Imidazole 5-fluoro-4-trifluoromethyl

Ethyl substitution at the imidazole 5-position (469) was found to increase potency over the unsubstituted analogue (468), while methyl substitution (470) had a slightly deleterious effect on binding (Table 6.41). Chloro (491), bromo (492), cyano (493) and fluoromethyl (494) substitution at this position were all well tolerated (Table 6.43). Introduction of a chloro-substituted pyridine (475) in place of the more usual / -chlorophenyl group (470) resulted in a slight loss of affinity for the CBi receptor, as did replacement of the p-chloro group of (470) with bromo (471), fluoro (472) and in particular, met-hoxy (473). Trifluoromethyl substitution (474) however, was well tolerated. 

An electron-deficient carbon bearing a trifluoromethyl group becomes part of an imidazole ring when Schiff bases (18) made from amidines and hexa-fluoroacetonc are reduced by tin(U) chloride (Scheme 2.2.7). The 5-fluoro-4-trifluoromethylimida2olcs (19) are isolated in 58-65% yields [9-11]. The fluoro substituents in the 5-position are readily displaced by nucleophiles such as alkoxy or cyanide, thereby extending the versatility of these syntheses [9j. 

Photochemical trifluoromethylation of 4-fluoro-5-methylimidazole 1572 provides the trifluoromethyl derivative 1573 in 53% yield. Similarly, 4-fluoro-2-methylimidazole 1574 gives 4-fluoro-2-methyl-5-(trifluoromethyl)imidazole 1575 in 26% yield (Scheme 406) <1998JOC9448>. 

Reddy, A.C.S. Rao, P.S. Venkataratnam, R. V. Fluoro organics facile syntheses of novel 2-or 4-trifluoromethyl-l//-arylo-l,5-diazepines, oxazepines, thiazepines, 2-(l,l,l-trifluor-oacetonyl)imidazoles, oxazoles and thiazoles. Tetrahedron 1997, 53(16), 5847-5854. 

Quan, M.L., et al. Discovery ofl-(3 -Aminobenzisoxazol-5 -yl)-3-trifluoromethyl-A-[2-fluoro-4-[(2 -dimethy-laminomethyl)imidazol-l-yl]phenyl-lF7-pyrazole-5-carboxamide Hydrochloride (Razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor. J. Med. Chem. 2005, 48, 1729-1744. 

Li and Boswell observed a base-promoted unusual de-trifluoromethylation of 4,4-bis(trifluoromethyl)-5-hydroxyimidazoline that afforded the corresponding 4-(trifluoromethyl)imidazole (Scheme 46) [60], Karsch reported the formation of iV-(fert-butyl)-5-fluoro-2-phenyl-4-trifluoromethylimidazole from a silaheterocycle under reductive conditions (Scheme 47) [61], The silaheterocycle was prepared by [4-1- l]-cycloaddition of 1,3-diazabutadiene with SiCls anion that was generated by the deprotonation of HSiC by DBU. 

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