Highly regio- and stereoselective intermolecular tandem reaction to synthesize chloro-substituted 1,3-butadienes

Article abstract of DOI:10.1039/b923464k

A palladium catalyzed highly regio- and stereoselective intermolecular tandem reaction of alkynes, CuCl₂ and alkenes by a sequence of chloropalladation/Heck reaction to produce chloro-substituted 1,3-dienes is achieved.

Full text of DOI:10.1039/b923464k

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Highly regio- and stereoselective intermolecular tandem reaction
to synthesize chloro-substituted 1,3-butadienesw
Jing-Mei Huang,* Yi Dong, Xu-Xiao Wang and Hui-Chao Luo
Received (in Cambridge, UK) 10th November 2009, Accepted 16th December 2009
First published as an Advance Article on the web 14th January 2010
DOI: 10.1039/b923464k
A palladium catalyzed highly regio- and stereoselective inter-
molecular tandem reaction of alkynes, CuCl2 and alkenes
by a sequence of chloropalladation/Heck reaction to produce
chloro-substituted 1,3-dienes is achieved.
Table 1 Optimization of the reaction conditions for the three-
component coupling reactiona
Diene-containing natural products which have been investigated
comprehensively recently due to their remarkable biological
activities are likely to play an important role in biological
processes.1 Especially, members of the leptomcyin family have
attracted a great deal of attention because of their potent
cell-cycle-regulating properties and apoptotic, antifungal,
and antiviral activities.2 Given that most diene-containing
natural products can be prepared from an array of 1,3-diene
fragments,1a,b,3 the effective and stereoselective synthesis of
multi-substituted 1,3-dienes appears to be a logical first choice.
In addition, tandem reaction has been proven to be a very
attractive method to construct polyfunctionalized molecules
in a convergent way. In connection with our interest in
chloropalladation chemistry on triple bonds,4 we herein
disclose a regio- and stereoselective intermolecular tandem
reaction of cupric chloride, alkynes and alkenes catalyzed by
palladium to produce chloro-substituted 1,3-dienes.5
Yieldb/
%
Entry [Pd]
[ClÀ]
Solvent
3a : 4ac
1
2
3
4
10% PdCl2
3 equiv. CuCl2 Toluene
3 equiv. CuCl2 Ethyl acetate 25
Trace
—
10% PdCl2
10% PdCl2
10% PdCl2
93 : 7
—
67 : 33
3 equiv. CuCl2 1,4-dioxane
3 equiv. CuCl2 THF–H2O = 32
1 : 1
Trace
5
10% PdCl2
3 equiv. CuCl2 2a : H2O =
3 : 1d
35
87 : 13
6
7
8
9
10
11
10% PdCl2
10% PdCl2
10% PdCl2
10% PdCl2
—
10%
Pd(OAc)2
10%
3 equiv. CuCl2 2a
6 equiv. CuCl2 2a
9 equiv. CuCl2 2a
1 equiv. CuCl2 2a
6 equiv. CuCl2 2a
6 equiv. CuCl2 2a
72
76
72
57
0
96 : 4
96 : 4
94 : 6
96 : 4
—
28
95 : 5
12
13
6 equiv. CuCl2 2a
Trace
62
—
Pd(PPh3)2Cl2
10% PdCl2
1 equiv. CuCl2 2a
4 equiv. LiCl
43 : 57
The reaction of methyl non-2-ynoate and methyl acrylate
was initially investigated in the presence of 10% PdCl2 and
3 equiv. CuCl2 in various solvents (entries 1–5, Table 1).
Obviously, this palladium catalyzed transformation showed
great dependence on the solvent used. Only trace amounts of
the desired dienes were detected in toluene and 1,4-dioxane
(entries 1 and 3, Table 1). The use of ethyl acetate led to a low
yield (25%), but with a high regio- and stereoselectivity at
93 : 7 (3a : 4a, entry 2, Table 1).6 The reactions were carried out
in aqueous media resulting in low yields (entries 4 and 5,
Table 1). When the reaction was performed in 2 mL methyl
acrylate in the absence of any other solvent, the yield of the
desired adduct was increased sharply to 72% with good
selectivity at 96 : 4 (entry 6, Table 1). Optimization of the
amount of cupric chloride showed that 6 equiv. cupric chloride
was optimal, with a small increase of yield to 76% at the same
isomeric ratio at 96 : 4 (entry 7, Table 1). In addition, no
reaction occurred in the absence of PdCl2 (entry 10, Table 1).
Pd(OAc)2 and Pd(PPh3)2Cl2 gave unsatisfactory results
(entries 11 and 12, Table 1). Adding LiCl resulted in lower
a
Reactions were carried out using [Pd] catalyst (10 mol%), MCln
(x equiv.), 2 mL solution, under N2 in a capped tube, heating at 60 1C
for 24 h. Isolated yield. Determined by 1H NMR analysis of the
d
crude reaction mixture before column separation. 1.5 mL methyl
b
c
acrylate and 0.5 mL H2O.
yield and very low selectivity (entry 13, Table 1). Hence, the
best conditions are shown in entry 7, Table 1.7
To examine the scope of this methodology, a variety of
