/

University of Southern California Dissertations and Theses

/

Synthesis of multifunctional heterocycles, amino phosphontes using boronic acids

(USC Thesis Other)

Synthesis of multifunctional heterocycles, amino phosphontes using boronic acids

PDF

Download

Open document

Flip pages

Contact Us

Copy asset link

Request this asset

Transcript (if available)

Content

SYNTHESIS OF MULTIFUNCTIONAL
HETEROCYCLES AND AMINO PHOSPHONATES
USING BORONIC ACIDS

by
Wei Huang
_____________________

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

May 2007

Copyright 2007 Wei Huang

ii

DEDICATION

This work is dedicated to my family

iii

ACKNOWLEDGEMENTS
I gratefully acknowledge the Professor Nicos A. Petasis for his support
and guidance throughout the years. I truly appreciate his advice and
encouragement, without which this would not have been possible. I would like to
thank him for discussion on chemistry and his help in the most difficult time of
my life.
I wish to thank my committee members, Professors G. K. S. Prakash,
William P. Weber, Robert Bau and Axel Schonthal for their time, and for their
suggestions. I especially thank Professors Prakash and Weber for their valuable
advice, friendly interactions and support. I would like to thank the faculty and
staff of the USC Chemistry Department and LHI for their help and support.
I would like to thank the colleagues at LHI, especially in my lab: Dr.
Walter Keung, Dr. Sougato Boral, Dr. Marko Friedrich, Dr. Giovanni Bernasconi,
Dr. Koji Sato, Dr. Raquel Keledjian, Dr. RongYang, Dr. Brad Douglas, Dr. Petros
Yiannikouros, Dr. Fortini Liepouri and for their support. I would like to thank Dr.
Xin Yao and Dr. Giovanni Bernasconi for their friendship and discussion.
I would especially like to thank Dr. Rong Yang for his friendship and
help.
I would like to thank my family for all their love, support and sacrifices.

iv

TABLE OF CONTENTS

DEDICATION ii
ACKNOWLEDGEMENTS iii
LIST OF TABLES iv
LIST OF SCHEMES vii
LIST OF FIGURES x
ABSTRACT xii

CHAPTER 1
Multicomponent Reaction Involving Organic Boronic Acid
1.1 Introduction of Organoboronic Acids 2
1.2 Preparation of Organoboronic Acids 2
1.3 Organoboronic Acids in Organic Synthesis 5
1.3.1 The Suzuki-Miyaura Cross-coupling Reaction and
Rhodium Catalyzed 1,4-addition of Organoboronic Acid
to α,β-unsaturated Carbonyl Compounds 5
1.3.2 One-pot reaction of boronic acids with Amines and
Carbonyl Compounds 7
1.3.3 Studies of Organoboronic Acid Mannich Type Reaction 8
1.4 Chapter 1 Reference 17

CHAPTER 2
New Synthesis of Heteroaryl Substituted Aminomethanes
2.1 Introduction 20
2.1.1 Background of Aryl or Heteroaryl Disubstituted 20
Aminomethanes
2.1.2 Synthesis of aryl or Heteroaryl Disubstituted 21
Aminomethanes
2.2 Results and Discussion 24
2.2.1 One-step three Component Synthesis of Aminomethyl
Pyridines 25
2.2.2 Reactions with Trifluoroborates 30
2.2.3 Three-component Reaction with Acid as Catalyst 32
2.3 Conclusion 33
2.4 Experimentals 34
2.4.1 General 34
2.4.2 Preparation and Physical Properties of Compounds 35
v

2.5 Chapter 2 References 58

CHAPTER 3
New Synthesis of Amino Phosphonates and Amino Biphosphonates 59
3.1 Introduction 60
3.1.1 General Background of Multisubstituted Amino
Phosphonates and Amino Biphosphonates 60
3.1.2 Synthesis of Substituted Amino Phosphonates and
Amino Biphosphonates 61
3.2 Results and discussion 63
3.2.1 One-step Three-component Synthesis of Multi-substituted
Amino Phosphonates 64
3.2.2 Synthesis of Multi-substituted Amino Biphosphonates 66
3.3 Conclusion 68
3.4 Experimentals 69
3.4.1 General 69
3.4.2 Preparation and Physical Properties of Compounds 70
3.5 Chapter 3 References 80

CHAPTER 4
The Synthesis of Heterocyclic Compounds with Products of The
Boronic Acid Three-component Reaction as Precursor 81
4.1 Introduction 82
4.1.1 Background of Tetrahydroisoquinolines 82
4.1.2 Synthesis of Tetrahydroisoquinolines by Cyclization 83
4.2 Results and Discussion 87
4.3 Cycloaddition Reactions Based on Three-component Reaction Products 90
4.4 Conclusion 92
4.5 Experimentals 93
4.5.1 General 93
4.5.2 Preparation and Physical Properties of Compounds 94
4.6 Chapter 4 Reference 110

COMPREHENSIVE BIBLIOGRAPHY 112

APPENDIX 119

vi

LIST OF TABLES

Table 2.1: Condition of the one-pot reaction with
2-pyridine-carboxyaldehyde 26

Table 2.2: The three-component reaction between
pyridine-2-carboxyaldehyde with secondary
amines and boronic acids 27

Table 2.3: The three-component reaction between
pyridine-2-carboxyaldehyde with primary amines
and boronic acids 29

Table 2.4: Reactions with styryl trifluoroborate and TMSCl 31
Table 3.1: Synthesis of multi-substituted amino phosphonates 65

vii

LIST OF SCHEMES

Scheme 1.1 3
Scheme 1.2 3
Scheme 1.3 4
Scheme 1.4 4
Scheme 1.5 5
Scheme 1.6 6
Scheme 1.7 6
Scheme 1.8 7
Scheme 1.9 8
Scheme 1.10 9
Scheme 1.11 10
Scheme 1.12 11
Scheme 1.13 11
Scheme 1.14 12
Scheme 1.15 13
Scheme 1.16 14
Scheme 1.17 14
Scheme 1.18 15
Scheme 1.19 16
Scheme 2.1 21
Scheme 2.2 22
viii

Scheme 2.3 23
Scheme 2.4 23
Scheme 2.5 25
Scheme 2.6 26
Scheme 2.7 31
Scheme 2.8 32
Scheme 2.9 33
Scheme 2.10 34
Scheme 3.1 61
Scheme 3.2 63
Scheme 3.3 63
Scheme 3.4 64
Scheme 3.5 65
Scheme 3.6 68
Scheme 4.1 84
Scheme 4.2 85
Scheme 4.3 86
Scheme 4.4 87
Scheme 4.5 87
Scheme 4.6 88
Scheme 4.7 89
Scheme 4.8 89
Scheme 4.9 90
ix

Scheme 4.10 92
Scheme 4.11 92
Scheme 4.12 93
Scheme 4.13 942

x

LIST OF FIGURES

NMR Spectrum 2.24 120

NMR Spectrum 2.32 121
NMR Spectrum 2.47 122
NMR Spectrum 2.54 123
NMR Spectrum 2.62 124
NMR Spectrum 2.65 125
NMR Spectrum 2.78 126
NMR Spectrum 2.80 127
NMR Spectrum 3.01 128
NMR Spectrum 3.28 129
NMR Spectrum 3.03 130
NMR Spectrum 3.34 131
NMR Spectrum 3.37 132
NMR Spectrum 3.36 133
NMR Spectrum 3.39 134
NMR Spectrum 3.47 135
NMR Spectrum 4.31 136
NMR Spectrum 4.37 137
NMR Spectrum 4.41 138
NMR Spectrum 4.43 139
NMR Spectrum 4.46 140
xi

NMR Spectrum 4.48 141
NMR Spectrum 4.49 142
NMR Spectrum 4.50 143

ABSTRACT
This dissertation describes the development of new, practical and
experimentally convenient methodologies for multi-functional molecules.
In the first chapter, the three-component reaction involving boronic acids
is reviewed.
Chapter 2 describes a novel approach to the multi-substituted pyridyl
aminomethanes.
Chapter 3 describes a new method to for synthesis of functionalized α-
aminophosphonates and α-aminobiphosphonates via three-component process.
Chapter 4 describes convenient approaches to diversified heterocylic
compounds involving the three-component reaction.

xii

CHAPTER 1

Multicomponent Reaction Involving Organic
Boronic Acid

1

1.1 Introduction of Organoboronic Acids
In recent years, organoboronic acids have become more and more
important in modern organic synthesis. Because they are generally thermally
stable, and are not sensitive to air and moisture, which makes them better choice
over other conventional organometallic reagents. Organoboronic acids also play
an important role in green chemistry since the byproduct of their reactions boric
acid is environmentally friendly.
1

According to the nature of “R” group (1.1), organoboronic acid can be
classified into different types such as alkyl (1.2), alkenyl (1.3), aryl (1.4) and
heteroaryl boronic acids (1.5).

B
R
1
HO
OH R
3
R
2
B
R
1
HO
OH
B
OH
OH
B
HO
OH
R
B
HO
OH
R
1
X
R
1
1.1
1.2 1.3 1.4 1.5

1.2 Preparation of Organoboronic Acids
Aryl, heteroaryl and alkenylboronic acids are often prepared from the
reaction of Grignard or lithium reagents with trialky borates, followed by
hydrolysis to give the corresponding boronic acids. Triisopropyl borate is often
2

used over other borates because it produces less unwanted stereoisomers or
bisalkylation products (Scheme 1.1).
2

R
1
B
HO
OH
R
1
Mgx
R
1
Li
1) B(OR
2
)
3
2) H
3
O
+
1.6
1.7
1.8
R
1
=alkyl, aryl, 1-alkenyl, heteroaryl
R
2
=methyl, isopropyl.

Scheme 1.1
Hydroboration of alkynes also can used to prepare alkenyl boronic acids.
This method is more convenient comparing to using Grignard or organolithium
reagents, and it provides alkenyl boronic acids in geometrically pure form after
hydrolysis.
3

R
O
B
O
H 1)
2) H
3
O
+
R
B(OH)
2
1.9 1.10

Scheme 1.2
Recently, Miyaura’s group developed an approach to boronic acids or
borates from corresponding haloarenes by palladium catalyzed cross coupling
with alkoxydiborons. This procedure tolerates more functional group (such as
ester, nitrile, nitro and acyl goups) than the conventional methods using Grignard
or lithium reagents, and since alkoxydiborons are thermally stable and easily
handled in air, it’s more operationally convenient (Scheme 1.3).
4

3

(RO)
2
B-B(OR)
2
,
PdCl
2
(dppf)
2,
ArX
KOAc, DMSO
ArB(OR)
2
1.11 1.12

Scheme 1.3

More recently, the groups of Hartwig and Miyaura reported a new
preparation of boronic acids from arenes and bis(pinacolato)diboron (1.14). An
iridium catalyst was used in this process. At room temperature, the iridium
catalyst activates the C-H bond of arenes to produce corresponding borates
(1.15)(Scheme 1.4).
5

ArH
Ar B
O
O
BB
O
O O
O
Ir(I) bpy cat
1.13 1.14 1.15

Scheme 1.4
Snieckus’ group used di(isopropylprenyl)borane (1.16) as hydroboration
reagent for synthesis of alkyl and alkenyl boronic acids. This borane (1.16) is
generated in situ, which turns into borane (1.17) after hydroboration. This
procedure produces corresponding boronic acids after treating intermediate (1.17)
with water then formaldehyde. This one-pot method allows quick access to alkyl
or alkenyl boronic acids and their esters under mild condition(Scheme 1.5).
6
4

NaBH
4
, (MeO)
2
SO
4
diglyme
or BH
4
THF complex
B H
Alkene
or
alkyne
B R
1.16 1.17
R
B
HO
OH
O
H H
1) H
2
O, 2)

Scheme 1.5

1.3 Organoboronic Acids in Organic Synthesis
1.3.1 The Suzuki-Miyaura Cross-coupling Reaction and Rhodium Catalyzed
1,4-addition of Organoboronic Acid to α, β-unsaturated Carbonyl
Compounds
The Suzuki-Miyaura cross coupling is one of the most widely used C-C
bond-forming reactions. The reaction makes boronic acids and their derivatives
more important reagents in organic synthesis. This process has been used for
preparing biaryl compounds, polyenes and ene-ynes. The general mechanism is
shown in scheme 1.6.
1
The B-Alkyl (as opposed to a vinyl or aryl borane) Suzuki-
Miyaura cross-coupling variation developed recently filled another niche for
involving an sp
3
carbon in the coupling event.
7
This reaction has been well
reviewed, and it will not be further discussed here.
1, 7, 8
5

PdL
2
PdL
2
R
1
X
PdL
2
R
1
OR
3
PdL
2
R
1
R
2
R
2
B(OH)
2
B(OH)
2
(OR
3
)
R
1
R
2
R
3
O
R
1
X

Scheme 1.6
Miyaura’s group reported the 1, 4-addition of aryl- or alkenylboronic
acids to α,β-unsaturated carbonyl compounds (1.18) catalyzed by
(acac)Rh(CO)
2
/dppb (Scheme 1.7).
9
The asymmetric form of this reaction also
was developed, using R and S-BINAP ligand, very high enantioselectivity was
achieved.
10
The reaction does not proceed without catalyst, and no 1,2-addition
product is observed.

R
2
B
HO
OH
R
1
O
(acac)Rh(CO)
2
/dppb
R
1
O R
2
1.18 1.19

Scheme 1.7

6

1.3.2 One-pot Reaction of Boronic Acids with Amines and Carbonyl
Compounds
In the early 1990’s Petasis and his group developed the first boronic acid
Mannich type reaction,
11, 12
also referred as “Petasis Reaction”. In this process, a
wide range of boronic acids and amines react with certain carbonyl compounds,
and produce corresponding multi-functional amine derivatives.

N
H
R
4
R
5
O
R
8
R
7
R
3
B(OH)
2
R
1
R
2
N
R
8
R
7
OH
R
4
R
5
N
R
8
R
7
R
4
R
5
R
3
B
R
1
R
2
OH
OH
OH
R
3
R
7
N
R
8
R
4
R
5
R
1
R
2 -B(OH)
3
1.20 1.21 1.22 1.23
1.24
1.25
1.26

Scheme 1.8
Based on proposed mechanism (scheme 1.8), an aminol (1.22) is formed
from amine (1.20) and carbonyl compound (1.21), which react with the boronic
acid (1.23) in situ to give an ion pair of an iminium salt (1.24) and a nucleophilic
borate species (1.25). The final irreversible C-C bond formation gives the amine
product (1.26) with extrusion of a boric acid.
The three reactants should have certain features: The R
7
and R
8
of the
carbonyl compound should be able to facilitate the formation of the aminol and
activation of the iminium salt for nucleophilic addition. R
4
and R
5
of amine can be
7

alkyl or aryl, electron-withdrawing substitutes will make reaction slower because
of the difficulty in forming the ion pair. The boronic acids can be alkenyl or aryl,
and election-donating substitute works better in this reaction.

1.3.3 Studies of Organoboronic Acid Mannich Type Reaction

R
3
B(OH)
2
R
1
R
2
1.23
N
H
R
4
R
5
1.20
O
O
OH
1.26
1.27
R
3
R
1
R
2
N
R
5
R
4
OOH
O
OH
N
Ph
O
O NH
O
OH
Ph
Ph
Br
NH
OH
O
Ph
Ph
O
OH
NH
Ph
MeO
94% 84% 71% 94%
1.28 1.29 1.30 1.31
O
OH
HN
Ph
78%(>99%de)
1.32
Ph
OH

Scheme 1.9

8

The α-keto acids were found as carbonyl component participating in this
multicomponent process. The glyoxylic acid (1.26) reacts with a variety of
boronic acid and amine to give corresponding α-amino acids (1.27) (Scheme 1.9).
The reaction is experimentally convenient. It proceeds in different solvents, such
as methanol, toluene, dichloromethane and water. Product precipitates when
dichloromethane used as solvent. The use of (S)-2-phenylglycinol gives product
as single distereomer with good yield (1.32).
13

O
R
4
OH
B(OH)
2
1.33
N
H
R
2
R
3
1.20
1.34
1.35
R
1
N
R
1
R
2
R
3
R
4
OH
OH
N
Ph
Ph
84%
1.36
NH
Ph
86%
1.37
OH
OH
Ph
O
Ph
N
OH
Ph
S
Ph
86%
1.38

Scheme 1.10

Furthermore, α-hydroxy aldehydes (1.34) were found to work well as
carbonyl compounds in this MCR process, to give the corresponding anti- β-amino
alcohols (1.35) (Scheme 1.10). This reaction proceeds with a high degree of
diastereocontrol, forming exclusively the anti products in greater than 99%de. The
9

products are obtained as a single enantiomer when optically pure α-hydroxy
aldehydes are used.
14
An extension of this reaction is explored by using
carbonhydrates as carbonyl compound to prepare aza-sugar and aminopolyols.
17

Another noteworthy efficient carbonyl component is salicylaldehyde
(1.39). This reaction proceeds in ethanol at room temperature. A variety of highly
functionalized amines are produced this way (Scheme 1.11).
15

O
B(OH)
2
1.33
N
H
R
2
R
3
1.20
1.39
1.40
R
1
N
R
1
R
2
R
3
OH
OH
N
Ph
Ph
81%
1.41
OH
N
Ph
88%
1.42
OH
O
N
Ph
70%
1.43
OH
Ph
S

Scheme 1.11
A one-step synthesis of α-amino ketone was developed. In this process,
boronic acids (1.33) react with amines (1.20) and glyoxal hydrates (1.44) in
methanol to give the corresponding amino ketones (1.45) with moderate to good
yields (Scheme 1.12).
16

10

O
B(OH)
2
1.33
N
H
R
2
R
3
1.20
1.44
1.45
R
1
N
R
1
R
2
R
3
O
R
4
OH
OH
R
4
N
84%
1.46
O
O
NH
58%
1.47
O O
N
41%
1.48
O
O

Scheme 1.12
A convenient way to generate novel peptides or peptidomimetics was
found recently by using glyoxamides (1.49) as the carbonyl in this one-pot
process. This reaction has been applied in both solution and on solid support. This
strategy allows introducing two different functional groups into product in one
reaction (Scheme 1.13).
17

O
2
S
N
H
H
N
O
Ph
O
O O
N
H
Ph
H
N
N
Ph
Ph
O
1.49 1.50

Scheme 1.13
11

For the synthesis of piperazinones (1.52) and benzopiperazinones (1.54),
our group explored the reaction among 1,2-diamines (1.51) (1.53), organoboronic
acids (1.23) and glyoxylic acid (1.26) (Scheme 1.14).
18
It is noteworthy that the
boronic acids (1.26) served as both reactants and catalyst for cyclization in this
one-pot synthesis of piperazinones (1.52).
R
3
B(OH)
2
R
1
R
2
1.23
1.51
O
O
OH
1.26
1.52
R
3
R
1
R
2
N
R
4
ON
HN NH R
4
R
5
R
6
R
7
R
6
R
5
R
7
R
3
B(OH)
2
R
1
R
2
1.23
1.53
O
O
OH
1.26
1.54
R
3
R
1
R
2
N
H
O
H
N
HN H
2
N Boc
conc. HCl
MeOH
then neutralize

Scheme 1.14
The benzodiazeopine structure can be found in a large number of
medicinally active molecules. As a extension of the synthesis of
benzopiperazinones (Scheme 1.14), boronic acids (1.33) and glyoxylic acid (1.26)
were reacted with proper amines to give novel benzodiazepin-3-ones (1.56)
(Scheme 1.15).
16, 19
An intramolecular version of boronic acid reaction using
12

glyoxamide as carbonyl component leads to benzodiazopin-2-ones (1.58)
(Scheme 1.15).
16, 17

N
H
N
R
2
O
R
1
N
H
N
R
3
R
2
R
1
O
N
H
R
2
NH
2
O
O
OH
1.26
N
H
R
3
R
2
NH
O
O
1.57
1.55
B(OH)
2
1.33
R
1
B(OH)
2
1.33
R
1
1.56
1.58

Scheme 1.15
A tandem Petasis-Ugi multi component reaction was reported. The
boronic acids react amines and glyoxylic acid to provide amino acids (1.60)
which further react with aldehydes, amines and isocyanides to give
pipetidomimetics (1.61) (Scheme 1.16).
20
The process (a six component
condensation in fact) expended considerably the synthetic versatility by leading
to a six dimensional library.

