Pyrazolo[1,5-d]triazines-1,2,4. II étude des pyrazolo[1,5-d]triazinones,des pyrazolo[1,5-d]triazinediones et des pyrazolo[1,5-d]triazinethiones

The synthesis of 1,2-dihydro-l-oxopyrazolo[1,5-d]-1,2,4-triaxine was achieved by rerrangment of 2-(5-pyrazolyl)-1,3,4-oxadiazole under alkaline condition. The cyclization of the N-carbethoxyhydrazone of the pyrazole-5-carboxaldehyde gave the 3,4-dihydro-4-oxopyrazolo[1,5-d]1,2,4-triazine. Electrophilic substitutions of the l-pyrazolotriazinome were made either on the lactam nitrogen with methylsulfate, benzylchloride and monochloracetic axid or on the pyrazole ring with bromine. The synthesis of pyrazolo[1,5-d]-1,2,4-triazine was made from teh l-pyrazolotrizinone via the l-pyrazolotrizinone. The methylation of l-pyrazolotrizinone and 8-bromo-l-pyrazolotrizinone afforded N-and S-methyl derivatives. The sysnthesis of 1,2,3,4-tetrahydropyrazolo[1,5-d]-1,2,4-triazine-1,4-diones was axhived by cyclising N-carbethoxyhydrazides of pyrrole-5-carboxylic acid. The structures of the derivatives were determined by ¹H-nmr.     

Tetrahydro‐1,5‐benzoxazepines and tetrahydro‐1H‐1,5‐benzodiazepines by a tandem reduction‐reductive amination reaction

A tandem reduction‐reductive amination reaction has been applied to the synthesis of (±)‐4‐alkyl‐2,3,4,5‐tetrahydro‐1,5‐benzoxazepines and (±)‐4‐alkyl‐1‐benzoyl‐2,3,4,5‐tetrahydro‐1H‐1,5‐benzodiazepines. The nitro aldehydes and ketones required for 1,5‐benzoxazepine ring closures were prepared by nucleophilic aromatic substitution of the alkoxides from several 3‐buten‐1‐ol derivatives with 2‐fluoro‐1‐nitrobenzene followed by ozonolysis. Precursors for the 1,5‐benzodiazepines were prepared by similar addition of N‐(3‐butenyl)benzamide anions to 2‐fluoro‐1‐nitrobenzene followed by ozonolysis. Catalytic hydrogenation of the nitro carbonyl compounds using 5% palladium‐on‐carbon in methanol then gave the target heterocycles by a tandem reduction‐reductive amination sequence. The 1,5‐benzoxazepines were isolated in high yield following chromatographic purification; the 1,5‐benzodiazepines were isolated as solids directly from the hydrogenation mixture and possessed differentiated functionality on the two nitrogen atoms.     

Synthesis of [1,5]benzothiazepine derivatives

Various derivatives of 2,3-dihydro[1,5]benzothiazepin-4(5H)-ones were synthesized. Alternative route for the synthesis of 5-dimethylaminoethyl-2,3-dihydro[1,5]benzothiazepin-4(5H)-ones and 4-dimethylaminopro-poxy-(2H,5H)-[1,5]benzothiazepines are described.     

Novel synthesis of 3‐phenylazo‐1,5‐benzothiazepines, ‐1,5‐benzoxazepines and ‐1,5‐benzodiazepines via a one‐pot reaction

Novel polysubstituted ‐1,5‐benzothiazepine, ‐1,5‐benzoxazepine, and ‐1,5‐benzodiazepine were prepared in good yields by the reaction of hydrazono derivatives with o‐thioaminophenol, o‐aminophenol and o‐phenylenediamine via a one‐pot reaction.     

