Isocyanide, trifluoromethyl, reaction with

Oxazoles.—Formation. ci)-Diazoacetophenone reacts with benzonitrile in the presence of trifluoromethanesulphonic acid to give 2,5-diphenyloxazole (514). Bi-, ter-, and quater-oxazoles have been synthesized from a-metallated isocyanides thus lithiobenzyl isocyanide (PhCHLiNC) and dimethyl oxazole-3,4-dicarboxylate afford compound (515). Stable methylene-oxazolines (516 R = Me or Ph) are obtained by heating the iminesHN=C(Ph)OCHRC=CH. The fluorinated oxazoline (518) results from the action of benzonitrile on the oxiran (517), and also from the reaction of bis(trifluoromethyl)carbene with the benzoylimine (CF3)2C=NCOPh/ Treatment of 2-acylamino-l-aryl-alkan-l-ols (519) under the conditions of the Pictet-Gams reaction, i.e. with phosphorus pentoxide in boiling toluene or xylene, results in cis- and trans-2-oxazolines (520), rather than isoquinolines, as claimed previously. The spiro-oxazolines (521 R = Me or Ph) are formed when the lithiated di-isocyanide CN—CH2CH2CHLi—NC is treated with acetone or benzophenone, respec-tively. ... 

The discovery synthesis of Almorexant starts with an Ugi three-component reaction (Ugi-3CR) between benzaldehyde (4), 2-(3,4-dimethoxyphenyl)ethanamine (5), and methyl isocyanide (6) affording product 7, which in a post-Pictet-Spengler reaction with 3-(4-(trifluoromethyl)phenyl)propanal (8) in the presence of strongly acidic conditions gives the end product Almorexant (9). Clearly, the synthesis is not stereoselective and yields four different stereoisomers, of which only one is biologically highly active (Scheme 15.3). 

Pyrolysis of the keten-A t-butylimines (39) and (40), prepared by reaction of bis(trifluoromethyl)keten with iV-(triphenylphosphoranylidene)-t-butyl-amine and from perfluorobut-2-yne and t-butyl isocyanide (see p. 52), respectively, yields isobutene and a nitrile " ... 

A related cyclization of p-ketoketimines 117, obtained by reaction of ferf-butyl isocyanide with 4-aryl-l,l,l-triflnorobutan-2,4-diones 116, afforded 2,3-diamino-4-aroyl-5-(trifluoromethyl)furans 118 [91],... 

The trifluoromethyl isocyanide thus formed isomerizes to trifluoromethyl cyanide when heated, reacts with mercuric oxide to yield trifluoromethyl isocyanate, and must be stored at low temperatures otherwise it polymerizes to a yellow solid which possibly has the structure [-C( NCF3)C( NCFj)-]n- Reference has already been made to the preparation of oxazetidines from trifluoronitrosomethane and A AT-bistrifluoromethylamino-substituted allenes (see p. 100). Possibly of greater interest is the preparation in low yield of the flrst perhalogeno oxazetidines bearing no per- or poly-fluoroalkyl substituent on nitrogen (see Scheme 8). Reaction of perfluoro-l, 2-oxazetidine, r. 

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