13

O
O
OH
1.26
B(OH)
2
1.33
R
1
N
H
R
3
R
2
O
OH
N
R
1
R
3
R
2
R
4
NH
2
R
5
CHO
R
6
NC
O
N
N
R
1
R
3
R
2
R
4
R
5
H
N
O
R
6
MeOH
DCM
1.59
1.60 1.61

Scheme 1.16
Tertiary aromatic amines (1.62) can serve as amine substrate for the
Petasis reaction, reacting with boronic acids and glyoxylic acid to provide
products (1.63) by forming two C-C bonds at one step (Scheme 1.17).
21(a)
1, 3, 5-
tri-oxygenated benzenes was further try as amine component replacement in the
one –pot process, the reaction proceeds with moderate to reasonably good
yield.
21(b)

O
O
OH
1.26
B(OH)
2
1.33
R
1
N
R
2
R
2
O
R
3
1.62
O
OH
R
1
N
R
2
R
2
O
R
3
1.63
Dioxane, reflux

Scheme 1.17
14

O
H
N Ph
H
O
O
B(OH)
2
RCHO, THF
O
N Ph
H
O
R
H
O
O
N Ph
H
O
R
H
O
R=Bu, Pr, BnCH
2
, t-BuCH
2,
BnOCH
2,
i-Pr
1.64
1.65
1.66
HN
OH
R
H
O
1.67
NH
2
R
H
1.68
HO
O
HBr

Scheme 1.18
Using (S)-5-phenylmorphlin-2-one (1.64) as amine component, the
reaction proceeds with 2-furylboronic acid and alky aldehydes (Scheme 1.18).
The reaction gives products in good yields and high diastereoselectivity (86-
>95%de) with compound (1.65) as major product, which can be turned to α-
amino acid (1.68) after deprotection of the amine and oxidation of the furan to
release carboxylic acid.
Batey’s group reported a reaction of boronic acids react with acyliminium
instead of iminium ions. The use of diethanolamine and ethylene glycol borate
(1.70) was found more efficient than corresponding boronic acid. Boron
trifluoride etherate was used to promote the addition. Product (1.71) was formed
as a single diastereomer (>98%de cis:trans).
23
22
15

N
CBZ
OH
OH
O
B
O
R
BF
3
Et
2
O, DCM
-78
o
C-r. t.
1.70
1.69
N
CBZ
OH
R
1.71

Scheme 1.19
Because of its experimental convenience and great diversity of products,
the boronic acid three-component reaction has been applied widely in organic
synthesis by many chemists.
24

16

1.4 Chapter 1 References
1
Suzuki, A.; Miyuara, N. Chem. Rev., 1995, 95, 2457

2
(a) Wytko, J. A.; Weiss, J. J. O. C., 1990, 55, 5200; (b) Pelter, A.; Smith, K.;
Brown, H. C. Borane Reagents, Academic Press, New York, 1988; (c) Brown, H.
C. et al. Organometallics, 1986, 5, 2300; (d) Brown, H. C. et al. Tetrahedron
Lett., 1988, 29, 21; (e) Brown, H. C. et al. Tetrahedron lett., 1988, 29, 2635.

3
(a) Brown, H. C. Organic Synthesis via Boranes, John wiley and Sons, New
York, 1975. (b) Brown, H. C. et al. J. Am. Chem. Soc., 1972, 94, 4370.

4
(a) Miyaura, N. et al. J. Am. Chem. Soc., 1993, 115, 11018; (b) Miyaura, N. et al.
J. O. C., 1995, 60, 7508.

5
(a) Miyaura, N. et al. Advanced Synthesis and Catalysis, 2003, 345, 1103; (b)
Miyaura, N. et al. J. Am. Chem. Soc., 2002, 124, 390; (c) Miyaura. N. et al. J. Am.
Chem. Soc., 2000, 122, 4990.

6
Snieckus, V. et al. Angew. Chem. Int. Ed., 2003, 42, 3399.

7
Diederich, F.; Stang, P. J. Metal-catalyzed Cross-coupling Reactions, Wiley-
VCH, Weinheim, 1998.

8
(a) Fu, G.; Littke, A. F. Angew. Chem. Int. Ed., 2002, 41, 4176; (b) Kotha, S et
al. Tetrahedron, 2002, 58, 9633; (c) Danishefsky, S. J. et al. Angew. Chem. Int.
Ed., 2001, 40, 4544.

9
Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics, 1997, 16, 4229.

10
(a)Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. O. C., 2000, 65, 5951; (b)
Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem.
Soc., 1998, 120, 5579.

11
Akritopoulou-Zanze, I. Synthetic Studies on Allylamines, Alkenylsilanes and
Lipoxins, Ph.D. Thesis, University of Southern California, 1994.

12
Petasis, N. A.; Akritopoulou-Zanze, I. Tetrahdron Lett., 1993, 34, 583.

13
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc., 1997, 119, 445.

14
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc., 1998, 120, 11798.

15
Petasis, N. A.; Sougato, B. Tetrahdron Lett., 2001, 42, 539.
17

16
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.

17
Yao, X. Synthetic Studies and Novel Application of Reactions of Boronic Acids
with Amines and Carbonyl Compounds, Ph.D. Thesis, University of Southern
California, 2002.

18
Petasis, N. A.; Zubin, P. Tetrahdron Lett., 2000, 41, 9607.

19
Patel, Z. D. Synthesis of Novel Compounds from boronic Acids, Amines, and
Carbonyl derivatives, Ph.D. Thesis, University of Southern California, 2002.

20
(a) Portlock, D. E.; Ostaszewski, R.; Naskar, D.; West, L. Tetrahdron Lett.,
2003, 44, 603; (b) Portlock, D. E.; Naskar, D.; West, L.; Ostaszewski, R.; Chen, J.
J. Tetrahdron Lett., 2003, 44, 5121.

21
(a) Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahdron Lett., 2003,
44, 5819; (b) Naskar, D.; Roy, A.; Seibel, W. L. Tetrahdron Lett., 2003, 44, 8861.

22
Currie, G. S.; Drew, M. G. B.; Harwood, L. M.; Hughes, D. J.; Luke, R. W. A.;
Vickers, R. J. J Chem. Soc. Perkin Trans 1, 2000, 2982.

23
Batey, R. A.; Mackay, D. B.; Santhakuma, V. J. Am. Chem. Soc., 1999, 121,
5075.

24
A few publications employing the boronic acid three-component reaction:
(a) Jiang, B.; Yang, C. G.; Gu, X. H. Tetrahdron Lett., 2001, 42, 2545; (b) Pye, P.
J. et al. Chem. Eur. J., 2002, 8, 1372; (c) Koolmeister, T.; Sodergren, M.; Scobie,
M. Tetrahdron Lett., 2002, 43, 5965; (d) Forns, P.; et al. Tetrahdron Lett., 2003,
44, 6907; (e) Jiang, B.; Ming, X. Angew. Chem. Int. Ed., 2004, 43, 2543; (f)
Prakash, G. K.; Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G. A. J. Org.
Chem., 2002, 67, 3718; (g) Davis, A. S.; Pyne, S. G.; Skelton, B. W.; White, A.
H. J. Org. Chem., 2004, 69, 3139; (h) Jiang, B.; Ming, X. Org. Lett., 2002, 4,
4077.

18

CHAPTER 2

New Synthesis of Heteroaryl Substituted
Aminomethanes

19

2.1 Introduction
2.1.1 Background of Aryl or Heteroaryl Disubstituted Aminomethanes
Aryl or heteroaryl disubstituted aminomethanes are important because of
their interesting structure for the development of pharmaceuticals and
agrochemicals. This structure can be found in large number of biologically active
compounds.

N
R
2
R
1
R
3
R
4
R1, R2=Aryl or heteroaryl
General structure
N
N
R
N N
N
N
R=Aryl or Heteroaryl
N
H
O
N
O
O
R
N
Cl
2.1 2.2

Scheme 2.1
Pyrazolo[3.4-d]pyrimidines (2.1) were developed as potential
antienteroviral agents. Compounds with structure (2.1) were found to possess
antiviral activity against enterovirus 71, coxsackievius A9, A10, A16, A24, B1-
B6, echovirus 9, 68.
1
N-methyl-D-aspartate (NMDA) antagonists which act at the
allosteric glycine co-agonist site are believed to have potential therapeutic value
in treating a range of disorders such as stroke, Parkinson’s disease, depression and
20

neurophathic pain. Recently the structure (2.2) were studied as NMDA glycine-
site antagonists by Astrazeneca Pharmaceuticals.
2

2.1.2 Synthesis of Aryl or Heteroaryl Disubstituted Aminomethanes
Traditionally, aryl or heteroaryl sisubstituted aminomethanes were
synthesized by the conventional Mannich reaction which involving a Schiff base
formed by an amine and an aldehyde followed by the attack of a nucleophile.
Normally the nucleophile has to be a very electron rich aromatic compound.
3
The
other method is to treat imines with organolithium
4
or Grignard reagents
5
, which
require moisture-free condition.
R
1
N
N
N
N
R
3
R
2
R
1
N
N
N
N
R
3
R
2
R
6
R
5
R
4
O
Na
Toluene, reflux
R
1
N
R
3
R
2
R
6
R
5
R
4
O
R
1
N
R
3
R
2
O R
6
R
5
R
4
R
1
N
R
3
R
2
OH R
6
R
5
R
4
2.3 2.4
2.5
2.6 2.7

Scheme 2.2
Using benzotriazole methodology, Katritzky’s group preformed
benzotriazole derivatives by mixing the aldehyde, secondary amine and
benzotriazole and azeotropic removal of water. The derivatives are then refluxed
21

with phenolate in toluene in presence of catalytic amount of 18-crown-6. This
procedure gives corresponding disubstituted aminomethanes.
6
In this methodology
the nucleophiles are limited to very electron-rich phenolates.

R
1
N
N
N
N
R
3
R
2
2.3
MgBr
R
4
N
R
1
R
4
R
3
R
2
2.8

Scheme 2.3
The other known method for the synthesis of functional aminothanes
involving benzotriazoles was developed by Rice group by treating performed
benzotriazole derivatives with Grignard reagents.
7
Using chiral amines, they have
been able to get products in moderate to good enantioselectivities.
O N
R
HO
O N
R
OH
O N
R
O
R
NH
2 O
R
NH
2
BH
3
-THF complex, catalyst
BH
3
-THF complex, catalyst
OH
Catalyst
Ph
OH H
2
N
N
H
HO
N
H
HO
N
H
HO
N
H
Ph
Ph
HO
2.9
2.10
2.11
2.13 2.14 2.15 2.16 2.17
2.12

Scheme 2.4
22

(E)- and (Z)-Oximes were selectively formed by treating ketones with
hydroxamine under different condition, then the ketone oximes were converted
into chiral amines by oxazaborolidine-catalyzed enantioselective reduction. This
methodology gives disubstitued aminomethanes in good to high
enantioselectivities.
8

In general, the existing approaches to aryl or heteroaryl substituted
aminomethanes are step-wise, and nucleophiles are limited to very electron-rich
species, or strict conditions required when organolithium or Gregnard reagents are
used.

2.2 Results and Discussion
Recently Petasis’s group reported a novel one-step multi-component
process involving the condensation of alkyenyl, aryl and heteroaryl boronic acid
with amines and certain carbonyl compounds such as paraformaldehyde, α-keto
acids,

α-hydroxy aldehydes, and salicylaldehydes, leading to allyamine,
9
α-amino
acids,
10
β-amino alcohols,
11
and aminomethylphenol derivatives.
12

These novel reactions take advantage of the special properties of
organoboronic acids. While organoboronic acids are weakly electrophilic, they
can become transiently nuleophilic species after boron coordination with other
electronically rich atoms. The oxygen in the α-hydroxy group of α-hydroxy
aldehydes and salicylaldehydes, the carbonyl group of α-keto acids and glyoxals,
23

provides an “anchor” for boronic acids during the reaction and same time activate
boronic acids to make reaction proceed.
Based on the discoveries we envisioned that the coordination between
electron deficient organoboronic acids and a lone pair electron donor close to
aldehyde could assist this reaction. Thus, we studied the reaction with aldehyde
with neighboring nitrogen atom, and we have found that 2-pyridine-
carboxaldehyde is an indeed effective carbonyl component for this reaction.

2.2.1 One-step Three Component Synthesis of Aminomethyl Pyridines
This one-step reaction among 2-pyridine-carboxaldehyde (2.18), amines
(2.19) and boronic acids (2.20) affords the corresponding aminomethy pyridine
derivatives (2.21) (Scheme 2.5). The reaction occurs by simple stirring of the
three components in proper solvents, it requires mild conditions and the products
is easy to separate using conventional flash chromatography.

N
O
R
2
R
3
B
R
1
HO
OH
N
H
R
4
R
5
N
N
R
4
R
5
R
1
R
2
R
3
2.18
2.19
2.20
2.21

Scheme 2.5
To identify the right conditions for this reaction, several variations were
tried (Table 2.1). The reaction of 2-pyridine-carboxaldehyde (2.18),
24

dibenzylamine (2.22) and styryl boronic acid (2.24) (Scheme 2.6) was monitored
by NMR or TLC, and was found that in room temperature and in refluxing
ethanol the reaction proceeds very slow (entries 1, 5), while moderate yield were
observed in refluxing toluene (entry 4). However, the reaction works better in
refluxing dichloromethane and acetonitrile (enties 2,3).

N
O
N
H
Ph
Ph
Ph
B
OH
OH
N
N
Ph
Ph
Ph
2.18
2.22
2.23
2.24

Scheme 2.6
Table 2.1 Conditions of the one-pot reaction with 2-pyridine-carboxaldehyde

Condition Solvent Yield
RT
reflux
acetonitrile
acetonitrile
reflux
reflux
dichloromethane
toluene
reflux ethanol
Time
48hr 70%
44hr
39% 5hr
b
Entry
1
2
3
4
568hr
19hr
a
a
73%
a: Tace of pruduct observed.
b: Reactant consumed after 5 hours.

Some typical examples are shown below (Table 2.2), a range of
secondary amines react with pyridine-2-carboxaldehyde (2.18) and alkenyl, aryl
25

and heteroaryl boronic acids with reasonably good yields (Table 2.2, entries 1, 6,
7, 8, 9, 10).
Table 2.2 The three-component reaction between pyridine-2-carboxaldehyde with
secondary amines and boronic acids
N
N
Ph
Ph
Ph
73%
N
N
Ph
49%
N
N
Ph
Ph
29%
N
N
Ph
Bn
N
49%
N
N
Ph
Ph
S
35%
N
N
S
63%
N
H
Ph
Ph
Ph
B(OH)
2
B(OH)
2
N
H
Ph
B(OH)
2
Ph
N
H
Ph
B(OH)
2
Ph
N
H
Bn
N
N
H
Ph
Ph
N
H
S
B(OH)
2
S
B(OH)
2
1
2
3
4
5
6
Boronic acid Product Yield Amine
Entry Solvent Reaction time
CH
3
CN 19 hr
CH
3
CN 4.5 hr
CH
3
CN 4 hr
CH
3
CN 5 hr
CH3CN 6 hr
CH3CN
44 hr
2.22 2.23 2.24
2.25 2.23
2.26
2.27 2.23 2.28
2.29
2.23 2.30
2.22 2.31 2.32
2.25 2.31 2.33

26

N
N
Ph
Ph
O
58%
N
H
Ph
Ph
B(OH)
2
O
7
18 hr
CH
3
CN
2.22 2.34
2.35
N
N
Boc
N
S
57%
N
N
Ph
Ph
Ph
67%
de20%
N
N
Bn
N
S
56%
N
H
Bn
N
N
H
Boc
N
N
H
Ph
Ph
B(OH)
2
Ph
S
B(OH)
2
S
B(OH)
2
8
9
10 CH3CN 19 hr
CH3CN
CH3CN 28 hr
24 hr
2.36 2.31
2.37
2.38
2.23
2.39
2.29 2.31
2.40

Chiral amine (2.38) (entry 9) was tried and resulted in good yield but poor
stereoslectivity (de 20%).
We found that 3- and 4-pyridine-carboxaldehyde do not work in this
reaction. The p- or m- postion where boronic acid coordinating on is too far from
the iminium carbon for the reaction to proceed. After we first presented it,
Hansen’s group has also separately come up with the process.
13

Presumably, the reaction proceeds by the initial aminal formation from
the amine and aldehyde, then boronic acid is activated by boron coordination, and
finally migration of the alkeny, aryl and heteroaryl group of the boronic acid leads
to the product.
27

Primary amines did not work similarly under the above conditions. We
have found, however, that by using MgSO
4
in toluene or dichloromethane at room
temperature, the reactions proceed slowly to give the expected products (Table
2.3).
We found that benzylamine (2.41) and diphenyl aminomethane (2.46) are
more reactive in this type of reaction (entries 1, 3, 4).
Table 2.3 The three-component reaction between pyridine-2-carboxyaldehyde
with primary amines and boronic acids
N
N
H
Ph
Ph
69%
N
HN
32%
N
N
H
Ph
Ph
Ph
81%
N
N
H
Ph
Ph
S 49%
B(OH)
2
Ph
B(OH)
2
Ph
B(OH)
2
S
B(OH)
2
H
2
N Ph
H
2
N
H
2
NPh
Ph
H
2
NPh
Ph
1
2
3
4
Entry Amine Boronic acid Product Yield Solvent Reaction time
Toluene
24 hr
5 d
Toluene
Toluene 3 d
Toluene 2 d
2.23 2.41 2.42
2.43 2.44 2.45
2.46 2.23
2.47
2.46 2.31 2.48

28

Table 2.3 continued
N
N
H
Ph
O
O O
21%
B(OH)
2
Ph
NH
2
O
O O
5 Toluene 2 d
2.49 2.23 2.50
N
N
H
O
O O
S
15%
N
N
H
Ph
Ph
50%
de 80%
N
N
H
Ph
S
36%
de 78%
S
B(OH)
2
S
B(OH)
2
B(OH)
2
Ph
NH
2
O
O O
NH
2
Ph
NH
2
Ph
6
7
8
Toluene 4 d
Toluene 6 d
3 d Toluene
2.49 2.31 2.51
2.52 2.23 2.53
2.52 2.31 2.54

When chiral amine (2.52) was used, a significant diastereoselectivity was
oberserved (entries 7, 8).

2.2.2 Reactions with Trifluoroborates
Under the usual one-step conditions, simple benzaldehyde derivatives
without neighboring o-hydroxy substituents, do not work well. It was found
earlier, however, that the desired products can be obtained by first reacting the
29

aldehyde with the amine to form an aminal, followed by a reaction with the
corresponding trifluroborate and 1 eq. of Me
3
SiCl (Scheme 2.7).
14
Further, we
found the reaction that the reaction will proceed by adding the three components
at one time with 1:1:1 ratio. Under such conditions even aldehydes less reactive
give the expected products (Table 2.4).

O
HN O
N
N
O
O
N
Ph
Ph
BF
3
K
O
THF, 1 eq TMSCl
2.55
2.56
2.57
2.58
2.59

Scheme 2.7
Table 2.4 Reactions with styryl trifluoroboate and TMSCl

30

N
N
Boc
N
69%
Ph
N
N
Boc
N
55%
Ph
Ph
N
O
37%
N
O
N
H
Boc
N
N
H
Boc
N
N
O
O
N
H
O
1
2
3
Amine Aldehyde Product Yield Entry Solvent Reaction time
CH
2
Cl
2
CH
2
Cl
2
4 hr
5 hr
18 hr Toluene
2.18 2.36 2.60
2.36 2.61 2.62
2.63 2.64 2.65
Ph

Table 2.4 continued
31

N
Ph
O
S
29%
N
H
O
S
O
4 21 hr Toluene
2.66 2.64 2.67
N
N
Ph
O
35%
N
O
N
H
O
5 Toluene 21 hr
2.68 2.64 2.69
N
N
Ph
O
29%
N
NH
Ph
COOMe Ph
23%
de 24%
N
NH
2
COOMe Ph
O
N
O
N
H
O
6
7
Toluene 2 d
Toluene 10 hr
2.70 2.64 2.71
2.18 2.72 2.73

Ph
BF
3
K
Ph
BF
2
TMSF KCl
+
+
+ TMSCl
2.58
2.74

Scheme 2.8

2.2.3 Three-component Reaction under acid catalysis
We found that the boronic acid three-component reaction with pyridine
carboxaldehyde proceeds very slowly when reacting with primary amines
especially anilines. This may due to the stability of imines formed in situ, and
32

because imines formed from pyridine carboxaldehyde and anilines are more
stable, the reaction goes even slower.

N
N
R M
N
B
R'
HO
N
R
H
HO

Scheme 2.9
We have tried Yb(OTf)
3
, one widely used Lewis’ acid to activate the
imine intermediate, but it was not successful. The use of TsOH however, gave us
the desired results. The reaction proceeded fast with good yields. This may be
because the multi-coordination of the metal actually blocked the site for boronic
acid to “anchor”, so the boronic acid couldn’t be activated (Scheme 2.9).
The reaction proceeds well in presence of TsOH (0.5 eq). A few examples
are shown in Scheme 2.10. Primary amine (2.41) and anilines (2.75) (2.76) work
well under the condition. Interestingly, the boronic acid having an electron-
withdrawing group (2.77) less reactive in normal conditions, reacted quite well to
give the desired product (2.80).

