Zoltan Meszaros

Nitrogen bridgehead compounds part 16. Facile total synthesis of 7,8-dihydro-13H-indolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-one (Rutecarpine).☆

Rutecarpine 1 has been synthetised from hydrazone 2, in high yield by Fischer indole synthesis, Hydrazone 2 has been prepared from 3 with benzenediazonium chloride or 5 with phenylhydrazine. 2 Shows a solvent dependent E-Z isomerism.

Chemistry of Pyrido[1,2-a]pyrimidines

Publisher Summary This chapter surveys the primary chemical literature of Pyrido [1,2- a ]pyrimidines. Certain types of pyrido[1,2- a ]pyrimidines have aroused much interest owing to their valuable pharmacological properties. They are also used as synthetic intermediates or as additives to photographic materials and dyes. The chapter presents methods for the preparation of different pyrido[1,2-a]pyrimidines such as (1) pyrido[1,2- a ] pyrimidinium salts, (2) 2-oxo-2 H -pyrido[1,2- a ]pyrimidines, (3) 4-oxo-4 H -pyrido [1,2- a ]pyrimidines, (4) 3,4-dihydro-2 H -pyrido[1,2- a ]pyrimidines (5) 2-oxo-3,4-dihydro-2 H - and 4-oxo-2,3-dihydro-4 H - pyrido[1,2- a ]pyrimidines, and (6) miscellaneous pyrido[1,2- a ]pyrimidines. In addition, the chapter discusses the stability of the bicyclic ring system; and the hydrogenation, reduction, dehydrogenation, oxidation, and quaternization of the compounds. The substitution reactions affecting the pyrido[1,2- a ]pyrimidine ring, transformations of the side chains, and ring transformation reactions are outlined and the characteristic physicochemical properties of pyrido[1,2- a ]pyrimidines are enlisted in the chapter. Pyrido[1,2- a ]pyrimidines are being studied because of the valuable biological properties.

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.

Saturated heterocycles. Part 88. Synthesis of a new ring system: dipyrido[1,2-a:4,3-d]pyrimidin-11-one derivatives

The synthesis of 1,2,3,4-tetrahydro-11H-dipyrido[1,2-a:4,3-d]pyrimidin-11-one derivatives (6a–s), a new class of ‘pyracridones’, i.e. 2-azapyracridones, was performed by the condensation of 3-methoxycarbonyl-4-piperidones (5) and 2-aminopyridines in polyphosphoric acid. Catalytic reduction of compounds (6) or ring closure of (5) with 2-iminopiperidine was found to give the 1,2,3,4,6,7,8,9-octahydro-11H-dipyrido[1,2-a:4,3-d]pyrimidin-11-ones (7a)–(7c). The seven-membered ring C homologue derivatives (7d), (7e) have also prepared by the latter method.

Studies on naphthyridines. An unexpected product in Hantzsch pyridine synthesis

Besides the expected pyridinedicarboxylate (4), triethyl 2,7,8a-trimethyl-1,4,4a,5,8,8a-hexahydro-1,8-naphthyridine-3,4a,6-tricarboxylate (6) was also isolated in the Hantzsch pyridine synthesis starting from ethyl acetoacetate and hexamethylenetetramine in acetic acid. The 1,8-naphthyridine (6) was probably formed in the [4 + 2]cycloaddition of heterodiene (5) and the 1,4-dihydropyridinedicarboxylate (3). The observed regioselectivity was explained in terms of simple Huckel molecular orbital calculations. Diethyl 2,6-dimethylpyridine-3,5-dicarboxylate (4) gave ethyl 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (9) in high yield in a one-step reaction with 1,3,5-triazine in the presence of ethanolic sodium ethoxide, or in a two-step procedure with DMF diethyl acetal followed by ring closure with ammonia.

Nitrogen bridgehead compounds. Part 45 [1]. Synthesis of 6-arylhydrazono-6,7,8,9-tetrahydro-11H-pyrido-[2,1-b]quinazolin-11-ones

Die Herstellung zahlreicher 6-Arylhydrazono-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]chinazolin-11-one der allgemeinen Formel (III) erfolgt nach verschiedenen Wegen.

Nitrogen bridgehead compounds. Part 6. Ring transformation. Part 3. Thermal cyclization of diethyl 2-(2-pyridylaminomethylene)-succinates and -glutarates

The pyridylsuccinates (1) and pyridylglutarates (2), with various substituents on the pyridine ring, were cyclized in Dowtherm A at 250 °C. The succinates cyclized in two competing reaction routes, giving rise to pyrido[1,2-a]pyrimidines (route A) and N-pyridylpyrrolinones (route B). The ratio of the two products varied with the nature of the substituent and its position. The N-pyridylpyrrolinones proved to be mixtures of the desmotropes (5) and (6) which were separated. The pyridylglutarates (2) gave only the pyrido[1,2-a]pyrimidines (4). The 6-substituted pyrido[1,2-a]pyrimidines underwent a ring-transformation reaction at or above 250 °C, forming the corresponding 1,8-naphthyridines (8) and (9).

