Reda Eslam

El-Sawy

Ahmed Bakr Abdelwahab

Gilbert Kirsch
email: gilbert.kirsch@univ-lorraine.fr

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms

Keywords: coumarins, benzopyrones, pyrazole, imidazole, thiazole, oxazole, triazole, thiadiazole

Coumarins are natural heterocycles that widely contribute to the design of various biologically active compounds. Fusing different aromatic heterocycles with coumarin at its 3,4-position is one of the interesting approaches to generating novel molecules with various biological activities. During our continuing interest in assembling information about fused five-membered aromatic heterocycles, and after having presented mono-hetero-atomic five-membered aromatic heterocycles in Part I. The current review Part II is intended to present an overview of the different synthetic routes to coumarin (benzopyrone)-fused five-membered aromatic heterocycles with multi-heteroatoms built on the pyrone ring, covering the literature from 1945 to 2021.

Introduction

The fusion of the pyrone ring with the benzene nucleus gives rise to a class of heterocyclic compounds known as benzopyrone [1]. Coumarin is one of the benzopyrones (1,2-benzopyrones or 2H- [1] benzopyran-2-ones) and represents an important family of oxygen-containing heterocycles widely distributed in nature [1]. The incorporation of another heterocyclic moiety into coumarin enriches the properties of the parent structure and the resulting compounds may exhibit promising properties [START_REF] Medina | Coumarin heterocyclic derivatives: Chemical synthesis and biological activity[END_REF][START_REF] Molnar | Green Chemistry Approaches to the Synthesis of Coumarin Derivatives[END_REF][START_REF] Salehian | A review: Biologically active 3,4-heterocycle-fused coumarins[END_REF][START_REF] Geetika | Review on Synthesis of Bio-Active Coumarin-Fused Heterocyclic Molecules[END_REF]. Certain derivatives of 3,4-heterocycle-fused coumarins play an important role in medicinal chemistry and have been extensively used as versatile building blocks in organic synthesis [START_REF] Medina | Coumarin heterocyclic derivatives: Chemical synthesis and biological activity[END_REF][START_REF] Molnar | Green Chemistry Approaches to the Synthesis of Coumarin Derivatives[END_REF][START_REF] Geetika | Review on Synthesis of Bio-Active Coumarin-Fused Heterocyclic Molecules[END_REF][START_REF] Lončar | Coumarins in Food and Methods of Their Determination[END_REF][START_REF] Trkovnik | Synthesis of new heterocyclocoumarins from 3,4-diamino-and 4-chloro-3-nitrocoumarins[END_REF]. Many examples of biologically active coumarins containing 3,4-heterocycles-fused were cited in the literature [START_REF] Medina | Coumarin heterocyclic derivatives: Chemical synthesis and biological activity[END_REF][START_REF] Molnar | Green Chemistry Approaches to the Synthesis of Coumarin Derivatives[END_REF][START_REF] Önder | Synthesis, and Molecular Modeling Studies of Novel Coumarin Carboxamide Derivatives as eEF-2K Inhibitors[END_REF] including antimicrobial [START_REF] Sahoo | Coumarin derivatives as promising antibacterial agent(s)[END_REF][START_REF] Mulwad | Synthesis of Some of the Antibacterial Compounds from 4-Hydroxycoumarins: Part II[END_REF][START_REF] Abunada | Synthesis and antimicrobial evaluation of some new pyrazole, pyrazoline and chromeno[3,4-c]pyrazole derivatives[END_REF][START_REF] El-Saghier | Synthesis and antibacterial activity of some new fused chromenes[END_REF], antiviral [START_REF] Mishra | Coumarin: An emerging antiviral agent[END_REF][START_REF] Reddy | Lamellarin α 20-Sulfate, an Inhibitor of HIV-1 Integrase Active against HIV-1 Virus in Cell Culture[END_REF], anticancer [START_REF] Boger | Total Synthesis of Ningalin B Utilizing a Heterocyclic Azadiene Diels-Alder Reaction and Discovery of a New Class of Potent Multidrug Resistant (MDR) Reversal Agents[END_REF][START_REF] Neagoie | Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues: A novel DYRK1A inhibitor class[END_REF][START_REF] Rajabi | Synthesis of a new class of furo[3,2-c]coumarins and its anticancer activity[END_REF], antioxidant [START_REF] Al-Ayed | Synthesis of New Substituted Chromen[4,3-c]pyrazol-4-ones and Their Antioxidant Activities[END_REF][START_REF] Hamdi | A rapid access to new coumarinyl chalcone and substituted chromeno[4,3c]pyrazol-4(1H)-ones and their antibacterial and DPPH radical scavenging activities[END_REF], and anti-inflammatory [START_REF] Hosni | Anti-inflammatory and analgesic activities of some newly synthesized pyridinedicarbonitrile and benzopyranopyridine derivatives[END_REF][START_REF] Khan | Synthesis and biological evaluation of novel angularly fused polycyclic coumarins[END_REF] activities.

The development of synthetic pathways towards active coumarins containing heterocyclics has attracted great interest from researchers [START_REF] Geetika | Review on Synthesis of Bio-Active Coumarin-Fused Heterocyclic Molecules[END_REF]. Significant efforts have been focused on developing new methodologies to enrich structural libraries and reduce the number of synthetic steps of novel coumarin derivatives [START_REF] Geetika | Review on Synthesis of Bio-Active Coumarin-Fused Heterocyclic Molecules[END_REF][START_REF] El-Sawy | Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part 1: Five-Membered Aromatic Rings with One Heteroatom[END_REF].

