asymmetric approaches towards ly290154 … · the work described in this thesis concerns the...

ASYMMETRIC APPROACHES TOWARDS LY290154

Antonio Garrido Montalban

A thesis submitted in partial fulfilment

of the requirements for the degree of

Doctor of Philosophy of the University of East Anglia

This copy of the thesis has been supplied on the conditions that anyone who consults it is understood to recognise that its copyright rests with the author and that no quotation from the thesis, nor any information derived therefrom, may be published without the author's prior written consent.

2

PREFACE

The research described in this thesis is, to the best of my knowledge, original

except where due reference is made, and has not previously been submitted for

any degree in this or any other university.

Antonio Garrido Montalban

Norwich, March 1995

3

ABSTRACT

The work described in this thesis concerns the development of asymmetric

approaches towards the synthesis of LY290154 35, a leukotriene antagonist.

The first chapter provides a general introduction to leukotrienes and leukotriene

antagonists, including racemic synthesis of 35 developed by Lilly.

In Chapter 2 a plausible synthetic route for the preparation of enantiomerically

enriched LY290154 from a corresponding optically active primary amine is

discussed. Chapter 3 describes the development and chapter 4 the synthesis of

the optically active amine 50b, which could in principle produce 35 in

enantiomerically enriched form.

In Chapter 5 the attempted construction of the key intermediate 48b, required to

achieve the asymmetric synthesis of LY290154 via the conversion of 3-

nitropyridinium salts into indoles is described. Unfortunately, the simple

unsubstituted pyridinium salt 153, essential for the formation of 48b, did not

undergo the reaction with imines derived from primary amines to yield the

corresponding indole derivatives.

Chapter 6 describes a new route for the preparation of 7-oxo-4,5,6,7-

tetrahydroindoles from reaction of primary amines with 7-oxo-4,5,6,7-

tetrahydrobenzofuran in a sealed tube at 150 °C. The aromatisation of 7-oxo-

4,5,6,7-tetrahydroindoles to the corresponding 7-hydroxyindoles could be achieved

via a novel selective halogenation/dehydrohalogenation sequence, which is

discussed in chapter 7.

In chapter 8 the results from attempted syntheses of the 7-oxotetrahydroindole

182, which would lead after aromatisation and alkylation to the required indole

derivative 48b from the amine 50b, are summarised. Unfortunately the amine 50b

could not be converted to 182 under the conditions used.

4

ABBREVIATIONS

Ac acetyl

anh anhydrous

aq aqueous

Ar aryl

BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

BDPP 2,4-bis(diphenylphosphino)pentane

bp boiling point

BPPM t-butyl-4-(diphenylphosphino)-2-

(diphenylphosphinomethy)-1-

pyrrolidinecarboxylate

br broad

t-BOC N-tert-butoxycarbonyl

Bu butyl

CI chemical ionisation

CHIRAPHOS 2,3-bis(diphenylphosphino)butane

conc concentrated

cycphos 1,2-bis(diphenylphosphino)-1-cyclohexylethane

Cys cysteine

d doublet (NMR)

d day(s)

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

δ chemical shift (NMR)

DIBAL diisobutylaluminium hydride

DIOP 2,2-dimethyl-4,5-bis(diphenylphosphinomethyl)-

1,3-dioxolane

5

DIP-Cl diisopinocampheylchloroborane

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

dmfdma N,N-dimethylformamide dimethyl acetal

DMSO dimethyl sulphoxide

DPPA diphenylphosphoryl azide

ee enantiomeric excess

e.g. for example

EI electron impact

eq equivalent(s)

Et ethyl

FTIR Fourier transform infrared

GGTP γ-glutamyl transpeptidase

Glu glutamic acid

Gly glycine

h hour(s)

5-HETE 5-hydroxy-6,8,11,14-eicosatetraenoic acid

5-HPET 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid

Hz Hertz

IR infrared

J coupling constant (NMR)

LA Lewis acid

LDA lithium diisopropylamide

lit literature

LTA4 leukotriene A4

LTB4 leukotriene B4

LTC4 leukotriene C4

LTD4 leukotriene D4

LTE4 leukotriene E4

6

LTF4 leukotriene F4

m multiplet (NMR)

M molarity of solution

Me methyl

min minute(s)

mp melting point

Ms mesyl

MS mass spectrometry

NORPHOS 5,6-bis(diphenylphosphino)norbornene

NMR nuclear magnetic resonance

Ph phenyl

PPA polyphosphoric acid

ppm parts per million

PROPHOS 1,2-bis(diphenylphosphino)propane

PTC phase-transfer catalysis

q quartet (NMR)

quin quintet (NMR)

RAMP (R)-1-amino-2-methoxymethylpyrrolidine

Rf retention factor

rt room temperature

s singlet (NMR)

SAMP (S)-1-amino-2-methoxymethylpyrrolidine

SAR structure activity relationship

SRS slow reacting substance

t triplet (NMR)

TFAA trifluoroacetic anhydride

TFAE 2,2,2-trifluoro-(9-anthryl)ethanol

THF tetrahydrofuran

tlc thin layer chromatography

7

TMS tetramethylsilane

TMSCl trimethylsilyl chloride

trityl triphenylcarbenium

Ts tosyl

8

CONTENTS

1. Introduction....................................................................................................10

1.1 Slow Reacting Substance (SRS)...............................................................10

1.2 Leukotrienes..............................................................................................13

1.3 Leukotriene Antagonists............................................................................17

1.4 Development of LY290154....................................................................... 29

1.5 Racemic Synthesis of LY290154.............................................................. 33

2. Retrosynthetic Analysis of LY290154........................................................ 36

3. Preliminary Results .................................................................................... 39

4. Asymmetric Amine Synthesis...................................................................... 46

4.1 Results and Discussion............................................................................ 61

5. Synthesis of Indoles..................................................................................... 72

5.1 Bartoli Indole Synthesis............................................................................ 72

5.2 Conversion of 3-Nitropyridinium Salts into Indoles................................... 74


6. Synthesis of 4- and 7-Oxo-4,5,6,7-tetrahydroindoles................................ 85


7. Aromatisation.............................................................................................106

8. The final Battle towards LY290154.......................................................... 112

9

9. Conclusions............................................................................................... 124

10. Experimental.............................................................................................. 125

10.1 Solvents and Reagents........................................................................ 125

10.2 Purification and Characterisation Techniques...................................... 125

10.3 Experimental for Chapter 1, Section 1.5............................................... 126

10.4 Experimental for Chapter 3.................................................................. 132






References........................................................................................................ 174

Appendix.......................................................................................................... 189

10

1. Introduction

1.1 Slow Reacting Substance (SRS)

In 1938 Feldberg and Kellaway introduced the term "slow reacting substance"

(SRS) for a material which was excreted from the lungs of guinea pigs after

treatment with cobra venom.1 Kellaway and Trethewie reported that SRS could

also be released by immunological challenge of sensitised lungs.2 The SRS

displayed smooth bronchial muscle contracting activity and subsequent studies

showed that it is an important mediator in asthma and other types of immediate

hypersensitivity reactions.3,4 Structural work on the SRS was initially severely

limited by the difficulty in obtaining sufficient quantities of pure substance.5 Murphy

et al., however, were able to biosynthesise relatively large amounts of SRS using

murine mastocytoma cells. Purification was achieved by high performance liquid

chromatography. The material obtained by this method produced a characteristic

contraction of guinea pig ileum which was reversed by FPL 55712.6 Experiments

with labelled precursors showed that arachidonic acid 1 and cysteine were

O

OH

1

incorporated into the products. Degradation of the SRS by desulfurisation on

Raney nickel afforded 5-hydroxyeicosanoic acid 2, which indicated that the

arachidonic acid derivative and cysteine were linked by a thioether bond. The

hydroxy group at C-5 in the fatty acid reinforced the hypothesis of a biogenetic

11

relationship between the arachidonic acid metabolites and the SRS. The positions

of the double bonds in the SRS were determined by ozonolysis and reduction of

the corresponding carbonyl derivatives. Isolation of 1-hexanol among the products

demonstrated that the C-14 double bond of arachidonic acid had been retained.

Murphy et al. also reported that arachidonic acid and related fatty acids containing

two cis double bonds at the C-5 and C-8 positions, separated by a methylene

group, are peroxygenated to give derivatives in which the C-5 double bond has

isomerised to C-6. Treatment of SRS with lipoxygenase resulted in isomerisation

of the C-14 double bond to form the 15-hydroperoxide of the conjugated tetraenoic

acid 3. The structural studies at this stage showed that SRS was a derivative of 5-

hydroxy-7,9,11,14-eicosatetraenoic acid with a cysteine-containing substituent

linked in a thioether-manner at C-6. That the cysteine is derivatised was suggested

by the failure to isolate alanine after desulfurisation. Additional studies involving

amino acid analyses of hydrolysed SRS demonstrated that in addition to cysteine,

glycine and glutamic acid were present in the ratio 1:1:1. The structure of the SRS

from murine mastocytoma cells was therefore 6-S-glutathionyl-5-hydroxy-

7,9,11,14-eicosatetraenoic acid, leukotriene C4 (LTC4) 47 (Scheme 1). The

stereochemistry proposed for LTC4 was confirmed and unambiguously assigned

from its total synthesis by Corey et al.8 The systematic name for LTC4 is thus

(5S,6R)-6-S-glutathionyl-5-hydroxy-(7E,9E,11Z,14Z)eicosatetraenoic acid. This

represented the first structure determination of an SRS.

12

Scheme 1

��

��

OH

O3/NaBH4

��

H2/Ni

Lipoxygenase

HCl

Cys

Glu

Gly

��

OH

OOH

OH

OOH

S

N

O O

OHNH2HN

O

OHO

H

��

R'

R"OOH

3

4

2

13

1.2 Leukotrienes

Polyunsaturated fatty acids play an important role as precursors of several

biologically active substances. Five main groups of metabolites, the

prostaglandins, the thromboxanes, the prostacyclins, the leukotrienes and the

lipoxins, are formed by oxygenation and further transformation of these compo-

unds, in particular arachidonic acid [(5Z,8Z,11Z,14Z)-eicosatetraenoic acid] 1, a

cascade, as it is often referred to.9-11 Arachidonic acid is formed in organisms from

linoleic and linolenic acids, which belong to the so-called essential fatty acids.

The leukotrienes exhibit three conjugated double bonds and were first detected in

the white blood cells (leukocytes). Lipoxygenase plays a central role in the

biosynthesis of the leukotrienes. This enzyme catalyses not only the formation of

5-hydroperoxy-6,8,11,14-eicosatetraenoic acid (5-HPET) 5 from arachidonic acid,

but also the subsequent conversion of 5-HPET to leukotriene A4 [LTA4, 5,6-epoxy-

(7E,9E,11Z,14Z)-eicosatetraenoic acid] 6. The expoxide 6 is formed from 5-HPET

via an intramolecular process, namely OH-elimination after abstraction of the

proton at C-10, which is activated by two allyl groups (Scheme 2). The structure of

LTA4 has been confirmed by chemical synthesis whereby the stereochemistry was

determined as the 5(S)-configuration.12 The enzyme glutathione peroxidase on the

other hand catalyses the conversion of the peroxide 5 to (S)-5-hydroxy-

(6E,8Z,11Z,14Z)-eicosatetraenoic acid (5-HETE) 7, a major metabolite isolated

OH

OOH

��

7

14

during the initial studies of the leukotriene biosynthesis.13 Leukotriene B4 [LTB4,

(5S,12R)-5,12-dihydroxy-(6Z,8E,10E,14Z)-eicosatetraenoic acid] 8 is formed en-

zymatically from compound 6. The configuration of the three conjugated double

bonds in LTB4 was also elucidated using a synthetic approach.14 The epoxide

function in LTA4 is also ring opened at the 6-position by the nucleophilic thio-

function of glutathione to form LTC4 4 (SRS). Leukotriene C4 is metabolised further

to leukotriene D4 [LTD4, (5S,6R)-6-S-cysteinylglycine-5-hydroxy-(7E,9E,11Z,14Z)-

eicosatetraenoic acid] 9 by enzymatic elimination of glutamic acid by g-glutamyl

transpeptidase (GGTP).15 The remaining peptide bond in leukotriene D4 is

hydrolysed by a renal dipeptidase to give leukotriene E4 [LTE4, (5S,6R)-6-S-

cysteinyl-5-hydroxy-(7E,9E,11Z,14Z)-eicosatetraenoic acid] 1016 (Scheme 3). Leu-

kotriene E4 can also act as an acceptor for γ-glutamic acid, thus forming the

glutamylcysteinyl derivative leukotriene F4 (LTF4) 11.17

OH

OOH

S

N OHOH

OO

O

NH2H

��

11

Following the structure determination of the SRS from mastocytoma cells6,7 and

the synthesis of LTC4, LTD4 and LTE4,7 all of these cysteine-containing

leukotrienes were identified in a variety of biological systems using comparison

with synthetic material. The SRS is therefore a mixture of leukotrienes containing

cysteine, e. g., the parent compound LTC4 and the metabolites LTD4 and LTE4.

15

The leukotrienes are not only formed from arachidonic acid, but in general from

C20-fatty acids possesing the same 5,8,11-double bond system with more or less

double bonds in the other half of the molecule. The index number, therefore, refers

to the unsaturation of the parent fatty acid from which they are derived. These

versatile, biologically active substances are also termed eicosanoids, after the

number of C atoms they contain.

Scheme 2

OOH

O��

��

Dehydrase��

Lipoxygenase��

O

OH

��

��

�� O

OH

O

H

H

OH

��

1

5

6

16

Scheme 3

OH O

OH

HO

��

��

��Hydrolase ��

OH

OOH

S

N

O O

OHNH2HN

O

OHO

H

��

8

GlutathioneS-transferase

�� GGTP

OH

OOH

S

NH2N

O

H O

OH

��

9

Dipeptidase

OH

OOH

S

H2NO

OH

��

10

��

6

4

17

1.3 Leukotriene Antagonists

In an asthma attack the production of the SRS is triggered by pollen or other

allergens, and constriction of the air passages results. The major component of the

SRS in the human lung is leukotriene D4 9 and accounts for almost all of the

OH

OOH

S

H2NN

OHO

H O

��

9

biological activity.6,18 The leukotrienes exert their potent biological effects through

interaction with specific cellular receptors; in the human lung they are thought to

act on a common one. Over the past several years, much effort has been made to

discover leukotriene antagonists. Two major chemical approaches to the

development of such receptor antagonists have been pursued. The first involved

structural modification of the initial prototype leukotriene antagonist FPL 55712 12,

O

HO O OOH

O

O

OH

O

12

18

discovered at Fisons Corp. in 1977.19,20 Lack of bioavailability and a short half-life

have hindered clinical evaluation of this synthetic material. Propionic acid

derivatives at the 2-position of the chromone ring in compound 12 have been

reported to have longer biological half-lives though they were less potent in vitro.21

Structure activity relationships (SAR) of some derivatives of FPL 55712 have been

reported by Marshall et al.22 When the propylhydroxyacetophenone moiety was

separated from an acidic carboxyl group by one or two methylene groups, no

response could be found. Detectable leukotriene antagonist activity was observed

with three methylenes and maximum activity with the five methylene compound,

followed by a gradual diminishing of activity through 10 methylenes (Figure 1).

Figure 1

O

HO O COOHn

n = 1-10

Aromatic substitution changes were then studied, keeping the five-methylene chain

length and terminal carboxylic acid intact. The saturated n-propyl group was shown

to be better than allyl or hydrogen. There was no loss in activity when the acetyl

group was changed to propionyl, but greatly reduced potency when it was

substituted with a carbomethoxy group. Removal of the 3-hydroxy substituent

abolished activity. When acetyl and hydroxy groups were interchanged, profound

loss of potency was again observed (Figure 2). Next, a number of terminal groups

19

were investigated, without changing of the aromatic substitution pattern. While the

Figure 2

R' O

R

R"COOH

R = acetyl, propionyl, CH3OCO or hydroxy

R' = hydroxy, hydrogen or acetyl

R" = n-propyl, allyl or hydrogen

nitrile group had no in vitro activity, compounds in which the chain ended with

hydroxyl, dimethylamine, morpholine, or N-methylpiperazine were found to have

significant activity. Substitution of the carboxyl group by the bioisosteric tetrazole

resulted in substantial improvement in in vitro and in vivo LTD4 antagonist activity.

In contrast to the carboxylic acid series, in which maximum activity was obtained in

the compound with five methylenes in the chain, among tetrazoles the best activity

resulted in compounds with four, six and seven methylenes in the connecting chain

(Figure 3). An extensive pharmacological evaluation of one of these compounds,

Figure 3

HO O X

O

X = CN, OH, NMe2, N(CH2CH2)2O, N(CH2CH2)2NMe or 5-tetrazolyl

20

LY171883 13, has been reported and showed a greater stability and biological

HO O

O

NN

NN

H

13

activity than observed for FPL 55712 12.23 The second approach centred on

structures related to the leukotrienes themselves, since their elucidation in 1980.8

In recent years a number of specific receptor antagonists of LTD4 have been

synthesised. The compound SKF 104353 14, for example, was designed with the

S OH

OH

OOHO

��

14

idea in mind, that shortening of the spatial separation between the eicosanoid

carboxyl and thioether functionality of the natural leukotrienes exhibited antagonist

properties.24 The (phenyloctyl)phenyl group was thought to mimic the unsaturated

planar triene moiety of LTD4. The compound 14, which posesses the same

stereochemistry as the agonist itself, showed high affinity for the receptor, while

the other enantiomer showed significantly reduced activity. SKF 104353 was

prepared from (phenyloctyl)benzaldehyde 15 as depicted in Scheme 4. Darzens

21

Scheme 4

other enantiomer

14 +

resolution�� OH

O

R

OH

SHO

O

NaOH��

18 17

+OMe

O

R

S

OH

OMe

O

OMe

O

R

OH

SMeO

O

HS(CH2)2CO2MeEt3N

��NaOMe

��

(CH2)7PhR =

1615

OMeO

O

R

NaOMe

ClCH2CO2Me��

O

R

22

condensation of compound 15 with methyl chloroacetate afforded the glycidic ester

16, which on reaction with methyl mercaptopropionate, gave a 1:1 mixture of the

regioisomers 17 and 18. Treatment of the mixture of regioisomers with methoxide

effected a retro-aldol degradation of the undesired isomer 18, affording compound

17 and recovered starting material. Ester hydrolysis of the intermediate 17 afforded

racemic 14, which was resolved to provide both enantiomers.

The discovery and preparation of the potent, specific and orally active leukotriene

D4 antagonist L-660,711 19, was originally carried out with a racemic mixture. As

classical resolution techniques failed to separate the racemate, an asymmetric

synthesis had to be developed in order to study the biological properties of each

enantiomer.25 Isophthalaldehyde was, therefore, reacted with one equivalent of

each of N,N-dimethyl-3-mercaptopropionamide and R-(-)-α-methoxyphenylthiola-

cetic acid 20 under acidic catalysis to provide a mixture of the diastereomeric

acylthioalkylthioacetals. Flash chromatography effected clean separation of the two

diastereoisomers, which were elaborated further individually. Reaction with sodium

methoxide and methyl acrylate gave the asymmetric dithioacetal 21. The

enantiomer 21 was then reacted with the ylid derived from (7-chloroquinolin-

2-yl)methyltriphenylphosphonium bromide (prepared from 7-chloroquinaldine by

photobromination and subsequent reaction with triphenylphosphine) to yield the

ester 22, which on hydrolysis provided the optically active product 19. The same

reaction sequence with the other diastereomer gave the opposite enantiomer of

the target molecule (Scheme 5).

Another orally active quinoline derivative, compound 23, has been reported by

White et al.26 The final step of the convergent synthesis was the coupling between

2-chloromethylquinoline 24 and the substituted phenol 25 (Scheme 6). The com-

pound 24 was conveniently prepared from quinaldine by conversion first to the N-

oxide, then reaction with benzenesulfonyl chloride. Synthesis of the phenol

derivative 25 began from m-hydroxyacetophenone via a kinetically controlled aldol

23

Scheme 5

OHCO

��

HSPh

O

MeO H

��

HS(CH2)2CON(CH3)2

20OHC

S

S

Ph

O

HMeO

N

OH

��

��

1. separation

2. NaOMe, COOMe

OHCS

SCON(CH3)2

COOMe��

S

SCON(CH3)2

COOMe

NCl

��

��

PPh3NCl

��

S

SCON(CH3)2

COOH

NCl

��

21

22

19

24

Scheme 6

OH

O

��

1. LDA

2. O

N

��H2O2

OH

O

NO

3. p-TsOH

��

H2, Pd/C

OH

OH

�� PhSO2Cl

NCl

��

K2CO3

NO

OH

23

24

25

25

condensation with n-butyraldehyde in the presence of LDA. Dehydration of the

crossed aldol product was carried out under acidic catalysis to give the α,β-

unsaturated kenone. Hydrogenation of the enone over palladium-on-carbon

yielded the desired alcohol 25.

Structure activity relationship studies are an important tool to improve the activity of

an initially discovered potent molecule. Very often, however, this approach is used

to modify an active compound towards reduced toxicity. Such an example is found

with L-695,499 26, which exhibited acute toxicity at high doses in mice. It was

N

S

COONa

OH

Et

Cl

��

��

26

noted that in comparison the ketone L-699,392 27 had a better overall biological

N

S

COONa

O

Et

Cl

��

��

27

profile.27 The stereospecific synthesis of 27 is shown in Scheme 7. The aldehyde

28 was prepared by condensation of 7-chloroquinaldine with 1,3-benzenedicarb-

26

aldehyde in the presence of acetic anhydride.28 Treatment of 28 with

vinylmagnesium bromide gave the allylic alcohol 29, which was treated with methyl

2-bromobenzoate in the presence of palladium acetate to give the keto-ester

30. The ketone was reduced to the alcohol 31 with high ee using Corey's reagent

(see p. 43). The ester was transformed into the activated amide 32 using the

magnesium salt of N,O-dimethylhydroxylamine. The thiol chain was introduced by

first converting the alcohol to a better leaving group, followed by displacement with

the thiolate to give compound 33. The synthesis of L-699,392 27 was completed by

reacting 33 with methylmagnesium bromide to form the methyl ketone.

A "third-generation" of receptor antagonists, which bear little structural

resemblance to hydroxyacetophenones or leukotrienes has been described by

Matassa et al.29 This new family of indole and indazole benzoic acids and their N-

arylsulfonyl amide derivatives are potent and selective LTD4 antagonists. A

compound for clinical trials, ICI 204,219 34, resulted from this investigation. The

34

N

NO

O

H

OMe

NS

O O

OH

study showed that the LTD4 receptor is surprisingly tolerant to changes in the

electronic constitution of the template.

27

Scheme 7

��

NCl

O

O+

Ac2O

NCl

O

28

��

R

MgBr ROH

29

��

CO2MeBr Pd(OAc)2

RO CO2Me

30

��Corey's

reagent

RCO2MeOH

EtMgClMeHNOMe

ROH

O NOMe

31

32

��1. MsCl, Et3N

2.HS

COOH

Me��

NaH

��

R

O NOMe

S

Me COOH

��

��

33

��

MeMgBr

27

28

This chapter covers the main approaches towards recently described leukotriene

antagonists and gives a general idea about how the activity and compatibility of a

compound, in connection with the human pathology, can be improved through SAR

studies. The significance of asymmetric synthesis is illustrated, since very often

only one enantiomer is able to interact in the desired manner with the "chiral"

environment of a biological system. Over the past few years, these efforts have

produced pharmacologically interesting molecules, some of which have been

important enough to warrant clinical evaluation.

29

1.4 Development of LY290154

In a search for novel potent leukotriene receptor antagonists, Eli Lilly developed a

highly active compound known as LY290154 35 for use to elucidate the role of the

SRS in human pathology and as a potential treatment for asthma. The structure of

NCl

N ON

NNN

NN N

N H

H

35

the LTD4 receptor site has not yet been determined. The design of binding

antagonists was, therefore, based on molecular modelling of both the natural

agonist and potential antagonists. The most important features of leukotriene D4 9

are probably an acidic group at one end, a lipophilic region at the other end and a

central planar triene-unit (Figure 4). A hypothetical receptor binding model was

designed based on these features. The low-energy conformations of potential

receptor antagonists were similarly derived and compared in size and shape with

the LTD4 structure. The initial structure activity exploration of a series of potential

antagonists led to the 2-thio-substituted quinoline compound LY231898 36.30 After

modelling of a number of possible groups the phenyltetrazole group was

selected as the part of the molecule that would fill the triene portion of the receptor.

It has approximately the same length as the triene of LTD4; each is similarly

unsaturated and flat. The phenyltetrazole also appeared to provide the appropriate

30

Figure 4

9

OH

OOH

S

H2NN

OHO

H O

��

lipophilic tail

planar region

steric determiner polar group

acid group

N S NN

NN

OHO

36

geometry for the acid and lipophilic groups. Quinoline, which is also part of the

lipophilic region of other receptor antagonists (see previous section), was shown to

increase activity. Compounds with aliphatic lipophilic substituents are essentially

inactive. Removal of the acidic group showed loss in activity, thus indicating the

significance of this substituent. Further optimisation of the compound 36 gave a

large increase in activity when the thiomethyl group was replaced by a

methyleneoxy group, possibly due in part to the shorter bond lengths associated

with the methyleneoxy linkage.31 No difference in activity was observed between

the methyleneoxy-linked compounds and those linked by a trans-olefin, a

phenomenon also found in other quinoline based series.32 Tetrazole analogues

exhibited somewhat better activity than their corresponding carboxylic acid

31

derivatives, a trend also observed in other SAR studies.22 Chlorine substitution of

the quinoline moiety at the 7-position resulted in increased activity. There is

possibly a lipophilic binding pocket at the receptor that acommodates this chlorine

atom. Other nitrogen-containing heterocycles may be substituted for quinoline

without loss of potency, e. g. benzothiazole.33 In summary, the SAR of a series of

highly potent quinoline-based, phenyltetrazole LTD4 receptor antagonists was

optimised and resulted in a 100-fold increase in activity over the parent compound

36, leading to the discovery of compound 37. Eli Lilly has since demonstrated that

NO

NN

NN

Cl

NN N

N Na

37

the incorporation of an indole moiety provided greater activity and further SAR

studies led subsequently to the development of LY290154 35. Compound 35

contains all of the important features of LTD4, namely, a lipophilic function, a

planar region, a steric determiner , an acid group, a polar group and an indole

linkage providing the correct steric orientation as shown in Figure 5.

32

Figure 5

NCl

N ON

NNN

NN N

N H

H

lipophilic tail

planarregion

steric

acid group

polar group

indole linkage

35

centre

33

1.5 Racemic Synthesis of LY290154

A racemic synthesis of LY290154 35 was achieved by Lilly and reproduced in our

laboratories using the same synthetic methodology (Scheme 8). The Finkelstein

reaction of 4-bromobutyronitrile 38 gave the corresponding iodo derivative 39 in

high yield. This was then converted into the organozinc reagent 40, which was

subsequently reacted with the aldehyde 28 to incorporate the pentanenitrile side

chain. Compound 28 was prepared from isophthalaldehyde and 7-chloroquinaldine

as described before (see p. 16). The resulting benzyl alcohol 41 was treated with

thionyl chloride to give the corresponding chloro compound 42 in essentially

quantitative yield. Coupling of the benzyl chloride 42 with 7-cyanomethoxyindole

45 in the presence of sodium hydride afforded the dinitrile 46 in very poor yield. By

far the major product from this reaction (in ~80% yield) is that derived from

dehydrohalogenation, namely the corresponding styrene . The low yielding nature

of this reaction is almost certainly a consequence of the severe steric congestion

present at the benzylic carbon in 46, and hence elimination is favoured rather than

substitution. The indole 45 was synthesised from 2-nitrophenol in three steps

according to the reported procedure.34 The cycloaddition reaction between the

dinitrile 46 and tributyltin azide proceeded smoothly to give LY290154 in modest

yield. It has recently become apparent that the yield of this last reaction can be

markedly increased just by using larger quantities of 46, and can be as high as

80%. The overall yield of racemic LY290154 35 following the Lilly procedure was

only 1% based on starting 7-chloroquinaldine.

34

Scheme 8

Br CN

��

3892%

i I CN

39

��

ii IZn CN

40

�� iii2862%

N

OHCN

Cl

41

N

ClCN

Cl

�� iv94%

42

NO2

OH

��

NO2

O

Ph

Ph

v48%

vi 54%

O

Ph

Ph

NH

��

��

ONC

NH vii

47%

��

N

N

Cl

CN

OCN

viii18%

��

35ix

38%

43

44

45

46 (i) NaI, acetone; (ii) Zn, (CH2)2Br2, Me3SiCl, THF, ; (iii) THF, TiCl4; (iv) SOCl2; (v) Ph2CHBr, K2CO3, acetone; (vi) CH2=CHMgCl, THF; (vii) H2, Pd(OH)2/C, PhMe, MeOH, BrCH2CN, K2CO3, butanone; (viii) NaH, DMF; (ix) Bu3SnN3, DME.

35

One of the most difficult decisions affecting drug companies is whether to proceed

with the development of a chiral drug as a single enantiomer or as a racemate.

Traditionally, most synthetic drugs containing chiral centres have been marketed

as racemates, despite the fact that the biological activity for the two enantiomers

can be markedly different. One obvious example is thalidomide 47, that had to be

NN

O

O O

O

H

47

withdrawn from the market as a sedative because of association of one of the

enantiomers with teratogenic effects. The separation of compound 35 into

enantiomers using classical resolution techniques has not yet been successful.

The aim of this project, was therefore, to develop a homochiral synthesis of

LY290154. This would allow full evaluation of the in vivo and in vitro biological

activities of each enantiomer.

36

2. Retrosynthetic Analysis of LY290154

LY290154 35 can in principle be synthesised from a coupling reaction between an

appropriately functionalised indole 48 and a quinoline 49 as exemplified in Scheme

9 with the dinitrile precursor 46. The two fragments could be joined together via

Scheme 9

+N O

CN

CN YNClX

NCl

N O

CN

CN

48

49

46

a) X: CHO, Y: CH2PPh3; b) X: halogen, Y: CH2=CH2

either a Wittig reaction or a Heck procedure. Wittig chemistry of this general type,

using the ylid derived from (7-chloroquinolin-2-yl)methyltriphenylphosphonium

37

bromide has already been described for the synthesis of the LTD4 antagonist

L-660,711 19. The palladium catalysed Heck coupling reaction between the halo

compound 48b and the 2-vinylquinoline 49b would need to be investigated in more

detail.

The second disconnection is rather more complex since it requires a method for

the introduction of the neccessary chirality and another for the construction of the

indole ring system (Scheme 10). Asymmetric reduction of the corresponding oxime

Scheme 10

N O

CN

CN +

NH2

CN

RCN

O

O

or NMe

NO2

48

50

X: a) CHO, b) halogen

R: NOMe or O

X

X

X

+X -

ether could directly afford the amine 50. On the other hand, reduction of the

corresponding ketone would first give the optically enriched alcohol. Substitution of

the hydroxy group with an appropiate nucleophile (e. g. azide) and reduction would

38

than led to the key intermediate 50. Reaction of compound 50 with

7-oxotetrahydrobenzofuran or an N-methyl-3-nitropyridinium salt (for details on the

synthesis of indoles from 3-nitropyridinium salts see chapter 5) could result in

formation of the required indole moiety, in the former case after aromatisation. All

of these transformations would need to proceed without racemisation of the

products in order to fulfil the aim of this project.

