A simple and efficient protocol to 1,2,4-substituted pyrroles via a sonogashira coupling-acid-catalyzed cyclization

Article abstract of DOI:10.1055/s-0030-1261175

A facile and efficient protocol for the synthesis of 1,2,4-substituted pyrrole derivatives was developed. As a result of the ready availability of materials and the simple operation, this type of reaction should have potential utility in organic synthesis. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1261175

LETTER
2185
A Simple and Efficient Protocol to 1,2,4-Substituted Pyrroles via a
Sonogashira Coupling–Acid-Catalyzed Cyclization
S
ynthesis of Subst
a
itute
d
Pyrrole
s
Zhu, Jie Zhao, Yuxiu Wei, Hongwei Zhou*
Department of Chemistry, Zhejiang University, (Campus Xixi), Hangzhou 310007, P. R. of China
Fax +86(571)88920271; E-mail: zhouhw@zju.edu.cn
Received 3 May 2011
Dedicated to the memory of Prof. Xian Huang
Table 1 Synthesis of 1,2,4-Substituted Pyrrolea
Abstract: A facile and efficient protocol for the synthesis of 1,2,4-
substituted pyrrole derivatives was developed. As a result of the
ready availability of materials and the simple operation, this type of
reaction should have potential utility in organic synthesis.
Pd(PPh3)2Cl2
R2
Br
+
R2
CuI, Et3N
r.t.
N
NH
R1
R1
3
Key words: pyrroles, Sonogashira reaction, gallium triflate, cy-
clization, 2-bromoallylamine
1
2
Entry R1
R2
Time (h) Yield of 3
1
2
n-Bu
Bn
Ph
4
4
6
6
6
4
7
8
8
8
3a 82
3b 76
3c 72
3d 81
3e 86
3f 68
3g 80
3h 85
3i 79
3j 77
Pyrroles may be one of the most important heterocyclic
compounds which are found in a broad range of natural
products and drug molecules, and are also of growing rel-
evance in materials science.1 Due to their applications in
pharmaceutical fields, investigations on the development
of synthetic methodologies for pyrrole derivatives have
continuously attracted the attention of organic chemists.
Ph
3
4-ClC6H4CH2
Bn
n-C6H13
HOCH2
HOCH2CH2
Ph
4
5
4-ClC6H4CH2
H
6
During our research, we tried to prepare a particular sub-
strate – 1-butyl-4-methyl-2-phenyl-1H-pyrrole. To our
surprise, this simple pyrrole is an unknown compound,
and even the methods about the synthesis of 1-substituted
4-methyl-2-phenylpyrrole are limited.2 However, it is
well-known that the indoles could be prepared via the
cyclization of 2-alkynylanilines3 or a metal-catalyzed cas-
cade reaction.4 This prompted us to investigate the possi-
bility of a cross-coupling of N-(2-bromoallyl)butan-1-
amine (1a) with phenylacetylene (2a) followed by subse-
quent cyclization of the coupling product.
7
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
8
cyclopropyl
n-C6H13
HOCH2
9
10
Ac
N
CH2
11
H
6
3k 72
2-Bromoprop-2-en-1-amine 1a is commercially available
and could be prepared readily via treatment of 2-bro-
moprop-2-en-1-amine with butyraldehyde in the presence
of NaBH3CN. Thus, we initiated our study using the
Sonogashira coupling procedure by reacting 1a with
phenylacetylene in the presence of CuI/PdCl2(PPh3)2.5
The coupling reaction proceeded smoothly at room tem-
perature, and the cyclization product, 1-butyl-4-methyl-2-
phenyl-1H-pyrrole (3a) was obtained in 82% yield. It
should be noted that the initial Sonogashira coupling
product N-butyl-2-methylene-4-phenylbut-3-yn-1-amine
could not be isolated from the reaction mixture. With this
result in hand, we examined the scope of the reaction and
obtained a variety of the expected pyrroles in good yields
under mild conditions (Table 1).6
12
13
14
H
H
H
4-ClC6H4
n-C5H11
4
4
4
3l 62
3m 58
4-PrC6H4
3n 66
a Substrate 1 (0.5 mmol) and alkyne 2 (0.6 mmol) in THF (5 mL) cat-
alyzed by 2 mol% of CuI/PdCl2(PPh3)2 under an N2 atmosphere.
It was envisaged that an electron-withdrawing group on
R1 position would disfavor the cyclization reaction. As a
result, we conducted the reaction of N-(2-bromoallyl)-
acetamide with oct-1-yne under similar conditions and
only the cross-coupling product N-(2-methylenedec-3-
ynyl)acetamide (4a) was obtained. We hypothesized that
a stronger Lewis acid than Pd(II) was required to promote
the subsequent cyclization.7 Hence, a series of Lewis ac-
ids were examined using 4a as the substrate and toluene
as the reaction solvent (Table 2).
SYNLETT 2011, No. 15, pp 2185–2186
x
x
.x
x
.2
0
1
1
Advanced online publication: 10.08.2011
DOI: 10.1055/s-0030-1261175; Art ID: W10811ST
© Georg Thieme Verlag Stuttgart · New York

