An Overview on the Synthesis of Fused Pyridocoumarins with Biological Interest

Pyridocoumarins are a class of synthetic and naturally occurring organic compounds with interesting biological activities. This review focuses on the synthetic strategies for the synthesis of pyridocoumarins and presents the biological properties of those compounds. The synthesis involves the formation of the pyridine ring, at first, from a coumarin derivative, such as aminocoumarins, hydroxycoumarins, or other coumarins. The formation of a pyranone moiety follows from an existing pyridine or piperidine or phenol derivative. For the above syntheses, [4 + 2] cycloaddition reactions, multi-component reactions (MCR), as well as metal-catalyzed reactions, are useful. Pyridocoumarins present anti-cancer, anti-HIV, antimalarial, analgesic, antidiabetic, antibacterial, antifungal, anti-inflammatory, and antioxidant activities.


Synthetic Strategies for the Preparation of Fused Pyridocoumarins
The synthesis of fused pyridocoumarins has been achieved by two main routes. One is the formation of a pyridine moiety from a coumarin derivative. The other is the formation of a pyranone moiety from a pyridine or piperidine or phenol derivative.

Pyridine-Ring Formation
The coumarin precursors for the formation of a pyridine ring are aminocoumarins, hydroxycoumarins or other coumarin derivatives.

Reaction with α,β-Unsaturated Carbonyl Compounds (Skraup-Doebner-von Miller Reaction)
The yield of the above Skraup reaction is relatively low. Doebner and von Miller, by replacing glycerol with α,β-unsaturated ketones in the presence of an acid catalyst, increased the yield of the resulted quinoline derivatives [72,73]. The Skraup-Doebner-von Miller reaction of anilines with 3-substituted α,β-unsaturated carbonyl compounds in the presence of protic acids or Lewis acids resulted mainly in 2-substituted quinolines. Introducing an electron-withdrawing group in the α,β-unsaturated carbonyl (as is the case for 3-subsituted α,β-unsaturated esters), in the presence of TFA, reversed the regioselectivity to give 4-substituted quinolines [73]. In 1994, Heber and Berghaus reported the synthesis of fused pyridocoumarins 11a-d and the azacannabinoidal tetrahydro derivatives 12a-d [74]. The Michael reaction of 4-aminocoumarin moiety of 8a,b with the double bond of arylvinylketone 9a,b gave an intermediate enaminone, which underwent an internal cyclization to form the 1,4-dihydroadduct 10a-d. The disproportionation of the latter under the applied conditions afforded the mixture of 11a-d (26-36% yield) and 12a-d (23-45% yield) (Scheme 2). The reduction of 11a-d with NaBH 3 CN in glacial acetic acid led to the tetrahydropyrido [3,2-c]coumarins 12a-d in 70-85% yield. In 2014, Hamama et al., studied the reactions of 4-aminocoumarin (13) with α,βunsaturated ketones in ethanol/acetic acid (1:1) under reflux [47]. The outcome of those reactions is a regiochemistry reversal to Skraup-Doebner-von Miller reaction (Scheme 3). The reaction started from a Michael addition of 13 to α,β-unsaturated ketone 14 to give A and B, tautomerization of the latter to C, followed by cyclization of C and removal of water to dihydropyridocoumarin D, which by oxidation led to pyridocoumarin 15 in 58% yield. The synthesis of 17 was achieved in 76% yield by the reaction of 13 with dibenzylideneacetone (16). The similar reaction of 2,6-dibenzylidenecyclohexanone (18) resulted in pyridocoumarin 19 in 73% yield. The new compounds were tested for their antitumor activity in vitro against Ehrlich ascites carcinoma cells (EAC) and were found to be three times more toxic than 5-fluorouracile 5-FU. In 2017, Samanta and coworkers reported the Cu(OTf) 2 (10 mol%)-catalyzed synthesis of fused pyridocoumarins 22a-z from aminocoumarins 13, 23a-d and β,γ-unsaturated α-ketoesters 20a-l under solvent-free conditions, microwave irradiation and open atmosphere [75]. The reaction mechanism was similar with the above applied. A Michael addition of 4-aminocoumarin (13) to the Lewis acid, Cu(Otf) 2 , activated 20 , led to the Michael adduct C (Scheme 4). The 1,4-dihydropyridocoumarin 21 was formed by the cyclization of the latter and water elimination. Oxidation of 21 in the presence of Cu(Otf) 2 under the reaction conditions afforded the pyridocoumarin 22a. It must be mentioned that the yield of this conversion was only 19% without the presence of the catalyst.
The following year, Adib et al., synthesized a series of fused pyridocoumarins 26a-p by the reactions of 4-aminocoumarins 13, 24a (prepared in situ from 4-hydroxycoumarin and ammonium acetate) with α-azidolactones 25a-j in the presence of NaOH under heating at 60 • C for 20 min [52]. According to the mechanism proposed (Scheme 5), the aminocoumarin 13 deprotonated by NaOH and the conjugate base A added in a Michael addition to the α-azidolactone 25a to give the intermediate B under removal of a nitrogen molecule. An imine-enamine tautomerization of the latter followed by cyclization led to tricyclic intermediate C, which by water elimination and tautomerization of imine resulted in amino-substituted pyridocoumarin 26a. The synthesized compounds were evaluated for their α-glucosidase inhibitory activity and exhibited in vitro yeast α-glucosidase inhibition with IC 50 = 101.0-227.3 µM, better than the standard drug acarbose (IC 50 = 750.0 µM). Compound 26i was the most potent.
