An Overview of the Synthesis of 3,4-Fused Pyrrolocoumarins of Biological Interest

Abstract

3,4-Fused pyrrolocoumarins, synthetically prepared or naturally occurring, possess interesting biological properties. In this review, the synthetic strategies for the synthesis of the title compounds are presented along with their biological activities. Two routes are followed for that synthesis. In one, the pyrrole ring is formed from coumarin derivatives, such as aminocoumarins or other coumarins. In the other approach, the pyranone moiety is built from an existing pyrrole derivative or through the simultaneous formation of coumarin and pyrrole frameworks. The above syntheses are achieved via 1,3-dipolar cycloaddition reactions, Michael reaction, aza-Claisen rearrangement reactions, multi-component reactions (MCR), as well as metal-catalyzed reactions. Pyrrolocoumarins present cytotoxic, antifungal, antibacterial, α-glucosidase inhibition, antioxidant, lipoxygenase (LOX) inhibition, and fluorescent activities, as well as benzodiazepine receptor ability.

1. Introduction

Coumarin derivatives are widely found in nature, coming as secondary metabolites from trees, plants, and microorganisms [1,2,3,4,5,6,7,8,9]. Both natural and synthetic coumarin derivatives present a wide range of biological properties [10,11,12,13,14,15], such as anticancer [16,17], anti-HIV [18,19], anti-SARS-CoV-2 [3], antidiabetic [20,21], anti-inflammatory [22,23], anticoagulant [24,25], antibiotic [26,27], antitubercular [28,29], neuroprotective [30,31], anti-infectious hematopoietic necrosis virus activities (IHNV) [32], etc. Fused coumarins possess also biological activities, and many of them, like furocoumarins [33,34], pyranocoumarins [35] or pyridocoumarins [36] are isolated from nature. Fused pyrrolocoumarins display interesting biological properties, such as cytotoxic [37,38,39,40,41,42], antibacterial [42], anti-HIV [37,42,43,44,45], multidrug resistance reversal (MDR) [37,42,45], antibiotic [42], antioxidant [42,46,47], antitumor [45], and anti-inflammatory activities [42,46,47]. Some of them act also as benzodiazepine receptor (BZR) ligands [48,49], angiogenesis inhibitors [50], DYRK1A inhibitors [45,51], Wnt signaling inhibitors [52] or fluorescent probes for live cell imaging [53]. Some of the fused pyrrolo[2,3-c]coumarins, the classes of lamellarins or ningalins, were isolated from sea snails and squirts. Especially, lamellarin D (Figure 1) was isolated from methanol extracts of marine prosobranch mollusks Lamellaria sp. by Pallaou [54]. Lamellarin K was isolated from the dichloromethane-methanol extracts of an ascidian Didemnum obscurum collected from Tamilnadu, India [55]. Ningalin B was obtained from methanol/chloroform extracts of the ascidian of the genus Didemnum collected in western Australia [56]. The fused pyrrolo[3,2-c]coumarin and pyrrolo[3,4-c]coumarin are the core moieties of biologically active isolamellarin A, azacoumestans and isolamellarin B, respectively (Figure 1) [57,58,59]. 3,9-Dihydroxyazacoumestan (I) is an angiogenesis inhibitor [50], while 1-aryl-3-phenylpyrrolo[3,2-c]coumarins II are benzodiazepine receptor ligands [48,49]. In the literature, many reviews have been published concerning the synthesis and biological activities of coumarin and fused coumarin derivatives, while fused pyrrolocoumarins have appeared in some reviews [1,14,45,60,61,62,63,64,65,66,67] and in a few specific reviews [57,58,68]. This review will present an overview of the synthesis and biological evaluation of fused pyrrolo[c]coumarins.

Figure 1.

Fused pyrrolocoumarins found in nature and/or presenting diverse biological activities.

2. Synthetic Strategies for the Preparation of [3,4]-Fused Pyrrolocoumarin Derivatives

The synthesis of [3,4]-fused pyrrolocoumarins has been achieved through two main routes. The formation of pyrrole moiety starting from a coumarin derivative is the first, while the second is the formation of pyranone ring starting from a pyrrole derivative.

2.1. Pyrrole Ring Formation

As starting materials for the formation of pyrrole moiety, different fused heterocyclic coumarin derivatives have been used: 3- or 4-aminocoumarins or hydroxycoumarins, chlorocoumarins, or other coumarin derivatives [69]. Multicomponent reactions (MCR) or metal-catalyzed reactions have been utilized for the synthesis of pyrrole ring of [3,4]-fused pyrrolocoumarins.

2.1.1. Synthesis from Aminocoumarin Derivatives

In 1978, Khan and de Brito Morley reported for the first time the synthesis of substituted fused pyrrolo[3,4-b]coumarins 4b–h via the Fischer indolization of in situ prepared coumarin-3-hydrazine hydrochloride with carbonyl compounds 3a–g in 33–51% yield [70]. The intermediate hydrazine hydrochloride was prepared by the reduction, with stannous chloride, of 3-coumarin diazonium salt (2) synthesized by diazotization of 3-aminocoumarin (1) at −30 °C (Scheme 1).

Scheme 1.

Synthesis of benzopyrano[3,4-b]pyrrol-4-ones 4a–h via Fischer indolization reaction.

Joshi et al. presented the synthesis of the 2,3-diaryl-4(H)-oxo[1]benzopyrano[4,3-b]pyrroles 7a–c by the reaction of 4-aminocoumarin (5) with benzoins 6a–c in the presence of p-toluene sulfonic acid (Scheme 2). These novel compounds produced a strongly fluorescent green solution in alkali [71].

Scheme 2.

Synthesis of 2,3-diaryl-4(H)-oxo[1]benzopyrano[4,3-b]pyrroles 7a–c from 4-aminocoumarin and benzoin.

Majumdar and Chattopadhyay prepared the pyrrolocoumarin derivatives 4b, 10a–d in excellent yield of 90–94% from the regioselective aza-Claisen rearrangement of 3-N-propargylaminocoumarin (9a) and 3-N-(aryloxybut-2-ynyl)aminocoumarins 9b–e (Scheme 3). An initial [3,3]-sigmatropic rearrangement of propargylamine moiety of 9a gave allene intermediate A, followed by a tautomerism to amine B. A subsequent 5-exo-trig cyclization resulted in the final product 4b. Starting compounds 9a–e was synthesized by refluxing 3-aminocoumarin (1) with propargyl bromide (8a) or 1-aryloxy-4-chlorobut-2-ynes 8b–e, respectively, in anhydrous ethyl methyl ketone [72].

Scheme 3.

Synthesis of benzopyrano[3,4-b]pyrrol-4-ones 4b, 10a–d via aza-Claisen rearrangement of propargylamino compounds 9a–e.

Soman et al. synthesized chromeno[3,4-b]pyrrol-4(3H)-ones 4e, 13 and 15a,b in 28–68% yield through cyclization, in the presence of catalytic amount of TFA, of 3-N-ketonylcoumarins 12a,b and 14a,b, respectively, which were obtained by the reaction of 3-aminocoumarins 1, 11 with a-haloketones (Scheme 4). The compounds 4e, 13 was tested for their cytotoxic activity using the MTT [3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] against cell lines of colon, lung, and breast cancer. Both compounds showed good activity against all the above cell lines [39].

Scheme 4.

Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones 4e, 13 and 15a,b by the cyclization of 3-N-ketonylcoumarins in the presence of TFA.

Paul and Das reported the synthesis of 3-aryl-4(H)-oxo[1]benzopyrano[4,3-b]pyrroles 17a–h from 4-aminocoumarin (5) and β-nitrostyrenes 16a–h in the presence of the polymer-supported catalyst PEG-SO₃H in 72–85% yield [73]. In the proposed mechanism, PEG-SO₃H catalyzed the Michael addition of 5 to the β-nitrostyrene. Subsequent intramolecular amine attack of the Michael adduct A afforded the cyclized intermediate B. Elimination of water and nitroxyl molecules resulted in the final product (Scheme 5).

Scheme 5.

Synthesis of 3-aryl-4(H)-oxo[1]benzopyrano[4,3-b]pyrroles 17a–h from 4-aminocoumarin and β-nitrostyrenes under PEG-SO₃H catalysis.

Chen et al. presented a regioselective synthesis of dihydrochromenoindeno[1,2-b]pyrroles 20, 21a–q in 70–92% yield via the reaction of N-substituted 4-aminocoumarin derivatives 5, 18a–q with ninhydrin (19) under microwave irradiation without the presence of a catalyst [74]. Nucleophilic addition of 4-aminocoumarin (5) to the more electrophilic middle carbonyl of indanetrione, which is in equilibrium with ninhydrin, gave the intermediate A. Tautomerization of A resulted in B. The addition of amine to one of the carbonyls led to the final product 20 (Scheme 6).

Scheme 6.

