Facile, eco-friendly, catalyst-free synthesis of polyfunctionalized 2-aminopyrroles

Article abstract of DOI:10.1016/j.tet.2012.11.041

Simple and eco-friendly synthesis of polyfunctionalized 2-aminopyrroles from vinyl azides and α-cyano derivatives has been accomplished with a good to excellent yield. The reaction was performed in ethanol/water co-solvent system without catalyst and the workup was facile. A plausible mechanism has been proposed.

Full text of DOI:10.1016/j.tet.2012.11.041

Tetrahedron 69 (2013) 1953e1957
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile, eco-friendly, catalyst-free synthesis of polyfunctionalized
2-aminopyrroles
*
Wanwan Yu, Wenteng Chen, Shen Liu, Jiaan Shao, Zhanying Shao, Haili Lin, Yongping Yu
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple and eco-friendly synthesis of polyfunctionalized 2-aminopyrroles from vinyl azides and a-cyano
Received 24 September 2012
Received in revised form 1 November 2012
Accepted 9 November 2012
Available online 15 November 2012
derivatives has been accomplished with a good to excellent yield. The reaction was performed in ethanol/
water co-solvent system without catalyst and the workup was facile. A plausible mechanism has been
proposed.
Ó 2012 Published by Elsevier Ltd.
Keywords:
2-Aminopyrroles
Vinyl azides
Catalyst-free
Eco-friendly
1. Introduction
product could be generated in a highly efficient and eco-friendly
manner without catalyst.
Pyrroles are important heterocycles that display various bi-
ological activities1 and are widely used in both organic chemistry
and material science.2 As the essential component of pyrroles,
aminopyrroles have been found to show valuable and diverse bi-
ological properties.3 Especially the 2-aminopyrrole fragments are
part of many bioactive compounds4 and have been used as pre-
cursors for the synthesis of purine analogues including pyrrolo-
pyrimidines, pyrrolotriazines, and pyrrolopyridines.5 In this regard,
efficient and facile methodologies for constructing 2-aminopyrrole
rings are valuable.
The use of vinyl azides with 1,3-dicarbonyl compounds has been
reported as an efficient method for the synthesis of pyrroles.6 During
the past decades, a certain number of aminopyrrole syntheses have
been reported.7 Some of the common synthetic approaches either
need a prolongedreactiontime, expensivetransition metaladditives,
complex substrates, or in unsatisfied yields.8 In addition, pyrrole
nitrate reduction methods result in low yields as well as isomers.9
Furthermore, polyfunctionalized aminopyrroles are not readily
available through general pyrrole ring-formation methods.
Herein, we report a novel, facile approach to provide poly-
2. Results and discussion
Initially, (Z)-ethyl-2-azido-3-(4-bromophenyl)acrylate and
malononitrile were selected as the reagents to optimize the reaction
condition. Firstly, a range of additives were screened. It was found
that additive-free was favored for this reaction (Table 1, entry 3) and
relatively high temperature could reduce the reaction time (Table 1,
entries 10 and 11). With this condition in hand, we screened other
aprotic and protic solvents (Table 1, entries 8 and 13e15). The result
revealed that ethanol was the most efficient solvent and water could
result in the transformation but with a lower yield. Next, we tried to
utilize the co-solvent system to optimize this reaction. Different
ratios of ethanol and water were tested. The best one verified by the
conversion and isolated yield was EtOH:H2O¼1:1 (Table 1, entry 10).
On the basis of this initial study, the most efficient and eco-friendly
reactivity was obtained in a co-solvent of ethanol and water at 80 ꢀC.
With the optimized reaction conditions in hand, the scope of the
reaction was studied using a set of vinyl azides 1,
rivatives with an electron-withdrawing group 2. The
a
-cyano de-
-azidovi-
a
functionalized 2-aminopyrroles using vinyl azides and
a-cyano
nylketones were readily prepared from the corresponding olefins
derivatives. An attractive feature of this protocol is that the desired
by successive reaction with bromine then with sodium azide. And
the
dehydes with ethyl azidoacetate.10,6a
When -azidovinylesters were applied in this reaction, almost
all aryl groups could be tolerant in this approach (Table 2, 3a to 3k).
a-azidovinylesters were prepared from the corresponding al-
a
* Corresponding author. Tel./fax: þ86 571 8820 8450; e-mail address: yyu@
zju.edu.cn (Y. Yu).
