Efficient synthesis of highly substituted pyrroles based on the tandem reactions: intermolecular amination and Pd(II)-catalyzed intramolecular hydroamidation

Article abstract of DOI:10.1016/j.tet.2008.12.018

A novel and efficient method for construction of polysubstituted pyrroles, which included an intermolecular amination and Pd(II)-catalyzed intramolecular hydroamidation, was developed. It was found that the reactions gave high yields (55-92%). Crown Copyr

Full text of DOI:10.1016/j.tet.2008.12.018

Tetrahedron 65 (2009) 1424–1429
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Efficient synthesis of highly substituted pyrroles based on the tandem reactions:
intermolecular amination and Pd(II)-catalyzed intramolecular hydroamidation
,
a
a
a
a,b
Yong-Jiang Bian a, Xue-Yuan Liu a , Ke-Gong Ji , Xing-Zhong Shu , Li-Na Guo , Yong-Min Liang
*
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
b State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient method for construction of polysubstituted pyrroles, which included an in-
termolecular amination and Pd(II)-catalyzed intramolecular hydroamidation, was developed. It was
found that the reactions gave high yields (55–92%).
Received 6 September 2008
Received in revised form 4 December 2008
Accepted 5 December 2008
Available online 10 December 2008
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
R2
R3
R2
R3
R5
R2
R3
R4
1. Introduction
PdCl2
KCl
R1
H2N R5
R4
R4
Pyrroles are important heterocycles broadly used in material
science1 and can be found in naturally occurring and biologically
important molecules.2 Accordingly, substantial attention has been
paid to develop efficient methods for the synthesis of pyrroles.
Recent strategies for the synthesis of pyrroles are based on metal-
catalyzed3 reactions and catalytic multicomponent coupling
approaches,3j,4 which can compensate for the classic synthetic
approaches nicely. Most known methods for the construction of the
pyrrole ring proceed via various types of cycloaddition and cyclo-
isomerization of acyclic precursors. An economical approach to
synthesize highly substituted pyrroles whose raw materials can be
accessed in few steps is still challenging.
N
AcO
HN
R5
R1
R1
Scheme 1.
dimethylaniline 2b, and 5 mol % PdCl2 and 10 mol % KCl in CH3CN at
room temperature, but no reaction was observed (Table 1, entry 1).
To our delight, the desired product 1,2,3,5-tetraphenyl-1H-pyrrole
3b was obtained in 55% yield in CH3CN/H2O (10:1) system at
60 ꢀC (entry 4). Gratifyingly, when the reaction was carried out in
Very recently, we reported a gold catalyzed tandem process of
1-en-4-yn-3-ols to afford highly substituted pyrroles.5 In order to
further study this reaction, we chose (Z)-2-en-4-ynyl acetate as the
raw substrate, which can be easily derived from 1-en-4-yn-3-ols6
and could undergo an amination process efficiently. We also envi-
sioned that this reaction could be applied in the synthesis of pyr-
roles by developing a domino process.
Herein, we aimed to report a novel and efficient method for the
construction of polysubstituted pyrroles, which combined an in-
termolecular amination and Pd (II)-catalyzed7 intramolecular
hydroamidation (Scheme 1).
Table 1
Optimization of reaction conditionsa
Ph
N
Ph
Pd(II)
Ph
+
H2N
AcO
Ph
Ph
1a
2b
3b
Ph
Entry
T (ꢀC)
t (h)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
25
60
25
60
60
60
60
60
15
15
15
15
15
15
15
15
MeCN
MeCN
0
0
0
55
80
45
39
24
MeCN/H2O (10:1)
MeCN/H2O (10:1)
MeCN/H2O (6:1)
MeCN/H2O (2:1)
DMF/H2O (6:1)
2. Results and discussion
We initially started our investigation by using 0.2 mmol of (Z)-
1,3,5-triphenylpent-2-en-4-ynyl acetate 1a and 0.8 mmol 3,4-
DMSO/H2O (6:1)
a
Reactions were carried out in 0.2 mmol of 1a, 0.8 mmol of 3,4-dimethylaniline
2b using 5 mol % PdCl2 and 10 mol % KCl.
* Corresponding author. Tel.: þ86 931 8912593; fax: þ86 931 8912582.
E-mail address: liuxuey@lzu.edu.cn (X.-Y. Liu).
b
Isolated yields.
0040-4020/$ – see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.018

Y.-J. Bian et al. / Tetrahedron 65 (2009) 1424–1429
1425
Table 2
Test of amine scopea
Ph
Ph
Pd(II)
H2N R5
Ph
+
Ph
MeCN/H2O (6:1)
Ph
N
AcO
R5
Ph
1a
2
3
Entry
R5
Product
Ph
15h
N
1
2
84%
3a
Ph
Ph
Ph
Ph
N
15h
80%
3b
Ph
Ph
12h
N
OMe
3
4
MeO
82%
3c
Ph
Ph
Ph
Figure 1. X-ray structure of 3b.
