Heterotricyclic systems. Part I. Synthesis of new dipyridopyrazines

Pursuing our previous research on azaquinoxalinones (1,2-dihydropyrido[2,3-b]/[3,4-b]pyrazinones) we prepared, through a reductive cyclization of N-(3′-nitropyridin-2′-yl)piperidine-2-carboxylic acids 3a-c , a set of derivatives of a new tricyclic structure, 7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-ones 4a-c. Starting from these compounds we obtained substituted amides 5a-c and, from 4a , the amidines 6a-c. In the synthesis of 6 , a dehydrogenation reaction occurred giving rise to 7. The compounds 9 and 10 , characterized by a different ring-fusion between the pyridine and pyrazine rings, were synthesized in a similar manner.     

Tricyclic heteroaromatic systems. 1,2,3,4-tetrahydropyrazolo[4,3-c][l]benzazepin-1-ones as potential antitumor agents

The synthesis of 1,2,3,4-tetrahydropyrazolo[4,3-c][1]benzazepin-1-ones 1 and that of its 10-methyl derivative 2 is reported. The preparation of the latter from 3-(2-aminobenzyl)3-pyrazolin-5-one and triethyl ortho-formate gave as the main product a derivative of the new tricyclic ring system, pyrazolo[1,5-c][1,3]benzo-diazepine. The structures of the new compounds synthesized were assigned by means of a ¹³C nmr study.     

New heterocyclic ring systems. XIII. 7,11-Dithiaazasteroid analogues

Synthesis of the tittle compounds has been achieved starting with the new tricyclic ring, 6-methyl-4-oxo-3,4-dihydro-2H,6H-thiopyrano[3,2-c][2,1]benzothiazine 5,5-dioxide (III). This compound was converted to the glyoxylate VI, the β-ketoester IX, a difluoride complex XIII and an enamino ketone XXIV which, by hydrazine, hydroxylamine and glycine treatment, gave 7,11-dithiaazasteroid analogues. Some unexpected products were also obtained from the ketone XVIII and the β-diketone XIX by treatment with chloroacetone and hydrazine respectively.     

Fused-ring systems containing 1,2,4-benzo thiadiazines. II. Reactions of o-amino-n-hydroxybenzenesulfonamides

o-Amino-N-hydroxybenzenesulfonamides have been treated with aldehydes to prepare 2-hydroxy-1,2,4-benzothiadiazine 1,1-dioxides. These products have permitted the fusion of an additional ring to the “b” face of the benzothiadiazine. Analogs of the tricyclic compounds have been made in other ways.     

Benzimidazole condensed ring systems. 2. New synthesis of substituted 1-oxo-1H,5H-pyrido[1,2-a]benzimidazole-4-carbonitriles and related derivatives

The synthesis of some 3-substituted and 2,3-disubstituted-1-oxo-1H,5H-pyrido[1,2-a]benzimidazole-4-carbo-nitriles 5,6 by fusing 1H-benzimidazole-2-acetonitrile 1 with some β-keto esters 2,4 in the presence of ammonium acetate or with ethyl β-aminocrotonate 3 is described. The tricyclic compounds were converted to their N-5 methyl of N-5 ethyl derivatives 8,9. Vilsmeir-Haack formylation of 3-methyl-1-oxo-1H,5H-pyrido[1,2-a]-benzimidazole-4-carbonitrile 5a afforded its 2-formyl derivative 10. Chlorination of 5 and 6 with phosphorus oxychloride yielded the respective 1-chloropyrido[1,2-a]benzimidazole-4-carbonitriles 11,12 which were utilized to prepare the 1-azido, 1-amino, 1-piperidino and 1-methoxy derivatives of the ring system. Compound 11a exhibited strong in vitro activity against S. aureus. Four compounds were screened against P-388 lymphocytic leukemia in mice but were inactive.     

Synthesis of new tricyclic ring systems containing the pyrimido[5, 4-b][1, 4]oxazine skeleton

Synthesis of derivatives 4 and 6 of two novel tricyclic ring systems, 1, 2, 4-triazolo[3, 4-c]pyrimido[5, 4-b]-[1, 4]oxazine and imidazo[1, 2-c]pyrimido[5, 4-b][1, 4]oxazine, respectively is described. Although the parent pyrimido[5, 4-b]oxazines possess positive inotropic activity, the tricyclic compounds are practically inactive.     

Novel heterocycles. 3. Synthesis of fused 1,3,2-benzodiazaphosphorin ring systems

Novel fused tricyclic phosphorus heterocycles 9 and 11 and the tetracycle 15 were synthesized by cyclization of 1-haloalkyl (or 3-haloalkyl)-2,3-dihydro-1,3,2-benzodiazaphosphorin-4(1H)one 2-oxides with sodium hydride. Some spectral data of the products are also discussed.     

Synthesis of certain tricyclic quinoline derivatives as potential antiamebal agents

Synthesis of the fused tricyclic systems, 1, 2, 3, 3a, 4, 5-hexahydropyrrolo[1, 2a]quinoline (I) and 2, 3, 4, 4a, 5, 6-hexahydro 1H-benzo[c]quinolizine (II), each bearing an ethoxyl substituent on the benzene ring, has been achieved. The compounds combine certain structural features of the alkaloid emetine and of 8-quinolinols.     

