Benzyl radical addition reaction through the homolytic cleavage of a benzylic C-H bond

Article abstract of DOI:10.1039/c0ob01148g

Direct generation of a benzyl radical by C-H bond activation of toluenes and the addition reaction of the resulting radical to an electron deficient olefin were developed. The reaction of dimethyl fumarate with toluene in the presence of Et₃B as a radical initiator at reflux afforded 2-benzylsuccinic acid dimethyl ester in good yield.

Full text of DOI:10.1039/c0ob01148g

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Benzyl radical addition reaction through the homolytic cleavage of a benzylic
C–H bond†‡
Masafumi Ueda, Eiko Kondoh, Yuta Ito, Hiroko Shono, Maiko Kakiuchi, Yuki Ichii,
Takahiro Kimura, Tetsuya Miyoshi, Takeaki Naito and Okiko Miyata*
Received 10th December 2010, Accepted 25th January 2011
DOI: 10.1039/c0ob01148g
Direct generation of a benzyl radical by C–H bond activation
of toluenes and the addition reaction of the resulting radical
to an electron deficient olefin were developed. The reaction
of dimethyl fumarate with toluene in the presence of Et3B
as a radical initiator at reflux afforded 2-benzylsuccinic acid
dimethyl ester in good yield.
atom to generate stable benzyl radical derivatives, which can be
used for the addition reaction. Although various strategies have
been developed for the generation of a carbon radical center, C–
H bond activation is a particularly promising and economically
attractive method for the direct generation of a carbon radical.5–9
Albini and co-workers have reported the generation of a benzyl
radical from toluene by photosensitization; however, the addition
reaction afforded a mixture of many products.10 Herein, we report
a novel approach for the generation of a benzyl radical and the
addition reaction to an electron deficient olefin in connection with
our recent efforts in radical chemistry.11
For our initial optimization studies, dimethyl fumarate 4 as a
radical acceptor and toluene as benzyl radical source and solvent
were selected (Table 1). When the radical reaction was carried out
with 2 equiv. of Et3B in toluene (concentration 0.05 M) at room
temperature, the dimethyl fumarate 4 was rapidly consumed but no
isolable products were afforded, probably due to the slow hydrogen
abstraction which led to the polymerization of an intermediate
radical (entry 1). The reaction was run at reflux to improve the
efficiency of hydrogen abstraction from toluene by an a-carbonyl
radical. The desired benzyl adduct 5a was obtained as expected,
albeit in 41% yield (entry 2). Upon decreasing the concentration
to 0.025 M and the amount of Et3B to 1 equiv., the yield increased
to 53% (entry 4). The reaction in the absence of Et3B proceeded
very slowly to give 5a in low yield (entry 6). This result indicates
that Et3B plays an important role at the radical initiation step. The
Free radical reactions represent one of the most straightforward
tools for carbon–carbon bond formation in organic synthesis.1,2
Consequently, extensive studies have been demonstrated for ob-
taining novel radical reactions. Among them, the radical reaction
mediated by triethylborane, which is recognized as an excellent
radical initiator, mediator and terminator, has recently led to many
novel and useful synthetic applications.3 However, Et3B-mediated
radical addition to a,b-unsaturated ester 1 generally does not give
the corresponding adduct 3 in the absence of a hydrogen donor
such as tributyltin hydride (Scheme 1).3a,4
Table 1 Benzyl radical addition to dimethyl fumarate 4
Scheme 1 Triethylborane-mediated radical addition to a a,b-unsaturated
ester.
This drawback is attributed to the observation that the interme-
diate enoxy radical A generated by the 1,4-radical addition cannot
be trapped by Et3B. Therefore, Et3B does not function as a radical
terminator. We postulated that the enoxy radical A and the a-
carbonyl radical B have the ability to extract a benzylic hydrogen
Entry
Concentration (M)
Et3B (equiv.)
Temp.
Yield (%)a
1
2
3
4
5
6
7
0.05
0.05
0.025
0.025
0.025
0.025
0.01
2
2
2
1
rt
—
41
48
53
reflux
reflux
reflux
reflux
reflux
reflux
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe, 658-
8558, Japan. E-mail: miyata@kobepharma-u.ac.jp; Fax: +81-78-441-7556
† This work is dedicated to the memory of Athel Beckwith, a teacher and
scientist from whom we learned how to study chemistry by example. His
pioneering advances in radical chemistry laid the foundation for much of
the current radical clock methodology.
0.5
none
1
48
8 (83)b
74
a Isolated yield. b Yield in parentheses is for the recovered starting material
