5,6-Dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4,4-diacetic acid diethyl ester,an useful synthon for the synthesis of new polycyclic nitrogen systems of pharmacological interest

This report describes the synthesis of derivatives of two nitrogen tetracyclic ring systems, respectively 9H,11H-pyrimido[4,3-c]pyrrolo[1,2-a][1,4]benzodiazepine and spiro[piperidine-4,4′-[4H]pyrrolo[1,2-a][1,4]-benzodiazepine], by the use of the diethyl ester of 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4,4-diacetic acid as a synthon. This compound was obtained by condensation of 1-(2-aminomethylphenyl)-1H-pyrrole with diethyl 1,3-acetonedicarboxylate in acid medium. Pyrimidopyrrolobenzodiazepine derivatives were obtained by treating either the pyrrolobenzodiazepine 4,4-diacetate or the related 4-methyl-4-acetate with phenylisocyanate in boiling diethyl ether in the presence of sodium metal. The structure of 12,13-dihydro-11,13-dioxo-12-phenyl-9H,11H-pyrimido[4,3-c]pyrrolo[1,2-a][1,4]benzodiazepine, a product formed by loss of an acetate unit when 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4,4-diacetate, sodium metal and phenyl-isocyanate reacted in boiling xylene, was proved by catalytic reduction to 11,13-dioxo-12-phenyl-12,13,14,14a-tetrahydro-9H,11H-pyrimido[4,3-c]pyrrolo[1,2-a][1,4]benzodiazepine, which was synthesized by unambiguous pathway via 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4-acetate. The 2,6-dioxospiro[piperidine-4,4′-[4H]pyrrolo[1,2-a][1,4]benzodiazepine] derivatives were synthesized from the N-BOC derivative of 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4,4-diacetic acid diethyl ester, by hydrolysis followed by treatment with 2 equivalents of 1,1′-carbonyldiimidazole (CDI) and then with aniline or benzylamine. Removal of BOC from the N-phenyl-2,6-dioxopiperidine derivative was obtained by heating the related spiroderivative in toluene in the presence of p-toluenesulphonic acid. Similar reaction failed when the N-benzyl-2,6-dioxopiperidine analog was used as substrate.     

1,2-fused pyrimidines. V. Synthesis of 1-alkyl or phenyl-2H-dipyrido-[1,2-a:2′,3′-d]pyrimidine-2,5(1H)-diones

The reaction of 2-[(N-acyl, N-alkyl or phenyl)amino]-4H-pyrido[1,2-a]pyrimidin-4-ones 8a-g with the N,N-dimethylformamide/phosphorus oxychloride Vilsmeier reagent 1 (95°, 90 minutes) afforded 1-alkyl or phenyl-2H-dipyrido[1,2-a:2′,3′-d]pyrimidine-2,5(1H)^?diones, 3-alkyl substituted or not, 10a-g . The starting compounds 8 were prepared by treating 2-amino-4H-pyrido[1,2-a]pyrimidin-4-ones N-alkyl substituted 7a,b or N-phenyl substituted 4 with excess anhydrides (130°, 7 hours) when the 2-(alkylamino) derivatives 7 were used in the reaction, compounds 8 were obtained along with very small amounts of 3-acyl-2-(alkylamino)-4H-pyrido[1,2-a]pyrimidin-4-ones 9 .     

Condensed isoquinolines. 38*. Azolo[<Emphasis Type="Italic">b</Emphasis>]isoquinolines from 2-(halomethyl)benzoic acid derivatives

On interacting 2-(chloromethyl)-, 2-(bromomethyl)benzonitrile or methyl 2-(bromomethyl)benzoate with 1-R-1H-imidazoles and 1-R-1H-benzimidazoles quaternary diazolium salts are formed, the heating of which with bases (K₂CO₃, Et₃N) led to the intramolecular acylation products, 1-alkyl-10-amino-1H-imidazo[1,2-b]isoquinolin-4-ium halides, 5-alkyl-6-amino-5H-benzimidazo[1,2-b]isoquinolin-12-ium halides, or 1-alkyl-1H-imidazo[1,2-b]isoquinolin-4-ium-10-olate halides.     

