Facile and simple synthesis of some new polyfunctionally heterocyclic derivatives incorporating 2‐imino‐2H‐chromene moiety

1,2‐Dihydro‐2‐imino‐6‐(2‐imino‐2H‐chromen‐3‐yl)‐1,4‐diphenyl‐pyridine‐3‐carbonitrile 4 has been synthesized and reacted with ethyl cyanoacetate to yield the new 5‐amino‐1,7‐dihydro‐2‐(2‐imino‐2H‐chromen‐3‐yl)‐7‐oxo‐1,4‐diphenyl‐1,8‐naphthyridine‐6‐carbonitrile 6 , which consider a good and available starting intermediate for synthesis of series of functionalized chromenes. So, the compound 6 was utilized as a key for the synthesis of some new pyrimido[5,4‐c][1,8]naphthyridinones, pyrido[2,3‐c][1,6]naphthyridinones, triazolo[3′,4′:1,6]triazino][5,4‐c][1,8]naphthyridinones, triazolo[2′,3′:1,6]pyrimido[4,5‐c][1,8]naphthyridinones, triazepino[6,5‐c][1,8]naphthyridinone, and triazino[5,4‐c][1,8]naphthyridinones. The structures of these compounds were established by elemental analysis, IR, MS, and NMR spectral analysis. J. Heterocyclic Chem., (2012).     

Synthesis of imidazo[5,4-d] [1,3]thiazines: X-ray structure of N-methyl-N′-[5-(methylamino)-3-nonylimidazo[5,4-d] [1,3]thiazin-7(3H)-ylidene]thiourea

N-Alkyl-N′-[5-(alkylamino)-3-alkylimidazo[5,4-d] [1,3]thiazin-7(3H)-ylidene]thioureas were obtained by the reaction of 1-substituted 5-amino-4-cyanoimidazoles with alkyl isothiocyanates. The structure of this heterocyclic system was confirmed by single crystal X-ray diffraction analysis.     

Synthesis of 4-hydrazino-5H-pyrimido[5,4-b]indole and related compounds

This paper describes the synthesis of two 4-amino-5H-pyrimido[5,4-b]indoles 5 , 4-hydrazino-5H-pyrimido[5,4-b]indole 6 , two 1,2,4-triazolo[4,3-c]pyrimido[5,4-b]indoles 8 , and tetrazolo[4,5-c]pyrimido[5,4-b]indole 10 . Starting with ethyl 3-aminoindole-2-carboxylate 1 , 5H-pyrimido[5,4-b]indol-4-one 2 was obtained (80%) by condensing with formamide. Reactions of 2 with phosphorus oxychloride and phosphorus pentasulfide gave respectively, 4-chloro-5H-pyrimido[5,4-b]indole 3 (70%) and 5H-pyrimido[5,4-b]indole-4-thione 4 (80%). Compound 3 reacted with amines (morpholine, piperidine) to give the respective 4-amino-5H-pyrimido[5,4-b]-indoles 5 , and compound 4 reacted with hydrazine to give 4-hydrazino-5H-pyrimido[5,4-b]indole 6 (80%). Two hydrazones of 6 (benzylidene, isopropylidene) 7 were also prepared (90%). Compound 6 reacted with formic and acetic acids to give (65–75%) the respective 1,2,4-triazolo[4,3-c]pyrimido[5,4-b]indoles 8 and with nitrous acid to give tetrazolo[4,5-c]pyrimido[5,4-b]indole 9 (85%). All the new compounds 2 to 9 were characterized by elemental analysis and spectral data (ir, nmr).     

Friedländer reaction of 3-acetyltropolones: Synthesis of naphthyridinyl- and allied heterocyclic-substituted tropolones

Five 3-acetyltropolones reacted with 2-amino-3-pyridinecarbaldehyde to afford the corresponding 3-(1,8-naphthyridin-2-yl)tropolones in excellent yields. In a similar manner, 1,6-naphthyridin-2-yl-,1,7-naphthyridin-2-yl-, 6-pyrido[2,3-b]pyrazinyl-, and 1-methyl-6-pyrazolo[5,4-b]pyridyl-substituted tropolones were prepared. Reactivities of amino-substituted heteroarenecarbaldehydes in these reactions and properties of the products are also discussed.     

