Org. Process Res. Dev. 2023, 27, 7, 1210–1219, https://doi.org/10.1021/acs.oprd.3c00206

Efficient and reliable methodologies for C–C bond formation are of utmost importance in industries such as pharmaceuticals, where the synthesis of complex molecules is crucial. To address the technical challenges associated with using organometallics for library synthesis and to maximize productivity, a team comprising Dixon, de la Hoz, Alcázar, and their colleagues from the University of Oxford, Universidad de Castilla-La Mancha, and Janssen Research and Development, respectively, developed an innovative C(sp3)–C(sp3) bond-forming procedure ( Org. Lett., DOI: 10.1021/acs.orglett.3c01390). This method involves the reductive coupling of tertiary amides with nucleophilic attack of organozinc reagents generated in situ from the corresponding alkyl halides and demonstrates excellent chemoselectivity and high functional group tolerance, making it suitable for late-stage functionalization. The procedure exhibits a wide scope with drug-like compounds and can be implemented in a fully automated multistep continuous flow setup for library generation and gram-scale synthesis of single targets. Remarkably, the process achieves high throughput, measured in grams per hour, further enhancing its applicability and efficiency in industrial settings.