A novel copper-catalysed C(sp³) -C(sp³) cross-coupling reaction using readily available starting materials David Fernandez Aguado 1,2 , David M. Lindsay 2 , Tim N. Barrett 1 1 GSK Medicines Research Centre, Stevenage, UK, 2 Department of Pure Applied Chemistry, University of Strathclyde, UK Transition metal-catalysed cross-coupling reactions between sp 2 carbon centres have transformed the synthesis of complex organic molecules over the past three decades. In contrast, advances in the development of general methods that form bonds between sp 3 -hybridised carbons (alkyl-alkyl bonds) remain one of the main challenges in the field of cross-coupling chemistry. 1 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 emerged as efficient methods to activate primary and secondary alkyl electrophiles for coupling with a variety of nucleophilic partners. However, there has been relatively little exploration of copper catalysis as related to sp 3 -sp 3 coupling. Indeed, this area has seen limited applications in the alkylation of electronically unbiased 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 challenge in synthetic chemistry. Herein, we have established a copper-catalysed hydroalkylation of olefins with radicals generated from alkyl “Katritzky”-type pyridinium salts, selectively prepared from aliphatic amines ( Figure 1 ). 2 In contrast to other electrophile-nucleophile methods described to date, which employ photoredox techniques and a copper catalyst to effect radical- and bond formation, 3 this copper-catalysed hydroalkylation of olefins represents a unique approach where copper underpins both the radical-generating single-electron transfer and the C-C bond construction. To achieve this goal, the design and modulation of the alkyl pyridinium salt structure, to enhance the single electron transfer process, was a key component of our studies ( Figure 1A ). Our developed method is operationally simple and uses mild reaction conditions, and has been applied to the preparation of a range of alkyl-alkyl bonds (>gt;30 examples) from a diverse array of alkyl amines and olefins, including the late-stage functionalization of drug-like compounds ( Figure 1B ). Given the current focus on pharmaceutically relevant molecules enriched in sp 3 character, this method will allow rapid access to novel regions of 3D chemical space, providing a diverse collection of molecules for compound libraries and leading optimization in drug discovery.
Figure 1 References 1. Choi, J.; Fu, G. C. Science 2017 , 356 , 152–160.
2. Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. J.Am. Chem. Soc . 2017 , 139 , 5313–5316. 3. Johnston, C. P.; Smith, R. T.; Allmendinger, S.; MacMillan, D. W. C. Nature 2016 , 536 , 322-325.
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