In 2019, Osyanin and coworkers received regioselectively the 3-substituted pyridocoumarins 28a-I by the reaction of 4-aminocoumarin (13), with the β-formyl substituted 4H-chromenes 27a-i in 52-74% yield [76]. The reaction proceeds through a Michael addition of 13 to the α-carbon of chromene carbaldehyde, e.g., 27i, leading to the Michael adduct A, according to their former work [77]. The condensation of the latter under cyclization possibly led to dihydropyridine B (Scheme 6). Aromatization of the pyridine ring under opening of the pyran ring furnished the final product 28i. Scheme 4. Synthesis of pyridocoumarins 22a-z by the reactions of aminocoumarins 13, 23a-d with β,γ-unsaturated α-ketoesters 20a-l in the presence of Cu(Otf) 2 under MW irradiation.

Povarov Reaction
A Povarov reaction is a Diels-Alder reaction between an N-aryl imine and an electronrich dienophile in the presence of Lewis acid as catalyst, used for the synthesis of quinolines [78][79][80][81][82]. The reaction is an inverse electron demand Diels-Alder (IEDDA). The one-pot synthesis using aromatic amine, aldehyde, and electron-rich alkene as a MCR is an advance of the Povarov reaction, leading to quinolines [83,84]. In 2008, Bodwell and coworkers prepared the 1,2,3,4-tetrahydopyridocoumarins 33a,b (36:64) from the Povarov reaction of imine 31, synthesized by the reaction of 3-aminocoumarin (29) with p-nitrobenzaldehyde (30), and the 3,4-dihydro-2H-pyran (32) in the presence of Yb(OTf) 3 as a catalyst (Scheme 7). Similar reactions of 31 with various electron-rich dienophiles resulted in the corresponding tetrahydropyridocoumarins in good yields and variable diastereomeric ratios [85]. They also prepared some of the products, such as 33a,b, by the one-pot three component version of this reaction. The reaction proceeds by an IEDDA [4 + 2] cycloaddition reaction of alkene to the imine A, catalyzed by Yb(OTf) 3 , to B, which upon tautomerization gave the products 34. Oxidation of these products led to the pyridocoumarins, e.g., 35 resulted in 36 by oxidation with bromine. Scheme 6. Synthesis of fused pyridocoumarins 28a-i by the reaction of 4-aminocoumarin (13) with β-formyl substituted 4H-chromenes 27a-i.
In 2011, Majumdar and coworkers used the BF 3 .Et 2 O (10 mol%) as a catalyst for the Povarov three-component reaction of 6-aminocoumarin (57a) with aromatic aldehydes 51 and phenylacetylene (54) to prepare the angular pyrido [3,2-f ]coumarins 58a-c [89]. The similar reaction of 7-amino-4-methylcoumarin (59a) with the anisaldehyde 51c and 54 resulted in linear pyridocoumarin 60 (Scheme 11). The intermediate imine A underwent a Diels-Alder reaction with 54 to give the dihydropyridine B. Tautomerization of the latter to C followed by oxidation by the air afforded the final product 58. In 2013, our group reported the synthesis of fused pyridocoumarins 62a-f, 63a,b and 64 under a three component Povarov-type reaction of 6-or 7-aminocoumarins 57a-f, 59a,b with n-butyl vinyl ether (61) in the presence of 10 mol% molecular iodine [90]. Iodine, a mild Lewis acid, catalyzes the reaction of 61 with the aminocoumarin 57b for the formation of the intermediate imine A (Scheme 12). The intermediate B is formed by an aza-Diels-Alder reaction of A with a second molecule of 61, under iodine catalysis, and tautomerization. Elimination of n-butanol resulted in 1,2-dihydropyridocoumarin C, which upon oxidation led to the final product 62b.
In 2014, our group used FeCl 3 as a catalyst for the three component domino reactions of 6-or 7-aminocoumarins 57 or 59 with benzaldehyde (51a) and phenylacetylene (54). The reactions were performed in toluene under reflux or under microwave irradiation at 170 • C in the presence of air or p-benzoquinone leading to the synthesis of 2,4-diphenylsubstituted fused pyridocoumarins 66, 67, 69 or 71, 72 [92]. The intermediate imine A underwent nucleophilic addition from alkynylated complex B to give propargylamine complex C. The C, through intramolecular arylation afforded the vinyl complex D, which on decomposition resulted in 1,4-dihydropyridocoumarin E. Tautomerization of the latter and oxidation by air led to pyridocoumarin 66a (Scheme 14). We had tested the new compounds as inhibitors of lipid peroxidation. Compound 66a, 67a, 69b presented 100% inhibition of antilipid peroxidation at 0.1 mM. The same year, Khan and coworkers synthesized furo-and pyrano-tetrahydropyrido [2,3-c]coumarin derivatives by the one-pot three-component reactions of 3-aminocoumarin (29) with aromatic aldehydes 30, 51 and 2,3-dihydrofuran or 3,4-dihydropyran (32) in the presence of Fe 2 (SO 4 ) 3 .xH 2 O in refluxing acetonitrile [93]. The reactions with 3,4-dihydropyran (32) resulted in tetrahydropyridocoumarins 74a-j and 75a-j as endo-exo and endo-endo diastereomeric products, respectively (Scheme 15). The 74 were the major products, while the 75 were the minor products, as established by the coupling constants of the 1 H-NMR spectra. The XRD crystallographic data of 74e revealed the endo-exo configuration. From the performed docking studies, it was found that most of the derivatives 75 present inhibition activity against human dopamine D3 receptor. The blockage of this receptor is effective for potential pharmacotherapy of several neuropsychiatric disorders.