Synthesis of dihydrochromenoindeno[1,2-b]pyrroles 20, 21a–q from 4-aminocoumarins and ninhydrin.

Ibrahim et al. reported that the reaction of 4-aminocoumarin (5) with chloroacetic acid resulted in 1,2-dihydrochromeno[4,3-b]pyrrole-3,4-dione (22) in 58% yield (Scheme 7). This compound was studied for cytotoxic activity and found to be 1.5-fold more toxic than the standard 5-fluorouracil [75].

Scheme 7.

Synthesis of 1,2-dihydrochromeno[4,3-b]pyrrole-3,4-dione (22).

Padilha et al. used p-toluenesulfonic acid for the synthesis of chromeno[4,3-b]pyrrol-4(1H)-ones 24a–f from 4-N-phenylaminocoumarins 23a,b and β-nitro alkenes 16 under solvent-free conditions in 6–77% yield (Scheme 8). The proposed mechanism for the synthesis of compounds 24 was like the one proposed in Scheme 5 [76].

Scheme 8.

Synthesis of chromeno[4,3-b]pyrrol-4(1H)-ones 24a–f from 4-N-phenylaminocoumarins 23a,b and β-nitro alkenes 16 using TsOH.H₂O as catalyst.

Yang et al. reported the synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones through the domino reaction of 3-aminocoumarins 1, 25a–c with aryl glyoxal monohydrates 26a–j [77]. The reactions were catalyzed by p-toluenesulfonic acid (p-TSA). The solvents toluene or ethanol are important, as they affect the synthesis of the products 2-aryl-1-hydroxychromeno[3,4-b]pyrrol-4(3H)-ones 27a–m or 2-aryl-1-(2-oxo-2H-chromen-3-ylamino) chromeno[3,4-b]pyrrol-4(3H)-ones 28a–m in 54–78% or 75–92% yield, respectively (Scheme 9). In the proposed mechanistic scheme, the common intermediate A is formed by the nucleophilic attack of aminocoumarin on glyoxal. In the presence of toluene, intramolecular cyclization of A to C followed by dehydration of D led to the adduct 27. In the presence of polar solvent, ethanol, protonation of the hydroxyl group of A afforded intermediate E. Nucleophilic attack of the amine group of 3-aminocoumarin furnished intermediate F, maybe for steric reasons. Intramolecular cyclization of F to G followed by dehydration of I resulted in the product 28.

Scheme 9.

Synthesis of 2-aryl-1-hydroxychromeno[3,4-b]pyrrol-4(3H)-ones 27a–m or 2-aryl-1-(2-oxo-2H-chromen-3-ylamino) chromeno[3,4-b]pyrrol-4(3H)-ones 28a–m from 3-aminocoumarins and aryl glyoxal monohydrates.

The same group of Dr. Chen presented the synthesis of 3-alkoxychromeno[4,3-b]pyrrol-4(1H)-ones 29a–o via the one-pot two-step reaction of 4-aminocoumarins 5, 18a,o with aryl glyoxal monohydrates 26 and p-toluene sulfonates (Scheme 10). In the first step of this reaction, an intermediate 3-hydroxychromeno[4,3-b]pyrrol-4(1H)-one, like 30, was formed in an analogous process as described in Scheme 9, followed by nucleophilic substitution from the alkylating agent in the second step [78].

Scheme 10.

Synthesis of 3-alkoxychromeno[4,3-b]pyrrol-4(1H)-ones 29a–o by the one-pot two-step reaction of 4-aminocoumarins with glyoxal monohydrates and p-toluene sulfonates.

Mukherjee et al. synthesized 3-arylaminochromeno[4,3-b]pyrrol-4(1H)-ones 32a–c by a similar one-pot two-step reaction of phenyl glyoxal monohydrate (26a) with arylamine 31a–c and 4-aminocoumarin (13) in the presence of Bronsted acid-surfactant reagent PEG-SO₃H [53]. In the first step, the reaction of phenyl glyoxal with arylamine afforded imine derivative A. Michael addition of 4-aminocoumarin (5) to A in the second step, followed by cyclization and removal of water, resulted in the final product (Scheme 11). Compounds 32a–c were found to be cell-permeable and exhibiting fluorescence “turn-off” in the presence of Cu²⁺ ions in fluorescent imaging of human cervical cancer (HeLa) cells.

Scheme 11.

Synthesis of 3-arylaminochromeno[4,3-b]pyrrol-4(1H)-ones 32a–c by the one-pot two-step reaction of phenyl glyoxal monohydrate (26a) with arylamines and 4-aminocoumarin (5).

Pandya et al. reported the synthesis of pyrrolo[2,3-c]coumarins derivatives 4g, 15a, 34a–c in 51–57% yield from the reactions of 3-aminocoumarin (1) with β-nitrostyrenes 16a,b,d,k, 33 in the presence of piperidine [79]. 1(H)[1]Benzopyrano[3,4-b][1]benzopyrano[3′,4′-b]pyrrole-7(H)-ones 37a–i were synthesized also, in 51–56% yield from the reactions of 4-hydroxycoumarins 35a–c with 3-nitro-2-aryl-2H-[1]benzopyrans 36a–c in the presence of acetic acid and ammonium acetate (Scheme 12). For the mechanism, Michael addition of 3-aminocoumarin (1) to β-nitrostyrene (16a) gave intermediate B after tautomerization of A. Intermediate aldehyde C was formed next, according to Nef reaction conditions [80]. Intramolecular cyclization to D followed by elimination of water resulted in the pyrrolo[2,3-c]coumarin 15a.

Scheme 12.

Synthesis of pyrrolo[2,3-c]coumarins 4g, 15a, 34a–c and 1(H)[1]benzopyrano[3,4-b][1]benzopyrano[3′,4′-b]pyrrole-7(H)-ones 37a–i from 3-aminocoumarin and 4-hydroxycoumarins, respectively, and β-nitrostyrenes.

Recently, Islam et al. synthesized 2-aryl-1-((2-oxo-2H-chromen-3-yl)amino)chromeno[3,4-b]pyrrol-4(3H)-ones 39a–c in 76–81% yield from the reaction of 3-aminocoumarin (1) with aryl methyl ketones 38a–c in the presence of a catalytic amount of iodine in dimethyl sulfoxide (DMSO) [81]. In the proposed mechanism, phenacyl iodide (A) was generated by an electrophilic iodination, followed by oxidation leading to the phenyl glyoxal hydrate (26a). Reaction of the latter with 3-aminocoumarin (1) gave imine B. Michael addition of a second molecule of 1 to B resulted in the intermediate D through the tautomerization of imine C. By cyclization of D, followed by tautomerization of E, the final product 39a was formed (Scheme 13).

Scheme 13.

Synthesis of 2-aryl-1-((2-oxo-2H-chromen-3-yl)amino)chromeno[3,4-b]pyrrol-4(3H)-ones 39a–c.

2.1.2. Synthesis from Other Coumarin Derivatives

Trkovnic et al. reported the synthesis of 2-phenyl-4H-pyrro1o[3,2-c][1]benzopyran-4-one (41) in 83% yield by the treatment of 4-hydroxy-3-phenacylcoumarin (40) with acetic acid in the presence of ammonium acetate [82]. Compound 40 was synthesized in 59% yield by the reaction of 4-hydroxycoumarin (35a) with phenacyl bromide (Scheme 14).

Scheme 14.

Synthesis of 2-phenyl-4H-pyrro1[3,2-c][1]benzopyran-4-one (41).

Grigg and Vipond synthesized the 1,3-diphenylpyrrolo[3,4-c]chromene-4-one (45) in 51% yield by the 1,3-dipolar cycloaddition reaction of nitrile imine 43, prepared in situ from phenylglycine and benzaldehyde [83]. Thermal elimination of phenylsulfenic acid from the intermediate dihydropyrrole derivative 44 followed by oxidation in the reaction conditions resulted in the final product 45 (Scheme 15).

Scheme 15.

Synthesis of 1,3-diphenylpyrrolo[3,4-c]chromene-4-one (45).

Alberola et al. prepared [1] benzopyrano[4,3-b]pyrrol-4(1H)-ones 17a,b, 49a–e from 4-acylamino- or 4-ketalaminocoumarin derivatives 48a–h under different conditions using acetic acid/water, or Me₃SiI in chloroform or TiCl₄ in dichloromethane (DCM) or EtONa in ethanol or silica gel in chloroform [84]. Compounds 49a–e were prepared in high yields of 71–92% through the method with acetic acid/water. TiCl₄ in DCM resulted in the synthesis of 49b,d in yields of 88% and 92%, respectively. Compounds 17a,b were synthesized from 48f,g under treatment with EtONa in ethanol in 75% and 89% yields, respectively. Compound 49e was prepared from 48h in silica gel and chloroform in 89% yield. One-pot reaction of 46 with 47c afforded compound 49c in 80% yield (Scheme 16). 4-Acylamino- and 4-ketalaminocoumarin derivatives 48a–h were synthesized from the reaction of 4-chlorocoumarin (46) with acylamine chlorohydrates or ketalamines 47a–h under treatment with Et₃N in refluxing ethanol.

