Tautomerism of Aza heterocycles: V. Structure of the spontaneous transformation products of 5-methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo-[4,3-c]pyridin-3-one in crystal and solution

5-Methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one exists as zwitterion with a proton localized on the nitrogen atom of the piperidine ring and negative charge delocalized over the pyrazololate fragment. The compound is stable in crystal but ustable in solution. Its chromatographic purification and attempts to recrystallize or synthesize by condensation of phenylhydrazine with alkyl 1-methyl-4-oxopiperidin-3-carboxylate on heating in alcohols or benzene lead to the formation of a complex mixture of products. Among these products, we isolated and identified 3a,3a′-methylenebis(5-methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one), 1-methyl-3-(2-phenylhydrazinylidene)pyrrolidin-2-one, and 5-methyl-2-phenyl-3,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine. The structure of methyl 3-(2-phenylhydrazinylidene)-4,5-dihydro-3H-pyrrole-2-carboxylate and 3a,5-dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was proved by NMR spectroscopy. 3a,5-Dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was isolated as hydrochloride hydrate whose structure was determined by X-ray analysis.     

3,5-Disubstituted 6H-pyrrolo[1,2-c][1,2,3]triazoles from Morita-Baylis-Hillman adducts of propargyl aldehydes

A simple method for synthesizing several 6H-pyrrolo[1,2-c][1,2,3]triazole derivatives having a methoxycarbonyl or an acetyl group at C-5 position and 7,8-dihydro-4H-[1,2,3]triazolo[1,5-a]indol-5(6H)-ones via an intramolecular 1,3-dipolar cycloaddition reaction of azido enynes, which were readily obtained from the Morita-Baylis-Hillman acetates of propargyl aldehydes with sodium azide, has been developed.     

Synthesis of 5-thioxo-6H-imidazo[1,2-c]quinazolines and related compounds based on cyclocondensations of 2-isothiocyanatobenzonitrile (ITCB) with α-aminoketones

Pharmacologically relevant 5-thioxo-6H-imidazo[1,2-c]quinazolines and 5-oxo-6H-imidazo[1,2-c]quinazolines were prepared by sequential reactions of α-aminoketones with 2-isothiocyanatobenzonitrile (ITCB) and 2-isocyanatobenzonitrile (ICB), respectively. The functionalization of the thioxo moiety allowed the synthesis of 5-amino-6H-imidazo[1,2-c]quinazolines and of 1,2,4-triazolo[4,3-a]-imidazo[1,2-c]quinazolines.     

Microwave-assisted generation and reactivity of aza- and diazafulvenium methides: heterocycles via pericyclic reactions

Azafulvenium methides and diazafulvenium methides have been generated under microwave irradiation from 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles and 2,2-dioxo-1H,3H-pyrazolo[1,5-c]thiazoles, respectively. Pericyclic reactions of these 1,7-dipole intermediates, namely, sigmatropic [1,8]H shifts, 1,7-electrocyclization or [8π+2π] cycloaddition led to the synthesis of a range of pyrrole and pyrazole derivatives. The first evidence for the azafulvenium methides by intermolecular trapping via [8π+2π] cycloaddition is reported.     

A novel one-pot synthesis of 2-arylpyrazoloquinolinone derivatives

Two regioisomers of 2-arylpyrazolo[3,4-c]quinolin-4(5H)-ones and 2-arylpyrazolo[4,3-c]quinolin-4(5H)-ones were synthesized by utilizing 3-arylsydnones, ethyl 3-bromopropynoate, and 2-aminophenylboronic acid pinacol ester in presence of catalytic agent Pd(PPh₃)₄. This efficient one-pot synthesis methodology involved 1,3-dipolar cycloaddition, Suzuki coupling reaction, and intramolecular cyclization three sequence steps.     

Preparation of 2,4,5-trisubstituted pyrazolo[4,3-c]quinolin-3-ones

The preparation of pyrazolo[4,3-c]quinolinones is reported starting from 2-substituted-5-(2-fluorophenyl)-3-oxo-2,4-dihydro-3H-pyrazol-3-ones. A one-pot protocol, in which condensation with an orthoamide followed by substitution with a primary amine and subsequent S_NAr-cyclization to provide rapid access to 4- and 5-substituted pyrazolo[4,3-c]quinolinones was developed.     

Thiazolo[4,3-c][1,4]benzodiazepines. I. Synthesis of amidine derivatives

Reactivity of 1,2,3,10,11,11a-hexahydro-5H-thiazolo[4,3-c][1,4]benzodiazepin-5-one-11-thione and 1,2,3,10,11,11a-hexahydro-5H-thiazolo[4,3-c][1,4]benzodiazepine-5,11-dithione was evaluated against various amines. The synthetic pathways involved in these reactions which led to new thiazolo[4,3-c]-[1,4]benzodiazepine amidines are described.     

