Cascade Reactions to Substituted 1 H -Pyrrole-3-carbonitriles via Ligand-Free Palladium(II)-Catalyzed C(sp)-C(sp 2) Coupling

Article abstract of DOI:10.1055/s-0039-1691731

An efficient and simple synthesis of substituted 1 H -pyrrole-3-carbonitriles was developed. This reaction is a palladium(II)-catalyzed cascade of C(sp)-C(sp ²) coupling followed by intramolecular C-N bond formation. The method can tolerate various substrates with satisfactory yields. Its ligand-free conditions and high efficiency make this method particularly attractive.

Full text of DOI:10.1055/s-0039-1691731

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–G
paper
A
en
Z. Wang et al.
Paper
Synthesis
Cascade Reactions to Substituted 1H-Pyrrole-3-carbonitriles via
Ligand-Free Palladium(II)-Catalyzed C(sp)–C(sp2) Coupling
Zijuan Wang
Wenteng Chen
Haofan Luo
R3
R1
CN
Chang He
O
CN
CN
Pd(OAc)2
R2 OH
B
Guolin Zhang*
Yongping Yu*
R2
+
R1
N
toluene, 100 °C
OH
R3
H
· tolerates various substrates
· ligand-free
17 examples
75–94% yield
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,
College of Pharmaceutical Science, Zhejiang University, Hangzhou
310058, P. R. of China
guolinzhang@zju.edu.cn
yyu@zju.edu.cn
Received: 26.11.2019
N
Accepted after revision: 08.01.2020
Published online: 25.02.2020
DOI: 10.1055/s-0039-1691731; Art ID: ss-2019-h0652-op
N
N
Abstract An efficient and simple synthesis of substituted 1H-pyrrole-
3-carbonitriles was developed. This reaction is a palladium(II)-catalyzed
cascade of C(sp)–C(sp2) coupling followed by intramolecular C–N bond
formation. The method can tolerate various substrates with satisfactory
yields. Its ligand-free conditions and high efficiency make this method
particularly attractive.
Br
F
O
N
F
F
F
O
N
N
Cl
F
N
O
Cl
HN
Fludioxonil
OH
Androgen receptor antagonists
Key words C–C coupling, palladium, ligand-free, cascade reactions,
substituted 1H-pyrrole-3-carbonitriles
Chlorfenapyr
Figure 1 Selected examples of bioactive molecules containing substi-
tuted 1H-pyrrole-3-carbonitriles
Pyrrole derivatives are a class of important nitrogen-
containing heterocyclic compounds and widely observed in
natural products and bioactive molecules.1–4 Due to their
wide range of biological properties such as antibacterial,5
antitumor, anti-inflammatory, and fluorescence character-
istics,6,7 pyrrole derivatives represent privileged structural
motifs that are frequently utilized in bioactive compounds
and pharmaceuticals.8–11 Substituted 1H-pyrrole-3-carbo-
nitriles are basic skeleton and key intermediates of many
drugs and pesticides, such as androgen receptor antago-
nists, chlorfenapyr and non-systemic fungicide fludioxonil
(Figure 1).12–15
Usually, the most widely used methods for the prepara-
tion of pyrroles include: (1) Hantzsch pyrrole synthesis;16
(2) Piloty–Robinson pyrrole synthesis;17 and (3) Paal–Knorr
pyrrole synthesis.18 In recent years, significant progresses
have been made in the preparation of substituted 1H-pyr-
role-3-carbonitriles from ,-dicyano ketones (Scheme 1).
Sharbatyan observed that catalyzed by triethylamine, sub-
stituted bis(3-cyano-2-pyrrolyl) disulfides were formed
when hydrogen sulfide was passed through solution of ,-
dicyano ketones in acetone.19 Then Foley and co-workers
reported a one-step synthesis of 2-chloro-3-cyanopyrroles
from ,-dicyano ketones with HCl gas in 2-propanol.20
Based on the former research, Ikemoto reported the cycliza-
tion of 2-(2-oxo-2-ethyl)malononitriles with HCl or mer-
captan or thionocarboxylic acids to get products in 49–87%
yields.21,22 However, all of these methods used acids with
lots of industrial wastes and pollution. Since the pioneering
work, Chen and co-workers reported the cyclization of 2-
(2-oxo-2-ethyl)malononitriles with HZSM-5 (SiO2/Al2O3
=
120) and Pd/C as catalysts.22 The synthesis of substituted
pyrroles from -dicyano ketones and boronic acids was
published previously by Menichincheri and co-workers.23
But this is a two-step synthesis achieved via the cyclization
of -dicyano ketones, followed by the Suzuki coupling reac-
tion. So it is still necessary to explore a new method, which
is more convenient and widely available to synthesize sub-
stituted 1H-pyrrole-3-carbonitriles.
