Pyridopyrimidines ring-opening

The mechanism of ring-opening of pyridopyrimidin-4(3H)-ones under alkaline conditions is presumably as follows ... 

Factors that affect the rate-determining step (171 172) will influence the overall rate of reaction. A stronger nucleophile, such as hydrazine, is certainly more efficient than hydroxide, but no studies have been reported on the alternative variation of the electrophilicity of the 4-carbonyl group. Ring-opening may occur at either the 3 4.35,91,136,136 qj. 1 2-bouds in pyridopyrimidine-2,4(lH,-... 

E. C. Taylor and his co-workers have demonstrated an important principle in the ring-opening of pyridopyrimidines and other fused pyrimidine systems to o-aminonitriles. They have demonstrated that based-catalyzed cleavage of a 4-substituted pyrimidine will occur provided that (a) the anion formed by the attack by the base at the 2-position can be stabilized by appropriate structural features in the remainder of the molecule and (b) that the substituent attached to the 4-position is capable of departure with its bonding pair of electrons in... 

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. 

On the action of water200-204-205 or ammonia,200 2-oxo-3,4-dihydro-2//-pyrido[l,2-a]pyrimidines (142) undergo a facile ring opening. The betaine-type products (143) can be recyclized to the parent pyridopyrimidines by heating with acids. Treatment with alkalis leads to 2-aminopyri-dines.200,205,208... 

As with other members of the pyridopyrimidine series, hydrolytic ring-opening reactions occur at the pyrimidine moiety. Thus, the sodium salt of 3-hydroxypyrido[3,4-ii]pyrimidine-2,4-(l//,3f/)-dione, obtained by alkaline hydrolysis of the 3-(benzenesulfonyl)oxy compound, is cleaved by heating with 6 M hydrochloric acid for 4 hours at 180 CC to give a 65% yield of 3-aminoisonicotinic acid.135... 

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