SCHEME 1. The Isomeric Forms of Metalated Oxazole and
Subsequent Reactions with Acylating Agents
Reactions between Weinreb Amides and
2-Magnesiated Oxazoles: A Simple and Efficient
Preparation of 2-Acyl Oxazoles
Daniel J. Pippel,* Christopher M. Mapes, and
Neelakandha S. Mani
Johnson & Johnson Pharmaceutical Research and DeVelopment,
L.L.C., 3210 Merryfield Row, San Diego, California 92121
ReceiVed March 28, 2007
oxazoles in some cases (e.g., deuterium oxide, trimethylsilyl
triflate, benzaldehyde) demonstrates that the two forms are in
equilibrium, despite the thermodynamic dominance of the ring-
opened form.6
The 2-acyl oxazole product family represents a specialized
challenge within this research area, and several attempts have
been made to provide a general entry into this class of
compounds. Direct reaction of the organolithium species with
acyl chlorides results in the corresponding O-acylated ring-
opened products.7 Two-step approaches involving initial reaction
with an aldehyde and subsequent oxidation have been more
successful.6b A particularly clever iteration of this strategy
involves precomplexation of the oxazole with borane to provide
a species that reacts through its closed form.8
The most successful synthesis of 2-acyl oxazoles to date has
been published by workers at Eli Lilly.9 An initially formed
lithiate is transmetalated to the zincate, and then permitted to
react with an acyl chloride in the presence of stoichiometric
copper iodide. The success of this approach stems from the fact
that, unlike the corresponding lithiates, oxazole zincates exist
in their closed form. Calculations suggest that the structural
discrepancies result primarily from differences in the hybridiza-
tion about carbon for the two types of organometallic reagents.5c
Despite the progress, the state-of-the-art for acyl oxazole
synthesis remains less than ideal. Charged with providing
multigram quantities of a potential new drug candidate bearing
this structural motif, we became interested in developing a new
approach to 2-acyl oxazoles. Because of the reported instability
of 2-lithio oxazoles in THF at temperatures above -40 °C,10
our first priority was to determine an alternative metal coun-
terion. On the basis of recently reported successful applications
of Grignard oxazole reagents in reactions with iminium or
trimethylsilyl triflate reagents,11 we undertook to characterize
the solution structure of these species at 0 °C in THF. In the
Treatment of oxazole or 5-aryl oxazoles with i-PrMgCl
smoothly generates the corresponding 2-Grignard reagents,
which react with Weinreb amides to provide exclusively
2-acyl oxazole products.
The oxazole motif occurs within the framework of numerous
important pharmacophores, natural products, and synthetic
intermediates.1 In light of this significance, numerous syntheses
of variously substituted oxazoles have been developed, with
Robinson-Gabriel cyclodehydration methods gaining wide
popularity.2 A fascinating subfield of oxazole chemistry involves
C2 functionalization of preformed oxazole cores.3 In fact, for
more than 30 years, chemists from various groups the world
over have been motivated and intrigued by the peculiarities of
2-metalated oxazoles and their subsequent reactions.4
It has been conclusively established through both solution
NMR spectroscopy and solid-state structural characterization
that 2-lithio-oxazoles exist predominantly as ring-opened enolate
isonitiriles and not as the expected cyclic structures (Scheme
1).5 The outcome of reactions between these metalated inter-
mediates and electrophiles is highly dependent on the nature of
the electrophile. The formation of the expected 2-substituted
(1) For leading references on oxazoles, see: (a) Turchi, I. J.; Dewar, M.
J. S. Chem. ReV. 1975, 75, 389-437. (b) Boyd, G. V. Science of Synthesis;
Schaumann, E., Ed.; Georg Thieme Verlag: New York, 2001; Vol. 11,
Chapter 12, pp 383-479. (c) Iddon, B. Heterocycles 1994, 37, 1321-1346.
(2) (a) Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Rao, P. B.; Rassias, G.;
Snyder, S. A.; Huang, X.; Chen, D. Y.-K.; Brenzovich, W. E.; Giuseppone,
N.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004, 126, 12897-
12906. (b) Brain, C. T.; Paul, J. M. Synlett 1999, 1642-1644.
(3) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60, 8991-9016.
(4) Schroder, R.; Schollkopf, U.; Blume, E.; Hoppe, I. Liebigs Ann. Chem.
1975, 533-546.
(6) (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.
J. Org. Chem. 1987, 52, 3413-3420. (b) Whitney, S. E.; Rickborn, B. J.
Org. Chem. 1991, 56, 3058-3063. (c) Dondoni, A.; Fantin, G.; Fogagnolo,
M.; Mastellari, A.; Medici, A.; Pedrini, P. J. Org. Chem. 1984, 49, 3478-
3483. (d) Hodges, J. C.; Patt, W. C.; Connolly, C. J. J. Org. Chem. 1991,
56, 449-452.
(5) (a) Crowe, E.; Hossner, F.; Hughes, M. J. Tetrahedron 1995, 32,
8889-8900. (b) Hilf, C.; Bosold, F.; Harms, K.; Marsch, M.; Boche, G.
Chem. Ber. 1997, 130, 1213-1221. (c) Boche, G.; Bosold, F.; Hermann,
H.; Marsch, M.; Harms, K.; Lohrenz, J. C. W. Chem. Eur. J. 1998, 4, 814-
817. (d) Similar findings have been reported for the corresponding lithium
magnesates. Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.; Bischoff, L.;
Tre´court, F.; Queguiner, G.; Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros,
R. J. Org. Chem. 2005, 70, 5190-5196.
(7) Dondoni, A.; Dall’Occo, T.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. J. Chem. Soc., Chem. Commun. 1984, 258-260.
(8) Vedejs, E.; Monahan, S. D. J. Org. Chem. 1996, 61, 5192-5198.
(9) (a) Harn, N. K.; Gramer, C. J.; Anderson, B. A. Tetrahedron Lett.
1995, 36, 9453-9456. (b) Anderson, B. A.; Harn, N. K. Synthesis 1996,
583-585.
(10) Reeder, M. R.; Gleaves, H. E.; Hoover, S. A.; Imbordino, R. J.;
Pangborn, J. J. Org. Process Res. DeV. 2003, 7, 696-699.
10.1021/jo070646a CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/22/2007
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