Fischer indolisation of 2,6-dialkyl and 2,4,6-trialkylphenylhydrazones of diketones and ketoesters

Article abstract of DOI:10.1016/S0040-4039(03)01364-9

Unlike the migration of a methyl group observed in the ZnCl₂ or acetic acid-catalysed indolisation of phenylhydrazones, dry ethanolic HCl catalysed indolisation of 2,6-dimethyl- and 2,4,6-trimethylphenylhydrazones of various substituted butane-2,3-diones and ethyl pyruvates yields 7-methyl- and 5,7-dimethyl-3-substituted indoles indicating elimination of an ortho-methyl group during indolisation.

Full text of DOI:10.1016/S0040-4039(03)01364-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5665–5668
Fischer indolisation of 2,6-dialkyl and
2,4,6-trialkylphenylhydrazones of diketones and ketoestersꢀ
Shambabu J. Maddirala,† Vidya S. Gokak,‡ Sharanabasava B. Rajur§ and
Linganagouda D. Basanagoudar*
Department of Chemistry, Karnatak University, Dharwad 580 003, India
Received 14 April 2003; revised 22 May 2003; accepted 30 May 2003
Abstract—Unlike the migration of a methyl group observed in the ZnCl2 or acetic acid-catalysed indolisation of phenylhydra-
zones, dry ethanolic HCl catalysed indolisation of 2,6-dimethyl- and 2,4,6-trimethylphenylhydrazones of various substituted
butane-2,3-diones and ethyl pyruvates yields 7-methyl- and 5,7-dimethyl-3-substituted indoles indicating elimination of an
ortho-methyl group during indolisation.
© 2003 Elsevier Ltd. All rights reserved.
The Fischer indole synthesis, which is based on the
discovery1 that cyclisations of arylhydrazones form
indoles, has become one of the most versatile and widely
studied reactions in organic chemistry as it provides a
versatile and convergent route to a wide variety of indole
derivatives. Owing to its numerous synthetic applications,
the mechanism of the reaction has attracted much
attention. A number of reaction pathways have been
proposed for the indolisation reaction, but the mechanism
proposed by Robinson and Robinson2a in its reformu-
lated form by Carlin and Fischer2c is the most widely
accepted and is well supported by polarisation studies,3
labelling experiments4 and isolation of reaction interme-
diates. Dienylimines of the kind 1,5a 2,5b and 35b have been
isolated and characterised providing good evidence for
the postulated reaction mechanism, including stereo-
chemical rationalisation.
In addition to group migration, some anomalous
reactions7d,e such as elimination and substitution reac-
tions have also been observed lending support to the
proposed mechanism. It has been ascertained that the
mechanistic details of the reaction depend upon the
reaction conditions, nature of hydrazone substrate,
nature of cyclising agent and the nature of the solvent.
So, it is doubtful if any definitive mechanism applies under
all conditions.
2,6-Dialkyl substituted phenyl hydrazones have been
important intermediates in mechanistic studies of Fischer
indolisation reactions.7 Indole derivatives are known to
be formed by migration of an alkyl group (usually a
methyl group) to the adjacent C-atom (i.e. a 1,2-shift)7a,b
or to the C-atom in the para position (a 1,4-shift).7c In
some cases a methyl group was observed to be lost but
its fate was not established.8
One of the strongest supports for Robinson’s mechanism
is from the studies of group migration during the
reaction, particularly of halogens6 and alkyl groups.7a,b
During the course of our studies9 on the synthesis of
indole-fused heterocycles, a number of 3-substituted
Keywords: indole; phenylhydrazones; Fischer indolisation; Japp–Klingemann procedure.
ꢀ Supplementary data associated with this article can be found at doi:10.1016/S0040-4039(03)01364-9
* Corresponding author.
† Present address: Ciba India Private Limited, Goregaon, Mumbai 400 063, India.
‡ Present address: Pearl Organics Limited, Patalganga Industrial Area, Mumbai 410207, India
§ Present address: CreaGen Biosciences, Inc. Needham, MA, USA
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01364-9

