N-H insertion reactions of rhodium carbenoids. Part 3. The development of a modified Bischler indole synthesis and a new protecting-group strategy for indoles

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N–H Insertion reactions of rhodium carbenoids. Part 3.¹

The development of a modiﬁed Bischler indole synthesis

and a new protecting-group strategy for indoles

1

Katherine E. Bashford,^aAnthony L. Cooper,^bPeter D. Kane,^bChristopher J. Moody,*^a

Sendogagounder Muthusamy†^aand Elizabeth Swann^a

^aSchool of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD.

E-mail: c.j.moody@ex.ac.uk

^bTripos Receptor Research Ltd, Bude-Stratton Business Park, Bude, Cornwall, UK EX23 8LY

Received (in Cambridge, UK) 15th March 2002, Accepted 13th May 2002

First published as an Advance Article on the web 18th June 2002

A modiﬁed version of the Bischler indole synthesis has been developed in which the key step is the N–H insertion

reaction of rhodium carbene intermediates derived from α-diazo-β-ketoesters with anilines. Thus N-methylanilines

1 react with diazoketoesters 2 in the presence of dirhodium() acetate to give (N-arylamino)ketones 3, cyclisation of

which using boron triﬂuoride–ethyl acetate or acidic ion exchange resin gives the indoles 4. In order to extend this

method to the synthesis of N-unsubstituted indoles, a new protecting group strategy for indoles was developed. In

this, anilines are reacted with α,β-unsaturated-esters or -sulfones to give the conjugate addition products 6 and 9,

cyclisation of which gives indoles 8 and 11. The N-(2-ethoxycarbonylethyl)- and -(2-sulfonylethyl)- protecting

groups are readily removed from indoles 8 and 11 by treatment with base.

since they do not require the presence of an additional

Introduction

ortho-substituent such as an alkyl group (Madelung reaction),

The wide-ranging biological activity associated with many

a halide (various transition-metal catalysed reactions such

indole derivatives, both naturally occurring and synthetic,

as the Larock method), or an acyl group.^2–4Although the

ensures that the synthesis of this important ring system con-

tinues to attract the attention of synthetic organic chemists

Among the many routes to indoles, those which start from

a simple aniline derivative are probably the most useful,

Fischer indole synthesis could be considered as starting

from an aniline, the need for prior conversion into the aryl-

hydrazine (there are relatively few arylhydrazines that are

commercially available), or into the hydrazone (via the

2–4

Japp–Klingemann method) renders it less attractive than

routes which start directly from anilines, such as the Bischler

indole synthesis (Scheme 1a). The Bischler reaction, discovered

† Permanent address: Central Salt and Marine Chemicals Research

Institute, G. B. Marg, Bhavnager 364 002, India.

Scheme 1

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J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

This journal is © The Royal Society of Chemistry 2002

DOI: 10.1039/b202666j

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Scheme 2 [Diazo compound 2; a, R²= R³= Me; b, R²= Me, R³= Et; c, R²= Et, R³= Ph.]

Table 1 Reaction of anilines 1 with diazoketoesters 2 in the presence of Rh₂(OAc)₄and cyclisation of the resulting (N-arylamino)ketones 3 to

indoles 4

Indole 4

Yield (%)

BF₃–Et₂

Indole 4

X

Yield (%)

2, 3

X

R¹

R²

R³

Yield (%)

4

Amberlyst^®15

a

b

c

H

2-Br

2-MeO

3-MeO

Me

82

78

60

84

H

7-Br

7-MeO

4-MeO

6-MeO

a

81

52

56

22

55

69

—

13

—

b

c

d

d¹

d²

e

f

g

h

i

j

k

4-Cl

Me

Bn

Me

Et

Me

Et

Ph

Me

77

75

76

70

89

75

73

5-Cl

e

f

g

h

i

j

k

87

80

82

50

54

31

23

62

0^a

88

49

42

—

4-NO₂

4-MeO

2,4-(MeO)₂

H

5-NO₂

5-MeO

5,7-(MeO)₂

H

^aStarting material recovered unchanged.

100 years ago,^5,6involves the reaction of anilines with

α-haloketones followed by acid catalysed cyclisation of the

resulting α-(N-arylamino)ketones. Subsequent modiﬁcation by

Nordlander and by Sundberg and their co-workers allowed

the formation of 2,3-unsubstituted indoles by using the corre-

sponding acetals (Scheme 1b).^7,8Examples of more recent

routes which also start from anilines are the Gassman

method (Scheme 1c),⁹the Sugasawa method (Scheme 1d),¹⁰the

Feldman method (Scheme 1e),¹¹and ruthenium catalysed

routes from ethanolamines (Scheme 1f ).¹²

We now report the details of a modiﬁcation of the Bischler

indole synthesis in which the key step is the N–H insertion

reaction of anilines with rhodium carbenes derived from

α-diazocarbonyl compounds,^13,14during which we have also

developed a new protecting group strategy for indoles.¹⁵

Table 1). For the most part, the ketones 3 were characterisable

solids that existed as keto–enol mixtures in solution; on

occasion, however, they were unstable oils (e.g. 3j) that

could not be completely characterised, and were therefore used

without further puriﬁcation.

A number of acids and Lewis acids have been used to eﬀect

the cyclisation of α-(N-arylamino)ketones or -acetals in the

classical Bischler reaction or in its Nordlander modiﬁcation.

Initially we used boron triﬂuoride–diethyl ether in toluene, but

in some cases the yields of product were unsatisfactory, with the

nitro-derivative 3f failing to cyclise at all under these conditions.

Therefore an alternative method using acidic ion-exchange

resin (Amberlyst^®15) was adopted.³²Thus the (N-arylamino)-

ketones 3 were heated with the ion-exchange resin in toluene to

give the corresponding N-methyl indoles 4a–j in a range of

yields (Scheme 2, Table 1). In the case of the m-substituted

aniline derivative 3d, a mixture of indoles was formed on cyclis-

ation with the 6-methoxyindole predominating (2.5 : 1). The

overall method also works for N-benzylanilines, with 1k under-

going N–H insertion (73%) followed by cyclisation to the

N-benzylindole 4k which is obtained in low yield (Table 1).

However the sequence fails when N-acetyl- or N-tosyl-anilines

are used as starting materials; 4-methoxyacetylanilide failed to

undergo the N–H insertion reaction, and N-tosyl-4-anisidine

gave the insertion product in only 27% yield.

One feature of the Bischler indole synthesis is the propensity

for rearrangements to occur.^2,3Thus α-anilinoacetophenones,

ArNRCH₂COPh, often give 2-phenylindoles upon cyclisation

in addition to, or instead of the expected 3-phenylindoles. In

order to conﬁrm that no similar rearrangements were occurring

in the present work, one indole-3-ester 5 was prepared

independently for comparison with its regioisomer 4g. Thus the

known ethyl 5-hydroxy-2-methylindole-3-carboxylate, prepared

by the Nenitzescu reaction of ethyl 3-aminobut-2-enoate with

1,4-benzoquinone, was hydrolysed to the corresponding acid,

and trimethylated to give 5 (Scheme 3) which is clearly spectro-

scopically distinguishable from regioisomer 4g.

Results and discussion

The reaction of anilines with diazocarbonyl compounds to give

products derived from an N–H insertion reaction is a known

reaction of carbene and metal carbene intermediates.¹⁶

Although the reaction of aniline with ethyl diazoacetate was

ﬁrst carried out by Curtius under thermal conditions over 100

years ago,¹⁷nowadays the reaction is usually carried out in the

presence of a metal catalyst, following Yates’ ﬁrst report of the

copper–bronze catalysed decomposition of diazoacetophenone

in the presence of aniline to give α-anilinoacetophenone in

33% yield.¹⁸Further reactions of anilines with diazocarbonyl

compounds catalysed by a range of transition-metal com-

plexes, including copper,^19–22rhodium,^1,23–29rhenium,³⁰and

ruthenium,³¹have been reported. The diazocarbonyl com-

pounds used in the present study were α-diazo-β-ketoesters 2,

readily prepared by a diazo-transfer reaction to the correspond-

ing β-ketoester. The initial substrates investigated were simple

N-methylanilines 1 (R¹= Me) which were reacted with the

α-diazo-β-ketoesters 2 in the presence of dirhodium() tetra-

acetate (2 mol%) in boiling chloroform or toluene. This resulted

in N–H insertion of the intermediate metal carbenes, and gave

the α-(N-arylamino)-β-ketoesters 3a–j in good yield (Scheme 2,

Although many synthetic routes to indoles lead directly to

N-unsubstituted derivatives, many also lead to N-substituted or

J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

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Scheme 3

-protected indoles, and whereas protecting group strategies

for basic nitrogen atoms are well worked out,^33,34the choice of

suitable protecting groups for non-basic heterocyclic NH

groups is more problematic. Electron-withdrawing carbonyl or

sulfonyl based protecting groups, although easy to remove,

often markedly aﬀect the reactions leading to, and the reactivity

of, the heterocyclic ring. Therefore one often has to resort to

alkyl based protecting groups which are usually more diﬃcult

to remove.³⁵

The modiﬁed Bischler indole synthesis described above

suﬀers from this exact problem, in that whereas N-methyl-

anilines were readily converted into N-methylindoles, indoles

with readily removable protecting groups (e.g. acetyl or tosyl)

could not be obtained. Although the reaction could be

extended to the synthesis of N-benzylindoles, the benzyl

protecting group can be diﬃcult to remove, and overall we

considered the N–H insertion–cyclisation sequence unsatis-

factory for the synthesis of N-unsubstituted indoles. Therefore,

in order to extend the methodology, we required an alkyl

protecting group that functioned as a simple N-alkylaniline

but was also readily removable following the conversion of the

aniline into the corresponding indole. Since indole is a much

better leaving group than aniline in a 1,2-elimination reaction,

as reﬂected in the diﬀerence of ca. 15 in their pK_avalues,

it seemed that a protecting group that could be removed in

a base-mediated elimination would be suitable. Therefore a

retro-Michael strategy involving a CH₂CH₂Z group (Z = CN,

CO₂R or SO₂R) was considered (Scheme 4).

Scheme 4

Similarly the 2-sulfonylethyl group has been used as a protect-

ing group for the NH group of amides, carbamates and β-

lactams,⁴¹tetrazoles,⁴⁰imidazoles,³⁶and pyrroles.^42,43Therefore

we investigated the use of such 2-substituted ethyl protecting

groups in our modiﬁed Bischler indole synthesis.

The 2-ethoxycarbonylethyl group was investigated ﬁrst. The

starting N-substituted anilines 6a–d were readily prepared by

conjugate addition of the aniline to ethyl acrylate in ethanol.⁴⁴

The amines 6e and 6f were similarly prepared by addition to

benzyl acrylate (Scheme 5, Table 2), the reactions taking some

three days to go to completion. Reaction of the anilines 6a–d

with methyl 2-diazo-3-oxobutanoate 2a in chloroform in the

presence of dirhodium() tetraacetate resulted in the formation

of the N–H insertion products 7; although these were separated

from catalyst and other polar impurities by chromatography,

no attempt was made to purify the amines 7 completely for

characterisation. Rather, they were cyclised directly to the

desired indoles 8 by heating in toluene with acidic ion-exchange

resin (Scheme 5, Table 2). With one exception, the indoles

8 were formed in good yield, although when the 2-benzyloxy-

carbonylethyl anilines 6e and 6f were subjected to the same

reaction sequence, the corresponding indoles were not

isolated.

Although there are reports of the base mediated removal

of the 2-cyanoethyl group from heteroaromatic rings such as

imidazoles³⁶and purines,³⁷we concentrated on the 2-ethoxy-

carbonyl- and 2-arylsulfonylethyl groups both of which have

found some use as protecting groups although not, as far as we

are aware, for indoles. Thus the 2-ethoxycarbonylethyl group

can be removed from 2-aminoprop-2-enoate esters by treatment

with sodium in xylene,³⁸from pyrroles by reaction with sodium

methoxide,³⁹and from tetrazoles by reaction with DBN.⁴⁰

The reaction was extended to the conversion of N-(2-phenyl-

sulfonylethyl)anilines 9a–f into indoles 11. Thus conjugate

addition of anilines to phenyl vinyl sulfone gave the anilines

9a–g in a range of yields (Scheme 6, Table 3), the reaction again

taking three days. Treatment with methyl 2-diazo-3-oxo-

butanoate 2a or -pentanoate 2b in boiling chloroform in the

presence of dirhodium() tetraacetate resulted in the formation

Scheme 5

Table 2 Conjugate addition of anilines to acrylates, reaction of the N-(2-ethoxycarbonylethyl)anilines 6 with diazoketoesters 2 in the presence of

Rh₂(OAc)₄and cyclisation of the resulting (N-arylamino)ketones 3 to indoles 8

6

7

Indole 8

X

Indole 8

Yield (%)

X

R

Yield (%)

Yield (%)^a

a

b

c

d

e

f

4-Me

Et

Bn

41

49

22

88

84

76

74

63

55

5-Me

76

60

22

64

4-MeO

4-MeO₂C

4-^tBu

4-Me

4-MeO

5-MeO

5-MeO₂C

5-^tBu

^aCompounds not characterised; yields refer to partially puriﬁed material.

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J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

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Scheme 6

Table 3 Conjugate addition of anilines to vinyl sulfones, reaction of the N-(2-sulfonylethyl)anilines 9 with diazoketoesters 2 in the presence of

Rh₂(OAc)₄and cyclisation of the resulting (N-arylamino)ketones 10 to indoles 11

9

10

Indole 11

X

Indole 11

Yield (%)

9

X

R

Yield (%)

R³

10

Yield (%)^a

11

a

b

c

d

e

f

4-Me

4-MeO

2-Me

2-MeO

4-Br

Ph

99

—

68

74

17

75

Me

Et

Me

a

b

c

d

e

f

62

63

78

73

90

36

63

a

b

c

5-Me

5-MeO

7-Me

7-MeO

5-Br

4-MeO (6%)

6-MeO (24%)

5-Me

5-MeO

7-Me

71

66

49

51

48

79

30

—

62

37

78

d

e

f

g

3-MeO

g

g¹

g²

h

i

h

i

j

k

4-Me

4-MeO

2-Me

Bn

87,74^b

89

Me

h

i

j

65

98

60

73,67^b

50^b

j

2-NO₂

^aCompounds not characterised; yields refer to partially puriﬁed material. ^bReaction carried out in the presence of DBU – see Experimental Section.

Scheme 7

Table 4 Base mediated deprotection of 1-(2-ethoxycarbonylethyl)- and 1-(2-sulfonylethyl)-indoles 8 and 11

8,11

Z

X

R³

12

Conditions

Yield (%)

8a

CO₂Et

SO₂Ph

5-Me

Me

12a

t-BuOK, DMF

DBN, Et₃N, DMF

DBU, Et₃N, DMF

t-BuOK, DMF

DBN, toluene

60

87

59

42

70^a

77

91

27

55

34

58^b

11a

11h

8b

11i

11b

11e

11g²

11j

SO₂Bn

CO₂Et

SO₂Bn

SO₂Ph

SO₂Bn

5-Me

Me

Et

Me

12a

12b

12c

12d

12e

12f

5-MeO

5-Me

7-MeO

6-MeO

7-Me

t-BuOK, DMF

^aCyclopent[a]indole 13a also formed (9%). ^bCyclopent[a]indole 13b also formed (11%).

of the N–H insertion products 10a–g in modest to good yields

(Table 3). Again the intermediate N-arylamino ketones 10 were

not completely puriﬁed, but were cyclised by treatment with

acidic ion-exchange resin to the indoles 11a–g (Scheme 6,

Table 3). As in the case of the meta-substituted N-methylaniline

derivative 3d, cyclisation of 10g produced a mixture of 4- and

6-substituted indoles with the 6-methoxy isomer predominating.

With a view to the development of a solid phase variant of

our modiﬁed Bischler indole synthesis (q.v.), the reaction was

extended to 1-(2-benzylsulfonylethyl)indoles. Thus benzyl vinyl

sulfone, prepared by a slight modiﬁcation of the literature

procedure,⁴⁵underwent conjugate addition of 4-toluidine in

boiling ethanol to give the N-substituted aniline 9h in good

yield (Scheme 6, Table 3). However, the reaction time was still

inconveniently long, and therefore the conjugate addition was

repeated in the presence of various additives [KOH, DBU,

Yb(OTF)₃]. Of these, the use of DBU in THF proved success-

ful, and reduced the reaction time to 13 hours. The addition

of other anilines to benzyl vinyl sulfone gave the expected

products 9i–k (Table 3). Conversion into the corresponding

N-(2-benzylsulfonylethyl) indoles 11h–j proved uneventful

(Table 3), although the 2-nitro compound 9k failed to give the

required indole.

With a range of appropriately N-substituted indoles 8 and 11

available, their base-mediated deprotection was investigated

(cf. Scheme 4). The use of potassium tert-butoxide in DMF

proved the most satisfactory, although amine bases could

also be used (Scheme 7, Table 4). Hence methyl 3,5-dimethyl-

indole-2-carboxylate 12a was obtained by deprotection of the

N-(2-ethoxycarbonylethyl)-, (2-phenylsulfonylethyl)-, and (2-

benzylsulfonylethyl)indoles 8a, 11a and 11h. Likewise, indoles

12b–12f were obtained by base-mediated deprotection of the

corresponding indoles 8 and 11 (Scheme 7, Table 4). During

the deprotection of indoles 11h and 11j using potassium tert-

J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

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butoxide in DMF, byproducts (ca. 10%) were also formed.