39

3. Preliminary Results

The racemic synthesis of the indole derivative 48a was required in order to study

the possibility of a Wittig reaction with the quinaldine derivative 49a. Coupling of

49a

NClPPh3

48a

N

CN

OCN

O

the chloride 51 with 7-cyanomethoxyindole (45) could result in formation of the

desired product 48a. Compound 51 should be readily accessible from the alcohol

51

ClCN

O OHCN

O

52

52, applying the Lilly methodology. 3-Bromobenzaldehyde was therefore reacted

with ethyleneglycol in the presence of p-toluenesulfonic acid (TsOH) to give the

acetal 53 in good yield, according to the published procedure35 (Scheme 11). This

acetal proved highly acid sensitive, and was cleaved under the most mild acidic

conditions. Lithiation of 53 with n-BuLi and quenching with N-formylpiperidine

gave the monoprotected isophthalaldehyde 54 in excellent yield. The reported

acidic work-up had to be avoided, because under these conditions complete

40

Scheme 11

O

Br BrO

O��

HOOH

TsOH

��n-BuLi

N

O

O

O

O

94% 93%53 54

hydrolysis of the acetal occurred.36 This two step route to 3-(1,3-dioxolan-2-

yl)benzaldehyde (54) was found to be superior to the one step acetalisation of

isophthalaldehyde using ethyleneglycol and TsOH in benzene, which required a

difficult chromatographic isolation of the product 54.37 Reaction of the aldehyde 54

with the zincate 40 in the presence of titanium tetrachloride, however, did not result

in formation of the expected alcohol 52 after hydrolysis, but gave the ether 55 in

low yield (Scheme 12). The organometallic reagent had reacted preferentially with

Scheme 12

��

IZn CN

40

TiCl4

OCN

OHO

22%

54

55

the acetal instead of the carbonyl group. The remaining product was shown to be

isophthalaldehyde, derived from hydrolysis of the acetal 54. When the reaction was

performed without Lewis acid catalyst only starting material could be recovered.

Treatment of 3-bromobenzaldehyde with the zincate 40, however, gave the

expected alcohol 56 in moderate yield (Scheme 13). The corresponding chloro

41

compound 57 was easily prepared, in almost quantitative yield, from 56 by simple

Scheme 13

BrO

��40TiCl4

Br CNOH

57%

56

stirring in thionyl chloride. Coupling of the indole 45 with the benzyl chloride 57 was

accomplished by preforming the sodium salt of 45 using sodium hydride, followed

by the addition of 57 (Scheme 14). The racemic dinitrile 48b was obtained in low

Scheme 14

40%

NaH��

98%57

Br CNCl

SOCl2��

56

BrN

CN

OCN

48b

45

yield, the major product being the olefin 58. Attempted coupling of the indoline 59

CNBr

58

42

with the benzyl chloride 57 under the same conditions, in the hope of obtaining a

better yield, led only to formation of 58. The indoline 59 was obtained by routine

reduction of the indole 45 with sodium cyanoborohydride in acetic acid (Scheme

15).38

Scheme 15

NHONC

��NaBH3CN

NHONC

90%45 59

AcOH

The failure to obtain the alcohol 52, required to exploit Wittig type chemistry, and

the successful preparation of the indole derivative 48b, indicated that the Heck

coupling was almost certainly going to be the method of choice for joining the

fragments 48 and 49 together. Nevertheless, reaction of 54 with 1,3-propanedithiol

in the presence of aluminium chloride, following the procedure described by Ong,39

yielded the corresponding monoprotected aldehyde 60 and the known bis-dithiane

61 in 8 and 28% yield respectively (Scheme 16). Several other spots were also

present in the reaction mixture, but the compounds could not be isolated. Again the

nucleophile reacted preferentially with the dioxolane instead of the aldehyde group.

None of the expected 1-(1,3-dioxolan-2-yl)-3-(1,3-dithiane-2yl)benzene (62) was

obtained. The same reaction, but with isophthalaldehyde and one equivalent of

the sulfur component, gave the desired product 60 in a slightly better yield (14%,

Scheme 16) together with the unwanted bis-dithiane 61 (14%). This reaction

proceeded much more cleanly than the previous one, and the only other

component in the product mixture was unreacted isophthalaldehyde. Reaction

43

Scheme 16

O

O

��HS SH

OO

O

54

S

SS

S

+

OS

S

60

AlCl3

61

S

SO

O

62

of compound 60 with the zincate 40 in the presence of titanium tetrachloride

afforded the alcohol 63 in low yield; most of the starting material was still present

in the product mixture (Scheme 17). This time no cleavage of the dithiane group

Scheme 17

63

S

S

OHCN

S

S

O

��40

60

TiCl4

22%

44

occurred, as had previously been observed with the dioxolane moiety. Now the

alcohol 52 could be accessible by conversion of the dithiane to the aldehyde

group, making the alternative Wittig reaction again a possibility.

The synthesis of the counterpart for the Heck coupling reaction, namely the

vinylquinoline 49b, was achieved by Dr. M. W. J. Urquhart at UEA using a novel

procedure.40 Thus, reaction of the anion derived from 7-chloroquinaldine with

diethyl chlorophosphonate gave a mixture of the ester 64 and unreacted quinaldine

(Scheme 18). The addition of a further equivalent of LDA to this mixture resulted in

Scheme 18

NCl

��1. LDA

NClP(OEt)2

O

2. (EtO)2POCl

71%

��

1. LDACH2O2.

NCl

58%49b

64

the disappearance of the quinaldine, and the ester 64 was isolated in good yield.

The ylid derived from 64 was then treated with paraformaldehyde to give the

desired vinylquinoline 49b in moderate yield. Work undertaken by Dr. R. A. Lewth-

waite at UEA showed that the vinylquinoline 49b could be successfully coupled

with the racemic dinitrile 48b in the presence of Pd(dppp)Cl2, to give the dinitrile

45

precursor 46 to LY290154 itself41 (Scheme 19). This important result made clear

Scheme 19

49b

60%46

NCl

N

CN

OCN

MeCNEt3NPd(dppp)Cl248b

��

BrN

CN

OCN

+ NCl

��

��

��

��

��

��

��

��

��

��

��

��

��

that the next goal in the asymmetric synthesis of the target compound 35 was to

achieve the homochiral preparation of the indole derivative 48b. This target would

be approach as outlined in the previous chapter (second disconnection). The

amine 50b had therefore to be synthesised. How we succeeded to produce this

crucial intermediate in a enantiomerically enriched form is discussed in the next

chapter.

46

4. Asymmetric Amine Synthesis

Extensive research during the past twenty five years has led to the discovery of a

number of catalysts based on transition metal complexes for the enantioselective

homogeneous hydrogenation of olefins and ketones. In contrast, the analogous

reduction of the C=N double bond, which represents a potentially important me-

thod for the synthesis of enantiomerically enriched amines, has received much less

attention. Most of the procedures reported so far involve the hydrogenation of

N-substituted imines under high pressure, using rhodium42-46 and iridium47,48

complexes of chiral bisphosphines to yield optically active secondary amines. The

proximity of an aromatic ring to the C=N bond appears to be essential for high

enantioselectivity. The RhI/(R)-cycphos (cycphos = 1,2-bis(diphenylphosphino)-1-

cyclohexylethane, 65) catalyst, for example, was shown to be inefficient for the

65

PPh2

PPh2

asymmetric hydrogenation of aliphatic imines.42,43 On the other hand, imines

derived from benzylamine and aniline were reduced with optical yields of up to

69% ee. The addition of halide ions, preferably iodide, can result in improved

enantioselectivity up to 91% ee.

The catalytic properties of water soluble complexes with sulfonated derivatives of

(1S,2S)-1,2-bis(diphenylphosphinomethyl)cyclobutane (66), (2S,4S)-2,4-bis(diphe-

nylphosphino)pentane (BDPP, 67), (2S,3S)-2,3-bis-(diphenylphosphino)butane

(CHIRAPHOS, 68) and (2R)-1,2-bis(diphenylphosphino)propane (PROPHOS, 69)

47

PPh2

PPh2

H

H

��

PPh2 PPh2

��

PPh2

PPh2

��

PPh2

PPh2

66 67 68 69

have been reported. Asymmetric hydrogenation of a benzylimine occurred in an

aqueous-organic two-phase solvent system using a rhodium complex of

tetrasulfonated 67 under high pressure, but only a 34% ee was obtained. The

same reaction, but with a mixture of the mono-, di- and trisulfonated ligand, gave

an optical yield of 58%.44 Other hydrogenations of N-benzylimines under similar

conditions, but using the monosulfonated derivative of 67, gave the corresponding

amines with 92-94% ee, whereas the disulfonated ligand showed no

enantioselectivity.45 The primary advantages of this catalytic system are the ease

of the workup and the ability to recover and reuse both the rhodium and the

optically active bisphosphine. Lensink and Vries reported the hydrogenation of

chiral imines derived from optically pure α-methylbenzylamines.46 With a rhodium-

BDPP 67 catalyst diastereoselectivity of up to 99.8% was obtained. The chiral

diphosphine ligand 2,2-dimethyl-4,5-bis(diphenylphosphinomethyl)-1,3-dioxolane

(DIOP, 70) was not as selective. Other 2-carbon bridged ligands like PROPHOS

O

O PPh2

PPh2

��

70

and CHIRAPHOS were not selective at all.

The results indicated that the selectivity of the hydrogenation of chiral imines is

mainly substrate controlled. Low enantioselectivities with catalysts prepared from

iridium(I) and 1,2-diphosphino ligands like CHIRAPHOS 68 and 5,6-bis(diphenyl-

48

phosphino)norbornene (NORPHOS, 71) have also been reported by Spindler et

71

Ph2P

Ph2P

��

al.47 With ligands which can form conformationally flexible six- or seven-membered

metallacycles, e. g. BDPP 67, DIOP 70 or t-butyl-4-(diphenylphosphino)-2-(diphe-

nylphosphinomethyl)-1-pyrrolidinecarboxylate (BPPM, 72) better results were

72

NBOC

Ph2PPPh2

��

��

obtained. Effective asymmetric reductions of N-substituted prochiral imines using

iridium(III)/diphosphino complexes (diphosphines = BDPP 67, DIOP 70 and

NORPHOS 71) in moderate to good optical yields have been carried out.48

Interestingly, Noyori's 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 73) was

PPh2

PPh2

��

��

��

��

��

73

49

ineffective in terms of both the rate and enantioselectivity of the hydrogenation.

Asymmetric hydrogenations of imines with a chiral titanium catalyst containing a

nonphosphine ligand have been studied by Willoughby and Buchwald.49-51 The

chiral auxiliary used was 2,2'-dihydroxy-1,1'-binaphthyl (74). While the reduction of

OHOH

��

��

��

��

74

acyclic N-substituted substrates proceeded with moderate to good enantioselec-

tivity, cyclic imines were transformed to the corresponding amines in excellent

optical yield. In the former case the enantiomeric excesses of the products with

large N-substituents correlated roughly with the anti/syn ratios of the imines. A

proposed model predicts that syn and anti imines react to give the amine with

opposite absolute configuration, thus lowering the optical purity. Furthermore, high

hydrogen pressures were required to achieve the maximum ees.

The chemical yields in the transition metal catalysed hydrogenations of imines are

generally high, making this process an attractive procedure for the synthesis of

homochiral amines. The major disadvantages are the necessity for expensive

chiral catalysts, the high pressures required, and the fact that only secondary ami-

nes can be prepared in this way.

A method for the preparation of optically active primary amines using a chiral

rhodium catalyst has been described by Burk and Feaster.52 In comparison with

other chiral diphosphines such as BDPP 67, CHIRAPHOS 68 or BINAP 73, Et-

DUPHOS 75 proved to be the most effective ligand. The synthesis consisted of the

50

P

P

EtEt

Et

Et

��

��

��

��

75

asymmetric hydrogenation of the C=N group of N-acylhydrazones of aryl alkyl

ketones and α-keto esters, followed by cleavage of the N-N bond with samarium

diiodide (Scheme 20). In contrast to the other procedures described so far, high

enantioselectivities were obtained at low hydrogen pressures. The reaction with

samarium diiodide occurred spontaneously with no loss of optical purity.

Scheme 20

R R'

NH2��

SmI2

��

R R'

NNH

R"

O

H ��

Rh(I) 75��

��

R R'

NNH

R"

OR"CNHNH2

O

��

R R'

O

H2

51

In 1985, Itsuno reported the enantioselective reduction of ketones and oxime

ethers with reagents prepared from borane and chiral vicinal amino alcohols. The

best results for the synthesis of optically active primary amines were obtained from

borane reduction of acetophenone O-methyloximes in the presence of the amino

alcohol 76.53 High stereoselectivity (up to 99% ee) was always attained with the

H2N OH

PhPh

��

76

reagent prepared from a 1:2 molar ratio of amino alcohol and borane, whereas the

reduction with a 1:1 molar ratio resulted in disappointingly low enantiomeric ex-

cesses. Reductions of oximes and their derivatives have also been carried out with

baker's yeast, but only modest ees were obtained.54

Corey et al. found that a fast reaction occurred between amino alcohol 76 and 2

equivalents of borane to give 2 equivalents of hydrogen gas and the

oxazaborolidine 7755 (Scheme 21). Solutions of 77 alone did not reduce ketones,

Scheme 21

7877

N O

PhPh

BHH3B

H

��BH3��

N O

PhPh

BH

H

��BH3

��

76

however, but mixtures of 77 and borane effected complete reduction of

acetophenone with rates comparable to the Itsuno mixtures. 11B-NMR spectra of

52

mixtures of 77 and borane clearly indicated the formation of a 1:1 complex 78. It is

now possible to derive a reasonable mechanism for the enantioselective reduction

of oxime ethers, analogous to that postulated for the reduction of ketones, based

on the above results. It could occur by coordination of the electrophilic ring boron in

complex 78 with the C=N nitrogen and hydrogen transfer from the NBH3- unit to

the carbon via a six-membered cyclic transition state, as formulated in Scheme

22. Further reaction with BH3 and hydrolysis of the borane intermediates would

Scheme 22

N O

PhPh

BH2B

H

H

H

R'R

NOR"

��

��

��NOR"

H

H

H2BB

PhPh

ON

R'R

H

��

��

��

H

H

H3BB

PhPh

ON

��

BH3N

R'R

H

H2B OR"

��

+

��BH3

N

R'R

H

OR"B

H

H2B

HH

��

��

��NHBH2

R'R

H

�� R"OBH2+

�� H2ONH2

R'R

H��

�� + R"OH

yield the corresponding alcohol and the optically active primary amine. The highly

effective oxazaborolidine catalyst 79, known as Corey's reagent, for the

N OB

PhPh

HH3B

79

53

asymmetric reduction of prochiral ketones resulted from this study. For the

enantioselective reduction of N-substituted imines, however, Itsuno's reagent 78

was found to be superior.56 All the ketimines examined were reduced to the

corresponding amines in essentially quantitative yields. In the reduction of N-

phenyl aromatic ketimines, consistently high optical yields were obtained. In

contrast, the reduction of N-alkyl ketimines provided lower optical induction. This

observation is in accordance with the transition metal catalysed hydrogenation of

imines, where the proximity of an aromatic ring to the C=N bond was also found to

give higher enantioselectivities.

More recently, a different approach for the synthesis of optically active primary

amines has been described. The general procedure is to condense a prochiral ke-

tone with a chiral amino alcohol to give a chiral Schiff base (Scheme 23).

Scheme 23

8280, 81 [H]

80: R" = Ph, R''' = H81: R" = iPr, R''' = H82: R" = Me, R''' = Ph

R R'

NH2��

NaIO4��

R R'

N

R"OH

R'''

H ��

��

R R'

N

R"OH

R'''

R"

R'''H2N

OH��

��

R R'

O

Reduction of the imine by an achiral catalyst such as Pd/C or PtO2, and oxidative

cleavage of the chiral auxiliary with periodate provides the corresponding amine.

Miao et al. obtained optical yields in the range of 40-60% using (R)-phenylglycinol

(80) and (R)-valinol (81),57 whereas Sreekumar and Pillai reported enantiomeric

54

excesses between 54 to 66% using norephedrine (82) as the chiral inducing

agent.58

A related procedure involves the diastereoselective addition of allylmetal

compounds to imines prepared by the condensation of aldehydes with esters of

(S)-valine.59 Excellent results were obtained with allyl bromide and zinc in the

presence of catalytic amounts of CeCl3 or SnCl2 (de up to 100%). Reduction of the

ester function in 83, followed by oxidative cleavage with periodic acid in the

presence of methylamine, afforded the primary homoallylic amine 84 86% optically

pure (Scheme 24). Further functionalisation of the C=C bond would allow the

Scheme 24

Ph NOR'

O

��M Ph NOR'

OH��

��

1.

2. H2O

LiAlH4

Ph NH

OH

��H5IO6

MeNH2

Ph NH2��

83

84

synthesis of a variety of derivatives of such homochiral amines.

An approach for the synthesis of homoallylic amines based on SAMP/RAMP

hydrazones has been described by Enders et al.60 As shown in Scheme 25 , the

reaction of aldehydes with SAMP [(S)-1-amino-2-methoxymethylpyrrolidine (85)] or

RAMP [(R)-1-amino-2-methoxymethylpyrrolidine (86)] gave the corresponding

55

Scheme 25

R

O ��

NNH2

OMe

85: (S)86: (R)

R

NN

OMe

��

R

NN

OMe

MeO

O

��

R

NMeO

OH

1. M2. MeOCOCl

88

87

Li

NH3

hydrazones in high yields. Subsequent 1,2-addition of the in situ prepared

allylcerium reagent or allyl Grignard reagent to the CN-double bond of the

hydrazone 87 occurred with good yields and with high diastereoselectivities. The

intermediates were trapped with methyl chloroformate to obtain the carbamate

protected hydrazines 88. In contrast to the previous method, where no reaction

between allylcerium reagents and homochiral imines occurred, in this study they

were found to be superior to the corresponding Grignard derivatives. The

carbamate-protected hydrazines were cleaved by lithium in ammonia to the homo-

allylamines in good yields and without racemisation. This work represents a

continuation of the asymmetric reductive amination of ketones for the synthesis of

optically active primary amines from the corresponding SAMP/RAMP-hydrazones

described previously by the same author.61

56

A different borane reagent for the asymmetric reduction of imines has been

described by Kawate et al.62 These authors found that treatment of N-substituted

imines with chiral dialkoxyborane reagents in the presence of MgBr2.OEt2 gave the

corresponding amines in high chemical yields and moderate to good enantiose-

lectivities. Without MgBr2.OEt2 the reaction did not take place. The borane reagent

of choice found in this study was the tartaric acid derivative 89.

89

OB

O OMeOMe

H��

Chiral sodium triacyloxyborohydrides 90, easily obtained from the reaction of

NaBH4 and N-acyl derivatives of optically active α-amino acis, are reported to be

90

NaBH

3

R N CO2

O

R'

R"

��

excellent reducing agents for cyclic imines, and optical yields of up to 95% have

been achieved. 63-65

The catalytic asymmetric hydrosilylation-hydrolysis procedure is an indirect method

of forming optically active secondary amines from N-substituted imines (Scheme

26). The reactions are carried out under mild conditions using a chiral

rhodium-phosphine catalyst such as [Rh(I)-DIOP] 91, with a best result of 65% ee

being obtained.66

57

Scheme 26

O

O

PRh

P

Cl

solvent

Ph

Ph Ph

Ph��

91

R R'

NHR"��H+ ��

R R'

NR" SiHPh2��

��

91

Ph2SiH2 ��

R R'

NR"

Chiral non-racemic sulfur reagents have found application in the asymmetric

synthesis of primary amines. Addition of the lithiated imine generated by the

reaction of methyllithium with benzonitrile to sulphinamide 92 resulted in clean

formation of the benzylidene sulphinamide 93 as a single diastereoisomer

(Scheme 27). Reduction of 93 with diisobutylaluminium hydride (DIBAL) gave the

diastereomeric products 94 and 95 in a 13:1 ratio. Treatment of this mixture with

methanolic trifluoroacetic acid, followed by the addition of hydrochloric acid,

resulted in formation of α-methylbenzylamine (96) with an optical purity of 86%.

The sulphinic acid 97 may be recycled after use and this method represents the

first example of a reagent of this type.67 More recently, Bolm and Felder have

reported the use of β-hydroxy sulfoximines in catalysed enantioselective amine

syntheses,68 as previously described for the asymmetric reduction of ketones.69,70

In the presence of (S)-98, reduction of ketimine derivatives with BH3.SMe2

occurred smoothly at ambient temperature. The N-substituent of a given ketimine

derivative had a major influence on the asymmetric induction. Ketoxime thioethers

58

Scheme 27

97

96

��

+

SO2H

N

OH

Ph NH2

��

2. HClCF3CO2H1. ��

��

9594

SN Ph

O

N

OH

H��

+

SN Ph

O

N

OH

H

��

��

DIBAL

��

93

SN Ph

O

N

OH

��

92

��+

Ph

NLi

NSO

O

��

��

59

98

PhS

Ph

N

O

OH H

Ph

��

gave the highest enantioselectivities (up to 70% ee). The more easily accessible

ketoxime O-ethers, however, gave significantly lower enantioselectivities.

Initial studies on the asymmetric addition of organolithium reagents to N-(4-

methoxybenzene)aldimines in the presence of bis-oxazolines 99 and (-)-sparteine

100 have been described by Denmark et al.71 Optical yields of the corresponding

N

O

N

O

R R

R' R'

NN

��

��

99 100

secondary amines in the range of 30-91% were obtained for aromatic, olefinic and

aliphatic aldimines.

A totally different method, where the chirality is not introduced via the nitrogen-

containing precursor, is to start with an optically active alcohol. Chelucci et al., for

example, converted homochiral hydroxyalkylpyridines 101 into the azides 102 via

the non-isolated mesylates72 (Scheme 28). The azides 102 were reduced by

hydrogen on Pd/C to the corresponding aminopyridines 103 in good overall yields

and enantiomeric excesses in the range 66-92%.

60

Scheme 28

103

102101

H2Pd/C

NaN3

NR'

NH2

R

��

NR'

OMsR

�

NR'

N3

R

��

Et3N

MsCl ��

NR'

OHR

��

61

4.1 Results and Discussion

The mild conditions and readily available reagents for the reduction of oxime

ethers to optically active primary amines made the Itsuno procedure the initial

method of choice for the synthesis of the required enantiomerically enriched amine

50b*. The homochiral auxiliary 76 was synthesised by reaction of commercially

available L-valine methyl ester hydrochloride with an 8 fold excess of phenyl-

magnesium bromide (prepared in situ) according to the reported procedure53

(Scheme 29). For a model study, the O-methyl oxime 104 was obtained in high

Scheme 29

40%

OMe

O

H2N

��

.HCl

��1. PhMgBr

2. NaOH OHH2N

PhPh

��

76

yield as a mixture of stereoisomers from valerophenone and methoxylamine

hydrochloride in the presence of sodium acetate using the method of Karabatsos

and Hsi73 (Scheme 30). Reduction of compound 104 with a borane-THF complex

led to racemic 105 in modest yield.74 Asymmetric reduction of 104 with Itsuno's

reagent 78, generated in situ from BH3.THF and the optically active amino alcohol

76, at room temperature gave the enantiomerically enriched amine 105* in similar

yield. The enantiomeric excess was determined by proton NMR spectroscopy

using 2,2,2-trifluoro-(9-anthryl)ethanol (TFAE, 106) as the chiral solvating agent

and found to be 70%. The chiral auxiliary 76 was recovered without loss of optical

purity.

62

Scheme 30

104

47%

BH3.THF

NH2

O

��OMe

N

105

.HCl

52%

ONB

Ph

Ph

H

H

H3B

��

78

��MeONH2

91%

NaOAc.H2O

70% ee

63

OHF3C

106

The ketone 110, required to study the real system, was prepared in 35% overall

yield as shown in Scheme 31. 3-Bromobenzaldehyde was reacted with sodium

Scheme 31

��

98%

83%86%

50%110 109

108107

BrO

CN BrCN

NMe2

CN

2.1. LDA/TMEDA

Br(CH2)3CN��

BrNMe2

CN

��

Me2NH

NaCN

BrSO3Na

OH

��

NaHSO3Br

O

CuSO4.5H2O

hydrogen sulphite to give the adduct 107. The crude sulphonate 107 was

treated with dimethylamine and then sodium cyanide to give the aminonitrile 108

in high yield. Treatment of 108 with LDA, generated in situ from reaction of

diisopropylamine and n-butyllithium, followed by reaction with 4-bromobutyronitrile

gave compound 109 in essentially quantitative yield.75 The ketone 110 was

obtained by refluxing 109 in the presence of copper(II) sulphate pentahydrate. The

64

corresponding O-methyl oxime ether 111 was obtained in good yield following the

same method as before (Scheme 32). Borane reduction of 111, however, did not

Scheme 32

CNNH2

Br

CNN

Br

OMe

��

77%MeONH2

��

��

BH3 THF or

NH4OAc

NaBH3CN

13%

110

111

50b

78

NaOAc

.

lead to the required amine 50b with either BH3.THF or reagent 78; instead, a

product was obtained which could not be characterised from its proton NMR

spectrum. Competitive reduction of, and/or complexation of the boron reagent with,

the nitrile group in 111 was probably the reason for the disappointing result. The

racemic synthesis of the amine 50b could be achieved through reductive amination

of the ketone 110 with sodium cyanoborohydride, but only in a very poor yield.76

The same result was found with valerophenone, and the amine 105 was obtained

in only 11% yield after the mixture was left to react for 3 days. This particular

reaction was found to be very slow and most of the starting ketone could be

recovered.

65

Further attempts to reduce the functionalised O-methyl oxime ethers 113 and 114

with borane were also unsuccessful, presumably for the same types of reasons as

referred to above (Scheme 33). The oxime ethers 113 and 114 were best

Scheme 33

BH3.THFor 78��

��

113: R' = H, 39%114: R' = (CH2)3CN, 86%(CH2)3CN112: R' =

28: R' = H

R

R'R

NH2

N

R'R

OMe

pyridine

��

O

R'NCl MeONH2.HCl

synthesised under non-aqueous conditions, because of the insolubility of the

starting materials 28 and 112.74 The ketone 112 was obtained in moderate yield

from Swern oxidation of the benzyl alcohol 4177 (Scheme 34).

Because of the failure to obtain the enantiomerically enriched amine 50b* via the

asymmetric reduction of the corresponding O-methyl oxime ether 111 using

Itsuno's reagent 78, a different approach had to be considered.

Condensation of 3-bromobenzaldehyde with amino alcohol 76 in the presence of

anhydrous MgSO4 gave the corresponding homochiral imine 115 in essentially

quantitative yield 57 (Scheme 35). It was hoped that diastereoselective addition of

66

Scheme 34

60%11241

DMSO

TFAA��

OR CNR CN

OH

R = 7-chloro-2-vinylquinoline

Scheme 35

116

NBr

Ph

OHPh

H

CN

��

TiCl4

40IZn CN

��

98%

OBr ��76

NBr

Ph

OHPh

��

115

MgSO4

��

67

the zincate 40 in the presence of titanium tetrachloride would afford the optically

active amine 116. The chiral auxiliary would then be removed, giving the required

enantiomerically enriched amine 50b*. Unfortunately, no reaction between

compound 115 and the organometallic reagent 40 was observed (for a review on

organozinc reagents see ref78). A different approach was therefore pursued.

Thompson et al. reported a new method for the conversion of alcohols into their

corresponding azides with inversion of configuration using diphenylphosphoryl

azide (DPPA) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).79 The method is

operationally simple and racemisation was typically less than 2%. Racemic benzyl

alcohol 56 was therefore converted to the azide 117 in good yield using the same

conditions (Scheme 36). Reduction of the azide 117, however, was not as

Scheme 36

5678%

DBU

Br CNN3

Br CNOH

117

��

DPPA

straightforward as expected (see Table 1). Stanovnik et al. found that the azido

group could be easily reduced by a diazo transfer reaction using acetylacetone in

the presence of triethylamine.80 The azide 117, however, did not react under the

conditions reported by Stanovnik (Entry 1). Attempts to hydrogenate 117

catalytically with Pd/C or Adam's catalyst led only to a mixture of products from

which the desired amine could not be isolated81,82 (Entries 2 and 3). Reduction

with sodium hydrogen telluride afforded the amine 50b, but only in a very poor

68

Table 1 Attempted reductions of azide 117 to amine 50b using different reducing

agents

50b

��

117

Br CNNH2

Br CNN3

Entry Reducing Agent Yield [%]

1 (CH3CO)2CH2 starting material

2 Pd/C/H2 "

3 PtO2/C mixture

4 NaBH4/Te 7

5 Ph3P/HCl 9

6 NaBH4/CuSO4 12

7 NaBH4/PTC 30

8 HS(CH2)3SH 60

yield83 (Entry 4). Most of the product was shown to be unreacted starting material.

When the azide 117 was reacted with triphenylphosphine spontaneous evolution of

nitrogen was observed, and tlc analysis showed that the reaction was complete

after one hour. The Staudinger product 118, however, was found to be very stable

69

BrN

CN

PPh

PhPh

118

towards hydrolysis (for reviews on azides and the Staudinger reaction see ref84

and ref85 respectively). Treatment of the iminophosphorane 118 with dilute

hydrochloric acid, for example, gave the required amine 50b in only 9% yield

(Entry 5). Reduction of 117 with sodium borohydride in the presence of copper(II)

sulphate, following the recent method described by Rao and Siva,86 gave again a

very low yield of the desired product (Entry 6). A better yield was obtained with

aqueous sodium borohydride under phase-transfer catalysis87 (PTC, Entry 7).

Finally, the amine 50b could be prepared in moderate yield by reaction of the

azide 117 with 1,3-propanedithiol in the presence of triethylamine88 (Entry 8).

The optically active series required the homochiral benzyl alcohol 56*. This

compound would be available from asymmetric reduction of the corresponding

ketone 110. The ketone 110 was obtained in a better overall yield than previously

described by oxidation of compound 56 under Swern conditions (Scheme 37).

Asymmetric reduction of 110 was best achieved with Itsuno's reagent 78 (see

Scheme 37

BrOH

CN

��DMSO

TFAA

BrO

CN

56 11084%

70

Table 2 Asymmetric reductions of ketone 110 to alcohol 56* using different chiral

reducing agents

O

CNBr CNBrOH

*

110 56*

Entry

Chiral reducing agent

Yield [%]

ee [%]

1

N COO-

O PhO3

NaBH

120

starting material

2

DIP-Cl 119

starting material

3

Corey's reagent 79

65

66

4

Itsuno's reagent 78

70

80

Table 2, Entry 4). Corey's reagent 79, however, was less effective89 (Entry 3). The

discovery of oxazaborolidines for the enantioselective reduction of prochiral

ketones has raised enormous interest in the synthetic community since the

pioneering work by Itsuno and Corey. Recently, new enantioselective catalysts of

this class have been developed using different optically active 1,2-amino alcohols

and borane reagents.90-101 Diaza analogues have also been reported.102 From the

many chiral borane reagents developed by Brown, commercially available (+)- or

(-)-diisopinocampheylchloroborane (DIP-Cl, 119) has been reported to be an

71

2

BCl

119

excellent reagent for the asymmetric reduction of aryl alkyl ketones.103-105

Reduction of aryl alkyl ketone 110 with this reagent, however, led only to recovery

of the starting material (Entry 2; for a review on asymmetric reductions with

organoborane reagents see ref106). The chiral sodium triacyloxyborohydride 120,

easily prepared from optically active N-benzyloxycarbonylproline and sodium

borohydride, which has been reported to reduce cyclic imines with excellent

enantioselectivities (see p. 47), did not react with compound 110 (Entry 1).

