Fused Five-Membered Aromatic Heterocycles Built on the Α-Pyrone Moiety

molecules

Review 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

Eslam Reda El-Sawy 1 , Ahmed Bakr Abdelwahab 2 and Gilbert Kirsch 3,*

1 National Research Centre, Chemistry of Natural Compounds Department, Dokki-Cairo 12622, Egypt; [email protected] 2 Plant Advanced Technologies (PAT), 54500 Vandoeuvre-les-Nancy, France; [email protected] 3 Laboratoire Lorrain de Chimie Moléculaire (L.2.C.M.), Université de Lorraine, 57050 Metz, France * Correspondence: [email protected]; Tel.: +33-03-72-74-92-00; Fax: +33-03-72-74-91-87

Abstract: This review gives an up-to-date overview of the different ways (routes) to the synthesis of coumarin(benzopyrone)-fused, ﬁve-membered aromatic heterocycles with one heteroatom, built on the pyrone moiety. Covering 1966 to 2020.

Keywords: coumarins; benzopyrones; ﬁve-membered aromatic heterocycles; furan; pyrrole; thiophene; selenophen

Citation: El-Sawy, E.R.; Abdelwahab, A.B.; Kirsch, G. Synthetic Routes to 1. Introduction Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Coumarins are a family of benzopyrones (1,2-benzopyrones or 2H-[1]benzopyran- Heterocycles Built on the α-Pyrone 2-ones), which represent an important family of oxygen-containing heterocycles, widely Moiety. Part 1: Five-Membered distributed in nature [1–4]. Coumarins display a broad range of biological and pharma- Aromatic Rings with One cological activities, [5,6] such as antiviral [7–10], anticancer [11–13], antimicrobial [14,15], Heteroatom. Molecules 2021, 26, 483. and antioxidant [16–18] activities. On the other hand, coumarin represents an ingredi- https://doi.org/10.3390/molecules26 ent in perfumes [19], cosmetics [20], and as industrial additives [21,22]. Furthermore, 020483 coumarins play a pivotal role in science and technology as ﬂuorescent sensors, mainly due to their interesting light-emissive characteristics, which are often responsive to the Academic Editor: Maria João Matos environment [23–26]. The coumarin (benzopyrane)-fused, membered aromatic heterocy- Received: 26 December 2020 cles built on the α-pyrone moiety are an important scaffold. The only fused heterocycle Accepted: 13 January 2021 with an α-pyrone moiety of coumarin that can be found in nature is the furan ring. One ex- Published: 18 January 2021 ample is the naturally occurring furan 4H-furo[3,2-c]benzopyran-4-one, which provides the main core of many natural compounds of so-called coumestans. These comestans include Publisher’s Note: MDPI stays neutral coumestan, wedelolactone, and coumestrol. The coumestans are found in a variety of plant with regard to jurisdictionalMolecules claims 2021 in, 26, x FOR PEER REVIEW 2 of 22 species that are commonly used in traditional medicine [27]. published maps and institutional afﬁl- iations.

Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). In order to enrich the limited versatility of the structures found in nature, synthesis of coumarin (benzopyrane)-fused, membered aromatic heterocycles has received considerable attention, including numerous reported routes. Molecules 2021, 26, 483. https://doi.org/10.3390/molecules26020483This review gives an up-to-datehttps://www.mdpi.com/journal/molecules overview of the different ways (routes) to the synthesis of benzopyrone-fused, five-membered aromatic heterocycles with one heteroatom, built on the pyrone moiety, from 1966 to 2020. Our main interest in this current work is to describe the components that have one heteroatom in an alicyclic-fused ring with the pyrone part of coumarin. The synthetic pathway of the investigated scaffold has provided systems containing oxygen, nitrogen, sulfur, and selenium in their core structure. The last heteroatom is less described in the output of the synthetic efforts. The fused heterocycles that contain more than one heteroatom will be detailed in the next part, which we intend to publish in the future. Many strategies have been developed for the synthesis of the fused, five-membered aromatic heterocycle-benzopyran-4-ones. There are two main approaches to constructing these skeletons: five-membered, aromatic heterocycle construction, and pyrone-ring construction.

2. Synthesis of Benzopyrone-Fused, Five-Membered Aromatic Heterocycles 2.1. Five-Membered Aromatic Rings with one Heteroatom 2.1.1. Furans Furobenzopyrone (or furocoumarins) comprises an important class of coumarins found in a wide variety of plants, particularly in the carrot (Apiaceae/Umbelliferae), legume (Fabaceae), and citrus families (Rutaceae) [27]. The chemical structure of furobenzopyrone (furocoumarins) consists of a furan ring fused with coumarin. The fusion of the furan ring to the α-pyrone moiety of coumarin forms the core structure of the three most common isomers, viz. 4H-furo[2,3-c]chromen(benzopyran)-4-one, 4H-furo[3,4-c]chromen(benzopyran)-4-one, and 4H-furo[3,2-c]chromen (benzopyran)-4-one (Figure 1).

Figure 1. The three most common isomers of a furan ring fused to the α-pyrone moiety of coumarin.

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In order to enrich the limited versatility of the structures found in nature, synthesis of coumarin (benzopyrane)-fused,In order to enrich membered the limited aromatic versatility heterocycles of the structures has received found considerable in nature, synthesis attention, includingof coumarin numerous (benzopyrane)-fused, reported routes. membered aromatic heterocycles has received con- This reviewsiderable gives an attention, up-to-date including overview numerous of the differentreported routes. ways (routes) to the synthesis of benzopyrone-fused,This five-memberedreview gives an aromaticup-to-date heterocycles overview of with the different one heteroatom, ways (routes) built to the on the pyronesynthesis moiety, fromof benzopyrone-fused, 1966 to 2020. Our five-membered main interest inaromatic this current heterocycles work iswith to one describe the componentsheteroatom, thatbuilt haveon the one pyrone heteroatom moiety, from in an 1966 alicyclic-fused to 2020. Our ringmain with interest the in this current work is to describe the components that have one heteroatom in an pyrone part of coumarin. The synthetic pathway of the investigated scaffold has provided alicyclic-fused ring with the pyrone part of coumarin. The synthetic pathway of the systems containinginvestigated oxygen, scaffold nitrogen, has sulfur, provided and system seleniums containing in their core oxygen, structure. nitrogen, The sulfur, last and heteroatom is lessselenium described in their in core the outputstructure. of The the last synthetic heteroatom efforts. is less The described fused heterocycles in the output of the that contain moresynthetic than oneefforts. heteroatom The fused will heterocycles be detailed that in contain the next more part, than which one heteroatom we intend will be to publish in thedetailed future. in the next part, which we intend to publish in the future. Many strategiesMany have strategies been developed have been fordeveloped the synthesis for the ofsynthesis the fused, of the five-membered fused, five-membered aromatic heterocycle-benzopyran-4-ones.aromatic heterocycle-benzopyran-4-ones. There are two There main are approaches two main to construct-approaches to ing these skeletons:constructing five-membered, these skeletons: aromatic five-membere heterocycled, construction,aromatic heterocycle and pyrone-ring construction, and construction. pyrone-ring construction.

2. Synthesis of2. Benzopyrone-Fused, Synthesis of Benzopyrone-Fused, Five-Membered Five-Membered Aromatic Aromatic Heterocycles Heterocycles 2.1. Five-Membered2.1. Five-Membered Aromatic Rings Aromatic with One Rings Heteroatom with one Heteroatom 2.1.1. Furans 2.1.1. Furans FurobenzopyroneFurobenzopyrone (or furocoumarins) (or furocoumarins) comprises comp an importantrises an important class of class coumarins of coumarins found in a widefound variety in a of wide plants, variety particularly of plants, particularly in the carrot in (theApiaceae/Umbelliferae carrot (Apiaceae/Umbelliferae), legume), legume (Fabaceae), and( citrusFabaceae families), and citrus (Rutaceae families)[27 (Rutaceae]. The chemical) [27]. The structurechemical structure of furobenzopyrone of furobenzopyrone (furocoumarins) consists of a furan ring fused with coumarin. The fusion of the furan (furocoumarins) consists of a furan ring fused with coumarin. The fusion of the furan ring ring to the α-pyrone moiety of coumarin forms the core structure of the three most to the α-pyrone moiety of coumarin forms the core structure of the three most common iso- common isomers, viz. 4H-furo[2,3-c]chromen(benzopyran)-4-one, mers, viz. 4H-furo[2,3-4H-furo[3,4-c]chromen(benzopyran)-4-one,c]chromen(benzopyran)-4-one, 4 H-furo[3,4-and 4Hc-furo[3,2-]chromen(benzopyran)-c]chromen (benzopy- 4-one, and 4H-furo[3,2-ran)-4-onec]chromen (Figure 1). (benzopyran)-4-one (Figure1).

FigureFigure 1.1. The three most most common common isomers isomers of a of furan a furan ring ring fused fused to the to α the-pyroneα-pyrone moiety moiety of coumarin. of coumarin.

4H-Furo[2,3-c]benzopyran-4-one Furan Construction The basic building block for the formation of 4H-furo[2,3-c]benzopyran-4-one is the 3- hydroxycoumarin (1)[28,29]. Pandya and coworkers [30] developed a method to synthesize some 4H-furo[2,3-c]benzopyran-4-ones starting with 3-hydroxycoumarin using the Nef

reaction. Thus, the reaction of 3-hydroxycoumarin (1) with various 2-aryl-1-nitro ethenes 2a,b, in the presence of piperidine and methanol as a solvent, followed the Nef reaction condition and afforded a series of 1-aryl-furo[2,3-c]benzopyran-4-ones 3a,b and 1-phenyl- 2-methyl-furo[2,3-c]benzopyran-4-one (4), respectively (Scheme1). The formation of these products was explained by the reaction mechanism (Scheme1). Molecules 2021, 26, x FOR PEER REVIEW 3 of 22 Molecules 2021, 26 , x FOR PEER REVIEW 3 of 22

4H-Furo[2,3-c]benzopyran-4-one 4H-Furo[2,3-c]benzopyran-4-one Furan Construction Furan Construction The basic building block for the formation of 4H-furo[2,3-c]benzopyran-4-one is the The basic3-hydroxycoumarin building block for (the1) [28,29]. formation Pandya of 4H and-furo[2,3- coworkersc]benzopyran-4-one [30] developed is a themethod to syn- 3-hydroxycoumarinthesize some(1) [28,29]. 4H-furo[2,3-c]benzopyran-4-ones Pandya and coworkers [30] developedstarting with a method 3-hydroxycoumarin to syn- using thesize somethe 4H Nef-furo[2,3-c]benzopyran-4-ones reaction. Thus, the reaction startiof 3-hydroxycoumarinng with 3-hydroxycoumarin (1) with various using 2-aryl-1-nitro the Nef reaction.ethenes Thus, 2a ,theb, in reaction the presence of 3-hydroxycoumarin of piperidine and (1 )methanol with various as a 2-aryl-1-nitrosolvent, followed the Nef Molecules 2021, 26, 483ethenes 2a,b,reaction in the presence condition of and piperidine afforded and a series methanol of 1-aryl-furo[2,3- as a solvent, cfollowed]benzopyran-4-ones the Nef 3a,b3 and of 21 reaction condition1-phenyl-2-methyl-furo[2,3- and afforded a series cof]benzopyran-4-one 1-aryl-furo[2,3-c]benzopyran-4-ones (4), respectively (Scheme3a,b and 1). The for- 1-phenyl-2-methyl-furo[2,3-mation of thesec products]benzopyran-4-one was explained (4), byrespectively the reaction (Scheme mechanism 1). The(Scheme for- 1). mation of these products was explained by the reaction mechanism (Scheme 1).

Scheme 1. TheThe Nef Nef reaction reaction to to synthesize synthesize furo[2,3- furo[2,3-c]benzopyran-4-onesc]benzopyran-4-ones 3a3a,b, bandand 4. 4Reagents. Reagents and and conditions conditions: MeOH,: MeOH, pi- Scheme 1. The Nef reaction to synthesize furo[2,3-c]benzopyran-4-ones 3a,b and 4. Reagents and conditions: MeOH, piperidine,piperidine, reflux, reﬂux, five ﬁve outputs outputs in in55%–61% 55%–61% yield. yield. peridine, reflux, five outputs in 55%–61% yield. Pyrone Construction Pyrone ConstructionPyrone Construction Dong et al., 2020 developed a novel and facile rhodium(III)-catalyzed process of Dong etsulfoxonium al., Dong2020 developed et ylide al., 2020 (5) a developedwith novel hydroquinone and a novelfacile andrhodium(III)-catalyzed (6). facile The carbonyl rhodium(III)-catalyzed in the process sulfoxonium of process ylide of sul-as- sulfoxonium sistedfoxoniumylide (the5) with ylideortho-C–H hydroquinone (5) with functionalization hydroquinone (6). The carbonyl ( 6of). Thethe sulfoxonium carbonylin the sulfoxonium in the ylide, sulfoxonium followedylide as- ylide by intramo- assisted sisted the ortho-C–Hlecularthe ortho-C–H functionalizationannulation functionalization of the ofsulfoxoniumwith the sulfoxonium ylide,hydroquinone followed ylide, followed by intramo- byto intramolecularafford annulation with hydroquinone to afford 8-hydroxy-4H-furo[2,3-c]benzopyran-4-one (7) lecular 8-hydroxy-4annulationH -furo[2,3-withc]benzopyran-4-one hydroquinone (7) (Scheme 2) [31].to afford 8-hydroxy-4H(Scheme-furo[2,3-2)[c]benzopyran-4-one31]. (7) (Scheme 2) [31].

Scheme 2. Rhodium(III)-catalyzed sequential ortho-C–H oxidative arylation/cyclization of sul- Scheme 2. Rhodium(III)-catalyzedScheme 2. Rhodium(III)-catalyzedfoxonium sequential ylide to ortho-C–Hafford sequential 4H-furo[2,3- oxidative ortho-C–Hc]benzopyran-4-one arylation/cyclization oxidative arylation/cyclization (7). of Reagents sulfoxonium and conditionsof ylidesul- to:afford [Cp*RhCl 4H- 2]2 (5 furo[2,3-c]benzopyran-4-onefoxonium ylidemol (to7). afford%), Reagents AgBF 4H and-furo[2,3-4 (20 conditions mol %),c]benzopyran-4-one Zn(OAc): [Cp*RhCl2 (0.2252]2 (5 mmol), mol(7). Reagents %), AcOH AgBF and4 (0.3(20 conditions mmol), mol %), :and Zn(OAc)[Cp*RhCl acetone2 2(0.225]2 (2(5 mL), mmol), 12 h, in a mol %), AgBF4 (20 mol %), Zn(OAc)2 (0.225 mmol), AcOH (0.3 mmol), and◦ acetone (2 mL), 12 h, in a AcOH (0.3 mmol), and acetonesealed (2 mL),Schlenk 12h, tube ina under sealed N Schlenk2 at 100 tube°C, 25% under yield. N2 at 100 C, 25% yield. sealed Schlenk tube under N2 at 100 °C, 25% yield.

4H-Furo[3,4-c]benzopyran-4-one Furan and Pyrone Construction

In the literature, a large number of reports described the synthesis of 4H-furo[2,3-c] and 4H-furo[3,2-c]benzopyran-4-ones, while synthesis of the 4H-furo[3,4-c]benzopyran-4- one was reported by only one study, that of Brahmbhatt and his coworkers [32]. The ﬁrst 4H-furo[3,4-c]benzopyran-4-ones (10) was synthesized by the demethylation–cyclization reaction of intermediates, 3-substituted-4-ethoxycarbonyl furans 9 (Scheme3). For the demethylation and in situ lactonization steps, several reagents were tried, of which pyridine hydrochloride and HBr in acetic acid were found to be the most promising. Molecules 2021, 26, x FOR PEER REVIEW 4 of 22

Molecules 2021, 26, x FOR PEER REVIEW 4 of 22

4H-Furo[3,4-c]benzopyran-4-one 4H-Furo[3,4-c]benzopyran-4-oneFuran and Pyrone Construction Furan and Pyrone ConstructionIn the literature, a large number of reports described the synthesis of 4H-furo[2,3-c] In the literature,and a large4H-furo[3,2- numberc of]benzopyran-4-ones, reports described the synthesiswhile of 4Hsynthesis-furo[2,3- c] of the and 4H-furo[3,2-4H-furo[3,4-c]benzopyran-4-ones,c]benzopyran-4-one waswhile reported bysynthesis only one study,of that ofthe Brahmbhatt and 4H-furo[3,4-c]benzopyran-4-onehis coworkers [32]. was The reported first 4H by-furo[3,4- only onec]benzopyran-4-ones study, that of Brahmbhatt (10) was and synthesized by his coworkers the[32]. demethylation–cyclization The first 4H-furo[3,4-c]benzopyran-4-ones reaction of intermediates, (10) was 3-substituted-4-ethoxycarbonyl synthesized by the demethylation–cyclizationfurans 9 (Scheme reaction 3). For ofthe in demethylationtermediates, 3-substituted-4-ethoxycarbonyl and in situ lactonization steps, several rea- Molecules 2021, 26,furans 483 9 (Schemegents 3). were For thetried, demethylation of which pyridine and in hydrochloride situ lactonization and HBrsteps, in several acetic acidrea- were found4 of to 21 gents were tried,be theof which most promising.pyridine hydrochloride and HBr in acetic acid were found to be the most promising.

