Indium metal as a reducing agent in organic synthesis

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Michael R. Pitts, Justin R. Harrison and Christopher J. Moody*

Department of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD

1

Received (in Cambridge, UK) 22nd February 2001, Accepted 12th March 2001

First published as an Advance Article on the web 11th April 2001

The low ﬁrst ionisation potential (5.8 eV) of indium coupled with its stability towards air and water, suggest that this

metallic element should be a useful reducing agent for organic substrates. The use of indium metal for the reduction

of C᎐N bonds in imines, the heterocyclic ring in benzo-fused nitrogen heterocycles, of oximes, nitro compounds and

᎐

conjugated alkenes and the removal of 4-nitrobenzyl protecting groups is described. Thus the heterocyclic ring in

quinolines, isoquinolines and quinoxalines is selectively reduced using indium metal in aqueous ethanolic ammonium

chloride. Treatment of a range of aromatic nitro compounds under similar conditions results in selective reduction of

the nitro groups; ester, nitrile, amide and halide substituents are unaﬀected. Likewise indium in aqueous ethanolic

ammonium chloride is an eﬀective method for the deprotection of 4-nitrobenzyl ethers and esters. Indium is also

an eﬀective reducing agent under non-aqueous conditions and α-oximino carbonyl compounds can be selectively

reduced to the corresponding N-protected amine with indium powder, acetic acid in THF in the presence of acetic

anhydride or di-tert-butyl dicarbonate. Conjugated alkenes are also reduced by indium in THF–acetic acid.

aza-pinacol coupling) to give 1,2-diamines.³⁶Subsequent work

Introduction

with nitrones showed that indium mediated both the initial

The metallic element indium has a number of useful properties

deoxygenation and the coupling of the resulting imine.²⁵

that suggest it should be useful in organic synthesis. It is

unreactive towards air and water, is non-toxic, and is readily

Although the aza-pinacol coupling can be eﬀected in other

ways, for example using samarium diiodide,^37–39titanium(0),⁴⁰

available in high purity due to the ease with which it zone

sodium metal,⁴¹niobium reagents,⁴²ytterbium⁴³or electro-

reﬁnes. However it is relatively rare, being the 63rd most

chemistry,⁴⁴the importance of vicinal diamines justiﬁed a more

abundant element in the Earth’s crust, and hence available at

prices similar to other rare elements such as silver.

detailed investigation of the indium mediated reaction. Thus

on treatment with indium powder in ethanolic aqueous

ammonium chloride, N-benzylideneaniline 1 gave the diamine 2

Despite its desirable chemical properties, indium has only

recently been exploited in organic synthesis,^1–3most notably in

as a mixture of (ϩ)/(Ϫ) and meso-isomers in good yield as

the generation of synthetically useful allylindium species.^4–12

reported in the literature.³⁶The same product could be

However, the ﬁrst ionisation potential of indium (5.8 eV),

which is lower than reducing metals such as zinc (9.4 eV) or tin

(7.3 eV) and close to that of alkali metals such as sodium (5.1

eV) suggests that the metal ought to participate readily in single

obtained, albeit in slightly lower yield (52%) simply by heating

aniline and benzaldehyde in the presence of indium. Attempted

extension of the reaction to the imines 3 and 5 resulted in

simple reduction of the C᎐N bond (Scheme 1). However, the

᎐

electron transfer processes. Hence we initiated a research pro-

gramme to explore this possibility, and we have reported, in

preliminary form, the selective reduction of aromatic nitro

groups,¹³the heterocyclic ring in quinolines, isoquinolines and

quinoxalines,¹⁴the deprotection of 4-nitrobenzyl ethers and

esters,¹⁵and the reductive acetylation of oximes¹⁶using indium

metal. The results of these, and related studies, are reported in

detail herein.

Subsequent to the publication of our preliminary results,

others have shown that indium metal can be used in the reduc-

tive elimination of 1,2-dibromides,¹⁷pinacol couplings,¹⁸ketone

deoxygenation,¹⁹reductive dehalogenation of α-halocarbonyl

compounds, benzyl halides and halomethylcephalosporins,^20,21

reduction of azides,^22,23and N-oxides,^24,25reductive coupling of

acyl cyanides,²⁶and in the reduction of nitrostyrenes,²⁷and

other nitro compounds.^23,28,29In complementary studies the use

of indium hydride reagents for reduction reactions in organic

synthesis has also been reported.^30–35

imine coupling reaction could be eﬀected intramolecularly.

Thus the bis-imines 7 and 8 derived from trans-1,2-diamino-

cyclohexane were treated with indium in THF in the presence

of acetic acid, the addition of the stronger acid being based on

related electrochemical coupling of imines reported by Shono

et al.⁴⁴The resulting decahydroquinoxalines 9 and 10 were

formed in good yield as single diastereomers, assigned as the

all-equatorial isomers (Scheme 1) on the basis of previous

work.⁴⁴Surprisingly, however, attempted intramolecular

coupling of a bis-imine derived from biphenyl-2,2Ј-dicarb-

aldehyde failed, suggesting that imine coupling using indium

metal is very substrate dependent and may not be a general

reaction.

Reduction of benzo-fused nitrogen heterocycles

The selective reduction of the heterocyclic ring in benzo-fused

heterocyclic compounds such as quinolines and isoquinolines

is an important transformation since the resulting tetrahydro

derivatives serve as useful synthetic intermediates.⁴⁵A number

of methods have been used for this transformation including

catalytic hydrogenation or transfer hydrogenation, alkali metals

such as sodium or lithium, diborane, sodium borohydride in the

presence of nickel() chloride, lithium triethylborohydride or

sodium cyanoborohydride.⁴⁶Given that indium can replace

alkali metals in the reductive coupling of imines (see above), it

Results and discussion

Reductive coupling of imines

One of the earliest reports on indium metal as a reducing agent

was by Kalyanam and Rao who found that indium was

extremely eﬀective in the reductive coupling of imines (the

DOI: 10.1039/b101712h

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

This journal is © The Royal Society of Chemistry 2001

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Table 2 Reduction of isoquinolines 13 and quinoxalines 15 to 1,2,3,4-

tetrahydro derivatives 14 and 16

Compounds

R

Yield (%)

13a/14a

13b/14b

13c/14c

13d/14d

15a/16a

15b/16b

H

78

74

1-Me

3-Me

3-Me^a

2-Me

2,3-Me₂

71

97^b

92

90^c

^aStarting material is methiodide salt. ^bProduct is 2,3-dimethyl-1,2,3,4-

tetrahydroisoquinoline. ^cProduct is formed as a 2 : 1 mixture of

cis : trans isomers.

Table 3 Reduction of indoles 17 to indolines 18

Scheme 1

Table 1 Reduction of quinolines 11 to 1,2,3,4-tetrahydroquinolines 12

17/18

R¹

R²

R³

R⁴

R⁵

Yield (%)

a

b

c

d

e

f

H

Me

–(CH₂)₄–

Me

H

OBn

H

OMe

H

0^a

64

0^a

Me

Ac

11/12

R

Yield (%)

H

CO₂Et

H

23

0^a

a

b

c

d

e

f

g

h

i

H

2-Me

3-Me

4-Me

52

46

76

73

30^a

55

49

39

40

42

60

25

72^b

H

^aNo reaction; starting material recovered.

2,4-Me₂

2-CH₂CH₂CH₃

2-CH₂CH₂CHMe₂

2-CH₂OCH₂CH᎐CH₂

2-Ph

6-MeO

6-AcNH

6-Cl

The reduction of isoquinolines 13 was also investigated, the

reactions generally proceeding in shorter reaction times and

higher yield than the corresponding quinolines (Table 2). The

isoquinolinium salt 13d was rapidly reduced to the N-methyl-

tetrahydroisoquinoline 14d in excellent yield. Again, nitro

groups were reduced in preference to the heterocyclic ring,

5-nitroisoquinoline giving the 5-amino derivative in excellent

(99%) yield. Carbonyl groups were also reduced under the

reaction conditions, isoquinolin-1-yl phenyl ketone giving the

corresponding alcohol in 72% yield.

᎐

j

k

l

m

3,4-C₆H₄

^aProduct is exclusively cis. ^bProduct is 1,2-dihydrophenanthridine.

was decided to investigate its use in the reduction of a range of

heterocyclic compounds.

The more electron deﬁcient heterocyclic ring in quinoxalines

15 was rapidly reduced to the tetrahydro derivatives 16 in excel-

lent yield (Table 2). These reductions were much more tolerant

of alternative reactions conditions: the use of In–Me₃NHCl–

aq EtOH and In–THF–AcOH giving comparable yields to the

usual conditions.

The reduction of monocyclic 6-membered heterocyclic

system was also brieﬂy investigated, but under the usual indium

conditions, both 2-phenylpyridine and 2,6-lutidine were

recovered unchanged. An isolated pyridine ring is generally

thought to be harder to reduce than the heterocyclic ring of

quinoline.⁴⁷

The reduction of a series of quinolines 11 was carried out by

simply heating the substrate with indium powder in aqueous

ethanol containing ammonium chloride, and gave, after

chromatography, the corresponding 1,2,3,4-tetrahydroquinol-

ines 12 in modest to good yield (Table 1). Attempts to vary the

reaction conditions, e.g. the use of THF–AcOH in place of

aqueous systems, usually resulted in lower yields. A number of

functional groups are tolerated including alkyl, aryl, alkoxy,

and acetylamino, although the yield from 6-chloroquinoline

was low, and 6-aminoquinoline was recovered unchanged.

2-Chloroquinoline, in which the halide is activated was reduced

to 1,2,3,4-tetrahydroquinoline in 79% yield. Nitro groups are

also reduced (see below); 6-nitroquinoline was cleanly reduced

to 6-aminoquinoline (82%).

When the indium reduction conditions were applied to

indoles 17, very mixed results were obtained. Whilst some

indoles were recovered unchanged, others were reduced to the

corresponding indoline 18 (Table 3). However, the reaction is

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J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

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unpredictable, and is not a suitable method. Likewise, a number

of pyrroles that have been successfully reduced under Birch

reduction conditions by Donohoe and co-workers⁴⁸were inert

to metallic indium.

Although there are some limitations, the reduction of the

nitrogen heterocyclic ring in benzo-fused heterocycles using

indium appears to be a useful reaction. The reaction is

assumed to proceed by single electron transfer to the electron

deﬁcient ring to give, after protonation, a stabilised radical 19.

A further electron transfer–protonation sequence could then

lead to the tetrahydro derivative as outlined for quinoline itself

in Scheme 2.

Scheme 4

products formed by coupling the heterocyclic rings, although

such coupling reactions are known to occur on treatment of

quinolines or isoquinolines with zinc metal.^49–51

Finally 2-cyclopropylquinoline 26 was investigated. This was

prepared by reaction of 2-chloroquinoline with cyclopropyl-

idenetriphenylphosphorane. Reactions of halo-heterocycles

with phosphorus ylides were ﬁrst developed by Taylor and

Martin,⁵²and we also used them to prepare the quinolines 11b

and 11f. When 2-cyclopropylquinoline 26 was treated under the

usual indium conditions two products were observed (Scheme

5). One was the corresponding 1,2,3,4-tetrahydroquinoline 27

Scheme 2

Scheme 5

Attempts were made to intercept the putative radical

intermediates derived from quinolines or isoquinolines either

in 5-exo-trig cyclisations or by cyclopropane ring opening as

illustrated by the radical structures 20 and 21, although it

had already been shown earlier (Table 1) that 2-(allyloxymethyl)-

quinoline 11h was reduced to the tetrahydro derivative 12h in

modest yield (39%) with no evidence for products derived from

the 5-exo-trig cyclisation process (Scheme 3).

(35%) and the other was identiﬁed as 2-propyl-1,2,3,4-tetra-

hydroquinoline 12f (24%), identical to the product obtained by

reduction of 2-n-propylquinoline 11f (Table 1). The formation

of the n-propyl compound 12f suggests that radical intermedi-

ates are involved, and the cyclopropane ring opens during the

reaction.

Reduction of oximes

Oximes were also thought to be potential substrates for reduc-

tion by indium despite the fact that they are generally regarded

as more resistant than imines to reduction. Nevertheless the

reduction of oximes and oxime ethers to amines is a useful

transformation in organic synthesis and has been achieved

using a range of reagents. Lithium aluminium hydride is eﬀec-

tive,⁵³although it is unselective with functionalised oximes since

it reacts with carbonyl groups faster and can lead to aziridines

with benzyl substituted oximes.⁵⁴Catalytic hydrogenation is

also commonly used,^55–57although the success of reaction is

sensitive towards catalyst, solvent and substrate. Again, ketone

groups in the substrate are susceptible to competing reduction.

Other reagents used include sodium borohydride in the pres-

ence of various additives,^58–60diborane,⁶¹and zinc and acetic

acid, often in the presence of acetic anhydride to eﬀect in situ

acetylation of the amine.^62–65

A range of oximes 28 was therefore chosen for reduction by

indium metal. The oximes were either commercially available

or obtained from the corresponding carbonyl compound by

standard methods; in cases where the oxime was obtained as an

E/Z-mixture, no attempt was made to separate such mixtures.

The reduction was carried out by simply heating the α-oximino

carbonyl compound 28 in THF containing 4 equivalents of

acetic acid and 2.5 equivalents of acetic anhydride, and a

Scheme 3

Likewise in the isoquinoline series, no radical intermediates

could be intercepted in cyclisation reactions. The 3,4-dihydro-

isoquinolines 22, readily prepared using a Bischler–Napieralski

reaction, were subjected to the usual indium reducing condi-

tions. In both cases, clean reduction of the C᎐N bond was

᎐

observed, with no evidence for cyclised products derived from

22b. The corresponding methiodide salts 24 were also investi-

gated, and whereas the 1-methyl derivative 24a was reduced to

the tetrahydro compound (carnegine) 25a, the pentenyl deriv-

ative 24b was recovered unchanged (Scheme 4). It is also noted

that in these studies there was no evidence for any dimeric

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

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Table 4 Reduction of oximes 28 to N-acetyl amines 29

Table 5 Reduction of nitrobenzene derivatives 30

30/31

R

Time/h

Yield (%)

28/29

R¹

R²

Yield (%)

a

b

c

d

e

f

g

h

i

4-Cl

3

19

72

1.5

18

0.5

1

18

1

48

3

95

75

70

60

98

92

95

90

92

83

95

84

90^a

a

b

c

d

e

f

CO₂Me

COⁱPr

COPh

Me

CO₂Me

COMe

CO₂Et

COPh

65

95

69

2-Me-3-Cl

2-Me-5-Br

2-I

2-MeO-5-MsO

4-MeS

98

Me

96^a

100

69

H

COPh

3-CN

b

g

h

3-CO₂H

4-CO₂Et

4-COMe

4-NHAc

4-MeOCH₂

2-Me-3-NO₂

c

87

j

k

l

^aAlso carried out in the presence of di-tert-butyl dicarbonate to give

the N-Boc product in 92% yield.

1

72

m

^aReaction carried out in THF–acetic acid and both nitro groups are

reduced; product is 2,6-diaminotoluene.

Reduction of nitro compounds

Although a large range of methods for the reduction of

aromatic nitro compounds have been developed,^66–68many

of these are incompatible with other functional groups in the

molecule. For example, the selective reduction of nitro groups

in the presence of carbonyl groups, nitriles, halides and alkenes

is often diﬃcult, and in such cases catalytic hydrogenation,

which is often the method of choice for nitro reduction, is

inappropriate. Thus hydrogenation of 4-chloro-3-nitroaceto-

phenone over palladium-on-carbon results in hydrogenolysis of

the halide and reduction of the ketone as well as the nitro

group.⁶⁸Consequently new methods for nitro group reduction

continue to be developed as a search of the recent literature

shows.^69–78Having already established that nitro-quinolines and

-isoquinolines were readily reduced to the corresponding

amino compounds without further reduction of the hetero-

cyclic ring (see above), we embarked upon a wider study of

nitro group reduction.⁷⁹

b

c

suspension of 4 equivalents of indium powder. The reactions

were complete in less than 30 minutes for compounds in which

the C᎐N bond was rendered more reactive by the presence of

᎐

two carbonyl groups, and within 18 hours for monocarbonyl

compounds, and gave the N-acetyl amines 29 in good to excel-

lent yield (Table 4). Hence the reaction can be used to prepare a

range of α-acetamido carbonyl compounds including a diester

29a, β-ketoester 29b, β-diketone 29c, ester 29d, ketones 29e, 29f,

29h, and amides 29g; the camphor derived oxime 28h gave a

single endo-diastereomer acetamide 29h. In the case of oxime

28c, some acetamide derivative 29f was formed (presumably via

a retro Claisen reaction) in addition to the expected product 29c

(69%). It is worth noting that the carbonyl group in all cases

was unaﬀected. The reaction is simple to carry out; there is no

need for exclusion of air or the use of dry solvents, and the

reaction is worked up by simply quenching with bicarbonate

and extraction into organic solvent. In most cases further puri-

ﬁcation by column chromatography was unnecessary. Attempts

to reduce simple oximes such as that derived from aceto-

phenone to the corresponding amine under the usual aqueous

reducing conditions with indium were unsuccessful. Also

attempts to eﬀect reduction and tosylation or triﬂuoroacetyl-

ation were unsuccessful. However, when the reduction of oxime

28e was carried out in the presence of di-tert-butyl dicarbonate,

the corresponding N-tert-butoxycarbonyl amine was formed

in excellent yield (92%), thereby extending the reaction to the

preparation of other N-protected amines.

As expected, reduction of aromatic nitro compounds 30

proceeded readily on heating the substrate with indium powder

in aqueous ethanolic ammonium chloride. The reactions are

extremely easy to carry out, are usually complete within 1–3

hours, and give the corresponding aniline 31 in good to

excellent yield (Table 5).

A wide range of functional groups remained unaﬀected by

the indium reducing conditions. Thus halogen substituents (Cl,

Br, I) are not reduced; a separate study on 3-bromobiphenyl

showed only ca. 8% cleavage (by GC-MS) of the bromine after

heating with indium in aqueous ethanolic ammonium chloride

for 96 h. Likewise mesylates survive the reaction conditions,

and the reaction is not aﬀected by the presence of sulfur sub-

stituents, e.g. 30f. Importantly, other reduction sensitive groups

were also unaﬀected; nitrile, acid, ester, ketone, and amide

groups all withstood the reaction conditions. However, one

functionality did appear incompatible. Although 4-methoxy-

methylnitrobenzene 30l gave the corresponding aniline 31l in

high yield after a reaction time of 1 hour, prolonged heating

resulted in the formation of 4-toluidine. This facile cleavage of

benzylic C–O bonds using indium forms the basis of a new

method of removal of 4-nitrobenzyl protecting groups (see

below). Use of the alternative reducing conditions (In, AcOH,

THF) was also brieﬂy investigated. The conversion of

4-nitroacetanilide 30k to 4-aminoacetanilide 31k was achieved

in quantitative yield under these conditions, and with 2,6-

dinitrotoluene 30m as substrate reduction of both nitro groups

occurred.

The use of indium in the presence of acetic acid–anhydride to

reduce oximes to the corresponding N-acetyl amines closely

mirrors the use of zinc metal under similar conditions. For

comparison, we conducted the reduction of oximes 28b and 28e

using both metals; in both cases yields were similar, although

in the case of oxime 28b, the zinc reduction proceeded slowly

at room temperature whereas the reaction mixture containing

indium required heating to eﬀect the conversion.

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Other nitro compounds were also investigated. The reduction

of 6-nitroquinoline 32 and 5-nitroisoquinoline 34 in 82 and

99% yield respectively was discussed above. The 4-nitroindoles

36 were readily reduced to the corresponding 4-aminoindoles

37 in (unoptimised) 30–45% yield. Aliphatic nitro compounds

were also readily reduced: nitrocyclohexane 38a and 1-nitro-

hexane 38b were reduced in high yield. 3-Methyl-1-nitrobutan-

2-ol 38c was only slowly reduced under the aqueous conditions;

with indium–AcOH–THF, however, the reaction was faster and

higher yielding. The reduction of these other nitro compounds

is summarised in Scheme 6.

Scheme 7

Scheme 8

The 4-nitrobenzyl protecting group has seen use in the

protection of alcohols, thiols, amines (as the 4-nitrobenzyl

carbamates), and carboxylic acids.^80–82For example, 4-nitro-

benzyl esters are much more stable to acidic hydrolysis than

other benzyl esters, and are recommended for glutamic acid and

aspartic acid side chain protection in solid-phase peptide syn-

thesis. Such protecting groups have also seen extensive use in

the β-lactam ﬁeld. Methods of deprotection include: Na₂S or

Na₂S₂O₄reduction, catalytic hydrogenolysis, TBAF, or oxid-

ative cleavage with alkaline hydrogen peroxide. Electrochemical

methods have also been used, especially for the unmasking

of alcohols, either direct electrolytic reduction, or oxidative

electrolysis following initial chemical reduction of the nitro

group. Despite the undoubted usefulness of the 4-nitrobenzyl

protecting group, many of the methods of deprotection have

drawbacks in that they are not compatible with the presence of

other functionality or protecting groups.

Scheme 6

Since the publication of our preliminary communication,

others have also reported the use of indium metal for the

reduction of nitro groups.^23,28,29

A series of alcohols, phenols and acids was protected as their

corresponding 4-nitrobenzyl ethers and esters 43. A variety of

standard methods was used for the protection step with no

attempt to optimise the yields (see Experimental section). The

ethane-1,2-diol derivatives 43b–d were used to probe the com-

patibility of other alcohol protecting groups. The deprotection

reactions were carried out using indium metal under the usual

aqueous conditions. Simple extractive work-up involving

acid–base wash to remove the 4-toluidine by-product gave the

deprotected material in good yield (Table 6).

In all cases, the substrates 43 were cleaved in good yield,

although the tert-butyldimethylsilyl protected diol 43e gave a

mixture of products. (When the reaction was carried out at

room temperature nitro compound 43e was simply reduced to

the corresponding aniline without further C–O bond cleavage.)

Benzyl ethers and carbamates, and benzoate esters remained

intact, and other functional groups were also unaﬀected by the

conditions. Thus carbonyl groups (in the form of ketone 43h

and aldehyde 43i) and chlorides were not reduced, and in the

case of the quinoline derivative 43l, the protecting group was

removed faster than the reduction of the aromatic ring.

Deprotection of 4-nitrobenzyl ethers and esters

As outlined above, under the usual aqueous conditions

prolonged treatment of 4-methoxymethylnitrobenzene 30l

resulted in formation of 4-toluidine 40a in 72% yield. Likewise,

4-toluidine was also formed from 4-nitrobenzyl alcohol 41a and

4-nitrobenzyl acetate 41b (Scheme 7). Presumably nitro group

reduction occurs ﬁrst, and this is followed by reductive cleavage

of the benzylic C–O bond to give a benzylic radical (stabilised

by the 4-amino group) which is further reduced and protonated.

In accord with this mechanism, 4-aminobenzyl alcohol 42a was

converted into 4-toluidine 40a (82%) under identical condi-

tions. Likewise 4-aminophenethyl alcohol 42b and 4-dimethyl-

aminobenzyl alcohol 42c both underwent reductive C–O bond

cleavage to give the corresponding 4-alkylamines 40b and 40c

(Scheme 8). 3-Aminobenzyl alcohol was, unsurprisingly, inert

to the reaction conditions. Evidence for the involvement of

benzylic radicals in such processes came from the indium

reduction of 4-nitrobenzyl chloride which gave in addition to

4-toluidine (46%), the ‘dimer’ 1,2-bis(4-aminophenyl)ethane

(32%). Therefore on the basis of the foregoing discussion it

seemed reasonable that our indium reducing conditions might

be useful for the removal of the 4-nitrobenzyl protecting group

from a range of substrates.

However, attempted removal of the 4-nitrobenzyl group

from the cysteine thiol group or from the indole nitrogen were

unsuccessful. The S-(4-nitrobenzyl)cysteine derivative 44 was

reduced to the corresponding 4-aminobenzyl derivative in

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

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Table 6 Deprotection of 4-nitrobenzyl ethers and esters

43

R

Yield (%)

a

b

c

d

e

f

g

h

i

j

k

l

m

n

PhCH₂CH₂

PhOCH₂CH₂

PhCH₂OCH₂CH₂

PhCOOCH₂CH₂

t-BuMe₂SiOCH₂CH₂

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl

4-MeO-C₆H₄

4-Ac-C₆H₄

3-OHC-C₆H₄

2,3,5-Me₃-C₆H₂

2,4,5-Cl₃-C₆H₂

6-Quinolinyl

87

98

100

99

a

93

81

97

61

100

90

97

90

96

4-Cl-C₆H₄CO

( )-CbzNHCHMeCO

^aInseparable mixture of desired product and tert-butyldimethylsilanol

formed.

Scheme 10

quantitative yield, and the 1-(4-nitrobenzyl)indole 46 similarly

underwent simple nitro group reduction without further bond

cleavage (Scheme 9).

viously in the reduction of chalcone using samarium diiodide,⁸⁴

zinc⁸⁵or electrochemistry,⁸⁶and their stereochemistry and

mechanism of formation discussed.⁸⁴Presumably the indium

mediated reaction follows a similar pathway initiated by single

electron transfer from the metal to the conjugated system.

