More Like this

1. Copper‐Catalyzed C(sp ³ )−H α‐Acetylation: Generation of Quaternary Centers

   https://doi.org/10.1002/anie.202418692  

   Okoromoba, Otome E; Chen, Ting‐An; Jang, Eun Sil; McMullin, Claire L; Cundari, Thomas R; Warren, Timothy H (January 2025, Angewandte Chemie International Edition)

   Abstract α‐substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in natural products and pharmaceuticals. We report the α‐acetylation of C(sp³)−H substrates R−H with arylmethyl ketones ArC(O)Me to provide α‐alkylated ketones ArC(O)CH₂R at RT with^tBuOO^tBu as oxidant via copper(I) ‐diketiminato catalysts. Proceeding via alkyl radicals R•, this method enables α‐substitution with bulky substituents without competing elimination that occurs in more traditional alkylation reactions between enolates and alkyl electrophiles. DFT studies suggest the intermediacy of copper(II) enolates [Cu^II](CH₂C(O)Ar) that capture alkyl radicals R• to give R−CH₂C(O)Ar outcompeting dimerization of the copper(II) enolate to give the 1,4‐diketone ArC(O)CH₂CH₂C(O)Ar. 

   more » « less
2. Transition-metal-free C(sp ³ )–H/C(sp ³ )–H dehydrogenative coupling of saturated heterocycles with N -benzyl imines

   https://doi.org/10.1039/D0SC00031K  

   Liu, Zhengfen; Li, Minyan; Deng, Guogang; Wei, Wanshi; Feng, Ping; Zi, Quanxing; Li, Tiantian; Zhang, Hongbin; Yang, Xiaodong; Walsh, Patrick J. (January 2020, Chemical Science)

   A unique C(sp 3 )–H/C(sp 3 )–H dehydrocoupling of N -benzylimines with saturated heterocycles is described. Using super electron donor (SED) 2-azaallyl anions and aryl iodides as electron acceptors, single-electron-transfer (SET) generates an aryl radical. Hydrogen atom transfer (HAT) from saturated heterocycles or toluenes to the aryl radical generates alkyl radicals or benzylic radicals, respectively. The newly formed alkyl radicals and benzylic radicals couple with the 2-azaallyl radicals with formation of new C–C bonds. Experimental evidence supports the key hydrogen-abstraction by the aryl radical, which determines the chemoselectivity of the radical–radical coupling reaction. It is noteworthy that this procedure avoids the use of traditional strong oxidants and transition metals. 

   more » « less
3. Iron-catalyzed C(sp ² )–C(sp ³ ) cross-coupling at low catalyst loading

   https://doi.org/10.1039/C8CY02374C  

   Bisz, Elwira; Kardela, Marlena; Piontek, Aleksandra; Szostak, Michal (March 2019, Catalysis Science & Technology)

   The iron-catalyzed C(sp 2 )–C(sp 3 ) cross-coupling provides a highly economical route to exceedingly valuable alkylated arenes that are widespread in medicinal chemistry and materials science. Herein, we report an operationally-simple protocol for the selective C(sp 2 )–C(sp 3 ) iron-catalyzed cross-coupling of aryl chlorides with Grignard reagents at low catalyst loading. A broad range of electronically-varied aryl and heteroaryl chlorides underwent the cross-coupling using challenging alkyl organometallics possessing β-hydrogens with high efficiency up to 2000 TON. A notable feature of the protocol is the use of environmentally-friendly cyclic urea ligands. A series of guidelines to predict cross-coupling reactivity of aryl electrophiles is provided. 

   more » « less
4. Migratory functionalization of unactivated alkyl bromides for construction of all-carbon quaternary centers via transposed tert-C-radicals

   https://doi.org/10.1038/s41467-020-18658-4  

   Zhu, Chuan; Liu, Ze-Yao; Tang, Luning; Zhang, Heng; Zhang, Yu-Feng; Walsh, Patrick J.; Feng, Chao (December 2020, Nature Communications)

   null (Ed.)

   Abstract Despite remarkable recent advances in transition-metal-catalyzed C(sp 3 )−C cross-coupling reactions, there remain challenging bond formations. One class of such reactions include the formation of tertiary -C(sp 3 )−C bonds, presumably due to unfavorable steric interactions and competing isomerizations of tertiary alkyl metal intermediates. Reported herein is a Ni-catalyzed migratory 3,3-difluoroallylation of unactivated alkyl bromides at remote tertiary centers. This approach enables the facile construction of otherwise difficult to prepare all-carbon quaternary centers. Key to the success of this transformation is an unusual remote functionalization via chain walking to the most sterically hindered tertiary C(sp 3 ) center of the substrate. Preliminary mechanistic and radical trapping studies with primary alkyl bromides suggest a unique mode of tertiary C-radical generation through chain-walking followed by Ni–C bond homolysis. This strategy is complementary to the existing coupling protocols with tert -alkyl organometallic or -alkyl halide reagents, and it enables the expedient formation of quaternary centers from easily available starting materials. 

   more » « less
5. General and selective nickel-electrocatalyzed cross-electrophile C*( sp ² )–C( sp ² ) coupling

   https://doi.org/10.1073/pnas.2515413123  

   Xie, Wenbin; Song, Zhe; Shi, Qinqin; Sheng, Panping; Xu, Gu; Wen, Kaikai; Zhao, Lutang; Marks, Tobin J; Wang, Zhi-Xiang; Huang, Hui (March 2026, Proceedings of the National Academy of Sciences)

   Berenbaum, May R (Ed.)

   Transition metal-catalyzed cross-coupling of two similar electrophiles (XEC) to construct C(sp²)–C(sp²) bonds is a powerful emerging synthetic methodology. However, efficient and selective XEC to create heterocoupled C*(sp²)–C(sp²) linkages from equimolar reagents while suppressing competing homocoupling, presents a synthetic challenge. Here, we describe a promising approach to address this challenge via electrocatalytic synthesis. This approach utilizes renewable and readily available electricity to replace traditional redox reagents, minimizing chemical use and chemical waste generation, while controlling the reaction pathway by the applied potential. This highly selective and general electrocatalytic eXEC process to construct C*(sp²)–C(sp²) bonds is enabled by sequential and controllable eXEC oxidative addition processes, and supported mechanistically by experiment and DFT computation. Generality and efficacy are demonstrated by more than 80 examples, including important biaryl, fluorophore, and pharmaceutical products. Notably, the stoichiometric precision of eXEC enables the first synthesis of solution-processable low polydispersity conjugated opto-electronic polymers. Therefore, this report provides a conceptually attractive method to selectively create diverse and useful C*(sp²)–C(sp²) coupled molecules and macromolecules. 

   more » « less