; Maliakal, A.; Reamer, R.A.;
Ball, R.; Tsou, N.N.; Volante, R.P.; Reider, P.J. Chemistry--A
European Journal 2002, 8, 1372.
118. Suzuki, M.; Yanagisawa, A.; Noyori, R. Journal of the American
Chemical Society 1988, 110, 4718.
119. Smith, A.B., III; Doughty, V.A.; Sfouggatakis, C.; Bennett, C.S.;
Koyanagi, J.; Takeuchi, M. Organic Letters 2002, 4, 783.
120. Gao, X.; Hall, D.G. Journal of the American Chemical Society 2003,
125, 9308.
121. Tietze, L.F.; Zhou, Y. Angewandte Chemie, International Edition
1999, 38, 2045.
122. Hong, C.Y.; Kishi, Y. Journal of the American Chemical Society
1992, 114, 7001.
54

123. Bauer, S.M.; Armstrong, R.W. Journal of the American Chemical
Society 1999, 121, 6355.

124. Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama,
T. Journal of the American Chemical Society 2002, 124, 6552.
125. Oro, J.; Kimball, A.P. Archives of Biochemistry and Biophysics 1961,
94, 217.
126. Dömling,A.; Ugi, I. Angewandte Chemie International Edition
in English 1993, 32, 563.
127. Dömling, A. Current Opinion in Chemical Biology 2002, 6, 306.

55

CHAPTER 2: Single-step synthesis of allenyl and propargylic amine
derivatives. Reactivity studies of allenic boron derivatives in a three-
component MCR with amines and carbonyl compounds.

2.1 Fast assembly of multifunctionalized molecules by a three
component reaction between boronic acids, amines and
aldehydes
In 1993 a fundamentally new reaction was introduced in the literature for
synthesizing allylamines. It involved a stepwise condensation between secondary
amines and paraformaldehyde followed by reaction with alkenyl boronic acids
1
. This
initial version of the reaction revealed interesting features such as high yields and
complete retention of the geometry of the alkene in the products. The reaction was
subsequently developed into a one-step, three-component process and it was further
explored and expanded to other components. In the initial paper this process was
named the “Boronic Acid Mannich Reaction” (BAM) and is currently cited as the
“Petasis Reaction”. This process has evolved into a more general and versatile
method towards various amine derivatives
2
. Scheme 2.1 depicts the general three-
component transformation between amines 2.1, oxo-compounds 2.2 and boronic
acids 2.3 towards the amine derivatives 2.4.

56

R
5
B
OH
OH
R
1
N
R
2
H
R
3
O
++
B(OH)
3
+
R
3
R
5
N
R
1
R
2
2.12.22.32.4
R
4
R
4
2.11

Scheme 2.1: The Petasis three-component reaction

Stepwise versions of the reaction as well as mechanistic experiments were
performed in order to gain insight about the mechanistic pathway of the process. The
mechanistic hypothesis about the elementary chemical transformations involves a
series of equilibria between the starting materials and various intermediates that are
formed in the course of the reaction. The reaction between the amine 2.1 and the oxo
component 2.2 can lead to two possible intermediates, the aminol 2.5 and the aminal
2.6 which are in equilibrium with the starting materials. In the presence of the
boronic acid component 2.3 these intermediates can be transformed to the
corresponding highly electrophilic iminium salt 2.7 with concomitant formation of
the nucleophilic organoboron-“ate” complex 2.8. These highly reactive transient
species then react irreversibly to form the final product, as is typical for type II
MCRs
3
. Successful variations of the process in which iminium electrophiles are
obtained in situ by stable precursors or by imine activation also support the
intermediacy of those species
4
. The mechanistic hypothesis is analyzed in Scheme
2.2.

57

R
1
N
R
2
H
+
R
3
O
R
1
N
R
2
H
R
3
OH
N
R
1
R
2
R
4
R
4
R
3
N
N
R
1
R
2
R
4
R
1
R
2
R
5
B
OH
OH
R
5
B
OH
OH
R
3
O
N
R
1
R
2
R
4
B
H
OH
R
5
OH
R
3
N
N
R
1
R
2
R
4
B
R
2
R
1
R
5
OH
OH
R
3
R
4
N
R
2
R
1
R
5
B
X
HO
OH
X: OH or NR
1
R
2
+
R
3
R
5
N
R
2
R
1
R
4
- B(OH)
3
2.1
2.2 2.1
2.5
2.3 2.3
2.6
2.7 2.8
2.4
2.9 2.10
2.11

Scheme 2.2: The mechanistic hypothesis of the Petasis reaction

The fact that a plethora of amines, oxo compounds and boronic acids are
either commercially available or can easily be obtained through short and well
established synthetic methodologies results in a highly diverse reaction with very
high exploratory power.
A wide variety of aliphatic as well as aromatic amines participate in the
process. In general, secondary amines are the best candidates. Primary amines also
react even though the yields are somewhat lower. Amino acids
5
and hydrazines
6
are
reactive as well and in some cases less nucleophilic amines such as sulfinamides
7,8

and electron poor aromatic amines
9
can be used. Interestingly, electron rich “amine
alternative” components such as meta alkoxy tertiary anilines
10
and 1,3,5 trialkoxy
benzenes
11
participate in the process and yield structurally modified condensation

58

products that result from a formation of two carbon-carbon bonds. Furthermore, the
use of certain chiral amines has been proven excellent for stereocontrolled synthesis,
yielding is some cases de>99%.
12,13,14

As far as the boron component is concerned, a plethora of alkenyl
15
, aryl
16

and heteroaryl
17
boronic acids behave very well in combination with glyoxylic acid
monohydrate, reacting smoothly at ambient temperatures, the only exception being
pyridyl boronic acids carrying an electron withdrawing substituent. In this case the
formation of very stable

boron complexes dominated and no coupling products were
obtained.
18
Remarkably, allyl boronic acid which is known to add to aldehydes
yielding homopropargylic alcohols participates in the three-component process
19
and
can selectively give the amine derivative as the sole product by controlling the
reaction conditions!
The use of alternative organoboron compounds such as organoboronates and
organotrifluoro borates salts carrying a variety of organic groups has also been
demonstrated thus expanding the pool of components to alternative, more stable
orgaboronon sources when the corresponding boronic acid cannot be synthesized or
stored.
19
The participation of boronic esters proved to be solvent dependent. The
initial observations of lack of reactivity

of boronic ester when primary amines were
used
20,21
were revised since the use of alcoholic solvents such as MeOH and
hexafluoroisopropanol yielded the three-component products in very good yields.
22

Potassium organotrifluoroborates, the air-stable and storable analogues of

59

organoboronic acids which are easily obtained from boronic acids as well as boronic
esters were also shown to participate in the three-component process expanding the
scope even more.
23

The carbonyl component is of major importance and many different scaffolds
have resulted by altering it. One of the most important classes of compounds that can
be obtained is artificial α-amino acids 2.12, by using glyoxylic acid monohydrate or
pyruvic acid as the carbonyl component.
24
This wide-scope one-step approach
towards this important kind of organic compounds is experimentally very easy to
perform and needs no protection/deprotection methodology, towards a variety of
aminoacids. A plethora of β,γ-unsaturated,
2,15
γ,δ-unsaturated,
19
aryl and heteroaryl
16

α-amino acids have been synthesized by altering the combination of the amine and
boronic acid components. Furthermore, the use of cleavable amines has been utilized
in obtaining the free α-amino acid by deprotection of the three-component product.
By incorporating glycoladehyde dimer and as the oxo compound, β-amino
alcohols 2.13 can be obtained.
25
This very versatile class of synthons finds a wide
variety of applications for synthetic purposes, since the functional groups can be
further derivatized or converted to alternative groups. Moreover, β-amino alcohols
constitute a scaffold often found in metal ligands and depending on the substitution
pattern present, biologically important compounds can result. Short routes to anti- α-
(trifluomethyl)
26
and anti- α-(difluromethyl)- β-amino alcohols
27
were also developed
due to their medicinal importance. Other types of amino alcohols were also obtained

60

when 1, 3 dihydroxy acetone, salicylaldehyde
28
and various 2-heterocyclic
carboxaldehydes
29
were used as the oxo component.
The use of substituted α-hydroxy aldehydes and sugars as the oxo
participants has revealed some of the most attractive features of this reaction. Anti β-
amino polyols 2.14 are selectively obtained (de>99%) which in the case of chiral α-
hydroxy aldehydes translates to optically pure products (ee>99%).
25
The use of α-
hydroxy aldehydes has been shown to yield diastereomerically pure products with a
variety of different boronic acids and this appears to be the component that induces
the strongest stereochemical control in the process. The concomitant use of
secondary amines results in higher yields. The use of the cleavable dibenzylamine
and diallylamine has been very efficient in achieving high yields and these are the
amines of choice when the free amine is needed at last. This high diastereoselectivity
lead to the development of short methodologies, by incorporating various post-
condensation modifications to a plethora of enantiomerically pure
multifunctionalized scaffolds. These include chiral α-amino acids, aza sugars 1.15,
anti- α-amino epoxides 2.16, α-amino aldehydes
30
2.17, polyhydroxy piperidines
2.18, polyhydroxy indolizidines 2.19, trihydroxy quinolizidine 2.20, trihydroxy
pipecolic acid
31
2.21, functionalized oxazolidinones 2.22 and C
2
-symmetric diamino
diols 2.23.
122

A variety of extensions and applications has been developed by the
inventors
32,33,34
and by others after the potential of the reaction was realized. Short

61

routes to a plethora of heterocycles (Scheme 2.3) including piperazinones
35
2.24,
benzopiperazinones 2.25, benzodiazepines 2.26, tetrahydropyrazines
30
2.27 and 2-
hydroxymorpholines
30,36
2.28 were synthesized based on the three-component
process. 2H-chromenes 2.29 were unexpectedly obtained by an alternative reaction
pathway in which the amine was not incorporated in the final skeleton but instead
acted catalytically and facilitated the formation of the heterocycle.
37

R
5
B
OH
OH
R
1
N
R
2
H R 3
O
+
2.1 2.2
2.3
R
5
OH
N
O
R
1
R
2
R 4
R 3
R
5
OH
N
R
1
R
2
R
3
R
5
OH
N
OH
R
2
R
1
OH
OH
2.12
2.13
2.14
2.15
2.16
2.17
2.24
2.23
2.22
2.21
2.20
2.19
2.18
2.27
2.26
2.25
2.29
2.28
O OH
NHBoc
OH
HO
OH
R
5
N
O
R
1
R
2
R
5
N
R
1
R
2
O
N R
5
HO
OH
OH
R
1
N
H
HO
HO
OH
HO OH
N
H
OH
HO OH
N
H
OH
HO OH
HO
O
HN O
O
OH R
5
R
5
R
5
N
N HO
OH
R
2
R
1
R
1 R
2
N
N O
R
1
R
1
R 6
R
7
R
5
N
N O
R
1
R
1
R
5
N
N
O
R
2
R
1
R
5
N
N
R
1
R
1
R
4
R
5
N
O
R
1
R
6
R
5
R 3
OH
O
R
7
R
8
R
6

Scheme 2.3: Types of compounds synthesized by the Petasis three-component reaction

Furthermore, the process has been performed both in solution and on solid
supports to form linear
38
as well as cyclic peptides
31,39
and peptidomimetics.
Different versions have been designed and all three components have been

62

immobilized on various solid supports
31,40
in order to serve various synthetic
purposes and to demonstrate the potential of the reaction for adaptation in solid
phase high throughput organic synthesis. Along with the classical solid phase
protocols where one component is immobilized, a resin-to-resin transfer reaction
(RRTR) was developed as well, based on the transesterification of boronates in the
presence of an alcoholic solvent as the transferring mechanism of the boron
component from the solid phase to the solution.
41,42
Also a short and highly diverse
methodology towards rigid β-turn peptidomimetics has been demonstrated based on
the Petasis reaction.
43

Union of the Petasis reaction with the Ugi process has also been attempted
yielding higher order MCRs both in solution
44
and on solid phase
45
in which as many
as six components converge in one pot. A methodology towards aza- β-Lactams was
developed based on that union concept.
46

The impressive molecular complexity and the plethora of skeletons that are
easily accessible by the multifunctionalized scaffolds obtained by the three-
component process were recently demonstrated in a diversity oriented synthesis
(DOS) paper.
47
The research illustrated the implementation of a strategy that enables
the synthesis, in only three to five steps, of a diverse collection of single isomer
small molecules whose members have over 15 different types of skeletons. The
Petasis reaction combined with an N-propargylation reaction yielded the densely
functionalized scaffold 2.27 which was subsequently subjected to a number of

63

different annulation reactions. The types of skeletons synthesized are depicted in
Scheme 2.4.

Ph
OH
N CO
2
Me
Ph
2.27
N
MeO
2
C
Ph
Ph
H
OH
N
MeO
2
C
Ph
Ph
H
OH
N
MeO
2
C
Ph
Ph
H
OH
O
Ph
OH
O
N
CO
2
Me
Ph
N
MeO
2
C
Ph
Ph
H
OH
O
N CO
2
Me
MeO
Ph
Ph
H
O
N
Ph
H
O
Ph
N
MeO
2
C
Ph
Ph
H
OH
NN
N
O O
O
N
O
Ph
Ph
H
O
N
O
Ph
Ph
H
O
O
N
O
Ph
Ph
H
O
N
O
Ph
Ph
H
O
N
CO
2
Me
Ph
Ph
OH
O
N
CO
2
Me
Ph
N
N
N OH
Ph
O
O
O
N
O
Ph
H NN
N
Ph
O O
2.30
2.31
2.32
2.33
2.34
2.35
2.36
2.37
2.38
2.39
2.40
2.41
2.42
2.43
2.44

Scheme 2.4: Implementation of the Petasis reaction in DOS

Based on the same concept, the combination of the Petasis reaction with
palladium catalyzed annulations has lead to the development of new methodologies
for synthesizing novel cyclic non-proteinogenic α-amino acids.
48

64

The high exploratory power of the process and the fact that densely
functionalized molecules with high diversity can be formed in one pot, nominate it as
a promising synthetic tool that can provide advanced and versatile synthons for
target oriented organic synthesis and methodology. Besides the substance P inhibitor
1.217 already mentioned in chapter 1, the Petasis reaction has been incorporated as
the key step in a number of other synthetic routes. In 2004 Sugiyama et al reported a
short synthetic route to both (+) and (-) enantiomers of cytoxazone 2.45 and 2.46
respectively, a immunomodulator taking advantage of the strong stereodirecting
effect that the use of α-hydroxyl aldehydes induces in that reaction.
49
The
immunosupressive agent FTY720 2.47 was synthesized by the same group in 2005 in
five steps in 28% overall yield based on that technology, which constituted a major
optimization compared to the previous approaches.
50
Synthetic efforts towards the
putative natural product Uniflorine A 2.48 by employing the stereoselective Pt-
three-componentR as a key step revealed after X-ray crystal structure data that the
wrong structure had been assigned to the natural product.
51
The structures of the
abovementioned synthetic targets are depicted in Scheme 2.5.

65

ONH
O
HO
OMe
ONH
O
HO
OMe
2.45
(+) Cytoxazone
2.46
(-) Cytoxazone
HO
(CH
2
)
7
CH
3
NH
2.
HCl
HO
2.47
FTY720
N
HO
OH
H
OH
OH
HO
2.48

Scheme 2.5: Application of the Petasis reaction in target oriented synthesis.

2.2 Allenic boronic acid. A potential partner for the Petasis
reaction
The appearance in the literature of allenic boronic acid derivatives such as
allenyl boronates 2.52 and 2.53 dates back to 1966.
52,53,54,55
These first preparative
reports concerned the use of magnesium 2.50 and lithium 2.51 organometallics
derived from propargylic bromides with magnesium-bromide exchange and from
internal alkynes after deprotonation respectively followed by nucleophilic attack to a
boron electrophile 2.49. The reaction scheme which constitutes a general method for
the preparation of other types of boronic acids and boronates as well is depicted in
Scheme 2.6.

66

Mg
•
R
1
R
2
Li
R
1
R
3
R
3
R
2
B
X
RO OR
cat. H
+
B
•
R
1
R
2
R
3
RO
OR
B
•
R
2
R
3
R
1
OR
RO cat. H
+
2.50
2.53
2.51
2.49 2.52

Scheme 2.6: Synthetic methodology for allenic boronic acid derivatives

Exploration of the chemistry employed for the synthesis of those
organoboron compounds revealed various challenges and limitations.
56
The
propargylic rearrangement (Scheme 2.7) that both the propargyl (2.54)/allenyl (2.55)
organometallics and final products undergo raised issues of configurational stability
as well as isomeric composition of the resulting boronate. The preference of one
isomer over the other depends on the substitution pattern of the starting material and
on the metal counterpart of the intermediate organometallic and unfortunately, only
in a few cases the equilibrium yields a sole isomer.
56

R
1
•
R
2
R
3
M
R
1
M
R
3
R
2
2.54 2.55

Scheme 2.7: The propargylic rearrangement

In addition, the substitution on the boron atom is crucial for the stability of
the product. As it was shown, the presence of a substituted cyclohexyl boronate,
among the ones tested gave the desired product as a stable and isolable compound
while efforts with acyclic esters resulted in disproportonation to trialkyl and
trialkoxy boranes. In addition, those compounds are prone to oxidation and

67

polymerization, especially the unsubstituted allenyl analogues. Certain boronic esters
exhibit significant stability and can be stored without extreme precautions while
hydrolysis to the corresponding boronic acids has only been reported for the parent,
nonsubstituted, allenic boronic acid. The process gives low to moderate yields
though due to the labile C-B which hydrolyzes readily in protic media and alcoholic
solvents (alcohololysis). As a consequence, the latter is the only allenic boronic acid
that has found synthetic applications while no data was found for substituted
analogues. Its sensitivity to air implies certain limitations in storing and handling. As
a registered pyrophoric material, exposure to air results in immediate ignition.
The first studies on this type of boron compounds were conducted with
boronic esters 2.53 and revealed significant reactivity towards aldehydes and
ketones. The reaction pattern is similar to the allyboration reaction but in this case,
allenylation and/or propargylation take place yielding α-allenyl 2.59 and/or
homopropargyl 2.58 alcohols (Scheme 2.8). In the case of unhindered aldehydes 2.57
the reaction is stereospecific and takes place with complete rearrangement. Thus, the
isomeric distribution of the resulting products reflects the composition of the allenyl
(2.53)/propargyl (2.56) boron compound (inversed ratios compared to the
organometallic).
57,58

68

R
1
•
R
2
R
3
B
R
1
B
R
3
R
2
O
RO
RO
R
4
H
2
O
O
R
4
OR
OR +
+
H
2
O
R
1
•
R
2
R
3
HO
R
4
R
4
HO
R
1
R
2
R
3
"Allenyl Alcohols" 2.59 "Homopropargylic alcohols" 2.58
2.56 2.53
2.57 2.57

Scheme 2.8: The addition of allenyl and propargyl boronates in unhindered oxo compounds

Morever the addition of γ n-propyl allenic butyl boronate 2.60 to aliphatic
aldehydes 2.57 showed stereoselectivity up to 91% towards the threo alcohol 2.63,
indicating chelation control and a cyclic transition state (Scheme 2.9).
59

B
•
BuO
OBu
O
R
1
C
3
H
7
+
H
O
R
1
B
•
C
3
H
7
H
OBu BuO
H
O
R
1
B
•
H
C
3
H
7
OBu BuO
R
1
OH
H
H
C
3
H
7
2.63
Threo isomer
favored
R
1
OH
H
C
3
H
7
H
2.64
Erythro isomer
disfavored
2.61
TS1-favored
2.62
TS1-disfavored
(steric hindrance)
2.57 2.60

Scheme 2.9: Chelation control during the addition to aldehydes favors formation of the threo isomer

The addition to ketones, with only a few exceptions, is somewhat more
erratic in terms of stereoselectivity. The process is under kinetic control and in this
case, the outcome of the addition depends highly on the degree of steric hindrance

69

present on the oxo compound, the proportion of the reactants as well as the
temperature and solvent used.
60

Allenic boronic acid 2.65 reacts very efficiently with aldehydes yielding
homopropargylic alcohols. Besides synthesizing racemic homopropargylic alcohols,
the use of tartaric boronic esters 2.67 and 2.68 has been demonstrated to induce
strong enantiocontrol yielding the corresponding alcohol 2.67 or 2.70 in
enantiomerically pure form in some cases.
61,62
Moreover, the addition of 2.65 to β-
hydroxy ketones 2.71 takes place with complete asymmetric induction indicating
strong directing effect of the β-hydroxy group through chelation with the oxophilic
boron atom of the boronic acid.
63
As a consequence, the use of allenic boronic acid
constitutes a leading methodology towards chiral homopropargylic alcohols and its
implementation in asymmetric synthesis is demonstrated by various literature
examples.
64,65,66
Natural products such as Lophotoxin,
67
(4E)-7-Methoxytetradec-4-
enoic acid,
68
Octalactins A and B
69
,
70
Corrosolin (both enantiomers),
71
and
Macrolactin analogues
72
,
73
are characteristic examples. A somewhat alternative
incorporation of the propargyl moiety on α-hydroxy epoxides 2.75 lead to 1, 3 diols
2.78 through a semipinacol rearrangement after reactions with 2.65.
74

70

Table 2.1: The reactions of allenic boronic acid and boronates
Transformation
R
1
O
•
B HO
OH
R
1
OH
+
R
1
O
•
B
R
1
OH
O
O
R
1
OH
COOR
ROOC
•
B
O
O
COOR
ROOC
1. Homopropargylation
1a. Use of allenyl boronic acid. Racemic homopropargylic alcohols
1b. Use of (+)-tartrate 2.?? and (-) tartrate 2.?? allenyl boronates. Chiral homopropargylic alcohols
1c. Stereoselective addition of allenyl boronic acid to β-hydroxy ketones
R
O OH
•
B HO
OH
+
OO
B
OH
R
H
R
O
OH
B
•
O
R
OH OH
H
1d. Reaction of allenyl boronic acid with a-hydroxy epoxides
O
R
3
R
4
R
1
R
2
OH
•
B HO
OH
+
O O
HO
B •
R
2
R
1
R
3
R
4
OO
R
2
R
3
H
R
4
R
1
B
HO
• OH OH
R
2
R
3
H
R
4
R
1
2. Homologation to homoallenyl boronates
•
LiCH
2
X +
B
RO
OR
•
B
OR
OR
•
B
OR
OR
X
M
+
•
MgBr
B
OR
RO
X +
3. Ru catalyzed [2+2] cyclodimerization to 1, 3 Dialkylidenecyclobutanes precursors
•
B
RO
OR
2
B
B
RO
OR
OR
RO
Ar
Ar
Ar-I
Pd
0
4. Three component reaction with aryl iodides and amines
•
B
Ar-I + + R
1
NH
2
O
O
B
Ar
N
H
R
1
O
O

71

Homologation of allenyl boronates to homoallenyl analogues 2.84 has also
been performed and the newly synthesized organoboranes have successfully been
employed for homoallenyl boration of aldehydes.
75
Ruthenium catalyzed head-to-
head [2+2] cyclodimerization of allenic pinacol boronate 2.87 has been utilized to
access 1,3 dimethylenecyclobutane derivatives 2.86. These constitute key precursors
for the formation of diradicals employed in material science and in applications
where paramagnetic building blocks are required.
76

The participation of allenyl pinacol boronates 2.87 in a multicomponent
process was recently reported in the literature. It concerns a palladium catalyzed
three-component coupling with amines
77
2.89 (example in Table 2.1) or carbon
nucleophiles
78
and aryl iodides 2.88 towards highly diverse amino alkenyl boronates
2.90 which can react further participating in a variety of transformations due to the
versatile and dense functionality of the resulting scaffolds.
A number of preparations have been developed for synthesizing the parent
allenic boronic acid 2.65 and modified boronates (Scheme 2.10)
79
. Most of the
methods involve reaction of an allenyl organometallic (Mg, Li, Sn) with an
electrophilic and Lewis acidic boron compound that results in a metal to boron
exchange.
52-55, 80
In this case the boronic acid is formed after hydrolysis of the
intermediate tetracoordinate boron “ate” complex in the presence of aqueous acid
while anhydrous conditions yield the corresponding boronates. Also, the synthesis of
allenic boronate by palladium catalyzed 1,4 hydroboration of enynes 2.99 has been

72

reported but this method has not proven general since it is very sensitive to
substitution and in many cases it gives mixture of products thus limiting the
implementation to higher analogues.
81,82,83
Gem-Silylborylation has also been
employed to yield silyl substituted allenyl boronates in moderate to good yields.
84

B(OR
4
)
2
•
R
1
R
2
R
3
+ B(OMe)
3
(R
1
=R
2
=R
3
=H)
Li
B(iOPr)
3
(R
1
=R
2
=H, R
3
=CH
3
)
1. Et
2
O(abs.)
-78
o
C
2. H+, H
2
O
Li
+
X
R
2
R
1
O
B
O
PhMe
2
Si
+
-110
o
C
(R
3
=SiMe
2
Ph)
R
1
O
B
O
H
+
(R
2
=Me, R
3
=H)
PdL
4
(cat.)
SnBu
3
•
(R
1
=R
2
=R
3
=H)
+
BBr
3
θ < -80
o
C
1. Et
2
O(abs.)
-78
o
C
2. H+, H
2
O
SnPh
3
OR
•
MgBr
2.92
2.93
2.94
2.95
2.96
2.97
2.98
2.99
2.100 2.101
2.102

Scheme 2.10: Preparation methods for allenic boronic acid and boronates

2.3Results and discussion
2.3.1Reactivity studies of allenic boronic acid in the Petasis reaction.
Based on the interesting chemistry that allenic boronic acid 2.65 has
demonstrated towards oxo compounds, we wished to explore its reactivity towards
the three-component condensation in combination with amines and carbonyl
compounds. Since this boronic acid is known to add to aldehydes and ketones,
selectivity issues arise and it would be of significant synthetic value to be able to

73

draw conclusions about its operational mode and reactivity towards the two or the
three-component processes.
Furthermore, the isomeric-products composition would provide us with
further insight about the reaction pathway and would enable us to draw conclusions
about the transition state and its possible resemblance with the addition to aldehydes.
Last but not least, the possible products are heavily functionalized and significantly
versatile synthons. Since conventional synthesis usually elaborates multiple steps
towards them, a MCR process would be ideal for fast and efficient assembly.
We started our reactivity studies by using the parent, non substituted allenic
boronic acid 2.65. This choice was based on various arguments. The basic reason
was the fact that an established synthetic route had already been demonstrated and
scaled up to 200 mmoles. A careful literature review over other analogues revealed
an actual lack of data for substituted analogues. A second very important fact about
2.65 is that it is configurationally stable and exists exclusively in the allenic form,
thus avoiding complications attributed to additional isomerization of the boron
partner prior to the reaction. Moreover, the absence of substituents eliminates steric
hindrance which has been shown to play important role in the reaction mode towards
carbonyl compounds and to the resulting isomeric product distribution.
The use of the boronic acid instead of the corresponding boronates was
initially preferred. Prior knowledge of the three-component process with other boron
components has revealed that the boronic acids are more reactive and robust partners

74

while the use of boronates is sometimes erratic and highly dependable on the
reaction conditions. The preparation of the boronic acid 2.65 was done according to
previously published procedure (Scheme 2.11).
61

Br
Mg, Et
2
O (abs.), 0
o
C
cat. HgCl
2
MgBr
•
1. B(OMe)
3
,
Et
2
O (abs.), -78
o
C
2. H
2
SO
4
,H
2
O, 0
o
C
B
•
HO
OH
2.65 2.103 2.92

Scheme 2.11: The preparation of allenic boronic acid

2.3.1.1 Selective synthesis of propargylic and allenyl α-amino acids
To our satisfaction, allenic boronic acid 2.65 proved to be a very reactive
starting material for the multi component reaction when combined with glyoxylic
acid mohohydrate 2.104 as the oxo partner yielding the corresponding α-amino
acids, while no side reaction of the corresponding two-component process
(propargylation of the aldehyde) was observed. The first studies involved the use of a
variety of primary 2.105 and secondary amines 2.106. Among them were more or
less nucleophilic, aliphatic as well as aromatic amines. Some of them exhibited
significant steric hindrance which was reflected in lower reaction yields, thus
providing useful information about the tolerance of the process to steric hindrance.
Impressively, the reaction proved to be robust and general, since only amines with
extremely low nucleophilicity such as amides and sulfonamides failed to react under
the standard conditions. Sulfinimines gave traces of the three-component product

75

while the two-component addition of the allenic boronic acid was the major product
in this case.
The most interesting and synthetically useful feature of this process is the
isomeric nature of the products obtained. The reaction exhibited remarkable
chemospecificity in synthesizing exclusively the propargylic α-amino acids 2.107
when primary amines were used while the use of secondary amines gave only the
corresponding allenyl products 2.108. This binary nature of the process in
combination with the use of cleavable amines, enables the synthesis of either
propargyl or allenic products in a totally predictable and controllable manner,
depending on the nature of the starting amine!
The reactions were carried out at RT since heating proved to be inappropriate
due to the low stability of the boronic acid thus leading to very low yields, even to no
reaction at all in some cases. Allenyl boronic acid 2.65 was stored as a suspension in
hexanes (no longer than two months after preparation) and treated under inert
atmosphere. It’s known that it’s easily oxidized and exposure to air leads to ignition
(pyrophoric material) so certain precautions should be taken during handling to
minimize decomposition. A number of different solvents (EtOH, MeOH, DCM,
toluene) were used and the reaction yielded the corresponding products in every
case. The usual reaction time was 24 hr. That was of significant importance when
primary amines were used since shorter reaction times gave lower yields. On the
other hand, extending the reaction time to more than 24 hr did not have a significant

76

impact on the yield since the competitive decomposition of the boronic acid takes
place as well. So, 24 hr was a reasonable compromise between the two factors, given
that almost in every case, the reaction did not reach to completion (residual amine
remained unreacted). In the case of the more reactive secondary amines, the yields
were slightly better compared to primary and higher conversions were obtained with
shorter reaction times. The only exceptions to that general trend were the cases
where the propargylic product (from primary amines) precipitated out of the reaction
mixture, thus driving the reaction to better conversions while this was not observed
for the three-component products originated from secondary amines, since these
were freely soluble in organic solvents. No extended optimization efforts were
conducted at this point to maximize the yields. According to our results, 2.65
operates according to Scheme 2.12 in reactions with 2.104 and various amines.
B(OH)
2
•
RNH
2
OH
OH
O
OH
NHR
O
•
N
R
1
R
2
OH
O
R
1
R
2
NH
"Allenic α-amino acids" "Propargylic α-amino acids"
2.65 2.104
HO
2.108 2.107
2.106 2.105

Scheme 2.12: Synthesis of propargyl and allenyl α-amino acids

The products obtained by the use of primary amines are shown in Table 2.2.

77

Table 2.2: Homopropargylic α-amino acids by the Petasis reaction
Entry Boronic Acid
component
Carbonyl
component
Amine
component
Product Yield
OH
HN
O
OH
NH
O
OH
NH
O
B(OH)
2
•
HO
OH
OH
O
43%
4
NH
2
B(OH)
2
•
HO
OH
OH
O
27% 5
B(OH)
2
•
HO
OH
OH
O
56%
6
NH
2
NH
2
O
O
2.120a
2.119a
2.118a 2.65
2.65
2.65
2.104
2.104
2.104
2.112
2.113
2.114
B(OH)
2
•
HO
OH
OH
O
81% 1
B(OH)
2
•
HO
OH
OH
O
Ph NH
2
OH
N
H
O
63%
2
OH
HN
O
Ph
Ph
OH
N
O
B(OH)
2
•
HO
OH
OH
O
45% 3
Ph NH
2
Ph
NH
2
2.65
2.65
2.65
2.109
2.104
2.104
2.104
2.110
2.111
2.115a
2.116a
(1)
OH
HN
O
Ph
Ph
•
2.116b
(0.47)
2.117a
Ph
H

In the case of primary amines, better yields were obtained in alcoholic
solvents such as MeOH and EtOH compared to DCM which is one of the mostly
used solvent for other versions of the process in the past. Furthermore, the fact that
some α-amino acids precipitated out of the reaction mixture, significantly simplified
their isolation through vacuum filtration. The reaction time varied in trials from 15-
48 hr but the best yields were obtained after 24h at RT. After the first positive results

78

obtained by primary amines, we moved to using secondary amines which in the past
have been proven better partners for the process. They reacted in an alternative
manner and yielded the isomeric allenic α-amino acids. These are depicted in Table
2.3.
Table 2.3: Allenic α-amino acids by the Petasis reaction
Entry Boronic Acid
component
Carbonyl
component
Amine
Component
Product Yield
B(OH)
2
•
HO
OH
OH
O
50% 1
B(OH)
2
•
HO
OH
OH
O
51% 2
B(OH)
2
•
HO
OH
OH
O
65% 3
B(OH)
2
•
HO
OH
OH
O
54%
•
N
OH
O
•
N
OH
O
•
N
OH
O
•
N
OH
O
O
Ph N
H
Ph
H
N
Ph N
H
N
H
O
4
2.65
2.65
2.65
2.65
2.104
2.104
2.104
2.104 2.121
2.122
2.123
2.124
2.125b
2.126b
2.127b
2.128b
Ph Ph
Ph

2.3.1.2 Mechanistic hypothesis
Based on our findings concerning the specificity of the reaction to yield
exclusively the propargylic products when primary amines were used and only the
allenic isomers in the case of secondary, we speculated two different pathways by
which this process can occur. Our mechanistic hypothesis involves a number of

79

intermediates whose rate of interconversion and relative rates of reaction can be
responsible for the product composition obtained in any case (Scheme 2.13).
R
1
N
R
2
H
H
O
+
HO
NH
R
2
R
1
k
1
k
-1
N
R
2
R
1
•
N
R
2
R
1
"Allenic Isomer"
k
7
N
H R
1
"Propargylic Isomer"
k
3
k
-3
OH OH
HO
OH
O
O
-
O
O O
N
R
2
R
1
O
-
O
OH
OH
B(OH)
2
•
k
9
2.1 2.104
2.129 2.130
2.132
HO
O
B
•
k
2
k
-2
HO
N
R
2
R
1
OH
O
(-H
2
O)
N
R
1
O
-
O
2.131
2.65
k
4
k
-4
k
5
k
-5
k
6
k
-6
2.134 2.135
(-H
+
)
(R
2
=H)
2.133a
2.107 2.108
N
R
1
OH HO
-O
O
B
•
k
8
k
-8
N
R
2
R
1
O
O
2.133b
OH
HO
B
•
+

Scheme 2.13: Mechanistic hypothesis for the synthesis of propargylic and allenic α-amino acids

According to the proposed mechanism, the relative reaction rates of the
different pathways determine the product composition.
When primary amines are used all the alternative pathways are possible. In
the case of glyoxylic acid 2.104, the complete propargylic rearrangement observed
with primary amines implies a cyclic transition state accompanied by boron induced
chelation control. In this case the corresponding electrophile and nucleophile coexist
in 2.133a in which both reactive species are in close proximity and have the essential

80

orientation to react with rearrangement of the allenyl group, thus yielding the
propargyl product. The presence of the neighboring carboxylic acid favors that
pathway since: It enhances the acidity of intermediate 2.131 and stabilizes the imine
by conjugation.
When secondary amines are involved the pathway leading to 2.133a cannot
participate but 2.133b could bring the reactive moieties in proximity and as a
consequence the allenic products 2.108 are obtained by direct transfer of the organic
group of the boron “ate” site to the highly reactive iminium salt site. Evidence that
the anionic carboxylate group is essential for our process was given by the negative
results obtained when ethyl glyoxalate was used as the carbonyl component. In that
case, under the same reaction conditions, no product was detected so we assume that
the free carboxylate plays a major role in activating the allenic boronic acid by
transforming it to a nucleophile through complexation.
Even though no direct mechanistic experiments were performed to test the
hypothesis, some support to the participation of the imine as an intermediate was
given by experiments conducted with hydroxyglycine and allenyl boronic acid.
Hydroxyglycine 2.138, whose actual structure had been the subject of
controversy until recently, was shown to be in equilibrium with a number of different
monomeric and oligomeric species and the dominant form is highly dependable on
the pH.
85
The distinction between the two isomeric forms, that of the ammonium salt
2.137 and that of the corresponding zwitter ion 2.138 both of which can be formed

81

by addition of ammonia 2.136 to glyoxylic acid monohydrate 2.104 was made
possible by extended NMR studies throughout a pH range that covers the whole
spectrum of reactions of the resulting species. At pH<6 the corresponding salt 2.137
is the actual species where the addition of ammonia to glyoxylic acid monohydrate
was detected at pH>6 by concomitant formation of 2.138. The formation of the
oligomer 2.141 was observed at pH>8 (Scheme 2.14).

HO
OH
OH
O
NH
3
HO
O
-
NH
3
+
O
pH<6
HO
O
-
OH
O
pH>6
O
-
NH
O
NH
3
+ H
2
N
O
-
NH
2
O
NH
3
, pH>8
HN
N
H
NH
COO
-
-OOC COO
-
2.104
2.136
2.137 2.138
2.139 2.140
NH
4
+
2.141

Scheme 2.14: The addition of ammonia to glyoxylic acid monohydrate with pH

As depicted in the previous Scheme, 2.141 results from the intermediate
species 2.139 and 2.140 which are also formed at high pH values. This observation
proved synthetically useful in synthesizing allyl glycines by reacting hydroxyglycine
with allylboronates since the addition of a catalytic amount of Et
3
N accelerated the
process and gave better yields.
86
The intermediacy of iminoacetate 2.139 was thus
proposed as the reactive species for the process.
Based on that hypothesis, we wished to test our theory about the reactivity of
iminoacetate 2.139 in the allenic version of the Petasis reaction by applying the same
exact conditions that presumably induce the intermediacy of 2.139 from
hydroxyglycine 2.138.

82

HO
O
-
NH
3
O
2.138
B(OH)
2
•
+
20% Et
3
N 2.142
MeOH, 15hr
RT, 72%
O
-
NH
3
O
2.143 2.65

Scheme 2.15: The reaction of hydroxyglycine with allenyl boronic acid

To our satisfaction the corresponding acetylenic free α-amino acid 2.143 was
exclusively formed in 72% yield when 20% Et
3
N was used as the catalyst, in
agreement with the literature findings concerning the allyl version of the process.
The presence of catalytic amount of Et
3
N (20%) in MeOH at RT proved to be the
best conditions among the ones examined while the comparative use of
stoichiometric amount yielded only a small amount of the three-component product,
most likely due to the significant formation of the unreactive oligomeric 2.141.
Morever, the use of less basic amines such as 2, 6 lutidine as catalysts was not as
efficient as Et
3
N.
2.3.1.3 Synthesis of allenic β-amino alcohols
After the first encouraging results obtained from the amino acid version of
the reaction we moved to developing a methodology towards the corresponding β-
amino alcohols. We utilized allenic boronic acid 2.65 with a variety of different
amines and glycolaldehyde dimer 2.144 as the carbonyl component. In this case, as
concluded by the crude reaction mixtures
1
H NMR spectra, both primary and
secondary aliphatic amines yielded exclusively the corresponding allenic product.

83

Aromatic amines 2.146 behaved differently and gave a mixture of both isomers
2.147 and 2.148, indicating alternative pathways by which that reaction can
potentially occur depending on the nature of the intermediate species.
The general reaction Scheme for synthesizing achiral β-amino alcohols is
depicted below.
B(OH)
2
•
R
1
R
2
NH
2.1
OH
N
•
N
H Ar
OH
ArNH
2
2.146
"Allenic
β-amino alcohols"
"Homopropargyl
β-amino alcohols"
2.65 2.144
O
O OH
HO
Ar H
•
N
R
1
R
2
OH
"Allenic
β-amino alcohols"
+
R
1
=alkyl,
R
2
=alkyl or H
2.147 2.148 2.145

Scheme 2.16: Synthesis of allenic and homopropargyl β- amino alcohols by the Petasis reaction

The allenic β-amino alcohols obtained from primary and secondary amines
are depicted in Tables 2.4 and 2.5 respectively.

84

Table 2.4: Allenic β-amino alcohols by utilizing primary amines
Entry Boronic Acid
component
Carbonyl
Component
Amine
component
Product Yield

B(OH)
2
•
46% 1
B(OH)
2
•
Ph NH
2
OH
N
H
46% 2
OH
N
OH
NH
OH
HN
OH
NH
OH
NH
B(OH)
2
•
36% 3
B(OH)
2
•
13%
4
Ph NH
2
Ph
NH
2
NH
2
B(OH)
2
•
15% 5
B(OH)
2
•
39%
7
NH
2
NH
2
O
O
O
O OH
HO
OH
HN
OH
HN
B(OH)
2
•
16% 6
39%
O
O
O OH
HO
O
O OH
HO
O
O OH
HO
O
O OH
HO
O
O OH
HO
O
O OH
HO
•
•
•
•
•
•
•
N
H
2
N
N
+
Ph
2.65
2.65
2.65
2.65
2.65
2.65
2.109 2.144
2.144
2.144
2.144
2.144
2.144
2.111
2.110
2.112
2.113
2.154
2.65 2.144 2.114
2.149b
2.150b
2.151b
2.152b
2.153b
2.155b
2.156
2.157
H
Ph
Ph

85

Table 2.5: Allenic β-amino alcohols by utilizing secondary amines
Entry Boronic Acid
component
Carbonyl
Component
Amine
component
Product Yield

B(OH)
2
•
93% 1
B(OH)
2
•
73% 2
B(OH)
2
•
83% 3
B(OH)
2
• 46%
•
N
OH
•
N
OH
•
N
OH
N
OH
O
Ph N
H
Ph
H
N
Ph N
H
N
H
O
4
O
O OH
HO
O
O OH
HO
O
O OH
HO
O
O OH
HO
B(OH)
2
• 44%
5
B(OH)
2
• >99%
6
•
N
OH
O
O OH
HO
O
O OH
HO
•
Ph N
H
NHBoc
Ph
NHBoc
Ph N
H
H
N Ph
N N
OH
Ph
Ph
Ph Ph
2.65
2.65
2.65
2.65
2.65
2.65
2.144
2.144
2.144
2.144
2.144
2.144
2.121
2.122
2.123
2.124
2.162
2.164
2.158
Ph
2.159
2.160
2.161
2.163
2.165

At this time, no optimizations studies were performed to optimize the yields
since we were primarily interested in studying the reactivity and selectivity of allenic
boronic acid towards this version of the multicomponent process. Once more, the
three-component reaction operated exclusively over the competing addition of

86

allenic boronic acid to the aldehyde in all the different combinations attempted even
though the two component process occurred and yielded the corresponding
homopropargyl diol in the control experiment. Secondary amines were shown to be
more efficient in that version as well compared to primary, which is in agreement
with previous results concerning the three-component process, when other boronic
acids were used.
In addition, our experiments revealed somewhat better yields when protic
solvents (EtOH, MeOH, MeOH/H
2
O) were used in combination with primary
amines compared to DCM, a solvent generally used for the process that gave
satisfactory results when employed in combination with secondary amines.
Among all the amines utilized, diamines-both primary and secondary- gave
somewhat erratic results. Even after repeatitive efforts, N,N dimethyl ethylene
diamine 2.154 gave only a poor 16% yield while with N-Boc, Ν’-benzyl ethylene
diamine 2.162 the yield did not exceed 44%, under the usual conditions employed.
Moreover N, N’ dibenzylethylene diamine 2.164 gave quantitatively the stable
adduct 2.165 depicted in Table 2.5 (entry 6). No three-component product was
detected in that reaction. Some efforts were made to activate the system for reaction
with the boronic acid by methods usually employed to activate aminals. Thus, the
adduct 2.165, after its formation was determined by
1
H NMR, was subjected to three
different variations. The first consisted of the addition of excess allenic boronic acid
2.65 in MeOH. The second concerned the addition of excess allenic boronic acid

87

2.65 and one equivalent of HCl in MeOH. In the third, the activation was attempted
by Yb(OTf)
3
. Some incorporation was only observed by the third attempt and the
three-component product was obtained in 12% while in the other two attempts, 2.165
remained unreacted.
As is known from the literature, glycolaldehyde exists as a dimer 2.144 in the
solid state,
87
but solvation is accompanied by a complex network of equilibria that
results in various transformation of the aldehyde, to a number of different species
that co exist.
88
As mentioned in the literature, the depolymerization rate of the dimer
is highly depended on the solvent as well as on the presence of acid or base
catalyst.
88
Furthermore, glycoladehyde participates in various competitive reactions
under the conditions of the Petasis reaction, especially in the case of primary amines
2.105. Slow irreversible oxidation has been observed in solution at ambient
temperature which is significantly promoted even by mild heating (70
o
C).
89
In
addition, the Amadori rearrangement, a process first observed between sugars and
the free NH
2
of proteins, is one more competitive side reaction between
glycolaldehyde
90
and primary amines that yields the highly polymerizable α-
aminoacetaldehyde 2.170 (Scheme 2.17). Thus, besides the sensitive allenyl boronic
acid 2.65, parallel consumption of both the amine 2.105 and aldehyde 2.166 in side
reactions which are unavoidable under the conventional conditions of the Petasis
reaction could be attributed for the low yields obtained from that process.

88

O
OH
R-NH
2
HO
OH
NH
R
OH
N
R H
H H
OH
NH
R
+
O
NHR
2.166 2.170 2.169 2.168 2.167 2.105

Scheme 2.17: The competing Amadori rearrangement of glycoladehyde with primary amines

As a consequence, we briefly examined the use of acid as an additive in the
β-amino alcohol version of the reaction in the hope that we may succeed in
improving the three-component-product yield or in enhancing the reaction rate, in an
effort to minimize the competitive aldehyde oxidation (which slows down in acidic
conditions) and decomposition occurring with time. The model reaction that was
examined was the one where benzylamine 2.109 was used. As it will be shown in
later chapter (Chapter 5) 2.149 was subjected to synthetic extensions and significant
amounts were necessary for those experiments that urged us to try a number of
variations towards yield improvement. Among the trials performed were:
• The use of a MeOH/H
2
O (6/1) solvent system with and without acid catalyst
(HCl, 0.3%).
• The use of 1, 2 dichloroethane (solvent employed in reductive amination) in
the presence of 1 eq. CH
3
COOH.
• The use of preformed benzylamine hydrochloride salt as the amine
component of the three-component-process.

89

The abovementioned experiments did not lead to a significant yield
improvement but the presence of catalytic amount of HCl in combination with
MeOH/H
2
O as the solvent system lead to a much faster reaction. This is in
consistence with the results reported by Stassinopoulou et al
88
about promotion of
the depolymerization of glycoladehyde dimer in MeOH as well as prevention of the
oxidation in the presence of acid.
89
The isolated yield after 1.5 hr was 32% while the
yield for the corresponding uncatalyzed process did not exceed 17%, even after 24hr
of reaction. In the case where 1,2 dichloro ethane and CH
3
COOH were used, the
product was obtained in very poor yield, most likely due to fast proton deboronation
of the boronic acid, which is known to occur. Finally, the attempt in which
benzylamine hydrochloride salt was used yielded the three-component-product in
inferior yield compared to the neutral conditions but also the two-component
competitive product was obtained as well. In that case the presence of acid also
activated the aldehyde towards nucleophilic attack.

90

2.3.2 Reactivity studies of potassium allenyl trifluoroborate salt in the
Petasis reaction.
2.3.2.1 Potassium organotrifluoroborate salts. General aspects
The air and water stable potassium organotrifluoroborate salts, are known
since the preparation of potassium trifluoromethyl trifluoroborate in 1960 by
Chambers et al
91
while the first non fluorinated analogue was potassium vinyl
organotrifluoroborates in 1963 by Stafford.
92
The initial synthetic approach involved
reaction between tin precursors 2.171 and boron trifluoride 2.172 followed by cation
exchange induced by subsequent reaction with KF (Scheme 2.18-equation 1). Even
though their existence and stability was known since the early 60s, their actual
synthetic potential and role was explored 40 years later, after the more practical and
less toxic preparation method developed by Vedejs,
93,94,95
(Scheme 2.18-equation 2)
in the course of generating chiral boron enolate equivalents. Their superior air and
water stability compared to the corresponding boronic acids made them promising
alternatives for processes that the later were employed.

