Mechanical activation of zinc and manganese and their application in nickel-catalysed cross-electrophile coupling Matthew T. J. Williams 1 , Louis C. Morrill 1 and Duncan L. Browne 2 1 Cardiff Catalysis Institute, School of Chemistry, Cardiff University, UK, 2 School of Pharmacy, University College London, UK So-called cross-electrophile coupling (XEC) has shown promise over traditional cross-coupling in recent years. This process involves two substrates that are electrophilic in nature, such as a C(sp 2 ) aryl halide and a C(sp 3 ) alkyl halide, reacting to selectively form the cross-coupled product. 1 A key benefit of this approach over traditional cross-coupling is the avoidance of a ‘nucleophilic’ reaction component e.g. boronic acids/esters, organozincs, Grignard reagents, etc., which can cause selectivity issues or poorer functional group tolerance in late-stage functionalisation processes. However, these XEC processes are not without their own drawbacks, such as the need for activation of a reducing species (typically zinc or manganese), use of inert glovebox set-ups, and the need for long reaction times. Previous work from our group has demonstrated direct activation of zinc and manganese using mechanochemical ball-milling, including nickel-catalysed XEC under ball-milling conditions. 2,3 Building on this work, we have successfully applied the mechanical activation of zinc and manganese to the synthesis of alkylated N -heteroarenes, for example pyridines, and 3,3-disubstituted oxindoles, respectively (see scheme). Both processes demonstrate good substrate scope and a variety of alkyl halide electrophiles are tolerated. Radical clock experiments revealed the likely presence of radical intermediates, which is in agreement with solution-based processes, as well as our previous work.
References 1. For some reviews on cross-electrophile coupling, see a) D. J. Weix, Acc. Chem. Res. , 2015, 48 , 1767–1775; b) D. A. Everson and D. J. Weix, J. Org. Chem., 2014, 79, 4793–4798. 2. W. I. Nicholson,J. L. Howard,G. Magri,A. C. Seastram,A. Khan,R. R. A. Bolt,L. C. Morrill,E. Richards,D. L. Browne, Angew. Chem. Int. Ed. , 2021, 60 ,23128-23133. 3. A. C. Jones, W. I. Nicholson, J. A. Leitch and D. L. Browne, Org. Lett. , 2021, 23 , 6337–6341.
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