33

B
OH
R' OH
RNH
2
N
O
+
TsOH, DCM
N
NH
R'
R
RNH
2
MeO
NH
2
MeO
NH
2
NNH
2
NH
2
B
OH
R' OH
B
OH
OH
MeO
B
OH
OH
MeO
B
OH
OH
MeO
B
OH
OH
Br
product
yield
2.18
2.34 2.34 2.77 2.34
2.75 2.76 2.75
2.41
2.78 2.79 2.80 2.81
83% 74% 60% 59%

Scheme 2.10

2.3 Conclusion
2-pyridine-carboxaldehyde readily reacts with a variety of organoboronic
acids and secondary amines and primary amine under different conditions. The
procedure is experimentally convienient and should be readily adaptable to
parallel synthesis. Some less reactive aldehydes react with amines and
organotrifluoroborates when treat with TMSCl. Also, the acid catalyzed reaction
was found beneficial in the case of primary amines and anilines.

34

2.4 Experimentals
2.4.1 General
All starting materials, unless otherwise noted, were purchased from
commercial suppliers and used without further purification. 2-Pyridine-
carboxaldehyde was redistilled before use. MgSO
4
was flamed and let cool down
under vacuum. Thin layer chromatography was performed on pre-coated TLC
plates (Silica gel 60 F
254
). Silica gel 60 (particle size 0.040-0.063 mm, 230-400
mesh) was used in flash column chromatography. NMR spectra were recorded on
a Bruker AMX-500 MHz, a Bruker AM-360 MHz and a Bruker AC-250 MHz
instruments. High-resolution mass spectra was obtained at the Southern California
Mass Spectrometry Facility, University of California, Riverside.

35

2.4.2 Preparation and Physical Properties of Compounds
Dibenzyl-(3-phenyl-1-pyridin-2-allyl)-amine (2.24)

N
N

Dibenzylamine (0.268ml, 1.35mmol), (E)-2-phenylvinylboronic acid (200mg,
1.35mmol) and pyridine 2-carboxaldehyde (0.128ml, 1.35mmol) were added into
a 25ml round bottom flask with 10ml of dichloromethane as solvent. The reaction
container was equipped with a reflux condenser and was heated to reflux. The
reaction was monitored by TLC (ethyl acetate:hexanes 1:4). After the reaction
was completed, the reaction mixture was allowed to cool to room temperature.
The mixture was washed with 0.1N NaOH solution (20ml) and the aqueous phase
was extracted with dichloromethane (2x10ml). The combined organic phase was
dried over sodium sulfate and concentrated. The product was isolated by flash
column chromatography using ethyl acetate-hexanes (1:9) to give 370mg oil (70%
yield).
1
H NMR (500MHz, CD
3
OD) δ 3.58-3.65(d, J=13.8Hz, 2H), 3.65-3.71(d,
J=14Hz, 2H), 4.43-4.48(d, J=6.1Hz, 1H), 6.48-6.57(m, 2H), 7.16-7.23(m, 3H),
7.24-7.31(m, 7H), 7.31-7.38(m, 6H), 7.70-7.77(d, J=7.7Hz, 1H), 7.80-7.87(t,
J=7.8HZ, 1H), 8.43-8.48(d, J=4.7Hz, 1H);
13
C NMR (126MHz, CDCl
3
) δ 55.76,
70.03, 123.83, 124.93, 127.57, 127.99, 128.69, 128.72, 129.31, 129.55, 129.90,
36

134.93, 138.21, 138.63, 140.99, 149.36, 163.28. HRMS/DEI (M
+
+1) calcd
391.2174, obsd 391.2170.

Diallyl-(3-phenyl-1-pyridin-2-yl-allyl)-amine (2.26)

N
N

Acetonitrile was used as reaction solvent, using a procedure similar to (2.24). The
product was purified by flash column chromatography using 8% ethyl acetate in
hexanes (49% yield).
1
H NMR (250MHz, CDCl
3
) δ 3.05-3.30 (dd, 4H), 4.46(d,
J=8.9Hz, 1H), 5.03-5.20(m, 4H), 5.73-5.92(m, 2H), 6.32-6.45(dd, J=8.5,
16.0Hz,1H), 6.51-6.61(d, J=15.8Hz, 1H), 7.05-7.40(m, 6H), 7.43-7.51(d,
J=7.8Hz, 1H), 7.56-7.65(t, J=7.7Hz, 1H), 8.50(d, J=4.9Hz, 1H);
13
C NMR
(62.9MHz, CDCl
3
) δ 52.04, 69.58, 117.34, 121.93, 122.60, 126.37, 127.38,
128.36, 129.25, 132.52, 136.35, 136.80, 149.10, 161.87. HRMS/DEI (M
+
+1)
calcd 291.1861, obsd 291.1874.

37

Benzyl-methyl-(3-phenyl-1-pyridin-2-yl-allyl)-amine (2.28)

N
N

Prepared similarly to (2.24) using acetonitrile as reaction solvent. Product was
purified by flash column chromatography using 8% ethyl acetate in hexanes (29%
yield).
1
H NMR (250MHz, CDCl
3
) δ 2.18(s, 3H), 3.50-3.68(m, 2H), 4.18-4.32(d,
J=7.5Hz, 1H), 6.38-6.55(dd, J=8.4, 16.2Hz, 1H), 6.67(d, J=16.2Hz, 1H), 7.10-
7.50(m, 1H), 7.56-7.80(m, 2H), 8.55(d, J=5Hz, 1H);
13
C NMR (62.9MHz, CDCl
3
)
δ 39.26, 59.27, 74.50, 122.12, 122.42, 126.45, 126.80, 127.50, 128.15, 128.43,
128.77, 129.96, 132.47, 136.66, 139.32, 149.15, 162.13. HRMS/DEI (M
+
+1)
calcd 315.1861, obsd 315.1851.

1-Benzyl-4-(3-phenyl-1-pyridin-2-yl-allyl)-piperazine (2.30)

N
N N

1-Benzylpiperazine (0.117ml, 0.676mmol), (E)-2-phenylvinylboronic acid
(100mg, 0.676mmol) and pyridine 2-carbaldehyde (0.064ml, 0.676mmol) were
38

added into a 25ml round bottom flask with 10ml of acetonitrile as solvent. The
reaction container was equipped with a reflux condenser and was heated to reflux
for 5 hours. The reaction was monitored by TLC (ethyl acetate:hexanes 3:7).
After the reaction was completed, the reaction mixture was allowed to cool to
room temperature. The mixture was concentrated, dissolved in methanol, and
filtered through Amberlite IRA-743 ion exchange resin to get rid of the rest of
boronic acid and boric acids. The resin was rinsed with methanol until no product
left. After the solvent was removed, it formed a gray solid, which was
recrystalized with 2-3ml acetonitrile to give a white solid, which was washed with
cold acetonitrile to give a 123mg white solid (49% yield).
1
H NMR (250MHz,
CDCl
3
) δ 2.10-2.80(m, 8H), 3.44(s, 2H), 3.93(d, J=8.9Hz, 1H), 6.24-6.38(dd,
J=8.9, 16Hz, 1H), 6.52-6.65(d, J=16Hz, 1H), 6.95-7.42(m, 12H), 7.48-7.62(t,
J=7.6Hz, 1H), 8.49(d, J=4.8Hz, 1H);
13
C NMR (62.9MHz, CDCl
3
) δ 51.40, 52.93,
62.88, 75.89, 122.02, 122.49, 126.32, 126.82, 127.43, 128.01, 128.35, 129.06,
130.37, 132.19, 136.45, 136.62, 137.92, 149.40, 161.39. HRMS/DEI (M
+
) calcd
369.2205, obsd 369.2193.

39

Dibenzyl-(pyridin-2-yl-thiophen-2-yl-methyl)-amine (2.32)

N
N
S

The procedure is similar to (2.24) using acetonitrile as reaction solvent. The
product was purified by flash column chromatography with 8% ethyl acetate in
hexanes (35% yield).
1
H NMR (250MHz, CDCl
3
) δ 3.37-3.48(d, J=14.1Hz, 2H),
3.71-3.83(d, J=14.2Hz, 2H), 5.21(s, 1H), 6.65-6.73(d, J=3.6Hz, 1H), 6.80-
6.89(dd, J=3.3, 5.1Hz, 1H), 7.05-7.50(m, 13H), 7.52-7.65(t, J=7.6Hz, 1H), 8.58(d,
J=4.8Hz, 1H);
13
C NMR (62.9MHz, CDCl
3
) δ 54.08, 64.34, 122.36, 124.15,
125.05, 126.30, 126.73, 126.90, 128.28, 128.70, 136.06, 139.55, 144.53, 149.13,
158.72. HRMS/DEI (M
+
+1) calcd 371.1582, obsd 371.1582

4-(pyeidin-2-yl-thiophen-2-yl-methyl)-piperazine-1-carboxylic acid tert-butyl
ester (2.37)

N
N N
O
S O

The procedure is similar to (2.24) using acetonitrile as reaction solvent. The
product was purified by flash column chromatography with 25% ethyl acetate in
40

hexanes (57% yield).
1
H NMR (360MHz, CDCl
3
) δ 1.47(s, 9H), 2.33-2.57(m,
4H), 3.44-3.52(t, J=4.9Hz, 4H), 4.80(s, 1H), 6.90-6.97(dd, J= 3.4, 5.1Hz, 1H),
6.92-6.99(d, J=3.2Hz, 1H), 7.05-7.14(dd, J=4.8, 7.4Hz, 1H), 7.15-7.22(d,
J=5.1Hz, 1H), 7.45-7.53 (d, J=7.8Hz, 1H), 7.56-7.65(m, 1H), 8.50(d, J=3.9Hz,
1H);
13
C NMR (90.6MHz, CDCl
3
) δ 28.29, 51.37, 72.65, 71.41, 122.33, 122.42,
125.82, 126.11, 126.19, 136.63, 144.36, 149.24, 154.59, 160.43. HRMS/DEI
(M
+
+1) calcd 360.1746, obsd 360.1735.

1-Benzyl-4-(pyridin-2-yl-thiophen-2-yl-methyl)-piperazine (2.40)

N
N N
S

The procedure is similar to (2.24) using acetonitrile as reaction solvent. The
product was purified by flash column chromatography with 8% ethyl acetate in
hexanes (56% yield).
1
H NMR (250MHz, CDCl
3
) δ 2.43(bs, 8H), 3.44(s, 2H),
4.69(s, 1H), 6.78-6.84(dd, J=3.4, 5.1Hz, 1H), 6.93(d, J=3.3Hz, 1H), 7.03-7.10(m,
1Hz), 7.12-7.30(m, 6H), 7.45-7.63(m, 2H), 8.47(d, J=4.7Hz);
13
C NMR
(62.9MHz, CDCl
3
) δ 51.62, 53.06, 62.97, 72.90, 122.27, 122.50, 125.68, 126.02,
126.21, 127.00, 128.16, 129.25, 136.61, 145.04, 149.24, 160.98. HRMS/DEI (M
+
)
calcd 349.1613, obsd 349.1606.

41

Dibenzyl-[(4-methoxy-phenyl)-pyridin-2-yl-methyl]-amine (2.35)

N
N
O

The procedure is similar to (2.24) using acetonitrile as reaction solvent. The
product was purified by flash column chromatography with 10% ethyl acetate in
hexanes (58% yield).
1
H NMR (250MHz, CDCl
3
) δ 3.57(s, 4H), 3.61(s, 3H),
4.95(s, 1H), 6.75(d, J=8.6Hz, 2H), 6.97(m, 1H), 7.05-7.35(m, 12H), 7.41-7.54(m,
2H), 8.42-8.52(d, J=4.8Hz, 1H);
13
C NMR (62.9MHz, CDCl
3
) δ 53.71, 54.97,
68.82, 113.47, 121.61, 123.22, 126.62, 128.06, 128.62, 129.99, 132.13, 135.97,
139.25, 148.85, 158.46, 161.30. HRMS/DEI (M
+
+1) calcd 395.2123, obsd
395.21718.

Diallyl-(pyridin-2-thiophen-2-yl-methyl)-amine (2.33)

N
N
S

The procedure is similar to (2.24). The product was purified by flash column
chromatography with 10% ethyl acetate in hexanes (63% yield).
1
H NMR
42

(250MHz, CDCl
3
) δ 2.96-3.10(dd, J=6.4, 14.2Hz, 2H), 3.10-3.25(dd, J=6.2,
14.4Hz, 2H), 5.00-5.15(m, 4H), 5.24(s, 1H), 5.70-5.95(m, 2H), 6.77-6.90(m, 2H),
7.02-7.11(dd, J=5.0, 7.3Hz, 1H), 7.12-7.17(dd, J=1.5, 4.8Hz, 1H), 7.39-7.47(d,
J=7.8Hz, 1H), 7.51-7.61(t, J=7.6Hz, 1H), 8.50(d, J=5.2Hz, 1H);
13
C NMR
(62.9MHz, CDCl
3
) δ 52.81, 66.27, 117.34, 122.08, 123.01, 125.11, 126.10,
135.42, 136.15, 145.25, 149.00, 160.44, 161.60. HRMS/DEI (M
+
+1) calcd
271.1269, obsd 271.1262.

Benzyl-(1(R)-phenyl-ethyl)-(3-phenyl-1-pyridin-2-yl-allyl)-amine(2.39)

N
N

The procedure is similar to (2.24). The product was purified by flash column
chromatography with 10% ethyl acetate in hexanes (67% yield, de 20%).
1
H
NMR (250MHz, CDCl
3
) δ 1.20-1.27(d, J=6.8Hz, 1.8H), 1.36-1.45(d, J=7Hz,
1.2H), 3.53-3.61(d, J=14.9Hz, 0.4H), 3.61-3.72(d, J=14.6Hz, 0.6H), 3.75-4.15(m,
3H), 4.48-4.55(d, J=8.5Hz, 0.4H), 4.55-4.63(d, J=9Hz, 0.6H), 6.03-6.20(dd,
J=9.1, 15.5Hz, 0.6H), 6.23-6.47(m, 1.4H), 6.92-7.70(m, 18H), 8.36-8.47(t,
J=5.7Hz, 1H).

43

Benzyl-(3-phenyl-1-pyridin-2-yl-allyl)-amine (2.42)

N
N
H

2g of magnesium sulfate (anhydrous) was added into 10ml of toluene, to this
mixture, pyridine-2-carboxaldehyde (0.095ml, 1mmol), benylamine (0.110ml,
1mmol) and (E)-styrylboronic acid (200mg, 1.35mmol) were added. The solution
was stirred at room temperature. The reaction was monitored by TLC with 30%
ethyl acetate in hexanes. After the reaction was completed, the solid was filtered
off and the solution was concentrated and was dissolved in dichloromethane. The
mixture was washed with 0.1N NaOH aqueous solution, and the aqueous phase
was extracted with dichloromethane (2x10ml), the combined organic phase was
washed with saturated NaCl solution and dried over sodium sulfate. After
evaporation of the solvent, the product was purified by flash column
chromatography (1%triethylamine, 8% ethyl acetate in hexanes) to afford 206mg
pure product (69% yield).
1
H NMR (250MHz, CDCl
3
) δ 2.30-2.52(bs, 1H), 3.62-
3.74(d, J=13.1Hz, 1H), 3.74-3.86(d, J=13.5Hz, 1H), 4.35-4.50(d, J=7.5Hz, 1H),
6.17-6.34(dd, J=7.9, 15.8Hz, 1H), 6.55(d, J=16.2Hz, 1H), 6.90-7.45(m, 12H),
7.48-7.59(m, 1H), 8.45-8.53(d, J=4.7Hz, 1H);
13
C NMR (62.9MHz, CDCl
3
) δ
51.31, 65.61, 121.98, 122.12, 126.40, 126.83, 127.49, 128.20, 128.32, 128.44,
131.11, 131.79, 136.58, 136.72, 140.21, 149.28, 161.67.
44

Allyl-(1-pyridin-2-yl-3-enyl)-amine (2.45)

N
HN

The procedure is similar to (2.42). The product was purified by flash column
chromatography with 1% triethylamine, 15% ethyl acetate in hexanes (32%
yield).
1
H NMR (250MHz, CDCl
3
) δ 1.90-2.15(bs, 1H), 2.30-2.57(m, 2H), 2.92-
3.15(m, 2H), 3.71-3.82(dd, J=7.3, 6.2Hz, 1H), 4.90-5.15(m, 4H), 5.56-5.92(m,
2H), 7.03-7.14(dd, J=5, 7.4Hz, 1H), 7.21-7.30(d, J=7.7Hz, 1H), 7.53-7.63(t,
J=7.6Hz, 1H), 8.46-8.56(d, J=4.7Hz, 1H);
13
C NMR (62.9MHz, CDCl
3
) δ 41.35,
50.09, 62.70, 115.70, 117.41, 121.85, 135.05, 136.13, 136.68, 149.28, 162.93.

Benzhydryl-(3-phenyl-1-pyridin-2-yl-ally)-amine (2.47)

N
N
H

The procedure is similar to (2.42). The product was purified by flash column
chromatography with 1% triethylamine, 12% ethyl acetate in hexanes (81%
yield).
1
H NMR (250MHz, CDCl
3
) δ 2.60-3.00(b, 1H), 4.27-4.43(d, J=7.6Hz,
45

1H), 4.83-4.95(s, 1H), 6.22-6.37(dd, J=7.6, 15.9Hz, 1H), 6.38-6.51(d, J=15.1Hz,
1H), 6.95-7.60(m, 18H), 8.48-8.58(d, J=4.8Hz, 1H);
13
C NMR (62.9MHz, CDCl
3
)
δ 63.33, 63.77, 122.02, 122.28, 126.39, 126.89, 127.41, 127.50, 127.53, 128.36,
128.40, 131.19, 131.54, 136.43, 143.63, 149.41, 161.54.

Benzyhydryl-(pyridin-2-yl-thiophen-2-yl-methyl)-amine (2.48)

N
N
H
S

The rocedure is similar to (2.42). The product was purified by flash column
chromatography with 25% ethyl acetate in hexanes (49% yield).
1
H NMR
(360MHz, CDCl
3
) δ 3.10-3.25(bs, 1H), 4.68(s, 1H), 4.95(s, 1H), 6.63-6.68(d,
J=3.6Hz, 1H), 6.77-6.83(dd, J=3.6, 5.3Hz, 1H), 7.01-7.07(m, 1H), 7.07-7.14(m,
4H), 7.14-7.22(m, 4H), 7.24-7.35(m, 4H), 7.44-7.52(t, J=7.5Hz, 1H), 8.47-8.52(d,
J=4.9Hz, 1H);
13
C NMR (90MHz, CDCl
3
) δ 60.68, 63.87, 122.28, 122.33, 125.00,
126.42, 126.99, 127.49, 127.60, 128.42, 136.41, 143.37, 143.41, 147.46, 149.51,
161.26

46

(3-phenyl-pyridin-2-yl-allyl)-(3,4,5-trimethoxy-benzyl)-amine (2.50)

N
N
H
O
O
O

The procedure is similar to (2.42). The product was purified by flash column
chromatography with 1% triethylamine, 40% ethyl acetate in hexanes (21%
yield).
1
H NMR (360MHz, CDCl
3
) δ 2.29-2.64(b, 1H), 3.75(s, 3H), 3.76(s, 6H),
4.40-4.45(d, J=7.5Hz, 1H), 6.23-6.32(dd, J=8, 15.7Hz, 1H), 6.52(s, 2H), 6.53-
6.58(d, J=15.8Hz, 1H), 7.05-7.34(m, 9H), 5.54-5.61(t, J=7.6Hz, 1H), 8.43-8.54(d,
J=5Hz, 1H);
13
C NMR (90MHz, CDCl
3
) δ 51.69, 56.08, 60.85, 65.58, 105.10,
122.18, 122.31, 126.48, 127.70, 128.57, 130.91, 132.13, 135.86, 136.68, 136.71,
136.80, 149.37, 153.21, 161.44.

