Next Article in Journal
The Chemical Compositions, and Antibacterial and Antioxidant Activities of Four Types of Citrus Essential Oils
Next Article in Special Issue
Curcumin–Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders
Previous Article in Journal
Toxic Metal Species and ‘Endogenous’ Metalloproteins at the Blood–Organ Interface: Analytical and Bioinorganic Aspects
Previous Article in Special Issue
Antiplatelet Activity of Coumarins: In Vitro Assays on COX-1
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 26
Issue 11
10.3390/molecules26113409
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms

by
Eslam Reda El-Sawy
1,
Ahmed Bakr Abdelwahab
2 and
Gilbert Kirsch
3,*
1
National Research Centre, Chemistry of Natural Compounds Department, Dokki, Cairo 12622, Egypt
2
Plant Advanced Technologies (PAT), 54500 Vandoeuvre-les-Nancy, France
3
Laboratoire Lorrain de Chimie Moléculaire (L.2.C.M.), Université de Lorraine, 57078 Metz, France
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(11), 3409; https://doi.org/10.3390/molecules26113409
Submission received: 11 May 2021 / Revised: 29 May 2021 / Accepted: 31 May 2021 / Published: 4 June 2021
(This article belongs to the Special Issue Coumarin and Its Derivatives)
Browse Figures
Versions Notes

Abstract

:
Coumarins are natural heterocycles that widely contribute to the design of various biologically active compounds. Fusing different aromatic heterocycles with coumarin at its 3,4-position is one of the interesting approaches to generating novel molecules with various biological activities. During our continuing interest in assembling information about fused five-membered aromatic heterocycles, and after having presented mono-hetero-atomic five-membered aromatic heterocycles in Part I. The current review Part II is intended to present an overview of the different synthetic routes to coumarin (benzopyrone)-fused five-membered aromatic heterocycles with multi-heteroatoms built on the pyrone ring, covering the literature from 1945 to 2021.

1. Introduction

The fusion of the pyrone ring with the benzene nucleus gives rise to a class of heterocyclic compounds known as benzopyrone [1]. Coumarin is one of the benzopyrones (1,2-benzopyrones or 2H-[1] benzopyran-2-ones) and represents an important family of oxygen-containing heterocycles widely distributed in nature [1]. The incorporation of another heterocyclic moiety into coumarin enriches the properties of the parent structure and the resulting compounds may exhibit promising properties [2,3,4,5]. Certain derivatives of 3,4-heterocycle-fused coumarins play an important role in medicinal chemistry and have been extensively used as versatile building blocks in organic synthesis [2,3,5,6,7]. Many examples of biologically active coumarins containing 3,4-heterocycles-fused were cited in the literature [2,3,8] including antimicrobial [9,10,11,12], antiviral [13,14], anticancer [15,16,17], antioxidant [18,19], and anti-inflammatory [20,21] activities.
The development of synthetic pathways towards active coumarins containing heterocyclics has attracted great interest from researchers [5]. Significant efforts have been focused on developing new methodologies to enrich structural libraries and reduce the number of synthetic steps of novel coumarin derivatives [5,22].
In proceeding to our interest in coumarin(benzopyrone)-fused five-membered aromatic heterocycles built on the α-pyrone ring, which was recently issued in Part I [22]. The present review, Part II, describes the components which have multi heteroatom in an aromatic fused ring with the pyrone part of coumarin. The synthetic pathways of the investigated scaffolds provided systems containing oxygen, nitrogen, and sulfur in their core structure.

2. Synthesis of Benzopyrone-Fused Five-Membered Aromatic Heterocycles

2.1. Five-Membered Aromatic Rings with Two Heteroatoms

2.1.1. Two Identical Heteroatoms (N-N)

Pyrazole

Fusion of pyrazole ring with the pyrone ring of coumarin results in formation of two structural isomers, namely chromeno[4,3-c]pyrazol-4(2H)-one, chromeno[4,3-c]pyrazol-4(1H)-one, (1H-benzopyrano[4,3-c]pyrazole), and chromeno[3,4-c]pyrazol-4(2H)-one, chromeno[3,4-c]pyrazol-4(3H)-one, (1H-benzopyrano[3,4-c]pyrazole) (Figure 1).
  • Chromeno[4,3-c]pyrazol-4(2H)-one; (1H-Benzopyrano[4,3-c]pyrazole)
Many synthetic protocols reported the synthesis of chromeno[4,3-c]pyrazol-4(2H)-one including the pyrazole and/or the pyrone-ring construction. The synthesis of the pyrazole ring in the literature started from coumarin, 4-hydroxy, 3-aldehyde, or 3-acetyl coumarin in addition to the chromone derivatives.
  • Pyrazole Construction
Shawali and his co-workers described the 1,3-dipolar additions of diphenylnitrilimine (DPNI) to coumarin (1) to afford 1,3-diphenyl-3a,9b-dihydro-4-oxo-1H-chromeno[4,3-c]pyrazol-4(1H)one (2) [23]. Upon dehydrogenation of 2 with lead tetra-acetate the corresponding 1,3-diphenyl-chromeno[4,3-c]pyrazol-4(1H)one (3) was obtained (Scheme 1).
3-Aminochromeno[4,3-c]pyrazol-4(1H)one (8) was prepared through multi-step reactions starting from 4-hydroxycoumarin (4) [24]. Vilsmeier–Haack formylation of 4 developed 4-chlorocoumarin-3-carboxaldehyde (5). The reaction of 5 with hydroxylamine hydrochloride followed with phosphorus oxychloride gave the corresponding 4-chlorocoumarin-3-carbonitrile (7). Compound 7 under the reaction with hydrazine hydrate provided the target compound, 3-aminochromeno[4,3-c]pyrazol-4(1H)one (8) (Scheme 2).
The preparation of chromen[4,3-c]pyrazol-4-ones 9 from the reaction of 3-formyl-4-chlorocoumarin (5) with the appropriate aryl or alkyl hydrazine hydrochloride in the presence of base was intensively investigated (Scheme 3) [10,18,19,25,26,27,28,29,30]. Compound 9a was employed as starting material to enrich the derivatives of chromen[4,3-c]pyrazol-4-ones 10–12 through the reaction with benzyl bromides [26], alkyl sulfonyl chlorides [28], or N-piperazine sulfonyl chlorides [30] (Scheme 4).
Steinfiihrer et al., synthesized chromeno[4,3-c]pyrazol-4(2H)-ones 16 in a three-step reaction starting from 4-hydroxycoumarin derivatives 13. The intermediate, 4-azido-3-coumarincarboxaldehydes 15 was produced in situ from 4-chlorocoumarin-3-carboxaldehydes 14 which subsequently reacted with some hydrazine derivatives to deliver the final products (Scheme 5) [31].
Additionally, 3-coumarinyl alkyl ketones, such as 4-hydroxy-3-acetylcoumarin (17a) [32], and 3-coumarinyl phenyl ketone (17b) [12] were the starting materials in the preparation of chromeno[4,3-c]pyrazol-4(2H)-ones 18 and 19 by the base-catalyzed reaction with hydrazine hydrate (Scheme 6).
The transformation of three-substituted chromone to chromeno[4,3-c]pyrazol-4(2H)-ones was within the scope of interest of Ibrahim’s research group [33,34,35,36]. In 2008, they studied the ring transformation of chromone-3-carboxylic acid (20) under the reaction with 2-cyanoacetohydrazide or the hydrazine hydrate as the nucleophile to give the corresponding chromeno[4,3-c]pyrazol-4(2H)-one (9a) (Scheme 7) [33]. Furthermore, they examined the chemical reactivity of chromone-3-carboxamide (21) towards hydrazine hydrate or phenylhydrazine and they could construct the pyrazole within the scaffold (Scheme 7) [34]. Furthermore, 3-cyano-2,6-dimethyl chromone (23) was allowed to react with the nucleophile S-benzyldithiocarbazate to afford the corresponding 6,8-dimethyl chromeno[4,3-c]pyrazol-4(2H)-one (24) (Scheme 7) [35,36].
Another synthetic pathway was performed by the dissociation of a large molecule in an acidic medium. [1]Benzopyrano[4,3-c][1,5]benzodiazepin-7(8H)-one (25) was prone to lose o-phenylenediamine in a reaction with some N-binucleophiles, such as hydrazine and methyl hydrazine that led exclusively to chromeno[4,3-c]pyrazol-4(2H)-ones 9a and 26 (Scheme 8) [37].
  • Pyrone Construction
Lokhande et al. introduced a simple and convenient method for the synthesis of fused chromeno[4,3-c]pyrazol-4(2H)-one. It was accomplished using iodine catalyzed oxidative cyclization of 3-(2-hydroxyaryl)-1-phenyl-1H-pyrazole-4-carbaldehydes 27 or 3-(2-(allyloxyaryl)-1-phenyl-1H-pyrazole -4-carbaldehydes 28 in dimethyl-sulfoxide that supplied the corresponding 2-phenyl-pyrazolo[4,3-c]coumarins 29 (Scheme 9) [38]. The reaction was initially performed with (5%) of iodin in dimethyl-sulfoxide in the presence of H2SO4 at 60 °C using known methods, but the reaction did not take place. To overcome this problem, the reaction was carried out by increasing the iodine ratio to 10% and raising the temperature to 120 °C, which gave good results. This pathway has an advantage over the previous pyrazole construction methods which were relatively unstable and gave a mixture of isomeric 1-aryl and 2-arylpyrazolo[4,3-c]coumarins [25,39].
Raju and his co-workers described the synthetic strategy for chromeno[4,3-c]pyrazol-4(1H)ones 34 and 2-tosyl-chromeno[4,3-c]pyrazol-4(1H)ones 35. The pathway started from a reaction between salicylaldehydes 30 and p-toluenesulfonyl hydrazide 31. It proceeded towards salicylaldehyde tosylhydrazone 32 which was in situ reacted with 3-oxobutanoates 33 in presence of lanthanum tris(trifluoromethanesulfonate) to deliver the desired coumarin (Scheme 10) [40].
  • Chromeno[3,4-c]pyrazol-4(2H)-one; (1H-Benzopyrano[3,4-c]pyrazole)
  • Pyrazole Construction
The literature reported numerous synthetic routes for chromeno[3,4-c]pyrazol-4(2H)-one. A simple pathway beginning from the 1,3-dipolar cycloaddition of diphenylnitrilimine (DPNI) to 3-ethoxy carbonyl coumarin (36) to build the pyrazole moiety 37. Treatment of the ester (37) with an aqueous solution of potassium hydroxide (10%) gave the corresponding acid (38). Decarboxylation of 37 was accompanied by dehydrogenation which facilitated the attainment of 1,3-diphenyl-chromeno[3,4-c]pyrazol-4(1H)one (39) in a considerable yield (Scheme 11) [41].
On the other hand, thermal conversion of 4-diazo-methyl coumarins 40 into the corresponding chromeno[3,4-c]pyrazol-4(2H)-ones 41 in toluene followed the pathway depicted in Scheme 12 [42,43]. The presence of the alkyl substituent at the peri position to the attached diazo-methyl group in coumarins markedly destabilized the diazo-methyl group and facilitated the pyrazole isomerization.
Hydrazonyl halides played an important role in the preparation of chromeno[3,4-c]pyrazol-4(2H)-ones [11]. This coumarin was accessible from the reaction of hydrazonyl halides 42 with 3-acetylcoumarin (43) or 3-benzoylcoumarin (17b) in the presence of triethylamine. Subsequently, the dihydro-products 44 were refluxed in aqueous potassium hydroxide (10%) solution, and toluene successively to give chromeno[3,4-c]pyrazol-4(2H)-ones 45 (Scheme 13). Alternatively, compounds 45 were synthesized via cycloaddition of the hydrazonyl halides 42 to the 3-phenylsuphonylcoumarin (46), or the 3-bromocoumarin (47). The thermal elimination of benzenesulfinic acid or hydrogen bromide from the corresponding cyclo-adducts 48 resulted in the target 45 (Scheme 13).

