A three-component one-pot synthesis of penta-substituted pyrroles via ring opening of α-nitroepoxides

Article abstract of DOI:10.1016/j.tet.2017.03.074

A novel and facile one-pot reaction has been developed to synthesize a variety of penta-substituted pyrroles from α-nitroepoxides, primary amines and dialkyl acetylenedicarboxylates under the conditions without catalyst. Furthermore, the controlled experi

Full text of DOI:10.1016/j.tet.2017.03.074

Accepted Manuscript
A three-component one-pot synthesis of penta-substituted pyrroles via ring opening of
α-nitroepoxides
Donghong Zhao, Yue Zhu, Shanshan Guo, Wenteng Chen, Guolin Zhang, Yongping
Yu
PII:
S0040-4020(17)30331-9
10.1016/j.tet.2017.03.074
TET 28580
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 February 2017
Revised Date: 20 March 2017
Accepted Date: 21 March 2017
Please cite this article as: Zhao D, Zhu Y, Guo S, Chen W, Zhang G, Yu Y, A three-component one-
pot synthesis of penta-substituted pyrroles via ring opening of α-nitroepoxides, Tetrahedron (2017), doi:
10.1016/j.tet.2017.03.074.
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A three-component one-pot synthesis of
penta-substituted pyrroles via ring opening
of α-nitroepoxides
Leave this area blank for abstract info.
Donghong Zhao, Yue Zhu, Shanshan Guo, Wenteng Chen, Guolin Zhang* and Yongping Yu*
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou 310058, P. R. China

1
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Tetrahedron
journal homepage: www.elsevier.com
A three-component one-pot synthesis of penta-substituted pyrroles via ring opening of
α-nitroepoxides
Donghong Zhao, Yue Zhu, Shanshan Guo, Wenteng Chen, Guolin Zhang and Yongping Yu*
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and facile one-pot reaction has been developed to synthesize a variety of penta-
substituted pyrroles from α-nitroepoxides, primary amines and dialkyl acetylenedicarboxylates
under the conditions without catalyst. Furthermore, the controlled experiments has been
performed and a possible mechanism has also been proposed.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
penta-substituted pyrroles
α-nitroepoxides
primary amines
dialkyl acetylenedicarboxylates
one-pot synthesis
1. Introduction
Pyrrole is one of the most important simple heterocycles, and
many substituted or functionalized pyrrole derivatives are widely
used in different fields.1 In pharmaceutical field, pyrrole ring as
an important structural unit widely exists in natural and unnatural
products showing different bioactivities, such as antibiotics,2
anti-HIV agents,3 anti-inflammatory agents,4 immunosuppressive
and anticancer agents.5 So the synthesis of various
polysubstituted pyrroles is improtant, and a variety of synthetic
strategies have been developed,6 such as the Hantzsch method or
modified Hantzsch methodologies using α-haloketones, ammonia
or primary amines and β-dicarbonyl compounds as substrates
(Scheme 1-A, Eq. 1),7 the reaction of aldehydes, N-(substituted
sulfonamido) acetophenones and α-activated nitriles (Scheme 1-
A, Eq. 2),8 the synthesis method using isonitriles as the source of
the heterocyclic nitrogen (Scheme 1-A, Eq. 3),9 the reaction of
nitroalkenes, amines and 1,3-dicarbonyl compounds (Scheme 1-
A, Eq. 4),10 the reaction of glyoxals or α-diketones, primary
amines and dialkyl acetylenedicarboxylates which needs other
additives (Scheme 1-A, Eq. 5).11 Although these strategies have
been developed, the synthesis of penta-substituted pyrroles from
readily available starting materials under simple conditions
remains in demand. So, we develop a facile one-pot method to
provide penta-substituted pyrroles via α-nitroepoxides, primary
amines and dialkyl acetylenedicarboxylates (Scheme 1-B).
Scheme 1. Previous and New Synthesis of Polysubstituted
pyrrole Derivatives
2. Results and discussion
———
Corresponding author. Tel./fax: +86-571-8820-8450, +86-571-8820-8452; e-mail addresses: guolinzhang@zju.edu.cn (G. Zhang),
yyu@zju.edu.cn (Y. Yu).

