A facile and efficient synthesis of multisubstituted pyrroles from enaminoesters and nitroolefins

Article abstract of DOI:10.1039/c1gc15278e

A facile and efficient method for the synthesis of substituted pyrroles from enaminoesters and nitroolefins is reported. This general procedure provides a wide variety of multisubstituted pyrroles in good to excellent yields under mild reaction conditions.

Full text of DOI:10.1039/c1gc15278e

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Green Chemistry
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COMMUNICATION
A facile and efficient synthesis of multisubstituted pyrroles from
enaminoesters and nitroolefins†
Zheng-Hui Guan,* Liang Li, Zhi-Hui Ren, Jianli Li and Mi-Na Zhao
Received 14th March 2011, Accepted 1st April 2011
DOI: 10.1039/c1gc15278e
A facile and efficient method for the synthesis of substituted
pyrroles from enaminoesters and nitroolefins is reported.
This general procedure provides a wide variety of multi-
substituted pyrroles in good to excellent yields under mild
reaction conditions.
Scheme 1 Addition and cyclization of enaminoesters to nitroolefins.
Table 1 Optimization of the reaction conditionsa
As one of the most important heterocycles, substituted
pyrroles are not only found in many natural products1 and
pharmaceuticals2 but are also widely used in material science,3
bioorganic chemistry,4 and supramolecular chemistry.5 A variety
of elegant methods for the synthesis of pyrroles have been
developed in the past decades,6,7 however, a facile and efficient
procedure for the synthesis of multisubstituted pyrroles remains
highly desirable.
Apart from the well-documented traditional methods, such
as the Knorr,8 Paal–Knorr,9 and Hantzsch reactions,10 the
modern approaches to the synthesis of substituted pyrroles are
mainly based on the transition-metal catalyzed cyclizations11,12
and multicomponent coupling reactions.13,14 However, the high
catalyst loading in some of these processes results in not only
high cost but also potential contamination of the products,
particularly in the pharmaceutical industry.15 Recently, a metal-
free synthesis of substituted pyrroles by the domino reac-
tion of cyclic enaminones with halogenated nitroolefins has
emerged.16 However, the procedure was not environmentally
benign due to using halogenated nitroolefins. We envision that
the Michael-type addition and cyclization of enaminones or
enaminoesters to nitroolefins would be a direct approach to
construct the pyrrole rings in accordance with the principles
of green chemistry (Scheme 1). There is limited precedent
for these transformations,17 but the reaction is still limited
in substrate scope and low yields.18 In this communication,
we have improved the synthetic method and developed an
environmentally benign, facile and efficient synthetic method for
Entry
Solvent
Additive
t (h)
Yield (%)
1
2
3
4
5
6
7
8
C2H5OH
H2O
DMSO
CH3CN
glycol
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
—
—
—
—
—
—
14
14
14
14
14
14
7
7
8
4
57
24
42
20
61
75
69
45
62
50
NaOAc
pyridine
CAN
Zn powder
9
10
a Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), additive
(0.6 mmol), in solvent (2 mL) at 120 ◦C.
the synthesis of multisubstituted pyrroles from readily available
enaminoesters and nitroolefins.
To begin our study, 1-(2-nitroprop-1-enyl)benzene 1a and
methyl 3-(phenylamino)but-2-enoate 2a were chosen as model
substrates to optimize the reaction conditions. Screening of
various solvents revealed that CH3OH was the most efficient one
for the transformation (Table 1, entries 1–6). Various additives,
such as NaOAc, pyridine, CAN (ammonium cerium(IV) nitrate),
and Zn powder were tested and failed to improve the efficiency
of the transformation (Table 1, entries 7–10). Therefore, the
combination of the nitroolefins 1a (0.3 mmol) and enaminoesters
2a (1.5 eq.) in CH3OH at 120 ◦C gave the best result.
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an, 710069, P. R. China.
E-mail: guanzhh@nwu.edu.cn
