Synthesis of propargyl silanes from terminal alkynes via a migratory Sonogashira reaction.

Herein we report a mild synthesis of propargyl silanes from terminal alkynes. We exploit a bromonaphthyl-substituted silane as a silylmethyl electrophile surrogate, which participates in a Sonogashira reaction after an aryl-to-alkyl Pd-migration. Twenty-seven propargyl silanes were obtained in up to 88% yield. The obtained products were versatile building blocks that can be used in addition to electrophiles, triple bond hydrogenation or silyl group cleavage with acid or fluoride sources.

1,3-Difunctionalization of Propargyl Silanes with Concomitant 1,2-Silyl Shift: Synthesis of Allyl Functionalized Vinyl Silanes.

Terminal alkynes with a silyl group at the propargylic position upon activation with electrophiles such as N-bromosuccinimide undergo (E)-selective 1,2-silyl group migration. Subsequently, an allyl cation is formed that is intercepted by an external nucleophile. This approach provides allyl ethers and esters with stereochemically defined vinyl halide and silane handles for further functionalization. The scope of propargyl silanes and electrophile-nucleophile pairs are investigated, and various trisubstituted olefins are prepared in up to 78% yield. The obtained products have been demonstrated to serve as building blocks for transition-metal-catalyzed cross-couplings of vinyl halides, silicon-halogen exchange, and allyl acetate functionalization reactions.

Palladium-Catalyzed trans-Hydroalkoxylation: Counterintuitive Use of an Aryl Iodide Additive to Promote C-H Bond Formation.

We report an enantioselective palladium-catalyzed trans-hydroalkoxylation of propargylic amines with a trifluoroacetaldehyde-derived tether to build chiral oxazolidines. Diastereoselective hydrogenation using a heterogeneous palladium catalyst then gave access to protected benzylic amino alcohols in 45-87% yields and 84-94% ee values. Hydroalkoxylation of the alkynes required a catalytic amount of aryl iodide, highlighting the counterintuitive key role played by a putative Pd(II)/ArI oxidative addition complex to promote oxypalladation/protodemetalation.

Asymmetric Cyclopropanation and Epoxidation via a Catalytically Formed Chiral Auxiliary.

For the enantioselective diversification of a single starting material, a different chiral catalyst is usually required for each transformation. Herein, we extend the concept of catalytically formed chiral auxiliary from hydrogenation to the asymmetric cyclopropanation and epoxidation of tetra-substituted olefins, alleviating the need for different chiral catalysts in the alkene functionalization step. The chiral auxiliary is catalytically constructed from propargylic amines in a Pd-catalyzed enantioselective carboetherification step using a commercially available trifluoroacetaldehyde hemiacetal tether. The installed auxiliary is then controlling the stereochemistry of the cyclopropanation and the epoxidation using standard highly reactive reagents to give enantioenriched spirocyclic aminomethylcyclopropanols and α-amino-α-hydroxy ketones.

Enantioselective Carboetherification/Hydrogenation for the Synthesis of Amino Alcohols via a Catalytically Formed Chiral Auxiliary.

Chiral auxiliaries and asymmetric catalysis are the workhorses of enantioselective transformations, but they still remain limited in terms of either efficiency or generality. Herein, we present an alternative strategy for controlling the stereoselectivity of chemical reactions. Asymmetric catalysis is used to install a transient chiral auxiliary starting from achiral precursors, which then directs diastereoselective reactions. We apply this strategy to a palladium-catalyzed carboetherification/hydrogenation sequence on propargylic amines, providing fast access to enantioenriched chiral amino alcohols, important building blocks for medicinal chemistry and drug discovery. All stereoisomers of the product could be accessed by the choice of ligand and substituent on the propargylic amine, leading to a stereodivergent process.

Brønsted Acid Catalyzed 1,2-Silyl Shift in Propargyl Silanes: Synthesis of Silyl Dienes and Silyl Indenes.

A general method for generation of allyl carbenium ions from propargyl silanes via a 1,2-silyl shift by Brønsted acids is reported. Two possible reaction pathways are described. Deprotonation results in silyl dienes with yields from 52% to 92%. Intramolecular Friedel-Crafts reactions of aryl-substituted systems give access to silyl indenes with yields of 18-90% depending on the substitution pattern. The obtained products have been shown to react as alkenyl silanes in Hiyama coupling and electrophilic substitution and as dienes in Diels-Alder cycloaddition.