Ph
Ph
MeCN/H2O (6:1) at 60 ꢀC, the desired product 3b was obtained in
80% yield after 15 h (entry 5). On further decreasing the ratio of
MeCN and H2O to 2:1, the yield decreased dramatically. On the
other hand, other mixed solvents were also investigated, but no
superior results were obtained (entries 7 and 8). Thus, the reaction
of (Z)-2-en-4-yn acetate 1a with 3,4-dimethylaniline 2b using
5 mol % PdCl2 and 10 mol % KCl in MeCN/H2O (6:1) at 60 ꢀC was
found to be the most effective and was utilized as the standard
conditions. The structure of 3b was further confirmed by its X-ray
crystal structure analysis (Fig. 1).
12h
N
77%
3d
Ph
Ph
Cl
Cl
12h
61%
3e
N
5
6
7
8
Ph
Ph
Ph
Ph
15h
76%
3f
N
Encouraged by our initial results, we sought to examine the
scope and the generality of the method under the optimized re-
action conditions. The reactions of 1a with various primary amines
2a–j were investigated. The results are summarized in Table 2. It
was found that aniline 2a showed good activity in this reaction
(84%, entry 1). The reactions of 1a with 2b–d resulted in 3b–d in
good yields (entries 2–4). When an amine with electron-with-
drawing substituent such as 3-chloroaniline 2e was used, the yield
was decreased (61%, entry 5). The alkylamines also showed good
reaction activity (entries 6–10).
Ph
20h
71%
3g
N
Ph
Ph
Ph
Ph
N
12h
81%
3h
Ph
Ph
The reactions of different substituted (Z)-2-en-4-yn acetates
were examined using aniline 2a as the nucleophilic component
(Table 3). It was found that the different substituted (Z)-2-en-
4-ynyl acetate 1a–g gave good yields (up to 93%).
20h
63%
3i
N
9
Ph
Ph
In order to confirm the mechanism for the one-pot reaction, we
next conducted the reactions in two steps, as shown in Scheme 2.
After the reaction was run with (Z)-1,3,5-triphenylpent-2-en-4-
ynyl acetate 1a and aniline 2a in CH3CN/H2O (10:1) system for 10 h,
an intermediate (Z)-N-(1,3,5-triphenyl-pent-2-en-4-ynyl)benzen-
amine 4a was obtained in excellent yield (up to 93%). Subsequently,
4a could be converted to 3a7b in 80% yield under the optimized
reaction conditions. These results strongly support our proposed
two-step mechanism, one-pot procedure.
Ph
Ph
30h
N
10
55%
3j
Ph
a
Reactions were carried out in 0.2 mmol of 1a, 0.8 mmol of amine 2 using 5 mol %
PdCl2 and 10 mol % KCl.
4. Experimental section
4.1. General
3. Conclusions
In summary, we have developed a simple, convenient, and ef-
ficient synthetic approach to synthesize highly substituted pyrroles
The materials were used as purchased. All reactions under
standard conditions were monitored by thin-layer chromatography
(TLC) on silica gel GF254 plates. The silica gel (200–300 mesh) is
used for column chromatography and the distillation range of
utilizing
a nucleophilic substitution forming (Z)-2-en-4-yn-1-
amine, followed by Pd(II)-catalyzed intermolecular hydroamid-
ation reaction.

1426
Y.-J. Bian et al. / Tetrahedron 65 (2009) 1424–1429
Table 3
Pd(II)-catalyzed synthesis of pyrrolesa
R2
R3
R2
R3
R4
Pd(II)
R1
R4
H2N Ph
+
MeCN/H2O (6:1)
N
Ph
3
AcO
R1
1
2a
Entry
1
1
Product
Ph
Ph
OAc
Ph
15h
84%
3a
Ph
N
1a
Ph
Ph
Ph
Ph
OAc
Ph
Ph
Cl
Cl
24h
72%
3k
N
1b
2
3
4
Ph
Ph
Ph
Ph
Ph
12h
67%
3l
OAc
N
1c
Ph
Ph
Ph
Ph
MeO
24h
OAc
MeO
Cl
N
1d
63%
Ph
3m
Ph
Ph
Cl
Cl
20h
81%
3n
N
1e
Ph
Cl
Cl
5
AcO
Cl
Cl
12h
92%
3o
N
Cl
Cl
1f
Ph
Cl
6
AcO
AcO
Cl
Cl
Ph
Ph
15h
Cl
Cl
82%
3p
7
1g
N
Ph
a
Reactions were carried out in 0.2 mmol of 1, 0.8 mmol aniline 2a using 5 mol % PdCl2 and 10 mol % KCl at 60 ꢀC.
petroleum is 60–90 ꢀC. 1H and 13C NMR spectra were recorded on
the Varian Mercury-300 MHz or Varian Mercury-400 MHz in-
struments, using CDCl3 as a solvent. The chemical shifts are
reported in TM (ppm) values relative to CHCl3 (TM 7.26 ppm for 1H
NMR and TM 77.0 ppm for 13C NMR). IR spectra were obtained on
Nicolet NEXUS 670 FT-IR instrument. Melting points were taken on
an X-4 melting point apparatus and are uncorrected. Elemental
analysis was performed using Germanic VARLIOLE instruments.