In proceeding to our interest in coumarin(benzopyrone)-fused five-membered aromatic heterocycles built on the α-pyrone ring, which was recently issued in Part I [START_REF] El-Sawy | Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part 1: Five-Membered Aromatic Rings with One Heteroatom[END_REF]. The present review, Part II, describes the components which have multi heteroatom in an aromatic fused ring with the pyrone part of coumarin. The synthetic pathways of the investigated scaffolds provided systems containing oxygen, nitrogen, and sulfur in their core structure.

Synthesis of Benzopyrone-Fused Five-Membered Aromatic Heterocycles

2.1. Five-Membered Aromatic Rings with Two Heteroatoms 2.1.1. Two Identical Heteroatoms (N-N) Pyrazole Fusion of pyrazole ring with the pyrone ring of coumarin results in formation of two structural isomers, namely chromeno [4,3-c]pyrazol-4(2H)-one, chromeno [4,3-c]pyrazol-4(1H)-one, (1H-benzopyrano [4,3-c]pyrazole), and chromeno [3,4-c]pyrazol-4(2H)-one, chromeno [3,4-c]pyrazol-4(3H)-one, (1H-benzopyrano [3,4-c]pyrazole) (Figure 1). 3-Aminochromeno[4,3-c]pyrazol-4(1H)one (8) was prepared through multi-step reactions starting from 4-hydroxycoumarin (4) [START_REF] El-Dean | Synthesis and antimicrobial activity of new heterocyclic compounds containing thieno[3,2-c]coumarin and pyrazolo[4,3-c]coumarin frameworks[END_REF]. Vilsmeier-Haack formylation of 4 developed 4-chlorocoumarin-3-carboxaldehyde [START_REF] Geetika | Review on Synthesis of Bio-Active Coumarin-Fused Heterocyclic Molecules[END_REF]. The reaction of 5 with hydroxylamine hydrochloride followed with phosphorus oxychloride gave the corresponding 4-chlorocoumarin -3-carbonitrile [START_REF] Trkovnik | Synthesis of new heterocyclocoumarins from 3,4-diamino-and 4-chloro-3-nitrocoumarins[END_REF]. Compound 7 under the reaction with hydrazine hydrate provided the target compound, 3-aminochromeno[4,3-c]pyrazol-4(1H)one (8) (Scheme 2). The preparation of chromen [4,3-c]pyrazol-4-ones 9 from the reaction of 3-formyl-4chlorocoumarin [START_REF] Geetika | Review on Synthesis of Bio-Active Coumarin-Fused Heterocyclic Molecules[END_REF] with the appropriate aryl or alkyl hydrazine hydrochloride in the presence of base was intensively investigated (Scheme 3) [START_REF] Mulwad | Synthesis of Some of the Antibacterial Compounds from 4-Hydroxycoumarins: Part II[END_REF][START_REF] Al-Ayed | Synthesis of New Substituted Chromen[4,3-c]pyrazol-4-ones and Their Antioxidant Activities[END_REF][START_REF] Hamdi | A rapid access to new coumarinyl chalcone and substituted chromeno[4,3c]pyrazol-4(1H)-ones and their antibacterial and DPPH radical scavenging activities[END_REF][START_REF] Strakova | Reactions of 4-Chloro-3-formylcoumarin with Arylhydrazines[END_REF][START_REF] Yin | Discovery and synthesis of a novel series of potent, selective inhibitors of the PI3K?: 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives[END_REF][START_REF] Chekir | synthesis and biological evaluation of novel 1,2,3-triazole linked coumarinopyrazole conjugates as potent anticholinesterase, anti-5-lipoxygenase, antityrosinase and anti-cancer agents[END_REF][START_REF] Yin | synthesis and biological evaluation of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing sulfonamido as potential PI3Kα inhibitors[END_REF][START_REF] Lu | Discovery of Chromeno[4,3-c]pyrazol-4(2H)-one Containing Carbonyl or Oxime Derivatives as Potential, Selective Inhibitors PI3Kα[END_REF][START_REF] Yin | Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates bearing sulfonylpiperazine as antitumor inhibitors targeting PI3Kα[END_REF]. Compound 9a was employed as starting material to enrich the derivatives of chromen [4,3-c]pyrazol-4ones 10-12 through the reaction with benzyl bromides [START_REF] Yin | Discovery and synthesis of a novel series of potent, selective inhibitors of the PI3K?: 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives[END_REF], alkyl sulfonyl chlorides [START_REF] Yin | synthesis and biological evaluation of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing sulfonamido as potential PI3Kα inhibitors[END_REF], or N-piperazine sulfonyl chlorides [START_REF] Yin | Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates bearing sulfonylpiperazine as antitumor inhibitors targeting PI3Kα[END_REF] (Scheme 4). C, 2 h, five outputs with 67-89% yield [START_REF] Al-Ayed | Synthesis of New Substituted Chromen[4,3-c]pyrazol-4-ones and Their Antioxidant Activities[END_REF], 14 outputs with 38-69% yield [START_REF] Strakova | Reactions of 4-Chloro-3-formylcoumarin with Arylhydrazines[END_REF]. Additionally, 3-coumarinyl alkyl ketones, such as 4-hydroxy-3-acetylcoumarin (17a) [START_REF] Mustafa | Pyrazolo-cumarine und Pyrazolyl-cumarone[END_REF], and 3-coumarinyl phenyl ketone (17b) [START_REF] El-Saghier | Synthesis and antibacterial activity of some new fused chromenes[END_REF] were the starting materials in the preparation of chromeno[4,3-c]pyrazol-4(2H)-ones 18 and 19 by the base-catalyzed reaction with hydrazine hydrate (Scheme 6). The transformation of three-substituted chromone to chromeno[4,3-c]pyrazol-4(2H)ones was within the scope of interest of Ibrahim's research group [START_REF] Ibrahim | Ring transformation of chromone-3-carboxylic acid under nucleophilic conditions[END_REF][START_REF] Ibrahim | Ring Transformation of Chromone-3-Carboxamide under Nucleophilic Conditions[END_REF][START_REF] Ibrahim | Studies on the Chemical Reactions of Some 3-Substituted-6,8dimethylchromones with Nucleophilic Reagents[END_REF][START_REF] Ibrahim | Reactivity of 6-Methylchromone-3-carbonitrile Towards Some Nitrogen Nucleophilic Reagents[END_REF]. In 2008, they studied the ring transformation of chromone-3-carboxylic acid (20) under the reaction with 2-cyanoacetohydrazide or the hydrazine hydrate as the nucleophile to give the corresponding chromeno[4,3-c]pyrazol-4(2H)-one (9a) (Scheme 7) [START_REF] Ibrahim | Ring transformation of chromone-3-carboxylic acid under nucleophilic conditions[END_REF]. Furthermore, they examined the chemical reactivity of chromone-3-carboxamide (21) towards hydrazine hydrate or phenylhydrazine and they could construct the pyrazole within the scaffold (Scheme 7) [START_REF] Ibrahim | Ring Transformation of Chromone-3-Carboxamide under Nucleophilic Conditions[END_REF]. Furthermore, 3-cyano-2,6-dimethyl chromone [START_REF] Shawali | Cycloaddition of diphenylnitrilimine to coumarins. The synthesis of 3a,9b-dihydro-4oxo-1H-benzopyrano [4,3-c]pyrazole derivatives[END_REF] was allowed to react with the nucleophile S-benzyldithiocarbazate to afford the corresponding 6,8-dimethyl chromeno[4,3-c]pyrazol-4(2H)-one (24) (Scheme 7) [START_REF] Ibrahim | Studies on the Chemical Reactions of Some 3-Substituted-6,8dimethylchromones with Nucleophilic Reagents[END_REF][START_REF] Ibrahim | Reactivity of 6-Methylchromone-3-carbonitrile Towards Some Nitrogen Nucleophilic Reagents[END_REF]. [START_REF] Lokhande | A novel and efficient approach for the synthesis of new halo substituted 2arylpyrazolo[4,3-c] coumarin derivatives[END_REF]. The reaction was initially performed with (5%) of iodin in dimethyl-sulfoxide in the presence of H 2 SO 4 at 60 • C using known methods, but the reaction did not take place. To overcome this problem, the reaction was carried out by increasing the iodine ratio to 10% and raising the temperature to 120 • C, which gave good results. This pathway has an advantage over the previous pyrazole construction methods which were relatively unstable and gave a mixture of isomeric 1-aryl and 2-arylpyrazolo[4,3-c]coumarins [START_REF] Strakova | Reactions of 4-Chloro-3-formylcoumarin with Arylhydrazines[END_REF][START_REF] Stadlbauers | Ring closure reactions of 3-arylhydrazonoalkyl-quinolin-2-ones to 1-aryl-pyrazolo[4,3-c]quinolin-2-ones[END_REF]. On the other hand, thermal conversion of 4-diazo-methyl coumarins 40 into the corresponding chromeno [3,4-c]pyrazol-4(2H)-ones 41 in toluene followed the pathway depicted in Scheme 12 [START_REF] Ito | 4-Diazomethylcoumarins and Related Stable Heteroaryldiazomethanes. Thermal Conversion into Condensed Pyrazoles[END_REF][START_REF] Ito | A Facile Intramolecular Cyclization of 4-Diazomethylcoumarins. A Convenient Route to Benzopyrano[3,4c]pyrazol-4(3H)-ones[END_REF]. The presence of the alkyl substituent at the peri position to the attached diazo-methyl group in coumarins markedly destabilized the diazo-methyl group and facilitated the pyrazole isomerization. Trimarco's research group developed a new method to synthesize substituted [1] benzopyrano [3,4-d]imidazol-4(3H)-ones bearing hydrogen or alkyl groups on N-3, and alkyl or amino substituents on C-2 in good yields [START_REF] Beccalli | 3-Nitrocoumarin Amidines: A New Synthetic Strategy for Substituted [1]Benzopyrano[3,4d]imidazol-4(3H)-ones[END_REF]. 2-Alkyl- [1]benzopyrano [3,4d]imidazol-4(3H)-ones 57 were obtained from acetamidines 56 carrying a 3-nitrocoumarin group at N-1 by reduction with sodium borohydride/palladium 10% (Scheme 15) [START_REF] Beccalli | 3-Nitrocoumarin Amidines: A New Synthetic Strategy for Substituted [1]Benzopyrano[3,4d]imidazol-4(3H)-ones[END_REF]. Benzopyranoimidazoles 58 of an amino substituent on C-2 were obtained by refluxing 56 in excess of triethyl phosphite (Scheme 15) [START_REF] Beccalli | 3-Nitrocoumarin Amidines: A New Synthetic Strategy for Substituted [1]Benzopyrano[3,4d]imidazol-4(3H)-ones[END_REF].