Scheme 3. Demethylation and in situ lactonization steps to prepare the first Scheme 3. DemethylationScheme 3. Demethylation and4H-furo[3,4- in situ and lactonizationc]benzopyran-4-one in situ lactonization steps to prepare10 steps. Reagents to the prepare ﬁrstand 4conditionsH the-furo[3,4- first: (a)c]benzopyran-4-one ethyl acetoacetate or10 ethyl. Reagents ben- and conditions4H:-furo[3,4- (a) ethylc acetoacetate]benzopyran-4-onezoylacetate, or ethylpiperidine, 10 benzoylacetate,. Reagents and MeOHand conditions piperidine, (the Nef: (a) reacti and ethyl MeOHon acetoacetate condition); (the Nef (b)or reaction ethylHBr, ben-AcOH condition); concentration, (b) HBr, 130 AcOH concentration,zoylacetate, 130 piperidine,◦C,°C, 4 h,4 h, 16 and16 outputs outputs MeOH with with(the 50%–65% Nef50%–65% reacti yield. onyield. condition); (b) HBr, AcOH concentration, 130 °C, 4 h, 16 outputs with 50%–65% yield. 4H-Furo[3,2-c]benzopyran-4-one 4H-Furo[3,2-c]benzopyran-4-one 4H-Furo[3,2-c]benzopyran-4-oneFuran Construction Furan Construction Furan ConstructionA wide range of research has demonstrated that 4-hydroxycoumarin is the key A wide rangecompound Aof wide research for range the hassynthesis of researchdemonstrat of has4H-furo[3,2-ed demonstrated that 4-hydroxycoumarinc]benzopyran-4-ones, that 4-hydroxycoumarin is whtheich key can is thereadily key react com- compound for withpoundthe synthesis the for C=C the bondof synthesis 4H -furo[3,2-of the of alkene, 4Hc-furo[3,2-]benzopyran-4-ones, or thec ]benzopyran-4-ones,C≡C bond ofwh theich alkyne can which readily [33–37]. can react readily react with with the C=C bondthe C=C Reischof the bond alkene, reported of the or alkene,the Cthe≡C or bond thecondensation C of≡ theC bond alkyne of theof[33–37]. alkyne4-hydroxycoumarin [33–37]. (11) with Reisch reported1-phenyl-2-propyn-1-olReisch the reported condensation the condensation(12) under of acidic of4-hydroxycoumarin 4-hydroxycoumarin conditions (a mixture (11)( 11 withof) glacial 1-phenyl-2-propyn-1-with acetic and con- 1-phenyl-2-propyn-1-olcentratedol (12) under (12) acidicundersulfuric conditions acidic conditions (aacid) mixture (a mixture ofto glacial of aceticdeliver glacial and acetic concentratedthe and con- sulfuriccorresponding acid) to centrated 2-methyl-3-phenylfuro[3,2-deliversulfuric the correspondingacid) 2-methyl-3-phenylfuro[3,2-cto]benzopyran-4-one deliver (13the)c ]benzopyran-4-one(Scheme corresponding 4) [38]. (13) (Scheme4) [ 38]. 2-methyl-3-phenylfuro[3,2-c]benzopyran-4-one (13) (Scheme 4) [38].

Scheme 4. SynthesisSynthesis ofof 2-methyl-3-phenylfuro[3,2-2-methyl-3-phenylfuro[3,2-cc]benzopyran-4-one]benzopyran-4-one ((1313).). ReagentsReagents andand conditionsconditions:: AcOH,AcOH, conc.conc. HH22SO4,, Scheme 4. Synthesis110 ◦°C, C,of 1 2-methyl-3-phenylfuro[3,2- h, 70% yield. c]benzopyran-4-one (13). Reagents and conditions: AcOH, conc. H2SO4, 110 °C, 1 h, 70% yield. A few studies employed the aliphatic aldehydes as building blocks with A few studies4-hydroxycoumarin employed (the11(11) to)aliphatic synthesizeto synthesize aldehydes 4H-furo[3,2- 4H-furo[3,2- asc ]benzopyran-4-onesbuildingc]benzopyran-4-ones blocks [with25,39 ].[25,39]. This method This 4-hydroxycoumarinmethodwas ineffective (11 was) to ineffective synthesize as it gave as a poor4itH gave-furo[3,2- yield a poor asc well]benzopyran-4-ones yield as aas mixture well as of a 2,3-dihydrofuran,mixture [25,39]. of This 2,3-dihydrofuran, 4H-furo[3,2- method was ineffective4c]benzopyran-4-ones,H-furo[3,2- as cit]benzopyran-4-ones, gave a poor and 4yieldH-furo[3,2- as and well c4 ]benzopyran-4-onesHas-furo[3,2- a mixturec]benzopyran-4-ones of 2,3-dihydrofuran, [39]. Conversely, [39]. inConverse- the case 4H-furo[3,2-c]benzopyran-4-ones,ly,of usingin the the aromaticcase andof aldehyde using4H-furo[3,2- the as a buildingcaromatic]benzopyran-4-onesblock, aldehyde the 4H [39].-furo[3,2-as aConverse- buildingc]benzopyran-4-one block, the ly, in the casewas obtainedof using [ 40the]. Kadamaromatic et al.aldehyde developed as atom-efﬁcienta building multicomponentblock, the reactions (MCRs) and step-efﬁcient, one-pot synthesis of 3-(4-bromophenyl)-2-(cyclohexylamino)-4H- furo[3,2-c]benzopyran-4-one (16) using 4-hydroxycoumarin (11) with 4-bromobenzaldehyde

(14) and cyclohexyl isocyanide (15) as an alkylene source (Scheme5)[40].

Molecules 2021, 26, x FOR PEER REVIEW 5 of 22

4H-furo[3,2-c]benzopyran-4-one was obtained [40]. Kadam et al. developed atom-efficient multicomponent reactions (MCRs) and step-efficient, one-pot synthesis of 4H3-(4-bromophenyl)-2-(cyclohexylamino)-4-furo[3,2-c]benzopyran-4-one was obtainedH-furo[3,2- [40].c ]benzopyran-4-oneKadam et al. developed (16) usingat- om-efficient4-hydroxycoumarin multicomponent (11) with reactions 4-bromobenzaldehyde (MCRs) and step-efficient, (14) and cyclohexyl one-pot isocyanide synthesis (of15 ) Molecules 2021, 26, 4833-(4-bromophenyl)-2-(cyclohexylamino)-4as an alkylene source (Scheme 5) [40]. H-furo[3,2-c]benzopyran-4-one (16) using 5 of 21 4-hydroxycoumarin (11) with 4-bromobenzaldehyde (14) and cyclohexyl isocyanide (15) as an alkylene source (Scheme 5) [40].

Scheme 5. Atom-efficient multicomponent reactions (MCRs) and step-efficient, one-pot synthesis of 4H-furo[3,2-c]benzopyran-4-one (16). Reagents and conditions: DMF or toluene, µw, 80 °C, 20 min, Scheme 5. Atom-efficientScheme97% yield. 5. Atom-efficient multicomponent multicomponent reactions reactions (MCRs) and(MCRs) step-efficient, and step-efficient, one-pot one-pot synthesis synthesis of 4H -furo[3,2- c]benzopyran-4-oneof 4H-furo[3,2- (16). Reagentsc]benzopyran-4-one and conditions: DMF(16). Reagents or toluene, andµ conditionsw, 80 ◦C,: 20DMF min, or 97% toluene, yield. µw, 80 °C, 20 min, 97% yield.4-Hydroxycoumarin derivatives have received significant attention from researchers, as these derivatives4-Hydroxycoumarin possess 1,3-dicarbonyl derivatives systems. have received It allows significant for the easy attention generation from researchers, of α4-Hydroxycoumarin,α′-dicarbonylas these radicals, derivatives derivatives which possess can have 1,3-dicarbonyl be receivreadiledy added significant systems. to the It attention allowsC=C bond for from the of easy research-the generationalkene of α,α0- ers,[41]. as Thethese first dicarbonylderivatives example radicals, possessof this reaction which1,3-dicarbonyl can was be described readily systems. added in It 1998, allows to the by C=Cfor Lee the bond and easy ofhis thegeneration coworkers. alkene [ 41 ]. The first ofThey α,α′ -dicarbonylreportedexample an radicals, ofefficient this reactionwhich way can wasto beprepare described readil y4 added inH-furo[3,2- 1998, to by the Leec]benzopyran-4-ones C=C and bond his coworkers. of the alkene 19 They by reported an [41].Ag 2TheCO3 /celitefirstefficient example (Fetizon’s way of tothis prepare reactionreagent)-mediated 4H was-furo[3,2- describedc]benzopyran-4-ones in oxidative1998, by Lee andcycloaddition19 by his Ag coworkers.2CO3 /celiteof (Fetizon’s They4-hydroxycoumarin reportedreagent)-mediated an efficient 17 to olefins, way oxidative suchto prepare as cycloaddition vinyl 4 sulfidH-furo[3,2-e and of 4-hydroxycoumarin cphenyl]benzopyran-4-ones propenyl sulfide.17 19to olefins,byThe such as Agresulting2CO3/celite dihydrofuro[3,2-vinyl (Fetizon’s sulfide and c]benzopyran-4-ones phenylreagent)-mediated propenyl sulfide. 18 wasoxidative The treated resulting by cycloaddition dihydrofuro[3,2-sodium periodate c]benzopyran-4-of in 4-hydroxycoumarinaqueous methanolones 18 was17to toform treated olefins, the by suchcorresponding sodium as vinyl periodate sulfid sulfoxides,e in and aqueous phenyl which, methanol propenyl upon torefluxing sulfide. form the Thewith corresponding resultingpyridine dihydrofuro[3,2- insulfoxides, carbon tetrachloride, which,c]benzopyran-4-ones upon directly refluxing delivered with 18 pyridinewas the treated 4H in-furo[3,2- carbon by sodium tetrachloride,c]benzopyran-4-one periodate directly in delivered aqueous19 in good methanol yieldsthe 4H (Scheme-furo[3,2-to form 6)cthe]benzopyran-4-one [41]. corresponding sulfoxides,19 in good yieldswhich, (Scheme upon refluxing6)[41]. with pyridine in carbon tetrachloride, directly delivered the 4H-furo[3,2-c]benzopyran-4-one 19 in good yields (Scheme 6) [41].

Scheme 6. A facileScheme synthesis 6. A facile of 4H -furo[3,2-synthesisc ]benzopyran-4-onesof 4H-furo[3,2-c]benzopyran-4-ones19 by silver(I)/celite 19 by promoted silver(I)/celite an oxidative promoted cycloaddition an reaction. Reagentsoxidative and conditions cycloaddition: (a) CHreaction.2=CHSPh Reagents and/or and conditions CH3CH=CHSPh,: (a) CH2=CHSPh Ag2CO3 and/or/celite, CH acetonitrile,3CH=CHSPh, reﬂux, 3 h; (b) NaIO4, MeOH,SchemeAg2 CClCO 36.4/celite,, A pyridine, facile acetonitrile, synthesis Al2O3, fourreflux,of 4H outputs-furo[3,2- 3 h; (b) with NaIOc]benzopyran-4-ones 71%–82%4, MeOH, yield. CCl4, pyridine, 19 by silver(I)/celite Al2O3, four promotedoutputs with an oxidative71%–82% cycloaddition yield. reaction. Reagents and conditions: (a) CH2=CHSPh and/or CH3CH=CHSPh, Ag2CO3/celite, acetonitrile,Recently, reflux, different 3 h; (b) catalytic NaIO4, MeOH, methodologies CCl4, pyridine, have Al been2O3, developedfour outputs for with the synthesis of 71%–82%Recently, yield.2H -chromenes,different catalytic and they methodologies are based on have three been main developed approaches: for the catalysis synthesis with of (transition) 2H-chromenes,metals, and metal-free they are based Brønsted on catalysis,three main and approaches: Lewis acid/base catalysis catalysis, with (transition) which includes exam- metals,Recently, metal-freeples different of nonenantioselectiveBrønsted catalytic catalysis, methodologies and organocatalysis Lewis have acid/base been and developed enantioselectivecatalysis, for which the synthesis organocatalysisincludes ofex- [42–44]. 2Hamples-chromenes, of Alkynesnonenantioselectiv and they have are been based widelye organocatalysis on three employed main as approaches:and building enanti blocks catalysisoselective for thiswith or reactionganocatalysis (transition) in most cases. metals,[42–44]. metal-free AlkynesTo haveBrønsted date, been different catalysis, widelytransition employed and Lewis metal as acid/basebuilding (Au,Pt, blockscatalysis, and for Cu) whichthis catalyzed/mediated reaction includes in mostex- method- amplescases. of nonenantioselectivologies for benzopyranee organocatalysis synthesis have and been enanti reportedoselective [27, 42or,45ganocatalysis,46]. Cheng and Hu de- [42–44].To Alkynes date,scribed different have a one-potbeen transition widely cascade metal employed of (Au, an addition/cyclization/oxidationPt,as buildingand Cu) blockscatalyzed/mediated for this reaction sequencemethodolo- in most using CuCl2 cases.gies for benzopyraneas the oxidant synthesis and CH have3SO 3beenH as reported the acid for[27,42,45,46]. regioselective Cheng synthesis and Hu of de- 2-substituted- scribedTo date, a one-pot4 differentH-furo[3,2- cascade transitionc]benzopyran-4-ones of an metal addition/cyclization/oxidation (Au, Pt,22 andfrom Cu) the catalyzed/mediated substituted sequence 3-alkynyl-4 using methodolo-H CuCl-benzopyran-4-one2 as giesthe foroxidant benzopyrane20 (Schemeand synthesis7CH)[473SO] .3 ThisH have strategyas beenthe includedreportedacid thefor[27,42,45,46]. CHregioselective3SO3H-acid-catalyzed Cheng synthesisand Hu construction de-of of the scribed2-substituted-4 a one-potfuranH -furo[3,2-cascade ring, followed ofc]benzopyran-4-ones an addition/cyclization/oxidation by oxidation of 21 with22 CuClfrom2 (Scheme sequence the7)[ using 47]. Whensubstituted CuCl2 the as reaction was the3-alkynyl-4 oxidantcarriedH -benzopyran-4-oneand outCH in3 theSO3 presenceH as20 of(Schemethe a catalyticacid 7) amountfor[47]. regioselectiveThis of CuCl strategy as a Lewis synthesisincluded acid and ofthe atmospheric 2-substituted-4CH3SO3H-acid-catalyzedoxygenH-furo[3,2- as anc oxidativeconstruction]benzopyran-4-ones reagent, of the compound furan 22ring, 22 followedwasfrom provided bythe oxidation directly.substituted of On21 with the other hand, 3-alkynyl-4CuCl2 (SchemeHthe-benzopyran-4-one presence 7) [47]. When of 10% the CuBr20 reaction and(Scheme an was excess 7)ca rried of[47]. CuCl outThis2 asin thethestrategy oxidant presence affordedincluded of a catalytic the the corresponding CH3SO3H-acid-catalyzed3-chloro-2-substituted- construction 4H of-furo[3,2- the furanc]benzopyran-4-ones ring, followed by oxidation23 (Scheme of7 21)[ 48with]. CuCl2 (Scheme 7) [47]. When the reaction was carried out in the presence of a catalytic

Molecules 2021, 26, x FOR PEER REVIEW 6 of 22

amount of CuCl as a Lewis acid and atmospheric oxygen as an oxidative reagent, com- amountpound 22 of wasCuCl provided as a Lewis directly. acid and On atmosphericthe other hand, oxygen the presenceas an oxidative of 10% reagent, CuBr and com- an amountpoundexcess 22ofof wasCuClCuCl provided 2as as a Lewisthe directly.oxidant acid and Onafforded atmosphericthe other the hand, correspondingoxygen the presenceas an oxidative 3-chloro-2-substituted- of 10% reagent, CuBr and com- an poundexcess 22of wasCuCl provided2 as the directly. oxidant On afforded the other the hand, corresponding the presence 3-chloro-2-substituted- of 10% CuBr and an Molecules 2021, 26, 483 4H-furo[3,2-c]benzopyran-4-ones 23 (Scheme 7) [48]. 6 of 21 excess4H-furo[3,2- of CuClc]benzopyran-4-ones2 as the oxidant 23afforded (Scheme the7) [48]. corresponding 3-chloro-2-substituted- 4H-furo[3,2-c]benzopyran-4-ones 23 (Scheme 7) [48].

