Synthesis of Trisubstituted Isoxazoles by Palladium(II)-Catalyzed Cascade Cyclization–Alkenylation of 2-Alkyn-1-one O-Methyl Oximes

Abstract

A palladium-catalyzed, cascade 5-endo-dig cyclization-alkenylation synthesis of isoxazoles has been developed. The addition of 1 equiv of n-Bu(4)NBr significantly increases the yield of the desired 4-alkenyl-3,4,5-trisubstituted isoxazoles. A variety of trisubstituted isoxazoles are prepared in moderate to excellent yields. One example of the synthesis of a naphthoisoxazole is reported by a cascade cyclization-alkenylation-Heck reaction.

Novel (N‐heterocyclic carbene)Pd(pyridine)Br2 complexes for carbonylative Sonogashira coupling reactions: Catalytic efficiency and scope for arylalkynes, alkylalkynes and dialkynes

“…Ynones (α,β‐acetylenic carbonyl compounds) are important structural moieties found in natural products, biologically active compounds and agrochemicals . They are also precursors for the synthesis of a variety of organic compounds, especially aromatic heterocycles such as pyrazoles, quinolones, furans and pyrimidines …”

Iron‐Mediated Ring‐Opening and Rearrangement Cascade Synthesis of Polysubstituted Pyrroles from 4‐Alkenylisoxazoles

“…A series of 4‐alkenylisoxazoles 1 were synthesized by a palladium‐catalyzed cascade cyclization‐alkenylation protocol previously reported by our group . We chose ( E )‐3‐( tert ‐butyl)‐5‐phenyl‐4‐styrylisoxazole 1 a as the model substrate for reaction condition optimization, and first employed the conditions reported in our previous iron‐catalyzed reductive ring‐opening of 3,5‐disubstituted isoxazoles .…”

Cyclocondensation of Hydroxylamine with 1,3‐Bis(het)arylmonothio 1,3‐Diketones and 1,3‐Bis(het)aryl‐3‐(methylthio)‐2‐prop­enones: Synthesis of 3,5‐Bis(het)arylisoxazoles with Complementary Regioselectivity

“…Fokin's group has reported routes to 3,5‐/3,4‐disubstituted and 3,4,5‐trisubstituted isoxazoles based on the copper‐8a,8b or ruthenium‐8ccatalysed [3+2] cycloaddition of various nitrile oxides with terminal/internal alkynes. Similarly, Larock9a,9b has described iodine‐catalysed electrophilic cyclization of O ‐methyloximes of acetylenic ketones to give 3,5‐substituted‐4‐iodooxazoles, which can be transformed further into 3,4,5‐substituted isoxazoles by palladium‐catalysed cross‐coupling 9b,9c. In parallel strategies, Miyata and co‐workers have developed a practical synthesis of 3,5‐disubstituted isoxazoles by silver‐catalysed cyclization of O ‐benzylalkynyloxime ethers,10a along with a gold‐catalysed domino reaction of O ‐allylalkynyloxime ethers involving cyclization and subsequent Claisen‐type rearrangement to give trisubstituted isoxazoles in a highly regioselective manner 10b.…”