47

(Pyridin-2-yl-thiophen-2-yl-methyl)-(3,4,5-trimethoxy-benzyl)-amine (2.51)

N
N
H
O
O O
S

The procedure is similar to (2.42). The product was purified by flash column
chromatography with 1% triethylamine, 30% ethyl acetate in hexanes (15%
yield).
1
H NMR (360MHz, CDCl
3
) δ 2.50-2.90(b, 1H), 3.75(s, 3H), 3.77(s, 6H),
5.10(s, 1H), 6.53(s, 2H), 6.81-6.89(m, 2H), 7.05-7.12(dd, J-4.8, 7.8Hz, 1H), 7.15-
7.19(d, J=4.9Hz, 1H), 7.20-7.25(d, J=7.8Hz, 1H), 7.52-7.59(t, J=7.6Hz, 1H),
8.49-8.53(d, J=5Hz, 1H);
13
C NMR (90MHz, CDCl
3
) δ 51.60, 55.93, 60.70,
62.52, 104.88, 121.99, 122.28, 124.97, 125.04, 126.47, 135.61, 136.59, 136.66,
147.07, 149.19, 153.06, 161.35.

48

[1(S)-Phenyl-ethyl]-(3-phenyl-1-pyridin-2-yl-allyl)-amine (2.53)

N
N
H

The procedure is similar to (2.42). The product was purified by flash column
chromatography with 1% triethylamine, 20% ethyl acetate in hexanes (50% yield,
de80%). Major distereomer NMR:
1
H NMR (360MHz, CDCl
3
) δ 1.29-1.40(d,
J=6.6Hz, 3H), 2.62-2.78(bs, 1H), 3.86-3.98(q, J=6.5Hz, 1H), 4.10-4.17(d,
J=8.2Hz, 1H), 6.14-6.25(dd, J=15.7, 8.3Hz, 1H), 6.26-6.35(d, J=15.7Hz, 1H),
6.94-7.02(dd, J=5.0, 7.4Hz, 1H), 7.03-7.33(m, 11H), 7.38-7.46(t, J=7.7Hz, 1H),
8.43-8.52(d, J=5.1Hz, 1H);
13
C NMR (90MHz, CDCl
3
) δ 24.71, 54.63, 63.02,
121.85, 121.95, 126.27, 126.66, 126.69, 127.41, 128.32, 128.37, 131.00, 131.11,
136.32, 136.61, 145.21, 149.05, 161.19.

49

(1-Phenyl-ethyl)-(pyridin-2-yl-thiophen-2-yl-methyl)-amine (2.54)

N
N
H
S

The procedure is similar to (2.42). The product was purified by flash column
chromatography with 1% triethylamine, 8% ethyl acetate in hexanes (36% yield,
de78%).
1
H NMR (250MHz, CDCl
3
) δ 1.23-1.29(d, J=6.3Hz, 0.33H), 1.29-
1.40(d, J=6.8Hz, 2.67H), 3.44-3.60(q, J=6.3Hz, 0.11H), 3.66-3.86(q, J=6.6Hz,
0.89H), 4.84(s, 0.11H), 4.89(s, 0.89H), 6.70-6.88(m, 2H), 6.92-7.04(m, 2H), 7.08-
7.33(m, 6H), 7.34-7.44(t, J=7.7Hz, 0.89H), 7.47-7.55(t, J=7.7Hz, 0.11H), 8.42-
8.50(d, J=4.8Hz, 0.89H), 8.50-8.58(d, J=4.8Hz, 0.11H);
13
C NMR (63MHz,
CDCl
3
) δ 24.43, 24.49, 54.87, 55.40, 60.36, 60.74,121.70, 121.92, 122.21, 122.58,
124.18, 124.56, 125.07, 125.39, 126.23, 126.32, 126.68, 126.72, 126.77, 126.89,
128.33, 136.37, 144.99, 147.25, 148.90, 149.66, 161.37.

50

4-(3-phenyl-1-pyridin-2-yl-allyl)-piperazine-1-carboxylic acid tert-butyl ester
(2.60)

N
N N
O
O

N-Boc piperazine (93mg, 0.5mmol), pyridine-2-carboxaldehyde (0.048ml,
0.5mmol) and potassium (E)-styryltrifluoroborate(105mg, 0.5mmol) were added
into 5ml of dry dichloromethane. 54mg of TMSCl(1 eq.) was then added into
mixture under nitrogen. The mixture was stirred at refluxing temperature for one
hour. The mixture was diluted with 10ml of dichloromethane and was washed
with 0.1N NaOH then with brine. Organic phase was dried over Sodium sulfate.
After the mixture was concentrated the product was isolated by flash column
chromatography with 1% triethylamine, 40% ethyl acetate in hexanes to give
130mg of oil-like product (69% yield).
1
H NMR (250MHz, CDCl
3
) δ 1.38-1.44(s,
9H), 2.15-2.40(m, 2H), 2.43-2.65(m, 2H), 3.35-3.50(t, J=5.2Hz, 4H), 3.91-3.99(d,
J=8.7Hz, 1H), 6.27-6.43(dd, J=8.7, 16.5Hz, 1H), 6.56-6.68(d, J=16.5Hz, 1H),
7.04-7.46(m, 7H), 7.57-7.68(t, J=7.6Hz, 1H), 8.52-8.59(d, J=4.9Hz, 1H).

51

4-(3-Phenyl-1-quinolin-2-yl-allyl)-piperazine-1-carboxylic acid tert-butyl
ester (2.62)

N
N N
O
O

The procedure was similarly to (2.60) (55% yield). The product was purified by
flash column chromatography with 25% ethyl acetate in hexanes.
1
H NMR
(360MHz, CDCl
3
) δ 1.35(s, 9H), 2.20-2.32(m, 2H), 2.50-2.62(m. 2H), 3,36(t,
J=5Hz, 4H), 4.09-4.15(d, J=9.5Hz, 1H), 6.27-6.38(dd, J=9.7, 16.5Hz, 1H), 6.63-
6.71(d, J=16.1Hz, 1H), 7.09-7.16(m, 1H), 7.16-7.23(m, 2H), 7.25-7.32(m, 2H),
7.40-7.47(m, 1H), 7.55-7.66(m, 2H), 7.69-7.74(d, J=7.5Hz, 1H), 8.01-8.06(d,
J=8.1Hz, 1H), 8.06-8.10(d, J=8.4Hz, 1H);
13
C NMR (90MHz, CDCl
3
) δ 28.35,
51.39, 76.53, 79.52, 120.31, 126.33, 126.43, 127.46, 127.51, 127.73, 128.48,
129.21, 129.37, 129.44, 133.24, 136.46, 136.89, 147.78, 154.71, 161.44

52

4-(1,3-Diphenyl-allyl)-morpholine (2.65)

N
O

The procedure was similarly to (2.60) (37% yield). The product was purified by
flash column chromatography with 10% ethyl acetate in hexanes.
1
H NMR
(250MHz, CDCl
3
) δ 2.25-2.55(m, 4H), 3,57-3.67(t, J=4.8Hz, 4H), 3.67-3.75(d,
J=8.8Hz, 1H), 6.14-6.27(dd, J=8.8, 15.6Hz, 1H), 6.44-6.55(d, J=15.6Hz, 1H),
7.07-7.38(m, 10H);
13
C NMR (62.9MHz, CDCl
3
) δ 52.14, 67.09, 74.77, 126.32,
127.25, 127.51, 127.97, 128.46, 128.61, 131.31, 131.50, 136.66, 141.57.

4-(3-Phenyl-1-thiophen-2-yl-ally)-morpholine (2.67)

N
O
S

The procedure was similarly to (2.60) (29% yield). The product was purified by
flash column chromatography with 10% ethyl acetate in hexanes.
1
H NMR
(250MHz, CDCl
3
) δ 2.43-2.70(m, 4H), 3.68-3.78(t, J=4.8Hz, 4H), 4.18-4.27(d,
53

J=8.7Hz, 1H), 6.28-6.40(dd, J=8.8, 15.6Hz, 1H), 6.54-6.65(d, J=15.5Hz, 1H),
6.90-7.00(m, 2H), 7.20-7.45(m, 6H);
13
C NMR (62.9MHz, CDCl
3
) δ 51.39,
67.10, 68.99, 124.95, 125.06, 126.43, 126.50, 127.74, 128.54, 129.35, 132.64,
136.45, 145.70.

4-(3-Phenyl-1-pyridin-4-yl-allyl)-morpholine (2.69)

N
N
O

The procedure was similarly to (2.60) (35% yield). The product was purified by
flash column chromatography with 1% triethylamine, 40% ethyl acetate in
hexanes.
1
H NMR (250MHz, CDCl
3
) δ 2.25-2.60(m, 4H), 3.66-3.74(t, J=4.8Hz,
4H), 3.77-3.84(d, J=9.4Hz, 1H), 6.08-6.22(dd, J=9.0, 15.8Hz, 1H), 6.54-6.65(d,
J=16Hz, 1H), 7.15-7.40(m, 7H), 8.45-8.65(b, 2H);
13
C NMR (62.9MHz, CDCl
3
) δ
51.84, 66.94, 73.59, 122.97, 126.38, 127.92, 128.53, 129.27, 132.97, 136.07,
150.08, 150.53.

54

4-(3-Phenyl-1-pyridin-3-yl-allyl)-morpholine (2.71)

N
N
O

The procedure was similarly to (2.60) (29% yield). The product was purified by
flash column chromatography with 25% ethyl acetate in hexanes.
1
H NMR
(360MHz, CDCl
3
) δ 2.27-2.58(m, 4H), 3.60-3.68(t, J=4.9Hz, 4H), 3.78-3.84(d,
J=9.1Hz, 1H), 6.11-6.22(dd, J=9.0, 16.0Hz, 1H), 6.50-6.58(d, J=16.0Hz, 1H),
7.12-7.32(m, 6H), 7.64-7.71(d, J=7.7Hz, 1H), 8.40-8.48(b, 1H), 8.52-8.63(b, 1H);
13
C NMR (90MHz, CDCl
3
) δ 51.99, 67.01, 72.14, 123.66, 126.40, 127.88, 128.57,
130.03, 132.53, 135.43, 136.26, 137.09, 148.78, 149.73.

Phenyl-(3-phenyl-1-pyridin-2-yl-allylamino)-acetic acid methyl ester (2.73)

N
NH
Ph
COOMe Ph

The procedure was similarly to (2.60) (23% yield, de 24%). The product was
purified by flash column chromatography with 20% ethyl acetate in hexanes.
1
H
NMR (360MHz, CDCl
3
) δ 3.57(s, 1.86H), 3.61(s, 1.14H), 4.27-4.32(d, J=8.4Hz,
55

0.63H), 4.35-4.39(d, J=8.0Hz, 0.37H), 4.41(s, 0.37H), 4.46(s, 0.63H), 6.17-
6.27(m, 1H), 6.43-6.50(d, J=16Hz, 0.63H), 6.51-6.58(d, J=16Hz, 0.37H), 7.05-
7.48(m, 12H), 7.50-7.62(m, 1H), 8.48-8.55(m, 1H);
13
C NMR (90MHz, CDCl
3
) δ
52.25, 52.29, 62.72, 62.82, 64.00, 64.08,

(4-Methoxy-phenyl)-[(4-methoxy-phenyl)-pyridin-2-yl-methyl]-amine (2.78)

HN
N
O
O

Pyridine-2-carboxyaldehyde (0.048ml, 0.5mmol) and 4-methoxy aniline (62mg,
0.5mmol) were added into dry DCM (5ml). The mixture was stirred for about 10
minutes. TsOH hydrate (48mg 0.5 eq.) and 4-methoxy phenyl boronic acid
(76mg, 1eq) were added to the mixture and the mixture was stirred at room
temperature. The reaction was monitored by TLC (40% ethyl acetate/hexanes).
The reaction was completed after 3 hours. The mixture was washed with saturate
sodium bicarbonate aqueous solution and extracted with DCM. The organic layers
were combined and dried over sodium sulfate. The product was isolated by flash
column chromatography (40% ethyl acetate/hexanes) in 83% yield.
1
H NMR
(360MHz, CDCl
3
) δ 3.69(s, 3H), 3,75(s, 3H), 5.464(s. 1H), 6.52-6.59(d, J=8.5Hz,
2H), 6.66-6.74(d, J=8.5Hz, 2H), 6.80-6.87(d, J=8.9Hz, 2H), 7.08-7.16(m, 1H),
7.28-7.38(m, 3H), 7.55-7.63(m, 1H), 8.54-8.59(d, J=4.8Hz, 1H);
13
C NMR
56

(90MHz, CDCl
3
) δ 55.18, 55.65, 63.55, 114.14, 114.68, 114.76, 121.67, 122.03,
128.46, 134.70, 136.77, 141.33, 149.13, 151.97, 158.85, 161.55.

[(4-Methoxy-phenyl)-pyridin-2-yl-methyl]-pyridin-2-yl-amine (2.79)

N
NH
N
O

The product was prepared similarly to (2.78). 74% yield.
1
H NMR (250MHz,
CD
3
OD) δ 3.74(s, 3H), 6.00(s, 1H), 6.55-6.67(m, 2H), 6.81-6.92(d, J=8.6Hz, 2H),
7.22-7.32(m, 3H), 7.41-7.52(m, 2H), 7.70-7.82(t, J=7.6Hz, 1H), 7.86-7.94(d,
J=4.6Hz, 1H), 8.45-8.54(d, J=4.5Hz, 1H);
13
C NMR (90MHz, CDCl
3
) 55.12,
60.11, 107.59, 113.03, 113.99, 121.86, 122.05, 128.35, 134.52, 136.68, 137.22,
148.08, 149.05, 157.62, 158.85, 160.72.

[(4-Bromo-phenyl)-pyridin-2-yl-methyl]-(4-methoxy-phenyl)-amine (2.80)

N
HN
Br
O

The product was prepared similarly to (2.78). 60% yield.
1
H NMR (360MHz,
CDCl
3
) δ 3.70(s, 3H), 5.48(s, 1H), 6.52-6.60(d, J=8.9Hz, 2H), 6.67-6.75(d,
57

J=8.9Hz, 2H), 7.13-7.22(m, 1H), 7.26-7.37(m, 3H), 7.38-7.46(d, J=8.7Hz, 2H),
7.58-7.66(t, J=8.0Hz, 1H), 8.56-8.61(d, J=5.1Hz, 1H);
13
C NMR (90MHz, CDCl
3
)
δ 55.66, 63.37, 114.74, 114.91, 121.38, 121.96, 122.46, 129.07, 131.89, 137.15,
140.80, 141.54, 149.10, 152.24, 160.36.

Benzyl-[(4-methoxy-phenyl)-pyridin-2-yl-methyl]-amine (2.81)

N
HN
O
Ph

The product was prepared similarly to (2.78). 59% yield.
1
H NMR (360MHz,
CDCl
3
) δ 3.67-3.75(d, J=13Hz, 1H), 3.75-3.83(d, J=13Hz, 1H), 3.79(s, 3H),
4.93(s, 1H), 6.82-6.92(d, J=8.9Hz, 2H), 7.08-7.15(m, 1H), 7.15-7.43(m, 8H),
7.53-7.65(t, J=7.9Hz, 1H), 8.45-8.60(d, J=4.8Hz, 1H);
13
C NMR (90MHz, CDCl
3
)
δ 58.11, 61.70, 73.07, 121.13, 129.60, 129.79, 132.97, 134.56, 135.58, 135.84,
136.17, 144.70, 155.73, 166.83, 168.35.

58

2.5 Chapter 2 References
1
Chern, J. H. et al. Bioorg. Med. Chem. Lett. 2004, 14, 2519.
2
Brown, D. G. et al. Bioorg. Med. Chem. Lett. 2003, 13, 3553.
3
(a) D. A. Leigh, P. Linnane, Tetrahedron Lett. 1993, 34, 5639. (b) Saidi. M. R.
et al. Tetrahedron: Asymmetry 2002, 13, 2417.

5
(a) Diego, A. et al. J. Org. Chem. 2003, 68, 6661. (b) Palmieri, G. et al. J. Org.
Chem. 2003, 68, 1200.

5
Tomioka, K. et al Tetrahedron: Asymmetry 1999, 10, 221.
6
Katritzky, A. R. et al J. Org. Chem. 1999, 64, 6071.
7
Rice, K. C. et al. J. Med. Chem. 2000, 43, 3193.
8
Demir, A. S. et al. Helv. Chim. Act. 2003, 86, 91.
9
Petasis, N.A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583.
10
Petasis, N.A.; Zavialov, I. A. J. A. C. S. 1997, 119, 445.
11
(a) Petasis, N.A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798. (b)
Prakash, G. K. et al. J. Org. Chem. 2002, 67, 3718. (c) Prakash, G. K. et al. Org.
Lett. 2000, 2, 3173.

12
Petasis, N.A.; Boral, S. Tetrahedron Lett. 2001, 42, 539.
13
Hansen, T. K. et al. Tetrahedron Lett. 2000, 41, 1303.
14
Zavialov, I. A. New Reactions of Organoboronic Acids and Their Derivatives,
Ph.D. Thesis, University of Southern California, 1998.

59

CHAPTER 3

New Synthesis of Amino Phosphonates and Amino
Biphosphonates

60

3.1 Introduction
3.1.1 α-Amino Phosphonates and α-Amino Biphosphonates
Because α-amino phosphonates have similar structure as α-amino acids,
the fundamental building blocks of peptides and proteins, they have long been
used as surrogates for amino acids in a variety of enzyme inhibitors.

N-substituted
amino phosphonates(3.1) (Scheme 3.1) have been used extensively as inhibitors
of protease and other enzymes
1
and have shown a range of useful activities as
pharmaceuticals and agrochemicals.

N
H
P HO
O
OH
General structure
P
N
H
R
1
H
N
O
CONHMe
R
2
O
OH
HO
3.1
3.2
3.3
N
NH
N
N
R
N
P R
1
R
2
R
3
O
O
O
R
4
R
5
N
R
1
R
2
R
3
O
OH
a-amino acid

Scheme 3.1
α-Amino phosphonates of structure 3.2 were investigated as inhibitors of
collagenase (MMP-1), an important target for drug discovery.
2
The synthesis and
activation of this enzyme causes excessive cartilage and bone destruction, an
event that takes place when the endogenous inhibitors generation are off balance
A series of N-phosphonoalkyl dipeptide collagenase inhibitors (3.2) were
61

developed and evaluated by SmithKline Pharmaceuticals.
3
It was found that some
N-phosphonoalkyl dipeptides are at least 10-fold more potent than their
corresponding N-carboxyalkyl analogues.
3
The mitogenic peptide endothelin (ET-1) was found to play a role in many
diseases, such as cardio- and cerebrovascular diseases,
4
renal failure
5
and ashma.
6

Besides blocking the actions of endithelin, another promising strategy is to
prevent ET-1 generation. Novartis has investigated the compound (3.3) and its
analogues inhibitors of endothelin-converting enzyme (ECE).
7
Various α-
aminophosphonates of (3.3) were further studied for bioactivity optimization and
increasing stability for oral use as a prodrug.
7,8
Bisphosphonates are also a class of compounds of great importance for
pharmaceuticals. They have long been used as biphosphates mimics. Having a
hydrolytically stable backbone of P-C-P, they behave as pyrophosphate analogues
and act by inhibiting farnesyl pyrophosphate synthase.
9
Some biphosphonates are
used widely to treat bone diseases,
10
such as Novartis’ Aredia and Merck’s
Fosamax, bisphonates were also studied as antiparasitic agents.
11

3.1.2 Synthesis of substituted α-amino phosphonates and α-amino
biphosphonates
One common method to prepare α-amino phosphonates is to add
phosphites to imines, catalyzed a base or by an acid. Ranu’s group developed a
one-pot reaction with carbonyl compounds (3.4), amines (3.5) and dialkyl
62

phosphite (3.6) catalyzed by indium (III) chloride, leading to corresponding α-
amino phosphonates (3.7) in good yields. The reaction takes place in mild
conditions, although both aldehydes and ketones work for this reaction,
12
only
primary amines seem to work in this procedure.

