Formation of Heptaleno[1,2-c]furans and Heptaleno[1,2-c]furanones

The dehydrogenation reaction of the heptalene-4,5-dimethanols 4a and 4d , which do not undergo the double-bond-shift (DBS) process at ambient temperature, with basic MnO₂ in CH₂Cl₂ at room temperature, leads to the formation of the corresponding heptaleno[1,2-c]furans 6a and 6d , respectively, as well as to the corresponding heptaleno[1,2-c]furan-3-ones 7a and 7d , respectively (cf. Scheme 2 and 8). The formation of both product types necessarily involves a DBS process (cf. Scheme 7). The dehydrogenation reaction of the DBS isomer of 4a , i.e., 5a , with MnO₂ in CH₂Cl₂ at room temperature results, in addition to 6a and 7a , in the formation of the heptaleno[1,2-c]-furan-1-one 8a and, in small amounts, of the heptalene-4,5-dicarbaldehyde 9a (cf. Scheme 3). The benzo[a]heptalene-6,7-dimethanol 4c with a fixed position of the C?C bonds of the heptalene skeleton, on dehydrogenation with MnO₂ in CH₂Cl₂, gives only the corresponding furanone 11b (Scheme 4). By [²H₂]-labelling of the methanol function at C(7), it could be shown that the furanone formation takes place at the stage of the corresponding lactol [3-²H₂]- 15b (cf. Scheme 6). Heptalene-1,2-dimethanols 4c and 4e , which are, at room temperature, in thermal equilibrium with their corresponding DBS forms 5c and 5e , respectively, are dehydrogenated by MnO₂ in CH₂Cl₂ to give the corresponding heptaleno[1,2-c]furans 6c and 6e as well as the heptaleno[1,2-c]furan-3-ones 7c and 7e and, again, in small amounts, the heptaleno[1,2-c]furan-1-ones 8c and 8e , respectively (cf. Scheme 8). Therefore, it seems that the heptalene-1,2-dimethanols are responsible for the formation of the furan-1-ones (cf. Scheme 7). The methylenation of the furan-3-ones 7a and 7e with Tebbe's reagent leads to the formation of the 3-methyl-substituted heptaleno[1,2-c]furans 23a and 23e , respectively (cf. Scheme 9). The heptaleno[1,2-c]furans 6a, 6d , and 23a can be resolved into their antipodes on a Chiralcel OD column. The (P)-configuration is assigned to the heptaleno[1,2-c]furans showing a negative Cotton effect at ca. 320 nm in the CD spectrum in hexane (cf. Figs. 3–5 as well as Table 7). The (P)-configuration of (–)- 6a is correlated with the established (P)-configuration of the dimethanol (–)- 5a via dehydrogenation with MnO₂. The degree of twisting of the heptalene skeleton of 6 and 23 is determined by the Me-substitution pattern (cf. Table 9). The larger the heptalene gauche torsion angles are, the more hypsochromically shifted is the heptalene absorption band above 300 nm (cf. Table 7 and 8, as well as Figs. 6–9).     

Synthesis of a Novel Heterocyclic System, [1,2,4] Triazino[1,2-a]Pyrimido [4,5-e] [1,3,4] Thiadiazines

Substituted 6-chloro-pyrimido[4,5-e][1,3,4] thiadiazine was converted to the corresponding 6-hydrazino derivative by treatment with hydrazine hydrate in DMF/Et ₃ N. The latter was converted to various substituted [1,2,4]triazino[1,2-a] pyrimido[4,5-e][1,3,4]thiadiazines.     

Synthesis of novel imidazo[1,2-a][3,1]benzothiazines 4, imidazo[1,2-a]-[1,2,4]benzotriazines 5, and 4H-imidazo[2,3-c]pyrido[2,3-e][1,4]oxazines 6

Starting from the readily available 2-aminobenzhydrols ( 7 ), 3-amino-1,2,4-benzotriazine ( 11 ) and 2-amino-3-pyridinol ( 12 ), novel derivatives of 5-phenyl-5H-imidazo[1,2-a][3,1]benzothiazine-2-carboxylic acid, ethyl ester ( 4 ), imidazo[2,1-c][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester ( 5 ) and 4H-imidazo[2,3-c]pyrido-[2,3-e][1,4]oxazine ( 6 ) were prepared.     

