Synthesis of 1-bromo-1,4-dienes via palladium-catalyzed bromoallylation of alkynes

Article abstract of DOI:10.1016/j.tetlet.2013.05.084

An efficient procedure for the synthesis of a series of 1-bromo-1,4-dienes by a simple Pd-catalyzed intermolecular tandem reaction of alkynes, CuBr ₂, and allylic alcohol has been developed. The reaction proceeds smoothly under mild condition to give the corresponding products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.05.084

Tetrahedron Letters 54 (2013) 4034–4037
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Tetrahedron Letters
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Synthesis of 1-bromo-1,4-dienes via palladium-catalyzed
bromoallylation of alkynes q
Yanmei Wen a, Huanfeng Jiang b,
⇑
a College of Science, Guangdong Ocean University, Zhanjiang 524088, China
b School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 February 2013
Revised 7 May 2013
Accepted 17 May 2013
Available online 23 May 2013
An efficient procedure for the synthesis of a series of 1-bromo-1,4-dienes by a simple Pd-catalyzed inter-
molecular tandem reaction of alkynes, CuBr2, and allylic alcohol has been developed. The reaction pro-
ceeds smoothly under mild condition to give the corresponding products in good to excellent yields.
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Pd-catalyzed
Bromoallylation
Alkyne
Allylic alcohol
Transition metal-catalyzed reactions have become powerful
tools for the formation of multiple carbon–carbon and carbon–het-
ero bonds in one transformation, and related approaches have at-
tracted tremendous attention over the past decades.1 In
particular, halopalladation reaction of acetylenes has been demon-
strated to be a versatile methodology, owing to its easy access to
highly functionalized haloalkenes in a rather efficient and atom
economical way.2 However, in these reported examples, the halo-
palladation reaction was mainly limited to the addition of allyl ha-
lides as allylating reagents3,9,8a to capture the vinylpalladium
intermediates generated from the halopalladation reaction of al-
kynes. Obviously, the utilization of allyl alcohols as coupling part-
ners in intermolecular tandem reaction of alkynes would be an
appealing approach.
alcohols as coupling partners, whereas, phenylacetylene was intact
under the reaction conditions.
Very recently, a novel stereo-selective bromoalkylation of inter-
nal alkynes and allylic alcohol derivatives has been demonstrated
to prepare the d-bromo c
,d-unsaturated carbonyl compounds.7 In
a subsequent study of the haloallylation of alkynes with allyl
alcohol, we found that alkynes were selectively allylated to give
1-bromo-1,4-dienes. Herein, we wish to report the first synthesis
of 1-bromo-1,4-dienes via palladium-catalyzed cis-bromoallyla-
tion reaction of alkynes and allylic alcohols (Scheme 1).
The reaction of methyl oct-2-ynoate (1a) with prop-2-en-1-ol
(2a) was initially performed in the presence of 5 mol % of PdCl2
and 1.0 equiv of CuBr2 in various solvents (Table 1, entries 1–7).
Apparently, the efficiency of this transformation strongly depends
Although allyl alcohols are readily available starting materials,
palladium-catalyzed reactions of allyl alcohols in allylating or
alkylating reactions have not been well developed.4 In 2006, we
reported a convenient method for the synthesis of 1-chloro-1,4-
dienes through Pd-catalyzed coupling of alkynes with allyl
alcohols, in which the products of trans addition were obtained.5
Zhu’s group6 implemented an example with the bromopalladation
of bromoalkynes as the key step, followed by the addition of allyl
R1
Ref [5]
(a)
Cl
Br
R1
R3
R3
R3
R2
R2
R1
O
OH
R3
Ref [7]
R1
R2
+
(b)
(c)
X
This work.
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
R2
X= Br, Cl
⇑
Corresponding author. Tel./fax: +86 20 87112906.
E-mail address: jianghf@scut.edu.cn (H. Jiang).
Scheme 1. Three halopalladation-initiated reactions of alkynes.
0040-4039/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.084