Me
3
Sn-R BF
3 +
Me
3
Sn R-BF
3
-196 to RT
KF
R-BF
3
K+ Me
3
SnF
(1)
2 KHF
2
+
(2)
R-BF
3
KKF 2 H
2
O + +
CH
3
CN/H
2
O
R-B(OH)
2
2.3
2.174
2.172 2.173 2.176 2.171 2.175
2.177 2.175 2.174

Scheme 2.18: Synthetic methodologies towards potassium organotrifluoroborate salts

91

Since then, they have been employed to a plethora of transformations,
showing exceptionally good reactivity in some cases. An early example was the
transformation of potassium alkenyl trifluoroborate salts to the corresponding
fluorinated alkenes after reaction with an electrophilic fluorine reagent.
96
Such
transformations also include multiple versions of Suzuki coupling protocols after the
first successful attempts by Genet et al.
97
Batey et al used the same compounds for
Rh(I) catalyzed conjugate addition to enones as well as to aldehydes.
98
Allylation
and crotylation of aldehydes was also demonstrated by the same group.
99
Other
interesting applications include: enantioselective synthesis of 2-substituted
pyrrolidines,
100
spiroketals formation,
101
copper(II) catalyzed synthesis of ethers
102

and amines,
103
Rh(I) catalyzed methyl C-H functionalization
104
as well as Rh(I)
promoted synthesis of ketones from aldehydes.
105

Furthermore, the oxidative tolerance of the tetracoordinate “ate” boron
functionality of the organotrifluoroborate salts to specific oxidants allows for a
variety of oxidative transformations on the organic group. Among these are:
epoxidation
106
and cis-dihydroxylation
107
of double bonds, Swern oxidation of
primary and secondary alcohols,
108
synthesis of triazole containing organotrifluoro
borate salts by the copper (I) catalyzed 1, 3 dipolar cycloaddition of alkynes with
azides
109
and Wittig type olefinations of oxo-functionalized aryl potassium
organotrifluoroborate salt.
110
Application of chloramines-T as the oxidant, in
combination with inorganic salts, lead to the replacement of the boron functionality

92

with iodide or bromide by which a number of aryl, alkenyl and alkynyl halides was
obtained.
111, 112, 113

The participation of potassium organotrifluoroborate salts in the Petasis
reaction has been demonstrated earlier. Two other groups reported additional studies.
Kabalka et al
114
reported the use of alkynyl potassium trifluoroborates with
salicylaldehyde and secondary amines in ionic liquid media. Shortly after, Tremblay
et al
115
reported a Lewis acid catalyzed version of the process where various
potassium organotrifluroborates were employed.
Interestingly, the abovementioned studies revealed one more interesting
feature. The fact that the process can potentially operate under different mechanistic
modes, depending on the components used, on the reaction medium as well as on the
presence of additives. In cases where the presence of Lewis acid catalyst was
mandatory for the reaction to occur it was concluded that the formation of an
electrophilic RBF
2
is necessary for the three-component transformation. However, in
a different study which demonstrated the effect of the solvent, the mechanistic
hypothesis involves the intermediacy of a nucleophilic “ate” boron complex
(RBF
2
OR
-
).
114

These initial demonstrations of reactivity were limited to secondary amines
only since primary did not participate and the full potential of the organotrifluoro
borate salts for that process is still to be revealed. But these observations confirmed

93

the potential of other boron analogues for the Petasis reaction as well as revealed the
role of the reaction medium and additives to the outcome of the process.

2.3.2.2 Reactivity of potassium allenyl trifluoroborate salt in the α-amino acid
version of the Petasis reaction
As a part of our continuous efforts to explore and reveal the full potential that
allenyl boron derivatives have to offer to the Petasis reaction, we moved to examine
the reactivity of potassium allenyl trifluoroborate salt 2.178 for the process. The
characteristic of those derivatives such as their air and water stability and extended
self lives were of significant importance in the case of the allenyl group, since as
previously mentioned, the corresponding boronic acid is pyrophoric and can only be
stored under hexanes, at low temperatures, for a relatively limited period of time. In
addition, 2.178 should be more tolerant to the presence of various acids, if needed for
the process where the corresponding boronic acid undergoes proton deboronation.
The synthesis of potassium allenyl trifluoroborate was performed by the
reaction of the corresponding boronic acid with KHF
2
in CH
3
OH/H
2
O (Scheme
2.19).

94

B(OH)
2
•
BF
3
K
•
3.3 eq. KHF
2
+
MeOH/H
2
O
0
o
C-RT,
3.5hr, 68%
2.178 2.65 2.177

Scheme 2.19: The synthesis of allenyl potassium organotrifluoroborate salt

The first attempts we did were in the synthesis of α-amino acids. We initially
used toluene as the solvent and performed the experiments in the presence of 10%
Yb(OTf)
3
, as well as control experiments without the catalyst. Toluene was not
proven to be the best solvent in our case so we shifted to MeOH and CH
3
CN for our
next experiments.
The choice of Yb(OTf)
3
was based on the fact that it has been shown to
selectively activate aldimines in the presence of aldehydes, which would
theoretically lead to better conversions and more selective processes towards the
three-component product. Furthermore, this Lewis acid is the most active in the
series of lanthanide triflates and is water-compatible so no precautions are needed to
exclude moisture while this exact feature allows for reactions that can be performed
in aqueous media.
116

The general reaction for the transformation is depicted in Scheme 2.20.

95

BF
3
K
•
R
O
R
N
•
R
N
R
1
R
2
N
H
"Allenic α-amino acids" "Propargyl α-amino acids"
2.178 2.57
+
R
1
R
2
2.1
R
2
R
1
2.179a 2.179b

Scheme 2.20: Participation of potassium allenyl trifluoroborate salt in the Petasis reaction

Table 2.6 summarizes the first reactivity studies of 2.178

Table 2.6: Potassium allenyl trifluoroborate salt in the α-amino acid version of the
Petasis reaction
# Boron
cmpd
Carbonyl
Cmpd
Amine
cmpd
Product Conditions

BF
3
K
•
HO
OH
OH
O
1
Ph NH
2
OH
N
H Bn
O
OH
N
H Bn
O
•
2.115a
2.115b
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
Toluene 10 66/33 72
Toluene 0 100/0 43
BF
3
K
•
HO
OH
OH
O
2
OH
N
H
O
OH
N
H
O
•
2.120a
2.120b
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
Toluene 10 100/0 40
Toluene 0 100/0 30
MeOH 10 100/0 48
MeOH 0 100/0 31
NH
2
OMe
OMe
OMe
2.178
2.178 2.104
2.104
2.109
2.114

96

Table 2.6 (continued)
# Boron
cmpd
Carbonyl
Cmpd
Amine
Cmpd
Product Conditions
BF
3
K
•
HO
OH
OH
O
3
OH
N
H
O
OH
N
H
O
•
2.181a
2.181b
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
CH
3
CN 0 80/20 93
NH
2
NO
2
NO
2
NO
2
BF
3
K
•
HO
OH
OH
O
4
OH
NH
2
O
OH
NH
2
O
•
2.143a
2.143b
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
EtOH 10 100/0 32
EtOH 0 100/0 traces
BF
3
K
•
HO
O
-
NH
3
+
O
5
OH
NH
2
O
OH
NH
2
O
•
2.143a
2.143b
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
MeOH
(+ 10% Et
3
N) 10 No reaction
MeOH
(+ 10% Et
3
N) 0 100/0 traces
NH
3
BF
3
K
•
HO
OH
OH
O
6
OH
N
O
OH
N
O
•
2.125a
2.125b
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
Toluene 10 49/51 69
Toluene 0 66/34 65
MeOH 10 39/61 99
MeOH 0 63/37 89
CH
3
CN 10 73/27 90
CH
3
CN 0 100/0 66
BF
3
K
•
HO
OH
OH
O
7
OH
N
O
OH
N
O
•
2.128a
2.128b
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
CH
3
CN 0 100/0 90
Ph N
H
Ph
Ph Ph
Ph Ph
N
H
O
O
O
2.178
2.178
2.178
2.178
2.178
2.104
2.104
2.104
2.104
2.138
2.180
2.136
2.121
2.124

97

Table 2.6 (continued)
# Boron
cmpd
Carbonyl
Cmpd
Amine
Cmpd
Product Conditions

BF
3
K
•
HO
OH
OH
O
8
OH
N
O
OH
N
O
•
2.126a
2.126b
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
CH
3
CN 0 100/0 60
NH
2
BF
3
K
•
HO
OH
OH
O
9
OH
N
O
OH
N
O
•
2.127a
2.127b
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
CH
3
CN 0 100/0 94
Ph
Ph
N
H
Ph
BF
3
K
•
HO
OH
OH
O
10
OH
N
O
OH
N
O
•
2.183a
2.183b
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
CH
3
CN 0 100/0 65
Ph
Ph
Ph
Ph
Ph
N
H
Ph
2.178
2.178
2.178
2.104
2.104
2.104
2.122
2.123
2.182

As concluded by the abovementioned studies, fluoroborate 2.178 can be used
as an alternative, more stable allenyl boron source for the amino acid version of the
Petasis reaction since it was proven reactive in all attempts. Our control experiments
showed that the reaction preceded smoothly in common organic solvents even in the
absence of catalyst with somewhat lower yields. For the moment, no optimization
studies were performed and no ionic liquids were used as alternative reaction media.
Conventional heating and microwave conditions were not proven efficient since we

98

only observed decomposition of the boron component. No product was detected at
all. So the trials were performed at ambient temperature, without any precautions to
exclude air or moisture. The reaction times varied from 27 to 30 hr.
Surprisingly, as shown in entries 1-3 in Table 2.6, our studies are the first to
demonstrate reactivity of an organotrifluroborate in this process when primary
amines are used. Both aliphatic and aromatic amines yielded the three-component
product in moderate to good yields. Even though the reactions are not optimized, the
isolated yield that potassium allenyl trifluoroborate 2.178 gave when used with p-
anisidine 2.114 is superior to that obtained with the corresponding boronic acid 2.65.
Benzylamine 2.109 gave comparable yield when Yb(OTf)
3
was used catalytically but
in this case the appearance of the allenyl amino acid was also observed. As seen
from all our trials, the use of Yb(OTf)
3
promoted formation of the allenyl three-
component product. The use of p-nitroaniline 2.180 in the absence of Yb(OTf)
3
gave
a mixture of both products indicating multiple mechanistic pathways for this version.
But even on this latter case, the main isomer obtained was the acetylenic one, so this
version followed the same trend as in the case of 2.65 favoring the acetylenic isomer.
More interesting results were obtained in the case of secondary amines and a
different outcome was observed as far as the isomeric composition of the products is
concerned. To our surprise, the use of 2.178 in combination with secondary amines
favors formation of the acetylenic α-amino acids, in contrast to the use of 2.65 which
in this case gives exclusively the corresponding allenic α-amino acids. In solvents

99

such as toluene or MeOH, our standard reaction with dibezylamine 2.121 gave
mixtures of both isomers. The use of Yb(OTf)
3
had the same effect here as well, thus
promoting the formation of the allenyl isomer and when MeOH was employed as the
solvent the affect was so dramatic that the isomeric ratio was reversed. From our
results there was not a case where the use of catalyst gave exclusively the allenic
product. It is worth mentioning that all the yields obtained by using 2.178 were
superior compared to 2.65 and MeOH gave excellent yields in some cases, probably
due to better solvation and dissolution of the highly polar and ionic boron salt.
As already mentioned the reaction proceeded in the absence of catalyst and
favored the acetylenic product. So the next thing that we turned our attention to was
to explore if by altering the reaction conditions, we would be able to obtain the
acetyllenic product exclusively. This would add significant synthetic value to our
process since by a simple alteration of the boron component someone can have
direct, one-step access to both isomers in very good yields. To our satisfaction a
significant solvent effect was observed and when CH
3
CN was employed. The control
experiment with dibenzylamine gave the acetylenic isomers as the sole product. We
were curious to see if the solvent effect would overcome the promotion of the allenic
isomer induced by Yb(OTf)
3
and concomitantly give us better yields but as we saw
the allenic isomer was indeed formed (even in lower ratio compared to MeOH and
toluene). Thus, we employed CH
3
CN in our next tests to check if this solvent effect
is general to the use of a number of different secondary amines. As seen in entries 7-

100

9 in Table 2.6 the use of CH
3
CN yielded only the complementary acetyllenic
products in good to excellent yields. In the case of N-phenyl benzylamine 2.182,
16% of the allenic isomer 2.183b was observed in the crude reaction mixture.

2.3.2.3 Mechanistic hypothesis
Based on the results obtained by employing potassium allenyl trifluoroborate
2.178 in the α-amino acid version of the Petasis reaction, a proposed mechanistic
scheme is depicted below (Scheme 2.21).
R
1
N
R
2
H
H
O
+
HO
NH
R
2
R
1
k
1
k
-1
N
R
1
•
NH
R
1
"Allenic Isomer"
N
R
2
R
1
"Propargylic Isomer"
k
2
k
-2
OH OH
OH
O
O
-
O
O O
N
R
2
R
1
O
-
O
k
7
2.1 2.104
2.129
HO
O
(-H
2
O)
2.131
k
-5
k
5
2.178
2.186
N
R
1
OH
O
2.185
(R
2
=H)
k
3
k
-3
Yb(OTf)
3
BF
3
K
• 2.178
k
4
k
-4
F
Yb
B
•
F
F
N
R
1
-O
O 2.178
2.131
F
R
2
B
•
F
F
N
R
1
-O
O
2.178
2.131
R
2
•
B
F
F
F
2.178
k
-6
k
6
k
9
k
8
BF
3
K
•

Scheme 2.21: Proposed mechanism for 2.178 in the Petasis reaction

101

Based on observations such as the diastereomeric distribution of the products,
the preference of the propargylic isomer even when secondary amines were
employed along with the promotion of the allenyl isomer in the Yb(OTf)
3
catalyzed
version and the tremendous solvent effect observed in CH
3
CN lead us to speculate
that multiple pathways can operate depending on the conditions and the reaction
medium. A descriptive, but by no means comprehensive mechanistic hypothesis is
depicted in Scheme 2.21. Taking into account that 2.178 is not hydrolyzed under the
applied conditions, we speculate that the formation of products mainly originates
from intermolecular processes while the promotion of the allenic products formation
when Yb(OTf)
3
is used to catalyze the reaction, could additionally be due to
complexation with one of the fluoride atoms on the boron apart from the
intermolecular process that can operate separately. Also the formation of the
propargyl products from the use of secondary amines in CH
3
CN reveals one more
possible mode of reaction for 2.178. That is the reaction of the γ-carbon atom of the
boron species as the attacking nucleophile in a concerted (shown in Scheme 2.21) on
a stepwise manner. Enhanced steric hindrance would probably favor this pathway.

102

2.3.2.4 Reactivity of potassium allenyl trifluoroborate salt in the β-amino
alcohol version of the Petasis reaction
Our next experiments involved the use of 2.178 with glycolaldehyde dimer
2.144 in synthesizing β-amino alcohols. Our efforts are summarized in Table 2.7
Table 2.7: Potassium allenyl trifluoroborate salt in the Petasis reaction
# Boron
cmpd
Carbonyl
Cmpd
Amine
Cmpd
Product Conditions

BF
3
K
• 1
Ph NH
2
OH
N
H Bn
OH
N
H Bn
•
2.149a
2.149b
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
Toluene 10 - 0
Toluene 0 - 0
2
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
MeOH 0 0/100 89
CH
3
CN 0 0/100 89
BF
3
K
• 3
OH
N
H
OH
N
H
•
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
Toluene 10 29/71 19
Toluene 0 65/35 20
NH
2
OMe
OMe
OMe
O
O OH
HO
BF
3
K
•
Ph NH
2.
HCl
OH
N
H Bn
OH
N
H Bn
•
O
O OH
HO
BF
3
K
•
OH
N
OH
N
•
Solvent Yb(OTf)
3
a/b Yield
(%) (%)
Toluene 10 0/100 35
Toluene 0 0/100 14
MeOH 10 0/100 55 (3.5hr)
CH
3
CN 10 0/100 20 (3.5 hr)
Ph N
H
Ph
Ph Ph
Ph Ph
4.
O
O OH
HO
O
O OH
HO
2.178 2.144 2.109
2.149a
2.149b
2.178 2.144 2.184
2.157
2.156
2.178 2.144 2.114
2.158a
2.158b
2.178 2.144 2.121

103

As seen by the abovementioned results, 2.178 participated in the process and
formed the allenic three-component products (as observed with 2.65 as well) but the
yields were inferior so the number of amines tested was limited and no further
studies were performed. All the reactions were conducted at ambient temperature
since heating (65
o
C, entry not included in Table 2.7) lead once more to complete
decomposition of the boron component and no product was detected at all. The
reaction times were in the range of 24-30 hr. In all the trials, even in the cases where
the reaction proceeded, the starting amine was never completely consumed.
Under conventional conditions, benzylamine 2.109 failed to react both in the
presence and absence of catalyst where p-anisidine 2.114 reacted poorly giving a
mixture of both isomers (this was also observed when 2.65 was employed in the
reaction). In the uncatalyzed process the acetyllenic isomer 2.157 is favored but in
the presence of Yb(OTf)
3
the ratio is almost reversed to favor the allenic 2.156, an
effect also observed in the α-amino acids series. The solvent did not have dramatic
results in these trials even though MeOH did give somewhat better conversion in
shorter time (55% isolated yield in 3.5 hr) compared to CH
3
CN and toluene (entry
4).
The only surprising and promising results ironically came from the last two
trials in this series. That was an attempt to employ modified Mannich conditions in
the process, in an effort to avoid the complications that accompany the use of
glycoladehyde in the presence of primary amines (see section 2.3.1.3) which lead to

104

the participation of the aldehyde to side reactions thus resulting in poorer yields and
very crude reaction mixtures. This is particularly important in the case of 2.178 since
it is less reactive compared to the boronic acid. To our satisfaction, using 2.5
equivalents of preformed benzylamine hydrochloride 2.184 in both CH
3
CN and
MeOH gave the expected allenyl three-component- product 2.149b in 89% yield
(both solvents gave the same yield). These results opens up new directions for the β-
amino alcohol version of this process that concern not only 2.178, for which a new
series of experiments is essential after that important outcome, but a plethora of
boron components since the use of glycolaldehyde dimer 2.144 is in general not as
efficient as that of glyoxylic acid monohydrate 2.104 for this transformation.
2.4 Experimental
2.4.1 General
All the reactions were performed at ambient temperature under N
2
. The
solvents were used without further purification and no dry conditions were necessary
unless otherwise stated. The allenyl boronic acid 2.65 was transferred as a
suspension in hexane. Hexane was removed and the solid was dried prior to the
reaction. It was not exposed to air as it is known to be a pyrophoric material. It was
always transferred as a suspension (in DCM) or as a solution (in EtOH and MeOH)
and added to the reaction mixture. The reactions were monitored by TLC on Silica
Gel 60 precoated plates with F
254
indicator. The product was purified by flash

105

chromatography on Silica 60 Å 32-63 µm unless otherwise stated.
1
H and
13
C NMR
were recorded on a Bruker AMX500 or an AM360 MHz, or an AC250 MHz or a
Varian Mercury 400 NMR. Chemical shifts of
1
H NMR are reported in parts per
million on the δ scale from an internal standard of either residual chloroform (7.24
ppm), DMSO d
6
(2.49 ppm), acetone d
6
(2.04 ppm) or partly deuterated MeOH (3.3
ppm). Data are reported as follows: chemical shift, multiplicity (s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet and br=broad), coupling constants in Hz
and integration. Chemical shifts of
13
C NMR are reported in ppm from the central
peak of either CDCl
3
(77.0 ppm), DMSO d
6
(39.5 ppm) or partly deuterated MeOH
(49.5 ppm). FAB and EI ionization techniques were used for the determination of the
molecular weights for some of the newly synthesized molecules.
2.4.2 Synthesis and physical data

BF
3
K
•
2.178

Potassium allenyl trifluoroborate (2.178). To a solution of 2.65 in MeOH
(0.524g, 6.2mmol in 2 ml MeOH) cooled at 0
o
C was slowly added 14.6 ml of an
aqueous solution of KHF
2
(0.1g/ml, 18.7 mmol, 3.3 eq.). The addition lasted for
30min and then the ice-water bath was removed and the system was allowed to warm
up to R.T. under stirring for an additional 3hr. The solvents were removed under

106

vacuum and the crude and wet solids were left to dry overnight under high vacuum.
The residue was subsequently extracted twice with dry acetone and the filtrate was
collected. After removal of the solvent under reduced pressure a, fluffy and shiny
light solid residue remained in the flask. This was further dried by transferring as a
suspension in DCM on a buchner funnel, under sunction filtration and further
standing in high vacuum. One more treatment was performed with dry acetone in
order to completely remove any residual inorganic salts. The filtrate was collected,
the solvent was removed under reduced pressure and the fluffy solid was finally
dried completely under high vacuum overnight. Yield: 0.618g or 68.2%.
1
H NMR (400 MHz, DMSO d
6
) δ 4.47 (bs, 1H), 3.94 (b, 2H),
13
C NMR (90
MHz, DMSO d
6
) δ 209.85, 65.52,
19
F NMR (??? MHz, DMSO, d
6
) δ -133.74 (q,
J=47.8 Hz)

O
-
NH
3
O
2.143a

2-Amino-pent-4-ynoic acid (2.143a). To a suspension of 0.057g (0.63mmol)
hydroxyglycine 2.138 in 1 ml of MeOH was added 0.2 equivalents of Et
3
N (18µl)
and the system was stirred at ambient temperature for 5 min. A solution of 2.65
(0.75mmol in 1.5 ml MeOH) was added in one portion to the abovementioned
suspension and the system was left under stirring at R.T. for a total 15 hr (at t=12hr

107

0.20mmol of 2.65 was added to the reaction mixture) and the white precipitate was
filtered off and washed with 2 ml of cold MeOH. Yield: 0.051g or 72%.
1
H NMR (250 MHz, MeOH d
4
, DCl) δ 4.20 (t, J= 5.2 Hz, 1H), 2.123 (dd,
J
1
=5.0 Hz, J
2
=2.8 Hz, 2H), 2.65 (t, J=2.8 Hz, 1H),
13
C NMR (62 MHz, MeOH d
4
,
DCl) δ 170.55, 77.55, 75.58, 52.128, 21.98.

OH
N
H
O
2.115a

2-benzylamino-pent-4-ynoic acid (2.115a). In a 25-ml round bottomed
flask equipped with a magnetic stirrer, 5 ml of DCM were placed followed by
glyoxylic acid monohydrate 2.104 (0.258 g, 2.8 mmol) and benzylamine 2.109
(0.300 g, 2.8 mmol). To that mixture, a suspension of allenyl boronic acid 2.65
(0.235 g, 2.8 mmol) in 4 ml DCM was added in one portion. The system was left
under stirring at R.T. for 24 hr. The white solid that precipitated out of the reaction
mixture was filtered under vacuum and was washed with DCM and cold MeOH. It
was dried under high vacuum. Yield: 0.460 g or 81%.
1
H NMR (500 MHz, MeOH d
4
, DCl) δ 7.6-7.5 (m, 2H), 7.5-7.4 (m, 3H), 4.35
(s, 2H), 4.19 (t, J=5.3 Hz, 1H), 3.04 (dd, J
1
=4.9 Hz, J
2
=2.1 Hz, 2H), 2.67 (t, J=2.1
Hz, 1H) .
13
C NMR (125 MHz, MeOH d
4
, DCl) δ 169.92, 132.27, 131.98, 131.35,

108

130.76, 77.44, 75.84, 59.06, 52.05, 20.93. FAB MS (M+1): 204.09 (expected mass),
204.19 (experimental value).

OH
N
H
O
2.116a
Ph
Ph
OH
N
H
O
2.116b
Ph
Ph
•
and

2-(Benzhydryl-amino)-pent-4-ynoic (2.116a) acid and 2-(Benzhydryl-
amino)-penta-3, 4-dienoic acid (2.116b). In a 25-ml round bottomed flask
equipped with a magnetic stirrer, 4 ml of MeOH were placed followed by glyoxylic
acid monohydrate 2.104 (0.166 g, 1.8 mmol) and aminodiphenyl methane 2.110
(0.330 g, 1.8 mmol). To that mixture, a suspension of allenyl boronic acid 2.65
(0.200 g, 2.4 mmol) in 2 ml MeOH was added in one portion. The system was left
under stirring at R.T. for 24 hr. The white solid that precipitated out of the reaction
mixture was filtered under vacuum and was washed with DCM and MeOH. From the
filtrate, another small amount of product was isolated after complete removal of
B(OH)
3
through continuous additions/evaporations of MeOH (5x10ml MeOH), and
washing the residue with acetone. The combined solid was completely dried under
high vacuum. The
1
H and
13
C NMR spectra showed the presence of both products.
Propargyl(2.116a)/Allenyl(2.116b)= 1/0.47. Yield: 0.330 g or 66%.
1
H NMR (500 MHz, MeOH d
4
, DCl) δ 7.67-7.61 (m, 6.3H), 7.49-7.37 (m,
9.1H), 5.70 (s, 1H), 5.67 (s, 0.5H), 5.47 (m, 0.45H), 5.15-5.08 (m, 1.14H), 4.10 (d,

109

J=9.7 Hz, 0.47H), 3.88 (t, J=5.5 Hz, 1H), 3.12-3.02 (m, 2H), 2.64 (t, J=2.4Hz, 1H).
13
C NMR (125 MHz, MeOH d
4,
DCl) δ 212.121, 169.75 (major) and 169.57 (minor),
137.06 (major) and 136.95 (minor), 136.40 (minor) and 136.17 (major), 131.14,
131.00, 130.93, 130.86, 129.86, 129.81, 129.71, 129.49, 84.00, 80.00, 77.49, 75.69,
67.73, 66.10, 59.92, 59.16, 21.27

OH
N
H
O
2.117a

2-allylamino-pent-4-ynoic acid (2.117a). In a 25-ml round bottomed flask
equipped with a magnetic stirrer, 2 ml of MeOH were placed followed by glyoxylic
acid monohydrate 2.104 (0.166 g, 1.8 mmol) and allylamine 2.111 (0.103 g, 1.8
mmol). To that mixture, a suspension of allenyl boronic acid 2.65 (0.200 g, 2.4
mmol) in 2 ml MeOH was added in one portion. The system was left under stirring at
R.T. for 24 hr. The white solid that precipitated out of the reaction mixture was
filtered under vacuum and was washed with DCM and cold MeOH. From the filtrate,
another small amount of product was isolated after complete removal of B(OH)
3

through continuous additions/evaporations of MeOH (5x10ml MeOH), and washing
the residue with acetone. The combined solid was completely dried under high
vacuum. Yield: 0.175 g or 64%.

110

1
H NMR (500 MHz, MeOH d
4
) δ 5.95 (m, 1H), 5.50 (m, 2H), 3.73 (m, 2H),
3.63 (t, J=4.8 Hz, 1H), 2.87 (m, 2H), 2.58 (bt, J=2.7 Hz, 1H).
13
C NMR (125 MHz,
MeOH d
4
) δ 171.97, 130.04, 124.68, 79.06, 74.83, 60.83, 50.62, 21.42

2.118a
N
H
O
OH

2-[(Adamantan-1-ylmethyl)-amino]-pent-4-ynoic acid (2.118a). In a 25-
ml round bottomed flask equipped with a magnetic stirrer, 6 ml of DCM were placed
followed by glyoxylic acid monohydrate 2.104 (0.214 g, 2.3 mmol) and 1-
Adamantylmethylamine 2.112 (0.214 g, 2.3 mmol). To that mixture, a suspension of
allenyl boronic acid 2.65 (0.196 g, 2.3 mmol) in 5 ml DCM was added in one
portion. The system was left under stirring at R.T. for 24 hr. The white solid that
precipitated out of the reaction mixture was filtered under vacuum and was washed
with DCM and cold MeOH. Yield: 0.260 g or 43%.
1
H NMR (500 MHz, MeOH d
4
) δ 4.20 (t, J=6.3 Hz, 1H), 3.04 (dd, J
1
=6.3 Hz,
J
2
=2.4 Hz, 2H), 2.121 (d, J=12.2 Hz, 1H), 2.81 (d, J=12.4 Hz, 1H), 2.69 (bt, J= 2.12
Hz, 1H), 2.04 (bs, 3H), 1.81-1.66 (m, 12H).
13
C NMR (125 MHz, MeOH d
4
) δ
169.90, 78.10, 75.49, 60.18, 59.58, 40.93, 37.88, 33.97, 29.83, 20.25, 20.19

111

OH
N
H
O
OH
N
H
O
•
2.181a 2.181b
NO
2
NO
2
and

2-(4-nitro-phenylamino)-pent-4-ynoic acid (2.181a, 73%) and 2-(4-nitro-
phenylamino)-penta-3, 4-dienoic acid, (2.181b, 17%). In a 10-ml round bottomed
flask equipped with a magnetic stirrer, 1.8 ml of CH
3
CN were placed followed by
glyoxylic acid monohydrate 2.104 (0.046 g, 0.5 mmol) and 4-nitroaniline 2.180
(0.069 g, 0.5 mmol). To that mixture, allenyl potassium organotrifluoroborate 2.178
(0.100 g, 0.68 mmol) was added in one portion. The system was left under stirring at
R.T. for 30 hr. The amine had not been completely consumed at that time but the
reaction was stopped. Everything was solubilized by addition of 5 ml of MeOH and
crude NMR was run. From that the isomeric composition of the products was
determined (Propargyl(2.181a)/Allenyl(2.181b)= 80/20). The impurities were
removed with gradient flash chromatography (EtOAc/MeOH/NH
4
OH, 85/10/5 to
80/15/5). Yield: 0.109 g, 93%.
1
H NMR (250 MHz, MeOH d
4
) δ 8.01 (d, J= 8.9Hz, 2.2H), 6.70-6.62 (d,
J=8.2Hz, 2.4H), 5.39 (q, J=6.5Hz, 0.2H), 4.93 (br, H
2
O peak), 4.90-4.78 (m, 0.6H),
4.4 (m, 0.21H), 4.09 (t, J=6.1 Hz, 1H), 2.85-2.65 (m, 2H), 2.30 (t, J=2.6Hz, 1H).
13
C
NMR (62.5 MHz, MeOH, d
4
) δ 210.32, 177.58 (major) and 176.72 (minor), 155.41
(major) and 154.95 (minor), 138.90 (major) and 138.82 (minor), 127.65 (major) and

112

127.53 (minor), 113.31 (minor) and 113.03 (major), 91.71, 81.72, 78.84, 72.37,
58.51, 23.96

•
N
OH
O
2.127b
Ph

2-(benzyl-methyl-amino)-penta-3,4-dienoic acid (2.127b). In a 25-ml
round bottomed flask equipped with a magnetic stirrer, 3.3 ml of EtOH were placed
followed by glyoxylic acid monohydrate 2.104 (0.110 g, 1.19 mmol) and N-methyl
benzylamine 2.123 (0.15 ml, 1.19 mmol). To that mixture, a suspension of allenyl
boronic acid 2.65 (0.100 g, 1.19 mmol) in 2.3 ml DCM was added in one portion.
The system was left under stirring at R.T. for 24 hr. The crude mixture was purified
with flash chromatography (MeOH/EtOAc/NH
4
OH, 10/85/5). Yield: 0.168 g or
65%.
1
H NMR (500 MHz, MeOH d
4
) δ 7.56 (m, 2H), 7.46 (m, 3H), 5.40 (m, 1H),
5.09 (m, 2H), 4.33 (d, J=12.5 Hz, 1H), 4.22 (d, J=12.7, 1H), 4.12 (d, J=9.9 Hz), 2.72
(s, 3H).
13
C NMR (125 MHz, MeOH d
4
) δ 214.36, 171.20, 132.50, 132.13, 131.50,
130.77, 84.21, 78.04, 70.89, 59.65, 38.81. FAB MS (M+1): 218.16 (expected mass),
218.21 (experimental value).

113

OH
N
O
2.127a
Ph

2-(benzyl-methyl-amino)-pent-4-ynoic acid (2.127a). The same exact
conditions as for synthesis of 2.181a/2.181b. The propargylic product was
exclusively obtained. Impurities and the residual starting materials were removed by
gradient flash chromatography (EtOAc/MeOH/NH
4
OH, 85/10/5 to 80/15/5). Yield:
0.102 g or 94%.
1
H NMR (250 MHz, MeOH d
4
) δ 7.58-7.54 (m, 2H), 7.45-7.43 (m, 3H), 4.94
(br, H
2
O peak), 4.43 (d, J=12.6 Hz, 1H), 4.31 (d, J=12.4 Hz, 1H), 3.75 (dd, J
1
=7.3
Hz, J
2
=4.9 Hz, 1H), 3.08-2.85 (m, 2H), 2.82 (s, 3H), 2.61 (t, J=2.7 Hz, 1H).
13
C
NMR (62.5 MHz, MeOH d
4
) δ 171.74, 133.11, 132.36, 131.18, 130.65, 80.88, 74.42,
68.02, 60.40, 39.06, 19.09.

OH
N
O
2.125a
Ph Ph

2-dibenzylamino-pent-4-ynoic acid(2.125a). The same exact conditions as
for synthesis of 2.181a/2.181b. The propargylic product was exclusively obtained.
Impurities and the residual starting materials were removed by gradient flash
chromatography (EtOAc/MeOH/NH
4
OH, 85/10/5 to 80/15/5). Yield: 0.096g or 66%.

114

1
H NMR (250 MHz, MeOH d
4
) δ 7.43-7.40 (m, 4H), 7.36-7.18 (m, 6H), 4.94
(br, H
2
O peak), 3.87 (d, J=13.7 Hz, 2H), 3.67 (d, J=13.6 Hz, 2H), 3.51 (dd, J
1
=7.9
Hz, J
2
=7.0 Hz, 1H), 2.74-2.52 (m, 2H), 2.31 (t, J=2.6 Hz, 1H).
13
C NMR (62.5 MHz,
MeOH d
4
) δ 174.62, 140.50, 130.65, 130.19, 129.82, 128.85, 82.67, 72.00, 62.26,
56.17, 20.67

OH
N
O 2.128b
O
•

2-Morpholin-4-yl-penta-3,4-dienoic acid (2.128b). In a 10-ml round
bottomed flask equipped with a magnetic stirrer, 2 ml of MeOH were placed
followed by glyoxylic acid monohydrate 2.104 (0.166 g, 1.8 mmol) and Morpholine
2.124 (0.157 g, 1.8 mmol). To that mixture, a solution of allenyl boronic acid 2.65
(0.200 g, 2.4 mmol) in 2 ml MeOH was added in one portion. The system was left
under stirring at R.T. for 24 hr. Complete removal of B(OH)
3
from the crude reaction
mixture was performed through continuous additions/evaporations of MeOH
(5x10ml MeOH). The product precipitated by treatment of the residue with DCM
and Hexanes. The solid was filtered through sunction filtration and washed with cold
EtOEt. It was completely dried under high vacuum. Yield: 0.230 g or 69.7%.

115

1
H NMR (500 MHz, MeOH d
4
) δ 5.50 (m, 1H), 5.22 (m, 2H), 4.71 (d, J=9.3
Hz, 1H), 4.08 (t, J=11.3 Hz, 2H), 3.93 (m, 2H), 3.59 (dd, J
1
=45.1 Hz, J
2
=12.1 Hz,
2H), 3.42-3.27 (m, 2H).
13
C NMR (125 MHz, MeOH d
4
) δ 214.14, 168.97, 82.38,
79.70, 68.84, 65.31, 53.06, 51.34

OH
N
O
2.128a
O

2-Morpholin-4-yl-pent-4-ynoic acid (2.128a). The same exact conditions as
for synthesis of 2.181a/2.181b. The propargylic product was exclusively obtained.
Impurities and the residual starting materials were removed by gradient flash
chromatography (EtOAc/MeOH/NH
4
OH, 80/15/5 to 75/20/5). Yield: 0.082g or 90%.
1
H NMR (250 MHz, MeOH d
4
) δ 3.85 (t, J=5.0 Hz, 4H), 3.54 (t, J=5.7 Hz,
1H), 3.14- 3.10 (m, 4H), 2.122-2.71 (m, 2H), 2.49 (t, J=2.12 Hz, 1H).
13
C NMR (62.5
MHz, MeOH d
4
) δ 172.43, 80.57, 73.75, 69.93, 66.80, 52.36, 19.77

116

OH
N
O
2.126b
•

2-diallylamino-penta-3, 4-dienoic acid (2.126b). In a 10-ml round bottomed
flask equipped with a magnetic stirrer, 2 ml of MeOH were placed followed by
glyoxylic acid monohydrate 2.104 (0.166 g, 1.8 mmol) and diallylamine 2.122
(0.175 g, 1.8 mmol). To that mixture, a solution of allenyl boronic acid 2.65 (0.200
g, 2.4 mmol) in 2 ml MeOH was added in one portion. The system was left under
stirring at R.T. for 24 hr. Complete removal of B(OH)
3
from the crude reaction
mixture was performed through continuous additions/evaporations of MeOH
(5x10ml MeOH). The product was purified by gradient flash chromatography
(EtOAc/MeOH/NH
4
OH, 85/10/5 to 80/15/5). Yield: 0.230 g or 66%.
1
H NMR (500 MHz, MeOH d
4
) δ 5.96 (m, 2H), 5.51 (m, 4H), 5.35 (m, 1H),
5.03 (d, J=6.4 Hz, 2H), 4.17 (d, J=10 Hz, 1H), 3.81 (dd, J
1
=13.8 Hz, J
2
=6.8 Hz, 2H),
3.62 (dd, J
1
=13.4, J
2
=8 Hz, 2H).
13
C NMR (125 MHz, MeOH d
4
) δ 213.70, 172.25,
130.02, 125.70, 84.78, 77.78, 67.57, 55.25

117

OH
N
O
2.126a

2-diallylamino-pent-4-ynoic acid (2.126a). The same exact conditions as for
synthesis of 2.181a/2.181b. The propargylic product was exclusively obtained.
Impurities and the residual starting materials were removed by gradient flash
chromatography (EtOAc/MeOH/NH
4
OH, 85/10/5 to 80/15/5). Yield: 0.058g or 60%.
1
H NMR (250 MHz, MeOH d
4
) δ 6.06-5.89 (m, 2H), 5.54-5.44 (m, 4H), 4.93
(br, H
2
O peak), 3.84 (dd, J1=7.2 Hz, J2=5.4 Hz, 1H), 3.79-3.76 (br.d, J=7.1 Hz, 4H),
3.00-2.76 (m, 2H), 2.55 (t, J=2.6 Hz, 1H).
13
C NMR (62.5 MHz, MeOH d
4
) δ 172.12,
131.44, 124.56, 80.85, 74.06, 64.57, 55.81, 19.15

OH
N
O
2.183a
Ph
Ph

2-(benzyl-phenyl-amino)-pent-4-ynoic acid(2.183a). The same exact
conditions as for synthesis of 2.181a/2.181b. The reaction was stopped at t=30 hr.
Everything was solubilized by addition of 5 ml of MeOH and crude
1
H NMR was
run. From that the isomeric composition of the products was determined
(Propargyl(2.183a)/Allenyl(2.183b)= 84/16). Impurities and the residual starting
materials were removed by conducting gradient flash chromatography twice. Flash 1:

118

(EtOAc/MeOH/NH
4
OH, 85/10/5 to 80/15/5). After that the product was not
completely purified so a second purification through flash chromatography was
attempted. The propargyl product was collected almost pure (traces of the allenyl
isomer were observed in the NMR spectra) but also the starting amine reappeared in
some samples (had been completely removed by the first purification attempt). Most
likely partial decomposition occurs on the silica. Yield: 0.09g or 65%.
1
H NMR (250 MHz, MeOH d
4
) δ 7.39 (d, J=7.3 Hz, 2H), 7.22 (t, J=7.2 Hz,
2H), 7.17 (d, J=7.3 Hz, 1H), 7.06 (dd, J
1
= 8.8 Hz, J
2
= 7.4 Hz, 2H), 6.83 (d, J=7.9 Hz,
2H), 6.62 (t, J=7.0 Hz, 1H), 4.93 (br, H
2
O peak), 4.62 (dd, J
1
=8.4 Hz, J
2
=5.8 Hz,
1H), 4.59 (s, 2H), 2.85 (ddd, J
1
=17.0 Hz, J
2
=5.7 Hz, J
3
=2.6 Hz, 1H), 2.65 (ddd,
J
1
=16.9 Hz, J
2
=8.4 Hz, J
3
=2.6 Hz, 1H), 2.25 (t, J=2.6 Hz, 1H).
13
C NMR (not
available)

OH
N
H
•
2.149b

2-benzylamino-penta-3,4-dien-1-ol (2.149b). In a 25-ml round bottomed
flask equipped with a magnetic stirrer, 10 ml of MeOH were placed followed by
glycolaldehyde dimer 2.144 (0.384 g, 3.2 mmol) and benzylamine 2.109 (0.568 g,
579 µl, 5.3 mmol). To that mixture, a solution of allenyl boronic acid 2.65 (0.538 g,

119

6.4 mmol) in 5.0 ml MeOH was added in one portion. The system was left under
stirring at R.T. for 15 hr. Impurities and the residual starting materials were removed
by gradient flash chromatography (MeOH/DCM, 2% to 5% to 10%). Yield: 0.459g
or 46%.
1
H NMR (400 MHz, CDCl
3
) δ 7.31 (d, J=4.5 Hz, 4H), 7.27-7.22 (m, 1H),
5.09 (q, J= 6.7 Hz, 1H), 4.85 (m, 2H), 3.92 (d, J=13.0 Hz, 1H), 3.71 (d, J=12.12 Hz,
1H), 3.62 (dd, J
1
=10.5 Hz, J
2
= 4.2 Hz, 1H), 3.35 (dd, J
1
=10.6 Hz, J
2
= 8.1 Hz, 1H),
3.29-3.24 (m, 1H).
13
C NMR (100 MHz, CDCl
3
) δ 208.07, 139.91, 128.40, 128.22,
127.08, 90.04, 76.94, 64.81, 57.60, 51.10

OH
HN
•
N
2.155b

2-(2-Dimethylamino-ethylamino)-penta-3,4-dien-1-ol(2.155b). In a 25-ml
round bottomed flask equipped with a magnetic stirrer, 10 ml of DCM were placed
followed by glycolaldehyde dimer 2.144 (0.178 g, 1.48 mmol) and N,N
dimethylethylene diamine 2.154 (0.261 g, 325 µl, 2.126 mmol). To that mixture, a
suspension of allenyl boronic acid 2.65 (0.249 g, 2.126 mmol) in 5.0 ml DCM was
added in one portion. The system was left under stirring at R.T. for 48 hr. Impurities
and the residual starting materials was attempted to be removed by gradient flash
chromatography. Flash chromatography was conducted twice but the product was

120

not eluted 100% pure. (EtOAc/MeOH/NH
4
OH, 10/85/5 to 15/80/5). Yield: 0.082g or
16%.
1
H NMR (500 MHz, CDCl
3
) δ 5.10 (q, J= 7.3 Hz, 1H), 4.74 (dd, J
1
=6.6 Hz,
J
2
= 2.2 Hz, 2H), 3.60-3.56 (dd, J
1
=11.1 Hz, J
2
= 4.2 Hz, 1H), 3.35 (dd, J
1
=10.6 Hz,
J
2
= 8.0 Hz, 2H), 3.19 (br.s, 1H), 2.82 (m, 1H), 2.56 (m, 1H), 2.43 (m, 1H), 2.33 (m,
1H), 2.18 (s, 6H).
13
C NMR (125 MHz, CDCl
3
) δ 208.09, 90.11, 76.34, 64.78, 59.11,
58.71, 45.20, 44.12

OH
N
H
OH
N
H
•
2.157 2.156
OMe OMe
and

2-(4-Methoxy-phenylamino)-pent-4-yn-1-ol (2.157) and 2-(4-Methoxy-
phenylamino)-penta-3,4-dien-1-ol (2.156). In a 25-ml round bottomed flask
equipped with a magnetic stirrer, 6.0 ml of DCM were placed followed by
glycolaldehyde dimer 2.144 (0.226 g, 1.88 mmol) and p-anisidine 2.114 (0.384 g,
3.12 mmol). To that mixture, a suspension of allenyl boronic acid 2.65 (0.262 g, 3.12
mmol) in 6.0 ml MeOH was added in one portion. The system was left under stirring
at R.T. for 27 hr. A sample was withdrawn from the crude reaction mixture and the
isomeric composition of the products was calculated by
1
H NMR. Both isomers were
obtained (propargyl/allenyl=50/50). Impurities and the residual starting materials

121

were removed by gradient flash chromatography (Et
2
O/DCM, 0% to 10% to 20%).
Both isomers were eluted and no complete separation was feasible from this
purification. Yield: 0.500g or 78%.
1
H NMR (250 MHz, CDCl
3
) δ 6.86-6.58 (m, J= 8.9Hz, 5.6H), 5.17 (q,
J=6.3Hz, 0.3H), 4.82 (dt, J
1
=6.8Hz, J
2
=2.6Hz, 0.7H), 3.95 (m, 0.4H), 3.83-3.73
(s&m, 6.6H), 3.58 (m, 1.4H), 2.46 (m, 2H), 2.03 (t, J=2.6Hz, 1H).

•
N
OH
2.158b

2-dibenzylamino-penta-3,4-dien-1-ol (2.158b). In a 25-ml round bottomed
flask equipped with a magnetic stirrer, 5.5 ml of DCM were placed followed by
glycolaldehyde dimer 2.144 (0.120 gr, 1 mmol) and dibenzylamine 2.121 (0.346 gr,
1.8 mmol). To that mixture, a suspension of allenyl boronic acid 2.65 (0.230 gr, 2.74
mmol) in 5.5 ml DCM was added in one portion. The system was left under stirring
at R.T. for 24 hr. DCM was evaporated and 50 ml of EtOAc were added. The
organic phase was extracted with aq. NaOH, 2N (3x20 ml), dried with MgSO4 and
the solvent was removed under reduced pressure. The product was dried under high
vacuum (0.449 gr, 90%).
1
H NMR (500 MHz, CDCl
3
) δ 7.33-7.22 (m, 5H), 5.13 (q,
J=6.4 Hz, 1H), 4.85-4.76 (m, 2H), 3.84 (d, J=12.8 Hz, 2H), 3.61 (t, J=11.7 Hz, 1H),

122

3.48 (m, 2H), 3.41 (d, J=13.0, 2H), 2.121 (br, 1H).
13
C NMR (125 MHz, CDCl
3
) δ
209.44, 138.88, 129.02, 128.46, 127.25, 83.69, 75.34, 60.96, 58.22, 53.64. FAB MS
(M+1): 280.16 (expected mass), 280.14 (experimental value).

•
N
OH
2.159b

2-diallylamino-penta-3, 4-dien-1-ol (2.159b). In a 25-ml round bottomed
flask equipped with a magnetic stirrer, 7 ml of DCM were placed followed by
glycolaldehyde dimer 2.144 (0.319 gr, 2.7 mmol) and diallylamine 2.122 (0.431 gr,
4.4 mmol). To that mixture, a suspension of allenyl boronic acid 2.65 (0.373 gr, 4.4
mmol) in 5 ml DCM was added in one portion. The system was left under stirring at
R.T. for 1 hr. At that time diallylamine was hardly observed on the TLC so the
reaction was stopped. 30 ml DCM were added to the crude reaction mixture. The
organic phase was extracted with aq. NaOH, 1N (3x20 ml) and once with brine,
dried with MgSO4 and the solvent was removed under reduced pressure. The
product was dried under high vacuum (0.578 gr, 73%).
1
H NMR (250 MHz, CDCl
3
)
δ 5.85-5.69 (m, 2H), 5.21-5.10 (m, 4H), 5.01 (q, J=6.8 Hz, 1H), 4.72 (m, 2H), 3.57-
3.45 (m, 3H), 3.34-3.25 (m, 2H), 2.121 (dd, J
1
=14.2, J
2
=8.4, 2H).
13
C NMR (62 MHz,
CDCl
3
) δ 209.11, 135.83, 117.80, 84.01, 75.29, 60.79, 58.79, 52.49.

123

•
N
OH
2.161b
O

2-Morpholin-4-yl-penta-3,4-dien-1-ol (2.161b). In a 25-ml round bottomed
flask equipped with a magnetic stirrer, 7 ml of DCM were placed followed by
glycolaldehyde dimer 2.144 (0.313 gr, 2.6 mmol) and morpholine 2.124 (0.374 gr,
4.3 mmol). To that mixture, a suspension of allenyl boronic acid 2.65 (0.361 gr, 4.3
mmol) in 5 ml DCM was added in one portion. The system was left under stirring at
R.T. for 17 hr. At that time morpholine was still observed on the TLC but the
reaction was stopped. 30 ml DCM were added to the crude reaction mixture. The
organic phase was extracted with aq. NaOH, 1N (3x20 ml) and once with brine,
dried with MgSO4 and the solvent was removed under reduced pressure. The
product was dried under high vacuum (0.331 gr, 46%).
1
H NMR (250 MHz, CDCl
3
) δ 5.04 (q, J=6.8 Hz, 1H), 4.73 (dd, J
1
= 6.7 Hz,
J
2
=1.7 Hz, 2H), 3.69 (m, 4H), 3.52 (m, 2H), 3.22 (qt, J
1
=7.8 Hz, J
2
=1.8 Hz, 1H), 3.01
(bs, 1H), 2.66 (m, 2H), 2.45 (m, 2H).
13
C NMR (62 MHz, CDCl
3
) δ 209.00, 83.77,
75.41, 67.09, 64.47, 60.15, 48.69

124

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132
CHAPTER 3: Chiral induction in the synthesis of allenyl and
propargyl amines. The effect of chiral amines and α-hydroxy
aldehydes in the allenyl version of the Petasis reaction

3.1 Diastereoselectivity in the Petasis reaction
Multicomponent reactions are theoretically very good and versatile candidate
reactions for asymmetric induction and diastereocontrol since many optically pure
reagents are commercially available and furthermore, chirality can be induced by any
of the different components. The situation becomes quite challenging if more than
one chiral components are used yielding in many cases complicated mixtures of
diastereomers raising issues of matched and mismatched combinations in order to
interpret the observed stereochemical outcome and to maximize the efficiency in
controlling the stereochemistry.
Diastereoselectivity issues have been explored for the condensation between
aldehydes, amines and boronic acids as well. The effect of chiral amines and that of
chiral α-hydroxyl aldehydes have been reported for a number of variations of the
process while this chapter concerns some initial studies to induce diastereoselectivity
for the propagyl/allenyl version of the Petasis reaction. After the studies already
mentioned in Chapter 2 that revealed reactivity of allenyl boronic acid 2.65 and the
corresponding potassium trifluoroborate salt 2.178 for the multicomponent process,

133
we turned our attention to diastereoselective synthesis by employing a number of
commercially available chiral amines and naturally occurring α-amino acids as well
as chiral α-hydroxy aldehydes.

