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

doi:10.1055/s-0030-1260584

LETTER

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;

Abstract

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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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References

References and Notes

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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).

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