In 2015, the same group reported an intramolecular Povarov reaction of 2-propargyloxybenzaldehydes 42, 76a-d with 3-aminocoumarins 29, 50a-f catalyzed by triflic acid (10 mol%) in acetonitrile under reflux for the synthesis of fused pyridocoumarin derivatives 45, 77a-p (Scheme 16). The structure of 45 and 77m was confirmed by X-ray diffraction analysis [94]. The plausible mechanism for this reaction is similar to the mechanism proposed in Scheme 7 with formation of intermediate imine, intramolecular Diels-Alder reaction, tautomerization and aromatization through air oxidation.  (79) in the presence of Ce(OTf) 3 as a catalyst [95] under refluxing toluene (Scheme 17). They studied the antioxidant activity of the ferrocenylcoumarin derivatives and it was found that these compounds can trap radicals and inhibit DNA oxidation. Derivatives with electron-donating group at 8-position, such as 80d, 80n, 80o, possess higher inhibitory effect on AAPH-induced oxidation of DNA.
In  (81) or diethylacetylenedicarboxylate (83) under BiCl 3 catalysis in acetonitrile at room temperature [96]. The reactions gave, stereoselectively, the endo-exo products 74, as it was established by 1 H-NMR experiments. The similar reaction with diisopropyldiazadicarboxylate (85) resulted in the fused triazinocoumarin derivatives 86a-d. A stepwise mechanism has been proposed for this reaction (Scheme 18). By the electrophilic interaction of 3,4-dihydropyran (32) to the intermediate imine A, activated as B by the Lewis acid, BiCl 3 , the intermediate C was formed. The latter underwent a ring closure in anti-mode via an intermolecular attack by the carbon-4 of coumarin ring to give the endo-exo product 74a. The synthesized compounds were evaluated for their antioxidant activity, determined by the DPPH radical scavenging activity. Compounds 84b and 86a exhibited good free radical scavenging activity, but lower than the reference compounds α-tocopherol and butylated hydroxytoluene (BHT). In 2016, Chen et al., reported the synthesis of substituted pyrido [2,3-c]coumarins 55a, 88a-x by a one-pot three-component reaction of acetophenones (mainly), aromatic aldehydes and 3-aminocoumarin (29) in the presence of equimolar amount methanesulfonic acid in refluxing acetonitrile [97]. As a plausible mechanism, they proposed the addition of enol 87a , formed in the presence of acid by the tautomerization of acetophenone 87a, to the intermediate imine A, the condensation product from 29 and benzaldehyde 51a, in an asynchronous [4 + 2] cycloaddition reaction. Subsequently, the coumarin ring of B added to the ketone carbonyl to give the intermediate C. The latter by tautomerization, elimination of water and oxidation under air resulted in the product 55a (Scheme 19).

Friedlander Reaction
Friedlander reaction is the reaction of o-aminobenzaldehydes with carbonyl compounds containing α-methylene group in the presence of base or acid, or without catalyst under heating, leading to the synthesis of quinolines [98][99][100]. For the mechanism of this reaction two routes are accepted, Schiff base formation or intermolecular aldol reaction. In both cases, a cyclodehydration follows to give quinoline.
In 2013, Siddiqui and Khan applied the Friedlander reaction of 4-amino-3-formylcoumarin (89) with active methylene carbonyl compounds 90a-m or malononitrile (91) under solventfree conditions at 80 • C in the presence of chitosan as a green catalyst to get the fused pyrido [3,2-c]coumarin 92a-n [101]. Barbituric acid (90b), Meldrum's acid (90e), 1,3-indandione (90f), dimedone (90g), 4-hydroxycoumarin (90h), ethyl acetoacetate (90k), acetylacetone (90l) were between the active methylene carbonyls. As a plausible mechanism the chitosan abstracted a hydrogen to give carbanion A, which added to the electrophilic carbon of formyl-group of B (Scheme 20). Elimination of water from the resulted specie C led to unsaturated coumarin intermediate D.  [102]. The latter was prepared by the asymmetric Sharpless dihydroxylation with AD-mix-α of 4-methyl-1 -azaseselin (95), which was formed by the aza-Claisen rearrangement and cyclization of propargylaminocoumarin 94 in the presence of CuCl in refluxing THF (Scheme 21). The substitution of 3-chlorobutyne 93 by the aminocoumarin 59a resulted in adduct 94. Compound 97 as well as analog pyran derivatives have been studied for their ant-HIV activity using the HIV-1 IIIB strain in H9 lymphocytes. It was found that 97 has an anti-HIV activity with EC 50 = 0.77 µM and therapeutic index (TI) > 42. In 2011, Majumdar and coworkers used iodine for the Claisen rearrangement and cyclization of 6-propargylaminocoumarins 102a-c and 105 to obtain selectively the angular dihydropyridocoumarins 103a-c and the pyridocoumarin 106, respectively [103]. For the mechanism, they suggested an initial formation of the iodonium The same year, our group using BF 3 .Et 2 O under microwave irradiation obtained, also selectively, the angular [5,6]-fused pyridocoumarins 108a,b through the aza-Claisen rearrangement of propargylaminocoumarins 107a,b [104]. The pyridocoumarins 110a,b were isolated similarly from the propargylaminocoumarins 109a-c. The imino-adduct A was formed through the aza-Claisen rearrangement of 107a, followed by tautomerization to B (Scheme 23). In 2013, our group utilized the Au-NPs for the catalyzed synthesis of the pyridocoumarins 108a,b and 110a,c-e in excellent yields from the propargylaminocoumarins 107a,b and 109a-d, respectively [105]. A plausible mechanism with electrophilic aromatic substitution of the benzene ring of coumarin with the activated alkyne-π complex of A to the vinyl-Au intermediate B through a 6-endo-dig cyclization is presented in Scheme 24. 1,3-H Shift under regeneration of the catalyst gave 1,2-dihydropyridocoumarin C, which by air-oxidation resulted in the isolation of [5,6]-fused pyridocoumarin. In 2014 Majumdar and Ponra synthesized the dihydropyrido [3,2-f ]coumarins 111d-j from the propargylaminocoumarins 102d-j in the presence of FeCl 3 [106]. The expected pyrido [3,2-f ]coumarins were not isolated during the above reactions. For the proposed mechanism, FeCl 3 activates the alkyne moiety of 102 to give the intermediate π-complex A (Scheme 25). An intramolecular 6-endo-dig cyclization of A produced the charged species B. Upon deprotonation of the latter, followed by an 1,3-H shift and elimination of FeCl 3 the final product 111 was formed.