Y. Wen, H. Jiang / Tetrahedron Letters 54 (2013) 4034–4037
4035
Table 1
Optimization of reaction conditionsa
Br
COOMe
Br
PdCl2/additive
n-C5H11
n-C5H11
COOMe
+
+
OH
25 oC, 12 h
n-C5H11
COOMe
4aa
3aa
1a
2a
Entry
Solvent
Bromide source
Yield of 3aab (%)
1
2
3
4
5
6
PhMe
MeCN
THF
DMF
1,4-Dioxane
1,2-Dichloroethane
DMSO
THF
THF
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
LiBr
40
10
90 (3aa/4aa 97:3)
23
56
34
n.p.
55
n.p.
15
7
8c
9
10d
THF
LiBr/CuBr2
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), PdCl2 (5 mol %), and bromide source (1.0 equiv) in 2 mL THF at room temperature for 12 h.
Determined by GC.
0.5 equiv CuBr2.
2.0 equiv LiBr, CuBr2 (10 mol %). n.p. = no desired product.
b
c
d
Table 2
Pd-catalyzed allylation of alkynes 1 with allyl alcohols 2a
Br
R2
5 mol %PdCl2
Br
OH
R3
1.0 equiv. CuBr2
+
R1
R3
R2
R1
+
R3
R1
THF
R2
25 oC, 12 h
4
1
3
2
Entry
1
Alkynes
Ally alcohol
Major product
3:4b (cis-add/trans-add)
Yield of pure 3c (%)
n-C5H11
COOMe
COOMe
COOMe
OH
Br
97:3
87
n-C5H11
COOMe
3aa
n-C5H11
n-C5H11
OH
Br
2
3
n-C5H11
93:7
84
76
MeOOC
Br
3ab
OH
n-C5H11
n-C5H11
n-C5H11
90:10
COOMe
3ac
n-C5H11
COOMe
COOMe
OH
Et
Br
Br
n-C5H11
Et
4
92:8
85
72
COOMe
COOMe
3ad
n-C5H11
OH
OH
n-C5H11
5
6
85:15
85:15
3ae
COOMe
Br
75
COOMe
3ba
(continued on next page)

4036
Y. Wen, H. Jiang / Tetrahedron Letters 54 (2013) 4034–4037
Table 2 (continued)
Entry
Alkynes
Ally alcohol
Major product
3:4b (cis-add/trans-add)
Yield of pure 3c (%)
COOEt
OH
Br
7
98:2
78
COOEt
Br
3ca
OH
COOEt
F
F
8
9
91:9
73
70
COOEt
3da
OH
Br
Cl
Cl
Cl
88:12
Cl
3ea
n-C5H11
COOMe
OH
OH
Cl
10d
11
97:3
95:5
90
83
n-C5H11
COOMe
3aa'
Br
3fa
OH
OH
Br
12
13
70:30
90:10
62
78
F
F
3ga
Br
O
O
3ha
OH
OH
Br
14
15
87:13
75:25
77
60
Et
Et
3ia
Br
O2N
O2N
3ja
Br
OH
OH
16
80:20
64
n-Pr
n-Pr
3ka
Cl
Cl
Br
17
18
96:4
92:8
83
80
3la
OH
Br
n-C5H11
n-C5H11
3ma
a
b
c
Reaction conditions: (1) (1.0 mmol), (2) (1.0 mmol), PdCl2 (5 mol %), and CuBr2 (1.0 equiv) in 2 mL THF at room temperature for 12 h.
Ratio of isomer was determined by GC.
Isolated yields.
1.0 equiv CuCl2ꢀ2H2O instead of CuBr2.
d
on the solvent used, and the reaction proceeds smoothly in THF. At
room temperature, the reaction afforded the product in 90% yield
with good cis-add/trans-add selectivity (Table 1, entry 3). When
0.5 equiv of CuBr2 was used in this reaction, a lower yield was ob-
tained (Table 1, entry 8). Efforts to further optimize the reaction
conditions revealed that CuBr2 was the best bromide source for