O
R
2
R
1
R
3
N
H
H
P
O
OEt H
OEt
P
R
2
HN
R
1
R
3
EtO O
OEt
+ +
InCl
3,
THF
3.4 3.5 3.6
3.7

Scheme 3.2
Using a benzotriazole-based strategy, Katritzky’s group firstly form
benzotrizolylmethyl derivatives (3.9) as intermediate by mixing benzotriazole
(BtH), formaldehyde and amine (3.8), then treating with phosphite (3.6) and zinc
bromide as Lewis acid.
H
2
N
R
O
O
N
H
R
O
O
Bt
N
H
R
O
O
P
EtO
O
OEt
P
O
OEt H
OEt
3.6
ZnBr
2
BtH, H
2
CO
CH
3
OH/H
2
O
3.8 3.9 3.10

Scheme 3.3
Another conventional method to prepare amino phosphonates is the
addition of metal (sodium, lithium etc.) derivatives of phosphates to imines. After
trying different chiral amines, Smith’s group found that chiral chelating imines
(3.12) prepared from aldehydes and (R)-(-)-1-amino-phenyl-2-methoxyethane
(3.11) after addition of lithium diethyl phosphite and followed by hydrogenolysis,

63

give amino phosphonates (3.13) in high enantiomeric purity (up to 97% ee)
(Scheme 3.4). A chelating mechanism (3.14) was proposed. The anti position of
the phenyl group and the phosphite make the addition to the re face of the imine,
leading to (R, R) diastereomers.
13

MeO
NH
2
Ph
RCHO
PhH, Na
2
SO
4
0-25
o
C, I h
MeO
N
Ph
R
3.11 3.12
MeO
H
N
Ph
P
O
OEt H
OEt
3.6
BuLi,
THF, 25
o
C, 18 h
P
R
3.13
O
N
Me
Li
O
P(OEt)
2
3.14
OEt
O
OEt

Scheme 3.4

3.2 Results and discussion
Herein, we introduce a novel synthesis of multi-substituted
aminophosphonates (3.18) via a three-component condensation between simple
amino phoshonates (3.15), carbonyl compounds (3.16) and organoboronic acid
(3.17) (Scheme 3.5).

64

3.2.1 One-step three component synthesis of multi-substituted α-amino
phosphonates
The reaction was found to be most efficient at room temperature in
acetonitrile and is experimentally simple. It is readily adaptable to parallel
synthesis. Some typical examples are shown below (Table 3.1). Several types of
aryl and heteroaryl boronic acids gave the expected products in variable yields
(not optimized). A number of amino phosphonates, both primary and secondary,
worked reasonably well in this process.

R
4
P NOR
OR
O
R
3
H
R
2
B
OH
OH
R
1
H
O
R
4
P NO
OR
O
R
3
R
1
R
2
3.15
3.16
3.17
3.18
R

Scheme 3.5
Table 3.1 Synthesis of multi-substituted α-amino phosphonates
Entry Aldehyde Boronic acid
Amino phophonate Time Yield(
%)
O
47 1
2 55
O
COOH
O
COOH
B(OH)
2
B(OH)
2
P(OEt)
2
H
2
N
O
P(OEt)
2
H
2
N
O
36 hr
24 hr
POEt HN
O
O
O
O
POEt HN
O
O
O
Product
3.20 3.21 3.23 3.24
3.20 3.25
3.23 3.26

65

Table 3.1 continued
3
O
67
O
COOH
B(OH)
2
P(OEt)
2
H
2
N
O
24 hr
P(OEt)
2
HN
O
COOH
O
3.20 3.27 3.23 3.28
O
71 4
5
O
COOH
B(OH)
2
P(OEt)
2
N
H
O
S
B(OH)
2
P(OEt)
2
H
2
N
O
30
N
6
P(OEt)
2
N
H
O
N
O
B(OH)
2
65
9
N
O
B(OH)
2
P(OEt)
2
H
2
N
O
92 48 hr
24 hr
48 hr
48 hr
P(OEt)
2
N
O
COOH
O
P(OEt)
2
HN
O
S
N
P(OEt)
2
H
2
N
O
38
N
O
B(OH)
2
7
24 hr
P(OEt)
2
HN
O
N
O
P(OEt)
2
N
H
O
8
Bn
91
N
O
B(OH)
2
24 hr
P(OEt)
2
BnN
O
O
N
P(OEt)
2
N
O
O
N
P(OEt)
2
HN
O
O
N
O
O
O
O
O
3.20 3.27 3.29 3.30
3.31
3.23
3.32
3.31
3.33
3.23
3.34
3.31
3.21
3.35
3.31
3.27 3.36
3.37
3.31
3.27
3.29
3.38 3.27 3.39

66

Table 3.1 continued
10
3.40
O
OH
OH
O
B(OH)
2
P(OEt)
2
H
2
N
O
88 30 hr
P(OEt)
2
HN
O
O
OH
OH
3.41 3.27 3.23

The use of glyoxylic acid (3.20) gave the corresponding amino acids
(entries 1-4), along with a compound consistent with a heterocyclic structure
(entries 1, 2).
The use of glyceraldehydes (3.41) gave the corresponding amino diol
(entry 11) in good yield.
Pyridyl aldehyde (3.31) reacted with primary or secondary amino
phosphonates to afford the corresponding pyridyl amine derivatives (entries 5-10).
We also investigated the distereocontrol of this reaction with a chiral
aldehyde (entry 10)(one diasteromer observed) or chiral amino phosphonate
(entry 9) (60% de), and obtained the corresponding products with high
stereochemical purity, but the relative stereochemistry has not yet been
established.

3.2.2 Synthesis of multi-substituted α-amino biphosphonates
We have also found that amino biphosphonates are also good substrates
for this three-component process, which leads to multi-substituted amino
biphospnonates. These reactions work well at room temperature in acetonitrile.
67

The substrate, benzyl amino biphosphonate (3.45) was prepared according
to a literature,
14
as shown in Scheme 3.6. The substrate reacts with glycol
aldehyde (3.46) or glyoxylic acid (3.20) to give amino alcohol or amino acid
derivatives (Scheme 3.6).
Ph
Ph
N
H
P
O
OEt
OEt
H
CH(OEt)
3,
150
o
C
53%
Ph
Ph
NP
P
O EtO
OEt
O
OEt
OEt
(a) cat. Pd/C
C
6
H
10,
MeOH
(b) PhCHO
NaBH(OAc)
3

60%
Ph N
H
P
P
O EtO
OEt
O
OEt
O
Et
O
B(OH)
2
Ph N
H
P
P
O EtO
OEt
O
OEt
OEt
O
OOH
HO
Ph N P
P
O EtO
OEt
O
OEt
OEt
OH O
reaction time: 36 hr
yield: 89%
(1)
(2)
R
B(OH)
2
Ph N
H
P
P
O EtO
OEt
O
OEt
OEt
Ph N P
P
O EtO
OEt
O
OEt
OEt
R
HO
O
COOH
O
R 4-methoxyphenyl 2-furan
reaction time: 24 hr 12 hr
yield: 90% 53%
3.43
3.44
3.45
3.27
3.45
3.46
3.47
3.45
3.20
3.48

Scheme 3.6

68

3.3 Conclusion
α-Amino phosphonates and α-amino biphosphonates react with certain
aldehydes and organoboronic acids in one-pot under mild conditions. This
experimentally simple procedure provides a unique approach to multi-functional
amino phosphonates and amino biphosphonates, and should be adaptable to
parallel synthesis.

69

3.4 Experimentals
3.4.1 General

All starting materials, unless otherwise noted, were purchased from
commercial suppliers and used without further purification. 2-Pyridine-
carboxyaldehyde was redistilled before use. Thin layer chromatography was
performed on pre-coated TLC plates (Silica gel 60 F
254
). Silica gel 60 (particle
size 0.040-0.063 mm, 230-400 mesh) was used in flash column chromatography.
NMR spectra were recorded on a Bruker AMX-500 MHz, a Bruker AM-360 MHz
and a Bruker AC-250 MHz instruments.

70

3.4.2 Preparation and physical properties of compounds
Aminomethyl-phosphonic acid diethyl ester (3.01)

H
2
N
PO
O
O

Prepared according to literaure.
15

1
H NMR (360MHz, CDCl
3
) δ 1.30-1.40(t,
J=7.1Hz, 6H), 1.56-1.67(bs, 2H), 2.98-3.07(d, J=10.1Hz, 2H), 4.07-4.22(m, 4H);
13
C NMR (126MHz, CDCl
3
) δ 16.05(d, J=5.5Hz), 37.38(d, J=149Hz), 61.51(d,
J=7.0Hz);
13
C NMR (126MHz, CDCl
3
) δ 16.03(d, J=5.1Hz), 37.37(d,
J=148.8Hz), 61.50(d, J=7.6Hz).

[(Diethoxy-phosphorylmethyl)-amino]-furan-2-yl-acetic acid (3.28)

O HN
O
OH
PO
O
O

Aminomethyl-phosphonic acid diethyl ester (3.28) (50mg, 0.3mmol), 2-furan
boronic acid (67mg, 0.6mmol), glyoxylic acid monohydrate (28mg, 0.3mmol)
was placed into a 10ml round bottom flask, dissolved with 5ml of acetonitrile.
The mixture was stirred at room temperature for one day. The solvent was
removed and the product was isolated by flash column chromatography using
NH
4
OH 5%, MeOH 20%, ethyl acetate 55%, dichloromethane 20% to afforded
71

compound 3.02 (60mg, clear oil, 67% yield).
1
H NMR (360MHz, CDCl
3
) δ
1.27(t, J=7.3Hz, 6H), 2.86-2.98(d, J=13.3Hz, 2H), 4.02-4.14(m, 4H), 4.49(s, 1H),
6.26-6.31(dd, J=3.2, 1.8Hz, 1H), 6.31-6.36(d, J=3.2Hz, 1H), 7.33-7.38(bs, 1H);
13
C NMR (126MHz, CDCl
3
) δ 16.30(d, J=6Hz), 41.51(d, J=156.5Hz), 60.81(d,
J=14.7Hz), 62.40(t, J=6.8Hz), 108.97, 110.27, 142.41, 151.19, 173.29.

2-Ethoxy-5-(4-methoxy-phenyl)-2-oxo-2 λ
5
-[1, 4, 2] oxazaphosphinan-6-one
(3.03)

POEt HN
O
O
O
O

Reaction was set up similarly to (3.28). After the mixture has been stirred at room
temperature for 36 hours, white solid precipitated. The solid was isolated by
filtration and washed with DCM. 55mg of compound 3.03 was obtained (55%
yield).
1
H NMR (250MHz, CD
3
OD) δ 1.20-1.35(t, J=7.0Hz, 3H), 2.90-3.03(dd,
J=3.8, 12.5Hz, 2H), 3.82(s, 3H), 3.85-4.05(m, 2H), 5.23(s, 1H), 6.98-7.07(d,
J=8.8Hz, 2H), 7.40-7.50(d, J=8.8Hz, 2H);
13
C NMR (63MHz, CDCl
3
) δ 17.05(d,
J=5.3Hz), 41.92(d, J=138.9Hz), 55.91, 61.87(d, J=5.8Hz), 64.28(d, J=5.0Hz),
115.80, 123.69, 131.55, 162.75, 170.52.

72

2-Ethoxy-2-oxo-5-phenyl-2 λ
5
-[1, 4, 2] oxazaphosphinan-6-one (3.26)

POEt HN
O
O
O

Prepared similarly to (3.28) (47% yield).
1
H NMR (360MHz, CDCl
3
) δ 1.17-
1.30(t, J=7.0Hz, 3H), 2.90-3.05(m, 1H), 3.83-4.00(m, 2H), 5.29(s, 1H), 7.40-
7.57(m, 5H).

({[(4-Methoxy-phenyl)-pyridin-2-yl-methyl]-amino}-methyl)-phosphonic acid
diethyl ester (3.34)

HN
P
O O
O
N
O

Prepared similarly to (3.28) (38% yield).
1
H NMR (500MHz, CDCl
3
) δ 1.30-
1.39(m, 6H), 2.93-3.00(d, J=13.3Hz, 2H), 3.76-3.81(s, 3H), 4.10-4.22(m, 4H),
4.95-4.99(s, 1H), 6.84-6.89(d, J=8.9Hz, 2H), 7.11-7.16(dd, J=4.8, 7.7Hz, 1H),
7.27-7.33(d, J=8.2Hz, 1H), 7.33-7.40(d, J=8.9Hz, 2H), 7.58-7.64(t, J=7.6Hz, 1H);
8.52-8.58(d, J=4.8Hz, 1H);
13
C NMR (126MHz, CDCl
3
) δ 16.44(d, J=5.9Hz),
73

43.00(d, J=155.1Hz), 55.30, 62.05(d, J=7.1Hz), 68.35(d, J=17.3Hz), 113.95,
121.62, 122.04, 128.91, 133.51, 136.60, 149.03, 159.00, 161.85.

{[(Pyridin-2-yl-thiophen-2-yl-methyl)-amino]-methyl}-phosphonic acid
diethyl ester (3.33)

S
HN
P
O O
O
N

Prepared similarly to (3.28) (30%yield).
1
H NMR (500MHz, CDCl
3
) δ 1.30-
1.42(td, J=7.0, 4.2Hz, 6H), 2.95-3.10(m, 2H), 4.12-4.25(m, 4H), 5.29(s, 1H),
6.93-6.97(dd, J=3.8, 5.2Hz, 1H), 6.98-7.02(d, J=3.6Hz, 1H), 7.16-7.22(dd, J=4.7,
7.5Hz, 1H), 7.23-7.27(d, J=5.0Hz, 1H), 7.33-7.40(d, J=8.2Hz, 1H), 7.62-7.72(t,
J=7.3Hz, 1H), 8.55-8.62(d, J=4.6Hz, 1H);
13
C NMR (126MHz, CDCl
3
) δ 16.49(d,
J=5.8Hz), 43.01(d, J=155.6Hz), 62.18(d, J=6.3Hz), 62.30(d, J=6.8Hz), 64.56(d,
J=17.2Hz), 121.87, 122.55, 125.73, 125.47, 126.58, 136.87, 145.66, 149.16,
160.70.

74

{[Benzyl-(furan-2-yl-pyridin-2-yl-methyl)-amino]-methyl}-phosphonic acid
diethyl ester (3.36)

O
N
P
O O
O
N
Ph

Prepared similarly to (3.28) (91% yield).
1
H NMR (360MHz, CDCl
3
) δ 1.21-
1.33(dt, J=4.2, 7.0Hz, 6H), 2.95-3.05(dd, J=7.1, 15.5Hz, 1H), 3.11-3.23(dd,
J=13.8, 15.7Hz, 1H), 3.71-3.80(d, J=13.3Hz, 1H), 3.98-4.12(m, 5H), 5.38(s, 1H),
6.35-6.39(dd, J=2.1, 3.5Hz, 1H), 6.39-6.42(d, J=3.5Hz, 1H), 7.13-7.19(m, 1H),
7.20-7.36(m, 3H), 7.40-7.46(m, 3H), 7.59-7.71(m, 2H), 8.53-8.59(d, J=4.8Hz,
1H);
13
C NMR (91MHz, CDCl
3
) δ 16.29(d, J=6.1Hz), 46.05(d, J=163.7Hz),
56.38(d, J=6.6Hz), 61.66(t, J=6.2Hz), 63.04(d, J=10.1Hz), 109.95, 110.52,
122.13, 123.42, 126.95, 128.13, 128.82, 136.25, 138.72, 142.26, 148.84, 152.07,
158.56.

75

{[(Furan-2-yl-pyridin-2-yl-methyl)-isobutyl-amino]-methyl}-phosphonic acid
diethyl ester (3.37)

O
N
P
O O
O
N

Prepared similarly to (3.28) (65% yield).
1
H NMR (360MHz, CDCl
3
) δ 0.83-
0.94(m, 6H), 1.27-1.36(m, 6H), 1.75-1.86(m, 1H), 2.40-2.60(m, 2H), 2.90-
3.13(m, 2H), 4.05-4.18(m, 4H), 5.44(s, 1H), 6.35-6.40(m, 2H), 7.16-7.22(m, 1H),
7.42-7.46(m, 1H), 7.65-7.74(m, 2H), 8.53-8.62(d, J=4.6Hz, 1H);
13
C NMR
(91MHz, CDCl
3
) δ 16.50(d, J=6.5Hz), 20.47(d, J=13.4Hz), 26.53, 47.42(d,
J=163.7Hz), 60.53, 61.69(d, J=7.7Hz), 61.74(d, J=7.7Hz), 64.45, 110.05, 110.41,
122.22, 123.76, 136.27, 142.24, 148.88, 152.52, 159.08.

[(Diethoxy-phosphorylmethyl)-isobutyl-amino]-furan-2-yl-acetic acid (3.30)

O
N
P
O O
O
O
OH

Prepared similarly to (3.28) (71% yield).
1
H NMR (360MHz, CDCl
3
) δ 0.80-
0.89(d, J=6.7Hz, 3H), 0.90-1.00(d, J=6.7Hz, 1H), 1.23-1.43(m, 6H), 1.67-1.88(m,
76

1H), 2.37-2.57(m, 2H), 2.84-3.24(m, 2H), 4.02-4.25(m, 4H), 4.88(s, 1H), 6.32-
6.39(m, 1H), 6.43-6.53(bs, 1H), 7.38-7.44(bs, 1H);
13
C NMR (91MHz, CDCl
3
) δ
16.32(d, J=5.9Hz), 16.35(d, J=5.9Hz), 20.16, 20.36, 26.37, 47.78(d, J=166.9Hz),
61.38, 62.36(d, J=7.1Hz), 62.56(d, J=7.1Hz), 62.92, 110.16, 111.01, 142.52.

(2S)-{1-[(Furan-2-yl-pyridin)-2-methyl)-amino]-ethyl}-phosphonic acid
diethyl ester (3.39)

P(OEt)
2
HN
O
O
N

Prepared similarly to (3.28) (92% yield, 60% de).
1
H NMR (major product)
(360MHz, CDCl
3
) δ 1.27-1.40(m, 9H), 2.90-3.02(m, 1H), 4.07-4.21(m, 4H),
5.35(s, 1H), 6.23-6.27(d, J=2.8Hz, 1H), 6.28-6.33(dd, J=2.7, 2.0Hz, 1H), 7.13-
7.21(m, 1H), 7.32-7.37(m, 1H), 7.38-7.44(d, J=7.7Hz, 1H), 7.60-7.70(t, J=7.7Hz,
1H), 8.53-8.59(d, J=4.7Hz, 1H);
13
C NMR (91MHz, CDCl
3
) δ 15.49, 16.4(d,
J=6.8Hz), 47.66(d, J=157.5Hz), 59.74, 62.02(d, J=6.9Hz), 62.10(d, J=7.1Hz),
107.50, 110.07, 122.04, 122.33, 136.54, 142.15, 148.97, 154.55, 159.33.

77

(2S)-[(1-Furan-2-yl-2,3-dihydroxy-propylamino)-methyl]-phosphonic acid
diethyl ester (3.41)

P(OEt)
2
HN
O
O
OH
OH

Prepared similarly to (3.28) (88% yield, one diasteromer observed).
1
H NMR
(500MHz, CDCl
3
) δ 1.28-1.38(m, 6H), 2.76-2.87(dd, J=11.9, 14.8Hz, 1H), 2.88-
2.99(dd, J=13.2, 15.1Hz, 1H), 3.62-3.77(m, 2H), 3.88-3.95(m, 2H), 4.05-4.20(m,
4H), 6.27-6.33(d, J=3.3Hz, 1H), 6.33-6.37(dd, J=2.0, 3.3Hz, 1H), 7.37-7.42(d,
J=2.1Hz, 1H);
13
C NMR (126MHz, CDCl
3
) δ 16.34, 42.05(d, J=160.1Hz),
60.05(d, J=15Hz), 62.23(d, J=6.8Hz), 62.38(d, J=6.8Hz), 64.04, 72.64, 108.59,
110.12, 142.21, 142.18, 152.53.

[[Benzyl-(1-furan-2-yl-2-hydroxy-ethyl)-amino]-(diethoxy-phosphoryl)-
methyl]-phosphonic acid diethyl ester (3.47)

O N
P
P
O
O
O
O
O
O
HO
Ph

Precedure similarly to (3.28) (89% yield).
1
H NMR (360MHz, CDCl
3
) δ 1.20-
1.45(m, 12H), 3.53-3.67(m, 1H), 3.90-4.15(m, 7H), 4.16-4.35(m, 5H), 4.40-
78

4.50(d, J=14.1Hz, 1H), 4.90-5.10(b, 1H), 6,12-6.22(b, 1H), 6.28-6.35(m, 1H),
7.22-7.40(m, 4H), 7.48-7.58(m, 2H).

{Benzyl-[bis-(diethoxy-phosphoryl)-methyl]-amino}-(4-methoxy-phenyl)-
acetic acid

Ph N P
P
O EtO
OEt
O
OEt
OEt
COOH
O

Prepared similarly to (3.28) (90% yield).
1
H NMR (360MHz, CDCl
3
) δ 1.15-
1.45(m, 12H), 3.65-3.85(m, 1H), 3.78(s, 3H), 3.80-4.15(m, 4H), 4.15-4.30(m,
5H), 4.33-4.43(d, J=13.7Hz, 1H), 5.10(s, 1H), 6.80-6.90(d, J=7.7Hz, 2H), 7.18-
7.50(m, 7H).