alkynes and alkenes were investigated to generate the diene
derivatives under the optimum conditions. Representative
results are shown in Table 2. The electron-deficient alkynes
gave good yields of chloro-substituted 1,3-dienes in excellent
stereoselectivities with trans-chloropalladation providing the
major products. The stereochemistry of 3c and 3d was further
confirmed by NOE studies.8 The regiochemistry was controlled
by the electron-withdrawing properties of the substituents
on the triple bond (entries 1–6 and 8–9, Table 2).4,9 For a
non-activated triple bond, the desired 1,3-diene (entry 10,
Table 2) can be obtained in good yield, but with low stereo-
selectivity. It is noteworthy that when acrylonitrile is applied
as olefin source, CN substituted 1,3-diene can be obtained. It is
the structural motif found in a variety of complex bioactive
natural products, such as Araceae, which offers protection
against herbivory and biforines.10
School of Chemistry and Chemical Engineering, South China
University of Technology, Guangzhou, Guangdong, 510640, China.
E-mail: chehjm@scut.edu.cn; Fax: +86 020 8711 0622;
Tel: +86 020 8711 0695
w Electronic supplementary information (ESI) available: General
methods, experimental procedure, spectroscopic data of products.
See DOI: 10.1039/b923464k
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Table 2 Highly regio- and stereoselective intermolecular tandem reaction to synthesize chloro-substituted 1,3-butadienesa
Entry
1
Alkyne
Alkene
Major product
Yielde/%
76
3 : 4f
96 : 4
2
3
4
78
73
53
97 : 3
96 : 4
99 : 1
5
6
41b
98 : 2
98 : 2
63b
7
8
74c
82d
96 : 4
87 : 13
9
62d
83 : 17
52 : 48
10
78d
a
PdCl2 (9 mg, 10 mmol%), CuCl2 (6 equiv., 400 mg) and 2 mL of methyl acrylate, alkynes (0.5 mmol), under N2 in a capped tube, heating at 60 1C
for 24 h. At 70 1C. In 2 mL of toluene. In 2 mL of 1,4-dioxane. Isolated yield. Determined by 1H NMR analysis of the crude reaction
mixture before column separation.
b
c
d
e
f
A
potential mechanism for the intermolecular three-
1,3-butadienes has been successfully achieved by a simple
manipulation. This method is attractive due to its high
atom efficiency, good regio- and stereoselectivity and tolerance
for a range of functional groups. Hence, it is a good alternative
for the synthesis of 1,3-butadienes. An investigation to
increase the scope of this methodology is underway in our
group.
component reaction is depicted in Scheme 1. (E)-Vinylpalladium
intermediate 1 was formed as a major product by trans-
chloropalladation of alkyne in the presence of excess halide
ion,6 followed by a Heck reaction with alkene through a b-H
elimination. Pd(II) was regenerated in the presence of CuCl2
for the next cycle.
In conclusion, a palladium catalyzed intermolecular three-
component coupling of alkyne, CuCl2 and alkene to synthesize
We are grateful to the National Natural Science Foundation
of China (Grant 20972055).
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7 General procedure for the tandem reaction to afford 3a: A mixture
of PdCl2 (8.9 mg, 10 mmol%), CuCl2 (6 equiv., 3 mmol) and 2 mL
methyl acrylate was stirred for 5 min in a capped tube (10 mL) at
room temperature, then methyl 2-nonynoate (87 ml, 0.5 mmol) was
added. The mixture was stirred under N2 at 60 1C for 24 h. The
reaction mixture was extracted with diethyl ether (2 Â 15 mL). The
combined organic layer was washed with water (15 mL), brine
(10 mL) and then dried over anhydrous magnesium sulfate. The
organic solvent was removed on a rotary evaporator under
vacuum. The residue was purified by column chromatography on
silica gel (petroleum ether–ethyl acetate 10 : 1) and 3a was obtained
as a yellow oil (110 mg, 76%).
8 Configuration of products 3c, 3d (2E,4Z) was further confirmed by
1H NMR and NOE studies. NOE studies for 3c:
Scheme 1 The possible reaction mechanism.
Notes and references
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5 During the course of preparing this manuscript, an intramolecular
process to produce 3-chloro-1-methyleneindenes was reported. See:
S. Ye, K. Gao, H. Zhou, X. Yang and J. Wu, Chem. Commun.,
2009, 5406.
6 Trans-chloropalladation of alkyne occurred predominantly in the
presence of excess halide ion, see: (a) Q. Zhang, W. Xu and X. Lu,
J. Org. Chem., 2005, 70, 1505; (b) J. E. Backvall, Y. I. M. Nilsson
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