Synthese von racemischen,isomeren Desoxo-4, 14-didemethyl-cassain-Derivaten. 4. Mitteilung über Cassain-Analoga

For the synthesis of demethyl analogues of Erythrophleum alkaloids, the tricyclic ketone 14 (trans-anti-trans) was prepared. The Horner reaction on 14 led to a mixture of cis/trans compounds, which could be separated into the homogeneous racemic isomers 21 and 22 . These compounds were transformed into the corresponding 2-dimethylamino-ethyl esters of their 3-dehydro and 3-O-carbamoyl derivatives.     

Quinazolines et benzodiazépines-1,4. LX Imidazo[5,1-c]benzodiazépines-1,4

Upon treatment with oxalyl chloride followed by reaction with the appropriate nucleophile, the 3-carbamoyl-benzodiazepines 6 , 7 and 8 were converted stereospecifically to the tricyclic compounds 12, 13, 14, 16 and 19 . Epimerization of 19 in presence of p-toluenesulfonic acid led to 21 . The stereochemistry of these tricyclic compounds and of some of their N(2)-alkyl derivatives ( 22-31 ) has been established by NMR. spectroscopy. Under proper reaction conditions, attack by bases on the tricyclic esters 13 and 26 was shown to cause an inversion of the chiral center C(11a) and to yield stereospecifically rearranged products, e.g. 23 from 26 and 33 from 13 .     

Synthesis of tricylic systems incorporating the azepine ring

Some tricyclic compounds (derivatives of pyrazino[2,1-a]benzazepine, diazepino[7,1-a]isoquinoline, and some pyrimido[6,1-a]isoquinolines) which are analogs of the anthelmintic praziquantel have been synthesized.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1665–1669, December, 1990.     

Heterocyclic systems. VII Synthesis of 1H-pyrazolo[3,4-e]indolizine derivatives

Suitable 1-phenyl-5-(1-pyrryl)pyrazole intermediates underwent Knoevenagel or Wittig intramolecular olefination to give derivatives of 1H-pyrazolo[3,4-e]indolizine, a hitertho unknown tricyclic heteroaromatic system.     

Chemistry of thienopyridines. XXXVI. Further studies on nitration in the thieno[2,3-b]- and thieno[3,2-b]pyridine systems

Three compounds, thieno[3,2-b]pyridine 4-oxide, 7-nitrothieno[3,2-b]pyridine 4-oxide ( 1 c), and 6-cyano-thieno[2,3-b]pyridine, undergo nitration by means of a mixture of nitric and sulfuric acids to yield 3,7-dinitro-thieno[3,2-b]pyridine (3%), 3,7-dinitrothieno[3,2-b]pyridine 4-oxide ( 1d ) (26%), and 6-carbamoyl-5-nitrothieno[2,3-b]pyridine ( 6b ) (11%), respectively. Structures of the products were ascertained by spectral means, notably infrared, ¹H nmr, and ¹³C nmr. It is proposed that 1d exists (at least in part) as a tricyclic structure and that 6b may result from an intramolecular mechanism of nitration. An attempt to de-N-oxygenate 1c with excess triphenylphosphine removes more than one oxygen atom per molecule (as triphenylphosphine oxide) without producing an identified thienopyridine product.     

Furopyridines. X. Synthesis of tricyclic heterocycles,furo[2,3-b:4,5-c']-, furo[3,2-b:4,5-c']-, furo[2,3-c:4,5-c']- and furo[3,2-c:4,5-c']dipyridine

This paper describes the synthesis of four tricyclic heterocycles, furo[2,3–6:4,5-c']- ( 5a ), furo[3,2-b:4,5-c']- ( 5b ), furo[2,3-c:4,5-c']- ( 5c ) and furo[3,2-c:4,5-c']dipyridine ( 5d ). Starting with 2-formylfuropyridines ( 1a-d ), β-(2-furopyridyl)acrylic acids 2a-d were obtained by condensing with malonic acid. The acrylic acids were converted to the acid azides by reaction with ethyl chloroformate and the subsequent reaction with sodium azide. Heating of the acid azides at 230–240° with diphenylmethane and tributylamine gave tricyclic pyridinones 3a-d , which were converted to the respective chloro derivatives 4a-d by reaction with phosphorus oxychloride. Reduction of the chloro compounds over palladium-charcoal yielded compounds 5a-d respectively. All the compounds 2 to 5 were characterized by elemental analysis and spectral data. The H and ¹³C nmr and electronic spectral features of the furodipyridines were discussed comparing with those of the parent furopyridines.     