1,2-Fused pyrimidines. III. Derivatives of 12H-pyrido[1′,2′:1,2]pyrimido[4,5-b]quinoline,a novel heterocyclic system

Reactivities of 2-amino-4H-pyrido[1,2-a]pyrimidin-4-ones and 4-amino-2H-pyrido[1,2-a]pyrimidin-2-ones, both N,N-dialkyl and (N-alkyl, N-phenyl)substituted, when treated with the N,N-dimethylformamide/phosphorus oxychloride Vilsmeier-Haack reagent XII were compared. Starting from 2-[(N-alkyl, N-phenyl)amino] compounds IXa,b , the expected XVIa,b and XVIIa,b were obtained, which are derivatives of 12H-pyrido[1′,2′:1,2]pyrimido[4,5-b]quinoline, a novel heterocyclic system. When 2-(phenylamino) compound IXc was used a mixture of 3-formylderivative XVIII and 12H-pyrido-[1′,2′:1,2]pyrimido[4,5-b]quinolin-12-one ( XIX ) resulted from the reaction. On the other hand, 2-(dialkylamino)-4H-pyrido[1,2-a]pyrimidin-4-ones IIIa-c plainly afforded high yields of 3-formylderivatives XIVa-c. In contrast, no significant reaction occurred when 4-(dialkylamino) and 4-[(N-alkyl,N-phenyl)amino] compounds IIa-c and VIIIa,b were treated with the reagent XII , under the same as well as more severe conditions. A clear difference in the nucleophilic reactivity of C-3 position between these two classes of isomers is pointed out by the above summarized results.     

Synthesis of 3H-thieno[3,2-c]-1,2-dithiole-3-thione and its reaction with n-butylamine

A convenient synthesis of 3H-thieno[3,2-c]-1,2-dithiole-3-thione (7) is proposed. The reaction of 7 with n-butylamine afforded the N-butylthieno[3,2-c]isothiazole-3(2H)-thione (7a) in dynamically equilibrium [1] with its 3H-thieno[3,2-c]-1,2-dithiole-N-butyl-3-imino isomer 7b. Characterizations and antimicrobial activities of the synthesized products are reported.     

Acetylenchemie. 9. Mitt. Anellierte imidazole aus N-propinylamid-vorstufen

The Compound 2-(N-Formyl-N-prop-2′-inyl)aminopyridine was cyclised in boiling formic acid to 3-methylimidazo[1,2-a]pyridine, with 3-methylene-2H-imidazo[1,2-a]pyridine as the intermediate. Under similar conditions the 1,3-diprop-2-inylpyrimido[4,5-b]quinoline-2,4-dione resulted from 1-methylimidazo[1,2-a]quinoline-4-carbonic acid-N-2-prop-2′-inylamide and from the 1-prop-2′-inylbenzo[b][1,8]naphthyridin-2-one the 1-methylbenzo[b]imidazo[1,2,3-ij]naphthyridine-4,7-dione as a new ring system, was obtained.     

Some novel heterocyclic systems derived from 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-α]benzimidazole and the corresponding diamine

The preparation of 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-a]benzimidazole from 1,4-diacetamido-2,3-dinitrobenzene is described. Reaction of this compound with 2,5-dimethoxytetrahydrofuran produces 2,3-dihydro-8-nitro-7-N-pyrrolo-1H-pyrrolo[1,2-a]benzimidazole, which can be cyclised to produce two new heterocyclic ring systems, 9,10-dihydro-8H-pyrrolo[1,2-a]pyrrolo(1′,2′:1,2]imidazo[5,4-f]quinoxaline and 9,10-dihydro-8H-pyrrolo[2,1-c]pyrrolo[1′,2′:1,2]imidazo[4,5-h][1,2,4]benzotriazine. The corresponding diamine, 7,8-diamino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole undergoes a variety of condensation reactions to produce several new heterocyclic systems, for example, with formic acid, 1,7,8,9-tetrahydroimidazo-[4,5-e]pyrrolo[2,1-6]benzimidazole is formed and with diacetyl, 9,10-dihydro-2,3-dimethyl-8H-pyrrolo-[1′,2′:1,2]imidazo[5,4-y]quinoxaline is obtained.     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

Syntheses of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines from methyl tetrahydro-4-oxo-3-thiophenecarboxylate and methyl tetrahydro-3-oxo-2-thiophenecarboxylate,respectively

A general synthesis of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]-thieno[3,2-d]pyrimidines is described. Methyl tetrahydro-4-oxo-3-thiophenecarboxylate ( 13 ) was condensed with 6-aminonicotinic acid ( 18 ) to give 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 19 ). Treatment of 19 successively with chlorotrimethylsilane, N-chlorosuccinimide and water gave 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 17 ). Methyl tetrahydro-3-oxo-2-thiophenecarboxylate ( 21 ) was converted to 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid ( 25 ) by an analogous route.     

