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Synlett 2004(14): 2570-2572  
DOI: 10.1055/s-2004-834788
LETTER
© Georg Thieme Verlag Stuttgart · New York

A New, Simple Procedure for the Synthesis of Formyl Amides

Lidia De Luca, Giampaolo Giacomelli*, Andrea Porcheddu, Margherita Salaris
Dipartimento di Chimica, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari, Italy
Fax: +39(079)229559; e-Mail: ggp@ uniss.it;
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Publication History

Received 30 July 2004
Publication Date:
28 September 2004 (online)

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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.

Key words

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

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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 DiscoverTM 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]