Merging TBADT hydrogen atom transfer with nickel catalysis for cross-coupling and hydroacylation Vetrivelan Murugesan, Anirban Ganguly, Ardra Karthika, Anjana Muralidharan, Tamilselvi Chinnusamy, Ramesh Rasappan IISER-TVM, India
Catalyst controlled site-selective C−H functionalization is a challenging but powerful tool in organic synthesis. Polarity-matched and sterically controlled hydrogen atom transfer (HAT) provides an excellent opportunity for site- selective functionalization. As such, the dual Ni/photoredox system was successfully employed to generate acyl radicals from aldehydes via selective formyl C−H activation and subsequently cross-coupled and hydroacylated to generate ketones, a ubiquitous structural motif presents in the vast majority of natural and bioactive molecules. However, only a handful of examples that are constrained to the use of aryl halides in cross-coupling are developed. Given the wide availability of amines, we developed a cross-coupling reaction via C−N bond cleavage using the economic nickel and TBADT catalyst for the first time. A range of alkyl and aryl aldehydes were cross- coupled with benzylic and allylic pyridinium salts to afford ketones with a broad spectrum of functional group tolerance. High regioselectivity toward formyl C–H bonds even in the presence of α-methylene carbonyl or α-amino/oxy methylene was obtained. Hydroacylation of alkynes is undoubtedly the simplest and most atom-efficient approach for synthesizing enones with diverse synthetic applications. Despite major advances in hydroacylations, there are currently no hydroacylations that utilize aldehydes without a chelating group, especially when combined with terminal alkynes. This adversely affects atom/step economy in addition to difficulties may arise from decarbonylation of aryl aldehydes, cyclotrimerization of terminal alkynes, and parallel HAT events due to the presence of multiple hydridic C−H bonds such as α-amino and α-oxy C−H bonds. We present here a synergistic nickel-photocatalytic system that enables a highly regio- and stereo-selective hydroacylation of unactivated aldehydes and alkynes under milder condition without a need for chelating groups. References 1. C–H Alkylation of Aldehydes by Merging TBADT Hydrogen Atom Transfer with Nickel Catalysis. Org. Lett. 2021 , 23 , 14, 5389–5393 ( most read article ). Vetrivelan Murugesan, Anirban Ganguly, Ardra Karthika, and Ramesh Rasappan * 2. Photoredox-Ni Dual Catalysis: Chelation Free Hydroacylation of Terminal Alkynes. Manuscript under review . Vetrivelan Murugesan, Anjana Muralidharan, Tamilselvi Chinnusamy, Ramesh Rasappan * 3. Selective sp3 C–H alkylation via polarity-match-based cross-coupling. Nature 2017 , 547 , 79–83. Chip Le, Yufan Liang, Ryan W. Evans, Ximing Li & David W. C. MacMillan * 4. Photoinduced Nickel-Catalyzed Chemo- and Regioselective Hydroalkylation of Internal Alkynes with Ether and Amide α-Hetero C(sp3)H Bonds. J. Am. Chem. Soc. 2017 , 139 , 38, 13579–13584. Hong-Ping Deng, Xuan-Zi Fan, Zhi-Hui Chen, Qing-Hua Xu, and Jie Wu*
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