Trifluoromethyl substituted pyridines

This method could successfully be extended to the conversion of methyl-substituted pyridines into (trifluoromethyl)-substituted pyridines.23,24... 

Examples of nitrogen-containing heterocycle syntheses based on condensation reactions continue to be forthcoming. Examples include a tandem oxidation-annulation of propargyl alcohols in a one-pot synthesis of pyridines (Equation 148) <2003SL1443>, trifluoromethyl-substituted pyridines (Scheme 94) <2003S1531>, and standard malononitrile additions to a,/3-unsaturated ketones <1995JCM392>. 

Other trifluoromethyl-substituted heterodienes, such as triazines69 and tetrazines.70 provide [4 + 2] cycloadducts under thermal conditions and allow the preparation of trifluoromethyl-substituted pyridines and pyridazines. 

Cottet, F., Marull, M., Lefebvre, O. and Schlosser, M. (2003) Recommendable routes to trifluoromethyl-substituted pyridine- and quinolinecarboxylic acids., European Journal of Organic Chemistry, 1559-1568. 

A facile one-pot synthesis of trifluoromethyl-substituted pyridine derivatives has been reported (93JHC71). The procedure depends on the high reactivity of trifluroacetoacetyl chloride, which is generated in situ from trifluoroacetyl chloride and ketene. Thus, the enaminone 391 gives the intermediate enamide 392, which is refluxed in triethylamine to give the... 

Schlosser, M. Marull, M. The direct metalation and subsequent functionalization of trifluoromethyl-substituted pyridines and quinolines. Eur. J. Org. Chem. 2003, (8), 1569-1575. 

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. 

A library of trifluoromethyl-substituted thieno[2,3- ]pyridines has been established <2000JC024>. Structures have been confirmed by a combination of H NMR and IR spectral analysis as well as single crystal X-ray diffraction analysis. 

The oxidative desulfurization-fluorination of methyl A,-alkyl-A,-pyridyl(or pyrimidin-yl)dilhiocarbamates produces the corresponding (trifluoromethyl)amino-substituted pyridines (or pyrimidines) 5.69... 

Pyridine and its derivatives react with 1,3-pentadienes forming cyclic products. This type of cyclization was observed by the authors of 95JFC(72)49. They showed that in the reaction of (Z)-1,1,2,5,5,5-hexafluoro-4-phenyl-3-trifluoromethyl-1,3-pentadiene 117 with pyridine the products are [ S,9aR]- and [lS,9tfS]-3-fluoro-9<2-hydro-l,2-bis(trifluoro-methyl)-l-phenyl-4//-quinolizin-4-ones 118 and 119 with 54 and 21% yields, respectively. The structure of the compounds was confirmed by X-ray analysis. Similarly, the reaction of (Z)-l,l,2,5,5,5-hexafluoro-4-iodo-3-trifhioromethyl-l,3-pentadiene 120 with 4-substituted pyridines gives the derivative of 4//-quinolizin-4-one 121 with quinoline, the product is derivative 122. 

With an eye toward more lipid-soluble bioactive molecules, various trifluoromethyl-substituted fused pyridines were synthesized <03S1531>. 

The aromatization of dihydro heterocycles was carried out using cerium ammonium nitrate (CAN) at ambient temperature and results in trifluoromethylated heterocycles in 18-68% yield (Fig. 7.32). While trifluoromethylation of 3-picoline is regioselective giving 5-methyl isomer in 41 % yield, the reaction of other 3-substituted pyridines leads to the mixture of — 3 and — 5 regioisomers. 

Methyl substituted pyridines such as 2,6-lutidine and 2,4,6-collidine can also afford undesirable by-products. These pyridines can react with Tf20 to generate sulfinate- and trifluoromethyl-substituted derivatives (eq 46). In such cases, the use of 2,6-di-... 

Common methods for the furan ring construction were applied to preparation of trifluoromethyl-substituted benzofurans starting from the substrates bearing appropriately located CFs-group. Thus, 2-(trifluoropropynyl)-phenol 170 was cyclized into trifluoromethylbenzofuran 171 by heating with pyridine [118]. 

In connection with trifluoromethyl chemistry, one has, from the synthetic point of view, to mention the large-scale preparation of numerous trifluo-romethoxypyridines. They can, via regioselective functionalization, provide large libraries of fluoro-substituted pyridine building blocks [260]. 

Photolysis of Ar matrix isolated trifluoromethyl-substituted 2-pyridyl azides/tetrazolo[l,5-a]pyridines at 12-18 K caused rapid and mostly clean... 

Evans, R. A. and Wentrup, C, Trifluoromethyl-substituted dehydroazepines and cyanopyrroles from azido-/tetrazolo-pyridines,/. Chem. Soc., Chem. Commun., 1062,1992. 

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