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33.4.18.1.1.1.1 Variation 1: Classical Hantzsch Reaction

DOI: 10.1055/sos-SD-033-00648

Quirion, J.-C.; Leclerc, E.; Jubault, P.Science of Synthesis, (200733601.

The Hantzsch reaction is the first reported dihydropyridine synthesis.[‌7‌] The product obtained from the condensation of acetaldehyde with 2 equivalents of ethyl acetoacetate and ammonia, first assigned by Hantzsch as a 2,3-dihydropyridine, has been identified since then as a 3,5-diacyl-1,4-dihydropyridine 1. A general survey of the scope and limitations of this three-component reaction, carried out during the course of a structureactivity relationship study, has been reported and sums up the voluminous literature published on the subject.[‌1‌,‌8‌,‌9‌] Aromatic and aliphatic aldehydes react with acetoacetates in the presence of aqueous ammonia in refluxing ethanol to afford the corresponding Hantzsch 1,4-dihydropyridines, with yields mostly dependent on the reactivity and steric hindrance of the aldehyde (Scheme 1).

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M8 Meeee (%) ee (°M) Mee
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8-eeeee 88 888888 [‌8‌]
8-MeM8M8 88 888888 [‌8‌]
8-MeMM8M8 88 888888 [‌8‌]
8,8-Me8M8M8 88 888888 [‌8‌]

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