Waste-Minimized Continuous-Flow Synthesis of Oxindoles Exploiting a Polymer-Supported N Heterocyclic Palladium Carbene Complex in a CPME/Water Azeotrope

Abstract

Herein, we report the development of an effective synthetic protocol for the synthesis of oxindoles in flow based on a C(sp 3 )−H activation process promoted by a supported Nheterocyclic carbene palladium heterogeneous catalytic system using cyclopentyl methyl ether (CPME) as the reaction medium. The design of the catalyst, the selection of the solvent medium, and the definition of a tailored continuous flow reactor have been all designed to establish an efficient waste-minimized process for the intramolecular cyclization of N-methyl-2-halo-acetanilides. The use of CPME in its aqueous azeotropic mixture has allowed us to reach high yields of products with a simplified precipitation workup that includes the downstream process separation and recycling of the solvent. An assessment of the environmental and safety hazard features has also been made in order to better clarify the implications in terms of sustainability of the newly developed process.

Valorisation of phenols to coumarins through one-pot palladium-catalysed double C–H functionalizations

“…Thus, with an increasing demand for sustainable synthesis of biologically active coumarins and in continuation of our interest in formic acid-assisted valorisation 15 of phenols and heterogeneous C–H functionalization processes, 16 we report herein the first heterogeneous palladium-based catalyst system for the synthesis of coumarins and its prenylated derivatives. At the core of this one-pot methodology is the use of commercially available Pd/C in both steps, namely the ortho -alkylation of phenols with alcohols under solvent-free reaction conditions and the coumarin skeleton formation using formic acid as a green reaction medium.…”

Recent Advances in the Synthesis of Five‐membered Nitrogen Heterocycles Induced by Palladium Ions and Complexes

“…The immobilized catalyst developed by the Vaccaro group and used in the synthesis of indolines (see Scheme 39), has also been utilized recently in the fabrication of oxindoles in a flow process to transform N ‐alkyl 2‐bromoacetanilides [108] . With the use of a cyclopentyl methyl ether (CPME)/water azeotrope (1 : 1), reactions were run until full conversion to produce oxindoles with varied substitution patterns (Scheme 82).…”

A General Enantioselective C−H Arylation Using an Immobilized Recoverable Palladium Catalyst

“…[52,53] Very recently, we reported the use of a heterogeneous carbene palladium catalyst (SP-NHC-Pd II ) for a continuous-flow C(sp 3 )À H arylation reaction giving access to oxindoles using cyclopentyl methyl ether (CPME)/ water azeotrope as a reaction medium. [54] Furthermore, in collaboration with the Baudoin group, we reported the first C(sp 3 )À H activation reaction giving access to indolines catalyzed by the same heterogeneous carbene catalyst. [55] In this work, mechanistic investigations provided insight into the mode of action of this catalyst.…”

“…We believe that tools like heterogeneous catalysis, environmentally‐friendly reaction media and continuous‐flow reactors can increase the overall sustainability of catalytic processes and can limit waste production [52,53] . Very recently, we reported the use of a heterogeneous carbene palladium catalyst (SP‐NHC‐Pd II ) for a continuous‐flow C(sp 3 )−H arylation reaction giving access to oxindoles using cyclopentyl methyl ether (CPME)/water azeotrope as a reaction medium [54] …”