2
Tetrahedron
Table 1. Optimization of Reaction Conditions a
products of all reactions were obtained in the yield of 64% ~
ACCEPTED MANUSCRIPT
91%.
Table 2. Scope of the Reaction of α-Nitroepoxides, Primary
amines and Dialkyl acetylenedicarboxylates Under Optimal
Conditions a
1a:2a:3a
(equiv.)
Conversionc
(%)
Entry Base (equiv.) Solvent
T(°C)
80
1
2
3
4
5
6
7
K2CO3 (1) MeOH
Et3N (1) MeOH
DIEA (1) MeOH
1:1:1.05
25
33
80
1:1:1.05
1:1:1.05
1:1:1.05
1:1:1.05
1:1:1.05
1:1:1.05
80
45
92(90)d
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
-
-
-
-
MeOH
80
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
EtOH
80
78
n-propanol
80
23
Cl
n-butyl
alcohol
80
trace
4c,88%
4b,77%
4a,82%
8
-
-
-
-
-
-
-
-
-
-
-
t-butanol
CH2Cl2
CH3CN
DMF
80
80
80
80
RT
50
1:1:1.05
1:1:1.05
1:1:1.05
1:1:1.05
1:1:1.05
1:1:1.05
12
n.r.
n.r.
n.r.
11
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
9
N
N
N
10
11
12
13
14b
15
16
17
18
4d,69%
4f,87%
4e,90%
N
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
F
12
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
N
Reflux 1:1:1.05
69
N
100
80
1:1:1.05
1:1:1
40
90(88)d
4i,76%
4g,75%
4h,74%
80
1:1.05:1
83
80
1:1.1:1.1
79
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
aReaction conditions: 3-(4-chlorophenyl)-2-methyl-2-nitrooxirane (0.5 mmol,
1.0 equiv.), p-toluidine and dimethyl acetylenedicarboxylate, base, 3 mL of
solvent, 10 h, in sealed tube. bReaction was performed in reflux device.
cDetermined by high-performance liquid chromatography, based on the
disappearance of the starting 3-(4-chlorophenyl)-2-methyl-2-nitrooxirane.
dIsolated yields.
N
N
N
Cl
4j,78%
4l,81%
4k,64%
CO2Et
CO2Et
CO2Me
CO2Me
CO2Et
CO2Et
N
N
N
Initially, 3-(4-chlorophenyl)-2-methyl-2-nitrooxirane 1a, p-
toluidine 2a and dimethyl acetylenedicarboxylate 3a were
selected as reagents to optimize the reaction conditions. Firstly,
screening of bases (Table 1, entries 1–4) revealed that the good
conversion occurred under the conditions without any additive
(Table 1, entry 4). Then, the optimization of solvent
demonstrated that MeOH (Table 1, entry 4) was superior to other
aprotic and protic solvents (Table 1, entries 5–11). In addition,
when the reaction was conducted at different temperatures, the
conversion decreased in different degrees (Table 1, entries 12–
15). Furthermore, when changing the ratio of reaction substrates,
the conversion of the reaction slightly decreased (Table 1, entries
16–18). On the basis of the initial study, the optimal reaction
conditions was obtained, that is, 3-(4-chlorophenyl)-2-methyl-2-
Cl
4n,84%
4o,79%
4m,90%
CO2Et
CO2Et
N
Cl
4p,91%
aReaction conditions: all reactions were conducted under the conditions from
Table 1, entry 4. Isolated yields.
No matter aryl or alkyl substitution at R1 and R2 positions of
nitroepoxides 1 could give the corresponding products in good
yields (4a-4e), especially, the yield of 4e with phenyl at the R1
and R2 positions was 90%. Moreover, both aliphatic amines and
aromatic amines were reactive (4a, 4f-4j), and aromatic amines
afforded the desired products in a higher yield than aliphatic
amines (4a compared to 4j, 4b compared to 4k, 4c compared to
4l). Furthermore, the yields of reactions using diethyl
acetylenedicarboxylate or dimethyl acetylenedicarboxylate were
basically the same and just had slightly difference (4n compared
to 4a, 4o compared to 4j, 4p compared to 4m). In our
experiments, the highest yield was obtained, when 3-(4-
nitrooxirane
1a,
p-toluidine
2a
and
dimethyl
acetylenedicarboxylate 3a were conducted in sealed tube at 80°C
for 10 h with MeOH as solvent (Table 1, entry 4).