These were identiﬁed as the pyrrolo[1,2-a]indoles 13, formed by

intramolecular acylation of the sulfone stabilised anion

(Scheme 8). Interestingly, when the reaction was repeated in

10). Subsequent treatment with diazo compound 2a in the

presence of dirhodium() tetraacetate resulted in a resin that

showed the absence of an NH absorption in its IR spectrum,

but which did contain a carbonyl absorption at 1740 cm^Ϫ1, con-

sistent with the desired structure 17. Unfortunately, cyclisation

with boron triﬂuoride–diethyl ether, followed by base-mediated

cleavage from the resin gave a solution which clearly did not

contain the expected indole 12a (Scheme 10). Further studies

are in progress.

Experimental

Scheme 8 [11h, 13a, R⁵= Me, R⁷= H; 11j, 13b, R⁵= H, R⁷= Me].

General experimental details

Commercially available reagents were used throughout without

further puriﬁcation unless otherwise stated; solvents were dried

by standard procedures. Light petroleum refers to the fraction

with bp 40–60 ЊC and ether refers to diethyl ether. Reactions

were routinely carried out under a nitrogen atmosphere.

Analytical thin layer chromatography was carried out using

aluminium-backed plates coated with Merck Kieselgel 60

GF₂₅₄. Plates were visualised under UV light (at 254 and/or

360 nm). Flash chromatography was carried out using Merck

Kieselgel 60 H silica or Matrex silica 60. Fully characterised

compounds were chromatographically homogeneous. IR

spectra were recorded in the range 4000–600 cm^Ϫ1using a

Nicolet Magna FT-550 spectrometer. ¹H and ¹³C NMR spectra

were recorded using Bruker 250, 300 and 400 MHz instruments

(¹H frequencies, corresponding ¹³C frequencies are 63, 75 and

100 MHz); J values were recorded in Hz. In the ¹³C NMR

spectra, signals corresponding to CH, CH₂or CH₃groups are

noted; all others are C. High and low-resolution mass spectra

were recorded on a Kratos HV3 instrument, or at the EPSRC

Mass Spectrometry Service (Swansea).

THF as solvent, the pyrrolo[1,2-a]indole 13 was the sole

product.

We also brieﬂy investigated the use of the 2-phenylsulfonyl-

ethyl protecting group on preformed indoles. The group was

readily introduced by reaction of the indole with 2-chloroethyl

phenyl sulfone in DMF using sodium hydride as base, and

removed using potassium tert-butoxide also in DMF. Two

examples are shown in Scheme 9 and Table 5.

Scheme 9

Table 5 Protection and deprotection of indoles using the 2-phenyl-

sulfonylethyl protecting group

Protection

Yield (%)

Deprotection

Yield (%)

X

R²

Preparation of ꢀ-(N-arylamino)-ꢁ-ketoesters 3 by N–H insertion

reactions

a

b

MeO

H

CO₂Et

73

67

91

100

General method. A mixture of the substituted aniline 1

(2 mmol), diazo compound 2 (2.6 mmol) and dirhodium()

acetate (0.04 mmol) in toluene or chloroform (25 ml) was

heated under reﬂux for 1 h. The solvent was removed in vacuo

and the residue puriﬁed by column chromatography to give the

α-(N-arylamino)-β-ketoesters 3.

Finally, given the current interest in solid-phase organic

synthesis, we attempted to adapt our modiﬁed Bischler indole

synthesis for use on resin. A number of other indole syntheses

have recently been adapted for resin, including the Fischer,⁴⁶

Nenitzescu,⁴⁷various palladium-mediated syntheses,^48–52includ-

ing one very recent example involving a rhodium carbene N–H

insertion reaction.²⁹Our original intention had been to use the

REM-resin, but in view of the failure to isolate any indoles

from the benzyl acrylate derived anilines 6e and 6f, we turned

our attention to vinylsulfonylmethyl polystyrene resin. Vinyl

sulfone resins were developed as traceless linkers for amine

synthesis,^53,54the ﬁrst step being conjugate addition of an

amine, and therefore seemed ideal for our purpose. Therefore

commercially available vinylsulfonylmethyl polystyrene resin

was treated with 4-toluidine in THF in the presence of DBU as

described above for benzyl vinyl sulfone. The appearance of a

signal at 3390 cm^Ϫ1in the IR spectrum of the resin suggested

the formation of the desired functionalised resin 16 (Scheme

Methyl 2-(N-methyl-N-phenylamino)-3-oxobutanoate 3a.

Reaction solvent toluene, puriﬁed by column chromatography

(light petroleum : ether, 9 : 1 elution), recrystallised (light

petroleum) to give the title compound (82%) as a colourless

crystalline solid, mp 52–53 ЊC (Found: C, 65.1; H, 6.7; N, 6.2.

C₁₂H₁₅NO₃requires C, 65.1; H, 6.8; N, 6.3%); ν_max(KBr)/cm^Ϫ1

2953, 2884, 1655, 1600, 1501; δ_H(250 MHz; CDCl₃) 12.26 (1H,

s, enol), 7.21 (2H, m, ArH), 6.73 (1H, t, J 7.7, ArH), 6.61 (2H,

d, J 8.2, ArH), 3.67 (3H, s, OMe), 3.03 (3H, s, NMe), 1.95 (3H,

s, Me); δ_C(100 MHz; CDCl₃) 175.9, 172.5, 148.8, 129.6 (CH),

116.7 (CH), 111.5 (CH), 110.6, 51.6 (Me), 38.7 (Me), 17.4 (Me);

m/z (EI) 221 (M^ϩ, 10%), 193 (15), 134 (100), 118 (51), 106 (52),

77 (65).

Scheme 10

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J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

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Methyl 2-[N-(2-bromophenyl)-N-methylamino]-3-oxobutano-

ate 3b. Reaction solvent toluene, puriﬁed by column chrom-

atography (dichloromethane : light petroleum, 1 : 1 elution) to

yield the title compound (78%) as a colourless oil (Found: MH^ϩ,

300.0235. C₁₂H₁₄⁷⁹BrNO₃ϩ H requires 300.0236); ν_max(KBr)/

cm^Ϫ13059, 3013, 2960, 2809, 1756, 1729, 1657, 1618, 1591; δ_H

(300 MHz; CDCl₃) (keto/enol) 9.85 (1H, s, enol), 7.58–6.69

(4H, m, ArH), 4.84 (1H, s, NCH), 3.75/3.74 (3H, 2 × s,

2 × OMe), 3.07/2.98 (3H, 2 × s, 2 × NMe), 2.41/1.92 (3H, 2 × s,

2 × Me); δ_C(100 MHz; CDCl₃) (keto/enol) 202.9, 174.2, 172.4,

169.0, 148.9, 148.4, 134.8 (CH), 133.9 (CH), 128.3 (CH),

127.8 (CH), 125.4 (CH), 124.2 (CH), 121.5 (CH), 119.8 (CH),

119.6, 113.0, 112.8, 110.7 (CH), 51.9 (Me), 51.6 (Me), 41.6

(Me), 37.4 (Me), 28.4 (Me), 18.2 (Me); m/z (CI) 302/300 (M^ϩ,

19%) 291/289 (42), 166 (91), 150 (100).

(1H, s, enol), 6.56 (4H, AAЈXXЈ, J 9.3, ArH), 3.72 (3H, s,

OMe), 3.15 (3H, s, NMe), 1.95 (3H, s, Me); δ_C(100 MHz;

CDCl₃) 175.9, 171.2, 154.0, 138.5, 126.1 (CH), 111.1 (CH),

109.9, 52.2 (Me), 39.6 (Me), 17.5 (Me); m/z (EI) 266 (M^ϩ, 34%),

206 (15), 163 (100).

Methyl 2-[N-(4-methoxyphenyl)-N-methylamino]-3-oxobut-

anoate 3g. Reaction solvent toluene, puriﬁed by column

chromatography (dichloromethane elution), recrystallised

(light petroleum) to yield the title compound (76%) as an oﬀ

white crystalline solid, mp 85–86 ЊC (Found: C, 62.2; H, 7.1; N,

5.5. C₁₃H₁₇NO₄requires C, 62.1; H, 6.8; N, 5.6%); ν_max(KBr)/

cm^Ϫ13006, 2904, 2835, 1655, 1600, 1511; δ_H(250 MHz; CDCl₃)

12.23 (1H, s, enol), 6.80 and 6.55 (4H, AAЈXXЈ, J 9.1,

ArH), 3.75 (3H, s, OMe), 3.66 (3H, s, OMe), 3.00 (3H, s, NMe),

1.97 (3H, Me); δ_C(100 MHz; CDCl₃) 176.3, 173.1, 152.0, 143.8,

115.2 (CH), 113.0 (CH), 111.5, 56.1 (Me), 52.0 (Me), 39.4 (Me),

17.8 (Me); m/z (EI) 251 (M^ϩ, 38%), 219 (19), 208 (14),

148 (100).

Methyl 2-[N-(2-methoxyphenyl)-N-methylamino]-3-oxobut-

anoate 3c. Reaction solvent toluene, puriﬁed by column

chromatography (dichloromethane : light petroleum, 1 : 1

elution) to yield the title compound (60%) as an oﬀ white

crystalline solid, mp 60–62 ЊC (Found: C, 61.5; H, 6.9; N, 5.5.

C₁₃H₁₇NO₄ؒ0.2H₂O requires C, 61.2; H, 6.9; N, 5.5%) (Found:

M^ϩ, 251.1158. C₁₃H₁₇NO₄requires 251.1157); ν_max(KBr)/cm^Ϫ1

3063, 3002, 2961, 2874, 1755, 1728, 1647, 1593; δ_H(300 MHz;

CDCl₃) (keto/enol) 9.91 (1H, s, enol), 7.07–6.77 (4H, m, ArH),

5.08 (1H, s, NCH), 3.85/3.77/3.74/3.70 (6H, 4 × s, 4 × OMe),

3.03/2.96 (3H, 2 × s, 2 × NMe), 2.33/1.94 (3H, 2 × s, 2 × Me);

δ_C(75.5 MHz; CDCl₃) (keto/enol) 173.3, 173.0, 169.4, 151.7,

150.7, 140.0, 139.6, 129.8, 122.9 (CH), 121.2 (CH), 121.1 (CH),

120.1 (CH), 120.0 (CH), 117.2 (CH), 113.7, 112.7 (CH), 111.6

(CH), 73.2 (CH), 56.1 (Me), 55.5 (Me), 51.8 (Me), 51.5 (Me),

40.9 (Me), 36.3 (Me), 28.2 (Me), 17.7 (Me); m/z (EI) 251 (M^ϩ,

8%), 180 (12), 138 (100), 134 (38), 124 (40).

Methyl 2-[N-(4-methoxyphenyl)-N-methylamino]-3-oxopent-

anoate 3h. Reaction solvent chloroform, puriﬁed by column

chromatography (dichloromethane elution), recrystallised

(light petroleum–ether) to yield the title compound (70%) as a

pale yellow solid, mp 74–75 ЊC (Found: C, 63.5; H, 7.0; N, 5.1.

C₁₄H₁₉NO₄requires C, 63.4; H, 7.2; N, 5.3%); ν_max(KBr)/cm^Ϫ1

2994, 1648, 1600, 1512; δ_H(250 MHz; CDCl₃) 12.33 (1H, s,

enol), 6.79 and 6.55 (4H, AAЈXXЈ, J 9.0, ArH), 3.75 (3H, s,

OMe), 3.66 (3H, s, OMe), 3.00 (3H, s, NMe), 2.32 (2H, q, J 7.6,

CH₂CH₃), 1.10 (3H, t, J 7.6, CH₂CH₃); δ_C(100 MHz; CDCl₃)

180.3, 173.3, 152.0, 144.1, 115.1 (CH), 113.1 (CH), 110.61, 56.1

(Me), 52.7 (Me), 39.9 (Me), 24.6 (CH₂), 10.9 (Me); m/z (EI) 265

(M^ϩ, 29%), 208 (23), 162 (14), 148 (71), 57 (100).

Methyl 2-[N-(3-methoxyphenyl)-N-methylamino]-3-oxobut-

anoate 3d. Reaction solvent toluene, puriﬁed by column

chromatography (dichloromethane : light petroleum, 1 : 1

elution), recrystallised (dichloromethane–light petroleum) to

yield the title compound (84%) as a colourless crystalline solid,

mp 39–40 ЊC (Found: C, 61.9; H, 6.8; N, 5.5. C₁₃H₁₇NO₄

requires C, 62.1; H, 6.8; N, 5.6%); ν_max(CH₂Cl₂)/cm^Ϫ13006,

2954, 2908, 2833, 1669, 1617, 1496; δ_H(300 MHz; CDCl₃) 9.75

(1H, s, enol), 7.12 (1H, t, J 8.2, ArH), 6.31 (1H, dd, J 8.2, 2.3,

ArH), 6.24 (1H, dd, J 8.2, 2.3, ArH), 6.18 (1H, t, J 2.3, ArH),

3.78 (3H, s, OMe), 3.69 (3H, s, OMe), 3.03 (3H, s, NMe), 1.96

(3H, s, Me); δ_C(75.5 MHz; CDCl₃) 175.9, 172.4, 160.8, 150.4,

129.8 (CH), 110.6, 105.1 (CH), 101.7 (CH), 98.6 (CH), 55.1

(Me), 51.8 (Me), 38.8 (Me), 17.4 (Me); m/z (EI) 251 (M^ϩ, 9%),

223 (38), 176 (19), 164 (100), 149 (96).

Ethyl

2-[N-(4-methoxyphenyl)-N-methylamino]-3-oxo-3-

phenylpropanoate 3i. Reaction solvent chloroform, puriﬁed by

column chromatography (dichloromethane elution) to yield the

title compound (89%) as a yellow oil (Found: M^ϩ, 327.1471.

C₁₉H₂₁NO₄requires 327.1470); ν_max(ﬁlm)/cm^Ϫ13400, 2984,

2936, 2905, 2833, 1748, 1640, 1572; δ_H(250 MHz; CDCl₃)

(keto/enol) 12.85 (1H, s, enol), 7.79–7.27 (5H, m, ArH), 6.87–

6.62 (4H, m, ArH), 5.72 (1H, s, NCH), 4.28–4.11 (2H, 2q, J 7.1,

CH₂CH₃), 3.79/3.76 (3H, 2 × s, 2 × OMe), 2.91 (3H, s, NMe),

1.30/1.11 (3H, 2 × t, J 7.1, 2 × CH₂CH₃); δ_C(100 MHz; CDCl₃)

(keto/enol) 173.3, 170.2, 169.7, 152.9, 151.8, 143.9, 142.9, 135.2

(CH), 133.9, 133.4, 130.6 (CH), 128.8 (CH), 128.7 (CH), 128.4

(CH), 128.3 (CH), 128.1 (CH), 128.0 (CH), 115.0 (CH), 114.8

(CH), 114.6 (CH), 113.3 (CH), 111.6, 61.4 (CH₂), 60.9 (CH₂),

55.7 (Me), 55.5 (Me), 39.2 (Me), 35.7 (Me), 14.2 (Me), 14.1

(Me); m/z (EI) 327 (M^ϩ, 9%), 281 (11), 222 (13), 148 (24), 105

(100), 77 (40).

Methyl 2-[N-(4-chlorophenyl)-N-methylamino]-3-oxobutano-

ate 3e. Reaction solvent toluene, puriﬁed by column chrom-

atography (light petroleum : ether, 1 : 1 elution), recrystallised

(light petroleum–ether) to yield the title compound (77%) as a

colourless crystalline solid, mp 109–111 ЊC (Found: C, 56.4; H,

5.4; N, 5.5. C₁₂H₁₄ClNO₃requires C, 56.3; H, 5.5; N, 5.5%); ν_max

(KBr)/cm^Ϫ12951, 2906, 2819, 1654, 1618, 1596; δ_H(250 MHz;

CDCl₃) 12.23 (1H, s, enol), 7.14 and 6.50 (4H, AAЈXXЈ, J 9.1,

ArH), 3.68 (3H, s, OMe), 3.0 (3H, s, NMe), 1.95 (3H, s, Me);

δ_C(100 MHz; CDCl₃) 176.0, 172.2, 147.6, 128.9 (CH), 122.0,

113.0 (CH), 110.5, 51.8 (Me), 39.0 (Me), 17.4 (Me); m/z (EI)

257/255 (M^ϩ, 4/9%), 154/152 (9/22), 113/111 (9/22), 75 (39).

Methyl 2-[N-(2,4-dimethoxyphenyl)-N-methylamino]-3-oxo-

butanoate 3j. Reaction solvent chloroform, puriﬁed by column

chromatography (dichloromethane : light petroleum, 1 : 1

elution) to yield the title compound (75%) as an unstable yellow

oil, δ_H(300 MHz; CDCl₃) (keto/enol) 9.97 (1H, s, enol),

7.08–6.37 (3H, m, ArH), 4.87 (1H, s, NCH), 3.85–3.36 (9H, m,

3 × OMe), 3.20/2.97 (3H, 2 × s, 2 × NMe), 2.32/1.97 (3H, 2 × s,

2 × Me); ν_max(ﬁlm)/cm^Ϫ13421, 3000, 2967, 1749, 1683, 1657.

The compound was used without further puriﬁcation.

Methyl 2-(N-benzyl-N-phenylamino)-3-oxobutanoate 3k.