In continuation of their work, the same group reported the synthesis of pyrido [3,2c]coumarins 124a-i by the AgNO 3 catalyzed cycloisomerization of 4-propargylaminocoumarins 123a-i [107]. Propargylaminocoumarins have been synthesized by the nucleophilic sub-stitution of 4-chlorocoumarins 121a-g with the propargylamine salts 122a-c (Scheme 27). Polynemoraline C (124i) is a natural product synthesized by this method. As a plausible mechanism, the alkyne moiety of 123a coordinated with silver catalyst to give intermediate A. An intramolecular attack of the enamine carbon atom to the electrophilic alkyne bond of A via a 6-endo-dig cyclization resulted in the 6-membered B. 1,3-H Shift under demetallation gave the 1,2-dihydro pyridocoumarin C, which oxidized to afford the final product 124a. Very recently, our group synthesized bis-fused pyridopyranocoumarins 128a,b, 131, 134a,b from the propargylaminocoumarin derivatives 126a,b, 127a,b, 120, 133a,b in excellent yields under Au-NPs catalyzed cycloisomerization reaction followed by air oxidation [108]. The propargylaminocoumarins have been synthesized from aminohydroxycoumarins 125a,b and 129 under propargylation with propargyl bromide (99) or 3-chloro-3-methylbutyne (93) (Scheme 28). The compounds were tested for their antioxidant and anti-AChE activities. The derivatives 128a, 132a, 134a,b presented promising anti-lipid peroxidation and anti-AChE activities.

Multi Component Reactions (MCR) of Aminocoumarin
Multicomponent reactions (MCRs) are an important method for the one-pot synthesis of organic compounds under atom economy of the three or more participating starting materials [109][110][111][112][113]. Povarov reaction, as we have mentioned earlier, is an application of MCRs for the synthesis of pyridocoumarins.

Metal-Catalyzed Reactions of Aminocoumarin Derivatives
In 2008, Majumdar and coworkers utilized the Pd-catalyzed intramolecular Heck reaction of 6-or 7-benzoylaminocoumarins 162a-c or 164a-c for the regioselective synthesis of angular 3H-pyrano [ [122]. In the case of no N-substituted amides 162a and 164a the Ag 2 CO 3 was used as a base in the place of KOAc at 160 • C (Scheme 37).  In 2017, Nath, a coworker of Majumdar, extended the former [66] regioselective Pdcatalyzed synthesis of linear 11-methyl-5H-pyrano [3,2-b]phenanthridine-5,9(6H)-diones 166a-g using Cs 2 CO 3 as a base at lower temperature, 95 • C for 6 h [124]. In the case of amidocoumarin 164a, the base was a mixture of Ag 2 CO 3 (2 equivalents) and Cs 2 CO 3 (2 equivalents) and the intramolecular Heck reaction performed at the elevated temperature of 120 • C (Scheme 39). In 2017 also, Xie, Su and coworkers synthesized 6H-chromeno [4,3-b]quinoline-6ones 170a-t by a copper-catalyzed cyclization of 4-arylaminocoumarins 169a-t using the N-methyl moiety of DMF as the source of methine group [125]. They tested N,N-dimethylacetamide and N,N-dimethylaniline as a possible source of methine moiety, obtaining low yields of the product, while N,N-diethylformamide did not give any conversion. A possible mechanism has been proposed with addition of 4-phenylaminocoumarin (169a) to the iminium salt A, generated from DMF (Scheme 40). The intermediate B formed after elimination of MeNHCH=O gave the α,β-unsaturated imine D, which upon attack from NaHSO 3 to adduct E followed by intramolecular cyclization generated the dihydropyridine intermediate F ( Recently, Ackermann and coworkers utilized 4-arylaminocoumarins 169, 171 for the synthesis of 6H-chromeno [4,3-b]quinoline-6-ones 170, 172 through electro-oxidative cyclization in the presence of DMF as a methine source in a glassy carbon (GC) anode and a platinum (Pt) cathode [126]. In the proposed mechanism, iodine radicals, generated anodically, afforded intermediate In 2019, Samanta, Kumar and coworkers reported the synthesis of substituted chromeno [4,3-b]pyridines 174a-p from 4-aminocoumarins 13, 23a-d and α-alkynyl-β-aryl nitroolefins 173a-e in the presence of copper acetate by heating in 2-methyltetrahydrofuran, as a green solvent, under aerobic conditions [127]. This reaction is a domino protocol via a [3 + 3] annulation reaction promoted by Cu(OAc) 2 , as is suggested by the authors (Scheme 42). The compounds were tested against CAG repeat RNAs that cause Hantington's disease. Derivatives 174c and 174o presented higher affinity (nanomolar) and selectivity for diseased r(CAG) exp RNA compared to regular duplex AU-paired RNA.  [128]. This method was faster and had better yields than the two-step procedure (Method B) (Scheme 43). In method B, the arylidene compounds 175a-f were formed at first and reacted under reflux in acetic acid with 120a in the presence of NH 4 OAc. It seems that 4-hydroxycoumarin (120a) reacted with NH 4 OAc to give 4-aminocoumarin, which then added to 175a-f in a Michael addition reaction type, followed by cyclization via dehydration to give the 1,4-dihydro pyridine derivatives 176a-f.
