University of Southern California Dissertations and Theses

New reactions of organoboron compounds

(USC Thesis Other)

New reactions of organoboron compounds

PDF

Download a page range

Download transcript

Copy asset link

Request this asset

Transcript (if available)

Content NEW REACTIONS OF ORGANOBORON COMPOUNDS

by
Petros C. Yiannikouros

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)

December 2006

Copyright 2006 Petros C. Yiannikouros

Dedication

To my lovely wife to be Amy Elizabeth and my brother Chrysostomos.

ii
Acknowledgements

I am deeply grateful to Professor Nicos A. Petasis because without his
encouragement, leniency, and guidance the completion of this dissertation would remain
just a dream to me. He supported every decision I took throughout my studies and he was
there to give me a wake up call whenever I was sidetracked. Especially I would like to
thank him for helping me mature, improve my way of thinking, and boost my confidence.
I wish to express my gratitude to Dr. G. K. Surya Prakash and Dr. William P.
Weber for their valuable advice and encouragement. I would also like to acknowledge the
other members of my committee Dr. Robert Bau and Dr. Axel H. Schonthal for their
valuable time and comments.
My years at USC were also interesting thanks to the present and past members of
my lab as well as some friends outside school, and of course the staff at Loker
Hydrocarbon Institute and the Chemistry Department.
Most importantly I would like to thank my family in Cyprus for their constant
support and encouragement. And last I would like to thank my brother in New York with
the promise that, big things are yet to come for us.

iii
Table of Contents
Dedication ii
Acknowledgements iii
List of Tables vii
List of Figures viii
List of Schemes ix
Abstract xii
Chapter 1. Synthesis and Reactions of Organoboron Compounds 1
1.1. Introduction 1
1.1.1. Types of organoboron compounds 1
1.1.2. Use of organoboron compounds 2
1.1.3. Types of boronic acids 3
1.1.3.1. Synthesis of boronic acids 4
1.1.3.2. Aryl and heteroaryl boronic acids 7
1.2. Metal catalyzed reactions 8
1.2.1. Suzuki coupling reaction 8
1.2.2. Rhodium catalyzed addition to olefins 9
1.2.3. Rhodium catalyzed addition to aldehydes and imines 10
1.2.4. Formation of carbonyl compounds 10
1.2.5. Chan-Evans-Lam-Modified Ullman condensation 11
1.2.6. Heck-type reactions 12
1.3. Reactions of boronic acids: Non metal catalyzed reactions 13
1.3.1. Reactions with amines and carbonyls (Petasis Reaction) 13
1.3.1.1. Synthesis of geometrically pure allylamines 13
1.3.1.2. Synthesis of anti- β-amino alcohols 14
1.3.1.3. Synthesis of novel aminophenol derivatives 15
1.3.1.4. Synthesis of β, γ-unsaturated α-amino acids 17
1.3.1.5. Mechanistic aspects 18
1.3.2. Other Reactions 19
1.3.2.1. Conversion of alkenyl boronic acids to alkenyl
halides with halosuccinimides 19
1.3.2.2. Ipso substitution of aryl boronic acids 20
1.3.2.3. Addition of allyl boronates to aldehydes 22
1.3.2.4. Addition of allyl boronates to imine derivatives 23
1.3.2.5. Stereoselective synthesis of enol acetates 25
1.3.2.6. Stereospecific synthesis of Vinyl(phenyl)iodonium
Tetrafluoroborates 26
1.4. Dissertation Overview 27
1.5. Chapter 1 References 28
iv

Chapter 2. Reactions of Boronic Acids with Formaldehyde and Amines 32
2.1. Introduction 32
2.1.1. Properties of benzylic amines 32
2.2. Results and discusion 33
2.2.1 Improving the reaction conditions 34
2.2.2. Synthesis of benzylic amines 36
2.2.3. Use of microwaves in the Petasis reaction 38
2.3. Conclusion 40
2.4. Experimentals 41
2.4.1. General 41
2.4.2. General procedures 41
2.4.2.1 Synthesis of boronic acids 41
2.4.2.2 Synthesis of amine derivatives 43
2.4.3 Specific synthesis and physical properties 45
2.5. Chapter 2 References 57

Chapter 3. Synthesis of Amino Imidazoles 58
3.1. Introduction 58
3.1.1. Imidazole 58
3.1.2. Importance of imidazole containing molecules 60
3.2. Results 62
3.2.1. Reactions with imidazole-4-carboxaldehyde 62
3.2.2. Reactions with imidazole-2-carboxaldehyde 66
3.3. Conclusion 68
3.4. Experimentals 69
3.4.1. General 69
3.4.2 General procedure 69
3.4.3. Specific Syntheses and Physical Properties 70
3.5. Chapter 3 References 76

Chapter 4. Use of Trifluoroborates in the Petasis Reaction 78
4.1. Introduction 78
4.2. Synthesis and reactivity of trifluoroborates 78
4.2.1. Formation of organotrifluoroborates 79
4.2.2. Reactions of organotrifluoroborates 82
4.2.2.1. Metal catalyzed reactions 83
4.2.2.1.1. Palladium-catalyzed reactions of
arenediazonium salts with trifluoroborates 83
4.2.2.1.2. Rhodium-catalyzed additions to enones,
aldehydes and dehydroamino esters 84
4.2.2.1.3. Suzuki-Miyaura cross-coupling reaction 84
4.2.2.1.4. Modified Ullmann condensation 85
4.2.2.2. Non-metal catalyzed reactions 85
4.2.2.2.1. Synthesis of alkenyl fluorides,
2,2-difluoroamides, and
2,2-difluoroalcohols 85
v
4.2.2.2.2. Diastereoselective allylation of aldehydes 87
4.2.3. Use of trifluoroborates in the Petasis reaction 87
4.2.4. The Eschenmoser’s salt and usefulness of dimethylamine
intermediates 88
4.3. Results 91
4.3.1. Reactions of trifluoroborates with formaldehyde 92
4.3.2. Reactions of trifluoroborates with the Eschenmoser’s salt 96
4.3.3. Reactions of trifluoroborates with glyoxylic acid 98
4.4. Conclusion 99
4.5. Experimentals 100
4.5.1. General 100
4.5.2. General procedure 100
4.5.3. Specific Synthesis and Physical Properties 101
4.6. Chapter 4 References 111

Chapter 5. New Three-Component Reactions of Imines and Aza-
Aromatic Compounds with Organotrifluoroborates 115
5.1. Introduction 115
5.1.1. Imines in chemistry 115
5.1.2. Aza-aromatic iminium ions 120
5.2. Results and discusion 123
5.2.1. The use of Imines in a multicomponent manner with
trifluoroborates 124
5.2.2. Addition reactions to aza-aromatic iminium ions 127
5.2.2.1. Use of isoquinolines 128
5.2.2.2. Use of quinolines 133
5.2.2.3. Use of phenanthridines 134
5.3. Conclusion 137
5.4. Experimentals 138
5.4.1. General 138
5.4.2. General procedure 138
5.4.3. Specific Syntheses and Physical Properties 139
5.5. Chapter 5 References 156

Bibliography 161
Appendix: Selected Spectra 176
vi
List of Tables
Table 2.1. Exploration of Reaction Conditions of the Petasis Reaction 35
Table 2.2. Synthesis of Benzylic Amines Between the Reaction of Amines, 37
Boronic Acids and Formaldehyde in Water

Table 2.3. Synthesis of Amino Acids 38
Table 2.4. Comparison of Microwave to Conventional Heating 39
Table 3.1. Imidazole and Some of its Analogues 60

Table 3.2. Solvent Effect on the Reaction with Imidazole-4-carboxaldehyde 65
Table 3.3. Products from the Reactions with Imidazole-4-carboxaldehyde 66
Table 3.4. Products from the Reactions with Imidazole-2-carboxaldehyde 67
Table 4.1. Comparison of Organoboranes in the Petasis Reaction 93
Table 4.2. Products of the Petasis reaction with Trifluoroborates, amines 95
and formaldehyde
Table 4.3. Formation of Dimethylamine Intermediates 97
Table 4.4. Formation of Amino Acids 98
Table 5.1. Imine Products with Trifluoroborates 126
Table 5.2. Equivalents of Chloroformate Required 129
Table 5.3. Comparison of Different Isoquinoline Analoqgs 130
Table 5.4. Products from Reactions of Isoquinolines, Chloroformates and 131
Trifluoroborates
Table 5.5. Comparison of 4-bromo Isoquinoline with 3-bromo Pyridine 132
Table 5.6. Interaction of Different Activating Agents with Isoquinolines 133
Table 5.7. Reactions of Activated Quinolines with Trifluoroborates 134
Table 5.8. Reaction of Phenanthridine, Chloroformates and 136
Organotrifluoroborates
vii
List of Figures
Figure 1.1. Types of Organoboron Compounds 2
Figure 1.2. Boronic Acids 3
Figure 1.3. Some General Structures of Commercially Available Boronic 8
Acids
Figure 1.4. Various applications of the Petasis reaction 27
Figure 2.1. General Reaction 33
Figure 3.1. Histidine and Histamine 61
Figure 3.2. On the left a Known MMP Inhibitor and on the right Imidazole- 62
Based Inhibitor with Enzyme Interactions
Figure 3.3. Imidazole Carboxaldehydes 63
Figure 4.1. The use of Lewis Acids and Trifluoroborates in the Petasis 88
Reaction
Figure 4.2. Dimethylamine Bearing Natural Products and Biologically 90
Active Molecules

viii
List of Schemes
Scheme 1.1. Electrophilic Borate Trapping of Organometallics from Halides 4
Scheme 1.2. Aryl Boronic Acids from Ortho-metallation 4
Scheme 1.3. Transmetallation of Organosilanes 5
Scheme 1.4. Transition Metal-catalyzed Coupling 5
Scheme 1.5. Boronylation by Metal-catalyzed C-H Functionalization 6
Scheme 1.6. Thermal or Transition Metal-catalyzed Cis-hydroboration 6
Scheme 1.7. Indirect Trans-hydroboration of Alkynyl Bromides 6
Scheme 1.8. Rhodium and Iridium Catalyzed Trans-hydroboration 6
Scheme 1.9. Alkene Metathesis 7
Scheme 1.10. Pd Catalyzed Suzuki Coupling with Boronic Acids 9
Scheme 1.11. Rhodium Catalyzed Addition to Enones 9
Scheme 1.12. Rhodium Catalyzed Addition to Aldehydes 10
Scheme 1.13. Rhodium Catalyzed Addition to Anhydrides 11
Scheme 1.14. Modified Ullmann Condensation 12
Scheme 1.15. Mizoroki-Heck Type Reaction 13
Scheme 1.16. Synthesis of Allylamines 14
Scheme 1.17. Formation of Anti- β-amino Alcohols 15
Scheme 1.18. Petasis Reaction with Salicylaldehyde Derivadives 16
Scheme 1.19. Formation of 2-H Chromenes 16
Scheme 1.20. Synthesis of Amino Acids 17
Scheme 1.21. Formation of Piperazinones 18
Scheme 1.22. Mechanism of the Petasis Reaction 19
ix
Scheme 1.23. Formation of Alkenyl Halides 20
Scheme 1.24. Ipso Substitution of Boronic Acids 21
Scheme 1.25. Allylboration Reactions 22
Scheme 1.26. Reaction of Allyl Boronates with Imine Derivatives 24
Scheme 1.27. Reaction of Chiral Allylboronate with N- 24
trimethylsilylaldimines
Scheme 1.28. Synthesis of Enol-acetates 25
Scheme 1.29. Synthesis of Vinyl-(phenyl) Iodonium Tetrafluoroborates 26
Scheme 2.1. Formation of Benzylic Amines 33
Scheme 3.1. Three-component Petasis Reaction with Imidazole 62
Carboxaldehydes
Scheme 4.1. Formation of Trifluoroborate Complexes 79
Scheme 4.2. Preparation of Trifluoroborates from Organosilanes and 80
Organostannanes
Scheme 4.3. Reaction with KHF
2
80
Scheme 4.4. Formation of Aryl Trifluoroborates 81
Scheme 4.5. Formation of Potassium Aryl Trifluoroborates in situ 82
Scheme 4.6. Cross-coupling Reaction of Arenediazonium Salts with 83
Trifluoroborates
Scheme 4.7. Rhodium Catalyzed 1,2 and 1,4 Additions 84
Scheme 4.8. Suzuki-Miyaura Cross-coupling Reaction with 85
Alkynyltrifluoroborates
Scheme 4.9. Copper-catalyzed Ether Synthesis 85
Scheme 4.10. Trifluoroborate Transformations 86
Scheme 4.11. Allylation of Aldehydes with Trifluoroborates 87
Scheme 4.12. Formation of Eschenmoser’s Salt 89
x
Scheme 4.13. Alternative Manich Reaction 89

Scheme 4.14. Reaction of Silyl Enol Ethers and Lactone Enolates with 90
Eschenmoser’s salt
Scheme 4.15. Trifluoroborates in the Petasis Reaction 92
Scheme 4.16. Reaction of Boronic Acids with the Eschenmoser’s Salt 96
Scheme 5.1. Addition of Grignard Reagents and Lithium Reagents to Imines 117
Scheme 5.2. Reaction of Imines with RCu
.
BF
3
117
Scheme 5.3. Lewis Acid Promoted Addition of Stannanes 117
Scheme 5.4. Palladium Catalyzed Coupling of Imines, Acid Chlorides and 118
Stannanes
Scheme 5.5. Rhodium Catalyzed Addition to Imines 119

Scheme 5.6. Copper Catalyzed Cross-coupling with Imines 119

Scheme 5.7. Friedlander Synthesis of Quinolines 120
Scheme 5.8. Reaction of Allylic Tin Reagents with Activated Quinoline and 121
Isoquinoline
Scheme 5.9. Addition Reaction of Allylsilanes to Quinolines and 122
Isoquinolines
Scheme 5.10. Indium Mediated Allylation of Quinolines and Isoquinolines 122
Scheme 5.11. N-acylazinium Salts as Intermediates in Ugi Processes 123
Scheme 5.12. Modified Petasis Reaction 124
xi
Abstract
This Dissertation describes some new variations of a three-component reaction
among boronic acids or trifluoroborates with amines and carbonyl compounds, known as
the Petasis reaction. This process has been extended to include imidazole-carboxaldehydes
as the carbonyl component, while trifluoroborate derivatives were shown to react with
preformed or in-situ generated iminium salts to give new amine products. Similar
reactions with quinoline or isoquinoline analogs were also shown to form new aza-
heterocyclic derivatives.
This Thesis consists of five Chapters: Chapter 1 gives a general introduction to the
chemistry of organoboron compounds and highlights some recent synthetic reactions
involving boronic acids and trifluoroborates with an emphasis on reactions with amines
and carbonyls.
Chapter 2 details an investigation on the use of formaldehyde and formaldehyde
equivalents in the Petasis reaction, including the use of microwaves and the conversion of
aryl and heteroaryl boronic acids to benzylic amines.
Chapter 3 describes the synthesis of promising medicinal scaffolds employing the
reaction of amines and boronic acids with imidazole-carboxaldehydes.
Chapter 4 is focused on the use of trifluoroborates as the active species in the three
component reaction with the help of a catalyst. These studies include the direct reaction of
trifluoroborates with preformed iminium salt such as Eschenmoser’s salt, as well as the use
iminium salts generated in situ from imines.
xii
Chapter 5 describes the three-component reaction of trifluoroborates with iminium
salts generated in-situ upon the reaction of quinolines or isoquinolines with chloroformates
to form aza-aromatic derivatives.

xiii
CHAPTER 1
Synthesis and Reactions of Organoboron Compounds
1.1 Introduction
Although, organoboron compounds have found widespread use in organic
synthesis, until recently their use in ionic reactions has been rather limited due to low
reactivity. Recent studies, however, have shown that organoboron compounds can be used
in many new reactions by manipulating their versatile reactivity. Due to its electrophilic
character, boron while being a three coordinate atom, changes to being nucleophilic when
it exists as a four coordinate “ate” complex. This tunability of the boron compounds
depends on the nature of the elements bound and coordinated to boron. By manipulating
the boron substituents it is indeed possible to design new reactions.

1.1.1 Types of organoboron compounds
The most commonly used organoboron compounds in organic synthesis (Figure
1.1) contain a boron atom connected to a carbon group (R
1
), and three or four other
substituents including halides, hydroxyl or alkoxy groups. If we have three fluorides
coordinated to boron, thus making the molecule a four-coordinate, the compound is
classified as a trifluoroborate, one of the most stable species of this family. In the case were
two –OH groups are attached to boron, then we have the boronic acids, the most widely
used molecules of this kind, and when the molecules have –OR groups they are called
boronates or boronate esters, which are very stable compounds. On the other hand if boron
is surrounded by carbons then the molecule is called a borane and it is usually the most
1
highly reactive species in comparison with the other members of the family. Depending on
what the R
1
group is (Figure 1.1) the compounds are further classified to alkyl, aryl,
alkenyl, allyl and alkynyl or allenyl.

B
B
BB
R
1
F
F
R
1
HO OH
R
1
RO OR
R
1
R
2
R
3 F

Figure 1.1: Types of organoboron compounds

1.1.2 Use of organoboron compounds
Organoboron compounds have been widely used for a variety of synthetic
transformations. Organoboranes will not be discussed in this thesis, which deals mainly
with boronates, boronic acids, and trifluoroborates.
Undoubtedly, the most broadly used process, resulted from the work of Suzuki and
Miyaura, who in 1979 have demonstrated that a huge variety of boron derivatives can
participate in metal catalyzed coupling reactions [1]. Besides such coupling reactions, these
unique molecules have found many other metal and non metal catalyzed applications in
organic synthesis. The fact that boron derivatives are easily accessible through commercial
sources, and relatively easy to make, boosted the interest of many chemists to explore their
reactivity. Above all, most of the members of this family, excluding maybe some allyl
boron derivatives, are easy to handle and show remarkable thermal, as well as, air and
water stability. Herein we will highlight some important reactions of organoboron
compounds that were discovered in the past few years.

2
1.1.3 Types of boronic acids
Boronic acids are trivalent, boron containing organic compounds that posses one
C-B bond and two hydroxyl groups. These three substituents are oriented in a trigonal
planar geometry around boron [2]. Boronic acids are not found in nature, but are
synthesized in the lab from various sources that will be mentioned later on. The boronic
acids can further be classified, depending on what the R group is (Figure 1.2), to aryl,
heteroaryl, alkyl, alkenyl, alkynyl or allyl.
B(OH)
2
O
B(OH)
2
R
'
B(OH)
2
R
'
B(OH)
2
B(OH)
2
B(OH)
2
R
'
R
'
B R
OH
OH

Figure 1.2: Boronic acids

Boronic acids are very attractive as synthetic intermediates due to their reactivity
and also their mildness as Lewis acids. They can even be considered to be environmentally
benign molecules since their toxicity is extremely low and they eventually degrade to boric
acid, an environmentally friendly compound.

3
1.1.3.1 Synthesis of boronic acids
Frankland was the first chemist to report the preparation and isolation of a boronic
acid in 1860, by treating diethylzinc with triethylborate and subsequently oxidizing the
resulting triethylborane to yield ethyl boronic acid [3].
Probably the cheapest and one of the earliest ways to synthesize boronic acids is
the reaction of organometallic reagents, like lithium and magnesium, with borate esters
(Scheme 1.1). Simple alkyl, alkenyl and aryl boronic acids can be synthesized with this
method.
B(OH)
2
R
H
3
O
+
B(OR
'
)
2
R
1. R
"
M
2. B(OR
'
)
3
RX
X= Br, I

Scheme 1.1: Electrophilic borate trapping of organometallics from halides

Directed metallation can give access to complex aryl boronic acids bearing groups
like amines, ethers, esters and amides, which serve as the ortho-directors (Scheme 1.2).
H
3
O
+
1. R
"
Li
B(OH)
2
R
B(OR
'
)
2
R
H
R
DG
DG
DG
2. B(OR
'
)
3
DG= directing group

Scheme 1.2: Aryl boronic acids from ortho-metallation

One more way widely used for the formation of organoboronic acids is the
transmetallation of organosilanes and organostannanes (Scheme 1.3). This class of
molecules is very suitable for efficient transmetallation with boron halides. What drives
this reaction to completion is the higher stability of C-B and Si(Sn)-halide bonds of the
products, compared to the B-halide and Si(Sn)-C bonds of the reactants.
4
B(OH)
2
R
H
3
O
+
BBr
2
R
RSiMe
3
BBr
3

Scheme 1.3: Transmetallation of organosilanes

At this point it is worth mentioning a few modern techniques of synthesizing
boronic acids. Due to the fact that the traditional methods of preparing boronic acids from
trapping organolithium and organomagnesium reagents with borate esters, have amble
limitations (compatibility issues of the organometallics with different functional groups
and harsh reaction conditions), the need of techniques with milder conditions compliant to
a broader range of substrates and functionalities emerged. Miyaura and coworkers found
that diboronyl esters as well as pinacolborane, undergo under mild catalytic conditions,
transition metal-catalyzed cross coupling reactions with halides and triflates to yield the
boronic acids in good yields (Scheme 1.4).
B(OH)
2
R
H
3
O
+
B(OR
'
)
2
R
(R
'
O)
2
B-B(OR
'
)
2
or
H-B(OR
'
)
2
transition metal
catalyst
RX
X= Br, I,OTf

Scheme 1.4: Transition metal-catalyzed coupling

Another technique, complementing the transition metal-catalyzed coupling
described above, is the direct boronylation via C-H activation catalyzed by transition metal
catalysts (Scheme 1.5). This method, besides the catalyst, requires a suitable boron donor
like diboronyl esters and dialkoxyboranes.
5
B(OH)
2
R
H
3
O
+
B(OR
'
)
2
R
(R
'
O)
2
B-B(OR
'
)
2
or
H-B(OR
'
)
2
transition metal
catalyst
RH

Scheme 1.5: Boronylation by metal-catalyzed C-H functionalization

A very convenient way to synthesize alkenyl boronic acids, is via hydroboration of
alkynes. Whether the hydroboration proceeds in a cis- (Scheme 1.6) or trans- (Scheme 1.7,
Scheme 1.8) manner, solely depends on the reaction conditions and on what catalyst is
used in the case were the reaction is catalytic.
H
3
O
+
R
HBX
2
R
'
X= Br, I
R
H BX
2
R
'
R
H B(OH)
2
R
'
temperature
or
HBX
2
, T.M.

Scheme 1.6: Thermal or transition metal-catalyzed cis-hydroboration

1. KBH(i-Pr)
3
R
1. HBBr
2
-SMe
2
Br
R
H B(OR
'
)
2
Br R
H H
B(OH)
2
2. H
3
O
+
2. R
'
OH

Scheme 1.7: Indirect trans-hydroboration of alkynyl bromides

H
3
O
+
R
HB(OR
'
)
2
H
H
R B(OR
'
)
2
H R
R B(OH)
2
H
Rh or Ir cat.

Scheme 1.8: Rhodium- and iridium-catalyzed trans-hydroboration

Alkene metathesis turned out to be very useful towards the synthesis of complex
alkenyl boronic acids (Scheme 1.9). Whether this reaction is chemoselective or not
6
depends on the substrates that the alkene bears. Ethylene and 1-propenyl pinacol borane
were found to be such substrates.
H
3
O
+
R
B(OR
'
)
2
R
B(OH)
2
R
B(OR
'
)
2
Ru CH
2
Scheme 1.9: Alkene metathesis

We have summarized here the most common ways chemists use nowadays to
synthesize boronic acids. Many other methods have been published, but since this is not
the main purpose of this thesis, these will not be discussed herein.

1.1.3.2 Aryl- and heteroaryl-boronic acids
Aryl and heteroaryl boronic acids compose an important class of compounds
widely used in the past 15 years as coupling reagents in the Suzuki reaction [4]. This
reaction constitutes an efficient and very selective method for aryl-aryl, aryl-heteroaryl and
heteroaryl-heteroaryl reductive couplings between halides and boronic acis. These biaryl
compounds often exhibit significant biological activity and exist in many natural products
and pharmaceuticals [5]. Aryl and heteroaryl boronic acids also participate in various C-C
bond formation reactions including the coupling of vinyl or alkyl halides and several
polymerization reactions [6]. As shown in Figure 1.3, this class of molecules exists in all
sizes and shapes making thus, any reaction, which uses them, more versatile.
7
X X
B(OH)
2
B(OH)
2
B(OH)
2
O
O
R
R
R
N
R
NN
R
X
N
R
B(OH)
2
R
X
X= O, S, N
R= any group or chain
B(OH)
2
B(OH)
2
B(OH)
2 B(OH)
2
B(OH)
2
N
B(OH)
2
N
N
N
R
B(OH)
2
N
S
B(OH)
2

Figure 1.3: Some general structures of commercially available boronic acids

1.2 Reactions of boronic acids: Metal-catalyzed reactions
1.2.1 Suzuki coupling reaction
The palladium catalyzed cross coupling reaction between organoboron compounds
and halides (the Suzuki Coupling), has achieved prominence as one of the most important
metal catalyzed carbon-carbon bond forming reactions in organic synthesis. Recent
developments regarding the catalyst, and conditions used, have broadened the possible
applications enormously, so that the scope of the reaction partners is not restricted to aryls,
but includes alkyl, alkenyl and alkynyl groups as well. Potassium trifluoroborates and
organoboranes or boronate esters can replace the boronic acids with success and also
triflates can be used instead of halides as coupling partners. An example is shown in
Scheme 1.10.

8
R
1
B(OH)
2
+
XR
2
Pd catalyst
base
solvent
R
1
R
2
X=halide, triflate

Example:
B(OH)
2
+
O I
O NEt
2
O
5% PdCl
2
(PPh
3
)
2
2M Na
2
CO
3
, DME
reflux, 16hours
O Ph
O NEt
2
O
89%

Scheme 1.10: Palladium-catalyzed Suzuki coupling with boronic acids

1.2.2 Rhodium-catalyzed addition to olefins
In 1997 Miyaura reported that rhodium (I) complexes can catalyze the 1,4-addition
of aryl and alkenyl boronic acids to activated olefins like enones [7]. In 1998 Hayashi
reported the first enantioselective variant of this transformation [8]. Lautens reported in
2001 that the same transformation can take place, with unactivated olefins, in aqueous
media [9]. Darses and Genet showed in 2002 that trifluoroborates can also be employed in
this transformation effectively [10].
R
1
R
2
O
+
R
3
B(OH)
2
or
R
3
BF
3
-
K
+
Rh / ligand
aqueous solvent
100
o
C
R
1
R
2
O R
3

Example:
+Ph B(OH)
2
[Rh
I
] / S-BINAP
dioxane / H
2
O (10 / 1)
100
o
C
O O
Ph

Scheme 1.11: Rhodium catalyzed addition to enones
9
1.2.3 Rhodium-catalyzed addition to aldehydes and imines
The addition of aryl and alkenyl boronic acids to aldehydes, facilitated by rhodium,
was achieved by Miyaura and coworkers in 1998 [11]. The products of this process,
secondary alcohols, were obtained in high yields. These reactions were expedited by the
presence of an electron withdrawing group on the aromatic aldehydes and an electron
donating group on the aryl boronic acids, suggesting nucleophilic attack of the aryl group
on the aldehyde [12]. The same protocol is followed in the case were instead of aldehyde
we have an imine [13].
R
1
H
O
+ R
2
B(OH)
2
[Rh(acac) / ligand]
DME/H
2
O or dioxane/H
2
O
R
1
R
2
OH

Example:
H
O
+
[Rh(acac)(CO)
2
/ dppf]
DME/H
2
O or dioxane/H
2
O
OH
NC NC
B(OH)
2
Me
Me
99%

Scheme 1.12: Rhodium catalyzed addition to aldehydes

1.2.4 Formation of carbonyl compounds
Frost has recently shown that Rhodium can be used to catalyze the addition of
alkenyl or aryl boronic acids to acid anhydrides giving ketones in high yields [14]. This
boron-rhodium transmetallation reaction, which is the equivalent of a Friedel-Crafts
acylation, would promote the acylation of deactivated aryl derivatives [15].

10
R
2
B(OH)
2
R
3
R
1
+
R
4
O R
4
O O
Rh catalyst
solvent
temperature
R
2
R
3
R
1
R
4
O

Example:
B(OH)
2
+
Me O Me
O O
[Rh(ethylene)Cl]
2
DME, 65
o
C
O
2
N
O
2
N
O
Me
56%

Scheme 1.13: Rhodium-catalyzed addition to anhydrides

1.2.5 Chan-Evans-Lam-modified Ullmann condensation
Aryl-Aryl bond formation is widely known to be one of the most important tools in
organic synthesis. These bonds are often found in natural products as well as
pharmaceutical compounds and agrochemicals. The Ullmann reaction involves the
coupling of two aryl halides to form a diaryl compound [16]. The Ullmann condensation is
the formation of ethers from the coupling of aryl halides with phenols [17]. The modified
Ullmann condensation is the formation of a C-N, a C-O or a C-S bond by the reaction of an
aryl or alkenyl boronic acid or trifluoroborate with an aniline, a phenol or a thiophenol
respectively, mediated by a copper species like copper acetate [18, 19, 20].

11
B(OH)
2
B(OH)
2
R
1
R
1
+
R
2
YH
Y=NH, O, S
0.1-1 eq. Cu(OAc)
2
1-10 eq. Et
3
N, DCM
4A M.S., RT
R
1
Y
R
2
Y
R
2
R
1

Example:
B(OH)
2
+
OH
10-20 mol % Cu(OAc)
2
1-10 eq. pyridine, DCM
4A M.S., reflux, air
O
AcHN
EtO
O
I
OH
I
NHAc
OEt
O
I O
I

Scheme 1.14: Modified Ullmann condensation

1.2.6 Heck-type reactions
The conventional Heck reaction involves the reaction of unsaturated compounds
with organic halides as electrophiles [21]. Several nucleophilic organometallic reagents
like silanols and organostannanes have also been used successfully in this conversion [22,
23]. Uemura showed, around 1994, that the reaction of boronic acids with alkenes and
alkynes, contrarily to the other organometallic reagents mentioned above that required
stoichiometric Pd(II) or catalytic amount of Pd(II) in the presence of an appropriate
oxidant, proceeds under Pd(0)-catalyzed conditions [24]. Mori later on showed that Pd(II)
12
can also be used for this process, in the presence of an oxidant like copper (II) acetate in an
aprotic polar solvent like DMF [25].

RB(OH)
2
+
Y
Pd(II)
Cu(OAc)
2
R
Y

Example:
B(OH)
2
+
Ph
Pd(II)
Cu(OAc)
2
Ph
F
3
C
F
3
C

Scheme 1.15: Mizoroki-Heck type reaction

1.3 Reactions of boronic acids: Non-metal catalyzed reactions
1.3.1 Reactions with amines and carbonyls (Petasis reaction)
1.3.1.1 Synthesis of geometrically pure allylamines
Allyl amines are an important group of molecules due to their synthetic utility and
biological activity. Although different methods to synthesize them exist, most of them give
mixtures of regio- and stereo- isomers, and the starting materials are either toxic, or
unstable, and in general difficult to prepare and handle [26]. Recently, it has been shown,
by Petasis and coworkers, that alkenyl boronic acids can be used in a Mannich-type
reaction, [initially called the “Boronic Acid Mannich (BAM) Reaction” and now called
the “Petasis Reaction”], for the production of geometrically pure allyl amines [27]. In the
initial report, this was a two-step process, where secondary amines were first reacted with
paraformaldehyde to generate an aminol, which exists in equilibrium with an iminium salt,
13
and N,N-aminal. Upon addition of an alkenyl boronic acid formation of the allyl amine is
observed with retention of the geometry of the alkenyl group.
R
3
B(OH)
2
NOH
R
1
R
2
N
R
1
R
2
N
R
1
R
2
N
R
2
R
1
N
R
1
R
2
R
3
R
1
R
2
NH
+
(CH
2
O)
n
dioxane or
toluene
90
o
C, 10 min
90
o
C, 30 min
or
25
o
C, 3 hrs
75-96%

Example:
NH
Me
Ph
B
Ph
OH
N Ph
Me
Ph
(CH
2
O)
n
+ +
dioxane or toluene
90
o
C, 30 min
96%
HO

Scheme 1.16: Synthesis of allylamines

1.3.1.2 Synthesis of anti- β-amino alcohols
β-Amino alcohols can be converted to many other molecules including amino
acids, amino aldehydes, and amino sugars. They are also subunits of a number of bioactive
compounds, such as protease inhibitors. They are also very useful as chiral auxiliaries and
as transition metal ligands for asymmetric synthesis and catalysis. The most common
synthetic routes to these versatile molecules are the reduction of carbonyl compounds, the
amino hydroxylation of olefins, nucleophilic ring opening of epoxides, cyclic sulfates, and
aziridines to name a few. Low stereoselectivity and many steps are the main characteristics
of these methods. On the contrary, the one-step three-component reaction between α-
hydroxy aldehydes, amines and alkenyl or aryl boronic acids gives exclusively anti- β-
amino alcohols in >99% de [28].

14
H
O
R
1
OH
R
B(OH)
2
R
R
1
N
OH
R
3
Ar
R
1
N
OH
R
3
R
2
or ArB(OH)
2
NHR
2
R
3
, EtOH
25
o
C, 63-88%
R
2
or

Example:
MeO
B
HO
OH
Ph N Ph
H
O
Me
OH
MeO
Me
OH
N
Ph
Ph
EtOH
25
o
C
+
+
>99% de

Scheme 1.17: Formation of anti- β-amino alcohols

1.3.1.3 Synthesis of novel aminophenol derivatives
Aminophenol derivatives are useful functionalized molecules for the development
of pharmaceuticals and agrochemicals. Their presence is noticeable in a number of natural
products and biologically active compounds. Although simple variants of these molecules
are accessible through mannich reactions with amines, and paraformaldehyde,
salicylaldehydes were found to participate in the three component (Petasis) condensation
reaction, with vinyl and aryl boronic acids, together with secondary amines to provide
more complex forms of these structures in good yields [29]. It is also known that
salicylaldehydes without an o-hydroxy substituent e.g. benzaldehyde do not participate
readily in the reaction, proving that a key intermediate is the boronic acid coordinated to
the oxygen of the phenol.

15
R
1
B
OH
N
H
R
2
R
3
OH
OH
R
4
OH
R
4
N
R
3
R
2
R
1
R
1
: vinyl, aryl, heteroaryl
O
H
+ +

Example:
S
B
OH
OH
O
N
H
NO
2
OH
H
O
S
N OH
NO
2
O
+ +
EtOH
25
o
C, 24h
62%

Scheme 1.18: Petasis reaction with salicylaldehyde derivatives

The products derived from the reaction of ο-hydroxyaromatic aldehydes, amines
and alkenyl boronic acids are shown to undergo cyclization to 2H-chromene compounds
after excessive heating and extraction of the amine moiety as shown by Finn and
coworkers [34]. This same transformation is shown, by the same group, to be taking place
in the presence of a catalytic amount of dibenzyl amine bound to a resin.

