Asmic addresses the long-standing challenge of alkylating isocyanides, providing access to isocyanides with diverse substitution patterns. The o-anisylsulfanyl group serves a critical dual role by facilitating deprotonation-alkylation and providing a latent nucleophilic site through an unusual arylsulfanyl-lithium exchange.
Metalated nitriles and enolates rapidly and efficiently abstract chlorine from 2-chloro-2-fluoro-2-phenylacetonitrile to afford a diverse range of chloronitriles and chloroesters. The method provides the first general anionic chlorination of alkylnitriles, tolerates numerous functional groups, and addresses the challenge of synthesizing alpha-chloronitriles under mild conditions.
Grignard reagents trigger an addition-elimination with α'-hydroxy acrylonitriles to selectively generate Z-alkenenitriles. The modular assembly of Z-alkenenitriles from a Grignard reagent, acrylonitrile, and an aldehyde is ideal for stereoselectively synthesizing alkenes as illustrated in the synthesis of the putative lignan "morinol I."
Alkylations of acyclic, lithiated 4-alkoxyalk-4-enenitriles are highly diastereoselective with an unusual electrophile-dependent preference. Alkyl halides, sulfur, chlorine, and acyl cyanide electrophiles intercept a series of lithiated 4-alkoxyalk-4-enenitriles to install contiguous tertiary-quaternary stereocenters with high diastereoselectivity, whereas acylations with ester and carbonate electrophiles are modestly selective. The diastereoselectivity is consistent with electrophilic attack on the most accessible face of the lithated nitrile for most electrophiles except ester and carbonate electrophiles, which likely precoordinate the lithiated nitrile before acylation. Intercepting the lithiated 4-alkoxyalk-4-enenitriles with a range of electrophiles provide insight into the criteria for otherwise challenging diastereoselective alkylations and acylations of acyclic nitriles.
A series of morinol-type lignans were rapidly assembled using a Grignard-based transmissive olefination. In combination with palladium-catalyzed arylations, the strategy provides stereoselective access to (7Z, 7′E), (7E, 7′E), (7E, 7′Z) morinol diastereomers and the (7Z, 8′E) and (7E, 8′E) conjugated analogs. Critical for the E/Z-stereoselectivity is a new, general method for converting alkenenitriles to alkenemethanols that circumvents the enal E/Z isomerization commonly encountered during conventional i-Bu2AlH reduction.
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