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.     

Tricyclic heteroaromatic systems. 5H-1,2,4-triazolo[5,1-c][1,4]benzodiazepine

The synthesis of the new tricyclic heteroaromatic system 5H-1,2,4-triazolo[5,1-c][1,4]benzodiazepine, diazaanalogue of 5H-pyrrolo[2,1-c][1,4]benzodiazepine, which is the common feature of some antitumor antibiotics, is reported. The structure of the new tricyclic system and of some of its key intermediates is assigned by means of nuclear magnetic resonance studies.     

Naphtho[1′,2′:5,6] pyrano[2,3-c] pyrazole derivatives

Reaction of 1-oxo-3-dialkylamino-1 H-naphtho[2,1-b]pyrans with N,N-dimethylformamide in the presence of phosphorus oxychloride afforded the corresponding 1-oxo-2-formyl-3-dialkyl-amino-1H-naphtho[2,1-b]pyrans. Condensation of 1-oxo-2-formyl-3-dimethylamino-1H-naphtho[2,1-b]pyran with hydrazine or monosubstituted hydrazines was found to lead to the formation of 8-alkyl(aryl)-1 1-oxo-8H,1 1H-naplitho[1′,2′:5,6] pyrano[2,3-c]pyrazoles through the intermediate hydrazones and subsequent cyclization. The same result was achieved starting from other 3-dialkylamino derivatives but in a lower yield.     

Synthesis of 4H-Pyrrolo[2,1-C][1,4]benzothiazines and 3-(Methylthio)oxindoles

The Pummerer reaction was carried out with α-acylsulfides and phenyl iodosyl bis(trifluoroacetate) instead of α-acylsulfoxides to prepare 4H-pyrrolo[2,1-c][1,4]benzothiazines and 3-(methyIthio)oxindoles.     

Reactions of 6-Amino-5-Cyano-3-Methyl-1,4-Diphenyl-1H 4H-Pyrano[2,3-C]Pyrazole and its Methanimidate

Reaction of 6-amino-5-cyano-3-methyl-1,4-diphenyl- 1H,4H-pyrano[2,3-c]pyrazole 1 with triethyl orthoformate in acetic anhydride gave its methanimidate 2, which reacts with primary aliphatic and aromatic amines to give 4,6-dihydro-3-methyl-1,4-diphenyl-6- (alkyl)pyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidine-5(lH)- imine 3 and the starting compound 1 , respectively. Treatment of 1 with o-aminophenol gave 5-(2-benzoxalyl)- 1,4-dihydro-3-methyl-1,4-diphenylpyrano[2,3-c]pyrazol- 6-amine 9.     

A practical synthesis of 1,3,4,14b-tetrahydro-2-methyl-10H-pyrazino-[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine (1:1) maleate

A practical synthesis of the anti-depressant, 1,3,4,14b-tetrahydro-2-methyl-10H-pyrazino[1,2-a]pyrrolo-[2,1-c][1,4]benzodiazepine (1:1) maleate (Aptazapine 10 ) is reported in seven steps and approximately 20% overall yield. The key step of the synthesis was the formation of the tricyclic intermediate methyl 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-11-carboxylate (7) via a “Pictet-Spengler” type condensation of o-aminobenzylpyrrole ( 6 ) and methyl glyoxylate or the methoxy hemiacetal thereof.     

Synthesis of 5H-imidazo[2,1-c]pyrrolo[1,2-a][1,4]benzodiazepine

We have synthesized 5H-imidazo[2,1-c]pyrrolo[1,2-a][1,4]benzodiazepine 1 in five steps from 1-(2-amino-methylphenyl) pyrrole 4 . Amidino derivatives 11-12 have also been prepared.     

Chemistry of Acyl(imidoyl)ketenes: IX. Synthesis and Thermolysis of 3-Aroyl-8-chloro-1,2-dihydro-4<Emphasis Type="Italic">H</Emphasis>-pyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazine-1,2,4-triones

Reactions of 3-Z-aroylmethylene-6-chloro-3,4-dihydro-2H-1,4-benzoxazine-2-ones with oxalyl chloride afford 3-aroyl-8-chloro-1,2-dihydro-4H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones and Z-3-(2-aryl-2-chlorovinyl)-6-chloro-2H-1,4-benzoxazine-2-ones. Aroyl(imidoyl)ketenes generated by decarbonylation of pyrrolobenzoxazinetriones undergo dimerization through [4+2]-cycloaddition to form 4-aroyl-3-aroyloxy-2-(2-oxo-2H-1,4-benzoxazin-3-yl)-1H, 5H-pyrido[2,1-c][1,4]benzoxazine-1,5-diones.     