3.1.1 The effect of chiral amines in the Petasis reaction
Chiral amines have been previously employed by our group and by others in
the Petasis reaction due to their wide availability and structural diversity, the non-
prohibitive cost and the fact that many chiral amines can be removed after the
reaction yielding the free amine group that can undergo further synthetic
modification to a number of multifunctionalized chiral synthons.
The diastereoselectivity observed varies significantly with the components
used as well as the solvent employed. This reaction, like most multicomponent
processes consists of a series of equilibria before the irreversible carbon-carbon bond
formation occurs, one can easily realize that besides the specific chiral source
employed, steric hindrance (to which the other two components can attribute),
solubility issues and differences in solvent stabilization of the different intermediates
come into play to effect the stereochemical outcome and drive the process. Also the
possibility of boron complexation with various functional groups present is another
factor that can in theory effect diastereoselectivity.

134
An impressive literature example that demonstrated the importance of solvent
for the diastereoselectivity obtained has been reported in a synthetic application by
Pye et al
1
in which the Petasis reaction was used as a key step of introducing
diastereoselectivity. Use of t-amyl alcohol as the solvent lead to synthesis of a single
isomer due to the selective precipitaton of only one diastereomer which ultimately
drove the process to that direction.
Most of the efforts to employ chiral amines as components in the Petasis
reaction and systematically study their effect on diastereoselection have been
performed in combination with alkenyl
2
and aryl boronic acids
3
,
4
as well as allyl
boronates.
5
Glyoxylic acid monohydrate
2,4,5
or phenyl glyoxal hydrate
3
are the only
oxo partners used resulting in synthesizing various α-amino acids and
hydroxymorpholine scaffolds. The pool of chiral amines involved the use of
commercially available, cleavable α-substituted benzylamines, various 1-phenyl-
aminoalcohols and some of the naturally occurring α-amino acids (thus yielding
iminodicarboxylic acids).
The degree of diasteoselection induced by chiral amines was proven to be
highly component-depended. As a general trend, α-alkyl substituted benzylamines
have given low to moderate diastereoselection. The most promising cleavable amines
were 1, 2 aminoalcohols like (R)-phenylglycinol 3.1 which were shown to induce
very high de (>99%)
6
when employed in combination with glyoxylic acid
monohydrate 2.104 and styril boronic acid 3.2 or various aryl boronic acids. This

135
exceptionally high de along with the fact that these amines can be readily cleaved by
different methods gave access to different kinds of optically pure α-amino acids in
just two steps (Scheme 3.1). In all the abovementioned cases the newly formed chiral
center had the opposite absolute configuration as the chiral amine used, as was
confirmed by transformation of the three-component adducts to known compounds
and comparison of the resulting Mosher amides.

3.1 2.104
3.2
3.3
H
2
N
OH
Ph
HO
OH
O
+
B(OH)
2
B(OH)
2
O
HN
COOH
OH
Ph
3.4, >99%de
O
HN
COOH
OH
Ph
H
5
IO
4
NH
2.
HCl
COOH
3.8, >99%de
O
NH
2
COOH
NH
2
COOH
3.7, >99%de
3.5, >99%de
3.6, >99%de
H
2
, Pd/C
H
5
IO
4
OH

Scheme 3.1: Methodology towards optically pure α-amino acids

However, when the same amines were employed in combination with allyl
boronates,
5
the % de obtained was low to moderate indicating a strong influence by
the boron component. For this version, α-amino acids gave the best
diastereoselection but the drawback of the later is that they are not cleavable.
Some trials were also performed by employing chiral amines in the β-
aminoalcohols synthesis by the Petasis reaction but low diastereosectivities were
observed so this version has not been explored further.
2

136
Southwood et al
7
tried to give a qualitative explanation of the factors that
effect diastreoselectivity in a systematic study that involved a number of branched
amines (chiral 1,2-amino alcohols were not included in this study) in synthesizing
alkenyl and aryl α-amino acids by employing the corresponding boronic acids and
their ethylene glycol and pinacol esters. A trend was observed in these series that
revealed once more that primary chiral α-alkyl benzylamines are not able to induce
high diastereoselection while the corresponding secondary ones with only one
branching substitutent gave de>95%. This study also revealed useful information
about the relative reactivity among boronic acids and boronates and their effect on
diastereoselection as well as the limits of the process with increasing steric
hindrance.
The importance of the solvent in combination with various chiral pyrrolidines
and piperidines on the diastereoselectivity and rate of the α-amino acid version of the
reaction was demonstrated by Nanda et al.
8
Their study showed a tremendous
reaction acceleration when 10% of hexafluoroisopropanol was employed as
cosolvent. The enhancement of the reaction rate did not only lead to better yields but
most importantly to higher diastereoselectivities, most likely due to minimizing
racemization with shorter reaction times. Once more, this proved to be limited to
pyrrolidines and piperidines where primary amines did not behave the same.
As can be concluded by the abovementioned observations regarding
diastereoselectivity induced by chiral amines in the Petasis reaction, the choice of

137
components, solvent and reaction conditions is critical in obtaining high
diastereoselectivity since the asymmetric induction originating from the amine
component is not robust and profound for different versions of the process.

3.1.2 The effect of chiral a-hydroxy aldehydes in the Petasis reaction
Diastereoselectivity originating from the aldehyde component has also been
employed in the Petasis reaction and exhibited remarkable and consistent
stereospecificity.
9
A plethora of commercially available chiral α-hydroxy aldehydes,
simple unprotected sugars and disaccharides along with protected analogues in the
form of 4-hydroxy-1,3- dioxolanes have been employed (Scheme 3.2).

3.9 3.10
3.12 3.14
3.11
3.13
Me
O
OH
OO
HO Me
OH
O
OH
O
OH
HO OH
O OH
HO
OH
OH
O OH
HO
OH
OH
HO
"D-Glyceraldehyde" "2,2,5-Trimethyl-
[1,3]dioxolan-4-ol"
"D-Erythrose"
(tetrose)
"D-Arabinose"
(pentose)
"D-Glucose"
(hexose)
"(R)-2-Hydroxy-
propionaldehyde"

Scheme 3.2: Representative α-hydroxy aldehydes employed in the Petasis reaction

The pool of boron components that most trials have been performed with
involved a variety of alkenyl, aryl, hetereoaryl and allyl organoboronates while the

138
amine partners can be primary, secondary, aliphatic or aromatic ones. In almost
every case (only a limited number of exceptions observed) the multicomponent
process resulted in the anti (erythro)-2-amino polyols 3.18 (or amino alcohols) with
de>99%, which in the case of chiral α-hydroxy aldehydes corresponds to ee>99%
(Scheme 3.3).
R
1
B
OH
OH
R
2
N
R
3
H
O
+
B(OH)
3
+
R
1
N
R
2
R
3
3.15 3.16 3.17 3.18
OH
R
4
+
3.19
OH
R
4
"anti- β-amino alcohol"
adducts,
>99%de, >99%ee

Scheme 3.3: The Petasis reaction with chiral α-hydroxyaldehydes

The diastereoselectivity in this case was proven to be more robust than that
induced by chiral amines, thus yielding diastereomerically pure products.
Interestingly, a study was performed to examine whether the use of chiral amines in
combination with chiral α-hydroxy aldehydes would alter or overcome the induced
stereoselection by the latter. As it was shown, even in cases where specific chiral
amines had previously given complete stereoselection, the diastereomer obtained
after double diastereoselection, was exclusively controlled by the stereochemistry of
the aldehyde component.
10
Thus, the stereochemical outcome of the Petasis reaction
when α-hydroxy aldehydes are employed is governed by the oxo component and
corresponds to the anti adduct.

139
The complete stereocontrol, in combination with the fact that the heavily
functionalized adducts resulting from this version can be synthetically manipulated
in many ways, enabled the development of a diversity oriented synthesis towards a
variety of scaffolds among which are different kinds of amino sugars,
11
various
heterocycles
12
and a number of enantiomerically pure synthons in only a few steps.
Furthemore, utilization of cleavable amines provided higly stereocontrolled synthetic
routes to the valuable and versatile, free β-aminopolyol, β-aminoalcohol and α-amino
acid scaffolds. Characteristic examples are depicted in Scheme 3.4
3.20 3.21
O OH
HO
OH
NHBoc
HO
O
OH
HO NH
Ph
Ph
R OH
N
OH
R
2
R
1
OH
OH
R
N
O
R
1
R
2
R
N
R
1
R
2
O
N
OH
OH
HO
R
1
N
H
HO
HO
OH
HO OH
N
H
OH
HO OH
HN O
O
OH R
R
R
N
N HO
OH
R
2
R
1
R
1 R
2
R
R
N
R
1
R
2
OH
3.28 3.27 3.26
3.22 3.23 3.24 3.25
3.30 3.29

Scheme 3.4: Scaffolds obtained by synthetic manipulation of the products
3.2 Results and discussion
3.2.1 Chiral amines in the allenyl/propargyl extention on the Petasis
reaction
After the first reactivity studies of allenyl boronic acid 2.65 already presented
in chapter 2 we wanted to explore the degree of diastereoselection that chiral amines

140
induce to that version of the Petasis reaction. Our results from the α-amino acids
series (Scheme 3.2) of experiments are summarized in Table 3.1.
•
B(OH)
2
+ + R
1
NHR*
HO
OH
O
OH
N
R* R
1
O
or
OH
N
R* R
1
O
•
R
1
: H or alkyl
2.65 3.31 2.104 3.32a 3.32b
OH

Scheme 3.5: Chiral amines in synthesizing propargyl and allenyl α-amino acids

Table 3.1: Chiral amines in synthesizing allenyl and homopropargyl α-amino acids
Entry Boron
component
Carbonyl
component
Amine
component
Product de(yield) %
B(OH)
2
•
HO
OH
OH
O
27 (40)
a
24 (81)
b
1
OH
HN
O
OH
HN
O
OH
HN
O
X
•
HO
OH
OH
O
27(34)
b
X=B(OH)
2
11(35)
b
X=BF
3
K
16(56)
c
X=BF
3
K
2
B(OH)
2
•
HO
OH
OH
O
12(20)
b
3
H
2
N Ph
Me
B(OH)
2
•
HO
OH
OH
O
6(59)
4
3.38
OH
H
2
N COOH
Ph
Me
OH
Ph
Ph
COOH
OH
HN
O
COOH
Ph
H
2
N
Ph
Ph
H
2
N
COOH
Ph
2.65 2.104 3.33
3.39
X=B(OH)
2
,

2.65 or
X=BF
3
K, 2.178 2.104 3.1
3.40 2.65 2.104 3.34
3.41 2.65 2.104 3.35

141
Table 3.1 (continued)
Entry Boron
component
Carbonyl
Component
Amine
component
Product de(yield)
%

B(OH)
2
•
HO
OH
OH
O
20(78)
5
Ph N
H
Ph
B(OH)
2
•
HO
OH
OH
O
44(32)
b
6
N
H
COOH
•
N
OH
O
Ph Ph
Me
•
N
OH
O
COOH
Me
3.42 2.65 2.104 3.36
3.43 2.65 2.104 3.37

a: DCM, b: MeOH, c: CH
3
CN

The reactions were performed at RT and the solvent used was DCM
(conditions A), MeOH (conditions B) or CH
3
CN (conditions C). The diastereomeric
excess values correspond to direct samples from the crude and homogenous reaction
mixture when the reaction was stopped. In the cases where precipitation occurred, in
order to prevent miscalculation of the diastereomeric excess which can occur by
selective crystallization, the crude reaction mixture was completely dissolved by
adding MeOH and in the case of the secondary α-amino acids, addition of DCl was
necessary to completely solubilize the products. Actually control experiments
showed that selective precipitation indeed takes place and the de values obtained
from the solid and the filtrate differ significantly. In any case, the % de was
calculated by comparing the corresponding integrals in the
1
NMR spectrum (most of
the times, the acetylenic or the α-protons were compared).

142
Purification was performed by flash chromatography of the neutral samples
and due to partial separation of the diastereomers, their ratio is not always the same.
Complete purification was feasible in one case while in most cases both
diastereomers were eluted together.
The stereochemistry of the reaction with (R)-phenylglycinol 3.1 with allenyl
boronic acid 2.65 in MeOH was determined by derivatization to known compounds.
In particular, the crude reaction mixture after 24 hr at ambient temperature was
subjected to exhausting hydrogenation (hydrogenation of the allenyl/acetylenic
group and hydrogenolysis of the derivatized N-benzyl groups).
13
Mixture or D and
L- Norvaline was obtained. This was derivatized with (S)-Mosher chloride.
14
The
stereochemistry of the preferred isomer that originated from the Petasis reaction was
identified by comparing the
19
F signals of the abovementioned residue with known
compounds. Pure D, L and racemic DL-norvaline (in order to determine the reaction
conditions and calibrate the process) were converted to the corresponding amides.
From that process, the preferred isomer of the Petasis reaction was shown to have the
S absolute configuration on the newly formed chiral center (de=31%), in accordance
with results previously obtained from that amine, with other boronic acids.
4

143

Scheme 3.6: Determination of the stereochemical preference by employing (R)-Phenylglycinol 3.1 in
combination with allenyl boronic acid 2.65 and glyoxylic acids monohydrate 2.104

COOH
HN
CF
3
O
Ph OCH
3 COOH
NH
2
L-Norvaline, 3.44
(S)-Mosher-Cl,
propylene oxide,
dry THF, reflux, 20'
δ
19
F= -69 ppm
3.45
COOH
HN
CF
3
O
Ph OCH
3
COOH
NH
2
D-Norvaline, 3.46
(S)-Mosher-Cl,
propylene oxide,
dry THF, reflux, 20'
δ
19
F= -68.6 ppm
3.47
S-S
-68.988
-68.6 -68.8 -69.0 -69.2 -69.4 PPM
R-S
-68.635
-68.6 -68.8 -69.0 -69.2 PPM
COOH
HN
CF
3
O
Ph OCH
3
COOH
NH
2
COOH
HN
CF
3
O
Ph OCH
3
+
DL-Norvaline, 3.48
(S)-Mosher-Cl,
propylene oxide,
dry THF, reflux, 20'
δ
19
F= -68.6 ppm δ
19
F= -68.9 ppm
3.47 3.45
-68.616
-68.906
1.03 1.00
-68.6 -68.8 -69.0 -69.2 PPM
COOH
HN
CF
3
O
Ph OCH
3
COOH
NH
2
(S)-Mosher-Cl,
propylene oxide,
dry THF, reflux, 20'
COOH
HN
CF
3
O
Ph OCH
3
+
B(OH)
2
•
H
2
N
OH
Ph
HO
O
OH
++
(R)-Phenylglycinol
3.1
1. MeOH, RT, 24hr
2. Pd(OH)
2
, HCOONH
4
EtOH, 70
o
C, 72 hr
δ
19
F= -68.6 ppm δ
19
F= -68.9 ppm
2.65
OH
2.104
3.49
3.45 3.47
S-S
R-S
de=31%
-68.620
-68.880
1.01 1.89
-68.6 -68.8 -69.0 -69.2 PPM

144
Diastereoselectivity studies were also performed for the corresponding
allenyl β-aminoalcohols series in order to see how chiral amines effect this version of
the process as well, even though previous efforts
2
were not promising. These results
are depicted in Table 3.2.

Table 3.2: Chiral amines in synthesizing allenyl and homopropargyl β-amino alcohols
Entry Boronic Acid
component
Carbonyl
component
Amine
component
Product de(yield)
%

B(OH)
2
•
7(NA)
a
1
OH
HN
OH
HN
OH
HN
B(OH)
2
•
63(61)
a
2
B(OH)
2
• 67(68)
b 3
H
2
N Ph
Me
B(OH)
2
•
67(43)
b
4
B(OH)
2
• 21(32)
a 5
3.50
OH
H
2
N COOH
Ph N
H
Ph
B(OH)
2
•
53(17)
b
6
N
H
COOH
Ph
Me
OH
Ph
Ph
COOH
OH
HN
COOH
Ph
•
N
OH
Ph Ph
Me
•
N
OH
COOH
H
2
N
Ph
Ph
H
2
N
COOH
Ph
Me
•
2.65 2.144 3.33
3.51 2.65 2.144 3.34
3.52 2.65 2.144 3.36
3.53 2.65 2.144 3.35
3.54 2.65 2.144 3.37
3.55 2.65 2.144 3.38
O
O OH
HO
O
O OH
HO
O
O OH
HO
O
O OH
HO
O
O OH
HO
O
O OH
HO

a: DCM, b: MeOH

145
As shown by the data collected, chiral amines under the conditions examined
don’t induce strong stereocontrol for the process, implying that most likely the chiral
center of the amine in not in close proximity with the newly formed chiral center and
that a geometrically defined transition state is most likely not involved. Interestingly,
in our case the same series of chiral amines gave better diastereoselectivities in the β-
amino alcohols series, especially when α- amino acids were used as the chiral amine
component.
(R)-Phenylglycinol 3.1 which induces complete stereocontrol when used in
combination with the less reactive styril and aryl boronic acids in synthesizing α-
amino acids gave low de in the allenyl version, something also observed with allyl
boronates. Also, for that specific amine, the diastereoselection was better when β-
amino alcohols were synthesized by the Petasis reaction compared to the α-amino
acids (63% vs 31%). The use of 2.178 gave low diastereoselection as well but
interestingly, when the solvent was switched from CH
3
CN to MeOH the
diastereoselection was inversed. In addition, α-amino acids gave the best de values,
as was also the case with allyl boronates.
Even though the degree of diastereocontrol resulted from those initial studies
was low to moderate, exploration of the factors that can be crucial for
diastereoselection is in its infancy. The solvent used can be critical along with a
number of parameters, including bulkier chiral amines, additives and alternative

146
boron sources to improve both conversions and de as well as to allow for more
experimental flexibility.

3.2.2 Chiral α-hydroxyaldehydes in the allenyl/propargyl extention on
the Petasis reaction
The exceptionally high diastereocontrol that the use of α-hydroxy aldehydes
exhibited in other versions of the Petasis reaction urged us to investigate their
utilization in the allenyl/propargyl version of the process.
Table 3.3: Chiral α-hydroxy aldehydes in the allenyl version of the Petasis reaction
Entry Boronic Acid
component
Carbonyl
component
Amine
component
Product de(yield)
%
HN
OH
NH
OH
B(OH)
2
•
>99(65) X=B(OH)
2
>99(74)

X=BF
3
K
1
B(OH)
2
•
28(30)
2
X
•
>99(25)
3
B(OH)
2
•
4
B(OH)
2
•
5
Ph
N
OH
Ph
3.58 2.65 3.56 2.109
3.59a
2.65 3.57 2.109
3.60
X=B(OH)
2
,

2.65
X=BF
3
K, 2.178
3.56
2.121
3.61 2.65 3.57 2.121
3.62 2.65 3.56 2.122
OH
O
OH
OH
O
OH
OH
O
OH
Ph NH
2
OH
Ph NH
2
O OH
OH
OH
HO
OH
OH
OH
Ph
NH
OH
>99(25)
3.59b
OH
OH
OH
Ph
•
Ph N
H
OH
•
Ph
Ph
O OH
OH
OH
HO
Ph N
H
Ph
N
OH
>99(21)
OH
OH
OH
Ph
Ph
N
OH
>99(70)
OH
H
N
•
•

a: DCM, b: MeOH

147
As seen by the abovementioned results, the strong stereochemical control of
α-hydroxy aldehydes is also observed when the highly reactive allenyl boronic acid
2.65 as well as the corresponding potassium allenyl trifluoroborate 2.178 are used as
the boron components. In all but one cases the diastereoselection was complete. The
only exception was the use of 2.109 in combination with glyceraldehyde 3.56 which
gave both diastereomers of the corresponding propargyl product, with de=28%. But
the use of the same amine in combination with D-arabinose 3.57 resulted in both
propargyl and allenyl products with de>99%. That dramatic increase of the
diastereoselectivity could probably be attributed to the bulkiness of D-arabinose
which most likely leads to the formation of geometrically pure intermediates (trans
imines or iminium salts only) thus preventing the formation of alternative products
(from reaction of the cis intermediates).
The stereochemistry of the products was consistent with that observed for
other boronic acids. The anti allenyl β-aminodiols were obtained as was proven by
formation of the cis oxazolidinone 3.63 (J
12
=8 Hz).

•
B(OH)
2
O
OH
N
OH
•
2.65
2.121
3.56
3.60
Ph N
H
Ph
OH
Ph Ph
OH
1. H
2
, 10% Pd/C,
EtOH (abs.),
RT, 72 hr
2. Boc
2
O,
Et
3
N,10 hr
3. KOt-Bu,
THF(dry), 4hr
HN O
O
H
1
H
2
OH
Cis oxazolidinone, 3.63
J
12
= 8 Hz

Scheme 3.7: Oxazolidinone formation originating from 3.60

148
The stereochemical outcome of the reaction involving chiral α-hydroxy
aldehydes indicates a non chelation model in which the least hindered plane of the
iminium salt is attacked by the allenyl boron “ate” nucleophile. The proposed model
is depicted in Scheme 3.8.
•
B(OH)
2
O
OH
N
OH
•
2.650 2.121 3.35
3.60
Ph N
H
Ph
OH
Ph Ph
OH
H OH
N
OH
Ph Ph
•
B(OH)
3
+
N
H
OH
H
Ph OH
Ph
N
H
H
HO
Ph
Ph
HO
N
H
HO
Ph
Ph
H
• OH
•
B(OH)
3
++
preferred side for attack
less hindrance
=
3.65
3.66 3.66
3.64
3.64
3.60
anti- β-amino diol adduct

Scheme 3.8: Proposed non chelation model of reaction of α-hydroxy aldehydes in the Petasis reaction
towards the anti- β- amino polyol products

3.3 Experimental
3.3.1 General
All the reactions were performed at ambient temperature under N
2
. The
solvents were used without further purification and no dry conditions were necessary
unless otherwise stated. THF was dried by final distillation of KOH pre-dried THF

149
over sodium/benzophenone ketyl system. The allenyl boronic acid 2.65 was
transferred as a suspension in hexane. Hexane was removed and the solid was dried
prior to the reaction. It was not exposed to air as it is known to be a pyrophoric
material. It was always transferred as a suspension (in DCM) or as a solution (in
EtOH and MeOH) and added to the reaction mixture. The reactions were monitored
by TLC on Silica Gel 60 precoated plates with F
254
indicator. The product was
purified by flash chromatography on Silica 60 Å 32-63 µm unless otherwise stated.
1
H and
13
C NMR were recorded on a Bruker AMX500 or an AM360 MHz, or an
AC250 MHz or a Varian Mercury 400 NMR. Chemical shifts of
1
H NMR are
reported in parts per million on the δ scale from an internal standard of either
residual chloroform (7.24 ppm), DMSO d
6
(2.49 ppm), acetone d
6
(2.04 ppm) or
partly deuterated MeOH (3.3 ppm). Data are reported as follows: chemical shift,
multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br=broad),
coupling constants in Hz and integration. Chemical shifts of
13
C NMR are reported
in ppm from the central peak of either CDCl
3
(77.0 ppm), DMSO d
6
(39.5 ppm) or
partly deuterated MeOH (49.5 ppm).

150
3.3.2 Synthesis and physical data

OH
HN
O 3.38
Ph
Me

2-(1-Phenyl-ethylamino)-pent-4-ynoic acid (3.38). To a solution of
glyoxylic acid monohydrate 2.104 (0.258g, 2.8mmol) and (R)-(+)- α-
methylbenzylamine 3.33 (0.339g, 2.8mmol) in 7 ml MeOH was added a solution of
2.65 (0.236g, 2.8mmol) in 6 ml MeOH. The system was allowed to stir to R.T. for
24hr.
1
H NMR spectrum was run from the crude homogeneous reaction mixture that
showed de=24% (from comparison of the integrals of the acetyllenic signals). The
reaction was split in two halves and flash chromatography was performed to one half
(gradient elution EtOAc/MeOH/NH
4
OH, 80/15/5 to 70/25/5 to final 65/30/5). Both
diastereomers were eluted together. Yield: 0.308g or 81% (corrected yield).
1
H NMR (500 MHz, MeOH d
4
, DCl) δ 7.59-7.34 (m, 11H), 4.62 (q, J= 7.1
Hz, 1H- major) & 4.58 (q, J= 7.3 Hz, 0.7H- minor), 4.00 (t, J=5.8 Hz, 0.6H- minor)
& 3.65 (t, J= 5.0 Hz, 1H-major), 3.00 (dd, J
1
= 5.0 Hz, J
2
= 2.3 Hz, 1H-minor) & 2.92
(m, 2H- major), 2.64 (m, 1.2H-both acetyllenic signals).
13
C NMR (125 Mz, MeOH
d
4
, DCl) δ 169.8, 137.4(minor) & 137.2(major), 131.5, 131.3, 131.2, 130.9, 129.74,
129.72, 77.5(minor) & 77.3(major), 75.73(major) & 75.70 (minor), 60.44 (minor) &

151
60.34 (major), 58.53(minor) & 58.01(major), 21.55(major) & 21.15(minor),
20.54(major) & 19.98 (minor)

OH
HN
O
OH
Ph
3.39

2-(2-Hydroxy-1-phenyl-ethylamino)-pent-4-ynoic acid (3.39). To a
solution of glyoxylic acid 2.104 monohydrate (0.247g, 2.68mmol) and (R)-(-)-2 -
Phenylglycinol 3.1 (0.368g, 2.68mmol) in 7 ml MeOH was added a solution of 2.65
(0.225g, 2.68mmol) in 4 ml MeOH. The system was allowed to stir to R.T. for 24hr.

1
H NMR spectrum was run from the crude homogeneous reaction mixture that
showed de=27% (from comparison of the integrals of the α H signals at 4.51(0.58)
and 4.37(1.00) ppm). The crude homogeneous reaction mixture was split in two
halves.
1
st
half: Purification was performed by gradient flash chromatography
(EtOAc/MeOH/NH
4
OH, 75/20/5 to 55/40/5). Both diastereomers were eluted
together (partial resolution was observed after column). Yield 0.105g or 34%
(corrected yield).
1
H NMR (500 Mz, MeOH d
4
) δ 7.49-7.36 (m, 8H), 4.42 (t, J=5.8 Hz, 0.7H-
minor) & 4.24 (dd, J
1
=7.6 Hz, J
2
=5.5 Hz 1H- major), 3.89 (m, 1.6H- minor) & 3.80

152
(m, 2H-major), 3.49 (dd, J
1
=5.6 Hz, J
2
=3.6 Hz, 0.6H-minor) & 3.29 (dd, J
1
= 6.1 Hz,
J
2
= 4.9 Hz, 1H- major), 2.86 (ddd, J
1
=17.5 Hz, J
2
=4.8 Hz, J
3
=3.1 Hz, 0.7H-minor) &
2.75 (ddd, J
1
=17.3 Hz, J
2
=6.6 Hz, J
3
=3.1 Hz, 0.7H-minor) & 2.67 (ddd, J
1
=17.3 Hz,
J
2
=6.8 Hz, J
3
=3.1 Hz, 1H-major) & 2.59 (ddd, J
1
=17.4 Hz, J
2
=5.4 Hz, J
3
=3 Hz, 1H-
major), 2.56 (t, J=2 Hz, 0.45H-minor) & 2.44 (t, J=2 Hz, 0.6H-major).
13
C NMR
(125 Mz, MeOH d
4
- dilute, quarternary carbons are not observed) δ 130.73, 130.65,
129.91, 129.85, 74.37(minor) & 73.91(major), 65.97(major) & 65.81(minor), 65.00
(major) & 64.80(minor), 60.47(major) & 59.95(minor), 23.38(major) &
21.83(minor).
2
nd
half: The second half of the crude reaction mixture was subjected to a
number of consecutive transformations in order to determine the stereochemistry of
the preferred diastereomer by comparison with derivatives of known
stereochemistry. MeOH was evaporated from the crude and 20 ml EtOH was added
followed by addition of 1.3 ml aq. HCl, 6N. The mixture was stirred for 5 min, the
solvent was evaporated and the crude salt was dried in high vacuum for 30 min. To
that, 3.10g (49 mmol) of HCOONH
4
was added followed by 160 mg Pd(OH)
2
, (20%
Pd/C-50% H
2
O) and 40ml EtOH. The system was heated to 70
o
C for 72hr. The
crude reaction mixture was purified by gradient (EtOAc/MeOH/NH
4
OH, 55/50/5 to
40/55/5).
Mosher amides formation (performed twice): 4 mg (0.034 mmol) of the
abovementioned purified mixture of the Norvaline enantiomers were put in a flame

153
dried r-b flask containing a magnetic stirrer and carrying a reflux condenser. 1 ml of
dry THF was added along with 9mg (S)-Mosher-Cl (0.034mmol) and 8 mg
(0.137mmol) propylene oxide. The system was refluxed for 20min.
19
F NMR
spectrum was run from the crude reaction mixture which showed that the preferred
isomer of the α-amino acid had the S absolute configuration on the on the α position
(control experiments were run with D, L and DL-norvaline to determine the reaction
conditions and the chemical shifts of the signals). The diastereoselectivity calculated
by the integrals in the
19
F spectrum was 31% (R-S Mosher amide: δ
19
F: 68.6 ppm
(Integral: 1.01), S-S Mosher amide: δ
19
F 68.9 ppm (Integral: 1.89)

OH
HN
O
COOH
Ph
3.41

2-(1-Carboxy-2-phenyl-ethylamino)-pent-4-ynoic acid (3.41). To a
solution of glyoxylic acid monohydrate 2.104 (0.246g, 2.67mmol) and L-
Phenylalanine 3.36 (0.441, 2.67mmol) in 7 ml MeOH was added a solution of 2.65
(0.450g, 5.36mmol) in 2 ml MeOH. The system was allowed to stir to R.T. for 24hr.

1
H NMR spectrum was run from the crude homogeneous reaction mixture that
showed de=6% (from comparison of the integrals of the α H signals). The solvent
was evaporated and then 1 ml MeOH was added to the crude residue. A small

154
amount of solid precipitated out (0.050 g). It was isolated through sunction filtration
and
1
H NMR showed that it was the major isomer. The rest of the reaction mixture
was purified by gradient flash chromatography (EtOAc/MeOH/NH
4
OH, 80/15/5 to
70/25/5 to final 50/45/5- both diastereomers were eluted together). Yield 0.409g or
59%
1
H NMR (500 MHz, MeOH d
4
, major isomer only) δ 7.37-7.28 (m, 5H), 4.42
(t, J=7.7Hz, 1H), 4.25 (t, J=5.0 Hz, 1H), 3.42 (dd, J
1
=14.5 Hz, J
2
=6.4 Hz, 1H), 3.31-
signal overlapping with the MeOH, d
4
signal- J
1
could not be calculated (dd, J
2
=6.4
Hz, 1H), 3.03 (m, 2H), 2.69 (bt, J=2.6 Hz, 1H).
13
C NMR (125 MHz, MeOH d
4
) δ
170.91, 169.97, 135.94, 130.97, 130.52, 129.36, 77.39, 75.86, 63.19, 59.93, 37.43,
21.59.

•
N
OH
O
COOH
3.43

1-(1-Carboxy-buta-2,3-dienyl)-pyrrolidine-2-carboxylic acid (3.43). To a
solution of glyoxylic acid monohydrate 2.104 (0.206g, 2.24mmol) and L-Proline
3.38 (0.258, 2.24mmol) in 7 ml MeOH was added a solution of 2.65 (0.188g,
2.24mmol) in 2 ml MeOH. The system was allowed to stir to R.T. for 48hr.
1
H NMR
spectrum was run from the crude homogeneous reaction mixture that showed

155
de=44% (from comparison of the integrals of the CH allenic signals). The reaction
mixture was purified by gradient flash chromatography (EtOAc/MeOH/NH
4
OH,
55/40/5 to 40/55/5 to final 35/60/5- both diastereomers were eluted together). Yield
0.140g or 32%
1
H NMR (500 MHz, MeOH d
4,
DCl) δ 5.59-5.53 (m, 1.6H), 5.22-5.15 (m,
3.4H), 4.96 (d, J=9.7Hz, 1H-major) & 4.85 (d, J=9.8Hz, 0.6H-minor), 4.60 (dd,
J
1
=8.7 Hz, J
2
=3.6 Hz, 1H-minor) & 4.49 (dd, J
1
=8.7 Hz, J
2
=5.3 Hz, 1H-major), 3.83
(m, 2.3H), 3.50 (m, 1.7H), 2.62-2.44 (m, 2H), 2.25-2.02 (m, 6H).

OH
HN
OH
Ph
3.51

2-(2-Hydroxy-1-phenyl-ethylamino)-pent-4-yn-1-ol (3.51). In a 25-ml
round bottomed flask equipped with a magnetic stirrer, 4 ml of DCM were placed
followed by glycolaldehyde dimer 2.144 (0.133 g, 1.1 mmol) and (R)-(-)-2 -
Phenylglycinol 3.1 (0.303 g, 2.11 mmol). To that mixture, a suspension of allenyl
boronic acid 2.65 (0.186 g, 2.21 mmol) in 3 ml DCM was added in one portion. The
system was left under stirring at R.T. for 23 hr.
1
H NMR spectrum was run from the
crude homogeneous reaction mixture that showed de=63% (from comparison of the
integrals of the acetyllenic signals). The reaction mixture was purified by gradient

156
flash chromatography (MeOH/DCM, 2% to 5% to final 10%- mostly the main
diastereomer). Yield: 0.147g or 61%.
1
H NMR – the main diastereomer’s signals are reported only-(360 MHz,
CDCl
3
) δ 7.26-7.19 (m, 5H), 3.87 (m, 1H), 3.62 (dd, J
1
=11.0 Hz, J
2
=4.3Hz, 1H),
3.50-3.43 (m, 3H), 2.90 (bs, 2H), 2.67 (m, 1H), 2.32-2.62 (m, 2H), 1.95 (bt, J=2.6
Hz, 1H).
13
C NMR (90 MHz, CDCl
3
) δ 139.79, 128.54, 127.63, 127.31, 80.59, 70.90,
66.98, 63.85, 61.35, 53.90, 19.97.

OH
HN
COOH
Ph
3.52

2-(1-Hydroxymethyl-but-3-ynylamino)-3-phenyl-propionic acid (3.52). In
a 10-ml round bottomed flask equipped with a magnetic stirrer, 3 ml of MeOH were
placed followed by glycolaldehyde dimer 2.144 (0.099 g, 0.82 mmol) and L-
Phenylalanine 3.36 (0.272 g, 1.65 mmol). To that mixture, a solution of allenyl
boronic acid 2.65 (0.139 g, 1.65 mmol) in 2 ml MeOH was added in one portion. The
system was left under stirring at R.T. for 24 hr.
1
H NMR spectrum was run from the
crude homogeneous reaction mixture that showed de=67% (from comparison of the
integrals of the acetyllenic signals). 20% of the crude reaction mixture was purified

157
by preparative TLC (MeOH/EtOAc/NH
4
OH, 55/40/5). After the purification the
major diastereomer was only detected. Yield 0.055g or 68% (corrected yield)
1
H NMR (500 MHz, MeOH d
4
) δ 7.36-7.29 (m, 5H), 4.55 (t, J=6 Hz, 1H),
3.91 (d, J=4.2 Hz, 2H), 3.66 (bs, 1H), 3.46 (bm, 1H), 3.40 (dd, J
1
=14.2 Hz, J
2
=5.7
Hz, 1H), 3.26 (dd, J
1
=14.1 Hz, J
2
=8.2 Hz, 1H) 2.73 (bd, J=5.6 Hz, 2H), 2.57 (bt, 1H).

13
C NMR (125 MHz, MeOH d
4
) δ 171.13, 135.90, 130.95, 130.45, 129.27, 79.00,
74.44, 61.80, 60.31, 59.83, 37.65, 20.17.

OH
HN
Ph
COOH
3.53

(1-Hydroxymethyl-but-3-ynylamino)-phenyl-acetic acid (3.53). In a 25-ml
round bottomed flask equipped with a magnetic stirrer, 4.5 ml of MeOH were placed
followed by glycolaldehyde dimer 2.144 (0.141 g, 1.18 mmol) and (R)-
Phenylglycine 3.35 (0.357 g, 2.36 mmol). To that mixture, a solution of allenyl
boronic acid 2.65 (0.198 g, 2.36 mmol) in 3 ml MeOH was added in one portion. The
system was left under stirring at R.T. for 24 hr.
1
H NMR spectrum was run from the
crude homogeneous reaction mixture that showed de=67% (from comparison of the
integrals of the acetyllenic signals). One half of the reaction mixture was purified by
gradient flash chromatography (MeOH/EtOAc, 5% to 10% to final 20%- both

158
diastereomers were eluted but the purified compound was further enriched with the
major). Yield: 0.118g or 43% (corrected yield).
1
H NMR- chemical shifts for the major diastereomer- (500 MHz, MeOH d
4
)
δ 7.51 (m, 5H), 5.40 (s, 1H), 3.93 (m, 2H), 3.37 (m, 1H), 2.75 (m, 2H), 2.59 (b, 1H).

13
C NMR (125 MHz, MeOH d
4
) δ 170.10, 132.10, 131.80, 130.93, 130.20, 78.79,
74.37, 63.52, 60.44, 59.10, 19.52.

•
N
OH
Ph Ph
Me
3.54

2-[benzyl-(1-phenyl-ethyl)-amino]-penta-3,4-dien-1-ol (3.54). In a 10-ml
round bottomed flask equipped with a magnetic stirrer, 2.3 ml of DCM were placed
followed by glycolaldehyde dimer 2.144 (0.139 g, 1.16 mmol) and (R)-(+)-N-
benzyl- α-methyl benzylamine 3.37 (0.244 g, 1.16 mmol). To that mixture, a
suspension of allenyl boronic acid 2.65 (0.097 g, 1.16 mmol) in 2.3 ml DCM was
added in one portion. The system was left under stirring at R.T. for 60 hr.
1
H NMR
spectrum was run from the crude homogeneous reaction mixture that showed
de=21% (from comparison of the integrals of the methyl signals). The reaction
mixture was purified by gradient flash chromatography (EtOEt/Hexanes, 10% to
20%- both diastereomers were eluted together). Yield: 0.110g or 32%.

159
1
H NMR (250 MHz, CDCl
3
) δ 7.29-7.12 (m, 12H), 5.16 (q, J=6.6 Hz, 1H),
4.68 (m, 2H-major), 4.56 (m, 0.7H-minor), 3.98-3.82 (overlapping quartets, 1.4H),
3.76 (d, J=13.7 Hz, 1.4H), 3.58 (d, J=13.6 Hz, 1.4H), 3.42-3.20 (m, 4H), 1.39 (d,
J=7.3 Hz, 3H-major) & 1.30 (d, J=7.1 Hz, 1.5H-minor).

HN
OH
Ph
3.58
OH

3-benzylamino-hex-5-yne-1,2-diol (3.58). In a 25-ml round bottomed flask
equipped with a magnetic stirrer, 10 ml of MeOH were placed followed by DL-
Glyceraldehyde dimer 3.56 (0.184 g, 1.02 mmol) and benzylamine 2.109 (0.219 g,
2.04 mmol). To that mixture, a solution of allenyl boronic acid 2.65 (0.214 g, 2.55
mmol) in 3 ml MeOH was added in one portion. The system was left under stirring at
R.T. for 24 hr.
1
H NMR spectrum was run from the crude homogeneous reaction
mixture that showed de=28% (from comparison of the integrals of the acetyllenic
signals). The reaction mixture was purified by initial acid/base workup followed by
flash chromatography. Two consecutive columns were needed to purify the products
with 5% MeOH/DCM. Both diastereomers were eluted together. Yield: 0.169g or
30%.
1
H NMR (360 MHz, CDCl
3
) δ 7.33-7.26 (m, 8H), 3.94 (d, J=12.8, 1H-major)
& 3.89 (d, J=12.5, 0.7H-minor), 3.79 (dd, J
1
=11.4 Hz, J
2
=3.5 Hz, 1H), 3.75-3.65 (m,

160
5H-overlapping signals), 3.63 (dd, J
1
=11.4 Hz, J
2
=3.6 Hz, 1H), 2.86 (m & bs, 6.4H),
2.64-2.40 (m, 3.7H), 2.02 (m, 1.2H-overlapping acetyllenic signals).
13
C NMR (125
MHz, CDCl
3
) δ 139.27(minor) & 139.20(major), 128.59(major) & 128.57(minor),
128.24, 127.41(major) & 127.35(minor), 80.35(minor) & 80.17(major), 71.25(major)
& 71.20(minor), 71.01(major) & 70.63(minor), 65.24(minor) & 64.33(major),
58.72(minor) & 57.37(major), 51.40(minor) & 51.11(major), 19.67(major) &
19.42(minor).

NH
OH
3.59a
OH
OH
OH
Ph
NH
OH
3.59b
OH
OH
OH
Ph
•
and

5-benzylamino-oct-7-yne-1,2,3,4-tetraol (3.59a) and 5-benzylamino-octa-
6,7-diene-1,2,3,4-tetraol (3.59b). In a 25-ml round bottomed flask equipped with a
magnetic stirrer, 20 ml of MeOH were placed followed by D-Arabinose 3.57 (0.760
g, 5.06 mmol) and benzylamine 2.109 (0.542 g, 5.06 mmol). To that mixture, a
solution of allenyl boronic acid 2.65 (0.425 g, 5.06 mmol) in 6 ml MeOH was added
in one portion. The system was left under stirring at R.T. for 18 hr.
1
H NMR
spectrum was run from the crude homogeneous reaction mixture that showed both
the propargyl and allenyl products 3.59a and 3.59b (the ratio could not be
determined since the signals were not clean). The reaction mixture was purified by
gradient flash chromatography (MeOH/DCM, 10% to 20% to final 30%). Both

161
products were diastereomerically pure (de>99%) as it was observed in the
1
H and
13
C
NMR spectra of the crude reaction mixture. The different isomers 3.59a and 3.59b
were separated by the chromatography. Yield for 3.59a: 0.341g or 24%. Yield for
3.59b: 0.356 g or 26%. Combined yield: 0.696 or 50%.
1
H NMR (500 MHz, MeOH d
4
, 3.59a-propargyl isomer) δ 7.36 (m, 2H),
7.30 (m, 2H), 7.22 (m, 1H), 3.91 (d, J= 12.8 Hz, 1H), 3.84 (m, 2H), 3.80-3.74 (m,
2H), 3.68-3.57 (m, 2H), 2.97 (m, 1H), 2.62 (m, 2H), 2.34 (t, J=2.7 Hz, 1H).
13
C
NMR (125 MHz, MeOH d
4
, 3.59a-propargyl isomer) δ 129.99, 129.94, 128.64,
82.34, 74.00, 72.53, 72.50, 72.07, 65.61, 59.40, 52.95, 21.04
1
H NMR (500 MHz, MeOH d
4
, 3.59b- allenyl isomer) δ 7.33-7.28 (m, 4H),
7.23 (m, 1H), 5.20 (q, J= 7.1 Hz, 1H), 4.86 (m, 2H), 3.92 (d, J=12.9 Hz, 1H), 3.77 (d,
J=6.5 Hz, 2H), 3.74 (dd, J
1
=11.5, J
2
=3.3 Hz, 1H), 3.70 (d, J=13.4 Hz, 1H), 3.65 (m,
1H), 3.59 (dd, J
1
=11.0 Hz, J
2
=5.9 Hz, 1H), 3.41 (m, 1H).
13
C NMR (125 MHz,
MeOH d
4
, 3.59a-allenyl isomer) δ 210.78, 141.50, 130.06, 129.91, 128.59, 91.16,
76.81, 73.80, 73.66, 73.30, 65.34, 61.82, 52.75

N
OH
Ph
3.60
OH
•
Ph

3-dibenzylamino-hexa-4,5-diene-1,2-diol (3.60). In a 25-ml round bottomed
flask equipped with a magnetic stirrer, 10 ml of MeOH were placed followed by DL-

162
Glyceraldehyde dimer 3.56 (0.234 g, 1.3 mmol) and dibenzylamine 2.121 (0.513 g,
2.6 mmol). To that mixture, a solution of allenyl boronic acid 2.65 (0.273 g, 3.25
mmol) in 5 ml MeOH was added in one portion. The system was left under stirring at
R.T. for 24 hr.
1
H NMR spectrum was run from the crude homogeneous reaction
mixture that showed the allenyl product with de>99% (only one diastereomer was
observed in the
1
H and
13
C NMR spectra taken from the crude reaction mixture). The
reaction mixture was purified by gradient flash chromatography (EtOAc/Hexanes,
5% to 10% to 20% to 30% to final 40%). Yield: 0.522g or 65%.
1
H NMR (250 MHz, CDCl
3
) δ 7.39-7.20 (m, 10H), 5.24 (m, 1H), 4.87 (m,
2H), 3.83 (m, 1H), 3.79 (d, J=13.6 Hz, 2H), 3.68 (bd, J=4.6 Hz, 2H), 3.38 (d, J=13.4
Hz, 2H), 3.26 (t, J=9.0 Hz, 1H).
13
C NMR (125 MHz, CDCl
3
) δ 210.34, 138.68,
129.02, 128.49, 127.33, 83.81, 75.01, 71.17, 65.33, 61.67, 54.80

3.61
N
OH OH
OH
OH
Ph
Ph
•

5-dibenzylamino-oct-7-yne-1,2,3,4-tetraol (3.61). In a 50-ml round
bottomed flask equipped with a magnetic stirrer, 20 ml of MeOH were placed
followed by D-Arabinose 3.57 (0.674 g, 4.49 mmol) and dibenzylamine 2.121 (0.481
g, 4.49 mmol). To that mixture, a solution of allenyl boronic acid 2.65 (0.377 g, 4.49
mmol) in 3 ml MeOH was added in one portion. The system was left under stirring at

163
R.T. for 48 hr.
1
H and
13
C NMR spectra were run from the crude homogeneous
reaction mixture that showed a single diastereomer of the allenyl product 3.61
(de>99%). The reaction mixture was purified by gradient flash chromatography
(MeOH/DCM, 2% to 5% to final 10%). Yield: 0.344 g or 21%.
1
H NMR (500 MHz, MeOH d
4
) δ 7.36 (bd, J=7.4 Hz, 4H), 7.28 (t, J=7.7 Hz,
4H), 7.20 (t, J=7.5 Hz, 2H), 5.25 (m, 1H), 4.85 (m, 1H), 4.77 (dd, J
1
=10.4 Hz, J
2
=
6.5 Hz, 1H), 4.04 (m, 2H), 3.77 (d, J=13.4 Hz, 2H), 3.73 (dd, J
1
=11.6 Hz, J
2
= 3.3 Hz,
1H), 3.63-3.53 (overlapping multiplets, 2H), 3.44 (t, J=9.7 Hz, 1H), 3.40 (d, J=13.4
Hz, 2H).
13
C NMR (125 MHz, CDCl
3
) δ 212.28, 141.17, 130.75, 129.78, 128.53,
86.20, 74.97, 73.53, 72.02, 65.50, 65.47, 61.84, 55.94

3.62
N
OH
OH
•

3-diallylamino-hexa-4,5-diene-1,2-diol (3.62). In a 50-ml round bottomed
flask equipped with a magnetic stirrer, 17 ml of MeOH were placed followed by DL-
Glyceraldehyde dimer 3.56 (0.400 g, 2.2 mmol) and Diallylamine 2.122 (0.428 g, 4.4
mmol). To that mixture, a solution of allenyl boronic acid 2.65 (0.745 g, 8.87 mmol)
in 5 ml MeOH was added in one portion. The system was left under stirring at R.T.
for 24 hr.
1
H and
13
C NMR spectra were run from the crude homogeneous reaction
mixture that showed the allenyl product with de>99% (only one diastereomer was

164
observed). The reaction mixture was purified by flash chromatography (5%
MeOH/DCM). Yield: 0.647g or 70%.
1
H NMR (500 MHz, CDCl
3
) δ 5.76 (m, 2H), 5.16 (m, 4H), 5.08 (m, 1H), 4.78
(m, 2H), 3.80-3.71 (overlapping multiplets, 2H), 3.66 (dd, J
1
=10.9 Hz, J
2
=6.2 Hz,
1H), 3.40 (t, J=8.6 Hz, 1H), 3.27 (m, 2H), 2.89 (dd, J
1
=14.4Hz, J
2
=8.7 Hz, 1H).
13
C
NMR (125 MHz, CDCl
3
) δ 209.96, 135.16, 118.31, 83.92, 74.87, 70.08, 66.33,
63.65, 53.64

HN O
O
H
1
H
2
OH
Cis oxazolidinone, 3.63
J
12
= 8 Hz

5-Hydroxymethyl-4-propyl-oxazolidin-2-one (3.63). In a 50-ml round
bottomed flask equipped with a magnetic stirrer, 10 ml of EtOH were placed
followed by a solution of 3.60 (0.500g, 1.62 mmol) in 10 ml EtOH and addition of
10% Pd/C (0.100 gr, 0.094 mmol). The solution was degassed by high vacuum and
set under nitrogen and consecutively under H
2
(1 atm). The system was left under
stirring at R.T. for 48 hr but the reaction did not go to completion. At that point the
H
2
was removed and replaced by N
2
and 0.100g of catalyst was added. The system
was set under H
2
and let under stirring for an additional 24hr. At that time the system

165
was set under N
2
and DCM was added. The catalyst was removed by filtration
through cellite and the filtrate was subjected to consecutive Boc protection. Thus, to
that residue was added Boc
2
O (0.354g, 1.62mmol) and Et
3
N (1.62mmol) and the
system was left under stirring for 10hr. The crude mixture was purified by gradient
flash chromatography (EtOAc/Hexanes, 5% to 10%). Yield: 0.122g or 32%. The
abovementioned product was dissolved in 8 ml dry THF and KOt-Bu (0.068g, 0.6
mmol) was added. The system was left under stirring at R.T. for 4 hr. THF was
evaporated and 50 ml EtOAc was added. The organic phase was washed with sat.
NH
4
Cl and brine, it was dried with MgSO
4
and was purified with gradient flash
chromatography (EtOAc/Hexanes, 20% to 40% to final 100% MeOH- essential for
oxazolidinone elution). Yield: 0.050 g, 60%.
1
H NMR (500 MHz, CDCl
3
) δ 6.09 (bs, 1H), 4.66 (dt, J
1
=8.0 Hz-cis
oxazolidinone, J
2
=4.0 Hz, 1H), 3.92 (dt, J
1
=9.3 Hz, J
2
=3.9 Hz, 1H), 3.86 (dd, J
1
=12.3
Hz, J
2
=6.9 Hz, 1H), 3.78 (dd, J
1
=12.4 Hz, J
2
=3.8 Hz, 1H), 1.63-1.09 (m, 4H), 0.94 (t,
J=7.2 Hz, 3H).
13
C NMR (125 MHz, CDCl
3
) δ 158.96, 79.63, 60.76, 54.52, 31.69,
19.90, 13.80.