Reaction solvent toluene, puriﬁed by column chromatography

(dichloromethane : light petroleum, 3 : 7 elution), recrystallised

(light petroleum) to yield the title compound (73%) as a colour-

less crystalline solid, mp 41–42 ЊC (Found: C, 72.3; H, 6.4; N,

4.7. C₁₈H₁₉NO₃requires C, 72.7; H, 6.4; N, 4.7%) (Found: M^ϩ,

297.1365. C₁₈H₁₉NO₃requires 297.1365); ν_max(KBr)/cm^Ϫ13068,

3027, 2951, 1667, 1597; δ_H(300 MHz; CDCl₃) 9.85 (1H, s, enol),

Methyl 2-[N-methyl-N-(4-nitrophenyl)amino]-3-oxobutanoate

3f. Reaction solvent toluene, puriﬁed by column chrom-

atography (light petroleum : ether, 1 : 1 elution), recrystallised

(light petroleum–ether) to yield the title compound (75%) as a

yellow crystalline solid, mp 138–140 ЊC (Found: C, 53.9; H, 5.1;

N, 10.5. C₁₂H₁₄N₂O₅requires C, 54.1; H, 5.3; N, 10.5%); ν_max

(KBr)/cm^Ϫ12825, 1648, 1597, 1508; δ_H(250 MHz; CDCl₃) 12.28

J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

1677

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7.33–7.18 (7H, m, ArH), 6.79–6.70 (3H, m, ArH), 4.72 (2H,

AB, J 15.4, CH₂Ph), 3.70 (3H, s, OMe), 1.84 (3H, s, Me);

δ_C(100 MHz; CDCl₃) 176.9, 172.6, 148.8, 138.3, 129.2 (CH),

128.3 (CH), 128.1 (CH), 127.1 (CH), 117.7 (CH), 113.0 (CH),

109.8, 56.2 (CH₂), 51.7 (Me), 18.2 (Me); m/z (EI) 297 (M^ϩ, 6%),

254 (5), 206 (32), 104 (100), 91 (90).

MHz; CDCl₃) 7.22 (1H, t, J 8.1, ArH), 6.91 (1H, d, J 8.4, ArH),

6.44 (1H, d, J 7.7, ArH), 3.94 (3H, s, OMe), 3.93 (3H, s, OMe),

3.92 (3H, s, NMe), 2.77 (3H, s, Me); δ_C(100 MHz; CDCl₃)

163.6, 156.7, 140.5, 126,0 (CH), 123.9, 122.0, 117.3, 103.0 (CH),

99.3 (CH), 55.1 (Me), 51.2 (Me), 32.3 (Me), 12.8 (Me); m/z (EI)

233 (M^ϩ, 100%), 219 (8), 218 (69), 174 (19), 130 (23), 89 (34).

Methyl 1,3-dimethyl-6-methoxyindole-2-carboxylate 4d².

Recrystallised (light petroleum) to give a colourless crystalline

solid, mp 93–94 ЊC; (Found : C, 66.9; H, 6.7; N, 5.9); ν_max(KBr)/

cm^Ϫ13019, 2954, 2848, 1710, 1637, 1571; δ_H(300 MHz; CDCl₃)

7.53 (1H, d, J 8.8, ArH), 6.81 (1H, dd, J 8.8, J 2.2, ArH), 6.72

(1H, d, J 6.7, ArH), 3.96 (3H, s, OMe), 3.92 (3H, s, OMe), 3.90

(3H, s, NMe), 2.28 (3H, s, Me); δ_C(100 MHz; CDCl₃) 163.4,

159.1, 139.9, 123.8, 121.6 (CH), 121.5, 111.0 (CH), 92.0 (CH),

55.5 (Me), 51.1 (Me), 32.0 (Me), 10.9 (Me); one ArC

unobserved; m/z (EI) 233 (M^ϩ, 100%), 219 (12), 218 (89), 190

(19), 131 (23), 89 (35).

Preparation of indoles 4

General method 1. To a stirring solution of α-(N-arylamino)-

β-ketoester 3 (1.5 mmol) in toluene (25 ml) was added boron

triﬂuoride–diethyl ether (0.2 ml). The solution was heated

under reﬂux overnight. The toluene was removed in vacuo and

the residue puriﬁed by column chromatography to give the

indole 4.

General method 2. To a stirring solution of α-(N-arylamino)-

β-ketoester 3 (1.5 mmol) in toluene (25 ml) was added

Amberlyst^®15 (0.3 g). The solution was heated under reﬂux

overnight. The resin was ﬁltered oﬀ and the ﬁltrate removed

in vacuo and the residue puriﬁed by column chromatography

to give the indole 4.

Methyl

5-chloro-1,3-dimethylindole-2-carboxylate

4e.

Method 1 (62%), method 2 (87%), puriﬁed by column chrom-

atography (light petroleum : ether, 1 : 1 elution), recrystallised

(light petroleum–ether) to give the title compound as an oﬀ

white solid, mp 64–66 ЊC (Found: C, 60.6; H, 4.8; N, 5.7.

C₁₂H₁₂ClNO₂requires C, 60.6; H, 5.1; N, 5.9%); ν_max(KBr)/

cm^Ϫ12951, 1701, 1527; δ_H(250 MHz; CDCl₃) 7.59 (1H, d, J 2.0,

ArH), 7.24 (2H, m, ArH), 3.95 (3H, s, OMe), 3.94 (3H, s,

NMe), 2.51 (3H, s, Me); δ_C(100 MHz; CDCl₃) 163.2, 137.1,

128.0, 126.0, 125.6, 125.5 (CH), 125.4, 120.0 (CH), 111.1 (CH),

51.5 (Me), 32.6 (Me), 10.7 (Me); m/z (EI) 239/237 (M^ϩ,

38/95%), 224/222 (27/83), 222 (83), 180/178 (19/54).

Methyl 1,3-dimethylindole-2-carboxylate 4a. Method

1

(69%), method 2 (81%), puriﬁed by column chromatography

(dichloromethane : light petroleum, 1 : 1 elution), recrystallised

(light petroleum) to give the title compound as a colourless

crystalline solid, mp 76–78 ЊC (lit.,⁵⁵mp 76–77 ЊC) (Found: C,

70.7; H, 6.4; N, 7.0. C₁₂H₁₃NO₂requires C, 70.9; H, 6.4; N,

6.9%); ν_max(KBr)/cm^Ϫ13061, 2949, 1720, 1603, 1570, 1530;

δ_H(250 MHz; CDCl₃) 7.65 (1H, m, ArH), 7.33 (2H, m, ArH),

7.13 (1H, m, ArH), 3.98 (3H, s, OMe), 3.93 (3H, s, NMe), 2.57

(3H, s, Me).

Methyl 1,3-dimethyl-5-nitroindole-2-carboxylate 4f. Method

1 gave only starting material. Method 2 (80%), puriﬁed by

column chromatography (dichloromethane : light petroleum,

1 : 1 elution), recrystallised (dichloromethane–light petroleum)

to give the title compound as a pale yellow crystalline solid, mp

178–180 ЊC (Found: C, 57.6; H, 4.6; N, 11.1. C₁₂H₁₂NO₄

requires C, 58.0; H, 4.9; N, 11.3%) (Found: M^ϩ, 248.0797.

C₁₂H₁₂N₂O₄requires 248.0797); ν_max(KBr)/cm^Ϫ13105, 2960,

1710, 1618, 1578; δ_H(300 MHz; CDCl₃) 8.66 (1H, d, J 2.2,

ArH), 8.22 (1H, dd, J 9.2, 2.2, ArH), 7.38 (1H, d, J 9.2, ArH),

4.05 (3H, s, OMe), 3.98 (3H, s, NMe), 2.62 (3H, s, Me); δ_C(100

MHz; CDCl₃) 162.6, 141.6, 140.8, 127.8, 126.2, 122.9, 120.1

(CH), 118.2 (CH), 110.1 (CH), 51.8 (Me), 32.6 (Me), 10.7 (Me);

m/z (EI) 248 (M^ϩ, 100), 234 (11), 233 (83), 187 (47), 143 (38),

115 (37).

Methyl

7-bromo-1,3-dimethylindole-2-carboxylate

4b.

Method 2; puriﬁed by column chromatography (dichloro-

methane : light petroleum, 3 : 7 elution), recrystallised (light

petroleum) to yield the title compound (52%) as a colourless

crystalline solid, mp 47–48 ЊC (Found: C, 51.2; H, 4.3; N, 5.0.

C₁₂H₁₂BrNO₂requires C, 51.2; H, 4.3; N, 5.0%); ν_max(KBr)/

cm^Ϫ13061, 2999, 2951, 1708, 1563; δ_H(300 MHz; CDCl₃)

7.58 (1H, dd, J 8.0, 1.0, ArH), 7.50 (1H, dd, J 7.5, 1.0, ArH),

6.95 (1H, t, J 7.8, ArH), 4.33 (3H, s, OMe), 3.95 (3H, s, NMe),

2.52 (3H, s, Me); δ_C(100 MHz; CDCl₃) 163.0, 135.6, 130.7

(CH), 130.3, 127.5, 120.7, 120.6 (CH), 120.1 (CH), 104.3, 51.6

(Me), 34.6 (Me), 10.6 (Me); m/z (EI) 283/281 (M^ϩ, 96), 268/266

(50), 224/222 (35), 143 (51), 115 (100).

Methyl 5-methoxy-1,3-dimethylindole-2-carboxylate 4g.

Method 1 (88%), method 2 (82%), puriﬁed by column chrom-

atography (dichloromethane elution), recrystallised (light

petroleum) to give the title compound as a colourless crystalline

solid, mp 81–82 ЊC (Found: C, 67.0; H, 6.3; N, 5.9. C₁₃H₁₅NO₃

requires C, 66.9; H, 6.5; N, 6.0%); ν_max(KBr)/cm^Ϫ12948, 1702,

1520, 1495; δ_H(400 MHz; CDCl₃) 7.23 (1H, m, ArH), 7.02 (2H,

m, ArH), 3.96 (3H, s, OMe), 3.93 (3H, s, OMe), 3.86 (3H,

NMe), 2.54 (3H, s, Me); δ_C(100 MHz; CDCl₃) 163.5, 154.2,

134.5, 127.2, 125.3, 120.0, 116.8 (CH), 111.0 (CH), 101.0 (CH),

55.8 (Me), 51.2 (Me), 32.2 (Me), 10.8 (Me); m/z (EI) 233 (M^ϩ,

100%), 218 (60), 190 (25).

Methyl 7-methoxy-1,3-dimethylindole-2-carboxylate 4c.

Method 1 (13%), method 2 (56%), puriﬁed by column chrom-

atography (dichloromethane : light petroleum, 3 : 7 elution),

recrystallised (light petroleum) to give the title compound as

a colourless crystalline solid, mp 61–63 ЊC (Found: C, 66.7;

H, 6.4; N, 5.9. C₁₃H₁₅NO₃requires C, 66.9; H, 6.5; N, 6.0%);

ν_max(KBr)/cm^Ϫ12954, 2848, 1729, 1584; δ_H(300 MHz; CDCl₃)

7.23 (1H, dd, J 8.1, 0.9, ArH), 7.01 (1H, t, J 7.8, ArH), 6.71 (1H,

d, J 7.8, ArH), 4.28 (3H, s, OMe), 3.93 (6H, s, NMe, OMe), 2.53

(3H, s, Me); δ_C(100 MHz; CDCl₃) 163.4, 148.0, 129.3, 129.2,

125.8, 120.8, 119.8 (CH), 113.2 (CH), 105.5 (CH), 55.5 (Me),

51.3 (Me), 35.0 (Me), 10.9 (Me); m/z (EI) 233 (M^ϩ, 100), 219

(9), 218 (65), 159 (19), 130 (29).

Methyl 3-ethyl-5-methoxy-1-methylindole-2-carboxylate 4h.

Method 1 (49%), method 2 (50%), puriﬁed by column chrom-

atography (dichloromethane elution), recrystallised (light

petroleum) to give the title compound as a pale crystalline solid,

mp 55–56 ЊC (Found: C, 66.8; H, 6.9; N, 5.7. C₁₄H₁₇NO₃ؒ

0.25H₂O requires C, 66.8; H, 7.0; N, 5.6%) (Found: M^ϩ,

247.1208. C₁₄H₁₇NO₃requires 247.1208); ν_max(KBr)/cm^Ϫ12952,

1702, 1523; δ_H(250 MHz; CDCl₃) 7.25 (2H, m, ArH), 7.05 (1H,

m, ArH), 3.97 (3H, s, OMe), 3.94 (3H, s, OMe), 3.88 (3H, s,

NMe), 3.05 (2H, q, J 7.5, CH₂CH₃), 1.24 (3H, t, J 7.5,

Methyl 1,3-dimethyl-4-methoxyindole-2-carboxylate 4d¹and

methyl

1,3-dimethyl-6-methoxyindole-2-carboxylate

4d².

Method 2 yielded a 77% mixture of 2 products in a 1 : 2.5 ratio,

puriﬁed by column chromatography (dichloromethane : light

petroleum, 1 : 1 elution).

Methyl 1,3-dimethyl-4-methoxyindole-2-carboxylate 4d¹.

Recrystallised (light petroleum), mp 90–92 ЊC (Found: C, 66.7;

H, 6.7; N, 5.9. C₁₃H₁₅NO₃requires C, 66.9; H, 6.5; N, 6.0%);

ν_max(KBr)/cm^Ϫ12999, 2980, 2841, 1703, 1611, 1578; δ_H(300

1678

J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

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CH₂CH₃); δ_C(100 MHz; CDCl₃) 171.1, 163.3, 154.2, 134.6,

126.6, 126.3, 116.7 (CH), 111.1 (CH), 101.0 (CH), 60.4 (CH₂),

55.9 (Me), 51.3 (Me), 32.2 (Me), 15.6 (Me); m/z (EI) 247 (M^ϩ,

24%), 232 (49), 202 (14), 200 (16), 172 (15).

δ_H(300 MHz; CDCl₃) 7.63 (1H, d, J 2.5, ArH), 7.18 (1H, d,

J 8.8, ArH), 6.87 (1H, dd, J 8.8, 2.5, ArH), 3.92 (3H, s, OMe),

3.89 (3H, s, OMe), 3.67 (3H, s, NMe), 2.74 (3H, s, Me); δ_C(100

MHz; CDCl₃) 166.5, 155.7, 145.3, 131.6, 127.4, 111.6 (CH),

109.7 (CH), 103.7 (CH), 103.5, 55.8 (Me), 50.6 (Me), 29.7 (Me),

12.0 (Me); m/z (EI) 233 (M^ϩ, 100%), 218 (54), 202 (93), 190

(37), 130 (42).

Ethyl 5-methoxy-1-methyl-3-phenylindole-2-carboxylate 4i.

Method 1 (42%), method 2 (54%), puriﬁed by column chrom-

atography (dichloromethane elution) to give the title compound

as a colourless oil (Found: M^ϩ, 309.1365. C₁₉H₁₉NO₃requires

309.1365); ν_max(CH₂Cl₂)/cm^Ϫ13059, 3032, 2986, 2960, 2900,

2848, 1703, 1617; δ_H(300 MHz; CDCl₃) 7.44–7.30 (6H, m,

ArH), 7.06 (1H, dd, J 9.0, 2.4, ArH), 6.92 (1H, d, J 2.4, ArH),

4.16 (2H, q, J 7.1, CH₂CH₃), 4.05 (3H, s, OMe), 3.78 (3H, s,

NMe), 1.04 (3H, t, J 7.1, CH₂CH₃); δ_C(100 MHz; CDCl₃)

162.6, 155.0, 135.2, 134.0, 130.5 (CH), 127.8 (CH), 126.8 (CH),

126.7, 125.3, 123.9, 116.9 (CH), 111.1 (CH), 101.4 (CH), 60.4

(CH₂), 55.7 (Me), 32.0 (Me), 13.7 (Me); m/z (EI) 309 (M^ϩ, 100),

281 (30), 181 (35), 165 (32), 152 (31).

Conjugate addition reactions to acrylates; preparation of

3-arylaminopropanoates 6

Ethyl 3-(4-methylphenylamino)propanoate 6a.

A stirred

solution of 4-toluidine (3.00 g, 28 mmol) and ethyl acrylate

(3.34 ml, 30.8 mmol, 1.1 equiv.) in EtOH (30 ml) was heated at

reﬂux for 3 days. The reaction mixture was then concentrated

in vacuo and puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 6) to give the title compound (2.39 g, 41%) as a

brown oil (lit.,⁵⁶bp 142–144 ЊC, 2–3 mmHg) (Found: MH^ϩ,

208.1337. C₁₂H₁₇NO₂ϩ H requires 208.1337); ν_max(ﬁlm)/cm^Ϫ1

3398, 2981, 2920, 1734, 1618, 1522, 1028, 810; δ_H(300 MHz;

CDCl₃) 6.97 (2H, m, ArH), 6.53 (2H, m, ArH), 4.13 (2H, q,

J 7.1, OCH₂Me), 3.40 (2H, t, J 6.4, NCH₂), 2.57 (2H, t, J 6.4,

NCH₂CH₂), 2.22 (3H, s, Me), 1.24 (3H, t, J 7.1, OCH₂Me); NH

not observed; δ_C(75 MHz; CDCl₃) 172.5, 145.4, 129.8 (CH),

126.9, 113.3 (CH), 60.6 (CH₂), 39.9 (Me), 33.9 (CH₂), 20.4

(CH₂), 14.3 (Me); m/z (EI) 207 (M^ϩ, 90%), 131 (42), 117 (100),

106 (33), 91 (95), 76 (52), 64 (52).

Methyl 5,7-dimethoxy-1,3-dimethylindole-2-carboxylate 4j.

Method 1, puriﬁed by column chromatography (dichlorometh-

ane : light petroleum, 1 : 1 elution) to yield the title compound

(31%) as a colourless crystalline solid, mp 102–104 ЊC (Found:

C, 63.8; H, 6.7; N, 5.2. C₁₄H₁₇NO₄requires C, 63.8; H, 6.5; N,

5.3%); ν_max(KBr)/cm^Ϫ13000, 2967, 2848, 1710, 1630, 1591; δ_H

(300 MHz; CDCl₃) 6.56 (1H, d, J 2.1, ArH), 6.41 (1H, d, J 2.1,

ArH), 4.23 (3H, s, OMe), 3.92 (3H, s, OMe), 3.90 (3H, s, OMe),

3.86 (3H, s, NMe), 2.49 (3H, s, Me); δ_C(100 MHz; CDCl₃)

163.3, 154.4, 148.6, 128.5, 125.9, 125.0, 120.1. 98.2 (CH), 92.1

(CH), 55.6 (Me), 55.5 (Me), 51.2 (Me), 34.9 (Me), 11.0 (Me);

m/z (EI) 263 (M^ϩ, 100), 248 (65), 220 (25), 205 (20).

