Regioselective synthesis of 1-bromo-1,4-dienes by free-radical-mediated bromoallylation of activated acetylenes

Article abstract of DOI:10.1021/ol1016096

The free-radical-mediated bromoallylation of acetylenes proceeded efficiently in the presence of V-65 (2,2-azobis(2,4-dimethylvaleronitrile)) as the radical initiator. The regioselective reaction, which yields 1-bromo-2-substituted 1,4-dienes, is complementary to the Pd-catalyzed bromoallylation reaction previously reported by Kaneda. The products of the free-radical-mediated bromoallylation of acetylenes could be converted into a variety of substituted dienes by subsequent Pd-catalyzed reactions.

Full text of DOI:10.1021/ol1016096

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4006-4009
Regioselective Synthesis of 1-Bromo-
1,4-dienes by Free-Radical-Mediated
Bromoallylation of Activated Acetylenes
Takashi Kippo, Takahide Fukuyama, and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture UniVersity,
Sakai, Osaka 599-8531, Japan
ryu@c.s.osakafu-u.ac.jp
Received July 13, 2010
ABSTRACT
The free-radical-mediated bromoallylation of acetylenes proceeded efficiently in the presence of V-65 (2,2-azobis(2,4-dimethylvaleronitrile)) as
the radical initiator. The regioselective reaction, which yields 1-bromo-2-substituted 1,4-dienes, is complementary to the Pd-catalyzed
bromoallylation reaction previously reported by Kaneda. The products of the free-radical-mediated bromoallylation of acetylenes could be
converted into a variety of substituted dienes by subsequent Pd-catalyzed reactions.
Bromoallylation of acetylenes, one of the most basic transforma-
tions, can lead to bromo-substituted 1,4-dienes, which are versatile
synthetic building blocks. In principle the bromoallylation of
terminal acetylenes can give type A and B of 1,4-dienes (eq 1).
Therefore, control of the regiochemistry is essential for the
bromoallylation reaction to be synthetically useful.
of zinc chloride2a and other palladium complexes2b,c as
catalysts and observed that the A dienes were favored in
these reactions. In the reactions that used supported Pd
complexes, such as Pd on diphenylbenzylphosphine-func-
tionalized polymer3 or Pd on Al2O3,4 a mixture of type A
and B 1,4-dienes formed, in which the A dienes were the
major products (>75%). However, the regioselective bro-
moallylation of acetylenes to give type B bromo-dienes has
yet to be achieved. Herein, we report that the free-radical-
mediated bromoallylation of acetylenes with allylbromide
proceeded regioselectivity to give type B 1-bromo-2-
substituted 1,4-dienes in good yields (Scheme 1).5
In 1974, Kaneda and co-workers reported that bis(ben-
zonitrile)palladium dibromide catalyzed bromo-allylation of
terminal acetylenes to selectively yield type A 4-bromo-1.4-
dienes.1 Subsequently, other research groups studied the use
(2) (a) Miller, A.; Moore, M. Tetrahedron Lett. 1980, 577. (b) Ba¨ckvall,
J.-E.; Nilsson, Y. I. M.; Gatti, R. G. P. Organometallics 1995, 14, 4242.
(c) For Pd-catalyzed chloroallylation reaction starting from allyl alcohol,
see: Huang, J.; Zhou, L.; Jiang, H. Angew. Chem., Int. Ed. 2006, 45, 1945.
(3) Kaneda, K.; Uchiyama, T.; Terasawa, M.; Imanaka, T.; Teranishi,
S. Chem. Lett. 1976, 449.
(1) (a) Kaneda, K.; Kawamoto, F.; Fujiwara, Y.; Imanaka, T.; Teranishi,
S. Tetrahedron Lett. 1974, 1067. (b) Kaneda, K.; Kobayashi, H.; Fujiwara,
Y.; Imanaka, T.; Teranishi, S. Tetrahedron Lett. 1975, 2833. (c) Kaneda,
K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.; Teranishi, S. J. Org. Chem.
1979, 44, 55. (d) Imanaka, T.; Kimura, T.; Kaneda, K.; Teranishi, S. J.
Mol. Catal. 1980, 9, 103.
(4) Fukuyama, T.; Kippo, T.; Ryu, I. Res. Chem. Intermed. 2009, 35,
1053.
(5) For the free-radical-mediated iodoallylation of alkynes to give type
A of iodo-1,4-dienes, see: Liu, S. Q.; Wang, S. W.; Qing, F. L. J. Fluorine
Chem. 2005, 126, 771.
10.1021/ol1016096  2010 American Chemical Society
Published on Web 08/16/2010

