Overview on developed synthesis procedures of coumarin heterocycles

Considering highly valuable biological and pharmaceutical properties of coumarins, the synthesis of these heterocycles has been considered for many organic and pharmaceutical chemists. This review includes the recent research in synthesis methods of coumarin systems, investigating their biological properties and describing the literature reports for the period of 2016 to the middle of 2020. In this review, we have classified the contents based on co-groups of coumarin ring. These reported methods are carried out in the classical and non-classical conditions particularly under green condition such as using green solvent, catalyst and other procedures.


Introduction
Coumarins or benzopyran-2-ones are a group of natureoccurring lactones first derived from Tonka beans in 1820. Those compounds are valuable kinds of oxygen containing heterocycles widely found in nature, so that they have been routinely employed as herbal medicines since early ages. More than 1300 coumarin derivatives have been identified, which are mainly obtained from the secondary metabolite in green plants, fungi and bacteria [1]. This led to an incentive for researchers around the world to investigate the nature and identification of this molecule. Since the reporting of the first synthetic route in 1882, this moiety has found its place in fabric conditioners, certain perfumes and in medicinal industry especially as anti-coagulants, viz. warfarin and dicoumarol; also some others such as naturally occurring coumarins moieties have been reported (Fig. 1). Also, many synthetic coumarins with a type of pharmacophoric groups at C-3, C-4 and C-7 positions have been intensively screened for different biological properties. In recent years, there has been considerable amount of researches with coumarins being tested for anti-HIV [2,3], anticancer [4][5][6][7][8], anti-microbial [9,10], anti-tumor [6,11], antioxidant [12,13], anti-Alzheimer [14], anti-tuberculosis [15], anti-platelet activity [16], COX inhibitors [17], anti-inflammatory [18], anti-asthmatic [19], anti-viral [20] and DNA gyrase inhibitors [21].
A series of potential anticancer triazolylcoumarins 52 have been synthesized as shown in Scheme 8. The starting 3-acetamido coumarin analogs 49 were prepared by using a choice of substituted salicylaldehyde 47 and N-acetyl Scheme 3 Synthesis of coumarins containing triazole derivatives Scheme 4 Synthetic route of coumarin-derived mono-azolyl ethanols glycine 48 in the presence of acetic anhydride under microwave conditions. These coumarins 49 were then refluxed with HCl/EtOH mixture and further treated with sodium nitrite followed by sodium azide to get the desired 3-azido coumarin derivatives 50. Finally, DBCO 51 was treated with 3-azidocoumarin analogs 50 in DMSO at ambient temperature for 30 min (Scheme 8). The results showed that compound 6 (R=H, R′=OH, R″=H and R=R″=Cl, R′=H) exhibited maximum quantum yield and strong cellular uptake in the MCF-7 cell line [29].
A new class of dihydroartemisinin-coumarin hybrids 55 were synthesized via cyclization reaction of azide-coumarin derivatives 53 with alkynes 54 in the presence of CuSO 4 ·5H 2 O and sodium ascorbate in DMF (Scheme 9). Those coumarins were identified to have a great anticancer activity against two cancer cell lines (MDA-MB-231 and HT-29) [30].
The synthesis of the bis-coumarins 65 is depicted in Scheme 1. 7-Hydroxycoumarin 3 was reacted with propargylbromide 4 to obtain coumarin derivatives 5. On the other hand, 7-hydroxycoumarin 62 was also reacted with alkyl bromides 30 and then it was treated with sodium azide to get other compound required for the synthesis of the target compounds. The bis-coumarin derivatives 65 were synthesized via copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction between coumarin 5 and compound 64 (Scheme 11) [32].
Chromen-triazol 69 was readily synthesized via click reaction of tripropagyl trindane 67 with coumarin azide 68 in the presence of Cu catalyst. The acetylenic substrate 67 was prepared for a high yield using condensing propagyl amine to tricarboxylic acid 66 in the presence of carbonyldiimidazole carbonyl activating reagent in DMA (Scheme 12) [33].
