Haloacetylated enol ethers. 13. Synthesis of N-[1-aryl(alkyl)-3-oxo-4,4,4-trichloro-1-buten-1-yl]-o-phenylenediamines and 2-trichloromethyl-4-aryl-3H-1,5-benzodiazepines

The synthesis and isolation of the intermediates N-[1-aryl(alkyl)-3-oxo-4,4,4-trichloro-1-buten-1-yl]-o-phenylenediamines 2a-f and the corresponding 2-trichloromethyl-4-aryl-3H-1,5-benzodiazepines 3c-g or benzimidazoles 4a-b derivatives obtained from the intramolecular cyclization of 2a-f or from direct cyclo-condensation reaction of β-alkoxyvinyl trichloromethyl ketones 1a-g with o-phenylenediamine, is reported. Depending of the structure of the β-alkoxyvinyl trichloromethyl ketones or the N-[1-aryl(alkyl)-3-oxo-4,4,4-trichloro-buten-1-yl]-o-phenylenediamines and the reactions conditions, benzimidazoles or 3H-1,5-benzodiazepines were obtained.     

Quinazolines and 1,4-benzodiazepines. XCIII. Synthesis of imidazo[1,5-a][1,4]benzodiazepines from nitrooximes

The displacement of the nitro group in nitrooximes by other nucleophiles was used to prepare various 2-(hydroxyimino)methyl- and 2-(methoxyimino)methyl-1,4-benzodiazepines. These compounds were converted to imidazo[1,5-a][1,4]benzodiazepines bearing a tertiary amine, methoxy or thiomethyl group in the 3-position.     

Fragmentation en Spectrométrie de Masse D'Imidazobenzodiazépines

The mass spectra of a series of imidazo[4,5,1-jk]1,4-benzodiazepines and imidazo[1,5,4-ef]1,5-benzodiazepines have been examined. The differences in the fragmentation patterns permit the isomeric structures to be identified.     

Synthesis of Substituted 5,6-Dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines

A one-pot synthetic approach to the novel 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines by thermal cyclization of 4-acylhydrazino-2,3-dihydro-1H-1,5-benzodiazepines is described.     

Quinazolines and 1,4-benzodiazepines. XCV. Synthesis of 1,4-benzodiazepines by ring expansion of 2-chloromethylquinazolines with carbanions

1,4-Benzodiazepines bearing a carbon substituent at the 2-position were obtained by reaction of 2-chloromethylquinazoline 3-oxides with stabilized carbanions. The carbanions of alkyl acetates, N,N-disubstituted acetamides, acetonitrile, dimethylsulfone, N,N-dimethyl methanesulfonamide and 2-methylpyridine were successfully applied. The conversion of some of the 2-carbon substituted 1,4-benzodiazepines to imidazo[1,5-a][1,4]benzodiazepines and [1,2,5]oxadiazino[5,4-a][1,4]benzodiazepines is described.     

Cycloaddition of benzoheteroazepine III Reaction of 2,3-dihydro-1H-15benzodiazepines with dichlorocarbene and stereo-structures of products

Reaction of 2, 3-dihydro-1H-1. 5-benzodiazepines with dichlorocarbene generated in situ using benzyltriethylammonium chloride (TEBA) as a phase transfer catalyst in chloroform-aqueous sodium hydroxide mixture gave mainly 1,2-cycloadducts, cis and trans-1a, 3-disubstituted-1, 1-dichloro-1a, 2,3,4-tetrahydro-1H-azirino[1,2-a][1,5]benzodiazepines (2.3), and formylated 1,2-cycloadducts, trans-1a,3-disubstituted-1, 1-dichloro-4-formyl-1a, 2, 3, 4–1 H-azirino[1, 2-a][1, 5]benzodiacepines (4). The stereo-structures of cycloadducts and the mechanism are also discussed.     

Synthesis of two novel bicyelic systems,imidazo[1,5-D]-as-triazine and imidazo[1,2-d]-as-triazine

4-Imidazolecarboxyaldehyde was condensed with methyl dithiocarbazinate and with ethyl carbazate, the resulting hydrazones were subjected to thermolysis in diphenyl ether at 175–240, to give imidazo[1,5-d]-as-triazine-4(3H)thione and imidazo[1,5-d]-as-triazin-4(3H)one, respectively. A number of 2-, 5-, and 2,5-substituted 4-imidazolecarboxaldehydes were also carried through this scheme. The same sequence of reactions with 2-imidazolecarboxaldehyde gave the novel system imidazo[1,2-d]-αs-triazine-5-(6H)-thione. Upon treatment with sodium hydride and methyl iodide, imidazo[1,5-d]-as-triazine-4(3H)thione and imidazo[1,2-d]-as-triazine-5(6H)-thione gave 4-methylthioimidazo[1,5-d]-as-triazine and 5-methylthioimidazo[1,2-d]-as-triazine, respectively. Displacement of the thiomethyl group was achieved with a selection of amine reagents in both of the above cases.     

