Published on Web 09/16/2004
Mechanistic Evidence for an r-Oxoketene Pathway in the
Formation of â-Ketoamides/Esters via Meldrum’s Acid
Adducts
Feng Xu,*,† Joseph D. Armstrong III,* George X. Zhou,*,‡ Bryon Simmons,
,†
†
†
‡
†
David Hughes, Zhihong Ge, and Edward J. J. Grabowski
Contribution from the Departments of Process Research and Analytical Research,
Merck Research Laboratory, Rahway, New Jersey 07065
Abstract: A practical, one-pot process for the preparation of â-keto amides via a three-component reaction,
including Meldrum’s acid, an amine, and a carboxylic acid, has been developed. Key to development of an
efficient, high-yielding process was an in-depth understanding of the mechanism of the multistep process.
Kinetic studies were carried out via online IR monitoring and subsequent principal component analysis
which provided a means of profiling the concentration of both the anionic and free acid forms of the Medrum’s
adduct 6 in real time. These studies, both in the presence and absence of nucleophiles, strongly suggest
that formation of â-keto amides from acyl Meldrum’s acids occurs via R-oxoketene species 2 and rule out
other possible reaction pathways proposed in the literature, such as via protonated R-oxoketene
intermediates 3 or nucleophilic addition-elimination pathways.
Introduction
â-Keto esters and amides are versatile intermediates in organic
synthesis and often are prepared from acyl Meldrum’s acid
1
adducts. This method involves reaction of Meldrum’s acid with
activated carboxylic acids followed by decarboxylation in the
presence of nucleophiles such as alcohols or amines (Scheme
Figure 1. Possible reaction intermediates proposed in the literature.
1). The ability of readily available acyl Meldrum’s acids adducts
Scheme 1 . Preparation of â-Keto Esters and Amides from Acyl
Meldrum’s Acids
to react with various nucleophiles allows quick access to a
variety of functionalized compounds. Application of this
methodology in synthetic chemistry has been widely exploited;
1
-4
however, the mechanism is not well understood.
Four
tentative reaction pathways have been proposed: (1) nucleo-
5
philic addition-elimination pathway via intermediate 1; (2)
9
(
0
259 °C) or under flash vacuum pyrolysis condition (600 °C,
3,5b,6
formation of R-oxoketene 2;
(3) formation of protonated
R-oxoketene 3; and (4) reaction via intermediate 4 (Figure 1).
R-Oxoketenes 2 have been the focus of numerous theoretical
and experimental studies. They have been observed by ther-
1
0,11
1
.01 Torr).
In light of these studies, 2 has been suggested
2
6a,7
as a possible intermediate in reactions in which acyl Meldrum’s
acid adducts react with amines, alcohols, and imines, etc.,
although the alternative pathway through nucleophilic addition
8
molysis of Meldrum’s acid derivatives in boiling diphenyl ether
5b,6
to intermediate 1 followed by elimination cannot be excluded.
†
Department of Process Research.
Department of Analytical Research.
(
6) For additional examples, see: (a) Yamamoto, Y.; Watanabe, Y.; Ohnishi,
S. Chem. Pharm. Bull. 1987, 35, 1860-1870. (b) Sato, M.; Ogsawara, H.;
Yoshizumi, E.; Kato, T. Chem. Pharm. Bull. 1983, 31, 1902-1909. (c)
Sato, M.; Ogsawara, H.; Yoshizumi, E.; Kato, T. Heterocycles 1982, 17,
297-300.
‡
(
1) For reviews, see: (a) Far, A. D. Angew. Chem., Int. Ed. Engl. 2003, 42,
2
340-2348. (b) Gaber, A. E. M.; McNab, H. Synthesis 2001, 2059-2074.
(
c) Chen, B. C. Heterocycles 1991, 32, 529-597. (d) Huang, X. Youji
Huaxue 1986, 329-334.
(7) (a) Hamilakis, S.; Kontonassios, D.; Sandris, C. J. Heterocycl. Chem. 1996,
33, 825-829. (b) Sato, M.; Takayama, K.; Abe, Y.; Furuya, T.; Inukai,
N.; Kaneko, C. Chem, Pharm. Bull. 1990, 38, 336-339. (c) Yamamoto,
Y.; Watanabe, Y. Chem. Pharm. Bull. 1987, 35, 1871-1879.
(8) For recent reviews, see: (a) Tidwell, T. T. Ketenes; John Wiley & Sons:
New York, 1995. (b) Wentrup, C.; Heilmayer, W.; Kollenz, G. Synthesis
1994, 1219-1249. (c) Tidwell, T. T. Acc. Chem. Res. 1990, 23, 273-279.
(9) Cassis, R.; Tapia, R.; Valderrama, J. A. Synth. Commun. 1985, 15, 125-
133.
(10) Gordon, H. J.; Martin, J. C.; McNab, H. J. Chem. Soc., Chem. Commun.
1983, 957-958.
(11) Bibas, H.; Kappe, C. O.; Wong, M. W.; Wentrup, C. J. Chem. Soc., Perkin
Trans. 2 1998, 493-498.
(
(
(
2) Emtenas, H.; Alderin, L.; Almqvist, F. J. Org. Chem. 2001, 66, 6756-
6
761.
3) Emtenas, H.; Soto, G.; Hultgren, S. J.; Marshall, G. R.; Almqvist, F. Org.
Lett. 2000, 2, 2065-2067.
4) The mechanism involving acyl Meldrum’s acids in solution was never
clarified. It is often to have several proposed reaction pathways in the same
publication.
(
5) For examples, see: (a) Pak, C. S.; Yang, H. C.; Choi, E. B. Synthesis 1992,
1
213-1214. (b) Svetlik, J.; Goljer, I.; Turecek, F. J. Chem. Soc., Perkin
Trans. 1 1990, 1315-1318. (c) Sato, M.; Yoneda, N.; Katagiri, N.;
Watanabe, H.; Kaneko, C. Synthesis 1986, 672-674. (d) Oikawa, Y.;
Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978, 43, 2087-2088.
13002
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J. AM. CHEM. SOC. 2004, 126, 13002-13009
10.1021/ja046488b CCC: $27.50 © 2004 American Chemical Society