SO₂F₂-Mediated N-Alkylation of Imino-Thiazolidinones

Abstract

The N-alkylation of ambident and weakly nucleophilic imino-thiazolidinones has been developed via substitution with alkyl fluorosulfonates. These reactive electrophiles are obtained through the transformation of non-toxic, economic, and commercially available alcohol derivatives on exposure to SO 2 F 2 gas. The use of electron-withdrawing groups and DMAc as solvent affords a (Z)-and N-endocyclic selectivity for the easy introduction of a variety of alkyl and polyfluoroalkyl chains.

Traceless N‐Polyfluoroalkylation of Weakly Nucleophilic Nitrogen Containing Compounds

“…Sulfonylated aminobenzothiazole afforded a mixture of regioisomers, with the endocyclic nitrogen preferentially polyfluoroalkylated in 35 % yield ( 2 aw ). This regioselectivity is consistent with previously reported N ‐alkylations of similar ambident nucleophiles [18c] . The methylamine‐derived sulfonamide also gave a low yield of 32 % ( 2 ay ).…”

“…Our group has begun to investigate SO 2 F 2 ‐mediated N ‐polyfluoroalkylation of challenging substrates that are highly relevant to agrochemical and pharmaceutical applications. In 2022, we reported the N ‐(polyfluoro)alkylation of ambident and weakly nucleophilic imino‐thiazolidinones [18c] . This first example of N ‐polyfluoroalkylation of weakly nucleophilic nitrogen compounds paved the way for a general method for N ‐polyfluoroalkylation of sulfonamides and derived N ‐sulfonyl carbamates using sulfuryl fluoride (SO 2 F 2 ), which is presented here (Scheme 1c).…”

New Chemical Transformations Involving SO2F2‐Mediated Alcohol Activation

“…The imino‐thiazolidinone core is present in diverse biologically active compounds, such as potential anticancer, antimicrobial, anti‐inflammatory, anticonvulsant, and hypertensive agents [60,61] . In 2022, our group reported on the N ‐polyfluoroalkylation of ambident and weakly nucleophilic imino‐thiazolidinones via substitution with polyfluoroalkyl fluorosulfonates [62] …”

“…Our study started by using the poorly nucleophilic saccharin moiety ( N =10.78 according to Mayr's scale) [71] as a model substrate for the optimization of the reaction conditions. This optimization mainly focused on the choice of the base, which shows significant effect on the reaction outcome for most SO 2 F 2 ‐alkylation processes reported to date [59,62,65,72] . Whereas DBU was very efficient for the N ‐alkylation of imino‐thiazolidinone moieties, [62] we were surprised to see that the same conditions gave only traces of the desired alkylated saccharin.…”

“…This optimization mainly focused on the choice of the base, which shows significant effect on the reaction outcome for most SO 2 F 2 ‐alkylation processes reported to date [59,62,65,72] . Whereas DBU was very efficient for the N ‐alkylation of imino‐thiazolidinone moieties, [62] we were surprised to see that the same conditions gave only traces of the desired alkylated saccharin. Replacing DBU by DIPEA and increasing the temperature to 50 °C resulted in a great yield improvement up to 95 % with a mixture of N ‐ and O ‐polyfluoroalkylation products in a 61 : 39 ratio.…”