Synthesis of 6-Chloro-5-(trifluoroacetyl)pyridine-3-carbonitrile: A Novel, Versatile Intermediate for the Synthesis of Trifluoromethylated Azaindazole Derivatives
Received: 19 March 2019
Accepted after revision: 12 April 2019
02 May 2019 (online)
A synthesis of 6-chloro-5-(trifluoroacetyl)pyridine-3-carbonitrile, a versatile building block for the synthesis of trifluoromethylated N-heterocycles, is described. The reactions of 6-chloro-5-(trifluoroacetyl)pyridine-3-carbonitrile with 1,2- and 1,3-bisnucleophiles were investigated.
Key wordspyridinecarbonitriles - pyrazolopyridines - trifluoromethylation - oxadiazoles - annulation
References and Notes
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- 14 6-Chloro-5-(trifluoroacetyl)pyridine-3-carbonitrile Hydrate (2.H2O) POCl3 (9.6 mL, 102.7 mmol, 2.5 equiv) was added over 15–20 min to a cooled (10 °C) slurry of enamine derivative 1 (10.0 g, 41.1 mmol, 1.0 equiv) and DIPEA (4.3 mL, 53.4 mmol, 1.3 equiv) in PhCl (70 mL), keeping the reaction temperature below 20 °C. The resulting suspension was stirred at 20 °C for 1 h, then heated to 100 °C and stirred for 24 h. The mixture was analyzed by TLC and GC–MS. (An aliquot of the mixture was sampled for reaction completion by quenching with sat. aq NaHCO3 and extracting with EtOAc). The mixture was then allowed to cool to 25 °C, concentrated, and neutralized with sat. aq NaHCO3. The resulting aqueous phase was extracted with EtOAc (3 × 60.0 mL). The combined organic layers were washed sequentially with H2O (20.0 mL) and brine (10.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography [silica gel, cyclohexane–EtOAc, (7:3)] to give a white solid; yield: 4.70 g (46%); mp 118–120 °C. IR (KBr): 3369, 3096, 2359, 2339, 1589, 1417, 1199, 850, 699 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 8.98 (d, J = 2.2 Hz, 1 H), 8.58 (d, J = 2.2 Hz, 1 H), 8.27 (s, 2 H). 13C NMR (101 MHz, DMSO-d6): δ = 153.7, 153.6, 144.1, 133.6, 123.4 (q, J = 290.9 Hz), 116.3, 108.6, 92.4 (q, J = 33.0 Hz). 19F NMR (377 MHz, DMSO-d 6): δ = –81.5 (s, 3 F). HRMS (ESI): m/z [M + H]+ calcd for C8H5ClF3N2O2: 251.9913; found: 251.9925. Full details of other preparations are given in the Supplementary Information.