In 2009  In 2011, Shafiee and coworkers prepared 4-aminocoumarin (13) by melting of 4-hydroxycoumarin (120a) in the presence of ammonium acetate. Then, they synthesized the chromeno [4,3-b]quinoline derivatives 180a-m by the reaction of 13 with 2-arylidenecy-clohexano1,3-dione derivatives 179a-m under heating at high temperature without solvent [131]. The Michael addition of 4-aminocoumarin (13) to α,β-unsaturated compound 179 gave the intermediate A, according to the proposed mechanism (Scheme 45). Isomerization of A to B, followed by intramolecular cycloaddition to C and subsequent elimination of water resulted in the final 1,4-dihydropyridocoumarin derivatives 180. The synthesized compounds were tested for their cytotoxic activity in human cancer cell lines (Hela, K562, LS180 and MCF-7). Some of them showed moderate cytotoxic capacity and, in parallel, very low calcium channel antagonist activity. Compound 180a presented the highest antitumorial activity (IC 50 = 25.4-58.6 µM).  [132]. In the proposed mechanism, according to reference [130], a condensation of aniline (181a) with benzaldehyde (51a) gave the imine A. The intermediate B was formed by the addition of 120a to A, followed by the removal of aniline to give the benzylidene intermediate C.
Addition of aniline to C, followed by intermolecular cyclization, led to the cyclized adduct E. Elimination of water from the latter resulted in the final product 182a (Scheme 46). Oxidation of 182a with DDQ afforded the pyridocoumarin 183a. The antitumor activity of the prepared compounds was evaluated in human cancer cell lines (A-549 and MCF-7). They exhibited moderate antitumor activities with IC 50 = 0.05-100 µmol/L. Next year, Choudhury and coworkers prepared similar dihydrochromeno [4,3-b]quinoline derivatives by the multi-component reaction of 4-hydroxycoumarin (120a) with aldehydes and anilines in water catalyzed by Bi(OTf) 3 (10 mol%) under microwave irradiation [133]. For the mechanism, they proposed the 1,2-addition of aniline to the alkylidene intermediate C, for the formation of imine D, followed by 6 π electrocyclization to the intermediate E. Tautomerization of the latter led to the dihydropyridine derivative 182a (Scheme 47). When some of the above reactions were performed without solvent by conventional heating at 140 • C, for 2-4 h the chromeno [4,3-b]quinoline-6-ones 183 were received, possibly by a radical mechanism. Treatment of some of the dihydropyridocoumarin derivatives with NBS at room temperature resulted rapidly in a more clean reaction to the chromeno [4,3-b]quinoline-6-ones 183. The fluorescent properties of the synthesized compounds were studied in different solvents. It was found that derivatives 182, 184 are more fluorescent than the corresponding 183 analogs. For the transformation of the above referred solvent-free oxidation of compounds 182, 184 to the chromeno [4,3-b]quinoline-6-ones 183, the authors suggested that a radical mechanism is taking place with the parallel reduction of Bi(III) to Bi(0), as depicted in Scheme 48.  The same year, Foroumadi and coworkers synthesized the coumarin-fused dihydropyridinones 192a-i via a multi-component reaction of 4-hydroxycoumarin (120a), ammonia, aromatic aldehydes, and Meldrum's acid (90e) in refluxing propan-1-ol [139]. In the proposed mechanism, the benzylidene  [141]. Except for the products presented in Scheme 56, they also prepared analogous derivatives using two different anilines with aldehydes, or two different aldehydes with aniline or aromatic diamines with aldehydes or dialdehydes with anilines. In the proposed mechanism, the activated benzaldehyde A condensed with aniline to give imine B. The same year, Zeynizadeh and Rahmani reported the Hantzsch synthesis of 1,4dihydropyridocoumarin derivatives 176, via the multi-component reaction of 4-hydroxycoumarin, aromatic aldehydes and ammonia, in the presence of a clay magnetic nanocatalyst [(NiFe 2 O 4 @Cu)SO 2 (MMT)] resulted from the reaction of sulfonated montmorillonite SO 2 (MMT) with copper immobilized nickel ferrite (NiFe 2 O 4 @Cu) [142]. The activated with clay nanocatalyst benzaldehyde A reacted in a Knoevenagel reaction with 120a to the benzylidene adduct B, which reacted with ammonia to give the imine C. This by activation with clay reacted with a second molecule of 120a and furnished the Michael adduct D. Tautomerization of the latter led to the enamine E, which under cyclization resulted in the final product 176a (Scheme 57).  [144]. GO could be recovered and reused up to five runs without losing the catalytic activity. In the proposed mechanism, the condensation of the activated benzaldehyde A with 4-hydroxycoumarin (120a) furnished after dehydration the unstable adduct C, which underwent nucleophilic attack from p-toluidine (181b) to give intermediate D (Scheme 59). After cyclization to E and dehydration, the intermediate F oxidized in the presence of GO and finally resulted in 9-methyl-7-phenyl-6H-chromeno [4,3-b]quinoline-6-one (183o).