Scheme 7. Transition metal Cu catalyzed/mediated methodologies for synthesis of the 4H-furo[3,2-c]benzopyran-4-ones

Scheme22 and 23 7.. ReagentsTransition and metal conditions Cu catalyzed/mediated: (a) CH3SO3H, H2O, methodologies DMF, 90 °C, 1–3 for h; synthesis (b) CuCl 2of, 90 the °C, 4 H20-furo[3,2- h; (c) CuCl,c]benzopyran-4-ones O2, DMF, H2O, 90 Scheme22°C, and 10–20 23 7.. h,TransitionReagents 10 outputs and metalmetal conditionswith Cu Cu 37 catalyzed/mediated %–88%catalyzed/mediated: (a) CH yield;3SO3 H,(d) H CuBr,2O, methodologies methodologies DMF, CuCl 902, DMF,°C, 1–3 for for H synthesish;2 O,synthesis (b) 75 CuCl °C, of 10 2of, the 90 h,the 4°C,13H 4 -furo[3,2-outputs H20-furo[3,2- h; (c) with cCuCl,]benzopyran-4-onesc]benzopyran-4-ones 45%–81% O2, DMF, yield. H2O, 22 90 ◦ ◦ and22°C, and 10–2023 .23Reagents. h,Reagents 10 outputs and and conditions conditions with 37:%–88% (a): (a) CH CH 3yield;SO3SO33H,H, (d) HH CuBr,22O, DMF, CuCl 902, °C,DMF,C, 1–3 1–3 H h; h;2O, (b) (a) 75 CuCl CuCl°C, 102,2 ,90 h, 90 °C, 13C, outputs20 20 h;h; (c) (c) withCuCl, CuCl, 45%–81% O2 O, DMF,2, DMF, yield. H2O, H2 90O, ◦ ◦ 90°C, 10–20C, 10–20 h, 10 h, outputs 10 outputs with with 37%–88% 37%–88%Brønsted-acid-catalyzed yield; yield; (d) (d)CuBr, CuBr, CuCl CuCl2 , propargylationsDMF,2, DMF, H2O, H2 75O, °C, 75 10C,of h, 10several 13 h, outputs 13 outputs organic with with 45%–81% substrates, 45%–81% yield. yield. including 1,3-dicarbonylBrønsted-acid-catalyzed compounds, with propargylations alkynols have ofbeen several reported organic [49]. Insubstrates, most cases, including the acid 1,3-dicarbonylcatalystBrønsted-acid-catalyzed is required compounds, to promote with propargylationspropargylations alkynols the prop haveargylation of ofbeen several several reported organic processorganic [49]. substrates, efficiently.Insubstrates, most cases, including Zhouincluding the acid 1,3-and dicarbonyl compounds, with alkynols have been reported [49]. In most cases, the acid 1,3-dicarbonylcatalystcoworkers is developedrequired compounds, ato one-pot promote with Yb(OTf)alkynols the 3prop havepropargylation–cycloisomerizationargylation been reported process [49]. efficiently.In most cases, sequenceZhou the acidand of catalystcoworkers4-hydroxycoumarin isis required developedrequired to promote (toa11 one-pot)promote with the Yb(OTf)the propargylationthe propargylic prop3 propargylation–cycloisomerizationargylation processalcohol process efﬁciently. (24) forefficiently. Zhouthe synthesis and sequenceZhou coworkers ofand ofa developed a one-pot Yb(OTf) propargylation–cycloisomerization3 sequence of 4-hydroxy coworkers4-hydroxycoumarin2-benzyl-3- developed phenyl-4 H (a11-furo[3,2- one-pot) with3 Yb(OTf)cthe]chromen-4-one propargylic propargylation–cycloisomerization (25alcohol) skeleton (24 )using for theYb(OTf) synthesis sequence3 as a Lewisof ofa 11 24 4-hydroxycoumarincoumarin2-benzyl-3-acid (Scheme ( phenyl-4) 8) with [50]. the H(11-furo[3,2- propargylic) with cthe]chromen-4-one alcoholpropargylic ( ) for (25alcohol the) skeleton synthesis (24) usingfor of a theYb(OTf) 2-benzyl-3- synthesis3 as phenyl-a Lewisof a 2-benzyl-3-4acidH-furo[3,2- (Scheme phenyl-4c]chromen-4-one 8) [50].H -furo[3,2- (25c)]chromen-4-one skeleton using Yb(OTf) (25) skeleton3 as a Lewisusing Yb(OTf) acid (Scheme3 as a8 Lewis)[ 50]. acid (Scheme 8) [50].

Scheme 8. One-pot synthesis of 4H-furo[3,2-c]chromen-4-one (25) using a Yb(OTf)3-catalyzed

SchemeSchemepropargylation 8.8. One-potOne-pot and synthesis synthesisallenylation of of 4 4Hreaction.H-furo[3,2--furo[3,2- Reagentsc]chromen-4-onec]chromen-4-one and conditions (25 (25): using )(a) using 5 amol Yb(OTf)a Yb(OTf) % Yb(OTf)3-catalyzed3-catalyzed3, CH3 propar-NO 2, Schemegylationpropargylationdioxane, 8. and 50 One-pot °C; allenylation (b)and Ksynthesis al2COlenylation3 reaction., 70 of°C, 4 reaction.H37%Reagents-furo[3,2- yield. Reagentsand c]chromen-4-one conditions and conditions: (a) 5(25 mol:) (a)using % 5 Yb(OTf)mol a Yb(OTf) % Yb(OTf)3, CH3-catalyzed3NO3, CH2, dioxane,3NO 2, ◦ ◦ propargylation50dioxane,C; (b) 50 K2 °C;CO and3(b), 70 K al2COlenylationC, 37%3, 70 yield.°C, reaction. 37% yield. Reagents and conditions: (a) 5 mol % Yb(OTf)3, CH3NO2, dioxane,Similarly, 50 °C; (b) 4 HK2-furo[3,2-CO3, 70 °C,c] 37%benzopyran-4-one yield. formation reactions proceeded in higher yieldsSimilarly,Similarly, and in 4 4HHa -furo[3,2--furo[3,2-one-pot cc]manner,] benzopyran-4-onebenzopyran-4-one employing formationformation a catalytic reactionsre actionssystem proceededproceeded composed inin higherhigherof the yieldsyields16-electronSimilarly, andand in in a 4 one-potHallyl–ruthenium(II)a -furo[3,2-one-pot manner, c]manner, benzopyran-4-one employing employincomplex a catalyticg formation a catalytic[Ru( systemη 3-2-Creactions composedsystem3H4Me)(CO)(dppf)][SbF proceeded composed of the 16-electron in higherof the6] 0 yieldsallyl–ruthenium(II)16-electron(dppf=1,1 and′-bis(diphenylphosphino)ferrocene) in aallyl–ruthenium(II) one-pot complex manner, [Ru(η3-2-C employin3complexH4Me)(CO)(dppf)][SbF andg a trcatalyticifluoroacetic[Ru(η3-2-C system6]3H (dppf=1,1acid4Me)(CO)(dppf)][SbF composed(TFA)-bis(diphenyl in the of reac-the6] 16-electronphosphino)ferrocene)(dppf=1,1tion of 4-hydroxycoumarin′-bis(diphenylphosphino)ferrocene) allyl–ruthenium(II) and triﬂuoroacetic (11), with 1-(4-methoxyphenyl)-2-propyn-1-olcomplex acid (TFA)and tr in[Ru(ifluoroacetic theη reaction3-2-C3H acid4 ofMe)(CO)(dppf)][SbF 4-hydroxycoumarin (TFA) (26 in) asthe an reac- ex-6] (dppf=1,1(tionample.11), withof 4-hydroxycoumarinThe′ 1-(4-methoxyphenyl)-2-propyn-1-ol-bis(diphenylphosphino)ferrocene) 4H-furo[3,2-c]benzopyran-4-one (11), with 1-(4-methoxyphenyl)-2-propyn-1-ol ( and26(27) as)tr ifluoroaceticwas an example. synthesized Theacid 4 H(TFA)with-furo[3,2- ( 26ain )72% theasc]benzo an reac-yield ex- tionpyran-4-oneample.(Scheme of 4-hydroxycoumarinThe 9) [50–52]. (274H)-furo[3,2- was synthesizedc]benzopyran-4-one (11), with with 1-(4-methoxyphenyl)-2-propyn-1-ol a 72% yield (27) (Schemewas synthesized9)[50–52]. with (26a )72% as an yield example.(Scheme The 9) [50–52].4H-furo[3,2- c]benzopyran-4-one (27) was synthesized with a 72% yield (Scheme 9) [50–52].

SchemeScheme 9. 9. The 16-electronThe 16-electron allyl–ruthenium( allyl–ruthenium(II)II) complexcomplex in preparation in preparation of of 4H -furo[3,2- cScheme4]benzopyran-4-oneH-furo[3,2- 9. Thec]benzopyran-4-one 16-electron (27). Reagents allyl–ruthenium( (27 and). Reagents conditionsII) andcomplex: 16-electron conditions in preparation: allyl–ruthenium(II) 16-electron of allyl–ruthenium(II) complex [Ru( com-η3-2- Scheme4H-furo[3,2- 9. Thec]benzopyran-4-one 16-electron allyl–ruthenium( (27). ReagentsII) complexand conditions in preparation: 16-electron of allyl–ruthenium(II)◦ com- C3H4Me)(CO)(dppf)][SbF6] (5 mol %), trifluoroacetic acid (TFA) (50 mol %), THF, 75 C, 5 h, 72% yield. 4H-furo[3,2-c]benzopyran-4-one (27). Reagents and conditions: 16-electron allyl–ruthenium(II) com- Extensive work has been done to investigate the utility of an aryl alkynyl ether as a furan substrate, instead of arylalkynol, in the synthesis of 4H-furo[3,2-c]benzopyran-

4-one [29,35]. The treatment of 3-iodo-4-methoxycoumarin (28) with phenylacetylene

by means of sequential Sonogashira C–C coupling conditions resulted in a high-yield formation of the 4H-furo[3,2-c]benzopyran-4-one (30) (Scheme 10)[53]. In this reaction, the triethylamine was used as a base to induce the SN2-type demethylation of the Sono- Molecules 2021, 26, x FOR PEER REVIEW 7 of 22 Molecules 2021, 26, x FOR PEER REVIEW 7 of 22

plex [Ru(η3-2-C3H4Me)(CO)(dppf)][SbF6] (5 mol %), trifluoroacetic acid (TFA) (50 mol %), THF, 75 plex°C, 5[Ru( h, 72%η3-2-C yield.3H4 Me)(CO)(dppf)][SbF6] (5 mol %), trifluoroacetic acid (TFA) (50 mol %), THF, 75 °C, 5 h, 72% yield. Extensive work has been done to investigate the utility of an aryl alkynyl ether as a furanExtensive substrate, work has insteadbeen done toof investigatearylalkynol, the utility in of an thearyl alkynylsynthesis ether as ofa furan4H-furo[3,2- substrate,c]benzopyran-4-one instead [29,35].of arylThe alkynol,treatment ofin 3-iodo-4-methoxycoumarinthe synthesis of Molecules 2021, 26, 483 4(H28-furo[3,2-) with phenylacetylenec]benzopyran-4-one by means [29,35]. of sequential The trea tmentSonogashira of 3-iodo-4-methoxycoumarin C–C coupling conditions7 of 21 (resulted28) with inphenylacetylene a high-yield formation by means ofof thesequential 4H-furo[3,2- Sonogashirac]benzopyran-4-one C–C coupling (30 conditions) (Scheme resulted10) [53]. inIn athis high-yield reaction, formation the triethylam of theine 4H was-furo[3,2- used cas]benzopyran-4-one a base to induce ( 30the) (SchemeSN2-type 10)demethylation [53]. In this ofreaction, the Sonogashira the triethylam couplingine was product, used followedas a base by to aninduce intramolecular the SN2-type at- demethylationgashiratack of the coupling enolate of product,the onto Sonogashira the followed cuprohalide coupling by anπ-complex intramolecular product, of followedthe triple attack bybond of an the (Schemeintramolecular enolate 10). onto theat- tackcuprohalide of the enolateπ-complex onto ofthe the cuprohalide triple bond π-complex (Scheme 10 of). the triple bond (Scheme 10).

Scheme 10. Et3N-induced demethylation–annulation of an aryl alkynyl ether in the synthesis of Scheme4H-furo[3,2- 10.10.Etc ]benzopyran-4-one3N-inducedEt3N-induced demethylation–annulation demethylation–annulation (30). Reagents and conditions of an aryl : of(a) alkynyl alkynean etheraryl (3 equiv.), inalkynyl the synthesis 8 molether % of PdCl 4Hin-furo[3,2- 2(PPhthe 3)2,synthesisc ]benzopyran-8 mol % CuI,of ◦ 4-one4EtH3-furo[3,2-N/DMF, (30). Reagents c80]benzopyran-4-one °C, 48 and h, conditions82% yield; (:30 (a)(b).) alkyneReagentsalkyne (3(3 and equiv.),equiv.), conditions 8 8 mol mol: % (a)% PdCl PdClalkyne22(PPh(PPh (3 33equiv.),))2,, 8 mol 8 % mol CuI, % Et PdCl3N/MeCN,N/DMF,2(PPh3) 80260, 8 °C,C,mol 4815 % h,h, CuI, 82%70% Et3N/DMF, 80 °C, 48 h, 82% yield; (b) alkyne (3 equiv.), 8 mol % PdCl2(PPh3)2, 8 mol◦ % CuI, Et3N/MeCN, 60 °C, 15 h, 70% yield;yield. (b) alkyne (3 equiv.), 8 mol % PdCl2(PPh3)2, 8 mol % CuI, Et3N/MeCN, 60 C, 15 h, 70% yield. yield. AsAs aa follow-upfollow-up toto thisthis typetype ofof reaction,reaction, aa novelnovel andand rapidrapid assemblyassembly ofof anan interestinginteresting classclassAs ofof 4a4H Hfollow-up-furo[3,2--furo[3,2- tocc]benzopyran-4-ones,]benzopyran-4-ones, this type of reaction, 3333 a, , novel waswas successfullysuccessfully and rapid assembly achievedachieved of usingusing an interesting aa one-potone-pot classsequentialsequential of 4H coupling/cyclization -furo[3,2-coupling/cyclizationc]benzopyran-4-ones, strategy strategy with with 33, 3-bromo-4-acetoxycoumarins was 3-bromo-4-acetoxycoumarins successfully achieved using31 and31 a and dialkyn-one-pot dial- sequentiallzincskynlzincs32 prepared coupling/cyclization32 prepared in situ asin reactive situ strategy as acetylides reactive with in3-bromo-4-acetoxycoumarins acetylides transition-metal-catalyzed in transition-metal-catalyzed crosscoupling. 31 and dial- kynlzincsThecrosscoupling. cascade 32 transformation prepared The cascade in reliessitutransformation as on reactive palladium/copper-catalyzed reliesacetylides on palladium/copper-catalyzed in transition-metal-catalyzed alkynylation and in-al- crosscoupling.tramolecularkynylation and hydroalkoxylation The intramolecular cascade transformation hydroalkoxylation (Scheme 11)[ 54relies]. (Scheme on palladium/copper-catalyzed 11) [54]. alkynylation and intramolecular hydroalkoxylation (Scheme 11) [54].