4.2. General procedure for preparation of (Z)-2-en-4-yn
acetates 1a–g
Acetic anhydride (0.5 mmol) and triethylamine (1.2 mmol) were
added to (Z)-2-en-4-yn-1-ol6 (0.4 mmol) in CH2Cl2 (10 mL) at room
temperature under argon atmosphere. After (Z)-2-en-4-yn-1-ol
disappeared by TLC, HCl (2 M, 10 mL) was added to the resulting
mixture, and the organic layer was separated followed by

Y.-J. Bian et al. / Tetrahedron 65 (2009) 1424–1429
1427
Ph
Ph
Ph
127.9, 127.7, 127.6, 126.0, 125.8, 125.7, 125.6, 123.9, 109.2, 31.3, 19.5,
19.4; IR (KBr, neat) cmꢁ1: 2921, 1601, 1496, 1451, 1024, 757, 697.
Anal. Calcd for C31H27N: C, 90.03; H, 6.58; N, 3.39. Found: C, 90.13;
H, 6.53; N, 3.34.
60 °C
H2N Ph
+
Ph
Ph
Ph
Ph
MeCN/H2O (6:1)
AcO
H
N
Ph
Ph
Ph
Ph
Ph
1a
2a
4a
4.3.3. 2-Benzyl-1-(4-methoxyphenyl)-3,5-diphenyl-1H-pyrrole (3c)
A yellow solid, mp: 102–103 ꢀC; 1H NMR (300 MHz, CDCl3,
Ph
PdCl2(5 mol%), KCl(10 mol%)
MeCN/H2O (6:1), 60 °C
ppm):
9H), 6.84–6.93 (m, 4H), 6.66–6.67 (m, 3H), 4.01 (s, 2H), 3.71 (s, 3H);
13C NMR (75 MHz, CDCl3, ppm):
158.6, 140.4, 136.6, 134.6, 133.0,
d
7.50 (d, J¼7.8 Hz, 2H), 7.32 (t, J¼7.5 Hz, 2H), 7.07–7.22 (m,
N
Ph
3a
H
N
Ph
d
4a
131.6, 130.2, 129.7, 128.4, 128.1, 123.0, 127.9, 127.7, 127.6, 125.8, 125.7,
125.6, 123.9, 113.7, 109.9, 55.2, 31.2; IR (KBr, neat) cmꢁ1: 3055, 3926,
1512, 1250, 697, 529. Anal. Calcd for C30H25NO: C, 86.71; H, 6.06; N,
3.37. Found: C, 86.42; H, 6.01; N, 3.47.
Scheme 2.
extraction of the aqueous layer with Et2O. The combined organic
extracts were washed with H2O and saturated solution of NaHCO3,
and dried over anhydrous Na2SO4. After removal of the solvent, the
residue was purified by the column chromatography on silica gel
(petroleum ether/ethyl acetate¼16:1) to furnish the expected
substrate.
4.3.4. 2-Benzyl-3,5-diphenyl-1-p-tolyl-1H-pyrrole (3d)
A yellow solid, mp: 166–168 ꢀC; 1H NMR (300 MHz, CDCl3,
ppm):
9H), 6.81–6.97 (m, 6H), 6.66 (s, 1H), 4.02 (br s, 2H), 2.27 (br s, 3H);
13C NMR (75 MHz, CDCl3, ppm):
140.5, 137.3, 136.7, 136.2, 134.5,
d
7.50 (d, J¼8.4 Hz, 2H), 7.32 (t, J¼7.5 Hz, 2H), 7.06–7.22 (m,
d
133.1, 130.1, 129.2, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 125.8, 125.0,
125.4, 124.0, 105.2, 31.2, 21.1; IR (KBr, neat) cmꢁ1: 3397, 2922, 1514,
1379, 1026, 757, 697, 520. Anal. Calcd for C30H25N: C, 90.19; H, 6.31;
N, 3.51. Found: C, 90.09; H, 6.29; N, 3.62.
