4- Aminopyrimidines pyrido pyrimidine

A rare type of reaction involves the photocyclization of the 5-(unsaturated acyl)aminopyrimidines (168) to reduced 7-methylpyrido[3,2-Similar reactions are known involving related 4-aminopyrimidine derivatives, leading to pyrido[2,3-[Pg.221]

There are two main classes here. Firstly, 5-substituted 4(6)-aminopyrimidines, e.g. the 5-ester (227), are reacted with esters in the presence of sodium (63CB1868), or with acetals in the presence of alkoxide (78KGS1549), to give pyrido[2,3-Keto esters give 6-ketones (229) (80USP4215216), whilst use of aminopyrimidine nitriles gives 7-oxo-5-amino derivatives (81USP4245094). 

The only other pyrimidine-based preparation of pyrido[3,2-d]pyrimidines involves reaction of 5-aminopyrimidine with crotonaldehyde to give (255) (70JHC1219). 

Reaction of 3-formyM/7-pyrido[ 1,2- ]pyrimidin-l-ones with hydroxylamine O-sulfonic acid at 5 °C, then 50 °C yielded 3-nitriles <2003T4113>. Treatment of 2-hydroxy-3-(dimethylamono)methyF4//-pyrido[l,2- ]pyrimidin-4-one with Mel, then with KCN gave the 3-cyanomethyl derivative <2004MI215>. A condensation product was obtained from 5-amino-l-ethyl-6-hydroxy-l,3-dihydrobenzimidazol-2-one and 3-lbrmyl-2-hydroxyA//-pyndo[ 1,2- ]pynmidin-l-one <2002W002/38549>. l-(2-Aminopyrimidin-4-yl)-8-phenyl-l,2,3,4-tetrahydro-6//-pyrido[l,2- ]pyrimidin-6-ones were prepared from l-(2-methylthiopyrimidin l-yl)-8-phenyl-l,2,3,4-tetrahydro-6//-pyrido[l,2- ]pyrimidin-6-one by treatment with MCPBA, and then with aralkylamines <2005W005/070932>. 

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>. 

Reaction of 2-oxo-4-thioxo-6-aminopyrimidine and the biselectrophile 218 under base catalysis formed either the pyrimido[l,6- ]pyrimidine 219 or the pyrido[2,3-<7]pyrimidine 220, depending on the X subsituent in 218. The N-bridgehead compound 219 formed if X = CONH2, CC Et, COPh, while 220 was obtained when X = CN, CSNH2 (Scheme 35) <2000HC0301>. 

Kappe et al. reported the microwave-assisted synthesis of pyrido[2,3-ri ]pyrimidines via a one-pot three component cyclocondensation of a,(3-unsaturated esters, amidines and malonitrile (or ethyl cyanoacetate) (Scheme 3.45)71. Quiroga et al. reported a similar three component cyclocondensation to synthesise regiospecif-ically 5,8-dihydropyrido[2,3-ri ]pyrimidines under solvent-free conditions, starting from a combination of aminopyrimidin-4-ones, benzoylacetonitrile and benzaldehyde (Scheme 3.45)72. 

The methods in this subsection utilize intramolecular cyclizations of 4-aminopyrimidine derivatives to give the pyrido[2,3-rf]pyrimidines. The functional group may exist on the 4-amino group or at the 5-position of the pyrimidine. 

Three general approaches to the synthesis of pyrido[2,3-d]pynmi-dines from pyrimidines are available, all of which utilize an appropriately substituted 4-aminopyrimidine. The pyridine ring may be formed by the addition of three (route i), or two (route ii) carbon atoms, or by the intramolecular cyclization of a propionyl derivative (route Hi). 

Amino-4-(3-oxoalkyl)-5-(phenyldiazenyl)pyrimidin-4(3//)-one I, prepared by azo coupling of the corresponding 2-aminopyrimidin-4(3W)-one and subsequent catalytic hydrogenation or reduction by dithionile, cyclizes to afford the fully aromatic 6-alkyl-2-aminopyrido[3,2-c/]pyrimidin-4(3//)-one 2.437,438 Pyrido[3,2-r/]pyrimidin-4(3//)-one 2 is probably formed via air oxidation of the expected 7,8-dihydro intermediate, since intentional treatment with air during workup seems to improve the yield.438... 

A further convenient synthesis is that developed by Taylor and Garcia who showed that pyrido[2,3-d]pyrimidines (86 and 87) were obtained by the action of malononitrile on 5-acetyl-4-aminopyrimidin-6(lJ )-one or 4-amino-5-benzoyl-l-methylpyrimidin-6(lff)-one. 

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