Inspired by the work of predecessors, we conducted a
palladium(II)-catalyzed and ligand-free tandem reaction for
the synthesis of substituted 1H-pyrrole-3-carbonitriles. In
the initial investigation, 5-phenyl-2-(p-tolyl)-1H-pyrrole-3-
carbonitrile (3a) was obtained when using 2-(2-oxo-2-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Z. Wang et al.
Paper
Synthesis
(entries 18 and 20). Therefore, the optimal conditions for
preparing 3a were as follows: Pd(OAc)2 (20 mol%) as a cata-
lyst in toluene and reaction at 100 °C for 24 hours (entry 4).
As for 2-arylacetylmalonitriles, the scope of the reaction
was examined with optimal conditions in hand (Table 2). As
shown in Table 2, substrates containing strongly electron-
withdrawing substituents on the aromatic ring of 2-aryl-
acetylmalonitrile such as nitro group reacted smoothly
giving the products in more satisfactory yield (3c, 92%).
Also all the corresponding products 3a–e were obtained in
Previous Work:
CN
H
N
O
CN
CN
(a)
Et3N, H2S
S
R
R
S
N
R
CN
acetone
H
NC
CN
O
O
(b)
HCl gas
Cl
R
CN
R
N
2-PrOH, R.T.
H
R2
CN
R2
CN
CN
HCl or thionocarboxylic
acids or mercaptan
(c)
(d)
Pd/C
Table 1 Optimization of the Reaction Conditionsa
R1
CN
R1
R1
X
N
N
H
R2
H
CN
X = Cl, SH, SR
O
CN
OH
+
R2
CN
B
CN
N
O
CN
H
HZSM-5, Pd/C, H2
1,4-dioxane
OH
R1
CN
R1
N
H
R2
3a
2a
1a
NH2
H2N
NH2
N
This Work: palladium(II)-catalyzed C(sp)–C(sp2) coupling and C–N condensation
cascade reactions
N
N
N
N
N
R3
CN
NH2
Pd(OAc)2
R2
OH
O
CN
B
+
R2
R1
toluene, 100 °C
R1
CN
L1
L2
L3
N
OH
L4
H
R3
Entry Catalyst
Equiv
1a:2a
Ligand Temp
(°C)
Solvent
Yield
(%)b
Scheme 1 Methods for the synthesis of substituted 1H-pyrrole-3-
carbonitriles
1
2
Pd(OAc)2
Pd(OAc)2
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.0
1:2.0
−
40
60
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
19
45
77
85
65
87
35
58
38
23
−
phenylethyl)malononitrile (1a) and 4-methylphenylboric
acid (4a) as starting materials to optimize the reaction
conditions (Table 1).
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)4
−
−
80
4
−
100
First, the starting materials 1a and 2a were treated with
Pd(OAc)2 (20 mol%) in toluene (15.0 mL) at 40 °C for 24
hours (Table 1, entry 1). As expected, the desired product 3a
was obtained in 19% yield. Increasing the reaction tempera-
ture from 40 to 100 °C significantly improved the reaction
yield to 85% (entries 1–4). But when the temperature was
raised to reflux, the reaction yield dropped to 65% (entry 5).
Subsequently, the reaction was carried out in the presence
of various ligands including TEMED, 2,2-dipyridyl, tris(2-
aminoethyl)amine, and 8-aminoquinoline (entries 6−9).
Surprisingly, even the best ligand TEMED (entry 6) did not
have a significant effect on the yields. Then a series of Pd
catalysts (entries 10–12) were screened. When Pd(OAc)2
was used, product 3a was isolated in the highest yield (en-
try 4, 85%). Furthermore, the investigation of the solvent ef-
fect on the reaction yield was carried out (entries 13–16).
