Synthesis of 6-Chloro-5-(trifluoroacetyl)pyridine-3-carbonitrile: A Novel, Versatile Intermediate for the Synthesis of Trifluoromethylated Azaindazole Derivatives

Abstract

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 words

pyridinecarbonitriles - 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.