Multicomponent Reactions of Acetoacetanilide Derivatives with Aromatic Aldehydes and Cyanomethylene Reagents to Produce 4<i>H</i>-Pyran and 1,4-Dihydropyridine Derivatives with Antitumor Activities

Abstract

The multi-component reaction of either acetoacetanilide derivative 1a or b with any of the aldehyde derivatives 2a-d and malononitrile 3 in the presence of triethylamine as a catalyst gave the 4H-pyran derivatives 4a-g, respectively. Carrying the same reaction but using a catalytic amount of ammonium acetate gave the 1,4-dihydropyridine derivatives 5a-f, respectively. The use of ethyl cyanoacetate instead of malononitrile in the presence of a catalytic amount of triethylamine gave the 4H-pyran derivatives 7a-d, respectively. Compound 4e was used to synthesize 1,4-dihydropyridine 9a-c and arylhydraone 11a-e derivatives were synthesized from 4a and e. The anti-tumor evaluations of the newly synthesized products were tested against six human cancer and normal cell lines. The results showed that compounds 4a, b, f, 5d, f, 9 and 11a-d had optimal cytotoxic effect against cancer cell lines with IC 50 <550 nM. The toxicity of the most active compounds was further measured against shrimp larvae.Key words 4H-pyran; 1,4-dihydropyridine; cyanomethylene; cytotoxicity Multicomponent reactions (MCRs) are one-pot reactions employing more than two starting materials, e.g. 3, 4, ... , 7, where most of the atoms of the starting materials are incorporated in the final product.1) Several descriptive tags are regularly attached to MCRs they are atom economic, e.g. the majority if not all of the atoms of the starting materials are incorporated in the product; they are efficient, e.g. they efficiently yield the product since the product is formed in onestep instead of multiple sequential steps; they are convergent, e.g. several starting materials combine in one reaction to form the product; they exhibit a very high bond-forming-index (BFI), e.g. several non-hydrogen atom bonds are formed in one synthetic transformation.2,3) Therefore MCRs are often a useful alternative to sequential multistep synthesis.In view of the increasing interest in the preparation of a large variety of heterocyclic compound libraries, the development of new synthetically valuable MCRs with several diversity points remains a challenge for both academic and industrial institutions.4) 4H-Pyran and its derivatives are an important class of heterocyclic compounds possessing broad biological activities, such as anti-inflammatory, 5) analgesic, 6) antioxidant,antiamoebic 11) and oral analgesic. 12) From the aforementioned reports, it seemed that the development of an efficient, rapid, and clean synthetic route towards focused libraries of such compounds is of great importance to both medicinal and synthetic chemists. The combination of multicomponent reactions (MCR 2 ), [13][14][15] which combines different types of MCRs in one pot process inheriting the high selectivity, efficiency, and atom economy of MCR, has gained more and more attention, since Dömling and Ugi reported the first MCR 2 of a modified four-component reaction (4CR) and the Ugi 4CR.16) However, most of the reported MCR 2 cases are limited in isonitrile based multicomponent reactions. [17][18][19][20]...

Fabrication of a Gold-Supported NiAlTi-Layered Double Hydroxide Nanocatalyst for Organic Transformations

“…Xanthene, 1,4-dihydropyridine, polyhydroquinoline, and 4 H -pyran derivatives are famous structural architectures found in many synthetic drugs, biologically active natural products, and essential units for chemical intermediates. 1 Therefore, many methods have been reported for their catalytic synthesis with different advantages. Still, each of them offers various limitations such as hazardous and long catalyst preparation, harsh conditions, extended workup, and toxic and expensive solvents and reagents.…”

“…Xanthene, 1,4-dihydropyridine, polyhydroquinoline, and 4 H -pyran derivatives are famous structural architectures found in many synthetic drugs, biologically active natural products, and essential units for chemical intermediates . Therefore, many methods have been reported for their catalytic synthesis with different advantages.…”

Crystal Structure and Hirshfeld Surface Analysis of Acetoacetanilide Based Reaction Products

“…Pyridone, piperidine, pyran, and isoquinoline moieties are functional components of various natural products [ 1 , 2 , 3 ], pharmaceuticals [ 4 , 5 , 6 ], and biologically active compounds [ 7 , 8 , 9 ]. Two-component [ 10 ] and multicomponent [ 11 , 12 , 13 ] tandem transformations leading to these heterocyclic systems are particularly attractive from the point of view of diversity-oriented synthesis because of their modularity and rapid buildup of molecular complexity. In this article, we disclose a high-yielding synthesis of a structurally novel bicyclic heterocycle from two simple starting materials.…”

Conventional and Microwave‐Assisted Synthesis and Biological Activity Study of Novel Heterocycles Containing Pyran Moiety

“…In the last several decades, 4 H ‐pyran derivatives are considered one of the most important family of heterocyclic compounds containing oxygen due to their wide‐range of biological and pharmacological activities, such as antitumor , antimicrobial , anticancer , antiviral , antimalarial , anti‐HIV , antidyslipidemic, antihyperglycemic , anti‐inflammatory , antifungal , antituberculosis , and cytotoxic activities.…”