Scheme 16.

Synthesis of [1] benzopyrano[4,3-b]pyrrol-4(1H)-ones 17a,b, 49a–e from 4-chlorocoumarin (46).

The same group of Alberola et al. reported the synthesis of [1] benzopyrano[4,3-b]pyrrol-4(1H)-ones 17a, 49c–p from the Weinreb α-aminoamides 52a–f [85]. The N(α)-(2-oxo-2H-1-benzopyran-4-yl) Weinreb α-aminoamides (52a–f) were prepared in 73–87% yield from the α-aminoacid derivatives 51a–f (generated from the reaction of 4-chlorocoumarin (46) with α-aminoacid potassium salt) under treatment with N,O-dimethyl hydroxylamine. Weinreb amides reacted with organomagnesium or organolithium compounds 53a–g to give 4-ketonylaminocoumarins 54a–h,o in 51–92% yield (Scheme 17). Cyclization of the latter under different conditions, EtONa in ethanol (for 54a–f,o), acetic acid/water (for 54g) or evaporation with silica gel in chloroform (for 54h), furnished the fused pyrrolocoumarins 17a, 49c–i,p in 69–92% yield. The reactions of Weinreb amides with organolithium compounds in silica gel and chloroform, in the case of the expected 4-ketonylaminocoumarins 54i–n, led through a one-pot process to the cyclization products 49j–o in 15–81% yield without the isolation of the intermediates.

Scheme 17.

Synthesis of [1] benzopyrano[4,3-b]pyrrol-4(1H)-ones 17a, 49c–p from N(α)-(2-oxo-2H-1-benzopyran-4-yl) Weinreb α-aminoamides.

The same group of researchers presented the synthesis of [1] benzopyrano[4,3-b]pyrrol-4(1H)-ones 57a–f by the Fischer–Fink reaction from 4-chloro-3-formylcoumarin (55) and a-amino derivatives as hydrochloric acid salts 47f,h–n [86]. Reaction of 55 with 47a,b,d–f,h–n in ethanol in the presence of Et₃N (three equivalents) mainly at 0 °C (60 °C for 56g or 20 °C for 56a–d, without Et₃N in chloroform) for 1–12 h resulted in the synthesis of 3-amino-4-formylcoumarins 56a–l in 73–95% yield (Scheme 18). The same reaction at 80 °C (or 20 °C for 24 h for 57b) for 2–12 h afforded the expected pyrrolocoumarins 57b–f in 71–90% yield. Sublimation of 56i at 240 °C/0.05 mm Hg furnished 57a in 25% yield. The similar reaction of 55 with 47n in the presence of one equivalent of Et₃N for 12 h led to the synthesis of 57d in 33% yield and to the isolation of 1-ethoxycarbonyl-2-methylchromeno[3,4-c]pyrrol-4(2H)-one (58a) in 51% yield. The reaction of 3-formyl-4-pyrrolidinylocoumarin (59) with 47n without the presence of base for 8 h resulted in the adducts 57d (29%) and 58a (58%). From the reaction of 59 with 47h without base for 8 h, products 57f (4%) and 1-benzoyl-2-methylchromeno[3,4-c]pyrrol-4(2H)-one (58b) (79%) were obtained. The cleavage of acetals or ketals 56a–d in the presence of acetic acid-water resulted in the fused pyrroles 57g–j and 60a–d in 30–87% yield under cyclization and elimination of water or formic acid, respectively. A possible mechanistic process for the formation of 4-amino-3-formylocoumarin 56l occurred through 1,4-addition of 47n to 55, which after elimination of water resulted in the pyrrolo[4,3-b]coumarin 57d. The less possible 1,2-addition of 47n to 55, for the formation of intermediate A, followed by elimination of HCl could produce pyrrolo[3,4-c]coumarin 58a.

Scheme 18.

Synthesis of [1] benzopyrano[4,3-b]pyrrol-4(1H)-ones 57a–f from 4-chloro-3-formylcoumarin.

Liao et al. synthesized [1] benzopyrano[4,3-b]pyrrol-4(1H)-ones 66a–e from 4-hydroxycoumarin (35a) in 30–40% yield through six steps (acylation, isomerization, protection of hydroxyl group, nucleophilic substitution) and the cyclization of enamines 65a–e followed by dehydration [87]. For the mechanism of the cyclization reaction, the intermediate hydroxy compound 69 was isolated during the treatment of enamine 65c with base (Et₃N) (Scheme 19). Hydroxy derivative 69 resulted in the final product 66c under elimination of water. N-Alkylation of 66a–e with halides 67a–c in the presence of K₂CO₃ at room temperature afforded the trisubstituted fused pyrrolocoumarins 68a–o.

Scheme 19.

Synthesis of [1] benzopyrano[4,3-b]pyrrol-4(1H)-ones 66a–e from 4-hydroxycoumarin (35a).

Cordaro et al. examined the 1,3-dipolar cycloaddition reaction of unsymmetrically N-unsubstituted and N-substituted 1,3-oxazolium-5-olates 71a,b with 3-substituted coumarins 70a–c, bearing electron-withdrawing group [88]. The products 72a,b were obtained with both reaction conditions in solution (69–77% yield) or without solvent (80–89% yield), while products 73a,b were obtained only in solution in 40% or 15% yield, respectively. In the proposed mechanism of oxazolone cycloaddition reaction, the formation of products 72a,b could be explained through exo-diastereoisomer A and the intermediate B leading to stable α-aminoacids (Scheme 20). Endo-diastereoisomer C with translactonization to D and elimination of CO₂ is responsible for the formation of products 73a,b.

Scheme 20.

Synthesis of fused dihydropyrrolo[3,4-c]coumarin derivatives 72a,b, 73a,b, 74.

Fan et al. prepared benzopyran [3,4-c]pyrrolidines 76a–l in 73–97% yield by the triethylamine-catalyzed 1,3-dipolar cycloaddition reaction of azomethine ylides with 3-substituted coumarins [89]. Azomethine ylides were formed in situ from α-amino malonate imines 75a–e. As they have been examined by X-ray analysis of 76e, the products have the cis stereochemistry (Scheme 21).

Scheme 21.

Synthesis of benzopyran [3,4-c]pyrrolidines 76a–l.

Bochkov et al. [90] synthesized 2-benzoylchromeno[4,3-b]pyrrol-4-ones 57e, 80a,b starting from 4-hydroxycoumarins 35a,d,e in four steps through 4-chloro-3-formylcoumarins 55, 77a,b in good yields, avoiding the formation of byproducts [85]. Wittig reaction of 55, 77a,b to give 78a–c, followed by azide formation of 79a–c, and thermal cyclization, furnished compounds 57e, 80a,b (Scheme 22). Reactions of the latter with pyrroles 81a,b resulted in 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes 82a–d presenting large Stokes shifts and good fluorescence quantum yields, especially for 82b,d.

Scheme 22.

Synthesis of 2-benzoylchromeno[4,3-b]pyrrol-4-ones 57e, 80a,b and coumarin-fused BODIPY dyes 82a–d.

Lin and Yang prepared 7-N,N-dimethylaminochromeno[4,3-b]pyrrol-4-ones 85a,b in excellent yields to study their photochemical and redox switching properties [91]. The synthesis was performed by the reaction of 3-acylcoumarins 83a,b with α-aminoketone hydrochloric salt 47p under microwave irradiation in the presence of diisopropyl ethyl amine (Scheme 23). The enamine derivatives 84a,b under reflux in the presence of a catalytic amount of p-toluenesulfonic acid afforded the final product. In the proposed mechanism, the acid-catalyzed cyclization of 84b furnished the intermediate A, which upon 1,4-elimination of water produced B. [1,5]-acyl migration afforded intermediate C. Methanolysis of C resulted in the fused pyrrolocoumarin 85b. The fused pyrrolocoumarins were found to be sensitive to UV light upon changing the light under this wavelength. The product 86 of the transformation was stable, and it has been isolated.

Scheme 23.

Synthesis of 7-N,N-dimethylaminochromeno[4,3-b]pyrrol-4-ones 85a,b.

Kamal El-Dean et al. synthesized ethyl 3-amino-4-oxo-1,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate (90) from 4-chloro-3-cyanocoumarin (88) through the adduct with glycine ethyl ester (47m) followed by cyclization (Scheme 24). This new compound presented low antifungal activity as tested against Candida albicans and Geotrichum candidum [92].

Scheme 24.

Synthesis of ethyl 3-amino-4-oxo-1,4-dihydrochromeno[4,3-b]pyrrole-2-carboxylate (90).

