2,2,2-Trifluoroacetaldehyde O-(Aryl)oxime: A Precursor of Trifluoroacetonitrile

Abstract

The preparation of 2,2,2-trifluoroacetaldehyde O-(aryl)oxime, a previously inaccessible precursor of trifluoroacetonitrile, via reaction of hydroxylamine and trifluoroacetaldehyde hydrate is reported. This precursor released CF 3 CN in quantitative yield under mildly basic conditions. The precursor was successfully used in the synthesis of trifluoromethylated oxadiazoles. The facile, cost-effective, scalable, and recyclable procedure makes these trifluoroacetonitrile precursors generally applicable.

Regioselective Synthesis of 5-Trifluoromethyl 1,2,4-Triazoles via [3 + 2]-Cycloaddition of Nitrile Imines with CF3CN

“…Based on the results obtained from these experiments and literature reports [ 38 , 43 ], a plausible mechanism for the formation of 5-trifluoromethyl 1,2,4-triazole ( 3 ) was proposed ( Scheme 5 ). The nitrile imine generated in situ from hydrazonyl chloride 2 in the presence of a base underwent regioselective [3 + 2] cycloaddition with the in situ-generated CF 3 CN from 1 to generate the desired product, 3 .…”

“…Our study commenced by choosing N -phenyl-benzohydrazonoyl chloride, 2a , and trifluoroacetaldehyde O -(2,4-dinitrophenyl) oxime, 1 , as the model substrates ( Table 1 ), using our previously reported optimized conditions for the synthesis of trifluoromethylated oxadiazoles [ 38 ]. To our delight, the reaction of 2a with 1 in a 1:2 ratio in the presence of 2.0 equiv of NEt 3 afforded the desired product, 5-trifluoromethyl 1,2,4-triazole, 3a , in 3% and 8% yields in THF and DMSO, respectively (Entries 1 and 2).…”

“…As part of our ongoing interest centered on the synthesis of trifluoromethylated heterocycles [ 37 ], we recently disclosed a novel protocol for the construction of trifluoromethylated oxadiazoles from the reaction of nitrile oxide derivatives using 2,2,2-trifluoroacetaldehyde O -(aryl)oxime as the precursor of trifluoroacetonitrile [ 38 ]. Based on these results and considering that nitrile imines, generated in situ via the treatment of the hydrazonyl halides with stoichiometric amounts of base [ 39 ], could serve as the attractive C1N2 synthons in [3 + 2] cycloaddition reactions [ 40 , 41 ], we now investigated the feasibility of this approach for the regioselective synthesis of 5-trifluoromethyl 1,2,4-triazoles ( Scheme 1 e).…”

Modular Access to 2-(Trifluoromethyl)pyrazolo[1,5-a]pyridines and Their Benzo Analogues through a Copper(I)-Catalyzed Radical Annulation

“…Then a base screening was carried out, and it was revealed that the weaker base Na 2 CO 3 performed best in this reaction, giving 3a in 65% yield (Table , entries 6–8, see Table S2 in the Supporting Information for more details). To our surprise, the organic base such as NEt 3 which was very effective for the release of CF 3 CN in situ in Weng’s report failed to give the desired product (Table , entry 8). This type of annulation reaction did not occur at all when DTBP was replaced by m -chloroperbenzoic acid ( m CPBA), tert -butyl hydroperoxide (TBHP), K 2 S 2 O 8 , N -fluorobenzenesulfonimide (NFSI), PhI­(OAc) 2 , molecular oxygen, or air (Table , entries 9–13, see Table S3 in the Supporting Information for more details).…”

“…Meanwhile, this reaction is also restricted by the use of a stoichiometric amount of Cu­(I) reagent and an excess amount of aromatic nitriles (15 equiv) . Inspired by the pioneering work of Weng and co-workers, who showed that CF 3 CN conveniently prepared in situ could be used in cycloaddition reactions, we assumed that such reactivity could be exploited to enable the production of desired 2-(trifluoromethyl)­pyrazolo­[1,5- a ]­pyridines. Herein we disclose the copper-catalyzed annulation of 2-pyridyl derivatives with CF 3 CN (generated in situ) for the first time (Scheme d).…”