4.3. Typical procedure for preparation of product 3b
(Z)-1,3,5-Triphenylpent-2-en-4-ynyl acetate 1a (0.2 mmol), 3,4-
dimethylaniline 2b (0.8 mmol), MeCN/H2O (6:1, 10 mL), 5 mol %
PdCl2, and 10 mol % KCl were placed in a 25 mL flask. The resulting
mixture was then heated at 60 ꢀC. When the reaction was com-
pleted as indicated by TLC analysis, water (10 mL) was added and
the resulting reaction mixture was extracted with ethyl acetate. The
extracts were concentrated to give a thick residue. The resulting
residue was purified by column chromatography using 20:1 pe-
troleum ether/ethyl acetate as an eluent to afford pure 1,2,3,5-tet-
raphenyl-1H-pyrrole 3b (80%).
4.3.5. 2-Benzyl-1-(3-chlorophenyl)-3,5-diphenyl-1H-pyrrole (3e)
Ayellow solid, mp: 141–143 ꢀC; 1H NMR (400 MHz, CDCl3, ppm):
d
7.51 (d, J¼9.2 Hz, 2H), 7.35 (t, J¼10.0 Hz, 2H), 7.01–7.28 (m, 11H),
6.94 (s, 1H), 6.78–6.90 (m, 3H), 6.64 (s, 1H), 4.02 (br s, 2H); 13C NMR
(100 MHz, CDCl3, ppm): 140.1, 139.9, 136.3, 134.6, 134.0, 132.5,
d
130.1,129.4,129.0,128.7,128.5,128.2,128.0,127.9,127.8,127.7,127.6,
127.1,126.2,125.9,124.7,109.8, 31.3; IR (KBr, neat) cmꢁ1: 3439, 3056,
1946, 1595, 1482, 1073, 761, 697. Anal. Calcd for C29H22ClN: C, 82.94;
H, 5.28; N, 3.34. Found: C, 83.10; H, 5.44; N, 3.26.
4.3.1. 2-Benzyl-1,3,5-triphenyl-1H-pyrrole (3a)
4.3.6. 1,2-Dibenzyl-3,5-diphenyl-1H-pyrrole (3f)
A yellow solid, mp: 139–140 ꢀC; 1H NMR (400 MHz, CDCl3,
A light yellow solid, mp: 130–131 ꢀC; 1H NMR (300 MHz, CDCl3,
ppm):
(m, 12H), 6.87–6.95 (m, 4H), 6.67 (s, 1H), 4.03 (s, 2H); 13C NMR
(100 MHz, CDCl3, ppm): 140.3, 138.8, 136.6, 134.5, 132.9, 129.9,
d
7.51 (d, J¼10.8 Hz, 2H), 7.33 (d, J¼10.0 Hz, 2H), 7.05–7.23
ppm):
d
7.44 (d, J¼6.0 Hz, 2H), 7.18–7.36 (m, 14H), 7.09 (d, J¼5.4 Hz,
2H), 6.86 (d, J¼5.7 Hz, 2H), 6.54 (s, 1H), 4.94 (s, 2H), 3.98 (s, 2H); 13C
d
NMR (75 MHz, CDCl3, ppm): d 139.9,139.0,136.9,135.0,133.3,128.8,
128.7, 128.6, 128.4, 128.1, 128.0, 127.9, 127.7, 127.5, 125.9, 125.7,
124.2, 109.4, 31.2; IR (KBr, neat) cmꢁ1: 3397, 2922, 1600, 1493, 1453,
1072, 757, 698, 515. Anal. Calcd for C29H23N: C, 90.35; H, 6.01; N,
3.63. Found: C, 90.19; H, 6.20; N, 3.61.
128.7, 128.4, 128.3, 127.9, 127.8, 127.7, 127.0, 126.2, 125.5, 124.3,
108.9, 47.7, 30.9; IR (KBr, neat) cmꢁ1: 2922, 16.1, 1491, 1353, 1027,
732, 698. Anal. Calcd for C30H25N: C, 90.19; H, 6.31; N, 3.51. Found:
C, 90.20; H, 6.21; N, 3.59.