Formylation of 4,7‐Dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidines Using Vilsmeier–Haack Conditions

Formylation of 5‐methyl‐7‐phenyl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidine 1a using Vilsmeier–Haack conditions yields 5‐methyl‐7‐phenyl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidin‐6‐ylcarbaldehyde 3a . 5,7‐Diaryl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidines 1b , 1c in this reaction apart from formylation undergo recyclization into 5‐aryl‐1,2,4‐triazolo[1,5‐a]pyrimidin‐6‐ylmethane derivatives 4b , 4c , 5b , 5c , and 6 . The structure of the synthesized compounds was determined on the basis of NMR, IR, and MS spectroscopic data and confirmed by the X‐ray analysis of the 6‐(ethoxy‐phenyl‐methyl)‐5‐phenyl‐[1,2,4]triazolo[1,5‐a]pyrimidine 6 , 5‐phenyl‐6‐(1‐phenyl‐vinyl)‐[1,2,4]triazolo[1,5‐a]pyrimidine 11 , and 7‐phenyl‐6‐(1‐phenyl‐vinyl)‐[1,2,4]triazolo[4,3‐a]pyrimidine 12 .     

Regioselective Synthesis of Some New Pyrazolo[1,5‐a]pyrimidines,Pyrazolo[1,5‐a]quinazoline and Pyrimido[4′,5′:3,4]pyrazolo[1,5‐a] pyrimidines Containing Thiazole Moiety

A regioselective synthesis of novel pyrazolo[1,5‐a]pyrimidines, pyrazolo[1,5‐a]quinazoline and pyrimido[4′,5′:3,4]pyrazolo[1,5‐a]pyrimidines incorporating a thiazole moiety was described via the reactions of the versatile, readily accessible 5‐amino‐3‐(phenylamino)‐N‐(4‐phenylthiazol‐2‐yl)‐1H‐pyrazole‐4‐carboxamide 3 with appropriate 1,3‐biselectrophilic reagents namely, β‐diketones, enaminones, and α,β‐unsaturated cyclic ketone. The newly synthesized compounds were elucidated by elemental analysis, spectral data, and alternative synthetic route whenever possible.     

Hetaryl‐1,5 Benzodiazepines—Part I: Synthesis of 3‐pyrimidinyl‐ and Imidazolyl‐1,5‐benzodiazepines

Nucleophilic substitution of 3‐bromo‐4‐phenyl‐1H‐[1,5]benzodiazepin‐2‐one ( 1 ) with thiourea or guanidine in presence of potassium carbonate afforded 1,5‐benzodiazepin‐3‐ylimidothiocarbamate 2 or 1,5‐benzodiazepin‐3‐ylguanidine 3 , respectively. Pyrimidylthiobenzodiazepines 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 were obtained via the reaction of compound 2 with malononitrile dimer, diethyl malonate, methylenemalononitriles, or a mixture of an aldehyde and β‐keto esters or acetylacetone, catalyzed using ceric ammonium nitrate. Reaction of compound 2 or 3 with α‐halo esters, nitriles, and/or ketones afforded imidazoles 14 , 15 , 16 , 17 , 18 , 19 , 20 , respectively.     

Synthesis and reactivity of 1,2,4-triazolo[1,5-c]quinazolines

The preparation of 1,2,4-triazolo[1,5-c]quinazolines 4a-d , 5 , 8a-d by cyclocondensation of 1a-c with carboxylic acids and carboxylic anhydrides, respectively, is described. By different pathways, the 5-thioxo-5,6-dihydro-1,2,4-triazolo[1,5-c]quinazolines 4a-d react with hydrazine hydrate or amines with the formation of 5-substituted 1,2,4-triazolo[1,5-c]quinazolines 9 and 10a-d . Cyclocondensation of 9 with carboxylic acids, carboxylic anhydrides, and nitrous acid, respectively, leads to the new anellated heterocycles bis-1,2,4-triazolo[4,3-a:1,5-c]quinazoline 13 and tetrazolo [1,5-a]-1,2,4-triazolo[1,5-c]quinazoline ( 14 ).     

Antifilarial and antimalarial agents. Basically substituted 10-aminobenzo[b] [1,5] naphthyridines, 10-Aminobenzo[b] [1,5] naphthyridine N-Oxides,and 8-Amino-1,5-naphthyridines

