Synthesis and Regioselective N- and O-Alkylation of 1H- or 3H-[1,2,3]Triazolo[4,5-d]pyrimidine-5,7(4H,6H)-diones (8-Azaxanthines) and Transformation of Their 3-Alkyl Derivatives into 1-Alkyl Isomers

Tomohisa Nagamatsu, Rafiqul Islam
2006 Synthesis (Stuttgart)  
Synthesis and regioselective N-and O-alkylation of 1H-or 3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H,6H)-diones (8-azaxanthines) and transformation of their 3-alkyl derivatives into 1-alkyl isomers Abstract: Several alkylating agents, e.g. alkyl halides and dimethyl sulfate, were employed in aprotic solvents under a variety of conditions for alkylation of mono and disubstituted 1H-or 3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H,6H)-diones, which were prepared by cyclization of the appropriate
more » ... iaminouracils with nitrous acid. The alkylation on the triazole ring in the presence of anhydrous potassium carbonate took place simultaneously at the 1-and 2-positions with the priority at the 2-position. The similar alkylation on the pyrimidine ring with an equivalent alkylating reagent took place only at the 4-position. The alkylation of the 3,6-disubstituted derivatives at room temperature led to the 5-O-alkylation accompanied with the 4-N-alkylation, but at high temperature only the 4-N-alkylation took place. The 3,4,6-trisubstituted derivatives underwent transformation with excess alkylating agents at high temperature leading to the formation of 1,4,6-trisubstituted derivatives with elimination of the 3-substituent. wide biological activities such as antiviral 1 and antitumor activities 1c,d, 2 as well as xanthine oxidase inhibitory activities. 3 In the past few decades, tremendous efforts have been directed to the search of potential anticancer and antiviral drugs without adverse effects, but very effective The desired 1H-and 3H-[1,2,3]triazolo[4,5-d]pyrimi-dine-5,7(4H,6H)-diones (8-azaxanthines) 2a-z were synthesized according to the previously outlined procedure. 10, 11 Namely, 6-chlorouracils 12 were converted to the requisite 6-aminouracils by heating with appropriate amines, which on subsequent treatment with nitrous acid gave the corresponding 6-amino-5-nitrosouracils. The reduction for nitroso group into amino group was carried out with sodium dithionite in dilute alkali solution, 13 but the reduction of some hydrophobic nitroso compounds, e.g. 6-n-heptyl and 6-n-octylamino derivatives in aqueous medium, did not proceed smoothly enough. In completing the reduction within the shorter time, an addition of methanol was necessary. The final cyclization of the appropriate 5,6-diaminouracils 1a-z leading to the Scheme 1 When 3-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione 2a was treated with an equivalent methyl iodide in the presence of anhydrous potassium carbonate in dry N,N-dimethylformamide at boiling temperature afforded only the 3,4-dimethyl derivative 4a in 62% yield (Scheme 2). Similarly, benzylation of 2a with an equivalent benzyl bromide under same conditions gave the 4-benzyl-3-methyl derivative 4b in 44% yield. Thus, the alkylation on the pyrimidine ring for the [1,2,3]triazolo[4,5-d]pyrimidine system took place not at the 6-position but at the 4-position in spite of steric repulsion of the substituents at the 3-position and the 4-position. In the 1 H NMR (DMSO-d 6 ) spectrum, the singlet signal at δ 3.60 of 4a, assigned to methyl protons at the 4-position, was closer to other 4-N-methylated derivatives (δ 3.33-3.45) than 6-N-methylated derivatives (δ 3.18-3.38), and the mp 254-255 °C was also identical with reported mp 256 °C. 10 It is noteworthy that the value ( δ 3.60) shifts from the usual value (δ 3.45 for methyl at the 4-position of 10) to 1.5 ppm low magnetic field due to the peri-interaction of the substituents between 3-and 4-position. The chemical shift at δ 5.40 due to the 4-N-CH 2 Ph protons of 4b was also consistent with the value at δ 5.33 for 4-N-CH 2 Ph protons of another derivative 12c. The similar reaction of 2c with 4 equivalent methyl iodide at 60 °C for overnight gave a mixture of 3-isopropyl-4-methyl 6 and 3-isopropyl-4,6-dimethyl derivative 7 in 24% and 35% yield, respectively. Even in the presence of excess methylating agent in the reaction, the monomethylated derivative 6 was isolated Scheme 2 The methylation of the 6-methyl derivative 2x with an equimolecular methyl iodide in N,N-dimethylformamide at boiling temperature resulted in the formation of two regioisomers of 1,6-dimethyl 8 and 2,6-dimethyl derivative 9 in 23% and 42% yield, respectively (Scheme 3). The same methylation of 4-methyl derivative 2y also led to two regioisomers of 1,4-dimethyl 10 and 2,4-dimethyl derivative 11 in 25% and 41% yield, respectively. Therefore, it is clear that the methylation on the [1,2,3]-triazolo[4,5-d]pyrimidine system with an equivalent alkylating reagent takes place not on the pyrimidine ring but only on the triazole ring. 1 H NMR spectra of the methylated products provided sufficient evidence for methylation at the triazole ring. That is, the chemical shifts for all N-CH 3 protons attached to the triazole ring usually appear at δ 4.0-4.4, whereas for N-CH 3 protons attached to the pyrimidine ring these appear at δ 3.2-3.8. We observed the chemical shift in the former region (δ 4.0-4.3) for the newly appeared N-CH 3 protons attributable to a methyl group on the triazole ring. Some di-N-alkyl derivatives (e.g. 4a,b, 8-11) were converted smoothly into tri-N-alkyl derivatives (5a,b, 12a-c, 13a,b) with appropriate 12.34 (s, 1 H, 4-NH). UV (EtOH): λ max (log ε) = 255 (4.23), 281 nm (3.97).
doi:10.1055/s-2006-950337 fatcat:wmrlv6i22rdh5ogje7muhjbzfq