HETEROCYCLES

Review | Regular issue | Vol. 87, No. 7, 2013, pp. 1415-1439
Received, 11th April, 2013, Accepted, 15th May, 2013, Published online, 27th May, 2013.
DOI: 10.3987/REV-13-768

■ Recent Application of 4-Hydroxycoumarin in Multi-Component Reactions

Ghodsi Mohammadi Ziarani* and Parvin Hajiabbasi

Department of Chemistry, Alzahra University, Vanak Square, Tehran, P.O. Box number 19938939973, Iran

Abstract

4-Hydroxycoumarin has been utilized in many heterocyclic preparations such as indole-containing compounds, furo- and pyran-annulated, and spiro-compounds. In addition, significant places of its derivatives as pharmaceutical compounds cause it more important. There are a diversity of multi-component reactions of this useful reagent which we highlight the recent reports of them in this review. Also, herein some asymmetric syntheses via 4-hydroxycoumarin is discussed.

CONTENTS
1 Introduction
2 Two-component reactions of 4-hydroxycoumarin
2.1 Two-component benzylation and propargylation of 4-hydroxycoumarin
2.2 Two-component arylation and sulfanylation of 4-hydroxycoumarin
2.3 Two-component cyclization reactions of 4-hydroxycoumarin
2.4 Two-component nucleophilic additions of 4-hydroxycoumarin
3 Three-component reactions of 4-hydroxycoumarin
3.1 Synthesis of indole-containing compounds
3.2 Synthesis of furo-annulated heterocyclic compounds
3.3 Synthesis of pyran-annulated heterocyclic compounds
3.4 Synthesis of spiro-compounds
3.5 Synthesis of 1,2-dihydroisoquinoline, benzylamino coumarin derivatives and pyrido-annulated heterocyclic compounds
4 Four-component reactions of 4-hydroxycoumarin
5 Asymmetric synthesis using 4-hydroxycoumarin
6 Conclusion
7 Acknowlegements
8 References and notes


1. INTRODUCTION
Substituted coumarin analogues have a lot of significant properties as they constitute valuable building blocks for potential pharmaceuticals such as anticoagulants,1-3 antifungal,4 pharmaceuticals including antimicrobial activity,5 and inhibiting clotting factor synthesis by interrupting the vitamin K1 epoxide cycle.6 They are also widely exist in plants, including edible vegetables and fruits7 and are used in drug discovery.8,9 Therefore, synthetic strategies involving multicomponent reactions (MCRs) attract many attentions as a powerful tool for the rapid introduction and expansive of molecular diversity.10-12
Thus, we decided to study the role of 4-hydroxycoumarin 1 in multi-component reactions and asymmetric syntheses.


2. TWO-COMPONENT REACTION OF 4-HYDROXYCOUMARIN

2.1 TWO-COMPONENT BENZYLATION AND PROPARGYLATION OF 4-HYDROXYCOUMARIN
Herein, Lewis acid-catalyzed propargylation of 1,3-dicarbonyl compounds such as 1 with propargylic alcohols 2 is demonstrated. Huang and co-workers obtained selective propargylation or allylation products 3 and 5 on the nature of propargylic alcohols using catalytic quantities of Yb(OTf)3 in a mixture of CH3NO2:dioxane (Scheme 1). This reaction is also a key step for the synthesis of multi-substituted furocoumarin 6 followed by addition of K2CO3 in a one-pot procedure (Scheme 2).13
Lewis or Brønsted acidic ionic liquid systems was studied in propargylation of 4-hydroxycoumarin 1 by Aridoss and co-workers (Scheme 1). Metallic triflates [in particular Sc(OTf)3 and Ln(OTf)3] and bismuth nitrate in imidazolium ionic liquid (ILs) such as [BMIM][PF6]/Bi(NO3)3•5H2O and [BMIM][PF6]/Sc(OTf)3 were the most effective system.14

