Chemistry and application of 4‐oxo‐4H‐1‐benzopyran‐3‐carboxaldehyde

The Chemistry and application of the title aldehyde and some simple derivatives thereof are reviewed.     

Synthesis and Chemical Reactivity of 4‐Oxo‐4H‐1‐benzopyran‐3‐carboxaldehyde

4‐Oxo‐4H‐1‐benzopyran‐3‐carboxaldehyde (chromone‐3‐carboxaldehyde or 3‐formylchromone) 1 is an important biologically active compound. It can serve as a precursor in the synthesis of a wide range of heterocyclic systems having chromone moiety, many of which exhibit broad spectrum of biological activities such as anti‐mutagenisity, cytotoxicity, thymidine phosphorylase inhibitor, and anti‐HIV activity. During the last decade, the title compound was studied extensively. The review presents an overall survey of the synthesis, chemical reactivity, and biological activities of 4‐oxo‐4H‐1‐benzopyran‐3‐carboxaldehydes and some of its derivatives.     

Studies on the Chemical Reactivity of 6,8‐dibromo‐7‐hydroxychromone‐3‐carboxaldehyde Towards Some Nitrogen Nucleophilic Reagents

The chemical reactivity of 6,8‐dibromo‐7‐hydroxychromone‐3‐carboxaldehyde ( 1 ) was studied towards some nitrogen nucleophilic reagents such as heterocyclic amines, 1,2‐N,N‐binucleophiles, 1,2‐N,O‐binucleophiles, 1,3‐N,N‐binucleophiles, 1,4‐N,N‐binucleophiles, 1,4‐N,O‐binucleophiles, and 1,4‐N,S‐binucleophiles under different reaction conditions.     

Transformation of 4‐oxo‐4H‐[1]‐benzopyran‐3‐carboxaldehydes into pyrazolo[3,4‐B]pyridines

Reaction of 6‐methyl‐4‐oxo‐4H‐[1]‐benzopyran‐3‐carboxaldehyde 1 with 5‐amino‐3‐methyl‐1‐phenylpyrazole 2 in alcoholic reaction media in the presence of 4‐toluenesulfonic acid as catalyst afforded 5‐(2‐hydroxy‐5‐methylbenzoyl)‐3‐methyl‐1‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine 3 and 2‐methoxy‐6‐methyl‐3‐(3‐methyl‐1‐phenylpyrazol‐5‐ylaminomethylene)chroman‐4‐one 7 . We explain the mechanism of formation of both products on the basis of kinetic study of individual reaction steps.     

Reactions of 2‐amino‐4h‐1‐benzopyran‐4‐one with 4‐oxo‐4h‐1‐benzopyran‐3‐carbaldehydes

The title aldehyde 1 reacts smoothly with the enamine moiety of 2 ‐aminochromone 2 to produce hitherto unreported 3‐(2‐hydroxybenzoyl)‐5H‐1‐benzopyrano[2,3‐b]pyridin‐5‐one (azaxanthone) 5 . This reaction has been extended for the synthesis of bisazaxanthone 9.     

7‐Hydr­oxy‐6‐methoxy‐3‐[(2‐oxo‐2H‐1‐benzopyran‐7‐yl)oxy]‐2H‐1‐benzopyran‐2‐one

The title compound, daphnoretin, C₁₉H₁₂O₇, was isolated from the leaves of Stellera chamaejasme L. Two independent mol­ecules are present in the asymmetric unit, with similar conformations. Each of the independent mol­ecules is composed of two chromene systems connected by an ether bridge. The dihedral angles between the mean planes of the two chromene systems are 86.9 (2) and 81.9 (3)°. Mol­ecules form chains via hydrogen bonds and adjacent chains are parallel to each other.     

Organocatalyzed Enantioselective Synthesis of 2‐Amino‐4H‐chromene Derivatives

Optically active 2‐amino‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene‐3‐carboxylates, 2‐amino‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene‐3‐carbonitriles, and 2‐amino‐8‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene‐3‐carbonitriles were synthesized. Using cinchona alkaloid‐derived bifunctional catalysts, the corresponding 2‐amino‐4H‐chromene derivatives were obtained in high yields and moderate to high ee values (up to 82% ee) from the tandem Michael addition–cyclization reaction between 1,3‐cyclohexanediones or 1,2‐cyclohexanediones and (E )‐3‐aryl‐2‐cyanoacrylate or alkylidene malononitrile derivatives.     

