Agnes Horvath

Nitrogen bridgehead compounds. 44. New antiallergic 4H-pyrido[1,2-a]pyrimidin-4-ones. 4

The weak antiallergic activity of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carbox yli c acid (1) in the rat reaginic passive cutaneous anaphylaxis test was enhanced by the introduction of an (arylamino)methylene moiety into position 9 of the pyridopyrimidine ring. Compound 34, (+)-6(S)-methyl-9-[(m-methylphenyl)-hydrazono]-4-oxo-4H-pyrido[1,2 -a] pyrimidine-3-carboxylic acid, displayed about 10 000 times the activity of the starting compound 1. A structure-activity relationship study of 9-[(arylamino)methylene]tetrahydropyridopyrimidine-3-carb ox ylic acids resulted in conclusions similar to those found for the 9-(arylhydrazono)tetrahydro-and 9-(arylamino)dihydropyridopyrimidine series. Replacement of the 3-carboxy group of 9-(phenylhydrazono)-tetrahydropyridopyrimidin-4-ones with an acrylic acid moiety caused slight increases in potency. In the 6-methyl-substituted series, a high stereospecificity was observed between the enantiomers with 6S and 6R absolute configurations, the former being responsible for the antiallergic activity. The effects of some 9-[(arylamino)-methylene]tetrahydropyridopyrimidine-3-car box ylic acids on the rat passive peritoneal anaphylaxis test were also investigated.

Nitrogen bridgehead compounds. Part 4. 1 → 3 N→C-acyl migration. Part 2

Ring closure of 2-substituted 3-(2-pyridylamino)acrylates (1) in phosphoryl chloride–polyphosphoric acid gives pyrido[1,2-a]pyrimidines (2), whereas (6-substituted 2-pyridyl) derivatives in Dowtherm A afford pyrido[1,2-a]-pyrimidines (2) and 1,8-naphthyridines (3). The 6-substituted pyrido[1,2-a]pyrimidines (2) can be converted thermally into 1,8-naphthyridines (3) by 1 → 3 N→C-acyl migration. Similar acyl migrations can be observed in other such systems.

Nitrogen bridgehead compounds. Part 30. Vilsmeier–Haack formylation of 6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones

Depending on the substituents at C(3) and on the reaction conditions, Vilsmeier–Haack formylation (POCl3–DMF) of 6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones (I) led to 9-(dimethylamino-methylene)- or 9-(ethoxymethylene)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidines (II) and (IV), respectively, or 9-formyl-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidines (III). Compounds (II) may be converted into (III) or (IV). Owing to the enhanced activity of their 9-CH2 group, the 3-carboxylic acid derivatives of (I) form compounds (II) even on the action of dimethylformamide diethyl acetal, and compounds (IV) on the action of triethyl orthoformate in Ac2O. Compounds (III) may be converted back into (I) by hydrolysing the 9-formyl group. Their spectral data show that compounds (II) and (IV) exist exclusively in the E-configuration, and compounds (III) predominantly in the 1,6,7,8-tetrahydrotautomeric form.

Nitrogen bridgehead compounds. Part 82. An unexpected ring transformation of 6-hydrazono-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidine-3-carboxylates

Treatment of 9-hydrazono-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates with the Vilsmeier-Haack reagent gave unsaturated 7-substituted 9-amino-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylates in a degenerate ring transformation, probably through ring opening via the N(5)-C(6) bond

Tautomerism of 9-formyltetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones and their ring homologues: a 1H, 13C, and 15N nuclear magnetic resonance study

By 1H, 13C and 15N n.m.r. studies we have established that tautomeric equilibria of 9-formyl-tetrahydro-4H-pyrido[1,2-a]pyrimidines and their homologues are controlled mainly by the size of the ring containing a single nitrogen atom. Thus in the pyrrolo analogues the enol imine form is predominant, with the azepino homologues the enamine, and with the azocino analogues the imine. The enol imine–enamine interconversion is relatively fast, whereas the imine–enamine interconversion is slow on the n.m.r. time-scale. The relative stabilities of the individual tautomers are explained by stereo-chemical factors and hydrogen bonding.