The reaction of anthranilic acids 70 and cyclohexanone 71 in refluxing POCl 3 gave 1,2,3,4-tetrahydroacridines 72. Compounds 72 were treated with propargylamine in phenol to afford propargylated acridine analogs 73. On the other hand, coumarins 3 were reacted with various dibromoalkanes in the presence of anhydrous K 2 CO 3 in acetonitrile to give compounds 74. Compounds 75 were obtained via the reaction of compounds 74 with NaN 3 in EtOH. Finally, the target molecules 76 were prepared by click reaction of compounds 73 with azide analogs 75 in the presence of Et 3 N along with a catalytic amount of CuI at room temperature. Some of the products displayed the good anti-BChE activity much more active than tacrine and donepezil as the reference drugs (Scheme 13) [34]. 4β-N 3 -4′-Demethyl-epipodophyllotoxin 78 was prepared via treating 4′-demethylepipodophyllotoxin 77 with a benzene solution of hydrazoic acid in the presence of boron trifluoride etherate (BF 3 [38]. An efficient method was reported by Chen et al. for the synthesis of pyrazoline-coumarin derivatives 95 by the reaction of 3-(1-(2-bromoacetyl)-5-phenyl-4,5-dihydro-1Hpyrazol-3-yl)-2H-chromen-2-one 94 and flavone or amine at 40-50 °C. Compound 94 was obtained as a result of the condensation of 3-cinnamoyl-2H-chromen-2-one compound 92 with hydrazine 20 in EtOH at 40-60 °C followed by cyclization with 2-bromoacetic acid 93 (Scheme 18). The results of initial evaluation showed that some derivatives exhibited better TNF-α and IL-6 inhibitory activity [18].
In another attempt, Saeed et al. synthesized a large series of coumarinyl-pyrazolinyl-substituted thiazoles derivatives 7. The acetylcoumarin 37 was treated with various aldehydes 119; this afforded the chalcones 124 in excellent yields. The chalcones 124 underwent inter-molecular cyclization with thiosemicarbazide 125 in the presence of KOH; this led to smooth formation of coumarinyl pyrazolines 100. Finally, the coumarinyl pyrazolinyl 126 condensed with α-halo ketones 127 provided the coumarinyl pyrazolinyl 1,3-thiazoles 128 in good yields (Scheme 24). The results showed that all of the coumarinyl-pyrazolinyl derivatives exhibited significant mushroom tyrosinase inhibitory activities [44].
To synthesize coumarin-pyrazole carboxamide derivatives 142, coumarin-3-carboxylic acid 140 with pyrazole analogs 141 was reacted in the presence of POCl 3 in pyridine as solvent and catalyst (Scheme 28) [48]. Final products 149 were prepared via the reaction of 147 with boric acid 148 in the presence of K 2 CO 3 and PdCl 2 at ambient temperature in dioxane/water (Scheme 29). Product 149 bearing imidazole moiety showed dramatic anticancer activity against HCT116 and MCF-7 [49].
Coumarin derivatives 169 containing imidazole skeleton as potential anti-bacterial agents were synthesized from 7-hydroxy coumarin 168 by reacting with corresponding amines and triethylamine in anhydrous EtOH at reflux conditions (Scheme 36) [56].
Four donor-acceptor triphenylamine-and N-phenyl carbazole-based coumarin dyes were synthesized from the reaction of aldehydes ( 3-Imidazolyl coumarin compounds 178 were synthesized through the condensation reaction of salicylaldehyde derivatives 1 into ethyl acetoacetate 2 catalyzed followed by the [3 + 2] cycloaddition reaction of 3-acetylcoumarin 37 and 2-aminopyridine 159 catalyzed by iodine. The compounds exhibited dual efficient luminescence, which was blue fluorescence with the highest fluorescence quantum yield being more than 0.9, and also displayed favorable yellow solid-state fluorescence (Scheme 38) [58].

Coumarins containing theophylline core
Mangasuli et al. synthesized new coumarin-theophylline hybrids 181 via the reaction of theophylline 180 with the substituted 4-bromomethyl coumarin 179 in the presence of K 2 CO 3 as activated catalyst (Scheme 39). All final products have shown excellent anti-tubercular activity, and of course, electron-donating compounds displayed significant anti-microbial activity [15].

