Facile Diversity-Oriented Synthesis and Antitubercular Evaluation of Novel Aryl and Heteroaryl Tethered Pyridines and Dihydro-6H-quinolin-5-ones Derived via Variants of the Bohlmann–Rahtz Reaction

Abstract

The diversity oriented synthesis of substituted pyridines and dihydro-6H-quinolin-5-ones tethered with aryls and heteroaryls was achieved in very good yields through CeCl(3)·7H(2)O-NaI catalyst via variants of the Bohlmann-Rahtz reaction. β-Enaminones derived from various aryl and heteroaryl methyl ketones were regioselectively reacted with ethyl acetoacetate or 5,5-dimethylcyclohexane-1,3-dione or 4,4-dimethylcyclohexane-1,3-dione and ammonium acetate refluxing in 2-propanol. Applicability of nontoxic cerium catalyst, high reactivity with wide range of aryl and heteroaryl β-enaminones leading to diverse analogues, operational simplicity, and shorter reaction time at comparatively low temperatures are prominent features of the developed protocol. These synthesized substituted pyridines and dihydro-6H-quinolin-5-one analogues have been evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) by agar dilution method. Among the 48 compounds screened, six compounds 2-(5-chlorothiophen-2-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 4{13,2}, 2-(5-bromothiophen-2-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 4{14,2}, 2-(5-chloro thiophen-2-yl)-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one 4{13,3}, and 2-(5-bromothiophen-2-yl)-6,6-dimethyl-7,8-dihydroquinolin-5(6H)-one 4{14,3}, 7,7-dimethyl-2-(naphthalen-2-yl)-7,8-dihydroquinoline-5(6H)-one 4{6,2}, 6,6-dimethyl-2-(naphthalen-2-yl)-7,8-di hydroquinolin-5(6H)-one 4{6,3} resulted as the most promising antitubercular agents.

Novel Synthesis of 6‐Substituted 2‐Picolines from Aryl/heteroaryl β‐Enaminones and Meldrum's Acid Using CeCl3.7H2O/NaI

“…β‐Enaminones 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l required for the study (Fig. ) are prepared by the condensation of respective aryl/heteroaryl methyl ketones with dimethylformamide dimethylacetal (DMF‐DMA) refluxing in xylene according to the general protocol standardized in our laboratory . All the new as well as literature described β‐enaminones 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l are fully characterized by 1 H, 13 C NMR, and mass spectral analysis.…”

“…β‐Enaminones , because of the presence of ambident nucleophilic character of enamine moiety and the ambident electrophilic character of enone moiety, turned out to be simple and reactive starting materials for the synthesis of diversely substituted heterocycles . Taking advantage of their electronic properties, we explored aryl and heteroaryl embodied β‐enaminones in our laboratory as polarized variants in one‐pot Bohlmann–Rahtz reaction. The Lewis acid catalyzed condensation β‐enaminones with cyclic and acyclic 1,3‐dicarbonyls and ammonium acetate resulted a series of 2,3,6‐trisubstituted pyridines and dihydro‐6 H ‐quinoline‐5‐ones in good to excellent yields .…”

“…Taking advantage of their electronic properties, we explored aryl and heteroaryl embodied β‐enaminones in our laboratory as polarized variants in one‐pot Bohlmann–Rahtz reaction. The Lewis acid catalyzed condensation β‐enaminones with cyclic and acyclic 1,3‐dicarbonyls and ammonium acetate resulted a series of 2,3,6‐trisubstituted pyridines and dihydro‐6 H ‐quinoline‐5‐ones in good to excellent yields . Encouraged by these results, we further examined the reaction of β‐enaminone with Meldrum's acid and ammonium acetate under similar reaction conditions.…”

Selectfluor-triggered fluorination/cyclization of o-hydroxyarylenaminones: A facile access to 3-fluoro-chromones

“…Compounds 1a-1r were prepared according to the literature. 83,84 Selectfluor was purchased from Adamas-beta and Aldrich Corporation Limited.…”

Application of Cyclohexane‐1,3‐diones in the Synthesis of Six‐Membered Nitrogen‐Containing Heterocycles

“…Additionally, pyridine derivatives made up from cyclohexan‐1,3‐diones are another class of biologically active six‐membered N ‐heterocycles [78] . Pyridine‐containing N ‐heterocycles are developed by electrochemically tempted condensation of various aromatic aldehydes, cyclohexane‐1,3‐diones and 6‐amino uracil, [79] by four‐component bicyclization reactions [80] .…”