2-Trifluoromethylimidazoles

This article is a summary of our recent extensive study of tumor specificity (TS) and the type of cell death induced by N-containing heterocycles such as 4-trifluoromethylimidazole [22] and phenoxazine derivatives [23], by O-containing heterocycles such as 3-formylchromone [24] and coumarin derivatives [25,26], and by other compounds such as vitamin K2 and prenyl-alcohols [27]. 

Among 14 4-trifluoromethylimidazole derivatives (Fig. 1), 4-trifluoromethyl-1,2-diphenylimidazole (IM5) showed the highest cytotoxicity, followed by... 

Table 1 Cytotoxic activity of 4-trifluoromethylimidazoles (IM1-14) against human tumor and normal cells... 

Heterocycles such as 4-trifluoromethylimidazole, phenoxazine, 3-formyl-chromone, coumarin derivatives, and vitamin K2 derivatives were investigated for their cytotoxicity against human normal and tumor cells. These compounds induced moderate tumor-specific cytotoxicity. VitaminK2 derivatives and prenylalcohols displayed disappointingly low tumor-specific cytotoxicity, although they have been reported to induce apoptosis-inducing activity. Human oral squamous cell carcinoma cell lines showed considerable variation in drug sensitivity. The type of cell death induced depended both on which types of cells and which inducers were used. 

Although a number of such radical reactions are known, few promise much synthetic potential, Examples include the 2-phenylation of imidazole and benzimidazole by benzoyl peroxide, but both products are more readily obtained by other routes. Homolytic alkylations of imidazole and benzimidazole also occur at C-2, but usually give indifferent yields [10]. A potentially useful reaction is the synthesis of 2- and 4-trifluoromethylimidazoles from imidazoles and photochemically generated trifluoromethyl radicals. 1-Substituted imidazoles are largely substituted at C-5 in these reactions benzimidazole reacts initially at the 4-position [11-14]. 

Trifluoro-2-oxopropanal l-(dimethylhydrazone) 1447 is a synthetic equivalent of trifluoropyruvaldehyde. Like its 1,2-dicarbonyl counterpart, compound 1447 participates in the condensation reaction with aldehydes and ammonium acetate to afford 4-trifluoromethylimidazoles 1448 in 42-72% yield <2003H(60)1185>. 1,1,1-Trifluoro-2,3-alkanediones 1449, also 1,2-dicarbonyl equivalents, condense with aldehydes and aqueous ammonia to yield 4-(trifluoromethyl)imidazoles 1450 <2001JHC773>. 3-(Dimethylhydrazono)-l,l,l,4,4,4-hexafluoro-2-butanone... 

Twelve 4-trifluoromethylimidazoles (1-12) were synthesized by the method of Kawase et al. [24,25]. Compound 13 was purchased from Aldrich, USA. Cytotoxicity assays and determination of 50% cytotoxic concentration (CC50) against human promyelocytic leukaemia HL-60 and human oral squamous cell carcinoma HSC-3 cell lines were performed as described elsewhere [23]. 

Fig-1 Structures of 4-trifluoromethylimidazole derivatives used in this study... 

Fig. 2 The most stable conformation of each 4-trifluoromethylimidazole derivative used...

Fig. 3 Relationship between CC50 and each descriptor of 4-trifluoromethylimidazole derivatives against HL-60 (a-m) and HSC-3 cells (n-p)...

Fig. 4 r] x activity diagram of 4-trifluoromethylimidazole derivatives against HL-60 cells. The box surrounds compounds with higher cytotoxicity (lower CC50)... 

A related synthesis leads to 4-trifluoromethylimidazoles. Trifluoracetylated aldehyde dimethyl-hydrazones thermally rearrange to give mixtures of oxadiazines and imidazoles. Higher temperatures and more polar solvents suppress formation of the six-membered rings, while solvent variation also alters the proportions of the imidazole regioisomers. In carbon tetrachloride the major product is... 

Fluorinated synthons have been used to access fluorinated imidazoles. Reduction of Schiff bases derived from amidines and hexafluoroacetone with SnCl2 gives rise to 5-fluoro-4-trifluoromethylimidazoles 110 (Fig. 3.57). ° ° Because the 5-fluoro substituent is readily displaced by nucleophiles such as alkoxide, cyanide, and others, this procedure provides access to a range of trifluoromefliyl-substituted imidazoles (also see below). 

Direct introduction of the trifluoromethyl group provides another general route. Irradiation of a methanolic solution of trifluoromethyl iodide and imidazole produces a mixture of 2- and 4-trifluoromethylimidazoles and 2,4-bistrifluoromethylimidazole. This can be applied to simple imidazoles and substituted imidazoles. The photochemical procedure provides a convenient synthesis of trifluoromethyl derivatives of histidine and histamine. ... 

Reaction of l,l,l-trifluoroalkane-2,3-dione 3-oximes with aldehydes in the presence of ammonium acetate and subsequent addition of IN HCl afforded 4-trifluoromethylimidazol-l-ols (Scheme 42) [56]. The prerequisite 1,1,1-trifluoro-alkane-2,3-dione 3-oximes were obtained from aldehyde dialkylhydrazones in three steps. Trifluoroacetylation of aldehyde dialkylhydrazones followed by hydrolysis... 

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. 

Kamitori Y, Hojo M, Masuda R, Kawamura Y, Fang X (1990) Convenient and selective synthesis of 4-trifluoromethylimidazoles. Heterocycles 31 2103-2106... 

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