Obviously, toluene stood out as the best choice of solvent
for further reactions with its highest product yield. De-
creasing catalyst loading or amount of 4-methylphenylboric
acid (2a) resulted in reduced yields (entries 17 and 19). And
increasing catalyst loading to 30% or the amount of 2a to 2.0
equivalents did not have a significant effect on the yields
5
−
reflux
100
100
100
100
100
100
100
100
reflux
reflux
100
100
100
100
100
6
L1
L2
L3
L4
−
7
8
9
10
11
12
13
14
15
16
17c
18d
19
20
−
Trace
−
Trace
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
−
−
MeCN
Trace
18
−
EtOH
−
DMSO
21
−
toluene
toluene
toluene
toluene
47
−
86
−
61
−
87
a Reaction conditions: 1a (1.0 mmol), catalyst (20 mol%), solvent (15 mL),
24 h.
b Isolated yield.
c Pd(OAc)2: 10 mol%.
d Pd(OAc)2: 30 mol%.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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Z. Wang et al.
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Synthesis
excellent yields (78–92%). When the substituents are at
different positions of the phenyl ring, the results showed
that the steric effects almost did not influence the progress
of the reaction (3b, 3f, and 3g: 90%, 88%, and 85%). Next, the
scope of the application of boronic acids was investigated.
Various boronic acids were subjected to the reaction under
identical conditions. The results showed that boronic acids
bearing different groups were all compatible with this
transformation and the corresponding products 3k–m were
obtained in excellent yields (77–94%). Substrates bearing
electron-donating groups gave slightly higher yields. Simi-
larly, there was also barely steric effect on the reaction
when the position of substituent groups on the benzene
ring was changed (3h–j: 79–83%).
Table 2 Synthesis of Substituted 1H-Pyrrole-3-carbonitrilesa,b
CN
R3
O
CN
R2
OH
Pd(OAc)2
B
R2
+
R1
CN
OH
toluene, 100 °C
N
H
R1
R3
2
1
3
CN
CN
CN
N
N
N
H
H
H
O2N
Cl
3a, 86%
3b, 90%
3c, 92%
CN
CN
CN
Cl
N
N
N
H
H
H
O
3d, 84%
3e, 78%
3f, 88%
CN
CN
CN
Cl
Cl
N
N
H
N
H
H
Cl
3g, 85%
3h, 79%
3k, 77%
3i, 82%
CN
CN
CN
CF3
Cl
N
H
N
H
N
H
3j, 83%
3l, 84%
CN
CN
CN
S
O
N
N
H
H
N
H
3m, 94%
3n, 81%
3o, 85%
CN
CN
O
N
H
N
N
H
H
3p, 75%
3qc, 76%
3r, no reaction
a Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), Pd(OAc)2 (20 mol%), solvent (15 mL), 100 °C, 24 h.
b Isolated yield.
c The starting materials were 4-oxo-4-phenylbutanenitrile and (4-methoxyphenyl)boronic acid.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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Z. Wang et al.
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Synthesis
To further examine the generality of this process, a se-
ries of other substrates such as tert-butyl and thiophene
groups were evaluated, with the results shown in Table 2
(3n–p, 75–85%). To our delight, this protocol could also be
applied to substrate 4-oxo-4-phenylbutanenitrile giving the
corresponding product (3q: 76%). Overall, all the products
demonstrated the potential and excellent compatibility of
this method across a wide application base. However, there
was also one substrate, methylboric acid, not compatible
with this process (3r), probably due to its low activity.
On the basis of the above experimental investigation
and previous literature,24 a plausible mechanism for the
construction of substituted 1H-pyrrole-3-carbonitriles is
proposed, as shown in Scheme 2. In the process of produc-
ing substituted 1H-pyrrole-3-carbonitriles, the transmeta-
lation reaction of the Pd(II) catalyst and arylboronic acid
generates intermediate B. The coordination of intermediate
B and the N atom of the cyano group affords C. The aryl
group inserts into the nitrile to generate the corresponding
ketimine Pd(II) complex D. Then intermediate D exchanges
with AcO– to produce ketimine derivative E and to regener-
ate the Pd(II) catalyst. Intermediates E and F tautomerize.
Eventually, the cyclization of F affords the corresponding
substituted 1H-pyrrole-3-carbonitrile G.
Figure 2 Photographs of the corresponding solutions at 10–4 M in
EtOAc, ex = 365 nm
All solvents were purified according to standard methods prior to use.