Scheme 1
.
Bromoallylation of Acetylenes
Table 2. Synthesis of Bromo-1,4-dienes by
Free-Radical-Mediated Bromoallylation of Acetylenesa
We examined the reaction of phenylacetylene (1a) and
allylbromide (2a) as a model system under a variety of radical
reaction conditions. The results are summarized in Table 1.
Table 1. Free-Radical-Mediated Bromoallylation Reaction of
Phenylacetylene (1a) and Allylbromide (2a) in the Presence of
Radical Initiator
entry 2a (mL) initiator (mol %) temp (°C) yielda (%) E/Zb
1
2
3
4
5
1
3
5
5
5
5
5
V-65 (30)
V-65 (30)
V-65 (30)
V-65 (20)
V-65 (10)
AIBN (20)
AIBN (20)
60
60
60
60
60
80
rt
37c
62
80
80
60
78
79
9/91
19/81
13/87
23/77
13/87
15/85
19/81
6
7d
a Isolated yield based on 1. b Determined by 1H NMR of the crude
reaction mixture. c Determined by 1H NMR using anisole as internal
standard. d Under photo irradiation (xenon lamp 300 W, Pyrex).
When a mixture of 1a (1 mmol), 2a (1 mL, 11.5 mmol), and
30 mol % V-65 (2,2-azobis(2,4-dimethyl-valeronitrile); half-
life ) 2 h at 60 °C) was stirred at 60 °C under an argon
atmosphere, the bromoallylated product 3a was obtained in 37%
yield (entry 1). Although the yields were rather low, we were
pleased that the reaction was regioselective for the type B diene,
as the regioisomer was not present in the crude reaction mixture.
When the amount of 2a was increased to 5 mL, the yield of 3a
was increased to 80% (entry 3). Reducing the amount of the
radical initiator to 20 mol % did not affect the yield of 3a (entry
4), whereas when 10 mol % of V-65 was used, a significant
amount of 1a remained unreacted (entry 5). The reaction using
AIBN (2,2-azobisisobutyronitrile; half-life ) 2 h at 80 °C) as
the radical initiator at 80 °C and photoirradiation conditions at
room temperature gave results similar to that obtained with V-65
(entry 6 and 7).
a Conditions: acetylenes 1 (1.0 mmol), allylbromides 2 (5 mL, 58.0
mmol), V-65 (0.2 mmol), 60 °C, 6 h under an argon atmosphere. b Isolated
After we identified the optimal reaction conditions, we
investigated the generality of the free-radical-mediated bro-
moallylation, the results of which are shown in Table 2.
c
1
yield by silica gel chromatography based on 1. Determined by H NMR
of the crude reaction mixture.
Org. Lett., Vol. 12, No. 18, 2010
4007