Coumarins containing quinolone core
In an interesting procedure, the reaction of various dibromides 30 with 7-hydroxy-4-methyl coumarins 3 under reflux condition yielded bis-coumarins 182 in the presence of an alkaline catalyst. The bromoalkoxy derivatives of 7-hydroxy-4-methyl coumarins 168 were prepared through the bromoalkylation of 7-hydroxy-4-methyl coumarin 3 with various dibromides 30. Finally, a complex catalyst system of KOH, KI and tetrabutyl ammonium bromide (TBAB) was developed to prepare compounds 184 and 186 in high yield. Compounds 184 and 186 were then prepared by the A simple method was developed for the synthesis of quinoline-coumarin derivatives 189 by an Ugi four-component reaction involving coumarin-3-carboxylic acid 187, 2-chloroquinoline-3-carbaldehyde derivatives 188, cyclohexyl isocyanide 8 and various amines 113 in methanol. Cytotoxic effects of all products were studied in A2780 human ovarian cancer cells (Scheme 41). Two synthesized compounds (R 1 =5,8-dimethyl and R 2 =H or m-CH 3 ) displayed more anticancer activity than other derivatives [60].  (192) and chromene-thiazol analogs (194) acetyl acetone or ethyl acetoacetate in glacial acetic acid in the presence of ammonium acetate furnished pyridine hybrids 206 (Scheme 44) [63].
The picolinonitrile derivatives 208 were prepared through the reaction of chalcone derivatives 207 with malononitrile 122 using ammonium acetate 151 in the presence of glacial acetic acid under reflux conditions (Scheme 45). The synthesized hybrids showed cytotoxic activity against liver cancer [63].
The coumarin derivative 3, having two pyridyl cores for metal coordination, was prepared by a nucleophilic substitution reaction and a subsequent Pd-catalyzed Sonogashira coupling (Scheme 46) [64].
According to Scheme 48, coumarin-based hybrids 219 were prepared via reaction between the pyridin-4(1H)-one (A) and 3-bromomethyl coumarin 218. The gathered intermediates 219 were refluxed in 50% acetone-water solution, subsequently treated with propargyl bromide or corresponding benzyl bromide in the presence of K 2 CO 3 to afford the intermediate 220. Then, the protecting group on pyridinone moiety was removed to obtain the final compounds 221 (Scheme 48) [66].
A new coumarin derivative 226 was synthesized through the condensation reaction of 8-formyl-7-hydroxycoumarin 222 with niacin hydrazide 225 under reflux conditions and used as an efficient turn-on fluorescent chemosensor for Al 3+ (Scheme 49) [67].

Coumarins containing thiazole and diazole core
A series of coumarinyl thiazoles 240 have been synthesized as shown in Scheme 30. First, the 3-(2-bromoacetyl)-2Hchromen-2-one 238 was readily synthesized through condensation between salicylaldehyde 13 and ethyl acetoacetate 2 catalyzed by piperidine and subsequent bromination. Then, condensation of intermediate 238 with various acetophenones 239 and thiosemicarbazide 125 in the presence of glacial acetic acid as catalyst led to the coumarinyl thiazole 240 (Scheme 54) [72].
In another attempt, coumarin-benzothiazole derivatives were synthesized in two steps (Scheme 59). In first step, substituted benzothiazole derivatives 264 were prepared via reacting substituted aniline 113, and potassium thiocyanate 263 in the presence of bromine in glacial acetic acid. In second step, substituted benzothiazole derivatives 264 were reacted with 4-methyl-7-(oxiran-2-ylmethoxy)-2H-chromen-2-one 261 to afforded final compounds 265 (Scheme 59). Products showed anti-inflammatory and analgesic activities. The presence of -OCH 3 and -Cl groups in 265 at C6-position of benzothiazole ring were found very important substitutions for potent activity [75].