SchemeScheme 11.11. A one-pot sequential coupling/cyclization strategy strategy in in the the synthesis synthesis of of4H 4-furo[3,2-H-furo[3,2-c]-c ]- ◦ Schemebenzopyran-4-onesbenzopyran-4-ones 11. A one-pot 33 sequential. ReagentsReagents and coupling/cyclization and conditions conditions: (a): (a) Pd(PPh Pd(PPh strategy3)23, )CuI,2 ,in CuI, the THF, THF,synthesis 60 °C; 60 (b) C;of K4 (b)H2CO-furo[3,2- K23CO, H23O,,Hc 13]-2 O, benzopyran-4-ones13outputs outputs with with 51%–96% 51%–96% 33. Reagents yield. yield. and conditions: (a) Pd(PPh3)2, CuI, THF, 60 °C; (b) K2CO3, H2O, 13 outputs with 51%–96% yield. AA transition-metal-freetransition-metal-free approach approach was developed was to achieve developed 4-H-furo[3,2- cto]benzopyran- achieve 4-ones4-H-furo[3,2-A via antransition-metal-freec iodine-promoted]benzopyran-4-ones one-pot viaapproach an cyclization iodine-p wasromoted between developed 4-hydroxycoumarinsone-pot cyclization to betweenachieve34 and 4-acetophenones4-hydroxycoumarinsH-furo[3,2-c]benzopyran-4-ones35. The 34 transformation and acetophenones via an spontaneously iodine-p 35. Theromoted transformation proceeded one-pot to cyclization producespontaneously (36 between) in pro- the 4-hydroxycoumarinspresenceceeded to of produce NH4OAc. ( 3634 The) andin possible the acetophenones presence reaction of mechanism NH35. 4TheOAc. transformation suggestedThe possible for thereactionspontaneously iodine-promoted mechanism pro- ceededone-potsuggested to cyclization producefor the iodine-promoted is(36 depicted) in the (Schemepresence one-pot 12 of)[ NHcy55clization].4OAc. The is depicted possible (Scheme reaction 12) mechanism [55]. suggestedAdditionally, for the iodine-promoted Traven et al. [56] providedone-pot cy aclization new short is waydepicted for the (Scheme synthesis 12) of [55]. 4H -furo- [3,2-c]benzopyran-4-one, employing the Fries rearrangement of 4-chloroacetoxycoumarin (37) to yield two products, namely 3-chloroacetyl4-hydroxycoumarin (38) and dihydrofuro [2,3-c]coumarin-3-one (39), in the ratio of 2:1. Compound (38), which underwent cyclization, led to the formation of (39). The latter, under reduction and dehydration conditions, afforded 4H-furo[3,2-c]chromen-4-one (41) (Scheme 13). A closely related reaction that allowed for the preparation of (41) was developed by Majumdar and Bhattacharyya [57], following a similar procedure but using chloroacetaldehyde instead of chloroactylchloride in the presence of aqueous potassium carbonate to give 3-hydroxy-2,3- dihydrofuro[3,2- c]benzopyran-4-one (40), which upon treatment with aqueous hydrochloric acid provided 4H-furo[3,2-c]benzopyran-4-one (41) with 72% yield (Scheme 13).

Molecules 2021, 26, x FOR PEER REVIEW 8 of 22

MoleculesMolecules 20212021, 26, 26, ,x 483 FOR PEER REVIEW 8 of 21 8 of 22

Scheme 12. Metal-free synthesis of 4-H-furo[3,2-c]benzopyran-4-ones 36. Reagents and conditions: I2, NH4OAc, PhCl, 120 °C, 18 outputs with 28%–90% yield.

Additionally, Traven et al. [56] provided a new short way for the synthesis of 4H-furo- [3,2-c]benzopyran-4-one, employing the Fries rearrangement of 4-chloroacetoxycoumarin (37) to yield two products, namely 3-chloroacetyl4-hydroxycoumarin (38) and dihydrofuro[2,3-c]coumarin-3-one (39), in the ratio of 2:1. Compound (38), which underwent cyclization, led to the formation of (39). The latter, under reduction and dehydration conditions, afforded 4H-furo[3,2-c]chromen-4-one (41) (Scheme 13). A closely related reaction that allowed for the preparation of (41) was developed by Majumdar and Bhattacharyya [57], following a similar procedure but using chloroacetaldehyde instead of chloroactylchloride in the

presence of aqueous potassium carbonate to give 3-hydroxy-2,3- dihydrofu- Schemero[3,2-Schemec 12. ]benzopyran-4-one12.Metal-free Metal-free synthesis synthesis ( of40 of 4-),H 4-which-furo[3,2-H-furo[3,2- uponc]benzopyran-4-onesc]benzopyran-4-ones treatment with36. Reagentsaqueous 36. Reagents and hydrochloric conditions and conditions: acid: I2, ◦ IprovidedNH2, NH4OAc,4OAc, PhCl, 4 PhCl,H-furo[3,2- 120 120 °C,C, 18 18c]benzopyran-4-one ou outputstputs withwith 28%–90% 28%–90% (41 yield. yield.) with 72% yield (Scheme 13). Additionally, Traven et al. [56] provided a new short way for the synthesis of 4H-furo- [3,2-c]benzopyran-4-one, employing the Fries rearrangement of 4-chloroacetoxycoumarin (37) to yield two products, namely 3-chloroacetyl4-hydroxycoumarin (38) and dihydrofuro[2,3-c]coumarin-3-one (39), in the ratio of 2:1. Compound (38), which underwent cyclization, led to the formation of (39). The latter, under reduction and dehydration conditions, afforded 4H-furo[3,2-c]chromen-4-one (41) (Scheme 13). A closely related reaction that allowed for the preparation of (41) was developed by Majumdar and Bhattacharyya [57], following a similar procedure but using chloroacetaldehyde instead of chloroactylchloride in the presence of aqueous potassium carbonate to give 3-hydroxy-2,3- dihydrofuro[3,2-c]benzopyran-4-one (40), which upon treatment with aqueous hydrochloric acid provided 4H-furo[3,2-c]benzopyran-4-one (41) with 72% yield (Scheme 13).

SchemeScheme 13. 13.Regioselective Regioselective synthesis synthesis of 4ofH -furo[3,2-4H-furo[3,2-c]chromen-4-onec]chromen-4-one (41). Reagents(41). Reagents and conditions and conditions: : ◦ (a)(a) ClCHClCH2COCl,2COCl, dry dry pyridine, pyridine, 40 min,40 min, reﬂux, reflux, 85% yield;85% yield; (b) AlCl (b)3 ,AlCl 140–1503, 140–150C, 60% °C, yield; 60% (c) yield; AlCl3 (c), AlCl3, ◦ 140–150140–150 °C,C, 30–40 30–40 min min or or K 2KCO2CO3,3 acetone,, acetone, 10 10 min, min, stirring, stirring, r.t., r.t., 50% 50% yield; yield; (d) NaBH (d) NaBH4, 85%4, yield;85% yield; (e) (e)H2 HSO2SO4 (30%),4 (30%), EtOH, EtOH, heat, heat, 30 30 min, 80%80% yield; yield; (f) (f) COCH COCH2Cl,2Cl, K2CO K23CO, 73%3, 73% yield; yield; (g) HCl, (g) 72%HCl, yield. 72% yield. Pyrone Construction Recently, much effort has been devoted to the development of oxidative intramolecular C–O bond-forming cyclization reactions for the synthesis of bioactive benzopyranones. These methods are limited to being used with arenes building blocks [58–60]. Fu et al. reported a ligand-enabled, site-selective carboxylation of 2-(furan-3-yl)phenols 42 under the atmospheric pressure of CO2. It was performed through an Rh(ii)-catalyzed C–H bond activation, assisted by the ligand chelation of the phenolic hydroxyl group to afford 4H-furo[3,2-c]benzopyran-4-ones 43 (Scheme 14)[61]. This reaction indicates the role of

Scheme 13. Regioselective synthesis of 4H-furo[3,2-c]chromen-4-one (41). Reagents and conditions: (a) ClCH2COCl, dry pyridine, 40 min, reflux, 85% yield; (b) AlCl3, 140–150 °C, 60% yield; (c) AlCl3, 140–150 °C, 30–40 min or K2CO3, acetone, 10 min, stirring, r.t., 50% yield; (d) NaBH4, 85% yield; (e) H2SO4 (30%), EtOH, heat, 30 min, 80% yield; (f) COCH2Cl, K2CO3, 73% yield; (g) HCl, 72% yield.

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Pyrone Construction Recently, much effort has been devoted to the development of oxidative intramolecular C–O bond-forming cyclization reactions for the synthesis of bioactive benzopyranones. These methods are limited to being used with arenes building blocks [58–60]. Fu et al. reported a ligand-enabled, site-selective carboxylation of 2-(furan-3-yl)phenols 42 Molecules 2021, 26, x FOR PEER REVIEW 9 of 22 under the atmospheric pressure of CO2. It was performed through an Rh(ii)-catalyzed Molecules 2021, 26, 483 9 of 21 C–H bond activation, assisted by the ligand chelation of the phenolic hydroxyl group to afford 4H-furo[3,2-Pyronec ]benzopyran-4-onesConstruction 43 (Scheme 14) [61]. This reaction indicates the Recently, much effort has been devoted to the development of oxidative intramo- role of phosphine ligands in combination with Rh2(OAc)4 in promoting the reactivity and phosphine ligandslecular in combination C–O bond-forming with cyclization Rh2(OAc) reactions4 in promoting for the synthesis the reactivity of bioactive and benzopy- the selectivitythe selectivity during during C–Hranones. carboxylation. These C–H methods carboxylation. are The limited right to being choice The us righted of with a suitable choice arenes building basicof a suitable catalystblocks [58–60]. is basic an Fu catalyst is an et al. reported a ligand-enabled, site-selective carboxylation of 2-(furan-3-yl)phenols 42 additionaladditional critical critical point. point. under the atmospheric pressure of CO2. It was performed through an Rh(ii)-catalyzed C–H bond activation, assisted by the ligand chelation of the phenolic hydroxyl group to afford 4H-furo[3,2-c]benzopyran-4-ones 43 (Scheme 14) [61]. This reaction indicates the role of phosphine ligands in combination with Rh2(OAc)4 in promoting the reactivity and the selectivity during C–H carboxylation. The right choice of a suitable basic catalyst is an additional critical point.

Scheme 14. Rhodium(II)-catalyzed aryl C–H carboxylation with CO in the synthesis of 4H-furo[3,2- Scheme 14. Rhodium(II)-catalyzed aryl C–H carboxylation2 with CO 2 in the synthesis of c] benzopyran-4-ones 43. Reagents and conditions: (a) Rh2(OAc)4 (1 mol %), tricyclohexylphosphine 4H-furo[3,2-c] benzopyran-4-onesScheme 14. Rhodium(II)-catalyzed 43. Reagents aryl C–H andcarboxylation conditions with CO: (a)2 in Rhthe synthesis2(OAc) of4 (1 mol %), tricyclohex- ◦ PCy3 (2 mol %), t-BuOK4H-furo[3,2- (4.5 equiv.),c] benzopyran-4-ones diglyme, 100 43. ReagentsC, 48 h, and six conditions outputs: (a) with Rh2(OAc) 70%–86%4 (1 molyield. %), tricyclohexylphosphine PCy3 (2 mol %), t-BuOK (4.5 equiv.), diglyme, 100 °C, 48 h, six outputs with 70%–86% ylphosphine PCy3 (2 mol %), t-BuOK (4.5 equiv.), diglyme, 100 °C, 48 h, six outputs with 70%–86% 2.1.2.yield. Pyrroles yield.

Fusion of the pyrrole2.1.2. Pyrroles ring with the pyrone ring of coumarin (benzopyrane) leads to three2.1.2. structural Pyrroles isomers, Fusion viz. of chromeno[3,4-the pyrrole ring withb]pyrrol-4( the pyrone3H ring)-one, of coumarin chromeno[3,4- (benzopyrane)c]pyrrol- leads to 4(2H)-one, and chromeno[4,3-b]pyrrol-4(1H)-one (Figure2). Fusion of thethree pyrrolestructural ring isomer withs, theviz. pyrone chromeno[3,4- ring ofb]pyrrol-4( coumarin3H)-one, (benzopyrane) chrome- leads to no[3,4-c]pyrrol-4(2H)-one, and chromeno[4,3-b]pyrrol-4(1H)-one (Figure 2). three structural isomers, viz. chromeno[3,4-b]pyrrol-4(3H)-one, chromeno[3,4-c]pyrrol-4(2H)-one, and chromeno[4,3-b]pyrrol-4(1H)-one (Figure 2).

Figure 2.FigureThe 2. three The three common common isomers isomers ofof th thee pyrrole pyrrole ring ring fused fused to the toα-pyrone the α-pyrone moiety of moietycoumarin. of coumarin.

3H,4H[1]Benzopyrano[3,4-3H,4H[1]Benzopyrano[3,4-b]pyrrol-4-oneb]pyrrol-4-one Pyrrole ConstructionPyrrole Construction The 3-Aminocoumarin (44) is considered the starting compound for the preparation The 3-Aminocoumarinof fused 3H,4H (44)[1]benzopyrano[3,4- is considered theb]pyrrol-4-ones. starting compound The amino for group the preparationrepresents the ofkey fused 3H,4H[1]benzopyrano[3,4-moiety of this cyclizationb]pyrrol-4-ones. process in The the amino reaction group with different represents reagents the key[30,62–64]. moi- Figure 2. The three common isomers of the pyrrole ring fused to the α-pyrone moiety of coumarin. ety of this cyclizationCompound process 45 in was the reactionprepared withby the different reaction of reagents 3-aminocoumarin [30,62–64 (44].) Compoundwith different 45 was prepared bycarbonyls the reaction via Fischer of 3-aminocoumarin indole synthesis afte (44r being) with diazotized different and carbonyls reduced to via couma- Fis- rin-3-yl-hydrazine [62]. The compound 1-Aryloxy-4-chlorobut-2-ynes reacted with cher3H,4 indoleH[1]Benzopyrano[3,4-b]pyrrol-4-one synthesis3-aminocoumarin after being diazotized (44) to afford and 47 through reduced amino-Claisen to coumarin-3-yl-hydrazine rearrangement [64]. Conden- [62]. ThePyrrole compound Construction 1-Aryloxy-4-chlorobut-2-ynessation of (44) with α-halo ketones, reacted followed with by cyclization 3-aminocoumarin catalyzed by (44 TFA,) to led afford to the 47 through amino-Claisenformation rearrangementof 49 [63], while 50 [64 was]. Condensationprepared under Nef of (conditions44) with usingα-halo 2-aryl-1- ketones, nitro followedThe by 3-Aminocoumarin cyclizationethenes catalyzed [30] (Scheme ( by44 15).) TFA, is considered led to the formation the starting of 49 [compound63], while 50 forwas the preparation preparedof fused under 3H,4H Nef[1]benzopyrano[3,4- conditions using 2-aryl-1-b]pyrrol-4-ones. nitro ethenes [30 ]The (Scheme amino 15). group represents the key moiety of this cyclization process in the reaction with different reagents [30,62–64]. Compound 45 was prepared by the reaction of 3-aminocoumarin (44) with different carbonyls via Fischer indole synthesis after being diazotized and reduced to coumarin-3-yl-hydrazine [62]. The compound 1-Aryloxy-4-chlorobut-2-ynes reacted with 3-aminocoumarin (44) to afford 47 through amino-Claisen rearrangement [64]. Conden- sation of (44) with α-halo ketones, followed by cyclization catalyzed by TFA, led to the formation of 49 [63], while 50 was prepared under Nef conditions using 2-aryl-1- nitro ethenes [30] (Scheme 15).

