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Vv CIO
Mfik-IM
SYNTHETIC APPROACHES TO THE
ALKALOIDS CYCLEANINE, INSULARINE
AND CISSACAPINE
by
MUNAKA CHRISTOPHER MAUMELA
THESIS
submitted in fulfilment
of the requirements for the degree
PHILOSOPHIAE DOCTOR
in
CHEMISTRY
in the
FACULTY OF SCIENCE
of
RAND AFRIKAANS UNIVERSITY
Supervisor: Professor F.R. van Heerden
MAY 2003
To my late sister Ndivhuwo Faith Maumela
22 May 1987 - 19 April 2000
ACKNOWLEDGEMENTS
I would like to thank my Creator, the Almighty God.
I would also like to express my sincere gratitude to Professor Fanie van Heerden for
her supervision, support and encouragement throughout this project. Her advice,
ideas, remarks and confidence torwards me are greatly appreciated.
My sincere thanks are aslo due to the following people:
Dr. Linda van der Merwe and Ian Voster of Rand Afrikaans University for
recording the NMR and MS spectra.
National Research Foundation (NRF), Medical Research Council (MRC) and
Rand Afrikaans University for financial support.
All the Organic Chemistry group members of Prof. Fanie van Heerden, Prof.
Cedric Holzapfel and Prof. Bradley Williams for the discussions and frienship.
My parents, Jonas and Emely for their love and support.
All my friends.
TABLE OF CONTENTS
Synopsis i
Samevatting iii
List of abbreviations v
CHAPTER 1: INTRODUCTION
1.1 Introduction 1
1.2 Malaria 2
1.3 Bisbenzylisoquinoline alkaloids 3
1.3.1 Nomenclature of bisbenzylisoquinoline alkaloids 4
1.3.2 Biosynthesis of bisbenzylisoquinoline alkaloids 4
1.3.3 Chemical constituents of Cissampelos capensis 8
1.4 Aim of this study 9
1.5 References 11
CHAPTER 2: SYNTHESIS OF BISBENZYLISOQUINOLINE ALKALOIDS:
A LITERATURE REVIEW
2.1 Introduction 13
2.2 Synthesis of isoquinoline ring 16
2.2.1 Bischler-Napieralski reaction 17
2.2.1.1 Reaction mechanism 19
2.2.1.2 Direction of ring closure 20
2.2.1.3 Enantioselective synthesis of optically-pure isoquinoline
alkaloids via Bischler-Napieralski reaction 22
2.2.2 Pictect-Spengler reaction 25
2.2.3 Pomeranz-Fritsch reaction 26
2.3 Diaryl ether synthesis 27
2.4 Methods for diaryl ether synthesis 28
2.4.1 Nucleophilic aromatic synthesis 28
2.4.2 Copper-catalysed Ullmann ether synthesis 29
2.4.3 Diaryl ether synthesis mediated by metal-arene complexes 35
2.4.4 Thallium(III) nitrate oxidative diaryl ether synthesis 35
2.4.5 Diaryl ether synthesis mediated by potassium fluoride-alumina
and 18-Crown-6 36
2.4.6 Palladium-catalysed diaryl ether synthesis 37
2.4.7 Conclusion 39
2.5 Previous synthesis of dl-cycleanine (1.28) 40
2.5.1 Conclusion 45
2.6 References 46
CHAPTER 3: SYNTHESIS OF PRECURSORS FOR THE BISBENZYLISO-
QUINOLINE
3.1 Introduction 50
3.2 Retrosynthetic analysis 50
3.3 Methyl 3 -(4-acetylphenoxy)-4,5 -dimethoxyb enzoate (3.8) 55
3.4 Methyl 4 -(5 -formy1-2,3 -dimethoxyphenoxy)phenyl acetate (3.10) 59
3.5 13-Phenethylamine derivatives of 3.2 63
3.5.1 Nitrostyrene method 63
3.5.2 Nitrile route 68
3.6 11H-dibenzo[b, e][1 , 4] di oxep in e 3.14 70
3.7 Unsuccessful attempted synthesis of acid derivative of 3.16 79
3.8 11H-dibenzo[b, e][1 , 4] di o xep in e 3.15 79
3.9 Conversion of 11H-dibenzo [b , e][1,4]dioxepine 3.15 to methyl acetate
derivative 3.16 83
3.10 13-Phenethylamine derivatives of 3.3 84
3.11 Model carboxamide formation and attempted Bischler-Napieralski
reaction 88
3.12 Synthesis of optically-pure benzyltetrahydroisoquinoline intermediates
3.98 and 3.103 91
3.13 Attempted phenoxylation of bisbenzyltetrahydroisoquinoline 3.98 96
3.14 Conclusion and Further Work 97
3.15 Conclusion 99
CHAPTER 4: EXPERIMENTAL
4.1 General 102
4.2 Synthetic procedures 103
4.2.1 Methyl 3,4,5-trihydroxybenzoate (3.27) 103
4.2.2 Methyl 3,4-dihydroxy-5-methoxybenzoate (3.30) 104
4.2.3 Methyl 3,4-bis(acetoxy)-5-methoxybenzoate (3.31) 104
4.2.4 Methyl 3-acetoxy-4,5-dimethoxybenzoate (3.33) 105
4.2.5 Methyl 3 -hydroxy-4,5-dimethoxyb enzoate (3.7) 106
4.2.6 Methyl 3-(4-acetylphenoxy)-4,5-dimethoxybenzote (3.8) 106
4.2.7 Methyl 3 [4-(1, 1-dimethoxyethyl)phenoxy]-4,5-dimethoxy
benzoate (3.34) 107
4.2.8 4-(5-Hydroxymethy1-2,3-dimethoxyphenoxy)acetophenone (3.35) 108
4.2.9 3 -(4-Acetylphenoxy)-4,5-dimethoxyb enzaldehyde (3.9) 109
4.2.10 Methyl 4-(5-formyl-2,3-dimethoxyphenoxy)phenylacetate (3.10) 110
4.2.10.1 Lead(IV) acetate oxidative rearrangement 110
4.2.10.2 TTN oxidative rearrangement 110
4.2.11 Methyl 4- 2,3 -dimethoxy-5-[(E)-2-nitrovinyl] phenoxylphenyl
acetate (3.48a) 111
4.2.12 Borohydride Exchange Resin (BER) 112
4.2.13 Methyl 442,3 -dimethoxy-5-(2-nitro ethyl)phenoxy]phenylacetate
(3.48b) 113
4.2.14 Methyl 4-[5-(2-amino ethyl)-2,3 -dimethoxyphenoxy] phenylacetae
(3.11c) 114
4.2.15 2- { 4-(2-aminoethyl)-2, 3 -dimethoxyphenoxy] } phenylethanol
(3.53a) 115
4.2.16 445-(2-tert-Butoxycarbonylaminoethyl)-2,3-dimethoxy
phenoxylethanol (3.53b) 116
4.2.17 4[2-tert-Butoxycarbonylaminoethyl)-2,3-dimethoxyphenoxy
phenylacetic acid (3.11b) 117
4.2.18 Methyl 4-(5-hydroxymethy1-2,3-dimethoxyphenoxy)phenyl
acetate (3.54) 118
4.2.19 Methyl 4-(5-chloromethy1-2,3-dimethoxyphenoxy)phenyl
acetate (3.55) 119
4.2.20 Methyl 4-(5-cyanomethy1-2,3-dimethoxyphenoxy)phenyl
acetate (3.54) 120
4.2.21 Methyl 4-(5-(2-tetr-butovcarbonylaminoethy1-2,3-
dimethoxyphenoxy)phenylacetate (3.11a) 121
4.2.22 Compound 3.11b via hydrolysis of methyl ester derivative 3.11a 122
4.2.23 Compound 3.11c via N-Boc removal of 3.11a 122
4.2.24 Methyl 3-acetoxy-4-(2-bromobenzyloxy)-5-methoxybenzoate
(3.63) 122
4.2.25 Methyl 4-(2-bromobenzyloxy)-3-hydroxy-5-methoxybenzoate
(3.64) 123
4.2.26 Methyl 9-methoxy-11H-dibenzo[b, e][1,4] dioxepine-7-carboxylate
(3.65) 124
4.2.27 1-Bromo-2,4-dimethylbenzene (3.66) 124
4.2.28 1-Bromo-2-bromomethy1-4-dibromomethylbenzene (3.67) 125
4.2.29 4-Bromo-3-bromomethylbenzaldehyde (3.68) 126
4.2.30 Methyl 3-acetoxy-4-hydroxy-5-methoxybenzoate (3.69) 126
4.2.31 Methyl 3-acetoxy-4-(2-bromo-5-formylbenzyloxy)-5-methoxy
benzoate (3.71) 127
4.2.32 Methyl 4-(2-bromo-5-formylbenzyloxy)-3-hydroxy-5-methoxy
benzoate (3.12) 128
4.2.33 Methyl 2-formy1-9-methoxy-11H-dibenzo[b,e][1,4]dioxepine-7-
carboxylate (3.14) 129
4.2.33.1 Copper-catalysed diaryl ether formation 129
4.2.33.2 Palladium-catalysed diaryl ether formation 129
4.2.34 Methyl 2-hydoxymethy1-9-methoxy-11H-dibenzo[b,e][1,4]
dioxepine-7-carboxylate (3.72a) 131
4.2.35 Methyl 2-hydoxymethy1-9-methoxy-11H-dibenzo[b,e][1,4]
dioxepine-7-carboxylate (3.72b) 132
4.236 4-Fluoro-3-methylacetophenone (3.76) 133
4.2.37 3 -B romomethy1-4-fluoro acetophenone (3.77) 133
4.2.38 Methyl 4-(acetyl-2-fluorobenzyloxy)-3-acetoxy-5-methoxy
benzoate (3.78) 134
4.2.39 Methyl 4-(5-acetyl-2-fluorobenzyloxy)-3-hydroxy-5-methoxy
benzoate (3.13) 135
4.2.40 Methyl 2-acetyl-9-methoxy-11H-dibenzo [b , e] [ 1,4]dioxepine-2-
carboxylate (3.15) 136
4.2.41 1-(7-Hydroxymethy1-9-methoxy-11H-dibenzo [b , e] [ 1,4]
dioxepin-2-yl)ethanone (3.79) 137
4.2.41.1 Acetalisation 137
4.2.41.2 LiA1H4 reduction 137
4.2.42 2-Acety-9-methoxy-11H-dibenzo [b , e][1,4]dioxepine-7-
carbaldehyde (3.80) 138
4.2.43 Methyl (7-formy1-9-methoxy-11H-dibenzo [b , e][ 1,4]dioxepin-2-
yl)acetate (3.16) 139
4.2.44 Methyl {9-methoxy-7-[(E)-2-nitroviny1]-11H-dibenzo [b , e][ 1,4]
Dioxepin-2-yl}acetate (3.81) 140
4.2.45 247-(2-Aminoethyl)-9-methoxy-11H-dibenzo [b , e][1,4]dioxepin-
yl]ethanol (3.82) 141
4.2.46 Methyl (7-hydroxymethy1-9-methoxy-11H-dibenzo [b , e] [ 1,4]
dioxepin-2-yl)acetate (3.83) 141
4.2.47 Methyl (7-chloromethy1-9-methoxy-11H-dibenzo [b , e][ 1,4]
dioxepin-2-yl)acetate (3.84) 142
4.2.48 Methyl (7-cyanomethy1-9-methoxy-11H-dibenzo [b , e] [ 1,4]
dioxepin-2-yl)acetate (3.85) 143
4.2.49 Methyl (7-tert-butoxycarbonylaminoethyl)-9-methoxy-11H-
dibenzo[b, e][ 1,4]dioxepin-2-yl)acetate (3.17) 144
4.2.50 Preparation of coupling reagent DMTMM (3.87) 145
4.2.50.1 2-Chloro-2,4-dimethoxy-1,3,5-triazene (3.86b) 145
4.2.50.2 DMTMM (3.87) 145
4.2.51 Methyl 4-{5-(2-{445-(2-tert-butoxycarbonylaminoethyl)-2,3-
dimethoxyphenoxy]phenyl}acetylamino)ethyl]-2,3-
dimethoxyphenoxy}phenylacetate (3.88a) 146
4.2.52 4- { 542- { 445-(2-tert-Butoxycarbonylaminoethyl)-2,3-
dimethoxyphenoxy]phenyl}acetylamino)ethy1]-2,3-
dimethoxyphenoxy}phenylacetic acid (3.88b) 147
4.2.53 4-{5-(2-{445-(2-Aminoethyl)-2,3-
dimethoxyphenoxy]phenyl}acetylamino)ethyl]-2,3-
dimethoxyphenoxy}phenylacetic acid (3.88c) 148
4.2.54 3-Bromo-4-hydroxy-5-methoxybenzaldehyde (3.89) 148
4.2.55 3 -B romo-4,5 -dimethoxyb enzaldehyde (3.90) 149
4.2.56 3-Bromo-4,5-dimethoxybenzyl alcohol (3.91) 150
4.2.57 3-Bromo-4,5-dimethoxybenzyl chloride (3.92) 150
4.2.58 3 -B romo-4,5-dimethoxyp henylacetonitril e (3.93) 151
4.2.59 3-Bromo-4,5-dimethoxyphenylacetic acid (3.23) 152
4.2.60 (S)-2-(3-Bromo-4,5-dimethoxyphenypethy1]-N-(1-phenylethyl)
acetamide (3.94) 152
4.2.61 (S)-N-[2-(3-Bromo-4,5-dimethoxyphenypethy1]-1-phenethyl
amine (3.95) 153
4.2.62 (S)-N-[2-(3-Bromo-4,5-dimethoxyphenypethy1]-2-(4-
isopropyloxypheny1)-N-(1-phenylethypacetamide (3.96) 154
4.2.63 (S)-8-B romo-1-(4-i sopropyl oxyb enzy1)-6, 7-dimethoxy-2-(1-
phenyl ethyl)-1, 2,3,4-tetrahydroi soquinoline (3.98) 155
4.2.64 (R)-2-(3-Bromo-4,5-dimethoxyphenypethyll-N-(1-phenethyl)
acetamide (3.99) 156
4.2.65 (R)-N-[2-(3-Bromo-4,5-dimethoxyphenypethy1]-1-phenethyl
ethylamine (3.100) 157
4.2.66 (R)-N-[2-(3-Bromo-4,5-dimethoxyphenypethy1]-2-(4-
isopropyloxypheny1)-N-(1-phenylethyl)acetamide (3.101) 157
4.2.67 (R)-8-Bromo-1-(4-isopropyloxybenzy1)-6,7-dimethoxy-2-
(1-phenyl ethyl)-1,2,3,4-tetrahydroisoquinoline (3.103) 158
4.3 References 159
SYNOPSIS
The objective of the research described in this thesis was to develop a synthetic
method that can be applied to the synthesis of the natural
bisbenzyltetrahydroisoquinoline alkaloids cissacapine, insularine, insularoline,
cycleanine and analogues thereof.
In this study two different strategies that allow easy entry to the precursors of these
alkaloids were developed, and these set the scene for future total synthesis of these
alkaloids. The key features of the first approach comprise the linkage of the two
appropriate rings to form the diaryl ether moiety as well as the preparation of the
11H-dibenzo[b,e][1,4]dioxepine tricyclic system. Previous approaches to the diaryl
ether formation are not suitable for large-scale reactions. We have herein described
the preparation of the diaryl ether precursors in high yields and our approach is
suitable for large-scale preparations.
A search of the literature method revealed only two published methods for the
preparation of the 11H-dibenzo[b,e][1,4]dioxepine system. Both these two methods
produce compounds containing this moiety in low yields. In our studies this aspect
was addressed satisfactorily. Unfortunately, our attempts to complete the synthesis of
these alkaloids through Bischler-Napieralski reaction was met with no success, the
problem been ascribed to the unoptimised Bischler-Napieralski conditions used.
Our second approach involves the preparation of benzylisoquinoline units that are
precursors of cycleanine. The published method to the derivatives of the cycleanine
precursors is non-stereopecific and produces racemic benzylisoquinolines.
Our synthetic route is a chiral auxiliary-based asymmetric version that produces the
optically-pure benzylisoquinoline monomers. The key features of this route involve
incorporation of the chiral auxiliary on the nitrogen atom, Bischler-Napieralski
cyclisation of the resultant chiral amides and finally stereoselective reduction of the
3,4-dihydroisoquinolinium ion possessing the chiral auxiliary. This route employs
both optically-pure (S)- and (R)-1-phenethylamine as the chiral source. Optically-
pure diastereomers were obtained. Our approach is a vast improvement compared to
the previously described non-stereospecific method since it allows easy and good
stereoselective access to both diastereomers in good yield. Unfortunately, one of the
concluding steps leading to the formation of the dimeric stereoisomers of cycleanine
through diaryl ether formation using the recently published methods was not
successful. This is ascribed to the electron-rich nature of the isoquinoline ring.
ii
SAMEVATTING
Die doel van die navorsing beskryf in hierdie verhandeling is die ontwikkeling van 'n
hoe-opbrengs sintetiese metode wat toegepas kan word op die sintese van die
natuurlike bisbensieltetrahidroisokwinolien alkaloIede cissacapine, insularine,
insularoline en derivate daarvan.
In hierdie studie is twee verskillende strategiee wat maklike toegang na die voorloper
verbindings verseker, gellustreer. Die sleuteleienskappe van die eerste benadering
bestaan uit die koppeling van twee gepaste ringe om 'n diarieleter groep te vorm,
sowel as die bereiding van 11H-dibenso[b,e][1,4]dioksepien trisikliese sisteem.
Vorige benanderings tot die diarieleter vorming is nie geskik vir reaksie op groot
skaal nie. Ons beskryf die bereiding van die diarieleter voorlopers en ons benadering
is geskik vir grootskaal bereidings.
'n Literatuur soektog het aan die lig gebring dat daar net twee gepubliseerde metodes
vir die bereiding van 11H-dibenso[b,e][1,4]dioksepien sisteem is. Beide hierdie
metodes is teleurstellend as gevolg van lae opbrengste. In ons studies is hierdie
aspekte suksesvol aangespreek. Ongelukkig was ons pogings om die sintese van die
alkaloIede deur die Bischler-Napieralskie reaksie te voltooi, onsuksesvol met die
probleem wat toegeskryf kan word aan die Bischler-Napieralskie kondisies.
Ons tweede benadering het die voorbereiding van bensielisokwinoliene ingesluit wat
`n voorloper is vir cycleanine. Die gepubliseerde metode vir die derivate van hierdie
cycleaninevoorlopers is nie stereospesifiek nie en produseer rasemiese
bensielisokwinolieneenhede.
Ons benadering is 'n chirale hulpreagensgebaseerde assimetriese weergawe wat opties
suiwer bensielisokwinolien monomere produseer. Die hoofeienskap van hierdie roete
sluit in die inkorporering van die chirale hulpreagens op die stikstof, Bischler-
Napieralski siklisering van die gevormde chirale amied en ook die reduksie van die
3,4-dihidroisokwinoliniumioon wat 'n chirale hulpreagens bevat. Ons sintetiese roete
iii
maak gebruik van beide optiese suiwer (S)- en (R)-fenetielamiene as die chirale bron.
Optiese-suiwer diastereoisomere is verkry. Ons benadering is 'n groot verbetering in
vergelyking met vorige nie-stereospesifieke metodes aangesien maklike en goeie
stereoselektiewe toegang gebied word na beide diastereoisomere in goeie opbrengs.
Ongelukkig was die stap wat lei na die vorming van die stereoisomere van die
cycleanine deur die diarieleter vorming deur gebruik to maak van onlangs
gepubliseerde metodes, onsuksesvol. Dit kan toegeskryf word aan die elektronryke
natuur van die isokwinolien ring.
iv
ABBREVIATIONS
abs absolute
Ac acetyl
aq. aqueous
Ar aryl
BBI bisbenzylisoquinoline
BER borohydride exchange resin
Boc tert-butoxycarbonyl
`Bu tert-butyl
Cbz benzyloxycarbonyl
conc concentrated
DCC 1,3-dicyclohexylcarbodiimide
DMAC N,N-dimethylacetamide
DMF N,N-dimethylformamide
DMSO dimethyl sulphoxide
DMTMM 4-(4,6-dimethoxy-1,3,5-triazen-2-y1)-4-methylmorpholinium chloride
EDC 1 -(3 -dimethylaminopropyl)-3 -ethylcarb odiimi de
eq. equivalent
Et ethyl
EtOAc ethyl acetate
Hz hertz
IR infrared spectroscopy
lit. literature
m.p. melting point
MS mass spectrometry
NBS N-bromosuccinimide
NMM N-methylmorpholine
NMP N-methylpyrrolidinone
NMR nuclear magnetic resonance spectroscopy
NOE nuclear Overhauser effect
OTf triflate
PCC pyridinium chlorochromate
v
Ph phenyl
iPr isopropyl
Py pyridine
rt room temperature
THE tetrahydrofuran
TMHD 2,2,6,6-tetramethylheptane-3,5-dione
p-TsOH para-toluene sulphonic acid
TLC thin-layer chromatography
TTN thallium(M) trinitrate
vi
CHAPTER 1
INTRODUCTION
1.1 Introduction
Traditional medicine has been the main form of treatment for several diseases in many
countries of the world for hundreds of years and currently many researchers throughout the
world are actively investigating traditional medicine in search of new biological active
compounds. 1 '2 Modem medicines in industrialised nations often find their origins in plant
alkaloids, either as purified alkaloids or as synthetic derivatives thereol 3
In our phytochemistry program we have developed an interest in the chemistry of the
bisbenzylisoquinoline alkaloids isolated from Cissampelos capensis (Menispermaceae).
Bisbenzylisoquinoline alkaloids isolated from this plant were found to have antimalarial
activity. 4 As judged by the long standing use of chloroquine (1.1) and quinine (1.2) and the
discovery of various other agents such as artemisinin (1.3), plant metabolites and their
synthetic derivatives are an extremely important source of new antimalarial agents. 2 ' 5
The fact that malaria is considered the world's most important tropical disease killing more
people than any other disease except tuberculosis and 1-11V/AIDS, 6 deemed it important that
synthetic studies of the bisbenzylisoquinoline alkaloids directed towards structure-activity
relationship be undertaken. Our choice of this study was also stimulated by recent reports
that showed that the change of configuration of the chiral centre, as well as modification of
the substituents, might lead to independent changes in the cytotoxicity and antimalarial
activity of the bisbenzyltetrahydroisoquinoline alkaloids. 5 '7 For this reason,
bisbenzylisoquinoline alkaloids can be regarded as a promising novel antimalarial and thus
constitute an attractive synthetic goal that merit further investigations.
1
Cl
TAN /./* N
1.1
1.2
1.2 Malaria
The deterioration in the efficacy of conventional antimalarial drugs is a matter of great
concern. At present there are no effective drugs that offer protection against malaria in all
regions of the world. 8 This implies that malaria is by far the most serious and widespread
parasitic disease and is one of the major health problems in the world. It is estimated that
300-500 million cases of malaria occur annually, with between one and two million deaths
every year. Most of the people who die are children and non-immune adults and about 90%
of the cases occur in Sub-Saharan Africa. Of the four species of Plasmodium (P. vivax, P.
ovale, P. fakzparum and P. malariae) that causes malaria in humans, Plasmodium falciparum
is the most dangerous, as the pathology it induces often leads to death. It causes Malaria
tropica, which, without treatment, is very often lethal for infected patients. 1 '5 '9' 1°' 11
Although a number of effective drugs have been developed, there is still a serious need for
the development of a new drugs since the resistance of the parasite to many of the older drugs
has now reached a point where it is virtually useless to apply these drugs in many malarious
2
regions. 29,10,11 In some malarial areas, 90% of parasite strains are already resistant to
chloroquine (1.1), the most widely-used drug for the treatment and protection against malaria
from the 1950's onward. 12 A similar situation applies for other drugs.
Chloroquine (1.1) has been the first-line drug since its synthesis in 1940, because it is very
efficacious, exhibits a quick onset of action and is inexpensive while having tolerable adverse
effects. The emergence of chloroquine-resistance and a world-wide scarcity of quinine have
led to the search for new antimalarial drugs. 9 A number of new drugs have been developed
and artemisinin (1.3) is the one that offers the best hope so far. An increasing number of
countries have been forced to adopt a different class of drugs as the first-line alternative to
chloroquine (1.1). However, the resistance of the parasite to various drugs has now increased
and this threatens to leave various countries, especially Africa, with no treatment affordable
on a mass scale. 9
Considering that chloroquine (1.1) is inexpensive, safe for use in pregnancy and was
previously highly efficacious, the loss of this drug has been a major setback to the effective
treatment and control of this disease.
The recognition and validation of traditional medical practices and the search for plant-
derived drugs could lead to new strategies in malaria contro1. 3' 5 ' 1° South Africa, with its rich
floral resources and ethnobotanical history, is an ideal place to screen plants for antimalarial
activity. 10
1.3 Bisbenzylisoquinoline alkaloids
Bisbenzylisoquinolines (BB1) alkaloids are a large and diverse group of natural alkaloids that
are found mainly in five plant families, the Menispermaceae, Berberidaceae, Ranunculaceae,
Annonaceae, and Monimiaceae. 7' 13 This family of alkaloids contains over 270 members and
is rich in pharmacologically active constituents that range in activity from cytotoxicity to
antihypertensive to antimalaria. 3 Many of the plants that contain these alkaloids enjoy a
folkloric reputation as medicinals in various cultures. They are used for the treatment of a
3
number of diseases, including amoebic dysentery, leishmaniasis, bacterial infections, and
cancer.
Bisbenzylisoquinoline alkaloids are made up of two benzylisoquinoline units linked by ether
bridges. The two units may be bonded together by one, two, or three diaryl ether
linkages. 14,15,16,17,18 In addition to these diaryl ether bridges, methylenoxy bridging or direct
carbon-carbon bonding are also found between the two benzylisoquinoline units. Individual
members in each group differ simply in the nature of the oxygenated substituents (OH,
OCH3, OCH2O), the nature of substitution of two nitrogen atoms (NH, NCH3, N +(CH3)2,
NO), the degree of unsaturation of the hetero rings, and the stereochemistry of the two
asymmetric centers. 14,15,16,17,18
1.3.1 Nomenclature of bisbenzylisoquinoline alkaloids
The numbering of the carbon skeleton of all bisbenzylisoquinoline alkaloids follow the
system established by Shamma and Moniot, 13 "14 19 as shown below (Scheme 1.1).
13
13'
SCHEME 1.1: Numbering of the bisbenzylisoquinoline alkaloids
1.3.2 Biosynthesis of bisbenzylisoquinoline alkaloids
Bisbenzylisoquinoline alkaloids are believed to arise in plants by the oxidation of phenolic
bases of the benzylisoquinoline group, and in particular all can be represented as being
derived from norcoclaurine (1.10) or coclaurine oll 43,1520,21 The initial step of the
4
HO
H2O
H COO- C°2
HO
CO2 >I" HO
1.55
COO- HO
HO
NH2 HO
1.6
1.7
1.4
HO
HO
H3C0
biosynthesis is the coupling of dopamine (1.7) and 4-hydroxyphenylacetaldehyde (1.8) in a
stereospecific manner to give (S)-norcoclaurine (1.10) as indicated in scheme 1.2. This
stereospecific condensation is catalysed by an enzyme called (S)-norcoclaurine synthase. 2°
L-Dopa (1.6) is an intermediate in primary metabolism. Dopamine (1.7) and 4-
phenylacetaldehyde (1.8) formation involve the decarbolxylation of tyrosine (1.4) and/or
dopa (1.6) by tyrosine/dopa decarboxylase.
1.9 1.8
1.11 (S)-Coclaurine
1.10 (S)-Norcoclaurine
SCHEME 1.2: Biosynthetic pathway of norcoclaurine from tyrosine. (a) (S)-norcoclaurine
synthase; (b) norcoclaurine-6-O-methyltransferase
The oxidation process may be represented as shown in Scheme 1.3. This process proceed via
a free radical that may be represented either by structure 1.13 or 1.14 and the pairing of the
radicals in these two forms could afford dienone 1.15, enolisation of which would lead to the
hydroxydiphenyl ether 1.16.
5
1.15 1.16
OH
SCHEME 1.3: Oxidative phenolic coupling in the biosynthesis process of the
bisbenzylisoquinoline alkaloids
When oxidative coupling of this type takes place with norclaurine (1.10), bases with one,
two, and diaryl ether linkages are formed (Scheme 1.4). Coupling in position 12 and 11' of
norcoclaurine (1.10) produces diaryl ether 1.17 of which further coupling can give di-ether
1.22 and tri-ether 1.24 while dehydration of the di-ether 1.22 can lead to another type of of
tri-ether 1.23. If the initial coupling to a mono-ether occurs in position 12 and 8' the product
1.18 can then couple further to a di-ether in two ways, either by 7 and 11' or 8 and 12'
combination to give 1.20 and 1.19 respectively. Due to steric reasons, neither
bisbenzylisoquinoline 1.20 nor 1.19 can undergo further oxidative coupling to a give tri-
ether.
6
1.18
,4:8' coupling
1.19 1.20
8/12'
OH
OH OH
OH
OH
NH FIN
12/11' ---ir.
8/7' OH
- H2O
OH
1.23 1.24
6 OH HO 6'
1411 0 11
12 OH H• 12
1.10
OH H
SCHEME 1.4: Oxidative phenolic coupling of norcoclaurine at various positions
7
H3 C OR
OCH3
1.26 R = CH3
1.27 R = H
H3CO
CH3
1.25
1.3.3 Chemical constituents of Cissampelos capensis
Members of the Menispermaceae are rich sources of unique alkaloids, and these plants are
globally often used in folk medicine. Cissampelos capensis is a dioecious, scandent shrub
that occurs naturally only in the western part of South Africa and the southern part of
Namibia. In ethnobotanical surveys of medicinal plants, it was found that C capensis is one
of the most important traditional medicines in this region. The fresh or dry rhizomes are
chewed directly, smoked, or used as infusions and tinctures for headache, pain, diabetes,
tuberculosis, dysentery, urinary stones, glandular swellings and even for stomach and skin
cancer. 22,23
A recent phytochemical investigation of Cissampelos capensis4 has led to the isolation of a
novel BBI cissacapine (1.25), along with the known compounds insularine (1.26),
insularoline (1.27), cycleanine (1.28) and glaziovine (1.29).
Bisbenzylisoquinolines containing a tricyclic dibenzodioxepine nucleus are extremely rare
and, to our knowledge, the three compounds cissacapine (1.25), insularine (1.26) and
8
insularoline (1.27), are the only three natural occurring compounds of this type that have been
identified so far."34'24
H3CO
HO CH3
1.29
1.28
1.4 Aim of this study
In a quest for biologically more potent antimalarial bisbenzylisoquinoline alkaloids, we
envisioned to study the synthesis of these compounds and their modified analogues with
variations of substituents. Bisbenzylisoquinoline alkaloid cissacapine (1.25) is a novel
compound and no synthetic study of this compound has been reported so far. A similar
situation applies for the bisbenzylisoquinolines insularine (1.26) and insularoline (1.27), even
though these compounds have been known for the number of years. 24'25 The total synthesis
of racemic cycleanine (1.28) has been reported previously. However, very low yields in the
formation of diaryl ether and other reactions as well as the lack of detail spectral evidence for
some of the synthesised compounds makes the published synthesis unattractive. 26 Low yields
in diaryl moiety formation make the synthesis not suitable for large-scale synthesis.
The objective of this study was to develop a synthetic pathway for the synthesis of suitable
precursors for the total synthesis of the bisbenzylisoquinoline cissacapine (1.25), insularine
(1.26), insularoline (1.27) and cycleanine (1.28). The developed synthetic routes will be of
9
importance not only to the total synthesis of the above-mentioned natural
bisbenzylisoquinoline compounds, but also as a vehicle for the access to modified analogues
for structure-activity investigations since it is known that change of configuration of the
chiral centre and change in substituents of the bisbenzylisoquinolines may lead to
independent changes in cytotoxicity and antiplasmodial activity.' As part of this study we
also needed to develop efficient methodology for the preparation of the tricyclic 1 1H-
dibenzo[b,e][1,4]dioxepine ring. The two available methods in the literature for the
preparation of this tricyclic system suffer from poor yields. 27'28
10
1.5 References
Y. Asakawa and M. Heidelberg, Progress in the Chemistry of Organic Natural
Products, Springer-Verlag, 1982, 42, p. 4.
M.C. Gessler, M.H.H. Nkuya, L.B. Mwasumbi, M. Heinrich and M. Tanner, Acta
Tropica, 1994, 56, 65.
T.M. Kutchan, Gene, 1996, 179, 73.
F.R. van Heerden, unpublished work.
5 S.J. Marshall, P.F. Russel, C.N. Wright, M.A. Anderson, J.D. Phillipson, G.C. Kiby
and P.L. Schiff, Antimicrob. Agents Chemother., 1994, 38, 96.
0. Schwarz, R. Brun, J.W. Bats and H.-G. Schmalz, Tetrahedron Lett., 2002, 43,
1009.
C.K. Angerhofer, H. Guinaudeau, V. Wongpanich, J.M. Pezutto and G.A. Cordell, J.
Nat. Prod., 1999, 62, 59.
J.C.P. Steele, M.S.J. Simmonds, N.C. Veitch and D.C. Warhurst, Planta Med., 1999,
65, 413.