C o u m a r i n s 2 9 6 r e a c t e d w i t h 3 -a r y l -5-(chloromethyl)-1,2,4-oxadiazole analogs 297 by using KI and K 2 CO 3 in acetone to give coumarin-1,2,4-oxadiazole hybrids 298 in good yields (Scheme 68). All synthesized compounds were screened for their anticonvulsant activities [84].
Coumarin-3-carboxamides bearing tryptamine moiety 310 were achieved in reasonable yields from the reaction of coumarin-3-carboxylic acids 187 with SOCl 2 and tryptamine in the presence of catalytic amounts of K 2 CO 3 in dry toluene under reflux condition (Scheme 73). Then, in vitro assessment of the synthesized compounds 310 revealed that most of them had notable activity toward acetylcholinesterase (AChE) [89].
The synthetic method of fused tricyclic coumarins 313 was outlined in Scheme 74. At first, a series of cyano acetamide derivatives 311 were prepared via simple reaction of amines with equivalent amount of ethylcyanoacetate 228.
Also, resorcinol 1 and ethylacetoacetate were treated under Pechmann conditions to give 7-hydroxy-4-methyl coumarin 3, and then compound 3 was treated with hexamethylenetetramine in glacial acetic acid and underwent Duff formylation, to provide 8-formyl-7-hydroxy-4-methyl coumarin 312. Subsequently, compound 312 was condensed with various N-substituted cyano acetamide derivatives 311 in the presence of Et 3 N afforded the final products 313 (Scheme 74). The biological evaluation showed that most of these molecules were potent and selective AChE inhibitors, which are 2-220 folds more potent than the positive control, galantamine [90].
The coumarin derivatives 333 were synthesized via reaction of substituted salicylaldehyde 13 and N-(substituted) phenyl malonic acid 332 through Knoevenagel condensation reaction in the presence of piperidine as catalyst (Scheme 80). All synthesized compounds showed moderate to good anti-bacterial and antifungal activities [96].
Anti-bacterial coumarins 339 were achieved in reasonable yields from one-pot, five-component sequential Knoevenagel-Ugi reaction of Meldrum's acid 338, salicylaldehyde 13, aniline 113, isocyanides 160 with aldehydes 119 in the absence of catalysts in EtOH (Scheme 82). The synthesized products displayed good anti-bacterial activities against both Gram-positive and Gram-negative strains [98]. The results showed that compound 340 could be used as a colorimetric chemosensor for Cu 2+ (Scheme 83) [99].
Dihydroxybenzyldehyde 13 was subjected to condensation reaction with Meldrum's acid in water to obtain carboxylic acid 187. It was then converted to a series of anti-austerity 7-hydroxycoumarins 341 via the condensation reaction with appropriate amines by using EDC and HOBt or HOAt (Scheme 84) [100].
Cyclobutanone oxime ester 361 reacted with coumarins 362 containing electron donating and electron withdrawing groups in the presence of iron as catalyst to give the target products 363 in moderate to good yields (Scheme 91) [107]. Also, 6-(aryl and heteryl)-4-methyl coumarins 371 were prepared according to the previous reported method, only with the difference that hydroquinone is used instead of resorcinol. The synthesized compounds 227 and 9 were tested for anti-proliferative activity against different human cancer cell lines such as SiHa, MDAMB-231, and PANC-1; some of the products displayed distinctive effects (Scheme 95) [110].

Coumarins containing alkyl and aryl groups
An effective synthesis of 2-acylated and sulfonated 4-hydroxycoumarins 373 has been achieved via the reaction of 4-hydroxycoumarin 33 with acyl chloride 372 in the presence of dry pyridine as catalyst at room temperature (Scheme 96) [111].
The preparation of coumarin-3-carboxylic acids 187 in excellent yields was realized by a triethylamine catalyzed Knoevenagel-intramolecular cyclization tandem reaction of various ortho-hydroxyaryl aldehydes 13 with Meldrum's acid 338. This method has advantages such as clean reaction conditions, using much less water as solvent, a cheap and eco-friendly catalyst, simple workup procedure and easy isolation (Scheme 97) [112].