Subsequently, the scope of the reaction was studied using a
set of α-nitroepoxides 1, primary amines
2 and dialkyl
acetylenedicarboxylates under the optimized reaction
3
conditions. The α-nitroepoxides were prepared through the
straightforward epoxidation of nitroalkenes, which could be
readily obtained by standard nitroaldol/Henry reaction.12 The
results were shown in Table 2. On the whole, the desired

3
4. Experimental section
chlorophenyl)-2-methyl-2-nitrooxirane, p-toluidine and diethyl
acetylenedicarboxylate were used as the reagents (4p).
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4.1 General
All solvents were purified according to standard methods prior
to use. Melting points were recorded on a BÜCHI B-540 melting
point apparatus. NMR spectra were recorded for 1H NMR at 500
MHz and 13C NMR at 125 MHz. For 1H NMR, tetramethylsilane
(TMS) served as internal standard (δ=0) and data are reported as
follows: chemical shift, integration, multiplicity (s=singlet,
d=doublet, t= triplet, q=quartet, m=multiplet), and coupling
constant(s) in Hertz. For 13C NMR, TMS (δ=0) or DMSO
(δ=40.45) was used as internal standard and spectra were
obtained with complete proton decoupling. LC-MS and HRMS
data was obtained using Agilent Technologies 6224 TOF
LC/MS. The starting material α-nitroepoxides were prepared
according to literature methods.11 The starting material primary
amines and dialkyl acetylenedicarboxylates were commercially
available. The intermediates 5 and 6 were prepared according to
literature methods.12, 13
In order to study the proposed mechanism of this reaction, the
controlled experiments were performed (Scheme 2). Firstly, the
possible intermediates 5 and 6 were obtained by separately
treating 3-(4-chlorophenyl)-2-methyl-2-nitrooxirane 1a and
dimethyl acetylenedicarboxylate 3a with p-toluidine 2a.13,14
Then, intermediate
5
and 3-(4-chlorophenyl)-2-methyl-2-
nitrooxirane 1a reacted under the optimal reaction conditions
above (Route 1), meanwhile, intermediate 6 and dimethyl
acetylenedicarboxylate 3a reacted under the same conditions
(Route 2). The result was that only the Route 2 proceeded
effectively to give the desired product 4m.
4.2 General procedure for the synthesis of penta-
substituted pyrroles 4
A mixture of α-nitroepoxide 1 (0.5 mmol, 1.0 equiv.) and
primary amine 2 (0.5 mmol, 1.0 equiv.) in MeOH (3 mL) was
stirred at 80°C oil bath. After
3
min, dialkyl
acetylenedicarboxylate 3 (0.525 mmol, 1.05 equiv.) was added
dropwise. The mixture was unceasingly stirred in sealed tube at
80°C oil bath for 10h (TLC monitoring). After completion, the
solvent MeOH was evaporated in vacuo and the residue was
treated with column chromatography (silica gel, 5–8%
EtOAc/hexane) to give pure penta-substituted pyrroles 4a-4p.
Scheme 2. Controlled Experiments
Based on the results presented above, a possible reaction
mechanism is proposed as shown in Scheme 3. In the case of
amine 2, the nitroepoxide 1 is attacked by the lone-pair electrons
on the nitrogen of amine 2 and undergoes a ring opening to give
the intermediate I. The intermediate I affords the intermediate II
driven by the excellent leaving ability of nitro.15 Then, the lone-
pair electrons on the nitrogen of intermediate II continues to
attack dialkyl acetylenedicarboxylates 3 orderly forming the
intermediate III and IV. Subsequently, intermediate IV
transforms into final product 4 by eliminating one molecule of
H2O.