Since an electron deﬁcient heteroaromatic ring such as

quinoline can fulﬁl the role of an electron withdrawing sub-

stituent, the reduction of alkenes conjugated to such rings was

next investigated. The 2-(butenyl)quinoline 55a, prepared by

dehydration of the alcohol 57a (see below), was readily reduced

to the 2-butyl derivative 56a (86%) on treatment with indium–

AcOH–THF. Under these conditions no further reduction of

the heteroaromatic ring was observed. Likewise, the 2-(alkenyl)-

quinolines 55b and 55c were reduced to the 2-alkyl derivatives

in excellent yield (Scheme 11). In the latter case, there was no

Scheme 9

Reduction of conjugated alkenes

The reduction of the C᎐C bond in conjugated alkenes, particu-

᎐

larly α,β-unsaturated carbonyl compounds, is a much studied

reaction in organic synthesis.⁸³Although catalytic hydrogen-

ation can be used, the methods of choice often involve electron

transfer from appropriate metals. Examples include the well

known reduction of α,β-unsaturated carbonyl compounds

under Birch reduction conditions or using magnesium in

methanol. In view of our success in using indium to replace

such reducing metals in other reactions, we investigated its use

in the reduction of conjugated alkenes.

The reaction was investigated using simple α,β-unsaturated

ketones, and although the usual aqueous conditions were

unsatisfactory, reduction using indium in THF in the presence

of acetic acid was successful. Thus benzylideneacetone 48 and

1-phenylbut-2-en-1-one 50 were reduced to the corresponding

ketones 49 and 51 in quantitative yield. However, when chal-

cone 52 was submitted to the same conditions only 23% of

the corresponding ketone 53 was formed, the major product

being the cyclopentane derivative 54 (59%) formed as a single

diastereomer (Scheme 10). Such ‘dimers’ have been noted pre-

Scheme 11

evidence for interception of radical intermediates by cyclisation

onto the terminal alkene. In accord with the requirement

for an electron deﬁcient aromatic ring to facilitate alkene

reduction, 2-(3-methylbut-1-enyl)naphthalene was recovered

unchanged.

The alkene 55a was prepared by dehydration of the corre-

sponding alcohol 57a, itself available by reaction of the anion

derived from 2-methylquinoline with propionaldehyde. Given

the acidic nature of the indium reduction conditions, it was

found that the alcohols 57 could be converted directly into the

2-alkylquinolines 56a and 56b in excellent yield (Scheme 11),

the reaction proceeding by initial dehydration followed by

reduction.

960

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

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concentrated in vacuo. The crude product was puriﬁed by ﬂash

chromatography to yield the desired product.

Conclusions

These studies have shown that indium metal can mediate a

range of synthetically useful, selective reductions in both aque-

ous and non-aqueous systems. The reactions are usually high

yielding, are easy to carry out usually avoiding the need for

exclusion of air or moisture or any other special precautions,

and involve simple work-up and product isolation.

General procedure 2: indium mediated reductions in THF–

acetic acid. The substrate (1.0 mmol) was dissolved in THF

(10 ml) with indium powder (1.0 g) and acetic acid (4.0 mmol–

1 equivalent per proton required) under an atmosphere of nitro-

gen. The mixture was stirred under reﬂux. When the reaction

appeared complete by TLC (typically 1–7 d) the cooled reaction

mixture was diluted with water (50 ml) and ethyl acetate (25 ml)

and decanted. The layers were separated and the aqueous layer

further extracted with ethyl acetate (25 ml). The combined

organic layers were dried (MgSO₄) and concentrated in vacuo.

The crude product was puriﬁed by ﬂash chromatography to

yield the desired product.

Experimental

General

Commercially available reagents and solvents were used

throughout without further puriﬁcation other than those

detailed below. Indium powder (100 mesh) was purchased

from Aldrich. Silver() oxide was prepared freshly from the

addition of sodium hydroxide solution to silver nitrate solution,

collected by ﬁltration, dried over P₂O₅, and stored in a brown

glass jar. Light petroleum refers to the fraction that boils

between 40 ЊC and 60 ЊC and was distilled from calcium

chloride through a 36 cm Vigreux column before use. Diethyl

ether (ether) and THF were distilled from sodium benzo-

phenone ketyl under nitrogen prior to use. Dichloromethane

was puriﬁed and dried by distillation from phosphorus pentox-

ide under nitrogen. Pyridine was distilled from calcium hydride

whilst under nitrogen prior to use.

Analytical thin layer chromatography was carried out using

aluminium or glass backed plates coated with Merck Kieselgel

60 GF₂₅₄. Developed plates were visualised under ultra-violet

light (254 nm) and/or potassium permanganate or ninhydrin

dip. Flash chromatography was carried out using Merck

Kieselgel 60 H silica. Fully characterised compounds were

chromatographically homogeneous.

General procedure 3: indium reductions of isoquinolinium salts.

The substrate (1.0 mmol) was dissolved in THF (10 ml) and

indium powder (1.0 g) added. The mixture was heated at reﬂux

under nitrogen for 4–5 d. The cooled reaction mixture was

washed through Celite^with ethyl acetate (30 ml) and washed

with water (30 ml) then dried (MgSO₄) and concentrated in

vacuo to the product.

General procedure 4: indium reduction and acetylation of

oximes. Indium powder (0.92 g, 8.0 mmol) was added to a

solution of the oxime substrate (2.00 mmol), acetic anhydride

(0.47 ml, ~0.51 g, 5.0 mmol) and acetic acid (0.46 ml, ~0.48 g,

8.0 mmol) in THF (10 ml) and the mixture heated at reﬂux for

18 h. Saturated aqueous sodium bicarbonate solution (10 ml)

was carefully added to the cooled reaction mixture, and stirring

continued for 1 h. The resulting mixture was diluted with water

(30 ml) and extracted with ethyl acetate (3 × 15 ml). Combined

organic layers were dried (MgSO₄) and concentrated in vacuo.

If required, the crude material was puriﬁed by ﬂash column

chromatography (silica eluting with ~20% ethyl acetate in

dichloromethane) to give the desired product.

IR Spectra were recorded on a Nicolet Magna 550 spec-

trometer with internal calibration. Spectra were recorded as

thin ﬁlms on sodium chloride plates, in solution or potassium

bromide discs. NMR spectra were recorded on a Bruker AM

300 or Bruker Advance DRX 400 spectrometer at the frequen-

cies stated. Chemical shifts are recorded in ppm and J values in

Hz. Multiplets less than 0.2 ppm in width were recorded from

the centre, those greater were reported as a range. Chemical

shift values are referenced against chloroform at 7.27 ppm for

CDCl₃, methanol at 3.35 ppm for CD₃OD, and DMSO at 2.50

ppm for d₆-DMSO, and are accurate to 0.01 ppm (δ_H) and

0.10 ppm (δ_C). High resolution mass spectra (CI and EI)

were either obtained on a Kratos Proﬁle HV3 spectrometer

or at the EPSRC National Mass Spectrometry Service at the

University of Wales, Swansea. Gas chromatography–mass

spectrometry was carried out on a ThermoQuest Finnigan

Trace 2000 series GCMS, with a 15 m Crossbond^5%

diphenyl–95% dimethylpolysiloxane column with a 0.25 mm

internal diameter and CI/EI detection, which was used to

obtain some of the low resolution spectra. Elemental analysis

was carried out on a Perkin-Elmer 2400 CHN analyser to

within 0.3% of the theoretical values. Speciﬁc rotations were

measured on an AA-1000 polarimeter and values are quoted

General procedure 5: indium reductions of nitro compounds.

To a solution of the substrate (2.5 mmol) in ethanol (10 ml)

was added saturated ammonium chloride solution (3 ml) and

indium powder (2.0 g). The mixture was stirred under reﬂux.

When the reaction appeared complete by TLC (typically 1–3 h)

the cooled reaction mixture was diluted with water (50 ml) and

ﬁltered through Celite^. The aqueous ﬁltrate was adjusted to

pH ~ 9 with aqueous sodium hydroxide (4 M) and extracted

with dichloromethane, ethyl acetate or ether (3 × 15 ml). Com-

bined organic layers were dried (MgSO₄) and concentrated in

vacuo. The crude product was puriﬁed by ﬂash chromatography

to yield the desired product. Known products were conﬁrmed

by comparison with literature data for mp and ¹H NMR.

General procedure 6: reductive removal of 4-nitrobenzyl

protecting groups. Indium powder (1.0 g) was added to a

solution of the substrate (1.0 mmol) in methanol (10 ml) and

saturated ammonium chloride solution (3 ml) and the mixture

heated at reﬂux. After 18 h the cooled reaction mixture was

ﬁltered through Celite^with water (50 ml) and the pH adjusted

to ~2 (7 for basic substrates) with hydrochloric acid (2 M) then

extracted with dichloromethane (or ethyl acetate) (3 × 15 ml).

Combined organic layers were dried (MgSO₄) and concentrated

in vacuo to give the desired product with no need for further

puriﬁcation. Deprotected compounds were compared with the

original unprotected substrate and literature data.

in 10^Ϫ1deg cm²g^Ϫ1

.

General procedures for indium metal reductions

General procedure 1: indium mediated reductions in aqueous

ethanolic ammonium chloride. To a solution of the substrate

(1.9 mmol) in ethanol (10 ml) was added saturated ammonium

chloride solution (3 ml) and indium powder (2.0 g). The mix-

ture was stirred under reﬂux. When the reaction appeared com-

plete by TLC (typically 1–5 d), the cooled reaction mixture was

diluted with water (50 ml) and ﬁltered through Celite^. The

aqueous ﬁltrate was adjusted to pH ~ 9 with aqueous sodium

hydroxide solution (4 M) and extracted with dichloromethane

(3 × 15 ml). Combined organic layers were dried (MgSO₄) and

General procedure 7: indium reduction of conjugated alkenes.

The substrate (1.0 mmol) was dissolved in THF (10 ml) with

indium powder (0.50 g) and acetic acid (4.0 mmol). The mixture

was stirred under reﬂux. When the reaction appeared com-

plete by TLC (typically 16 h–4 d), the cooled reaction mixture

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

961

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was diluted with water (50 ml) and ethyl acetate (25 ml) and

decanted. The layers were separated and the aqueous layer

further extracted with ethyl acetate (25 ml). The combined

organic layers were dried (MgSO₄) and concentrated in vacuo.

If required, the crude product was puriﬁed by ﬂash chrom-

atography to yield the desired product.

N-Phenyl-3,4-dimethoxybenzylamine 4. According to the

general procedure 1, the title compound was obtained from

N-(3,4-dimethoxybenzylidene)aniline 3 as a colourless oil

(70%); δ_H(300 MHz; CDCl₃) 7.21–6.64 (8 H, m, ArH), 4.56

(2 H, s, CH₂), 3.88 (3 H, s, OMe), 3.87 (3 H, s, OMe), 1.64 (1 H,

br s, NH) (cf. lit.⁹⁰).

Preparation of imines

N-(4-Methoxyphenyl)-4-methylbenzylamine 6. According to

the general procedure 1, the title compound was obtained from

N-(4-methylbenzylidene)-4-methoxyaniline 5 as a colourless oil

(99%); δ_H(300 MHz; CDCl₃) 7.30 (2 H, d, J 6.3, 2&6-ArH-

CH₂N), 7.22 (2 H, d, J 6.3, 3&5-ArH-CH₂N), 6.79 (2 H, m,

3&5-ArH-N), 6.64 (2 H, m, 3&5-ArH-N), 4.28 (2 H, s, CH₂),

3.77 (3 H, s, OMe), 3.11 (1 H, br s, NH), 2.37 (3 H, s, ArMe) (cf.

lit.⁹¹).

N,NЈ-Bis(4-methylphenyl)biphenyl-2,2Ј-dicarbaldehyde

bisimine. Biphenyl-2,2Ј-dicarbaldehyde, prepared by the

ozonolysis of phenanthrene⁸⁷(0.781 g, 3.72 mmol) and

4-toluidine (0.796 g, 7.44 mmol) were dissolved in benzene

(30 ml) with a few crystals of toluene-4-sulfonic acid. The mix-

ture was heated under reﬂux with a Dean–Stark trap for 2 d.

The cooled reaction mixture was poured onto water (50 ml)

and extracted with dichloromethane (3 × 20 ml). The com-

bined organic layers were dried (MgSO₄) and concentrated

in vacuo. The crude material was recrystallised twice from ether

to give the title compound as colourless prisms (0.936 g, 65%);

mp 155–157 ЊC (Found: C, 86.2; H, 6.2; N, 7.0. C₂₈H₂₄N₂

requires C, 86.6; H, 6.2; N, 7.2%) (Found: M^ϩ, 388.1920.

C₂₈H₂₄N₂requires 388.1939); ν_max(KBr)/cm^Ϫ13065, 3020

(ArH), 2880, 1620 (imine), 1580, 1500 (Ar), 810 (ArH), 760

(ArH); δ_H(300 MHz; CDCl₃) 8.35 (2 H, dd, J 5.3, 4.0, 3-Ph-Ph),

2,3-Bis(4-methylphenyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroquin-

oxaline 9. Indium powder (2.00 g) was added to a solution of

N,NЈ-(4-methylbenzylidene)-trans-1,2-diaminocyclohexane

7

(0.544 g, 1.71 mmol) and acetic acid (0.205 g, 3.42 mmol, ~0.20

ml) in THF (10 ml). The mixture was heated at reﬂux for 18 h

then cooled and washed through Celite^with ethyl acetate

(50 ml). The ﬁltrate was washed with sodium hydroxide solu-

tion (1 M; 20 ml) and water (20 ml) then dried (MgSO₄) and

concentrated in vacuo. The crude material was passed down a

ﬂash chromatography column (silica, 2% methanol in chloro-

form) to give the title compound 9 as a clear oil which solidiﬁed

on standing (0.440 g, 80%); mp 52–53 ЊC (Found: MH^ϩ,

321.2337. C₂₂H₂₉N₂requires 321.2331); ν_max(KBr)/cm^Ϫ13260

(NH), 3015 (ArH), 2920, 2840 (CH), 2810, 1515 (Ar), 820

(ArH); δ_H(300 MHz; CDCl₃) 7.02 (4 H, d, J 8.0, ArH), 6.93

(4 H, d, J 8.0, ArH), 3.82 (2 H, s, ArCH), 2.60 (2 H, m,

CH₂CHN), 2.23 (6 H, s, ArMe), 1.84 (2 H, br s, NH), 1.73 (4 H,

br m, CH₂CHN), 1.39 (4 H, br m, CH₂CH₂CHN); δ_C(100

MHz; CDCl₃) 138.6 (C), 136.5 (C), 128.5 (CH), 128.0 (CH),

67.9 (CH), 61.6 (CH), 31.8 (CH₂), 24.9 (CH₂), 21.1 (Me); m/z

(EI) 320 (M^ϩ, 12%), 201 (32), 186 (29), 120 (100), 105 (33), 91

(49); (CI) 321 (MH^ϩ, 100), 200 (10), 120 (12).

8.22 (2 H, s, N᎐CH), 7.53 (4 H, m, 4&5-Ph-Ph), 7.35 (2 H,

᎐

dd, J 5.3, 3.5, 6-Ph-Ph), 7.09 (4 H, d, J 8.3, 2&6-NArH), 6.93

(4 H, d, J 8.3, 3&5-NArH), 2.31 (6 H, s, Me); δ_C(75 MHz;

CDCl ) 158.0 (N᎐CH), 149.4 (C), 140.9 (C), 135.9 (C), 134.9

᎐

3

(C), 130.9 (CH), 130.6 (CH), 129.7 (CH), 128.4 (CH), 126.9

(CH), 120.8 (CH), 21.0 (Me); m/z (EI) 388 (M^ϩ, 8%), 282 (84),

270 (30), 267 (81), 190 (17), 178 (24), 165 (48), 106 (38), 91

(100), 65 (62).

N,NЈ-Bis(4-methylbenzylidene)-trans-1,2-diaminocyclohexane

7. 4-Tolualdehyde (5.0 ml, ~5.09 g, 42.4 mmol) and (ϩ/Ϫ)-trans-

1,2-diaminocyclohexane (2.53 ml, ~2.42 g, 21.2 mmol) were

heated at reﬂux in benzene (30 ml) with a Dean–Stark trap for

24 h. The cooled mixture was concentrated in vacuo and the

resulting crude material recrystallised from ether to give the

title compound 7 as colourless prisms (5.53 g, 82%); mp 95–

96 ЊC (lit.,⁸⁸mp not given); δ_H(300 MHz; CDCl₃) 8.17 (2 H,

2,3-Bis(4-methoxyphenyl)-1,2,3,4,4a,5,6,7,8,8a-decahydro-

quinoxaline 10. Indium powder (1.00 g) was added to a solution

of N,NЈ-(4-methoxybenzylidene)-trans-1,2-diaminocyclohex-

ane 8 (0.366 g, 1.05 mmol) and acetic acid (0.12 ml, ~0.13 g, 2.1

mmol) in THF (10 ml). The mixture was heated at reﬂux for

48 h then cooled and washed through Celite^with ethyl acetate

(50 ml). The ﬁltrate was washed with sodium hydroxide solu-

tion (1 M; 20 ml) and water (20 ml) then dried (MgSO₄) and

concentrated in vacuo. The crude material was passed down a

ﬂash chromatography column (silica, 2→10% methanol in

chloroform) to give the title compound 10 as a colourless solid

(0.20 g, 54%); mp 179–180 ЊC (Found: MH^ϩ, 353.2226.

C₂₂H₂₉N₂O₂requires 353.2229); ν_max(KBr)/cm^Ϫ13230 (NH),

3005 (ArH), 2940, (CH), 2860, 1605, 1510 (Ar), 820 (ArH);

δ_H(400 MHz; CDCl₃) 7.08 (4 H, d, J 8.6, ArH), 6.61 (4 H, d,

J 8.6, ArH), 3.93 (2 H, s, ArCH), 3.71 (6 H, s, ArOMe), 3.31

(2 H, br s, NH), 2.75 (2 H, m, CH₂CHN), 1.70 (4 H, br m,

CH₂CHN), 1.33 (4 H, br m, CH₂CH₂CHN); δ_C(100 MHz;

CDCl₃) 158.8 (C), 131.6 (C), 129.3 (CH), 113.4 (CH), 66.4

(CH), 60.7 (CH), 55.1 (OMe), 30.8 (CH₂), 24.6 (CH₂); m/z (EI)

352 (M^ϩ, 5%), 217 (15), 162 (22), 134 (100), 121 (39), 91 (40), 77

(41); (CI) 353 (MH^ϩ, 100), 136 (22), 98 (29).

s, N᎐CH), 7.48 (4 H, d, J 8.1, 2&6-ArH), 7.11 (4 H, d, J 8.1,

᎐

3&5-ArH), 3.48 (2 H, m, ᎐N-CH), 2.31 (6 H, s, ArMe), 1.83

(6 H, m, ring-CH₂), 1.47 (2 H, ring-CH₂).

᎐

N,NЈ-Bis(4-methoxybenzylidene)-trans-1,2-diaminocyclo-

hexane 8. 4-Anisaldehyde (2.27 ml, ~2.54 g, 18.7 mmol) and

(ϩ/Ϫ)-trans-1,2-diaminocyclohexane (1.07 g, 9.4 mmol) were

heated at reﬂux in benzene (30 ml) with a Dean–Stark trap for

22 h. The cooled mixture was concentrated in vacuo and the

resulting crude material recrystallised from methanol to give

the title compound 8 as colourless prisms (2.89 g, 88%); mp

169–170 ЊC (lit.,⁸⁸mp not given); δ_H(300 MHz; CDCl₃) 8.13

(2 H, s, N᎐CH), 7.53 (4 H, m, 2&6-ArH), 6.82 (4 H, m, 3&5-

᎐

ArH), 3.78 (6 H, s, OMe), 3.34 (2 H, m, ᎐N-CH), 1.84 (6 H, m,

ring-CH₂), 1.47 (2 H, ring-CH₂).

᎐

Reduction of imines

N,NЈ,1,2-Tetraphenylethane-1,2-diamine 2. (a) According to

the literature procedure,³⁶the title compound was obtained as a

1 : 1 mixture of ( )/meso isomers from N-benzylideneaniline 1

as a colourless solid (87%); mp 157–160 ЊC (lit.,⁸⁹mp meso 169–

170 ЊC, (ϩ),(Ϫ) 152.5–153.5 ЊC); δ_H(300 MHz; CDCl₃) 7.26–

6.54 (20 H, m, ArH), 5.01 (1 H, d, J 6.8, [with D₂O shake—1 H,

s] meso-NCH), 4.61 (3 H, br, [with D₂O shake—1 H, s] (ϩ),(Ϫ)-

NCH and NH).

Preparation of nitrogen heterocycles

2-n-Propylquinoline 11f. n-Butyllithium (1.55 M in hexanes;

10.4 ml, ~16.1 mmol) was added to a stirred suspension of

n-propyltriphenylphosphonium bromide (6.20 g, 16.1 mmol) in

DME (30 ml) under a nitrogen atmosphere so as to keep the

temperature at ~Ϫ35 ЊC. After 1 h, 2-chloroquinoline (1.32 g,

8.0 mmol) was added and the mixture allowed to warm to room

(b) The title compound was also obtained directly from anil-

ine and benzaldehyde (52%) by the same procedure (aniline 2.0

mmol and benzaldehyde 2.0 mmol).

962

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

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temperature over 2 h. The mixture was then heated at reﬂux for

18 h, then sodium carbonate (1.71 g, 16.1 mmol) in water (20

ml) was added and the mixture kept at reﬂux for a further 6 h.

The cooled reaction mixture was diluted with dilute hydro-

chloric acid (0.5 M) until pH ~ 2 (ca. 100 ml), then washed with

chloroform (3 × 30 ml). The aqueous layer was then adjusted to

pH 8/9 with sodium carbonate and extracted with ether (3 × 50

ml). The combined ethereal layers were dried (MgSO₄), and

concentrated in vacuo. The crude material was puriﬁed by ﬂash

column chromatography (silica, dichloromethane) to give the

title compound 11f as a colourless oil (0.23 g, 17%); δ_H(300

MHz; CDCl₃) 8.07 (1 H, d, J 8.3, 4-ArH), 8.05 (1 H, d, J 8.2,

8-ArH), 7.78 (1 H, dd, J 7.9, 1.4, 5-ArH), 7.69 (1 H, ddd, J 8.2,

7.2, 1.4, 7-ArH), 7.49 (1 H, ddd, J 7.9, 7.2, 0.8, 6-ArH), 7.30

(1 H, d, J 8.3, 3-ArH), 2.96 (2 H, m, ArCH₂), 1.86 (2 H, m,

ArCH₂CH₂), 1.03 (3 H, t, J 7.4, Me) (cf. lit.⁹²).

(1.62 g, 9.9 mmol) was added and the mixture was allowed to

stir at room temperature over 2 h, then heated under reﬂux for

a further 16 h. Sodium carbonate (1.05 g, 9.91 mmol) in water

(20 ml) was added, and reﬂux continued for 3 h. Hydrochloric

acid (0.2 M) was added to the cooled reaction mixture to

pH < 3 and the resulting solution was washed with chloroform

(2 × 30 ml). The aqueous layer was basiﬁed with sodium

carbonate to pH ~ 9, and extracted with ether (3 × 20 ml). The

combined ethereal layers were dried (MgSO₄) and concentrated

in vacuo. The crude material was puriﬁed by ﬂash column

chromatography (silica, 1% methanol in chloroform) to give the

title compound 13b as a yellow oil (0.78 g, 55%); bp 110 ЊC/3.0

mmHg (lit.,⁹⁴bp 71–72 ЊC/1.0 mmHg); δ_H(300 MHz; CDCl₃)

8.40 (1 H, d, J 5.8, 3-ArH), 8.14 (1 H, dd, J 8.2, 1.4, 8-ArH),

7.83 (1 H, dd, J 8.3, 1.4, 5-ArH), 7.69 (1 H, ddd, J 8.3, 6.9, 1.4,

6-ArH), 7.61 (1 H, ddd, J 8.2, 6.9, 1.4, 7-ArH), 7.53 (1 H, d,

J 5.8, 4-ArH), 3.00 (3 H, s, Me).