Various 2-alkoxy 7-chloro-10-[[[(dialkylamino)alkyl]amino]]benzo[b][1,5]naphthyridines (XI) and N-oxides (XV, XVII, XVIII, XXII), 4-[(2-alkoxy-7-chlorobenzo[b][1,5]naphthyridin-10-yl)-amino]-α-(diethylamino)-o-cresol derivatives (XII-XIV, XXI) and N-oxides (XIX, XX, XXV), 2-butoxy-8-[[[(dialkylamino)alkyl]amino]]-1,5-naphthyridines (XXVIa and b), and 2-butoxy-8–[[3-[(diethylamino)methyl]-p-anisidino]]-1,5-naphthyridine (XXVII) were synthesized for antifilarial and antimalarial evaluation. The compounds were obtained in 13–91% yield by the condensation of 2-alkoxy-7,10-dichlorobenzo[b][1,5]naphthyridines, 2-alkoxy-7,10-dichlorobenzo[b][1,5]naphthyridine 5-oxides, and 2-butoxy-8-chloro-1,5-naphthyridine with the appropriate diamine in phenol, or by perbenzoic acid oxidation of the parent 10-amino-7-chlorobenzo-[b][1,5] naphthyridines in chloroform. Among them, eight compounds killed adult Litomosoides carinii in gerbils when administered in daily gavage doses of 25–400 mg./kg. for 5 days. Azacrine 5-oxide (XVII), the most active compound, was equipotent with amodiaquine (1a), azacrine (IX), and quinacrine 10-oxide (VI). Twelve substances were active orally against Plasmodium berghei in mice at doses ranging from 3.8–155 mg./kg./day for 6 days. 7-Chloro-10-[[-3-[(diethylamino)-methyl]-p-anisidino]]-2-methoxybenzo[b][1,5]naphthyridine 5-oxide dihydrochloride (XX) was approximately 12 times as potent as quinine against P. berghei, but was highly cross-resistant with chloroquine (IV). Structure-activity relationships are discussed.     

Asymmetric Ruthenium‐Catalyzed Hydrogenation of 2,6‐Disubstituted 1,5‐Naphthyridines: Access to Chiral 1,5‐Diaza‐cis‐Decalins

The first asymmetric hydrogenation (AH) of 2,6‐disubstituted and 2,3,6‐trisubstituted 1,5‐naphthyridines, catalyzed by chiral cationic ruthenium diamine complexes, has been developed. A wide range of 1,5‐naphthyridine derivatives were efficiently hydrogenated to give 1,2,3,4‐tetrahydro‐1,5‐naphthyridines with up to 99 % ee and full conversions. This facile and green protocol is applicable to the scaled‐up synthesis of optically pure 1,5‐diaza‐cis‐decalins, which have been used as rigid chelating diamine ligands for asymmetric synthesis.     

Synthesis of thieno[2,3‐b][1,5]benzoxazepine derivatives

A new series of 4‐(4‐methylpiperazin‐1‐yl)thieno[2,3‐b][1,5]benzoxazepines 1a‐k has been synthesized from 4‐bromo‐2‐methylthiophene 6 or ethyl 2‐amino‐4,5‐dimethyl‐3‐thiophencarboxylate 10 . Preparation of the key intermediate thieno[2,3‐b][1,5]benzoxazepine‐4(5H)‐ones 4a‐i, 4k were carried out by treatment of 2‐bromo‐N‐(2‐hydroxyphenyl)‐3‐thiophencarboxamides 5a‐i, 5k with potassium carbonate in DMSO. Compounds 1 are thienoanalogues of loxapine, a potent antipsychotic drug. Of these compounds, the neu‐roleptic activity of 2‐methyl‐4‐(4‐methylpiperazin‐l‐yl)thieno[2,3‐b][1,5]benzoxazepine 1a (R¹, R³=H, R²=CH₃) demonstrated potent antipsychotic activity.     

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.     

Synthesis of 3‐Carboxylic derivatives of 1,5‐benzodiazepines

A series of 3‐carboxylic derivatives of disubstituted 1,5‐benzodiazepines (5–9) was synthesized by hetero‐cyclisation from 1,2‐diaminobenzene (1) with dibenzoylmethane (2) followed by bromination on position 3 and by introduction of the carboxylic group or introduction of the malonic moiety. Reduction of the hetero‐cycle gave the perhydro derivative diethyl (2,4‐diphenyl‐1,2,4,5‐tetrahydro‐3H‐1,5‐benzodiazepin‐3‐yl)malonate (9) .     