Imidazole

Fusion of the imidazole ring with the pyrone ring of coumarin leads to one structural isomer, namely chromeno[3,4-d]imidazol-4-one, chromeno[3,4-d]imidazole-4(3H)-one, (1H-benzopyrano[3,4-d]imidazole) (Figure 2).
  • Chromeno[3,4-d]imidazol-4-one; (1H-Benzopyrano[3,4-d]imidazole)
  • Imidazole Construction
Few synthetic routes to prepare benzo-pyrano-imidazoles were reported. The main synthetic approach involved the condensation of 3,4-diaminocoumarin (49) with different reagents [7,44]. Kitan and his coworkers elaborated a simple synthetic route of novel 1H-benzopyrano[3,4-d]imidazole-4-one starting from the in situ prepared 3,4-diaminocoumarin (49) by catalytic hydrogenation of 4-amino-3-nitrocoumarin. The condensation of 3,4-diaminocoumarin (49) with different acids including formic acid, acetic acid, or formaldehyde in presence of concentrated hydrochloric acid established 1H-benzopyrano[3,4-d]imidazoles 50 (Scheme 14) [7]. On the other hand, different series of 3-N-(4-aminocoumarin-3-yl)aroylamides 51 and 3-N-arylidenamino-4-aminocoumarins 52 were prepared from 3,4-diaminocoumarin 49. Cyclization of 51 and 52 under heating, or in the presence of lead tetraacetate resulted in the fused 2-substituted 4H-chromeno[3,4-d]oxazol-4-ones 53 (Scheme 14) [44].
Trimarco’s research group developed a new method to synthesize substituted [1]benzopyrano[3,4-d]imidazol-4(3H)-ones bearing hydrogen or alkyl groups on N-3, and alkyl or amino substituents on C-2 in good yields [45]. 2-Alkyl-[1]benzopyrano[3,4-d]imidazol-4(3H)-ones 57 were obtained from acetamidines 56 carrying a 3-nitrocoumarin group at N-1 by reduction with sodium borohydride/palladium 10% (Scheme 15) [45]. Benzopyranoimidazoles 58 of an amino substituent on C-2 were obtained by refluxing 56 in excess of triethyl phosphite (Scheme 15) [45].

2.1.2. Two Different Heteroatoms

Thiazole and Isothiazole

4H-chromeno[3,4-d]thiazol-4-one (1H-benzopyrano[3,4-d]thiazole), 4H-chromeno[3,4-c]isothiazol-4-one (1H-benzopyrano[3,4-c]isothiazole), and 4H-chromeno[3,4-d]isothiazol-4-one (1H-benzopyrano[3,4-d]isothiazole) are isomers of the fused five-member ring (containing N and S atoms) with the pyrone ring of coumarin (Figure 3).
  • 4H-Chromeno[3,4-d]thiazol-4-one
  • Thiazole Construction
The reaction of 4-chloro-3-nitrocoumarin (59) with carbon disulfide in ethanol in the presence of sodium hydrogen sulfate produced 4H-chromeno[3,4-d]thiazol-4-one (60) (Scheme 16) [7].
In situ prepared 4-aroylthio-3-nitrocoumarins 62 which was obtained from the reaction of 4-mercapto-3-nitrocoumarin (61) with different aroyl chlorides were allowed to cyclize in the presence of iron and glacial acetic acid that gave 2-aryl-4H-benzopyrano[3,4-d]thiazol-4-ones 63 (Scheme 17) [44].
Anwar et al. employed a facile, green, and efficient, one-pot multicomponent reaction (MCR) catalyzed by iron(III) chloride to synthesize the coumarin annulated 2-aminothiazole (65) (Scheme 18) [46].
Transition metal-free oxidative coupling for the formation of C–S bonds was employed to synthesize different 4H-chromeno[3,4-d]thiazol-4-ones. The key point in C–H bond activation of 3-(benzylamino)-4-bromo-substituted chromenone derivatives 66 was the presence of sodium sulfide as a source of sulfur, and iodine as a catalyst. The terminal oxidation was performed by H2O2 to form various 2-phenyl-4H-chromeno(3,4-d)thiazol-4-one derivatives 67 (Scheme 19) [47].
  • 4H-Chromeno[3,4-c]isothiazol-4-one
  • Pyrone Construction
The 1,3-dipolar cycloaddition reactions of nitrile sulfides (RC-N≡S-) played a particular role in the synthesis of 4H-chromeno[4,3-c]isothiazole [48,49,50]. For example, heating of acetylenic oxathiazolone (68) in xylene afforded 4-oxo-3-phenyl-4H-chromeno[4,3-c]isothiazole (69) [48]. The initial step of the reaction was decarboxylation of the oxathiazolone followed by intramolecular 1,3-dipolar cycloaddition of the resulting nitrile sulfide (70) to the adjacent alkyne (Scheme 20).
In 2010, Fordyce et al. improved a synthetic approach of 4H-chromeno[4,3-c]isothiazole as a result of the 1, 3-dipolar cycloaddition reactions of o-hydroxybenzonitrile sulfide (72), generated by microwave-assisted decarboxylation of oxathiazolone (71) [51]. The reaction of the o-hydroxyphenyloxathiazolone (73) with dimethyl acetylenedicarboxylate DMAD (1:2) in ethyl acetate supplied methyl 4-oxo-4H-chromeno[4,3-c]isothiazole-3-carboxylate (74) (Scheme 21).
In 2017, Lee and his coworkers reported an efficient intramolecular Rh-catalyzed transannulation of thiadiazoles linked to cyanoalkoxycarbonyl. The ring closure of compound 75 was catalyzed by 1,1′-bis(diphenylphosphino) ferrocene DPPF to form the corresponding 8-substituted-3-phenyl-4H-chromeno[4,3-c]isothiazol-4-ones 76 in good yields of 90–99% (Scheme 22) [52].
  • 4H-Chromeno[3,4-d]isothiazol-4-one
Up to our knowledge, only one article discussed the synthesis of 4H-chromeno[3,4-d]isothiazol-4-one [53]. The reported method included cyclization of 4-mercapto-2-oxo-2H-chromene-3-carboxamide (77) on heating with bromine in ethyl acetate to form 2-hydroxy-4H-chromeno[3,4-d]isothiazol-4-one (78) (Scheme 23).