2186
D. Zhu et al.
LETTER
Table 2 Cyclization of 4a Catalyzed by Lewis Acida
simple operation, this type of reaction presented here
should have potential utility in organic synthesis.
Lewis acid
n-C6H13
N
toluene
temperature
NH
n-C6H13
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Ac
Ac
4a
5a
Entry
Lewis acid
BF3·OEt2
AlCl3
Temp (°C)
Yield of 5a (%)
Acknowledgment
1
2
r.t.
r.t.
r.t.
r.t.
60
60
90
90
90
90
23
18
35
26
42
78
51
68
75
85
Financial support was received from the Natural Science Foundati-
on of China (Nos. 20702046 and 20972134).
3
GaCl3
References and Notes
4
ZnCl2
(1) (a) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc.
Rev. 2010, 39, 4402. (b) Beck, E. M.; Gaunt, M. J. C–H
Activation 2010, 292, 85. (c) Shinohara, K. I.; Bando, T.;
Sugiyama, H. Anti-Cancer Drugs 2010, 21, 228.
5
Zn(OTf)2
Ga(OTf)3
Zn(OTf)2
In(OTf)3
Cu(OTf)2
Ga(OTf)3
6
(d) Cadierno, V.; Crochet, P. Curr. Org. Synth. 2008, 5, 343.
(e) Yalcinkaya, S.; Tuken, T.; Yazici, B.; Erbil, M. Prog.
Org. Coat. 2008, 63, 424. (f) Fan, H.; Peng, J.; Hamann,
M. T.; Hu, J. F. Chem. Rev. 2008, 108, 264. (g) Grigg, R.;
Savic, V. Chem. Commun. 2000, 873.
7
8
9
(2) (a) Perveev, F. Ya.; Kuznetsova, E. M. Zh. Obshch. Khim.
1958, 28, 2360. (b) Miocque, M.; Duchon-d’Engenieres,
M.; Sauzieres, J. Bull. Soc. Chim. Fr. 1975, 7, 1777.
(3) (a) Li, G. T.; Huang, X. G.; Zhang, L. M. Angew. Chem. Int.
Ed. 2008, 47, 346. (b) Trost, B. M.; McClory, A. Angew.
Chem. Int. Ed. 2007, 46, 2074. (c) Ohno, H.; Ohta, Y.;
Oishi, S.; Fujii, N. Angew. Chem. Int. Ed. 2007, 46, 2295.
(d) Cariou, K.; Ronan, B.; Mignani, S.; Fensterbank, L.;
Malacria, M. Angew. Chem. Int. Ed. 2007, 46, 1881.
(e) Nakamura, I.; Yamagishi, U.; Song, D.; Konta, S.;
Yamamoto, Y. Angew. Chem. Int. Ed. 2007, 46, 2284.
(4) (a) Barluenga, J.; Jimenez-Aquino, A.; Aznar, F.; Valdes, C.
J. Am. Chem. Soc. 2009, 131, 4031. (b) Okuma, K.; Seto,
J. I.; Sakaguchi, K. I.; Ozaki, S.; Nagahora, N.; Shioji, K.
Tetrahedron Lett. 2009, 50, 2943. (c) Chen, Y.; Wang,
Y. J.; Sun, Z. M.; Ma, D. W. Org. Lett. 2008, 10, 625.
(d) Fayol, A.; Fang, Y. Q.; Lautens, M. Org. Lett. 2006, 8,
4203. (e) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc.
2005, 127, 5776. (f) Coleman, C. M.; O’Shea, D. F. J. Am.