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 new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.     

Pyrolytic desulfurization ring contraction of condensed thiadiazines as a general route towards pyrazoloazines and pyrazoloazoles with a bridgehead (ring junction) nitrogen atom

Pyrolytic conversion of [1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, [1,3,4]thiadiazino[2,3-b]quinazolin-10-ones and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines into their corresponding pyrazolo[5,1-c][1,2,4]triazin-4-ones, pyrazolo[4,3-b]quinazolin-9-ones and pyrazolo[5,1-b][1,2,4]triazoles via desulfurization ring contraction is described. The starting condensed 1,3,4-thiadiazines were prepared from the corresponding readily available 4-amino-3-thioxo-1,2,4-triazin-5(4H)-ones, 3-amino-2,3-dihydro-2-thioxoquinazolin-4(1H)-one and 4-amino-3(2H)-thioxo-1,2,4-triazoles upon reaction with the appropriate α-haloketones in two steps, or directly in one step in ethylpyridinium tetrafluoroborate (ionic liquid, IL).     

Reactions of 4-Chloro-3-formylcoumarin with Arylhydrazines

The interaction of 3-formyl-4-coumarin with arylhydrazine hydrochlorides in the presence of sodium acetate gave the corresponding 3-arylhydrazonomethyl-4-chlorocoumarin, and with phenylhydrazine, 4-bromo- and 4-chlorophenylhydrazine hydrochlorides in the presence of two equivalents of triethylamine gave either 1-aryl- or 2-aryl[1]benzopyrano[4,3-c]pyrazol-4-ones depending on the reaction conditions. In reactions of 4-chloro-3-formylcoumarin with 2,4-dichloro-, 2,4-difluoro-, 2-hydroycarbonyl-, 4-nitro- and 3,5-di(trifluoromethyl)phenylhydrazine, 2-pyridyl- and 2-quinoxalylhydrazine in the presence of excess of triethylamine the 2-aryl[1]benzopyrano[4,3-c]pyrazol-4(2H)-ones were obtained exclusively. The structures of 1-phenyl- and 2-(2-pyridyl)[1]benzopyrano[4,3-c]pyrazolo-4(1H)ones were confirmed by X-ray crystallography. A simple method is proposed to distinguish between 1- and 2-substituted [1]benzopyrano[4,3-c]pyrazolo-4-ones on the basis of the ¹H NMR chemical shifts of the C(3)-H proton in two solvents - DMSO-d₆ and CDCl₃.     

Reactivity of sarcosine and 1,3-thiazolidine-4-carboxylic acid towards salicylaldehyde-derived alkynes and allenes

The reaction of sarcosine and 1,3-thiazolidine-4-carboxylic acid with salicylaldehyde-derived alkynes and allenes opened the way to new chromeno[4,3-b]pyrrole and chromeno[2,3-b]pyrrole derivatives. Tetrahydro-chromeno[4,3-b]pyrroles were obtained from the reaction of these secondary amino acids with O-propargylsalicylaldehyde. Interestingly, sarcosine reacted with ethyl 4-(2-formylphenoxy)but-2-ynoate to give a monocyclic pyrrole resulting from rearrangement of the initially formed 1,3-dipolar cycloadduct. Decarboxylative condensation of ethyl 4-(2-formylphenoxy)but-2-ynoate with 1,3-thiazolidine-4-carboxylic acid afforded in a stereoselective fashion the expected chromeno-pyrrolo[1,2-c]thiazole, which structure was unambiguously established by X-ray crystallography. However, the 1H,3H-pyrrolo[1,2-c]thiazole resulting from the opening of the pyran ring was also isolated. The reaction with O-buta-2,3-dienyl salicylaldehyde afforded 3-methylene-hexahydrochromeno[4,3-b]pyrrole. O-Allenyl salicylaldehyde reacted with sarcosine and 1,3-thiazolidine-4-carboxylic acid to give a new type of chromeno-pyrroles. A mechanism proposal for the synthesis of these chromeno[2,3-b]pyrroles has been presented.     

Dehydrative intramolecular nitrone cycloaddition in confined aqueous media: a green chemical route to cis-fused chromano[4,3-c]isoxazoles

An efficient synthetic route to the formation of cis-fused chromano[4,3-c]isoxazoles via dehydrative intramolecular 1,3-dipolar nitrone cycloaddition in organized aqueous media in the presence of a surfactant (viz. CTAB) as catalyst was developed, which indeed appeared to be green and a more sustainable method than the existing methods with the additional advantage of easy isolation of products.     

