Chemistry of 3-carbonyl-2-methyl-4-oxo-4 H -1-benzopyrans

The review article gives a comprehensive survey of the synthesis and chemistry of the title benzopyrans covering the literature published during 1980 – August 2015


Introduction
2-Methyl-1-benzopyran-4-ones 1-5 belong to the chromone family, and, like their respective 2unsubstituted homologues 6, possess an activated endocyclic olefinic bond, three electrophilic centres, namely pyran C-2, exocyclic carbonyl carbon and an endocyclic carbonyl carbon.In chromone 6, C-2 is much more electrophilic than the exocyclic carbonyl carbon, and C-4 is the least electrophilic position.Electrophilicity at the methyl substituted C-2 of chromones 1-5 is evidently less than that at C-2 of their lower homologues 6 due to the positive inductive effect and hyperconjugation of the methyl group.The 2-methyl group in 1-5, being vinylogous to two carbonyl groups, is more acidic than that in 2-methylchromone 8, and functions as a nucleophile in the presence of an appropriate base.Because of these functionalities (activated olefinic bond, electrophilicity at three centres and nucleophilicity at the 2-methyl group), the chemistry of 2methylchromones 1-5 is more varied than that of the lower homologues 6.Of the several review articles on chromones, the latest one on 2-methylchromone 8 1 , two on the nitrile 7a 2,3 and three on 3-formylchromone 6a [4][5][6] are noteworthy.In contrast, a full, complete and up-to-date survey on the chemistry of the title chromones 1-5 is still lacking.
Research in the chemistry of the title topic started in 1921 with the synthesis of 3-acetyl-2methylbenzo[f]chromone by treatment of 2-methoxynaphthalene with acetic anhydride and sulfoacetic acid.Here the methoxy group of the initially formed 1-acetyl-2-methoxynaphthalene probably undergoes hydrolysis under the reaction conditions and the resultant intermediate by further acetylation and cyclization gives the final product. 7Over the following six decades research has mainly revolved around the synthesis of 3-acylchromones 2 and 3 and their reactions with simple nitrogen nucleophiles.The present article is a comprehensive survey of the chemistry and applications of the chromones 1-5, and covers the literature published during the period 1980 to August 2015.Patented works on the chromones 1-5 are excluded, and the biological activity of compounds 1-5 and the products obtainable therefrom are less emphasized.Most of the reactions described here for the chromones 1-5 generally do not affect any alkyl, alkoxy and halogeno substituents if present in the benzene ring, or on aromatic or heterocyclic rings if fused with the benzene ring of these chromones.

Synthesis
The easily available o-hydroxyacetophenone can serve as a synthon for the title chromones 1-5.
Another method for the preparation of the aldehyde 1 involves acid hydrolysis of the hydrazone 24 arising through an aza-Michael addition of 1,1-dimethylhydrazine to the α,βunsaturated ketone functionality of 6b with concomitant opening of the pyran ring and recyclization (Scheme 4). 14

Scheme 5
Kostanecki-Robinson synthesis of 2 by just heating 25 with Ac 2 O-AcONa involves all the above three steps.3-Acetyl-2-methylchromone 2 and its variously substituted analogues have been synthesized by the Kostanecki-Robinson method.Ganguly et al. 15 have used MeCOCl in DBU-pyridine, instead of Ac 2 O-AcONa, for preparing some 5-or 7-mono and 5,7-disubstituted analogues of 2 from the corresponding o-hydroxyacetophenones.

Scheme 7
Treatment of the diacetoxyacetophenone 45 with sodamide results in cyclization and an intermolecular acetyl group transfer to give 46 admixed with 47, the deacylated product from 45 (Equation 1). 25 TiCl 4 -catalyzed Friedel-Crafts acylation of some substituted phenols with either AcCl 26 or AcOH 27 is often followed by Allan-Robinson reaction to some extent so as to form 3-acetyl-2methylchromones (Equations 2 and 3).
3-Benzoyl-2-methylchromone 3 has also been prepared from 2-methylchromone 8 as well as 3-benzoylchromone 6c.Lithium diisopropylamide (LDA, from diisopropylamine and butyl lithium) can cause vinylic deprotonation and classical deprotonation of the active methylene group.Costa et al. 42 prepared 3-benzoyl-2,6-dimethylchromone 64 in 46% yield by sudden addition of ethyl benzoate to a LDA solution in hexane kept at -78°C followed immediately by the addition of 2,6-dimethylchromone 63 and quenching the reaction after 3 h with AcOH-H 2 O (Equation 5).This is an example wherein vinylic deprotonation predominates over deprotonation of a sufficiently active 2-methyl group of chromone 63.The chromone 3 along with three other products is obtained by treating 3-benzoylchromone 6c with diazomethane. 32