B(OH)
2
R
1
R
2
CHO
OH
R
3
O
R
3
R
2
R
1
+
R
2
NH (cat)
dioxane, 90
o
C

Example:
B(OH)
2
CHO
OH O
+
dioxane, 90
o
C
24h, 99%
NHBn

Scheme 1.19: Formation of 2-H Chromenes

16
1.3.1.4 Synthesis of β, γ-unsaturated α-amino acids
The demand for practical and stereoselective methods to prepare non-natural α-
amino acids is an area which is constantly being pursued. These interesting compounds can
serve as building blocks in combinatorial chemistry and drug discovery. Multistep routes
and specialized methods, such as the “Strecker” and “Ugi” condensation, are some of the
ways to synthesize amino acids and their derivatives [30, 31]. A relatively new and
practical method for the synthesis of these molecules is the three component Petasis
reaction involving the condensation of a boronic acid or boronate with an amine and an α-
keto acid (glyoxylic or pyruvic acid) (Scheme 1.20) [32]. Primary, secondary, and even
sterically hindered amines can participate in this process. The reaction with aryl or
heteroaryl boronic acids provides a simple route to an important category of non-
proteinogenic amino acids, the α-arylglycines. In the case where 1,2-diamines are used
with glyoxylic acid, this leads in one step to highly functionalized piperazinones as shown
in Scheme 1.21 [33]. It is important to mention here the dual role of the boronic acid in
this process, serving both as the source of the alkenyl or aryl nucleophile and as the
catalyst for cyclization of the intermediate.
R
2
B
OR
R
3
OR
R
1
R
2
R
3
R
1
R
4
OH
O
O
N
H
R
5
R
6
HO
O
R
4
N
R
5
R
6

Example:
Ph
Br
B
OH
OH
Ph
Ph
NH
2
PhMe
25
o
C Ph
Br
COOH
HN
Ph
Ph
80%
+ + CHOCOOH.H
2
O

Scheme 1.20: Synthesis of amino acids
17
H
OH
O
O
R
2
R
3
B(OH)
2
R
1
R
5
R
6
NH NH
R
7
R
4
H
2
N NHBoc R
2
R
3
R
1
N
H
O OH
NHBoc
R
2
R
3
N
R
1
O OH
R
6
R
5
NH
R
4
+
R
7
H
N
N
H
N
N R
5
R
6
R
4
O
R
1
R
3
R
2
O
R
1
R
3
R
2
R
7
conc HCl
MeOH
then pH~7
BA

Example:
MeCN
80
o
C, 2h
B
OH
OH
MeO
MeO
HN
HN
Bn
Bn
MeO
MeO
N
N
Bn
Bn
O
50%
+ +
CHOCOOH.H
2
O

Scheme 1.21: Formation of piperazinones

1.3.1.5 Mechanistic aspects
A mechanistic hypothesis for the one-step three-component Petasis reaction is
shown in Scheme 1.22. The amine initially reacts with the carbonyl component to form an
aminol that then reacts with the boronic acid to generate in-situ an iminium and borate
species that react irreversibly to form the product and the boric acid by-product. A similar
transformation is also possible through an aminal intermediate which can be formed from
the iminium ion species.
18
N
R
2
R
1
OH
R
3
R
4
N
R
2
R
1
R
4
R
3
N
R
2
R
1
N
R
3
R
4
R
2
R
1
N
R
2
R
1
N
R
3
R
4
B
R
5
R
1
OH
R
2
OH
R
3
R
4
O
R
2
N
R
1
H
N
R
2
R
1
OH
R
3
R
4
B
R
5
OH
OH
OH
B
R
5
OH
OH
B
R
5
OH
OH
B
R
5
OH
OH
R
2
N
R
1
H
- B(OH)3
R
1
N
R
2
R
5
R
3
R
4

Scheme 1.22: Mechanism of the Petasis reaction

1.3.2 Other reactions of boronic acids
1.3.2.1 Conversion of alkenyl boronic acids to alkenyl halides with
halosuccinimides
Alkenyl halides are useful intermediates for coupling reactions e.g. Suzuki
coupling, for stereoselective synthesis of functionalized alkenes and dienes. Some methods
for the preparation of alkenyl halides involve the use of highly reactive halogens, strong
bases, oxidizing agents or mercury salts [39]. The use of alkenyl boronic acids for this
conversion seems to be more practical and environmentally safer due to the compounds’
properties such as chemical and configurational stability, crystallinity, and ease of
19
purification. A method for the preparation of these compounds is the interaction of the
corresponding halogen (I
2
, Br
2
, Cl
2
), in basic medium, with the boronic acid. A
complimentary and sometimes milder conversion of alkenyl boronic acids to geometrically
pure alkenyl halides is with the use of N-iodo-, N-bromo- or N-chloro- succinimides [40].

Example:
N
O O
X
R
2
B
OH
R
3
OH
R
1
R
2
X
R
3
R
1
X=I, Br, Cl
B
OH
OH
Br
NBS/MeCN
25
o
C

Scheme 1.23: Formation of alkenyl halides

1.3.2.2 Ipso substitution of aryl boronic acids
Ipso substitution is the attack of an electrophile directly at the position bearing the
substituent in a substituted aromatic ring. In literature we can find many methods for the
preparation of haloarenes, a group of very important synthetic intermediates [35]. While
chloro- and bromo-arenes are easy to make through electrophilic aromatic halogenation,
the iodo- ones are not. Some methods for the preparation of iodo-arenes include the use of
strong oxidizing reagents for activation of the halogens, the use of highly active and toxic
metal compounds, and the Sandmeyer reaction which takes place under acidic conditions
[36]. A milder method for synthesizing these intermediates is with ipso- substitution of
boronic acids [37] was developed (Scheme 1.24).
20
Y
B
N
MeCN
MeCN
NH
4
NO
3
+
(CF
3
CO)
2
O
OH
OH
O O
X
Y
X
NO
2
NO
2
Y
Y
NO
2
+
X= Br, I

Examples:
B
OH
OH
Cl
Cl
NH
4
NO
3
/(CF
3
CO)
2
O/CH
3
CN
-35
o
C r.t.
NO
2
65%

B
OH
OH
1.0 eq NIS/CH
3
CN
S
25
o
C, 14 h
I
S
72%

Scheme 1.24: Ipso substitution of boronic acids

Aryl and heteroaryl boronic acids were found to react with N-iodo- and N-bromo-
succinimides to give haloarenes in very good yields, under mild conditions. The reaction is
highly regio-selective and yields only the ipso-substituted product. Also, esters of aryl
boronic acids react similarly, but less readily.
Another very important reaction in industrial processes is the nitration of aromatic
rings [38]. The methods used so far were harsh and leading to isomeric products. However,
using aryl boronic acids, a mild regioselective reaction with nitrating agent (trifluoroacetic
anhydride, ammonium nitrate, and acetonitrile) gave mono- and di-nitrated products. Low
concentrations of the nitrating agent yield mono-nitro, while excess agent results to a
mixture of mono- and di-nitro aromatic compounds.

21
1.3.2.3 Addition of allyl boronates to aldehydes
The most widely used reaction of allylboron compounds is the allylboration
reaction, in which allylic boranes and boronic esters undergo rapid reactions with carbonyl
compounds, delivering the allyl group to the carbonyl carbon, resulting to a homoallylic
alcohol or aldol [41]. The resulting molecules can then facilitate the synthesis of more
complex molecules. This kind of reaction is the synthetic equivalent of an aldol reaction, a
fundamental carbon-carbon bond-forming process. Allylborations result in the creation of a
new C-C bond. The reactions proceed chemo- and regioselectively and with the right
choice of reagents, stereo- and enantioselectively. For example the use of chiral auxiliaries
attached to boron, can lead to products with high enantiomeric purity.
B R
2
R
1
R
3
R
4
R
R
-78
o
C
toluene
R
4
R
3
R
1
R
5
OH
R
2
R
5
CHO

Example:
O
B
O
O
O
O
OH
H -78
o
C
toluene
t-Bu
O
H
+ B
O
O
25
o
C
t-Bu
OH
t-Bu
OH
+
99 : 1

Scheme 1.25: Allylboration reactions

22
1.3.2.4 Addition of allyl boronates to imine derivatives
Although the diastereofacial selectivity in the reaction of allylic boron compounds
with aldehydes has been extensively investigated over the past years, not that many
attempts have been made to elucidate such selectivity with imines and derivatives like
oximes, sulfenimides and N-trimethylsilylbanzaldimines. Reactions with this family of
compounds are practically useful for the synthesis of nitrogen-containing natural products,
e.g., amino sugars, amino acids, β-lactams etc. Allyl boron compounds were found to react
with aldoximes, imines, sulfenimides, and N-trimethylsilylbenzaldimines (Scheme 1.27,
Scheme 1.28) to yield the amine products [42, 43]. These reactions are found to be slower
than that of the direct reaction with aldehydes. For instance the reaction of sulfenimides
with allyl boronates occurs only in refluxing toluene or carbon tetrachloride for 3-11 days.
The products of the reaction, the homoallyl sulfenimides are potentially versatile
intermediates for alkaloid synthesis. This methodology compliments the existing
allylborane chemistry with simple imines in that sulfenimides are readily hydrolyzed to
primary amines, whereas imine based chemistry yields only secondary amines in general.
Addition of allyl boronates to oximes of protected glyceraldehydes gives Cram products
predominantly. The selectivities for the reaction are better with chiral boronates than with
achiral ones but, they still are worse in comparison with the corresponding reactions with
aldehydes. On the other hand, the asymmetric allylboration of N-trimethylsilylaldimines
proceeds with very good ee. It is found that this derivative is the most reactive species for
such allylborations.

23
B R
4
R
3
R
5
R
R
toluene, reflux
R
4
3-11 days
R
1
NXR
2
R
3
R
1
R
2
XHN
R
5
X= S, O

Example:
B
O
O
toluene, reflux
9 days
NH +
O
NO
2
N
S
O
S
NO
2
94%

O
H
NOH
O
+ B
O
O
HO
OH
HO
OH
+
NH
2
NH
2
Cram anti-Cram
70 30

Scheme 1.26: Reaction of allyl boronates with imine derivatives

H
NSiMe
3
1.
R
3
R
2
R
1
B R
R
2. H
2
O dropwise
100
o
C
rt, THF
3. NaOH/H
2
O
2
Ar
NH
2
R
3
R
2
R
1
94% ee

Example:
H
NSiMe
3
+
N
B
O
Ph
Ph
Ts
1) -78
o
C, 3h
2)H
3
+
O
3)OH
-
NH
2
89%, 92% ee

Scheme 1.27: Reaction of chiral allylboronate with N-trimethylsilylaldimines
24
1.3.2.5 Stereoselective synthesis of enol acetates
Nowadays organoboron compounds are found to be useful intermediates in many
transformations, but yet no procedure is available for the direct synthesis of the
corresponding alkenyl acetates. There have been several reports in the literature of
reactions in which enol esters serve as intermediates for carbon-carbon or carbon-
heteroatom bond formations so there is a great need for methods and new approaches
towards these versatile intermediates [44]. These useful compounds are usually being
prepared from carbonyl compounds or alkynes, but the synthesis of stereo defined ones,
especially E-isomers has been very difficult. The treatment of alk-1-en-1-yl boronic esters
with (diacetoxy-iodo)-benzene in the presence of sodium iodide and DMF as solvent,
yields the alk-1-en-1-yl acetate in high yields and excellent isomeric purity [45].

R
1
H
H
B(OR)
2
R
1
H
B(OR)
2
H
R
1
H
OCOCH
3
H
R
1
H
H
OCOCH
3
+ PhI(OCOCH
3
)
2
NaI/DMF
r.t.

Example:
NC(CH
2
)
2
H
H
B(O i-Pr)
2
Bu
H
B(O i-Pr)
2
H
NC(CH
2
)
2
H
OCOCH
3
H
Bu
H
H
OCOCH
3
+
PhI(OCOCH
3
)
2
NaI/DMF
r.t.
85%, >99% isomeric purity
72%, >99% isomeric purity

Scheme 1.28: Synthesis of enol-acetates
25
1.3.2.6 Stereospecific synthesis of vinyl-(phenyl) iodonium tetrafluoroborates
The phenyliodonyl group is known to be an excellent leaving group. Because of
the properties of this group, vinyl-(phenyl) iodonium salts can undergo nucleophilic vinylic
substitutions under mild conditions, providing a useful route for the synthesis of olefins
with different functionalities like α-cyano and α-nitro olefins, vinyl sulphides and
sulphones, and vinyl halides. Also base-induced α-elimination generates
alkylidenecarbenes, which undergo 1,5-carbon-hydrogen insertion yielding cyclopentenes.
Unfortunately, the efficient methods available for the synthesis of these useful salts are
limited to reactions of vinylsilanes or stannanes with hypervalent organoiodanes for their
stereoselective production, and Michael additions or Diels-Alder reactions for the synthesis
of functionalized ones [46]. Recently, alkenyl boronates have been found to undergo
smooth boron-iodine exchange by the reaction with hypervalent phenyliodanes in the
presence of BF
3
.
Et
2
O [47]. The transfer of the alkenyl group takes place with complete
retention of stereochemistry, and the products are generally produced in excellent yields.
R
1
R
2
H
B(OH)
2
R
1
R
2
H
I
+
(Ph)BF
4
-
1)PhI(OAc)
2
BF
3
-Et
2
O
CH
2
Cl
2
, 0
o
C
2) aq. NaBF
4

Example:
t-Bu
H
H
B(OH)
2
t-Bu
H
H
I
+
(Ph)BF
4
-
1)PhI(OAc)
2
BF
3
-Et
2
O
CH
2
Cl
2
, 0
o
C
2) aq. NaBF
4
96%

Scheme 1.29: Synthesis of Vinyl-(phenyl) iodonium Tetrafluoroborates
26
1.4 Dissertation overview
The versatile character, reactivity, ease of availability, and environmental
properties of organoboron compounds such as organoboronic acids and trifluoroborates,
make them attractive intermediates in modern organic synthesis and more specifically in
combinatorial chemistry, and create a clear demand for the development and utilization of
new synthetic methodologies involving these versatile reagents.
In this dissertation various applications of the Petasis Reaction are being explored,
including the demonstration of the reactivity of various aryl and alkenyl boronic acids
towards the formation of several types of interesting molecules including benzylic amines
and imidazole containing derivatives. A number of reactions involving trifluoroborates are
also described, including, three-component reactions to form aminoacids and allyl amines,
as well as reactions with quinolines and imines in the presence of chloroformates to form
novel heterocycles.

Figure 1.4: Various applications of the Petasis reaction
RBF
3
-
K
+
N
Me
Me R
N
R
1
R
2
N
R
1
R
2
R
R
O
O
R
0
O O R
0
N
R
1
R
2
N
R
1
R
2
R
R COOH
N
R
2
R
1
R
O
R
0
RB(OH)
2
N
R
1
R
2
Ar
N
R
1
R
2
Het
N
R
1
R
2
R
N
R
1
R
2
R
HN
N
HN
N
27
1.5 Chapter 1 References

1. Miyaura, N. “Organoboron Compounds.” Journal of Organometallic Chemistry,
2002, 653(219), p. 11-57.

2. Hall, D. G. “Boronic Acids.” Copyright 2005, WILEY-VGH verlag Gmb H&C,
KGaA, Weinheim, ISBN 3-527-30992-8.

3. Frankland, E. Journal of Chemical Society, 1862, 15, p. 363.

4. Suzuki, A. “Carbon-Carbon Bonding Made Easy.” Chemical Communications,
2005, 38, p. 4759-4763.

5. Miyaura, N. “Organoboron Compounds.” Journal of Organometallic Chemistry,
2002, 653(219), p. 11-57.

6. Allen, I., Pounds, T., Murtagh, L., Wallace, P., Towns, C. “Modified Suzuki
Method for Polymerization of Aromatic Monomers” PCT Int. Appl. 2003, 20pp.
CODEN: PIXXD2 WO 2003035796 A1 20030501 CAN 138:354447.

7. Sakai, M., Hayashi, H., Miyaura, N. “Rhodium-Catalyzed Conjugate Addition of
Aryl- or 1-Alkenylboronic Acids to Enones.” Organometallics, 1997, 16, p. 4229-
4231.

8. Takaya, Y., Ogasawara, M., Hayashi, T., Sakai, M., Miyaura, N. “Rhodium-
Catalyzed Asymmetric 1,4-Addition of Aryl- and Alkenylboronic Acids to
Enones.” Journal of the American Chemical Society, 1998, 120, p. 5579-5580.

9. Lautens, M., Roy, A., Fukuoka, K., Fagnou, K., Martin-Matute, B. “Rhodium-
Catalyzed Coupling Reactions of Arylboronic Acids to Olefins in Aqueous
Media.” Journal of the American Chemical Society, 2001, 213(22), p. 5358-5359.

10. Pucheault, M., Darses, S., Genet, J. P. “Potassium Organotrifluoroborates: New
Partners in Catalytic Enantioselective Conjugate Additions to
Enones.“Tetrahedron Letters, 2002, 43, p. 6155-6157.

11. Sakai, M., Ueda, M., Miyaura, N. “Rhodium-Catalyzed Addition of
Organoboronic Acids to Aldehydes.”Angewandte Chemie- International Edition,
1998, 37(23), 3279-3281.

12. Ueda, M., Miyaura, N.“A Large Accelerating Effect of Tri(tert-butyl)phosphine in
the Rhodium-Catalyzed Addition of Arylboronic Acids to Aldehydes.”Journal of
Organic Chemistry, 2000, 65, p. 4450-4452.

13. Beenen, M. A., Weix, D. J., Ellman, J. A. “Asymmetric Synthesis of Protected
Arylglycines by Rhodium-Catalyzed Addition of Arylboronic Acids to N-tert-
28
Butanesulfinyl Imino Esters.” Journal of the American Chemical Society, 2006,
128(19), p. 6304-6305.

14. Frost, C. G., Wadsworth, K. J. “Rhodium Catalysed Addition of Boronic Acids to
Anhydrides: A New Method for the Synthesis of Ketones.” Chemical
Communications, 2001, p. 2316-2317.

15. Effenberger, F., Eberhard, J. K., Maier, A. H. “The First Unequivocal Evidence of
the Reacting Electrophile in Aromatic Acylation Reactions.” Journal of the
American Chemical Society, 1996, 118(50), p. 12572-12579.

16. Zhiming, W., Weiliang, B., Yong, J. “L-Proline Promoted Ullmann-type Reaction
of Vinyl Bromides with Imidazoles in Ionic Liquids.” Chemical Communications,
2005, 22, p. 2849-2851.

17. Weingarten, H. “Ullmann Condensation.” Journal of Organic Chemistry, 1964,
29(4), p. 977-978.

18. Chan, D. M. T., Monaco, K. L., Wang, R., Winters, M. P. “New N- O-Arylations
with Phenylboronic Acids and Cupric Acetate.” Tetrahedron Letters, 1998, 39, p.
2933-2936.

19. Evans, D. A., Katz, J. L., West, T. R. “Synthesis of Diaryl Ethers Through the
Copper-Promoted Arylation of Phenols with Arylboronic Acids. An Expedient
Synthesis of Thyroxine.” Tetrahedron Letters, 1998, 39, p. 2937-2940.

20. Lam, P. Y. S., Clark, C. G., Saubern, S., Adams, J., Winters, M. P., Chan, D. M. T.
New Aryl/Heteroaryl C-N Bond Cross-Coupling Reactions via Arylboronic
Acid/Cupric Acetate Arylation.” Tetrahedron Letters, 1998, 39, p. 2941-2944.

21. Heck, R. F., Nolley, J. P. “Palladium-Catalyzed Vinylic Hydrogen Substitution
Reactions with Aryl, Benzyl, and Styryl Halides.” Journal of Organic Chemistry,
1972, 37, p. 2320-2322.

22. Hirabayashi, K., Nishihara, Y., Mori, A., Hiyama, T. “A Novel C-C Bond Forming
Reaction of Aryl- and Alkenylsilanols. A Halogen-Free Mizoroki-Heck Type
Reaction.” Tetrahedron Letters, 1998, 39, p. 7893-7896.

23. Hirabayashi, K., Ando, J., Nishihara, Y., Mori, A., Hiyama, T. “A Coupling
Reaction of Aryltributyltin with Olefins Mediated by Palladium(II) Acetate.”
Synlett, 1999, 1, p. 99-101.

24. Cho, C. S., Uemura, S. “Palladium-Catalyzed Cross-Coupling of Aryl and Alkenyl
Boronic Acids with Alkenes via oxidative addition of a Carbon-Boron Bond to
Palladium(0).” Journal of Organometallic Chemistry, 1994, 465, p. 85-92.

29
25. Du, X., Suguro, M., Hirabayashi, K., Mori, A. “Mizoroki-Heck type Reaction of
Organoboron Reagents with Alkenes and Alkynes. A Pd(II)-Catalyzed Pathway
with Cu(OAc)
2
as an Oxidant.” Organic Letters, 2001, 3(21), p. 3313-3316.

26. Zavialov, I. A. “New Reactions of Organoboronic Acids and their Derivatives.”
Ph.D. Thesis, University of Southern California, 1998, p. 127-130.

27. Petasis, N. A., Akritopoulou-Zanze, I. “The BAM reaction: A New Method for the
Synthesis of Geometrically Pure Allylamines.” Tetrahedron Letters, 1993, 34(4),
p. 583-586.

28. Petasis, N. A., Zavialov, I. A. “Highly Stereocontrolled One-Step Synthesis of
Anti- β-Amino Alcohols from Organoboronic Acids, Amines, and α-Hydroxy
Aldehydes.” Journal of the American Chemical Society, 1998, 120, p. 11798-
11799.

29. Petasis, N. A., Boral, S. “One-Step Three-Component Reaction Among
Organoboronic Acids, Amines and Salicylaldehydes.” Tetrahedron Letters, 2001,
42(4), p. 539-542.

30. Yet, L. “Recent Developments in Catalytic Asymmetric Strecker-Type Reactions.”
Angewandte Chemie, International Edition, 2001, 40(5), p. 875-877.

31. Domling, A., Ugi, I. “Multicomponent Reactions with Isocyanides.” Angewandte
Chemie, International Edition, 2000, 39, p. 3168-3210.

32. Petasis, N. A., Zavialov, I. A. “A New and Practical Synthesis of α-Amino Acids
from Alkenyl Boronic Acids.” Journal of the American Chemical Society, 1997,
119, p. 445-446.

33. Petasis, N. A., Patel, Z. D. “One-Step Three-Component Reaction Among
Organoboronic Acids, Amines and Salicylaldehydes.” Tetrahedron Letters, 2000,
41(49), p. 9607-9611.

34. Wang, Q., Finn, M. G. “2H-Chromenes from Salicylaldehydes by a Catalytic
Petasis Reaction.” Organic Letters, 2000, 2(25), p. 4063-4065.

35. De la Mare, P. B. D. “Pathways in Electrophilic Aromatic Substitution.
Cyclohexadienes and Related Compounds as Intermediates in Halogenation.”
Accounts of Chemical Research, 1974, 7(11), p. 361-368.

36. Merkushev, E. B. “Advances in the Synthesis of Iodoaromatic Compounds.”
Synthesis, 1988, 12, p. 923-937.

37. Thiebes, C., Prakash, G. K. S., Petasis, N. A., Olah, G. A. “Mild Preparation of
Haloarenes by Ipso-Substitution of Arylboronic Acids with N-Halosuccinimides.”
Synlett, 1998, 2, p. 141-142.
30
38. Prakash, G. K., Panja, C., Mathew, T., Surampudi, V., Petasis, N. A., Olah, G. A.
“Ipso-Nitration of Arylboronic Acids with Chlorotrimethylsilane-Nitrate Salts.”
Organic Letters, 2004, 6(13), p. 2205-2207.

39. Zavialov, I. A. “New Reactions of Organoboronic Acids and their Derivatives.”
Ph.D. Thesis, University of Southern California, 1998, p. 78-85.

40. Petasis, N. A., Zavialov, I. A. “Mild Conversion of Alkenyl Boronic Acids to
Alkenyl Halides with Halosuccinimides.” Tetrahedron Letters, 1996, 37(5), p.
567-570.

41. Brown, H. C., Jadhav, P. K. “Asymmetric Carbon-Carbon Bond Formation via
Beta-Allyldiisopinocampheylborane. Simple Synthesis of Secondary Homoallylic
Alcohols with Excellent Enantiomeric Purities.” Journal of the American Chemical
Society, 1983, 105(7), p. 2092-2093.

42. Huts, P. G. M., Jung, Y. W. “Additions of Allyl Boronates to Sulfenimides.”
Tetrahedron Letters, 1986, 50(19), p. 2079-2082.

43. Sougato, B. “Synthesis of Polyfunctional Molecules Using Organoboron
Compounds.” Ph.D. Thesis, University of Southern California, 2001, p. 16-26.

44. Balaban, T. S., Hiegemann, M. “Hydrogen Peroxide Oxidation of Polysubstituted
Pyrylium Salts: Formation of Enol Esters and Furans.” Tetrahedron, 1992, 48(45),
p. 9827-9840.

45. Murata, M., Satoh, K., Watanabe, S., Masuda, Y. “Stereoselective Synthesis of
Enol Acetates by the Reaction of Alkenylboronates with (Diacetoxyiodo)Benzene
and Sodium Iodide.” Journal of the Chemical Society, Perkin Transaction 1:
Organic and Bio-Organic Chemistry. 1998, 9, p. 1465-1466.

46. Ochiai, M., Toyonari, M., Nagaoka, T., Chen, D., Kida, M. “Stereospecific
Synthesis of Vinyl(phenyl)iodonium Tetrafluoroborates via Boron-Iodane
Exchange of Vinylboronic Acids and Esters with Hypervalent Phenyliodanes.“
Tetrahedron Letters, 1997, 38(38), p. 6709-6712.

47. Ochiai, M., Toyonari, M., Nagaoka, T., Chen, D., Kida, M. “Stereospecific
Synthesis of Vinyl(phenyl)iodonium Tetrafluoroborates via Boron-Iodane
Exchange of Vinylboronic acids and esters with Hypervalent Phenyliodanes.”
Tetrahedron Letters, 1997, 38(38), p. 6709-6712.
31
CHAPTER 2
Reactions of Boronic Acids with Formaldehyde and
Amines
2.1 Introduction
The two step reaction of amines with formaldehyde and alkenyl boronic acids for
the formation of geometrically pure allylamines, was the first example of this type of
chemistry (Petasis reaction) that was reported [1]. The work described in this Thesis
concentrated on further investigation of this reaction, including mechanistic studies, the
improvement of reaction conditions, and the introduction of aryl and heteroaryl boronic
acid moieties for the formation of unique benzylic amine derivatives.

2.1.1 Properties of benzylic amines
Over the past twenty years, the development of combinatorial chemistry has
facilitated the rapid production of compounds to serve as scaffolds for the formation of
more complex molecules, which would possibly have certain biological activity to serve as
pharmaceuticals [2]. Amines and their derivatives are very widespread functional groups
and have always been amongst the favorite scaffolds and rank as one of the most important
classes of molecules in organic synthesis [3, 4]. The benzylic amine moiety is found in
various natural products, pharmaceuticals and fine biologically important chemicals [5].
The most common ways to synthesize benzylic amines are: (a) the reductive
amination which involves the reaction of amines with benzylic aldehydes and formation of
an imine intermediate, followed by its reduction to the final benzylic amine species
32
(Scheme 2.1) [6]. (b) the nucleophilic substitution which involves the reaction of amines
with benzyl halides [7].
N
R
'
H
R
+
Ar
O
H
N
R
'
R
Ar
+
Ar X
X= halide
NaBH(OAc)
3
DCM
CH
3
CN

Scheme 2.1: Formation of benzylic amines

2.2 Results and discussion
Herein we introduce the one-step three-component synthesis of benzylic amines
which involves the reaction of aryl- or heteroaryl- boronic acids, amines and formaldehyde
or paraformaldehyde (Scheme 2.2). Improved reaction conditions were developed,
including a better solvent and the use of microwaves to make this process faster and
possibly more efficient.
N
R
'
H
R
N
R
'
R
Ar
Ar
B
H
2
O
HCHO
90
o
C
or
Het
B
N
R
'
R
Het
+
HO
OH
HO
OH

Figure 2.1: General reaction

33
2.2.1 Improving the reaction conditions
The main concern of this project was the reaction of aryl and heteroaryl boronic
acids with amines and formaldehyde or paraformaldehyde. Although similar reactions with
alkenyl boronic acids were reported earlier [1], the simple replacement of the alkenyl
boronic acids with aryl and heteroaryl ones was not straightforward and reguired further
investigation.
Previously, this reaction was mainly done in dioxane under dry conditions and in
two steps. At first the amine was mixed with paraformaldehyde and refluxed to 90
o
C until
an intermediate was formed and then the boronic acid was added and continued refluxing
until completion. In an effort to make the two-step process to a one step three-component
one, we found that the resulting yields were similar. We found that there was no need of
premixing the amine with the formaldehyde and then adding the boronic acid half an hour
or one hour later. Similar results were obtained by performing the reaction open to air,
eliminating the need for flame dried flasks and reactions under argon or nitrogen. However
the one-step three components process could not be performed without heat and there was
no reaction, even after several days of stirring.
We also investigated other solvents for this process, since dioxane is not exactly an
ideal solvent due to its toxicity. For this test, styryl-boronic acid, N-benzyl-methylamine
and paraformaldehyde or formaldehyde were used. The results as shown in Table 2.1 were
somewhat surprising. Not only dry conditions were not needed but the experiment could
also be done in water using, instead of paraformaldehyde, formaldehyde 37% wt in water.
34
N
Me
H
Ph
Ph
B(OH)
2
1. (CH
2
O)
n
, dioxane
dry conditions
2 steps, reflux
Conditions % yield
2. (CH
2
O)
n
, dioxane
air
2 steps, reflux
3. (CH
2
O)
n
, dioxane
air
1 step, reflux
4. (CH
2
O)
n
, dioxane
air
1 step, R.T
5. HCHO, DMF
air
1 step, reflux
6. HCHO, toluene
air
1 step, reflux
7. HCHO, Cyclohexane
air
1 step, reflux
8. HCHO, H
2
O
air
1 step, reflux
87
85
86
traces
47
87
65
86
+
Table 2.1: Exploration of reaction conditions
of the Petasis reaction
Entry

35
2.2.2 Synthesis of benzylic amines
The benzylic amines were simply formed by mixing the amine with the aryl or
heteroaryl boronic acid and formaldehyde in water refluxing the reaction mixture. As
mentioned above the reaction does not work at room temperature.
In all cases some excess of the aldehyde and the boronic acid was used thus
helping for the full transformation (in some occasions) of the amine to product. The
reaction in many examples was very clean without any side products and the product was
easily separated with a simple base extraction or flash chromatography (ethyl acetate /
hexanes) when needed.
Table 2.2 shows the benzylic amines that have been synthesized. The amines used
were mostly secondary since these were found to be working better in this reaction.
Primary amines and anilines also worked with giving mainly the monosubstituted product
in good yields. A diamine, like piperazine was employed as well, yielding the disubstituted
product in excellent yields.
Amino acids were possible to be synthesized using this technique as well. The
carboxylic group could equally be present either in the amine species or in the boronic acid
moiety (Table 2.3).
Most of the benzylic amines synthesized, can further be manipulated to more
complex molecules, thus making them great scaffolds for use in industry for the formation
of pharmaceutically useful compounds [8].
36
Table 2.2: Synthesis of benzylic amines between the reaction of amines,
boronic acids and formaldehyde in water

ON
O
67%
ON
O
94%
N
Ph
Ph
N
Ph
Ph
O
O
O
86%
66%
HN
O
O
65%
HN
O
5%
NN
O
O
97%
N
Ph
Ph
S
73%
NN
Ph
S
N
S
70%
NN Boc
37%
NN Boc
O
97%
HN
Ph
O
45%
21%
N
O Br
22%
NN
O
74%

Reaction conditions: Boronic acid, amine and formaldehyde were added in water
and refluxed for 1-24 hours.

37
Table 2.3: Synthesis of amino acids

52%
N
Me
COOH
46%
N
O
COOH
B
COOH
B
O
N
COOH
N
Me
H
H
OH
HO
OH
HO
1
4
Amine Boronic acid Product time(days) Yield

Reaction conditions: Boronic acid, amine and formaldehyde were added in water and refluxed for
8-24 hours.

2.2.3 Use of microwaves in the Petasis reaction
Since microwaves were known from the literature to be speeding up
transformations and this was done best when water was used as solvent, due to water’s
high dielectric constant, we thought that this would be ideal for our chemistry and very
beneficial. The reaction times could be cut down drastically.
Indeed that was the case. Not only the reaction times from several hours were cut
down to several minutes, but also the yields in some cases were improved significantly.
The microwaves proved to be superior compared to the conventional ways of heating not
because of the yields but because of their practicality and time of the reactions (Table 2.4).
38
Table 2.4: Comparison of microwave to conventional heating
N
Ph
Ph
N
Ph
Ph
N
Ph
Ph
O
O
O
N
Ph
Ph
S
NN
Ph
S
Product
Microwave heating Conventional heating
time(min) yield(%) time(hours) yield(%)
60
87
90
42
56
86
73
86
66
21
4
8
8
2
18
8
15
12
13
20

Microwave heating conditions: Boronic acid, amine and formaldehyde added in
water in a microwave tube and heated for 5-20 minutes.
Conventional heating conditions: Boronic acid, amine and formaldehyde refluxed
in water for 1-24 hours.
39
2.3 Conclusion
In this chapter we discussed the evolution of a two step three component reaction
to a one step three component reaction. We showed that aryl and heteroaryl boronic acids
can work well in this process for the formation of benzylic amines, showing at the same
time that this three component reaction is very versatile and practical. Microwaves were
also introduced for the first time in this process as a form of heating tool with some very
promising results.
40
2.4 Experimentals
2.4.1 General
All reagents and commonly available starting materials were purchased from
available commercial sources. Thin layer chromatography was performed on pre-coated
TLC plates (silica gel 60 F
254
) and flash chromatography using Silica gel 60, which has a
particle size range between 0.040 – 0.063 mm. NMR spectra were obtained on either a
Bruker AMX-500 MHz, a Bruker AM-360 MHz or a Bruker AC-250 MHz instrument.
High resolution mass spectra were obtained at the University of California at Los Angeles
Mass Spectrometry facility.

2.4.2 General procedures
2.4.2.1 Synthesis of boronic acids

(E)-Styryl-boronic acid

Ph
B OH
HO
Procedure I [9]: A sealed flask containing phenylacetylene (4,791 mg, 45.90
mmol), and catechol-borane (5 ml, 45.97 mmol) under argon was heated at 80
o
C for 2 h
during which time the colorless mixture turned brown. It was then cooled to 25
o
C and
opened to the air. Water was added and the mixture was heated again at 80
o
C for 30 min.
41
Cooling at 25
o
C led to a brownish solid, which was filtered, washed with cold water and
recrystallized from hot water, then dried under vacuum to give fluffy white crystals of the
boronic acid (2,412 mg, 40%).
Procedure II[10]: All glassware used, were flame dried. BCl
3
(1.0 mol, 150 ml)
was added to a 500 ml round bottom flask and cooled to 0
o
C. Triethyl silane (150 mmol,
23.95 ml) and phenyl-acetylene (150 mmol, 16.47 ml) were pre-mixed in a 100 ml round
bottom flask, and then transferred dropwise via syringe to the BCl
3
flask. After addition the
solution was removed from the ice bath and let to warm to room temperature for 10
minutes, then cooled back to 0
o
C. 150 ml of 3N NaOH were injected to the mixture and let
stir for 5 minutes. The mixture was then poured into a separatory funnel and extracted with
ethyl ether anhydrous (3 x 50 ml). The water layer was then decolorized with carbon, and
upon addition of 6N HCl, until neutral, white precipitate formed. The precipitate was then
filtered and dried to yield a fine white powder.
1
H NMR (250 MHz, CDCl
3
) δ 7.77 (d,
J=18.17 Hz), 7.62-7.25 (m), 6.34 (d, J=18.11 Hz), 6.12 (d, J=18.40 Hz), 4.31 (s), 1.55 (s);
13
C NMR (250 MHz, CDCl
3
) δ 152.3, 137.2, 129.5, 128.7, 127.6, 127.1.

2-Bromo-2-phenyl-vinyl-boronic acid

Ph
B OH
HO
Br
Everything was done in flame dried flask under argon atmosphere.
Phenylacetylene (39.2 mmol, 4.3 ml) was added dropwise to a solution of 1M BBr
3
(40
42
mmol, 10 gr) in dichloromethane at -78
o
C. The reaction mixture was stirred at that
temperature for 20 minutes and then let warm to room temperature and stir for another 30
minutes. Water (15 ml) was carefully added to the mixture, after it was cooled to 0
O
C in ice
bath, resulting to a biphasic system. The biphasic system was then stirred rigorously for 20
minutes at room temperature. The mixture was then added to a separatory funnel and the
organic layer was separated, washed with brine, dried over Na
2
SO
4
and evaporated. The
resulting brownish solid was transferred to a buchner funnel and washed with hexanes to
yield a white solid (7.0 gr, 80%).
1
H NMR (500 MHz, CDCl
3
) δ 7.24-6.80 (m, 5H), 6.63 (s,
1H).

