A highly efficient green synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives and their photophysical studies

A task-specific ionic liquid, [Bmim]OH, has been used for an efficient synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones by one-pot cyclocondensation reaction of phthalhydrazide, aromatic aldehydes, and malononitrile or ethyl cyanoacetate under microwave irradiation. The advantages of this method include the use of green catalyst, no organic solvent, easy work-up and excellent yields. The photophysical properties for some 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives have been investigated for the first time.     

Solvent-free sonochemical one-pot three-component synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11-triones and 1H-pyrazolo[1,2-b]phthalazine-5,10-diones

A rapid and efficient one-pot three-component protocol for the synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11-triones 4 and 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 6 has been developed by domino coupling of phthalhydrazide, 1,3-diketones, and aldehydes under solvent-free conditions at 80 °C as well as under solvent-free ultrasound irradiation at room temperature promoted by (S)-camphorsulfonic acid.     

Synthesis and reactivity of 3-amino-1H-pyrazolo[4,3-c]pyridin-4(5H)-ones: development of a novel kinase-focussed library

3-Amino-1H-pyrazolo[4,3-c]pyridin-4(5H)-ones represent a potentially attractive heteroaromatic scaffold for drug-discovery chemistry. In particular, the arrangement of hydrogen bond donor and acceptor groups in the bicyclic core can fulfil the requirements for ATP competitive binding to kinase enzymes. Efficient and regioselective routes from simple starting materials to novel functionalised 3-amino-1H-pyrazolo[4,3-c]pyridin-4(5H)-ones and related 3-amino-2H-pyrazolo[4,3-c]pyridines were explored and adapted for parallel synthesis, resulting in a library of compounds suitable for screening against kinases and other cancer drug targets. Methods for substituent variation at five distinct positions around the bicyclic core were devised to generate sets of compounds containing two- or three-point diversity.     

A novel synthesis of new 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile derivatives

New 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitriles are synthesized in good yields, via cyclocondensation of 5-amino-1-(2-oxo-2-arylethyl)-3-(arylamino)-1H-pyrazole-4-carbonitriles, which are prepared by the reaction of 5-amino-3-arylamino-1H-pyrazole-4-carbonitriles and α-bromoacetophenone derivatives in the presence of K₂CO₃ using acetone as the solvent.     

Efficient syntheses of novel indeno[1,2-b]chromenone derivatives via hetero-Diels-Alder reactions of 2-(arylmethylene)-1H-indene-1,3(2H)-diones with enaminones

Efficient syntheses of novel 10-aryl-5a-(arylamino)-9-hydroxy-5a,6,7,8-tetrahydroindeno[1,2-b]chromen-11(10H)-one derivatives has been reported by [4+2] cycloaddition reactions of electron-deficient 2-(arylmethylene)-1H-indene-1,3(2H)-dione heterodienes with electron-rich enaminones in [bmim]BF₄ at 80?°C and in acetic acid at 80?°C. Dimedone/cyclohexane-1,3-dione enaminones have been used as dienophiles in Inverse Electron Demand hetero-Diels-Alder reactions. The products were obtained in high yields by a simple work up.     

One-pot four-component synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives

The synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives by NiCl₂-catalyzed novel one-pot four-component condensation reaction of phthalimide, hydrazine, malononitrile (or ethyl cyanoacetate), and aromatic aldehydes was reported. This work provides a simple, efficient, and eco-friendly method for the construction of pyrazolo[1,2-b]phalazine-5,10-dione derivatives.     

One-pot three-component reaction of isocyanides, dialkyl acetylenedicarboxylates and phthalhydrazide: synthesis of highly functionalized 1H-pyrazolo[1,2-b]phthalazine-5,10-diones

Protonation of the highly reactive 1:1 intermediate produced in the reaction between alkyl isocyanides and electron-deficient acetylenic esters with phthalhydrazide, leads to a vinylisonitrilium cation, which undergoes an addition reaction with the conjugate base of the phthalhydrazide to produce dialkyl 3-(alkylamino)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-1,2-dicarboxylates in fairly good yields at room temperature.     

