Oxetane Synthesis via Alcohol C-H Functionalization.

Oxetanes are strained heterocycles with unique properties that have triggered significant advances in medicinal chemistry. However, their synthesis still presents significant challenges that limit the use of this class of compounds in practical applications. In this Letter, we present a methodology that introduces a new synthetic disconnection to access oxetanes from native alcohol substrates.

Palladium-Catalyzed Synthesis of α-Carbonyl-α'-(hetero)aryl Sulfoxonium Ylides: Scope and Insight into the Mechanism.

Despite recent advances, a general method for the synthesis of α-carbonyl-α'-(hetero)aryl sulfoxonium ylides is needed to benefit more greatly from the potential safety advantages offered by these compounds over the parent diazo compounds. Herein, we report the palladium-catalyzed cross-coupling of aryl bromides and triflates with α-carbonyl sulfoxonium ylides. We also report the use of this method for the modification of an active pharmaceutical ingredient and for the synthesis of a key precursor of antagonists of the neurokinin-1 receptor.

Palladium-Catalyzed Synthesis of Bis-Substituted Sulfoxonium Ylides.

The lack of general access to bis-substituted sulfoxonium ylides is addressed by developing a palladium-catalyzed C-H cross-coupling of α-ester sulfoxonium ylides with (hetero)aryl iodides, bromides, and triflates. Three different catalysts have been evaluated. This method is amenable to the late-stage functionalization of active pharmaceutical ingredients.

Cross-Coupling of α-Carbonyl Sulfoxonium Ylides with C-H Bonds.

The functionalization of carbon-hydrogen bonds in non-nucleophilic substrates using α-carbonyl sulfoxonium ylides has not been so far investigated, despite the potential safety advantages that such reagents would provide over either diazo compounds or their in situ precursors. Described herein are the cross-coupling reactions of sulfoxonium ylides with C(sp )-H bonds of arenes and heteroarenes in the presence of a rhodium catalyst. The reaction proceeds by a succession of C-H activation, migratory insertion of the ylide into the carbon-metal bond, and protodemetalation, the last step being turnover-limiting.