W. W. K. R. Mederski et al. / Tetrahedron Letters 44 (2003) 2133–2136
2135
Scheme 2. Reaction of compound 6a with diglycolic acid 3d and iminodiacetic acid 3e to analogue 8 of Tro¨ger’s base.
Scheme 3. Reaction of amines 6k–m with glutaric acid 3a to the open chain acids 10a–c and amines 6a and 6e with maleic acid
to pyrrolediones 11a and 11b.
In summary, we have developed a novel, facile method-
ology for the one step synthesis of 4-nitroaryl substi-
tuted cyclic imides in high purity and yield. However,
application to other aryl and heteroaryl compounds has
to be confirmed. The subsequent reduction to the corre-
sponding anilines offers an easy entry into the design of
factor Xa inhibitors bearing a cyclic imide in the S4
pocket. The results of this investigation will be reported
in due course.
We next expanded this cyclocondensation to maleic
acid (Scheme 3). Starting from anilines 6a and 6e the
preparation of maleimides 11a and 11b proceeded in
good to moderate yields, respectively.
A different course of reaction was observed for aniline
substrates 6k–m with a hydroxy-, carboxy- or benzoyl
substituent at the 2 position (Scheme 3). In these cases
the intermediate monoamides 10a–c were formed as the
sole products in moderate yields. The outcome of this
reaction can be better ascribed to electronic effects than
to steric factors.
References
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Having obtained this overall encouraging result, we
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tions and examined the crude product by HPLC MS.
2-Nitro-, 3-nitro-, 4-ethyl-, 3-chloro- and 4-chloroani-
lines were transformed into the corresponding cyclic
imides in 38–78% yield. The products of 2-ethyl, 3-
ethyl, 2-chloroanilines and the parent aniline contained
a mixture of the intermediate monoamides and the
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The nitro group of a variety of succinimides or glu-
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10. Representative experimental procedure: A mixture of 4-
nitro-phenylamine 6a (1.0 g, 7.2 mmol), glutaric acid 3a
(0.951 g, 7.2 mmol) and 86% polyphosphoric acid (10 g)