LETTER
Rapid Entry to C-Alkyl Pyrroles
2427
Table 1 Michael Addition of Pyrroles with Electron-Deficient Olefins Using Silica Gel Supported Reagents under MW12 (continued)
Entry
12
Nucleophile
Electrophile
Product
Catalyst
–
Time (min)
1
Isolated yield (%)
85
O
N
N
O
O
CH2Ph
CH2Ph
l
13
–
1
70
O
Ph
N
N
Ph
CH2Ph
CH2Ph
m
14
15
–
–
1
1
90
88
NO2
Ph
NO2
NO2
N
H
N
H
Ph
n
p-MeO-Ph
N
H
N
H
p-MeO-Ph
o
a Isolated yields of corresponding 2,5-dialkylpyrroles.
prepared by reaction of pyrryl salts with iodoalkanes, see:
(c) Candy, C. F.; Jones, A. R. J. Org. Chem. 1971, 36, 3990.
(d) Hobbs, C. F.; McMillin, C. K.; Papadopoulos, E. P.;
VanderWerf, C. A. J. Am. Chem. Soc. 1962, 84, 43.
(6) Yadav, J. S.; Abraham, S.; Subba Reddy, B. V.; Sabitha, G.
Tetrahedron Lett. 2001, 42, 8063.
BiCl3 has been used as a Lewis acid catalyst in many
chemical transformations,13 nevertheless, so far no exam-
ples were described that BiCl3 was employed to promote
the Michael reaction of pyrroles with electron-deficient
olefins. Our experimental results indicated that BiCl3 ex-
hibited a high catalytic activity and did not induce poly-
merization and polyalkylation under microwave.
(7) Palomo, C.; Oiarbide, M.; Kardak, B. G.; García, J. M.;
Linden, A. J. Am. Chem. Soc. 2005, 127, 4154.
(8) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001,
123, 4370.
In conclusion, we have developed a new fast and efficient
microwave-assisted method for the synthesis of C-alkyl-
pyrroles using silica gel as support reagent. The procedure
has the advantages of short reaction times, high regio-
selectivity, high yields, operational simplicity and sol-
vent-free conditions, which makes it a useful and
attractive process for the synthesis of alkylated pyrrole
derivatives.
(9) (a) Poondra, R. R.; Turner, N. J. Org. Lett. 2005, 7, 863.
(b) Kudrimoti, S.; Bommena, V. R. Tetrahedron Lett. 2005,
46, 1209. (c) Saxena, I.; Borah, D. C.; Sarma, J. C.
Tetrahedron Lett. 2005, 46, 1159. (d) Bengtson, A.;
Hallberg, A.; Larhed, M. Org. Lett. 2002, 4, 1231.
(10) (a) Kaval, N.; Dehaen, W.; Matyus, P.; Eycken, E. V. Green
Chem. 2004, 6, 125. (b) Ju, Y.; Varma, R. S. Green Chem.
2004, 6, 219. (c) Miao, G.; Ye, P.; Yu, L.; Baldino, C. M. J.
Org. Chem. 2005, 70, 2332. (d) Poondra, R. R.; Fischer, P.
M.; Turner, N. J. J. Org. Chem. 2004, 69, 6920.
Acknowledgment
(11) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.;
Mingos, D. M. P. Chem. Soc. Rev. 1998, 27, 213.
(12) Typical Experimental Procedure.
The project was supported by the Natural Science Foundation of
Fujian Province of China (No. C0510002).
Catalyst-free: To a solution of pyrrole (2 mmol) or N-benzyl
pyrrole (2 mmol) or 2-alkylpyrroles (1 mmol) in CH2Cl2 (1
mL) was added electron-deficient olefin (1 mmol for pyrrole
and N-benzyl pyrrole, 1.2 mmol for 2-alkylpyrroles) and
silica gel (0.25 g). Then the mixture was mixed thoroughly
and dried under reduced pressure. The contents were taken
in a 5 mL conical flask and was placed in a microwave oven
(cooking type, Galanz WP 700P 21-6) and irradiated for 1–
4 min at 680 W. After completion of the reaction indicated
by TLC, the reaction mixture was allowed to cool, diluted
with CH2Cl2 and passed through a short silica gel column
using CH2Cl2 as eluent. The solvent was evaporated under
reduced pressure and the residue was purified by column
chromatography to afford the corresponding 2-alkylpyrroles
or 2,5-dialkylpyrroles.
References
(1) (a) Sundberg, R. D. Pyrroles and their Benzo Derivatives:
Synthesis and Applications, In Comprehensive Heterocyclic
Chemistry, Vol. 4; Katrizky, A. R.; Rees, C. W., Eds.;
Pergamon: Oxford, 1984, 313–376. (b) Saxton, J. E. Nat.
Prod. Rep. 1997, 14, 559. (c) Toyota, M.; Ihara, N. Nat.
Prod. Rep. 1998, 15, 327. (d) Leonid, I.; Belen, K.
Heterocycles 1994, 37, 2029.
(2) Signaigo, F. K.; Adkins, H. J. Am. Chem. Soc. 1936, 58, 709.
(3) Patterson, J. M.; Soedigdo, S. J. Org. Chem. 1968, 33, 2057.
(4) Reinecke, M. G.; Johnson, H. M.; Sebastian, J. F. J. Am.
Chem. Soc. 1963, 85, 2859.
(5) (a) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic
Chemistry, 3rd ed.; Chapman and Hall: London, 1995, 231–
232. (b) Schofield, K. Hetero-Aromatic Nitrogen
Compounds: Pyrroles and Pyridines; Plenum Press: New
York, 1967, 3. N-Alkylpyrroles, however, are readily
Spectral data for selected compound.
4-(1H-Pyrrol-2-yl)butan-2-one (a): yield 123 mg (90%).
IR (film): 3377, 1707 cm–1. 1H NMR (500 MHz, CDCl3):
d = 2.17 (s, 3 H), 2.81 (t, J = 6.5 Hz, 2 H), 2.87 (t, J = 6.5 Hz,
Synlett 2005, No. 16, 2425–2428 © Thieme Stuttgart · New York