Covalent amination of 3,6-dinitro-1,8-naphthyridines

The preparation of 3,6-dinitro-2-R-1,8-naphthyridines ( 1 , R = OH, NH₂, OC₂H₅, Cl) is described and their addition patterns with liquid ammonia are studied. Compound 1 (R = OH, NH₂) gives with liquid ammonia at - 45° as well as at room temperature formation of the covalent ó-adduct 4-amino-1,4-dihydro-3,6-dinitro-2-R-1,8-naphthyridine ( 2 , R = OH, NH₂). Compound 1 (R = OC₂H₅) yields with ammonia at - 45° two σ-adducts, i.e. the C-4 adduct ( 2 , R = OC₂H₅) and the C-5 adduct 5-amino-5,8-dihydro-3,6-dinitro-2-R-1,8-naphthyridine ( 3 , R = OC₂H₅). The ratio is about 50:50. This ratio depends on the temperature; at room temperature the C-5 adduct is more favoured. After staying overnight the ethoxy group has been exchanged for the amino group, yielding 2 (R = NH₂). With 1 (R = Cl) both adducts 2 (R = CI) and 3 (R = CI) were formed, the C-4 adduct 2 (R = CI) is more favoured at room temperature. Prolonged treatment with liquid ammonia leads to an exchange of the chloro atom by the amino group, yielding 2 (R = NH₂).     

Synthesis of 1,8-, 1,6- and 3,6-dichloro-9H-thioxanthen-9-ones

Cyclization of 2-chloro-6-[(3-chlorophenyl)thio]benzoic acid ( 2 ) gave a mixture of 1,8-, 3 , and 1,6-dichloro-9H-thioxanthen-9-ones 4 . The mixture was converted to 1,8-diamino- 7 , and 1-amino-6-chloro-9H-thioxanthen-9-ones 8 , from which 3 and 4 were prepared separately, respectively. From a mixture of 4 and 3,6-dichloro-9H-thioxanthen-9-one ( 11 ) obtained by cyclizing 4-chloro-2-[(3-chlorophenyl)thio]benzoic acid ( 10 ) was separated 11 by conversion of 4 to 8 .     

Oxidations of 3,6-diamino-1,2,4,5-tetrazine and 3,6-bis(s,s-dimethylsulfilimino)-1,2,4,5-tetrazine

Oxidation of 3,6-diamino-1,2,4,5-tetrazine ( 1 ) with most peracids gave 3,6-diamino-1,2,4,5-tetrazine 1,4-dioxide ( 3 ) as the major product; however, treatment of 1 with peroxytrifluoroacetic acid (PTFA) gave 3,6-diamino-1,2,4,5-tetrazine 1-oxide ( 4 ) as the major product along with a small amount of 3-amino-6-nitro-1,2,4,5-tetrazine 2,4-dioxide ( 5 ). Oxidation of 3,6-bis(S,S-dimethylsulfilimino)-1,2,4,5-tetrazine ( 6 ) with 3-chloroperoxybenzoic acid (MCPBA) gave 3-S,S-(dimethylsulfilimino)-6-nitroso-1,2,4,5-tetrazine ( 7 ), which was oxidized further with dimethyldioxirane to 3-(S,S-dimethylsulfoximino)-6-nitro-1,2,4,5-tetrazine ( 8 ). All attempts to obtain 3,6-dinitro-1,2,4,5-tetrazine ( 2 ) by further oxidation of 7 or 8 failed.     

On the synthesis and animation of 5-chloro-and 5-bromo-1,7-naphthyridine

A new synthesis of 5-chloro- and 5-bromo-1,7-naphthyridine, using 8-amino-1,7-naphthyridine as starting material is described. On amination with potassium amide in liquid ammonia, the 5-bromo compound undergoes a tele-amination into 8-amino- and 2-amino-1,7-naphthyridine and a Chichibabin reaction yielding 8-amino-5-bromo-1,7-naphthyridine. The reaction with the 5-chloro compound occurs at a much lower rate than the 5-bromo compound and only gives 8-amino-5-chloro-1,7-naphthyridine in a small yield. Convincing ¹H-nmr evidence is presented, showing that the 5-bromo- and 5-chloro-1,7-naphthyridine give addition of the amide ion at position 8 and that the 5-chloro compound also gives addition at position 2.     

