Pyrido pyrimidines nucleophilic substitution

Pyrido[3,4-d]pyrimidine-2,4-dione synthesis, 3, 215 Pyridopyrimidines, 3, 201 iV-alkylations, 3, 206 biological activity, 3, 260-261 1-electron reductions, 3, 207 IR spectra, 3, 204 mass spectra, 3, 204 MO calculations, 3, 204 NMR, 3, 202, 203 nucleophilic substitution, 3, 213 8-nucleosides synthesis, 3, 206 physical properties, 3, 201-205 protonation, 3, 206 radical reactions, 3, 215 reactions with water, 3, 207 reduced... 

A large number of nucleophilic substitution reactions involving interconversions of pyridopyrimidines have been reported, the majority of which involve substituents in the pyrimidine ring. This subject has been reviewed previously in an earlier volume in this series which dealt with the theoretical aspects of nucleophilic re-activiti in azines, and so only a summary of the nucelophilic displacements of the substituent groups will be given here. In general, nucleophilic substitutions occur most readily at the 4-position of pyrido-... 

Triazanaphthalene (449) is the most unstable of the pyrido-pyrimidines to ring-degradation at pH 2 or pH 7.7 The 4-oxo derivative was converted into the 4-thioxo compound via nucleophilic displacement of the acyloxy intermediate formed with phosphorus pentasulfide. The 4-carboxymethylthio-pyridopyrimidine underwent some substitution by hydroxide ion but primarily gave the ring-opening reaction, which is facilitated by resonance activation of the 2-position by the 6-aza moiety. 

The C-2 atom of the 4-oxo-4//-pyrido[I,2-[Pg.300]

Due to the activating influence of the ring nitrogens, pyrido[2,3-c/]pyrimidine derivatives are good substrates for nucleophilic substitution reactions. For a general study, see ref 544. 

As generally observed with nucleophilic substitutions in the pyrido[2,3-J]pyrimidine system, exchange occurs most readily at the 4-position.77,79 Thus, under mild conditions, 2,4-dichloropyrido[2,3-rf]pyrimidine (21) with dilute aqueous sodium hydroxide gives 2-chloropy-rido[2,3-c ]pyrimidin-4(3// )-one (24).7-79... 

In contrast to the normal amino function which in nucleophilic substitution reactions is a rather poor leaving group, azolyl substituents represent a special case. Thus, the triazolyl group in 6-bromo-2-(pivaloylamino)-4-(l,2,4-triazoI-l-yl)pyrido[2,3-c/]pyrimidine (30) is substituted by a methoxy substituent.331... 

Three kinds of sulfur substituents are used as leaving groups in nucleophilic substitution reactions in the pyrimidine moiety of pyrido[2,3-d]pyrimidines, i.e. the free sulfanyl group,29,249,364,365 alkylsulfanyl,7,335,366 and alkylsulfonyl substituents.326,367... 

One of the less common leaving groups in aromatic nucleophilic substitution reactions is the cyano group. However, a 4-cyano substituent in pyrido[2,3-t/]pyrimidine can be exchanged for methoxy or hydroxy functions by refluxing in methanolic sodium methoxide or aqueous sodium hydroxide solution.296... 

As already evident from the course of nucleophilic substitution reactions (see Section 7.2.2.2.1.5.4.) in pyrido[3,2-d]pyrimidines, the position most susceptible for the addition of nucleophiles is the C4 atom. This is confirmed by the addition of 5,5-dimethylcyclohexa-1,3-dione (dimedone) to pyrido[3,2-d]pyrimidine, which yields the corresponding 3,4-dihydro derivative.469... 

In cases where there is a suitable leaving group, such as chloro, alkoxy, or amino, the nucleophilic attack at the activated vinyl system of the C—C —C fragment will be followed by the reestablishment of the C—C double bond, the result being a vinylic substitution. In these cases the final cyclization affords the pyrido[2,3-d]pyrimidine compound, or otherwise its dihydro derivative. 

---