Polycyclic N-heterocyclic compounds. XLI. Synthesis of 4-substituted 6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepines, 1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzazepines and their related compounds as a series of potential blood platelet aggregation inhibitors

As a series of polyheterocyclic compounds for exploitation as anti-platelet agents, tricyclic heterocyclic compounds, 4-substituted 6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepines 3–6, 9, 12–14 , and 16–26 , having nitrogen, oxygen, or sulfur containing functional groups at the 4-position, were prepared. In addition, tetra-cyclic heterocyclic compounds, 3-methyl-1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzaze-pinium chloride ( 7 ), 1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzazepines 10a-e , 2,3,6,7-tetrahydro-1H 5H-pyrimido[1′,2′:1,6]pyrimido[5,4-d][1]benzazepine ( 11 ), and 1,2,5,6-tetrahydro-4H-thiazolo-[3′,2′:1,6]pyrimido[5,4-d][1]benzazepinium chloride ( 15 ) via ring closure of 4-(hydroxyalkylamino)- 6, 9a-e , and 3c , and 4-(2-hydroxyethylthio)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine ( 14 ) with phosphoryl chloride or thionyl chloride, respectively, were also prepared. Their inhibitory activities against collagen-induced aggregation of rabbit blood platelets in vitro were investigated. Among them, compound 5 having a morpholino group at the 4-position on the tricyclic nucleus, which enhanced the activity more than 14-fold as compared with aspirin, was found to have the most satisfactory in inhibitory activity.     

Synthesis of substituted pyrimido[4,5‐b] and [5,4‐c]‐[1,8]naphthyridines

Ethyl 1‐ethyl‐7‐methyl‐4‐oxo‐1,4‐dihydro[1,8]naphthyridine‐3‐carboxylate ( 1 ), precursor of nalidixic acid, has been converted in two steps through ([1,8]naphthyridin‐3‐yl)carbonylguanidine derivatives into substituted pyrimido[4,5‐b] and [5,4‐c][1,8]naphthyridines.     

On the amination of pyrimido[5,4-e]1,2,4-triazines in liquid ammonia

When dissolved in liquid ammonia 5-chloro-1,2-dihydropyrimido[5,4-e]-1,2,4-triazine ( 1 ) and 5-methoxy-pyrimido[5,4e]-1,2,4-triazine ( 4 ) quickly convert into 5-aminopyrimido[5,4-e]-1,2,4-triazine ( 2 ). When 2 is kept in liquid ammonia containing an excess of potassium permanganate, 3,5-diaminopyrimido[5,4-e]-1,2,4-triazine ( 5 ) is formed.     

Fused 1,2,4-triazole heterocycles. IV. Synthesis of four new heterocyclic ring systems of [1,2,4]triazolo[1,3]thiazinoquinolines

Syntheses of 5H-[1,2,4]triazolo[5′,1′:2,3][1,3]thiazino[5,4-c]quinolines 8, 5H-[1,2,4]triazolo[3′,4′:2)3][1,3]thiazino[5,4-c]quinolines 9, 5H-[1,2,4]triazolo[5′,1′:2,3][1,3]thiazino[5,6-c]quinolines 14 and 5H-[1,2,4]triazolo[3′,4′:2,3][1,3]thiazino[5,6-c]quinolines 15 are described starting from 4-chloro-3-chloromethylquinaldine (4) and 1,2,4-triazole-5-thiols 5 taking advantage of different reactivity of the chlorine atoms of 4 under different reaction conditions. The structures of products 8, 9, 14 and 15 and the intermediates leading to them were confirmed by desulfurization, unequivocal syntheses and nmr spectroscopy as well.     

Pyrido[1′,2′:1,2]pyrimido[5,4-d]indoles. A new heterocyclic ring system

The preparation of the novel pyrido[1′,2′:1,2]pyrimido[5,4-b]indole ring system is described -via fusion at 180° of ethyl 3-amino-1H-indole-2-carboxylate 8a and several 6-chloronicotinic acid derivatives. Similar fusion of 8a and thiourea yielded a 2-mercaptopyrimido[5,4-b]indole 18 .     

Synthesis and properties of thiazolo[5,4-d]pyrimidine 1-oxides

Synthesis and properties of hitherto unknown thiazolo[5,4-d]pyrimidine 1-oxides are described. For example, the reaction of 6-chloro-1,3-dimethyl-5-nitrouracil (I) with methyl thioglycolate in the presence of excess triethylamine afforded 2-methoxycarbonyl-4,6-dimethylthiazolo[5,4-d]pyrimidine-5,7-(4H,6H)dione 1-oxide (IIIa), which is a versatile intermediate for the preparation of various thiazolo[5,4-d]pyrimidine derivatives.     