4.3.2. 2-Benzyl-1-(3,4-dimethylphenyl)-3,5-diphenyl-1H-
pyrrole (3b)
4.3.7. 2-Benzyl-1-butyl-3,5-diphenyl-1H-pyrrole (3g)
A yellow solid, mp: 87–89 ꢀC; 1H NMR (400 MHz, CDCl3, ppm):
The molecular structure of the corresponding product 3a was
determined by X-ray crystallography (Fig. 1). X-ray data for com-
d 7.38–7.44 (m, 6H), 7.28–7.36 (m, 5H), 7.18–7.23 (m, 4H), 6.38 (s,
1H), 4.22 (s, 2H), 3.73 (t, J¼7.8 Hz, 2H), 1.25–1.34 (m, 2H), 0.97–1.03
pound 3a: C31H27N, MW¼413.54, T¼294(2) K,
l
¼0.71073 Å,
(m, 2H), 0.64 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
monoclinic space group, P21/c, a¼18.967(3) Å, b¼11.7217(16) Å,
d 140.2, 137.0, 134.1, 134.0, 129.0, 128.6, 128.3, 128.2, 127.9, 127.7,
c¼21.485(3) Å,
a
¼90ꢀ,
b
¼90ꢀ,
g
¼90ꢀ, V¼4776.6(12) Å3, Z¼8,
127.4, 126.8, 126.1, 125.4, 123.7, 108.9, 44.2, 33.2, 31.0, 19.8, 13.4; IR
(KBr, neat) cmꢁ1: 3429, 2924, 1704, 1601, 1459, 1363, 1208, 1026,
760, 698, 521. Anal. Calcd for C27H27N: C, 88.72; H, 7.45; N, 3.83.
Found: C, 88.90; H, 7.51; N, 3.59.
rcald¼1.150 mg mꢁ3
,
m
¼0.066 mmꢁ1
F(000)¼1760, crystal size
,
0.45ꢂ0.40ꢂ0.40 mm3,
independent
reflections
3525
[R(int)¼0.0505], reflections collected 19,583, refinement method,
full-matrix least-squares on F2, goodness-of-fit on F2 0.983, final R
indices [I>2
s
(I)] R1¼0.0711, wR2¼0.1602, R indices (all date)
4.3.8. 2-Benzyl-1-octyl-3,5-diphenyl-1H-pyrrole (3h)
R1¼0.0966, wR2¼0.1784, largest diff. peak and hole 0.734 and
ꢁ0.290 e Åꢁ3. Supplementary crystallographic data have been de-
posited at the Cambridge Crystallographic and allocated the de-
position number CCDC 694218.
A yellow oil; 1H NMR (400 MHz, CDCl3, ppm):
d 7.35–7.44 (m,
6H), 7.22–7.31 (m, 5H), 7.17–7.20 (m, 4H), 6.38 (s, 1H), 4.21 (s, 1H),
3.72 (t, J¼8.0 Hz, 2H), 1.31–1.34 (m, 2H), 1.18–1.23 (m, 2H), 1.02–1.13
(m, 4H), 0.97–0.98 (m, 4H), 0.84 (t, J¼7.4 Hz, 3H); 13C NMR
A white solid, mp: 140–141 ꢀC; 1H NMR (400 MHz, CDCl3, ppm):
(100 MHz, CDCl3, ppm): d 140.2, 137.1, 134.1, 134.0, 128.9, 128.6,
d
7.51 (d, J¼10.8 Hz, 2H), 7.33 (t, J¼10.0 Hz, 2H), 7.04–7.22 (m, 9H),
6.92 (t, J¼9.8 Hz, 3H), 6.65–6.69 (m, 3H), 4.00 (s, 2H), 2.18 (s, 3H),
2.00 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm):
140.7, 136.9, 136.8,
136.5, 136.0, 134.4, 133.2, 130.2, 129.8, 129.6, 128.5, 128.1, 128.0,
128.3, 127.9, 127.7, 127.4, 126.8, 126.1, 125.3, 123.7, 108.9, 44.4, 31.6,
31.0, 28.8, 28.7, 26.5, 22.5, 14.0; IR (neat) cmꢁ1: 3058, 2925, 1949,
1602, 1490, 1357, 1208, 1026, 758, 699, 509. Anal. Calcd for C31H35N:
C, 88.31; H, 8.37; N, 3.32. Found: C, 88.40; H, 8.41; N, 3.19.
d

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Y.-J. Bian et al. / Tetrahedron 65 (2009) 1424–1429
4.3.9. 2-Benzyl-1-tert-butyl-3,5-diphenyl-1H-pyrrole (3i)
2H), 6.60 (s, 1H), 3.96 (s, 2H), 2.33 (s, 3H); 13C NMR (75 MHz, CDCl3,
ppm): 138.6, 138.5, 135.5, 133.3, 133.2, 131.7, 131.4, 131.3, 129.6,
A yellow solid, mp: 117–118 ꢀC; 1H NMR (400 MHz, CDCl3, ppm):
d
d
7.41–7.43 (m, 2H), 7.21–7.34 (m,11H), 7.10–7.11 (m, 2H), 6.15 (s,1H),
129.3, 129.2, 128.8, 128.6, 128.2, 128.1, 127.8, 127.8, 124.4, 109.7, 30.6,
21.0; IR (KBr, neat) cmꢁ1: 3410, 3402, 2923, 2852, 1899, 1713, 1595,
1490, 1426, 1375, 1221, 1092, 1012, 823, 698, 527. Anal. Calcd for
C30H23Cl2N: C, 76.92; H, 4.95; N, 2.99. Found: C, 77.01; H, 4.99; N,
2.95.