A.R. Bilia, D. Lazari, L. Messori, V. Tagliohi, C. Tempereni and F.F. Vincieri, Life
Sci., 2002, 70, 769.
E.A. Prozesky, J.J.M. Meyer and A.I. Louw, J. Enthopharm., 2001, 76, 239.
T. Lemcke, I.T. Christensen and F.S. Jorgensen, Bioorg. Med. Chem., 1999, 7, 1003.
M. Hesse, Alkaloids, Verlag Helvetica Acta, Zurich, 2002, p. 309.
P.L. Shiff, J Nat. Prod., 1983, 46, 1.
K.P. Guha, B. Mukherjee and R. Mukherjee, J. Nat. Prod., 1979, 42, 1.
K.W. Bentley, The Isoquinoline, Pergamon Press, New York, 1965, p. 41.
M. Shamma and V. Georgiev in The Alkaloids, R.H.F. Manske, Ed., Academic Press,
New York, 1977, 16, p. 319.
M. Shamma and J.L. Moniot, Isoquinoline Alkaloids Research, Plenum Press, New
York, 1978, p. 1.
T. Kametani in The Total Synthesis of Natural Products, J. apSimon, Ed., John Wiley
& Sons, New York, 1977, 3, p. 1.
M. Shamma and J.L. Moniot, Heterocycles, 1976, 4, 1817.
11
20. R. Stadler, T.M. Kutchan, S. Loeffler, N. Nagakura, B. Cassels and M.H. Zenk,
Tetrahedron Lett., 1987, 28, 1251.
21 P.M. Dewick, Medicinal Natural Products, A Biosynthetic Approach, 2nd Ed, John
Wiley and Sons, New York, p. 323.
B.-E. van Wyk, B. van Oudtshoorn and N. Gericke, Medicinal Plants of Southern
Africa, Briza Publications, Pretoria, 1997, p. 87.
B.-E. van Wyk and N. Gericke, People 's Plants. A guide to useful plants of Southern
Africa, Briza Publications, Pretoria, 2000, p. 124.
Dictionary of Natural Products on CD-ROM, J. Buckingham, Ed., Chapmann and
Hall, London, 2000.
M. Tomita and S. Uyeo, J. Chem. Soc. Jpn., 1943, 64, 147.
M. Tomita, K. Fujitani and Y. Aoyagi, Chem. Pharm. Bull., 1968, 16, 62.
W.K. Hagmann, C.P. Dorn, R.A. Frankshun, L.A. O'Grady, P.J. Bailey, A. Rackham
and H.W. Dougherty, J Med.. Chem., 1986, 29, 1436.
W.K. Hagmann, L.A. O'Grady, C.P. Dom and J.P. Springer, J. Heterocycl. Chem.,
1986, 23, 673.
12
— CH3 H3C''
Cu(I)C1, K2CO3 165 °C al' 5.2%
CH3
2.1 RI = R3 = Br, R2 = R4 = CH3 2.2 RI = R2 = R3 = Rs = H
CHAPTER 2
SYNTHESIS OF BISBENZYLISOQUINOLINE ALKALOIDS:
A LITERATURE REVIEW
2.1 Introduction
Although many bisbenzylisoquinoline alkaloids have been isolated,' the total synthesis of
these compounds has received little attention. However, several partial syntheses have been
reported recently.
Bisbenzylisoquinoline alkaloids have been prepared through routes mainly involving
condensation of two appropriate benzylisoquinoline monomers through diaryl ether
formation using the copper-catalysed Ullmann ether synthesis. 2 In most cases this approach
has presented problems as the desired bisbenzylisoquinoline alkaloids were formed in low
yields because of the limitations of the Ullmann reaction. This approach is demonstrated by
the condensation of two racemic benzylisoquinoline alkaloids 2.1 and 2.2 to give the
bisbenzylisoquinoline (±)-0,0-dimethylcurine (2.3) in 5.2% yield (Scheme 2.1). 3
SCHEME 2.1
13
2.7 2.8 2.9
OCH3
CuO p-TsOH
13% OBut
OH
Another example is the Ullmann condensation of compounds 2.4 and 2.5 to produce
bisbenzylisoquinoline 2.6 in 10.7% yield (Scheme 2.2). 4
H3C0
R30
R20
R
CH3 H3C
Cu powder, K2CO3 a. KI, 70 h, 180 °C
10.7%
CH3
2.4 R 1 = Br, R2 = R3 = CH2Ph
2.5 R1 = R2 = H, R3 = CH2Ph 2.6 R 1 = R2 = CH2Ph
SCHEME 2.2
Alternatively, two appropriately substituted diaryl ethers are first synthesised through the
Ullmann reaction, one containing a carboxymethyl group and the other containing an 2-
aminoethyl group. The two diaryl ether precursors are then combined via amide linkages,
and the two isoquinoline rings are constructed by either Bischler-Napieralski 5 or Pictect-
Spengler6 reactions. Similarly as in the above strategy, most diaryl ether formation reactions
presented problem as the starting materials were not suitable for Ullmann coupling.
SCHEME 2.3
14
CuO • HC1/CH3OH 27%
2.10 2.11 2.12
OCH3 O-\
O 0
DCC, 70% aq. Na2CO3, 90% (i) DCC, p-nitrophenol
2.12 (ii) HBr/HOAc ' (iii) pyridine
43%
2.9 +
One example of this approach is in the total synthesis of dl-cepharanthine (2.14) in which
diaryl ether formation via Ullmann reaction to form precursors 2.9 and 2.12 resulted in 13%
and 27% yields, respectively (Schemes 2.3 and 2.4). 7'8
SCHEME 2.4
Diaryl ethers 2.9 and 2.12 were then combined via amide linkage to give cyclobisamide 2.13,
which in turn was converted to di-cepharanthine (2.14) in three steps via Bischler-Napieralski
conditions. The dl-cepharanthine (2.14) was obtained in 0.5% yield from cyclobisamide 2.13
(Schemes 2.5 and 2.6).
2.13
SCHEME 2.5
15
H3C" CH3
H3 CO
0
H3 CO
2.14
SCHEME 2.6
2.13
POC13 , CHC13 Reduction CH20, NaBH4
0.5% V
2.2 Synthesis of isoquinoline ring
The general methods for the preparation of the isoquinoline ring system based on formation
of a tetrahydropyridine can be divided into five types (2.15 to 2.19)." ° The dotted lines
indicate the bond formation by cyclisation.
16
2.15
2.16
2.17
2.18
2.19
Although examples of all these reactions are known, the most popular ones are of type 2.15
and 2.19. These two types usually gives dihydro- or tetrahydroisoquinoline compounds.
Type 2.15 involves ring cyclisation between the benzene ring and the carbon atom that forms
C-1 of the resulting isoquinoline ring. The very useful Bischler-Napieralski and Pictect-
Spengler reactions fall in this category. 5'
6
'
9
'
10
'
11 Type 2.19 involve ring closure between the
benzene ring and C-4 of the resulting isoquinoline ring, and includes the Pomeranz-Fritsch
reaction. 9' 1°
Of the three methods mentioned above, only the Bischler-Napieralski reaction will be
discussed in detail, as this reaction has been widely used in the synthesis of
bisbenzylisoquinoline alkaloids.
2.2.1 Bischler-Napieralski reaction
The Bischler-Napieralski reaction is one of the methods of choice for the preparation of
isoquinoline compounds. This method consists of the cyclodehydration of an N-acyl-f3-
phenethylamine 2.20 with Lewis acids such as phosphorus oxychloride, phosphorus
pentoxide, polyphosphoric acid or zinc chloride in an inert solvent to give the corresponding
3,4-dihydroisoquinoline 2.21 (Scheme 2.7). These compounds must be reduced to the
1,2,3,4-tetrahydroisoquinolines 2.22 since the isoquinoline alkaloids exist as the tetrahydro
17
2.20 2.21 2.23
Lewis acid NH A No N N
0 R R2
derivatives in most cases. 5,9,10,12,13,14 Of the Lewis acid, phosphorus oxychloride is the most
widely used. The 3,4-dihydroisoquinoline 2.21 can also be dehydrogenated to the
corresponding isoquinoline 2.23. The Biscler-Napieralski conditions usually require
electron-donating substituents such as the alkoxy on the aromatic ring and substrates lacking
electron-donating groups often fail to cyclise or cyclise in low yields."
iBeckmann rearrangement
R 1 = H, Alkoxy, Alky
R2 = Alkyl, Aryl
2.24
2.22
SCHEME 2.7: Bischler-Napieralski reaction
Oximes 2.24 that are capable of undergoing a Beckmann rearrangement 16' 17 to N-acyl-fl-
phenethylamine 2.20 can also be used as starting material for the Bischler-Napieralski
reaction as indicated in Scheme 2.7. 5 '9' 10' 12
Cortes" has recently developed a one-pot methodology in which the N-acyl-P-
phenethylamine 2.20 (R2 = benzyl) cyclised to give the 3,4-dihydroisoquinolines 2.21 which,
without isolation, undergoes reduction-alkylation to give 1,2,3,4-tetrahydroisoquinolines
alkaloids as their N-allcylated derivatives. This process is usually carried out in more than
one step with isolation of the intermediate or product of each step. The one-pot cyclisation-
reduction-alkylation procedure is carried out using the commonly used Bischler-Napieralski's
18
Lewis acid phosphorus oxychloride followed by the addition of sodium borohydride in
methanol or ethanol. N-alkylation (N-methylation, N-ethylation) is assumed to be effected by
PO(OCH3)3 or P0(0C2H5)3 generated from phosphorus oxychloride and methanol or ethanol.
2.2.1.1 Reaction mechanism
The first mechanism proposed for the Bischler-Napieralski reaction consists of the
protonation of the amide oxygen by an acid, followed by cyclisation to 1-
hydroxytetrahydroisoquinoline 2.25 and dehydration to the 3,4-dihydroisoquinoline 2.21
(Scheme 2.8). 5'9' 1213,14
-
O R2H
2.20 -
2.25
R I = H, Alkoxy, Alkyl R2 = Alkyl, Aryl
POC13 A
2.21
SCHEME 2.8: First proposed mechanism of the Bischler-Napieralski reaction
19
2.20
NH Lewis acid R1 NH A
Cl-
2.21
2.26
RI = H, Alkoxy, Alkyl R2 = Alkyl, Aryl
SCHEME 2.9: Revised mechanism of the Bischler-Napieralski reaction
In contrast to the mechanism in Scheme 2.8, Fodor 123334 showed that a variety of N-acyl-P-
phenethylamine 2.20 give the imidoyl halides or their hydrohalides under milder conditions
with various Lewis acids such as phosphorus oxychloride, phosphorus pentoxide, thionyl
chloride and carbonyl bromide (Scheme 2.9). Dehydration or loss of carbonyl oxygen must
precede ring closure. The imidoyl chlorides cyclise to give 3,4-dihydroisoquinoline
2.21. 12,13,14 The reaction goes via nitrilium ion 2.26.
2.2.1.2 Direction of ring closure
Cyclisation to form 3,4-dihydroisoquinoline 2.21 under Bischler-Napieralski conditions
depends on the nature and position of the substituents on the aromatic ring. Cyclisation
occurs at the ortho or para position to the substituent with more electron donating properties.
An example of this is m-methoxy-p-phenethylamide (2.27), which cyclise to give exclusively
6-methoxyisoquinoline (2.28). 5'" In this case, both ortho and para position to the methoxy
20
2.27
Rl = Alkyl, Aryl = CH2Ph (81%) 2.29
H3CO
SCHEME 2.10
OCH3 CH3
POC13
82% NH
O OCH3 CH3
group are available for cyclisation but the para position becomes the preferred position
(Scheme 2.10).
When the para position is blocked as in N-acetyl-2,5-dimethoxyphenethylamine (2.30),
cyclisation will proceed ortho to the methoxy group (Scheme 2.11)."'"
2.30 2.31
SCHEME 2.11
21
NH POC13
OR R'
H3CO
H3CO
If both available position are activated to a similar extent, a mixture of both cyclised products
are obtained. For example, amide 2.32 cyclise to give a mixture of 2.33 and 2.34. 19
2.32 R = CH2Ar 2.33 R2 = CH3 2.34 R2 = CH2Ar
R3 = CH2Ar
R3 = CH3
SCHEME 2.12
2.2.1.3 Enantioselective synthesis of optically-pure isoquinoline alkaloids
via the Bischler-Napieralski reaction
Most natural occurring 1-substituted 1,2,3,4-tetrahydroisoquinoline alkaloids possess the 1 S
absolute configuration, but some have the 1R configuration. Although many 1-substituted
1,2,3,4-tetrahydroisoquinoline alkaloids, among which 1 -benzyl derivatives are most widely
distributed, exhibit totally different biological activities between 1S and 1R enantiomers,
most synthetic methods for their preparation are suitable only for the synthesis of the racemic
compounds requiring resolution of the resulting products by chiral acids.9.10,11
A number of asymmetric syntheses for optically-pure isoquinoline have been developed. 2° '2I
Many of the synthetic methods are based on the procedures employing chiral building blocks,
auxiliaries, or reagents. For example, in the Pictect-Spengler,20,22,23 asymmetric synthesis
using as the key step sodium borohydride reduction of optically-pure a-alkylbenzylamine
derivatives ,24,25,26,27 reduction of 1-substituted 3,4-dihydroisoquinolines by chiral reagents
such as chiral sodium (triacyloxy)borohydrides 28 '29 '3° and BH3 :THF-thiazazincolidine, 31
addition of organometallic reagents to chiral iminium compounds,32 ' 33 '34 '35 ' 36 catalytic
22
asymmetric hydrogenation of 1-substituted 3,4-dihydroisoquinolines by Buchwald's chiral
titanocene complex, 37 • 38 '39 '4° Morimoto's chiral BINAP-Ir-phthalimide or diphosphine-lr-
phthalimide complexes,4I '42 or Noyori's chiral BINAP-metal complexes. 43,44,45,46
All of the above asymmetric approaches, with exception of the Pictect-Spengler, proceed
through the Bischler-Napieralski reaction. Although all these approaches are important in
producing optically-pure isoquinoline alkaloids in good chemical and optical yields, the ones
that are very concise and highly stereoselective include:
approach via reduction of 1-substituted 3,4-dihydroisoquinolinium ion possessing a chiral
auxiliary by Polniaszek 25 '26'" and Cortes 24 and
enantioselective synthesis via catalytic asymmetric hydrogenation of 1-substituted 3,4-
dihydroisoquinolines with chiral catalyst by Buchwald, 37,38.38,39.40 Morimoto41 '42 or
Noyori.43 '44
Polniaszek 's approaches involves preparation of chiral N-acy1-13-phenethylamines from either
(S)-1-phenethylamine or (R)-1-phenethylamine and acid chlorides as shown in Scheme 2.13.
The chiral amides 2.37 are converted to chiral 3,4-dihydroisoquinolinium ions 2.38 by a
Bischler-Napieralski reaction. Reduction of the iminium ions 2.38 with sodium borohydride
at —78 °C gives optically-pure tetrahydroisoquinolines 2.39 with very high stereoselectivity.
The diastereoselection of the hydride reduction (NaBH 4, -78 °C) ranged from 88:12 to 94:6.
Cortes' approach 24 follows in a similar manner but employs the (S) and (R) stereoisomers of
phenylglycinol instead of the 1-phenethylamines.
23
2.35 2.36 2.37
0 H3CO ab
H3 CO
H3CO c or d or
HN Ph e or f H3 CO
R = CH3 (97%) R = CH2CH3 (98%) R = i-Pr (98%) R = 3,4-(CH3O)2PhCH2 (88%)
H 3 CO
H 3CO
H3CO
Ph -413--
r'CH3 H3CO
ig
2.40 2.39
2.38
R = CH3 (85%) R = CH2CH3 (76%) R = i-Pr (89%) R = 3,4-(CH3O)2PhCH2 (82%)
R = CH3 (77%) R = CH2CH3 (75%) R = i-Pr (61%) R = 3,4-(CH3O)2PhCH2 (72%)
Reagents: (a) (S)-(-)-1-phenethylamine, Et 3N, DMAP; (b) BH 3 :THF, reflux, 3 days; (c) Ac20, DMAP, Et 3N (d) Propionyl chloride, DMAP, Et 3N; (e) Isobutyryl chloride, DMAP, Et3N; (f) 3,4-Dimethoxyphenylacetyl chloride, DMAP, Et3N; (g) POC13, benzene, 5-24 h; (h) NaBH4, Me0H, -78 °C; (i) 10% Pd-C, H2, 10% HCl
SCHEME 2.13: Chiral auxiliary mediated synthesis of optically-pure isoquinoline by
Polniaszek approach.
An example of the catalytic asymmetric hydrogenation of the 3,4-dihydroisoquinolines is
shown in Scheme 2.14 in the synthesis of the 1,2,3,4-tetrahydroisoquinolines 2.41 and 2.42.
This transformation was effected by Morimoto's BINAP catalysts. 41 '42
24
H3 CO
H3CO
H3 CO H2 (100 atm)
(R)-BINAP-Ir(I)-F 4-pthalimidea 2-5 °C, toluene-MeOH H3CO
85%
OCH2Ph
H3CO
H3 CO
H3 CO H2 (.100 atm)
(S)-BINAP-Ir(I)-paranabic acid 2-5 °C, toluene-MeOH H3 CO
99%
2.41 86% ee
2.42 89% ee
SCHEME 2.14: Morimoto's asymmetric catalytic hydrogen of 3,4-dihydroisoquinolines
2.2.2 Pictect-Spengler reaction
The Pictet-Spengler reaction involves formation of 1,2,3,4-tetrahydroisoquinoline derivatives
2.22 by the condensation of P-arylethylamines 2.43 with carbonyl compounds. The Schiff
bases 2.44 are the intermediate in the reaction. The reaction is acid-catalysed. 6,9,10,22,23
H+ RI R I
R1 = H, Alkyl, Alkoxy R2 = H, Alkyl, Aryl
2.43
2.44
2.22
SCHEME 2.15: Pictect-Spengler reaction
25
OEt H2N
NH2
OEt
rLOEt H+
N
2.45
2.46
-311.
OEt
OEt
I )OEt OEt
OEt
2.2.3 Pomeranz-Fritsch reaction
The Pomeranz-Fritsch reaction involves cyclisation of benzalaminoacetals 2.45 and 2.46 in
the presence of acid to yield aromatic isoquinolines (Scheme 2.16). This cyclisation is
generally carried out with sulphuric acid. Although only moderate yields are obtained, the
use of polyphosphoric acid as the cyclising agent is successful in all cases, particularly for the
preparation of 8-substituted isoquinolines. The Schiff base can be formed either by
condensation of the aromatic aldehyde with aminoacetals or from benzylamine with glyoxal
hemiacetals, as shown below. 9' 10
SCHEME 2.16: Pomeranz-Fritsch reaction
The Pomeranz-Fritsch reaction offers the possibility of preparing isoquinolines with
substituents that would be difficult to obtain by the Bischler-Napieralski or the Pictect-
Spengler reaction. For example, the 8-substituted isoquinolines are obtained from the ortho-
substituted benzaldehyde, whereas 8-substituted isoquinolines are generally not obtained
from meta-substituted arylethylamines by the Bischler-Napieralski reaction (Scheme 2.10). In
addition, this method yields a product that is a fully aromatic isoquinoline, whereas the
partially or fully hydrogenated isoquinolines are obtained in case of the above two reactions
using phenethylamines.
26
important natural compounds such as vancomycin (2.47) has
development of new methodology for its preparation.
Cl
renewed efforts in the
OH
NH
O ..„ NHCH3
-----r-
2.3 Diaryl ether synthesis
The presence of diaryl ether linkage in a number of synthetically challenging and medicinally
2.47
As mentioned in chapter 1, bisbenzylisoquinoline alkaloids are built up of one or more diaryl
ether linkages. Various methods for the construction of diaryl ethers are known.
Unfortunately, each of these methods has its problems; generally every method is limited to
certain substrates. This section will discuss various methods for construction of diaryl ethers
and their limitations.
27
2.4 Methods for diaryl ether synthesis
Despite limitations under the original conditions, such as high temperatures and generally
low yields, the Ullmann ether synthesis e has been the most important method for the
preparation of diaryl ethers of a variety of naturally occurring and medicinally important
compounds. A number of interesting and useful technique for diaryl ether synthesis have
been recently reported. 47'48
The common reactions that generate diary] ethers 2.50 from aryl halides 2.48 and phenols
2.49 are nucleophilic aromatic substitutions and copper-catalysed Ullmann reaction.
Unfortunately, nucleophilic aromatic substitutions are most favourable with the more
expensive and less available aryl fluorides. 47,48,49,50,51
X HO
A
X =Br,I,F
2.48
2.49
2.50
SCHEME 2.17: Diaryl ether preparation
2.4.1 Nucleophilic aromatic substitution
Aryl fluorides bearing an electron withdrawing groups ortho orpara to the fluoride group can
easily undergo nucleophilic displacement to give diaryl ether compounds in the presence of
base without added catalyst. 47,48,49,50,51,52 For example, p-fluoroacetophenone or p-
fluorobenzaldehyde combine with a variety of phenols 2.51 to afford diaryl ethers 2.52 in
high yields (Scheme 2.18). 49
28
CO2CH3
2.53
K2CO3, CuO 31. pyr., reflux
1.5% , NHB oc
CO2CH3
2.55
CO2CH3
2.54
OH
+ K2CO3, DMAC 3...
0 reflux, 5.5-10 h RI 70-93 %
2.51 R1 = H, Cl, Br, '13u, OCH 3, OPh, CO2Et
2.52
R2 = H, CH3
SCHEME 2.18
2.4.2 Copper-catalysed Ullmann ether synthesis
This method involves reaction of the aryl halides 2.48 (X = I, Br) with phenols 2.49 under
basic conditions in the presence of copper salt catalysts as shown in Scheme 2.17. The
classical Ullmann conditions require high temperature (-115-260 °C) and long reaction times
(up to 24 h) and often produces low to moderate yields for substituted aryl halides unless the
strongly electron withdrawing group is present on the aryl halides para or ortho to the
halogen. Furthermore, the Ullmann reaction is limited to electron-deficient aryl halides. In
other words, electron-rich aryl halides do no work wel1. 49'5"3'54'55 '56 For example, Ullmann
condensation of the electron-rich aryl bromide 2.53 with phenol 2.54 gave the desired diaryl
ether 2.55 in 1.5% yield. 55
SCHEME 2.19
29
K2CO3, CuO pyr., reflux
93%
ii. CHO
OCH3
OH
+
, NHCbz
CO2But
CHO
2.56
2.57
SCHEME 2.20
Under similar conditions diaryl ether 2.57 was obtained in 93% yield when an electron-
deficient aryl bromide 2.56 was used. 55
Recently, a number of groups have reported the use of other copper salts in the presence of
additives and this has made it possible to carry out these reactions under milder conditions
with a wider variety of substrates in moderate to good yield. Smith and Jones 57 reported that
the use of catalytic copper(I) iodide and ultrasound in the absence of solvent gave better
yields of diaryl ethers than Ullmann conditions at 140 °C. The authors speculated that the
role of sonification was primarily to break up particles of the base (K2CO3) and catalyst
(cuprous iodide). Coupling of electron-rich o-bromoanisole with phenol gave 75% of the
corresponding diaryl ether.
A procedure developed by Palomo 58 involves the use of CuBr and phosphazene P4-Bu t base
in refluxing toluene. The authors indicated that the method is particularly suitable for
electron-neutral aryl halides and ortho-substituted phenols although p-iodoanisole combined
with p-cresol to give the desired diaryl ether in 70% yield.
Another copper-catalysed methodology developed by Buchwald 59 is based on the reaction of
cesium phenoxides with aryl bromides or iodides 2.58 in the presence of air-labile copper(11)
triflates (Scheme 2.21). In certain cases equimolar amounts of 1-naphthoic acid has been
30
(CuOTf)2.PhH, cat. EtOAc Cs2CO3, toluene, reflux
R2 20-93%
HO
added to increase the reactivity of the phenoxides. Toluene was found to be the effective
solvent when catalytic amount of ethyl acetate (5 mol %) was included in the reaction
mixture. The formation of more soluble copper(I) complexes, resulting from the formation of
an adduct between the added ester and the alkoxide, has been proposed to be responsible for
the rate enhancement. However, addition of more than 5 mol % of ethyl acetate results in
low conversions. Electron-deficient aryl bromides or iodides reacted to give diaryl ethers
2.59 in high yields. This method was also found to tolerate unactivated aryl halides. For
example, o-bromoanisole and p-cresol reacted to give 79% of the diaryl ether compound.
Sterically hindered phenols react in low yields. For example, 2,6-dimethylphenol reacts with
5-iodo-m-iodoxylene to give 20-30% of the diaryl ether. The author assumed the formation
of a cuprate-like intermediate [(ArO)2Cu]Cs as a reactive species.
2.58
2.59
X = Br, I
R1 = H; 2-CO2H; 4-CH3; 4- tBu; 2-OCH3; 4-CN; 4-CO CH3; 2,5-(CH3)2; 3 ,5 (CH3)2 R2 = H; 2-CH3; 4-CH3; 4-Cl; 2,6-(CH3)2; 3,4-(CH3)
SCHEME 2.21
Nicolaou's group" developed an approach based on the activation of aryl halides with a
triazene unit. Aryl bromides and iodides substituted with ortho-triazene and phenols react to
give good yields of diaryl ethers at 80 °C in the presence of CuBr.SMe2 and K2CO3. The 2,6-
dihaloaryltriazenes react faster and more efficiently than the corresponding monosubstituted
triazenes as shown in the following two examples (Schemes 2.22 and 2.23).
31
OH Br
CuBr.SMe2, K2CO3 MeCN:pyr. (5:1), 2 h, 80°Cpw
91%
OH
2.62
Br
2.63
2.60 2.61
SCHEME 2.22
The use of this approach requires the preformation of the requisite triazene unit and the
removal of this group after diaryl ether formation, unless the target compound bears this
functional group (triazene).
CuBr.SMe2, K2CO3 au.
MeCN:pyr. (5:1), 16 h, 80°C 65%
SCHEME 2.23
Snieckus' group61 reported a procedure that uses catalytic CuPF6(CH3CN)4 in the presence of
obligatory cesium carbonate to facilitate coupling of phenols to o-halo tertiary and secondary
benzamides and sulphonamides (i.e. ArCONHEt, ArCONEt2, ArSO2NHEt2, ArSO2NEt2).
32
Both iodine, bromine and chlorine can be used as leaving group. Diaryl ethers were obtained
in 47-97% yields. Gujadhur and Venkataraman 62 reported the use of Cu(PPh3)3Br and
cesium carbonate in NMP. Electron-deficient aryl halides reacted in high yields. Reactions
ofp-bromotoluene with electron-deficient phenols were unsuccessful. Electron-rich o- andp-
bromoanisole react with p-cresol to give the corresponding diaryl ethers in 61% and 75%
yields, respectively.
Remarkable improvements with regard to the diaryl ether synthesis with copper salts came
from Song, 63 Hauptman,64and Evans. 65 The methods by Song 63 and Hauptman" allow diaryl
ether formation from aryl bromides or iodides and phenols using cuprous chloride and cesium
carbonate in the presence of ligands. Song 63 employed 2,2,6,6-tetramethylheptane-3,5-dione
(TMHD) (2.64) as the ligand and NMP as the solvent. Electron-rich aryl halides were
reacted with various phenols in the presence of TMHD (2.64) to form good yields of diaryl
ethers.
2.64
Hauptman' s methodology" use pyridine-type ligands in place of TMHD (Scheme 2.24). For
example, a highly electron rich, unprotected aniline 2.65 react with potassium phenoxide in
anhydrous diglyme at 90-95 °C to produce diaryl ether 2.66 in 69% yield.
NH2 NH2
H3C Br KO H3C
CuCI, v. 8-hydroxyquinoline
69%
CH3
2.65
CH3
2.66
SCHEME 2.24
33
BocHN,,
Cu(OAc)2, pyr. BocHN
CH2C12, 4 A mol sieves 95%
1-1 3 C 2 C
2.69
OH
CO2CH3
2.67
2.68
BocHN,, 2.70 R = Cl 2.71 R = OCH3
CO2CH3
2.67
OH
Cu(OAc)2, pyr.
CH2C12, 4 A mol sieves
SCHEME 2.26
BocHN
H 3 C 2 C
Evans 's method65 allows preparation of diaryl ethers by reactions of arylboronic acids
(instead of aryl halides) and phenols in the presence of copper (II) acetate, triethyl amine or
pyridine and 4A powdered molecular sieves at room temperature in dichloromethane. This
method is tolerant of a wide range of substituents on both coupling partners with the
exception of ortho-heteroatom substituted arylboronic acids although ortho-alkyl substituent
appear to be tolerated. An example of this is the formation of diaryl ether 2.69 from 2.67 and
2.68.
SCHEME 2.25
Poor yields of 7% and 37% of diaryl ethers 2.72 and 2.73 resulted from coupling of ortho-
heteroatom substituted arylboronic acids 2.70 and 2.71 with phenol 2.67.
2.72 R = CI 7% 2.73 R = OCH3 37%
34
2. decomplexation RI 1. Phenoxides
ONa
Cb 1 CO2CH3
2.76
88% Fe+Cp PF6
CI
2.77 2.78
CI
Fe+Cp PF6
Cl
CbzHN CO2CH3
2.4.3 Diaryl ether synthesis mediated by metal-arene complexes
Aryl chlorides can be activated towards nucleophilic substitution via complexation with MCp
(M = Fe, Ru; Cp = cyclopentadienyl) or Mn(CO)3. Ruthenium complexes are superior to Mn
and Fe because the attachment of chloroarene derivatives to cyclopentadienyl ruthenium can
be effected under very mild conditions. Diaryl ethers formed from this methodology are 4 obtained in good yield. 7,66,67,68,69,70,71,72
2.74
2.75
SCHEME 2.27: Formation of diaryl ethers mediated by metal-arene complexes
For, example
SCHEME 2.28
2.4.4 Thallium(III) nitrate oxidative diaryl ether synthesis
This method involves oxidative coupling of 2,6-dihalogenated phenols with thallium trinitrate
(TTN) to afford quinones, which are subsequently reduced to the corresponding diaryl ethers
35
OH
Cl OH
C l
B OH Br
TTN, CH3OH, 45%
CH3 Cl Zn, HOAc, 73%
N NCH3Cbz
H3C0' H3C0'
2.79 2.80
SCHEME 2.29
in low to moderate yields. 47'73'74 This can be illustrated by the following example in which
2.79 cyclise via diaryl formation to produce 2.80. 75
Unfortunately, the use of dihalogenated phenol coupling partners is obligatory, and as a
consequence, only the dihalo-substituted coupling product can be obtained by this approach.
Complex mixtures of products are obtained when phenols with a mono halogen substituent
such as vancomycin core (2.47) are used. 73
2.4.5 Diaryl ether formation mediated by potassium fluoride-alumina and
18-Crown-6
Potassium fluoride-alumina (ICF.A1203) has been shown to be an effective mediator of the
SNAr addition of phenols to electron-deficient aryl fluorides in the presence of 18-crown-6.
Fluorobenzonitriles and fluoronitrobenzenes are favourable substrates on this procedure.
When using DMSO as the solvent, other electron-withdrawing groups for the electrophile
may be used in place of nitro or nitrile, such as aldehyde, ester, acetate and amide.
Chlorobenzonitriles and bromobenzonitriles can also be used when using DMSO. In certain
cases this method requires long reaction time (2 days to 10 days). 76 For example, formation
of diaryl ether 2.82 (Scheme 2.30).
36
OH F A H3CO KF.A1203, 18-crown-6 CH3CN, reflux, 4 days 31.'
NC 82% H3CO
OCH3
2.82
H3C0
H3CO
OCH3
2.81
CN
SCHEME 2.30
2.4.6 Palladium-catalysed diaryl ether synthesis
Palladium has recently been used to catalyse the synthesis of diaryl ethers from aryl halides
or triflates and phenols. Phoshine ligands have been employed to effect this transformation
(Scheme 2.31).
X HO Pd(OAc)2 or Pd2(dba)3 base, ligand, toluene,
reflux
X = OTf, I, Br, CI
2.49
2.50
SCHEME 2.31
Hartwig"' 78 developed two methods that use palladium catalysts and phosphine ligands. The
first method involves coupling of aryl bromides and sodium phenoxides in the presence of
catalytic amounts of Pd(dba)2 and dppf or modified dppf ligands. This method is limited to
electron-deficient aryl bromides.'" For example, p-bromobenzonitrile reacts with sodium
phenoxide 2.83 in the presence of Pd(dba)2 and dppf to give 92% of the diaryl ether 2.84
(Scheme 2.32).
37
NC
Br NaO Pd(dba)2, dppf toluene/THF (9:1)
OCH3 92% NC OCH 3
2.83
2.84
SCHEME 2.32
However, reactions of aryl bromides and ortho-substituted phenols do not work as indicated
by sodium phenoxides 2.85 (Scheme 2.33). Modified dppf ligand such as CF3-dppf was also
introduced for the coupling of electron-deficient aryl bromides with electron-neutral
phenoxides. 77
Pd(dba)2, dppf no reaction NC
toluene/THF (9:1)
2.85 R = CI, OCH3
SCHEME 2.33
Another palladium-catalysed approach by Hartwig 78 forms diaryl ethers by the use of a
ferrocenyldi-tert-butylphosphine or tri-tert-butylphosphine ligand. These phosphine ligands
allow coupling of aryl chlorides or bromides with electron-withdrawing groups or electron
donating alkyl groups and phenols in good yields.