Chem. Soc. 2003, 125, 4054.
10
a Substrate 4a (0.5 mmol) and Lewis acid (0.025 mmol) in toluene (3
mL) under an N2 atmosphere.
It was found that optimal results could be obtained when
using gallium(III) triflate as the catalyst and 90 °C as the
reaction temperature. Under these conditions, pyrroles
with an electron-withdrawing group in 1-position could
also be synthesized in satisfactory yields (Table 3).
In summary, we developed a facile and efficient protocol
for the synthesis of 1,2,4-substituted pyrrole derivatives.
As a result of the ready availability of materials and the
Table 3 Cyclization of 4 Catalyzed by Gallium Triflatea
Ga(OTf)3
R2
(5) Elangovan, A.; Wang, Y. H.; Ho, T. I. Org. Lett. 2003, 5,
1841.
(6) General Procedure for the Synthesis of 3a
toluene
90 °C
N
R1
5
NH
R2
R1
4
To a solution of 1a (0.5 mmol) and 2a (0.6 mmol) in 5 mL
of THF was charged CuI (2 mg. 0.01 mmol) and PdCl2(PPh3)2
(7 mg, 0.01 mmol), then charged 1 mL of Et3N under an N2
atmosphere at r.t. The reaction was monitored by TLC until
it went to completion (4 h). The reaction mixture was
quenched with H2O, extracted with Et2O (30 mL), and dried
over anhyd Na2SO4. After evaporation of the Et2O,
chromatography on silica gel (PE) of the crude product
afforded 3a. 1H NMR (400 MHz, CDCl3): d = 7.35–7.32 (m,
4 H), 7.27–7.23 (m, 1 H), 6.52–6.52 (d, J = 0.8 Hz, 1 H),
6.01–6.00 (d, J = 2.0 Hz, 1 H), 3.84–3.81 (t, J = 7.4 Hz, 2 H),
2.12 (s, 3 H), 1.64–1.56 (m, 2 H), 1.23–1.17 (q, J = 7.5 Hz,
2 H), 0.83–0.79 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): d = 134.6, 134.2, 129.1, 128.6, 126.9, 120.4, 118.7,
110.3, 47.0, 34.0, 20.2, 14.0, 12.2. IR (neat): 1491, 1342 cm–1.
HRMS: m/z calcd for C15H19N: 213.1517; found: 213.1518.
(7) Peng, H. M.; Zhao, J.; Lia, X. Adv. Synth. Catal. 2009, 351,
1371.
Entry
R1
R2
Time (h) Yield of 5 (%)
1
2
3
4
5
6
7
Ac
n-C6H13
Ph
8
8
5a 85
5b 80
5c 68
5d 71
5e 73
5f 66
5g 65
4-Tol-CO
4-Ts
Bz
n-C6H13
cyclopropyl
Ph
10
10
8
Bz
Ms
cyclopropyl
n-C6H13
12
12
Ms
a Substrate 4a (0.5 mmol) and Lewis acid (0.025 mmol) in toluene (3
mL) under an N2 atmosphere at 90 °C.
Synlett 2011, No. 15, 2185–2186 © Thieme Stuttgart · New York

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