C–H Activation: A Versatile Tool for the Synthesis of Niclosamide and Its Derivatives

Abstract

A novel strategy has been developed for the direct and regioselective ortho-acetoxylation of N-(2-benzoylphenyl)benzamides through C–H activation using a catalytic amount of Pd(OAc)₂ (5 mol%) and a stoichiometric amount of PhI(OAc)₂ in a mixture of acetic anhydride and acetic acid. By using this protocol, a new series of niclosamide derivatives was produced in good yields. This is the first report on the synthesis of niclosamide and its derivatives by means of C–H functionalization. This newly developed method offers several advantages such as high regioselectivity, operational simplicity, and good to excellent yields. It provides a short three-step process for the synthesis of niclosamide involving acid–amine coupling, ortho-acetoxylation through C–H activation, and deacylation.

Key words

C–H bond activation - transition-metal catalysis - acetoxylation - niclosamide

Publication History

Received: 25 July 2024

Accepted after revision: 16 September 2024

Accepted Manuscript online:
16 September 2024

Article published online:
07 October 2024

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• 27 4-Chloro-2-{[(2-chloro-4-nitrophenyl)amino]carbonyl}phenyl Acetate (2); Typical Procedure PhI(OAc)₂ (1.14 g, 3.54 mmol) was added with stirring to 3-chloro-N-(2-chloro-4-nitrophenyl)benzamide (1; 1.0 g, 3.22 mmol) in 1:1 AcOH–Ac₂O (10 mL), and the mixture was stirred for 5 min. Pd(OAc)₂ (5 mol%, 36 mg) was then added at r.t., and the mixture was heated to 100 °C for 12 h until the reaction was complete (TLC). The resulting mixture was extracted with EtOAc (2 × 150 mL), and the combined organic layers were washed with H₂O (50 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 10–15% EtOAc–hexane) to give a white solid; yield: 0.71 g (60%); mp 156–157 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.05 (s, 1 H), 8.85 (d, J = 9.2 Hz, 1 H), 8.35 (d, J = 2.5 Hz, 1 H), 8.23 (dd, J = 9.2, 2.5 Hz, 1 H), 7.97 (d, J = 2.6 Hz, 1 H), 7.55 (dd, J = 8.7, 2.6 Hz, 1 H), 7.18 (d, J = 8.7 Hz, 1 H), 2.40 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 168.3, 162.2, 146.4, 143.4, 140.1, 133.2, 132.4, 130.6, 128.1, 125.1, 124.8, 123.8, 122.3, 120.7, 21.3. HRMS (ESI): m/z [M – H]⁺ calcd for C₁₅H₉Cl₂N₂O₅: 366.98940; found: 366.99077.