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1.2.4 Using a Nitrile and Sulfur as Nucleophiles (Gewald Reaction)

DOI: 10.1055/sos-SD-210-00323

Huang, Y.; Dömling, A.Science of Synthesis: Multicomponent Reactions, (20141531.

General Introduction

In 1966, the German chemist Karl Gewald discovered that carbonyl compounds 1 (aliphatic ketones, aldehydes, or 1,3-dicarbonyl compounds) react with activated nitriles 2 and sulfur in the presence of a secondary amine at room temperature to give thiophen-2-amines 3 (Scheme 1).[‌1‌] This was a remarkable finding since sulfur is rather inert and only a few organic reactions were known involving elemental sulfur under mild conditions, for example the Willgerodt–Kindler reaction (Section 1.2.1.8) and the Asinger condensation.[‌2‌] In an alternative procedure, carbonyl compound 1 and nitrile 2 are condensed to form an acrylonitrile derivative 4, which is then combined with sulfur and an amine to give 3. In most cases however, it is unnecessary to isolate the acrylonitrile compound 4; the one-pot reaction gives the thiophenamine derivative 3 in sometimes very good yields. Many reactive carbonyl compounds with a free α-methylene moiety can be used in the Gewald three-component reaction. The most important nitrile components are malononitrile, cyanoacetic esters, primary cyanoacetamide, and 3-oxo-3-phenylpropanenitrile (ω-cyanoacetophenone).[‌3‌]

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References