0040-4020/$ e see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2012.11.041

1954
W. Yu et al. / Tetrahedron 69 (2013) 1953e1957
Table 1
Table 2
Optimization of reaction conditionsa
Synthesis of polyfunctionalized 2-aminopyrroles 3a,b,c
Entry
Additive
Solvent
T (ꢀC)
t (h)
Conversion (%)b
1
2
3
4
5
6
7
8
Mn(OAc)2$4H2O
Ni(OAc)2$4H2O
d
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
DMF
H2O
EtOH:H2O¼3:1
EtOH:H2O¼1:1
EtOH:H2O¼1:1
EtOH:H2O¼1:3
n-Butanol
1,4-Dioxane
DMF
80
80
80
80
80
rt
3
3
3
3
3
12
12
3
3
3
48
3
2
3
2
90
94
94 (85)c
91
AcOH
K2CO3
K2CO3
DBU
d
Trace
Trace
n.r.
rt
100
80
80
60
80
120
80
120
75
9
d
97 (80)c
96 (91)c
59
10
11
12
13
14
15
d
d
d
90 (78)c
97d
d
d
93d
43
d
a
Reaction conditions:
a-azidovinylester (0.2 mmol, 1.0 equiv), malononitrile
(0.24 mmol, 1.2 equiv), 2 mL of solvent.
b
Determined by LC-MS, based on the disappearance of the starting
a-
azidovinylester.
c
Isolated yields.
d
Product could not precipitate from the reaction mixture. The most efficient
entry is highlighted in bold.
The result reveals that not only electron-withdrawing groups,
electron-donating groups, but also steric effects have no influence
on the yields. While
efficiently in these conditions,
cient with decreased yields (compare 3a to 3l).
The scope of -azidovinylketones examined in the reaction is
a
-azidovinylesters seem in general to work
a
-azidovinylketones seem less effi-
a
summarized as follows. 1 with electron-withdrawing groups at the
R1 position performed slightly better (3p compared to 3s; 3m, 3n
compared to 3l). While at the R2 position, relatively strong electron-
donating groups gave slight increases inyields (3m compared to 3q).
The morpholinylcarbonyl group and acetyl group at the R2 position
were also utilized in this approach. Unfortunately, we could not get
the desired product with an acetyl group at the R2 position (Table 2,
3x). Meanwhile, the morpholinylcarbonyl substitution (Table 2, 3t)
resulted in a lower yield compared to 3a and 3l.
We also found that
a-cyano derivatives 2 bearing a strong
electron-withdrawing group on the R3 position were converted
into the corresponding products with better efficiency (3g com-
pared to 3u, 3v, 3w), in a shorter time.
The structures of the polyfunctionalized 2-aminopyrroles 3
were characterized by 1H NMR, 13C NMR, and HRMS. The structure
of 3 was proved by the 2D 1He1H NOESY result of 3c. Furthermore,
the structure of 3i was confirmed by X-ray crystal structure analysis
as shown in Fig. 1.
On the basis of the results above, we proposed the following
possible mechanism for this reaction, as shown in Scheme 1.
It is proposed that vinyl azides 1 could transform to the 2H-
azirines II via the intermediate I under the heating condition.6,10a,11
The 2H-azirines then reacted with the
a-cyano derivatives 2 by
a sequential domino cyclization to provide the intermediate IV.
Subsequently, the reaction underwent an intramolecular electronic
rearrangement to produce the desired product 3.
novel reaction can be realized in good yields via a domino process
involving sequential cyclization and intramolecular rearrange-
ment. Short reaction time, eco-friendly reaction conditions, and
facile substituent variation are all notable aspects of this meth-
odology. Furthermore, the synthesis is economical both in lost
atom count and the reaction materials. This simple synthesis with
the ability to incorporate multiple functional groups into a de-
sired pyrrole ring system provides an attractive strategy for
3. Conclusion
In summary, we have developed a facile and catalyst-free
strategy to prepare polyfunctionalized 2-aminopyrroles. This

W. Yu et al. / Tetrahedron 69 (2013) 1953e1957
1955
combined organic extracts were washed with brine, dried over
Na2SO4, concentrated, and recrystallized in the same solvent.