Melting points were recorded on a Büchi B-540 melting point appara-
tus. NMR spectra were recorded for 1H NMR at 500 MHz and 13C NMR
at 125 MHz. For 1H NMR, TMS served as internal standard ( = 0) and
data are reported as follows: chemical shift, integration, multiplicity
(standard abbreviations), and coupling constant(s) in hertz (Hz). For
13C NMR, TMS ( = 0) or DMSO-d6 ( = 40.45) was used as internal
standard and spectra were obtained with complete proton decou-
pling. LC-MS and HRMS data were obtained using Agilent Technolo-
gies 6224 TOF LC/MS spectrometer. IR spectra were recorded with a
Bruker VEC TOR 22 FT-IR spectrophotometer. The starting material 2-
arylacetylmalonitriles were prepared according to the literature.22
The starting material boronic acids were commercially available.
R2
HO
OH
Pd(OAc)2
NH
B
O
R2
N
A
Substituted 1H-pyrrole-3-carbonitriles 3; General Procedure
R1
R2
R3
AcO–
E
AcO
N
A mixture of 2-arylacetylmalonitrile 1 (1.0 mmol), boronic acid 2 (1.5
mmol, 1.5 equiv) and Pd(OAc)2 (0.2 mmol, 0.2 equiv) was stirred in
toluene (15 mL) at 100 °C for 24 h. After completion of the reaction,
the mixture was filtered through diatomite. The filtrate was concen-
trated and purified by flash chromatography (PE/EtOAc) on silica gel
to afford the desired product 3.
Pd
O
R2PdOAc
R2
N
NH2
B
R1
O
R3
N
R3
D
O
N
R1
R3
N
F
R1
N
O
5-Phenyl-2-(p-tolyl)-1H-pyrrole-3-carbonitrile (3a)
R3
CN
R3
R1
N
White solid; yield: 0.222 g (86%); mp 197.5–198.3 °C.
R2
– H2O
Pd
R1
IR (KBr): 3233, 2226, 1614, 1493, 1466, 814, 763 cm–1
.
R2
OAc
N
H
1H NMR (500 MHz, CDCl3):  = 8.89 (s, 1 H, NH), 7.64 (d, J = 8.5 Hz, 2 H,
Ar CH), 7.52 (d, J = 7.0 Hz, 2 H, Ar CH), 7.42 (t, J = 7.5 Hz, 2 H, Ar CH),
7.31 (t, J = 7.5 Hz, 1 H, Ar CH), 7.27 (d, J = 8.0 Hz, 2 H, Ar CH), 6.74 (d,
J = 2.5 Hz, 1 H, pyrrole CH), 2.40 (s, 3 H, CH3).
C
G
Scheme 2 Proposed mechanism
13C NMR (125 MHz, DMSO-d6):  = 140.29, 138.70, 133.94, 131.25,
129.94, 129.23, 127.69, 127.40, 126.87, 125.23, 118.24, 110.51, 90.19,
21.35.
HRMS (ESI): m/z calcd for C18H15N2 [M + H]+: 259.1230; found:
259.1228.
Surprisingly, most of the products have fluorescence
properties. The photographs of 3c, 3e, 3n, 3o are shown in
Figure 2. Thus, the products can be further examined as flu-
orescent compounds.
In conclusion, an efficient method to access substituted
1H-pyrrole-3-carbonitriles has been demonstrated. This
palladium(II)-catalyzed cascade reaction involves C(sp)–
C(sp2) coupling followed by intramolecular C–N bond for-
mation. A plausible mechanism is also proposed. In particu-
lar, the reaction tolerates a wide range of functional groups.
With excellent yields and ligand-free reaction conditions,
this protocol is quite attractive.
5-(4-Chlorophenyl)-2-(p-tolyl)-1H-pyrrole-3-carbonitrile (3b)
White solid; yield: 0.263 g (90%); mp >250 °C.
IR (KBr): 3232, 3034, 2917, 2225, 1611, 1492, 1466, 823, 728 cm–1
1H NMR (500 MHz, DMSO-d6):  = 12.17 (s, 1 H, NH), 7.84 (d, J = 8.5
Hz, 2 H, Ar CH), 7.74 (d, J = 8.5 Hz, 2 H, Ar CH), 7.50 (d, J = 8.5 Hz, 2 H,
Ar CH), 7.36 (d, J = 8.0 Hz, 2 H, Ar CH), 7.10 (s, 1 H, pyrrole CH), 2.38 (s,
3 H, CH3).
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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Synthesis
13C NMR (125 MHz, DMSO-d6):  = 140.60, 138.84, 132.68, 132.07,
130.14, 129.96, 129.23, 127.25, 126.88, 126.84, 118.08, 111.14, 90.33,
21.35.