Benzylation and propargylation of 4-hydroxycoumarin 1 was also carried out in the presence of [Ir(COD)(SnCl3)Cl(µ-Cl)]2 as Ir-Sn bimetallic catalyst in 1,2-dichloroethane (DCE). Nucleophilic substitution of propargylic alcohols with 1,3-dicarbonyl compounds was employed as the key step for the synthesis of substituted furans and pyrroles (Scheme 3).15

Two other efficient methods for benzylation of 4-hydroxycoumarin 1 using benzylic alcohols 7 were demonstrated in the Scheme 4. Compound 1 in the presence of Fe(ClO4)3•H2O in MeCN or Bi(OTf)3 in DCE were applied to synthesis anticoagulant compounds such as 4-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-1-yl)-2H-chromen-2-one (Coumatetralyl (B))16 and numerous differently substituted warfarin derivatives. Two widely used anticoagulants phenprocoumon and coumatetralyl were synthesized by applying the latter method.17

2.2 TWO-COMPONENT ARYLATION AND SULFANYLATION OF 4-HYDROXY-COUMARIN
Direct arylation of 4-hydroxycoumarins 1 with arylboronic acids 9 via C-OH bond activation was catalyzed by PdCl2 to provide 4-arylcouamrins 10 in good to excellent yields (Scheme 5).18

Direct sulfanylation of 4-hydroxycoumarins 1 with thiols 11 was performed via C-OH bond activation in the presense of Et3N in H2O at room temperature to provide 4-sulfanylcoumarins 12 (Scheme 6).19

2.3 TWO-COMPONENT CYCLIZATION REACTIONS OF 4-HYDROXYCOUMARIN
The reaction between dialkyl acetylenedicarboxylates 13 and 4-hydroxycoumarin 1 in the presence of isoquinoline was reported by Anary-Abbasinejad and co-workers to produce new fused coumarin derivatives 14 in excellent yield (Scheme 7).20 In this additional reaction between acetylene derivative and enolic system followed by δ-lactonization, isoquinoline was used as catalyst.

As demonstrated in Scheme 8, after stirring an ethanolic solution of NaOEt and 4-hydroxycoumarin 1 at room temperature, compound 15 was added and stirred for 24 h to produce new functionalized antimicrobial active furo[2,3-c]pyrazoles 16.21

A new one-pot synthesis of polycyclic structures containing nitrogen and oxygen related to eight-membered hydroquinolines 18 via tandem C-alkylation and intramolecular O-alkylation of 4-hydroxycoumarin 1 with quinolinium salts 17 (71–89%) was reported. The products were produced in excellent yields using K2CO3 at room temperature (Scheme 9).22

Propylsulfonic silica (PSS) as a reusable solid catalyst was used in a solvent-free method for the synthesis of substituted quinoline 20, 21 derivatives via Friedländer cyclization (Scheme 10). The reaction of 4-hydroxycoumarin 1, a masked β-ketoester, and o-aminobenzophenone 19 afforded tetracyclic derivative 20, the product of lactone hydrolysis-decarboxylation 21, and o-hydroxyacetophenone 22 as the main product (about 50%). 23

2.4 TWO-COMPONENT NUCLEOPHILIC ADDITION OF 4-HYDROXYCOUMARIN
Nucleophilic addition of 4-hydroxycoumarin 1 to Baylis–Hillman (BH) acetate adducts 23 in the presence of K2CO3 as base afforded the corresponding 3-substituted 4-hydroxycoumarins 24 and 25 in good yields (Scheme 11).24 In addition, 2D NMR studies showed that the reactions of adducts with ester group gave the E-isomers selectively while the BH acetate adduct with nitrile group produced
Z-isomer predominantly.