4.2.1. Ethyl 5-amino-4-cyano-2-phenyl-1H-pyrrole-3-carboxylate
(3a). White solid [Rf¼0.5 (CH2Cl2/MeOH¼15:1)]; mp: 216e217 ꢀC;
1H NMR (500 MHz, DMSO)
d
11.26 (s, 1H), 7.50 (d, J¼7.5 Hz, 2H),
7.40e7.33 (m, 3H), 5.84 (s, 2H), 4.10 (q, J¼7.0 Hz, 2H), 1.15 (t,
J¼7.0 Hz, 3H); 13C NMR (125 MHz, DMSO)
d 163.1, 149.5, 131.3,130.9,
129.5,128.4,128.2,117.4,109.0, 71.9, 59.9,14.3; HRMS (EI): found: m/
z 255.1003. Calcd for C14H13N3O2 (M)þ: 255.1008.
4.2.2. Ethyl 5-amino-4-cyano-2-(4-fluorophenyl)-1H-pyrrole-3-
carboxylate (3b). Light pink solid [Rf¼0.3 (CH2Cl2/MeOH¼15:1)];
mp: 194e195 ꢀC; 1H NMR (500 MHz, DMSO)
d 11.30 (s, 1H),
Fig. 1. X-ray crystal structure of 3i.
7.58e7.51 (m, 2H), 7.25e7.22 (m, 2H), 5.86 (s, 2H), 4.10 (q, J¼7.0 Hz,
2H), 1.15 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, DMSO)
d 163.0, 162.3
(d, J¼244), 149.5, 131.8 (d, J¼8 Hz), 130.0, 127.8 (d, J¼3 Hz), 117.3,
115.1 (d, J¼21 Hz), 109.0, 71.7, 59.9, 14.3; HRMS (EI): found: m/z
273.0905. Calcd for C14H12FN3O2 (M)þ: 273.0914.
4.2.3. Ethyl 5-amino-2-(4-bromophenyl)-4-cyano-1H-pyrrole-3-
carboxylate (3c). Light yellow solid [Rf¼0.4 (CH2Cl2/MeOH¼15:1)];
mp: 254e256 ꢀC; 1H NMR (400 MHz, DMSO)
d 11.33 (s, 1H), 7.88 (d,
J¼8.8 Hz, 2H), 7.45 (d, J¼8.4 Hz, 2H), 5.90 (s, 2H), 4.11 (q, J¼7.2 Hz,
2H), 1.16 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, DMSO)
d 162.9, 149.6,
131.4, 131.1, 130.3, 129.4, 121.5, 117.1, 109.4, 71.9, 59.9, 14.2; HRMS
(EI): found: m/z 333.0121. Calcd for C14H12BrN3O2 (M)þ: 333.0113.
Scheme 1. The proposed reaction mechanism.
4.2.4. Ethyl 5-amino-4-cyano-2-(4-nitrophenyl)-1H-pyrrole-3-
carboxylate (3d). Light yellow solid [Rf¼0.4 (CH2Cl2/MeOH¼15:1)];
mp: 227e229 ꢀC; 1H NMR (500 MHz, DMSO)
d 11.58 (s, 1H), 8.24 (d,
pharmaceutical building blocks and medicinal chemistry
applications.
J¼8.5 Hz, 2H), 7.78 (d, J¼9.0 Hz, 2H), 6.11 (s, 2H), 4.16 (q, J¼7.0 Hz,
2H), 1.19 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, DMSO)
d 162.9, 150.4,
146.6, 137.6, 130.2, 127.7, 123.5, 116.9, 111.7, 73.2, 60.4, 14.3; HRMS
(EI): found: m/z 300.0850. Calcd for C14H12N4O4 (M)þ: 300.0859.
