Highly efficient chemoselective synthesis of polysubstituted pyrroles via isocyanide-based multicomponent domino reaction

Article abstract of DOI:10.1021/ol401976w

A multicomponent domino reaction for the chemoselective, catalyst-free synthesis of polysubstituted pyrroles from readily available isocyanides, primary or secondary amines, and gem-diactivated olefins has been developed. Structurally diverse pyrroles were obtained in moderate to good yields under mild conditions.

Full text of DOI:10.1021/ol401976w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Efficient Chemoselective
Synthesis of Polysubstituted Pyrroles
via Isocyanide-Based Multicomponent
Domino Reaction
Xiang Wang, Xiao-Ping Xu, Shun-Yi Wang,* Weiqun Zhou, and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University,
Suzhou 215123, China
shunyi@suda.edu.cn; shunjun@suda.edu.cn
Received July 19, 2013
ABSTRACT
A multicomponent domino reaction for the chemoselective, catalyst-free synthesis of polysubstituted pyrroles from readily available isocyanides,
primary or secondary amines, and gem-diactivated olefins has been developed. Structurally diverse pyrroles were obtained in moderate to good
yields under mild conditions.
Efficient construction of complex molecules from inex-
pensive, readily available starting materials via the gener-
ation of several bonds in a single process is a major
challenge1 in modern organic chemistry. For this purpose,
multicomponent domino reactions2 are considered to be
an ideal tool. These reactions3 can efficiently furnish
complex structures of chemical and pharmaceutical inter-
est in a single operation by means of a cascade of processes
without the need for protection/deprotection of functional
groups or time-consuming and costly operations.
Many natural products, biologically important molecules,4
and pharmaceuticals (e.g., Lipitor)5 contain a pyrrole core
(Figure 1). Pyrroles are also versatile as components of
polymers6 and assyntheticintermediates formanykinds of
pharmaceuticals.7
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10.1021/ol401976w
XXXX American Chemical Society