The same year, Lee and coworkers reported the synthesis, between other fused pyridine derivatives, of pyrido [3,2-

Synthesis with Krohnke's-Type Reaction
Krohnke's reaction is the reaction of α-pyridinium methyl ketone salts with α,βunsaturated ketones in the presence of ammonium acetate in acetic acid for the synthesis of substituted pyridines [147][148][149]. 1,3-Dicarbonyl compounds are used also in place of pyridinium salts for the synthesis of pyridines under these reactions [149].  [45]. The proposed mechanism for this reaction was the same as that presented in Scheme 62. The synthesized derivatives were evaluated for their antimicrobial properties. The antibacterial activity was checked against bacteria Escherichia coli, Salmonella typhi, Staphylococcus aureus and Bacillus subtilis. Salmonella typhimurium, Antifungal activity was tested against Aspergillus niger, Aspergillus flavus, Penicillium chrysogenum, and Fusarium moniliforme . Compounds 203b, 203d-f, 203h,  203j, 203l showed good antibacterial activity against one or more bacteria. Most of the compounds presented inhibitory effect against fungi. In 2011, Brahmbhadtt and coworkers applied Krohnke's reaction, changing the chalcone to 2-arylidene tetralones 204a-c, and synthesized the fused aza-phenanthrocoumarins 205a-l [151]. According to the proposed mechanism, the anion A formed from 4-hydroxycoumarin (120a) and ammonium acetate reacted with 204a in a Michael addition to give intermediate B (Scheme 64). Addition of ammonia furnished the adduct C, which cyclized to D, through the addition of amine-group to the coumarin carbonyl. Dehydration led to the 1,4dihydro intermediate E. Oxidation of the latter resulted in the final product 205a. Recently, the same group demonstrated the crystal structure of compound 205a [152]. All the compounds were tested for their antibacterial activity against Escherichia coli (gram − ve bacteria) and Bacillus subtilis (gram + ve bacteria) and antifungal activity against Candida albicans (Fungi). Compounds 205i-l, with chlorine atom in coumarin moiety, showed better activity against E. coli and B. subtilis. All the compounds presented moderate activity against fungi C. albicans, except compound 205e with poor activity and 205b with no activity.
In 2014, Yin and coworkers demonstrated the one-pot synthesis of pentacycle coumarin derivatives 207a-k from the multi-component reaction of 4-hydroxycoumarin (120a), 2hydroxychalcones 206a-k and aqueous ammonia in refluxing n-propanol under catalystfree conditions [153]. In the proposed mechanism, the intermediate A was In 2019, Giri and Brahmbhadtt synthesized bipyridyl-fused coumarins 209a-l by the Krohnke' reaction of 4-hydroxycoumarins 120 with chalcones 208a-c and ammonium acetate in glacial acetic acid [154]. In the proposed plausible mechanism, the intermediate B was formed by the Michael reaction of carbanion A to the chalcone 208a. Addition of ammonia to the 4-carbonyl of coumarin (Scheme 66), and not to the benzoyl carbonyl as in Scheme 62, gave the intermediate C, which cyclized to D upon nucleophilic addition of amine to the benzoyl carbonyl. Dehydration of the latter gave 1,4-dihydropyridocoumarin E, which by oxidation resulted in the final product 209a. The synthesized compounds were tested for their antimicrobial activity against grampositive bacteria (Bacillus subtilis and Staphylococcus aureus) and gram-negative bacteria (Escherichia coli and Salmonella typhimurium) and antifungal activity against Aspergillus niger and Candida albicans. Compounds 209c, 209f, 209i exhibited the better antimicrobial activity. Scheme 65. Synthesis of pentacycle coumarin derivatives 207a-k by a catalyst-free three-component reaction.

Synthesis from Various Coumarin Derivatives
In 1994, Heber and Berghaus reported the synthesis of pyridocoumarins 212a-c by the treatment of 4-aminocoumarin derivatives 210a-c with a mixture of DMF and phosphorus oxychloride under Vilsmeier conditions [74]. Reduction of 212b,c with sodium cyanoborohydride resulted in azacannabinoids 213b,c (Scheme 67).
In a Chinese patent of 2019 [164], Li, Yang and Chen referred the synthesis of pyrido [3,4-c] In 2020, Vala and coworkers performed the reaction of 3-ethylaminomethyl-4-hydroxycoumarins 259a-d with aroylmethyl pyridinium salts 261a-d in the presence of ammonium acetate and acetic acid and synthesized the 2-arylpyrido [3,2-c]coumarins 262a-p [165]. In 2013, Brahmbhatt and coworkers utilized, also, the 3-ethylaminomethyl-4-hydroxycoumarins 259a-d to synthesize in moderate yields 2-(2-oxo-2H-chromen-3-yl)-5Hchromeno [4,3-b]pyridin-5-ones 264a-l through the reaction with the pyridinium salts 263a-c, in the presence of ammonium acetate and acetic acid [43]. For the reaction pathway, decomposition of 259a resulted in the intermediate coumarin methide A, which then reacted with 263a in the presence of NH 4 OAc and AcOH to give the 1,5-dicarbonyl intermediate B. The latter was converted to the final product 264a via a Krohnke's-type reaction (Scheme 79). The new compounds 264a-l were tested for their antibacterial activity and presented potent inhibitory activity against gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus. They showed also appreciable activity against gram-negative bacteria, Escherichia coli and Salmonella typhimurium, as well as antifungal activity against Aspergillus niger and Candida albicans . Compounds 264e, 264f, 264i, 264k, 264l were found to be the more proficient. In the same presentation, Brahmbhatt and coworkers used another route for the synthesis of compounds 264a-l with the 4-chloro-3-formylcoumarins 251a-d and pyridinium salts 263a-c as starting materials [43]. The reaction of 251a and 263a resulted in the intermediate C, which then was converted to the final product 264a (Scheme 79).

