Misra and Ila
JOCArticle
method12 improved by Yokoyama,13 the biomimetic dehy-
drative cyclization of β-hydroxy amides to oxazolines and
their oxidative dehydrogenation,14-16 the Hantsch-type re-
action of R-halo/acyloxy carbonyl compounds with amides,
the rhodium-catalyzed decomposition of R-diazocarbonyl
compounds in the presence of nitriles,18 and the photolysis/
pyrolysis of R-acylisoxazolones.19 However, these methods
genuinely lack universality and suffer from one or more
drawbacks such as modest to poor yields, harsh reaction
conditions, longer reaction time, and reactive starting mate-
rials with limited stability, which make them incompatible
for the range of tolerated functional groups in the target
oxazole. Recently, several new synthetic protocols have been
devised to overcome these drawbacks such as improved and
modified Robinson-Gabriel synthesis (Wipf’s dehydrating
agent, PPh3/I2/Et3N),16 Rh-catalyzed NH insertion of
amides to R-diazocarbonyl compounds,20 direct conversion
of ketones to oxazoles without isolation of reactive
intermediates,17b,21 cycloaddition of activated methylene
SCHEME 1. Diverse Reaction Pathways from 4-Bis(methylthio)-
methylene-2-substituted Oxazol-5-one
isocyanides,22 Ru23a and Cu23b catalyzed reactions, and
Lewis acid24a,b/base,24c Pd,25 gold26,27 catalyzed cycloisomer-
ization of propargyl amides along with the transition metal-
catalyzed cross-coupling reactions on the built-in oxazole
ring.28 However, most of these reactions are inherently more
specific in scope and lack generality. Therefore more robust,
practical general methods for substituted oxazoles with
wider scope for elaboration of various sites from readily
available starting materials are very much desirable.
Our own interest in oxazole synthesis is driven by our long-
standing research program aimed at devising new synthetic
strategies for five- and six-membered heterocycles employing
polarized ketene dithioacetals as versatile intermediates.29,30
During the course of these studies, we set out to explore the
feasibility of utilizing ketene dithioacetal 1 (R = Ph) derived
from 2-phenyl-4,5-dihydrooxazol-5-one31 as a versatile tem-
plate to access a broad range of heterocycles with diverse
functionalities. A close look at the structure of 1 reveals that
it contains many reactive sites allowing for a diverse set of
possible transformations. Thus, it was envisaged that the
oxazolone ring in 1 could be readily opened by the regiose-
lective attack of various carbon and hetero nucleophiles at
the carbonyl group (1,2-addition, path a) to furnish acyclic
polyfunctional intermediates 2 with multiple reactive sites,
which can be exploited for the construction of diversly
substituted heterocycles (Scheme 1). Alternatively, a conjugate
(12) Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1947, 96.
(13) (a) Yokoyama, M.; Menjo, Y.; Watanabe, M.; Togo, H. Synthesis
1994, 1467. (b) Shin, C.-G.; Sato, Y.; Sugiyama, H.; Nanjo, K.; Yoshimura,
J. Bull. Chem. Soc. Jpn. 1977, 50, 1788.
(14) Review on oxazolines: Gant, T. G.; Meyers, A. I. Tetrahedron 1994,
50, 2297.
(15) (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. (b) Kashima, C.; Arao,
H. Synthesis 1989, 873. (c) Barrish, J. C.; Singh, J.; Spergel, S. H.; Han,
W.-C.; Kissick, T. P.; Kronenthal, D. R.; Mueller, R. H. J. Org. Chem. 1993,
58, 4494. (d) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996, 61, 8207. (e)
Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron Lett.
1997, 38, 331. (f) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams,
D. R. Org. Lett. 2000, 2, 1165.
(16) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
(17) (a) Liu, P.; Celatka, C. A.; Panek, J. S.; Panek, J. S. Tetrahedron Lett.
1997, 38, 5445. (b) Lee, J. C.; Choi, H. J.; Lee, Y. C. Tetrahedron Lett. 2003,
44, 123 and references cited therein.
(18) (a) Doyle, K. J.; Moody, C. J. Synthesis 1994, 1021. (b) Doyle, M. P.;
Buhro, W. E.; Davidson, J. G.; Elliot, R. C.; Hoekstra, J. W.; Oppenhuizen,
M. J. Org. Chem. 1980, 45, 3657. (c) Clemencon, I. F.; Ganem, B. Tetra-
hedron 2007, 63, 8665. (d) Doyle, K. J.; Moody, C. J. Tetrahedron 1994, 50,
3761.
(19) Prager, R. H.; Smith, J. A.; Weber, B.; Williams, C. M. J. Chem. Soc.,
Perkin Trans. I 1997, 2665 and 2659.
(20) (a) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J. J. Chem.
Soc., Perkin Trans. I 1998, 591. (b) Davies, J. R.; Kane, P. D.; Moody, C. J.
Tetrahedron 2004, 60, 3967. (c) Davies, J. R.; Kane, P. D.; Moody, C. J.;
Slawin, A. M. Z. J. Org. Chem. 2005, 70, 5840. (d) Clapham, B.; Spanka, C.;
Janda, K. D. Org. Lett. 2001, 3, 2173. See also oxazoles by azide decom-
position: (e) Dhar, T. G. M.; Guo, J.; Shen, Z.; Pitts, W. J.; Gu, H. H.; Chen,
B.-C.; Zhao, R.; Bednarz, M. S.; Iwanowicz, E. J. Org. Lett. 2002, 4, 2091.