Oxazole and Isoxazole

Fusion of a five-member ring containing (N and O atoms) with the pyrone ring of coumarin leads to four structural isomers, viz. 4H-chromeno[3,4-d]oxazol-4-one, 4H-chromeno[4,3-d]oxazol-4-one, 4H-chromeno[3,4-d]isoxazol-4-one and 4H-chromeno[4,3-c]isoxazol-4-one (Figure 4).
  • 4H-Chromeno[3,4-d]oxazol-4-one
  • Oxazole Construction
Rhodium(II)-catalyzed reactions of 3-diazo-2,4-chromenedione (79) with several nitriles, such as acetonitrile, chloroacetonitrile and phenylacetonitrile established 2-substituted-4H-chromeno[3,4-d]oxazol-4-ones 80 (Scheme 24) [54]. The 3-diazo-2,4-chromenedione (79) was prepared by the diazo-transfer reaction of the corresponding 4-hydroxycoumarin (4) with mesyl azide according to Taber’s method [55].
3-Nitro-4-hydroxycoumarin was crucial for the preparation of 2-substituted-4H-chromeno[3,4-d]oxazol-4-one. In 1961, Dallacker et al. reported the preparation of 3-nitrocoumarin (73) from 4-hydroxycoumarin (4) upon nitration with nitric acid in glacial acetic acid. Reduction of 81 by Raney nickel in presence of propionic anhydride afforded the corresponding N-(4-hydroxy-2-oxo-2H-chromen-3-yl)- propionamide (82). Intramolecular cyclization of amide 82 by heating in acetic anhydride afforded 2-ethyl-4H-chromeno[3,4-d]oxazol-4-one (83) (Scheme 25) [56].
In 2018, Litinas and his coworkers summarized the previous scheme in a green chemistry methodology [57]. They described the reaction of 4-hydroxy-3-nitrocoumarin (81) with acids in a one-pot reaction in the presence of PPh3 and P2O5 under microwave irradiation. Another one-pot two-step reaction was accomplished in the presence of Pd/C and hydrogen, followed by treatment with P2O5 under microwave irradiation (Scheme 26) [57].
  • Pyrone and Oxazole Construction
Wilson and his coworkers reported a high yield six-step synthesis of 7-hydroxy-2,6-dimethylchromeno[3,4-d]oxazol-4-one (91) from commercially available 2,4-dihydroxy-3-methyl-acetophenone [58]. The chemoselective benzylation of 2,4-dihydroxy3-methylacetophenone (85) gave the corresponding 4-benzyloxy derivative (86). Compound 86 was converted into the 4-hydroxycoumarin derivative (87) using diethyl carbonate and sodium hydride. Nitration of 87 with fuming nitric acid in chloroform at room temperature afforded the nitro derivative (88). Reduction of 88 using zinc in refluxing acetic acid afforded 3-acetamido-4,7-dihydroxycoumarin (89). Cyclization of 89 was achieved using pyridine-buffered POCl3 in THF under the Robinson–Gabriel mechanism. Finally, 7-hydroxy-2,6-dimethylchromeno[3,4-d]oxazol-4-one (91) was attainable through the debenzylation of oxazole 90 (Scheme 27) [58].
  • 4H-Chromeno[4,3-d]oxazol-4-one
  • Oxazole Construction
Regarding 4H-chromeno[4,3-d]oxazole-4-one, only one article mentioned the preparation of such a fused system [59]. In 2004, Ray and Paul reported the synthesized 4H-chromeno[4,3-d]oxazole-4-one (92) via the reaction of 4-hydroxycoumarin (4) with formamide under reflux (Scheme 28).
  • 4H-Chromeno[3,4-d]isoxazol-4-ones
  • Isoxazole Construction
4-Chromanone (93) was found to be one of the key compounds for the preparation of fused coumarin-isoxazole. 4-chromanone (93) was treated by a lower alkyl oxalate such as ethyl oxalate, in the presence of a suitable base (e.g., sodium amide, sodium methoxylate, or sodium hydride) in an anhydrous reaction medium. The obtained 4-oxo-chroman-3-glyoxylate (94) was refluxed with hydroxylamine hydrochloride in ethanol to create the fused isoxazole ring and ethyl 4H-chromeno[3,4-d]isoxazole-3-carboxylate (95) was formed (Scheme 29) [60].
Additionally, Sosnovskikh et al. studied the chemical transformation of the 3-cyanochromone (96) when reacted with hydroxylamine hydrochloride in basic condition. The cyclization at the CN group linked to the opened pyrone ring gave the corresponding 2-amino-3-carbamoylchromone (98). The re-cyclization of 98 exploiting another molecule of hydroxylamine led to the formation of 2-amino-4H-chromeno[3,4-d]isoxazol-4-one (99) (Scheme 30) [61].
On the other hand, the reactivity of 3-ethoxycarbonyl-2-methyl substituted 5,6,7,8-tetrafluorochromone (100) toward hydroxylamine in an alkaline medium was explored [62]. Wherever the pyrone ring was firstly opened, hydroxylamine was involved in the isoxazole ring formation of 101. Moreover, the cyclization to the corresponding 2-methyl-4H-6,7,8,9-tetrafluorochromeno[3,4-d]isoxazol-4-one (102) was performed by sulfuric acid treatment (Scheme 31) [62].
  • 4H-Chromeno[4,3-c]isoxazol-4-one
  • Isoxazole Construction
The synthesis of 4H-chromeno[4,3-c]isoxazol-4-one starting from 4-azido-3-hydroxycoumarin was scarcely reported. Vilsmeier–Haack reagent supplied the system with chloride and formyl moieties (14). The chloride was replaced by azido when compound 14 was treated by NaN3 to produce 4-azido-3-coumarin carboxaldehyde 15. This last decomposed thermally to be depleted from nitrogen and spontaneously cyclized to 4H-chromeno[4,3-c]isoxazol-4-ones 103 (Scheme 32) [31].

2.2. Five-Membered Aromatic Rings with Three Heteroatoms

2.2.1. Three Identical Heteroatoms

Triazole

Fusion of the triazole ring with the pyrone ring of coumarin leads to one structural isomer (chromeno[3,4-d][1,2,3]triazol-4(9bH)-one) (Figure 5).
  • Chromeno[3,4-d][1,2,3]triazol-4(9bH)-one
  • Triazole Construction
Dean and Park indicated the elimination of the sulphenic acid moiety during the addition of the corresponding 3-(4-methylphenylsulphinyl)coumarin (104) to sodium azide forming 4H-chromeno[3,4-d][1,2,3]triazol-(3H)4-one (105) (Scheme 33) [63].
A low to moderate yield of 4H-chromeno[3,4-d][1,2,3]triazol-(3H)4-ones 107 was obtained when 1,5-dipolar electro-cyclization took place within 4-azidocoumarins 106 that was induced by t-butoxide (Scheme 34) [64].
A wide range of research demonstrated that 3-nitrocoumarin was the key compound for the synthesis of fused coumarin-triazole [65,66,67]. Vaccaro and his coworkers subjected the 3-nitrocoumarins 108 to a [3 + 2] cycloaddition with trimethylsilyl azide (TMSN3) under a solvent-free condition (SFC). Tetrabutylammonium fluoride (TBAF) acted as a catalyst during the reaction to supply a series of 4H-chromeno[3,4-d][1,2,3]triazol-(3H)4-ones 109 (Scheme 35) [65]. This method confirmed that ammonium halogen TBAF salt can be efficaciously employed as a non-metallic catalyst for activating the silicon–nitrogen bond under SFC.
In 2012, the formation of 4H-chromeno[3,4-d][1,2,3]triazol-(3H)4-ones 111 was described through a catalyst-free 1,3-dipolar cycloaddition of 3-nitrocoumarins 110 to sodium azide (Scheme 36). It was found that good yields were obtained in the presence of electron-withdrawing substituent on the aryl ring of 3-nitrocoumarins 110. The reaction gave the best yield in DMSO at 80 °C after three lower temperatures attempts [66]. By applying this reaction, a novel group of 4H-chromeno[3,4-d][1,2,3]triazol-(3H)4-ones was achieved using microwave-assisted green chemistry procedures (Scheme 36) [67].

2.2.2. Three Different Heteroatoms

Thiadiazole

Fusion of thiadiazole ring with the pyrone ring of coumarin furnishes one structural isomer, namely 4H-chromeno[3,4-c][1,2,5]thiadiazol-4-one (Figure 6).
  • 4H-Chromeno[3,4-c][1,2,5]thiadiazol-4-one
  • Thiadiazole Construction
Synthesis of the 4H-chromeno[3,4-c][1,2,5]thiadiazol-4-one was reported by only one research article that belongs to Smirnov and his co-workers [68]. The reaction of 3,4-diaminocoumarin (49) with thionyl chloride in pyridine gave 4H-chromeno[3,4-c][l, 2,5]thiadiazol-4-one (112) (Scheme 37).
In summary, coumarins are one of the heterocyclic structures of great interest in the development of valuable biologically active structures. Since coumarins have versatile applications, synthesis trials of different structures of the coumarin-based scaffold were attempted. The different synthetic routes to synthesize coumarin (benzopyrone)-fused five-membered aromatic heterocycles with multi-heteroatoms built on the pyrone ring were discussed in this review to shed light on the evolution in synthetic methods. We found that the starting scaffolds for this preparation were mainly 4-hydroxy, 4-amino, 3,4-diamino, and 3-nitro derivatives of coumarin. Moreover, other various methods of building the pyrone ring from simple functionalized compounds were discussed. To date, 4H-chromeno[4,3-d]thiazol-4-one, 4H-chromeno[3,4-c][1,2,5]selenadiazol-4-one, and 4H-chromeno[3,4-c][1,2,5]oxadiazol-4-one (Figure 7) have not been feasible by any synthetic procedures.