4.2.1
Dimethyl
4-methyl-1,5-diphenyl-1H-pyrrole-2,3-
dicarboxylate (4a). Pale yellow solid; yield: 82% (0.1431g); mp:
1
134.3~134.7°C; H NMR (500 MHz, CDCl3) δ 7.26 – 7.23 (m,
3H), 7.22 – 7.19 (m, 3H), 7.11 – 7.09 (m, 2H), 7.04 (m, 2H), 3.90
(s, 3H), 3.67 (s, 3H), 2.19 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
165.98, 161.72, 137.99, 135.89, 130.73, 130.60, 128.44, 128.11,
127.96, 127.67, 125.86, 119.55, 118.46, 52.01, 51.73, 10.66.
HRMS (ESI): m/z calcd for C21H20NO4 [M+H]+: 350.1387, found:
350.1387.
4.2.2
Dimethyl 4-methyl-1-phenyl-5-(p-tolyl)-1H-pyrrole-2,3-
dicarboxylate (4b). Pale yellow solid; yield: 77% (0.1398g); mp:
1
149.7~150.3°C; H NMR (500 MHz, CDCl3) δ 7.28 – 7.24 (m,
3H), 7.12 – 7.09 (m, 2H), 7.01 (d, J = 7.9 Hz, 2H), 6.94 – 6.91
(m, 2H), 3.89 (s, 3H), 3.66 (s, 3H), 2.27 (s, 3H), 2.18 (s, 3H). 13
C
NMR (125 MHz, CDCl3) δ 166.08, 161.70, 138.10, 137.47,
136.06, 130.55, 128.71, 128.42, 128.14, 128.07, 127.57, 125.53,
119.67, 118.27, 51.97, 51.73, 21.19, 10.67. HRMS (ESI): m/z
calcd for C22H22NO4 [M+H]+: 364.1543, found: 364.1549.
4.2.3
Dimethyl
5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-
Scheme 3. Proposed Mechanism
pyrrole-2,3-dicarboxylate (4c). Pale yellow solid; yield: 88%
(0.1685g); mp: 156.8~157.6°C; H NMR (500 MHz, CDCl3) δ
1
3. Conclusion
7.29 – 7.26 (m, 3H), 7.20 – 7.17 (m, 2H), 7.10 – 7.07 (m, 2H),
6.98 – 6.95 (m, 2H), 3.89 (s, 3H), 3.67 (s, 3H), 2.18 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 165.77, 161.63, 137.72, 134.44,
133.82, 131.92, 129.07, 128.64, 128.36, 128.33, 128.05, 126.34,
119.45, 118.80, 52.09, 51.77, 10.66. HRMS (ESI): m/z calcd for
C21H19ClNO4 [M+H]+: 384.0997, found: 384.0999.
In conclusion, we have developed a novel, one-pot three-
component strategy to synthesize penta-substituted pyrroles from
α-nitroepoxides,
acetylenedicarboxylates. This reaction was finished in good
yields via a ring opening, an intermolecular nucleophilic attack
and an intramolecular condensation. Due to the advantage of
operational simplicity and no need for any additives, this reaction
would be a practical strategy for pharmaceutical building blocks.
primary
amines
and
dialkyl
4.2.4
Dimethyl 4-methyl-1-phenyl-5-propyl-1H-pyrrole-2,3-
dicarboxylate (4d). Yellow liquid; yield: 69% (0.1087g); 1H
NMR (500 MHz, CDCl3) δ 7.46 – 7.42 (m, 3H), 7.22 – 7.19 (m,
2H), 3.87 (s, 3H), 3.60 (s, 3H), 2.31 (t, 2H), 2.15 (s, 3H), 1.33 –
1.25 (m, 2H), 0.75 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz,
The structures of the penta-substituted pyrroles
4 were
characterized by 1H NMR, 13C NMR, and HRMS.

4
Tetrahedron
ACCEPTED MANUSCRIPT
CDCl3) δ 166.70, 161.05, 138.16, 136.82, 128.80, 128.67,
Hz, 2H), 4.03 – 3.99 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.41 (s,
128.02, 122.98, 120.89, 116.55, 51.87, 51.66, 26.35, 22.68, 13.79,
9.96. HRMS (ESI): m/z calcd for C18H22NO4 [M+H]+: 316.1543,
found: 316.1543.