A remarkably improved palladium diaryl ethers approach has been developed by Buchwald 79
Electron-rich, bulky aryldialkylphosphine ligands in which the two alkyl groups are either
tert-butyl or adamantyl (2.86 to 2.89) are the key to the success of this transformation. Both
Pd(OAc)2 and Pd2(dba)3 can be used. A wide range of electron-deficient, electronically-
neutral and electron-rich aryl halides or triflates have been coupled with phenols using
sodium hydride or potassium phosphate as the base in refluxing toluene.
38
p(tBu)2
N(CH3)2
P(tBu)2 P(1-Adamanty1)2
2.86
2.87
2.88
2.89
Ligands 2.86 and 2.88 are not suitable for coupling of an aryl halide or triflate lacking an
ortho substituent. Ligand 2.87 is an effective ligand for such substrates. Neither of ligands
2.86, 2.87 and 2.88 are effective in the reactions of highly electron-rich aryl halides, for
example p-chloroanisole and p-bromoanisole. Ligand 2.89 has been developed for reactions
involving the use of highly electron-rich aryl halides or triflates. However, preparation of
this ligand 2.89 is troublesome and the authors 79 could only prepare this ligand in 6% yield
after 2 days. The authors found that all these ligands (2.86 to 2.89) were not effective for
reactions involving aryl halides having an electron-withdrawing group at ortho position with
the exception of o-bromobenzotrifluoride which reacted with o-cresol to form the
corresponding diaryl ether in 75% yield.
2.4.7 Conclusion
While a number of interesting and useful technique for diaryl ether synthesis have been
developed, a need for a high yielding, mild and less expensive, general method for the
formation of this moiety is highly desirable.
Of all the methods described here, the very old but still useful Ullmann reaction predominates
in terms of publications. By careful choosing the suitable starting materials, compounds
containing this moiety can be formed in high yields using the original Ullmann conditions.
Furthermore, the recent developments, for example [THMD (2.64), CuCI, Cs2CO3] that has
been reported to tolerates a wide range of coupling partners has proved the copper-catalysed
39
Ullmann reaction to be a method of choice for diaryl ether formation and this would
undoubtedly increase the utility of this method.
The use of palladium catalysts in the formation of diaryl ethers is also promising. However,
there is a need for the development of ligands (inexpensive) that would facilitate the
preparation of the diaryl ether moiety from all types of aryl halides or triflates and phenols.
Based on the recent developments of Cu and Pd diaryl ether chemistry, undoubtedly the
development of a new simple and straightforward method is on the way.
2.5 Previous synthesis of dl-cycleanine (1.28)
The bisbenzylisoquinoline alkaloid cycleanine (1.28) was first isolated from Cyclea insularis
and Stephania cepharantha by Kondo et al.8° in 1937.
Since 1937, only one successful total synthesis of this compound has been reported. This
non-stereospecific total synthesis was published by Tomita et a1. 81 in 1968. Prior to this, they
reported their initial unsuccessful attempt and this is represented in Schemes 2.34 and 2.35. 82
Both of their synthetic routes follow the two general approaches discussed in this chapter (§
2.1.)
In Schemes 2.34 and 2.35, they have adopted a strategy of first synthesising the
benzylisoquinoline d/-8-bromoarmepavine (2.94), which they had hoped will dimerise under
Ullmann condensation to form the desired d/-cycleanine (1.28). Unfortunately, Ullmann
condensation of d/-8-bromoarmrpavine with both metallic copper and copper(II) oxide in
refluxing pyridine was not successful. Only one diaryl ether coupling was possible and that
resulted in formation of 2.95 in 3.9% yield.
40
H3CO
H3CO
H3CO
H3CO
2.93
I CH20, NaBH4 69%
2.92
OH
H3CO
POC13, CHC13 reflux, 45 min H3CO
ic NaBH4, CH3OH
28%
OH OAc
H3CO NO2
Zn-Hg. HC1 93%
H3CO
Br
2.90
2.91
Decalin, p-hydroxyphenyl acetic acid, reflux, 1 h Ac20, pyridine
25%
2.94
SCHEME 2.34
41
H3C,
OCH3
dl- Cycleanine (1.28)
H3CO
H3CO CH3
OCH3
2.95
H3 CO
H3CO
OH 2.94
CuO, pyr., reflux 3.9%
SCHEME 2.35
The synthetic route (Schemes 2.34) leading to the key intermediate dl-8-bromoarmeparvine
(2.94) comprises 6 steps from P-nitrostyrene 2.90 (not a commercially available starting
material). However, reactions on this route suffer from low yields with the exception of only
two reactions, namely, Clemmensen reduction of 2.90 to amine 2.91 in 93% yield and N-
methylation of 1,2,3,4-tetrahydroisoquinoline 2.93 in 69% yield.
42
H3CO
H3CO CHO
OEt H3CO
CuO, K2CO3 H3CO
pyr., reflux 35%
2.101 R = CH3, R 1 = Cbz 2.102 R = H, R 1 = Cbz 2.103 R = CH3, R 1 = H
SCHEME 2.36
Br
2.96
OH
OEt
CH2CO2CH3
2.97 CH2CO2CH3
OH
CH2CO2CH3
CH2C 02R
CH2CO2H
2.98
4' H3CO
NHR 1 H3CO
CH2CO2H
2.99
OEt H3CO
OH" H3CO
H+
Br
2.100
H3CO
H3CO CuO, K2CO3 pyr., reflux
23%
H3CO
H3CO
Scheme 2.36 represents the successful total synthesis that was published in 1968 by the same
group. 81 The route outlines the strategy of first preparing the diaryl ether key precursors. As
indicated in Scheme 2.36 diaryl ethers 2.97 and 2.101 were obtained by Ullmann
condensation of highly electron-rich aryl bromides 2.96 and 2.100 with methyl p-
hydroxyphenylacetate in low yields of 35% and 23%, respectively.
OEt
NO2
Condensation of diaryl ethers 2.102 and 2.103 with DCC produced amide 2.104 in a high
yield of 94%, and the resulted amide 2.104 was hydrolysed to the corresponding carboxylic
acid 2.105. The carboxylic acid 2.105 was esterified (DCC, p-nitrophenol) to p-nitrophenyl
43
2.102 + 2.103 DCC
OCH3
OCH3
OCH3
OCH3
H3CO
NHCbz NHR H3C0 v H3C
CH2CO2CH3 CH2CO2H
SCHEME 2.37
OCH3
OCH3
2.104
2.107
2.105 R = Cbz
2.106 R = H
H3 CO
OCH3
dl-cy leanine (1.28)
ester followed by removal of the Cbz group with HBr-HOAc and subsequently cyclised to
cyclobisamide 2.107 by treatment of the resulted product with 40:1 pyridine:triethylamine.
The cyclobisamide 2.107 was obtained in 17% yield from 2.105.
Cyclisation of amide 2.106, which was obtained by catalytic hydrogenolysis of compound
2.105, with DCC and POC13-E3N gave the same cyclobisamide 2.107 in 4% and 10% yields,
respectively.
44
The cyclobisamide 2.107 was converted to dl-cycleanine 1.28 in 0.067% yield via Bischler-
Napieralski reaction, after reduction of the intermediate 3,4-dihydroisoquinoline and N-
methylation.
2.5.1 Conclusion
The two routes described in § 2.1 and 2.5 constitute a simple and direct approach to the
synthesis of bisbenzylisoquinoline alkaloids. However, low yields particularly in diaryl ether
and isoquinoline ring formations make the reactions described unattractive and therefore, not
suitable for large-scale preparations. Furthermore, the two routes are not stereoselective in
the formation of the isoquinoline ring and therefore are not suitable for the synthesis of
natural optically-pure bisbenzylisoquinolines. Stereoselective routes are of great importance
since the chirality in optically-pure bisbenzylisoquinoline alkaloids plays a major role in the
biological activity of these alkaloids. 83 We would like to mention that the poor yields of
diaryl ethers obtained in the previous synthesis of alkaloids described in § 2.1 and 2.5 is
attributable to the use of the highly electron-rich aryl bromides, which are highly
unfavourable for Ullmann ether reaction. We think that an efficient process for the synthesis
of these alkaloids can result:
by careful identifying suitable aryl halides and phenols coupling substrates for diaryl
ether moiety synthesis
by employing a stereoselective approach, which produce optically-pure isoquinolines (§
2.2.1.3).
45
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A.V. Kalinin, J.F. Bower, P. Riebel and V. Snieckus, J. Org. Chem, 1999, 64, 2986.
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122, 5043.
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A.J. Pearson, S.-H. Lee and F. Gouzoules, J. Chem. Soc., Perkin Trans 1, 1990, 2251.
A.J. Pearson and H. Shin, Tetrahedron, 1992, 48, 7527.
A.J. Pearson and G. Bignan, Tetrahedron Lett., 1996, 37, 735.
A.J. Pearson, P. Zhang and K. Lee, J. Org. Chem., 1996, 61, 6582.
A.J. Pearson and P.O. Belmont, TetrahedronLett., 2000, 41, 1671.
A.J. Pearson and S. Zigmantas, Tetrahedron Lett., 2001, 42, 8765.
48
S. Venkatraman, F.G. Njoroge and V. Girijavallabhan, Tetrahedron, 2002, 58, 5453.
H. Konishi, T. Okuno, S. Nishiyama, S. Yamamura, K. Koyashu and Y. Terada,
Tetrahedron Lett., 1996, 37, 8791.
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Soc., 1997, 119, 3417.
T. Inoue, T. Sasaki, H. Takayanagi, Y. Harigaya, O.Hoshino, H. Hara and T. Inaba, J.
Org. Chem., 1996, 61, 3936.
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63, 6338.
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Nat. Prod., 1999, 62, 59.
49
CHAPTER 3
SYNTHESIS OF PRECURSORS FOR THE
BISBENZYLISOQUINOLINE
3.1 Introduction
From the literature, it is clear that the synthesis of bisbenzylisoquinoline alkaloids
revolves on either the initial preparation of diaryl ether precursors followed by
isoquinoline nucleus formation or the preparation of the benzylisoquinoline monomers,
which are then linked via diaryl formation to produce the dimeric alkaloids (Chapter 2,
literature review). In this chapter, we present our investigations on two different routes
that provide convenient access to useful intermediates that may serve as a vehicle towards
the total the synthesis of the bisbenzyltetrahydroisoquinoline alkaloids cissacapine (1.25),
insularine (1.26), insularoline (1.27) and cycleanine (1.28).
3.2 Retrosynthetic analysis
Taking into account the structural similarities between cissacapine (1.25), insularine
(1.26), insularoline (1.27) and cycleanine (1.28), one prerequisite to our synthetic route
was that advanced intermediates should give access to more than one alkaloids. Two
aproaches towards the synthesis of the target alkaloids were explored.
For Approach 1, our retrosynthetic analysis as illustrated for insularine (1.26) in Scheme
3.1 involves cyclisation to form the isoquinolines through the Bischler-Napieralski
reaction of the cyclobisamide 3.1. Cyclobisamide 3.1 can be synthesised via
condensation of derivatives of 3.2 and 3.3. This approach is similar to that published for
dl-cycleanine (1.28) (§ 2.5, Schemes 2.36 and 2.37). 1.2 We hope that the chirality can be
incorporated via asymmetric catalytic hydrogenation of 3,4-dihydroisoquinolines using
chiral reagents as discussed in Chapter 2 (§ 2.2.1.3).
50
51
3.1 1.26
V HO
HO
OH
3.4
OCH3
OCH3
HO
HO a = Bischler-Napieralski cyclisation b = Carboxamide formation c = Benzylic ether coupling d = Diaryl ether coupling or S NAr coupling e = Diaryl ether coupling
3.3 3.5 R = Electron withdrawing group
X = Halogen
CO2H
3.2
OH
3.4
SCHME 3.1
COCH3
3.6
CHO CHO H3CO
H3CO H3CO
OCH3
H3CO H3CO
NHR H3 CO
OR' COCH3
3.9
Both intermediates 3.2 and 3.3 are required for the total synthesis of insularine (1.26) and
insularoline (1.27), whereas only 3.2 is required for cycleanine (1.28) and 3.3 for
cissacapine (1.25). In this approach we envisioned that the main challenge would be the
formation of diaryl ether moieties as well as the synthesis of 1 1H-
dibenzo[b,e][1,4]clioxepine system, a unique feature of these compounds. It was
envisaged that inexpensive commercially available gallic acid (3.4) and aryl halides 3.5
and 3.6 could be useful starting materials. We planned our synthesis as shown in
Schemes 3.2 and 3.3.
HO C 02H C 02 CH3 H3 CO C 02 CH3
HO
H3 CO
OH
3.4
OH
3.7
COCH3
3.8
V
3.11a R = Boc, R 1 = CH3 3.10
3.11b R = Boc, R 1 = H 3.11c R= H, RI = CH3
SCHEME 3.2
52
CO2CH3 H3CO CO2CH3
4.-
HO CO2H
HO
OH
3.4
H3CO CHO
OCH3
0
3.12 R = CHO, X = Br 3.13 R = COCH3 , X = F
3.14 R = CHO 3.15 R = COCH3
3.17 3.16
SCHEME 3.3
For Approach 2, our retrosynthetic analysis in Scheme 3.4 involves initial preparation of
benzyltetrahydroisoquinoline units. In contrast to the attempt to prepare dl-cycleanine
previously described by Tomita et al.,3 our approach is a chiral auxiliary-based
asymmetric version that gives optically-pure isoquinolines whereas the former 3 is only
suitable for preparation of racemic isoquinolines. As illustrated in Scheme 3.4, the key
features of this approach comprises diaryl ether coupling and asymmetric Bischler-
Napieralski cyclisation. Recent developments on diaryl ether formation of electron-rich
53
OH
3.18
H3CO
H3 CO
H3CO
H3 CO
H3CO
HO
CHO
Br
3.20
OH
OH
3.19
aryl halides with phenols can allow dimerisation of the benzylisoquinoline units to give
derivatives of 1.28. 4 Incorporation of the chiral auxiliary in bromovanillin derivative 3.20
was planned to be done following procedures developed by Polniaszek 5'6'7 and Cortes 8 .
1.28
3.22 O'Pr R = Chiral 1-phenethylamine
3.21
a = Diaryl ether coupling b = Bischler-Napieralski cyclisation c = Carboxamide formation d = C-C disconnection
SCHEME 3.4
54
3.26 3.25
CHO
Br Br
3.22 3.24 3.23
,
0
H3CO
H3CO
Br
O'Pr O i Pr
H3CO
HO
H3CO
H3CO
OH H3CO
OD.
H3CO
Based on the retrosynthetic analysis in Scheme 3.4, we planned our synthesis as outlined
in Scheme 3.5. Vanillin (3.22) was chosen as the starting material.
R = Chiral 1-phenethylamine
SCHEME 3.5
3.3 Methyl 3-(4-acetylphenoxy)-4,5-dimethoxybenzoate (3.8)
For Approach 1, our first target was to obtain compound 3.7, which was required as the
upper half of diaryl ether 3.8. As the starting material, we chose the readily available
gallic acid (3.4).
Standard acid-catalysed esterification yielded the methyl ester 3.27. Since catechol
groups can be protected by complexation with borax, it is possible to differentiate
between the phenolic groups of 3,4,5-trihydroxybenzene derivatives. Compound 3.27
was treated with 10% aq. borax to block two ortho hydroxy groups. In situ methylation
with dimethyl sulphate and subsequent acid hydrolysis afforded the desired compound
55
HO
abs CH3OH lo cat. H2SO4 HO
97%
CO2CH3
OH
3.27
110% aq. Na213407
3.4
HO
HO
CO2H
OH
CO2CH3
..c aq. NaOH
0 (CH3)2SO4 0 B\-0 B
\ —0
/ /
HO HO
H3CO
3.29
H3CO
HO
CO2CH3
3.30 in 84% yield (Scheme 3.6). 9' 1° The 'H NMR spectrum of the product 3.30 confirmed
the presence of two methoxy groups, two aromatic protons and two phenolic protons.
The phenolic protons resonated at 514 5.55 and 51-1 5.89 as broadened singlets. In the 13 C
NMR spectrum of the compound the methoxy group of the methyl ester resonated at Sc
52.1 while the methoxy at C-5 appeared at Sc 56.4. The characteristic carbonyl signal of
the ester was observed at S c 166.8.
CO2CH3
3.28
OH
3.30
SCHEME 3.6
56
H3CO
HO
OH
3.30
CO2CH3
Ac2O Et3N 100%
H3CO
AcO
CO2CH3
OAc
3.31
K2CO3, DMF
Iv-
- -
3.32
The next step was the chemoselective methylation at the 4-position. Although, in the
presence of the para electron-withdrawing ester function, the plc of the 4-OH is lower
than that of 3-OH, the difference in reaction rate between these two phenols is not
sufficient to get selective methylation at the 4-OH in a reaction with K 2CO3 and CH3 I.
Therefore, the method developed by Zhu l "2 and Pearson° on selective alkylation of the
4-OH group of gallic acid derivatives was followed. This approach involves heating of
the diacetate 3.31 in DMF at low temperature in the presence of K 2CO3 and CH3I to give
exclusively the 4-methoxylated compound 3.33.
H3CO
H3CO
OAc
3.33
CO2CH3
OAc
CH3I .4 96%
K2CO3, CH3OH-H20 30 min, rt
le 99%
H3CO
H3CO
CO2CH3
OH
3.7
SCHEME 3.7
57
This selectivity may be explained by the trace of water present in the reaction medium
that may selectively hydrolyse the 4-acetyl group in 3.31 leading to the intermediate 3.32
stabilised by the conjugation effect of the ester function. Methylation then gave the
product 3.33. The 1H NMR spectrum of the compound 3.33 displayed the expected
signals including a single acetoxy methyl at SH 2.29, three methoxy (OH 3.84, SH 3.85 and
SH 3.88) and two protons in the aromatic region (OH 7.35 and OH 7.46). Two carbonyl
(acetoxy and methyl ester), one methyl (acetoxy), three methoxy signals and six aromatic
carbon signals were observed in the 13C NMR spectrum. Unambiguous proof of this
structure was derived from the 1H NMR spectrum. If the isomeric 3,5-dimethoxy
analogue were formed, it would have resulted in a compound with C2 symmetry, in which
case single signals would have been observed for both the two methoxy groups and the
two aromatic protons. Deacetylation of the monoacetate 3.33 afforded the desired
phenolic compound 3.7 needed for the formation of the diaryl ether. The 1H and 13C
NMR spectra of this compound confirmed the loss of the acetyl group, and the mass
spectrum showed an NC base peak of m/z 212, corresponding to the molecular mass of
3.7.
Given the harsh conditions required and poor yields obtained in copper-mediated Ullmann
coupling reactions when electron-rich aryl halides or electron-deficient phenols are
used, 14,15,16,17 we chose electron-deficient p-bromoacetophenone (3.6) as the second
component for the diaryl ether formation. The acetyl group can easily be transposed in
one or two steps to the required arylacetic acid derivatives by the Willgerodt or related
reactions. 18,19'20
Ullmann condensation of the electron-rich phenol 3.7 with p-bromoacetophenone (3.6) in
the presence of CuO and K2CO3 in pyridine according to Evans and Ellman's conditions"
allowed formation of the diaryl ether 3.8 in 88% yield (Scheme 3.8). The 1H NMR
spectrum of the diaryl ether showed the expected six aromatic protons (two doublets from
four aromatic protons of the lower half resonating as an A2B2 system and another two
doublets from two aromatic protons of the upper half meta coupled to one another). In
addition, the spectrum indicated the presence of three methoxy signals (OH 3.81, O H 3.85
and OH 3.92) and an acetyl group resonating at OH 2.53. The structure was consistent with
13C NMR and MS data, the latter showing the required M ± peak of m/z 330.
58
CO2CH3
OH CH3
3.7 3.6
H3CO
H3CO
H3 CO
H3CO
CuO, K2CO3 pyridine, reflux
88%
3.8
SCHEME 3.8
It should be mentioned that the key success to the preparation of product 3.8 is
attributable to the use of the electron-rich phenol (3.7) derived from gallic acid (3.4) and
the electron-deficient p-bromoacetophenone (3.6), substrates that are highly suitable for
the Ullmann conditions.
Our approach to the diaryl ether formation (Scheme 3.8) is a vast improvement to the
published approach of Tomita et aL 2' 14 as applied in the synthesis of d/-cycleanine (1.28).
It is evident the low yields of diaryl ethers 2.97 (35% yield) and 2.101 (23% yield)
observed by Tomita et al.2' 14 can be ascribed to the use of the electron-rich bromovanillin
derivatives 2.96 and 2.100 as the aryl halides coupling materials (Scheme 2.36). These
substrates are highly unfavourable for this process since the Ullmann reaction is limited to
electron-deficient aryl halides (Chapter 2, diaryl ether synthesis § 2.4.2). Furthermore,
our reaction is suitable for multigram scale preparation.
3.4 Methyl 4-(5-formyl-2,3-dimethoxyphenoxy)phenylacetate (3.10)
To prepare compound 3.10, the methyl ester of compound 3.8 should be selectively
transformed into an aldehyde prior to the conversion of the aryl methyl ketone to the
corresponding phenylacetate derivative. Failing to do this transformation first would have
landed our synthesis in trouble since chemoselectivity between the aromatic methyl ester
59
CHO H3CO CH2OH
H3CO PCC or Dess-Martin .1E periodinane,
CH2C12 86%
COCH3 COCH3
moiety of the upper half and the newly generated aliphatic ester moiety derived from the
aryl methyl ketone would not be possible.
H3CO
H3CO
CO2CH3
(CH30)1CH, CH3OH . p-TsOH
95%
H3CO
H3CO
CO2CH3
COCH3 C (OCH3)2C H3
3.8 3.34
LiAIH4 aq. HO 83%
3.9 3.35
SCHEME 3.9
The ketone group of compound 3.8 was protected by acetalisation and the ester group of
the resulted acetal 3.34 was transformed into the aldehyde 3.9 through LiA1H4 reduction
followed by pyridinium chlorochromate oxidation (Scheme 3.9). The oxidation with
Dess-Martin periodinane 21 '22 gave comparable results. The NMR spectrum of 3.9
confirmed the disappearance of the methyl ester and the presence of the aldehyde. The
60
MS spectrum showed the expected M+ peak of m/z 300 consistent with the molecular,
mass of structure 3.9.
Next, the aryl methyl ketone of 3.9 needed to be converted into its phenylacetic acid
derivative and this process needed to be achieved without affecting the benzaldehyde
moiety. This process is known as Willgerodt-Kindler 18 reaction (Scheme 3.10) and the
classical conditions have found only limited application because of the necessity of high
temperatures, frequently high pressure, long reaction periods required and low to
moderate yields of products obtained. 18 Unfortunately, the aldehydes are also reactive
towards reaction conditions described in Scheme 3.10. 18
S, Morpholine
OH
3.36 3.37
3.38
SCHEME 3.10: Willgerodt-Kindler reaction
A remarkable solution to this problem came from McKillop 19 and Junjappa2° who
independently developed a convenient method for the conversion of the acetophenones to
the corresponding methyl arylacetates in moderate to excellent yields using thallium(III)
nitrate (TTN) and lead(IV) acetate, respectively.
The proposed mechanism of the thallium(III) oxidative reaction involves initial
enolisation assisted by acid (Scheme 3.11). The enol 3.40 of the acetophenone 3.39 reacts
electrophilically with thallium(III) to give the carbonium ion 3.41. The hemiacetal 3.42,
formed by uptake of methanol, then decomposes with migration of the aryl group to
produce the methyl arylacetates 3.43 and simultaneous reduction of thallium(III) to
thallium(I) nitrate.
61
A similar mechanism applies for the oxidation with lead(IV) acetate. Enolisation assisted
by boron trifluoride etherate followed by oxyplumbation and finally, aryl group migration
will give methyl aryl acetates 3.43 and lead(II) acetate.
0 OH I I I
Ar—C—CH3 Ar—C=-- CH2 TTN
OH
Ar— C— CH2– TI(NO3)2 -NO3-
3.39 3.40 3.41
CH3OH
-H+
V
0 NO3 I I T1NO3 + ArCH2— C— OC H3 H3C0- C-CH2--- Tl
Arm(NO3i:2
3.43 3.42
SCHEME 3.11: TTN oxidative rearrangement of acetophenones to methyl arylacetates
From the mechanism shown in Scheme 3.11, it is evident that the benzaldehyde will be
inert to this oxidative rearrangement process since benzaldehydes lack alpha hydrogens
and therefore cannot enolise as compared to acetophenones.
Treatment of compounds 3.9 with lead(IV) acetate produced the methyl phenylacetate
derivative 3.10 in 89% yield. When thallium(III) nitrate-mediated oxidation reaction was
used, product 3.10 was obtained in 88% yield. The assigned structure 3.10 was confirmed
by and 13C NMR spectra featuring, amongst others, the aldehyde and the CH 2CO2CH3
signals. The important CH2CO2CH3 signals were displayed in the ' 3C NMR at Sc 40.3
(CH2), Sc 52.0 (OCH3) and Sc 171.8 (CO2), while in the 'H NMR they appeared at OH
3.58 (CH2) and 6•H 3.67 (methoxy). The MS showed l‘e peak of m/z 330, which is in full
agreement with the assigned structure 3.10.
62
H3CO
CHO H3CO
Pb(OAc)4, CH3OH, BF3.Et20 3. 89%
or
TTN, CH3OH, HC104 3,..
88%
H3CO
H3CO
COCH3
3.9
CHO
OCH3
3.10
SCHEME 3.12
3.5 13-Phenethylamine derivatives of 3.2
Many methods have been developed for the preparation of 13-phenethylamines. Of these
methods, the nitrostyrene and the nitrile methods probably have been the most widely
used. Judging from the information in the literature, neither of the processes possess a
clear advantage over the other and, therefore, we have investigated both routes.
3.5.1 Nitrostyrene method
The most versatile preparation of nitrostyrenes involves the Henry condensation 23 '24 of a
carbonyl compound 3.44 with nitroalkane 3.45 to give the 13-nitro alcohol 3.46, which
undergoes dehydration producing the conjugated nitroalkene 3.47 (Scheme 3.13).
R1 0 + RCH2NO2
R2
3.44 3.45
base R1 R RI
H2O HO ( R2 NO2 R2
3.46
R
C— NO2
3.47
SCHEME 3.13: Henry condensation reaction
63
Henry condensation of benzaldehyde 3.10 with nitromethane in the presence of
ammonium acetate afforded the bright yellow product 3.48a in only 40% yield. The best
method for this transformation proved to be the condensation with nitromethane in 5% aq.
KOH solution at 0 °C followed by dehydration with 10% aq. HC1 at room temperature.
Using these conditions, the nitrostyrene 3.48a was prepared in 98% yield. The 'H NMR
spectrum of 3.48a showed the characteristic alkene doublets resonating at 6H 7.44 and OH
7.85, with a coupling constants of 13.8 Hz, indicating a trans orientation, while the MS
spectrum displayed the required M + of m/z 373 corresponding to the molecular mass of
the product.
NO2 CHO H3CO
H3CO CH3NO2, 5% aq. KOH I. 10% aq. HCl
98%
OCH3 OCH3
H3CO
H3CO
3.10
3.48a
SCHEME 3.14
With the nitrostyrene 3.48a in hand, we needed to reduce both the nitro and alkene
moieties to produce the required key intermediate 13-phenethylamine derivatives of 3.2.
The reduction of conjugated nitroalkenes such as nitrostyrenes in a single step is known to
be problematic. It is possible to reduce the double bond while keeping the nitro group
intact. 25 '26'27 However, the inverse reaction is not as easily accomplished. The difficulties
in reducing the nitro group in conjugated nitroalkenes with common reducing agents is
thought to arise from the fact that the reaction can lead to an enamine or to an unsaturated
hydroxylamine, and these products are in a generally unfavourable equilibrium with the
64
respective imine or oxime. All these intermediates can interact to give complex mixtures,
especially with terminal nitroalkenes (R = H, Scheme 3.13). 28,29
For a one-step transformation of conjugated nitroalkene to alkyamines, reduction can be
carried out with lithium aluminium hydride. However, the process often produces
mixtures of products in modest yields. 3°'31 '32 Catalytic hydrogenation has also been used
on occasion with limited success. 33 '34'35 Reduction conditions using amalgamated zinc
have also been reported. 1 '3 A two-step process involving reduction of the double bond
followed by reduction of the nitro group is the other option. For this, a convenient
method is the sodium borohydride-catalysed borane reduction reported by Kabalka's
group. 36,37,38 This reduction provides a simple solution to this rather difficult problem,
although other functionalities such as carbonyl, carboxyl, nitrile, etc. are also affected.
The reaction proceeds via nitronates or nitro salts 3.50, which is then reduced to the
hydroxylamines 3.51 with a borane complex (Scheme 3.15). 39 In the presence of excess
borane the reaction proceeds to 'give the amines 3.52 upon further reaction of
hydroxylamine derivatives 3.51 with borane. Saturated nitro compounds are
unreactive. 36 '37'38'39
R2 R3 , I I
R'—C=C—NO2 NaBH4
R2 R3 I
t.
R 1 - CH—C= N-0-- BH3- Na+
3.49 O
3.50
BH3
R2 R3 H , I I I
R'—CH—CH—N—H
R2 R3 H BH3 , I I I
R CH—CH—N-0—B H2 A
3.52 3.51
SCHEME 3.15: Sodium borohydride-catalysed borane reduction of conjugated
nitroalkenes
65
Initial attempts to the reduction of the nitrostyrene 3.48a with a retention of the aliphatic
methyl ester moiety proved to be problematic, as this reaction could not be accomplished
with a range of reducing agents (H 2, Pd-C; H2, Pt20; H2, Raney-Ni; NiC12.6H2O-NaBH4,
NaBH4, Pd-C). All these conditions resulted in either mixture of products, poor yields of
amines or products resulting from only double bond reduction. Although amalgamated
zinc (Clemmensen reduction) has been reported to reduce the ethyl ester derivative of
3.48a to the corresponding amine derivative of 3.11c in 65% yield, we have repeatedly
been unable to reproduce these results.'
However, selective reduction of the double bond of 3.48a with borohydride exchange
resin26'4° (BER) gave 79% yield of the phenylnitroethane derivative 3.48b, which was
then reduced with amalgamated aluminium (Al/Hg) under sonification 41 to give the
desired key precursor 3.11c in 39% yield (Scheme 3.16). The 1H NMR spectrum of 3.11c
exhibited two sets of triplets at 81-1 2.63 and 81-1 2.90 in the place of the alkene doublets of
the nitrostyrene, indicating the reduction of the alkene. The 13C NMR spectrum indicated
the shift of two alkene signals from the downfield aromatic region to the expected upfield
region 8c 39.5 and Sc 43.4. The IR spectrum showed a pair of sharp absorption bands at
3350 cm" 1 indicating the presence of primary amine (NI -12).
H3CO
H3CO
NO2
BER, CH3OH, 79% 0.
H3CO
H3CO
0
Al-Hg, ultrasound, 39% • 3.48a
p.-3.11c R = NH2
SCHEME 3.16
3.48b R = NO2
66
H3CO NH2
3.48a 3.53a
OH
H3CO
SCHEME 3.17
The structure 3.11c was further confirmed by the MS spectrum exhibiting the required IVI ±
(m/z 345) consistent with the molecular mass of the compound.
Due to the low yield of amine 3.11c, a better method 'was therefore required for this
reaction. Improved results were obtained when the borohydride-catalysed borane
reduction discussed in Scheme 3.15 was used, giving the amino alcohol 3.53a in 70%
yield. The absence of the CH2CO2CH3 signals in both 'H and 13C NMR spectra of this
compound was evident and this clearly suggested the undesired reduction of the ester with
borane. The presence of additional set of two triplets (OH 2.80 and SH 3.82) in the 'H
NMR spectra confirmed the reduction of ester to the alcohol. The NMR spectra were in
good agreement with those of compound 3.11c, except for the signals due to the loss of
the CH2CO2CH3 group. The assigned structures 3.53a was in full agreement with the MS
and IR data.
To regenerate the carboxymethyl moiety lost during the borane reduction, the amino
function of 3.53a was protected as N-Boc followed by the two-step oxidation to give the
required N-Boc amino acid 3.11b (Scheme 3.18). A one-step oxidation using various
oxidation agents proved troublesome yielding a mixture of products. The presence of the
NHBoc group was confirmed by the broad singlet resonance at 611 4.59 and a singlet
67
H3CO
H3CO
OH
resonance integrating for nine protons at 8H 1.40 assigned to three equivalent methyl of
the tert-butyl group. The tert-butyl group signals were observed in the 13C NMR
spectrum at 8c 28.4 (three methyl) and 8c 79.5 (tertiary carbon), while the carbonyl
signals of the NHBoc and carboxylic acid were evident at 8c 156.9 and 8c 176.8,
respectively. The disappearance of the two triplets due to CH2CH2OH was clearly visible
in the '1-1NMR spectrum of product 3.11b.