2.4.2.2 Synthesis of amine derivatives
General procedure A: In a flame dried flask under argon equipped with a
condenser the amine, dioxane and paraformaldehyde were added. The resulting slurry was
heated at 90
o
C for 5 to 10 minutes at which point the solution cleared and TLC indicated
consumption of most of the amine and formation of a new spot. The reaction flask was
then removed from the oil heating bath and boronic acid was added from the top of the
condenser followed by more dioxane. The mixture was heated at 90-95
o
C and the progress
of the reaction was followed by TLC. Upon completion, 1N HCl was added until pH=0 and
the aqueous phase was washed three times with EtOAc. Then NaOH was added to the
aqueous phase till pH=14 while being in ice bath. The product was extracted with DCM
and dried over MgSO
4
. Filtration and removal of the solvents afforded the pure product. In
some occasions additional purification was carried, through the means of flash column
chromatography or preparative TLC.
43
General procedure B: The amine, boronic acid, and solution of formaldehyde in
water were added at the same time in a flask open to the air, equipped with a condenser.
More water was added to the reaction which was heated to 90-95
o
C. The progress was
followed by TLC and upon completion, NaOH was added till pH=14 (or pH=7 in case of
amino-acid as product). The product was extracted with DCM and dried over MgSO
4
.
Filtration and removal of the solvents afforded the pure product. In some occasions
additional purification was carried, through the means of flash column chromatography or
preparative TLC.
General procedure C: The amine, boronic acid, and formaldehyde were added to
a microwave tube with 3ml of water and sealed. The microwave settings used were: a)
Power between 100-200 Watts, b) Temperature between 100-150
o
C, c) Pressure 250 Psi,
and d) Time of reaction 10-20 minutes. After the reaction was done, followed by TLC, the
mixture was let to cool for a few minutes at room temperature. Then the cup was removed
after releasing the pressure with a needle and the mixture was poured to a separatory
funnel. NaOH was added to the mixture and then extraction took place with 3 x 10 ml
dichloromethane. Further purification was necessary in all cases through flash column
chromatography, since microwave reactions yielded more byproducts in most of the
reactions in comparison with conventional ways.

44
2.4.3 Specific syntheses and physical properties

1,4-Bis-furan-2-ylmethyl-piperazine.

NN
O
O

The product was prepared on 0.5 mmol scale using general procedure B. The
reaction time was 12 hours. 6N NaOH was used instead of 3N NaOH. Following the base
extraction with DCM the residue was purified via silica chromatography at first with 100%
EtOAc, followed by 1:1 EtOAc / MeOH, and finally 9:1 MeOH / NH
4
OH to yield 87 mg
of desired product (97%).
1
H NMR (250 MHz, CD
3
OD) δ 7.45(m, J=1.7, 0.9 Hz, 2H), 6.35
(dd, J=3.2, 1.9 Hz, 2H), 6.28 (dd, J=2.4, 0.7 Hz, 2H), 3.55 (s, 4H), 2.53 (br. s, 8H);
13
C
NMR (250 MHz, CD
3
OD) δ 154.7, 147.1, 11.4, 110.5, 55.0, 53.6.

1-Benzyl-4-(5-methyl-thiophene-2-ylmethyl)-piperazine

NN
Ph
S
The product was prepared on 0.5 mmol scale using general procedure B and
general procedure C. For procedure B reaction time was 18 hours. 6N NaOH was used
instead of 3N NaOH. Following the base extraction with DCM the residue was purified via
45
silica chromatography (20% Hexanes in EtOAc) to yield the product (30 mg, 21%). For
procedure C reaction time was 20 minutes (Power = 200 Watt, Temperature = 140
o
C,
Pressure = 40 Psi). After base extraction with 6N NaOH the residue was dried and then
purified with silica chromatography (70% EtOAc in hexanes) to yield the product (82mg,
56%).
1
H NMR (250 MHz, CD
3
OD) δ 7.32-7.20 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.60-
6.57 (m, 1H), 3.63 (s, 2H), 3.52 (s, 2H), 2.62-2.42 (br. s, 8H), 2.41 (s, 3H);
13
C NMR (250
MHz, CD
3
OD) δ 141.0, 138.6, 138.3, 130.7, 129.3, 128.4, 128.1, 125.8, 63.8, 57.7, 53.6,
53.2, 15.2.

1-(4-methoxy-benzyl)-4-methyl-piperazine

N
O
N

The product was prepared on 0.31 mmol scale using the reaction conditions similar
to general procedure B. The reaction was refluxed for 4 hours. After base extraction (3N
NaOH), with 3 x 10 ml DCM, the residue was purified via silica chromatography (10%
MeOH in Dichloromethane) to yield the product (50 mg, 74%).
1
H NMR (250 MHz,
CD
3
OD) δ 7.22 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 3.77 (s, 3H), 3.47 (s, 2H), 2.86-
2.23 (m, 8H), 2.29 (s, 3H);
13
C NMR (250 MHz, CD
3
OD) δ 131.9, 114.7, 63.1, 55.7, 55.5,
53.2, 45.8.

46
4-(4-Methoxy-benzyl)-morpholine

ON
O

The product was prepared on 1.0 mmol scale using the reaction conditions similar
to general procedure A. Base extraction yielded the product without the need of any
further purification (139 mg, 67%).
1
H NMR (250 MHz, CD
3
OD) δ 7.31 (m, 2H), 6.92 (m,
2H), 3.87 (s, 3H), 3.79 (t, J=4.6 Hz, 4H), 3.51 (s, 2H), 2.49 (t, J=4.6 Hz, 4H);
13
C NMR
(250 MHz, CD
3
OD) δ 160.7, 132.0, 129.9, 114.7, 67.7, 63.8, 55.8, 54.6.

4-[(Benzyl-methyl-amino)-methyl]-benzoic acid

N
Ph
COOH

The product was prepared on 0.8 mmol scale using the reaction conditions similar
to general procedure B. After neutralization and extraction with EtOAc, the residue was
purified via silica chromatography (85% EtOAc : 10% MeOH : 5% NH
4
OH), to yield the
product (93 mg, 46%).
1
H NMR (250 MHz, CD
3
OD) δ 7.99 (d, J=8.2 Hz, 2H), 7.45 (d,
J=8.2 Hz, 2H), 7.43-7.29 (m, 5H), 3.89 (s, 2H), 3.86 (s, 2H), 2.38 (s, 3H);
13
C NMR (250
MHz, CD
3
OD) δ 172.4, 138.7, 135.1, 131.3, 131.0, 130.9, 130.0, 129.9, 129.8, 61.8, 61.3,
41.0.

47
Benzyl-(4-methoxy-benzyl)-amine

HN
Ph
O

The product was prepared on 0.5 mmol scale using the reaction conditions similar
to general procedure B. The reaction was refluxed for 3 days. After base extraction (1N
NaOH), with 3 x 10 ml DCM, the residue was purified via silica chromatography (20%
EtOAc in Hexanes) to yield the product (49 mg, 45%).
1
H NMR (250 MHz, CD
3
OD) δ
7.49-7.23 (m, 7H), 6.96-6.87 (m, 2H), 3.83 (s, 3H), 3.57 (s, 2H), 3.52 (s, 2H);
13
C NMR
(250 MHz, CD
3
OD) δ 160.1, 141.0, 132.5, 131.5, 130.3, 129.6, 128.4, 114.7, 58.9, 58.3,
55.9.

Benzofuran-2-ylmethyl-dibenzyl-amine

N
Ph
Ph
O

The product was prepared on 0.8 mmol scale using the reaction conditions similar
to general procedure B and general procedure C. For procedure B reaction time was 4
hours. After base extraction (1N NaOH), with 2 x 10 ml DCM, product was isolated (as
yellow liquid), without any further purification (228 mg, 86%). For procedure C reaction
time was 8 min (employed power equal to 100 Watts, temperature 130
o
C, and pressure 250
48
Psi). After base extraction with 6N NaOH, flush column chromatography was needed for
further purification (5% EtOAc in Hexanes) of the product (160 mg, 60%).
1
H NMR (250
MHz, CD
3
OD) δ 7.55-7.51 (dd, J=7.6, 1.3 Hz, 1H), 7.48-7.44 (dd, J=8.2 Hz, 0.7 Hz, 1H),
7.44-7.39 (m, 4H), 7.34-7.28 (m, 4H), 7.26-7.15 (m, 4H), 6.64 (s, 1H), 3.73 (s, 2H), 3.65
(s, 4H);
13
C NMR (250 MHz, CD
3
OD) δ 157.9, 157.0, 141.2, 130.8, 130.5, 130.3, 129.0,
125.7, 124.6, 122.6, 113.2, 107.2, 59.7, 51.7.

Benzo[b]thiophen-2-ylmethyl-benzyl-phenyl-amine

N
Ph
Ph
S

The product was prepared on 0.5 mmol scale using the reaction conditions similar
to general procedure B and general procedure C. For procedure B reaction time was 8
hours in which time TLC showed the boronic acid being consumed. After base extraction
(3N NaOH), with 3 x 10 ml DCM, the residue was dried over magnesium sulfate and
evaporated. Further purification was needed employing silica chromatography using 5%
EtOAc in Hexanes, to isolate the product (120 mg, 73%). For procedure C reaction time
was 15 minutes (Power = 200 Watt, Temperature = 150
o
C, Pressure = 40 Psi). After base
extraction with 3N NaOH the residue was dried and then purified with silica
chromatography (5% EtOAc in hexanes) to yield the product (143 mg, 87%).
1
H NMR
(250 MHz, CD
3
OD) δ 7.75 (d, J=7.5 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.10-7.33 (m, 10H),
49
6.85 (m, 2H), 6.67 (m, 1H), 4.84 (s, 2H), 4.65 (s, 2H);
13
C NMR (250 MHz, CD
3
OD) δ
141.1, 138.5, 138.2, 130.8, 129.3, 128.5, 128.3, 125.7, 63.7, 57.8.

(4-Methoxy-phenyl)-naphthalen-2-ylmethyl-amine

HN
O

The product was prepared on 0.8 mmol scale using the reaction conditions similar
to general procedure B. The reaction time was 2 hours in which time TLC showed the
boronic acid being consumed. After base extraction (3N NaOH), with 3 x 10 ml DCM, the
residue was dried over magnesium sulfate and evaporated. Further purification was
necessary with silica chromatography (30% EtOAc in Hexanes) to isolate traces of the
desired product (10 mg, 5%).
1
H NMR (250 MHz, CD
3
OD) δ 7.83-7.75 (m, 4H), 7.52-7.47
(m, 1H), 7.44-7.39 (m, 2H), 6.74-6.63 (m, 4H), 4.41 (s, 2H), 3.67 (s, 3H);
13
C NMR (250
MHz, CDCl
3
) δ 152.2, 133.5, 130.8, 128.4, 127.8, 127.7, 126.1, 126.0, 125.8, 125.7, 114.9,
114.2, 55.8, 49.4.

Benzo[1,3]dioxol-5-ylmethyl-dibenzyl-amine

N
Ph
Ph
O
O

50
The product was prepared on 0.8 mmol scale using the reaction conditions similar
to general procedure B and general procedure C. For procedure B reaction time was 2
hours in which time TLC showed the amine being consumed. After base extraction (1N
NaOH), with 2 x 10 ml DCM, the residue was dried over magnesium sulfate and
evaporated. No further purification was needed to isolate the product (222 mg, 66%). For
procedure C reaction time was 13 minutes (Power = 150 Watt, Temperature = 100
o
C,
Pressure = 250 Psi). After base extraction with 3N NaOH the residue was dried and then
purified with silica chromatography (5% EtOAc in hexanes) to yield the product (71 mg,
42%).
1
H NMR (250 MHz, CD
3
OD) δ 7.41-7.14 (m, 10H), 6.86 (s, 1H), 6.78 (d, J=7.8 Hz,
1H), 6.70 (d, J=7.8 Hz, 1H), 5.87 (s, 2H), 3.44 (s, 4H), 3.36 (s, 2H);
13
C NMR (250 MHz,
CD
3
OD) δ 149.1, 148.0, 140.8, 134.7, 129.9, 129.2, 128.0, 122.9, 109.9, 108.7, 102.1,
58.7, 58.5.

Diallyl-benzo[b]thiophen-2-ylmethyl-amine

N
S

The product was prepared on 0.5 mmol scale using the reaction conditions similar
to general procedure B. The reaction time was 8 hours in which time TLC showed the
boronic acid being consumed. After base extraction (2N NaOH), with 3 x 15 ml DCM, the
residue was dried over magnesium sulfate and evaporated. Further purification was needed
employing silica chromatography using 100% Hexanes at first, followed by 40% EtOAc in
Hexanes, to isolate the product (84 mg, 70%).
1
H NMR (250 MHz, CD
3
OD) δ 7.81-7.75
51
(m, 1H), 7.72-7.66 (m, 1H), 7.33-7.22 (m, 2H), 7.8 (d, J=1.1 Hz, 1H), 5.91 (ddt, J=17.5,
10.3, 6.5 Hz, 2H), 5.30-5.15 (m, 4H), 3.88 (d, J=0.7 Hz, 2H), 3.16 (dt, J=6.4, 1.4 Hz,
4H);
13
C NMR (250 MHz, CD
3
OD) δ 136.4, 125.1, 125.0, 124.1, 123.6, 123.1, 118.5, 57.3,
53.4.

4-Naphthalen-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester

N N Boc

The product was prepared on 0.315 mmol scale using the reaction conditions
similar to general procedure B. The reaction time was 8 hours. After base extraction (1N
NaOH), with 3 x 15 ml DCM, the residue was dried over magnesium sulfate and
evaporated. Further purification was necessary with silica chromatography (20% EtOAc in
Hexanes) to isolate product (38 mg, 37%).
1
H NMR (250 MHz, CD
3
OD) δ 7.44-7.17 (m,
5H), 6.59 (d, J=15.6 Hz, 1H), 6.34-6.20 (dt, J=15.6 Hz, J=6.9 Hz, 1H), 3.45 (t, J=5 Hz,
4H), 3.19 (d, J=6.9 Hz, 2H), 2.48 (t, J=5 Hz, 4H), 1.45 (s, 9H).

Diallyl-(5-bromo-2-methoxy-benzyl)-amine

N
O Br

52
The product was prepared on 0.5 mmol scale using the reaction conditions similar
to general procedure B. The reaction time was 48 hours. After base extraction (3N
NaOH), with 3 x 10 ml DCM, the residue was dried over magnesium sulfate and
evaporated. Further purification was needed employing preparative TLC using 10% EtOAc
in Hexanes as solvent system, to isolate the product (33 mg, 22%).
1
H NMR (250 MHz,
CD
3
OD) δ 7.47 (d, J=2.8 Hz, 1H), 7.33 (dd, J=8.9, 2.3 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H),
5.89 (ddt, J=17.5, 10.3, 6.5 Hz, 2H), 5.25-5.13 (m, 4H), 3.80 (s, 3H), 3.55 (s, 2H), 3.1 (dt,
J=6.2, 1.4 Hz, 4H);
13
C NMR (250 MHz, CD
3
OD) δ 158.6, 136.5, 134.0, 131.9, 130.6,
118.4, 113.6, 113.5, 57.8, 56.0, 51.7; ICR-M m/z calcd for C
14
H
18
BrNO 295.06, found
295.06.

4-Furan-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester

NN Boc
O

The product was prepared on 0.3 mmol scale using the reaction conditions similar
to general procedure B. The reaction time was 24 hours in which time TLC showed the
amine being consumed. After base extraction (3N NaOH), with 3 x 5 ml DCM, the residue
was dried over magnesium sulfate and evaporated. No further purification was needed to
isolate the product (78 mg, 97%).
1
H NMR (250 MHz, CD
3
OD) δ 7.46 (dd, J=1.8, 0.8 Hz,
1H), 6.36 (dd, J=3.3, 1.9 Hz, 1H), 6.29 (d, J=2.9 Hz, 1H), 3.58 (s, 2H), 3.41 (t, J=4.7 Hz,
53
4H), 2.43 (t, J=5.2 Hz, 4H), 1.44, (s, 9H);
13
C NMR (250 MHz, CD
3
OD) δ 156.9, 152.1,
143.7, 111.3, 110.5, 81.3, 55.1, 53.8, 28.6

2(S)-1-Furan-2-ylmethyl-pyrrolidine-2-carboxylic acid

N
COOH
O

The product was prepared on 0.5 mmol scale using the reaction conditions similar
to general procedure B. Solvents were evaporated with the help of methanol and the
residue was purified via silica chromatography (75% EtOAc : 15% MeOH : 10% NH
4
OH),
to yield the product (51 mg, 52%).
1
H NMR (250 MHz, CDCl
3
) δ 7.41 (d, J=1.0 Hz, 1H),
6.47 (d, J=3.2 Hz, 1H), 6.35 (dd, J=3.5, 1.9 Hz, 1H), 4.54-4.36 (m, 2H), 4.00 (dd, J=8.9,
7.7 Hz, 1H), 3.91-3.79 (m, 1H), 3.20-3.04 (m, 1H), 2.44-2.29 (m, 2H), 2.21-1.92 (m, 2H);
13
C NMR (250 MHz, CDCl
3
) δ 172.1, 146.5, 144.0, 112.5, 110.8, 66.8, 53.4, 49.4, 29.6,
23.8.

4-Furan-2-ylmethyl-morpholine

ON
O

54
The product was prepared on 0.8 mmol scale using the reaction conditions similar
to general procedure B. The reaction time was 2 hours in which time TLC showed the
amine being consumed. After base extraction (1N NaOH), with 3 x 10 ml DCM, the
residue was dried over magnesium sulfate and evaporated. No further purification was
needed to isolate the product (126 mg, 94%).
1
H NMR (250 MHz, CD
3
OD) δ 7.46 (dd,
J=2.1 Hz, J=1.0 Hz, 1H), 6.34 (dd J=3.4 Hz, J=2.1 Hz, 1H), 6.29 (dd, J=3.4 Hz, J=1.0 Hz,
1H), 3.63 (t, J=4.8 Hz, 4H), 3.55 (s, 2H), 2.44 (t, J=4.8 Hz, 4H).

Furan-2-ylmethyl-(4-methoxy-phenyl)-amine

HN
O
O
The product was prepared on 0.8 mmol scale using the reaction conditions similar
to general procedure B. The reaction time was 2 hours in which time TLC showed the
amine being consumed. After base extraction (1N NaOH), with 2 x 10 ml DCM, the
residue was dried over magnesium sulfate and evaporated. No further purification was
needed to isolate the product (168 mg, 65%).
1
H NMR (250 MHz, CD
3
OD) δ 7.46 (dd,
J=2.0 Hz, J=1.0 Hz, 1H), 6.77-6.65 (m, 4H), 6.30 (dd J=3.4 Hz, J=2.0 Hz, 1H), 6.29 (dd,
J=3.4 Hz, J=1.0 Hz, 1H), 4.21 (s, 2H), 3.69 (s, 3H).
55
Benzyl-methyl-(3-phenyl-allyl)-amine

N
Ph
Ph
The product was prepared on 0.8 mmol scale using the reaction conditions similar
to general procedure B and 0.5 mmol scale using general procedure C. For procedure
B reaction time was 8 hours in which time TLC showed the amine being consumed. After
base extraction (1N NaOH), with 2 x 10 ml DCM, the residue was dried over magnesium
sulfate and evaporated. Further purification was needed to isolate the product in the form
of silica chromatography (35% EtOAc in hexanes) (163 mg, 86%). For procedure C
reaction time was 12 minutes ( Power = 150 Watt, Temperature = 100
o
C, Pressure = 250
Psi). After base extraction with 3N NaOH the residue was dried and then purified with
silica chromatography (30% EtOAc in hexanes) to yield the product (107 mg, 90%).
1
H
NMR (250 MHz, CDCl
3
) δ 7.42-7.22 (m, 10H), 6.56 (d, J=15.9 Hz, 1H), 6.34 (dt,
J= 15.9, 6.54 Hz, 1H), 3.57 (s, 2H), 3.21 (d, J=6.64 Hz, 2H), 2.26 (s, 3H);
13
C
NMR (250 MHz, CDCl
3
) δ 138.9, 137.0, 132.5, 129.1, 128.5, 128.2, 127.5, 127.3,
127.0, 126.3, 61.8, 59.8, 42.2.
56
2.5 Chapter 2 References

1. Petasis, N. A., Akritopoulou-Zanze, I. “The BAM Reaction: A New Method for
the Synthesis of Geometrically Pure Allylamines.” Tetrahedron Letters, 1993,
34(4), p. 583-586.

2. Dolle, R. E. “Comprehensive Survey of Combinatorial Library Synthesis. 2004.”
Journal of Combinatorial Chemistry, 2005, 7(6), p. 739-798.

3. Tagat, J. R., Steensma, R. W., McCombie, S. W., Nazareno, D. V., Lin, S.,
Neustadt, B. R., Cox, K., Xu, S., Wojcik, L., Murray, M. G., Vantuno, N.,
Baroudy, B. M., Strizki, J. M. “Piperazine-Based CCR5 Antagonists as HIV-1
Inhibitors. II. Discovery of 1-[(2,4-Dimethyl-3-pyridinyl)carbonyl]-4-methyl-4-
[3(S)-methyl-4-[1(S)-[4-(trifluoro-methyl)phenyl]ethyl]-1-piperazinyl]-piperidine
N1-Oxide (Sch-350634), an Orally Bioavailable, Potent CCR5 Antagonist.”
Journal of Medicinal Chemistry, 2001, 44, p. 3343-3346.

4. Seayad, A., Ahmed, M., Klein, H., Jackstell, R., Gross, T., Beller, M. “Internal
Olefins to Linear Amines.” Science, 2002, 297(5587), p. 1676-1678.

5. Prashad, M., Liu, Y., Har, D., Repic, O., Blacklock, T. J. “1,2,3-Triazole as a Safer
and Practical Substitute for Cyanide in the Bruylants Reaction for the Synthesis of
Tertiary Amines Containing Tertiary Alkyl or Aryl Groups.” Tetrahedron Letters,
2005, 46, p. 5455-5458.

6. Rizzi, G. P. “A Novel Synthesis of Benzylamines from Benzaldehydes.” Journal
of Organic Chemistry, 1971, 36(12), p. 1710-1711.

7. Ju, Y., Varma, R., J. “Aqueous N-Alkylation of Amines Using Alkyl Halides:
Direct Generation of Tertiary Amines Under Microwave Irradiation.” Green
Chemistry, 2004, 6, p. 219-221.

8. Rueckle, T., Biamonte, M., Grippi-Vallotton, T., Arkinstall, S., Cambet, Y.,
Camps, M., Chabert, C., Church, D. J., Halazy, S., Jiang, X., Martinou, I., Nichols,
A., Sauer, W., Gotteland, J. “Design, Synthesis, and Biological Activity of Novel,
Potent, and Selective (Benzoylaminomethyl)thiophene Sulfonamide Inhibitors of
c-Jun-N-Terminal Kinase.” Journal of Medicinal Chemistry, 2004, 47(27), p.
6921-6934.

9. Brown, H. C., Gupta, S. K. “Hydroboration. XXXIX. 1,3,2-Benzodioxaborole
(catecholborane) as a new hydroboration reagent for alkenes and alkynes. General
synthesis of alkane- and alkeneboronic acids and esters via hydroboration.
Directive effects in the hydroboration of alkenes and alkynes with
catecholborane.” Journal of the American Chemical Society, 1975, 97(18), p.
5249-5255.

57
CHAPTER 3
Synthesis of Amino Imidazoles
3.1 Introduction
As presented in Chapter 1 of this thesis, the Petasis reaction is a very versatile and
promising multicomponent transformation useful towards the synthesis of interesting
molecules with pharmaceutical properties. This chapter discusses a new pathway towards
the formation of biologically active molecules with the help of this three component
transformation, by exploring the incorporation of a versatile and biologically active
heterocyclic molecule, imidazole. This heterocycle could take part in this reaction as the
amine species or as part of the carbonyl component. We found that when we used
imidazole in the amine species no reaction took place. To our delight however, imidazole
carboxaldehydes proved to be active resulting in the expected three component product.

3.1.1 Imidazole: An important 5-membered N-heterocycle
Imidazole is a heterocyclic aromatic molecule with a five-membered ring N-
heterocyclic structure (Table 3.1), composed of three carbon atoms and two nitrogen
atoms at nonadjacent positions. The simplest member of the imidazole family is imidazole
itself, a white crystalline solid with a weak amine-like odor. It is further classified as an
alkaloid (a nitrogenous organic molecule that has a pharmacological effect on humans and
animals) [1]. Imidazole can act as a base and as a weak acid and it exists in two tautomeric
forms with the hydrogen atom moving between the two nitrogens. Imidazoles are poorly
soluble in water generally, but are dissolved in organic solvents [2].
58
A number of other 5-membered N-heterocycles related to imidazole are shown in
Table 3.1. These include:
Pyrazole or 1,2-diazole, an isomer of imidazole having the nitrogen at positions 1
and 2. This heterocycle is not common in nature. Derivatives of pyrazole are used for their
analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing,
psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and
antibacterial activities [7].
Triazole, with three nitrogen atoms and two carbon atoms at nonadjacent positions
in the ring. Molecules containing this system were shown to have a very high antifungal
activity. The triazole antifungal drugs include fluconazole, itraconazole, voriconazole and
posaconazole. The triazole plant protection fungicides include epoxiconazole, triadimenol,
propiconazole, cyproconazole, tebuconazole and flusilazole [3].
Tetrazole, having four nitrogen atoms and one carbon atom. The tetrazole
ring system was found to be a good pharmacophore replacement for the carboxylate
group and it has been used in a number of pharmaceuticals, such as the the
angiotensin II receptor blockers, including losartan and candesartan.
Pyrrole, having only one nitrogen atom in the ring system. Pyrroles are
components of larger aromatic rings, including the porphyrins of heme, the chlorins and
bacteriochlorins of chlorophyll, and the corrin ring of vitamin B12 [4].
Isoxazole, having a nitrogen atom and an oxygen atom at adjacent positions.
Isoxazoles are found in some natural products, such as ibotenic acid. Isoxazoles also form
the basis for a number of drugs, including the COX-2 inhibitor valdecoxib (Bextra) [10].
59
Isothiazole, having a nitrogen atom and a sulfur atom at adjacent positions. The
ring structure of isothiazole is incorporated into larger compounds with biological activity
such as the pharmaceutical drugs ziprasidone and perosiprone [11].
Oxazole, an analogue of imidazole having the nitrogen atom in position 1 replaced
by oxygen. In natural products, oxazoles result from the cyclization and oxidation of serine
or threonine nonribosomal peptides [9].
Table 3.1: Imidazole and other 5-membered N-heterocycles
N
H
N O N
O
N
S
N
N
H
N
H
N
N
N
N
H
N N
N
N
H
Imidazole Pyrazole Triazole Tetrazole
Pyrrole Isoxazole Isothiazole Oxazole

3.1.2 Importance of imidazole containing molecules
Imidazole has two nitrogen atoms, one being slightly acidic and the other being
basic. The imidazole ring system is present in important biological building blocks such as
histidine (an essential amino acid) and histamine, the decarboxylated compound from
histidine (Figure 3.1) [12].
60
N
H
N
N
H
N
H
2
N
COOH
H
2
N
Histamine Histidine

Figure 3.1: Histidine and histamine

Some imidazole compounds inhibit the biosynthesis of ergosterol, required in cell
membrane in fungi [13]. They have antibacterial, antifungal, antiprotozoal, and
anthelmintic activity [14]. Several distinct phenylimidazoles are therapeutically useful
antifungal agents against either superficial or systemic infections [15]. Thiabendazoles
which have anthelmintic and antifungal properties are imidazole class compounds as well
[16]. Benzimidazole is a bicyclic compound having an imidazole ring fused to benzene.
Benzimidazole structure is a part of the nucleotide portion of vitamin B
12
and the nucleus
in some drugs such as proton pump inhibitors and anthelmintic agents [17].
Imidazole and its derivatives are widely used as intermediates in synthesis of
organic target compounds including pharmaceuticals, agrochemicals, dyes, photographic
chemicals, corrosion inhibitors, epoxy curing agents, adhesives and plastic modifiers. A
simple example is shown in Figure 3.2 where a general structure of an imidazole-based
inhibitor (Matrix MetalloProteinase or MMP inhibitor) is shown with a schematic
representation of the important interactions between it and an enzyme [18]. MMPs are a
family of zinc-containing proteinases, classified into three groups – collagenases,
stromelysins and gelatinases, and they are connected intimately with diseases such as
61
rheumatoid arthritis and osteoarthritis, tumor metastases, periodontal diseases, and multiple
sclerosis.
N
N
R
N
H
O
H
H
O
H
O
N
N
HN
N
N
Me
Me
H
O
Me Me
OH
O

Figure 3.2: On the left a known MMP inhibitor and on the right Imidazole based
inhibitor with enzyme interactions

3.2 Results
Herein we introduce the one-step three-component synthesis of imidazole
derivatives, which involves the reaction of boronic acids, amines and imidazole-2-
carboxaldehyde or imidazole-4-carboxaldehyde for the formation of products with general
structures as shown in Scheme 3.1.
N
N
R
N
R
1
R
2
H
N
N
R
N
R
1
R
2
H
N
N
H
N
N
H
OHC
OHC
N
R
1
H
R
2
RB
OH
OH
+
or
Toluene
or

Scheme 3.1: Three-component Petasis reaction with imidazole carboxaldehydes

3.2.1 Reactions with imidazole-4-carboxaldehyde
Towards our ongoing efforts to diversifying the three component Petasis reaction
we were interested in investigating more versatile components. In connection with another
62
project in our lab that was under way at the time, we came across imidazoles as useful
scaffolds to produce desired compounds.
At that time we had stumbled upon a series of problems. Despite the fact that
imidazoles are simple molecules, a survey of the literature revealed a lack of general
methodologies for the expedient synthesis of imidazoles with different substitution patterns
[19, 20]. This luck of methodologies and in general literature evolving around different
transformations with imidazole compounds and the difficulty people faced to isolate the
products prompted our interest.
We started thinking that maybe we could use our three-component chemistry
towards certain target molecules we had in mind and also give chemists another tool for
utilizing imidazole by involving our methodology. We then decided to start an
investigation of imidazole containing compounds as possible candidates in respect to the
Petasis reaction.
The first and most obvious thought was to use the imidazole as the amine species.
We soon found out that this didn’t work so we changed our direction towards imidazole
carboxaldehydes to play the role of the carbonyl group in the Petasis reaction. Both
compounds imidazole-4-carboxaldehyde and imidazole-2-carboxaldehyde are
commercially available (Figure 3.3).

N
HN
O
H
N
HN
O
H

Figure 3.3: Imidazole carboxaldehydes

63
Imidazole-4-carboxaldehyde was the first compound we decided to investigate.
Some initial runs we performed were very confusing and could not identify any product.
Imidazole containing compounds throughout the literature are mostly isolated as
precipitates after being transformed to the salts of the final products mainly because of
their very high polarity. In our case that was almost impossible to do since we were
working at a mmol scale yielding only a few milligrams of the desired product.
TLC monitoring of the reaction showed many new spots and crude NMR showed
formation of the desired product. After column chromatography and isolation of all layers
we found out that none of these spots was the product. Even after developing the TLC
using 100% MeOH as solvent system the baseline spot would not move. Preparative TLC
was the clear solution to our problem and the results were very promising since we were
able to get the product easily and without any sign of impurity.
Some improvement of the reaction conditions took place in the form of solvent
choice. Several runs showed that solvents with low polarity like toluene and DCM were
slightly favored (Table 3.2) so they were the solvents of choice for all the runs.

64
N
Me
H
Ph
Ph
B(OH)
2
1. H
2
O
Solvent % yield
2. MeOH
3. THF
4. CH
3
CN
5. Toluene
6. DCM
7. DMF
27
21
0
31
39
33
traces
+
Table 3.2 Solvent effect on the reaction with imidazole-4-carboxaldehyde
Entry
+
HN
N
OHC
HN
N
N
Ph
Me
Ph

The results are shown in Table 3.3. Unfortunately we were not able to get any
primary amines to work as well as different secondary amines than the ones shown, so we
turned our attention to the other aldehyde of the family.

65
Table 3.3: Products from the reactions with imidazole-4-carboxaldehyde

N
N
HN
21%
NN
N
HN
39%
NN
N H
H
Ph
B HO
OH
N
HN
O
H
1
2
Ph
B HO
OH
N
HN
O
H
entry amine boronic acid aldehyde product yield

Reaction conditions: Amine, boronic acid and aldehyde were mixed in toluene and stirred in room
temperature.

3.2.2 Reactions with imidazole-2-carboxaldehyde
Since imidazole-4-carboxaldehyde results were not very promising our attention
was turned to imidazole-2-carboxaldehyde hoping that this member of the family would
work better.
Indeed that was the case. Mixing the amine, the boronic acid and the imidazole-2-
carboxaldehyde and refluxing them with toluene as solvent would give the product in
moderate yields (Table 3.4). Primary as well as secondary amines would take part in this
process with similar results. In the case of the primary amines we didn’t notice any
formation of the disubstituted product and that was very comforting since we could, in the
future, further manipulate these products without the need of deprotections.
It is worth noting here that the products of this process were less polar than the
ones with imidazole-4-carboxaldehyde thus making the isolation and the monitoring of the
reactions much easier.
66
Table 3.4: Products from the reactions with imidazole-2-carboxaldehyde
NN
N
HN
48%
N
N
HN
25%
ON
N
HN
36%
N
N
N
17%
N
N
N
31%
N
N
N
30%
H
H
H
H
H
H
N
H
N
H
N
H
NN
ON
N
H
H
H
H
H
H
Ph
B HO
OH
N
HN
O
H
1
2
3
4
5
6
Ph
B HO
OH
N
HN
O
H
Ph
B HO
OH
N
HN
O
H
Ph
B HO
OH
N
HN
O
H
Ph
B HO
OH
N
HN
O
H
Ph
B HO
OH
N
HN
O
H
entry amine boronic acid aldehyde product yield
Reaction conditions: Amine, boronic acid and aldehyde were mixed in toluene and stirred in room
temperature or refluxed when needed.
67
3.3 Conclusion
Herein we introduced the use of imidazole carboxaldehydes as the carbonyl
component in our three component chemistry, giving access to very useful molecules with
possible biological activity. This is one of only a few existing methodologies for the
formation of diversified amino imidazole compounds and can lead to the synthesis of novel
potentially biologically active molecules.
68
3.4 Experimentals
3.4.1 General
All reagents and commonly available starting materials were purchased from
available commercial sources. Thin layer chromatography was performed on pre-coated
TLC plates (silica gel 60 F
254
) and flash chromatography using Silica gel 60, which has a
particle size range between 0.040 – 0.063 mm. NMR spectra were obtained on a Bruker
AC-250 MHz instrument. High resolution mass spectra were obtained at the University of
California at Los Angeles Mass Spectrometry facility.

3.4.2 General procedure
In a 20 ml round bottom flask under argon, with toluene as solvent, the amine, the
imidazole-4-carboxaldehyde or imidazole-2-carboxaldehyde and styryl boronic acid were
added. Some excess of aldehyde was used in all cases. The resulting mixture was stired at
room temperature, and sometimes refluxed as needed for 1-2 days at which point TLC
indicated consumption of most of the amine and formation of a new spot. The reaction
mixture was then transferred to a separatory funnel and 15ml of 3N NaOH were added.
After extraction with 3 x 10 ml DCM, the organic layers were collected, dried over
MgSO
4
, and evaporated. Further purification was necessary with flash chromatography or
preparative TLC.
69
3.4.3 Specific Syntheses and Physical Properties

Benzyl-[1-(3H-imidazol-4-yl)-3-phenyl-allyl]-methyl-amine

N
Ph
N
HN
Ph

The compound was prepared on 0.25 mmol scale with imidazole-4-
carboxaldehyde. The reaction mixture was refluxed for 16 hours. Following the base
extraction with DCM the residue was purified via silica chromatography (92:6:2, DCM /
MeOH / NH
4
OH) to yield 16 mg of desired product (21%).
1
H NMR (250 MHz, CD
3
OD) δ
7.59 (s, 1H), 7.49-7.18 (m, 10H), 7.01 (s, 1H), 6.50 (d, J=15.9 Hz, 1H), 6.42-6.32 (dd,
J=15.9, 8.2 Hz, 1H), 4.03 (d, J=8.2 Hz, 1H), 3.56-3.45 (m, 2H), 2.12 (s, 3H);
13
C NMR
(250 MHz, CD
3
OD) δ 130.1, 130.0, 129.6, 129.5, 129.3, 129.2, 128.9, 128.3, 128.0, 127.6,
74.0, 60.1, 39.8.

1-[1-(3H-Imidazol-4-yl)-3-phenyl-allyl]-4-methyl-piperazine

NN
N
HN
Ph

This product was prepared on 0.25 mmol scale with imidazole-4-carboxaldehyde.
The reaction mixture was stirred to room temperature for 12 hours at which time no
70
significant amount of product was formed and then refluxed for 17 hours. The mixture was
let to cool and then trnsfered to a separatory funnel were 10 ml of 3N NaOH were added
and extraction with DCM followed. The residue was dried and then purified with silica
chromatography (99:1, MeOH / NH
4
OH), to yield the product (28 mg, 39%).
1
H NMR
(250 MHz, CD
3
OD) δ 7.57 (s, 1H), 7.43-7.20 (m, 5H), 6.99 (s, 1H), 6.49 (d, J=15.6 Hz,
1H), 6.30-6.20 (dd, J=15.6, 8.8 Hz, 1H), 3.78 (d, J=8.8 Hz, 1H), 2.62-2.30 (br. s, 8H), 2.25
(s, 3H);
13
C NMR (250 MHz, CD
3
OD) δ 138.0, 136.7, 133.8, 129.6, 129.5, 129.3, 129.1,
128.9, 127.6, 68.0, 56.0, 51.3, 45.9.

