Palladium-catalyzed three-component domino reaction for the preparation of benzo[b]thiophene and related compounds

Article abstract of DOI:10.1039/c1ob05571b

A simple and efficient palladium-catalyzed three-component domino reaction of bromothiophenes with internal alkynes has been developed to produce benzo[b]thiophenes in moderate to good yields. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05571b

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Palladium-catalyzed three-component domino reaction for the preparation of
benzo[b]thiophene and related compounds†
Huanan Huang, Jing Li, Weining Zhao, Yanbo Mei and Zheng Duan*
Received 11th April 2011, Accepted 17th May 2011
DOI: 10.1039/c1ob05571b
A simple and efficient palladium-catalyzed three-component
domino reaction of bromothiophenes with internal alkynes
has been developed to produce benzo[b]thiophenes in moder-
ate to good yields.
with alkynes to form benzo[b]thiophenes selectively. The only by-
product is HBr (Scheme 1).
Benzo[b]thiophenes display numerous applications in materials
and biological chemistry.1 The development of efficient and simple
methods to synthesize these compounds has received considerable
attention in recent years.2–6,12
Scheme 1
Transition metal-catalyzed multi-component domino reactions
are becoming more and more popular in modern organic
synthesis.7 In particular, the palladium-catalyzed reaction of
aryl halides with alkynes to afford various polycyclic aromatic
compounds has been highlighted in numerous reports.8 The
attractive points of these reactions are simplicity, efficiency,
atom and step economy. Triggered by oxidative addition of
palladium species to C–X (X = Br, I) bonds, all of the reactants
are “automatically assembled” in one pot to produce the final
polycyclic p-conjugated products. There is no need to isolate the
intermediates. Several bonds (at least 3 bonds) are formed with
the loss of only one molecule of HX (X = Br, I). This advantage
has been previously used to construct different polycyclic aromatic
hydrocarbons (PAHs),1b but there are limited examples of catalytic
three-component domino reactions of alkynes with heteroaryl
halides, especially the reaction with halothiophenes to produce
benzo[b]thiophenes.3,4,8a
We checked the reaction of 3-bromothiophene (1a) and 2-
bromothiophene (1b), respectively, with diphenylacetylene (2a).
As shown in Table 1, the reaction with 2-bromothiophene (1b)
provided only a trace amount of the desired product (entry 11).
But a promising result was obtained with 3-bromothiophene
(entry 1). Encouraged by this result, we carried out a series
of experiments with 3-bromothiophene to optimize the reaction
parameters. Typical results are summarized in Table 1.
As a ligand, PCy3 showed better results than PPh3 (Table 1,
entry 3 vs. entry 4) in terms of yield (according to GC analysis).
Table 1 Reactions of bromothiophenes(1) with diphenylacetylene (2a)a
Palladium-catalyzed reaction of comparatively expensive o-
dihalothiophenes with alkynes provided a simple and direct
access to benzothiophenes,3,8a but the similar reaction with 2-
iodothiophene was less effective.4 Ir-catalyzed reaction of 2-
thenoyl chloride with alkynes provided another efficient method.5
Very recently, decarboxylation of heteroarene carboxylic acids
and subsequent reactions with alkynes provided an efficient
method for the preparation of various highly substituted indoles
and benzofurans, but the reactions with thiophene derivatives
were sluggish.6 Herein, we would like to report the palladium-
catalyzed three-component domino reaction of bromothiophenes
Entry
1
Ligandb
LiBr (mmol)
Yield (%)c
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
P(Ph)3
P(Ph)3
P(Ph)3
P(Cy)3
P(Cy)3
P(Cy)3
P(Cy)3
P(Cy)3
61
31d
0.7
0.7
1.0
0.7
0.5
58
76(63)
16
89(82)e
67e
10e
9
10
11
0.7
44(41)e
—
P(Ph)3
P(Cy)3
tracef
a Unless otherwise noted, Pd(OAc)2 (5 mol%), ligand, and Na2CO3 were
added to the DMF solution of 3-bromo- (1a) or 2-bromothiophene (1b)
(1 mmol) and 2a (3.0 mmol). The reaction mixture was stirred under N2
at 120 ◦C for 24 h. b The ratio of ligand : Pd : Na2CO3 = 2 : 1 : 20. c GC
yields. Isolated yields are given in parentheses. d The reaction was carried
out under air. e 10 mol% Pd(OAc)2 was used. f Reacted for 40 h.
Chemistry Department, the Key Lab of Chemical Biology and Organic
Chemistry of Henan Province, Zhengzhou University, Zhengzhou 450001,
