The synthesis of 5,10-dihydro- and 2,3,5,10-tetrahydrothiazolo-[3,2-b] [2,4]benzodiazepines, 1,2,3,4,7,12-hexahydrobenzothiazolo-[3,2-b] [2,4] benzodiazepine,and 9,14-dihydro-6H-[1]benzothiopyrano-[4′,3′:4,5]thiazolo[3,2-b] [2,4] benzodiazepine via 1,2,4,5-Tetrahydro-3H-2,4-benzodiazepine-3-thione

Catalytic reductive scission of phthalazine (II) utilizing a two-stage palladium-Raney nickel procedure afforded o-xylene-α,α′-diamine (III) in 97% yield. Treatment of III with carbon disulfide gave [o-(aminomethyl)benzyl]dithiocarbamic acid (IV), which upon thermal cyclization furnished 1,2,4,5-tetrahydro-3H-2,4-benzodiazepine-3-thione (V). Reaction of V with 1,2-dibromoethane, chloro-2-propanone, ethyl 2-chloroacetoacetate, ethyl chloroacetate, and ethyl 2-bromohexanoate gave 2,3,5,10-tetrahydrothiazolo[3,2-b][2,4]benzodiazepine (VII) and substituted 5,10-dihydrothiazolo[3,2-b][2,4]benzodiazepines (Villa and b, IX, and X), respectively. Condensation of V with 2-chlorocyclohexanone and 3-bromothiochroman-4-one afforded 1,2,3,4,7,12-hexahydrobenzothiazolo[3,2-b][2,4]benzodiazepine (XII) and 9,14-dihydro-6H-[1]benzothiopyrano[4′,3′:4,5]thiazolo[3,2-b][2,4]benzodiazepine(XIll). None of the compounds possessed appreciable biological activity.     

Substituted ethyl 2-acyl-3-amino-6-methylthieno[2,3-b]pyridine-4-carboxylates as synthons for novel heterocycles

The triethylamine-catalyzed reaction of 4-substituted ethyl 2-acyl-3-amino-6-methylthieno[2,3-b]pyridine-4-carboxylates IIIa-h with 2,2,6-trimethyl-4H-1,3-dioxin-4-one IV gave 4-substituted ethyl 3-acetyl-2-hydroxy-7-methylthieno[2,3-b:4,5-b′]dipyridine-9-carboxylates Va-h. Some of the thienodipyridines ( V ) reacted with excess IV to give 5-substituted ethyl 3-acetyl-4,8-dimethyl-2-oxo-2H-pyrano[2,3-b]-pyrido[3′,2′:4,5]thieno[2,3-e]pyridine-10-carboxylates VI .     

Unambiguously confirmed structure of 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

To determine the structures of two isomeric products, 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (2) and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (3) obtained by condensation of 2,3-diaminopyridine (1) with ethyl benzoylpyruvate [1–3], these compounds were hydrolyzed to give 2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (4) and 3-methyl-1H-pyrido[2,3-b]pyrazin-2-one (5) , respectively [4,5]. Both hydrolysates 4 and 5 were hydrogenated to afford 2-methyl-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (6) and 3-methyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (7) . The latter compound was identical with an unequivocally synthesized compound providing proof for the structures of all these compounds.     

A new one-step synthesis of 2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one and 3,4-dihydro-2h,6h[1,3]thiazino[2,3-b] quinazolin-6-one

2,3-Dihydro-5H-thiazolo[2,3-b]quinazolin-5-one and 3,4-dihydro-2H,6H[1,3] thiazino[2,3-b]-quinazolin-6-one have been synthesized in one step by the reaction of methyl anthranilate with ehloroalkyl isothiocyanates.     

Synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-b][1,4]diazepine-6,8-diones

The sodium ethoxide catalyzed condensation of 4,5-diaminopyrimidine ( 3 ) with diethyl malonate afforded 6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 4 ). Methylation of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 4 ) using sodium hydride and two equivalents of iodomethane gave 5,9-dimethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 5 ) which on further methylation using sodium hydride and one equivalent iodomethane yielded 6,7,8,9-tetrahydro-5,7,9-trimethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 6 ). Reaction of 6,7,8,9-tetrahydro-5H-pyrirnido[4,5-b][1,4]diazepine-6,8-dione ( 4 ) with 4.2 equivalents of sodium hydride and 4.1 equivalents of iodomethane afforded 6,7,8,9-tetrahydro-5,7,7, 9-tetramethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 7 ). 6,7,8,9-Tetrahydro-5,7,7,9-tetramethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 7 ) exhibited weak anticonvulsant activities in the subcutaneous pentylenetetrazole and maximal electroshock anticonvulsant screens indicating it is a partial bioisostere of the anticonvulsant drug clobazam ( 2 ).     

Convenient selective synthesis of 5,7,8,9-tetrahydro-4H,6H-chromeno[2,3-d][1,3]oxazin-4-ones

A method for the synthesis of 5,7,8,9-tetrahydro-4H,6H-chromeno[2,3-d][1,3]oxazin-4-ones was developed. The method involves acid-catalyzed acylation of substituted ethyl 2-amino-4-aryl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylates with acetic anhydride.     

1,3-Benzothiazole-2-selenenyl chloride in the synthesis of 2,3-dihydrobenzo[d][1,3]selenazolo[2,3-b][1,3]thiazolium-4 derivatives

Cycloaddition of 1,3-benzothiazole-2-selenenyl chloride to alkenes leads to 2,3-dihydrobenzo[d][1,3]selenazolo[2,3-b][1,3]thiazolium-4 derivatives.     

The photo cycloaddition of alkenes to s-triazolo[4,3-b] and [2,3-b]pyridazines

s-Triazolo[4,3-b]pyridazine (I) reacted with cyclohexene under the influence of ultraviolet light to yield 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[1,5-a]indole (IV) and 9-cyanomethyl-4a,5,7,8,8a,9-hexahydro-6H-s-triazolo[1,5-a]indole (V). These products were formed by the addition of the alkene to the 1,8 positions of I with a concurrent cleavage of the N₄? N₅ bond. Similar additions were observed with cyclopentene and 2,3-dimethyl-1,3-butadiene. The isomeric s-triazolo[2,3-b]pyridazine (III) reacted with cyclohexene to form an isomer of IV, 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[4,3-a]indole (XV) and two [2 + 2] cycloadducts (XVI and XVII).     

Synthesis of 2-Aryl-2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-ones and 7-Aryl-2,3,6,7-tetrahydro-5H-imidazo[2,1-b]-1,3-thiazin-5-ones

The reaction of 2-mercaptobenzimidazole, 5-ethoxy-2-mercaptobenzimidazole, and 2-mercaptoimidazoline with cinnamoyl chloride, its derivatives, and heteroanalogs was studied. Convenient methods were found for the synthesis of 2-aryl-2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-ones and 7-aryl-2,3,6,7-tetrahydro-5H-imidazo[2,1-b]-1,3-thiazin-5-ones.     

Intramolecular 1,3-Dipolar Cycloaddition of Azomethine Ylides Leading to Pyrido[2,3-b]quinolines

A convenient six-step route to the previously unknown 1H-pyrrolo[2,3-f]benzo[b][1,8]naphthyridine ring system using an intramolecular 1,3-dipolar cycloaddition of nonstabilized azomethine ylides has been described.     

Naphthyridine chemistry: Ring enlargement to a pyrido[2,3-b] azepine

The boron trifluoride-catalyzed rearrangement of the epoxide derived from 3-benzylidene- 7-methyl-2,3-dihydro-1,8-naphthyridin-4-(1H)one (II) is described. The structure of the obtained 8-methyl-4-phenyl-1,2,3,4-tetrahydro-5H-pyrido[2,3,-b]-azepin-3, azepin-3,5-dione (X) has been elucidated with aid of chemical and spectral evidence.     

