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Recyclable NHC catalyst for the development of a generalized approach to continuous Buchwald-Hartwig reaction and work-up

Chartoire, Anthony and Claver, Carmen and Corpet, Martin and Krinsky, Jamin and Mayen, Julie and Nelson, David and Nolan, Steven P. and Peñafiel, Itziar and Woodward, Robert and Meadows, Rebecca E. (2015) Recyclable NHC catalyst for the development of a generalized approach to continuous Buchwald-Hartwig reaction and work-up. Organic Process Research and Development. ISSN 1083-6160

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    A generalized approach to the optimization and implementation of Buchwald-Hartwig reactions in flow is reported, through the combination of three key factors: a highly active palladium catalyst; a universal approach for continuous work-up and purification, and a methodology for catalyst recycling and reuse. The palladium N-heterocyclic carbene (NHC) pre-catalyst [Pd(IPr*)(cin)Cl] 4 (IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene; cin = η3-cinnamyl) is an excellent choice for continuous Buchwald-Hartwig reactions, due to its inherent high activity and stability. In preparation for running this reaction in flow (published concurrently), a detailed study has been carried out into its water stability, ultimately allowing the recycling of the catalyst in the organic phase up to 3 times in batch mode. A “right-first-time” work-up methodology has also been developed, resulting in a universal protocol that allows the selective extraction of the Buchwald-Hartwig product into the aqueous stream as a salt, while retaining the aryl bromide starting material in the organic stream with the catalyst, thus negating the requirement for further purification. It is therefore envisaged that this approach will particularly amenable to exploitation in the Pharmaceutical industry. An optimized, scalable synthesis of [Pd(IPr*)(cin)Cl] is also reported on multi-hundred gram scale.