An Efficient Method for the Preparation of N-Formamides using Propylphosphonic Anhydride (T3P®)

Abstract

The synthesis of N-formamides from aromatic amines and formic acid using propylphosphonic anhydride (T3P®) as a green coupling reagent is described. By using this method, aryl, heteroaryl and fluorinated aryl-containing formamides were synthesized in high yield and purity. The significant features of this method include easy work up, high purity and reduced toxicity of the reaction.

Key words

N-formylation - T3P - formic acid - aromatic amine - formamide

• References and Notes

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• 19 Preparation of 3-Formyl-pyrazole (2t); Typical Procedure: To a solution of compound 1t (300 mg, 3.61 mmol) in dichloromethane (5 mL) was added HCO₂H (199 mg, 4.33 mmol), T3P^® (2.3 g, 7.2 mmol) and TEA (730 mg, 7.2 mmol) at 0 °C, and the reaction mixture was then stirred at r.t. for 12 h. The progress of the reaction was monitored by TLC (30% EtOAc/petroleum ether). Upon completion of the reaction, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate three times. The combined organic extracts were washed with water and brine, and dried over Na₂SO₄. After filtration, the solvent was evaporated to afford the crude product, which was triturated with pentane to give pure 2t (295 mg, 74 %) as a brown solid; mp 181–183 °C. IR (KBr): 3396, 2961, 2106, 1687, 1596, 1492, 1388, 1299, 1199, 1046, 765 cm^–1; ¹H NMR (400 MHz, DMSO): δ = 12.37 (br. s, 1 H), 10.5 (br. s, 1 H), 8.66 (br. s, 1 H), 7.62 (d, J = 9.2 Hz, 1 H), 5.99 (br. s, 1 H); MS (EI): m/z (%) = 112 (100) [M+1]
• 20 Typical experimental procedure for the preparation N-formylbenzamide (2a): To a solution of compound 1a (200 mg, 2.17 mmol) in dichloromethane (5 mL) was added HCO₂H (118 mg, 2.58 mmol), T3P^® (1.38 g, 4.34 mmol) at 0 °C and TEA (434 mg, 4.30 mmol), and the reaction mixture was stirred at r.t. for 12 h. The progress of the reaction was monitored by TLC (30% EtOAc/petroleum ether). Upon completion of reaction, water (50 mL) was added and the reaction mixture was extracted with ethyl acetate three times. The combined organic extracts were washed with water and brine, and dried over Na₂SO₄. After filtration, the solvent was evaporated to afford the crude product, which was purified by silica gel chromatography, eluting with 30% EtOAc/petroleum ether to give pure 2a (250 mg, 95 % yield) as a brown semisolid. Analytical data of N-phenyl formamide (2a): IR (KBr): 3271, 2921, 1683, 1600, 1543, 1440, 1270, 754 cm^–1; ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.7 (br. s, 1 H), 8.3 (br. s, 1 H), 7.5 (br. s, 2 H), 7.2 (t, 2 H), 7.0 (t, 1 H); MS (EI): m/z (%) = 122 (100) [M+1]