† Electronic supplementary information (ESI) available: Experimental
procedure, 1H and 13C NMR spectra for all compounds. See DOI:
10.1039/c1gc15278e
Under the optimized reaction conditions, we have explored
the substrate scope. The reaction results of enaminoester 2a with
various nitroolefins19 1a–1j are summarized in Table 2. These
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Table 2 Reactions of enaminoester 2a with various nitroolefins 1a
Entry
1
Nitroolefin 1
Pyrrole 3
t (h)
Yield (%)
75
14
2
22
83
3
4
5
22
23
35
80
78
79
6
7
8
24
24
30
74
65
67
9
35
12
79
78
10
a Reaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), in CH3OH (2 mL) at 120 ◦C.
transformations displayed high functional group tolerance.
Nitroolefins with methyl, methoxyl, amino, fluoro and chloro
groups on the arene all gave the corresponding pyrroles in good
yields (Table 2, entries 2–8). For the electronic effects of the
transformation, we found that electron-rich nitroolefins showed
better reactivity and gave higher yields than electron-deficient
ones (Table 2, entries 2–8). In addition, the nitroolefin possessing
a furanyl group also underwent the desired reaction to give the
corresponding pyrrole product 3ia in good yield (Table 2, entry
9). An extensive investigation of the reaction shows that the
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Table 3 Reactions of various enaminoesters 2 with nitroolefin 1aa
Entry
1
Enaminoester 2
Pyrrole 3
t (h)
Yield (%)
81
12
2
3
4
13
24
13
77
79
83
5
6
7
8
24
24
24
25
82
73
63
50
9
30
24
29
75
10
11
30(54)b
60(68)b
12
27
82
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Table 3 (Contd.)
Entry
13
Enaminoester 2
Pyrrole 3
t (h)
Yield (%)
92
7
14
15
16
6
89
86
58
12
24
a Reaction conditions: 1a (0.3 mmol), 2 (0.45 mmol), in CH3OH (2 mL) at 120 ◦C. b NaOAc (0.6 mmol) was added.
nitroolefin 1j also worked well, and a 78% yield of the desired
pyrrole 3ja was obtained (Table 2, entry 10).
multisubstituted pyrroles were synthesized in good to excellent
yields in an environmentally benign manner.
For extending the substrate scope, we have investigated the
reactions of various enaminoesters20 2b–2q with nitroolefin 1a
as well, and the results are illustrated in Table 3. Satisfactorily,
the reactions displayed high functional group tolerance and
afforded the corresponding pyrroles with great efficiency. In gen-
eral, the electron-rich enaminoesters show better reactivity and
gave higher yields than electron-deficient ones, and the reactions
were insensitive to the steric hindrance of the substitutes on
the aromatic rings (Table 3, entries 1–9). Pyrrole 3ak was only
obtained in low yield because NO2 substituted enaminoester
2k was partially decomposed in the reaction. This issue has
been resolved by using NaOAc as an additive (Table 3, entry
10). The reaction of enaminoesters 2l and 2m, which derived
from naphthalen-1-amine and naphthalen-2-amine respectively,
also gave the corresponding pyrrole products 3al and 3am in
good yields (Table 3, entries 11–12). It is worth noting that
N-benzyl substituted pyrroles were obtained in excellent yields
in the transformations (Table 3, entries 13–14). Similarly, N-
cyclohexanyl substituted pyrrole 3ap was achieved in 86% yield
(Table 3, entries 15). Moreover, the reaction of nitroolefin 1a
with enaminone 2q also gave the pyrrole product 3aq in good
yield (Table 3, entry 16).
Acknowledgements
This research was supported by National Natural Science
Foundation of China (NSFC-21002077), Northwest University
(PR09037, NF0913), and Education Department of Shaanxi
Provincial Government (2010JK869).
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In conclusion, we have demonstrated a facile and efficient
procedure for the synthesis of multisubstituted pyrroles. This
general protocol employs readily available starting materials and
shows good functional group tolerance. Under the transition
metal-free and non-halogenation conditions, a wide variety of
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