High‐Pressure‐Promoted Multicomponent and Metal‐Free Synthesis of Polyfunctionalized Biaryls

Abstract

An efficient and metal‐free synthesis of biaryls and heterobiaryls has been developed through a key three‐component reaction involving benzylideneacetones, isopropenyl acetate and methyl propiolate under high pressure (9 kbar) and mild reaction temperatures (40 °C). The described synthetic protocol provides rapid access to novel, highly functionalized and metal‐uncontamined 1,1′‐biaryls and heterobiaryls in an energy‐ and step‐economic fashion.

Scalable Multicomponent Synthesis of (Hetero)aryl‐Substituted Phenyls: Focus on Metal‐Free Halogenated Biaryls, 3‐Arylindoles, and Isourolithine A Synthesis

“…GC–MS analysis of the crude mixture showed the presence of unreacted 1a and the corresponding enol acetate intermediate in 1:1 ratio, as well as traces of 2a . Next, the reaction was carried out under hyperbaric conditions in a DCM filled Teflon vial (Entry 2) following a previously reported procedure . The substrate was regioselectively converted into the corresponding 2,5‐substituted cycloadduct which was quickly filtered through a silica pad and oxidised with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) to give biaryl 2a in good yield.…”

“…Benzylidene acetones 1a , 1g–h and 1k are commercially available. Benzylidene acetones 1b‐d and 1j were prepared by base‐catalysed aldol condensation with acetone from the corresponding aldehydes . (Hetero)arylidene acetones 1e–f and 1l–s were prepared by Wittig reaction with 1‐(triphenylphosphoranylidene)propan‐2‐one from the corresponding aldehydes .…”

“…Our research group has recently identified high pressure‐promoted Diels‐Alder reaction as a key step to accomplish metal‐free synthesis of biaryls, even achieving the total synthesis of biaryl‐containing biologically active natural compounds in a few steps , . Coupling this strategy with the advantages of multicomponent reactions to generate in situ an electron‐rich diene, a palette of functionalised aromatics has been prepared under hyperbaric conditions , …”

Transition‐Metal‐Free Heterobiaryl Synthesis via Aryne Coupling

“…Recently, the drive for sustainable alternatives avoiding the use of expensive and potentially toxic transition metals has stimulated efforts for the development of metal‐free “greener” synthetic methods, such as the direct arylation of heteroarenes . These processes often rely on radical‐type mechanisms combining for example the use of aryl halides with a diaryliodonium salt, or a metal‐alkoxide with amine bases .…”

New Revolution in Biaryl Synthesis: Transition Metal‐Free C–C Bond Formation Promoted by the Mixture of 2‐Mercaptoethanol/KOH/DMSO

“…Additionally, a number of aromatic C−C cross‐coupling reactions by the electrochemical approach have been developed, such as anodic oxidation can be used to produce cross‐coupling products, but their exhibit low selectivity. Also, other routes have been developed for biaryl synthesis, include photosplicing (can be performed in a standard chemistry laboratory without the need of a flow photoreactor) and high‐pressure‐promoted multicomponent combination (through a key three‐component reaction involving benzylideneacetones, isopropenyl acetate, and methyl propiolate). The described synthetic process required longer reaction time to obtain a reasonable yield.…”