Reaction of 4-hydroxycoumarin 1 with aromatic aldehydes 26 using sulfonic acid functionalized nanoporous silica (SBA-Pr-SO3H) in EtOH/H2O was performed to prepare the α,α-bis(4-hydroxycoumarin-3-yl)toluene derivatives 27 in excellent yields (Scheme 12).25 Also catalyst-free reaction with similar procedure in aqueous media under microwave irradiation was performed by Gong and co-workers to produce the desired product 27 in high yields.26

Photochemical reaction of 4-hydroxycoumarin 1 with 3,4-dihydro-2H-pyran 28 was performed to afford 4-hydroxy-3-(oxan-3-yl)coumarin 29 whose formation was explained by considering a hydrogen shift and keto-enol isomerization from a head-tail biradical intermediate (Scheme 13).27

3. THREE-COMPONENT REACTION OF 4-HYDROXYCOUMARIN
3.1 SYNTHESIS OF INDOLE-CONTAINING COMPOUNDS
4-Hydroxycoumarin, indole, and various aliphatic and aromatic aldehydes representative of various electronic and steric conditions were employed. Thus, a new class of indole-containing antibacterial agents 31 was prepared by Yamamoto and co-workers to reveal their in vitro antibacterial activities (MIC) against Staphylococcus aureus and Enterococcus faecium including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) (Scheme 14).28 Two years later, Appendino and co-workers modified the reaction condition to produce the desired product 31 as follow: (1) CHCl3 at room temperature for 6 h, and (2) in CHCl3:H2O 1:1 at 40 ºC overnight.29

A three-component domino allylation reaction of 1H-indole-3-carbaldehyde 32 with the stabilized C-nucleophiles such as 4-hydroxycoumarin 1 as electron-rich (hetero)arenes and allylbromide 33 was reported to prepare variously functionalized indolylbutenes 34 using indium powder (Scheme 15).30

Three-component reaction of 2-formyl benzoic acid 35, ammonia and 4-hydroxycoumarin 1 or indole in aqueous medium was reported by Lin and co-workers to produce a series of isoindolinone derivatives 36 in good to excellent yields (Scheme 16).31

3.2 SYNTHESIS OF FURO-ANNULATED HETEROCYCLIC COMPOUNDS
The isocyanide-based multicomponent reaction (I-MCRs) of 4-hydroxycoumarin 1, 2-halobenzaldehyde 37, and isocyanide 38 was reported by Xu and co-workers as a key step toward furo[2,3-b]indole scaffold synthesis of compound 39 in moderate to good yields (Scheme 17).32

Three-component reaction of chromone-3-carbaldehyde 40, 4-hydroxycoumarin 1 and cyclohexyl isocyanide 41 was performed to produce furocoumarin derivatives 42. Cyclohexyl isocyanide was found to act as a masked source of cyclohexylamine in this procedure (Scheme 18).33

Regio and diastereoselective synthesis of functionalized 2,3-dihydrofuro[3,2-c]coumarins (46-48) was achieved via a one-pot three-component condensation of aromatic aldehydes 26, 4-hydroxycoumarin 1, and α-chloromethyl ketones (43-45) in refluxing n-PrOH (Scheme 19). The reaction proceeded using pyridine or a mixture of AcOH and AcONH4 as a basic catalyst.34

Functionalized phosphorus zwitterions were prepared by the reaction of 4-hydroxycoumarin 1, aldehydes 49, and tributylphosphine 50 in dry THF under nitrogen to synthesis polysubstituted furo[3,2-c]coumarins 51 in good to excellent yields via a tandem three-component reaction (Scheme 20).35

In addition M. H. Mosslemin reported a three-component reaction between 4-hydroxycoumarin 1, or 5,5-dimethyl-1,3-cyclohexandione, arylglyoxals 52, and alkyl isocyanides 53 in refluxing MeCN to afford furocoumarin or benzofuran derivatives in high yields (Scheme 21).36