1,5‐Bis(4‐dithiocarboxylate‐5‐hydroxypyrazolyl)pentane derivatives of 5‐pyrazolones

3‐Methyl‐1‐phenyl‐2‐pyrazolin‐5‐one 1b and 1‐dodecyl‐3‐methyl‐2‐pyrazolin‐5‐one 1c react with carbon disulfide and 1,5‐dibromopentane in the presence of sodium acetate in dimethylfor‐mamide or n‐butyllithium in tetrahydrofuran to afford 1,5‐bis(4‐dithiocarboxylate‐5‐hydroy‐pyrazolyl)pentane derivatives 6b‐c.     

Researches on thiazolobenzodiazepines: Behavior of tetrahydro‐1,5‐benzodiazepinethiones with aromatic α‐haloketones

A number of 1‐substituted 4H,5H,6H‐[1,3]thiazolo[3,2‐a][1,5]benzodiazepinium‐11‐bromides and S‐(2‐oxo‐2‐phenyl‐X‐(p)‐ethyl)‐3‐(2‐methyl‐1H‐benzimidazol‐1‐yl) propane (or butane) thioate hydrobromides were obtained by direct reaction of the 5‐acetyl(or formyl, or anilinocarbonyl)‐substituted tetrahydro‐1,5‐benzodiazepine‐2‐thiones with aromatic α‐bromoketones. 2‐[(1‐Acetyl‐2(or 3)‐methyl‐2,3‐dihydro‐1H‐1,5‐benzodiazepin‐4‐yl) sulfanyl]‐1‐phenylethanones as intermediates of the formation of thiazolo [3,2‐a][1,5]benzodiazepine and N‐substituted 2‐methyl‐1H‐benzimidazole derivatives have been synthesized. Semiempirical AM1 calculations of a mechanism and energetic parameters for the heptatomic nucleus rearrangement to benzimidazole ring are presented. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:72–81, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20414     

Synthesis of 1,5-dideazariboflavin

1,5-Dideazariboflavin, an analog of riboflavin containing the original conjugated double bond system between positions 1 and 5, was synthesized by the condensation of 4,5-dimethyl- N-ribitylanthranilaldehyde and the sodium salt of 2,4,6-piperidinetrione.     

Study of the Reaction of 5‐Aryl‐7‐hydrazino‐2‐phenylpyra‐zolo[1,5‐c]pyrimidines with 1,3‐Dicarbonyl Compounds

A novel synthetic method for the preparation of 5‐aryl‐7‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐2‐phenylpyrazolo[1,5‐c]‐pyrimidines and 1‐(5‐aryl‐2‐phenylpyrazolo[1,5‐c]pyrimidin‐7‐yl)‐3‐methyl‐1H‐pyrazol‐5‐ols is provided by condensative cyclization of 5‐aryl‐7‐hydrazino‐2‐phenylpyrazolo[1,5‐c]pyrimidines with 1,3‐dicarbonyl compounds. The study of the more reactive position for electrophilic substitusion reactions on such ring system was also achieved.     

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 ).     

Synthesis of imidazo[1,5-c]pyrimidine derivatives

Two complementary procedures, each starting from 6-aminomethyluracil ( 2 ), have been used to prepare imidazo[1,5-c]pyrimidines with a variety of substituents at positions 3, 5, 6, and 7. The starting material, 2 , can be readily prepared from commercially available 6-chloromethyluracil by reaction with anhydrous ammonia. In the first procedure, 2 is acylated and then cyclodehydrated by reaction with phosphorus oxychloride to give a separable mixture of a 3-substituted 5,7-dichloroimidazo[1,5-c]pyrimidine and a 3-substituted 7-chloroimidazo[1,5-c]pyrimidin-5(6H)-one. The relative product distribution is subject to some control by the choice of the acyl substituent on the starting uracil. The resulting dichloro compounds were derivatized by reaction at the 5-position with various nucleophiles, although the 7-chloro substituent is unreactive. An alternative synthetic method proceeds from 2 in six efficient steps (protection as the phthalimide, chlorination, nucleophilic substitution, deprotection, acylation, and cyclodehydration) to 3-substituted-5,7-bis(methylthio)imidazo[1,5-c]pyrimidines. These compounds may also be derivatized by nucleophilic substitution at the 5-position.