Tetrahydropyridines’ Stereoselective Formation, How Lockdown Assisted in the Identification of the Features of Its Mechanism

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 14; p. 4367
• Main Authors: Vereshchagin, Anatoly N., Iliyasov, Taigib M., Karpenko, Kirill A., Akchurin, Radmir N., Minyaev, Mikhail E.
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 07-07-2022; MDPI
• Subjects: 1,4,5,6-tetrahydropyridines; Acetic acid; Acids; Aldehydes; Ammonium; Ammonium acetate; C-H acids; Cascade chemical reactions; Chromatography; Condensates; Dehydration; domino processes; Esters; Intermediates; Isomerization; multicomponent reactions; Nitrogen; Stereoselectivity; Tetrahydropyridines; X-ray diffraction
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27144367

The multicomponent reaction of aldehydes, cyano-containing C-H acids, esters of 3-oxocarboxylic acid and ammonium acetate led to unexpected results. The boiling of starting materials in methanol for one to two hours resulted in the formation of polysubstituted 1,4,5,6-tetrahydropyridines with two or three stereogenic centers. During the 2020 lockdown, we obtained key intermediates of this six-step domino reaction. A number of fast and slow reactions occurred during the prolonged stirring of the reaction mass at rt. Sequence: 1. Knoevenagel condensation; 2. Michael addition; 3. Mannich reaction; 4. cyclization—fast reactions and cyclization of the product polysubstituted 2-hydroxypiperidine—was isolated after 40 min stirring at rt. Further monitoring proved the slow dehydration of 2-hydroxypiperidine to obtain 3,4,5,6-tetrahydropyridine after 7 days. Then, four-month isomerization occurred with 1,4,5,6-tetrahydropyridine formation. All reactions were stereoselective. Key intermediates and products structures were verified by X-ray diffraction analysis. Additionally, we specified conditions for the selective intermediates’ preparation.