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2-acetylindoles and substituted ethyl indole-2-carboxyl-
ates were synthesised via Fischer indolisation of appro-
priate N-unsubstituted phenyl hydrazones using HCl as
the cyclising agent. Although, Fischer indolisation of
2,6-dimethylphenylhydrazones of ethyl pyruvates has
been studied, 2,6-dimethylphenylhydrazones of dike-
tones that would yield 2-acetylindoles on Fischer
indolisation have not been explored. It was, therefore,
decided to undertake Fischer indolisation of such ortho
disubstituted phenylhydrazones, namely, 2,6-dimethyl-
phenylhydrazones of various substituted butane-2,3-
diones 4–7 with the purpose of checking the course of
indolisation and the effect of the nature of the sub-
stituents of these diones on the reaction course. The
hydrazones were obtained by the modified Japp–
Klingemann procedure.10a Fischer indolisation of these
hydrazones 4a–7a, using ethanolic hydrogen chlo-
ride,10b furnished products, in 15–35% yields, whose
analytical data and in particular NMR spectral data
indicated the presence of only one (instead of two)
aromatic methyl groups, suggesting the loss of one of
the ortho-methyl groups during cyclisation. This fact
was confirmed by the independent synthesis of these
indoles 12–15, in 32–62% yields, from the appropriate
hydrazones 8a–11a under identical conditions. The ele-
when 2,4,6-trimethyl analogues of the above phenylhy-
drazones 4b–7b were subjected to similar indolisation,
the same type of products, with methyl groups having
been lost, were obtained and were again confirmed by
independent syntheses of the indoles from hydrazones
8b–11b as depicted in Scheme 1.
To verify the generality of this loss of methyl groups
during cyclisation, we subjected 2,6-dimethylphenylhy-
drazones of ethyl pyruvates 4c–7c and the 2,4,6-
trimethyl analogues of ethyl 2-ketobutyrates 4d–7d,
prepared using the Japp–Klingemann procedure, to
Fischer indolisation. Ethyl indole-2-carboxylates 12c–
15c, 12d–15d in 12–40% yields, respectively, were the
products of these reactions as concluded from 1H NMR
spectral and analytical data. The structures of the ethyl
indole-2-carboxylates 12c–15c and 12d–15d were confi-
rmed by independent syntheses from appropriate
hydrazones 8c–11c and 8d–11d in 22–87% yields.
We could not trace the fate of the eliminated methyl
groups but the formation of products forces us to
accept the view proposed by Bajwa and Brown8 that
the ortho-methyl group is eliminated as a methyl carbo-
cation whose mechanism may be depicted as shown in
Scheme 2. The cyclisation and subsequent amortisation
of the dienone-imine intermediate appears to be the
main driving force for the elimination of the methyl
1
mental analyses, IR and H NMR spectra of indoles
12–15 obtained from hydrazones 4a–7a agreed well
with those obtained from hydrazones 8a–11a confirm-
ing the elimination of the ortho-methyl groups. Further,
Scheme 1. Reagents: (i) NaOH–ethanol/AcONa; (ii) KOH–ethanol; (iii) ethanolic dry HCl.