Y. Wen, H. Jiang / Tetrahedron Letters 54 (2013) 4034–4037
4037
Br
presence of excess halide ions.5 Then, the following carbopallada-
tion reaction of vinylpalladium intermediate A with allyl alcohol
2 resulted in an alkylpalladium complex B.10 Finally, the b-OH elim-
ination furnished the product 3 and regenerated PdCl2 in the pres-
ence of CuBr2.
In conclusion, we have discovered a novel bromoallylation reac-
tion of alkynes using allylic alcohols as alkylating agents. This reac-
tion proceeds via cis-bromopalladation and sequential insertions of
allylic alcohols. The reactions are operationally simple, and can tol-
erate a broad range of functional groups. Hence, it is an alternative
method for the synthesis of 1-bromo-1,4-dienes.
R1
R2
Y
Pd(II)
3
R1
Y
CuBr2
Br
Y = H, EWG
1
CuBr2
OH
R2
R1
Y
PdCl
B
Acknowledgments
Br
PdCl
R1
We thank the National Natural Science Foundation of China
(21172076), and Guangdong Ocean University for financial
support.
A
Y
OH
R2
2
Supplementary data
Scheme 2. Proposed mechanism.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.
084.
this reaction. When LiBr was used as the bromide source, no prod-
uct was obtained (Table 1, entry 9). When the amount of CuBr2 was
decreased to 10 mol %, only 15% of the expected product 3aa was
detected (Table 1, entry 10). Therefore, the optimized condition
for the haloallylation reaction of alkynes was as follows: 5 mol %
of PdCl2 as the catalyst, 1.0 equiv of CuBr2 as the bromide source,
and THF as the solvent.
References and notes
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With the optimized reaction conditions in hand (Table 1, entry 3),
we proceed to examine the scope of the alkynes and allylic alcohols
in this bromopalladation/allylation protocol. Representative results
are summarized in Table 2. Firstly, we decided to employ a series of
allyl alcohols 2 in this transformation. When primary, secondary,
and tertiary allyl alcohols were utilized under the optimal condi-
tions, the desired products were obtained (3aa, 3ab, 3ac, 3ad, and
3ae) in good to excellent yields. Unfortunately aromatic allyl alco-
hols such as 1-phenylprop-2-en-1-ol, did not obtain the desired
products. The scope of the palladium-catalyzed bromoallylation of
alkynes leading to 1-bromo-1,4-dienes was further expanded to a
range of alkynes 1. To our delight, not only aliphatic alkynoates
but also aromatic alkynoates afford good yields of the desired prod-
uct (3aa, 3ba, 3ca, and 3da). Subsequently, a comparative reaction
with CuCl2ꢀ2H2O instead of CuBr2 gave the desired 1,4-diene product
to achieve comparable yield (3aa0). Inspired by these results, we be-
came interested in further expanding the substrate scope of this
methodology to alkynes 1. It is noteworthy that the standard condi-
tions were compatible with the terminal acetylenes, and the elec-
tronic properties of the substituents on the benzene ring do not
have significant influence on the reaction efficiency (3fa, 3ga, 3ha,
3ia, 3ja, 3ka, 3la, and 3ma). However, when terminal aliphatic al-
kyne such as 1-octyne was employed in this transformation, a mix-
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The stereochemistry of 3ma was confirmed by NMR and NOESY
methods. NOE enhancements were observed between the olefin
proton on C2 and protons of the benzene ring of 3ma indicating a
cis-relationship between these substituents (see Supporting infor-
mation). The regioselectivity of 3aa was confirmed by NOESY
methods also, which indicated no-relationship between methyl-
enes on C3 and other methylenes. This result provided an addi-
tional proof for the proposed cis-halopalladation of the alkyne in
Scheme 2.
A plausible mechanism for the allylation of alkynes in THF cata-
lyzed by PdCl2 is shown in Scheme 2. Vinylpalladium intermediate
A is initially formed by cis-halopalladation of the alkyne 1 in THF8,9
instead of trans-halopalladation in aqueous media system in the
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