1-[1-(1H-Imidazol-2-yl)-3-phenyl-allyl]-4-methyl-piperazine

NN
Ph
N
HN
This product was prepared on 0.25 mmol scale with imidazole-2-carboxaldehyde.
The reaction mixture was stirred to room temperature for 2days, at which time most amine
was consumed. After base extraction with DCM, residue was dried and then purified with
silica chromatography (100% MeOH), to yield the product (34 mg, 48%).
1
H NMR (250
MHz, CD
3
OD) δ 7.45-7.17 (m, 5H), 6.99 (s, 2H), 6.65 (d, J=15.9 Hz, 1H), 6.48-6.39 (dd,
J=15.9, 8.4 Hz, 1H), 4.18 (d, J=8.4 Hz, 1H), 2.65-2.32 (m, 8H), 2.24 (s, 3H);
13
C NMR
(250 MHz, CD
3
OD) δ 148.6, 137.9, 135.1, 129.8, 129.6, 128.9, 127.7, 127.6, 68.0, 55.9,
51.3, 45.8.
71
Benzyl-[1-(1H-imidazol-2-yl)-3-phenyl-allyl]-methyl-amine

Ph
N
Ph
N
HN

This product was prepared on 0.25 mmol scale with imidazole-2-carboxaldehyde.
The reaction mixture was stirred to room temperature for 2 days. After base extraction with
DCM, residue was dried and then purified with silica chromatography (95:5, DCM /
MeOH), to yield the product (19 mg, 25%).
1
H NMR (250 MHz, CD
3
OD) δ 7.49-7.16 (m,
10H), 7.02 (s, 2H), 6.64 (d, J=15.6 Hz, 1H), 6.58-6.49 (dd, J=15.6, 7.5 Hz, 1H), 4.36 (d,
J=7.5 Hz, 1H), 3.59-3.43 (m, 2H), 2.12 (s, 3H);
13
C NMR (250 MHz, CD
3
OD) δ 149.4,
140.2, 138.0, 135.2, 130.0, 129.8, 129.6, 129.3, 128.8, 128.1, 127.6, 127.5, 66.8, 59.9,
39.3.

4-[1-(1H-Imidazol-2-yl)-3-phenyl-allyl]-morpholine

ON
Ph
N
HN

This product was prepared on 0.25 mmol scale with imidazole-2-carboxaldehyde.
The reaction mixture was stirred to room temperature for 24 hours. After base extraction
with DCM, residue was dried and then purified with silica chromatography (95:5, DCM /
MeOH), to yield the product (24 mg, 36%).
1
H NMR (250 MHz, CD
3
OD) δ 7.43-7.16 (m,
72
5H), 7.00 (s, 2H), 6.65 (d, J=15.7 Hz, 1H), 6.46-6.36 (dd, J= 15.7, 8.8 Hz, 1H), 4.13 (d,
J=8.8 Hz, 1H), 3.67 (t, J=4.8 Hz, 4H), 2.61-2.51 (dt, J=11.7, 4.4 Hz, 2H), 2.36-2.27 (dt,
J=11.7, 4.4 Hz, 2H);
13
C NMR (250 MHz, CD
3
OD) δ 148.5, 137.8, 135.2, 129.6, 128.9,
127.6, 127.5, 123.0, 68.6, 68.0, 52.6.

Benzyl-[1-(1H-imidazol-2-yl)-3-phenyl-allyl]-amine

Ph
HN
Ph
N
HN
This product was prepared on 0.25 mmol scale with imidazole-2-carboxaldehyde.
The reaction mixture was stirred to room temperature for 1 day. After base extraction with
DCM, residue was dried and then purified with preparative TLC (95:5, DCM / MeOH), to
yield the product (12 mg, 17%).
1
H NMR (250 MHz, CD
3
OD) δ 7.43-7.14 (m, 10H), 7.02
(s, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.40-6.30 (dd, J=16.0, 7.4 Hz, 1H), 4.55 (d, J=7.4 Hz,
1H), 3.77-3.67 (m, 2H);
13
C NMR (250 MHz, CD
3
OD) δ 140.5, 137.9, 134.1, 129.6, 129.5,
129.4, 129.3, 129.2, 128.9, 128.2, 128.2, 127.6, 59.5, 52.0.
73
[1-(1H-Imidazol-2-yl)-3-phenyl-allyl]-phenyl-amine

Ph
HN
Ph
N
HN

This product was prepared on 0.25 mmol scale with imidazole-2-carboxaldehyde.
The reaction mixture was stirred to room temperature for 1 day. After base extraction with
DCM, residue was dried and then purified with silica chromatography (97:3, DCM /
MeOH), followed by preparative TLC (95:5, DCM / MeOH), to yield the product (21 mg,
31%).
1
H NMR (250 MHz, CD
3
OD) δ 7.42-7.01 (m, 7H), 6.99 (s, 2H), 6.70-6.61 (m, 3H),
6.57 (d, J=16.0 Hz, 1H), 6.50-6.41 (dd, J=16.0, 5.8 Hz, 1H), 5.26 (d, J=5.8 Hz, 1H);
13
C
NMR (250 MHz, CD
3
OD) δ 148.6, 137.9, 133.3, 129.9, 129.8, 129.6, 129.4, 129.0, 128.8,
127.6, 118.9, 114.8, 56.2.

Allyl-[1-(1H-imidazol-2-yl)-3-phenyl-allyl]-amine

HN
Ph
N
HN

This product was prepared on 0.25 mmol scale with imidazole-2-carboxaldehyde.
The reaction mixture was stirred to room temperature for 1 day. After base extraction with
DCM, residue was dried and then purified with preparative TLC (92:8, DCM / MeOH), to
74
yield the product (18 mg, 30%).
1
H NMR (250 MHz, CD
3
OD) δ 7.46-7.18 (m, 5H), 7.01
(s, 2H), 6.55 (d, J=16.0 Hz, 1H), 6.38-6.29 (dd, J=16.0, 7.6 Hz, 1H), 6.00-5.82 (m, 1H),
5.22-5.09 (m, 2H), 4.55 (d, J=7.6 Hz, 1H), 3.23-3.15 (m, 2H);
13
C NMR (250 MHz,
CD
3
OD) δ 148.7, 134.9, 133.3, 129.0, 128.8, 127.6, 126.2, 123.3, 118.9, 114.8, 59.6, 50.4.
75
3.5 Chapter 3 References

1. http://www.chemicalland21.com/specialtychem/finechem/imidazole.htm

2. http://en.wikipedia.org/wiki/Imidazole

3. Torres, H. A., Hachem, R. Y., Chemaly, R. F., Kontoyiannis, D. P., Raad, I. I.
“Posaconazole: A Broad-Spectrum Triazole Antifungal.” Lancet Infectious
Diseases, 2005, 5(12), p. 775-785.

4. Aylward, N., Bofinger, N. “Possible Origin for Porphin Derivatives in Prebiotic
Chemistry-A Computational Study.” Origins of Life and Evolution of Biospheres,
2005, 35(4), p. 345-368.

5. Mixson, J. A., Phang, J. M. “Structural Analog of Pyrroline 5-Carboxylate
Specifically Inhibit its Uptake Into Cells.” Journal of Membrane Biology, 1991,
121(3), p. 269-277.

6. Boswell, H. D., Drager, B., Eagles, J., McClintock, C., Parr, A., Portsteffen, A.,
Robins, D. J., Robins, R. J., Walton, N. J., Wong, C. “Biosynthesis of Novel
Alkaloids: Metabolism of N-Alkyldiamines and N-Alkylnortropinones by
Transformed Root Cultures of Nicotiana and Brugmansia.” Phytochemistry, 1999,
52(5), p. 855-869.

7. Larsen, S. D., Connell, M. A., Cudahy, M. M., Evans, B. R., May, P. D.,
Meglasson, M. D., O’Sullivan, T. J., Schostarez, H. J., Sih, J. C., Stevens, F. C.,
Tanis, S. P., Tegley, C. M., Tucker, J.A., Vaillancourt, V. A., Vidmar, T. J., Watt,
W., Yu, J. H. “Synthesis and Biological Activity of Analogs of the
Antidiabetic/Antiobesity agent 3-Guanidinopropionic Acid: Discovery of a Novel
Aminoguanidinoacetic Acid Antidiabetic Agent.” Journal of Medicinal Chemistry,
2001, 44(8), p. 1217-1230.

8. Clark, M. P., Laughlin, S. K., Golebiowski, A., Brugel, T., Sabat, M. “Preparation
of Bicyclic Pyrazolone as Proinflamatory cytokine Inhibitors for Treating Various
Diseases.” U.S. Pat. Appl. Publ. 2005, 34pp. CODEN: USXXCO US 2005113392
A1 20050526.

9. Biron, E., Chatterjee, J., Kessler, H. “Solid-Phase Synthesis of 1,3-Azole-Based
Peptides and Peptidomimetics.” Organic Letters, 2006, 8(11), p. 2417-2420.

10. Selvam, C., Jachak, S. M., Thilagavathi, R., Chakraborti, A. K. “Design,
Synthesis, Biological Evaluation and Molecular Docking of Curcumin Analogues
as Antioxidant, Cyclooxygenase Inhibitory and Anti-Inflamatory Agents.”
Bioorganic & Medicinal Chemistry Letters, 2005, 15(7), p. 1793-1797.

76
11. Tyagi, O. D., Srivastava, T. K., Chauhan, Y. K., Nalam, V. K. “Process for the
Preparation of Aryl Piperazinyl-Heterocyclic Compounds via Coupling Reaction.”
PCT Int. Appl. 2006, 10pp. CODEN: PIXXD2 WO 200611157 A2 200602.

12. Xie, S., Ghovai, P., Ye, Q., Buschauer, A., Seifert, R. “Probing Ligand-Specific
Histamine H
1
- and H
2
-Receptor Conformation with N-Acylated
Imidazolylpropylguanidines.” Journal of Pharmacology and Experimental
Therapeutics, 2006, 317(1), p. 139-146.

13. Bammert, G. F., Fostel, J. M. “Genome-Wide Expression Patterns in
Sacharomyces Cerevisiae: Comparison of Drug Treatments and Genetic
Alterations Affecting Biosynthesis of Ergosterol.” Antimicrobial Agents and
Chemotherapy, 2000, 44(5), p. 1255-1265.

14. Dhanak, D., Christmann, L. T., Darcy, M., G., Keenan, R. M., Knight, S. D., Lee,
J., Ridgers, L. H., Sarau, H. M., Shah, D. H., White, J. R., Zhang, L. “Discovery of
Potent and Selective Phenylalanine Derived CCR3 Receptor Antagonists. Part 2.”
Bioorganic and Medicinal Chemistry Letters, 2001, 11(11), p. 1445-1450.

15. Kinnamon, K. E., Robert, R., Poon, B. T.,Ellis, W. Y., McCall, J. W., Dzimianski,
M. T. “Anticancer Agents Suppresive for Adult Parasites of Filariasis in
Mongolian Jrds.” Proceedings of the Society for Experimantal Biology and
Medicine, 2000, 224(1), p. 45-49.

16. Albanese, G., Venturi, C. “Albendazole: A New Drug for Human Parasitoses.”
Dermatologic Clinics, 2003, 21(2), p. 283-290.

17. Shin, J. M., Cho, Y. M., Sachs, G. “Chemistry of Covalent Inhibition of the
Gastric (H
+
, K
+
)-ATPase by Proton Pump Inhibitors.” Journal of the American
Chemical Society, 2004, 126(25), p. 7800-7811.

18. Chen, J. J., Zhang, Y., Hammond, S., Dewdney, N., Ho, T., Lin, X., Browner, M.
F., Castelhano, A. L. “Design, Synthesis, Activity, and Structure of a Novel Class
of Matrix Metalloproteinase Inhibitors Containing a Heterocyclic P
2
’
-P
3
’
Amide
Bond Isostere.” Bioorganic and Medicinal Chemistry Letters, 1996, 6(13), p.
1601-1606.

19. Frutos, R. P., Gallou, I., Reeves, D., Xu, Y., Krishnamurthy, D., Senanayake, C. H.
“Expedient Synthesis of Substituted Imidazoles from Nitriles.” Tetrahedron
Letters, 2005, 46(48), p. 8369-8372.

20. Youngman, M. A., Dax, S. L. “Solid-Phase Mannich Condensation of Amines,
Aldehydes, and Alkynes: Investigation of the Diverse Aldehyde Inputs.” Journal
of Combinatorial Chemistry, 2001, 3(5), p. 469-472.

77
CHAPTER 4
Use of trifluoroborates in the Petasis reaction
4.1 Introduction
Recently potassium organo-trifluoroborates are emerging as useful leading
components in a number of organic transformations, previously involving other boron
based compounds [1, 2]. As the advantages of using these compounds became apparent,
we decided to explore the possibility of their utilization in the Petasis three component
reaction.

4.2 Synthesis and reactivity of organotrifluoroborates
Organotrifluoroborate salts are a relatively new class of air-stable non hygroscopic
boronic derivatives that can be stored in room temperature for a long time. These mainly
crystalline salts, have become promising alternatives to other organoboron reagents, and
show high solubility in polar solvents such as MeOH, CH
3
CN, acetone, DMF and DMSO,
while they are insoluble in DCM, diethylether and hydrocarbons [3].
In general organoboranes are not very stable molecules. This is due to the vacant
orbital on the boron atom, resulting to succeptibility to several oxidants, which can attack
the reagents and decompose them, limiting further transformation of boron-containing
compounds [4]. Around the 1960s chemists thought that the use of potassium
trifluoroborates could serve as a good solution [5]. Organotrifluoroborates, thanks to the
strong B-F bonds they possess (can serve as protection of the boron’s vacant orbital from
78
electrophilic reactions with strong oxidants), can undergo several transformations without
any limitations. So unlike trivalent boron substituents they are very good nucleophiles [6].

4.2.1 Formation of organotrifluoroborates
The first report of the preparation of a trifluoroborate complex as can be found in
literature was in 1940 by Fowler and Krauss. A tetramethyl ammonium and tetrabutyl
ammonium triphenyl fluoroborates were prepared by treatment of triphenylborane-
ammonia complex with 1 equivalent of tetraalkylammonium fluoride [7].
Ph
3
B
.
NH
3
R
4
NF
EtOH
reflux
Ph
3
-
BF
3
.
N
+
R
4

Scheme 4.1: Formation of trifluoroborate complexes

It wasn’t until twenty years later that Chambers et al. reported the formation of
potassium trifluoro-(trifluoromethyl) borate from a stannane [5]. Later on silanes were
reported to be undergoing the same transformation [8, 9, 10]. As can be seen in Scheme
4.2 the organostannane or silane would react with trifluoroborate gas in chloroform to yield
the difluoroborane which was then treated with potassium fluoride in water to give the
organotrifluoroborate. This technique later on was improved by Stafford et al. and the
authors were able to synthesize methyl, vinyl and phenyl trifluoroborates.
79
Me
3
MCF
3
BF
3
gas
CCl
4
Me
3
M(CF
3
BF
3
)
Me
3
MF + CF
3
BF
2
KF
H
2
O
CF
3
BF
3
-
K
+
M= Sn, Si
R-SnMe
3
BF
3
gas
CCl
4
R-BF
2
KF
H
2
O
R-BF
3
-
K
+
R= methyl, vinyl, phenyl

Scheme 4.2: Preparation of trifluoroborates from organosilanes and organostannanes

In 1967 Thierig and Umland reported the preparation of potassium difluoro-
diphenyl borate after treating the ethanolamine complex of Ph
2
BOH with KHF
2
[1]. The
authors at the same time discovered that the same reaction contacted in refluxing acetic
acid led to the formation of potassium phenyl trifluoroborate.
B
Ph
Ph
O
N
H
2
KHF
2
H
2
O
KHF
2
AcOH
reflux
PhBF
3
-
K
+
Ph
2
BF
2
-
K
+

Scheme 4.3: Reactions with KHF
2

This discovery a few years later was meant to revolutionize the ways of formation
of trifluoroborates. An inexpensive compound like KHF
2
could function as a fluoride ion
80
source and could activate a relatively unreactive boronate structure for ligand exchange
under weakly acidic conditions.
The only problem that needed to be solved was the fact that these initial
approaches for the preparation of these salts were not satisfactory since they implied the
intermediate preparation of the highly reactive and unstable organodihalo boranes.
The solution for this problem came in 1995 when Vedejs et al. reported that aryl
boronic acids were efficiently converted into aryl trifluoroborates upon treatment with
KHF
2
in aqueous methanol [11]. Treatment of a concentrated solution of boronic acid in
methanol with saturated aqueous KHF
2
resulted in an exothermic reaction and immediate
formation of a precipitate. Collection of the crystals by filtration and recrystallization from
acetonitrile afforded pure trifluoroborate salts. The authors showed that the hydroxyl
ligands on the trivalent boronic acids could not be displaced by KF; KHF
2
was needed
instead. So by using readily available boronic acids it was possible to obtain a great variety
of trifluoroborates.

Scheme 4.4: Formation of aryl trifluoroborates
B
OH
OH
Ar
KHF
2
MeOH/H
2
O
Ar BF
3
-
K
+
O
X X X
X X
X
F
3
C CF
3
Cl Cl
X= BF
3
-
K
+
CHO
OMe
3
NO
2
81
The same procedure for generation of potassium trifluoroborates was feasible in
situ by use of classical methods for organoboron synthesis as shown by Darses and Genet
[12]. Commercially available aryl bromides were converted to the lithium reagents by
exchange with n-butyl lithium or tert-butyl lithium. Reaction of these reagents with
trimethyl borate or triisopropyl borate and hydrolysis afforded the boronic acids. The crude
boronic acids were used without purification for the conversion to potassium
trifluoroborates on treatment with aqueous KHF
2
. The by-products from the formation of
the boronic acids such as trimeric or oligomeric boronic anhydrides also appeared to be
reactive in the KHF
2
fluoride exchange procedure making the one-pot approach even more
attractive. Aryl lithium reagents can also be formed by direct ortho-metallation of activated
C-H bonds using n-butyl or sec-butyl lithium. The hydrolysis step could be avoided before
the treatment with KHF
2
when not necessary. The same protocols can be followed for the
formation of alkyl, allyl, alkenyl, and alkynyl trifluoroborates. Grignard reagents can also
be employed in most cases with similar results. Commercially available organomagnesium
halides or in situ ones (addition of magnesium to organohalides) would react with a
boronate and then aqueous addition of KHF
2
would result to the trifluoroborate [11].
1. RLi
2. B(OR)
3
3. H
3
O
+
Ar BF
3
-
K
+
Ar-Br
or
Ar-H
ArB(OH)
2
aq. KHF
2

Scheme 4.5: Formation of potassium aryl trifluoroborates in situ

4.2.2 Reactions of organo-trifluoroborates
Recently, Darses and Genet reported that trifluoroborates can substitute boronic
acids in palladium-catalyzed cross-coupling reactions with great results [1]. Before that,
82
the only utility of potassium organotrifluoroborates had been their ability to release
organodifluoroboranes after being heated or treated with chlorotrimethylsilane [11]. Petasis
et al. also reported that they could be used for the formation of fluoroalkenes [13]. Several
other uses of trifluoroborates have emerged the past decade and are summarized herein.

4.2.2.1 Metal catalyzed reactions
4.2.2.1.1 Palladium-catalyzed reactions of arenediazonium salts with
trifluoroborates
As mentioned above, Genet and Darses have recently shown that trifluoroborates
can substitute boronic acids in palladium-catalyzed cross-coupling reactions. More
specifically the authors reported that arenediazonium salts can participate in palladium-
catalyzed cross-coupling reactions with potassium aryl- and alkenyltrifluoroborates more
efficiently than the corresponding organoboronic acids [14]. They demonstrated the ability
of accessing biaryl and styrene derivatives, starting from inexpensive aromatic diazonium
salts.
BF
3
-
K
+
R
BF
3
-
K
+
R
or
R
'
N
2
BF
4
R
'
R
'
R
R
Pd(OAc)
2
dioxane, rt

Scheme 4.6: Cross-coupling reaction of arenediazonium salts with trifluoroborates

83
4.2.2.1.2 Rhodium-catalyzed 1,4 additions to enones, aldehydes and
dehydroamino esters
In 1999 Batey et al. reported that organotrifluoroborates would react with enones
and aldehydes with the use of rhodium as catalyst [15]. Later on Darses and Genet
developed the asymmetric version of the 1,4 addition to enones with great results. This was
achieved by the use of cationic rhodium(I) complexes which would chelate with chiral
diphosphane ligands [16]. In 2004 Darses and Genet also reported that potassium
organotrifluoroborates can carbometallate dehydroamino esters giving access to various
alanine derivatives in high yields [17].
RBF
3
-
K
+
cat. Rh
ligand
O
+
solvent
O
R
*
R
'
CHO
R
'
OH
R
CO
2
R
3
NR
1
R
2
R
3
O
2
C
N
R
R
2
R
1

Scheme 4.7: Rhodium catalyzed 1,2 and 1,4 additions

4.2.2.1.3 Suzuki-Miyaura cross-coupling reactions
The Suzuki coupling reaction with trifluoroborates was demonstrated by several
authors [18], including Molander [19, 20, 21]. Besides the alkyl, alkenyl and aryl or
heteroaryltrifluoroborates that were shown repeatedly to participate in this transformation
he also demonstrated the use of alkynyltrifluoroborates in aryl alkynylations [22].
84
RBF
3
-
K
+
X
cat. Pd
+
solvent, base
R
'
X= halide, OTf
R
R
'
R= alkyl, alkenyl, aryl, alkynyl

Scheme 4.8: Suzuki-Miyaura cross-coupling reaction with alkynyltrifluoroborates

4.2.2.1.4 Modified Ullmann condensation
In 2003 Batey et al. proposed that potassium organotrifluoroborates can be ideal
partners for coupling with phenols for formation of ethers. This was achieved with
treatment of 2 equivalents of aryl- or alkenyltrifluoroborate with 1 equivalent of aliphatic
alcohol in the presence of catalytic ammont of copper(II) and DMAP in room temperature
[23].
RBF
3
-
K
+
Cu(OAc)
2
.
H
2
O
+
DMAP, DCM, rt
R
O
R
'
R
'
OH
R= alkenyl, aryl
R
'
= alkyl, aryl

Scheme 4.9: Copper catalyzed ether synthesis

4.2.2.2 Non-metal catalyzed reactions
4.2.2.2.1 Synthesis of alkenyl fluorides, 2,2-difluoroamides, and 2,2-
difluoroalcohols
Fluorine containing molecules are very valuable in many applications in the
pharmaceutical industry, agrochemistry, and material science due to their properties. In
view of the unique characteristics of these compounds, there has been an increasing interest
85
in the development of new and practical methods for their synthesis. A variety of N-fluoro
compounds have been introduced as electrophilic fluorinating agents of enolates,
carbanions [24], and also for the conversion of organotin derivatives to the corresponding
fluorides at elevated temperatures [25]. The reaction of alkenyl boron compounds with
certain electrophilic fluorinating reagents provides a simple and experimentally convenient
route to alkenyl fluorides as well as 2,2-difluoroalcohols and amides [26]. While the
reaction of alkenyl boronic acids with selectfluor produces the desired alkenyl fluorides, it
usually is very slow and the product is contaminated with the fluorine-free alkene. On the
other hand, conversion of the alkenyl boronic acid to the corresponding alkenyl
trifluoroborate and reaction with selectfluor gives the desired product in good yields [27].
Reaction with one equivalent of selectfluor gives a mixture of E/Z alkenyl fluorides, while
the use of two equivalents in water or a nitrile solvent yields difluoromethyl-substituted
alcohols and amides respectively.
R
2
BF
3
-
K
+
R
3
R
1
N
+
N
+
F
Cl
2BF4-
H
2
O, rt
MeCN, rt
R
2
F R
3
R
1
R
2
R
1
R
2
R
1
H
HN
R
4
H
HO
F
F
O
F
F
58%
77%
71%
(1.0 eq.)
MeCN, rt
(2.0 eq.)
(2.0 eq.)

Scheme 4.10: Trifluoroborate transformations

86
4.2.2.2.2 Diastereoselective allylation of aldehydes
The reaction of aldehydes with different allylmetal compounds for the production
of homoallylic alcohols has always had several drawbacks like the sensitivity of the
organometallic compounds to air and moisture. Batey et al. developed the use of potassium
allyl- and crotyltrifluoroborates in these allylation reactions, circumventing this way the
problems mentioned above since trifluoroborates are known to be air and water stable [28].
R
3
O
H
R
2
R
1
BF
3
-
K
+
+
n
Bu
4
NI (10 mol%)
CH
2
Cl
2
/H
2
O, rt
R
3
OH
R
1
R
2
d.r. > 98:2

Scheme 4.11: Allylation of aldehydes with trifluoroborates

4.2.3 Use of trifluoroborates in the Petasis reaction
In order for potassium organotrifluoroborates to be good candidates in the Petasis
reaction for nucleophilic addition, the presence of Lewis Acids was assumed to be
necessary as it was shown previously that these organoboron compounds can take part in
the reaction in the presence of TMSCl. The reason behind this is that in order for the
Petasis reaction to proceed, the iminium ion species has to be formed by some means [29].
The boronic acids having the dual role of the Lewis acid and the nucleophile candidate can
move the reaction to completion. On the other hand trifluoroborates being already
nucleophilic cannot react unless the iminium ion species is already formed with the help of
another Lewis acid.
Throughout the literature several Lewis Acids are known to have the ability of
stabilizing iminium ions in different nucleophilic additions to C=N bonds [30, 31]. A
87
possible mechanism of how would trifluoroborates in the presence of Lewis acids work is
shown in Figure 4.1.
N
R
2
R
1
OH
R
3
R
4
N
R
2
R
1
R
4
R
3
N
R
2
R
1
N
R
3
R
4
R
2
R
1
N
R
2
R
1
N
R
3
R
4
L.A.
R
1
R
2
R
3
R
4
O
R
2
N
R
1
H
N
R
2
R
1
OH
R
3
R
4
L.A.
F
B
R
5
F
F
R
2
N
R
1
H
R
1
N
R
2
R
5
R
3
R
4
L.A.
L.A.

Figure 4.1: The use of Lewis Acids and trifluoroborates in the Petasis Reaction

4.2.4 The Eschenmoser’s salt and usefulness of dimethylamine
intermediates
Eschenmoser in 1970 reported the formation of dimethyl(methylene)ammonium
iodide from trimethylamine and its use as a Manich reagent with very high reactivity [32].

88
N
Me Me
Me
+CH
2
I
2
N
Me
Me
Me
CH
2
I
I
150
o
C
NCH
2
Me
Me
I
+CH
3
I
Me N Me
Me
CH
2
-I
I

Scheme 4.12: Formation of Eschenmoser’s salt

Mixing trimethylamine and diiodomethane in tetrahydrothiophene dioxide resulted
in the formation of (iodomethyl)trimethylammonium. Consecutive heating of the product
at 150
o
C for 10-15 minutes followed by cooling led to the production of
dimethyl(methylene)ammonium iodide or “Eschenmoser’s Salt”, a thermally stable
(<350
o
C) salt, upon removal of methyl iodide in the form of distillate.
Eschenmoser’s salt was shown to be an inexpensive and extremely convenient
reagent for aminoalkylation of ketones and aldehydes [33]. This method would be an
alternative of the already existing Manich reaction which involves the reaction of an amine,
an aldehyde (mostly formaldehyde), and a C-H acidic compound [34].
O
R
1
R
2
H
2
CN
Me
Me
Cl
+
O
R
1
R
2
N
H
Me
Me
Cl

Scheme 4.13: Alternative Manich reaction

The reaction of silyl enol ethers and lactone enolates with Eschenmoser’s salt was
also reported by Danishefsky et al. in 1976 [35]. The silyl enol ethers would yield the
89
dimethylamine intermediate (Mannich base) after direct reaction with the Eschenmoser’s
salt followed by treatment with aqueous acid and neutralization. In the lactone cases, their
enolates were treated with lithium diisopropylamide (LDA), followed by addition of the
salt and quenching with aqueous sodium bicarbonade to affort the product.
R
2
TMSO
H
2
CN
Me
Me
I
+
R
1
R
2
TMSO
R
1
N
H
Me
Me
I
aq. HCl
base
R
2
TMSO
R
1
N
Me
Me
O
O
O
O
H
2
CN
Me
Me
I
+
H
N
Me
H
Me
I
O
O
H
N
Me Me

Scheme 4.14: Reaction of silyl enol ethers and lactone enolates with Eschenmoser’s
salt

The Mannich bases can serve as intermediates for the α-methylenation of the
starting lactones by simply treating them with 1,5-diazabicyclo[5.4.0]-undec-5-ane (DBU).
The dimethylamine moiety is also shown in literature to serve as a good hydrophobic
group in biologically active molecules [36, 37, 38, 39].
Br
HO
N
Me
Me
N
Me
O
O
S
Arbitol
Br
Br
O N
Me
Me
N
Me
Me
Apsylamine-1
S
Cl
HO N
Me
Me
403U76

Figure 4.2: Dimethylamine bearing natural products and biologically active molecules
90
As shown in Figure 4.2, arbitol, a natural product that bears the dimethylamine
moiety, is a molecule with antiviral effects, immunostimulative and interferon-induced
activities and its derivatives were shown to be potent inhibitors of HBV (Hepatitis B virus)
replication in vitro. Apsylamine-1 is a marine natural product which possesses a wide
range of biological activities, including acetylholinesterase inhibition, anti-HIV activity
and histamine H
3
receptor antagonism. The diphenyl sulfide 403U76 is a molecule that was
synthesized in the lab and has been reported as a SERT (serotonin transporter) and NET
(nonepinefrine transporter) inhibitor. These transporters play a pivotal role in the
regulation of neurotransmission, which is responsible for several neurodegenerative and
psychiatric disorders.

4.3 Results
The preparation of libraries of small molecules having either allylic or benzylic
amine moieties has been one of our objectives not only for this project but since the early
discovery of the Petasis reaction. This transformation poses as an attractive alternative to
the reductive amination reaction as well as the Mannich reaction [40]. The wide range of
molecular diversity that can be achieved is well known but, there is always room for
improvement and expansion.
The use of boronic acids in this chemistry has certain drawbacks that exist were
limiting further expansion to more diverse molecules. The most important of these
drawbacks are the presence of some non reactive boronic acids and boronic acids that
couldn’t exist due to high instability.
91
In order to expand the scope of this process, we investigated the use of potassium
trifluoroborates to replace the boronic acids. Formaldehyde and glyoxilic acid were used as
the carbonyl species to evaluate this multi-component reaction (Scheme 4.15). Since a
Lewis acid was necessary for the reaction to take place we decided to use ytterbium triflate
mainly because it is known to be less sensitive in the presence of water and it is also
inexpensive [41].
R
3
N
BF
3
K
+
HCHO
CHOCOOH
+
R
1
Yb(OTf)
3
10mol%
solvent
or
R
2
or
NH
R
3
R
2
R
1
R
3
N
R
1
R
2
HOOC
Scheme 4.15: Trifluoroborates in the Petasis reaction

4.3.1 Reactions of trifluoroborates with formaldehyde
Before we moved forward to examine the trifluoroborates we wanted to run some
comparison tests with boronic acids, boronates and trifluoroborates to figure out what the
reactivities are for individual species as well as conditions to be used in the reaction to be
designed. The results can be seen in Table 4.1 where morpholine, formaldehyde and 4-
methoxyphenyl boron derivatives were compared directly under similar conditions.

92
Table 4.1: Comparison of organoboron compounds in the Petasis reaction
ONH +
B
B(OH)
2
BF
-
3
K
+
O
O
H
2
O/ 5 h
H
2
O/ 5 days
H
2
O/ 24h
65%
63%
85%
BF
-
3
K
+
toluene/ 3 days no rxn
BF
-
3
K
+
toluene/ 2h
89%
Yb(OTf)
3
O
N
+
Organoboron
compound
Conditions
O
CH
2
CO
Entry
Conditions Yield
BXn O
BXn
2.
3.
1.
4.
5.

The reaction of amine, formaldehyde and boronic acid under refluxing conditions
(entry 1) gave the product in 85% yield in about 5 hours. The same reaction in the same
solvent (water) with pinacolboronate even after 5 days of refluxing gave only 65% yield
(entry 2). Interestingly, the trifluoroborate, without the use of a Lewis acid, worked better
than the pinacolboronate (entry 3). This might seem confusing since trifluoroborates do not
93
work in the absence of a Lewis acid in an organic solvent even after several days of
refluxing (entry 4). Presumably in entry 3, the trifluoroborate in water hydrolyzes slowly to
boronic acid moving the reaction to completion something that cannot happen in an
organic solvent under dry conditions. When we run the reaction in toluene in the presence
of a catalytic amount of a Lewis acid, like ytterbium triflate we got the product in about
two hours and the yields were comparable to the boronic acid run.
Now that it was established that trifluoroborates could indeed be helpful we
wanted to try synthesize a trifluoroborate that the corresponding boronic acid cannot be
used. For that reason we picked potassium vinyl trifluoroborate. The products from the
reactions with the vinyl trifluoroborate would be the allyl amines which have always been
very attractive molecules and useful scaffolds for further manipulation. The results of the
reaction of two potassium organotrifluoroborates, the vinyl and the 4-methoxy-phenyl with
primary and secondary amines are shown in Table 4.2.

94
Table 4.2: Products of the Petasis reaction with trifluoroborates, amines
and formaldehyde

ON
O
89%
HN
Ph
O
87%
NN
Ph
78%
ON 89%
N
O
O
52%
N
O
60%
Entry Amine Trifluoroborate Product Yield
1.
2.

3.
4.
5.
6.
NN
Ph
H
ON H
N
H
H
N
H
Ph H
NH
ON H
O
BF
3
-
K
+
BF
3
-
K
+
>>
>>
>>
>>

1 equivalent of amine was mixed with excess paraformaldehyde, 1.3 equivalents
trifluoroborate and 10 mol % ytterbium triflate and refluxed in toluene for 1-8 hours

95
Although benzyl amine gave the mono-substituted product, that was not the case
with allyl amine. The later gave the di-substituted product, probably because of less
hinderance from the allylic group in comparison to the benzylic one.

4.3.2 Reactions of trifluoroborates with the Eschenmoser’s salt
In order to confirm our assumption, that trifluoroborates react readily with iminium
salts, and establish that indeed this is the actual intermediate in the three component
reaction we decided to get a formaldehyde derived iminium salt and put it to the test.
Eschenmoser’s salt was the right solution since it is readily available and stable for a long
time in an oxygen free environment.
Previous tests that were run in our lab showed that styryl boronic acid reacts rather
slowly and in elevated temperatures with this preformed iminium salt [42]. The need for
water was immense in order to form the aminol species which would then react with the
boronic acid.

H
2
CN
Me
Me
I +
B
Ph OH
OH
Ph
H
2
O, 70
o
C
24 hours
68%
N
Me
Me
HO N
Me
Me

Scheme 4.16: Reaction of boronic acids with the Eschenmoser’s salt

96
However, we have found that upon mixing of the trifluoroborates with
Eschenmoser’s salt resulted in all cases to the formation of the dimethylamine product in
good yields at room temperature. Electron donating as well as electron withdrawing groups
could be introduced to the aromatic rings. The most surprising result was with 3-
nitrophenyl trifluoroborate, probably the least reactive species of this family. The
equivalent boronic acid is non reactive but the trifluoroborate gave the desired product in
the addition to the Eschenmoser’s salt.
Table 4.3: Formation of dimethylamine intermediates
N
93
N
N
N
O
F
NO
2
96
79
39 1
2
Entry Iminium salt Trifluoroborate Product Yield(%)
3
4
NCH
2
Me
Me
I
O
2
N
BF
3
-
K
+
O
BF
3
-
K
+
F
BF
3
-
K
+
BF
3
-
K
+

1 equivalent of the Eschenmoser’s salt was mixed with some excess of trifluoroborate in
dichloromethane and stirred at room temperature for 24 hours
97
4.3.3 Reactions of trifluoroborates with glyoxylic acid
The vinyl- and 4-methoxyphenyl trifluoroborates were also employed for the
formation of aminoacids after reaction with amines and glyoxylic acid. The reactions were
run in acetonitrile or toluene making the isolation of the product very easy since it would
precipitate. Preparative TLC would be employed for certain products that did not
precipitate.