Scheme 8
The intermediate β,β'-diketoester 70, resulting from 2-fluorobenzoyl chloride 69 and methyl acetoacetate in the presence of sodium hydride, undergoes cyclization via ipso-fluorine substitution to give the ester 5a.When the acid chloride 69 is similarly reacted with t-butyl acetoacetate and the reaction mixture treated with HClO 4 , the acid 4 results (Scheme 9). 47

Scheme 9
A Russian group [48][49][50][51] adopted this method for the preparation of tetrafluoro-and trifluorochromones 71 and extensively studied their reactions with several nitrogen nucleophiles.Lin and Long 52 subjected the β-ketoester 72 with AcCl in DMF containing K 2 CO 3 and DIPEA to obtain the 7-fluorochromone derivative 73.

Conjugate Addition to the Pyran 2,3-Olefinic Bond of Chromones without
Pyran Ring Opening

Conjugate reduction
Conjugate reduction of chromone 3 with sodium borohydride in pyridine at room temperature is both regio-and chemo-selective giving the chromanone 80. Methanesulfonic acid triggers the pyranone ring opening of 80 followed by recyclization to give the 3-ethenylflavone 81. 36The ester 5a with NaBH 4 in methanol gives 82. 55e conjugate reduction of the ester 5a to 84 followed by its Michael addition to an α,βunsaturated ketone 85, derived from a biocatalytic oxidation of methylcatechol 83 in a H-Cube Pro flow system, leading to the trisubstituted chromanone 86 (96% yield; dr > 99:1) (Scheme 12) deserves special mention.Crombie et al. 59,60 have developed a conjugate addition -radical cyclization approach to construct the naturally occurring sesquiterpene-phenol carbon framework.To an ether -pentane solution of the mixed ligand cuprate reagent 92, derived from the alkyl iodide 90, lithium cuprate 91 and t-butyllithium, was added the ester 5a to obtain the chromanone 93 as a mixture of four stereoisomers.Treatment of this mixture with Mn(OAc) 3 -HOAc affords the hemiacetal 94 in 30% yield (Scheme 13).In another approach the 2-alkyl ester 96 prepared from 2-fluorobenzoyl chloride 69 and the ester 95, is converted into the 2,2-dialkylated chromanone 97 by treatment with Me 2 CuLi.Radical cyclization of 97 as an unresolved stereoisomeric mixture affords the polycyclic lactone 98 in nearly 30% yield (Scheme 14). 59 A lithium dialkynylcuprate as [(TMS-C≡C) 2 CuLi], though capable of transferring its alkynyl group in a conjugate addition to the ester 6e, failed to react with 3-alkoxycarbonyl-2methylchromone 5. 61 3-Acetylchromone 2 on treatment with the silyl enol ether 99 in the presence of trimethylsilyl triflate (TMSOTf) affords in 16% yield the chromonanone 100 as a diastereoisomeric mixture (Equation 7). 62eteroannulation of the chromone A (≡ 2, 3, 5a) with 2-chloroethanol in the presence of K 2 CO 3 to the corresponding furobenzopyranone 101 (Equation 8) proceeds via the conjugate addition of the haloethanol to the chromone followed by intramolecular alkylation. 63ransformation of the chromone ester 102 on treatment with MeI -K 2 CO 3 in refluxing acetone into the spiroacetals 103 and 104 in a ratio of 5:1 (in 60% total yield) (Equation 9) also involves a sequential intramolecular conjugate addition and enolate alkylation. 64kaline hydrogen peroxide with the esters 5a and 102 forms the epoxides 105 and 106, respectively.Acid catalyzed oxirane ring opening of 106 results in the formation of the spiroacetals 107 and 108 (Scheme 15).