Ethyl 3-(4-methoxyphenylamino)propanoate 6b. A stirred

solution of 4-anisidine (4.44 g, 36.1 mmol) and ethyl acrylate

(3.97 g, 39.7 mmol, 1.1 equiv.) was heated at reﬂux in ethanol

(30 ml) for 3 days. The reaction mixture was then concentrated

in vacuo and puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 4) to give the title compound (3.91 g, 49%) as an

orange oil (lit.,⁴⁴bp 155–159 ЊC, 0.5 mmHg); ν_max(ﬁlm)/cm^Ϫ1

3383, 2983, 2937, 1730, 1514, 1236, 1180, 1035, 822; δ_H(300

MHz; CDCl₃) 6.78 (2H, m, ArH), 6.60 (2H, m, ArH), 4.15 (2H,

q, J 7.1, OCH₂Me), 3.74 (3H, s, OMe), 3.39 (2H, t, J 6.38,

NCH₂), 2.59 (2H, t, J 6.4, NHCH₂CH₂), 1.26 (3H, t, J 7.1,

OCH₂Me); NH not observed.

Methyl 1-benzyl-3-methylindole-2-carboxylate 4k. Method 1,

puriﬁed by column chromatography (dichloromethane : light

petroleum, 3 : 7 elution), recrystallised (light petroleum) to yield

the title compound (23%) as a colourless crystalline solid, mp

43–45 ЊC (Found: C, 77.4; H, 6.2; N, 5.1. C₁₈H₁₇NO₂requires C,

77.4; H, 6.1; N, 5.0%); ν_max(KBr)/cm^Ϫ13079, 3039, 2947, 1696,

1552; δ_H(300 MHz; CDCl₃) 7.72 (1H, dt, J 8.0, 1.0, ArH), 7.33

(2H, m, ArH), 7.22 (4H, m, ArH), 7.04 (2H, m, ArH), 5.97 (2H,

s, CH₂Ph), 3.89 (3H, s, OMe), 2.64 (3H, s, Me); δ_C(100 MHz;

CDCl₃) 163.3, 138.8, 138.7, 128.5 (CH), 127.4, 127.0 (CH),

126.2 (CH), 125.6 (CH), 124.5, 121.7, 120.9 (CH), 120.1 (CH),

110.6 (CH), 51.4 (Me), 48.2 (CH₂), 11.0 (Me); m/z (EI) 279

(M^ϩ, 14), 188 (8), 128 (10), 91 (100).

Ethyl 3-(4-methoxycarbonylphenylamino)propanoate 6c. A

stirred solution of methyl 4-aminobenzoate (2.0 g, 13.2 mmol)

and ethyl acrylate (2.15 ml, 14.6 mmol, 1.5 equiv.) in EtOH (10

ml) was heated at reﬂux for 3 days. The reaction mixture was

concentrated in vacuo and puriﬁed on silica eluting with ethyl

acetate–light petroleum (1 : 4) to give the title compound

(727 mg, 22%) as a pale yellow crystalline solid, mp 80 ЊC

(Found: MH^ϩ, 252.1234. C₁₃H₁₇NO₄ϩ H requires 252.1236);

ν_max(KBr)/cm^Ϫ13391, 2950, 1706, 1610, 1280, 1180, 1110, 773;

δ_H(300 MHz; CDCl₃) 7.87 (2H, m, ArH), 6.58 (2H, m, ArH),

4.60 (1H, br s, NH), 4.17 (2H, q, J 7.1, OCH₂Me), 3.86 (3H, s,

OMe), 3.51 (2H, t, J 6.4, NCH₂), 2.63 (2H, t, J 6.4, NCH₂CH₂),

1.27 (3H, t, J 7.1, OCH₂Me); δ_C(75 MHz; CDCl₃) 172.1, 167.3,

151.4, 131.6 (CH), 118.6, 111.6 (CH), 60.8 (CH₂), 51.6 (Me),

38.8 (CH₂), 33.7 (CH₂), 14.2 (CH₂); m/z (EI) 251 (M^ϩ, 56%),

220 (25), 165 (46), 164 (100), 162 (33), 132 (49), 91 (26), 77 (27).

Methyl 5-methoxy-1,2-dimethylindole-3-carboxylate 5.

A

solution of ethyl 5-hydroxy-2-methylindole-3-carboxylate (0.56

g, 2.5 mmol) in THF (15 ml) and sodium hydroxide solution

(5%; 10 ml) was heated under reﬂux overnight. The mixture was

acidiﬁed with hydrochloric acid (3 M) and extracted with ethyl

acetate. The organic layer was dried (MgSO₄) and concentrated

to yield 5-hydroxy-2-methylindole-3-carboxylic acid as a pale

brown solid (0.41 g, 85%) which was used directly in the next

step without puriﬁcation; δ_H(300 MHz; CD₃OD) 7.44 (1H, d,

J 2.4, ArH), 7.12 (1H, d, J 8.6, ArH), 6.66 (1H, dd, J 8.6, 2.4,

ArH), 2.64 (3H, s, Me).

A solution of the above acid (0.10 g, 0.52 mmol), potassium

hydroxide (0.12 g, 2.1 mmol) and iodomethane (0.30 g, 2.1

mmol) in DMSO (5 ml) was stirred overnight. Hydrochloric

acid (3 M; 20 ml) was added and the mixture extracted with

ethyl acetate. The organic layer was washed twice with hydro-

chloric acid (1 M) and then water. The organic layer was separ-

ated, dried (MgSO₄) and concentrated. The residue was puriﬁed

by column chromatography (dichloromethane elution) and

recrystallised (light petroleum–ethyl acetate) to yield the title

compound (0.075 g, 62%) as a colourless solid, mp 127–128 ЊC

(Found: C, 66.9; H, 6.1; N, 5.9. C₁₃H₁₅NO₃requires C, 66.9;

H, 6.5; N, 6.0%) (Found: M^ϩ, 233.1052. C₁₃H₁₅NO₃requires

233.1052); ν_max(KBr)/cm^Ϫ13006, 2947, 2841, 1710, 1624, 1585;

Ethyl 3-(4-tert-butylphenylamino)propanoate 6d. A solution

of 4-tert-butylaniline (2.13 ml, 13.4 mmol) and ethyl acrylate

(2.18 ml, 20.10 mmol, 1.5 equiv.) in EtOH (10 ml) was heated at

reﬂux for 3 days. The reaction mixture was concentrated

in vacuo and puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 6) to give the title compound (741 mg, 22%) as a

pale yellow solid, mp 52–54 ЊC (Found: MH^ϩ, 250.1806.

C₁₅H₂₃NO₂ϩ H requires 250.1807); ν_max(KBr)/cm^Ϫ13398,

2962, 1720, 1525, 1319, 1192; δ_H(300 MHz; CDCl₃) 7.22 (2H,

m, ArH), 6.59 (2H, m, ArH), 4.14 (2H, q, J 7.2, OCH₂Me), 3.44

(2H, t, J 6.4, NCH₂), 2.62 (2H, t, J 6.4, NCH₂CH₂), 1.30 (9H, s,

CMe₃), 1.26 (3H, t, J 7.2, OCH₂Me); NH not observed; δ_C(75

MHz; CDCl₃) 172.5, 145.3, 140.5, 126.1 (CH), 112.8 (CH), 60.6

J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

1679

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(CH₂), 39.7 (CH₂), 34.1 (CH₂), 33.9, 31.5 (CMe₃), 14.2 (Me);

m/z (EI) 249 (M^ϩ, 40%), 234 (100), 162 (86), 146 (98), 118 (34),

91 (34).

reﬂux for 1.5 h. The reaction mixture was concentrated in vacuo

and puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 9) to give the intermediate 7b (298 mg, 71%).

The intermediate 7b was then heated at reﬂux overnight in

toluene (3 ml) in the presence of Amberlyst^®(110 mg). The

reaction mixture was ﬁltered, concentrated in vacuo and puri-

ﬁed on silica eluting with ethyl acetate–light petroleum (1 : 9) to

give the title compound (178 mg, 63%) as a yellow solid, mp

44–45 ЊC (from ethyl acetate–light petroleum) (Found: C, 63.8;

H, 6.6; N, 4.3. C₁₇H₂₁NO₅requires C, 63.9; H, 6.6; N, 4.4%);

ν_max(KBr)/cm^Ϫ12981, 2953, 2833, 1733, 1700, 1441, 1213;

δ_H(300 MHz; CDCl₃) 7.32 (1H, m, ArH), 7.02 (2H, m, ArH),

4.77 (2H, t, J 7.3, NCH₂), 4.08 (2H, t, J 7.1, OCH₂Me), 3.95

(3H, s, OMe), 3.89 (3H, s, OMe), 2.79 (2H, t, J 7.3, NCH₂CH₂),

2.55 (3H, s, Me), 1.19 (3H, t, J 7.1, OCH₂Me); δ_C(75 MHz;

CDCl₃) 171.6, 163.3, 154.3, 133.6, 130.1, 124.2, 120.8, 117.0

(CH), 111.2 (CH), 100.9 (CH), 60.7 (CH₂), 55.8 (Me), 51.4

(Me), 40.9 (CH₂), 35.6 (CH₂), 14.1 (Me), 11.0 (Me); m/z (EI)

319 (M^ϩ, 86%), 260 (70), 233 (41), 232 (100), 187 (25), 172 (30).

Benzyl 3-(4-methylphenylamino)propanoate 6e.

A stirred

solution of 4-toluidine (3.00 g, 28 mmol) and benzyl acrylate

(14.03 g, 84 mmol) in EtOH (40 ml) was heated at reﬂux for

3 days. The reaction mixture was then concentrated in vacuo

and puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 10) to give the title compound (6.63 g, 88%) as an orange

crystalline solid, mp 49–50 ЊC (Found: MH^ϩ, 270.1492.

C₁₇H₁₉NO₂ϩ H requires 270.1494); ν_max(KBr)/cm^Ϫ13447,

3392, 1720, 1618, 1522, 1321, 1186, 796, 723 (ArH); δ_H(300

MHz; CDCl₃) 7.36 (5H, m, PhH), 7.01 (2H, d, J 8.5, ArH), 6.56

(2H, d, J 8.5, ArH), 5.15 (2H, s, CH₂), 3.47 (2H, t, J 6.3,

NCH₂), 2.68 (2H, t, J 6.3, NCH₂CH₂), 2.25 (3H, s, Me); NH

not observed; δ_C(75 MHz; CDCl₃) 172.1, 135.6, 129.8 (CH),

128.6 (CH), 128.4, 128.3 (CH), 128.2 (CH), 128.1, 114.0 (CH),

66.5 (CH₂),40.4 (CH₂), 33.6 (CH₂), 20.4 (Me); m/z (CI) 270

(MH^ϩ, 32%), 135 (20), 120 (46), 108 (100), 91 (70), 78 (19).

Dimethyl

1-(2-ethoxycarbonylethyl)-3-methylindole-2,5-di-

carboxylate 8c. A solution of 6c (100 mg, 0.40 mmol), diazo

compound 2a (113 mg, 0.80 mmol, 2 equiv.) and dirhodium()

acetate (10 mg) in chloroform (6 ml) was heated at reﬂux for 1.5

h. The reaction mixture was then concentrated in vacuo and

puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 3) to give the intermediate 7c (91 mg, 63%) as a pale yellow

oil.

Benzyl 3-(4-methoxyphenylamino)propanoate 6f. A stirred

solution of 4-anisidine (333 mg, 2.7 mmol) and benzyl acrylate

(500 mg, 3.0 mmol) in EtOH (15 ml) was heated at reﬂux for

3 days. The reaction mixture was then concentrated in vacuo

and puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 4) to give the title compound (663 mg, 84%) as a pale brown

crystalline solid, mp 38–39 ЊC (ethyl acetate–light petroleum)

(Found: MH^ϩ, 286.1445. C₁₇H₁₉NO₃ϩ H requires 286.1443);

ν_max(KBr)/cm^Ϫ13377, 2953, 2910, 1722, 1515, 1268, 1236, 1211,

808, 732; δ_H(300 MHz; CDCl₃) 7.39 (5H, m, PhH), 6.82 (2H, d,

J 8.8, ArH), 6.62 (2H, d, J 8.8, ArH), 5.18 (2H, s, CH₂), 3.77

(3H, s, OMe), 3.45 (2H, t, J 6.3, NCH₂), 2.68 (2H, t, J 6.3,

NCH₂CH₂); NH not observed; δ_C(75 MHz; CDCl₃) 172.2,

152.5, 141.5 (CH), 135.7, 128.6 (CH), 128.3 (CH), 128.2 (CH),

114.9 (CH), 114.7 (CH), 66.4 (CH₂), 55.7 (Me), 40.6 (CH₂), 33.9

(CH₂); m/z (EI) 285 (M^ϩ, 90%), 226 (33), 195 (27), 194 (39), 149

(29), 148 (45), 134 (99), 120 (99), 107 (66), 91 (100), 77 (67), 64

(64).

This was then dissolved in toluene (5 ml) and Amberlyst^®

(110 mg) added and the mixture heated at reﬂux overnight. The

reaction mixture was ﬁltered, the ﬁltrate concentrated in vacuo

and then puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 6) to give the title compound (30 mg, 22%) as a

pale yellow solid, mp 85–86 ЊC (Found: MH^ϩ, 348.1448.

C₁₈H₂₁NO₆ϩ H requires 348.1447); ν_max(KBr)/cm^Ϫ13437,

2945, 1731, 1701, 1319, 1259, 1244, 1180, 1134, 768; δ_H(300

MHz; CDCl₃) 8.44 (1H, d, J 1.5, H-4), 8.02 (1H, dd, J 8.8, 1.5,

H-6), 7.44 (1H, d, J 8.8, H-7), 4.81 (2H, t, J 7.4, NCH₂), 4.07

(2H, q, J 7.1, OCH₂Me), 3.96 (3H, s, OMe), 3.95 (3H, s, OMe),

2.82, (2H, t, J 7.4, NCH₂CH₂), 2.61 (3H, s, Me), 1.17 (3H, t,

J 7.1, OCH₂Me); δ_C(75 MHz; CDCl₃) 171.4, 167.7, 163.0,

140.2, 126.9, 126.3 (CH), 125.3, 124.2 (CH), 123.2, 122.1, 109.9

(CH), 60.8 (CH₂), 52.0 (Me), 51.7 (Me), 41.1 (CH₂), 35.4 (CH₂),

14.1 (Me), 10.9 (Me); m/z (EI) 347 (M^ϩ, 36%), 288 (40), 260

(100), 242 (12), 156 (16), 128 (14), 83 (20), 59 (12).

Preparation of indoles 8

Methyl 1-(2-ethoxycarbonylethyl)-3,5-dimethylindole-2-carb-

oxylate 8a. A solution of 6a (100 mg, 0.48 mmol), diazo

compound 2a (137 mg, 0.96 mmol, 2 equiv.) and dirhodium()

acetate (10 mg) in chloroform (6 ml) was heated at reﬂux for 1.5

h. The reaction mixture was concentrated in vacuo and puriﬁed

on silica eluting with ethyl acetate–light petroleum (1 : 9) to give

the intermediate 7a (118 mg, 76%) as a pale yellow oil.

Methyl

5-tert-butyl-1-(2-ethoxycarbonylethyl)-3-methyl-

indole-2-carboxylate 8d. A solution of 6d (100 mg, 0.40 mmol),

diazo compound 2a (113 mg, 0.80 mmol, 2 equiv.) and

dirhodium() acetate (10 mg) in chloroform (6 ml) was heated

at reﬂux for 1.5 h. The reaction mixture was then concentrated

in vacuo and puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 9) to give the intermediate 7d (80 mg, 55%) as a

pale yellow oil.

This was then dissolved in toluene (5 ml), Amberlyst^®

(110 mg) added and the mixture heated at reﬂux overnight. The

reaction mixture was ﬁltered, the ﬁltrate concentrated in vacuo

and puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 10) to give the title compound (84 mg, 76%) as a colourless

solid, mp 45–46 ЊC (Found: MH^ϩ, 304.1551. C₁₇H₂₁NO₄ϩ H

requires 304.1549); ν_max(KBr)/cm^Ϫ13446, 2956, 1734, 1700,

1257, 1188, 1124, 773; δ_H(300 MHz; CDCl₃) 7.43 (1H, s, ArH),

7.33 (1H, m, ArH), 7.19 (1H, m, ArH), 4.78 (2H, t, J 7.4,

NCH₂), 4.10 (2H, q, J 7.1, OCH₂Me), 3.94 (3H, s, OMe), 2.80

(2H, t, J 7.4, NCH₂CH₂), 2.56 (3H, s, Me), 2.47 (3H, s, Me),

1.20 (3H, t, J 7.1, OCH₂Me); δ_C(75 MHz; CDCl₃) 171.7, 163.4,

136.6, 129.3, 127.5 (CH), 127.4, 123.9, 121.1, 120.2 (CH), 109.9

(CH), 60.7 (CH₂), 51.4 (Me), 40.8 (CH₂), 35.5 (CH₂), 21.4 (Me),

14.1 (Me), 10.9 (Me); m/z (EI) 303 (M^ϩ, 54%), 244 (42), 216

(100).

