Titanocene‐Catalyzed Alkylation of Aryl‐Substituted Alkenes with Alkyl Halides.

Terao, Jun; Watabe, Hiroyasu; Miyamoto, Masako; Kambe, Nobuaki

doi:10.1002/chin.200409047

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“…13,14 Applications involving unactivated alkyl electrophiles were rare, however, and required the use of superstoichiometric amounts of reactive alkylmetal reagents. [15][16][17] In this account, we detail our work focused on developing general alkyl-Mizoroki-Heck-type reactions under mild conditions and the revealing mechanistic studies involved. These studies subsequently led to our group developing several other C-C constructions in the hybrid organometallicradical manifold, which will also be discussed.…”

Section: Introductionmentioning

confidence: 99%

Transition-Metal (Pd, Ni, Mn)-Catalyzed C–C Bond Constructions Involving Unactivated Alkyl Halides and Fundamental Synthetic Building Blocks

Kwiatkowski

Alexanian

2019

Acc. Chem. Res.

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The catalytic construction of C-C bonds between organo-halide or -pseudohalide electrophiles and fundamental building blocks such as alkenes, arenes, or CO are widely utilized metal-catalyzed processes. The use of simple, widely available unactivated alkyl halides in these catalytic transformations has significantly lagged behind the use of aryl or vinyl electrophiles. This difference is primarily due to the relative difficulty in activating alkyl halides with transition metals under mild conditions. This account details our group's work towards developing a general catalytic manifold for the construction of C-C bonds using unactivated alkyl halides and a range of simple chemical feedstocks. Critical to the strategy was the implementation of new modes of hybrid organometallic-radical reactivity in catalysis. Generation of carbon-centered radicals from alkyl halides using transition metals offers a solution to challenges associated with the application of alkyl electrophiles in classical two-electron reaction modes.A major focus of this work was the development of general, palladium-catalyzed carbocyclizations and intermolecular cross-couplings of unactivated alkyl halides (alkyl-Mizoroki-Heck-type reactions). Initial studies centered on the use of alkyl iodides in these processes, but subsequent studies determined that the use of an electron-rich, ferrocenyl bisphosphine (dtbpf) enables the palladium-catalyzed carbocyclizations of unactivated alkyl bromides. Mechanistic studies of these reactions revealed interesting details regarding a difference in mechanism between reactions of alkyl iodides and alkyl bromides in carbocyclizations. These studies were consistent with alkyl bromides reacting via an auto-tandem catalytic process involving atom-transfer radical cyclization (ATRC) followed by catalytic dehydrohalogenation. Reactions of alkyl iodides, on the other hand, involved metal-initiated radical chain pathways.Recent studies have expanded the scope of alkyl-Mizoroki-Heck-type reactions to the use of a first-row metal. Inexpensive nickel precatalysts, in combination with the bisphosphine ligand Xantphos, efficiently activate alkyl bromides for both intra-and intermolecular C-C bond-forming reactions. The reaction scope is similar to the palladium-catalyzed system, but in addition, alkene regioisomeric ratios are dramatically improved over those in reactions with palladium, solving one of the drawbacks of our previous work. Initial mechanistic studies were consistent with a hybrid organometallic-radical mechanism for the nickel-catalyzed reactions.

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Section: Introductionmentioning

confidence: 99%