An Efficient One-Pot Synthesis of Azidoformates from Alcohols Using
Triphosgene: Synthesis of N-Carbobenzyloxy Azetidin-2-ones

Abstract

An efficient use of triphosgene for the preparation of various azidoformates from alcohols and sodium azide is described. The method is applied to various chiral alcohols including glucose diacetonide to get the corresponding azidoformates. One of these azidoformates has been successfully utilized for the synthesis of N-carbobenzyloxy-β-lactams.

Key words

azidoformate - alcohol - sodium azide - triphosgene - azetidin-2-one

References

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9

General Experimental Procedure for the Preparation of Azidoformates: To a stirred solution of alcohol (1 mmol) and sodium azide (2 mmol) in acetone (10 mL) was added triethylamine (1.5 mmol) at 0 °C. The reaction mixture was stirred at this temperature for 15 min and a solution of triphosgene (0.5 mmol) in acetone (5 mL) was added dropwise at 0 °C over about 15 min. The reaction mixture was stirred at this temperature for 1 h and slowly allowed to warm up to room temperature. It was stirred for 24 h at room temperature. The reaction mixture was filtered to remove insoluble salts and the filtrate was diluted with an equal volume of water. It was extracted with EtOAc (3 × 20 mL) and the organic extract was washed with water (10 mL) and brine (10 mL) and dried (Na₂SO₄). The solvent was removed and the residue was purified by column chromatography to get pure azidoformate in good yield (Table [1] ). [CAUTION: We did not observe any untoward incidence while working with azidoformates. However, the use of hood and safety shield is recommended as tert-butyl azidoformate is known to decompose above 80 °C with apparent detonation. [13] ].
Spectral data for benzyl azidoformate ¹H NMR (CDCl₃, 200MHz): δ 5.25 (s, 2 H), 7.45 (s, 5 H); IR (KBr, CHCl₃) 2166, 2140, 1736, 1498, 1456, 1377, 1236 cm^-1; Anal. Calcd for C₈H₇N₃O₂: C, 54.23; H, 3.98; N, 23.71. Found: C, 54.47; H, 3.95; N, 23.67.

12

General Experimental Procedure for the Synthesis of N-Carbobenzyloxy-β-lactams (4a-f): To a solution of benzyl azidoformate (1 mmol) in toluene (10 mL) was added triphenyl phosphine (1 mmol) and the reaction mixture was stirred at room temperature for 3 h. Aldehyde (1 mmol) was added to the reaction and refluxed for 8-10 h. Solvent was removed under reduced pressure and dry diethyl ether
(15 mL) was added to the residue. The solid triphenyl phosphineoxide separated was removed by filtration and the solvent was removed to get imine 3. These imines were found to be unstable and used further without purification.
A solution of above imine (1 mmol) in dichloromethane (15 mL) and triethylamine (4 mmol) was cooled to 0 °C and a solution of acid chloride in CH₂Cl₂ (10 mL), was added slowly with stirring in about 20 min. The reaction mixture was allowed to warm up to room temperature and stirred for 18 h. It was washed with water (15 mL), saturated sodium bicarbonate solution (10 mL), brine (10 mL) and dried over sodium sulfate. Solvent was removed under reduced pressure and the crude product was purified by column chromatography to get β-lactams 4a-f in good yield.
Spectral data for β-lactam (4a): ¹H NMR (CDCl₃, 200 MHz): δ 3.87 (d, J = 14.7 Hz, 1 H), 4.75 (d, J = 4.4 Hz, 1 H), 4.91 (d, J = 14.7 Hz, 1 H), 5.40 (d, J = 4.4 Hz, 1 H), 6.70 (d, J = 7.8 Hz, 2 H), 6.85 (t, J = 7.8 Hz, 1 H), 7.10-7.33 (m, 12 H); ¹³C NMR (CDCl₃, 50.3 MHz) 44.10, 61.34, 82.04, 115.45, 121.84, 127.84, 128.13, 128.53, 128.76, 129.05, 132.61, 134.67, 156.80, 159.56, 165.48; IR (KBr, CHCl₃) 1758, 1596, 1494, 1236 cm^-1; Anal. Calcd for C₂₃H₁₉NO₄: C, 73.98; H, 5.12; N, 3.75. Found: C, 73.79; H, 4.98; N, 3.77.