166
3.4 Chapter 3 References

1. Pye, P.J.; Rossen, K.; Weissman, S.A.; Maliakal, A.; Reamer, R.A.; Ball, R.;
Tsou, N.N.; Volante, R.P.; Reider, P.J. Chemistry--A European Journal 2002, 8,
1372.
2. Zavialov, I.A. Ph.D., University of Southern California, 1998.
3. Raber, J.C. Ph.D., University of Southern California, 2002.
4. Patel, Z.D. Ph.D., University of Southern California, 2002.
5. Boral, S. Ph.D., University of Southern California, 2001
6. Petasis, N.A.; Zavialov, I.A. Journal of the American Chemical Society 1997,
119, 445-446.
7. Southwood, T.J.; Curry, M.C.; Hutton, C.A. Tetrahedron 2005, 62, 236-242.
8. Nanda, K.K.; Wesley Trotter, B. Tetrahedron Letters 2005, 46, 2025-2028.
9. Petasis, N.A.; Zavialov, I.A. Journal of the American Chemical Society 1998,
120, 11798-11799.
10. Yao, X. Ph.D., University of Southern California, 2002.
11. Petasis, N.A.; Zavialov, I.A.; Patel, Z.D.; (USA). Application: US
US, 2004, p 18 pp , Cont -in-part of u S Ser No 699,076.
12. Petasis, N.A.; Yao, X.; Raber, J.C.; (University of Southern California, USA).
Application: US, 2005, p 22 pp.
13. Adger, B.M.; O'Farrell, C.; Lewis, N.J.; Mitchell, M.B. Synthesis 1987, 53-5.
14. Vernier, J.M.; Hegedus, L.S.; Miller, D.B. Journal of Organic Chemistry 1992,
57, 6914-20.

167

CHAPTER 4: Substituted allenyl boron derivatives. Synthetic
methodology and reactivity studies in the Petasis reaction

4.1 Substituted allenyl boron derivatives. Their role and potential
in organic synthesis
As already mentioned in chapter 2, allenyl boronic acid 2.65 and various
boronate derivatives
1,2,3
constitute very useful synthetic tools for a variety of
transformations. Utilized mainly in propargylation of aldehydes
4,5
and ketones
6,7
and
in the asymmetric version of this process through diastereoselective additions
8,9
as
well as enantioselective additions of its tartrate
10,11
and chiral diamine
12
derived
esters, 2.65 has gained significant popularity in the synthesis of natural products and
various chiral synthons. Even though the propargyl and allenyl moieties are highly
versatile and can be transformed to many different kinds of scaffolds through further
synthetic manipulations, these aspects have not been explored due to the lack in
practical synthetic methods towards substituted allenyl boron derivatives.
Some initial limited efforts in synthesizing such analogues were made, after
their reactivity towards aldehydes had been realized.
2
But the low yields and the
complications originating from the configurational instability of the Grignard
reagents employed initially, most likely constitute the key reasons to explain the lack

168

of further research in this field. In particular, the propargylic rearrangement already
introduced in Chapter 2, (Scheme 2.7), the degree of which is directly related to the
substitution pattern of the corresponding Grignard gives mixtures of propargyl and
allenyl boronates.
3, 5
In addition, the air and moisture sensitivity of some of those
compounds makes purification problematic thus limiting their synthetic potential. As
a consequence, a very limited number of such analogues are mentioned in the
literature in the form of cyclic boronates,
2,3
in order to study their additions to
aldehydes and ketones while no data about the corresponding boronic acids and
trifluoroborate salts are available. Furthermore, no data is available for other types of
processes that these compounds are theoretically expected to participate.
As part of our reactivity studies of allenyl boronic acid 2.65 in the Petasis
reaction, we wished to explore the reactivity of substituted analogues in this process.
The employment of substituted allenyl boron sources was desirable for a number of
reasons such as:
Synthesis of novel highly functionalized allenyl and propargyl amine
derivatives in one step.
Exploration of their reactivity and selectivity in the process compared
to the competitive two-component addition to the oxo component.
Exploration of the reactivity among the different boron derivatives in
the three-component reaction.

169

Examination of the degree of control that different components and
conditions induce to the isomeric products distribution obtained, in the presence of a
substituent.
Mechanistic insight about the effect of substitution on the reaction
rate, mode and outcome (isomeric and diastereomeric composition).
Examination of stereoselectivity aspects in the cases of potentially
chiral allenyl boron sources.
Based on the abovementioned arguments we initially decided to synthesize
the monosubstituted analogues of types 4.1 ( α-substituted) and 4.2 ( γ-substituted)
(Scheme 4.1)
4.1
B
•
O
OR
RO
4.2
B
•
OR
RO
nC
5
H
11

Scheme 4.1: Novel α and γ-substituted allenyl boron sources for the Petasis reaction

If the boron derivatives of types 4.1 and 4.2 are reactive in the Petasis
reaction they are expected to yield scaffolds of the types presented in Scheme 4.2.
The vinyl ether moiety of 4.3 can be further synthetically manipulated to yield an
α,β-unsaturated ketone while the use the γ-substituted boron source 4.2 is in addition
expected to yield diastereomeric products due to the axial chirality of the allene
moiety, addressing stereochemical issues.

170

4.3
•
O
N
R
3
R
2
R
1
4.4
N
R
3
R
2
R
1
O
4.5
•
N
R
3
R
2
R
1
nC
5
H
11
4.6
N
R
3
R
2
R
1
nC
5
H
11
Scheme 4.2: The types of scaffolds that can be synthesized by utilizing 4.1 and 4.2 in the Petasis
reaction

But besides the Petasis reaction, the development of efficient synthetic
protocols for substituted allenyl boron derivatives is expected to have a broader
synthetic impact. As a consequence, novel allenyl and propargyl alcohols can be
prepared from additions to aldehydes. In addition, those analogues would potentially
constitute novel starting materials for Suzuki, Heck and other metal catalyzed
couplings, as well as for the applications of the parent allenyl boronic acid 2.65
mentioned in Chapter 2 (paragraph 2.2).
4.2 Results and discussion
4.2.1 Synthetic attempts towards substituted boron derivatives
The synthesis of 2-(1-methoxy-propa-1,2-dienyl)-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane 4.10, an α-substituted allenyl boronate began with the
commercially available methoxy-propargyl ether 4.7, which is known to undergo
base-catalyzed isomerization to the isomeric methoxy allene 4.8.
13,14
Furthermore,

171

literature data
15
supported by calculations
16,17
concerning 4.8, suggest that in the
presence of strong bases 4.8 deprotonates selectively in the α position so this MeO-
directed deprotonation would in theory give us a single type of allenyl
organometallic avoiding complications from deprotonation of the allene in multiple
sites. Furthermore, the synthetic potential of this boronate, if reactive in the Petasis
reaction, is important since the resulting vinyl ether adducts give easy access to
novel, multifunctionalized α,β unsaturated ketones in a single synthetic step.
So based on that approach, we developed a novel synthetic protocol towards
4.10 (Scheme 4.3).
4.10
B
•
O
O
O
OMe
10% KOt-Bu
45-50
o
C, 4.5 hr
Shlenck tube
neat, 81%
OMe
•
1. n-BuLi, Et
2
O(abs.)
-40
o
C
O
B
O
O
2.
Et
2
O(abs.), -78
o
C
3. HCl/Et
2
O, -78
o
C
4.7 4.8
4.9

Scheme 4.3: Synthesis of 2-(1-methoxy-propa-1,2-dienyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

The type of boron electrophile employed was critical since the use of
B(OMe)
3
or B(OiPr)
3
was proven inappropriate in this methodology.
Disproportonation, which is known to occur to various methyl and isopropyl
boronates probably took place in our case as well since by a simple substitution of
4.9 with B(OMe)
3
or B(OiPr)
3
, no product was detected. Both aqueous and
anhydrous conditions were employed in order to obtain the corresponding acid or

172

ester from the “ate” complex (when B(OMe)
3
or B(OiPr)
3
were used) but the
outcome was the same. As a consequence, the possibility of decomposition during
aq. hydrolysis can be ruled out and disproportonation seems more likely to have
taken place.
Compound 4.10 was stored as a solution at 0
o
C. Complete removal of the
solvent was avoided since as it was noticed, a dark and thick residue of uknown
composition was obtained when test samples were subjected to this treatment. At this
point no effords were made to convert 4.10 to the corresponding boronic acid or
potassium organotrifluoroborate salt.
The γ-substituted allenyl boron derivative 4.11 (Scheme 4.4) is another,
highly promising type or organoboron compound as potential component in the
Petasis reaction. Besides the fact that novel analogues which are not easily
synthesized can be accessible by a single transformation, other interesting aspects
come into play as well.
The potential binary mode of reaction that these analogues can undergo in the
Petasis reaction adds one extra point of diversity thus giving direct access to both
propargyl as well as allenyl multifunctionalized scaffolds. Moreover, it would be
interesting to explore the role of substitution on the stability and reactivity of those
compounds.
But besides the basic features of reactivity, the axial chirality of α, γ
unsymetrically disubstituted allenes introduces one more aspect which is that of

173

diastereoselectivity originating from the organic group of the boron component. Such
studies have not been conducted for the Petasis reaction so far.
The first synthetic approach towards these analogues involved the use of
Grignard organometallics. Taking into consideration the propargylic rearrangement
and the potential complications associated with the configurational stability of both
the Grignard as well as the boron derivative, our retrosynthetic analysis is shown in
Scheme 4.4.
4.11
B
•
OR
RO
R
4.12
MgBr
•
R
R
MgBr
R
Br
4.13 4.14

Scheme 4.4: The retrosynthetic path towards boronates of type 4.11

Even though the propargyl bromides of type 4.14 are not commercially
available, the plethora of the corresponding alcohols gives access to the former in a
few synthetic steps.
The model reaction that we chose to study was that of 1-octyn-3-ol 4.15. The
corresponding propargyl bromide 4.16 was synthesized according to Scheme 4.5.
18

nC
5
H
11
OH
4.15
nC
5
H
11
Br
4.16
NBS, PPh
3
,
CH
2
Cl
2
(dry),
0
o
C to RT
24hr, 66%

Scheme 4.5: Synthesis of 4.16

174

Employing 4.16 in the classic conditions under which the Grignard
organometallic is formed and subsequently reacts with the boron electrophile was not
successful in synthesizing the desired γ-substituted allenyl boron compound.
Different conditions were applied in our efforts to efficiently form the
organomagnesium species such as:
Mg metal in the presence of catalytic amounts of HgCl
2
or I
2
.
Slow addition of preformed Grignards.
As it was concluded by control experiments the Grignard is not efficiently
formed at ambient temperature but when heat was applied (40-65
o
C) the coupling
byproducts 4.17 and 4.18 were preferentially formed (even when the addition of 4.16
lasted for more than 10hr) indicating fast reaction of the in situ formed Grignard with
the starting bromide. The desired product 4.19 was detected in traces (yield: 2.7%).

nC
5
H
11
Br
1. Mg, Et
2
O (abs)
HgCl
2
, RT to 0
o
C
2. B(OiPr)
3
, -78
o
C
3. HCl/Et
2
O(abs.)
4. Pinacol
•
traces (2.7%)
•
coupling products (major products)
++
4.16 4.17 4.19 4.18
B
nC
5
H
11
O
O

Scheme 4.6: Higher hydrocarbons are the mostly obtained when Grignard reagents are employed

Since the formation of the propargyl Grignard proved erratic and
synthetically impractical we envisioned the use of the corresponding allenyl bromide
4.22 as a precursor of allenyl Grignard or allenyl lithium organometallics. 4.22 was

175

synthesized according to Scheme 4.5 through a Cu
I
promoted S
N
’
2
displacement of
the propargylic mesylate 4.20.
19

nC
5
H
11
OMs
•
Br
+
nC
5
H
11
4.20 4.22 (75%)
CuLiBr
2
, 4.21
CH
3
CN (dry),
RT, 1hr, 74%
nC
5
H
11
Br
4.16 (25%)
nC
5
H
11
OH
4.15
MsCl, Et
3
N
CH
2
Cl
2
(dry)
-78
o
C to RT,
quantitatively

Scheme 4.7: Synthesis of the allenyl bromide 4.22

The abovementioned transformation gave a mixture of both allenyl and
propargyl bromides in an approximate ratio 3:1 which was used without further
purification since separation of the two isomers was not successful through flash
chromatography.
Attempts to employ the corresponding allenyl Grignard towards the synthesis
of 4.19 was once more inadequate since only residual 4.22 and higher hydrocarbons
and were obtained from undesired coupling side reactions.
The next step was to utilize the corresponding organolithium since allenyl
bromides are known to undergo lithiation in the presence of n-BuLi or t-BuLi.
20
That
approach was proven suitable, even though a set of strict reaction conditions are
absolutely necessary in order to minimize the side reactions and drive the process to
the desired direction. The synthetic protocol developed is shown in Scheme 4.8.

176

1. n-BuLi, -110
o
C,
THF(dry), 5min
•
nC
5
H
11
+
Br
4.22 (75%)
nC
5
H
11
Br
4.16 (25%)
O
B
O
O
2.
-110
o
C to RT,
4.5 hr, 34%
4.9
4.19
B
•
O
O
nC
5
H
11

Scheme 4.8: Synthesis of 4,4,5,5-Tetramethyl-2-octa-1,2-dienyl-[1,3,2]dioxaborolane 4.19

Exploring the optimal conditions to promote the abovementioned
transformation, the following are of major importance:
The temperature. -110 to -120
o
C proved to be optimal for achieving
the desired dehalogenation and concomitant boron transmetallation without any
competing coupling side reactions. When the reaction was conducted at temperature
> -95
o
C only dimerization of the starting material was observed.
The boron electrophile. 2-Isopropoxy-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane 4.9 proved to be ideal giving better product purity and yield,
while B(OiPr)
3
resulted in a crude reaction along with the fact that the resulting γ-
alkyl isopropyl boronate showed less stability and suffered from significant
decomposition during isolation attempts.
The formation of higher hydrocarbons even though suppressed under the
abovementioned conditions, is unavoidable. As was shown by control experiments
the propargyl bromide 4.16 present in the starting material reacts faster than the
allenyl and selectively couples. No propargylic boronate was observed and as it was

177

shown from the byproducts and by monitoring the metallation process with
1
H NMR,
the propargyl bromide was consumed first. In addition, coupling of the propargyl
lithium with the allenyl bromide consumes the latter thus reducing the yield of the
desired boronate.
Having established a synthetic protocol for 4.19 we turned our attention to
developing synthetic methodology towards the corresponding boronic acid 4.23 and
the potassium trifluoroborate salt 4.24 and explore their potential as well as boron
components in the Petasis reaction.
By following literature procedures we were pleased to find out that obtaining
4.23
21
and 4.24
22
from 4.19 is feasible in a simple transformation (Scheme 4.9) with
quantitative yields.

•
B
nC
5
H
11
O
O
•
BF
3
K
nC
5
H
11
•
B
nC
5
H
11
OH
HO
4.23
4.19
4.24
NaIO
4
,
CH
3
CN/H
2
O (4/1)
aq. HCl, RT,
0.5hr, 96%
KHF
2
(3.1 eq.),
CH
3
CN/H
2
O (8/1)
RT, 28hr, 99.9%

Scheme 4.9: Synthesis of 4.23 and 4.24 from 4.19

The corresponding (-)pinanediol boronate 4.26 was also synthesized
according to Scheme 4.10.

178

•
B
nC
5
H
11
4.23
DCM, RT
RT, 24hr,
78%
1. n-BuLi, -110
o
C,
THF(dry), 5min
•
nC
5
H
11
+
Br
4.22 (75%)
nC
5
H
11
Br
4.16 (25%)
2.
-110
o
C to RT,
3.5 hr, 50%
4.25
4.26
O
B
O
O
O
O
B
•
nC
5
H
11
OH
OH
+
HO
OH
4.27

Scheme 4.10: Synthesis of 4.26 with two alternative pathways

Comparing the four newly synthesized organoboron compounds it was
concluded that 4.19, 4.24 and 4.26 are stable allowing complete purification by flash
chromatography (4.19 and 4.26) and recrystallization (4.24). Also, no special
precautions have to be taken for their storage. On the contrary, 4.23 as was observed
by
1
H NMR, undergoes significant decomposition with time (gradual loss of the
allenyl signals was observed even in the first 24 hr). As a consequence 4.23 must be
used immediately after its synthesis. From the purification attempts it was shown that
an aqueous work up can be performed to remove the inorganic residues from the
preparation step but complete decomposition occurs with flash chromatography.
Furthermore, the usual purification of boronic acids through recrystallization does
not apply in this case since 4.23 is a liquid due to the five-carbon lipophilic chain but
this is expected not to be the cases for smaller analogues.

179

4.2.2 Reactivity of novel allenyl boron derivatives in the Petasis reaction
4.10, the α-MeO allenyl pinacol boronate was initially employed in the
multicomponent process. The reactivity of 4.10 was explored in a number of
attempts with both primary and secondary amines aliphatic as well as aromatic
amines in combination with glycolaldehyde dimer and/or glyceraldehydes dimer to
synthesize the corresponding β-amino alcohols and/or β-amino diols respectively.
Unfortunately, complete lack of reactivity was observed under the conditions
investigated and the expected products were not detected at all. Instead, the starting
amine was the major component that could be identified in the crude mixtures
obtained after the reactions were stopped.
4.10
B
•
O
O
O
+
R
1
O
OH
R
2
H
N
R
3
+ NO REACTION
4.28 2.1

Scheme 4.11: 4.10 does not constitute a reactive boron source for the Petasis reaction

After the disappointing results of using 4.10 in the multicomponent process,
we moved to utilizing the γ-substituted boron derivatives 4.19, 4.23 and 4.24.
The first studies that were conducted by employing the novel boron
derivatives 4.19, 4.23 and 4.24 with glyoxylic acid monohydrate 2.104 and various
amines in an effort to explore the reactivity of those analogues in synthesizing novel
allenyl and propargyl α-amino acids.

180

The model reaction that was chosen to explore the reactivity of primary
amines in combination with 4.19, 4.23 or 4.24 was that of benzylamine 2.109, an
amine that can be cleaved later and whose α-substituted chiral analogues are
commercially available for diastereoselectivity studies.
•
C
5
H
11
n
X
OH
OH
O
++
HN
nC
5
H
11
COOH
HN
COOH
• nC
5
H
11
+
X= Bpin, 4.19 or
X= B(OH)
2
, 4.23 or
X= BF
3
K, 4.24
2.104
Ph NH
2 HO
2.109
4.29a-anti 4.29b-anti
Ph Ph
HN
nC
5
H
11
COOH
HN
COOH
• nC
5
H
11
+
4.29a-syn 4.29b-syn
Ph Ph

Scheme 4.12: Synthesis of novel propargyl and/or allenyl α-amino acids by employing 4.19, 4.23
and/or 4.24 in the Petasis reaction with 2.104 and 2.109

The observations from this series of experiments are summarized in Table 4.1
Table 4.1: Reactivity studies of 4.19, 4.23 and 4.24 in combination with 2.104 and 2.109
Entry Boron
compd
Amine Time
(hr)
Yield
(%)
4.29a/4.29b %de
(a)
%de
(b)
1
a
4.19 BnNH
2
72 49 67/33
d
53 N.D.
2
b
4.19 BnNH
2
72 Decomposition - - -
3
a
4.19 BnNH
2
360 55 83/17
d
45 N.D.
4
a
4.19 BnNH
2.
HCl 360 No rxn - - -
5
a
4.23 BnNH
2
72 34 100/0 70 -
6
a
4.24 BnNH
2
24 No rxn - - -
7
c
4.24 BnNH
2
24 No rxn - - -
8
a, e
4.24 BnNH
2
144 No rxn - - -
9
b, e
4.24 BnNH
2
48 6 100/0 42 -

Conditions. a: MeOH, R.T., b: MeOH, 60
o
C, c: CH
3
CN, R.T., d: isolated compounds, e: 20% Yb(OTf)
3
.
N.D.: Not determined due to signals overlap in the
1
H NMR spectra

181

From our initial efforts a number of observations were made.
To our satisfaction 4.19 behaved very well and participated in the
process at ambient temperature. It’s noteworthy that this result is in contrast with
numerous reports that state lack of reactivity of pinacol boronates in the Petasis
reaction when primary amines are used. Our results agree with the data reported by
Jourdan et al
23
who also observed reactivity of alkenyl and heteroaryl pinacol
boronates in alcoholic solvents. The yield (49-55%) and diastereoselectivity (53-
45%) observed in that variation slightly changed after the first 72hr so that time is a
good compromise for satisfactory conversion. As observed, both isomers were
obtained in the case of 4.19 with the propargyl isomer 4.29a being the main product.
Slight change was observed in the isomeric ratio with time. In particular at t=72hr,
4.29a/4.29b=67/33 while at t=360 hr, 4.29a/4.29b=83/17. The presence of the five-
carbon substituent allowed complete separation of the isomeric adducts in this case,
through flash chromatography. Once more, heating was shown to be inappropriate
for this version, even when the relatively more stable 4.19 was used. Complete
decomposition was observed by raising the temperature to 60
o
C. Also replacing
BnNH
2
with BnNH
2
.HCl resulted in no conversion.
After the encouraging results obtained by 4.19 we turned our attention
to utilizing 4.23 which is expected to show enhanced reactivity compared to 4.19.
4.23 indeed participated and in addition, yielded exclusively 4.29a with higher
diastereoselectivity (70%) compared to 4.19. That value was the highest observed in

182

this series and indicates that the presence of the axial chirality of 4.23 can induce
significant enantioselectivity if enantiomerically pure 4.23 is used instead of the
racemate. The trade off in using 4.23 is the fact that an additional synthetic step is
required for its preparation along with the use of large excess due to the fast
decomposition it undergoes. In order to drive those processes to higher conversions,
frequent additions of 4.23 are essential, something that limits their practicality.
Furthermore, control experiments were performed that showed competitive
reaction of 4.23 through two-component addition to glyoxylic acid monohydrate
(Scheme 4.13), even though with low yield (20%), thus indicating one more pathway
of consumption of 4.23 to side reactions.
•
nC
5
H
11
B(OH)
2
OH
OH
O
+
OH
nC
5
H
11
COOH
+
2.104
HO
4.30-syn
(+enantiomer)
4.23
OH
nC
5
H
11
COOH
4.30-anti
(+enantiomer)
MeOH, RT
48hr, 20%
syn/anti=1
(0% de)

Scheme 4.13: Addition of 4.23 to glyoxylic acid monohydrate

The corresponding potassium trifluoroborate salt 4.24 was also examined in
this variation due to the appealing characteristics of air and moisture stability.
Unfortunately, the conditions we applied (MeOH or CH
3
CN at ambient temperature)
did not lead to any conversion in the absence of catalyst. When 20% Yb(OTf)
3
was
used as a catalyst the expected products were detected only upon heating to 60
o
C for

183

48 hr but the yield was very low, thus making this variation synthetically impractical.
In the absence of heat, the reaction did not occur at all even after 4 days of stirring.
Since secondary amines constitute the best candidates for many different
versions of the Petasis reaction, we examined their use in synthesizing a new series
of allenyl and propargyl α-amino acids. Our initial efforts concerned the use of
cleavable amines (dibenzylamine 2.121 and diallylamine 2.122) as well as non
cleavable, such as morpholine 2.124 in combination with the different boron
derivatives 4.19, 4.23 and 4.24.
Secondary amines indeed participated in the process yielding in most cases,
exclusively the allenyl α-amino acid product. The yields obtained were moderate to
high and at this point no optimization attempts were performed to obtain better
conversions. From the experimental data available so far, the use of CH
2
Cl
2
as the
solvent with 4.19 was shown to give almost quantitative yields where employed, so it
seems to be the best combination for high conversions.

B(OH)
2
•
OH
O
OH
OH
N
O
Bn
2
NH •
N
OH
O
nC
5
H
11
Ph Ph
4.23
BF
3
K
•
nC
5
H
11
4.24
CH
3
CN
Ph Ph
HO
4.31a 4.31b 2.104 2.121
nC
5
H
11
nC
5
H
11

Scheme 4.14: Control in the selective synthesis of allenyl or propargyl α-amino acids

184

The solvent effect that had been observed when 2.178 was used in CH
3
CN
was also observed in the case of 4.24. Thus, in the case of dibenzylamine 2.121,
direct access to both isomers is feasible by altering the boron source (Scheme 4.14).
Our observations from using secondary amines are summarized in Table 4.2.
Table 4.2: Reactivity studies of 4.19, 4.23 and 4.24 in combination with 2.104 and secondary amines
Transformation Results

X
•
HO
OH
OH
O
1
OH
N
O
OH
N
O
•
4.31a
4.31b
X
•
HO
OH
OH
O
3
OH
N
O
OH
N
O
•
Ph NH
Ph Ph
Ph Ph
N
H
O
O
O
X
•
2
OH
N
O
OH
N
O
•
NH
2
nC
5
H
11
nC
5
H
11
nC
5
H
11
++
++
HO
OH
OH
O
nC
5
H
11
nC
5
H
11
nC
5
H
11
4.32a
nC
5
H
11
4.32b
nC
5
H
11
nC
5
H
11
4.33a
4.33b
++
4.19 or
4.23 or
4.24
4.19 or
4.24
Boron source Solvent T t Yield a/b de, a de, b
(
o
C) (hr) (%) (%) (%)
X=B(OH)
2
, 4.23 MeOH RT 88 28 0/100 - 59
X=BF
3
K, 4.24 CH
3
CN RT 14 18 100/0 24 - 2
Boron source Solvent T t Yield a/b de, a de, b
(
o
C) (hr) (%) (%) (%)
X=Bpin, 4.19 CH
3
CN RT 48 10 0/100 - 49
X=Bpin, 4.19 CH
2
Cl
2
RT 48 95 0/100 - 51
Boron source Solvent T t Yield a/b de, a de, b
(
o
C) (hr) (%) (%) (%)
X=Bpin, 4.19 CH
2
Cl
2
RT 60 93 0/100 - ND
X=BF
3
K, 4.24 CH
3
CN RT 48 30 28/72 25 ND
4.19
2.104
2.104
2.104
2.121
2.122
2.124

185

Initial attempts were performed in employing aromatic amines in this version
of the Petasis reaction. From our results, participation of those amines was indeed
recorded but the products were decomposing during flash chromatography. Partly
purified samples showed the desired signals (the α-H, the amine as well as the
signals originating from the boron component in the expected ratios) but complete
purification was not feasible for most of those compounds since the attempts through
flash chromatography on silica lead to reappearance of the starting amine along with
unidentified material. The following conclusions can be made from this series of
experiments
The use of p-anisidine 2.114 in combination with 4.19 yielded the propargyl
α-amino acid exclusively. A partly purified sample showed the presence of the two
propargyl diastereomers with de=82%. No quantitative conclusions can be made
concerning the yield due to the abovementioned sensitivity of those compounds to
flash chromatography which finally resulted to complete decomposition. The
conversion, as monitored by
1
H NMR was higher and much faster in MeOH
compared to DCM. The use of Yb(OTf)
3
did not promote the reaction.
Furthermore, in a test reaction the corresponding preformed imine of p-
anisidine 4.34 was subjected to reaction with both 4.19 and 4.23 but in both cases no
conversion was observed according to the
1
H NMR, indicating an additional reason
for the low conversion since the corresponding imine is readily formed under the
conditions employed in the Petasis reaction.

186

X
•
nC
5
H
11
OH
N
O
O
NO REACTION
X: B(OH)
2
, 4.23 or
X: Bpin, 4.19
4.34
X: B(OH)
2
, 4.23
CH
2
Cl
2
, RT
X: Bpin, 4.19
MeOH, RT
OR

Scheme 4.15: The preformed imine 4.34 is not reactive towards 4.23 or 4.19

The use of p-nitroaniline 2.180 gave useful information concerning the
reactiviy of anilines in the process. The reaction is depicted below:
•
nC
5
H
11
2.180
CH
3
CN, RT
4.19
B O
O
HO
OH
OH
O
++
48hr, 27%
NH
nC
5
H
11
COOH
NH
COOH
• C
5
H
11
n
+
4.35a 4.35b
O
2
N O
2
N
4.35a/4.35b=27/73
2.104
NH
2
O
2
N

Scheme 4.16: The reaction of p-nitroaniline 2.180 with 2.104 and 4.19

The allenyl α-amino acid was the major isomer (4.35a/4.35b=27/73) while
the diastereoselectivity was low for both pairs of diastereomeric products. For the
propargyl isomers 4.35a de=23% while for the allenyl 4.35b, de=21%.
The use of N-phenyl benzylamine 2.182 in combination with 4.19 gave
exclusively the allenyl isomer 4.36b, in moderate yield (30%) and
diastereoselectivity (47%) when CH
3
CN was used as the solvent while no data are
available in DCM which seems to be the best solvent when secondary amines are
used.

187

As mentioned in 4.4.1 the corresponding (1R, 2R, 3S, 5R)-(-)-pinanediol
boronate 4.26 was also synthesized and subjected to reaction with benzylamine 2.109
or morpholine 2.124 in combination with glyoxylic acid monohydrate 2.104.
Unfortunately this boronate gave no reaction. Besides the conventional conditions
that involve stirring at RT (for up to 4 consecutive days), heat was applied (60
o
C for
48 hr and 100
o
C for 72 hr) as well as trials with the presence of Yb(OTf)
3
or KOH
(for the activation of the intermediate imine or the bulky boronate respectively).
Neither benzylamine, nor morpholine gave any conversion indicating that the
enhanced steric hindrance of 4.26 inhibits the reaction. 4.26 is significantly stable
and survives after heating unlike other less hindered allenyl boron analogues.
2.109
HO
OH
OH
O
+
2.104 4.26
O
O
B
•
nC
5
H
11
N
H
O
NH
2
2.124
NO REACTION NO REACTION

Scheme 4.17: 4.26 is not reactive in the Petasis reaction

Finally, a limited number of experiments were performed by utilizing 4.19 or
4.24 and glycolaldehyde dimer 2.144 in synthesizing γ-substituted allenyl β-
aminoalcohols 4.36b and 4.37b. From both experiments, the allenyl isomers were the
sole isomers observed. Besides the participation of secondary amines which was
straightforward, we observed that benzylamine 2.109 gave very satisfactory
conversion taking into consideration the intrinsic reduced reactivity of primary

188

amines in the process and the considerable decomposition usually observed in this
variation. Last but not least, this result was surprising for us considering the
demonstrated lower reactivity of the pinacol boronate 4.19 compared to other more
promising boron candidates, such as the corresponding boronic acid 4.23 (for which
no experiments have been performed so far). To our satisfaction 4.19 constitutes a
reactive component which further expands the synthetic potential of the reaction.
The conventional conditions usually employed for the multicomponent
process were also applied in this case. In fact, modified Mannich conditions
24
were
applied in the first attempts in order to promote the transformation (entries 2 and 3 in
table 4.3) but the reaction did not proceed. Those attempts are summarized below.
X
•
R
1
NH
2
O
O OH
HO
R
1
R
2
NH
nC
5
H
11
•
N
R
1
R
2
OH nC
5
H
11
•
NH
R
1
OH nC
5
H
11
4.37b 4.36b
2.144 X= Bpin, 4.19 or
X= BF
3
K, 4.24

Scheme 4.18: Reactivity studies of 4.19 and 4.24 in synthesizing novel allenyl β-amino alcohols.
Table 4.3: Reactivity studies of 4.19 and/or 4.24 in combination with 2.144 and 2.109
Entry Boron
compound
Amine Product Solvent θ
(
o
C)
Time
(hr)
Yield
(%)
de
(%)
1 X=Bpin, 4.19 BnNH
2
4.38b MeOH RT 20 36 30
2 X=Bpin, 4.19 BnNH
2
.HCl - MeOH RT 48 No rxn -
3
a
X=Bpin, 4.19 BnNH
2
.HCl - CH
3
CN RT 24 No rxn -
4 X=Bpin, 4.19 Morpholine 4.39b
CH
2
Cl
2

RT 60 56
ND
5 X=BF
3
K, 4.24 (Bn)
2
NH - CH
3
CN RT 96 No rxn -
6 X=BF
3
K, 4.24 (Bn)
2
NH - CH
3
CN 60 144 No rxn -
Conditions. a: CH
3
CN, RT, Me
3
SiCl/NaI/Et
3
N (modified Mannich reaction conditions)

189

4.3 Experimental
4.3.1 General
All the reactions were performed under N
2
. The solvents were used without
further purification and no dry conditions were necessary unless otherwise stated.
The reactions were monitored by TLC on Silica Gel 60 precoated plates with F
254

indicator. The product was purified by flash chromatography on Silica 60 Å 32-63
µm unless otherwise stated.
1
H and
13
C NMR were recorded on a Bruker AMX500
or an AM360 MHz, or an AC250 MHz or a Varian Mercury 400 NMR. Chemical
shifts of
1
H NMR are reported in parts per million on the δ scale from an internal
standard of either residual chloroform (7.24 ppm), DMSO d
6
(2.49 ppm), acetone d
6

(2.04 ppm) or partly deuterated MeOH (3.3 ppm). Data are reported as follows:
chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet
and br=broad), coupling constants in Hz and integration. Chemical shifts of
13
C
NMR are reported in ppm from the central peak of either CDCl
3
(77.0 ppm), DMSO
d
6
(39.5 ppm) or partly deuterated MeOH (49.5 ppm).

4.3.2 Experimental observations
1. The
1
H and
13
C NMR data suggest that both diastereomers are present in
all experiments performed do far. The reported diastereoselectivity values

190

correspond to the crude reaction mixture at the time the reaction was stopped unless
otherwise stated (in some cases where the reaction mixture was significantly crude
and no diastereoselectivity determination was feasible in the crude, the
corresponding ratio is reported after purification). For some products no quantitative
de determination was feasible since the H signals overlapped but the presence of
both diastereomers was identified by the appearance of “double peaks” in the
13
C
NMR) before and after purification. Partial separation was usually observed after
purification which excludes the possibility of rotamers of any kind.
2. Significant decomposition of the boronic acid 4.23 was observed upon
standing (by recording the
1
H NMR in CDCl
3
) as well as during the three-component
process. In particular, after flash chromatography performed for the purification of
4.31b, 74 mg of boron and amine free, hydrocarbon byproducts were collected which
can only originate from the boronic acid decomposition (114mg of BA was used for
that reaction). Proton deboronation and polymerization are side reactions that
consume the boron component.
3. Intermediate additions of 4.23 were done in order to obtain better
conversion due to the competing decomposition processes. Further conversion was
actually obtained as noticed from the
1
H NMR spectra but after 72 hr, no significant
changes were recorded even when big amounts of 4.23 were added. The reaction was
stopped at 72hr.

191

4.3.3 Synthesis and physical data

4.10
B
•
O
O
O

2-(1-Methoxy-propa-1,2-dienyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(4.10). In a flame dried 250-ml round bottomed flask equipped with a magnetic
stirrer, 50 ml of dry Et
2
O were placed followed by 4.8 (3.50 g, 50 mmol). The
system was degassed, cooled to -40
o
C with an external acetonitrile/solid CO
2
bath
and n-BuLi (2.5 M in Hexanes, 20ml, 50mmol) was added through syringe (addition
time: 15 min). The color of the solution turned yellow after the addition of n-BuLi.
The reaction mixture was left under stirring at that temperature for an additional 15
min.
A flame dried 500-ml round bottom equipped with magnetic stirrer was
charged with 150 ml dry Et
2
O and 2-Isopropoxy-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane 4.9 (10g, 53.7mmol). The solution was cooled to -78
o
C through
an acetone/solid CO
2
external bath and slow addition of the abovementioned
organolithium was added through syringe (10 ml portions were transferred from the
flask while the rest was kept at -40
o
C). The addition was completed after 30 min and
the system was left under stirring at -78
o
C for 3hr. Subsequently, slow addition of

192

anhydrous HCl (2M in Et
2
O, 25ml, 50mmol) at -78
o
C was performed that lasted 1 hr
and finally the system was allowed to gradually reach ambient temperature.
Precipitation of LiCl was observed as the reaction mixture was warming up. The
solids were removed under sunction filtration and the filtrate was collected. This
crude bulk was kept in the refrigerator as a solution in Et
2
O since attempts to
completely evaporate the solvent lead to a darkened residue. No yield determination
was performed on the whole. From 10ml aliquots it was deduced that 0.4g of non
volatile residue was contained in 10ml of the crude solution. From that, the quantity
of the boronate used in the various reactions was calculated since the
1
H NMR
showed the expected product in 80% purity. No further purification was feasible due
to decomposition.
1
H NMR (250 MHz, CDCl
3
) δ 5.39 (s, 2H), 3.347 (s, 3H), 1.22(s, 12H).
13
C
NMR (60 Mz, CDCl
3
) δ 206.55, 88.33, 84.30, 24.50

4.19
B
•
O
O
nC
5
H
11

4,4,5,5-Tetramethyl-2-octa-1,2-dienyl-[1,3,2]dioxaborolane (4.19). In a
flame dried 500-ml round bottomed flask equipped with a magnetic stirrer, 140 ml of
dry THF were placed followed by 4.22 & 4.16 (4.370 g, 23.1 mmol). The system
was degassed and cooled to -110
o
C with an external Hexanes/liquid N
2
bath. The

193

system was degassed once more at -110
o
C as well and n-BuLi (1.6 M in Hexanes,
17.5ml, 28mmol) was added through syringe (addition time: 1-2 min). It was left
under stirring at that temperature for 5 min and subsequently 2-isopropoxy-4,4,5,5-
tetramethyl-[1,3,2]dioxaborolane 4.9 (5.8 ml, 28mmol) was added in 2-3 min. The
temperature was monitored by a Pt electrode and care was taken so that it was
maintained at -110
o
C throughout both additions. After the end of the addition the
bath was left on and the system was allowed to slowly warm up to ambient
temperature for a total of 3.5hr. The mixture was then diluted with 150ml Et
2
O and
treated with aq. NH
4
Cl (2x100ml), NaHCO
3
(1x100ml) and brine (1x100ml). It was
dried with MgSO
4
and the volatiles were removed under reduced pressure. Further
purification was essential so the crude residue was subjected to flash
chromatography (gradient elution: Et
2
O/Hex, 0% to 2% to final 5%). Yield: 1.635g
or 30%.
1
H NMR (250 MHz, CDCl
3
) δ 5.05 (q, J=6.8 Hz, 1H)), 4.87 (m, 1H), 2.00
(m, 2H), 1.47-1.08 (s & s & m-overlapping peaks, 23H).
13
C NMR (100 MHz,
CDCl
3
) δ 216.50, 85.98, 83.46, 31.14, 28.75, 27.19, 24.84, 24.55, 22.48, 14.06.

194

4.23
B
•
OH
HO
nC
5
H
11

Octa-1,2-dienyl-boronic acid (4.23). Sodium periodate (0.815g, 3.81 mmol)
was added to a room temperature solution of 4,4,5,5-Tetramethyl-2-octa-1,2-dienyl-
[1,3,2]dioxaborolane 4.19 (0.300g, 1.27 mmol) in THF/H
2
O (8:2, 10 mL). The
mixture was stirred until homogeneous, and then 2N aq. HCl (0.4 mL) was added.
After 1 hr, the reaction mixture was diluted with 50ml EtOAc, washed with H
2
O and
treated with aq. NH
4
Cl (2x50ml), NaHCO
3
(1x50ml) and brine (1x50ml). It was
dried with MgSO
4
and the volatiles were removed under reduced pressure. No
further purification was performed since the product decomposes during flash
chromatography. Crude yield: 0.184g or 94%.
1
H NMR (250 MHz, CDCl
3
) δ 5.10 (s, 1H), 4.92 (s, 1H), 2.02 (m, 2H), 1.74
(m, 1H), 2.41-1.21 (m, 19H), 0.87 (t, J=6.7Hz, 9H)

4.24
BF
3
K
•
nC
5
H
11

Potassium octa-1,2-dienyl-trifluoroborate (4.24). In a 50-ml round
bottomed flask equipped with a magnetic stirrer, 20 ml acetonitrile were placed
followed by 4,4,5,5-Tetramethyl-2-octa-1,2-dienyl-[1,3,2]dioxaborolane 4.19

195

(0.780g, 3.3 mmol). To that solution, KHF
2
(0.799g, 10.2 mmol, 3.1 equiv) was
added at room temperature followed by the slow addition of water (2.5 mL) over 1 h.
The mixture was left to stir at ambient temperature for 28 hr. The solvents were
removed under reduced pressure and the crude residue was left overnight under high
vacuum for complete evaporation of residual H
2
O. Then, the mixture was extracted
several times with EtOAc/CHCl
3
(2/1). The extracts were combined, concentrated,
and then held under high vacuum for 1 h. The resulting white solid was pure
according to
1
H and
19
F NMR. Yield: 0.712g

or 99.9%.
1
H NMR (400 MHz, Acetone d
6
) δ 4.62 (bs, 1H), 4.38 (bq, 1H), 1.86 (m,
2H), 1.41-1.20 (m, 6H), 0.87 (t, J=6.9 Hz, 3H).
19
F NMR (376 MHz, CDCl
3
) δ -
137.65 (q, J= 46.5Hz)

4.26
O
O
B
•
nC
5
H
11

2,9,9-Trimethyl-4-octa-1,2-dienyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]-
decane (4.26). ). A 10-ml round bottomed flask equipped with a magnetic stirrer,
was charged with 2 ml DCM followed by octa-1,2-dienyl-boronic acid 4.23 (0.045 g,
0.29 mmol) and (1R, 2R, 3S, 5R)-(-)-Pinanediol 4.27 (0.050 g, 0.29 mmol). The
mixture was left under stirring at ambient temperature for 24 hr. The residue was

196

purified with gradient flash chromatography (EtOAc/Hexanes, 0% to final 2%).
Yield: 0.065g or 78%.
1
H (400 MHz, CDCl
3
) δ 5.05 (dq, J
1
= 6.6Hz, J
2
= 2.4Hz, 1H), 4.89 (m, 1H),
4.26 (ddd, J
1
= 27.1Hz, J
2
= 8.4Hz, J
3
= 1.9Hz, 1H), 2.31 (m, 1H), 2.19 (m, 1H), 2.01
(m, 2H), 1.87 (m, 2H), 1.45-1.18 (overlapping signals, 12H), 1.12 (dd, J
1
= 24.6Hz,
J
2
= 11.0Hz, 1H), 0.86 (t, J= 7.2Hz, 3H), 0.81 (s, 3H).
13
C NMR (62 MHz, CDCl
3
) δ
216.548 & 216.377, 85.966 & 85.893, 77.955, 77.514, 51.282, 39.534 & 39.453,
38.088, 35.551 & 35.465, 31.213 & 31.141, 29.676, 28.817, 28.735, 28.684, 28.578
& 28.546, 27.224 & 27.168, 27.070, 26.455, 26.387 & 26.346, 25.416, 23.982,
22.466, 14.047 & 14.010, 13.866.

OH
HN
O nC
5
H
11
4.29a
Ph

2-benzylamino-3-ethynyl-octanoic acid (4.29a). A 5-ml round bottomed
flask equipped with a magnetic stirrer, was charged with 2 ml MeOH followed by
glyoxylic acid monohydrate 2.104 (0.028 g, 0.30 mmol) and benzylamine 2.109
(0.032 g, 0.30 mmol). To that mixture, octa-1, 2-dienyl-boronic acid 4.23 (0.060 g,
0.39 mmol) was added in one portion. The system was left under stirring at R.T. Two
additions of 4.23 were done (20mg at 24hr and 40mg at 48 hr) in order to obtain

197

better conversion. The reaction was stopped at 72hr since no significant change was
observed after the last addition of 4.23. The crude residue showed two diastereomers
of the propargyl product (de= 70%) while no allenyl product was observed. The
diastereomers were purified and partly resolved by flash chromatography (gradient
elution, EtOAc/MeOH/NH
4
OH, 85/10/5 to final 80/15/5). The chemical shifts of the
both diastereomers are mentioned below. Yield: 0.060 g or 28%.
1
H NMR (4.29a-both diastereomers, 400 MHz, MeOH, d
4
) δ 7.50-7.42 (m,
7H), 4.34 (d, J= 13.2Hz, 1H-major) & 4.32 (d, J=13.2Hz, 0.3H-minor), 4.22 (d,
J=13.2 Hz, 1H-major) & 4.17 (d, J= 13.0Hz, 0.3H-minor), 3.52 (d, J=3.5 Hz, 1H-
major) & 3.34 (d, J= 5.1Hz, 0.3H-minor), 3.03 (m, 1.3H-overlapping signals, H),
2.70 (d, J= 2.6Hz, 0.3H-minor) & 2.64 (d, J= 2.3Hz, 1H-major), 1.61-1.21 (m,
overlapping signals, 12H), 0.90-0.86 (t, overlapping signals, 4.3H).
13
C NMR (4.29a-
both diastereomers, 100 MHz, MeOH, d
4
) δ 170.251(minor) & 169.258 (major),
130.985, 129.963, 129.210, 128.823, 81.471 (major) & 80.651 (minor), 74.074
(minor) & 73.428 (major), 63.330 (minor) & 63.278 (major), 50.950 (major) &
50.601 (minor), 33.389 (minor) & 32.944 (major), 31.640 (minor), 30.945, 29.575
(major), 26.945 (major) & 26.461 (minor), 22.085, 12.890.

198

•
HN
OH
O
nC
5
H
11
4.29b
Ph

2-benzylamino-deca-3,4-dienoic acid (4.29b). A 5-ml round bottomed flask
equipped with a magnetic stirrer, was charged with 3 ml MeOH followed by
glyoxylic acid monohydrate 2.104 (0.060 g, 0.65 mmol) and benzylamine 2.109
(0.070 g, 0.65 mmol). To that mixture, 4,4,5,5-tetramethyl-2-octa-1,2-dienyl-
[1,3,2]dioxaborolane 4.19 (0.200 g, 0.85 mmol) was added in one portion. The
system was left under stirring at R.T. for a total of 72hr (no further conversion was
obtained the last 24hr). The crude residue showed both propargyl 4.29a and allenyl
4.29b products (the signals were overlapping- no quantitative determination of the
products ratio was feasible at that point). Gradient flash chromatography was
performed to separate the isomeric products (elution with 5% MeOH/DCM switched
to EtOAc/MeOH.NH
4
OH, 100/0/0 to final 85/10/5). For the propargyl adduct 4.29a:
de=53% from the crude reaction mixture while after purification some resolution had
occurred and the value changed to de=57%. For the allenyl adduct the de could not
be determined due to overlapping signals. Combined yield: 0.086 g or 49%
(4.29a/4.29b=2, ratio of isolated pure compounds). NMR data are presented for the
main allenyl diastereomer 4.29b (for 4.29a refer to the previous preparation).
1
H NMR (4.29b-both diastereomers, 400 MHz, MeOH d
4
) δ 7.49-7.41 (m,
5H), 5.51-5.46 (m, 1H), 5.33-5.29 (m, 1H), 4.18 (m, 2H), 3.93 (dd, J
1
= 8.3 Hz, J
2
=

199

1.4 Hz, 1H), 2.10 (m, 2H), 1.46 (m, 2H), 1.36-1.28 (m, 6H), 0.91-0.88 (t,
overlapping peaks, 3H).
13
C NMR (4.29b-both diastereomers, 125 MHz, MeOH d
4
)
δ 207.764 (major) & 207.644 (minor), 172.197, 133.475, 131.510, 130.929, 130.676,
96.551 (minor), 96.391 (major), 87.341 (minor), 87.286 (major), 63.069 (major) &
62.901 (minor), 51.090 (minor) & 51.012 (major), 33.044 (minor) & 33.007 (major),
30.440 (minor) & 30.404 (major), 29.961 (minor) & 29.806 (major), 24.038(minor)
& 24.008 (major), 14.888.

