Pyridopyrimidines oxidation

Again, as with pyridopyrimidines, the main reaction is oxidation of di- or poly-hydro derivatives to fully aromatic structures, often merely by air or oxygen. In some cases the reagent of choice is mercury(II) oxide, whilst other reagents used include sulfur, bromine, chloranil, chromium trioxide-acetic acid, hydrogen peroxide, and potassium ferricyanide, which also caused oxidative removal of a benzyl group in the transformation (306) (307)... 

Oxidations of pyridopyrimidines are rare, but the covalent hydrates of the parent compounds undergo oxidation with hydrogen peroxide to yield the corresponding pyridopyrimidin-4(3 T)-ones. Dehydrogenation of dihydropyrido[2,3-(i]pyrimidines by means of palladized charcoal, rhodium on alumina, or 2,3-diehloro-5,6-dicyano-p-benzo-quinone (DDQ) to yield the aromatic derivatives have been reported. Thus, 7-amino-5,6-dihydro-1,3-diethylpyrido[2,3-d]-pyri-midine-2,4(lif,3f/)-dione (177) is aromatized (178) when treated with palladized charcoal in refluxing toluene for 24 hours. 

Piperidine derivatives 161 and 164 could be cyclized to hexahydropyridooxadiazines 162, 165 via a dehydrogenation process by six oxidation equivalents of Hg(n)-EDTA. However, in both reactions, side products were also formed. From 161, piperidone derivative 163 was obtained, whereas starting from the amide 164, pyridopyrimidine 166 was isolated via cyclization by the amide nitrogen instead of oxime oxygen (Scheme 21) <1999ZNB632>. 

Methyl 5-(3-fluorophenyl)-7-methyl-l,2,3,4,5,8-hexahydropyrido[2,3-tetrahydro derivative 137 by the action of sodium nitrite in acetic acid <1994T8085>. Oxidation of 2,7-disubstituted-5-trifluoromethyl-l,2-dihydropyrido[2,3-r/]pyrimidin (3//)-ones using active Mn02 in CH2CI2 gave the corresponding pyridopyrimidin-4(3//)-ones 138 <1995IJB587>. 

Microwave-assisted multicomponent reaction of 6-amino- or hydroxy-aminouracil derivatives with benzaldehyde and malononitrile or ethyl cyanoacetate in the solid state in the absence or presence of Et3N for 5-8 min afforded the pyridopyrimidine derivatives 463 <2003TL8307>. Similarly, 6-aminouracil derivatives or 6-hydroxyamino analogues were reacted with HC(OEt)3 and active methylene compounds [CH2(CN)2 or NCCH2C02Et] in the presence of AcOH under microwave-assisted conditions to give the pyrido[2,3-r7 pyrimidines 464 and their iV-oxides 465 within 2 or 8 min, respectively. The reaction proceeded under thermal conditions in ethanol or without solvent for 1—4h to give 464 and 465 in 45-70% and 35-50% yield, respectively <2004SL283>. 

The carboxylic group of 6-aryl-2-methylthiopyrido[2,3- s1pyrimidine-7-carboxylic acid 563 was amidated with (i )-2-(aminomethyl)-l-( /t-butoxycarbonyl)pyrrolidine 564, followed by sulfide oxidation of the resulting amide 565 and reaction with 4-morpholinoaniline to give the substituted pyridopyrimidine 566 as a kinase inhibitor (Scheme 26) <2005W02005090344>. 

The reaction of isoxazolopyrimidine and cyanoalkenes, in the presence of triethylamine as a catalyst, afforded pyridopyrimidine V-oxides in excellent yields. The reaction likely involves a [4-1-2] cycloaddition of the starting isoxazole as azadiene on keteneimine intermediates, derived from cyanoalkenes and NEts (Equation 5) <2003TL1847>. 

In the above reactions of enamine derivatives with oxazolidines and oxazinanes, pyridine systems did not constitute direct targets but were formed, in a few cases, by air oxidation of initially formed dihydropyridine derivatives. Oxazolidines 30, possessing electron-withdrawing groups in C-2 substituents, exist mainly as tautomeric acyclic enamines 28 (Section II.C.2), which in the presence of an acid would also generate iminium cations such as 54 that should react with nucleophiles. Thus, it has been found that such oxazolidines in presence of an acid, react with acyclic, cyclic, and heterocyclic enamine derivatives in 1 1 stoichiometry to provide a unique synthesis of pyridine, quinolinone, and pyridopyrimidine derivatives (98T935). 

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