Studies on the Reactivity of Amino‐1‐(6‐phenyl‐pyridazin‐3‐yl)‐1H‐pyrazole‐4‐carboxylic Acid Hydrazide Towards Some Reagents for Biological Evaluation

Novel 5‐amino‐1‐(6‐phenyl‐pyridazin‐3‐yl)‐1H‐pyrazole‐4‐carboxylic acid ethyl ester ( 2 ) was formed using (6‐phenyl‐pyridazin‐3‐yl)‐hydrazine ( 1 ) and ethyl(ethoxymethylene)cyanoacetate. The β‐enaminoester derivative 2 was in turn used as precursor for the preparation of 1‐(6‐phenyl‐pyridazin‐3‐yl)‐pyrazoles ( 3 , 4 , 7 , 8 , 9 , 10 , 11 , 12 , 15 , 16 ), 1‐(6‐phenyl‐pyridazin‐3‐yl)‐pyrazolo[3,4‐d]pyrimidines ( 5 , 6 , 14 ) and 1‐(6‐phenyl‐pyridazin‐3‐yl)‐pyrazolo[3,4‐d][1,2,3]triazine ( 13 ). The in vitro antimicrobial activity of the synthesized compounds was evaluated by measuring the inhibition zone diameters where some of them showed potent antimicrobial activity in compared with well‐known drugs (standards).     

Synthesis of some new azole,azepine, pyridine,and pyrimidine derivatives using 6‐hydroxy‐4H‐4‐oxo[1]‐benzopyran‐3‐ carboxaldehyde as a versatile starting material

Condensation of 3‐formyl chromone 1 with hydroxylamine hydrochloride afforded the corresponding oxime 2 that was converted to nitrile 3 . Refluxing of oxime 2 and/or nitrile 3 with aceturic or hippuric acid gave 16 and 17 . Treatment of 1 with semicarbazide hydrochloride and thiosemicarbazide afforded the corresponding carbazones 5–6 that underwent cyclization with ethyl bromoacetate and/or chloroacetone yielding 7–8 . Also 1 reacted with acyclic active methylene reagents, e.g. malononitrile, ethyl cyanoacetate, and ethyl acetoacetate to form compounds 11, 12 , and 13 . Reaction of 1 with bifunctional reagents, e.g. benzil, o‐phenylenediamine, o‐aminophenol, and o‐aminothiophenol yielding the corresponding imidazolyl bezopyranone and azepine derivatives 14–20 . Condensation of 1 with acyclic or heterocyclic compounds containing active methylene group, e.g. hippuric acid forming the condensed products 21–27 . © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:20–27, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20048     

Stereoselective Synthesis of (3R)‐3,4‐Dihydro‐6,8‐dimethoxy‐3‐undecyl‐ 1H‐[2]benzopyran‐1‐one and Derivatives,Metabolites from Ononis natrix

A short stereoselective synthesis of (3R)‐3,4‐dihydro‐6,8‐dimethoxy‐3‐undecyl‐1H‐[2]benzopyran‐1‐one and derivatives isolated from Ononis natrix has been described. Condensation of dodecanoyl chloride with 3,5‐dimethoxyhomophthalic acid afforded 6,8‐dimethoxy‐3‐undecylisocoumarin 3 , which, on sequential saponification and esterification, yielded the keto ester 5 . Enantioselective reduction of 5 with TarB‐NO₂/LiBH₄ directly furnished the title dihydroisocoumarin 1a in 80% ee (82% yield). Partial as well as complete demethylation of the latter provided the dihydroisocoumarins 1b and 1c , respectively. Diastereotopy of the CH₂ H‐atoms on either side of the stereogenic center (C(3)) and the mass‐fragmentation pattern of the dihydroisocoumarins have also been described. All of the compounds synthesized were examined in vitro for antifungal activity.     