Pyranone Ring Formation
The formation of a pyranone ring could be obtained using the cyclization of suitable aryl-substituted pyridine or piperidine derivatives. Phenol derivatives, also, as well as salicylaldehydes could be the starting material, resulting in the construction of the pyranone ring. An analogous starting material, the 3,5-dicyano-4-(o-methoxyphenyl) pyridines 298a-c, were used by Courts and Petrow for the synthesis of pyrido [3,4-c]coumarin 299a-c [175]. Gorlinger and coworkers, in 2006, utilized the pyridine derivative 300 to synthesize the pyrido [3,4-c]coumarin 302 by the reaction with novaldiamine (301) (Scheme 91). These compounds together with other prepared were tested for in vitro antimalarial activity against Plasmodium falciparum strain Dd2 and 3D7 [50]. Compounds 302 and 303 presented quite good activity with IC 50 = 1.1 µM, 3.4 µM and 6.2 µM, 7.0 µM, respectively. In 2007, Kelly and coworkers synthesized the natural product santiagonamine (315) using the pyridine derivative 304 (prepared from pyridine-3-carboxylic acid) as starting material, and benzaldehyde derivatives 305 or 307 (prepared from isovanillin) via a Pdcatalyzed Ullmann cross-coupling reaction [57]. After deprotection of 306, Wittig reaction of 308 to 309, bromination to 310, cyclization in the presence of TFA to the pyrido [2,3c]coumarin 311, the 312 was obtained by photocyclization. Stille reaction of 312 with allyl tributyltin gave the allyl derivative 313. Transformation of the latter with OsO 4 and sodium periodate afforded aldehyde 314, which under reductive amination with dimethylamine led to santiagonamine (315) (Scheme 92). This was the first total synthesis of santiagonamine in 12 steps from isovanillin and 2.6% overall yield.
In 1966, Pars et al., synthesized the nitrogen analogs of tetrahydrocannabinol 319 [176]. The Pechmann-type reaction of olivetol (316) with 4-carbethoxy-N-methyl-piperid-3-one hydrochloride (317) in the presence of concentrated sulfuric acid and phosphorus oxychloride resulted in the tetrahydropyrido [4,5- Mandal et al., used the piperidin-4-one derivatives 320 for the synthesis of fused tetrahydropyrido [3,4-c]coumarin derivatives 322a-c and 324a-d in order to study their fungicidal activity against Xanthomonas malvacearum, Fusarium maniliform, Rhizoctonia solanis, Powdery mildew of cucumber, Phytopthora infection of tomatoes and grey mold of beans [177]. The Pechmann reaction of 320 with m-cresol (321) or a-naphthol (323) led to the fused coumarin derivatives 322a and 324a, respectively (Scheme 94). Methylation of them with Me 2 SO 4 or MeI resulted in the N-methyl derivatives 322b or 324b, while N-acylation with acetic anhydride or propionic anhydride gave N-acyl derivatives 322c or 324c,d, respectively. Tetrahydrobenzopyridicoumarins 324 presented higher fungicidal activity than compounds 322. The substituents in the amine group led to a lowering of the fungicidal action in green plants. The phenols A derived after the base-catalyzed rearrangement of 3-carbomethoxy N-(aryloxy) pyridinium tetrafluoroborate 327a,b cyclized spontaneously to the fused pyrido [3,2-c]coumarins 124d,k, according to Abramovitch and coworkers [178]. The N-(aryloxy) pyridinium salts 327a,b were prepared by the reaction of pyridine-N-oxide 325 with the diazonium salts 326a,b in dry acetonitrile (Scheme 95).
In 2007, the fused pyrido [3,2-h]coumarin 330 and pyrido [3,2-f]coumarin 332 were prepared by our group from the reaction of triphenylphosphine (329) and DMAD (232) with quinolinol-8 (328) and quinolinol-6 (331), respectively, as starting material [179]. The coumarin skeleton is possibly produced by lactonization of the intermediate D, according to an analogous reaction of phenols by Yavari et al. [180]. Intermediate D was achieved by an 1,2-H shift and elimination of PPh 3 from C, which was formed by the reaction of intermediates A and B (Scheme 96).