HRMS (ESI): m/z calcd for C18H14ClN2 [M + H]+: 293.0840; found:
293.0838.
5-(2-Chlorophenyl)-2-(p-tolyl)-1H-pyrrole-3-carbonitrile (3g)
White solid; yield: 0.249 g (85%); mp 205.3–206.1 °C.
IR (KBr): 3256, 3033, 2926, 2219, 1612, 1465, 812, 745 cm–1
.
1H NMR (500 MHz, DMSO-d6):  = 12.24 (s, 1 H, NH), 7.74 (d, J = 8.0
Hz, 2 H, Ar CH), 7.67 (d, J = 7.5 Hz, 1 H, Ar CH), 7.58 (d, J = 8.0 Hz, 1 H,
Ar CH), 7.45 (t, J = 7.5 Hz, 1 H, Ar CH), 7.39 (t, J = 7.5 Hz, 1 H, Ar CH),
7.35 (d, J = 8.0 Hz, 2 H, Ar CH), 6.90 (s, 1 H, pyrrole CH), 2.37 (s, 3 H,
CH3).
5-(4-Nitrophenyl)-2-(p-tolyl)-1H-pyrrole-3-carbonitrile (3c)
Yellow solid; yield: 0.279 g (92%); mp >250 °C.
IR (KBr): 3231, 3023, 2924, 2226, 1614, 1503, 1456, 1345, 722 cm–1
.
13C NMR (125 MHz, DMSO-d6):  = 139.40, 138.36, 131.24, 130.97,
130.25, 129.84, 129.59, 129.42, 127.37, 126.82, 126.24, 117.67,
113.76, 89.05, 20.90.
HRMS (ESI): m/z calcd for C18H14ClN2 [M + H]+: 293.0840; found:
293.0835.
1H NMR (500 MHz, DMSO-d6):  = 12.44 (s, 1 H, NH), 8.28 (d, J = 9.0
Hz, 2 H, Ar CH), 8.08 (d, J = 8.5 Hz, 2 H, Ar CH), 7.75 (d, J = 8.0 Hz, 2 H,
Ar CH), 7.40 (s, 1 H, pyrrole CH), 7.38 (d, J = 7.5 Hz, 2 H, Ar CH), 2.38 (s,
3 H, CH3).
13C NMR (125 MHz, DMSO-d6):  = 145.64, 141.70, 138.92, 136.99,
131.18, 129.56, 126.69, 126.42, 125.07, 124.28, 117.21, 113.75, 90.76,
20.93.
HRMS (ESI): m/z calcd for C18H13N3O2 [M + H]+: 304.1081; found:
304.1072.
2-(2-Chlorophenyl)-5-phenyl-1H-pyrrole-3-carbonitrile (3h)
White solid; yield: 0.220 g (79%); mp 181.4–182.1 °C.
IR (KBr): 3293, 3053, 2958, 2215, 1599, 1455, 753 cm–1
.
1H NMR (500 MHz, DMSO-d6):  = 12.42 (s, 1 H, NH), 7.76 (d, J = 7.0
Hz, 2 H, Ar CH), 7.68 (d, J = 8.0 Hz, 1 H, Ar CH), 7.62 (dd, J = 7.0, 2.0 Hz,
1 H, Ar CH), 7.58–7.50 (m, 2 H, Ar CH), 7.42 (t, J = 7.5 Hz, 2 H, Ar CH),
7.29 (t, J = 7.0 Hz, 1 H, Ar CH), 7.10 (s, 1 H, pyrrole CH).
2,5-Di-p-tolyl-1H-pyrrole-3-carbonitrile (3d)
White solid; yield: 0.229 g (84%); mp 197.3–198.0 °C.
IR (KBr): 3234, 3024, 2916, 2225, 1617, 1506, 1466, 814 cm–1
.
