One-pot five-component high diastereoselective synthesis of polysubstituted 2-piperidinones from aromatic aldehydes, nit
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ORIGINAL ARTICLE
One‑pot five‑component high diastereoselective synthesis of polysubstituted 2‑piperidinones from aromatic aldehydes, nitriles, dialkyl malonates and ammonium acetate Anatoly N. Vereshchagin1 · Kirill A. Karpenko1 · Michail N. Elinson1 · Alexandra P. Minaeva1,2 · Alexander S. Goloveshkin3 · Karl A. Hansford4 · Mikhail P. Egorov1 Received: 13 July 2019 / Accepted: 24 September 2019 © Springer Nature Switzerland AG 2019
Abstract A novel five-component diastereoselective synthesis of polysubstituted 2-piperidinones is reported. The Knoevenagel condensation–Michael addition–Mannich cascade of two equivalents of aromatic aldehydes, nitriles, dialkyl malonates and ammonium acetate or aqueous ammonia in alcohols provides convenient access to alkyl (3SR,4RS,6SR)-5,5-dicyano-2-oxo4,6-diarylpiperidine-3-carboxylates with three stereocenters in 52–90% or dialkyl (2SR,3RS,4RS,5SR)-2,4-diaryl-3-cyano6-oxopiperidine-3,5-dicarboxylates with four stereocenters in 38–88%. The formation of products was highly stereoselective, with only one diastereomer formed. Ammonium acetate or aqueous ammonia plays a role both as a catalyst and as a nitrogen source. 2,4,6-triaryl-3,3,5,5-tetracyanopiperidines were obtained as a side products in the reactions with nitro-substituted aldehydes or with ethyl and n-propyl cyanoacetates. A series of 14 2-piperidinones and piperidines was assessed for antimicrobial activity against a panel of five bacteria and two fungi; no significant activity was observed. Two side piperidines with nitro substituents in aromatic ring possess bacteriostatic action against S. aureus ATCC 43300 and A. baumannii ATCC 19606 at 32 ug/mL. Graphic abstract
Formation of 3C-C, 2C-N bonds
Keywords Five-component reaction · Substituted 2-piperidinones · Nitriles · Dialkyl malonates · Aromatic aldehydes · Ammonium acetate · Stereoselectivity Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-019-09997-6) contains supplementary material, which is available to authorized users. * Anatoly N. Vereshchagin [email protected] Extended author information available on the last page of the article
Introduction The piperidine framework is one of the most frequently found in the structure of active substances in pharmaceutical compositions [1–3]. At present, piperidine-containing
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Molecular Diversity
Fig. 1 Biologically active 4-arylpiperidine-3-carboxylic acid derivatives
Scheme 1 Our previous work on the multicomponent synthesis of polysubstituted piperidines
compounds having antihistaminic, antispasmodic, analgesic and other effects are known [4]. There are piperidine derivatives as a factor Xa inhibitor, which make it possible to use them in the treatment of thrombosis-related diseases [5]. The piperidine framework is one of the most frequently found in the structure of active substances in pharmaceutical compositions [6]. Among medications, 4-phenylpiperidine derivatives are of great importance, because they resemble the morp
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