A practical preparation of highly versatile N-acylpyrroles from 2,4,4-trimethoxybutan-1-amine

Article abstract of DOI:10.1021/ol3005613

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

Full text of DOI:10.1021/ol3005613

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
fukuyama@mol.f.u-tokyo.ac.jp
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.
(2) Evans, D.; Borg, G.; Scheidt, K. Angew. Chem., Int. Ed. 2002, 41,
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

of primary amides with succinaldehyde equivalents.1a,2,6,7
However, these methods have rather serious limitations.
The former requires activation of carboxylic acids as acid
chlorides and, in some cases, metalation of pyrrole. The
latter requires harsh conditions such as heating in acetic
acid or treatment with strong acids. These drawbacks
precluded the application of N-acylpyrroles to the synthesis
of complex molecules. Herein we report a novel method for
preparing N-acylpyrroles under mild conditions from read-
ily available 2,4,4-trimethoxybutan-1-amine.8
Table 1. Substrate Scope of the N-Acylpyrrole Synthesisa
2,4,4-Trimethoxybutan-1-amine (1), a key reagent, was
prepared in two steps from inexpensive 1,1,3,3-tetra-
methoxypropane (2, Scheme 2). Treatment of 2 with
trimethylsilyl cyanide in the presence of boron trifluoride
etherate afforded nitrile 3 in 92% yield.9 Reduction of 3
withLiAlH4 afforded, after distillation, the requisite amine
1 in 73% yield.
Scheme 2. Preparation of 2,4,4-Trimethoxybutan-1-amine (1)
Scheme 3. Typical Procedure for Preparation of N-Acylpyrrole
a Reaction conditions: (1) 1 (1.0 equiv), EDCI (1.5 equiv), Et3N
(1.35 equiv), CH2Cl2, 0 °C to rt, 1.5 h. (2) CSA (0.1 equiv), quinoline
(0.1 equiv), toluene, reflux, 0.5 h. b Isolatedyield. c HOBT (1.0 equiv) was
added in the first step. d >99% ee, determined by HPLC analysis.
(6) For a copper-catalyzed synthesis of di- or trisubstituted N-
acylpyrroles, see: Yuan, X.; Xu, X.; Zhou, X.; Yuan, J.; Mai, L.; Li,
Y. J. Org. Chem. 2007, 72, 1510.
(7) For the synthesis of R,β-unsaturated N-acylpyrroles via a Wittig
reaction, see ref 5d. For the synthesis of R,β-unsaturated N-acylpyrroles
via a HornerÀWadsworthÀEmmons reaction, see ref 5f.
Preparation of N-acylpyrroles involves condensation
of carboxylic acids with amine 1, followed by the
(8) Baran and coworkers reported the construction of a pyrrole-2-
carboxylic acid moiety using a similar strategy in their synthesis of
Palau’amine. Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.; Yamaguchi,
J.; Baran, P. S. Angew. Chem., Int. Ed. 2010, 49, 1095.
(9) Hiyama, T.; Oishi, H.; Suetsugu, Y.; Nishide, K.; Saimoto, H.
Bull. Chem. Soc. Jpn. 1987, 60, 2139.
Org. Lett., Vol. 14, No. 7, 2012
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acid-mediated cyclization. A typical procedure is illu-
strated in Scheme 3. Condensation of carboxylic acid 4
with amine 1 proceeded smoothly by means of EDCI
and Et3N. Treatment of the resulting amide 5 with CSA
(0.1 equiv) and quinoline (0.1 equiv) in refluxing
toluene10 afforded N-acylpyrrole 6 in good to excellent
yields.
The substrate scope of the N-acylpyrrole synthesis is
summarized in Table 1. A variety of aromatic carboxylic
acids with both electron donating and withdrawing sub-
stituents on the aromatic ring were compatible with the
reaction conditions, providing the corresponding products
in high yield (entries 1À5). Aliphatic and R,β-unsaturated
carboxylic acids could also be converted into N-acylpyr-
roles in good yields (entries 7, 8, and 10À12). Although
condensation of sterically crowded carboxylic acids with 1
gave the corresponding amides in relatively low yields,
formation of the pyrrole ring proceeded without difficul-
ties (entries 6 and 9). A variety of functional groups,
including Boc, MOM, and TBS groups, were compatible
with the mild reaction conditions (entries 13 and 14).
Furthermore, Boc-L-phenylalanine could be converted
into the corresponding N-acylpyrrole without racemiza-
tion (entry 15).
In conclusion, we have demonstrated the utility of 2,4,4-
trimethoxybutan-1-amine for the preparation of N-acyl-
pyrroles. A variety of functional groups could survive the
mild conditions required for the transformation. Because
N-acylpyrroles can readily be converted to carbonyl com-
pounds such as aldehydes, ketones, esters, and amides, it is
safe to say that our novel method provides access to carbonyl
functionalities in the synthesis of complex molecules.
Acknowledgment. This work was financially supported
by Grants-in-Aid for Scientific Research (20002004,
22590002) from the Japan Society for the Promotion of
Science (JSPS), the Research Foundation for Pharmaceu-
tical Sciences, the Mochida Memorial Foundation for
Medical and Pharmaceutical Research, and the Uehara
Memorial Foundation.
Supporting Information Available. Experimental de-
1
tails and H and 13C NMR spectra for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) Fukuyama, T.; Liu, G.; Linton, S.; Lin, S.; Nishino, H. Tetra-
hedron Lett. 1993, 34, 2577.
The authors declare no competing financial interest.
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Org. Lett., Vol. 14, No. 7, 2012