Regioselective reduction of maleimide and citraconimide
derivatives: general preparation of 5-hydroxy-1,5-dihydropyrrol-
2-one
1
Nobuyuki Mase, Toshiki Nishi, Masaomi Hiyoshi, Kazuhiro Ichihara, Junichiro Bessho,
Hidemi Yoda and Kunihiko Takabe*
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku,
Hamamatsu 432-8561, Japan. E-mail: tcktaka@ipc.shizuoka.ac.jp; Fax: ϩ81-53-478-1148;
Tel: ϩ81-53-478-1148
Received (in Cambridge, UK) 21st January 2002, Accepted 4th February 2002
First published as an Advance Article on the web 12th February 2002
NaBH4 reduction of citraconimide derivatives regio-
selectively afforded 5-hydroxy-4-methyl-1,5-dihydropyrrol-
2-ones, whereas NaBH4–CeCl3 or DIBAL-H reduction
gave 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-ones.
mentioned above. Results are shown in Table 2. In all cases
of citraconimide derivatives, no formation of the saturated
hydroxylactam derivatives was observed. Treatment of N-
benzylcitraconimide 6a with NaBH4 gave a mixture of the
C2-adduct 7a and C5-adduct 8a in a ratio of 88 : 12 (entry 1).
On the other hand, reverse regioselectivity was obtained by
addition of CeCl3ؒ7H2O with the 7–8 ratio of 29 : 71 (entry 2).
Higher regioselectivity up to a 7–8 ratio of 9 : 91 was observed
when diisobutylaluminium hydride (DIBAL-H) was used as a
reducing agent (entry 4). These tendencies were observed in the
reduction of N-diphenylmethyl, N-phenyl, N-allyl-, and N-H
citraconimides 6b–e. Complete reverse regioselectivity was
revealed in the reduction of citraconimide 6e (entries 9–11).
Previously Speckamp et al. reported a remarkably regioselec-
tive reduction of gem-disubstituted succinimides, in which the
hydride attacks the hindered carbonyl group.9 Their pioneering
work and interpretation of the regiochemistry may explain our
results. The regioselectivity could be ascribed to the depicted
models as shown in Scheme 2. The complete coplanarity of the
Introduction
5-Hydroxy-1,5-dihydropyrrol-2-one derivatives 3 are important
building blocks1 for the preparation of a wide variety of
natural products with potential pharmaceutical applications.
Generally, 5-hydroxy-1,5-dihydropyrrol-2-one derivatives 3 are
synthesized by photooxygenation of pyrrole derivatives 1;2
however, formation of a number of other side products has
limited the overall yield of 3. In spite of the limitations of
availability of substrate, singlet-oxygen addition to the furan
derivatives following ammonolysis is an alternative method
Scheme 1 Synthesis of 5-hydroxy-1,5-dihydropyrrol-2-one derivatives
3.
(Scheme 1).3,4 We describe herein a convenient and direct
synthesis of 5-hydroxy-1,5-dihydropyrrol-2-one derivatives 3
by a hydride addition to maleimide derivatives 4.
Results and discussion
Results of the reduction of maleimide derivatives 45 are shown
in Table 1.6 Reduction of N-benzylmaleimide 4a with sodium
borohydride (1 equiv.) gave the unsaturated hydroxylactam 3a
as well as the saturated hydroxylactam 5a in 41% and 59% yield,
respectively (entry 1).7 Addition of Lewis acid dramatically
changed the chemoselectivity. In the presence of cerium()
chloride heptahydrate (CeCl3ؒ7H2O, commercially available
without further purification),8 the unsaturated hydroxylactam
3a was obtained in 91% yield (entry 2). No other side product
was observed. Samarium() chloride was also an effective
Lewis acid to give 3a in 62% yield (entry 3). In the cases of
N-allyl- and N-methylmaleimide 4b,c, the reduction proceeded
smoothly under the same reaction conditions, giving excellent
yields of the desired unsaturated hydroxylactam 3b,c (entries
4 and 5). The yield of 3 was reduced in the absence of the
N-protection (entry 6).
Scheme 2 Proposed mechanism of regioselectivity in the reduction of
6 with NaBH4.
carbonyl groups and the double bond moiety in maleimide
and citraconimide derivatives is well-established; therefore,
a mechanism based on a general proposal for nucleophilic
addition to carbonyl groups offers a satisfactory explanation.10
The hydride anion approaches from the less hindered carbonyl
group and attacks the more hindered C2 atom as depicted in
model A virtually along a straight line through the carbonyl
bond (Scheme 2).
We also investigated the reduction of citraconimide deriv-
atives 6. The reduction was carried out in the same manner
On the other hand, in the reduction with NaBH4–CeCl3
or DIBAL-H the regioselectivity is explained by the effect
DOI: 10.1039/b200729k
J. Chem. Soc., Perkin Trans. 1, 2002, 707–709
This journal is © The Royal Society of Chemistry 2002
707
Mase, Nobuyuki