3.3 SYNTHESIS OF PYRAN-ANNULATED HETEROCYCLIC COMPOUNDS
Synthesis of some pyrano[3,2-c]coumarin derivatives 55 in aqueous medium was reported by Sarma and co-workers via a three-component reaction of an isocyanide 53, dialkyl acetylenedicarboxylate 54, and 4-hydroxycoumarin 1 using a phase-transfer catalyst (PTCs) of tetrabutylammonium bromide (TBAB) as catalyst to provide pyrano[3,2-c]coumarins 55 in good yields (Scheme 22).37

In the following protocol, a selective multicomponent reaction of 4-hydroxycoumarin 1, formaldehyde 56, and α-methylstyrene 57 is illustrated in Scheme 23. Formaldehyde 56 is able to methylenate a large variety of electron-rich carbons, such as 4-hydroxycoumarin 1 which was then trapped by means of a hetero-Diels-Alder reaction with alkene 57 to produce the desired product in excellent yields.38

Synthesis and identification of pyrano[3,2-c]chromene derivatives 61 as a new class of antimicrobial and antituberculosis agents was described (Scheme 24). In this protocol β-aryloxyquinoline-3-carbaldehyde 59, malononitrile 60, 4-hydroxycoumarin 1, and a catalytic amount of piperidine in EtOH were heated under reflux to produce product 61.39

The reaction of 4-hydroxycoumarin 1, DMAD 53, and triphenylphosphite 62 afforded compound 63 (Scheme 25). This reaction proceeds by an initial addition of the 4-hydroxycoumarin conjugate base to the vinyl triphenylphosphonium salt leads to the formation of the corresponding ylide which affords compound 63 as a desirable product via a 1,2-H shift transformation by PPh3 elimination and lactonization.40 Recently the similar protocol in multicomponent reactions of dialkyl acetylenedicarboxylate with 4-hydroxycoumarin 1 in the presence of trimethyl or triphenyl phosphate (PPh3O4) was reported by Rostami-Charati and co-workers in H2O.41

Recently, 3,4-dihydropyrano[c]chromene derivatives 64 were synthesized by the reaction of 4-hydroxycoumarin 1, malononitrile 60, and aromatic aldehydes 26 in various conditions such as: (1) using microwave irradiation in aqueous K2CO3,42 (2) heating in H2O at 80 ºC without any catalyst,43 (3) heating in H2O or solvent-free neat condition at 100 ºC using tetrabutylammonium bromide (TBAB) as catalyst,44 (4) refluxing in H2O using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst,45 (5) refluxing in EtOH using catalytic amount of 4-(dimethylamino)pyridine (DMAP),46 (6) using silica gel in EtOH at room temperature,47 (7) refluxing in H2O using morpholine as catalyst,48 (8) refluxing in anhydrous EtOH using morpholine as catalyst,49 (9) refluxing in aqueous EtOH in the presence of trisodium citrate,50 (10) refluxing in EtOH in the presence of a catalytic amount of hexamethylenetetramine,51 (11) heating in H2O/EtOH in the presence of potassium sodium tartrate,52 (12) under ultrasound conditions in H2O using catalytic amount of sodium acetate,53 (13) catalyzed by 3-hydroxypropanaminium acetate (HPAA) as an ionic liquid at room temperature,54 (14) refluxing in aqueous EtOH (1:1 v/v) using silica-bonded N-propylpiperazine sodium n-propionate (SBPPSP) as a basic catalyst,55 (16) using catalytic amounts of sodium dodecyl sulfate (SDS) in aqueous medium,56 (17) in the presence of low loading of potassium phthalimide-N-oxyl (POPINO), as a new organocatalyst, in aqueous media,57 and (18) in the presence of catalytic amounts of ruthenium complexes (RuBr2(PPh3)4) (Scheme 26).58