Conversion of the optically active alcohol 56* to its corresponding enantiomerically

enriched azide 117* was successfully achieved following the same method as for

the racemic series. Reduction of the azide 117* with 1,3-propanedithiol gave the

required amine 50b* in moderate yield without loss of optical activity. The

enantiomeric excesses of 117* and 50b* using TFAE as the chiral solvating agent

could not be determined because of lack of complexation.

With the chiral building block 50b* in hand, the remaining major challenge was to

construct the indole ring system in 48b. This is discussed in the following chapters.

72

5. Synthesis of Indoles

From the many methods which have been developed for the preparation of

indoles, the two that were of particular interest for the present project, namely the

Bartoli indole synthesis and the synthesis of indoles by the reaction of 3-

nitropyridinium salts with N-alkylketimines, are discussed in this chapter (for a

review on recent developments in indole synthesis see ref107).

5.1 Bartoli Indole Synthesis

In 1989 Bartoli and his co-workers discovered that reaction of three equivalents of

vinylmagnesium bromide with one equivalent of a nitroarene resulted in formation

of an indole.108 With less Grignard reagent no indoles could be isolated.

Satisfactory results were only obtained when the nitroarene was ortho substituted.

4-Chloro- and 4-bromonitrobenzene, for example, gave the corresponding indoles

in only 17 and 12% yield respectively. With 3-substituted arenes mixtures of the 4-

and 6-substituted indoles were obtained, but also in very low yields. Preliminary

mechanistic studies showed that nitroso arenes reacted with two equivalents of the

Grignard reagent to afford the corresponding indoles, suggesting that the first

stage of the reaction with nitroarenes involved reduction to nitrosoarenes by one

equivalent of the vinylmagnesium reagent.109,110 Direct evidence of nitrosoarene

involvement was obtained from GC-MS analysis of the reaction mixtures.

Nitrosoarene 121 could arise by attack of the carboanionic vinyl Grignard reagent

at the oxygen atoms of the nitro group, followed by elimination of the enolate of the

O-alkylated derivative (Scheme 38). The proposed mechanism explains the indole

formation via a 1,2-addition to the N=O double bond of 121 followed by an oxaza

[3,3] sigmatropic rearrangement of the N-aryl-O-vinylhydroxylamino magnesium

73

Scheme 38

OMgBr��

RN

O

��

RN

O

OMgBr

��

��

BrMgR

NO

O

121

MgBr

N

R H

H+

��

RN

O

MgBr

��

122

��

RNMgBr

O

��

��N

R

OMgBr

H

MgBr��

��

��

��

��

N

R

OMgBr

H

MgBr

123

124 125

salt 122. Attack of the aldehyde group by the negatively polarised nitrogen gives

the cyclised product 123. Aromatisation of the benzene ring, assisted by the third

equivalent of the vinyl Grignard reagent, leads to the intermediate 124, acidic

workup of which yields the corresponding indole 125.

In conclusion, the Bartoli indole synthesis represents one of the best methods for

the preparation of 7-substituted indoles, as exemplified in the Lilly synthesis of the

7-cyanomethoxyindole 45.34

74

5.2 Conversion of 3-Nitropyridinium Salts into Indoles

The mechanism of an earlier reported synthesis of indoles, by the reaction of 3-

nitropyridinium salts with N-alkyl-2-ketimines (Method A) or with mixtures of the

corresponding ketones and amines (Method B), has been discussed at length by

Yurovskaya et al.111 Table 3 summarises some of the results reported by the

Table 3 Conversion of 3-nitropyridinium salts into polyalkylindoles

MeNH2

NR

Me

RR

RR

2

4

5

6

7

RN

Me

7

NMe

R

RR

R NO2

2

4

5

6

��

X

+ HXHNO2

Entry

R2

R4

R5

R6

R7

Yield [%] A B

1

H

H

H

H

H

0

2

Me

H

H

H

H

3

7

3

H

Me

H

H

H

11

5

4

H

H

Me

H

H

0

5

Me

Me

H

H

H

22

6

Me

H

H

Me

H

4

6

7

H

Me

H

Me

H

13

10

75

8

Me

Me

H

Me

H

62

9

Me

H

Me

Me

H

87

10

Me

Me

Me

Me

H

55

11

11

Me

Me

Me

Me

Me

57

52

Russian workers. The yield of the reaction generally increases with the number of

alkyl substituents, and can be up to 87% (Entry 9). With non-substituted 3-

nitropyridinium salts, however, no indole formation was observed (Entry 1).

Initially, a "molecular design" for the formation of the indole skeleton from the

structural fragments of the starting materials was described (Scheme 39).

Scheme 39

��

��

NR

R

RR

R NO2

2

4

5

6+

��

1R R

N

��

��

72

34

5

6

��

��

NR

R

RR

RR

��

��

��

1

2

4

5

6

7

234

5

6

Reaction of 1,2,4,6-tetramethyl-3-nitropyridinium iodide with N-cyclohexyl

isopropylimine showed that the nitrogen atom in the resulting indole originated

from the imine moiety and not from the pyridinium salt. The C2-C3 moiety of the

pyridinium cation is incorporated in the construction of the pyrrole ring, and the C4-

C5-C6 block in the formation of the benzene ring. The three carbon moiety of the

imine is inserted between the above mentioned fragments, that is, in the formation

of both rings of the indole molecule, with R7 occupying the 7 position. These rules

76

were established by the introduction of alkyl substituents into different positions of

the 3-nitropyridinium ring, and by using a mixture of acetone-d6 and methylamine.

The suggested mechanism of this rather complex process involves a presumably

stepwise 4,6-meta-bridging of the enamine form of the 2-ketimine to the 3-nitro-

pyridinium cation 126 to give the bicyclic compound 127, as shown in Scheme 40.

Ring opening of compound 127 in a retro-Michael type fashion generates the

intermediate 128 with a non-aromatic six-membered ring. Attack of the β-carbon of

the cyclic enamine 129 at the carbon adjacent to the nitro group eliminates nitrite

and forms the fused cyclopropane system 130. Opening of the three-membered

ring takes place with aromatisation of the six-membered ring to give 131.

Compound 131 then undergoes spontaneous cyclisation, leading to the indole 132.

Some experimental data obtained by Yurovskaya et al. elucidates certain mecha-

nistic features of the reaction. When mixtures of secondary amines and the

appropriate ketones were used, o-N,N-(dialkylaminobenzyl) ketones were isolated

among other products. The formation of such compounds, which may be regarded

as stable, non-cyclisable analogues of the indole precursors, provides evidence

that the elimination of the nitro group takes place prior to the pyrrolidine ring

closure and aromatisation steps. Moreover, in addition to 4,6-meta-bridging,

necessary for indole formation, p-nitroanilines, resulting from a possible 2,4-meta-

bridging, were in some cases obtained. Elimination of the nitro group as nitrite was

confirmed by acidic treatment of the reaction mixtures. The presence of primary

amines caused N2 evolution due to the decomposition of intermediate

alkyldiazonium salts.

77

Scheme 40

132

131 130

129128

127

126

MeNH2-

RR

RR

NR

R

1

2

4

5

6

7

RR

RR

NR

R

MeHN

H

1

2

4

5

6

7

��

��

��

RHNR

R

RR

MeN

R 1

4

5

6

7

��

��

RHNR

R

R

RMeN

HR H

1

45

6

7

��

��

RHNR

R

R

R

NMeN

R

OHO

1

2

45

6

7

��

��

��

NR

R

R

R

NMeHN

OO

HR

R1

45

6

7

��

�� -H

1R H

NMe

RR

NO2N

R

R

26

5R

7

4

��

��

1R H

26

5R

N

R

RNO2

R RMeN

7

4

��

��

��

NMe

R

RR

R NO2

2

4

5

6

N

R

H1R

7

��

��

��

1R H

NMe

R

NO2N

H

R

RR

2

5R

4

��

��

��

41R H

26

5R

N

R

NO2

R RMeN

HR

7

67

��

��

2 ��

��

��

2

��

RHNR

R

R

R

NMeN

R

OOH

1

2

45

6

7

��

-H

NO2-

��

2

��

��

��

78


Reaction of the optically active imine 133 with a 3-nitropyridinium salt, using the

method described by Yurovskaya et al., could in principle result in formation of the

required enantiomerically enriched indole derivative 48b* (Scheme 41). The imine

Scheme 41

Br CNNH2��

��

50b*

OR7

Br CNN

R

��

7��

��

N

NO2

MeX

133

BrN

CN

R��

7

48b*

133 would be synthesised from condensation of the optically active amine 50b*

with an appropriate ketone.

The synthetic strategy outlined in Scheme 41 requires use of an unsubstituted 3-

nitropyridinium salt. It was therefore necessary first to validate the general results

claimed by the Russian chemists, because of their failure to observed any indole

79

formation from such pyridinium cations and, if successful, to then reexamine the

reactions with the simple 1-methyl-3-nitropyridinium salt.

Nitration of 2,4,6-trimethylpyridine (2,4,6-collidine) 134, following the method

described by Plazek, gave the corresponding 3-nitro derivative 135 in 26%

yield.112 Reaction of compound 135 in a sealed tube with an excess of methyl

iodide, gave the 3-nitropyridinium salt 136 in good yield113 (Scheme 42). The

reactions of com-

Scheme 42

N

Me

MeMe N

Me

MeMe

NO2

��

N

Me

MeMe

NO2

MeI

MeI

��oleum

KNO326% 71%

134 135136

pound 136 with various imines under different conditions are summarised in Table

4. Reaction with N-methyl-2-propylimine (137), prepared in 76% yield by

condensation of acetone with methylamine,114 gave as expected 1,2,4,6-

tetramethylindole (138), but in a much lower yield than reported by the Russian

workers (Entry 3). Treatment of compound 136 with N-methyl-2-butylimine (142),

synthesised by the same method, also resulted in a lower yield of the desired

product 143 (Entry 7). When 136 was treated with mixtures of methylamine and the

corresponding ketones (Method B) the yields were even lower, an observation that

was in general also made by the Russian chemists. Reaction of 137 with

compound 136 under acidic conditions resulted in decreased yield (Entry 1 and 2).

The desired catalytic effect, by shifting the equilibrium of the initial intermediates,

as proposed in the reaction mechanism, towards product formation, was not

observed. When the reaction was carried out in the presence of sodium 3-

nitrobenzenesulfonate (139) or 2,4-dinitrobenzenesulfonic acid (140) (10 mol%

80

respectively), however, the expected catalytic effect was obtained (Entries 4 and

5). These reagents probably assisted in the aromatisation of the proposed

intermediate 130. The best result in terms of catalysis was achieved with the

sodium salt of 2,4-dinitrobenzenesulfonic acid (141) (Entry 6). No changes in yield

SO3Na

NO2

SO3NaNO2

NO2

NO2

NO2

SO3H

139140 141

were observed by using larger amounts (2 equivalents) of the catalysts. Similar

improved results were also obtained from reaction of 136 with the imine 142 in the

presence of the catalyst 139 (Entry 8).

Attempts to introduce larger groups than methyl into the 7-position of the product

failed. Reaction of compound 136 with N-methyl-4-methyl-2-pentylimine (144,

prepared following the same method as previously described) or N-cyclohexyl-1-

phenyl-2-propylimine (145) did not lead to indole formation even in the presence

of the catalysts 139 or 141 (Entries 9-13). Compound 145 was prepared following

a literature procedure.115 When 136 was treated with a mixture of hydroxyacetone

and methylamine again no product was obtained (Entry 14). On the other hand,

from imines that contained a large substituent only on nitrogen, the corresponding

indoles could be isolated in moderate yields using method A or B (Entries 15 and

17 respectively). Treatment of compound 136 with N-cyclohexyl-2-propylimine

(146)116 or N-benzyl-2-propylimine (148)117 in the presence of sodium 3-

nitrobenzenesulfonate (139), however, did not significantly improve the yields

(Entries 16 and 18 respectively). When 136 was reacted with a mixture of acetone

and (+)-α-methylbenzylamine the corresponding optically active indole 150 was

81

Table 4 Reactions of 1,2,4,6-tetramethyl-3-nitropyridinium iodide 136 with different

imines

��

NMe

NO2

Me

MeMe

RN

R1

7

NRR

Me

Me

Me 17

136

Entry

Imine

R1

R7

Catalyst

Indole

Yield [%] A B

1

137

Me

H SO3H

Me 138

13

-

2

137

Me

H

EtCO2H

138

29

-

3

137

Me

H

-

138

38

4

4

137

Me

H

139

138

57

-

5

137

Me

H

140

138

60

-

6

137

Me

H

141

138

92

-

7

142

Me

Me

-

143

32

17

8

142

Me

Me

139

143

47

-

9

144

Me

iPr

-

-

0

-

10

144

Me

iPr

139

-

0

0

82

11

144

Me

iPr

141

-

0

-

12

145

C6H11

Ph

-

-

0

-

13

145

C6H11

Ph

139

-

0

-

14

-

Me

OH

-

-

-

0

15

146

C6H11

H

147

59

71

16

146

C6H11

H

139

147

65

-

17

148

PhCH2

H

-

149

58

48

18

148

PhCH2

H

139

149

62

-

19

-

PhCHCH3

H

-

150

-

40

20

-

PhCH(CH2)3CH3

H

-

-

-

0

obtained in 40% yield (Entry 19). From reaction of the pyridinium salt 136 with α-

butylbenzylamine (105) and acetone a product was obtained in low yield, the

structure of which could not be assigned to the expected indole from its proton

NMR spectrum (Entry 20). The mass fragmentation, however, showed a molecular

ion that could correspond to the desired product.

83

Having established the general accuracy of the Russian work with 1,2,4,6-

tetramethyl-3-nitropyridinium iodide (136), and shown that the transformation can

be effectively catalysed with nitrobenzenesulfonic acids, we next turned attention

to the reactivity of the simple unsubstituted pyridinium salt (153), essential for the

formation of 48b*.

Oxidation of 3-aminopyridine (151) with hydrogen peroxide in oleum, gave 3-

nitropyridine (152) in low yield.118 Compound 152 was methylated in high yield to

give 1-methyl-3-nitropyridinium iodide (153), following the same procedure as

before (Scheme 43). Table 5 summarises the results obtained from reaction of

Scheme 43

��

MeI

93%15%H2O2

��oleum

N

NO2

MeI

N

NO2

N

NH2

151 152153

the 3-nitropyridinium cation 153 with different imines. Unfortunately, compound 153

did not undergo the reaction to yield the corresponding indoles, not even in the

presence of the catalyst 139 (Entries 2 and 4). These findings are thus in full

accordance with those reported by Yurovskaya et al.

The above results clearly indicate that although an optically active product and, in

some cases, improved yields using various catalysts could be obtained, this

synthesis was not going to be the method for the construction of the required 7-

substituted indole derivative 48b*. The reaction is limited to the preparation of

polyalkylindoles.

84

Table 5 Reactions of 1-methyl-3-nitropyridinium iodide 153 with different imines

��

NMe

NO2 RN

Me

7

N

R Me7

153

Entry

Imine

R7

Catalyst

Yield [%] A B

1

137

H

-

0

0

2

137

H

139

0

-

3

142

Me

-

0

-

4

142

Me

139

0

-

85

6. Synthesis of 4- and 7-Oxo-4,5,6,7-tetrahydroindoles

The first generally useful method for the preparation of 4-oxo-4,5,6,7-tetrahydro-

indoles was described by Stetter and Lauterbach in 1962.119 In this procedure, 1,3-

cyclohexanediones were alkylated with α-halo ketones to give the 4-oxo-4,5,6,7-

tetrahydrobenzofuran derivatives 154, which on treatment with ammonia or primary

amines, in a steel bomb at 150 °C, gave the corresponding tetrahydroindoles 155

in high yields (Scheme 44). In contrast, reaction of 1,3-cyclohexanedione with

Scheme 44

155

154

R"'NH2

OX

R'R"

H+

��

2)

1)

O

NR'

R'

R"

R"'

O

O

R'

R"R'

O

OHR

��

ethyl bromopyruvate gave 4-oxotetrahydrobenzofuran-3-carboxylic acid 156, from

initial aldol condensation. Reaction of 156 with ammonia resulted in formation of

86

the decarboxylated parent 4-oxotetrahydroindole 157 in moderate yield (Scheme

45). Matsumoto and Watanabe synthesised the indole 157 in 96% yield by heating

Scheme 45

NH3

��

��

158

O

O

2) H+

1) ClO

��

156

NH3

O

OH

O

O

CO2H

O

NH

1)

2)��

H+

OBr

CO2Et

157

4-oxo-4,5,6,7-tetrahydrobenzofuran (158) in the presence of ammonia under

similar conditions as described above.120 The furan 158 was obtained in good yield

from initial aldol condensation of 1,3-cyclohexanedione with chloroacetaldehyde in

the presence of sodium bicarbonate (Scheme 45). Analogous reaction of 158 with

a variety of primary amines afforded the corresponding 1-substituted 4-

oxotetrahydroindoles in high yields.

Torii et al. described the synthesis of novel cyclohexanone derivatives via an

electrochemical C-C coupling reaction.121,122 When a basic mixture of, for

example, 1,3-cyclohexanedione, ethyl vinyl ether and ethanol was electrolysed at

room temperature under a constant current, a 3:4 mixture of the products 159 and

87

160 was obtained (Scheme 46). Both compounds could be easily converted to 4-

Scheme 46

O

OH

��OEt

EtOH

O

OOEt +

O

OH

OEt

OEt

159 160

oxotetrahydroindoles in moderate to good yields by reaction with ammonia or the

corresponding primary amines in a sealed tube at 150 °C.

When 1,3-cyclohexanediones are condensed with aminoacetaldehyde dimethyl

acetals the corresponding enamines 161 are obtained, which can be cyclised with

acid to 4-oxo-4,5,6,7-tetrahydroindoles in moderate yields123 (Scheme 47). The

use of 1,2-cyclohexanediones can result in formation of the corresponding 7-

oxotetrahydroindoles. 1-Methyl-7-oxo-4,5,6,7-tetrahydroindole (162), for example,

was obtained using this general method, but only in very low yield124 (Scheme 48).

Recently a modification of this method, for the synthesis of 3-substituted 4-

oxotetrahydroindoles, has been reported by Edstrom.125 Reaction of 1,3-

cyclohexanedione with the sodium salt derived from sarcosine (N-methylglycine)

afforded the condensation adduct 163, which was isolated as its crude acid.

Compound 163 was heated in acetic anhydride to give 3-acetoxy-4-oxo-4,5,6,7-

tetrahydroindole (164) in 80% yield (Scheme 49).

88

Scheme 47

161

H+

R'NH OMe

OMe O

N

OMeMeO

R'R

R

��

O

NRR R'

O

OHRR

��

Scheme 48

Me

NH OMe

OMe

N

OMeMeO

MeO

��

NMeO

OHO

�� CH3COOH

16213%

89

Scheme 49

164

163

O

OH

��

MeN CO2NaH

O

N

CO2H

Me

��

Ac2O

O

NH

OAc

A different approach for the synthesis of 4- and 7-oxotetrahydroindoles, starting

from pyrrole, was found by Julia and Pascal.126 When the pyrrole N-magnesium

derivative 165 was reacted with 4-chlorobutyronitrile, a mixture of the 2- and 3-

substituted pyrrole isomers was obtained (Scheme 50). Conversion of the nitrile to

the carboxylic acid group and subsequent ring closure gave the corresponding 4-

and 7-oxotetrahydroindoles 157 and 166.

In another procedure, Friedel-Crafts acylation of the trisubstituted pyrrole 167 gave

the derivative 168 (Scheme 51). Reduction of the carbonyl group in 168 was found

to proceed best via hydrogenation with Pd/C. The diester 169 was cyclised in

polyphosphoric acid (PPA) to give the 7-oxotetrahydroindole 170 in moderate

yield.127

90

Scheme 50

H2O2)

165 ��

+

��

NMgX

Cl CN1)

NH

CN

NH

CN

NH

CO2H

NH

CO2H

+

N

O

H

NHO

��

+

157 166

91

Scheme 51

N

O H

Me

Et

��

NEt

Me

EtO2C

H

MeO2C

NEt

Me

EtO2C

H

MeO2C

O

��

N

Me

EtO2C

H

Et

PPA

��

H2Pd/C

MeO2C Cl

O

AlCl3

167 168

169170

A more elegant method involves the regioselective AlCl3-catalysed 3-acylation of

1-(phenylsulfonyl)pyrrole (171)128 (Scheme 52). Clemmensen reduction of 172

gave 173 in high yield. Treatment of 173 with oxalyl chloride gave 174, which

cyclised even in the absence of any catalyst to give the 7-oxotetrahydroindole 175.

The production of 175 was found to be more efficient when 174 was reacted with

trifluoroacetic anhydride. Subsequent hydrolysis gave 166 in high yield.

Reaction of 2,3-epoxy-3-methylcyclohexanones 176 with benzylamine has been

reported to yield 2-amino-3-methylcyclohex-2-enones 177, which on treatment with

dimethylformamide dimethyl acetal (dmfdma) cyclised to the corresponding 1-

benzyl-7-oxotetrahydroindoles 178 in high yields129 (Scheme 53). Benedetti et al.

prepared 7-oxotetrahydroindoles 180 from reaction of N-substituted enamines 179

92

Scheme 52

NaOH

(COCl)2

Zn/HCl��

AlCl3

NSO2Ph

O

O

O

��

+NSO2Ph

O

O

HO

NSO2Ph

O

HO��

NSO2Ph

O

Cl

��

NSO2PhO

��

NHO

171 172

173174

175 166

(CF3CO)2O

93

Scheme 53

��

O

RR

��

O

OR

R

H2O2 ��

ONHBn

RR

O

NBn

RR

dmfdma

K2CO3

BnNH2

176 177

178

(analogous to 177) with nitroolefins130 (Scheme 54). The reaction was found to be

Scheme 54

3

2

1O

NR

R

R

O

O ��

ONHR

RNH21

1 NO2

R

R2

3

179 180

��

very substrate dependent. In fact, when R1 was n-butyl, the reaction proceeded

rapidly and almost quantitatively.

94


The shortest and most effective method for the synthesis of 1-substituted 4-

oxotetrahydroindoles is that described by Matsumoto and Watanabe, from reaction

of an aqueous ethanolic solution of 4-oxo-4,5,6,7-tetrahydrobenzofuran (158) with

primary amines in a sealed tube at 150 °C for twelve hours.120 In principle, it

should be possible to perform the analogous reaction with the 7-oxo isomer 181,

thus opening a new and better route for the synthesis of 1-substituted 7-

oxotetrahydroindoles. Reaction of the optically active amine 50b* with 181 could

therefore give the 7-oxotetrahydroindole derivative 182*, and this in turn could be

converted into the required enantiomerically enriched 1,7-disubstituted indole 48b*,

after aromatisation and alkylation (Scheme 55).

Scheme 55

48b*

182*

181

50b*

BrN

CN

OCN

��

BrN

CN

O��

O

O

��BrNH2

CN

95

Initial studies towards the synthesis of 7-oxo-4,5,6,7-tetrahydrobenzofuran (181)

were carried out by Justin Cowell.131 The best result was obtained from reaction of

1,2-cyclohexanedione with chloroacetaldehyde in the presence of sodium

bicarbonate, as previously reported for the synthesis of the 4-oxo isomer 158

(Scheme 56). The modest yield stems probably from the lower acidity of the

Scheme 56

181

O

O

��

OOH

ClO

1)

2) H+

40%

hydrogens at C-3 in 1,2-cyclohexanedione compared to the highly activated

methylene hydrogens at C-2 in 1,3-cyclohexanedione. A longer-winded Wittig

approach gave 181 in only 26% overall yield (Scheme 57). Thus, reaction of

commercially available (but expensive) furan-3-carbaldehyde with the ylid derived

from 3-chloropropanoic acid gave the 4-(3-furyl)butenoic acid (183) in 36% yield.

Compound 183 was hydrogenated at atmospheric pressure over a palladised

charcoal catalyst to yield the butanoic acid 184. The saturated acid proved to be

fairly unstable and was thus reacted in crude form with oxalyl chloride to produce

4-(3-furyl)butanoyl chloride (185). The desired 7-oxotetrahydroindole 181 was

obtained from intramolecular tin(IV) chloride catalysed Friedel-Crafts reaction of

185 as reported by Walsh and Stone.132 A possible alternative Paal-Knorr

approach had to be abandoned because of failure to obtain the required tricarbonyl

intermediate 186.

96

Scheme 57

185 184

183

O

O

��

Ph3P OH

OCl

OHO

O

NaH

��

Pd/CH2

OHO

O�� (COCl)2

OCl

O

��

SnCl4

181

186

O

OOH

97

The next step was to find out if condensation of the furan 181 with primary amines

would give the corresponding 7-oxotetrahydroindoles, and if chirality would be

retained during the course of the reaction. Homochiral α-methylbenzylamine was

chosen as the condensation partner for the initial model studies, because it is

benzylic and one of the cheapest optically pure amines available. Cowell showed

that treatment of 181 with an excess of α-methylbenzylamine under an inert

atmosphere and different conditions such as use of a solvent (MeOH), addition of

protic acid catalysts (HCl, acetic acid) and variation of temperature and reaction

time, always gave complex mixtures from which the desired product could not be

isolated. Three other products were instead obtained, which were found to be 7-

(N-α-methylbenzylimino)-4,5,6,7-tetrahydrobenzofuran (187), acetophenone and

N-(α-methylbenzyl)-α-methylbenzylimine (188) (Scheme 58). From reaction with

Scheme 58

Ph NH2

181188

187

Ph O+Ph N Ph+

N

O

Ph

O

O

��

the less sterically demanding benzylamine, however, the desired reaction took

place to some extent to give 1-benzyl-7-(N-benzylimino)-4,5,6,7-tetrahydroindole

(189), in addition to the expected two other products (Scheme 59). A large excess

of benzylamine was required in order to consume all the starting furan 181. The

desired 7-oxotetrahydroindole 190 was obtained from hydrolysis of 189 with

saturated ammonium chloride, but only in 10% yield. Attempts to increased the

nucleophilicity of α-methylbenzylamine by using its lithium salt, prepared in situ

98

Scheme 59

��PhCH2NH2

O

O

N

N

Ph

Ph

+ Ph N Ph + Ph O

��

aq NH4Cl

N

PhO

189181

190

from reaction with LDA, led only to the recovery of starting material. In this case

the lithium species acted as a base rather than a nucleophile and simply

deprotonated 181, as indicated from reaction with methyl iodide where the only

product isolated was shown to be 6-methyl-7-oxo,4,5,6,7-tetrahydrobenzofuran

(191).

191

O

O

From the above results obtained by Cowell, it seemed that the drastic conditions

previously reported by Matsumoto and Watanabe were going to be necessary. An

aqueous ethanolic solution of 7-oxo-4,5,6,7-tetrahydrobenzofuran (181) and

homochiral α-methylbenzylamine was therefore heated in a sealed tube for twelve

99

hours. Purification of the product mixture gave indeed the desired 7-oxo-4,5,6,7-

tetrahydroindole (192) along with starting material and acetophenone, but only in

12% yield (see Table 6, Entry 5). In contrast to the previous experiments carried

out by Cowell, no complications due to imine formation were observed under the

aqueous conditions; furthermore, the product was found to be enantiomerically

pure. Determination of the enantiomeric purity was carried out using proton NMR

spectroscopy with TFAE 106 as the chiral solvating agent.

The numerous variations of the reaction that were carried out in attempts to

increase the disappointing yield are summarised in Table 6. On increasing the

reaction time, a slightly better yield was obtained, although there was not much

difference between 24, 36 or 48 hours (Entries 10, 12 and 9 respectively). All the

further experiments were, therefore, carried out for 36 hours. When the

temperature was dropped to 100 °C almost no reaction occurred (Entry 1). At a

higher temperature (200 °C) the same reactivity as before was observed (Entry 6).

Attempts to catalyse the reaction with Lewis acids were also disappointing.

Reaction in the presence of one equivalent of AlCl3, under anhydrous conditions,

gave the product in only 3% yield (Entry 2). The low yield could be explain by the

fact that the amine complexed with the metal salt to give an insoluble precipitate,

thus lowering the amount of available free amine for nucleophilic attack. The same

conditions, but without the Lewis acid, gave the desired product in similar yield,

indicating that AlCl3 did not catalyse the reaction at all and that use of non-

aqueous solvent systems was disadvantageous, as reported by Matsumoto and

Watanabe (Entry 3). This was confirmed by reaction in dry methanol with or

without molecular sieves (Entries 8 and 11). Reaction with one equivalent of the

more oxophilic Lewis acid CeCl3.7H2O as the catalyst in aqueous ethanol also

resulted in a lower yield (Entry 4). The insoluble complex was formed again, when

the amine was added to the solution of the metal salt and the furan 181. Doubling

the excess of the amine did not influence the result (Entry 7). The HCl-catalysed

version of the reaction, although it gave the best yield so far (25%), was not a

100

Table 6 Attempted reactions of 7-oxo-4,5,6,7-tetrahydrobenzofuran (181) with α-

methylbenzylamine under different reaction conditions

Ph

NH2

O

O

181��

O

N

Ph

192

Entry

Solvent

Time [h]

Equiv amine.

Temp. [C]

Catalyst

Yield [%]

192

1

EtOH/H2O

36

3

100

-

2

2

(CH2)2Cl2

36

3

150

AlCl3

3

3

(CH2)2Cl2

36

3

150

-

5

4

EtOH/H2O

36

3

150

CeCl3

8

5

EtOH/H2O

12

3

150

-

12

6

EtOH/H2O

36

3

200

-

17

7

EtOH/H2O

36

6

150

-

19

8

MeOH

36

3

150

A4 sieves

19

9

EtOH/H2O

48

3

150

-

19

10

EtOH/H2O

24

3

150

-

21

101

11

MeOH

36

3

150

-

22

12

EtOH/H2O

36

3

150

-

23

13

EtOH/H2O

36

3

150

HCl

25

significant improvement (Entry 13). Despite all the attempts, no real success was

achieved in terms of optimisation.

The furan 181 was then reacted with ammonia and a variety of simple primary

amines in a sealed tube at 150 °C for 36 h. The yields of 7-oxotetrahydroindoles

were, as expected, not very high and in general much lower than those obtained

with the 4-oxo isomer 158 (See Table 7). The synthesis of the corresponding 4-

oxotetrahydroindole derivatives was carried out by Sven Baum,133 except for

compound 196. When both 7- and 4-oxotetrahydrobenzofuran were treated with

the more complex amine 199, the products obtained were those derived from

HCl.H2N Ph

CO2Me

199

hydrolysis and decarboxylation of the ester group, namely the corresponding N-

benzyloxotetrahydroindoles 190 and 198. This could be potentially a problem,

since ultimately the functionalised amine 50b would need to survive the harsh

conditions, in order to yield the required 7-oxotetrahydroindole 182. As previously

mentioned, besides formation of the 7-oxotetrahydroindoles the formation of the

corresponding carbonyl compounds derived from the benzylic amines used was

also observed (Entries 1, 3 and 4). In the case where the amine was not benzylic,

no carbonyl compounds were obtained (Entries 2, 5, 6 and 7). In the 4-oxo series

102

Table 7 Reactions of 7-oxo-4,5,6,7-tetrahydrobenzofuran (181) with various

primary amines

O

NR

��RNH2

O

O EtOH/H2Osealed tube

36 h181

Entry R Product Yield [%] Product

*

Yield [%]*

1 PhCHC4H9 193 17 196 8

2 CH3 162 22 197 89

3 PhCHCH3 192 23 83

4 PhCH2 190 30 198 83

5 C6H11 194 34 36

6 H 166 36 157 91

7 PhCH2CH2 195 46 71

*Yields obtained from reaction of 4-oxo-4,5,6,7-tetrahydrobenzofuran (158) with the corresponding amines under the same conditions, except that the reaction mixture was left to react for twelve hours.

the corresponding carbonyl compounds were never formed, whether the amine

was benzylic or not. With this information it is now possible to propose a

reasonable mechanism for the oxidation of benzylic amines to the corresponding

carbonyl derivatives during the course of the reaction, as shown in Scheme 60.