Construction of a combinatorial library of 2‐(4‐oxo‐4H‐1‐benzopyran‐3‐yl)‐4‐thiazolidinones by microwave‐assisted one‐pot parallel syntheses

A one‐pot liquid‐phase combinatorial synthesis of 2‐(4‐oxo‐4H‐1‐benzopyran‐3‐yl)‐4‐thiazolidinones bearing diverse substituents at the 3‐position under microwave irradiation was successfully performed using 3‐formyl chromone, primary amine, and mercaptoacetic acid as reactants. Compared to an identical library generated by conventional parallel synthesis, the microwave‐assisted parallel synthesis approach dramatically decreased the reaction time from an average of 9 h to 5 min, and substantially increased the product yields. The coupling of microwave technology with liquid‐phase combinatorial synthesis constitutes a novel and particularly attractive avenue for the rapid generation of structurally diverse libraries. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:381–389, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20309     

Antibacterial 4‐amino‐N‐(5‐methyl­isoxazol‐3‐yl)‐N‐[(4‐oxo‐2‐phenyl‐4H‐1‐benzopyran‐6‐yl)methyl]benzenesulfonamide

In the mol­ecule of the title compound, C₂₆H₂₁N₃O₅S, a new type of sulfonamide derivative with potential antibacterial activity, the flavone moiety is almost planar. The isoxazole and amino­phenyl rings are also planar and make dihedral angles of 77.0 (2) and 81.4 (1)°, respectively, with the best plane of the flavone ring system. The crystal structure is stabilized by intra‐ and inter­molecular hydrogen bonds.     

Simple,Efficient, and Catalyst‐Free Synthesis of (2‐Amino‐4H‐1‐benzopyran‐4‐yl)phosphonates in Polyethylene Glycol

Several (2‐amino‐4H‐1‐benzopyran‐4‐yl)phosphonates were efficiently synthesized by employing a multicomponent protocol involving a salicylaldehyde, malononitrile or ethyl cyanoacetate, and a trialkyl phosphite in polyethylene glycol. The latter could be recovered and re‐used. No additional solvent or catalyst was required. To the best of our knowledge, this is the first report of the one‐pot preparation of (2‐amino‐4H‐1‐benzopyran‐4‐yl)phosphonic acid dimethyl esters.     

2‐Amino‐4‐(4‐chlorophenyl)‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene‐3‐carbonitrile

The supramolecular structure of the title compound, C₁₈H₁₇ClN₂O₂, is determined by the intersection of two chains formed by N—H⋯O and N—H⋯N hydrogen bonds, forming a two‐dimensional sheet.     

Further Studies with Ethyl 5‐Amino‐3‐phenyl‐lH‐pyrazole‐4‐carboxylate1

The newly synthesized ethyl 3‐amino‐5‐phenylpyrazole‐4‐carboxylate 1 was diazotized and coupled with β‐naphthol, active methylene reagents 6 , 9 , 12 , 15 , and the active methine 19 to afford the pyrazolo[5,1‐c]triazines 5 , 8 , 11 , 14 , 17 , 18 , and the pyrazolo[5,1‐ c ]‐1,2,4‐triazoles 21 , 22 , and 23 , respectively. Structures are elucidated and mechanisms are discussed.     

Sesquiterpenoids and 2‐(2‐Phenylethyl)‐4H‐chromen‐4‐one (=2‐(2‐Phenylethyl)‐4H‐1‐benzopyran‐4‐one) Derivatives from Aquilaria malaccensis Agarwood

The four new sesquiterpenoids 1 – 4 , and the new 2‐(2‐phenylethyl)‐4H‐chromen‐4‐one (=2‐(2‐phenylethyl)‐4H‐1‐benzopyran‐4‐one) derivative 5 , together with the two known sesquiterpenoids 6 and 7 , the five known chromenones 8 – 12 , and 1‐hydroxy‐1,5‐diphenylpentan‐3‐one ( 13 ), were isolated from a 70% MeOH extract of Aquilaria malaccensis agarwood chips. Their structures were elucidated on the basis of comprehensive spectral analyses and comparison with literature data.