Table 4.4: Formation of aminoacids
NH
2
1.
2.
Entry Amine Trifluoroborate Aldehyde Product Yield
HN
O
COOH
69%
HN
O
COOH
65%
HN
COOH
18%
3.
OHCCOOH
OHCCOOH
OHCCOOH
NH
2
NH
2
BF
3
-
K
+
O
BF
3
-
K
+
BF
3
-
K
+
O

1 equivalent of amine was mixed with 1.2 equivalents of glyoxylic acid and 1.3 equivalents of
trifluoroborate. The mixture was refluxed or stirred to room temperature for 1-10 hours.

98
Secondary amines were not effective in this transformation. That is probably due
to steric hinderance. Also the vinyl trifluoroborate reactions were very messy, resulting to
observation of a lot of new spots on the TLC. Upon isolation we couldn’t assign the NMR
spectra for most of them. Only with aminodiphenyl methane we were able to isolate the
desired product in low yields.

4.4 Conclusion
We have demonstrated the ability of using organo-trifluoroborates in our three
component reaction with some interesting results. A major advantage of this variation that
was derived from this work, is the fact that we can use the trifluoroborates instead of
boronic acids that are unreactive or otherwise wouldn’t exist or cannot be used in this
chemistry.
99
4.5 Experimentals
4.5.1 General
All reagents and commonly available starting materials were purchased from
available commercial sources. Thin layer chromatography was performed on pre-coated
TLC plates (silica gel 60 F
254
) and flash chromatography using Silica gel 60, which has a
particle size range between 0.040 – 0.063 mm. NMR spectra were obtained on either a
Bruker AMX-500 MHz, a Bruker AM-360 MHz or a Bruker AC-250 MHz instrument.
High resolution mass spectra were obtained at the University of California at Los Angeles
Mass Spectrometry facility.

4.5.2 General procedure
In a flame dried flask under argon equipped with a condenser the amine, glyoxylic
acid or paraformaldehyde, and 10 mol % ytterbium triflate were added. The solvent used
was either acetonitrile or toluene. Trifluoroborate was then mixed with the resulting slurry
which was then refluxed until TLC indicated consumption of most of the amine and
formation of a new spot. The reaction flask was then removed from the oil heating bath and
let to cool to room temperature. Upon cooling, wherever formaldehyde was used, 3N
NaOH was added to the reaction mixture till pH=14. The product was extracted with DCM
and dried over MgSO
4
. Filtration and removal of the solvents afforded the pure product. In
some occasions additional purification was carried, through the means of flash column
chromatography or preparative TLC. In the cases where glyoxilic acid was used instead of
formaldehyde, the product was filtered out of the reaction mixture or was isolated after
flash column chromatography.
100
4.5.3 Specific Syntheses and Physical Properties

Vinyl-trifluoroborate

BF
3
-
K
+

The product was prepared on 0.1 mol scale. To a solution of B(OMe)
3
(17 ml, 0.15
mol), in anhydrous THF (100 ml), a solution of vinyl-magnesium chloride in 1.6 M THF
(62.5 ml, 0.1 mol) was added dropwise maintaining temperature below -60
o
C. The
resulting mixture was stirred under Argon for 30 minutes and then allowed to warm to
room temperature and stirred for another 30 minutes. KHF
2
(47 g, 0.6 mol) was added at
0
o
C to the slurry, followed by slow addition of 100 ml water. The white slurry that formed
was let to stir for 30 minutes at 0
o
C and another 30 minutes at room temperature. Solvents
were then evaporated and resulting solid was washed two times with cold acetone and two
times with warm acetone. All portions of acetone were collected, filtered, and evaporated
to yield a yellowish solid which was then recrystalized from acetone/ethyl ether to yield
the pure product as white fluffy crystals (9 g, 69%).

4-methoxy-phenyl-trifluoroborate

BF
3
-
K
+
O
Me

101
The product was prepared on 154 mmol scale. In a flame-dried 3-necked 250 ml
flask, were inserted 4 gr of Mg turnings (grounded), and 60 mg HgCl
2
with 50 ml Et
2
O.
Then 1 ml of 4-bromoanisole was added to initiate the reaction. After about 5 minutes the
solution became cloudy. In the meanwhile a solution of 4-bromoanisole was prepared in
the addition funnel by dissolving 19.3 ml of 4-bromoanisole in 30 ml of Et
2
O (dry). The
system was cooled to 0
o
C with the help of an ice-bath and slow addition, over a period of 1
hour started, of the mixture to the Mg. When the addition was over the system was let to
stir at room temperature for 1 more hour. The same apparatus was setup like before. The
Grignard reagent previously prepared was transferred to the addition funnel with a double
ended needle. To a solution of B(OMe)
3
(22.4 ml, 0.2 mol), in dry Et
2
O (100 ml), the
solution of the Grignard reagent was added dropwise maintaining temperature below -
60
o
C. The resulting mixture was stirred under Argon for 30 minutes and then allowed to
warm to room temperature and stirred for another 30 minutes. KHF
2
(47 g, 0.6 mol) was
added at 0
o
C to the slurry, followed by slow addition of 100 ml water. The yellowish slurry
that formed was let to stir for 30 minutes at 0
o
C and another 30 minutes at room
temperature. Solvents were then evaporated and resulting solid was washed two times with
cold acetone and two times with warm acetone. All portions of acetone were collected,
filtered, and evaporated to yield a brownish solid which was then recrystalized from
acetone/ethyl ether to yield the pure product as white solid.

102
1-Allyl-4-benzyl-piperazine

NN
Ph
The product was prepared on 0.25 mmol scale using the general procedure and
acetonitrile as the solvent. Reaction time was six hours at which time TLC showed full
conversion of the amine to the product. After base extraction with 3N NaOH the residue
was dried and then purified with silica chromatography (10% MeOH in EtOAc) to yield
the product (42 mg, 78%).
1
H NMR (250 MHz, CDCl
3
) δ 7.35-7.23 (m, 5H), 6.00-5.80
(m, 1H), 5.27 (dd, J=14.3, 2.3 Hz, 2H), 3.60 (s, 2H), 3.20 (d, J=6.9 Hz, 2H), 2.85-2.60 (m,
8H).

4-Allyl-morpholine

N O

The product was prepared on 0.25 mmol scale using the general procedure and
toluene as the solvent. The reaction time was three hours at which time TLC showed full
conversion of the amine to the product. After base extraction with 3N NaOH the residue
was dried and then purified with silica chromatography (10% MeOH in EtOAc) to yield
103
the product (28 mg, 89%).
1
H NMR (250 MHz, CDCl
3
) δ 6.99-5.98 (m, 1H), 5.56-5.39 (m,
2H), 4.03 (m, 4H), 3.47 (d, J=6.4 Hz, 2H), 2.99 (m, 4H).

4-(4-Methoxy-benzyl)-morpholine

ON
O

The product was prepared on 0.125 mmol scale using the reaction conditions
similar to general procedure in acetonitrile. The reaction was refluxed for a bit over two
hours. TLC showed consumption of all the amine. Base extraction followed by flash
column chromatography (35% EtOAc in Hexanes) yielded the product (23 mg, 89%).
1
H
NMR (250 MHz, CDCl
3
) δ 7.31 (m, 2H), 6.92 (m, 2H), 3.87 (s, 3H), 3.79 (t, J=4.6 Hz,
4H), 3.51 (s, 2H), 2.49 (t, J=4.6 Hz, 4H);
13
C NMR (250 MHz, CDCl
3
) δ 160.7, 132.0,
129.9, 114.7, 67.7, 63.8, 55.8, 54.6.

Diallyl-(4-methoxy-benzyl)-amine

N
O

The product was prepared on 0.25 mmol scale using the reaction conditions similar
to general procedure and toluene as the solvent. The reaction time was eight hours. After
base extraction with dichloromethane, the residue was purified via silica chromatography
104
(10% EtOAc in Hexanes), to yield the product (32 mg, 60%).
1
H NMR (250 MHz, CDCl
3
)
δ 7.22 (d, J=9.0 Hz, 2H), 6.83 (d, J=9.0 Hz, 2H), 5.94-5.78 (ddt, J=16.9, 10.3, 6.4 Hz, 2H),
5.22-5.09 (m, 4H), 3.78 (s, 3H), 3.49 (s, 2H), 3.04 (dt, J=6.4, 1.4 Hz, 4H);
13
C NMR (250
MHz, CDCl
3
) δ 158.5, 135.9, 131.2, 130.1, 117.3, 113.5, 56.8, 56.2, 55.2.

Benzyl-(4-methoxy-benzyl)-amine

HN
Ph
O

The product was prepared on 0.0625 mmol scale using the reaction conditions
similar to general procedure in acetonitrile. The reaction was refluxed for three hours.
After base extraction (3N NaOH), with 3 x 10 ml DCM, the residue was purified via silica
chromatography (20% EtOAc in Hexanes) to yield the product (12 mg, 87%).
1
H NMR
(250 MHz, CDCl
3
) δ 7.49-7.23 (m, 7H), 6.96-6.87 (m, 2H), 3.83 (s, 3H), 3.57 (s, 2H), 3.52
(s, 2H);
13
C NMR (250 MHz, CDCl
3
) δ 160.1, 141.0, 132.5, 131.5, 130.3, 129.6, 128.4,
114.7, 58.9, 58.3, 55.9.

Allyl-bis-(4-methoxy-benzyl)-amine

N
O
O

105
The product was prepared on 0.25 mmol scale. The reaction was refluxed for eight
hours with one equivalent of trifluoroborate in toluene. After base extraction (3N NaOH),
with 3 x 10 ml DCM, the residue was purified via silica chromatography (10% EtOAc in
Hexanes) to yield the product (18 mg, 24%). In the case where two equivalents of
trifluoroborate were used the yield was 52%.
1
H NMR (250 MHz, CDCl
3
) δ 7.24 (d, J=8.9
Hz, 4H), 6.83 (d, J=8.9 Hz, 4H), 5.98-5.79 (ddt, J=17.5, 10.2, 6.4 Hz, 1H), 5.24-5.08 (m,
2H), 3.78 (s, 6H), 3.47 (s, 4H), 3.01 (dt, J= 6.4, 1.6 Hz, 2H);
13
C NMR (250 MHz, CDCl
3
)
δ 158.5, 136.1, 131.6, 129.9, 117.2, 113.5, 56.8, 56.0, 55.2.

Benzylamino-(4-methoxy-phenyl)-acetic acid

N
H
Ph
O
COOH

The product was prepared on 0.0625 mmol scale. The reaction was refluxed for 45
minutes in acetonitrile at which time TLC showed consumption of the amine. The mixture
was purified with preparative TLC (20% MeOH in EtOAc) to isolate 12 mg of the product
(69%).
1
H NMR (250 MHz, DMSO) δ 7.51-7.35 (m, 7H), 7.03 (d, J=8.4 Hz, 2H), 5.05 (s,
1H), 3.97 (m, 2H), 3.77 (s, 3H).

106
(Benzhydryl-amino)-(4-methoxy-phenyl)-acetic acid

HN
Ph
O
Ph COOH

The product was prepared on 0.125 mmol scale using the reaction conditions
similar to general procedure with toluene as solvent. The reaction time was 8 hours in
which time TLC showed the amine being consumed and precipitate formed. Precipitate
was collected by filtration and washed with acetone to yield the product (28 mg, 65%).
1
H
NMR (250 MHz, CD
3
OD with DCl) δ 7.54-7.40 (m, 10H), 7.27 (d, J=8.8 Hz, 2H), 7.01 (d,
J=8.8 Hz, 2H), 5.36 (s, 1H), 4.68 (s, 1H), 3.83 (s, 3H).

2-(Benzhydryl-amino)-but-3-enoic acid

N
H
Ph
Ph
COOH

The product was prepared on 0.25 mmol scale using the reaction conditions similar
to general procedure with acetonitrile as solvent. The reaction time was 10 hours.
Precipitates were collected by filtration to yield the product (12 mg, 18%).
1
H NMR (250
MHz, CD
3
OD) δ 7.52-7.32 (m, 10H), 6.00-5.82 (m, 1H), 5.46 (s, 1H), 5.45-5.31 (m, 2H),
3.8 (d. J=7.9 Hz, 1H).
107
Allyl-dimethyl-amine

N
Me
Me

The product was prepared on 0.5 mmol scale. The Eschenmoser’s salt was mixed
with excess of vinyl trifluoroborate in dichloromethane and stirred to room temperature for
24 hours. The reaction mixture was then base extracted with 3N NaOH and 3 x 10 ml
DCM. Residue was then dried over MgSO
4
and evaporated to yield the desired product
without any further purification (40 mg, 93%).
1
H NMR (250 MHz, CDCl
3
) δ 6.05-5.86
(m, 1H), 5.54-5.37 (m, 2H), 3.49 (d, J=7.6 Hz, 2H), 2.54 (s, 6H).

(4-Methoxy-benzyl)-dimethyl-amine

N
O
Me
Me

The product was prepared on 0.5 mmol scale. The Eschenmoser’s salt was mixed
with some excess of 4-methoxy-phenyl-trifluoroborate in acetonitrile and stirred to room
temperature for 3 hours. The reaction mixture was then base extracted with 3N NaOH and
3 x 5 ml DCM. Residue was then dried over MgSO
4
and evaporated to yield the desired
product without any further purification (79 mg, 96%). Same reaction with boronic acid
instead of trifluoroborate yielded the desired product in 63%.
1
H NMR (250 MHz, CDCl
3
)
108
δ 7.19 (d, J=8.9 Hz, 2H), 6.83 (d, J=8.9 Hz, 2H), 3.78 (s, 3H), 3.34 (s, 2H), 2.20 (s, 6H);
13
C NMR (250 MHz, CDCl
3
) δ 158.6, 130.8, 130.2, 113.5, 63.7, 55.2, 45.2.

(4-Fluoro-benzyl)-dimethyl-amine

N
Me
Me
F

The product was prepared on 0.125 mmol scale. The Eschenmoser’s salt was
mixed with some excess of 4-fluoro-phenyl-trifluoroborate in toluene and refluxed for 8
hours at which time TLC monitoring showed full conversion to the product. The reaction
mixture was then base extracted with 2N NaOH and 3 x 5 ml DCM. Residue was then
dried over MgSO
4
and evaporated to yield the desired product without any further
purification (15 mg, 79%).
1
H NMR (250 MHz, CDCl
3
) δ 7.62 (m, 2H), 7.14 (m, 2H), 3.04
(s, 2H), 2.72 (s, 6H).

Dimethyl-(3-nitro-benzyl)-amine

Me
N
Me
NO
2

109
The product was prepared on 0.125 mmol scale. The Eschenmoser’s salt was
mixed with some excess of 3-nitro-phenyl-trifluoroborate in toluene and refluxed for 24
hours at which time TLC monitoring showed formation of a new spot. The reaction
mixture was then base extracted with 2N NaOH and 3 x 5 ml DCM. Residue was then
dried over MgSO
4
and purified with flush column chromatography (15% MeOH in
dichloromethane) to yield the desired product (10 mg, 39%).
1
H NMR (250 MHz, CDCl
3
)
δ 8.18 (s, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.73 (m, 1H), 7.50 (m, 1H), 3.57 (s, 2H), 2.31(s,
6H).
110
4.6 Chapter 4 References

1. Darses, S., Genet, J. P. “Potassium Trifluoro(organo)borates: New Perspectives in
Organic Chemistry.” European Journal of Organic Chemistr, 2003, p. 4313-4327.

2. Batey, R. A., Thadani, A. N., Smil, D. V., Lough, A. J. “Diastereoselective
Allylation and Crotylation Reactions of Aldehydes with Potassium Allyl- and
Crotyltrifluoroborates Under Lewis Acid Catalysis.” Synthesis, 2000, 7, p. 990-
998.

3. Molander, G. A., Figueroa, R. “Organotrifluoroborates: Expanding Organoboron
Chemistry. Aldrichimica Acta, 2005, 38(2), p. 49-56.

4. Hall, D. G. “Boronic Acids.” Copyright 2005, WILEY-VGH verlag Gmb H&C,
KGaA, Weinheim, ISBN 3-527-30992-8.

5. Chambers, R. D., Clark, H. C., Willis, C. J. “Some Salts of
Trifluoromethylfluoroboric Acids.” Journal of the American Chemical Society,
1960, 82(20), p. 5298-5301.

6. Frohn, H. J., Franke, H., Fritzen, P., Bardin, V. V. “(Fluoroorgano)fluoroboranes
and –fluoroborates I: Synthesis and Spectroscopic Characterization of Potassium
Fluoroaryltrifluoroborates and Fluoroaryldifluoroboranes.” Journal of
Organometallic Chemistry, 2000, 598(1), p. 127-135.

7. Leigh, D., Kraus, F. A., Kraus, C. A. “Quaternary Ammonium Salts with Anions
Containing Triphenylboron.” Journal of the American Chemical Society, 1940,
62(5), p. 1143-1144.

8. Brauer, D. J., Buerger, H., Pawelke, G. “Vibrational Spectra and Normal-
Coordinate Analysis of Trifluoromethyl Compounds. 17. Crystal and Molecular
Structure, Reinvestigated Vibrational Spectra, and Normal-Coordinate Analysis of
Potassium (trifluoromethyl)trifluoroborate, K[CF
3
BF
3
].” Inorganic Chemistry,
1977, 16(9), p. 2305-2314.

9. Brauer, D. J., Burger, H., Pawelke, G. “Vibrational Spectra and Normal Coordinate
Analysis of CF
3
Compounds: XXXIV. The Bis(Trifluoromethyl)Difluoroborate
Anion: X-Ray Structure of Cs[(CF
3
)
2
BF
2
].” Journal of Organometallic Chemistry,
1980, 192(3), p. 305-315.

10. Pawelke, G., Heyder, F., Burger, H. “Das Bis(Trifluoromethyl)-Difluoroborat-
Anion.” Journal of Organometallic Chemistry, 1979, 178(1), p. 1-4.

11. Vedejs, E., Chapman, R. W., Fields, S. C., Lin, S., Schrimpf, M. R. “Conversion of
Arylboronic Acids into Potassium Aryltrifluoroborates: Convenient Precursors of
Arylboron Difluoride Lewis Acids.” Journal of Organic Chemistry, 1995, 60(10),
p. 3020-3027.
111

12. Darses, S., Genet, J. P., Brayer, J. L., Demoute, J. P. “Cross-Coupling Reactions of
Arenediazonium Tetrafluoroborates with Potassium Aryl- or
Alkenyltrifluoroborates Catalyzed by Palladium.” Tetrahedron Letters, 1997,
38(25), p. 4393-4396.

13. Petasis, N. A., Yudin, A. K., Zavialov, I. A., Prakash, G. K. S., Olah, G. A. “Facile
Preparation of Fluorine-Containing Alkenes, Amides, and Alcohols via the
Electrophilic Fluorination of Alkenylboronic Acids and Trifluoroborates.” Synlett,
1997, 5, p. 606-608.

14. Darses, S., Michaud, G., Genet, J. P. “Potassium Organotrifluoroborates: New
Partners in Palladium-Catalyzed Cross-Coupling Reactions.” European Journal of
Organic Chemistry, 1999, 8, p. 1875-1883.

15. Batey, R. A., Thadani, A. N., Smil, D. V. “Potassium Alkenyl- and
Aryltrifluoroborates: Stable and Efficient Agents for Rhodium-Catalyzed Addition
to Aldehydes and Enones.” Organic Letters, 1999, 1, p. 1683-1686.

16. Pucheault, M., Darses, S., Genet, J. P. “Potassium Organotrifluoroborates in
Rhodium-Catalyzed Asymmetric 1,4 Additions to Enones.“European Journal of
Organic Chemistry, 2002, 19, p. 3552-3557.

17. Navarre, L., Darses, S., Genet, J. P. “Efficient Access to Alanine Derivatives by
1,4-Additions of Potassium Trifluoro(organo)borates.” European Journal of
Organic Chemistry, 2004, p. 69-73.

18. Puentener, K., Scalon, M. (Hoffmann-La Roche AG), Patent EP1057831A2, May
2000.

19. Molander, G. A., Bernardi, C. R. “Suzuki-Miyaura Cross-Coupling Reactions of
Potassium Alkenyltrifluoroborates.“Journal of Organic Chemistry, 2002, 67, 24, p.
8424-8429.

20. Molander, G. A., Ito, T. “Cross-Coupling Reactions of Potassium
Alkyltrifluoroborates with Aryl and 1-Alkenyltrifluoromethanesulfonates.”
Organic Letters, 2001, 3, 3, p. 393-396.

21. Molander, G. A., Yun, C. S., Ribagorda, M., Biolatto, B. “B-Alkyl Suzuki-
Miyaura Cross-Coupling Reactions with Air-Stable Potassium
Alkyltrifluoroborates.” Journal of Organic Chemistry, 2003, 68, 14, p. 5534-5539.

22. Molander, G. A., Katona, B. W., Machrouhi, F. “Development of the Suzuki-
Miyaura Cross-Coupling Reaction: Use of Air-Stable Potassium
Alkynyltrifluoroborates in Aryl Alkynylations.” Journal of Organic Chemistry,
2002, 67, p. 8416-8423.

112
23. Quach, T. D., Batey, R. A. “Copper(II)-Catalyzed Ether Synthesis from Aliphatic
Alcohols and Potassium Organotrifluoroborate Salts.” Organic Letters, 2003, 5, 8,
p. 1381-1384.

24. Lai, G. S., Pez, G. P., Syvret, R. G. “Electrophilic NF Fluorinating Agents.”
Chemical Reviews, 1996, 96(5), p. 1737-1756.

25. Matthews, D. P., Miller, S. C., Javri, E. T., Sabol, J. S., McCarthy, J. R. “A New
Method for the Electrophilic Fluorination of Vinyl Stannanes.” Tetrahedron
Letters, 1993, 34(19), p. 3057-3060.

26. Petasis, N. A., Yudin, A. K., Zavialov, I. A., Prakash, G. K. S., Olah, G. A. “Facile
Preparation of Fluorine-Containing Alkenes, Amides, and Alcohols via the
Electrophilic Fluorination of Alkenylboronic Acids and Trifluoroborates.” Synlett,
1997, 5, p. 606-608.

27. Zavialov, I. A. “New Reactions of Organoboronic Acids and their Derivatives.”
Ph.D. Thesis, University of Southern California, 1998, p. 93-98.

28. Thadani, A. N., Batey, R. A. “A Mild Protocol for Allylation and Highly
Diastereoselective Syn or Anti Crotylation of Aldehydes in Biphasic and Aqueous
Media Utilizing Potassium Allyl- and Crotyltrifluoroborates.” Organic Letters,
2002, 4, 22, p. 3827-3830.

29. Batey, R. A. “Boronic Acids: 7. Nucleophilic Addition Reactions of Aryl and
Alkenylboronic Acids and their Derivatives to Imines and Iminium Ions.” WILEY-
VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8, 2005, p. 279-
304.

30. Billard, T., Langlois, B. R. “Reactivity of Stable Trifluoroacetaldehyde
Hemiaminals. 2. Generation and Synthetic Potentialities of Fluorinated Iminiums.”
Journal of Organic Chemistry, 2002, 67(3), p. 997-1000.

31. Lautens, M., Ouellet, S. G., Raeppel, S. “Amphoteric Character of 2-
Vinyloxiranes: Synthetic Equivalents of β, γ-Unsaturated Aldehydes and a
Vinylogous Enolate. ” Angewandte Chemie International Edition, 2000, 39(22), p.
4079-4082.

32. Schreiber, J., Maag, H., Hashimoto, N., Eschenmoser, A. “Dimethyl
(Methylene)Ammonium Iodide.” Angewandte Chemie International Edition, 1971,
10(5), p. 330-331.

33. Kinast, G., Tietze, L.F. “A New Variant of the Mannich Reaction.” Angewandte
Chemie International Edition, 1976, 15(4), p. 239-240.

34. Arend, M., Westerman, B., Risch, N. “Modern variants of the Mannich Reaction.”
Angewandte Chemie International Edition, 1998, 37(8), p. 1045-1070.
113

35. Danishefsky, S., Kitahara, T., McKee, R., Schuda, P. F. “Reactions of Silyl Enol
Ethers and Lactone Enolates with Dimethyl(Methylene) Ammonium Iodide. The
Bis- α-Methylenation of Pre-Vernolepin and Pre-Vernomenin.” Journal of the
American Chemical Society, 1976, 98(21), p. 6715-6717.

36. Swanson, D. M., Wilson, S. J., Boggs, J. D., Xiao, W., Apodaca, R., Barbier, A. J.,
Lovenberg, T. W., Carruthers, N. I. “Aplysamine-1 and Related Analogs as
Histamine H
3
Receptor Antagonists.” Bioorganic & Medicinal Chemistry Letters,
2006, 16, p. 897-900.

37. Vercouillie, J., Mavel, S., Galineau, L., Ragusa, T., Innis, R., Kassiou, M., Chalon,
S., Dolle, F., Besnard, J. C., Guilloteau, D., Emond, P. “Synthesis and in Vitro
Evaluation of Novel Derivatives of Diphenylsulfide as Serotonin Transporter
Ligands.” Bioorganic & Medicinal Chemistry Letters, 2006, 16, p. 1297-1300.

38. Wu, B., Sosa, A. C. B., Boschelli, D. H., Boschelli, F., Honores, E. E., Golas, J.
M., Powell, D. W., Wang, Y. D. “7-(Aryl/Heteroaryl-2-ylethynyl)-4-Phenylamino-
3-Quinolinecarbonitriles as New Src Kinase Inhibitors: Addition of Water
Solubilizing Groups.” Bioorganic & Medicinal Chemistry Letters, 2006, 16, p.
3993-3997.

39. Zhao, C., Zhao, Y., Chai, H., Gong, P. “Synthesis and in Vitro Anti-Hepatitis B
Virus Activities of Some Ethyl 5-Hydroxy-1H-Indole-3-Carboxylates.” Bioorganic
& Medicinal Chemistry Letters, 2006, 14, p. 2552-2558.

40. Abdel-Magid, A. F., Carson, K. G., Harris, B. D., Maryanoff, C. A., Shah, R. D.
“Reductive Amination of Aldehydes and Ketones with Sodium
Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination
Procedures.” Journal of Organic Chemistry, 1996, 61(11), p. 3849-3862.

41. Wang, L., Liu, J., Tian, H., Qian, C., Sun, J. “One-Pot Synthesis of cis-Isoquinolic
Acid Derivatives via Three-Component Reaction of Homophthalic Anhydride with
Aldehydes and Amines using Ytterbium(III) Triflate as Catalyst.” 2005, 347(5), p.
689-694.

42. Zavialov, I. A. “New Reactions of Organoboronic Acids and their Derivatives.”
Ph.D. Thesis, University of Southern California, 1998, p. 134-136.
114
Chapter 5
New Three-Component Reactions of Imines and Aza-
Aromatic Compounds with Organotrifluoroborates
5.1 Introduction
The development of new methods for the synthesis of diverse functionalized
amines and N-heterocycles is of great importance to the synthesis of complex molecules,
particularly in drug discovery.
Our continuous efforts, towards utilization of organotrifluoroborates in
multicomponent reactions, led us to investigate their reactivity with iminium salts. Being
encouraged by the recent results we had from the reaction of the Eschenmoser’s salt with
organotrifluoroborates we looked into investigating other iminium salts in this process. In
situ formation of iminium salts as can be found in literature can be achieved by the reaction
of imines or aza-aromatics with various electrophiles like chloroformates. Herein we will
demonstrate the use of such compounds to an alternative multi-component process.

5.1.1 Imines in chemistry
Imines have always been useful building blocks and readily modified entities for
organic synthesis. Carbon-carbon bond formation with imines provides a convenient way
to prepare α-substituted amines and/or amides, compounds that their vast majority
represents the most common core structures in biologically active molecules [1, 2].
The nucleophilic 1,2 addition of organometallic reagents to the C=N bond of
imines is a well known reaction and a valuable method for the synthesis of primary and
secondary amines [3]. The poor electrophilicity of the azomethine carbon and the tendency
115
of the enolizable imines and imine derivatives to undergo deprotonation rather than
addition, has limited the expansion of these transformations. As a result a great variety of
organometallic reagents and activating additives have been tested in these reactions in
order to improve this electrophilicity and in general the reactivity of the C=N bond. Our
intend here is not to give a comprehensive review of the literature, but to demonstrate the
variety of methods that have been developed towards this goal.
In general the electrophilicity of the carbon atom of the C=N bond was shown to
be improved by N-alkylation, N-oxidation, N-acylation or N-sulfonylation, to give the
more reactive species like iminium salts, nitrones, acylimines and sulfonimines. Another
method used for activation of the C=N bond of imines and imine derivatives was by
coordination of a Lewis acid with the nitrogen lone pair. The use of more reactive
organometallic reagents like the allyl ones for the addition to imines also supplied a
solution to the low electrophilicity, as well as the use of external ligands complexing these
reagents [4].
In order to overcome the obstacle of deprotonation, less basic reagents were shown
to have good results. Such reagents like boranes, boronates, stannanes, cuprates and
organomagnesium reagents could minimize secondary reactions due to proton abstraction.
Some illustrative examples are the following:
In 1988, trimethylsilyl triflate (TMSOTf) was used to facilitate the addition of
Grignard reagents to several aryl aldimines (Scheme 5.1). The mechanism proposed by the
authors involved the formation of an iminium salt [5].

116
N
R
1
H Ar
TMSOTf
N
R
1
H Ar
TMS
TfO
RMgX
or RLi
N
R
1
R Ar
H

Scheme 5.1: Addition of Grignard reagents and lithium reagents to imines

Akiba and collaborators recommended the use of RCu
.
BF
3
, a reagent with low
basicity, which can activate imines by coordination and makes simultaneous addition
possible as shown in Scheme 5.2 [6].
R
1
N
R
2
+ RCu
.
BF
3
CN
H
R
1
R
2
RBF
3
Cu R
1
R
H
N
R
2
H

Scheme 5.2: Reaction of imines with RCu
.
BF
3

Lewis acid promoted reactions of allyl stannanes to imines have been
described in 1995 [7]. It was shown that allyltributyl stannane reacts with aldimines
promoted by chloromethyl (or phenyl) silane to give the corresponding
homoallylamine (Scheme 5.3). Lanthanide triflates were shown to be effective
catalysts for this reaction as well.
N
R
1
H R
Me
3
SiCl
N
R
1
H R
Me
3
Si
N
R
1
R
H
Cl
SnBu
3
NH
4
F

Scheme 5.3: Lewis acid promoted addition of stannanes
117
Palladium-catalyzed cross-coupling routes to α-substituted amines and amides
from non imine based compounds have been developed, such as the α-arylation or
allylation of glycine derivatives [8, 9]. While imines themselves are incompatible with
palladium catalyzed Stille couplings with organotin reagents, they can be triggered to
undergo cross-coupling by the simple addition of acid chlorides and the consecutive
formation of the iminium salts as can be seen in Scheme 5.4 [10]. Unfortunately with this
technique only vinyl groups could be introduced to the imine.
N
R
2
H R
1
+
R
3
Cl
O N
R
2
H R
1
R
3
O
Cl
Pd
0
Pd
O
N
Pd
O
N
R
2
R
1
H
R
3
S
Cl
R
3
R
2
R
1
H
S
R
4
N
R
2
R
4
R
1
R
3
O
Bu
3
Sn-R
4
Bu
3
Sn-Cl

Scheme 5.4: Palladium catalyzed coupling of imines, acid chlorides and stannanes

The rhodium-catalyzed reactions of organoboranes or organostannanes with
imines, allows for the formation of α-substituted amines through an alternative mechanism
[11, 12, 13]. The nature of the N-substituent was determined to be important to the
outcome of the reaction. While less than 10% conversions occurred with N-butyl, benzyl,
or phenyl aldimines, good outcomes were obtained with N-sulfonyl and benzoyl substrates.
Aryl and alkenyl groups could be introduced to the imines with good yields. The R
’
group
in Scheme 5.5 could be either Me- or Bu-.
118
[Rh]
+
BF
4
-
[Rh-R]
R-SnR
'
3
R
'
3
SnBF
4
N
R
2
H R
1
N
R
2
R R
1
[Rh]
R
'
3
SnBF
4
N
R
2
R R
1
R
'
3
Sn
N
R
2
R R
1
H
H
2
O

Scheme 5.5: Rhodium-catalyzed addition to imines

A mild and efficient multicomponent method for the preparation of α-substituted
amides and N-protected amines is the Copper catalyzed coupling of organotin or
organoindium reagents with imines and acid chlorides [14, 15]. This method is very
regiospecific and atom efficient and can be readily diversified as it was shown by the
authors (Scheme 5.6).
N
R
2
H R
1
+
R
3
Cl
O
N
R
2
H R
1
R
3
O
Cl
N
R
2
R
4
R
1
R
3
O
Bu
3
Sn-R
4
or
InCl
x
R
4
(3-x)
Bu
3
Sn-Cl
or
InCl
(x+1)
R
4
(2-x)
Cu-Cl
Cu-R
4

Scheme 5.6: Copper-catalyzed cross-coupling with imines

119
5.1.2 Aza-Aromatic iminium ions
Aza-aromatic compounds like quinoline and isoquinoline derivatives have been
well known not only in medicinal chemistry, because of their broad occurrence in natural
products [16, 17] and pharmaceuticals [18], but also in polymer chemistry, electronics and
optoelectronics for their excellent mechanical properties [19]. Quinoline it self was used as
food preservative and in making antiseptics and dyes and could be obtained from coal tar
[20].
Particularly attractive is their ability to provide enough diversity to address
different biological issues. In this context, access to diversified heterocyclic molecules,
used as scaffolds for further manipulation, is one of the leading strategies in drug synthesis
and discovery and of great importance in synthetic organic chemistry and medicinal
chemistry [21, 22].
A classic method for synthesizing quinolines is the Friedlander synthesis which
involves the reduction of an o-nitro aryl- aldehyde followed by the condensation of
enolizable carbonyl compounds in presence of a Bronsted or a Lewis acid catalyst
(Scheme 5.7). These reactions are rather complicated though due to the tendency of the
intermediate (o-amino aldehyde) to undergo self-condensation [23].
NO
2
O
R
1
NH
2
O
R
1
R
3
O
R
2
N
R
1
R
2
R
3
+ H
2
O

Scheme 5.7: Friedlander synthesis of quinolines

120
Several methods have been developed for preparation of analogues of quinolines
and isoquinolines. A few of these methods will be reviewed here. One method for the
preparation of these analogues is C-C bond formation using organometallic compounds.
Addition reactions of organometallic reagents with aza-aromatics activated by electrophiles
have been of great importance for the synthesis of a variety of biologically active nitrogen
heterocycles, including alkaloids [24, 25, 26, 27, 28].
In the 1990s, organometallic reagents like organosilanes and organotins were
widely utilized as useful carbon nucleophiles (Scheme 5.8) [29, 30, 31, 32].
X
Y
R
1
+
R
2
R
3
R
4
SnBu
3
ClCO
2
Me
N
N
CO
2
Me
CO
2
Me
R
1
R
3
R
2
R
4
R
1
R
4
R
2
R
3
or

Scheme 5.8: Reaction of allylic tin reagents with activated quinoline and isoquinoline

However, these reagents suffer from several problems such as poor nucleophilicity,
toxicity and limited commercial availability. In addition to the above, a huge drawback of
the allylation with allylsilanes (Scheme 5.9), using catalytic amounts of triflate ion as
promoter, was observed in the process with activated isoquinolines, which instead of the
allylated dihydroisoquinoline, it gave benzoisoquinuclidine as the major product [33].