Hetero-Cope-Umlagerungen. 4. Mitteilung. Regiokontrollierte Indolsynthesen

Hetero-Cope-Rearrangements, Regio-Controlled Synthesis of Indoles The reaction of O-deprotonated N-phenylhydroxylamines 1 with various electron-deficient allenes 2 , 14 , 16 gives, via Michael addition and Cope-rearrangement, substituted anilines 5 , which are easily convertible into indoles 6 . In this manner, sulfoxides 17 , serve as equivalents of 2-vinylindoles. Diels-Alder reaction with this 2-vinylindole equivalent followed by indolisation affords isoquinuclidine derivative 21 which may be a useful precursor for the preparation of Iboga alkaloids.     

Synthesis of imidazo[4,5-c]quinolin-4(5H)-one via radical cyclization

The tributyltin radical-induced cyclization of N-(2-bromophenyl)-Nbutyl-1H-1-methylimidazole-4-carbox-amide 3 gave 5-butyl-3-methyl-3H-imidazo[4,5-c]quinolin-4(5H)-one 5 via [1,2]-acyl rearrangement.     

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.     

Methyl and Phenylmethyl 2-Acetyl-3-{[2-(dimethylamino)-1-(methoxycarbonyl)ethenyl]amino}prop-2-enoate in the Synthesis of heterocyclic systems: Preparation of 3-amino-4H-pyrido-[1,2-a]pyrimidin-4-ones

Methyl 2-acetyl-3-{[2-(dimethylamino)-1-(methoxycarbonyl)ethenyl]amino}prop-2-enoate ( 4 ) and phenyl-methyl 2-acetyl-3-{[2-(dimethylamino)-1(methoxycarbonyl)ethenyl]amino}prop-2-enoate ( 5 ) were prepared in three steps from the corresponding acetoacetic esters, and used as reagents for the preparation of N³-protected 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 10 – 12 , 5H-thiazolo[3,2-a]pyrimidin-5-one 13 , 4H-pyrido[1,2-a]-pyridin-4-one 19 and 2H-1-benzopyran-2-ones 20 – 23 . Free 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 24 – 26 were prepared from 10 – 12 by removal of the 2-(methoxycarbonyl)-3-oxobut-1-enyl or 3-oxo-2-[(phenyl-methoxy)carbonyl]but-1-envl as N-protecting group by various methods.     

Reaction of sulfene with heterocyclic N,N-disubstituted α-aminomethyleneketones. VII. Synthesis of 1,2-oxathiino-[5,6-g]benzothiazole derivatives

The polar 1,4-cycloaddition of sulfene to N,N-disubstituted 6-aminomethylene-5,6-dihydro-2-phenylbenzothiazol-7-(4H)ones gave, generally in good yield, N,N-disubstituted 3,4,5,6-tetrahydro-8-phenyl-1,2-oxathiino-[5,6-g]benzothiazol-4-amine 2,2-dioxides, which are derivatives of the new heterocyclic system 1,2-oxathiino-[5,6-g]benzothiazole. This reaction did not occur only with the N,N-diphenylenaminone.     

Directed metalation of pyridinesulphonamides. Synthesis of pyridine-fused isothiazoles and 1,2-oxathioles

4-Lithio-N-t-butylpyridine-3-sulphonamide reacted with benzophenone and carbon dioxide respectively to give the corresponding intermediates which on appropriate treatment gave isothiazolo[5,4-c]pyridin-3-one 1,1-dioxides. Metalation of 2- and 4-(N,N-dialkylaminosulphonyl)pyridines with lithium diisopropylamide (LDA) gave anions which reacted with benzophenone to give carbinols which thermally cyclised to 1,2-oxathiolo[3,4-b]pyridine and 1,2-oxathiolo[4,3-c]pyridine respectively.     

Regioselectivity of cyclization of 3-allyl(propargyl)sulfanyl-5<Emphasis Type="Italic">H</Emphasis>-[1,2,4]triazino[5,6-<Emphasis Type="Italic">b</Emphasis>]indoles

The interaction of 3-allylsulfanyl-5H-[1,2,4]triazino[5,6-b]indole with iodine led to 1-iodomethyl-1,2-dihydro[1,3]thiazolo[2',3':3,4][1,2,4]triazino[5,6-b]indol-11-ium pentaiodide with an angular structure, on the basis of which 1-iodomethyl-1,2-dihydro[1,3]thiazolo-, 1-methylidene-1,2-di-hydro[1,3]thiazolo, and 1-methyl[1,3]thiazolo derivatives were obtained. The intramolecular cyclization of 3-propargyl(allyl)sulfanyl-5H-[1,2,4]triazino[5,6-b]indoles under the influence of concentrated sulfuric acid led to linear annelated products:3-methyl[1,3]thiazolo[3',2':2,3][1,2,4]tri-azino[5,6-b]indole or its 2,3-dihydro derivative.     

