Synthesis 2009(9): 1445-1458  
DOI: 10.1055/s-0028-1088162
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Preparation of 5-Substituted 2-(2-Alkyl/aryl-1H-imidazol-4-yl)oxazoles and 5-Substituted 2-(2-Alkyl/arylthiazol-4-yl)oxazoles by Utilizing 5-Substituted 2-(2-Bromo-1,1-diethoxyethyl)oxazole as a Synthon

Denis R. St. Laurent*, Jeffrey L. Romine
Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
Fax: +1(203)6777702; e-Mail: [email protected];
Further Information

Publication History

Received 20 October 2008
Publication Date:
25 March 2009 (online)

Abstract

Synthetic access to oxazolyl-substituted heterocycles including oxazolylimidazoles, -thiazoles, and -oxazoles is gained from a masked α-halo ketone attached to the 2-position of the oxazole ring. 3-Bromo-2,2-diethoxy-N-(2-oxoalkyl)propionamides readily cyclize to generate the key 5-substituted 2-(2-bromo-1,1-diethoxyethyl)oxazole intermediate.

    References

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5

Compound 4 was prepared exactly as described in ref. 3a, except, in our hands, the product contained approximately 25% of ethyl ester, which could not be purified by recrystallization from cyclohexane without significant loss of product. Adding an additional 25-30% of 4 to the reaction mixture did compensate adequately for our stock source of 4.

9

After an initial aqueous workup, precursor amides 6 were often pure enough to be used in further reactions, but to obtain samples for characterization they were most often subjected to flash column chromatography, for which either Biotage or Thomson silica gel cartridges were used (Biotage 25M silica gel cartridges, Biotage Company; Single-Step Thomson 80 g silica gel cartridges, Thomson Instrument Company).

11

The intrinsic instability of the ketal moiety was sometimes noted in liquid chromatography mass spectra, which where frequently complicated (with shoulders) by the partial or full substitution of the ethoxy groups with water or methanol arising from the liquid chromatography solvent system, but in all cases the predominant signal was the parent.

12

The 5-substituted 2-(2-bromo-1,1-diethoxyethyl)oxazoles and their respective 2-bromo-1-oxazol-2-ylethanones were also refrigerated at -10 ˚C as an added precaution.

13

The liquid chromatography mass spectra were sometimes complicated by the partial or full addition of methanol or water arising from the liquid chromatography solvent system, but, as with precursors 7, the predominant signal was the parent.

15

Waters Oasis MCX (60 µm) 35-cc (6 g) Extraction cartridges (Sulfonic Acid). The crude residue was taken up in methanol and added to an equilibrated (with methanol) extraction cartridge. Methanol (100 mL) was used to elute off all of the nonbasic byproducts, and Aldrich 2 N ammonia in methanol (100 mL) was used to remove the product from the resin. Concentration of the eluent afforded the desired product free of its benzamide contaminant.