121
X
Y
ClCO
2
Ph
N
CO
2
Ph
OTf
AgOTf
N
OTf
CO
2
Ph
SiMe
3
N
CO
2
Ph
or
or
N
CO
2
Ph
SiMe
3

Scheme 5.9: Addition reaction of allylsilanes to quinolines and isoquinolines

Indium mediated allylation of quinolines and isoquinolines activated by phenyl or
ethyl chloroformate was recently published by Yoon and collaborators [34]. The problem
with this process (use of Indium and allyl bromide), as was reported by the authors, was
the formation of mixtures of adducts (1,2- and 1,4- adducts) in the reactions of quinolines
(Scheme 5.10).
X
Y
ClCO
2
R
N
CO
2
R
Cl
N
Cl
CO
2
R
Br
N
CO
2
R
or
or
N
CO
2
R
In
N
CO
2
R
+

Scheme 5.10: Indium-mediated allylation of quinolines and isoquinolines

Very recently Lavilla and co-workers reported that N-acylazinium salts could serve
as intermediates in Ugi like reactions [35]. The N-acylazinium salts were derived from the
reaction of activating agents (chloroformates, acid halides and sulfonyl halides) with azines
(quinolines, isoquinolines and phenanthridines). The products of this process, α-
122
carbamoylated-1,2-dihydroazines, were the result of the addition of the isocyanide partner
to the iminium salt followed by hydrolysis (Scheme 5.11).
X
Y
ClCO
2
R
N
Cl
N
Cl
N
or
or
N R
O
R O
R O
R
O
R
'
NC
H
2
O
quenching
H
N
O
R
'
O N
H
R
'

Scheme 5.11: N-acylazinium salts as intermediates in Ugi processes

5.2 Results and discussion
Considering that organotrifluoroborates are generally more stable, less toxic and
more easily handled than other organometallic reagents like Grignard, organolithium and
organotin reagents, we thought that it would be highly advantageous that such organoboron
reagents could be utilized in the above reactions (coupled with preformed iminium salts
either from imines or from N-heterocycles).
Following this logic, we introduced the development of a new modified three-
component reaction involving the interaction of in-situ formed iminium salts with
trifluoroborates for the formation of useful, diverse functionalized N-protected amines and
N-heterocycles, compounds that are very important for the synthesis of complex
molecules, particularly in drug discovery (Scheme 5.12).
123
N
R
2
R
1
N
R
2
R
1
N
R
2
R
1
R
3
R
4
BF
3
-
K
+
R
4 x
O
R
3
O
R
3
O
X

Scheme 5.12: Modified Petasis reaction

5.2.1 The use of Imines in a multicomponent manner with
trifluoroborates
Multicomponent reactions (MCRs), processes that involve sequential reactions
among three or more reactants that co-exist in the same reaction mixture, display many of
the most desired features for the chemical and pharmaceutical industries like access to a
large number of unique structures and lower costs. For these reasons and many others the
MCRs have been intensively studied in recent years [36, 37, 38].
Imines have previously been used in several MCRs with a number of
organometallic reagents but not with trifluoroborates. The activation in situ of imines with
a range of acid halides would yield reactive electrophiles (iminium salts) towards addition
by trifluoroborates. This would represent a good way to add an alkyl or aryl group to such
systems.
The imines of choice were the commercially available N-benzylidenebenzyl amine
and N-benzilidenemethyl amine. A few runs we did with different solvents (water and
alcohols cannot be used since they hydrolyze our srarting materials) showed insignificant
difference in reactivity so we decided to use dichloromethane and toluene in dry conditions
at room temperature. We also went ahead and picked three activating agents (allyl
chloroformate, phosphinoyl chloride and benzoyl chloride) to be tested. The results shown
124
in Table 5.1 gave moderate yields and we also noticed the yields dropping, as the days
went by, as a result of the decomposition of the imines. The decomposition of the products
was also observed only 24 hours after isolation.
All the reactions were run at room temperature for 24 hours. The reaction mixtures
were base-extracted and the products were purified with preparative TLC or flush column
chromatography. In comparing entries 1, 2, and 3 we can see that phosphinoyl chloride was
better activating reagent (as can be translated by yields) followed by allyl chloroformate.
Also the reaction with phosphinoyl chloride yielded the unprotected secondary amine as
product and that was due to deprotection of the phosphinoyl group after the base
extraction. It is worth noting here that the reactants were added in the mixture at the same
time since acid chlorides and imines did not interact with the trifluoroborates unless the
iminium salt was formed first, making this a pure multicomponent process and not a
stepwise one.

125
Table 5.1: Imine products with trifluoroborates

Ph
N
Ph O
O
Ph
N
Ph
O
Ph
HN
Ph
Ph
N
Me
O
O
Ph
N
Me
O
O
O
50
43
61
58
54
Ph
N
Me
Ph
O
Ph
N
O
O
O
Ph
29
38
Ph
BF
3
-
K
+
BF
3
-
K
+
BF
3
-
K
+
BF
3
-
K
+
BF
3
-
K
+
BF
3
-
K
+
O
BF
3
-
K
+
O
O
O Cl
O
O Cl
O
O Cl
O
O Cl
Ph
O Cl
Ph
O Cl
P Cl
Ph
Ph
O
Ph
N
Ph
Ph
N
Ph
Ph
N
Ph
Ph
N
Ph
Ph
N
Me
Ph
N
Me
Ph
N
Me
1.
2.
3.
7.
5.
4.
6.
Entry Imine Acid chloride Trifluoroborate Product Yield (%)

Imine was mixed with X equivalents of acid chloride and 1.5 equivalents of trifluoroborate in
different solvents and stirred to room temperature for 2-24 hours.
126
In comparing entries 1 and 4 we can see that allyl trifluoroborate was more
effective than 4-methoxy phenyl trifluoroborate. Also as can be seen from entries 5, 6, and
7 the N-benzylidenemethyl amine would give slightly higher yields than the N-
benzylidenebenzyl amine. This possibly happened because of higher stability of the
starting imine but it could also be due to less bulkiness.
Some huge drawbacks of this process like the instability of the starting materials,
as well as the very high sensitivity of the products and also the messy NMR spectra led us
to explore different imine species like the aza-aromatics (more stable than imines) to
further explore this chemistry.

5.2.2 Addition reactions to aza-aromatic iminium ions
The addition reactions of organometallic reagents with quaternary aza-aromatic
ions acylated by chloroformates, and acyl chlorides have been of great importance for
synthesizing a variety of physiologically active nitrogen heterocycles [39]. While our work
on this project was in progress, a paper was published claiming that organotrifluoroborates
cannot take part in such addition reactions [40]. By activating quinolines, isoquinolines and
phenanthridines with chloroformates (generation in situ of an N-acylazinium salt
containing the reactive C=N
+
moiety) we were indeed able to react them with several
organotrifluoroborates to yield the α-carbamoylated-1,2-dihydroazines.

127
5.2.2.1 Use of isoquinolines
Isoquinolines are one of the most important basic skeletons of many
physiologically active compounds [41-47]. So we initially picked them, to study their
interaction with a simple activating agent like ethyl chloroformate and trifluoroborates.
In order to figure out how many equivalents of chloroformate were needed we
reasoned that we should use those components that would possibly react slow in order for
us to extract more reliable results. Thus, we picked 4-fluorophenyl trifluoroborate to be our
boron species. A few runs with isoquinoline with different equivalents of ethyl
chloroformate showed no formation of any product even after several days. We then
decided to explore different isoquinoline species. Some research in the literature revealed
that 4-bromo isoquinoline could possibly be a more reactive species. Indeed using this
isoquinoline with ethyl chloroformate and 4-fluorophenyl trifluoroborate we were able to
monitor the reaction and the results are shown in Table 5.2. As can be depicted by the
table, 5 equivalents of chloroformate were needed, in order for the reaction to work the
best. This probably happens because chloroformates are very unstable compounds and tend
to hydrolyze easily overtime; thus, by adding more equivalents we just simply ensure that
enough chloroformate molecules are present in order to react with all the isoquinoline
molecules. At the same time a change of several solvents led us to the conclusion that
dichloromethane is the ideal solvent but THF could be used as well.

128
Table 5.2: Equivalents of chloroformate required

1.
2.
3.
4.
Entry chloroformate(equiv) solvent yield (%) rxn time
1
3
3
3
traces
21
22
traces
5 days
5 days
5 days
1 week
5.
6.
3
5
0
35
5 days
3 days
7. 10
31
3 days
DCM
DCM
DCM
DCM
dioxane
acetone
THF

4-Bromo-isoquinoline was mixed with X equivalents of ethyl
chloroformate and 1.5 equivalents of 4-fluorophenyl trifluoroborate
in different solvents and stirred to room temperature for Y days.

Three isoquinolines were tested for their reactivity as can be seen in Table 5.3. As
we anticipated 4-bromo isoquinoline was the most reactive from the three followed by
isoquinolin-5-ol and last the isoquinoline with no substituents. What was also observed in
the case of the isoquinolin-5-ol was that the hydroxyl group was protected by the
chloroformate. Also to our delight the reactions were highly regioselective yielding only
the 1,2 addition product.

129
Table 5.3: Comparison of different Isoquinoline analogs

N O
O
Br
N O
O
N
O
O
O
O
O
90
75
53
1.
2.
3.
Entry Isoquinoline acid chloride trifluoroborate product yield (%)
N
Br
N
OH
N
O
O
Cl
O
O
Cl
O
O
Cl
BF
3
-
K
+
BF
3
-
K
+
BF
3
-
K
+

Isoquinoline was mixed with 5 equivalents of ethyl chloroformate and 1.5 equivalents of allyl
trifluoroborate in toluene and stirred to room temperature for 24 hours.

Several isoquinoline derivatives were prepared with the use of different
trifluoroborates in good to modest yields. 4-Fluorophenyl trifluoroborate gave no product
with the other isoquinolines even after several days of refluxing. In most cases though
refluxing was not necessary and it was avoided mainly due to the chloroformate’s
sensitivity. Also even though in many of the reaction mixtures the starting materials were
not completely soluble, the reactions would proceed normally to yield the products in high
conversions. Some of these isoquinoline derivatives are shown in Table 5.4.

130
Table 5.4: Products from reactions of isoquinolines, chloroformates and
trifluoroborates

N N
O O
O
O
O
O
O
O
O
O
O
N
O
O
O
N
O
O
O
Br
N O
O
Br
N
F
O
O
Br
85%
35% 56%
76%
73%
88%
N O
O
38%

Isoquinoline was mixed with 5 equivalents of chloroformate and 1.5 equivalents of
trifluoroborate in various solvents and stirred to room temperature or refluxed for 2-24 hours.

After the great results we had with the 4-bromo isoquinoline we were interested to
find out if a similar compound like 3-bromo pyridine would give the expected product. A
lot of examples in the literature suggested that both molecules can be activated with
chloroformates giving the iminium salt intermediate, for the addition reaction with
organometallics. Unfortunately as shown in Table 5.5 that was not the case with the
trifluoroborates. Even after refluxing the reaction mixture for several days no product
formed.
131
Table 5.5: Comparison of 4-bromo isoquinoline with 3-bromo pyridine

N
O
O
O
Br
85
1.
2.
Entry Aza-aromatic acid chloride trifluoroborate product yield (%)
N
Br
O
O
Cl
O
O
Cl
BF
3
-
K
+
BF
3
-
K
+
No reaction N
Br
O
O

4-bromo isoquinoline and 3-bromo pyridinewere mixed with 5 equivalents of ethyl chloroformate
and 4-methoxyphenyl trifluoroborate in toluene and stirred to room temperature

To explore the practical limits of this methodology we modified the activating
agent. So, besides chloroformates we tried to employ several other electrophiles like alkyl
and acyl halides as well as anhydrides. 4-bromo isoquinoline as well as isoquinoline and
quinoline were used for this purpose. The results are summarized in Table 5.6.

132
Table 5.6: Interaction of different activating agents with isoquinolines

1.
2.
3.
4.
Entry Activating agent Product Yield (%)
76
5.
6.
7.
Ethyl chloroformate
Benzyl bromide
Benzoyl chloride
1-bromobenzyl bromide
Allyl bromide
NR
NR
traces
NR
NR
NR
(CF
3
CO)
2
O
(Boc)
2
O

For the purposes of this experiment different isoquinolines were mixed with 5 equivalents of
the activating agents and 1.5 equivalents of either vinyl or 4-methoxyphenyl trifluoroborate
and stirred for several days in room temperature. (NR = no reaction)

5.2.2.2 Use of quinolines
Being encouraged by the good results we had from the reaction of several
isoquinoline analogs with chloroformates and organotrifluoroborates we were hopeful that
quinolines would follow the same pattern. Although the results were not as we expected,
the addition reactions took place at the 2-position of quinolines selectively, showing high
regioselectivity (Table 5.7). Quinolines proved to be less reactive and we were able only to
isolate a few products. We were being very optimistic though so we tried to find a
quinoline analoque that would possibly be more reactive. A quinoline like 5,8-dibromo
quinoline was a commercially available species and although it was demonstrated in
transformations with other organometallics as being a highly reactive species again that
was not the case here.
133
Table 5.7: Reactions of activated quinolines with trifluoroborates

67
1.
2.
Entry Aza-aromatic Chloroformate Trifluoroborate Product Yield (%)
N O
O
Cl
O
O
Cl
BF
3
-
K
+
BF
3
-
K
+
O
N
O O
N
O O O
N
50
3.
N
Br
Br
O
O
Cl
BF
3
-
K
+
NR
4.
N O
O
Cl
BF
3
-
K
+
NR

1 equivalent of the quinoline was mixed with 5 equivalents of the chloroformate and 1.5 equivalent
of the trifluoroborate and stirred to room temperature or refluxed for 1-24 hours

5.2.2.3 Use of phenanthridines
We next turned our attention to phenanthridine systems hoping for better
reactivity. Phenanthridine (C
13
H
9
N) is a three-ring aromatic compound structurally
analogous to phenanthrene, but having a nitrogen atom in the outside edge of the central
ring. It could also be considered a quinoline as well as isoquinoline analog.
Dihydrophenanthridine derivatives were recently shown to be useful for the
treatment of the inflammatory component of diseases and particularly useful in treating
134
atherosclerosis, myocardial infraction, congestive heart failure, inflammatory bowel
disease, arthritis, type II diabetes, and autoimmune diseases such as multiple sclerosis and
rheumatoid arthritis [48].
We soon were delighted to find out that the phenanthridine reactions were cleaner
than the quinoline and isoquinoline equivalents. So to further expand the practicality of the
process we tried some other chloroformates like allyl and propargyl as well as a
trifluoroborate that showed no reactivity previously like potassium phenyl trifluoroborate.
The results are shown in Table 5.8. The propargyl chloroformate did not work as well as
the other two activating agents, but it did give the propargyl carbamate as a single product.
Also the potassium phenyl trifluoroborate gave the phenyl substituted
dihydrophenanthridine in moderate yields.
Overall, this methodology allows for the facile construction of several aza-
aromatic derivatives, highly functionalized, in an experimentally convenient and very
simple one step process. The materials and reagents used were all inexpensive and the
conditions were very mild since in most occasions no heating was employed or required.
Any unreacted chloroformate or potassium trifluoroborate was readily removed during the
base extraction thus making the isolation of the products very convenient.

135
Table 5.8: Reaction of phenanthridine, chloroformates and organotrifluoroborates

N O
O
O
93
N O
O
70
N O
O
O
92
N O
O
O
61
N O
O
41
1.
2.
Entry Aza-aromatic Chloroformate Trifluoroborate Product Yield (%)
O
O
Cl
O
O
Cl
BF
3
-
K
+
O
3.
O
O
Cl
BF
3
-
K
+
4.
O
O
Cl
BF
3
-
K
+
BF
3
-
K
+
O
BF
3
-
K
+
O
O
O
Cl
N
N
N
N
N
5.

1 equivalent of phenanthridine was mixed with 5 equivalents of chloroformate and 1.5 equivalents
of trifluoroborate and stirred to room temperature for 6-48 hours
136
5.3 Conclusion
In summary, a new multicomponent reaction involving the interaction of imines
and azines (quinolines, isoquinolines and phenanthridines) with activating agents, like
chloroformates or acyl chlorides, and trifluoroborates was described. The products of this
process α-substituted amides, N-protected amines and α-carbamoylated-1,2-dihydroazines,
are the result of the addition of the trifluoroborate to the N-acylazinium salt formed in-situ.
This represents a new source of iminium ion equivalent for a Petasis type reaction
and an effective method for introduction of various groups like allylic, benzylic and
vinylic, into iminium salts. The reactions are shown to be highly chemo- and regio-
selective and can tolerate various functional groups like alcohols and halides.
The method involving the aza-aromatics, maintains the intracyclic double bond
free for further transformations contrary to other techniques resulting the tetrahydro
quinoline or isoquinoline products [49].
Finally, most of the products obtained by this methodology, either with the imines
or the azines, can readily be converted to more complex heterocycles and other otherwise
difficult to obtain compounds requiring multiple steps.
137
5.4 Experimentals
5.4.1 General
All reagents and commonly available starting materials were purchased from
available commercial sources. Thin layer chromatography was performed on pre-coated
TLC plates (silica gel 60 F
254
) and flash chromatography using Silica gel 60, which has a
particle size range between 0.040 – 0.063 mm. NMR spectra were obtained on a Bruker
AC-250 MHz instrument. High resolution mass spectra were obtained at the University of
California at Los Angeles Mass Spectrometry facility.

5.4.2 General procedure
In a flame dried flask equipped with a balloon filled with argon, guinoline,
isoquinoline or imine was added with 1-5 equivalents chloroformate and 1.5 equivalents
trifluoroborate with dichloromethane as solvent. The mixture was stirred in room
temperature for 8-24 hours, after which time the resulting slurry was filtered and the
volatiles removed in vacuum. The product was purified, by flash column chromatography
or preparative TLC.
138
5.4.3 Specific Syntheses and Physical Properties

Benzyl-(1-phenyl-but-3-enyl)-carbamic acid allyl ester

Ph
N
Ph O
O

In a flame dried 20ml round bottom flask 0.2mmol (38 µl) of N-Benzylidene-
benzylamine were added with 5eq. (106 µl) of allyl-chloroformate and 1.5 eq. (45 mg) of
allyl-trifluoroborate with toluene as solvent (8 ml). The mixture was stirred at room
temperature for 6 hours under nitrogen, after which time it was filtered and the volatiles
removed. The product was purified by preparative TLC using 25% ethyl acetate : hexane
(32mg, 50%).
1
H NMR (CDCl
3
) δ 7.37-6.98 (m, 10H), 6.01-5.77 (m, 1H), 5.77-5.58 (m,
1H), 5.51-5.07 (m, 3H), 4.96 (d, J=7.6 Hz, 2H), 4.64 (s, 2H), 4.41 (d, J=15.6 Hz, 1H), 4.12
(d, J=15.6 Hz, 1H), 2.65 (dd, J=7.1, 6.8 Hz, 2H);
13
C NMR (CDCl
3
) δ 156.7, 139.8, 138.9,
134.8, 132.9, 128.4, 128.3, 127.8, 127.6, 126.8, 126.5, 117.4, 117.3, 66.2, 59.3, 47.4, 35.8.

Benzyl-(1-phenyl-but-3-enyl)-amine

Ph
HN
Ph

In a flame dried 20ml round bottom flask 0.2mmol (38 µl) of N-Benzylidene-
benzylamine were added with 2 eq. (76 µl) of diphenyl-phosphinic chloride and 1.5 eq. (45
139
mg) of allyl-trifluoroborate with toluene as solvent (8 ml). The mixture was stirred at room
temperature for 5 hours under nitrogen, after which time TLC monitoring showed full
consumption of the imine. Base extraction with 1N NaOH followed by purification via
preparative TLC using 20% ethyl acetate : hexane, afforded the deprotected product (29
mg, 61%).
1
H NMR (CDCl
3
) δ 7.34-7.12 (m, 10H), 5.72-5.54 (m, 1H), 5.04-4.93 (m, 2H),
3.62 (dd, J=7.5, 6.5 Hz, 1H), 3.58 (d, J=13.4 Hz, 1H), 3.44 (d, J=13.4 Hz, 1H), 2.39-2.30
(m, 2H), 1.85 (br s, 1H);
13
C NMR (CDCl
3
) δ 135.5, 128.4, 128.3, 128.1, 127.3, 127.1,
126.8, 117.6, 61.6, 51.3, 43.0.

Benzyl-[(4-methoxy-phenyl)-phenyl-methyl]-carbamic acid allyl ester

Ph
N
O
O
O
Ph

In a flame dried 20ml round bottom flask 0.2mmol (38 µl) of N-Benzylidene-
benzylamine were added with 5 eq. (106 µl) of allyl-chloroformate and 1.5 eq. (64 mg) of
4-methoxy-phenyl-trifluoroborate with dichloromethane as solvent (8 ml). The mixture
was stirred at room temperature for 5 hours under nitrogen. Base extraction with 2N NaOH
followed by purification via preparative TLC using 20% ethyl acetate : hexane, afforded
the product (23 mg, 29%).
1
H NMR (CDCl
3
) δ 7.28-7.00 (m, 10H), 6.90-6.71 (m, 4H),
6.50 (s, 1H), 5.86-5.69 (m, 1H), 5.16-5.05 (m, 2H), 4.59 (dt, J=5.5, 1.4 Hz, 2H), 3.74 (s,
3H).

140
N-Methyl-N-(1-phenyl-but-3-enyl)-benzamide

Ph
N
Ph
O

In a flame dried 20ml round bottom flask 0.2mmol (25 µl) of N-Benzylidene-
methylamine were added with 2 eq. (46 µl) of benzoyl-chloride and 1.5 eq. (45 mg) of
allyl-trifluoroborate with toluene as solvent (8 ml). The mixture was stirred at room
temperature for 24 hours under nitrogen, after which time TLC monitoring showed full
consumption of the imine. Base extraction with 1N NaOH followed by purification via
preparative TLC using 20% ethyl acetate : hexane, afforded the product (29 mg, 54%).
1
H
NMR (CDCl
3
) δ 7.63-7.23 (m, 10H), 6.06-5.83 (m, 1H), 5.31-4.93 (m, 3H), 2.98-2.51 (m,
5H).
13
C NMR (CDCl
3
) δ 133.4, 130.1, 129.3, 128.6, 128.4, 127.8, 127.6, 126.8, 118.4,
117.3, 60.7, 54.1, 34.0.

[(4-Methoxy-phenyl)-phenyl-methyl]-methyl-carbamic acid allyl ester

Ph
N
O
O
O

In a flame dried 20ml round bottom flask 0.2mmol (25 µl) of N-Benzylidene-
methylamine were added with 5 eq. (106 µl) of allyl-chloroformate and 1.5 eq. (64 mg) of
4-methoxy-phenyl-trifluoroborate with dichloromethane as solvent (8 ml). The mixture
141
was stirred at room temperature for 10 hours under nitrogen, after which time it was
filtered and the volatiles removed. The product was purified by preparative TLC using
25% ethyl acetate : hexane (24 mg, 38%)
1
H NMR (CDCl
3
) δ 7.37-7.25 (m, 3H), 7.21-7.06
(m, 4H), 6.80 (d, J=9.0 Hz, 2H), 6.61 (s, 1H), 6.01-5.83 (m, 1H), 5.33-5.12 (m, 2H), 4.63
(dt, J=5.4, 1.4 Hz, 2H), 3.80 (s, 3H), 2.72 (s, 3H).
13
C NMR (CDCl
3
) δ 133.2, 128.5, 128.4,
127.4, 117.3, 113.9, 66.3, 62.4, 55.4, 29.8.

Methyl-(1-phenyl-but-3-enyl)-carbamic acid allyl ester

Ph
N
O
O

In a flame dried 20ml round bottom flask 0.2mmol (25 µl) of N-Benzylidene-
methylamine were added with 5 eq. (106 µl) of allyl-chloroformate and 1.5 eq. (45 mg) of
allyl-trifluoroborate with toluene as solvent (8 ml). The mixture was stirred at room
temperature for 10 hours under nitrogen, after which time it was filtered and the volatiles
removed. The product was purified by preparative TLC using 20% ethyl acetate : hexane
(10 mg, 58%)
1
H NMR (CDCl
3
) δ 7.38-7.21 (m, 5H), 6.03-5.69 (m, 2H), 5.58-5.02 (m, 5H),
4.61 (m, 2H), 2.72-2.63 (m, 2H), 2.61 (s, 3H).
13
C NMR (CDCl
3
) δ 139.5, 134.7, 134.6,
129.7, 129.0, 128.4, 127.4, 126.3, 117.4, 116.9, 66.0, 57.2, 34.6, 28.3.

142
5-Ethoxycarbonyloxy-1-(4-methoxy-phenyl)-1H-isoquinoline-2-carboxylic acid
ethyl ester

N
O
O
O
O
O
O
In a flame dried 20 ml round bottom flask 0.3 mmol (43.5 mg) of isoquinolin-5-ol
were added with 3 eq. (86 µl) of ethyl-chloroformate and 1.5 eq. (96.3 mg) of 4-methoxy-
phenyl trifluoroborate with dichloromethane as solvent (8 ml). The mixture was stirred at
room temperature for 12 hours under nitrogen, after which time the reaction mixture was
filtered and the volatiles removed. The product was purified, by flash column
chromatography using 25% ethyl acetate : hexane, as clear oil (89 mg, 73%).
1
H NMR
(CDCl
3
) δ 7.22-6.70 (m, 8H), 6.45 (s, 1H), 5.95 (d, J=8.2 Hz, 1H), 4.3 (q, J=7.2 Hz, 2H),
4.25 (q, J=7.2 Hz, 2H), 3.7 (s, 3H), 1.38 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H);
13
C
NMR (CDCl
3
) δ 159.1, 153.5, 145.5, 133.6, 128.7, 128.1, 127.7, 126.0, 125.0, 124.9,
123.1, 120.8, 113.7, 101.4, 65.1, 62.6, 60.0, 55.2, 14.5, 14.3. EI-M m/z calcd for
C
22
H
23
NO
6
397.2, found 396.9.

143
5-Ethoxycarbonyloxy-1-vinyl-1H-isoquinoline-2-carboxylic acid ethyl ester

N
O
O
O
O
O

In a flame dried 50 ml round bottom flask 1.0 mmol (145 mg) of isoquinolin-5-ol
were added with 5 eq. (480 µl) of ethyl-chloroformate and 1.2 eq. (160 mg) of vinyl
trifluoroborate with dichloromethane as solvent (12 ml). The mixture was stirred at room
temperature for 24 hours under nitrogen, after which time the reaction mixture was filtered
and the volatiles removed. The product was purified, by flash column chromatography
using 18% ethyl acetate : hexane, as clear oil (241 mg, 76%).
1
H NMR (CDCl
3
) δ 7.22-
6.82 (m, 4H), 5.96-5.70 (m, 2H), 5.09-4.88 (m, 2H), 4.30 (q, J=7.4 Hz, 2H), 4.25 (m, 2H),
1.37 (t, J=7.4 Hz, 3H), 1.30 (t, J=7.4 Hz, 3H).

1-Allyl-5-ethoxycarbonyloxy-1H-isoquinoline-2-carboxylic acid ethyl ester

N
O
O
O
O
O

We followed same procedure as in the previous example. Reaction was done on a
0.2 mmol scale. The product was purified by flash column chromatography using 20%
144
ethyl acetate : hexane, as clear oil mixture of rotamers (49.5 mg, 75%).
1
H NMR (CDCl
3
) δ
7.23-6.80 (m, 4H), 5.98 and 5.9 (2d, J=7.7 Hz, 1H), 5.6-5.8 (m, 1H), 5.4 and 5.27 (2t,
J=6.7 Hz, 1H), 5.02-4.88 (m, 2H), 4.36-4.18 (m, 4H), 2.24-2.48 (m, 2H), 1.41-1.22 (m,
6H);
13
C NMR (CDCl
3
) δ 149.9, 134.1, 133.9, 127.4, 127.3, 124.5, 123.8, 117.9, 117.7,
114.4, 114.2, 102.8, 102.6, 62.3, 62.2, 55.7, 55.0, 39.8, 39.5, 29.7, 14.5, 14.2. CI-M m/z
calcd for C
18
H
21
NO
5
331.1, found 331.1.

4-Bromo-1-vinyl-1H-isoquinoline-2-carboxylic acid ethyl ester

N O
O
Br

In a flame dried 20 ml round bottom flask 0.2 mmol (41.6 mg) of 4-bromo-
isoquinoline were added with 3 eq. (57.4 µl) of ethyl-chloroformate and 1.5 eq. (40.2 mg)
of vinyl trifluoroborate with dichloromethane as solvent (8 ml). The mixture was stirred at
room temperature for 8 hours under nitrogen. After which time the reaction mixture was
base extracted with 2N NaOH and the organic layers were collected and evaporated. The
product was purified by flash column chromatography using 15% ethyl acetate : hexane, as
yellowish oil (34.2 mg, 56%).
1
H NMR (CDCl
3
) δ 7.45 (dd, J=8.0 Hz, J=1.6 Hz, 1H), 7.34-
7.16 (m, 3H), 7.07 (d, J=6.1 Hz, 1H), 5.90-5.69 (m, 2H), 5.11-4.90 (m, 2H), 4.26 (q, J=7.2
Hz, 2H), 1.32 (t, J=7.2 Hz, 3H);
13
C NMR (CDCl
3
) δ 136.7, 135.3, 130.8, 129.1, 128.4,
128.2, 126.5, 125.5, 124.9, 124.8, 115.9, 62.8, 57.3, 14.5. EI-M m/z calcd for C
14
H
14
BrNO
2

307.0, found 307.6.
145
4-Bromo-1-(4-methoxy-phenyl)-1H-isoquinoline-2-carboxylic acid ethyl ester

N O
O
Br
O

In a flame dried 20 ml round bottom flask 0.2 mmol (41.6 mg) of 4-bromo-
isoquinoline were added with 5 eq. (63 µl) of ethyl-chloroformate and 1.5 eq. (64 mg) of 4-
methoxy-phenyl trifluoroborate with dichloromethane as solvent (8 ml). Mixture was
stirred at room temperature for 11 hours under nitrogen. After which time the reaction
mixture was filtered and the organic solvents were collected and evaporated. The product
was purified by flash column chromatography using 15% ethyl acetate : hexane, as
yellowish oil (66 mg, 85%).
1
H NMR (CDCl
3
) δ 7.53 (d, J=8.0 Hz, 1H), 7.38-7.18 (m, 3H),
7.12 (d, J=8.9 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.75 (d, J=8.9 Hz, 2H), 6.46 (s, 1H), 4.25
(q, J=7.2 Hz, 2H), 3.72 (s, 3H), 1.30 (t, J=7.2, 3H);
13
C NMR (CDCl
3
) δ 159.2, 128.6,
128.5, 128.1, 127.0, 125.6, 125.0, 124.9, 113.8, 62.8, 57.4, 55.2, 14.5.

4-Bromo-1-(4-fluoro-phenyl)-1H-isoquinoline-2-carboxylic acid ethyl ester

N O
O
Br
F

146
In a flame dried 20 ml round bottom flask 0.1 mmol (28 mg) of 4-bromo-
isoquinoline were added with 5 eq. (31.5 µl) of ethyl-chloroformate and 1.5 eq. (30 mg) of
4-fluoro trifluoroborate with dichloromethane as solvent (8ml). Mixture was stirred at
room temperature for 3 days and then refluxed for 24 hours under nitrogen. After which
time the reaction mixture was filtered and the organic solvents were collected and
evaporated. The product was purified by flash column chromatography using 15% ethyl
acetate : hexane, as yellowish oil (13 mg, 35%).
1
H NMR (CDCl
3
) δ 7.53 (d, J=7.7 Hz,
1H), 7.38-7.11 (m, 5H), 7.06 (d, J=7.7 Hz, 1H), 6.96-6.85 (m, 2H), 6.48 (s, 1H), 4.26 (q,
J=7.3 Hz, 2H), 1.30 (t, J=7.3 Hz, 3H).

1-Allyl-4-bromo-1H-isoquinoline-2-carboxylic acid ethyl ester

N O
O
Br

In a flame dried 20 ml round bottom flask 0.2 mmol (41.6 mg) of 4-bromo-
isoquinoline were added with 3 eq. (57.4 µl) of ethyl-chloroformate and 1.5 eq. (44.4 mg)
of allyl trifluoroborate with dichloromethane as solvent (8 ml). Mixture was stirred at room
temperature for 4 hours under nitrogen. After which time the reaction mixture was base
extracted with 2N NaOH and the organic layers were collected and evaporated. The
product was purified by flash column chromatography using 20% ethyl acetate : hexane, as
yellowish oil, mixture of rotamers (58 mg, 90%).
1
H NMR (CDCl
3
) δ 7.52-7.43 (m, 1H),
7.32-7.12 (m, 3H), 7.04-6.98 (m, 1H), 5.80-5.61 (m, 1H), 5.24 and 5.38 (2t, J=7 Hz, 1H),
147
5.02-4.88 (m, 2H), 4.32-4.18 (m, 2H), 2.48-2.26 (m, 2H), 1.40-1.20 (m, 3H);
13
C NMR
(CDCl
3
) δ 152.1, 133.3, 133.1, 132.3, 129.3, 128.0, 127.9, 127.8, 126.2, 126.0, 125.9,
125.4, 124.7, 124.6, 118.4, 118.2, 103.8, 103.5, 62.6, 62.5, 56.1, 55.4, 40.2, 39.8, 14.4. CI-
M m/z calcd for C
15
H
16
BrNO
2
321.0, found 321.0.

2-Allyl-2H-quinoline-1-carboxylic acid ethyl ester

N
O O
In a flame dried 10 ml microwave tube, 0.2 mmol (25.8 mg) of quinoline were
added with 3 eq. (57.4 µl) of ethyl-chloroformate and 1.5 eq. (44.4 mg) of allyl
trifluoroborate with dichloromethane as solvent (4 ml). The tube was sealed and heated at
80
o
C for 2 hours under nitrogen. After which time the reaction mixture was let to cool and
base extracted with 2N NaOH and the organic layers were collected and evaporated. The
product was purified by flash column chromatography using 20% ethyl acetate : hexane, as
clear oil (24 mg, 50%).
1
H NMR (CDCl
3
) δ 7.60-7.50 (m, 1H), 7.24-7.14 (m, 1H), 7.08-
7.00 (m, 2H), 6.47 (d, J=9.5 Hz, 1H), 6.02 (dd, J=9.7, 6.3 Hz, 1H), 5.84-5.66 (m, 1H),
5.10-4.90 (m, 3H), 4.34-4.14 (m, 2H), 2.26-2.06 (m, 2H), 1.36-1.24 (m, 3H);
13
C NMR
(CDCl
3
) δ 154.4, 134.5, 133.7, 129.3, 127.4, 127.2, 126.2, 125.0, 124.7, 124.1, 117.6, 62.0,
52.1, 37.6, 14.5. CI-M m/z calcd for C
15
H
17
NO
2
243.1, found 243.0.

148
2-(4-Methoxy-phenyl)-2H-quinoline-1-carboxylic acid allyl ester

N
O O O

The same procedure as in the previous example was used but in this case 5
equivalents of allyl-chloroformate and 1.5 equivalents of 4-methoxyphenyl-trifluoroborate
were used. Reaction was done on a 0.2 mmol scale, and let stir at room temperature for 16
hours. The product was purified by flash column chromatography using 5% ethyl acetate :
hexane (43 mg, 67%).
1
H NMR (CDCl
3
) δ 7.52-7.42 (m, 1H), 7.22-7.00 (m, 5H), 6.78-6.60
(m, 3H), 6.18-6.12 (m, 2H), 6.06-5.90 (m, 1H), 5.38-5.20 (m, 2H), 4.82-4.64 (m, 2H), 3.72
(s, 3H);
13
C NMR (CDCl
3
) δ 159.2, 134.5, 132.4, 131.5, 128.5, 128.4, 127.7, 127.2, 126.2,
125.2, 124.7, 124.3, 118.1, 113.8, 66.9, 55.2, 55.1. EI-M m/z calcd for C
20
H
19
NO
3
321.1,
found 321.0.

6-Phenyl-6H-phenanthridine-5-carboxylic acid allyl ester

N O
O
In a flame dried 20ml round bottom flask 0.2 mmol (36 mg) of phenanthridine
were added with 3 eq. (64 µl) of allyl-chloroformate and 1.5 eq. (55 mg) of phenyl
trifluoroborate with dichloromethane as solvent (8 ml). The mixture was stirred at room
149
temperature for 2 days under nitrogen. After which time the reaction mixture was filtered
and the volatiles removed. The product was purified by flash column chromatography
using 8% ethyl acetate/hexane as clear oil (28 mg, 41%).
1
H NMR (CDCl
3
) δ 7.84 (d, J=7.4
Hz, 1H), 7.72 (dd, J=6.5, 2.0 Hz, 1H), 7.47-7.30 (m, 3H), 7.20-7.00 (m, 8H), 6.75 (s, 1H),
6.03-5.87 (m, 1H), 5.36-5.16 (m, 2H), 4.80-4.60 (m, 2H);
13
C NMR (CDCl
3
) δ 139.7,
132.3, 131.3, 128.4, 128.2, 127.9, 127.8, 127.7, 127.3, 127.2, 126.0, 125.1, 125.0, 123.8,
123.6, 118.1, 67.0, 58.4. EI-M m/z calcd for C
23
H
19
NO
2
341.1, found 341.1.