4. Experimental section
4.2.5. Ethyl 5-amino-4-cyano-2-(3-nitrophenyl)-1H-pyrrole-3-
4.1. General
carboxylate (3e). Light yellow solid [Rf¼0.3 (CH2Cl2/MeOH¼15:1)];
mp: 227e229 ꢀC; 1H NMR (500 MHz, DMSO)
d 11.58 (s, 1H), 8.38
All solvents were purified according to standard methods prior
(t, J¼2.0 Hz, 1H), 8.20e8.19 (m, 1H), 7.98e7.96 (m, 1H), 7.69
€
to use. Melting points were recorded on a BUCHI B-540 melting
(t, J¼8.5 Hz, 1H), 6.04 (s, 2H), 4.14 (q, J¼7.5 Hz, 2H), 1.16 (t,
point apparatus. NMR spectra were recorded for 1H NMR at
500 MHz and 13C NMR at 125 MHz (compound 3c was recorded for
1H NMR at 400 MHz and 13C NMR at 100 MHz). For 1H NMR, tet-
J¼7.0 Hz, 3H); 13C NMR (125 MHz, DMSO)
d 162.9, 150.0, 147.7,
136.0, 132.6, 129.8, 127.9, 124.0, 122.9, 117.0, 110.6, 72.5, 60.3, 14.2;
HRMS (EI): found: m/z 300.0853. Calcd for C14H12N4O4 (M)þ:
300.0859.
ramethylsilane (TMS) served as internal standard (
are reported as follows: chemical shift, integration, multiplicity
d
¼0) and data
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet), and
4.2.6. Ethyl 5-amino-4-cyano-2-(2,3,4-trifluorophenyl)-1H-pyrrole-3-
carboxylate (3f). Light brown solid [Rf¼0.3 (CH2Cl2/MeOH¼15:1)];
coupling constant(s) in Hertz. For 13C NMR, TMS (
d¼0) or DMSO
(d
¼40.45) was used as internal standard and spectra were obtained
mp: 224e226 ꢀC; 1H NMR (500 MHz, DMSO)
d 11.48 (s, 1H),
with complete proton decoupling. LC-MS and HRMS data was ob-
tained using Agilent Technologies 6224 TOF LC/MS. Single-crystals
of compound 3i were measured on a Rigaku RAXIS-RAPID single-
crystal diffractometer. The starting material vinyl azides 1aet were
prepared according to literature methods. The starting material 2
were commercially available.
7.41e7.36 (m, 1H), 7.33e7.29 (m, 1H), 6.07 (s, 2H), 4.07 (q, J¼7.0 Hz,
2H), 1.09 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, DMSO)
d 162.5, 149.9,
126.8e126.7 (m), 121.5 (d, J¼2 Hz), 118.1e118.0 (m), 116.8, 112.6 (d,
J¼3 Hz), 112.9 (d, J¼3 Hz), 112.0, 71.6, 60.0, 14.1; HRMS (EI): found:
m/z 309.0718. Calcd for C14H10F3N3O2 (M)þ: 309.0725.
4.2.7. Ethyl 5-amino-4-cyano-2-(p-tolyl)-1H-pyrrole-3-carboxylate
4.2. General procedure for the synthesis of 2-aminopyrroles
(3g). Light yellow solid [Rf¼0.3 (CH2Cl2/MeOH¼15:1)]; mp:
218e219.5 ꢀC; 1H NMR (500 MHz, DMSO)
d 11.16 (s, 1H), 7.40 (d,
A
mixture of
a
-azidovinylester or
a
-azidovinylketone
1
J¼8.0 Hz, 2H), 7.19 (d, J¼8.0 Hz, 2H), 5.78 (s, 2H), 4.10 (q, J¼7.0 Hz,
(0.4 mmol), -cyano derivative 2 (0.48 mmol) was stirred in a co-
a
2H), 2.33 (s, 3H), 1.16 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, DMSO)
solvent (ethanol 2 mL and water 2 mL) at 80 ꢀC for several hours.
After the completeness of the reaction, the reaction was diluted
with water (16 mL). The crude product was filtered from the re-
action mixture and purified by recrystallization (petroleum ether/
diethyl ether¼2:1) to afford 3. The reaction mixture of compound
3s or 3u was extracted three times with ethyl acetate. The
d 163.2, 149.4, 137.9, 131.1, 129.3, 128.8, 128.5, 117.4, 108.6, 71.8, 59.8,
21.3, 14.4; HRMS (EI): found: m/z 269.1167. Calcd for C15H15N3O2
(M)þ: 269.1164.
