InBr3/Cu(OTf)2-catalyzed C-alkylation of pyrroles and indoles with α-diazocarbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2003.09.031

Pyrroles and indoles react smoothly with α-diazocarbonyl compounds in the presence of 10 mol% of InBr₃ under mild conditions to afford the corresponding 2- and 3-alkyl pyrrole and 3-alkyl indole derivatives, respectively, in good yields with high selectivity.

Full text of DOI:10.1016/j.tetlet.2003.09.031

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8331–8334
InBr3/Cu(OTf)2-catalyzed C-alkylation of pyrroles and indoles
with a-diazocarbonyl compounds
J. S. Yadav,* B. V. S. Reddy and G. Satheesh
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 20 June 2003; revised 20 August 2003; accepted 1 September 2003
Abstract—Pyrroles and indoles react smoothly with a-diazocarbonyl compounds in the presence of 10 mol% of InBr3 under mild
conditions to afford the corresponding 2- and 3-alkyl pyrrole and 3-alkyl indole derivatives, respectively, in good yields with high
selectivity.
© 2003 Elsevier Ltd. All rights reserved.
a-Diazocarbonyl compounds are extremely versatile in
organic synthesis especially in the total synthesis of
complex natural products.1 The ready availability, rela-
tive stability and facile decomposition of a-diazocar-
bonyl compounds under thermal, photochemical, acid,
base and transition metal catalysis conditions make
them useful intermediates in organic synthesis.2 a-Dia-
zoketones undergo a variety of transformations such as
cyclopropanation, aziridine formation, ylide formation,
C–H, X–H insertion reactions and cyclization reac-
tions.3 Carbene-insertion reactions are of great interest
as these methods allow new carbonꢀcarbon and car-
bonꢀhetero atom bond formation under mild condi-
tions. Typically, transition metal catalysts, mostly
rhodium and copper salts, are employed to promote the
carbene-insertion reactions.4 However, there are no
examples on the alkylation of indoles with a-diazocar-
bonyl compounds. Recently, indium halides have
emerged as mild and water-tolerant Lewis acids impart-
ing high regio-, stereo- and chemoselectivity in various
organic transformations.5 Compared to conventional
Lewis acids, indium tribromide has advantages of low
catalyst loading, moisture stability and catalyst recy-
cling. Recently, indium tribromide has been found to be
a more efficient catalyst over conventional Lewis acids
in promoting various transformations including glycosi-
dation, thioacetalization, cyanation of ketones and con-
jugate addition reactions.6,7
In this paper, we wish to report a simple and straight-
forward method for the alkylation of pyrroles and
indoles with a-diazocarbonyl compounds using indium
tribromide as the catalyst. Accordingly, treatment of
pyrrole with ethyl diazoacetate in the presence of 10
mol% of InBr3 afforded C-alkylated pyrroles as a mix-
ture of ethyl 2-(2-pyrrolyl)acetate 3 and ethyl 2-(3-
pyrrolyl)acetate 4 in 60 and 25% yields, respectively
(Scheme 1).
In a similar manner, pyrrole reacted smoothly with
a-diazoketones to produce the corresponding 2- and
3-substituted pyrroles in fairly good yields (Table 1).
Pyrrole also underwent alkylation with the a-diazoke-
tone derived from cyhalothric acid (entry b). Both aryl
and alkyl substituted diazoketones worked well under
the reaction conditions and the results are presented in
Table 1. In all cases, the reactions proceeded efficiently
at room temperature with high selectivity. No N-alkyla-
tion of pyrrole was observed under these reaction con-
ditions. The reaction probably proceeds through the
formation of the cyclopropyl adduct from the diazocar-
bonyl compound and pyrrole. Then, the cyclopropyl
adduct can undergo either C-2 or C-3 cleavage through
activation of the carbonyl group by indium(III) result-
ing in the formation of the 2- and 3-substituted pyrroles
(Scheme 2).
Keywords: indium compounds; diazo compounds; C-alkylation; het-
eroaromatics.
* Corresponding author. Fax: 91-40-27160512; e-mail: yadav@
iict.ap.nic.in
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.031