13C NMR (125 MHz, DMSO-d6):  = 137.43, 133.85, 133.19, 132.83,
131.53, 131.18, 130.45, 129.55, 129.37, 127.88, 127.75, 124.87,
117.14, 109.34, 93.71.
HRMS (ESI): m/z calcd for C17H12ClN2 [M + H]+: 279.0684; found:
279.0688.
1H NMR (500 MHz, DMSO-d6):  = 12.06 (s, 1 H, NH), 7.74 (d, J = 8.5
Hz, 2 H, Ar CH), 7.70 (d, J = 8.0 Hz, 2 H, Ar CH), 7.35 (d, J = 8.0 Hz, 2 H,
Ar CH), 7.24 (d, J = 8.0 Hz, 2 H, Ar CH), 6.98 (d, J = 2.5 Hz, 1 H, pyrrole
CH), 2.37 (s, 3 H, CH3), 2.32 (s, 3 H, CH3).
HRMS (ESI): m/z calcd for C19H17N2 [M + H]+: 273.1386; found:
273.1389.
2-(3-Chlorophenyl)-5-phenyl-1H-pyrrole-3-carbonitrile (3i)
White solid; yield: 0.229 g (82%); mp 202.1–203.0 °C.
5-(4-Methoxyphenyl)-2-(p-tolyl)-1H-pyrrole-3-carbonitrile (3e)
White solid; yield: 0.225 g (78%); mp 195.1–195.7 °C.
IR (KBr): 3249, 3054, 2218, 1569, 1476, 806, 757 cm–1
.
1H NMR (500 MHz, DMSO-d6):  = 12.27 (s, 1 H, NH), 7.94 (t, J = 2.0 Hz,
1 H, Ar CH), 7.86–7.78 (m, 3 H, Ar CH), 7.58 (t, J = 8.0 Hz, 1 H, Ar CH),
7.50 (d, J = 8.0 Hz, 1 H, Ar CH), 7.45 (t, J = 8.0 Hz, 2 H, Ar CH), 7.32 (t, J =
7.5 Hz, 1 H, Ar CH), 7.11 (s, 1 H, pyrrole CH).
13C NMR (125 MHz, DMSO-d6):  = 137.98, 134.82, 134.17, 132.01,
131.35, 130.99, 129.27, 128.71, 128.00, 126.43, 125.40, 125.35,
117.81, 110.99, 91.37.
IR (KBr): 3217, 3033, 2924, 2866, 2229, 1610, 1506, 1458, 1249, 821
cm–1
.
1H NMR (500 MHz, DMSO-d6):  = 11.99 (s, 1 H, NH), 7.73 (d, J = 8.5
Hz, 4 H, Ar CH), 7.35 (d, J = 8.0 Hz, 2 H, Ar CH), 7.00 (d, J = 8.5 Hz, 2 H,
Ar CH), 6.90 (d, J = 2.5 Hz, 1 H, pyrrole CH), 3.79 (s, 3 H, OCH3), 2.37 (s,
3 H, CH3).
13C NMR (125 MHz, DMSO-d6):  = 159.09, 139.64, 138.48, 134.03,
129.92, 127.52, 126.71, 126.63, 123.99, 118.39, 114.66, 109.21, 89.90,
55.67, 21.34.
HRMS (ESI): m/z calcd for C17H12ClN2 [M + H]+: 279.0684; found:
279.0692.
HRMS (ESI): m/z calcd for C19H17N2O [M + H]+: 289.1335; found:
2-(4-Chlorophenyl)-5-phenyl-1H-pyrrole-3-carbonitrile (3j)
289.1332.
White solid; yield: 0.231 g (83%); mp 223.3–224.2 °C.
IR (KBr): 3228, 3058, 2224, 1596, 1535, 1482, 809, 761, 726 cm–1
.
5-(3-Chlorophenyl)-2-(p-tolyl)-1H-pyrrole-3-carbonitrile (3f)
1H NMR (500 MHz, DMSO-d6):  = 12.26 (s, 1 H, NH), 7.88 (d, J = 9.0
Hz, 2 H, Ar CH), 7.81 (d, J = 7.5 Hz, 2 H, Ar CH), 7.64 (d, J = 8.5 Hz, 2 H,
Ar CH), 7.45 (t, J = 7.5 Hz, 2 H, Ar CH), 7.32 (t, J = 7.5 Hz, 1 H, Ar CH),
7.10 (s, 1 H, pyrrole CH).