Unequivocal syntheses of 6-methyl- and 6-phenylisoxanthopterin

Although 6-methyl- ( 1 ) and 6-phenylisoxanthopterin ( 2 ) have previously been synthesized, the requirement of high purity necessary for immunological testing has necessitated our development of the first reported synthesis of these compounds by unequivocal methods. In the process of so doing four new pyrazines, ethyl 3-amino-5-chloro-6-methyl-2-pyrazinecarboxylate ( 11 ), N,N-dimethyl-N'-(6-chloro-3-cyano-5-phenylpyrazin-2-yl)methanimidamide ( 16 ), 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide ( 19 ), and ethyl 3-amino-5-chloro-6-phenyl-2-pyrazinecarboxylate ( 20 ) were synthesized. Four new pteridines, 7-methoxy-6-methyl-2,4-pteridinediamine ( 7 ), 7-methoxy-6-phenyl-2,4-pteridinediamine ( 17 ), 2-amino-7-ethoxy-6-methyl-4(3H)-pteridinone ( 12 ), and 2-amino-7-ethoxy-6-phenyl-4(3H)-pteridinone ( 21 ) have also been synthesized enroute to these isoxanthopterins.     

Naphthyridine chemistry. XVI. A literature correction —The preparation of 2,4-Dimethyl-7-ethoxy-1,8-naphthyridine 1-Oxides

The N-oxidation of 2,4-dimethyl-7-ethoxy-1,8-naphthyridine has been shown to afford the 1-oxide rather than the 1,8-dioxide as reported by others.     

Quinazolines. XI. Synthesis of 2,4-diamino-5, 10-diliydrobenzo[g] quinazolines

An unequivocal synthesis of 2,4-diamino-5,10-dihydrobenzo[g]quinazolines is described, starting from methyl 2-tetralone-3-carboxylates. Condensation with guanidine yielded 2-amino-4-hydroxy derivatives, which were thiated with phosphorus pentasulfide and S-alkylated with dimethyl sulfate. The resultant 2-amino-4-methylthio compounds were converted into 2,4-diamino derivatives by amination at elevated temperature and pressure. Attempted synthesis from 3-cyano-1,4-dihydro-2-methoxynaphthalene and guanidine was unsuccessful.     

Synthesis and antitumor evaluation of some 1,3-disubstituted tetrahydropyrimido[4,5-c]isoquinolines

Cyclocondensation of 6-amino-2,4-dioxopyrimidine or 2,4,6-triaminopyrimidine with 1-cyclohexenecarbox-aldehyde 13 afforded regiospecifically, tricyclic, angular 1,3-disubstituted tetrahydropyrimido[4,5-c]isoquin-olines 5 and 6 respectively. In addition, 2,4,6-triaminopyrimidine when condensed with 2-chloro-1-cyclohex-enecarboxaldehyde 14 , regiospecifically afforded the angular isomer 6 . However, the cyclocondensation of 2,6-diamino-4-oxopyrimidine with 13 was regioselective and afforded a mixture of the linear and angular tetrahydropyrimidoisoquinolines 2 and 4 . The growth of leukemia L-1210 cells in culture were inhibited 50% by 6 at 9 × 10^?8 M. Compounds 4 and 5 were not significantly active.     

On the bromination of 1,7- and 1,8-Naphthyridine in nitrobenzene

By application of the Kress procedure for bromination it has been found that from the hydro-bromide of 1,7-naphthyridine with 1.1 equivalents of bromine in nitrobenzene a mixture of 3-and 5-bromo- and 3,5-dibromo-1,7-naphthyridine is obtained in reasonable yield. With an excess of bromine 3,5-dibromo-1,7-naphthyridine is nearly exclusively formed. Similar brominations of the hydrobromide of 1,8-naphthyridine with 1.1 equivalents of bromine gave 3-bromo- and 3,6-dibromo-1,8-naphthyridine. By using an excess of bromine a high-yield conversion into 3,6-dibromo-1,8-naphthyridine is observed. Bromination of the hydrochloride salt of 1,7- and 1,8-naphthyridine affords the same bromo derivatives.     