3H), 1.97 (s, 3H), 1.55 – 1.47 (m, 2H), 0.68 (t, J = 7.4 Hz, 3H).
13C NMR (125 MHz, CDCl3) δ 166.91, 161.78, 138.39, 136.82,
130.58, 129.29, 128.03, 121.41, 121.27, 117.70, 51.79, 47.50,
24.79, 21.34, 10.95, 10.22. HRMS (ESI): m/z calcd for
C19H24NO4 [M+H]+: 330.1700, found: 330.1703.
4.2.5
Dimethyl 1,4,5-triphenyl-1H-pyrrole-2,3-dicarboxylate
(4e). Yellow solid; yield: 90% (0.1850g); mp: 162.1~162.9°C. 1H
NMR (500 MHz, CDCl3) δ 7.31 – 7.28 (m, 3H), 7.20 – 7.15 (m,
7H), 7.12 – 7.08 (m, 1H), 7.07 – 7.03 (m, 2H), 6.92 – 6.89 (m,
2H), 3.80 (s, 3H), 3.69 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
166.77, 160.49, 138.04, 137.10, 133.26, 131.13, 130.14, 129.85,
128.50, 128.42, 128.37, 128.00, 127.83, 127.79, 126.76, 123.04,
122.86, 122.49, 52.33, 51.91. HRMS (ESI): m/z calcd for
C26H22NO4 [M+H]+: 412.1543, found: 412.1545.
4.2.12 Dimethyl
5-(4-chlorophenyl)-4-methyl-1-propyl-1H-
pyrrole-2,3-dicarboxylate (4l). Pale yellow solid; yield: 81%
(0.1414g); mp: 66.7~67.4°C; 1H NMR (500 MHz, CDCl3) δ 7.46
– 7.42 (m, 2H), 7.22 – 7.19 (m, 2H), 4.02 – 3.98 (m, 2H), 3.86 (s,
3H), 3.85 (s, 3H), 1.97 (s, 3H), 1.54 – 1.46 (m, 2H), 0.68 (t, J =
7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ166.60, 161.74,
135.16, 134.72, 132.05, 129.51, 128.95, 122.20, 121.14, 118.12,
51.92, 51.84, 47.54, 24.79, 10.93, 10.19. HRMS (ESI): m/z calcd
for C18H21ClNO4 [M+H]+: 350.1154, found: 350.1156.
4.2.6
Dimethyl 4-methyl-5-phenyl-1-(p-tolyl)-1H-pyrrole-2,3-
dicarboxylate (4f). Pale yellow solid; yield: 87% (0.1580g); mp:
132.7~133.2°C; H NMR (500 MHz, CDCl3) δ 7.23 – 7.20 (m,
1
4.2.13 Dimethyl 5-(4-chlorophenyl)-4-methyl-1-(p-tolyl)-1H-
pyrrole-2,3-dicarboxylate (4m). White solid; yield: 90%
(0.1787g); mp: 132.4~133.0°C; H NMR (500 MHz, CDCl3) δ
3H), 7.06 – 7.03 (m, 4H), 6.98 (m, 2H), 3.89 (s, 3H), 3.68 (s, 3H),
2.29 (s, 3H), 2.18 (s, 3H).13C NMR (125 MHz, CDCl3) δ 166.03,
161.82, 137.98, 135.89, 135.33, 130.74, 130.70, 129.10, 127.94,
127.77, 127.59, 125.90, 119.31, 118.34, 52.03, 51.71, 21.13,
10.69. HRMS (ESI): m/z calcd for C22H22NO4 [M+H]+: 364.1543,
found: 364.1548.
1
7.19 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 7.98 – 6.95 (m,
4H), 3.88 (s, 3H), 3.68 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 165.88, 161.75, 138.30, 135.03,
134.48, 133.71, 131.93, 129.32, 129.14, 128.33, 127.72, 126.30,
119.22, 118.65, 52.16, 51.81, 21.19, 10.71. HRMS (ESI): m/z
calcd for C22H21ClNO4 [M+H]+: 398.1154, found: 398.1159.
