Synthesis 2009(9): 1445-1458  
DOI: 10.1055/s-0028-1088162
© 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)


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.


  • For examples of 2,5′-bioxazole analogs, see:
  • 1a Panek JS. Beresis RT. J. Org. Chem.  1996,  61:  6496 
  • 1b Nicolaou KC. Hao J. Reddy MV. Rao PB. Rassias G. Snyder SA. Huang X. Chen DY.-K. Brenzovich WE. Giuseppone N. Giannakakou P. O’Brate A. J. Am. Chem. Soc.  2004,  126:  12897 
  • 1c Nicolaou KC. Chen DY.-K. Huang X. Ling T. Bella M. Snyder SA. J. Am. Chem. Soc.  2004,  126:  12888 
  • 1d Liu P. Celatka CA. Panek JS. Tetrahedron Lett.  1997,  38:  5445 
  • 1e Boto A. Ling M. Meek G. Pattenden G. Tetrahedron Lett.  1998,  39:  8167 
  • 2 No analogues of 2-(1H-imidazol-4-yl)oxazole were found with a CrossFire database search and only a limited number of 2-(thiazol-4-yl)oxazole analogs were found. See: Gorb LT. Romanov NN. Tolmachev AI. Chem. Heterocycl. Compd.  1979,  15:  1081 ; and references cited therein
  • 3a LaMattina JL. Mularski CJ. Tetrahedron Lett.  1983,  24:  2059 
  • 3b LaMattina JL. Mularski CJ. Muse DE. Tetrahedron  1988,  44:  3073 
  • 3c LaMattina JL. Mularski CJ. J. Org. Chem.  1984,  49:  4800 
  • 3d LaMattina JL, and Weeks PD. inventors; US Patent  4443621.  1984; Chem. Abstr. 1984, 101, 22994
  • 3e LaMattina JL. Mularski CJ. J. Org. Chem.  1986,  51:  413 
  • 3f LaMattina JL. Muse DE. J. Org. Chem.  1987,  52:  3479 
  • For examples of other masked α-bromo ketones, such as 2-bromo-1-(thiazol-2-yl)ethanone, see:
  • 4a Menasse R. Prijs B. Erlenmeyer H. Helv. Chim. Acta  1957,  40:  554 
  • For 2-bromo-1-(furan-2-yl)ethanone, for example, see:
  • 4b Devi SKC. Rajasekharan KN. Synth. Commun.  2002,  32:  1523 
  • For 2-bromo-1-(2-methyl-1H-imidazol-4-yl)ethan-one, for example, see:
  • 4c Lipinski CA. LaMattina JL. Oates PJ. J. Med. Chem.  1986,  29:  2154 
  • 6a Li B. Chiu CK.-F. Hank RF. Murry J. Roth J. Tobiassen H. Org. Synth.  2004,  81:  105 
  • 6b Weinstein DS. Liu W. Ngu K. Langevine C. Combs DW. Zhunang S. Chen C. Madsen CS. Harper TW. Robl JA. Bioorg. Med. Chem. Lett.  2007,  17:  5115 
  • 7 Geilen H. Alonso-Alija C. Hendrix M. Niewöhner U. Schauss D. Tetrahedron Lett.  2002,  43:  419 ; and references cited therein
  • 8 Han S.-Y. Kim Y.-A. Tetrahedron  2004,  60:  2447 
  • 10 Wipf P. Methot JL. Org. Lett.  2001,  3:  1261 
  • 14a Grimett MR. Imidazoles, In Comprehensive Heterocyclic Chemistry II   Vol. 3:  Katritzky AR. Rees CW. Scriven EFV. Pergamon/Elsevier; Oxford: 1996.  Chap. 2 (3.02). ; and references cited therein
  • 14b Bellina F. Cauteruccio S. Rossi R. Tetrahedron  2007,  63:  4571 
  • 16a Poitout L. Roubert P. Contour-Galcéra M.-O. Moinet C. Lannoy J. Pommier J. Plas P. Bigg D. Thurieau C. J. Med. Chem.  2001,  44:  2990 
  • 16b Fevig JM. Pinto DJ. Han Q. Quan ML. Pruitt JR. Jacobson IC. Galemmo RA. Wang S. Orwat MJ. Bostrom LL. Knabb RM. Wong PC. Lam PYS. Wexler RR. Bioorg. Med. Chem.  2001,  11:  641 
  • 16c Trukhin DV. Bagryanskaya IY. Gatilov YV. Mikhalina TV. Rogozhnikova OY. Troitskaya TI. Tormyshev VM. Synlett  2005,  2072 
  • 17 Fresneda PM. Molina P. Sanz M. Synlett  2001,  218 ; and references cited therein
  • 18 Zav’yalov SI. Sitkareva IV. Dorofeeva OV. Rumyantseva EE. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.)  1987,  36:  1750 
  • 19a Prakash R. Kumar A. Aggarwal R. Prakash O. Singh SP. Synth. Commun.  2007,  37:  2501 ; and examples therein
  • 19b Mukkala V.-M. Liitti P. Hemmilä I. Takalo H. Matachescu C. Kankare J. Helv. Chim. Acta  1996,  79:  295 
  • 20 For the preparation of 2-amino, 2-(alkylamino)-, and 2-(dialkylamino)thiazoles, see: Aoyama T. Murata S. Arai I. Araki N. Takido T. Suzuki Y. Kodomari M. Tetrahedron  2006,  62:  3201 ; and references cited therein
  • 21 Hammar WJ. Rustad MA. J. Heterocycl. Chem.  1981,  18:  885 

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.


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).


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.


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.


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.


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.