Potowski et al. synthesized benzopyrano[3,4-c]pyrrolidines via AgTFA-catalyzed 1,3-dipolar cycloaddition reaction of coumarin 70a with azomethine ylides formed from α-imino esters 91a–s [93]. The trans diastereoisomers 92a–s were obtained in 37–72% yield, while the cis diastereoisomers 93a–i were isolated in only 9–34% yield. The configuration of the trans-product 92f was confirmed by X-ray crystallographic analysis. A stepwise mechanism has been proposed for these reactions (Scheme 25). In particular, a-imino ester 91e was coordinated to Ag(I) ion, and deprotonation from Et₃N resulted in the intermediate azomethine ylide A. Nucleophilic attack of the latter to 4-C of coumarin furnished B, which upon cyclization afforded the trans-product 92e.

Scheme 25.

Synthesis of benzopyrano[3,4-c]pyrrolidines via Ag(I)-catalyzed 1,3-dipolar cycloaddition reaction.

El Azab and Elkanzi presented the synthesis and biological evaluation of 1-mercapto- or 1-thiochromeno[3,4-c[pyrrol-3,4-dione derivatives 95–98 as antimicrobial agents [94]. The reaction of coumarin-3-ylcarboxamide (94) with CS₂ led via the intermediate A to 1-mercaptopyrrolo[3,4-c]chromene-3,4-dione (95) in 85% yield (Scheme 26). Derivative 94 was the key compound for the synthesis of chloroacetylthio-derivative 96, the heterocyclic derivatives 97, 98 and other N-heterocycle derivatives. All the new compounds were tested for their in vitro antibacterial activity against two Gram-positive species, Bacillus subtilis RCMB 010067 and Staphylococcus aureus RCMB 0100010, and two Gram-negative species, Pseudomonas aeuroginosa RCMB 010043 and Escherichia coli RCMB 010052. Compound 98 presented high activity, greater against Gram-positive bacteria than the Gram-negative ones. The compounds were also evaluated for their in vitro antifungal activity against two fungal species, Aspergillus fumigatus RCMB 02568 and Candida albicans RCMB 05036. Compound 96 demonstrated high antifungal activity, while compound 98 presented moderate activity, and compound 97 had low activity.

Scheme 26.

Synthesis of 1-mercapto- or 1-thiochromeno[3,4-c[pyrrol-3,4-dione derivatives 95–98.

Mohamed and Elbialy synthesized benzo[5,6]chromeno[4,3-b]pyrrol-4(1H)-one derivatives 100a–d under treatment of 3-bromoacetylcoumarin derivative 99 with amines 31a–d [38]. Nucleophilic substitution of bromine in 99 from amine afforded the intermediate A, which upon intramolecular Michael addition furnished intermediate B. The latter under autoxidation and enolization resulted in the product 100 (Scheme 27). New compounds 100a–d were examined in vitro against HepG2 (hepatoma cell line) and MCF7 (human breast adenocarcinoma cell line) cell lines, exhibiting moderate cytotoxic activity.

Scheme 27.

Synthesis of 3-hydroxy-1-arylbenzo[5,6]chromeno[4,3-b]pyrrol-4(1H)-ones 100a–d.

Shaabani et al. reported the regioselective reaction of tosylmethyl isocyanide (TosMIC) (101) with the double bond of 3-carbonyl coumarin derivatives for the synthesis of chromeno[3,4-c]pyrroles 102a–c (Scheme 28). The above reaction is a Van Leusen type [3 + 2] cycloaddition reaction of TosMIC with the 3,4-double bond of coumarin [95].

Scheme 28.

Synthesis of chromeno[3,4-c]pyrroles 102a–c by [3 + 2] cycloaddition reaction of TosMIC with coumarins.

Recently, Borkotoki et al. reported the synthesis of 2-benzoyl chromeno[4,3-b]pyrrol-4(1H)-ones 105a–v in 67–84% yield through the DBU-mediated coupling of 3-formylocoumarin derivatives 103a–c with phenacyl azides 104a–j [96]. As a possible mechanistic interpretation, the DBU-mediated coupling of azide 104a with coumarin-3-carbaldehyde 103a afforded the intermediate azidoalcohol A (Scheme 29). Dehydration of A furnished B. Elimination of nitrogen produced nitrene C, which upon intramolecular cyclization led to intermediate D. Reduction by DBU in acetonitrile resulted in the final product 105a.

Scheme 29.

Synthesis of 2-benzoyl chromeno[4,3-b]pyrrol-4(1H)-ones 105a–v.

2.1.3. Synthesis through MCR Reactions

The use of multicomponent reaction (MCR) was reported for the first time by Che et al. for the synthesis of fused pyrrolocoumarins. Chromeno[3,4-c]pyrrol-2,4-dione derivatives 109a–ad were synthesized in 45–82% yield during the one-pot process via the Ugi-4CR followed by intramolecular Michael addition of coumarin-3-carboxylic acid 106a–d, anilines 31a–d, nitriles 108a–c, and aldehydes 107a,b [97]. The acylaminoamide A was formed by the Ugi reaction of 106a, 31a, 107a, and 108a, and after enolization, the intermediate B was cyclized to afford the final product 109a (Scheme 30).

Scheme 30.

Synthesis of chromeno[3,4-c]pyrrol-2,4-dione derivatives 109a–ad.

Chen et al. reported the use of aryl glyoxals in the MCR synthesis of fused pyrrolocoumarins [98]. Aryl glyoxals have been used extensively for the synthesis of fused pyrrolocoumarins [61]. In this work, trisubstituted chromeno[4,3-b]pyrrol-4(H)-ones 32a–w have been synthesized in 34–93% yield via one-pot three-component reaction of 4-aminocoumarins, aryl glyoxal monohydrates, and aryl amines 31a–m (Scheme 31). In the proposed mechanism, an initial condensation in the presence of KHSO₄ of phenyl glyoxal monohydrate (26a) with aniline (31a) furnished the intermediate imine A. The reaction of A with 4-aminocoumarin (5) provided the intermediate B. Intramolecular cyclization of C, tautomer of intermediate B, afforded dihydropyrrolocoumarin D, which upon dehydration resulted in the final product 32a.

Scheme 31.

Synthesis of fused pyrrolocoumarins 32a–w via MCR.

Mishra et al. reported the synthesis of coumarin-3-yl-substituted fused pyrrolocoumarin derivatives 110a–e or 111 in 90–95% yield by the three-component reaction of 4-hydroxycoumarin, aryl glyoxal monohydrates, and 3-aminocoumarin (1) or 4-aminocoumarin (5), respectively, under microwave irradiation (Scheme 32). Discrete Fourier transform (DFT) calculations proved that both ketone and aldehyde group of arylglyoxal participate in the formation of the final products [99].

Scheme 32.

Synthesis of coumarin-3-yl-substituted fused pyrrolocoumarin derivatives 110a–e and 111.

Yahyavi et al. synthesized 2,3-disubstituted chromeno[4,3-b]pyrrol-4(H)-ones 114a–o in 73–89% yield via the iodine-catalyzed one-pot MCR of aryl glyoxals 112a–g, prepared in situ by the Kornblum oxidation of acetophenones 38a–g, active methylene compounds 113a–d and 4-aminocoumarin (5) [100]. In the proposed mechanism, the initially formed phenyl glyoxal (112a) was condensed in a Knoevenagel reaction assisted by iodine with dimedone (113a) to give intermediate A. Michael addition of 4-aminocoumarin (5) to A afforded imine B, which upon tautomerization to C and cyclization with elimination of water furnished intermediate D. 1,3-H Shift of the latter resulted in the final product 114a (Scheme 33).

Scheme 33.

Synthesis of 2,3-disubstituted chromeno[4,3-b]pyrrol-4(H)-ones 112a–o via iodine-catalyzed multicomponent reaction.

A similar MCR without catalyst in refluxing ethanol was reported by Yang et al. for the synthesis of chromeno[4,3-b]pyrrol-4(H)-one derivatives [101]. The one-pot reaction of 4-aminocoumarins, aryl glyoxal monohydrates and 1,3-dicarbonyl compounds resulted in the synthesis of substituted chromeno[4,3-b]pyrrolo-4(H)-ones 114c,i and 115a–u in 35–89% yield (Scheme 34). The proposed mechanism resembles the above mechanistic scheme.

Scheme 34.

Synthesis of substituted chromeno[4,3-b]pyrrol-4(H)-ones 114c,i and 115a–u via multicomponent reaction under catalyst-free conditions.

Belal and Khan reported analogous, iodine-catalyzed, multicomponent reactions for the synthesis of pyrrolo[2,3-c]coumarin derivatives 110 in 78–86% yield from 3-aminocoumarin, aryl glyoxal 112, and 4-hydroxycoumarin (35a) [102]. The mechanism for this one-pot three-component iodine-catalyzed reaction is like the one presented in Scheme 33 (Scheme 35).

Scheme 35.

Synthesis of pyrrolo[2,3-c]coumarin derivatives 110 by iodine-catalyzed three-component reaction.