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MoleculesMolecules2021 26 2021, 26, x FOR PEER REVIEW 10 of 22 , , 483 10 of 21

SchemeScheme 15. Different15. Different pathways pathways to to synthesize synthesize3H,4H 3H,4H[1]benzo-[1]benzopyrano[3,4-pyrano[3,4-b]pyrrol-4-onesb]pyrrol-4-ones 45,45 47, , 4749, , 49and, and 50 50via via 3- 3-aminocoumarin. Reagents and conditions: (a) i: NaNO2, HCl, −30 ◦°C, ii: SnCl2, −10 °C,◦ HCl, 2 h, iii: carbonyl compounds, aminocoumarin. Reagents and conditions: (a) i: NaNO2, HCl, −30 C, ii: SnCl2, −10 C, HCl, 2 h, iii: carbonyl compounds, Schemepolyphosphoric 15. Different acid, pathways 1 h, 130 °C, to se vensynthesize outputs with3H,4H 33%–51%[1]benzo- yield; pyrano[3,4- (b) anhydrideb]pyrrol-4-ones ethyl methyl ketone, 45, 47 K2, CO493, NaI,and re- 50 via polyphosphoric acid, 1 h, 130 ◦C, seven outputs with 33%–51% yield; (b) anhydride ethyl methyl ketone, K CO , NaI, reflux, 3-aminocoumarin.flux, 24–30 h, fiveReagents outputs and with conditions 51%–63%: (a) yield; i: NaNO (c) N,2N, -dimethylaniline,HCl, −30 °C, ii: SnClreflux,2, −6–910 h,°C, five HCl, outputs 2 h, iii:with carbonyl 90%–94%2 3compounds, yield; polyphosphoric24–30(d) h, fiveKI (cat.), outputs acid, reflux, with1 h,5 h; 130 51%–63% (e) °C,TFA se (cat.),ven yield; outputsAcOH, (c) N 12, Nwith h,-dimethylaniline, reflux 33%–51%, four outputs yield; reflux, with(b) anhydride 28%–86% 6–9 h, five yield; ethyl outputs (f) methyl MeOH, with ketone, piperidine, 90%–94% K2CO yield;reflux,3, NaI, (d) re- KI (cat.),flux, 24–30five reflux, outputs h, 5five h; (e)with outputs TFA 55%–61% (cat.), with yield. AcOH,51%–63% 12 yield; h, reflux, (c) N four,N-dimethylaniline, outputs with 28%–86% reflux, 6–9 yield; h, five (f) MeOH, outputs piperidine, with 90%–94% reflux, yield; five (d)outputs KI (cat.), with reflux, 55%–61% 5 h; yield.(e) TFA (cat.), AcOH, 12 h, reflux, four outputs with 28%–86% yield; (f) MeOH, piperidine, reflux, five outputs with 55%–61% yield.3H ,4H[1]Benzopyrano[3,4-e]pyrrol-4-one Pyrrole Construction 33HH,4,4H[1]Benzopyrano[3,4-e]pyrrol-4-one[1]Benzopyrano[3,4-A one-pot, three-componente]pyrrol-4-one reaction of phenylsulphinyl-2H-benzopyran-2-one (51), PyrrolePyrrolephenylglycine Construction (52 ), and benzaldehyde (53) led to the formation of 1,3-diphenyl[l]benzopyrano[3,4-e]pyrrol-4-one (55) (Scheme 16) [65]. AA one-pot, one-pot, three-component three-component reaction reaction of of phenylsulphinyl-2 phenylsulphinyl-2HH-benzopyran-2-one-benzopyran-2-one ( (5151),), phenylglycine (52(),52 and), benzaldehydeand benzaldehyde (53) led to the(53) formation led to of 1,3-diphenyl[l]benzopy-the formation of 1,3-diphenyl[l]benzopyrano[3,4-rano[3,4-e]pyrrol-4-one (55) (Schemee]pyrrol-4-one 16)[65]. (55) (Scheme 16) [65].

Scheme 16. Synthesis of 1,3-diphenyl[l]benzopyrano[3,4-e]pyrrol-4-one (55). Reagents and conditions: DMF, stirring, 120 °C, 24 h, 51% yield.

Xue et al. developed an efficient and straightforward synthetic protocol for the Scheme 16.16. SynthesisSynthesis ofof 1,3-diphenyl[l]benzopyrano[3,4-1,3-diphenyl[l]benzopyrano[3,4-preparation of [1]benzopyrano[3,4-e]pyrrol-4-onee]pyrrol-4-onee]pyrrol-4-ones (55 (55). ).Reagents Reagents and and59 conditions conditionsthrough: DMF, : DMF,FeCl stirring,3 -promoted,stirring, 120 120◦C, three-component reactions between substituted 2-(2-nitrovinyl)phenols 58, acetylene °C,24h, 24 51% h, 51% yield. yield.

XueXue etet al.al. developeddeveloped an an efﬁcient efficient and and straightforward straightforward synthetic synthetic protocol protocol for the for prepa- the

preparationration of [1]benzopyrano[3,4- of [1]benzopyrano[3,4-e]pyrrol-4-onese]pyrrol-4-ones59 through FeCl59 3-promoted,through three-componentFeCl3-promoted, three-componentreactions between reactions substituted between 2-(2-nitrovinyl)phenols substituted 2-(2-nitrovinyl)phenols58, acetylene dicarboxylate 58, acetylene (57), and amines 58 (Scheme 17)[66]. This reaction involved the sequential FeCl3-mediated

Molecules 2021, 26, x FOR PEER REVIEW 11 of 22

Molecules 2021, 26, 483dicarboxylate (57), and amines 58 (Scheme 17) [66]. This reaction involved the sequential 11 of 21 dicarboxylateFeCl3-mediated (57 ), andnucleophilic amines 58 addition(Scheme 17)of [66]. ac etylenedicarboxylates,This reaction involved theamines, sequential and FeCl2-(2-nitrovinyl)phenols,dicarboxylate3-mediated (57nucleophilic), and aminesfollowing addition 58 (Schemeintramolecul of 17) ac [66].aretylenedicarboxylates, transesterifcation This reaction involved to formamines, the a sequentialcoumarin and 2-(2-nitrovinyl)phenols,core.FeCl 3-mediatedThis strategy nucleophilic followingoffers a additionintramolecul complementary of ar actransesterifcationetylenedicarboxylates, approach to to formsubstituted amines,a coumarin pyr-and core.rolo[3,4-2-(2-nitrovinyl)phenols, Thisc]coumarin strategynucleophilic compounds, offers following addition a with complementary ofintramolecul acetylenedicarboxylates, advantagesar transesterifcationthatapproach include amines, toa variety tosubstituted and form of 2-(2-nitrovinyl)phenols, acheap coumarin pyr- and fol- rolo[3,4-readilycore. c availableThis]coumarin lowingstrategy reactants compounds, intramolecular offers and awith awide complementary transesterifcationadvantages range of substrates that approach toinclude form with aa dense coumarinvarietyto orsubstituted offlexible core. cheap This substi- andpyr- strategy offers a readilytutionrolo[3,4- availablepatternsc]coumarincomplementary [66].reactants compounds, and approacha wide with range toadvantages substituted of substrates that pyrrolo[3,4- includewith dense ac ]coumarinvariety or flexible of compounds,cheap substi- and with advan- tutionreadily patterns available tages[66]. reactants that include and a varietywide range of cheap of substrates and readily with available dense or reactants flexible andsubsti- a wide range of tution patternssubstrates [66]. with dense or ﬂexible substitution patterns [66].

Scheme 17. Synthesis of [1]benzopyrano[3,4-e]pyrrol-4-ones 59 by a FeCl3-promoted,

Schemethree-component 17. Synthesis reaction. of [1]benzopyrano[3,4- Reagents and conditionse]pyrrol-4-ones: FeCl3, toluene, 59 by a110 FeCl °C,3-promoted, 6 h, 17 outputs with Scheme 17.three-componentSynthesis62%–92%Scheme 17. ofyield. [1]benzopyrano[3,4-Synthesis reaction. of [1]benzopyrano[3,4-Reagentse]pyrrol-4-ones and conditionse]pyrrol-4-ones: 59FeClby3, a toluene, FeCl3 59-promoted, 110by a °C, FeCl 6 h, three-component3-promoted, 17 outputs with reaction. Reagents ◦ and conditions62%–92%three-component: FeCl3 ,yield. toluene, 110reaction.C, 6 h,Reagents 17 outputs and conditions with 62%–92%: FeCl3 yield., toluene, 110 °C, 6 h, 17 outputs with 62%–92%Alizadeh yield. et al. reported a sequential three-component reaction of salicylaldehydes 60, Alizadehβ-keto esters et al. 61, Alizadehreported and p-toluenesulfonylmethyl eta sequential al. reported th aree-component sequential isocyanide three-component reaction (TosMIC) of salicylaldehydes ( reaction62) via [1,3] of salicylaldehydes acyl 60, 60shift, β-keto Alizadehto giveesters 2-acyl[1]β et-keto61, al. and estersreported pbenzopyrano[3,4--toluenesulfonylmethyl 61, a and sequentialp-toluenesulfonylmethyle]pyrrol-4-ones three-component isocyanide 63 isocyanide(TosMIC)(Scheme reaction 18)of( (TosMIC)62 salicylaldehydes )[67]. via [1,3]A ( 62simple acyl) via [ 1 ,3] acyl shift shiftworkup60, toβ-keto give procedure, esters 2-acyl[1]to give 61, mild and 2-acyl[1]benzopyrano[3,4- preaction-toluenesulfonylmethyl benzopyrano[3,4- conditions,e]pyrrol-4-ones lacke]pyrrol-4-ones isocyanide of side 63 (Schemeproducts, (TosMIC)63 (Scheme 18) and ([67].62 good) 18via A)[ yields[1,3]67simple]. Aacyl of simple workup workup62%–95%shift to procedure, give are theprocedure,2-acyl[1] main mild aspects benzopyrano[3,4-reaction mild reaction of conditions,this method. conditions,e]pyrrol-4-ones lack lackof side of side 63products, (Scheme products, and 18) and good [67]. good yields A yields simple of of 62%–95% are 62%–95%workup areprocedure, thethe main main mild aspects aspects reaction of of this this conditions, method. method. lack of side products, and good yields of 62%–95% are the main aspects of this method.

Scheme 18. A sequential three-component reaction to synthesize Scheme 18.Scheme[1]benzopyrano[3,4-A sequential 18. A sequential three-componente]pyrrol-4-ones three-component reaction 63. Reagents toreaction synthesize and to conditionssynthesize [1]benzopyrano[3,4-: TEA, piperidine,e]pyrrol-4-ones DMF, r.t., 8 h,63 .10Reagents and conditions: TEA,[1]benzopyrano[3,4-outputsScheme piperidine, with 18. A 62%–95% sequential DMF,e]pyrrol-4-ones r.t., yield. 8three-component h, 10 outputs 63. Reagents with reaction 62%–95% and conditions to synthesize yield.: TEA, piperidine, DMF, r.t., 8 h, 10 outputs[1]benzopyrano[3,4- with 62%–95%e ]pyrrol-4-onesyield. 63. Reagents and conditions: TEA, piperidine, DMF, r.t., 8 h, 10 outputsRecently, with 62%–95% KhavasiRecently, yield. and Khavasihis coworkers and his investigated coworkers the investigated reactivity, thechemo-, reactivity, region-, chemo-, region-, andRecently, diastreo-selectivity Khavasiand diastreo-selectivity and of hisp-toluenesulfonylmethyl coworkers of p-toluenesulfonylmethyl investigated isocyanide the reactivity, isocyanide (TosMIC) chemo-, (TosMIC) (62 region-,) in (Van62) in Van Leusen- andLeusen-type diastreo-selectivityRecently, [3type Khavasi + [32] +cycloaddition 2] ofand cycloadditionp-toluenesulfonylmethyl his coworkers reactions reactions investigated with with isocyanidethe the the 3-acetylcoumarins reactivity, (TosMIC) chemo-, (62 6464) to in toregion-, give Vangive [1]benzopyrano Leusen-type[1]benzopyrano[3,4-and diastreo-selectivity [3[3,4- + 2]e]pyrrol-4-ones ecycloaddition]pyrrol-4-ones of p-toluenesulfonylmethyl65 reactions65(Scheme (Scheme 19with )[19)68 the[68].]. isocyanide This 3-acetylcoumarinsThis method method (TosMIC) offers offers several 64 (several62 to) in advantages,give Vanad- such as [1]benzopyrano[3,4-vantages,Leusen-type such being[3 as +being e]pyrrol-4-ones inexpensive,2] cycloaddition inexpensive, providing 65 providing(Schemereactions good 19) goodwith to excellent[68]. tothe Thisexcellent 3-acetylcoumarins yields, method yields, producing offers producing several short64 toreaction short ad-give times, high vantages,reaction[1]benzopyrano[3,4- suchtimes, atomas highbeing economy, eatom]pyrrol-4-ones inexpensive, economy, and ease providing 65 and of(Scheme product ease good of19) isolationproduct to[68]. excellent This underisolation method yields, catalyst-free under producingoffers catalyst-free several conditions short ad- without any reactionconditionsvantages, times, suchwithout activationhigh as being anyatom activation atinexpensive, economy, ambient at temperature. ambientand providing ease temperature. of good product to excellent isolation yields, under producing catalyst-free short conditionsreaction times,without high any atomactivation economy, at ambient and eatemperature.se of product isolation under catalyst-free conditions without any activation at ambient temperature.

Scheme 19. TheScheme Van 19. Leusen The Van protocol Leusen for protocol the synthesis for the of synthesis [1]benzopyrano[3,4- of [1]benzopyrano[3,4-e]pyrrol-4-onese]pyrrol-4-ones65. Reagents 65and . conditions:

K2CO3, EtOH,SchemeReagents 15 min, 19. and The r.t, conditions three Van outputsLeusen: K2CO protocol with3, EtOH, 72%–86% for 15 the min, yield.synthesis r.t, three of outputs [1]benzopyrano[3,4- with 72%–86%e]pyrrol-4-ones yield. 65. ReagentsScheme and 19. conditions The Van: LeusenK2CO3, EtOH,protocol 15 for min, the r.t, synthesis three outputs of [1]benzopyrano[3,4- with 72%–86% yield.e]pyrrol-4-ones 65. Reagents and conditions: K2CO3, EtOH, 15 min, r.t, three outputs with 72%–86% yield.

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[1]Benzopyrano[4,3-b]pyrrol-4-one [1]Benzopyrano[4,3-b]pyrrol-4-one Pyrrole Construction[1]Benzopyrano[4,3- b]pyrrol-4-one Pyrrole Construction Many syntheticPyrrole protoc Constructionols have been reported for the synthesis of [l]benzopyrano Many synthetic protocols have been reported for the synthesis of [l]benzopyrano [4,3-b]pyrrole-4(1HMany)-ones,synthetic including protocols the reaction have of beenβ-nitroalkenes reported 67 for and the 4-phenylamino synthesis of [l]benzopyrano [4,3-b]pyrrole-4(1H)-ones, including the reaction of β-nitroalkenes 67 and 4-phenylamino coumarins 66 [4,3-underb]pyrrole-4(1 solvent-freeH )-ones,conditions including to afford the 68 reaction (Scheme of β 20)-nitroalkenes [69]. Moreover,67 and the 4-phenylamino coumarins 66 under solvent-free conditions to afford 68 (Scheme 20) [69]. Moreover, the reaction of thecoumarins 4-aminocoumarin66 under (69 solvent-free), amines 70 conditions, and glyoxal to afford monohydrates68 (Scheme 71 20in )[the69 ]. Moreover, reaction of the 4-aminocoumarin (69), amines 70, and glyoxal monohydrates 71 in the presence of thenanocrystalline reaction of the CuFe 4-aminocoumarin2O4 [70], or (69KHSO), amines4, led70 ,to and the glyoxal formation monohydrates of 71 in the presence of nanocrystalline CuFe2O4 [70], or KHSO4, led to the formation of [l]benzopyranopresence [4,3-b]pyrrole-4(1 of nanocrystallineH)-ones CuFe 72 (Scheme2O4 [70], 21) or KHSO[71]. The4, led synthesis to the formation of 71 using of [l]benzopyrano [l]benzopyrano [4,3-b]pyrrole-4(1H)-ones 72 (Scheme 21) [71]. The synthesis of 71 using nanocrystalline[4,3- CuFeb]pyrrole-4(12O4 disclosesH)-ones a rapid,72 (Schemehigh-yielding, 21)[71 green]. The synthetic synthesis protocol of 71 using for nanocrystallinea nanocrystalline CuFe2O4 discloses a rapid, high-yielding, green synthetic protocol for a variety of chromeno[4,3-CuFe2O4 disclosesb]pyrrol-4(1 a rapid,H)-one high-yielding, derivatives green by asse syntheticmbling protocol the basic for building a variety of chromeno variety of chromeno[4,3-b]pyrrol-4(1H)-one derivatives by assembling the basic building blocks in an aqueous[4,3-b]pyrrol-4(1 mediumH using)-one derivativesnano CuFe2 byO4 assemblingas the efficient, the basic magnetically building blocksrecov- in an aqueous blocks in an aqueous medium using nano CuFe2O4 as the efficient, magnetically recoverable catalystmedium [70]. using nano CuFe2O4 as the efﬁcient, magnetically recoverable catalyst [70]. erable catalyst [70].

