Aromatic Pummerer-Promoted Stereospecific Cross-Coupling of Thiazoles With Boronic Esters
Mark John P Mandigma1, Julien Lefranc2, Louise Eagling2
1School of Chemistry, University of Bristol, Bristol, UK.
Abstract:
Thiazoles are ubiquitous motifs in bioactive molecules, making strategies for the stereospecific installation of chiral C(sp3)-rich substituents on this scaffold particularly valuable for drug discovery. However, achieving such transformations remains nontrivial, as conventional C(sp2)-C(sp3) cross-coupling approaches are often compromised by catalyst deactivation and deleterious side reactions, such as β-hydride elimination. Although electrophile-mediated coupling of alkyl boronic esters with lithiated aromatic compounds offers a potential route to C(sp2)-C(sp3) bond formation, it is ineffective for thiazoles because the heteroaromatic core lacks sufficient nucleophilicity to engage electrophiles and promote productive 1,2-migration. Herein, we report a lithiation-borylation-aromatic Pummerer (LiBAP) strategy that enables stereospecific C5 cross-coupling of thiazoles with boronic esters. A pendant sulfinyl group enables exocyclic electrophilic activation, triggering a Pummerer-type 1,2-migration while avoiding unproductive C─B bond fragmentation. The reaction proceeds with complete stereospecificity and broad functional-group tolerance, furnishing a C2 sulfide handle on thiazole that serves as a versatile linchpin for downstream C-S diversification. A formal asymmetric synthesis of a bioactive thiazole γ-secretase inhibitor was demonstrated to further highlight the synthetic utility of our LiBAP protocol.
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