•
N
OH
O
nC
5
H
11
4.31b
Ph Ph

2-dibenzylamino-deca-3, 4-dienoic acid (4.31b). A 5-ml round bottomed
flask equipped with a magnetic stirrer, was charged with 3.4 ml MeOH followed by
glyoxylic acid monohydrate 2.104 (0.054 g, 0.59 mmol) and dibenzylamine 2.121
(0.116 g, 0.59 mmol). To that mixture, octa-1,2-dienyl-boronic acid 4.23 (0.114 g,
0.74 mmol) was added in one portion. The system was left under stirring at R.T. for
88 hr. The crude residue was purified by flash chromatography (gradient elution,
MeOH/DCM, 0% to 1% to 2% final 5%). It was dried under high vacuum. Yield:
0.060 g or 28%.

200

Note: NMR data from the crude reaction mixture suggests that only the
allenyl product 4.31b is present with de= 59% (after flash, not feasible to determine
de in the crude). The chemical shifts of the main diastereomer are mentioned below.
1
H NMR (4.31b, 400 MHz, CDCl
3
) δ 7.36-7.26 (m, 10H), 5.39-5.31 (m, 2H),
4.01 (dd, J
1
= 8.2Hz, J
2
= 2.1Hz, 1H), 3.83 (d, J= 13.3Hz, 2H), 3.58 (d, J
1
= 13.1Hz,
2H), 2.07 (dq, J
1
= 6.8Hz, J
2
= 2.9Hz, 2H), 1.44-1.23 (overlapping signals, m, 6H),
0.86 (t, J= 7.1Hz, 3H).
13
C NMR (4.31b, 100 MHz, CDCl
3
) δ 207.571, 172.380,
136.697, 129.146, 128.761, 128.009, 92.463, 83.063, 62.198, 54.738, 31.260,
28.850, 28.411, 22.433, 14.018.

OH
N
O nC
5
H
11
4.31a
Ph Ph

2-dibenzylamino-3-ethynyl-octanoic acid (4.31a). A 10-ml round bottomed
flask equipped with a magnetic stirrer, was charged with 3 ml CH
3
CN followed by
by glyoxylic acid monohydrate 2.104 (0.060 g, 0.65 mmol) and dibenzylamine 2.121
(0.128 g, 0.65 mmol). To that mixture, potassium octa-1, 2-dienyl-trifluoroborate
4.24 (0.100 g, 0.65 mmol) was added in one portion. The system was left under
stirring at R.T. for 14 hr. The crude residue was purified by multiple attempts. Firstly
preparative TLC was performed with 10% MeOH/DCM and the bands that contained

201

the expected signals were combined. This partly purified residue was subsequently
subjected to flash chromatography (gradient elution, EtOAc/DCM, 10% to
EtOAc/MeOH/DCM, 9/1/90) and finally aqueous work up. It was dried under high
vacuum. Yield: 0.042 g or 18%.
Note: NMR data from the crude reaction mixture suggests that only the
propargyl product 4.31a is present with (de=24% calculated from the crude, 32%
after flash).
1
H NMR (4.31a-both diastereomers, 400 MHz, CDCl
3
) δ 7.48 (d, J= 7.1Hz,
2H), 7.38-7.17 (overlapping signals, 18H), 4.13 (d, J= 13.8Hz, 1H-minor) & 3.92 (d,
J= 13.7Hz, 2H-major), 3.59 (d, J=13.8 Hz, 1H-minor) & 3.51 (d, J=13.7 Hz, 2H-
major), 3.40 (d, J= 9.4Hz, 0.65H-minor) & 3.39 (d, J= 10.1Hz, 1H-major), 3.04 (m,
0.44H-minor) & 2.92 (m, 1H-major), 2.25 (d, J= 2.4Hz, 0.44H-minor) & 2.06 (d, J=
2.5Hz, 1H-major), 1.44-1.12 (overlapping signals, 19H), 0.90-0.80 (overlapping
signals, 6H).
13
C NMR (4.31a-both diastereomers, 100 MHz, CDCl
3
) δ
175.630(minor) & 175.004 (major), 138.852 (minor) & 138.499 (major), 129.100,
128.433, 128.244, 127.357, 84.675 (minor) & 84.464 (major), 72.031 (minor)&
71.361 (major), 64.220 (major) & 63.440 (minor), 54.836 (minor) & 54.656 (major),
31.659, 31.454 (minor) & 30.868 (major), 30.521(minor) & 29.721 (major), 26.774
(minor) & 25.974 (major), 22.604, 14.120 (major) & 14.059 (minor).

202

•
N
OH
O
nC
5
H
11
4.32b

2-diallylamino-deca-3, 4-dienoic acid (4.32b). A 5-ml round bottomed flask
equipped with a magnetic stirrer, was charged with 1 ml DCM followed by glyoxylic
acid monohydrate 2.104 (0.041 g, 0.44 mmol) and diallylamine 2.122 (0.093µl, 0.75
mmol). To that mixture, 4,4,5,5-tetramethyl-2-octa-1,2-dienyl-[1,3,2]dioxaborolane
4.19 (0.130 g, 0.55 mmol) was added in one portion. The system was left under
stirring at R.T. for 24 hr.
1
H NMR was run from the crude residue that showed two
diastereomers (de=49% approximately from the crude) of the allenyl product only
4.32b. The residue was purified by flash chromatography (gradient elution,
EtOAc/MeOH/NH
4
OH, 90/5/5 to final 85/10/5). Separation of the two diastereomers
was feasible in that case. They were dried in high vacuum. Yield: 0.110g or 95%.
1
H NMR (400 MHz, MeOH, d
4
, 4.32b-major diastereomer) δ 5.96 (m, 2H),
5.53 (m, 4H), 5.48 (q, J= 7.0Hz, 1H), 5.29 (m, 1H), 4.12 (dd, J
1
= 9.2Hz, J
2
= 0.7Hz,
1H), 3.82 (dd, J
1
= 13.6Hz, J
2
= 6.6Hz, 2H), 3.65 (dd, J
1
= 13.5Hz, J
2
= 7.6Hz, 2H),
2.09 (dq, J
1
= 7.0Hz, J
2
= 2.7Hz, 2H), 1.46 (m, 2H), 1.37-1.28 (m, 4H), 0.90(t, J=
7.0Hz, 3H).
13
C NMR (100 MHz, MeOH, d
4
, 4.32b-major diastereomer) δ 209.986,
171.915, 129.394, 126.272, 95.192, 85.070, 68.131, 55.108, 32.975, 30.305, 29.474,
23.995, 14.904.

203

1
H NMR (400 MHz, MeOH, d
4
, 4.32b-minor diastereomer) δ 5.96 (m, 2H),
5.52 (m, 4H), 5.46 (q, J= 6.9Hz, 1H), 5.29 (m, 1H), 4.10 (dd, J
1
= 9.3Hz, J
2
= 0.5Hz,
1H), 3.82 (dd, J
1
= 13.6Hz, J
2
= 6.8Hz, 2H), 3.65 (dd, J
1
= 13.5Hz, J
2
= 7.3Hz, 2H),
2.11 (m, 2H), 1.47 (m, 2H), 1.38-1.28 (m, 4H), 0.91(t, J= 7.0Hz, 3H).
13
C NMR (100
MHz, MeOH, d
4
, 4.32b-minor diastereomer) δ 209.936, 171.719, 129.166,
126.367, 95.077, 84.870, 68.369, 55.111, 33.034, 30.622, 29.885, 24.063, 14.853.

•
N
OH
O
O
nC
5
H
11
4.33b

2-Morpholin-4-yl-deca-3,4-dienoic acid (4.33b). ). A 5-ml round bottomed
flask equipped with a magnetic stirrer, was charged with 0.5 ml DCM followed by
by glyoxylic acid monohydrate 2.104 (0.28 g, 0.3 mmol) and morpholine 2.124
(0.044 g, 0.5 mmol). To that mixture, 4,4,5,5-tetramethyl-2-octa-1,2-dienyl-
[1,3,2]dioxaborolane 4.19 (0.065 g, 0.28 mmol) was added in one portion. The
system was left under stirring at R.T. for 24 hr. The crude residue was purified by
flash chromatography (gradient elution, MeOH/DCM, 5% to final 10%). It was dried
under high vacuum. Yield: 0.065 g or 93%.

204

The NMR data suggest that both diastereomers are present. No quantitative
de determination was feasible since the H signals overlapped (both isomers observed
in the
13
C NMR spectrum).
1
H NMR (4.33b, 400 MHz, CDCl
3
) δ 8.92 (bs, 1H), 5.30-5.17 (m, 2H), 3.89
(s, 4H), 3.78 (dd, J
1
= 12.5Hz, J
2
= 9.2Hz, 1H), 3.12 (bs, 2H), 2.97 (bs, 2H), 2.02-1.96
(m, 2H), 1.36 (m, 2H), 1.25 (m, 4H), 0.84 (m, 3H).
13
C NMR (4.33b, 100 MHz,
CDCl
3
) δ 207.585 & 207.432, 170.559 & 170.198, 93.287 & 93.037, 84.390 &
84.215, 71.420 & 71.023, 64.947 & 64.824, 50.423 & 50.246, 31.222, 28.775 &
28.641, 28.412, 28.131, 22.348, 13.998 & 13.962.

OH
N
O
O
nC
5
H
11
4.33a

3-Ethynyl-2-morpholin-4-yl-octanoic acid (4.33a). A 5-ml round bottomed
flask equipped with a magnetic stirrer, was charged with 1 ml CH
3
CN followed
glyoxylic acid monohydrate 2.104 (0.036 g, 0.39 mmol) and morpholine 2.124
(0.034 g, 0.39 mmol). To that mixture, potassium octa-1,2-dienyl-trifluoroborate
4.24 (0.060 g, 0.39 mmol) was added in one portion. The system was left under
stirring at R.T. for 48 hr. The crude residue was purified by flash chromatography

205

(gradient elution, MeOH/DCM, 5% to 10% final 15%). It was dried under high
vacuum. Combined yield: 0.030g or 30%.
Note: NMR data from the crude reaction mixture suggests that both isomeric
products are present. Propargylic/Allenyl= 28/72. For the propargyl product 4.33a,
de=25% as deduced from the integrals of the acetylenic signals in the crude. This
ratio changed slightly after purification (de=20% after flash). For the allenyl product
4.33b no quantitative de determination was feasible since the H signals overlapped
(both isomers observed in the
13
C NMR spectrum after flash).
1
H NMR (4.33a, 400 MHz, MeOH, d
4
) δ 3.78-3.68 (m, 4H), 3.23 (dd, J
1
=
8.6Hz, J
2
= 4.9Hz, 1H), 2.96-2.82 (m, 4H), 2.78-2.72 (m, 1H), 2.53 (d, J= 2.4Hz,
0.32H) & 2.47 (d, J= 2.4Hz, 0.54H), 1.78-1.27 (m, 8H), 0.93-0.88 (m, 3H).
13
C NMR
(4.33a, 62 MHz, MeOH, d
4
) δ 173.097 & 172.379, 85.194, 73.943, 73.593, 73.322
& 73.227, 68.209 & 67.967, 51.974 & 51.867, 33.595, 33.247, 33.071, 32.397,
32.063, 28.258, 27.985, 24.091, 24.028, 14.853 & 14.825.

•
HN
OH
nC
5
H
11
4.38b
Ph

2-benzylamino-deca-3,4-dien-1-ol (4.38b). A 5-ml round bottomed flask
equipped with a magnetic stirrer, was charged with 1 ml MeOH followed by
glycolaldehyde dimer 2.144 (0.027 g, 0.22 mmol) and benzylamine 2.109 (0.080 g,

206

0.75 mmol). To that mixture, 4,4,5,5-tetramethyl-2-octa-1,2-dienyl-
[1,3,2]dioxaborolane 4.19 (0.130 g, 0.55 mmol) was added in one portion. The
system was left under stirring at R.T. for 20 hr.
1
H NMR was run from the crude
residue that showed two diastereomers of the allenyl product only 4.38b. The residue
was finally purified by flash chromatography (gradient elution, MeOH/DCM, 1% to
2% final 3%). The presence of two diastereomers was observed in the
13
C NMR
(double peaks) but de determination was not feasible since the
1
H signals were not
resolved. Yield: 0.052 g 36%.
1
H NMR (400 MHz, CDCl
3
, 4.38b-both diastereomers) δ 7.25 (m, 4H), 7.18
(m, 1H), 5.21-5.18 (m, 1H), 5.00-4.96 (m, 1H), 3.87 (d, J= 12.6Hz, 0.28H-minor),
3.86 (d, J= 12.9Hz, 0.7H-major), 3.642 (d, J= 12.8Hz, 0.7H-major), 3.636 (d, J=
12.9Hz, 0.28H-minor), 3.55 (dd, J
1
= 10.6Hz, J
2
= 4.1Hz, 1H), 3.27 (m, 1H), 3.17 (m,
1H), 1.95 (m, 2H), 1.33 (m, 2H), 1.22 (m, 4H), 0.81 (t, J= 6.7Hz, 3H).
13
C NMR (100
MHz, CDCl
3
, 4.38b-both diastereomers) δ 203.84 (minor) & 203.726 (major),
139.898, 128.471, 128.278, 127.163, 93.543 (major) & 93.415 (minor), 90.589,
64.986, 58.321 (minor) & 58.225 (major), 51.098, 31.306, 29.71 (minor), 28.856,
28.795 (major), 22.498, 14.076.

207

•
N
OH
O
nC
5
H
11
4.39b

2-Morpholin-4-yl-deca-3,4-dien-1-ol (4.39b) A 5-ml round bottomed flask
equipped with a magnetic stirrer, was charged with 0.5 ml DCM followed by
glycolaldehyde dimer 2.144 (0.036 g, 0.30 mmol) and morpholine 2.124 (0.044 g,
0.50 mmol). To that mixture, 4,4,5,5-tetramethyl-2-octa-1,2-dienyl-
[1,3,2]dioxaborolane 4.19 (0.065 g, 0.28 mmol) was added in one portion. The
system was left under stirring at R.T. for 60 hr.
1
H NMR was run from the crude
residue that showed only the allenyl product only 4.39b. The residue was diluted
with Et
2
O and washed with aq. NaOH 3N and finally purified by flash
chromatography (gradient elution, MeOH/DCM, 1% to 2% final 5%). The presence
of two diastereomers was observed in the
13
C NMR (double peaks) but de
determination was not feasible in that case since the
1
H signals are not resolved.
Yield: 0.037 g 56.3%.
1
H NMR (400 MHz, CDCl
3
, 4.39b- both diastereomers) δ 5.19-5.12 (m,
1H), 5.04-4.96 (m, 1H), 3.71 (m, 4H), 3.55-3.50 (m, 2H), 3.23-3.17 (m, 1H), 2.84
(bs, 1H), 2.68 (m, 2H), 2.48 (m, 2H), 2.01-1.93 (m, 2H), 1.36 (m, 2H), 1.31-1.22 (m,
4H), 0.88-0.84 (t, overlapping signals, 3H).
13
C NMR (90 MHz, CDCl
3
, 4.39- both
diastereomers) δ 205.163 (minor) & 205.073 (major), 91.970 (major) & 91.725

208

(minor), 84.385 (major) & 84.192 (minor), 67.145, 65.223, 64.919, 60.262, 48.720,
31.245, 28.827 (minor), 28.733, 28.537 (major), 22.443, 14.017.

209

4.4 Chapter 4 References

1. Favre, E.; Gaudemar, M. Comptes Rendus des Seances de l'Academie des
Sciences, Serie C: Sciences Chimiques 1966, 262, 1332-4.
2. L'Honore, A.; Soulie, J.; Cadiot, P. Comptes Rendus des Seances de l'Academie
des Sciences, Serie C: Sciences Chimiques 1972, 275, 229-31.
3. Blais, J.; L'Honore, A.; Soulie, J.; Cadiot, P. Journal of Organometallic Chemistry
1974, 78, 323-37.
4. Favre, E.; Gaudemar, M. Comptes Rendus des Seances de l'Academie des
Sciences, Serie C: Sciences Chimiques 1966, 263, 1543-5.
5. Favre, E.; Gaudemar, M. Comptes Rendus des Seances de l'Academie des
Sciences, Serie C: Sciences Chimiques 1971, 272, 111-14.
6. Favre, E.; Gaudemar, M. Journal of Organometallic Chemistry 1974, 76, 297-
304.
7. Favre, E.; Gaudemar, M. Journal of Organometallic Chemistry 1974, 76, 305-13.
8. Favre, E.; Gaudemar, M. Journal of Organometallic Chemistry 1975, 92, 17-25.
9. Ikeda, N.; Omori, K.; Yamamoto, H. Tetrahedron Letters 1986, 27, 1175-8
10. Haruta, R.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. Journal of the American
Chemical Society 1982, 104, 7667-9.
11. Ikeda, N.; Arai, I.; Yamamoto, H. Journal of the American Chemical Society
1986, 108, 483-6.
12. Corey, E.J.; Yu, C.M.; Lee, D.H. Journal of the American Chemical Society
1990, 112, 878-9.
13. Hoff, S.; Brandsma, L.; Arens, J.F. Recueil des Travaux Chimiques des Pays-
Bas 1968, 87, 1179-84.
14. Zimmer, R. Synthesis 1993, 165-78.

210

15. Hoff, S.; Brandsma, L.; Arens, J.F. Recueil des Travaux Chimiques des Pays-
Bas 1968, 87, 916-24.
16. Lambert, C.; Schleyer, P.v.R.; Wuerthwein, E.U. Journal of Organic Chemistry
1993, 58, 6377-89.
17. Friesen, R.W. Journal of the Chemical Society, Perkin Transactions 1 2001,
1969-2001.
18. Larock, R.C. Comprehensive Organic Transformations, 1996
19. Elsevier, C.J.; Meijer, J.; Tadema, G.; Stehouwer, P.M.; Bos, H.J.T.; Vermeer,
P.; Runge, W. Journal of Organic Chemistry 1982, 47, 2194-6.
20. Krause, N.; Hashmi, A.a.; Stephen, K. Modern Allene Chemistry, 2004.
21. Eddarir, S.; Cotelle, N.; Bakkour, Y.; Rolando, C. Tetrahedron Letters 2003, 44,
5359-5363.

22. Vedejs, E.; Chapman, R.W.; Fields, S.C.; Lin, S.; Schrimpf, M.R. Journal of
Organic Chemistry 1995, 60, 3020-7.
23. Jourdan, H.; Gouhier, G.; Van Hijfte, L.; Angibaud, P.; Piettre, S.R. Tetrahedron
Letters 2005, 46, 8027-8031.
24. Kobayashi, K.; Takanohashi, A.; Hashimoto, K.; Morikawa, O.; Konishi, H.
Tetrahedron 2006, 62, 3158-3161.

211

CHAPTER 5: Studies in Palladium catalyzed three-component
annulations of α- allenyl amine derivatives

5.1 Multicomponent Pd promoted transformations of allenes
Palladium catalysis has become significantly popular and applicable in
organic synthesis and in the development of new synthetic methods in the last
decades, shortly after the reactivity of Pd with various organic functional groups was
realized. The ability of bond insertion in combination with reversible complexation
of unsaturated organic functionality with Pd along with the formation of labile and
reactive transient species that can undergo carbon-carbon or carbon-heteroatom bond
formation in the coordination sphere of the metal are among the basic features for the
plethora of Pd catalyzed processes known so far.
Moreover, Pd catalysis is highly preferable due to the mild reaction
conditions, the high functional group tolerance as well the high degree of regio-,
chemo- and stereoselectivity it exhibits. In addition, the use of chiral ligands on the
metal center enables asymmetric catalysis, one of the most atom economical
methods of asymmetric induction.
Furthermore, domino processes on the Pd coordination sphere result in highly
diverse multifunctional scaffolds from one pot procedures and permit the design of

212

novel multicomponent processes. However, those reactions are frequently
accompanied by by-products formed by side reactions among the different
components which can limit the efficiency of the method. The other drawback of the
Pd promoted reactions is the fact that strict conditions and a number of different
parameters need to be investigated in order to establish a selective and efficient
mutlicomponent process thus making optimization a multidimensional puzzle.
Pd promoted multicomponent reactions that incorporate allenes constitute an
important synthetic tool for assembling a wide variety of multifunctionalized
adducts.
1,2
The appearance of those methods occurred shortly after the reactivity of
Pd towards allenes was realized based on the various stable complexes that the metal
forms with 1, 2 dienes. In particular, allene insertion into Pd-C bonds containing
phosphine ligands, bidentate or tridentate nitrogen ligands occurs very efficiently
leading to π-allyl palladium species. Subsequent reaction of the abovementioned
complexes with various nucleophiles leads to carbon-carbon or carbon-heteroatom
bond formation which constitutes the basic mode of reactivity for those types of
processes. Based on those concepts, one can easily imagine the diversity emerging
from those types of multicomponent reactions considering the plethora of allenes and
the plethora of possible nucleophiles, not to mention the possible carboxylative and
carbonylative variations in the presence of carbon monoxide. Last but not least, the
number of possible scaffolds from the multiple intramolecular versions that can be

213

designed further increases the number of possible adducts directly obtained by the
abovementioned process.
3

Regioselectivity is of primary importance in the additions of nucleophiles to
allenes. The three types of possible adducts that can be obtained are depicted in
Scheme 5.1.

A combination of factors determines the types of products favored from those
reactions.
4
As it was observed α-alkoxy and α-aryloxy substituted allenes of type 5.5
yield the α- adduct 5.2
5
where aryl allenes of type 5.6 carrying electron withdrawing
groups (EWG) in the para position favor formation of the β adduct 5.3.
6
γ adducts
5.4 are selectively obtained in the cases of mono and dialkyl substituted allenes 5.7
and aryl allenes of type 5.8 carrying electron donating groups (EDG) in the para
position.
7,8
However, increased steric effects overcome the electronic effects and
yield the γ-adducts while mixtures of regioisomers are obtained when opposing
factors are present in the structure of the allene.

•
α β γ Nu-H
Nu
H
α
β
γ
" α adduct"
H
α β
γ
Nu
" β adduct"
αβ
γ
Nu
H
" γ adduct"
•
α β γ
EWG
•
RO
α β γ
R: Alkyl or Aryl
•
α β γ
R
1
or
R
1
: H or alkyl,
R
2
: Alkyl
5.1
5.2 5.3 5.4
5.5 5.6 5.7 5.8
•
R
2
α β γ
R
1
EDG
R
1
: Alkyl or H

Scheme 5.1: The possible adducts from addition of nucleophiles to allenes

214

Mechanistically, two different Schemes have been proposed for the additions
of nucleophiles to allenes. The carbopalladation and the hydropalladation pathways.
Depending on the operating mechanism, the possible adducts and their precursors are
all depicted in Scheme 5.2.

•
Ar
H
α β γ
Ar
Nu
H
α
β
γ
" α adduct"
" β adduct"
5.9
•
Ar
α β γ
•
Ar
α β γ
Pd Nu
Pd Nu H
•
Ar
α β γ
Pd Nu H H
•
Ar
α β γ
Pd Nu H
Nu
Ar
PdH
α
β
γ
Ar PdH
Nu
Ar
PdH
Nu
Ar Nu
PdH
α
β
γ
α
β
γ
α
β
γ
Ar
H
Nu
α
β
γ Ar
Nu
α
β
γ
" β adduct"
Ar Nu
α
β
γ
" γ adduct"
The carbopalladation mechanism
•
Ar
H
α β γ
Ar
H
Nu
α
β
γ
" β adduct"
"a adduct"
5.9
•
Ar
α β γ
•
Ar
α β γ
Pd H
Pd H Nu
•
Ar
α β γ
Pd H Nu Nu
•
Ar
α β γ
Pd H Nu
H
Ar
PdNu
α
β
γ
Ar PdNu
H
Ar
PdNu
H
Ar H
PdNu
α
β
γ
α
β
γ
α
β
γ
Ar
Nu
H
α
β
γ
The hydropalladation mechanism
Ar Nu
α
β
γ
" γ adduct"
Ar
Nu
α
β
γ
" β adduct"
5.10
5.11
5.12
5.13
5.14
5.15
5.16
5.17
5.18
5.18 5.19
5.19
5.20
5.20
5.21
5.21

Scheme 5.2: The mechanisms of additions of nucleophiles to allenes

For some reactions, the operating mechanism had been proposed by the
regioselectivity observed. Such an example is the hydrocarbonation of allenes with
malonates as the carbon nucleophile source. This process was initially assumed to
operate through the carbopalladation pathway
7
but modification of the procedure by
the addition of base changed the regioisomeric ratio, thus implying that the
hydropalladation mechanism can operate as well under specific conditions.
9

215

Based on the same principles are various three-component addition to allenes
that have been developed. In these cases a third component such as an aryl (or
alkenyl) halide (or triflate) or carbon monoxide is also present. When aryl halides or
triflates constitute the additional component oxidative addition of the aryl halide to
the Pd catalyst prior to the allene insertion leads to alternative Pd species that
undergo the same chemistry as in the case of the two-component additions. The
presence of the third component results in formation of structurally different
products with one more point of diversity that are actually styril derivatives, since
overall an aryl group and a nucleophile add to the allene system. The general
reaction Scheme for this type of Pd promoted three-component reaction is depicted
in Scheme 5.3
•
R
Ar-X NuH ++
R
Ar
Nu
5.22 5.24 5.23
5.25

Scheme 5.3: Three-component additions to allenes

Various types of nucleophiles and aryl/alkenyl halides/triflates have been
employed in those reactions. The use of active methylene compounds as carbon
pronucleophiles
10
leads to carbon-carbon bond formation where the use of other
types of nucleophiles such as amines, alcohols or sulfides results in carbon-
heteroatom bond formation.

216

The reaction involving carbon pronucleophiles proceeds through the
carbopalladation pathway. Allene insertion to arylpalladium(II) species results in the
formation of intermediate π-allyl palladium intermediates that are eventually
intercepted by the nucleophile employed in the process (Scheme 5.4).
11

Ar-X
Pd(PPh
3
)
4
(PPh
3)2
Pd
II
Ar
X
(PPh
3)2
Pd
II
Ar
•
R
Ar
Ar
R
(Ph
3
P)
2
Pd
II
Nu
+
Ar
R
Nu
5.25
•
R
X
R
(PPh
3
)
2
Pd
II
X
NuH
-HX
5.26 5.23 5.27 5.28
5.29 5.30

Scheme 5.4: The carbopalladation mechanism operates in the three-component additions to allenes

The formation of a carbon-carbon bond in the central allene carbon with
concomitant attack of the nucleophile at the α or γ position of the allene moiety is
usually the case for the three-component carbopalladation of allenes. The
regioselectivity of these processes depends on different factors such as the nature of
the ligand (electron donor or acceptor), the nucleophile the substitution pattern of the
allene as well as steric and electronic effects.
12

Intramolecular versions have also been developed by incorporating at least
two of the components in the starting material where bicyclic structures can also be
envisioned if an appropriately designed departing scaffold is employed containing all
three reacting functional groups. Allenes carrying nucleophilic centers have been

217

used for the construction of various ring sizes ranging from 3 to 20.
2,13
Palladium
promoted annulation of allenes carrying carbon pronucleophiles of type 5.31 in the
presence of aryl halides can potentially lead to two types of ring systems, 5.34 and
5.35 (Scheme 5.5). Steric factors, the nature of the third component, the solvent and
the strain present in both possible Pd
II
intermediates that yield the different ring
systems determine the outcome of the reaction.
Pd(PPh
3
)
4,
5.26
•
EWG
n
EWG Ar-X, 5.23
EWG
Ar
α
β γ
n
EWG
α
β
γ
Ar
n
α
β
γ
EWG
(PPh
3
)
2
PdX
(PPh
3
)
2
PdX
EWG
and/or
n
Ar
EWG
EWG
Ar
α
β
γ α
β γ
n
EWG
EWG
5.31
5.32 5.33
5.34 5.35
α cyclization γ cyclization

Scheme 5.5: The ring systems from allenes carrying carbon pronucleophiles and their precursors

Allenes bearing nitrogen nucleophiles are very useful synthons that also
undergo the abovementioned transformation yielding a number of structurally
diverse and densely functionalized heterocycles.
14,15

The outcome of those annulations has been shown to be closely related to
various structural features of the starting allenyl amine derivative, such as the tether
length, the substituent of the nitrogen,
16
the aryl halide partner as well as the
conditions employed (type of catalyst, ligand, solvent
17,18
etc.). As a consequence,

218

even though in most cases the nucleophilic attack occurs either at the α or at the γ
position, nitrogen attack on the central allene carbon has also been documented in
the case of allenyl lactams 5.38.
19,20

Characteristic examples of some ring types obtained by utilizing allenyl
amines and amides are depicted in Scheme 5.7
•
R
2
R
2
N
H
R
1
γ addition
Ar-X
Pd(PPh
3
)
4
, K
2
CO
3
DMF, 70
o
C
R
1
: Ts, Bn, Boc
X: I, Br, OTf
+
5.36 5.23
N
R
1
Ar
R
2
R
2
5.37
NH
O
•
n
N
O
n
N
O
n
Ar
Ar
Ar-I +
Pd(PPh
3
)
4
, K
2
CO
3
n-Bu
4
NCl, MeCN,
reflux
5.38 5.39 5.40 5.41
H H
n=1, 5.40/5.41=100/0
n=2, 5.40/5.41=88/12
and/or
β addition
α or γ addition
NHMts
•
K
2
CO
3
,
1,4 Dioxane
Ar-I, Pd(PPh
3
)
4
,
or Pd
II
/PPh
3
K
2
CO
3
, DMF
N
Mts
Ar
5.43 5.42
N
Mts
Ar
5.44
N
Mts
Ar
5.45
+
Ar-I, Pd(PPh
3
)
4
,
or Pd
II
/PPh
3
"pyrroline" "trans aziridine"
major
"cis aziridine"
minor

Scheme 5.6: Pd catalyzed annulations of allenyl amine derivatives.

Besides the variations mentioned above, a plethora of conceptually similar
transformations applied on slightly altered starting materials have been developed to
demonstrate the synthetic potential of the chemistry. Also, a significant number of
intramolecular variations have been demonstrated in the literature, taking advantage

219

of the different ways the reacting functionalities can be introduced in the departing
scaffolds. The purpose of this limited discussion was to introduce the main principles
of the chemistry of Pd catalyzed transformations of allenes while the strict choice of
the reactions discussed is directly related to the potential applications that we chose
to perform on the allenyl products that the Petasis reaction gives. Those attempts are
discussed in the following section.

5.2 Results and discussion
5.2.1 Pd catalyzed three-component annulations of the allenyl amines
with carbon pronucleophiles. Synthesis of five and seven-membered
nitrogen heterocycles.
Our initial experiments involved a conceptually similar three-component
process with the one already presented in Scheme 5.5 but with a slightly altered
structure that can give different types of rings. For an intramolecular process to take
place, at least two of the reactive sides should coexist in the same starting material.
We chose to incorporate the allene and the carbon pronucleophile on the same
molecule, which required derivatization of the Petasis reaction products with and
appropriate acylating compound. The starting materials of type 5.46 were then
subjected to the palladium catalyzed cyclization in the presence of phenyl iodide.

220

This type of departing scaffolds can potentially yield two ring systems, 5.47a and
5.47b. Scaffolds of type 5.47a constitute useful synthons for synthesizing kainoid
analogues in two steps.
21
The generic reaction Scheme is depicted below.
R
1
N
R
2
•
O
O O
N
O
O
O
R
2
R
1
N O
O O
R
2
R
1
5.47a
(5-membered ring)
5.47b
(7-membered ring)
Pd cat.
Ph-I
Base
+
5.46

Scheme 5.7: Palladium catalyzed annulation of the allenyl amine derivatives 5.46

Having established the basic features of the participation of allenyl boron
derivatives in the Petasis reaction, we chose to study the palladium promoted
annulations of the corresponding allenyl β-aminoalcohols obtained when primary
amines were used in the multicomponent process. Moreover, the employment of
cleavable amines allows for more versatile nitrogen heterocycles that can be further
synthetically altered on the nitrogen atom, in addition to all the other functional
groups present. So in our first attempts we utilized 2.151b since the N-allyl group
can be cleaved or used for various other transformations.
For an intramolecular process, incorporation of the carbon nucleophile on the
same molecule was required so derivatization of 2.151b was attempted according to
Scheme 5.8.

221

HO
NH
• HO
N
•
O
O O
O
N
•
O
O O
O
O O
ClCOCH
2
COOMe
(2eq.), 5.48
Et
3
N(dry, 1.1eq.), 5.49
DCM(dry),
0
o
C to RT,
24 hr, 30%
2.151b
5.51 (minor, 29%) 5.50 (major,71%)
+

Scheme 5.8: Derivatization of 2.151b to 5.50 and 5.51

During this preparation, both 5.50 and 5.51 are formed. 5.50 was the main
product (71%) while the monoacylated 5.51 was formed as minor (29%). Under
these conditions, low selectivity was observed even by altering the amounts of the
base and that of the acylating agent used. In all our efforts, diacylation was favored.
Most likely, under the conditions examined a highly reactive ketene intermediate is
formed which reacts with low selectivity. Flash chromatography was proven
inappropriate to separate the two compounds. So the residue obtained after removal
of the rest of the impurities through flash chromatography was subjected to the
palladium catalyzed annulations without further purification attempts. The presence
of both 5.50 and 5.51 in the starting material was also confirmed by analyzing the
mixture obtained after the palladium catalyzed cyclization. In particular, all possible
five-member heterocycles were identified along with the corresponding Heck
byproducts (from further reaction on the allyl amine site, Scheme 5.9), a process that
seems to be favored when Pd(OAc)
2
/2PPh
3
was employed as the catalytic system in
high temperature. This side reaction was completely suppressed when the
temperature was lowered to 60
o
C even though longer reaction times were essential

222

for the process. Interestingly, when Pd(PPh
3
)
4
was used for the catalysis, the seven-
member ring product 5.52b was selectively formed (no Heck byproducts were
detected even at 90
o
C) thus allowing for control of the reaction outcome by
employing the appropriate catalyst.

OX
N
•
O
O O
X=COCH
2
COOCH
3
, 5.50
X=H, 5.51
N O
O
O
OH
N O
O
O
N O
O O
OX
X=H, 5.53c
Pd(PPh
3
)
4
PhI, Na
2
CO
3
,
n-Bu
4
NCl,
90
o
C, 8 hr
OX
20%Pd(OAc), 40%(PPh
3
)
4
PhI, Na
2
CO
3
, n-Bu
4
NCl,
80
o
C,12 hr
30%Pd(OAc) 5.54,
120%(PPh
3
)
4
5.55,
PhI 5.56,
Na
2
CO
3
5.57
n-Bu
4
NCl 5.58
60
o
C,72 hr
X=COCH
2
COOCH
3

5.52a
X=H 5.53a
X=COCH
2
COOCH
3
,
5.52b

Scheme 5.9: Palladium catalyzed cyclizations of 5.50 and 5.51

The Heck by-products contained the same five-membered heterocycle but the
alkene region of the allylamine moiety was altered. Two new olefinic signals

223

appeared along with one more phenyl ring while the characteristic pattern of the
allylamine was no longer observed.
1
H,
13
C and MS data agree with structure 5.53c.
The characteristic regions of the
1
H NMR spectra of the Heck byproduct and the
expected product are both included for comparison in Scheme 5.10.

Scheme 5.10: Characteristic signals of 5.53a and 5.53c from the
1
H NMR spectra

The conditions attempted for 5.50 and 5.51 are summarized in table 5.1
Table 5.1: Annulation attempts of the allylamine derivatives 5.50 and 5.51
Conditions: Base: Na
2
CO
3
, additive: n-Bu
4
NCl, solvent: DMF

The corresponding two-component version of Pd catalyzed
hydrocarbonation
22
was attempted for the same substrate under typical conditions
Compound Catalyst

Ligand

Temperature
(
o
C)
Time
(hr)
a/b/c/d Yield
(%)
5.51
Pd(OAc)
2
, (20%) PPh
3
(40%)
80-85 12 33/0/67/0 27
5.50
Pd(OAc)
2
, (30%) PPh
3
(120%)
60 74
100/0/0/0
19
5.50
Pd(PPh
3
)
4
(14%)
- 85-90 5
0/100/0/0
20
7.334
7.313
7.299
7.287
7.267
7.256
7.240
7.214
6.578
6.515
6.126
6.104
6.095
6.073
6.040
6.033
5.323
5.183
4.491
4.486
4.468
4.463
4.429
4.425
4.408
4.403
3.887
3.857
3.849
3.831
3.797
3.781
3.744
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 PPM
5.705
5.697
5.693
5.679
5.433
5.334
5.251
5.247
5.243
5.239
5.215
5.212
5.208
5.204
5.200
5.196
5.190
5.187
5.184
5.181
5.175
5.173
5.141
5.138
4.272
4.268
4.264
4.259
4.255
4.251
4.233
4.229
4.226
4.220
4 217
7.0 6.5 6.0 5.5 5.0 4.5 4.0 PPM
N O
O O
HO
5.53c
H
2
H
1
H
4
H
3
H
1

H
2

H
3
, H
4

H
1

N O
O O
HO
5.53a
H
3
H
2
H
1
H
5
H
4
H
2
, H
3
, H
4
,
H
5

224

(Pd(OAc)
2
, dppb, DCM) both at RT and at 80
o
C in a sealed tube. Even though in
both cases, 5.51 was completely consumed within 24hr, the resulting crude reaction
mixture contained unidentified material while the expected heterocycles were not
detected at all. These experiments showed the sensitivity of the allenyl adducts in the
presence of Pd, the high reactivity of the allenyl moiety towards these conditions (the
allene moiety had completely disappeared even at ambient temperature) and most
likely indicated that side processes such as Pd promoted oligomerization compete
with the desired process even at mild conditions.
The presence of significant amounts of unidentified material was also
observed in the experiments already summarized in Table 5.1. As a consequence,
low yields of the desired products were observed in all our attempts even when the
reaction time was reduced to 5 hr (entry 3).
Since the reactions of the allylamine derivatives yielded multiple products
and significantly crude reaction mixtures, we turned our attention to the
corresponding benzylamine derivatives 5.59, 5.60 and 5.63 in order to examine their
participation and reactivity in the process since it’s known that structure alterations
can be of significant importance for such processes. Their synthesis is depicted in
Scheme 5.11

225

NH
•
N
•
O
O O
HO HO
N
•
O
O O
O O
O O
N
•
O
O O
O
Si
1. TMSOTf (1.2 eq.) 5.61,
2,6 Lutidine (dry, 1.4eq.) 5.62,
DCM (dry), 0
o
C to RT, 24 hr, 87%
ClCOCH
2
COOMe
(1.5eq.)
2,6 Lutidine (dry, 1.2 eq.),
DCM(dry), 0
o
C to RT,
48 hr, 99%
ClCOCH
2
COOMe
(1.2eq.)
Et
3
N(dry, 1.2 eq.),
DCM(dry),
0
o
C to RT,
24hr, 60%
2. ClCOCH
2
COOMe (1.5eq.)
Et
3
N(dry, 1.2 eq.), DCM(dry),
0
o
C to RT, 48 hr, 88%
2.149b 5.59 5.60
5.63

Scheme 5.11: Derivatization of 2.149b to 5.59, 5.60 and 5.63

Running into the undesired complication of the low selectivity that resulted in
a mixture of 5.50 and 5.51, we altered the conditions in the case of 2.149b by
substituting Et
3
N with a milder organic base, 2, 6 Lutidine in order to examine the
possibility of a more selective process towards the monoacylated analogue 5.60. To
our satisfaction, the base substitution gave 5.60 in almost quantitative yield. Since
interpretation and quantitative conclusions are not profound from the NMR spectra
of those compounds due to complicated mixtures of possible rotamers in
combination with enol forms that can coexist, we independently synthesized the
monosubstituted analogue 5.60. In particular, the initial Petasis product 2.149b was
subjected to a three-step sequence of protection/acylation/deprotection and the
1
H
NMR spectrum of the final adduct was identical to the one obtained from the
alteration of the original process by employing 2, 6 lutidine as the base.

226

NH
•
N
•
O
O O
HO
HO
N
•
O
O O
O
Si
2.149b
5.60
5.63
NH
•
O
Si
5.64
NH
•
HO
2.149b
Cl O
O O
+
TMSOTf (1.2 eq.),
2,6 Lutidine (dry, 1.4eq.)
DCM (dry), 0
o
C to RT,
24 hr, 87%
2,6 Lutidine (dry, 1.2 eq.),
DCM(dry), 0
o
C to RT,
48 hr, 99%
ClCOCH
2
COOMe (1.5eq.)
Et
3
N(dry, 1.2 eq.),
DCM(dry), 0
o
C to RT,
48 hr, 88%
AcOH:THF:H
2
O
(3:1:1), RT to
65
o
C, 3d
5.48
(1.5 eq.)

Scheme 5.12: Synthesis of 5.60 by two different routes

Having 5.59, 5.60 and 5.63 in hand, we subsequently proceeded in employing
these in the Pd promoted three-component annulations in the presence of PhI as the
third component. The general reaction Scheme with the expected product structures
is shown below.
XO
N
•
O
O O
Products
5.65a and 5.66b, X=H
5.66a and 5.66b, X=COCH
2
COOMe
5.67a and 5.67b, X=TBDMS
N O
O
O
N O
O O
a b
Pd cat.
Ph-I
Base XO XO
Starting allenyl amine
5.60, X=H
5.59, X=COCH
2
COOMe
5.63, X=TBDMS
+

Scheme 5.13: Palladium catalyzed cyclizations of 5.59, 5.60 and 5.63

227

The attempts summarized in Table 5.2 concern basically the comparison of
the two catalytic systems and the effect on the regioselectivity of the cyclization. As
already mentioned in the case of allylamine derivatives the use of Pd(OAc)
2
in
combination with phosphine ligands yielded the five-membered heterocycle 5.52a
while when Pd(PPh
3
)
4
was employed, the seven-membered heterocycle 5.52b was
selectively obtained.
In the case of the annulations of the benzyl analogues 5.59, 5.60 and 5.63 the
same trend was obtained for 5.60 (even though the 5-membered heterocycle was
detected in this case, as minor product) but both 5.59 and 5.63 gave the 5-membered
heterocycle no matter what catalyst was used. Thus, both the catalyst as well the
structure of the substrate are determining for the annulation outcome, even if the
alteration of the starting material is only subtle. Another useful observation from this
series of experiments is the fact that significantly short reaction times can be used
since complete consumption of the allene moiety was noticed in some experiments
within 0.5hr of reaction time. This could be important in minimizing the side
processes that consume the starting material in undesired routes. Furthermore,
protection of the alcohol as a silyl-ether was shown to give a less crude reaction
mixture and better yields compared to the unprotected starting material. At this time,
no further optimization studies and/or exploration of the annulation reaction was
performed, even though many more factors can be altered in order to tune the

228

process and improve its synthetic potential. Our initial attempts are summarized in
Table 5.2.

Table 5.2: Annulation attempts of the benzyl amine derivatives 5.59, 5.60 and 5.63
Compound Catalyst

Ligand

Temperature
(
o
C)
Time
(hr)
a/b Yield
(%)
5.60 Pd(OAc)
2
, (10%)
PPh
3
,

(10%)
80 0.5 100/0 20
5.60 Pd(PPh
3
)
4
, (10%)
-
80 6 100/0 23
5.59 Pd(OAc)
2
, (26%)
PPh
3
, (110%)
80 18 100/0 traces
5.59 Pd(PPh
3
)
4
, (14%)
-
85- 90 7.5 25/75 21
5.59 Pd(PPh
3
)
4
, (16%)
-
85- 90 5.5 12/88 18
5.59 Pd(OAc)
2
, (16%)
PPh
3
,

(16%)
85- 90 0.5 100/0 24
5.63 Pd(PPh
3
)
4
, (10%)
-
70 72 100/0 33
5.63 Pd(OAc)
2
, (10%)
PPh
3,
(10%)
85- 90 0.5 100/0 45
Conditions: Base: Na
2
CO
3
, additive: n-Bu
4
NCl, solvent: DMF

5.2.2 Pd catalyzed three-component annulations of the allenyl amines
with nitrogen nucleophiles. Synthesis of piperazines, pyrrolines and
aziridines
The next series of experiments we performed involved the participation of the
allenyl adducts in Pd catalyzed three-component cyclizations where nitrogen
intercepts the intermediate Pd-species, thus resulting in different types of nitrogen
heterocycles. The results presented herein concern the transformation of the allenyl
β-amino alcohols to functionalized piperazines, pyrrolines and aziridines.

229

4.771
4.764
4.759
4.755
4.748
4.743
4.737
4.732
4.606
3.843
3.810
3.534
3.518
3.508
3.483
3.480
3.471
3.460
3.448
3.442
3.426
3.196
3.183
3.172
3.157
3.143
3.132
3.118
3.112
3.107
3.097
2.870
2.703
2.688
5.0 4.5 4.0 3.5 3.0 PPM
5.261
3.910
3.875
3.764
3.744
3.738
3.718
3.606
3.572
3.539
3.527
3.356
3.330
3.304
3.295
3.292
3.157
3.145
2.742
2.722
2.711
2.691
2.532
5.5 5.0 4.5 4.0 3.5 3.0 2.5 PPM
For piperazine synthesis, the corresponding Petasis adduct should contain a
second nitrogen atom on the amine side along with a spacer long enough to ensure a
selective cyclization towards a six-member ring after intramolecular nucleophilic
trapping of the intermediate Pd species. Thus, ethylene diamine derivatives were
employed in the Petasis process. N, N’ dibenzyl ethylene diamine 2.164 was used
but the three-component reaction did not occur. The process yielded the
corresponding five-member cyclic aminal intermediate 2.165 which was stable and
could be obtained quantitatively from the reaction mixture.
So we then utilized N-benzyl, Ν΄-boc ethylene diamine (2.162) as the amine
component and the resulting adduct 2.163 was subsequently employed in the Pd
catalyzed three component annulation, according to Scheme 5.14.

Scheme 5.14: Palladium catalyzed cyclizations of 2.163
Unfortunately, these experiments yielded once more complex crude reaction
mixtures for which multiple stages of purification were necessary and the desired
HO
N Ph
NHBoc
•
Pd(PPh
3
)
4
PhI, K
2
CO
3
,
DMF
N N
Ph
Boc
HO Ph
2.163 5.68

230

product was observed in traces. The allene moiety was consumed and transformation
to the piperazine heterocycle took place as can be concluded by the changes in the
1
H
NMR spectra shown above.
Protection of the free alcohol in the form of a tert-butyl dimethyl silyl ether
(TBDMSO) gave a less crude reaction mixture, somewhat higher yield and complete
suppression of the formation of an aziridine byproduct detected when 2.163 was
employed in the annulation reaction.
For pyrroline and aziridine synthesis, the Petasis products that contain a free
NH group along with the allenyl functional group can be used directly, without
further manipulation, thus yielding this type of heterocycles in just two synthetic
steps. The Pd catalyzed reaction is again a three component transformation among an
aryl halide, an allene and a nitrogen nucleophile.
Control experiments by employing 2.158b showed that the β-allenyl amino
alcohols synthesized by the multicomponent reaction could potentially be good
candidates for this type of Pd promoted cyclization without the need of protection. In
particular, the free OH group which can theoretically participate and thus give rise to
byproducts of types 5.69a and 5.69b, was shown by control experiments not to
compete with the NH functionality for the interception of the intermediate Pd
species, the step that determines the type of heterocycle formed. Both catalytic
systems were tested (Pd(OAc)
2
/PPh
3
and Pd(PPh
3
)
4
) but no oxygen heterocycles
were formed. Complete decomposition of the staring material was noticed for 2.158b

231

as well, in both control experiments. The allenyl signals vanished and the crude
1
H
NMR spectra showed basically aromatic signals and signals with δ<2ppm something
that supports our assumption for competitive Pd catalyzed oligomerization of the
unsubstituted allene moiety of these adducts.
N
•
Pd cat.
Ph-I
Base
Ph Ph
HO
O
N Ph
Ph
Ph
O
N Ph Ph
Ph
and/or
NOT OBSERVED
2.158b 5.69a 5.69b

Scheme 5.15: The free OH group does not interfere in the Pd catalyzed three-component cyclizations.