4.2.8. Ethyl 5-amino-4-cyano-2-(4-methoxyphenyl)-1H-pyrrole-3-
carboxylate (3h). Light brown solid [Rf¼0.4 (CH2Cl2/MeOH¼15:1)];

1956
W. Yu et al. / Tetrahedron 69 (2013) 1953e1957
mp: 200e202 ꢀC; 1H NMR (500 MHz, DMSO)
d
11.15 (s, 1H), 7.45 (d,
5.5 Hz, 4H), 6.01 (s, 2H), 2.28 (s, 3H); 13C NMR (125 MHz, DMSO)
d 190.5, 149.8, 143.2, 135.8, 131.5, 130.4, 130.2, 130.0, 129.2, 127.7,
J¼9.0 Hz, 2H), 6.95 (d, J¼8.5 Hz, 2H), 5.78 (s, 2H), 4.10 (q, J¼7.5 Hz,
2H), 3.78 (s, 3H), 1.17 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, DMSO)
120.8, 119.4,117.2, 72.8, 21.5; HRMS (EI): found: m/z 379.0324. Calcd
d
163.2, 159.5, 149.2, 131.2, 130.8, 123.7, 117.5, 113.7, 108.1, 71.5, 59.8,
for C19H14BrN3O (M)þ: 379.0320.
55.6, 14.4; HRMS (EI): found: m/z 285.1107. Calcd for C15H15N3O3
(M)þ: 285.1113.
4.2.16. 2-Amino-4-benzoyl-5-(4-bromophenyl)-1H-pyrrole-3-
carbonitrile (3p). Light yellow solid [Rf¼0.4 (CH2Cl2/MeOH¼15:1)];
4.2.9. Ethyl 5-amino-4-cyano-2-(3,4,5-trimethoxyphenyl)-1H-pyr-
mp: 278e281 ꢀC; 1H NMR (500 MHz, DMSO)
d 11.41 (s, 1H),
role-3-carboxylate (3i). Light pink solid [Rf¼0.5 (CH2Cl2/
7.57e7.55 (m, 2H), 7.44 (t, J¼7.5 Hz, 1H), 7.34 (d, J¼8.5 Hz, 2H), 7.27
MeOH¼15:1)]; mp: 197e199 ꢀC; 1H NMR (500 MHz, DMSO)
d 11.15
(t, J¼7.5 Hz, 2H), 7.08 (d, J¼8.5 Hz, 2H), 6.02 (s, 2H); 13C NMR
(s, 1H), 6.85 (s, 2H), 5.80 (s, 2H), 4.12 (q, J¼7.0 Hz, 2H), 3.79 (s, 6H),
(125 MHz, DMSO) d 190.7, 149.9, 138.6, 132.7, 131.4, 130.5, 130.3,
3.69 (s, 3H), 1.17 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, DMSO)
129.7, 128.7, 128.5, 121.0, 119.2, 117.2, 72.7; HRMS (EI): found: m/z
d
163.2,152.6,149.2,138.0,130.8,126.6,117.4,108.9,107.2, 72.0, 60.6,
365.0157. Calcd for C18H12BrN3O (M)þ: 365.0164.
59.9, 56.4, 14.4; HRMS (EI): found: m/z 345.1318. Calcd for
C17H19N3O5 (M)þ: 345.1325.