Chen et al. also reported the synthesis of 3-(indol-3-yl)substituted chromeno[4,3-b]pyrrol-4(H)-ones, like 118 (Scheme 36), via a three-component reaction of aminocoumarins, aryl glyoxal monohydrates and indoles [103].

Scheme 36.

Synthesis of 3-(indol-3-yl)substituted chromeno[4,3-b]pyrrol-4(H)-ones.

Wu et al. presented the one-pot synthesis of 1-phenylchromeno[3,4-b]pyrrol-4(3H)-one (15a) through the three-component reaction of phenylacetaldehyde, pyrrolidine, and 4-chloro-3-nitrocoumarin (119) in three steps and 78% yield [104]. Similarly, they also synthesized the chromeno[3,4-b]pyrrol-4(3H)-one derivatives 122-124 and 126-128 from compound 125 (Scheme 37). They utilized this method for the synthesis of ningalin B. The key step of this reaction was the coupling between the intermediate 1-styrylpyrrolidine A and 4-chloro-3-nitrocoumarin (119). Diphenyl derivative 128 exhibits electrochromic properties.

Scheme 37.

One-pot synthesis of 1-phenylchromeno[3,4-b]pyrrol-4(3H)-one (15a).

Lai and Che synthesized substituted chromeno[4,3-b]pyrrol-4(H)-ones 131a–au in 35–82% yield, via a one-pot MCR of 3-formylcoumarins 129a–d, anilines (two equivalents) and isocyanides 130a,b [105]. By the four-component reaction, an intermediate like 132 was formed, which through cyclization under Michael addition resulted in the final products (Scheme 38).

Scheme 38.

Synthesis of chromeno[4,3-b]pyrrol-4(H)-ones 131a–au via one-pot multicomponent reaction.

Recently, Karami et al. prepared chromeno[4,3-b]pyrrol-3-yl derivatives 135a–e and 136a–f in 90–98% yield through the one-pot MCR of aminocoumarins, aryl glyoxals and malono derivatives 134a–c [106]. In the proposed mechanism, a Knoevenagel reaction of phenyl glyoxal (112a) with malono derivatives afforded the intermediate A. Michael addition of 4-aminocoumarin (5) to A furnished intermediate B, which tautomerized to C. The latter, in the case of malononitrile (134a), resulted in the final adduct 135a. In the case of esters 134a,b, hydrolysis furnished α-cyanoacid D, which upon elimination of CO₂ afforded the nitrile derivative 136a (Scheme 39). The above received pyrrolocoumarin derivatives were evaluated as α-glucosidase inhibitors. Most of the compounds presented potent inhibitory activity with IC₅₀ = 48.65–733.83 μM. Compound 136d was the most potent with an IC₅₀ = 48.65 μM, 19-fold more potent than the standard inhibitor acarbose. Furthermore, they found that the presence of para-methoxy or para-chloro substituent on the phenyl ring improved the inhibitory activity.

Scheme 39.

Synthesis of chromeno[4,3-b]pyrrol-3-yl derivatives 135a–e and 136a–f.

2.1.4. Synthesis through Metal-Catalyzed Reactions

The palladium-catalyzed synthesis of chromeno[3,4-b]pyrrol-4(3H)-one derivatives 143a–k was presented by Chen and Hu and used further to synthesize lamellarin analogues [107]. The pyrrole ring was formed in 56–83% yield by the palladium-catalyzed intramolecular hydro-amination of 4-acetylenic 3-aminocoumarins 140, synthesized during the reduction of 4-acetylenic 3-nitrocoumarins 139a–d or by Sonogashira coupling of 141 with aryl iodides 142a–h in 75–90% yield (Scheme 40). Desilylation of compound 140d led to the 4-ethynyl-3-aminocoumarin (141). The 4-acetylenic coumarin derivatives 139a–d were obtained by the Sonogashira coupling of 4-chloro-3-nitrocoumarin (137) with acetylene derivatives 138a–d.

Scheme 40.

Pd-Catalyzed synthesis of chromeno[3,4-b]pyrrol-4(3H)-one derivatives 143a–k.

Majumdar et al. prepared 2-phenylchromeno[3,4-b]pyrrol-4(3H)-one (143d) from 3-amino-4-(phenylethynyl)-2H-chromen-2-one (140e) under PdCl₂ catalysis in the presence of FeCl₃ along with other [5,6]-fused pyrrolocoumarin derivatives [108]. In the proposed mechanistic scheme, Pd(II) species coordinated with the triple bond of 140e, activating it to form intermediate A (Scheme 41). Nucleophilic attack of the amine to the electron-deficient triple bond through a 5-endo-dig cyclization furnished the organopalladium (II) complex B. Reductive elimination afforded the final product 143d. PdCl₂ was reactivated by oxidation of Pd (0) with FeCl₃. Reoxidation of the intermediate FeCl₂ by air resulted in the formation of FeCl₃, used in the catalytic cycle.

Scheme 41.

Iron/Palladium catalyzed synthesis of 2-phenylchromeno[3,4-b]pyrrol-4(3H)-one (143d).

Paul et al. utilized magnetic copper ferrite (CuFe₂O₄) nanoparticles for the three-component synthesis of chromeno[4,3-b]pyrrol-4(1H)-one derivatives 17a–k in 81–95% yield via one-pot three-component domino reaction of 4-aminocoumarin (5), aromatic aldehydes 144a–k and nitromethane (145) [109]. The catalyst was recycled six times, maintaining its catalytic activity. In the proposed mechanism, nitrostyrene A was formed through Knoevenagel reaction of benzaldehyde and nitromethane catalyzed by Fe³⁺ of CuFe₂O₄. The subsequent Michael addition of aminocoumarin 5 to A was catalyzed by Cu²⁺ of copper ferrite to give intermediate B (Scheme 42). By the interaction of Fe³⁺ with B, the electron-deficient complex C was generated, which upon electrophilic intramolecular cyclization resulted in the formation of dihydropyrrole-adduct D. Elimination of water and nitroxyl molecules afforded the final product 17a.

Scheme 42.

Preparation of chromeno[4,3-b]pyrrol-4(1H)-one derivatives 17a–k through magnetic copper ferrite (CuFe₂O₄) nanoparticle catalysis.

Peng et al. reported the synthesis of 2,3-disubstituted chromeno[4,3-b]pyrrol-4(1H)-one derivatives by the Pd-catalyzed, with Pd(OAc)₂, oxidative reaction of 4-aminocoumarins with internal alkynes 147a–s in the presence of Cu(OAc)₂ under an atmosphere of oxygen [110]. The yields were good to excellent (60–99%). With different substituents of the internal alkynes, two regioisomers were obtained for compounds 7b,d,e and 148v,w. Two possible mechanistic schemes were proposed (Scheme 43). In path A, palladation of 4-aminocoumarin (5) afforded the palladium intermediate A. Subsequent syn-addition to diphenylacetylene generated the vinylpalladium species B, which by intramolecular palladation furnished palladium cyclohexene intermediate C. Reductive elimination in the latter resulted in the final product 7a. In path B, alkyne was activated by Pd(II), acting as Lewis acid, and by the reaction with 4-aminocoumarin (5) afforded intermediate D. Electrophilic palladation of the latter under abstraction of proton furnished the intermediate E, which by reductive elimination resulted in the product 7a. The generated Pd (0) was later oxidized to Pd (II), completing the catalytic cycle.

Scheme 43.

Synthesis of 2,3-disubstituted chromeno[4,3-b]pyrrol-4(1H)-one derivatives by the Pd-catalyzed oxidative reaction of 4-aminocoumarins with internal alkynes.

Ngo et al. synthesized chromeno[3,4-b]pyrrol-4(3H)-ones in 40–82% yield by the Pd-catalyzed domino C-N coupling/hydroamination reactions of 4-alkynyl-3-bromocoumarins 151a–f with amines [111]. More nucleophilic anilines with electron-donating substituents resulted in better yields than anilines with electron-withdrawing substituents. Starting coumarins 151a–f were isolated from the Sonogashira reaction of 3-bromo-4-(trifluoromethanesulfonyloxy) coumarin (150) with terminal alkynes (Scheme 44).

Scheme 44.

Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones by Pd-catalyzed domino C-N coupling/hydroamination reactions.

Pradhan et al. used nano-materials, the tin oxide quantum dots (SnO₂ QDs), as a catalyst for the synthesis of dihydroxy fused pyrrolo[3,2-c]coumarins containing indene or acenaphthene moieties [112]. The reaction of 4-hydroxycoumarin (5) with ninhydrin (19) or acenaphthene quinone (154) resulted in the synthesis of compounds 20 and 155 in 90% and 83% yield, respectively (Scheme 45). The mechanism for these reactions follows a pattern similar to the one in Scheme 6.

Scheme 45.

Synthesis of dihydroxy fused pyrrolo[3,2-c]coumarins containing indene or acenaphthene moieties by SnO₂ quantum dot catalysis.