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J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 8331–8334
Table 1. InBr3-catalyzed alkylation of pyrrole and indoles with a-diazocarbonyl compounds
N-Methyl pyrrole also reacted smoothly with p-tolyl
diazoketone to produce a C-alkylated product (entry
g). These results encouraged us to study further the
decomposition of various a-diazocarbonyl compounds
with indoles. Interestingly, alkyl and aryl substituted
diazo compounds underwent reaction with indoles in
the presence of 10 mol% of InBr3 to give 3-alkylated
products in high yields (Scheme 3).
Similarly, various a-diazocarbonyl compounds reacted
readily with indoles to furnish 3-alkyl indoles, with only
3-alkylated products being obtained. No side products

J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 8331–8334
8333
Scheme 2.
Scheme 3.
1991, 56, 6269; (c) Pirrung, M. C.; Florian, B. J. Org.
Chem. 1999, 64, 3642; (d) Muthusamy, S.; Gunanathan, C.
Synlett 2002, 1783.
5. (a) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149; (b)
Babu, G.; Perumal, P. T. Aldrichima Acta 2000, 33, 16; (c)
Ghosh, R. Indian J. Chem. 2001, 40B, 550–557.
6. (a) Bandini, M.; Giorgio Cozzi, P.; Melchiorre, P.; Umani-
Ronchi, A. Tetrahedron Lett. 2001, 42, 3041–3043; (b)
Ceschi, M. A.; Felix, L. A.; Peppe, C. Tetrahedron Lett.
2000, 41, 9695–9699; (c) Bandini, M.; Giorgio Cozzi, P.;
Giocomini, M.; Melchiorre, P.; Selva, S.; Umani-Ronchi,
A. J. Org. Chem. 2002, 67, 3700–3704.
7. (a) Yadav, J. S.; Reddy, B. V. S.; Raju, A. K.; Rao, C. V.
Tetrahedron Lett. 2002, 43, 5437–5440; (b) Yadav, J. S.;
Reddy, B. V. S. Synthesis 2002, 511–514.
arising either from Wolff rearrangement or carbene
dimerization was observed under these conditions. As a
solvent, dichloromethane appeared to give the best
1
results. All products were characterized by H NMR,
IR and mass spectroscopy. To compare the efficiency of
this procedure, we performed the reactions with various
indium salts such as indium tribromide, indium trichlo-
ride and indium triflate. Among these catalysts, indium
tribromide was found be the most effective and gave
the best results. Copper triflate (5 mol%) was also
equally effective for this conversion and the results are
presented in Table 1. The scope and generality of the
method is illustrated with respect to various diazocar-
bonyl compounds, pyrroles and indoles and the results
are summarized in Table 1.8
8. General procedure: A mixture of the pyrrole or indole (2
mmol), the a-diazocarbonyl compound (2.5 mmol), InBr3
(10 mol%) or Cu(OTf)2 (5 mol%) in dichloromethane (10
mL) was stirred at room temperature for the appropriate
time (Table 1). After completion of the reaction, as indi-
cated by TLC, the reaction mixture was diluted with water
(10 mL) and extracted with dichloromethane (2×15 mL).
Evaporation of the solvent followed by purification on
silica gel (Merck, 100–200 mesh, ethyl acetate:hexane,
1.5:8.5) afforded the pure alkyl pyrrole or indole deriva-
tive. Spectroscopic data for selected products: 3a: IR
In summary, this paper describes a novel method for
the alkylation of indoles and pyrrole with a-diazocar-
bonyl compounds using indium tribromide as catalyst.
This method provides a new route to indoles and
pyrroles functionalize at the 3- and 2-positions
respectively.
1
(KBr) w: 3364, 2924, 1745, 1679, 1462, 1280, 772 cm−1; H
NMR (200 MHz, CDCl3): l 1.25 (t, 3H, J=6.9 Hz), 3.60
(s, 2H), 4.20 (q, 2H, J=6.9 Hz), 5.95 (d, 1H, J=2.5 Hz),
6.08 (dd, 1H, J=2.5, 2.9 Hz), 6.67 (dd, 1H, J=2.9, 3.7
Hz), 8.80 (brs, NH, 1H). EIMS: m/z: 153, M+, 151, 139,
79, 56, 42. HRMS calcd for C8H11NO2: 153.0789. Found:
Acknowledgements
1
153.0735. 4a: H NMR (200 MHz, CDCl3): l 1.27 (t, 3H,
J=6.8 Hz), 3.45 (s, 2H), 4.18 (q, 2H, J=6.8 Hz), 6.15 (dd,
1H, J=2.5, 2.9 Hz), 6.65–6.70 (m, 2H), 8.20 (brs, NH,
1H). 3b: IR (KBr) w: 3370, 2931, 1721, 1695, 1454, 1379,
B.V.S thanks CSIR, New Delhi for the award of
fellowship.
1
1271, 1138, 1091, 770 cm−1; H NMR (200 MHz, CDCl3):
l 1.20 (s, 3H), 1.30 (s, 3H), 2.20 (dd, 1H, J=8.1, 8.5 Hz),
2.30 (d, 1H, J=8.1 Hz), 3.80 (Abq, 2H, J=13.5 Hz), 5.95
(d, 1H, J=2.5 Hz), 6.10 (dd, 1H, J=2.5, 2.9 Hz), 6.65 (dd,
1H, J=2.9, 3.7 Hz), 6.95 (d, 1H, J=8.5 Hz), 8.45 (brs,
NH, 1H). EIMS: m/z: 306 M+, 305, 225, 141, 122, 80, 53.
HRMS calcd for C14H15NOF3Cl: 305.0794. Found:
References
1. (a) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96,
223; (b) Padwa, A. Top. Curr. Chem. 1997, 189, 121; (c)
Calter, M. A. Curr. Org. Chem. 1997, 1, 37.
2. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds from
Cyclopropanes to Ylides; Wiley-Inter-Science: New York,
1998.
3. (a) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091;
(b) Padwa, A.; Hornbuckle, S. A. Chem. Rev. 1991, 91,
263; (c) Doyle, M. P. Chem. Rev. 1986, 86, 919.
4. (a) Maryanoff, B. E. J. Org. Chem. 1982, 47, 3000; (b)
Pirrung, M. C.; Zhang, J.; McPhail, A. T. J. Org. Chem.
1
305.0856. 4b: H NMR (200 MHz, CDCl3): l 1.18 (s, 3H),
1.25 (s, 3H), 2.18 (dd, 1H, J=8.1, 8.5 Hz), 2.38 (d, 1H,
J=8.1 Hz), 3.60 (Abq, 2H, J=13.5 Hz), 6.05 (dd, 1H,
J=2.5, 2.9 Hz), 6.60 (d, 1H, J=2.5 Hz), 6.78 (dd, 1H,
J=2.9, 3.7 Hz), 7.05 (d, 1H, J=8.5 Hz), 8.25 (brs, NH,
1H). 3d: IR (KBr) w: 3418, 2923, 1745, 1685, 1450, 1267,
1026, 762 cm−1 1H NMR (200 MHz, CDCl3): l 4.20 (s,
;
2H), 5.90 (d, 1H, J=2.5 Hz), 5.98 (dd, 1H, J=2.5, 2.9
Hz), 6.60 (dd, 1H, J=2.9, 3.7 Hz), 7.40–7.60 (m, 3H), 8.0