Scheme 20. SyntheticScheme 20. protocol Synthetic to synthesize protocol to [l]benzopyrano[4,3- synthesize [l]benzopyrano[4,3-b]pyrrole-4(1Hb)-ones]pyrrole-4(168. ReagentsH)-ones and 68. conditions Reagents: TsOH.H O, Scheme 20. Synthetic protocol to synthesize [l]benzopyrano[4,3-b]pyrrole-4(1H)-ones 68. Reagents 2 solvent-free,and 24 outputsconditions with: TsOH.H 6%–77%2O, yield.solvent-free, 24 outputs with 6%–77% yield. and conditions: TsOH.H2O, solvent-free, 24 outputs with 6%–77% yield.

Scheme 21. Synthetic protocol to synthesize [l]benzopyrano[4,3-b]pyrrole-4(1H)-ones 72. Reagents Scheme 21. SyntheticScheme protocol21. Synthetic to synthesize protocol [l]benzopyrano[4,3-to synthesize [l]benzopyrano[4,3-b]pyrrole-4(1Hb)-ones]pyrrole-4(172. ReagentsH)-ones and 72 conditions. Reagents: CuFe2O4, ◦ and conditions: CuFe2O4, H2O, 70 °C, 25 outputs with 68%–94% yield; or KHSO4, toluene, reflux, 23 H O, 70 C, 25and outputs conditions with: CuFe 68%–94%2O4, H yield;2O, 70 or °C, KHSO 25 outputs, toluene, with reﬂux, 68%–94% 23 outputs yield; or with KHSO 37%–93%4, toluene, yield. reflux, 23 2 outputs with 37%–93% yield. 4 outputs with 37%–93% yield. Many articles have found that the 4-chlorocoumarin is the key compound for the Many articles have found that the 4-chlorocoumarin is the key compound for the Many articlespreparation have offound various that [l]benzopyrano[4,3- the 4-chlorocoumarinb]pyrrol-4-ones is the key compound by Knorr- or for Fischer–Fink-type the preparation of various [l]benzopyrano[4,3-b]pyrrol-4-ones by Knorr- or Fisch- preparation reactionsof various [72,73 [l]benzopyrano[4,3-]. Albrola et al. indicatedb]pyrrol-4-ones the preparation by ofKnorr- N(α)-(2-oxo-2 or Fisch-H-l-benzopyran- er–Fink-type reactions [72,73]. Albrola et al. indicated the preparation of Molecules 2021, 26, x FORer–Fink-type PEER REVIEW4-yl)Weinreb- reactions α[72,73].-aminoamides Albrola75 fromet 4-chlorocoumarinal. indicated the (73 ) andpreparation different α-aminoacidsof 13 of 7422. N(α)-(2-oxo-2H-l-benzopyran-4-yl)Weinreb-α-aminoamides 75 from 4-chlorocoumarin N(α)-(2-oxo-2TheH-l-benzopyran-4-yl)Weinreb- reaction of 75 with various organometallicα-aminoamides compounds, 75 from 4-chlorocoumarin followed by cyclization, led to (73) and different α-aminoacids 74. The reaction of 75 with various organometallic (73) and differentthe formation α-aminoacids of [l]benzopyrano[4,3- 74. The reactionb]pyrrol-4-ones of 75 with 76various(Scheme organometallic 22)[74,75]. compounds, followed by cyclization, led to the formation of compounds, followed by cyclization, led to the formation of [l]benzopyrano[4,3-b]pyrrol-4-ones 76 (Scheme 22) [74,75]. [l]benzopyrano[4,3-b]pyrrol-4-ones 76 (Scheme 22) [74,75].

Scheme 22.22. SynthesisSynthesis of of [l]benzopyrano[4,3- [l]benzopyrano[4,3-b]pyrrol-4-onesb]pyrrol-4-ones76 from76 from 4-chlorocoumarin. 4-chlorocoumarin.Reagents Reagents and conditions and conditions: (a) i:: EtOH,(a) i:

TEA,EtOH, HCl.N(Me)OMe, TEA, HCl.N(Me)OMe, ii: CH2Cl ii:2 ,CH TEA,2Cl DCC;2, TEA, (b) DCC; i: organometallic (b) i: organometallic compounds compounds (R3M), THF, (R3 NM),2, -HTHF,2O, N ii:2, NaOEt, -H2O, ii: EtOH, NaOEt, r.t., 2EtOH, h, reﬂux, r.t., 2 1 h, reflux, nine outputs 1 h, nine with outputs 27%–92% with yield. 27%–92% yield.

On the other hand, the 4-amino-2H-benzopyran-2-one is employed as a key compound for the preparation of [l]benzopyrano[4,3-b]pyrrol-4-one [76,77]. Peng et al. synthesized a series of [l]benzopyrano[4,3-b]pyrrol-4-ones 79 via a palladium-catalyzed oxidative annulation reaction of 4-amino-2H-benzopyran-2-ones 77, with elec-

tron-withdrawing or electron-donating groups with different alkynes 78 (Scheme 23) [76]. The method utilizes simple and readily available enamines and alkynes, and employs direct Pd(II)-catalyzed oxidative annulation to synthesize [l]benzopyrano[4,3-b]pyrrol-4-ones in high yields of 72%–99%.

Scheme 23. The scope of 4-aminocoumarins in the preparation of [l]benzopyrano[4,3-b]pyrrol-4-ones 79. Reagents and conditions: Pd(OAc)2, oxidant, DMSO, 100 °C, 12 outputs with 72%–99% yield.

Recently, Yang et al. reported a one-pot, two-step reaction of 4-amino-2H-benzopyran-2-one (69) with arylglyoxal monohydrates 80 and p-toluenesulfonates 81 to afford a series of 3-alkoxy-substituted [l]benzopyrano[4,3-b]pyrrol-4-ones 82 and 83, respectively (Scheme 24) [78]. On the other hand, Yahyavi et al. described the Knoevenagle treatment of the arylglyoxals 84 with active methylene compounds and consequently an iodine-activated Michael-type reaction with 4-aminocoumarin (69) in a one-pot manner to afford disubstituted [l]benzopyrano[4,3-b]pyrrol-4-ones 85 (Scheme 24) [79].

Scheme 24. Various arylglyoxals in the synthesis of [l]benzopyrano[4,3-b]pyrrol-4-ones 82, 83, and 85. Reagents and conditions: (a) i: AcOH, reflux, 40 min; ii: an appropriate alkyl p-toluenesulfonate (TsOR2), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), toluene, reflux, 1.5 h, 14 outputs with 73%–89% yield; (b) R1=Ph, 4-CH3OC6H4, 4-CH3C6H4, 4-FC6H4, 4-ClC6H4,

Molecules 2021, 26, x FOR PEER REVIEW 13 of 22

Scheme 22. Synthesis of [l]benzopyrano[4,3-b]pyrrol-4-ones 76 from 4-chlorocoumarin. Reagents and conditions: (a) i: EtOH, TEA, HCl.N(Me)OMe, ii: CH2Cl2, TEA, DCC; (b) i: organometallic compounds (R3M), THF, N2, -H2O, ii: NaOEt, SchemeEtOH, 22. Synthesis r.t., 2 h, reflux, of [l]benzopyrano[4,3- 1 h, nine outputs bwith]pyrrol-4-ones 27%–92% yield.76 from 4-chlorocoumarin. Reagents and conditions: (a) i: Molecules 2021, 26, 483 13 of 21 EtOH, TEA, HCl.N(Me)OMe, ii: CH2Cl2, TEA, DCC; (b) i: organometallic compounds (R3M), THF, N2, -H2O, ii: NaOEt, EtOH, r.t., 2 h, reflux, 1 h, nine outputs withOn the27%–92% other yield.hand, the 4-amino-2H-benzopyran-2-one is employed as a key compound for the preparation of [l]benzopyrano[4,3-b]pyrrol-4-one [76,77]. Peng et al. syn- Onthesized theOn other thea series otherhand, of hand, the [l]benzopyrano[4,3- 4-amino-2 the 4-amino-2H-benzopyran-2-oneH-benzopyran-2-oneb]pyrrol-4-ones is 79 employed is via employed a palladium-catalyzed as as a akey key com- compound ox- poundidativefor for the the preparation preparationannulation of of [l]benzopyrano[4,3-reaction [l]benzopyrano[4,3- of 4-amino-2b]pyrrol-4-oneb]pyrrol-4-oneH-benzopyran-2-ones [ 76[76,77].,77]. Peng Peng et 77et al., al. synthesizedwith syn- elec- thesizedtron-withdrawinga series a series of [l]benzopyrano[4,3-of [l]benzopyrano[4,3- or electron-donatb]pyrrol-4-onesb]pyrrol-4-onesing groups79 withvia79 via a palladium-catalyzeddifferent a palladium-catalyzed alkynes 78 oxidative(Scheme ox- 23) an- idative[76].nulation annulation The reactionmethod reaction utilizes of 4-amino-2 simpleof 4-amino-2H -benzopyran-2-onesand readHily-benzopyran-2-ones available77 enamines, with electron-withdrawing77 and, withalkynes, elec- and em- or tron-withdrawingployselectron-donating direct or electron-donat groupsPd(II)-catalyzed withing different groups alkynesoxidative with different78 (Schemeannulation alkynes 23)[76 78]. The (Schemeto method synthesize 23) utilizes [76]. The[l]benzopyrano[4,3-simple method and readilyutilizes availablebsimple]pyrrol-4-ones and enamines read inily high andavailable yields alkynes, ofenamines 72%–99%. and employs and alkynes, direct Pd(II)-catalyzed and employs oxidativedirect annulationPd(II)-catalyzed to synthesize oxidative [l]benzopyrano[4,3- annulationb]pyrrol-4-ones to synthesize in high yields of [l]benzopyrano[4,3-72%–99%. b]pyrrol-4-ones in high yields of 72%–99%.

Scheme 23. The scope of 4-aminocoumarins in the preparation of [l]benzopyrano[4,3-b]pyrrol-4-ones 79. Reagents and conditions: Pd(OAc)2, oxidant, DMSO, 100 °C, Scheme 23. The scopeScheme of 4-aminocoumarins12 23. outputs The scope with of 72%–99% 4-aminocoumarins in the preparation yield. in of the [l]benzopyrano[4,3- preparation of b]pyrrol-4-ones 79. Reagents and ◦ conditions: Pd(OAc)2,[l]benzopyrano[4,3- oxidant, DMSO, 100b]pyrrol-4-onesC, 12 outputs 79 with. Reagents 72%–99% and yield.conditions: Pd(OAc)2, oxidant, DMSO, 100 °C, 12 outputs withRecently, 72%–99% Yangyield. et al. reported a one-pot, two-step reaction of 4-amino-2Recently,H-benzopyran-2-one Yang et al. reported ( a69 one-pot,) with two-step arylglyoxal reaction ofmonohydrates 4-amino-2H-benzopyran- 80 and Recently,p2-one-toluenesulfonates (69 ) withYang arylglyoxalet 81al. monohydratesreportedto afford a 80one-pot, anda pseries-toluenesulfonates two-step of 3-alkoxy-substitutedreaction81 to affordof a se- 4-amino-2[l]benzopyrano[4,3-riesH of-benzopyran-2-one 3-alkoxy-substitutedb]pyrrol-4-ones (69 [l]benzopyrano[4,3-) with 82 and arylglyoxal 83, respectivelyb]pyrrol-4-ones monohydrates (Scheme82 24)and [78].8380, On respectivelyand the other p-toluenesulfonateshand,(Scheme Yahyavi 24)[ 78 et]. 81 Onal. described theto other afford hand,the Knoevenagle Yahyavia etseries al.treatment described of of the the3-alkoxy-substituted arylglyoxals Knoevenagle 84 treatment with ac- [l]benzopyrano[4,3-tiveof the methylene arylglyoxalsb]pyrrol-4-ones compounds84 with and active82 and consequently methylene 83, respectively an compounds iodine-activated (Scheme and 24)consequently [78]. Michael-type On the other an reaction iodine- hand, withYahyaviactivated 4-aminocoumarin et Michael-type al. described reaction the ( 69Knoevenagle) within 4-aminocoumarina one-pottreatment mannerof the (69 )arylglyoxals in ato one-pot afford 84 manner withdisubstituted ac- to afford tive methylene[l]benzopyrano[4,3-disubstituted compounds [l]benzopyrano[4,3-b]pyrrol-4-ones and consequentlyb]pyrrol-4-ones 85 (Scheme an iodine-activated 24)85 [79].(Scheme Michael-type24)[79]. reaction with 4-aminocoumarin (69) in a one-pot manner to afford disubstituted [l]benzopyrano[4,3-b]pyrrol-4-ones 85 (Scheme 24) [79].

Scheme 24.24. VariousVarious arylglyoxalsarylglyoxals in in the the synthesis synthesis of of [l]benzopyrano[4,3- [l]benzopyrano[4,3-b]pyrrol-4-onesb]pyrrol-4-ones82, 8283,, and83, and85. Reagents85. Reagents and conditionsand condi-: (a)tions i:: AcOH, (a) i: AcOH, reﬂux, reflux, 40 min; 40 ii: min; an appropriate ii: an appropriate alkyl p -toluenesulfonatealkyl p-toluenesulfonate (TsOR2 ),(TsOR 1,8-diazabicyclo[5.4.0]undec-7-ene2), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), (DBU), toluene, reflux, 1.5 h, 14 outputs with 73%–89% yield; (b) R1=Ph, 4-CH3OC6H4, 4-CH3C6H4, 4-FC6H4, 4-ClC6H4, Schemetoluene, 24. Various reﬂux, arylglyoxals 1.5 h, 14 outputs in the with synthesis 73%–89% of [l]benzopyrano[4,3- yield; (b) R1=Ph, 4-CHb]pyrrol-4-ones3OC6H4, 4-CH 82,3 83C6,H and4, 4-FC 85. 6ReagentsH4, 4-ClC and6H condi-4, 4-BrC6H4, ◦ tions: (a)2-thienyl; i: AcOH, dimedone, reflux, 40 2-hydroxy-1,4-naphtoquinone min; ii: an appropriate alkyl barbituricp-toluenesulfonate acid, 1,3 dimethyl(TsOR2), barbituric1,8-diazabicyclo[5.4.0]undec-7-ene acid, I2, DMSO, stirring, 100 C, (DBU),7 toluene, h, 15 outputs reflux, with 1.5 15%–80%h, 14 outputs yield. with 73%–89% yield; (b) R1=Ph, 4-CH3OC6H4, 4-CH3C6H4, 4-FC6H4, 4-ClC6H4,

2.1.3. Thiophenes

Fusion of the thiophene ring with the pyrone ring of coumarin(benzopyrane) leads to three structural isomers, viz. 4H-thieno[2,3-c]chromen(benzopyran)-4-one, 4H-thieno[3,4- c]chromen(benzopyran)-4-one, and 4H-thieno[3,2-c] chromen(benzopyran)-4-one (Figure3) Molecules 2021, 26, x FOR PEER REVIEW 14 of 22

MoleculesMolecules 2021 2021, ,26 26, ,x x FOR FOR PEER PEER REVIEW REVIEW 1414 ofof 2222

