A stereoselective thiocyanate conjugate addition to electron deficient alkynes and concomitant cyclization to N,S-heterocycles

Abstract

A regio- and stereoselective thiocyanate addition to ynones is achieved using KSCN in AcOH at 70 °C. The reaction is extendable to ynals, ynesulfones, ynoic acids and ynoates. Adducts from ynones were readily transformed into thiazine-2-thione derivatives under slightly modified reaction conditions. In contrast, thiocyanated adducts from ynamides underwent an in situ decyanative amido cyclization towards isothiazolones. None of these events needed any transition metal or catalyst, attaining a high synthetic value.

Recent Advances in the Synthesis and Reactivity of Isothiazoles

“…An interesting synthesis of isothiazolones by a stereoselective conjugate addition of thiocyanate to α,β‐alkynyl amides was reported by Reddy and co‐workers (Scheme , top ) . The proposed mechanism involves (i) alkyne thiocyanation and (ii) decyanative intramolecular cyclization by the amide nitrogen atom.…”

“…The group has also described a separate method for the synthesis of isothiazoles capitalizing on the rapid assembly of thiazene‐2‐thiones by conjugate addition of thiocyanate to α,β‐alkynyl ketones (Scheme , bottom ) …”

Copper‐Catalyzed Thioannulation of Propynamides with Sodium Sulfide for the Synthesis of Isothiazol‐3‐ones

“…Based on the observed results and the reported mechanism, [8] a possible mechanism was proposed, as outlined in Scheme 3. When N-methyl-N, 3diphenylpropionamide 4 was used as a substrate under standard conditions, neither product 2 a nor 5-methyl-N-phenylisothiazol-3(2H)-one could be detected (Eq.…”

“…[6] However, applications of isothiazol-3-ones are limited by the insufficient methods available for their efficient preparation. [8] As part of our continued interest in sulfur-containing molecules [9] and inspired by the synthesis of S-heterocycles from metal sulfides, [10] we questioned whether ynamides could undergo sulfur addition and intramolecular cross-dehydrogenative coupling reactions [11] with metal sulfides to produce isothiazol-3-ones. [7] Therefore, a simple and efficient protocol for the construction of the isothiazol-3-one framework is highly desirable.…”

“…of KSCN (Scheme 1, a). [8] As part of our continued interest in sulfur-containing molecules [9] and inspired by the synthesis of S-heterocycles from metal sulfides, [10] we questioned whether ynamides could undergo sulfur addition and intramolecular cross-dehydrogenative coupling reactions [11] with metal sulfides to produce isothiazol-3-ones. Herein, we report a method for the copper-catalyzed thioannulation of propynamides using sodium sulfide, which is inexpensive and odorless, for the concise, one-pot synthesis of isothiazol-3-one derivatives (Scheme 1, b).…”