Pyridine Pyridopyrimidines

There appear to be no reports of direct radical attack on the pyridopyrimidine ring system, but radical bromination of methyl substituents in the 7-position of the pyridine ring has been utilized in the synthesis of deaza analogues of natural products (62JCS4678, 79JHC133). 

The vast majority of this type of cyclization start from pyridines. One obvious route converts o- acylaminopyridine acids, esters or their equivalents to pyridopyrimidines using a one-atom ammonia or amine fragment, e.g. (173) (174). Examples are known mainly... 

The pyridopyrimidines discussed in this review are derived by the ortho fusion of the pyridine and pyrimidine rings through ring carbon atoms. There are four such compounds for which the nomenclature and numbering of Chemical Abstracts (1-4) will be used. Alternative names used in the literature are 1,3,8-triazanaphthalene (1), 1,3,5-tri-azanaphthalene (2), 1,3,7-triazanaphthalene or copazoline (3), and 1,3,6-triazanaphthalene (4). There has been no previous review of the... 

This is the least investigated system and the few known derivatives have been synthesized from 3,4-disubstituted pyridines (routes i or ii). The first recorded pyridopyrimidine of any system was pyrido[3,4-d]-... 

The intramolecular displacement of the pyrimidine chloride by a tethered pyridine, as in substrate 42 or various other nitrogen-containing heterocycles, was reported by Vdovenko and co-worker to produce a variety of condensed pyridopyrimidines such as compound 43 <00T5185>. 

Two complementary routes to the synthesis of pyrido[, y-i/ pyridazines have been developed, the first of which begins by constructing the pyridine ring, and the second by constmcting the pyridazine ring. In addition, ring transformations of pyrrolopyridine, pyridooxazine, pyridopyrimidine, and tetrazine derivatives to the pyrido[x,y-t7 pyridazines have also been reported. 

Reaction of 2-amino-3,5-dicyano-6-substituted pyridine derivatives with formamide led to pyridopyrimidines 365 <1993JHC253>. 

It has been reported that compounds bearing the pyrido[2,3- pyrimidine moiety such as RS-25344 766 exhibited excellent PDE 4 inhibitory activity <1994MI510>. Pyridopyrimidine analogues 767 bearing substituents at C-3 and/ or C-4 positions on the pyridine ring were found to be potent PDE 4 inhibitors <2001BML611>. 

The vast majority of this type of cyclization start from pyridines. One obvious route converts o- acylaminopyridine acids, esters or their equivalents to pyridopyrimidines using a one-atom ammonia or amine fragment, e.g. (173) -> (174). Examples are known mainly in the pyrido[2,3-rf]pyrimidine field (e.g. 73GEP2248497, 74MI21502) but also in [3,4-d] and [4,3-rf] cases (74GEP2348U1). Sometimes pyridooxazine intermediates similar to (113) are involved, especially in the few examples with pyrido[3,2-rf]pyrimidines (65JCS4240). 

The hydroxy group of 3-(2-hydroxyethyl)-47/-pyrido[l,2-a]pyrimidin-4-one 104 was mesylated by mesyl chloride in pyridine at 0°C, then the mesylated derivative 446 was reacted with 1,2-benzisoxazole hydrochloride 447 in methanol in the presence of diisopropylamine at 60°C for 68 hours to yield 3-(2-aminoethyl)pyridopyrimidin-4-one derivative 448 (91EUP453042). 

Acting as 1,3-biselectrophile in a combined substitution and condensation, different tertiary aminopropenones give the corresponding pyridopyrimidines after treatment with aminouracil, diaminohydroxypyiimidine or aminothiouracil in acetic acid (equation 150). This is similar to the reaction of aminoacroleins with 1,3-dicarbonyls to give pyridines. 

In addition to several general reviews on enamine chemistry, all of which include heterocyclic syntheses, there is an extensive survey by Hickmott which is entirely concerned with the formation of heterocycles. More specialized reviews deal with heterocyclic enamines, enaminones, the photochemistry of enamides , heterocyclic jS-enamino esters , enamino thiones , the synthesis of indole alkaloids via enamines , formation of pyrimidines, pyridopyrimidines, pyridines and pyrrolizines from enamines , synthesis of lactams , formation of heterocycles from cyclic enamino ketones and 2-acetylcyclohexen-l-ones, the synthesis of 3-cyano-2(l -pyrimidine-thiones and -selenones from jS-enamino ketones and the chemistry of cyclic en-aminonitriles. ... 

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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