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J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 8331–8334
(d, 2H, J=8.0 Hz), 10.20 (brs, NH, 1H). EIMS: m/z:
(KBr) w: 3409, 3056, 2981, 1728, 1459, 1247, 1161, 1028,
932, 744 cm−1 1H NMR (200 MHz, CDCl3): l 1.25 (t,
185 M+, 146, 105, 90, 80, 77, 53. HRMS calcd for
;
3H, J=6.9 Hz), 3.69 (s, 2H), 4.20 (q, 2H, J=6.9 Hz),
6.95 (d, 1H, J=1.5 Hz), 7.05–7.22 (m, 3H), 7.60 (d, 1H,
J=8.1 Hz), 8.10 (brs, NH, 1H). EIMS: m/z: 203 M+,
130, 77. HRMS calcd for C12H13NO2: 203.0946. Found:
203.0969.
C12H11NO: 185.0840. Found: 185.0879. 4d: IR (KBr) w:
3364, 2924, 1743, 1679, 1462, 1247, 1071, 772 cm−1 1H
;
NMR (200 MHz, CDCl3): l 4.20 (s, 2H), 6.15 (dd, 1H,
J=2.5, 2.9 Hz), 6.65–6.70 (m, 2H), 7.40–7.60 (m, 3H),
8.10 (d, 2H, J=8.0 Hz), 8.20 (brs, NH, 1H). 5h: IR