The research group of Dr. Das again used the earlier-referred nanocrystalline CuFe₂O₄ catalyst for the one-pot three-component reaction synthesis of chromeno[4,3-b]pyrrol-4(1H)-ones in 68–94% yield from 4-aminocoumarins, amines and aryl glyoxal monohydrates in water as solvent [113]. In the proposed mechanism, an imine intermediate A was formed from the reaction of amine with phenyl glyoxal monohydrate, activated by the Fe³⁺ center of the catalyst. Michael addition of 4-aminocoumarin (5) to A, catalyzed by Cu²⁺, afforded intermediate B. Tautomerization of the latter furnished intermediate C, which upon cyclization to D under Fe³⁺ catalysis, followed by elimination of water, resulted in the final product 32a (Scheme 46).

Scheme 46.

Synthesis of trisubstituted chromeno[4,3-b]pyrrol-4(1H)-ones by nano crystalline CuFe₂O₄ catalysis.

Jin et al. presented the synthesis of coumarin derivatives fused with 9H-pyrrolo[1,2-a]indoles 159a–u in 34–99% yield under a copper-catalyzed tandem reaction of 3-aroylcoumarins 157a–u with 3-methylindole (158) [114]. In the proposed mechanism, 3-benzoylcoumarin was activated by CuBr₂ to form an intermediate A. A Friedel–Crafts reaction of C-2-carbon of 3-methylindole (158) to A afforded intermediate B, which upon 1,2-addition of indole amine to benzoyl carbonyl furnished the cyclized adduct C. Dehydration of the latter resulted in intermediate D, releasing the catalyst. Isomerization of intermediate D afforded the final product 159a (Scheme 47).

Scheme 47.

Synthesis of coumarin fused with 9H-pyrrolo[1,2-a]indoles.

Mukherjee et al. used Fe₃O₄@SiO₂-SO₃H magnetic nanoparticles as catalyst under solvent-free conditions for the synthesis of chromeno[4,3-b]pyrrol-4(1H)-one derivatives substituted with arylamine, methylene nitrile, or hydroxy substituents in 59–80% yield (Scheme 48, Scheme 49 and Scheme 50). The mechanism for the synthesis of 3-arylamino- or 3-hydroxychromeno[4,3-b]pyrrol-4(1H)-one derivatives is similar to that presented in Scheme 31 with the initial formation of imino derivative or phenylglyoxal, respectively, from phenylglyoxal hydrate [115]. The mechanism for the formation of 3-cyanomethylenochromeno[4,3-b]pyrrol-4(1H)-one derivatives is analogous to that provided in Scheme 38. They also synthesized fused indolo[3,2-c]coumarin derivatives 163a–f by refluxing of 3-cyanomethylenochromeno[4,3-b]pyrrolo-4(1H)-ones in diphenyl ether upon elimination of ethanol (from ethyl esters) or ammonia (from amide) (Scheme 51).

Scheme 48.

Synthesis of 3-arylaminochromeno[4,3-b]pyrrol-4(1H)-one derivatives using Fe₃O₄@SiO₂-SO₃H magnetic nanoparticles as catalyst.

Scheme 49.

Synthesis of 3-cyanomethylenochromeno[4,3-b]pyrrol-4(1H)-one derivatives using Fe₃O₄@SiO₂-SO₃H magnetic nanoparticles as catalyst.

Scheme 50.

Synthesis of 3-hydroxychromeno[4,3-b]pyrrol-4(1H)-one derivatives using Fe₃O₄@SiO₂-SO₃H magnetic nanoparticles as catalyst.

Scheme 51.

Synthesis of indolo[3,2-c]coumarin derivatives 163a–f.

Yadav et al. presented the synthesis of 2,3-disubstituted chromeno[4,3-b]pyrrol-4(1H)-one derivatives 165a–u in 75–88% yield by the reaction of 4-aminocoumarins with aroylidene/acetylidene malonates 164a–l, catalyzed by a Lewis acid, In(OTf)₃, under microwave irradiation and solvent-free conditions [116]. In the possible mechanism, Michael addition of 4-aminocoumarin (5) to the reactive intermediate A, having lower LUMO energy due to coordination of 164a with In(OTf)₃, afforded adduct B. Cyclization of the latter under elimination of water to intermediate C and [1,3]-H shift resulted in the product 165a (Scheme 52).

Scheme 52.

Synthesis of 3-disubstituted chromeno[4,3-b]pyrrol-4(1H)-one derivatives 165a–u catalyzed by In(OTf)₃.

Watanabe et al. developed the preparation of 1-arylchromeno[3,4-b]pyrrol-4(3H)-ones in 81–98% yield by the ruthenium-catalyzed cycloisomerization of 4-alkynyl-3-amino-2H-chromen-2-ones 140, 166 through 1,2-carbon migration [117]. For the mechanism of these reactions, a vinylidene rearrangement of internal alkyne by 1,2-carbon migration to form intermediate A (Scheme 53) and subsequent cyclization resulted in the final product 15a. Additionally, they prepared Ningalin B and Lamellarin H by this method.

Scheme 53.

Synthesis of 1-arylchromeno[3,4-b]pyrrol-4(3H)-ones.

In 2022, our group reported the synthesis of 1-aryl-2-methyl- and 3-methyl chromeno[4,3-b]pyrrol-4(1H)-ones 169a–j and 170a–e in 91–95% yield by the Pd-catalyzed intramolecular Aza-Wacker-type cyclization of 3-allyl-4-arylaminocoumarins 169a–j or C-H insertion/oxidative cyclization of N-allyl-N-aryl-4-aminocoumarins 168a–j, respectively [46]. In the proposed mechanism, N-H activation of 167a and coordination to double bond afforded intermediate A, which upon aminopalladation via 5-exo-trig cyclization furnished adduct B. Reductive elimination with β-hydride abstraction from the latter generated exo-methylene intermediate C, which through [1,3]-H shift resulted in the aromatic product 169a. For the transformation of 168e to 170b, the palladated species A was formed, followed by insertion of double bond through 5-exo-trig cyclization to give intermediate B. Reductive elimination to C and tautomerization afforded the final product (Scheme 54). The above-prepared intermediate and final products presented interesting antioxidant activity while inhibiting soybean lipoxygenase (LOX). Compounds 159h, 160b, and 160a presented the most interesting IC₅₀ values (38, 41, and 45 μM, respectively) in LOX inhibition. The allyl-compounds 157e, 157j, and 158c showed higher anti-LOX activities with IC₅₀ values 10, 6, and 5.6 μM, respectively.

Scheme 54.

Synthesis of 1-aryl-2-methyl- or 3-methyl chromeno[4,3-b]pyrrol-4(1H)-ones catalyzed by palladium (II).

D. Das and A. R. Das synthesized 1,2-disubstituted chromeno[3,4-b]pyrrol-4(3H)-one derivatives from 3-acetamidocoumarins 171a–h and internal alkynes 147 under Rh(III)-catalyzed C-H activation reactions using Ac-group as traceless directing group [118]. In the proposed mechanism, the active metalating species A formed from the precatalyst [CpRhCl₂]₂ and by interaction with Lewis basic carbonyl oxygen afforded intermediate B. C-H Bond cleavage produced species C, which coordinated with alkyne 147a to form complex D and Rhoda-cycle E in the presence of AcO⁻ (Scheme 55). Reductive elimination of the latter furnished N-acyl adducts G, which upon hydrolysis resulted in the final product 123. They performed fluorometric studies and found that compound 172p is capable of differentiating the noxious Cr(VI) ions from Cr(III) ions.

Scheme 55.

Synthesis of 1,2-disubstituted chromeno[3,4-b]pyrrol-4(3H)-one derivatives from 3-acetamidocoumarins and intermediate alkynes under Rh(III)-catalysis.

Recently, Guan et al. presented the synthesis of chromeno[4,3-b]pyrrol-4(1H)-ones 174a–t under AlCl₃-catalyzed reactions of 4-anilinocoumarins with 2-furylcarbinols 173a–f (Scheme 56). The reaction proceeded via chemoselective intermolecular α-carbon nucleophilic attack/ring-opening of furan ring/Michael addition/deprotonation aromatization processes [119].

Scheme 56.

Synthesis of chromeno[4,3-b]pyrrol-4(1H)-ones 174a–t.

2.2. Pyranone Ring Formation

In 1990 for the first time, Colotta et al. reported the synthesis of [1]benzopyranopyrrol-4-ones 24a, 180a–g, 185, achieving the pyranone ring formation from pyrrole-3-carboxylic acids 179a–h, 184 by refluxing in the presence of thionyl chloride (Scheme 57). The intermediate pyrrole derivatives 177a–h were synthesized from ethyl 3-[2-(benzyloxy)-phenyl]-3-oxopropanoate (165) and phenacyl arylamines 176a–h. Pyrrole-3-carbocylic acid 182 was obtained by the Paal–Knorr pyrrole synthesis from 181 and aniline. Compounds 24a, 180a–g were tested for their activity as BZR ligands [49]. These compounds demonstrated potent BZR binding activity, as they were examined for their ability to displace [³H]flunitrazepam from bovine brain membranes, showing IC₅₀ values lower than that of diazepam (for 180c and 180d, IC₅₀ = 8.6 and 10 μΜ, respectively; diazepam IC₅₀ = 13 μΜ). The next year, the same group presented the synthesis of some different 1,3- and 1,2-disubstituted [1]benzopyrano-pyrrol-4-ones along with their BZR affinity, monitoring their ability to displace [³H]flunitrazepam [120].