4-BrC6H4, 2-thienyl; dimedone, 2-hydroxy-1,4-naphtoquinone barbituric acid, 1,3 dimethyl barbituric acid, I2, DMSO, stirring, 100 °C, 7 h, 15 outputs with 15%–80% yield. 4-BrC6H4, 2-thienyl; dimedone, 2-hydroxy-1,4-naphtoquinone barbituric acid, 1,3 dimethyl barbituric acid, I2, DMSO, 4-BrC6H4, 2-thienyl; dimedone, 2-hydroxy-1,4-naphtoquinone barbituric acid, 1,3 dimethyl barbituric acid, I2, DMSO, stirring,stirring, 100100 °C,°C, 77 h,h, 1515 outputsoutputs2.1.3. Thiophenes withwith 15%–80%15%–80% yield.yield. Fusion of the thiophene ring with the pyrone ring of coumarin(benzopyrane) leads 2.1.3.2.1.3. ThiophenesThiophenes to three structural isomers, viz. 4H-thieno[2,3-c]chromen(benzopyran)-4-one, Molecules 2021, 26, 483 FusionFusion ofof thethe thiophenethiophene ringring withwith thethe pypyronerone ringring ofof coumarin(benzopyrane)coumarin(benzopyrane)14 leadsleads of 21 4Hto-thieno[3,4- three cstructural]chromen(benzopyran)-4-one, isomers, viz. 4H-thieno[2,3- c]chromen(benzopyran)-4-one,and 4H-thieno[3,2- c] chromen(benzopyran)-4-oneto three structural isomers, (Figure viz.3) 4H-thieno[2,3-c]chromen(benzopyran)-4-one, 4H4H-thieno[3,4--thieno[3,4-cc]chromen(benzopyran)-4-one,]chromen(benzopyran)-4-one, andand 4H4H-thieno[3,2--thieno[3,2-cc]] chromen(benzopyran)-4-onechromen(benzopyran)-4-one (Figure(Figure 3)3)

FigureFigure 3. The 3. Thethree three common common isomers isomers of of the the thiophene thiophene ringring fused fused to to the theα-pyrone α-pyrone moiety moiety of coumarin. of coumarin. FigureFigure 3.3. TheThe threethree commoncommon isomersisomers ofof thethe thiophenethiophene ringring fusedfused toto thethe αα-pyrone-pyrone moietymoiety ofof coumarin.coumarin. 4H-Thieno[2,3-c]benzopyran-4-one 44HH-Thieno[2,3-c]benzopyran-4-one-Thieno[2,3--Thieno[2,3-c]benzopyran-4-onec]benzopyran-4-one Thiophene Construction ThiopheneThiophene ConstructionConstruction TheTheThe one-pot one-potone-pot cascade cascadecascadecascade addition/condensation/intramolecular addition/condensation/addition/condensation/addition/condensation/intramolecularintramolecularintramolecular cyclization cyclization cyclization sequence sequence sequence ofof of chromonechromonechromone (86((86)86) with)) withwithwith ethyl ethylethyl 2-mercaptoacetateethyl 2-mercaptoacetate2-mercaptoacetate2-mercaptoacetate (87) using ((87 a87( complexing)87) )usingusing using aa ligand complexingacomplexing complexing 1,8-diazabicyclo ligandligand ligand 1,8-diazabicyclo[5.4.0]undec-7-ene1,8-diazabicyclo[5.4.0]undec-7-ene[5.4.0]undec-7-ene1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 1,4-dioxane (DBU)(DBU) led to inin thein 1,4-dioxane formation1,4-dioxane1,4-dioxane of 4ledledH -thieno[2,3- led toto tothethe thecformationformation]benzopyran- formation ofof of 4H44-one-thieno[2,3-4HH-thieno[2,3--thieno[2,3- (88) (Schemec]benzopyran-4-onecc]benzopyran-4-one]benzopyran-4-one 25)[80]. ((8888)) ) (Scheme (Scheme(Scheme 25)25) 25) [80].[80]. [80].

SchemeScheme 25.25. 25. SynthesisSynthesisSynthesis ofof 44HH of-thieno[2,3--thieno[2,3- 4H-thieno[2,3-cc]benzopyran-4-one]benzopyran-4-onec]benzopyran-4-one ((8888).). ReagentsReagents (88). andandReagents conditionsconditions and:: conditions: Scheme1,8-diazabicyclo[5.4.0]undec-7-ene 25. Synthesis of 4H-thieno[2,3- (DBU),c]benzopyran-4-one 1,4-dioxane, 60 ◦°C, 12(88 h,). NReagents2, 95% yield. and conditions: 1,8-diazabicyclo[5.4.0]undec-7-ene1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),(DBU), 1,4-dioxane,1,4-dioxane, 6060 °C,C, 1212 h,h, NN22,, 95%95% yield.yield. 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-dioxane, 60 °C, 12 h, N2, 95% yield. PyronePyrone ConstructionConstruction PyroneThe TheConstruction Suzuki–MiyauraSuzuki–MiyauraSuzuki–Miyaura cross couplingcrosscross ofcouplingcoupling bromoarylcarboxylates ofof bromoarylcarboxylatesbromoarylcarboxylates and o-hydroxy(methoxy) andand oarylboronico-hydroxy(methoxy)arylboronic-hydroxy(methoxy)arylboronicThe Suzuki–Miyaura acids is one of the methods cross acidsacids isis that oneonecoupling plays ofof thethe an methods methods importantof thatthatbromoarylcarboxylates role playsplays in the anan important preparationimportant rolerole of and in the preparation of 4H-thieno[2,3-c] 91 and 4H-thieno[3,4-c]benzopyran-4-ones 92 o-hydroxy(methoxy)arylboronic4inH -thieno[2,3-the preparationc] 91 and of 44HH-thieno[3,4--thieno[2,3- acidsc c]benzopyran-4-onesis] one91 and of the4H -thieno[3,4-methods92 (Scheme thatc]benzopyran-4-ones plays 26)[ an81– important83]. 92 role (Scheme 26) [81–83]. in (Schemethe preparation 26) [81–83]. of 4H-thieno[2,3-c] 91 and 4H-thieno[3,4-c]benzopyran-4-ones 92 (Scheme 26) [81–83].

Scheme 26. 4H-thieno[3,4-c]benzopyran-4-ones 91 and 92 via a Suzuki–Miyaura cross coupling reaction. Reagents and conditions: SchemeScheme 26.26. 44HH-thieno[3,4--thieno[3,4-cc]benzopyran-4-ones]benzopyran-4-ones 9191 andand 9292 viavia aa ◦ Suzuki–MiyauraSuzuki–Miyaura crosscross couplingcoupling reaction.reaction. ReagentsReagents andand (a) Pd(PPh3)4 (10 mol %), Cs2CO3 (4 equiv.), DME, H2O, MW 125 C, 15 min, 86% yield; (b) i: Pd(PPh3)4 (5 mol %),K3PO4 conditions: a) Pd(PPh3)4 (10 mol %), Cs2CO3 (4 equiv.), DME, H2O, MW 125 °C, 15 min, 86% yield; (b) i: Pd(PPh3)4 (5 mol (1.5conditions equiv.),: a) 1,4-dioxane, Pd(PPh3)4 (10 90 ◦molC, 4 %), h; ii: Cs (a)2CO BBr3 (4, CHequiv.),Cl ,DME, (b) KO HtBu,2O, HMWO, 125 ﬁve °C, outputs 15 min, with 86% 75%–81% yield; (b) yield i: Pd(PPh [83]. 3)4 (5 mol %), K3PO4 (1.5 equiv.), 1,4-dioxane, 90 °C, 4 h;3 ii: (a)2 BBr2 3, CH2Cl2, (b) KO2 tBu, H2O, five outputs with 75%–81% yield [83]. %), K3PO4 (1.5 equiv.), 1,4-dioxane, 90 °C, 4 h; ii: (a) BBr3, CH2Cl2, (b) KOtBu, H2O, five outputs with 75%–81% yield [83]. Scheme 26. 4H-thieno[3,4-c]benzopyran-4-ones 91 and 92 via a Suzuki–Miyaura cross coupling reaction. Reagents and conditions: a) Pd(PPh3)4 (10 mol %), Cs2CO3 (4 equiv.), DME, H2O, MW 125 °C, 15 min, 86% yield; (b) i: Pd(PPh3)4 (5 mol 44HH-Thieno[3,4-c]benzopyran-4-one-Thieno[3,4--Thieno[3,4-c]benzopyran-4-onec]benzopyran-4-one %), K3PO4 (1.5 equiv.), 1,4-dioxane, 90 °C, 4 h; ii: (a) BBr3, CH2Cl2, (b) KOtBu, H2O, five outputs with 75%–81% yield [83]. ThiopheneThiophene ConstructionConstruction 4H-Thieno[3,4-c]benzopyran-4-one44HH-thieno[3,4--thieno[3,4--thieno[3,4-cc]benzopyran-4-ones]benzopyran-4-ones ( (9494)) werewere meanlymeanly prepared prepared throughthrough thethe GewaldGewald reactionreaction (Scheme(Scheme 27)27) [84–90].[84–90]. LowLow yieldsyields ofof 37%37% andand 48%48% werewere observedobserved usingusing thesethese Thiophenereaction (Scheme Construction 27) [84– 90]. Low yields of 37% and 48% were observed using these methods. methods.methods. 4H-thieno[3,4-c]benzopyran-4-ones (94) were meanly prepared through the Gewald reaction (Scheme 27) [84–90]. Low yields of 37% and 48% were observed using these

methods.

MoleculesMolecules 2021 2021, ,26 26,Molecules ,x x FOR FOR PEER PEER2021 REVIEW ,REVIEW26, 483 1515 ofof 2222 15 of 21

Molecules 2021, 26, x FOR PEER REVIEW 15 of 22

OO SS NN NHNH22 aa bb +O+ SS S ++ SS 88 N 88 OHOH OO OO NH2 a b OO OO + S + S 9292 8 9494 9393 8 OH O O O O Scheme 27.SchemeSchemeThe Gewald 27. 27. The The reactionGewald Gewald reaction toreaction synthesize to to synthesize synthesize 4H-thieno[3,4- 4 4HH-thieno[3,4--thieno[3,4-c]benzopyran-4-onecc]benzopyran-4-one]benzopyran-4-one (94). Reagents( (9494).). Reagents Reagents and conditionsand and : (a) 92 94 93 CNCH COOEt,conditionsconditions base;: : (b)(a) (a) NHCNCH CNCH, EtOH,2COOEt,2COOEt, 48% base; base; yield (b) (b) [85 NH NH], 37%3,3 ,EtOH, EtOH, yield 48% [48%90]. yield yield [85], [85], 37% 37% yield yield [90]. [90]. 2 Scheme 27. 3The Gewald reaction to synthesize 4H-thieno[3,4-c]benzopyran-4-one (94). Reagents and conditions: (a) CNCH2COOEt, base; (b) NH3, EtOH, 48% yield [85], 37% yield [90]. YuYu etet al.al. createdcreatedYu et al. aa creatednewnew technique atechnique new technique forfor the forthe thepreparationpreparation preparation ofof 444HHH-thieno[3,4--thieno[3,4--thieno[3,4-cc]c] [1]benzopyran-] [1]benzopyran-4(4[1]benzopyran-4(4Yu 4(4et Hal.HH)-ones )-ones)-onescreated97 9797 bya byby applyingnew applyingapplying technique achemoselective aa chemoselective chemoselectivefor the preparation reaction reactionreaction ofof thioamides of4ofH -thieno[3,4-thioamidesthioamides95 withc] 9595 α -bromoaceto- withwith α α[1]benzopyran-4(4-bromoacetophenones-bromoacetophenonesphenonesH)-ones96 (Scheme 96 9697 (Scheme (Schemeby 28applying)[ 9128) 28)]. [91]. [91].a chemoselective reaction of thioamides 95 with α-bromoacetophenones 96 (Scheme 28) [91].

Scheme 28.SchemeSchemeSynthesisScheme 28. 28. ofSynthesis Synthesis 428.H-thieno[3,4- Synthesis of of 4 4H Hof-thieno[3,4--thieno[3,4- c4]H [1]benzopyran-4(4-thieno[3,4-cc]] [1]benzopyran-4(4 c[1]benzopyran-4(4] [1]benzopyran-4(4H)-ones 97HH)-onesvia)-ones [4 +97 971] viavia via annulations. [4 [4 [4 + + 1]+ 1] 1]annulations. annulations. annulations.Reagents Re- Re- Re- and conditions: NaOH, diethylagentsagents azodicarboxylate and agentsand conditions conditions and conditions: :NaOH, (DEAD),NaOH,: NaOH, diethyl diethyl MeCN, diethyl azodicarboxylate azodicarboxylate r.t., azodicarboxylate 20 min, 17 outputs (DEAD), (DEAD), (DEAD), with MeCN, MeCN, 68%–95% r.t.,r.t., r.t., 20 20 20 yield.min, min, min, 17 17 17outputs outputs outputs with with with 68%–95%68%–95%68%–95% yield. yield. yield. A rhodium-catalyzed intramolecular transannulation reaction of alkynyl thiadiazoles A rhodium-catalyzed intramolecular transannulation reaction of alkynyl thiadia- AA rhodium-catalyzedrhodium-catalyzed98 provided 4 intramolecularHintramolecular-thieno[3,4-c][1]benzopyran-4(4 transatransannulationnnulation Hreactionreaction)-ones 99 ofof. Aalkynylalkynyl plausible thiadia-thiadia- reaction mechanism zoles 98 provided 4H-thieno[3,4-c][1]benzopyran-4(4H)-ones 99. A plausible reaction zoleszoles 9898 providedprovidedproposed 44HH-thieno[3,4--thieno[3,4- for the Rh-catalyzedcc][1]benzopyran-4(4][1]benzopyran-4(4 intramolecularHH)-ones)-ones transannulation 9999. . AA plausibleplausible of alkynylreactionreactionthiadiazoles is mechanism proposed for the Rh-catalyzed intramolecular transannulation of alkynyl mechanismmechanismthiadiazoles proposedproposedoutlined is outlined for infor (Scheme theinthe (Scheme Rh-catalyzedRh-catalyzed 29)[ 29)92 [92].]. intramolecularintramolecular transannulationtransannulation ofof alkynylalkynyl thiadiazolesthiadiazoles is is outlined outlined in in (Scheme (Scheme 29) 29) [92]. [92].

Scheme 29. A plausibleScheme reaction 29. A plausible mechanism reaction proposed mechanism for pr theoposed preparation for the preparation of 4H-thieno[3,4- of 4H-thieno[3,4-c][1] benzopyran-4(4c][1] H)-ones benzopyran-4(4H)-ones 99. Reagents and conditions: [Rh(COD)Cl]2 (5 mol %), 99. Reagents and conditions: [Rh(COD)Cl] (5 mol %), 1,10-Ferrocenediyl-bis(diphenylphosphine) (DPPF) (12 mol %), PhCl, 1,1′-Ferrocenediyl-bis(diphenylphosphine)2 (DPPF) (12 mol %), PhCl, 130 °C, 30 min, three outputs ◦ 130 C, 30 min, threewith outputs 75%–90% with yield. 75%–90% yield. SchemeScheme 29. 29. A A plausible plausible reaction reaction mechanism mechanism pr proposedoposed for for the the preparation preparation of of 4 4HH-thieno[3,4--thieno[3,4-cc][1]][1] benzopyran-4(4benzopyran-4(4HH)-ones)-ones 99 99. .Reagents Reagents and and conditions conditions: :[Rh(COD)Cl] [Rh(COD)Cl]2 2(5 (5 mol mol %), %), 1,11,1′-Ferrocenediyl-bis(diphenylphosphine)′-Ferrocenediyl-bis(diphenylphosphine) (DPPF) (DPPF) ( (1212 mol mol %), %), PhCl, PhCl, 130 130 °C, °C, 30 30 min, min, three three outputs outputs

withwith 75%–90% 75%–90% yield. yield.