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.     

Five-membered 2,3-dioxo heterocycles: CI. Reaction of 3-aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with arylhydrazines. Crystal and molecular structure of substituted 2-hydrazonopyrrolo[2,1-c][1,4]benzoxazine

A new direction of nucleophilic attack was revealed in the reactions of 3-aroylpyrrolo[2,1-c][1,4]-benzoxazine-1,2,4-triones with o-tolylhydrazine and 2-hydrazinylbenzoic acid hydrochloride, which afforded the corresponding hydrazones at the C²=O carbonyl group, substituted 2-(2-o-tolylhydrazono)pyrrolo[2,1-c]-[1,4]benzoxazine-1,4(2H)-diones and pyrrolo[2,1-c][1,4]benzoxazin-2(4H)-ylidenehydrazinylbenzoic acids. The structure of (Z)-2-{2-[3-benzoyl-1,4-dioxo-1H-pyrrolo[2,1-c][1,4]benzoxazin-2(4H)-ylidene]hydrazinyl}-benzoic acid was determined by X-ray analysis.     

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.     

Synthesis of indeno[2,1-b][1,4]benzothiazine derivatives from 2-bromoinden-1-ones

2-Bromoinden-1-ones 2 were condensed with 6-substituted 3-aminopyridine-2(1H)-thiones to produce a new type of 4-azaindeno[2,1-b][1,4]benzothiazine derivatives 3 . Substituted 6-phenylindeno[2,1-b][1,4]benzothiazines 4 were also prepared by reacting 2-bromo-5-methoxy- and 2,6-dibromo-5-methoxyinden-1-ones with o-aminobenzenethiol.     

Proton magnetic resonance studies of compounds with bridgehead nitrogen atoms—XIX Configurational and conformational studies with derivatives of hexahydropyrido [2,1-c][1,4]oxazin-4(3H)-ones

A series of substituted hexahydropyrido [2,1-c][1,4]oxazin-4(3H)-ones has been prepared by reaction of the sodio derivative of the appropriate piperidyl carbinol with ethyl chloroacetate. From a study of their NMR spectra the configurations of these compounds have been assigned and the conformation of the perhydro-1, 4-oxazinone moiety shown to be that with the ring oxygen atom and the angular hydrogen on the same side of the plane defined by C3? C(O)? N. The synthesis and NMR spectra of hexahydro-2H-pyrido [1,2-d][1,4]oxazepin-5(4H)-one, 1,6,11,11a-tetrahydro [1,4]-oxazino [4,3-b]isoquinolin-4(3H)-one and of hexahydropyrido [2,1-c][1,4]thiazin-4(3H)-one are also discussed. cis-6,9a-H-6-Methyl-hexahydropyrido[2,1-c][1,4]oxazin-4(3H)-one is shown to exist in a conformation containing a deformed perhydropyridine ring.     

Synthesis and selected properties of N-substituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]pyrazinones

The reactions of methyl α-(2-formyl-1H-pyrrol-1-yl)carboxylates with N-substituted aliphatic 1,2-, 1,3-, and 1,4-diamines afford new pyrrole-containing heterocyclic systems: 1,2,3,10b-tetrahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-ones, 1,3,4,11b-tetrahydro-2H-pyrrolo[2′,1′:3,4]pyrazino[1,2-a]pyrimidin-6(7H)-ones, and 1,2,3,4,5,12b-hexahydro-pyrrolo[2′,1′:3,4]pyrazino[1,2-a][1,3]diazepin-7(8H)-ones. The reduction of these compounds with different reagents was studied.     

Research on nitrogen containing heterocyclic compounds. XVIII. Synthesis of 9H-pyrrolo[2,1-c]-s-triazolo[4,3-a][1,4]benzodiazepine,a novel tetracyclic ring of pharmaceutical interest

Reaction of di-4-morpholinylphosphinic chloride on 5,10-dihydro-9H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one 9 afforded 11-(di-4-morpholinylphosphinyloxy)-5H-pyrrolo[2,1-c][1,4]benzodiazepine 10 . Displacement of di-4-morpholinylphosphinyloxy group of 10 by formylhydrazine with concomitant intramolecular cyclization led directly to 9H-pyrrolo[2,1-c]-s-triazolo[4,3-a][1,4]benzodiazepine 7, a novel nitrogen heterocyclic ring of pharmaceutical interest. A new procedure for the synthesis of 9 is also described.     