Saturated heterocycles, 75. Preparation of tetracyclic thiophene derivatives with bridgehead nitrogen. Synthesis of polymethylenethieno[2,3—d]dihydropyrrolo-, tetrahydropyrido- and tetrahydroazepino[1,2—a]pyrimidin-4-ones and -4-thiones

The following tetracyclic ring systems and their derivatives have been synthesized for pharmacological investigations: Trimethylenethieno[2,3—d]dihydropyrrolo[1,2—a]pyrimidin-4-one and -4-thione (1 a, 5 a); Tetramethylenethieno[2,3—d]dihydropyrrolo[1,2—a]pyrimidin-4-one and -4-thione (1 b, 1 j, 5 b); Pentamethylenethieno[2,3—d]dihydropyrrolo[1,2—a]pyrimidin-4-one and-4-thione (1 c, 5 c); Trimethylenethieno[2,3—d]tetrahydropyrido[1,2—a]pyrimidin-4-one and -4-thione (1 d, 5 d); Tetramethylenethieno[2,3—d]tetrahydropyrido[1,2,—a]pyrimidin-4-one and -4-thione (1 e, 5 e); Pentamethylenethieno[2,3—d]tetrahydropyrido[1,2—a]pyrimidin-4-one and -4-thione (1 f, 5 f); Trimethylenethieno[2,3—d]tetrahydroazepino[1,2—a]pyrimidin-4-one and -4-thione (1 g, 5 g); Tetramethylenethieno[2,3—d]tetrahydroazepino[1,2—a]pyrimidin-4-on and -4-thione (1 h, 5 h); Pentamethylenethieno[2,3—d]tetrahydroazepino[1,2—a]pyrimidin-4-one and -4-thione (1 i, 5 i); Tentamethylenethieno[2,3—d]tetrahydroazepino[1,2—a]pyrimidin-4-one (7 b); Pentamethylenethieno-[2,3—d]tetrahydropyrido[1,2—a]pyrimidin-4-one (7 c).Compounds1 a–i were synthesized from 2-amino-3-ethoxycarbonyl-4,5-polymethylenethiophene2 a–c with the corresponding lactim ethers (3 a–c) in chlorobenzene in the presence of polyphosphoric acid (PPA). Compounds7 b and7 c were obtained in the reaction of β-amino acid esters2 b and2 c with 2-bromopyridine (6). The thione derivatives (5 a–i) were prepared from compounds1 a–i with phosphorus(V) sulphide.ZusammenfassungFür pharmakologische Untersuchungen synthetisierten wir die folgenden tetracyclischen Ringsysteme und deren Derivate: Trimethylen-thieno-[2,3—d]dihydropyrrolo[1,2—a]pyrimidin-4-on und -4-thion (1 a, 5 a); Tetramethylen-thieno[2,3—d]dihydropyrrolo[1,2—a]pyrimidin-4-on und 4-thion (1 b, 1 j, 5 b); Pentamethylen-thieno[2,3—d]dihydropyrrolo[1,2—a]pyrimidin-4-on und-4-thion (1 c, 5 c); Trimethylen-thieno[2,3—d]tetrahydropyrido[1,2—a]pyrimidin-4-on und -4-thion (1 d, 5 d); Tetramethylen-thieno[2,3—d]tetrahydropyrido-[1,2–a]pyrimidin-4-on und -4-thion (1 e, 5 e); Pentamethylen-thieno[2,3—d]tetrahydropyrido[1,2–a]pyrimidin-4-on und -4-thion (1 f, 5 f); Trimethylenthieno[2,3—d]tetrahydroazepino[1,2—a]pyrimidin-4-on und -4-thion (1 g, 5 g); Tetramethylen-thieno[2,3—d]tetrahydroazepino[1,2—a]pyrimidin-4-on und -4-thion (1 h, 5 h); Pentamethylen-thieno[2,3—d]tetrahydroazepino[1,2—a]pyrimidin-4-on und -4-thion (1 i, 5 i); Tetramethylen-thieno[2,3—d]-tetrahydropyrido[1,2—a]pyrimidin-4-on (7 b); Pentamethylen-thieno[2,3—d]-tetrahydropyrido[1,2—a]pyrimidin-4-on (7 c).Die Verbindungen1 a–i wurden aus 2-Amino-3-(ethoxycarbonyl)-4,5-polymethylenthiophenen (2 a–c) mit den entsprechenden Lactimethern in Chlorbenzol mit Polyphosphorsäure-Katalysator dargestellt. Die Verbindungen7 b und7 c wurden aus β-Aminosäureestern2 b–c und 2-Brompyridin (6) synthetisiert. Die Thionderivate (5 a–i) erhielten wir durch die Reaktion der Verbindungen1 a–i mit Phosphor(V)-sulfid.

Nitrogen bridgehead compounds part 21. Preparation of new quaternary 2,3a,6a-triazaphenalenium salts

Abstract The first representatives of a new ring system, the 2,3a,6a-triazaphenalenium quaternary salts are prepared by the cycloaddition of tetrahydro-4H-pyrido[1,2-a] pyrimidin-4-ones containing an α-chloroenamine moiety with azomethines.