The photochemical synthesis of novel heterocyclic compounds from s-triazolo[4,3-b]pyridazine (II)

s-Triazolo[4,3-b Jpyridazine (I) photochemically reacted with dihydropyran; 2,3-dihydro-p-dioxin; 2,5-dihydrofuran; 2,5-dimethoxy-2,5-dihydrofuran; and 1,3-dioxep-5-ene to give a new series of substituted pyrrolo[1,2-b]-.s-triazoles (II-IX). In most reactions, two or more products were formed. The following compounds have been prepared from I: 9-methylene-4a,5,6,7,8a,9-hexahydropyrano[2,3 :4,5]pyrrolo[1,2-b]-s-triazole (Ha), the corresponding 9-cyanomethyl product (III), and 9-methylene-4a,7,8,8a-tetrahydro-6H,9H-pyrano[3′,2′:4,5]pyrrolo[1,2-b]-s-triazole (IIb) from dihydropyran; 9-methylene-4a,6,7,8a-tetrahydro-9H-p-dioxino[2′,3′:4,5]-pyrrolo[1,2-6]-s-triazole (IV) from 2,3-dihydro-p-dioxin; 8-methylene-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]pyrrolo[1,2-b]-s-triazole (V) and the corresponding 8-cyanomethyl product (VI) from 2,5-dihydrofuran; 8-cyanomethyl-5,7-dimethoxy-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]-pyrrolo[1,2-6]-s-lriazole (VII) from 2,5-dimethoxy-2,5-dihydrofuran; and 10-methylene-4a,5,9a,10-tetrahydro-9H-[1,3]dioxepino[5′,6′:4,5]pyrrolo[1,2-b]-s-triazole (VIII) and the corresponding 10-cyanomethyl product (IX) from 1,3-dioxep-5-ene. The addition of several other compounds (1,2,3,6-tetrahydropyridine, 1-acetylimidazole, 3-sulfolene, 2,3-dihydro-p-dithiin, and vinylene carbonate) was attempted, but no reactions were observed.     

5H-Thiazolo [3,2-b]- and 2H-Thiazolo [2,3-c]-as-triazines

Derivatives of the 5H-thiazolo[3,2-b]- and 2H-thiazolo[2,3-c]-as-triazine systems were synthesized via condensation of tetrahydro-I-methyl-as-triazine-3(2H)-thione with ethylene dibromide and ethyl bromoacetate, respectively. An hypothesis is given for the formation of the [3,2-b] system in one of these reactions and the [2,3-c] system in the other. Structure proof was accomplished by an unequivocal synthesis of one of the [2,3-c] derivatives.     

Synthesis and transformations of 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines

Reactions of 2,5-dimethoxytetrahydrofuran with 3-aminothieno[2,3-b]pyridines afford a number of substituted 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines. The possibility of the reaction and the yield of the product are determined by the character of a substituent in position 2 of thieno[2,3-b]pyridine. The Curtius rearrangement of 2-acylazido-3(1H-pyrrol-1-yl)thieno[2,3-b]pyridines yields 4,5-dihydropyrido[3",2":4,5]thieno[2,3-e]pyrrolo[1,2-a]pyrazin-4-ones. The molecular and crystal structures of ethyl 4-methoxymethyl-6-methyl-3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridine-2-carboxylate were determined by X-ray diffraction analysis.     

A convenient synthesis of novel pyridazino[3,4-b]quinoxaline and pyrazolo[3,4-b]quinoxaline utilizing 1,3-dipolar cycloaddition reaction

The reaction of 2,6-dichloroquinoxaline 4-oxide 4 with methylhydrazine gave 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5, whose reaction with dimethyl acetylenedicarboxylate or 2-chloroacrylonitrile resulted in the 1,3-dipolar cycloaddition reaction to afford 7-chloro-3,4-bismethoxycarbonyl-1-methyl-1,2-dihydropyridazino[3,4-b]quinoxaline 6 or 6-chloro-3-hydroxymethylene-1-methyl-2,3-dihydro-1H-pyrazolo[3,4-b] quinoxaline hydrochloride 7, respectively.     

Synthesis of furo[2,3-b]pyridine

Two routes were employed to synthesize unsubstituted furo[2,3-b]pyridine (IV). The first method started with ethyl 5-aminofuro[2,3-b] pyridine-2-carboxylate (1) and involved successive deamination, hydrolysis, and decarboxylation. The second method began with 5-nitrofuro[2,3-b ]-pyridine-2-carboxylic acid (V) and consisted of successive decarboxylation, reduction, and deamination reactions.     