4.42 (s, 2H), 1.35 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm):
d
142.2,
139.2,137.5,136.0,130.8,128.5,128.4,128.1,128.0,127.4,126.9,126.0,
125.8, 125.5, 113.1, 59.5, 48.2, 34.4, 33.3; IR (KBr, neat) cmꢁ1: 3413,
2922,1599,1448,1366,1206,1070, 699, 520. Anal. Calcd for C27H27N:
C, 88.72; H, 7.45; N, 3.83. Found: C, 88.60; H, 7.41; N, 3.99.
4.3.16. 2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-1,5-diphenyl-1H-
pyrrole (3p)
4.3.10. 2-Benzyl-1-hexamethylene-3,5-diphenyl-1H-pyrrole (3j)
A yellow solid, mp: 140–141 ꢀC; 1H NMR (400 MHz, CDCl3,
A yellow solid, mp: 119–120 ꢀC; 1H NMR (300 MHz, CDCl3, ppm):
ppm):
2H), 3.91 (br s, 1H), 1.42–1.61 (m, 6H), 0.79–0.97 (m, 4H); 13C NMR
(100 MHz, CDCl3, ppm): 140.9, 137.2, 135.6, 134.2, 130.0, 128.4,
d
7.19–7.44 (m, 11H), 7.14–7.17 (m, 4H), 6.27 (s, 1H), 4.27 (s,
d
7.46 (d, J¼7.8 Hz, 2H), 7.36 (t, J¼8.1 Hz, 2H), 7.80–7.23 (m,12H), 6.77
(d, J¼8.1 Hz, 2H), 6.63 (s, 1H), 3.98 (s, 2H); 13C NMR (75 MHz, CDCl3,
d
ppm): d 138.6, 138.5, 136.2, 133.5, 131.8, 131.5, 131.2, 129.8, 129.2,
128.2, 128.0, 127.9, 127.7, 127.2, 126.9, 126.0, 125.3, 110.1, 57.9, 33.5,
31.8, 26.5, 25.2; IR (KBr, neat) cmꢁ1: 3440, 3055, 2934, 1954, 1600,
1448, 1361, 1206, 1026, 895, 757, 697, 505. Anal. Calcd for C29H29N:
C, 88.96; H, 7.47; N, 3.58. Found: C, 88.95; H, 7.41; N, 3.64.
128.9, 128.6, 128.5,128.2, 128.1,127.9,127.8, 126.0, 124.5,109.7, 30.6;
IR (neat) cmꢁ1: 3411, 2922, 1955, 1713, 1595, 1495, 1375, 1222, 1092,
1013, 801, 697, 517. Anal. Calcd for C29H21Cl2N: C, 76.65; H, 4.66; N,
3.08. Found: C, 76.61; H, 4.60; N, 2.98.
4.3.11. 2-Benzyl-3-(4-chlorophenyl)-1,5-diphenyl-1H-pyrrole (3k)
4.4. Procedure for preparation of the intermediate 4a
A yellow solid, mp: 134–135 ꢀC; 1H NMR (300 MHz, CDCl3,
ppm):
d
7.39–7.43 (dd, J¼5.7 Hz, 2H), 7.28–7.30 (d, J¼8.4 Hz, 2H),
(Z)-1,3,5-Triphenylpent-2-en-4-ynyl acetate 1a (0.2 mmol), an-
iline 2a (0.8 mmol), and MeCN/H2O (6:1, 10 mL) were placed in
a 25 mL flask. The resulting mixture was then heated at 60 ꢀC.
When the reaction was completed as indicated by TLC analysis,
water (10 mL) was added and the resulting reaction mixture was
extracted with ethyl acetate. The extracts were concentrated to give
a thick residue. The resulting residue was purified by column
chromatography using 20:1 petroleum ether/ethyl acetate as an
eluent to afford pure (Z)-N-(1,3,5-triphenyl-pent-2-en-4-ynyl)-
benzenamine 4a (93%).
7.07–7.24 (m, 11H), 6.93–6.96 (dd, J¼4.8 Hz, 2H), 6.87 (d, J¼6.3 Hz,
2H), 6.62 (s, 1H), 4.00 (s, 2H); 13C NMR (75 MHz, CDCl3, ppm):
d
140.4, 138.7, 135.1, 134.8, 132.7, 131.4, 130.0, 128.9, 128.7, 128.6,
128.5, 128.2, 128.0, 127.9,127.8,127.6,126.0,125.8,123.0,109.2, 31.2;
IR (KBr, neat) cmꢁ1: 3029, 2923, 1948, 1599, 1492, 1122, 984, 813,
759, 695, 465. Anal. Calcd for C29H22ClN: C, 82.94; H, 5.28; N, 3.34.
