Addition of pyrroles to electron deficient olefins employing InCl3

Article abstract of DOI:10.1016/S0040-4039(01)01697-5

Pyrroles undergo conjugate addition with electron deficient olefins in the presence of a catalytic amount of indium trichloride at ambient temperature to afford the corresponding Michael adducts in excellent yields with high selectivity without polymerisa

Full text of DOI:10.1016/S0040-4039(01)01697-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8063–8065
Addition of pyrroles to electron deficient olefins employing InCl3
J. S. Yadav,* Sunny Abraham, B. V. Subba Reddy and G. Sabitha
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 25 June 2001; revised 31 August 2001; accepted 7 September 2001
Abstract—Pyrroles undergo conjugate addition with electron deficient olefins in the presence of a catalytic amount of indium
trichloride at ambient temperature to afford the corresponding Michael adducts in excellent yields with high selectivity without
polymerisation. © 2001 Elsevier Science Ltd. All rights reserved.
The syntheses and reactions of pyrroles have attracted
much research interest for over a century because a
number of pyrrole containing compounds such as
chlorophyll, haemin, vitamin B12, indigo and bile pig-
ments are widely distributed in nature.1 Since the 2-
position of pyrrole is the preferred site for electrophilic
substitution, 2-alkyl or 2-acyl pyrroles are versatile
intermediates for the synthesis of a wide range of
pyrrole derivatives.2 Generally C-alkyl pyrroles are
synthesised3 by Wolff–Kishner reduction of 2-formyl or
2-acetyl pyrroles that are obtained by the Vilsmeier–
Haack method.4 Other methods for C-alkylation of
pyrroles involve the isomerisation of N-alkyl pyrroles5
by thermal rearrangement at high temperature, result-
ing in the 2- and 3-alkyl pyrroles. Alternatively, 2- and
3-alkyl pyrroles are prepared6 using pyrrolylmagnesium
halides. These indirect methods are used to obtain
C-alkylated pyrroles as they tend to polymerise under
most reaction conditions.
dichloromethane gave 4-(2%-pyrrolyl)butan-1-one in
85% yield. Similarly, various a,b-unsaturated com-
pounds reacted well with pyrrole to give the corre-
sponding 2-alkylated products in high yields (Scheme 1,
Table 1).8
The reactions proceeded smoothly at ambient tempera-
ture with high selectivity. Other electron deficient
olefins like phenyl vinyl ketone, benzyl vinyl ketone,
2-benzylidenemalononitrile and bis(benzylidene) ketone
afforded the products in good yields. In the case of
bis(benzylidene) ketone, no bis-alkylated product was
observed under the reaction conditions (Table 1, entry
f). Furthermore, treatment of b-nitrostyrene with
pyrrole in the presence of 10 mol% InCl3 produced the
corresponding 2-alkylated pyrrole in 78% yield (Scheme
2).
The reactions are clean and the products are obtained
in high yields without the formation of any side prod-
ucts such as dimers or trimers that are normally
observed under the influence of strong acids. In addi-
tion, the reaction conditions are very mild so that no
side products or decomposition of the products are
observed.
To date, the direct synthesis of 2-alkyl pyrroles remains
a challenge for synthetic chemists because of their
sensitivity to air and acids. Acid-catalysed reactions of
pyrrole are limited and require careful control of acidity
to prevent side reactions. As such, there is no report on
the conjugate addition of pyrrole with electron deficient
olefins to give 2-alkylated derivatives. Following the
The procedure does not require any acidic promoters or
activators or anhydrous conditions. The reaction of
pyrrole with a,b-unsaturated ketones probably pro-
7
recent surge in activity on the use of InCl3 as a mild
Lewis acid, we report herein a simple and direct method
for the synthesis of 2-alkyl pyrroles using InCl3.
Treatment of pyrrole with methyl vinyl ketone in the
presence of
a
catalytic amount of InCl3 in
Keywords: indium trichloride; pyrrole; a,b-unsaturated compounds.
* Corresponding author. Fax: +91-040-7170512; e-mail: yadav@
iict.ap.nic.in
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01697-5

8064
J. S. Yada6 et al. / Tetrahedron Letters 42 (2001) 8063–8065
Table 1. InCl3-catalysed alkylation of pyrroles with a,b-unsaturated compounds
in high yields by increasing the reaction time and
changing the molar ratio of reactants (Scheme 4).
ceeds through an intermediate s-complex, as shown in
Scheme 3.
It should be noted that the reaction of a,b-unsaturated
ketones with pyrroles afforded 2,5-dialkylated products
In general, a,b-unsaturated ketones, b-nitrostyrenes
and benzylidene malononitrile worked well under the