Author Contributions

E.R.E.-S. and G.K. collected publications and sorted them. E.R.E.-S. analyzed the literature and wrote the first draft. A.B.A. and G.K. developed the concept of the review. E.R.E.-S., A.B.A. and G.K. wrote the final draft and corrected the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sethna, S.M.; Shah, N.M. The Chemistry of Coumarins. Chem. Rev. 1945, 36, 1–62. [Google Scholar] [CrossRef]
  2. Medina, F.G.; Marrero, J.G.; Macías-Alonso, M.; González, M.C.; Córdova-Guerrero, I.; García, A.G.T.; Osegueda-Robles, S. Coumarin heterocyclic derivatives: Chemical synthesis and biological activity. Nat. Prod. Rep. 2015, 32, 1472–1507. [Google Scholar] [CrossRef]
  3. Molnar, M.; Lončarić, M.; Kovač, M. Green Chemistry Approaches to the Synthesis of Coumarin Derivatives. Curr. Org. Chem. 2020, 24, 4–43. [Google Scholar] [CrossRef]
  4. Salehian, F.; Nadri, H.; Jalili-Baleh, L.; Youseftabar-Miri, L.; Bukhari, S.N.A.; Foroumadi, A.; Küçükkilinç, T.T.; Sharifzadeh, M.; Khoobi, M. A review: Biologically active 3,4-heterocycle-fused coumarins. Eur. J. Med. Chem. 2021, 212, 113034. [Google Scholar] [CrossRef]
  5. Geetika, P.; Subhash, B. Review on Synthesis of Bio-Active Coumarin-Fused Heterocyclic Molecules. Curr. Org. Chem. 2020, 24, 2566–2587. [Google Scholar]
  6. Lončar, M.; Jakovljevi, Ć.M.; Šubarić, D.; Pavlić, M.; Služek, V.B.; Cindrić, I.; Molnar, M. Coumarins in Food and Methods of Their Determination. Foods 2020, 9, 645. [Google Scholar] [CrossRef]
  7. Trkovnik, M.; Kalaj, V.; Kitan, D. Synthesis of new heterocyclocoumarins from 3,4-diamino- and 4-chloro-3-nitrocoumarins. Org. Prep. Proced. Int. 1987, 19, 450–455. [Google Scholar] [CrossRef]
  8. Önder, F.C.; Durdaği, S.; Sahin, K.; Özpolat, B.; Ay, M. Design, Synthesis, and Molecular Modeling Studies of Novel Coumarin Carboxamide Derivatives as eEF-2K Inhibitors. J. Chem. Inf. Model. 2020, 60, 1766–1778. [Google Scholar] [CrossRef] [PubMed]
  9. Sahoo, C.R.; Sahoo, J.; Mahapatra, M.; Lenka, D.; Sahu, P.K.; Dehury, B.; Padhy, R.N.; Paidesetty, S.K. Coumarin derivatives as promising antibacterial agent(s). Arab. J. Chem. 2021, 14, 102922. [Google Scholar] [CrossRef]
  10. Mulwad, V.; Shirodkar, J. Synthesis of Some of the Antibacterial Compounds from 4-Hydroxycoumarins: Part II. Ind. J. Chem. 2002, 41B, 1263–1267. [Google Scholar]
  11. Abunada, N.M.; Hassaneen, H.M.; Abu Samaha, A.S.M.; Miqdad, O.A. Synthesis and antimicrobial evaluation of some new pyrazole, pyrazoline and chromeno[3,4-c]pyrazole derivatives. J. Braz. Chem. Soc. 2009, 20, 975–987. [Google Scholar] [CrossRef] [Green Version]
  12. El-Saghier, A.M.M.; Naili, M.B.; Rammash, B.K.; Saleh, N.A.; Kreddan, K.M. Synthesis and antibacterial activity of some new fused chromenes. Arkivoc 2007, 2007, 83–91. [Google Scholar] [CrossRef] [Green Version]
  13. Mishra, S.; Pandey, A.; Manvati, S. Coumarin: An emerging antiviral agent. Heliyon 2020, 6, e03217. [Google Scholar] [CrossRef] [Green Version]
  14. Reddy, M.V.R.; Rao, M.R.; Rhodes, D.; Hansen, M.S.T.; Rubins, K.; Bushman, F.D.; Venkateswarlu, Y.; Faulkner, D.J. Lamellarin α 20-Sulfate, an Inhibitor of HIV-1 Integrase Active against HIV-1 Virus in Cell Culture. J. Med. Chem. 1999, 42, 1901–1907. [Google Scholar] [CrossRef] [PubMed]
  15. Boger, D.L.; Soenen, D.R.; Boyce, C.W.; Hedrick, M.P.; Jin, Q. Total Synthesis of Ningalin B Utilizing a Heterocyclic Azadiene Diels−Alder Reaction and Discovery of a New Class of Potent Multidrug Resistant (MDR) Reversal Agents. J. Org. Chem. 2000, 65, 2479–2483. [Google Scholar] [CrossRef] [PubMed]
  16. Neagoie, C.; Vedrenne, E.; Buron, F.; Mérour, J.-Y.; Roşca, S.; Bourg, S.; Lozach, O.; Meijer, L.; Baldeyrou, B.; Lansiaux, A.; et al. Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues: A novel DYRK1A inhibitor class. Eur. J. Med. Chem. 2012, 49, 379–396. [Google Scholar] [CrossRef]
  17. Rajabi, M.; Hossaini, Z.; Khalilzadeh, M.A.; Datta, S.; Halder, M.; Mousa, S.A. Synthesis of a new class of furo[3,2-c]coumarins and its anticancer activity. J. Photochem. Photobiol. B Biol. 2015, 148, 66–72. [Google Scholar] [CrossRef] [PubMed]
  18. Al-Ayed, A.S. Synthesis of New Substituted Chromen[4,3-c]pyrazol-4-ones and Their Antioxidant Activities. Molecules 2011, 16, 10292–10302. [Google Scholar] [CrossRef] [Green Version]
  19. Hamdi, N.; Fischmeister, C.; Puerta, C.; Valerga, P. A rapid access to new coumarinyl chalcone and substituted chromeno[4,3-c]pyrazol-4(1H)-ones and their antibacterial and DPPH radical scavenging activities. Med. Chem. Res. 2010, 20, 522–530. [Google Scholar] [CrossRef]
  20. Hosni, H.M.; Abdulla, M. Anti-inflammatory and analgesic activities of some newly synthesized pyridinedicarbonitrile and benzopyranopyridine derivatives. Acta Pharm. 2008, 58, 175–186. [Google Scholar] [CrossRef]
  21. Khan, I.A.; Kulkarni, M.V.; Gopal, M.; Shahabuddin, M.; Sun, C.-M. Synthesis and biological evaluation of novel angularly fused polycyclic coumarins. Bioorg. Med. Chem. Lett. 2005, 15, 3584–3587. [Google Scholar] [CrossRef] [PubMed]
  22. El-Sawy, E.; Abdelwahab, A.; Kirsch, G. Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part 1: Five-Membered Aromatic Rings with One Heteroatom. Molecules 2021, 26, 483. [Google Scholar] [CrossRef]
  23. Shawali, A.S.; Elanadouli, B.E.; Albar, H.A. Cycloaddition of diphenylnitrilimine to coumarins. The synthesis of 3a,9b-dihydro-4-oxo-1H-benzopyrano [4,3-c]pyrazole derivatives. Tetrahedron 1985, 41, 1877–1884. [Google Scholar] [CrossRef]
  24. El-Dean, A.M.K.; Zaki, R.M.; Geies, A.A.; Radwan, S.M.; Tolba, M.S. Synthesis and antimicrobial activity of new heterocyclic compounds containing thieno[3,2-c]coumarin and pyrazolo[4,3-c]coumarin frameworks. Russ. J. Bioorg. Chem. 2013, 39, 553–564. [Google Scholar] [CrossRef]
  25. Strakova, I.; Petrova, M.; Belyakov, S.; Strakovs, A. Reactions of 4-Chloro-3-formylcoumarin with Arylhydrazines. Chem. Heterocycl. Compd. 2003, 39, 1608–1616. [Google Scholar] [CrossRef]
  26. Yin, Y.; Wu, X.; Han, H.-W.; Sha, S.; Wang, S.-F.; Qiao, F.; Lü, A.-M.; Lv, P.-C.; Zhu, H.-L. Discovery and synthesis of a novel series of potent, selective inhibitors of the PI3K?: 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives. Org. Biomol. Chem. 2014, 12, 9157–9165. [Google Scholar] [CrossRef] [PubMed]
  27. Chekir, S.; Debbabi, M.; Regazzetti, A.; Dargère, D.; Laprévote, O.; Ben Jannet, H.; Gharbi, R. Design, synthesis and biological evaluation of novel 1,2,3-triazole linked coumarinopyrazole conjugates as potent anticholinesterase, anti-5-lipoxygenase, anti-tyrosinase and anti-cancer agents. Bioorg. Chem. 2018, 80, 189–194. [Google Scholar] [CrossRef]
  28. Yin, Y.; Hu, J.-Q.; Wu, X.; Sha, S.; Wang, S.-F.; Qiao, F.; Song, Z.-C.; Zhu, H.-L. Design, synthesis and biological evaluation of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing sulfonamido as potential PI3Kα inhibitors. Bioorg. Med. Chem. 2019, 27, 2261–2267. [Google Scholar] [CrossRef] [PubMed]
  29. Lu, L.; Sha, S.; Wang, K.; Zhang, Y.-H.; Liu, Y.-D.; Ju, G.-D.; Wang, B.; Zhu, H.-L. Discovery of Chromeno[4,3-c]pyrazol-4(2H)-one Containing Carbonyl or Oxime Derivatives as Potential, Selective Inhibitors PI3Kα. Chem. Pharm. Bull. 2016, 64, 1576–1581. [Google Scholar] [CrossRef] [Green Version]
  30. Yin, Y.; Sha, S.; Wu, X.; Wang, S.-F.; Qiao, F.; Song, Z.-C.; Zhu, H.-L. Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates bearing sulfonylpiperazine as antitumor inhibitors targeting PI3Kα. Eur. J. Med. Chem. 2019, 182, 111630. [Google Scholar] [CrossRef] [PubMed]