NH2 H3CO
H3CO
Boc2O, CHC13 1 00%
Dess-Martin periodinane, 92% KMnO4, tBuOH, 51%
NI-113°c
R 3.53b R = CH2CH2OH
3.11b R = CH2CO2H
3.53a
SCHEME 3.18
3.5.2 Nitrile route
Nitriles are easily prepared through the nucleophilic substitution reactions of primary
alkyl halides with cyanide ions. Reduction of the nitrile group may be effected by
catalytic hydrogenation, 42 '43 sodium borohydride in the presence of metal salts, 44,45,46
lithium aluminium hydride, 42 etc. Dimerisation is the common by-product in the
hydrogenation reaction unless an acylating reagent is added to trap the resultant amine.
The nitrile 3.56 was prepared in good yield from the benzaldehyde 3.10 by the standard
reduction-chlorination-cyanation sequence (Scheme 3.19) and the expected structure was
confirmed by the NMR, IR and MS data. The latter exhibited the M 4- peak of m/z 341,
which is in good agreement with the molecular of the structure 3.56. Reduction of the
nitrile group with nickel boride 47 generated from nickel chloride and sodium borohydride
and trapping the resultant amine with Boc2O gave the desired product 3.11a in 78% yield.
68
CHO H3 CO
H3 CO
NaBH4, CH3OH 89%
H3CO
H3 CO
The carboxylic ester group was inert. The compound was characterised by comparison
with spectra of the N-Boc amine 3.11b. All structural features of this compound were
consistent with the NMR, IR and MS data. The MS spectrum showed the required M +
peak of m/z 445 for 3.11a.
0 0
3.10 n— 3.54 R = CH2OH SOC12, CHC13, 66% I
NaCN, DMSO, 76% 3.56 R = CH2CN NiC12.6H20, NaBH4 Boc2O, CH3OH, 78% 3.11a R = CH2CH2NHB oc
SCHEME 3.19
Treatment of compound 3.11a with aqueous K2CO3 produced acid 3.11b in 83% yield
while stirring 3.11a with trifluoroacetic acid in dichloromethane overnight gave 97% of
the free amine 3.11c.
In summary, we have shown a simple and straightforward preparation for derivatives of
3.2 needed as key precursors for the synthesis of a right hand part of insularine (1.26) and
insularoline (1.27). For cycleanine (1.28), these precursors serve as both the left hand and
right hand parts of the compound.
Although both the nitrostyrene and nitrile approaches led to the desired precursors, the
latter seem to be the superior route. As mentioned in § 3.5.1, reduction of the nitrostyrene
is not always successful with common reducing agents. A convenient method for this
3.55 R = CH2C1
69
reaction requires the use of excess amount of BH 3 .THF complex (at least four equivalents
for each nitrostyrene moiety), which is expensive, not easily available in all laboratories
and requires special handling. In addition, isolation of the free amine after the reduction
with the BH3 complex requires hydrolysis of the amine-borane complex under harsh
conditions, preferably reflux in aqueous acidic solution. These conditions will not be
suitable for nitrostyrenes with acid-sensitive moieties. Although proper methods may be
found, the use of a two-step oxidation (Scheme 3.18) to regenerate the ester moiety lost
due to poor selectivity shown by BH3 complex, further makes this route inferior to the
nitrile approach. Furthermore, the use of the efficient Dess-Martin periodinane as an
oxidising agent also requires an additional two steps for the preparation of this reagent.
With all the abovementioned facts in hand, the nitrile approach presented here is
recommended for the preparation of derivatives of 3.2 since it employs well-established
experimental conditions that are easy to perform at room temperature with reagents that
does not require very dry solvents. It is also known that nickel boride reduction offers
better selectivity with esters, acetals, amides, etc. as compared to the borane complex at
high temperatures.
3.6 11H-dibenzo [b,e][1,4] dioxepine 3.14
Before embarking on the synthesis of the title compound, an extensive search of the
available literature procedures for the preparation of the 11H-dibenzo[b,e][1,4] dioxepine
moiety was undertaken. This search revealed that the synthesis of the 11H-
dibenzo[b,e][1,4]dioxepine derivatives has received almost no attention and only two
papers by Hagmann and his co-workers 48'49 describing the preparation of the 11H-
dibenzo[b,e][1,4]dioxepine moiety were found. These authors have prepared anti-
inflammatory/analgesic compounds containing this nucleus by two methods as indicated
in Scheme 3.20.
The first approach involved formation of both the benzylic ether and diaryl ether moieties
in a one-pot process by reacting catechol with 2-chloro-5-nitrobenzyl chloride (3.57) in
the presence of lituOK to give the cyclised compound 3.58 in 28% yield." In another
approach, the diaryl ether moiety was initially formed followed by ring closure of the
70
benzylic ether formation to give the tricyclic compound 3.60 in 2.5% yield. 49 The latter
approach produced substantial amounts of dimeric product.
02N CI HO
HO
43u0K, DMF 02N 28%
3.57
3.58
3.59 R = CH2Br 3.60
SCHEME 3.20
We reasoned that the failure of their first approach leading to product 3.58 might be
attributable to the fact that diaryl ether formation by 'reaction between aryl halides and
phenols is usually favoured by the presence of the catalyst such as Cu or Pd. Although an
electron-withdrawing group is present in 3.57, aryl chlorides are not very reactive towards
aromatic nucleophilic substitution reactions.
We planned our approach for the preparation of the tricyclic system as shown in Scheme
3.21. We envisaged that a more efficient process would result if we could adopt a
strategy of first forming the benzylic ether compound 3.61 and subsequently cyclise via
diaryl ether formation between an electron-deficient aryl halide (I, Br or F) nucleus or aryl
halide bearing moderate electron-donating group and the electron-rich phenol.
In a model reaction, we synthesised the simple tricyclic compound 3.65 as depicted in
Scheme 3.22. Benzylation of the diacetate 3.31 with 2-bromobenzyl bromide using the
procedure of Zhu 11,12 and Pearson 13 as described for the synthesis of 3.33 (Scheme 3.7),
gave the 4-benzyloxy derivative 3.63 in 58% yield. The 1HNMR spectrum confirmed the
presence of the expected six aromatic protons (as multiplet resonances), two methoxy
71
CO2CH3 CO2CH3 H3CO
HO
CO2CH3
> OP X
R
groups, one acetyl group and two benzylic ether protons resonating at 5H 5.18 as a singlet.
In the 13C NMR the benzylic ether signal resonated at Sc 73.8. Hydrolysis of the resultant
product 3.63 afforded the phenolic compound 3.64. The loss of the acetyl group was
evident in the 11-1 NMR spectrum. The product was further consistent with the 13C NMR
and MS data. When compound 3.64 was subjected to Ullmann conditions (CuO, K 2CO3,
pyridine, 115 °C), ring closure proceeded to give the cyclised 11H-dibenzo[b,e][1,4]
dioxepine 3.65 in 55% yield (Scheme 3.22). The product was fully characterised on the
basis of NMR and MS data. The presence of six aromatic protons OH 7.26-7.53), two
methoxy groups OH 3.87 and 5H 3.88) and a singlet for two protons of the benzylic ether
(OH 5.40) was evident from the '14 NMR spectrum. The 13 C NMR spectrum showed the
presence of two methoxy, one benzylic ether, twelve aromatic carbons and the ester
carbonyl (resonating at Sc 166.2) signals. There was no indication of the formation of the
dimeric product as compared to Hagmann's approach 49 and the MS data confirmed the
formation of only 3.65 by displaying an Nr peak (m/z 286) corresponding to the
molecular mass of the tricyclic compound 3.65.
3.62 X = Halogen 3.61
R = Electron-withdrawing or moderate electron-donating group
P = Protecting group
SCHEME 3.21
72
CuO, K2CO3 OH pyridine Br
55%
CO2CH3 H3CO CO2CH3
H3CO
AcO
CO2CH3
K2CO3, DMF 2-bromobenzyl bromide
58%
CO2CH3
OAc
3.31
3.63 K2CO3, CH3OH-H20 fe
70%
3.65 3.64
SCHEME 3.22
Upon successful completion of the model reaction (Scheme 3.22), we then directed our
efforts to the preparation of the tricyclic system 3.14, which we identified as a possible
precursor for the preparation of compound 3.16. We envisaged that the readily available
m-xylene could be used as the starting material for the preparation of 4-bromo-3-
bromomethylbenzaldehyde (3.68) that we identified as the benzylic bromide starting
material for the preparation of the 11H-dibenzo[b,e][1,4]dioxepine derivative 3.14. The
synthetic pathway for the preparation of the benzyl bromide 3.68 is outlined in Scheme
3.23.
73
CH2Br • CH2Br
H2SO4 -4 75%
CHO
3.68
CHBr2
3.67
Bromination of m-xylene with bromine in the presence of K10-montmorillonite clay
according to the method of Venkatachalapathy and Pitchumani 5° yielded exclusively the
ring brominated product 3.66 in 73% yield. The bromination of m-xylene in the absence
of K10-montmorillonite clay has been reported to give only the side-chain brominated
product in 67% yield. 50 The montmorillonite clay probably acts as a Lewis acid, thereby
facilitating ionic bromination as oppose to radical bromination that would lead to side-
chain brominated products. The 'H NMR spectrum was in complete agreement to the
published data. 51 The structure was further consistent with the 13C NMR and MS data.
Treatment of bromo-m-xylene (3.66) with three equivalents of bromine under radical
conditions (irradiation with 100W lamp) yielded the tetrabromo derivative 3.67, which
after hydrolysis of the benzylic dibromide function, gave the desired 4-bromo-3-
bromomethylbenzaldehyde 3.68 (Scheme 3.23).
CH3
Br2, K10-Mont. CC14, r.t.
73%
CH3
CH3
CH3
3.66
3 eq. Br2 CC14, hv
90%
SCHEME 3.23
74
H3CO
AcO K2CO3, DMF
Br Br
CHO
3.68
H3CO
HO
OAc
3.69
OAc Br
CO2CH3
CO2CH3
OAc
3.31
The 1H NMR spectrum of 3.68 showed the presence of the expected three protons in the
aromatic region, two benzylic protons resonating at SH 4.63 and one aldehyde proton at OH
9.96. The MS data confirmed the presence of two bromines, as the M ± peak exhibited the
characteristic 79Br/81 Br isotope pattern. The m/z 280 corresponding to M+4 was displayed
in the MS data. In an NOE experiments, irradiation of the aldehyde proton (OH 9.96) gave
positive enhancements of the H-6 OH 7.64, dd, J = 2.1 and 8.1 Hz) and H-2 (OH 7.93, d, J
= 2.1 Hz) proton signals, thereby confirming the structure 3.68.
Surprisingly, benzylation of the diacetate 3.31 with benzyl bromide 3.68 under the same
conditions described in Scheme 3.22, 'resulted in the acetolysis of the benzylic bromide
producing a mixture of 4-bromo-3-acetoxymethyl derivative 3.70 and the phenolic
compound 3.69 (Scheme 3.24). The characteristic peak of the 4-acetyl group was no
longer present in the 1H and 13 C NMR spectra of 3.69. The infrared spectrum further
confirmed the presence of the phenolic OH group, which was indicated by the strong
absorption at 3590 cm-1 . In the 1H NMR spectrum the phenolic proton resonated at OH
5.94 as a broad singlet.
CHO
3.70
SCHEME 3.24
The acetolysis of the benzylic bromide of 3.68 was indicated by the characteristic shifting
of the CH2Br signal from 6H 4.63 to 611 5.19 and the presence of additional signal at 6H
75
2.14 due to the methyl protons of the acetyl group. This was further confirmed by the 13C
NMR spectrum, which in addition to the expected aromatic carbon and aldehyde signals
showed three signals at 5c 20.8, Sc 65.0 and 5c 170.2 due to the acetoxymethyl group. At
this stage we have no explanation why reaction of benzyl bromide 3.68 and diacetate 3.31
does not give the 4-O-alkylated derivative, the product previously obtained when alkyl
halides (MeI and 2-BrPhCH 2Br) were used (Schemes 3.7 and 3.22). More interestingly,
phenol 3.69 could be produced in pure form and high yield (92%) by treatment of the
diacetate 3.31 with K2CO3 in DMF without added alkyl halide at low temperature. 11,12,13
Therefore, benzylation was carried out directly by heating phenol 3.69 with benzylic
bromide 3.68 to produce the desired O-benzylated compound 3.71 in 77% yield (Scheme
3.25).
H3CO
HO
CO2CH3
Li2CO3, DMF 77%
CO2CH3
OAc
3.69
CHO
3.68
CHO
3.71
CO2CH3 1. K2CO3, CH3OH-H20
2. H+ 84%
CHO
3.12
SCHEME 3.25
76
CO2CH3 CO2CH3
CHO CHO
CuO, K2CO3 pyridine
73% THF:CH3OH 90%
The mass spectrum of 3.71 showed the expected peaks of m/z 436 and 438 corresponding
to M+ and M+2 peaks, exhibiting the characteristic 79Br/81Br isotope pattern. The 1 11
NMR spectrum was characterised by the expected one acetyl, two methoxy, two benzylic
protons, five aromatic protons and the aldehyde signals. The structure was further
consistent with the 13C NMR spectrum.
The cyclisation step leading to the formation of the 11H-dibenzo[b,e][1,4]dioxepine
derivative 3.14 was achieved via diaryl ether bond formation. Compound 3.12 was
cyclised (Scheme 3.26) in a high yield under the same conditions described for the
tricyclic compound 3.65 in Scheme 3.22. The high yield of 3.14 compared to 3.65
(described in Scheme 3.22) is due to the presence of the electron-withdrawing formyl
group para to the bromine of 3.12. Ullmann reaction of electron-deficient aryl halides
and electron-rich phenols allow formation of the diaryl ether moiety in good yields
(Chapter 2).
3.12 3.14 SOC12, CHC13 NaCN, DMSO
68%
3.72a R = CH2OH
3.72b R = CH2CN
SCHEME 3.26
The 114 NMR spectrum of 3.14 displayed the presence of the five aromatic protons with
the expected splitting pattern, two methoxy groups, two benzyl ether protons and the
aldehyde proton. The carbonyl carbons of the ester and aldehyde were clearly evident at
Sc 165.9 and Sc 190.1, respectively. The MS spectrum of the product indicated the
disappearance of the bromine isotopic peaks that were present in the starting material,
77
clearly suggesting displacement of bromine in the reaction. An M -1- base peak of m/z 314
corresponding to the molecular mass of 3.14 confirmed the assigned structure.
Alternatively, compound 3.12 could be efficiently cyclised in 78% yield using the
palladium-catalysed diaryl ether method [Pd(OAc)2, K3PO4, 2.86) recently developed by
Buchwald's group 52, which involve the use of electron-rich bulky phosphine ligands. The
bulky nature of the phosphine ligands is thought to be responsible for increasing the rate
of reductive elimination of the diaryl ether from the palladium. 52
The 2-(di-tert-butylphosphino)biphenyl (2.86), readily available in 67% from 2-
bromobiphenyl (3.73) following the literature procedure, 52 was found to be effective for
this transformation. The m.p. and NMR ( 1 H, 13C and 31P) data of the compound were
identical to that reported by Buchwald. 52
Mg Cu(I)Cl, P( tBu)2C1
67%
3.73
2.86
SCHEME 3.27
The 11H-dibenzo[b,e][1,4]dioxepine 3.14 was converted to the benzyl cyanide derivative
3.72b (Scheme 3.26) via the sequential reduction-chlorination-cyanation reactions similar
to those given in Scheme 3.19. The product 3.72b was in full agreement with the NMR
data. The 1H NMR displayed four singlets resonating at 5H 3.71 (benzyl cyanide protons),
OH 3.88 and 5H 3.89 (two methoxy), and 5H 5.37 assigned to two benzylic ether protons.
The important benzylic cyanide (CH2CN) signal was evident at Sc 23.0, while that of the
benzylic ether (CH2OPh) was observed in the expected region at Sc 69.7.
78
CH2CN
3.72b
H3C0 CHO
CH2CN
3.74
H3C0 CHO
CH2CO2H
3.75
CO2CH3
x fo.
3.7 Unsuccessful attempted synthesis of acid derivative of 3.16
We planned to convert the methyl ester group in compound 3.72b to the aldehyde 3.74
and hydrolyse the nitrile group of 3.74 to the corresponding acid 3.75 (Scheme 3.28). As
we had limited success in reducing the methyl ester group of compound 3.72b selectively
to 3.74 without affecting the nitrile group, we finally abandoned this route. Both lithium
N,N-dimethylaminoborohydride 53'54 and modified lithium aluminium hydride-silica gel"
reductions that are known to be effective for this transformation, failed to give the desired
3.74. These reagents gave complex mixtures of products. An alternative approach was
therefore sought. Given that the acetophenone moiety of 3.9 was converted to the methyl
phenylacetate derivative 3.10 without difficulties, we decided to substitute the formyl
group in 11H-dibenzo[b,e][1,4]dioxepine 3.14 by an acetyl group. Thus the 11H-
dibenzo[b,e][1,4]dioxepine 3.15 was then synthesised as described in the following
paragraph.
SCHEME 3.28
3.8 11H-dibenzo[b,e] [1,4]dioxepine 3.15
For the preparation of compound 3.15, we required a 4-halo-3-bromomethylacetophenone
as our benzyl bromide component. Although the bromo or the iodo derivatives could be
effective benzyl bromide coupling partners, we chose the fluoro compound because of the
ease with which electron-deficient aryl fluorides undergoes displacement reaction in
diaryl ether formation without added catalyst. 4
79
CH3 CH3C0C1 AlCl3 , C S2 a'
100%
CH3 NB S CC14, hv
74%
CH-)13r
COCH3
3.77
COCH3
3.76
3-Methyl-4-fluorooacetophenone (3.76) was prepared in excellent yield by the Friedel-
Crafts acylation of o-fluorotoluene and was converted to the bromomethyl derivative 3.77
by benzylic bromination with NBS under radical conditions (Scheme 3.29). The acetyl
proton (5H 2.57) and carbon (Sc 26.5 and Sc 195.8) resonances were evident in the 1 11 and
13C NMR spectra, while the signals at 5H 4.51 integrating for two protons and Sc 31.6 are
due to the benzylic bromide moiety. In the NMR spectrum, complex splitting patterns
were observed due to the additional H-F couplings. However, all splitting patterns were
consistent with structure 3.77.
SCHEME 3.29
The unusual substitution of the acetyl group para to the halogen in Friedel-Crafts
acylation of the o-halotoluenes have been previously studied in detail by other researchers
and it has been accepted that Friedel-Crafts acylation of o-haloalkyl aromatics does in fact
proceed para to the halogen instead of being directed to the ortho or para position with
respect to the alkyl substituent with more electron donating properties. 56'57
This effect in which the halogen adjacent to a methyl group affects the methyl such that it
no longer exerts its usual activating effect has been explained by the partial rate factors of
methyl group and halo substituents in Friedel-Crafts acylation. 56'57 In the Friedel-Crafts
acylation of o-chlorotoluene, Todd and Pickering 57 observed that the methyl group of
toluene enhances attack para to it by a factor of about 700 and also enhances attack at any
one ortho and meta position by a factors of about 25 and 10, respectively. The chloro
group deactivates the position para to it by a factor of about 100, and the other positions
by a very much larger factors (probably 10 4 or greater). Multiplication of the appropriate
80
partial rate factors leads to the result that the position para to the chloro of o-chloro-
toluene is by a wide margin the favoured position for attack in this reaction.
Benzylation of the phenolic compound 3.69 with 3.77 followed by O-deacetylation under
similar conditions described in Scheme 3.25 gave the desired 4-O-benzylated product
3.13 in good yield. The MS spectrum of product 3.13 showed the desired M + peak of m/z
390. The NMR ('H and 13C) signals for the upper half of this compound were in good
agreement to those of product 3.12. In addition, complex splitting patterns ascribed to the
lower half of the compound was in good agreement with those observed in 3.77 (H-F
coupling). The acetophenone methyl signal resonated at SH 2.58 as a singlet.
CO2CH3
+
CO2CH3
OAc
3.69
COCH3
3.78
CO2CH3 K2CO3, CH3OH-H20
H+ 96%
COCH3
3.13
SCHEME 3.30
81
K2CO3, DMF 92%
CO2CH3
COCH3
3.13
CO2CH3
COCH3
3.15
In contrast to the cyclisation of 3.12 described in Scheme 3.26 (requiring the use of the
copper salts or palladium catalysts), ring closure of compound 3.13 to give 3.15 was
effected in 92% yield by heating 3.13 in DMF at 70 °C in the presence of K2CO3. As
mentioned before, electron-deficient aryl fluorides are very reactive and undergoes
nucleophiclic aromatic substitution reactions in the absence of the catalyst. 4'58'59'60 This
compound 3.15 exhibited NMR spectral features almost similar to those of 3.14 except for
the signal at OH 2.56 and, Sc 26.5 and Sc 196.2 due to the acetyl group in 3.15 as
compared to the formyl group in 3.14. The M± base peak of m/z 328 is consistent with the
molecular mass of 3.15. Furthermore, and 13C NMR spectra were devoid of the
H-F and C-F coupling patterns observed in the starting material 3.13, indicating the
absence of fluorine in the product.
SCHEME 3.31
As shown in § 3.6 and 3.8, we have succeeded in developing procedures for the
preparation of the 11H-dibenzo[b, e] [1,4]dioxepine tricyclic system. These methods are
simple to perform, proceed in high yields and are viable for large-scale preparations. This
represents a significant improvement compared to the available methods that have been
shown to produce this moiety in disappointing yields (Scheme 3.20). 48,49 It should be
mentioned that the key success to this transformations is the utilisation of the suitable
electron-deficient aryl halides and electron-rich phenols in the cyclisation reaction
82
CO2 C113
(CH3 O)3CH, CH3 OH, H+, 98% LiA1H4, then aq. HC1, 83% 31..
H3 CO
through diaryl ether formation. In both approaches, the utility of the diaryl ether
formation has been fully demonstrated.
We believe this approach will provide an entry to a wide range of medicinally important
compounds containing this tricyclic system. However, this approach will require further
elaboration of the electron-withdrawing groups in the aryl halides ring to the desired
functionality unless the target compounds possess such groups.
3.9 Conversion of 11H-dibenzo[b,e][1,4]dioxepine 3.15 to methyl
acetate derivative 3.16
The preparation of phenylacetate derivative 3.16 from 11H-dibenzo[b,e][1,4]dioxepine
3.15 was done using similar methods described for the preparation of 3.10 from
acetophenone 3.9 (Schemes 3.9 and 3.12). A four-step process comprising acetalisation,
reduction, hydrolysis and oxiditation afforded compound 3.80 in good yield (Scheme
3.32). The NMR spectra showed the disappearance of the methyl ester that was present in
the starting material. The aldehyde signals were observed at 51-1 9.79 and Sc 190.0 in the
NMR spectra while the acetyl signal resonated at 5H 2.58, Sc 26.6 (CH3) and Sc 196.5
(COCH3). The mass spectrum showed the expected M + base peak of m/z 298 consistent
with structure 3.80.
COCH3
3.15
COCH3
3.79 R = CH2OH
_D. 3.80 R = CHO PCC, CH2C12 , 95%
SCHEME 3.32
83
Treatment of 3.80 with a mixture of Pb(OAc) 4, BF3 .Et20 and CH3OH in benzene afforded
the desired product 3.16 in 52% yield, whereas 97% yield was obtained via thallium(III)
nitrate oxidative rearrangement method described in Scheme 3.11.
The moderate yield obtained in the oxidation with lead(IV) acetate may be attributed to
the poor solubility of the starting material in the benzene solvent. The presence of the
expected two carboxymethyl protons, two methoxy signals, two benzylic ether protons,
five aromatic protons with expected splitting patterns and the aldehyde proton was clearly
visible in the 111 NMR spectrum. The 13C NMR showed, amongst others, the presence of
the important ester carbonyl at Sc 171.0, carboxymethyl at Sc 40.3 (CH2CO2), methoxy of
the methyl ester at Sc 52.2 and the aldehyde at Sc 190.2. The MS spectrum showed the
M+ peak of m/z 328 consistent with the assigned structure 3.16.
H3CO CHO
H3CO CHO
Pb(OAc)4, CH3OH, BF1.Et9 0 11...
52%
or
TTN, CH3OH, HC104 30,
97% OCH3
COCH3
3.80
3.16
SCHEME 3.33
3.10 f3-phenethylamine derivatives of 3.3
The 13-phenethylamines were prepared by methods similar to those used for the synthesis
of derivatives of 3.2 (§ 3.5). Condensation of benzaldehyde 3.16 by Henry condensation
in aq. KOH solution gave the nitrostyrene 3.81 in 83% yield (Scheme 3.34). The 1H
84
H3CO CHO
CH3NO2, 5% aq. KOH lo. 10% aq. HC1
83%
OCH3
NO2
NMR spectrum exhibited the alkene doublets resonating at SH 7.50 and S H 7.84, with the
coupling constants of 13.5 Hz, confirming the trans orientation.
3.16
3.81
SCHEME 3.34
Reduction of the nitrostyrene 3.81 with the borane method (Scheme 3.15) afforded the
amino alcohol 3.82 (Scheme 3.35). The 1H NMR spectra displayed four triplets due to
CH2CH2OH (OH 2.82 and .511 3.77) and CH2CH2NH2 OH 2.62 and OH 2.91), methoxy
singlet (OH 3.81), two benzyl ether protons resonating as singlet OH 5.27) and five protons
in the aromatic region. The assigned structure was in complete agreement with the MS
data showing the M+ of m/z 315. The structure was also in good accord with the 13 C
NMR and IR data. The methyl ester lost during the reduction can be regenerated via
oxidation of the primary alcohol moiety using the same conditions described for the
preparation of compound 3.11b (Scheme 3.18).
Due to the inherent disadvantages of the borane reduction step as described in § 3.5.1 this
reaction sequence was not further pursued and we have opted for the nitrile approach (§
3.5.2).
85
3.81
OH
3.82
BH3.THF, cat. NaBH4 67%
H3CO NO2 H3CO NH2
SCHEME 3.35
In the alternate approach to the phenethylamines, the one-pot reduction-acylation of the
phenylacetonitrile 3.85 derived from the benzaldehyde 3.16 via sequential reduction-
chlorination-cyanation processes afforded the desired intermediate 3.17 (Schemes 3.6 and
3.37).
The spectrum of 3.17 exhibited the expected signals. The important NHBoc signals
appeared as a singlet at 6H 1.41 (three methyl of tert-butyl group) and a broadened singlet
6H 4.51 (NH). Two signals integrating for two protons each resonating at OH 2.63 and OH
3.32 were assigned to CH2CH2NHBoc and CH2NHBoc, respectively. The other structural
features of the compound were already assigned in the previous starting material.
86
OCH3
NaBH4, CH3OH 78%
H3CO CHO
Boc2O, CH3OH 88%
3.16 SOC12, CHC13, 100%
NaCN, DMSO, 87%
3.83 R = CH2OH 3.84 R = CH2C1
3.85 R = CH2CN
SCHEME 3.36
3.85
3.17
SCHEME 3.37
It should also be mentioned here that both the nitrostyrene and the nitrile route are
suitable for the preparation of the phenethylamine derivatives of 3.2 and 3.3, the possible
key intermediate for the preparations of the bisbenzylisoquinoline. However, the lack of
chemoselectivity observed in the reduction reactions in Schemes 3.17 and 3.35 as well
87
other disadvantages associated with the use of borane, make the nitrile route more
attractive.
Once more, we have succeeded in preparing another key precursor 3.17 required for the
synthesis of cissacapine (1.25). In addition, this precursor 3.17 together with either 3.11a,
3.11b or 3.11c serve as the right and left hand parts of insularine (1.26) and insularoline
(1.27).
3.11 Model carboxamide formation and attempted Bischler-
Napieralski cyclisation
Having successfully prepared our key precursors, we were now in a stage to synthesise
cyclobisamides derivatives of 3.1 followed by cyclisation to produce the isoquinoline
compounds. We planned to do our coupling studies to form the carboxamide moiety in
the same way Tomita et al. 2 did in the synthesis of dl-cycleanine (1.28) as described in
Chapter 2. In contrast to Tomita et al. 2 , we chose 4-(4,6-dimethoxy-1,3,5-triazen-2-y1)-4-
methylmorpholinium chloride61 '62 (DMTMM) (3.87) instead of DCC as the coupling
agent. This reagent has been reported to be more efficient than DCC and EDC and it is
easily prepared at a low cost from cyanuric chloride (3.86a) following literature methods
as shown in Scheme 3.38. 62 '63 This water-soluble reagent allows formation of
carboxamides (in high yields and high purity) in alcohol, THE or water by mixing the
acids and amines without any additives at atmospheric conditions.
Cl
N
Cl
N
N
CH3
Cl N
2 eq. NaHCO3 .j■
N (0) N
C1-/L
0
+) N-- CH3
N N
N OCH3 Cl CH3OH/H2OH
ro. 100%
74% H3CON%L
OCH3 H3CO
3.86a 3.86b 3.87
SCHEME 3.38
88
OCH3
OCH3
3.11c 0
3.11b
DMTMM (3.87), CH3OH 94%
H3CO
H3CO
3.88d 3.88a RI = CH3, R2 = Boc
3.88b R 1 = H, R2 = Boc
3.88c Ri = H, R2 = H
K2CO3, CH3OH-H20 79%
TFA, CH2C12 quantitative
...4
SCHEME 3.39
Condensation of compounds 3.11b and 3.11c in methanol with DMTMM (3.87) gave the
amide 3.88a (Scheme 3.39). The 111 NMR spectrum features the expected five methoxy,
six methylene, NHBoc, one carboxamide NH, and twelve aromatic protons signals. The
89
important carboxamide (NHCO) signal generated from the coupling was observed as
broad singlet at 5H 5.58, while that of the NHBoc resonated at 5H 4.62 in the 1H NMR
spectrum. The 13 C NMR showed presence of three carbonyl groups resonating at Sc
156.9 (NHBoc), Sc 171.4 and Sc 171.9 (carboxamide and ester).
Hydrolysis of the carboxylic methyl ester followed by deprotection of the amine afforded
3.88c. The loss of the OCH 3 and NHBoc signals was established by 1 H NMR spectrum.
The MS spectrum showed the M + peak of m/z 644 corresponding to the molecular mass of
structure 3.88c.
At this stage, we had two options. The first option was to form the first 3,4-
dihydroisoquinoline by a Bischler-Napieralski reaction, followed by a second sequence of
amide formation and Bischler-Napieralski ring closure. In our reaction, we attempted the
Bischler-Napieralski reaction of derivatives of 3.88 hoping to form 3.88d. We chose
POC13 as our cyclisation agent. Disappointingly, our reactions indicated the formation of
complex mixtures on TLC. Attempts to identify the mixtures with the NMR was met
with no success. At this stage it was clear that the conditions for the Bischler-Napieralski
reaction need to be optimised before this reaction can be attempted. This study will be
pursued in our RAU laboratories.
In the alternative approach, the formation of the second carboxamide will precede the
double Bischler-Napieralski reaction to form the bisbenzyldihydroisoquinoline. The use
of the Bischler-Napieralski reaction to convert cyclobisamides 2.13 and 2.107 to the
alkaloids dl-cepharanthine (2.14) and dl-cycleanine (1.28) (Schemes 2.6 and 2.37) has
been reported. In these reactions, the cyclobisamides were cyclised followed by reduction
of the corresponding 3,4-dihydroisoquinoline and finally N-methylation to give the
corresponding alkaloids 2.14 and 1.28. It is clear that the low yields obtained are due to
the Bischler-Napieralski reaction since it was mentioned that the TLC for the Bischler-
Napieralslci-reduction reactions showed the formation of several spots. Unfortunately,
due to time constraints, we did not have enough material of derivatives of 3.88 to
investigate this route. However, this will be pursued as soon as the optimal Bischler-
Napieralski conditions have been found.
90
H3CO
HO
3.89
Br
3.90
NaBH4 CH3OH
96%
CHO H3CO
Br2, HOAc 95% HO
3.22
CHO
Br
3.93 3.92
CH2OH CH2C1 H3CO SOC12 CHC13 82% H3CO
3.91
CH2CN H3CO
Nom— aCN DMSO
74% H3CO
3.12 Synthesis of optically-pure benzyltetrahydroisoquinoline
intermediates 3.98 and 3.103
As shown in Scheme 3.5, our Approach 2 features preparation of the optically-pure
benzyltetrahydroisoquinoline intermediates by introducing an appropriate chiral auxiliary
on the nitrogen atom. We decided to utilise both of (5)- and (R)-1-phenethylamine
enantiomers using Polniaszek's method. 5 '6'7
25% , acCNa0H, EtOH 81%
OH
Br
3.23
SCHEME 3.40
Vanillin (3.22) proved to be a very effective starting point for a convenient preparation of
the phenylacetic acid 3.23 (Scheme 3.40). Bromination 64,65,66 of vanillin (3.22) followed
by methylation gave the benzaldehyde 3.90. Conversion of benzaldehyde 3.90 to
91
phenylacetic acid 3.23 requires one carbon homologation, which was achieved by a
standard reduction-chlorination-cyanation-hydrolysis sequence. The 'H NMR spectrum
of the product 3.23 was in agreement with the assigned structure with the aromatic
protons resonating as a set of meta coupled doublets at SH 6.78 and 8 H 7.05. The 1 H NMR
further revealed the presence of two methoxy (OH 3.80 and OH 3.85) and carboxymethyl
(OH 3.57) signals.
The carbonyl signal of the carboxylic acid was evident at 8c 179.0 in the 13C NMR
spectrum of 3.23. The MS spectrum confirmed the presence of bromine, as the M +
showed the characteristic 79Br/81 Br isotope pattern.