2-(Allyloxymethyl)quinoline 11h. Allyl alcohol (0.16 ml, ~0.14

g, 2.4 mmol) in DMF (20 ml) was added to sodium hydride

(60% dispersion in mineral oil, 0.250 g, 6.25 mmol) previously

rinsed with hexane under nitrogen. 2-(Chloromethyl)quinoline

hydrochloride (0.48 g, 2.2 mmol) in DMF (15 ml) was added

after 1 h and stirring continued for 1 h at room temperature,

after which time TLC (silica, 40% ethyl acetate in light petrol-

eum) showed completion. The reaction mixture was poured

onto saturated ammonium chloride solution (50 ml). Water

(20 ml) was added and the mixture extracted with ethyl acetate

(3 × 15 ml). The combined organic layers were washed with

brine (20 ml), dried (MgSO₄), and concentrated in vacuo. The

crude product was puriﬁed by ﬂash column chromatography

(silica, 25% ethyl acetate in light petroleum) to give the title

compound 11h as a colourless oil (0.23 g, 52%) (Found: M^ϩ,

199.0997. C₁₃H₁₃NO requires 199.0997); ν_max(neat)/cm^Ϫ13054,

3008, 2846 (OCH₂), 1604, 1506, 1426, 1094, 987, 924, 822, 749

(ArH); δ_H(300 MHz; CDCl₃) 8.17 (1 H, d, J 8.5, 4-ArH), 8.06

(1 H, dd, J 8.4, 0.7, 8-ArH), 7.81 (1 H, br d, J 8.0, 5-ArH), 7.70

(1 H, ddd, J 8.4, 7.0, 1.4, 7-ArH), 7.63 (1 H, d, J 8.5, 3-ArH),

7.52 (1 H, br dd, J 8.0, 7.0, 6-ArH), 6.01 (1 H, ddt, J 10.4, 17.2,

2,3-Dimethylisoquinolinium iodide 13d. Methyl iodide (2.1 ml,

~4.78 g, 33.7 mmol) was added in one portion to a stirred

solution of 3-methylisoquinoline 13c (0.47 g, 3.3 mmol) in

butanone (20 ml). The mixture was stirred and heated under

reﬂux for 3 h. The resulting yellow precipitate was collected by

ﬁltration and washed with ether to give the title compound 13d

as yellow crystals (0.93 g, 98%); mp 228–230 ЊC (lit.,⁹⁵mp 222–

230 ЊC); δ_H(300 MHz; d₆-DMSO) 10.05 (1 H, s, 1-ArH), 8.47

(1 H, s, 4-ArH), 8.41 (1 H, d, J 8.3, 8-ArH), 8.21 (2 H, m, 5&6-

ArH), 8.00 (1 H, ddd, J 8.3, 5.0, 3.3, 7-ArH), 4.40 (3 H, s,

NMe), 2.85 (3 H, s, ArMe).

9-Methyl-1,2,3,4-tetrahydrocarbazole 17c. Methyl iodide (0.8

ml, 12.8 mmol) was added after 1 h to a stirred solution of

1,2,3,4-tetrahydrocarbazole (1.00 g, 5.8 mmol) and sodium

hydride (60% dispersion in mineral oil, 0.50 g, 12.5 mmol) in

anhydrous THF (10 ml) under nitrogen at room temperature.

After 15 min the reaction was quenched with saturated

ammonium chloride solution (40 ml), and extracted with

dichloromethane (3 × 15 ml). The combined organic layers

were dried (MgSO₄) and concentrated in vacuo. The crude

product was puriﬁed by ﬂash chromatography (silica, 1 : 1

dichloromethane–light petroleum) to give the title compound

17c as a colourless solid (1.01 g, 93%); mp 50–51 ЊC (lit.,⁹⁶mp

50–51 ЊC); δ_H(300 MHz; CDCl₃) 7.56 (1 H, d, J 7.7, 8-ArH),

7.33 (1 H, d, J 8.2, 5-ArH), 7.24 (1 H, ddd, J 1.1, 7.7, 8.0,

7-ArH), 7.16 (1 H, ddd, J 1.1, 8.0, 8.2, 6-ArH), 3.63 (3 H, s,

NMe), 2.74 (4H, m, CH₂), 1.92 (4 H, m, CH₂).

5.7, CH᎐CH ), 5.36 (1 H, ddt, J 3.0, 17.2, 1.6, trans-CH᎐CHH),

᎐

2

5.24 (1 H, ddt, J 3.0, 10.4, 1.6, cis-CH᎐CHH), 4.83 (2 H, s,

᎐

ArCH O), 4.16 (2 H, ddd, J 1.6, 1.6, 5.7, OCH CH᎐CH );

᎐

2

δ (100 MHz; CDCl ) 159.2 (C), 147.6 (C), 136.7 (᎐CH), 134.4

᎐

C

3

(CH), 129.5 (CH), 129.0 (CH), 127.6 (CH), 127.5 (C), 126.3

(CH), 119.4 (CH), 117.4 (᎐CH ), 73.7 (CH ), 71.9 (CH ); m/z

᎐

2

(EI) 199 (M^ϩ, 3%), 170 (2), 143 (100), 128 (9), 115 (11), 101 (4),

83 (6).

N-Quinolin-6-ylacetamide 11k. To a stirred solution of

6-aminoquinoline (1.00 g, 6.9 mmol) in glacial acetic acid (10

ml) was added acetic anhydride (2.00 g, 19.6 mmol) in glacial

acetic acid (5 ml). The solution was allowed to stir at room

temperature for 5 h then poured onto ice–water (100 ml) and

neutralised with aqueous ammonia. The crystals were collected

by vacuum ﬁltration and recrystallised twice from water to yield

the title compound 11k (0.68 g, 53%) as colourless needles, mp

138–139 ЊC (from water) (lit.,⁹³mp 138 ЊC); ν_max(KBr)/cm^Ϫ1

3283 (NH), 3088, 1665, 1568, 1373, 1276, 871, 835, 820, 743;

δ_H(400 MHz; CDCl₃) 8.80 (1 H, dd, J 4.2, 1.6, 2-ArH), 8.39

(1 H, br s, NH), 8.36 (1 H, d, J 2.2, 5-ArH), 8.07 (1 H, dd, J 8.4,

1.6, 4-ArH), 7.99 (1 H, d, J 9.0, 8-ArH), 7.57 (1 H, dd, J 9.0,

2.2, 7-ArH), 7.35 (1 H, dd, J 8.4, 4.2, 3-ArH), 2.23 (3 H, s,

6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline 22a. (a)

Acetyl chloride (0.30 ml, ~0.33 g, 4.2 mmol) was added drop-

wise to a stirred solution of 2-(3,4-dimethoxyphenyl)ethyl-

amine (0.495 g, 2.73 mmol) and triethylamine (0.275 g, ~0.38

ml, 2.72 mmol) in dichloromethane (10 ml). The mixture was

stirred for 1.5 h then washed with water and concentrated in

vacuo to give N-acetyl-3,4-dimethoxyphenethylamine (0.880 g,

100%) as a colourless solid, mp 95–96 ЊC (lit.,⁹⁷95–96 ЊC);

δ_H(300 MHz; CDCl₃) 6.84–6.69 (3 H, m, ArH), 6.01 (1 H, br s,

NH), 3.84 (3 H, s, OMe), 3.83 (3 H, s, OMe), 3.46 (2 H, m,

CH₂N), 2.74 (2 H, t, J 6.9, ArCH₂), 1.95 (3 H, s, COMe).

(b) A solution of N-acetyl-3,4-dimethoxyphenethylamine

(0.607 g, 2.72 mmol) in phosphoryl chloride (40 ml) was stirred

at room temperature for 18 h, then the solution was heated at

reﬂux for 2 h. The cooled mixture was concentrated in vacuo

and the residue taken up in saturated aqueous sodium

bicarbonate (40 ml) and extracted with dichloromethane

(2 × 20 ml). Combined organic layers were dried (MgSO₄) and

concentrated in vacuo, then puriﬁed by ﬂash chromatography

(silica, 5% methanol in chloroform) to give the title compound

22a (0.307 g, 58%) as a colourless solid; mp 101–103 ЊC (lit.,⁹⁸

102–104 ЊC); δ_H(300 MHz; CDCl₃) 6.98 (1 H, s, 5-ArH), 6.68

(1 H, s, 8-ArH), 3.91 (3 H, s, OMe), 3.90 (3 H, s, OMe), 3.62

CH CO); δ (100 MHz; CDCl ) 169.0 (C᎐O), 149.3 (CH), 145.4

᎐

3

C

3

(C), 136.1 (C), 135.9 (CH), 129.9 (CH), 128.9 (C), 123.3 (CH),

121.6 (CH), 116.2 (CH), 24.6 (Me).

1-Methylisoquinoline 13b. n-Butyllithium (1.6 M solution in

hexanes; 15.0 ml, 24.0 mmol) was added to a stirred suspension

of methyltriphenylphosphonium bromide (8.21 g, 23.0 mmol)

in DME (30 ml) under an atmosphere of nitrogen, so as to

keep the temperature at ~35 ЊC. After 1 h, 1-chloroisoquinoline

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

963

View Article Online

(2 H, t, J 7.4, NCH₂), 2.63 (2 H, t, J 7.4, ArCH₂), 2.36 (3 H, s,

yellow precipitate was collected by ﬁltration and washed with

Me).

cold acetone then dried at 60 ЊC for 18 h to give the title com-

pound 24b (0.530 g, 39%) as yellow crystals; mp 168–170 ЊC

(Found: MH^ϩϪ I, 275.1878. C₁₇H₂₅NO₂requires 275.1885);

ν_max(KBr)/cm^Ϫ13001, 2966, 2935, 2822, 1634, 1568, 1526, 1383,

1280, 1220, 999, 886, 420; δ_H(300 MHz; d₆-DMSO) 7.41 (1 H, s,

ArH), 7.15 (1 H, s, ArH), 5.87 (1 H, ddt, J 16.8, 10.2, 6.6,

6,7-Dimethoxy-1-(pent-4-enyl)-3,4-dihydroisoquinoline 22b.

(a) 2-(3,4-Dimethoxyphenyl)ethylamine (1.12 g, 6.2 mmol) and

hex-5-enoic acid (0.76 g, 6.6 mmol) were stirred together at

150 ЊC for 4 h. The cooled mixture was taken up in chloroform

(25 ml) and washed successively with hydrochloric acid (2 M; 20

ml), dilute ammonia solution (20 ml) and water (20 ml). The

organic layer was dried (MgSO₄) and concentrated in vacuo

to give 3,4-dimethoxy-N-(pent-4-enylcarbonyl)phenethylamine

(1.57 g, 91%) as a dark oil (Found: M^ϩ, 277.1658. C₁₆H₂₃NO₃

requires 277.1678); ν_max(neat)/cm^Ϫ13294 (NH), 3079, 2931,

CH᎐CH ), 5.08 (2 H, m, CH᎐CH ), 3.96 (2 H, t, J 8.0, CH N),

᎐

2

3.91 (3 H, s, OMe), 3.86 (3 H, s, OMe), 3.71 (3 H, s, Me), 3.19

(2 H, t, J 7.7, CH C᎐N), 3.07 (2 H, t, J 8.0, ArCH ), 2.21 (2 H,

᎐

2

td, J 7.4, 6.6, CH CH᎐CH ), 1.68 (2 H, tt, J 7.7, 7.4, CH -

᎐

2

CH CH᎐CH ); δ (100 MHz; d -DMSO) 176.5 (C᎐N), 155.9

᎐

2

C

6

(C), 148.5 (C), 138.0 (᎐CH), 133.7 (C), 118.8 (C), 116.6 (᎐CH ),

᎐

2

2828, 1658 (C᎐O), 1510, 1461, 1259, 1147, 1022, 914, 807, 762;

δ_H(300 MHz; CDCl₃) 6.86 (1 H, d, J 8.7, ArH), 6.74 (1 H, dd,

J 8.7, 1.8, ArH), 6.71 (1 H, d, J 1.8, ArH), 5.75 (1 H, ddt, J 17.1,

113.1 (CH), 111.7 (CH), 56.8 (2 × OMe), 52.5 (CH₂-N), 44.5

(MeN), 33.0 (CH₂), 29.8 (CH₂), 26.7 (CH₂), 25.3 (CH₂); m/z

(CI) 275 (MH^ϩϪ I^Ϫ, 100%), 261 (6), 204 (9), 165 (12), 152 (16).

᎐

10.4, 6.7, CH᎐CH ), 5.45 (1 H, br s, NH), 4.99 (1 H, dd, J 17.1,

᎐

2

1.7, trans-CH᎐CHH), 4.97 (1 H, dd, 10.4, 1.7, cis-CH᎐CHH),

3.86 (6 H, 2 s, 2 × OMe), 3.47 (2 H, dt, J 6.9, 6.9, ArCH₂), 2.76

(2 H, t, J 6.9, ArCH₂), 2.15 (2 H, t, J 7.7, COCH₂), 2.05 (2 H,

2-Cyclopropylquinoline 26. n-Butyllithium (1.6 M solution in

hexanes; 12.0 ml, 19.2 mmol) was added to a stirred suspension

of (cyclopropyl)triphenylphosphonium bromide (6.13 g, 16.0

mmol) in DME (30 ml) under an atmosphere of nitrogen, so as

to keep the temperature at ~Ϫ35 ЊC. After 1 h, 2-chloroquinol-

ine (1.03 g, 6.3 mmol) was added and the mixture allowed to stir

to room temperature over 2 h, then heated under reﬂux for

a further 19 h. Sodium carbonate (0.71 g, 6.7 mmol) in water

(10 ml) was added, and reﬂux continued for 4 h. Hydrochloric

acid (0.5 M; 100 ml) was added to the cooled reaction and the

resulting solution was washed with chloroform (2 × 70 ml). The

aqueous layer was basiﬁed with sodium carbonate to pH ~ 9,

and extracted with ether (3 × 50 ml). The combined ethereal

layers were dried (MgSO₄) and concentrated in vacuo. The

crude material was puriﬁed by ﬂash column chromatography

(silica, dichloromethane) to give the title compound 26 as a

colourless oil (0.44 g, 41%) (lit.,¹⁰⁰bp 145–148 ЊC at 17 mmHg);

ν_max(neat)/cm^Ϫ13045 (cyclopropane), 3000 (ArH), 1600, 1500

᎐

dt, J 6.7, 7.7, CH CH᎐CH ), 1.71 (2 H, quintet, J 7.7,

᎐

2

CH CH CH᎐CH ); δ (75 MHz; CDCl ) 172.8 (CO), 149.0 (C),

᎐

2

C

3

147.7 (C), 137.9 (᎐CH), 131.4 (C), 120.6 (CH), 115.3 (᎐CH ),

᎐

2

111.8 (CH), 111.3 (CH), 55.92 (OMe), 55.86 (OMe), 40.6

(CH₂), 36.0 (CH₂), 35.3 (CH₂), 33.1 (CH₂), 24.7 (CH₂); m/z (EI)

277 (M^ϩ, 5%), 164 (100), 151 (31), 149 (16), 107 (9); (CI) 278

(MH^ϩ, 100%).

(b) A solution of 3,4-dimethoxy-N-(pent-4-enylcarbonyl)-

phenethylamine (0.430 g, 1.55 mmol) in phosphoryl chloride

(20 ml) was stirred at room temperature for 4 d. The mixture

was concentrated in vacuo and the residue taken up in saturated

aqueous sodium bicarbonate (40 ml) and extracted with

dichloromethane (2 × 15 ml). Combined organic layers were

dried (MgSO₄) and concentrated in vacuo, then puriﬁed by ﬂash

chromatography (silica, 5% methanol in chloroform) to give the

title compound 22b (0.285 g, 71%) as a brown oil (Found: M^ϩ,

259.1567. C₁₆H₂₁NO₂requires 259.1572); ν_max(neat)/cm^Ϫ13067,

2929, 2828, 1510, 1464, 1271, 1208, 1141, 906, 864, 809; δ_H(300

MHz; CDCl₃) 6.99 (1 H, s, ArH), 6.70 (1 H, s, ArH), 5.84 (1 H,

ddt, J 17.1, 10.3, 7.4, CH᎐CH ), 5.04 (1 H, dd, J 17.1, 1.0, trans-

(C᎐C), 815 (ArH), 750 (ArH); δ (300 MHz; CDCl ) 8.00 (1 H,

᎐

H

3

d, J 8.3, 4-ArH), 7.97 (1 H, d, J 8.5, 8-ArH), 7.74 (1 H, dd,

J 8.0, 1.4, 5-ArH), 7.64 (1 H, ddd, J 8.5, 7.0, 1.4, 7-ArH), 7.43

(1 H, ddd, J 8.0, 7.0, 1.2, 6-ArH), 7.16 (1 H, d, J 8.3, 3-ArH),

2.25 (1 H, m, cyclopropane-CH), 1.13 (4 H, m, cyclopropane-

CH₂); δ_C(75 MHz; CDCl₃) 163.4 (C), 147.9 (C), 135.9 (CH),

129.3 (CH), 128.6 (CH), 127.5 (CH), 126.7 (C), 125.2 (CH),

119.3 (CH), 18.1 (CH), 10.3 (CH₂).

᎐

2

CH᎐CHH), 4.98 (1 H, dd, J 10.3, 1.0, cis-CH᎐CHH), 3.92

᎐

(3 H, s, OMe), 3.90 (3 H, s, OMe), 3.64 (2 H, t, J 7.4, NCH₂),

2.72 (2 H, t, J 7.4, N᎐CCH ), 2.63 (2 H, t, J 7.4, ArCH ), 2.16

᎐

2

(2 H, q, J 7.4, CH CH᎐CH ), 1.77 (2 H, quintet, J 7.4,

᎐

2

CH CH CH᎐CH ); δ (75 MHz; CDCl₃) 167.3 (C), 151.1 (C),

᎐

2

C

Reduction of nitrogen heterocycles

147.5 (C), 138.3 (᎐CH), 131.8 (C), 121.6 (C), 115.1 (᎐CH ),

᎐

2

1,2,3,4-Tetrahydroquinoline 12a. (a) According to the general

procedure 1 the title compound was obtained as a yellow oil

(52%) from quinoline 11a; δ_H(400 MHz; CDCl₃) 6.95 (2 H,

m, 7&5-ArH), 6.62 (1 H, ddd, J 7.6, 7.4, 1.1, 6-ArH), 6.47

(1 H, dd, J 7.5, 1.1, 8-ArH), 3.52 (1 H, br s, NH), 3.31 (2 H,

m, NHCH₂CH₂), 2.77 (2 H, t, J 6.4, ArCH₂), 1.95 (2 H, m,

NHCH₂CH₂) (cf. lit.¹⁰¹).

(b) The title compound was also formed in 79% yield from

2-chloroquinoline according to general procedure 1 (spectro-

scopic data identical).

110.4 (CH), 108.9 (CH), 56.3 (OMe), 56.0 (OMe), 46.5 (CH₂),

35.0 (CH₂), 33.5 (CH₂), 26.5 (CH₂), 25.9 (CH₂); m/z (EI) 259

(M^ϩ, 27%), 258 (47), 244 (26), 205 (100), 204 (78), 190 (50), 174

(53), 159 (31), 115 (37), 91 (30), 77 (50), 54 (43); (CI) 260 (MH^ϩ,

100%).

6,7-Dimethoxy-1,2-dimethyl-3,4-dihydroisoquinolinium iodide

24a. Iodomethane (0.12 ml, ~0.27 g, 1.9 mmol) was added to

a solution of 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline

22a (0.062 g, 0.30 mmol) in butanone (10 ml) and the solution

was stirred and heated at reﬂux for 9 h. The cooled reaction

mixture was concentrated in vacuo and the residue recrystallised

from ethanol–light petroleum to give the title compound 24a

(0.101 g, 96%) as yellow needles, mp 100–101 ЊC (lit.,⁹⁹101–

102 ЊC); δ_H(300 MHz; CDCl₃) 7.44 (1 H, s, 5-ArH), 7.08 (1 H, s,

8-ArH), 4.03 (2 H, t, J 7.7, CH₂N), 3.96 (3 H, s, OMe), 3.92

(3 H, s, OMe), 3.75 (3 H, s, MeN), 3.18 (2 H, t, J 7.7, ArCH₂),

2.85 (3 H, s, Me).

2-Methyl-1,2,3,4-tetrahydroquinoline 12b. According to the

general procedure 1 the title compound was obtained as a clear

oil (46%) from 2-methylquinoline 11b; δ_H(400 MHz; CDCl₃)

6.96 (2 H, m, 7&5-ArH), 6.62 (1 H, ddd, J 7.6, 7.4, 1.2, 6-ArH),

6.47 (1 H, dd, J 7.2, 1.2, 8-ArH), 3.67 (1 H, br s, NH), 3.41 (1 H,

m, NHCHMe), 2.82 (1 H, m, ArCHH), 2.74 (1 H, m, ArCHH),

1.94 (1 H, m, ArCH₂CHH), 1.61 (1 H, m, ArCH₂CHH), 1.22

(3 H, dd, J 4.0, 2.3, Me) (cf. lit.¹⁰¹).

6,7-Dimethoxy-2-methyl-1-(pent-4-enyl)-3,4-dihydroisoquin-

olinium iodide 24b. Methyl iodide (0.85 ml, ~1.93 g, 13.6 mmol)

was added to a stirred solution of 6,7-dimethoxy-1-(pent-4-

enyl)-3,4-dihydroisoquinoline 22b (0.880 g, 3.40 mmol) in acet-

one (20 ml). The mixture was heated at reﬂux for 24 h and the

3-Methyl-1,2,3,4-tetrahydroquinoline 12c. (a) According to

the general procedure 1 the title compound was obtained as a

yellow oil (76%) from 3-methylquinoline 11c; δ_H(400 MHz;

CDCl₃) 6.95 (2 H, m, 7&5-ArH), 6.61 (1 H, ddd, J 7.4, 7.6, 1.2,

964

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

View Article Online

6-ArH), 6.48 (1 H, dd, J 7.4, 1.2, 8-ArH), 3.6-4.0 (1 H, br s,

NH), 3.27 (1 H, ddd, J 11.0, 3.7, 2.0, NHCHH), 2.90 (1 H, dd,

J 9.6, 10.9, ArCHH), 2.77 (1 H, ddd, J 16.0, 4.8, 1.8,

NHCHH), 2.43 (1 H, dd, J 10.1, 16.0, ArCHH), 2.07 (1 H, m,

CHMe), 1.06 (3 H, d, J 6.6, Me) (cf. lit.¹⁰²).

(b) The title compound was formed in 30% yield using aque-

ous trimethylamine hydrogen chloride solution (4 M) in place

of saturated aqueous ammonium chloride solution according

to the general procedure 1 (spectroscopic data identical).

(c) The title compound was also formed in 21% yield accord-

ing to the general procedure 2, after a reaction time of 7 days

(spectroscopic data identical).

as a clear oil (39%) from 2-allyloxymethylquinoline 11h (Found:

M^ϩ, 203.1310. C₁₃H₁₇NO requires 203.1310); ν_max(neat)/cm^Ϫ1

3396 (NH), 3020, 2925, 2843 (C–H), 1600, 1480, 1305, 1100

(C᎐O), 995, 935 (CH᎐CH ), 738 (ArH); δ (300 MHz; CDCl₃)

᎐

2

H

7.01 (1 H, dd, J 8.6, 1.2, 5-ArH), 6.97 (1 H, ddd, J 8.0, 7.3, 1.2,

7-ArH), 6.63 (1 H, ddd, J 8.6, 7.3, 1.1, 6-ArH), 6.54 (1 H, d,

J 8.0, 8-ArH), 5.97 (1 H, ddt, J 17.3, 10.5, 5.8, CH᎐CH ), 5.33

᎐

2

(1 H, ddt, J 17.3, 1.7, 1.7, trans-CH᎐CHH), 5.24 (1 H, ddt,

᎐

J 10.5, 1.7, 1.4, cis-CH᎐CHH), 4.20 (1 H, br s, NH), 4.06 (2 H,

᎐

ddd, J 5.8, 1.7, 1.4, CH CH᎐CH ), 3.57 (2 H, m, N-CH and

᎐

2

NCHCHH), 3.37 (1 H, dd, J 10.2, 9.9, NCHCHH), 2.81 (2 H,

m, ArCH₂), 1.91 (1 H, m, ArCH₂CHH), 1.65 (1 H, m, ArCH₂-

CHH); δ_C(100 MHz; CDCl ) 144.2 (C), 134.6 (᎐CH), 129.2

᎐

3

4-Methyl-1,2,3,4-tetrahydroquinoline 12d. According to the

general procedure 1 the title compound was obtained as a

yellow oil (73%) from 4-methylquinoline 11d; δ_H(400 MHz;

CDCl₃) 7.06 (1 H, ddd, J 7.4, 1.8, 0.9, 5-ArH), 6.97 (1 H, ddd,

J 8.0, 7.8, 1.8, 7-ArH), 6.64 (1 H, ddd, J 7.8, 7.4, 1.2, 6-ArH),

6.48 (1 H, dd, J 8.0, 1.2, 8-ArH), 3.9 (1 H, br s, NH), 3.33 (2 H,

m, NHCH₂), 2.93 (1 H, m, CHMe), 1.99 (1 H, m, NHCH₂-

CHH), 1.70 (1 H, m, NHCH₂CHH), 1.30 (3 H, d, J 4.8, Me)

(cf. lit.¹⁰³).

(CH), 126.8 (CH), 121.2 (C), 117.2 (᎐CH ), 117.1 (CH), 114.2

᎐

2

(CH), 74.5 (OCH₂), 72.2 (OCH₂), 50.9 (CH), 26.0 (CH₂), 24.7

(CH₂); m/z (CI) 204 (MH^ϩ, 100%), 146 (16), 132 (24); (EI) 203

(M^ϩ, 7%), 132 (100), 130 (19), 117 (15), 91 (11), 77 (12).

