Pyrimidine oxidation

It has been shown already that C-2 of ribose is the precursor of the methyl group, and C-l is eliminated in the biosynthesis. The following observation can be pertinent to the point. Pyrimidine (58) is very unstable and quickly decar-boxylates in aqueous solution at room temperature to give pyramine (Scheme 32).67 Thus, if a C-l -C-2 fragment of the ribose part of AIRs became attached by C-2 to C-2 of a pyrimidine, oxidation of C-l to produce a carboxylic acid function could result in its smooth elimination. 

The addition of organometaiiics to unactivated pyrimidines normally produces unstable dihydro derivatives which readily oxidize back to the pyrimidine oxidation level, although successful conjugate addition to pyrimidinone derivatives can occur. Thus, the addition of lithium trimethylsilyldiazomethane [TMSC(Li)N2] to 1,3-dimethyluracil 418 occurred at the 6-position to produce a mixture of the two pyrazolo[4,3-rf]pyrimidine-5,7-diones 419 and 420, where the initial addition had been accompanied by cyclization <1997T7045>. 

When there is an N-oxide function present in an azine, another site becomes available for proton attack. Although pyridazine iV-oxides often react at the free nitrogen, pyrimidine oxides frequently form the hydroxy salts (83CHE1012). 

The highly acidic conditions required to generate peracids in situ from carboxylic acids and hydrogen peroxide are usually not conducive to efficient amine oxidation. In situ generation from anhydrides in neutral solution or other acylated agents in alkali can be employed. In situ perphthalic or permaleic have been reported for pyrimidine oxidation.332... 

Phenyl 2-hydroxy-4-(3,3,3-trifluoromethyl-2-hydroxy-2-methylpropionylamino)benzoic acid is the latest chemical agent designed to treat alopecia supplanting 6-amino-1,2 dihydro-l-hydroxy-2-aminopyrimidine (Minoxidil) (I) (1) and pyrimidine oxide derivatives (II) (2), (III) (3), and (IV) (4). 

Isoxazolo[3,4-c/]pyrimidine 39 when treated with cyanoolefins 40, in the presence of TEA as catalyst, gave biologically interesting pyrido[2,3-c/]pyrimidine oxides 41 in excellent yields. Probably, a [4+2] cycloaddition of the azadiene moiety of 39 with keteneimine intermediates, derived from 40 and TEA, is involved in the process <03TL1847>. 

From these specificity trends, some predictions can be made about the rate at which xanthine oxidase or aldehyde oxidase might oxidize any given heterocycle. For example, it is clear that with most C-disubstituted condensed-pyrimidines, oxidation by aldehyde oxidase in vivo is improbable, while oxidation by xanthine oxidase is a parameter which must be carefully considered. 

Interesting structures can be formed by combinations of ring and side-chain substituents in special relative orientations. As indicated above, structures (28) contain the elements of azomethine or carbonyl ylides, which are 1,3-dipoles. Charge-separated species formed by attachment of an anionic group to an azonia-nitrogen also are 1,3-dipoles pyridine 1-oxide (32) is perhaps the simplest example of these the ylide (33) is another. More complex combinations lead to 1,4-dipoles , for instance the pyrimidine derivative (34), and the cross-conjugated ylide (35). Compounds of this type have been reviewed by Ramsden (80AHCl26)l). 

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). 

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