Chaudhari and co-worker introduced calcium nitrate (Ca(NO 3 ) 2 .4H 2 O as a mild and regioselective reagent to nitration of hydroxycoumarin 374 in the presence of acetic acid at 60 °C (Scheme 98) [113]. 6,7-Dihydroxy coumarin derivatives 378 were obtained as a result of cyclization of benzene-1,2,4-triyl triacetate 376 and 1,3-diketone 2 followed by reaction with formaldehyde and appropriate amines. Also, a new series of hydroxy coumarins 380 and 381 were synthesized in one-pot procedure from the reaction of phloroglucinol 379 with propiolic acid or ethyl acetoacetate, respectively (Scheme 99). Synthesized compounds containing the CH 2 Cl group showed high antioxidants activity [114].
Hydroxy-3-arylcoumarins 384 were synthesized via a two-step strategy. The first step is a Perkin-Oglialoro condensation of various hydroxybenzaldehydes 216 and arylacetic acids 382, using potassium acetate in acetic anhydride under reflux conditions, to obtain the precursor acetoxy-3-arylcoumarins 383. The second step is hydrolysis The β-keto ester 396 was obtained using reacting p-hydroxyacetophenone 393 with ethyl 2-bromoisobutyrate 394 in the presence of K 2 CO 3 in acetonitrile, followed via reacting with diethyl carbonate in the presence of sodium hydride. The subsequent Knoevenagel condensation reaction of β-keto ester 396 into various salicylaldehydes yielded the favorite coumarin-chalcone fibrates 397. Furthermore, compounds 398 and 399 were prepared from the corresponding fibrates 397 by reduction and hydrolysis, respectively (Scheme 103) [118].
Coumarins containing a hydroxy group at positions 3, 4 or 6 (33) reacted with commercially available various substituted sulfonyl chlorides 230 in THF in the presence of triethyl amine as base to afford the desired coumarin sulfonates 421 (Scheme 109). The products were investigated for their effects on oxidative burst activity of zymosan-stimulated whole blood phagocytes using a luminol-enhanced chemiluminescence technique [124].
Anti-inflammatory coumarins with short-and longchain hydrophobic groups were obtained by oxidation reaction of compounds 444 and 447 in the presence of NaIO 4 and OsO 4 (Scheme 115) [130].
An efficient strategy for the synthesis of trifluoromethylated coumarins via visible-light photoredox catalysis was developed using fac-Ir(ppy) 3 as the photocatalyst and trifluoromethanesulfonyl chloride as the trifluoromethylation reagent under mild conditions (Scheme 117) [132].
The condensation reaction between 3-acetylcoumarin 37 with various benzene sulfonyl hydrazide derivatives 455 was carried out in the presence of acetic acid glacial in EtOH to give novel coumarin-benzenesulfonohydrazide derivatives 456 (Scheme 118) [133].
A metal-and oxidant-free photo catalysis procedure for the direct trifluoromethylation of coumarin derivatives by
The chemodosimeter 458 was prepared via the esterification of coumarin 3 using phenyl chloromethanethioate 457 and N-Ethyldiisopropylamine in CH 2 Cl 2 solvent at room temperature (Scheme 120). The compound 458 could be used to detect the concentrations of Hg 2+ in water [135].
An efficient and convenient strategy for the preparation of 3-sulfonyl coumarins 461 through ipso-cyclization/1,2-ester migration from substituted phenyl-3-phenylpropiolates 459 Coumarin derivatives 464 were prepared of 7-hydroxy-4-methyl coumarin 3 as a precursor, which was synthesized from resorcinol 1 and ethyl acetoacetate 2 in the presence of H 2 SO 4 . Further, the formed compound 3 was acylated using acetic acid in the presence of phosphorus oxychloride. Acylatedcoumarin 312 was reacted with various hydrazides 20 to afford the final compounds 464 (Scheme 124). All the compounds showed good to moderate anticancer activities against A-549, Hela, SKNSH, MCF-7 human cancer cell lines [139].
Phloroglucinol 379 was treated with ethyl cetoacetate or trifluoroacetoacetate 2 in acetic acid and catalyzed by H 2 SO 4 to give coumarin 381. Methylation of compound 381 yielded 5,7-dimethoxycoumarin 468, and then nitration of 468 obtained compound 469. Reduction of 469 yielded aminocoumarin 470 (Scheme 126). The results displayed that the target molecules can suppress colon cancer cells [5].