Also 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives 66 was produced in good yields via a one-pot condensation of 4-hydroxycoumarin 1, aromatic aldehydes 26, and 5,5-dimethylcyclohexane-1,3-dione 65 in different conditions such as: (1) refluxing in H2O using sulfonic acid functionalized ionic liquids 1,3-dimethyl-2-oxo-1,3-bis(4-sulfobutyl)imidazolidine-1,3-diium hydrogen sulfate ([DMDBSI]•2HSO4),59 (2) refluxing and microwave irradiation in AcOH using molecular iodine as a catalyst,60 and (3) refluxing in EtOH using catalytic amount of heteropolyacids (HPAs) (Scheme 27).61

The reaction of 4-hydroxycoumarin 1 with Meldrum’s acid 67 and aromatic aldehydes 26 in aqueous EtOH in the presence of proline (10 mol%) as catalyst afforded 4-aryl-3,4-dihydro-2H,5H-pyrano[3,2-c]chromene-2,5-diones 68 in good yields (Scheme 28).62

3.4 SYNTHESIS OF SPIRO-COMPOUNDS
In recent years, a series of three-component procedure was performed to prepare spirooxindoles scaffold 70 by the reaction of 4-hydroxycoumarin 1 with isatin 69 and activated methylene reagent 60 in different conditions such as: (1) in the presence of a catalytic amount of triethylbenzylammonium chloride (TEBA) in H2O at 60 ºC,63 (2) polyethylene glycol (PEG) was utilized as an efficient and convenient medium,64 (3) alum [KAl(SO4)2•12H2O] was used as catalyst to afforded spirooxindoles in H2O or aqueous EtOH at rt or 60 ºC,65 (4) under microwave conditions using basic alumina as solid support,66 (5) using sulfonic acid functionalized SBA-15 (SBA-Pr-SO3H) as a nanoporous solid acid catalyst in H2O,67 and (6) in H2O using alum as catalyst at 25 or 60 °C (Scheme 29).68

Two procedure was described for the synthesis of spiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-2,6′(1′H)-diones 72 by a three-component reaction of 4-hydroxycumarin 1, isatins 69 and 1H-pyrazol-5-amines 71 as follow: (1) in the presense of p-TSA in H2O under ultrasonic irradiation,69 (2) refluxing of the reaction mixture and p-TSA in H2O for 24 h (Scheme 30).70

4-Hydroxycumarin 1, acenaphthequinone 73, malononitrile 60 reacted in the presence of Et3N as catalyst via a one-pot three component synthesis to form new spiroacenaphthylene derivatives 74 (Scheme 31).71

3.5 MISCELLANEOUS
Synthesis of 1,2-dihydroisoquinoline derivatives 76 via the three-component reaction of isoquinoline 75, isocyanides 54, and strong CH-acids such as 4-hydroxycoumarin 1 in water was reported (Scheme 32).72

Non-ionic surfactant catalyzed three-component synthesis of (benzylamino)coumarin derivative 78 was reported via Mannich type reaction in aqueous media without formation of any side product (Scheme 33). The mixture of secondary amines 77, aromatic aldehyde 26, and 4-hydroxycoumarin 1 were taken in water at room temperature using non-ionic surfactant triton X-100 (C14H22O(C2H4O)n). Non-ionic surfactant (triton X-100) is a valuable surfactant to form a stable colloidal medium which stabilizes imine intermediate to increase the speed of reaction in water.73

A chemoselective synthesis of poly-substituted pyrido[2,3-d]pyrimidines 80 and 81 is accomplished via a microwave-assisted three-component reaction. Aldehyde 26, 2,6-diaminopyrimidin-4(3H)-one 79, and 4-hydroxycoumarin 1 were taken under microwave irradiation to show solvent nature on chemoselectivity such as: (1) in DMF at 140 °C to produce 10-amino-7-aryl-7,12-dihydro-6H-chromeno[3′,4′:5,6]pyrido[2,3-d]pyrimidine-6,8(9H)-diones 80 and (2) in AcOH and DMF at 140 °C to produce 2-amino-5-aryl-6-(2-hydroxybenzoyl)-5,8-dihydropyrido[2,3-d]pyrimidine-4,7(3H,6H)-dione 81 (Scheme 34).74

