Highly efficient synthesis of polysubstituted pyrroles via four-component domino reaction

Article abstract of DOI:10.1021/ol4010382

A highly efficient, catalyst-free synthesis of polysubstituted pyrroles by means of a novel four-component domino reaction of an arylglyoxal monohydrate, an aniline, a dialkyl but-2-ynedioate, and malononitrile is reported. This transformation proceeded via a 6,6a-dihydrofuro[2,3-b]pyrrole as the key intermediate.

Full text of DOI:10.1021/ol4010382

ORGANIC
LETTERS
2013
Vol. 15, No. 10
2542–2545
Highly Efficient Synthesis of
Polysubstituted Pyrroles via
Four-Component Domino Reaction
Xian Feng,† Qian Wang,† Wei Lin,† Guo-Lan Dou,‡ Zhi-Bin Huang,*,† and
Da-Qing Shi*,†
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
P. R. China, and School of Safety Engineering, China University of Mining &
Technology, Xuzhou 221116, P. R. China
zbhuang@suda.edu.cn; dqshi@suda.edu.cn
Received April 15, 2013
ABSTRACT
A highly efficient, catalyst-free synthesis of polysubstituted pyrroles by means of a novel four-component domino reaction of an arylglyoxal
monohydrate, an aniline, a dialkyl but-2-ynedioate, and malononitrile is reported. This transformation proceeded via a 6,6a-dihydrofuro[2,3-b]-
pyrrole as the key intermediate.
Multicomponent reactions, in which multiple reactions
are combined into a single synthetic operation, have been
extensively used in organic synthesis, as well as in combina-
torial and medicinal chemistry. Obviation of the need for
isolation and purification of the intermediates results in
maximization of yields and reduction of waste, and thus
renders the protocols ecofriendly.1 These features make
multicomponent reactions well suited for the construction
of complex molecules from readily available starting
materials.2 In the past decade, many new three- and four-
component reactions have been reported, and efforts to
develop new multicomponent reactions are continuing.3
Pyrroles are an important class of heterocycles that
are widely distributed in various natural products
and biologically important molecules such as porphyrins,
bile pigments, coenzymes, and alkaloids.4 The traditional
methods for the construction of a pyrrole ring include the
Knorr reaction,5 the Hantzsch reaction,6 the PaalÀKnorr
(3) (a) Nair, V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001, 66,
4427. (b) Shestopalov, A. M.; Emeliyanova, Y. M.; Shestiopolov, A. A.;
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(f) Jiang, B.; Tu, S. J.; Kaur, P.; Wever, W.; Li, G. J. Am. Chem. Soc.
2009, 131, 11660. (g) Li, M.; Cao, H.; Wang, Y.; Lv, X. L.; Wen, L. R.
Org. Lett. 2012, 14, 3470. (h) Hao, W. J.; Xu, X. P.; Bai, H. W.; Wang,
S. Y.; Ji, S. J. Org. Lett. 2012, 14, 4894. (i) Jiang, B.; Feng, B. M.; Wang,
S. L.; Tu, S. J.; Li, G. Chem.;Eur. J. 2012, 18, 9823. (j) Wen, L. R.; Shi,
Y. J.; Liu, G. Y.; Li, M. J. Org. Chem. 2012, 77, 4252. (k) Jiang, B.; Yi,
M. S.; Shi, F.; Tu, S. J.; Pindi, S.; McDowell, P.; Li, G. Chem. Commun.
2012, 48, 808. (l) Jiang, B.; Li, Q. Y.; Zhang, H.; Tu, S. J.; Pindi, S.; Li, G.
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13, 848. (n) Li, S.; Wu, J. Org. Lett. 2011, 13, 712. (o) Han, X.; Li, H.;
Hughes, R. P.; Wu, J. Angew. Chem., Int. Ed. 2012, 51, 10390. (p) Knapp,
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London, 1977; pp 1À5. (b) Boger, D. L.; Boyce, C. W.; Labrili, M. A.;
Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54. (c) Lehuede, J.;
Fauconneau, B.; Barrier, L.; Ourakow, M.; Piriou, A.; Vierfond, J. M.
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† Soochow University.
‡ China University of Mining & Technology.
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Chem. 2003, 1133. (c) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed.
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2005, 44, 1602. (e) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
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Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899.
(2) (a) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem.
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2010, 14, 332.
r
10.1021/ol4010382
Published on Web 05/01/2013
2013 American Chemical Society

