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Synlett 2011(10): 1454-1458  
DOI: 10.1055/s-0030-1260584
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Highly Efficient Carbamate Formation from Alcohols and Hindered Amino Acids or Esters Using N,N′-Disuccinimidyl Carbonate (DSC)

Hongmei Li*, Cheng-yi Chen, Jaume Balsells Padros
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065-0900, USA
Fax: +1(732)5941499; e-Mail: hongmei_li@merck.com;
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Publication History

Received 7 February 2011
Publication Date:
26 May 2011 (online)

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Abstract

A highly efficient and straightforward protocol to prepare carbamates from alcohols and hindered amino acids/esters mediated by N,N′-disuccinimidyl carbonate (DSC) in the presence of catalytic amount of pyridine is described. This method could be carried out under mild conditions in one pot, and a wide variety of carbamates were obtained in high yield with excellent purity.

Key words

carbamate - N,N′-disuccinimidyl carbonate - DSC - hindered amino acids/esters - pyridine

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6

General Procedure for Preparation of Carbamate 4 To a solution of alcohol 5 (0.5 g, 3.9 mmol) in anhyd DMF (3 mL) was added DSC (1.2 g, 1.2 equiv) and pyridine (63 µL, 0.2 equiv). The mixture was heated and aged at 40 ˚C
for 15 h until complete activation of 5 was observed as monitored by GC (>99% conversion). The mixture was cooled to ambient temperature for addition of H2O (3 mL), keeping temperature below 30 ˚C. l-tert-Leucine (0.53 g, 1.0 equiv) and K3PO4 (1.66 g, 2 equiv), keeping the reaction temperature below 30 ˚C. The reaction mixture was then stirred at ambient temperature for 3-6 h until complete carbamate formation was observed as monitored by HPLC or TLC. To the reaction mixture was charged H2O (10 mL) and EtOAc (10 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (5 mL). Both organic layers were combined, washed sequentially with 1 N HCl, H2O and brine, and dried (MgSO4). Concentration of the organic solution afforded the carbamate 4 as an oil, amide rotamers exists by NMR spectrum. ¹H NMR (500 MHz, CDCl3): δ = 0.93 (s, 6 H), 1.05 (s, 9 H), 1.35-1.38 (m, 2 H), 2.01-2.06 (m, 2 H), 3.80-3.82 (d, J = 10.0 Hz, 1 H), 3.87-3.89 (d, J = 10.0 Hz, 1 H), 3.98 (br, 0.3 H, minor rotamer), 4.21-4.23 (d, J = 10.0 Hz, 0.7 H, major rotamer), 4.93-4.95 (d, J = 10.0 Hz, 1 H), 5.01-5.04 (d, J = 15.0 Hz, 1 H), 5.27-5.29 (d, J = 10.0 Hz, 0.7 H, major rotamer), 5.78-5.86 (m, 1 H), 6.21-6.22 (br, 0.3 H, minor rotamer). ¹³C NMR (125 MHz, CDCl3): δ = 24.1, 24.3 (minor rotamer), 26.5, 26.9 (minor rotamer), 28.30, 34.0, 34.6, 38.2, 62.0, 63.3 (minor rotamer), 73.2, 73.9 (minor rotamer), 114.1, 139.2, 139.9 (minor rotamer), 156.7, 176.4, 177.2 (minor rotamer).