Scheme 2. Proposed Reaction Mechanism
Scheme 3. Three-Component Processes with the Subsequent
Pd-Catalyzed Reactions
Irrespective of whether the substituents of the aryl acetylenes
were electron-donating or electron-withdrawing, the bromoal-
lylation reaction proceeded well to give the corresponding 1,4-
dienes in good yield. (entries 2-5). The reactions with the Cl-
phenyl-substituted terminal alkynes proceeded smoothly regardless
of the position of the Cl on the ring of the phenyl group (entries
6-8). The reaction of 2,5-dimethoxyphenyl acetylene (1i) with
2a gave 1-bromo-2-(2,5-dimethoxyphenyl)-1,4-pentadiene (3i)
in 90% yield (entry 9). The reactions of the 1- and 2-naphtyl-
substituted acetylenes, 1j and 1k also proceeded well (entries
10 and 11). Interestingly, the reaction of 1j with 2a gave the E
isomer almost exclusively, unlike the other reaction shown in
Table 2 (vide infra).
The reaction also worked well for acetylenes with a
heteroaromatic substituent, such as 1l (entry 12). The reaction
with ethyl propiolate (1m) and with DMAD (dimethyl
acetylenedicarboxylate, 1n) gave the corresponding 1,4-
dienes in 86% and 49% yield, respectively (entries 13 and
14). Aliphatic acetylenes, such as 1-hexyne, gave only traces
of the bromoallylated product (2%). We also examined
several substituted allylic bromides. The reaction using
ꢀ-methallyl bromide (2b) proceeded smoothly to give
1-bromo-1,4-diene 3o in 95% yield (entry 15). In contrast,
no reaction took place with crotyl bromide or prenyl bromide,
presumably due to the steric hindrance caused by the
substitution at the 3-position. Surprisingly, the reaction of
1a with 3-bromo-1-hexene (2c) was unsuccessful. The
reaction did not proceed because of radical-mediated isomer-
ization of 2c to the unreactive crotyl like 2d during the
reaction. This isomerization behavior was confirmed by a
separate experiment (eq 2).
A reaction mechanism for the free-radical-mediated bro-
moallylation of acetylenes is outlined in Scheme 2, which
employs the reaction of 1a with 2a as an example. Tanko
and co-workers recently reported that bromine radicals act
as chain propagators,6 and this mechanism might be operative
even in our system. Thus, thermal decomposition of V-65
generates the initiating radicals, which add to allylbromide
to generate bromo radicals. The bromo radicals then selec-
tively attack the acetylene terminus to form vinyl radicals.
The resulting vinyl radicals react with allylbromide in an
SH2′ manner, which gives 1-bromo-2-phenyl-1,4-diene and
regenerates bromo radicals, thus creating a radical chain.7
In general, Z-forms are preferred because the site of attack
by allylbromide is less hindered.
(6) (a) Tanko, J. M.; Sadeghipour, M. Angew. Chem., Int. Ed. 1999,
38, 159. (b) Struss, J. A.; Sadeghipour, M.; Tanko, J. M. Tetrahedron Lett.
2009, 50, 2119.
(7) A similar mechanism was proposed in radical addition of allylic
sulfones to phenylacetylene; see: Harvey, I. W.; Philips, E. D.; Whitham,
G. H. Tetrahedron 1997, 53, 6493.
4008
Org. Lett., Vol. 12, No. 18, 2010

For the exception 1j, the E-vinyl radical was preferred
due to the steric hindrance caused by bromine and peri-
hydrogen (eq 3).
reaction,12 and the Suzuki-Miyaura coupling reaction,13
respectively.
In conclusion, the free-radical-mediated bromo-allylation
reactions of acetylenes with allylbromides gave regioselective
1-bromo-2-substituted-1,4-dienes. The observed regioselec-
tivity was complementary to that previously reported for
palladium-catalyzed reactions. The bromoallylation procedure
was successfully combined with carbonylation, a Pd-
catalyzed reduction, the Sonogashira reaction, or the
Suzuki-Miyaura coupling reaction to provide a variety of
substituted 1,4-dienes, in a two-step process.
The products 3 that resulted from the present radical
reaction involved terminal vinyl bromide substructures,
which readily undergo Pd-catalyzed reactions (Scheme 3).8,9
Indeed, the carbonylation10 of 3n proceeded smoothly under
10 atm of carbon monoxide to yield the corresponding R,ꢀ-
unsaturated ester 4 in 80% yield. One-pot syntheses of 2-aryl-
1,4-pentadiene (5a, 5b), 2-methyl-6-phenyl-5,8-nonadiene-
3-yn-2-ol (6), and 1-(4-methoxy-phenyl)-2-phenyl-1,4-
pentadiene (7) were successfully achieved via a palladium-
catalyzed, formic acid reduction,11 the Sonogashira
Acknowledgment. This work was supported by the Grant-
in-Aid for Scientific Research on Innovative Areas (No.
2105) from the MEXT.
Supporting Information Available: Experimental pro-
cedure and compound characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
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1988, 29, 5811. (b) Llebaria, A.; Camps, F.; Moreto´, J. M. Tetrahedron
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OL1016096
(11) Clasby, M. C.; Chackalamannil, S.; Czarniecki, M.; Doller, D.;
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4321
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(9) For related one-pot methods, see: (a) Bazin, M.-A.; Jouanne, M.;
El-Kashef, H.; Rault, S. Synlett 2009, 2789. (b) Kuang, C.; Yang, Q.;
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4467.
(10) Silveira, P. B.; Monteiro, A. L. J. Mol. Catal. 2006, 247, 1.
(13) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 3437.
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