ORGANIC
LETTERS
2005
Vol. 7, No. 21
4673-4676
Oxidative Dehydrogenation of
Dihydropyrimidinones and
Dihydropyrimidines
Kana Yamamoto,* Ye Grace Chen,† and Fre´de´ric G. Buono
Process Research and DeVelopment, Bristol-Myers Squibb Pharmaceutical Research
Institute, One Squibb DriVe, New Brunswick, New Jersey 08903
Received August 4, 2005
ABSTRACT
A mild, practical procedure for oxidative dehydrogenation with catalytic amounts of a Cu salt, K2CO3, and tert-butylhydroperoxide (TBHP) as
a terminal oxidant has been developed. This oxidation procedure is generally applicable to dihydropyrimidinones and most dihydropyrimidines.
The production of heteroaromatics by oxidative dehydroge-
nation is of fundamental importance in organic synthesis.
While a number of methods have been developed,1 most
procedures require stoichiometric reagents and/or harsh
reaction conditions. Therefore the development of mild,
catalytic oxidation systems is highly desirable.2
facile access via the Biginelli three-component coupling,3
dihydropyrimidines and their derivatives are widely used for
diversity- and target-oriented synthesis. In addition, they have
shown various biological activities, and are a common motif
in drug substances.4
In contrast to Hantzsch-type dihydropyridines, where
aromatization to pyridines is typically facile, the dehydro-
genation of dihydropyrimidines is known to be nontrivial.3a,5
Previously identified oxidants for this process include HNO3,6
DDQ,7 CAN,8 and Pd/C9 as well as electrochemical oxida-
tion.10 None of these oxidations are ideal, particularly for
scale-up, due to their safety profile11 and/or difficulty in
product isolation. Therefore, an alternative procedure was
The dehydrogenation of dihydropyrimidines and dihydro-
pyrimidinones has received much attention.3 Because of their
† Recipient of a Bristol-Myers Squibb 2004 summer internship.
(1) (a) ComprehensiVe Organic Syntheses; Trost, B. M., Fleming, I., Eds;
Pergamon: Oxford, UK, 1992; Vol. 7. (b) Organic Syntheses by Oxidation
with Metal Compounds; Mijs, W. J., De Jonge, C. R. H. I., Eds; Plenium
Press: New York, 1986.
(2) For representative examples of oxidative aromatization of thiazolines
and oxazolines: (a) Evans, D. L.; Minster, D. K.; Jordis, U.; Hecht, S. M.;
Mazzu, A. L., Jr.; Meyers, A. I. J. Org. Chem. 1979, 44, 497-501. (b)
Meyers, A. I.; Taveres, F. X. Tetrahedron Lett. 1994, 35, 2481-2484. (c)
Meyers, A. I.; Tavares, F. X. J. Org. Chem. Soc. 1996, 61, 8207-8215.
(d) Barrish, J. C.; Singh, J.; Spergel, S. H.; Han, W. C.; Kissik, T. P.;
Kronenthal, D. R.; Mueller, R. H. J. Org. Chem. 1993, 58, 4494-4496. (e)
Williams, D. R.; Lowder, P. D.; Gu, Y.; Brooks, D. A. Tetrahedron Lett.
1997, 38, 331-334. (f) North, M.; Pattenden, G. Tetrahedron, 1990, 46,
8267-8290. (g) McGarvey, G. J.; Wilson, K. J.; Shanholtz, C. E.
Tetrahedron Lett. 1992, 33, 2641-2644. Dihydropyridines and pyrazo-
lines: (h) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Synthesis 2004, 7,
1015-1020. (i) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002,
4, 22, 3955-3957. (j) Nakamichi, N.; Kawabata, H.; Hayashi, M. J. Org.
Chem. 2003, 68, 8272-8273. A related oxidative synthesis of benzox-
azoles: (k) Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M. Org.
Lett., 2003, 5, 3713-3715.
(4) For representative drugs and pharmacologically active compounds,
see The Merck Index Online. The structure search with pyrimidine gave
177 hits, including Bleomycin (glycopeptide antibiotics), Buspirone (anxi-
olytic), Pyrithiobac (herbicide), and Monastrol (Kinesin EG5 inhibitor).
(5) Vanden Eynde, J. J.; Audiart, N.; Canonne, V.; Michel, S.; Van
Haverbeke, Y.; Kappe, C. O. Heterocycles 1997, 45, 1967-1978.
(6) (a) Puchala, A.; Belaj, F.; Bergman, J.; Kappe, C. O. J. Heterocycl.
Chem. 2001, 38, 1345-1352. (b) Matsushima, A.; Oda, M.; Kawachi, Y.;
Chika, J. PCT WO 03/006439 A1.
(7) Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T.; Seo, S.; Hirai, K.
Bioorg. Med. Chem. 1997, 5, 437-444.
(8) Yamamoto, K. Unpublished results.
(9) Kappe, C. O.; Roschger, P. J. Heterocycl. Chem., 1989, 26, 1555-
1560. This Pd/C dehydrogenation without the use of oxidant requires
rigorous conditions (210 °C) in Ph2O.
(10) Kadis, V.; Strandins, J.; Khanina, E. L.; Duburs, G. Electrochim.
Acta 1989, 34, 899-904.
(3) (a) Kappe, C. O. Tetrahedron Lett. 1993, 49, 6937-6963. (b) Kappe,
C. O.; Stadler, A. Org. React. 2004, 63, 1-116.
10.1021/ol051879w CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/13/2005