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.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XVII. Synthesis of 2H-[1]benzothiepino[5,4-b]pyran derivatives

1,4-Cycloaddition of dichloroketene to a number of N,N-disubstituted (E)-4-amino methylene-3,4-dihydro-[1]benzothiepin-5(2H)-ones gave in excellent yield N,N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-2H-[1]benzothiepino[5,4-b]pyran-2-ones III, which are derivatives of the 2H-[1]benzothiepino[5,4-b]pyran system. Dehydrochlorination of III with DBN afforded N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-2H-[1]-benzothiepino[5,4-b]pyran-2-ones, generally in excellent yield.     

The synthesis of pyrimido[4,5-c]pyridazines and pyrimido[5,4-c]pyridazines

The Hofmann reaction on 6-methylpyridazine-3,4-dicarboxamide (1) gave a mixture of 3-methylpyrimido[4,5-c]pyridazine-5,7-dione (2), 3-methylpyrimido[5,4-c]pyridazine-6,8-dione (3) and an acid (4) of unknown structure. The Hofmann reaction on pyridazine-3,4-dicarboxamide (9) gave a mixture of pyrimido[4,5-c]pyridazine-5,7-dione ( 10 ) and an acid ( 11 ) of unknown structure. The reaction of 3-amino-6-methylpyridazine-4-carboxamide ( 18 ) with ethyl orthoformate gave 3-methylpyrimido[4,5-c]pyridazin-5-one ( 21 ). 4-Aminopyridazine-3-carboxamide ( 36 ) upon fusion with urea gave pyrimido[5,4-c]pyridazine-6,8-dione ( 37 ) while with ethyl orthoformate 36 gave pyrimido[5,4-c]pyridazin-8-one ( 38 ). Pyrimido[5,4-c]-pyridazine-8-thione ( 39 ) was obtained by the action of phosphorus pentasulfide on 38. 4-Amino-3-cyanopyridazine ( 16 ) when treated with formamide produced 8-aminopyrimido[5,4-c]-pyridazine ( 41 ). The synthesis of 4-aminopyridazine-3-carboxamide ( 36 ) and 4-amino-3-cyanopyridazine ( 16 ), both key intermediates in the synthesis of the novel pyrimido[5,4-c]pyridazine ring system was accomplished by the Reissert reaction of 4-aminopyridazine-2-oxides and subsequent conversion of the nitrile to the amide.     

Interaction of 7-Chloro-9-methylthio-3-phenylpyrimido[5,4-f][1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine with Some Nucleophiles

The reactions of 7-chloro-9-methylthio-3-phenylpyrimido[5,4-f][1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine (1) with some nucleophiles have been studied. Substitution of the chlorine atom with hydrogen occurs with ammonia in DMSO to give 9-methylthio-3-phenylpyrimido[5,4-f][1,2,4]triazolo[3,4-b][1,3,4]thiadiazepin-7(8H)-one. With a methanolic solution of ammonia the 7-methoxy derivative is formed. Reaction of compound 1 with an excess of sodium methoxide in methanol gave 6,7-dimethoxy-9-methylthio-3-phenyl-5,6-dihydropyrimido[5,4-f][1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine. The corresponding 7-substituted derivatives were obtained when compound 1 was heated with morpholine or 2-(dimethylamino)ethylamine. The azomethine bond of the thiadiazepine ring is reduced by sodium borohydride to give the corresponding 5,6-dihydro derivatives.     

Synthesis of some 2-(heteroarylamino)benzimidazoles and their cyclization with phosgene

2-(Benzimidazol-2-ylamino)pyridine (4a) , 2-(benzimidazol-2-ylamino)pyrazine (4b) , and 2-(benzimidazol-2-ylamino)thiazole (4c) underwent a ring-closure reaction on treatment with phosgene affording 6H-pyrimido-[1′,2′:5,4][1,3,5]triazino[1,2-a]benzimidazol-6-one (1a) , 6H-pyrazino[1′,2′:5,4][1,3,5]triazino[1,2-a]benzimidazol-6-one (1b) , and 5H-thiazolo[2′,3′:4,5][1,3,5]triazino[1,2-a]benzimidazol-5-one (1c) respectively. The structure of these hitherto unknown heterocyclic systems was confirmed by their ir and mass spectra.     

Thermal and photochemical reaction of isoxazolone with indole-2,3-dione derivatives

The reaction of indole-2,3-dione derivatives with five membered heterocycle, viz isoxazolone under ther mal as well as photochemical conditions is described. While under refluxing ethanol these conditions afforded 2,3-dihydro-3-(5′-oxo-3′-phenylisoxazolidyl)indol-2-one 3 and a spiro product 2′,3′-dihydro-3,7-diphenylspiro[diisoxazolo[4,5-e:4,5-b]pyran-8,3′-indol]-2′-one 4 , the uv light induced irradiation mainly produced 4,5-dioxo-3-phenylisoxazolo[5,4-b][1]benzazepine 5 and 3-phenylisoxazolo[5,4-b]quinoline-4-carboxylic acid 6 . The products have been characterised on the basis of spectral data and elemental analyses.     