{Benzyl-[bis-(diethoxy-phosphoryl)-methyl]-amino}-furan-2-yl-acetic acid

Ph N P
P
O EtO
OEt
O
OEt
OEt
COOH
O

Prepared similarly to (3.28) (53% yield).
1
H NMR (360MHz, CDCl
3
) δ 1.18-
1.38(m, 12H), 3.55-3.83(m, 1H), 3.87-4.25(m, 9H), 4.31-4.40(d, J=13.2Hz, 1H),
79

5.24(s, 1H), 6.36-6.43(dd, J=2.2, 3.0Hz, 1H), 6.55-6.60(d, J=2.3Hz, 1H), 7.23-
7.46(m, 6H).

80

3.5 Chapter 3 References
1
(a)

Bartlett, P. A. et al. Chem. Rev. 1997, 97, 1281. (b) Powers, J. C.; Asgian, J.
L.; Ekici, O. D.; James, K. E. Chem. Rev. 2002, 102, 4639. (c) Bartelett, P. A. J.
Am. Chem. Soc. 1998, 120, 4610.

2
Henderson, B.; Docherty, A. J. P.; Beely, N. R. A. Design of Inhibitors of
Articular Cartilge Destruction, Drugs of The Future 1990, 15, 495.

3
Bird, J. et al. J. Med. Chem. 1994, 37, 158.
4
(a) Gary, G. A.; Webb, D. J. Pharmacol. Ther. 1996, 72, 109. (b) Patel, T. CNS
Drugs 1996, 5, 293.

5
Rabelink, T. J. et al. Kidney Int. 1996, 50, 1827.
6
Hay, D. W. P. et al. Am. J. Respir. Crit. Care Med. 1996, 154, 1594.
7
(a) Lombaert, S. De. Et al. Bioorg. Med. Chem. Lett. 1997, 7, 1059. (b)
Lombaert, S. De. Et al. Bioorg. Med. Chem. Lett. 1995, 5, 151.

8
(a) Lombaert, S. De. Et al. J. Med. Chem. 2000, 43, 488. (b) Wallace, E. M. et
al. . J. Med. Chem. 1998, 41, 1513.

9
(a) Van Beek, E. et al. Biochem. Biophys. Res. Commum. 1999, 264, 108. (b)
Keller, R. K. Fliesler, S. J. Biochem. Biophys. Res. Commum. 1999, 266, 560.

10
Roden, G. A.; Martin, T. J. Science 2000, 289, 1508.
11
(a) Martin, M. B. et al. J. Med. Chem. 2002, 45, 2904. (b) Szabo, C. M. et al. J.
Med. Chem. 2002, 45, 2894. (c) Martin, M. B. et al. J. Med. Chem. 2001, 44, 909.

12
Ranu, B. C. et al. Org. Lett. 1999, 1, 1141.
13
Smith, A. B. III, et al. J. Am. Chem. Soc. 1995, 117, 10879.
14
Kantoci, D. et al. Syn. Comm. 1996, 2037.
15
Davidsen, S. K. et al. Organic Syntheses CV8, 451

81

CHAPTER 4
The Synthesis of Heterocyclic Compounds Starting from
The Boronic Acid Three-component Reactions: A
practice for Diversity Oriented Synthesis

82

4.1 Introduction
4.1.1 Tetrahydroisoquinolines
The tetrahydroisoquinoline structure is present in large group of the
alkaloids, found in different plants around the world. Shamma et al listed 99
natural or synthetic structures of this type.
1
In Shulgin’s paper there are over 150
compounds from plants listed,
2
whose structures display a wide range of structural
diversity and can be found in numerous natural products.
3
For this reason, there is
a great interest in the synthesis of tetrahydroisoquinolines.

N
O
O
4.1
Carnegine
NH
O
4.2
Longimammatine
NH
HO
O
Isocoryplalline
4.3
O
O
N
4.4
Hydrohydrastinine
NH
O
O
(+)-Salsolidine
4.5
NH
O
O
OH
(+)-Calycotomine
4.6
Examples of natural tetrahydroisoquinolines

Scheme 4.1
The tetrahydroisoquinoline structure can also be found in many
bioactive compounds. A series of such compounds (4.7) were explored by Bristol-
Myers-Squibb as potent and selective antagonists for MT
2
receptor, which is one
of the two melatonin (N-acetyl-5-methoxytryptamine) G-protein coupled
83

receptors. This study provided a useful pharmacological tool to further investigate
the treatment of sleep and chronobiotic disorders.
4
Also, alkaloids (4.8), (4.9)
were found in the aquatic crop nelumbo nucifera which is consumed throughout
Asia. These compounds were found to display significant anti-HIV activity
4
.
N
CH
2
R
1
R
2
R
3
R
4
O
Ph Ph
4.7
R
1
, R
2
, R
3
, R
4
=H, OMe, Br.
N
R
H
O
HO
OH
R=H, Me
4.8
NH
H
HO
HO
OH
4.9

Scheme 4.2

4.1.2 Synthesis of Tetrahydroisoquinolines by Cyclization
There are numerous published approaches of tetrahydroisoquinoline. The
synthesis of tetrahydroisoquinoloines includes elaboration of established ring
systems, such as reduction of isoquinolines and their benzopyrylium precursors,
alkylation of hydroisoquinoline derivatives, and construction of the fused ring
system by cyclization.
For the synthesis of tetrahydroquinolines by cyclization, one of the most
widely used reactions is the Pictet-Spengler reaction.
5
A modification of the
Pictet-Spengler reaction called “activated Pictet-Spengler”
6
is carried out using
phenylethylamines with electron withdrawing groups such as amides, carbamates
84

and sulfonamides. The more reactive N-acyliminium or N-sulfonyliminium ion is
generated during this process.
For example, the N-formyl phenethylamine (4.10) reacts with aldehyde
under acidic conditions to give carnegine (4.12), one of the natural occurring
tetrahydroisoquinolines,
7
via N-formyliminium ion (4.11) formed in situ (Scheme
4.3).
O
O
H
N
CHO
O
O
N
CHO
O
O
N
CHO
MeCHO
AcOH/TFA(8:1)
4.10 4.11 4.12

Scheme 4.3
Another interesting and efficient variation of the activated Pictet-Spengler
reaction involving use of chiral sulfinyl groups, is described by Koomen at el.
8

The sulfinylamine (4.15) was prepared from (S)-Anderson’s reagent (4.14) and
amine (4.13), which was then reacted with aldehydes under BF
3
etherate
activation. The product of cyclization was treated with acid to give the final
compound (4.16) with ee>98% (Scheme 4.4). It is noteworthy that the sulfinyl
goup works as both activator and chiral auxiliary in this method.
85

O
O
NH
2
S
O
BuLi, THF
O
O
HN
S
O
1. RCHO, BF
3
. Et
2
O
2. HCl, EtOH
4.13
O
O
NH
R
4.15
4.14
4.16

Scheme 4.4
Bobbit reported a preparation of salsolidine (4.20) via modified
Pomerantz-Fritsch isoquinolone synthesis.
9
As shown in Scheme 4.5, substrate
(4.17) was treated with Grignard reagent after its condensation with aminoacetal
to give (4.18). The cyclization then proceeded in the presence of HCl

O
OCHO
NH
2
OEt
EtO
MeMgBr
Et
2
O
O
O
NH
OEt
OEt
O
O
NH
OH
5% Pd/C
O
O
NH
4.17 4.18
4.19 4.20
4N HCl

Scheme 4.5
86

In Scheme 4.6, the amide (4.21) was cyclized by the Bischler-Napieralski
reaction to form isoquinolinium salt (4.22), which was then treated with NaBH
4
to
give compound (4.23) in high diastereoselectivity (up to 96% de). The final
product (4.24) was produced after deprotection.

4.21
O
O
N
N
O
R
O
O
N
N
R
O
O
N
N
R
O
O
NH
1. BF
3.
THF
2. HCl
Hydride, solvent
POCl
3,
PhH
4.22
4.23
4.24

Scheme 4.6
N, N-dibenzyl -1,2-aminols (4.25) were transferred into
tetrahydroisoquinolines (4.26) at the presence of Lewis’ acids such as AlCl
3
. This
Friedel-Crafts type cyclization resulted in one diastereomer (Scheme 4.7).
11
Other
Lewis’ acids have been tried such as H
2
SO
4
,
12
polyphosphoric acid
13
beside
AlCl
3.
11, 14
But in all of the reported examples, the R
/
group is aryl substituted,
which suggests that the cations formed in this process should be stabilized by the
substituted aryl goup (scheme 4.7).

87

N
OH
Ph
R
R'
N
R'
R
Ph AlCl
3
, DCM, RT
R=alkyl, aryl
R'=aryl
4.25 4.26

Scheme 4.7

4.2 Results and Discussion
One key advantage of the Petasis three-component reaction is its ability of
assembling more functional groups into the product in one step. As a result, this
process is ideal for further intramolecular reactions including cyclization
reactions.
Chandrasekhar’s group reported that N, N-dibenzylaminols (4.27)
reacted with tosyl chloride to give tetrahydroisoquinolines (4.28). They proposed
that tosylation of the alcohol followed by nucleophilic attack of the aryl group
completes the cyclization.
15
Gmeiner reported that the reaction actually went
through an aziridinium mechanism and formed β-chloro amines (4.29) instead of
tetrahydroisoquinolines (Scheme 4.8).
16

N
HO
R
N
R
N
Cl
R
4.27 4.29 4.28
TsCl TsCl

88

Scheme 4.8
We envisioned the possibility of performing such cyclizations by better
activating reagent than TsCl. The triflates are about 40,000 times more reactive
than tosylates as leaving groups,
17
and much less reactive for nucleophilic attack
than chlorine ions. Therefore we explored the use of trifluoromethanesulfonic
anhydride as a better choice for the cyclization of N-benyl aminols, which is
easily prepared in one step by the three-component reaction of boronic acids,
benzylamines and glycol aldehyde.
18
Thus, we found that the cyclization proceeds
smoothly when using trifluoromethanesulfonic anhydride as cyclization reagent in
the presence of excess 2,6-lutidine (Scheme 4.9). It appeared that the use of
excess trifluoromethanesulfonic anhydride made the reaction more complete. A
total yield of 81% was achieved.
S
B
OH
OH
O
OOH
HO
N
H
Ph
O
O
S N
Ph
HO
O
O
S N
Ph
O
O
EtOH,
reflux
4.30 4.31
Tf
2
O,
2,6-lutidine,
DCM, -78
o
C
Tf
2
O 1eq, 1.2eq. 2eq.
2, 6-lutidine 2eq. 2eq. 3eq.
yield 52% 73% 85%
95% yield

Scheme 4.9
More examples are shown in Scheme 4.10. Five-membered ring (4.43) can
also be prepared by this procedure as well as six-membr rings. Heteroaryl groups
such as furan worked as nucleophile in cyclization and resulted in good yields
89

(4.45), (4.47). In comparison to previous methods, this process is experimentally
easier, shorter (only 2 steps), and gives more diversified products.
O N
O
O
O N
O
O
HO
O
B
OH
OH O
OOH
HO
N
H
Ph
O
O
4.32 4.33
98%
90%
S N
O
N
O
Ph
4.35
4.37
S
B
OH
OH O
OOH
HO
N
H
Ph
S N
O
4.34
HO
O
N
O
Ph
4.36
HO
B
OH
OH O
OOH
HO
N
H
Ph
O
Ph
89%
97%
96%
41%
O N
O
O
4.41
N
O
O
O
4.39
N
O
O
O
4.38
HO
B
OH
OH
O
OOH
HO
N
H
Ph
O
O
O
O
O
4.40
N
OH
O
O
B
OH
OH
N
H
Ph
O
O
O
OH
56%
88%
96%
56%

90

N
Ph
O
O
O
4.43
N
Ph
O
O
O
4.42
OH
B
OH
OH
O
OOH
HO
N
H
Ph
O
O
O
86% 52%

Scheme 4.10

4.3 Cycloaddition Reactions Based on Three-component Reaction
Products
α-Amino aldehydes are very useful building blocks in organic synthesis.
The α-amino aldehydes with N-allyl groups have proven to be excellent
precursors for cycloaddtions. One example is the reactions reported by Bartlett’s
group
19, 20
shown in (Scheme 4.11).

N
H
Ph
1. Acetoxyacetic acid,
EDC
2. K
2
CO
3
3. Swern
NPh
O
O
Ph
4.43 4.44
R
NH
2
H
N
N
O
Ph
R
TFA or Yb(OTf)
3
Ph
4.45
Ph

Scheme 4.11
Based on our three-component process, we developed a novel approach to
heterocyclic compounds, by employing amino diols derived via boronic acid
three-component reaction. As shown in scheme 4.12, boronic acid reacted with
glyceraldehydes and amine (4.43) to give the corresponding amino diol (4.46),
18
91

which is readily converted to amino aldehyde (4.47) by sodium periodate
dispersed on silica gel.
21
This amino aldehyde is now ready to participate in a
number of cycloaddition reactions.
O
N
OH
OH
B
OH
OH
O
O
OH
OH
N
H
Ph
4.43
Ph
O
N
O
EtOH,
reflux
NaIO
4,
silca gel
4.46 4.47

Scheme 4.12
Scheme 4.13 shows some results of cycloaddition from amino aldehyde
(4.47). It seems that better conversion from amino diol (4.46) to amino aldehyde
(4.47) is achieved at lower temperature and with excess oxidant. The use of
Yb(OTf)
3
results in better yield comparing to TFA. Both the (4+2)-cycloaddition
(4.48) (4.49) and the 1,3-dipolar cycloaddition (4.50) reactions proceeded with
good yields.
These results show that starting from products of boronic acid three-
component reaction, the approaches to heterocyclic compounds via cycloaddition
processes are more concise and can provide more diversified products.
92

4.47
4.47
4.47
N
H
N
Ph
Ph
O
N
H
N
Ph
Ph
O
Br
O
N
N
O
N
H
OH
HCl
TEA, 0
o
C-RT
95% yield
NH
2
Br
0
o
C-RT
TFA: 82% yield
Yb(OTf)
3
91%
NaIO
4
1.5eq.
NaIO
4
1.3eq.
NH
2
TFA, 0
o
C-RT
41% yield
4.48
4.49
4.50
NaIO
4
1.5eq.
4.46
4.46
4.46
RT
0
o
C
0
o
C

Scheme 4.13
.
4.4 Conclusion
Several processes to prepare heterocyclic compounds were investigated.
Employing our unique boronic acid three-component methodology, the new
approaches to heterocycle compounds by Friedel-Crafts type cyclization, (4+2)
cycloadditions and (3+2) cycloadditions lead to more convenient routes to give
more diversified products.

93

4.5 Experimentals
4.5.1 General
All starting materials, unless otherwise noted, were purchased from
commercial suppliers and used without further purification. Thin layer
chromatography was performed on pre-coated TLC plates (Silica gel 60 F
254
).
Silica gel 60 (particle size 0.040-0.063 mm, 230-400 mesh) was used in flash
column chromatography. NMR spectra were recorded on a Bruker AMX-500
MHz, a Bruker AM-360 MHz and a Bruker AC-250 MHz instruments.

94

4.5.2 Preparation and Physical Properties of Compounds
2-[Benzyl- (3,4-dimethoxy-benzyl)-amino]-2-thiophen-2-yl-ethanol (4.30)

S N
HO
O
O

Benzyl-(3,4-dimethoxy-benzyl)-amine(1mmol, 257mg), glycoaldehyde dimmer
(0.5mmol, 60mg), 2-thiopheneboronic acid (1mmol, 128mg) was added into 5ml
of ethanol, and stirred at room temperature for 2 days. The mixture was then
concentrated, the product was isolated by flash column

chromatography with 20%
ethyl acetate in hexanes to give compound (4.30) (365mg, oil, 95% yield).
1
H
NMR (360MHz, CDCl
3
) δ 3.20-3.30(t, J=13.2Hz, 2H), 3.62-3.72(m, 1H), 3.81-
3.93(m, 2H), 3.86(s, 3H), 3.88(s, 3H), 3.97-4.51(t, J=10.3Hz, 1H), 4.17-4.25(dd,
J=10.2, 5.6Hz, 1H), 6.80-6.92(m, 3H), 6.94-6.97(d, J=3.5Hz, 1H), 7.06-7.12(dd,
J=3.4, 4.6Hz, 1H), 7.20-7.40(m, 6H);
13
C NMR (126MHz, CDCl
3
) δ 53.32, 53.52,
55.73, 58.14, 61.15, 110.97, 111.92, 121.07, 124.76, 126.33, 126.65, 127.21,
128.44, 128.93, 131.20, 137.56, 138.85, 148.14, 148.97.

95

2-[Benzyl-(3, 4-dimethoxy-benzyl)-amino]-2-furan-2-eyl-thanol (4.32)

O N
HO
O
O

Prepared similarly to (4.30) (98% yield).
1
H NMR (500MHz, CDCl
3
) δ 3.18-
3.28(t, J=13.3Hz, 2H), 3.57-3.67(dd, J=4.5, 10.1Hz, 1H), 3.80-3.84(s, 3H), 3.84-
3.86(s, 3H), 3.86-4.02(m, 4H), 6.18-6.23(d, J=3.4Hz, 1H), 6.36-6.42(dd, J=3.4,
2.1Hz, 1H), 6.75-6.91(m, 3H), 7.20-7.36(m, 5H), 7.44-7.48(d, J=2.1Hz, 1H);
13
C
NMR (126MHz, CDCl
3
) δ 53.32, 53.51, 55.70, 55.75, 58.14, 61.14, 110.97,
111.91, 121.06, 124.76, 126.33, 126.65, 127.20, 128.44, 128.93, 131.19, 137.56,
138.85, 148.13, 148.96.

2-(Benzyl-furan-2-ylmethyl-amino)-2-thiophen-2-yl-ethanol (4.34)

S N
HO
O

Prepared similarly to (4.30) (89% yield). H NMR (500MHz, CDCl
3
) δ 3.10-
3.18(d, J=8.4Hz, 1H), 3.20-3.28(d, J=13.4Hz, 1H), 3.33-3.43(d, J=14.1Hz, 1H),
96

3.58-3.70(m, 1H), 3.75-3.83(d, J=13.4Hz, 1H), 3.84-3.93(d, J=14.0Hz, 1H), 3.93-
4.03(t, J=10.3Hz, 1H), 4.15-4.25(dd, J=10.3, 5.4Hz, 1H), 6.87-6.95(d, J=3.7Hz,
1H), 7.02-7.09(m, 2H), 7.10-7.17(s, 1H), 7.20-7.37(m, 7H);
13
C NMR (126MHz,
CDCl
3
) δ 48.38, 53.37, 57.96, 60.99, 122.64, 124.61, 125.90, 126.13, 125.46,
126.98, 127.63, 128.24, 128.61, 137.45, 138.56, 139.53.

2-[Benzyl- (3,4-dimethoxy-benzyl)-2-amino]-2-(4-methoxy-phenyl)-ethanol
(4.38)

N
HO
O
O
O

Prepared similarly to (4.30)(56% yield).
1
H NMR (500MHz, CDCl
3
) δ 2.95-
3.10(m, 2H), 3.44-3.54(dd, J=10.6, 5.2Hz, 1H), 3.71-3.86(m, 12H), 3.96-4.04(t,
J=10.6Hz, 1H), 6.71-6.81(m, 3H), 6.83-6.90(d, J=9Hz, 2H), 7.02-7.13(d, J=9Hz,
2H), 7.13-7.19(m, 1H), 7.20-7.33(m, 4H);
13
C NMR (126MHz, CDCl
3
) δ 53.03,
53.30, 55.08, 55.11, 55.73, 60.41, 62.24, 110.92, 111.80, 113.57, 120.93, 127.01,
127.08, 128.40, 128.82, 130.19, 131.55, 139.19, 148.04, 148.94, 159.13.

97

2-(Benzyl-furan-2-ylmethyl-amino)-4-phenyl-but-3-en-1-ol (4.36)

N
HO
O

Prepared similarly to (4.30). The product was isolated by flash column

chromatography with 15% ethyl acetate in hexanes (97% yield)
1
H NMR
(360MHz, CDCl
3
) δ 3.10-3.25(bs, 1H), 3.34-3.46(d, J=13.4Hz, 1H), 3.46-3.64(m,
3H), 3.64-3.73(d, J=11.7hz, 1H), 3.78-3.89(d, J=11.7Hz, 1H), 3.89-4.02(d,
J=13.2Hz, 1H), 6.08-6.26(dd, J=8.2, 15.7hz, 1H), 6.44-6.60(d, J=15.7Hz, 1H),
7.01-7.08(dd, J=1.2, 5.0Hz, 1H), 7.09-7.15(bs, 1H), 7.18-7.58(m, 11H).