  31. Steinfiihrer, T.; Hantschmann, A.; Pietsch, M.; WeiDenfels, M. Heterocyclisch [c]-Anellierte Cumarine Aus 4-Azido-3-Cumarincarbaldehyden. Liebigs Ann. Chem. 1992, 1992, 23–28. [Google Scholar] [CrossRef]
  32. Mustafa, A.; Hishmat, O.H.; Nawar, A.A.; Khalil, K.H.M.A. Pyrazolo-cumarine und Pyrazolyl-cumarone. Eur. J. Org. Chem. 1965, 684, 194–200. [Google Scholar] [CrossRef]
  33. Ibrahim, M.A. Ring transformation of chromone-3-carboxylic acid under nucleophilic conditions. Arkivoc 2008, 2008, 192. [Google Scholar] [CrossRef] [Green Version]
  34. Ibrahim, M.A. Ring Transformation of Chromone-3-Carboxamide under Nucleophilic Conditions. J. Braz. Chem. Soc. 2013, 24, 1754–1763. [Google Scholar] [CrossRef]
  35. Ibrahim, M.; Badran, A.; El-Gohary, N.; Hashiem, S. Studies on the Chemical Reactions of Some 3-Substituted-6,8-dimethylchromones with Nucleophilic Reagents. J. Heterocycl. Chem. 2018, 55, 2315–2324. [Google Scholar] [CrossRef]
  36. Ibrahim, M.A.; El-Gohary, N.M.; Said, S. Reactivity of 6-Methylchromone-3-carbonitrile Towards Some Nitrogen Nucleophilic Reagents. Heterocycles 2018, 96, 690. [Google Scholar] [CrossRef]
  37. Trimeche, B.; Gharbi, R.; Martin, M.-T.; Nuzillard, J.M.; Mighri, Z.; El Houla, S. Reactivity of [1]benzopyrano[4,3-c][1,5]benzodiazepin-7(8H)-ones towards some N-binucleophiles. J. Chem. Res. 2004, 2004, 170–173. [Google Scholar] [CrossRef]
  38. Lokhande, P.; Hasanzadeh, K.; Konda, S.G. A novel and efficient approach for the synthesis of new halo substituted 2-arylpyrazolo[4,3-c] coumarin derivatives. Eur. J. Chem. 2011, 2, 223–228. [Google Scholar] [CrossRef]
  39. Stadlbauers, W.; Hojas, G. Ring closure reactions of 3-arylhydrazonoalkyl-quinolin-2-ones to 1-aryl-pyrazolo[4,3-c]quinolin-2-ones. J. Heterocycl. Chem. 2004, 41, 681–690. [Google Scholar] [CrossRef]
  40. Hariprasad, K.S.; Anand, A.; Rathod, B.B.; Zehra, A.; Tiwari, A.K.; Prakasham, R.S.; Raju, B.C. Neoteric Synthesis and Biological Activities of Chromenopyrazolones, Tosylchromenopyrazolones, Benzoylcoumarins. ChemistrySelect 2017, 2, 10628–10634. [Google Scholar] [CrossRef]
  41. Fathi, T.; An, N.D.; Schmitt, G.; Cerutti, E.; Laude, B. Regiochemistry of the cycloadditions of diphenylnitrilimine to coumarin, 3-ethoxycarbonyl and 3-acetyl coumarins. Tetrahedron 1988, 44, 4527–4536. [Google Scholar] [CrossRef]
  42. Ito, K.; Maruyama, J. 4-Diazomethylcoumarins and Related Stable Heteroaryldiazomethanes. Thermal Conversion into Condensed Pyrazoles. J. Heterocycl. Chem. 1988, 25, 1681–1687. [Google Scholar] [CrossRef]
  43. Ito, K.; Maruyama, J. A Facile Intramolecular Cyclization of 4-Diazomethylcoumarins. A Convenient Route to Benzopyrano[3,4-c]pyrazol-4(3H)-ones. Heterocycles 1984, 22, 1057. [Google Scholar] [CrossRef]
  44. Colotta, V.; Catarzi, D.; Varano, F.; Cecchi, L.; Filacchioni, G.; Martini, C.; Giusti, L.; Lucacchini, A. Tricyclic heteroaromatic systems. Synthesis and benzodiazepine receptor affinity of 2-substituted-1-benzopyrano[3,4-d]oxazol-4-ones, -thiazol-4-ones, and -imidazol-4-ones. IL Farm. 1998, 53, 375–381. [Google Scholar] [CrossRef]
  45. Beccalli, E.M.; Contini, A.; Trimarco, P. 3-Nitrocoumarin Amidines: A New Synthetic Strategy for Substituted [1]Benzopyrano[3,4-d]imidazol-4(3H)-ones. Eur. J. Org. Chem. 2003, 2003, 3976–3984. [Google Scholar] [CrossRef]
  46. Anwar, S.; Paul, S.B.; Majumdar, K.C.; Choudhury, S. Green, One-Pot, Multicomponent Synthesis of Fused-Ring 2-Aminothiazoles. Synth. Commun. 2014, 44, 3304–3313. [Google Scholar] [CrossRef]
  47. Belal, M.; Khan, A.T. Oxidative cross coupling reaction mediated by I2/H2O2: A novel approach for the construction of fused thiazole containing coumarin derivatives. RSC Adv. 2015, 5, 104155–104163. [Google Scholar] [CrossRef]
  48. Brownsort, P.A.; Paton, R.; Sutherland, A.G. Intramolecular cycloaddition reactions involving nitrile sulphides. Tetrahedron Lett. 1985, 26, 3727–3730. [Google Scholar] [CrossRef]
  49. Brownsort, P.A.; Michael Paton, A. Nitrile Sulphides. Part 7. Synthesis of [I ]Benzopyrano[4,3-c]Isothiazoles and Isothiazolo[4,3-c]Quinolines. J. Chem. Soc. Perkin Trans. 1987, 2339–2344. [Google Scholar] [CrossRef]
  50. Brownsort, P.A.; Paton, R.M.; Sutherland, A.G. Nitrile Sulphides. Part 1O. Intramolecular 1.3-Dipolar Cycloadditions. J. Chem. Soc. Perkin Trans. 1989, 1679–1686. [Google Scholar] [CrossRef]
  51. Fordyce, E.A.; Morrison, A.J.; Sharp, R.D.; Paton, R.M. Microwave-induced generation and reactions of nitrile sulfides: An improved method for the synthesis of isothiazoles and 1,2,4-thiadiazoles. Tetrahedron 2010, 66, 7192–7197. [Google Scholar] [CrossRef]
  52. Seo, B.; Kim, H.; Kim, Y.G.; Baek, Y.; Um, K.; Lee, P.H. Synthesis of Bicyclic Isothiazoles through an Intramolecular Rhodium-Catalyzed Transannulation of Cyanothiadiazoles. J. Org. Chem. 2017, 82, 10574–10582. [Google Scholar] [CrossRef] [PubMed]
  53. Checchi, S.; Pecori Vettori, L.; Vincieri, F. 4-Hydroxycoumarins. VIII. Substitution Reactions of 4-Chloro-3-Cyanocoumarins. Gazz. Chim. Ital. 1968, 98, 1488–1502. [Google Scholar]
  54. Lee, Y.R.; Suk, J.Y.; Kim, B.S. Rhodium(II)-catalyzed reactions of 3-diazo-2,4-chromenediones. First one-step synthesis of pterophyllin 2. Tetrahedron Lett. 1999, 40, 6603–6607. [Google Scholar] [CrossRef]
  55. Taber, D.F.; Ruckle, R.E.; Hennessy, M.J. Mesyl azide: A superior reagent for diazo transfer. J. Org. Chem. 1986, 51, 4077–4078. [Google Scholar] [CrossRef]
  56. Dallacker, F.; Kratzer, P.; Lipp, M. Derivate des 2.4-Pyronons und 4-Hydroxy-cumarins. Eur. J. Org. Chem. 1961, 643, 97–109. [Google Scholar] [CrossRef]
  57. Balalas, T.D.; Stratidis, G.; Papatheodorou, D.; Vlachou, E.-E.; Gabriel, C.; Hadjipavlou-Litina, D.J.; Litinas, K.E. One-pot Synthesis of 2-Substituted 4H-Chromeno[3,4-d]oxazol-4-ones from 4-Hydroxy-3-nitrocoumarin and Acids in the Presence of Triphenylphosphine and Phosphorus Pentoxide under Microwave Irradiation. SynOpen 2018, 2, 0105–0113. [Google Scholar] [CrossRef] [Green Version]
  58. Gammon, D.W.; Hunter, R.; Wilson, S.A. An efficient synthesis of 7-hydroxy-2,6-dimethylchromeno[3,4-d]oxazol-4-one—a protected fragment of novenamine. Tetrahedron 2005, 61, 10683–10688. [Google Scholar] [CrossRef]
  59. Ray, S.; Paul, S.K. Studies on Reaction of Hydroxycoumarin Compounds with Formamide. Cheminform 2005, 36. [Google Scholar] [CrossRef]
  60. Freedman, J.; Milwaukee, W. 3-Substituted-4H(1)Benzopyrano(3,4-d) Isoxazoles 1971. U.S. Patent 3,553,228, 5 January 1971. [Google Scholar]
  61. Sosnovskikh, V.Y.; Moshkin, V.S.; Kodess, M.I. A reinvestigation of the reactions of 3-substituted chromones with hydroxylamine. Unexpected synthesis of 3-amino-4H-chromeno[3,4-d]isoxazol-4-one and 3-(diaminomethylene)chroman-2,4-dione. Tetrahedron Lett. 2008, 49, 6856–6859. [Google Scholar] [CrossRef]
  62. Saloutin, V.; Skryabina, Z.; Bazyl’, I.; Kisil’, S. Interaction of 3-ethoxycarbonyl(carboxy)-substituted 5,6,7,8-tetrafluorochromones with N-nucleophiles: Synthesis of fluorocoumarins. J. Fluor. Chem. 1999, 94, 83–90. [Google Scholar] [CrossRef]
  63. Dean, F.M.; Park, B.K. Activating groups for the ring expansion of coumarin by diazoethane: Benzoyl, pivaloyl, arylsulphonyl, arylsulphinyl, and nitro. J. Chem. Soc. Perkin Trans. 1976, 1, 1260–1268. [Google Scholar] [CrossRef]
  64. Ito, K.; Hariya, J. Electrocyclization of 4-Azidocoumarins Leading to Benzopyrano[3,4-d]-1,2,3-triazol-4-ones. Heterocycles 1987, 26, 35. [Google Scholar] [CrossRef]
