Pyrimidine opening, oxidative

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. 

In 1,2,4-triazines it is essential that the 5-position is blocked (cf. pyrimidines without 4- or 6-substituents) to prevent nucleophilic ring opening, oxidation, and ring contractions from competing with N-oxidation (72LA111 86H951). Products include l,2,4-triazin-5-ones and -5,6-diones (72LA111). Whereas... 

In amidines transamination is possible,especially useful for such purposes are imidoylimid-azolides, e.g. (341 equation 172). In some cases it is usefiil to prepare amidines by ring opening of suitable heterocycles, which can be achieved by treatment with amines or other nucleophilic (basic) compounds. Examples are the synthesis of amidines firom 1,3,5-oxadiazinium salts (342), 3-amino-l,2-benzisothiazoles (343), 2-ethoxycarbonyl-3,l-benzoxazin-4(4//) one (344), 1,2,5-oxa-diazolo[3,4]pyrimidine 1-oxides (pyrimidofuroxans 345) and l,2,4,6-thiatriazenium-5-olate 1,1-dioxides (345) as shown in Scheme 58. 

Pyrido[2,3-d]pyrimidine 3-oxide (7) undergoes several ring-opening reactions. 2-Aminonicoti-nonitrile is obtained in very low yield with hot acetic anhydride, whereas aqueous sodium hydroxide at room temperature gives AT-[3-(hydroxyunino)-2-pyridyl]formamide (8) in 76% yield.309... 

Pyrimidine 1-oxides 72, which are less electrophilic than triazines, do not react with cyanamide in the presence of a base. However, treatment of 72 with cyanamide under acidic conditions (dry HCl) results in the formation of 4-aryl-2-ureidopyrimidines 75 (Scheme 49) [107]. It is evident that in situ protonation of these N-oxides significantly enhances their ability to give ring opening process (73 74 75), thus resulting in the formation of 75. Hydrolysis of the latter on reflux in formic acid provides the corresponding 2-aminoperimidines. 

Pyrimidine iV-oxides often behave anomalously, giving ring-opened products. ... 

The first step of cyclization involves the electrophilic attack of NO and the opening of the three-membered ring resulting in the formation of the intermediates type 119. Than intermediate 119 is trapped by solvent, resulting in the formation of nitrilium species 120, which undergo intramolecular cyclization into final pyrimidine N-oxides 122 (Scheme 26). 

The analog program on pyrimidines included some open-chain versions of this heterocycle as well. These last, the biguanides, were found to be quite active in their own right. (It was subsequently established that these compounds undergo oxidative cyclization to dihydropyrimidines in the body to give the actual antimalarial—see cycloguanyl). 

When 1,2,5-thia- and selena-diazolo[3,4- pyrimidine-5,7-dione W-oxides are treated with sodium hypochlorite, the respective S or Se atom is replaced by O to give 1,2,5-oxadiazoles, as shown in Scheme 82 (precise yields not given) <2000CHE1359>. A more vigorous oxidation leads to ring-opening of the fused five-membered ring (see Section 10.13.5.4). 

Cycloaddition of methyl orotate or its 1,3-dimethyl derivative with 2,6-dichlorobenzonitrile oxide (generated in situ Scheme 79), or with the corresponding isocyanate, gives an oxazolo[4,5-d]pyrimidine. This intermediate undergoes ring opening under the reaction conditions, and recyclization occurs to provide a pyrimido[5,4-r/][l,2]oxazine <1992H(34)1423>. 

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