Reaction of dichloroketene and sulfene with N,N-disubstituted α-aminomethyleneketones. Synthesis of pyrano[2,3-e]indazole and 1,2-oxathiino[6,5-e]indazole derivatives

The polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted (E)-5-aminomethylene-1,5,6,7-tetrahydro-(1-methyl)(1-phenyl)-4H-indazol-4-ones V, prepared from 1,5,6,7-tetrahydro-(1-methyl)(1-phenyl)-4H-indazol-4-ones via the 5-hydroxymethylene derivatives, gave in good yield N,N-disubstituted 4-amino-3,3-dichloro-4,5,6,7-tetrahydro-(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-(3H)ones VI, which are derivatives of the new heterocyclic system pyrano[2,3-e]indazole. Dehydrochlorination of VI with DBN afforded N,N-disubstituted 4-amino-3-chloro-6,7-dihydro(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-2(5H]-ones VII generally in satisfactory yield. Full aromatization with DDQ of VII was tried only in the case of dimethylamino derivatives, giving a moderate yield of 3-chloro-4-dimethylamino(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-2(7H)-ones. Cycloaddition of sulfene to V occurred only in the case of aliphatic N-substitution to give in moderate yield 4-dialkylamino-4,5,6,7-tetrahydro-(7-methyl)(7-phenyl)-3H-1,2-oxathiino[6,5-e]indazole 2,2-dioxides, which are derivatives of the new heterocyclic system 1,2-oxathiino[6,5-e]indazole.     

Reactions of 2 -dichloromethylbenzimidazole with certain primary amines

An investigation of the reactions of 2,2-dichloromethylbenzimidazole with primary amines has led to the synthesis of 2(N-t-butylformimidoyl)benzimidazole, 2-N-(2-phenylethyl)formimdoylbenzimidazole, and 1-(ethoxyearbonylmethyl)-2-(N-t-butylformimidoyl)benzimidazole. Under mild alkali conditions, 2,2-dichloromethylbenzimidazole was rapidly converted into a dimer, namely, 6H,13H-pyrazino[1,2-a:4,5-a']bisbenzimidazole-6,13-diol.     

Reaction of N-Heterocycles with Acetylenedicarboxylates in the Presence of N-Alkylisatins or Ninhydrin. Efficient Synthesis of Spiro Compounds

Summary. The 1,3-dipolar intermediates generated by addition of isoquinoline, to dialkyl acetylenedicaboxylates are trapped by N-alkylisatins to produce dialkyl 1,2-dihydro-2-oxo-1-alkylspiro[3H-indol-3,2′-[2H,11bH][1,3]oxazino[2,3-a]isoquinoline]-3′,4′-dicarboxylates in excellent yields. The reaction of isoquinoline, quinoline, or pyridine with dimethyl acetylenedicarboxylate in the presence of ninhydrin led to dimethyl 1,2-dihydro-1,3-dioxospiro[3H-indene-3,2′-[2H,11bH][1,3]oxazino[2,3-a]isoquinoline]-3′,4′-dicarboxylate, dimethyl 1,2-dihydro-1,3-dioxospiro[3H-indene-3,3′[3H,4aH][1,3]oxazino[3,2-a]quinoline]-1,2-dicarboxylate, or dimethyl 1,2-dihydro-1,3-dioxospiro[3H-indene-3,2′-[2H,9aH]pyrido[2,1-b][1,3]oxazino]-3,4-dicarboxylate.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XVIII. Synthesis of N,N-disubstituted 4-amino-3-phenyl-2H-naphtho[1,2-b]pyran-2-ones

1,4-Cycloaddition of phenylchloroketene to N,N-disubstituted 2-aminomethylene-3,4-dihydro-1(2H)naphthalenones gave the corresponding adducts, namely N,N-disubstituted 4-amino-3-chloro-3,4,5,6-tetrahydro-3-phenyl-2H-naphtho[1,2-b]pyran-2-ones II, in the case of aliphatic N,N-disubstitution or aromatic N-monosubstitution. Apart from IIf (NR₂ = NMePh), adducts II were unstable and were dehydrochlorinated in situ with DBN to give N,N-disubstituted 4-amino-5,6-dihydro-3-phenyl-2H-naphtho[1,2-b]pyran-2-ones III in fair overall yields. Compounds III were dehydrogenated with Pd/C in boiling p-cymene to afford the title compounds generally in high yields.