After the abovementioned observations, we directly utilized 2.149b in our
attempts to form unprotected pyrrolines and aziridines (entries 1-10, Table 5.3). We
also performed experiments with the protected analogue 5.64 (entries 11-14, Table
5.3) in order to examine possible effects on yield, regioselectivity and
stereoselectivity. The general reaction Scheme is depicted below.
XO
N
•
H N
N
HO
H
H
HO
N
H H
OH
X= H, 5.70a
X= TBDMS, 5.71a
(Pyrroline)
X= H, 5.70b
X= TBDMS, 5.71b
(trans aziridine)
X= H, 5.70c
X= TBDMS, 5.71c
(cis aziridine)
Pd cat.
Ph-I
Base
++
X= H, 2.149b
X= TBDMS, 5.64

Scheme 5.16: Synthesis of pyrroline and aziridines by Palladium catalyzed intamolecular cyclizations
of 2.149 and 5.64

232

The regioselectivity of the annulation reaction as well as the possibilities of
cis and trans aziridine isomers were examined in our initial attempts. The role of the
catalytic system and the reaction conditions were explored to an extent in order to
examine the possibility of tuning the reaction towards a specific direction.
Table 5.3: Intramolecular cyclization attempts of 2.149 and 5.64
Compound Catalyst
(10%)
Solvent Temperature
(
o
C)
Time
(hr)
a/b/c Yield
(%)
2.149b
Pd(PPh
3
)
4

Dioxane 73 3 100/0/0 24
2.149b
Pd(PPh
3
)
4

Dioxane 47 58 100/0/0 10
2.149b
Pd(PPh
3
)
4

Dioxane RT 48 N.R. 0
2.149b
Pd(PPh
3
)
4

DMSO RT 6 N.R. 0
2.149b
Pd(PPh
3
)
4

DMSO 50 6 - 0
e

2.149b
Pd(PPh
3
)
4

DMF 73 8.5 76/16/8 25
2.149b
Pd(PPh
3
)
4

DMF 60 20 90/10/0 26
2.149b
Pd(OAc)
2
b

DMF 60 9 50/50/0 19
2.149b
Pd(OAc)
2
C

DMF 60 3 50/50/0 33
2.149b
Pd(OAc)
2
d

DMF 60 1 - 0
e

5.64
Pd(OAc)
2
C

DMF 80 120 75/25/0 33
5.64
Pd(OAc)
2
b

DMF 80 7 73/27/0 48
5.64
Pd(OAc)
2
f

DMF 80 1 - 0
e

5.64
Pd(OAc)
2
b

Dioxane 80 6 100/0/0 23
Conditions: Base: K
2
CO
3
,

b: ligand: PPh
3
(10%), c: ligand: PPh
2
(CH
2
)
4
PPh
2
(10%), d: No ligand
added, N.R.=No reaction, e: decomposition, f: ligand: Ph
3
As
From the studies performed so far we observed that under the conditions
examined the pyrroline ring (5.70a or 5.71a) was always obtained (as the sole
product in some cases) where the aziridine ring was observed as minor product in
some cases. The percentage of the aziridine isomer reached up to 50% when
Pd(OAc)
2
was used in combination with phosphine ligands in DMF(entries 8 and 9,
Table 5.3) and in most cases (except entry 6, Table 5.3), only the trans stereoisomer

233

was formed. From what can be concluded from our trials, the regioselectivity of the
reaction depends significantly on the catalyst as well as the solvent used. DMF
seems to promote aziridine formation compared to Dioxane in which, no matter
which catalyst was used, the pyrroline was only detected. Remarkably, this is in
direct opposition to some literature data on very similar systems in which Dioxane
was shown to selectively promote the formation of the aziridine heterocycle,
17
thus
indicating once again the strong connection between structure, conditions and
reaction outcome that give literally endless opportunities for tuning these processes.
Also the use of Pd(OAc)
2
/PPh
3
gave higher percentages of the aziridine
heterocycle compared to the ones obtained by Pd(PPh
3
)
4
. Temperature variations did
not have a tremendous effect on the regioselectivity but rather in the rate of the
reaction. Lowering the temperature did not favor formation of the aziridine and in
addition longer reaction times were required for consumption of the starting material.
No conversion was observed at ambient temperature.
Protection of the free OH to the corresponding tert-butyl dimethyl-silyl ether
on the starting material gave somewhat cleaner reactions and better yields indicating
some suppression of the competitive decomposition/oligomerization processes but
again, from the experiments performed so far, the pyrroline system is clearly
favored. The bulky silicon protecting group on the alcohol seems to slow down the
reaction, so higher temperature and longer reaction times are required. In this series,
triphenyl arsine was also used as a ligand but was proven inappropriate since no

234

products were detected. The starting material decomposed rapidly under those
conditions, something also observed when Pd(OAc)
2
was employed in the absence of
a ligand (entry 10, Table 5.3) as well as when the solvent was switched to DMSO
(entry 5, Table 5.3).
Thus, this series of experiments gave some interesting insight about the
factors that favor one direction of the process compared to the other and indicate that
this transformation is tunable. Many more parameters that could potentially alter the
outcome need to be examined based on the limited foundation built by our
observations. Also the fact that trans aziridines are the only stereoisomers formed
can be further utilized in an asymmetric extension of the process in the presence of a
chiral ligand.

5.3 Experimental
5.3.1 General
All reagents were handled and weighed under inert atmosphere (N
2
purged
glove bag) and all the reactions were performed in a dry, sealed tube degassed and
set under Ar unless otherwise stated. Dry solvents were employed, unless otherwise
stated. The reactions were monitored by TLC on Silica Gel 60 precoated plates with
F
254
indicator.
1
H and
13
C NMR were recorded on a Bruker AMX500 or an AM360

235

MHz, or an AC250 MHz or a Varian Mercury 400 NMR. Chemical shifts of
1
H
NMR are reported in parts per million on the δ scale from an internal standard of
either residual chloroform (7.24 ppm), DMSO d
6
(2.49 ppm), acetone d
6
(2.04 ppm)
or partly deuterated MeOH (3.3 ppm). Data are reported as follows: chemical shift,
multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br=broad),
coupling constants in Hz and integration. Chemical shifts of
13
C NMR are reported
in ppm from the central peak of either CDCl
3
(77.0 ppm), DMSO d
6
(39.5 ppm) or
partly deuterated MeOH (49.5 ppm).

5.3.2 Synthesis and physical data

O
N
•
O
O O
O
O O
5.50

Malonic acid 2-[allyl-(2-methoxycarbonyl-acetyl)-amino]-penta-3,4-
dienyl ester methyl ester (5.50). A flame-dried 50-ml round bottomed flask
equipped with a magnetic stirrer was charged with 24ml dry CH
2
Cl
2,
2.151b (0.214g,
1.54mmol) and methyl-3-chloro-3-oxopropionate 5.48 (247µl, 2.31mmol). The
mixture was stirred for 3min and Et
3
N 5.49 (236µl, 1.69mmol) was added in one
portion. Immediate formation of smoke was noticed right after the addition of the

236

base which soon afterwards disappeared. The reaction mixture was left under stirring
at ambient temperature for 24hr.
The solvent was removed under reduced pressure and the crude residue was
diluted with 100ml EtOAc. The organic phase was washed with H
2
O (2x200ml), aq.
HCl 3N (2x100ml), sat. NaHCO
3
, H
2
O (1x100ml) and finally brine (1x20ml). It was
dried with MgSO
4
and the volatiles were removed under reduced pressure. Further
purification was performed with flash chromatography (gradient elution, 30%
EtOAc/Hexanes to 50% to final 70%). Yield: 0.142g or 30%.
1
H NMR (250 MHz, CDCl
3
) δ 5.77-5.64 (m, 1H), 5.28-5.20 (m, 1H), 5.17-
4.97 (m, 3H), 4.87 (dd, J
1
= 6.3Hz, J
2
= 3.1Hz, 0.7H), 4.80 (m, 1.5H), 4.21 (d, J=
5.9Hz, 2H), 3.80 (m, 2H), 3.65-3.63 (s, 6H), 3.53 (d, J= 16.0Hz, 0.5H), 3.42 (d, J=
15.3Hz, 0.5H), 3.38-3.30 (3s, 4H).
13
C NMR (63 MHz, CDCl
3
) δ 208.64, 208.00,
167.78, 167.69, 167.22, 166.56, 165.90, 165.72, 133.76, 133.71, 116.92, 116.30,
86.90, 86.54, 78.62, 77.80, 63.67, 63.52, 54.50, 52.45, 52.27, 52.24, 52.15, 51.10,
47.15, 44.55, 41.17, 41.01, 40.86

237

N O
O
O
HO
5.53a

1-Allyl-5-hydroxymethyl-2-oxo-4-(1-phenyl-vinyl)-pyrrolidine-3-
carboxylic acid methyl ester (5.53a). A flame-dried 10-ml microwave tube
equipped with a magnetic stirrer that was kept under inert atmosphere (N
2
glove box)
was charged with 0.8 ml dry DMF, Pd(OAc)
2
5.54 (0.013 g, 0.058 mmol), PPh
3
5.55
(0.030g, 0.116mmol), PhI 5.56 (33µl, 0.29 mmol), n-Bu
4
NCl 5.58 (0.081 g, 0.29
mmol) and Na
2
CO
3
5.57 (0.031 g, 0.29 mmol). The tube was sealed under N
2
and
stirred for 3min. Subsequently, a degassed solution of 5.51 (0.070g, 0.29mmol) in
0.5 ml dry DMF was added in one portion to the abovementioned reaction mixture
and the sealed tube was heated to 80-85
o
C for 12 hr. The reaction mixture was
diluted with 50 ml EtOAc and washed with H
2
O (5x50ml) and brine (1x20ml). It
was dried with MgSO
4
and the volatiles were removed under reduced pressure.
Crude
1
H NMR was run at that point which showed a complex and significantly
crude reaction mixture while 5.51 had been completely consumed at that time.
Further purification was performed with flash chromatography (gradient
elution, 5% EtOAc/CH
2
Cl
2
to 10% to 15% to 20% to final 100%). Among several
column samples containing unidentified material, two types of compounds were
traced. The expected product 5.53a and the byproduct of further Heck reaction on the

238

allylamine side 5.53c. Further purification attempts were made to completely purify
the two abovementioned compounds.
Purification of 5.53a: Preparative TLC was run with 10%Acetone/Et
2
O.
Yield: 0.016g or 18%.
Purification of 5.53c: Preparative TLC was run with EtOAc/Hexanes/Et
2
O,
3/4/3. Yield: 0.008g or 9%. Combined yield: 27%
1
H NMR (5.53a, 400 MHz, CDCl
3
) δ 7.35-7.27 (m, 5H), 5.73 (m, 1H), 5.33
(s, 1H), 5.25-5.18 (m, 2H), 5.18 (d, J= 0.7Hz, 1H), 4.24 (ddt, J
1
= 15.6Hz, J
2
= 5.3Hz,
J
3
= 1.3Hz, 1H), 3.83-3.79 (m, 1H), 3.76-3.69 (s&m, 5H), 3.64-3.58 (m, 2H), 3.54-
3.52 (3s, 1H).
13
C NMR (5.53a, 100 MHz, CDCl
3
) δ 170.78, 168.70, 148.52, 140.21,
132.29, 128.62, 128.18, 126.85, 118.72, 114.29, 63.33, 61.25, 54.19, 53.07, 44.10,
42.66

N O
O
O
O
5.52a
O O
O

Malonic acid 1-allyl-4-methoxycarbonyl-5-oxo-3-(1-phenyl-vinyl)-
pyrrolidin-2-ylmethyl ester methyl ester (5.52a). A flame-dried 10-ml microwave
tube equipped with a magnetic stirrer that was kept under inert atmosphere (N
2
glove
box) was charged with 3 ml dry DMF, Pd(OAc)
2
5.54 (0.045 g, 0.2 mmol), PPh
3

239

5.55 (0.210g, 0.80mmol), PhI 5.56 (112µl, 1.00 mmol), n-Bu
4
NCl 5.58 (0.278 g,
1.00 mmol) and Na
2
CO
3
5.57 (0.106 g, 1.00 mmol). The tube was sealed under N
2

and stirred for 3min. Subsequently, a degassed solution of 5.50 (0.240g, 0.7mmol) in
1 ml dry DMF was added in one portion to the abovementioned reaction mixture and
the sealed tube was heated to 60
o
C for 74 hr.
The reaction mixture was diluted with 50 ml EtOAc and washed with H
2
O
(5x50ml) and brine (1x50ml). It was dried with MgSO
4
and the volatiles were
removed under reduced pressure. Crude
1
H NMR was run at that point which
showed a complex and significantly crude reaction mixture while 5.50 had been
completely consumed at that time.
Further purification was performed with flash chromatography (gradient
elution, 30% EtOAc/Hexanes to 40% to final 50%). Among several column samples
containing unidentified material, 5.52a was traced. The Heck byproduct was
completely suppressed under these conditions, most likely due to the lower
temperature. The product was subjected to further purification. Preparative TLC was
run with 70% EtOAc/Hexanes. Yield: 0.040g or 20%.
1
H NMR (250 MHz, CDCl
3
) δ 7.37-7.23 (m, 5H), 5.66 (m, 1H), 5.32 (s, 1H),
5.22-5.16 (m, 3H), 4.38-4.25 (m, 2H), 4.14 (dd, J
1
= 12.4Hz, J
2
= 4.2Hz, 1H), 3.77-
3.68 (m, 7H), 3.64-3.38 (m, 3H), 3.33 (s, 2H).
13
C NMR (63 MHz, CDCl
3
) δ 169.55,
168.45, 166.43, 165.97, 147.64, 139.91, 131.63, 128.60, 128.17, 126.91, 126.19,
118.84, 114.86, 63.44, 59.97, 53.79, 52.85, 52.61, 44.03, 43.07, 40.96.

240

N
O
O
O
O
O
O
O
5.52b

Malonic acid 1-allyl-6-methoxycarbonyl-7-oxo-4-phenyl-2,5,6,7-
tetrahydro-1H-azepin-2-ylmethyl ester methyl ester (5.52b). A flame-dried 10-ml
microwave tube equipped with a magnetic stirrer that was kept under inert
atmosphere (N
2
glove box) was charged with 1.5 ml dry DMF, Pd(PPh
3
)
4
5.26,
(0.104 g, 0.09 mmol), PhI 5.56 (375µl, 1.84 mmol), n-Bu
4
NCl 5.58 (0.256 g, 0.92
mmol) and Na
2
CO
3
5.57 (0.098 g, 0.92 mmol). The tube was sealed under N
2
and
stirred at 85
o
C for 1min. Subsequently, a degassed solution of 5.50 (0.221g,
0.65mmol) in 1 ml dry DMF was added in one portion to the abovementioned
reaction mixture and the sealed tube was heated to 85
o
C for 4.5 hr.
The reaction mixture was diluted with 100 ml EtOAc and washed with H
2
O
(5x50ml) and brine (1x20ml). It was dried with MgSO
4
and the volatiles were
removed under reduced pressure. Further purification was performed with flash
chromatography (gradient elution, 30% EtOAc/Hexanes to 40% to final 50%). Yield:
0.055g or 20%.
1
H NMR (250 MHz, CDCl
3
) δ 7.38-7.21 (m, 5H), 5.89 (m, 1H), 5.44 (d, J=
9.7Hz, 1H), 5.23-5.08 (m, 2H), 4.22 (dd, J
1
= 10.5Hz, J
2
= 4.8Hz, 1H), 4.10 (dd, J
1
=

241

10.6Hz, J
2
= 7.2Hz, 1H), 3.89 (m, 1H), 3.71 (s, 3H), 3.59 (s, 3H), 3.32 (ddt, J
1
=
14.3Hz, J
2
= 5.5Hz, J
3
= 2.0Hz, 1H), 3.18 (ddt, J
1
= 14.0Hz, J
2
= 6.2Hz, J
3
= 1.0Hz, 1H),
2.85 (t, J= 7.8Hz, 2H), 2.30 (t, J= 8.6Hz, 2H).
13
C NMR (63 MHz, CDCl
3
) δ 173.16,
166.81, 166.24, 142.89, 141.02, 136.69, 128.45, 128.25, 127.61, 126.53, 116.12,
67.93, 54.14, 52.55, 51.60, 49.83, 41.27, 33.00, 25.53
MS data: Expected m/z for C
22
H
26
NO
7
+
[M+H]
+
= 416.17. Experimental m/z
found [M+H]
+
= 416.2.

O
NH Ph
•
5.64
Si

benzyl-[1-(tert-butyl-dimethyl-silanyloxymethyl)-buta-2,3-dienyl]-amine
(5.64). A 10-ml flame-dried round-bottomed flask equipped with a magnetic stirrer,
was charged with 4 ml dry CH
2
Cl
2
followed by 2-benzylamino-penta-3,4-dien-1-ol
2.149b (0.180 g, 0.95 mmol) and 2, 6 Lutidine 5.62 (0.154ml, 1.33 mmol). The
system was cooled down to 0
o
C and tert-butyl dimethylsilyl triflate (TBDMSOTf)
5.61 (0.262 ml, 1.14 mmol) was added in one portion. The mixture was allowed to
warm up to ambient temperature and was left under stirring for 24 hr.
CH
2
Cl
2
was removed under reduced pressure and EtOAc was added (100ml).
The organic phase was subsequently treated with H
2
O (2x50ml), aq. HCl 1N

242

(3x50ml), sat. NaHCO
3
(2x50ml), H
2
O (1x50ml) and brine (1x20ml). Yield: 0.250g
or 87%.
1
H (400 MHz, CDCl
3
) δ 7.34-7.30 (m, 4H), 7.27-7.22 (m, 1H), 5.05 (q, J=
6.7Hz, 1H), 4.80 (m, 2H), 3.95 (d, J= 13.6Hz, 1H), 3.74 (d, J= 13.3Hz, 1H), 3.67
(dd, J
1
= 9.8Hz, J
2
= 4.4Hz, 1H), 3.57 (dd, J
1
= 9.7Hz, J
2
= 7.4Hz, 1H), 3.29 (m, 1H),
2.16 (bs, 1H), 0.89 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H).
13
C NMR (100 MHz, CDCl
3
) δ
208.73, 140.46, 128.29, 128.11, 126.73, 90.19, 75.83, 66.33, 58.31, 51.09, 25.83,
18.25, -5.38, -5.45

O
N Ph
•
O
O O
Si
5.63

N-benzyl-N-[1-(tert-butyl-dimethyl-silanyloxymethyl)-buta-2,3-dienyl]-
malonamic acid methyl ester (5.63). A 25-ml flame-dried round-bottomed flask
equipped with a magnetic stirrer, was charged with 10 ml dry CH
2
Cl
2
, benzyl-[1-
(tert-butyl-dimethyl-silanyloxymethyl)-buta-2,3-dienyl]-amine 5.64 (0.386g,
1.27mmol) and methyl-3-chloro-3-oxopropionate 5.48 (205µl, 1.91mmol). The
system was cooled to 0
o
C and Et
3
N 5.49 (213µl, 1.53mmol) was added in one
portion. The system was left under stirring at ambient temperature for 24hr.

243

CH
2
Cl
2
was removed under reduced pressure and EtOAc was added (50ml).
The organic phase was subsequently treated with H
2
O (3x20ml), aq. HCl 3N
(3x20ml), sat. NaHCO
3
(2x20ml), H
2
O (1x20ml) and brine (1x10ml). Yield: 0.449g
or 88%.
1
H NMR (400 MHz, CDCl
3
) δ 7.34-7.16 (m, 5H), 5.29 (q, J= 6.7Hz, 0.46H),
5.11 (q, J= 6.7Hz, 0.54H), 5.00 (m, 0.45H), 4.81 (m, 1.1H), 4.71 (dd, J1= 6.7Hz, J2=
2.7Hz, 0.9H), 4.65-4.50 (m, 2H), 4.47 (m, 0.5H), 3.84 (d, J= 15.6Hz, 0.6H), 3.80
(dd, J1= 6.2Hz, J2= 4.1Hz, 1H), 3.75 (s, 1.6H), 3.67-3.64 (s&dd, 2H), 3.60-3.53
(1H), 3.30 (s, 0.9H), 0.85-0.84 (s&s, 9H), 0.01-(-0.06) (4s, 6H).
13
C NMR (100
MHz, CDCl
3
) δ 209.21, 208.25, 167.34, 167.29, 138.60, 137.45, 128.75, 128.28,
127.33, 127.05, 126.66, 126.12, 87.63, 87.29, 77.76, 77.21, 63.40, 62.81, 58.27,
56.48, 52.38, 52.32, 50.03, 45.52, 41.82, 41.69, 25.77, 18.10, -5.55, -5.65, -5.73

N O
O
O
Ph
O
5.67a
Si

1-benzyl-5-(tert-butyl-dimethyl-silanyloxymethyl)-2-oxo-4-(1-phenyl-
vinyl)-pyrrolidine-3-carboxylic acid methyl ester (5.67a). A flame-dried 10-ml
microwave tube equipped with a magnetic stirrer that was kept under inert
atmosphere (N
2
glove box) was charged with 2.0 ml dry DMF, Pd(OAc)
2
5.54

244

(0.008g, 0.04mmol), PPh
3
5.55 (0.010g, 0.04mmol), PhI 5.56 (207µl, 1.85mmol), n-
Bu
4
NCl 5.58 (0.156g, 0.56mmol) and Na
2
CO
3
5.57 (0.059g, 0.56mmol). The tube
was sealed under N
2
and stirred for 3min. Subsequently, a degassed solution of 5.63
(0.150g, 0.37mmol) in 0.6 ml dry DMF was added in one portion to the
abovementioned reaction mixture and the sealed tube was heated to 85
o
C for 0.5hr.
The reaction mixture was diluted with 100 ml EtOAc and washed with H
2
O
(5x50ml) and brine (1x50ml). It was dried with MgSO
4
and the volatiles were
removed under reduced pressure. Crude
1
H NMR was run at that point which
showed complete consumption of the starting material while new signals appeared
that could be attributed to the five-member heterocycle. Purification was essential.
Flash chromatography was performed (gradient elution, 10% EtOAc/Hexanes
to final 15%) followed by preparative TLC (30% EtOAc/Hexanes) in order to
completely purify the product. Yield: 0.080g or 45%.
1
H NMR (400 MHz, CDCl
3
) δ 7.38-7.22 (m, 10H), 5.27 (s, 1H), 5.10 (d, J=
14.6Hz, 1H), 5.07 (s, 1H), 4.10 (d, J= 14.6Hz, 1H), 3.83 (m, 1H), 3.74-3.71 (s&m,
4H), 3.60-3.53 (m, 2H), 3.48 (m, 1H), 0.88 (s, 9H), -0.01 (s, 3H), -0.03 (s, 3H).
13
C
NMR (90 MHz, CDCl
3
) δ 169.79, 169.11, 148.10, 140.51, 136.12, 128.62, 128.39,
128.08, 127.85, 127.56, 126.79, 114.46, 62.70, 61.67, 54.19, 52.64, 45.02, 42.25,
25.72, 18.11, -5.72

245

N O
O
O
Ph
HO
5.65a

1-benzyl-5-hydroxymethyl-2-oxo-4-(1-phenyl-vinyl)-pyrrolidine-3-
carboxylic acid methyl ester (5.65a). A flame-dried 10-ml microwave tube
equipped with a magnetic stirrer that was kept under inert atmosphere (N
2
glove box)
was charged with 2.0 ml dry DMF, Pd(OAc)
2
5.54 (0.009g, 0.04mmol), PPh
3
5.55
(0.010g, 0.04mmol), PhI 5.56 (213µl, 1.90mmol), n-Bu
4
NCl 5.58 (0.158g,
0.57mmol) and Na
2
CO
3
5.57 (0.060g, 0.57mmol). The tube was sealed under N
2
and
stirred for 3min. Subsequently, a degassed solution of 5.60 (0.110g, 0.38mmol) in
0.6 ml dry DMF was added in one portion to the abovementioned reaction mixture
and the sealed tube was heated to 80
o
C for 0.5hr.
The reaction mixture was diluted with 50 ml EtOAc and washed with H
2
O
(5x20ml) and brine (1x20ml). It was dried with MgSO
4
and the volatiles were
removed under reduced pressure. Crude
1
H NMR was run at that point which
showed complete consumption of the starting material while new signals appeared
that could be attributed to the five-member heterocycle. Purification was essential.
Flash chromatography was performed (gradient elution, 20% EtOAc/Hexanes
to 30 to 40 to final 50%) followed by preparative TLC (10% Acetone/CH
2
Cl
2
) in
order to completely purify the product. Yield: 0.028g or 20%.

246

1
H NMR (400 MHz, CDCl
3
) δ 7.32-7.18 (m, 10H), 5.26 (s, 1H), 5.05 (s, 1H),
4.87 (d, J= 15.1Hz, 1H), 4.25 (d, J= 15.0Hz, 1H), 3.75 (s, 3H), 3.75 (m, 2H), 3.59-
3.56 (m, 2H), 3.47 (m, 1H).
13
C NMR (100 MHz, CDCl
3
) δ 170.82, 169.19, 148.23,
128.92, 128.59, 128.17, 128.07, 127.94, 114.44, 63.11, 61.22, 54.18, 53.11, 42.64,
29.17

N O
O
O
Ph
O
5.66a
O O
O

Malonic acid 1-benzyl-4-methoxycarbonyl-5-oxo-3-(1-phenyl-vinyl)-
pyrrolidin-2-ylmethyl ester methyl ester (5.66a). A flame-dried 10-ml microwave
tube equipped with a magnetic stirrer that was kept under inert atmosphere (N
2
glove
box) was charged with 1.0 ml dry DMF, Pd(OAc)
2
5.54 (0.008g, 0.03mmol), PPh
3

5.55 (0.009g, 0.03mmol), PhI 5.56 (187µl, 1.67mmol), n-Bu
4
NCl 5.58 (0.092g,
0.33mmol) and Na
2
CO
3
5.57 (0.035g, 0.33mmol). The tube was sealed under N
2
and
stirred for 3min. Subsequently, a degassed solution of 5.59 (0.080g, 0.21mmol) in
0.5 ml dry DMF was added in one portion to the abovementioned reaction mixture
and the sealed tube was heated to 85
o
C for 0.5hr.
The reaction mixture was diluted with 50 ml EtOAc and washed with H
2
O
(5x20ml) and brine (1x20ml). It was dried with MgSO
4
and the volatiles were

247

removed under reduced pressure. Crude
1
H NMR was run at that point which
showed complete consumption of the starting material but the reaction mixture was
significantly crude. Purification was essential.
Flash chromatography was performed (gradient elution, 30% EtOAc/Hexanes
to 40 to 50 to final 70%). Yield: 0.023g or 24%.
1
H NMR (400 MHz, CDCl
3
) δ 7.35-7.25 (m, 6H), 7.20 (m, 2H), 7.16 (m,
2H), 4.33 (dd, J
1
= 12.1Hz, J
2
= 3.7Hz, 1H), 4.08 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H),
3.58 (m, 2H), 3.29 (s, 2H).
13
C NMR (100 MHz, CDCl
3
) δ 169.63, 169.01, 166.54,
166.07, 147.36, 139.80, 135.60, 128.84, 128.61, 128.19, 128.12, 127.96, 126.90,
126.24, 115.01, 63.24, 59.73, 53.78, 52.98, 52.71, 45.25, 43.00, 40.97.

N O
O
O
O
O
O
O
5.66b
Ph

Malonic acid 1-benzyl-6-methoxycarbonyl-7-oxo-4-phenyl-2,5,6,7-
tetrahydro-1H-azepin-2-ylmethyl ester methyl ester (5.66b). A flame-dried 10-ml
microwave tube equipped with a magnetic stirrer that was kept under inert
atmosphere (N
2
glove box) was charged with 1.5 ml dry DMF, Pd(PPh
3
)
4
5.26
(0.035g, 0.03mmol), PhI 5.56 (67µl, 0.60mmol), n-Bu
4
NCl 5.58 (0.083 g,
0.30mmol) and Na
2
CO
3
5.57 (0.032 g, 0.30mmol). The tube was sealed under N
2
and

248

stirred at 85
o
C for 1min. Subsequently, a degassed solution of 5.59 (0.087g,
0.22mmol) in 0.5 ml dry DMF was added in one portion to the abovementioned
reaction mixture and the sealed tube was heated to 85
o
C for 7.5 hr.
The reaction mixture was diluted with 100 ml EtOAc and washed with H
2
O
(5x50ml) and brine (1x20ml). It was dried with MgSO
4
and the volatiles were
removed under reduced pressure. Further purification was performed with flash
chromatography (gradient elution, 30% EtOAc/Hexanes to 40% to final 50%). Yield:
0.0??g or 21%.
1
H NMR (400 MHz, CDCl
3
) δ 7.33-7.21 (m, 10H), 5.50 (d, J= 9.1Hz, 1H),
4.24 (dd, J
1
= 10.8Hz, J
2
= 4.6Hz, 1H), 4.14 (dd, J
1
= 11.2Hz, J
2
= 7.4Hz, 1H), 3.91 (m,
1H), 3.86 (d, J= 12.9Hz, 1H), 3.75-3.70 (m, 2H), 3.68 (s, 3H), 3.58 (s, 3H), 2.80 (m,
2H), 2.26 (t, J= 8.1Hz, 2H).
13
C NMR (100 MHz, CDCl
3
) δ 173.10, 166.81, 166.25,
143.01, 141.05, 140.08, 128.45, 128.31, 128.11, 127.61, 127.06, 126.57, 67.87,
54.30, 52.50, 51.58, 51.39, 41.27, 32.94, 25.49.
MS (ESI
+
ionization mode): Expected m/z for C
22
H
26
NO
7
[M+H]
+
=466.19.
Experimental m/z found [M+H]
+
=466.2.

249

N N
O
O
Ph
O
Si
5.75

4-benzyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-2-(1-phenyl-vinyl)-
piperazine-1-carboxylic acid tert-butyl ester (5.75). A flame-dried 10-ml
microwave tube equipped with a magnetic stirrer that was kept under inert
atmosphere (N
2
glove box) was charged with 1.5 ml dry DMF, Pd(PPh
3
)
4
5.26
(0.017g, 0.02mmol), PhBr 5.73 (61µl, 0.91mmol) and K
2
CO
3
5.74 (0.080 g,
0.582mmol). The tube was sealed under N
2
and stirred at 80
o
C for 1min.
Subsequently, a degassed solution of (2-{benzyl-[1-(tert-butyl-dimethyl-
silanyloxymethyl)-buta-2,3-dienyl]-amino}-ethyl)-carbamic acid tert-butyl ester 5.72
(0.065g, 0.146mmol) in 0.5 ml dry DMF was added in one portion to the
abovementioned reaction mixture and the sealed tube was heated to 80
o
C for 8 hr.
The reaction mixture was diluted with 100 ml EtOAc and washed with H
2
O
(5x50ml) and brine (1x20ml). It was dried with MgSO
4
and the volatiles were
removed under reduced pressure. Further purification was performed with
preparative TLC (development with 20% EtOAc/Hexanes). Yield: 0.014g or 18%.
1
H NMR (400 MHz, CDCl
3
) δ 7.39-7.15 (m, 10H), 5.29 (s, 1H), 5.16 (s, 1H),
3.82 (m, 1H), 3.72 (m, 3H), 3.64 (d, J= 13.5Hz, 1H), 3.55 (d, J= 13.5Hz, 1H), 3.30
(m, 1H), 2.92 (b, 1H), 2.56 (m, 2H), 1.42 (s, 9H), 0.90 (s, 9H), 0.04 (s, 3H), -0.02 (s,

250

3H).
13
C NMR (100 MHz, CDCl
3
) δ 156.28, 148.04, 141.09, 138.96, 128.37, 128.10,
127.21, 126.85, 113.95, 79.66, 59.89, 59.43, 58.17, 54.57, 44.83, 38.93, 28.23,
25.89, 18.13, -5.53.

N
Ph
Ph
HO
5.70a

(1-benzyl-4-phenyl-2,5-dihydro-1H-pyrrol-2-yl)-methanol (5.70a). A
flame-dried 10-ml microwave tube equipped with a magnetic stirrer that was kept
under inert atmosphere (N
2
glove box) was charged with 1.7 ml dry DMF, Pd(PPh
3
)
4

5.26 (0.037g, 0.03mmol), PhBr 5.73 (133µl, 1.27mmol) and K
2
CO
3
5.74 (0.176 g,
1.27mmol). The tube was sealed under N
2
and stirred at 80
o
C for 1min.
Subsequently, a degassed solution of 2.149b (0.065g, 0.146mmol) in 0.5 ml dry
DMF was added in one portion to the abovementioned reaction mixture and the
sealed tube was heated to 60
o
C for 20 hr.
The reaction mixture was diluted with 100 ml EtOAc and washed with H
2
O
(5x50ml) and brine (1x20ml). It was dried with MgSO
4
and the volatiles were
removed under reduced pressure. Further purification was performed with flash
chromatography (gradient elution with EtOAc/Hexanes 20% to 30 to final 50%).
Yield: 0.020g or 24%.

251

1
H NMR (400 MHz, CDCl
3
) δ 7.38-7.22 (m, 10H), 6.05 (m, 1H), 4.11-4.07
(m&d, J= 13.1Hz, 2H), 3.97 (m, 1H), 3.70 (d, J= 13.5Hz, 1H), 3.68-3.61 (m, 3H).
13
C
NMR (100 MHz, CDCl
3
) δ 140.25, 139.12, 133.65, 128.53, 128.39, 127.83, 127.23,
125.53, 72.34, 61.52, 60.46, 58.34.

N
H
H N
H
H
HO
HO
5.70b 5.70c
and

(rac)-[1-benzyl-3-(1-phenyl-vinyl)-trans-aziridin-2-yl]-methanol (5.70b)
and (rac)-[1-benzyl-3-(1-phenyl-vinyl)-cis-aziridin-2-yl]-methanol (5.70c).
A flame-dried 10-ml microwave tube equipped with a magnetic stirrer that
was kept under inert atmosphere (N
2
glove box) was charged with 3 ml dry DMF,
Pd(PPh
3
)
4
5.26 (0.069g, 0.06mmol), PhBr 5.73 (238µl, 2.26mmol) and K
2
CO
3
5.74
(0.312 g, 2.26mmol). The tube was sealed under N
2
and stirred at 73
o
C for 1min.
Subsequently, a degassed solution of 5.149b (0.107g, 0.57mmol) in 1 ml dry DMF
was added in one portion to the abovementioned reaction mixture and the sealed tube
was heated to 73
o
C for 8.5 hr.
The reaction mixture was diluted with 100 ml EtOAc and washed with H
2
O
(5x50ml) and brine (1x20ml). It was dried with MgSO
4
and the volatiles were

252

removed under reduced pressure. Crude 1H NMR was run from that residue that
showed three products (the pyrroline heterocycle and both the cis and trans
aziridines) Further purification was performed with flash chromatography (gradient
elution with EtOAc/Hexanes 20% to 2% MeOH/CH
2
Cl
2
to final 5%) followed by
preparative TLC (70% EtOAc/Hexanes).Combined yield 25% (pyrroline 5.70a:
21%, trans aziridine 5.70b: 2.7%, cis aziridine 5.70c: 1.3%).
1
H NMR (trans aziridine 5.70b-400 MHz, CDCl
3
) δ 7.33-7.22 (m, 8H), 7.11
(m, 2H), 5.47 (t, J= 0.9Hz, 1H), 5.36 (s, 1H), 5.29 (d, J= 5.0Hz, 1H), 4.59 (d, J=
15.1Hz, 1H), 4.27 (d, J= 15.1Hz, 1H), 3.61 (dt, J
1
= 12.0Hz, J
2
= 3.2Hz, 1H), 3.34 (m,
1H), 3.28 (m, 1H).
13
C NMR (100 MHz, CDCl
3
) δ 158.18, 145.46, 128.94, 128.71,
128.38, 128.01, 127.67, 127.38, 115.91, 61.18, 60.60, 46.52, 29.71.
1
H NMR (cis aziridine 5.70c-400 MHz, CDCl
3
) δ 7.34-7.29 (m, 10H), 5.73
(dd, J
1
= 1.8Hz, J
2
= 0.6Hz, 1H), 5.67 (t, J=0.9Hz, 1H), 5.57 (dt, J
1
= 8.1Hz, J
2
= 1.4Hz,
1H), 4.93 (d, J= 15.2, 1H), 4.19 (d, J= 15.2Hz, 1H), 3.64 (dt, J
1
= 8.1Hz, J
2
= 3.4Hz,
1H), 3.49 (m, 2H).

253

5.4 Chapter 5 References

1. Krause, N.; Hashmi, A.a.; Stephen, K. Modern Allene Chemistry, 2004.
2. Zimmer, R.; Dinesh, C.U.; Nandanan, E.; Khan, F.A. Chemical Reviews
(Washington, D. C.) 2000, 100, 3067-3125.
3. Balme, G.; Bossharth, E.; Monteiro, N. European Journal of Organic Chemistry
2003, 4101-4111.
4. Yamamoto, Y.; Radhakrishnan, U. Chemical Society Reviews 1999, 28, 199-207.
5. Yamamoto, Y.; Al-Masum, M. Synlett 1995, 969-70.

6. Yamamoto, Y.; Al-Masum, M.; Fujiwara, N.; Asao, N. Tetrahedron Letters 1995,
36, 2811-14.
7. Yamamoto, Y.; Al-Masum, M.; Asao, N. Journal of the American Chemical
Society 1994, 116, 6019-20.
8. Yamamoto, Y. Pure and Applied Chemistry 1996, 68, 9-14.
9. Besson, L.; Gore, J.; Cazes, B. Tetrahedron Letters 1995, 36, 3853-6.
10. Ahmar, M.; Cazes, B.; Gore, J. Tetrahedron Letters 1984, 25, 4505-8.
11. Cazes, B. Pure and Applied Chemistry 1990, 62, 1867-78.
12. Chaptal, N.; Colovray-Gotteland, V.; Grandjean, C.; Cazes, B.; Gore, J.
Tetrahedron Letters 1991, 32, 1795-8.
13. Ma, S.; Jiao, N. Angewandte Chemie, International Edition 2002, 41, 4737-
4740.
14. Davies, I.W.; Scopes, D.I.C.; Gallagher, T. Synlett 1993, 85-7.
15. Ma, S.; Yu, F.; Gao, W. Journal of Organic Chemistry 2003, 68, 5943-5949.

254

16. Rutjes, F.P.J.T.; Tjen, K.C.M.F.; Wolf, L.B.; Karstens, W.F.J.; Schoemaker,
H.E.; Hiemstra, H. Organic Letters 1999, 1, 717-720.
17. Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Osawa, E.; Yamaoka, Y.; Fujii, N.;
Ibuka, T. Journal of Organic Chemistry 1999, 64, 2992-2993.
18. Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.;
Ibuka, T. Journal of Organic Chemistry 2001, 66, 4904-4914.
19. Karstens, W.F.J.; Rutjes, F.P.J.T.; Hiemstra, H. Tetrahedron Letters 1997, 38,
6275-6278.
20. Karstens, W.F.J.; Stol, M.; Rutjes, F.P.J.T.; Hiemstra, H. Synlett 1998, 1126-
1128.
21. Cook, G.R.; Sun, L. Organic Letters 2004, 6, 2481-2484.
22. Kamijo, S.; Yamamoto, Y. Tetrahedron Letters 1999, 40, 1747-1750.

255
CHAPTER 6: Reactivity of Methoxy alkynyl boronates in the
Petasis Reaction. One-step synthesis of functionalized propargyl
amines. Scope and limitations.

6.1 Propargyl amines. General aspects
6.1.1 The biological importance of propargyl amines
Propargyl amines and their derivatives constitute a class of medicinally
important compounds since they exhibit considerable biological activity. In
particular, they inhibit the action of mitochondrial monoamine oxidases (MAO), a
class of enzymes that regulates the metabolism of neurotransmitter amines through
deamination and is implicated in controlling depression,
1
hypertension and in the
treatment of Parkinson’s disease.
2
The propargylic amine moiety was found to play
pivotal role in the enzyme deactivation through irreversible formation of covalently
attached adducts (suicide inhibitors).
3
Alternative mechanisms of action for those
compounds have also been reported that involve the regulation of phosphorylation of
protein kinase C through interaction with various proteins.
4

Furthermore, propargylic amines have been found to act as anti-apoptotic
agents, thus revealing a neuroprotective role which can be of significant importance
for prophylaxis and treatment of neurodegenerative diseases that are known to

256
involve neuron loss such as Parkinson’s,
5
Alzheimer’s, and Huntington’s disease.
6

The neuroprotective action of propargylic aliphatic amines
7
has also been shown to
prolong the life span of various species through enhancing the activity of antioxidant
enzymes in various tissues such as the brain,
8,9
the kidneys and the heart, thus
reducing the oxidative stress originating from reactive oxygen species, a known
process implicated in cellular aging and apoptosis mechanisms.
10

Apart from the neuroprotective activity, a number of non-nucleosidic HIV
reverse transcriptase inhibitors have been discovered that contain the propargyl
amine moiety in their structure. Among them are Efavirenz (Sustiva®) 6.6, a DuPont
marketed drug prescribed to AIDS patients
11
and DPC963 6.7, a second-generation
and potential successor of Efavirez. Some bioactive propargyl amine derivatives are
shown in Scheme 6.1
N
H
"Rasagaline (Agilect)" 6.2
N
"R(-) Deprenyl" 6.1
N
O
N
"JSAK648" 6.3
N
H
O N
O
"Ladostigil" 6.4
N
OH
N
"M30" 6.5
N
H
O
Cl
F
3
C
O
"Efavirenz (Sustiva)" 6.6
N
H
NH
F
F
3
C
O
"DCP963" 6.7
F

Scheme 6.1: Some biologically active propargyl amines

257
6.1.2 Synthetic approaches towards propargyl amines
Numerous synthetic methods towards propargyl amines have been developed
by different research groups due to the synthetically flexible moiety which can be
further synthetically transformed to more advanced synthons. Short methodologies
towards various heterocycles such as functionalized halopyrroles
12
,
13
spiro-
[indoline-2, 4]-piperidines,
14
fluorinated 3,4 proline analogues
15
chiral a-
aminoalkylpyrimidines,
16
(S)-(+)-coniine
17
, as well as various internal alkynes,
18

functionalized allenes,
19,20,21,22
biologically active

fluorinated α-aminoacids
23
have
been developed in which propargyl amines constitute the key synthons. Moreover,
the biological properties that some of these compounds exhibit urged for new, more
efficient, versatile, low cost methods where issues of stereochemistry come into play
and enantiocontrol is of high importance.
Table 6.1 outlines the major synthetic approaches to synthesize propargyl
amines of structure 6.10. Early attempts involved the employment of highly reactive
alkynyl organometallics 6.8
24
and their addition to preformed imines 6.9 has been
extensively studied.
25
Lithium, sodium and magnesium organometallics have been
mostly employed and conditions have been developed to successfully add them to
structurally variable imines.
26,27,28
Stereoselective approaches from addition to chiral
imines
29
(diastereocontrol) or employment of cinchona alkaloids (enantiocontrol)
have also been reported with ranging selectivitites, depending on the structure of the
imine as well as the organometallic species.

258
Additions of the abovementioned organometallics to other types of
electrophiles have also been reported. α- Amidoalkyl sulfones 6.12 (prepared from
aldehydes, carbamates and sodium benzenesulfinate) give high yields of the
corresponding N-acyloxy protected propargyl amines 6.13 after reaction with lithium
alkynyl organometallics.
30
Introduction of two different substituents through highly
selective sequential addition of lithium and magnesium organometallics 6.11 and
6.17 to thioamides 6.14 constitutes and alternative methodology for synthesizing
tertiary propargyl amines 6.18.
31

Transmetallation of lithium alkynyl organometallics to the corresponding less
reactive titanium species 6.19 and subsequent conjugate addition to various
pyrimidin-2(1H)-ones leads to alkynyl pyrimidin-2(1H)-ones 6.21 (a or b) but with
somehow erratic regioselectivity.
32
The use of bis-trimethylacetylene 6.22 activated
by BF
3
.OEt
2
has also been employed in a methodology towards trifluoromethylated
propargyl amines in combination with oxazolines 6.23 but low conversions and
modest diastereoselectivities were obtained.
33

The alternative methodology of 1, 2 addition of alkyl organometallics to
preformed α, β alkynyl imines 6.26 has also been employed as a method to assemble
the propargyl amine moiety. In particular, organozinc
34
and organocerium reagents
(formed after transmetallation of the corresponding organolithium reagents) add
successfully to the abovementioned imines. Enantiopure free propargyl amines have
been formed in the latter case after a short route originating from cleavable N-chiral

259
aldimines.
35, 36
Also, the use of a chiral Zr catalyst in combination with N-aryl imines
and organozinc reagents yields tertiary propargyl amines with moderate to high
enantioselectivities.
37,38

A somehow alternative methodology that still employs lithium
39
or
magnesium
40
organometallics but is conceptually different was firstly introduced by
Katritzky in 1989. This method requires the preparation of 1-(dialkylaminomethyl)
benzotriazoles 6.27, a iminium salt precursor which subsequently reacts with various
alkynyl lithium reagents yielding 6.18. The evolution of the methodology involved
the employment of more regioselective alkynylaluminates nucleophiles, especially in
the presence of other electrophilic functional groups (e.g. epoxides, esters etc).
41

Apart from the use of benzotriazole aminals as iminium salt precursors, use
of the Mannich reaction both in solution
42,43,44,45
and on solid support
46,47,48
or
varations of the classic process have given access to propargyl amines. In situ
formation of iminium salts from preformed N,N aminals
49
(induced by ZnI
2
) or N,O
acetals
50,51,52
by a variety of conditions, followed by nucleophilic attack by a terminal
alkyne constitute alternative approaches to the propargylic amine moiety.
In situ formation of highly electrophilic acyl iminium or related salts have
been demonstrated to be susceptible to attack by in situ or preformed metal
alkynylides such as zinc-
53
or copper-
54,55
derived organometallics yielding N-
protected propargylic amides. O-Acetylation of ∆
2
-piperidinones followed by
nucleophilic attack by an alkynyl lithium is a representative example that resulted in

260
alkynyl substituted piperidinones through the intermediacy of the corresponding O-
Acetoxy-5, 6-dihydropyridinium salts.
56

Metal catalyzed processes have also been employed in synthesizing propargyl
amines based on various concepts. The mild and neutral conditions by which most of
the catalytic reactions proceed in combination with the fact that these methods are
more compatible with functionality nominate this wide class of transformations as
very promising alternatives for various synthetic challenges.
As a result of copper to coordinate with triple bonds, Cu
I
salts have been
shown efficient in promoting various conceptually different transformations leading
to propargyl amines, through common organometallic intermediates and various
preformed or in situ formed electrophiles. Cu
I-
dppe catalyzed addition of terminal
alkynes to nitrones was one of the first demonstrations of the synthetic role that Cu
I

salts could play in developing short, potentially enantioselective and atom
economical routes to multifunctionalized synthons such as propargyl imines.
57

The addition of alkynes 6.29 to N,N dialkyl enamines 6.32 in the presence of
Cu
I
catalysts is another well documented method
58
and this transformation is one of
the few that is compatible with the presence of some synthetically useful functional
groups due to the mild reaction conditions while the use of chiral ligands lead to
significant enantioselectivity providing access to enantiomerically enriched
products.
59,60

261
The evolution of the abovementioned methodology was a three-component
reaction among secondary amines 6.35, non-enolizable aldehydes 6.34 and terminal
alkynes 6.29.
61
Besides the practical issues already discussed about multicomponent
processes, this methodology yields excellent enantioselectivity when used in the
presence of quinap ligands, thus providing fast and easy access to the corresponding
chiral scaffolds. Many studies for further exploration of the potential of this
transformation have been performed by a number of research groups, investigating
several aspects and attempting to optimize and further expand the reaction scope.
Various monosubstituted and protected terminal alkynes participated while both
aromatic and aliphatic aldehydes were reactive with the latter giving better
enantioselectivities.
62
The use of certain cleavable amines also gave access to
enantiopure free propargyl amines.
63,64
Furthermore, limited attempts to employ the
three-component protocol with primary amines which are less reactive and usually
lead to byproducts and various adducts, have been reported. A CuI catalyzed
Mannich reaction
65
,
66
gave the expected adducts when aliphatic amines were used
while aromatic amines were successfully employed in a chiral version of the three-
component process yielding good yields and excellent enantioselectivities.
67

For the limited cases of imines that are stable and can be isolated, a two-
component imine-alkyne version of the Cu
I
catalyzed reaction was developed.
68
The
transformation is highly enantioselective when chiral tridentate
bis(oxazolinyl)pyridine (pybox) and ligands are employed. A plethora of other

262
binapthyl diimine,
69,70
and binapthyl diamine
71
ligands have been synthesized and
screened for the process with ranging enantioselectivities in the addition of phenyl
acetelyllene and other terminal alkynes indicating in some cases tremendous
substrate-related differences.
A binary CuBr-RuCl
3
catalytic system was shown to be efficient in
promoting the addition of terminal alkynes to aniline-derived imines by double
activation of both the alkyne (through Ru insertion to the acetylenic C-H bond) and
the imine nitrogen (through complexation with Cu).
72

C-H activation of the bond adjacent to the nitrogen atom of tertiary amines, a
type of activation that is more typical in Rh and Ir catalysis, has been also achieved
by inexpensive Cu
I
and Cu
II
salts
73
in the presence of t-BuOOH yielding proparyl
amines efficiently with moderate enantioselectivity.
74

Even though Cu
I
catalysis is considered one of the mostly preferred methods
for fast assembly of propargyl amines, its scope remains limited since it’s not
compatible with functionality and furthermore the chiral version might even require
6 days for high conversions to be reached. Microwave conditions have been
attempted in order to minimize the reaction time of the non-chiral version which lead
to significant conversion in as fast as 6 min but no data are available in the presence
of chiral ligands.
75,76

Besides Cu
I
salts, other catalytic systems have been shown to facilitate the
synthesis of propargyl amines.
77

263
The ability of Ir complexes to insert to the acetyllenic C-H bond of TMS
acetylene lead to the development of an alternative synthetic protocol for addition of
the resulting Ir acetylide to preformed imines.
78
The presence of MgI
2
as an additive
was proven very efficient in significantly accelerating and promoting the process.
79

A three-component version was also demonstrated in which both primary and
secondary amines can participate in combination with aldehydes and TMS acetylene
yielding the corresponding propargyl amines with high efficiency.
80
The only
drawback of the method is that is restricted to TMS acetylene only since when other
types of terminal alkynes are utilized an alternative path operates leading to
allylamines.
81

Au
I
, Au
III
and Ag
I
catalysts have also been employed in the three-component
assembly of propargyl amines and the exceptionally high activity they exhibit allow
for as low as 1% catalyst loading while almost quantitative conversions can be
achieved in 2-12hr.
82
Ag
I
catalysts show a reversal of reactivity compared to Au-
based catalysts that favors aliphatic aldehydes.
83
Another characteristic of the both
Ag and Au catalyzed transformations is the very mild conditions which enabled the
incorporation of various propargylic amines moieties on Artemicinin thus yielding a
number if analogues that exhibited significant anticancer properties.
84

The abovementioned synthetic approaches are schematically summarized in
table 6.1

264
Table 6.1: The major synthetic approaches towards propargyl amines
Transformation

1. Addition of alkynyl organometallics to preformed imines
R
1
M +
N
R
3
R
2
R
2
R
1
N
H R
3
6.8 6.9 6.10
M: Li, MgX, Na
2. Addition of alkynyl lithiums to a-aminoalkyl sulfones
R
1
Li +
R
3
R
1
N
H
6.11 6.12 6.13
R
2
O N
H
R
3
O OSOPh
THF
-68
o
C
3. Sequential addition of alkynyl lithiums and alkynyl Grignards to thioamides
+
6.14
R
2
O
O
R
2
N
S
R
3
R
1
Li
6.11
R
4
MgBr
R
2
N
S
R
3
R
1
N
R
2
R
3
R
1
R
4
MeOTf 6.15
Et
2
O, RT 35
o
C, 6hr
6.16
6.17
6.18
4. Utilization of alkynyl titaniuma in synthesizing propargyl amines
R
1
Ti(OiPr)
3
6.19 6.20
THF
-68
o
C
N
N O
R
2
X
+
6.21a
HN
N O
R
2
X
R
1
NH
N
O
R
2
X
R
1
or
6.21b
R
1
=H, 6.21a only
R
1
=Ph, 6.21b only
5. BF
3
.OEt
2
induced addition of bis-TMS acetyllene to 2-trifluoromethyl oxazolines
+
6.23
TMS TMS
6.22
F
3
C
N
H
TMS
6.24
O
H
N
F
3
C
Ph
BF
3.
OEt
2
DCM,
Reflux, 4d
OH
Ph
6. Addition of organozincs or organoceriums to preformed α-alkynyl imines
+
N
R
3
R
1
R
2
N
H R
3
6.25 6.26 6.10
R
2
R
1
-M
M: CeCl
2
or ZnR'
7. Addition of alkynylithiums to preformed 1-(dialkylaminomethyl) benzotriazoles
+
R
4
R
1
N
R
2
R
3
6.27 6.18
R
1
Li
6.11 N
N
N
R
4
N
R
3
R
2
THF
-78
o
C
THF
-100
o
C

265
Table 6.1(…continued)
Transformation

8. N,N aminals and N,O acetals in the synthesis of propargyl amines
R
1
+
N
R
3
R
4
R
4
R
1
N
R
2
R
3
6.28 6.29 6.18
X: NR
2
R
3
, cat: ZnI
X: OR, cat: InBr
3
-Et
3
N
9. Addition of alkynylorganometallics to in situ formed acyl iminiums
R
1
M
+
R
2
R
1
N
R
3
6.30 6.9 6.32
10. Cu
I
catalyzed addition of alkynes to enamines
+
6.32
R
4
O
R
1
6.29 6.33
11. Metal catalyzed 3C-MC synthesis of propargyl amines
12. Cu
I
catalyzed synthesis of propargyl amines through sp3 C-H activation
X
R
2
cat.
R
2
N
R
3
+
R
4
O
Cl
6.31
M: Cu, Zn
R
2
R
6
N
R
5
R
3
R
4
CuCl
Benzene,
100
o
C
R
1
N
R
3
R
4
R
2
R
6
R
5
+
6.34
Non enolizable
R
1
6.29
R
2
R
1
N
R
2
R
3
6.18
O
R
2
+
R
3
N
H
R
4
1-5% cat.
6.35
cat.: CuBr or AuCl or AuBr
3
or AgI
R
1
6.29
R
2
R
1
N
6.37
+
N
5% CuBr
6.36
R
2
t-BuOOH
100
o
C, 3hr
decane

266
6.2 Results and discussion
6.2.1 An alternative approach to propargyl amines. Reactivity of alkynyl
boron derivatives in the Petasis Reaction
Even though several approaches towards propargylic amines have been
developed, the field is still active due to the limitations of the existing methods. A
common drawback is the fact that even in the case where mild organometallics are
employed the lack of compatibility with many functional groups limits the generality
and versatility of these methods. Furthermore upon reviewing the chemistry
employed in the methodologies above we run into a major limitation which is the
types of alkynes employed. In most of the studies phenylacetylene and TMS-
acetylene were used while there is significant lack of data for functionalized alkynes.
As a consequence, the resulting scaffolds need to undergo multistep transformations
in order to accommodate functionality and be synthetically valuable.
Inspired by the mild conditions employed in the Petasis Reaction and the fact
that some data on alkynyl boron derivatives exist in the literature we attempted to
apply this type of chemistry and develop an alternative methodology towards
propargylic amines in the hope that this approach would allow for accommodation of
functional groups leading to multifuctionalized scaffolds through a one-pot
multicomponent process.

