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1. Reductive Alkylation of 2-Bromoazoles via Photoinduced Electron Transfer: A Versatile Strategy to C sp 2 –C sp 3 Coupled Products

   https://doi.org/10.1021/acs.orglett.5b01711  

   Arora, Amandeep ; Teegardin, Kip A. ; Weaver, Jimmie D. ( July 2015 , Organic Letters)

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2. Nickel‐Catalyzed C( sp 2 )−C( sp 3 ) Kumada Cross‐Coupling of Aryl Tosylates with Alkyl Grignard Reagents

   https://doi.org/10.1002/adsc.201801586  

   Piontek, Aleksandra ; Ochędzan‐Siodłak, Wioletta ; Bisz, Elwira ; Szostak, Michal ( April 2019 , Advanced Synthesis & Catalysis)

   Aryl tosylates are an attractive class of electrophiles for cross‐coupling reactions due to ease of synthesis, low price, and the employment of C−O electrophiles, however, the reactivity of aryl tosylates is low. Herein, we report the Ni‐catalyzed C(sp²)−C(sp³) Kumada cross‐coupling of aryl tosylates with primary and secondary alkyl Grignard reagents. The method delivers valuable alkyl arenes by cross‐coupling with challenging alkyl organometallics possessing β‐hydrogens that are prone to β‐hydride elimination and homo‐coupling. The reaction is catalyzed by an air‐ and moisture stable‐Ni(II) precatalyst. A broad range of electronically‐varied aryl tosylates, including bis‐tosylates, underwent this transformation, and many examples are suitable at mild room temperature conditions. The combination of Ar−X cross‐coupling with the facile Ar−OH activation/cross‐coupling strategy permits for orthogonal cross‐coupling with challenging alkyl organometallics. Furthermore, we demonstrate that the method operates with TON reaching 2000, which is one of the highest turnovers observed to date in Ni‐catalyzed cross‐couplings.

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3. Iron‐Catalyzed C( sp 2 )−C( sp 3 ) Cross‐Coupling of Chlorobenzamides with Alkyl Grignard Reagents: Development of Catalyst System, Synthetic Scope, and Application

   https://doi.org/10.1002/adsc.201800849  

   Bisz, Elwira ; Szostak, Michal ( November 2018 , Advanced Synthesis & Catalysis)

   Direct preparation of alkylated amide‐derivatives by cross‐coupling chemistry using sustainable protocols is challenging due to sensitivity of the amide functional group to reaction conditions. Herein, we report the synthesis of alkyl‐substituted amides by iron‐catalyzed C(sp²)−C(sp³) cross‐coupling of Grignard reagents with aryl chlorides. The products of these reactions are broadly used in the synthesis of pharmaceuticals, agrochemicals and other biologically‐active molecules. Furthermore, amides are used as versatile intermediates that can participate in the synthesis of valuable ketones and amines, providing access to motifs of broad synthetic interest. The reaction is characterized by its good substrate scope, tolerating a range of amide substitution, including sterically‐bulky, sensitive and readily modifiable amides. The reaction is compatible with challenging organometallics possessing β‐hydrogens, and proceeds under very mild, operationally‐simple conditions. Optimization of the catalyst system demonstrated the beneficial effect of O‐coordinating ligands on the cross‐coupling. The reaction was found to be fully chemoselective for the mono‐substitution at the less sterically‐hindered position. Mechanistic studies establish the order of reactivity and provide insight into the role of amide to control mono‐selectivity of the alkylation. The protocol provides the possibility for convenient access to alkyl‐amide structural building blocks using sustainable cross‐coupling conditions with high efficiency.

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4. 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. 

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5. N -Butylpyrrolidone (NBP) as a non-toxic substitute for NMP in iron-catalyzed C(sp 2 )–C(sp 3 ) cross-coupling of aryl chlorides

   https://doi.org/10.1039/D1GC02377B  

   Bisz, Elwira ; Koston, Martina ; Szostak, Michal ( October 2021 , Green Chemistry)

   Although iron catalyzed cross-coupling reactions show extraordinary promise in reducing the environmental impact of more toxic and scarce transition metals, one of the main challenges is the use of reprotoxic NMP (NMP = N -methylpyrrolidone) as the key ligand to iron in the most successful protocols in this reactivity platform. Herein, we report that non-toxic and sustainable N -butylpyrrolidone (NBP) serves as a highly effective substitute for NMP in iron-catalyzed C(sp 2 )–C(sp 3 ) cross-coupling of aryl chlorides with alkyl Grignard reagents. This challenging alkylation proceeds with organometallics bearing β-hydrogens with efficiency superseding or matching that of NMP with ample scope and broad functional group tolerance. Appealing applications are demonstrated in the cross-coupling in the presence of sensitive functional groups and the synthesis of several pharmaceutical intermediates, including a dual NK1/serotonin inhibitor, a fibrinolysis inhibitor and an antifungal agent. Considering that the iron/NMP system has emerged as one of the most powerful iron cross-coupling technologies available in both academic and industrial research, we anticipate that this method will be of broad interest. 

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