This was then dissolved in toluene (5 ml), Amberlyst^®

(110 mg) added and the mixture heated at reﬂux overnight. The

reaction mixture was ﬁltered, the ﬁltrate concentrated in vacuo

and then puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 6) to give the title compound (49 mg, 64%) as a

pale yellow oil (Found: MH^ϩ, 346.2023. C₂₀H₂₇NO₄ϩ H

requires 346.2018); ν_max(ﬁlm)/cm^Ϫ13446, 2962, 1733, 1701,

1541, 1178, 1132, 802; δ_H(300 MHz; CDCl₃) 7.61 (1H, d, J 1.9,

H-4), 7.47 (1H, dd, J 8.8, 1.9, H-6), 7.38 (1H, d, J 8.8, H-7),

4.78 (2H, t, J 7.4, NCH₂), 4.10 (2H, q, J 7.1, OCH₂Me), 3.95

(3H, s, OMe), 2.80 (2H, t, J 7.4, NCH₂CH₂), 2.59 (3H, s, Me),

1.40 (9H, s, CMe₃), 1.19 (3H, t, J 7.1, OCH₂Me); δ_C(75 MHz;

CDCl₃) 171.7, 163.4, 142.9, 136.5, 126.9, 124.3 (CH), 123.9,

121.7, 116.1 (CH), 109.8 (CH), 60.6 (CH₂), 51.4 (Me), 40.8

(CH₂), 35.5 (CH₂), 34.7, 31.7 (Me), 14.1 (Me), 10.9 (Me); m/z

(EI) 345 (M^ϩ, 82%), 330 (100), 258 (53), 256 (58), 242 (44).

Methyl 1-(2-ethoxycarbonylethyl)-5-methoxy-3-methylindole-

2-carboxylate 8b. A solution of 6b (277 mg, 1.24 mmol), diazo

compound 2a (353 mg, 2.48 mmol, 2 equiv.) and dirhodium()

acetate (10 mg) in distilled chloroform (10 ml) was heated at

1680

J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

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2-Benzylsulfanylethanol. Benzyl bromide (3.8 ml, 31.9 mmol)

and 2-mercaptoethanol (2.24 ml, 32.0 mmol) were added to a

stirred suspension of potassium carbonate (11.05 g, 80 mmol),

18-crown-6 (100 mg) and potassium iodide (100 mg) in dry

acetone (80 ml). The mixture was stirred at reﬂux for 15 h,

cooled to room temperature, ﬁltered and concentrated under

reduced pressure. Water (75 ml) was then added to the residue

and this was then extracted with ether (3 × 75 ml). The

combined organic layers were washed with water (75 ml), brine

(75 ml) and dried (MgSO₄). This was then concentrated under

reduced pressure and puriﬁed on a silica gel column eluting

with ethyl acetate–light petroleum (1 : 3) to give the title com-

pound (4.75 g, 88%) as a yellow oil; δ_H(300 MHz; CDCl₃)

7.33–7.28 (5H, m, ArH), 3.73 (2H, s, CH₂), 3.68 (2H, t, J 6.0,

CH₂OH), 2.64 (2H, t, J 6.0, SCH₂), 2.02 (1H, br s, OH).

heated at reﬂux for 3 days. The reaction mixture was concen-

trated in vacuo and puriﬁed on silica eluting with ethyl acetate–

light petroleum (1 : 4) to give the title compound (218 mg, 68%)

as an oﬀ-white solid, mp 86–88 ЊC (Found: MH^ϩ, 292.1004.

C₁₅H₁₇NO₃S ϩ H requires 292.1007); ν_max(KBr)/cm^Ϫ13361,

2937, 1516, 1308, 1240, 1145, 742; δ_H(300 MHz; CDCl₃) 7.93

(2H, m, PhH), 7.69 (1H, m, PhH), 7.59 (2H, m, PhH), 6.77 (2H,

m, ArH), 6.53 (2H, m, ArH), 3.75 (3H, s, OMe), 3.56 (2H, t,

J 6.3, NCH₂), 3.35 (2H, t, J 6.3, NCH₂CH₂); NH not observed;

δ_C(75 MHz; CDCl₃) 152.8, 140.5, 139.1, 134.0 (CH), 129.5

(CH), 128.0 (CH), 115.0 (CH), 114.8 (CH), 55.7 (Me), 54.8

(CH₂), 38.8 (CH₂); m/z (EI) 291 (M^ϩ, 60%), 276 (25), 150 (46),

148 (100), 135 (99), 133 (83), 122 (50), 107 (48), 76 (75), 51 (46).

2-Methyl-N-(2-phenylsulfonylethyl)aniline 9d. A solution of

2-toluidine (0.57 ml, 5.35 mmol) and phenyl vinyl sulfone

(900 mg, 5.35 mmol) in ethanol (20 ml) was heated at reﬂux for

3 days. The reaction mixture was concentrated in vacuo and

puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 4) to give the title compound (996 mg, 68%) as a grey crystal-

line solid, mp 57–59 ЊC (Found: MH^ϩ, 276.1059. C₁₅H₁₇NO₂S

ϩ H requires 276.1058); ν_max(KBr)/cm^Ϫ13417, 2913, 1508,

1299, 1282, 1139, 755; δ_H(300 MHz; CDCl₃) 7.94 (2H, m,

PhH), 7.69 (1H, m, PhH), 7.59 (2H, m, PhH), 7.09 (2H, m,

ArH), 6.70 (1H, m, ArH), 6.48 (1H, m, ArH), 4.21 (1H, br s,

NH), 3.64 (2H, t, J 6.2, NCH₂), 3.43 (2H, t, J 6.2, NCH₂CH₂),

2.11 (3H, s, Me); δ_C(75 MHz; CDCl₃) 144.7, 138.9, 134.1 (CH),

130.5 (CH), 129.5 (CH), 128.0 (CH), 127.1 (CH), 122.9, 117.9

(CH), 109.4 (CH), 54.9 (CH₂), 37.6 (CH₂), 17.4 (Me); m/z (EI)

275 (M^ϩ, 55%), 133 (60), 120 (71), 117 (100), 91 (62), 77 (61), 65

(30).

2-Benzylsulfonylethanol. To a stirred solution of 2-benzyl-

sulfanylethanol (3.5 g, 20 mmol) in dichloromethane (70 ml),

m-chloroperbenzoic acid (17.3 g, 100 mmol) in dichlorometh-

ane (200 ml) was added dropwise at room temperature. The

reaction mixture was stirred further for 3 h. The reaction was

quenched using saturated sodium sulﬁte solution and washed

with water, sodium hydrogen carbonate and water to obtain the

crude product as a colourless solid (3.9 g, 94%), mp 65–66 ЊC

(ethyl acetate–light petroleum); [lit.,⁴⁵mp 70 ЊC (ethyl acetate)];

ν_max(neat)/cm^Ϫ13533 (br), 2925, 1790, 1763, 1574; δ_H(300

MHz; CDCl₃) 7.95–7.30 (5H, m, ArH), 4.26 (2H, s, CH₂), 3.97

(2H, t, J 5.2, CH₂OH), 2.99 (2H, t, J 5.2, SO₂CH₂), 2.28 (1H,

br s, OH).

Benzyl vinyl sulfone. Methanesulfonyl chloride (3.5 ml,

45 mmol) was added to a stirred solution of 2-benzylsulfonyl-

ethanol (4.6 g, 23 mmol) in dry dichloromethane (150 ml) at

0 ЊC under nitrogen, and the reaction mixture stirred at room

temperature for 15 h. Water (100 ml) was added and the

aqueous layer extracted with dichloromethane (3 × 100 ml).

The combined organic layers were washed with water (120 ml),

brine (100 ml), dried (MgSO₄) and concentrated under reduced

pressure to give a pale yellow solid. This was then puriﬁed by

silica gel chromatography (1 : 4, ethyl acetate : light petroleum)

to obtain the title compound (3.0 g, 72%) as a colourless solid,

mp 93–95 ЊC (ethyl acetate–light petroleum) [lit.,⁴⁵94–95 ЊC

(ethyl acetate–light petroleum)]; ν_max(KBr)/cm^Ϫ13058, 2966,

2925, 1603, 1491, 1455, 1388, 1312, 1260, 1153, 1107, 968, 784,

692; δ_H(300 MHz; CDCl₃) 7.36 (5H, s, ArH), 6.51 (1H, dd,

2-Methoxy-N-(2-phenylsulfonylethyl)aniline 9e.

A stirred

solution of 2-anisidine (0.60 ml, 5.32 mmol) and phenyl vinyl

sulfone (900 mg, 5.32 mmol) in EtOH was heated at reﬂux for

3 days. The reaction mixture was concentrated in vacuo and

puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 4), and recrystallised from light petroleum–ethyl acetate to

give the title compound as a grey crystalline solid (1.14g, 74%),

mp 76–77 ЊC (Found: MH^ϩ, 292.1007. C₁₅H₁₇NO₃S ϩ H

requires 292.1007); ν_max(KBr)/cm^Ϫ13429, 2943, 1603, 1140,

744; δ_H(300 MHz; CDCl₃) 7.94 (2H, m, PhH), 7.68 (1H, m,

PhH), 7.57 (2H, m, PhH), 6.84 (1H, m, ArH), 6.73 (2H, m,

ArH), 6.47 (1H, m, ArH), 4.59 (1H, br s, NH), 3.81 (3H, s,

OMe), 3.63 (2H, t, J 6.6, NCH₂), 3.41 (2H, t, J 6.6, NCH₂CH₂);

δ_C(75 MHz; CDCl₃) 147.2, 139.1, 136.3, 133.9 (CH), 129.4

(CH), 128.0 (CH), 121.2 (CH), 117.5 (CH), 109.7 (CH), 109.6

(CH), 55.4 (CH₂), 54.9 (CH₂), 37.3 (Me); m/z (EI) 291 (M^ϩ,

28%) 149 (56), 134 (57), 120 (55), 85 (46), 83 (68).

J 16.5, 9.9, ᎐CH), 6.29 (1H, d, J 16.5, ᎐CHH), 6.09 (1H, d,

᎐

J 9.9, ᎐CHH ), 4.24 (2H, s, CH ).

᎐

2

Conjugate addition reactions to vinyl sulfones; preparation of N-

(2-phenylsulfonylethyl)- and N-(2-benzylsulfonylethyl)anilines 9

4-Bromo-N-(2-phenylsulfonylethyl)aniline 9f.

A

stirred

4-Methyl-N-(2-phenylsulfonylethyl)aniline 9a.

A

stirred

solution of 4-bromoaniline (500 mg, 2.9 mmol) and phenyl

vinyl sulfone (978 mg, 5.8 mmol) in ethanol (20 ml) was heated

at reﬂux for 3 days. The reaction mixture was concentrated

in vacuo and puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 4) to give the title compound (172 mg, 17%)

as a pale orange solid, mp 91–93 ЊC (Found: M^ϩ, 338.9934.

C₁₄H₁₄⁷⁹BrNO₂S requires 338.9929); ν_max(KBr)/cm^Ϫ13367,

2991, 2946, 1594, 1292, 1147, 808; δ_H(400 MHz; CDCl₃) 7.91

(2H, m, PhH), 7.67 (1H, m, PhH), 7.57 (2H, m, PhH), 7.23 (2H,

m, ArH), 6.40 (2H, m, ArH), 3.55 (2H, t, J 6.2, NCH₂), 3.34

(2H, t, J 6.2, NCH₂CH₂); NH not observed; δ_C(100 MHz;

CDCl₃) 145.5, 138.9, 134.1 (CH), 132.1 (CH), 129.5 (CH), 127.9

(CH), 114.6 (CH), 110.0, 54.5 (CH₂), 37.7 (CH₂); m/z (EI)

340/338 (M^ϩ, 34%), 196 (100), 195 (17), 183 (54), 117 (20).

solution of 4-toluidine (1.86 g, 17.3 mmol) and phenyl vinyl

sulfone (3.5 g, 20.8 mmol) in EtOH (20 ml) was heated at reﬂux

for 3 days. The reaction mixture was concentrated in vacuo and

puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 3) to give the title compound (4.76 g, 99%) as a colourless

solid, mp 78–79 ЊC (from light petroleum – ethyl acetate)

(Found: MH^ϩ, 276.1061. C₁₅H₁₇NO₂S ϩ H requires 276.1058);

ν_max(KBr)/cm^Ϫ13410, 2967, 2927, 1616, 1519, 1288, 1142, 1082,

808, 752; δ_H(300 MHz; CDCl₃) 7.93 (2H, m, PhH), 7.69 (1H,

m, PhH), 7.59 (2H, m, PhH), 6.99 (2H, d, J 8.5, ArH), 6.47 (2H,

d, J 8.5, ArH), 3.59 (2H, t, J 6.3, NCH₂), 3.37 (2H, t, J 6.3,

NCH₂CH₂), 2.24 (3H, s, Me); NH not observed; δ_C(75 MHz;

CDCl₃) 144.2, 139.0, 134.0 (CH), 129.9 (CH), 129.5 (CH), 128.0

(CH), 127.7, 113.4 (CH), 54.8 (CH₂), 38.0 (CH₂), 20.4 (Me); m/z

(CI) 275 (M^ϩ, 100%), 134 (2), 132 (10).

3-Methoxy-N-(2-phenylsulfonylethyl)aniline 9g.

A stirred

4-Methoxy-N-(2-phenylsulfonylethyl)aniline 9c.

solution of 4-anisidine (133 mg, 1.1 mmol), and phenyl vinyl

sulfone (200 mg, 1.2 mmol, 1.1 equiv.) in ethanol (5 ml) was

A

stirred

solution of 3-anisidine (0.46 ml, 4.04 mmol) and phenyl vinyl

sulfone (1.36 g, 8.12 mmol) in ethanol (20 ml) was heated at

reﬂux for 3 days. The reaction mixture was concentrated

J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

1681

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in vacuo and puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 3) to give the title compound (887 mg, 75%) as

a grey crystalline solid, mp 48–49 ЊC (Found: M^ϩ, 291.0923.

C₁₅H₁₇NO₃S requires 291.0929); ν_max(KBr)/cm^Ϫ13439, 2952,

1618, 1515, 1294, 1169, 1143, 756; δ_H(400 MHz; CDCl₃) 7.91

(2H, m, PhH), 7.67 (1H, m, PhH), 7.57 (2H, m, PhH), 7.06 (1H,

t, J 8.1, ArH), 6.30 (1H, dd, J 8.1, 2.3, ArH), 6.14 (1H, dd,

J 8.1, 2.2, ArH), 6.08 (1H, m, ArH), 3.74 (3H, s, OMe), 3.56

(2H, t, J 6.2, NCH₂), 3.36 (2H, t, J 6.2, NCH₂CH₂); NH not

observed; δ_C(100 MHz; CDCl₃) 160.8, 147.9, 138.9, 134.0

(CH), 130.1 (CH), 129.4 (CH), 127.9 (CH), 106.0 (CH), 103.4

(CH), 99.1 (CH), 55.1 (Me), 54.7 (CH₂), 37.6 (CH₂); m/z (EI)

291 (M^ϩ, 72%), 150 (14), 149 (100), 148 (56), 136 (83), 135 (10),

134 (12), 77 (40).

6.55 (1H, d, J 7.9, ArH), 4.25 (2H, s, CH₂Ph), 3.73 (2H, t, J 6.0,

NCH₂), 3.15 (2H, t, J 6.0, NCH₂CH₂), 2.15 (3H, s, Me); NH

not observed; δ_C(75 MHz; CDCl₃) 144.6, 130.7 (CH), 130.6

(CH), 129.2 (CH), 129.1 (CH), 127.6, 127.2 (CH), 123.0, 118.1

(CH), 109.6 (CH), 60.8 (CH₂), 49.8 (CH₂), 37.3 (CH₂), 17.5

(Me); m/z (EI) 289 (M^ϩ, 42%), 134 (18), 133 (28), 120 (41), 118

(100), 106 (14), 77 (9).

Method B. A stirred solution of 2-toluidine (260 mg,

2.4 mmol) and benzyl vinyl sulfone (365 mg, 2.0 mmol) in dry

THF (15 ml) was heated at reﬂux in the presence of DBU

(30 mg, 0.2 mmol) for 50 h. The reaction mixture was con-

centrated and the residue puriﬁed by silica gel column

chromatography to aﬀord the title compound (390 mg, 67%).

2-Nitro-N-(2-benzylsulfonylethyl)aniline 9k.

A

stirred

solution of 2-nitroaniline (345 mg, 2.5 mmol) and benzyl vinyl

sulfone (365 mg, 2.0 mmol) in dry THF (15 ml) was heated at

reﬂux in the presence of DBU (45 mg, 0.3 mmol) for 6 days. The

reaction mixture was concentrated and the residue puriﬁed by

silica gel column chromatography to aﬀord the title compound

(320 mg, 50%) as a yellow crystalline solid, mp 172–173 ЊC

(dichloromethane–light petroleum) (Found: M^ϩ, 320.0822.

C₁₅H₁₆N₂O₄S requires 320.0831); ν_max(KBr)/cm^Ϫ13385, 1624,

1568, 1358, 1312, 1265, 1224, 1127, 738, 697, 513; δ_H(400 MHz;

CDCl₃) 8.20 (1H, dd, J 8.5, 2.0, ArH), 8.17 (1H, br s, NH), 7.47

(1H, t, J 8.5, ArH), 7.42–7.36 (5H, m, PhH), 6.81 (1H, d, J 8.5,

ArH), 6.74 (1H, dt, J 7.5, 2.0, ArH), 4.30 (2H, s, CH₂Ph), 3.82

(2H, t, J 6.8, NCH₂), 3.18 (2H, t, J 6.8, NCH₂CH₂); δ_C(100

MHz; CDCl₃) 144.0, 136.5 (CH), 130.6 (CH), 129.4 (CH), 129.3

(CH), 127.4, 127.2 (CH), 116.5 (CH), 113.0 (CH), 61.1 (CH ₂),

49.6 (CH₂), 36.0 (CH₂); 1 C not observed; m/z (EI) 320 (M^ϩ,

23%), 286 (4), 221 (6), 164 (17), 134 (51), 91 (100).

4-Methyl-N-(2-benzylsulfonylethyl)aniline 9h. Method A.