13C NMR (125 MHz, DMSO-d6):  = 138.61, 134.59, 133.60, 131.05,
129.49, 129.27, 128.94, 128.59, 127.92, 125.33, 117.92, 110.87, 91.01.
White solid; yield: 0.258 g (88%); mp 223.7–224.6 °C.
IR (KBr): 3282, 3030, 2918, 2218, 1597, 1533, 1487, 809, 708 cm–1
.
1H NMR (500 MHz, DMSO-d6):  = 12.19 (s, 1 H, NH), 7.96 (s, 1 H, Ar
CH), 7.76–7.74 (m, 3 H, Ar CH), 7.45 (t, J = 8.0 Hz, 1 H, Ar CH), 7.37 (d,
J = 8.0 Hz, 2 H, Ar CH), 7.34 (d, J = 8.0 Hz, 1 H, Ar CH), 7.18 (s, 1 H,
pyrrole CH), 2.38 (s, 3 H, CH3).
13C NMR (125 MHz, DMSO-d6):  = 140.79, 138.93, 134.20, 133.26,
132.27, 131.07, 129.95, 127.26, 127.19, 126.92, 124.60, 123.74,
118.01, 111.72, 90.40, 21.35.
HRMS (ESI): m/z calcd for C17H12ClN2 [M + H]+: 279.0684; found:
279.0687.
5-Phenyl-2-[4-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbo-
nitrile (3k)
HRMS (ESI): m/z calcd for C18H14ClN2 [M + H]+: 293.0840; found:
293.0835.
Pale yellow solid; yield: 0.240 g (77%); mp >250 °C.
IR (KBr): 3241, 3035, 2961, 2221, 1610, 1457, 1334, 810, 758 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

F
Z. Wang et al.
Paper
Synthesis
1H NMR (500 MHz, DMSO-d6):  = 12.40 (s, 1 H, NH), 8.07 (d, J = 8.5
Hz, 2 H, Ar CH), 7.92 (d, J = 8.5 Hz, 2 H, Ar CH), 7.82 (d, J = 7.5 Hz, 2 H,
Ar CH), 7.45 (t, J = 7.5 Hz, 2 H, Ar CH), 7.32 (t, J = 7.5 Hz, 1 H, Ar CH),
7.14 (s, 1 H, pyrrole CH).
13C NMR (125 MHz, DMSO-d6):  = 137.48, 134.87, 133.44, 130.49,
128.88, 128.42 (q, J = 31.25 Hz), 127.70, 126.98, 125.98 (q, J = 3.75
Hz), 125.07, 124.19 (q, J = 270.00 Hz), 117.30, 110.88, 91.56.
HRMS (ESI): m/z calcd for C16H13N2S [M + H]+: 265.0794; found:
265.0787.
5-tert-Butyl-2-(p-tolyl)-1H-pyrrole-3-carbonitrile (3p)
Pink solid; yield: 0.179 g (75%); mp 177.9–178.8 °C.
IR (KBr): 3231, 3052, 2911, 2226, 1614, 1503, 1453, 1391, 1362, 711
cm–1
.
HRMS (ESI): m/z calcd for C13H17ClN3 [M + H]+: 250.1106; found:
250.1112.
1H NMR (500 MHz, DMSO-d6):  = 11.47 (s, 1 H, NH), 7.63 (d, J = 8.0
Hz, 2 H, Ar CH), 7.30 (d, J = 8.0 Hz, 2 H, Ar CH), 6.20 (d, J = 2.5 Hz, 1 H,
pyrrole CH), 2.34 (s, 3 H, CH3), 1.28 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, DMSO-d6):  = 143.96, 138.25, 137.63, 129.36,
127.40, 126.09, 118.26, 106.73, 87.05, 31.41, 29.70, 20.84.
2,5-Diphenyl-1H-pyrrole-3-carbonitrile (3l)
White solid; yield: 0.205 g (84%); mp 206.1–206.8 °C.
IR (KBr): 3225, 3031, 2219, 1605, 1579, 1465, 808 cm–1
.
