Jim Clark

Heterocyclic studies. Part XIX. Some 6-(substituted phenyl)-uracil and -thiouracil derivatives

Ten β-(m- and p-substituted phenyl)-β-oxopropionates (I and II; X = F, Cl, Br, Me, or OMe) were synthesised and condensed with thiourea to yield the corresponding 6-(m- and p-substituted phenyl)thiouracils [(V) and (VI)], which were converted into the analogous uracils [(VII) and (VIII)] by treatment with chloroacetic acid. Nitration of 6-(p-substituted phenyl)uracil derivatives gave 5-nitro- or m,5-dinitro-compounds according to reaction conditions. 1H N.m.r. spectra of most of the compounds are recorded.

Heterocyclic studies. Part VIII. 2-Phenylpteridine and some related compounds

Syntheses of 2-phenylpteridine and its 4- and 7-monomethyl, 4,7- and 6,7-dimethyl, and 4,6,7-trimethyl derivatives are described. Oxidation of 2-phenyl-, 7-methyl-2-phenyl-, and 6,7-dimethyl-2-phenyl-pteridine with hydrogen peroxide in glacial acetic acid gave the corresponding 4-hydroxy-derivatives. Further oxidation of 4-hydroxy-2-phenylpteridine gave 4,6,7-trihydroxy-2-phenylpteridine.In acid solution 2-phenylpteridine gave a mixture of 3,4-monohydrated and 5,6,7,8-dihydrated cations which rapidly changed to a solution almost free of the monohydrate. 4-Methyl- and 4,7-dimethyl-2-phenylpteridine also gave essentially all 5,6,7,8-dihydrated cations but mainly 3,4-hydrated species were present in the equilibrium mixtures of cations formed from 7-methyl- and 6,7-dimethyl-2-phenylpteridine. 1 H N.m.r. and u.v. spectra and pKa values are recorded.

Heterocyclic studies. Part X. 4-Phenylpteridine and some methyl derivatives

Suitable nitration conditions for obtaining two mononitro- and two dinitro-derivatives of 2,4-dihydroxy-6-phenyl-pyrimidine are described. The 5-nitro-compound was converted into 4-phenylpteridine and its 2- and 7-methyl, 2,7- and 6,7-dimethyl, and 2,6,7-trimethyl derivatives.None of the compounds was appreciably hydrated in aqueous solution as the neutral molecule but 4-phenyl-pteridine and its 2-methyl derivative formed 5,6,7,8-dihydrated cations. The compounds containing 6- or 7-methyl groups were unstable as cations and apparently underwent dimerisation and oxidation in strongly acidic solutions.

Heterocyclic studies. Part V. Desulphuration of heterocyclic thiols with nickel boride

Desulphuration of a number of heterocyclic thiols by treatment with nickel boride in aqueous solution at 200° is reported. Some other were unchanged after similar treatment. Refluxing ethylene glycol provided an alternative reaction medium.

Heterocyclic studies. Part VI. Some 2-substituted derivatives of ethyl pteridine-4-carboxylate

Syntheses of seven 2-substituted derivatives of ethyl pteridine-4-carboxylate (III; X = Cl, OH, OEt, NH2, NMe2 SH, or SMe) are described. The 2-hydroxy- and 2-mercapto-derivatives were obtained as 3,4-covalently hydrated species and the latter could not be dehydrated. The other compounds were prepared both as anhydrous and 5,6:7,8-dihydrated species, which were interconvertible. The influence of the 2-substituent on the position and extent of hydration is discussed. 1H N.m.r. spectra are recorded.

Heterocyclic studies. Part IV. The action of hydroxylamine on 4-hydroxypteridine and its methyl derivatives