synthesis,7 and various cycloaddition methods.8 Recently,
newapproachesbasedon transition-metal-catalyzedcyclo-
isomerization of alkyne- and allene-containing substrates,9
multicomponent reactions,10 and various other methods11
have been developed. However, some of these new
methods have significant limitations, such as tedious work-
up procedures, harsh reaction conditions, low yields, long
reaction times, and the requirement for an inert atmo-
sphere. Therefore, a simple, efficient method for pyrrole
synthesis remains an attractive goal. As a part of our
ongoing research on the development of multicomponent
approaches to heterocycles,12 we investigated the rapid
construction of a polysubstituted pyrrole ring via a four-
component domino reaction of an arylglyoxal mono-
hydrate, an aniline, a dialkyl but-2-ynedioate, and malo-
nonitrile under catalyst-free conditions.
We initially evaluated the four-component reaction of
a 1:1:1:1 mixture of phenylglyoxal monohydrate (1a),
4-methylaniline (2a), dimethyl but-2-ynedioate (3a), and
malononitrile (4) under a variety of conditions (Scheme 1,
Table 1). When the reaction was carried out in water with-
out any catalyst, the yield of product was low (entry 1).
Adding the phase-transfer catalyst TEBAC improved the
Scheme 1. Model Reaction
Table 1. Optimization of the Reaction Conditions for the
Synthesis of 5aa
temp
catalyst
(mol %)
isolated
entry
solvent
water
(°C)
yield (%)
1
2
80
80
;
39
54
water
TEBAC
(10)
;
3
DMF
80
69
63
42
55
81
17
43
66
4
acetonitrile
chloroform
methanol
ethanol
reflux
reflux
reflux
reflux
rt
;
5
;
6
;
7
;
8
ethanol
;
(6) (a) Hantzsch, A. Ber. 1890, 23, 1474. (b) Palacios, F.; Aparico, D.;
Santos, J. M.; Vicario, J. Tetrahedron 2001, 57, 1961. (c) Trautwein,
9
ethanol
40
;
10
ethanol
60
;
€
A. W.; Sussmuth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8,
2381.
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J. Am. Chem. Soc. 2000, 122, 3801. (c) Bimal, K. B.; Susanta, S.; Indrani, B.
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L. F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 5277.
yield only slightly (entry 2). Ethanol provided higher yields
than did other organic solvents (compare entry 7 with
entries 3À6), so ethanol was used as the solvent for all
further reactions. When the reaction was carried out at
room temperature, at 40 °C, at 60 °C, and at reflux
temperature, 5aa was obtained in yields of 17%, 43%,
66%, and 81% (entries 8À10 and 7), respectively. These
experiments revealed that refluxing ethanol without any
catalyst provided the highest yield.
Using the optimal conditions, we investigated the sub-
strate scope of the transformation (Table 2). Methoxy,
methyl, chloro, and fluoro substituents on the phenyl-
glyoxal ring and heteroarylglyoxal ring as well as an
n-butyl group and phenyl groups bearing either electron-
withdrawing or -donating groups on the aniline ring were
well tolerated under the reaction conditions and afforded
the expected final products in satisfactory yields (up to
93%). However, when the methyl(orethyl) 2-cyanoacetate
was reacted with phenylglyoxal monohydrate, 4-methyla-
niline, and dimethyl but-2-ynedioate under the standard
conditions, the desired products were not obtained.
To expand the scope of the current method, alkyl
acetoacetate (6) was examined as a replacement for the
dialkyl but-2-ynedioate (3). The desired polysubstituted
pyrroles 7 were obtained with moderate yields (Table 3).
Recently, Alizadeh13 and Perumal14 reported the efficient
syntheses of pyrroles and dihydropyridines via a one-pot
(8) (a) Bullington, J. L.; Wolff, R. R.; Jackson, P. F. J. Org. Chem.
2002, 67, 9439. (b) Katritzky, A. R.; Zhang, S.; Wang, M.; Kolb, H. C.;
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Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron 1999, 55, 969.
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Org. Lett. 2004, 6, 2957. (b) Ishikawa, T.; Aikawa, T.; Watanabe, S.;
Saito, S. Org. Lett. 2006, 8, 3881. (c) Hiroya, K.; Matsumoto, S.;
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ꢀ
Corbella-Pane, M.; Dake, G. R. J. Org. Chem. 2006, 71, 4525.
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Marrero-Tellado, J. J.; Rodriguez, M. L. J. Am. Chem. Soc. 2004, 126,
8390. (b) Yamamoto, Y.; Hayashi, H.; Saigoku, T.; Nishiyama, H.
J. Am. Chem. Soc. 2005, 127, 10804. (c) Cadierno, V.; Gimeno, J.; Nebra,
N. Chem.;Eur. J. 2007, 13, 9973. (d) Cyr, D. J.; Arndtsen, B. A. J. Am.
Chem. Soc. 2007, 129, 12366. (e) Lu, Y.; Arndtsen, B. A. Angew. Chem.,
Int. Ed. 2008, 47, 5430. (f) Liu, W.; Jiang, H.; Huang, L. Org. Lett. 2010,
12, 312. (g) Dou, G.; Shi, C.; Shi, D. J. Comb. Chem. 2008, 10, 810. (h)
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430. (b) Chen, H.; Shi, D. J. Comb. Chem. 2010, 12, 571. (c) Li, Y.; Chen,
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Org. Lett., Vol. 15, No. 10, 2013
2543

