A bromine-radical mediated three-component reaction comprising allenes, electron-deficient alkenes and allyl bromides: Facile synthesis of 2-bromo-1,7-dienes

Article abstract of DOI:10.1039/c4cc01597e

A bromine-radical mediated three-component coupling reaction was effectively achieved by the use of allenes, electron-deficient alkenes, and allyl bromides and led to the synthesis of 2-bromo-1,7-dienes in good to high yields. This protocol was extended to the three-component process using alkylidenecyclopropane, which gave 2-bromo-1,8-diene along with alkylidenecyclopentane. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01597e

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A bromine-radical mediated three-component
reaction comprising allenes, electron-deficient
alkenes and allyl bromides: facile synthesis of
2-bromo-1,7-dienes†
Cite this: Chem. Commun., 2014,
50, 5993
Received 3rd March 2014,
Accepted 16th April 2014
Takashi Kippo and Ilhyong Ryu*
DOI: 10.1039/c4cc01597e
www.rsc.org/chemcomm
A bromine-radical mediated three-component coupling reaction
was effectively achieved by the use of allenes, electron-deficient
alkenes, and allyl bromides and led to the synthesis of 2-bromo-1,7-
dienes in good to high yields. This protocol was extended to the three-
component process using alkylidenecyclopropane, which gave
2-bromo-1,8-diene along with alkylidenecyclopentane.
Dienes are ubiquitous in nature but also useful as building blocks in
organic synthesis. Recently, we reported radical bromoallylation of
alkynes, allenes and alkylidenecyclopropanes, which led to bromo-
substituted 1,4-, 1,5-, and 1,6-dienes, respectively.1 In these reactions,
the bromine radical serves as a radical chain carrier2–4 that is
incorporated into product dienes as a vinyl bromide moiety, which
Scheme 1 A three-component radical strategy for the synthesis of 1,7-dienes.
can be further functionalized by cross-coupling reactions and radical In this reaction, a small amount of 5-bromo-6-butyl-2-methyl-
reactions. To extend the bromoallylation strategy to the synthesis of 1,5-decadiene was formed as a byproduct, which originated
1,7-dienes, a three-component process comprising allenes, alkenes from 1a and 3a.
and allyl bromides seems attractive (Scheme 1). Key allyl radicals are
expected to gravitate to the more electron-poor alkenes rather than
allyl bromides, which would lead the reaction in a given sequence.5
For a related three-component reaction leading to 1,7-dienes, to
our knowledge, only one example is known. In 1988, Mizuno,
Otsuji and coworkers reported the synthesis of 1,7-dienes by
a radical three-component reaction comprising allyl iodide,
benzylidenemalononitrile, and allyltributyltin.6,7 Herein we report
a novel three-component coupling reaction, which can provide
access to a wide variety of 2-bromo-1,7-dienes.
(1)
Under an Ar atmosphere, a benzene solution containing
3-butyl-1,2-heptadiene (1a, 1.0 M), acrylonitrile (2a, 1.8 equiv.),
Next, we examined the generality of the present three-component
b-methallyl bromide (3a, 1.8 equiv.) and AIBN (2,20-azobis- coupling reaction for a variety of allenes 1, electron-deficient alkenes
isobutylonitrile, 20 mol%) was heated at 80 1C for 4 hours. 2 and allyl bromides 3 (Table 1). Ethyl acrylate (2b) and methyl vinyl
After silica gel chromatography, 5-bromo-6-butyl-2-(2-methallyl)- ketone (2c) exhibited modest reactivity in a reaction with 1a and 3a,
5-decenenitrile (4a) was obtained in a 79% yield (eqn (1)). and as a result, four equivalents of 2b and 2c were used to obtain
good yields of products 4b and 4c (entries 2 and 3). Other electron-
deficient alkenes, such as diethyl 2-methylenemalonate (2d), acrolein
(2e) and benzylidenemalononitrile (2f), were all reactive enough
with 1.8 equiv., giving the corresponding 2-bromo-1,7-dienes 4d–e
Department of Chemistry, Graduate School of Science, Osaka Prefecture University,
Sakai, Osaka 599-8531, Japan. E-mail: ryu@c.s.osakafu-u.ac.jp;
Fax: +81-72-254-9695
and 4k in excellent yields (entries 4, 5 and 11). Other allyl bromides
such as a-bromomethylstyrene (3b), 3-bromo-2-chloropropene (3c),
† Electronic supplementary information (ESI) available: Experimental section
and spectroscopic data. See DOI: 10.1039/c4cc01597e
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Table 1 Substrate scope of three-component reactiona
Entry
1
1
2
3
4
Yieldb (%)
79
2c
3c
4
1a
1a
1a
1a
3a
3a
3a
3a
57
72
76
78
5
6
7
1a
1a
2d
2d
84
56
8
1a
1a
2e
83
9d
2d
2d
83
88
10
3a
3a
82
11
12
E/Z = 14/86e
82
2d
3a
E/Z = 28/72e
13
2d
2d
3a
3a
80
60
14
a
b
Conditions: 1 (1.0 mmol), 2 (1.8 mmol), 3 (1.8 mmol), AIBN (0.2 mmol), C6H6 (1.0 mL) 80 1C, 4 h under an argon atmosphere. Isolated yield after