Scheme 57.

Synthesis of [1]benzopyranopyrrol-4-ones 24a, 180a–g, 185.

The research group of Prof. Steglich synthesized the pyrrolo[2,3-c]coumarin derivative 189, as intermediate for the synthesis of lamellarin G trimethyl ether in a biomimetic synthesis [121]. Oxidative coupling of two molecules of 3-(3,4-dimethoxyphenyl) pyruvic acid (186) furnished intermediate A, which reacted with 2-phenylethylamine 187 to give the pyrrole derivative 188 (Scheme 58). Treatment of 188 with Pb(OAc)₄ afforded pyrrolo[2,3-c]coumarin derivative 189.

Scheme 58.

Synthesis of pyrrolo[2,3-c]coumarin derivative 189.

Boger et al. used the heterocyclic azadiene Diels–Alder reaction for the synthesis of ningalin B [122] (Scheme 4). Diels–Alder reaction of ethynyl derivative 190 with tetrazine derivative 191 furnished diazine adduct 192. Reductive ring contraction of the latter with zinc afforded the pyrrole 193, which upon N-alkylation with aryl ethyl bromide 194 resulted in the compound 195 (Scheme 59). Lactonization of 195 furnished the pyrrolo[2,3-c]coumarin derivative 196, intermediate for the synthesis of ningalin B. Compounds 195 and 196 were found to reverse the multidrug-resistant (MDR) phenotype, resensitizing a human colon cancer cell line (HCT116/VM46) to vinblastine and doxorubicin.

Scheme 59.

Synthesis of pyrrolo[2,3-c]coumarin derivative 195.

Gupton et al. provided an alternative pathway for the synthesis of ningalin B hexamethyl ether (205) in 18% overall yield, acting as multidrug-resistant (MDR) phenotype reversal agent [123]. The trisubstituted pyrrole derivative 201 was prepared regioselectively, starting from desoxyveratroin (197) (Scheme 60). The latter, after reaction with N,N-dimethyl formamide dimethyl acetal, furnished enamine 198, which upon chlorination with POCl₃ to 199 and hydrolysis afforded β-chloroenal 200. Reaction of 200 with glycine methyl ester hydrochloride resulted in the pyrrole 201 via the vinylogous iminium salt intermediate A and the dihydro pyrrole B. Alkylation of pyrrole 201 with mesylate ester 202 afforded N-aryl ethyl pyrrole 203, which upon basic hydrolysis led to acid 204. Oxidation of the latter with lead tetraacetate, as in Scheme 58, resulted in the pyrrolo[2,3-c]coumarin derivative, the ningalin B hexamethyl ether (205).

Scheme 60.

Synthesis of ningalin B hexamethyl ether (205).

Peschko et al. developed the synthesis of marine alkaloids ningalin B, lamellarin G and lamellarin K utilizing as a key step in their earlier-applied method for the formation of 3,4-diarylpyrrole-2,5-dicarboxylic acids 207, 212, and 213 from arylpuruvic acids 186, 208, and 209 and 2-arylethylamines 206, 210, and 211, respectively [124]. Oxidation of acids 207, 212, and 213 by led to tetraacetate-furnished pyrrolo[2,3-c]coumarin derivatives 196, 214, and 215 (Scheme 61), which are precursors for the synthesis of ningalin B, lamellarin G and lamellarin K, respectively.

Scheme 61.

Synthesis of pyrrolo[2,3-c]coumarin derivatives 196, 214, 215.

Li et al. reported the total synthesis of lamellarins D and H and ningalin B from 2-(4-isopropoxy-3-methoxyphenyl) acetaldehyde (216) and 2-(3-isopropoxy-4-methoxyphenyl) ethylamine (217) [125]. The key steps for this procedure are three oxidative reactions, first involving AgOAc-mediative oxidative coupling of 216 with 217 to form pyrrole derivative 218, followed by a microwave-accelerated Vilsmaier–Haack reaction to aldehyde 219, which by Lindgren oxidation at 10 °C afforded the acid 220 (Scheme 62). A second oxidative cyclization of the latter with Pb(OAc)₄ furnished pyrrolo[2,3-c]coumarin compound 221, which was the intermediate for the synthesis of lamellarins D and H and ningalin B.

Scheme 62.

Synthesis of pyrrolo[2,3-c]coumarin derivative 221.

Ghandi et al. reported the synthesis of 5-hydroxy-N-substituted-2H-dihydrochromeno[3,4-c]pyrrol-2-one derivatives 224a–l in 52–65% yield by the three-component reactions of salicylaldehydes 222a–d with ethyl acetoacetate (223) and isonitriles 130a–c (Scheme 63). They found that the coumarin ring, like compound 70b, was formed in situ during the reaction of salicylaldeyde (222a) with ethyl acetoacetate (223) [126].

Scheme 63.

Synthesis of 5-hydroxy-N-substituted-2H-dihydrochromeno[3,4-c]pyrrole-2-ones 224a–l.

Alizadeh et al. reported the preparation of 2-acylchromeno[3,4-c]pyrrol-4(2H)-one derivatives 226a–j in 62–95% yield by the one-pot, three-component reaction of salicylaldehyde 222 with β-keto esters 225a,b and tosylmethyl isocyanide (TosMIC) (101) [127]. In the plausible mechanism, Knoevenagel condensation of salicylaldehyde (222a) with methyl acetoacetate (225a) afforded 3-acetylcoumarin A. [3 + 2] Cycloaddition of TosMIC anion B to A furnished intermediate C. Desulfonylation of C with triethylamine produced intermediate D, which upon [1,3]-acyl shift resulted in the product 226a (Scheme 64).

Scheme 64.

Synthesis of 2-acylchromeno[3,4-c]pyrrol-4(2H)-one derivatives 226a–j.

Yu et al. isolated chromeno[4,3-b]pyrrol-4(1H)-one (49a) in 36% yield by treating sulfamate-fused dihydropyrrole (229) with t-BuOK [128]. Compound 229 was prepared by the reaction of sulfamate-derived cyclic imine 227 with ethyl allenoate 228 catalyzed by PPh₃ (Scheme 65).

Scheme 65.

Synthesis of chromeno[4,3-b]pyrrol-4(1H)-one (49a) by treating sulfamate-fused dihydropyrrole (229).

Vidadala and Waldmann synthesized trisubstituted chromeno[3,4-b]pyrrol-4(3H)-one derivatives 234a–ar in 48–88% yield by the one-pot intramolecular 1,3-cycloaddition reaction of azomethine ylides 233a–ar [129]. The latter were prepared in situ from N-Boc-N-alkylated glycine esters 232a–f and aromatic aldehydes 144 (Scheme 66). For the elucidation of the reaction sequence, they performed the deprotection of compound 232a with TFA and the reaction of the produced adduct with benzaldehyde (144a) to isolate a mixture of dihydropyrrolocoumarines A and B. Oxidation of this mixture resulted in the product 234a.

Scheme 66.

Synthesis of chromeno[3,4-b]pyrrol-4(3H)-one derivatives 234a–ar.

Xue et al. developed the FeCl₃-catalyzed synthesis of pyrrolo[3,4-c]coumarins 236a–q in 50–92% yield by the three-component reaction of 2-(2-nitrovinyl)phenols 16l–p, dimethyl acetylenedicarboxylate (235) and amines under formation of a pyranone ring [130]. In the proposed mechanism, nucleophilic addition of 152a to 235 in the presence of FeCl₃ generated intermediate A, which upon nucleophilic addition to 16l afforded intermediate B (Scheme 67). FeCl₃-mediated transesterification formed the pyranone ring with elimination of methanol in adduct C, during Path A. Subsequent nucleophilic attack with abstraction of nitro group furnished dihydropyrrole D, which upon air oxidation resulted in the product 236a. In an alternative mechanism (Path B), intramolecular nucleophilic attack in B and elimination of nitro group afforded dihydropyrrole intermediate E. Air oxidation furnished pyrrole intermediate F, which by transesterification in the presence of FeCl₃ resulted in the product 236a.

Scheme 67.

Synthesis of pyrrolo[3,4-c]coumarins 236a–q.