4.2.17. 2-Amino-4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1H-pyr-
role-3-carbonitrile (3q). Light yellow solid [Rf¼0.25 (CH2Cl2/
4.2.10. Ethyl 5-amino-2-(benzo[d][1,3]dioxol-5-yl)-4-cyano-1H-pyr-
MeOH¼15:1)]; mp: 295e297 ꢀC; 1H NMR (500 MHz, DMSO)
d 11.48
role-3-carboxylate (3j). Light yellow solid [Rf¼0.3 (CH2Cl2/
(s, 1H), 7.55e7.53 (m, 2H), 7.33e7.31 (m, 2H), 7.25e7.23 (m, 2H),
MeOH¼15:1)]; mp: 166e169 ꢀC; 1H NMR (500 MHz, DMSO)
d
11.17
7.17e7.15 (m, 2H), 6.06 (s, 2H); 13C NMR (125 MHz, DMSO)
d 189.3,
(s,1H), 7.09 (d, J¼1.5 Hz,1H), 6.99e6.94 (m, 2H), 6.05 (s, 2H), 5.79 (s,
150.0, 137.5, 137.3, 132.7, 131.5, 130.6, 129.8, 129.4, 128.6, 128.5,
118.8, 117.1, 72.4; HRMS (EI): found: m/z 355.0276. Calcd for
C18H11Cl2N3O (M)þ: 355.0279.
2H), 4.10 (q, J¼7.0 Hz, 2H), 1.17 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz,
DMSO)
d 163.1, 149.2, 147.5, 147.1, 130.8, 125.1, 123.3, 110.1, 108.2,
101.7, 99.7, 92.6, 71.6, 59.8, 14.3; HRMS (EI): found: m/z 299.0900.
Calcd for C15H13N3O4 (M)þ: 299.0906.
4.2.18. 2-Amino-4-(4-chlorobenzoyl)-5-(4-methoxyphenyl)-1H-pyr-
role-3-carbonitrile (3r). Light yellow solid [Rf¼0.4 (CH2Cl2/
MeOH¼15:1)]; mp: 263e265 ꢀC; 1H NMR (500 MHz, DMSO)
4.2.11. Ethyl 5-amino-2-(5-bromothiophen-2-yl)-4-cyano-1H-pyr-
role-3-carboxylate (3k). Light yellow solid [Rf¼0.45 (CH2Cl2/
d
11.31 (s, 1H), 7.50 (d, J¼8.5 Hz, 2H), 7.27 (d, J¼8.5 Hz, 2H), 7.07
MeOH¼15:1)]; mp: 181e183 ꢀC; 1H NMR (500 MHz, DMSO)
d
11.42
(d, J¼8.5 Hz, 2H), 6.73 (d, J¼9.0 Hz, 2H), 5.94 (s, 2H), 3.68 (s,
(s,1H), 7.28 (d, J¼4.0 Hz,1H), 7.22 (d, J¼4.0 Hz,1H), 6.00 (s, 2H), 4.22
3H); 13C NMR (125 MHz, DMSO)
d
189.2, 159.3, 149.7, 137.8,
(q, J¼7.5 Hz, 2H), 1.27 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, DMSO)
136.8, 131.4, 130.5, 128.4, 123.4, 117.6, 117.5, 114.0, 71.8, 55.7;
HRMS (EI): found: m/z 351.0770. Calcd for C19H14ClN3O2 (M)þ:
351.0775.
d
163.0, 149.9, 133.9, 130.2, 127.4, 123.6, 117.0, 113.0, 109.2, 71.7, 60.4,
14.4; HRMS (EI): found: m/z 338.9681. Calcd for C12H10BrN3O2S
(M)þ: 338.9677.
4.2.19. 2-Amino-4-benzoyl-5-isopropyl-1H-pyrrole-3-carbonitrile
4.2.12. 2-Amino-4-(4-methoxybenzoyl)-5-phenyl-1H-pyrrole-3-
(3s). Light brown solid [Rf¼0.3 (CH2Cl2/MeOH¼15:1)]; mp:
carbonitrile (3l). Light pink solid [Rf¼0.35 (CH2Cl2/MeOH¼15:1)];
115e118 ꢀC; 1H NMR (500 MHz, DMSO)
d 10.97 (s, 1H), 7.62e7.61
mp: 214e217 ꢀC; 1H NMR (500 MHz, DMSO)
d
11.26 (s, 1H), 7.60 (d,
(m, 2H), 7.59e7.56 (m, 1H), 7.50e7.46 (m, 2H), 5.72 (s, 2H),
J¼9.0 Hz, 2H), 7.22e7.12 (m, 5H), 6.81 (d, J¼9.0 Hz, 2H), 5.92 (s, 2H),
2.81e2.76 (m, 1H), 1.07 (d, J¼7.0 Hz, 6H); 13C NMR (125 MHz,
3.74 (s, 3H); 13C NMR (125 MHz, DMSO)
d
189.7, 163.0, 149.6, 132.1,
DMSO) d 189.9, 148.5, 140.1, 138.9, 131.7, 128.3, 128.1, 117.0, 116.1,
131.3, 131.2, 128.6, 128.3, 128.1, 127.6, 119.0, 117.3, 113.9, 72.7, 55.9;
HRMS (EI): found: m/z 317.1159. Calcd for C19H15N3O2 (M)þ:
317.1164.
