4-Aminopyrimidine 3-oxides

There is a scattered body of data in the literature on ordinary photochemical reactions in the pyrimidine and quinazoline series in most cases the mechanisms are unclear. For example, UV irradiation of 4-aminopyrimidine-5-carbonitrile (109 R=H) in methanolic hydrogen chloride gives the 2,6-dimethyl derivative (109 R = Me) in good yield the 5-aminomethyl analogue is made similarly (68T5861). Another random example is the irradiation of 4,6-diphenylpyrimidine 1-oxide in methanol to give 2-methoxy-4,6-diphenyl-pyrimidine, probably by addition of methanol to an intermediate oxaziridine (110) followed by dehydration (76JCS(P1)1202). 

Triamterene (31) is a diuretic that has found acceptance because it results in enhanced sodium ion excretion without serious loss of potassium ion or significant uric acid retention. Tautomerism of aminopyrimidines (e.g., 27a and 27b) serves to make the "nonenolized" amine at the 5 position more basic than the remaining amines. Thus, condensation of 27 with benzaldehyde goes at the most basic nitrogen to form 28. Addition of hydrogen cyanide gives the a-aminonitrile (29). Treatment of that intermediate with base leads to the eyelized dihydropirazine compound (30). This undergoes spontaneous air oxidation to afford triamterene (31). ... 

The diazotization of amino derivatives of six-membered heteroaromatic ring systems, particularly that of aminopyridines and aminopyridine oxides, was studied in detail by Kalatzis and coworkers. Diazotization of 3-aminopyridine and its derivatives is similar to that of aromatic amines because of the formation of rather stable diazonium ions. 2- and 4-aminopyridines were considered to resist diazotization or to form mainly the corresponding hydroxy compounds. However, Kalatzis (1967 a) showed that true diazotization of these compounds proceeds in a similar way to that of the aromatic amines in 0,5-4.0 m hydrochloric, sulfuric, or perchloric acid, by mixing the solutions with aqueous sodium nitrite at 0 °C. However, the rapidly formed diazonium ion is hydrolyzed very easily within a few minutes (hydroxy-de-diazonia-tion). The diazonium ion must be used immediately after formation, e. g., for a diazo coupling reaction, or must be stabilized as the diazoate by prompt neutralization (after 45 s) to pH 10-11 with sodium hydroxide-borax buffer. All isomeric aminopyridine-1-oxides can be diazotized in the usual way (Kalatzis and Mastrokalos, 1977). The diazotization of 5-aminopyrimidines results in a complex ring opening and conversion into other heterocyclic systems (see Nemeryuk et al., 1985). 

JA4209 81AHC141). A different process occurs when some enaminoke-tones react with sodium ethoxide in ethanol. Compounds 148 (R = = Me R = Me, Ph) give aminopyrimidine A/-oxides 147,... 

Aryl-l, 2,4-triazolo[l, 5-a]pyrimidines (17) were prepared by oxidative cyclization, by the action of lead tetraacetate (LTA), of 2-pyrimidylary-lamidines (16), first prepared by the reaction of 2-aminopyrimidines (15) with aryl cyanides in the presence of A1C13 (90SC2617) (Scheme 6). 

Polystyrene-bound isothiuronium chloride, which is readily prepared from chloro-methyl polystyrene and thiourea, has been used as a starting material for the preparation of various substituted pyrimidines (Entries 9-11, Table 15.28). After oxidation to the corresponding sulfones, nucleophilic cleavage with amines proceeds smoothly to yield substituted 2-aminopyrimidine derivatives (see Section 3.8). 

Stepwise pyrazine ring-formation using 5-nitropyrimidine was applied to the synthesis of 4a-hydroxytetrahydrobiopterin (95), which is an interesting intermediate in the metabolism of aromatic amino acids (see Sect. 5.2). As illustrated in Scheme 18, the 5-aminopyrimidine 97 prepared from chloroni-tropyrimidine 96 by nucleophilic substitution followed by catalytic hydrogenation was oxidized under acidic conditions to o-quinone derivative 98. 

Another important synthesis involves the reductive cyclization of 4-ethoxyalkylidinehydrazino-5-nitropyrimidines of type (372), which are obtained readily by reaction of 4-hydrazino-5-nitro-pyrimidines (371) with ortho esters. Catalytic reduction of the nitro group in (372) affords the 5-aminopyrimidine intermediate (373), which cyclizes in situ to the dihydro product (374). This may be oxidized without isolation to give the fully aromatic product (375). These reactions are shown in... 

Similar reactions have been carried out with amidines (67NEP6610627). Thus tri-chloroacetamidine (309) reacts with chlorothioformate esters to produce thioacyl products (310) which are readily oxidized to 5-alkoxy-3-trichloromethyl-l,2,4-thiadiazoles (311). The yields in both steps are about 80% (Scheme 111). The bromine oxidation of N-thiocarbamyl derivatives (312) of cyclic amidines (2-aminopyridine, 2-aminothiazole, 2-aminopyrimidine) yields thiadiazolium salts (313) (71JPR1148). In the 2-aminopyridine series, products of type (230 Scheme 81) are obtained in 20-73% yield when R is an ethoxycar-bonyl group (750PP55). 

Azine approach. The fused pyrimidines can be synthesized in the same way as the pyridines, e.g. by the cyclization of vicinal aminothiocyanates (70JCS(C)2478>. Another useful method for aminoazines is the reaction with chlorocarbonylsulfenyl chloride, e.g. with the aminopyrimidine (440) (73LA1018). The reaction can be rationalized by initial acylation of the amino group which is then cyclized with formation of the 2(3//)-one (441). Another case is the reaction of the 6-aminouracil (442) with thionyl chloride (69JOC3285). The reaction is rationalized as an initial electrophilic substitution at the 5-position of the activated pyrimidine. Subsequently the chlorosulfinyl derivative (443) is cyclized to a thiazoline S-oxide which loses water to yield the thiazole. 

Azine approach. Phosgene (80JAP(K)8017386> or ethyl chloroformate reacts with 2-aminopyrimidine 1-oxide to form (607) (78GEP2804519) the triazine (608) is similarly formed (80EUP7643). 

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