Synthesis of spiro[benzopyrazolonaphthyridine-indoline]-diones and spiro[chromenopyrazolopyridine-indoline]-diones by one-pot, three-component methods in water

The synthesis of spiro[benzo[h]pyrazolo[3,4-b][1,6]naphthyridine-7,3′-indoline]-2′,6(5H)-diones and spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3′-indoline]-2′,6(6aH,10H)-diones via a one-pot, three-component reaction of 4-hydroxycoumarin or 4-hydroxy-1-methylquinolin-2(1H)-one, isatins and 1H-pyrazol-5-amines in water is reported.     

Unexpected behaviour of the oxidizing agent sodium m-nitrobenzenesulfonate: Synthesis of a new class of 5-hydroxy benzopyrano-[4,3-c]pyridazin-3(2H)-ones

Sodium m-nitrobenzene sulfonate, widely used in dehydrogenation of 4,5-dihydro-3(2H)-pyridazinones to their corresponding aromatic derivatives, behaves in an unexpected way when 4,4a-dihydro-5H[1]benzopyrano[4,3-c]pyridazin-3(2H)-ones are employed as substrate. The synthesis of a new class of 5-hydroxy[1]benzopyrano[4,3-c]pyridazin-3(2H)-ones is described.     

A novel tandem cyclization of condensed 2,3-dialkynylpyrazines into [1,2,3]triazolo[1′,5′;1,2]pyrido[3,4-b]pyrazines promoted by sodium azide

6,7-Dialkynyl-1,3-dimethylpteridine-2,4(1H,3H)-diones and 2,3-dialkynylquinoxalines have been shown to react with sodium azide in DMF at room temperature giving rise 9,11-dimethyl-[1,2,3]triazolo[1′,5′;1,2]pyrido[4,3-g]pteridine-8,10(9H,11H)-diones and [1,2,3]triazolo[1′,5′;1,2]pyrido[3,4-b]quinoxalines. A novel tandem cyclization involves 1,3-dipolar cycloaddition of an azide ion to the carbon-carbon triple bond followed by intramolecular nucleophilic addition of the intermediate 1,2,3-triazole N-anion to another CC bond.     

Synthesis of [1,2,4]triazoloquinazoline and [1,2,4]-triazolo-1,4-benzodiazepine derivatives

Some [1,2,4]triazolo[1,5-c]quinazolin-5(6H)-ones 7 , the corresponding isomers [1,2,4]triazolo[4,3-c]quinazo-lin-5(6H)-ones and the 5-amino derivatives 8, 9 and 11 have been synthesized starting from the acylamidrazones 5 . The preparation of 5H-[1,2,4]triazolo[1,5-d]-1,4-benzodiazepin-6(7H)-ones 15 and of 5-cyclicaminomethyl-[1,2,4]triazolo[1,5-c]quinazolines 16 and 17 is also reported.     

Stereoselective synthesis of tetrahydro-2H-[2]benzopyrano[3,4-c]pyrrol-3-ones and related compounds as precursors of serotonin 5-HT2C receptor agonists

Tetrahydro-2H-[2]benzopyrano[3,4-c]pyrrol-3-ones and the related 3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole analogues were synthesised by an intramolecular Diels-Alder reaction. The observed stereoselectivity was dependent upon the nature of the tethered dienophile as well as the judicious placement of the amide.     

Stereoselective synthesis of dihydrothiadiazinoazines and dihydrothiadiazinoazoles and their pyrolytic desulfurization ring contraction

Intramolecular base catalyzed C-C bond formation led to exclusive stereoselective syntheses of trans-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, trans-7,8-dihydro-6H-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, and trans-3,4-dihydro-2H-[1,3,4]thiadiazino[2,3-b]quinazolin-10-one. trans-6,7-Dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines isomerize slowly in CDCl₃ and more rapidly in DMSO-d₆ into the corresponding cis-stereoisomers. The other trans-6,7-dihydro-[1,3,4]thiadiazines isomerize also in DMSO-d₆ into the corresponding cis-stereoisomers. Pyrolytic conversion of these heterocyclic condensed dihydrothiadiazines into their corresponding pyrazolo[5,1-b][1,2,4]triazoles, pyrazolo[5,1-c][1,2,4]triazin-4-ones and pyrazolo[4,3-b]quinazolin-9-ones via desulfurization ring contraction is described.     

Metal-free synthesis of chromeno[4,3-c]pyrazol-3(2H)-one derivatives

An unprecedented metal-free synthesis of 4-(methylthio)chromeno[4,3-c]pyrazol-3(2H)-one is reported via sequential one-pot desulfitative [5+1] hetero-annulation. The present strategy consists of one-pot sequential, base catalysed dithioketene formation from active methylene of pyrazolone followed by methylation and [5+1] heteroannulative cyclization. The resulting substrate undergoes facile nucleophilic substitution with various amines to yield 4-(substituted-amine)-chromeno[4,3-c]pyrazol-3(2H)-one derivatives under metal free condition.