Synthesis of [1,2,5]selena(or thia)diazolo[3,4‐e][1,4]diazepines, [1,2,5]selena(or thia)diazolo[3,4‐e][1,4]oxazepines and [1,2,5]selena(or thia)diazolo[3,4‐c] [1,2,6]thiadiazines

Novel heterocycles [1,2,5]selenadiazolo[3,4‐e][1,4]diazepines 3a‐c , [1,2,5]thiadiazolo[3,4‐e]‐[1,4]diazepines 7a‐c , [1,2,5]selenadiazolo[3,4‐e][1,4]oxaepines 4a,b , [1,2,5]thiadiazolo[3,4‐e]‐[1,4]oxazepines 9a‐c and [1,2,5]selena(or thia)diazolo[3,4‐c][1,2,6]thiadiazines 10a,b were synthesized starting form 4,6‐dimethyl[1,2,5]se]enadiazolo[3,4‐d]pyrimidine‐5,7(4H,6H)‐dione 1 or 4,6‐dimethyl‐[1,2,5]thiadiazolo[3,4‐d]pyrimidine‐5,7(4H,6H)‐dione 5 .     

Novel polycyclic heterocycles. XI. Synthesis of 11,12-dihydropyrido[2,1-b] [1,3]benzodiazepines, 6H-pyrido[1,2-c] [1,3,5]benzoxadiazepines,and 6H-Pyrido[1,2-c] [1,3,5]benzothiadiazepines

An unusually facile dehydrobromination, involving the ortho-bromine atom and the = NH proton of a 2-imino-1-(phenethyl)-, 2-imino-1-(phenoxymethyl)-, or 2-imino-1-(phenylthiomethyl)-pyridine ( 2a-e ) has led to the synthesis of three novel bridgehead nitrogen tricyclic systems: 11,12-dihydropyrido[2,1-b] [1,3]benzodiazepines ( 3a,b ), 6H-pyrido[1,2-c] [1,3,5]benzoxadiazepines ( 3c,d ) and 6H-pyrido[1,2-c][1,3,5]benzothiadiazepines ( 3e ). As anticipated, these cyclizations required a base, e.g., potassium carbonate, and a catalyst, e.g., copper bronze. What was unusual, was that these reactions occurred in methanol or n-propanol, under reflux, either under anhydrous conditions, or in the presence of large amounts of water. The pmr spectra of these compounds are discussed.     

Diethyl ethoxymethylenemalonate in triheterocycles: A new synthesis of pyrido[3,2-e]pyrimido[1,2-c]pyrimidines

Diethyl ethoxymethylenemalonate was used for the novel synthesis of the triheterocyclic 3-carbethoxy-9,ll-disubstituted-4-oxo-4H-pyrido[3,2-e]pyrimido[1,2-c]pyrimidines from 4-aminopyrido[2,3-d]pyrim-idines via thermal cyclization of the intermediate ethyl 2-carbethoxy-3-[5,7-disubstituted-4-amino-pyrido[2,3-d]pyrimidin-4-yl]acrylates. The alkaline hydrolysis of 3-carbethoxy-4-oxo-4H-pyrido[3,2-e]-pyrimido[1,2-c]pyrimidines was performed to give corresponding acid derivatives.     

Synthesis of 1-arylacenaphtho[1,2-d]pyrazoles and 5,7-Dehydro-5H,7H-benzo[b]acenaphtho[1,2-e]-1,3a,6a-triazapentalenes

2-Benzoyl- 5 and 2-acetylacenaphthenone 6 , prepared from the corresponding 1-acyl-2-(1-pyrrolidinyl)-acenaphthylenes 2 and 3 , reacted with arylhydrazines 8 under acidic conditions to give the corresponding 1-arylacenaphtho[1,2-d]pyrazoles 9 and 10 . Novel heteropentalene mesomeric betaines, 5,7-dehydro-5H,7H-benzo[b]acenaphtho[1,2-e]-1,3a,6a-triazapentalenes 13 and 14 were prepared by reductive cyclization of 1-(o-nitrophenyl)acenaphtho[1,2-d]pyrazoles 9d and 10d , respectively.     

Synthesis of new imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one derivatives by iodocyclization of 6-alkenyl(alkynyl)-aminopyrazolo[3,4-d]pyrimidin-4(5H)-ones

6-Allyl(diallyl, prop-2-yn-1-yl)amino-1-R-pyrazolo[3,4-d]pyrimidin-4(5H)-ones reacted with iodine to give angularly fused 8-iodomethyl-7,8-dihydro-1-R-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones which were treated with sodium acetate to obtain 8-methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(6H)-ones as a result of elimination of hydrogen iodide. 8-Methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones were converted into 8-methyl-1-R-imidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(5H)-ones on heating to the melting point. 8-Methylidene-1-phenyl-7,8-dihydroimidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one underwent isomerization into linearly fused 6-methyl-1-phenyl-1,8-dihydro-4H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-4-one on heating in sulfuric acid.     