Nucleophilic attack of the amine at the 2-position of 181 would result in formation

103

Scheme 60

202

201

200

181

Ph

O+

OOH

NH2

��

��

OOH

N PhH

OH

��

��

��

��

HOHO

OH

N Ph

��

OOH

N Ph

��

��

��

�� O

O

NPh

H H��

��

��

��

H2N PhO

O

OOH

N PhH

104

of the enamine 200. A sequence of tautomeric equilibrium reactions would give the

imine 201 as the key intermediate, the driving force being the conjugation to the

phenyl ring. This compound would then be readily hydrolysed by the water present

to form the corresponding carbonyl derivative of the amine and compound 202.

The amine 202, however, could never be isolated since it is probably far too

reactive under the conditions to survive unchanged. Furthermore, the reactivity of

the 7-oxotetrahydrobenzofuran 181 is certainly lower than that of the 4-oxo isomer

158. The two intermediates involved in the cyclisation reaction are quite different.

Initial nucleophilic attack of the amine to 7-oxotetrahydrobenzofuran 181 forms

203, where the equilibrium lies preferentially to the left, thus preventing ring closure

203O

O

NHR

��

OOH

NHR

and decreasing reactivity. In the case of 4-oxotetrahydrobenzofuran 158, the initial

intermediate from attack of the amine is 204 with the tautomer on the right being

204

O

NHR

OH

��

O

NHR

O

the major component, therefore, increasing reactivity and product formation. All of

these observations account for the lower yields obtained in the reaction of 181

with primary amines compared with 158.

105

Although the yields of 7-oxotetrahydroindoles were not as high as desired, the

synthesis of a series of 1-substituted 7-oxotetrahydroindoles could be achieved

successfully with this novel route. The fact that the reaction is enantiospecific fulfils

all the conditions needed for the synthesis of the required enantiomerically

enriched 1-substituted 7-oxo derivative 182*. But first, it was necessary to

investigate the aromatisation of such systems into 7-substituted indoles and to see

if this transformation would proceed without racemisation. How we developed a

novel procedure for this purpose is described in the next chapter.

106

7. Aromatisation

The classical method for dehydrogenation of 4-oxo-4,5,6,7-tetrahydroindoles to the

corresponding 4-hydroxyindoles, involves heating with palladium on charcoal in an

aromatic hydrocarbon solvent such as cumene or mesitylene.134 4-Hydroxyindole

was thus prepared from 157 in good yield when mesitylene was used.135

Treatment of a 7-oxotetrahydroindole under similar conditions also gave the co-

rresponding aromatised product.127 When Baum attempted to aromatise the 4-

oxotetrahydroindoles 157 and 197 using this general method, however, only

starting materials were recovered133 (Scheme 61). Different concentrations of

Scheme 61

RN

O

Pd/C

157: R = H197: R = Me

NR

OH

��

Pd/C systems (5 and 10%) as well as different solvent mixtures (cumene/mesi-

tylene) and reaction times were tried, but in no case was the desired result

obtained. As catalytic dehydrogenation is quite sensitive to the catalyst, it is

probable that our particular sample of catalyst was inferior in activity.

Baum further showed that treatment of 197 with dichlorodicyanobenzoquinone

(DDQ) yielded a polymeric black residue. Reaction of the corresponding silyl enol

ether 205, prepared from reaction of 197 with LDA and trimethylsilyl chloride

(TMSCl) following a procedure described by Fleming and Paterson,136 with DDQ

or trityl tetrafluoroborate137 in the presence of collidine gave a similar result

107

(Scheme 62). Remers et al. reported that 4-hydroxyindoles were found to be

Scheme 62

197 205

DDQ

N

OTMS

Me

2)TMSCl

1) LDA ��

N

O

MeNMe

OH

��

unstable to DDQ unless they contained an additional electron-withdrawing group at

C-5.138 It seems therefore likely that dehydrogenation occurred, but the products

were unstable in the presence of DDQ. On the other hand, when a solution of 7-

oxotetrahydrobenzofuran (181) in dichloromethane was treated with DDQ at room

temperature or under reflux conditions, no decomposition took place and all the

starting material was recovered. The corresponding silyl enol ether 206, prepared

using the same method as before, could be aromatised to 7-hydroxybenzofuran

(207) with Pd(OAc)2139,140 (Scheme 63).

Scheme 63

��

O

OH

O

O

��1) LDA

2)TMSCl O

OTMS

206181

Pd(OAc)2

207

108

Reaction of the 4-oxotetrahydroindole 197 with LDA at -40 °C and subsequent

quenching with phenylselenium chloride following the general procedure described

by Williams and Nishitani,141 gave the corresponding α-phenylseleno derivative

208 (Scheme 64). Oxidative elimination of 208 with hydrogen peroxide, however,

Scheme 64

197 208

N

O

Me

PhSe

2) PhSeCl

1) LDA��

N

O

Me

NMe

OH

��

H2O2

��

N

O

Me

PhSeO

gave only a multispot tlc as shown by Baum.133 Probably the same reasons as

referred to above (instability of the 4-hydroxyindole under the oxidative conditions)

were responsible for the observed result.

When a solution of the 7-oxotetrahydroindole 192 in benzene was treated with

commercially availalbe MnO2 at room temperature or under reflux conditions no

reaction occurred.142,143 Treatment of 192 with ferric hexafluorophosphate in

109

dichloromethane at room temperature and under nitrogen, led also only to recovery

of the starting material.144,145

Kotnis reported that 1,3-cyclohexanediones can be aromatised to the corres-

ponding resorcinols in high yields with iodine and methanol.146 Attempted aroma-

tisation of the homochiral 7-oxotetrahydroindole 192 following this method,

however, gave only a mixture of the 6- and 3-iodo isomers 209 and 210, which

could be separated by column chromatography (Scheme 65). The 6-iodo derivative

Scheme 65

21020919260%

I2

LDA

��

10%

O

N

Ph

I

+

O

N

Ph

II2

MeOH��

O

N

Ph

209, which was shown to be a diastereomeric mixture from its proton NMR

spectrum, gave a single spot on tlc and could not be separated into the single

diastereomers. This was not a problem, since base catalysed dihydroiodination of

the mixture 209 would produce the same 7-hydroxyindole. Treatment of 192 with

LDA, prepared in situ from reaction of diisopropylamine and n-butyllithium, followed

by addition of iodine gave 209 in 15% yield; none of the 3-iodo isomer or 7-

hydroxyindole was formed. This particular reaction was found to proceed very

slowly, most of the starting material being recovered unchanged. When 209 was

heated in dichloromethane in the presence of triethylamine, however, the desired

110

7-hydroxyindole 211 was obtained, but only in low yield, the starting material being

the major component of the reaction mixture. Treatment of 209 with neat 1,8-

diazabyciclo[5.4.0]-undec-7-ene (DBU) at 80 °C resulted in consumption of all the

starting material, but still the product 211 was isolated in low yield. Reaction with

DBU under the same conditions as above, followed by in situ alkylation with

bromoacetonitrile resulted in formation of the corresponding 7-cyanomethoxyindole

212 but only in 20% yield. The 7-hydroxyindole 211 was found to decompose

readily, as did also the 6-iodo precursor 209, and this was probably the reason for

the low yields obtained. Finally, the reaction was carried out at room temperature.

After 15 min all the starting material 209 had disappeared by tlc and the reaction

mixture was worked up. Subsequent alkylation of the crude isolated 7-

hydroxyindole 211 with bromoacetonitrile in the presence of potassium carbonate

gave the desired 7-cyanomethoxyindole 212 in 48% overall yield (Scheme 66). A

very good result, however, was the fact that aromatisation and introduction of the

required O-nitrile chain proceeded without loss of optical activity ( α D20 132.5).

Aromatisation of several 4-oxotetrahydro- into the corresponding 4-hydroxyindoles,

including an optically active one, using this procedure was achieved by Baum.133

The yields were in general higher than obtained with 192 (up to 83%), since no

pyrrole ring iodination and instability problems were encountered with either the 5-

iodo-4-oxo-tetrahydro- or the 4-hydroxyindoles. This represents a novel and milder

route for the synthesis of 4- and 7-substituted indoles, via a selective

halogenation/dehydrohalogenation sequence of the 4- and 7-oxo derivatives,

compared with other known methods based on the same stragegy.147-149

111

Scheme 66

48%212

K2CO3

��

O

N

Ph

CN

Br CN

211

OH

N

Ph

DBU��

209

O

N

Ph

I

112

8. The final Battle towards LY290154

Having established a route for the synthesis of homochiral 1-substituted 7-

oxotetrahydroindoles and shown that aromatisation of the latter proceeds without

loss of optical activity, we finally turned our attention to the preparation of the

enantiomerically enriched 7-cyanomethoxyindole derivative 48b*, required as the

key intermediate for the asymmetric synthesis of LY290154 35. An aqueous

ethanolic solution of racemic 50b was therefore reacted with 7-oxotetrahydro-

benzofuran (181) in a sealed tube at 150 °C in the hope of producing the desired

7-oxotetrahydroindole derivative 182, which would be converted to 48b after

aromatisation and O-alkylation as described in the previous chapter. The same

reaction sequence with the optically active amine 50b* would thus give 48b*.

Unfortunately the desired transformation did not take place; instead the lactam 213

was obtained in modest yield (Scheme 67).

The intramolecular cyclisation of 50b could in principle be avoided by converting

the nitrile into the tetrazoyl group,150-152 which is present in the target molecule 35.

When a dimethoxyethane solution of the amine 50b was refluxed with tributyltin

azide, prepared from reaction of sodium azide with tributyltin chloride, an oil was

obtained, the structure of which could not be assigned unambiguously to the

desired aminotetrazole 214 on the basis of its proton NMR or mass spectra

(Scheme 68). Reaction without solvent gave the same result. On the other hand,

reaction of the ketone 110 and the oxime ether 111 using the same conditions as

above resulted in formation of the corresponding tetrazoles 215 and 216

respectively (Scheme 69). The reaction was found to give better yields when no

solvent was employed. The aminotetrazole 214 could now be approached via

reduction of the oxime ether 216 (Scheme 70). Unfortunately, all the attempts to

reduce 216 with a borane-THF complex, following the same method as described

in Chapter 4.1, failed. Instead, a solid was isolated which could not be identified

from its proton NMR spectrum.

113

Scheme 67

48b

��

BrN

CN

OCN

��

��

182

BrN

CN

O

��

50b

Br CNNH2

O

O

BrN

OH

��181

21351%

Scheme 68

21450b

Br CNNH2

��Bu3SnN3 BrN

NNN

H

NH2

114

Scheme 69

Br CNR ��

��Bu3SnN3 BrR

NN

NN

H

110: R = O111: R = NOMe

215: R = O216: R = NOMe

Scheme 70

214

BrN

NNN

H

NH2

BrN

NN

NN

H

OMe

216

BH3.THF

��

Finally, the aminotetrazole 214 was obtained as outlined in Scheme 71. Reaction

of the azide 117 with neat tributyltin azide at 80 °C gave the desired azidotetrazole

217 as a yellow oil. Reduction of 217 with 1,3-propanedithiol , following the same

procedure as for the synthesis of the amine 50b, resulted in formation of the

required aminotetrazole 214 in moderate yield. Unfortunately, when 214 was

treated with 7-oxotetrahydrobenzofuran (181) in a sealed tube at 150 °C for 36

hours basically no reaction occurred. Only traces of the desired 7-

oxotetrahydroindole 218 were detected in the proton NMR spectrum of the crude

reaction mixture, the main component being 181. Most of the insoluble

aminotetrazole 214 was recovered unchanged by simple filtration. The insolubility

of 214 was certainly responsible for the failure of the reaction. N-Trityl protection of

115

Scheme 71

181

214

117

Bu3SnN3

BrN

NNN

H

NH2

��

HS SH

217

BrN

NNN

H

N3

BrN3

CN ��

43%

55%

O

O��

BrN

NN N

N H

O

218

��

BrN

NN N

N H

OCN

116

the tetrazole moiety could result in increased solubility. Treatment of a suspension

of 214 in dichloromethane at room temperature with pyridine followed by trityl

chloride resulted in formation of the N-protected derivative 219153 (Scheme 72).

Scheme 72

214

BrN

NNN

H

NH2 ��Ph3CCl

pyridine

BrN

NNN

CPh3

NH2

219

Sealed tube reaction of 219, however, was not attempted because the trityl group

dropped off very easily under aqueous conditions.

The results obtained so far indicated that the required 7-oxotetrahydroindole

derivative 182 was not going to be produced from sealed tube reaction of the

amine 50b with 7-oxotetrahydrobenzofuran (181). A different approach for the

construction of 182 had therefore to be considered. Based on the work reported by

Kasum et al.129 (see Chapter 6), commercially available 3-methyl-2-cyclohexene-

1-one was treated with basic hydrogen peroxide to give the 2,3-epoxy ketone 220

in moderate yield154 (Scheme 73). Reaction of 220 with benzylamine in aqueous

methanol under reflux conditions gave the expected enamine 221, but in a much

lower yield than previously reported by the Australian chemists. When 221 was

treated with N,N-dimethylformamide dimethyl acetal (dmfdma) at 150 °C the

desired 1-benzyl-7-oxotetrahydroindole 190 could be isolated, but again in a much

lower yield than obtained by Kasum et al.

.

117

Scheme 73

19018%

22113%

22047%

O

��

O

O

��

ONHBn

N

O Bn

BnNH2

Me2NCH(OMe)2�� 150 ºC

H2O2

K2CO3

Having shown that 1-substituted 7-oxotetrahydroindoles could be prepared via this

general method, the remaining question was: would it also be stereospecific?

Reaction of 220 with homochiral α-methylbenzylamine using the same conditions

as before gave the expected enamine 222, but again in very low yield (see Table

8, Entry 3). A good result, however, was the fact that the product was shown to be

optically active. The yield of the enamine formation had therefore to be improved.

The results obtained from reaction of 222 with α-methylbenzylamine under

different reaction conditions are summarised in Table 8. Since at room temperature

no product formation was observed, all the experiments were carried out under

reflux conditions. An attempt to catalyse the reaction with the Lewis acid

CeCl3.7H2O155 (10 mol%) failed; instead a multispot tlc was obtained from which

the desired product could not be isolated (Entry 1). Reaction in the presence of

118

Table 8 Attempted reactions of 2,3-epoxy-3-methylcyclohexanone (220) with

α-methylbenzylamine under different reaction conditions

222

Ph NH2

220

O

O ��

ONH

Ph

Entry

Solvent Catalyst Yield [%]

1

MeOH/H2O CeCl3.7H2O 0

2

MeOH/H2O HCl 0

3

MeOH/H2O - 20

4

CH3CN/H2O

- 21

HCl gave a similar result (Entry 2). Using aqueous acetonitrile instead of aqueous

methanol as the solvent gave the same yield as before (Entry 4). When the

reaction was carried out with one equivalent CeCl3.7H2O in refluxing aqueous

methanol, a totally unexpected result was obtained. None of the desired enamine

222 was formed; instead, the cyclic 2-chloro-2-ene-1-one 223 and the toluidine

derivative 224 were isolated through column chromatography (Scheme 74). At

room temperature no reaction occurred. Compound 224 showed no optical activity,

indicating that racemisation of the benzylic position of the amine occurred during

119

Scheme 74

9%35%

+

OCl��

��

O

OCeCl3.7H2O

MeOH/H2Oreflux

Ph NH2

NH

Ph

220 223 224

the transformation. When the reaction was repeated in the absence of the amine

the expected chloro derivative 223 was obtained in high yield. Use of CeCl3 under

anhydrous conditions, however, gave the 2-chloro-3-hydroxy-1-one 225 in good

yield (Scheme 75). Simple refluxing of 225 in aqueous methanol did not produce

Scheme 75

1

OCl

OHMeCN

CeCl3 ��

O

O

220 22574%

��MeOH/H2O

OCl

HCl

223

223. In the presence of acid, however, the enone 223 was obtained quantitatively.

Based on the observation that CeCl3.7H2O is somehow involved in the elimination

step to give 223 from 225, it is now possible to postulate a reasonable mechanism

for the formation of racemic 224. The mechanism proposed by the Australian

chemists for the synthesis of the enamines 227 is shown in Scheme 76. The first

120

Scheme 76

O

NHR��

NRHO

OH

��

��

��

O

NHRHO

H2O��

NR

O

226 227

step is straightforward imine formation from reaction of the 2,3-epoxy ketone with

the amine, after which reaction with water ring opens the epoxide via the

aziridine intermediate 226. Compound 226 is then converted into the enamine 227

after opening of the three membered ring followed by elimination of water. It is

likely that in the CeCl3.7H2O catalysed reaction of 220 with homochiral α-

methylbenzylamine, the initial step is also the formation of imine 228 (Scheme 77),

Scheme 77

N PhH

��

O HH��

��

��

N Ph

H

��

��

O HH

��

O HH

��

��

��

N Ph

H

��

��

N Ph

OH

H

LA

��

O

N PhH

LA

��

��

��

N Ph

O

H

228 229

230224

121

which, assisted by the Lewis acid (LA), tautomerises to the conjugated, more

stable imine 229, with destruction of the stereogenic centre. Ring opening of the

epoxide and elimination of water produces the intermediate 230, which aromatises

spontaneously to give the racemic product 224.

Not having been able to improve the yield for the formation of the enamine 222, we

next turned attention to the synthesis of the corresponding 7-oxotetrahydroindole.

Reaction of optically active 222 with neat dmfdma gave 192, but as expected in

very low yield (Scheme 78). The reaction, however, was shown to be

Scheme 78

222

��

ONH

Ph

dmfdma

O

N

Ph

19214%

stereospecific, the product having the same optical rotation as that obtained via

sealed tube methodology. When the reaction was carried out in refluxing DMF, the

same yield was obtained. Refluxing of the more sterically hindered N,N-

dimethylformamide diisopropyl or di-tert-butyl acetals with 222 in methanol in the

presence of one equivalent of triethylamine, however, led only to recovery of the

starting material.

Since, again, attempts to improved the yield of 192 were unsuccessful, it was

decided to investigated the synthesis of the required 7-oxotetrahydroindole 182

using this methodology without optimisation of the reaction. The amine 50b was

therefore reacted with the α,β-epoxy ketone 220 in refluxing aqueous acetonitrile to

give a yellow oil in low yield, the proton NMR spectrum of which showed it to be a

122

complex mixture (Scheme 79). The mass fragmentation, however, showed a

Scheme 79

BrNH2

CN �� Br

N

CN

O

HO

O

MeCN/H2O

��

dmfdma

BrN

CN

O

182

220

50b231

BrNH2

CN �� Br

N

CN

O

HO

O

MeCN/H2O

��

dmfdma

BrN

CN

O

182

220

50b231

peak that could correspond to the desired enamine 231. Attempts to purify the

material through column chromatography were unsuccessful, and hence the crude

product was treated with dmfdma in the hope of producing some of the required 7-

oxotetrahydroindole 182. Unfortunately, a dark brown oil was obtained from which

the desired product could not be isolated. Instead two fractions were obtained after

123

column chromatography, which were shown by proton NMR spectroscopy to be

complex mixtures.

Due to the failure to produce the optically active key intermediate 48b*, required to

achieved the asymmetric synthesis of LY290154 35, from the amine 50b* via its

corresponding 7-oxotetrahydroindole derivative 182*, it was clear that this

particular synthetic strategy was not going to be the method to provide the desired

target molecule in enantiomerically enriched form.

124

9. Conclusions

The work described in this thesis demonstrates that a variety of 1-substituted 7-

oxotetrahydroindoles are accessible from reaction of primary amines with 7-

oxotetrahydrobenzofuran (181), using the same method as reported by Matsumoto

and Watanabe for the synthesis of the 4-oxo derivatives (see Chapter 6.1).

Aromatisation to give the corresponding 4- and 7-hydroxyindoles can be achieved

via a new procedure based on an iodination/dihydroiodination sequence (see

Chapter 7). Furthermore, when homochiral amines are employed the

corresponding optically active 4- and 7-hydroxyindoles are obtained.

Unfortunately, construction of the 7-cyanomethoxyindole derivative 48b, the key

intermediate for the asymmetric synthesis of LY290154 35, using this methodology

was unsuccessful (see Chapter 8). The reason was the failure to obtain the

precursor 182 from reaction of the amine 50b, which was prepared in racemic and

enantiomerically enriched form (see Chapter 4.1), with 181. The explanation as to

why 50b did not react in the desired manner with 181, was that it cyclised

intramolecularly under the harsh conditions employed to give the lactam 212.

Since other methods also failed (see Chapter 5 and 8), further attempts to

synthesise the required enantiomerically enriched LY290154 precursor 48b* from

amine 50b* had to be abandoned.

125

10. Experimental

10.1 Solvents and Reagents

Commercially available materials were used without further pufirication unless

stated otherwise. Reference to the supplier is made when appropiate.

All solvents were of reagent or analytical grade and were used as supplied

commercially unless specified as dry, in which case they were dried and distilled

before use under oxygen-free nitrogen as follows: acetonitrile and dichloromethane

from calcium hydride and stored over A4 molecular sieves; DMF from and stored

over magnesium sulphate; toluene from sodium, and acetone from and stored over

potassium carbonate; diethyl ether and THF from sodium/benzophenone.

Triethylamine was distilled from sodium hydroxide.

Air- and moisture-sensitive reagents were handled under oxygen-free nitrogen in

flame-dried glassware. Sensitive liquids were transferred with thoroughly dried (in

a desiccator at room temperature in vacuo) gas-tight Hamilton syringes and added

through a rubber septum. Brine refers to a saturated aqueous solution of sodium

chloride.

10.2 Purification and Characterisation Techniques

Melting points were determined on a Kofler hot-stage microscope apparatus and

are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1720X FTIR

spectrometer using the standard nujol mull technique between sodium chloride

plates. 1H-NMR and 13C-NMR spectra were recorded using Jeol PMX60, EX90Q,

EX270 and GX400 NMR spectrometers. Tetramethylsilane (TMS) was used as the

internal standard in all NMR spectra run in CDCl3, DMSO-d6, acetone-d6 or MeOD,

126

and the chemical shifts (δ) are quoted in parts per million (ppm) from TMS (TMS=0

ppm). Low resolution EI mass spectra (Kratos MS25 mass spectrometer with an

ionisation potential of 70 eV at 200 °C) and microanalyses (Carlo Erba 1106

Elemental Analyser) were performed as a service by Mr. A. W. R. Saunders at the

University of East Anglia. High resolution mass spectra were recorded at the

SERC Mass Spectrometry Service Centre at the University College of Swansea.

Chemical Ionisation (CI) mass spectra and proton NMR chiral shift experiments

were carried out by Dr. J. Gilmore at Lilly Research Centre Limited in Surrey.

Optical rotations were determined on a Jasco DIP-370 digital polarimeter.

Column chromatography at atmospheric pressure was performed using Merck

7734 silica gel (200-600 microns). Flash column chromatography was performed

on Sorbsil C60 silica gel (40-60 microns). Thin layer chromatography (tlc) was

performed on Merck 60F254 backed silica plates, compounds being visualised by

UV irradiation (254 nm) or exposure to iodine.

10.3 Experimental for Chapter 1, Section 1.5

3-(2(E)-(7-Chloroquinolin-2-yl)ethenyl)benzenecarbaldehyde (28)

A magnetically stirred suspension of 7-chloroquinaldine (49.4 g, 0.28 mol),

isophthalaldehyde (55.7 g, 0.41 mol), dry toluene (320 ml) and acetic anhydride

(80 ml) was refluxed overnight under a nitrogen atmosphere. After cooling to rt the

solid present was separated by filtration and washed with a small amount of

toluene. The dried material was then slurried in boiling dichloromethane (1000 ml)

and the mixture filtered hot to separate the product from the less soluble

bisadduct. The filtrate was acidified with 2 M HCl to give the product as the

hydrochloride salt, which was readily removed from unreacted isophthalaldehyde

by filtration. The salt was then poured into a mixture of CH2Cl2 (1000 ml) and 2 M

NaOH (500 ml) and the resulting two-phase suspension heated under stirring until

127

most of the material was dissolved. The layers were separated and insoluble

residues removed by filtration. The organic phase was dried over anh MgSO4 and

concentrated under vacuo to yield the crude product as a yellow solid.

Recrystallisation from ethyl acetate and petroleum ether (40-60 °C) afforded the

pure compound as a yellow solid (30. 5 g, 37%), mp 136-142 °C, lit28 mp 156-7 °C;

1H-NMR (60 MHz, CDCl3, δH): 7.26-8.26 (11H, m, 11 x ArH), 10.14 (1H, s, CHO);

IR (nujol): 1688 (CHO),1640 (C=C), 1598 (C=C), 1590, 1498, 870, 785, 686 cm-1;

m/z (%): 293/295 (72/25, M+), 292 (100, M+-H), 264/266 (22/8, M+-CHO), 228 (10,

M+-CHO-Cl), 163 (13, 7-chloroquinoline); Anal calcd for C18H12ClNO (%): C, 73.60;

H, 4.12; N, 4.77; Cl, 12.07; Found (%): C, 73.43; H, 3.85; N, 4.65; Cl, 12.35; tlc

(SiO2, cyclohexane/EtOAc 1:1, Rf): 0.49.

4-Iodobutyronitrile (39)

A magnetically stirred mixture of 4-bromobutyronitrile (25.0 g, 0.17 mol) and

sodium iodide (38.2 g, 0.26 mol) in dry acetone (170 ml) in a flask closed with a

calcium chloride tube was refluxed overnight. After cooling, the inorganics were

filtered off and the organic yellow solution concentrated in a rotary evaporator.

Further inorganic material which precipitated was removed by filtration. The

residual yellow liquid was taken up in diethyl ether (50 ml), and the resulting

solution was washed with aq sodium thiosulphate (3 x 30 ml) and brine (3 x 30 ml).

The organic layer was dried over anh MgSO4 and the solvent evaporated under

reduced pressure. Vacuum distillation of the crude product gave the title compound

as a colourless liquid (23.5 g, 71%), bp 74 °C/0.8 mm; 1H-NMR (60 MHz, CDCl3,

δH): 1.96-2.70 (4H, m, 2 x CH2), 3.32 (2H, t, 3J 6.0 Hz, CH2I); IR (neat): 2250

(CN), 1430, 1230 cm-1; m/z (%): 195 (53, M+), 127 (10, I), 68 (100, M+-I), 41 (64,

M+-I-CN-H); Anal calcd for C4H6IN (%): C, 24.64; H, 3.10; N, 7.18; Found (%): C,

24.80; H, 3.01; N, 7.19.

128

5-Hydroxy-5-{3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl}valeronitrile (41)

A mixture of zinc dust (2.75, 42.0 mmol) in dry THF (4 ml) containing

dibromoethane (150 ml, 1.6 mmol) was refluxed under nitrogen for 1 min. After

cooling to rt, trimethylsilyl chloride (160 ml, 1.3 mmol) was added dropwise and the

resulting mixture was stirred for 15 min. Neat iodobutyronitrile (7.8 g, 40.0 mmol)

was added dropwise over 15 min (exothermic) and the mixture was stirred

overnight at 50 °C. The crude zincate 40 was obtained as a viscous orange oil and

subsequently used in the next step after being cooled to rt.

The aldehyde 28 (7.84 g, 26.7 mmol) was dissolved in dry THF (40 ml) and the

solution stirred under nitrogen as the zincate 40, diluted in dry THF (5 ml), was

added rapidly. After cooling in an ice-bath, a 1.0 M solution of titanium tetrachloride

in CH2Cl2 (26.7 ml, 26.7 mmol) was added dropwise over 15 min, keeping the

temperature between 0-10 °C. After stirring for 30 min at 0 °C, the dark brown

solution was further stirred for 5 h at rt under a nitrogen atmosphere. Water (100

ml) was added, and the solution was made basic with aq sodium carbonate,

whereby a deep blue colour arose. The aqueous mixture was extracted with

dichloromethane (3 x 80 ml), when the deep blue colour disappeared. The organic

extracts were washed with brine (3 x 30 ml), dried over anh MgSO4 and

concentrated under vacuo to yield a brown oil. The pure product was obtained after

flash column chromatography on silica, eluting with 25-60% ethyl acetate in light

petroleum ether (40-60 °C), as a pale yellow oil that solidified upon standing (6.0 g,

62%), mp 93-96 °C; 1H-NMR (60 MHz, DMSO-d6, δH): 1.52-1.82 (4H, m, 2 x CH2),

2.40-2.76 (2H, m, CH2CN), 4.54-4.92 (1H, m, OCHCH2), 5.40 (1H, d, 3J 4.8 Hz,

D2O exch, OH), 7.26-8.20 (10H, m, 10 x ArH), 8.44 (1H, d, 3J 8.4 Hz, quinoline 4-

H); IR (nujol): 3260 (OH), 2246 (CN), 1608 (C=C), 1592, 1499, 860, 797, 698 cm-1;

m/z (%): 362/364 (8.7/2.8, M+), 294 (12, M+- (CH2)3CN), 292 (14, M+-(CH2)3CN-

2H), 264 (6.0, M+-(CH2)3CN-2H-CO), 163 (29, 7-chloroquinoline); Anal calcd for

C22H19ClN2O (%): C, 72.80; H, 5.28; N, 7.72; Cl, 9.77; Found (%): C, 72.74; H,

5.19; N, 7.52; Cl, 9.68; tlc (SiO2, cyclohexane/EtOAc 1:1, Rf): 0.16.

129

5- Chloro-5-{3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl}valeronitrile (42)

The alcohol 41 (5.70 g, 15.8 mmol) was placed in a round bottomed flask and

cooled in an ice-bath. Thionyl chloride (15 ml) was added dropwise (cautiously,

exothermic) and the mixture was stirred for 1 h at 0 °C. It was then warmed to rt

and stirred for a further 1 h. The excess SOCl2 was evaporated under reduced

pressure. The brown residue obtained was poured into water (50 ml) and the two

phase mixture extracted with dichloromethane (3 x 20 ml). The organic extracts

were combined and washed with aq sodium bicarbonate (3 x 20 ml), brine (3 x 20

ml), dried over anh MgSO4, and concentrated in a rotary evaporator to yield a

brown oil after being dried under vacuo (4.57 g, 76%). The crude product was

used in the next step without further purification. 1H-NMR (400 MHz, CDCl3, δH):

1.70-1.80 (1H, m, CHCHHCH2), 1.90-2.00 (1H, m, CHCHHCH2), 2.20-2.35 (2H, m,

CH2CH2CH2), 2.42 (2H, t, 3J 8.0 Hz, CH2CH2CN), 4.91 (1H, dd, 3J 8.4 and 8.6 Hz,

ClCHCH2), 7.30-8.16 (11H, m, 11 x ArH); IR (neat): 2950, 2250 (CN), 1640 (C=C),

1600 (C=C), 1500, 865, 775, 700 cm-1; m/z (%): 281 (14, M+), 279 (16, M+-2H),

343 (88, M+-2H-Cl), 302 (25, M+-3H-Cl-CH2CN), 290 (16, M+- 3H-Cl-(CH2)2CN),

264 (14, M+-Cl-CH-(CH2)3CN), 36/38 (100/34, Cl); tlc (SiO2, cyclohexane/EtOAc

1:1, Rf): 0.58.

