ORGANIC
LETTERS
2012
Vol. 14, No. 7
1946–1948
A Practical Preparation of Highly
Versatile N-Acylpyrroles from
2,4,4-Trimethoxybutan-1-amine
Tomoaki Maehara, Rentaro Kanno, Satoshi Yokoshima, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received March 5, 2012
ABSTRACT
A novel method for the preparation of N-acylpyrrole is described. The method involves condensation of carboxylic acids with 2,4,4-trimethoxybutan-1-
amine, followed by acid-mediated cyclization to form the pyrrole ring. The preparative procedure is highly tolerant of a variety of functional groups.
The unique reactivities and usefulness of N-acylpyrroles
have been widely explored (Scheme 1). N-Acylpyrroles are
activated acid derivatives that can react with a variety of
Scheme 1. Versatility of N-Acylpyrrole
nucleophiles, including alcohols or amines to generate the
corresponding esters or amides, respectively.1 Reactions of
N-acylpyrroles with lithium borohydride or organometal-
lic reagents give tetrahedral pyrrolyl carbinols with sufficient
stability for isolation,2 which could in turn be converted to
aldehydes and ketones.3 In addition, N-acylpyrroles have
ketone-like reactivities because of the limited donation of
the lone pairelectronsonthe nitrogen atomtothe carbonyl
(1) (a) Lee, S.; Brook, M.; Chan, T. Tetrahedron Lett. 1983, 24, 1569.
(b) Hodous, B.; Fu, G. J. Am. Chem. Soc. 2002, 124, 10006.
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3188.
(3) Dixon, D. J.; Scott, M. S.; Luckhurst, C. A. Synlett 2003, 2317.
(4) Phippen, C. B. W.; Goldys, A. M.; Mcerlean, C. S. P. Eur. J. Org.
Chem. 2011, 6957.
(5) (a) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595. (b) Evans,
D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc.
2001, 123, 4480. (c) Arai, Y.; Kasai, M.; Ueda, K.; Masaki, Y. Synthesis
2003, 1511. (d) Kinoshita, T.; Okada, S.; Park, S.-R.; Matsunaga, S.;
Shibasaki, M. Angew. Chem., Int. Ed. 2003, 42, 4680. (e) Matsunaga, S.;
Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 7559. (f) Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shibasaki,
M. J. Am. Chem. Soc. 2005, 127, 13419. (g) Park, S. Y.; Morimoto, H.;
Matsunaga, S.; Shibasaki, M. Tetrahedron Lett. 2007, 48, 2815.
(h) Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M.
group. This property of N-acylpyrroles plays an important
role in organic synthesis4 as well as in the field of asym-
metric synthesis.5
ꢀ
J. Am. Chem. Soc. 2007, 129, 13410. (i) Vakulya, B.; Varga, S.; Soos, T.
J. Org. Chem. 2008, 73, 3475. (j) Zhao, D.; Wang, Y.; Mao, L.; Wang, R.
Chem.;Eur. J. 2009, 15, 10983. (k) Tanaka, Y.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2010, 132, 8862.
Typical methods for the preparation of the N-acylpyr-
rolesincludedirectacylationofapyrroleand condensation
r
10.1021/ol3005613
Published on Web 03/26/2012
2012 American Chemical Society