2-Phenyl-1,2,3,4-tetrahydroquinoline 12i. According to the

general procedure 1 the title compound was obtained as a

yellow oil (40%) from 2-phenylquinoline 11i; δ_H(400 MHz;

CDCl₃) 7.42–7.29 (5 H, m, Ph), 7.01 (2 H, m, 7&5-ArH), 6.67

(1 H, dd, J 7.4, 1.1, 6-ArH), 6.55 (1 H, dd, J 7.5, 1.1, 8-ArH),

4.45 (1 H, dd, J 9.3, 3.3, NHCHPh), 4.04 (1 H, br s, NH), 2.90

(1 H, m, ArCHH), 2.76 (1 H, m, ArCHH), 2.12 (1 H, m,

ArCH₂CHH), 2.00 (1 H, m, ArCH₂CHH) (cf. lit.¹⁰⁶).

cis-2,4-Dimethyl-1,2,3,4-tetrahydroquinoline 12e. According

to the general procedure 1 the title compound was obtained as a

yellow oil (30%) from 2,4-dimethylquinoline 11e; ν_max(neat)/

cm^Ϫ13393 (NH), 3017, 2959, 2927, 2848, 1607, 740 (ArH);

δ_H(400 MHz; CDCl₃) 7.19 (1 H, dd, J 7.6, 1.4, 5-ArH), 7.02

(1 H, ddd, J 8.0, 7.4, 1.4, 7-ArH), 6.71 (1 H, ddd, J 7.6, 7.4, 1.2,

6-ArH), 6.51 (1 H, dd, J 8.0, 1.2, 8-ArH), 3.9–3.2 (1 H, br s,

NH), 3.51 (1 H, m, NHCHMe), 3.02 (1 H, m, ArCHMe), 1.98

(1 H, ddd, J 12.7, 5.4, 2.6, CHH), 1.39 (1 H, m (obscured),

CHH), 1.38 (3 H, d, J 6.8, cis 4-Me), 1.25 (3 H, d, J 6.2, cis

2-Me) (cf. lit.¹⁰⁴); δ_C(100 MHz; CDCl₃) 144.8 (C), 126.9 (CH),

126.8 (CH), 126.3 (C), 117.3 (CH), 113.9 (CH), 47.5 (CH), 40.7

(CH₂), 30.9 (CH), 22.8 (Me), 20.3 (Me).

6-Methoxy-1,2,3,4-tetrahydroquinoline 12j. According to the

general procedure 1 the title compound was obtained as a yel-

low oil (42%) from 6-methoxyquinoline 11j; δ_H(400 MHz;

CDCl₃) 6.60 (1 H, dd, J 8.5, 2.7, 7-ArH), 6.57 (1 H, d, J 2.7,

5-ArH), 6.45 (1 H, d, J 8.5, 8-ArH), 3.73 (3 H, s, OMe), 3.69

(1 H, br s, NH), 3.26 (2 H, m, NHCH₂CH₂), 2.76 (2 H, t, J 6.5,

ArCH₂), 1.93 (2 H, m, NHCH₂CH₂) (cf. lit.¹⁰⁷).

N-(1,2,3,4-Tetrahydroquinolin-6-yl)acetamide 12k. According

to the general procedure 1 the title compound was obtained as

a colourless oil following preparative TLC (60% by H NMR)

from N-(quinolin-6-yl)acetamide 11k; δ_H(300 MHz; CDCl₃)

7.14 (1 H, br s, CONH), 7.08 (1 H, d, J 2.5, 5-ArH), 6.97 (1 H,

dd, J 8.5, 2.4, 7-ArH), 6.41 (1 H, d, J 8.5, 8-ArH), 3.78 (1 H, br

s, NH), 3.26 (2 H, m, NHCH₂CH₂), 2.72 (2 H, t, J 6.4, ArCH₂),

2.11 (3 H, s, MeCO), 1.90 (2 H, m, NHCH₂CH₂) (cf. lit.¹⁰⁸).

2-n-Propyl-1,2,3,4-tetrahydroquinoline 12f. (a) According to

the general procedure 1 the title compound was obtained as a

clear oil (55%) from 2-n-propylquinoline 11f; δ_H(300 MHz;

CDCl₃) 6.98 (2 H, m, 7&5-ArH), 6.62 (1 H, ddd, J 7.4, 7.2, 1.1,

6-ArH), 6.49 (1 H, dd, J 8.3, 1.1, 8-ArH), 3.50 (1 H, br s, NH),

3.27 (1 H, m, NCH), 2.89–2.70 (2 H, m, ArCH₂), 2.00 (1 H, m,

ArCH₂CHH), 1.63 (1 H, m, ArCH₂CHH), 1.58–1.41 (4 H, m,

CH₂CH₂Me), 0.98 (3 H, t, J 6.9, Me) (cf. lit.¹⁰⁵); δ_C(75 MHz;

CDCl₃) 144.7 (C), 129.3 (CH), 126.7 (CH), 121.4 (C), 116.9

(CH), 114.1 (CH), 51.3 (CH), 38.9 (CH₂), 28.1 (CH₂), 26.5

(CH₂), 18.9 (CH₂), 14.2 (Me).

6-Chloro-1,2,3,4-tetrahydroquinoline 12l. According to the

general procedure 1 the title compound was obtained as a clear

oil (25%) from 6-chloroquinoline 11l; δ_H(300 MHz; CDCl₃)

6.91 (1 H, dd, J 3.0, 1.5, 5-ArH), 6.90 (1 H, dd, J 7.3, 3.0,

7-ArH), 6.38 (1 H, dd, J 7.3, 1.5, 8-ArH), 3.50 (1 H, br s, NH),

3.27 (2 H, m, NHCH₂CH₂), 2.73 (2 H, t, J 6.5, ArCH₂), 1.92

(2 H, m, NHCH₂CH₂) (cf. lit.¹⁰⁹).

(b) The title compound was also obtained (24%) from

2-cyclopropylquinoline 26 according to general procedure 1

(spectroscopic data identical; see below).

1,2-Dihydrophenanthridine 12m. According to the general

procedure 1 the title compound was obtained as a pale yellow

solid (72%) from phenanthridine 11m; mp 119–121 ЊC (lit.,¹¹⁰

mp 123.5–124.5 ЊC); δ_H(300 MHz; CDCl₃) 7.69 (1 H, dd, J 7.7,

1.2, 6-ArH), 7.68 (1 H, dd, J 8.0, 1.5, 7-ArH), 7.31 (1 H, ddd,

J 7.7, 7.3, 1.4, 5-ArH), 7.21 (1 H, ddd, J 7.5, 7.3, 1.2, 4-ArH),

7.11 (2 H, m, 9- and 3-ArH), 6.84 (1 H, ddd, J 8.0, 7.6, 1.1,

8-ArH), 6.67 (1 H, dd, J 7.9, 1.1, 10-ArH), 4.40 (2 H, s, CH₂),

3.94 (1 H, br s, NH).

2-(3-Methylbutyl)-1,2,3,4-tetrahydroquinoline 12g. According

to the general procedure 1 the title compound was obtained as

a colourless oil (49%) from 2-(3-methylbutyl)quinoline 11g

(Found: M^ϩ, 203.1665. C₁₄H₂₁N requires 203.1674); ν_max(neat)/

cm^Ϫ13400 (NH), 3017, 2950, 2925, 2841, 1604, 1480, 1312, 745

(ArH); δ_H(300 MHz; CDCl₃) 6.97 (2 H, m, 5&7-ArH), 6.60

(1 H, ddd, J 7.4, 7.3, 1.1, 6-ArH), 6.47 (1 H, dd, J 6.3, 1.1,

8-ArH), 3.72 (1 H, br s, NH), 3.21 (1 H, m, NCH), 2.77 (2 H,

m, ArCH₂CH₂), 1.98 (1 H, m, ArCH₂CHH), 1.46–1.67 (4 H, m,

ArCH₂CHH and alkyl chain), 1.29 (2 H, m, CH₂CHMe₂), 1.00

(6 H, d, J 6.8, CHMe₂); δ_C(75 MHz; CDCl₃) 144.7 (C), 129.3

(CH), 126.7 (CH), 121.4 (C), 116.9 (CH), 114.0 (CH), 51.9

(CH), 34.9 (CH₂), 34.6 (CH₂), 28.3 (CH), 28.1 (CH₂), 26.5

(CH₂), 22.7 (Me); m/z (CI) 204 (MH^ϩ, 100%); (EI) 203 (M^ϩ,

8%), 132 (100), 117 (13).

1,2,3,4-Tetrahydroisoquinoline 14a. According to the general

procedure 1 the title compound was obtained as a clear oil

(78%) from isoquinoline 13a; δ_H(300 MHz; CDCl₃) 7.15–7.00

(4 H, m, ArH), 4.02 (2 H, s, ArCH₂N), 3.14 (2 H, t, J 6.0,

NHCH₂CH₂), 2.80 (2 H, t, J 6.0, NHCH₂CH₂), 1.95 (1 H, s,

NH) (cf. lit.¹¹¹).

2-(Allyloxymethyl)-1,2,3,4-tetrahydroquinoline 12h. Accord-

ing to the general procedure 1 the title compound was obtained

1-Methyl-1,2,3,4-tetrahydroisoquinoline 14b. According to

the general procedure 1 the title compound was obtained as a

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

965

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colourless oil (74%) from 1-methylisoquinoline 13b; bp 105 ЊC,

1.5 mmHg (lit.,¹¹²78–80 ЊC, 0.06 mmHg); δ_H(300 MHz;

CDCl₃) 7.17 (4 H, m, ArH), 4.12 (1 H, q, J 7.2, CHMe), 3.39–

2.61 (4 H, m, CH₂CH₂), 1.82 (1 H, br s, NH), 1.51 (3 H, d, J 7.2,

CHMe).

(1 H, dd, J 15.4, 8.2, cis-NCHCHH), 2.74 (3 H, s, N-Me), 2.61

(1 H, dd, J 15.4, 10.4, trans-NCHCHH), 1.34 (3 H, d, J 6.2,

NCHMe) (cf. lit.¹¹⁹); δ_C(75 MHz; CDCl₃) 196.4 (C), 129.3 (C),

127.3 (CH), 124.0 (CH), 117.8 (CH), 107.2 (CH), 62.9 (CH),

37.4 (Me), 33.8 (CH₂), 18.8 (Me).

3-Methyl-1,2,3,4-tetrahydroisoquinoline 14c. According to

the general procedure 1 the title compound was obtained as a

yellow oil (71%) from 3-methylisoquinoline 13c; δ_H(400 MHz;

CDCl₃) 7.07–6.97 (4 H, m, ArH), 3.96 (2 H, 2d, J 15.8,

ArCH₂N), 2.89 (1 H, m, CHCH₃), 2.69 (1 H, dd, J 12.5, 3.5,

anti-ArCHHCH), 2.42 (1 H, dd, J 12.5, 5.5, syn-ArCHHCH),

1.16 (3 H, d, J 6.3, Me) (cf. lit.¹¹³).

4-Benzyloxy-1,2-dimethyl-5-methoxyindoline 18d. According

to the general procedure 1 the title compound was obtained as

a

brown oil (23%) from 4-benzyloxy-1,2-dimethyl-5-

methoxyindole 17d (Found: M^ϩ, 283.1578. C₁₈H₂₁NO₂requires

283.1572); ν_max(neat)/cm^Ϫ13030, 2957, 2831, 2795, 1615, 1485,

1258, 1197, 1076, 1019, 739, 699; δ_H(300 MHz; CDCl₃) 7.40

(5 H, m, OCH₂Ph), 6.71 (1 H, d, J 8.3, 6-ArH), 6.16 (1 H, d,

J 8.3, 7-ArH), 5.08 (1 H, d, J 11.1, OCH₂Ph), 5.06 (1 H, d,

J 11.1, OCH₂Ph), 3.83 (3 H, s, OMe), 3.28 (1 H, m, NCHMe),

3.06 (1 H, dd, J 7.9, 12.0, trans-NCHCHH), 2.66 (3 H, s, NMe),

2.40 (1 H, dd, J 9.8, 12.0, cis-NCHCHH), 1.28 (3 H, d, J 6.1,

NCHMe); δ_C(75 MHz; CDCl₃) 149.1 (C), 145.9 (C), 144.8 (C),

138.1 (C), 128.3 (CH), 128.2 (CH), 127.9 (CH), 122.8 (C), 112.5

(CH), 102.2 (CH), 74.5 (CH₂), 63.6 (CH), 57.1 (OMe), 34.9

(CH₂), 34.6 (NMe), 18.6 (Me); m/z (EI) 283 (M^ϩ, 95%), 268

(40), 240 (12), 192 (17), 176 (13), 164 (88), 148 (26), 134 (21), 91

(100), 77 (10).

2,3-Dimethyl-1,2,3,4-tetrahydroisoquinoline 14d. According

to the general procedure 1 the title compound was obtained as

a colourless oil (97%) from 2,3-dimethylisoquinolinium iodide

13d; δ_H(300 MHz; CDCl₃) 7.15–7.00 (4 H, m, ArH), 3.82 (1 H,

d, J 15.4, NCHH), 3.57 (1 H, d, J 15.4, NCHH), 2.85 (1 H, m,

CHCHH), 2.68 (1 H, m, CHCHH), 2.63 (1 H, m, NCH), 2.42

(3 H, s, N-Me), 1.18 (3 H, d, J 6.1, CH-Me) (cf. lit.¹¹⁴).

1-Isoquinolinyl(phenyl)methanol. According to the general

procedure 1 the title compound was obtained as a colourless

solid (72%) from 1-isoquinolinyl phenyl ketone; mp 108–110 ЊC

(lit.,¹¹⁵mp 108–109 ЊC); δ_H(400 MHz; CDCl₃) 8.55 (1 H, d,

J 5.7, 3-ArH), 7.97 (1 H, dd, J 8.0, 1.0, 8-ArH), 7.83 (1 H, d,

J 7.9, 5-ArH), 7.65 (1 H, d, J 5.7, 4-ArH), 7.63 (1 H, ddd, J 7.9,

6.0, 1.0, 6-ArH), 7.48 (1 H, ddd, J 8.0, 6.0, 1.1, 7-ArH), 7.36

(2 H, m, Ph), 7.27 (3 H, m, Ph), 6.39 (1 H, s, HOCH), 4.51 (1 H,

br s, NH).

1-Methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 23a.

According to the general procedure 1 the title compound was

obtained as

a colourless oil (100%) from 1-methyl-6,7-

dimethoxy-3,4-dihydroisoquinoline 22a; δ_H(300 MHz; CDCl₃)

6.62 (1 H, s, ArH), 6.57 (1 H, s, ArH), 4.04 (1 H, q, J 6.6,

CHMe), 3.86 (3 H, s, OMe), 3.85 (3 H, s, OMe), 3.25 (1 H, m,

NCHH), 3.00 (1 H, m, NCHH), 2.79 (1 H, m, ArCHH), 2.64

(1 H, m, ArCHH), 1.68 (1 H, br s, NH), 1.44 (3 H, d, J 6.6, Me)

(cf. lit.¹²⁰).

2-Methyl-1,2,3,4-tetrahydroquinoxaline 16a. According to the

general procedure 1 the title compound was obtained as a

brown solid (92%) from 2-methylquinoxaline 15a; mp 71–72 ЊC

(lit.,¹¹⁶mp 70 ЊC); δ_H(400 MHz; CDCl₃) 6.59 (2 H, m, ArH),

6.51 (2 H, m, ArH), 4.05 (2 H, br s, 2NH), 3.52 (1 H, m,

NCHMe), 3.32 (1 H, dd, J 8.0, 2.2, trans-CHHCHMe), 3.04

(1 H, dd, J 8.0, 6.1, cis-CHHCHMe), 1.19 (3 H, d, J 6.3, Me).

6,7-Dimethoxy-1-(pent-4-enyl)-1,2,3,4-tetrahydroisoquinoline

23b. According to the general procedure 1 the title compound

was obtained as a yellow oil (83%) from 6,7-dimethoxy-1-(pent-

4-enyl)-3,4-dihydroisoquinoline 22b (Found: M^ϩ, 261.1720.

C₁₆H₂₃NO₂requires 261.1729); ν_max(neat)/cm^Ϫ13319 (NH),

3078, 2996, 2919, 2832, 1634, 1516, 1465, 1260, 1220, 1112, 912,

856, 789; δ_H(300 MHz; CDCl₃) 6.60 (1 H, s, ArH), 6.56 (1 H, s,

2,3-Dimethyl-1,2,3,4-tetrahydroquinoxaline 16b. (a) Accord-

ing to the general procedure 1 the title compound was obtained

as a yellow solid (90%) from 2,3-dimethylquinoxaline 15b; 2 : 1

(cis/trans); mp 107–109 ЊC (lit.,¹¹⁷cis: 111–114 ЊC); ν_max(neat)/

cm^Ϫ13337, 3280 (NH), 2973, 2850, 1599, 1514, 739 (ArH);

δ_H(400 MHz; CDCl₃) 6.58 (2 H, m, ArH), 6.50 (2 H, m, ArH),

3.50 (2 H, br s, exchange in D₂O, 2NH), 3.48 (1.4 H, m, cis-

NHCHMe), 3.02 (0.6 H, m, trans-NHCHMe), 1.17 (1.8 H, m,

trans-Me), 1.12 (4.2 H, m, cis-Me) (cf. lit.¹¹⁸); δ_C(100 MHz;

CDCl₃) 133.5 (C), 132.7 (C), 118.6 (CH), 118.5 (CH), 114.4

(CH), 113.9 (CH), 52.0 (trans-CH), 49.0 (cis-CH), 19.0 (trans-

Me), 17.2 (cis-Me); m/z (EI) 162 (M^ϩ, 57%), 147 (100), 132 (35),

119 (23), 66 (23).

(b) The title compound (2 : 1, cis/trans) was formed in 81%

yield using aqueous trimethylamine hydrogen chloride solution

(4 M) in place of saturated aqueous ammonium chloride solu-

tion according to the general procedure 1 (spectroscopic data

identical).

(c) The title compound (2 : 1, cis/trans) was formed in 83%

yield according to the general procedure 2 (spectroscopic data

identical).

ArH), 5.83 (1 H, m, CH᎐CH ), 5.00 (2 H, m, CH᎐CH ), 3.87

᎐

2

(1 H, m, ArCHN), 3.85 (3 H, s, OMe), 3.84 (3 H, s, OMe),

3.20 (1 H, m, NCHH), 2.96 (1 H, m, NCHH), 2.69 (2 H,

m, ArCH ), 2.13 (2 H, m, CH CH᎐CH ), 1.62–1.48 (4 H, m,

᎐

2

CH₂CH₂CHN), NH not observed; δ_C(75 MHz; CDCl₃) 147.2

(C), 147.1 (C), 138.7 (᎐CH), 131.5 (C), 127.2 (C), 114.7 (᎐CH ),

᎐

2

111.7 (CH), 109.2 (CH), 56.0 (OMe), 55.8 (OMe), 55.3 (CH),

41.1 (CH₂), 35.9 (CH₂), 33.8 (CH₂), 29.5 (CH₂), 25.4 (CH₂); m/z

(EI) 261 (M^ϩ, 1%), 192 (100); (CI) 262 (MH^ϩ, 100%).

6,7-Dimethoxy-1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline

(carnegine) 25a. According to the general procedure 3 the title

compound was obtained as a yellow oil (83%) from 6,7-

dimethoxy-1,2-dimethyl-3,4-dihydroisoquinolinium iodide 24a;

δ_H(300 MHz; CDCl₃) 6.58 (1 H, s, ArH), 6.56 (1 H, s, ArH),

3.842 (3 H, s, OMe), 3.838 (3 H, s, OMe), 3.56 (1 H, q, J 6.3,

NCH), 3.04 (1 H, ddd, J 11.3, 6.0, 5.2, NCHH), 2.79 (2 H, m,

ArCH₂), 2.65 (1 H, ddd, J 11.3, 7.1, 5.0, NCHH), 2.48 (3 H, s,

NMe), 1.38 (3 H, d, J 6.3, CHMe) (cf. lit.¹²¹).

(d) The title compound (2 : 1, cis/trans) was formed in 8%

yield with tert-butyl alcohol in place of acetic acid according to

the general procedure 2 (spectroscopic data identical).

2-Cyclopropyl-1,2,3,4-tetrahydroquinoline 27. According to

general procedure 1 the title compound was obtained as a

colourless oil (35%) from 2-cyclopropylquinoline 26 (Found:

MH^ϩ, 174.1282. C₁₂H₁₆N requires 174.1283); ν_max(neat)/cm^Ϫ1

3400 (NH), 3075 (cyclopropyl C–H), 2990, 2920, 2840 (C–H),

1600 (Ar), 745 (ArH); δ_H(300 MHz; CDCl₃) 6.99 (2 H, m, 7&5-

ArH), 6.62 (1 H, ddd, J 7.5, 7.4, 1.1, 6-ArH), 6.52 (1 H, dd,

J 7.7, 1.1, 8-ArH), 3.91 (1 H, br s, NH), 2.79 (2 H, m, ArCH₂),

2.43 (1 H, ddd, J 9.6, 9.1, 2.7, NCH), 2.11 (1 H, m, ArCH₂-

1,2-Dimethylindoline 18b. According to the general pro-

cedure 1 the title compound was obtained as a colourless oil

(64%) from 1,2-dimethylindole 17b; δ_H(300 MHz; CDCl₃) 7.07

(2 H, m, ArH), 6.68 (1 H, ddd, J 8.0, 7.4, 1.1, ArH), 6.47 (1 H,

d, J 8.0, ArH), 3.41 (1 H, ddq, J 10.4, 8.2, 6.2, NCHMe), 3.10

966

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

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CHH), 1.83 (1 H, m, ArCH₂CHH), 0.93 (1 H, m, cyclopropyl

CH), 0.55 (2 H, m, cyclopropyl CH₂), 0.27 (2 H, m, cyclopropyl

CH₂); δ_C(75 MHz; CDCl₃) 144.6 (C), 129.3 (CH), 126.8 (CH),

121.3 (C), 116.9 (CH), 113.9 (CH), 57.5 (CH), 28.4 (CH₂), 26.7

(CH₂), 17.1 (CH), 3.0 (CH₂), 2.0 (CH₂); m/z (EI) 173 (M^ϩ,

42%), 132 (100), 117 (13), 77 (10); (CI) 174 (MH^ϩ, 100%).

2-n-Propyl-1,2,3,4-tetrahydroquinoline 12f was also pro-

duced in this reaction (24%), see above for spectroscopic data.

temperature for 3 h then extracted with dichloromethane

(3 × 10 ml). The combined organic layers were washed with

water (20 ml), dried (MgSO₄) and concentrated in vacuo to give

the title compound 28d as colourless crystals (E/Z, 8.3 : 1) (2.36

g, 98%); mp 94–96 ЊC (lit.,¹²³mp 95 ЊC); δ_H(300 MHz; CDCl₃)

9.70 (1 H, br s, NOH), 4.30 (2 H, q, J 7.2, E-CH₂Me), 3.75 (0.24

H, q, J 7.2, Z-CH₂Me), 2.12 (0.36 H, s, Z-Me), 2.10 (3 H, s,

E-Me), 1.34 (3 H, t, J 7.2, E-CH₂Me), 1.24 (0.36 H, t, J 7.2,

Z-CH₂Me).

Preparation of oximes

Reduction of oximes

Dimethyl hydroxyiminomalonate 28a. A solution of sodium

nitrite (1.40 g, 20.2 mmol) in water (3.2 ml) was added dropwise

to a cooled (0 ЊC) solution of dimethyl malonate (2.0 ml, 17.5

mmol) in acetic acid (2.5 ml) so that the temperature of the

reaction mixture did not rise above 20 ЊC. The reaction mixture

was stirred at 0 ЊC for 30 min and then 1 h at room temperature.

Water (9 ml) was added and the reaction mixture was stirred

at room temperature overnight. The resulting solution was

extracted with ether (3 × 15 ml). The combined organic phases

were washed sequentially with water (15 ml), saturated aqueous

sodium hydrogen carbonate (3 × 15 ml), water (15 ml) and

brine (15 ml), dried (MgSO₄), concentrated and the residue

puriﬁed by ﬂash chromatography (50% ethyl acetate–light

petroleum) to give the oxime as a colourless oil, which solidiﬁed

on standing overnight in the freezer (1.108 g, 39%); mp 65–

67 ЊC (lit.,¹²²66–67 ЊC); δ_H(300 MHz; CDCl₃) 10.56 (1 H, s,

OH), 3.94 (3 H, s, OMe), 3.91 (3 H, s, OMe).

Dimethyl acetamidomalonate 29a. According to general

procedure 4, dimethyl hydroxyiminomalonate 28a (0.213 g,

1.32 mmol) was reduced to give the acetamide 29a (0.163 g,

65%) as a colourless solid after puriﬁcation by ﬂash chrom-

atography (50% dichloromethane–ethyl acetate); mp 131–

132 ЊC (lit.,¹²⁴130–132 ЊC); δ_H(300 MHz; CDCl₃) 6.71 (1 H,

br d, J ca. 6, NHAc), 5.21 (1 H, d, J 7.2, CH), 3.81 (6 H, s,

2 × OMe), 2.07 (3 H, s, COCH₃).

