Synthesis of 6-Phenyl Substituted 2-Formylnicotinates

Abstract

A versatile synthesis of 2-formylnicotinates 6 (R' = Me) and 7 (R' = Et) is described. 6-Phenyl substituted 2-diethoxymethylnicotinates 14/15 are prepared first starting by cyclocondensation of 3-amino-4,4-diethoxybut-2-enoates 12/13 with Mannich base hydrochlorides 1 or ß-aminovinyl ketones 16. Subsequent hydrolysis of the acetal function in 14/15 gives rise to the title compounds.

Copper Catalysis for Nicotinate Synthesis through β‐Alkenylation/Cyclization of Saturated Ketones with β‐Enamino Esters

“…Figure depicts several drug molecules that contain a nicotinate scaffold, including dexamethasone isonicotinate (an anti‐inflammatory, anti‐allergic glucocorticoid), morniflumate (an analgesic, antipyretic and anti‐inflammatory agent), flunixin meglumin (a cyclooxygenase inhibitor), vitamin E nicotinate (an antioxidants), nicorandil (a vasodilatory drug), and hepronicate (a hypolipidemic drug) . To date, many of approaches have been successfully developed to produce nicotinate skeletons by employing electron‐deficient β ‐enamino esters ( β ‐EAEs) as the readily accessible C,N ‐dinucleophilic synthons combined with the condensation of 1,3‐dicarbonyl compounds, α,β ‐unsaturated ketones, alkynones, Mannich base hydrochlorides, and IBX‐mediated oxidative annulation of allylic alcohols (Scheme ) . However, most of these methods have been compromised by harsh reaction conditions, stoichiometric halogenated reagents, functionalized starting materials, which could not fulfill the requirements of reagent efficiency.…”

“…To date, many of approaches have been successfully developed to produce nicotinate skeletons by employing electron‐deficient β ‐enamino esters ( β ‐EAEs) as the readily accessible C,N ‐dinucleophilic synthons combined with the condensation of 1,3‐dicarbonyl compounds, α,β ‐unsaturated ketones, alkynones, Mannich base hydrochlorides, and IBX‐mediated oxidative annulation of allylic alcohols (Scheme ) . However, most of these methods have been compromised by harsh reaction conditions, stoichiometric halogenated reagents, functionalized starting materials, which could not fulfill the requirements of reagent efficiency. Therefore, simple, practical approaches for the synthesis of nicotinates from readily available substrates have remained elusive, but highly desirable.…”

Mannich Bases as Enone Precursors for Water-Mediated Efficient Synthesis of 2,3,6-Trisubstituted Pyridines and 5,6,7,8-Tetrahydroquinolines

“…6 Keuper and Nikolaus also used Mannich bases to prepare polycyclic pyridines from β-amino ketone hydrochlorides, cyclic ketones and ammonium acetate in boiling acetonitrile. However in many cases, yields were low, and the best results have been obtained in absolute ethanol.…”

Microwave‐assisted regioselective one‐pot synthesis of trisubstituted pyridine scaffolds using K5CoW12O40.3H2O under solvent free conditions

“…Enaminoketones are readily available versatile intermediates and play an important role in the synthesis of a number of heterocyclic compounds [5]. 6-Aryl-2-methylnicotinates are synthesized by the condensation of 3-aminocrotonate with acetophenone Mannich base hydrochlorides in refluxing ethanol [6,7], with acetylenic ketones [8] at higher temperatures, from oxazolidines in refluxing acetonitrile in the presence of acetic acid [9] and its microwave modification [10] in DMSO. Recently these compounds are prepared by the condensation of enaminoketones, -dicarbonyl compounds and ammonium acetate in refluxing acetic acid [11], and later by montmorillonite K10 in refluxing isopropanol [12].…”