An Efficient Access to 3,5‐Disubstituted Isoxazoles with Anthranilate Ester Moiety: Alkaloid Lappaconitine – Aryl Conjugates with an Isoxazole Linker

Abstract

Alkynones have gained great attention as useful building blocks in organic synthesis. They have been emerged as key intermediates in the synthesis of various heterocycles. In the present study, the alkynylketones derived from antranylic acids esters or alkaloid lappaconitine were employed as a platform for late‐stage derivatisation. The synthesis of regioisomeric 3,5‐diarylisoxazoles was achieved starting from ethyl N‐acetyl‐5‐iodoanthranilate. A range of 3,5‐disubstituted isoxazoles, containing the plant alkaloid lappaconitine moiety at the C‐3 position were convenience synthesized by a consecutive three‐component alkynylation‐cyclocondensation sequence starting from of 5′‐ethynyllappaconitine, aroyl chlorides, and hydroxylamine hydrochloride. Notably, several 5‐hydroxy‐4,5‐dihydroisoxazoles were obtained in good yields as main products in this three component reaction by using Et3N as the base and i‐PrOH as the solvent in cyclocondensation step.

Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine–1,5-Benzodiazepine Hybrids

“…These processes suffer from one or other limitations, such as requiring harsh conditions, expensive reagents, low or moderate yields, relatively long reaction times, and the occurrence of several side reactions. As a model reaction for synthesis of lappaconitine-3 H -1,5-benzodiazepine hybrids, which are exemplified in the present article, we studied the synthesis of 1,3-diarylprop-2-yn-1-one 3 by the acyl Sonogashira reaction of methyl 2-( N -acetylamino)-5-ethynylbenzoate 4 [ 46 ] with 4-bromobenzoyl chloride 5a , in previously described conditions [ 47 , 48 ], and the cyclocondensation reaction of alkynyl ketone 3 with o -phenylenediamine 6 ( Scheme 1 ). For the last step, the choice of acetic acid has been beneficial to facilitate the cyclization step of the non-cyclic intermediate—Michael addition product.…”