A stirred solution of 4-toluidine (120 mg, 1.1 mmol) and benzyl

vinyl sulfone (182 mg, 1.0 mmol) in absolute ethanol (15 ml)

was heated at reﬂux for 3 days. The reaction was then concen-

trated under reduced pressure and the residue puriﬁed on silica

gel eluting with ethyl acetate–light petroleum (1 : 2) to give the

title compound (250 mg, 87%) as a pale yellow solid, mp

96–98 ЊC (Found: M^ϩ, 289.1124. C₁₆H₁₉NO₂S requires

289.1137); ν_max(KBr)/cm^Ϫ13355, 2940, 2909, 1609, 1522, 1291,

1112, 810, 692, 513; δ_H(300 MHz; CDCl₃) 7.42–7.34 (5H, m,

PhH), 7.03 (2H, d, J 8.1, ArH), 6.55 (2H, d, J 8.1, ArH), 4.26

(2H, s, CH₂Ph), 3.64 (2H, t, J 6.0, NCH₂), 3.10 (2H, t, J 6.0,

NCH₂CH₂), 2.27 (3H, s, Me); NH not observed; δ_C(75 MHz;

CDCl₃) 144.2, 130.7 (CH), 130.1 (CH), 129.13 (CH), 129.07

(CH), 127.9, 127.8, 113.5 (CH), 60.8 (CH₂), 49.9 (CH₂), 37.9

(CH₂), 20.4 (Me); m/z (EI) 289 (M^ϩ, 53%), 133 (95), 120 (41),

106 (13), 91 (100), 77 (15).

Method B. A stirred solution of 4-toluidine (40 mg,

0.37 mmol) and benzyl vinyl sulfone (60 mg, 0.33 mmol) in dry

THF (8 ml) was heated at reﬂux in the presence of DBU (10 mg,

0.07 mmol) for 13 h. The reaction mixture was concentrated

and the residue puriﬁed by silica gel column chromatography to

aﬀord the title compound (70 mg, 74%), mp 96–98 ЊC.

Preparation of indoles 11

Methyl 3,5-dimethyl-1-(2-phenylsulfonylethyl)indole-2-carb-

oxylate 11a. A solution of 4-methyl-N-(2-phenylsulfonyl-

ethyl)aniline 9a (500 mg, 1.82 mmol), diazo compound 2a (522

mg, 3.67 mmol) and dirhodium() acetate (10 mg) in chloro-

form (25 ml) was heated at reﬂux for 1.5 h. The reaction was

concentrated in vacuo and puriﬁed on silica eluting with ethyl

acetate–light petroleum (1 : 4) to give the intermediate 10a

(440 mg, 62%) as a yellow oil.

This was then immediately dissolved in toluene (15 ml) and

Amberlyst^®(110 mg) was then added and the mixture heated

at reﬂux overnight. The reaction mixture was cooled, concen-

trated in vacuo and puriﬁed on silica eluting with ethyl acetate–

light petroleum (1 : 5) to give the title compound (296 mg, 71%)

as a colourless solid, mp 139–140 ЊC (from ethyl acetate–light

petroleum) (Found: [M ϩ NH₄]^ϩ, 389.1532. C₂₀H₂₁NO₄S ϩ

NH₄requires 389.1535); ν_max(KBr)/cm^Ϫ13446, 2954, 2918,

1691, 1259, 1146, 1126, 1084; δ_H(300 MHz; CDCl₃) 7.86 (2H,

m, PhH), 7.66 (1H, m, PhH), 7.55 (2H, m, H-6,7), 7.39 (1H, ∼s,

H-4), 7.18 (2H, m, PhH), 4.82 (2H, t, J 7.4, NCH₂), 3.86 (3H, s,

OMe), 3.60 (2H, t, J 7.4, NCH₂CH₂), 2.48 (3H, s, Me), 2.45

(3H, s, Me); δ_C(75 MHz; CDCl₃) 163.1, 139.0, 136.3, 133.8

(CH), 129.3 (CH), 128.0, 127.8 (CH), 127.5 (CH), 123.5, 121.9,

120.3, 109.5 (CH), 97.4 (CH), 55.6 (CH₂), 51.5 (Me), 38.9

(CH₂), 21.3 (Me), 10.7 (Me); m/z (EI) 371 (M^ϩ, 17%), 229 (22),

198 (17), 170 (17), 142 (22), 115 (23), 77 (100), 51 (37), 42 (39).

4-Methoxy-N-(2-benzylsulfonylethyl)aniline 9i.

A stirred

solution of 4-anisidine (245 mg, 2.0 mmol) and benzyl vinyl

sulfone⁴⁵(545 mg, 3.0 mmol) in ethanol (20 ml) was heated at

reﬂux for 3 days. The reaction mixture was concentrated

in vacuo and puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 2) to give the title compound (541 mg, 89%) as

a pale orange solid, mp 84–86 ЊC (Found: M^ϩ, 305.1091.

C₁₆H₁₉NO₃S requires 305.1086); ν_max(KBr)/cm^Ϫ12286, 2913,

1515, 1241, 1114, 815, 703; δ_H(300 MHz; CDCl₃) 7.33–7.35

(5H, m, PhH), 6.81 (2H, m, ArH), 6.60 (2H, m, ArH), 4.28 (2H,

s, CH₂Ph), 3.77 (3H, s, OMe), 3.63 (2H, t, J 6.0, NCH₂), 3.09

(2H, t, J 6.0, NCH₂CH₂); NH not observed; δ_C(75 MHz;

CDCl₃) 152.9, 140.6, 130.7 (CH), 129.1 (CH), 129.0 (CH),

127.8, 115.0 (CH), 114.8 (CH), 60.8 (CH₂), 55.8 (Me), 49.9

(CH₂), 38.5 (CH₂); m/z (EI) 305 (M^ϩ, 100), 150 (25), 149 (82),

136 (45), 134 (23), 122 (28), 119 (20), 91 (66), 85 (21), 71 (26), 69

(22).

2-Methyl-N-(2-benzylsulfonylethyl)aniline 9j. Method A. A

stirred solution of 2-toluidine (360 mg, 3.4 mmol) and benzyl

vinyl sulfone (546 mg, 3.0 mmol) in absolute ethanol (20 ml)

was heated at reﬂux for 8 days. The reaction was followed by

NMR spectroscopy for the disappearance of distinct vinyl

protons. The reaction mixture was then concentrated under

reduced pressure and the residue puriﬁed on silica gel eluting

with ethyl acetate–light petroleum (1 : 2) to give the title

compound (630 mg, 73%) as a pale orange solid, mp 113–115 ЊC

(Found: M^ϩ, 289.1130. C₁₆H₁₉NO₂S requires 289.1137);

ν_max(KBr)/cm^Ϫ13360, 3027, 2971, 2909, 1603, 1516, 1450, 1327,

1286, 1112, 748, 687, 477; δ_H(300 MHz; CDCl₃) 7.32–7.20 (5H,

m, PhH), 7.16–7.08 (2H, m, ArH), 6.73 (1H, t, J 7.4, ArH),

Methyl

3-ethyl-5-methyl-1-(2-phenylsulfonylethyl)indole-2-

carboxylate 11b. A solution of 4-methyl-N-(2-phenylsulfonyl-

ethyl)aniline 9a (623 mg, 2.26 mmol), diazo compound 2b (530

mg, 3.39 mmol) and dirhodium() acetate (10 mg) in chloro-

form (25 ml) was heated at reﬂux for 1.5 h. The reaction mixture

was concentrated in vacuo and puriﬁed on silica eluting with

ethyl acetate–light petroleum (1 : 5) to give the intermediate 10b

(575 mg, 63%) as a yellow oil.

This was then immediately dissolved in toluene (15 ml) and

Amberlyst^®(110 mg) was added and the mixture heated at

1682

J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

View Online

reﬂux overnight. The reaction mixture was cooled, concen-

trated in vacuo and puriﬁed on silica eluting with ethyl acetate–

light petroleum (1 : 6) to give the title compound (361 mg, 66%)

as a pink solid, mp 134–135 ЊC (ethyl acetate–light petroleum)

(Found: MH^ϩ, 386.1426. C₂₁H₂₃NO₄S ϩ H requires 386.1426);

ν_max(KBr)/cm^Ϫ13435, 2968, 1695, 1540, 1437, 1363, 1151, 744;

δ_H(300 MHz; CDCl₃) 7.90 (2H, m, PhH), 7.66 (1H, m, PhH),

7.55 (2H, m, PhH), 7.41 (2H, br, ArH), 7.18 (1H, br s, H-4),

4.81 (2H, t, J 7.4, NCH₂), 3.86 (3H, s, OMe), 3.62 (2H, t, J 7.4,

NCH₂CH₂), 2.99 (2H, q, J 7.4, CH₂Me), 2.45 (3H, s, Me), 1.18

(3H, t, J 7.4, CH₂Me); δ_C(75 MHz; CDCl₃) 162.9, 139.2, 136.4,

133.8, 129.9 (CH), 129.3, 128.4, 127.9 (CH), 127.8, 127.8 (CH),

126.6 (CH), 120.2, 109.6 (CH), 55.6 (CH₂), 51.5 (Me), 38.9

(CH₂), 21.4 (Me), 18.6 (CH₂), 15.5 (Me); m/z (EI) 385 (M^ϩ,

35%), 326 (63), 228 (34), 184 (28), 143 (25), 115 (26), 77 (100).

acetate (10 mg) in chloroform (5 ml) was heated at reﬂux for

1.5 h. The reaction mixture was then concentrated in vacuo

and puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 4) to give the intermediate 10e (189 mg, 90%) as a yellow

solid.

This was then dissolved in toluene (5 ml) and Amberlyst^®

(110 mg) added and the mixture heated at reﬂux overnight. The

reaction mixture was ﬁltered, the ﬁltrate concentrated in vacuo

and then puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 4) to give the title compound (88 mg, 48%)

as a colourless oil (Found: MH^ϩ, 388.1217. C₂₀H₂₁NO₅S ϩ H

requires 388.1219); ν_max(ﬁlm)/cm^Ϫ13448, 2951, 1733, 1701,

1350, 1306, 1232, 1159, 1087, 769, 534; δ_H(300 MHz; CDCl₃)

7.97 (2H, m, PhH), 7.70 (1H, m, PhH), 7.61 (2H, m, PhH), 7.20

(1H, d, J 8.0, ArH), 7.02 (1H, ∼t, J 8.0, H-5), 6.70 (1H, d, J 8.0,

ArH), 5.04 (2H, m, NCH₂), 3.86 (3H, s, Me), 3.84 (3H, s, Me),

3.73 (2H, m, NCH₂CH₂), 2.48 (3H, s, Me); δ_C(75 MHz; CDCl₃)

162.7, 147.3, 139.5, 133.7 (CH), 129.5, 129.3 (CH), 128.1 (CH),

124.8, 122.1, 120.6 (CH), 113.2 (CH), 105.6 (CH), 57.0 (Me),

55.2 (Me), 51.6 (CH₂), 41.4 (CH₂), 10.9 (Me); 1 C unobserved;

m/z (EI) 387 (M^ϩ, 15%), 248 (78), 220 (100), 186 (50), 125 (21),

94 (43), 78 (80), 44 (19).

Methyl 5-methoxy-3-methyl-1-(2-phenylsulfonylethyl)indole-

2-carboxylate 11c. A solution of 4-methoxy-N-(2-phenyl-

sulfonylethyl)aniline 9c (525 mg, 1.80 mmol), diazo compound

2a (384 mg, 2.7 mmol, 1.5 equiv.) and dirhodium() acetate

(10 mg) in chloroform (10 ml) was heated at reﬂux for 1.5 h the

reaction mixture was then concentrated in vacuo and puriﬁed

on silica eluting with ethyl acetate–light petroleum (1 : 2) to give

the intermediate 10c (544 mg, 78%) as a pale yellow oil.

This was then dissolved in toluene (5 ml) and Amberlyst^®

(110 mg) added and the mixture heated at reﬂux overnight. The

reaction mixture was ﬁltered, the ﬁltrate concentrated in vacuo

and then puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 4) to give the title compound (365 mg, 49%)

as a colourless solid, mp 118–119 ЊC (Found: [M ϩ NH₄]^ϩ,

405.1479. C₂₀H₂₁NO₅S ϩ NH₄requires 405.1484); ν_max(KBr)/

cm^Ϫ13427, 1707, 1444, 1209, 1146, 737; δ_H(300 MHz; CDCl₃)

7.85 (2H, m, PhH), 7.65 (1H, m, PhH), 7.53 (2H, m, PhH), 7.20

(1H, d, J 9.1, H-7), 7.03 (1H, dd, J 9.1, 2.2, H-6), 6.97 (1H, d,

J 2.2, H-4), 4.82 (2H, m, NCH₂), 3.87 (6H, s, OMe), 3.61 (2H,

m, NCH₂CH₂), 2.47 (3H, s, Me); δ_C(75 MHz; CDCl₃) 162.0,

154.6, 139.0, 133.8 (CH), 133.3, 129.3 (CH), 127.8, 127.5, 123.9,

121.6, 117.4 (CH), 110.8 (CH), 101.1 (CH), 55.8 (Me), 55.7

(CH₂), 51.5 (Me), 39.0 (CH₂), 10.9 (Me); m/z (ES) 410 (M^ϩNa,

100%), 405 (10), 388 (15), 269 (10), 215 (7), 161 (7), 129 (23), 97

(38).

Methyl 5-bromo-3-methyl-1-(2-phenylsulfonylethyl)indole-2-

carboxylate 11f. A solution of 4-bromo-N-(2-phenylsulfonyl-

ethyl)aniline 9f (126 mg, 0.37 mmol), diazo compound 2a (79

mg, 0.56 mmol, 1.5 equiv.) and dirhodium() acetate in chloro-

form (5 ml) was heated at reﬂux for 1.5 h. The reaction mixture

was then concentrated in vacuo and puriﬁed on silica eluting

with ethyl acetate–light petroleum (1 : 3) to give the inter-

mediate 10f (61 mg, 36%) as a yellow oil.

The intermediate 10f was then immediately dissolved in

chloroform (5 ml), Amberlyst^®(110 mg) added and the mixture

heated at reﬂux overnight. The reaction mixture was then

ﬁltered, the ﬁltrate concentrated in vacuo and then puriﬁed on

silica eluting with ethyl acetate–light petroleum (1 : 3) to give

the title compound (44 mg, 79%) as a pale orange solid, mp 188–

189 ЊC (Found: M^ϩ, 435.0147. C₁₉H₁₈⁷⁹BrNO₄S requires

435.0140); ν_max(KBr)/cm^Ϫ13411, 2927, 1697, 1145; δ_H(300

MHz; CDCl₃) 7.84 (2H, m, PhH), 7.74 (1H, d, J 1.9, H-4), 7.65

(1H, m, PhH), 7.52 (2H, m, PhH), 7.43 (1H, dd, J 8.9, 1.9, H-6),

7.21 (1H, d, J 8.9, H-7), 4.83 (2H, t, J 7.2, NCH₂), 3.88 (3H, s,

OMe), 3.61 (2H, t, J 7.2, NCH₂CH₂), 2.44 (3H, s, Me); δ_C(100

MHz; CDCl₃) 162.7, 138.9, 136.4, 133.8 (CH), 133.1, 129.3

(CH), 128.9 (CH), 127.7 (CH), 124.4, 123.5 (CH), 121.5, 113.6,

111.5 (CH), 55.6 (CH₂), 51.7 (Me), 39.1 (CH₂), 10.7 (Me); m/z

(EI) 437/435 (M^ϩ, 97%), 295 (92), 294 (30), 293 (100), 281 (33),

279 (49), 261 (31), 236 (23), 234 (25), 233 (32), 77 (49).

Methyl 3,7-dimethyl-1-(2-phenylsulfonylethyl)indole-2-carb-

oxylate 11d. A solution of 9d (150 mg, 0.55 mmol), diazo

compound 2a (200 mg, 1.4 mmol, 2.8 equiv.) and dirhodium()

acetate (10 mg) in chloroform (5 ml) was heated at reﬂux for

1.5 h. The reaction mixture was then concentrated in vacuo and

puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 4) to give the intermediate 10d (156 mg, 73%) as a pale

yellow oil.

Methyl 4-methoxy-3-methyl-1-(2-phenylsulfonylethyl)indole-

2-carboxylate 11g¹and methyl 6-methoxy-3-methyl-1-(2-

phenylsulfonylethyl)indole-2-carboxylate 11g². A solution of

3-methoxy N-(2-phenylsulfonylethyl)aniline 9g (430 mg,

1.5 mmol) and diazo compound 2a (315 mg, 2.2 mmol) and

dirhodium() acetate (10 mg) in chloroform (7 ml) was heated

at reﬂux for 1.5 h. The reaction was then concentrated in vacuo

and puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 4) to give the intermediate 10g (383 mg, 63%) as a colourless

solid. This was then dissolved in toluene (10 ml), Amberlyst^®

(110 mg) added and the mixture heated at reﬂux overnight. The

reaction mixture was ﬁltered, the ﬁltrate concentrated in vacuo

and then puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 5) to give the title compounds methyl 4-methoxy-

3-methyl-1-(2-phenylsulfonylethyl)indole-2-carboxylate (21 mg,

6%) and methyl 6-methoxy-3-methyl-1-(2-phenylsulfonylethyl)-

indole-2-carboxylate (87 mg, 24%).

This was then dissolved in toluene (5 ml) and Amberlyst^®

(110 mg) added and the mixture heated at reﬂux overnight. The

reaction mixture was ﬁltered, the ﬁltrate concentrated in vacuo

and then puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 3) to give the title compound (76 mg, 51%)

as a colourless solid, mp 103–104 ЊC (Found: MH^ϩ, 372.1266.

