Synthesis of ω-(1,1,3-trioxo-1,3-dihydrobenzo[d]isothiazol-2-yl)-alkanecarboxylic acids: conventional versus microwave heating

Abstract

The alkylation of sodium saccharin with alkyl halides to produce the intermediates ω-(1,1,3-trioxo-1,3-dihydrobenzo[d]isothiazol-2-yl)-alkanecarboxylic acids can be markedly improved by using microwave irradiation, both in terms of product yield and reaction time. While the process produces high yields with halo esters and halonitriles, the reaction with haloacids, which proceeds smoothly by conventional reflux, gives poorer yields with microwaves. This is due to an acid-base equilibrium produced by the rapid heating of the mixture under irradiation. Esters and nitriles can be converted into the acids by acid hydrolysis, without appreciable loss of the 1,1,3-trioxo-1,3-dihydrobenzo[d]isothiazole ring.

Synthesis, Anticancer, Antioxidant, Anti-Inflammatory, Antimicrobial Activities, Molecular Docking, and DFT Studies of Sultams Derived from Saccharin

“…In this work, the 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2( 3H )-yl) acetonitrile 2 ( Scheme 1 ) was synthesized following modified literature conditions by heating the saccharin sodium salt 1 with bromoactanitrile in DMF at 80–90 °C. The reaction was completed with excellent yield (96%) of high purity compared to the previously reported method (66%, 72%, 82%, 88%) [ 32 , 37 , 38 ]. Whereas, 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2( 3H )-yl) acetate derivatives 3a – g were obtained in moderate to excellent yields following a modified literature procedure [ 38 ] by acidic hydrolysis of 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2( 3H )-yl) acetonitrile 2 with concentrated sulfuric acid and excess different alcohols (methanol, ethanol butanol, pentanol, propan-2-ol, pentan-2-ol, respectively) at 100 °C ( Scheme 1 ).…”

“…The reaction was completed with excellent yield (96%) of high purity compared to the previously reported method (66%, 72%, 82%, 88%) [ 32 , 37 , 38 ]. Whereas, 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2( 3H )-yl) acetate derivatives 3a – g were obtained in moderate to excellent yields following a modified literature procedure [ 38 ] by acidic hydrolysis of 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2( 3H )-yl) acetonitrile 2 with concentrated sulfuric acid and excess different alcohols (methanol, ethanol butanol, pentanol, propan-2-ol, pentan-2-ol, respectively) at 100 °C ( Scheme 1 ). Furthermore, esters 3d – g were synthesized by an alternative method of refluxing of 3b in concentrated hydrochloric acid at 120 °C, followed by hydrolysis of 4 with different alcohols in concentrated sulfuric acid at 120 °C ( Scheme 2 ).…”

“…Therefore, different alkyl side chains, with either electron-withdrawing or electron-donating groups, can easily be bonded to the nitrogen atom in the isothiazaole ring of the saccharin moiety. Hence, a variety of N -alkyl saccharins with nitrile, ester alkoxy, and heteroaryls have been prepared by this method in refluxing dimethylformamide [ 37 , 38 , 39 , 40 , 41 , 42 ]. In some literature reports, sodium or potassium salts of saccharin can be prepared in situ by heating the saccharin with the alkyl halides in DMF directly [ 32 ].…”