A Straightforward Access to [¹⁴C]- and [¹³C]-Labeled 2-Aminobenzoxazoles and Benzothiazoles via a KCN Polarity Inversion Strategy

Abstract

A convenient one-pot synthetic access to 2-aminobenzoxazoles and 2-aminobenzothiazoles has been developed. The protocol uses KCN as starting material and proceeds through an in situ polarity inversion step. This approach provides a new valuable and straightforward entry to carbon-14-radiolabeled pharmaceutically relevant heterocycles and substantially reduces as well the amount of radioactive wastes generated.

Key words

2-aminobenzoxazoles - 2-aminobenzothiazoles - electrophilic cyanating agent - isotopic labeling - carbon - cyanide

• References and Notes

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• 20 General Procedure: The One-Pot Synthesis of 2-Aminobenzoxazoles To a stirred suspension of finely ground [¹²C]-KCN or [¹³C]-KCN (1 mmol, 1 equiv) in anhydrous MeCN (5 mL) was added 1-chloro-1H-benzo[d][1,2,3]triazole (1 mmol, 1 equiv) at 0 °C. After 3 h, the mixture was allowed to warm to room temperature and stirred overnight (20 h). The 2-aminophenol or 2-aminothiazole derivative (1.2 mmol, 1.2 equiv) was added to the suspension, and the resulting mixture was refluxed for 3 h. After dilution with EtOAc (50 mL), the organic phase was washed three times with 1 N NaOH aq solution (25 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. Purification of the crude material by column chromatography on silica gel (CH₂Cl₂–MeOH = 20:1) gave the expected benzo[d]oxazol-2-amine or benzo[d]thiazol-2-amine derivative. [2-¹³C]-Benzo[d]oxazol-2-amine (1a) White solid (82 mg, 61% yield); mp 130–131 °C. Isotopic enrichment: 99% (based on MS-ESI); TLC (silica gel Merck 60F254, CH₂Cl₂–MeOH = 20:1); R_f  = 0.27. ¹H NMR (400 MHz, CDCl₃): δ = 7.35 (m, 1 H), 7.28 (m, 1 H), 7.19 (dt, J = 7.7, 1.2 Hz, 1 H), 7.07 (dt, J = 7.7, 1.2 Hz, 1 H), 5.35 (br s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 162.18 (¹³C enriched), 148.45 and 148.40 (d, J = 4.6 Hz), 142.49, 123.92, 121.14, 116.24 and116.15 (d, J = 9.2 Hz), 108.93 and 108.88 (d, J = 4.6 Hz). IR: ν = 3319, 3161, 1679, 1640, 1547, 1463, 1379, 1358, 1255, 1110, 959, 897, 740, 669, 536 cm^–1. ESI-MS: m/z 136 [M + H]⁺. MS (EI): m/z = 135 (100) [M]⁺.