2-Benzhydroloxynitrobenzene (43)

A magnetically stirred suspension of 2-nitrophenol (20.9 g, 0.15 mol), anhydrous

K2CO3 (69 g, 0.5 mol) and benzhydryl bromide (39.5 g, 16 mol) in acetone (400 ml)

was refluxed under nitrogen for 5 h. The cooled reaction mixture was filtered and

concentrated under reduced pressure to give an orange/brown solid. This residue

was taken up in diethyl ether (100 ml) and solids removed by filtration. The filtrate

was again concentrated to dryness and the residue triturated with petroleum ether

(60-80 °C, 200 ml). The product was obtained as brown crystals after filtration and

being dried under vacuo at rt (30.6 g, 67%), mp 92-102 °C, lit34 mp 96-98 °C. 1H-

130

NMR (60 MHz, CDCl3, δH): 6.44 (1H, s, OCHPh2), 6.96-8.04 (14H, m, 14 x ArH);

tlc (SiO2, 30% EtOAc in hexane, Rf): 0.53.

7-Benzhydroloxyindole (44)

Following the procedure reported by Dobson et al.,34 to a magnetically stirred

solution of 43 (9.15 g, 30.0 mmol) in dry THF (200 ml) 1.7 M vinylmagnesium

chloride in THF (62.5 ml, 0.11 mol) was added dropwise over 30 min at -40 °C

under nitrogen. After stirring for a further 40 min at -40 °C the reaction solution was

poured into aqueous ammonium chloride (200 ml) and the two phase mixture

extracted with diethyl ether (3 x 100 ml). The combined organic phases were dried

over anh MgSO4 and concentrated under reduced pressure to yield a yellow oil.

Flash column chromatography on silica with 12.5% ethyl acetate in light petroleum

ether (40-60 °C) as eluent afforded the desired product as a pale yellow oil (4.1 g,

46%); 1H-NMR (60 MHz, CDCl3, δH): 6.36 (1H, s, OCHPh2), 6.44-7.60 (15H, m, 15

x ArH), 8.32 (1H, br s, NH); IR (neat): 3436 (NH), 3063, 1578, 1494, 1248, 1065

cm-1; tlc (SiO2, CH2Cl2, Rf): 0.76.

7-Cyanomethoxyindole (45)

According to the same paper as above, a solution of 44 (17.8 g, 59.5 mmol) in

methanol (150 ml)/toluene (150 ml) was hydrogenated at 50 psi for 1 h at rt in the

presence of 1.5 g Pd(OH)2 (Pearlman's catalyst). The reaction mixture was filtered

through Celite and the filtrate concentrated in vacuo to give a brown oil. The crude

7-hydroxyindole [1H-NMR (60 MHz, CDCl3, δH): 5.00 (1H, br s, OH), 6.40-7.60

(5H, m, 5 x ArH), 8.46 (1H, br s, NH); tlc (SiO2, CH2Cl2, Rf): 0.1] was taken up in

butanone (200 ml) and degassed with N2. Anhydrous potassium carbonate (21.0 g,

0.15 mol) and bromoacetonitrile (6.5 ml,93.3 mmol) were added, and the reaction

mixture refluxed under nitrogen for 1h. The cooled brown solution was slowly

poured into 2 M hydrochloric acid (200 ml) and the resulting mixture extracted with

CH2Cl2 (3 x 100 ml).. The combined organic extracts were dried over anh MgSO4

131

and concentrated under reduced pressure to yield a brown oil. Flash column

chromatography on silica with 12.5% ethyl acetate in light petroleum ether (40-60

°C) as eluent afforded the desired product as a brown solid (7.3 g, 72%), mp 64 °

C, lit34 mp 63-5 °C; 1H-NMR (60 MHz, CDCl3, δH): 4.80 (2H, s, OCH2CN), 6.36-

7.40 (5H, m, 5 x ArH), 8.40 (1H, br s, NH); IR (nujol): 3369 (NH), 1578, 1462,

1377, 1347, 1247 cm-1; tlc (SiO2, CH2Cl2, Rf): 0.49.

7-Chloro-2-(2-{3-[1-(7-cyanomethoxyindol-1-yl)-4-cyanobutyl]phenyl}ethenyl)-

quinoline (46)

7-Cyanomethoxyindole (45, 2.01 g, 11.7 mmol) was dissolved in dry DMF (55 ml)

and the solution stirred as sodium hydride (60% dispersion in oil, 0.47 g, 11.7

mmol) was added in portions over 10 min under nitrogen. The resulting suspension

was stirred for 30 min at rt. The crude benzyl chloride 42 (4.47 g, 11.7 mmol),

dissolved in dry DMF (10 ml), was added dropwise over 10 min. The resulting

mixture was stirred for 20 h in an oil-bath at 60 °C under nitrogen, then diluted with

ethyl acetate (100 ml) and the solution washed with water (3 x 50 ml) and brine (3

x 50 ml). The organic layer was dried over anh MgSO4 and concentrated in a

rotary evaporator to give a dark brown oil. The residue was flash column

chromatographed on silica with 20-40% ethyl acetate in light petroleum ether (40-

60 °C) as eluent to yield the title compound as a pale yellow oil after being dried

under vacuo (1.09 g, 18%). A satisfactory elemental analysis could not be

obtained. 1H-NMR (270 MHz, CDCl3, δH): 1.76 (2H, m, CH2CH2CH2), 2.42 (2H, m,

CHCH2CH2), 2.42 (2H, m, CH2CN), 4.86 (2H, s, OCH2CN), 6.31 (1H, t, 3J 5.6 Hz,

CH2CHN), 6.61 (1H, d, 3J 3.3 Hz, indole 3-H), 6.69 (1H, d, 3J 7.6 Hz, indole 6-H),

7.04 (1H, t, 3J 7.9. Hz, 5'-H), 7.17 (1H, d, 3J 7.6 Hz, indole 4-H), 7.25-7.73 (10H,

m, 10 x ArH), 8.09 (2H, m, quinoline 4-H and 8-H); IR (nujol): 2245 (CN), 1607

(C=C), 1575, 1485, 888, 781, 722 cm1; m/z (%): 347 (0.71, M+-(7-cyanomethoxyin-

dole)), 333 (0.85, M+-(7-cyanomethoxyindole)-N), 292 (0.92, M+-(7-cyanomethoxy-

132

indole)-(CH2)2CN-H), 278 (2.0, M+-(7-cyanomethoxyindole)-(CH2)3CN-H), 264

(2.7, M+-(7-cyanomethoxyindole)-CH(CH2)3CN-2H); tlc (SiO2, cyclohexane

/EtOAc 1:1, Rf): 0.40.

7-Chloro-2-(2-{3-[1-(7-{1H-tetrazol-5-ylmethoxy}indol-1-yl)-4-(1H-tetrazol-5-yl)-

butyl]phenyl}ethenyl)quinoline (35)

A magnetically stirred solution of the dinitrile 46 (0.75 g, 1.45 mmol) and tributyltin

azide (1.45 g, 4.36 mmol) in dimethoxyethane ( 5 ml) was heated at 150 °C for 5 h,

allowing the solvent to evaporate. After cooling of the reaction mixture to rt, the

crude product was taken up in methanol (15 ml) containing acetic acid (1 ml) and

the solution left overnight. The orange microcrystalline product which had

separated was filtered off, washed with dichloromethane (3 x 1 ml) and dried under

vacuo (0.87 g, 40%). A satisfactory elemental analysis could not be obtained for

this compound. 1H-NMR (270 MHz, MeOD, δH): 1.80 (2H, m, CH2CH2CH2), 2.11

(1H, m, CHCHHCH2), 2.29 (1H, m, CHCHHCH2), 2.90 (2H, t, 3J 7.3 Hz,

CH2CH2Tet), 5.47 (2H, s, OCH2Tet), 6.40 (1H, t, 3J 8.1 Hz, NCHCH2), 6.49 (1H, d,

3J 3.3 Hz, indole 3-H), 6.83 (1H, d, 3J 7.3 Hz, indole 6-H), 6.92 (2H, m, 2 x ArH),

7.16 (4H, m, 4 x ArH), 7.44 (4H, m, 4 x ArH), 7.76 (1H, d, 3J 8.4 Hz, 1 x ArH), 7.87

(1H, d, 3J 8.9 Hz, quinoline 3-H), 7.90 (1H, d, 4J 2.0 Hz, quinoline 8-H), 8.17 (1H,

d, 3J 8.9 Hz, quinoline 4-H); IR (nujol): 3406 (br NH), 1635 (C=C), 1608 (C=C),

1573, 1488, 845, 783, 722 cm-1.

10.4 Experimental for Chapter 3

3-(1,3-Dioxolan-2-yl)bromobenzene (53)

Following the same procedure as for the preparation of the o-isomer,35 a

magnetically stirred solution of 3-bromobenzaldehyde (10.0 g, 54.1 mmol), ethane-

1,2-diol (9.40 g, 0.15 mol) and 4-toluenesulfonic acid monohydrate (0.20 g, 1.08

133

mmol) in benzene (80 ml) was heated under reflux for 3.5 h, using a Dean & Stark

trap to removed the water formed during the reaction. After cooling to rt the

reaction mixture was diluted with water (50 ml) and the organic layer separated.

The water phase was back extracted with ethyl acetate (3 x 20 ml) and the

combined organic extracts washed with brine (3 x 40 ml) and dried over anh

MgSO4. Evaporation of the solvent under reduced pressure gave an oily residue

(11.6 g, 94%). Vacuum distillation of the crude material yielded the title compound

as a colourless oil (11.4 g, 92%), bp 180 °C/0.35 mm, lit156 bp 98-101 °C/0.01 mm;

1H-NMR (60 MHz, CDCl3, δH): 4.04 (4H, s, 2 x CH2), 5.76 (1H, s, CH), 7.18-7.70

(4H, m, 4 x ArH); IR (neat): 2887, 1573, 1474, 1212, 1103, 1080, 883, 786, 696

cm-1; tlc (SiO2, 5% EtOAc in hexane, Rf): 0.21.

3-(1,3-Dioxolan-2-yl)benzaldehyde (54)

According to the method described for the o-isomer,36 to a magnetically stirred

solution of 3-(1,3-dioxolan-2-yl)bromobenzene (53) (6.00 g, 26.2 mmol) in dry

tetrahydrofuran (50 ml) at -74 °C under a nitrogen atmosphere was added

dropwise a 1.6 M solution of n-butyllithium in hexane (17.2 ml, 27.5 mmol)

maintaining the addition temperature below -60 °C. The resulting pale yellow

solution was stirred below -70 °C for 30 min, during which time the lithium salt

separated, then treated dropwise with a solution of N-formylpiperidine (3.26 g, 28.8

mmol) in dry THF (8 ml) keeping the internal temperature below -60 °C. The

reaction mixture was stirred below -40 °C for 1 h, then quenched with aq NH4Cl

(50 ml), and the resulting mixture was extracted with ethyl acetate (3 x 30 ml). The

combined organic extracts were washed with aq NH4Cl (3 x 30 ml), brine (3 x 30

ml), dried over anh MgSO4 and concentrated in a rotary evaporator to yield a

yellow oil (4.46 g, 96%). Bulb to bulb distillation gave the product as a colourless

oil (4.35 g, 93%), bp 210-2 °C/1.2 mm, lit156 bp 95-9 °C/0.01 mm; 1H-NMR (60

MHz, CDCl3, δH): 4.04 (4H, s, 2 x CH2), 5.82 (1H, s, CH), 7.36-8.06 (4H, m, 4 x

134

ArH), 9.98 (1H, s, CHO); IR (neat): 2889, 1700 (CHO), 1609, 1590, 1451, 1151,

1097, 907, 795, 694 cm-1; tlc (SiO2, 20% EtOAc in hexane, Rf): 0.32.

Attempted synthesis of 5-(3-formylphenyl)-5-hydroxypentanenitrile (52)

The same method was followed as for the preparation of the benzyl alcohol 41.

Thus, the aldehyde 54 (4.0 g, 22.4 mmol) was reacted with the zincate 40 (33.6

mmol) in the presence of TiCl4 (22.4 ml, 22.4 mmol). After the usual work up, two

products were isolated after flash column chromatography on silica with 25-60%

EtOAc in light petroleum ether (40-60 °C). Spectroscopic analysis showed them to

be isophthalaldehyde (0.85 g, 28%) and the aldehyde 55 (1.15 g, 22%).

Compound 55 was isolated as a yellow oil from which a satisfactory elemental

analysis could not be obtained due to decomposition of the material. 1H-NMR (90

MHz, CDCl3, δH): 1.87 (4H, m, 2 x CH2), 2.42 (2H, t, 3J 6.5 Hz, CH2CN), 3.07 (1H,

s, D2O exch, OH), 3.47 and 3.73 (4H, AB t, OCH2CH2O), 4.47 (1H, t, 3J 6.5 Hz,

OCHCH2), 7.24-8.00 (4H, m, 4 x ArH), 10.04 (1H, s, CHO); IR (neat): 3477 (OH),

2934, 2246 (CN), 1695 (CHO), 1603, 1454, 1240, 1112, 1058, 890, 803, 699 cm-1;

m/z (%): 247 (5.6, M+), 202 (2.4, M+-(CH2)2OH), 186 (M+-O(CH2)2OH), 179 (94,

M+-(CH2)3CN), 135 (100, M+-(CH2)3CN-(CH2)2OH), 117 (31, M+-(CH2)3CN-

O(CH2)2OH); tlc (SiO2, EtOAc/light petroleum ether [40-60 °C] 1:1, Rf): 0.18.

5-(3-Bromophenyl)-5-hydroxypentanenitrile (56)

Following the same procedure as above, reaction of the zincate 40 (40.0 mmol)

with 3-bromobenzaldehyde (4.95 g, 26.7 mmol) in the presence of titanium

tetrachloride (26.7 ml, 26.7 mmol) yielded the title compound as a yellow oil (3.87

g, 57%) after flash column chromatography on silica with 25% EtOAc in light

petroleum ether (40-60 °C) as eluent. 1H-NMR (270 MHz, CDCl3, δH): 1.77 (4H, m,

2 x CH2), 2.35 (2H, t, 3J 7.1 Hz, CH2CN), 2.96 (1H, s, D2O exch, OH), 4.63 (1H, t,

3J 7.1 Hz, OCHCH2), 7.20-7.60 (4H, m, 4 x ArH); 13C-NMR (22.4 MHz, CDCl3, δC):

17.1 (CH2CN), 21.8 (CH2CH2), 37.5 (CHCH2), 72.5 (CH), 119.6 (CN), 122.9 (3'-C),

135

124.3 (6'-C), 128.9 (5'-C), 130.7 (2'-C), 131.1 (4'-C), 146.4 (1'-C); IR (neat): 3435

(OH), 2939, 2247 (CN), 1595, 1475, 1098, 886, 786, 698; m/z (%): 253/255

(13.8/13.2, M+-H), 185/187 (100/90, M+-H-(CH2)3CN), 157/159 (19/14,

bromophenyl), 77 (60, phenyl); Anal calcd for C11H12BrNO (%): C, 51.99; H, 4.76;

N, 5.51; Found (%): C, 51.79; H, 4.86; N, 5.69; tlc (SiO2, EtOAc/light petroleum

ether [40-60 °C] 1:1, Rf): 0.49.

5-(3-Bromophenyl)-5-chloropentanenitrile (57)

The same procedure as for the synthesis of the benzyl chloride 42 was followed.

Thus, reaction of the benzyl alcohol 56 (1,93 g, 7.59 mmol) with thionyl chloride (5

ml) gave the title compound as a brown oil (1.85 g, 89%). Column chromatography

on silica with 25% EtOAc in light petroleum ether (40-60 °C) yielded the product as

a yellow oil. A satisfactory elemental analysis was not obtained. 1H-NMR (270

MHz, CDCl3, δH): 1.61-1.81 (1H, m, CHCHH), 1.81-2.0 (1H, m, CHCHH), 2.08-

2.28 (2H, m, CH2CH2CH2), 2.40 (2H, t, 3J 6.9 Hz, CH2CN), 4.81 (1H, dd, 3J 6.9

and 7.1 Hz, ClCHCH2), 7.15-7.40 (2H, m, 2 x ArH), 7.45 (1H, m, 1 x ArH), 7.55

(1H, m, 1 x ArH); IR (neat): 2941, 2247 (CN), 1592, 1477, 879, 788, 695; m/z (%):

271/273 (11/15, M+-H), 236/238 (31/30, M+-Cl), 157 (26, M+-Cl-Br), 116 (100, M+-

Cl-Br-CH2CN-H); tlc (SiO2, EtOAc/light petroleum ether [40-60 °C] 1:1, Rf): 0.70.

N-(1-[3-Bromophenyl]-4-cyanobutyl)-7-cyanomethoxyindole (48b)

According to the procedure for compound 46, the indole 45 (1.0 g, 5.80 mmol) was

treated successively with NaH (0.23 g, 5.80 mmol) and the benzyl chloride 57 (1.5

g, 5.50 mmol) to give a dark brown oil. Column chromatography on silica with 25%

EtOAc in light petroleum ether (40-60 °C) as eluent yielded the product as a yellow

oil (0.90 g, 40%). 1H-NMR (270 MHz, CDCl3, δH): 1.66 (2H, m, CH2CH2CH2), 2.34

(2H, t, 3J 6.9 Hz, CH2CN), 2.35 (2H, m, CHCH2), 4.78 (2H, s, OCH2CN), 6.18 (1H,

dd, 3J 6.6 and 8.9 Hz, NCHCH2), 6.59 (1H, d, 3J 3.3 Hz, 3-H), 6.65 (1H, d, 3J 7.6

Hz, 6-H), 7.01 (1H, t, 3J 7.7 Hz, 5'-H), 7.12 (2H, m, 4-H and 6'-H), 7.20 (1H, d, 3J

136

3.3 Hz, 2-H), 7.30 (3H, m, 2'-, 4'- and 5'-H); 13C-NMR (67.8 MHz, CDCl3, δC): 16.8

(CH2CN), 22.4 (CH2CH2), 34.5 (CHCH2), 53.6 (OCH2CN), 59.7 (CH), 103.7 (3-C),

104.4 (6-C), 114.9 (OCH2CN), 116.3 (4-C), 119.1 (CN), 120.0 (5-C), 122.8 (3'-C),

125.0 (2-C), 125.3 (6'-C), 125.7 (3a-C), 129.3 (5'-C), 130.4 (4'-C), 130.8 (2'-C),

131.5 (1'-C), 143. 9 (7a-C), 144.0 (7-C); IR (neat): 2934, 2247 (CN), 1594, 1572;

m/z (%): 407/409 (1.88/1.86, M+-H), 236/238 (1.7/1.5, M+-[7-cy-

anomethoxyindole]), 43 (100); Anal calcd for C21H18BrN3O (%): C, 61.78; H, 4.44;

N, 10.29; Found (%): C, 61.60; H, 4.34; N, 10.29; tlc (SiO2, EtOAc/light petroleum

ether [40-60 °C] 1:1, Rf): 0.45.

7-Cyanomethoxyindoline (59)

A magnetically stirred solution of the indole 45 (4.0 g, 23.2 mmol) in glacial acetic

acid (200 ml) at 10 °C under a nitrogen atmosphere was treated portionwise with

sodium cyanoborohydride (7.30 g, 0.12 mol). The resulting solution was stirred at rt

for 1 h, quenched with water (50 ml) and the AcOH removed under reduced

pressure. The brown residue was basified with 2 M NaOH and the resulting

solution extracted with ethyl acetate (3 x 30 ml). The combined organic extracts

were dried over anh MgSO4 and concentrated to give a yellow/brown oil. The crude

product was passed through silica on a short column using 30-50% EtOAc in light

petroleum ether (40-60 °C) as eluent to afford the title compound as an orange oil

(3.6 g, 90%). 1H-NMR (60 MHz, CDCl3, δH): 3.12 (2H, m, 3-CH2), 3.56 (2H, m, 2-

CH2), 4.70 (2H, s, OCH2CN), 6.60-7.00 (3H, m, 3 x ArH); IR (neat): 3375 (NH),

2850, 1620, 1593, 1490, 1292, 945, 747 cm-1; tlc (SiO2, EtOAc/light petroleum

ether [40-60 °C] 1:1, Rf): 0.26.

Attempted synthesis of 1-(1,3-dioxolan-2yl)-3-(1,3-dithiane-2-yl)benzene (62)

A solution of the aldehyde 54 (1.0 g, 5.61 mmol) and 1,3-propanedithiol (0.79 g,

7.28 mmol) in 1,2-dichloroethane (8 ml) was stirred at rt under nitrogen. AlCl3 (0.25

137

g, 1.90 mmol) was added in small portions (exothermic) and the reaction mixture

stirred for a further 15 min. The turbid liquid was poured into water (30 ml) and the

resulting two-phase mixture extracted with dichloromethane (3 x 20 ml). The

combined organic layers were washed with brine (3 x 20 ml), dried over anh

MgSO4 and concentrated in a rotary evaporator to give a yellow oil that solidified

upon standing. Column chromatography on silica with CH2Cl2 as eluent yielded

two products. The first compound was obtained as a white solid and shown to be

the known bisdithioacetal 61 (0.50 g, 28%), mp 133 °C, lit157 mp 129.0-129.5 °C,

1H-NMR (270 MHz, CDCl3, δH): 1.76-1.99 (2H, m, 2 x SCH2CHHCH2S), 2.03-2.20

(2H, m, 2 x SCH2CHHCH2S), 2.77-2.90 (4H, m, 4 x SCHH), 2.90-3.10 (4H, m, 4 x

SCHH), 5.07 (2H, s, 2 x CH), 7.17-7.29 (1H, m, 5-H), 7.30 (2H, d, 3J 7.9 Hz, 4-

and 6-H), 7.51 (1H, s, 2-H); 13C-NMR (22.4 MHz, CDCl3, δC): 25.1

(SCH2CH2CH2S), 31.9 (SCH2), 51.2 (CH), 127.5 (5-C), 127.8 (4-C), 129.0 (2-C),

139.6 (1-C); IR (nujol): 909, 750, 707 cm-1; m/z (%): 314 (30, M+), 196 (100, M+-

dithiane), 122 (83, [PhCHS]+), 106 (25, [S(CH2)3S]+), 91 (37, tropylium), 77 (30,

phenyl); Anal calcd for C14H18S4 (%): C, 53.46; H, 5.77; S, 40.77; Found (%): C,

53.70; H, 5.54; S, 40.66; tlc (SiO2, CH2Cl2, Rf): 0.54. The second compound was

isolated as a yellow oil that solidified upon standing and was shown to be 3-(1,3-

dithiane-2-yl)benzaldehyde (60) (0.10 g, 8%), mp 57 °C; 1H-NMR (270 MHz,

CDCl3, δH): 1.83-2.03 (1H, m, SCH2CHHCH2S), 2.07-2.23 (1H, m,

SCH2CHHCH2S), 2.85-2.98 (2H, m, 2 x SCHH), 2.98-3.13 (2H, m, 2 x SCHH),

5.23 (1H, s, CH), 7.45 (1H, t, 3J 9.0 Hz, 5-H), 7.73 (1H, d, 3J 9.0 Hz, 4-H), 7.83

(1H, d, 3J 9.0 Hz, 6-H), 8.0 (1H, s, 2-H), 10.00 (1H, s, CHO); 13C-NMR (67.8 MHz,

CDCl3, δC): 24.9 (SCH2CH2), 31.9 (SCH2), 50.6 (CH), 129.39 (6-C), 129.44 (5-C),

129.5 (2-C), 133.8 (4-C), 136.8 (1-C), 140.3 (3-C), 191.8 (CHO); IR (nujol): 1688

(CHO), 1600, 874, 751, 689 cm-1; m/z (%): 224 (100, M+), 150 (43, M+-(CH2)3S),

105 (24, M+-dithiane); Anal calcd for C11H12OS2 (%): C, 58.89; H, 5.39; S, 28.58;

Found (%): C, 58.61; H, 5.22; S, 28.47; tlc (SiO2, CH2Cl2, Rf): 0.41.

138

3-(1,3-Dithiane-2-yl)benzaldehyde (60)

Following the same procedure as above, reaction of isophthalaldehyde (1.0 g, 7.46

mmol) with 1,3-propanedithiol (0.81 g, 7.46 mmol) gave the desired product as a

yellow solid (0.24 g, 14%). Compound 61 was also isolated from this reaction in

14% yield (0.32 g). The remainder of the reaction mixture was shown to be starting

material.

5-(3-[1,3-Dithiane-2-yl]phenyl)-5-hydroxypentanenitrile (63)

Analogous to the procedure used for compound 41, 3-(1,3-dithiane-2-

yl)benzaldehyde (60) (0.15 g, 0.67 mmol) was reacted with the zincate 40 (8.0

mmol) in the presence of TiCl4 (0.67 ml, 0.67 mmol). Column chromatography on

silica with 10% EtOAc in light petroleum ether (40-60 °C) as eluent gave the

desired product as a yellow oil (43.7 mg, 22%). A satisfactory elemental analysis

for this compound could not be obtained. 1H-NMR (270 MHz, CDCl3, δH): 1.62-

2.26 (6H, m, 6 x aliph), 2.37 (2H, t, 3J 7.7 Hz, CH2CN), 2.86-2.98 (2H, m, 2 x

SCHH), 3.00-3.14 (2H, m, 2 x SCHH), 4.71 (1H, dd, 3J 6.8 and 7.4 Hz, OCHCH2),

5.17 (1H, s, SCHS), 7.25-7.48 (4H, m, 4 x ArH); 13C-NMR (67.8 MHz, CDCl3, δC):

17.1 (CH2CN), 21.9 (CHCH2CH2), 25.1 (SCH2CH2), 32.1 (SCH2), 37.6 (CHCH2),

51.4 (SCH), 73.4 (OCH), 119.6 (CN), 125.1 (6'-C), 125.8 (5'-C), 127.3 (2'-C), 129.1

(4'-C), 139.6 (3'-C), 144.7 (1'-C); IR (neat): 3438 (OH), 2932, 2245 (CN), 1604,

705, 760, 907 cm-1; m/z (%): 279 (6.7, M+-N), 224 (1.4, M+-H-(CH2)3CN), 183 (3.8,

M+-(CH2)3CN)-(CH2)3), 167 (11, M+-(CH2)3CN)-(CH2)3-O); tlc (SiO2, EtOAc/light

petroleum ether [40-60 °C] 1:1, Rf): 0.46.

139


S-(-)-2-Amino-3-methyl-1,1-diphenylbutanol (76)

According to the procedure reported by Itsuno et al.,53 in a round bottomed flask

fitted with an addition funnel, magnetic stirrer bar and reflux condenser carrying a

calcium chloride tube, were place magnesium tunnings (6.70 g, 0.28 mol), dry THF

(50 ml) and a crystal of iodine. A solution of bromobenzene (39.3 g, 0.25 mol) in

dry THF (50 ml) was added dropwise until the formation of the Grignard started.

The remaining bromobenzene solution was added at such a rate as to maintain a

gentle reflux. After the addition was complete, the reaction mixture was refluxed for

a further 30 min, then cooled to 0 °C and L-valine methyl ester hydrochloride (5.25

g, 31.3 mmol) added slowly with a spatula, keeping the temperature between 0-10

°C. After 5 h stirring at rt, the reaction mixture was poured into ice (200 ml) and the

resulting suspension was extracted with ethyl acetate (3 x 100 ml). The combined

organics were dried over anh MgSO4 and concentrated in a rotary evaporator to

give a yellow oil that solidified upon standing. The crude product was dissolved in

dichloromethane (20 ml), and 2 M HCl added to precipitate the product as the

hydrochloride salt; this was collected under suction and washed with CH2Cl2 (3 x 5

ml). The free base was released by treatment of the hydrochloride salt with a

boiling mixture of 2 M NaOH (50 ml) and dichloromethane (50 ml). The layers were

separated and the organic solvent evaporated under reduce pressure to yield the

title compound as a white solid after being dried in an oven at 80 °C (3.23 g, 40%),

mp 96 °C, α D23 -127.8 (c 0.006262 gml-1, CHCl3), lit53 mp 95-6 °C, α D

25 -127.7 (c

0.00639 gml-1, CHCl3); 1H-NMR (90 MHz, CDCl3, δH): 0.89 (3H, d, 3J 3.8 Hz,

CH3), 0.97 (3H, d, 3J 3.8 Hz, CH3), 1.80 (1H, m, (CH3)2CH), 3.86 (1H, d, 3J 2.5 Hz,

CHCHNH2), 7.11-7.77 (10H, m, 10 x ArH); IR (nujol): 3338 (br, NH2, OH), 1593,

1489, 693, 743 cm-1; m/z (%): 238 (0.67, M+-OH), 222 (4.4, M+-OH-NH2), 72 (100,

phenyl); Anal calcd for C17H21NO (%): C, 79.96; H, 8.29; N, 5.49; Found (%): C,

79.64; H, 8.30; N, 5.59; tlc (SiO2, EtOAc, Rf): 0.44.

140

1-O-Methyloximino-1-phenylpentan (104)

Ethanol was added dropwise to a mixture of valerophenone (4.86 g, 30.0 mmol),

methoxylamine hydrochloride (2.92 g, 33.0 mmol) and sodium acetate trihydrate

(4.50 g, 33.0 mmol) in water (30 ml) until the solution cleared. The reaction mixture

was refluxed for 5 h and after cooling to rt extracted with diethyl ether (3 x 20 ml).

The combined organic extracts were washed with brine (3 x 20 ml), 5% aq

NaHCO3 (3 x 20 ml) and dried over anh MgSO4. The solvent was removed in a

rotary evaporator to leave a yellow liquid. Bulb to bulb distillation of the crude

product yielded the pure material as a mixture of stereoisomers (5.08 g, 89%), bp

60 °C/0.02 mm; 1H-NMR (90 MHz, CDCl3, δH): 0.80-1.00 (3H, m, CH3), 1.20-1.60

(4H, m, 2 x CH2), 2.74 (2H, t, 3J 7.8 Hz, N=CCH2), 3.80 and 3.97 (3H, s, OCH3),

7.26-7.43 (3H, m, 3 x ArH), 7.51-7.64 (2H, m 2 x ArH); IR (neat): 2957, 1596

(C=N), 1466, 1054 (OMe), 765, 696; m/z (%): 191 (26, M+), 176 (2.8, M+-CH3), 162

(12, M+-CH3CH2), 149 (100, M+-CH3CH2CH), 119 (47, M+-CH3CH2CH2CH2-CH3),

104 (96, M+-CH3CH2CH2CH2-OCH3), 91 (22, M+-CH3CH2CH2CH2-OCH3-N), 77

(39, phenyl); Anal calcd for C12H17NO (%): C, 75.36; H, 8.96; N, 7.32; Found (%):

C, 75.48; H, 8.91; N, 7.36; tlc (SiO2, 10% EtOAc in light petroleum ether [40-60 °

C], Rf): 0.39 and 0.54.

1-Phenylpentylamine (105)

A) A solution of valerophenone (100.0 mg, 0.62 mmol) in methanol (1.4 ml) was

stirred with 4A molecular sieves (75.5 mg) as ammonium acetate was added (0.48

g, 6.2 mmol). After the addition of sodium cyanoborohydride (39.0 mg, 0.62 mmol),

the reaction mixture was stirred at rt for 3 d under a nitrogen atmosphere. The

resulting suspension was filtered through Celite, and the inorganics washed with

CH2Cl2 (10 ml). The organic filtrate was washed with water (3 x 5 ml), dried over

anh MgSO4 and concentrated in a rotary evaporator to yield a yellow liquid. The

crude mixture was acidified with 2 M HCl (5 ml) and the solution extracted with

dichloromethane (1 x 5 ml) . Basification of the aqueous layer with 2 M NaOH and

141

extraction with CH2Cl2 (3 x 5 ml) yielded the product as a clear liquid after being

dried under reduced pressure (10.7 mg, 11%).

