The first systematic study of the thermal rearrangement/fragmentation of 5,5‐disubstituted 1,4,2‐oxathiazoles into isothiocyanates is reported. Structure–activity relationships reveal that the choice of substituent at the 5‐position of the 1,4,2‐oxathiazoles is the predominant factor to influence the ease of fragmentation.

Stabilized Wittig olefination holds great potential as a bioconjugation reaction. We demonstrate that the reaction of stabilized phosphorus ylides (or phosphonium salts) with aryl aldehydes is sufficiently robust to be used for live cell affinity isolation and fluorescence tagging of a protein, FKBP12.

Several previously inaccessible 1,4,2-oxathiazoles have been prepared by [3 + 2] cycloaddition of nitrile oxides and highly reactive thioaldehydes and thioketones. Generated via photolytic cleavage of 2-phenacyl sulfides (Norrish type II photolytic cleavage), these reactive thiocarbonyls provide a broad library of 1,4,2-oxathiazole structures which other methods have failed to achieve. We also report the thermal fragmentation of these 1,4,2-oxathiazoles, in which both fragmentation to nitrile or isothiocyanate may occur. 5H-1,4,2-Oxathiazoles have shown to fragment to nitrile even in the absence of base. At elevated temperatures, fragmentation to isothiocyanates occurred in preference to nitriles.