4H-Chromeno[3,4-c]isothiazol-4-one Pyrone Construction

The 1,3-dipolar cycloaddition reactions of nitrile sulfides (RC-N≡S-) played a particular role in the synthesis of 4H-chromeno[4,3-c]isothiazole [START_REF] Brownsort | Intramolecular cycloaddition reactions involving nitrile sulphides[END_REF][START_REF] Brownsort | Nitrile Sulphides. Part 7. Synthesis of [I ]Benzopyrano[4[END_REF][START_REF] Brownsort | Nitrile Sulphides. Part 1O. Intramolecular 1.3-Dipolar Cycloadditions[END_REF]. For example, heating of acetylenic oxathiazolone [START_REF] Savel'ev | Synthesis of 4H[END_REF] in xylene afforded 4-oxo-3-phenyl-4H-chromeno[4,3c]isothiazole (69) [START_REF] Brownsort | Intramolecular cycloaddition reactions involving nitrile sulphides[END_REF]. The initial step of the reaction was decarboxylation of the oxathiazolone followed by intramolecular 1,3-dipolar cycloaddition of the resulting nitrile sulfide (70) to the adjacent alkyne (Scheme 20).

Oxazole and Isoxazole

Fusion of a five-member ring containing (N and O atoms) with the pyrone ring of coumarin leads to four structural isomers, viz. 4H-chromeno [3,4-d]oxazol-4-one, 4Hchromeno [4,3-d]oxazol-4-one, 4H-chromeno [3,4-d]isoxazol-4-one and 4H-chromeno [4,3c]isoxazol-4-one (Figure 4). 4) with mesyl azide according to Taber's method [START_REF] Taber | Mesyl azide: A superior reagent for diazo transfer[END_REF]. In 2018, Litinas and his coworkers summarized the previous scheme in a green chemistry methodology [START_REF] Balalas | One-pot Synthesis of 2-Substituted 4H-Chromeno[3,4-d]oxazol-4-ones from 4-Hydroxy-3-nitrocoumarin and Acids in the Presence of Triphenylphosphine and Phosphorus Pentoxide under Microwave Irradiation[END_REF]. They described the reaction of 4-hydroxy-3-nitrocoumarin (81) with acids in a one-pot reaction in the presence of PPh 3 and P 2 O 5 under microwave irradiation. Another one-pot two-step reaction was accomplished in the presence of Pd/C and hydrogen, followed by treatment with P 2 O 5 under microwave irradiation (Scheme 26) [START_REF] Balalas | One-pot Synthesis of 2-Substituted 4H-Chromeno[3,4-d]oxazol-4-ones from 4-Hydroxy-3-nitrocoumarin and Acids in the Presence of Triphenylphosphine and Phosphorus Pentoxide under Microwave Irradiation[END_REF].

Pyrone and Oxazole Construction

Wilson and his coworkers reported a high yield six-step synthesis of 7-hydroxy -2,6-dimethylchromeno [3,4-d]oxazol-4-one (91) from commercially available 2,4dihydroxy-3-methyl-acetophenone [START_REF] Gammon | An efficient synthesis of 7-hydroxy-2,6-dimethylchromeno[3,4-d]oxazol-4-one-a protected fragment of novenamine[END_REF]. The chemoselective benzylation of 2,4-dihydroxy3 -methylacetophenone (85) gave the corresponding 4-benzyloxy derivative (86). Compound 86 was converted into the 4-hydroxycoumarin derivative (87) using diethyl carbonate and sodium hydride. Nitration of 87 with fuming nitric acid in chloroform at room temperature afforded the nitro derivative (88). Reduction of 88 using zinc in refluxing acetic acid afforded 3-acetamido-4,7-dihydroxycoumarin (89). Cyclization of 89 was achieved using pyridine-buffered POCl 3 in THF under the Robinson-Gabriel mechanism. Finally, 7hydroxy-2,6-dimethylchromeno [3,4-d]oxazol-4-one (91) was attainable through the debenzylation of oxazole 90 (Scheme 27) [START_REF] Gammon | An efficient synthesis of 7-hydroxy-2,6-dimethylchromeno[3,4-d]oxazol-4-one-a protected fragment of novenamine[END_REF].

4H-Chromeno[4,3-d]oxazol-4-one Oxazole Construction

Regarding 4H-chromeno [4,3-d]oxazole-4-one, only one article mentioned the preparation of such a fused system [START_REF] Ray | Studies on Reaction of Hydroxycoumarin Compounds with Formamide[END_REF]. In 2004, Ray and Paul reported the synthesized 4H-chromeno [4,3-d]oxazole-4-one (92) via the reaction of 4-hydroxycoumarin (4) with formamide under reflux (Scheme 28). On the other hand, the reactivity of 3-ethoxycarbonyl-2-methyl substituted 5,6,7,8tetrafluorochromone (100) toward hydroxylamine in an alkaline medium was explored [START_REF] Saloutin | Interaction of 3-ethoxycarbonyl(carboxy)-substituted 5,6,7,8-tetrafluorochromones with N-nucleophiles: Synthesis of fluorocoumarins[END_REF]. Wherever the pyrone ring was firstly opened, hydroxylamine was involved in the isoxazole ring formation of 101. Moreover, the cyclization to the corresponding 2-methyl-4H-6,7,8,9tetrafluorochromeno [3,4-d]isoxazol-4-one (102) was performed by sulfuric acid treatment (Scheme 31) [START_REF] Saloutin | Interaction of 3-ethoxycarbonyl(carboxy)-substituted 5,6,7,8-tetrafluorochromones with N-nucleophiles: Synthesis of fluorocoumarins[END_REF]. The synthesis of 4H-chromeno [4,3-c]isoxazol-4-one starting from 4-azido-3hydroxycoumarin was scarcely reported. Vilsmeier-Haack reagent supplied the system with chloride and formyl moieties [START_REF] Reddy | Lamellarin α 20-Sulfate, an Inhibitor of HIV-1 Integrase Active against HIV-1 Virus in Cell Culture[END_REF]. The chloride was replaced by azido when compound 14 was treated by NaN 3 to produce 4-azido-3-coumarin carboxaldehyde 15 . This last decomposed thermally to be depleted from nitrogen and spontaneously cyclized to 4H-chromeno [4,3-c]isoxazol-4-ones 103 (Scheme 32) [START_REF] Steinfiihrer | Anellierte Cumarine Aus 4-Azido-3-Cumarincarbaldehyden[END_REF]. In 2012, the formation of 4H-chromeno [3,4-d][1,2,3]triazol-(3H)4-ones 111 was described through a catalyst-free 1,3-dipolar cycloaddition of 3-nitrocoumarins 110 to sodium azide (Scheme 36). It was found that good yields were obtained in the presence of electronwithdrawing substituent on the aryl ring of 3-nitrocoumarins 110. The reaction gave the best yield in DMSO at 80 • C after three lower temperatures attempts [START_REF] Wang | Efficient synthesis of functionalized 1,2,3-triazoles by catalyst-free 1,3-dipolar cycloaddition of nitroalkenes with sodium azide[END_REF]. By applying this reaction, a novel group of 4H-chromeno [3,4-d][1,2,3]triazol-(3H)4-ones was achieved using microwave-assisted green chemistry procedures (Scheme 36) [START_REF] Schwendt | Intensified synthesis of [3,4-d]triazole-fused chromenes, coumarins, and quinolones[END_REF].

