Simple and versatile electrochemical synthesis of highly substituted 2,1-benzisoxazoles

Abstract

A sustainable, general and scalable electrochemical protocol for direct access to 3-(acylamidoalkyl)-2,1-benzisoxazoles by cathodic reduction of widely accessible nitro arenes is established. The method is characterised by a simple undivided set-up under constant current conditions, inexpensive and reusable carbon-based electrodes, and environmentally benign reaction conditions. The versatility of the developed protocol is demonstrated on 39 highly diverse examples with up to 81% yield. A 50-fold scale-up electrolysis highlights its relevance for preparative applications.

Fig. 1. Biologically active isoxazoles and anthranils: potent hallucinogen muscimol (1), neurological modulator for the treatment of mental disorders (2), and the drug candidate showing anti-cancer activity (3).

Fig. 2. Previous work on the electrochemical synthesis of 2,1-benzisoxazoles.

Fig. 3. Possible reaction pathways for the electrochemical reduction of N-(2-nitrophenacyl)acetamide 4a and a control experiment of the reduction of N-(2-hydroxy-2-(2-nitrophenyl)ethyl)acetamide 6a′.

Fig. 4. Scope of the electrochemical synthesis of 3-(acetamidomethyl)benzo[c]isoxazoles by cathodic reduction of nitro arenes; isolated yields. ^aThe corresponding N-Boc-protected substrate was used as the starting material.

Fig. 5. Scope of the electrochemical synthesis of 3-alkyl/-aryl substituted 2,1-benzisoxazoles; isolated yields; ^a3.0 mmol scale, ^b0.15 mmol scale.

Scheme 1. Proposed mechanism for the electrochemical formation of 2,1-benzisoxazoles 5 from 2-nitroacetophenones 4.