Synthesis of 6-substituted 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones using the Vilsmeier reaction

The reaction of 6-amino-1,3-dimethyluracil with equimolar amounts of arylalkanone Mannich bases under optimized reaction conditions leads to 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidines in a yield of 50-80%. Functionalization of these dihydropyridopyrimidine(1H,3H)-2,4-diones with the Vilsmeier reagent affords, depending on the reaction conditions, either 6-dimethylaminomethylidene substituted 5H-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones or the corresponding pyridopyrimidine(1H,3H)-2,4-diones bearing a carboxaldehyde function in position 6 of the heterocycle. Some further transformations of the aldehyde function demonstrate the synthetic potential of the synthesized structures, introducing pharmacologically relevant basic substituents into the side chain of these pyrido[2,3-d]pyrimidine derivatives.     

A new, one-pot, three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines

A new, one-pot and three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by N-(2-heteroaryl)amides to yield a ketenimine intermediate, which was cyclized and then rearranged under the reaction conditions to afford the title compounds under mild reaction conditions in good yields. Single-crystal X-ray analysis conclusively confirms the structure of the obtained bridgehead bicyclic 6-6 heterocyclic compounds.     

Facile synthesis of 1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives by a one-pot, three-component reactions

Protonation of the highly reactive 1:1 intermediate produced in the reaction between alkyl or aryl isocyanides and electron-deficient acetylenic esters with 3,6-dihydroxypyridazine, leads to a vinylisonitrilium cation, which undergoes an addition reaction with the conjugate base of the 3,6-dihydroxypyridazine to produce dialkyl 3-(alkyl or arylamino)-5,8-dioxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylates in good yields at room temperature.     

An efficient route to diverse H-pyrazolo[5,1-a]isoquinolines via sequential multi-component/cross-coupling reactions

Multi-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, electrophile (bromine or iodine), and ketone or aldehyde under mild conditions proceeds smoothly to afford the functionalized H-pyrazolo[5,1-a]isoquinolines in good yields. This one-pot process involves intermolecular condensation, electrophilic cyclization, nucleophilic addition, intramolecular condensation, and aromatization. The resulting halo-containing H-pyrazolo[5,1-a]isoquinolines could be further elaborated via palladium-catalyzed cross-coupling reactions.     

DBU: a highly efficient catalyst for one-pot synthesis of substituted 3,4-dihydropyrano[3,2-c]chromenes, dihydropyrano[4,3-b]pyranes, 2-amino-4H-benzo[h]chromenes and 2-amino-4H benzo[g]chromenes in aqueous medium

We have reported DBU catalyzed one-pot synthesis of 3,4-dihydropyrano[3,2-c]chromenes, dihydropyrano[4,3-b]pyranes, 2-amino-4H-benzo[h]chromenes and 2-amino-4H-benzo[g]chromenes from aldehydes, active methylene compounds malononitrile/ethyl cyanocacetate, and 4-hydroxycoumarin/4-hydroxy-6-methylpyrone/1-naphthol/2-hydroxynaphthalene-1,4-dione in water under reflux. The attractive features of this process are mild reaction conditions, reusability of the reaction media, short reaction times, easy isolation of products, and excellent yields.     

Synthesis of annelated [a]aza-anthracenones and thieno[3,2-g]aza-naphthalenones through ring transformation of 2H-pyran-2-one followed by photocyclization

A concise synthesis of some new classes of heterocycles (4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a-diaza-cyclopenta[a]anthracen-6-carbonitriles and 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a-diazabenzo[a]anthracene-7-carbonitriles) has been developed by the ring transformation of suitably functionalized 2H-pyran-2-one with α-oxoketene cyclic aminals to intermediates (8-aroyl-5-aryl-2,3-dihydro-1H-imidazo[1,2-a]pyridine-7-ylidene)-acetonitriles and (9-aroyl-6-aryl-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-8-ylidene)-acetonitriles) followed by their photocyclization either in CHCl₃ or acetonitrile. This reaction was further explored for the synthesis of methyl 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclopenta[a]anthracene-6-carboxylate, 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclopenta[a]anthracene-6-carbonitriles, 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a,10-triazabenzo[a]anthracene-7-carbonitriles, 4-aryl-10-oxo-1,2,3,10-tetrahydro-9-thia-1,3a-diazadicyclopenta[a,g]naphthalene-6-carbonitriles and 5-aryl-11-oxo-1,3,4,11-tetrahydro-2H-10-thia-1,4a-diazacyclopenta[b]phenanthrene-7-carbonitriles from the similar reactions.     

