ganese dioxide, and phenylselenation/elimination have pro-
vided modest results for this oxidation. Recent modifications
using copper bromide8 or bromotrichloromethane and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU)9 have improved yields
but require carboxy functionality at the 4 position. Hantzsch-
type reactions of R-halocarbonyl derivatives with amides
have also been used for the synthesis of 2,4-disubstituted
oxazoles,10 but the method is not as robust as for the synthesis
of thiazoles. Other recent examples are inherently more
specific in scope.11 Our requirements for a robust, general
method incorporating a large commercial reagent pool were
not satisfied by these protocols.
activation with carbonyldiimidazole. Deprotection was gen-
erally accomplished by treatment with HCl in dioxane or
ether or TFA in dichloromethane. The free amines were then
acylated either by an acid chloride or an in situ generated
acyl imidazole. Subsequent reduction with LAH17 provided
the desired aldehydes (d).
Cyclodehydration of the aldehydo amide (d) was initially
attempted using triphenylphosphine and iodine. We experi-
enced only moderate success with this reagent (Table 1,
Table 1. Conversion of R-acylamino Aldehydes to Oxazolesa
Historically, one of the most useful procedures for the
synthesis of oxazoles has been the cyclodehydration of
R-acylaminoketones, or the Robinson-Gabriel synthesis.12
Wipf has demonstrated that the difficult cyclodehydration
of R-acylaminoaldehydes to oxazoles unsubstituted at the
5-position is possible using triphenylphosphine and iodine.13
We recognized an opportunity for the synthesis of our targets
using Wipf’s modification, if a suitable method for prepara-
tion of the requisite aldehydes could be found. Our approach
to the acyclic aldehydes (Scheme 1)14 evolved as an
Scheme 1a
a Key: (i) carbonyldiimidazole, N-methyl-O-methylhydroxyl-
amine hydrochloride, CH2Cl2; (ii) HCl, ether; (iii) R2 acid chloride,
TEA, CH2Cl2 or R2 acid, carbonyldiimidazole, pyridine, CH2Cl2;
(iv) LAH, THF.
adaptation of a method described by Buchanan for the
synthesis of peptide thiazoles.15 The Boc-protected acids (a)
were converted to their Weinreb amides (b),16 following
(8) (a) 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.
(9) Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron
Lett. 1997, 38, 331. (b) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.;
Williams, D. R. Org. Lett. 2000, 2, 1165.
(10) Liu, P.; Celatka, C. A.; Panek, J. S.; Tetrahedron Lett. 1997, 38,
5445.
(11) (a) Hermitage, S. A.; Cardwell, K. S.; Chapman, T.; Cooke, J. W.
B.; Newton, R. Org. Process Res. DeV. 2001, 5, 37. (b) Lee, J. C.; Song,
I.-G. Tetrahedron Lett. 2000, 41, 5891. (c) Pei, W.; Li, S.; Nie, X.; Li, Y.;
Pei, J.; Chen, B.; Wu, J.; Ye, X. Synthesis 1998, 1298. (d) Swaminathan,
S.; Singh, A. K.; Li, W.-S. Venit, J. J.; Natalie, K. J., Jr.; Simpson, J. H.;
Weaver, R. E.; Silverberg, L. J. Tetrahedron Lett. 1998, 39, 4769.
(12) Robinson, R. J. Chem. Soc. 1909, 95, 2167.
a All yields are isolated products. Reaction mixtures were heated if
conversion was incomplete after the designated time at room temperature.
b See the Supporting Information for examples of the methods. c 13% of
the chloro-oxazoline was also isolated. d 24% of the chloro-oxazoline was
also isolated.
method A). More recent examples have employed the milder
reagent system, triphenylphosphine and dibromotetrachloro-
ethane to generate a bromo-oxazoline, which is subsequently
dehydrohalogenated.18 We used a similar reagent combina-
tion, triphenylphosphine and hexachloroethane (Table 1,
(13) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
(14) Due to price/availability, only the nonracemic (S) amino acids were
used in all cases. Integrity of the asymmetric center was not confirmed for
the intermediates (Schemes 1-4), and therefore, absolute stereochemistry
is not depicted. However, literature precedence would suggest aldehydes d
and ketones m would be nonracemic. For a review of Weinreb amide
chemistry, see: Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15-40. (b)
Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997, 339 517-524.
(15) Buchanan, J. L.; Mani, U. N.; Plake, H. R.; Holt, D A. Tetrahedron
Lett. 1999, 40, 3985.
2666
Org. Lett., Vol. 4, No. 16, 2002