C₂₀H₂₁NO₄S ϩ H requires 372.1270); ν_max(KBr)/cm^Ϫ13448,

2958, 1701, 1451, 1306, 1228, 1147, 741; δ_H(300 MHz; CDCl₃)

7.94 (2H, m, PhH), 7.68 (1H, m, PhH), 7.58 (2H, m, PhH), 7.47

(1H, m, ArH), 7.06 (2H, m, ArH), 5.07 (2H, m, NCH₂),

3.87 (3H, s, OMe), 3.58 (2H, m, NCH₂CH₂), 2.64 (3H, s, Me),

2.49 (3H, s, Me); δ_C(75 MHz; CDCl₃) 162.9, 139.1, 137.3, 133.9

(CH), 133.7, 129.3 (CH), 128.6, 128.0 (CH), 124.7, 123.3, 121.3

(CH), 20.5 (CH), 119.0 (CH), 56.8 (CH₂), 52.0 (Me), 40.2

(CH₂), 20.4 (Me), 10.9 (Me); m/z (EI) 371 (M^ϩ, 80%), 229 (88),

216 (99), 198 (94), 170 (71), 142 (64), 115 (86), 77 (100).

Methyl 4-methoxy-3-methyl-1-(2-phenylsulfonylethyl)indole-

2-carboxylate 11g¹. Mp 140–142 ЊC (ethyl acetate–light

petroleum) (Found: M^ϩ, 387.1139. C₂₀H₂₁NO₅S requires

387.1140); ν_max(KBr)/cm^Ϫ13430, 2942, 1297, 1249, 1147, 736;

Methyl 7-methoxy-3-methyl-1-(2-phenylsulfonylethyl)indole-

2-carboxylate 11e. A solution of 9e (150 mg, 0.52 mmol), diazo

compound 2a (200 mg, 1.4 mmol, 2.7 equiv.) and dirhodium()

J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

1683

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δ_H(400 MHz; CDCl₃) 7.90 (2H, m, PhH), 7.66 (1H, m, PhH),

7.55 (2H, m, PhH), 7.22 (1H, t, J 8.0, H-6), 6.83 (1H, d, J 8.0,

ArH), 6.46 (1H, d, J 8.0, ArH), 4.77 (2H, m, NCH₂), 3.90 (3H,

s, OMe), 3.84 (3H, s, OMe), 3.60 (2H, m, NCH₂CH₂), 2.69 (3H,

s, Me); δ_C(100 MHz; CDCl₃) 163.0, 156.7, 139.5, 138.9, 133.8

(CH), 129.2 (CH), 127.8 (CH), 126.8 (CH), 123.6, 122.5, 117.5,

102.4 (CH), 100.0 (CH), 55.5 (CH₂), 55.2 (Me), 51.4 (Me), 39.2

(CH₂), 12.8 (Me); m/z (EI) 387 (M^ϩ, 100), 328 (21), 245 (39),

232 (18), 230 (13), 214 (27), 187 (13), 186 (15), 149 (10), 77 (26).

Methyl 6-methoxy-3-methyl-1-(2-phenylsulfonylethyl)indole-

2-carboxylate 11g². Mp 122–123 ЊC (Found: M^ϩ, 387.1138);

ν_max3431, 2950, 1697, 1309, 1222, 1162; δ_H(300 MHz; CDCl₃)

7.87 (2H, m, PhH), 7.64 (1H, m, PhH), 7.52 (2H, m, PhH), 7.47

(1H, d, J 8.8, H-4), 6.80 (1H, dd, J 8.8, 2.0, H-5), 6.72 (1H, d,

J 2.0, H-7), 4.80 (2H, t, J 7.3, NCH₂), 3.87 (3H, s, OMe), 3.84

(3H, s, OMe), 3.62 (2H, t, J 7.3, NCH₂CH₂), 2,45 (3H, s, Me);

δ_C(100 MHz; CDCl₃) 162.9, 159.5, 139.0, 138.9, 133.7 (CH),

129.2 (CH), 127.7 (CH), 123.1, 122.4, 121.9 (CH), 121.7, 111.9

(CH), 91.6 (CH), 55.6 (Me), 55.5 (CH₂), 51.3 (Me), 38.9 (CH₂),

10.9 (Me); m/z (EI) 387 (M^ϩ, 100%), 328 (15), 246 (14), 245

(39), 232 (18), 214 (29), 187 (14), 186 (18), 77 (23).

133.4, 130.8 (CH), 129.0 (CH), 128.9 (CH), 127.5, 127.4, 124.0,

121.7, 117.7 (CH), 111.2 (CH), 111.2 (CH), 101.2 (CH),

60.1 (CH₂), 55.8 (Me), 51.8 (CH₂), 51.6 (Me), 51.6 (Me), 39.2

(CH₂), 11.0 (Me); m/z (EI) 401 (M^ϩ, 100%), 245 (57), 232 (30),

219 (13), 215 (9), 214 (48), 199 (7), 188 (16), 173 (8), 160 (8), 145

(13), 144 (12).

Methyl 3,7-dimethyl-1-(2-benzylsulfonylethyl)indole-2-carb-

oxylate 11j. A solution of 2-methyl N-(2-benzylsulfonylethyl)-

aniline 9j (100 mg, 0.35 mmol), diazo compound 2a (98 mg,

0.7 mmol) and dirhodium() acetate (6 mg) in chloroform

(15 ml) was heated at reﬂux for 2 h. The same reaction can also

be performed at room temperature for 6 h. The reaction

mixture was then ﬁltered, concentrated in vacuo and puriﬁed on

a silica gel column eluting with ethyl acetate–light petroleum

(1 : 3) to give the intermediate 10j (84 mg, 60%) as a yellow oil.

This was then immediately dissolved in dry toluene (15 ml)

and Amberlyst^®(50 mg) was added and the mixture heated

at reﬂux for 12 h. The reaction mixture was cooled, ﬁltered,

concentrated under reduced pressure and puriﬁed on a silica gel

column eluting with ethyl acetate–light petroleum (1 : 4) to

obtain the title compound (62 mg, 78%) as a colourless solid, mp

180–181 ЊC (Found: M^ϩ, 385.1351. C₂₁H₂₃NO₄S requires

385.1348); ν_max(KBr)/cm^Ϫ12945, 2920, 1706, 1455, 1450, 1301,

1224, 1107, 784, 743, 692, 523; δ_H(300 MHz; CDCl₃) 7.53–7.50

(1H, m, ArH), 7.39–7.37 (5H, m, PhH), 7.09–7.05 (2H, m,

ArH), 5.17 (2H, t, J 7.7, NCH₂), 4.22 (2H, s, CH₂Ph), 3.95 (3H,

s, OMe), 3.37 (2H, t, J 7.7, NCH₂CH₂), 2.72 (3H, s, Me), 2.54

(3H, s, Me); δ_C(75 MHz; CDCl₃) 163.3, 137.2, 130.9 (CH),

130.6, 129.5 (CH), 129.1 (CH), 129.0 (CH), 127.4, 124.6, 123.2,

121.5, 120.6 (CH), 119.1 (CH), 60.1 (Me), 52.8 (CH₂), 51.7

(CH₂), 39.7 (CH₂), 20.6 (Me), 11.0 (Me); m/z (EI) 385 (M^ϩ,

27%), 354 (100), 232 (16), 204 (43), 200 (14), 183 (16), 172 (25).

Methyl 1-(2-benzylsulfonylethyl)-3,5-dimethylindole-2-carb-

oxylate 11h. A solution of 4-methyl N-(2-benzylsulfonylethyl)-

aniline 9h (60 mg, 0.21 mmol), diazo compound 2a (59 mg,

0.42 mmol) and dirhodium() acetate (4 mg) in chloroform (15

ml) was heated at reﬂux for 2 h. The same reaction can also be

performed at room temperature for 6 h. The reaction mixture

was then ﬁltered, concentrated in vacuo and puriﬁed on a silica

gel column eluting with ethyl acetate–light petroleum (1 : 3)

to give the intermediate 10h (55 mg, 65%) as a yellow oil. This

was then immediately dissolved in dry toluene (10 ml) and

Amberlyst^®(30 mg) was added and the mixture heated at reﬂux

for 12 h. The reaction mixture was cooled, ﬁltered, concen-

trated under reduced pressure and puriﬁed on a silica gel col-

umn eluting with ethyl acetate–light petroleum (1 : 4) to obtain

the title compound (33 mg, 62%) as a colourless solid, mp 160–

162 ЊC (Found: M^ϩ, 385.1345. C₂₁H₂₃NO₄S requires 385.1348);

ν_max(KBr)/cm^Ϫ12950, 2925, 1706, 1537, 1429, 1358, 1306, 1250,

1122, 784, 697; δ_H(300 MHz; CDCl₃) 7.45–7.22 (8H, m, ArH),

4.89 (2H, t, J 7.0, NCH₂), 4.07 (2H, s, CH₂Ph), 3.94 (3H, s,

OMe), 3.39 (2H, t, J 7.0, NCH₂CH₂), 2.57 (3H, s, Me), 2.47

(3H, s, Me); δ_C(75 MHz; CDCl₃) 163.3, 136.5, 130.8 (CH),

130.0, 129.2, 129.0 (CH), 128.9 (CH), 128.2 (CH), 127.5, 123.7,

121.9, 120.4 (CH), 109.9 (CH), 60.0 (Me), 51.7 (CH₂), 51.6

(CH₂), 39.0 (CH₂), 21.4 (Me), 10.9 (Me); m/z (EI) 385 (M^ϩ,

28%), 326 (7), 229 (28), 207 (73), 198 (27), 178 (30), 142 (15),

115 (35), 91 (100).

Deprotection of 1-(2-ethoxycarbonylethyl)-, (2-phenylsulfonyl-

ethyl)- and (2-benzylsulfonylethyl)-indoles 11

Methyl 3,5-dimethylindole-2-carboxylate 12a. (a) From

methyl

1-(2-ethoxycarbonylethyl)-3,5-dimethylindole-2-carb-

oxylate 8a. Potassium tert-butoxide (55 mg, 0.49 mmol) was

added to a stirred solution of indole 8a (50 mg, 0.16 mmol) in

DMF (5 ml) at room temperature under N₂and the mixture

stirred at this temperature overnight. Hydrochloric acid (1 M;

15 ml) was then added and the aqueous layer extracted with

ethyl acetate (3 × 20 ml). The combined organic layers were

then washed with hydrochloric acid (1 M; 2 × 20 ml), water

(20 ml), dried (Na₂SO₄) and concentrated in vacuo. The residue

was then puriﬁed on silica eluting with ethyl acetate–light

petroleum (1 : 11.5) to give the title compound (20 mg, 60%) as a

colourless solid, mp 122–123 ЊC (Found: MH^ϩ, 204.1021.

C₁₂H₁₃NO₂ϩ H requires 204.1024); ν_max(KBr)/cm^Ϫ13431,

3319, 1683, 1469, 1263, 800, 779; δ_H(300 MHz; CDCl₃) 8.58

(1H, br s, NH), 7.44 (1H, m, H-4), 7.27 (1H, d, J 8.5, H-7), 7.16

(1H, dd, J 8.5, 1.7, H-6), 3.95 (3H, s, OMe), 2.59 (3H, s, Me),

2.47 (3H, s, Me); δ_C(75 MHz; CDCl₃) 163.1, 134.3, 129.2,

128.7, 127.6 (CH), 123.3, 120.1 (CH), 119.9, 111.3 (CH), 51.7

(Me), 21.5 (Me), 9.9 (Me); m/z (EI) 203 (M^ϩ, 55), 171 (100), 143

(31), 142 (42), 115 (25).

Methyl 1-(2-benzylsulfonylethyl)-5-methoxy-3-methylindole-

2-carboxylate 11i. A solution of 4-methoxy-N-(2-benzylsulf-

onylethyl)aniline 9i (133 mg, 0.44 mmol) and diazo compound

2a (124 mg, 0.87 mmol) and dirhodium() acetate (10 mg) in

chloroform (10 ml) was heated at reﬂux for 1.5 h. The reaction

was then concentrated in vacuo and puriﬁed on silica eluting

with ethyl acetate–light petroleum (1 : 3) to give the inter-

mediate 10i (181 mg, 98%) as a pale yellow oil.

This was dissolved in toluene (5 ml), Amberlyst^®(110 mg)

added and the mixture heated at reﬂux overnight. The reaction

mixture was ﬁltered, the ﬁltrate concentrated in vacuo and then

puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 3) and recrystallised (dichloromethane–hexane) to give

the title compound (66 mg, 37%) as a colourless solid, mp

159–161 ЊC (Found: M^ϩ, 401.1298. C₂₁H₂₃NO₅S requires

401.1297); ν_max(KBr)/cm^Ϫ13853, 3750, 2949, 1700, 1436, 1218,

1120, 667; δ_H(300 MHz; CDCl₃) 7.41 (1H, d, J 9.0, H-7), 7.36

(3H, m, PhH), 7.24 (2H, m, PhH), 7.09 (1H, dd, J 9.0, 2.4, H-6),

7.03 (1H, d, J 2.4, H-4), 4.89 (2H, t, J 6.9, NCH₂), 4.05 (2H, s,

CH₂), 3.94 (3H, s, OMe), 3.88 (3H, s, OMe), 3.39 (2H, t, J 6.9,

NCH₂CH₂), 2.57 (3H, s, Me); δ_C(75 MHz; CDCl₃) 163.2, 154.7,

(b) From methyl 3,5-dimethyl-1-(2-phenylsulfonylethyl)-

indole-2-carboxylate 11a. (i) A solution of methyl 3,5-dimethyl-

1-(2-phenylsulfonylethyl)indole-2-carboxylate 11a (80 mg,

0.22 mmol) and potassium tert-butoxide (73 mg, 0.65 mmol) in

DMF (5 ml) was stirred for 17 h at room temperature. Work-up

as above gave the title compound (39 mg, 87%) as a colourless

solid.

(ii) To a stirred solution of methyl 3,5-dimethyl-1-(2-

phenylsulfonylethyl)indole-2-carboxylate 11a (50 mg, 0.13

mmol) and triethylamine (0.19 ml, 1.35 mmol) in DMF (1 ml)

was added DBN (0.10 ml, 0.77 mmol) and the resulting mixture

was then heated at reﬂux for 2 h. The reaction mixture was

then cooled and diluted with ether (20 ml), washed with water

1684

J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

View Online

(2 × 20 ml), dried (Na₂SO₄) and concentrated in vacuo. This was

then puriﬁed on silica eluting with ethyl acetate–light petroleum

(9 : 1) to give the title compound (15 mg, 59%) as a colourless

solid.

cm^Ϫ13326, 2966, 2952, 1700, 1677, 1652, 1558, 1540, 1251, 667;

δ_H(400 MHz; CDCl₃) 8.56 (1H, br s, NH), 7.47 (1H, br s, H-4),

7.27 (1H, d, J 8.4, H-7), 7.16 (1H, dd, J 8.4, 1.5, H-6), 3.95 (3H,

s, OMe), 3.10 (2H, q, J 7.4, CH₂Me), 2.46 (3H, s, Me), 1.28 (3H,

t, J 7.4, CH₂Me); δ_C(100 MHz; CDCl₃) 162.8, 134.3, 129.2,

127.7, 127.5 (CH), 126.6, 122.4, 120.0 (CH), 111.4 (CH), 51.6

(Me), 21.5 (Me), 18.0 (CH₂), 15.4 (Me). This compound could

not be obtained completely pure.

(iii) To a stirred solution of methyl 3,5-dimethyl-1-(2-

phenylsulfonylethyl)indole-2-carboxylate 11a (50 mg, 0.13

mmol) and triethylamine (0.19 ml, 1.35 mmol) in DMF (3 ml)

was added DBU (0.12 ml, 0.81 mmol) and the mixture heated at

reﬂux for 2 h. The reaction mixture was then cooled, diluted

with ether (20 ml), washed with water (2 × 30 ml), dried

(Na₂SO₄) and concentrated in vacuo. This was then puriﬁed on

silica eluting with ethyl acetate–light petroleum (1 : 6) to give

the title compound (11 mg, 42%) as a colourless solid.

(c) From methyl 1-(2-benzylsulfonylethyl)-3,5-dimethyl-

indole-2-carboxylate 11h. A solution of indole 11h (70 mg,

0.18 mmol) and potassium tert-butoxide (41 mg, 0.36 mmol) in

dry DMF (15 ml) was stirred for 15 min at room temperature.

The reaction mixture was carefully acidiﬁed using dilute HCl

(pH 5) and diluted with water (35 ml). The aqueous layer was

extracted with ethyl acetate (3 × 15 ml). The combined organic

layers were then washed with water, brine, dried (MgSO₄) and

concentrated under reduced pressure. The residue was then

puriﬁed on silica gel column eluting with ethyl acetate–light

petroleum (1 : 4) to obtain (i) the title compound (26 mg, 70%)

as a colourless solid, and (ii) pyrrolo[1,2-a]indol-1-one 13a

(6 mg, 9%) as a colourless solid, mp 165–167 ЊC (data given

below).

Methyl 7-methoxy-3-methylindole-2-carboxylate 12d. Potas-

sium tert-butoxide (44 mg, 0.39 mmol) was added to a stirred

solution of indole 11e (51 mg, 0.13 mmol) in DMF (5 ml) at

room temperature under N₂and the mixture stirred at this tem-

perature overnight. Hydrochloric acid (1 M; 15 ml) was then

added and the aqueous layer extracted with ethyl acetate

(3 × 30 ml). The combined organic layers were then washed

with hydrochloric acid (1 M; 2 × 20 ml), water (30 ml), dried

(Na₂SO₄) and concentrated in vacuo. The residue was then

puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 5) to give the title compound (31 mg, 55%) as a colourless

solid: mp 143–144 ЊC (lit.,⁵⁷mp 144–145 ЊC) (Found: MH^ϩ,

220.0978. C₁₂H₁₃NO₃ϩ H requires 220.0974); δ_H(300 MHz;

CDCl₃) 8.86 (1H, br s, NH), 7.26 (1H, d, J 8.2, H-6), 7.07 (1H,

dd, J 8.2, 7.4, H-5), 6.74 (1H, d, J 7.4, H-4), 3.97 (3H, s, OMe),

3.95 (3H, s, OMe), 2.61 (3H, s, Me); δ_C(75 MHz; CDCl₃) 160.2,

147.3, 136.9, 135.8, 127.0, 120.7, 120.4 (CH), 113.1 (CH), 104.4

(CH), 55.4 (Me), 51.6 (Me), 10.2 (Me); m/z (EI) 219 (M^ϩ, 16%),

158 (21), 100 (35), 98 (62), 52 (100).