  65. D’Ambrosio, G.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. TBAF-catalyzed [3 + 2]cycloaddition of TMSN3 to 3-nitrocoumarins under SFC: An effective green route to chromeno[3,4-d][1,2,3]triazol-4(3H)-ones. Green Chem. 2005, 7, 874–877. [Google Scholar] [CrossRef]
  66. Wang, T.; Hu, X.-C.; Huang, X.-J.; Li, X.-S.; Xie, J.-W. Efficient synthesis of functionalized 1,2,3-triazoles by catalyst-free 1,3-dipolar cycloaddition of nitroalkenes with sodium azide. J. Braz. Chem. Soc. 2012, 23, 1119–1123. [Google Scholar] [CrossRef] [Green Version]
  67. Schwendt, G.; Glasnov, T. Intensified synthesis of [3,4-d]triazole-fused chromenes, coumarins, and quinolones. Mon. Für Chem. Chem. Mon. 2017, 148, 69–75. [Google Scholar] [CrossRef]
  68. Savel’Ev, V.L.; Samsonova, O.L.; Troitskaya, V.S.; Vinokurov, V.G.; Lezina, V.P.; Smirnov, L.D. Synthesis of 4H-[1]benzopyrano[3,4-c][1,2,5]thyadiazol-4-one and its reactions with some nucleophilic and electrophilic agents. Chem. Heterocycl. Compd. 1988, 24, 805–810. [Google Scholar] [CrossRef]
Molecules 26 03409 g001 550
Figure 1. The isomers of fused chromeno-pyrazole.
Figure 1. The isomers of fused chromeno-pyrazole.
Molecules 26 03409 g001
Molecules 26 03409 sch001 550
Scheme 1. Cycloaddition of diphenylnitrilimine to coumarin. Reagents and conditions. (a) diphenylnitrilimine (DPNI), benzene, TEA, compound 2, 65% yield, compound 5, 65% yield; (b) lead tetraacetate, dichloromethane, r.t., 12 h, 83% yield.
Scheme 1. Cycloaddition of diphenylnitrilimine to coumarin. Reagents and conditions. (a) diphenylnitrilimine (DPNI), benzene, TEA, compound 2, 65% yield, compound 5, 65% yield; (b) lead tetraacetate, dichloromethane, r.t., 12 h, 83% yield.
Molecules 26 03409 sch001
Molecules 26 03409 sch002 550
Scheme 2. Synthesis of 3-aminochromeno[4,3-c]pyrazol-4(1H)one (8). Reagents and conditions. (a) POCl3, DMF, CHCl3; (b) NH2OH. HCl, AcONa, EtOH; (c) POCl3; (d) N2H4. H2O, EtOH, 80% yield.
Scheme 2. Synthesis of 3-aminochromeno[4,3-c]pyrazol-4(1H)one (8). Reagents and conditions. (a) POCl3, DMF, CHCl3; (b) NH2OH. HCl, AcONa, EtOH; (c) POCl3; (d) N2H4. H2O, EtOH, 80% yield.
Molecules 26 03409 sch002
Molecules 26 03409 sch003 550
Scheme 3. Synthesis of chromeno[4,3-c]pyrazol-4(1H)ones 9. Reagents and conditions. (a) POCl3, DMF, CHCl3; (b) NH2NHR, EtOH, TEA or NaOAc, 25 °C, 2 h, five outputs with 67–89% yield [18], 14 outputs with 38–69% yield [25].
Scheme 3. Synthesis of chromeno[4,3-c]pyrazol-4(1H)ones 9. Reagents and conditions. (a) POCl3, DMF, CHCl3; (b) NH2NHR, EtOH, TEA or NaOAc, 25 °C, 2 h, five outputs with 67–89% yield [18], 14 outputs with 38–69% yield [25].
Molecules 26 03409 sch003
Molecules 26 03409 sch004 550
Scheme 4. Synthesis of 2-substituted-1H-chromeno[4,3-c]pyrazol-4(1H)ones 10–12. Reagents and conditions. (a) Benzyl bromides, DMF, Cs2CO3, 100 °C, 10–12 h, 13 outputs; (b) benzene(alkyl)sulfonyl chlorides, DCM, TEA, 0 °C, 6–8 h, 28 outputs with 33–52% yield; (c) N-alkyl sulfonyl piperazines, HCHO, EtOH, rt, 4–6 h, 26 outputs with 37–65% yield.
Scheme 4. Synthesis of 2-substituted-1H-chromeno[4,3-c]pyrazol-4(1H)ones 10–12. Reagents and conditions. (a) Benzyl bromides, DMF, Cs2CO3, 100 °C, 10–12 h, 13 outputs; (b) benzene(alkyl)sulfonyl chlorides, DCM, TEA, 0 °C, 6–8 h, 28 outputs with 33–52% yield; (c) N-alkyl sulfonyl piperazines, HCHO, EtOH, rt, 4–6 h, 26 outputs with 37–65% yield.
Molecules 26 03409 sch004
Molecules 26 03409 sch005 550
Scheme 5. Synthesis of chromeno[4,3-c]pyrazol-4(2H)-ones 16. Reagents and conditions. (a) POCl3, DMF, CHCl3, 4 outputs with 65–80% yield; (b) NaN3, DMF, 4 outputs with 50–80% yield; (c) R1NHNH2, DMF, 40–50 °C, six outputs with 70–90% yield.
Scheme 5. Synthesis of chromeno[4,3-c]pyrazol-4(2H)-ones 16. Reagents and conditions. (a) POCl3, DMF, CHCl3, 4 outputs with 65–80% yield; (b) NaN3, DMF, 4 outputs with 50–80% yield; (c) R1NHNH2, DMF, 40–50 °C, six outputs with 70–90% yield.
Molecules 26 03409 sch005
Molecules 26 03409 sch006 550
Scheme 6. 3-Coumarinyl alkyl ketone in the synthesis of chromeno[4,3-c]pyrazol-4(2H)-ones 18 and 19. Reagents and conditions. NH2NH2.H2O, EtOH, TEA, 18: 75% yield, 19: 58% yield.
Scheme 6. 3-Coumarinyl alkyl ketone in the synthesis of chromeno[4,3-c]pyrazol-4(2H)-ones 18 and 19. Reagents and conditions. NH2NH2.H2O, EtOH, TEA, 18: 75% yield, 19: 58% yield.
Molecules 26 03409 sch006
Molecules 26 03409 sch007 550
Scheme 7. Synthesis of chromeno[4,3-c]pyrazol-4(2H)-ones 9a, 22, and 24. Reagents and conditions. (a) AcOH, 2 h, reflux, 48% yield; (b) NH2NH2. H2O, AcOH, 2 h, reflux, 48% yield; (c) NH2NH2. H2O, or NH2NHPh, EtOH, 2 h, reflux, R=H: 56%, R=Ph: 46% yield; (d) DMF, 30 min, reflux, 63% yield.
Scheme 7. Synthesis of chromeno[4,3-c]pyrazol-4(2H)-ones 9a, 22, and 24. Reagents and conditions. (a) AcOH, 2 h, reflux, 48% yield; (b) NH2NH2. H2O, AcOH, 2 h, reflux, 48% yield; (c) NH2NH2. H2O, or NH2NHPh, EtOH, 2 h, reflux, R=H: 56%, R=Ph: 46% yield; (d) DMF, 30 min, reflux, 63% yield.
Molecules 26 03409 sch007
Molecules 26 03409 sch008 550
Scheme 8. [1]Benzopyrano[4,3-c][1,5]benzodiazepin-7(8H)-one in the synthesis of chromeno[4,3-c]pyrazol-4(2H)-ones 9a and 26. Reagents and conditions. (a) NH2NH2.H2O, AcOH, reflux, 10 min, 48% yield; (b) NH2NHCH3, AcOH, reflux, 10 min, 48% yield.
Scheme 8. [1]Benzopyrano[4,3-c][1,5]benzodiazepin-7(8H)-one in the synthesis of chromeno[4,3-c]pyrazol-4(2H)-ones 9a and 26. Reagents and conditions. (a) NH2NH2.H2O, AcOH, reflux, 10 min, 48% yield; (b) NH2NHCH3, AcOH, reflux, 10 min, 48% yield.
Molecules 26 03409 sch008
Molecules 26 03409 sch009 550
Scheme 9. Synthesis of 2-phenyl-chromeno[4,3-c]pyrazol-4(1H)ones 29. Reagents and conditions. R = H, or CH2-CH=CH2, 10 mol%, DMSO, conc. H2SO4, 120 °C, 5 h, seven outputs with 88–93% yield.
Scheme 9. Synthesis of 2-phenyl-chromeno[4,3-c]pyrazol-4(1H)ones 29. Reagents and conditions. R = H, or CH2-CH=CH2, 10 mol%, DMSO, conc. H2SO4, 120 °C, 5 h, seven outputs with 88–93% yield.
Molecules 26 03409 sch009
Molecules 26 03409 sch010 550
Scheme 10. Synthesis of chromeno[4,3-c]pyrazol-4(1H)ones 34 and 35. Reagents and conditions. (a) CH3CN, 2 h, r.t.; (b) La(OTf)3, 130 °C, 8 h; 25 outputs with 22–78% yield.
Scheme 10. Synthesis of chromeno[4,3-c]pyrazol-4(1H)ones 34 and 35. Reagents and conditions. (a) CH3CN, 2 h, r.t.; (b) La(OTf)3, 130 °C, 8 h; 25 outputs with 22–78% yield.
Molecules 26 03409 sch010
Molecules 26 03409 sch011 550
Scheme 11. Synthesis of 1,3-diphenyl-chromeno[3,4-c]pyrazol-4(1H)one (39). Reagents and conditions. (a) Diphenylnitrilimine (DPNI), benzene, TEA, 65% yield; (b) KOH (10%), 1 h, reflux, 80% yield; (c) heat, 98% yield.
Scheme 11. Synthesis of 1,3-diphenyl-chromeno[3,4-c]pyrazol-4(1H)one (39). Reagents and conditions. (a) Diphenylnitrilimine (DPNI), benzene, TEA, 65% yield; (b) KOH (10%), 1 h, reflux, 80% yield; (c) heat, 98% yield.
Molecules 26 03409 sch011
Molecules 26 03409 sch012 550
Scheme 12. Thermal conversion of 4-diazo-methyl coumarin. Reagents and conditions. Toluene, heat, stirring, R = H: 85% yield, R = Me: 98% yield.
Scheme 12. Thermal conversion of 4-diazo-methyl coumarin. Reagents and conditions. Toluene, heat, stirring, R = H: 85% yield, R = Me: 98% yield.
Molecules 26 03409 sch012
Molecules 26 03409 sch013 550
Scheme 13. The role of hydrazonyl halides in the preparation of chromeno[3,4-c]pyrazol-4(2H)-ones. Reagents and conditions. (a) Benzene, reflux, TEA, two outputs Y = CH3 (51%), Y = Ph (48%); (b) i: KOH (10%), 12 h, reflux; ii: toluene, 2 h, reflux; (c) benzene, reflux, TEA, two outputs Ar = C6H4F-p, Ar1 = C6H4NO2-p (48%), Ar = C6H3Cl2-2,4, Ar1 = C6H4NO2-p (51%).