Ackermann and his colleagues presented the synthesis of lamellarin D and H precursors 241 and 243 [131]. The Ru-catalyzed C-H/N-H activation in an oxidation alkyne annulation process afforded the synthesis of pyrrole 239 from diaryl acetylene 237 and 2-aminoacrylate 238. The Pd-catalyzed annulated formation of lactones 241 and 243 was achieved from 239 in a one-pot bromination/Suzuki cross-coupling procedure with NBS and boronates 240 and 242, respectively (Scheme 68).

Scheme 68.

Synthesis of pyrrolo[2,3-c]coumarin derivatives 172a, 241, and 243.

Lade et al. also used the Ru(II)-catalyzed strategy for the synthesis of pyrrole 250a,b and pyrrolo[2,3-c]coumarin 241 and 251, intermediates for the synthesis of lamellarin D, lamellarin D trimethyl ether, and lamellarin H [132]. The central pyrrole rings of compounds 247a,b were prepared by the [3 + 2] cycloaddition reaction of enamide 246 with diaryl alkynes 237 and 245 under Ru-catalysis and in the presence of Cu(OAc)₂.H₂O as oxidant (Scheme 69). After bromination with NBS to bromo derivatives 248a,b, followed by Suzuki–Miyaura cross-coupling with boronates 249a,b, tetra-substituted pyrrole adducts 250a,b were produced. Deprotection of the latter with TsOH in methanol and subsequent lactonization resulted in the preparation of pyrrolo[2,3-c]coumarin derivatives 241 and 251. In an analogous process, pyrrolo[2,3-c]coumarins 253a–c were prepared in 37–49% yield starting from diaryl alkynes 147c,e,x and enamides 238 and 246.

Scheme 69.

Synthesis of pyrrolo[2,3-c]coumarin derivatives 241, 251, and 253a–c.

Reddy et al. synthesized the chromeno[3,4-b]pyrrol-4(3H)-ones 256a–k in 67–82% yield by the 1,5-electrocyclization of azomethine ylides derived from 3-formyl chromenes 254a–h and N-alkyl glycine methyl esters 255a–c [133]. In the proposed mechanism, the azomethine ylide 257, formed from 3-formyl chromene (254h) and N-Me glycine methyl ester (255a) by 1,5-electrocyclization, led to the intermediate A, which by opening of the pyran ring afforded intermediate B (Scheme 70). Formation of an aromatic pyrrole ring in the intermediate D, followed by lactonization, resulted in the final product 256j.

Scheme 70.

Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones 256a–k.

Morikawa et al. reported the synthesis of ningalin B and lamellarins S and Z using the dibromopyrrolo derivative 260 as starting material [134]. Compound 260 was prepared by bromination of ethyl 1H-pyrrole-3-carboxylate (258) followed by protection of nitrogen with 2-(trimethylsilyl)ethoxymethyl (SEM) to give 259 and subsequent treatment with LDA for the “halogen dance” via the unstable intermediates A and B (Scheme 71). Suzuki–Miyaura coupling of 260 with boronate 261 afforded the diarylated pyrrole ester 262, which upon hydrolysis and Pb(OAc)₄-mediated lactonization furnished pyrrolocoumarin derivative 263, intermediate for the synthesis of ningalin B and lamellarin S. Regioselective Suzuki–Miyaura coupling of 260 with boronate 264 afforded, under monoarylation, pyrrole derivative 265. Second Pd-catalyzed arylation of the latter with boronate 261 furnished diarylated pyrrole 266. Similar treatment of 266 like the above-referred synthesis of compound 263 followed by Mitsunobu N-alkylation with aryl ethanol 267 resulted in the pyrrolocoumarin derivative 268, which was the precursor for the synthesis of lamellarin Z.

Scheme 71.

Synthesis of pyrrolo[2,3-c]coumarin derivatives 263 and 268.

Silyanova et al. presented the synthesis of chromeno[3,4-b]pyrrol-4(3H)-one derivatives in 71–83% yield via selective O-demethylation of 3-(2-methoxyphenyl)pyrrole derivatives 270a–l and treatment of the resulting phenolic derivatives 271a–l with ethanolic NaOH at room temperature [135]. Compounds 270a–l were prepared by the Barton–Zard reaction of nitrostilbenes 269a–l with ethyl isocyanoacetate (Scheme 72).

Scheme 72.

Synthesis of chromeno[3,4-b]pyrrol-4(3H)-one derivatives via Barton–Zard reaction and selective O-demethylation.

Rusanov et al. reported the synthesis of 1-methylchromeno[3,4-b]pyrrol-4(3H)-ones 276a–d and 277 via the Barton–Zard reaction of nitroso compounds 273a–d [136]. Compounds 273a–d were synthesized from styrenes 272a–d and, after the in situ formation of nitrostyrenes A, reacted with isocyano ethyl acetate to give trisubstituted pyrrole derivatives 274a–d (Scheme 73). O-Demethylation of the latter with BBr₃ followed by lactonization resulted in the synthesis of compounds 276a–d in 9–31% yield from 272a–d. When four equivalents of BBr₃ were used in the case of 274d, complete O-demethylation occurred to give dihydroxy derivative 277 in 72% yield.

Scheme 73.

Synthesis of 1-methylchromeno[3,4-b]pyrrol-4(3H)-ones 276a–d and 277.

Recently, Das et al. reported the synthesis of 1-acylchromeno[3,4-b]pyrrol-4(3H)-one derivatives 34j, 279a–ah in 37–84% yield by the [3 + 2] cycloaddition reaction of ethyl isocyanoacetate with the double bond of 2-hydroxychalcones 278a–ai followed by intramolecular lactonization, in a tandem process in the presence of AgOAc and Cs₂CO₃ [137]. In the proposed reaction mechanism, AgOAC with ethyl isocyanoacetate generated the 1,3-dipole A, which underwent [3 + 2] cycloaddition at the double bond of chalcone 278a, affording intermediate B. Reaction of the latter with acetic acid furnished the intermediate C, which by tautomerization and oxidation afforded the pyrrole intermediate D. Intramolecular lactonization in the presence of Cs₂CO₃ resulted in the final product 34j (Scheme 74).

Scheme 74.

Synthesis of 1-ketylchromeno[3,4-b]pyrrol-4(3H)-one derivatives 34j, 279a–ah by tandem [3 + 2] cycloaddition/lactonization.

Very recently, Scalzullo et al. synthesized chromenone-fused pyrrolizines like 280 by oxidation of the corresponding pyrrole carboxylic acid 279 in low yield of 34% to prepare pyrrolizine-lamellarin analogues [138]. The phenolic enaminones 283a,b, prepared by the reaction of iodide 281a,b with thiolactam 282, resulted in the preparation of 9,10-dihydrochromeno[4,3-b]pyrrolizin-6(8H)-ones 284a,b in 86% yield after the formation of dihydropyrrolizine moiety, followed by lactonization (Scheme 75).

Scheme 75.

Synthesis of chromenone-fused pyrrolizines.

3. Conclusions

The present literature review showcases that the synthesis of 3,4-fused pyrrolocoumarins is achieved mainly by two routes. The formation of pyrrole moiety by one route is accomplished from a coumarin derivative, such as aminocoumarin, hydroxycoumarin, chlorocoumarin, or other coumarins. In the other route, a pyranone framework is formed from an existing pyrrole derivative. 1,3-Dipolar cycloaddition reactions, Michael reaction, aza-Claisen rearrangement reactions, MCR, as well as metal-catalyzed reactions are used in these syntheses. Name reactions, such as Fischer indole synthesis, Van Leusen type reaction, Ugi reaction, Aza-Wacker type cyclization, and Barton–Zard reaction, are useful for the synthesis of intermediates or final products.

Pyrrolocoumarins present cytotoxic, antifungal, antibacterial, α-glucosidase inhibition, antioxidant, lipoxygenase (LOX) inhibition, and fluorescent activities, and are used as BZR ligands. Especially, chromeno[3,4-b]pyrrol-4(3H)-one derivatives exhibited cytotoxic activity, and chromeno[4,3-b]pyrrol-4(1H)-one derivatives showed cytotoxic, fluorescence, antifungal, and lipoxygenase inhibitory activities or acted as BZR ligands, while 1-thiochromeno[3,4-c]pyrrole-3,4-dione derivatives revealed antibacterial and antifungal activities. 1,2-Dihydrochromeno[4,3-b]pyrrole-3,4-dione (22) was found to be 1.5-fold more toxic than 5-fluorouracil. 2-(2-(4-Methoxyphenyl)-4-oxo-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)acetonitrile (136d) was 19-fold more potent than acarbose in α-glucosidase inhibitory activity. 7-Methoxy-1,2-diphenylchromeno[3,4-b]pyrrol-4(3H)-one (172p) differentiated Cr(VI) ions from Cr(III) ions in fluorometric studies.

We want this review to benefit researchers in the field not only of pyrrolocoumarin derivatives but in coumarins in general.

Author Contributions

Investigation, resources, writing—original draft preparation, E.K.; supervision, project administration, writing—review and editing, K.E.L. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding Statement

This research received no external funding.