flash column chromatography on SiO2 and preparative HPLC. 2b or 2c (4.0 equiv.). 3e (10.0 equiv.). E/Z ratio was determined by 1H-NMR
c
d
e
analysis of the crude reaction mixture.
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2,3-dibromopropene (3d) and allyl bromide (3e) also worked well. cross-coupling reaction of 4a with 4-methoxyphenylboronic
For instance, 3b reacted with 1a and 2d to give the expected three- acid,10 which worked quite well to give diene 5 in a 96% yield
component coupling product 4f in an 84% yield (entry 6). The (eqn (2)).
reaction of 3-bromo-2-chloropropene (3c) with 1a and 2d gave 4g
in a modest yield (entry 7). The reaction of 2,3-dibromopropene
(3d) with 1a and 2e also proceeded well to give 4h in an 83% yield
(entry 8). In these cases, two types of carbon–halogen bonds were
incorporated into the product structure. The reactivity of simple
allyl bromide (3e) was quite low,8 however, the reaction of
10 equivalents of 3e with allene 1a gave the desired 1,7-diene 4i
in an 83% yield (entry 9). A wide variety of allenes can participate
in the present three-component coupling reaction. Vinylidene-
cyclohexane (1b) afforded an 88% yield of 1,7-diene 4j (entry 10).
1,2-Nonadiene (2c) reacted with 2f and 3a efficiently to give 4k in
an 82% yield. Cyclohexylallene (1d) underwent a three-component
(2)
coupling reaction with 2d and 3a to give 4l in an 82% yield.
We then thought that if alkylidenecyclopropane 6 was used as a
Products 4k and 4l were obtained as E/Z mixtures favoring the Z
substrate, a similar three-component coupling reaction with acrylo-
isomer (entries 11 and 12). The reaction of 1,2-cyclononadiene
nitrile (2a) and b-methallyl bromide (3a) would give 2-bromo-1,8-
(1e) also worked well to produce the corresponding product 4m
diene 7. Indeed, when a solution of 6-undecanylidenecyclopropane
in an 80% yield (entry 13). The reaction of 1,1,3-trisubstituted
(6), acrylonitrile (2a) and b-methallyl bromide (3a) and Na3PO4 with
allene 1f with 2d and 3a also proceeded well to give 1,7-diene 4n
V-70 (2,20-azobis(4-methoxy-2,4-dimethylvaleronitrile)) was heated at
(entry 14).
40 1C for 6 h, 1,8-diene 7 was obtained in a 44% yield together with a
The polarity-matched radical chain mechanism can account
19% yield of methylenecyclopentane 8, which is derived from 6 and
for the present three-component coupling reaction, which is
2a (Scheme 3). This result can be explained by the initial formation
illustrated in Scheme 2. Initially, the cyanopropyl radical
of a cyclopropylcarbinyl radical by the regioselective addition of a
formed by the thermal decomposition of AIBN adds to allyl
bromine radical to alkylidenecyclopropane and its rapid ring-
bromide 3 to generate a bromine radical, which attacks the
opening to give a homoallyl radical,11 which then underwent con-
central carbon of allene 1 to give an allyl radical A.9 Allyl radical
secutive additions to 2a and 3a. b-Fission of the resultant radical Y
A, with a nucleophilic character, first reacts with electron-
produced 2-bromo-1,8-diene 7 and the bromine radical (path a). On
deficient alkene 2, which leads to electrophilic radical B. Then,
the other hand, radical X can also undergo 5-exo cyclization/b-fission
radical B adds to the relatively electron-rich allyl bromide 3
to give methylenecyclopentane 8 (path b).12
to produce intermediate radical C, which follows b-fission to
give 2-bromo-1,7-diene 4 and regenerate the bromine radical,
sustaining the chain.
Since all these 1,7-dienes have a vinyl bromide moiety,
conversion to dienes having a tetra-substituted C–C double
bond is feasible. For instance, we examined a Suzuki–Miyaura
Scheme 3 Bromine radical-mediated three-component process leading
Scheme 2 Polarity-matched radical reaction mechanism.
to 1,8-diene.
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In conclusion, we have developed a general, concise, one-pot
method to access 2-bromo-substituted 1,7-dienes by a radical
three-component reaction between allenes, electron-deficient
alkenes and allyl bromides. Alkylidenecyclopropanes can also
be employed in this reaction, which lead to 2-bromo-substituted
1,8-dienes. Thus, bromine-radical mediated C–C bond forming
reactions permit the design of multi-component processes based
on polarity-matching and can provide useful synthetic access to
tetrasubstituted and functionalized alkenes.
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We gratefully acknowledge a Grant-in-Aid for Scientific
Research from the MEXT for financial support. TK acknowl-
edges the Research Fellowship of the Japan Society for the
Promotion of Science for Young Scientists.
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5996 | Chem. Commun., 2014, 50, 5993--5996
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