Synthesis and structure of 6-substituted 9-(2-ethoxy-1,3-dioxan-5-yl)purines

The reaction of 4-chloro-5-amino-6-(1,3-dihydroxy-2-propyl)aminopyrimidine with excess ethyl orthoformate gave a cyclic acetal, viz., 6-chloro-9-(2-ethoxy-1,3-dioxan-5-yl)purine, amination of which yielded 6-amino-9-(2-ethoxy-1,3-dioxan-5-yl)purine. The presence of two configurational isomers with a diaxial orientation of the purine ring and the ethoxy group in the trans isomer and an equatorial orientation of the ethoxy group in the cis isomer was established for these compounds by ¹H and ¹³C NMR and IR spectroscopy. The three-dimensional structure of trans-6-chloro-9-(2-ethoxy-1,3-dioxan-5-yl)purine was determined by an x-ray difraction study, and the trans-diaxial orientation of the purine ring and the ethoxy group was confirmed; it is shown that the dioxane ring is in an anti conformation relative to the purine ring.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 976–983, July, 1979.     

Cu(I) and Pb(II) complexes containing new tris(7-naphthyridyl)methane derivatives: synthesis, structures, spectroscopy and geometric conversion

Two novel facial-capping tris-naphthyridyl compounds, 2-chloro-5-methyl-7-((2,4-dimethyl-1,8-naphthyridin-7(1H)-ylidene)(2,4-dimethyl-1,8-naphthyridin-7-yl))methyl-1,8-naphthyridine (L(1)) and 2-chloro-7-((2-methyl-1,8-naphthyridin-7(1H)-ylidene)(2-methyl-1,8-naphthyridin-7-yl))methyl-1,8-naphthyridine (L(2)), as well as their Cu(i) and Pb(ii) complexes, [CuL(a)(PPh(3))]BF(4) (1) (PPh(3) = triphenylphosphine, L(a) = bis(2,4-dimethyl-1,8-naphthyridin-7-yl)(2-chloro-5-methyl-1,8-naphthyridin-7-yl)methane), [CuL(b)(PPh(3))]BF(4) (2) (L(b) = bis(2-methyl-1,8-naphthyridin-7-yl)(2-chloro-1,8-naphthyridin-7-yl)methane), [Pb(OL(a))(NO(3))(2)] (3) (OL(a) = bis(2,4-dimethyl-1,8-naphthyridin-7-yl)(2-chloro-5-methyl-1,8-naphthyridin-7-yl)methanol) and [Pb(L(b))(2)][Pb(CH(3)OH)(NO(3))(4)] (4), have been synthesized and characterized by X-ray diffraction analysis, MS, NMR and elemental analysis. The structural investigations revealed that the transfer of the H-atom at the central carbon to an adjacent naphthyridine-N atom affords L(1) and L(2) possessing large conjugated architectures, and the central carbon atoms adopt the sp(2) hybridized bonding mode. The reversible hydrogen transfer and a geometric configuration conversion from sp(2) to sp(3) of the central carbon atom were observed when Pb(II) and Cu(I) were coordinated to L(1) or L(2). The molecular energy changes accompanying the hydrogen migration and titration of H(+) to different receptor-N at L(1) were calculated by density functional theory (DFT) at the SCRF-B3LYP/6-311++G(d,p) level in a CH(2)Cl(2) solution, and the observed lowest-energy absorption and emission for L(1) and L(2) can be tentatively assigned to an intramolecular charge transfer (ICT) transition in nature.     

Novel 7-substituted quinolone antibacterial agents. Synthesis of 7-alkenyl,cycloalkenyl, and 1,2,3,6-tetrahydro-4-pyridinyl-1,8-naphthyridines

A convergent synthesis of 1,8-naphthyridine antibacterials bearing a carbon-carbon bonded, acyclic or cyclic vinyl substituent at the C-7 position has been achieved. The synthetic methodology is based upon the palladium-catalyzed cross coupling of a 7-chloro-1,8-naphthyridine with an appropriately substituted organotin reagent.     