Addition of ammonia and amines
The aza-Michael adduct 110 resulting from tetrafluorobenzopyran-3-carboxylic acid 109 and ammonia undergoes decarboxylative pyran ring opening to give the enaminoketone 111 that on acid treatment affords 2-methylchromone 112 (Scheme 16). 65Piperidine brings about substitution of fluorine at the 7-position of 109 and conjugate addition, the adduct 113 undergoing decarboxylative elimination of the piperidine moiety to give 114 (Scheme 16). 65

Scheme 20
The ester 5a with methylhydrazine 142a gives 144a (20%) and 145a (64%), the former product (144a) arising by lactonization of the non-isolable intermediate 143a and the latter (145a) lactonizing to 146a only by base (like triethylamine) treatment (Scheme 21). 79,80Both 144a and 145a can serve as ligand L to form with Pd(PhCN) 2 Cl 2 trans-PdL 2 Cl 2 complexes, only the doubly-bonded nitrogen of L being co-ordinated to Pd(II). 79,80Treatment of the ester 5a with 2-hydrazinopyridine 142b gives exclusively the 1-(2-pyridyl)pyrazole 145b that forms with K 2 PtCl 4 , K 2 PdCl 4 and CuCl 2 the metal complex of the general formula 147.A molecule of dimethylformamide can also coordinate with Cu(II) of the complex 147 (M = Cu) giving the pentacordinated Cu(II) complex 148. 81,82The structures of all these metal complexes have been confirmed by X-ray analysis.

Scheme 28
Thiourea brings about substitution reaction in 186 giving 188 (Scheme 28) that survives heating under reflux even in a high boiling solvent such as ethylene glycol.In contrast, a mixture of 186 and thioacetamide on being heated under reflux in ethanol containing AcONa produces the thieno [3,4-b][1]benzopyranone 195.Here the intermediate 193, initially resulting from substitution of bromine by thioacetamide, undergoes base catalyzed acetonitrile eliminative cyclization (to 194) and subsequent water elimination to 195 (Scheme 29). 93

Scheme 29
A Russian group 94 has treated the chromone 3 with 2.2 equivalents of bromine to obtain 3benzoyl-2-(dibromomethyl)chromone 196 that condenses with thioacetamide to give the thienochromone 195, instead of the normally expected bromothiophene 197 (Scheme 30); the formation of 195 is not rationalized.Scheme 30

Benzopyrans 1-5 as Nucleophiles
The 2-methyl group of the chromones 1-5, being vinylogous to two carbonyl groups, functions as a nucleophilic centre even under weakly basic conditions so as to undergo addition to various electrophilic compounds as described in the following subsections.

Addition to the carbonyl compounds
The ester 5a condenses with cyclohexanone 198 in the presence of t-butoxide in butanol/dimethoxyethane giving the spirolactone 199; it in polar media exists in equilibrium with the acid 200 so that its treatment with diazomethane in diethyl ether leads to the cyclohexylidene ester 201 cyclizable by polyphosphoric acid to the tetrahydrobenzoxanthone 202 (Scheme 31). 95

Scheme 31
3-Formylchromone 6a functions as an aromatic aldehyde to condense with 3-acetyl-2methylchromone 2 in Ac 2 O-AcONa giving the 2-ethenylchromone 203 (Equation 13). 35This mode of addition differs from the one described in the following subsection.

Addition to unsaturated carbonyl compounds
3-Acetylchromone 6b dissolved in ethanol or dioxane on treatment with triethylamine or pyridine at room temperature or by percolation through Brockmann neutral alumina affords, without acid treatment, the xanthone 204.Here 6b undergoes acyl-acyl rearrangement under base catalysis to 1 and condensation between these two chromone derivatives leads to the xanthone 204. 14Again the aldehyde 1 on treatment with alumina also affords the xanthone 204. 96The formation of 204 may be rationalized in the following way.Alumina (alumina lattice oxide anion, represented by LO ¯) catalyzed isomerization of 1 to 6b and a subsequent Michael initiated ring closure between 1 and 6b leads to the intermediate 203 that on base catalyzed deacylative hydroxy elimination and pyran ring opening (or deacylative pyran ring opening and water elimination) gives 204 (Scheme 32). 96