Acid-catalyzed reactions of 3-(hydroxymethyl)- and 3-(1-hydroxyethyl)pyrazolo[1,5-a]pyridines

Treatment of 3-(hydroxymethyl)pyrazolo[1,5-a]pyridines with trifluoroacetic acid in refluxing dichloro-methane led to the formation of bis(pyrazolo[1,5-a]pyrid-3-yl)methanes or bis[(pyrazolo[1,5-a]pyrid-3-yl)]-methyl ethers depending upon the concentration of trifluoroacetic acid. In contrast, similar treatment of 3-(1-hydroxyethyl)pyrazolo[1,5-a]pyridines gave a mixture of 3-vinylpyrazolo[1,5-a]pyridines and 1,3-bis(pyrazolo-[1,5-a]pyrid-3-yl)-1-butenes.     

Reactions with diazoazoles. Part VI. Unequivocal synthesis of 3-methyl-3h-azolotetrazoles. Correction of the formerly described 3-methylazolotetrazoles in favour of mesoionic 2-methylazolotetrazoles

3-Methyl-3H-pyrazolo[1,5-d]tetrazoles 2 and 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) have been unequivocally synthesized by annulation of the tetrazole moiety to the pyrazole resp. 1,2,4-triazole system. The constitution of some N-methyl substituted azolotetrazoles, formerly described as 3-methyl-3H-pyrazolo[1,5-d]tetrazoles 2, 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) and 1-methyl-6-phenyl-1H-1,2,4-triazolo[4,3-d]tetrazole (5), has to be revised in favour of the corresponding mesoionic 2-methyl derivatives 2′, 4′, 5′. The structures of 3-methyl-3H- as well as of 2-methyl-2H-pyrazolo[1,5-d]tetrazole derivatives 2a, 2c, 2′a have been determined by X-ray analyses. The azapentalenic system is aromatic in all three measured compounds and mesoionic in the case of the 2-methyl-2H- substitution pattern. The phenyl and ester substituents are coplanar with the azapentalene system. 3-, 2-, and 1-Methylpyrazolo[1,5-d]tetrazoles exhibit different behaviour when allowed to react with stannous chloride or sodium ethoxide. Azolotetrazoles with a methyl substituent at N-1, N-2 or N-3 of the tetrazole moiety can be distinguished by a combination of ¹H and ¹³C nmr with respect to the chemical shifts of the N-methyl group and the bridgehead carbon. Results of semiempirical calculations of the pyrazolo[1,5-d]tetrazole anion and of its N-methyl derivatives are discussed.     

The chemistry of 4-hydrazino-7-phenylpyrazolo[1,5-a] -1,3,5-triazines

The reaction of 4-hydrazino-7-phenylpyrazolo[1,5-a]-1,3,5-triazine ( 4 ) with nitrous acid gave 8-phenyltetrazolo[1,5-e]pyrazolo[1,5-a]-1,3,5-triazine ( 5b ), which was determined by pmr and ir spectra to be in equilibrium with 4-azido-7-phenylpyrazolo[1,5-a]-1,3,5-triazine ( 5a ). The equilibrium between the tetrazolo ( 5b ) and azido ( 5a ) forms was studied by pmr and an attempt was made to determine if substituents in the pyrazole nucleus could sufficiently stabilize the tricyclic tetrazolo form ( 5b ) over the bicyclic azido form ( 5a ). Thermal degradation of 5 (a ? b) in an aprotic solvent gave 4-amino-7-phenylpyrazolo[1,5-a]-1,3,5-triazine ( 7 ), indicating the probability of a nitrene mechanism involved in the decomposition. Heating 5 in aqueous base gave both 7 and the “hydroxy” analog, 7-phenylpyrazolo[1,5-a]-1,3,5-triazin-4(3H)one ( 6 ), further substantiating the existence of a nitrene intermediate with a competing nucleophilic displacement of the azido group by a hydroxyl group. Cyclization of 4 with diethoxymethylacetate (DEMA) gave 8-phenyl-s-triazolo[4,3-e]pyrazolo[1,5-a]-1,3,5-triazine ( 8 ), which underwent thermal rearrangement to 8-phenyl-s-triazolo[2,3-e]pyrazolo[1,5-a]-1,3,5-triazine ( 9 ). Acid catalyzed ring opening of 9 with formic acid gave 3-N-formamido-5-phenyl-2(2-s-triazolyl)pyrazole ( 10 ). The failure of 10 to recyclize to 9 with the resultant loss of water, supported the theory that the rearrangement of 8 to 9 might occur simply as a concerted, thermally induced “anhydrous” rearrangement rather than via a covalently hydrated intermediate or a Dimroth type mechanism (in the base catalyzed rearrangement).     