Nitrogen bridgehead compounds. Part 29. Tautomerism and Z–E isomerism of ethyl 9-aminomethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates and their homologues

1 H and 13C n.m.r. studies have proved that ethyl 9-dimethylaminomethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates (2)–(5) and the corresponding pyrrolo homologue (6) exist in the form of E-isomers whereas the azepino[1,2-a]pyrimidine derivative (7) appears as an equilibrium mixture of Z-and E-isomers. On the basis of 15N chemical shifts an analogous tautomeric structure has been established for the 9-dimethylaminomethylene derivatives (2)–(7) and the ethyl 9-arylaminomethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates (8)–(12) as well. 15N Shifts were sensitively affected by the Z–E isomerism and structural changes in remote parts of the molecule, too. Protonation of compounds (2)–(12) takes place on the N(1) atom, forming a 1,6,7,8-tetrahydro structure.

Nitrogen bridgehead compounds. Part 5. Cyclization of 2-(2-pyridylaminomethylene)-succinates and -glutarates

A study has been made of the cyclization reactions of some 2-(2-pyridylaminomethylene)-succinates (7) and -glutarates (8) in phosphoryl chloride–polyphosphoric acid. In the cyclization of the succinates (7) we have found that of the possible cyclic products pyrido[1,2-a]pyrimidines (9) and pyridylpyrrolinones (13) are formed, and the latter, subsequently, may form pyridylpyrroles (15) although the reaction conditions favour the formation of pyridopyrimidines (9). The ratio of pyridopyrimidines (9) and pyridylpyrroles [(13) : (15)] was independent of the geometry of the starting succinates (7), but was dependent upon the substituent of the pyridine ring, and on its position. Substituents in position 6 hindered the formation of pyridopyrimidines (9) while those in position 3 inhibited the formation of pyridylpyrrolinones (13). From the homologous glutarates (8) only pyrido[1,2-a]pyrimidines (10) are formed.

Isomerism of 9-arylaminomethylene-6,7,8,9-tetrahydro-4-oxo-4H-pyrido[1,2-a]pyrimidines

Several 9-arylaminomethylnene-6,7,8,9-tetrahydro-4-oxo-4H-pyrido[1,2-a]pyrimidines have been synthesized and studied by 1H and 13C n.m.r. spectroscopy. The dominant tautomeric form has been established. Fast Z–E isomerisation has been found around the enamino CC double bond. The effect of the solvent, temperature, and various structural modifications on the equilibrium Z : E isomeric ratios has been measured.

Nitrogen bridgehead compounds. Part 64. Protonation of 9-formyltetrahydropyrido[1,2-a]pyrimidin-4-ones and their analogues

As shown by 1H, 13C, and 15N n.m.r. spectroscopy, protonation of 9-formyltetrahydropyrido[1,2-a] pyrimidin-4-ones takes place at the formyl oxygen atom. As a result, the enamine tautomer, predominant in the base form, is transformed into a protonated enolimine tautomer having an exocyclic double bond. 15N N.m.r. shifts reflect not only the state of the tautomeric equilibria but also the state of Z/E isomerism and the effect of remote substituents.

Nitrogen bridgehead compounds. Part 34. A study of tautomerism in 9-formyltetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones by 1H, 13C, and 15N nuclear magnetic resonance spectroscopy

It has been established (1H and 13C n.m.r.) that for 9-formyltetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones the tautomeric system imine ⇌ enamine ⇌ enol-imine [(A)⇌(B)⇌(C)] is dominated by form (B) which is stabilized by internal hydrogen bonds. The presence of ca. 15% of (C) in the equilibrium was shown by 15N n.m.r. While no (A) could be detected.