6-(4-Methoxy-phenyl)-6H-phenanthridine-5-carboxylic acid allyl ester

N O
O
O

In a flame dried 20ml round bottom flask 0.2 mmol (36 mg) of phenanthridine
were added with 5 eq. (106 µl) of allyl-chloroformate and 1.5 eq. (64 mg) of 4-methoxy-
phenyl trifluoroborate with dichloromethane as solvent (8 ml). The mixture was stirred at
room temperature for 6 hours under nitrogen. TLC monitoring of the reaction showed
formation of new spot and consumption of the phenanthridine. The reaction mixture was
then filtered and the volatiles removed. The product was purified by flash column
chromatography using 25% ethyl acetate : hexane as clear oil (68 mg, 92%).
1
H NMR
(CDCl
3
) δ 7.76 (d, J=7.3 Hz, 1H), 7.66 (dd, J=7.2, 1.8 Hz, 1H), 7.42-7.03 (m, 6H), 6.87 (d,
J= 8.1 Hz, 2H), 6.72 (s, 1H), 6.56 (d, J=8.1 Hz, 2H), 6.00-5.79 (m, 1H), 5.33-5.07 (m, 2H),
150
4.76-4.53 (m, 2H), 3.65 (s, 3H);
13
C NMR (CDCl
3
) δ 158.8, 135.9, 134.7, 132.4, 132.0,
131.3, 128.6, 128.4, 128.2, 127.9, 127.8, 127.6, 126.1, 125.1, 123.8, 123.6, 118.1, 113.6,
66.9, 58.0, 55.1.

6-(4-Methoxy-phenyl)-6H-phenanthridine-5-carboxylic acid prop-2-ynyl ester

N O
O
O

In a flame dried 20 ml round bottom flask 0.2 mmol (36 mg) of phenanthridine
were added with 5 eq. (98 µl) of propargyl-chloroformate and 1.5 eq. (64 mg) of 4-
methoxy-phenyl trifluoroborate with dichloromethane as solvent (8 ml). The mixture was
stirred at room temperature for 24 hours under nitrogen, after which time it was filtered and
the volatiles removed. The product was purified, by flash column chromatography using
15% ethyl acetate : hexane, as clear oil (45 mg, 61%).
1
H NMR (CDCl
3
) δ 7.83 (d, J=7.2
Hz, 1H), 7.74 (dd, J=7.2, 1.8 Hz, 1H), 7.47-7.12 (m, 6H), 6.94 (d, J= 8.2 Hz, 2H), 6.66 (s,
1H), 6.64 (d, J=8.2 Hz, 2H), 4.95-4.67 (m, 2H), 3.66 (s, 3H), 2.48 (s, 1H);
13
C NMR
(CDCl
3
) δ 158.8, 132.0, 131.3, 128.5, 128.4, 128.2, 128.0, 127.8, 127.5, 126.0, 125.3,
123.8, 123.6, 113.5, 77.9, 75.1, 58.2, 55.1, 53.6.

151
6-(4-Methoxy-phenyl)-6H-phenanthridine-5-carboxylic acid ethyl ester

N O
O
O

In a flame dried 20 ml round bottom flask 0.2 mmol (36 mg) of phenanthridine
were added with 5 eq. (63 µl) of ethyl-chloroformate and 1.5 eq. (64 mg) of 4-methoxy-
phenyl trifluoroborate with dichloromethane as solvent (8 ml). The mixture was stirred at
room temperature for 24 hours under nitrogen, after which time it was filtered and the
volatiles removed. The product was purified by flash column chromatography using 15%
ethyl acetate : hexane as clear oil (66 mg, 93%).
1
H NMR (CDCl
3
) δ 7.85 (d, J=7.2 Hz,
1H), 7.74 (dd, J=7.5, 1.8 Hz, 1H), 7.46-7.09 (m, 6H), 6.94 (d, J= 8.0 Hz, 2H), 6.70 (s, 1H),
6.64 (d, J=8.0 Hz, 2H), 4.32 (q, J=7.1 Hz, 2H), 3.65 (s, 3H), 1.31 (t, J=7.1 Hz, 3H);
13
C
NMR (CDCl
3
) δ 158.7, 132.0, 131.3, 128.4, 128.2, 128.1, 127.8, 127.7, 127.5, 125.9,
124.8, 123.7, 123.5, 113.5, 62.3, 57.8, 55.1, 14.5.

6-Allyl-6H-phenanthridine-5-carboxylic acid ethyl ester

N O
O

152
In a flame dried 20 ml round bottom flask 0.2 mmol (36 mg) of phenanthridine
were added with 2eq. (63 µl) of ethyl-chloroformate and 1.5 eq. (45 mg) of allyl-
trifluoroborate with dichloromethane as solvent (8 ml). The mixture was stirred at room
temperature for 11 hours under nitrogen, after which time it was filtered and the volatiles
removed. The product was purified by flash column chromatography using 10% ethyl
acetate : hexane as clear oil (41 mg, 70%).
1
H NMR (CDCl
3
) δ 7.76 (dd, J=7.9, 1.6 Hz,
2H), 7.63-7.49 (m, 1H), 7.39-7.18 (m, 5H), 5.86-5.68 (ddt, J=17.3, 10.2 , 7.1 Hz, 1H), 5.55
(t, J=7.1 Hz, 1H), 5.04-4.81 (m, 2H), 4.23 (q, J=7.2 Hz, 2H), 2.20 (dd, J=7.1, 7.1 Hz, 2H),
1.27 (t, 7.2 Hz, 3H);
13
C NMR (CDCl
3
) δ 154.1, 137.4, 134.5, 134.1, 130.5, 127.9, 127.8,
127.6, 126.2, 126.1, 124.9, 123.6, 123.5, 117.7, 62.0, 55.8, 38.5, 14.5.

1-Allyl-1H-isoquinoline-2-carboxylic acid ethyl ester

N O
O

In a flame dried 20 ml round bottom flask 0.2 mmol (25 mg) of isoquinoline were
added with 2eq. (38 µl) of ethyl-chloroformate and 1.0 eq. (30 mg) of allyl-trifluoroborate
with dichloromethane as solvent (8ml). Mixture was stirred at room temperature for 24
hours under nitrogen. The reaction mixture was then filtered and solvents were collected
and evaporated. The product was purified by flash column chromatography using 20%
ethyl acetate : hexane, as yellowish oil, mixture of rotamers (26 mg, 53%).
1
H NMR
(CDCl
3
) δ 7.23-6.76 (m, 5H), 5.90-5.61 (m, 2H), 5.42-5.22 (2 t, J=6.5 Hz, 1H), 5.02-4.88
153
(m, 2H), 4.32-4.18 (m, 2H), 2.48-2.26 (m, 2H), 1.37-1.23 (m, 3H);
13
C NMR (CDCl
3
) δ
153.6, 153.0, 134.0, 133.8, 132.2, 130.5, 130.2, 127.7, 127.5, 126.7, 126.5, 126.4, 126.2,
125.2, 124.7, 124.5, 118.0, 117.7, 108.7, 108.4, 62.2, 62.1, 55.8, 55.1, 40.1, 39.8, 14.5.

1-Vinyl-1H-isoquinoline-2-carboxylic acid ethyl ester

N O
O

In a flame dried 20 ml round bottom flask 0.2 mmol (25 mg) of isoquinoline were
added with 5eq. (63 µl) of ethyl-chloroformate and 1.5 eq. (40 mg) of vinyl-trifluoroborate
with dichloromethane as solvent (8ml). The mixture was stirred at room temperature for 3
days under nitrogen. The reaction mixture was then filtered and solvents were collected
and evaporated. The product was purified by preparative TLC using 25% ethyl acetate :
hexane (26 mg, 53%).
1
H NMR (CDCl
3
) δ 7.23-6.79 (m, 5H), 5.93-5.66 (m, 3H), 5.07-4.86
(m, 2H), 4.25 (q, J=7.4 Hz, 2H), 1.30 (t, J=7.4 Hz, 3H).

1-(4-Methoxy-phenyl)-1H-isoquinoline-2-carboxylic acid ethyl ester

N O
O
O

154
In a flame dried 20 ml round bottom flask 0.2 mmol (25 mg) of isoquinoline were
added with 2eq. (38 µl) of ethyl-chloroformate and 1.0 eq. (43 mg) of 4-methoxy-phenyl-
trifluoroborate with dichloromethane or THF as solvent (8ml). The mixture was stirred at
room temperature for 8 hours under nitrogen. The reaction mixture was then filtered and
solvents were collected and evaporated. The product was purified by flash column
chromatography using 20% ethyl acetate : hexane (54 mg, 88%).
1
H NMR (CDCl
3
) δ 7.23-
7.00 (m, 6H), 6.82 (m, 1H), 6.74 (d, J=8.9 Hz, 2H), 6.46 (s, 1H), 5.87 (m, 1H), 4.30-4.18
(q, J=6.9 Hz, 2H), 3.72 (s, 3H), 1.29 (t, J=6.9 Hz, 3H);
13
C NMR (CDCl
3
) δ 156.9, 128.7,
128.6, 127.9, 127.4, 125.0, 124.9, 113.9, 108.6, 64.1, 58.3, 55.3, 14.6.

155
5.5 Chapter 5 References

1. Bloch, R. “Additions of Organometallic Reagents to C=N Bonds: Reactivity and
Selectivity.” Chemical Reviews, 1998, 98(4), p. 1407-1438.

2. Fischer, C., Carreira, E. M. “Zn-Alkynylide Additions to Acyl Iminiums.” Organic
Letters, 2004, 6(9), p. 1497-1499.

3. Itoh, T., Miyazaki, M., Nagata, K., Ohsawa, A. “Addition Reaction of Imidazoles
and Thiazoles with Silyl Enol Ethers in the Presence of Alkyl Chloroformate.”
Tetrahedron, 2000, 56(26), p. 4383-4395.

4. Yamamoto, Y., Asao, N. “Selective Reactions Using Allylic Metals.” Chemical
Reviews, 1993, 93(6), p. 2207-2293.

5. Brook, M. A., Jahangir. “Activation of Imines to Nucleophilic Attack by Grignard
Reagents.” Synthetic Communications, 1988, 18(9), p. 893-898.

6. Wada, M., Sakurai, Y., Akiba, K. “Addition of Boron Trifluoride Complexes of
Organocopper Reagents to Aldimines Containing α-Hydrogens.” Tetrahedron
Letters, 1984, 25(10), p. 1079-1082.

7. Wang, D. K., Dai, L. X., Hou, X. L. “Allylstannane Allylation of Aldimines
Activated by Chlorotrimethylsilane.” Tetrahedron Letters, 1995, 36(47), p. 8649-
8652.

8. Fox, J. M., Huang, X., Chieffi, A., Buchwald, S. L. “Highly Active and Selective
Catalysts for the Formation of α-Aryl Ketones.” Journal of the American Chemical
Society, 2000, 122(7), p. 1360-1370.

9. Shaughnessy, K. H., Hamann, B. C., Hartwig, J. F. “Palladium-Catalyzed Inter-
and Intramolecular α-Arylation of Amides. Application of Intramolecular Amide
Arylation to the Synthesis of Oxindoles.” Journal of Organic Chemistry, 1998,
63(19), p. 6546-6553.

10. Davis, J. L., Dhawan, R., Arndtsen, B. A. “Imines in Stille-Type Cross-Coupling
Reactions: A Multicomponent Synthesis of α-Substituted Amides.”Angewandte
Chemie- International Edition, 2004, 43(5), 590-594.

11. Shuichi, O., Mitsutoshi, M., Hiroe, F., Takanori, K., Yoshio, I. “Rhodium-
Catalyzed Arylation and Alkenylation of Imines with Organostannanes.”
Tetrahedron Letters, 1999, 40(52), p. 9259-9262.

12. Hayashi, T., Mitsuo, I. “Rhodium-Catalyzed Asymmetric Arylation of Imines with
Organostannanes. Asymmetric Synthesis of Diarylmethylamines.” Journal of the
American Chemical Society, 2000, 122(5), p. 976-977.

156
13. Fagnou, K., Lautens, M. “Rhodium-Catalyzed Carbon-Carbon Bond Forming
Reactions of Organometallic Compounds.” Chemical Reviews, 2003, 103(1), p.
169-196.

14. Black, D. A., Arndtsen, B. A. “Copper-Catalyzed Cross-Coupling of Imines, Acid
Chlorides, and Organostannanes: A Multicomponent Synthesis of α-Substituted
Amides.” Journal of Organic Chemistry, 2005, 70(13), p. 5133-5138.

15. Black, D. A., Arndtsen, B. A. “General Approach to the Coupling of
Organoindium Reagents with Imines via Copper Catalysis.” Organic Letters,
2006, 8(10), p. 1991-1993.

16. Michael, J. P. “Quinoline, Quinazoline and Acridone Alkaloids.” Natural Product
Reports, 1997, 14(6), p. 605-618.

17. Markees, D. G., Dewey, V. C., Kidder, G. W. “Antiprotozoal 4-Aryloxy-2-
Aminoquinolines and Related Compounds.” Journal of Medicinal Chemistry,
1970, 13(2), p. 324-326.

18. Campbell, S. F., Hardstone, J. D., Palmer, M. J. “2,4-Diamino-6,7-
Dimethoxyquinoline Derivatives as Alpha.1-Adrenoceptor Antagonists and
Antihypertensive Agents.” Journal of Medicinal Chemistry, 1988, 31(5), p. 1031-
1035.

19. Jegou, G., Jenekhe, S. A. “Highly Fluorescent Poly(arylene ethylene)s Containing
Quinoline and 3-Alkylthiophene.” Macromolecules, 2001, 34(23), p. 7926-7928.

20. http://en.wikipedia.org/wiki/Quinoline.

21. Wanner, K. T., Beer, H., Hofner, G., Ludwig, M. “Asymmetric Synthesis and
Enantioselectivity of Binding of 1-Aryl-1,2,3,4-tetrahydroisoquinolines at the PCP
Site of the NMDA Receptor Complex.”European Journal of Organic Chemistry,
1998, 9, p. 2019-2029.

22. Gray, N. M., Cheng, B. K., Mick, S. J. Lair, C. M., Contreras P. C.
“Phencyclidine-like Effects of Tetrahydroisoquinolines and Related Compounds.”
Journal of Medicinal Chemistry, 1989, 32(6), p. 1242-1248.

23. Bergstreom, F. W. “Heterocyclic Nitrogen Compounds. Part IIA. Hexacyclic
Compounds: Pyridine, Quinoline, and Isoquinoline.” Chemical Reviews, 1944,
35(2), p. 77-277.

24. Stout, D. M., Meyers, A. I. “Recent Advances in the Chemistry of
Dihydropyridines.” Chemical Reviews, 1982, 82(2), p. 223-243.

157
25. Comins, D. L., Zhang, Y., Joseph, S. P. “Enantiopure N-Acyldihydropyridones as
Synthetic Intermediates: Asymmetric Synthesis of Benzomorphans.” Organic
Letters, 1999, 1(4), p. 657-660.

26. Nishikawa, T., Yoshikai, M., Obi, K., Kawai, T., Unno, R., Jomori, T., Isobe, M.
“Synthesis and Biological Evaluation of Both Enantiomers of Dynemicin a Model
Compound.” Tetrahedron, 1995, 51(34), p. 9339-9352.

27. Magnus, P., Rodriguez-Lopez, J., Mulholland, K., Matthews, I. “Biomimetic
Synthesis of the Pentacyclic Alkaloid (.+.-)-Nirurine and Possible Biogenetic
Rearrangement of a Precursor into (.+.-)-Norsecurinine.” Journal of the American
Chemical Society, 1992, 114(1), p. 382-383.

28. Brana, M. F., Moran, M., Jesus Perez de Vega, M., Pita-Romero, I. “Enediynes as
Antitumor Compounds: Synthesis of Tetrahydropyridine Derivatives.” Journal of
Organic Chemistry, 1996, 61(4), p. 1369-1374.

29. Yamaguchi, R., Moriyasu, M., Yoshioka, M., Kawanisi, M. “Reactions of Allylic
Tin Reagents with Nitrogen Heteroaromatics activated by Alkyl Chloroformates:
Regioselective Synthesisof .alpha.-Allylated 1,2-Dihydropyridines and Change of
the Regioselectivity Depending on Methyl Substituents on the Allylic moiety.”
Journal of Organic Chemistry, 1988, 53(15), p. 3507-3512.

30. Itoh, T., Hasegawa, H., Nagata, K., Ohsawa, A. “Allylation of Azoles with
Allyltributyltin via Unstable N-(Alkoxycarbonyl)Azolium Salts.” Journal of
Organic Chemistry, 1994, 59(6), p. 1319-1325.

31. Yamaguchi, R., Mochizuki, K., Kozima, S., Takaya, H. “Divergent Change of
Regioselectivity in Nucleophilic Addition of Electron Deficient Allylic Tin
Reagents to 4-Acylpyridinium Salts; Selective Formation of 4,4-Disubstituted 1,4-
Dihydropyridines.” Chemical Communications, 1993, 12, p. 981-982.

32. Makoto, W., Masayuki, N., Kinya, A. “Reaction of Trimethylsilyl Enol Ethers
with Isoquinolinium Salts. A Facile Synthesis of Ethyl 1-(2-Oxoalkyl)-1,2-
Dihydroisoquinoline-2-Carboxylates and their Cyclization.” Chemistry Letters,
1983, 1, p. 39-42.

33. Yamaguchi, R., Nakayasu, T., Hatano, B., Nagura, T., Kozima, S., Fujita, K.
“Facile Addition Reactions of Allylsilanes to Quinolines and Isoquinolines
Activated by Chloroformate Esters and a Catalytic Amount of Triflate Ion.”
Tetrahedron, 2001, 57(1), p. 109-118.

34. Lee, S. H., Park, Y. S., Nam, M. H., Yoon, C. M. “Indium Mediated Allylation of
Quinoline and Isoquinoline Activated by Phenyl Chloroformate.” Organic
Biomolecular Chemistry, 2004, 2, p. 2170-2172.

158
35. Dias, J. L., Miguel, M., Lavilla, R. “N-Acylazinium Salts: A New Source of
Iminium Ions for Ugi-Type Processes.” Journal of Organic Chemistry, 2004,
69(10), p. 3550-3553.

36. Weber, L., Illgen, K., Almstetter, M. “Discovery of New Multi Component
Reactions with Combinatorial Methods.” Synlett, 1999, 3, p. 366-374.

37. Orru, R. V. A., de Greef, M. “Recent advances in Solution-Phase Multicomponent
Methodology for the Synthesis of Heterocyclic Compounds.” Synthesis, 2003, 10,
p. 1471-1499.

38. Zhu, J., Bienayme, H. “Multicomponent Reactions.” Wiley-VCH Verlag GmbH &
Co. KgaA, Weinheim, 2005, p. 197-223.

39. Ulaczyk-Lesanko, A., Hall, D. G. “Wanted. New Multicomponent Reactions for
Generating Libraries of Polycyclic Natural Products.” Current Opinion in
Chemical Biology, 2005, 9(3), p. 266-276.

40. Chang, Y. M., Lee, S. H., Nam, M. H., Cho, M. Y., Park, Y. S., Yoon, C. M.
“Petasis Reaction of Activated Quinoline and Isoquinoline with Various Boronic
Acids.” Tetrahedron Letters, 2005, 46(17), p. 3053-3056.

41. Pauvert, M., Collet, S., Guingant, A. “Silver Nitrate-Promoted Ring Enlargment of
1-Tribromomethyl-1,2-Dihydro- and 1-Tribromomethyl-1,2,3,4-Tetrahydro-
Isoquinoline Derivatives: Application to the Synthesis of the Anti-Anginal
Zatebradine.” Tetrahedron Letters, 2003, 44(22), p. 4203-4206.

42. Alexakis, A., Amiot, F. “Enantioselective Addition of Organolithium Reagents on
Isoquinoline.” Tetrahedron Asymmetry, 2002, 13(19), p. 2117-2122.

43. Itoh, T., Nagata, K., Yokoya, M., Miyazaki, M., Kameoka, K., Nakamura, S.,
Ohsawa, A. “The Synthesis of Isoquinoline Alkaloid and Its Related Compounds
Using Alanine Derivatives as Chiral Auxiliaries.” Chemical and Pharmaceutical
Bulletin, 2003, 51(8), p. 951-955.

44. Hidekazu, O., Yukako, S., Yutaka, Y., Hiroki, T. “1-Tert-Butoxy-2-Tert-
Butoxycarbonyl-1,2-Dihydroisoquinoline: A Novel and Chemoselective Tert-
Butoxycarbonylation Reagent.” Organic Letters, 2002, 4(4), p. 585-587.

45. Knolker, H. J., Agarwal, S. “Total Synthesis of the Antitumor Active Pyrrolo[2,1-
α]Isoquinoline Alkaloid (±)-Crispine A.” Tetrahedron Letters, 2005, 46(7), p.
1173-1175.

46. Itoh, T., Nagata, K., Miyazaki, M., Kameoka, K., Ohsawa, A. “Asymmetric
Addition of Nucleophiles to C-1 Position of Isoquinolines Using (S)-Alanine
Derivatives as Chiral Auxiliaries.” Tetrahedron Letters, 2001, 57(42), p. 8827-
8839.
159
47. Rozwadowska, M. D. “Recent Progress in the Enantioselective Synthesis of
Isoquinoline Alkaloids.” Heterocycles, 1994, 39(2), 903-931.

48. Molinari, A. J., Ashwell, M. A., Ridgway, B. H., Failli, A. A., Moore, W. J.
“Substituted Dihydrophenanthridine Sulfonamides.” United States Patent
Application Publication, 2004, US 2004/0167155 A1.

49. Barbier, D.,Marazano, C., Riche, C., Das, B. C., Potier, P. “An Enantioselective
Access to 1-Alkyl-1,2-Dihydroisoquinolines and 1-Alkyl-, 3-Alkyl-, and 1,3-
Dialkyl-1,2,3,4-Tetrahydroisoquinolines.” Journal of Organic Chemistry, 1998,
63(6), p. 1767-1772.

160
Bibliography
Abdel-Magid, A. F., Carson, K. G., Harris, B. D., Maryanoff, C. A., Shah, R. D.
“Reductive Amination of Aldehydes and Ketones with Sodium
Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination
Procedures.” Journal of Organic Chemistry, 1996, 61(11): p. 3849-3862.

Albanese, G., Venturi, C. “Albendazole: A New Drug for Human Parasitoses.”
Dermatologic Clinics, 2003, 21(2): p. 283-290.

Alexakis, A., Amiot, F. “Enantioselective Addition of Organolithium Reagents on
Isoquinoline.” Tetrahedron Asymmetry, 2002, 13(19): p. 2117-2122.

Allen, I., Pounds, T., Murtagh, L., Wallace, P., Towns, C. “Modified Suzuki
Method for Polymerization of Aromatic Monomers” PCT Int. Appl. 2003, 20pp.
CODEN: PIXXD2 WO 2003035796 A1 20030501 CAN 138:354447.

Arend, M., Westerman, B., Risch, N. “Modern variants of the Mannich Reaction.”
Angewandte Chemie International Edition, 1998, 37(8): p. 1045-1070.

Aylward, N., Bofinger, N. “Possible Origin for Porphin Derivatives in Prebiotic
Chemistry-A Computational Study.” Origins of Life and Evolution of Biospheres,
2005, 35(4): p. 345-368.

Balaban, T. S., Hiegemann, M. “Hydrogen Peroxide Oxidation of Polysubstituted
Pyrylium Salts: Formation of Enol Esters and Furans.” Tetrahedron, 1992, 48(45):
p. 9827-9840.

Bammert, G. F., Fostel, J. M. “Genome-Wide Expression Patterns in
Sacharomyces Cerevisiae: Comparison of Drug Treatments and Genetic
Alterations Affecting Biosynthesis of Ergosterol.” Antimicrobial Agents and
Chemotherapy, 2000, 44(5): p. 1255-1265.

Barbier, D.,Marazano, C., Riche, C., Das, B. C., Potier, P. “An Enantioselective
Access to 1-Alkyl-1,2-Dihydroisoquinolines and 1-Alkyl-, 3-Alkyl-, and 1,3-
Dialkyl-1,2,3,4-Tetrahydroisoquinolines.” Journal of Organic Chemistry, 1998,
63(6): p. 1767-1772.

Batey, R. A. “Boronic Acids: 7. Nucleophilic Addition Reactions of Aryl and
Alkenylboronic Acids and their Derivatives to Imines and Iminium Ions.” WILEY-
VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8, 2005: p. 279-
304.

Batey, R. A., Thadani, A. N., Smil, D. V., Lough, A. J. “Diastereoselective
Allylation and Crotylation Reactions of Aldehydes with Potassium Allyl- and
161
Crotyltrifluoroborates Under Lewis Acid Catalysis.” Synthesis, 2000, 7: p. 990-
998.

Batey, R. A., Thadani, A. N., Smil, D. V. “Potassium Alkenyl- and
Aryltrifluoroborates: Stable and Efficient Agents for Rhodium-Catalyzed Addition
to Aldehydes and Enones.” Organic Letters, 1999, 1: p. 1683-1686.

Beenen, M. A., Weix, D. J., Ellman, J. A. “Asymmetric Synthesis of Protected
Arylglycines by Rhodium-Catalyzed Addition of Arylboronic Acids to N-tert-
Butanesulfinyl Imino Esters.” Journal of the American Chemical Society, 2006,
128(19): p. 6304-6305.

Bergstreom, F. W. “Heterocyclic Nitrogen Compounds. Part IIA. Hexacyclic
Compounds: Pyridine, Quinoline, and Isoquinoline.” Chemical Reviews, 1944,
35(2): p. 77-277.

Billard, T., Langlois, B. R. “Reactivity of Stable Trifluoroacetaldehyde
Hemiaminals. 2. Generation and Synthetic Potentialities of Fluorinated Iminiums.”
Journal of Organic Chemistry, 2002, 67(3): p. 997-1000.

Biron, E., Chatterjee, J., Kessler, H. “Solid-Phase Synthesis of 1,3-Azole-Based
Peptides and Peptidomimetics.” Organic Letters, 2006, 8(11): p. 2417-2420.

Black, D. A., Arndtsen, B. A. “Copper-Catalyzed Cross-Coupling of Imines, Acid
Chlorides, and Organostannanes: A Multicomponent Synthesis of α-Substituted
Amides.” Journal of Organic Chemistry, 2005, 70(13): p. 5133-5138.

Black, D. A., Arndtsen, B. A. “General Approach to the Coupling of
Organoindium Reagents with Imines via Copper Catalysis.” Organic Letters,
2006, 8(10): p. 1991-1993.

Bloch, R. “Additions of Organometallic Reagents to C=N Bonds: Reactivity and
Selectivity.” Chemical Reviews, 1998, 98(4): p. 1407-1438.

Boswell, H. D., Drager, B., Eagles, J., McClintock, C., Parr, A., Portsteffen, A.,
Robins, D. J., Robins, R. J., Walton, N. J., Wong, C. “Biosynthesis of Novel
Alkaloids: Metabolism of N-Alkyldiamines and N-Alkylnortropinones by
Transformed Root Cultures of Nicotiana and Brugmansia.” Phytochemistry, 1999,
52(5): p. 855-869.

Brana, M. F., Moran, M., Jesus Perez de Vega, M., Pita-Romero, I. “Enediynes as
Antitumor Compounds: Synthesis of Tetrahydropyridine Derivatives.” Journal of
Organic Chemistry, 1996, 61(4): p. 1369-1374.

Brauer, D. J., Buerger, H., Pawelke, G. “Vibrational Spectra and Normal-
Coordinate Analysis of Trifluoromethyl Compounds. 17. Crystal and Molecular
Structure, Reinvestigated Vibrational Spectra, and Normal-Coordinate Analysis of
162
Potassium (trifluoromethyl)trifluoroborate, K[CF
3
BF
3
].” Inorganic Chemistry,
1977, 16(9): p. 2305-2314.

Brauer, D. J., Buerger, H., Pawelke, G. “Vibrational Spectra and Normal
Coordinate Analysis of CF
3
Compounds: XXXIV. The
Bis(Trifluoromethyl)Difluoroborate Anion: X-Ray Structure of Cs[(CF
3
)
2
BF
2
].”
Journal of Organometallic Chemistry, 1980, 192(3): p. 305-315.

Brook, M. A., Jahangir. “Activation of Imines to Nucleophilic Attack by Grignard
Reagents.” Synthetic Communications, 1988, 18(9): p. 893-898.

Brown, H. C., Jadhav, P. K. “Asymmetric Carbon-Carbon Bond Formation via
Beta-Allyldiisopinocampheylborane. Simple Synthesis of Secondary Homoallylic
Alcohols with Excellent Enantiomeric Purities.” Journal of the American Chemical
Society, 1983, 105(7): p. 2092-2093.

Campbell, S. F., Hardstone, J. D., Palmer, M. J. “2,4-Diamino-6,7-
Dimethoxyquinoline Derivatives as Alpha.1-Adrenoceptor Antagonists and
Antihypertensive Agents.” Journal of Medicinal Chemistry, 1988, 31(5): p. 1031-
1035.

Chambers, R. D., Clark, H. C., Willis, C. J. “Some Salts of
Trifluoromethylfluoroboric Acids.” Journal of the American Chemical Society,
1960, 82(20): p. 5298-5301.

Chan, D. M. T., Monaco, K. L., Wang, R., Winters, M. P. “New N- O-Arylations
with Phenylboronic Acids and Cupric Acetate.” Tetrahedron Letters, 1998, 39: p.
2933-2936.

Chang, Y. M., Lee, S. H., Nam, M. H., Cho, M. Y., Park, Y. S., Yoon, C. M.
“Petasis Reaction of Activated Quinoline and Isoquinoline with Various Boronic
Acids.” Tetrahedron Letters, 2005, 46(17): p. 3053-3056.

Chen, J. J., Zhang, Y., Hammond, S., Dewdney, N., Ho, T., Lin, X., Browner, M.
F., Castelhano, A. L. “Design, Synthesis, Activity, and Structure of a Novel Class
of Matrix Metalloproteinase Inhibitors Containing a Heterocyclic P
2
’
-P
3
’
Amide
Bond Isostere.” Bioorganic and Medicinal Chemistry Letters, 1996, 6(13): p.
1601-1606.

Cho, C. S., Uemura, S. “Palladium-Catalyzed Cross-Coupling of Aryl and Alkenyl
Boronic Acids with Alkenes via oxidative addition of a Carbon-Boron Bond to
Palladium(0).” Journal of Organometallic Chemistry, 1994, 465: p. 85-92.

Clark, M. P., Laughlin, S. K., Golebiowski, A., Brugel, T., Sabat, M. “Preparation
of Bicyclic Pyrazolone as Proinflamatory cytokine Inhibitors for Treating Various
Diseases.” U.S. Pat. Appl. Publ. 2005, 34pp. CODEN: USXXCO US 2005113392
A1 20050526.
163
Comins, D. L., Zhang, Y., Joseph, S. P. “Enantiopure N-Acyldihydropyridones as
Synthetic Intermediates: Asymmetric Synthesis of Benzomorphans.” Organic
Letters, 1999, 1(4): p. 657-660.

Danishefsky, S., Kitahara, T., McKee, R., Schuda, P. F. “Reactions of Silyl Enol
Ethers and Lactone Enolates with Dimethyl(Methylene) Ammonium Iodide. The
Bis- α-Methylenation of Pre-Vernolepin and Pre-Vernomenin.” Journal of the
American Chemical Society, 1976, 98(21): p. 6715-6717.

Darses, S., Genet, J. P., Brayer, J. L., Demoute, J. P. “Cross-Coupling Reactions of
Arenediazonium Tetrafluoroborates with Potassium Aryl- or
Alkenyltrifluoroborates Catalyzed by Palladium.” Tetrahedron Letters, 1997,
38(25): p. 4393-4396.

Darses, S., Genet, J. P. “Potassium Trifluoro(organo)borates: New Perspectives in
Organic Chemistry.” European Journal of Organic Chemistr, 2003, 22: p. 4313-
4327.

Darses, S., Michaud, G., Genet, J. P. “Potassium Organotrifluoroborates: New
Partners in Palladium-Catalysed Cross-Coupling Reactions.” European Journal of
Organic Chemistry, 1999, 8: p. 1875-1883.

Davis, J. L., Dhawan, R., Arndtsen, B. A. “Imines in Stille-Type Cross-Coupling
Reactions: A Multicomponent Synthesis of α-Substituted Amides.”Angewandte
Chemie- International Edition, 2004, 43(5): 590-594.

De la Mare, P. B. D. “Pathways in Electrophilic Aromatic Substitution.
Cyclohexadienes and Related Compounds as Intermediates in Halogenation.”
Accounts of Chemical Research, 1974, 7(11): p. 361-368.

Dhanak, D., Christmann, L. T., Darcy, M., G., Keenan, R. M., Knight, S. D., Lee,
J., Ridgers, L. H., Sarau, H. M., Shah, D. H., White, J. R., Zhang, L. “Discovery of
Potent and Selective Phenylalanine Derived CCR3 Receptor Antagonists. Part 2.”
Bioorganic and Medicinal Chemistry Letters, 2001, 11(11): p. 1445-1450.

Dias, J. L., Miguel, M., Lavilla, R. “N-Acylazinium Salts: A New Source of
Iminium Ions for Ugi-Type Processes.” Journal of Organic Chemistry, 2004,
69(10): p. 3550-3553.

Dolle, R. E. “Comprehensive Survey of Combinatorial Library Synthesis. 2004.”
Journal of Compinatorial Chemistry, 2005, 7(6): p. 739-798.

Domling, A., Ugi, I. “Multicomponent Reactions with Isocyanides.” Angewandte
Chemie, International Edition, 2000, 39: p. 3168-3210.

164
Douglass, B. J. “Synthetic Molecular Programming and Substrate-Dependent
Drug-Discovery: From Multicomponent Reactions to Cyclic Peptides.” Ph.D.
Thesis, University of Southern California, 2006.

Du, X., Suguro, M., Hirabayashi, K., Mori, A. “Mizoroki-Heck type Reaction of
Organoboron Reagents with Alkenes and Alkynes. A Pd(II)-Catalyzed Pathway
with Cu(OAc)
2
as an Oxidant.” Organic Letters, 2001, 3(21): p. 3313-3316.

Effenberger, F., Eberhard, J. K., Maier, A. H. “The First Unequivocal Evidence of
the Reacting Electrophile in Aromatic Acylation Reactions.” Journal of the
American Chemical Society, 1996, 118(50): p. 12572-12579.

Evans, D. A., Katz, J. L., West, T. R. “Synthesis of Diaryl Ethers Through the
Copper-Promoted Arylation of Phenols with Arylboronic Acids. An Expedient
Synthesis of Thyroxine.” Tetrahedron Letters, 1998, 39: p. 2937-2940.

Fagnou, K., Lautens, M. “Rhodium-Catalyzed Carbon-Carbon Bond Forming
Reactions of Organometallic Compounds.” Chemical Reviews, 2003, 103(1): p.
169-196.

Fischer, C., Carreira, E. M. “Zn-Alkynylide Additions to Acyl Iminiums.” Organic
Letters, 2004, 6(9): p. 1497-1499.

Fox, J. M., Huang, X., Chieffi, A., Buchwald, S. L. “Highly Active and Selective
Catalysts for the Formation of α-Aryl Ketones.” Journal of the American Chemical
Society, 2000, 122(7): p. 1360-1370.

Frankland, E. Journal of Chemical Society, 1862, 15: p. 363.

Frohn, H. J., Bailly, F. “A Convenient and General Approach to Alkyl-, Alk-1-
enyl-, and Aryldifluoroboranes.” Zeitschrift fur Anorganische und Allgemeine
Chemie, 2002, 628: p. 723-724.

Frohn, H. J., Franke, H., Fritzen, P., Bardin, V. V. “(Fluoroorgano)fluoroboranes
and –fluoroborates I: Synthesis and Spectroscopic Characterization of Potassium
Fluoroaryltrifluoroborates and Fluoroaryldifluoroboranes.” Journal of
Organometallic Chemistry, 2000, 598(1): p. 127-135.

Frost, C. G., Wadsworth, K. J. “Rhodium Catalysed Addition of Boronic Acids to
Anhydrides: A New Method for the Synthesis of Ketones.” Chemical
Communications, 2001,22: p. 2316-2317.

Frutos, R. P., Gallou, I., Reeves, D., Xu, Y., Krishnamurthy, D., Senanayake, C. H.
“Expedient Synthesis of Substituted Imidazoles from Nitriles.” Tetrahedron
Letters, 2005, 46(48): p. 8369-8372.

