Bromine radical-mediated sequential radical rearrangement and addition reaction of alkylidenecyclopropanes

Article abstract of DOI:10.1021/ja311821h

Bromine radical-mediated cyclopropylcarbinyl-homoallyl rearrangement of alkylidenecyclopropanes was effectively accomplished by C-C bond formation with allylic bromides, which led to the syntheses of 2-bromo-1,6-dienes. A three-component coupling reaction

Full text of DOI:10.1021/ja311821h

Communication
pubs.acs.org/JACS
Bromine Radical-Mediated Sequential Radical Rearrangement and
Addition Reaction of Alkylidenecyclopropanes
Takashi Kippo, Kanako Hamaoka, and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
S
* Supporting Information
substituted 1,6-dienes 3 via radical bromoallylation of
ABSTRACT: Bromine radical-mediated cyclopropylcar-
binyl-homoallyl rearrangement of alkylidenecyclopropanes
was effectively accomplished by C−C bond formation with
allylic bromides, which led to the syntheses of 2-bromo-
1,6-dienes. A three-component coupling reaction compris-
ing alkylidenecyclopropanes, allylic bromides, and carbon
monoxide also proceeded well to give 2-bromo-1,7-dien-5-
ones in good yield.
alkylidenecyclopropanes 1 with allylic bromides 2. We also
report that alkylidenecyclopropanes 1 undergo sequential
addition to carbon monoxide and allylic bromides 2 to give
2-bromo-1,7-dien-5-ones 4 in good yield, representing the first
bromine radical-mediated carbonylation reaction.9,10
Initially, (1-butylpentylidene)cyclopropane (1a) and ethyl 2-
(bromomethyl)acrylate (2a) were chosen to test the feasibility
of our hypothesis. When a benzene (1.0 mL) solution of 1a
(1.0 mmol), 2a (1.8 mmol), and V-70 (2,2′-azobis(4-methoxy-
2,4-dimethylvaleronitrile)), 0.1 mmol) was stirred for 2 h at 40
°C under an argon atmosphere, ethyl 6-bromo-7-butyl-2-
methylene-6-undecenoate (3a) was obtained in 30% yield
(Table 1, entry 1). Since the ring-opening products from the
lkylidenecyclopropanes are useful building blocks in
1
2
Aorganic synthesis and are found in bioactive compounds.
Based on their high reactivity derived from ring strain, the ring-
opening reactions of alkylidenecyclopropanes by transition
metal catalysts have been pursued vigorously. However, in
contrast the utilization of alkylidenecyclopropanes in radical
C−C bond forming reactions has received much less
attention.1i,3−5 Inspired by the work of Tanko and co-workers,6
we have previously developed the radical bromoallylation of
alkynes7 and allenes8 affording 1-bromo-substituted 1,4- and 2-
bromo-substituted 1,5-dienes respectively, in which the
bromine radical serves as a chain propagator6 and the source
of the vinyl bromide moiety in the products. In the hope of
extending radical-mediated diene synthesis further, we believed
that 2-bromo-substituted 1,6-dienes would be obtained by the
reaction of alkylidenecyclopropanes and allylic bromides in the
presence of a radical initiator, via regioselective bromine radical
addition so as to form cyclopropylcarbinyl radicals with their
resulting ring opening leading to homoallyl radicals (Scheme
1).3h Herein we report an efficient synthesis of 2-bromo-
Table 1. Optimization of Reaction Conditions Using (1-
Butylpentylidene)cyclopropane (1a) and Ethyl 2-
a
(Bromomethyl)acrylate (2a)
b
entry
initiator (mol %)
Na3PO4 (equiv)
temp (°C)
yield (%)
1
2
3
4
5
6
V-70, 10
V-70, 10
V-65, 10
AIBN, 10
V-65, 30
AIBN, 30
−
40
40
60
80
60
80
30
c
0.2
0.2
0.2
3.0
3.0
74
38
30
63
54
a
Conditions: 1a (1.0 mmol), 2a (1.8 equiv), V-70 (2,2′-azobis(4-
methoxy-2,4-dimethylvaleronitrile)) or V-65 (2,2′-azobis(2,4-dime-
thylvaleronitrile)) or AIBN (2,2′-azobisisobutyronitrile), Na3PO4,
degassed C6H6 (1.0 mL) under an argon atmosphere. NMR yield
b
Scheme 1. Bromoallylation and Carbonylative
Bromoallylation of Alkylidenecyclopropanes 1
c
using anisole as an internal standard. Isolated yield by column
chromatography on SiO2 and preparative HPLC.
reaction of 1a with hydrogen bromide were observed as
byproducts, we added anhydrous trisodium phosphate as an
HBr scavenger, which improved the yield of 1,6-diene 3a up to
74% (entry 2). Maintaining the reaction temperature at 40 °C
or lower is very important to obtain a good yield of 3a, since, at
temperatures such as 60 and 80 °C, the isomerization of 1a
becomes serious (entries 3 and 4). The use of increased
amounts of base improved the yields of 3a (entries 5 and 6) but
no better than that obtained by the reaction at 40 °C.
Received: December 4, 2012
