Pyrido pyrimidines ring transformations

Within the following subsections the stability of the bicyclic ring system, plus the hydrogenation, reduction, dehydrogenation, oxidation, and quater-nization of the compounds are reviewed. This is followed by discussion of substitution reactions affecting the pyrido [ 1,2-a]pyrimidine ring, transformations of the side chains, and finally ring transformation reactions. 

Reaction of 6-methyl-4-oxo-4//-pyrido[l, 2-n]pyrimidine-3-acetic acid (295) with phenylethylamine in boiling xylene afforded ring-transformed product 296 (98ACH515). 

Photolysis of the zwitterionic pyrido[l,2-h]pyridazines (89) and their 5,6-benzo and 2,3-tetramethylene derivatives afforded 6,7,8,9-tetrahydro-4//-pyrido[l,2-fl]pyrimidin-4-ones (90) and their 8,9-benzo [77H(8)377] and 2,3-tetramethylene derivatives (75JOC2201). Photoinduced ring transformation of 2-phenylpyrido[l,2-fe]pyridazinium-4-olate (73) was investigated in methanol (94T4699). 

Ring transformation of ethyl 2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3- pyrimidine-5-carboxylates 317 with 80% hydrazine hydrate in boiling ethanol gave a mixture of 5-methyl/allyl/benzylamino-l,2,3,4-tetrahydro-l,4-dioxopyr-ido[3,4-i/ pyridazines 318, pyrido[2,3,4-< <7]pyridazino[3,4-/ [l,2,4]triazepines 319, and a low yield of 2,3,4,6,7-penta-azaphenalene 320. The reaction of 317 with hydrazine hydrate was also performed without a solvent in an oil bath at 125 °C for 1 h to give the same products, but higher yields of 318 and lower yield of 319 as well as traces of 320 were obtained (Equation 25) <1997FA657>. 

Mandereau et a/.193 prepared the alcohol (133) by reducing ethyl 2-pyridylaminopropionate with lithium aluminum hydride. The alcohol was then transformed with thionyl chloride to the chloride (134) and cyclized with an equimolar amount of sodium hydroxide in methanol to the pyrido-[l,2-u]pyrimidine (135). The 4-phenyl and 4-(p-tolyl) analogs were prepared in a similar fashion. The 4-(p-methoxyphenyl) derivative could only be obtained by heating the alcohol of type 133 in acetic anhydride. The pyrido[l,2-a]pyrimidine-4-carboxylicacid (137) was prepared by ring transformation of the pyridylpyrrolidinone (136) with methanolic sodium hydroxide.193... 

Other reactions of 4-oxo-4T/-pyrido[1.2-ri]pyrimidines accompanied by cleavage of the pyrimidine ring are discussed under the heading Ring transformations (Section III.C. 10). 

As part of their study on aza-transfer reactions, Tisler and co-work-ers289 290 reacted 2-hydrazino-4-oxo-4//-pyrido[l,2-u]pyrimidine with various diazo derivatives and obtained 2-azido- and 2-amino-4-oxo-4/f-pyrido[l,2-u]pyrimidines. From 2-azido-4-oxo-4/f-pyrido[l,2-u]pyrimi-dines various derivatives of 2-(l,2,3-triazol-l-yl)-4-oxo-4//-pyrido[1.2- ]-pyrimidine (221) were prepared by reaction with acetylene,287 1,3-dioxo compounds,166 ordiethylamine.291 For further ring transformation reactions of the 2-azido-4-oxo-4//-pyrido[l,2- ]pyrimidine (102), see Section lll.C.lO. 

Substituted-4-oxo-4//-pyrido[l,2-a]pyrimidines of type 74 (6-R H) are transformed to l,4-dihydro-4-oxo-l,8-naphthyridines on the action of heat.bl)-71-7l, 1 29 1 33 323 325 Ring transformation is facilitated by the nearly coplanar disposition of the 4-CO group and the 6-substituent of the pyrido-[l,2-u]pyrimidines. The steric interaction of these groups is shown by the relatively long C-4—N-5 bond (e.g., 147 pm for ethyl 6-methyl-4-oxo-4/f-pyrido[l,2-u]pyrimidine-3-carboxylate, as determined by X-ray study326). The strain caused by this interaction is relieved when the C-4—N-5 bond cleaves. Ring transformation probably takes place via the reactive imino-ketene intermediate (75).130... 