The synthesis of certain 8-cyano-2,4-disubstituted-imidazo[1,5-a] pyrimidines

A number of imidazo[1,5-a]pyrimidine-8-carboxamides were synthesized by reacting various β-dicarbonyl compounds with 5(4)-aminoimidazole-4(5)carboxamide (AICA, 1 ), the non-ribosylated form of AICAR, a key intermediate in the metabolic pathway of purine biosynthesis. Cyclization of 1 with ethylacetoacetate yielded 2-methylimidazo[1,5-a]pyrimidin-1H-4-one-8-carboxamide ( 2 ). The treatment of 2 with phosphorus oxychloride gave 4-chloro-8-cyano-2-methylimidazo[1,5-a]pyrimidine ( 3 ). Various nucleophiles displaced the 4-chloro substituent of 3 under mild conditions. However, the 4-methylthio group of 8-cyano-2-methyl-4-methylthioimidazo[1,5-a)pyrimidine ( 8a ) was also displaced under very mild conditions. Even more strangely, the 4-diethylamino group of 8-cyano-4-diethylamino-2-methylimidazo[1,5-a]pyrimidine ( 5a ) was displaced by ammonia to give 4-amino-8-cyano-2-methylimidazo[1,5-a]pyrimidine ( 7 ).     

On the bromination of thieno[c]-fused 1,5-naphthyridines and their isomeric N-oxides using dibromoisocyanuric acid in fuming sulfuric acid

Thieno[2,3-c]-1,5-naphthyridine ( 3 ), thieno[2,3-c]1,5-naphthyridine 5-oxide ( 7 ), thieno[3,2-c]-1,5-naphthyridine ( 5 ) and thieno[3,2-c]-1,5-naphthyridine 5-oxide ( 9 ) could conveniently be brominated at room temperature using dibromoisocyanuric acid in fuming sulfuric acid. Bromination occurred in good to moderate yields at the β position in the thiophene ring. Thieno[2,3-c]-1,5-naphthyridine 9-oxide ( 12 ) and thieno[3,2-c]-1,5-naphthyridine 9-oxide ( 13 ) also gave substitution in the thiophene ring at 95°. It was also found that 12 was deoxygenated under these reaction conditions. Direct oxidation of the brominated thieno[c]naphthyridines with m-chloroperbenzoic acid gave the 5-oxides in high yield.     

Synthesis of 1,2-dihydroindolo [1,7-AB] [1,5] benzodiazepines and related structures. A new heterocyclic ring system

The synthesis of the novel 1,2-dihydroindolo [1,7-ab][1,5]benzodiazepine ring system 4 is described. Condensation of 2-fluoronitrobenzene with indoline provided the starting material for the synthesis, 1-(2-nitrophenyl)indoline (1a) in high yield. The nitro group was reduced catalytically and the resulting amino function was acylated to afford the heterocycle percursor amide 3. Refluxing this amide in phosphorus oxychloride brought about a Bischler-Napieralski type cyclodehydration to form the target 1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine ring system. Dehydrogenation of the latter led to the fully aromatic indolo[1,7-ab][1,5]benzodiazepine structure 5, while reduction with sodium borohydride provided the 1,2,6,7-tetrahydroindolo[1,7-ab]-[1,5]benzodiazepine tetracycle 6.     

Synthesis of 1,3-dialkylpyrazolo [1,5-a]-1,3,5-triazine-2,4-diones isomers of 1,3-dialkylxanthines

The synthesis of a new series of alkylxanthine analogs containing a bridgehead nitrogen atom is reported. 1,3-Dialkylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones, were prepared by the treatment of 3-methylpyrazolo[1,5-a]-1,3,5-triazine-2,4-dione (3) with the corresponding alkyl iodide. Similarly, the reaction of 3-methyl-7-phenylpyrazolo[1,5-a]-1,3,5-dialkyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones. The starting materials, 3 and 17 , were prepared via the reaction of an appropriate 3-aminopyrazole with ethoxycarbonyl isothiocyanate. Several 8-bromo derivatives were prepared by direct bromination of the 1,3-dialkylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones.     