Scheme 13. The role of hydrazonyl halides in the preparation of chromeno[3,4-c]pyrazol-4(2H)-ones. Reagents and conditions. (a) Benzene, reflux, TEA, two outputs Y = CH3 (51%), Y = Ph (48%); (b) i: KOH (10%), 12 h, reflux; ii: toluene, 2 h, reflux; (c) benzene, reflux, TEA, two outputs Ar = C6H4F-p, Ar1 = C6H4NO2-p (48%), Ar = C6H3Cl2-2,4, Ar1 = C6H4NO2-p (51%).
Molecules 26 03409 sch013
Molecules 26 03409 g002 550
Figure 2. The common isomer of fused chromeno-imidazole.
Figure 2. The common isomer of fused chromeno-imidazole.
Molecules 26 03409 g002
Molecules 26 03409 sch014 550
Scheme 14. Simple synthetic routes of novel 1H-benzopyrano[3,4-d]imidazoles 50 and 53. Reagents and conditions. (a) i: Formic acid, conc. HCl, heating, 12 h, R = R1 = H, 87% yield; ii: glacial AcOH, conc. HCl, heating, 12 h, R = CH3, R1 = H, 92% yield; iii: HCHO, EtOH, conc. HCl, heating, 2 h, R = H, R1 = CH3, 82% yield; (b) (AcO2)2O or RCOCl, benzene, heat, 40 °C, 1 h, 4 outputs with 50–84% yield; (c) appropriate aldehyde, EtOH, reflux, 1 h, 4 outputs with 59–81% yield; (d) oil bath, 310–320 °C, 30 min; (e) lead tetraacetate, benzene, stirring, r.t., 2 h, 4 outputs with 59–91% yields.
Scheme 14. Simple synthetic routes of novel 1H-benzopyrano[3,4-d]imidazoles 50 and 53. Reagents and conditions. (a) i: Formic acid, conc. HCl, heating, 12 h, R = R1 = H, 87% yield; ii: glacial AcOH, conc. HCl, heating, 12 h, R = CH3, R1 = H, 92% yield; iii: HCHO, EtOH, conc. HCl, heating, 2 h, R = H, R1 = CH3, 82% yield; (b) (AcO2)2O or RCOCl, benzene, heat, 40 °C, 1 h, 4 outputs with 50–84% yield; (c) appropriate aldehyde, EtOH, reflux, 1 h, 4 outputs with 59–81% yield; (d) oil bath, 310–320 °C, 30 min; (e) lead tetraacetate, benzene, stirring, r.t., 2 h, 4 outputs with 59–91% yields.
Molecules 26 03409 sch014
Molecules 26 03409 sch015 550
Scheme 15. [1]Benzopyrano[3,4-d]imidazol-4(3H)-ones 57 and 58 bearing hydrogen or alkyl groups on N-3, and alkyl or amino substituents on C-2. Reagents and conditions. i, R1 = Ph, R2 = H; ii, R1 = 4-BrC6H4, R2 = H; iii, R1 = CH2Ph, R2 = H; iv, R1 = CH2CH3, R2 = H; v, R1 = R2 = CH3; (a) CH2Cl2, −40°C, five outputs with 67–89% yields; (b) NaBH4, Pd/C, MeOH, H2O, five outputs with 55–65% yield; (c) N2, P(OC2H3)3, reflux, five outputs with 57–65% yields.
Scheme 15. [1]Benzopyrano[3,4-d]imidazol-4(3H)-ones 57 and 58 bearing hydrogen or alkyl groups on N-3, and alkyl or amino substituents on C-2. Reagents and conditions. i, R1 = Ph, R2 = H; ii, R1 = 4-BrC6H4, R2 = H; iii, R1 = CH2Ph, R2 = H; iv, R1 = CH2CH3, R2 = H; v, R1 = R2 = CH3; (a) CH2Cl2, −40°C, five outputs with 67–89% yields; (b) NaBH4, Pd/C, MeOH, H2O, five outputs with 55–65% yield; (c) N2, P(OC2H3)3, reflux, five outputs with 57–65% yields.
Molecules 26 03409 sch015
Molecules 26 03409 g003 550
Figure 3. The common three isomers of fused the thiazole and isothiazole ring to the α-pyrone moiety of the coumarin.
Figure 3. The common three isomers of fused the thiazole and isothiazole ring to the α-pyrone moiety of the coumarin.
Molecules 26 03409 g003
Molecules 26 03409 sch016 550
Scheme 16. Synthesis of 4H-chromeno[3,4-d]thiazol-4-one (60). Reagents and conditions. EtOH, NaHSO3, pH 3, reflux, 3 h, 78% yield.
Scheme 16. Synthesis of 4H-chromeno[3,4-d]thiazol-4-one (60). Reagents and conditions. EtOH, NaHSO3, pH 3, reflux, 3 h, 78% yield.
Molecules 26 03409 sch016
Molecules 26 03409 sch017 550
Scheme 17. Synthetic pathway of 2-aryl-4H-chromeno[3,4-d]thiazol-4-ones 63. Reagents and conditions. (a) THF, stirring, 30 min, five outputs with 40–73% yield; (b) Fe, conc. AcOH, reflux, 60 °C for 1 h, 90 °C for 3–4 h, five outputs with 45–95% yield.
Scheme 17. Synthetic pathway of 2-aryl-4H-chromeno[3,4-d]thiazol-4-ones 63. Reagents and conditions. (a) THF, stirring, 30 min, five outputs with 40–73% yield; (b) Fe, conc. AcOH, reflux, 60 °C for 1 h, 90 °C for 3–4 h, five outputs with 45–95% yield.
Molecules 26 03409 sch017
Molecules 26 03409 sch018 550
Scheme 18. Synthetic pathway of 2-amino-4H-chromeno[3,4-d]thiazol-4-ones 65. Reagents and conditions. CS2 (1.2 mmol) and K2CO3 (3.0 mmol), FeCl3 (1.5 mmol), 110 °C, 6–8 h, N2, pyrrolidine 64% yield, N-ethylaniline 74% yield.
Scheme 18. Synthetic pathway of 2-amino-4H-chromeno[3,4-d]thiazol-4-ones 65. Reagents and conditions. CS2 (1.2 mmol) and K2CO3 (3.0 mmol), FeCl3 (1.5 mmol), 110 °C, 6–8 h, N2, pyrrolidine 64% yield, N-ethylaniline 74% yield.
Molecules 26 03409 sch018
Molecules 26 03409 sch019 550
Scheme 19. Oxidative cross-coupling reaction to synthesis of 4H-chromeno[3,4-d]thiazol-4-ones 67. Reagents and conditions. Na2S (3 equiv.), I2 (20 mmol%), 30% aq. H2O2 (5 equiv), DMF, 120 °C, 22 outputs with 65–89% yields.
Scheme 19. Oxidative cross-coupling reaction to synthesis of 4H-chromeno[3,4-d]thiazol-4-ones 67. Reagents and conditions. Na2S (3 equiv.), I2 (20 mmol%), 30% aq. H2O2 (5 equiv), DMF, 120 °C, 22 outputs with 65–89% yields.
Molecules 26 03409 sch019
Molecules 26 03409 sch020 550
Scheme 20. Synthesis of 4-oxo-3-phenyl-4H-chromeno[4,3-c]isothiazole (70). Reagents and conditions. Xylene, heat, 16 h, 70% yield.
Scheme 20. Synthesis of 4-oxo-3-phenyl-4H-chromeno[4,3-c]isothiazole (70). Reagents and conditions. Xylene, heat, 16 h, 70% yield.
Molecules 26 03409 sch020
Molecules 26 03409 sch021 550
Scheme 21. Synthesis of methyl 4-oxo-4H-chromeno[4,3-c]isothiazole-3-carboxylate (74). Reagents and conditions. (a) Heat, -CO2, 84% yield; (b) EtOAc, DMAD,10 min, 160 °C, microwave, 94% yield.
Scheme 21. Synthesis of methyl 4-oxo-4H-chromeno[4,3-c]isothiazole-3-carboxylate (74). Reagents and conditions. (a) Heat, -CO2, 84% yield; (b) EtOAc, DMAD,10 min, 160 °C, microwave, 94% yield.
Molecules 26 03409 sch021
Molecules 26 03409 sch022 550
Scheme 22. Synthesis of 8-substituted-3-phenyl-4H-chromeno[4,3-c]isothiazol-4-ones 76. Reagents and conditions. An amount of 5.0 mol% [Rh(COD)Cl]2, 12.0 mol% DPPF, PhCl (1.0 mL), N2, 80 °C; R = H 90% yield; R = Me 99% yield; R = Br 90% yield.
Scheme 22. Synthesis of 8-substituted-3-phenyl-4H-chromeno[4,3-c]isothiazol-4-ones 76. Reagents and conditions. An amount of 5.0 mol% [Rh(COD)Cl]2, 12.0 mol% DPPF, PhCl (1.0 mL), N2, 80 °C; R = H 90% yield; R = Me 99% yield; R = Br 90% yield.
Molecules 26 03409 sch022
Molecules 26 03409 sch023 550
Scheme 23. Synthesis of 4H-chromeno[3,4-d]isothiazol-4-one (78). Reagents and conditions. Br2, EtOAc, heat, 4 h, 96% yield.
Scheme 23. Synthesis of 4H-chromeno[3,4-d]isothiazol-4-one (78). Reagents and conditions. Br2, EtOAc, heat, 4 h, 96% yield.
Molecules 26 03409 sch023
Molecules 26 03409 g004 550
Figure 4. The common four isomers of fused oxazole and isoxazole ring to the α-pyrone moiety of the coumarin.
Figure 4. The common four isomers of fused oxazole and isoxazole ring to the α-pyrone moiety of the coumarin.
Molecules 26 03409 g004
Molecules 26 03409 sch024 550
Scheme 24. 3-Diazo-2,4-chromenedione in the preparation of 4H-chromeno[3,4-d]oxazol-4-ones 72. Reagents and conditions. Rh2(OAc)4, 60 °C, 5 h, three outputs, R = CH3 50% yield, R = CH2Cl 95% yield, R = CH2Ph 73% yield.
Scheme 24. 3-Diazo-2,4-chromenedione in the preparation of 4H-chromeno[3,4-d]oxazol-4-ones 72. Reagents and conditions. Rh2(OAc)4, 60 °C, 5 h, three outputs, R = CH3 50% yield, R = CH2Cl 95% yield, R = CH2Ph 73% yield.
Molecules 26 03409 sch024
Molecules 26 03409 sch025 550
Scheme 25. 3-Nitrocoumarin in the preparation of 4H-chromeno[3,4-d]oxazol-4-one (83). Reagents and conditions. (a) HNO2, glacial AcOH; (b) Raney Ni, CH3CH2COOCOCH2CH3; (c) acetic acid anhydride, heat, 96% yield.
Scheme 25. 3-Nitrocoumarin in the preparation of 4H-chromeno[3,4-d]oxazol-4-one (83). Reagents and conditions. (a) HNO2, glacial AcOH; (b) Raney Ni, CH3CH2COOCOCH2CH3; (c) acetic acid anhydride, heat, 96% yield.