Table 2. Preparation of Polysubstituted Pyrroles 5
Table 3. Preparation of Polysubstituted Pyrroles 7
isolated
isolated
product
Ar
R1
R2
yield (%)
product
Ar
R1
R2
yield (%)
7a
7b
C6H5
C6H5
4-CH3C6H4
4-ClC6H4
CH3
CH2CH3
79
84
5aa
5ab
5ac
5ad
5ae
5af
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-CH3C6H4
CH3
CH3
81
83
75
88
76
84
73
81
67
64
73
75
78
84
93
80
82
76
81
75
76
78
74
70
72
73
70
81
85
74
77
72
80
71
68
4-CH3OC6H4
4-(CH3)2CHC6H4 CH3
4-CH3CH2OC6H4 CH3
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4-FC6H4
5ag
5ah
5ai
4-ClC6H4
4-BrC6H4
4-NO2C6H4
3-ClC6H4
5aj
5ak
5al
3-Cl-4-CH3C6H3
3,5-(CH3)2C6H3
5am
5an
5ao
5ap
5aq
5ar
5as
5at
3,4-OCH2OC6H3 CH3
4-CH3CH2OC6H4 CH3CH2
4-CH3C6H4
C6H5
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
4-FC6H4
4-ClC6H4
3-Cl-4-CH3C6H3
3-CH3C6H4
3-HOC6H4
4-FC6H4CH2
2,4-(CH3)2C6H3
2-CH3CH2C6H4
5au
5av
5aw
5ax
5ay
5ba
5bb
5ca
5cb
5cc
5da
5db
5ea
5eb
5fa
Figure 1. X-ray structure of compound 5ar.
CH3CH2CH2CH2 CH3
4-CH3OC6H4 3,5-(CH3)2C6H3
4-CH3OC6H4 4-BrC6H4
CH3
CH3
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-FC6H4
4-CH3C6H4
4-CH3OC6H4
4-FC6H4
CH3
Scheme 2. Proposed Mechanism of the Reaction
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3
C6H5
4-FC6H4
4-ClC6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
CH3
thiophen-2-yl 4-ClC6H4
CH3
four-component reaction of ninhydrin or mono/di/triketone,
malononitrile, primary amines, and dialkyl acetylenedicar-
boxylates under similar conditions. The divergent outcomes
in the obtained products appear to derive from the nature
of the 1,2-dicarbonyl substrate, where the first use of an
“aldehydic” substrate is likely key toward obtaining the
pyrrole products.
The structures of the products were determined by means
of IR, 1H NMR, 13C NMR, and HRMS. The structure of
compound 5ar was confirmed by X-ray analysis (Figure 1).
In accordance with reports from the literature,15 we pro-
pose the following mechanism for the reaction (Scheme 2).
First, intermediate A is formed by the addition of the
aniline to the dialkyl but-2-ynedioate; simultaneously,
intermediate B is formed by means of a Knoevenagel
condensation between the arylglyoxal monohydrate and
(15) Shu, W. M.; Yang, Y.; Zhang, D. X.; Wu, L. M.; Zhu, Y. P.; Yin,
G. D.; Wu, A. X. Org. Lett. 2013, 15, 456.
2544
Org. Lett., Vol. 15, No. 10, 2013