4.2.7
Dimethyl
1-(4-fluorophenyl)-4-methyl-5-phenyl-1H-
pyrrole-2,3-dicarboxylate (4g). White solid; yield: 75%
(0.1377g); mp: 135.5~136.0°C; H NMR (500 MHz, CDCl3) δ
1
4.2.14 Diethyl
dicarboxylate (4n). Pale yellow solid; yield: 84% (0.1584g); mp:
99.8~100.6°C; H NMR (500 MHz, CDCl3) δ 7.26 – 7.23 (m,
4-methyl-1,5-diphenyl-1H-pyrrole-2,3-
7.24 – 7.21 (m, 3H), 7.10 – 7.07 (m, 2H), 7.04 – 7.02 (m, 2H),
6.96 – 6.91 (m, 2H), 3.90 (s, 3H), 3.69 (s, 3H), 2.17 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 166.06, 162.94, 161.47, 160.96,
136.34, 133.99, 133.96, 130.71, 130.32, 129.94, 129.87, 128.12,
127.88, 125.28, 120.29, 118.46, 115.55, 115.37, 52.08, 51.90,
10.61. HRMS (ESI): m/z calcd for C21H19FNO4 [M+H]+:
368.1293, found: 368.1294.
1
3H), 7.22 – 7.19 (m, 3H), 7.12 – 7.09 (m, 2H), 7.05-7.02 (m, 2H),
4.37 (q, J = 7.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.19 (s, 3H),
1.38 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H). 13C NMR (125
MHz, CDCl3) δ 165.61, 161.22, 138.12, 135.65, 130.73, 130.65,
128.42, 128.19, 128.08, 127.96, 127.62, 125.91, 119.71, 118.31,
60.97, 60.63, 14.32, 13.84, 10.65. HRMS (ESI): m/z calcd for
C23H24NO4 [M+H]+: 378.1700, found: 378.1701.
4.2.8
Dimethyl 1-benzyl-4-methyl-5-phenyl-1H-pyrrole-2,3-
1
dicarboxylate (4h). Colorless liquid; yield: 74% (0.1344g); H
NMR (500 MHz, CDCl3) δ 7.38 – 7.35 (m, 3H), 7.22 – 7.16 (m,
5H), 6.80 (d, J = 6.8 Hz, 2H), 5.33 (s, 2H), 3.88 (s, 3H), 3.72 (s,
3H), 2.05 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 166.57, 161.66,
138.10, 137.14, 130.75, 130.58, 128.61, 128.54, 128.43, 127.12,
126.04, 122.51, 121.58, 118.28, 51.85, 49.30, 10.39. HRMS
(ESI): m/z calcd for C22H22NO4 [M+H]+: 364.1543, found:
364.1543.
4.2.15 Diethyl
4-methyl-5-phenyl-1-propyl-1H-pyrrole-2,3-
1
dicarboxylate (4o). Pale yellow liquid; yield: 79% (0.1356g); H
NMR (500 MHz, CDCl3) δ 7.47 – 7.40 (m, 3H), 7.27 – 7.24 (m,
2H), 4.32 (dq, J = 12.0, 7.1 Hz, 4H), 4.03 – 3.99 (m, 2H), 1.97 (s,
3H), 1.56 – 1.48 (m, 2H), 1.35 (dt, J = 12.7, 7.1 Hz, 6H), 0.68 (t,
J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.52, 161.29,
136.53, 131.16, 130.75, 128.56, 128.46, 121.60, 121.50, 117.51,
60.70, 60.69, 47.52, 24.82, 14.35, 14.15, 10.99, 10.16. HRMS
(ESI): m/z calcd for C20H26NO4 [M+H]+: 344.1856, found:
344.1856.
4.2.9
Dimethyl 1-cyclohexyl-4-methyl-5-phenyl-1H-pyrrole-
2,3-dicarboxylate (4i). White solid; yield: 76% (0.1350g); mp:
124.0~126.5°C; H NMR (500 MHz, CDCl3) δ 7.46 – 7.41 (m,
1
3H), 7.26 – 7.23 (m, 2H), 3.98 -3.91 (m, 1H), 3.90 (s, 3H), 3.82
(s, 3H), 1.97 (s, 3H), 1.86 – 1.82 (m, 4H), 1.72 (d, J = 12.8 Hz,
2H), 1.53 (d, J = 10.4 Hz, 1H), 1.11 – 1.04 (m, 3H). 13C NMR
(125 MHz, CDCl3) δ 165.89, 164.14, 134.76, 132.04, 131.12,
128.47, 128.42, 125.31, 118.07, 117.58, 59.06, 52.49, 51.43,
32.71, 26.23, 25.02, 10.70. HRMS (ESI): m/z calcd for
C21H26NO4 [M+H]+: 356.1856, found: 356.1857.