Molecules 26 03409 sch025
Molecules 26 03409 sch026 550
Scheme 26. One-pot synthesis of 2-substituted 4H-chromeno[3,4-d]oxazol-4-ones 84. Reagents and conditions: (a) PPh3 (2.5 equiv), P2O5 (4 equiv), MW irradiation, 130 °C or 140 °C, 1.5 h; (b) 5 mole % Pd/C (10%), H2 1 atm, r.t., 1–3 h, then P2O5 (4 equiv), MW irradiation, 130 °C, 1 h, ten outputs with up to 91% yield.
Scheme 26. One-pot synthesis of 2-substituted 4H-chromeno[3,4-d]oxazol-4-ones 84. Reagents and conditions: (a) PPh3 (2.5 equiv), P2O5 (4 equiv), MW irradiation, 130 °C or 140 °C, 1.5 h; (b) 5 mole % Pd/C (10%), H2 1 atm, r.t., 1–3 h, then P2O5 (4 equiv), MW irradiation, 130 °C, 1 h, ten outputs with up to 91% yield.
Molecules 26 03409 sch026
Molecules 26 03409 sch027 550
Scheme 27. Synthesis of 7-hydroxy-2,6-dimethylchromeno[3,4-d]oxazol-4-one (91). Reagents and conditions: (a) BnCl, K2CO3, KI, acetone, 56 °C, 88% yield; (b) NaH, CO(OEt)2, toluene, 110 °C, 76%yield; (c) HNO3, H2SO4, CHCl3, room temperature, 93% yield; (d) Zn, AcOH, 110 °C, 86% yield; (e) POCl3, pyridine, THF, 66 °C, 87% yield; (f) 10% Pd/C, H2, THF/CH2Cl2, room temperature, 74% yield.
Scheme 27. Synthesis of 7-hydroxy-2,6-dimethylchromeno[3,4-d]oxazol-4-one (91). Reagents and conditions: (a) BnCl, K2CO3, KI, acetone, 56 °C, 88% yield; (b) NaH, CO(OEt)2, toluene, 110 °C, 76%yield; (c) HNO3, H2SO4, CHCl3, room temperature, 93% yield; (d) Zn, AcOH, 110 °C, 86% yield; (e) POCl3, pyridine, THF, 66 °C, 87% yield; (f) 10% Pd/C, H2, THF/CH2Cl2, room temperature, 74% yield.
Molecules 26 03409 sch027
Molecules 26 03409 sch028 550
Scheme 28. Synthesis of 4H-chromeno[4, 3-d]oxazol-4-one (84). Reagents and conditions. HCONH2, 160 °C, 84% yield.
Scheme 28. Synthesis of 4H-chromeno[4, 3-d]oxazol-4-one (84). Reagents and conditions. HCONH2, 160 °C, 84% yield.
Molecules 26 03409 sch028
Molecules 26 03409 sch029 550
Scheme 29. 4-Chromanone in the synthesis of ethyl 4H-chromeno[3,4-d]isoxazol-3-carboxylate (95). Reagents and conditions. (a) Toluene, NaH, N2, stirring, r.t., 94% yield; (b) NH2OH.HCl, EtOH, reflux, 10 h, 91% yield.
Scheme 29. 4-Chromanone in the synthesis of ethyl 4H-chromeno[3,4-d]isoxazol-3-carboxylate (95). Reagents and conditions. (a) Toluene, NaH, N2, stirring, r.t., 94% yield; (b) NH2OH.HCl, EtOH, reflux, 10 h, 91% yield.
Molecules 26 03409 sch029
Molecules 26 03409 sch030 550
Scheme 30. Synthesis of 2-amino-4H-chromeno[3,4-d]isoxazol-4-one (99). Reagents and conditions. NH2OH. HCl, NaOH, Ethanol, reflux, 45% yield.
Scheme 30. Synthesis of 2-amino-4H-chromeno[3,4-d]isoxazol-4-one (99). Reagents and conditions. NH2OH. HCl, NaOH, Ethanol, reflux, 45% yield.
Molecules 26 03409 sch030
Molecules 26 03409 sch031 550
Scheme 31. Synthesis of polyfluorochromeno[3,4-d]isoxazol-4-one (102). Reagents and conditions. (a) NH2OH. HCl, TEA, MeOH, 2 h, rt, 85% yield; (b) H2SO4, H2O, reflux, 1.5 h, 82% yield.
Scheme 31. Synthesis of polyfluorochromeno[3,4-d]isoxazol-4-one (102). Reagents and conditions. (a) NH2OH. HCl, TEA, MeOH, 2 h, rt, 85% yield; (b) H2SO4, H2O, reflux, 1.5 h, 82% yield.
Molecules 26 03409 sch031
Molecules 26 03409 sch032 550
Scheme 32. Synthetic pathway of 4H-chromeno[4,3-c]isoxazol-4-ones 103. Reagents and conditions. (a) POCl3, DMF, H2O, four outputs with 65–80% yields; (b) NaN3, DMF, four outputs with 50–80% yield; (c) DMF, heat, 60–90 °C, -N2, four outputs with 30–65% yields.
Scheme 32. Synthetic pathway of 4H-chromeno[4,3-c]isoxazol-4-ones 103. Reagents and conditions. (a) POCl3, DMF, H2O, four outputs with 65–80% yields; (b) NaN3, DMF, four outputs with 50–80% yield; (c) DMF, heat, 60–90 °C, -N2, four outputs with 30–65% yields.
Molecules 26 03409 sch032
Molecules 26 03409 g005 550
Figure 5. The common isomer of the fused chromeno-triazole system.
Figure 5. The common isomer of the fused chromeno-triazole system.
Molecules 26 03409 g005
Molecules 26 03409 sch033 550
Scheme 33. Synthesis of 4H-chromeno[3,4-d][1,2,3]triazol-(3H)4-one (105). Reagents and conditions. NaN3, DMF, 95 °C, 5 h, N2, 84% yield.
Scheme 33. Synthesis of 4H-chromeno[3,4-d][1,2,3]triazol-(3H)4-one (105). Reagents and conditions. NaN3, DMF, 95 °C, 5 h, N2, 84% yield.
Molecules 26 03409 sch033
Molecules 26 03409 sch034 550
Scheme 34. 4-Azidocoumarins in the preparation of 4H-chromeno[3,4-d][1,2,3]triazol-(3H)4-ones 107. Reagents and conditions. DMF or DMSO, t-BuOK, 50–60 °C, 5 h, stirring, six outputs with 12–41% yields.
Scheme 34. 4-Azidocoumarins in the preparation of 4H-chromeno[3,4-d][1,2,3]triazol-(3H)4-ones 107. Reagents and conditions. DMF or DMSO, t-BuOK, 50–60 °C, 5 h, stirring, six outputs with 12–41% yields.
Molecules 26 03409 sch034
Molecules 26 03409 sch035 550
Scheme 35. TBAF-catalyzed cycloadditions of 3-nitrocoumarins with TMSN3 under SFC. Regents and conditions. An amount of (10 mol%) TBAF, TMSN3 (2 equiv), 50 °C, eleven outputs with 76–94% yields.
Scheme 35. TBAF-catalyzed cycloadditions of 3-nitrocoumarins with TMSN3 under SFC. Regents and conditions. An amount of (10 mol%) TBAF, TMSN3 (2 equiv), 50 °C, eleven outputs with 76–94% yields.
Molecules 26 03409 sch035
Molecules 26 03409 sch036 550
Scheme 36. 1,3-Dipolar cycloaddition of 3-nitrocoumarins with sodium azide. Reagents and conditions. a) NaN3, DMSO, 80 °C, 1 h, five outputs with 66–89% yields; b) NaN3 (1.2 equiv), DMF, Pyrex microwave vial equipped with a magnetic stir bar, stirred for 10 s, 160 C, 1 min, R = H, R1 = CH3 94% yield; R = OCH3, R1 = H 69% yield.
Scheme 36. 1,3-Dipolar cycloaddition of 3-nitrocoumarins with sodium azide. Reagents and conditions. a) NaN3, DMSO, 80 °C, 1 h, five outputs with 66–89% yields; b) NaN3 (1.2 equiv), DMF, Pyrex microwave vial equipped with a magnetic stir bar, stirred for 10 s, 160 C, 1 min, R = H, R1 = CH3 94% yield; R = OCH3, R1 = H 69% yield.
Molecules 26 03409 sch036
Molecules 26 03409 g006 550
Figure 6. The common isomer of the fused chromeno-thiadiazole system.
Figure 6. The common isomer of the fused chromeno-thiadiazole system.
Molecules 26 03409 g006
Molecules 26 03409 sch037 550
Scheme 37. Synthetic pathway to 4H-chromeno[3,4-c][l,2,5]thiadiazol-4-one (112). Reagents and conditions. SOCl2, pyridine, stirring for 3 h, r.t., 87% yield.
Scheme 37. Synthetic pathway to 4H-chromeno[3,4-c][l,2,5]thiadiazol-4-one (112). Reagents and conditions. SOCl2, pyridine, stirring for 3 h, r.t., 87% yield.
Molecules 26 03409 sch037
Molecules 26 03409 g007 550
Figure 7. Coumarin-fused five-membered aromatic heterocycles have not been feasible by any synthetic procedures.
Figure 7. Coumarin-fused five-membered aromatic heterocycles have not been feasible by any synthetic procedures.
Molecules 26 03409 g007
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

El-Sawy, E.R.; Abdelwahab, A.B.; Kirsch, G. Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms. Molecules 2021, 26, 3409. https://doi.org/10.3390/molecules26113409

AMA Style

El-Sawy ER, Abdelwahab AB, Kirsch G. Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms. Molecules. 2021; 26(11):3409. https://doi.org/10.3390/molecules26113409

Chicago/Turabian Style

El-Sawy, Eslam Reda, Ahmed Bakr Abdelwahab, and Gilbert Kirsch. 2021. "Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms" Molecules 26, no. 11: 3409. https://doi.org/10.3390/molecules26113409

APA Style

El-Sawy, E. R., Abdelwahab, A. B., & Kirsch, G. (2021). Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms. Molecules, 26(11), 3409. https://doi.org/10.3390/molecules26113409

Article Metrics

Back to TopTop