The synthesis of ω-dialkylaminoalkylaminopyrazino[2,3-d]-, pyrido[2,3-d]-, imidazo[4,5-c]- and imidazo[4,5-d]pyridazines

The synthesis of 5-chloro-8-(ω-dialkylaminoalkylamino)pyrazino[2,3-d]pyridazine (II) proceeded smoothly when 5,8-dichloropyrazino[2,3-d]pyridazine (I) was allowed to react with ω-dialkylaminoalkylamines. Similarly, the reaction of 5,8-dichloropyrido[2,3-d]pyridazine (IV) with ω-dialkylaminoalkylamines gave the two expected products 8-chloro-5-(ω-dialkylaminoalkylamino)pyrido[2,3-d]pyridazine (V) and 5-chloro-8-(ω-dialkylaminoalkylamino)pyrido[2,3-d]pyridazine (VI) in a 2:3 ratio. 4,7-Dichloroimidazo[4,5-d]pyridazine (XII) was found to be much less reactive towards nucleophilic substitutions and more vigorous conditions resulted in disubstituted products (XIII). 7-Chloroimidazo[4,5-c]pyridazine (XVIII) was also found to be much less reactive towards nucleophilic substitution. In both of these cases one of the imidazole nitrogen atoms was blocked by a tetrahydropyranyl group which increased the reactivities and led to the desired monosubstituted products XVII from XII and in the latter case the expected products (XIX).     

The synthesis of pyridazino[4,5-d] pyridazines,pyrazino [2,3-d] pyridazines and a pyrimido [4,5-d] pyridazine

The synthetic chemistry of the relatively unknown pyridazino [4,5-d]pyridazine ring system has been extended. 1,4-Diaminopyridazino [4,5-d]pyridazine (VIII) has been prepared by two routes, the most interesting of these being the one-step conversion of 4,5-dicyanopyridazine into VIII with hydrazine. Upon nitration VIII gave only the mononitramine (X). Attempts to prepare 1,4-dichloropyridazino [4,5-d]pyridazine gave only 4-chloro-2H-pyridazino [4,5-d]pyridazin-1-one (XII). Pyrimido [4,5-d]pyridazine-1,3-dione (XIV) was prepared from pyridazine-4,5-dicarboxamide (IV). The hydrolysis of 5,8-dichloropyrazino [2,3-d]pyridazine (XV) gave 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) and likewise the ammonolysis of XV gave 5-amino-8-chloropyrazino [2,3-d]pyridazine (XX). As expected the hydrolysis of 5,8-dibromo-pyrazino [2,3-d]pyridazine (XXI) gave 5-bromopyrazino [2,3-d]pyridazin-8-one (XXII). Attempted catalytic dechlorination of 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) gave 1,2,3,4-tetrahydropyrazino [2,3-d]pyridazin-5-one (XIX).     

Condensed Pyridazines. Part I. Synthesis of 2-Oxo-2H-pyrano[2,3-D]-pyridazine and 2-Oxo-2H-pyrano[2,3-c] pyridazine

The reaction of 4,7-diehlorofuro[2,3-d]pyridazine (1) with potassium cyanide in DMSO gave two products, (E)-3,6-diehloro-5-(2-cyanovinyl)-4-hydroxypyridazine (II) and 5,8-dichloro-2-oxo-2H-pyrano[2,3-d]pyridazine (III) as a result of ring opening or ring expansion. A new ring system, 2-oxo-2H-pyrano[2,3-c]pyridazines (IX, XII, XIII) was obtained from 5,8-dichloro-3-methyl-2-oxo-2H-pyrano[2,3-d]pyridazine (VI).     

Synthesis and reactions of fluoroaryl substituted 2-amino-3-cyanopyrroles and pyrrolo[2,3-d]pyrimidines

Some fluoroaryl substituted 2-amino-3-cyanopyrroles 2 were synthesized from the reaction between (2-bromo-1-arylalkylidene)propanedinitriles 1 and fluoroaryl substituted aromatic amines under Gewald reaction condition, which on reaction with formamide and formic acid gave 4-aminopyrrolo[2,3-d]pyrimidines 3 and pyrrolo[2,3-d]-pyrimidin-4(3H)-ones 4 respectively. 4-Chloropyrrolo[2,3-d]pyrimidines 5 were prepared by chlorination of 4 with phosphorus oxychloride, which on hydrazinolysis provided 4-hydrazinopyrrolo[2–3-d]pyrirnidines 6 .     

Pyrrolopyridazines. 1. Synthesis and reactivity of pyrrolo[2,3-d]pyridazine 5-oxides

Reaction of ethyl 4-ethoxymethyleneamino-3-methoxy-5-pyridazinylpyruvate 1-oxide ( 8 ) under various conditions constitutes a new approach to substituted pyrrolo[2,3-d]pyridazines. The resulting substituted pyrrolo[2,3-d]pyridazine 5-oxides were allowed to react further to provide a number of new compounds in this ring system.     