Three Different Heteroatoms Thiadiazole

Fusion of thiadiazole ring with the pyrone ring of coumarin furnishes one structural isomer, namely 4H-chromeno [3,4-c][1,2,5]thiadiazol-4-one (Figure 6). In summary, coumarins are one of the heterocyclic structures of great interest in the development of valuable biologically active structures. Since coumarins have versatile applications, synthesis trials of different structures of the coumarin-based scaffold were attempted. The different synthetic routes to synthesize coumarin (benzopyrone)-fused five-membered aromatic heterocycles with multi-heteroatoms built on the pyrone ring were discussed in this review to shed light on the evolution in synthetic methods. We found that the starting scaffolds for this preparation were mainly 4-hydroxy, 4-amino, 3,4-diamino, and 3-nitro derivatives of coumarin. Moreover, other various methods of building the pyrone ring from simple functionalized compounds were discussed. To date, 4H-chromeno [4,3-d]thiazol-4-one, 4H-chromeno [3,4-c][1,2,5]selenadiazol-4-one, and 4Hchromeno [3,4-c][1,2,5]oxadiazol-4-one (Figure 7) have not been feasible by any synthetic procedures.

Figure 1 .Scheme 1 .

 11 Figure 1. The isomers of fused chromeno-pyrazole. Chromeno[4,3-c]pyrazol-4(2H)-one; (1H-Benzopyrano[4,3-c]pyrazole) Many synthetic protocols reported the synthesis of chromeno[4,3-c]pyrazol-4(2H)-one including the pyrazole and/or the pyrone-ring construction. The synthesis of the pyrazole ring in the literature started from coumarin, 4-hydroxy, 3-aldehyde, or 3-acetyl coumarin in addition to the chromone derivatives. Pyrazole Construction Shawali and his co-workers described the 1,3-dipolar additions of diphenylnitrilimine (DPNI) to coumarin (1) to afford 1,3-diphenyl-3a,9b-dihydro-4-oxo-1H-chromeno[4,3c]pyrazol-4(1H)one (2) [23]. Upon dehydrogenation of 2 with lead tetra-acetate the corresponding 1,3-diphenyl-chromeno[4,3-c]pyrazol-4(1H)one (3) was obtained (Scheme 1).

Scheme 2 .

 2 Scheme 2. Synthesis of 3-aminochromeno[4,3-c]pyrazol-4(1H)one (8). Reagents and conditions. (a) POCl 3 , DMF, CHCl 3 ; (b) NH 2 OH. HCl, AcONa, EtOH; (c) POCl 3 ; (d) N 2 H 4 . H 2 O, EtOH, 80% yield.

Scheme 3 .

 3 Scheme 3. Synthesis of chromeno[4,3-c]pyrazol-4(1H)ones 9. Reagents and conditions. (a) POCl 3 , DMF, CHCl 3 ; (b) NH 2 NHR, EtOH, TEA or NaOAc, 25• C, 2 h, five outputs with 67-89% yield[START_REF] Al-Ayed | Synthesis of New Substituted Chromen[4,3-c]pyrazol-4-ones and Their Antioxidant Activities[END_REF], 14 outputs with 38-69% yield[START_REF] Strakova | Reactions of 4-Chloro-3-formylcoumarin with Arylhydrazines[END_REF].

Scheme 4 .

 4 Scheme 4. Synthesis of 2-substituted-1H-chromeno[4,3-c]pyrazol-4(1H)ones 10-12. Reagents and conditions. (a) Benzyl bromides, DMF, Cs 2 CO 3 , 100 • C, 10-12 h, 13 outputs; (b) benzene(alkyl)sulfonyl chlorides, DCM, TEA, 0 • C, 6-8 h, 28 outputs with 33-52% yield; (c) N-alkyl sulfonyl piperazines, HCHO, EtOH, rt, 4-6 h, 26 outputs with 37-65% yield. Steinfiihrer et al., synthesized chromeno[4,3-c]pyrazol-4(2H)-ones 16 in a three-step reaction starting from 4-hydroxycoumarin derivatives 13. The intermediate, 4-azido-3coumarincarboxaldehydes 15 was produced in situ from 4-chlorocoumarin-3-carboxaldehydes 14 which subsequently reacted with some hydrazine derivatives to deliver the final products (Scheme 5) [31].

Scheme 5 .

 5 Scheme 5. Synthesis of chromeno[4,3-c]pyrazol-4(2H)-ones 16. Reagents and conditions. (a) POCl 3 , DMF, CHCl 3 , 4 outputs with 65-80% yield; (b) NaN 3 , DMF, 4 outputs with 50-80% yield; (c) R 1 NHNH 2, DMF, 40-50 • C, six outputs with 70-90% yield.

Scheme 6 . 3 -

 63 Scheme 6. 3-Coumarinyl alkyl ketone in the synthesis of chromeno[4,3-c]pyrazol-4(2H)-ones 18 and 19. Reagents and conditions. NH 2 NH 2 .H 2 O, EtOH, TEA, 18: 75% yield, 19: 58% yield.

Scheme 7 .