4.
‡ Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/c0ob01148g
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Table 2 Radical addition to dimethyl fumarate with various toluene
derivatives
Entry
R1
R2
Product
Yield (%)a
1b
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Bn
Me
4-OMe
3-OMe
2-OMe
3,4-di-OMe
4-Me
3-Me
2-Me
4-Cl
4-Br
4-F
4-I
3-Cl
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
88
77
77
39
68
52
19
63
66
36
30
57
43
64
2c
3c
4c
Scheme 2 Competition experiment.
5b
6b
reaction with an equimolar mixture of 4-methoxytoluene and
4-chlorotoluene, the 4-methoxybenzyl radical exhibited higher
reactivity in the formation of 5b. This indicated that the methoxy
group as an electron donating group increased the SOMO energy
level of the nucleophilic benzyl radical; thus, interaction of the
LUMO of the olefin with the SOMO of the benzyl radical would
be enhanced.
7c
8d
9d
10d
11d
12d
13c
14d
15b
16e
2-Cl
4-CO2Me
H
65 (6 : 1)d
28 (1 : 1)d
We have also extended the acceptor tolerance to 1,2-dicyano-
and 1,2-diketo olefins (Scheme 3). Fumaronitrile 6 showed
excellent reactivity giving the desired product 7 in quantita-
tive yield. 1,2-Diketone 8 was also found to react with 4-
methoxytoluene to afford the adduct 9, albeit in relatively lower
yield due to the competition with the ethyl radical addition
reaction.
H
a Isolated yield. b Reactions carried out with 0.3 equiv. of Et3B. c Reactions
carried out with 0.9 equiv. of Et3B. d Ratio was determined by 1H NMR.
The relative stereoconfiguration was not determined. e Reactions carried
out with 0.6 equiv. of Et3B.
best result was obtained when the concentration was 0.01 M with 1
equiv. of Et3B (entry 7). The product, 2-benzylsuccinate, represents
an important compound because of its utility as an intermediate
in the synthesis of biologically active compounds and functional
materials.12 Although several synthetic methods including multi-
step processes have been reported,13 the direct introduction of
the benzyl group to fumarate has been less frequently reported.14
Thus, our direct benzylation reaction is characterized as atom
economical, straightforward and a valuable reaction.
To examine the scope of this direct benzylation, various toluene
derivatives were subjected to the radical reaction (Table 2). We were
pleased to observe that electron rich or poor toluene derivatives
were readily accommodated, producing the expected adducts 5b–
o. It should be noted that the reaction proceeded with even less
than 1 equivalent of Et3B, owingto the higher reaction temperature
employed. Reactions of 2-, 3- and 4-methoxytoluenes proceeded
effectively with good yields (entries 1–3), while a lower yield was
observed in the reaction with 3,4-dimethoxytoluene (entry 4). p-
and m-Xylene were also suitable reagents to use; however, o-xylene
gave a low yield of product 5h because of its steric properties
(entries 5–7). A halogen and an ester substituent showed tolerance
towards this radical reaction (entries 8–14). Notably, the bromo
and the iodo groups, which did not affect the course of the reaction,
could serve as a handle for further transformations. Interestingly,
the addition of dibenzyl produced the adduct 5p in 68% yield with
a 6 : 1 mixture of stereoisomers, although a reduced yield of 5q
and no stereoselectivity were observed with ethylbenzene (entries
15 and 16).
Scheme 3 4-Methoxybenzyl radical addition to the electron deficient
olefins.
A possible reaction pathway is presented in Scheme 4. The
first step involves the generation of an ethoxy radical and an
ethylperoxy radical by the oxidative decomposition of Et3B with
molecular oxygen. The radicals then abstract a hydrogen atom
from the toluene derivatives to produce a benzyl radical C. The
benzyl radical can add to fumarate to form the a-carbonyl radical
D. The trapping of the radical D by toluene derivatives gave
product 5 and the regeneration of the benzyl radical which is
used for the radical chain cycle.
In conclusion, we have demonstrated the direct generation of
a benzyl radical by C–H bond activation of toluenes and the
addition reaction of the resulting radical to an electron deficient
olefin.
Acknowledgements
A competition experiment was conducted to study the influence
of the electronic nature of the benzyl radical on reactivity towards
the electron deficient olefin (Scheme 2). As a result of the
This work was supported in part by Grants-in Aid from the
Ministry of Education, Culture, Sports, Science and Technology
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