The pyrido[l,2-a]pyrimidines (256) undergo an essentially similar ring transformation, with the difference being that the ring closure of the intermediate iminoketene (257) takes place not to the C-3 atom of the pyridine ring but to the more reactive phenyl ring, and thus a quinoline derivative (258) is isolated.327... 

When the base was diethylamine, the pyrido[l,2-a]pyrimidine (221 R = R1, R2 = H) was formed with the tetrazole (269 R = CONEt2). The ring transformation also took place as a result of photocatalysis.291 When the azido compound (102) was heated in ethanolic hydrogen chloride for 1.5h, the tetrazolylacetic acid (269 R = COOH) and its ethyl ester were obtained, while on prolonged treatment the methyl derivative (269 R = H) was the product.11 6... 

When the quaternary salt (272) or the l,6,7,8-tetrahydro-pyrido[l,2- ]-pyrimidine (273) was heated in sodium hydrogen carbonate solution, the pyrido[l,2-a]pyrimidine (274) was formed. This transformation proceeded via addition of water to the C-9a=N-l or the C-9=C-9a double bond, followed by opening of the pyrimidine ring and finally by recyclization through condensation between the carbamoyl group and the oxo function of the piperidine ring.330... 

Ferrarini et al. studied the reaction of 2,6-diamino- and 2-amino-6-acetamidopyridine with different jS-oxo esters in polyphosphoric acid at 80°C (90JHC881). Generally, complex reaction mixtures that contained different bi- and tricyclic products were obtained (see Scheme 7 and Table IX). The products were separated by flash chromatography. In the case of 2-amino-6-acetamidopyridine, the 2,6-diacetamidopyridine 97 was the main product. This compound 97 was also obtained by transamidation in good yield when 2-amino-6-acetamidopyridine was heated in polyphosphoric acid at 80°C. 2-Hydroxy-1,8-naphthyridines 98 were formed in a Conrad-Limpach-type cyclocondensation of 2-aminopyridines and /3-keto ester, while 4-hydroxy-1,8-naphthyridines 99 were probably formed by a ring transformation of 4//-pyrido[l,2-a]pyrimidin-4-ones 100 obtained by the cyclocondensation of 2-aminopyridines and a /3-keto ester. The cyclocondensation of 7-amino-4-hydroxy-l,8-naphthyridine 99 (R = H) and a... 

Investigating the role of the substituent at position 3 of 4/f-pyrido [l,2-a]pyrimidin-4-ones, it was found that the resonance effect of the 3-substituent also plays a role in the ring transformation, as well as the steric property of the 6-substituent [88JCS(P2)1287]. 

Ring transformation of the initial 6-substituted 4//-pyrido[l,2-a] pyrimidin-4-ones also occurred when 2-[(6-substituted 2-pyridyl)acrylates were heated in a high-boiling solvent. For example, heating diethyl [(4,6-dimethyl-2-pyridyl)amino]malonate in boiling diphenyl ether afforded ethyl 5,7-dimethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate... 

Vilsmeier-Haack formylation of 9-phenylhydrazonotetrahydropyr-ido[ 1,2-a]pyrimidin-4-ones 636 with a mixture of phosphoryl chloride and dimethylformamide at 60°C for 2 hours, then at 90°C for 0.5 hour, led to the formation of unsaturated dichlorinated 4//-pyrido[l,2-a]pyrimidin-4-ones 331 (91H1455). Because the analog 9-(phenylaminomethylene)tetra-hydropyrido[l,2-a]pyrimidin-4-one 558 (R = COOEt) did not give a similar product, it was assumed that the 6,7-dihydro form 637 was involved in the ring transformation. 

Methanolysis of 8-acetoxymethyl-5,6,7,8-tetrahydro-lH,4aH-pyrido[l,2-a] pyrimidin-l-one 78 under Zemplen condition in MeOH with catalytic amount of Na yielded 8-hydroxymethyl derivative 79, which underwent ring transformation by intramolecular attack of the hydroxy group on the carbonyl group to give oxazino[3,4-a]pyridinone 80 in 70% yield (07CAR1813). 

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