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

The catalytic construction of C-C bonds between organohalide 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 of activating alkyl halides with transition metals under mild conditions. This Account details our group's work toward 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 autotandem 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 transition 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. The novel reactivity of the palladium catalysts in the alkyl-Mizoroki-Heck-type reactions have also paved the way for the development of other C-C bond-forming processes of unactivated alkyl halides, including aromatic C-H alkylations as well as low-pressure alkoxycarbonylations. Related hybrid organometallic-radical reactivity of manganese has led to an alkene dicarbofunctionalization using alkyl iodides.

Nickel-Mediated Cross-Coupling of Boronic Acids and Phthalimides for the Synthesis of Ortho-Substituted Benzamides.

The decarbonylative coupling of phthalimides with aryl boronic acids provides ready access to a broad range of ortho-substituted benzamides. This nickel-mediated methodology extends reactivity from previously described air-sensitive diorganozinc reagents of limited availability to easily handled and widely commercially available boronic acids. The decarbonylative coupling is tolerant of a broad range of functional groups and demonstrates little sensitivity to steric factors on either of the coupling partners.

Nickel-Catalyzed Mizoroki-Heck-Type Reactions of Unactivated Alkyl Bromides.

The development of a general, nickel-catalyzed alkyl-Mizoroki-Heck reaction of unactivated alkyl bromides is described. The mild reaction proceeds efficiently using a wide range of primary and secondary alkyl bromides, and examples of intermolecular cross-couplings are provided. Reaction alkene regioselectivity is significantly enhanced over prior carbocyclizations using palladium catalysis. Mechanistic investigations are consistent with a direct carbocyclization in contrast to the auto-tandem atom-transfer cyclization and halide elimination previously observed with palladium catalysis.

Palladium-Catalyzed Carbocyclizations of Unactivated Alkyl Bromides with Alkenes Involving Auto-tandem Catalysis.

The development of a general catalytic system for the palladium-catalyzed carbocyclization of unactivated alkyl bromides with alkenes is described. This approach uses a commercially available bisphosphine ligand and avoids the use of carbon monoxide atmosphere present in prior studies involving alkyl iodides. Detailed mechanistic studies of the transformation are performed, which are consistent with auto-tandem catalysis involving atom-transfer radical cyclization followed by catalytic dehydrohalogenation. These studies also suggest that reactions involving alkyl iodides may proceed through a metal-initiated, rather than metal-catalyzed, radical chain process.