Pyrimidine N-oxide

Pyrimidine N-oxides may be made directly or via their N-alkoxy analogues by means of the Principal Synthesis or other primary synthesis. The alternative route is peroxide oxidation of the parent pyrimidine but this can lead to a mixture of 1- and 3-oxides if the substrate is unsymmetrical about the 2,5-axis of the molecule. 

The one-pot MCR of methylene active nitriles 47 has been used in the synthesis of both pyrano- and pyrido[2,3-d]pyrimidine-2,4-diones in a single-mode microwave reactor [90]. Microwave irradiation of either barbituric acids 61 or 6-amino- or 6-(hydroxyamino)uracils 62 with triethyl-orthoformate and nitriles 47 (Z = CN, C02Et) with acetic anhydride at 75 °C for 2-8 min gave pyrano- and pyrido[2,3-d]pyrimidines in excellent yield and also provided a direct route to pyrido[2,3-d]pyrimidine N-oxides (Scheme 27). 

Cyanations of quinoline 877 and isoquinoline N-oxide 879 in DMF or N-methyl-pyrrolidone provides the cyano compounds 878 and 880 in 90 and 79% yield, respectively (Scheme 7.4) it was expected, e.g., that pyrimidine N-oxides would react analogously [6]. 

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

Pyrimidine N-oxides cannot be nitrated unless they possess electron-donating substituents, e.g.,... 

The synthetic uses of pyrimidines in the construction of non-heterocycles appear to be relatively small. While the ring opening reaction of a pyrimidine N-oxide with phenylmag-nesium bromide has been reported to give benzaldehyde upon hydrolysis (it thus plays the same role as DMF) (67JOC3788) the Diels-Alder capabilities of the pyrimidines do, on the other hand, appear to hold considerable promise in organic chemistry. 

The synthesis of target imidazoles can be also realized by photoinduced ring-contraction of the pyrimidine nucleus. For example, significant yield of 4(or 5)-acetylimidazoles 64 are isolated from the photolysis, at 254 nm in methanol or benzene, of 4-substituted 2,6-dimethyl-pyrimidine-N-oxides 62 (Scheme 12.18) [43],... 

When the 6-position is unsubstituted, oxidative degradation is most common, and peracetic acid treatment leads to ring contraction to form 2,4-disubstituted imidazoles and their N-oxides (81H573). For example, 2-methyl-4-phenylpyrimidine (28) reacts in this way with peracetic acid, but with m-chloroperbenzoic acid in chloroform, pyrimidine N-oxides were formed as well (Scheme 12). Even pyrimidine itself gave the oxide in 48% yield under these latter conditions 2-methylpyrimidine gave 55% of the N-oxide (81H573). 

Yamanaka, H., Ogawa, S., and Konno. S Studies on pyrimidine derivatives. XVIII. Reaction of active methyl groups on pyrimidine N-oxides, Chem Pharm. Bull. Tokyo, 28. 1526, 1980. 

Highly activated pyrimidine derivatives such as the diquaternary salt (406) and the monoquaternary salt (407) underwent ring contraction at a lower temperature and gave isoxazole in much better yields. Pyrimidine N-oxides (408) also underwent ring contraction in a similar fashion to give isoxazoles (338). It was found, using l,3-lsN-labelled (408b) as... 

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