Published: December 26, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
With the optimized reaction conditions for 1 (Table 1, entry
2) in hand, we examined the generality of the present allylative
ring-opening reaction for a wide range of alkylidenecyclopro-
panes 1 and allylic bromides 2 (Table 2). Cyclopropylidene-
cycloheptane (1b) produced the desired 2-bromo-substituted
1,6-diene 3b in 86% yield (entry 2). Similarly, 4-cyclo-
propylidenetetrahydropyran (1c) reacted with 2a to give 3c
in 87% yield (entry 3). The reaction of sterically hindered
adamantylidenecyclopropane 1d also proceeded well to give 3d
in 97% yield (entry 4). Some other allylic bromides such as α-
bromomethylacrylonitrile (2b), α-bromomethylstyrene (2c),
allyl bromide (2d) were also tested, all of which worked well.
For example, the bromoallylation reaction of 1d with 2b gave
the expected diene 3e in 89% yield (entry 5). Since 2-phenyl-
substituted allyl bromide 2c exhibited modest reactivity, we
used 3 equiv of 2c to increase the yield of the addition product
3f (entry 6). In the case of allyl bromide (2d), the use of a large
excess of 2d compensated for the lack of reactivity toward
nucleophilic alkyl radicals (entry 7).11 Monosubstituted
alkylidenecyclopropanes 1e, 1f, and 1g gave the corresponding
products, 3h, 3i, and 3j, in high yields, all of which were
obtained as E/Z mixtures favoring the Z isomer (entries 8−10).
Phenyl-functionalized methylenecyclopropane 1h gave 2-
bromo-4-phenyl-1,6-dienes 3k as a sole product (entry 11),
which originated from the more stable benzylic radical.
Table 2. Generality of the Reaction of
Alkylidenecyclopropanes and Allylic Bromides To Give 2-
a
Bromo-1,6-dienes
Since the ring-opening reaction generates homoallylic
radicals, we believed that these radicals could trap CO. Indeed,
the three-component coupling reaction comprising alkylidene-
cyclopropanes 1, CO, and 2a worked well to give good yields of
2-bromine-substituted 1,7-dien-5-ones 4 (Table 3). For
a
Table 3. Radical Carbonylation Reaction of 1 with 2a
a
Conditions: 1 (0.5 mmol), 2a (1.0 mmol), V-65 (0.25 mmol),
Na3PO4 (0.1 mmol), CO (80 atm), C6H6 (20 mL), 60 °C, 6 h under
an argon atmosphere.
instance, treatment of a benzene solution of (1-
butylpentylidene)cyclopropane (1a), ethyl 2-(bromomethyl)-
acrylate (2a), anhydrous trisodium phosphate, and V-65 with
80 atm of CO at 60 °C for 6 h resulted in the synthesis of ethyl
7-bromo-8-butyl-2-methylene-4-oxo-7-dodecenoate (4a) in
72% yield after purification by column chromatography on
SiO2.
A proposed reaction mechanism for the present bromoally-
lation and the carbonylative bromoallylation of alkylidenecy-
clopropanes is shown in Scheme 2. Initially, a bromine radical is
generated from allylic bromide 2 through a radical initiation
process. Then the bromine radical adds to the central carbon of
alkylidenecyclopropane 1 to give cyclopropylmethyl radical A,
which undergoes rearrangement leading to homoallyl radical
B.12 The homoallyl radical B adds to CO to form acyl radical D.
D then adds to 2 to produce intermediate E, which undergoes
β-fission to give 2-bromo-substituted 1,7-dien-5-one 4 and a
bromine radical. In the absence of CO, the path to give
intermediate C operates to sustain the radical chain.
a
Conditions: 1 (1.0 mmol), 2 (1.8 mmol), V-70 (0.1 mmol), Na3PO4
(0.2 mmol), C6H6 (1.0 mL), 40 °C, 2 h under an argon atmosphere.
b
c
See Supporting Information for details. Isolated yield. 50 °C, 6 h.
d
e
2c (3.0 equiv), 6 h. 2d (58 equiv), 6 h, neat.
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Journal of the American Chemical Society
Communication
Scheme 2. Radical Chain Reaction Mechanisms
ACKNOWLEDGMENTS
■
This work has been supported by a Grant-in-Aid for Scientific
Research on Innovative Areas (No. 2105) from the MEXT.
T.K. acknowledges the Research Fellowship of the Japan
Society for the Promotion of Science for Young Scientists.
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synthesis of 2-bromo-1,6-dienes from alkylidenecyclopropanes
and allylic bromides via radical ring-opening and SH2′ reactions.
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incorporated in the reaction sequence, leading to 2-bromo-1,7-
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedure and compound characterization. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
ryu@c.s.osakafu-u.ac.jp
■
Notes
The authors declare no competing financial interest.
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