Found: C, 83.01; H, 5.32; N, 3.34.
4.3.12. 2-Benzyl-3-(4-methylphenyl)-1,5-diphenyl-1H-pyrrole (3l)
A yellow solid, mp: 134–136 ꢀC; 1H NMR (300 MHz, CDCl3,
ppm):
d
7.41 (d, J¼8.1 Hz, 2H), 7.04–7.18 (m, 13H), 6.92–6.95 (m,
4.4.1. (Z)-N-(1,3,5-Triphenylpent-2-en-4-ynyl)benzenamine (4a)
2H), 6.88 (d, J¼6.3 Hz, 2H), 6.64 (s, 1H), 4.02 (s, 2H), 2.33 (s, 3H); 13C
A yellow oil; 1H NMR (300 MHz, CDCl3, ppm):
d 6.66–7.80 (m,
21H), 5.88 (d, J¼9.0 Hz, 1H), 4.31 (br s, 1H); 13C NMR (75 MHz,
NMR (75 MHz, CDCl3, ppm): d 140.4, 138.9, 135.2,134.4,133.6,133.0,
129.8,129.2,128.7,128.5,128.1,128.0,127.9,127.7,127.6,127.4,125.8,
125.6, 124.1, 109.4, 31.2, 21.0; IR (KBr, neat) cmꢁ1: 3369, 3029, 2967,
1949, 1598, 1491, 1379, 1091, 912, 761, 697, 518. Anal. Calcd for
C30H25N: C, 90.19; H, 6.31; N, 3.51. Found: C, 90.22; H, 6.32; N, 3.46.
CDCl3, ppm):
d 147.4, 142.0, 138.7, 137.0, 131.5, 129.2, 128.8, 128.6,
128.4, 128.1, 127.5, 126.8, 126.2, 124.7, 122.8, 117.8, 113.6, 97.3, 86.0,
59.0; IR (neat) cmꢁ1: 3406, 3055, 1600, 1498, 1413, 909, 754, 693,
511. Anal. Calcd for C29H23N: C, 90.35; H, 6.01; N, 3.63. Found: C,
90.33; H, 6.0; N, 3.67.
4.3.13. 2-Benzyl-3-(4-methoxyphenyl)-1,5-diphenyl-1H-
pyrrole (3m)
Acknowledgements
A white solid, mp: 102–103 ꢀC; 1H NMR (300 MHz, CDCl3, ppm):
d
7.49 (d, J¼8.7 Hz, 2H), 7.14–7.25 (m, 11H), 6.94–7.02 (m, 6H), 6.68
(s, 1H), 4.07 (s, 2H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm):
157.8, 140.4, 138.9, 134.3, 132.9, 129.5, 129.1, 128.8, 128.7, 128.5,
We thank the NSFC (No. 20621091, 20672049) and 0710RJZA019
for financial support.
d
128.1, 127.9, 127.8, 127.7, 127.4, 125.8, 125.6, 123.8, 113.9, 109.4, 55.1,
31.2; IR (KBr, neat) cmꢁ1: 3397, 3027, 2919, 1949, 1599, 1496, 1027,
760, 696, 19. Anal. Calcd for C30H25NO: C, 86.71; H, 6.06; N, 3.37.
Found: C, 86.72; H, 6.12; N, 3.41.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.12.018.
4.3.14. 2-(4-Chlorobenzyl)-3,5-bis(4-chlorophenyl)-1-phenyl-1H-
pyrrole (3n)
References and notes
A yellow solid, mp: 108–109 ꢀC; 1H NMR (300 MHz, CDCl3,
1. (a) Butler, M. S. J. Nat. Prod. 2004, 67, 2141; (b) Joule, J. A.; Mills, K. Heterocyclic
Chemistry; Blackwell Science: Oxford, 2000; (c) Lee, C.-F.; Yang, L.-M.; Hwu, T.-Y.;
Feng, A.-S.; Tseng, J.-C.; Luh, T.-Y. J. Am. Chem. Soc. 2000, 122, 4992.
ppm):
2H), 6.63 (s, 1H), 3.99 (s, 2H); 13C NMR (75 MHz, CDCl3, ppm):
138.7, 138.6, 135.1, 134.0, 132.4, 132.1, 132.0, 131.4, 130.2, 129.5,
d
7.03–7.43 (m, 13H), 6.97 (d, J¼8.1 Hz, 2H), 6.80 (d, J¼8.7 Hz,
2. (a) Gossauer, A. Pyrrole; Houben-Weyl; Thieme: Stuttgart, 1994; Vol. E6a/1,
p 556; (b) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am.