One-pot synthesis of novel 1,2,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridine-3,4(5H)-diones

A facile synthesis of novel 1,2,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridine-3,4(5H)-diones has been achieved. The operationally simple procedure, using readily available intermediates, allows for rapid derivatisation of the pharmacophore with alkyl, aryl and heteroaryl substituents.     

Reaction between isocyanides and dialkyl acetylenedicarboxylates in the presence of 2,4-dihydro-3H-pyrazol-3-ones. One-pot synthesis of highly functionalized 7-oxo-1H,7H-pyrazolo[1,2-a]pyrazoles

The reactive 1:1 intermediate produced in the reaction between isocyanides and dialkyl acetylenedicarboxylates was trapped by 2,4-dihydro-3H-pyrazol-3-ones to yield highly functionalized 7-oxo-1H,7H-pyrazolo[1,2-a]pyrazoles in fairly good yields.     

Synthesis and ring transformations of 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-ones

Heating 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolinium chloride in the presence of hydrazine bishydrate produces regioselectively the five-membered heterocycle 1-amino-1,2,3,9a-tetrahydro-9,9,9a-trimethylimidazo[1,2-a]indol-2(9H)-one. The assignment of the structure is based on extensive ¹H, ¹³C and ¹⁵N NMR spectroscopic studies. No ring-chain tautomerism of the 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-one was observed to open-chain hydrazides or the corresponding six-membered 1,2,10,10a-tetrahydro[1,2,4]triazino[4,3-a]indol-3(4H)-one. Further transformations of 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-one were performed by treatment with aromatic aldehydes, acid chlorides and isocyanates giving access to 40 novel hydrazones, N,N′-diacylhydrazines, N-acyl-N′-carbamoylhydrazines and 1,3,4-oxadiazoles.     

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

A novel one-pot isocyanide-based four-component reaction: synthesis of highly functionalized 1H-pyrazolo[1,2-b]phthalazine-1,2-dicarboxylates and 1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylates

A new protocol has been developed for the efficient synthesis of structurally diverse 1H-pyrazolo[1,2-b]phthalazine-1,2-dicarboxylates and 1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylates via a four-component reaction of hydrazine hydrate, dialkyl acetylenedicarboxylates, isocyanides and various cyclic anhydrides such as succinic anhydride, maleic anhydride and phthalic anhydride in ethanol/acetone (1:1) at room temperature in good to moderate yields.     

Synthesis of seven- and eight-membered [1,2-a] alicyclic ring-fused benzimidazoles and 3-aziridinylazepino[1,2-a]benzimidazolequinone as a potential antitumour agent

Azepino and azocino[1,2-a]benzimidazoles were obtained either by treatment of 1-nitrophenyl-2-azacycloalkanes via a one-pot catalytic hydrogenation/acetylation or by treatment of the acetamides generated in the latter reaction with performic acid. This represents the first facile synthesis of eight-membered [1,2-a] alicyclic ring-fused benzimidazoles. 3-Methoxy-azepino[1,2-a]benzimidazole was elaborated to the novel potential cytotoxin, 3-(N-aziridinyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazole-1,4-dione. The synthesis included clarification of the reactivity of methoxy-substituted benzimidazoles towards nitration.     

An alternative approach toward 2-aryl-2H-pyrazolo[4,3-c]-quinolin-3-ones by a multistep synthesis

A series of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones derivatives 6 and 7 was conveniently prepared. A multistep synthesis was carried out starting from dichloro- and bromoanilines (1a-b) and diethyl 2-(ethoxymethylene)malonate using a slightly modified Gould-Jacobs reaction. In this work we present a novel chlorination strategy to prepare quinoline derivatives 4 in excellent yields as key intermediates in the synthesis of the target compounds. Several reaction conditions were evaluated to optimize the formation of pyrazoloquinolinone nucleus. Differences in chemical behavior of both chloroquinolinones 4a-b with aryl and benzyl-hydrazines are also discussed.