2-[Benzyl-(3,4-dimethoxy-benzyl)-amino]-2-furan-2-yl-1-phenyl-ethanol
(4.40)

O
N
HO
Ph
O
O

Prepared similarly to (4.30). The product was isolated by flash column

chromatography with 10% ethyl acetate in hexanes (88% yield)
1
H NMR
(360MHz, CDCl
3
) δ 3.00-3.11(t, J=12.9Hz, 2H), 3.65(s, 3H), 3.67-3.75(d,
98

J=13.9Hz, 1H), 3.81(s. 3H), 3.78-3.92(t, J=13.7Hz, 2H), 4.00-4.07(d, J=9.6Hz,
1H), 5.19-5.27(d, J=9.6Hz, 1H), 6.35-6.39(d, J=3.4Hz, 1H), 6.44-6.49(m, 2H),
6.57-6.63(d, J=7.8Hz, 1H), 6.66-6.72(d, J=7.8Hz, 1H), 6.88-6.98(m, 2H), 7.10-
7.22(m, 5H), 7.27-7.38(m, 3H), 7.53-7.55(d, J=2.2Hz, 1H);
13
C NMR (90.6MHz,
CDCl
3
) δ 54.44, 54.70, 55.54, 55.75, 61.52, 73.63, 109.99, 110.29, 110.31,
111.36, 120.69, 126.77, 127.77, 127.85, 127.92, 128.05, 128.86, 131.74, 139.02,
141.72, 142.34, 147.76, 148.67, 151.80.

2-[isobutyl-(3, 4, 5-trimethoxy-phenyl)-amino]-4-phenyl-but-3-en-1-ol (4.42)

N
OH
O
O
O

Prepared similarly to (4.30). (86% yield).
1
H NMR (500MHz, CDCl
3
) δ 0.90-
0.93(d, J=1.8Hz, 3H), 0.93-0.96(d, J=1.8Hz, 3H), 1.75-1.93(m, 1H), 2.65-
2.75(dd, J=8.8, 13.5Hz, 1H), 2.75-2.85(bs, 1H), 2.95-3.05(dd, J=4.9, 13.5Hz, 1H),
3.67-3.85(m, 2H), 3.81(s, 6H), 3.83(s, 3H), 4.02-4.15(m, 1H), 6.08-6.17(dd,
J=7.3, 16.1Hz, 1H), 6.30(s, 2H), 6.38-6.48(d, J=16.1Hz, 1H), 7.17-7.37(m, 5H);
13
C NMR (90.6MHz, CDCl
3
) δ 20.68, 20.84, 25.96, 54.99, 56.00, 60.88, 61.90,
68.19, 99.51, 124.94, 126.25, 127.79, 128.56, 133.24, 133.30, 136.45, 145.66,
153.19.
99

2-Benzyl-6, 7-dimethoxy-3-thiophen-2-yl-1, 2, 3, 4, -tetrahydro-isoquinoline
(4.31)

S N
O
O

76mg (0.2mmol) of (4.30) in a 10ml round bottom flask was dissolved in 3ml dry
dichloromethane. At cooling to –78
o
C, under nitrogen, 2,6-lutidine (0.071ml,
3eq.) and trifluoromethanesulfonic anhydride (0.068ml, 2eq.) was added, and the
mixture was stirred at –78
o
C for 30 min. and then it was allowed to warm up to
room temperature. The mixture was then treated with 1N HCl then neutralized
with saturated sodium bicarbonate solution, and extracted with dichloromethane
twice (20mlX2). The organic phase was dried with MgSO
4
, and after the volatiles
were removed, product was isolated by flash column chromatography with 1%
triethylamine, 12% ethyl acetate in hexanes and to give compound (4.31) (62mg,
clear oil, 85% yield).
1
H NMR (500MHz, CDCl
3
) δ 2.85-2.93(dd, J=6.4, 11.2Hz,
1H), 3.00-3.08(dd, J=4.8, 11.3Hz, 1H), 3.50-3.58(d, J=14.8hz, 1H), 3.65-3.79(m,
6H), 3.80-3.85(s, 3H), 4.42-4.47(t, J=5.2Hz, 1H), 6.51(s, 1H), 6.58(s, 1H), 6.92-
6.97(m, 2H), 7.16-7.21(d, J=4.7Hz, 1H), 7.24-7.45(m, 5H).
13
C NMR (90.6MHz,
CDCl
3
) δ 40.74, 55.55, 55.82, 55.92, 59.19, 62.70, 108.92, 111.77, 124.34,
100

124.81, 126.01, 126.67, 127.13, 128.29, 128.99, 129.06, 138.25, 147.57, 147.71,
148.85.

2-Benzyl-3-furan-2-yl-6, 7-dimethoxy-1, 2, 3, 4-tetrahydro-isoquinoline (4.33)

O N
O
O

Prepared similarly to (4.31). (90% yield).
1
H NMR (360MHz, CDCl
3
) δ 2.90-
2.97(d, J=5.7Hz, 2H), 3.57-3.73(m, 4H), 3.75(s, 3H), 3.81(s, 3H), 4.20-4.26(t,
J=5.8Hz, 1H), 5.99-6.02(d, J=2.9Hz, 1H), 6.28-6.31(dd, J=1.9, 2.9hz, 1H), 6.53(s,
1H), 6.60(s, 1H), 7.10-7.33(m, 6H);
13
C NMR (90.6MHz, CDCl
3
) δ 38.69, 55.38,
55.76, 55.80, 55.83, 62.22, 106.66, 109.10, 110.06, 111.45, 126.42, 127.00,
127.15, 128.20, 128.78, 138.16, 141.09, 147.69, 147.49, 157.37.

101

6-Benzyl-5-thiophen-2-yl-4, 5, 6, 7-tetrahydro-furo[2,3-c]pyridine (4.35)

S N
O

Prepared similarly to (4.31) (96% yield).
1
H NMR (500MHz, CDCl
3
) δ 2.81-
2.90(dd, J=7.0, 11.4Hz, 1H), 3.12-3.20(dd, J=5.0, 11.4Hz, 1H), 3.60(s, 2H), 3.67-
3.74(d, J=13.2Hz, 1H), 3.74-3.82(d, J=13.2Hz, 1H), 4.56-4.63(t, J=6.2Hz, 1H),
6.66-6.75(d, J=5.1Hz, 1H), 6.90-6.94(dd, J=5.1, 3.6Hz, 1H), 6.94-7.00(d,
J=3.6Hz, 1H), 7.06-7.13(d, J=5.2Hz, 1H), 7.14-7.19(d, J=5.2Hz, 1H), 7.20-
7.44(m, 5H); NMR (126MHz, CDCl
3
) δ 38.48, 52.84, 59.32, 62.04, 123.95,
124.22, 124.79, 124.88, 126.14, 127.14, 128.28, 128.95, 134.46, 137.76, 138.14,
147.10.

6-Benzyl-5-styryl-4, 5, 6, 7-tetrahydro-furo[2, 3-c]pyridine (4.37)

N
O

Prepared similarly to (4.31) (41% yield).
1
H NMR (360MHz, CDCl
3
) δ 2.52-
2.64(dd, J=8.2, 11.4Hz, 1H), 3.00-3.10(dd, J=4.9, 11.4Hz, 1H), 3.44-3.56(d,
102

J=14.9Hz, 1H), 3.62-3.78(d, J=14.7Hz, 1H), 3.73(s, 2H), 3.80-3.90(m, 1H), 6.20-
6.31(dd, J= 8.8, 16.1Hz, 1H), 6.51-6.62(d, J=15.9Hz, 1H), 6.71-6.77(d, J=4.8Hz,
1H), 7.10-7.15(d, J=4.8Hz, 1H), 7.15-7.46(m, 10H);
13
C NMR (90.6MHz, CDCl
3
)
δ 40.92, 53.00, 56.77, 62.03, 123.76, 125.31, 126.33, 127.20, 127.37, 128.30,
128.49, 129.03, 131.17, 134.05, 137.01, 137.37, 138.24.

2-Benzyl-6, 7-dimethoxy-3-(4-methoxy-phenyl)-1, 2, 3, 4-tetrahydro-
isoquinoline (4.39)

N
O
O
O

Prepared similarly to (4.31). (96% yield).
1
H NMR (500MHz, CDCl
3
) δ 2.56-
2.65(dd, J=11.4, 7.4Hz, 1H), 2.99-3.06(dd, J=11.4, 5.4Hz, 1H), 3.58-3.72(m, 7H),
3.80(s, 3H), 3.83(s, 3H), 4.08-4.18(t, J=6.3Hz, 1H), 6.38(s, 1H), 6.53(s, 1H),
6.80-6.88(d, J=8.8Hz, 2H), 7.07-7.15(d, J=8.8Hz, 2H), 7.20-7.35(m, 5H);
13
C
NMR (90.6MHz, CDCl
3
) δ 44.58, 55.16, 55.72, 55.76, 55.94, 59.68, 62.43,
108.75, 111.87, 113.45, 126.94, 127.34, 128.16, 128.84, 129.52, 129.89, 137.04,
138.20, 147.33, 147.45, 158.05

103

2-Benzyl-3-furan-2-yl-6, 7-dimethoxy-4-phenyl-1, 2, 3, 4-tetrahydro-
isoquinoline (4.41)

O N
O
O

Prepared similarly to (4.31). (56% yield).
1
H NMR (360MHz, CDCl
3
) δ 3.17-
3.24(d, J=14.0Hz, 1H), 3.55-3.64(d, J=15.3Hz, 1H), 3.66-3.73(d, J=15.3Hz, 1H),
3.74(s, 3H), 3.75-3.81(d, J=14.0Hz, 1H), 3.82(s, 3H), 4.03-4.08(d, J=6.7Hz, 1H),
4.35-4.40(d, J=6.5Hz, 1H), 5.82-5.85(d, J=3.0Hz, 1H), 6.21-6.25(dd, J=3.0,
1.9Hz, 1H), 6.49(s, 1H), 6.52(s, 1H), 7.12-7.35(m, 11H);
13
C NMR (90.6MHz,
CDCl
3
) δ 46.33, 53.10, 55.75, 55.85, 59.19, 67.74, 107.85, 108.76, 109.92,
111.19, 126.45, 126.83, 126.90, 127.35, 128.23, 128.29, 128.54, 139.07, 139.46,
140.21, 140.78, 141.19, 147.65, 156.53.

104

1-Isobutyl-4, 5, 6-trimethoxy-2-styryl-2, 3-dihydro-1H-indole (4.43)

N
O
O
O

Prepared similarly to (4.31). (52% yield).
1
H NMR (360MHz, CDCl
3
) δ 0.37-
0.45(d, J=6.8Hz, 3H), 0.46-0.52(d, J=6.8Hz, 3H), 1.45-1.60(m, 1H), 2.43-
2.53(dd, J=6.9, 12.2Hz, 1H), 2.62-2.71(dd, J=6.9, 12.2Hz, 1H), 3.18-3.29(d,
J=18Hz, 1H), 3.53-3.63(d, J=20Hz, 1H), 3.88(s, 3H), 3.90(s, 3H), 3.92(s, 3H),
5.15-5.22(d, J=8.7Hz, 1H), 5.70-5.80(d, J=11.2Hz, 1H), 6.13-6.25(dd, J=8.6,
11.1Hz, 1H), 6.41(s, 1H), 7.05-7.13(m, 1H), 7.15-7.31(m, 4H);
13
C NMR
(91MHz, CDCl
3
) δ 20.17, 20.75, 26.21, 39.00, 55.17, 55.94, 60.90, 61.35, 62.88,
100.22, 125.01, 126.66, 127.28, 127.65, 128.29, 129.61, 138.06, 144.85, 147.24,
150.96, 151.69.

105

3-[Benzyl-(3-phenyl-allyl)-amino]3-(4-methoxy-phenyl)-propane-1,2dio(4.46)

O
N
OH
OH

Prepared similarly to (4.30). (64% yield).
1
H NMR (360MHz, CDCl
3
) δ 2.73-
2.83(dd, J=14.5, 8.9Hz, 1H), 3.02-3.09(d, J=13.2Hz, 1H), 3.45-3.56(dd, J=4.4,
14.3Hz, 1H), 3.77-3.81(d, J=4.4Hz, 2H), 3.81-3.85(s, 3H), 3.88-3.95(d, J=13.8Hz,
2H), 4.24-4.38(m, 1H), 6.13-6.25(m, 1H), 6.45-6.54(d, J=16.9Hz, 1H), 6.94-
7.00(d, J=9.1Hz, 2H), 7.15-7.40(m, 12H);
13
C NMR (90MHz, CDCl
3
) δ 52.74,
54.68, 55.18, 66.35, 66.47, 68.95, 113.84, 125.64, 126.24, 127.06, 127.23, 127.52,
128.49, 128.52, 128.87, 130.93, 133.36, 136.67, 138.74, 159.25.

106

2-Benzyl-3-(4-methoxy-phenyl)-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-
pyrrolo[3,4-b]quinoline (4.48)

N
HN
O

Sodium periodate (NaIO
4
) 27 mg (1.3 eq.) was dissolved in water (0.2 ml), and
the solution was added into a mixture of silica gel 60 (0.4 g) and dichloromethane
(1.6 ml), the mixture turned into a flaky suspension. The starting material (4.46)
was dissolved in 0.2 ml dichloromethane and was added into the above mixture,
while stirring. After 10 minutes, the reaction was completed as monitored by TLC
(40% ethyl acetate/hexanes). The mixture was then filtered. Aniline (0.008ml,
1eq.) and sodium sulfate were added to the solution, and after 30 minutes TFA
(1ml) was added to the solution. The mixture was stirred at room temperature for
1 hour. Sodium bicarbonate was then added. The mixture was extract with
dichloromethane, and dried the over sodium sulfate. After the volatiles were
removed, the product was separated by prep. TLC (30% ethyl acetate/hexanes)
(41% yield).
1
H NMR (360MHz, CDCl
3
) δ 2.54-2.62(t, J=9.6Hz, 1H), 2.62-
2.77(m, 1H), 2.99-3.07(t, J=9.6Hz, 1H), 3.31-3.38(d, J=13.8Hz, 1H), 3.38-
3.47(dd, J=10.4, 8.7Hz, 1H), 3.66-3.72(d, J=8.9Hz, 1H), 3.80-3.87(d, J=13.8Hz,
1H), 3.84(s, 3H), 3.99-4.06(d, J=11.5Hz, 1H), 6.53-6.63(m, 3H), 6.93-7.02(m,
107

3H), 7.10-7.16(m, 2H), 7.16-7.32(m, 8H), 7.48-7.54(d, J=8.2Hz, 2H);
13
C NMR
(90MHz, CDCl
3
) δ 47.43, 49.89, 54.18, 55.31, 57.72, 64.41, 73.23, 114.18,
115.97, 118.87, 126.59, 126.61, 126.95, 127.17, 128.13, 128.15, 128.54, 128.62,
128.73, 130.43, 132.47, 139.95, 144.19, 145.54, 159.44.

2-Benzyl-7-bromo-3-(4-methoxy-phenyl)-9-phenyl-2,3,3a,4,9,9a-hexahydro-
1H-pyrrolo[3,4-b]quinoline (4.49)

N
HN
O
Br

Procedure A is similar to (4.48) with a small change: 1.5 eq. of NaIO
4
was used.
The oxidation, imine formation and cyclization step were performed at 0
o
C.
(82% yield). Procedure B: The oxidation and imine formation were the same as
procedure A. After the imine formed, the solvent was removed and the mixture
was dissolved in CH
3
CN (1ml), and Yb(OTf)
3
(6mg, 0.1eq.) was added at 0
o
C.
The mixture then was stirred overnight from 0
o
C to r.t.. After solvent was
removed, the residue was dissolved in DCM and washed with water. The solvent
was dried over sodium sulfate, the solvent was evaporated and the product was
separated by prep. TLC (30% ethyl acetate/hexanes) to give (4.49) in 91% yield.
1
H NMR (360MHz, CDCl
3
) δ 2.50-2.58(t, J=9.5Hz, 1H), 2.58-2.72(m, 1H), 2.95-
108

3.04(t, J=9.4Hz, 1H), 3.29-3.42(m, 2H), 3.63-3.69(d, J=8.9Hz, 1H), 3.77-3.85(d,
J=14.2Hz, 1H), 3.82(s, 3H), 3.93-4.00(d, J=10,9Hz, 1H), 6.38-6.43(d, J=9.1Hz,
1H), 6.67-6.70(s, 1H), 6.93-6.98(d, J=8.6Hz, 2H), 7.00-7.06(m, 1H), 7.07-7.13(m,
2H), 7.14-7.32(m, 8H), 7.45-7.52(d, J=8.6Hz, 2H);
13
C NMR (90MHz, CDCl
3
) δ
47.06, 49.70, 53.94, 55.30, 57.64, 64.34, 73.03, 110.67, 114.27, 117.47, 126.67,
126.93, 128.11, 128.15, 128.49, 128.68, 128.77, 129.03, 129.99, 132.22, 132.81,
139.80,, 143.20, 144.71, 159.53.

5-Benzyl-6-(4-methoxy-phenyl)-1-methyl-3-phenyl-hexahydro-pyrrolo[3,4-
c]isoxazole (4.50)

O
N
N
O

The procedure used was similar to (4.48). After oxidation, silica gel was filtered
off. N-methyl-hydroxyamine hydrogen chloride (16mg, 2eq.) was added to the
solution at 0
o
C, followed by the addition of triethylamine (40mg, 4eq.) and
sodium sulfate. The mixture then was allowed slowly to warm up to room
temperature and was kept stirring overnight. After it was washed with water and
extracted with DCM, the mixture was dried over sodium sulfateand the product
was isolated in 95% yield by prep. TLC, after solvent was removed.
1
H NMR
109

(360MHz, CDCl
3
) δ 2.53-2.62(m, 1H), 2.62-2.68(s. 3H), 3.13-3.35(m, 4H), 3.61-
3.66(d, J=4.3Hz, 1H), 3.66-3.74(d, J=13.0Hz, 1H), 3.78-3.85(s, 3H), 4.86-4.91(d,
J=6.1Hz, 1H), 6.88-6.95(d, J=8.4Hz, 2H), 7.15-7.33(m, 10H), 7.34-7.40(d,
J=8.4Hz, 2H);
13
C NMR (90MHz, CDCl
3
) δ 44.91, 55.26, 55.62, 56.60, 57.13,
72.71, 83.26, 84.91, 114.06, 126.45, 126.87, 127.92, 128.17, 128.45, 128.58,
129.01, 133.03, 138.97, 139.39, 159.11.

110

4.6 Chapter 4 References
1
Shamma, M. et al. J. Nat. Prod. 1986, 49, 475.
2
Shulgin, A.; Perry, W. E. The Simple Plant Isoquinolines; Transform: Berkeley,
CA, USA, 2002; p 164.

3
(a) Shamma, M. The isoquinoline alkaloids, chemistry and Pharmacology;
Academic: New Nork, 1977, (b) Deulofeu, V. et al. The alkaloids; Manske, R.
H. F., Ed.; Academic: New York, 1969, Vol. 10.

4
(a) Karageorge, G. N.et al. Bioorg. Med. Chem. Lett., 2004, 14, 5881, (b)
Kashiwada Yoshiki et al. Bioorg. Med. Chem., 2005, 13(2), 443.

5
Pictet, A.; Spengler, T. Ber., 1911, 44, 2030.
6
(a)

Silveira, C. C.; Bernardi, C. R.; Baraga, A. L.; Kaufman, T. S. Tetrahedron
Lett., 2001, 42, 8947; (b) Silveira, C. C.; Bernardi, C. R.; Baraga, A. L.; Kaufman,
T. S. Tetrahedron Lett., 1999, 40, 4969; (c) Cox, E. D.; Cook, J. M. Chem. Rev.,
1995, 95, 1797.

7
Lukanov, L. K.; Venkov, A. P.; Mollov, N. M. Synthesis, 1987, 1031.
8
Gremmen, C.; Wanner, M. J.; Koomen, G. J. Tetrahedron Lett., 2001, 42, 8885.
9
Bobbit, J. M.; Steinfield, A. S.; Weisgraber, K. H.; Dutta, S. J. J. Org. Chem.,
1969, 34, 2478.

10
Suzuki, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett., 1995, 36, 6709.
11
Chandrasekhar, S.; Reddy, N. R.; Reddy, M. V.; Jagannadh, B.; Nagaraju, A.;
Sankar, A. R.; Kunwar, A. C. Tetrahedron Lett., 2002, 43, 1885.

12
Charifson, P. S. et al. J. Med. Chem., 1988, 31, 1941.
13
Brewer, M. D.; Burgess, M. N.; Dorgan, R. J. J.; Elliott, R. L.; Mamalis, P.;
Manger, B. R.; Webster, R. A. B. J. Med. Chem., 1989, 32, 2058.

