Azole-N-Acetonitriles as Carbonyl Synthons: A One-Pot Preparation of ­Heteroaryl Amides from Halides

Abstract

Azole-N-acetonitrile derivatives were utilized as synthons for an ambident carbonyl moiety via a strategy relying upon sequential base-mediated S_NAr substitution of a 2-halo heterocycle, in situ oxidation, and amine displacement. This strategy allows prompt and efficient synthesis of N-containing heteroaryl amides directly from the corresponding halides via a one-pot process.

azole-N-acetonitrile - carbonyl synthon - heteroaryl amide - acyl anion equivalent

References

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This assumption was further confirmed with an addition of excess of EtOH prior to oxidation under the same condition. The formation of 19a (51%) and the ethyl ester (31%) was detected by LC-MS.

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General Procedure for the Preparation of Heteroaryl Amides: NaHMDS (2.5 mL, 1.0 M in THF, 2.5 mmol) was added into a solution of 2-chloro-benzooxazole (153 mg, 1.0 mmol), and (4,5-dichloro-imidazol-1-yl)-acetonitrile (264 mg, 1.5 mmol) in dry THF (15 mL). After stirring for 10 h at r.t. dimethylamine (1.5 mL, 2 M in THF, 3.0 mmol) and HOOAc (0.84 mL, 32 wt.% in HOAc, 4.0 mmol) were subsequently added and the mixture stirred a further 10 h at r.t. The reaction mixture was quenched with sat. Na₂SO₃ solution and neutralized by sat. NaHCO₃ solution, the aqueous layer extracted with EtOAc (3 × 20 mL) and the combined organic layer dried over MgSO₄. Concentration in vacuo afforded a residue which was purified by silica gel chromatography to provide benzoxazole-2-carboxylic acid dimethylamide (16g, 165 mg, 87%). ¹H NMR (500 MHz, CDCl₃): δ = 7.71 (d, 1 H, J = 8.0 Hz), 7.52 (d, 1 H, J = 8.0 Hz), 7.33 (m, 2 H), 3.39 (s, 3 H), 3.10 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 157.6, 155.2, 149.9, 140.3, 127.0, 125.2, 121.2, 111.4, 38.8, 36.4. HRMS: m/z [M + H]⁺ calcd for C₁₀H₁₁N₂O₂: 191.0821; found: 191.0824.

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The reaction and the subsequent work-up should be undertaken with care in a well-ventilated hood due to the possibility of HCN liberation.

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