The synthesis and characterization of the cationic cobalt(I) arene complex, [(dppf)Co(η 6 -C 7 H 8 )][BAr F 4 ] (dppf = 1,1′-bis(diphenylphosphino)ferrocene; BAr F 4 = B[(3,5-(CF 3 ) 2 )-C 6 H 3 ] 4 ) from an air-stable cobalt precursor is described. Dissolution in benzene-d 6 or tetrahydrofuran (THF) resulted in rapid arene substitution and generated [(dppf)Co(η 6 -C 6 H 6 )]-[BAr F 4 ] or [(dppf)Co(THF) 2 ][BAr F 4]. The latter compound was characterized by a combination of X-ray diffraction and magnetometry and established an S = 1 cobalt(I) derivative. The isolated bis(phosphine)cobalt complexes were evaluated as precatalysts for carbon−carbon bond-forming reactions. The [2 + 2] cycloaddition of internal alkynes and olefins was observed with cobalt precatalyst loadings of 0.25 mol % with high chemoselectivity. The catalytic method was compatible with Lewis basic functional groups, an advantage over in situ-generated catalysts that rely on excess trialkyl aluminum activators. The cationic bis(phosphine) cobalt arene complex was also an effective catalyst precursor for the hydrovinylation of isoprene with ethylene. In both C−C bondforming reactions, the corresponding cobalt(0) complex, [(dppf)Co(COD)] (COD = 1,5-cyclooctadiene), was inactive, providing strong evidence of the role of cobalt(I) during catalysis. In both catalytic reactions, deuterium crossover experiments provide experimental evidence of the role of metallacyclic intermediates during turnover.

Carbon–heteroatom bonds, most often amide and ester bonds, are the standard method to link together two complex fragments because carboxylic acids, amines, and alcohols are ubiquitous and the reactions are reliable. However, C–N and C–O linkages are often a metabolic liability because they are prone to hydrolysis. While C(sp2)–C(sp3) linkages are preferable in many cases, methods to make them require different starting materials or are less functional-group-compatible. We show here a new, decarbonylative reaction that forms C(sp2)–C(sp3) bonds from the reaction of activated carboxylic acids (via 2-pyridyl esters) with activated alkyl groups derived from amines (via N-alkyl pyridinium salts) and alcohols (via alkyl halides). Key to this process is a remarkably fast, reversible oxidative addition/decarbonylation sequence enabled by pyridone and bipyridine ligands that, under reaction conditions that purge CO (g) , lead to a selective reaction. The conditions are mild enough to allow coupling of more complex fragments, such as those used in drug development, and this is demonstrated in the coupling of a typical Proteolysis Targeting Chimera (PROTAC) anchor with common linkers via C–C linkages.

Carbon heteroatom bonds, most often amide and ester bonds, are the standard method to link together two complex fragments because carboxylic acids, amines, and alcohols are ubiquitous and the reactions are reliable. However, C–N and C–O linkages are often a metabol-ic liability because they are prone to hydrolysis. While C(sp2)–C(sp3) linkages are preferable in many cases, methods to make them re-quire different starting materials or are less functional-group compatible. We show here a new, decarbonylative reaction that forms C(sp2)–C(sp3) bonds from the reaction of activated carboxylic acids (via O-pyridyl esters) with activated alkyl groups derived from amines (via N-alkyl pyridinium salts) and alcohols (via alkyl halides). The key to this process is a remarkably fast, reversible oxidative addi-tion/decarbonylation sequence enabled by pyridone and bipyridine ligands that, under conditions that purge CO(g) from the reaction, lead to a selective reaction. The conditions are mild enough to allow coupling of more complex fragments, such as those used in drug development, and this is demonstrated in the coupling of a typical PROTAC anchor with common linkers via C–C linkages.

Carbonheteroatom bonds, most often amide and ester bonds, are the standard method to link together two complex fragments be-cause carboxylic acids, amines, and alcohols are ubiquitous and the reactions are reliable. However, CN and CO linkages are often a metabolic liability because they are prone to hydrolysis. While C(sp2)–C(sp3) linkages are preferable in many cases, methods to make them require different starting materials or are less functional-group compatible. We show here a new, decarbonylative reaction that forms C(sp2)–C(sp3) bonds from the reaction of activated carboxylic acids (via 2-pyridyl esters) with activated alkyl groups derived from amines (via N-alkyl pyridinium salts) and alcohols (via alkyl halides). Key to this process is a remarkably fast, reversible oxidative addi-tion/decarbonylation sequence enabled by pyridone and bipyridine ligands that, under reaction conditions that purge CO(g), lead to a selective reaction. The conditions are mild enough to allow coupling of more complex fragments, such as those used in drug develop-ment, and this is demonstrated in the coupling of a typical Proteolysis Targeting Chimera (PROTAC) anchor with common linkers via CC linkages.

This chapter describes the procedure for nickel‐catalyzed cross‐coupling of aryl halides with alkyl halides: ethyl 4‐(4‐(4‐methylphenylsulfonamido)‐phenyl)butanoate. It presents some of the important points to be considered, the conditions that need to be maintained, characterization data, and the reagents required, as well as the techniques used and the equipment setup that are vital to carrying out the process. The chapter also describes the hazards associated with working with chemicals and the ways to deal with these hazards. While alkyl halides are far more abundant than alkyl organometallic reagents, the largest commercially available pools of aliphatic electrophile diversity are alcohols, amines, and alkanoic acids.