267
While composing this dissertation and performing a more recent literature
search, we run into an article mentioning the preparation of chiral propargyl amides
by utilizing chiral binapthol alkynyl boronates. This is a two-component process that
concerns the reaction of preformed N-acyl imines with the corresponding boronate
derived for 1-octyne (Scheme 6.2).
85

.
R
1
N Me
O
Ph
O
O
Ph
B R
2
+
-78
o
C to RT,
DCM, 24hr
R
1
HN
R
2
Me
O
6.38 6.39 6.40
R
1
= Ar, or PhCH=CR- R
2
= Ph, or n-C
6
H
13
-

Scheme 6.2: two-component-process for synthesizing propargyl amides by utilizing chiral binapthol
octyl boronates
6.2.1.1 Synthesis of methoxy alkynyl diisopropyl boronate
Alkynyl boron derivatives are usually synthesized by displacement of alkynyl
Grignard
86,87
or alkynylithium
88
reagents with borate esters (Scheme 6.3).
R
1
M
M: Li or MgBr
B(OR
2
)
3
+ R
1
B
OR
2
OR
2
dryTHFor dryEt
2
O,
-78
o
C to RT
HCl(anhydrous)/Et
2
O,
-78oC to RT
6.8 6.41 6.42
R
2
: alkyl

Scheme 6.3: Synthesis of alkynyl boronates from alkynyl organometallics

268
A slightly different, more recent preparation concerns the transesterification
of alkynyldiaminoboranes with silyl protected diols under strict anhydrous acidic
conditions (Scheme 6.4),
89
catechols or binapthols.
90

+ R
1
B
HCl(anhydrous)/Et
2
O,
6.44 6.45
R
1
B
NiPr
2
NiPr
2
6.43
OSiMe
3
OSiMe
3
-80
o
C
O
O

Scheme 6.4: Alkynyl boronates from reaction of alkynyldiaminoboranes with TMS protected diols

The C-B linkage is stable in acidic or neutral conditions but hydrolyzes
readily in aqueous media or in the presence of oxygen nucleophiles such as
alcohols
.
91
Due to the labile character of the sp C-B bond no literature data is
available on the corresponding alkynyl boronic acids since the boronate precursors
decompose during hydrolysis.

+ OiPr B
6.46 6.47
R
1
B
OiPr
OiPr
6.42
OH
OH
O
O
R
1
6.29
++
iPrOH

Scheme 6.5: Decomposition of alkynyl boronates during transesterfication attempts

In our synthetic attempts to develop methodology towards substituted allenyl
boron derivatives 3-methoxy-propyne 4.7 was used as precursor of α-methoxy
allenyl boronate 4.10. The poor results obtained from utilizing the latter derivative in
the Petasis Reaction urged us to explore the use of the same starting material 4.7 in
the synthesis of a novel alkynyl boronate and the participation of the latter in the

269
Petasis Reaction for assembling the multifunctionalized products usually obtained by
the process.
This time, synthesizing the alkynyl boronate was not as erratic as the
corresponding allenyl derivative 4.10. Conversion of the 3-methoxy-propyne 4.7 to
the lithium organometallic by addition of a solution of n-BuLi in dry Et
2
O at -78
o
C
followed by addition of triisopropoxy borane 6.50 and addition of anhydrous HCl
yielded the corresponding boronate 6.51 in satisfactory yield and purity (Scheme
6.6).
MeO
4.7
1. n-BuLi, -78
o
C
abs. Et
2
O
MeO
6.51
B
O
O
2. B(OiPr)
3
6.50,
-78
o
C, abs. Et
2
O
3.HCl/abs. Et
2
O,
-78
o
C to RT

Scheme 6.6: The synthesis of 3-methoxy-prop-1-ynyl diisopropyl boronate 6.51

An attempt was performed to hydrolyze the in situ formed “ate” complex to
the corresponding boronic acid but the resulting residue did not contain the expected
product. Instead, only B(OH)
3
was detected since the corresponding alkyne is very
volatile. Furthermore, substitution of triisopropoxy borane with trimethoxy borane

gave a more complicated crude mixture while the expected boronate was not
detected.

270
6.2.1.2 One-step synthesis of propargyl amines by the Petasis Reaction.
Scope and limitations
Following the synthesis of the novel alkynyl boronate 6.51, we wished to
explore its reactivity towards the Petasis Reaction.
Our initial attempts concerned use of glyoxylic acid monohydrate 2.104 as
the oxo component in combination with morpholine 2.124 which is one of the best
amines for this process and constitutes a diagnostic tool for every new variation
attempted. Unfortunately, the expected product was not detected at all in the crude
1
H NMR, even after 12 hr at RT. Heating at 40
o
C in a sealed tube was also attempted
but this trial was unsuccessful as well. Based on the known sensitivity of alkynyl
boronates in the presence of H
2
O or other nucleophiles, we suspected possible
decomposition due to the presence of H
2
O in the monohydrate of glyoxylic acid so
we substituted it with ethyl glyoxalate 6.52. Once more the reaction failed to yield
the corresponding three-component product but in this case, an intermediate N, O
acetal 6.53 was isolated where the isoproxy group had intercepted the iminium salt
intermediate. From this observation we concluded that if the intermediate
tetracoordinate boron “ate” complex is actually formed, it preferentially delivers the
bulky isopropoxy group in order to effectively reduce the steric repulsions among the
four substituents. Since no mechanistic experiments were perfomed, we cannot
exclude the possibility of in situ decomposition of the boronate with concomitant

271
release of iPrOH which can trap the iminium intermediate or formation of other
types of intermediates that could deliver the isoproproxy group.

MeO
6.51
B
O
O
N
H
O
2.124
HO
OH
OH
O
OEt
O
O
+
2.104 6.52
OEt
N
O
6.53
O
O
NO REACTION
DCM, RT
12hr
dry Toluene,
RT, 12hr

Scheme 6.7: 3-methoxy-prop-1-ynyl diisopropyl boronate failed to yield the three-component product
when combined with glyoxylic acid monohydrate or ethyl glyoxalate

The next aldehyde we turned our attention to was glycolaldehyde dimer
2.144, in order to explore the possibility of synthesizing the corresponding β-amino
alcohols from the three-component proccess. In the trials performed we observed
lack of reactivity in combination with primary aliphatic amines (even in the presence
of 1 equivalent of acetic acid). Secondary amines were shown to participate in the
process. Aromatic amines also behaved very well yielding excellent conversions in
some cases.
Chiral amines were also tested to explore the degree of diastereoselectivity
that can be accomplished. From the results we concluded that even secondary amines
with a free hydroxyl group don’t yield the three-component product at all,
demonstrating once more that decomposition of the boronate is probably taking
place. As a consequence, amines such as (R)-(-)-N-benzyl-2-phenyl glycinol and
(1R, 2R)-(-)-pseudoephedrine which could potentially lead to high diastereocontrol
through boron complexation are not applicable for this version of the Petasis

272
Reaction. On the contrary, (R)-(+)-N-allyl-α-methyl benzyl amine 6.60 and (S)-(-)-
N-benzyl- α-methyl benzyl amine 6.58 gave the corresponding three-component
product but with low diastereoselectivity (22% and 28% respectively) as is usually
the case with this kind of chiral amines.
The use of chiral α-OH aldehydes was also tested. Aliphatic amines, (both
primary and secondary) failed to give the expected products both at ambient
temperature as well as after heating. From aromatic amines, only p-NO
2
aniline
2.180 was tested and gave excellent conversion but no diastereoselectivity was
observed. Thus, primary aromatic amines should be further explored since they
constitute possible amine component for this variation of the multicomponent
condensation. Secondary aromatic amines were not tested at this point but are
promising candidates for diastereocontrol since primary were proven reactive. In an
effort to check if the bulkiness of the chiral aldehyde affects the diastereoselectivity,
we employed p-NO
2
aniline in combination with D-arabinose. Even though the
conversion was excellent, there was no diastereoselectivity and both diastereomers
were present in equal amounts in the crude
1
H NMR. The successful attempts for this
version of the Petasis Reaction are summarized in Table 6.2

273
Table 6.2: 3-methoxy-prop-1-ynyl diisopropyl boronate in the Petasis Reaction
Entry Boronic Acid
component
Carbonyl
component
Amine
component
Product Yield
(de) %

65
a
1 OH
N
2
95
b
3
96
b
4
60(28)
b 5
6.54
Ph N
H
Ph
52(22)
b
6
Me
6.51 2.144 2.124
2.121
2.182
6.58
O
O OH
HO
MeO
B(OiPr)
2
6.51 2.144
O
O OH
HO
MeO
B(OiPr)
2
6.51 2.144
O
O OH
HO
MeO
B(OiPr)
2
6.51 2.144
O
O OH
HO
MeO
B(OiPr)
2
6.51 2.144
O
O OH
HO
MeO
B(OiPr)
2
6.51 2.144
O
O OH
HO
MeO
B(OiPr)
2
MeO
47
a
59
b
7
97
b 8
2.114
2.180
6.51 2.144
O
O OH
HO
MeO
B(OiPr)
2
6.51 2.144
O
O OH
HO
MeO
B(OiPr)
2
Ph N
H
Ph
N
H
O
O
OH
N
6.55
MeO
Ph Ph
OH
N
6.56
MeO
2.122
N
H
OH
N
6.57
MeO
Ph
Ph
OH
N
6.59 MeO
Ph Ph
Ph
N
H
Ph
Me
N
H
Ph
Me
6.60
OH
N
6.61
MeO
Ph
Me
NH
2
MeO
NH
2
O
2
N
OH
HN
6.62
MeO
OH
HN
6.63
MeO
OMe
NO
2
58
a
49b

274
Table 6.2: (…continued)
Entry Boronic Acid
component
Carbonyl
component
Amine
component
Product Yield
(de) %

98
b 9
2.180 6.51 2.144
O
O OH
HO
MeO
B(OiPr)
2
NH
2
O
2
N
xs
10
2.180 6.51 2.144
MeO
B(OiPr)
2
NH
2
O
2
N
OH
O
OH
OH
N
6.64 MeO
89(0)
b
HN
6.65
MeO
HO
OH
NO
2
OH
OH
NO
2

a: RT, b: 70
o
C

Summarizing our observations, we can conclude that there is potential for
utilizing alkynyl boronates in the Petasis Reaction. The process does not show the
generality observed with other boronic acids but with the right choice of amine
components, the process can be of significant synthetic value, since the use of
cleavable amines can give a synthetic route to many structurally variable synthons.
Furthemore, the role of secondary amines in obtaining improved
diastereoselectivity/enantioselectivity in the case of chiral α-OH aldehydes and
sugars is one of the first things that should be explored. As has been observed in the
case of different boron components, high diastereoselectivity has been obtained with
certain secondary amines when combined with sugars or glyceraldehydes dimer and
this might be applicable in the case of alkynyl boronates as well.

275
6.3 Experimental
6.3.1 General
All the reactions were performed at ambient temperature under N
2
. The
solvents were used without further purification and no dry conditions were necessary
unless otherwise stated. The reactions were monitored by TLC on Silica Gel 60
precoated plates with F
254
indicator. The product was purified by flash
chromatography on Silica 60 Å 32-63 µm unless otherwise stated.
1
H and
13
C NMR
were recorded on a Bruker AMX500 or an AM360 MHz, or an AC250 MHz or a
Varian Mercury 400 NMR. Chemical shifts of
1
H NMR are reported in parts per
million on the δ scale from an internal standard of either residual chloroform (7.24
ppm), DMSO d
6
(2.49 ppm), acetone d
6
(2.04 ppm) or partly deuterated MeOH (3.3
ppm). Data are reported as follows: chemical shift, multiplicity (s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet and br=broad), coupling constants in Hz
and integration. Chemical shifts of
13
C NMR are reported in ppm from the central
peak of either CDCl
3
(77.0 ppm), DMSO d
6
(39.5 ppm) or partly deuterated MeOH
(49.5 ppm).

276
6.3.2 Synthesis and physical data

B
O
O
O
6.51

3-methoxy-prop-1-ynyl diisopropyl boronate (6.51). Dry and inert
conditions were applied. In a flame-dried 250ml round bottomed flask containing a
magnetic stirrer that was set under Argon, 5 ml of 3-methoxy-propyne (57.3mmol)
4.7 and 60 ml of dry Et
2
O were put. The system was cooled to -78
o
C and BuLi (1.6
M in Hexanes, 36 ml, 57.3mmol) was slowly added through a syringe at that
temperature (addition time: 20min). The system was left under stirring at -78
o
C for
an additional 10min.
In another flame-dried 250ml round bottomed flask containing a magnetic
stirrer that was set under Argon, 13.2 ml of triisopropoxy borane (57.3mmol) 6.50
and 60 ml of dry Et
2
O were put. The system was cooled to -78
o
C. To that was added
through syringe the solution of the organolithium compound, in 10ml portions. The
addition was completed after 50min and the system was allowed to stir at -78
o
C for
2hr. The boronate “ate” complex was subjected to slow addition (~1hr addition time)
of anhydrous HCl (1M in Et
2
O, 57.3 ml, 57.3mmol) to free the boronate at -78
o
C
and subsequently the reaction mixture was allowed to stir for additional 1hr and

277
warm up to ambient temperature. The precipitated salt (LiCl) was removed by
sunction filtration. The filtrate was concentrated under reduced pressure (bath
temperature up to 45
o
C) and finally dried under high vacuum until no weight change
was observed. Yield: 5.026g or 44%.
1
H NMR (250 MHz, CDCl
3
) δ 4.54 (m, 2H), 4.13 (s, 2H), 3.37 (s, 3H)
,
1.17
(d, J=6.2 Hz).
13
C NMR (90 Mz, CDCl
3
) δ 67.58, 59.99, 57.39, 24.16

OH
N
MeO
Ph Ph
6.55

2-dibenzylamino-5-methoxy-pent-3-yn-1-ol (6.55). In a 10-ml round
bottomed flask equipped with a magnetic stirrer, 3 ml of DCM were placed followed
by glycolaldehyde dimer 2.144 (0.055 g, 0.46 mmol) and dibenzylamine 2.121
(0.081 g, 0.76 mmol). To that mixture, 3-methoxy-prop-1-ynyl diisopropyl boronate
6.51 (0.150 g, 0.76mmol) was added in one portion. The system was left under
stirring at R.T. for 24 hr. At that time, 150 ml of DCM was added to the crude
reaction mixture and the organic phase was washed 3 times with aqueous NaOH, 3N
and once with water. The organic phase was collected, dried with MgSO
4
, the
solvent was removed under reduced pressure and the product was dried under high
vacuum. Yield: 0.136g or 58%.

278
1
H NMR (500 MHz, CDCl
3
) δ 7.29-7.21 (m, 8H), 7.18 (m, 2H), 4.14 (d,
J=1.3 Hz, 2H), 3.81 (d, J=13.9 Hz, 2H), 3.65 (m, 1H), 3.57 (t, J=10.6 Hz, 1H), 3.47
(dd, J
1
=10.5 Hz, J
2
=5.1 Hz, 1H), 3.42-3.34 (overlapping d&s, 5H) 2.67 (b, 1H).
13
C
NMR (125 MHz, MeOH d
4
) δ 138.50, 128.96, 128.52, 127.37, 82.62, 80.61, 61.52,
59.93, 57.61, 57.59, 54.86, 53.39.

OH
N
MeO
O
6.54

5-Methoxy-2-morpholin-4-yl-pent-3-yn-1-ol (6.54). The same conditions
and procedure were applied as for 6.55. This experiment was performed in 0.5mmol
scale. Flash chromatography was needed for complete purification (gradient elution,
MeOH/DCM, 1% to final 2%) Yield 0.065g or 65%
1
H NMR (500 MHz, CDCl
3
) δ 4.06 (s, 2H), 3.75-3.61 (m, 4H), 3.58-3.47 (m,
3H), 3.31 (s, 3H), 2.99 (s, 1H), 2.64 (m, 2H), 2.45 (m, 2H).
13
C NMR (125 MHz,
CDCl
3
) δ 83.34, 79.84, 60.59, 59.63, 58.65, 57.47, 57.45, 49.18

279
N
OH
MeO
6.56

2-diallylamino-5-methoxy-pent-3-yn-1-ol (6.56). In a 10-ml round
bottomed flask equipped with a magnetic stirrer, 5 ml dry toluene were placed
followed by glycolaldehyde dimer 2.144 (0.036 g, 0.3 mmol) and diallylamine 2.122
(0.049 g, 0.50 mmol). The mixture was heated to 70
o
C for 1min and then, 3-
methoxy-prop-1-ynyl diisopropyl boronate 6.51 (0.100 g, 0.50mmol) was added in
one portion. The system was left under stirring at 70
o
C for 17 hr. At that time, 100
ml of EtOAc was added to the crude reaction mixture and the organic phase was
washed with aqueous NaOH, 3N (3x50ml), H
2
O (1x50ml) and brine (1x20ml). The
organic phase was collected, dried with MgSO
4
, the solvent was removed under
reduced pressure and the product was dried under high vacuum. Yield: 0.099g or
95%.
1
H NMR (500 MHz, CDCl
3
) δ 5.76 (m, 2H), 5.16 (m, 4H), 4.10 (s, 2H), 3.79
(m, 1H), 3.54 (m, 2H), 3.35 (s, 3H), 3.31 (m, 2H), 2.92 (dd, J
1
=13.9 Hz, J
2
=7.9 Hz,
2H).
13
C NMR (90 MHz, CDCl
3
) δ 135.59, 117.88, 82.14, 80.91, 61.42, 59.78,
57.43, 53.58, 53.47

280
OH
NH
MeO
MeO
6.62

5-Methoxy-2-(4-methoxy-phenylamino)-pent-3-yn-1-ol (6.62). In a 10-ml
round bottomed flask equipped with a magnetic stirrer, 5 ml dry toluene was placed
followed by glycolaldehyde dimer 2.144 (0.036 g, 0.3 mmol) and p-anisidine 2.114
(0.061 g, 0.50 mmol). The mixture was heated to 70
o
C for 1min and then, 3-
methoxy-prop-1-ynyl diisopropyl boronate 6.51 (0.100 g, 0.50mmol) was added in
one portion. The system was left under stirring at 70
o
C for 3 hr. At that time, 100 ml
of EtOAc was added to the crude reaction mixture and the organic phase was washed
with aqueous NaOH, 3N (3x50ml), H
2
O (1x50ml) and brine (1x20ml). The organic
phase was collected, dried with MgSO
4
, the solvent was removed under reduced
pressure and the residue was further purified with gradient flash chromatography
(MeOH/DCM, 1% to final 2%). Yield: 0.069g or 59%.
1
H (500 MHz, CDCl
3
) δ 6.77 (d, J=9.1 Hz, 2H), 6.71 (d, J=9.0 Hz, 2H), 4.13
(m, 1H), 4.02 (d, J=1.4 Hz, 2H), 3.78 (dd, J
1
=11.1 Hz, J
2
=4.1 Hz, 1H), 3.75 (dd,
J
1
=11.6 Hz, J
2
=7.0 Hz, 1H), 3.72 (s, 3H), 3.26 (s, 3H).
13
C NMR (90 MHz, CDCl
3
) δ
153.35, 140.20, 116.59, 114.64, 84.57, 79.90, 64.86, 59.80, 57.47, 55.59, 49.51.

281
OH
NH
MeO
O
2
N
6.63

5-Methoxy-2-(4-nitro-phenylamino)-pent-3-yn-1-ol (6.63). In a 10-ml
round bottomed flask equipped with a magnetic stirrer, 5 ml dry toluene was placed
followed by glycolaldehyde dimer 2.144 (0.030 g, 0.25 mmol) and p-nitroaniline
2.180 (0.069 g, 0.50 mmol). The mixture was heated to 80
o
C for 1min and then, 3-
methoxy-prop-1-ynyl diisopropyl boronate 6.51 (0.100 g, 0.50mmol) was added in
one portion. The system was left under stirring at 80
o
C for 24 hr. At that time, 100
ml of EtOAc was added to the crude reaction mixture and the organic phase was
washed with aqueous NaOH, 3N (3x50ml), H
2
O (1x50ml) and brine (1x20ml). The
organic phase was collected, dried with MgSO
4
, the solvent was removed under
reduced pressure and the residue was further purified with gradient flash
chromatography (MeOH/DCM, 1% to final 2%). Yield: 0.112g or 90%.
1
H NMR (250 MHz, CDCl
3
) δ 8.08 (d, J=9.3 Hz, 2H), 6.65 (d, J=10 Hz, 2H),
4.33 (m, 1H), 4.06 (d, J=1.8 Hz, 2H), 3.90 (dd, J
1
=4.9 Hz, J
2
=1.7 Hz, 2H), 3.30 (s,
3H).
13
C NMR (62 MHz, CDCl
3
) δ 151.77, 139.07, 126.14, 112.46, 82.69, 80.64,
64.58, 59.78, 57.82, 47.21.

282
OH
N
MeO
O
2
N
6.64
OH
OH

(1-[(1-Hydroxymethyl-4-methoxy-but-2-ynyl)-(4-nitro-phenyl)-amino]-
ethane-1,2-diol (6.64). In a 10-ml round bottomed flask equipped with a magnetic
stirrer, 5 ml dry toluene was placed followed by glycolaldehyde dimer 2.144 (0.060
g, 0.50 mmol) and p-nitroaniline 2.180 (0.069 g, 0.50 mmol). The mixture was
heated to 70
o
C for 1min and then, 3-methoxy-prop-1-ynyl diisopropyl boronate 6.51
(0.100 g, 0.50mmol) was added in one portion. The system was left under stirring at
70
o
C for 3 hr. At that time, 100 ml of EtOAc was added to the crude reaction mixture
and the organic phase was washed with aqueous NaOH, 3N (3x50ml), H
2
O (1x50ml)
and brine (1x20ml). The organic phase was collected, dried with MgSO
4
, the solvent
was removed under reduced pressure and the residue was further purified with
gradient flash chromatography (MeOH/DCM, 1% to final 2%). Yield: 0.106g or
76%.
1
H NMR (250 MHz, CDCl
3
) δ 8.11 (d, J=9.2 Hz, 2H), 6.73 (d, J=9.7 Hz,
2H), 5.35 (t, J=3.7 Hz, 1H), 4.54 (m, 1H), 4.39-4.21 (m, 2H), 4.09 (d, J=1.8 Hz, 2H),
3.81 (m, 2H), 3.33 (s, 3H), 2.21 (b, 1H).
13
C NMR (62 MHz, CDCl
3
) δ 148.93,
139.17, 125.97, 111.98, 91.14, 82.47, 81.29, 71.14, 61.98, 59.73, 57.82, 49.84.

283
OH
N
MeO
Ph
Ph
6.57

2-(benzyl-phenyl-amino)-5-methoxy-pent-3-yn-1-ol (6.57). In a 10-ml
round bottomed flask equipped with a magnetic stirrer, 5 ml dry toluene was placed
followed by glycolaldehyde dimer 2.144 (0.036 g, 0.30 mmol) and N-phenyl
benzylamine 2.182 (0.092 g, 0.50 mmol). The mixture was heated to 70
o
C for 1min
and then, 3-methoxy-prop-1-ynyl diisopropyl boronate 6.51 (0.100 g, 0.50mmol)
was added in one portion. The system was left under stirring at 70
o
C for 20 hr. At
that time, 100 ml of EtOAc was added to the crude reaction mixture and the organic
phase was washed with aqueous NaOH, 3N (3x50ml), H
2
O (1x20ml) and brine
(1x20ml). The organic phase was collected, dried with MgSO
4
, the solvent was
removed under reduced pressure and the product was dried under high vacuum.
Yield: 0.141g or 96%.
1
H NMR (250 MHz, CDCl
3
) δ 7.28-7.10 (m, 7H), 6.90 (d, J=7.7 Hz, 2H),
6.78 (t, J=7.0 Hz, 1H), 4.62 (t, J=6.5 Hz, 1H), 4.44 (s, 2H), 4.01 (d, J=1.8Hz, 2H),
3.62 (d, J=7.2 Hz, 2H), 3.22 (s, 3H), 2.12 (bs, 1H).
13
C NMR (125 MHz, CDCl
3
) δ
149.17, 139.45, 129.07, 128.64, 127.05, 126.90, 120.13, 117.00, 82.34, 82.09, 63.18,
59.82, 57.56, 55.31, 52.86.

284
OH
N
MeO
Ph
6.61
Me

2-[allyl-(1-phenyl-ethyl)-amino]-5-methoxy-pent-3-yn-1-ol (6.61).
In a 10-ml round bottomed flask equipped with a magnetic stirrer, 5 ml dry
toluene was placed followed by glycolaldehyde dimer 2.144 (0.036 g, 0.30 mmol)
and (R)-(+)-N-allyl- α-methylbenzyl amine 6.60 (0.080 g, 0.50 mmol). The mixture
was heated to 70
o
C for 1min and then, 3-methoxy-prop-1-ynyl diisopropyl boronate
6.51 (0.100 g, 0.50mmol) was added in one portion. The system was left under
stirring at 70
o
C for 27 hr.
1
H NMR spectrum was run from the crude homogeneous
reaction mixture that showed de=22% (from comparison of the integrals of the
signals at 3.8 ppm-minor and 3.61-major). The reaction mixture was purified by
flash chromatography (elution with 1% MeOH/DCM). The main diastereomer was
eluted pure in some flash tubes (NMR mentioned below) while the minor was eluted
with the residual amount of the main. Yield: 0.071g or 52%.
1
H NMR (250 MHz, CDCl
3
-major diastereomer only) δ 7.34-7.23 (m, 5H),
5.88 (m, 1H), 5.28-5.14 (m, 2H), 4.12 (s, 2H), 3.62 (t, J=8.2 Hz, 1H), 3.50-3.19
(s&m, 8H-overlapping signals), 2.52 (bd, 1H), 1.46 (d, J=6.9 Hz, 3H).
13
C NMR (62
MHz, CDCl
3
) δ 143.45, 136.96, 128.42, 127.78, 127.24, 117.63, 83.26, 82.15, 61.97,
59.93, 57.54, 57.31, 50.13, 13.43

285
OH
N
MeO
Ph Ph
6.59
Me

2-[benzyl-(1-phenyl-ethyl)-amino]-5-methoxy-pent-3-yn-1-ol (6.59). In a
10-ml round bottomed flask equipped with a magnetic stirrer, 5 ml dry toluene was
placed followed by glycolaldehyde dimer 2.144 (0.036 g, 0.30 mmol) and (S)-(-)-N-
benzyl- α-methylbenzyl amine 6.58 (0.106 g, 0.50 mmol). The mixture was heated to
70
o
C for 1min and then, 3-methoxy-prop-1-ynyl diisopropyl boronate 6.51 (0.100 g,
0.50mmol) was added in one portion. The system was left under stirring at 70
o
C for
9 hr.
1
H NMR spectrum was run from the crude homogeneous reaction mixture that
showed de=27% (from comparison of the integrals of the signals at 3.40 ppm-major
and 3.27 ppm-minor). The reaction mixture was purified by gradient flash
chromatography (elution with EtOAc/Hexanes, 15% to 20%). No complete
separation of the two diastereomers was feasible. Some flash tubes were enriched
with the main diastereomer (NMR mentioned below) while the minor was eluted
with the residual amount of the main. Yield: 0.097g or 60%.
1
H NMR (250 MHz, CDCl
3
) δ 7.26-7.06 (m, 10H), 4.06 (d, J=1.7 Hz, 2H),
3.89 (m, 1H), 3.78 (d, J=13.7 Hz, 1H), 3.66 (d, J=13.5 Hz, 1H), 3.52 (m, 1H), 3.90-
3.21 (m&s, 4H-overlapping signals), 2.31 (b, 1H), 1.43 (d, J=7.0 Hz, 1H).
13
C NMR

286
(62 MHz, CDCl
3
) δ 143.06, 139.53, 129.14, 128.58, 128.42, 127.76, 127.36, 127.31,
83.33, 82.32, 62.10, 60.00, 57.60, 56.51, 51.22, 49.90, 12.11

NH
MeO
O
2
N
6.65
OH
OH

6-Methoxy-3-(4-nitro-phenylamino)-hex-4-yne-1,2-diol (6.65). In a 10-ml
round bottomed flask equipped with a magnetic stirrer, 5 ml dry toluene was placed
followed by DL-glyceraldehyde dimer 2.56 (0.054 g, 0.30 mmol) and p-nitroaniline
2.180 (0.069 g, 0.50 mmol). The mixture was heated to 70
o
C for 1min and then, 3-
methoxy-prop-1-ynyl diisopropyl boronate 6.51 (0.100 g, 0.50mmol) was added in
one portion. The reaction was heated at 70
o
C for 26hr. At that time the reaction was
stopped and MeOH was added and evaporated under reduced pressure (5x20ml) in
order to completely remove the byproduct B(OH)
3
.
1
H NMR spectrum was run from
the crude homogeneous reaction mixture that showed the presence of both
diastereomers in about 1:1 ratio (no diastereoselectivity). The reaction mixture was
purified by gradient flash chromatography (elution with MeOH/DCM, 2% to 5%).
Both diastereomers were eluted together. Yield: 0.097g or 60%.The residue was
further purified with gradient flash chromatography (MeOH/DCM, 1% to final 2%).
Yield: 0.125g or 89%.

287
1
H NMR (250 MHz, MeOH d
4
) δ 8.04 (d, J=9.2 Hz, 2H), 6.76 (d, J=9.5 Hz,
2H), 4.54 (m, 0.55H-major) & 4.46 (dt, J
1
=6.0 Hz, J
2
=1.6 Hz, 0.43H-minor), 4.09
(m, 2H), 3.86 (m, 1H), 3.78-3.69 (m, 2H), 3.30 (s, 3H).
13
C NMR (62 MHz, MeOH
d
4
) δ 155.28 (major) & 154.78 (minor), 139.58 (minor) & 139.52 (major), 127.45 &
127.40, 113.59, 85.50 (major) & 84.39 (minor), 81.83 (major) & 81.34 (minor),
75.15 (major) & 74.38 (minor), 64.67 (minor) & 64.51 (major), 61.02 (minor) &
60.98 (major), 58.20, 49.15 (minor) & 48.92 (major)

288
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317
Appendix- Selected Spectra

BF
3
K
•
2.178
4.4 7 3
3.9 4 8
10 8 6 4 2 PPM
209.847
65.521
200 150 100 50 0 PPM
1
H NMR, 360 MHz, DMSO d
6

13
C NMR, 90 MHz, DMSO d
6

318

BF
3
K
•
2.178
19
F NMR, 376MHz, DMSO d
6

32.0 -132.5 -133.0 -133.5 -134.0 -134.5 -135.0 -135.5PPM
-133.557
-133.684
-133.809
-133.958
0 -50 -100 -150 PPM

319

O
-
NH
3
O
2.143a
1
H NMR, 250 MHz, MeOH d
4

13
C NMR, 63 MHz, MeOH d
4

4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 PPM
4 .2 1 5
4 .1 9 5
4 .1 7 3
2 .9 4 3
2 .9 3 2
2 .9 2 3
2 .9 1 2
2 .6 5 7
2 .6 4 5
2 .6 3 6
10 8 6 4 2 0 PPM
170.558
77.560
75.598
52.980
21.724
200 150 100 50 PPM

320

OH
N
H
O
2.115a
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4
169.917
132.274
131.985
131.347
130.755
77.437
75.842
59.089
59.059
52.048
52.015
20.928
200 150 100 50 0 PPM
4.5 4.0 3.5 3.0 PPM
7.563
7.556
7.549
7.544
7.458
7.452
7.446
5.575
4.346
4.204
4.193
4.183
3.043
3.039
3.034
3.029
2.667
10 8 6 4 2 0 -2 PPM

321

1
H NMR, 500 MHz, MeOH d
4
13
C NMR, 125 MHz, MeOH
d
4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 PPM
5.7 5.6 5.5 5.4 5.3 5.2 5.1PPM
5.959
5.699
5.685
5.669
5.492
5.479
5.474
5.466
5.461
5.448
5.153
5.139
5.138
5.127
5.114
5.101
5.088
5.076
5.063
4.111
4.092
3.889
3.878
3.866
3.124
3.118
3.114
3.108
3.089
3.083
3.079
3 073
10 8 6 4 2 0 -2 PPM
OH
N
H
O
2.116a
Ph
Ph
OH
N
H
O
2.116b
Ph
Ph
•
and
212.914
169.751
169.572
137.064
136.952
136.402
136.171
131.141
130.999
130.953
130.925
130.860
129.964
129.859
129.810
129.708
129.492
129.460
84.003
79.995
77.486
75.688
67.733
66.101
59.916
59.155
21.267
200 150 100 50 PPM

322

OH
N
H
O
2.117a
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

3.8 3.6 3.4 3.2 3.0 2.8 2.6 PPM
5.994
5.979
5.973
5.966
5.960
5.946
5.940
5.932
5.925
5.912
5.538
5.503
5.474
5.454
4.918
3.770
3.756
3.743
3.730
3.716
3.704
3.690
3.641
3.631
3.620
2.881
2.876
2.871
2.866
2.585
2.579
2.575
10 8 6 4 2 0 PPM
171.968
130.037
124.677
79.062
74.831
60.830
50.620
21.424
200 150 100 50 PPM

323

2.119a
N
H
OH
O
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

156.201
79.492
73.259
55.241
52.212
43.239
41.304
39.942
39.886
37.135
36.325
36.283
36.109
30.566
30.290
30.068
150 100 50 0 PPM
4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 PPM
7.690
4.930
4.650
3.761
3.752
3.748
3.738
3.339
3.300
2.755
2.747
2.731
2.717
2.520
2.155
2.116
1.965
1.942
1.860
1.834
1.795
1.769
10 8 6 4 2 0 PPM

324

2.118a
N
H
O
OH
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 PPM
4 .213
4 .201
4 .188
3 .049
3 .044
3 .037
3 .032
2 .920
2 .896
2 .822
2 .797
2 .692
2 .687
2 .035
1 .806
1 .782
1 .739
1 .714
1 .681
1 .656
12 10 8 6 4 2 0 PPM
169.902
78.104
75.488
60.175
59.578
50.012
49.942
49.842
49.813
49.672
49.634
49.500
49.468
49.322
49.302
49.160
49.121
48.987
40.933
37.881
33.972
200 150 100 50 PPM

325

OH
N
H
O
OH
N
H
O
•
2.181a 2.181b
NO
2
NO
2
and
1
H NMR, 250 MHz, MeOH d
4

13
C NMR, 63 MHz, MeOH d
4

5.5 5.0 4.5 4.0 3.5 3.0 2.5 PPM
8.030
7.993
6.698
6.686
6.649
6.623
6.615
5.406
5.381
4.931
4.911
4.900
4.883
4.865
4.855
4.834
4.828
4.823
4.809
4.796
4.410
4.110
4.086
4.064
2.833
2.822
2.786
2.776
2.765
2.753
2.740
2.725
2.714
2.684
2.674
2.658
2.647
2.307
2.297
2.286
10 8 6 4 2 0 PPM
210.132
177.581
155.406
154.954
138.900
127.645
127.529
113.311
113.032
91.712
81.715
78.835
72.365
58.511
23.955
200 150 100 50 PPM

326

•
N
OH
O
2.127b
Ph
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 PPM
7.571
7.564
7.561
7.557
7.552
7.472
7.466
7.460
5.426
5.413
5.406
5.400
5.393
5.380
5.101
5.088
4.838
4.347
4.322
4.235
4.209
4.129
4.110
2.716
10 8 6 4 2 0 PPM
214.361
171.205
132.501
132.134
131.495
130.767
84.211
78.037
70.894
59.647
38.805
200 150 100 50 PPM

327

OH
N
O
2.127a
Ph
1
H NMR, 250 MHz, MeOH d
4

13
C NMR, 63 MHz, MeOH d
4

4.5 4.0 3.5 3.0 PPM
7 .579
7 .564
7 .558
7 .549
7 .539
7 .492
7 .485
7 .452
7 .436
7 .426
7 .410
4 .939
4 .456
4 .405
4 .333
4 .283
3 .777
3 .758
3 .748
3 .727
3 .084
3 .072
3 .064
3 .053
3 .011
3 .000
2 .991
2 .981
2 .963
2 .952
2 .934
2 .924
2 .891
2 .880
2 .862
2 .851
2 .824
2 .618
2 .607
2 .597
10 8 6 4 2 PPM
171.740
133.112
132.509
132.363
131.183
130.727
130.645
80.875
74.421
68.017
60.395
39.057
19.094
200 150 100 50 PPM

328

OH
N
O
2.125a
Ph Ph
1
H NMR, 250 MHz, MeOH d
4

13
C NMR, 63 MHz, MeOH d
4

3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4PPM
7.433
7.426
7.400
7.356
7.321
7.314
7.307
7.288
7.280
7.257
7.246
7.240
7.235
7.224
7.213
7.198
7.188
7.183
3.913
3.857
3.699
3.643
3.538
3.511
3.507
3.480
3.312
3.306
3.300
3.293
3.286
2.737
2.725
2.710
2.699
2.669
2.657
2.642
2.630
2.616
2.597
2.585
2.559
2.548
2.528
2.517
2.319
2.309
2.298
8 6 4 2 PPM
174.615
140.501
131.123
130.653
130.194
129.817
129.718
128.846
82.666
71.998
62.259
56.174
20.666
200 150 100 50 PPM

329

OH
N
O 2.128b
O
•
1
H NMR, 250 MHz, MeOH d
4

13
C NMR, 63 MHz, MeOH d
4

5.5 5.0 4.5 4.0 3.5 PPM
6.633
5.522
5.516
5.508
5.502
5.495
5.489
5.476
5.267
5.254
5.240
5.227
5.219
5.205
5.192
5.179
4.715
4.696
4.100
4.077
4.055
3.966
3.941
3.932
3.907
3.881
3.652
3.628
3.562
3.539
3.418
3.412
3.394
3.371
3.304
3.300
3.298
3.272
10 8 6 4 2 PPM
214.136
168.973
82.378
79.700
68.841
65.310
53.057
51.341
200 150 100 50 PPM

330

OH
N
O
2.128a
O
1
H NMR, 250 MHz, MeOH d
4

13
C NMR, 63 MHz, MeOH d
4

4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 PPM
4.879
3.854
3.834
3.816
3.565
3.542
3.518
3.143
3.128
3.111
3.095
2.918
2.907
2.894
2.882
2.846
2.837
2.822
2.814
2.805
2.791
2.780
2.745
2.734
2.721
2.710
2.504
2.492
2.483
8 6 4 2 PPM
172.428
80.570
73.753
69.925
66.803
52.362
19.769
200 150 100 50 PPM

331

OH
N
O
2.126b
•
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

6.0 5.5 5.0 4.5 4.0 PPM
6.009
5.995
5.988
5.975
5.960
5.954
5.946
5.941
5.927
5.528
5.510
5.492
5.380
5.366
5.360
5.353
5.347
5.334
5.035
5.022
4.944
4.171
4.151
3.827
3.813
3.799
3.787
3.637
3.621
3.611
3.595
8 6 4 2 PPM
213.703
172.252
130.016
125.704
84.776
77.782
67.568
55.249
50.008
49.839
49.670
49.500
49.330
49.161
48.991
200 150 100 50 0 PPM

332

OH
N
O
2.126a
1
H NMR, 250 MHz, MeOH d
4

13
C NMR, 63 MHz, MeOH d
4

6.0 5.5 5.0 4.5 4.0 3.5 3.0 PPM
6.055
6.028
6.014
6.000
5.987
5.960
5.946
5.932
5.919
5.892
5.537
5.531
5.474
5.462
5.437
4.927
3.864
3.842
3.835
3.813
3.786
3.763
3.758
3.729
3.701
3.002
2.992
2.981
2.970
2.930
2.919
2.908
2.897
2.870
2.860
2.841
2.830
2.797
2.787
2.770
2.759
2.562
2.551
2.540
10 8 6 4 2 0 PPM
172.117
131.438
124.561
80.847
74.062
64.570
55.812
19.149
200 150 100 50 PPM

333

OH
N
O
2.183a
Ph
Ph
1
H NMR, 250 MHz, MeOH d
4

5.0 4.5 4.0 3.5 3.0 2.5 2.0 PPM
7.402
7.373
7.301
7.256
7.251
7.245
7.223
7.218
7.193
7.156
7.138
7.127
7.116
7.099
7.091
7.083
7.071
7.062
7.056
7.034
7.026
7.017
6.811
6.780
6.644
6.616
6.588
4.651
4.628
4.617
4.594
2.902
2.892
2.879
2.869
2.834
2.824
2.812
2.800
2.709
2.698
2.675
2.664
2.641
2.630
2.606
2.597
2.257
2.247
2.236
10 8 6 4 2 0 PPM

334

OH
N
H
•
2.149b
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.0 4.5 4.0 3.5 PPM
7.3 1 7
7.3 0 6
7.2 4 0
5.0 9 6
5.0 7 9
4.8 5 2
4.8 5 0
4.8 4 7
4.8 4 4
4.8 3 4
4.8 2 9
3.9 3 8
3.9 0 6
3.7 2 2
3.6 8 9
3.6 3 1
3.6 1 6
3.6 0 6
3.3 7 1
3.3 5 0
3.3 2 4
8 6 4 2 0 PPM
208.074
139.913
128.400
128.221
127.083
90.041
76.940
64.809
57.600
51.097
200 150 100 50 PPM

335

OH
HN
•
N
2.155b
1
H NMR, 500 MHz, CDCl
3

13
C NMR, 125 MHz, CDCl
3

5.0 4.5 4.0 3.5 3.0 2.5 PPM
5.029
5.015
5.002
4.988
4.749
4.744
4.736
4.731
3.596
3.585
3.576
3.563
3.555
3.367
3.351
3.346
3.329
3.318
3.185
2.842
2.831
2.819
2.806
2.585
2.574
2.561
2.549
2.538
2.457
2.443
2.433
2.422
2.418
2.407
2.350
2.339
2.326
2.314
2.304
2.216
2.209
2.181
2.153
2.129
8 7 6 5 4 3 2 1 0 -1 PPM
208.087
90.109
76.343
64.783
59.105
58.714
45.205
44.116
200 150 100 50 0 PPM

336

OH
N
H
OH
N
H
•
2.157 2.156
OMe OMe
and
1
H NMR, 250 MHz, CDCl
3

5 4 3 2 PPM
5.179
5.155
4.844
4.834
4.822
4.817
4.806
4.797
4.561
3.978
3.968
3.955
3.951
3.827
3.820
3.818
3.813
3.808
3.799
3.791
3.777
3.765
3.757
3.750
3.744
3.732
3.700
3.637
3.612
3.600
3.594
3.579
3.568
3.557
3.534
2.525
2.515
2.476
2.465
2.458
2.452
2.446
2.441
2.044
2.033
2.022
8 6 4 2 PPM

337

•
N
OH
2.158b
1
H NMR, 500 MHz, CDCl
3

13
C NMR, 125 MHz, CDCl
3

5.0 4.5 4.0 3.5 3.0 PPM
7.270
7.254
7.240
7.236
7.223
7.196
7.183
7.170
5.080
5.067
4.770
4.768
4.756
4.738
4.726
3.794
3.769
3.552
3.528
3.425
3.412
3.369
3.343
2.860
8 6 4 2 PPM
20 9.42 8
13 8.87 4
12 9.01 2
12 8.45 2
12 7.24 1
83.679
75.326
60.952
58.204
53.642
200 150 100 50 PPM

338

•
N
OH
2.159b
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 63 MHz, CDCl
3

6.0 5.5 5.0 4.5 4.0 3.5 3.0 PPM
5.850
5.831
5.817
5.810
5.799
5.791
5.781
5.778
5.763
5.758
5.750
5.741
5.730
5.721
5.708
5.690
5.206
5.199
5.194
5.191
5.187
5.171
5.166
5.160
5.146
5.144
5.138
5.130
5.126
5.118
5.105
5.102
5.046
5.019
4.994
4.965
4.739
4.733
4.712
4.707
3.565
3.557
3.552
3.543
3.535
3.524
3.515
3.490
3.471
3.448
3.418
3.407
3.407
3.336
3.329
3.322
3.318
3.309
3.303
3.280
3.273
3.265
3262
8 6 4 2 PPM
209.113
135.826
117.802
84.009
75.288
60.790
58.786
52.493
200 150 100 50 PPM