New heterocyclic structures. [1,3]Thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine

Derivatives of two new molecular structures, namely, [1,3]thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d]-[1,3]thiazino[3,2-a]pyrimidine, were synthesized together with other heterocyclic compounds. Retrosynthetic analysis of their molecular skeletons suggested a simple way of obtaining 3,4-dihydro-7,8-diamino-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, which is a useful intermediate for their synthesis. This intermediate and the thiazole homologue were obtained directly by reaction of 5,6-diamino-2,3-dihydro-2-thioxo-4(lH)-pyrimidi-none with 1,3- or 1,2-dibromoalkane, respectively.     

A facile synthesis of novel 1,2-diazepino[3,4-b]quinoxalines by a 1,3-dipolar cycloaddition reaction

The 1,3-dipolar cycloaddition reaction of the quinoxaline 4-oxides 4a,b with 2-chloroacrylonitrile gave the 2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxalines 5a,b , respectively, which were converted into the 2,3,4,6-tetrahydro-1H-1,2-diazepino[3,4-b]quinoxalines 7a,b and 8a,b , respectively.     

The Synthesis of pyrimido[4,5-b][1,4]diazocines and pyrido[2,3-b][1,4]diazoeines

The reaction conditions for the preparation of 7H,8H-1,3-dimethyl-2,4,6,9-tetraoxopyrimidino[4,5-b][1,4]-diazocine ( 9 ), 1,3-dimethy 1–2,4,6,11-tetraoxobenzo[f]pyrimidino[4,5-b][1,4]diazocine ( 10 ), 7H,8H-1,3-dimethyl-2,4,6,10-tetraoxopyrimidino[4,5-b][1,4]diazonine ( 16 ), and 7H,8H-6,9-dioxopyridino[2,3-b][1,4]diazocine ( 19 ) were determined. The mechanism of the formation of these compounds was established. The scope of these reactions was found to be general for eight and nine ring formation from 2,3-diamino-N-heterocycles.     

A NOVEL SYNTHESIS OF 2-SUBSTITUTED-4H-THIENO [2,3-d][1,3] OXAZIN-4-ONE AND 2,3-DISUBSTITUTED THIENO [2,3-d]PYRIMIDIN-4(3H)-ONE DERIVATIVES

Abstract

The synthesis of acetic 2-{[1-methyl-2-(4-oxo-5,6,7,8-tetrahydro-4H-benzo [4,5]-thieno [2,3-d] [1,3-oxazin-2-yl)ethylidene]amino}-4,5,6,7-tetrahydrohenzo[b]thiophene ?3-carboxylic acid anhydride 5 and 2-(oxopropyl)-5,6,7,8-tetrahydro-4H-benzo-[4,5] thieno[2,3-d][1,3]oxazin-4-one 7, has been achieved in three steps from ethyl 2-amino-4,5,6,7-tetrahydrobenzo(b]thiophene-3-carboxlate 1 via the reaction with ethyl acetoacetate followed by hydrolysis and acetic anhydride-induced cyclization. The 2-substituent in compound 5 has two functional groups i.e. active methylene and acid anhydride which are suitably located for intramolecular transformation. Thermal and/or base catalyzed intramolecular cyclization of 5 afforded 2-(4-acetoxy-(hydroxyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5] thieno[2,3-b]pyridin-3-yl)-5,6,7,8- tetrahydro-4H-benzo[4,5]thieno[2,3-d] [1,3]oxazin-4-one 10 and 9 respectively. Treatment of 5 with hydrazine hydrate, aromatic and/or heterocyclic amines induced the same intramolecular cyclization with a concomitant oxazine-pyrimidine interconversion to give 3-amino(aryl or heteryl)-2-(4-hydroxy-5,6,7,8-tetrdhydrobenzo-[4,5]thieno[2,3-b]pyridin-3-yl)-3,4,5,6,7,8-hexahydrobenzo[4,5] thieno[2,3-d] pyrimid in-4-one 11–14 respectively.