One-pot reaction of 4-hydroxycoumarin 1 and aromatic aldehydes 26 with 2-aminobenzimidazole 82, 3-amino-1H-1,2,4-triazole 83, or 6-aminouracil 84 in MeCN using sulfamic acid as catalyst led to a chemoselective synthesis of chromeno[4,3-d]pyrimidine-6-one 85, triazolo[1,5-a]pyrimidin-5-one 86, and pyrido[2,3-d]pyrimidine-2,4,7-trione derivatives 87, respectively, in good yields (Scheme 35).75

As illustrated in the Scheme 35, three-component reaction of aromatic aldehyde 26, 6-aminoquinoline 88 and 4-hydroxycoumarin 1 in H2O, under microwave irradiation was achieved to synthesize chromeno[3,4-b][4,7]phenanthroline derivatives 89 (Scheme 36).76

Sulfonic acid functionalized ionic liquid L-2-(hydroxymethyl)-1-(4-sulfobutyl) pyrrolidinium hydrogen sulfate [HYSBPI]·HSO4 catalyzed synthesis of coumarin derivatives 91 via a three-component condensation of 4-hydroxycoumarin 1, aldehydes 26 and aromatic amines 90 in H2O under microwave irradiation condition in excellent yields. The product 91 had weak-to-good antitumor activities and their IC50 ranged from 0.05 to more than 100 µmol·L−1 (Scheme 37).77

Three-component reaction of aromatic aldehydes 26, 4-hydroxycoumarins 1 and diverse pyrazolone derivatives 93 under ultrasonic irradiation in H2O was described to produce 3-substituted chroman-2,4-diones 94 which found out to be an edaravone moiety represent an exploitable source of brand anticancer agents (Scheme 38).78

The unusual formation of 4-oxo-2-aryl-4H-chromene-3-carboxylate (flavone-3-carboxylate) derivatives 96 was achieved from the treatment of 4-hydroxycoumarins 1, β-nitroalkenes 95 in an alcoholic medium using Et3N (Scheme 39). The transformation arises via the following processes: in situ Michael addition and then the alkoxide ion mediated rearrangement of the intermediate.79

L-Proline was utilized as catalyst in the three-component reaction of salicylaldehyde 97, 1,3-cyclohexanedione 65 and a sulfur, carbon, or nitrogen-based nucleophile (such as 4-hydroxycoumarin 1, 2-hydroxy-1,4-naphthoquinone and barbituric acid) to generate various substituted 4H-chromene derivative 98 in good to excellent yields in ethanol under mild and metal-free condition (Scheme 40). Replacing L-proline with other acids or bases resulted in the formation of many side products.80

A three-component reaction of 4- hydroxycoumarin 1, aldehydes 26 and naphthol 99 in the presence of piperidine 100 as catalyst under microwave irradiation is described by Mohammed and co-workers (Scheme 41).81

In addition aryl aldehydes, 4-hydroxycoumarin 1, and acetonitrile as another reagent reacted to synthesize 3-[(acetylamino)(aryl)methyl]-4-hydroxycoumarins via two following procedures: (1) in the presence of chlorosulfonic acid,82 and (2) using phosphorus pentoxide and hexamethyldisiloxane (P2O5-HMDS) (Scheme 42).83

4. FOUR-COMPONENT REACTION OF 4-HYDROXYCOUMARIN
2′-Aminospiro[11H-indeno[1,2-b]quinoxaline-11,4′-[4H]pyran] derivatives 104 was synthesized in good yields in the presence of NH4OAc as a neutral catalyst via a one-pot four-component reaction of ninhydrin 102, benzene-1,2-diamine 103, malono derivatives 60, and α-methylenecarbonyl compounds 1 (Scheme 43).84