Cyclocondensation reaction of 1,2-diamino-4-methylbenzene and p-substituted acetophenones

1,2-Diamino-4-methylbenzene 1 reacts in the presence of sulphuric acid with 4-substituted acetophenones 2a-e yielding 2,4-diaryl-2,3-dihydro-2,8-dimethyl-1H-1,5-benzodiazepines 3a-e and as minor component 2,4-diaryl-2,3-dihydro-2,7-dimethyl-1H-1,5-benzodiazepines 4a-e . The ratio 3:4 is in the range of 7:3. The structure determination of the regioisomers was performed by NOE measurements.     

Synthesis of N-Alkylated Derivatives of Pyrazolo[1,5-a]pyrimidine and Their Reaction with Methylamine

With the object of studying the factors influencing the course of enamine rearrangements, we have carried out the N-alkylation of alkyl- and aryl-substituted pyrazolo[1,5-a]pyrimidines. Using the NOEDIF NMR spectroscopic method for the cases of 5,7-dimethyl-2-phenyl- and 2,5,7-triphenylpyrazolo[1,5-a]pyrimidines it was found that addition of the alkyl group occurs at the N₍₄₎ atom of the pyrimidine fragment in the pyrazolo[1,5-a]pyrimidine. It was shown that, when reacting with an alcoholic solution of methylamine, the 5,7-dimethyl-2-phenyl- and 2,5,7-triphenylpyrazolo[1,5-a]pyrimidine iodomethylates undergo decomposition to give 5-methylamino-3-phenylpyrazole and 5-(1,3-diphenyl-3-methylamino-2-propenylid-1-ene)amino-3-phenylpyrazole.     

NEW HETEROCYCLIC SYSTEM SYNTHESIS I REACTION OF DIHYDRO-1,5-BENZO-DIAZEPINES AND THIAZEPINES WITH (ETHOXYCARBONYL)CARBENES

Dihydro-1-benzoyl-1,5-benzodiazepines react with (ethoxycarbonyl)carbenes to give 4H-azirino-[1,2-a][1,5]-benzodiazepines and unexpected new tin9 system 1H-pyrrolo-[1,2-a][1,5]-benzodiazepines. Dihydro-1,5-benzothiazepines react with (ethoxycarbonyl)carbenes in cyclohexane to gire unexpected rin9 cleavage products ethyl (2E, 4E)-3-aryl-2-arylthiohexadienoates.     

On triazoles. XVII . The reaction of 5-amino-1,2,4-triazoles with N-heterocyclic β-oxo-esters

Pyrrolo[3,4-d]-1,2,4-triazolo[1,5-a]pyrimidinone ( 3d ), pyrido[3,4-d]-1,2,4-triazolo[1,5-a]pyrimidinone ( 3e ) and pyrido[4,3-e]-1,2,4-triazolo[1,5-a]pyrimidinone ( 4e ) derivatives representing three new ring systems were synthesised. Their structure was proved by comparing their uv and cmr spectra with those of the known benzo- and thieno-1,2,4-triazolo[1,5-a]pyrimidinones used as model compounds.     

Synthesis and transformations of substituted 4,6-dimethylpyrazolo[3,4-b]pyridyl-3-azides and -sulfonyl chlorides

Diazotization of the amino group of 3-amino-4,6-dimethylpyrazolo[3,4-b]pyrimidines and subsequent replacement of the diazo group in the formed diazonium chlorides by an azide group gave the corresponding 3-azido derivatives. Their reactions with active methylene compounds have been studied. Substitution of the diazo group by a sulfo group gave the related 4,6-dimethylpyrazolo-[3,4-b]pyridyl-3-sulfonyl chlorides and sulfonylamides. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1556–1565, October, 2008.     

Synthesis of 5H-Triazolo[1,5-d]- and 5H- Tetrazolo- [1,5-d]thieno[3,2-f]-1,4-diazepin-6(7H)-ones

5H-Triazolo[1,5-d]- and 5H-tetrazolo[1,5-d]thieno[3,2-f]-1,4-diazepin-6(7H)-ones have been obtained by the base catalysed ring expansion reaction of 5-chloromethyl-1,2,4-triazolo[1,5-c]- and 5-chloromethyltetrazolo- [1,5-c]thieno[3,2-e]pyrimidines. The required thienopyrimidine derivatives were synthesized from 2-amino-3-triazolyl- and 2-amino-3-tetrazolylthiophenes by acylation, followed by dehydrative cyclization.