Tri and bis-coumarins
Zolfigol et al. developed effective methods for the synthesis of bis-coumarin derivatives 478 via the reaction between 4-hydroxycoumarin 33 with aromatic aldehydes 119 in the presence of trityl bromide (TrBr) as a homogenous and neutral organocatalyst or [Fe 3 O 4 @SiO 2 @ (CH 2 ) 3 -Im-SO 3 H]Cl (MNPs) as a heterogeneous, acidic and nano-magnetic catalyst under solvent-free conditions. The advantages of the proposed method are efficiency, generality, high yields, short reaction times, cleaner reaction profile and simplicity (Scheme 130) [144].
Biscoumarin derivatives 482 and 484 were prepared via coupling reaction of two equiv. 7-Substituent coumarin 481 and 483 in the presence of Pd catalyst in DMF (Scheme 134). Synthesized compounds showed aromatase inhibitory activities [148].

Coumarins containing furan core
Synthesis of angular furocoumarins 530, 531 and 532 and difurocoumarins 533 has been carried out starting from substituted coumarins 367 and phenyl acetylene 8 leading to the target compounds via styrylcoumarin intermediates (Scheme 149). Synthesized derivatives were evaluated for inhibition of cell proliferation of human breast carcinoma, human gastric carcinoma and human lung cancer, exhibiting anti-proliferative activity. 3-Furyl coumarin derivatives 534 were formed in one-pot four-component reaction of 4-chloro-3-formylcoumarin 308, secondary amines 244, dialkyl acetylenedicarboxylates 476 and diversely substituted isocyanides 160 in benzene under reflux conditions in reasonable yields (Scheme 150) [163].
The synthesis of furo [3,2-c]coumarins 539 was carried out via one-pot three-component reaction of two equiv. 4-hydroxycoumarin 33 and one equiv. of various aldehydes 119 in the presence of a catalytic amount of I 2 in DMSO (Scheme 153) [166].
A new and efficient method for the synthesis of furo [3,2c]coumarin derivatives 540 was developed via coppercatalyzed radical/radical cross-coupling of ketoxime
The coumarin-thiophene hybrids 545 were synthesized using the one-pot, three-component reaction of 3-acetylcoumarins 37, malononitrile 122 and elemental sulfur under MWI conditions. All the synthesized compounds 3 have high thermal stability, and they can be applicable as optical dyes (Scheme 156) [169].
Bromobenzene was reacted into indole derivative 546 under Pd(OAc) 2 as catalysis to give N-phenylindoline derivative 551. After the bromination, 551 was transformed into boronate with B(OMe) 3 . The boronate of 551 reacted directly with 6-bromo-3-thiophenylcoumarin via Suzuki coupling reaction to synthesize compound 554. The aldehyde group was reacted into the thiophene ring of 554 via Vilsmeier reagent to afford the aldehyde 555. Dye 556 was synthesized through Knoevenagel condensation of 555 into
A series of coumarin-based disperse disazo dyes 571 were synthesized by coupling reaction to 4-hydroxycoumarin 33 with diazonium salt of The studies have shown that the synthesized azo coumarins can be used in optical storage devices [174].
A series of α-aminocarbonitriles 576 were obtained via condensation reaction of 4-hydroxycoumarin 33 into malononitrile 122 and various arylaldehydes 119, which was reacted with Lawesson's reagent to give the diazaphosphinanes 577 as diastereoisomers (Scheme 163). The synthesized compounds were appraised for their cytotoxic activities in vitro against two tumor cell lines HCT-116 and MCF-7. The results display a medium cytotoxic activity for most compounds [176].
Several coumarin-substituted silver (I) N-heterocyclic carbene (NHC) complexes 582 and 585 were synthesized via the interaction of the corresponding imidazolium 583 or benzimidazolium chlorides 580 and Ag 2 O in dichloromethane at room temperature (Scheme 164). The anti-microbial activities of carbene precursors and silver NHC complexes were examined against standard strains: Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli and the fungi Candida tropicalis and Candida albicans. Results indicated that all the compounds inhibited the growth of all bacteria and fungi strains and some complexes performed good activities against various microorganisms [177].