Scheme 1. Methods for the Construction of Cyano-Substituted
Pyrroles
Figure 1. Biologically active pyrrole-containing products.
Traditional methods for pyrrole synthesis include the
Knorr,8 PaalꢀKnorr,9 and Hantzsch10 syntheses, which
generally require the initial preparation of an intermediate
that subsequently undergoes a cyclization reaction. Thus,
the development of new, single-process routes to construct
the pyrrole skeleton from simple starting materials is
highly desired.
Some interesting new approaches to pyrroles have
recently been developed, including multicomponent reac-
tions (MCRs)11 and metal-catalyzed routes.12 For example,
Anderson et al.13 recently reported an iridium-catalyzed two-
or three-step method for the synthesis of substituted pyrroles
from ketones and allyl hydroxylamine. Zhu et al.14 reported
an oxidative Strecker reaction (mediated by 2-iodoxybenzoic
acid and tetrabutylammonium bromide) followed by
a [4þ1]-cycloaddition of the resulting R,β-unsaturated
imidoyl cyanides (2-cyano-1-azadienes) with various iso-
cyanides to provide polysubstituted 2-amino-5-cyanopyr-
roles (Scheme 1). However, some of these new approaches
have significant limitations, such as the need for expensive
catalysts, harsh reaction conditions, and tedious workup
procedures, and poor selectivity and low yield.
MCRs involving isocyanides have become an important
area of research in modern organic chemistry.15 The iso-
cyanide functional group is an extraordinarily useful synthon
for the design of novel MCRs. The most commonly used
isocyanide-based MCR is the Ugi-4CR, which involves an
aldehyde, an amine, a carboxylic acid, and an isocyanate.16
Ugi-4CR-type reactions in which malononitrile is used in-
stead of an amine, have also been described; these reactions,
which are always terminated by water as a nucleophile, can
be considered as variants of the Ugi-4CR.17 Over the past
several years, various other nucleophiles have also been used
in these reactions, including phenol18 and thiophenol.19
However, the use of amines as nucleophiles in these reactions
is rare. In this paper, we report a novel one-pot isocyanide-
based multicomponent domino reaction for the catalyst-
free synthesis of polysubstituted pyrroles from simple and
readily available isocyanides, amines, and gem-diactivated
olefins with high chemoselectivity and moderate to good
yields (Scheme 1).
(8) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474.
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Kel’in, A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440. (c) Shu,
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F.; Shen, T.; Cui, Y.; Jiao, N. Org. Lett. 2012, 14, 4926. (g) Feng, X.;
Wang, Q.; Lin, W.; Dou, G.-L.; Huang, Z.-B.; Shi, D.-Q. Org. Lett.
2013, 15, 2543. (h) Marchand, E.; Morel, G.; Sinbandhit, S. Eur. J. Org.
Chem. 1999, 1729. (i) Shaabani, A.; Teimouri, M. B.; Arab-Ameri, S.
Tetrahedron Lett. 2004, 45, 8409. (j) Nair, V.; Vinod, A. U.; Rajesh, C.
J. Org. Chem. 2001, 66, 4427. (k) Nair, V.; Rajesh, C.; Vinod, A. U.;
Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem.
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Cadierno, V.; Gimeno, J.; Nebra, N. Chem.;Eur. J. 2007, 13, 9973. (c)
Cyr, D. J.; Arndtsen, B. A. J. Am. Chem. Soc. 2007, 129, 12366. (d) Lu,
Y.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2008, 47, 5430. (e) Liu, W.;
Jiang, H.; Huang, L. Org. Lett. 2010, 12, 312. (f) Hong, D.; Zhu, Y.; Li,
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R. J.; Klein, K. R.; Kaplan, D.; Lou, Y. Org. Lett. 2013, 15, 1421.
(13) Wang, H. Y.; Mueller, D. S.; Sachwani, R. M.; Londino, H. N.;
Anderson, L. L. Org. Lett. 2010, 12, 2290.
We started by studying the three-component reaction
of tert-butylisonitrile 1a (1 mmol), 2-benzylidenemalononi-
trile 2a (1 mmol), and piperidine 3a (1 mmol) in EtOH under
reflux conditions for 30 min. To our delight, the reaction
afforded 2-amino-1-(tert-butyl)-4-phenyl-5-(piperidin-1-yl)-
1H-pyrrole-3-carbonitrile 4a in 42% yield. Polysubstituted
(16) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.;
Keating, T. A. Acc. Chem. Res. 1996, 29, 123.
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2011, 52, 4186–4188. (b) Soleimani, E.; Zainali, M. J. Org. Chem. 2011,
76, 10306.
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2006, 4, 615.
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J. Comb. Chem. 2010, 12, 822. (b) Kolontsova, A. N.; Ivantsova, M. N.;
Tokareva, M. I.; Mironov, M. A. Mol Divers. 2010, 14, 543.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of the Solvent for the MCRa
Scheme 2. Construction of Polysubstituted Pyrroles 4
entry
solvent
4a, yieldb (%)
1
2
3
4
5
1,4-dioxane
toluene
EtOH
24
27
42
35
74
MeOH
MeCN
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3a (1 mmol),
solvent (2 mL). b Isolated yield.
pyrrole 4a was fully characterized by 1H NMR, 13C NMR,
and IR spectroscopy. To determine the ideal solvent for the
transformation, we investigated this model reaction in var-
ious other solvents (Table 1). The desired product 4a was
obtained in all the tested solvents, but MeCN gave the best
isolated yield (74%), (Table 1, entry 5).
Using the optimized solvent conditions, we evaluated
the substrate scope of the reaction by using readily avail-
able starting materials (Scheme 2). The reaction of iso-
cyanides 1 with primary or secondary amines 3 and various
substituted gem-diactivated olefins 2 afforded the desired
polysubstituted pyrroles 4 in moderate to good yields, in
most cases. The structure of 4k was confirmed by single-
crystal X-ray diffraction.
Scheme 3. Substrate Limitations of the MCR
Notably, 2-benzylidenemalononitrile substrates with a
strongly electron-donating substituent (ꢀOCH3, 2c) or an
electron-withdrawing substituent (ꢀCl or ꢀBr, 2d or 2e)
afforded desired products 4cꢀe in 61%, 57%, and 79%
yields, respectively.
Reactions of a variety of substituted secondary amines 3
with tert-butylisonitrile 1a and 2-(4-methylbenzylidene)-
malononitrile 2h were also surveyed. When cyclic second-
ary amines pyrrolidine, morpholine, and 1,2,3,4-tetra-
hydroisoquinoline were used in the reaction, the desired
products (4h, 4i, and 4j, respectively) were obtained
in moderate yields (62%ꢀ74%). When acyclic secondary
amines N-methyl-1-phenylmethanamine and dibenzyla-
mine were used, the desired products 4l and 4k, respec-
tively, were also obtained in good yields (75% and 79%).
When tert-butylisonitrile 1a was replaced with 2-isocyano-1,
3-dimethylbenzene 1b, which possesses methyl substituents
at the ortho positions of the aryl ring, and was used in the
reaction with 2-(4-methylbenzylidene)malononitrile and
piperidine 3a under the optimized conditions, the desired
polysubstituted pyrrole derivative 4m was obtained in 23%
yield; and the reaction of isocyanocyclohexane 1c and
benzylisocyanide 1d afforded polysubstituted pyrrole deri-
vatives 4n and 4o in 69% and 23% yield, respectively.
However, when isocyanoacetate was employed in
this reaction, no desired product was obtained. Other
secondary amines, such as 1,2,3,4-tetrahydroquinoline
and diphenylamine, did not afford the corresponding
pyrrole products, perhaps owing to the low nucleophilicity
of these amines. Sterically hindered amines such as 2,2,6,6-
tetramethylpiperidine and diisopropylamine were also
unsuitable. When aliphatic aldehydes, such as n-butyral-
dehyde and pivalaldehyde, were used, the corresponding
polysubstituted pyrroles were not obtained (Scheme 3).
We also surveyed reactions of benzylamine, a primary
amine, with tert-butylisonitrile 1a and various gem-diacti-
vated olefins 2 (Scheme 4). Notably, olefins bearing an
electron-donating group or an electron-withdrawing
group at various positions on the aryl ring provided the
desired polysubstituted pyrrole products 5aꢀc in moder-
ate to good yields (56%ꢀ78%). When phenylethylamine
was used instead of benzylamine, polysubstituted pyrrole
Org. Lett., Vol. XX, No. XX, XXXX
C

