Decarbonylative C–P Bond Formation Using Aromatic Esters and Organophosphorus Compounds

Ni-catalyzed C–P bond formation was achieved using aromatic esters as unconventional aryl sources. The key to success was the use of a thiophene-based diphosphine ligand (dcypt). Several aromatic esters including heteroaromatics can be coupled with phosphine oxides and phosphates, providing aryl phosphorus compounds. The synthetic utility of the method was demonstrated by application of the present protocol to the sequential coupling reactions

Pd-Catalyzed Dearomative Allylation of Benzyl Phosphates

Dearomative C–C bond formation of benzyl phosphates has been developed. In the presence of a palladium/PAr₃ catalyst, benzyl phosphates reacted with allyl borates to generate the allylated product in a dearomative fashion. The resulting dearomatized molecules were successfully derivatized by Simmons–Smith cyclopropanation and oxidation

Decarbonylative Methylation of Aromatic Esters by a Nickel Catalyst

A Ni-catalyzed decarbonylative methylation of aromatic esters was achieved using methylaluminums as methylating agents. Dimethylaluminum chlorides uniquely worked as the methyl source. Because of the Lewis acidity of aluminum reagents, less reactive alkyl esters could also undergo the present methylation. By controlling the Lewis acidity of aluminum reagents, a chemoselective decarbonylative cross-coupling between alkyl esters and phenyl esters was successful

Nickel-Catalyzed C–H/C–O Coupling of Azoles with Phenol Derivatives

The first nickel-catalyzed C–H bond arylation of azoles with phenol derivatives is described. The new Ni­(cod)₂/dcype catalytic system is active for the coupling of various phenol derivatives such as esters, carbamates, carbonates, sulfamates, triflates, tosylates, and mesylates. With this C–H/C–O biaryl coupling, we synthesized a series of privileged 2-arylazoles, including biologically active alkaloids. Moreover, we demonstrated the utility of the present reaction for functionalizing estrone and quinine

Cyanation of Phenol Derivatives with Aminoacetonitriles by Nickel Catalysis

Generation of useful arylnitrile structures from simple aromatic feedstock chemicals represents a fundamentally important reaction in chemical synthesis. The first nickel-catalyzed cyanation of phenol derivatives with metal-free cyanating agents, aminoacetonitriles, is described. A nickel-based catalytic system consisting of a unique diphosphine ligand such as dcype or dcypt enables the cyanation of versatile phenol derivatives such as aryl carbamates and aryl pivalates. The use of aminoacetonitriles as a cyanating agent leads to an environmentally and easy-to-use method for arylnitrile synthesis

Synthesis of Dragmacidin D via Direct C–H Couplings

Dragmacidin D, an emerging biologically active marine natural product, has attracted attention as a lead compound for treating Parkinson’s and Alzheimer’s diseases. Prominent structural features of this compound are the two indole–pyrazinone bonds and the presence of a polar aminoimidazole unit. We have established a concise total synthesis of dragmacidin D using direct C–H coupling reactions. Methodological developments include (i) Pd-catalyzed thiophene–indole C–H/C–I coupling, (ii) Pd-catalyzed indole–pyrazine <i>N</i>-oxide C–H/C–H coupling, and (iii) acid-catalyzed indole–pyrazinone C–H/C–H coupling. These regioselective catalytic C–H couplings enabled us to rapidly assemble simple building blocks to construct the core structure of dragmacidin D in a step-economical fashion

Synthesis of Dragmacidin D via Direct C–H Couplings

Dragmacidin D, an emerging biologically active marine natural product, has attracted attention as a lead compound for treating Parkinson’s and Alzheimer’s diseases. Prominent structural features of this compound are the two indole–pyrazinone bonds and the presence of a polar aminoimidazole unit. We have established a concise total synthesis of dragmacidin D using direct C–H coupling reactions. Methodological developments include (i) Pd-catalyzed thiophene–indole C–H/C–I coupling, (ii) Pd-catalyzed indole–pyrazine <i>N</i>-oxide C–H/C–H coupling, and (iii) acid-catalyzed indole–pyrazinone C–H/C–H coupling. These regioselective catalytic C–H couplings enabled us to rapidly assemble simple building blocks to construct the core structure of dragmacidin D in a step-economical fashion

Isolation, Structure, and Reactivity of an Arylnickel(II) Pivalate Complex in Catalytic C–H/C–O Biaryl Coupling

We describe mechanistic studies of a C–H/C–O biaryl coupling of 1,3-azoles and aryl pivalates catalyzed by Ni­(cod)₂/dcype. This study not only supports a catalytic cycle consisting of C–O oxidative addition, C–H nickelation, and reductive elimination but also provides insight into the dramatic ligand effect in C–H/C–O coupling. We have achieved the first synthesis, isolation and structure elucidation of an arylnickel­(II) pivalate, which is an intermediate in the catalytic cycle after oxidative addition of a C–O bond. Furthermore, kinetic studies and kinetic isotope effect investigations reveal that the C–H nickelation is the turnover-limiting step in the catalytic cycle

Isolation, Structure, and Reactivity of an Arylnickel(II) Pivalate Complex in Catalytic C–H/C–O Biaryl Coupling

We describe mechanistic studies of a C–H/C–O biaryl coupling of 1,3-azoles and aryl pivalates catalyzed by Ni­(cod)₂/dcype. This study not only supports a catalytic cycle consisting of C–O oxidative addition, C–H nickelation, and reductive elimination but also provides insight into the dramatic ligand effect in C–H/C–O coupling. We have achieved the first synthesis, isolation and structure elucidation of an arylnickel­(II) pivalate, which is an intermediate in the catalytic cycle after oxidative addition of a C–O bond. Furthermore, kinetic studies and kinetic isotope effect investigations reveal that the C–H nickelation is the turnover-limiting step in the catalytic cycle

Synthesis of Thiophene-Based TAK-779 Analogues by C–H Arylation

A rapid synthesis of thiophene-based TAK-779 analogues <b>1</b> is reported using a late-stage diversification strategy. At the end of the synthesis, the key building block <b>2</b>, which was prepared in six steps from thiophene, was arylated regioselectively at the α-position directly with iodoarenes. Since <b>2</b> offers several reactive positions, various established catalyst systems were tested. It was found that Crabtree catalyst (an Ir catalyst) converted efficiently and selectively the thiophene system <b>2</b> into 2-aryl-substituted compounds <b>9</b>. The direct C–H arylation of <b>2</b> with electron-rich iodoarenes led to high yields, whereas electron-deficient iodoarenes required longer reaction times for complete conversion. A small set of diverse amides <b>1</b> was synthesized by hydrolysis of <b>9</b> and subsequent HATU coupling with primary amines <b>4</b>