Thermal Reaction of Highly Alkylated Azulenes with Dimethyl Acetylenedicarboxylate: HOMO(Azulene) vs. SHOMO(Azulene) Control in the Primary Thermal Addition Step

The reaction of highly alkylated azulenes with dimethyl acetylenedicarboxylate (ADM) in decalin or tetralin at 180–200° yields, beside the expected heptalene- and azulene-1,2-dicarboxylates, tetracyclic compounds of type ‘anti’- V and tricyclic compounds of type E (cf. Schemes 2–4 and 8–11). The compounds of type ‘anti’- V represent Diels-Alder adducts of the primary tricyclic intermediates A with ADM. In some cases, the tricyclic compounds of type E also underwent a consecutive Diels-Alder reaction with ADM to yield the tetracyclic compounds of type ‘anti’- or ‘syn’- VI (cf. Schemes 2 and 8–11). The tricyclic compounds of type E , namely 4 and 8 , reversibly rearrange via [1,5]-C shifts to isomeric tricyclic structures (cf. 18 and 19 , respectively, in Scheme 6) already at temperatures > 50°. Photochemically 4 rearranges to a corresponding tetracyclic compound 20 via a di-π-methane reaction. The observed heptalene- and azulene-1,2-dicarboxylates as well as the tetracyclic compounds of type ‘anti’'- V are formed from the primary tricyclic intermediates A via rearrangement (→heptalenedicarboxylates), retro-Diels-Alder reaction (→ azulenedicarboxylates), and Diels-Alder reaction with ADM. The different reaction channels of A are dependent on the substituents. However, the main reaction channel of A is its retro-Diels-Alder reaction to the starting materials (azulene and ADM). The highly reversible Diels-Alder reaction of ADM to the five-membered ring of the azulenes is HOMO(azulene)/LUMO(ADM)-controlled, in contrast to the at 200° irreversible ADM addition to the seven-membered ring of the azulenes to yield the Diels-Alder products of type E . This competing reaction must occur on grounds of orbital-symmetry conservation under SHOMO(azulene)/LUMO(ADM) control (cf. Schemes 20–22). Several X-ray diffraction analyses of the products were performed (cf. Chapt. 4.1).     

Synthesis of new heterocyclic ring systems. Reaction of indolines and hexahydrocarbazole with α,β-unsaturated acids

Reactions of indoline (I), 2-methylindoline (II) and hexahydrocarbazole (III) with α,β-unsaturated acids in the presence of polyphosphoric acid have been investigated. Reaction of 1 with acrylic acid afforded two compounds which were identified as 1,2,4,5-tetrahydro-6H-pyrrolo-[3,2,1-ij] quinolin-6-one (IV) and 2,3,5,6,9,10-hcxahydro-1H-cyclopenta[f lpyrrolo [3,2,1-ij|-quinoline-1,8-dione (VII). The reaction oi 1 with crotonic acid gave compounds V and VIII, analogous-to IV and VII. The reaction of II with acrylic acid yielded two compounds VI and IX, whereas with crotonic acid, only X was isolated. With 111, acrylic acid afforded 5,6,8,9,10. 11,8a,11a-octahydro-4H-pyrido[3,2,1-jk]carbazol-4-one (XI) and a compound with a heretofore unknown ring system, viz., 2,3,5,6,7,8,11,12,5a,8a-decahydro-1H-cyclopenta[h] pyrido [3,2,1-jk |earbazole-1,10-dione. The structures of these compounds were deduced on the basis of their spectral and analytical data.     

Synthesis of tricyclic pyrido[2,3‐b][1,4]‐thiazines via nucleophilic substitution of activated precursors

Pyrido‐anellated compounds analogous to tricyclic 1,4‐benzothiazine derivatives were synthesized. Thus, under mild reaction conditiones substitution of thiolactim 3 with different N‐nucleophiles yielded the precursors for compounds, which were cyclized in a further step to the corresponding tricyclic derivatives.     

4-Diazomethylcoumarins and related stable heteroaryldiazomethanes. Thermal conversion into condensed pyrazoles

4-Diazomethyl-substituted coumarins, 1-methyl-2(1H)-quinolinones, 1 -thiocoumarin and their tricyclic analogs were found to be easily cyclized into the corresponding pyrazole isomers condensed with heteroaromatics. Thermodependent feature of these conversions and the remarkably accelerating effect of the alkyl substituent peri to the diazomethyl group were realized. Some other diazomethyl compounds connected with 2-pyridinone, 3-pyrazolone, chromone and 1-thiochromone were prepared, and their stability and thermal properties were compared.     

Tricyclic heteroaromatic systems. 5H-1,2,3-triazolo[5,1-c][1,4]benzodiazepine

The synthesis of the new tricyclic system 5H-1,2,3-triazolo[5,1-c][1,4]benzodiazepine, diaza-analogue of 5H-pyrrolo[2,1-c][1,4]benzodiazepine, which is the common feature of some antitumor antibiotics, is reported. The structure of the new tricyclic system and of some of its key intermediates is assigned by means of a ¹³C nmr study.     

Studies in sulphur heterocycles. Part 7 . Tricyclic compounds related to 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene

Synthesis of a number of tricyclic compounds with a fused thiophene ring starting from 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-one and benzosuberone is described. Biological testing of these compounds for their antiparasitic activities has been carried out.