339

•
N
OH
2.161b
O
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 63 MHz, CDCl
3

5.0 4.5 4.0 3.5 3.0 2.5 PPM
5.076
5.049
5.023
5.019
4.992
4.745
4.739
4.719
4.711
3.761
3.748
3.737
3.716
3.700
3.693
3.685
3.677
3.663
3.641
3.630
3.618
3.527
3.501
3.493
3.263
3.232
3.204
2.699
2.686
2.676
2.655
2.640
2.618
2.485
2.470
2.449
2.425
8 6 4 2 0 PPM
208.998
83.771
75.412
67.089
64.466
60.151
48.691
200 150 100 50 PPM

340

OH
HN
O 3.38
Ph
Me
1
H NMR, 500 MHz, MeOH d
4
& DCl
13
C NMR, 125 MHz, MeOH d
4
& DCl
4.5 4.0 3.5 3.0 2.5 2.0 PPM
7.5 8 7
7.5 8 4
7.5 7 2
7.5 6 9
7.5 4 2
7.5 3 8
7.5 2 6
7.5 2 3
7.4 9 5
7.4 8 9
7.4 7 8
7.4 6 4
7.4 5 7
7.4 4 2
7.4 1 8
7.3 4 0
7.3 1 5
5.9 1 3
4.6 4 0
4.6 2 5
4.6 1 2
4.5 9 9
4.5 8 5
4.5 7 0
4.5 5 7
4.0 1 2
4.0 0 0
3.9 9 0
3.6 5 7
3.6 4 7
3.6 3 7
3.3 3 9
3.3 0 7
3.3 0 4
3.3 0 0
3.2 9 8
3.2 9 3
3.0 0 1
2.9 9 7
2.9 9 1
2.9 8 5
2.9 3 4
2.9 2 9
2.9 2 4
2.9 1 9
2.9 1 4
2.9 0 8
2.6 5 0
2.6 4 5
2.6 4 2
2.6 3 7
2.6 3 2
1.7 7 5
1.7 6 1
1.7 4 3
1.7 2 8
1.7 1 4
8 6 4 2 PPM
169.764
137.377
137.154
131.509
131.335
131.169
130.891
129.744
129.721
77.344
75.728
75.696
60.438
60.342
58.528
58.013
21.545
21.150
20.537
19.984
200 150 100 50 PPM

341

OH
HN
O
COOH
Ph
3.41
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

4.5 4.0 3.5 3.0 PPM
7.369
7.366
7.352
7.339
7.332
7.315
7.297
7.284
5.243
4.433
4.417
4.405
4.263
4.253
4.243
3.440
3.427
3.411
3.398
3.338
3.323
3.306
3.303
3.300
3.297
3.279
3.032
3.029
3.025
3.022
2.685
2.680
10 8 6 4 2 0 -2 PPM
170.913
169.968
135.939
131.009
130.970
130.646
130.608
130.518
129.364
77.390
75.856
73.078
63.191
59.931
37.430
21.585
200 150 100 50 PPM

342

OH
HN
O
OH
Ph
3.39
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

4.5 4.0 3.5 3.0 2.5PPM
7.428
7.421
7.415
7.404
7.401
7.395
7.392
7.383
7.375
7.366
4.948
4.935
4.878
4.432
4.420
4.409
4.247
4.236
4.232
4.220
3.905
3.894
3.882
3.880
3.867
3.854
3.809
3.800
3.794
3.770
3.637
3.501
3.492
3.488
3.478
3.274
2.881
2.874
2.871
2.866
2.846
2.840
2.835
2.831
2.779
2.773
2.766
2.760
2.745
2.739
2.731
2.726
2.690
2.684
2.676
2.672
2.655
2.650
2.642
2.637
2.609
8 6 4 2 PPM
130.729
130.654
129.909
129.853
74.373
73.913
65.970
65.810
64.997
60.466
59.952
59.939
52.660
23.376
21.827
200 150 100 50 PPM

343

•
N
OH
O
COOH
3.43
1
H NMR, 500 MHz, MeOH d
4
& DCl
5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 PPM
5.924
5.591
5.586
5.572
5.558
5.539
5.526
5.224
5.211
5.193
5.179
5.166
5.153
4.971
4.951
4.862
4.842
4.606
4.597
4.589
4.579
4.503
4.493
4.486
4.475
3.872
3.788
3.780
3.506
3.493
3.338
3.300
3.148
3.142
3.139
2.603
2.588
2.578
2.561
2.474
2.462
2.444
2.277
2.247
2.239
2.224
2.213
2.201
12 10 8 6 4 2 0 PPM

344

OH
HN
OH
Ph
3.51
1
H NMR, 360 MHz, CDCl
3

13
C NMR, 90 MHz, CDCl
3

4.0 3.5 3.0 2.5 2.0 PPM
7.277
7.255
7.239
7.209
7.204
7.191
7.184
3.884
3.874
3.859
3.850
3.654
3.639
3.627
3.609
3.598
3.561
3.557
3.547
3.530
3.500
3.487
3.469
3.455
3.448
3.428
3.417
3.399
2.898
2.702
2.687
2.682
2.670
2.657
2.639
2.365
2.358
9 8 7 6 5 4 3 PPM
208.459
140.397
139.793
139.443
128.535
128.484
128.293
127.631
127.533
127.310
127.163
127.122
89.015
81.327
80.589
76.261
70.896
70.503
70.217
66.980
66.901
66.740
65.189
63.850
62.111
61.660
61.352
61.229
55.390
55.032
53.901
21.998
19.974
200 150 100 50 PPM

345

OH
HN COOH
Ph
3.52
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

4.5 4.0 3.5 3.0 PPM
7.357
7.342
7.330
7.299
7.285
4.566
4.554
4.551
4.539
3.910
3.902
3.686
3.660
3.476
3.455
3.432
3.419
3.408
3.391
3.380
3.280
3.264
3.252
3.235
2.738
2.727
2.723
2.574
8 6 4 2 PPM
171.128
135.898
130.945
130.448
129.274
79.003
74.440
61.817
61.799
60.306
59.826
37.645
20.174
200 150 100 50 PPM

346

OH
HN
Ph
COOH
3.53
1
H NMR, 500 MHz, MeOH d
4
& DCl
13
C NMR, 125 MHz, MeOH d
4
& DCl
4.0 3.5 3.0 2.5 PPM
7.565
7.551
7.509
7.475
5.484
4.093
4.079
3.956
3.932
3.919
3.910
3.895
3.886
3.381
3.371
3.363
2.817
2.782
2.772
2.754
2.738
2.720
2.708
2.593
2.561
10 8 6 4 2 0 -2 PPM
170.102
132.105
131.917
131.798
131.243
130.981
130.932
130.691
130.330
130.250
130.198
129.379
78.894
78.787
74.735
74.371
63.517
60.435
59.100
50.350
19.564
19.522
200 150 100 50 PPM

347

•
N
OH
Ph Ph
Me
3.54
1
H NMR, 250 MHz, CDCl
3

5.0 4.5 4.0 3.5 PPM
1.6 1.5 1.4 1.3 1.2 1.1 1.0 PPM
7.289
7.266
7.240
7.210
7.181
7.146
7.121
5.166
5.140
5.117
4.696
4.678
4.667
4.659
4.569
4.560
4.545
4.537
4.481
3.981
3.954
3.926
3.897
3.880
3.851
3.778
3.723
3.666
3.598
3.544
3.510
3.451
3.388
3.359
3.336
3.295
3.285
3.243
3.224
1.400
1.371
1.312
1.284
8 6 4 2 0 PPM

348

HN
OH
Ph
3.58
OH
1
H NMR, 360 MHz, CDCl
3

13
C NMR, 125 MHz, CDCl
3

3.5 3.0 2.5 2.0 PPM
7.281
7.276
7.266
7.262
7.258
7.255
7.245
7.240
7.230
7.226
7.222
7.216
7.209
7.202
7.196
7.192
7.180
7.176
7.169
4.681
3.894
3.859
3.841
3.807
3.745
3.735
3.713
3.705
3.673
3.662
3.655
3.639
3.634
3.629
3.619
3.609
3.602
3.594
3.583
3.573
3.550
3.542
2.825
2.812
2.809
2.795
2.779
2.762
2.565
2.557
2.546
2.540
2.517
2.508
2.505
2.499
2.491
2.481
2.474
2.465
2.418
2.411
9 8 7 6 5 4 3 2 1 PPM
139.272
139.196
128.587
128.566
128.243
127.410
127.353
80.347
80.170
71.254
71.204
71.012
70.634
65.237
64.332
58.723
57.369
51.403
51.138
51.107
51.086
19.666
19.417
200 150 100 50 PPM

349

NH
OH
3.59a
OH
OH
OH
Ph
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

4.0 3.5 3.0 2.5 PPM
7.363
7.347
7.314
7.299
7.284
7.241
7.226
7.213
4.860
3.918
3.892
3.845
3.841
3.839
3.829
3.826
3.788
3.782
3.766
3.759
3.670
3.663
3.658
3.652
3.642
3.635
3.627
3.616
3.605
3.595
2.992
2.982
2.976
2.972
2.966
2.956
2.672
2.666
2.661
2.656
2.637
2.632
2.628
2.621
2.612
2.607
2.601
2.596
2.578
2.572
2.567
2.562
2 341
8 6 4 2 PPM
129.995
129.944
128.644
82.342
73.996
72.530
72.496
72.070
65.611
59.402
52.947
52.920
21.041
200 150 100 50 PPM

350

NH
OH 3.59b OH
OH
OH
Ph
•
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

5.0 4.5 4.0 3.5 PPM
7.332
7.318
7.307
7.293
7.277
7.236
7.234
7.220
7.205
5.218
5.204
5.189
5.174
4.863
4.853
4.851
4.839
4.836
3.929
3.903
3.774
3.761
3.757
3.751
3.734
3.728
3.707
3.680
3.661
3.649
3.646
3.642
3.634
3.627
3.611
3.599
3.589
3.577
3.426
3.422
3.414
3.410
3.399
3.307
3.304
3.300
3.298
3.293
8 6 4 2 PPM
209.913
140.631
129.193
129.044
127.727
90.293
75.941
72.931
72.791
72.438
64.471
60.950
51.888
200 150 100 50 0 PPM

351

N
OH
Ph
3.60
OH
•
Ph
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 125 MHz, CDCl
3

5.0 4.5 4.0 3.5 PPM
7.318
7.315
7.308
7.300
7.289
7.269
7.258
7.251
7.240
5.283
5.255
5.247
5.230
5.221
5.194
4.948
4.942
4.921
4.916
4.903
4.898
4.876
4.871
4.864
4.861
4.838
4.835
4.820
4.816
4.794
4.790
3.874
3.854
3.835
3.818
3.797
3.764
3.732
3.686
3.668
3.403
3.349
3.296
3.260
3.223
8 6 4 2 PPM
210.343
138.683
129.023
128.840
128.493
127.332
83.806
75.010
71.174
65.334
61.673
54.799
200 150 100 50 0 PPM

352

3.61
N
OH OH
OH
OH
Ph
Ph
•
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

5.0 4.5 4.0 3.5 PPM
7.364
7.349
7.291
7.275
7.261
7.210
7.195
7.180
5.270
5.256
5.250
5.243
5.238
5.225
4.866
4.847
4.832
4.786
4.773
4.765
4.751
4.053
4.048
4.038
4.031
3.786
3.760
3.744
3.738
3.721
3.715
3.614
3.602
3.591
3.580
3.568
3.561
3.557
3.552
3.546
3.541
3.535
3.456
3.437
3.417
3.390
8 6 4 2 PPM
212.278
141.167
130.749
129.780
128.534
86.196
74.971
73.532
72.023
65.498
61.843
55.940
200 150 100 50 0 PPM

353

3.62
N
OH
OH
•
1
H NMR, 500 MHz, CDCl
3

13
C NMR, 125 MHz, CDCl
3

6.0 5.5 5.0 4.5 4.0 3.5 3.0 PPM
7.240
5.795
5.786
5.779
5.775
5.769
5.766
5.760
5.759
5.752
5.750
5.745
5.741
5.735
5.731
5.724
5.714
5.178
5.158
5.141
5.107
5.093
5.090
5.080
5.075
5.062
4.785
4.772
3.796
3.784
3.780
3.774
3.769
3.756
3.737
3.728
3.716
3.705
3.674
3.662
3.653
3.640
3.421
3.404
3.386
3.285
3.281
3.275
3.257
3.253
3.248
2.911
2.893
2.882
2.866
8 6 4 2 PPM
209.955
135.162
118.313
83.924
74.873
70.077
66.326
63.649
53.644
200 150 100 50 0 PPM

354

HN O
O
H
1
H
2
OH
Cis oxazolidinone, 3.63
J
12
= 8 Hz
1
H NMR, 500 MHz, CDCl
3

13
C NMR, 125 MHz, CDCl
3

4.8 4.6 4.4 4.2 4.0 3.8 PPM
7.240
6.090
4.679
4.671
4.663
4.657
4.649
4.642
3.941
3.933
3.922
3.916
3.905
3.897
3.875
3.861
3.850
3.836
3.820
3.801
3.793
3.776
3.769
1.605
1.596
1.585
1.576
1.569
1.559
1.549
1.539
1.529
1.517
1.507
1.497
1.487
1.481
1.470
1.462
1.449
1.435
1.424
1.413
1.409
1.403
1.399
8 6 4 2 PPM
156.033
76.704
57.829
51.593
28.763
16.975
10.868
200 150 100 50 PPM

355

4.10
B
•
O
O
O
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 63 MHz, CDCl
3

5.385
3.347
1.216
8 6 4 2 0 PPM
206.546
88.327
84.295
56.169
24.495
200 150 100 50 0 PPM

356

4.19
B
•
O
O
nC
5
H
11
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.3 5.2 5.1 5.0 4.9 4.8 4.7 PPM
7.240
5.087
5.060
5.032
5.005
4.893
4.879
4.866
4.852
4.838
2.046
2.031
2.019
2.004
1.990
1.976
1.964
1.948
1.416
1.387
1.356
1.320
1.305
1.295
1.276
1.253
1.243
0.890
0.861
0.834
8 6 4 2 0 PPM
216.496
85.978
83.462
31.141
28.750
27.192
24.835
24.548
22.478
14.063
200 150 100 50 PPM

357

4.23
B
•
OH
HO
nC
5
H
11
1
H NMR,250 MHz, CDCl
3

5.120
5.099
5.094
5.076
4.928
4.921
4.908
2.038
2.024
2.010
1.996
1.982
1.969
1.759
1.733
1.728
1.700
1.689
1.409
1.386
1.380
1.352
1.306
1.288
1.279
1.231
1.211
0.893
0.866
0.839
0.787
0.755
8 6 4 2 0 PPM

358

4.24
BF
3
K
•
nC
5
H
11
1
H NMR, 400 MHz, (CH
3
)
2
CO d
6

19
F NMR, 376 MHz, (CH
3
)
2
CO d
6

1.8 1.6 1.4 1.2 1.0 PPM
5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 PPM
4.621
4.386
4.373
2.880
2.847
2.061
2.056
2.050
2.044
2.039
1.892
1.883
1.875
1.867
1.857
1.848
1.840
1.831
1.370
1.368
1.363
1.353
1.339
1.333
1.326
1.318
1.312
1.302
1.296
1.287
1.276
1.268
0.886
0.878
8 6 4 2 0 PPM
-135 -136 -137 -138 -139 -140 PPM
-137.484
-137.607
-137.743
-137.871
0 -50 -100 -150 PPM

359

4.26
O
O
B
•
nC
5
H
11
1
H NMR,4500 MHz,CDCl
3

13
C NMR, 63 MHz, CDCl
3

5.0 4.8 4.6 4.4 4.2 PPM
4.869
4.303
4.284
4.235
4.230
4.214
4.209
2.338
2.332
2.326
2.322
2.316
2.309
2.303
2.295
2.290
2.280
2.274
2.269
2.230
2.220
2.214
2.211
2.200
2.195
2.186
2.179
2.173
2.168
2.162
2.158
2.152
2.144
2.060
2.048
2.039
2.032
2.027
2.014
2.009
2.004
2.000
1.992
1.983
1.973
1.963
1.898
1.892
1.882
1.870
1.861
1.856
1.848
1.844
1.840
1.835
1.829
1.826
1.821
1.797
1.793
1.789
1.785
1.533
8 6 4 2 0 PPM
216.548
216.377
85.966
85.893
77.955
77.514
77.000
76.486
51.282
39.534
39.453
38.088
35.551
35.465
31.213
31.141
28.817
28.735
28.684
28.578
28.546
27.224
27.168
27.071
26.455
26.387
26.347
25.416
23.982
22.466
14.047
14.010
200 150 100 50 0 PPM

360

OH
HN
O nC
5
H
11
4.29a
Ph
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

4.5 4.0 3.5 3.0 PPM
7.498
7.496
7.488
7.480
7.475
7.466
7.462
7.445
7.438
7.435
7.431
7.427
7.421
4.911
4.354
4.332
4.321
4.299
4.234
4.201
4.186
4.153
3.526
3.518
3.347
3.334
3.043
3.037
3.028
3.017
3.011
3.001
2.703
2.697
2.643
2.638
1.606
1.599
1.576
1.567
1.555
1.541
1.528
1.518
1.379
1.371
1.355
1.347
1.341
1.334
1.325
1.319
1.314
1.307
1.292
1.282
1 270
8 6 4 2 0 PPM
169.258
130.985
129.963
129.210
128.823
81.471
80.651
74.074
73.428
63.330
63.278
50.950
50.601
48.218
48.002
47.825
47.592
47.359
47.167
46.951
33.389
32.944
31.640
30.945
29.575
26.945
26.461
22.085
12.890
200 150 100 50 PPM

361

•
HN
OH
O
nC
5
H
11
4.29b
Ph
1
H NMR, 400 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0PPM
7.532
7.522
7.512
7.508
7.500
7.496
7.482
7.473
7.467
7.465
7.460
7.455
5.554
5.550
5.545
5.536
5.533
5.520
5.517
5.503
5.500
5.376
5.369
5.361
5.354
5.348
5.340
5.331
4.252
4.219
4.209
4.176
3.982
3.978
3.961
3.957
2.171
2.165
2.152
2.148
2.135
2.128
2.118
2.110
1.978
1.968
1.537
1.520
1.502
1.485
1.466
1.405
1.393
1.384
1.378
1.367
1.359
1.353
1.342
1.335
1.323
0954
8 6 4 2 0 PPM
207.764
207.644
172.197
133.475
131.510
130.929
130.675
96.551
96.391
87.341
87.286
63.069
63.039
62.901
62.869
51.012
33.044
33.008
30.440
30.405
29.962
29.806
26.223
24.038
24.008
14.888
200 150 100 50 0 PPM

362

•
N
OH
O
nC
5
H
11
4.31b
Ph Ph
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.5 5.0 4.5 4.0 PPM
2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8PPM
7.240
5.410
5.406
5.393
5.389
5.377
5.372
5.359
5.355
5.351
5.343
5.338
5.336
5.331
5.327
5.323
5.320
5.315
5.309
5.305
5.295
5.279
4.024
4.019
4.004
4.000
3.992
3.904
3.852
3.842
3.819
3.809
3.593
3.560
3.529
2.176
2.169
2.162
2.155
2.143
2.096
2.089
2.079
2.071
2.060
2.052
2.041
2.034
1.543
1.524
1.514
1.506
1.461
1.456
1.444
1.426
1.408
1.389
1.383
1.374
1.371
1.366
1.356
1348
8 6 4 2 0 PPM
95 90 85 80 75 70 65 PPM
207.565
172.381
136.697
129.739
129.146
129.095
128.964
128.762
128.505
128.010
92.954
92.464
83.064
82.589
77.318
77.205
77.000
76.682
62.582
62.199
54.739
31.448
31.261
29.670
29.265
29.107
28.851
28.412
22.687
22.532
22.434
14.084
14.018
200 150 100 50 PPM

363

OH
N
O nC
5
H
11
4.31a
Ph Ph
1
H NMR, 500 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

4.5 4.0 3.5 3.0 2.5 PPM
7.434
7.430
7.413
7.409
7.406
7.388
7.370
7.351
7.335
7.331
7.324
7.317
7.304
7.297
7.291
7.283
7.279
7.262
7.242
7.225
4.459
4.448
4.206
4.171
3.997
3.963
3.665
3.631
3.587
3.553
3.472
3.458
3.448
3.433
3.102
3.085
2.999
2.997
2.990
2.983
2.973
2.967
2.959
2.953
2.949
2.943
2.305
2.299
2.122
2.115
1.906
1.901
1.891
1.882
1.871
1.496
1.481
1.474
1.461
1.443
1.331
1.320
1.304
0957
8 6 4 2 0 PPM
85 80 75 70 65 60 55 50 PPM
175.630
175.004
138.852
138.697
138.499
137.386
129.246
129.100
128.748
128.524
128.433
128.367
128.244
127.671
127.357
127.242
127.163
84.464
77.314
76.996
76.677
72.031
71.361
64.220
63.440
54.836
54.656
31.659
31.454
30.868
30.521
29.721
26.774
25.974
22.604
14.120
200 150 100 50 PPM

364

•
N
OH
O
nC
5
H
11
4.32b
Major diastereomer
1
H NMR, 400 MHz, MeOH d
4

13
C NMR, 100 MHz, MeOH d
4

6.0 5.5 5.0 4.5 4.0 PPM
6.010
5.993
5.991
5.985
5.975
5.967
5.958
5.950
5.942
5.931
5.925
5.923
5.907
5.553
5.550
5.543
5.515
5.510
5.507
5.490
5.472
5.456
5.455
5.314
5.307
5.299
5.292
5.284
5.276
5.268
5.260
4.910
4.128
4.127
4.105
4.103
3.849
3.833
3.816
3.799
3.672
3.653
3.639
3.619
3.308
3.304
3.300
3.295
3.291
2.123
2.116
2.106
2.098
2.087
2.079
2.069
2.061
1.486
1.480
1.469
1.463
1.451
9 8 7 6 5 4 3 2 1 PPM
209.986
171.915
129.394
126.272
95.192
85.070
68.131
55.108
50.123
49.896
49.713
49.500
49.274
49.041
48.846
32.975
30.305
29.474
23.995
200 150 100 50 PPM

365

•
N
OH
O
nC
5
H
11
4.32b
minor diastereomer
1
H NMR, 400 MHz, MeOH d
4

13
C NMR, 100 MHz, MeOH d
4

6.0 5.5 5.0 4.5 4.0 PPM
5.985
5.979
5.972
5.967
5.958
5.952
5.946
5.935
5.928
5.910
5.539
5.537
5.510
5.499
5.496
5.482
5.464
5.447
5.431
5.311
5.305
5.297
5.288
5.280
5.273
5.265
5.258
4.110
4.108
4.086
4.085
3.846
3.829
3.812
3.794
3.677
3.659
3.643
3.625
3.308
2.144
2.137
2.131
2.126
2.119
2.113
2.107
2.101
2.095
2.088
2.083
2.082
2.077
1.492
1.486
1.483
1.474
1.467
1.456
1.437
1.380
1.365
1.356
1351
8 6 4 2 0 PPM
209.936
171.719
129.166
126.367
95.077
84.870
68.369
55.111
55.026
50.129
49.894
49.691
49.500
49.275
49.042
48.845
33.034
30.622
29.885
24.063
14.853
200 150 100 50 PPM

366

•
N
OH
O
O
nC
5
H
11
4.33b
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.0 4.5 4.0 3.5 3.0 PPM
8.925
7.240
5.305
5.296
5.288
5.281
5.272
5.264
5.256
5.246
5.236
5.228
5.220
5.213
5.206
5.197
5.178
3.899
3.889
3.878
3.818
3.795
3.762
3.737
3.127
2.978
2.027
2.020
2.010
2.002
1.991
1.984
1.965
1.959
1.403
1.386
1.368
1.351
1.332
1.308
1.301
1.282
1.272
1.263
1.255
1.245
1.236
1.227
1.219
1 208
8 6 4 2 0 PPM
207.644
207.491
170.257
93.346
93.096
84.449
84.274
71.479
71.082
65.006
64.883
50.482
50.305
31.281
28.834
28.700
28.471
28.190
22.407
14.057
14.021
200 150 100 50 PPM

367

OH
N
O
O
nC
5
H
11
4.33a
1
H NMR,400 MHz, MeOH d
4

13
C NMR, 125 MHz, MeOH d
4

3.8 3.6 3.4 3.2 3.0 2.8 2.6 PPM
3.715
3.706
3.701
3.693
3.685
3.677
3.248
3.236
3.226
3.211
2.969
2.961
2.954
2.940
2.931
2.924
2.916
2.900
2.891
2.885
2.876
2.868
2.862
2.852
2.847
2.834
2.822
2.775
2.764
2.752
2.734
2.722
2.537
2.531
2.471
2.465
1.788
1.775
1.770
1.761
1.756
1.752
1.746
1.736
1.731
1.722
1.627
1.620
1.612
1.606
1.600
1.597
1.591
1.582
1.575
1.558
1.538
1.528
1.522
1.513
1.505
1.504
1.496
1.493
8 6 4 2 0 PPM
85 80 75 70 65 60 55 PPM
173.097
172.379
85.194
73.943
73.593
73.322
73.227
68.209
67.967
51.974
51.867
33.595
33.247
33.071
32.397
32.063
28.258
27.985
24.091
24.028
14.853
14.825
200 150 100 50 0 PPM

368

•
HN
OH
nC
5
H
11
4.38b
Ph
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.0 4.5 4.0 3.5 PPM
7.204
7.195
7.185
7.178
7.174
7.163
7.152
5.213
5.208
5.203
5.196
5.192
5.180
5.175
5.163
5.159
5.008
5.001
4.993
4.985
4.977
4.969
4.962
3.888
3.878
3.856
3.846
3.658
3.653
3.626
3.620
3.566
3.556
3.540
3.529
3.295
3.274
3.270
3.248
3.196
3.191
3.179
3.175
3.169
3.164
3.160
3.148
2.809
2.296
1.978
1.974
1.963
1.961
1.958
1.943
1.941
1.926
1.920
1.350
1.343
1.334
1317
8 6 4 2 0 PPM
95 90 85 80 75 70 65 60 55 PPM
203.652
139.853
128.389
128.230
127.084
93.498
93.352
90.523
77.318
77.000
76.683
64.919
58.265
58.169
51.053
31.260
29.644
28.802
28.748
22.440
14.018
200 150 100 50 PPM

369

•
N
OH
O
nC
5
H
11
4.39b
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 90 MHz, CDCl
3

5.0 4.5 4.0 3.5 3.0 PPM
5.042
5.034
5.026
5.023
5.018
5.016
5.008
4.999
4.992
4.989
4.984
4.981
4.977
4.974
4.969
4.961
3.759
3.751
3.743
3.730
3.723
3.715
3.708
3.701
3.693
3.685
3.672
3.665
3.657
3.553
3.537
3.525
3.518
3.511
3.502
3.496
3.468
3.228
3.223
3.209
3.204
3.200
3.194
3.190
3.172
2.842
2.835
2.707
2.699
2.691
2.679
2.670
2.664
2.655
2.504
2.494
2.489
2.480
2.466
2.461
2.452
2.438
2.413
2.009
8 6 4 2 0 PPM
205.163
205.073
91.970
91.725
84.385
84.192
67.145
66.886
65.223
64.919
60.262
48.720
31.245
28.827
28.733
28.537
22.443
14.017
200 150 100 50 0 PPM

370

O
N
•
O
O O
O
O O
5.50
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 90 MHz, CDCl
3

5.5 5.0 4.5 4.0 PPM
5.773
5.761
5.752
5.733
5.721
5.712
5.702
5.691
5.682
5.670
5.662
5.651
5.642
5.294
5.281
5.270
5.264
5.253
5.247
5.240
5.228
5.215
5.204
5.167
5.164
5.151
5.123
5.112
5.106
5.098
5.072
5.038
5.033
5.026
5.020
5.015
4.980
4.974
4.888
4.875
4.863
4.849
4.820
4.815
4.808
4.803
4.792
4.790
4.776
4.221
4.197
4.192
4.172
4.166
3.815
3.807
3.805
3.794
3.646
3.639
3.632
3.561
3.498
3444
8 6 4 2 PPM
208 .6 42
208 .0 01
167 .7 78
167 .6 85
167 .2 16
166 .5 64
165 .9 00
165 .7 15
133 .7 63
133 .7 12
116 .9 22
116 .3 01
86 .8 96
86 .5 37
78 .6 19
77 .8 03
63 .6 69
63 .5 18
54 .5 01
52 .4 48
52 .2 70
52 .2 39
52 .1 45
51 .0 98
47 .1 45
44 .5 51
41 .1 73
41 .0 10
40 .8 63
200 150 100 50 PPM

371

N O
O
O
HO
5.53a
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.5 5.0 4.5 4.0 PPM
7.231
7.225
5.778
5.765
5.761
5.752
5.748
5.740
5.736
5.722
5.718
5.710
5.705
5.697
5.693
5.679
5.251
5.247
5.243
5.239
5.215
5.212
5.208
5.204
5.200
5.196
5.190
5.187
5.184
5.181
5.175
5.173
4.279
4.272
4.268
4.264
4.259
4.255
4.251
4.233
4.229
4.226
4.220
4.217
4.213
3.844
3.832
3.830
3.822
3.810
3.799
3.792
3.789
3.763
3.761
3.755
3.747
3.745
3.730
3.717
3.707
3.705
3.690
3687
8 6 4 2 0 PPM
170.780
168.705
148.519
140.212
132.286
128.621
128.176
126.853
118.717
114.289
63.32 7
61.25 4
54.19 2
53.06 8
44.10 5
42.66 5
150 100 50 PPM

372

N O
O
O
O
5.52a
O O
O
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 63 MHz, CDCl
3

5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 PPM
7.320
7.305
7.299
7.282
7.278
7.273
7.262
7.254
7.240
7.234
5.733
5.715
5.705
5.694
5.684
5.675
5.665
5.646
5.636
5.624
5.614
5.606
5.596
5.575
5.324
5.226
5.221
5.200
5.197
5.176
5.156
4.377
4.370
4.362
4.351
4.344
4.337
4.330
4.315
4.289
4.284
4.276
4.270
4.263
4.257
4.171
4.154
4.122
4.107
3.769
3.743
3.727
3.719
3.709
3.704
3.680
3.642
3.612
3.579
3.550
3.541
3.533
3.505
3.445
8 6 4 2 PPM
169.548
168.452
166.434
165.972
147.639
139.906
131.627
128.591
128.173
126.911
118.842
114.857
63.443
59.974
53.791
52.845
52.605
44.034
43.068
40.962
200 150 100 50 PPM

373

N O
O
O
O
O
O
O
5.52b
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 63 MHz, CDCl
3

6.0 5.5 5.0 4.5 4.0 3.5 PPM
7.240
5.969
5.947
5.945
5.928
5.923
5.903
5.879
5.861
5.853
5.834
5.813
5.455
5.417
5.226
5.220
5.158
5.151
5.145
5.138
5.129
5.125
5.119
5.084
5.078
4.251
4.232
4.209
4.190
4.131
4.103
4.089
4.060
3.931
3.912
3.902
3.895
3.883
3.875
3.866
3.847
3.728
3.593
3.423
3.410
3.393
3.358
3.350
3.342
3.336
3.331
3.308
3.301
3.296
3.286
3.279
3.274
3.227
3.224
3.218
3.199
3.192
3.172
3.168
8 6 4 2 0 PPM
173.159
166.810
166.244
142.894
141.021
136.686
128.452
128.249
127.610
126.525
116.122
67.932
54.135
52.553
51.603
49.830
41.273
32.999
25.534
200 150 100 50 PPM

374

O
NH Ph
•
5.64
Si
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.0 4.5 4.0 3.5 PPM
7.299
7.296
7.272
7.261
7.259
7.254
7.253
7.250
7.248
7.240
7.235
7.232
7.228
7.227
7.219
5.077
5.060
5.041
5.025
4.837
4.833
4.820
4.816
4.811
4.806
4.801
4.796
4.794
4.789
4.784
4.780
4.774
4.770
4.758
4.753
3.961
3.927
3.756
3.723
3.684
3.673
3.660
3.649
3.592
3.573
3.567
3.548
3.313
3.308
3.304
3.302
3.298
3.294
3.290
3.285
3.283
3.279
3.275
3.271
3.267
3.264
3.259
2.161
0.891
8 6 4 2 0 PPM
208.729
140.461
128.294
128.109
126.727
90.192
75.825
66.332
58.307
51.086
25.827
18.246
-5.375
-5.445
200 150 100 50 PPM

375

O
N Ph
•
O
O O
Si
5.63
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.0 4.5 4.0 3.5 PPM
7.255
7.248
7.240
7.229
7.192
7.186
7.177
7.175
7.170
7.161
7.155
5.320
5.303
5.286
5.277
5.270
5.128
5.111
5.097
5.080
5.002
4.995
4.989
4.818
4.813
4.809
4.805
4.800
4.797
4.792
4.788
4.721
4.714
4.704
4.697
4.653
4.614
4.609
4.576
4.536
4.496
4.480
4.469
4.457
3.857
3.818
3.809
3.799
3.794
3.786
3.746
3.669
3.650
3.639
3.600
3.579
3.561
3.556
3.553
3.530
3.295
0.848
0.843
0005
8 6 4 2 0 PPM
209.208
208.250
167.340
167.285
138.598
137.444
128.744
128.279
127.333
127.054
126.664
126.115
87.631
87.285
77.760
63.400
62.810
58.269
56.483
52.377
52.319
50.033
45.524
41.822
41.684
25.772
18.091
13.628
-5.549
-5.654
-5.735
200 150 100 50 PPM

376

N O
O O
Ph
O
5.67a
Si
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 90 MHz, CDCl
3

5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 PPM
7.380
7.370
7.339
7.323
7.314
7.305
7.291
7.289
7.283
7.281
7.276
7.269
7.264
7.259
7.256
7.240
5.273
5.272
5.120
5.083
5.070
4.107
4.070
3.851
3.830
3.812
3.743
3.719
3.710
3.601
3.589
3.587
3.580
3.567
3.556
3.539
3.529
3.497
3.488
3.480
3.472
3.462
0.879
0.877
-0.006
-0.034
8 6 4 2 0 PPM
169 .79 1
169 .10 9
148 .09 1
140 .50 5
136 .12 4
128 .61 5
128 .44 1
128 .38 6
128 .08 2
127 .84 5
127 .76 5
127 .55 9
126 .79 2
126 .07 9
114 .46 0
77 .34 6
77 .00 0
76 .65 1
62 .69 9
61 .67 3
54 .18 9
52 .64 3
45 .02 4
42 .24 8
25 .71 9
18 .11 7
5722
200 150 100 50 PPM

377
120 100 80 60 40 20 PPM
N O
O O
Ph
O
5.67a
Si
DEPT NMR data, 100 MHz, CDCl
3

378

N O
O O
Ph
HO
5.65a
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 PPM
7.392
7.375
7.371
7.361
7.358
7.349
7.345
7.341
7.333
7.328
7.322
7.316
7.310
7.306
7.296
7.291
7.265
7.256
7.254
7.246
7.240
5.318
5.113
5.110
4.940
4.903
4.325
4.287
3.855
3.810
3.803
3.801
3.787
3.785
3.641
3.624
3.618
3.538
3.531
3.524
3.517
8 7 6 5 4 3 PPM
170.803
169.168
148.206
128.905
128.572
128.051
127.921
114.417
63.096
61.206
54.166
53.078
42.601
29.687
200 150 100 50 PPM

379

N O
O
O
Ph
O
5.66a
O O
O
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.2 5.0 4.8 4.6 4.4 4.2 PPM
7.359
7.355
7.346
7.338
7.332
7.327
7.323
7.310
7.307
7.304
7.296
7.292
7.284
7.280
7.277
7.272
7.268
7.267
7.262
7.259
7.255
7.245
7.240
7.213
7.209
7.193
7.191
7.177
7.168
7.166
7.163
7.160
7.156
7.153
7.147
7.145
7.142
7.048
5.252
5.049
5.010
4.973
4.351
4.342
4.321
4.311
4.101
4.095
4.085
4.064
4.055
3.739
3.720
3.706
3.609
3.599
3.593
3.588
3.583
3.573
3.569
3.565
3.289
9 8 7 6 5 4 3 PPM
170.803
169.168
148.206
128.905
128.572
128.149
128.051
127.921
127.883
126.768
126.658
114.417
63.096
61.206
54.166
53.078
42.601
29.687
200 150 100 50 PPM

380

N O
O
O
O
O
O
O
5.66b
Ph
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.5 5.0 4.5 4.0 3.5 3.0 2.5 PPM
7.330
7.320
7.312
7.297
7.292
7.276
7.264
7.256
7.247
7.240
7.234
5.509
5.487
4.257
4.246
4.230
4.218
4.157
4.138
4.129
4.111
3.934
3.923
3.916
3.912
3.899
3.894
3.878
3.846
3.751
3.721
3.717
3.679
3.582
3.401
2.822
2.817
2.799
2.782
2.778
2.280
2.260
2.240
8 6 4 2 0 PPM
173 .1 30
166 .8 11
166 .2 51
143 .0 11
141 .0 53
140 .0 76
128 .5 48
128 .4 48
128 .3 05
128 .1 12
127 .6 07
127 .0 59
126 .5 66
67 .8 69
54 .8 98
54 .2 98
52 .5 04
51 .5 77
51 .3 86
41 .5 05
41 .2 66
32 .9 35
25 .4 93
200 150 100 50 PPM

381

N N
O
O
Ph
O
Si
5.75
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.5 5.0 4.5 4.0 3.5 3.0 2.5 PPM
7.359
7.338
7.333
7.323
7.297
7.293
7.290
7.279
7.272
7.268
7.256
7.254
7.250
7.240
7.227
7.219
7.201
7.187
7.171
7.164
7.157
7.146
5.315
5.290
5.158
3.848
3.820
3.809
3.772
3.720
3.697
3.656
3.623
3.561
3.527
3.340
3.329
3.313
3.308
3.302
3.297
3.281
3.270
2.920
2.616
2.606
2.586
2.577
2.559
2.550
2.533
1.417
0.896
0.035
-0.016
8 6 4 2 0 PPM
156.282
148.044
141.086
139.968
138.961
128.369
128.103
127.212
126.853
113.946
79.656
59.886
59.431
58.170
54.574
44.828
38.934
29.677
28.472
28.230
25.968
25.891
18.134
-5.532
200 150 100 50 PPM

382

N
Ph
Ph
HO
5.70a
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

4.2 4.1 4.0 3.9 3.8 3.7 3.6 PPM
7.361
7.344
7.324
7.322
7.316
7.311
7.298
7.296
7.291
7.290
7.284
7.272
7.253
7.240
7.238
7.233
7.229
7.223
7.216
7.199
6.054
6.050
4.115
4.100
4.082
4.067
3.984
3.979
3.972
3.967
3.960
3.717
3.684
3.676
3.671
3.664
3.658
3.649
3.642
3.631
3.625
8 6 4 2 0 PPM
140.246
139.121
133.646
128.533
128.394
127.832
127.227
125.530
123.269
72.339
61.523
60.455
58.341
200 150 100 50 PPM

383

N
H
H
HO
5.70b
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.5 5.0 4.5 4.0 3.5 PPM
7.32 5
7.31 3
7.30 8
7.30 4
7.29 8
7.29 5
7.29 0
7.28 7
7.28 3
7.27 8
7.27 1
7.26 4
7.26 0
7.25 5
7.25 1
7.24 8
7.24 3
7.24 0
7.23 7
7.23 5
7.23 2
7.22 7
7.22 2
7.21 7
7.12 6
7.12 1
7.11 3
7.11 1
7.10 2
7.09 7
5.47 3
5.47 0
5.46 7
5.35 9
5.29 7
5.28 4
4.60 8
4.57 0
4.28 8
4.25 1
3.62 2
3.59 2
3.36 8
3.36 1
3.35 0
3.34 2
3.33 0
3.31 9
3.31 2
3.29 3
3.28 6
3.27 9
3.27 2
3.26 4
9 8 7 6 5 4 3 PPM
15 8.183
14 5.455
12 8.937
12 8.714
12 8.384
12 8.007
12 7.671
12 7.384
11 5.909
6 1.175
6 0.598
4 6.521
2 9.706
150 100 50 PPM

384

N
H
H
HO
5.70c
1
H NMR, 400 MHz, CDCl
3

13
C NMR, 100 MHz, CDCl
3

5.5 5.0 4.5 4.0 3.5 PPM
7.364
7.360
7.356
7.343
7.339
7.334
7.326
7.321
7.317
7.313
7.309
7.304
7.297
7.290
7.287
7.240
5.731
5.730
5.727
5.726
5.676
5.673
5.671
5.578
5.575
5.571
5.558
5.555
4.943
4.905
4.211
4.173
3.655
3.647
3.638
3.626
3.618
3.509
3.501
3.491
3.484
3.471
3.463
9 8 7 6 5 4 3 PPM
129.114
128.896
128.805
128.124
125.662
77.308
77.196
77.000
76.876
76.652
59.465
58.351
46.748
29.669
200 150 100 50 PPM

385
B
O
O
O
6.51
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 90 MHz, CDCl
3

4.6 4.4 4.2 4.0 3.8 3.6 3.4 PPM
7.240
4.585
4.561
4.536
4.512
4.487
4.134
3.373
1.184
1.159
8 6 4 2 0 PPM
77.358
77.000
76.655
67.579
59.994
57.389
24.164
24.002
200 150 100 50 PPM

386
OH
N
MeO
Ph Ph
6.55
1
H NMR, 500 MHz, CDCl
3

13
C NMR, 125 MHz, CDCl
3

4.2 4.0 3.8 3.6 3.4 PPM
7.265
7.250
7.246
7.240
7.206
7.197
7.190
7.180
7.174
7.161
4.135
4.132
3.822
3.794
3.661
3.651
3.641
3.631
3.586
3.565
3.544
3.482
3.471
3.461
3.450
3.388
3.365
8 6 4 2 PPM
138.500
128.957
128.518
127.367
82.624
80.611
61.522
59.965
59.934
59.908
57.609
57.588
54.857
53.394
200 150 100 50 PPM

.

387

OH
N
MeO
O
6.54
1
H NMR, 500 MHz, CDCl
3

13
C NMR, 125 MHz, CDCl
3

4.0 3.5 3.0 2.5 PPM
4.063
4.061
3.713
3.708
3.691
3.686
3.680
3.672
3.663
3.657
3.651
3.634
3.545
3.532
3.509
3.493
3.308
2.985
2.644
2.636
2.627
2.470
2.460
2.452
2.441
2.436
2.430
8 6 4 2 PPM
83.339
79.843
66.800
60.590
59.632
58.646
57.468
57.445
49.179
49.147
200 150 100 50 PPM

388

N
OH
MeO
6.56
1
H NMR, 500 MHz, CDCl
3

13
C NMR, 90 MHz, CDCl
3

6.0 5.5 5.0 4.5 4.0 3.5 3.0 PPM
5.806
5.797
5.787
5.778
5.771
5.762
5.755
5.753
5.745
5.744
5.736
5.727
5.212
5.179
5.142
5.122
4.101
3.806
3.787
3.775
3.557
3.547
3.537
3.519
3.498
3.352
3.327
3.322
3.318
3.297
3.294
3.290
2.945
2.929
2.917
2.901
8 6 4 2 PPM
135.586
117.875
82.138
80.910
61.420
59.776
57.431
53.583
53.468
200 150 100 50 PPM

389

OH
NH
MeO
MeO
6.62
1
H NMR, 500 MHz, CDCl
3

13
C NMR, 125 MHz, CDCl
3

4.2 4.0 3.8 3.6 3.4 3.2 PPM
6.780
6.762
6.713
6.700
6.695
4.139
4.135
4.130
4.127
4.118
4.024
4.021
3.826
3.818
3.804
3.795
3.762
3.748
3.739
3.736
3.722
3.710
3.260
8 6 4 2 PPM
153.353
140.201
116.589
114.775
114.644
84.570
79.895
64.862
59.799
57.473
55.588
55.563
49.506
200 150 100 50 PPM

390

OH
NH
MeO
O
2
N
6.63
1
H NMR, 500 MHz, CDCl
3

13
C NMR, 125 MHz, CDCl
3

4.6 4.5 4.4 4.3 4.2 4.1 4.0 3.9 3.8 PPM
8.105
8.092
8.084
8.063
8.055
8.043
6.686
6.673
6.665
6.644
6.636
6.623
4.345
4.335
4.328
4.321
4.310
4.303
4.058
4.051
3.916
3.909
3.897
3.893
3.298
8 6 4 2 0 PPM
151.773
139.066
126.140
112.456
82.688
80.636
64.581
59.778
57.823
47.214
200 150 100 50 PPM

391

OH
N
MeO
O
2
N
6.64
OH
OH
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 63 MHz, CDCl
3

5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 PPM
8.138
8.123
8.115
8.095
8.087
8.073
6.766
6.753
6.745
6.724
6.714
6.703
5.362
5.346
5.327
4.561
4.555
4.549
4.532
4.528
4.512
4.506
4.500
4.362
4.336
4.328
4.302
4.284
4.263
4.250
4.228
4.091
3.815
3.801
3.325
8 6 4 2 PPM
148.928
125.970
125.699
111.977
91.144
82.470
81.289
77.514
77.000
76.496
71.137
61.979
59.727
59.604
57.815
49.836
200 150 100 50 0 PPM

392

OH
N
MeO
Ph
Ph
6.57
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 125 MHz, CDCl
3

4.6 4.4 4.2 4.0 3.8 3.6 PPM
7.275
7.268
7.240
7.214
7.204
7.189
7.183
7.175
7.165
7.157
7.148
7.136
7.132
7.110
7.101
7.094
6.914
6.883
6.809
6.781
6.752
4.641
4.615
4.586
4.469
4.443
4.015
4.007
3.636
3.607
3.225
8 6 4 2 PPM
149.167
149.111
139.454
139.318
129.305
129.288
129.067
128.899
128.833
128.636
128.425
128.267
128.086
127.859
127.788
127.048
126.899
126.663
126.441
120.126
117.757
116.998
82.337
82.192
82.092
77.694
77.653
77.549
77.245
76.998
76.743
63.180
63.062
59.816
57.559
55.782
55.314
55.004
52.859
52.497
12.575
200 150 100 50 0 PPM

393

OH
N
MeO
Ph
6.61
Me
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 63 MHz, CDCl
3

7.336
7.313
7.240
5.276
5.207
5.179
4.118
4.111
3.370
3.309
3.274
3.252
1.479
1.451
8 6 4 2 0 PPM
143.447
136.961
128.421
127.778
127.239
117.634
83.263
82.147
62.298
61.974
59.930
59.723
57.537
57.311
50.127
13.429
200 150 100 50 PPM

394

OH
N
MeO
Ph Ph
6.59
Me
1
H NMR, 250 MHz, CDCl
3

13
C NMR, 63 MHz, CDCl
3

4.2 4.0 3.8 3.6 3.4 3.2 PPM
7.257
7.240
7.211
7.197
7.179
7.173
7.163
7.149
7.127
7.097
7.090
4.059
4.052
3.935
3.907
3.897
3.891
3.879
3.853
3.805
3.780
3.750
3.721
3.684
3.631
3.560
3.546
3.539
3.532
3.522
3.514
3.509
3.502
3.486
3.479
3.473
3.362
3.320
3.299
3.282
3 238
9 8 7 6 5 4 3 2 1 PPM
143.057
139.534
129.141
128.578
128.426
128.164
127.998
127.763
127.361
127.311
127.035
83.328
82.323
77.520
77.357
77.211
77.000
76.930
76.507
62.561
62.103
60.916
60.003
59.898
59.787
57.598
57.468
56.516
53.282
51.218
49.903
12.116
12.004
200 150 100 50 PPM

395

NH
MeO
O
2
N
6.65
OH
OH
1
H NMR, 250 MHz, MeOH d
4

13
C NMR, 63 MHz, MeOH d
4

4.6 4.4 4.2 4.0 3.8 PPM
8.056
8.047
8.043
8.010
7.997
6.788
6.776
6.765
6.757
6.746
6.737
6.728
4.860
4.547
4.540
4.532
4.524
4.517
4.465
4.458
4.451
4.443
4.434
4.429
4.090
4.083
4.075
3.890
3.870
3.850
3.845
3.828
3.802
3.781
3.757
3.738
3.732
3.716
3.708
3.696
3.306
3.300
3.290
3.282
9 8 7 6 5 4 3 2 1 PPM
155.284
154.780
139.582
139.517
127.452
127.404
113.587
85.497
84.393
81.832
81.342
75.149
74.375
64.667
64.505
61.024
60.983
58.203
49.245
48.812
200 150 100 50 PPM

Abstract (if available)

Abstract This dissertation presents our efforts in the field of multicomponent reactions and more specifically in the three-component condensation among amines, carbonyl compounds and organoboron derivatives. This process is referred as Petasis reaction in the literature. This thesis describes new extensions of the Petasis reaction to allenyl and alkynyl boron components.

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University of Southern California Dissertations and Theses

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