Ligand Relay for Nickel-Catalyzed Decarbonylative Alkylation of Aroyl Chlorides.

Transition metal-catalyzed direct decarboxylative transformations of aromatic carboxylic acids usually require high temperatures, which limit the substrate's scope, especially for late-stage applications. The development of the selective decarbonylative of carboxylic acid derivatives, especially the most fundamental aroyl chlorides, with stable and cheap electrophiles under mild conditions is highly desirable and meaningful, but remains challenging. Herein, a strategy of nickel-catalyzed decarbonylative alkylation of aroyl chlorides via phosphine/nitrogen ligand relay is reported. The simple phosphine ligand is found essential for the decarbonylation step, while the nitrogen ligand promotes the cross-electrophile coupling. Such a ligand relay system can effectively and orderly carry out the catalytic process at room temperature, utilizing easily available aroyl chlorides as an aryl electrophile for reductive alkylation. This discovery provides a new strategy for direct decarbonylative coupling, features operationally simple, mild conditions, and excellent functional group tolerance. The mild approach is applied to the late-stage methylation of various pharmaceuticals. Extensive experiments are carried out to provide insights into the reaction pathway and support the ligand relay process.

Carbon-Carbon Bond Cleavage for Late-Stage Functionalization.

Late-stage functionalization (LSF) introduces functional group or structural modification at the final stage of the synthesis of natural products, drugs, and complex compounds. It is anticipated that late-stage functionalization would improve drug discovery's effectiveness and efficiency and hasten the creation of various chemical libraries. Consequently, late-stage functionalization of natural products is a productive technique to produce natural product derivatives, which significantly impacts chemical biology and drug development. Carbon-carbon bonds make up the fundamental framework of organic molecules. Compared with the carbon-carbon bond construction, the carbon-carbon bond activation can directly enable molecular editing (deletion, insertion, or modification of atoms or groups of atoms) and provide a more efficient and accurate synthetic strategy. However, the efficient and selective activation of unstrained carbon-carbon bonds is still one of the most challenging projects in organic synthesis. This review encompasses the strategies employed in recent years for carbon-carbon bond cleavage by explicitly focusing on their applicability in late-stage functionalization. This review expands the current discourse on carbon-carbon bond cleavage in late-stage functionalization reactions by providing a comprehensive overview of the selective cleavage of various types of carbon-carbon bonds. This includes C-C(sp), C-C(sp2), and C-C(sp3) single bonds; carbon-carbon double bonds; and carbon-carbon triple bonds, with a focus on catalysis by transition metals or organocatalysts. Additionally, specific topics, such as ring-opening processes involving carbon-carbon bond cleavage in three-, four-, five-, and six-membered rings, are discussed, and exemplar applications of these techniques are showcased in the context of complex bioactive molecules or drug discovery. This review aims to shed light on recent advancements in the field and propose potential avenues for future research in the realm of late-stage carbon-carbon bond functionalization.

Manganese-promoted reductive cross-coupling of disulfides with dialkyl carbonates.

Manganese is a cheap and environmentally friendly metal on Earth. Herein, we report a manganese-promoted reductive cross-coupling using easily available and odorless disulfides as thiolating agents in an excellent 100% sulfur atom economy. The protocol featured a broad substrate scope, including various alkyl disulfides and excellent functional group compatibility, constructing diverse thioethers under simple conditions. Ultimately, thioethers can be prepared in gram-scale reactions and further transformed into structurally complex molecules.

Iron-catalysed reductive coupling for the synthesis of polyfluorinated compounds.

Herein we reported the use of Earth-abundant iron as the catalytic metal in the presence of Mn to induce difluorobromoacetates to form carbon radicals, which reacted with trifluoromethyl olefins followed by ß-F elimination to generate the corresponding gem-difluoroolefins. The cross-electrophile coupling displayed excellent functional group tolerance and broad substrate scope under mild reductive conditions, affording a large number of polyfluorinated compounds, which could be further transformed to other valuable molecules.

Copper-catalyzed oxidative multicomponent reaction: synthesis of imidazo fused heterocycles with molecular oxygen.

An oxidative cascade that involves multicomponent reaction comprising a terminal alkyne, 2-amino N-heterocycle, benzyl or allylic bromide with molecular oxygen, delivering densely functionalized imidazo fused heterocycles, is described. This reaction features a cheap catalyst, a green oxidant, and readily available starting materials, which make the overall synthesis applicable in the quick access to relevant pharmaceutical molecules with imidazole derived heterocycles.