Hydroxylamine reacted with 4-hydroxypteridine, and its 2- or 6-methyl derivative (I), (II), or (III) to give the corresponding 3-hydroxypteridin-4(3H)-one (VII), (VIII), or (IX) by pyrimidine ring cleavage and recyclisation. 4,5-Diamino-6-hydroxypyrimidine (XIII; R = H) or its 2-methyl derivative (XIII; R = Me) was formed simultaneously by a competing pyrazine ring cleavage. The 3-hydroxypteridine derivatives (VII)—(IX) underwent further reactions with hydroxylamine to yield, ultimately, 5,6-diamino-3-hydroxypyrimidin-4(3H)-one (XIV) or its 2-methyl derivative (XV). Each pyrazine ring cleavage also gave the dioxime of glyoxal or pyruvaldehyde. 3-Hydroximinomethylamino-6-methylpyrazine-2-carboxylic acid (XXIV) was obtained as a by-product from the reaction of hydroxylamine with 4-hydroxy-6-methylpteridine (III). 4-Hydroxy-7-methyl-, 6-, 7-dimethyl- and -2,7-dimethylpteridine (IV)—(VI) gave only the corresponding 3-hydroxypteridin-4(3H)-ones (X)—(XII) which were not degraded by hydroxylamine under the reaction conditions. Spectral data and pKa values are tabulated.

Heterocyclic studies. Part XXIII. 5-Trifluoromethylpyrimido[5,4-e]-as-triazines

Syntheses of several 7-substituted 5-trifluoromethylpyrimido[5,4-e]-as-triazines and 1,2-dihydro-derivatives are described. The heteroaromatic compounds were usually unstable in acidic solution and each was completely covalently hydrated across the 5,6-bond at equilibrium in aqueous solution at all pH values.

Heterocyclic studies. Part XXI. Synthesis and covalent hydration of some 2-substituted 4-trifluoromethylpteridines

Syntheses of eight 2-substituted 4-trifluoromethylpteridine derivatives [(1; X = Cl, NH2, NMe2, OMe, OEt, SMe, or NH·CH2Ph) and (VI; X = CF3)] are described. The 2-thione (VI; X = CF3) was obtained as a 3,4-covalently hydrated species which could not be dehydrated. The rest of the compounds formed equilibrium mixtures with their 3,4-hydrates in aqueous solution, but the position of the equilibrium varied widely with the nature of the 2-substituent. 3,4-Hydrated cations were formed in acidic solutions but, in some cases, only after transformation of more rapidly formed 5,6,7,8-dihydrated cations.

Heterocyclic studies. Part XVIII. Some 6,7-diaminoimidazo[1,2-a]-pyrimidines and derived tricyclic compounds

Reduction of the 7-(substituted amino)-2,3-dihydro-5-methyl-6-nitroimidazo[1,2-a]pyrimidines (I; X = NO2, R = H, Me, Et, Ch2Ph, or CH2·CH2·OH) gave the corresponding 6-amino-derivatives (I; X = NH2). The same compounds were obtained by simultaneous reduction and cyclisation of 4-(substituted amino)-2-(2-chloroethylamino)-6-methyl-5-nitropyrimidines (II; R = H, Me, Et, CH2Ph, or CH2·CH2·OH). Some of the diamines (I; X = NH2) were treated with nitrous acid, thionyl chloride, urea, carbon disulphide, formic acid, oxalic acid, or biacetyl to give imidazo[1,2-a]triazolo[4,5-d]pyrimidines (IV; R1= CH2Ph or Et, R2= CHN·OH), imidazo-[1,2-a]isothiazolo[3,4-e]pyrimidines (V; R = CH2Ph or Me), imidazo[1,2-a]purines [e.g.(VI; R1= CH2Ph or Me, R2= SH)] and imidazo[2,1-b]pteridines [(VIII) and (IX)]. Several of these reactions involved the 5-methyl group of the starting diamine (I; X = NH2).

Heterocyclic studies. Part XIV. Novel tri- and tetra-cyclic compounds derived from a pteridine derivative by nucleophilic addition reactions

Nucleophiles containing two functional groups were added across the 5,6- and 7,8-bonds of ethyl pteridine-4-carboxylate. In some cases only one molecule of the addendum was involved and the products contained new heterocyclic systems with three or four rings. In other cases two molecules of the addendum added separately across the 5,6- and 7,8-bonds of the pteridine. Thus, ethylene glycol gave a 1,4-dioxinopteridine or a bis-(2-hydroxyethoxy)-adduct according to conditions. Ethane-1,2-dithiol, 1,2-diaminoethane and o-phenylenediamine gave 1,4-dithiino-, pyrazino-, and quinoxalino-pteridines respectively. 2-Thioethanol probably gave a 1,4-thioxino[2,3-g]pteridine rather than its [3,2-g] isomer. 2-Aminoethanol gave a bis-(2-hydroxyethylamino)-adduct.U.v., 1H n.m.r., and mass spectral data are presented.