B) According to the general procedure described by Feuer and Braunstein,74 to a

solution of the oxime ether 104 (1.35 g, 7.06 mmol) in dry THF (6 ml) at 0 °C under

nitrogen, BH3.THF (1.0 M in THF, 21.2 ml, 10.6 mmol) was added dropwise by

syringe at such a rate that the temperature did not exceed 10 °C. The reaction

mixture was refluxed for 2 h and then cooled to 0 °C. Water (4 ml) was added

cautiously followed by aq KOH (20%, 4 ml) and the resulting mixture was refluxed

for 1 h. The cooled mixture was then extracted with diethyl ether (3 x 20 ml). The

combined organics were washed with brine (3 x 20 ml), dried over anh MgSO4 and

concentrated under reduced pressure to yield a pale yellow liquid. Bulb to bulb

distillation afforded the title compound as a colourless liquid (0.70 g, 61%), bp 90

°C/2 mm, lit158 bp 120 °C/20 mm. The product could also be successfully purified

by flash column chromatography on silica with EtOAc as eluent. A satisfactory

elemental analysis for carbon was not obtained. 1H-NMR (90 MHz, CDCl3, δH):

0.88 (3H, t, 3J 7.1 Hz, CH3), 1.28 (4H, m, 2 x CH2), 1.66 (2H, m, NCHCH2), 3.85

(1H, t, J 7.1 Hz, NCHCH2), 7.30 (5H, m, 5 x ArH); 13C-NMR (22.4 MHz, CDCl3,

dC): 14.0 (CH3), 22.7 (CH2CH3), 28.8 (CH2CH2) , 39.4 (CHCH2), 56.3 (CHNH2),

126.3 (4'-C), 126.8 (2'-C), 128.4 (3'-C), 147.0 (1'-C); IR (neat): 3386 (NH2), 3333

(NH2), 2957, 1602, 1453, 757, 696 cm-1; m/z (%): 165 (1.0, M++2H), 106 (100,

M+-(CH2)3CH3), 77 (12, phenyl); tlc (SiO2, 10% EtOAc in light petroleum ether [40-

60 °C], Rf): 0.10.

(-)-1-Phenylpentylamine (105*)

A solution of BH3.THF (1.0 M solution in THF, 13.08 ml, 13.08 mmol) was added

dropwise to a stirred solution of the S-(-)-aminoalcohol 76 (1.67 g, 6.54 mmol) in

dry THF (6.5 ml) at 0°C under a nitrogen atmosphere. The resulting mixture was

stirred at the same temperature for 8 h, then a solution of the oxime ether 104 (1.0

142

g, 5.23 mmol) in dry THF (3 ml) was added by syringe, keeping the internal

temperature between 0 and 10 °C. The reaction mixture was stirred at rt for 24 h

and then decomposed by the addition of 2 M HCl (10 ml). Evaporation of the THF

deposited the hydrochloride salt of the chiral auxiliary 76 as a white solid, which

was collected under suction and washed with water (10 ml). The aqueous acidic

filtrate was basified with 2 M NaOH and the solution extracted with diethyl ether (3

x 20 ml). The combined organic extracts were dried over anh MgSO4 and

evaporated under reduced pressure to yield a pale yellow liquid. The product was

obtained as a colourless liquid after being purified as above (0.44 g, 52%), α D25

-11.41 (c 0.008410 gml-1, CHCl3) 70% ee, lit159 α D22 -13.9 (neat) 83% ee. The

enantiomeric excess was determined by proton NMR spectroscopy with 10

equivalents of 2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE, 106) as the chiral

solvating agent at 60 °C. All the other spectroscopic data were identical to those of

the racemate 105.

5-(3-Bromophenyl)-5-oxopentanenitrile (110)

A) A solution of NaHSO3 (5.62 g, 54.0 mmol) in water (4 ml) was added to 3-

bromobenzaldehyde (10.0 g, 54.0 mmol). The reaction mixture spontaneously

warmed up with formation of a white solid. The precipitate of (107) was filtered off

under suction, washed with petroleum ether (40-60 °C, 10 ml), then ethanol (10 ml)

and subsequently used in the next step; mp 165 °C; IR (nujol): 3249 (OH), 1572,

1198, 1069, 880, 762, 698 cm-1; m/z (%): 264 (0.84, M+-Na-2H), 183 (94, M+-

SO3Na-2H), 155/157 (47/46, bromophenyl), 77 (29, phenyl), 64 (29, SO2).

The crude sulfonate 107 was suspended in water (7 ml) and an aq solution of

dimethylamine (25%, 11.2 ml, 58.3 mmol) added dropwise. The white suspension

was stirred at rt for 1.5 h, then a solution of NaCN (2.53 g, 56.2 mmol) in water (5

ml) was added dropwise at 0 °C. The reaction mixture was stirred overnight at rt

and extracted with diethyl ether (3 x 20 ml). The combined organic extracts were

washed with aq NaHSO3 (3 x 20 ml), brine (3 x 20 ml) and dried over anh MgSO4.

143

Evaporation of the solvent under reduced pressure yielded a clear oil (108) after

being dried under vacuo (10.8 g, 83%). 1H-NMR (270 MHz, CDCl3, δH): 2.33 (6H,

s, 2 x CH3), 4.83 (1H, s, CH), 7.29 (1H, t, 3J 8.3 Hz, 5-H), 7.50 (2H, m, 4- and 6-H),

7.70 (1H, s, 2-H); 13C-NMR (67.8 MHz, CDCl3, δC): 42.0 (CH3), 62.7 (CH), 114.7

(CN), 123.2 (3'-C), 126.6 (6'-C), 130.6 (4'-C), 131.0 (5'-C), 132.4 (2'-C), 136.3 (1'-

C).

To a solution of diisopropylamine (7.0 ml, 49.6 mmol) in dry THF (30 ml) containing

TMEDA (14.0 ml, 90.0 mmol), n-BuLi (2.5 M solution in hexane, 20.0 ml, 49.6

mmol) was added dropwise keeping the temperature below -10 °C under a

nitrogen atmosphere. The reaction mixture was stirred for 30 min and allowed to

warm up to 0 °C, then cooled down to -78 °C and a solution of the aminonitrile 108

(9.18 g, 38.4 mmol) in dry THF (10 ml) added drowise under nitrogen. After 10 min

neat bromobutyronitrile (3.8 ml, 38.4 mmol) was added slowly and the reaction

mixture was stirred for a further 1 h at -78 °C. The yellow solution was warmed up

to rt and poured into aq NH4Cl (50 ml). The resulting two phase mixture was

extracted with diethyl ether (3 x 30 ml), and the combined organics were dried over

anh MgSO4 and concentrated in a rotary evaporator to give a yellow oil. Column

chromatography on silica with 20% EtOAc in light petroleum ether (40-60 °C)

afforded compound 109 as a yellow oil (11.5 g, 98%). A satisfactory elemental

analysis for nitrogen could not be obtained. 1H-NMR (270 MHz, CDCl3, δH): 1.20-

1.30 (1H, m, NCCCHH), 1.50-1.70 (1H, m, NCCCHH), 2.20-2.40 (10H, m, 10 x

aliph H), 7.30 (1H, t, 3J 7.4 Hz, 5-H), 7.50 (2H, m, 4- and 6-H), 7.70 (1H, s, 2-H);

13C-NMR (67.8 MHz, CDCl3, δC): 16.9 (CH2CN), 20.7 (CH2CH2CH2), 39.0

(Me2NCCH2), 40.9 (NCH3), 70.9 (Me2NC), 116.9 (CCN), 118.6 (CH2CN), 123.2

(3'-C), 125.2 (6'-C), 129.4 (4'-C), 130.5 (5'-C), 132.2 (2'-C), 140.2 (1'-C); IR (neat):

2962, 2246 (CN), 1594, 1473, 892, 788, 698 cm-1; m/z (%): 305/307 (0.37/0.34,

M+-H), 278/280 (14/12, M+-CN-2H), 238/240 (100/97, M+-(CH2)3CN), 159 (15, M+-

(CH2)3CN-Br), 116 (44, M+-(CH2)3CN-Br-NMe2), 44 (21, NMe2).

144

To a solution of 109 (11.5 g, 37.6 mmol) in ethanol (190 ml) was added

CuSO4.5H2O (24.0 g, 96.1 mmol) and the reaction mixture was refluxed for 2 h.

After being cooled to rt, the inorganics were filtered through Celite and washed

with ethanol (3 x 10 ml). The filtrate was diluted with diethyl ether (200 ml) and the

organic solution was washed with brine (3 x 80 ml). The organic phase was dried

over anh MgSO4 and concentrated in a rotary evaporator to give a brown residue.

Column chromatography on silica with 20% EtOAc in light petroleum ether (40-60

°C) as eluent yielded the title compound 110 as a yellow solid (4.80 g, 50%).

B) According to the procedure described for the synthesis of compound 112, the

benzyl alcohol 56 (1.0 g, 3.93 mmol) was oxidised with DMSO (0.57 ml, 7.87

mmol) in the presence of TFAA (0.86 ml, 5.90 mmol), to yield the product (0.83 g,

84%) as a yellow solid, mp 68 °C, after column chromatography on silica with 25%

EtOAc in light petroleum ether (40-60 °C) as eluent. 1H-NMR (270 MHz, CDCl3,

δH): 2.12 (2H, quin, 3J 5.9 Hz, CH2CH2CH2), 2.53 (2H, t, 3J 5.9 Hz, CH2CN), 3.16

(2H, t, 3J 5.9 Hz, COCH2), 7.38 (1H, t, 3J 7.9 Hz, 5-H), 7.72 (1H, ddd, 3J 7.9 Hz

and 4J 1.3 and 1.3 Hz, 4-H), 7.89 (1H, tt, 3J 7.9 Hz and 4J 1.3 Hz, 6-H), 8.10 (1H, t,

4J 1.3 Hz, 2-H); 13C-NMR (22.4 MHz, CDCl3, δC): 16.6 (CH2CN), 19.7 (CH2CH2),

36.5 (COCH2), 119.2 (CN), 123.2 (3'-C), 126.5 (6'-C), 130.4 (5'-C), 131.1 (2'-C),

136.6 (4'-C), 138.3 (1'-C), 196.7 (CO); IR (nujol): 2246 (CN), 1689 (CO), 1565,

786, 683 cm-1; m/z (%): 251/253 (13.8/13.2, M+-H), 183/185 (100/98, M+-H-

(CH2)3CN), 76 (17, phenyl); Anal calcd for C11H10BrNO (%): C, 52.41; H, 4.00; N,

5.56; Found (%): C, 52.47; H, 3.84; N, 5.44; tlc (SiO2, EtOAc/light petroleum ether

[4-60 °C] 1:1, Rf): 0.55. The product can also be recrystallised from ethanol, but

large quantities are required.

145

5-(3-Bromophenyl)-5-O-methyloximinopentanenitrile (111)

According to the preparation of compound 104, reaction of the ketone 110 (0.50 g,

1.98 mmol) with methoxylamine hydrochloride (0.17 g, 2.05 mmol) gave the

desired product after column chromatography on silica with 25% EtOAc in light

petroleum ether (40-60 °C) as eluent, as a pale yellow oil (0.43 g, 77%). 1H-NMR

(90 MHz, CDCl3, δH): 2.95 (2H, m, CH2CH2CH2), 2.38 ( 2H, t, 3J 7.9 Hz, CH2CN),

2.92 (2H, t, 3J 7.9 Hz, MeONCCH2), 3.86 and 4.00 (3H, s, OCH3), 7.25-7.62 (3H,

m, 4'-, 5'- and 6'-H), 7.83 (1H, t, 4J 2.6 Hz, 2'-H); 13C-NMR (22.4 MHz, CDCl3, δC):

17.0 (CH2CN), 22.4 (CH2CH2), 25.1 (MeONCCH2), 62.2 (OCH3), 119.0 (CN),

122.9 (3'-C), 124.6 (6'-C), 129.1 (5'-C), 130.1 (2'-C), 132.3 (4'-C), 137.0 (1'-C),

154.9 (CNOMe); IR (neat): 2938, 2247 (CN), 1589 (C=N), 1458, 1051 (OMe), 903,

787, 693 cm-1; m/z (%): 280/282 (88/87, M+-H), 249/251 (29/28, M+-OMe-H),

197/199 (57/51, M+-OMe-(CH2)2CN), 182/184 (100/97, M+-OMe-(CH2)3CN),

155/157 (58/57, bromophenyl), 102 (81, M+-OMe-(CH2)3CN-Br), 76 (67, phenyl);

Anal calcd for C12H13BrN2O (%): C, 51.27; H, 4.66; N, 9.96; Found (%): C, 51.38;

H, 4.53; N, 9.95; tlc (SiO2, EtOAc in light petroleum ether [40-60 °C] 1:1, Rf): 0.57

and 0.66.

5-{3-[2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}-5-oxopentanenitrile (112)

Using the method described by Swern et al.,77 to a magnetically stirred solution of

dry DMSO (1.60 ml, 21.5 mmol) in dry CH2Cl2 (12 ml) at -60 °C under nitrogen,

trifluoroacetic anhydride (2.30 ml, 16.2 mmol) was added dropwise, keeping the

temperature between -50 to -60 °C. After 10 min below -60 °C, a solution of the

benzyl alcohol 41 (3.90 g, 10.8 mmol) in dichloromethane (20 ml) was added

dropwise, maintaining the temperature below -50 °C. The reaction mixture was

stirred below -60 °C for 30 min, followed by addition of triethylamine (4.30 ml, 30.8

mmol), keeping the temperature between -50 to -60 °C. After warming up to rt, the

reaction mixture was washed with water (3 x 20 ml) and the aqueous layer back

extracted with CH2Cl2 (3 x 10 ml). The combined organics were dried over anh

146

MgSO4 and concentrated under vacuo to give a yellow residue. Flash column

chromatography of the crude material on silica with 25-40% EtOAc in light

petroleum ether (40-60 °C) as eluent, yielded the pure product as a yellow solid

(2.31 g, 60%), mp 128 °C. 1H-NMR (90 MHz, CDCl3, δH): 2.0-2.40 (2H, m,

CH2CH2CH2), 2.57 (2H, t, 3J 5.6 Hz, CH2CN), 3.23 (2H, t, 3J 7.0 Hz, COCH2), 7.30

(1H, d, 3J 4.2 Hz, quinoline 3-H), 7.36-8.30 (10H, m, 10 x ArH); 13C-NMR (22.4

MHz, CDCl3, δC): 16.7 (CH2CN), 19.8 (CH2CH2CH2), 36.6 (COCH2), 119.3 (CN),

119.7 (quinoline 3-C), 125.9 (quinoline 4a-C), 127.0 ,127.5, 128.1, 128.3, 128.8,

129.4, 129.9, 132.0, 133.9, 135.8 (quinoline 7-C), 136.4 (quinoline 4-C), 137.1,

149.3 (quinoline 8a-C), 156.9 (quinoline 2-C), 198.3 (CO); IR (nujol): 2245 (CN),

1679 (CO), 1591, 1495 cm-1; m/z (%): 360 (0.64, M+), 195 (51, M+-[7-

chloroquinoline]), 126 (100, M+-[7-chloroquinoline]-(CH2)3CN); Anal calcd for

C22H17ClN2O (%): C, 73.23; H, 4.75; N, 7.76; Found (%): C, 73.30; H, 4.54; N,

7.65; tlc (SiO2, EtOAc/light petroleum ether [40-60 °C] 1:1, Rf): 0.44.

3-(2-(7-Chloroquinolin-2-yl)ethenyl)-benzaldehyde-O-methyloximinobenzene (113)

Following the same procedure as for compound 114, the aldehyde 28 (1.0 g, 3.40

mmol) was reacted with methoxylamine hydrochloride (0.29 g, 3.52 mmol) to yield

the product, after the usual workup, as a yellow solid. Recrystallisation from

EtOH/H2O (1:1) afforded the pure compound (0.43 g, 39%), mp 104 °C. 1H-NMR

(60 MHz, CDCl3, δH): 4.06 (3H, s, OCH3), 7.20-8.32 (12H, m, 11 x ArH and 1 x

CHN); IR (nujol): 1608 (C=C), 1592 (C=N), 1497, 1065 (OMe), 832, 787, 690 cm-1;

m/z (%): 322/324 (24/8, M+), 289 (100, M+-OMe-2H), 264/266 (11/3, M+-

CHNOMe), 228 (5.7, M+-CHNOMe-Cl); Anal calcd for C19H15ClN2O (%): C, 70.70;

H, 4.68; N, 8.68; Found (%): C, 70.98; H, 4.50; N, 8.33; tlc (SiO2, 30% EtOAc in

light petroleum ether [40-60 °C], Rf): 0.18 and 0.50.

147

5-{3-[2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}-5-O-methyloximinopentanenitrile

(114)

A solution of the ketone 112 (1.0 g, 2.77 mmol) and methoxylamine hydrochloride

(0.24 g, 2.87 mmol) in pyridine (10 ml) and ethanol (10 ml) was refluxed for 4 h.

After cooling to rt, the solvent was removed under reduce pressure in a rotary

evaporator and the residue taken up in CH2Cl2 (50 ml). The organic phase was

washed with water (3 x 20 ml) and concentrated under vacuo to give a brown oil.


°C) as eluent yielded the desired product as a pale yellow oil after being dried

under reduced pressure with a vacuum pump (0.93 g, 86%). A satisfactory

elemental analysis was not obtained. 1H-NMR (270 MHz, CDCl3, δH): 1.78 (2H, m,

CH2CH2CH2), 2.24 (2H, m, CH2CN), 2.80 (NCCH2), 3.73 and 3.89 (3H, s, OCH3),

7.67-8.00 (11H, m, 11 x ArH); IR (neat): 2936, 2247 (CN), 1611 (C=C), 1596

(C=N), 1496, 1050 (OMe), 844, 705 cm1; m/z (%): 105 (35, [PhCH2N]+), 43 (100,

[CHNO]+); tlc (SiO2, EtOAc/light petroleum ether [40-60 °C] 1:1, Rf): 0.50 and 0.61.

2-(3-Bromobenzylideneamino)-3-methyl-1,1-diphenylbutanol (115)

A suspension of 3-bromobenzaldehyde (0.50 g, 2.70 mmol), the S-aminoalcohol

76 (0.69 g, 2.70 mmol) and anh MgSO4 (0.65 g, 5.40 mmol) in CHCl3 (10 ml) was

refluxed for 48 h under a nitrogen atmosphere. After cooling to rt, the reaction

mixture was filtered through Celite and the filtrate concentrated in a rotary

evaporator to give a yellow oil after being dried under vacuo (1.12 g, 98%). 1H-

NMR (90 MHz, CDCl3, δH): 0.50 (3H, d, 3J 5.6 Hz, CH3), 1.03 (3H, d, 3J 5.6 Hz,

CH3), 1.86 (1H, m, (CH3)2CH), 2.60 (1H, br s, D2O exch, OH), 3.92 (1H, d, 3J 5.6

Hz, CHCH), 7.00-8.00 (15H, m, 14 x ArH and CH=N); IR (neat): 3338 (OH), 2959,

1653 (C=N), 1597, 1491, 881, 785, 701; m/z (%): 329/331 (1.20/1.18, M+-Ph-Me-

H), 184/186 (93/91, [BrPhCHNH]+), 155/157 (45/45, bromophenyl), 91 (54,

tropylium); tlc (SiO2, EtOAc, Rf): 0.50.

148

(-)-5-(3-Bromophenyl)-5-hydroxypentanenitrile (56*)

According to the procedure for compound 105*, reaction of the ketone 110 (100.0

mg, 0.40 mmol) with BH3.THF (0.80 ml, 0.80 mmol) and the chiral auxiliary 76

(102.1 mg, 0.40 mmol) gave the title compound, after the usual workup, as a

yellow oil (74.2 mg, 74%), α D25 -14.87 (c 0.007420 gml-1, CHCl3), 80% ee (see

Table 2, Entry 4). The enantiomeric excess was determined at rt as described

previously. The spectroscopic data for this product were in accordance with those

of the racemic material 56.

(+)-5-(3-Bromophenyl)-5-hydroxypentanenitrile (56*)

Asymmetric reduction of compound 110 (0.20 g, 0.79 mmol) as described above,

except that commercially available S-(-)-a,a-diphenyl-2-pyrrolidinemethanol (0.20

g, 0.79 mmol) was used as the chiral auxiliary, gave the title compound as a yellow

oil (0.13 g, 65%), α D25 +12.27 (c 0.007660 gml-1, CHCl3), 66% ee (see Table 2,

Entry 3). The enantiomeric excess was determined as above. The spectroscopic

data corresponded to those of the racemate 56.

5-Azido-5-(3-bromophenyl)pentanenitrile (117)

The benzyl alcohol 56 (2.33 g, 9.17 mmol) and diphenylphosphoryl azide (2.50 ml,

11.14 mmol) were dissolved in dry toluene (30 ml). The resulting reaction mixture

was cooled to 0 °C, neat DBU (1.70 ml, 11.14 mmol) was added and the mixture

was stirred for 2 h at the same temperature under a nitrogen atmosphere. After

being stirred overnight at rt, the resulting two-phase mixture was washed with

water (3 x 20 ml) and 5% HCl (3 x 20 ml). The organic layer was dried over anh

MgSO4 and concentrated under reduced pressure to give a brown oil. Column

chromatography of the crude product on silica with CH2Cl2 as eluent yielded the

title compound as a yellow oil (2.0 g, 78%). 1H-NMR (270 MHz, CDCl3, δH): 1.56-

1.95 (4H, m, 2 x CH2), 2.37 (2H, t, 3J 6.7 Hz, CH2CN), 4.46 (1H, dd, 3J 5.6 and 7.6

Hz, N3CHCH2), 7.24-7.32 (2H, m , 5'- and 6'-H), 7.45-7.51 (2H, m, 2'- and 4'-H);

149

13C-NMR (67.8 MHz, CDCl3, δC): 16.9 (CH2CN), 22.1 (CH2CH2), 35.2 (CHCH2),

64.8 (CH), 119.0 (CN), 123.1 (3'-C), 125.4 (6'-C), 129.8 (5'-C), 130.6 (2'-C), 131.7

(4'-C), 141.2 (1'-C); IR (neat): 2941, 2247 (CN), 2104 (N3), 1595, 1476, 884, 788,

698 cm-1; m/z (%): 278/280 (4.23/4.14, M+-H), 250/252 (11.7/9.5, M+-N2-H),

236/238 (16.3/15.7, M+-N3-H), 223/225 (86/81, M+-N4), 197 (97, M+-Br-H), 182/184

(92/89, M+-N3-(CH2)2CN-H), 155/157 (51/50, bromophenyl), 116 (100, M+-Br-N3-

CH2CN-H); Anal calcd for C11H11BrN4 (%): C, 47.33; H, 3.97; N, 20.07; Found (%):

C, 47.32; H, 3.91; N, 19.72; tlc (SiO2, CH2Cl2, Rf): 0.59.

(-)-5-Azido-5-(3-bromophenyl)pentanenitrile (117*)

The title compound was obtained from the (+)-alcohol 56* according to the above

procedure, α D25 -49.12 (c 0.006393 gml-1, CHCl3). The spectroscopic data for this

compound corresponded to those of the racemate 117. The enantiomeric excess

could not be determined, as there was no complexation with TFAE 106.

5-Amino-5-(3-bromophenyl)pentanenitrile (50b)

A) Reduction of ketone 110 (100.0 mg, 0.40 mmol), following method A) as

described for the synthesis of compound 105, gave the desired product as a pale

yellow oil (13.5 mg, 14%). Attempts to purify the crude material by column

chromatography on silica or neutral alumina led to decomposition.

B) A mixture of powdered tellurium (0.11 g, 0.90 mmol), sodium borohydride (81.0

mg, 2.14 mmol) and dry ethanol (1.7 ml) was refluxed under a nitrogen

atmosphere until the tellurium disappeared. After cooling to rt, a solution of the

azide 117 (100.0 mg, 0.36 mmol) in dry diethyl ether (1 ml) was added dropwise

and the reaction mixture was stirred overnight. The suspension was filtered

through Celite, the inorganics washed with ethanol (3 x 5 ml), and the filtrate

concentrated to yield a brown oil. Acidic workup of this residue, as described for

150

the amine 105, yielded the title compund as a pale yellow oil (6.4 mg, 7%, see

Table 1, Entry 4).

C) The azide 117 (100.0 mg, 0.36 mmol) was mixed with triphenylphosphine

(94.42 mg, 0.36 mmol), which resulted in spontaneous evolution of nitrogen. THF

(3 ml) and water (1 ml) were added to the resulting suspension and the two-phase

mixture was stirred overnight at rt under a nitrogen atmosphere. The product was

obtained as a pale yellow oil following the same acidic workup as above (8.2 mg,

9%, see Table 1, Entry 5).

D) A magnetically stirred solution of CuSO4.5H2O (0.90 mg, 3.6.10-3 mmol) in

methanol (1 ml) was cooled in an ice bath and treated portionwise with NaBH4

(13.62 mg, 0.36 mmol). A solution of the azide 117 (100.0 mg, 0.36 mmol) in

methanol (0.5 ml) was added dropwise to the resulting black suspension and the

mixture was stirred overnight under N2. After the usual acidic workup the product

was obtained as a pale yellow oil after being dried under vacuo (10.7 mg, 12%,

see Table 1, Entry 6).

E) To a magnetically stirred solution of the azide 117 (0.20 g, 0.72 mmol) and

hexadecyltributylphosphonium bromide (36.55 mg, 0.072 mmol) in toluene (1 ml),

a solution of NaBH4 (81.71 mg, 2.16 mmol) in water (2 ml) was added dropwise at

80 °C. The reaction mixture was stirred at the same temperature for a further 2 h.

After cooling to rt the layers were separated and the organic phase exposed to the

usual acidic work up. The product was obtained as a pale yellow oil (54.41 mg,

30%, see Table 1, Entry 7).

F) A magnetically stirred solution of the azide 117 (2.0 g, 7.16 mmol) in dry MeOH

(18 ml), was treated with a 3-fold excess of 1,3-propanedithiol (2.2 ml, 21.48 mmol)

under a nitrogen atmosphere. Triethylamine ( 2.75 ml, 21.48 mmol) was added by

151

syringe and the reaction mixture was stirred overnight under N2 at rt. The

precipitated 1,2-dithiolane160 was filtered under suction and washed with CH2Cl2 (3

x 5 ml). The filtrate was diluted with CH2Cl2 (20 ml) and the resulting solution was

washed with water (3 x 10 ml) and dried over anh MgSO4. The solvent was

removed under reduced pressure in a rotary evaporator to yield a yellow liquid.

The usual acidic treatment of the crude material, gave the product as a pale

yellow oil (1.09 g, 60%, see Table 1, Entry 8). A satisfactory elemental analysis

could not be obtained. 1H-NMR (270 MHz, CDCl3, δH): 1.50-1.90 (4H, m, 2 x CH2),

2.34 (2H, t, 3J 6.8 Hz, CH2CN), 3.90 (1H, t, 3J 6.8 Hz, H2NCHCH2), 7.23 (2H, m,

4'- and 6'-H), 7.39 (1H, m, 5'-H), 7.48 (1H, s, 2'-H); 13C-NMR (67.8 MHz, CDCl3,

δC): 17.3 (CH2CN), 22.3 (CH2CH2), 38.0 (CHCH2), 55.3 (CH), 119.5 (CN), 123.0

(3'-C), 125.0, 129.5, 130.03, 130.04, 148.0 (1'-C); IR (neat): 3377 (NH2), 3310

(NH2), 2933, 2246 (CN), 1593, 1474, 886, 785, 698 cm-1; m/z (%): 252/254

(4.7/4.0, M+), 223/225 (2.4/2.4, M+-NH2-N+H), 184/186 (100/93, M+-(CH2)3CN),

105 (8, M+-Br-(CH2)3CN+H), 77 (20, phenyl), [Found: m/z (EI) 252.0260; Calc for

C11H13BrN2: 252.0262]; tlc (SiO2, CH2Cl2, Rf): 0.08.

(-)-5-Amino-5-(3-bromophenyl)pentanenitrile (50b*)

Reduction of the (-)-azide 117* following the above method F) gave the desired

product in 58% yield, α D25 -10.69 (c 0.004210 gml-1, CHCl3). The spectroscopic

data for this compound corresponded to those of the racemate 50b. The

enantiomeric excess could not be determined, as there was no complexation with

TFAE 106.

152


2,4,6-Trimethyl-3-nitropyridine (135)

In accordance with the method described by Plazek,112 2,4,6-trimethylpyridine

(16.4 ml, 0.12 mol) was dropped slowly into 70 ml of fuming sulphuric acid (20%

SO3), and the resulting mixture was heated to 100C. During the next 30 min

potassium nitrate (30.0 g, 0.30 mol) was added portionwise, and the solution

further heated at the same temperature for 5 h. The reaction mixture was cooled,

poured slowly into ice (1000 ml), and the resulting mixture carefully made alkaline

with a mixture of sodium and potassium hydroxide pellets. The inorganics were

filtered under suction, and the aqueous layer extracted with diethyl ether (3 x 200

ml). The combined organic layers were dried over potassium hydroxide, and

concentrated in a rotary evaporator to give a brown residue. Distillation of the

crude material yielded the product as a white crystalline solid (5.35 g, 26%), bp

200C, mp 37 C, lit112 bp 228-30 C, mp 38 C. 1H-NMR (60 MHz, CDCl3, δH): 2.30

(3H, s, 4-CH3), 2.56 (6H, s, 2-CH3 and 6-CH3), 6.96 (1H, s, 5-H); IR (nujol): 1604,

1528 (NO2), 1457 (NO2), 1322, 934, 834 cm-1; tlc (SiO2, EtOAc, Rf): 0.61.

1,2,4,6-Tetramethyl-3-nitropyridinium iodide (136)

A solution of the 3-nitropyridine 135 (2.16 g, 13.0 mmol) in MeI (7 ml) was heated

for 4 h in a sealed tube at 100C. After cooling of the reaction mixture to rt, the

precipitated product was collected under suction, washed with ethanol (5 ml), and

dried in an oven at 70C to give the crude material as orange crystals ( 3.20 g,

80%). Recrystallisation from ethanol afforded the pure product as orange plates

(2.86 g, 71%), mp 240 C, lit113 mp 210-11 C. 1H-NMR (60 MHz, DMSO-d6, δH):

2.52 (3H, s, 6-CH3), 2.74 (3H, s, 4-CH3), 2.84 (3H, s, 2-CH3), 4.12 (3H, s, NCH3),

8.18 (1H, s, 5-H); IR (nujol): 1640, 1550 (NO2), 1020, 850 cm-1; m/z (%): 180

(12.5, M+-H-I), 166 (31.2, M+-CH3-I), 120 (100, M+-H-I-CH3-NO2); Anal calcd for

C9H13IN2O2 (%): C, 35.08; H, 4.25; N, 9.09; Found (%): C, 35.32; H, 4.05; N, 8.90.

153

N-Methyl-2-propylimine (137)

A 25-30% aqueous solution of methylamine (66.8 ml, 0.50 mol) was

added dropwise to magnetically stirred acetone (18.4 ml, 0.25 mol) at 0C under a

nitrogen atmosphere. Then solid KOH was poured into the reaction mixture until

the bottom of the flask was covered, keeping the same temperature. The flask was

filled with nitrogen, securely stoppered, and allowed to stand at rt for 48 h with

occasional agitation. After cooling in an ice bath the flask was opened, the layers

separated, and the organic phase distilled under a nitrogen atmosphere to yield the

desired product as a clear liquid (13.6g, 76%), bp 67-8 C, nD20 1.4021, lit114 bp

65-6 C, nD20 1.4023. 1H-NMR (60 MHz, CDCl3, δH): 1.88 (3H, s, CH3), 2.04 (3H, s,

CH3), 3.12 (3H, s, NCH3); IR (neat): 1675 cm-1 (C=N).