Synthesis from Phenol or Salicylaldehyde Derivatives
In 1998, El-Saghier et al. reported the synthesis of dihydro pyrido [3,4-c]coumarin derivatives 335a-d starting from o-hydroxyarylidenemalononitrile 333a,c or o-hydroxyarylidenecyanoester 333b,d and ethyl 2-(4-aminosulfonylcarbanilide)acetate (334) in the presence of piperidine [181]. A transesterification of 334 with phenol followed by addition of the produced carbanion to the vinyl group is probably responsible for the formation of intermediate A. Addition of amine of benzanilide moiety to the cyano group led to the product 335a-d, as referred in the reference (Scheme 97). Possibly, these products are in the tautomeric form of 337a-d, due to the proton peak of the dihydropyridine moiety at 4.50-5.10 ppm. The same products were synthesized, also, by the reaction of coumarin-3-(4-aminosulfonyl) carbanilide (336a) or benzo[f] coumarin-3-(4-aminosulfonyl) carbanilide (336b) with malononitrile (91) or ethyl cyanoacetate (272b). Analogous coumarin derivatives were obtained also in this work from the reaction of 336a,b with some active methylene compounds.
Hosni et al., synthesized the fused pyrido [3,4-c]coumarins 339a-f with thienyl or furyl substituents and studied their anti-inflammatory and analgesic activity [49]. The stirring of propenones 338-c and malononitrile (91) in alcoholic potassium hydroxide at room temperature resulted in 338a-f via the intermediate A (Scheme 98). The compounds showed moderate potency in anti-inflammatory activity. They exhibited also analgesic activity more than the diclofenac, the standard reference. Compounds 339f and 339e were safer than diclofenac, having higher LD 50 .  348, 349a,b, 350a-c, 351 via a Pictet-Spengler condensation of 4-(2-aminoethyl)coumarins, such as 343, 347, which have a C-7 activating amino or N,N-dialkylamino group [182]. 4-(2-Aminoethyl)coumarins were prepared from the corresponding phenols by treating with methyl sulfonic acid and methyl ester 341 (Scheme 99). They studied, also, reactions of 343, 347 with 5α-androstane-3-ones. Computational modelling has been used for the new molecules, analogs to 5α-dihydrotestosterone, as a tool to study 17-oxidoreductases for intracrine, androgen metabolism. The mechanism of the Pictet-Spengler reaction is interpreted for the case of cyclohexanone with 347 through the intermediates A, B and C for the synthesis of 349b (Scheme 99).
In 1969, Sakurai and Midorikawa utilized the condensation of salicylaldehydes with active methylene compounds for the synthesis of fused benzoquinazoline derivatives [183]. In the case of ethyl acetoacetate (90k) they have synthesized the fused pyrido [3,2- The same group studied the reaction of salicylaldehydes with ethyl cyanoacetate (272b) in the presence of aldehydes 186 and ammonium acetate to obtain the aminosubstituted pyrido [3,4-c]coumarins 358a-j [185]. The reflux in ethanol was for 0.5-1. In 1987, O'Callaghan studied the reaction of salicylaldehydes with alkyl acetoacetate and excess of ammonia in acetic acid at room temperature, which yielded the dihydropyridine derivatives 365a-h and their zwitterions 364a-d. Zwitterions in solution changed slowly to the hydroxy derivatives [187]. Mild oxidation of them with 2 N HNO 3 resulted in pyrido [3,2-c]coumarin derivatives 367a-e. The same derivatives were obtained by the reaction of salicylaldehydes with alkyl 3-aminocrotonate (Scheme 103). Navarrete-Encina et al., performed, also, the reaction of salicylaldehydes with ethyl 3-aminocrotonate (368a) to get pyrido [3,4-c]coumarin 371a,b or pyrido [5,6-c]coumarin derivatives 372a-l [188]. Using acetic acid in ethanol they obtained dihydropyrido derivatives 370a,b, which upon oxidation with CrO 3 led to 371a,b. With glacial acetic acid and heating, they synthesized the pyridocoumarins 372a-l. In the proposed mechanism, a condensation of carbonyl group of salicylaldehyde (51w) with the 3-aminocrotonate 368a gave the intermediate A, which upon cyclization led to coumarin intermediate imine B (Scheme 104). In glacial acetic acid 1,4-addition of amine group of 368a to the coumarin B, followed by intramolecular cyclization of the isomer D of intermediate C to E and elimination of ammonia afforded to the dihydropyridine moiety F. Oxidation of the latter furnished the pyridocoumarin 372a. Upon 1,4-addition of the α-carbon of 3-aminocrotonate to B in acetic acid/ethanol with decreased acidity the intermediate G was formed. Intramolecular cyclization of its isomer H to tetrahydropyridine I, followed by elimination of ammonia from intermediate J, led to dihydropyridocoumarin 370a.

Conclusions
From the literature review, pyridocoumarins, naturally occurring or synthetic, were found to have interesting biological activities. The synthetic strategies for the synthesis of pyridocoumarins involve two main routes. The formation of the pyridine ring in one route is achieved from a coumarin derivative, such as aminocoumarins, hydroxycoumarins, or other coumarins. In the other route, the pyranone moiety is formed from an existing pyridine or piperidine or phenol derivative. [4 + 2] Cycloaddition reactions, multi-component reactions (MCR), as well as metal-catalyzed reactions are useful for the above syntheses. Name reactions, such as Skraup, Skraup-Doebner-von Miller, Povarov, Friedlander, and Krohnke, are useful for these syntheses.
Pyridocoumarins present anti-cancer, anti-HIV, antimalarial, analgesic, antidiabetic, antibacterial, antifungal, antioxidant, and anti-inflammatory activities. Especially, pyrido [3,4- We hope that this review will benefit researchers, not only in the field of pyridocoumarin derivatives, but generally, in the area of coumarins.
Author Contributions: The contribution of the authors is equal investigation, writing, original draft preparation, review, and editing. All authors have read and agreed to the published version of the manuscript.