 7 Scheme 7. Synthesis of chromeno[4,3-c]pyrazol-4(2H)-ones 9a, 22, and 24. Reagents and conditions. (a) AcOH, 2 h, reflux, 48% yield; (b) NH 2 NH 2 . H 2 O, AcOH, 2 h, reflux, 48% yield; (c) NH 2 NH 2 . H 2 O, or NH 2 NHPh, EtOH, 2 h, reflux, R=H: 56%, R=Ph: 46% yield; (d) DMF, 30 min, reflux, 63% yield.

Scheme 9 .Scheme 10 .Scheme 11 .

 91011 Scheme 9. Synthesis of 2-phenyl-chromeno[4,3-c]pyrazol-4(1H)ones 29. Reagents and conditions. R = H, or CH 2 -CH=CH 2 , 10 mol%, DMSO, conc. H 2 SO 4 , 120 • C, 5 h, seven outputs with 88-93% yield. Raju and his co-workers described the synthetic strategy for chromeno[4,3-c]pyrazol-4(1H)ones 34 and 2-tosyl-chromeno[4,3-c]pyrazol-4(1H)ones 35. The pathway started from a reaction between salicylaldehydes 30 and p-toluenesulfonyl hydrazide 31. It proceeded towards salicylaldehyde tosylhydrazone 32 which was in situ reacted with 3-oxobutanoates 33 in presence of lanthanum tris(trifluoromethanesulfonate) to deliver the desired coumarin (Scheme 10) [40].

Scheme 12 .

 12 Scheme 12. Thermal conversion of 4-diazo-methyl coumarin. Reagents and conditions. Toluene, heat, stirring, R = H: 85% yield, R = Me: 98% yield.Hydrazonyl halides played an important role in the preparation of chromeno[3,4c]pyrazol-4(2H)-ones[START_REF] Abunada | Synthesis and antimicrobial evaluation of some new pyrazole, pyrazoline and chromeno[3,4-c]pyrazole derivatives[END_REF]. This coumarin was accessible from the reaction of hydrazonyl halides 42 with 3-acetylcoumarin (43) or 3-benzoylcoumarin (17b) in the presence of triethylamine. Subsequently, the dihydro-products 44 were refluxed in aqueous potassium hydroxide (10%) solution, and toluene successively to give chromeno[3,4-c]pyrazol-4(2H)ones 45 (Scheme 13). Alternatively, compounds 45 were synthesized via cycloaddition of the hydrazonyl halides 42 to the 3-phenylsuphonylcoumarin[START_REF] Anwar | One-Pot, Multicomponent Synthesis of Fused-Ring 2-Aminothiazoles[END_REF], or the 3-bromocoumarin[START_REF] Belal | Oxidative cross coupling reaction mediated by I 2 /H 2 O 2 : A novel approach for the construction of fused thiazole containing coumarin derivatives[END_REF]. The thermal elimination of benzenesulfinic acid or hydrogen bromide from the corresponding cyclo-adducts 48 resulted in the target 45 (Scheme 13).

Scheme 13 .

 13 Scheme 13. The role of hydrazonyl halides in the preparation of chromeno[3,4-c]pyrazol-4(2H)-ones. Reagents and conditions. (a) Benzene, reflux, TEA, two outputs Y = CH 3 (51%), Y = Ph (48%); (b) i: KOH (10%), 12 h, reflux; ii: toluene, 2 h, reflux; (c) benzene, reflux, TEA, two outputs Ar = C 6 H 4 F-p, Ar 1 = C 6 H 4 NO 2 -p (48%), Ar = C 6 H 3 Cl 2 -2,4, Ar 1 = C 6 H 4 NO 2 -p (51%).ImidazoleFusion of the imidazole ring with the pyrone ring of coumarin leads to one structural isomer, namely chromeno[3,4-d]imidazol-4-one, chromeno[3,4-d]imidazole-4(3H)-one, (1Hbenzopyrano[3,4-d]imidazole) (Figure2).

Figure 2 .

 2 Figure 2. The common isomer of fused chromeno-imidazole.Chromeno[3,4-d]imidazol-4-one; (1H-Benzopyrano[3,4-d]imidazole) Imidazole ConstructionFew synthetic routes to prepare benzo-pyrano-imidazoles were reported. The main synthetic approach involved the condensation of 3,4-diaminocoumarin[START_REF] Brownsort | Nitrile Sulphides. Part 7. Synthesis of [I ]Benzopyrano[4[END_REF] with different reagents[START_REF] Trkovnik | Synthesis of new heterocyclocoumarins from 3,4-diamino-and 4-chloro-3-nitrocoumarins[END_REF][START_REF] Colotta | Tricyclic heteroaromatic systems. Synthesis and benzodiazepine receptor affinity of 2-substituted-1-benzopyrano[3,4-d]oxazol-4-ones, -thiazol-4-ones, and -imidazol-4-ones[END_REF]. Kitan and his coworkers elaborated a simple synthetic route of novel 1H-benzopyrano[3,4-d]imidazole-4-one starting from the in situ prepared 3,4diaminocoumarin (49) by catalytic hydrogenation of 4-amino-3-nitrocoumarin. The condensation of 3,4-diaminocoumarin (49) with different acids including formic acid, acetic acid, or formaldehyde in presence of concentrated hydrochloric acid established 1Hbenzopyrano[3,4-d]imidazoles 50 (Scheme 14) [7]. On the other hand, different series of 3-N-(4-aminocoumarin-3-yl)aroylamides 51 and 3-N-arylidenamino-4-aminocoumarins 52 were prepared from 3,4-diaminocoumarin 49. Cyclization of 51 and 52 under heating, or in the presence of lead tetraacetate resulted in the fused 2-substituted 4H-chromeno[3,4d]oxazol-4-ones 53 (Scheme 14) [44].

Scheme 15 .