Thienopyrimidines. VII. Reactions of the 4-hydrazinothieno[2,3-d]pyrimidines

The cyclization reactions of the 4-hydrazinothieno[2,3-d]pyrimidines give s-triazolo[1,2-c]-thieno[3,2-e]pyrimidines and tetrazolo[1,5-c]thieno[3,2-e]pyrimidines.     

One-pot synthesis of chromeno[2,3-b]isoindolo[1,2-e]pyrrole-12,13-dione derivatives by sequential reaction of ninhydrin, 2-aminochromen-4-ones and arylamines

Stirring an equimolar mixture of ninhydrin 1 and 2-aminochromen-4-ones 2 in CH₃COOH at room temperature produced 6a,11a-dihydroxy-6H-chromeno[2,3-b]indeno[2,1-d]pyrrole-11,12(6aH,11aH)-diones 3, which on heating with aromatic amines 6 in acetic acid produced 11b-hydroxy-7-N-arylimino-6H-chromeno[2,3-b]isoindolo[1,2-e]pyrrole-12,13(11bH)-diones 7.     

6H-indeno[1,2-b]pyrido[3,2-e]pyrazines. A new heterocyclic ring system

Condensation of 1,2-indanedione and 1,2,3-indanetrione hydrate (ninhydrin) with 2,3-diamino-pyridines gave a number of compounds belonging to the hitherto unknown 6H-indeno[1,2-b]-pyrido[3,2-e]pyrazine ring system. The unsymmetrical nature of the reactants can theoretically result in isomeric ring closure products. Assignment of the 6H- ring system was based upon the identity of 6H-indeno[1,2-b]pyrido[3,2-e]pyrazin-6-one obtained from 2,3-diaminopyridine and ninhydrin with material prepared by unequivocal synthesis. The direction of cyclization of ninhydrin and 1,2-indanedione with the diamines was shown to be the same by reduction of the indenopyridopyrazinones to the corresponding indenopyridopyrazines. Some physical, chemical, and tumor growth-inhibitory properties of the products are reported.     

Quino[1,2-c]quinazolines. I. Synthesis of quino[1,2-c]quinazolinium derivatives and the related indazolo[2,3-a]quinoline derivatives as analogs of the antitumor benzo[c]phenanthridine alkaloids

9,10-Dimethoxy-1,2,3,4,12,13-hexahydro-1-oxoquino[1,2-c]quinazolinium perchlorate, 1,2,3,4,13,24-hexahydro-1-oxo[1,3]dioxolo[4,5-g]quino[1,2-c]quinazolinium perchlorate, 6-methyl-2,3,9,10-tetramethoxyquino-[1,2-c]quinazolinium perchlorate and 2,3-dimethoxy-13-methyl[1,3]dioxolo[4′,5′:6,7]quino[1,2-c]quinazolinium perchlorate were synthesized as analogs of the potent antitumor benzo[c]phenanthridine alkaloids nitidine and fagaronine. The related 2,3,8,9-tetramethoxyindazolo[2,3-a]quinoline and 2,3-dimethoxy[1,3]dioxolo-[4,5-g]indazolo[2,3-a]quinoline were also synthesized. Further, the novel formation of 6,7-dimethoxy-2-(2-ethylamino-4,5-dimethoxyphenyl)quinoline via reductive alkylation with Raney nickel in refluxing ethanol is also reported.     

Benzo[1,2‐c:3,4‐c']bis[1,2,5]selenadiazole, [1,2,5]selenadiazolo‐[3,4‐e]‐2,1,3‐benzothiadiazole,furazanobenzo‐2,1,3‐thiadiazole,furazanobenzo‐2,1,3‐selenadiazole and related heterocyclic systems

The first synthesis of benzo[1,2‐c:3,4‐c']bis[1,2,5]selenadiazole has been developed starting from commercially available 4‐nitrobenzo‐2,1,3‐selenadiazole. Improved syntheses of the related heterocycles [1,2,5]selenadiazolo[3,4‐e]‐2,1,3‐benzothiadiazole, furazanobenzo‐2,1,3‐thiadiazole and furazanobenzo‐2,1,3‐selenadiazole are also reported.     

New [g]-fused [1,2,4]triazolo[1,5-c]pyrimidines: Synthesis of pyrido[3,2-e] and [4,3-e][1,2,4]triazolo[1,5-c]pyrimidine,pyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine and [1,2,4]triazolo[1,5-c]pteridine derivatives

A number of 2-aryl-substituted pyrido[3,2-e] and [4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and [1,2,4]triazolo[1,5-c]pteridines 11,12a,b,e , their corresponding 5-carbonyl derivatives 7,8a,b,e and some pyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-5-ones 7,8c,d have been synthesized, according to different pathways. The new tricyclic heterocycles were prepared with the aim of studying their possible benzodiazepine receptors affinity.     