The synthesis and some reactions of 2,3-substituted 1-phenylbenzo[f]quinoline

A series of 2,3-substituted 1-phenylbenzo[f]quinolines was synthesized by the Friedlander condensation of 1-benzoyl-2-naphthylamine with β-keto esters. Some chemical transformations of these compounds and the preparation of 13H-benzo[f]indeno[2,1-c]quinoline-13-one and its 9-methyl derivative are described.     

Novel routes to 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines and 5,6,9,10,11,11a-hexahydro-8H-pyrido[1,2-a]pyrrolo[2,1-c]pyrazines

Condensation reactions of benzotriazole and 2-(pyrrol-1-yl)-1-ethylamine (1) with formaldehyde and glutaric dialdehyde, respectively, afforded intermediates 2 and 6. Subsequent nucleophilic substitutions of the benzotriazole group in 2 and 6 with Grignard reagents, sodium cyanide, and sodium borohydride gave 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines 3a-e, 4, 5 and 5,6,9,10,11,11a-hexahydro-8H-pyrido[1,2-a]pyrrolo[2,1-c]pyrazines 7a-c, 8, 9, respectively, in good yields.     

Novel heterocycles. Synthesis of 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide and related compounds

The reaction of 2-chloro-4-(methylsulfonyl)benzoyl chloride ( 5 ) with 1-methyl-1H-2,1-benzothiazin-4-(3H)-one 2,2-dioxide ( 4 ) gave the O-benzoyl compound, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 2-chloro-4-(methylsulfonyl)benzoate ( 6 ), which rearranged to give the C-benzoyl isomer, [2-chloro-4-(methylsulfonyl)phenyl] (4-hydroxy-1-mefhyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)methanone ( 7 ). The O-cinnamoyl compound 13 that resulted from the addition of 2,4-dichlorocinnamoyl chloride ( 11 ) to compound 4 rearranged to give the C-cinnamoyl compound, 3-(2,4-dichlorophenyl)-1-(4-hydroxy-1-methyl-2,2-dioxido-1H-2,1-benzothiazin-3yl)-2-propen-1-one ( 15 ). On the other hand, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 3-phenyl-2-propenoate ( 19 ) (from cinnamoyl chloride ( 17 ) and compound 4 ) rearranged to give 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide ( 21 ), an example of a hitherto unknown ring system. Additional examples of this novel heterocycle were prepared from 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 23 ) and 1-methyl-1H-thieno[3,2-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 8 ).     

Research on nitrogen containing heterocyclic compounds. XVII. Synthesis of 8H-diimidazo[1,5-a:2′,1′-c][1,4]benzodiazepine,a novel tetracyclic ring of pharmaceutical interest

The synthesis of 8H-diimidazo[1,5-a:2′,1′-c][1,4]benzodiazepine 6 , a novel nitrogen-containing tetracyclic ring, is reported starting from 5H-imidazo[2,1-c][1,4]benzodiazepine 7. Reaction of this compound with nitromethane and subsequent reduction of the obtained nitromethyl derivative 8 afforded 11-aminomethyl-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine 9. Treatment of the latter compound with formaldehyde led to 1,2,3,3a-tetrahydro-8H-diimidazo[1,5-a:2′,1′-c][1,4]benzodiazepine 10 , which was then oxidized to the title compound.     

New heterocyclic structures. [1,2,5]Thiadiazolo[3′,4′:4,5]pyrimido-[2,1-b][1,3]thiazine and thiazolo[3,2a][1,2,5]thiadiazolo[3,4-d]pyrimidine

Derivatives of two new molecular structures, namely, 7,8-dihydro-6H,10H-[1,2,5]thiadiazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-10-one and 6,7-dihydro-9H-thiazolo[3,2-a][1,2,5]thiadiazolo[3,4-d][pyrimidin-9-one, and derivatives of N-substituted sulfamic acid, namely, (8-amino-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-on-7-yl)sulfamic acid and (7-amino-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-on-6-yl)sulfamic acid, were separated out as by-products in the reduction reaction of 8-amino-3,4-dihydro-7-nitroso-2H,6H-pyrimido[2,1- b][1,3]thiazin-6-one and 7-amino-2,3-dihydro-6-nitroso-5H-thiazolo[3,2-a]pyrimidin-5-one derivatives, respectively, with sodium hydrosulfite. A mechanism of reaction, which hypothesizes the action of sodium hydrosulfite in an asymmetic form, is proposed. The results of single-crystal X-ray investigation on 7,8-dihydro-6H,10H-[1,2,5]thiadiazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-10-one (R = 0.032 for 863 reflections) and (8-amino-3,4-dihydro-2H,6H-pyrimido[2,1-b]- [1,3]thiazin-6-on-7-yl)sulfamic acid, sodium salt (R = 0.028 for 3507 reflections) are reported.