 15 Scheme 15.[1]Benzopyrano[3,4-d]imidazol-4(3H)-ones 57 and 58 bearing hydrogen or alkyl groups on N-3, and alkyl or amino substituents on C-2. Reagents and conditions. i, R1 = Ph, R 2 = H; ii, R 1 = 4-BrC 6 H 4 , R 2 = H; iii, R 1 = CH 2 Ph, R 2 = H; iv, R 1 = CH 2 CH 3 , R 2 = H; v, R 1 = R 2 =CH 3 ; (a) CH 2 Cl 2 , -40 • C, five outputs with 67-89% yields; (b) NaBH 4 , Pd/C, MeOH, H 2 O, five outputs with 55-65% yield; (c) N 2 , P(OC 2 H 3 ) 3 , reflux, five outputs with 57-65% yields.

Figure 3 .Scheme 16 .Scheme 17 .

 31617 Figure 3. The common three isomers of fused the thiazole and isothiazole ring to the α-pyrone moiety of the coumarin. 4H-Chromeno[3,4-d]thiazol-4-one Thiazole ConstructionThe reaction of 4-chloro-3-nitrocoumarin (59) with carbon disulfide in ethanol in the presence of sodium hydrogen sulfate produced 4H-chromeno[3,4-d]thiazol-4-one (60) (Scheme 16)[START_REF] Trkovnik | Synthesis of new heterocyclocoumarins from 3,4-diamino-and 4-chloro-3-nitrocoumarins[END_REF].

Scheme 18 .Scheme 19 .

 1819 Scheme 18. Synthetic pathway of 2-amino-4H-chromeno[3,4-d]thiazol-4-ones 65. Reagents and conditions. CS 2 (1.2 mmol) and K 2 CO 3 (3.0 mmol), FeCl 3 (1.5 mmol), 110 • C, 6-8 h, N 2 , pyrrolidine 64% yield, N-ethylaniline 74% yield. Transition metal-free oxidative coupling for the formation of C-S bonds was employed to synthesize different 4H-chromeno[3,4-d]thiazol-4-ones. The key point in C-H bond activation of 3-(benzylamino)-4-bromo-substituted chromenone derivatives 66 was the presence of sodium sulfide as a source of sulfur, and iodine as a catalyst. The terminal oxidation was performed by H 2 O 2 to form various 2-phenyl-4H-chromeno(3,4-d)thiazol-4one derivatives 67 (Scheme 19) [47].

Scheme 20 .

 20 Scheme 20. Synthesis of 4-oxo-3-phenyl-4H-chromeno[4,3-c]isothiazole (70). Reagents and conditions. Xylene, heat, 16 h, 70% yield. In 2010, Fordyce et al. improved a synthetic approach of 4H-chromeno[4,3-c]isothiazole as a result of the 1, 3-dipolar cycloaddition reactions of o-hydroxybenzonitrile sulfide (72), generated by microwave-assisted decarboxylation of oxathiazolone (71) [51]. The reaction of the o-hydroxyphenyloxathiazolone (73) with dimethyl acetylenedicarboxylate DMAD (1:2) in ethyl acetate supplied methyl 4-oxo-4H-chromeno[4,3-c]isothiazole-3-carboxylate (74) (Scheme 21).

Scheme 21 .Scheme 22 .

 2122 Scheme 21. Synthesis of methyl 4-oxo-4H-chromeno[4,3-c]isothiazole-3-carboxylate (74). Reagents and conditions. (a) Heat, -CO 2 , 84% yield; (b) EtOAc, DMAD,10 min, 160 • C, microwave, 94% yield. In 2017, Lee and his coworkers reported an efficient intramolecular Rh-catalyzed transannulation of thiadiazoles linked to cyanoalkoxycarbonyl. The ring closure of compound 75 was catalyzed by 1,1 -bis(diphenylphosphino) ferrocene DPPF to form the corresponding 8-substituted-3-phenyl-4H-chromeno[4,3-c]isothiazol-4-ones 76 in good yields of 90-99% (Scheme 22) [52].

Scheme 23 .

 23 Scheme 23. Synthesis of 4H-chromeno[3,4-d]isothiazol-4-one (78). Reagents and conditions. Br 2 , EtOAc, heat, 4 h, 96% yield.

Figure 4 .

 4 Figure 4. The common four isomers of fused oxazole and isoxazole ring to the α-pyrone moiety of the coumarin. 4H-Chromeno[3,4-d]oxazol-4-one Oxazole Construction Rhodium(II)-catalyzed reactions of 3-diazo-2,4-chromenedione (79) with several nitriles, such as acetonitrile, chloroacetonitrile and phenylacetonitrile established 2-substituted-4H-chromeno[3,4-d]oxazol-4-ones 80 (Scheme 24) [54]. The 3-diazo-2,4-chromenedione (79) was prepared by the diazo-transfer reaction of the corresponding 4-hydroxycoumarin (4) with mesyl azide according to Taber's method[START_REF] Taber | Mesyl azide: A superior reagent for diazo transfer[END_REF].

Scheme 24 . 3 -

 243 Scheme 24. 3-Diazo-2,4-chromenedione in the preparation of 4H-chromeno[3,4-d]oxazol-4-ones 72. Reagents and conditions. Rh 2 (OAc) 4 , 60 • C, 5 h, three outputs, R = CH 3 50% yield, R = CH 2 Cl 95% yield, R = CH 2 Ph 73% yield. 3-Nitro-4-hydroxycoumarin was crucial for the preparation of 2-substituted-4H -chromeno[3,4-d]oxazol-4-one. In 1961, Dallacker et al. reported the preparation of 3nitrocoumarin (73) from 4-hydroxycoumarin (4) upon nitration with nitric acid in glacial acetic acid. Reduction of 81 by Raney nickel in presence of propionic anhydride afforded the corresponding N-(4-hydroxy-2-oxo-2H-chromen-3-yl)propionamide (82). Intramolecular cyclization of amide 82 by heating in acetic anhydride afforded 2-ethyl-4H-chromeno[3,4d]oxazol-4-one (83) (Scheme 25) [56].