Incorporation of the chiral auxiliary via DMTMM (3.87) condensation of phenylacetic
acid 3.23 with (S)-(-)-1-phenethylamine afforded the optically-pure amide 3.94 in
excellent yield (Scheme 3.41). The 'H NMR spectrum showed the expected seven
aromatic protons resonating as a set of meta coupled doublets (OH 6.74 and OH 6.98) and a
multiplet integrating for five protons at OH 7.18-7.29. Apart from the aromatic protons,
the 'H NMR also displayed methyl doublet, two methoxy singlets, CH quartet and NH
broad singlet. The structure 3.94 was consistent with the 13C NMR, MS and IR data. The
product gave optical rotation of [4 325 = -24.5 (c = 1.46 CHC13).
The amide 3.94 was reduced with BH 3 .THF complex in the presence of the BF3.Et20
complex to give the chiral amine 3.95 with [4325 = -36.1 (c = 0.89 CHC13) in 54% yield.
The 13C NMR spectrum of the product indicated the disappearance of the amide carbonyl
signal, which was present in the starting material at Sc 169.2 and as a result, two
methylene signals appearing at Sc 35.9 and Sc 48.4 indicated the formation of amine. The
shift of the broad singlet NH from 8H 5.95 to OH 1.48 was evident in the 'H NMR. The
signal integrating for four protons resonating at OH 2.60-2.65 were assigned as the two
methylenes.
92
H3CO
H3CO
Br
0 Ph
H CH3
Br
Ph
-r..CH3
OH
DMTMM, THE-H20 84%
3.96
POC13, PhCH3
Br 3.95
O'Pr
H2N Ph OH H3CO
h CH3
DMTMM, CH3 OH-H20 H3CO 100%
3.23 3.94
BH3.THF BF3 . Et20
54%
H3 CO
H3 CO
3.97 3.98
SCHEME 3.41
The amine 3.95 was acylated with p-isopropyloxyphenylacetic acid using DMTMM
(3.87) to give acetamide 3.96 in 84% yield as an inseparable mixtures of cis, trans
configurational isomers (Scheme 3.41). The next step was the Bischler-Napieralski
formation of the isoquinoline nucleus. At this stage we had enough material of the chiral
acetamide 3.96 and we could afford playing around with various factors of this reaction in
order to obtain the optimal conditions. It was found that the use of an excess amount of
93
POC13 in anhydrous benzene and long reaction periods gives the isoquinoline compounds
in good yields. With these conditions in hand, we hope we shall also be able to further
elaborate our precursors (Approach 1) to the desired bisbenzyltetrahydroisoquinoline
alkaloids.
Treatment of the chiral acetamide 3.96 with excess POC13 (23 eq.) in refluxing anhydrous
benzene overnight under the Bischler-Napieralski cyclisation reaction afforded the chiral
iminium ion 3.97, which was used for the next step without further purification.
Stereoselective reduction of the iminium ion 3.97 with NaBH4 in methanol at —78 °C
afforded the (5)-N-substituted tetrahydroisoquinoline 3.98 in 70% yield based on amide
3.96. The product 3.98 gave an optical rotation of [a]D 25 = +78.6 (c = 1.56 CHC13). The
assigned structure was in good agreement with the NMR and MS data. The 1H NMR
spectrum exhibited the expected ten aromatic protons compared to eleven found in
starting material 3.96, isopropyloxy, two methoxy, chiral auxiliary (methine and methyl)
and seven protons (two a-H and five tetrahydropyridine protons). Neither the amide
carbonyl nor the imine (C=N) present in the starting material 3.96 and the intermediate
3,4-dihydroisoquinolinium ion 3.97, respectively were present in the 13C NMR spectra of
3.98. Instead two signals at 5 58.9 and 5 60.4, assigned to C-1 and NCHCH3 were
observed. In the NMR, only a single compound was observed. The presence of a second
diastereomer could not be detected by either TLC or NMR. Therefore, it is clear that the
reduction proceeded with high stereoselectivity.
Repeating the synthetic route in Scheme 3.41, the diastereomer 3.103 was prepared using
chiral (R)-(+)-1-phenethylamine as shown in Scheme 3.42. The spectral data of all chiral
compounds derived from (R)-1-phenethylamine were in full agreement with those derived
from the (5)-1-phenethylamine. However, these compounds showed optical rotations in
opposite direction as compared to those obtained from (5)-enantiomer. Optical rotations
for products 3.99, 3.100, 3.101 and 3.103 were [a]D25 = +21.8 (c = 1.03 CHC1 3), +31.2 (c
= 4.32 CHC13), +42.9 (c = 1.10 CHCI3) and —83.7 (c = 1.33 CHC13), respectively. A
slight differences were observed in the absolute value of the enantiomeric products.
However, this could be attributed to the starting materials. The (5)-(+1-phenetyhlamine
showed an [a]D25 = -36.3 (c = 1.23 CHC1 3) whereas the (R)-isomer gave [a]D 25 = +34.3 (c
1.70 CHC13).
94
Br
H3CO
NaBH4, CH3OH H3CO -78 °C 70%
3.23
POC13, PhCH3
H3CO
H3CO
3.102 3.103
OH
H3CO CH3
H3C0 ."Ph DMTMM, THE-H20 O H 84%
O'Pr
3.101
3.99
BH3.THF BF3 .Et20
61%
Br
3.100
OiPr
OH H2NCH3 H3CO 0 r . '"' Ph CH3
DMTMM, CH3OH-H20 H3C0 fiNT—('Ph 100%
H
SCHEME 3.42
We presented an efficient and stereoselective preparation of optically-pure
benzytetrahydroisoquinolines 3.98 and 3.103 that we believe will provide an easy access
to both stereoisomers of cycleanine derivatives (1.28). This approach shows a major
improvement in terms of yields and stereoselectivity obtained as compared to the
previously-published method in Scheme 2.34. For the alkaloids of cissacapine type
(1.25) we would recommend the use of the other approach outlined in Scheme 3.1. This
95
CH3
is in view of the fact that it might be impractical to employ our methods for thee
construction of the 11H-dibenzo[b,e][1,4]dioxepine moiety as the concluding reactions in
Approach 2.
3.13 Attempted phenoxylation of benzyltetrahydroisoquinoline 3.98
With both optical-pure 3.98 and 3.103 available, we were now in position to proceed with
the formation of dimeric compounds. Compound 3.98 (3.103) can serve as both the aryl
halide (the isoquinoline nucleus) and the phenol (the benzyl aryl, after removal of the
isopropyl protecting group). Catalytic hydrogenation in the presence of palladium would
remove the N-benzyl group of the chiral auxiliaries. We decided to do a model
phenoxylation reaction to obtain optimal conditions for this process (Scheme 3.43).
CH3
SCHEME 3.43
It is known that diaryl ether formation between phenols and electron-rich aryl halides is
problematic (Chapter 2, § 3.4 and Scheme 2.35). For this transformation, we also needed
a method that would not lead to racemisation. Buchwald 52, Hauptman67 and Song68 have
independently developed methods that allow coupling of phenols with the electron-rich
aryl halides. Buchwald52 mentioned that phosphine ligand 2.89 can be used effectively
for coupling of electron-rich aryl halides with phenols. Unfortunately, we could not
utilise this approach as we were unable to prepare ligand 2.89 following the literature
method, 52 which described the preparation of this ligand in 6% yield only. Our reaction
resulted in the formation of four non-identified oxidised product ( 31 P NMR spectrum,
96
crude product). Attempted coupling of 3.98 with p-cresol in the presence of CuCl,
Cs2CO3 and 8-hydroxyquinoline in diglyme at 90 °C (Hauptman method 67) was met with
no success. Similarly, Song 's procedure 68 that involves the use of CuCI, Cs 2CO3 and
TMHD (2.64) in NMI' failed to effect coupling. Although boronic acids were shown to
couple well with phenols (Chapter 2), the boronic derivative of 3.98 that was derived by
lithium-halogen exchange and borylation of 3.98 did not give the coupled product when it
was reacted with the p-cresol. These results were not surprising to us since ortho-
heteroatom boronic acids do not work well in this reactions (For example, see Scheme
2.26).
At this stage we are still searching for a method that would be suitable for this
transformation. This study will be a priority in our laboratories at RAU.
3.14 Conclusion and Further Work
The results discussed in this thesis involved the establishment of the convenient, good
yielding and straightforward methodologies for the synthesis of the suitable key
intermediates that we hope will facilitate future total synthesis of the natural
bisbenzyltetrahydroisoquinoline alkaloids and modified analogues for the study of the
structure-activity relationship.
We succeeded in preparing the key precursors containing all the functionalities required
for the further elaboration towards the total synthesis of cissacapine (1.25), insularine
(1.26), insularoline (1.27) and cycleanine (1.28). Two different synthetic strategies were
illustrated and both routes possess the advantages of using well-established experimental
conditions, which are easy to perform, are good yielding, offer better chemoselectivity
and an easy protection-deprotection sequences and are requiring inexpensive, readily-
available starting material and reagents.
Having succeeded in preparing all the key precursors identified in retrosynthetic Scheme
3.1, we carried out the model carboxamide formation reaction and Bischler-Napieralski
reaction. We were able to prepare the carboxamide derivatives of 3.88 from 3.11a and
3.11b. Bischler-Napieralski cyclisation of the dimeric carboxamide derivative of 3.88
97
was not successful and this reaction will be studied in detail following the Bischler-
Napieralski conditions used in Schemes 3.41 and 3.42 to get the optimal conditions.
Although the preparation of precursor 3.11a seems to be longer than the previously
described method 2, it represents a considerable achievement in terms of yields in the key
steps involving linkage of two ring units to form the diaryl ether moiety as well as having
the above-mentioned advantages making it suitable for moderate to large-scale
preparations. It should be mentioned that the utility of diaryl ether formation was fully
demonstrated, a process which was met with disappointment on the synthesis of diaryl
ether compounds of type 3.11a by the previous methods 2' 14. In addition, the efficient
diaryl ether moiety cyclisation through copper-mediated Ullmann, Pd-catalysed reaction
and SNAr reaction in the synthesis of 11H-dibenzo[b,e][1,4]dioxepine system is quite
remarkable and we believe that the developed approach will allow access to the synthesis
of other compounds containing this 11H-dibenzo[b,e][1,4]dioxepine nucleus.
The second synthetic strategy, which produced benzyltetrahydroisoquinolines 3.98 and
3.103, is short and more efficient in terms of yields and enantioselectivity. This approach
provides the availability of both stereoisomers and this would allow access to various
bisbenzyltetrahydroisoquinolines with different absolute configuration. In this process
the Bischler-Napieralski reaction reactions proceeded smoothly to give the desired chiral
benzylisoquinoline monomers. Coupling of the monomers to their corresponding dimeric
alkaloids via diaryl ether formation was unsuccessful, but we hope that by careful
modifications of the recently-published procedures that tolerate electron-rich aryl halides,
this route will become viable for the preparation of the desired alkaloids. These studies
will be pursued at RAU laboratories.
We strongly believe that both the protocols we developed put us in position to synthesise
the natural alkaloids and a wide range of their analogues and explore their structure-
activity relationship. Further research in this field will be actively pursued at the RAU
laboratories as we strongly believe that the synthesis of bisbenzyltetrahydroisoquinoline
alkaloids warrants greater attention than it has been receiving to date.
98
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101
CHAPTER 4
EXPERIMENTAL
4.1 General
All reactions requiring anhydrous solvents were performed under nitrogen pressure in an oven
dried or flame-out glass apparatus, unless otherwise mentioned.
All required chemicals or reagents were obtained from ACROS, FLUKA, ALDRICH or
MERCK and used without further purification unless otherwise specified. All solvents were
purified and distilled before use. Anhydrous solvents were obtained from appropriate drying
agents as follows. 1 Tetrahydrofuran, diethyl ether, toluene and benzene were distilled under
nitrogen from sodium wire and benzophenone. Pyridine and dichloromethane were refluxed
over calcium hydride. Chloroform, carbon tetrachloride and carbon disulfide were refluxed
over phosphorus(V) oxide. N,N-Dimethylformamide and acetone were stored over sodium
sulphate and distilled. Dimethyl sulphoxide was dried over two batches of 4A molecular
sieves and distilled under reduced pressure.
Thin-layer chromatography (TLC) was performed on Merck silica gel plates (60 F254). Flash
chromatography was performed using Merck Kieselgel 60 (230-400 mesh) with hexane and
increasing amounts of ethyl acetate unless otherwise stated. Detection of the developed TLC
plate was accomplished using UV254 light followed by spraying with chromic acid and heating
in an oven. Iodine was also used as an alternative method for detection. Alkaloids and
amines were detected using either ninhydrin or cobalt(II) thiocyanate spraying reagents.
NMR spectra ('H and 13C) were recorded on a Varian Gemini 300 MHz spectrometer in
deuterated chloroform using tetramethylsilane as internal standard, unless otherwise stated.
Chemical shifts are reported in parts per million (ppm, 5). Where required, nuclear
Overhauser effect (NOE) spectroscopy were employed to determine position of substituents.
Coupling constants are calculated as observed in the 11-INMR spectra.
102
The following abbreviations are used for the mutiplicity of signals:
s singlet br broadened
d doublet dd doublet of doublets
t triplet ddd doublet of doublets of doublets
q quartet m multiplet
Electron impact mass spectra (EI-MS) were recorded on either a Finingan-MAT 8200
spectrometer or a Shimadzu GCMS QP2010 apparatus. Melting points were determined
using a Reichert Kofler hot-stage apparatus and are uncorrected. Optical rotations were
measured on a JASCO DIP 370 digital polarimeter. The measurement were obtained at the
sodium (Na) D line=589 nm. Infrared spectra were recorded on a Perkin Elmer 881
spectrometer in spectroscopic grade CHC13 solutions.
4.2 Synthetic procedures
4.2.1 Methyl 3,4,5-trihydroxybenzoate (3.27)
CO2CH3
OH
3,4,5-Trihydroxybenzoic acid (10.0 g, 58.8 mmol) was dissolved in absolute CH3OH and
conc. H2SO4 (0.3 ml) was added. After refluxing overnight, the solvent was evaporated to
give a white solid. The residue was dissolved in ether, washed with sodium bicarbonate
solution and brine. The organic phase was dried (MgSO 4) and evaporated to afford methyl
gallate (3.27) (10.5 g, 97%) as a white solid.
Mp: 96-97 °C (lit. 2 95-97 °C).
'H NMR (CD3OD) 5: 7.86 (3H, br s, OH), 7.03 (2H, s, H-2, H-6, ArH), 3.80 (3H, s,
CO2CH3).
13C NMR (CD30D) 5:52.3 (CO2CH 3), 109.9 (2C, C-2 and C-6), 121.3 (C-1), 131.2 (C-4),
146.3 (2C, C-3 and C-5), 168.9 (CO 2CH3).
103
MS m/z: 184 (1\e, 90), 153 (100), 125 (37), 107 (10), 79 (26).
4.2.2 Methyl 3,4-dihydroxy-5-methoxybenzoate (3.30)
CO2CH3
OH
Methyl gallate (3.27) (5.0 g, 27 mmol) was dissolved in 10% aq. sodium tetraborate
decahydrate (borax) solution (400 ml) and stirred for 30 min. Dimethyl sulphate (15 ml) and
a solution of sodium hydroxide (7.0 g in 50 ml of H2O) were each added dropwise to the
stirred solution over 2.5 h and stirring was continued overnight. Conc. H2SO4 (25 ml) was
added and stirring continued for an additional hour. The product was extracted with
chloroform and the combined extracts were washed with 20% aq. sodium bicarbonate
solution, brine, dried (MgSO4) and concentrated to give 3.30 (4.5 g, 84%) as a white solid.
The compound showed single spot on TLC (1:1 hexane:EtOAc).
Mp: 110 °C (lit. 3 110-111 °C).
NMR 5: 3.86 (3H, s, OCH3), 3.90 (3H, s, OCH3), 5.55 (1H, br s, OH), 5.89 (1H, br s,
OH), 7.19 (1H, d, J = 1.8 Hz, H-2 or H-6, ArH), 7.32 (1H, d, J = 1.8 Hz, H-6
or H-2, ArH).
13 C NMR 5: 52.1 (CO2CH3), 56.4 (OCH3), 104.8, 110.9, 121.7, 136.8, 143.3, 146.3, (6ArC)
166.8 (CO2CH3).
MS m/z: 198 (M+, 84), 183 (7), 167 (93), 155 (5), 139 (18), 124 (8), 85 (97), 83 (100),
77 (6), 67 (9), 47 (72).
IR vma. (cm-1 ): 3400, 1700.
4.2.3 Methyl 3,4-bis(acetoxy)-5-methoxybenzoate (3.31)
H3CO CO2CH3
OAc
104
To the solution of phenol 3.30 (10.0 g, 50 mmol) in acetic anhydride (19.0 ml, 202 mmol)
was added triethylamine (42.5 ml, 305 mmol) at 0 °C. The solution was stirred at room
temperature for 1 h. The excess of acetic anhydride was destroyed by addition of EtOH (3m1).
The reaction mixture was poured into water and extracted with EtOAc. The organic extracts
were washed with brine, dried (MgSO4) and evaporated in vacuo to give white solid (14.2 g,
100%) of diacetate 3.31.
Mp: 86-87 °C.
1 H NMR 8: 2.27 (3H, s, OAc), 2.29 (3H, s, OAc), 3.87 (3H, s, OCH3), 3.89 (3H, s, OCH3),
7.45 (1H, d, J= 1.8 Hz, H-2•or H-6, ArH), 7.52 (1H, d, 1= 1.8 Hz, H-2 or H-6,
ArH).
"C NMR 8: 20.3 (OCOCH3), 20.5 (OCOCH3), 52.4 (CO2CH3), 56.4 (OCH3), 110.7, 116.8,
128.1, 135.8, 143.1, 152.2, (6ArC), 165.5 (CO2), 167.1 (CO2), 167.9 (CO2).
MS m/z: 282 (r, 8), 251 (3), 240 (40), 198 (100), 167 (69), 139 (9), 43 (86).
IR Vmax (cm 1): 1790, 1730.
4.2.4 Methyl 3-acetoxy-4,5-dimethoxybenzoate (3.33)
CO2CH3
OAc
The mixture of the diacetate 3.31 (10.0 g, 35 mmol), K2CO3 (15.0 g, 101 mmol) and CH3I
(4.5 ml, 105 mmol) in DMF was heated at 40 °C for 8 h. The inorganic salt was filtered out
and the filtrate was diluted with EtOAc. The organic extract was washed several times with
water to remove most of the DMF, dried (MgSO4), evaporated and flash chromatographed
(4:1 hexane:EtOAc) to afford 3.33 (8.6 g, 96%).
1 11 NIVIR 8: 2.29 (3H, s, OAc), 3.84 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.88 (3H, s,
OCH3), 7.35 (1H, d, J= 2.1 Hz, H-2 or H-6, ArH), 7.46 (1H, d, J= 2.1 Hz, H-
2 or H-6, ArH).
13C NMR 8: 20.6 (OCOCH3), 52.2 (CO2CH3), 56.2 (OCH3), 60.7 (OCH3), 111.2, 116.9,
124.9, 143.4, 145.0, 153.0, (6ArC), 165.8 (CO2), 168.8 (CO2).
105
MS m/z: 254 (M+, 78), 226 (68), 212 (100), 198 (56), 197 (87), 181 (82), 153 (52), 125,
(67), 109 (36), 77 (30).
IR v„,a,c (cm-1 ): 1790, 1730, 1500.
4.2.5 Methyl 3-hydroxy-4,5-dimethoxybenzoate (3.7)
H3CO
H3CO
CO2CH3
OH
To the solution of compound 3.33 (8.0 g, 31.5 mmol) in CH3OH (100 ml) and H2O (25 ml)
was added K2CO3 (13.0 g, 94 mmol). The mixture was stirred at room temperature for 30
min. After removal of the volatiles, the aqueous solution was acidified with 5% aq. HC1. The
organic compound was extracted with EtOAc, dried (MgSO4) and evaporated to give
compound 3.7 as white solid (6.6 g, 99%)
Mp: 66-68 °C.
NMR 6: 3.85 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.91 (3H, s, OCH3), 6.06 (1H, OH),
7.15 (1H, d, J= 1.8 Hz, H-2 or H-6, ArH), 7.27 (1H, d, J= 1.8 Hz, H-2 or H-6,
ArH).
13C NMR 6: 52.2 (CO2CH3), 56.0 (OCH3), 60.9 (OCH3), 105.54, 109.8, 125.5, 139.3,
148.8, 151.8, (6ArC), 166.6 (CO2CH3).
MS m/z: 212 (M+, 100), 197 (58), 181 (92), 169 (10), 141 (37), 137 (17), 123 (11), 109
(12), 93 (10), 67 (22), 59 (17), 28 (30).
IR vmax (cm-1 ): 3550, 1725.
4.2.6 Methyl 3-(4-acetylphenoxy)-4,5-dimethoxybenzoate (3.8)
COCH3
106
A mixture of methyl 3-hydroxy-4,5-dimethoxybenzoate (3.7) (5.5 g, 26 mmol), p-bromo-
acetophenone (3.6)(6.2 g, 31 mmol), anhydrous K2CO3 (7.2 g, 52 mmol) in anhydrous
pyridine (80 ml) was heated at 80 °C for 10 min. Copper(II) oxide (5.1 g, 65 mmol) was
added and the mixture was refluxed for 24 h. After cooling to room temperature, the solution
was filtered and poured into water. The aqueous mixture was extracted with EtOAc, washed
successively with copper sulphate solution, brine and dried (MgSO4). Evaporation of the
solvent gave a brown residue which was flash chromatographed (4:1-7:3 hexane:EtOAc) to
give diaryl ether 3.8 (7.6 g, 88%) as a pale yellow oil.
11-1 NMR 5: 2.53 (3H, s, COCH3), 3.81 (3H, s, OCH3), 3.85 (3H, s, OCH3), 3.92 (3H, s,
OCH3), 6.91 (2H, d, J= 9.0 Hz, H-2', H-6', ArH), 7.36 (1H, d, J= 2.1 Hz, H-2
or H-6, ArH), 7.46 (1H, d, J= 2.1 Hz, H-2 or H-6, ArH), 7.90 (2H, d, J= 9.0
Hz, H-3', H-5', ArH).
13C NMR 6: 26.5 (COCH3), 52.3 (CO2CH3), 56.3 (OCH3), 61.0 (OCH3), 110.0, 116.2 (2C,
C-2', C-6'), 116.3, 125.4, 130.5 (2C, C-3', C-5'), 131.9, 145.4, 147.3, 153.5,
161.6, (12ArC), 165.9 (CO2CH3), 196.5 (COCH 3).
MS m/z: 330 (Nr, 88), 315 (100), 299 (12), 285 (11), 271 (5), 241 (5), 229 (3), 214 (7),
185 (5), 167 (10), 149 (27), 137 (12),111 (22), 97 (36), 71 (52).
IR vm.(cm-1): 1725, 1710.
4.2.7 Methyl 3-[4-(1,1-dimethoxyethyl)phenoxy]-4,5-dimethoxybenz-
oate (3.34)
C(OCH3)2CH3
Diaryl ether 3.8 (7.0 g, 21 mmol), anhydrous CH3OH (70 ml), trimethyl orthoformate (15 ml)
and p-toluene sulphonic acid (100 mg) were refluxed for 18 h. The solution was cooled to
room temperature and triethyl amine (0.5 ml) was added. The solvent was evaporated in
107
CCH3
vacuo to give 3.34 as a white solid (7.2 g, 91%). The product was used for the next step
without purification.
Mp: 91-92 °C.
NMR 5: 1.51 (3H, s, CH3), 3.16 (6H, s, 20CH3, acetal), 3.83 (3H, s, OCH3), 3.88 (3H,
s, OCH3), 3.92 (3H, s, OCH3), 6.88 (2H, d, J= 9.0 Hz, H-2', H-6', ArH), 7.31
(1H, d, J = 2.1 Hz, H-2 or H-6, ArH), 7.41 (1H, d, J = 2.1 Hz, H-2 or H-6,
ArH), 7.42 (2H, d, J = 9.0 Hz, H-3', H-5', ArH).
13 C NMR 5: 26.1 (CH3), 48.9 (2C, OCH3, acetal), 52.3 (CO2CH3), 56.3 (OCH3), 61.1
(OCH3), 101.5 [C(OCH3)2], 108.9, 115.5, 117.0 (2C, C-2', C-6'), 125.1, 127.7
(2C, C-3', C-5'), 137.5, 145.0, 148.8, 153.4, 156.8, (12C), 166.1 (CO2CH3).
MS m/z:
376 (M±, 21), 361 (31), 345 (100), 340 (26), 315 (52), 287 (12), 271 (5), 157
(30), 89 (16), 43 (62).
1R vinax (cm-1 ): 1730.
4.2.8 4-(5-Hydroxymethyl-2,3-dimethoxyphenoxy)acetophenone
(3.35)
H3C0 CH2OH
Diaryl ether 3.34 (2.5 g, 6.6 mmol) in anhydrous THE (10 ml) was added to an ice cold
suspension of LiA1H4 (700 mg) in anhydrous THE (40 ml)over 30 min. After stirring for 2 h
at room temperature, the excess reagent was destroyed by careful addition of water. The
precipitates formed was dissolved by addition of 1M NaOH. The organic components were
extracted with ether and evaporated to give benzyl alcohol as colourless oil. The benzyl
alcohol was dissolved in CH3OH (15 ml) and 15% aq. HC1 was added. The mixture was
stirred at room temperature for 4 h. The volatiles were evaporated in vacuo and the organics
were extracted with EtOAc. The organic phase was dried (MgSO4) and evaporated in vacuo
108
to give the residue which was flash chromatographed (7:3-1:1 hexane:EtOAc) to give (1.65 g,
83%) of 3.35 as white solid.
Mp: 97 °C
114 NMR 5: 2.54 (3H, s, COCH3), 3.75 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.62 (2H, s,
Cf_120H), 6.65 (1H, d, J= 2.1 Hz, H-4' or H-6', ArH), 6.83 (1H, d, J= 2.1 Hz,
H-4' or H-6', ArH), 6.95 (2H, d, J= 9.0 Hz, H-3, H-5, ArH), 7.90 (2H, d, J=
9.0 Hz, H-2, H-6, ArH).
13C NMR 5: 26.5 (COCH3), 56.2 (OCH3), 61.0 (OCH3), 64.7 (CH2OH), 107.5, 112.5, .116.2
(2C, C-3, C-5), 130.5 (2C, C-2, C-6), 131.6, 137.0, 140.5, 147.8, 154.0, 161.9,
(12ArC), 196.7 (COCH3).
MS m/z: 302 (MI-, 100), 287 (53), 271 (5), 255 (4), 227 (15), 198 (8), 185 (12), 43 (90).
vmax (crn-1): 3495, 1680.
4.2.9 3-(4-Acetylphenoxy)-4,5-dimethoxybenzaldehyde (3.9)
To the stirred orange mixture of PCC (740 mg, 3.44 mmol) and anhydrous NaOAc (50 mg) in
anhydrous CH2C12 (5 ml) was added at once a solution of benzyl alcohol 3.35 (800 mg, 2.60
mmol) in anhydrous CH2Cl2 (5 ml). The resulting dark brown solution was stirred at room
temperature for 2.5 h and then quenched by addition of anhydrous ether (10 ml). The solvent
was decanted and the black solid was washed with ether. The combined organics were
evaporated to give a brown residue which was passed through a short silica column (1:1
hexane: EtOAc) to give compound 3.9 (684 mg, 86 %) as a yellow oil.
NMR 5: 2.55 (3H, s, COCH3), 3.87 (3H, s, OCH3), 3.95 (3H, s, OCH3), 6.97 (2H, d, J=
9.0 Hz, H-2', H-6', ArH), 7.19 (1H, d, J= 1.8 Hz, H-2 or H-6, ArH), 7.33 (1H,
109
d, J = 1.8 Hz, H-2 or H-6, ArH), 7.94 (2H, d, J = 9.0 Hz, H-3', H-5', ArH),
9.81 (1H, s, CHO).
13C NMR .5 26.5 (COCH3), 56.3 (OCH3), 61.2 (OCH3), 107.8, 116.3 (2C, C-2', C-6'),
117.7, 130.6 (2C, C-3', C-5'), 131.8, 132.1, 146.8, 147.9, 154.3, 161.4,
(12ArC), 190.1 (CHO), 196.5 (COCH3).
MS m/z: 300 (Mt, 63), 285 (100), 240 (8), 198 (36), 167 (9), 142 (7), 43 (40).
IR vm. (cm 1): 1725, 1680.
Dess-Martin periodinane oxidation 4'5 in CH2C12 gave similar results.
4.2.10 Methyl 4-(5-formy1-2,3-dimethoxyphenoxy)phenylacetate (3.10)
4.2.10.1 Lead(IV) acetate oxidative rearrangement
A mixture of acetophenone 3.9 (350 mg, 1.16 mmol), anhydrous CH3OH (2 ml) and BF3.Et20
(1 ml) was added at once to a stirred suspension of Pb(OAc)4 (540 mg, 1.22 mmol) in
anhydrous benzene (5 ml). The reaction mixture was stirred at room temperature for 24 h and
diluted with ice water. The organic phase was extracted with benzene, washed with 5% aq.
Na2CO3 and brine, and then dried (MgSO4). Removal of the solvent in vacuo followed by
flash chromatography (7:3 hexane:EtOAc) gave 3.10 as a yellow oil (342 mg, 89%).
4.2.10.2 TTN oxidative rearrangement
Acetophenone 3.9 (5.0 g, 16.6 mmol) in CH3OH (20 ml) was added dropwise to a solution of
TTN (7.7 g, 16.7 mmol) and 70% perchloric acid (20 ml) in CH3OH (50 ml). After stirring
overnight, the thallium(I) nitrate which precipitated was filtered out and water was added.
110
The mixture was extracted with CH2C12. The CH2C12 extract was washed with saturated,
NaHCO3, brine and water. Evaporation of the solvent in vacuo gave the residue which was
flash chromatographed (7:3 hexane:EtOAc) to give oily phenylacetate 3.10 (4.84 g, 88%).
1 H NMR 6: 3.58 (2H, s, CH2CO2CH3), 3.67 (3H, s, CH2CO2CH3), 3.91 (3H, s, OCH3),
3.93 (3H, s, OCH3), 6.93 (2H, d, J = 9.0 Hz, H-3, H-5, ArH), 7.08 (1H, d, J =
1.8 Hz, H-4' or H-6', ArH), 7.20-7.32 (3H, H-2, H-6 and H-4' or H-6', ArH),
9.75 (1H, s, CHO).
13C NMR 8: 40.3 (CH2CO2), 52.0 (CO2CH3), 56.3 (OCH3), 61.2 (OCH3), 106.6, 116.6,
117.8 (2C, C-3, C-5), 128.2, 128.9 (2C, C-2, C-6), 130.6, 131.7, 149.5, 154.1,
156.1, (12ArC), 171.8 (CO2CH3), 190.4 (CHO).
MS m/z: 330 (Nr, 22), 271 (29), 198 (39), 185 (96), 183 (100), 155 (44), 107 (22), 75
(38), 43 (50).
IR vmax (cm.): 1730, 1685.
4.2.11 Methyl 4-12,3-dimethoxy-5-1(E)-2-nitrovinyliphenoxy)phenyl-
acetate (3.48a)
Method A
A mixture of 3.10 (250 mg, 0.76 mmol), ammonium acetate (234 mg, 3.0 mmol),
nitromethane (0.25 ml, 4.56 mmol) in glacial acetic acid was refluxed for 1.5 h. The solvent
was evaporated in vacuo and the resulting dark red residue was dissolved in CH2C12 and
washed with saturated NaHCO3. The CH2C12 extract was dried (MgSO4), evaporated and
flash chromatographed (CH2C12) to give nitrostyrene 3.48a(100 mg, 40%) as a bright yellow
solid.
111
Method B
To a solution of benzaldehyde 3.10 (1.0 g, 3.03 mmol) and nitromethane (1 ml, 18.7 mmol) in
EtOH (25 ml) at 0 °C was added 5% aq. KOH solution (10 ml). After stirring for 1 h at the
same temperature, the reaction mixture was poured into 15% aq. HC1 solution and yellow
precipitate formed. The precipitate was filtered and dried in vacuo to give nitrostyrene 3.48a
(1.10 g, 98%).
Mp: 110-112 °C.
1H NMR 5: 3.59 (2H, s, CH2CO2CH3), 3.68 (3H, s, CH2CO2CH3), 3.88 (3H, s, OCH 3),
3.92 (3H, s, OCH3), 6.77 (1H, d, J= 2.1 Hz, H-4' or H-6', ArH), 6.84 (1H, d, J
= 2.1 Hz, H-4' or H-6', ArH), 6.90 (2H, d, J = 9.0 Hz, H-3, H-5, ArH), 7.21
(2H, d, J = 9.0 Hz, H-2, H-6, ArH), 7.44 (1H, d, J = 13.8 Hz, a-H, trans), 7.85
(1H, d, J = 13.8 Hz, 13-H, trans).
13C NMR 5: 40.3 (CH2CO2), 52.0 (CH2CO2CH3), 56.3 (OCH 3), 61.2 (OCH3), 107.9, 114.7,
117.7 (2C, C-3, C-5), 125.2, 129.0, 130.6 (2C, C-2, C-6), 136.5, 138.4, 144.2,
149.8, 154.1, 156.0, (12ArC and C=C), 171.8 (CO2CH3).