Synthesis of novel imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines and pyrimido[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines

Several 1 1-amino-5H-pyrrolo[2,1-c][1,4]benzodiazepines have been used as starting material to prepare a number of derivatives of 9H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines and 10H-pyrimido[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines. The imidazole nucleus was built by reaction of amidines with ethyl bromopyruvate or aminoacetaldehyde dimethylacetal. Several derivatives of imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine have been prepared by formylation of the pyrrole ring followed by formation of thioamides. Condensation of 11-amino-5H-pyrrolo[2,1-c][1,4]benzodiazepines with diethyl ethoxymethylenemalonate afforded intermediate diesters which were transformed into the corresponding 10H-pyrimido[1,2-a]pyrrolo[2,1-c]-benzodiazepines.     

Compounds with bridgehead nitrogen. 40—Stereochemistry of perhydronaphthaleno[3,4-e]pyrido[1,2c]-[1,3]oxazines

Seven of the possible diastereoisomeric perhydronaphthaleno[3,4-e]pyrido[1,2-c][1,3]oxazines have been synthesized and the configurations and preferred conformations of these assigned on the basis of IR and ¹H NMR spectroscopy and the application of conformational principles.     

The synthesis of 7,8-dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]triazines

Cyclic hydrazino amidines were converted to the corresponding aminopyrazolyl derivatives. Ring closure between the amino groups of pyrazoline moieties and NH groups of cyclic amidines afforded the following ring systems: 7,8-Dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines.     

Polycyclic N‐Heterocyclic Compounds. Part 81: Synthesis and Evaluation of Pentacyclic 1,2,4,5‐Tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]imidazo[1,2‐c]pyrimidine and Related Compounds as Potential Antiplatelet Aggregators

Dehydrative ring closure reactions were carried out on fused 4‐(2‐hydroxyethylamino) (or 2‐hydroxyethoxy or 2‐hydroxyethylthio)pyrimidines ( 2a , 2b , 2c ) to give fused 2,3‐dihydroimidazo[1,2‐c] (or 2,3‐dihydrooxazolo[3,2‐c] or 2,3‐dihydrothiazolo[3,2‐c])pyrimidines. This reaction produced the pentacyclic 1,2,4,5‐tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]imidazo[1,2‐c]pyrimidine ( 3a ) and 1,2,4,5‐tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]thiazolo[3,2‐c]pyrimidinium chloride ( 3c ) from the 2‐hydroxyethylamino‐derivative and 2‐hydroxyethylthio‐derivative, respectively. In contrast, 2‐hydroxyethoxy‐derivative ( 2b ) gave the rearrangement product, 3‐(2‐chloroethyl)‐5,6‐dihydro[1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidin‐4(3H)‐one ( 4 ). Effects of the synthesized compounds on collagen‐induced platelet aggregation were also evaluated.     

New polyheterocyclic series based on 4,5,6,7-tetrahydrothieno[2,3-c]pyridine

4,8-Dimethyl-6,7,8,9-tetrahydropyrido[4′,3′:4,5]thieno[2,3-e][1,2,4]triazolo[3,4-a]-4H-pyrimidin-5-ones, 7-methyl-2,3,6,7,8,9-hexahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrrolo[1,2-a]-1H, 10H-pyrimidin-10-one, 8-methyl-1,2,3,4,7,8,9,10-octahydropyrido[4′,3′:4,5]thieno[2,3-d]-11H-pyrimidin-11-one, and 9-methyl-2,3,4,5,8,9,10,11-octahydro[4′,3′:4,5]thieno[2,3-d]azepino-[1,2-a]-1H, 12H-pyrimidin-12-one which consist four new heterocyclic ring systems were synthesized from 2-amino-3-carbethoxy-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine.     

Polycyclic N-hetero compounds. XXXV. Syntheses and anti-platelet aggregation activity of 5,6-Dihydro-4H-benzo[3,4]cyclohept[1,2-e]imidazo[1,2-c]pyrimidines with an oxygen function at the 1-position

Various 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d][pyrimidines bearing amino acid group at the 4-position of the skeleton were synthesized by the reaction of 4-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]-pyrimidine with some amino acid, which were cyclized to 5,6-dihydro-4H-benzo[3,4]cyclohept[1,2-e]imidazo-[1,2-c]pyrimidines, corresponding to B-homo-11,13,15-triazasteroids. Their inhibitory activities against platelet aggregation induced by collagen were also investigated.