Scheme 26 .

 26 Scheme 26. One-pot synthesis of 2-substituted 4H-chromeno[3,4-d]oxazol-4-ones 84. Reagents and conditions: (a) PPh 3 (2.5 equiv), P 2 O 5 (4 equiv), MW irradiation, 130 • C or 140 • C, 1.5 h; (b) 5 mole % Pd/C (10%), H 2 1 atm, r.t., 1-3 h, then P 2 O 5 (4 equiv), MW irradiation, 130 • C, 1 h, ten outputs with up to 91% yield.

Scheme 27 .

 27 Scheme 27. Synthesis of 7-hydroxy-2,6-dimethylchromeno[3,4-d]oxazol-4-one (91). Reagents and conditions: (a) BnCl, K 2 CO 3 , KI, acetone, 56 • C, 88% yield; (b) NaH, CO(OEt) 2 , toluene, 110 • C, 76%yield; (c) HNO 3 , H 2 SO 4 , CHCl 3 , room temperature, 93% yield; (d) Zn, AcOH, 110 • C, 86% yield; (e) POCl 3 , pyridine, THF, 66 • C, 87% yield; (f) 10% Pd/C, H 2 , THF/CH 2 Cl 2 , room temperature, 74% yield.

Scheme 28 .Scheme 30 .

 2830 Scheme 28. Synthesis of 4H-chromeno[4, 3-d]oxazol-4-one (84). Reagents and conditions. HCONH 2 , 160 • C, 84% yield. 4H-Chromeno[3,4-d]isoxazol-4-ones Isoxazole Construction 4-Chromanone (93) was found to be one of the key compounds for the preparation of fused coumarin-isoxazole. 4-chromanone (93) was treated by a lower alkyl oxalate such as ethyl oxalate, in the presence of a suitable base (e.g., sodium amide, sodium methoxylate, or sodium hydride) in an anhydrous reaction medium. The obtained 4-oxo-chroman-3glyoxylate (94) was refluxed with hydroxylamine hydrochloride in ethanol to create the fused isoxazole ring and ethyl 4H-chromeno[3,4-d]isoxazole-3-carboxylate (95) was formed (Scheme 29) [60].

Scheme 31 .

 31 Scheme 31. Synthesis of polyfluorochromeno[3,4-d]isoxazol-4-one (102). Reagents and conditions. (a) NH 2 OH. HCl, TEA, MeOH, 2 h, rt, 85% yield; (b) H 2 SO 4 , H 2 O, reflux, 1.5 h, 82% yield. 4H-Chromeno[4,3-c]isoxazol-4-one Isoxazole Construction

Scheme 32 .

 32 Scheme 32. Synthetic pathway of 4H-chromeno[4,3-c]isoxazol-4-ones 103. Reagents and conditions. (a) POCl 3 , DMF, H 2 O, four outputs with 65-80% yields; (b) NaN 3 , DMF, four outputs with 50-80% yield; (c) DMF, heat, 60-90 • C, -N 2 , four outputs with 30-65% yields.

2. 2 .

 2 Five-Membered Aromatic Rings with Three Heteroatoms 2.2.1. Three Identical Heteroatoms Triazole Fusion of the triazole ring with the pyrone ring of coumarin leads to one structural isomer (chromeno[3,4-d][1,2,3]triazol-4(9bH)-one) (Figure5).

Figure 5 .

 5 Figure 5. The common isomer of the fused chromeno-triazole system. Chromeno[3,4-d][1,2,3]triazol-4(9bH)-one Triazole Construction Dean and Park indicated the elimination of the sulphenic acid moiety during the addition of the corresponding 3-(4-methylphenylsulphinyl)coumarin (104) to sodium azide forming 4H-chromeno[3,4-d][1,2,3]triazol-(3H)4-one (105) (Scheme 33) [63].

Scheme 36 . 1 , 3 -

 3613 Scheme 36. 1,3-Dipolar cycloaddition of 3-nitrocoumarins with sodium azide. Reagents and conditions. a) NaN 3 , DMSO, 80 • C, 1 h, five outputs with 66-89% yields; b) NaN 3 (1.2 equiv), DMF, Pyrex microwave vial equipped with a magnetic stir bar, stirred for 10 s, 160 C, 1 min, R = H, R 1 = CH 3 94% yield; R = OCH 3 , R 1 = H 69% yield.

Figure 6 .

 6 Figure 6. The common isomer of the fused chromeno-thiadiazole system. 4H-Chromeno[3,4-c][1,2,5]thiadiazol-4-one Thiadiazole Construction Synthesis of the 4H-chromeno[3,4-c][1,2,5]thiadiazol-4-one was reported by only one research article that belongs to Smirnov and his co-workers [68]. The reaction of 3,4-diaminocoumarin (49) with thionyl chloride in pyridine gave 4H-chromeno[3,4-c][l, 2,5]thiadiazol-4-one (112) (Scheme 37).

Scheme 37 .

 37 Scheme 37. Synthetic pathway to 4H-chromeno[3,4-c][l,2,5]thiadiazol-4-one (112). Reagents and conditions. SOCl 2 , pyridine, stirring for 3 h, r.t., 87% yield.

Figure 7 .

 7 Figure 7. Coumarin-fused five-membered aromatic heterocycles have not been feasible by any synthetic procedures.

Molecules 2021, 26, 3409. https://doi.org/10.3390/molecules26113409 https://www.mdpi.com/journal/molecules

Funding: This research received no external funding.

Conflicts of Interest:

The authors declare no conflict of interest.