MS m/z: 373 (M+, 52), 330 (86), 314 (33), 298 (13), 271 (100), 255 (29), 239 (9), 151
(10), 135 (12), 107 (25), 89 (27), 77 (20).
vn.(cm-1 ): 1700, 1620.
4.2.12 Borohydride Exchange Resin (BER)
4-CH-CH2-31,
N( CH3)3BH4
An aqueous solution of NaBH4 (1M, 200 ml) was stirred with wet chloride-form resin
(Amberlite IRA 400) (40.0 g) for 1 h. The resulting resin was thoroughly washed with
distilled water until free of excess NaBH4. The borohydride exchange resin was then dried in
vacuo at 60 °C for 6 h. The dried resin (40.0 g) was stored under nitrogen in a refrigerator.
112
4.2.13 Methyl 4[2,3-dimethoxy-5-(2-nitroethyl)phenoxyl phenyl-
acetate (3.48b)
To the solution of nitrostyrene 3.48a (100 mg, 0.268 mmol) in CH3OH:CH2C12 (10:1) (5 ml)
was added BER (150 mg) at once. The reaction mixture was stirred at room temperature for 1
h after which the TLC indicated consumption of starting material. The resin was filtered off
and the filtrate was evaporated to give pure compound 3.48b (79 mg, 79%) as a colourless oil.
1H NMR 6: 3.18 (2H, t, J= 7.2 Hz, CH2CH2NO2), 3.57 (2H, s, CH2CO2CH3), 3.68 (3H, s,
CH2CO2CH3), 3.78 (3H, s, OCH3), 3.85 (3H, s, OCH3), 4.53 (2H, t, J= 7.2 Hz,
CH2CH2NO2), 6.41 (1H, d, J= 2.1 Hz, H-4' or H-6', ArH), 6.53 (1H, d, J=
2.1 Hz, H-4' or H-6', ArH), 6.88 (2H, d, J= 9.0 Hz, H-3, H-5, ArH), 7.24 (2H,
d, J= 9.0 Hz, H-2, H-6, ArH).
13 C NMR 6: 33.3 (CH2CH2NO2), 40.3 (CH2CO2), 52.0 (CH2CO2CH3), 56.2 (OCH3), 61.0
(OCH3), 76.1 (CH2CH2NO2), 108.2, 113.3, 117.5 (2C, C-3, C-5), 128.4, 1304
(2C, C-2, C-6), 131.3, 140.1, 149.6, 154.0, 156.6, (12ArC), 171.9 (CO2CH3)
MS m/z: 375 (M+, 85), 361 (100), 328 (58), 314 (72), 269 (33), 253 (75), 241 (14), 149
(18), 77 (19).
IR v.(cm-1 ): 1705, 1625.
113
4.2.14 Methyl 4-15-(2-aminoethyl)-2,3-dimethoxyphenoxylphenyl-
acetate (3.11c)
CH2CO2CH3
Food grade aluminium foil (100 mg) was cut into strips and spirally wound around a glass
stirring rod to make coils. All coils were soaked in diethyl ether to remove oils and
individually amalgamated by immersing in 2% aq. mercuric chloride solution for 20 sec.
After each 20 sec interval the individual coil was washed with diethyl ether and rapidly added
to a THF:H20 (9:1) (10 ml) solution of the nitro compound 3.48b (150 mg, 0.40 mmol). The
probe tip of the ultrasonic processor was inserted into the reaction mixture and activated for
2.5 h. The resulting gray suspension was filtered and acid-base extraction gave the amine
3.11c (54 mg, 39%) as an oil.
111 NMR 5: 1.73 (2H, br s, NH2), 2.63 (2H, t, J= 6.9 Hz, C132CH2NH2), 2.90 (2H, t, J= 6.9
Hz, CH2CH2NH2), 3.56 (2H, s, CH2CO2), 3.67 (3H, s, CH2CO2CH3), 3.78 (3H,
s, OCH3), 3.86 (3H, s, OCH3), 6.41 (1H, d, J = 1.8 Hz, H-4'or H-6', ArH),
6.54 (1H, d, J= 1.8 Hz, H-6' or H-4', ArH), 6.87 (2H, d, J= 8.7 Hz, H-3, H-5,
ArH), 7.16 (2H, d, J = 8.7 Hz; H-2, H-6, ArH).
13C NMR 5: 40.1 (CH2CO2), 39.5 (CH2CH2NH2), 43.4 (CH2CH2NH2), 52.1 (OCH3,
CH2CO2CH3), 56.2 (OCH3), 61.0 (OCH3), 108.6, 113.6, 117.4 (2C, C-3, C-5),
128.0, 130.4 (2C, C-2,C-6), 135.1, 139.4, 149.2, 153.7, 156.9, (12ArC), 172.0
(CO2CH3).
MS m/z: 345 (M+, 49), 332 (8), 330 (9), 316 (82), 315 (23), 301 (18), 269 (84), 253
(12), 241 (24), 237 (37), 211 (11), 181 (52), 165 (26), 137 (47), 121 (53), 89
(54), 77 (92), 45 (100).
IR vmax (cm-1 ): 3350, 1710.
114
4.2.15 2-{4-15-(2-Aminoethyl)-2,3-dimethoxyphenoxyl}phenylethanol
(3.53a)
CH2CH2OH
To the flask cooled to 0 °C in an ice bath was added BH3.THF complex (16 ml of 1M
BH3.THF, 16 mmo) via syringe. This was followed by addition of cc,r3-nitrostyrene 3.48a
(750 mg, 2 mmol) in anhydrous THF. After the addition, the ice bath was removed and
catalytic amount (-40 mg) of NaBH4 was added. The yellow solution was stirred at room
temperature for 2 h and allowed to reflux overnight. After cooling to room temperature, the
solution was poured into ice water and acidified with 10% aq. HCl and refluxed for 2.5 h.
The aqueous mixture was cooled to room temperature, washed with ether and was basified
with 15% aq. NaOH. The aqueous phase was extracted with EtOAc, dried (MgSO4) and
evaporated in vacuo to give amine 3.53a (446 mg, 70 %) as an oily substance.
1H NMR 8: 1.76 (2H, br s, NH2), 2.62 (2H, t, J= 6.9 Hz, CH2CH2NH2), 2.80 (2H, t, J= 6.6
Hz, CH2CH2OH), 2.89 (2H, t, J= 6.9 Hz, CH2CLI2NH2), 3.78 (3H, s, OCH3),
3.82 (2H, t, J= 6.6 Hz, CH2CH2OH), 3.85 (3H, s, OCH3), 6.40 (1H, d, J= 1.8
Hz, H-4' or H-6', ArH), 6.53 (1H, d, J= 1.8 Hz, H-6' or H-4', ArH), 6.87 (2H,
d, J = 8.7 Hz, H-3, H-5, ArH), 7.14 (2H, d, J = 8.7 Hz, H-2, H-6, ArH)
13C NMR 8: 38.4 (CH2CH2OH) 39.4 (CH2CH2NH2), 43.0 (CH2CH2NH2), 56.2 (OCH3),
61.0 (OCH3), 63.5 (CH2OH), 108.3, 113.3, 117.6 (2C, C-3, C-5), 130.0 (2C, C-
2, C-6), 132.8, 134.9, 139.2, 149.2, 153.7, 156.8, (12ArC).
MS m/z: 317 (M+, 75), 300 (15), 288 (100), 273 (10), 257 (70), 241 (33), 151 (21), 135
(12), 83 (54), 69 (25).
IR vmax (cm-1): 3350, 3260.
115
4.2.16 4-15-(2-tert-Butoxycarbonylaminoethy1)-2,3-dimethoxy-
phenoxylphenylethanol (3.53b)
To the stirred, ice-cold solution of amino alcohol 3.53a (420 mg, 1.32 mmol) in CHC13 was
added solid Boc2O (289 mg, 1.32 mmol). The solution was stirred at 0 °C for 30 min and
stirring was continued at room temperature overnight. The CHC13 solution was washed with
20% aq. H3PO4, saturated NaHCO3 solution, brine, dried (MgSO4), and evaporated in vacuo to
give 3.53b as colourless oil (548 mg, 100%).
IH NMR 5: 1.42 (9H, s, tBu), 2.64 (2H, t, J= 6.9 Hz, CH2CH2NHBoc), 2.80 (2H, t, J= 6.6
Hz, CF_12CH2OH), 2.89 (2H, q, J = 6.6 Hz, CH2C1_1_2NHB0c), 3.78 (3H, s,
OCH3), 3.80 (2H, J= 6.6 Hz, CH2C1_120H), 3.85 (3H, s, OCH3), 4.59 (1H, br s,
NH), 6.40 (1H, d, J= 1.8 Hz, H-6' or H-4', ArH), 6.62 (1H, d, J= 1.8 Hz, H-
6' or H-4', ArH), 6.86 (2H, d , J = 8.7 Hz, H-3, H-5, ArH), 7.10 (2H, d, J =
8.7Hz, H-2, H-6).
13 C NMR 5: 28.4 (3C, 13u), 36.1 (CH2CH2NH), 38.4 (CH2CH2OH), 41.7 (CH2CH2NH),
56.0 (OCH3), 61.0 (OCH 3), 63.6 (CH2CH2OH), 79.2 [OC(CH3)3], 108.2,
113.2, 117.5 (2C, C-3, C-5), 130.0 (2C, C-2, C-6), 132.6, 134.7, 139.2, 146.6,
149.4, 153.6, (12ArC), 156.2 (HNCO2).
MS m/z: 417 (M+, 58), 400 (2), 387 (2), 361 (29), 343 (13), 331 (29), 316 (13), 300
(100), 287 (42), 269 (28), 255 (20), 241 (13), 179 (4), 151 (4), 91 (8), 57 (91).
IR vff.(cm-1): 3390, 3260, 1680.
116
4.2.17 4-15-(2-tert-Butoxycarbonylaminoethyl)-2,3-dimethoxy-
phenoxylphenylacetic acid (3.11b)
4.2.17.1 Phenylacetaldehyde derivative
The N-Boc amino alcohol 3.53b (308 mg, 0.74 mmol) in CH2C12 (3 ml) was added to the
solution of Dess-Martin periodinane (350 mg, 0.82 mmol) in CH2C12. The reaction was
stirred for 1 h at room temperature and diluted with ether. The resulting suspension of
iodinane was washed with 1M NaOH to hydrolyse the water-soluble iodinane to 2-
iodosobenzoate. After stirring for 10 min, the ether layer was extracted with 1M NaOH, with
water and dried (MgSO4). Evaporation of ether yielded crude phenylacetaldehyde (283 mg,
92%) which was used for the next step without purification.
NMR 5: 1.40 (9H, 'Bu), 2.65 (2H, t, J = 7.2 Hz, CI-J2CH2NHBoc), 3.3 (2H,
CH2CH2NHBoc), 3.63 (2H, CH2CH0), 3.77 (3H, s, OCH3), 3.85 (3H, s,
OCH3), 4.58 (1H, br s, NH), 6.40 (1H, J = 1.8 Hz, H-4' or H-6', ArH), 6.54
(1H, d, J = 1.8 Hz, H-4' or H-6', ArH), 6.92 (2H, d, J = 8.7 Hz, H-3, H-5,
ArH), 7.13 (2H, J = 8.7 Hz, H-2, H-6, ArH), 9.70 (1H, CHO).
MS m/z: 415 (Mr, 14), 400 (2), 389 (3), 357 (2), 354 (43), 361 (15), 344 (18), 328 (9),
314 (15), 300 (45), 287 (25), 271 (11), 255 (10), 241 (12), 231 (6), 151 (9),
135 (8), 111 (9), 85 (14), 71 (18), 57 (100).
4.2.17.2 Phenylacetic acid (3.11b)
To the solution of above phenylacetaldehyde (200 mg, 0.48 mmol) in t-butanol (3 ml) was
added 5% aq. NaH2PO4 (1 ml) and 1M KMn04 solution (1 ml) at room temperature. The
117
mixture was stirred for 2 h at room temperature and quenched by addition of aqueous Na2SO3
and extracted with ethyl acetate. Evaporation of the solvent and flash chromatography (2:3
hexane:EtOAc) gave the acid 3.11b (105 mg, 51%)
1H NMR 5: 1.40 (9H, tBu), 2.66 (2H, br, CI-I2CH2NHBoc), 3.28 (2H, br, CH2CLI2NHBoc),
3.57 (2H, s, CH2CO2H), 3.77 (3H, s, OCH3), 3.84 (3H, s, OCH3), 4.59 (1H, br
s, NH), 6.39 (1H, d, J = 1.8 Hz, H-4' or H-6', ArH), 6.53 (1H, d, J = 1.8 Hz,
11-4' or H-6', ArH), 6.92 (2H, d, J = 8.4 Hz, H-3, H-5, ArH), 7.21 (2H, d, J =
8.4 Hz, H-2, ArH).
13C NMR 5: 28.4 (3C, 13u), 36.4 (CH2CH2NH), 40.4 (CH2CO2 or CH2NHCO2), 41.7
(CH2CO2 or CH2NHCO2), 56.0 (OCH3), 61.1 (OCH3), 79.5 [OC(CH3)3],
108.4, 113.5, 117.4 (2C, C-3, C-5), 127.5, 130.4, 130.5 (2C, C-2, C-6), 134.8,
139.3, 149.1, 153.6, (12ArC), 156.9 (IINCO2), 176.8 (CO2H).
MS m/z: 431 (Nr, 13), 375 (10), 358 (4), 345 (2), 330 (7), 314 (62), 301 (24), 287 (3),
270 (6), 253 (8), 241 (22), 77 11), 57 (100).
IR v„.(cm-1): 3350, 1695, 1660.
4.2.18 Methyl 4-(5-hydroxymethy1-2,3-dimethoxyphenoxy)phenyl-
acetate (3.54)
CH2CO2CH3
To the ice cold solution of diaryl ether 3.10 (1.10 g, 3.33 mmol) in EtOH was added NaBH4
(317 mg, 8.39 mmol) in portions. The solution was stirred for 1.5 h at room temperature and
the excess reagent was destroyed by addition of 10% aq. HCI. The volatiles were removed
and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and
evaporated in vacuo to give product 3.54 (983 mg, 89%) as a yellow oil.
118
1H NMR 6: 1.84 (1H, br s, OH), 3.56 (2H, s, Cli2CO2CH3), 3.66 (3H, s, CH2CO2CH.3),
3.79 (3H, s, OCH3), 3.87 (3H, s, OCH3), 4.54 (2H, s, CI-120H), 6.57 (1H, d, J=
1.8 Hz, H-4' or H-6', ArH), 6.75 (1H, J = 1.8 Hz, H-4' or H-6', ArH), 6.88
(2H, d, J = 8.4 Hz, H-3, H-5, ArH), 7.16 (2H, d, H-2, H-6, J= 8.4 Hz, ArH).
13C NMR 6: 40.3 (CH2CO2), 52.0 (CH2CO2CH3), 56.1 (OCH3), 61.1 (OCH3), 64.9
(CH2OH), 106.3, 111.5, 117.6 (2C, C-3, C-5), 128.2, 130.3 (2C, C-2, C-6),
136.7, 140.1, 149.3, 153.8, 156.6, (12ArC), 172.0 (CO2CH3).
MS m/z: 332 (M+, 100), 315 (3), 304 (4), 289 (2), 273 (41), 257 (22), 241(4).
IR v.(cm-1 ): 3395, 1705.
4.2.19 Methyl 4-(5-chloromethy1-2,3-dimethoxyphenoxy)phenylacetate
(3.55)
CI-12CO2CH3
To the solution of 3.54 (570 mg, 1.63 mmol) in anhydrous CHC13 (5 ml), thionyl chloride
(0.15 ml, 2.08 mmol) in anhydrous CHCI3 (3 ml) was added dropwise, and the solution was
stirred at room temperature for 1.5 h. The CHC13 solution was washed with saturated sodium
bicarbonate solution. After evaporation of the solvent, the product was passed through a short
silica column (CHC13) to give benzyl chloride 3.55 (394 mg, 66%).
1 H NMR 6: 3.57 (2H, s, CH2CO2CH3), 3.68 (3H, s, CH2CO2CH3), 3.80 (3H, s, OCH3),
3.88 (3H, s, OCH3), 4.45 (2H, s, CH2C1), 6.59 (1H, d, J= 1.8 Hz, H-4' or H-6',
ArH), 6.75 (1H, d, J= 1.8 Hz, H-4' or H-6', ArH), 6.89 (2H, d, J= 8.4 Hz, H-
3, H-5, ArH), 7.19 (2H, d, J = 8.4 Hz, H-2, H-6, ArH).
13C NMR 6 40.3 (CH2CO2), 46.1 (CH2C1), 52.0 (CH2CO2CH3), 56.1 (OCH3), 61.0 (OCH3),
108.0, 113.4, 117.6 (2C, C-3, C-5), 128.4, 130.4 (2C, C-2, C-6), 132.9, 140.8,
149.2, 153.8, 156.4, (12ArC), 171.9 (CO2CH3).
119
H2CO2CH3
MS m/z: 352 (M+2, 36), 350 (W, 100), 329 (2), 315 (83), 291 (34), 283 (19), 275 19),
255 (5), 241 (14), 224 (6), 214 (9), 181 (3), 89 (13), 77 (13).
IR vmax (cm-1 ): 1720.
4.2.20 Methyl 4-(5-cyanomethy1-2,3-dimethoxyphenoxy)phenylacetate
(3.56)
H3CO A CH2CN
A solution of benzyl chloride 3.55 (270 mg, 0.79 mmol) and sodium cyanide (350 mg, 7.9
mmol) in anhydrous DMSO (6 ml) was heated at 80-90 °C for 3 h, allowed to cool to room
temperature, diluted with water, and extracted with EtOAc. The EtOAc extracts were washed
several times with water, brine and evaporated in vacuo to give benzyl cyanide 3.56 (200 mg,
76%) as a yellow oil.
1H NMR 6: 3.57 (2H, s, CH2CO2CH3), 3.62 (2H, s, CH2CN), 3.67 (3H, s, CH2CO2CH3),
3.79 (3H, s, OCH3), 3.88 (3H, s, OCH3), 6.48 (1H, d, J= 2.1 Hz, H-4' or H-6',
ArH), 6.75 (1H, d, J = 2.1 Hz, H-6' or H-4', ArH), 6.90 (2H, d, J = 9.0 Hz, H-
3, H-5, ArH), 7.18 (2H, d, J = 9.0 Hz, H-2, H-6, ArH).
13C NMR 6: 23.4 (CH2CN), 40.3 (CH2CO2), 52.0 (CH2CO2CH3), 56.2 (OCH3), 61.0
(OCH3), 107.3, 112.8, 117.5, 117.6 (2C, C-3, C-5), 125.3, 128.5, 130.3 (2C, C-
2, C-6), 140.3, 149.2, 154.1, 156.2, (13C, 12ArC and CN), 171.9 (CO2CH3).
MS m/z: 341 (Mr, 26), 322 (3), 313 (2), 298 (2), 282 (100), 266 (18), 241 (3), 214 (16),
161 (3), 146 (6), 90 (15).
IR vmax (cm-1 ): 2250, 1720.
120
4.2.21 Methyl 4-[5-(2-tert-butoxycarbonylaminoethyl)-2,3-dimethoxy- ,
phenoxy]phenylacetate (3.11a)
CH2CO2C1-13
NaBH4 (65 mg, 1.72 mmol) was cautiously added to a stirred solution of NiC12.6H20 (57 mg,
0.240 mmol), Boc2O (105 mg, 0.481 mmol) and benzyl cyanide 3.56 (80 mg, 0.235 mmol) in
CH3OH at 0 °C. Stirring was continued at room temperature overnight. Methanol was
removed in vacuo and the residue dissolved in EtOAc and saturated NaHCO3 solution,
filtered and repeatedly washed with EtOAc. The combined EtOAc extract was dried
(Na2SO4) and evaporated in vacuo to give N-Boc phenethylamine 3.11a (81 mg, 78%) as a
colourless oil.
1 H NMR 5: 1.40 (9H, s, 2.65 (2H, t, J= 7.2 Hz, CLICH2NHBoc), 3.33 (2H, q, J= 6.6
Hz, CH2C1i2NHBoc), 3.56 (2H, s, CH2CO2CH3), 3.67 (3H, s, CH2CO20-13),
3.78 (3H, s, OCH3), 3.86 (3H, s, OCH3), 4.55 (1H, br s, NH), 6.40 (1H, d, J=
1.8 Hz, H-4' or H-6', ArH), 6.57 (1H, d, J= 1.8 Hz, H-4' or H-6', ArH), 6.88
(2H, d, J= 8.7 Hz, H-3, H-5, ArH), 7.16 (2H, d, J=8.7 Hz, H-2, H-6, ArH).
13 C NMR 5: 28.4 (3C, 13u), 36.1 (CH2CH2NHBoc), 40.4 (CH2CO2), 41.7 (CH2NHBoc),
52.0 (CH2CO2CH3), 56.1 (OCH3), 61.1 (OCH3), 79.3 [OC(CH3)3], 108.4,
113.5, 117.4 (2C, C-3, C-5), 128.0, 130.2 (2C, C-2, C-6), 134.7, 139.3, 149.2,
153.7, (12ArC), 156.8 (HNCO2), 172.0 (CO2CH3).
MS m/z: 445 (M4-, 29), 417 (1), 403 (3), 389 (23), 372 (6), 342 (15), 328 (100), 315
(36), 301 (5), 283 (8), 269 (6), 253 (11), 241 (17), 151 (4), 135 (3), 105 (3), 90
(7), 77 (6).
IR v.(cm-1):3390, 1710, 1650.
121
4.2.22 Compound 3.11b (§ 4.2.17) via hydrolysis of methyl ester
derivative 3.11a
A solution of phenyl acetate 3.11a (2.77 g, 6.22 mmol) in CH3OH:H20 (3:1, 20 mll was
stirred overnight at room temperature in the presence of K2CO3 (1.29 g, 9.33 mmol), followed
by reflux for 30 min. The volatiles were removed, 0.5N NaOH was added and the mixture
was washed with ether. The aqueous was acidified with 10% aq. HCI, extracted with EtOAc
and the combined organic phases were washed with brine, dried (Na 2SO4), and evaporated to
give pure phenylacetic acid 3.11b (2.16 g, 83%) as a light brown oil.
4.2.23 Compound 3.11c (§ 4.2.14) via N-Boc removal of 3.11a
To a stirred, ice cold solution of N-Boc compound 3.11a (600 mg, 1.35 mmol) in CH2C12 (2
ml) was added trifluoroacetic acid (2 ml). The solution was stirred at room temperature for
20 h. The volatile components were removed in vacuo and the residue was dissolved in
EtOAc and washed with 1M NaOH. The organic phase was dried (Na2SO 4) and evaporated
in vacuo to give 3.11c (450 mg, 97%) as an oily compound showing a single spot on TLC.
4.2.24 Methyl 3-acetoxy-4-(2-bromobenzyloxy)-5-methoxybenzoate
(3.63)
H3OCI CO2CH3
Br
The mixture of the diacetate 3.31 (1.0 g, 3.5 mmol), anhydrous K2CO3 (1.5 g, 10.5 mmol) and
2-bromobenzyl bromide (1.75 g, 7 mmol) in DMF (15 ml) was heated at 40 °C for 8 h. The
inorganic salt was filtered out and the filtrate was diluted with EtOAc. The organic extract
was washed several times with water to remove most of the DMF, dried (MgSO 4) and
evaporated in vacuo to give the residue, which was purified via flash column (4:1
hexane:EtOAc) to give 3.53 (0.84 g, 58%).
122
1H NMR 8: 2.17 (3H, s, OAc), 3.87 (3H, s, OCH3), 3.92 (3H, s, OCH3), 5.18 (2H, s,
OCI-J2Ph), 7.10-7.55 (6H, m, ArH).
13C NMR 8: 20.5 (OCOCH3), 52.2 (CO2CH3), 56.2 (OCH3), 73.8 (OCH2Ph), 111.2, 117.1,
122.5, 123.8, 126.5, 128.7, 128.8, 132.5, 136.7, 139.6, 143.6, 149.3, (12ArC),
165.9 (CO2), 168.7 (CO2).
MS m/z: 411 (10), 409 (M+1, 11), 368 (35), 366 (37), 197 (49), 171 (100), 169 (96), 43
(73).
IR Aim. (cm 1 ): 1765, 1715.
4.2.25 Methyl 4-(2-bromobenzyloxy)-3-hydroxy-5-methoxybenzoate
(3.64)
H300 CO2CH3
To the solution of 3.63 (500 mg, 10.5 mmol) in CH3OH (4 ml) and H2O (1 ml) was added
K2CO3 (420 mg, 3 mmol). The reaction mixture was stirred for 30 min at room temperature.
The volatiles were evaporated and the aqueous solution was acidified with 10% aq. HC1. The
aqueous was extracted with EtOAc and organic phase was washed with brine, flash
chromatographed (4:1 hexane:EtOAc), dried (MgSO4) and evaporated in vacuo to afford the
title compound 3.64 (310 mg, 70%).
1H NMR: 3.86 (3H, s, OCH3), 3.92 (3H, s, OCH3), 5.23 (2H, s, OCH2Ph), 7.18-7.58 (6H,
ArH).
MS m/z: 369 (12), 367 (M+1,12), 197 (30),169 (100), 141 (4), 90 (20).
IR vmax (cm 1 ): 3520, 1725.
123
4.2.26 Methyl 9-methoxy-11H-dibenzo[b,e] [1,4]dioxepine-7-carboxy-
late (3.65)
H3C0 CO2CH3
A mixture of compound 3.64 (200 mg, 0.54 mmol) and anhydrous K2CO3 (113 mg, 0.81
mmol) in anhydrous pyridine (20 ml) was heated to 80 °C. Copper(II) oxide (85 mg, 1.08
mmol) was added and the reaction mixture was heated at 115 °C for 24 h. After cooling to
room temperature, the mixture was filtered, diluted with EtOAc, washed with 10% aq. HC1
and concentrated to give a brown residue. The residue was purified by flash chromatography
(9:1-4:1 hexane:EtOAc) to give white solid of 3.65 (86 mg, 55%).
Mp: 107-108 °C.
1H NMR 6: 3.87 (3H, s, OCH3), 3.88 (3H, s, OCH3), 5.40 (2H, s, OCH2Ph), 7.26 (1H, d, J
= 2.1 Hz, H-6 or H-8, ArH), 7.08-7.19 and 7.27-7.35 (4H, m, H-1, H-2, H-3,
H-4, ArH), 7.53 (1H, d, J= 2.1 Hz, H-6 or H-8, ArH)
13 C NMR 5:
Ms m/z:
IR vmax (cm-1 ): 1720.
4.2.27 1-Bromo-2,4-dimethylbenzene (3.66)
Br
52.1 (CO2CH3), 56.5 (OCH3), 69.8 (OCH2Ph), 107.6, 116.8, 119.9, 122.3,
124.6, 128.8, 128.9, 130.5, • 142.6, 145.0, 150.5, 158.3, (12ArC), 166.2
(CO2CH3)
286 (M t, 39), 226 (28), 211 (10), 195 (8), 168 (6), 155 (11), 85 (31), 71 (55).
124
m-Xylene (50.0 g, 0.47 mol) and K10-montmorillonite clay (50.0 g) in anhydrous CC14 (200
ml) were placed in round bottomed flask covered with aluminium foil. Bromine (24 ml, 0.47
mol) in anhydrous CC14 (60 ml) was added dropwise for 30 min to the stirred mixture. After
stirring for 2 h, the reaction mixture was extracted with ether and evaporated in vacuo to give
the title compound 3.66 as a yellow oil (64.0 g, 73%). The product showed a single spot on
TLC (hexane).
1H NMR 5: 2.29 (3H, s, CH3), 2.38 (3H, s, CH3), 6.86 (1H, br s, ArH), 7.05 (1H, br d, J=
8.1 Hz, ArH), 7.39 (1H, d, J= 8.1 Hz, ArH).
13C NMR 5: 20.8 (CH3), 22.8 (CH3), 121.4, 127.9, 131.5, 131.9, 136.9, 137.3, (6ArC).
MS m/z:
186 (M+2, 100), 184 (Mt, 87), 171 (9), 169 (9), 105 (91), 103 (41), 79 (34), 77
(46).
4.2.28 1-bromo-2-bromomethy1-4-dibromomethylbenzene (3.67)
Br
CH2Br
Bromine (1.5 ml, 30 mmol) dissolved in CC14 (20 ml) was added over 1 hour to the boiling
solution of 4-bromo-m-xylene 3.66 (1.85 g, 10 mmol) and benzoyl peroxide (240 mg, 1
mmol) in CC14 under irradiation using a 100W lamp. After 3 h of heating and irradiation the
yellow solution was allowed to cool to room temperature followed by solvent removal,
affording crude product 3.67 as an oily material (3.67 g, 90%).
1 H NMR 5: 4.57 (2H, s, CH2Br), 6.56 (1H, s, CHBr2), 7.38 (1H, dd, J= 2.4, 8.1 Hz, ArH),
7.55 (1H, d, J= 8.1 Hz, ArH), 7.61 (1H, d, J= 2.4 Hz).
13 C NMR 8: 32.5 (CH2Br), 38.9 (CHBr2), 125.6, 128.0, 128.8, 133.6, 137.3, 141.6, (6ArC).
MS m/z: 426 (M+8, 6), 424 (15), 422 (19), 421 (52), 420 (31), 418 (Mt, 6), 345 (26),
343 (92), 341 (93), 339 (24), 265 (50), 263 (100), 261 (44), 230 (12), 228 (14),
199 (12), 197 (15), 171 (37), 169 (38), 103 (34), 90 (24), 89 (23), 77 (37), 63
(29), 51 (46).
125
4.2.29 4-Bromo-3-bromomethylbenzaldehyde (3.68)
CH2Br
A mixture of tetrabromo compound 3.67 (2.0 g, 4.9 mmol) in conc. H2SO4 (10 ml) was stirred
at 55 °C for 5 h. The mixture was cooled to room temperature and poured into an ice cold
water. After standing overnight, a white precipitate formed and was collected by suction and
air-dried to give 3.68 (1.0 g, 75%).
Mp: 80-83 °C.
1H NMR 5: 4.63 (2H, s, CH2Br), 7.64 (1H, dd, J = 2.1, 8.1 Hz, H-6, ArH), 7.77 (1H, d, J =
8.1 Hz, H-5, ArH), 7.93 (1H, d, J = 2.1 Hz, H-2, ArH), 9.96 (1H, s, CHO).
13C NMR 5: 32.2 (CH2Br), 130.3, 131.3, 131.9, 134.3, 135.9, 138.3, (6ArC), 190.4 (CHO).
MS m/z: 280 (M+4, 24), 278 (M+2, 10), 276 (M+, 22), 199 (100), 197 (93), 171 (7), 169
(8), 168 (4), 134 (6), 118 (13), 89 (39), 63 (31).
1R vin. (cm-1): 1700.
4.2.30 Methyl 3-acetoxy-4-hydroxy-5-methoxybenzoate (3.69)
CO2C H3
OAc
The mixture of the diacetate 3.31 (20.0 g, 70 mmol) and anhydrous K2CO3 (30 g, 210 mmol)
in DMF (150 ml) was heated at 40 — 50 °C for 2.5 h and then neutralised with 5% aq. HC1.
The aqueous phase was extracted with EtOAc. The organic extract was washed several times
with water to remove most of the DMF, dried (MgSO4) and evaporated. Flash
chromatography (7:3-1:1 hexane:EtOAc) gave the monoacetate 3.69 (15.7 g, 92%) as a white
solid.
126
Mp: 105 °C.
1H NMR 5: 2.33 (3H, s, OAc), 3.86 (3H, s, OCH3), 3.93 (3H, s, OCH3), 5.94 (1H, br s,
OH), 7.42 (1H, d, J = 1.8 Hz, H-2 or H-6, ArH), 7.45 (1H, d, J = 1.8 Hz, H-2
or H-6, ArH).
13C NMR 5: 20.6 (OCOCH3), 52.2 (CO2CH3), 56.5 (OCH3), 109.5, 117.9, 121.4, 137.0,
141.9, 147.2, (6ArC), 166.0 (CO2), 168.5 (CO2).
MS m/z: 240 (M+, 25), 209 (9), 198. (100), 183 (6), 167 (85), 139 (13), 111 (3), 81 (4),
67 (11), 43 (66).
IR vmax (cm-1 ): 3590, 1775, 1755, 1720.
4.2.31 Methyl 3-acetoxy-4-(2-bromo-5-fo rmylbenzyloxy)-5-methoxy-
benzoate (3.71)
H3C0 CO2CH3
OM Br
CHO
To the solution of monoacetate 3.69 (1.0 g, 4.2 mmol) in anhydrous DMF (15 ml) were added
anhydrous Li2CO3 (780 mg, 10.5 mmol) and 4-bromo-3-bromomethylbenzaldehyde (3.68)
(2.89 g, 10.5 mmol). The resulting mixture was heated at 60 °C for 18 h. The inorganic salt
was removed by filtration and the filtrate was diluted with EtOAc. The organic phase was
washed with water, dried (Na2SO4), evaporated and flash chromatographed (8:2-7:3
hexane:EtOAc) to give 3.71 (1.40 g, 77%) as a white solid.
