A. G. Neo et al. / Tetrahedron Letters 46 (2005) 23–26
25
"
"
"
"
Synthesis 2003, 1471; (c) Do¨mling, A. Curr. Opin. Chem.
Biol. 2002, 6, 306; (d) Weber, L. Drug Discov. Today 2002,
O
O
O
O
R'
R'
+
R
N
H
N
H
R
´
7, 143; (e) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt,
P. Chem. Eur. J. 2000, 6, 3321; (f) Do¨mling, A.; Ugi, I.
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Pepino, R.; Polo, C.; Torroba, T. Synthesis 2003, 691; (b)
Marcaccini, S.; Pepino, R.; Polo, C.; Pozo, C. Synthesis
2001, 85; (c) Bossio, R.; Marcos, C. F.; Marcaccini, S.;
Pepino, R. Heterocycles 1997, 45, 1589; (d) Bossio, R.;
Marcos, C. F.; Marcaccini, S.; Pepino, R. Synthesis 1997,
1389; (e) Bossio, R.; Marcos, C. F.; Marcaccini, S.;
Pepino, R. Tetrahedron Lett. 1997, 38, 2519; (f) Barriga,
S.; Fuertes, P.; Marcos, C. F.; Rakitin, O. A.; Torroba, T.
J. Org. Chem. 2002, 67, 6439; (g) Barriga, S.; Marcos, C.
F.; Riant, O.; Torroba, T. Tetrahedron 2002, 58, 9785.
6. (a) Marcaccini, S.; Pepino, R.; Marcos, C. F.; Polo, C.;
Torroba, T. J. Heterocycl. Chem. 2000, 37, 1501; (b)
Bossio, R.; Marcaccini, S.; Pepino, R. Liebigs Ann. Chem.
1994, 527; (c) Bossio, R.; Marcaccini, S.; Pepino, R.;
Torroba, T. Synthesis 1993, 783.
7. (a) Bossio, R.; Marcaccini, S.; Pepino, R.; Polo, C.;
Torroba, T. Org. Prep. Proced. Int. 1992, 24, 188; (b)
Bossio, R.; Marcaccini, S.; Pepino, R. Liebigs Ann. Chem.
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8. Passerini, M. Gazz. Chim. Ital. 1921, 51(II), 126.
9. This strategy has been also used recently by another
group: Beck, B.; Magnin-Lachaux, M.; Herdtweck, E.;
Do¨mling, A. Org. Lett. 2001, 3, 2875.
Scheme 2. Formal double-Umpolung disconnection for the synthesis
of b-keto amides.
involves two separate reaction steps, in some cases it
may be advantageous relative to apparently more
straightforward procedures, as the one-step thermal
reaction of b-keto esters with primary amines; for exam-
ple, in combinatorial chemistry applications. Several
examples combining different arylglyoxals and aliphatic
an aromatic isocyanides are reported in Table 1 and the
yields for both the Passerini condensation and zinc
reduction are given. All the isocyanides employed were
obtained from commercial sources, while glyoxals were
made by oxidation of the corresponding acetophenones
with HBr in DMSO.30
In summary, a simple and versatile two-step synthesis of
b-keto amides has been developed. This method for-
mally involves the formation of a new bond between a
b-keto-carbocation and a carbamoyl anion. This means
that the b-keto amide moiety is built through an unusual
double Umpolung process (Scheme 2). To our knowl-
edge, such disconnection has never been employed be-
fore in the preparation of b-keto amides. The use of
recyclable polymer supported carboxylic acids in the
Passerini condensation, which would spare the sacrificial
use of acetic acid, is currently under research in our
laboratory.
10. Trautwein, A. W.; Sussmuth, R. D.; Jung, G. Bioorg.
Med. Chem. Lett. 1998, 8, 2381.
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J. Chem. Soc., Perkin Trans. 2 1991, 1377.
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Peters, E. M.; Peters, K.; von Schnering, H. G. Z.
Naturforsch., B 1996, 51, 1084; (b) Zaleska, B.; Lis, S.
Synthesis 2001, 811.
Acknowledgements
´
We thank financial support from the Consejerıa de San-
idad y Consumo (03/72) and Consejerıa de Educacion
´
Ciencia y Tecnologıa (2PR04A003) of the Junta de
Extremadura and FEDER.
´
´
15. Dekhane, M.; Douglas, K. T.; Gilbert, P. Tetrahedron
Lett. 1996, 37, 1883.
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56, 1713.
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Chem. Pharm. Bull. 1984, 32, 3848.
Supplementary data
Supplementary data associated with this article can be
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