The most common problem in Lewis base catalyzed reactions is the narrow scope for the nucleophilic reaction partner that must be less nucleophilic than the catalyst.&lt;span style="font-size:10.8333px"&gt; &lt;/span&gt;We proposed that this problem can be addressed by the use of latent nucleophiles, the derivatives of otherwise nucleophilic molecules which are not nucleophilic themselves but can be activated to participate in the reaction as a nucleophile. If activation of a latent nucleophile is dependent on the activation of electrophilic reaction partner, activated nucleophile is produced only when activated electrophile is already present in the reaction mixture and the fast reaction between the two activated species outcompetes other reaction pathways. This improves reaction efficiency, selectivity and, most importantly, expands the scope of Lewis base catalyzed reactions. We have applied this concept to the Lewis base catalyzed allylation of challenging N- and C-nucleophiles. N-silyl pyrroles, indoles and carbazoles serve as latent N-centered nucleophiles in substitution of allylic fluorides catalyzed by Lewis bases.[2a] N-allyl pyrroles, produced with chiral cinchona catalysts, are transformed to the biologically active enantioenriched pyrrolizin-1-ones. The use of diethyl (difluoro(trimethylsilyl)methyl)phosphonate as a latent C-pronucleophile in substitution of allylic fluorides enables the first enantioselective phosphonyldifluoromethylation and produces the enantioenriched bioisosteres of alkyl phosphates. In this talk, we describe the development of the reaction system for the combination of silylated latent N- and C-nucleophiles and allylic fluorides, and we discuss the extension of the concept to other heteroatom nucleophiles and other combinations of latency conferring groups and activators.

Latent nucleophiles in lewis base catalysis

ACS Fall 2020 Virtual Meeting

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