N-Methyl-2-butylimine (142)

Following the same procedure as above, butanone (44.7 ml, 0.50 mol) was reacted

with aqueous methylamine (133.6 ml, 1.0 mol) to give the title compound after

distillation as a colourless liquid (14.2 g, 43%), bp 78-80 C, nD20 1.404; 1H-NMR

(270 MHz, CDCl3, δH): 0.84 (3H, t, 3J 8.3 Hz, CH3CH2), 1.81 (3H, s, CH3C=N),

2.24 (2H, q, 3J 8.3 Hz, CH3CH2C=N), 3.08 (3H, s, NCH3); IR (neat): 1669 cm-1

(C=N).

N-Methyl-4-methyl-2-pentylimine (144)

Following the same procedure as for the preparation of compound 137, 4-methyl-

2-pentanone (15.6 ml, 0.13 mol) was reacted with aqueous methylamine (33.4 ml,

0.25 mol) in the presence of solid KOH to yield the desired product after distillation

as a colourless liquid (9.02 g, 65%), bp 98 C; 1H-NMR (60 MHz, CDCl3, δH): 0.94

(6H, d, 3J 7.2 Hz, (CH3)2CH), 1.82 (3H, s, CH3C=N), 2.00-2.28 (3H, m,

(CH3)2CHCH2C=N), 3.12 (3H, s, NCH3); IR (neat): 1665 cm-1 (C=N).

154

N-Cyclohexyl-1-phenyl-2-propylimine (145)

To a magnetically stirred solution of cyclohexylamine (12.6 ml, 0.11 mol) in 30 ml

of dry diethyl ether, 20 g of anh Na2SO4 and phenylacetone ( 13.4 ml, 0.10 mol)

were added at -20 °C. The reaction mixture was allowed to stand at rt for 40 h, the

inorganics were filtered off, and the solvent was evaporated under reduced

pressure. The residue was distilled under vacuo to yield the product as a

colourless liquid (0.60 g, 2.8%), bp 75-80 C/0.3 mm, lit115 bp 155-160 C/15 mm.

The product was found to polymerise readily during distillation. 1H-NMR (60 MHz,

CDCl3, δH): 0.92-2.02 (10H, m, 5 x CH2), 1.70 (3H, s, CH3C=N), 3.15-3.27 (1H, m,

CHN), 3.52 (2H, s, PhCH2C=N ), 7.26 (5H, s, 5 x ArH); IR (neat): 1660 cm-1 (C=N).

N-Cyclohexyl-2-propylimine (146)

The same procedure as above was followed. Reaction of cyclohexylamine (12.6

ml, 0.11 mol) with dry acetone (7.3 ml, 0.10 mol) in the presence of anh Na2SO4

gave the desired product after distillation under reduced pressure as a colourless

liquid (4.80 g, 35%), bp 28 C/0.3 mm, lit116 bp 181 or 67-9 C/17 mm. 1H-NMR (270

MHz, CDCl3, δH): 0.96-1.82 (10H, m, 5 x CH2), 1.84 (3H, s, CH3C=N), 1.99 (3H, s,

CH3C=N), 3.15-3.27 (1H, m, CHN); IR (neat): 1665 cm-1 (C=N).

N-Benzyl-2-propylimine (148)

Following the same procedure, benzylamine (12.0 ml, 0.11 mol) was condensed

with acetone (7.3 ml, 0.10 mol) to give the title compound after vacuum distillation

as a clear liquid (3.80 g, 23%), bp 52 C/0.2 mm, lit117 bp 107 C/13 mm. 1H-NMR

(60 MHz, CDCl3, δH): 1.88 (3H, s, CH3C=N); 2.04 (3H, s, CH3C=N); 4.40 (2H, s,

PhCH2N); 7.24 (5H, s, 5 x ArH); IR (neat): 1663 cm-1 (C=N).

Note: GC and spectroscopic analyses of the prepared imines showed them always

to be contaminated with the corresponding ketone, presumably due to the easy

hydrolysis of the Schiff bases.

155

3-Nitropyridine (152)

Based on the procedure described by Schickh et al.,118 to a magnetically stirred

solution of fuming sulphuric acid (100 ml, 20% SO3) and 30% aq H2O2 (50 ml), a

solution of 3-aminopyridine (5.0 g, 52.6 mmol) in conc sulphuric acid (14 ml) was

added dropwise at 0 C. The reaction mixture was kept at 0 C for 5 h, for 4 d at rt,

and then poured slowly onto ice (1000 ml). The acidic aqueous solution was

carefully made alkaline with NaOH pellets, and the resulting mixture extracted with

diethyl ether (3 x 200 ml). The combined organic extracts were dried over anh

MgSO4 and the solvent evaporated under reduced pressure to leave a brown

residue. The crude material was purified by column chromatography on silica gel

with ethyl acetate as eluent to afford the product as a yellow solid (1.0 g, 15%), mp

37 C, lit118 mp 35-6 C. 1H-NMR (60 MHz, CDCl3, δH): 7.52 (1H, dd, 3J 4.8 and 8.4

Hz, 5-H), 8.48 (1H, dd, 4J 2.4 and 3J 8.4 Hz, 4-H), 8.90 (1H, d, 3J 4.8 Hz, 6-H),

9.40 (1H, d, 4J 2.4 Hz, 2-H); tlc (SiO2, EtOAc, Rf): 0.58.

1-Methyl-3-nitropyridinium iodide (153)

The same procedure as for compound 136 was followed. Reaction of 152 (0.98 g,

7.9 mmol) with MeI (5 ml) gave the title compound after recrystallisation from EtOH

as yellow crystals (1.96 g, 93%), mp 208 C, lit161 mp 212-15 C; 1H-NMR (60 MHz,

DMSO-d6, δH): 4.52 (3H, s, NCH3), 8.24-8.64 (1H, m, 5-H), 9.12-9.52 (2H, m, 4-H

and 6-H), 10.10 (1H, s, 2-H); IR (nujol): 1647, 1588, 1548 (NO2), 1356 (NO2),

1030, 729, 689 cm-1; m/z (%): 143 (100, M+-I+3H), 139 (4.1, M+-I), 127 (25, M+-I-

CH3+3H), 124 (6.3, M+-I-CH3); Anal calcd for C6H7IN2O2 (%): C, 27.09; H, 2.65; N,

10.53; Found (%): C, 27.09; H, 2.47; N, 10.27.

General Procedures for the Synthesis of Polyalkylindoles111

A) The 3-nitropyridinium salt (100.0 mg) was dissolved in 1.2 ml of dry DMF. To

this orange solution 3 mol equivalents of the corresponding N-methylketimine was

156

added at rt, which resulted in spontaneous darkening of the solution (dark brown).

The reaction mixture was kept at rt for 3 d then poured onto ice (10 ml); when the

product precipitated out of solution it was collected under suction, otherwise it was

extracted with CH2Cl2 (3 x 10 ml). The combined organic layers were washed with

brine (3 x10 ml), dried over anh MgSO4 and concentrated under vacuo to leave a

brown residue. The crude material was column chromatographed on silica with

cyclohexane/ethyl acetate (2.5:1) as eluent to yield the pure product.

B) A mixture of the 3-nitropyridinium salt (100.0 mg), 3 mol equivalents of the

corresponding amine, and 15 mol equivalents of the appropriate ketone (15.0

mmol) was kept at rt for 4 d. Again spontaneous darken of the reaction mixture

was observed. The 3-nitropyridium salt, contrary to the previous procedure,

dissolved only very slowly, and needed the whole reaction time to completely

disappear. The same work up method as described above was then followed.

Modifications of the above procedures and yields of the corresponding

polyalkylindoles obtained are summarised in Table 4.

1,2,4,6-Tetramethylindole (138)

The product was obtained as a pale yellow solid, mp 81 °C, lit162 mp 82-3 °C;

1H-NMR (60 MHz, CDCl3, δH): 2.46 (9H, m, 2-, 4- and 6-CH3), 3.62 (3H, s, NCH3),

6.22 (1H, s, 3-H), 6.72 (1H, s, 5-H), 6.92 (1H, s, 7-H); m/z (%): 173 (100,M+), 158

(33, M+-CH3); tlc (SiO2, cyclohexane/EtOAc 2.5:1, Rf): 0.27.

1,2,4,6,7-Pentamethylindole (143)

The product was obtained as a pale yellow solid, mp 132 °C, lit163 mp 132-34 °C;

1H-NMR (60 MHz, CDCl3, δH): 2.36 (9H, m, 4-, 6- and 7-CH3), 2.62 (3H, s, 2-CH3),

3.90 (3H, s, NCH3), 6.18 (1H, s, 3-H), 6.70 (1H, s, 5-H); IR (nujol): 1591, 1557,

157

1329, 1303, 1208, 1060, 1020, 824, 772, 739 cm-1; m/z (%): 187 (100, M+), 172

(64, M+-CH3); Anal calcd for C13H17N (%): C, 83.37; H, 9.15; N, 7.48; Found (%):

C, 83.14; H, 9.27; N, 7.14; tlc (SiO2, cyclohexane/EtOAc 2.5:1, Rf): 0.26.

1-Cyclohexyl-2,4,6-trimethylindole (147)

The product was obtained as a yellow oil, lit164 mp 53-5 °C; 1H-NMR (270 MHz,

CDCl3, δH): 1.20-2.38 (10H, m, 5 x CH2), 2.44 (9H, m, 2-, 4- and 6-CH3), 4.09 (1H,

m, CHN ), 6.17 (1H, s, 3-H), 6.74 (1H, s, 5-H), 7.18 (1H, s, 7-H); IR (neat): 2932,

2359, 1653, 1609, 1558, 1447, 1400, 1381, 1333, 1313, 1286, 1233, 1054, 827,

772, 736 cm-1; m/z(%): 241 (100, M+), 198 (3.5, M+-(CH3)2CH), 159 (57, M+-

cyclohexyl+H), 158 (38, M+-cyclohexyl); tlc (SiO2, cyclohexane/EtOAc 2.5:1, Rf):

0.64.

1-Benzyl-2,4,6-trimethylindole (149)

The product was obtained as a yellow oil, 1H-NMR (270 MHz, CDCl3, δH): 2.34

(3H, s, 6-CH3), 2.38 (3H, s, 4-CH3), 2.50 (3H, s, 2-CH3), 5.26 (2H, s, PhCH2N),

6.28 (1H, s, 3-H), 6.73 (1H, s, 5-H), 6.85 (1H, s, 7-H), 6.98 (2H, dd, 4J 1.8 Hz and

3J 8.0 Hz, 2'- and 6'-H), 7.05-7.48 (3H, m, 3'-, 4'- and 5'-H); 13C-NMR (67.8 MHz,

CDCl3, δC): 12.8 (6-CH3), 18.6 (4-CH3), 21.8 (2-CH3), 46.4 (CH2), 98.7 (3-C),

106.9 (7-C), 121.7 (5-C), 126.0 (4'-C), 126.4 (3a-C), 126.7 (6-C), 127.1 (3'-C),

128.7 (2'-C), 130.6 (4-C), 135.3 (7a-C), 137.3 (2-C), 138.1 (1'-C); IR (neat): 2923,

2359, 1716, 1662, 1604, 1551, 1527, 1495, 1453, 1400, 1381, 1332, 1295, 1241,

1207, 1072, 1028, 826, 775, 731, 697 cm-1; m/z (%): 249 (65, M+), 173 (100, M+-

phenyl), 91 (87, tropylium) [Found: m/z (EI) 249.1517; Calc for C18H19N:

249.1517]; tlc (SiO2, cyclohexane/EtOAc 2.5:1, Rf): 0.57.

(+)-1-(a-Methylbenzyl)-2,4,6-trimethylindole (150)165

The product was obtained as a yellow oil, α D25 18.6 (c 0.00335 gml-1, CHCl3); 1H-

NMR (270 MHz, CDCl3, δH): 1.94 (3H, d, 3J 6.7 Hz, CH3CHN), 2.30 (6H, s, 4- and

158

6-CH3), 2.48 (3H, s, 2-CH3), 5.73 (1H, q, 3J 6.7 Hz, CH3CHN), 6.25 (1H, s, 3-H),

6.68 (1H, s, 5-H), 6.73 (1H, s, 7-H), 7.15 (2H, d, 3J 7.3 Hz, 2'- and 6'-H), 7.20-7.35

(3H, m, 3'-, 4'- and 5'H); 13C-NMR (67.8 MHz, CDCl3, δC): 14.1 (6-CH3), 18.6 (4-

CH3), 18.7 (CH3), 21.8 (2-CH3), 52.3 (CH), 99.4 (3-C), 108.5 (7-C), 121.3 (5-C),

126.2 (4'-C), 126.8 (3a-C), 127.0 (6-C), 128.5 (3'-C), 128.6 (2'-C), 130.0 (4-C),

135.4 (7a-C), 136.2 (2-C), 141.7 (1'-C); IR (neat): 2916, 2361, 1714, 1655, 1605,

1550, 1527, 1495, 1448, 1393, 1376, 1333, 1278, 1237, 1057, 1027, 832, 773,

740, 698 cm-1; m/z (%): 263 (55, M+), 159 (100, M+-phenethyl), 105 (56,

phenethyl), 77 (11, phenyl); tlc (SiO2, 30% EtOAc in light petroleum ether (40-60 °

C), Rf): 0.60.


7-Oxo-4,5,6,7-tetrahydrobenzofuran (181)

An aqueous solution of chloroacetaldehyde (50%, 14.0 ml, 0.11 mol) and sodium

hydrogen carbonate (10.0 g, 0.12 mol) were added to water (80 ml) at 0-5 °C. To

this mixture, a solution of 1,2-cyclohexanedione (11.2 g, 0.10 mol) in water (90 ml)

was added dropwise under stirring, keeping the same temperature as above. The

resulting yellow solution was stirred overnight at rt to give a red solution, which was

diluted with EtOAc (100 ml). The reaction mixture was acidified with concentrated

sulphuric acid (pH 1) and stirred for a further 1 h at rt. The layers were separated,

the organic phase washed with aqueous sodium carbonate solution (3 x 50 ml) and

dried over anh MgSO4. Evaporation of the solvent under reduced pressure yielded

a brown oil. Flash column chromatography of the crude material on silica with 10%

EtOAc in light petroleum ether (40-60 °C) as eluent yielded the title compound as a

yellow oil that solidified upon standing (2.40 g, 18%), mp 60 °C, lit132 mp 58-61 °C.

1H-NMR (270 MHz, CDCl3, δH): 2.16 (2H, m, 5-CH2), 2.57 (2H, t, 3J 6.14 Hz, 4-

CH2), 2.78 (2H, t, 3J 6.14 Hz, 6-CH2), 6.43 (1H, d, 3J 2.45 Hz, 3-CH), 7.58 (1H, d,

159

3J 2.45 Hz, 2-CH); 13C-NMR (67.8 MHz, CDCl3, δC): 23.0 (5-C), 24.4 (4-C), 38.3

(6-C), 111.6 (3-C), 140.0 (7a-C), 147.4 (2-C), 147.7 (3a-C), 186.3 (CO); IR (neat):

3122, 2941, 1663 (CO), 1434, 1108, 889, 810 cm-1; m/z (%): 136 (100, M+), 121

(21, M++H-O); Anal calcd for C8H8O2 (%): C, 70.57; H, 5.92; Found (%): C, 70.60;

H, 5.86; tlc (SiO2, 50% EtOAc in light petroleum ether (40-60 °C), Rf): 0.36.

General Procedure for the Synthesis of N-Substituted 4- and 7-Oxo-4,5,6,7-

tetrahydroindoles

A solution of 4- or 7-oxo-4,5,6,7-tetrahydrobenzofuran (100.0 mg, 0.73 mmol) and

three equivalents of the corresponding amine in 20% aqueous ethanol (~2 ml) was

heated in a sealed tube at 150 °C for 12 or 36 h respectively. The reaction mixture

was poured into water (10 ml) and the resulting solution extracted with

dichloromethane (3 x 10 ml). The combined organic extracts were dried over anh

MgSO4, concentrated in a rotary evaporator and the brown residue

chromatographed on silica gel to give the corresponding 4- or 7-oxo-4,5,6,7-

tetrahydroindole.

1-Methyl-7-oxo-4,5,6,7-tetrahydroindole (162)


°C) as eluent afforded the title compound as a yellow oil (23.9 mg, 22%). 1H-NMR

(270 MHz, CDCl3, δH): 2.06 (2H, m, 5-CH2), 2.47 (2H, t, 3J 5.94 Hz, 4-CH2), 2.73

(2H, t, 3J 5.94 Hz, 6-CH2), 3.91 (3H, s, NCH3), 5.96 (1H, d, 3J 2.18 Hz, 3-H), 6.72

(1H, d, 3J 2.18 Hz, 2-H); 13C-NMR (67.8 MHz, CDCl3, δC): 24.0 (5-C), 25.3 (4-C),

36.6 (6-C), 39.3 (NCH3), 106.6 (3-C), 130.3 (2-C), 131.1 (7a-C), 137.7 (3a-C),

189.3 (CO); IR (neat): 2920, 1650 (CO), 1510, 1440, 1410, 1210, 1005, 760 cm-1;

m/z (%): 149 (100, M+), 134 (8.1, M+-CH3); tlc (SiO2, 5% EtOAc in light petroleum

160

ether (40-60 °C), Rf): 0.07. The 1H-NMR and the IR spectra were in agreement

with the published spectroscopic data.124

7-Oxo-4,5,6,7-tetrahydroindole (166)


°C) as eluent yielded the title compound as a white solid (35.5 mg, 36%), mp 92-5

°C, lit126 mp 95 °C. 1H-NMR (270 MHz, CDCl3, δH): 2.11 (2H, m, 5-CH2), 2.52

(2H, t, 3J 5.70 Hz, 4-CH2), 2.77 (2H, t, 3J 5.7 Hz, 6-CH2), 6.10 (1H, d, 3J 2.28 Hz,

3-H), 7.07 (1H, d, 3J 2.28 Hz, 2-H), 10.78 (1H, br s, D2O exch, NH); 13C-NMR

(22.4 MHz, CDCl3, δC): 23.5 (5-C), 25.4 (4-C), 37.9 (6-C), 108.6 (3-C), 126.2 (2-

C), 128.2 (7a-C), 137.6 (3a-C), 189.0 (CO); IR (nujol): 3270 (NH), 1680 (CO) cm-1;

m/z (%): 135 (100, M+), 118 (10, M+-O-H), 79 (64, cyclohexyl); tlc (SiO2, 50%

EtOAc in light petroleum ether (40-60 °C), Rf): 0.36.

1-Benzyl-7-oxo-4,5,6,7-tetrahydroindole (190)




(2H, t, 3J 6.16 Hz, 6-CH2), 5.52 (2H, s, PhCH2N), 6.01 (1H, d, 3J 2.16 Hz, 3-H),

6.81 (1H, d, 3J 2.16 Hz, 2-H), 7.14-7.35 (5H, m, 5 x ArH); 13C-NMR (67.8 MHz,

CDCl3, δC): 24.0 (5-C), 25.0 (4-C), 39.4 (6-C), 52.0 (PhCH2N), 107.4 (3-C), 126.5

(7a-C), 127.5 (4'-C), 128.6 (3'-C), 129.5 (2'-C), 138.1 (1'-C), 189.0 (CO); IR (neat):

2933, 1646 (CO), 1499, 1411, 1304, 1213, 1005, 759, 732, 708 cm-1; m/z (%): 225

(100, M+), 91 (65, tropylium); tlc (SiO2, 5% EtOAc in light petroleum ether (40-60

°C), Rf): 0.09. The 1H-NMR and the IR spectra were in agreement with the

published spectroscopic data.129

161

(+)-1-(α-Methylbenzyl)-7-oxo-4,5,6,7-tetrahydroindole (192)


°C) as eluent afforded the title compound as a yellow oil. Modifications of the

general procedure and yields are summarise in Table 6. α D20 140.7 (c 0.006610

gml-1, CHCl3). 1H-NMR (270 MHz, CDCl3, δH): 1.75 (3H, d, 3J 7.07 Hz, CH3CHN),

2.03 (2H, m, 5-CH2), 2.45 (2H, t, 3J 6.71 Hz, 4-CH2), 2.73 (2H, t, 3J 6.36 Hz, 6-

CH2), 6.01 (1H, d, 3J 2.83 Hz, 3-H), 6.60 (1H, q, 3J 7.07 Hz, CH3CHN), 6.94 (1H,

d, 3J 2.83 Hz, 2-H), 7.18-7.35 (5H, m, 5 x ArH); 13C-NMR (22.4 MHz, CDCl3, δC):

21.6 (CH3), 24.0 (5-C), 25.0 (4-C), 39.6 (6-C), 55.5 (NCH), 107.3 (3-C), 126.0 (2-

C), 126.5 (2'-C), 127.3 (3'-C), 128.5 (4'-C), 138.1 (3a-C), 142.6 (1'-C), 188.8 (CO);

IR (neat): 2934, 1645 (CO), 1495, 1411, 1285, 1205, 1003, 759 cm-1; m/z (%): 239

(75, M+), 224 (4.3, Me+-CH3), 135(100, M++H-phenethyl), 105 (73, phenethyl);

Anal calcd for C16H17NO (%): C, 80.30; H, 7.16; N, 5.85; Found (%): C, 80.50; H,

7.19; N, 6.15; tlc (SiO2, 5% EtOAc in light petroleum ether (40-60 °C), Rf): 0.09.

1-(α-Butylbenzyl)-7-oxo-4,5,6,7-tetrahydroindole (193)



(270 MHz, CDCl3, δH): 0.87 (3H, t, 3J 7.38 Hz, CH3), 1.20-1-41 (4H, m, 2 x CH2),

1.97-2.17 (4H, m, 2 x CH2), 2.45 (2H, tt, 2J 2.11 Hz and 3J 6.33 Hz, 4-CH2), 2.72

(2H, tt, 2J 1.99 Hz and 3J 6.33 Hz, 6-CH2), 6.02 (1H, d, 3J 2.51 Hz, 3-H), 6.50 (1H,

t, 3J 7.85 Hz, NCH), 7.03 (1H, d, 3J 2.51 Hz, 2-H), 7.28 (5H, m, 5 x ArH); 13C-NMR

(67.8 MHz, CDCl3, δC): 13.9 (CH3), 22.4 (CH3CH2), 24.1 (5-C), 24.9 (4-C), 28.6

(CH2CH2), 35.4 (CHCH2), 39.8 (6-C), 59.9 (NCH), 107.5 (3-C), 125.9 (2-C), 126.7

(7a-C), 127.0 (2'-C), 127.4 (3'-C), 128.5 (4'-C), 137.9 (3a-C), 141.9 (1'-C), 189.1

(CO); IR (neat): 2931, 1646 (CO), 1491, 1411, 1282, 1202, 1009, 757 cm-1; m/z

(%): 281 (61, M+), 146 (50, phenylpentyl), 117 (45, phenylpropyl), 104 (22,

phenethyl), 91 (100, tropylium), 77 (13, phenyl); tlc (SiO2, 5% EtOAc in light

petroleum ether (40-60 °C), Rf): 0.12.

162

1-Cyclohexyl-7-oxo-4,5,6,7-tetrahydroindole (194)


°C) as eluent afforded the title compound as a green oil that solidified upon

standing (54.6 mg, 34%), mp 58-60 °C. 1H-NMR (270 MHz, CDCl3, δH): 1.49 (4H,

m, 2 x CH2), 1.17-1.43 (4H, m, 2 x CH2), 2.00-2.14 (4H, m, 2 x CH2), 2.47 (2H, t,

3J 6.00 Hz, 4-CH2), 2.74 (2H, t, 3J 6.00 Hz, 6-CH2), 4.95-5.10 (1H, m, NCH), 5.99

(1H, d, 3J 2.91 Hz, 3-H), 7.04 (1H, d, 3J 2.91 Hz, 2-H); 13C-NMR (67.8 MHz,

CDCl3, δC): 24.1 (5-C), 25.0 (4-C), 25.6 (4'-C), 25.8 (3'-C), 34.4 (2'-C), 39.9 (6-C),

56.5 (1'-C), 106.9 (3-C), 125.0 (2-C), 126.1 (7a-C), 137.8 (3a-C), 188.8 (CO); IR

(nujol): 1646 (CO), 1494, 1430, 1412, 1205, 1004, 753 cm-1; m/z (%): 217 (63,

M+), 135 (100, M+-cyclohexyl); tlc (SiO2, 5% EtOAc in light petroleum ether (40-60

°C), Rf): 0.13. A satisfactorily elemental analysis could not be obtained.

1-Phenethyl-7-oxo-4,5,6,7-tetrahydroindole (195)




(2H, t, 3J 6.75 Hz, 6-CH2), 3.01 (2H, t, 3J 7.40 Hz, CH2Ph), 4.44 (2H, t, 3J 7.40 Hz,

NCH2), 5.89 (1H, d, 3J 2.16 Hz, 3-H), 6.55 (1H, d, 3J 2.16 Hz, 2-H), 7.09-7.31 (5H,

m, 5 x ArH); 13C-NMR (67.8 MHz, CDCl3, δC): 24.0 (5-C), 25.2 (4-C), 38.1 (6-C),

39.4 (CH2Ph), 51.0 (NCH2), 106.5 (3-C), 126.2 (7a-C), 126.4 (2-C), 128.4 (4'-C),

129.0 (3'-C), 129.7 (2'-C), 138.3 (3a-C), 138.5 (1'-C), 188.6 (CO); IR (neat): 2936,

1645 (CO), 1499, 1411, 1309, 1211, 1004, 754 cm-1; m/z (%): 239 (78, M+), 148

(100, M+-benzyl), 135 (96, M+-phenethyl+H), 92 (17, tropylium), 77 (14, phenyl);

Anal calcd for C16H17NO (%): C, 80.30; H, 7.16; N, 5.85; Found (%): C, 80.00; H,

7.12; N, 6.17; tlc (SiO2, 5% EtOAc in light petroleum ether (40-60 °C), Rf): 0.09.

163

1-(α-Butylbenzyl)-4-oxo-4,5,6,7-tetrahydroindole (196)

Column chromatography on silica with 5% and then 50% EtOAc in light petroleum

ether (40-60 °C) as eluent afforded the title compound as a yellow oil (14.4 mg,

8%). 1H-NMR (270 MHz, CDCl3, δH): 0.91 (3H, t, 3J 7.34 Hz, CH3), 1.24-1.44 (4H,

m, 2 x CH2), 2.02-2.24 (4H, m, 2 x CH2), 2.40-2.80 (4H, m, 2 x CH2), 5.35 (1H, t,

3J 7.71 Hz, CHN), 6.62 (1H, d, 3J 3.44 Hz, 3-H), 6.79 (1H, d, 3J 3.44 Hz, 2-H),

7.08-7.40 (5H, m, 5 x ArH); 13C-NMR (67.8 MHz, CDCl3, δC): 13.9 (CH3), 22.1

(CH3CH2), 22.4 (5-C), 23.6 (4-C), 28.8 (CH2CH2), 35.2 (CHCH2), 37.8 (6-C), 60.6

(NCH), 105.7 (3-C), 119.5 (2-C), 120.9 (7a-C), 126.3 (2'-C), 127.8 (3'-C), 128.9 (4'-

C), 141.0 (3a-C), 143.7 (1'-C), 194.4 (CO); IR (neat): 2931, 1653 (CO), 1496,

1413, 1111 700 cm-1; m/z (%): 281 (17, M+), 147 (16, phenylpentyl), 117 (23

phenylpropyl), 104 (11, phenylethyl), 91 (100, tropylium), 77 (18, phenyl); tlc (SiO2,

50% EtOAc in light petroleum ether (40-60 °C), Rf): 0.49.


7-Hydroxybenzofuran (207)

To a magnetically stirred solution of diisopropylamine (0.35 ml, 2.50 mmol) in dry

THF (10 ml), n-butyllithium (2,5 M solution in hexane, 1.10 ml, 2.75 mmol) was

added at -40 °C under a nitrogen atmosphere. After stirring at the same

temperature for 1 h, a solution of 7-oxo-4,5,6,7-tetrahydrobenzofuran (181, 0.34 g,

2.50 mmol) in dry THF (5 ml) was added dropwise keeping the temperature below

-20 °C. The deep yellow solution was stirred for a further 1 h, then

chlorotrimethylsilane (0.32 ml, 2.50 mmol) was added slowly below -20 °C. The

reaction mixture was allowed to warm up to room temperature, and after stirring for

1 h the solvent was distilled under reduced pressure. Dry hexane (20 ml) was

added and the insoluble material removed by filtration. The organic filtrate was

concentrated under vacuo to yield a yellow oil (206) that was subsequently used in

164

the next step without further purification [tlc (SiO2, 30% EtOAc in light petroleum

ether (40-60 °C), Rf): 0.88].

The crude silyl enol ether 206 was taken up in dry acetonitrile (10 ml) and stirred in

the presence of Pd(OAc)2 (0.56 g, 2.50 mmol) for 4 h at rt. The inorganics were

filtered through Celite, washed with CH2Cl2 (5 ml), and the filtrate concentrated

under reduce pressure to yield a yellow oil. Column chromatography of this residue

on silica with 30% EtOAc in light petroleum ether (40-60 °C) as eluent gave the title

compound as a white solid, mp 42-45 °C, lit166 mp 43 °C ; 1H-NMR (60 MHz,

CDCl3, δH): 6.80-7.20 (5H, m, 5 x ArH); IR (neat): 3400 (br, OH), 2959, 1625,

1595, 1476, 1251, 1075, 843; tlc (SiO2, 30% EtOAc in light petroleum ether (40-60

°C), Rf): 0.34.

(+)-6-Iodo-7-oxo-1-(a-methylbenzyl)-4,5,6,7-tetrahydroindole (209)

A) The title compound was prepared according to the above procedure by reaction

of the 7-oxotetrahydroindole 192 (0.44 g, 1.84 mmol) with LDA [n-butyllithium (0.88

ml, 2.2 mmol), diisopropylamine (0.28 ml, 2.20 mmol)] and iodine (0.51 g, 2.02

mmol). Column chromatography on silica with 5% EtOAc in light petroleum ether

(40-60 °C) as eluent gave the product as a yellow oil (99.0 mg, 15%).

B) Following the method described by Kotnis,146 iodine crystals (0.48 g, 1.9 mmol)

were added to a solution of 192 (0.23 g, 0.95 mmol) in methanol (3 ml). The

reaction mixture was refluxed and stirred for 4 h under N2. After cooling of the dark

brown solution to rt the solvent was removed under vacuo, the dark brown residue

thus obtained was dissolved in CH2Cl2 (10 ml), and the mixture was washed with a

saturated solution of sodium bicarbonate (3 x 10 ml), sodium thiosulfate (3 x 10

ml), 5% sodium hydroxide (3 x 10 ml) and water (3x 10 ml) before being dried over

anh MgSO4. The solvent was distilled in a rotary evaporator to give a brown oil.