4.2.16 Diethyl
pyrrole-2,3-dicarboxylate (4p). White solid; yield: 91%
(0.1934g); mp: 128.7~129.4°C; H NMR (500 MHz, CDCl3) δ
5-(4-chlorophenyl)-4-methyl-1-(p-tolyl)-1H-
1
7.20 – 7.17 (m, 2H), 7.05 (d, J = 8.2 Hz, 2H), 6.98 – 6.95 (m,
4H), 4.35 (q, J = 7.1 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.31 (s,
3H), 2.17 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz,
3H). 13C NMR (125 MHz, CDCl3) δ 165.45, 161.22, 138.23,
135.18, 134.26, 133.64, 131.93, 129.25, 128.30, 127.81, 126.41,
119.39, 118.51, 61.05, 60.62, 21.17, 14.31, 13.86, 10.66. HRMS
(ESI): m/z calcd for C24H25ClNO4 [M+H]+: 426.1467, found:
426.1467.
4.2.10 Dimethyl 4-methyl-5-phenyl-1-propyl-1H-pyrrole-2,3-
1
dicarboxylate (4j). Colorless liquid; yield: 78% (0.1229g); H
NMR (500 MHz, CDCl3) δ 7.47 – 7.40 (m, 3H), 7.28 – 7.25 (m,
2H), 4.02 (dd, J = 8.4, 6.7 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H),
1.98 (s, 3H), 1.55 – 1.47 (m, 2H), 0.67 (t, J = 7.4 Hz, 3H). 13C
NMR (125 MHz, CDCl3) δ 166.83, 161.79, 136.68, 131.07,
130.74, 128.58, 128.51, 121.64, 121.23, 117.80, 51.84, 51.82,
47.53, 24.78, 10.94, 10.21. HRMS (ESI): m/z calcd for
C18H22NO4 [M+H]+: 316.1543, found: 316.1548.
Acknowledgements
This project was supported from Zhejiang Provincial Natural
Science Foundation of China (LY16H300001) to G. Zhang,
National Natural Science Foundation of China (No. 81273356
and 81473074), National Science & Technology Major Projects
for "Major New Drugs Innovation and Development" of China
4.2.11 Dimethyl 4-methyl-1-propyl-5-(p-tolyl)-1H-pyrrole-2,3-
1
dicarboxylate (4k). Colorless liquid; yield: 64% (0.1053g); H
NMR (500 MHz, CDCl3) δ 7.27 – 7.24 (m, 2H), 7.14 (d, J = 8.0

5
Chem. 2012, 9, 2239. (d) Azizian, J.; Hosseini, J.;
(2014ZX09304002-007) and Osteoporosis & Breast Cancer
Research Center, USA to Y. Yu, National Natural Science
Foundation of China (No. 81402778) to W. Chen.
ACCEPTED MANUSCRIPT
Mohammadi, M.; Sheikhoelslami, F.; Synth. Commun. 2010,
40, 3472. (e) Ramesh, K.; Naryana, S.; Karnakar, M. K.;
Nageswar, Y. V. D. Tetrahedron Lett. 2011, 52, 3937. (f)
Eligeti, R.; Baireddy, K.; Saini, R. Chin. Chem. Lett. 2013,
24, 134.
Supplementary data
12. (a) Sprang, C. A.; Degering, E. F. J. Am. Chem. Soc. 1942,
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Ratcliffe, P. D. Org. Lett. 2008, 10, 4141. (c) Desai, U. V.;
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Supplementary
data
(Experimental
procedures,
1
characterization data, and copies of H and 13C NMR spectra for
all products.) associated with this article can be found in online
version at http://dx.doi.org/
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