Synthesis and Properties of 6-Amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

We have established that when 5-chloro-6-[cyano(2,3-dihydro-1-R-benzo[d]azol-2-yl)methyl]-2,3-pyrazinedicarbonitriles are reacted with nucleophilic reagents (aliphatic and aromatic amines, hydrogen sulfide), annelation of the five-membered ring occurs on the [b] face of the pyrazine with formation of 6-amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles and 6-amino-7-(1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyrazine-2,3-dicarbonitrile respectively. Further heating with excess of acylating reagent leads to formation of a novel heterocyclic system 1H-benzo[4,5]imidazo[1,2-c]pyrazino[2',3':4,5]pyrrolo[3,2-e]pyrimidine. Reaction of vicinal dinitriles with hydrazine hydrate leads to the novel system 1H-pyrrolo[2',3':5,6]pyrazino[2,3-d]pyridazine.     

Condensed pyridazines. Part II. Synthesis of pyrido[2,3-C] pyridazines

The synthesis of some pyrido[2,3-c]pyridazines from 5,8-diehloro-3-methyl-2-oxo-2H-pyrano-[2,3-d]pyridazine (I) is described. Attempted oxidation of 8-amino-3-chloro-1,6-dimethyl-4,7-dioxo-1,4,7,8-tetrahydropyrido[2,3-c]pyridazine (VI) with LTA led only to the deaminated compound VII. Treatment of VI with LTA A in the presence of cyclohexene gave the nitrene adduct XI.     

Synthesis and Reactions of 1,6-Dibenzoyl-5H,10H-diimidazo[1,5-a;1',5'-d;]pyrazine-5,10-dione

5,10-Dioxo-5H,10H-diimidazo[1,5-a;1',5'-d]pyrazine-5,10-dicarboxylic acid dichloride in Friedel-Crafts reaction conditions formed with benzene the corresponding 1,6-dibenzoyl derivative 2, which reacted with alcohols and amines to give the keto esters and keto amides of 4(5)-benzoylimidazol-5(4)-carboxylic acids. The reaction of compound 2 with hydrazine gave substituted imidazo[4,5-f]pyridazine, and with o-phenylenediamine gave a derivative of imidazo[4,5-f]-1,4-benzodiazocine - a new heterocyclic system.     

Novel synthesis modes and properties of [1,4]benzodioxinopyridazines

A simple synthesis involving fusion of catechol and derivatives with 3,4,5-trichloropyridazine has furnished 4-chloro[1,4]benzodioxino[2,3-c]pyridazines 5 for the first time. This new method complements the previously reported base promoted procedure for preparing 4-chloro[1,4]benzodioxino-[2,3-d]pyridazines 3 . Employing both methods, 4-(trifluoromethyl)catechol was converted to the four regio isomers 3b,c and 5c,d . Structure assignment of these four was aided by the remarkably consistent influence of the pyridazine 4-chlorine substituent and diazo-linkage in inducing ¹H nmr downfield shifts of their nearest neighbor phenyl ring protons. Finally, contrary to what might be expected from previously reported results, reaction of methoxide with either 3 or 5 , gave chlorine substitution with formation of methoxybenzodioxinopyridazines 6 and 7 respectively. However, these reactions both give what appears to be an unprecedented rearrangement, with conversion of [2,3-c]-pyridazine to [2,3-d]pyridazine, and vice versa.     

Thieno[2,3-d]pyrimidines. I. A new method for the preparation of esters and amides of thieno[2,3-d] pyrimidine-6-carboxylic acids

A novel method for the preparation of esters and amides of thieno[2,3-d]pyrimidine-6-carb-oxylic acids was described. A typical example was the direct formation of ethyl 5-amino-2-methylthiothieno[2,3-d]pyrimidine-6-earboxylate(IIIa) from 4-chloro-2-methylthio-5-pyrimidine-carbonitrile (Ia) and ethyl mercaptoacetate in refluxing ethanol containing sodium carbonate. Displacement of the methylthio group in IIIa by various amines gave the corresponding amino derivatives. The reactions of IIIa and related compounds with acetylating agents such as acetic anhydride or chloroacetyl chloride gave various products. Treatment of 5-carbethoxy-4-chloro-2-phenylpyrimidine(IV) with methyl mercaptoacetate afforded the dechloro intermediate diester Va, which cyclized on reaction with sodium ethoxide to form methyl 5-hydroxy-2-phenylthieno-[2,3-d]pyrimidine-6-carboxylate (Vla). The synthesis was expanded to include the preparation of various new 2,4,5-trisubstituted thieno[2,3-d]pyrimidine-6-carboxylic acid esters and amides (Charts I-V).     