Column chromatography as above afforded the desired product as a

diastereomeric mixture (0.21 g, 60%), α D22 151.2 (c 0.008030 gml-1, CHCl3). 1H-

165

NMR (270 MHz, CDCl3, δH): 1.77 (3H, t, 3J 7.10 Hz, CHCH3), 2.00-2.29 (2H, m, 5-

CH2), 2.50-2.77 (2H, m, 4-CH2), 4.81 (1H, t, 3J 3.59 Hz, CHI), 6.05 and 6.06 (1H,

d, 3J 2.63 Hz, 3-H), 6.54 (1H, q, 3J 7.10 Hz, CH3CH), 6.98 and 7.05 (1H, d, 3J 2.63

Hz, 2-H), 7.14-7.35 (5H, m, 5 x Ar'H); IR (neat): 2930, 1646 (CO), 1495, 1425,

1285, 765, 701 cm-1; m/z (%): 365 (1.5, M+), 238 (100, M+-I), 105 (56,

phenylethyl), 77 (13, phenyl), [Found: m/z (EI) 365.0277; Calc for C16H16INO:

365.0277]; tlc (SiO2, CH2Cl2, Rf): 0.55.

A second fraction was isolated in low yield (35.0 mg, 10%) after column

chromatography and identified as 3-iodo-7-oxo-1-(a-methylbenzyl)-4,5,6,7-

tetrahydroindole (210): 1H-NMR (270 MHz, CDCl3, δH): 1.75 (3H, d, 3J 7.43 Hz,

CHCH3), 2.06 (2H, m, 5-CH2), 2.48 (2H, t, 3J 6.75 Hz, 4-CH2), 2.60 (2H, t, 3J 6.62

Hz, 6-CH2), 6.60 (1H, q, 3J 7.43 Hz, CHCH3), 7.00 (1H, s, 2-H), 7.20-7.38 (5H, m,

5 x Ar'H); 13C-NMR (67.8 MHz, CDCl3, δC): 21.7 (CH3), 24.6 (5-C), 24.9 (4-C),

39.2 (6-C), 56.1 (CH), 63.1 (3-C), 126.6 (2'-C), 127.2 (7a-C), 127.7 (3'-C), 128.7

(4'-C), 130.0 (2-C), 140.5 (3a-C), 141.7 (1'-C), 188.5 (CO); IR (neat): 2930, 1653

(CO), 1452, 1375, 1074, 697 cm-1; m/z (%): 365 (64, M+), 261 (100, M++H-

phenylethyl), 105 (92, phenylethyl), 77 (23, phenyl); tlc (SiO2, CH2Cl2, Rf): 0.34.

(+)-7-Cyanomethoxy-1-(a-methylbenzyl)indole (212)

A mixture of compound 209 (95.9 mg, 0.26 mmol) and neat DBU (2 ml) was stirred

for 15 min at rt under a nitrogen atmosphere. The dark brown solution was poured

into water (10 ml) and the solution was extracted with CH2Cl2 (3 x 10 ml). The

combined organic layers were washed with saturated aqueous NH4Cl solution (3 x

10 ml), dried over anh MgSO4 and concentrated in a rotary evaporator to give a

brown oil (211). This residue was subsequently used in the next step without

further purification. 1H-NMR (270 MHz, CDCl3, δH): 1.85 (3H, d, 3J 7.11 Hz,

CH3CH), 6.46 (1H, d, 3J 3.41 Hz, 3-H), 6.60 (1H, dd, 4J 1.14 Hz and 3J 7.82 Hz, 6-

H), 6.68 (1H, q, 3J 7.11 Hz, CH3CH), 6.86 (1H, t, 3J 7.82 Hz, 5-H), 7.08-7.31 (7H,

m, 7 x ArH); tlc (SiO2, CH2Cl2, Rf): 0.40.

166

A solution of the crude 7-hydroxyindole 211 in butanone (2 ml) was degassed with

N2. Anhydrous K2CO3 (90.0 mg, 0.65 mmol) and bromoacetonitrile (0.03 ml, 0.43

mmol) were added and the mixture refluxed for 1h under N2. The cooled reaction

mixture was poured into 2 M HCl (10 ml) and the resulting solution was extracted

with dichloromethane (3 x 10 ml). The combined organic extracts were dried over

anh MgSO4 and concentrated in vacuo to give a brown oil. Column

chromatography of this residue on silica with 5% EtOAc in light petroleum ether

(40-60 °C) as eluent afforded the title compound as a yellow oil (35.1 mg, 48%),

α D20 132.5 (c 0.001940 gml-1, CHCl3). 1H-NMR (270 MHz, CDCl3, δH): 1.90 (3H,

d, 3J 6.97 Hz, CH3CH), 4.69 (2H, d, 2J 6.75 Hz, OCH2), 6.31 (1H, q, 3J 6.97 Hz,

CH3CH), 6.55 (1H, d, 3J 3.22 Hz, 3-H), 6.64 (1H, d, 3J 7.72 Hz, 6-H), 7.00 (1H, t,

3J 7.72 Hz, 5-H), 7.04-7.09 (2H, m, 2 x Ar'H), 7.20-7.32 (4H, m, 3-H and 3 x Ar'H),

7.35 (1H, dd, 4J 1.07 Hz and 3J 7.72 Hz , 4-H); 13C-NMR (67.8 MHz, CDCl3, δC):

22.5 (CH3), 54.0 (OCH2), 56.8 (CHN), 102.2 (3-C), 104.6, 115.0 (CN), 116.3,

119.7, 125.7, 126.0 (3a-C), 126.1, 127.2, 128.6, 131.9 (7a-C), 144.1 (1'-C), 144.8

(7-C); IR (neat): 2930, 1573, 1453, 1233, 721, 699 cm-1; m/z (%): 276 (30, M+),

172 (17, M+-phenylethyl+H), 132 (20, M+-phenylethyl-CH2CN+H), 105 (100,

phenylethyl), 77 (14, phenyl), [Found: m/z (EI) 276.1263; Calc for C18H16N2O:

276.1263]; tlc (SiO2, CH2Cl2, Rf): 0.59.


Attempted preparation of 5-(3-bromophenyl)-5-(7-oxo-4,5,6,7-tetrahydroindol-1-yl)-

pentanenitrile (182)

Reaction of the benzofuran 181 with the benzylamine 50b in a sealed tube at 150

°C following the general procedure described previously for the synthesis of 4- and

7-oxotetrahydroindoles gave, after column chromatography on silica with 50%

EtOAc in light pet ether (40-60 °C) as eluent, exclusively the lactam 213 as a white

167

solid (0.28 g, 51%), mp 104 °C. 1H-NMR (270 MHz, CDCl3, δH): 1.51-1.90 (3H, m,

3 x aliph H), 1.99-2.13 (1H, m, 1 x aliph H), 2.35 (2H, m, CH2CO), 4.67 (1H, dd, 3J

7.41 and 7.80 Hz, CH2CHN), 7.22-7.49 (5H, m 5 x ArH); 13C-NMR (67.8 MHz,

CDCl3, δC): 19.0, 31.1, 31.7 (CH2CO), 56.6 (CHN), 122.7 (3-C), 124.8, 129.1,

130.3, 130.7, 145.1 (1-C), 172.8 (HNCO); IR (nujol): 3193 (NH), 3071 (NH), 1649

(CO), 1593, 1400, 880, 789, 698 cm-1; m/z (%): 253/255 (42/39, M+), 174 (100,

M+-Br); Anal calcd for C11H12BrNO (%): C, 51.99; H, 4.76; N, 5.51, Br, 31.44;

Found (%): C, 52.09; H, 4.52; N, 5.35; Br, 31.27; tlc (SiO2, 50% EtOAc in light

petroleum ether (40-60 °C), Rf): 0.09.

1-(3-Bromophenyl)-4-(1H-tetrazol-5-yl)butan-1-one (215)

According to the procedure for the bis-tetrazole 35, reaction of 110 (100.0 mg, 0.40

mmol) with Bu3SnN3 (132.8 mg, 0.40 mmol) gave a brown oil. After treatment of

the crude material with glacial acetic acid in methanol for several days, the desired

product separated as a yellow solid (64.3 mg, 55%), mp 122 °C. 1H-NMR (270

MHz, DMSO-d6, δH): 2.05 (2H, m, CH2CH2CH2), 2.95 (2H, t, 3J 6.75 Hz, CH2Tet),

3.16 (2H, t, 3J 6.75 Hz, COCH2), 7.50 (1H, t, 3J 8.10 Hz, 5'-H), 7.85 (1H, d, 3J 8.10

Hz, 4'-H), 7.96 (1H, d, 3J 8.10 Hz, 6'-H), 8.08 (1H, s, 2'-H); 13C-NMR (67.8 MHz,

DMSO-d6, δC): 37.0, 122.1 (3'-C), 126.8 (6'-C), 130.3 (5'-C), 130.9 (2'-C), 135.7

(4'-C), 138.5 (1'-C), 155.6 (tetrazole-C), 198.2 (CO); IR (neat): 2955, 1692 (CO),

1590, 1464, 878, 779, 680 cm-1; m/z (CI, %): 295/297 (100/95, M+); tlc (SiO2, 50%

EtOAc in light petroleum ether (40-60 °C), Rf): 0.15. A satisfactory elemental

analysis for nitrogen was not obtained.

1-(3-Bromophenyl)-4-(1H-tetrazol-5-yl)butan-1-one-O-methyloxime (216)

Following the same procedure as above, reaction of the oxime ether 111 (1.75 g,

6.22 mmol) with tributyltin azide (2.30 g, 6.85 mmol) with or without solvent gave a

brown oil. Column chromatography of the residue on silica with 10-40% EtOAc in

light petroleum ether (40-60 °C) as eluent yielded the title compound as a white

168

solid (1.31 g, 65%), mp 115-7 °C. 1H-NMR (270 MHz, acetone-d6, δH): 2.05 (2H,

m, CH2CH2CH2), 2.89 (2H, t, 3J 7.20 Hz, CH2Tet), 3.04 (2H, t, 3J 7.20 Hz,

CNCH2), 3.94 (3H, s, OCH3). 7.37 (1H, t, 3J 7.20 Hz, 5'-H), 7.59 (1H, d, 3J 7.20

Hz, 4'-H), 7.71 (1H, d, 3J 7.20 Hz, 6'-H), 7.91 (1H, s, 2'-H); 13C-NMR (67.8 MHz,

acetone-d6, δC): 23.9, 25.0, 25.8, 62.4 (OCH3), 123.1 (3'-C), 126.0 (6'-C), 129.7

(5'-C), 131.3 (2'-C), 132.9 (4'-C), 138.5 (1'-C), 156.7 (tetrazole-C); IR (nujol): 1732,

1587, 1459, 889, 787, 685 cm-1; m/z (CI, %): 324/326 (100/100, M+); tlc (SiO2,

50% EtOAc in light pet ether (40-60 °C), Rf): 0.24. A satisfactory elemental

analysis for carbon could not be obtained, presumably due to the tin residues in

the product.

1-(3-Bromophenyl)-4-(1H-tetrazol-5-yl)butyl azide (217)

The same procedure as above gave the title compound from reaction of the azide

31 (1.00 g, 3.50 mmol) with Bu3SnN3 (1.20 g, 3.60 mmol). Column

chromatography on silica with 50% EtOAc in light petroleum ether (40-60 °C) as

eluent afforded the product as a yellow oil (0.50 g, 43%). 1H-NMR (270 MHz,

CDCl3, δH): 1.77-2.10 (4H, m, 2 x CH2), 3.11 (2H, t, 3J 7.00 Hz, CH2Tet), 4.48 (1H,

t, 3J 7.00 Hz, N3CHCH2). 7.20 (2H, m, 2 x Ar'H), 7.40 (2H, m,2 x Ar'H), 9.13 (1H,

br s, NH); 13C-NMR (67.8 MHz, CDCl3, δC): 23.1, 24.2, 35.4, 65.1 (CHN3), 122.9

(3'-C), 125.5 (6'-C), 129.8 (5'-C), 130.5 (2'-C), 131.6 (4'-C), 141.5 (1'-C), 156.5

(tetrazole-C); IR (neat): 2916, 2100 (N3), 1569, 1476 cm-1; m/z (CI, %): 322 (81,

M+), 294 (65, M+-N2); tlc (SiO2, 50% EtOAc in light petroleum ether (40-60 °C), Rf):

0.12. A satisfactory elemental analysis could not be obtained. This type of

compound lose nitrogen gradually, so that when analysed the result is high in

carbon and low in nitrogen.

169

1-(3-Bromophenyl)-4-(1H-tetrazol-5-yl)butylamine (214)

Following the same procedure as for the synthesis of the amine 50b, reduction of

the azide 217 (0.31 g, 0.95 mmol) with 1,3-propanedithiol (0.30 ml, 2.85 mmol) in

the presence of Et3N (0.40 ml, 2.85 mmol) gave the desired product as a white

solid (0.16 g, 55%), mp 216-20 °C, after the neutralised aqueous solution was kept

overnight in a refrigerator. 1H-NMR (270 MHz, DMSO-d6, δH): 1.40-1.93 (4H, m, 2

x CH2), 2.70 (2H, t, 3J 7.12 Hz, CH2Tet), 4.13 (1H, t, 3J 7.12 Hz, H2NCH). 7.31-

7.46 (2H, m, 4'- and 5'-H), 7.55 (1H, d, 3J 7.12 Hz, 6'-H), 7.68 (1H, s, 2'-H); 13C-

NMR (67.8 MHz, DMSO-d6, δC): 24.0, 24.4, 35.3, 53.7 (H2NCH), 121.7 (3'-C),

126.1 (6'-C), 129.8 (5'-C), 130.65 (2'-C), 130.71 (4'-C), 143.2 (1'-C), 158.9

(tetrazole-C); IR (nujol): 3308 (NH), 1650, 1571, 1402, 896, 787, 697 cm-1; m/z (CI,

%): 296/298 (67/65, M+), 279/281 (42/40, M+-NH2-H), 184/186 (100/96, 3-

bromobenzylamine-H); tlc (SiO2, 50% EtOAc in light petroleum ether (40-60 °C),

Rf): 0. The product is not uv active but colours red on exposure to ninhydrin. A

satisfactory elemental analysis could not be obtained.

2,3-Epoxy-3-methylcyclohexanone (220)

The title compound was prepared following the procedure described by Yamazaki

et al.154 for the synthesis of 2,3-epoxy-3-methylcyclopentanone. 3-Methyl-2-

cyclohexene-1-one (10.0 g, 90.9 mmol) was therefore dissolved in MeOH (37 ml).

To this magnetically stirred light yellow solution aq H2O2 (30%, 30.5 g, 269 mmol)

was added dropwise at 0 °C. Then aq K2CO3 solution (5%, 19.2 g, 6.95 mmol) was

added slowly at the same temperature to the reaction mixture, whereby the colour

disappeared . The clear solution was stirred for 5 h at rt and then extracted with

ethyl acetate (3 x 30 ml). The combined organic extracts were washed with brine

(3 x 20 ml) and concentrated to give a yellow liquid. Column chromatography on

silica with 25% EtOAc in light petroleum ether (40-60 °C) as eluent afforded the

pure product as a colourless liquid (5.35 g, 47%), bp 85 °C/15, lit167 bp 85 °C/15.

1H-NMR (270 MHz, CDCl3, δH): 1.45 (3H, s, CH3), 1.60-2.20 (6H, m, 3 x CH2),

170

3.09 (1H, s, CH); 13C-NMR (67.8 MHz, CDCl3, δC): 17.2 (5-C), 22.2 (CH3), 28.4 (4-

C), 35.7 (6-C), 62.0 (2-C), 62.4 (3-C), 206.7 (CO); IR (neat): 2948, 1700 (CO),

1400, 1287, 1088, 809 cm-1; m/z (%): 126 (81, M+), 111 (8.1, M+-CH3); tlc (SiO2,

50% EtOAc in light petroleum ether (40-60 °C), Rf): 0.55. The product is not uv

active but colours blue when treated with an ammonium molybdate solution in 2N

H2SO4.

2-Benzylamino-3-methyl-2-cyclohexen-1-one (221)

A solution of the epoxy ketone 220 (0.30 g, 2.38 mmol) and benzylamine (0.31 ml,

2.86 mmol) in MeOH/H2O (1.5 ml and 0.5 ml respectively) was refluxed for 4 h

under a nitrogen atmosphere. After cooling to rt, the reaction mixture was extracted

with dichloromethane (3 x 10 ml). The combined organic layers were washed with

brine (3 x 10 ml), dried over anh MgSO4 and concentrated in a rotary evaporator to

yield a red oil. The residue was column chromatographed on silica or alumina with

CH2Cl2 as eluent to yield the product as a brown oil (60.0 mg, 13%). 1H-NMR (270

MHz, CDCl3, δH): 1.84 (2H, m, 5-CH2), 1.96 (3H, s, CH3), 2.35 (4H, m, 2 x CH2),

3.98 (2H, s, CH2Ph), 7.27 (5H, m, 5 x Ar'H); 13C-NMR (67.8 MHz, CDCl3, δC): 20.3

(CH3), 21.9 (5-C), 32.2 (4-C), 37.0 (6-C), 52.4 (CH2Ph), 127.0 (2'-C), 127.7 (3'-C),

128.4 (4'-C), 139.0 (2-C), 139.8 (3-C), 140.2 (1'-C), 196.1 (CO); IR (neat): 3322

(NH), 2929, 1664 (CO), 1635, 1453, 739, 699 cm-1; m/z (%): 215 (70, M+), 200

(6.9, M+-CH3), 138 (8.6, M+-Ph), 106 (64, [PhCH2NH]+), 91 (100, tropylium); tlc

(SiO2, CH2Cl2, Rf): 0.17. The spectroscopic data were in agreement with those

reported.129

171

3-Methyl-2-(a-methylbenzylamino)-2-cyclohexen-1-one (222)

According to the above procedure, reaction of 220 (0.30 g, 2.38 mmol) with R(+)-α-

methylbenzylamine (0.37 ml, 2.86 mmol) gave the title compound as a brown oil,

after being column chromatographed on silica with CH2Cl2 as eluent. Different

reaction conditions and yields are summarise in Table 8. 1H-NMR (270 MHz,

CDCl3, δH): 1.43 (3H, d, 3J 6.75 Hz, CHCH3), 1.49-1.64 (1H, m, 5-CHH), 1.73-1.88

(1H, m, 5-CHH), 1.90 (3H, s, CH3), 2.19-2.36 (4H, m, 2 x CH2), 4.16 (1H, q, 3J

6.75 Hz, CHPh), 7.15-7.25 (5H, m, 5 x Ar'H); 13C-NMR (67.8 MHz, CDCl3, δC):

20.5 (CHCH3), 21.9 (5-C), 23.9 (CH3), 32.3 (4-C), 36.9 (6-C), 56.6 (CHPh), 126.0

(2'-C), 126.8 (3'-C), 128.2 (4'-C), 138.8 (2-C), 145.3 (1'-C), 196.3 (CO); IR (neat):

3330 (NH), 2929, 1663 (CO), 1635, 1452, 763, 701 cm-1; m/z (%): 229 (49, M+),

214 (48, M+-CH3), 125 (34, M+-phenylethyl), 105 (100, [PhCH2CH]+), 77 (14,

phenyl), [Found: m/z (EI) 229.1467; Calc for C15H19NO: 229.1467]; tlc (SiO2,

CH2Cl2, Rf): 0.15.

Reaction of 220 in the presence of 1 equivalent CeCl3.7H2O

The same reaction as above was repeated with the exception that 1 equivalent of

CeCl3.7H2O (0.90 g, 2.38 mmol) was added. Directly after the clear solution

started refluxing a white precipitate was formed. After cooling to rt the reaction

mixture was filtered through Celite and the inorganics washed with CH2Cl2 (3 x 5

ml). After the usual workup a yellow oil was obtained. Column chromatography on

silica with CH2Cl2 as eluent yielded two new products which were identified as: (1)

2-chloro-3-methyl-2-cyclohexene-1-one (223, 121.5 mg, 35%), 1H-NMR (270 MHz,

CDCl3, δH): 2.02 (2H, q, 3J 6.75 Hz, 5-CH2), 2.14 (3H, s, CH3), 2.55 (4H, quin, 3J

6.75 Hz, 2 x CH2); 13C-NMR (67.8 MHz, CDCl3, δC): 21.6 (5-C), 22.4 (CH3), 33.3

(4-C), 37.8 (6-C), 128.9 (2-C), 156.9 (3-C), 190.9 (CO); IR (neat): 2929, 1685

(CO), 1611 (C=C), 1278, 810 cm-1; m/z (%): 144/146 (67//22, M+), 116/118

(100/32), 102/102 (16/5), 88/90 (36/12); tlc (SiO2, CH2Cl2, Rf): 0.39. A satisfactory

172

elemental analysis could not be obtained. (2) N-(α-Methylbenzyll)-3-toluidine (224,

42.7 mg, 9%), 1H-NMR (270 MHz, CDCl3, δH): 1.49 (3H, d, 3J 6.75 Hz, CHCH3),

2.20 (3H, s, ArCH3), 4.48 (1H, q, 3J 6.75 Hz, NCHCH3), 6.30 (1H, dd, 4J 2.14 Hz

and 3J 7.86 Hz, 4-H), 6.36 (1H, s, 2-H), 6.47 (1H, d, 3J 7.86 Hz, 6-H), 6.98 (1H, t,

3J 7.86 Hz, 5-H) 7.18-7.40 (5H, m, 5 x Ar'H); 13C-NMR (67.8 MHz, CDCl3, δC):

21.6 (CHCH3), 24.9 (ArCH3), 53.4 (CHN), 110.4 (6-C), 114.2 (2-C), 118.3 (4-C),

125.9 (2'-C), 126.8 (3'-C), 128.6 (4'-C), 129.0 (5-C), 138.8 (5-C), 145.3 (1'-C),

147.3 (1-C); IR (neat): 3412 (NH), 2966, 1607, 1490, 1325, 767, 700 cm-1; m/z

(%): 211 (63, M+), 196 (100, M+-CH3), 180 (2.1, M+-2 x CH3-H), 134 (11, M+-Ph),

107 (56, M+- phenylethyl-H), 91 (20, tropylium), 77 (21, phenyl); Anal calcd for

C15H17N (%): C, 85.26; H, 8.11; N, 6.63; Found (%): C, 85.17; H, 8.14; N, 6.73; tlc

(SiO2, CH2Cl2, Rf): 0.65.

2-Chloro-3-hydroxy-3-methylcyclohexanone (225)

To a solution of 220 (100.0 mg, 0.79 mmol) in dry acetonitrile (2 ml) anhydrous

CeCl3 (0.19 g, 0.79 mmol) was added. The resulting suspension was refluxed for 6

h under a nitrogen atmosphere. After being cooled to rt, the reaction mixture was

filtered through Celite and the inorganics washed with CH2Cl2 (3 x 5 ml). The

organic filtrate was concentrated under reduce pressure to give the title compound

as a yellow oil (95.2 mg, 74%) after being dried under vacuo. 1H-NMR (270 MHz,

CDCl3, δH): 1.31. (3H, s, CH3), 1.60-2.80 (6H, m, 3 x CH2), 4.26 (1H, s, CHCl);

13C-NMR (67.8 MHz, CDCl3, δC): 20.4 (5-C), 24.1 (CH3), 35.0 (4-C), 37.4 (6-C),

70.8 (2-C), 76.4 (3-C), 203.0 (CO); IR (neat): 3444 (br, OH), 2950, 1729 (C=O),

1378, 1140, 949.

173

1-Benzyl-7-oxo-4,5,6,7-tetrahydroindole (190)

A mixture of 2-benzylamino-3-methyl-2-cyclohexen-1-one (221) (50.0 mg, 0.25

mmol) and dmfdma (0.20 ml, 0.80 mmol) was heated at 150 °C overnight under a

nitrogen atmosphere. Removal of the excess acetal under vacuum left a red oil.

Purification as described previously gave the title compound in 18% yield (9.8 mg).

(+)-1-(α-Methylbenzyl)-7-oxo-4,5,6,7-tetrahydroindole (192)

Reaction of 3-methyl-2-(a-methylbenzylamino)-2-cyclohexen-1-one (222) (50.0 mg,

0.22 mmol) with dmfdma (0.20 ml, 0.80 mmol) following the same procedure as

above gave the title compound as a yellow oil (7.4 mg, 14%). The spectroscopic

data were identical with those reported previously.

174

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189

Appendix

O

OH

1

OH

OH O

2

R'

OOHR"

3

OH

OOH

S

N OHN

O O

NH2H

O OH

H

O

��

4

190

OH

OOOH��

5

OH

OO��

��6

OH

OOH��

7

OH

OH OH O��

��

8

OH

OOH

S

H2NN

OHO

OH

��

9

191

OH

OOH

S

H2NO

OH

��

10

OH

OOH

S

N OHOH

OO

O

NH2H

��

11

O

HO O OOH

O

O

OH

O

12

192

HO O

O

NN

NN

H

13

S OH

OH

OOHO

��

14

O

15

OMe

OO

16

193

OMe

O

OH

S

O

OMe17

OMe

O

S

OH

OMe

O

18

19

S

SCON(CH3)2

COOH

NCl

��

20

HSPh

O

MeO H

��

21

OHCS

SCON(CH3)2

COOMe��

194

22

S

SCON(CH3)2

COOMe

NCl

��

23

NO

OH

24

NCl

25

OH

OH

N

S

COONa

OH

Et

Cl

��

��

26

195

N

S

COONa

O

Et

Cl

��

��

27

NCl

O

28

29

NCl

OH

30

O CO2Me

NCl

196

CO2MeOH

NCl

31

OHNOOMe

NCl

32

NCl

O NOMe

S

Me COOH

��

��

33

34

N

NO

O

H

OMe

NS

O O

OH

197

NCl

N ON

NNN

NN N

N H

H

35

N S NN

NN

OHO

36

NO

NN

NN

Cl

NN N

N Na

37

Br CN

38

I CN

39

IZn CN

40

198

NCl

OHCN

41

NCl

ClCN

42

O

Ph

PhNO2

43

O

Ph

Ph

NH

44

ONC

NH

45

NCl

N O

CN

CN

46

199

NN

O

O O

O

H

47

N O

CN

CN

O

48a

BrN O

CN

CN

48b

NClPPh3

49a

NCl

49b

NH2

CNO

50a

BrNH2

CN

50b

200

ClCN

O

51

OHCN

O

52

O

O Br

53

O

O

O

54

OCN

OOH

55

CNOH

Br

56

CNCl

Br

57

CNBr

58

ONC

NH

59

S

S

O

60

S

S S

S

61

201

S

SO

O

62

S

S

OHCN

63

NClP(OEt)2

O

64 65

PPh2

PPh2

PPh2

PPh2

H

H

��

PPh2 PPh2

�� PPh2

PPh2

��

PPh2

PPh2

66 67 68 69

O

O PPh2

PPh2

��

70 71

Ph2P

Ph2P

��

72

NBOC

Ph2PPPh2��

��

202

PPh2

PPh2

��

��

��

73

OHOH

��

��

��

74

P

P

EtEt

Et

Et

��

��

��

��

75

H2N OH

PhPh

��

76

N O

PhPh

BH

H

��

77

N O

PhPh

BHH3B

H

��

78

N OB

PhPh

HH3B

79

Ph

HH2N

OH

��

80

HH2N

OH

��

81

PhH2N

OH��

82

83

Ph NOR'

OH

��

84

Ph NH2��

NNH2

OMe

��

85

203

NNH2

OMe

86

R

NN

OMe

87

R

NN

OMe

MeO

O

88

89

OB

O OMeOMe

H

��

90

NaBH

3

R N CO2

O

R'

R"

��

O

O

PRh

P

Cl

solvent

Ph

Ph Ph

Ph��

91

NSO

O

��

��

92

SN Ph

O

N

OH

��

93

SN Ph

O

N

OH

H

��

94

SN Ph

O

N

OH

H

��95

204

Ph NH2

��

96

SO2H

N

OH

97 98

PhS

Ph

N

O

OH H

Ph

��

N

O

N

O

R R

R' R'

NN

��

��

99 100

NR'

OHR

��

101

NR'

N3

R

102

NR'

NH2

R

103 104

OMeN

NH2

105

OHF3C

106

BrSO3Na

OH

107

205

BrNMe2

CN

108

BrCN

NMe2

CN

109

BrO

CN

110

BrN

CN

OMe

111

O

NClCN

112

N

NCl

OMe

113

206

N

NCl

OMe

CN

114

115

NBr

Ph

OHPh

��

��

NBr

Ph

OHPh

H

CN

��

116

117

Br CNN3

BrN

CN

PPh

PhPh

118

2

BCl

119

NaBH

3

N COO-

O PhO

120

207

121

RN

O

RN

O

MgBr

122 123

N

R

OMgBr

124

N

R

OMgBr

MgBr

125

N

R H

126

6

5

4

2NMe

R

RR

R NO2

127

4

7R

5

6 2NMe

RR

NO2N

R

RHR1

2

128

7

6

54

1RN

R

R

R

R

NO2

MeHN

R

RHNR

R

R

R

NMeN

R

OHO

1

2

45

6

7

129

2

RHNR

R

R

RMeN

R1

45

6

7

130

208

2

131

7

6

5

4

1RHN

RR

RR

MeN

R

132

7

6

5

4

2

1R

R

RR

NR

R

133

7

��Br CN

N

R

N

134

N

NO2

135

N

NO2

Me

136

NMe

137

NMe

Me

Me

Me

138

SO3Na

NO2

SO3NaNO2

NO2

NO2

NO2

SO3H

139140 141

209

NMe

142

NMe

Me

Me

MeMe

143

NMe

144

N

Ph

145

N

146 147

NMe

Me

Me

N Ph

148

NMe

Me

MePh

149

NMe

Me

MePh

150 151

N

NH2

152

N

NO2

153

N

NO2

MeI

O

O

R'

R"R'

154

210

O

NR'

R'

R"

R"'

155

O

O

CO2H

156 157

O

NH

O

O

158

159

O

OOEt

160

O

OH

OEt

OEt

O

N

OMeMeO

R'R

R

161

162

NMeO

O

N

CO2H

Me

163

O

NH

OAc

164

NMgX

165

166

NHO

167

N

Me

EtO2C

H

Et

168

NEt

Me

EtO2C

H

MeO2C

O

211

169

NEt

Me

EtO2C

H

MeO2C

170

N

O H

Me

Et

171

NSO2Ph

172

NSO2Ph

O

O

HO

173

NSO2Ph

O

HO

174

NSO2Ph

O

Cl

175

NSO2PhO

176

O

OR

R

177

ONHBn

RR

178

O

NBn

RR

179

1

ONHR

212

180

3

2

1O

NR

R

R

O

O181

N

CN

OBr

182

OHO

O

183

OHO

O

184

OCl

O

185

186

O

OOH

N

O

Ph187

Ph N Ph

188 189

N

N

Ph

Ph

190

N

PhO

191

O

O

N

O Ph

192

N

O Ph

193

213

N

O

194

N

OPh

195 196

N

Ph

O

NMe

O

197

N

Ph

O

198

HCl.H2N Ph

CO2Me

199

OOH

N PhH

200

OOH

N Ph

201

OOH

NH2

202

OOH

NHR

203

O

NHR

O

204

214

N

OTMS

Me

205 206

O

OTMS

207

O

OH

N

O

Me

PhSe

208

O

N

Ph

I

209

O

N

Ph

I

210

OH

N

Ph

211

O

N

Ph

CN

212 213

BrN

OH

BrN

NNN

H

NH2

214

BrO

NN

NN

H

215

215

BrN

NN

NN

H

OMe

216

BrN

NNN

H

N3

217

218

BrN

NN N

N H

O

219

BrN

NNN

CPh3

NH2

O

O

220

ONHBn

221 222

ONH

Ph

223

OCl

216

224

NH

Ph

225

OCl

OH

226

NRHO

OH

227

ONHR

228

N Ph

O

229

O

N Ph

230

N Ph

BrN

CN

O

H

231

BrN

CN

O

H

231

asymmetric approaches towards ly290154 … · the work described in this thesis concerns the...

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