A challenging redox neutral CpCo(III)-catalysed alkylation of acetanilides with 3-buten-2-one: synthesis and key insights into the mechanism through DFT calculations

• Published in: Beilstein journal of organic chemistry 2018-09, Vol.14 (1), p.2366-2374
• Main Authors: Kenny, Andrew, Pisarello, Alba, Bird, Arron, Chirila, Paula G, Hamilton, Alex, Whiteoak, Christopher J
• Format: Article
• Language: English
• Subjects: acetanilides; Alcohol; Alkylation; Catalysis; Chemistry; Cobalt; cobalt catalysis; C–H activation; DFT studies; Full Research Paper; Metals; Palladium
• ISSN: 1860-5397; 2195-951X; 1860-5397
• DOI: 10.3762/bjoc.14.212

Traditional, established palladium cross-coupling procedures are widely applied in complex molecule synthesis; however, there is a significant disadvantage in the requirement for pre-functionalised substrates (commonly halides/triflates). Direct C-H activation protocols provide the opportunity for a novel approach to synthesis, although this field is still in its relative infancy and often transferability between substrate classes remains unresolved and limitations not fully understood. This study focuses on the translation of an established Cp*Co(III)-catalysed alkylation of benzamides to related acetanilides using 3-buten-2-one as coupling partner. The developed procedure provides a wide substrate scope in terms of substituted acetanilides, although the optimised conditions were found to be more forcing than those for the corresponding benzamide substrates. Interestingly, density functional theory (DFT) studies reveal that the major impediment in the mechanism is not the C-H activation step, but instead and unexpectedly, effective competition with more stable compounds (resting states) not involved in the catalytic cycle.