Methyl 2-acetamido-3-oxo-4-methylpentanoate 29b. Accord-

ing to general procedure 4, oxime 28b as a mixture of isomers

(0.353 g, 2.04 mmol) was reduced to give the acetamide 29b

(0.388 g, 95%) as a waxy colourless solid, which did not require

chromatographic puriﬁcation; mp 38–39 ЊC (lit.,¹²⁵no mp);

ν_max(CHCl₃)/cm^Ϫ13425 (NH), 2979, 1757s (ester), 1722s

(ketone), 1678s (amide), 1498, 1436, 1333, 1213, 1165; δ_H(300

MHz; CDCl₃) 6.72 (1 H, br s, NHAc), 5.44 (1 H, d, J 6.9,

CHNH), 3.81 (3 H, s, OMe), 3.07 (1 H, septet, J 6.9, CHMe₂),

2.08 (3 H, s, COCH₃), 1.21 (3 H, d, J 7.2, CH₃), 1.11 (3 H, d,

J 6.9, CH₃); δ_C(75 MHz; CDCl₃) 205.2, 169.9, 167.0, 60.6, 53.2,

38.8, 22.7, 18.8, 17.6.

(E)- and (Z)-Methyl 2-hydroxyimino-3-oxo-4-methylpentan-

oate 28b. A solution of sodium nitrite (1.20 g, 17.4 mmol) in

water (2.7 ml) was added dropwise to a cooled (0 ЊC) solution

of methyl isobutyrylacetate (2.1657 g, 15.0 mmol) in acetic

acid (2.1 ml) so that the temperature of the reaction mixture

did not rise above 20 ЊC. The reaction mixture was stirred at

0 ЊC for 30 min and then 1 h at room temperature. Water (8 ml)

was added and the reaction mixture was stirred at room

temperature overnight. The resulting yellow solution was

extracted with ether (3 × 15 ml). The combined organic phases

were washed sequentially with water (15 ml), saturated aqueous

sodium hydrogen carbonate (3 × 15 ml), water (15 ml) and

brine (15 ml), dried (MgSO₄) and concentrated to give a colour-

less oil which was puriﬁed by ﬂash chromatography (5% ether–

dichloromethane) to give a mixture of isomeric oximes as a

colourless oil (1.47 g, 57%). For analytical purposes, pure

samples of each oxime isomer were obtained by further ﬂash

chromatography (2% ether–dichloromethane). The oximes were

found to interconvert signiﬁcantly within a few days on stand-

ing at room temperature either neat or in a solution of CDCl₃.

Less polar isomer. Colourless oil (Found: MH^ϩ(mixture

of isomers), 174.0766. C₇H₁₂NO₄requires 174.0766); R_f0.4

(5% ether–dichloromethane); ν_max(CHCl₃)/cm^Ϫ13546s, 3315br,

2979, 1747vs (ester), 1695 (ketone), 1628w (oxime), 1363, 1302,

1213, 1005, 972; δ_H(300 MHz; CDCl₃) 9.88 (1 H, br s, OH),

3.91 (3 H, s, OMe), 3.43 (1 H, septet, J 6.9, CHMe₂), 1.16 (6 H,

d, J 7.1, CHMe₂); δ_C(75 MHz; CDCl₃) 200.2 (ketone), 162.5

(ester), 149.5 (oxime), 52.9 (OMe), 35.5 (CH), 18.3 (CH₃); m/z

(CI; mixture of isomers) 174 (MH^ϩ, 80%), 158 (100).

1-Phenyl-2-acetamidobutane-1,3-dione 29c. According to

general procedure 4 the title compound was obtained as a

colourless oil (69%) from 1-phenylbutane-1,2,3-trione 2-oxime

28c (Found: MH^ϩ, 220.0973. C₁₂H₁₄NO₃requires 220.0974);

ν_max(neat)/cm^Ϫ13290 (NH), 3050, 2920 (C–H), 1725 (C᎐O),

᎐

1655 (C᎐O), 1510 (NH), 1370 (COMe), 755, 700 (ArH); δ (300

᎐

H

MHz; CDCl₃) 8.11 (2 H, m, 2&6-PhH), 7.66 (1 H, m, 4-PhH),

7.54 (2 H, m, 3&5-PhH), 7.07 (1 H, br d, J 6.6, NH), 6.18 (1 H,

d, J 6.6, NCH), 2.20 (3 H, s, COMe), 2.13 (3 H, s, NAc); δ_C(75

MHz; CDCl ) 200.1 (C᎐O), 192.7 (C᎐O), 170.0 (NC᎐O), 134.6

᎐

3

(CH), 134.4 (C), 129.5 (CH), 129.0 (CH), 66.0 (CH), 27.3 (Me),

22.9 (Me); m/z (CI) 220 (MH^ϩ, 14%), 178 (40), 105 (100).

The mass balance was found to be acetamidoacetophenone

29f—spectroscopic data identical to below.

N-Acetyl-D,L-alanine ethyl ester 29d. According to general

procedure 4 the title compound was obtained as a colourless

solid (98%) from ethyl pyruvate 2-oxime 28d; mp 35–37 ЊC

(from ether) (lit.,¹²⁶34–35 ЊC); δ_H(300 MHz; CDCl₃) 6.38 (1 H,

br, NH), 4.51 (1 H, quintet, J 7.2, NCH), 4.14 (2 H, q, J 7.2,

OCH₂Me), 1.97 (3 H, s, COMe), 1.34 (3 H, d, J 7.2, MeCH),

1.24 (3 H, t, J 7.2, OCH₂Me).

2-Acetamidopropiophenone 29e. According to general pro-

cedure 4 the title compound was obtained as a colourless solid

(96%) from 1-phenylpropane-1,2-dione 2-oxime 28e; mp 89–

90 ЊC (lit.,¹²⁷mp 87–89 ЊC); δ_H(300 MHz; CDCl₃) 7.98 (2 H, m,

2&6-PhH), 7.62 (1 H, m, 4-PhH), 7.50 (2 H, m, 3&5-PhH), 6.67

(1 H, br, NH), 5.57 (1 H, quintet, J 7.1, CHN), 2.06 (3 H, s, Ac),

1.43 (3 H, d, J 7.1, Me).

More polar isomer. Colourless oil; R_f0.2 (5% ether–

dichloromethane); ν_max(CHCl₃)/cm^Ϫ13548, 3317br, 2978,

1736vs (ester), 1712s (ketone), 1628w (oxime), 1441, 1365, 1304,

1281, 1213, 1016s; δ_H(300 MHz; CDCl₃) 10.33 (1 H, br s, OH),

3.87 (3 H, s, OMe), 2.94 (1 H, septet, J 7.0, CHMe₂), 1.19 (6 H,

d, J 7.1, CHMe₂); δ_C(75 MHz; CDCl₃) 198.2 (ketone), 161.3

(ester), 149.95 (oxime), 53.2 (OMe), 40.7 (CH), 16.7 (CH₃).

2-N-(tert-Butoxycarbonyl)aminopropiophenone. According to

general procedure 4, but replacing acetic anhydride with di-tert-

butyl dicarbonate (1.12 g, 5.1 mmol), the title compound

was obtained as a colourless solid (92%) from 1-phenyl-

propane-1,2-dione 2-oxime 28e after puriﬁcation by ﬂash

Ethyl pyruvate 2-oxime 28d. Hydroxylamine hydrochloride

(1.59 g, 22.9 mmol) and sodium acetate (1.50 g, 18.3 mmol) in

water (10 ml) were added to ethyl pyruvate (2.00 ml, 2.120 g,

18.3 mmol) in ethanol (10 ml). The mixture was stirred at room

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

967

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chromatography (10% ethyl acetate–light petroleum); mp 81–

83 ЊC (lit.,¹²⁸mp 81 ЊC); δ_H(400 MHz; CDCl₃) 7.97 (2 H,

d, J 7.4, 2&6-PhH), 7.59 (1 H, dt, J 7.4, 1.1, 4-PhH), 7.48 (2 H,

t, J 7.4, 3&5-PhH), 5.57 (1 H, br d, J 6.8, NH), 5.29 (1 H,

quintet, J 7.3, CHN), 1.45 (9 H, s, CMe₃), 1.39 (3 H, d, J 7.1,

CHMe).

3-Amino-4-methoxyphenyl methanesulfonate 31e. According

to the general procedure 5 the title compound was obtained

as a colourless crystalline solid (98%) from 4-methoxy-3-

nitrophenyl methanesulfonate 30e; mp 85–86 ЊC (from toluene)

(lit.,¹³⁶mp 84 ЊC (from benzene)); δ_H(300 MHz; CDCl₃) 6.73

(1 H, d, J 8.8, ArH), 6.64 (1 H, d, J 2.8, ArH), 6.60 (1 H, dd,

J 8.8, 2.8, ArH), 3.85 (3 H, s, OMe), 3.09 (3 H, s, OSO₂Me).

Acetamidoacetophenone 29f. According to general pro-

cedure 4 the title compound was obtained as a colourless solid

(100%) from phenylglyoxaldehyde oxime 28f; mp 83–84 ЊC

(lit.,¹²⁹mp 83–84 ЊC); δ_H(300 MHz; CDCl₃) 7.98 (2 H, m, 2&6-

PhH), 7.62 (1 H, m, 4-PhH), 7.49 (2 H, m, 3&5-PhH), 6.69

(1 H, br d, J 4.3, NH), 4.78 (2 H, d, J 4.3, COCH₂N), 2.09 (3 H,

s, Ac).

4-Methylthioaniline 31f. According to the general procedure

5 the title compound was obtained as a brown oil (92%) from

4-methylthionitrobenzene 30f (Found: M^ϩ, 139.0453. C₇H₉NS

requires 139.0454); ν_max(neat)/cm^Ϫ13447, 3350, 3217, 3022,

2981, 2910, 1620, 1588, 1490, 1275, 1170, 825; δ_H(300 MHz;

CDCl₃) 7.17 (2 H, d, J 8.7, ArH), 6.64 (2 H, d, J 8.7, ArH), 3.60

(2 H, br s, NH₂), 2.42 (3 H, s, SMe); δ_C(75 MHz; CDCl₃) 145.1

(C), 131.1 (CH), 130.7 (C), 115.8 (CH), 18.8 (Me); m/z (EI) 139

(M^ϩ, 87%), 124 (100), 97 (7), 80 (29), 65 (8).

3-(Acetamido)indol-2(3H)-one 29g. According to general

procedure 4 the title compound was obtained as a colour-

less solid (69%) from isatin 3-oxime 28g; mp 246–248 ЊC

(from methanol–ethyl acetate) (lit.,¹³⁰248–249.5 ЊC (from

isopropanol–benzene)); δ_H(300 MHz; d₆-DMSO) 10.42 (1 H, s,

ArNH), 8.66 (1 H, d, J 7.9, NHAc), 7.20 (1 H, dd, J 7.7, 7.5,

5-ArH), 7.12 (1 H, d, J 6.7, 7-ArH), 6.94 (1 H, dd, J 7.5, 6.7,

6-ArH), 6.81 (1 H, d, J 7.7, 4-ArH), 5.08 (1 H, d, J 7.9,

NCHCO), 1.90 (3 H, s, COMe).

3-Aminobenzonitrile 31g. According to the general procedure

5 the title compound was obtained as a colourless crystalline

solid (95%) from 3-nitrobenzonitrile 30g; mp 52–54 ЊC (from

1 : 1 ethanol–water) (lit.,¹³⁷mp 53–54 ЊC); δ_H(300 MHz;

CDCl₃) 7.22 (1 H, ddd, J 8.1, 7.6, 0.5, ArH), 7.01 (1 H, ddd,

J 7.6, 1.4, 1.1, ArH), 6.90 (1 H, ddd, J 2.2, 1.4, 0.5, ArH), 6.86

(1 H, ddd, J 8.1, 2.2, 1.1, ArH), 3.95 (2 H, br s, NH₂).

(1S)-(؊)-3-endo-Acetamidocamphor 29h. According to gen-

eral procedure 4 the title compound was obtained as a colourless

solid (87%) from anti-(1S)-(Ϫ)-camphorquinone 3-oxime 28h;

mp 113–115 ЊC (from ether) (Found: C, 66.0; H, 9.5; N, 6.3.

C₁₂H₁₉NO₂ؒ0.5H₂O requires C, 66.0; H, 9.2; N, 6.4%) (Found:

MH^ϩ, 210.1491. C₁₂H₂₀NO₂requires 210.1494); [α]_D²⁰Ϫ12.0

(c 0.75 in ethanol); ν_max(KBr)/cm^Ϫ13300 (amide), 3075, 2960

3-Aminobenzoic acid 31h. According to the general procedure

5 the title compound was obtained as a colourless crystalline

solid (90%) from 3-nitrobenzoic acid 30h; mp 173–174 ЊC

(lit.,¹³⁸mp 174 ЊC); δ_H(300 MHz; d₄-MeOH) 7.38 (1 H, dd,

J 1.3, 1.0, ArH), 7.32 (1 H, ddd, J 7.3, 1.3, 1.2, ArH), 7.16 (1 H,

dd, J 7.3, 7.2, ArH), 6.90 (1 H, ddd, J 7.2, 1.2, 1.0, ArH).

(C–H), 1750 (C᎐O), 1650 (amide), 1550, 1380, 1270, 705, 540;

᎐

Ethyl 4-Aminobenzoate 31i. According to the general

procedure 5 the title compound was obtained as an orange

crystalline solid (92%) from ethyl 4-nitrobenzoate 30i; mp 87–

89 ЊC (lit.,¹³⁹mp 88–90 ЊC); δ_H(300 MHz; CDCl₃) 7.86 (2 H, d,

J 8.8, ArH), 6.64 (2 H, d, J 8.8, ArH), 4.31 (2 H, q, J 7.1,

OCH₂Me), 4.03 (2 H, br s, NH₂), 1.36 (2 H, t, J 7.1, OCH₂Me).

δ_H(400 MHz; CDCl₃) 6.10 (1 H, br, NH), 4.46 (1 H, m, NCH),

2.49 (1 H, m, NCHCH), 2.01 (3 H, s, NHCOMe), 1.77–1.21

(4 H, m, CH₂CH₂), 1.00 (3 H, s, anti-Me), 0.96 (3 H, s, syn-Me),

0.93 (3 H, s, COCMe) (cf. lit.¹³¹); δ_C(100 MHz; CDCl₃) 218.5

(C᎐O), 170.7 (NC᎐O), 58.9 (C), 58.6 (CH), 48.0 (CH), 44.3 (C),

᎐

32.4 (CH₂), 23.0 (Me), 19.7 (Me), 19.4 (CH₂), 19.0 (Me), 9.3

(Me); m/z (CI) 210 (MH^ϩ, 100%), 122 (45).

4-Aminoacetophenone 31j. According to the general

procedure 5 the title compound was obtained as a colourless

crystalline solid (83%) from 4-nitroacetophenone 30j; mp 104–

105 ЊC (lit.,¹⁴⁰mp 104–106 ЊC); δ_H(300 MHz; CDCl₃) 7.80 (2 H,

m, ArH), 6.64 (2 H, m, ArH), 4.24 (2 H, br s, NH₂), 2.50 (3 H, s,

COMe).

Nitro group reductions

4-Chloroaniline 31a. According to the general procedure 5 the

title compound was obtained as a colourless crystalline solid

(95%) from 4-chloronitrobenzene 30a; mp 69–70 ЊC (lit.,¹³²mp

70–71 ЊC); δ_H(300 MHz; CDCl₃) 7.10 (2 H, dd, J 6.7, 2.2, ArH),

6.61 (2 H, dd, J 6.7, 2.1, ArH), 3.62 (2 H, br s, NH₂).

4-Aminoacetanilide 31k. According to the general procedure

5 the title compound was obtained as a colourless crystalline

solid (95%) from 4-nitroacetanilide 30k; mp 161–163 ЊC (from

water) (lit.,¹⁴¹mp 162 ЊC from water); δ_H(400 MHz; d₄-MeOH)

7.21 (2 H, 2 dd, J 8.7, 2.0, 8.7, 2.2, ArH), 6.68 (2 H, 2 dd,

J 8.7, 2.0, 8.7, 2.2, ArH), 4.53 (2 H, br s, NH₂), 2.06 (3 H, s,

NHCOMe).

The title compound was also formed in 100% yield from

4-nitroacetanilide 30k with indium and acetic acid (6 equiv-

alents) in THF (spectroscopic data identical).

3-Chloro-2-methylaniline 31b. According to the general

procedure 5 the title compound was obtained as a yellow oil

(75%) from 6-chloro-2-nitrotoluene 30b; δ_H(300 MHz; CDCl₃)

6.93 (1 H, dd, J 7.9, 7.8, ArH), 6.81 (1 H, d, J 7.8, ArH), 6.58

(1H, d, J 7.9, ArH), 3.75 (2 H, br s, NH₂), 2.23 (3 H, s, Me)

(cf. lit.¹³³).

5-Bromo-2-methylaniline 31c. According to the general pro-

cedure 5 the title compound was obtained as a pale crystalline

solid (70%) from 2-nitro-4-bromotoluene 30c; mp 32–33 ЊC

(lit.,¹³⁴mp 33 ЊC); δ_H(300 MHz; CDCl₃) 6.93 (1 H, d, J 7.2,

ArH), 6.84 (2 H, m, ArH), 3.66 (2 H, br s, NH₂), 2.13 (3 H, s,

ArMe).

4-(Methoxymethyl)aniline 31l. According to the general pro-

cedure 5 the title compound was obtained as a yellow oil (84%)

from 4-(methoxymethyl)nitrobenzene 30l (for preparation see

below); bp 115–120 ЊC, 3 mmHg (lit.,¹⁴²bp 131–132 ЊC, 11

mmHg); δ_H(300 MHz; CDCl₃) 7.13 (2 H, d, J 8.4, ArH), 6.66

(2 H, d, J 8.4, ArH), 4.34 (2 H, s, ArCH₂O), 3.50 (2 H, br s,

NH₂), 3.34 (3 H, s, OMe).

2-Iodoaniline 31d. According to the general procedure 5 the

title compound was obtained as a colourless crystalline solid

(60%) from 2-iodonitrobenzene 30d; mp 56 ЊC (sharp) (lit.,¹³⁵

mp 56.5 ЊC); δ_H(300 MHz; CDCl₃) 7.64 (1 H, dd, J 7.9, 1.4,

ArH), 7.13 (1 H, ddd, J 7.9, 7.3, 1.4, ArH), 6.75 (1 H, dd, J 7.9,

1.5, ArH), 6.47 (1 H, ddd, J 7.9, 7.3, 1.5, ArH), 3.90 (2 H, br s,

NH₂).

2,6-Diaminotoluene 31m. 2,6-Dinitrotoluene 30m (0.208 g,

1.14 mmol) was dissolved in THF (10 ml) with indium powder

(Ϫ100 mesh, 1.0 g) and acetic acid (0.377 g, 0.36ml, 6.28 mmol)

under nitrogen. The mixture was heated under reﬂux for 3 d.

968

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The cooled reaction mixture was ﬁltered through Celite^with

water (50 ml). The ﬁltrate was extracted with ethyl acetate

(3 × 15 ml). Combined organic layers were dried (MgSO₄) and

concentrated in vacuo to yield the title compound 31m as a

colourless solid (0.125 g, 90%); mp 103–104 ЊC (lit.,¹⁴³106 ЊC);

δ_H(300 MHz; CHCl₃) 6.84 (1 H, t, J 8.3, 4-ArH), 6.22 (2 H, d,

J 8.3, 3&5-ArH), 5.06 (4 H, br s, NH₂), 1.98 (3 H, s, ArMe).

Preparation of 4-nitrobenzyl derivatives

4-(Methoxymethyl)nitrobenzene 30l. Dimethyl sulfate (0.75

ml, ~1.00 g, 7.9 mmol) was added dropwise after 30 min to a

stirred solution of 4-nitrobenzyl alcohol (0.53 g, 3.4 mmol) and

potassium carbonate (0.73 g, 5.3 mmol) in acetone (20 ml) at

0 ЊC under an atmosphere of nitrogen until the orange colour

no longer persisted. The mixture was allowed to stir to room

temperature over 18 h, then diluted with aqueous sodium

hydroxide solution (4 M; 20 ml) and extracted with dichloro-

methane (2 × 20 ml). Combined organic layers were dried

(MgSO₄) and concentrated in vacuo, then puriﬁed by ﬂash

chromatography (silica, 20% ethyl acetate in light petroleum) to

give the title compound 30l as a yellow solid (0.42 g, 74%); mp

25–26 ЊC (lit.,¹⁴⁹23–24 ЊC); ν_max(neat)/cm^Ϫ12929, 2824 (OMe),

1603, 1523, 1347 (NO₂), 1103, 847 (ArH); δ_H(300 MHz;

CDCl₃) 8.21 (2 H, dd, J 8.6, 1.9, ArH), 7.50 (2 H, d, J 8.6,

ArH), 4.56 (2 H, s, ArCH₂O), 3.45 (3 H, s, OMe); δ_C(75 MHz;

CDCl₃) 145.9 (C), 131.5 (C), 127.7 (CH), 123.6 (CH), 73.4

(CH₂), 58.7 (Me).

6-Aminoquinoline 33. According to the general procedure 5

the title compound was obtained as a colourless solid (82%)

from 6-nitroquinoline 32; mp 117–120 ЊC (lit.,¹⁴⁴mp 116–

118 ЊC); δ_H(300 MHz; CDCl₃) 8.65 (1 H, dd, J 4.3, 1.7, 2-ArH),

7.91 (1 H, d, J 9.0, 8-ArH), 7.89 (1 H, d, J 8.3, 4-ArH), 7.26

(1 H, dd, J 8.3, 4.3, 3-ArH), 7.15 (1 H, dd, J 9.0, 2.6, 7-ArH),

6.90 (1 H, d, J 2.6, 5-ArH), 3.95 (2 H, br s, NH₂).

5-Aminoisoquinoline 35. According to the general procedure

5 the title compound was obtained as a pale orange solid (99%)

from 5-nitroisoquinoline 33; mp 125–127 ЊC (lit.,¹⁴⁵mp 128 ЊC);

δ_H(300 MHz; CDCl₃) 9.18 (1 H, d, J 1.0, 1-ArH), 8.48 (1 H, dd,

J 6.0, 1.0, 3-ArH), 7.57 (1 H, d, J 6.0, 4-ArH), 7.41 (2 H, 2d,

J 4.2 and 4.1, 6&8-ArH), 6.95 (1 H, dd, J 4.2, 4.1, 7-ArH), 4.25

(2 H, br s, NH₂).

4-Nitrobenzyl acetate 41b. Acetyl chloride (0.52 ml, ~0.58 g,

7.4 mmol) was added to a stirred solution of 4-nitrobenzyl

alcohol 41a (0.750 g, 4.90 mmol) and triethylamine (1.02 ml,

~0.74 g, 7.4 mmol) in dichloromethane (30 ml) at room tem-

perature. The mixture was stirred for 3 h, then washed with

water (20 ml), dried (MgSO₄) and concentrated in vacuo to give

the title compound 41b as a yellow solid (0.96 g, 100%); mp 76–

77 ЊC (from ether) (lit.,¹⁵⁰mp 76–77 ЊC); δ_H(300 MHz; CDCl₃)

8.22 (2 H, m, 3&5-ArH), 7.52 (2 H, m, 2&4-ArH), 5.20 (2 H, s,

CH₂O), 2.15 (3 H, s, MeCO).

Ethyl 4-amino-5-methoxy-1,2-dimethylindole-3-carboxylate

37a. According to the general procedure 5 the title compound

was obtained as a yellow crystalline solid (33%) from ethyl

5-methoxy-1,2-dimethyl-4-nitroindole-3-carboxylate 36a;¹⁴⁶δ_H

(300 MHz; CDCl₃) 6.88 (1 H, d, J 8.6, indole ring), 6.52 (1 H, d,

J 8.6, indole ring), 5.78 (2 H, br s, NH₂), 4.36 (2 H, q, J 7.1,

OCH₂Me), 3.87 (3 H, s, OMe), 3.58 (3 H, s, NMe), 2.64 (3 H,

s, indole-Me), 1.41 (3 H, t, J 7.1, OCH₂Me) (as authentic

sample¹⁴⁶).

4-(N,N-Dimethylamino)benzyl alcohol 42c. Sodium borohy-

dride (0.74 g, 19.5 mmol) was added in portions to a stirred

solution of 4-(N,N-dimethylamino)benzaldehyde (2.43 g, 16.3

mmol) in methanol (30 ml) at 0 ЊC. After 10 min, water (20 ml)

was added and the resulting solution extracted with ethyl

acetate (3 × 15 ml). Combined organic layers were dried

(MgSO₄) and concentrated in vacuo to give the title compound

42c as a colourless oil (2.05 g, 83%); δ_H(300 MHz; CDCl₃) 7.26

(2 H, d, J 8.8, 3&5-ArH), 6.74 (2 H, d, J 8.8, 2&4-ArH), 4.58

(2 H, s, CH₂O), 2.96 (6 H, s, NMe₂), 1.65 (1 H, br s, OH)

(cf. lit.¹⁵¹).