Molecules 2021, 26Molecules, x FOR PEER 2021 ,REVIEW 26, x FOR PEER REVIEW 16 of 22 16 of 22 Molecules 2021, 26, 483 16 of 21 Molecules 2021, 26, x FOR PEER REVIEW 16 of 22

4H-Thieno[3,2-c][1]benzopyran-4(4H)-one4H-Thieno[3,2-c][1]benzopyran-4(4H)-one 4H-Thieno[3,2-c][1]benzopyran-4(4H)-one Thiophene4H-Thieno[3,2-c][1]benzopyran-4(4H)-one ConstructionThiophene Construction Thiophene Construction ThiopheneNumerous Construction articlesNumerous state thearticles use ofstate 4-chloro-2- the use Hof-benzopyran-3-carboxaldehydes 4-chloro-2-H-benzopyran-3-carboxaldehydes 101 101 Numerous articles state the use of 4-chloro-2-H-benzopyran-3-carboxaldehydes 101 as as aNumerous keyas articlescompounda statekey the usecompoundin of 4-chloro-2-the inpreparationH -benzopyran-3-carboxaldehydesthe preparationof a seriesof 101a of series of a key compound in the preparation of a series of 4H-thieno[3,2-c][1]benzopyran-4(4H)-ones. 4Has-thieno[3,2- a key4cH][1]benzopyran-4(4-thieno[3,2- compoundc][1]benzopyran-4(4 Hin)-ones. the This Hpreparationcompound)-ones. This was compoundof prepared a was seriesby aprepared Vilsmei-of by a Vilsmei- This compound was prepared by a Vilsmeier–Haack reaction, and the cyclization process er–Haack4H-thieno[3,2- reaction,er–Haackc][1]benzopyran-4(4 and reaction,the cyclization andH)-ones. the proc cyclization Thisess compoundwas performedprocess was was prepared through performed by a rectiona Vilsmei-through with a rection with was performed through a rection with thioglycolate or dithiane to produce 102 and 103, thioglycolateer–Haack reaction, orthioglycolate dithiane and tothe orproduce cyclizationdithiane 102 to procand produce ess103 ,was respectively 102 performed and 103 ,(Scheme respectively through 30) a [25,26,93,94].rection (Scheme with 30) [25,26,93,94]. thioglycolaterespectively or dithiane (Schemeto produce 30 102)[25 and,26 ,10393,94, respectively]. (Scheme 30) [25,26,93,94].

Scheme 30. TheSchemeScheme synthesis 30. 30. The ofTheScheme 4synthesisH synthesis-thieno[3,2- 30. of ofThe 4 4cHH][1]benzopyran-4(4H)-ones synthesis-thieno[3,2--thieno[3,2- ofc 4][1]benzopyran-4(4H)-onesH-thieno[3,2-102c][1]benzopyran-4(4H)-onesand 103 via102 102 theand andcyclization 103 103 via via the 102 the ofcy- and Vilsmeier–Haackcy- 103 via the cy- clizationclization of of Vilsmeier–Haack Vilsmeier–Haackclization of Vilsmeier–Haack products. products. Reagents◦ products. and conditionsconditions Reagents: :(a) (a)and POCl POCl conditions3, 3DMF,, DMF,: 60(a) 60 °C, POCl °C, overnight; overnight;3, DMF, 60 °C, overnight; products. Reagents and conditions: (a) POCl3, DMF, 60 C, overnight; (b) SHCH2COOR1, EtOH, base, 90% yield [25], 88% (b)(b) SHCH SHCH2COOR2COOR(b)1 ,SHCH 1EtOH,, EtOH,2 COORbase, base, 90% 90%1, EtOH, yieldyield base, [25], 88%90%88% yieldyield [94]; [25],[94]; (c) 88%(c) 1,4-dithiane-2,5-diole, 1,4-dithiane-2,5-diole, yield [94]; (c) 1,4-dithiane-2,5-diole, K2 KCO2CO3, ac-3, ac- K2CO3, ac- yield [94]; (c) 1,4-dithiane-2,5-diole, K CO , acetone, stirring, 1 h, r.t., 45 ◦C, 3 h, 85% yield. etone,etone, stirring, stirring, 1etone, 1h, h, r.t., r.t., stirring, 45 452 °C, °C,3 3 13 h, h, 85%85%r.t., 45yield.yield. °C, 3 h, 85% yield.

PyronePyrone Construction ConstructionPyronePyrone ConstructionConstruction TheThe palladium-catalyzed palladium-catalyzedTheThe palladium-catalyzedpalladium-catalyzed oxidativeoxidative carbonylation oxidativeoxidative carbonylationcarbonylation ofof 2-(thiophen-3-yl)phenol 2-(thiophen-3-yl)phenol ofof 2-(thiophen-3-yl)phenol2-(thiophen-3-yl)phenol (104 (104) ) ((104104)) underunder acid-base-freeacid-base-freeunderunder acid-base-freeacid-base-free andand mild andmild mildandconditions conditionsmild yieldedconditionsyielded the the correspondingthe yielded correspondingcorresponding the 4H -thieno[3,2- corresponding c][1] 4H4-thieno[3,2-H-thieno[3,2-benzopyran-4(44cH][1]benzopyran-4(4c][1]benzopyran-4(4-thieno[3,2-cH][1]benzopyran-4(4)-oneHH)-one (105) ( (Scheme105)) (Scheme(SchemeH)-one 31)[ 5831)( 10531)]. [58]. )[58]. (Scheme 31) [58].

Scheme 31. One-pot synthesis of 4H-thieno[3,2-c][1]benzopyran-4(4H)-one (105) by CO insertion Schemeinto phenol. 31. One-pot ReagentsSchemeScheme synthesis and 31.31. conditions One-pot of 4H: synthesis-thieno[3,2-10 mol % Pd(OAc)of c 4][1]benzopyran-4(4 4HH-thieno[3,2--thieno[3,2-2, AgOAc,cc ][1]benzopyran-4(4CH][1]benzopyran-4(43HCN,)-one 80 °C,(105) 48 by h,H 62%COH)-one)-one insertionyield. (105) (105) by by CO CO insertion insertion 2 3 ◦ into phenol. Reagentsintointo phenol.phenol. and conditions ReagentsReagents: 10andand mol conditionsconditions % Pd(OAc):: 1010 molmol, AgOAc, %% Pd(OAc)Pd(OAc) CH CN,22,, AgOAc,AgOAc, 80 °C, CHCH48 h,3CN, 62% 80 yield. °C,C, 48 48 h, h, 62% 62% yield. yield. 2.1.4. Selenophene 2.1.4. Selenophene 2.1.4. SelenopheneThe fusion2.1.4. of Selenophene the selenophene ring with the pyrone ring of coumarin leads to two structuralThe fusion isomers, ofThe Thethe fusion fusionselenopheneviz. of of the 4Hthe selenophene-selenophen[2,3- ringselenophene with the ring ringpyronec]chromen(benzopyran)-4-one with with the ring the pyrone of pyrone coumarin ring ring of coumarin leadsof coumarin toand leadstwo leads to two to struc- two structural4H-selenophen[3,2- isomers,turalstructural isomers,c]chromen(benzopyran)-4-one viz.isomers, viz. 4H4H-selenophen[2,3--selenophen[2,3- viz. 4H-selenophen[2,3- (Figurec]chromen(benzopyran)-4-onec]chromen(benzopyran)-4-one 4). c]chromen(benzopyran)-4-one and 4Hand-selenophen[3,2- and 4H-selenophen[3,2-c4H]chromen(benzopyran)-4-one-selenophen[3,2-c]chromen(benzopyran)-4-onec]chromen(benzopyran)-4-one (Figure (Figure4). 4). (Figure 4).

Figure 4. The two common isomers of the selenophene ring fused to the α-pyrone moiety of coumarin. FigureFigure 4. The 4. The two two commonFigure common 4. isomersThe isomers two of common the of selenophenethe seisomerslenophene of ring the ring fused selenophene fused to the to αthe -pyronering α-pyrone fused moiety to moiety the of α coumarin.-pyrone of cou- moiety of coumarin. marin.

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44HH-Selenophen[2,3-c]-Selenophen[2,3-c] and and [3,2-c]benzopyran-4-ones [3,2-c]benzopyran-4-ones 4H-Selenophen[2,3-AA fewfew articlesarticles c ]havehave and [3,2-discusseddiscussedc]benzopyran-4-ones thethe possibipossibilitylity ofof synthesizingsynthesizing thethe fusedfused seleno-selenophen-chromen-(benzopyran)-4-onephen-chromen-(benzopyran)-4-oneA few articles have discussed themoiety.moiety. possibility AA simplesimple of synthesizing methodmethod forfor the thethe fused synthesissynthesis selenophen- ofof sub-sub- stitutedchromen-(benzopyran)-4-onestituted 44HH-selenopheno[2,3--selenopheno[2,3- moiety.cc] ] benzopyran-4-onesbenzopyran-4-ones A simple method for108108 the is synthesisis byby thethe of substitutedtreatmenttreatment 4Hofof- 3-ethynylcoumarinsselenopheno[2,3-3-ethynylcoumarinsc] benzopyran-4-ones 107 107 with with selenium selenium 108(IV) (IV)is oxide oxide by the and and treatment concentrated concentrated of 3-ethynylcoumarins hydrobromic hydrobromic acid acid107 at at roomwithroom seleniumtemperature temperature (IV) [16,95]. oxide[16,95]. and Similarly, Similarly, concentrated 4 4HH-selenopheno-[3,2--selenopheno-[3,2- hydrobromic acidcc]benzopyran-4-ones]benzopyran-4-ones at room temperature 111 111 [16 was ,was95]. preparedSimilarly,prepared under 4underH-selenopheno-[3,2- the the same same condit conditcions]benzopyran-4-onesions using using 4-ethynylcoumarins 4-ethynylcoumarins111 was prepared 110 110. .The The underalkenyl alkenyl the deriva- deriva- same tivesconditionstives were usingwere 4-ethynylcoumarinsobtainedobtained from110from. The alkenylbromocoumarinbromocoumarin derivatives were(106( obtained106) ) fromandand 4-(trifluoromethane-bromocoumarin4-(trifluoromethane- (106sulfonyl)coumarinsulfonyl)coumarin) and 4-(triﬂuoromethane-sulfonyl)coumarin (109(109) ) byby SonogashiraSonogashira coupling.coupling. (109) All byAll Sonogashira thethe reactionreaction stepscoupling.steps werewere All carriedcarried the reaction outout inin steps situsitu from werefrom the carriedthe ststartingarting out in materialsmaterials situ from andand the until startinguntil thethe materials endend productproduct and (Schemeuntil(Scheme the 32) end32) [16,95]. [16,95]. product (Scheme 32)[16,95].

Scheme 32. Reagents and reaction conditions: a: PdCl2 (10 mol %), Ph3P (20 mol %), CuI (10 mol %), SchemeScheme 32.32. ReagentsReagents and reaction conditions :: a: a: PdCl PdCl2 2(10(10 mol mol %), %) Ph, Ph3P3 P((2020 mol mol %), % ),CuI CuI (10 (10 mol mol %), % ), terminal acetylene (1.5 equiv.), NMP, Et3N, 55 °C,◦ 20 h; b: (Ph3P)4Pd (5 mol %), CuI (20 mol %), terminalterminal acetyleneacetylene (1.5 equiv.), NMP, NMP, Et 33N,N, 55 55 °C,C, 20 20 h; h; b: b:(Ph (Ph3P)4Pd3P)4Pd (5 mol (5 mol %), %),CuI CuI (20 (20mol mol %), %), terminal acetylene (1.5 equiv.), DMF, Et3N, r.t., 20 h; c: SeO2 (2 equiv.), conc. HBr, dioxane, r.t., terminalterminal acetylene acetylene (1.5 (1.5 equiv.), equiv.), DMF, DMF, Et EtN,3N, r.t., r.t., 20 20 h; ch;: SeOc: SeO(22 equiv.),(2 equiv.), conc. conc. HBr, HBr, dioxane, dioxane, r.t., 24–48r.t., h, 24–48 h, compounds 108, four outputs3 with 68%–75% yield;2 compounds 111, four outputs with compounds24–48 h, compounds108, four outputs108, four with outputs 68%–75% with yield; 68%–75% compounds yield; compounds 111, four outputs 111, four with outputs 64%–70% with yield. 64%–70%64%–70% yield. yield. Additionally, Kirsch and his coworkers reported the synthesis of selenopheno[2,3- Additionally, Kirsch and his coworkers reported the synthesis of selenophe- c]benzopyran-4-onesAdditionally, Kirsch (115) viaand ahis multistep coworkers reaction. reported This the reaction synthesis cascade of startedselenophe- by no[2,3-c]benzopyran-4-ones (115) via a multistep reaction. This reaction cascade started Vilsmeierno[2,3-c]benzopyran-4-ones formylation of 4-hydroxycoumarine (115) via a multistep (111 ).reaction. The formylated This reaction product cascade reacted started with by Vilsmeier formylation of 4-hydroxycoumarine (111). The formylated product reacted hydroxylby Vilsmeier amine formylation to afford (113of 4-hydroxycoumarine) according to the reaction (111). conditions,The formylated which product subsequently reacted with hydroxyl amine to afford (113) according to the reaction conditions, which subse- transformedwith hydroxyl into amine 3-cyano-4-coumarinselenol to afford (113) according (114 ),to by the reﬂuxing reaction with conditions, selenium which and sodium- subse- quently transformed into 3-cyano-4-coumarinselenol (114), by refluxing with selenium borohydridequently transformed in ethanol into (Scheme 3-cyano-4-coumarinselenol 33). It was the precursor (114 of selenopheno[2,3-), by refluxing withc]benzopyran- selenium and sodiumborohydride in ethanol (Scheme 33). It was the precursor of selenophe- 4-onesand sodiumborohydride (115) as it was reactive in towardsethanol a(Scheme series of haloacids,33). It was such the as precursor chloroacetonitrile, of selenophe- ethyl no[2,3-c]benzopyran-4-ones (115) as it was reactive towards a series of haloacids, such as chloroacetoacetate,no[2,3-c]benzopyran-4-ones and chloroacetamide (115) as it was [96 reactive]. towards a series of haloacids, such as chloroacetonitrile,chloroacetonitrile, ethyl ethyl chloroacetoacetate, chloroacetoacetate, and and chloroacetamide chloroacetamide [96]. [96].

Scheme 33. Synthesis of selenopheno[2,3-c]benzopyran-4-ones (115) from 4-hydroxycoumarin. Reagents and reaction Scheme 33. Synthesis of selenopheno[2,3-c]benzopyran-4-ones (115) from 4-hydroxycoumarin. Reagents and reaction con- conditionsScheme :33. a: Synthesis POCl , DMF, of selenopheno[2,3- 84% yield; b: NHc]benzopyran-4-onesOH.HCl, 80% yield; (115 c: Se,) from NaBH 4-hydroxycoumarin., EtOH, 85% yield; Reagents d: ClCH andCN(R), reaction DMF, conditions: a: POCl3, DMF,3 84% yield; b: NH2OH.HCl,2 80% yield; c: Se, NaBH4, EtOH,4 85% yield; d: ClCH2CN(R),2 DMF, stir- ditions: a: POCl3, DMF, 84% yield; b: NH2OH.HCl, 80% yield; c: Se, NaBH4, EtOH, 85% yield; d: ClCH2CN(R), DMF, stir- stirring, r.t., 2 h, three outputs with 80%–88% yield. ring,ring, r.t., r.t., 2 2 h, h, three three outputs outputs with with 80%–88% 80%–88% yield. yield. In conclusion, since coumarins have versatile applications, the synthesis of different InIn conclusion, conclusion, since since coumarins coumarins have have versatil versatilee applications, applications, the the synthesis synthesis of of different different structuresstructures ofof thethe coumarin-based coumarin-based scaffold scaffold was was attempted. attempted. Among Among all theall heterocyclesthe heterocycles built onstructures the α-pyrone of the moiety coumarin-based of coumarin, scaffold the furan was ring attempted. is the only Among available all structure the heterocycles in nature. builtbuilt on on the the α α-pyrone-pyrone moiety moiety of of coumarin, coumarin, the the furan furan ri ringng is is the the only only available available structure structure in in nature.Thus, it Thus, has inspired it has ainspired lot of researchers a lot of resear to replacechers theto replace oxygen the atom oxygen with other atom heteroatoms. with other Widenature. varieties Thus, ofit heterocycleshas inspired werea lot constructedof researchers by ato synthetic replace pathwaythe oxygen to introduceatom with furans, other pyrroles, thiophenes, and selenophenes as a fused ring that is characterized by a single

Molecules 2021, 26, 483 18 of 21

heteroatom to the α-pyrone moiety of coumarin. The fused heterocycles that contain more than one heteroatom will be described in the next part, which we intend to publish in the future.

Author Contributions: E.R.E.-S. and G.K. collected publications and sorted them. E.R.E.-S. analyzed the literature and wrote the first draft. A.B.A. and G.K. developed the concept of the review. E.R.E.-S., A.B.A., and G.K. wrote the final draft and corrected the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: The APC was funded by MDPI. Conflicts of Interest: The authors declare no conflict of interest.

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