Pyrido pyrimidines, formation

When heated with bases, the 2-azidopyrido[l,2- ]pyrimidine (102) yields pyridyltetrazoles (269 R = CONR R2). This reaction is initiated by nucleophilic addition of the base to the carbonyl group it is followed by ring opening between the C-4 and N-5 atoms and formation of the tetrazole ring involving the azido group and the N-l atom of the starting pyrido-pyrimidine.166 291... 

Zimmerman and coworkers studied the dimer formed from ureido pyrido-pyrimidine 6 and its tautomer (Scheme 10.2d) [21]. They pointed out that prototropy can be detrimental to hydrogen-bonded complex formation. Therefore, heterocycle 6 was designed to contain only one self-complementary hydrogen-bonding array (DDAA) eliminating others. They measured the self-association constant by employing H NMR dilution studies in chloroform, which was estimated to be more than 10 IVT. ... 

The use of acrolein in the technical gas-phase synthesis of pyridine derivatives has been reviewed, as has the formation of pyridines, pyrimidines, pyrido-pyrimidines, and pyrazolopyrimidines by ring-closure of jS -enol- and /3 -enamino-carbonyl compounds. ... 

Enzymic oxidations at the 7-position of pyrido[2,3-oxygenated derivatives and of the 8-N-oxide have been observed in the metabolism of the pyrido[2,3-e/]pyrimidine analogues of the antiepileptic drug methaqualone (75MI21502, 74MI21500). 

The final step in the syntheses of pyrido[2,3-d]pyrimidines from pyridines has involved the formation of the bonds l-8a, 1-2, and 4—4a, but the most useful methods are those which form the 2-3 (i) and 3-4 (ii) bonds. 

Flash vacuum thermolysis (FVT) of 2-substituted 4//-pyrido[l,2-n]pyrimidin-4-ones 126 above 800 °C afforded (2-pyridyl)iminopropadie-none (130) (99JCS(P2)1087). These reactions were interpreted in terms of reversible ring opening of 4//-pyrido[l,2-n]pyrimidin-4-ones to imidoyl-ketenes 127. A 1,5-H shift in 127 generated the N(l)H-tautomeric methylene ketene 128, in which facile elimination of HX took place via a six-membered cyclic transition state 129 to yield 130. In the case of 2-methoxy derivative 126 (X = OMe) another competing pathway was also identified at lower temperature, which resulted in the formation C3O2 and 2-methylaminopyr-idine via mesoionic isomer 131 (Scheme 9). The products were identified by IR spectroscopy. 

Reaction of 2-(A -alkyl-A -benzylamino)- and 2-[A -(rraM-crotyl)-A -ben-zylamino]-3-formyl-4/7-pyrido[l,2-n]pyrimidin-4-ones (260, R = H, Me) with tosylamine gave compounds 268 via compounds 266 and 267 (96T13097). The results of kinetic studies and MP3 calculations on the 3-formyl derivatives 252, 260 and the imines 262, 263 suggested a concerted nature for azepine-ring formation. 

Reaction of 2-[A -(rra -crotyl)-A -benzylamino]-3-formyl-4/f-pyrido[l,2-n]pyrimidin-4-one (269) with chiral primary amines 270 and 271 gave mixtures of diastereoisomers of tetracyclic compounds 273 and tricyclic 275 (96T131]]). The chiral centers in 272 and 274 did not provide any stereocontrol for the formation of diastereomers 273 and 275, respectively. 

Flash vacuum thermolysis of 2-dialkylamino-4//-pyrido[l, 2-u]pyrimidin-4-ones 126 (X = NMe2, NEt2) at 850 °C led to the formation of 4H-pyrido[],2-u]pyrimidin-4-one (Scheme 13). The product was identified by NMR and GC-MS (99JCS(P2)1087). 

Treatment of 8-azidomethylperhydropyrido[l,2-f]pyrimidin-l-one 127 with MeOTf and catalytic hydrogenation of the azide group led to the formation of the tricyclic guanidine derivative 128 (Equation 23) <2001JA8851, 2002JA3939>. A similar tricyclic compound was prepared from an 8-azidomethyl-l-methoxy-4,4a,5,6,7,8-hexahy-dro-37/-pyrido[l,2-f]pyrimidine under catalytic hydrogenation conditions over Pd/C catalyst <2002JA4950,... 

Several studies deal with the reactivity of 2,4-disubstituted-6-aminopyrimidines, which have competing sites for ring formation with 1,3-biselectrophiles. Treatment of 2,4,6-triaminopyrimidine with ethyl acetoacetate in acetic acid formed the pyrimido[l,6-tf]pyrimidin-4-one 216, while the expected pyrido[2,3-r/]pyrimidin-7-one 217 was obtained under thermal conditions (Scheme 34) <1999JOC634>. 

The reaction of 2-aminopyridine with 2-chloropyridine 102 furnishes pyrido[l,2- 3,2- ]pyrimidine derivative 104 in good yield (Scheme 10) <1998T5775, 2003CHE328>. The first step is quaternization with the formation of salt 103. Then 103 undergoes intramolecular cyclization with participation of cyano and amino groups. 

Classical methodology was used to prepare the dibenz[b,f]azepine derivative 21 (R = substituted pyrido[2,3-d]pyrimidine) utilising amide ion formation from dibenz[b,f]azepine itself with sodium hydride and then iV-alkylation with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine. The bulky bis-fused azepine moiety was required to introduce steric bulk in the system and to study the effect of this on inhibition of the enzyme dihydrofolate reductase <00JHC921>. 

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