Condensed pyridazines. Part IV. Reductive cyclization of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-rnethylacrylatc (I) to pyrido[2,3-c] pyridazines and the acid-catalysed cyclization of I to a pyrano[2,3-d] pyridazine

Reduction followed by cyclization of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate (I) to pyrido[2,3-c]pyridazines by treatment with triethyl phosphite or hydrazine hydrate as the reducing agents is described. Compound I was also reductively cyclized with sodium borohydride. Treatment of I with concentrated sulfuric acid gave 8-chloro-3,6-dimethyl-2,5-dioxo-5,6-dihydro-2H-pyrano[2,3-d] pyridazine (VII) which also could be synthesized by another independent route. A mechanism for the cyclization is proposed.     

Synthesis and some reactions of naphth[1,2-d]oxazole-5-sulfonic acids

Naphth[1,2-d]oxazole-5-sulfonic acid ( 1 ) has been prepared by the fusion of 4-amino-3-hydroxynaphthalene-1-sulfonic acid with formamide. Interaction of 1 with a number of arenesulfonyl chlorides, aryloxyacetyl chlorides, 1-naphthyloxyacetyl chloride, and chloroacetyl chloride gave 2-(arylsulfonyl)-, 2-(aryloxyacetyl)-, 2-(1-naphthyloxyacetyl)- and 2-(chloroacetyl)naphth[1,2-d]oxaxole-5-sulfonic acids ( 2, 3, 4 and 5 ), respectively. The corresponding sulfonyl chloride of 2 was condensed with amines giving the expected 2-(arylsulfonyl)-naphth[1,2-d]oxazole-5-sulfonamides ( 6 ). Interaction of 5 with hydrazine gave 2-hydrazinoacetyl and disubstituted hydrazine derivatives 7 and 8 . Condensation of 7 with aromatic aldehydes yielded substituted hydrazonoacetyl derivatives 9 . Two moles of 5 react with one mole of hydroquinone in dry acetone in the presence of anhydrous potassium carbonate and potassium iodide gave 1,4-bis[5-sulfonaphth[1,2-d]oxazol-2-ylcarbonyl-methoxy]benzene ( 10 ).     

Acetylenic chemistry: Part 15 [1]. Reactions of 1,2,3,4-Tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine with 3-bromoprop-1-yne

Reaction of 1,2,3,4-tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine with 3-bromoprop-1-yne gave 1-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4a ), 3-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4b ), and 1,3-diprop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4c ). Subsequent boiling of 1,3-diprop-2′-ynylpyrido-[2,3-d]pyrimidine-2,4-dione ( 4c ) in formic acid afforded 1-methylimidazo[1,2-a]pyridyl-N-prop-2′-ynylamide ( 5 ) and 1-acetonyl-3-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 6 ).     

Synthesis of 6-amino-2-aryl-1,2-dihydro-3H-pyrido[2,3-d]pyrimidin-4-one derivatives

This paper reports the synthesis of new pyrido[2,3-d]pyrimidin-4-one derivatives as diuretic agents. Starting with 1,2-dihydro-5-nitro-2-oxo-3-pyridinecarboxylic acid 1 , ethyl 2-ethoxy-5-nitro-3-pyridincarboxylate 4 was obtained. Compound 4 reacts with ammonia, methylamine or S-methylpseudothiourea to give the respective 2-amino-5-nitro-3-pyridinecarboxamide derivatives 5 and 6 or 2-methylthio-6-nitro-3H-pyrido[2,3-d]pyrimidin-4-one 8. Treating carboxamide 5 with arylaldehydes and zinc dichloride, new 2-aryl-1,2-dihydro-6-nitro-3H-pyrido[2,3-d]pyrimidin-4-ones 9 were synthetised. These compounds reduced with iron(II) hydroxide gave 6-amino-2-aryl-1,2-dihydro-3H-pyrido[2,3-d]pyrimidin-4-ones 10 as expected.     

New heterocyclic syntheses from hydrazidoyl halides. Convenient syntheses of fused pyrimidines,pyridazines, and quinazolines

Aminocyanopyrazole derivatives and pyrazolo[2,3-a]quinazolones were obtained in good yields from hydrazidoyl halides and malononitrile. Pyrazolo[3,4-d]pyridazine and pyridazo[4′,5′: 1,2]pyrazolo[1,5-a]quinazoline derivatives were synthesized in quantitative yields by reaction of hydrazine hydrate with 2 and 16 , respectively. A novel ring system, a 3-substituted tetrahydro derivative of 7-oxo-6H,8H-pyridazo[3′,4′,5′-c'd']-pyrazolo[3,4-d]pyrimidine was prepared by reaction of 6 with dimethyl carbonate. Pyrazolo[3,4-d]pyrimidine-4,6-dithiones were obtained in good yields by reaction of 2 with carbon disulfide. The structures of the products were assigned and confirmed on the basis of their elemental analyses, spectral data, and alternate synthesis wherever possible. The structures of the parent fused heterocyclic systems discussed in this work are summarized in Scheme 1 .     