69.2, 25.3, 21.8; HRMS (EI): found: m/z 253.1207. Calcd for
C15H15N3O (M)þ: 253.1215.
4.2.20. 2-Amino-4-(morpholine-4-carbonyl)-5-phenyl-1H-pyrrole-
4.2.13. 2-Amino-5-(4-chlorophenyl)-4-(4-methoxybenzoyl)-1H-pyr-
3-carbonitrile (3t). Light brown solid [Rf¼0.2 (CH2Cl2/
role-3-carbonitrile (3m). Light yellow solid [Rf¼0.3 (CH2Cl2/
MeOH¼15:1)]; mp: 244e247 ꢀC; 1H NMR (500 MHz, DMSO)
d 11.03
MeOH¼15:1)]; mp: 262e264 ꢀC; 1H NMR (500 MHz, DMSO)
d
11.36
(s, 1H), 7.39e7.36 (m, 2H), 7.34e7.32 (m, 2H), 7.25e7.22 (m, 1H),
(s, 1H), 7.62e7.59 (m, 2H), 7.27e7.25 (m, 2H), 7.19e7.17 (m, 2H),
5.90 (s, 2H), 3.55 (s, 4H), 3.20 (s, 4H); 13C NMR (125 MHz, DMSO)
6.86e6.84 (m, 2H), 6.01 (s, 2H), 3.76 (s, 3H); 13C NMR (125 MHz,
d
164.8, 149.3, 131.3, 129.2, 127.1, 125.7, 121.9, 117.2, 114.4, 71.5, 66.3;
DMSO)
d
189.6, 163.2, 149.7, 132.2, 132.1, 131.0, 130.1, 129.7, 128.6,
HRMS (EI): found: m/z 296.1264. Calcd for C16H16N4O2 (M)þ:
126.9, 119.5,117.2, 114.0, 72.9, 55.9; HRMS (EI): found: m/z 351.0765.
296.1273.
Calcd for C19H14ClN3O2 (M)þ: 351.0775.
4.2.21. Ethyl 5-amino-4-benzoyl-2-(p-tolyl)-1H-pyrrole-3-carboxylate
4.2.14. 2-Amino-5-(2-bromophenyl)-4-(4-methoxybenzoyl)-1H-pyr-
role-3-carbonitrile (3n). Light gray solid [Rf¼0.25 (CH2Cl2/
MeOH¼15:1)]; mp: 260e262 ꢀC; 1H NMR (500 MHz, DMSO)
(3u). Light yellow solid [Rf¼0.5 (CH2Cl2/MeOH¼15:1)]; mp:
75e77 ꢀC; 1H NMR (500 MHz, DMSO)
d
11.15 (s,1H), 7.50 (d, J¼7.0 Hz,
2H), 7.44e7.39 (m, 5H), 7.20 (d, J¼7.5 Hz, 2H), 6.46 (s, 2H), 3.28 (t,
d
11.28 (s, 1H), 7.47 (d, J¼7.5 Hz, 3H), 7.19e7.11 (m, 3H), 6.69 (d,
J¼7.5 Hz, 2H), 2.32 (s, 3H), 0.67 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz,
J¼8.5 Hz, 2H), 5.97 (s, 2H), 3.70 (s, 3H); 13C NMR (125 MHz,
DMSO) d 189.6, 165.6, 149.6, 142.6, 137.4, 130.6, 129.2, 128.6, 128.5,
DMSO)
d
188.6, 162.4, 149.4, 133.5, 133.0, 132.9, 131.6, 131.5,
128.4,128.3,127.7,110.6,102.8, 59.9, 21.3,13.8; HRMS (EI): found: m/z
130.4, 128.4, 127.6, 124.0, 120.6, 117.4, 113.3, 71.7, 55.8; HRMS
(EI): found: m/z 395.0268. Calcd for C19H14BrN3O2 (M)þ:
395.0269.
