Novel radical alkylation of carboxylic imides

Article abstract of DOI:10.1021/ja028396x

Although alkylation is one of the most important and fundamental organic reactions, radical-mediated alkylations of carboxylic acid derivatives have not been well studied. The first successful radical alkylation of carboxylic imides is achieved by the add

Full text of DOI:10.1021/ja028396x

Published on Web 11/06/2002
Novel Radical Alkylation of Carboxylic Imides
Sunggak Kim,* Chae Jo Lim, Changsik Song, and Won-jin Chung
Center for Molecular Design & Synthesis and Department of Chemistry, School of Molecular Science,
Korea AdVanced Institute of Science and Technology, Taejon 305-701, Korea
Received September 4, 2002
Scheme 1
Alkylation is one of the most important and fundamental organic
reactions for the formation of carbon-carbon bonds and is routinely
performed with metal enolates and alkylating agents.1 Despite
extensive studies of radical reactions during the last two decades,2
radical-mediated alkylations of carboxylic acid derivatives have not
been well studied.3,4
To develop a novel approach for the alkylation of carboxylic
acid derivatives, we designed a new type of carboxylic amide
derivatives. Our approach is outlined in Scheme 1 and is based on
the homolytic cleavage of the N-Y bond rather than that of the
O-X bond, generating imino ether 3 to provide amide derivative
4. Among several candidates for group Y, an alkoxy group seems
to be the most attractive because of a facile cleavage of N-O bond
along with the stability of ketene O,N-acetal 1.5 Furthermore, 1,2-
phenyl transfer from silyl to oxygen was previously reported, but
its synthetic application has not been examined to date.6 Thus, we
intended to utilize the tert-butyldiphenylsilyloxy group (TBDPS)7
for group Y to investigate the possibility of achieving the radical
alkylation under tin-free conditions. For group Z, we have chosen
a benzyloxy carbonyl group (Cbz) not only to increase the stability
of 1 but also to reduce the electron density of the carbon-carbon
double bond in 1 to some extent. Herein we report that this strategy
is indeed promising and permits the radical alkylation of carboxylic
imides with alkyl halides bearing an electron-withdrawing group
Scheme 2
8,9
under tin-free conditions for the first time.
With these ideas in mind, we prepared two ketene O,N-acetals,
1a and 1b (Scheme 2).10 Coupling of acetyl chloride with 5 and
triethylamine in dichloromethane at room temperature gave imide
6 in 95% yield. The imide 6 was treated with LHMDS in THF at
-78 °C in the presence of TBSOTf to afford 1a in 90% yield.11
1b was similarly prepared in 95% yield. As we expected, 1a and
1b were stable compounds and could be kept in a refrigerator for
one week without any noticeable decomposition.
We began with our study with 4-phenoxybutyl iodide (7a) using
1a and 1b (eq 1). Irradiation of a solution of 7a, 1a (1.5 equiv),
and hexamethylditin (1.0 equiv) in benzene at 300 nm for 6 h
afforded alkylated product 8a in 76% yield, while the use of 1b
gave a low yield (50%). Although a nucleophilic alkyl radical was
known to be reluctant to add to an electron-rich alkene,12 1a turned
out to be a relatively good acceptor for both electrophilic and
nucleophilic alkyl radicals. Irradiation of 7b with 1a (1.5 equiv)
and hexamethylditin (1.0 equiv) in benzene for 3 h at 300 nm gave
8b in 86% yield. To confirm the generation of a silyl radical by
1,2-phenyl transfer,6 the reaction was carried out with 7b and
hexamethylditin (0.1 equiv), and 8b was obtained in 67% yield. In
the case of 7a, 0.3 equiv of hexamethylditin was required for
completion.
Encouraged by these results, we studied the feasibility of tin-
free radical alkylation. Reaction of 7b with 1a using AIBN (0.1
equiv) as the initiator in benzene at 80 °C for 6 h afforded 8b in
64% yield. However, somewhat disappointingly, reaction of 7a
using AIBN as the initiator under the same conditions did not
proceed.13
From the results obtained here, it is clear that tin-free radical
alkylation of 7b occurred due to conversion of a silyloxy radical
into a silyl radical (Scheme 3). In the tin-mediated radical reaction,
trimethyltin radical could be generated not only by photochemical
cleavage of hexamethylditin but also by the reaction of tert-
butyldiphenylsilyloxy radical with hexamethylditin.14 In the tin-
catalyzed radical chain reaction, an alkyl radical could be generated
by the reaction of an alkyl iodide with silyl radical mainly or with
trimethyltin radical to some extent.
Table 1 summarizes the experimental results and illustrates the
efficiency and scope of the present method. Alkyl iodides and
bromides bearing an R-electron-withdrawing group underwent
alkylation under tin-free conditions (method A). Tin-mediated
radical reactions (method B and C) worked well with simple alkyl
* To whom correspondence should be addressed. E-mail: skim@mail.kaist.ac.kr
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J. AM. CHEM. SOC. 2002, 124, 14306-14307
10.1021/ja028396x CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Table 1. Radical Alkylation of Alkyl Halides with 1aa
Acknowledgment. This work was supported by the Center for
Molecular Design and Synthesis (CMDS-KOSEF) at KAIST.
Supporting Information Available: Typical experimental proce-
dures and spectral data for products (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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a Method A: AIBN/C6H6, 80 °C, 6 h, method B: 1 equiv (Me3Sn)2/
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group. For most of the cases observed, method B gave the best
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alkylation product due to the low reactivity of the benzylic radical.15
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TBS, PO(OEt)2) which were somewhat less stable than 1a and 1b.
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isolated in 40% yield. Thus, it is essential to generate lithium enolate of
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We examined sequential radical reactions involving the cycliza-
tion and alkylation sequence, which cannot be achieved with
conventional methods (eq 2 and 3). Treatment of 11 with 1a (1.5
equiv), Me3SnSnMe3 (1.0 equiv) in benzene at 300 nm for 5 h
afforded 12 in 61% yield. Similarly, the radical reaction of 13 gave
14 in 75% yield under similar conditions, and 14 was further
converted into 15 by treatment with DBU and triethylamine.
In conclusion, we have discovered the first successful radical
alkylation of carboxylic imides, in which alkyl halides activated
with an electron-withdrawing group underwent alkylations under
tin-free conditions. Further detailed studies on the radical alkylation
of carboxylic derivatives are in progress.
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relatively slow, the alkyl radical might react with a silyloxy radical, thereby
stopping the radical chain reaction.
(14) (Me3Sn)2 (1.0 equiv) was almost completely consumed during the reaction.
The structures of 9 and 10 are tentatively assigned.
(15) Reaction of p-bromobenzyl iodide with 1a and (Me3Sn)2 in benzene at
300 nm for 6 h gave 4,4′-bromodibenzyl in 80% yield.
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