P. R. China. E-mail: duanzheng@zzu.edu.cn; Fax: +86 371 67783391;
Tel: +86 371 67783391
† Electronic supplementary information (ESI) available: Synthesis and
characterization of products, 1H and 13C NMR, IR and UV spectra. See
DOI: 10.1039/c1ob05571b
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Table 2 Palladium-catalyzed reactions of bromothiophenes with
In the presence of Pd(OAc)2 (10 mol%), PCy3 (20 mol%), LiBr
(0.7 mmol), and Na2CO3(2 mmol), the DMF solution of 1a
(1 mmol) and 2a (3 mmol) was stirred at 120 ◦C for 24 h, leading
to an 82% yield of benzothiophene 3aa (entry 6). The reaction
without phosphine ligand provided the desired product in low
yield (entry 9). As shown in Table 1, LiBr additive plays an
important role in this reaction (entries 3–8).9 In all of the cases,
only compound 3aa was obtained selectively. The formation of
3aa¢ was not observed (Scheme 2).10 The different results obtained
from 2- and 3-bromothiophenes, as well as the selective formation
of 3aa, may be due to the different reactivity of the a- and b-C–H
bonds of thiophene.11
alkynesa
Entry Thiophene(1)
Alkyne(2)
Product Yield (%)b
1
2a
3aa
89(82)
2
3
1a
1a
3ab
3ac
(54)
(61)
4
5
1a
3ad
3ca
(73)
Scheme 2 The regioselective formation of 3aa.
The reaction conditions of entry 6, Table 1, were chosen for
further examination of the reaction scope with a variety of bro-
mothiophenes and internal alkynes. Table 2 summarizes the results
of the palladium-catalyzed reactions of bromothiophenes with
alkynes. Clearly, various 3-bromothiophenes reacted smoothly
with methyl- (2b), methoxy- (2c), and fluoro-substituted (2d)
diphenylacetylenes to afford the corresponding benzothiophenes
(entries 1–6) in moderate to good yields. Both CHO (entry 9) and
CN (entry 10) groups are compatible with the present catalytic
system. The versatile transformations of these functional groups
will provide ready access to a wider range of benzothiophenes. It
is worth noting that the reaction of 4-bromo-2-cyanothiophene
(entry 10, 1g) with diphenylacetylene was carried out without
PCy3 and the desired product could be isolated in 43% yield. The
reaction with PCy3 was sluggish.
2a
75(71)
6
7
1c
2c
2a
3cc
3da
(57)
(64)
8
2a
2a
2a
3ea
3fa
3ga
(52)c
(47)
9
This catalytic system could also be used to synthesize indoles
from the corresponding bromopyrroles (Scheme 3).
10
(43)d
a Unless otherwise noted, Pd(OAc)2 (10 mol%), PCy3 (20 mol%) and
Na2CO3 (200 mol%) were added to the DMF solution of 1 (1 mmol)
and 2 (3 mmol). The reaction mixture was stirred under N2 at 120 ◦C for
24 h. b GC yields. Isolated yields are given in parentheses. c The reaction
was carried out at 140 ◦C for 36 h with 10 mol% of PCy3. d The reaction
was carried out for 2 h without PCy3.
Scheme 3 The selective formation of indoles. Reagents and conditions: (i)
Pd(OAc)2 (10 mol%), PCy3 (20 mol%), LiBr (0.7 mmol), Na2CO3(2 mmol),
DMF, 120 ◦C, 24 h.
We propose the following reaction mechanism (Scheme 4):
(1) oxidative addition of 3-bromothiophene 1 to Pd(0) gives a
thienylpalladium(II) intermediate 6; (2) cis-carbopalladation of
the alkyne gives a vinylic palladium intermediate 7; (3) next,
cyclopalladation affords a five-membered palladacycle 8; (4) the
subsequent reaction with alkyne and reductive elimination affords
the corresponding product 3 with regeneration of the Pd(0) species.
The reaction pathway may also involve successive insertion of two
molecules of alkynes to form 9, which can also give 3.4
In conclusion, a new and highly regioselective catalytic proce-
dure was developed. It provides a simple and straightforward ring
extension method for constructing substituted benzothiophenes
from simple starting materials with high atom economy. Further
studies to elucidate the optical and electronic properties of the
resulting compounds and extension of the current scope towards
the construction of polycyclic heteroaromatic compounds are now
under way in our group.
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Acknowledgements
We would like to thank the National Natural Science Foundation
of China (No. 21072179) for financial support. The authors thank
Prof. Feng Shi for language polishing of this manuscript.
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5038 | Org. Biomol. Chem., 2011, 9, 5036–5038
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The Royal Society of Chemistry 2011
©