Ethyl 4-amino-2-(biphenyl-4-yl)-5-methoxy-1-methylindole-3-

carboxylate 37b. According to the general procedure 5 the

title compound was obtained as a yellow crystalline solid

(45%) from ethyl 2-(biphenyl-4-yl)-5-methoxy-1-methyl-4-

nitroindole-3-carboxylate 36b;¹⁴⁷δ_H(300 MHz; CDCl₃) 7.68

(4 H, m, biPh), 7.54 (2 H, m, biPh), 7.50 (3 H, m, biPh), 7.02

(1 H, d, J 8.5, indole ring), 6.44 (1 H, d, J 8.5, indole ring), 5.89

(2 H, br s, NH₂), 3.99 (2 H, q, J 7.2, OCH₂Me), 3.91 (3 H, s,

NMe), 3.48 (3 H, s, OMe), 0.81 (3 H, t, J 7.2, OCH₂Me) (as

authentic sample¹⁴⁷).

O-(4-Nitrobenzyl)-2-phenylethanol 43a. Silver() oxide (1.04

g, 4.5 mmol) was added to a solution of 2-phenylethanol (0.54

g, 4.5 mmol) and 4-nitrobenzyl bromide (0.96 g, 4.4 mmol) in

dichloromethane (10 ml). The mixture was heated at reﬂux

under nitrogen for 5 d then cooled and ﬁltered through Celite^,

washed successively with hydrochloric acid (2 M; 15 ml),

sodium hydroxide solution (4 M; 15 ml) and water (10 ml),

dried (MgSO₄) and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (silica, light

petroleum–dichloromethane, 2 : 3) to give the title compound

43a as a colourless oil (0.74 g, 65%) (Found: M^ϩ, 257.1052.

C₁₅H₁₅NO₃requires 257.1052); ν_max(neat)/cm^Ϫ13034, 2917,

2853, 1598, 1516 (NO₂), 1340 (NO₂), 1103, 857, 844, 736, 698;

δ_H(300 MHz; CDCl₃) 8.20 (2 H, d, J 8.2, 3&5-ArHNO₂), 7.44

(2 H, d, J 8.2, 2&6-ArHNO₂), 7.36–7.25 (5 H, m, Ph), 4.64 (2 H,

s, OCH₂Ar), 3.77 (2 H, t, J 7.1, CH₂CH₂O), 2.99 (2 H, t, J 7.1,

CH₂CH₂O); δ_C(75 MHz; CDCl₃) 147.6 (C), 146.2 (C), 138.7

(C), 129.0 (CH), 128.4 (CH), 127.6 (CH), 126.4 (CH), 123.6

(CH), 71.9 (OCH₂), 71.7 (OCH₂), 36.4 (CH₂); m/z (EI) 257 (M^ϩ,

22%), 136 (31), 106 (33), 91 (100), 78 (28), 65 (11).

Cyclohexylamine 39a. According to the general procedure 5

the title compound 39a was obtained as a clear oil (100%)

from nitrocyclohexane 38a; δ_H(300 MHz; CDCl₃) 2.61 (1 H, m,

CHNH₂), 1.83–1.61 (6 H, m, CH₂and NH₂), 1.28–1.00 (6 H, m,

CH₂) (as authentic sample).

n-Hexylamine 39b. According to the general procedure 5 the

title compound 39b was obtained as a clear oil (82%) from

1-nitrohexane 38b; δ_H(300 MHz; CDCl₃) 2.61 (2 H, m, CH₂-

NH₂), 1.45 (2 H, m, CH₂CH₂NH₂), 1.40 (6 H, m, CH₂CH₂CH₂),

1.07 (2 H, br s, NH₂), 0.90 (3 H, t, J 7.2, Me) (as authentic

sample).

1-Amino-3-methylbutan-2-ol 39c. According to general pro-

cedure 5 the title compound was obtained as a clear oil (59%)

from 3-methyl-1-nitrobutan-2-ol 38c; bp 125–130 ЊC, 60

mmHg; δ_H(300 MHz; CDCl₃) 5.01 (3 H, br, NH₂& OH), 3.48

(1 H, ddd, J 7.8, 6.3, 4.7, CHOH), 2.87 (1 H, dd, J 11.6, 4.7,

syn-CH(OH)CHHNH₂), 2.64 (1 H, dd, J 11.6, 7.8, anti-

CH(OH)CHHNH₂), 1.68 (1 H, septet-d, J 6.9, 6.3, CHMe₂),

0.91 (3 H, d, J 6.9, Me), 0.97 (3 H, d, J 6.9, Me) (cf. lit.¹⁴⁸).

The title compound was also obtained (84%) from 3-methyl-

1-nitrobutan-2-ol 38c by heating at reﬂux with indium

(6 equivalents) and acetic acid (6 equivalents) in THF for

50 h.

O-(4-Nitrobenzyl)-2-phenoxyethanol 43b. Silver() oxide

(0.600 g, 2.59 mmol) was added to a solution of 2-phenoxy-

ethanol (0.350 g, 2.54 mmol) and 4-nitrobenzyl bromide (0.549

g, 2.54 mmol) in dichloromethane (10 ml). The mixture was

heated at reﬂux under nitrogen for 6 d then cooled and ﬁltered

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

969

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through Celite^, washed successively with hydrochloric acid

(1 M; 20 ml), sodium hydroxide solution (1 M; 20 ml) and water

(10 ml), dried (MgSO₄) and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (silica, light

petroleum–dichloromethane, 1 : 1) to give the title compound

43b as a colourless oil (0.483 g, 70%) (Found: M^ϩ, 273.0995.

C₁₅H₁₅NO₄requires 273.1001); ν_max(neat)/cm^Ϫ13070, 2918,

2860, 1595, 1520 (NO₂), 1490, 1345 (NO₂), 1241, 1106, 858,

754, 688; δ_H(300 MHz; CDCl₃) 8.22 (2 H, d, J 8.5, 3&5-

ArHNO₂), 7.54 (2 H, d, J 8.5, 2&6-ArHNO₂), 7.31 (2 H, m,

3&5-PhH), 6.96 (3 H, m, 2, 4&6-PhH), 4.76 (2 H, s, OCH₂Ar),

4.21 (2 H, m, PhOCH₂), 3.91 (2 H, m, PhOCH₂CH₂); δ_C(75

MHz; CDCl₃) 158.6 (C), 147.7 (C), 145.8 (C), 129.5 (CH), 127.7

(CH), 123.7 (CH), 121.1 (CH), 114.6 (CH), 72.1 (CH₂), 69.4

(CH₂), 67.3 (CH₂); m/z (EI) 273 (M^ϩ, 69%), 229 (6), 151 (12),

136 (100), 120 (18), 106 (55), 94 (57), 90 (53), 77 (82), 65 (38),

51 (34).

(CH), 71.9 (CH₂), 68.8 (CH₂), 63.9 (CH₂); m/z (CI) 302 (MH^ϩ,

15%), 167 (23), 108 (21), 106 (100), 58 (94).

O-(tert-Butyldimethylsilyl)-2-(4-nitrobenzyloxy)ethanol 43e.

tert-Butyldimethylsilyl triﬂuoromethanesulfonate (1.73 ml,

~1.99 g, 7.5 mmol) was added dropwise to a stirred solution of

2-(4-nitrobenzyloxy)ethanol (0.74 g, 3.8 mmol) in pyridine (20

ml) under nitrogen at ~Ϫ35 ЊC. The mixture was stirred for 4 h

then the pyridine was removed in vacuo and the residue tritur-

ated with ether (4 × 15 ml). The combined ethereal layers were

washed with water (20 ml) and dried (MgSO₄) then concen-

trated in vacuo. The residue was puriﬁed by ﬂash column

chromatography (silica, light petroleum–dichloromethane, 1 : 1

(the column was prepared with the solvent system containing

0.001% triethylamine)) to give the title compound 43e as a col-

ourless oil (1.07 g, 92%) (Found: MH^ϩ, 312.1628. C₁₅H₂₆NO₄Si

requires 312.1631); ν_max(neat)/cm^Ϫ12954, 2926, 2847 (C–H),

1516, 1340 (NO₂), 1104, 952, 836 and 776 (ArH); δ_H(300 MHz;

CDCl₃) 8.20 (2 H, m, 3&5-ArHNO₂), 7.52 (2 H, m, 2&6-

ArHNO₂), 4.68 (2 H, s, ArCH₂), 3.82 (2 H, m, CH₂CH₂OSi),

3.61 (2 H, m, CH₂CH₂OSi), 0.91 (9 H, s, Si^tBu), 0.08 (6 H, s,

SiMe₂); δ_C(75 MHz; CDCl₃) 147.5 (C), 146.4 (C), 127.6 (CH),

123.6 (CH), 72.4 (CH₂), 72.0 (CH₂), 62.8 (CH₂), 25.9 (Me₃),

18.4 (CMe₃), Ϫ5.3 (SiMe); m/z (CI) 312 (MH^ϩ, 53%), 254 (13),

177 (40), 106 (100).

O-(4-Nitrobenzyl)-2-benzyloxyethanol 43c. Silver() oxide

(0.870 g, 3.75 mmol) was added to a solution of 2-benzyloxy-

ethanol (0.566 g, 3.72 mmol) and 4-nitrobenzyl bromide (0.808

g, 3.74 mmol) in dichloromethane (10 ml). The mixture was

heated at reﬂux under nitrogen for 5 d. The cooled reaction

mixture was ﬁltered through Celite^and washed with hydro-

chloric acid (1 M; 20 ml), sodium hydroxide solution (2 M;

20 ml) and water (10 ml) then dried (MgSO₄), concentrated

in vacuo and puriﬁed by ﬂash chromatography (silica, dichloro-

methane–light petroleum, 2 : 1) to give the title compound 43c

as a colourless oil (0.893 g, 84%) (Found: M^ϩ, 287.1155.

C₁₆H₁₇NO₄requires 287.1157); ν_max(neat)/cm^Ϫ13031, 2857,

1613, 1520 (NO₂), 1448, 1337 (NO₂), 1100, 838, 736, 698;

δ_H(300 MHz; CDCl₃) 8.21 (2 H, d, J 8.8, 3&5-ArHNO₂), 7.53

(2 H, d, J 8.8, 2&6-ArHNO₂), 7.37–7.30 (5 H, m, PhH), 4.69

(2 H, s, OCH₂Ar), 4.60 (2 H, s, OCH₂Ph), 3.76–3.67 (4 H, m,

OCH₂CH₂O); δ_C(100 MHz; CDCl₃) 147.4 (C), 146.1 (C), 138.1

(C), 128.4 (CH), 127.71 (2 × CH), 127.67 (CH), 123.6 (CH),

73.4 (CH₂), 72.0 (CH₂), 70.3 (CH₂), 69.5 (CH₂); m/z (EI) 287

(M^ϩ, 1%), 196 (20), 151 (35), 136 (10), 107 (40), 91 (100), 78

(13), 65 (14), 51 (8).

L-O-(4-Nitrobenzyl)menthol 43f. Silver() oxide (0.624 g, 2.69

mmol) was added to a solution of -menthol (0.420 g, 2.69

mmol) and 4-nitrobenzyl bromide (0.580 g, 2.69 mmol) in

dichloromethane (15 ml). The mixture was heated at reﬂux

under nitrogen for 7 d then cooled and ﬁltered through Celite^,

washed successively with 1 M hydrochloric acid (20 ml), 1 M

sodium hydroxide solution (20 ml) and water (10 ml), dried

(MgSO₄) and concentrated in vacuo. The residue was puriﬁed

by ﬂash column chromatography (silica, light petroleum–

dichloromethane, 2 : 1) to give the title compound 43f as a

colourless solid (0.453 g, 58%); mp 60–61 ЊC (from light petrol-

eum); [α]_D²⁵Ϫ80.0 (c 1.0 in ethanol) (Found: C, 70.0; H, 8.9; N,

4.6. C₁₇H₂₅NO₃requires C, 70.1; H, 8.6; N, 4.8%) (Found: M^ϩ,

291.1830. C₁₇H₂₅NO₃requires 291.1834); ν_max(KBr)/cm^Ϫ12955,

2920, 2858, 1598, 1521 (NO₂), 1455, 1332 (NO₂), 1112, 835,

737, 570; δ_H(400 MHz; CDCl₃) 8.22 (2 H, d, J 8.5, 3&5-

ArHNO₂), 7.53 (2 H, d, J 8.5, 2&6-ArHNO₂), 4.76 (1 H, d,

J 13.0, OCH₂), 4.49 (1 H, d, J 13.0, OCH₂), 3.23 (1 H, td, J 10.4,

4.1, OCH), 2.30 (1 H, m, CHMe), 2.17 (1 H, m, CH₂CHOR),

1.67 (1 H, m, CHHCH₂CHMe), 1.65 (1 H, m, CH₂-

CHHCHMe), 1.38 (1 H, m, CHMe₂), 1.30 (1 H, m, CHⁱPr),

1.03 (1 H, m, CH₂CHHCHMe), 0.95 (3 H, d, J 6.7, CHMe₂),

0.92 (3 H, d, J 6.7, CHMe₂), 0.90 (1 H, m, CH₂CHOR), 0.89

(1 H, m, CHHCH₂CHMe), 0.76 (3 H, d, J 7.0, CHMe); δ_C(100

MHz; CDCl₃) 147.2 (C), 147.0 (C), 127.8 (CH), 123.5 (CH),

79.7 (OCH), 69.1 (OCH₂), 48.3 (CH), 40.3 (CH₂), 34.5 (CH₂),

31.6 (CH), 25.7 (CH), 23.3 (CH₂), 22.3 (Me), 20.9 (Me), 16.2

(Me); m/z (EI) 291 (M^ϩ, 5%), 261 (2), 206 (67), 138 (100), 136

(92), 123 (19), 106 (38), 95 (48), 81 (90), 69 (78).

2-(4-Nitrobenzyloxy)ethyl benzoate 43d. (a) Potassium

hydroxide (0.290 g, 5.18 mmol) was added to a solution of

4-nitrobenzyl bromide (1.024 g, 4.74 mmol) in ethylene glycol

(10 ml), and the resulting mixture heated at 80 ЊC for 20 h. The

cooled reaction mixture was diluted with water (50 ml) and

extracted with dichloromethane (2 × 30 ml). Combined organic

layers were dried (MgSO₄) and concentrated in vacuo to give

2-(4-nitrobenzyloxy)ethanol as a colourless oil (0.856 g, 92%);

δ_H(300 MHz; CDCl₃) 8.21 (2 H, m, 2&6-ArHNO₂), 7.52 (2 H,

m, 3&5-ArHNO₂), 4.69 (2 H, s, ArCH₂), 3.83 (2 H, m,

CH₂CH₂OH), 3.67 (2 H, m, CH₂CH₂OH), 2.01 (1 H, br s, OH)

(cf. lit.¹⁵²).

(b) Benzoyl chloride (0.125 ml, ~0.15 g, 1.1 mmol) was added

to a stirred solution of 2-(4-nitrobenzyloxy)ethanol (0.211 g,

1.07 mmol) and triethylamine (0.15 ml, ~0.11 g, 1.1 mmol) in

dichloromethane (10 ml) at room temperature. After 18 h water

(50 ml) was added and the mixture extracted with further

dichloromethane (2 × 15 ml). Combined organic extracts

were dried (MgSO₄), and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography (silica, light

petroleum–dichloromethane, 1 : 2) to give the title compound

43d as colourless needles (0.32 g, 99%); mp 74–75 ЊC (Found: C,

63.6; H, 4.9; N, 4.5. C₁₆H₁₅NO₅requires C, 63.8; H, 5.0; N,

4.6%); ν_max(KBr)/cm^Ϫ12922, 2875, 2845 (C–H), 1717 (ester),

O-(4-Nitrobenzyl)-4-methoxyphenol

43g.

Potassium

hydroxide (0.230 g, 4.11 mmol) was added to a stirred solution

of 4-methoxyphenol (0.508 g, 4.10 mmol) in ethanol (20 ml) at

room temperature. After 1 h, 4-nitrobenzyl bromide (0.886 g,

4.10 mmol) was added and the mixture stirred and heated under

reﬂux. After 72 h the cooled reaction mixture was diluted with

water (30 ml) and extracted with dichloromethane (3 × 15 ml).

Combined organic layers were dried (MgSO₄), concentrated in

vacuo and puriﬁed by ﬂash chromatography (silica, dichloro-

methane–light petroleum, 1 : 1) to give the title compound 43g

(1.021 g, 96%) as pale yellow crystals, mp 85–87 ЊC (lit.,¹⁵³mp

88 ЊC); δ_H(300 MHz; CDCl₃), 8.24 (2 H, m, 3&5-ArHNO₂),

7.60 (2 H, m, 2&6-ArHNO₂), 6.92–6.83 (4 H, m, ArHOMe),

5.13 (2 H, s, OCH₂), 3.78 (3 H, s, OMe).

1509 (NO ), 1442, 1345 (NO ), 1273, 1100 (C᎐O), 850, 733, 720;

᎐

2

δ_H(300 MHz; CDCl₃); 8.18 (2 H, m, 2&6-ArHNO₂), 8.06 (2 H,

m, 2&6-ArHCOO), 7.59–7.44 (5 H, m, ArH), 4.71 (2 H, s,

ArCH₂), 4.55 (2 H, m, COOCH₂), 3.88 (2 H, m, COOCH₂CH₂);

δ_C(75 MHz; CDCl₃) 166.5 (C), 147.4 (C), 145.7 (C), 133.2

(CH), 129.9 (C), 129.7 (CH), 128.4 (CH), 127.7 (CH), 123.7

970

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

View Article Online

3-(4-Nitrobenzyloxy)benzaldehyde 43i. Diethyl azodicarbox-

ylate (0.63 ml, ~0.70 g, 4.0 mmol) was added quickly to a stirred

solution of 3-hydroxybenzaldehyde (0.407 g, 3.34 mmol),

4-nitrobenzyl alcohol (0.507 g, 3.31 mmol) and triphenyl-

phosphine (0.874 g, 3.34 mmol) in THF (15 ml) at room

temperature. After 2 d the reaction mixture was concentrated

in vacuo and the residue taken up in ethyl acetate (20 ml)

and washed successively with sodium hydroxide solution (1 M;

50 ml), hydrochloric acid (1 M; 20 ml), water (15 ml) and

brine (15 ml), dried (MgSO₄) and concentrated in vacuo. The

residue was puriﬁed by ﬂash column chromatography (silica,

dichloromethane) to give the title compound 43i as a colourless

solid (0.468 g, 55%); mp 109–110 ЊC (Found: C, 65.0; H, 4.2;

N, 5.2. C₁₄H₁₁NO₄requires C, 65.4; H, 4.3; N, 5.4%) (Found:

M^ϩ, 257.0690. C₁₄H₁₁NO₄requires 257.0688); ν_max(KBr)/cm^Ϫ1

2920, 2835, 2742 (CHO), 1687 (CHO), 1590, 1513 (NO₂), 1450,

1345 (NO₂), 1260, 1150, 1045, 863, 836, 783, 760, 675; δ_H(300

MHz; CDCl₃) 10.0 (1 H, s, CHO), 8.29 (2 H, m, 3&5-ArHNO₂),

7.65 (2 H, m, 2&6-ArHNO₂), 7.52 (3 H, m, ArHCHO), 7.29

(1 H, m, ArHCHO), 5.26 (2 H, s, OCH₂); δ_C(75 MHz; CDCl₃)

191.9 (CHO), 158.7 (C), 147.7 (C), 143.7 (C), 137.9 (C), 130.4

(CH), 127.7 (CH), 124.6 (CH), 123.9 (CH), 122.2 (CH), 112.7

(CH), 68.8 (CH₂); m/z (EI) 257 (M^ϩ, 32%), 229 (2), 136 (100),

121 (8), 106 (35), 90 (25), 89 (23), 78 (60), 63 (18).

ethanol (20 ml) and the mixture heated under reﬂux. After 2 d

the cooled reaction mixture was diluted with water (30 ml) and

extracted with ethyl acetate (3 × 15 ml). Combined organic

layers were dried (MgSO₄), concentrated in vacuo, then puriﬁed

by ﬂash chromatography (silica, ethyl acetate–light petroleum,

3 : 1) to give the title compound 43l as a colourless solid (0.457 g,

77%); mp 159–160 ЊC (Found: C, 68.5; H, 4.1; N, 9.8. C₁₆H₁₂-

N₂O₃requires C, 68.6; H, 4.3; N, 10.0%) (Found: M^ϩ, 280.0850.

C₁₆H₁₂N₂O₃requires 280.0848); ν_max(KBr)/cm^Ϫ13013, 2900,

2837, 1625, 1503, 1335, 1230, 1045, 856, 835, 738, 620, 550, 460;

δ_H(300 MHz; CDCl₃) 8.81 (1 H, dd, J 4.4, 1.7, 2-quinH), 8.29

(2 H, m, 3&5-ArHNO₂), 8.06 (1 H, d, J 9.3, 8-quinH), 8.05

(1 H, dd, J 8.2, 1.7, 4-quinH), 7.68 (2 H, m, 2&6-ArHNO₂),

7.48 (1 H, dd, J 9.3, 2.9, 7-quinH), 7.38 (1 H, dd, J 8.2, 4.4,

3-quinH), 7.13 (1 H, d, J 2.9, 5-quinH), 5.32 (2 H, s, OCH₂);

δ_C(100 MHz; CDCl₃) 156.2 (C), 148.5 (CH), 146.9 (C), 144.7

(C), 143.9 (C), 134.8 (CH), 131.4 (CH), 129.1 (C), 127.7 (CH),

123.9 (CH), 122.2 (CH), 121.6 (CH), 106.7 (CH), 68.9 (CH₂);

m/z (EI) 280 (M^ϩ, 20%), 144 (61), 135 (100), 91 (30).

4-Nitrobenzyl 4-chlorobenzoate 43m. 4-N,N-Dimethylamino-

pyridine (DMAP, 0.75 g, 6.1 mmol) was added to a stirred

solution of 4-nitrobenzyl alcohol (0.93 g, 6.1 mmol), 4-

chlorobenzoic acid (0.95 g, 6.1 mmol) and 1-(3-dimethyl-

aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.170

g, 6.1 mmol) in dichloromethane (20 ml). After 24 h the solu-

tion was washed with water (30 ml) and brine (15 ml), dried

(MgSO₄) and concentrated in vacuo. The crude material was

passed through a pad of silica with dichloromethane and con-

centrated in vacuo to yield the title compound 43m as colourless

crystals (1.62 g, 91%); mp 130–132 ЊC (Found: C, 57.6; H, 3.4;

N, 4.7. C₁₄H₁₀ClNO₄requires C, 57.6; H, 3.5; N, 4.8%) (Found:

M^ϩ, 291.0280. C₁₄H₁₀ClNO₄requires 291.0298); ν_max(KBr)/

cm^Ϫ13088, 3047, 2935, 2838, 1726 (C᎐O), 1588, 1516 (NO ),

O-(4-Nitrobenzyl)-2,3,5-trimethylphenol 43j. Diethyl diazo-

dicarboxylate (0.65 ml, ~0.72 g, 4.1 mmol) was added quickly

to a stirred solution of 2,3,5-trimethylphenol (0.435 g, 3.20

mmol), 4-nitrobenzyl alcohol (0.487 g, 3.18 mmol) and tri-

phenylphosphine (0.838 g, 3.20 mmol) in THF (20 ml) at room

temperature. Stirring was continued for 3 h then the solution

was concentrated in vacuo. The residue was taken up in ethyl

acetate (30 ml) and washed successively with sodium hydroxide

solution (1 M; 20 ml), hydrochloric acid (1 M; 20 ml), water

(10 ml), and brine (10 ml), dried (MgSO₄), and concentrated

in vacuo. The residue was puriﬁed by ﬂash column chrom-

atography (silica, dichloromethane–light petroleum, 1 : 2) to

give the title compound 43j as a colourless solid (0.833 g, 96%);

mp 128–129 ЊC (Found: C, 70.7; H, 6.4; N, 5.0. C₁₆H₁₇NO₃

requires C, 70.8; H, 6.3; N, 5.2%) (Found: M^ϩ, 271.1219.

C₁₆H₁₇NO₃requires 271.1208); ν_max(KBr)/cm^Ϫ12976, 2919,

2843, 1603, 1573, 1516 (NO₂), 1342 (NO₂), 1142, 1107, 830,

727; δ_H(300 MHz; CDCl₃) 8.26 (2 H, d, J 8.2, 3&5-ArHNO₂),

7.63 (2 H, d, J 8.2, 2&6-ArHNO₂), 6.68 (1 H, s, ArH), 6.56 (1 H,

s, ArH), 5.16 (2 H, s, OCH₂), 2.28 (3 H, s, Me), 2.27 (3 H, s,

Me), 2.20 (3 H, s, Me); δ_C(100 MHz; CDCl₃) 156.0 (C), 147.5

(C), 145.2 (C), 138.0 (C), 135.6 (C), 127.3 (CH), 123.84 (CH),

123.77 (CH), 122.3 (C), 110.2 (CH), 68.9 (CH₂), 21.3 (Me), 20.0

(Me), 11.5 (Me); m/z (EI) 271 (M^ϩ, 76%), 256 (12), 225 (7), 137

(61), 135 (100), 106 (31), 91 (40).