165
Gray, N. M., Cheng, B. K., Mick, S. J. Lair, C. M., Contreras P. C.
“Phencyclidine-like Effects of Tetrahydroisoquinolines and Related Compounds.”
Journal of Medicinal Chemistry, 1989, 32(6): p. 1242-1248.

Hall, D. G. “Boronic Acids.” Copyright 2005, WILEY-VGH verlag Gmb H&C,
KGaA, Weinheim, ISBN 3-527-30992-8.

Hayashi, T., Mitsuo, I. “Rhodium-Catalyzed Asymmetric Arylation of Imines with
Organostannanes. Asymmetric Synthesis of Diarylmethylamines.” Journal of the
American Chemical Society, 2000, 122(5): p. 976-977.

Heck, R. F., Nolley, J. P. “Palladium-Catalyzed Vinylic Hydrogen Substitution
Reactions with Aryl, Benzyl, and Styryl Halides.” Journal of Organic Chemistry,
1972, 37: p. 2320-2322.

Hirabayashi, K., Ando, J., Nishihara, Y., Mori, A., Hiyama, T. “A Coupling
Reaction of Aryltributyltin with Olefins Mediated by Palladium(II) Acetate.”
Synlett, 1999, 1: p. 99-101.

Hirabayashi, K., Nishihara, Y., Mori, A., Hiyama, T. “A Novel C-C Bond Forming
Reaction of Aryl- and Alkenylsilanols. A Halogen-Free Mizoroki-Heck Type
Reaction.” Tetrahedron Letters, 1998, 39: p. 7893-7896.

Hidekazu, O., Yukako, S., Yutaka, Y., Hiroki, T. “1-Tert-Butoxy-2-Tert-
Butoxycarbonyl-1,2-Dihydroisoquinoline: A Novel and Chemoselective Tert-
Butoxycarbonylation Reagent.” Organic Letters, 2002, 4(4): p. 585-587.

http://www.chemicalland21.com/specialtychem/finechem/imidazole.htm

http://en.wikipedia.org

http://en.wikipedia.org/wiki/Quinoline

Huts, P. G. M., Jung, Y. W. “Additions of Allyl Boronates to Sulfenimides.”
Tetrahedron Letters, 1986, 50(19): p. 2079-2082.

Itoh, T., Hasegawa, H., Nagata, K., Ohsawa, A. “Allylation of Azoles with
Allyltributyltin via Unstable N-(Alkoxycarbonyl)Azolium Salts.” Journal of
Organic Chemistry, 1994, 59(6): p. 1319-1325.

Itoh, T., Miyazaki, M., Nagata, K., Ohsawa, A. “Addition Reaction of Imidazoles
and Thiazoles with Silyl Enol Ethers in the Presence of Alkyl Chloroformate.”
Tetrahedron, 2000, 56(26): p. 4383-4395.

166
Itoh, T., Nagata, K., Miyazaki, M., Kameoka, K., Ohsawa, A. “Asymmetric
Addition of Nucleophiles to C-1 Position of Isoquinolines Using (S)-Alanine
Derivatives as Chiral Auxiliaries.” Tetrahedron Letters, 2001, 57(42): p. 8827-
8839.

Itoh, T., Nagata, K., Yokoya, M., Miyazaki, M., Kameoka, K., Nakamura, S.,
Ohsawa, A. “The Synthesis of Isoquinoline Alkaloid and Its Related Compounds
Using Alanine Derivatives as Chiral Auxiliaries.” Chemical and Pharmaceutical
Bulletin, 2003, 51(8): p. 951-955.
Jegou, G., Jenekhe, S. A. “Highly Fluorescent Poly(arylene ethylene)s Containing
Quinoline and 3-Alkylthiophene.” Macromolecules, 2001, 34(23): p. 7926-7928.

Ju, Y., Varma, R., J. “Aqueous N-Alkylation of Amines Using Alkyl Halides:
Direct Generation of Tertiary Amines Under Microwave Irradiation.” Green
Chemistry, 2004, 6: p. 219-221.

Kinast, G., Tietze, L.F. “A New Variant of the Mannich Reaction.” Angewandte
Chemie International Edition, 1976, 15(4): p. 239-240.

Kinnamon, K. E., Robert, R., Poon, B. T.,Ellis, W. Y., McCall, J. W., Dzimianski,
M. T. “Anticancer Agents Suppresive for Adult Parasites of Filariasis in
Mongolian Jrds.” Proceedings of the Society for Experimantal Biology and
Medicine, 2000, 224(1): p. 45-49.

Knolker, H. J., Agarwal, S. “Total Synthesis of the Antitumor Active Pyrrolo[2,1-
α]Isoquinoline Alkaloid (±)-Crispine A.” Tetrahedron Letters, 2005, 46(7): p.
1173-1175.

Lai, G. S., Pez, G. P., Syvret, R. G. “Electrophilic NF Fluorinating Agents.”
Chemical Reviews, 1996, 96(5): p. 1737-1756.

Lam, P. Y. S., Clark, C. G., Saubern, S., Adams, J., Winters, M. P., Chan, D. M. T.
New Aryl/Heteroaryl C-N Bond Cross-Coupling Reactions via Arylboronic
Acid/Cupric Acetate Arylation.” Tetrahedron Letters, 1998, 39: p. 2941-2944.

Larsen, S. D., Connell, M. A., Cudahy, M. M., Evans, B. R., May, P. D.,
Meglasson, M. D., O’Sullivan, T. J., Schostarez, H. J., Sih, J. C., Stevens, F. C.,
Tanis, S. P., Tegley, C. M., Tucker, J.A., Vaillancourt, V. A., Vidmar, T. J., Watt,
W., Yu, J. H. “Synthesis and Biological Activity of Analogs of the
Antidiabetic/Antiobesity agent 3-Guanidinopropionic Acid: Discovery of a Novel
Aminoguanidinoacetic Acid Antidiabetic Agent.” Journal of Medicinal Chemistry,
2001, 44(8): p. 1217-1230.

Lautens, M., Ouellet, S. G., Raeppel, S. “Amphoteric Character of 2-
Vinyloxiranes: Synthetic Equivalents of β, γ-Unsaturated Aldehydes and a
Vinylogous Enolate. ” Angewandte Chemie International Edition, 2000, 39(22): p.
4079-4082.
167
Lautens, M., Roy, A., Fukuoka, K., Fagnou, K., Martin-Matute, B. “Rhodium-
Catalyzed Coupling Reactions of Arylboronic Acids to Olefins in Aqueous
Media.” Journal of the American Chemical Society, 2001, 213(22): p. 5358-5359.

Lee, S. H., Park, Y. S., Nam, M. H., Yoon, C. M. “Indium Mediated Allylation of
Quinoline and Isoquinoline Activated by Phenyl Chloroformate.” Organic
Biomolecular Chemistry, 2004, 2: p. 2170-2172.

Leigh, D., Kraus, F. A., Kraus, C. A. “Quaternary Ammonium Salts with Anions
Containing Triphenylboron.” Journal of the American Chemical Society, 1940,
62(5): p. 1143-1144.

Lidstrom, P., Tierney, J., Wathey, B., Westman, J. “Microwave Assisted Organic
Synthesis-A Review.” Tetrahedron, 2001, 57: p. 9225-9283.

Magnus, P., Rodriguez-Lopez, J., Mulholland, K., Matthews, I. “Biomimetic
Synthesis of the Pentacyclic Alkaloid (.+.-)-Nirurine and Possible Biogenetic
Rearrangement of a Precursor into (.+.-)-Norsecurinine.” Journal of the American
Chemical Society, 1992, 114(1): p. 382-383.

Makoto, W., Masayuki, N., Kinya, A. “Reaction of Trimethylsilyl Enol Ethers
with Isoquinolinium Salts. A Facile Synthesis of Ethyl 1-(2-Oxoalkyl)-1,2-
Dihydroisoquinoline-2-Carboxylates and their Cyclization.” Chemistry Letters,
1983, 1: p. 39-42.

Markees, D. G., Dewey, V. C., Kidder, G. W. “Antiprotozoal 4-Aryloxy-2-
Aminoquinolines and Related Compounds.” Journal of Medicinal Chemistry,
1970, 13(2): p. 324-326.

Matthews, D. P., Miller, S. C., Javri, E. T., Sabol, J. S., McCarthy, J. R. “A New
Method for the Electrophilic Fluorination of Vinyl Stannanes.” Tetrahedron
Letters, 1993, 34(19): p. 3057-3060.

Merkushev, E. B. “Advances in the Synthesis of Iodoaromatic Compounds.”
Synthesis, 1988, 12: p. 923-937.

Mixson, J. A., Phang, J. M. “Structural Analog of Pyrroline 5-Carboxylate
Specifically Inhibit its Uptake Into Cells.” Journal of Membrane Biology, 1991,
121(3): p. 269-277.

Michael, J. P. “Quinoline, Quinazoline and Acridone Alkaloids.” Natural Product
Reports, 1997, 14(6): p. 605-618.

Miyaura, N. “Organoboron Compounds.” Journal of Organometallic Chemistry,
2002, 653(219): p. 11-57.

168
Molander, G. A., Figueroa, R. “Organotrifluoroborates: Expanding Organoboron
Chemistry. Aldrichimica Acta, 2005, 38(2): p. 49-56.

Molander, G. A., Katona, B. W., Machrouhi, F. “Development of the Suzuki-
Miyaura Cross-Coupling Reaction: Use of Air-Stable Potassium
Alkynyltrifluoroborates in Aryl Alkynylations.” Journal of Organic Chemistry,
2002, 67, 24: p. 8416-8423.

Molander, G. A., Bernardi, C. R. “Suzuki-Miyaura Cross-Coupling Reactions of
Potassium Alkenyltrifluoroborates.“Journal of Organic Chemistry, 2002, 67, 24: p.
8424-8429.

Molander, G. A., Ito, T. “Cross-Coupling Reactions of Potassium
Alkyltrifluoroborates with Aryl and 1-Alkenyltrifluoromethanesulfonates.”
Organic Letters, 2001, 3, 3: p. 393-396.

Molander, G. A., Yun, C. S., Ribagorda, M., Biolatto, B. “B-Alkyl Suzuki-
Miyaura Cross-Coupling Reactions with Air-Stable Potassium
Alkyltrifluoroborates.” Journal of Organic Chemistry, 2003, 68, 14: p. 5534-5539.

Molinari, A. J., Ashwell, M. A., Ridgway, B. H., Failli, A. A., Moore, W. J.
“Substituted Dihydrophenanthridine Sulfonamides.” United States Patent
Application Publication, 2004, US 2004/0167155 A1.

Murata, M., Satoh, K., Watanabe, S., Masuda, Y. “Stereoselective Synthesis of
Enol Acetates by the Reaction of Alkenylboronates with (Diacetoxyiodo)Benzene
and Sodium Iodide.” Journal of the Chemical Society, Perkin Transaction 1:
Organic and Bio-Organic Chemistry. 1998, 9: p. 1465-1466.

Navarre, L., Darses, S., Genet, J. P. “Efficient Access to Alanine Derivatives by
1,4-Additions of Potassium Trifluoro(organo)borates.” European Journal of
Organic Chemistry, 2004, p. 69-73.

Nishikawa, T., Yoshikai, M., Obi, K., Kawai, T., Unno, R., Jomori, T., Isobe, M.
“Synthesis and Biological Evaluation of Both Enantiomers of Dynemicin a Model
Compound.” Tetrahedron, 1995, 51(34): p. 9339-9352.

Ochiai, M., Toyonari, M., Nagaoka, T., Chen, D., Kida, M. “Stereospecific
Synthesis of Vinyl(phenyl)iodonium Tetrafluoroborates via Boron-Iodane
Exchange of Vinylboronic Acids and Esters with Hypervalent Phenyliodanes.“
Tetrahedron Letters, 1997, 38(38): p. 6709-6712.

Orru, R. V. A., de Greef, M. “Recent advances in Solution-Phase Multicomponent
Methodology for the Synthesis of Heterocyclic Compounds.” Synthesis, 2003, 10:
p. 1471-1499.

169
Patel, Z.D. Synthesis of Novel Compounds from Boronic Acids, Amines and
Carbonyl Derivatives, Ph.D. Thesis, University of Southern California 2002.

Pauvert, M., Collet, S., Guingant, A. “Silver Nitrate-Promoted Ring Enlargment of
1-Tribromomethyl-1,2-Dihydro- and 1-Tribromomethyl-1,2,3,4-Tetrahydro-
Isoquinoline Derivatives: Application to the Synthesis of the Anti-Anginal
Zatebradine.” Tetrahedron Letters, 2003, 44(22): p. 4203-4206.

Pawelke, G., Heyder, F., Burger, H. “Das Bis(Trifluoromethyl)-Difluoroborat-
Anion.” Journal of Organometallic Chemistry, 1979, 178(1): p. 1-4.

Petasis, N.A. and I. Akritopoulou. The boronic acid Mannich reaction - A new
method for the synthesis of geometrically pure allylamines. Tetrahedron Letters,
1993.34(4): p. 583-586.

Petasis, N.A. and I.A. Zavialov, New reactions of alkenyl boronic acids, in
Advances in Boron Chemistry, W. Siebert, Editor. 1997, Royal Society of
Chemistry: London. p. 179-182.

Petasis, N.A. and I.A. Zavialov. A new and practical synthesis of α-amino acids
from alkenyl boronic acids. J. Am. Chem. Soc., 1997.119(2): p. 445-446.

Petasis, N.A. and I.A. Zavialov. Highly stereocontrolled one-step synthesis of anti-
β-amino alcohols from organoboronic acids, amines, and α-hydroxy aldehydes. J.
Am. Chem. Soc., 1998.120(45): p. 11798-11799.

Petasis, N. A., Zavialov, I. A. “Mild Conversion of Alkenyl Boronic Acids to
Alkenyl Halides with Halosuccinimides.” Tetrahedron Letters, 1996, 37(5): p.
567-570.

Petasis, N.A. and Z.D. Patel. Synthesis of piperazinones and benzopiperazinones
from 1,2-diamines and organoboronic acids. Tetrahedron Lett., 2000.41(49): p.
9607-9611.

Petasis, N.A. and S. Boral. One-step three-component reaction among
organoboronic acids, amines and salicylaldehydes. Tetrahedron Lett., 2001.42(4):
p. 539-542.

Petasis, N.A. and I.A. Zavialov. Method for the synthesis of amines and amino
acids with organoboron derivatives. US 2001: 6,232,467.

Petasis, N.A. and X. Yao. Preparation of Amino Amides, Peptides and
Peptidomimetics. US 2004: 2004010162.

Petasis, N.A., I.A. Zavialov, and Z.D. Patel. Preparation of Amino Polyols and
Amino Sugars via Condesation Reaction with Organoboron Compounds. US 2004:
2004053330.
170
Petasis, N. A., Yudin, A. K., Zavialov, I. A., Prakash, G. K. S., Olah, G. A. “Facile
Preparation of Fluorine-Containing Alkenes, Amides, and Alcohols via the
Electrophilic Fluorination of Alkenylboronic Acids and Trifluoroborates.” Synlett,
1997, 5: p. 606-608.

Petasis, N.A. Amino Phosphonate and Amino bis-Phosphonate Derivatives. US
2005: 2005234021.

Petasis, N.A., X. Yao, and J.C. Raber. Preparation of nitrogen-containing
heterocycles. US 2005: 6,927,294.

Prakash, G. K., Panja, C., Mathew, T., Surampudi, V., Petasis, N. A., Olah, G. A.
“Ipso-Nitration of Arylboronic Acids with Chlorotrimethylsilane-Nitrate Salts.”
Organic Letters, 2004, 6(13): p. 2205-2207.

Prashad, M., Liu, Y., Har, D., Repic, O., Blacklock, T. J. “1,2,3-Triazole as a Safer
and Practical Substitute for Cyanide in the Bruylants Reaction for the Synthesis of
Tertiary Amines Containing Tertiary Alkyl or Aryl Groups.” Tetrahedron Letters,
2005, 46: p. 5455-5458.

Pucheault, M., Darses, S., Genet, J. P. “Potassium Organotrifluoroborates in
Rhodium-Catalyzed Asymmetric 1,4 Additions to Enones.“European Journal of
Organic Chemistry, 2002, 12: p. 3552-3557.

Pucheault, M., Darses, S., Genet, J. P. “Potassium Organotrifluoroborates: New
Partners in Catalytic Enantioselective Conjugate Additions to
Enones.“Tetrahedron Letters, 2002, 43: p. 6155-6157.

Puentener, K., Scalon, M. (Hoffmann-La Roche AG), Patent EP1057831A2, May
2000.

Quach, T. D., Batey, R. A. “Copper(II)-Catalyzed Ether Synthesis from Aliphatic
Alcohols and Potassium Organotrifluoroborate Salts.” Organic Letters, 2003, 5, 8,
p. 1381-1384.

Raber, J.C. Design and Synthesis of Novel Heterocycles and Peptidomimetics
From Organoboronic Acids, Amines and Carbonyl Compounds, Ph.D. Thesis,
University of Southern California 2002.

Rizzi, G. P. “A Novel Synthesis of Benzylamines from Benzaldehydes.” Journal
of Organic Chemistry, 1971, 36(12), p. 1710-1711.

Rozwadowska, M. D. “Recent Progress in the Enantioselective Synthesis of
Isoquinoline Alkaloids.” Heterocycles, 1994, 39(2): p. 903-931.

Rueckle, T., Biamonte, M., Grippi-Vallotton, T., Arkinstall, S., Cambet, Y.,
Camps, M., Chabert, C., Church, D. J., Halazy, S., Jiang, X., Martinou, I., Nichols,
171
A., Sauer, W., Gotteland, J. “Design, Synthesis, and Biological Activity of Novel,
Potent, and Selective (Benzoylaminomethyl)thiophene Sulfonamide Inhibitors of
c-Jun-N-Terminal Kinase.” Journal of Medicinal Chemistry, 2004, 47(27): p.
6921-6934.

Sakai, M., Hayashi, H., Miyaura, N. “Rhodium-Catalyzed Conjugate Addition of
Aryl- or 1-Alkenylboronic Acids to Enones.” Organometallics, 1997, 16: p. 4229-
4231.

Sakai, M., Ueda, M., Miyaura, N. “Rhodium-Catalyzed Addition of
Organoboronic Acids to Aldehydes.”Angewandte Chemie- International Edition,
1998, 37(23): 3279-3281.

Schreiber, J., Maag, H., Hashimoto, N., Eschenmoser, A. “Dimethyl
(Methylene)Ammonium Iodide.” Angewandte Chemie International Edition, 1971,
10(5): p. 330-331.

Seayad, A., Ahmed, M., Klein, H., Jackstell, R., Gross, T., Beller, M. “Internal
Olefins to Linear Amines.” Science, 2002, 297(5587): p. 1676-1678.

Selvam, C., Jachak, S. M., Thilagavathi, R., Chakraborti, A. K. “Design,
Synthesis, Biological Evaluation and Molecular Docking of Curcumin Analogues
as Antioxidant, Cyclooxygenase Inhibitory and Anti-Inflamatory Agents.”
Bioorganic & Medicinal Chemistry Letters, 2005, 15(7): p. 1793-1797.

Shaughnessy, K. H., Hamann, B. C., Hartwig, J. F. “Palladium-Catalyzed Inter-
and Intramolecular α-Arylation of Amides. Application of Intramolecular Amide
Arylation to the Synthesis of Oxindoles.” Journal of Organic Chemistry, 1998,
63(19): p. 6546-6553.

Shin, J. M., Cho, Y. M., Sachs, G. “Chemistry of Covalent Inhibition of the
Gastric (H
+
, K
+
)-ATPase by Proton Pump Inhibitors.” Journal of the American
Chemical Society, 2004, 126(25): p. 7800-7811.

Shuichi, O., Mitsutoshi, M., Hiroe, F., Takanori, K., Yoshio, I. “Rhodium-
Catalyzed Arylation and Alkenylation of Imines with Organostannanes.”
Tetrahedron Letters, 1999, 40(52): p. 9259-9262.

Sougato, B. “Synthesis of Polyfunctional Molecules Using Organoboron
Compounds.” Ph.D. Thesis, University of Southern California, 2001.

Stout, D. M., Meyers, A. I. “Recent Advances in the Chemistry of
Dihydropyridines.” Chemical Reviews, 1982, 82(2): p. 223-243.

Suzuki, A. “Carbon-Carbon Bonding Made Easy.” Chemical Communications,
2005, 38: p. 4759-4763.

172
Swanson, D. M., Wilson, S. J., Boggs, J. D., Xiao, W., Apodaca, R., Barbier, A. J.,
Lovenberg, T. W., Carruthers, N. I. “Aplysamine-1 and Related Analogs as
Histamine H
3
Receptor Antagonists.” Bioorganic & Medicinal Chemistry Letters,
2006, 16: p. 897-900.

Tagat, J. R., Steensma, R. W., McCombie, S. W., Nazareno, D. V., Lin, S.,
Neustadt, B. R., Cox, K., Xu, S., Wojcik, L., Murray, M. G., Vantuno, N.,
Baroudy, B. M., Strizki, J. M. “Piperazine-Based CCR5 Antagonists as HIV-1
Inhibitors. II. Discovery of 1-[(2,4-Dimethyl-3-pyridinyl)carbonyl]-4-methyl-4-
[3(S)-methyl-4-[1(S)-[4-(trifluoro-methyl)phenyl]ethyl]-1-piperazinyl]-piperidine
N1-Oxide (Sch-350634), an Orally Bioavailable, Potent CCR5 Antagonist.”
Journal of Medicinal Chemistry, 2001, 44: p. 3343-3346.

Takaya, Y., Ogasawara, M., Hayashi, T., Sakai, M., Miyaura, N. “Rhodium-
Catalyzed Asymmetric 1,4-Addition of Aryl- and Alkenylboronic Acids to
Enones.” Journal of the American Chemical Society, 1998, 120: p. 5579-5580.

Thadani, A. N., Batey, R. A. “A Mild Protocol for Allylation and Highly
Diastereoselective Syn or Anti Crotylation of Aldehydes in Biphasic and Aqueous
Media Utilizing Potassium Allyl- and Crotyltrifluoroborates.” Organic Letters,
2002, 4, 22: p. 3827-3830.

Thiebes, C., Prakash, G. K. S., Petasis, N. A., Olah, G. A. “Mild Preparation of
Haloarenes by Ipso-Substitution of Arylboronic Acids with N-Halosuccinimides.”
Synlett, 1998, 2: p. 141-142.

Torres, H. A., Hachem, R. Y., Chemaly, R. F., Kontoyiannis, D. P., Raad, I. I.
“Posaconazole: A Broad-Spectrum Triazole Antifungal.” Lancet Infectious
Diseases, 2005, 5(12): p. 775-785.

Tyagi, O. D., Srivastava, T. K., Chauhan, Y. K., Nalam, V. K. “Process for the
Preparation of Aryl Piperazinyl-Heterocyclic Compounds via Coupling Reaction.”
PCT Int. Appl. 2006, 10pp. CODEN: PIXXD2 WO 200611157 A2 200602.

Ueda, M., Miyaura, N.“A Large Accelerating Effect of Tri(tert-butyl)phosphine in
the Rhodium-Catalyzed Addition of Arylboronic Acids to Aldehydes.”Journal of
Organic Chemistry, 2000, 65: p. 4450-4452.

Ulaczyk-Lesanko, A., Hall, D. G. “Wanted. New Multicomponent Reactions for
Generating Libraries of Polycyclic Natural Products.” Current Opinion in
Chemical Biology, 2005, 9(3): p. 266-276.

Vedejs, E., Chapman, R. W., Fields, S. C., Lin, S., Schrimpf, M. R. “Conversion of
Arylboronic Acids into Potassium Aryltrifluoroborates: Convenient Precursors of
Arylboron Difluoride Lewis Acids.” Journal of Organic Chemistry, 1995, 60(10):
p. 3020-3027.

173
Vercouillie, J., Mavel, S., Galineau, L., Ragusa, T., Innis, R., Kassiou, M., Chalon,
S., Dolle, F., Besnard, J. C., Guilloteau, D., Emond, P. “Synthesis and in Vitro
Evaluation of Novel Derivatives of Diphenylsulfide as Serotonin Transporter
Ligands.” Bioorganic & Medicinal Chemistry Letters, 2006, 16: p. 1297-1300.

Wada, M., Sakurai, Y., Akiba, K. “Addition of Boron Trifluoride Complexes of
Organocopper Reagents to Aldimines Containing α-Hydrogens.” Tetrahedron
Letters, 1984, 25(10): p. 1079-1082.

Wang, D. K., Dai, L. X., Hou, X. L. “Allylstannane Allylation of Aldimines
Activated by Chlorotrimethylsilane.” Tetrahedron Letters, 1995, 36(47): p. 8649-
8652.

Wang, L., Liu, J., Tian, H., Qian, C., Sun, J. “One-Pot Synthesis of cis-Isoquinolic
Acid Derivatives via Three-Component Reaction of Homophthalic Anhydride with
Aldehydes and Amines using Ytterbium(III) Triflate as Catalyst.” 2005, 347(5): p.
689-694.

Wang, Q., Finn, M. G. “2H-Chromenes from Salicylaldehydes by a Catalytic
Petasis Reaction.” Organic Letters, 2000, 2(25): p. 4063-4065.

Wanner, K. T., Beer, H., Hofner, G., Ludwig, M. “Asymmetric Synthesis and
Enantioselectivity of Binding of 1-Aryl-1,2,3,4-tetrahydroisoquinolines at the PCP
Site of the NMDA Receptor Complex.”European Journal of Organic Chemistry,
1998, 9: p. 2019-2029.

Weber, L., Illgen, K., Almstetter, M. “Discovery of New Multi Component
Reactions with Combinatorial Methods.” Synlett, 1999, 3: p. 366-374.

Weingarten, H. “Ullmann Condensation.” Journal of Organic Chemistry, 1964,
29(4): p. 977-978.

Wu, B., Sosa, A. C. B., Boschelli, D. H., Boschelli, F., Honores, E. E., Golas, J.
M., Powell, D. W., Wang, Y. D. “7-(Aryl/Heteroaryl-2-ylethynyl)-4-Phenylamino-
3-Quinolinecarbonitriles as New Src Kinase Inhibitors: Addition of Water
Solubilizing Groups.” Bioorganic & Medicinal Chemistry Letters, 2006, 16: p.
3993-3997.

Xie, S., Ghovai, P., Ye, Q., Buschauer, A., Seifert, R. “Probing Ligand-Specific
Histamine H
1
- and H
2
-Receptor Conformation with N-Acylated
Imidazolylpropylguanidines.” Journal of Pharmacology and Experimental
Therapeutics, 2006, 317(1): p. 139-146.

Yamaguchi, R., Moriyasu, M., Yoshioka, M., Kawanisi, M. “Reactions of Allylic
Tin Reagents with Nitrogen Heteroaromatics activated by Alkyl Chloroformates:
Regioselective Synthesisof .alpha.-Allylated 1,2-Dihydropyridines and Change of
174
the Regioselectivity Depending on Methyl Substituents on the Allylic moiety.”
Journal of Organic Chemistry, 1988, 53(15): p. 3507-3512.

Yamaguchi, R., Mochizuki, K., Kozima, S., Takaya, H. “Divergent Change of
Regioselectivity in Nucleophilic Addition of Electron Deficient Allylic Tin
Reagents to 4-Acylpyridinium Salts; Selective Formation of 4,4-Disubstituted 1,4-
Dihydropyridines.” Chemical Communications, 1993, 12: p. 981-982.

Yamaguchi, R., Nakayasu, T., Hatano, B., Nagura, T., Kozima, S., Fujita, K.
“Facile Addition Reactions of Allylsilanes to Quinolines and Isoquinolines
Activated by Chloroformate Esters and a Catalytic Amount of Triflate Ion.”
Tetrahedron, 2001, 57(1): p. 109-118.

Yamamoto, Y., Asao, N. “Selective Reactions Using Allylic Metals.” Chemical
Reviews, 1993, 93(6): p. 2207-2293.

Yet, L. “Recent Developments in Catalytic Asymmetric Strecker-Type Reactions.”
Angewandte Chemie, International Edition, 2001, 40(5): p. 875-877.

Youngman, M. A., Dax, S. L. “Solid-Phase Mannich Condensation of Amines,
Aldehydes, and Alkynes: Investigation of the Diverse Aldehyde Inputs.” Journal
of Combinatorial Chemistry, 2001, 3(5): p. 469-472.
Zavialov, I. A. “New Reactions of Organoboronic Acids and their Derivatives.”
Ph.D. Thesis, University of Southern California, 1998.

Zhao, C., Zhao, Y., Chai, H., Gong, P. “Synthesis and in Vitro Anti-Hepatitis B
Virus Activities of Some Ethyl 5-Hydroxy-1H-Indole-3-Carboxylates.” Bioorganic
& Medicinal Chemistry Letters, 2006, 14: p. 2552-2558.

Zhiming, W., Weiliang, B., Yong, J. “L-Proline Promoted Ullmann-type Reaction
of Vinyl Bromides with Imidazoles in Ionic Liquids.” Chemical Communications,
2005, 22: p. 2849-2851.

Zhu, J., Bienayme, H. “Multicomponent Reactions.” Wiley-VCH Verlag GmbH &
Co. KgaA, Weinheim, 2005: p. 197-223.
175

Appendix: Selected Spectra

176
177
1
H NMR
(CDCl
3
, 250 MHz)

ON
O

13
C NMR
(CD
3
OD, 500 MHz)

1
H NMR
(CD
3
OD, 250 MHz)

N
Ph
Ph O

13
C NMR
(CDCl
3
, 500 MHz)

178
179
1
H NMR
(CD
3
OD, 250 MHz)

N
Ph
Ph
O
O

13
C NMR
(CDCl
3
, 500 MHz)

180
1
H NMR
(CD
3
OD, 250 MHz)

N
H O
O

13
C NMR
(CD
3
OD, 500 MHz)
1
H NMR
(CD
3
OD, 250 MHz)

N N
S
Ph

13
C NMR
(CD
3
OD, 500 MHz)

181
1
H NMR
(CD
3
OD, 250 MHz)

N
S

13
C NMR
(CD
3
OD, 500 MHz)
182

1
H NMR
(CD
3
OD, 250 MHz)

N N
O

13
C NMR
(CD
3
OD, 500 MHz)
183
1
H NMR
(CD
3
OD, 250 MHz)

N
Ph
COOH

13
C NMR
(CD
3
OD, 500 MHz)

184

1
H NMR
(CDCl
3
, 250 MHz)

N
Ph
O
H

13
C NMR
(CD
3
OD, 500 MHz)
185

1
H NMR
(CDCl
3
, 250 MHz)

N
O
O

13
C NMR
(CDCl
3
, 500 MHz)
186
1
H NMR
(CDCl
3
, 250 MHz)

N
O

187
13
C NMR
(CDCl
3
, 250 MHz)

1
H NMR
(CDCl
3
, 250 MHz)

N
O

13
C NMR
(CDCl
3
, 250 MHz)

188

1
H NMR
(CD
3
OD, 250 MHz)

N
Ph
N
HN N

13
C NMR
(CD
3
OD, 250 MHz)

189
1
H NMR
(CD
3
OD, 250 MHz)

N
Ph
Ph
N
HN

13
C NMR
(CD
3
OD, 250 MHz)
190
1
H NMR
(CD
3
OD, 250 MHz)

N
Ph
N
HN N

13
C NMR
(CD
3
OD, 250 MHz)
191

1
H NMR
(CD
3
OD, 250 MHz)

N
Ph
Ph
N
HN

13
C NMR
(CD
3
OD, 250 MHz)

192
1
H NMR
(CD
3
OD, 250 MHz)

N
Ph
N
HN O

13
C NMR
(CD
3
OD, 250 MHz)
193
194
1
H NMR
(CD
3
OD, 250 MHz)

H
N
Ph
N
HN
Ph

13
C NMR
(CD
3
OD, 250 MHz)
1
H NMR
(CD
3
OD, 250 MHz)

H
N
Ph
N
HN
Ph

13
C NMR
(CD
3
OD, 250 MHz)

195
1
H NMR
(CDCl
3
, 250 MHz)

N
O
Ph
Ph
O

13
C NMR
(CDCl
3
, 250 MHz)
196
1
H NMR
(CDCl
3
, 250 MHz)

HN
Ph
Ph

13
C NMR
(CDCl
3
, 250 MHz)

197
1
H NMR
(CDCl
3
, 250 MHz)

N
Ph
O
O

13
C NMR
(CDCl
3
, 250 MHz)

198
199
1
H NMR
(CDCl
3
, 250 MHz)

N
Ph
O
O
O

13
C NMR
(CDCl
3
, 250 MHz)
1
H NMR
(CDCl
3
, 250 MHz)

N O
O
O
O
O
O

13
C NMR
(CDCl
3
, 250 MHz)
200
1
H NMR
(CDCl
3
, 250 MHz)

1
H NMR
(CDCl
3
, 250 MHz)

N O
O
O

13
C NMR
(CDCl
3
, 250 MHz)

201

1
H NMR
(CDCl
3
, 250 MHz)

N O
O
O
Br

13
C NMR
(CDCl
3
, 250 MHz)
202
1
H NMR
(CDCl
3
, 250 MHz)

N O
O
Br

13
C NMR
(CDCl
3
, 250 MHz)
203
1
H NMR
(CDCl
3
, 250 MHz)

N O
O
Br

13
C NMR
(CDCl
3
, 250 MHz)
204

1
H NMR
(CDCl
3
, 250 MHz)

N
O O

13
C NMR
(CDCl
3
, 250 MHz)

205
1
H NMR
(CDCl
3
, 250 MHz)

N O
O

206
13
C NMR
(CDCl
3
, 250 MHz)

1
H NMR
(CDCl
3
, 250 MHz)

N O
O
O
O
O

13
C NMR
(CDCl
3
, 250 MHz)
207
1
H NMR
(CDCl
3
, 250 MHz)

N O
O

13
C NMR
(CDCl
3
, 250 MHz)

208
1
H NMR
(CDCl
3
, 250 MHz)

N O
O
O

13
C NMR
(CDCl
3
, 250 MHz)

209
1
H NMR
(CDCl
3
, 250 MHz)

N O
O
O
Br

210
13
C NMR
(CDCl
3
, 250 MHz)

1
H NMR
(CDCl
3
, 250 MHz)

N O
O
Br

211
13
C NMR
(CDCl
3
, 250 MHz)

1
H NMR
(CDCl
3
, 250 MHz)

N
O O O

13
C NMR
(CDCl
3
, 250 MHz)

212

Abstract (if available)

Abstract This Dissertation describes some new variations of a three-component reaction among boronic acids or trifluoroborates with amines and carbonyl compounds, known as the Petasis reaction. This process has been extended to include imidazole-carboxaldehydes as the carbonyl component, while trifluoroborate derivatives were shown to react with preformed or in-situ generated iminium salts to give new amine products. Similar reactions with quinoline or isoquinoline analogs were also shown to form new aza-heterocyclic derivatives.

Linked assets

University of Southern California Dissertations and Theses

Conceptually similar

PDF

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

PDF

Multicomponent reactions in the synthesis of nitrogen heterocycles and their application to drug discovery

PDF

New organoboron based multicomponent methodologies for the synthesis of novel heterocycles

PDF

Synthesis of multifunctional heterocycles, amino phosphontes using boronic acids

PDF

Palladium mediated methods for the total synthesis of lipid mediators and organoboron compounds

PDF

Synthesis of organofluorine compounds via Lewis/Bronsted acid and base catalysed reactions and related chemistry

PDF

New synthetic methods for organonitrogen compounds

PDF

New organic transformations based on electrophilic and superelectrophilic activation in strong acids

PDF

Progess towards the total synthesis of the antifungal natural product (-)-pramanicin

Asset Metadata

Creator Yiannikouros, Petros C. (author)

Core Title New reactions of organoboron compounds

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Publication Date 11/20/2006

Defense Date 08/07/2006

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag acid,boron,boronic,imidazole,OAI-PMH Harvest,quinoline,trifluoroborate

Language English

Advisor Petasis, Nicos A. (committee chair), Bau, Robert (committee member), Schonthal, Axel L. (committee member)

Creator Email pyiannik@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m179

Unique identifier UC164184

Identifier etd-Yiannikouros-20061120 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-37905 (legacy record id),usctheses-m179 (legacy record id)

Legacy Identifier etd-Yiannikouros-20061120.pdf

Dmrecord 37905

Document Type Thesis

Rights Yiannikouros, Petros C.

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email cisadmin@lib.usc.edu