Mp: 99-101 °C.
1 11 NMR: 2.22 (3H, s, OAc), 3.89 (3H, s, OCH3), 3.93 (3H, s, OCH3), 5.23 (2H, s,
OCH2Ph), 7.40 (1H, d, J= 2.1 Hz, H-6 or H-2, ArH), 7.53 (1H, d, J= 2.1 Hz,
H-6 or H-2, ArH), 7.67 (1H, dd, J = 1.8, 8.1 Hz, H-4', ArH), 7.72 (1H, d, J =
8.1 Hz, H-3', ArH), 8.13 (1H, d, J= 1.8 Hz, H-6', ArH), 9.99 (1H, s, CHO).
127
13C NMR: 20.7 (OCOCH3), 52.3 (CO2CH3), 56.3 (OCH3), 73.10 (OCH2Ph), 111.3, 117.1,
125.7, 128.9, 129.5, 129.8, 133.3, 135.4, 138.4, 143.4, 153.1, 165.7, (12ArC),
168.7 (OCOCH3), 190.9 (CHO).
MS m/z: 438 (M+2, 19), 436 (Mt, 22), 396 (97), 394 (100), 315 (6), 197(47).
IR vniax (cm 1 ): 1740, 1680, 1675.
4.2.32 Methyl 4-(2-bromo-5-formylbenzyloxy)-3-hydroxy-5-methoxy
benzoate (3.12)
H300 CO2CH3
OH Br
CHO
To the solution of 3.71 (500 mg, 1.15 mmol) in CH3OH (8 ml) and H2O (2 ml) was added
K2CO3 (450 mg, 3 mmol). The reaction mixture was stirred for 30 min at room temperature.
The volatiles were evaporated and the aqueous solution was acidified with 10% aq. HC1. The
organic was extracted with EtOAc, washed with brine, dried (MgSO4), evaporated and flash
chromatographed (4:1-3:2 hexane:EtOAC) to afford 3.12 (380 mg, 84%).
111NMR 8: 3.87 (3H, s, OCH3), 3.92 (3H, s, OCH3), 5.29 (2H, s, OCH2Ph), 7.20 (1H, d, J
= 1.8 Hz, ArH), 7.26 (1H, d, J = 1.8 Hz, ArH), 7.68 (1H, dd, J = 2.1, 8.1 Hz,
H-4', ArH), 7.78 (1H, d, J = 8.1 Hz, H-3', ArH), 8.00 (1H, d, J = 2.1 Hz, H-6',
ArH), 9.7 (1H, s, CHO).
13C NMR 8: 52.3 (CO2CH3), 56.2 (OCH3), 73.4 (OCH2Ph), 105.5, 110.1, 126.2, 130.3,
130.5, 131.1, 133.8, 135.6, 137.3, 137.4, 149.2, 151.9, (12ArC), 166.4
(CO2CH3), 190.7 (CHO).
MS m/z: 396 (M+2, 10), 394 (M+, 10), 382
(5), 213 (5), 199 (75), 197 (100),
(18), 71 (19).
IR vmax (cm-1 ):3490, 1715, 1700.
(5), 380 (10), 315 (3), 299 (2), 283 (4), 256
167 (13), 151 (17), 137 (11), 105 (21), 89
128
4.2.33 Methyl 2-formy1-9-methoxy-11H-dibenzo [b , el [1,4]dioxepine-7-
carboxylate (3.14)
H300 A CO2CH3
CHO
4.2.33.1 Copper-catalysed Ullmann diaryl ether cyclisation
A mixture of compound 3.12 (250 mg, 0.63 mmol) and anhydrous K 2CO3 (131 mg, 0.95
mmol) in anhydrous pyridine (20 ml) was stirred and heated to 80 °C. Copper(II) oxide (100
mg, 1.26 mmol) was added and the reaction mixture was refluxed for overnight. After
cooling to room temperature, the mixture was filtered, diluted with EtOAc, washed with 10%
aq. HC1 and concentrated to give a brown residue. The residue was purified by
chromatography (9:1 hexane:EtOAc) to give white solid of 3.14 (145 mg, 73%).
4.2.33.2 Palladium-catalysed diaryl ether cyclisation
(a) Ligand preparation: 1,1'-bipheny1-2-yl(di-tert-
butyl)phosphine6 (2.86)
To the flask containing a mixture of magnesium turnings (115 mg, 5.08 mmol) and a small
crystal of iodine in anhydrous THE (10 ml), was added a solution of 2-bromobiphenyl (3.73)
129
(1.0 g, 4.62 mmol) in anhydrous THE (10 ml). The mixture was refluxed with stirring for 2 h
and then allowed to cool to room temperature. Anhydrous copper(I) chloride (450 mg, 4.84
mmol) and di-tert-butylchlorophosphine (930 mg, 5.54 mmol) were added and the mixture
was refluxed for 12 h. The mixture was cooled to room temperature and diluted with 1:1
hexane/ether (40 ml). The resulting suspension was filtered, and the solid was washed with
hexane, transferred to a flask containing 1:1 hexane:EtOAc (40 ml), and H2O (30 ml) and
30% aq. NaOH (15 ml) were added. The organic phase was separated, washed with brine,
dried (MgSO4) and evaporated to give a white solid which was recrystallised from methanol
to give 2.86 (890 mg, 67 %).
Mp: 82 ° C (lit. 6 86-86.5 °C).
1H NMR 5: 1.15 (18H, d, J= 11.6 Hz, 2tBu), 7.21-7.35 (8H, m, ArH), 7.89 (1H, m, ArH).
31P NMR 5: 18.7.
13 C NMR 5: 30.6, 30.8, 32.4, 32.7, (2 tBu), 125.6, 126.0, 126.2, 126.5, 126.7, 127.0, 128.3,
130.1, 130.4, 130.5, 135.2, 135.6, 143.5, 143.6, 150.9, 151.4 (observed
complexity due to P-C splitting).
(b) Cyclisation
A mixture of compound 3.12 (250 mg, 0.63 mmol), Pd(OAc)2 (2.86 mg, 1.3 mol %), o-(di-
tert-butylphosphinobiphenyl) 2.86 (5.7 mg) and K3PO4 (270 mg, 1.27 mmol) in anhydrous
toluene (20 ml) was heated at 80 °C for 28 h. After cooling to room temperature the mixture
was diluted with ether and washed with 1M NaOH and brine, and the organic phase was dried
(MgSO4) and evaporated in vacuo to give the pure product as white solid 3.14 (154.9 mg,
78%).
Mp: 186-187 °C.
11-INMR 5: 3.89 (6H, s, 20CH3), 5.39 (2H, s, OCI-1_2Ph), 7.29 (1H, d, J= 1.8 Hz, H-6 or H-
8, ArH), 7.32 (1H, d, J = 8.4 Hz, H-4, ArH), 7.55 (1H, d, J = 1.8 Hz, H-8 or H-
6, ArH), 7.79 (1H, d, J = 2.1 Hz, H-1, ArH), 7.86 (1H, dd, J = 2.1 Hz, 8.4 Hz,
H-3, ArH), 9.94 (1H, s, CHO).
130
13C NMIR 6: 52.3 (CO2CH3), 56.6 (OCH3), 70.3 (OCH2Ph), 107.8, 116.4, 120.9, 123.2;
129.2, 130.2, 132.4, 132.5, 142.4, 144.9, 150.9, 162.2, (12ArC), 165.9
(CO2CH3), 190.1 (CHO).
MS m/z: 314 (M+, 100), 283 (28), 255 (29), 183 (29), 169 (43), 149 (45), 105 (42), 85
(33).
IR vmax (cm 1 ): 1730, 1675, 1640.
4.2.34 Methyl 2-hydroxymethy1-9-methoxy-11H-dibenzo[b, e][1 , 4] diox-
epine-7-carboxylate (3.72a)
H300 A CO2CH3
CH2OH
To the ice cold solution of diaryl ether 3.14 (1.60 g, 5.09 mmol) in CH3OH:THF (1:1, 50 ml)
was added NaBH4 (290 mg, 7.64 mmol) in portions. The solution was stirred for 2 h at room
temperature and the excess reagent was destroyed by addition of 10% aq. HCI. The volatiles
were removed and the product was extracted with chloroform. The organic phase was dried
(Na2SO4) and evaporated in vacuo to give product 3.72a (1.45g, 90%) as a yellow oil.
1H NMR 6: 3.87 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.62 (2H, br s, CH2OH), 5.39 (2H, s,
CH2OPh), 7.15-7.33 (4H, ArH), 7.53 (1H, d, J = 2.1 Hz, ArH).
13C NMR 6: 52.2 (CO2CH3), 56.5 (OCH3), 64.5 (CH2OH), 69.8 (CH2OPh), 107.6, 116.6,
119.9, 122.3, 127.6, 128.8, 128.9, 137.2, 142.5, 145.0, 150.6, 157.7, (12ArC),
166.2 (CO2CH3).
MS m/z: 316 (Mt, 22), 285 (12), 259 (80), 219 (7), 187 (3.5), 173 (12), 149 (6), 113 17),
101 (100), 87 (26), 59 (36).
131
4.2.35 Methyl 2-cyanomethy1-9-methoxy-11H-dibenzo[b,e][1,4] dioxe-
pine-7-carboxylate (3.72b)
H300 CO2CH3
CH2CN
Thionyl chloride (0.225 ml, 3.11 mmol) in an anhydrous CHC13 (6 ml) was added to the
solution of 3.72a (219 mg, 0.693 mmol) in CHC13 (25 ml). The solution was stirred at room
temperature for 1.5 h. After evaporation of the solvent the product was passed through a short
silica column (CHC13) to give the benzyl chloride, which was used for the next step without
further purification.
The benzyl chloride (200 mg, 0.60 mmol) and sodium cyanide (268 mg, 5.46 mmol) in
dimethyl sulphoxide (5 ml) were heated at 60 °C for 4 h. The reaction mixture was poured
into water and extracted with EtOAc. The EtOAc extract was washed several times with
water, brine, evaporated and flash chromatographed (7:3 hexane:EtOAc) to give
phenylacetonitrile 3.72b (147 mg, 68% from 3.72a)
'H NMR 5: 3.71 (2H, s, CH2CN), 3.87 (3H, s, OCH3), 3.89 (3H, s, OCH3), 5.37 (2H, s,
CH2OPh), 7.07-7.27 (4H, ArH), 7.53 (1H, d, J= 2.1 Hz, ArH).
13C NMR 5: 52.2 (CO2CH3), 56.5 (OCH3), 69.6 (CH2OPh), 107.7, 116.5, 117.8, 120.7,
122.7, 125.9, 128.4, 129.5, 129.9, 142.4, 144.9, 150.6, 157.9, (12ArC), 166.2
(CO2CH3).
132
4.2.36 4-Fluoro-3-methylacetophenone (3.76)
To the solution of o-fluorotoluene (1 ml, 9 mmol) and acetyl chloride (0.87 ml, 10.8 mmol)
in anhydrous carbon disulphide (10 ml) at 0 °C was added anhydrous aluminium trichloride
(1.79 g, 13.5 mmol) in portions. The mixture was stirred at 0 °C for 30 min. The ice bath
was removed and the reaction was stirred overnight at room temperature. The reaction was
diluted with dichloromethane, followed by addition of 10% aq. HC1. The organic phase was
extracted with dichloromethane, evaporated and dried (MgSO4) to give the title compound as
a colourless oil (1.3 g, 100%).
11-1NMR 5: 2.30 (3H, d, JHF = 2.1 Hz, CH3), 2.55 (3H, s, COCH3), 7.00 (1H, t, Jim = 8.7,
JHF = 8.7 Hz, H-5, ArH), 7.51-7.81 (2H, m, H-2, H-6, ArH).
13C MAR 5: 14.6 (CH3), 26.5 (COCH3), 115.2, 126.7, 128.3, 131.9, 133.1, 165.9 (d, JCF =
251 Hz, C-4), (6ArC), 196.6 (COCH3).
MS m/z: 152 (W, 35), 137 (100), 123 (11), 109 (60), 97 (26), 83 (44).
1R vn,a„ (cm-1): 1690.
4.2.37 3-Bromomethyl-4-fluoroacetophenone (3.77)
CH2Br
The mixture of 3.76 (200 mg, 1.31 mmol), N-bromosuccinimide (250 mg, 1.41 mmol),
benzoyl peroxide (15 mg) in carbon tetrachloride (10 ml) refluxed and irradiated with 100W
lamp for 4 h. The reaction was cooled to room temperature and the suspended succinimide
was filtered out. Evaporation of the solvent gave the crude bromomethyl compound 3.77
(224 mg, 74%) as a yellow oil. The compound was used for the next step without
purification
133
1 H NMR 5:
'C NMR 5:
MS m/z:
IR vmax (cm'):
2.57 (3H, s, COCH3), 4.51 (2H, d, JHF = 0.9 Hz, CH2Br), 7.13 (1H, t, JHH
9.0, JHF = 9.0 Hz, H-5, ArH), 7.91 (1H, ddd, JHH = 2.1, JHF = 5.1, JHH = 8 .7
Hz, H-6, ArH), 8.02 (1H, dd, JHH= 2.1, JHF = 6.9 Hz, H-2, ArH).
26.5 (COCH3), 31.6 (CH2Br), 116.2, 125.8, 130.9, 131.8, 133.8, 165.1 (d, JCF
= 257 Hz, C-4), (6ArC), 195.8 (COCH3).
231 (M+1, 12), 229 (11), 217 (41), 215 (43), 198 (10), 186 (1), 167 (58), 151
(23), 136 (22), 105 (100), 77 (22).
1685.
4.2.38 Methyl 4-(5-acetyl-2-fluorobenzyloxy)-3-acetoxy-5-methoxy-
benzoate (3.78)
H3C0 A CO2CH3
OAc F
COCH3
To the solution of monoacetate 3.69 (10.0 g, 42 mmol) in anhydrous acetone was added
anhydrous K2CO3 (7.80 g, 105 mmol) and 4-fluoro-3-bromomethylbenzaldehyde 3.77 (10.6 g,
46 mmol). The resulting mixture was heated at 60 °C for 18 h. The inorganic salt was
removed by filtration, and the filtrate was diluted with EtOAc. The organic phase was
washed with water, dried (MgSO4), evaporated and flash chromatographed (7:3
hexane:EtOAc) to give 3.78 (14.0 g, 84%).
Mp:
1H NMR 5:
123-124 °C.
2.22 (3H, s, OAc), 2.58 (3H, s, COCH3), 3.87 (3H, s, OCH3), 3.93 (3H, s,
OCH3), 5.20 (2H, s, OCH2Ph), 7.15 (1H, t, JHH = 9.0, JHF = 9.0 Hz, H-3',
ArH), 7.38 (1H, d, J = 2.1 Hz, H-2 or H-6, ArH), 7.51 (1H, d, J = 2.1 Hz, H-2
or H-6, ArH), 7.92 (1H, ddd, JHH = 2.4, JHF = 5.1, JHH = 7.5 Hz, H-4', ArH),
8.14 (1H, dd, JH H = 2.1, JHF = 6.9 Hz, H-6', ArH).
134
13C NMR 6: 20.5 (OCOCH3), 26.6 (COCH3), 52.3 (CO2CH3), 56.3 (OCH3), 67.8
(OCH2Ph), 111.2, 115.4, 115.7, 124.8, 125.7, 130.5, 130.6, 131.1, 133.4,
143.4, 143.7, 165.2 (d, JCF = 254 Hz, C-2), (12ArC), 165.8 (CO2), 168.8
(CO2), 196.2 (COCH3).
MS m/z: 390 (M+, 8), 359 (3), 348 (44), 288 (7), 197 (27), 151 (100), 136 (8), 108 (9),
43 (31).
IR vmax (cm 1 ): 1725, 1715, 1675.
4.2.39 Methyl 4-(5-acetyl-2-fluorobenzyloxy)-3-hyd roxy-5-methoxy-
benzoate (3.13)
H3C0 A CO2CH3
COCH3
To the solution of 3.78 (350 mg, 0.96 mmol) in Me0H (4 ml) and H2O (1 ml) was added
K2CO3 (266 mg, 1.93 mmol). The reaction mixture was stirred for 20 min at room
temperature. The volatiles were evaporated and the aqueous solution was acidified with 10%
aq. HC1. The organic was extracted with EtOAc, washed with brine, dried (MgSO4) and
evaporated to afford 3.13 (300 mg, 96%) as white solid.
Mp: 104-106 °C.
1H NMR 5: 2.55 (3H, s, COCH3), 3.85 (3H, s, OCH3), 3.92 (3H, s, OCH3), 5.24 (2H, s,
OCI-J2Ph), 7.12 (1H, t, JHF = 8.4, JHH = 8.4 Hz, H-3', ArH), 7.17 (1H, d, J = 1.8
Hz, H-2 or H-6, ArH), 7.243 (1H, d, J =1.8 Hz, H-2 or H-6, ArH), 7.90-7.96
(1H, ddd, JHH = 2.4, JHF = 5.1, JHH = 7.5 Hz, H-4', ArH), 8.06 (1H, dd, JHH =
2.4, JHF = 6.9 Hz, H-6', ArH).
13C NIV1R 6: 26.5 (COCH3), 52.2 (CO2CH3), 56.0 (OCH 3), 68.3 (OCH2Ph), 105.2, 110.0,
115.9, 124.3, 126.0, 130.6, 131.1, 133.5, 137.4, 149.2, 151.9, 165.6 (d, JCF =
254 Hz, C-2), (12ArC), 166.5 (CO2CH3), 196.2 (COCH3).
135
MS m/z: 348 (Nr,20), 330 (6), 198 (23), 167 (23), 151 (100), 136 (8), 108 (10), 43 (8).
IR vm.(cm-1 ): 3380, 1685, 1660.
4.2.40 Methyl 2-acetyl-9-methoxy-11H-dibenzo [b,e][1,41 dioxepine-7-
carboxylate (3.15)
H3C0 CO2CH3
COCH3
To the solution of compound 3.13 (1.0 g, 2.87 mmol) in anhydrous DMF (30 ml) was added
anhydrous K2CO3 (397 mg, 2.87 mmol). The mixture was heated at 85 °C for 30 h and
poured into ice-water and the white precipitate formed were filtered and dried to give cyclic
compound 3.15 (870 mg, 92%).
Mp: 144 °C.
1H NMR 2.56 (3H, s, COCH3), 3.88 (6H, s, 20CH3), 5.38 (2H, s, OCH2Ph), 7.28 (1H, d,
J= 8.4 Hz, H-4, ArH), 7.29 (1H, J= 1.8 Hz, H-6 or H-8, ArH), 7.54 (1H, J=
1.8 Hz, H-6 or H-8, ArH), 7.89 (1H, d, J = 2.1 Hz, H-1, ArH), 7.97 (1H, dd, J
= 2.1 Hz, 8.4 Hz, H-3, ArH).
13C NMR 8: 26.5 (COCH3), 52.2 (CO2CH3), 56.5 (OCH3), 70.4 (OCH2Ph), 107.7, 116.4,
120.2, 123.0, 128.5, 129.3, 130.9,
166.0 (CO2CH3), 196.2 (COCH3).
133.2, 142.5, 144.9, 150.8, 161.3, (12ArC),
MS m/z: 328 (M+, 100),
(12), 183 (15),
317
168
(10),
(25),
297
155
(18),
(10),
288 (31), 269 (26),
89 (10), 77 (17).
257 (19), 241 (15), 197
IR vina„ (cm-1 ): 1720, 1705.
136
4.2.41 1-(7-Hydroxymethy1-9-methoxy-11H-dibenzo[b,el[1,41dioxepin-
-2-y1)ethanone (3.79)
H3C0 A CH2OH
COCH3
4.2.41.1 Acetalisation
Dibenzodioxepine 3.15 (5 g, 15.2 mmol), anhydrous CH3OH (30 ml), trimethyl orthoformate
(15 ml) and p-toluene sulphonic acid (30 mg) were refluxed for 8 h using the same method
described for the acetalisation of 3.8. The resultant acetal was isolated as a white solid (5.4 g,
98%). This compound was used in the next step without further purification.
1 H NMR 8: 1.48 (3H, s, CH3), 3.14 (6H,s, 20CH3, acetal), 3.86 (3H, s, OCH3), 3.87 (3H, s,
OCH3), 5.39 (2H, s, OCH2Ph), 7.15 (1H, d, J= 8.1 Hz, H-4, ArH), 7.25 (1H, d,
J= 2.1 Hz, H-6 or H-8, ArH), 7.40 (1H, d, J= 2.1 Hz, H-1, ArH), 7.45 (1H,
dd, J= 2.1, 8.1 Hz, H-3, ArH), 7.53 (1H, d, J= 2.1 Hz, H-6 or H-8, ArH).
13C NMR 8: 26.1 (CH3), 48.9 (2C, OCH3, acetal), 52.2 (CO2CH3), 56.4 (OCH3), 70.0
(OCH2Ph), 101.2 (C, acetal), 107.5, 116.7, 119.4, 122.3, 127.0, 128.2, 128.4,
139.4, 142.6, 145.0, 150.6, 157.5, (12ArC), 166.2 (CO2CH3).
MS m/z: 374 (M+, 22), 359 (10), 343 (100), 328 (55), 285 (22), 168 (18), 151 (39).
1R vmax (cm 1 ): 1700, 1665.
4.2.41.2 LiA1H4 reduction
The above dimethyl acetal (750 mg, 2.1 mmol) in anhydrous THE (20 ml) was reduced to
benzyl alcohol with LiA1H4 (300 mg) using the same method as described for the preparation
137
of the benzyl alcohol 3.35. The acetal functionality of the resultant benzyl alcohol was
hydrolysed with 15% aq. HCI (5 ml) solution containing CH3OH (15 ml) to give 3.79 (1.65 g,
83%) as a white solid.
Mp: 142 °C.
NMR 8: 2.56 (3H, s, COCH3), 3.85 (3H, s, OCH3), 4.59 (2H, s, CH2OH), 5.29 (2H, s,
OCH2Ph), 6.65 (1H, d, J= 1.8 Hz, H-6 or H-8, ArH), 6.80 (1H, d, J= 1.8 Hz,
H-6 or H-8, ArH), 7.21 (1H, d, J= 8.4 Hz, H-4, ArH), 7.82 (1H, d, J= 2.1 Hz,
H-1, ArH), 7.90 (1H, dd, J= 2.1, 8.4 Hz, H-3, ArH).
13 C NMR 5: 26.5 (COCH3), 56.4 (OCH3), 64.8 (CH2OH), 71.2 (OCH2Ph), 105.6, 112.2,
120.1, 128.3, 129.2, 130.5, 132.6, 134.8, 138.0, 146.1, 151.4, 160.7, (12ArC),
196.3 (COCH3).
MS m/z: 300 (1\e, 100), 269 (40), 257 (15), 198 (40), 167 (31), 153 (63), 107 (33).
vn,ax (cm 1 ): 3400, 1690.
4.2.42 2-Acetyl-9-methoxy-11H-dibenzo[b,e][1,4]dioxepine-7-
carbaldehyde (3.80)
H300 CHO
COCH3
The orange mixture of PCC (540 mg, 2.5 mmol), anhydrous sodium acetate (40 mg) and
benzyl alcohol 3.79 (500 mg, 1.67 mmol) in anhydrous CH2Cl2 (5 ml) was reacted as
described for oxidation of benzyl alcohol 3.35. Compound 3.80 (470 mg, 95%) was isolated
as a white solid.
Mp: 172 °C.
1H NMR 8: 2.58 (3H, s, COCH3), 3.90 (3H, s, OCH3), 5.40 (2H, s, OCH2Ph), 7.15 (1H, d,
J= 1.8 Hz, H-6 or H-8, ArH), 7.25 (1H, d, J= 8.4 Hz, H-4, ArH), 7.35 (1H, J
138
112CO2CH3
= 1.8 Hz, H-6 or H-8, ArH), 7.90 (1H, d, J= 2.1 Hz, H-1, ArH), 7.97 (1H, dd,
J= 2.1, 8.4 Hz, H-3, ArH), 9.79 (1H, s, CHO).
13C NMR 8: 26.6 (COCH3), 56.6 (OCH3), 70.3 (OCH2Ph), 105.3, 118.6, 120.2, 128.5,
129.4, 129.7, 131.1, 133.5, 143.9, 145.3, 151.8, 161.3, (12ArC), 190.0 (CHO),
196.5 (COCH3).
MS m/z: 298 (Mt, 100), 281 (9), 269 (20), 255 (45), 227 (16), 198 (21), 167 (14), 151
(25), 69 (23), 43 (62).
IR vmax (cm-1 ): 1720, 1710.
4.2.43 Methyl (7-formy1-9-methoxy-11H-dibenzo[b,e]11,41dioxepin-2-
yl)acetate (3.16)
H3C0 CHO
The title compound was prepared from acetophenone 3.80 (200 mg, 0.67 mmol), Pb(OAc)4
(313 mg), anhydrous CH3OH (2 ml) and BF3.Et20 (4 ml) in anhydrous benzene (5 ml) as
described for the preparation of phenylacetate 3.10. Purification by flash chromatograph (4:1
hexane:EtOAc) afforded a cream white solid 3.16 (115 mg, 52%).
Phenylacetate 3.16 was also obtained in 97% from compound 3.80 using TTN as described
for compound 3.10.
Mp: 132-134 °C.
111 NMR 8: 3.58 (2H, s, CH2CO2CH3), 3.66 (3H, s, CH2CO2CH3), 3.87 (3H, s, OCH3),
5.40 (2H, s, OCH2Ph), 7.12-7.31 (5H, m, ArH), 9.77 (1H, s, CHO).
13C NMR 8: 40.3 (CH2CO2CH3), 52.20 (CH2CO2CH3), 56.5 (OCH3), 69.7 (OCH2Ph),
105.0, 119.0, 119.9, 128.6, 129.2, 129.8, 130.4, 131.4, 144.0, 145.0, 151.4,
157.4, (12ArC), 171 (CO2CH3), 190.2 (CHO).
139
H3C0 NO2
H2CO2CH3
MS m/z: 328 (W, 100), 298 (22), 269 (20), 240 (20), 198 (58), 167 (24), 139 (41), 109
(26), 69 (34).
IR v.(cm-1 ): 1695, 1680.
4.2.44 Methyl (9-methoxy-7-[(E)-2-nitroviny1]-11H-dibenzo[b,e] [1,4]-
dioxepin-2-yl}acetate (3.81)
A solution of benzaldehyde 3.16 (50 mg, 0.152 mmol) and nitromethane (0.1 ml) in
EtOH:THF (3:1, 20 ml) containing 5% aq. KOH solution (0.5 ml) was reacted as described
for the preparation of nitrostyrene 3.48a to give 3.81 as ayellow solid (46 mg, 83%).
Mp: 127-129 °C
1 1-1 NMR 5: 3.58 (2H, s, CI-J2CO2), 3.67 (3H, s, CH2CO2CH3), 3.86 (3H, s, OCH3), 5.37
(2H, s, OCH2Ph), 6.72 (1H, d, J= 2.4 Hz, H-6 or H-8, ArH), 7.04 (1H, d, J=
2.4 Hz, H-6 or H-8, ArH), 7.14 (1H, d, J= 8.1 Hz, H-4, ArH), 7.21-7.25 (2H,
m, H-1, H-3, ArH), 7.50 (1H, d, J= 13.5 Hz, oc-H, trans), 7.84 (1H, d, J= 13.5
Hz, 13-H, trans).
13 C NMR 5: 52.2 (OCH3), 56.6 (OCH3), 69.8 (OCH2Ph), 106.5 (2C, C-6, C-8), 116,7,
119.9, 122.5, 128.6, 129.9, 130.4, 131.4, 133.4, 135.9, 138.5, '145.6, 151.5,
157.1, (12ArC and C=C), 171.5 (CO2CH3).
MS m/z: 371 (Mt, 100), 354 (7), 341 (12), 328 (30), 312 (20), 298 (8), 181 (7), 165 (5),
151 (14), 131 (9), 91 (7), 69 (9), 59 (32), 43 (12).
IR v.(cm-1 ): 1695, 1625.
140
4.2.45 2-[7-(2-Aminoethyl)-9-methoxy-11H-dibenzo[b,e] [1,4]dioxepin-
2-y11-ethanol (3.82)
The title compound (427 mg, 67%) was obtained from a,f3-nitrostyrene 3.81 (750 mg, 2
mmol) as an oily substance using the method described for amino alcohol 3.53a.
'H NMR 5: 1.83 (2H, br s, NH2), 2.62 (2H, t, J = 6.9 Hz, CH2CH2NH2), 2.82 (2H, t, J = 6.6
Hz, CH2CH2OH), 2.91 (2H, t, J = 6.9 Hz, CH2CH2NH2), 3.77 (2H, t, J = 6.6
Hz, CH2CH2OH), 3.81 (3H, s, OCH3), 5.27 (2H, s, OCH2Ph), 6.41 (1H, d, J=
2.1 Hz, H-6 or H-8, ArH), 6.61 (1H, d, J = 2.1 Hz, H-6 or H-8, ArH), 7.08-
7.13 (3H, m, H-1, H-3, H-4, ArH)
13C NMR 5: 38.4 (CH2CH2OH), 39.5 (CH2CH2NH2), 43.2 (CH2CH2NH2), 56.3 (OCH3),
63.4 (CH2OH), 70.3 (OCH2Ph), 107.3, 114.0, 119.9, 128.8, 129.1, 130.3,
132.7, 134.3, 136.8, 146.1, 150.8, 156.4, (12ArC).
MS m/z: 315 (NC, 83), 286 (100), 271 (44), 255 (90), 241 (39), 115 (37), 65 (41), 56
(76).
IR vn.(cm 1 ): 3350, 3270.
4.2.46 Methyl(7-hydroxymethy1-9-methoxy-11H-dibenzo [1),e] [1,4]-
dioxepin-2-yl)acetate (3.83)
H3C0 CH2OH
.H2CO2CH3
141
.H2CO2CH3
Prepared from 3.16 as described for benzyl alcohol 3.54. Purified by flash chromatography
(1:1 hexane:EtOAc) and isolated as a white solid (1.80 g, 78 %)
Mp: 79-80 °C.
1H NMR 8: 2.02 (1H, br s, OH), 3.55 (2H, s, CH2CO2CH3), 3.64 (3H, s, CH2CO2CH3),
3.80 (3H, s, OCH3), 4.53 (2H, s, CH2OH), 5.26 (2H, s, OCH2Ph), 6.59 (1H, d,
J = 2.1 Hz, H-6 or H-8, ArH), 6.78 (1H, d, J = 2.1 Hz, H-6 or H-8, ArH), 7.0
(3H, m, H-1, H-3, H-4, ArH).
13C NIVIR 5: 40.2 (CH2CO2), 52.1 (CH2CO2CH3), 56.3 (OCH3), 64.7 (CH2OH), 70.2
(OCH2Ph), 105.3, 112.4, 119.9, 128.8, 129.4, 129.6, 130.7, 133.9, 137.7,
145.9, 150.9, 156.8, (12ArC), 171.7 (CO2CH3).
MS m/z: 330 (Ivr, 100), 313 (17), 299 (62), 284 (15), 271 (31), 257 (14), 241 (10), 225
(8), 211 (10), 197 (6), 181 (13), 165 (6), 149 (9), 131 (11), 115 (10), 91 (13),
77 (12), 53 (12).
1R vin.(cm 1 ): 3500, 1705, 1650.
4.2.47 Methyl (7-chloromethy1-9-methoxy-11H-dibenzo[b, el 11,41dio-
xepin-2-yl)acetate (3.84)
H3C0 A CH2CI
Prepared from benzyl alcohol 3.83 as described for the preparation of 3.55. Isolated as a
white solid (1.55 g, 100 %).
Mp: 85 °C.
111 NMR 8: 3.58 (2H, s, CH2CO2CH3), 3.68 (3H, s, CH2CO2CH3), 3.85 (3H, s, OCH3),
4.49 (2H, s, CH2C1), 5.30 (2H, s, OCH2Ph), 6.61 (1H, d, J = 2.1 Hz, H-6 or H-
142
B2CO2CH3
8, ArH), 6.80 (1H, d, J= 2.1 Hz, H-6 or H-8, ArH), 7.11-7.23 (3H, m, H-1, H-
3, 11-5, ArH).
13C NMR 8: 40.3 (CH2CO2), 46.1 (CH2C1), 52.1 (CH2CO2CH3), 56.3 (OCH3), 70.0
(OCH2Ph), 106.9, 114.5, 119.9, 128.8, 129.5, 129.8, 130.2, 130.8, 138.5,
145.6, 151.0, 156.8, (12ArC), 171.6 (CO2CH3)
MS m/z: 350 (M+2, 35), 348 (M+, 100), 331 (3), 313 (39), 299 (26), 289 (14), 281 (15),
275 (4), 261 (10), 253 (35), 239 (9), 225 (24), 211 (15), 196 (13), 165 (19),
153 (15), 131 (17), 115 (19), 91 (31), 77 (33)
4.2.48 Methyl (7-cyanomethy1-9-methoxy-11H-dibenzo[b,e][1,41 diox
epin-2-yl)acetate (3.85)
H3C0 CH2CN
The title compound (1.31 g, 87%) was prepared from compound 3.84 as described for benzyl
cyanide 3.56. Isolated as a white solid.
Mp: 88 °C.
