Synthesis of Trifluoromethylated Azines via Nucleophilic Oxidative Substitution of Hydrogen by Trifluoromethyl Carbanions

Abstract

A novel, three-step method of trifluoromethylation of azines via oxidative nucleophilic substitution of hydrogen in the heteroaromatic ring by a CF3- carbanion is presented. The key reaction of this process is the addition of the CF3- carbanion, generated by treatment of Me3SiCF3 with KF(s) and Ph3SnF catalyst, to N-alkylazinium salts. The resulting dihydroazines containing a trifluoromethyl group are relatively stable compounds and can be isolated in a pure form. Deprotection of the N-p-methoxybenzyl substituent and aromatization of the heterocyclic ring upon treatment with CAN provides azines with a CF3 group in the ring position originally occupied by hydrogen. The whole process can be thus considered as a nucleophilic oxidative displacement of hydrogen by a CF3- carbanion.

Synthesis of CF3-substituted 1,2,3,4-tetrahydroisoquinolines and 1,2,3,6-tetrahydropyridines

“…To confirm the structure of enamine 6, a sample of this compound was obtained by the reaction of iminium salt 5 with Me 3 SiCF 3 in the presence of potas sium fluoride. 13 At the same time, tetrahydroisoquinoline 7 was known earlier. 14 It was also reasonable to apply the alkylation-nucleo philic addition-trifluoromethylation sequence for the syn thesis of CF 3 substituted tetrahydropyridines.…”

“…11, November, 2010 proach competitive (as compared to the earlier described methods). 13 C, and 19 F NMR spectra were recorded on a Bruker AM 300 or Bruker AM 200 spectrometers in CDCl 3 . When NMR spectra of diastereomeric mixtures were described, the signals for two diastereomers were distinguished using the´ sign.…”

“…The residue was subjected to chromato graphy on silica gel. 13 2 Methyl 4 phenyl 1 trifluoromethyl 1,2 dihydroisoquino line (6). Potassium fluoride (82 mg, 1.5 mmol) and Me 3 SiCF 3 (221 μL, 1.5 mmol) were added to a solution of salt 5 (347 mg, 1 mmol) in DMF (2 mL).…”

“…Chromatography: hexane-EtOAc (25 : 1), R f 0.19. 1 H NMR (300 MHz, CDCl 3 ), δ: 1.49 (d, 3 H, CHCH 3 , J = 6.8 Hz); 2.40 (s, 3 H, NMe); 2.90-3.02 (m, 2 H, CH 2 ); 3.46 (qdd, 1 H, CHCF3 , J = 7.7 Hz, J = 6.6 Hz, J = 6.6 Hz); 3.92 (q, 1 H, CHMe, J = 6.9 Hz); 7.10-7.29 (m, 4 H, Ar) 13. C NMR (75 MHz, CDCl 3 ), δ: 19.7, 25.0 (q, J = 2.1 Hz); 38.8 (q, J = 1.4 Hz); 57.1, 58.3 (q, J = 27.8 Hz); 126.2, 126.6, 126.7 (q, J = 284.3 Hz); 128.2, 131.8, 139.1.…”

New Synthesis of 2‐Heteroarylperfluoropropionic Acids Derivatives by Reaction of Azine N‐Oxides with Hexafluoropropene

“…We have already described the oxidative nucleophilic trifluoromethylation of nitroarenes [9] and reactions of azinium (pyridinium, quinolinium etc.) salts with CF 3 À [10] or with perfluoroispropyl carbanions, generated in the reaction mixture from hexafluoropropene (CF 2 =CFCF 3 , HFP) and KF (s) . [11] The two crucial steps of these reactions were, nucleophilic addition of the carbanions to the electrophilic homo-or heteroaromatic ring and subsequent aromatisation of the negatively charged s H complexes or neutral dihydroazines upon addition of an oxidant.…”