Metal chelates 623 were prepared via reaction of compound 622 with copper and nickel acetates in MeOH. Crystallization of complex 623, when the nucleus is  tetra-iodo zinc(II) or tetra-iodo indium(III) acetate phthalocyanines 633 through the Sonogashira coupling reaction for the preparation of the coumarin-substituted phthalocyanines 634, respectively (Scheme 174) [187].
Imidazol-coumarin 639 was obtained conveniently by condensation reaction of coumarin 618 into 1H-imidazole-2-carbaldehyde 638. Subsequently, the complex Cu 2+ was also synthesized via reaction of imidazol-coumarin 639 with Cu(ClO 4 ) 2 ·6H 2 O under reflux condition (Scheme 176). The fluorescence experiments of the product to various amino acid indicated that it had good selectivity and sensitivity to GSH [189].
The target molecule 4 was prepared via a synthetic route as shown in Scheme 176. Condensation reaction 2,4-dihydroxybenzaldehyde 216 with ethyl benzoylacetate 641 catalyzed by piperidine produced compound 642 in good yield. Imination of coumarin 642 with benzhydrazide in the presence of tosic acid afforded the target molecule 643. Among various metal ions, product 643 is able to detect Cu 2+ ion by the naked eye with high selectivity and sensitivity (Scheme 177) [190].
A series of novel organoplatinum (II) complexes bearing quinoline-coumarin derivatives were first designed. The designed complexes selectively displayed obvious cytotoxicities in comparison with cisplatin for A549/DDP cells and HeLa cervical carcinoma cells (Scheme 180) [193].
A series of novel coumarin-oxime ether conjugates 679 with therapeutically interesting properties were synthesized via SN 2 reaction of bromomethyl coumarins 179 with butane-2,3-dione monoxime 678 in the presence of anhydrous K 2 CO 3 (Scheme 187). Most of the synthesis compounds exhibited notable activities with minimum inhibitory concentration (MIC) in the range of 0.04-3.12 μg/mL −1 [198].
7-Hydroxy coumar ins 62 reacted with α,ωdibromoalkanes 30 under reflux conditions in the presence of K 2 CO 3 to yield key intermediates 440 in high yield, and further reaction of 440 with commercially available compounds 680 in the presence of potassium carbonate in acetonitrile led to the target compounds 681 (Scheme 188). Donepezil-coumarin hybrids 681 were Scheme 177 Synthesis of coumarin-based multi-functional chemosensor Scheme 178 Synthesis of the ferrocene-coumarin designed as multi-target agents for the treatment of Alzheimer's disease [199].
The reaction of 7-hydroxycoumarin 62 with epichlorohydrin in the presence of K 2 CO 3 led to the formation of oxiranes 684, which on regioselective nucleophilic ring opening with a series of suitable amines such as cyclopropyl amine, butyl amine, cyclohexyl amine and morpholine in EtOH at room temperature afforded coumarinyl amino alcohols 685 with good yield (Scheme 190). The products showed significant results for its biological properties assessed in terms of decent anti-bacterial, antioxidant cytotoxicity activities [13].
Coumarin derivatives 692 were reacted with the corresponding α,ω-dibromoalkanes 30 under reflux conditions to give compounds 693. In next step, compounds 693 were treated with the appropriate amines, carbon disulfide and triethylamine in DMF to obtain coumarin-dithiocarbamate hybrids 694 (Scheme 194) [204].

Conclusions
This review article contains the effective procedures of the synthesis of several symmetrical and asymmetrical coumarins containing heterocycles core such as triazole, pyrazole and imidazole, and applications testify the strength and vitality of this area of organic chemistry. However, the challenges of discovering new symmetrical systems and of understanding their properties also continue to stimulate research in the area. As it was observed in this study, coumarins and its derivatives are energetic compounds with a wide range of biological activities.