1H NMR 8: 3.59 (2H, s, CH2CO2CH3), 3.62 (2H, s, CH2CN), 3.66 (3H, s, CH2CO2CH3),
3.85 (3H, s, OCH3), 5.30 (2H, s, OCH2Ph), 6.50 (1H, d, J= 2.1 Hz, H-6 or H-
8, ArH), 6.69 (11-1, d, J= 2.1 Hz, H-6 or H-8, ArH), 7.10-7.22 (3H, m, H-1, H-
3, H-4, ArH).
13 C NMR 8: 23.2 (CH2CN), 40.3 (CH2CO2), 52.1 (CH2CO2CH3), 56.5 (OCH3), 70.2
(OCH2Ph), 106.2, 113.8, 117.6, 119.9, 122.4, 128.7, 129.6, 129.8, 130.9,
138.2, 146.0, 151.4, 156.7, (13C, 12ArC and CN), 171.6 (CO2CH3).
MS m/z: 339 (Mt, 100), 322 (15), 308 (16), 299 (23), 280 (53), 279 (44), 252 (23), 236
(10), 221 (9), 197 (8), 181 (11), 165 (6), 149 (25), 131 (19), 115 (11), 91 (20),
77 (19).
143
H2CO2C1-13
IR vina„(cm-1): 2240, 1685.
4.2.49 Methyl 7-(tert-butoxycarbonylaminoethyl)-9-methoxy-11H-
dibenzo[b,e][1,4]dioxepin-2-yll acetate (3.17)
H3C0 NHBoc
Prepared from compound 3.85 as described for the preparation of N-Boc product 3.11a.
Isolated as a yellow solid (1.21 g, 88%).
Mp: 93 °C.
NMR 5: 1.41 (9H, s, tBu), 2.63 (2H, t, J= 6.9 Hz, CH2CH2NHBoc), 3.32 (2H, q, J= 6.0
Hz, CH2CH2NHBoc), 3.55 (2H, s, CH2CO2CH3), 3.65 (3H, s, CH2CO2CH3),
3.79 (3H, s, OCH3), 4.58 (1H, br s, NH), 5.25 (2H, s, OCH2Ph), 6.40 (1H, br s,
H-6 or H-8, ArH), 6.60 (1H, br s, H-6 or H-8, ArH), 7.07-7.18 (3H, m, H-1,
H-3, H-4, ArH).
13C NMR 5: 28.4 (3C, `Bu), 36.0 (CH2CH2NHBoc), 40.3 (CH2CO2), 41.6 (CH2NHBoc),
52.0 (CH2CO2CH3), 56.2 (OCH3), 70.0 (OCH2Ph), 79.2 [OC(CH3)3], 107.2,
113.4, 119.2, 128.8, 129.5, 130.6, 132.0, 136.9, 146.0, 150.8, 155.7, (12ArC),
156.7 (HNCO2, NIffloc), 171.6 (CO2CH3).
MS m/z: 443 (Nr, 100), 387 (71), 370 (18), 355 (6), 342
(17), 283 (12), 266 (12), 253 (31), 225 (13), 210
77 (7).
(25), 326 (78), 313 (65), 299
(7), 181 (5), 165 (5), 91 (5),
144
4.2.50 Preparation of coupling reagent DMTMM (3.87)
4.2.50.1 2-Chloro-4,6-dimethoxy-1,3,5-triazene(3.86b)
2,4,6-Trichloro-1,3,5-triazene (3.86a)(18.5 g, 0.1 mol) and NaHC 0 3 (16.9 g, 0.2 mol) were
added to CH3OH (56 ml) containing H2O (5 ml). The reaction mixture was stirred at room
temperature. Carbon dioxide was given off as the temperature rose above 30 °C. After
stirring for 35 min at room temperature, the reaction mixture was refluxed for 30 min and
cooled to room temperature. Water (250 ml) was added and the white crystalline product that
formed was filtered, dried in vacuo overnight to give 3.86b (13.0 g, 74%), that was used for
the next step without purification.
Mp: 71 °C (lit. 7'8 72-76 °C).
NMR 8: 4.04 (20CH3).
4.2.50.2 DMTMM (3.87)
H3C0 CH3 1) 5-- Ni/—\0
CI'
NMM (2.85 ml, 26 mmol) was added dropwise to a solution of 3.86b (5.0 g, 28 mmol) in
THE (80 ml) at room temperature. After stirring for 30 min at the same temperature, the
white solid formed was filtered and washed twice with THE and dried in vacuo to give
DMTMM (3.87) (7.15 g, 100%).
Mp: 116 °C (lit. 9 ' 1° 116 °C)
1H NMR (CD3OD) 8: 3.54 (3H, s, NCH3), –3.90 (4H, m, 2CH2), 4.07 (2H, m, CH2), 4.10
(6H, s, 20CH3), 4.52 (2H, m, CH2).
145
4.2.51 Methyl 4-{5-[2-(2-{4-15-(2-tert-butoxycarbonylaminoethyl)-2,3-
dimethoxyphenoxylphenyl}acetylamino)ethy1]-2,3-dimethoxy
phenoxy} phenylacetate (3.88a)
DMTMM (3.87) (310 mg, 1.12 mmol) was added to a mixture of phenylacetic acid 3.11b
(430 mg, 1 mmol) and phenethylamine 3.11a (360 mg, 1.05 mmol) in CH3OH. After stirring
overnight at room temperature, the Me0H was evaporated. The mixture was poured into
water and extracted with EtOAc. The organic phase was washed with saturated sodium
carbonate, water, 10 % aq. HC1, water, and brine and dried (Na2SO4). Evaporation of the
solvent in vacuo gave pure compound 3.88a (695 mg, 94%).
1HNMR 8: 1.38 (9H, s, tBu), 2.58-2.66 (4H, m, 2 CH2, Cf_12CH2NHCO), 3.23-3.39 (4H,
m, 2CH2NHCO), 3.42 and 3.51 (4H, 2CH2, CH2C0), 3.65 (3H, s,
CH2CO2CH3), 3.74 (6H, s, 20CH3), 3.79 (3H, s, OCH 3), 3.83 (3H, s, OCH3),
4.62 (1H, br s, NH), 5.58 (1H, br s, NH), 6.31 (1H, d, J = 1.8 Hz, ArH), 6.39
(1H, d, J = 1.8 Hz, ArH), 6.46 (1H, d, J= 1.8 Hz, ArH), 6.53 (1H, d, J = 1.8
Hz, ArH), 6.82 (4H, d, J = 8.1 Hz, ArH), 7.06 (2H, d, J = 8.7 Hz, ArH), 7.17
(2H, d, J = 8.4 Hz, ArH).
13C NMR 8: 28.2 (3C, 13u), 35.4 and 36.0 (2CH2CH2NHCO), 40.2 and 40.6 (2CH2CO),
41.6 and 42.7 (2CH2NHCO), 51.9, 55.9, 56.0, 60.2 and 60.9 (50CH3), 79.0
[OC(CH3)3], 108.3, 108.5, 113.3, 113.5, 117.2 (2C, C-3"and C-5" or C-3 and
C-5, 117.4 (2C, C-3" and C-5" or C-3 and C-5), 127.9, 128.2, 128.6, 130.2 (C-
2" and C-6" or C-6 or C-2), 130.3 (C-2" and C-6" or C-2 and C-6), 134.4,
146
134.8, 139.2, 139.3, 148.8, 149.0, 153.6, 156.6, 156.7, 156.9 (HNCO2), 171.4
(IINCO or CO2CH3), 171.9 (HNCO or CO2CH3)
IR v,.(cm-1 ): 3380, 3360, 1720, 1675, 1670.
4.2.52 4-(5-[2-(2-{445-(2-tert-Butoxycarbonylaminoethyl)-2,3-dime-
thoxyphenoxylphenyl}acetylamino)ethy11-2,3-dimethoxy-
phenoxy}phenylacetic acid (3.88b)
A solution of 3.88a (625 mg, 0.843 mmol) in CH3OH: H2O (3:1, 15 ml) was refluxed in the
presence of 25% aq. K2CO3 (500 mg in 2 ml H2O) for 1.45 h. The volatiles were removed
and the residue was dissolved in 2% aq. NaOH and washed with EtOAc. The aqueous layer
was acidified with 10% aq. HCI, extracted with ether and then ether extract was washed with
brine and dried over Na2SO4. Evaporation of the solvent in vacua gave pure compound 3.88b
(479 mg, 79%) as a white solid.
1H NMR 5: 1.41 (9H, s, 13u), 2.65 (4H, 2CH2CH2NHCO), 3.20-3.39 (4H, 2CH.2NHCO),
3.43 and 3.54 (4H, 2CH2CO), 3.77-3.85 (12H, 40CH3), 4.60 (1H, br s, NH),
5.55 (1H, br s, NH), 6.23-6.60 (4H, 4 br s, ArH), 6.80 (4H, m, ArH), 7.07-7.17
(4H, ArH).
IR vmax (cm-1): 3400, 3360, 3050, 1690, 1675, 1660.
147
4.2.53 4-{5-[2-(2-14-15-(2-Aminoethyl)-2,3-dimethoxyphenoxyl-
phenyl)-acetylamino)ethy11-2,3-dimethoxyphenoxy}phenyl
acetic acid (3.88c)
To a stirred, ice cold solution of N-BOC compound 3.88b (93 mg, 0.13 mmol) in CH2C12 (2
ml) was added trifluoroacetic acid (0.300 ml). The solution was stirred at room temperature
overnight. The volatile components were removed and the product was isolated in
quantitative yield without any further purification as a brownish TFA salt.
11-1 NMR (DMSO) 5: 2.60-3.43 (12H, 6CH2), 3.65 (6H, 20CH3), 3.81 (6H, 20CH3), 5.50
(1H, br s, NH), 6.40 (2H, ArH), 6.60-6.78 (6H, ArH), 7.18 (4H, ArH),
NH2).
MS m/z: 644 (Mt, 8), 630 (5), 615 (2), 525 (6), 494 (15), 480 (8), 467 (9), 419
(61), 360 (68), 346 (75), 332 (16), 318 (14), 257 (13), 181 (11), 167
(14), 139 (45), 113 (100).
IR vmax (cm-1 ): 3380, 1695, 1660.
4.2.54 3-Bromo-4-hydroxy-5-methoxybenzaldehyde (3.89)
H3C0 CHO
148
Bromine (11.2 ml, 220 mmol) in glacial acetic (25 ml) was added dropwise for a period of 20
min to the stirred solution of vanillin (3.22) (30.0 g, 0.20 mol) in glacial acetic acid (160 ml).
Stirring was continued for 1 h after which the TLC indicated consumption of the starting
material. The precipitate formed during the process. Water was added to the mixture and the
solid product was filtered, washed several times with water and dried in vacuo to give
bromovanillin (3.89) (43.4 g, 95%) as a white solid.
Mp: 162 °C (lit. 1132 162-163 °C).
1H NMR (DMSO) 5 3.89 (6H, s, 20CH3), 7.39 (1H, d, J = 1.8 Hz, H-2 or H-6, ArH), 7.69
(1H, d, J = 1.8 Hz, H-2, or H-6, ArH), 9.75 (1H, s, CHO).
MS m/z: 232 (M+2, 97), 230 (NC, 100), 203 (6), 201 (7), 189 (14), 187 (14), 161
(9), 159 (10), 135 (10), 79 (17) .
IR v.a.„ (cm 1 ): 3590, 1730.
4.2.55
3-Bromo-4,5-dimethoxybenzaldehyde (3.90)
H3C0 CHO
H3CO
Bromovanillin (3.89) (30.0 g, 130 mmol), anhydrous K2CO3 (26.9 g, 195 mmol) and
iodomethane (12.1 ml, 195 mmol) in anhydrous DMF (200 ml) was heated at 50 °C overnight.
The reaction mixture was poured into water and extracted with ether. The ether layer was
washed with aqueous 5% aq. NaOH, brine, water and dried. Removal of the solvent in vacuo
afforded pure dimethoxybenzaldehyde (3.90) (25.0 g, 91%) as a white solid.
Mp:
114 NMR 6:
13 C NMR 5:
MS m/z:
IR yin. (cm-1 ):
58 °C (lit. 13 62°C)
3.90 (3H, s, OCH3), 3.92 (3H, s, OCH3), 7.33 (1H, d, J= 1.8 Hz, H-2 or H-6,
ArH), 7.61 (1H, d, J= 1.8 Hz, H-2 or H-6), 9.81 (1H, s, CHO)
56.1 (OCH3), 60.7 (OCH3), 109.9, 117.8, 128.5, 132.8, 151.6, 153.9, (6ArC),
189.6 (CHO)
246 (M+2, 99), 244 (Mt, 100), 231 (22),229 (23), 175 (3), 173 (3).
1710, 1585.
149
4.2.56 3-Bromo-4,5-dimethoxybenzyl alcohol (3.91)
H3C0 A CH2OH
H3CO
Br
To the well stirred solution of benzaldehyde 3.90 (20.0 g, 82 mmol) in CH3OH (100 ml) was
slowly added NaBH4 (9.3 g, 244 mmol) at 0 °C. After stirring for 1.5 h, the excess of NaBH 4
was destroyed by careful addition of 10% aq. HC1. The volatiles were evaporated and the
residue was extracted with EtOAc. The EtOAc extract was washed with saturated aq.
NaHCO3 and water. Drying of the solvent over MgSO4 followed by the removal of the
solvent gave pure benzyl alcohol 3.91 (9.4 g, 96%) as an oily substance.
I HNMR 8: 3.80 (3H, s, OCH3), 3.82 (3H, s, OCH3), 4.55 (2H, s, C1I2OH), 6.79 (1H, d, J=
2.1 Hz, H-2 or H-6, ArH), 7.0 (1H, d, J= 2.1 Hz, H-2 or H-6, ArH).
13C NMR 8: 55.8 (OCH3), 60.4 (OCH3), 63.8 (CH2OH), 109.9, 117.09, 122.4, 138.2, 144.9,
153.2, (6ArC).
MS m/z: 248 (M+2, 70), 244 (M% 71), 232 (35), 230 (35), 217 (6), 215 (7), 201 (6), 199
(7), 175 (10), 167 (16), 151 (100), 137 (41), 124 (28), 96 (61), 77 (30), 69 (27)
1R vn,a„ (cm 1): 3500 (OH).
4.2.57 3-Bromo-4,5-dimethoxybenzyl chloride (3.92)
H300 CH2C1
• H3CO
To the solution of benzyl alcohol 3.91 (13.7 g, 56 mmol) in anhydrous CHC13 (20 ml) was
added thionyl chloride (12.3 ml, 167 mmol) in anhydrous CHC13 (10 ml) at 0 °C. The
solution was stirred for 1 h at the same temperature, poured into ice water and extracted with
CHC13. The CHC13 extract was washed with saturated NaHCO3 solution, brine, water and
evaporated. Flash chromatography (4:1 hexane:EtOAc) gave benzyl chloride 3.92 (12.0 g, 82
%) as a white solid.
150
Mp: 53 °C
1H NMR 8: 3.85 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.48 (2H, s, CH2C1), 6.75 (111, J= 2.1
Hz, H-2 or H-6, ArH), 7.15 (1H, d, J= 2.1 Hz, H-2 or H-6, ArH).
13C NMR 8: 45.0 (CH2C1), 55.7 (OCH3), 60.1 (OCH3), 111.4, 117.6, 124.2, 133.8, 146.0,
153.2, (6ArC).
MS m/z: 268 (M+2, 10), 266 (40), 231 (94), 229 (100), 215 (1), 142 (2), 120 (4), 107
(5) .
4.2.58 3-Bromo-4,5-dimethoxyphenylacetonitrile (3.93)
H300 A CH2CN
H3CO
Br
Benzyl chloride 3.92 (10.8 g, 41 mmol) and sodium cyanide (10.0 g, 204 mmol) in dimethyl
sulphoxide (50 ml) were heated at 40 °C overnight. The reaction mixture was poured into
water and extracted with EtOAc. The EtOAc extract was washed several times with water,
brine, evaporated and flash chromatographed (7:3 hexane:EtOAc) to give phenylacetonitrile
3.93 (7.8 g, 74%)
1H NMR 8: 3.66 (2H, s, CH2CN), 3.82 (3H, s, OCH3), 3.86 (3H, s, OCH3), 6.79 (1H, J=
2.1 Hz, H-2 or H-6, ArH), 7.06 (1H, d, J= 2.1 Hz, H-2 or H-6, ArH).
13 C NMR 8: 23.1 (CH2CN), 56.1 (OCH3), 60.6 (OCH3), 111.2, 117.2, 118.0, 124.0, 126.7,
146.2, 153.9, (7C, 6ArC and CN).
MS m/z: 257 (M+2, 94), 255 (M+, 97), 242 (51), 240 (51), 231 (6), 229 (6), 187 (10),
185 (11), 167 (10), 149 (75), 133 (100), 104 (19), 90 (43), 77 (24), 71 (29).
IR vnia„ (cm-1 ): 2250.
151
H3C
4.2.59 3-Bromo-4,5-dimethoxyphenylacetic acid (3.23)
H3CO OH
Br
To the solution of phenylacetonitrile 3.93 (4.5 g, 18 mmol) in CH3OH (100 ml) was added
25% aq. NaOH (35 ml) and the reaction was heated at reflux until the evolution of ammonia
has ceased (indicator paper, 24 h). The CH3OH was evaporated and the aqueous residue was
washed with ether. The aqueous layer was acidified with 15% aq. HC1 and extracted with
EtOAc. The EtOAc extract was washed with brine, water and evaporated in vacuo to give the
acid as a pale yellow solid 3.23 (3.91 g, 81%).
Mp: 99-100 °C.
1HNMR E.: 3.57 (2H, s, CH2CO2H), 3.80 (3H, s, OCH3), 3.85 (3H, s, OCH3), 6.78 (1H, d,
J = 1.8 Hz, H-2 or H-6, ArH), 7.05 (1H, d, J = 1.8 Hz, H-2 or H-6, ArH).
13C NMR 5: 40.4 (CH2CO2), 56.1 (OCH3), 60.5 (OCH3), 112.8, 117.5, 125.4, 130.0, 145.0,
153.5, (6ArC), 179.0 (CO2H).
MS m/z: 276 (M+2, 97), 274 (M+, 100), 261 (18), 259 (19), 231 (64), 229 (63), 217 (5),
185(11), 167 (3), 149 (7), 108 (14), 89 (10), 77 (31).
IR vn.(cm-1 ): 3050, 1715.
4.2.60 (S)-2-[3-Bromo-4,5-dimethoxypheny1)-N-(1-phenylethyl)
acetamide (3.94).
Commercial S-(-)-1-phenethylamine used was found to have [a]D 25 = -36.3 (c = 1.23 CHC1 3).
To a solution of S-(-)-1-phenylethylamine (1.26, 10.4 mmol) and phenylacetic acid 3.23 (2.6
g, 9.4 mmol) in CH3OH:H20 (10:1, 50 ml) was added DMTMM (3.87) (2.6 g, 9.4 mmol) and
stirred overnight at room temperature. The resulting residue was poured into water and
152
extrated with ether. The ether layer was washed successively with saturated Na2CO3, water,
10% aq. HC1, water, brine and dried (MgSO4). Evaporation of the solvent gave amide 3.94
(3.6 g, 100%) as a white solid.
Mp: 122 °C.
1H NMR 8: 1.42 (3H, d, J = 6.9 Hz, CHCH3), 3.44 (2H, s, CH2C0), 3.79 (3H, s, OCH3),
3.82 (3H, s, OCH3), 5.11 (1H, q, J = 6.9 Hz, CHCH3), 5.95 (1H, br s, NH),
6.74 (1H, d, J= 1.8 Hz, H-2 or H-6, ArH), 6.98 (1H, d, J= 1.8 Hz, H-2 or H-6,
ArH), 7.18-7.29 (5H, m, ArH).
13 C NMR 8: 21.6 (CH3), 42.9' (CH2CO2), 48.8 (CHNH), 56.0 (OCH3), 60.5 (OCH3), 112.4,
117.6, 125.1, 125.2, 126.1 (2C), 127.3, 128.5 (2C), 130.8, 142.8, 153.4,
(12ArC), 169.2 (HNCO).
MS m/z: 379 (M+2, 33), 377 (Mt, 34), 231 (75), 229 (74), 217 (5), 214 (6), 161 (4), 151
(6), 120 (11), 105 (100), 90 (6), 77 (30).
IR vm.(cm-1 ):1705, 1680.
[4325 = -24.5 (c = 1.46 CHC1 3).
4.2.61 (S)-N42-(3-Bromo-4,5-dimethoxyphenyl)ethyll-1-phenylethyl-
amine (3.95)
1;r CH3 }13
To a solution of acetamide 3.94 (1.3 g, 3.4 mmol) in anhydrous THE (10 ml) was slowly
added BF3.Et20 complex (0.6 ml, 20 mmol) and 1M solution of BH3.THF (15 ml, 15 mmol)
complex at room temperature. After cooling to room temperature, the excess reagent was
decomposed with 6N aq. HC1. The aqueous solution was washed with EtOAc, basified with
10% aq. KOH and extracted with CH2C12. The CH2C12 was washed with water and
evaporated in vacuo to give pure amine 3.95 (630 mg, 54%) as an oily substance.
1H NMR 8: 1.34 (3H, d, J = 6.6 Hz, CHCH3), 1.48 (1H, br s, NH), 2.60-2.75 (4H, m,
CH2C1I2NH), 3.71 (1H, m, CH), 3.80 (3H, s, OCH3), 3.82 (3H, s, OCH3), 6.63
153
(1H, d, J = 2.1 Hz, H-2 or H-6, ArH), 6.92 (1H, d, J = 2.1 Hz, H-2 or H-6,
ArH), 7.18-7.29 (5H, m, ArH).
'3C NMR 8: 24.3 (CH3), 35.9 (CH2CH2NH), 48.4 (CH2CH2NH), 55.9 (OCH3), 58.1
(CH2NHCH), 60.4 (OCH3), 112.0, 117.3, 124.3, 126.3 (2C), 126.8, 128.2 (2C),
137.3, 144.5, 145.3, 153.3, (12ArC).
MS m/z: 366 (3), 364 (M+1, 2), 231 (12, 229 (12), 149 (2), 118 (5), 105 (100), 91 (9),
77 (30), 57 (8).
[4325 = -36.1 (c = 0.89 CHC13).
4.2.62 (S)-N-[2-(3-Bromo-4,5-dimethoxyphenyl)ethy1]-2-(4-isopropyl-
oxyphenyI)-N-(1-phenyl-ethyl)acetamide (3.96)
(S)-amine 3.95 (1.0 g, 2.74 mmol) and 4-isopropyloxyphenylacetic acid (529 mg, 2.73 mmol),
prepared from 4-hydroxyphenylacetic acid and isopropyl bromide in 25% aq. ethanolic
solution and DMTMM (3.87) (769 mg, 2.88 mmol) in THF:H20 (10:1, 30 ml) was stirred
overnight to obtain title amide (1.25 g, 85%) under the same conditions described for (5)-
amide 3.94. The compound was isolated as an oily substance and was used without further
purification.
'H NMR 8: Inseparable mixtures of two rotamers (E and Z): 1.37 [6H, d, J = 6.0 Hz,
CH(CH3)2], 1.45 (3H, J= 6.6 Hz, CHCLI3), 2.15-2.74, 3.19-3.3 (4H, m, 2CH2),
3.78, 3.80 (6H, s, 20CH3), 3.99 (2H, CH2), 4.50 (1H, m, OCH), 5.20 (1H, q, J
= 6.6 Hz, CHCH3), 6.25-7.15 (6H, m, ArH), 7.20-7.41 (5H, m, ArH).
MS m/z: 541 (M+2, 7), 539 (1\e, 7), 504 (1), 502 (1), 376 (5), 374 (5), 297 (27), 244
(60), 242 (60), 231
(98), 107 (100), 91
(16),
(19),
229 (20), 206 (11),
77.
183 (2), 169 (20), 164 (79), 134
111. v.(cm 1): 1640.
154
[a]D25 = -44.6 (c = 1.01 CHC13).
4.2.63 (S)-8-Bromo-1-(4-isopropyloxybenzy1)-6,7-dimethoxy-2-( 1-
phenylethy1)1,2,3,4-tetrahydroisoquinoline (3.98)
The mixture of 3.96 (500 mg, 0.926 mmol) and excess POC13 (2 ml, 23 eq.) in anhydrous
benzene (5 ml) was refluxed overnight. The volatiles were evaporated on rotary evaporator
and then on a high vacuum pump for 3 h. The residue was dissolved in anhydrous CH3OH
and cooled to —78 °C. NaBH4 was added in portions and stirring was continued at the same
temperature for 3 h. After cooling to room temperature, the excess of NaBH4 was
decomposed with 10% aq. HCI and the volatiles were evaporated. The residue was basified
with 15% aq. KOH and extracted with CHC13. The CHC13 extract was washed with water and
evaporated in vacuo and the residue obtained was chromatographed with hexane:EtOAc (4:1)
to give the 1,2,3,4-tetrahydroisoquinoline 3.98 (340 mg, 70%) as a yellow oil.
1 H NMR 8: 1.25 (3H, d, J= 6.6 Hz, CHCH3), 1.38 [6H, d, J= 6.0 Hz, CH(CH3)2], 2.40-3.0
(5H, m), 3.10-3.63 (3H, m), 3.84 (3H, s, OCH3), 3.87 (3H, s, OCH3), 4.58 [1H,
m, CH(CH3)2], 6.65 (1H, s, H-5, ArH), 6.76-7.14 (9H, m, ArH).
13C NMR 8: 21.7 (CHCH3), 22.2 [CH(CH3)2], 23.0 (C-4), 38.1 (C-3), 38.7 (C-a), 55.9
(OCH3), 58.9 (NCHCH3 or C-1), 60.4 (OCH3), 60.4 (C-1 or NHCHCH3), 69.8
[OC(CH3)2], 111.8, 115.3 (2C, C-3', C-5'), 119.7, 126.3, 127.3 (2C, C-2' and
C-6' or C-2" and C-6"), 127.7 (2C, C-2' and C-6' or C-2" and C-6"), 130.1,
130.3 (2C, C-3", C-5"), 132.1, 132.2, 144.4, 145.3, 151.3, 155.8, (18ArC).
MS m/z: 526 (25), 524 (M+1, 27), 376 (100), 374 (99), 296 (61), 289 (6), 279 (18), 272
(50), 270 (52), 258 (6), 192 (4), 149 (3).
[a]D25 = +78.6 (c = 1.56 CHC13).
155
4.2.64 (R)-2-(3-Bromo-4,5-dimethoxypheny1)-N-(1-phenylethyl)
acetamide(3.99)
Commercial R-(+)-1-phenethylamine used was found to have [c(]13 25 = +34.3 (c = 1.70
CHC13).
The title compound (1.19 g, 100%) was prepared from R-(+)-1-phenylethylamine (420 mg,
3.5 mmol) and phenylacetic acid 3.23 (867 mg, 3.13 mmol) in CH3OH:H20 (10:1, 20 ml)
using DMTMM (3.87) (864 mg, 3.13 mmol) as descibed for compound 3.94. The compound
was isolated as a white solid.
Mp: 122 °C.
'H NMR 8: 1.43 (3H, d, J= 6.9 Hz, CHCH3), 3.43 (2H, s, CH2CO2), 3.80 (3H, s, OCH3),
3.82 (3H, s, OCH3), 5.11 (1H; q, J = 6.9 Hz, CHCH3), 5.95 (1H, br s, NH),
6.74 (1H, d, J= 1.8 Hz, H-2 or H-6, ArH), 6.99 (1H, d, J= 1.8 Hz, H-2 or H-6,
ArH), 7.18-7.29 (5H, m, ArH).
13C NMR 8 21.7 (CH3), 42.9 (CH2CO2), 48.8 (CHNH), 55.9 (OCH3), 60.5 (OCH3, 112.4,
117.6, 125.1, 125.2, 126.0 (2C), 127.3, 128.5 (2C), 132.0, 142.8, 153.6, 169.2
(NHCO).
MS m/z: 379 (M+2, 33), 377 (Mt, 34), 231 (75), 229 (74), 217 (5), 214 (6), 161 (4), 151
(6), 120 (11), 105 (100), 90 (6), 77 (30).
lR vn.(cm-1 ): 1705, 1670.
[a]D25 = +21.8 (c = 1.03 CHC13).
156
4.2.65 (R)-N-[2-(3-Bromo-4,5-dimethoxyphenyl)ethy1]-1-phenyl-
ethylamine(3.100)
- iii,. :13
The title compound 3.100 (4.2 g, 61%) was prepared from acetamide 3.99 (7.2 g, 19 mmol) as
described for amine 3.95.
1 11 NMR 5: 1.35 (3H, d, J = 6.6 Hz, CHCH3), 1.50 (1H, br s, NH), 2.60-2.75 (4H, m,
CLI2CH2NH), 3.71 (1H, m, CH), 3.80 (3H, s, OCH3), 3.82 (3H, s, OCH3), 6.64
(1H, d, J = 2.1 Hz, H-2 or H-6, ArH), 6.94 (1H, d, J = 2.1 Hz, H-2 or H-6,
ArH), 7.18-7.29 (5H, m, ArH).
13C NMR 5: 24.3 (CH3), 35.9 (CH2CH2NH), 48.4 (CH2NH), 55.9 (OCH 3), 58.1 (NHCH),
60.4 (OCH3), 112.0, 117.3, 124.3, 126.3 (2C), 126.8, 128.3 (2C), 137.3, 144.5,
145.3, 153.3, (12ArC).
MS m/z: Identical to 3.95.
[a]D25 = +31.2 (c = 4.32 CHCI3).
4.2.66 (R)-N-[2-(3-Bromo-4,5-dimethoxyphenyl)ethy1]-2-(4-isopropyl-
oxypheny1)-N-(1-phenylethyl)acetamide (3.101)
The title amide (85%) was obtained from amine 3.100 and 4-isopropyloxyphenylacetic acid
under the same conditions described for amide 3.96.
1H NMR 5: Identical chemical shifts to 3.96.
157
MS m/z: Identical to 3.96.
IR vm. (cm-1): 1640.
[a]D25 = +42.9 (c = 1.10 CHC13).
4.2.67 (R)-8-Bromo-1-(4-isopropyloxybenzy1)-6,7-dimethoxy-2-(1-
phenylethyl)-1,2,3,4-tetrahydroisoquinoline (3.103)
Amide 3.101 was cyclised and reduced to give an oily 1,2,3,4-tetrahydroisoquinoline 3.103 in
70 % yield as described for tetrahydroisoquinoline 3.98.
IHNNIR 8: 1.25 (3H, d, J = 6.3 Hz, CHCH3), 1.39 (6H, d, J = 6.3 Hz, CH(CH3)2), 2.41-
3.00 (5H, m), 3.10-3.65 (3H, m), 3.84 (3H, s, OCH3), 3.86 (3H, s, OCH3), 4.58
(1H, m, CH(CH3)2), 6.65 (1H, s, H-5, ArH), 6.76-7.15 (9H, m, ArH).
13C NMEt 6: 21.8 (CHCH3), 22.9 [CH(CH3)2], 23.0 (C-4), 38.2 (C-3), 38.8 (C-a), 55.9
(OCH3), 58.9 (NCHCH3 or C-1), 60.4 (C-1 or NHCHCH3), 60.5 (OCH3), 69.9
[OC(CH3)2], 111.9, 115.3 (2C, C-3', C-5'), 119.8, 126.3, 127.4 (2C, C-2' and
C-6' or C-2" and C-6"), 127.8 (2C, C-2' and C-6' or C-2" and C-6"), 130.2,
130.4 (2C, C-3", C-5"), 132.2, 132.3, 144.4, 145.4, 151.4, 155.9, (12ArC).
MS m/z: Identical to 3.98.
[4325 = -83.7 (c = 1.33 CHC13).
158
4.3 References
D.D. Perrin and W.L.F. Armarego, Purification of Laboratory Chemicals (3rd Ed),
Pergamon, Oxford, 1988.
H.N. Elsohly, G.-E. Ma, C.E. Turner and M.A. Elsohly, J. Nat. Prod, 1984, 47, 445.
G.R. Pettit and S.B. Singh, Can. J. Chem., 1987, 65, 2390.
R.K. Boeckman, P. Shao and J.J. Mullins, Org. Synth., 1999, 77, 141.
D.B. Dess and J.C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
A. Aranyos, D.W. Old, A. Kiyomori, J. Wolfe, J.P. Sadighi and S.L. Buchwald, J. Am.
Chem. Soc., 1999, 121, 4369
J.S. Cronin, F.O. Ginah, A.R. Murray and J.D. Copp, Synth. Commun., 1996, 26,
3491.
J.R. Dudley, J.T. Thuyrston, F.C. Schaefer, D. Holm-Hansen, C.J. Hull and P. Adams,
J. Am. Chem. Soc., 1951, 73, 2986.
M. Kunishima, C. Kawachi, J. Morita, K. Terao, F. Iwasaki and S. Tani, Tetrahedron,
1999, 55, 13159.
M. Kunishima, C. Kawachi, K. Hioki, K. Terao and S. Tani, Tetrahedron, 2001, 57,
1551.
Z. Yang, H.B. Liu, C.M. Lee, H.M. Chang and H.N.C. Wong, J. Org. Chem, 1992, 57,
7248.
D.V. Rao and F.A. Stuber, Synthesis, 1983, 308.
D.P. Venter and J.H. Langenhoven, S. Afr. J. Chem., 1996, 49, 40.
159
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