Methyl 5-methoxy-3-methylindole-2-carboxylate 12b. (a)

From methyl 1-(2-ethoxycarbonylethyl)-5-methoxy-3-methyl-

indole-2-carboxylate 8b. A solution of indole 8b (0.065 g, 0.20

mmol) and potassium tert-butoxide (0.68 g, 0.60 mmol) in

DMF (5 ml) was stirred overnight. Hydrochloric acid (1 M;

15 ml) was added and the mixture extracted with ethyl acetate.

The organic layer was washed twice with hydrochloric acid

(1 M) and then with water. The organic layer was separated,

dried (MgSO₄) and concentrated. The residue was puriﬁed by

column chromatography (dichloromethane–light petroleum) to

yield the title compound as a colourless solid (0.34 g, 77%), mp

151–153 ЊC (lit.,⁵⁷mp 156 ЊC) (Found: C, 65.2; H, 6.0; N, 6.0.

C₁₂H₁₃NO₃requires C, 65.7; H, 6.0; N, 6.4%); ν_max(KBr)/cm^Ϫ1

3342, 2993, 2960, 2933, 1670, 1631; δ_H(300 MHz; CDCl₃) 8.56

(1H, br s, NH), 7.26 (1H, m, ArH), 7.00 (2H, m, ArH), 3.94

(3H, s, OMe), 3.88 (3H, s, OMe), 2.58 (3H, s, Me); δ_C(100

MHz; CDCl₃) 163.0, 154.3, 131.3, 128.7, 123.7, 119.7, 117.2

(CH), 122.6 (CH), 101.0 (CH), 55.8 (Me), 51.6 (Me), 10.0 (Me);

m/z (EI) 219 (M^ϩ, 15%), 188 (9), 187 (53), 172 (23), 144 (23),

89 (100).

Methyl 6-methoxy-3-methylindole-2-carboxylate 12e. To a

stirred solution of methyl 6-methoxy-3-methyl-1-(2-phenyl-

sulfonylethyl)indole-2-carboxylate 11g²(30 mg, 0.08 mmol) in

DMF (5 ml) at room temperature under nitrogen, was added

potassium tert-butoxide (26 mg, 0.23 mmol) and stirring was

continued overnight. HCl (1 M; 15 ml) was then added and the

aqueous layer extracted with ethyl acetate (3 × 30 ml). The

organic extracts were then combined, washed with HCl (1 M;

2 × 20 ml), water (30 ml), dried (Na₂SO₄) and concentrated

in vacuo. This was then puriﬁed on silica eluting with ethyl

acetate–light petroleum (1 : 4) to give the title compound (6 mg,

34%) as a colourless solid, mp 146–148 ЊC (Found: M^ϩ,

219.0890. C₁₂H₁₃NO₃requires 219.0895); ν_max(KBr)/cm^Ϫ13430

(br), 3336, 1674, 1540, 1471, 1257, 1216, 667; δ_H(300 MHz;

CDCl₃) 8.56 (1H, br s, NH), 7.53 (1H, d, J 9.3, ArH), 6.81 (2H,

m, ArH), 3.94 (3H, s, OMe), 3.87 (3H, s, OMe), 2.58 (3H, s,

Me); δ_C(75 MHz; CDCl₃) 154.2, 148.9, 119.7(C), 117.2 (CH),

112.6 (CH), 100.9 (CH), 55.7 (Me), 51.6 (Me), 9.9 (Me); 3 C

unobserved; m/z (ES) 219 (M^ϩ, 100%), 60 (3).

(b) From methyl 1-(2-benzylsulfonylethyl)-5-methoxy-3-

methylindole-2-carboxylate 11i. A solution of methyl 1-(2-

benzylsulfonylethyl)-5-methoxy-3-methylindole-2-carboxylate

11i (30 mg, 0.07 mmol) and potassium tert-butoxide (25 mg,

0.22 mmol) in DMF (5 ml) was stirred at room temperature

overnight under nitrogen. HCl (1 M; 5 ml) was then added and

the aqueous layer extracted with ethyl acetate (3 × 15 ml). The

combined organic layers were then washed with HCl (1 M;

2 × 20 ml), water (20 ml), dried (Na₂SO₄) and concentrated

in vacuo. This was then puriﬁed on silica eluting with ethyl

acetate–light petroleum (1 : 6) to give the title compound (15 mg,

91%) as a colourless solid.

Methyl 3,7-dimethylindole-2-carboxylate 12f. A solution of

indole carboxylate 11j (50 mg, 0.13 mmol) and potassium

tert-butoxide (30 mg, 0.27 mmol) in dry DMF (8 ml) was stirred

for 15 min at room temperature. Work-up as above gave the title

compound (15 mg, 58%) as a colourless solid, mp 117–118 ЊC

(Found: M^ϩ203.0954. C₁₂H₁₃NO₂requires 203.0946); ν_max

(KBr)/cm^Ϫ13360, 2925, 1680, 1547, 1460, 1373, 1317, 1240,

1209, 784, 743, 615; δ_H(300 MHz; CDCl₃) 8.62 (1H, br, NH),

7.53 (1H, d, J 7.7, ArH), 7.14–7.05 (2H, m, ArH), 3.97 (3H, s,

OMe), 2.62 (3H, s, Me), 2.51 (3H, s, Me); δ_C(100 MHz; CDCl₃)

163.2, 135.7, 128.1, 125.9 (CH), 123.0, 121.0, 120.9, 120.2 (CH),

118.4 (CH), 51.7 (Me), 16.6 (Me), 10.1 (Me); m/z (EI) 203 (M^ϩ,

64%), 171 (100), 143 (46), 115 (35), and (ii) and pyrrolo-

[1,2-a]indol-1-one 13b (5 mg, 11%) as a colourless solid, mp

195–196 ЊC (data given below).

Methyl 3-ethyl-5-methylindole-2-carboxylate 12c. A stirred

solution of methyl 3-ethyl-5-methyl-1-(2-phenylsulfonylethyl)-

indole-2-carboxylate 11b (100 mg, 0.26 mmol) and DBN

(0.3 ml, 2.59 mmol) in DMF (5 ml) was heated at reﬂux for 2 h.

The reaction mixture was then diluted with ether (20 ml),

washed with water (2 × 40 ml), dried (Na₂SO₄) and concen-

trated in vacuo. This was then puriﬁed on silica eluting with

ethyl acetate–light petroleum (1 : 9) to give the title compound

(15 mg, 27%) as a colourless solid, mp 109–112 ЊC; ν_max(KBr)/

7,9-Dimethyl-2-benzylsulfonyl-2,3-dihydro-1H-pyrrolo[1,2-a]-

indol-1-one 13a. A solution of methyl 3,5-dimethyl-1-(2-

benzylsulfonylethyl)indole-2-carboxylate 11h (30 mg, 0.08

mmol) and potassium tert-butoxide (20 mg, 0.18 mmol) in

freshly prepared dry THF (10 ml) was stirred for 20 min at

J. Chem. Soc., Perkin Trans. 1, 2002, 1672–1687

1685

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room temperature. The solvent was concentrated under reduced

pressure and the residue was taken in water and carefully

acidiﬁed (pH 5) using dilute HCl. The aqueous acidic solution

was extracted with ethyl acetate (3 × 15 ml). The combined

organic layers were washed with water, brine, dried (MgSO₄)

and concentrated in vacuo. The residue was then puriﬁed on

silica gel column eluting with ethyl acetate–light petroleum

(1 : 4) to obtain the title compound (25 mg, 91%) as a colourless

solid, mp 165–167 ЊC (Found: C, 67.8; H, 5.3; N, 3.8.

C₂₀H₁₉NO₃S requires C, 68.0; H, 5.4; N, 4.0); ν_max(KBr)/cm^Ϫ1

2925, 2848, 1696, 1573, 1301, 1132, 794, 697, 651, 518;

δ_H(400 MHz; CDCl₃) 7.66–7.63 (2H, m, ArH), 7.47 (1H, d,

J 8.5, H-5 or H-6), 7.43–7.42 (3H, m, ArH), 7.23–7.22 (2H,

m, ArH), 5.05 (1H, d, J 14.1, CHHPh), 4.82 (1H, m, H-2),

4.52–4.41 (3H, m, H-3, including 1H, d, J 14.1, CHHPh), 2.58

(3H, s, Me), 2.46 (3H, s, Me); δ_C(100 MHz; CDCl₃) 182.4,

134.5, 132.7, 131.4 (CH), 131.1, 130.9, 129.3 (CH), 129.2 (CH),

129.1 (CH), 127.6, 121.5 (CH), 115.8, 110.3 (CH), 65.8 (CH),

58.3 (CH₂), 38.9 (CH₂), 21.6 (Me), 9.0 (Me); m/z (EI) 353 (M^ϩ,

57%), 198 (100), 170 (14), 154 (16), 142 (20), 115 (16), 91 (46).

in dry DMF (4 ml) was added slowly to a stirred solution of

NaH (60% in oil, 37 mg, 0.92 mmol) in DMF (5 ml) under

a nitrogen atmosphere. After 10 min 2-phenylsulfonylethyl

chloride (189 mg, 0.92 mmol) in DMF (5 ml) was added and the

reaction mixture stirred at room temperature overnight. Ether

(10 ml) was then added and the reaction mixture washed with

water (2 × 50 ml). The combined aqueous layer was then

extracted with ether (2 × 50 ml) and ethyl acetate (2 × 40 ml).

The combined organic layers were then washed with brine (50

ml), dried (MgSO₄), concentrated in vacuo and puriﬁed on silica

eluting with ethyl acetate–light petroleum (1 : 7) to give the title

compound (219 mg, 67%) as a pale yellow solid, mp 109–111 ЊC

(Found: [M ϩ NH₄]^ϩ, 375.1380. C₁₉H₁₉NO₄S ϩ NH₄requires

375.1379); ν_max(KBr)/cm^Ϫ13431(b), 3049, 1701, 1448, 1308,

1147, 1085, 744, 702; δ_H(400 MHz; CDCl₃) 7.90 (2H, m, PhH),

7.64 (2H, m, PhH and ArH), 7.54 (2H, m, PhH), 7.36 (2H, m,

ArH), 7.24 (1H, s, H-3), 7.17 (1H, m, ArH), 4.93 (2H, t, J 7.4,

NCH₂), 4.33 (2H, q, J 7.0, OCH₂Me), 3.66 (2H, t, J 7.4,

NCH₂CH₂), 1.39 (3H, t, J 7.1, OCH₂Me); δ_C(100 MHz;

CDCl₃) 161.7, 138.9, 138.6, 133.8 (CH), 129.3 (CH), 127.7

(CH), 127.0, 126.0, 125.6 (CH), 122.7 (CH), 121.2 (CH), 111.5

(CH), 110.0 (CH), 60.8 (CH₂), 55.5 (CH₂), 38.5 (CH₂), 14.3

(Me); m/z (CI) 375 (M ϩ NH₄, 4%), 358 (10), 218 (36), 188 (48),

186 (100), 143 (10), 125 (45), 95 (8), 94 (68), 78 (63), 44 (22).

5,9-Dimethyl-2-benzylsulfonyl-2,3-dihydro-1H-pyrrolo[1,2-a]-

indol-1-one 13b. A solution of methyl 3,7-dimethyl-1-(2-

benzylsulfonylethyl)indole-2-carboxylate 11j (50 mg, 0.08

mmol) and potassium tert-butoxide (30 mg, 0.27 mmol) in

freshly prepared dry THF (10 ml) was stirred for 15 min at

room temperature. Work-up as above gave the title compound

(40 mg, 87%) as a colourless solid, mp 195–196 ЊC (Found: C,

67.8; H, 5.4; N, 3.9. C₂₀H₁₉NO₃S requires C, 68.0; H, 5.4; N,

4.0); ν_max(KBr)/cm^Ϫ12914, 1701, 1562, 1342, 1317, 1291, 1153,

779; δ_H(400 MHz; CDCl₃) 7.65–7.63 (2H, m, ArH), 7.52 (1H,

d, J 8.1, H-6 or H-8), 7.43–7.42 (3H, m, ArH), 7.09–7.03 (2H,

m, ArH), 5.10 (1H, m), 5.05 (1H, d, J 14.0, CHHPh), 4.76 (1H,

m), 4.48–4.43 (2H, m, including 1H, d, J 14.0, CHHPh), 2.64

(3H, s, Me), 2.59 (3H, s, Me); δ_C(100 MHz; CDCl₃) 182.4,

136.0, 132.7, 131.3 (CH), 129.3 (CH), 129.2 (CH), 127.9 (CH),

127.6, 122.3, 121.5 (CH), 120.1 (CH), 116.7, 65.7 (CH), 58.3

(CH₂), 41.5 (CH₂), 17.9 (Me), 9.0 (Me); 1 C not observed;

m/z (EI) 353 (M^ϩ, 68%), 198 (100), 170 (17), 154 (14), 142 (18),

115 (22), 91 (55).

5-Methoxyindole 14a. To a stirred solution of 5-methoxy-1-

(2-phenylsulfonylethyl)indole 15a (106 mg, 0.34 mmol) in

DMF (5 ml) at room temperature under nitrogen was added

potassium tert-butoxide (113 mg, 1.01 mmol), stirring was then

continued overnight. Hydrochloric acid (1 M; 30 ml) was

then added and the aqueous layer extracted with ethyl acetate

(3 × 40 ml). The combined organic layers were then washed

with hydrochloric acid (1 M; 2 × 40 ml), water (2 × 100 ml),

dried (Na₂SO₄) and concentrated in vacuo. This was then

puriﬁed on silica eluting with ethyl acetate–light petroleum

(1 : 9) to give the title compound (46 mg, 91%) as a colourless

solid, mp 54–56 ЊC, identical with an authentic sample.

Ethyl indole-2-carboxylate 14b. To a stirred solution of ethyl

1-(2-phenylsulfonylethyl)indole-2-carboxylate 15b (55 mg,

0.15 mmol) in DMF (5 ml) at room temperature, under nitrogen

was added potassium tert-butoxide (52 mg, 0.46 mmol) and

stirring was continued overnight. Hydrochloric acid (1 M; 5 ml)

was then added and the aqueous layer washed with ethyl acetate

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

with hydrochloric acid (1 M; 2 × 20 ml), water (20 ml), dried

(Na₂SO₄) and concentrated in vacuo. This was then puriﬁed on

silica eluting with ethyl acetate–light petroleum (1 : 7) to give

the title compound (28 mg, 100%) as a pale yellow solid,

mp 121–123 ЊC, identical with an authentic sample.

Protection and deprotection of indoles 14

5-Methoxy-(2-phenylsulfonylethyl)indole 15a. A solution of

5-methoxyindole 14a (100 mg, 68 mmol) in dry DMF (1.0 ml)

was added to a stirred solution of NaH (60% in oil, 30 mg,

1.23 mmol) in dry DMF (3 ml) at room temperature under

a nitrogen atmosphere. When gas evolution had stopped,

2-phenylsulfonylethyl chloride (278 mg, 1.36 mmol) in dry

DMF (2 ml) was added and stirring continued overnight. The

reaction mixture was then diluted with ether (50 ml), washed

with water (2 × 50 ml) and concentrated in vacuo. Ethyl acetate

was then added to the residue, the mixture ﬁltered and the

ﬁltrate concentrated in vacuo. This was then puriﬁed on silica

eluting with ethyl acetate–light petroleum (1 : 6) to give the

title compound (157 mg, 73%) as a brown oil (Found: MH^ϩ,

316.1011. C₁₇H₁₇NO₃S ϩ H requires 316.1007); ν_max(KBr)/

cm^Ϫ13412, 2935, 2832, 1487, 1446, 1307, 1240, 1147, 728;

δ_H(300 MHz; CDCl₃) 7.85 (2H, m, PhH), 7.64 (1H, m, PhH),

7.52 (2H, m, PhH), 7.05 (2H, m, ArH), 6.96 (1H, d, J 3.0, ArH),

6.85 (1H, dd, J 8.8, 2.7, H-6), 6.35 (1H, d, J 3.0, ArH), 4.53

(2H, t, J 7.4, NCH₂), 3.83 (3H, s, OMe), 3.53 (2H, t, J 7.4,

NCH₂CH₂); δ_C(75 MHz; CDCl₃) 154.4, 138.8, 134.1 (CH),

130.6, 129.5 (CH), 129.3, 127.9 (CH), 127.7 (CH), 112.3 (CH),

109.4 (CH), 103.0 (CH), 102.2 (CH), 55.9 (Me), 55.5 (CH₂),

40.0 (CH₂); m/z (EI) 315 (M^ϩ, 52%), 173 (100), 158 (46), 129

(45), 117 (26), 102 (57), 77 (43), 51 (30).

Acknowledgements

We thank the EPSRC and Tripos Receptor Research Ltd for

a CASE award (K.E.B.), the Cancer Research Campaign

(now Cancer Research UK) for support of our work (E.S.), the

Royal Society and the Indian National Science Academy for an

international exchange grant (S.M.), and the EPSRC Mass

Spectrometry Service at Swansea for mass spectra. We also

thank Professor Richard Taylor (University of York) for details

of the preparation of benzyl vinyl sulfone.

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Article Doi

N-H insertion reactions of rhodium carbenoids. Part 3. The development of a modified Bischler indole synthesis and a new protecting-group strategy for indoles

DOI: 10.1039/b202666j

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