Solvent-free synthesis of novel 5-oxo-5H-chromeno[4,3-b]pyridine derivatives

Abstract

An efficient and simple method for the synthesis of new 5-oxo- 5H-chromeno[4,3-b]pyridine derivatives via Michael addition of 4-aminocoumarin to arylidenemalononitrile for 20 min at 150°C without any solvent is proposed. The advantages of this procedure are mild reaction conditions, high yields of products, and operational simplicity.Keywords: 5-oxo-5H-chromeno [4,3-b]pyridine, Michael addition, solvent-free synthesis.Various coumarin derivatives, particularly those fused with other heterocycles, have attracted much attention in recent years due to their biological activities [1,2], and encouraged research to improve the availability of these compounds with regard to procedures and substrates. Coumarins condensed to pyridine ring (chromeno[3,4-b]pyridin-5-ones) are also under investigation, as they constitute the backbone of naturally occurring alkaloids, e.g. santiagonamine [3]. Some of them, both natural and non-natural products, are currently in clinical trials [4][5][6][7].Previously we reported the synthesis and cytotoxic activity of novel coumarin derivatives, chromeno[4,3-b]-quinolines, benzopyrano[3,2-c]chromene-6,8-diones and chromeno[3',4']pyrano[2,3-b]quinoline-6,9-diones [8-10]. In continuation of our studies, and owing to the importance of chromenopyridines, we decided to investigate the synthesis of new 5-oxo-5H-chromeno[4,3-b]pyridine derivatives by a simple method.The literature data on existing synthetic routes to 5-oxo-5H-chromeno[4,3-b]pyridines can be classified based on the functionality of the starting materials. Synthetically significant approaches include multistep ring formation by reaction of 4-aminocoumarin with alkyl vinyl ketones [11], 4-amino-3-formylcoumarin with C-H acids [12], 4-chloro-3-formylcoumarin with Wittig phosphoranes [13], or 4-oxo-4H-chromene-3-carbaldehydes with enamines followed by oxidation [14]. In another procedure, 7-trifluoromethyl group-containing 5-oxo-5H-chromeno[4,3-b]pyridine derivatives were prepared by reaction of 4-chloro-3-(trifluoroacetyl)-2H-chromen-2-one and aniline followed by intramolecular cyclization in the presence of concentrated sulfuric acid [15]. However, these methods have disadvantages such as harsh reaction conditions, sensitivity of starting materials and reagents to moisture, and use of toxic reagents (POCl 3 , TMSCl) or oxidants (CrO 3 , conc. H 2 SO 4 ).In the present work, we have developed the synthesis of new 2-amino-4-aryl-5-oxo-5H-chromeno-[4,3-b]pyridine-3-carbonitriles 3a-n via Michael addition of 4-aminocoumarin (1) to arylidenemalononitrile 2a-n in 60-80% yields in a solvent-free system at 150°C.

The Chromenopyridine Scaffold: A Privileged Platform in Drug Design

“…It was suggested that lactic acid aids the process by interacting with the adduct via hydrogen bonding, facilitating the Michael addition step. Motamendi presented a solvent-free methodology for the synthesis of chromenopyridine derivatives 122, through the reaction of 4-aminocoumarin 114 with arylidenemalononitriles 121, at 150 °C [93]. The final product was obtained after flash chromatography purification, with isolated yields of 60-80%.…”

Domino Reactions of Chromone‐3‐carboxylic Acids with Aminoheterocycles: Synthesis of Heteroannulated Pyrido[2,3‐c]coumarins and their Optical and Biological Activity

“…pounds of this type are usually obtained from 3-substituted coumarins, [23,[26][27][28][29] 4-substituted coumarins, [30][31][32][33][34][35] salicylic aldehydes, [36] 2-halobiarylcarboxylates, [37] or halogenated arenecarboxylates [38] by means of catalytic processes. Several authors have communicated the synthesis of 5-hydroxy-5Hbenzopyrano [4,3-b]pyridine, a reduced precursor of the pyrido [3,2-c]coumarin core structure, starting from 3-formylchromone.…”

“…Pyrido[3,2‐ c ]coumarins are important because of their photophysical and biological effects as well as their potential applications, for example, bright fluorescence, chemosensory properties, fluorescence imaging in living cells, decrease of blood sugar levels, and positive inotropic effects . Compounds of this type are usually obtained from 3‐substituted coumarins,, 4‐substituted coumarins, salicylic aldehydes, 2‐halobiarylcarboxylates, or halogenated arenecarboxylates by means of catalytic processes. Several authors have communicated the synthesis of 5‐hydroxy‐5 H ‐benzopyrano[4,3‐ b ]pyridine, a reduced precursor of the pyrido[3,2‐ c ]coumarin core structure, starting from 3‐formylchromone .…”