Aminothiazole derivatives. I. A convenient synthesis of monocyclic and condensed 5-aminothiazole derivatives

Treatment of diamides derived from α-amino acids with phosphorus pentasulfide or Lawesson's reagent was shown to provide a convenient method to prepare 5-aminothiazoles. By this method, in addition to mono-cyclic 5-aminothiazoles 19 , novel bicyclic 5-aminothiazole derivatives such as 4,5,6,7-tetrahydrothiazolo[5,4-b]pyridines 11 , 5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]azepines 7 , 4,5,6,7,8,9-hexahydrothiazolo[5,4-b]azocine 16 and related compounds were prepared in moderate to good yields from simple diamides, suggesting the wide versatility of the method.     

Synthèse et propriétés photochromiques de 1, 3-dihydrospiro[2H-indole-2,3′-[3H]pyrimido[5,4-f][1,4]benzoxazines] et de 1,3-dihydrospiro[2H-indole-2,7′-[7H]thiazolo[5,4-f][1,4]benzoxazines]

Synthesis and Photochrmic Characteristics of 1,3-Dihydrospiro[2H-indole-2,3′-[3H-]pyrimido[5,4-f][1,4]benzoxazines] and 1,3-Dihydrospiro[2H-indole-2,7′[7H]thiazolo[5,4-f][1,4]benzoxazines] Two new series of 1,3-dihydrospiro[2H-indole-ozazine] derivatives were synthesized, the 1,3-dihydrospiro[2H-indole-2,3′-[3H]pyrimido[5,4]pyrimido[5,4-f][1,4]benzoxaines] 4-10 and the 1,3-dihydrospiro[2H-indole2,7′-[7H]thiazolo-[5,4-f][1,4]benzoxaines] 11–17 . These series extend the available range of photochromic properties (rate constant of thermal bleaching, UV/VIS spectrum of the opened coloured form, and photocoloration yield), an interesting feature of variable-transmission materials. The synthesis of these compounds (Scheme 1) required the preliminary synthesis of intermediate β-hydroxy-α-nitrosotherocycles 18 and 19 (Scheme 2). Important amounts of a coloured, non-photochromic, stable secondary product (See 20 ) were found in the condensation in the spiro[indole-thiazolobenzoxazine] series. The photochromic characteristics of the new derivatives were determined using a flash-photolysis apparatus coupled to a fast-scanning spectrometer. The role of the heteroatoms in the oxazine moiety and the role of substitutents in the indole moiety were investigated quantitatively through the study of the photochromic properties and the solvent effects. The presence of an S-atom gives rise to interesting properties which open up new prospects for synthesis and application.     

Synthesis and spectral properties of substituted 4-chlorooxazoloquinolines

Summary The treatment of a mixture of linearly and angularly annelated 2-substituted oxazolo[4,5-f]quinolones (5a–c) and oxazolo[5,4-g]quinolones (6a–c) and similarly the treatment of 2-substituted oxazolo[5,4-f]quinolones (7a–c) and oxazolo[4,5-g]quinolones (8b,c) with POCl₃ afforded substituted 4-chlorooxazolo[4,5-f]quinolines (9a–c) and 2-substituted 4-chlorooxazolo[5,4-f]quinolines (10b,c), respectively. Spectral characteristics of the synthesized derivatives (¹H and¹³C NMR, IR, UV, and MS) are discussed.Dedicated to Prof.Fritz Sauter on the occasion of his 65th birthday     

Synthesis of imidazobenzothiazine and primidobenazothiazine derivatives via the classic Ullmann cross-coupling reaction of 1,8-diiodonaphthalene with 1H-benzo[d]imidazole-2-thiols or 2-thiouracils

A feasible protocol for the synthesis of imidazobenzothiazine and primidobenazothiazine derivatives via the classic copper(I)-catalyzed Ullmann cross-coupling process has been developed. 1,8-Diiodonaphthalene could couple with 2-mercaptobenzimidazoles or 2-thiouracils to give the corresponding benzo[4,5]imidazo[2,1-b]naphtho[1,8-de][1,3]thiazines and 11H-naphtho[1,8-de]pyrimido[2,1-b][1,3]thiazin-11-ones in moderate yields.