The development of novel copper-catalysed Csp3 -Csp3 cross- coupling reactions using accessible coupling partners
David Fernandez Aguado 1,2 , David Lindsay 2 and Tim Barrett 1 1 GSK Medicines Research Centre, UK, 2 University of Strathclyde, UK
Transition metal-catalysed cross-coupling reactions have emerged as one of the most reliable and powerful synthetic tools in organic chemistry. In contrast, advances in the development of general methods that form bonds between sp 3 -hybridized carbons (alkyl-alkyl bonds) remain one of the main challenges in the field of cross- coupling chemistry. These drawbacks are mainly due to the slow oxidative addition of alkyl electrophiles and the propensity of metal alkyl species to undergo β -hydride elimination. In recent times, nickel-catalysed cross-couplings have been revealed as efficient methods to activate primary and secondary alkyl electrophiles ( e.g. , alkyl halides) with a variety of nucleophilic coupling partners. 1,2 However, little has been done in the field of copper catalysis. Indeed, this area has seen limited applications in the alkylation of unactivated electrophiles. Thereby, the development of novel platforms that allow the synthesis of alkyl-alkyl bonds through the use of copper, and the expansion to more general and readily accessible cross-coupling partners that are bench-stable, inexpensive, and easily procured, comprises a key area in synthetic chemistry. Herein, we have established that, with the aid of alkyl Katritzky pyridinium salts, selectively prepared from aliphatic amines, 3 and terminal olefins, a copper-based catalyst derived from commercially available components can facilitate Csp 3 –Csp 3 cross-coupling reactions in good yields. In contrast to other electrophile-nucleophile methods described to date, which employ photoredox and a copper catalyst to effect radical and bond formation, 4 this copper-catalysed hydroalkylation of olefins provides a unique disconnection where copper is responsible for the single-electron transfer and bond construction, simultaneously. To achieve this goal, the design and modulation of the alkyl pyridinium salt structure to enhance single electron transfer processes was a key component of our research. The method is operationally simple and uses mild reaction conditions. It has subsequently been used to synthesize a range of novel alkyl-alkyl bonds from a diverse array of alkyl amines and olefins with excellent outcomes. References 1. Choi, J.; Fu, G. C. Science 2017 , 356 , 152–160. 2. Zhang, Z.; Bera, S.; Fan, C.; Hu, X. J. Am. Chem. Soc . 2022 , 144 , 7015–7029. 3. Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. J. Am. Chem. Soc . 2017 , 139 , 5313–5316. 4. Johnston, C. P.; Smith, R. T.; Allmendinger, S.; MacMillan, D. W. C. Nature 2016 , 536 , 322-325.
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