Pyridazine Derivatives and Related Compounds,Part 1. Some Reactions with 4-Cyano-5,6-Diphenyl-2,3-Dihydropyridazine-3-One

4-Cyano-5,6-diphenyl-2,3-dihydropyridazine-3-onc 1 reacts with phosphorous oxychloride to give 70% of the corresponding 3-chloro derivative 2. Treating 2 with anthranilic acid in butanol, 4-cyano-2,3-diphenyl-10H-pyridazino[6,1-b]quinoxaline-10-one, 3 was obtained. Compound 1 reacts with phosphorous pentasulphide to give 3-mercapto derivative 4, which was converted by acrylonitrile to S-(2-cyanoethyl)pyridazine derivative 5. Compound 4 reacts with ethyl bromoacetate and with phenacyl bromide gave the corresponding thieno[2,3-c] pyridazine derivatives 8, 9, Alkylation of 1 with ethyl chloroacetate afforded 3-0-carbethoxymethyl derivative 10. Compound 10 reacts with amines (aniline, hydrazine) to give the corresponding amide and acid hydrazide 13, 12 respectively. Hydrolysis of 10 with sodium hydroxide gave the corresponding acid derivative 11. Treating 1 with methyl iodide, 3-0-methyl derivative 14 was obtained, which was converted by ammonium acetate/acetic acid to 3-amino-4-cyano-5,6-diphenyl pyridazine 15. Compound 1 reacts with methyl magnesium iodide gave 4-acetyl derivative 16, which was reacted with hydrazine, phenyl hydrazine and with hydroxylamine to give the substituted I H pyrazolo [3,4-c] pyridazine 17 a,b and isoxazolo [5,4-c] pyridazine 18 derivatives respectively.     

Synthesis and Transformations of 3-Ethoxycarbonyl-2-(N-R-thioureido)thiophenes

3-Ethoxycarbonyl-2-(N-R-thioureido)-4,5,6,7-tetrahydrobenzo[b]thiophenes were obtained by the reaction of 2-amino-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene with isothiocyanates and of 3-ethoxycarbonyl-2-isothiocyanato-4,5,6,7-tetrahydrobenzo[b]thiophene with primary and secondary amines. The cyclization paths of the products leading to derivatives of thieno[2,3-d]pyrimidine and thieno[2,3-d]-1,3-thiazine were studied. The corresponding S-substituted derivatives were obtained by the alkylation of 3-R-2-thioxo-3,4,5,6,7,8-hexahydrobenzo[b]thieno[2,3-d]pyrimidin-4-ones.     

Synthesis of a novel series of 3-substituted [1]benzothieno[3,2-d]pyrimidine derivatives

A series of 3-substituted [1]benzothieno[3,2-d]pyrimidine derivatives has been synthesized as possible antileukemic agents by condensation of methyl 3-(ethoxymethylene)amino-2-benzothiophene carboxylate (II) with a variety of amines to afford the corresponding 3-aryl and 3-alkyl [I]benzothieno[3,2-d]pyrimidin-4(3H)-ones, Ill and IV, respectively. In addition, Mannich reactions of [I]benzothieno[3,2-d]pyrimidin-4(3H)-one (VIII) with formaldehyde and secondary amines gave the expected derivatives, IX. 3-Amino[I]benzothieno[3,2-d]-pyrimidin-4(3H)-one (VI) reacted with substituted aromatic aldehydes in the presence of boron trifluoride to yield the corresponding imines VII.     

Polycyclic pyridazines. II [3]. Synthesis of pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrid-azine derivatives from dimethyl pyrazolo[3,4-d]pyrid-azine-5,6-dicarboxylates as the key intermediates

The synthesis of the novel pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine ring system and some of its derivatives has been accomplished such as 4-amino-1-phenyl-5,8-dioxo-, 4-amino-5,8-dioxo-, 1-phenyl-5,8-dioxo-, 5,8-dioxo-, 5,8-dichloro-1-phenyl-, 5-ethoxy-1-phenyl- and 8-ethoxy-1-phenylpyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrid-azines.     

Preparation of some tricyclic fused ring iminopyrido[3,2-e]pyrimidines

The preparation of a number of tricyclic fused ring iminopyrido[3,2-e]pyrimidines is described. Treatment of 2-chloronicotinonitrile with primary amines afforded the corresponding 2-amino derivative which was condensed with ethylenediamine or higher congeners to give substituted cyclic amidines. The latter on treatment with cyanogen bromide gave the desired imino-pyrido[3,2-e]pyrimidines. The preparation of diaminopyrido[2,3-d]pyrimidines and tricyclic quinazolines by related procedures is discussed.