Reaction of Hetareno[e]pyrrole‐2,3‐diones with Thiols: An Approach to Two Distinct 5‐Thio‐Substituted Pyrrole‐2‐one Derivatives

Abstract

Recently, 3‐hydroxy‐1,5‐dihydro‐2H‐pyrrol‐2‐ones have become an object of close scrutiny in medicinal chemistry due to their diverse biological activity. In the present paper, we describe a substrate‐switchable reaction of hetareno[e]pyrrole‐2,3‐diones with aromatic and aliphatic thiols that afforded two series of novel 5‐thio‐substituted 3‐hydroxy‐1,5‐dihydro‐2H‐pyrrol‐2‐ones. The reaction of pyrroloquinaxolinetriones with thiols led to the formation of adducts. The initially formed adducts of pyrrolobenzoxazinetriones with thiols were subjected to hydrolysis with the oxazine ring opening and decarboxylation. Based on the latter reaction, a synthetic approach to pharmaceutically interesting monocyclic non‐fused 3‐hydroxy‐1,5‐dihydro‐2H‐pyrrol‐2‐ones bearing conformationally free thio‐substituents at C‐5 was proposed for the first time. The synthesized compounds were screened in vitro for their antimicrobial activity. Some of them were found to exhibit moderate activity against S. aureus and C. albicans. Thus, the results of current study confirm that the search for new biologically active compounds among 5‐thio‐substituted 3‐hydroxy‐1,5‐dihydro‐2H‐pyrrol‐2‐ones is promising.

Switchable Synthesis of Benzothiazoles, Benzothiazines and Benzothiazepines through the Reaction of Hetareno[e]pyrrole‐2,3‐Diones with o‐Aminothiophenol

“…The N/S selectivity of o-aminothiophenol towards distinct electrophilic centers is consistent with literature data on reactions of hetareno[e]pyrrole-2,3-diones with amines [10] and mercaptans [28] and can be explained by the HSAB theory. According to this theory, the α,β-unsaturated carbonyl compounds have a carbonyl carbon (hard electrophilic center) and a β-carbon (soft electrophilic center).…”

“…Previously, we have shown that aryl mercaptan adducts of substrates 3 are unstable and readily degrade to the starting compounds in solution. [28] Although attack of the less nucleophilic nitrogen atom is less preferred, it can cause almost irreversible opening the pyrrole cycle to form the intermediate I2 (Scheme 5, path B). Further sequential attack of the NH and SH groups on the carbonyl carbon atom of the benzoyl substituent results in a more stable compound 5 a.…”

“…The subsequent attack of the amino group on the aroyl carbonyl with the formation of a more stable product 4 a can occur (especially when heated) in the absence of basic additives (Scheme 5, path A). Previously, we have shown that aryl mercaptan adducts of substrates 3 are unstable and readily degrade to the starting compounds in solution [28] . Although attack of the less nucleophilic nitrogen atom is less preferred, it can cause almost irreversible opening the pyrrole cycle to form the intermediate I2 (Scheme 5, path B).…”