᎐

2

1338 (NO₂), 1255, 754; δ_H(300 MHz; CDCl₃) 8.26 (2 H, d,

J 9.1, 3&5-ArHNO₂), 8.02 (2 H, d, J 9.1, 3&5-ArHCl), 7.60

(2 H, d, J 9.1, 2&6-ArHNO₂), 7.45 (2 H, d, J 9.1, 2&6-ArHCl),

5.45 (2 H, s, OCH₂Ar); δ_C(75 MHz; CDCl₃) 165.3 (C), 143.0

(C), 140.0 (C), 131.1 (CH), 129.0 (CH), 128.4 (CH), 127.9 (C),

123.9 (CH), 65.4 (CH₂); m/z (EI) 291 (M^ϩ, 8%), 256 (5), 152 (3),

141 (30), 139 (92), 111 (16), 91 (22).

N-Benzyloxycarbonyl-D,L-alanine 4-nitrobenzyl ester 43n.

4-Dimethylaminopyridine (0.098 g, 0.80 mmol) was added to a

stirred solution of N-benzyloxycarbonyl-DL-alanine (0.176 g,

0.79 mmol), 4-nitrobenzyl alcohol (0.121 g, 0.79 mmol) and

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

(EDCI, 0.156 g, 0.81 mmol) in dichloromethane (20 ml). After

stirring at room temperature for 20 h the mixture was washed

with hydrochloric acid (1 M; 20 ml), water (30 ml) and brine

(20 ml), dried (MgSO₄), then concentrated in vacuo to give the

title compound 43n as a colourless solid (0.282 g, 100%); mp

78–79 ЊC (from ethyl acetate–light petroleum) (lit.,¹⁵⁵mp 78–

80 ЊC); δ_H(300 MHz; CDCl₃) 8.22 (2 H, d, J 8.7, 3&5-

ArHNO₂), 7.53 (2 H, d, J 8.7, 2&6-ArHNO₂), 7.35 (5 H, m,

Ph), 5.27 (2 H, s, OCH₂Ar), 5.11 (2 H, s, OCH₂Ph), 4.47 (1 H,

m, CHMe), 1.65 (1 H, br s, NH), 1.45 (3 H, d, J 7.2, CHMe).

O-(4-Nitrobenzyl)-2,4,5-trichlorophenol

43k.

Potassium

hydroxide (0.200 g, 3.57 mmol) was added to a stirred solution

of 2,4,5-trichlorophenol (0.500 g, 2.53 mmol) and 4-nitrobenzyl

chloride (0.434 g, 2.53 mmol) in ethanol (15 ml). The mixture

was heated under reﬂux. After 30 min the reaction mixture

was cooled and diluted with water (50 ml) then extracted

with dichloromethane (3 × 15 ml). Combined organic layers

were dried (MgSO₄), concentrated in vacuo, and puriﬁed by

ﬂash chromatography (silica, dichloromethane–light petrol-

eum, 1 : 2) to give the title compound 43k as a colourless solid

(0.316 g, 38%); mp 139–142 ЊC (lit.,¹⁵⁴mp 145–146 ЊC); δ_H(300

MHz; CDCl₃) 8.29 (2 H, d, J 8.8, 3&5-ArHNO₂), 7.66 (2 H, d,

J 8.8, 2&6-ArHNO₂), 7.52 (1 H, s, ArH), 7.05 (1 H, s, ArH),

5.23 (2 H, s, OCH₂).

N-Acetyl-S-(4-nitrobenzyl)-L-cysteine ethyl ester 44. (a) A

solution of 4-nitrobenzyl chloride (0.775 g, 4.51 mmol) in

1,4-dioxane (10 ml) was added in 2 ml portions over 30 min to a

vigorously stirred solution of N-acetyl--cysteine (0.735 g, 4.51

mmol) in sodium hydroxide solution (2 M; 2.25 ml) at 0 ЊC. The

dioxane was removed in vacuo and the resulting solution diluted

with water (50 ml), the pH adjusted to ~12 with 4 M sodium

hydroxide solution and then extracted with ether (2 × 10 ml).

The aqueous layer was acidiﬁed to pH ~ 2 with 2 M hydro-

chloric acid and extracted with dichloromethane (3 × 15 ml).

Combined organic layers were dried (MgSO₄) and concentrated

in vacuo to give N-acetyl-S-(4-nitrobenzyl)--cysteine (0.518 g,

6-(4-Nitrobenzyloxy)quinoline 43l. 4-Nitrobenzyl bromide

(0.458 g, 2.12 mmol) was added after 30 min at room temper-

ature to a stirred solution of 6-hydroxyquinoline (0.308 g,

2.11 mmol) and potassium hydroxide (0.130 g, 2.32 mmol) in

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

971

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39%); mp 130–131 ЊC (lit.,¹⁵⁶mp 132 ЊC); [α]_D²³Ϫ48.0 (c 1.0 in

ethanol) (lit.,¹⁵⁶[α]_D²⁴Ϫ53.8 (c 1.0 in ethanol)); δ_H(300 MHz;

CDCl₃/d₆-DMSO) 8.22 (1 H, d, J 8.0, NH), 8.16 (2 H, m, 2&6-

ArH), 7.58 (2 H, m, 3&5-ArH), 4.39 (1 H, ddd, J 8.3, 8.0, 5.2,

CHCH₂S), 3.88 (2 H, s, ArCH₂), 3.33 (1 H, br s, COOH), 2.78

(1 H, dd, J 13.7, 5.2, anti-CHCHHS), 2.65 (1 H, dd, J 13.7, 8.3,

syn-CHCHHS), 1.85 (3 H, s, MeCO).

1-(4-aminophenyl)ethanol 42b; δ_H(300 MHz; CDCl₃) 7.02

(2 H, d, J 8.6, ArH), 6.64 (2 H, d, J 8.6, ArH), 3.48 (2 H, br s,

NH₂), 2.56 (2 H, q, J 7.4, CH₂Me), 1.20 (3 H, t, J 7.4, CH₂Me)

(cf. lit.¹⁵⁹).

4-Methyl-N,N-dimethylaniline 40c. According to the general

procedure 5 the title compound was obtained as a dark oil

(53%) from 4-N,N-dimethylaminobenzyl alcohol 42c; δ_H(300

MHz; CDCl₃) 7.07 (2 H, d, J 8.5, ArH), 6.71 (2 H, d, J 8.5,

ArH), 2.91 (6 H, s, NMe₂), 2.27 (3 H, s, ArMe) (cf. lit.¹⁶⁰).

(b) Thionyl chloride (0.21 ml, ~0.35 g, 2.9 mmol) was added

to a stirred solution of N-acetyl-S-(4-nitrobenzyl)--cysteine

(0.58 g, 1.95 mmol) in ethanol (20 ml). After 16 h the solvent

was removed in vacuo and the residue was taken up in dichloro-

methane (50 ml) and washed with sodium hydroxide solution

(2 M; 20 ml). The organic layer was dried (MgSO₄) and concen-

trated in vacuo to give the title compound 44 as a yellow solid

(0.53 g, 83%); mp 87–88 ЊC; [α]_D²²Ϫ26.0 (c 1.04 in chloroform)

(Found: C, 51.4; H, 5.4; N, 8.4. C₁₄H₁₈N₂O₅S requires C, 51.5;

H, 5.6; N, 8.6%); ν_max(KBr)/cm^Ϫ13335 (NH), 3005, 2930, 1770

(ester), 1655 (amide), 1510, 1350 (NO₂), 1020, 855, 800, 585;

δ_H(300 MHz; CDCl₃) 8.18 (2 H, m, 2&6-ArH), 7.48 (2 H, m,

3&5-ArH), 6.28 (1 H, br d, J 7.3, NH), 4.80 (1 H, ddd, J 7.3,

5.7, 5.1, CHCH₂S), 4.22 (2 H, m, CH₂Me), 3.79 (2 H, s,

CH₂Ar), 2.93 (1 H, dd, J 13.9, 5.1, anti-CHCHHS), 2.80 (1 H,

dd, J 13.9, 5.7, syn-CHCHHS), 2.03 (3 H, s, MeCO), 1.27 (3 H,

t, J 7.1, CH₂Me); δ_C(75 MHz; CDCl₃) 170.7 (CO), 169.9 (CO),

147.1 (C), 145.5 (C), 129.8 (CH), 123.9 (CH), 62.1 (CH₂),

51.6 (CH), 35.9 (CH₂), 33.7 (CH₂), 23.2 (Me), 14.2 (Me);

m/z (CI) 327 (MH^ϩ, 6%), 164 (11), 122 (17), 112 (23), 108 (65),

106 (100).

1,2-Bis-(4-aminophenyl)ethane. According to the general

procedure 5 the title compound was obtained as a colourless

solid (32%) from 4-nitrobenzyl chloride (also obtained was

4-methylaniline (46%), spectroscopic data as above); mp 133–

134 ЊC (lit.,¹⁶¹mp 134 ЊC); δ_H(300 MHz; CDCl₃) 6.99 (4 H, d,

J 8.3, ArH), 6.64 (4 H, d, J 8.3, ArH), 3.57 (4 H, br s, NH₂),

2.78 (4 H, s, CH₂).

2-Phenylethanol. According to the general procedure 6 the

title compound was obtained as a colourless oil (87%) from

O-(4-nitrobenzyl)-2-phenylethanol 43a; δ_H(300 MHz; CDCl₃)

7.37–7.25 (5 H, m, PhH), 3.89 (2 H, t, J 6.6, OCH₂), 2.90 (2 H, t,

J 6.6, PhCH₂), 1.62 (1 H, br s, OH)—(as original sample).

2-Phenoxyethanol. According to the general procedure 6 the

title compound was obtained as a colourless oil (98%) from

O-(4-nitrobenzyl)-2-phenoxyethanol 43b; δ_H(300 MHz;

CDCl₃) 7.32 (2 H, m, 3&5-ArH), 6.98 (3 H, m, 2, 4&6-ArH),

4.11 (2 H, m, CH₂OH), 3.99 (2 H, m, PhOCH₂), 2.24 (1 H, br s,

OH)—(as original sample).

Ethyl 1-(4-nitrobenzyl)-5-hydroxy-2-methylindole-3-carboxyl-

ate 46. Ethyl acetoacetate (1.20 ml, ~1.24 g, 9.5 mmol), was

added to a stirred mixture of 4-nitrobenzylamine hydrochloride

(1.79 g, 9.5 mmol) and triethylamine (1.32 ml, ~0.96 g, 9.5

mmol) at room temperature. After the initial exothermic reac-

tion had subsided (~1 h), the mixture was diluted with ether

(40 ml) and after a further 30 min the resulting solution was

washed with water (20 ml). The ether layer was dried (MgSO₄)

and concentrated in vacuo. The resulting crude ethyl 3-(4-

nitrobenzylamino)but-2-enoate (2.51 g, 9.5 mmol) was added

to a solution of p-benzoquinone (1.03 g, 9.5 mmol) in

nitromethane (10 ml) and allowed to stand at room temperature

for 18 h. The solvent was removed under a stream of nitrogen

and the residue recrystallised from ethyl acetate to give the title

compound 46 as a yellow powder (0.81 g, 24%); mp 221–222 ЊC

(from ethyl acetate) (lit.,¹⁵⁷mp 222–224 ЊC); δ_H(300 MHz;

CDCl₃/d₆-DMSO) 7.97 (1 H, s, OH), 7.20 (2 H, m, 3&5-

ArHNO₂), 6.47 (1 H, d, J 2.4, 4-indoleH), 6.25 (2 H, m, 2&6-

ArHNO₂), 6.22 (1 H, d, J 8.7, 7-indoleH), 5.67 (1 H, dd, J 8.7,

2.4, 6-indoleH), 4.63 (2 H, s, NCH₂Ar), 3.33 (2 H, q, J 7.1,

CH₂Me), 1.68 (3 H, s, Me), 0.43 (3 H, t, J 7.1, CH₂Me).

2-Benzyloxyethanol. According to the general procedure 6

the title compound was obtained as a colourless oil (100%)

from O-(4-nitrobenzyl)-2-benzyloxyethanol 43c; δ_H(300 MHz;

CDCl₃) 7.42–7.28 (5 H, m, PhH), 4.57 (2 H, s, PhCH₂), 3.76

(2 H, t, J 4.1, CH₂OH), 3.60 (2 H, t, J 4.1, CH₂OBn), 2.23 (1 H,

br s, OH)—(as original sample).

2-Hydroxyethyl benzoate. According to the general pro-

cedure 6 the title compound was obtained as a colourless solid

(99%) from 2-(4-nitrobenzyloxy)ethyl benzoate 43d; mp 35–

36 ЊC (lit.,¹⁶²mp 36–37 ЊC); δ_H(300 MHz; CDCl₃) 8.06 (2 H, m,

2&6-ArH), 7.60 (1 H, m, 4-ArH), 7.45 (2 H, m, 3&5-ArH), 4.47

(2 H, m, CH₂CH₂OH), 3.97 (2 H, m, CH₂CH₂OH), 2.24 (1 H,

br s, OH).

O-(tert-Butyldimethylsilyl)-2-(4-aminobenzyloxy)ethanol.

According to the general procedure 6 (reaction stirred at room

temperature—not reﬂuxed) the title compound was obtained as

a colourless oil (80%) from O-(tert-butyldimethylsilyl)-2-(4-

nitrobenzyloxy)ethanol 43e (Found: MH^ϩ, 282.1891. C₁₅H₂₈-

NO₂Si requires 282.1889); ν_max(neat)/cm^Ϫ13448, 3360 (NH₂),

3222, 2954, 2917, 2856, 1608, 1515, 1464, 1250, 938, 827, 776;

δ_H(300 MHz; CDCl₃) 7.14 (2 H, m, 2&6-ArH), 6.66 (2 H, m,

3&5-ArH), 4.45 (2 H, s, ArCH₂), 3.80 (2 H, t, J 5.5, CH₂-

CH₂OSi), 3.52 (2 H, t, J 5.5, CH₂CH₂OSi), 0.90 (9 H, s, t-Bu),

0.07 (6 H, s, SiMe₂), NH₂not observed; δ_C(75 MHz; CDCl₃)

146.5 (C), 129.4 (CH), 128.7 (C), 115.0 (CH), 73.2 (CH₂), 71.1

(CH₂), 62.8 (CH₂), 26.0 (CMe₃), 18.6 (CMe₃), Ϫ5.2 (SiMe₂);

m/z (CI) 282 (MH^ϩ, 41%), 176 (43), 167 (20), 115 (13) and 106

(100).

Reduction of 4-nitrobenzyl derivatives

4-Methylaniline 40a. (a) The title compound was also

obtained (72%) from 4-(methoxymethyl)nitrobenzene 30l

according to the general procedure 5 after a reaction time of

18 h (rather than 1–2 h).

(b) According to the general procedure 5 the title compound

was obtained as a colourless crystalline solid (47%) from

4-nitrobenzyl alcohol 41a; mp 41–42 ЊC (lit.,¹⁵⁸mp 42 ЊC);

δ_H(300 MHz; CDCl₃) 6.98 (2 H, d, J 7.8, ArH), 6.62 (2 H, d,

J 7.8, ArH), 3.42 (2 H, br s, NH₂), 2.25 (3 H, s, ArMe).

(c) The title compound was also obtained (83%) from

4-(acetoxymethyl)nitrobenzene 41b according to the general

procedure 5.

L-Menthol. According to the general procedure 6 the title

compound was obtained as colourless needles (93%) from -O-

(4-nitrobenzyl)menthol 43f; mp 42–43 ЊC (lit.,¹⁶³mp 43 ЊC); [α]_D²⁵

Ϫ49.0 (c 1.0 in ethanol) (lit.,¹⁶⁴[α]_DϪ50.0 (c 10 in ethanol));

δ_H(300 MHz; CDCl₃) 3.44 (1 H, td, J 10.7, 4.4, OCH), 2.19

(1 H, m, CHMe), 1.98 (1 H, m, CH₂CHOR), 1.67 (1 H, m,

CH₂CH₂CHMe), 1.65 (1 H, m, CH₂CH₂CHMe), 1.44 (1 H, m,

(d) The title compound was also obtained (82%) from 4-

aminobenzyl alcohol 42a according to the general procedure 5.

4-Ethylaniline 40b. According to the general procedure 5

the title compound was obtained as a yellow oil (31%) from

972

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

View Article Online

CHMe₂), 1.13 (1 H, m, CHⁱPr), 1.03 (1 H, m, CH₂CH₂CHMe),

0.95 (3 H, d, J 7.2, CHMe₂), 0.93 (3 H, d, J 7.2, CHMe₂), 0.92

(1 H, m, CH₂CHOR), 0.89 (1 H, m, CH₂CH₂CHMe), 0.83 (3 H,

d, J 6.9, CHMe)—(as original sample).

(NH₂), 1510, 1370, 1025, 830 (ArH); δ_H(300 MHz; CDCl₃)

7.12–7.07 (2 H, m, 3&5-ArH), 6.68–6.64 (2 H, m, 2&6-ArH),

6.18 (1 H, br d, J 7.6, NH), 4.79 (1 H, dt, J 7.6, 5.1, NCH), 4.21

(2 H, q, J 7.2, CH₂Me), 3.64 (2 H, s, SCH₂Ar), 2.90 (2 H, d,

J 5.1, NCHCH₂S), 2.02 (3 H, s, MeCO), 1.30 (3 H, t, J 7.2,

CH₂Me), NH₂not observed; δ_C(75 MHz; CDCl₃) 170.9 (CO),

169.9 (CO), 145.6 (C), 130.0 (CH), 127.3 (C), 115.2 (CH), 61.8

(CH₂), 51.7 (CH), 36.4 (CH₂), 33.4 (CH₂), 23.1 (Me), 14.1 (Me);

m/z (CI) 297 (MH^ϩ, 1%), 158 (100), 116 (29).

4-Methoxyphenol. According to the general procedure 6 the

title compound was obtained as colourless crystals (81%) from

O-(4-nitrobenzyl)-4-methoxyphenol 43g; mp 54–55 ЊC (lit.,¹⁶⁵

mp 54 ЊC); δ_H(300 MHz; CDCl₃) 6.79 (4 H, m, ArH), 4.52

(1 H, br s, OH), 3.77 (3 H, s, OMe)—(as original sample).

Ethyl

1-(4-aminobenzyl)-5-hydroxy-2-methylindole-3-carb-

4-Hydroxyacetophenone. According to the general procedure

6 the title compound was obtained as a colourless solid (97%)

from 4-(4-nitrobenzyloxy)acetophenone 43h; mp 107–108 ЊC

(lit.,¹⁶⁶mp 107–109 ЊC); δ_H(300 MHz; CDCl₃) 10.35 (1 H, br s,

OH), 7.83 (2 H, m, ArH), 6.85 (2 H, m, ArH), 2.46 (3 H, s,

COMe)—(as original sample).

oxylate 47. According to the general procedure 6 the title

compound was obtained as a colourless solid (62%) from ethyl-

N-(4-nitrobenzyl)-5-hydroxy-2-methylindole-3-carboxylate 46;

mp 196–198 ЊC (Found: M^ϩ, 324.1475. C₁₉H₂₀N₂O₃requires

324.1474); ν_max(KBr)/cm^Ϫ13415, 3335 (NH₂), 3230 (OH), 2970,

2920, 2850, 1650, 1610, 1515, 1470, 1250, 1026, 877 (ArH); δ_H

(300 MHz; d₆-DMSO) 8.95 (1 H, br s, OH), 7.37 (1 H, d, J 2.5,

4-indoleH), 7.28 (1 H, d, J 8.5, 7-indoleH), 6.74 (2 H, m, 3&5-

ArHNH₂), 6.62 (1 H, dd, J 8.5, 2.5, 6-indoleH), 6.46 (2 H, m,

2&6-ArHNH₂), 5.20 (2 H, s, NCH₂), 5.03 (2 H, br s, NH₂),

4.26 (2 H, q, J 7.2, CH₂Me), 2.66 (3 H, s, Me), 1.35 (3 H, t,

J 7.2, CH₂Me); δ_C(100 MHz; d₆-DMSO) 165.6 (C), 153.1

(C), 148.2 (C), 145.3 (C), 130.8 (C), 127.7 (CH), 124.5 (C),

114.5 (CH), 111.9 (CH), 111.3 (CH), 105.9 (CH), 102.8 (C),

79.6 (C), 59.1 (CH₂), 46.2 (CH₂), 15.0 (Me), 12.4 (Me); m/z (EI)

324 (M^ϩ, 12%), 309 (10), 295 (12), 218 (57), 203 (100), 145 (60),

91 (42).

3-Hydroxybenzaldehyde. According to the general procedure

6 the title compound was obtained as a colourless solid (61%)

from 3-(4-nitrobenzyloxy)benzaldehyde 43i; mp 104–106 ЊC

(lit.,¹⁶⁷mp 103–105 ЊC); δ_H(300 MHz; d₄-MeOH) 9.89 (1 H, s,

CHO), 7.37 (2 H, m, ArH), 7.27 (1 H, m, ArH), 7.08 (1 H, m,

ArH), 4.93 (1 H, br s, OH)—(as original sample).

2,3,5-Trimethylphenol. According to the general procedure 6

the title compound was obtained as a pale solid (100%) from

O-(4-nitrobenzyl)-2,3,5-trimethylphenol 43j; mp 93–95 ЊC

(lit.,¹⁶⁸mp 94–95 ЊC); δ_H(300 MHz; CDCl₃) 6.63 (1 H, s, ArH),

6.49 (1 H, s, ArH), 4.88 (1 H, br s, OH), 2.27 (6 H, s, Me), 2.16

(3 H, s, Me)—(as original sample).

Preparation of conjugated alkenes

1-Phenylbut-2-en-1-one 50. Aluminium trichloride (freshly

ground, 5.48 g, 41.1 mmol) was suspended in benzene (20 ml),

then stirred vigorously at room temperature while trans-

crotonyl chloride (3.09 ml, ~3.35 g, 32.1 mmol) was added

dropwise over 5 min. After a further 15 min the resulting clear

solution was poured onto a mixture of ice (100 ml) and hydro-

chloric acid solution (2 M; 50 ml). The resulting mixture was

extracted with ether (2 × 30 ml), washed with sodium hydroxide

solution (4 M; 30 ml), dried (MgSO₄) and concentrated in

vacuo. The crude material was puriﬁed by distillation to give the

title compound 50 as a clear oil (2.86 g, 61%); bp 85–90 ЊC, 0.7

mmHg (lit.,¹⁷³bp 90–95 ЊC, 2.0 mmHg); δ_H(300 MHz; CDCl₃)

7.93 (2 H, m, 3&5-ArH), 7.55 (1 H, m, 4-ArH), 7.47 (2 H,

2,4,5-Trichlorophenol. According to the general procedure 6

the title compound was obtained as a colourless solid (90%)

from O-(4-nitrobenzyl)-2,4,5-trichlorophenol 43k; mp 63–64 ЊC

(lit.,¹⁶⁹mp 63–65 ЊC); δ_H(300 MHz; CDCl₃) 7.43 (1 H, s, ArH),

7.15 (1 H, s, ArH), 5.63 (1 H, br s, OH)—(as original sample).

6-Hydroxyquinoline. According to the general procedure 6

the title compound was obtained as an orange solid (97%) from

6-(4-nitrobenzyloxy)quinoline 43l; mp 191–193 ЊC (from ether)

(lit.,¹⁷⁰mp 193 ЊC); δ_H(300 MHz; d₆-DMSO) 10.06 (1 H, br s,

OH), 8.65 (1 H, dd, J 4.1, 1.6, 2-ArH), 8.13 (1 H, dd, J 8.6, 1.6,

4-ArH), 7.86 (1 H, d, J 9.1, 8-ArH), 7.39 (1 H, dd, J 8.6, 4.1,

3-ArH), 7.31 (1 H, dd, J 9.1, 2.8, 7-ArH), 7.14 (1 H, d, J 2.8,

5-ArH)—(as original sample).

m, 2&6-ArH), 7.09 (1 H, dq, J 15.4, 6.9, MeCH᎐CH), 6.92

᎐

(1 H, dq, J 15.4, 1.7, MeCH᎐CH), 2.01 (6 H, dd, J 6.9, 1.7,

᎐

MeCH᎐CH).

᎐

4-Chlorobenzoic acid. According to the general procedure 6

the title compound was obtained as a colourless solid (90%)

from 4-nitrobenzyl 4-chlorobenzoate 43m; mp 240–241 ЊC

(lit.,¹⁷¹mp 240 ЊC); δ_H(300 MHz; d₆-DMSO) 8.79 (1 H, br s,

COOH), 7.95 (2 H, m, ArH), 7.58 (2 H, m, ArH)—(as original

sample).