HRMS (ESI): m/z calcd for C16H19N2 [M + H]+: 239.1543; found:
1H NMR (500 MHz, DMSO-d6):  = 12.21 (s, 1 H, NH), 7.85 (d, J = 7.5
Hz, 2 H, Ar CH), 7.82 (d, J = 7.0 Hz, 2 H, Ar CH), 7.56 (t, J = 8.0 Hz, 2 H,
Ar CH), 7.48–7.40 (m, 3 H, Ar CH), 7.31 (t, J = 7.0 Hz, 1 H, Ar CH), 7.09
(d, J = 2.5 Hz, 1 H, pyrrole CH).
HRMS (ESI): m/z calcd for C17H13N2 [M + H]+: 245.1073; found:
245.1074.
239.1551.
2-(4-Methoxyphenyl)-5-phenyl-1H-pyrrole (3q)
White solid; yield: 0.189 g (76%); mp 162.2–163.1 °C.
IR (KBr): 3221, 3044, 2946, 1543, 1244, 1069, 821, 766 cm–1
1H NMR (500 MHz, DMSO-d6):  = 11.13 (s, 1 H, NH), 7.74 (d, J = 7.5
Hz, 2 H, Ar CH), 7.69 (d, J = 9.0 Hz, 2 H, Ar CH), 7.35 (t, J = 7.5 Hz, 2 H,
Ar CH), 7.16 (t, J = 7.5 Hz, 1 H, Ar CH), 6.96 (d, J = 9.0 Hz, 2 H, Ar CH),
6.56 (dd, J = 3.5, 2.5 Hz, 1 H, pyrrole CH), 6.46 (dd, J = 3.5, 2.5 Hz, 1 H,
pyrrole CH), 3.78 (s, 3 H, OCH3).
.
2-(4-Methoxyphenyl)-5-phenyl-1H-pyrrole-3-carbonitrile (3m)
White solid; yield: 0.258 g (94%); mp 182.4–183.0 °C.
IR (KBr): 3219, 3056, 2857, 2213, 1605, 1571, 1458, 1249, 805, 755
cm–1
.
HRMS (ESI): m/z calcd for C17H16NO [M + H]+: 250.1226; found:
1H NMR (500 MHz, DMSO-d6):  = 12.05 (s, 1 H, NH), 7.78 (d, J = 9.0
Hz, 4 H, Ar CH), 7.42 (t, J = 7.5 Hz, 2 H, Ar CH), 7.28 (t, J = 7.5 Hz, 1 H,
Ar CH), 7.11 (d, J = 8.5 Hz, 2 H, Ar CH), 7.01 (d, J = 2.5 Hz, 1 H, pyrrole
CH), 3.83 (s, 3 H, OCH3).
13C NMR (125 MHz, DMSO-d6):  = 160.01, 140.38, 133.59, 131.31,
129.23, 128.48, 127.59, 125.13, 122.72, 118.37, 114.84, 110.29, 89.65,
55.80.
250.1235.
Funding Information
This study was supported by the National Natural Science Foundation
of China (No. 81602959 to J.S.), Natural Science Foundation of Zheji-
ang Province (LY18H300001), and Multiple Sclerosis National Re-
HRMS (ESI): m/z calcd for C18H15N2O [M + H]+: 275.1179; found:
275.1179.
search Institute, USA (to W.C.).
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Supporting Information
Brown solid; yield: 0.271 g (81%); mp 240.5–241.3 °C.
IR (KBr): 3237, 3039, 2922, 2213, 1596, 1498, 1449, 818, 767 cm–1
1H NMR (500 MHz, DMSO-d6):  = 12.28 (s, 1 H, NH), 7.80 (d, J = 8.0
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691731.
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Hz, 2 H, Ar CH), 7.41–7.30 (m, 12 H, Ar CH), 2.38 (s, 3 H, CH3).
13C NMR (125 MHz, DMSO-d6):  = 139.29, 138.36, 133.06, 130.83,
130.09, 129.53, 129.30, 128.63, 128.44, 128.29, 127.63, 127.26,
126.83, 126.45, 124.39, 117.52, 90.46, 20.92.
HRMS (ESI): m/z calcd for C24H19N2 [M + H]+: 335.1543; found:
335.1547.
References
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White solid; yield: 0.225 g (85%); mp 208.5–209.3 °C.
IR (KBr): 3224, 3108, 3048, 2916, 2225, 1607, 1507, 1464, 724 cm–1
.
1H NMR (500 MHz, DMSO-d6):  = 12.27 (s, 1 H, NH), 7.72 (d, J = 8.0
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G