Pyrido 2,3-</ pyrimidines, halogenation

Aminopyridines and the lactone (43) in polyphosphoric acid at 160 C gave 3-(2-hydroxyethyl)-4-oxo-4//-pyrido[l,2-a]pyrimidines (44). At lower temperature (120 C) the furan derivative (46) was formed.65 When effected with phosphoryl halides (POCl3 or POBr3), reaction of 2-aminopyridines and 43 afforded products of type 44 where the hydroxyl group was replaced by a halogen atom.49-83,85... 

The C-3 atom of 4-oxo-4/f-pyrido[l,2-a]pyrimidines readily takes part in electrophilic substitutions. 4-Oxo-4//-pyrido[ 1,2-a]pyrimidines unsubstituted at position 3 may be transformed by nitrating agents to the 3-nitro derivatives37 42,52 96,1 16,293 and by halogenating agents to the 3-halo derivatives.18,34 108 253,255,294 Nitration of 2-benzyloxy-4-oxo-4H-pyrido-[ 1,2-a] pyrimidine was accompanied by debenzylation.116 Halogenation of the pyrido[l,2-a]pyrimidine (63 R = H) under forced conditions afforded the 2,3-dichloro derivatives.253,255... 

Depending on the molar ratio, halogenation of 4-oxo-6,7,8,9-tetra-hydro-4//-pyrido[l,2-n]pyrimidines gave 9-halo or 9,9-dihalo compounds.75,133,316-319 9-Bromo- or 9-chloro-6-methyl-4-oxo-6,7,8,9-tetra-hydro-4if-pyrido[l,2-a]pyrimidine-3-carboxylic acids were obtained as 4 1 mixtures of the thermodynamically more stable 6,9-diaxial and the 6-axial, 9-equatorial-substituted diastereoisomers.317... 

Investigations of the chiroptical properties of 9-halogen derivatives of 6-methyltetrahydro-4//-pyrido[ 1,2-a]pyrimidin-4-ones 28 (X and X1 = Cl, Br) established that the sign of the most characteristic CD bands is determined by the axial halogen atom in position 9 to the inherently achiral pyrimidinone chromophore (87JHC393). 

Conformational analysis of some 9-chloro- and 9-bromo-6,7,8,9-tetrahy-dro-4//-pyrido[ 1,2-a]pyrimidin-4-ones 31 and their 9,9-dichloro and 9,9-dibromo derivatives was also carried out by I3C NMR spectroscopy (83JHC619). The halogen atoms in the 9-chloro and 9-bromo derivatives 31 (R = H) in the predominantly half-chair conformation occupy the pseudoaxial position. This conformer is probably stabilized by a favorable orbital interaction, while the other one, with a presudoequatorial halogen atom, is destabilized by the unfavorable dipole-dipole interaction between the 9-halogen and C(9a)=N(l) bonds. The methyl group in the 6-methyl derivatives in predominantly half-chair conformations is in the pseudoaxial position (83JHC619). 

The halogen atom at position 2 of 4-oxo-4//-pyrido[ 1,2-a]pyrimidin-4-ones 370 easily reacts with N- and O-nucleophiles to yield 2-amino- and 2-alkoxy-4H-pyrido[l,2-tf]pyrimidin-4-ones (82FES747 86JHC1295 ... 

Chloropyrido[l,2-a]pyrimidin-4-ones 399 (R = Me, Cl R1 = 6-Me X = Cl) were prepared in excellent yields when 3-unsubstituted derivatives reacted with phosphorus pentachloride in phosphoryl chloride at 105-110°C for 1.5 hours (85JHC481). Other 3-bromo- and 3-chloro-2-(chloromethyl)-4//-pyrido[l,2-a]pyrimidin-4-ones were also prepared from 3-unsaturated derivatives with halogenation agents (e.g., with N-chlorosuccinimide (NCS) in a mixture of carbon tetrachloride and ethyl acetate) (83EUP81945). 

The hydroxy group of 4-oxo-4//-pyrido[l,2-a]pyrimidine-3-alcohols may be exchanged for a halogen or transformed to a tosyloxy ... 

The most important method for the introduction of halogen substituents into pyrido[2,3-c/]-pyrimidines 5 is the reaction of pyridone or pyrimidone functions with halogenating agents such as phosphoryl halides39-77,79 131, l34,200,237,332 or thionyl chloride238,333,569 to furnish the corresponding halogen compounds 6. 

Halogen, mostly chlorine, in the pyrimidine part of pyrido[2,3-J]pyrimidines may be displaced by amino groups.77,79, i34--24-8.34.4-149... 

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