14
Riggs, R. M.; Nichols, D. E.; Foreman, M. M.; Truex, L. L.; Glock, D.; Kohli,
J. D. J. Med. Chem., 1987, 30, 1454.

15
Chandrasekhar, S.; Mohanty, P. K.; Harikishan, K.; Sasmal, P. K. Org. Lett.,
1999, 1, 877.

111

16
Weber, K.; Kuklinski, S.; Gmeiner, P. Org. Lett., 2000, 1, 647.
17
Crossland, R. K.; Wells, W.E.; Shiner, V. J. J. Am. Chem. Soc., 1971, 93, 4217.
18
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc., 1998, 120, 11798.
19
Chiacchio, U.; Corsaro, A.; Rescifina, A.; Bkaithan, M.; Grassi, G.; Piperno, A.
Privitera, T.; Romeo, G. Tetrahedron, 2001, 57, 3425.

20
Spaller, M. R.; Thielemann, W. T.; Brennan, P. E.; Bartlett, P. A. J. Comb.
Chem., 2002, 4, 516.

21
Danmas, M.; Vo-Quang, Y.; Vo-Quang, L.; Le Goffic, F. Synthesis, 1989, 64.

112

Comprehensive Bibliography

113

1
Akritopoulou-Zanze, I. Synthetic Studies on Allylamines, Alkenylsilanes and
Lipoxins, Ph.D. Thesis, University of Southern California, 1994.

2
Bartlett, P. A. et al. Chem. Rev., 1997, 97, 1281.
3
Bartelett, P. A. J. Am. Chem. Soc., 1998, 120, 4610.
4
Batey, R. A.; Mackay, D. B.; Santhakuma, V. . J. Am. Chem. Soc., 1999, 121,
5075.

5
Bird, J. et al. J. Med. Chem., 1994, 37, 158.
6
Bobbit, J. M.; Steinfield, A. S.; Weisgraber, K. H.; Dutta, S. J. J. Org. Chem.,
1969, 34, 2478.

7
Brewer, M. D.; Burgess, M. N.; Dorgan, R. J. J.; Elliott, R. L.; Mamalis, P.;
Manger, B. R.; Webster, R. A. B. J. Med. Chem., 1989, 32, 2058.

8
Brown, D. G. et al. Bioorg. Med. Chem. Lett., 2003, 13, 3553.
9
Brown, H. C. et al. Tetrahedron Lett., 1988, 29, 21.
10
Brown, H. C. et al. Tetrahedron lett., 1988, 29, 2635.
11
Brown, H. C. et al. J. Am. Chem. Soc., 1972, 94, 4370.
12
Brown, H. C. et al. Organometallics, 1986, 5, 2300
13
Brown, H. C. Organic Synthesis via Boranes, John wiley and Sons, New York,
1975.

14
Chandrasekhar, S.; Mohanty, P. K.; Harikishan, K.; Sasmal, P. K. Org. Lett.,
1999, 1, 877.

15
Chandrasekhar, S.; Reddy, N. R.; Reddy, M. V.; Jagannadh, B.; Nagaraju, A.;
Sankar, A. R.; Kunwar, A. C. Tetrahedron Lett., 2002, 43, 1885.

16
Charifson, P. S. et al. J. Med. Chem., 1988, 31, 1941.

17
Chern, J. H. et al. Bioorg. Med. Chem. Lett., 2004, 14, 2519.
18
Chiacchio, U.; Corsaro, A.; Rescifina, A.; Bkaithan, M.; Grassi, G.; Piperno,
A.; Privitera, T.; Romeo, G. Tetrahedron, 2001, 57, 3425.

19
Cox, E. D.; Cook, J. M. Chem. Rev., 1995, 95, 1797.
114

20
Crossland, R. K.; Wells, W.E.; Shiner, V. J. J. Am. Chem. Soc., 1971, 93, 4217.
21
Currie, G. S.; Drew, M. G. B.; Harwood, L. M.; Hughes, D. J.; Luke, R. W. A.;
Vickers, R. J. J Chem. Soc. Perkin Trans. 1, 2000, 2982.

22
Miyaura. N. et al. J. Am. Chem. Soc., 2000, 122, 4990.
23
Danishefsky, S. J. et al. Angew. Chem. Int. Ed., 2001, 40, 4544.
24
Danmas, M.; Vo-Quang, Y.; Vo-Quang, L.; Le Goffic, F. Synthesis, 1989, 64.
25
Davis, A. S.; Pyne, S. G.; Skelton, B. W.; White, A. H. J. Org. Chem., 2004, 69,
3139.

26
Demir, A. S. et al. Helv. Chim. Act., 2003, 86, 91.
27
Diederich, F.; Stang, P. J. Metal-catalyzed Cross-coupling Reactions, Wiley-
VCH, Weinheim, 1998.

28
Diego, A. et al. J. Org. Chem., 2003, 68, 6661.
29
Deulofeu, V. et al. The alkaloids, Manske, R. H. F., Ed.; Academic: New York,
1969, Vol. 10.

30
Forns, P.; et al. Tetrahdron Lett., 2003, 44, 6907.

31
Fu, G.; Littke, A. F. Angew. Chem. Int. Ed., 2002, 41, 4176.
32
Gary, G. A.; Webb, D. J. Pharmacol. Ther., 1996, 72, 109.
33
Gremmen, C.; Wanner, M. J.; Koomen, G. J. Tetrahedron Lett., 2001, 42, 8885.
34
Hansen, T. K. et al. Tetrahedron Lett., 2000, 41, 1303.
35
Hay, D. W. P. et al. Am. J. Respir. Crit. Care Med., 1996, 154, 1594.
36
Henderson, B.; Docherty, A. J. P.; Beely, N. R. A. Design of Inhibitors of
Articular Cartilge Destruction, Drugs of The Future, 1990, 15, 495.

37
Jiang, B.; Ming, X. Angew. Chem. Int. Ed., 2004, 43, 2543

38
Jiang, B.; Ming, X. Org. Lett., 2002, 4, 4077.

39
Jiang, B.; Yang, C. G.; Gu, X. H. Tetrahdron Lett., 2001, 42, 2545
115

40
Karageorge, G. N.et al. Bioorg. Med. Chem. Lett., 2004, 14, 5881.
41
Katritzky, A. R. et al J. Org. Chem., 1999, 64, 6071.
42
Keller, R. K. Fliesler, S. J. Biochem. Biophys. Res. Commum., 1999, 266, 560.
Kotha, S et al. Tetrahedron, 2002, 58, 9633.
43
Koolmeister, T.; Sodergren, M.; Scobie, M. Tetrahdron Lett., 2002, 43, 5965.
44
Leigh, D. A.; Linnane, P. Tetrahedron Lett., 1993, 34, 5639.
45
Lombaert, S. De. Et al. Bioorg. Med. Chem. Lett., 1995, 5, 151.
46
Lombaert, S. De. Et al. Bioorg. Med. Chem. Lett., 1997, 7, 1059.
47
Lombaert, S. De. Et al. J. Med. Chem., 2000, 43, 488.
48
Lukanov, L. K.; Venkov, A. P.; Mollov, N. M. Synthesis, 1987, 1031.
49
Martin, M. B. et al. J. Med. Chem., 2001, 44, 909.
50
Martin, M. B. et al. J. Med. Chem., 2002, 45, 2904.
51
Miyaura, N. et al. Advanced Synthesis and Catalysis, 2003, 345, 1103.
52
Miyaura, N. et al. J. Am. Chem. Soc., 1993, 115, 11018.
53
Miyaura, N. et al. J. Am. Chem. Soc., 2002, 124, 390.
54
Miyaura, N. et al. J. O. C., 1995, 60, 7508.
55
Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahdron Lett., 2003, 44,
5819.

56
Naskar, D.; Roy, A.; Seibel, W. L. Tetrahdron Lett., 2003, 44, 8861.
57
Palmieri, G. et al. J. Org. Chem., 2003, 68, 1200.
58
Patel, T. CNS Drugs, 1996, 5, 293.
59
Patel, Z. D. Synthesis of Novel Compounds from boronic Acids, Amines, and
Carbonyl derivatives, Ph.D. Thesis, University of Southern California, 2002.
Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents, Academic Press, New
York, 1988.
116

60
Petasis, N. A.; Akritopoulou-Zanze, I. Tetrahdron Lett., 1993, 34, 583.
61
Petasis, N. A.; Patel, Z. Tetrahdron Lett., 2000, 41, 9607.
62
Petasis, N.A.; Boral, S. Tetrahedron Lett. 2001, 42, 539.
63
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc., 1997, 119, 445.
64
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc., 1998, 120, 11798.
65
Pictet, A.; Spengler, T. Ber., 1911, 44, 2030
66
Powers, J. C.; Asgian, J. L.; Ekici, O. D.; James, K. E. Chem. Rev., 2002, 102,
4639.

67
Portlock, D. E.; Naskar, D.; West, L.; Ostaszewski, R.; Chen, J. J. Tetrahdron
Lett., 2003, 44, 5121.

68
Portlock, D. E.; Ostaszewski, R.; Naskar, D.; West, L. Tetrahdron Lett., 2003,
44, 603.

69
Prakash, G. K.; Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G. A. J. Org.
Chem., 2002, 67, 3718

70
Prakash, G. K. et al. Org. Lett., 2000, 2, 3173.
71
Pye, P. J. et al. Chem. Eur. J., 2002, 8, 1372.
72
Rabelink, T. J. et al. Kidney Int., 1996, 50, 1827.
73
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.

74
Ranu, B. C. et al. Org. Lett., 1999, 1, 1141.
75
Rice, K. C. et al. J. Med. Chem., 2000, 43, 3193.
76
Riggs, R. M.; Nichols, D. E.; Foreman, M. M.; Truex, L. L.; Glock, D.; Kohli,
J. D. J. Med. Chem., 1987, 30, 1454.

77
Roden, G. A.; Martin, T. J. Science, 2000, 289, 1508.
78
Saidi. M. R. et al. Tetrahedron: Asymmetry, 2002, 13, 2417.
117

79
Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics, 1997, 16, 4229.
80
Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. O. C., 2000, 65, 5951.
81
Shamma, M. et al. J. Nat. Prod., 1986, 49, 475.
82
Shamma, M. The isoquinoline alkaloids, chemistry and Pharmacology;
Academic: New Nork, 1977.

83
Shulgin, A.; Perry, W. E. The Simple Plant Isoquinolines, Transform: Berkeley,
CA, USA, 2002; p 164.

84
Silveira, C. C.; Bernardi, C. R.; Baraga, A. L.; Kaufman, T. S. Tetrahedron
Lett., 2001, 42, 8947.

85
Silveira, C. C.; Bernardi, C. R.; Baraga, A. L.; Kaufman, T. S. Tetrahedron
Lett., 1999, 40, 4969.

86
Smith, A. B. III, et al. J. Am. Chem. Soc., 1995, 117, 10879.
87
Snieckus, V. et al. Angew. Chem. Int. Ed., 2003, 42, 3399.

88
Spaller, M. R.; Thielemann, W. T.; Brennan, P. E.; Bartlett, P. A. J. Comb.
Chem., 2002, 4, 516.

89
Suzuki, A.; Miyuara, N. Chem. Rev., 1995, 95, 2457.
90
Suzuki, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett., 1995, 36, 6709.
91
Szabo, C. M. et al. J. Med. Chem., 2002, 45, 2894.
92
Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem.
Soc., 1998, 120, 5579.

93
Tomioka, K. et al Tetrahedron: Asymmetry, 1999, 10, 221.
94
Van Beek, E. et al. Biochem. Biophys. Res. Commum., 1999, 264, 108.
95
Wallace, E. M. et al. J. Med. Chem. 1998, 41, 1513.
96
Weber, K.; Kuklinski, S.; Gmeiner, P. Org. Lett., 2000, 1, 647.
97
Wytko, J. A.; Weiss, J. J. O. C., 1990, 55, 5200.
118

98
Yao, X. Synthetic Studies and Novel Application of Reactions of Boronic Acids
with Amines and Carbonyl Compounds, Ph.D. Thesis, University of Southern
California, 2002.

99
Zavialov, I. A. New Reactions of Organoboronic Acids and Their Derivatives,
Ph.D. Thesis, University of Southern California, 1998.

119

APPENDIX

NMR SPECTRUM

120

2.24 Dibenzyl-(3-phenyl-1-pyridin-2-allyl)-amine

N
N

1
H NMR (500MHz, CD
3
OD)

13
C NMR (126MHz, CDCl
3
)

121

2.32 Dibenzyl-(pyridin-2-yl-thiophen-2-yl-methyl)-amine

N
N
S

1
H NMR (250MHz, CDCl
3
)

13
C NMR (63MHz, CDCl
3
)

122

2.47 Benzhydryl-(3-phenyl-1-pyridin-2-yl-ally)-amine

N
N
H

1
H NMR (250MHz, CDCl
3
)

13
C NMR (62.9MHz, CDCl
3
)

123

2.54 (1-Phenyl-ethyl)-(pyridin-2-yl-thiophen-2-yl-methyl)-amine

N
N
H
S

1
H NMR (250MHz, CDCl
3
)

13
C NMR (63MHz, CDCl
3
)

124

2.62 4-(3-Phenyl-1-quinolin-2-yl-allyl)-piperazine-1-carboxylic acid tert-butyl
ester

N
N
Boc
N

1
H NMR (360MHz, CDCl
3
)

13
C NMR (90MHz, CDCl
3
)

125

2.65 4-(1,3-Diphenyl-allyl)-morpholine

N
O

1
H NMR (250MHz, CDCl
3
)

13
C NMR (62.9MHz, CDCl
3
)

126

2.78 (4-Methoxy-phenyl)-[(4-methoxy-phenyl)-pyridin-2-yl-methyl]-amine

HN
N
O
O

1
H NMR (360MHz, CDCl
3
)

13
C NMR (90MHz, CDCl
3
)

127

2.80 [(4-Bromo-phenyl)-pyridin-2-yl-methyl]-(4-methoxy-phenyl)-amine

N
HN
Br
O

1
H NMR (360MHz, CDCl
3
)

13
C NMR (90MHz, CDCl
3
)

128

3.01 Aminomethyl-phosphonic acid diethyl ester

H
2
N
PO
O
O

1
H NMR (360MHz, CDCl
3
)

13
C NMR (126MHz, CDCl
3
) δ

129

3.28 [(Diethoxy-phosphorylmethyl)-amino]-furan-2-yl-acetic acid

O HN
O
OH
PO
O
O

1
H NMR (360MHz, CDCl
3
)

13
C NMR (126MHz, CDCl
3
)

130

3.03 2-Ethoxy-5-(4-methoxy-phenyl)-2-oxo-2 λ
5
-[1, 4, 2] oxazaphosphinan-6-one

POEt HN
O
O
O
O

1
H NMR (250MHz, CD
3
OD)

13
C NMR (63MHz, CDCl
3
)

131

3.34 ({[(4-Methoxy-phenyl)-pyridin-2-yl-methyl]-amino}-methyl)-phosphonic
acid diethyl ester

HN
P
O O
O
N
O

1
H NMR (500MHz, CDCl
3
)

13
C NMR (126MHz, CDCl
3
)

132

3.37 {[(Furan-2-yl-pyridin-2-yl-methyl)-isobutyl-amino]-methyl}-phosphonic
acid diethyl ester

O
N
P
O O
O
N

1
H NMR (360MHz, CDCl
3
)

13
C NMR (91MHz, CDCl
3
)

133

3.36 {[Benzyl-(furan-2-yl-pyridin-2-yl-methyl)-amino]-methyl}-phosphonic acid
diethyl ester

O
N
P
O O
O
N
Ph

1
H NMR (360MHz, CDCl
3
)

13
C NMR (91MHz, CDCl
3
)

134

3.39 (2S)-{1-[(Furan-2-yl-pyridin)-2-methyl)-amino]-ethyl}-phosphonic acid
diethyl ester

P(OEt)
2
HN
O
O
N

1
H NMR (360MHz, CDCl
3
)

13
C NMR (91MHz, CDCl
3
)

135

3.47 [[Benzyl-(1-furan-2-yl-2-hydroxy-ethyl)-amino]-(diethoxy-phosphoryl)-
methyl]-phosphonic acid diethyl ester

O N
P
P
O
O
O
O
O
O
HO
Ph

1
H NMR (360MHz, CDCl
3
)

136

4.31 2-Benzyl-6, 7-dimethoxy-3-thiophen-2-yl-1, 2, 3, 4, -tetrahydro-isoquinoline

S N
O
O

1
H NMR (500MHz, CDCl
3
)

13
C NMR (91MHz, CDCl
3
)

137

4.37 6-Benzyl-5-styryl-4, 5, 6, 7-tetrahydro-furo[2, 3-c]pyridine

N
O

1
H NMR (360MHz, CDCl
3
)

13
C NMR (126MHz, CDCl
3
)

138

4.41 2-Benzyl-3-furan-2-yl-6, 7-dimethoxy-4-phenyl-1, 2, 3, 4-tetrahydro-
isoquinoline

O N
O
O

1
H NMR (360MHz, CDCl
3
)

13
C NMR (91MHz, CDCl
3
)

139

4.43 1-Isobutyl-4, 5, 6-trimethoxy-2-styryl-2, 3-dihydro-1H-indole

N
O
O
O

1
H NMR (360MHz, CDCl
3
)

13
C NMR (91MHz, CDCl
3
)

140

4.46 3-[Benzyl-(3-phenyl-allyl)-amino]3-(4-methoxy-phenyl)-propane-1,2diol

O
N
OH
OH

1
H NMR (360MHz, CDCl
3
)

13
C NMR (91MHz, CDCl
3
)

141

4.48 2-Benzyl-3-(4-methoxy-phenyl)-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-
pyrrolo[3,4-b]quinoline

N
HN
O

1
H NMR (360MHz, CDCl
3
)

13
C NMR (91MHz, CDCl
3
)

142

4.49 2-Benzyl-7-bromo-3-(4-methoxy-phenyl)-9-phenyl-2,3,3a,4,9,9a-hexahydro-
1H-pyrrolo[3,4-b]quinoline

N
HN
O
Br

1
H NMR (360MHz, CDCl
3
)

13
C NMR (91MHz, CDCl
3
)

143

4.50 5-Benzyl-6-(4-methoxy-phenyl)-1-methyl-3-phenyl-hexahydro-pyrrolo[3,4-
c]isoxazole

O
N
N
O

1
H NMR (360MHz, CDCl
3
)

13
C NMR (91MHz, CDCl
3
)

144

Abstract (if available)

Abstract This dissertation describes the development of new, practical and experimentally convenient methodologies for multi-functional molecules. -- In the first chapter, the three-component reaction involving boronic acids is reviewed. -- Chapter 2 describes a novel approach to the multi-substituted pyridyl aminomethanes. -- Chapter 3 describes a new method to for synthesis of functionalized a-aminophosphonates and a-aminobiphosphonates via three-component process. -- Chapter 4 describes convenient approaches to diversified heterocylic compounds involving the three-component reaction.

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

New organoboron based multicomponent methodologies for the synthesis of novel heterocycles

PDF

New reactions of organoboron compounds

PDF

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

PDF

Multicomponent synthesis of optically pure aminodicarboxylic acids in water and total synthesis of 15-EPI-benzo-lipoxin A4 and aspirin-triggered neuroproctectin D1/protectin D1

PDF

Multicomponent synthesis of fluorinated organic compounds using novel lewis acid catalysis and related chemistry

PDF

Studies of yamamoto and suzuki polymerizations of dibromofluorenes: synthesis and spectroscopy of fluorene macrocycles and copolymers

PDF

Superacid promoted synthetic transformations and the development of new solid supported Brønsted acids

PDF

Design and synthesis of novel anti-inflammatory lipid mediators and anticancer small molecules

PDF

Design and synthesis of novel heterocycles and peptidomimetics from organoboronic acids, amines and carbonyl compounds

PDF

Synthesis of protein-protein interaction inhibitors and development of new catalytic methods

PDF

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

PDF

Total synthesis of specialized pro-resolving lipid mediators and their analogs

PDF

Synthesis and photophysical characterization of phosphorescent cyclometalated iridium (III) complexes and their use in OLEDs

PDF

Design, synthesis, and biological evaluation of novel therapeutics for cancer

PDF

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

PDF

Analytical investigation of the proteasome inhibitor Bortezomib and the total synthesis of specialized pro-resolving lipid mediators

PDF

Total synthesis of specialized pro-resolving lipid mediators and their analogs

PDF

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

PDF

Activation of methane by homogeneous catalyst in weakly acidic solvents