348.1480. Calcd for C21H20N2O3 (M)þ: 348.1474.
4.2.22. Diethyl 2-amino-5-(p-tolyl)-1H-pyrrole-3,4-dicarboxylate
(3v). Light yellow solid [Rf¼0.5 (CH2Cl2/MeOH¼15:1)]; mp:
4.2.15. 2-Amino-5-(4-bromophenyl)-4-(4-methylbenzoyl)-1H-pyr-
44e46 ꢀC; 1H NMR (500 MHz, DMSO)
d 10.86 (s, 1H), 7.28 (d,
role-3-carbonitrile (3o). Light yellow solid [Rf¼0.4 (CH2Cl2/
J¼8.5 Hz, 2H), 7.17 (d, J¼8.0 Hz, 2H), 5.73 (s, 2H), 4.15 (q, J¼7.0 Hz,
MeOH¼15:1)]; mp: 287e289 ꢀC; 1H NMR (500 MHz, DMSO)
d 11.38
2H), 4.09 (q, J¼7.0 Hz, 2H), 2.29 (s, 3H), 1.20 (q, J¼7.0 Hz, 6H); 13C
(s, 1H), 7.50 (d, J¼8.0 Hz, 2H), 7.37 (d, J¼8.0 Hz, 2H), 7.10 (dd, J¼7.0,
NMR (125 MHz, DMSO) d 167.3, 164.7, 147.7, 136.4, 129.6, 128.9,

W. Yu et al. / Tetrahedron 69 (2013) 1953e1957
1957
J.; Lee, W.; Lowinger, T. B.; Lyons, J.; Marsh, V.; Rogers, D. H.; Swartz, S.; Walling,
T.; Wild, H. Bioorg. Med. Chem. Lett. 2001, 11, 2775.
125.9,123.3, 111.6, 92.3, 60.7, 58.8, 21.1, 14.8,14.4; HRMS (EI): found:
m/z 316.1425. Calcd for C17H20N2O4 (M)þ: 316.1423.
4. (a) Cocco, M. T.; Congiu, C.; Onnis, V. Bioorg. Med. Chem. 2003, 11, 495; (b)
Mohamed, M. S.; El-Domany, R. A.; El-Hameed, R. H. Acta Pharm. 2009, 59, 145;
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4.2.23. Ethyl 5-amino-4-carbamoyl-2-(p-tolyl)-1H-pyrrole-3-carbox-
ylate (3w). Light yellow solid [Rf¼0.3 (CH2Cl2/MeOH¼15:1)]; mp:
194e196 ꢀC; 1H NMR (500 MHz, DMSO)
d 11.04 (s, 1H), 8.38 (s, 1H),
7.23 (d, J¼7.0 Hz, 2H), 7.19 (d, J¼7.0 Hz, 2H), 6.67 (s, 1H), 6.08 (s, 2H),
3.99 (q, J¼6.5 Hz, 2H), 2.33 (s, 3H), 0.91 (t, J¼7.0 Hz, 3H); 13C NMR
(125 MHz, DMSO)
d 168.2, 167.7, 148.0, 137.3, 132.2, 130.5, 129.4,
128.7, 106.5, 94.1, 60.3, 21.3, 13.9; HRMS (EI): found: m/z 287.1265.
Calcd for C15H17N3O3 (M)þ: 287.1270.
Acknowledgements
We gratefully acknowledge the National Science Foundation of
China (No. 81072516) and Natural Science Foundation of Zhejiang
Province (No. Z2110655) for financial support. Mr. Jianming Gu of
the X-ray crystallography facility of Zhejiang University is ac-
knowledged for the assistance on crystal structural analysis. We
also thank Jianyang Pan (Pharmaceutical Informatics Institute,
Zhejiang University) for performing NMR spectrometry for struc-
ture elucidation.
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