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Synthesis of beta-hidroxyesters and beta-ketoesters via Reformatsky reaction under continuous flow conditions
Juan Munoz, Postdoctoral Researcher, Janssen Cilag
The Reformatsky reaction is an efficient approach to C–C bond formation and has been used extensively for the synthesis of a wide range of different compounds.
In recent years flow chemistry has appeared as a novel technology that, among other advantages, allows very efficient heat transfer, good control of reaction temperature and enhanced mass transfer. It resolves the problems associated with highly exothermic reactions and dangerous or air- and moisture-sensitive compounds, commonly present in Reformatsky type reactions.
A safe flow version of the Reformatsky reaction is described avoiding competing side reactions and the exothermicity. The Reformatsky reaction takes place in a Zn filled column, with the in situ formation of the organozinc reagent and further reaction with the correspondent electrophile. The procedure can be applied to a wide variety of ketones and nitriles. Different alpha-bromoesters can be used as well. The compounds obtained are used for the preparation of novel heterocyclic scaffolds in a one pot procedure.
Selective Debenzylation of N-Benzyloxypyrazinones in Flow
Cedrick Veryser , PhD student,
By using flow technology, we have succeeded in delivering a reproducible methodology for the selective debenzylation of O-benzyl protected cyclic hydroxamates, with a potential of scaling up from milligram scale to gram scale via suitable flow operations. This solved reproducibility problems experienced earlier using batch reaction conditions and finally allowed the efficient, safe, and reproducible synthesis of a library of 28 N-hydroxypyrazin-2(1H)-one analogues.
Mechanistic Understanding and Scaling of C-H Bond Activation Reactions
Jacek Zakrzewski, Student, University of Cambridge
Continuous flow processes represent a paradigm change in the manufacture of fine chemicals, specialties and pharmaceuticals due to the demonstrable gains in efficiency and product quality. Despite this, the transition of novel synthetic organic transformations of potential impact to drug synthesis into continuous flow processes is often slow due to the apparent complexity and poor understanding of the new reactions. Therefore, the parallel development of new catalytic transformations and continuous flow processes in an important challenge to the continued advance of synthetic organic chemistry and reaction engineering.
Here we describe our initial studies towards the merger of palladium-catalyzed C–H activation and continuous flow synthesis. Based on thorough mechanistic understanding, we have developed a palladium catalyzed C–H amination reaction for the continuous flow synthesis of aziridines. Designing the process from first principles using quantum mechanical modelling and microkinetic model provided us with an in-depth understanding of the investigated reaction and allowed sensible process design and easier translation into continuous flow system.
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