Synthesis of 4-chloro-7-ethoxy-2(3H)-benzoxazolone-6-carboxylic acid

As a part of metabolic studies of mosapride ( 1 ), a potential gastroprokinetic agent, the synthesis of 4-chloro-7-ethoxy-2(3H)-benzoxazolone-6-carboxylic acid ( 7 ) as a derivative of 4-amino-5-chloro-2-ethoxy-3-hydroxybenzoic acid ( 6 ), which has served a benzoic acid part of the metabolites 4 and 5 , is described. Treatment of methyl 3-amino-4-substituted amino-5-chloro-2-ethoxybenzoate derivatives 11a-c with sodium nitrate in acidic medium gave the benzotriazole derivatives 13x,y instead of the objective 3-hydroxy counterpart. The synthesis of 7 started from o-vanillin acetate ( 15 ) and proceeded through the intermediates 2-hydroxy-3-methoxy-4-nitrobenzaldehyde ( 18 ), methyl 4-amino-2,3-dihydroxybenzoate ( 23 ), and methyl 7-hydroxy-2(3H)-benzoxazolone-6-carboxylate ( 30 ). Compound 30 was alternatively prepared from 23 via methyl 4-ethoxycarbonylamino-2-ethoxycarbonyloxy-3-hydroxybenzoate ( 29 ), which is the product resulting from the migration of the ethoxycarbonyl group of methyl 4-amino-2,3-diethoxycar-bonyloxybenzoate ( 27 ).     

Direct amination of 1-substituted 3,5-dinitrobenzenes by 1,1,1-trimethylhydrazinium iodide

The amination of 1-X-3,5-dinitrobenzenes via the vicarious nucleophilic substitution of hydrogen (VNS) with 1,1,1-trimethylhydrazinium iodide (TMHI) in the presence of t-BuOK or NaOMe in DMSO was studied. It was observed (when X = OMe, OCH(2)CF(3), OCH(2)CF(2)CF(2)H, OPh) that the amination occurs regioselectively (ratio of ortho/para-isomers is approximately 9:1) and with high yield. For X = SPh or SCH(2)Ph, the reaction proceeded with a low yield (less than 20%), with a ratio of ortho/para-isomers approximately 1:1. For X = PhSO(2) and 2 equiv of TMHI, a double amination occurs and 2,4-diamino-3,5-dinitro-1-phenylsulfonylbenzene predominates in the mixture of isomers. Under the same conditions, 1,3,5-trinitrobenzene undergoes a double amination to yield 2,4-diamino-1,3,5-trinitrobenzene. A proposed mechanism for this reaction is discussed.     

Investigation of nitrogen- and sulfur-containing heterocycles

The reaction of 5-amino-4-chloro- and -4-methoxy-6~mercaptopyrimidines with 4-methoxy-, 4-amino-, and 2,4-diethoxyphenacyl chlorides has yielded 5-amino-4-chloro- and -4-methoxy-6-phenacylthiopyrimidines. The reaction of 2, 5-diamino-4-methyl-6-mercaptopyrimidine with 4-methoxyphenacyl chloride has yielded 2-amino-6-hydroxy-6-(4-methoxyphenyl)-4-methyl-5, 6-dihydropyrimido[4, 5-b]-1,4-thiazine, and that with 4-aminophenacyl chloride has yielded the corresponding 7H-pyrimido[4, 5-b]-1,4-thiazine.For part IV, see [1].     