derivatives 5d and 5e were obtained in 68% and 55%
yields, respectively.
the resulting intermediate undergoes nucleophilic attack
by the amine to afford intermediate 7 in the case of
secondary amines or 70 in the case of primary amines.
Then the cyano group of 7 undergoes nucleophilic attack
by the nitrogen atom derived from the isocyanide group
to afford polysubstituted pyrroles 4, and the cyano group
of 70 undergoes nucleophilic attack by the nitrogen atom
derived from the primary amine to afford polysubstituted
pyrroles 5. The difference between the behaviors of 7 and
70 may be due to the steric bulk of the tert-butyl group.
The density functional theory calculations on 5a are con-
sistent with the experimental results in this transformation
(70 to 80 vs 7 to 8).20
Scheme 4. Construction of Polysubstituted Pyrroles 5
In conclusion, we have developed a novel catalyst-free
multicomponent domino reaction for the construction of
polysubstituted pyrroles from readily available isocya-
nides, primary or secondary amines, and gem-diactivated
olefins. The reaction proceeded under mild conditions and
afforded the desired products in moderate to good yields.
Scheme 5. Proposed Mechanism for the Formation of Pyrroles 4
and 5
Acknowledgment. We gratefully acknowledge the
Natural Science Foundation of China (No. 21172162), the
Young National Natural Science Foundation of China (No.
21202111, 21202113), the Young Natural Science Founda-
tion of Jiangsu Province (BK2012174), Key Laboratory of
Organic Synthesis of Jiangsu Province (KJS1211), PAPD,
and Soochow University for financial support.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new compounds
and X-ray crystallographic details of 4k (CIF; atomic
coordinates, displacement parameters, bond lengths and
angles, and torsion angles). This material is available free
of charge via the Internet at http://pubs.acs.org.
On the basis of the above-described results, we propose
that this multicomponent domino reaction proceeds by the
mechanism shown in Scheme 5. First, isocyanide 1 under-
goes nucleophilic addition to gem-diactivated olefin 2, and
(20) For details, see the Supporting Information.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX