Science of Synthesis

Favre-Réguillon, A., Science of Synthesis Knowledge Updates, (2024) 3, 285.

The Willgerodt–Kindler reaction[‌111‌] involves the oxidation/rearrangement of a ketone to form a terminal thioamide using elemental sulfur (S8) and a secondary amine, such as morpholine, under thermal conditions. The Willgerodt–Kindler reaction was used for the first large-scale synthesis (~500 kg) of naproxen,[‌112‌] but it has still found only limited application because of the harsh conditions and long reaction times required. However, new protocols have been proposed with higher yields and milder reaction conditions.[‌113‌,‌114‌] A microwave-assisted preparation of thioamides ‌34‌ by the Willgerodt–Kindler reaction and a subsequent rapid microwave-assisted hydrolysis furnishes 2-arylacetic acids ‌35‌ (‌Scheme 35‌).[‌115‌] Aldehydes can also be transformed under these conditions (‌Scheme 36‌), but the atom economy of this protocol is questionable compared to previously described methods (see Section 20.2.1.3.1). Interestingly, benzaldehydes are reactive when water is used as the solvent for the Willgerodt–Kindler reaction, but aryl methyl ketones are not.[‌116‌]

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References