2-(trans-But-1-enyl)quinoline 55a. According to general pro-

cedure 7 without indium (reﬂux for 4 days) the title compound

55a was obtained as a clear oil (56%) from 1-(quinolin-2-yl)-

butan-2-ol 57a (prepared as described below); δ_H(300 MHz;

CDCl₃) 8.05 (1 H, d, J 8.7, 4-ArH), 8.03 (1 H, dd, J 8.5, 1.0,

8-ArH), 7.74 (1 H, dd, J 8.0, 1.5, 5-ArH), 7.66 (1 H, ddd, J 8.5,

7.1, 1.5, 7-ArH), 7.52 (1 H, d, J 8.7, 3-ArH), 7.45 (1 H, ddd,

N-Benzyloxycarbonyl-D,L-alanine. According to the general

procedure 6 the title compound was obtained as a colourless

solid (96%) from N-benzyloxycarbonyl--alanine 4-nitro-

benzyl ester 43n; mp 112–113 ЊC (lit.,¹⁷²mp 112–114 ЊC);

δ_H(300 MHz; CDCl₃) 7.36 (5 H, m, PhH), 6.52 (1 H, br s,

COOH), 5.31 (1 H, d, J 7.4, NH), 5.13 (2 H, m, CH₂), 4.43 (1 H,

quintet, J 7.4, CHMe), 1.48 (3 H, d, J 7.4, CHMe)—(as original

sample).

J 8.0, 7.1, 1.0, 6-ArH), 6.87 (1 H, dt, J 16.0, 6.2, ArCH᎐CH),

᎐

6.72 (1 H, dt, J 16.0, 1.4, ArCH᎐CH), 2.35 (2 H, qdd, J 7.5, 6.2,

᎐

1.4, CH₂Me), 1.17 (3 H, t, J 7.5, CH₂Me) (cf. lit.⁵²).

trans-3-Methyl-1-(quinolin-2-yl)but-1-ene 55b. (a) n-Butyl-

lithium (1.6 M in hexanes; 3.0 ml, 4.8 mmol) was added to a

stirred suspension of (isobutyl)triphenylphosphonium bromide

(1.83 g, 4.6 mmol) in dry ether (20 ml) under an atmosphere of

nitrogen at 0 ЊC. After 30 min the mixture was cooled to Ϫ78 ЊC

and quinoline-2-carbaldehyde (0.72 g, 4.6 mmol) in dry ether

(10 ml) was added dropwise over 30 min. The reaction mixture

was stirred, while warming to room temperature over 3 h,

washed with water (50 ml), dried (MgSO₄) and concentrated

in vacuo. The crude material was puriﬁed by ﬂash column

chromatography (silica, 6% ethyl acetate in light petroleum) to

N-Acetyl-S-(4-aminobenzyl)-L-cysteine ethyl ester 45.

According to the general procedure 6 the title compound was

obtained as a yellow solid (100%) from N-acetyl-S-(4-nitro-

benzyl)--cysteine ethyl ester 44; mp 89–91 ЊC; [α]_D²⁴ϩ23.7

(c 0.97 in chloroform) (Found: C, 56.9; H, 6.8; N, 9.2. C₁₄H₂₀-

N₂O₃S requires C, 56.7; H, 6.8; N, 9.5%); ν_max(KBr)/cm^Ϫ13470

(amide), 3385, 3345 (NH₂), 2985, 2915, 1735 (ester), 1635

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

973

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give cis-3-methyl-1-(quinolin-2-yl)but-1-ene as a colourless oil

added over 10 min. The reaction mixture was allowed to warm

(0.53 g, 59%) (Found: MH^ϩ, 198.1283. C₁₄H₁₆N requires

to room temperature over 4 h, and then water (50 ml) was

added and the layers separated. The aqueous layer was further

extracted with ether (2 × 15 ml). Combined organic layers were

dried (MgSO₄) and concentrated in vacuo. The crude material

was passed down a ﬂash chromatography column (silica, light

petroleum) to give the title compound as a colourless solid

(0.261 g, 60%), a mixture of cis and trans isomers (4.5 : 1); mp

36–38 ЊC (lit.,¹⁷⁴mp 38.5–39 ЊC); δ_H(300 MHz; CDCl₃) cis 7.81

(3 H, m, ArH), 7.71 (1 H, s, 1-ArH), 7.45 (3 H, m, ArH),

198.1285); ν_max(neat)/cm^Ϫ13060 (᎐C–H), 2955, 2860 (C–H),

᎐

1650 (C᎐C), 1600, 1500 (Ar), 800 (cis CH᎐CH), 815, 750 (ArH);

᎐

δ_H(300 MHz; CDCl₃) 8.09 (1 H, d, J 8.5, 4-ArH), 8.06 (1 H, dd,

J 8.6, 1.0, 8-ArH), 7.78 (1 H, dd, J 7.9, 1.2, 5-ArH), 7.69 (1 H,

ddd, J 8.6, 7.0, 1.2, 7-ArH), 7.50 (1 H, ddd, J 7.9, 7.0, 1.0, 6-

ArH), 7.39 (1 H, d, J 8.5, 3-ArH), 6.54 (1 H, dd, J 11.7, 1.1,

ArCH᎐CH), 5.83 (1 H, dd, J 11.7, 10.1, ArCH᎐CH), 3.50 (1 H,

᎐

d-septet-d, J 10.1, 6.6, 1.1, CHMe₂), 1.13 (6 H, d, J 6.6,

CHMe₂); δ_C(75 MHz; CDCl₃) 157.1 (C), 148.1 (C), 145.8 (CH),

6.46 (1 H, d, J 11.6, ArCH᎐CH), 5.57 (1 H, dd, J 11.6, 10.3,

᎐

135.8 (᎐CH), 129.42 (CH), 129.38 (CH), 127.4 (CH), 126.7

ArCH᎐CH), 3.02 (1 H, d-septet, J 10.3, 6.6, CHMe ), 1.09

᎐

2

(CH), 126.5 (C), 126.0 (᎐CH), 122.2 (CH), 27.6 (CH), 22.9

(6 H, d, J 6.6, CHMe₂); trans 7.83–7.38 (7 H, m, ArH), 6.52

᎐

(Me); m/z (CI) 198 (MH^ϩ, 100%).

(1 H, d, J 15.9, ArCH᎐CH), 6.33 (1 H, dd, J 15.9, 6.7,

᎐

(b) Acetic acid (0.50 ml, ~0.53 g, 8.8 mmol) and cis-3-methyl-

1-(quinolin-2-yl)but-1-ene (0.515 g, 2.61 mmol) were heated at

reﬂux in THF (20 ml) for 94 h. The cooled solution was washed

with saturated sodium bicarbonate solution (20 ml), dried

(MgSO₄) and concentrated in vacuo to give the title compound

55b as a colourless oil (0.495 g, 96%) (Found: MH^ϩ, 198.1282.

ArCH᎐CH), 2.53 (1 H, septet, J 6.8, CHMe ), 1.09 (6 H, d,

J 6.8, CHMe₂).

᎐

2

1-(Quinolin-2-yl)butan-2-ol 57a. n-Butyllithium (1.6 M in

hexanes; 3.5 ml, 5.6 mmol) was added slowly to a stirred solu-

tion of 2-methylquinoline (0.68 ml, ~0.72 g, 5.0 mmol) in ether

(20 ml) at 0 ЊC under an atmosphere of nitrogen. After stirring

for 30 min, the reaction mixture was cooled to Ϫ78 ЊC and

propionaldehyde (0.36 ml, ~0.29 g, 5.0 mmol) was added drop-

wise over 5 min. Stirring was continued at Ϫ78 ЊC for 1 h, then

the mixture was allowed to warm to room temperature, poured

onto saturated ammonium ﬂuoride solution (100 ml), and

extracted with ether (2 × 30 ml). Combined ethereal layers were

dried (MgSO₄), and concentrated in vacuo. The residue was

puriﬁed by ﬂash column chromatography (silica, 10% ethyl

acetate in light petroleum) to give the title compound 57a as a

colourless solid (0.61 g, 61%); mp 36–37 ЊC (Found: C, 77.1; H,

7.7; N, 6.6. C₁₃H₁₅NOؒ0.1H₂O requires C, 76.9; H, 7.5; N,

6.9%); ν_max(KBr)/cm^Ϫ13360 (OH), 3050, 2950, 2920, 1600,

1505, 1425, 1115, 820, 755 (ArH); δ_H(300 MHz; CDCl₃) 8.08

(1 H, d, J 8.3, 4-ArH), 8.01 (1 H, dd, J 8.6, 1.1, 8-ArH), 7.78

(1 H, dd, J 8.2, 1.4, 5-ArH), 7.69 (1 H, ddd, J 8.6, 7.0, 1.4,

7-ArH), 7.50 (1 H, ddd, J 8.2, 7.0, 1.1, 6-ArH), 7.26 (1 H, d,

J 8.3, 5-ArH), 5.65 (1 H, br s, OH), 4.14 (1 H, m, CHOH), 3.11

(1 H, dd, J 15.6, 2.9, anti-ArCHHCHOH), 3.01 (1 H, dd,

J 15.6, 8.9, syn-ArCHHCHOH), 1.76-1.53 (2 H, m, CHOH-

CH₂Me), 1.05 (3 H, t, J 7.4, Me); δ_C(75 MHz; CDCl₃) 161.1

(C), 147.0 (C), 136.6 (CH), 129.7 (CH), 128.7 (CH), 127.6 (CH),

126.7 (C), 126.1 (CH), 122.1 (CH), 72.0 (CHOH), 43.2 (CH₂),

29.9 (CH₂), 10.1 (Me); m/z (CI) 202 (MH^ϩ, 100%), 184 (70), 144

(61), 143 (28), 57 (90).

C₁₄H₁₆N requires 198.1285); ν_max(neat)/cm^Ϫ13060 (᎐C–H),

᎐

2950, 2860 (C–H), 1650 (C᎐C), 1600, 1500 (Ar), 970 (trans

᎐

CH᎐CH), 815, 750 (ArH); δ_H(300 MHz; CDCl₃) 8.07 (1 H, d,

᎐

J 8.6, 4-ArH), 8.03 (1 H, dd, J 8.4, 1.0, 8-ArH), 7.75 (1 H, dd,

J 7.9, 1.3, 5-ArH), 7.67 (1 H, ddd, J 8.4, 7.0, 1.3, 7-ArH), 7.55

(1 H, d, J 8.6, 3-ArH), 7.47 (1 H, ddd, J 7.9, 7.0, 1.0, 6-ArH),

6.81 (1 H, dd, J 16.0, 6.2, ArCH᎐CH), 6.68 (1 H, d, J 16.0,

᎐

ArCH᎐CH), 2.59 (1 H, septet-d, J 6.8, 6.2, CHMe ), 1.17 (6 H,

᎐

2

d, J 6.8, CHMe₂); δ_C(75 MHz; CDCl₃) 156.7 (C), 148.1 (C),

144.5 (CH), 136.2 (᎐CH), 129.5 (CH), 129.1 (CH), 128.3 (CH),

᎐

127.4 (CH), 127.1 (C), 125.8 (᎐CH), 118.7 (CH), 31.6 (CH),

᎐

22.1 (Me); m/z (CI) 198 (MH^ϩ, 100%).

cis-1-(Quinolin-2-yl)hepta-1,6-diene 55c. n-Butyllithium (1.6

M solution in hexanes; 0.76 ml, 1.21 mmol) was added to a

stirred suspension of (hex-5-enyl)triphenylphosphonium brom-

ide (0.514 g, 1.21 mmol) in ether (15 ml) at 0 ЊC under an

atmosphere of nitrogen. After 15 min, the mixture was cooled

to Ϫ78 ЊC and quinoline-2-carbaldehyde (0.190 g, 1.21

mmol) in ether (15 ml) was added over 10 min. The reaction

mixture was allowed to warm to room temperature over 4 h,

and then water (50 ml) was added and the layers separated. The

aqueous layer was further extracted with ether (2 × 15 ml).

Combined organic layers were dried (MgSO₄) and concentrated

in vacuo. The crude material was passed down a ﬂash chrom-

atography column (silica, 5% ethyl acetate in light petroleum) to

give the title compound 55c as a colourless oil (0.087 g, 32%)

(Found: MH^ϩ, 224.1443. C₁₆H₁₈N requires 224.1439); ν_max

(neat)/cm^Ϫ13060 (᎐CH), 3010 (ArH), 2915, 2850 (CH ), 1625

3-Methyl-1-(quinolin-2-yl)butan-2-ol 57b. n-Butyllithium (1.6

M in hexanes; 3.5 ml, 5.6 mmol) was added slowly to a solution

of 2-methylquinoline (0.715 g, 5.00 mmol, 0.68 ml) in ether

(20 ml) at 0 ЊC under an atmosphere of nitrogen. After 30 min

the solution was cooled to Ϫ78 ЊC. Isobutyraldehyde (0.45 ml,

~0.36 g, 5.0 mmol) was added dropwise over 10 min. Stirring

was continued for 1 h at Ϫ78 ЊC, then the mixture was allowed

to warm to room temperature over 2 h. The reaction mixture

was quenched by pouring onto saturated ammonium ﬂuoride

solution (100 ml). The layers were separated and the aqueous

layer extracted with ether (2 × 50 ml). The combined ethereal

layers were dried (MgSO₄), and concentrated in vacuo. The

crude material was recrystallised from ether to give the title

compound 57b as a colourless solid (0.634 g, 59%); mp 94–

96 ЊC (lit.,¹⁷⁵mp 93 ЊC); ν_max(KBr)/cm^Ϫ13237 (OH), 2945, 2875

(C–H), 1600, 1505 (Ar), 1430, 1380, 1045 (C–O), 810, 750

(ArH); δ_H(300 MHz; CDCl₃) 8.09 (1 H, d, J 8.5, 4–ArH), 8.01

(1 H, d, J 8.4, 8-ArH), 7.79 (1 H, d, J 8.2, 5-ArH), 7.70 (1 H, dd,

J 8.4, 8.2, 7-ArH), 7.51 (1 H, dd, J 8.2, 8.2, 6-ArH), 7.28 (1 H,

d, J 8.5, 3-ArH), 5.65 (1 H, br s, OH), 3.95 (1 H, ddd, J 8.9, 5.8,

2.8, CHOH), 3.09 (1 H, dd, J 15.5, 2.8, anti-ArCHHCHOH),

3.03 (1 H, dd, J 15.5, 8.9, syn-ArCHHCHOH), 1.81 (1 H,

septet-d, J 6.8, 5.8, CHMe₂), 1.07 (3 H, d, J 6.8, Me), 1.04 (3 H,

d, J 6.8, Me); δ_C(75 MHz; CDCl₃) 161.5 (C), 147.1 (C), 136.7

᎐

2

(C᎐C), 1600, 1500 (Ar), 970 (CH᎐CH ), 750 (HC᎐CH); δ (300

᎐

2

H

MHz; CDCl₃) 8.10 (1 H, d, J 8.5, 4-ArH), 8.07 (1 H, dd, J 8.3,

1.0, 8-ArH), 7.79 (1 H, dd, J 8.1, 1.3, 5-ArH), 7.70 (1 H,

ddd, J 8.3, 7.0, 1.3, 7-ArH), 7.50 (1 H, ddd, J 8.1, 7.0, 1.0,

6-ArH), 7.39 (1 H, d, J 8.5, 3-ArH), 6.66 (1 H, dt, J 11.8, 1.8,

ArCH᎐CH), 6.04 (1 H, dt, J 11.8, 7.4, ArCH᎐CH), 5.84 (1 H,

᎐

ddt, J 17.0, 10.2, 6.6, CH᎐CH ), 5.01 (1 H, ddt, J 17.0, 2.0, 1.5,

᎐

2

trans-CH᎐CHH), 4.95 (1 H, ddt, J 10.2, 2.0, 1.5, cis-CH᎐

᎐

CHH), 2.73 (2 H, m, ArCH᎐CHCH ), 2.17 (2 H, m,

᎐

2

CH CH᎐CH ), 1.64 (2 H, m, CH CH CH᎐CH ); δ (100 MHz;

᎐

2

C

CDCl₃) 156.4 (C), 148.0 (C), 138.4 (CH), 137.7 (CH), 136.3

(CH), 131.2 (CH), 129.6 (CH), 129.1 (CH), 129.0 (CH), 127.2

(CH), 126.0 (C), 118.7 (CH), 114.8 (᎐CH ), 33.3 (CH ), 32.4

᎐

2

(CH₂), 28.1 (CH₂); m/z (CI) 224 (MH^ϩ, 100%).

3-Methyl-1-(2-naphthyl)but-1-ene. n-Butyllithium (1.6

M

solution in hexanes; 1.50 ml, 2.4 mmol) was added to a stirred

suspension of isobutyltriphenylphosphonium bromide (0.889 g,

2.23 mmol) in ether (30 ml) at ~10 ЊC under an atmosphere of

nitrogen. After 30 min, the mixture was cooled to Ϫ78 ЊC and

2-naphthaldehyde (0.348 g, 2.23 mmol) in ether (10 ml) was

974

J. Chem. Soc., Perkin Trans. 1, 2001, 955–977

View Article Online

(CH), 129.7 (CH), 128.7 (CH), 127.6 (CH), 126.8 (C), 126.1

(CH), 122.2 (CH), 75.5 (CHOH), 40.7 (CH₂), 33.6 (CH), 18.7

(Me), 18.1 (Me).

(99%) according to general procedure 7 (reﬂux for 4 d) (spectro-

scopic data below).

(b) According to the general procedure 7 the title compound

56b was obtained as a yellow oil (99%) from 3-methyl-1-

(quinolin-2-yl)butan-2-ol 57b after 17 h (lit.,¹⁸⁰bp not given);

ν_max(neat)/cm^Ϫ12960, 2910 (C–H), 1620, 1600, 1500 (Ar), 1465,

1370, 815, 745 (ArH); δ_H(300 MHz; CDCl₃) 8.10 (2 H, m,

4-ArH), 7.79 (1 H, dd, J 8.0, 1.4, 5-ArH), 7.70 (1 H, ddd, J 8.5,

7.1, 1.4, 7-ArH), 7.50 (1 H, ddd, J 8.0, 7.1, 1.4, 6-ArH), 7.33

(1 H, d, J 8.2, 3-ArH), 3.00 (2 H, m, ArCH₂), 1.69 (3 H, m,

CH₂CHMe₂), 0.99 (6 H, d, J 6.6, Me₂) (cf. lit.¹⁷⁹); δ_C(100 MHz;

CDCl₃) 163.4 (C), 147.9 (C), 136.2 (CH), 129.3 (CH), 128.8

(CH), 127.5 (CH), 126.7 (C), 125.6 (CH), 121.4 (CH), 39.3

(CH₂), 37.5 (CH₂), 28.0 (CH), 22.6 (Me).

Reduction of conjugated alkenes

Benzylacetone 49. According to general procedure 7, the title

compound 49 was obtained as a colourless oil (100%) from

benzylideneacetone 48; δ_H(300 MHz; CDCl₃) 7.29 (2 H, m,

ArH), 7.20 (3 H, m, ArH), 2.89 (2 H, m, PhCH₂), 2.77 (2 H, m,

COCH₂), 2.16 (3 H, s, Me) (cf. lit.¹⁷⁶).

1-Phenylbutan-1-one 51. According to general procedure 7,

the title compound 51 was obtained as a colourless oil (100%)

from 1-phenylbut-2-en-1-one 50; δ_H(300 MHz; CDCl₃) 7.97

(2 H, m, ArH), 7.55 (1 H, m, ArH), 7.46 (2 H, m, ArH), 2.96

(2 H, t, J 7.3, COCH₂), 1.78 (2 H, sextet, J 7.3, COCH₂CH₂),

1.01 (3 H, t, J 7.3, Me) (cf. lit.¹⁷⁷).

2-(Hept-6-enyl)quinoline 56c. According to general procedure

7 the title compound 56c was obtained as a colourless oil (98%)

from cis-1-(quinolin-2-yl)hepta-1,6-diene 55c (Found: MH^ϩ,

226.1595. C₁₆H₂₀N requires 226.1596); ν_max(neat)/cm^Ϫ13050

Reaction of chalcone 52 with indium. (a) Indium powder

(1.00 g) was added to a stirred solution of chalcone 52 (0.345 g,

1.66 mmol) in ethanol (10 ml) and saturated ammonium

chloride solution (3 ml). The mixture was heated under reﬂux.

After 24 h the cooled reaction mixture was washed through

Celite^with dichloromethane (30 ml) and water (50 ml). The

layers were separated and the aqueous layer extracted with

further portions of dichloromethane (2 × 10 ml). Combined

organic layers were dried (MgSO₄) and concentrated in vacuo.

The crude material was passed down a ﬂash chromatography

column (silica, dichloromethane–light petroleum 2 : 1) to give

two products: 1,3-diphenylpropan-1-one 53 (0.053 g, 15%) and

(1S,2R,3S,4R/1R,2S,3R,4S)-2-benzoyl-1,3,4-triphenylcyclo-

pentan-1-ol 54 (0.215 g, 62%).

(b) The same two products were obtained from chalcone 52

according to general procedure 7 (2 equivalents of acetic acid):

1,3-diphenylpropan-1-one 53 (23%) and (1S,2R,3S,4R/1R,2S,

3R,4S)-2-benzoyl-1,3,4-triphenylcyclopentan-1-ol 54 (59%).

1,3-Diphenylpropan-1-one 53. mp 70–71 ЊC (lit.,¹⁷⁸mp 71–

72 ЊC); δ_H(300 MHz; CDCl₃) 8.03–7.24 (10 H, m, 2 × Ph), 3.35

(2 H, m, COCH₂), 3.13 (2 H, m, PhCH₂).

(᎐CH), 3010 (ArH), 2920, 2850 (CH ), 1715, 1620 (C᎐C), 1595,

᎐

2

1500 (Ar), 1430 (CH ), 910 (CH᎐CH ), 825, 755 (ArH); δ (300

᎐

2

H

MHz; CDCl₃) 8.08 (1 H, d, J 8.4, 4-ArH), 8.07 (1 H, dd, J 8.3,

1.0, 8-ArH), 7.78 (1 H, dd, J 8.1, 1.4, 5-ArH), 7.69 (1 H, ddd,

J 8.3, 7.0, 1.4, 7-ArH), 7.49 (1 H, ddd, J 8.1, 7.0, 1.0, 6-ArH),

7.31 (1 H, d, J 8.4, 3-ArH), 5.80 (1 H, ddt, J 17.1, 10.1, 6.6,

CH᎐CH ), 4.99 (1 H, ddt, J 17.1, 2.6, 1.6, trans-CH᎐CHH),

᎐

2

4.93 (1 H, ddt, J 10.1, 2.6, 1.6, cis-CH᎐CHH), 2.99 (2 H, m,

᎐

ArCH ), 2.07 (2 H, m, CH CH᎐CH ), 1.90–1.42 (6 H, m,

᎐

2

CH₂CH₂CH₂); δ_C(100 MHz; CDCl₃) 153.0 (C), 147.6 (C), 139.0

(᎐CH), 136.5 (CH), 129.5 (CH), 128.5 (CH), 127.5 (CH), 126.7

᎐

(C), 125.7 (CH), 121.4 (CH), 114.3 (᎐CH ), 39.0 (CH ), 33.6

᎐

2

(CH₂), 29.9 (CH₂), 29.0 (CH₂), 28.8 (CH₂); m/z (CI) 226 (MH^ϩ,

100%), 143 (6), 52 (28).

Acknowledgements

We thank the EPSRC for funding, and the EPSRC Mass

Spectrometry Service at Swansea for mass spectra. We also

thank Christopher Davis (University of Exeter) for carrying

out the reduction of nitro compound 30e, and Dr Alison

Franklin for helpful discussions.

(1S,2R,3S,4R/1R,2S,3R,4S)-2-Benzoyl-1,3,4-triphenylcyclo-

pentan-1-ol 54. mp 196–198 ЊC (from ether–light petroleum)

(lit.,⁸⁶mp 195 ЊC); ν_max(KBr)/cm^Ϫ13430 (OH), 3060, 3020,

2970, 2945, 2920, 1640 (C᎐O), 1590, 1490, 1380, 1050 (C–O),

᎐

References

750, 700 (ArH); δ_H(400 MHz; CDCl₃) 7.68–7.09 (20 H, m,

4 × Ph), 5.20 (1 H, d, J 1.3, OH), 4.54 (1 H, d, J 12.0,

CHCOPh), 4.11 (1 H, dd, J 12.0, 10.2, CHCHCOPh), 3.79

(1 H, ddd, J 11.4, 10.2, 6.1, CH₂CHPh), 3.01 (1 H, ddd, J 14.6,

11.4, 1.3, CHHCHPh), 2.59 (1 H, dd, J 14.6, 6.1, CHHCHPh)

(cf. lit.⁸⁴); δ_C(100 MHz; CDCl₃) 204.9 (CO), 145.3 (C), 144.0

(C), 139.9 (C), 137.6 (C), 133.2 (CH), 128.43 (CH), 128.37

(CH), 128.3 (CH), 128.13 (CH), 128.07 (CH), 127.9 (CH), 127.6

(CH), 127.0 (CH), 126.9 (CH), 126.3 (CH), 124.9 (CH), 84.3

(C), 63.6 (CH), 59.5 (CH), 51.4 (CH₂and CH).

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Indium metal as a reducing agent in organic synthesis

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