Direct Synthesis of Acyl Azides from Carboxylic Acids by the Combination of Trichloroacetonitrile, Triphenylphosphine and Sodium Azide

Abstract

Various carboxylic acids were converted into acyl azides in excellent yields by treating with trichloroacetonitrile, triphen­ylphosphine and sodium azide at room temperature. The reaction was applicable to the preparation of dipeptide without rearrangement.

carboxylic acids - azides - peptides - acylations - trichloroacetonitrile

References and Notes

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14

Typical Experimental Procedure: To a mixture of benzoic acid (122 mg, 1.0 mmol), triphenylphosphine (525 mg, 2.0 mmol) and sodium azide (78 mg, 1.2 mmol) in anhyd acetone (2 mL) under argon was added trichloroacetonitrile (0.2 mL, 2.0 mmol) dropwise at r.t. The reactants were allowed to react for 30 min. After concentration of the reaction mixture by a rotary evaporator, the residue was then diluted with CH₂Cl₂ (4 mL), and washed with H₂O (2 mL). The organic layer was dried over anhyd MgSO₄. After filtration, the solvent was removed and the residue was purified by column chromatography on silica gel (hexanes-EtOAc, 2:1) to give benzoyl azide (141 mg, 96%).

15

N-Fmoc-l-Ala-N₃: mp 162-164 ˚C (lit.^¹7 mp 162 ˚C); [α]_D ^²5 16.3 (c = 1, CHCl₃) (lit.^¹7 [α]_D -16). ^¹H NMR (300 MHz, CDCl₃): δ = 1.41 (d, J = 2.2 Hz, 3 H), 3.86 (m, 1 H), 4.22 (t, J = 2.3 Hz, 1 H), 4.41 (d, J = 2.3 Hz, 2 H), 5.28 (s, 1 H), 7.22-7.84 (m, 8 H).

16

N-Fmoc-Ala-Leu-OMe: mp 124-126 ˚C (lit.^²c mp 123-126 ˚C); [α]_D ^²5 -28.1 (c = 1, CHCl₃) (lit.^²c [α]_D -25.2). ^¹H NMR (300 MHz, CDCl₃): δ = 0.92 (s, 6 H), 1.42 (d, J = 2.2 Hz, 3 H), 1.55 (m, 1 H), 1.64 (m, 2 H), 3.71 (s, 3 H), 4.23 (t, J = 2.4 Hz, 1 H), 4.30 (t, J = 2.2 Hz, 1 H), 4.40 (d, J = 2.4 Hz, 2 H), 4.61 (q, J = 1.6 Hz, 1 H), 5.42 (s, 1 H), 6.37 (s, 1 H), 7.25-7.82 (m, 8 H).

17 Cho DH. Jang DO. Tetrahedron Lett.  2004,  45:  2285