Trifluoromethyl group reaction with ammonia

Reaction of the imidazole (7-4) with the benzofuran derivative (6-7) leads to the displacement of the benzylic halogen and the formation of the alkylation product (8-1). Treatment of that intermediate with trifluoroacetic acid breaks open the urethane to afford the corresponding free amine. This is allowed to react with ttiflic anhydride to afford the trifluoromethyl sulfonamide (8-2). The ester group on the imdidazole is then saponified, and the newly formed acid is reacted with carbonyl diimidazole. Reaction with ammonia converts the activated carboxyl group to the amide. There is thus obtained the angiotensin antagonist saprisartan (8-3) [6]. 

The synthetic scheme often applied for the preparation of 3-aryl-3-(trifluoromethyl)-3//-diazirine nowadays is shown in Scheme 5a [60]. It starts by lithiation of an aryl bromide (38), which subsequently reacts with /V-ftrifluoroacetyl)piperidine 39 (easily prepared from trifluoroacetic anhydride and piperidine) under the formation of trifluoroacetophenone 40. Next, the ketone is converted into the corresponding oxime 41, after which the hydroxyl group is converted into its tosylate (42). Reaction with liquid ammonia (usually under pressure) allows the installment of the diaziridine group (43). Subsequent oxidation with iodine finally results in the diazirine (44). This five-step reaction sequence is especially compatible with acid-labile protective groups, which are often used to protect and/or install functionalities at the R position. 

Reaction of 2-trifluoromethylindole with sodium ethoxide led to ortho-ether 209, while ethyl 3-indolylcarboxilate 212 was isolated in case 3-lrifluoromethylindole. Reaction of 2-trifluoromethylindole with NaBlL, in ethanol led to ethyl 2-indolylcarboxilate 211. In contrast, reduction of trifluoromethyl group was observed to form 3-methylindole 213 in case of 3-isomer. Treatment of 3-trifluoromethylindol with sodium amide in liquid ammonia led to 3-cyanoindole 214, whereas 2-trifluoroindole did not reacted with sodium amide at all [46]. 

A long series of studies of aromatic nucleophilic substitution included the kinetics of reactions of l-chloro-2,4-bis(trifluoromethylsulfonyl)benzene, 3-nitro-4-chlorophenyl trifluoromethyl sulfone and 2-chlorophenyl trifluoromethyl sulfone with sodium methox-ide or ammonia in methanol . The SO2CF3 group was found to have an enormous accelerating effect, in accord with the value of 1.65, based on the dissociation of anilinium ion. Further examples of the promotion of nucleophilic aromatic substitution by fluoro-substituted sulfonyl groups are given by Yagupol skii and coworkers . 

Ammonia adds across the nitroso group to form an addition product, tri-fluoromethylaminohydroxylamine. This condenses with another molecule of trifluoronitrosomethane to form 3-hydroxy-l,3-bis(trifluoromethyl)-l-tri-azene, which decomposes to nitrogen and bis(trifluoromethyl)hydroxyl-amine A. Another mechanism of the reaction has also been proposed [737]. 

Prop-2-ynyl)-5-(trifluoromethyl)-l,3,4-thiadiazol-2(3//)-one 322 reacts with nucleophiles (ammonia, pyrrolidine, or potassium methylthiolate) to form 6-methylene-2-(trifluoromethyl)-5,6-dihydro-4//-l,3,4-thiadiazine-4-carbox-amides or j -methyl 6-methylene-2-(trifluoromethyl)-5,6-dihydro-4//-l,3,4-thiadiazine-4-thiocarboxylates 323. The reaction of aqueous sodium hydroxide with 322 gives the 4//-l,3,4-thiadiazine 324, which also bears an exocyclic methylene group (Scheme 43) <1998HOU(E9c)483>. 

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