subsequently undergoes intramolecular nucleophilic addi-
tion to form intermediate D. Intramolecular cyclization of
intermediate D then leads to the formation of intermediate
E, which tautomerizes to more-stable intermediate F.
In the last step, polysubstituted pyrrole 5 is formed by a
ring-opening reaction of intermediate F.
The key reaction is the ring-opening of intermediate F, a
6,6a-dihydrofuro[2,3-b]pyrrole, to give 5. A similar ring-
opening reaction of a 3a,6a-dihydrofuro[2,3-b]furan cata-
lyzed by HCl was reported by Shu et al.15 To evaluate the
likelihood that this transformation occurred in our system,
we carried out density functional theory calculations of the
possible configurations of E, F and 5ar at the B3LYP/
6-31G level of theory. First, we optimized the geometries
of three possible configurations and then calculated the
lowest-energy minima of those configurations (Figure 2).
We found that the most stable configuration of 5ar was
166.41 and 131.69 kJ/mol lower in energy than the most
stable configuration of intermediate E and F, respectively.
This result suggests that intermediate F could be easily
transformed to more stable product 5.
In conclusion, we have developed a method for the
facile, efficient synthesis of polysubstituted pyrroles
by means of a novel four-component domino reaction.
Using this method, we rapidly constructed a diverse col-
lection of polysubstituted pyrroles in excellent yields
simply by refluxing a mixture of an arylglyoxal monohy-
drate, an aniline, a dialkyl but-2-ynedioate or alkyl acet-
oacetate, and malononitrile in ethanol under catalyst-free
conditions.
Acknowledgment. We are grateful for financial support
from the Major Basic Research Project of the Natural
Science Foundation of the Jiangsu Higher Education
Institutions (No. 10KJA150049), the Natural Science
Foundation of the Jiangsu Higher Education Institutions
(No. 11KJB150014), and a project fund from the Priority
Academic Project Development of the Jiangsu Higher
Education Institutions and the Foundation of the Key
Laboratory of Organic Synthesis of Jiangsu Province (No.
JSK1210).
Supporting Information Available. Experimental pro-
cedures; characterization, crystallographic data, and CIF
file for the products. This materials is available free of
charge via the Internet at http://pubs.acs.org.
Figure 2. Lowest energy minimum of intermediates E, F and
product 5ar.
malononitrile. Then, Michael addition of β-enamino
ester A to intermediate B gives intermediate C, which
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 10, 2013
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