S. J. Maddirala et al. / Tetrahedron Letters 44 (2003) 5665–5668
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Scheme 2. Mechanism for the elimination of the methyl group.
group as a carbocation, probably, coordinated with a
good nucleophile (H2O) via a concerted path. It
appears that the nature of the ketone or pyruvate has
no influence on the course of indolisation.
dar, L. D. Indian J. Chem. 1990, 29B, 1113; (d) Rajur, S.
B.; Merwade, A. Y.; Basanagoudar, L. D.; Kulkarni, PV.
J. Pharm. Sci. 1989, 78, 780; (e) Rajur, S. B.; Merwade,
A. Y.; Basanagoudar, L. D. J. Pharm. Sci 1990, 79, 168.
10. (a) General procedure: The phenylhydrazones 4–11a,b
were prepared in 62–88% yields by a modified Japp–
Klingemann procedure, while the hydrazones 4–11c,d
were obtained by the usual Japp–Klingemann procedure
in 60–90% yields. Hydrazones 4a, 6a–8a, 10a, 11a, 6b, 7b,
8b, 10b, 11b and 8d were solids and all other hydrazones
were viscous oils.
References
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Soc. 1943, 65, 611; (c) Carlin, R. B.; Fischer, E. E. J. Am.
Chem. Soc. 1948, 70, 3421.
(b) General procedure for cyclisation of phenylhydrazones:
Dry hydrogen chloride gas was passed into a solution of
appropriate phenylhydrazone in ethanol until saturated.
The solution was then heated under reflux on a steam
bath for 3 h, then cooled and poured onto crushed ice.
The whole solution was extracted with ether. The ether
solution was washed with water, dried over anhydrous
Na2SO4 and the ether was removed by distillation under
reduced pressure. The residual solid was purified by
column chromatography over alumina using benzene as
eluant. (c) With phenylhydrazones 4a and 8a cyclisation
could not be effected. Attempted cyclisation did not give
the expected product, but the starting phenylhydrazone
was recovered (100%).
3. Arbuzov, A. E.; Kitaev, Y. P. J. Gen. Chem. USSR. 1957,
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Am. Chem. Soc. 1959, 81, 4673; (c) Miller, B.; Matjeka,
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S. B. Indian J. Chem. 1991, 30B, 883; (b) Rajur, S. B.;
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Spectroscopic data for selected compounds (analytical and
spectroscopic data for all the compounds associated with
this article can be found on-line.):
Compound 13a from 5a Yield 23% (35% from 9a), melt-
ing point 158°C; IR (cm−1) 3352, 1635; 1H NMR (CDCl3)
200 MHz: l 2.47 (s, 3H), 2.64 (s, 6H), 7.05 (t, J=7.9 Hz,
1H), 7.13 (d, J=7.0 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H),
8.85 (brs, 1H). Anal. calcd for C12H13NO: C, 77.00; H,
6.95; N, 7.49. Found: C, 77.52, H, 7.02, N, 7.71%.
Compound 13b from 5b Yield 21% (32% from 9b), melt-
ing point 198°C; IR (cm−1) 3342, 1645; 1H NMR (CDCl3)
200 MHz: l 1.88 (s, 3H), 2.12 (s, 3H), 2.23 (s, 3H), 2.35
(s, 3H), 7.1–7.2 (m, 2H), 9.0 (brs, 1H). Anal. calcd for
C13H15NO: C, 77.61; H, 7.46; N, 6.96. Found: C, 77.81,
H, 7.76; N, 7.19%. Compound 13c from 5c Yield 28%
(48% from 9c), melting point 148°C; IR (cm−1) 3335,

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S. J. Maddirala et al. / Tetrahedron Letters 44 (2003) 5665–5668
(62% from 9d), melting point 153°C; IR (cm−1) 3450,
1705; H NMR (CDCl3) 200 MHz: l 1.44 (t, J=7.1 Hz,
3H), 2.43 (s, 3H), 2.46 (s, 3H), 2.57 (s, 3H), 4.42 (q,
J=7.1 Hz, 2H), 6.96–7.28 (2s, 2H), 8.51 (brs, 1H). Anal.
calcd for C14H17NO2: C, 72.73; H, 7.36, N, 6.06. Found:
C, 72.91, H, 7.65, N, 6.16%.
1
1688; H NMR (CDCl3) 200 MHz: l 1.44 (t, J=7.1 Hz,
3H), 2.49 (s, 3H), 2.60 (s, 3H), 4.42 (q, J=7.1 Hz, 2H),
7.06 (t, J=7.7 Hz, 1H), 7.11 (d, J=7.0 Hz, 1H), 7.50 (d,
J=7.6 Hz, 1H), 8.58 (brs, 1H). Anal. calcd for
C13H15NO2: C, 71.89; H, 6.91, N, 6.45. Found: C, 72.06,
H, 7.04, N, 6.58%. Compound 13d from 5d Yield 22%
1