A New, Simple Procedure for the Synthesis of Formyl Amides

Abstract

A simple and mild method for the N-formylation of amines and α-amino esters is described via reaction with 2-chloro-4,6-dimethoxy[1,3,5]triazine and formic acid. The reaction can be accelerated under microwave irradiation and yields the N-formyl species in high yields and without racemization in the case of optically active α-amino esters.

amines - formyl amides - cyanuric acid - formylamino esters - microwave

References

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22

A. Conventional Procedure: Formic acid (0.35 g, 7.62 mmol), benzylamine (0.71 g, 7.62 mmol), 2-chloro-4,6-dimethoxy[1,3,5] triazine (CDMT, 1.47 g, 8.30 mmol), 4-dimethylaminopyridine (DMAP, 0.03 g, 0.2 mmol) and N-methylmorpholine (NMM, 0.92 mL, 8.30 mmol) were placed in this order in a flask containing CH₂Cl₂ (20 mL) and maintained at r.t. The mixture was stirred at reflux (6 h), monitored by TLC in order to control the end of the conversion, then diluted with CH₂Cl₂, washed twice with aq HCl (15 mL), aq NaHCO₃ (15 mL), and brine (10 mL). The organic layer was dried (Na₂SO₄). Removal of the solvent in vacuo gave 0.98 g of chemically pure N-benzylformamide, (95%), mp 57 °C. [12]
B. Microwave Procedure: TEA (1.2 mL, 8.38 mmol) and l-valine methyl ester hydrochloride (1.27 g, 7.62 mmol) were placed in a flask equipped with a reflux condenser, containing CH₂Cl₂ (20.0 mL). Then formic acid (0.35 g, 7.62 mmol), CDMT (1.47 g, 8.30 mmol), DMAP (0.03 g, 0.20 mmol) and N-methylmorpholine (NMM, 0.92 mL, 8.30 mmol) were added in this order. The open flask was irradiated at 35 °C (by modulation of the power) for 6 min in a self-tuning single mode CEM Discover^TM Focused Synthesizer. The solution was cooled rapidly at r.t. by passing compressed air through the 25 microwave cavity for 1 min, then diluted with CH₂Cl₂ and worked up as above. ¹H NMR (300 MHz, CDCl₃): δ = 8.27 (s, 1 H), 6.23 (br s, 1 H), 4.67 (dd, 1 H, J = 9.0, 4.8 Hz), 3.76 (s, 3 H), 2.24-2.17 (m, 1 H), 0.97 (d, 3 H, J = 6.8 Hz), 0.92 (d, 3 H, J = 6.6 Hz).
(S)-Methyl 2-formamido-3-methylbutanoate from method A had [α]_D ²⁵ -27.2 (c 2.0, EtOH). Similarly, (S)-methyl 2-formamidobutanoate, (S)-methyl 2-formamido-3-phenyl-propanoate, and (S)-methyl 2-formamido-4-methyl-pentanoate were recovered and had [α]_D ²⁵ values of -36.1
(c 3.5, EtOH), [13] +85.3 (c 2.3, EtOH), [14] and -43.2 (c 1.2, EtOH), respectively. [13]