A series of 1-methyl-pterin derivatives (6-13) have been synthesized by condensation and methylation reactions. The compounds have been characterized by elemental analyses, pKa deterimations and UV spectra. Comparisons of the physical data of the corresponding N-1 and N-3 methyl-pterins indicate why the normal pterins exist in aqueous solution preferentially in the N3-H tautomeric configuration. The thermodynamical stability of the lactam group forces the acidic H-atom to adapt the nitrogen adjacent to the carhonyl function but no other vinylogous position. A lactam group does not participate in heteroaromatic cyclic resonance, in general.
Various hydropyrano [3.2-g] pteridines (7, 10, 12, 21 , 33) were oxidized to the corresponding 6-(1,2,3- trihydroxypropyl)pteridine derivatives (8,9, 11, 13,32, 34), which are valuable intermediates for the synthesis of new 6-substituted pteridines (15 - 46). Periodate oxidation led to pteridine-6-carboxaldehydes (15, 16, 17, 38), which easily formed oximes (19 - 22, 39, 40). The aldehydes were further oxidized to 6-carboxylic acids (25,26,42) or reduced to 6-hydroxymethyl derivatives (27, 28, 43). Reductive condensations of the aldehydes (15, 16, 38) with p-aminobenzoylglutamic acid afforded folic acid analogues (29, 30, 44). Dehydration of the oximes (19, 20, 39) resulted in the formation of 6-carbonitriles (23, 24, 41, 46). The newly synthesized compounds were characterized by elemental analysis and by UV and NMR spectra.
A new efficient synthesis for 2-thiopteridine-4,6,7-triones (6-10, 15) has been found in the condendation of the appropriate 5,6-diaminopyrimidine (1-5, 14) with oxalic acid in DMF. Analogous condensations with dimethyl oxalate led to S-alkylation probably via an intermediate O-methylation of the DMF. 8-Methyl-2- thiopteridine-4,6,7-trione (10) shows a ring contraction to 9-methyl-2-thioxanthine (13) on base treatment. Oxidations by H20 2 and KMn04 respectively lead to the corresponding 2-sulfinate 22 and the 2-sulfonates 17 -19. Oxidative desulfurization takes place in formic acid with H 20 2 forming first the sulfinate 22, which then eliminates S02 to give pteridine-4,6,7-trione (23). Nucleophilic displacements of the 2-sulfonate group by ammonia and amines form the corresponding leucopterin derivatives 20, 21 and 24. The newly synthesized compounds have been characterized by elemental analyses, UV-spectra and pKa-determinations. The ionization sequences of the acidic hydrogens have been assigned based on these physical data .
Selective oxidations of 2-thiolumazines (10-12) by H20 2 and KMn04 respectively in basic medium led to the corresponding stable pteridin-4-one-2-sulfinates (13-15) and -sulfonates (16-18), which can be isolated in the form of their potassium salts. On oxidation of 6,7-diphenyl-2-thiolumazine (12) with 1 equivalent of H20 2 resulted the 6,7-diphenyl-pteridin-4-one-2-sulfenate (22), which is regarded as an intermediate in the formation of the sulfinates. Characterization was done by elemental analysis, pKa determination, and UV-, IR- and IH-NMR-spectra.
Acid and base hydrolyse the sulfinate and sulfonate groups to the 2-hydroxy derivative. Treatment of the pteridin-4-one-2-sulfinate with strong anhydrous acids such as formic acid or sulfuric acid affects S02 elimination to the corresponding 2-H-pteridin-4-one (19-21).
The oxidative desulfurization of 2-thiolumazines can be achieved directly with H20 2 and m-chloroperbenzoic acid in formic acid. Analogously nucleophilic displacement reactions of the 2-thione group proceeded under mild conditions by H20 2 oxidation in the presence of various amines to give the corresponding pterin derivatives (25.-;-32, 36-39). 6,7-Diphenyl-4-thiolumazine (44) shows similar reactions on oxidation in the presence of amines (43, 54), but the corresponding 4-sulfinate and sulfonate are too unstable in this series to be isolated. S02 elimination does not take place since hydrolysis is the preferred reaction mode.
Various 6-(10, 11) and 7-hydroxy-2-thiolumazines (8,9) have been synthesized and oxidations of the thioamide function studied . H20 2 Oxidation of 7-hydroxy-2-thiolumazine (8) in basic medium leads to pteridine-4,7- dione-2-sulfinate (12), which eliminates S02 in anhydrous acids. Oxidative desulfurization of 8 and its 8- methyl derivative 9 proceeds directly in formic acid with H20 2 and m-chloroperbenzoic acid to give 16 and 17 respectively. KMn04 oxidation forms the pteridine-4,7,dione-2-sulfonates (14, 15), which react under hydrolytic conditions to give the corresponding 2-hydroxy derivtives (18, 19) and on displacement with ammonium acetate/ammonia at elevated temperature form the pterin derivatives 20 and 21.
2-Thio-pteridine-4,6-dione (10) oxidizes also to the corresponding 2-sulfonate (22), which could only be isolated after addition of potassium bisulfite in the form of the dipotassium 7,8-dihydropteridine-4,6-dione- 2,7-disulfonate (23) adduct.
The newly synthesized compounds have been characterized by elemental analyses, pKa determinations, UVand IH-NMR-spectra.