Typ e 2 In tr a m olecu la r N-Acyln itr oso Diels-Ald er Rea ction : Scop e
a n d Ap p lica tion to th e Syn th esis of Med iu m Rin g La cta m s
Steven M. Sparks, Chun P. Chow, Liang Zhu, and Kenneth J . Shea*
Department of Chemistry, University of California, Irvine, California 92697-2025
kjshea@uci.edu
Received J anuary 16, 2004
Heteroatom variants of the type 2 intramolecular Diels-Alder reaction provide an efficient method
for the preparation of bridged bicyclic heterocycles. The type 2 variant of the intramolecular
N-acylnitroso Diels-Alder reaction is an effective method for the synthesis of bridged bicyclic
oxazinolactams. Structural studies of the cycloadducts have allowed for quantification of the
deformations of the bridgehead functionalities and provided a strategy for the stereoselective
synthesis of substituted seven- and eight-membered ring lactams. Diastereoselective cycloadditions
followed by cleavage of the oxazine ring afford azepin-2-ones or azocin-2-ones.
In tr od u ction
strong electron-donating groups on the diene and union
of the diene and dienophile have been applied to mediate
this deficiency.
Diels-Alder reactions employing nitroso dienophiles
provide an efficient method for the synthesis of numerous
heterocycles.1 N-Acylnitroso dienophiles, pioneered by
Kirby for the preparation of 3,6-dihydro-1,2-oxazine ring
systems (oxazinolactams), are reactive dienophiles that
are generated in situ via oxidation of a hydroxamic acid
and trapped with a diene to afford the heterocyclic
cycloadduct.2 These multifunctional adducts have been
transformed into a variety of biologically active molecules
including azasugars, pyrrolidines, piperidines, tropanes,
and benzodiazepines. They have also been utilized in the
synthesis of a variety of natural products.3
The utility of oxazinolactams as key intermediates in
the synthesis of heterocyclic compounds prompted our
study of the type 2 variant of the intramolecular N-
acylnitroso Diels-Alder reaction. Type 2 intramolecu-
larity provides an opportunity to control the regiochem-
istry of the cycloaddition and access to bridged bicyclic
molecules incorporating medium sized rings, in one step
from acyclic precursors.6
Heteroatom variants of the type 2 IMDA cycloaddition
provide a general route into bridged bicyclic heterocycles.7
We report the scope of the type 2 intramolecular N-
acylnitroso Diels-Alder reaction and its utility for the
stereoselective preparation of azepin-2-ones and azocin-
2-ones.8
Poor regioselectivity exhibited with N-acylnitroso cy-
cloadditions employing unsymmetrical dienes has re-
stricted applications of this reaction in more complex
settings.4,5 Several methods including the placement of
Resu lts a n d Discu ssion
(1) (a) Boger, D. L.; Weinreb, S. M. Hetero-Diels-Alder Methodology
in Organic Synthesis; Academic Press: San Diego, 1987. (b) Weinreb,
S. M.; Staib, R. P. Tetrahedron 1982, 38, 3087-3128. (c) Boger, D. L.
In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:
Oxford, 1991; Vol. 5, pp 451-512. (d) Weinreb, S. M. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 5,
pp 401-449. (e) Orena, M. In Methods of Organic Chemistry (Houben-
Weyl), 4th ed.; Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann,
E., Eds.; Thieme: Stuttgart, 1995; Vol. E21e, pp 5547-5587. (f) Tietze,
L. F.; Kettschau, G. In Topics in Current Chemistry; Metz, P., Ed.;
Springer: Berlin, 1997; Vol. 189, pp 1-120.
Syn th esis of th e Diels-Ald er P r ecu r sor s. The
overall strategy for the assembly of the Diels-Alder
precusor hydroxamic acids involved attachment of four
to six atom tethered nitriles to the 2-position of a
2-metallo-1,3-butadiene, followed by conversion of the
nitrile functionality to a hydroxamic acid (Scheme 1).
Chloroprene Grignard was coupled with iodonitriles (1a -
c) mediated by Li2CuCl4 to afford diene nitriles 2a -c in
moderate to high yield.9 Basic hydrolysis of the nitrile
(2) Kirby, G. W. Chem. Soc. Rev. 1977, 6, 1-24.
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10.1021/jo049897z CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/26/2004
J . Org. Chem. 2004, 69, 3025-3035
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