Chem. Soc. 1999, 121, 54; (c) Furstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120,
2817; (d) Sayah, B.; Pelloux-Leon, N.; Vallee, Y. J. Org. Chem. 2000, 65, 2824; (e)
Liu, J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem. 2000, 65, 3587;
(f) Eicher, T.; Hauptmann, S. The Chemistry of HeterocyclesdStructure, Reactions,
Synthesis and Application (translated by Suschitzky H., Suschitzky J.); VCH:
Weinheim, 2003; (g) Fu¨rstner, A. Angew. Chem. 2003, 115, 3706; Angew. Chem.,
Int. Ed. 2003, 42, 3582.
d
129.3, 129.1, 128.9, 128.7, 128.6, 128.4, 123.7, 109.4, 30.9; IR (KBr,
neat) cmꢁ1: 3392, 3059, 2926, 1952, 1600, 1498, 1379, 1246, 1178,
1033, 835, 761, 697, 533. Anal. Calcd for C29H20Cl3N: C, 71.25; H,
4.12; N, 2.87. Found: C, 71.11; H, 4.09; N, 2.90.
3. For most recent work on the metal-catalyzed synthesis of pyrroles, see: (a)
Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127; (b) Gilchrist, T. L.
J. Chem. Soc., Perkin Trans. 1 1999, 2849; (c) Hartwig, J. F. Synlett 2006, 1283;
(d) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123,
2074; (e) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
4.3.15. 2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-1-phenyl-5-p-tolyl-
1H-pyrrole (3o)
A yellow solid, mp: 113–135 ꢀC; 1H NMR (300 MHz, CDCl3,
ppm):
d
7.36 (d, J¼7.8 Hz, 2H), 6.89–7.20 (m, 11H), 6.75 (d, J¼8.1 Hz,

Y.-J. Bian et al. / Tetrahedron 65 (2009) 1424–1429
1429
11260; (f) Cyr, D. J. S.; Arndtsen, B. A. J. Am. Chem. Soc. 2007, 129, 12366; (g)
Hiroya, K.; Matsumoto, S.; Ashikawa, M.; Ogiwara, K.; Sakamoto, T. Org. Lett.
2006, 8, 5349; (h) Istrate, F. M.; Gagosz, F. Org. Lett. 2007, 9, 3181; (i) Braun,
R. U.; Zeitler, K.; Muller, T. J. J. Org. Lett. 2001, 3, 3297; (j) Kamijo, S.; Kana-
zawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260; (k) Dhawan, R.;
Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468; (l) Takaya, H.; Kojima, S.;
Murahashi, S.-I. Org. Lett. 2001, 3, 421; (m) Siriwardana, A. I.; Kathriarachchi,
K. K. A. D. S.; Nakamura, I.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc.
2004, 126, 13898; (n) Paulus, O.; Alcaraz, G.; Vaultier, M. Eur. J. Org. Chem.
2002, 2565; (o) Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313; (p)
Ramanathan, B.; Keith, A. J.; Armstrong, D.; Odom, A. L. Org. Lett. 2004, 6,
2957; (q) Martı´n, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem. 2006, 118,
7237; Angew. Chem., Int. Ed. 2006, 45, 7079; (r) Lu, L.-H.; Chen, G.-F.; Ma, S.-M.
Org. Lett. 2006, 8, 835; (s) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151.
4. (a) Balme, G. Angew. Chem. 2004, 116, 6396; Angew. Chem., Int. Ed. 2004, 43,
6238; (b) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai, M.;
Uemura, S. Angew. Chem. 2003, 115, 2663; Angew. Chem., Int. Ed. 2003, 42, 2681;
(c) Tejedor, D.; Gonzalez-Cruz, D.; Garcia-Tellado, F.; Marrero-Tellado, J. J.; Ro-
driguez, M. L. J. Am. Chem. Soc. 2004, 126, 8390; (d) Yamamoto, Y.; Hayashi, H.;
Saigoku, T.; Nishiyama, H. J. Am. Chem. Soc. 2005, 127, 10804; (e) Larionov, O. V.;
Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 5664.
5. Shu, X.-Z.; Liu, X.-Y.; Xiao, H.-Q.; Ji, K.-G.; Guo, L.-N.; Liang, Y.-M. Adv. Synth. Catal.
2008, 350, 243.
6. Wang, S.-H.; Tu, Y.-Q.; Chen, P.; Hu, X.-D.; Zhang, F.-M.; Wang, A.-X. J. Org. Chem.
2006, 71, 4343.
7. (a) Gabriele, B.; Salerno, G.; Fazio, A. J. Org. Chem. 2003, 68, 7853; (b) Gabriele, B.;
Salerno, G.; Fazio, A.; Bossio, M. R. Tetrahedron Lett. 2001, 42, 1339; (c) Utimoto,
K.; Miwa, H.; Nozaki, H. Tetrahedron Lett. 1981, 22, 4277.