Miri and co-workers synthesized chromeno[4,3-b]quinoline derivatives 107 and tested their cytotoxic activity on human cancer cell lines. In this protocol 1,3-cyclohexadione 65 and aryl aldehydes 26 yield 2-benzylidene-cyclohexane-1,3-dione derivatives 105 (80-90%). In the other hand, a mixture of 4-hydroxycoumarin 1 and ammonium acetate were stirred at 200-210 ºC for 30 min to produce 4-aminocoumarin 106 which reacted with 2-benzylidene-cyclohexane-1,3-dione derivatives 105 to afford chromeno[4,3-b]quinoline derivatives 107 in 30-50% yield (Scheme 44).85

One-pot four-component reaction of arylhydrazine/hydrazine hydrate 108, ethyl acetoacetate 109, aromatic aldehydes 26 and 4-hydroxycoumarin 1 in H2O and glacial AcOH as catalyst was reported by Das and co-workers (Scheme 45).86

A synthetic method for the densely substituted 3-arylaminoacrylates 113 was developed via the one-pot reaction of arylamines 111, methyl propiolate 112, aromatic aldehydes 26, and 4-hydroxycoumarin 1 (Scheme 46). The key step of the reaction involve the formation of α,β-enamino ester followed by a sequential Michael addition to prepare the arylidene dicarbonyl compound.87

5. ASYMMETRIC SYNTHESIS VIA 4-HYDROXYCOUMARIN
Intramolecular domino Knoevenagel-hetero-Diels-Alder reaction of 1,3-diketones 1 and O-propargylated sugar aldehyde 114 in the presence of 0.3 equiv of CuI and a stoichiometric amount of triethylamine resulted in the formation of a stereoselective synthesis of sugar-annulated furo[3,2-b] pyrano[4,3-d]pyran derivatives 115 in good yields (Scheme 47).88

Enantioselective organocatalytic reaction of 4-hydroxycoumarin 1 with α,β-unsaturated aldehydes 116 was performed by Rueping and co-workers (Scheme 48). Diarylprolinol ether 117 catalyzed Michael addition-acetalization of 4-hydroxycoumarin 1 with α,β-unsaturated aldehydes 116 led to chromenones 118 in good yields and high enantioselectivities.89

A Diastereoselective sequential one-pot, two-step tandem reaction of aromatic aldehyde 26, 4-hydroxycoumarin 1 and α-phenacyl bromide or p-nitrobenzyl bromide 119 with triethylamine and pyridine as catalyst was proceeded in boiling acetonitrile (Scheme 49). The reaction based on Michael addition and intramolecular cyclization of pyridinium ylide formed in situ. Diastereoselective formation of trans-2,3-dihydrofuran derivatives 120 due to steric hindnace in the cyclization step confirmed by the analysis of the vicinal coupling constant of the two methine protons and further confirmed by the X-ray analysis. 2,3-Dihydrofuro[3,2-c]chromen-4-ones is a natural product that have various biological activities.90

A one-pot diastereoselective multi-comoponent reaction of aromatic aldehydes 26, 4-hydroxycoumarin 1, and α-tosyloxyacetophenones 121 in the presence of pyridine and triethylamine as catalysts was achieved to synthesize differently substituted trans-2,3-dihydrofuro[3,2-c]coumarins 122 (Scheme 50). In this protocol, α-tosyloxyacetophenones may be generated in situ from acetophenones and [hydroxyl(tosyloxy)iodo]benzene (HTIB, Koser's reagent), avoiding the use of α-haloacetophenones.91

6. CONCLUSION
In summary, we gave an overview on two, three, and four-component reaction of 4-hydroxycoumarin as a useful skeletal motif. In addition, research on MCRs is an opportunity in the field of green organic reactions or green chemistry due to minimizing waste of cost and time. These are also valuable factors in the chemical and pharmaceutical industries. From the reported results it can be concluded that substituted coumarin analogues has a significant place due to their diversity of organic compounds synthesis.

7. ACKNOWLEGEMENTS
We gratefully acknowledge for financial support of Alzahra University Research Council.

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