(21) (a) Lee, J. C.; Song, I.-G. Tetrahedron Lett. 2000, 41, 5891. (b) Lee,
J. C.; Lee, Y. C. Bull. Korean Chem. Soc. 2003, 24, 893. (c) Kawano, Y.; Togo,
H. Synlett 2008, 217 and references cited therein. (d) Herrera, A.; Martinez-
Alvarez, R.; Ramiro, P.; Molero, D.; Almy, J. J. Org. Chem. 2006, 71, 3026.
(22) (a) Barrett, A. G. M.; Cramp, S. M.; Hennessy, A. J.; Procopiou,
P. A.; Roberts, R. S. Org. Lett. 2001, 3, 271. (b) Baumann, M.; Baxendale,
I. R.; Ley, S. V.; Smith, C. D.; Tranmer, G. K. Org. Lett. 2006, 8, 5231. (c)
Atkins, J. M.; Vedejs, E. Org. Lett. 2005, 7, 3351. (d) Wang, S.-X.; Wang,
M.-X.; Wang, D.-X.; Zhu, J. Eur. J. Org. Chem. 2007, 4076 and references
cited therein. (e) Bonne, D.; Dekhane, M.; Zhu, J. Angew. Chem., Int. Ed.
2007, 46, 2485.
(23) (a) Kumar, M. P.; Liu, R.-S. J. Org. Chem. 2006, 71, 4951. (b)
Martin, R.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 5521. (c) Schuh,
K.; Glorius, F. Synthesis 2007, 2297.
(24) (a) Wipf, P.; Aoyama, Y.; Benedum, T. E. Org. Lett. 2004, 6, 3593.
(b) Coqueron, P.-Y.; Didier, C.; Ciufoleni, M. A. Angew. Chem., Int. Ed.
2003, 42, 1411. (c) Nilsson, B. M.; Vargas, H. M.; Ringdahl, B.; Hacksell, U.
J. Med. Chem. 1992, 35, 285.
(25) Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F. Org.
Lett. 2001, 3, 2501.
(26) Milton, M. D.; Inada, Y.; Nishibayashi, Y.; Uemura, S. Chem.
Commun. 2004, 2712.
(28) (a) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 2905. (b)
Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2006, 8, 2495. (c)
Besselievre, F.; Mahuteau-Betzer, F.; Grierson, D. S.; Piguel, S. J. Org.
Chem. 2008, 73, 3278. (d) Ohnmacht, S. A.; Mamone, P.; Culshaw, A. J.;
Greaney, M. F. Chem. Commun. 2008, 1241. (e) Hoffman, T. J.; Rigby, J. H.;
Arseniyadis, S.; Cossy, J. J. Org. Chem. 2008, 73, 2400. (f) Araki, H.; Katoh,
T.; Inoue, M. Tetrahedron Lett. 2007, 48, 3713. (g) Pippel, D. J.; Mapes,
C. M.; Mani, N. S. J. Org. Chem. 2007, 72, 5828.
(29) Reviews: (a) Ila, H.; Junjappa, H.; Mohanta, P. K. In Progress in
Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon
Press: Oxford, UK, 2001; Vol 13, Chapter 1, pp 1-24. (b) Junjappa, H.; Ila,
H.; Asokan, C. V. Tetrahedron 1990, 46, 5423.
(30) Recent papers: (a) Kumar, S.; Ila, H.; Junjappa, H. J. Org. Chem.
2009, 74, 7046. (b) Singh, P. P.; Yadav, A. K.; Ila, H.; Junjappa, H. J. Org.
Chem. 2009, 74, 5496. (c) Kumar, S.; Peruncheralathan, S.; Ila, H.; Junjappa,
H. Org. Lett. 2008, 10, 965. (d) Yadav, A. K.; Yadav, S. K. S.; Siddiqui, I.;
Peruncheralathan, S.; Ila, H.; Junjappa, H. Synlett 2008, 2674. (e) Misra,
N. C.; Panda, K.; Ila, H.; Junjappa, H. J. Org. Chem. 2007, 72, 1246. (f)
Yadav, A. K.; Peruncheralathan, S.; Ila, H.; Junjappa, H. J. Org. Chem.
2007, 72, 1388. (g) Sundaram, G. S. M.; Singh, B.; Venkatesh, C.; Ila, H.;
Junjappa, H. J. Org. Chem. 2007, 72, 5020. (h) Kumar, S.; Ila, H.; Junjappa,
H. Tetrahedron 2009, 63, 10067.
(27) (a) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett.
2004, 6, 4391. (b) Kang, J.-E.; Kim, H.-B.; Lee, J.-W.; Shin, S. Org. Lett.
2006, 8, 3537.
(31) For a recent review on the chemistry of oxazol-5-(4H)-ones see: Fisk,
J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. Rev. 2007, 36, 1432.
5196 J. Org. Chem. Vol. 75, No. 15, 2010