Synthesis of some novel halogenated 2,4-diaminoquinazolines

Three new 2,4-diaminoquinazolines, the 5,6-difluoro, 6,7-difluoro and 7,8-difluoro isomers were prepared by the reaction of the requisite trifluorobenzonitrile and guanidine carbonate. Surprisingly, 2,3,6-trifluorobenzonitriles gave 2,4-diamino-5,6-difluoroquinazoline exclusively as determined by high resolution nuclear magnetic resonance spectroscopy. On the other hand, 3-amino-2,6-difluorobenzonitrile on reaction with guanidine carbonate yielded only 5-fluoro-2,4,8-triaminoquinazoline. This compound was subsequently converted to 8-chloro-2,4-diamino-5-fluoroquinazoline using the Sandmeyer procedure. The nitration of 2,4-diamino-8-fluoroquinazoline occurred exclusively at position six yielding 2,4-diamino-8-fluoro-6-nitroquinazoline, which upon reduction with stannous chloride afforded 8-fluoro-2,4,6-triaminoquinazoline. In a similar fashion 7-fluoro-2,4-diaminoquinazoline underwent nitration at position six and was then reduced to give 7-fluoro-2,4,6-triaminoquinazoline. Finally, both of these triaminoquinazolines were converted to the 6-chloro derivatives under Sandmeyer conditions to yield 6-chloro-2,4-diamino-8-fluoroquinazoline and 6-chloro-2,4-diamino-7-fluoroquinazoline, respectively.     

Synthesis of 2,4-diamino-9H-indeno[2,1-d]pyrimidines

As part of a search for new antifolic, antimalarial, and antitumor agents, a series of 2,4-diamino-9H-indeno[2,1-d]pyrimidines was prepared by condensation of guanidine with substituted 2-alkoxy-3-cyano-1H-indenes. Base-catalyzed cyclization of 1,2-bis(cyanomethyl)benzenes afforded 2-amino-3-cyano-1H-indenes, which were converted into 3-cyano-2-methoxy-1H-indenes by acid hydrolysis and treatment of the resultant 1-cyano-2-indanones with diazomethane. Alternatively, 2-amino-3-cyano-1H-indenes could be transformed directly into 2-ethoxy-3-eyano-1H-indenes by reaction with ethanol and sulfuric acid. The 2,4-diamino-9H-indeno[2,1-d]-pyrimidines represent a new type of planar, tricyclic pyrimethamine analog, in which free rotation of the phenyl and pyrimidine rings is prevented by means of a methylene bridge.     

Brominated trimetrexate analogues as inhibitors of pneumocystis carinii and toxoplasma gondii dihydrofolate reductase

Five previously undescribed trimetrexate analogues with bulky 2′-bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2-[2-(2-bromo-3,4,5-trimethoxyphenyl)ethyl]-1,l-dicyanopropene with sulfur in the presence of N,N-diethylamine afforded 2-amino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methyl-thiophene-3-carbonitrile ( 15 ) and 2-amino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethyl]thiophene-3-car-bonitrile ( 16 ). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methylthieno[2,3-d]pyrimidine ( 8a ) and 2,4-diamino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethylthieno[2,3-d]pyrimidine ( 12 ) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4-diaminoquinazoline-6(or 5)-carbonitriles with 2-bromo-3,4,5-trimethoxyaniline, were 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)-5-chloro-quinazoline ( 9a ), 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 10 ), and 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 11 ). Enzyme inhibition assays revealed that space-filling 2′-bromo substitution in this limited series of dicyclic 2,4-diaminopyrimidines with a 3′,4′,5′-trimethoxyphenyl side chain and a CH₂, CH₂CH₂, or CH₂NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.     

1,8-Naphthyridines. Part I. Synthesis of some trifluoromethyl-1,8-naphthyridine derivatives

The synthesis of some 2-amino-1,8-naphthyridine derivatives substituted in the 5- and/or 7-positions with trifluoromethyl is described along with their conversions to the corresponding 1,8-naphthyridin-2(1H)ones. A modified procedure for oxidizing electron-deficient heterocyclic compounds to their N-oxides is presented.     

An improved synthesis of 3,6-diamino-1,2,4,5-tetrazine. I

Treatment of 1,3-diaminoguanidine monohydrochloride ( 1 ) with 2,4-pentanedione ( 2 ) in alcohols under carefully controlled conditions gave 3,6-diamino-1,2-dihydro-1,2,4,5-tetrazine monohydrochloride ( 3 ) in 45-50% yields along with 3,5-dimethyl-1H-pyrazole ( 4 ) and its hydrochloride 5 . Oxidation of 3 with sodium perborate produced 3,6-diamino-1,2,4,5-tetrazine ( 6 ) in quantitative yield.