Typically, disulfide bonds have been known as electrophiles so that they can react with nucleophiles. For example, disulfide bonds can be cleaved by reducing agents such as sodium borohydride and lithium aluminum hydride. In addition, they can often undergo disulfide shuffling with thiolates in biological system. However, it is little known that disulfide bond functions as nucleophile. Herein, we present intramolecular nucleophilic reaction of disulfide bond with isocyanate moiety. We synthesized conformationally-constrained disulfide derivatives shown in Figure below. It is possible to juxtapose the disulfide bond and isocyanate moiety produced by Curtius rearrangement when both functional groups are <i>endo</i>. Eventually, the intramolecular nucleophilic attack of the disulfide could produce the corresponding thiocarbamate in one-pot synthesis from the carboxylic acid. In order to investigate the neighboring effect, we also studied nucleophilicity of disulfide bond with two different distances between HOMO of disulfide and LUMO of isocyanate. Intermolecular reaction started from bicyclo[2.2.1]heptane-2-carboxylic acid and dimethyl disulfide showed no reaction. Moreover, intramolecular reaction started from 4-(methyldisulfanyl)butanoic acid did not show the corresponding thiocarbamate either. Therefore, when disulfide bonds are enforced in a proximity of electrophiles, it became clear that they have good nucleophilicity. DFT calculations supported this neighboring effect by showing interaction between HOMO of disulfide bond and LUMO of isocyanate moiety.

Neighboring group effect on nucleophilicity of disulfide bond

ACS Spring Meeting 2021

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