Short and Simple Preparation of N-Boc-Protected Anthranilic Acid tert-Butyl Esters from 2-Bromo-Anilines

Abstract

A novel two-step procedure for the preparation of diprotected anthranilic acid derivatives from ortho-bromoanilines is ­described.

Key words

alkyl halides - carboxylic acids - metalations - rearrangements - protecting groups

References

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3

General Procedure - Preparation of 2- tert -butoxy-carbonylamino-5-chlorobenzoic acid tert -butyl ester (3a).
A solution of n-BuLi in hexane (340 µL of 1.6 M) were added dropwise at -78 °C under argon to a solution of N,N-di-tert-butyloxycarbonyl-2-bromo-4-chloroaniline (203 mg, 0.5 mmol) in THF (5 mL). The reaction turned yellow, was stirred for 15 min at -78 °C and treated with sat. aq NH₄Cl solution. The reaction was warmed to r.t., diluted with H₂O and extracted twice with Et₂O. The combined organic layers were washed with sat. aq NaCl solution, dried over Na₂SO₄, filtered and the solvent was evaporated to yield 169 mg (0.5 mmol) of 2-tert-butoxycarbonylamino-5-chlorobenzoic acid tert-butyl ester as a white crystalline solid.
IR (CHCl₃): 3289, 2924, 2854, 1736, 1723, 1683, 1586, 1512, 1457, 1367, 1320, 1249, 1167, 1048, 1025, 898, 824, 786, 772, 717, 653, 532, 498 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 10.28 (br s, 1 H), 8.41 (d, 1 H), 7.88 (d, 1 H), 7.41 (dd, 1 H), 1.61 (s, 9 H), 1.43 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.2, 152.8, 140.8, 133.7, 130.6, 125.9, 120.2, 117.2, 82.9, 80.7, 28.3, 28.2. MS (EI): m/z = 327 (25), 271 (20), 215 (90), 171 (100), 153 (40). HRMS (EI, Q-TOF): m/z calcd for C₁₆H₂₁ClNO₄ [M - H]^-: 326.1159; found: 326.1175.