J. S. Yada6 et al. / Tetrahedron Letters 42 (2001) 8063–8065
8065
Scheme 4.
Scheme 2.
Scheme 3.
influence of InCl3 at ambient temperature. Some
Michael acceptors such as methyl acrylate and acryloni-
trile, failed to react with pyrroles under the present
reaction conditions. Among various Lewis acids such as
YbCl3, YCl3, CeCl3·7H2O and TaCl5 used for this
transformation, InCl3 was found to be the most effec-
tive in terms of yield and reaction times. The catalyst
was recovered from the aqueous layer during work-up
and recycled in subsequent reactions without loss of
activity.
5. Patterson, J. M.; Soedigdo, S. J. Org. Chem. 1968, 33,
2057.
6. Reinecke, M. G.; Johnson, H. M.; Sebastian, J. F. J. Am.
Chem. Soc. 1963, 85, 2859.
7. (a) Loh, T. P.; Wei, L. L. Synlett 1998, 975; (b) Loh, T. P.;
Pei, J.; Lin, M. J. Chem. Soc., Chem. Commun. 1996, 2315;
(c) Babu, G.; Perumal, P. T. Aldrichim. Acta 2000, 33, 16.
8. General experimental procedures: (a) Monoalkylation of
pyrroles: To a stirred solution of vinyl ketone (5 mmol) or
b-nitrostyrene or benzylidene malononitrile and indium
trichloride (10 mol%) in dichloromethane (10 mL), a solu-
tion of pyrrole was added at 0°C and stirred at ambient
temperature for an appropriate time (Table 1). After com-
plete conversion, as indicated by TLC, the reaction mix-
ture was diluted with water (10 mL) and extracted with
dichloromethane (2×15 mL). The combined organic layers
were dried over anhydrous Na2SO4, concentrated in vacuo
and purified by column chromatography on silica gel
(Merck, 100–200 mesh, ethyl acetate–hexane, 1:9.) to
afford the pure product.
In summary, we have demonstrated that indium chlo-
ride is a superior Lewis acid for the alkylation of
pyrroles with electron deficient olefins. The procedure
has the advantages of mild reaction conditions, high
yields of products, cleaner reactions with greater selec-
tivity, short reaction times, operational simplicity, com-
patibility with acid sensitive substrates, recoverability of
the catalyst and simple experimental/product isolation
procedures which makes it a useful and attractive pro-
cess for the synthesis of alkylated pyrrole derivatives.
(b) Dialkylation of pyrroles: To a stirred solution of vinyl
ketone (5 mmol) and indium trichloride (10 mol%) in
dichloromethane (10 mL), a solution of pyrrole was added
at 0°C and stirred at ambient temperature for an appropri-
ate time (Table 1). After complete conversion, as indicated
by TLC, the reaction mixture was diluted with water (10
mL) and extracted with dichloromethane (3×15 mL). The
combined organic layers were dried over anhydrous
Na2SO4, concentrated in vacuo and purified by column
chromatography on silica gel (Merck, 100–200 mesh, ethyl
acetate–hexane, 2:8) to afford the pure product.
Acknowledgements
Authors S.A. and B.V.S.R. thank CSIR for the award
of the fellowship.
References
1H NMR of compound 3d (200 MHz, CDCl3): l 3.05 (t,
J=6.7 Hz, 2H), 3.25 (t, J=6.7 Hz, 2H), 3.85 (s, 3H), 5.85
(m, 1H), 6.05 (m, 1H), 6.60 (d, J=1.7 Hz, 1H), 6.95 (d,
J=7.8 Hz, 2H), 7.95 (d, J=7.8 Hz, 2H), 8.70 (brs, NH).
1H NMR of compound 4d (200 MHz, CDCl3): l 2.98 (t,
J=6.5 Hz, 4H), 3.10 (t, J=6.5 Hz, 4H), 3.87 (s, 6H), 5.70
(d, J=1.7 Hz, 2H), 6.90 (d, J=7.7 Hz, 4H), 7.95 (d,
J=7.7 Hz, 4H), 8.65 (brs, NH).
1. Livingstone, R. In Rodd’s Chemistry of Carbon Com-
pounds; Ansell, M. F., Ed.; Elsevier: Oxford, 1984; Vol.
IV.
2. Leonid, I.; Belen, K. Heterocycles 1994, 37, 2029.
3. Signaigo, F. K.; Adkins, H. J. Am. Chem. Soc. 1936, 58,
709.
4. White, J.; McGillivvray, C. J. Org. Chem. 1977, 42, 4248.