Scheme 32
Interestingly, when a mixture of the aldehyde 1 or the corresponding hydrazone 24 and any of the chromones 6a,b,d is heated in dioxane in the absence of any catalyst, the xanthone 204 also results.Here 1 as well as 24 tautomerizes to 205 that having an o-quinodimethane structure undergoes a facile Diels-Alder reaction with the pyranodienophiles; the resultant adduct 206 gives 204 by an elimination process (Scheme 33). 14

Scheme 38
The ester 220e (R = OMe) gives 1-benzopyranopyridine N-oxide 237 with hydroxylamine, benzopyranopyridine N-acetylimide 238 with acethydrazide and coumarin-3-ylpyrazole 239 with phenylhydrazine. 100e dienaminoketone 220b when heated with DMAD (240a) in DMF gives a mixture of the xanthone dicarboxylates 244 and 249 admixed with a small amount (~5%) of 1-hydroxyxanthone 221 whereas 220c under similar conditions gives exclusively the xanthone 250.Here the diene 220 behaves as an unconjugated enamine in undergoing [2+2] cycloaddition with the electron deficient acetylene 240 to give the adduct 241 (Scheme 39). 101having respectively the octahedral, distorted square pyramidal and square pyramidal geometry.Each metal in these complexes is coordinated to the deprotonated carboxylate oxygen and pyridine oxygen of cip, two carbonyl oxygens of chromone ligand L and one nitrogen of piperazine.Piperazine by coordination through its second nitrogen to the other metallic centre tethers two metal centres in the said dimeric complexes.The ferric ion in Fe(III) complex is additionally bonded to one hydroxyl anion.DNA binding activity as well as biological activities against several gram-positive and gram-negative bacterial cultures of the metal complexes have been assessed.

Conclusions
Syntheses of all the members 1-5 belonging to the title chromone family and their various reactions as electrophilic as well as nucleophilic substrates studied during the last thirtyfive years have been comprehended.
having an electron withdrawing group at its 3-position.He has so far sixty six publications in this field.

73 Preparation of the acid 4
Scheme 10

1 . 17 18 AScheme 19 .
Scheme 17 obtained exclusively the pyrazole 140 by heating under reflux a mixture of 4 and PhNHNH 2 .HCl in ethanol containing sodium acetate.The acid 4 with NH 2 OH follows a reaction course similar to Scheme 20-path b to yield the isoxazole 141.

Table of Contents
2.1 Dinucleophiles having adjacent nucleophilic centres 4.2.2Dinucleophiles with two nucleophilic centres separated by one carbon 4.2.3Dinucleophiles with two nucleophilic centres separated by two carbons 1,4-dihydroquinoline-3-carboxylic acid 255 and piperazine 256 (abbreviated respectively as cip and pip); the last named two ligands are obtained by splitting ciprofloxacin hydrochloride (cpf.HCl) 257 with alkali.This ligand mixture gives [Fe 2 L 2 (cip) 2 (OH) 2 (pip)].5H 2 O with ferric nitrate in the presence of alkali, 102 [Fe 2 L 2 (cip) 2 (pip)].5H 2 O with ferrous sulfate 103 and [Cu 2 L 2 (cip) 2 (pip)].5H 2 O with cupric nitrate Chakraborty received his B.Sc. and M.Sc. in Chemistry from Vidyasagar University, India in 2002 and 2004 respectively.After obtaining Ph.D. in 2011 for his work on organometallic chemistry with Professor Amitabha Sarkar in Indian Association for the Cultivation of Science (IACS), Kolkata, he moved to Radboud University, Netherlands for his postdoctoral research with Professor Jan C. M. van Hest.Then he joined the laboratory of Professor Amitabha Sarkar as a Research Associate in the Department of Organic Chemistry at IACS, Kolkata.Currently he is an Assistant Professor at the Department of Basic Sciences and Humanities in the Institute of Engineering & Management (IEM), Salt Lake, Kolkata, India.His current research interest is focused on synthetic organic and organometallic chemistry as well as the synthesis of novel heterocycles from 1-benzopyran-4-ones.