Quinazolines. VII. Synthesis of 1,3-Diamino-5,6-dihydrobenzo[f]quinazolines

Eighteen new 1,3-diamino-5,6-dihydrobenzo[f] quinazolines ( 6 , R. = alkyl, Cl, MeO) were synthesized via the condensation of appropriate 2-tetralones with cyanoguanidine under fusion conditions. Methods were developed for the preparation of a number of heretofore undescribed 2-tetralones as precursors. The final products can be viewed as conformationally rigid analogs of pyrimethamine ( 2 ), and are of interest as inhibitors of dihydrofolate reductase and as potential antimalarial and antitumor agents.     

Synthesis and fluorescence properties of novel benzo[a]phenoxazin-5-one derivatives

Thirteen, benzo[a]phenoxazin-5-one derivatives 3a-m were synthesized from 4-nitrosoaniline hydrochlorides 1a-m and ethyl 1,3-dihydroxynaphthoate 2 and their fluorescence properties were discussed in terms of the electronic effect of substituents. A coupling reaction was carried out with 6-carbethoxy-9-N-(2-hydroxyethyl)-N-methylamino-5H-benzo[a]phenoxazin-5-one (3k) and acetyl-DL-alanine to afford N-[(6-carbethoxy-5-oxo-5H-benzo[a]phenoxazin)-9-yl]-N-methylaminoethylene acetyl-DL-alanine ester (4).     

Synthesis of 1,3-diamino-7,8,9,10-tetrahydropyrido[3,2-f]-quinazolines. Inhibitors of Candida albicans dihydrofolate reductase as potential antifungal agents

A series of novel 1,3-diamino-7,8,9,10-tetrahydropyrido[3,2-f]quinazolines were synthesized starting from 6-amino-5-cyanoquinoline (4). These compounds inhibited Candida albicans dihydrofolate reductase with K_i values of ≤0.60 aM. One analogue exhibited moderate in vivo efficacy in a C. albicans-infected mouse model.     

Condensation of N-monosubstituted 2-naphthylamines,formaldehyde, and cyclic β-diketones. One-pot synthesis of 2,4-disubstituted derivatives of 1,2,3,4-tetrahydrobenzo[<Emphasis Type="Italic">f</Emphasis>]quinoline

Various spirocyclic derivatives of 1,2,3,4-tetrahydrobenzo[f]quinoline containing substituents in the positions 2 and 4 of the ring were obtained by one-pot multicomponent condensation of available N-benzyl-2-naphthylamines, formaldehyde, and cyclic β-diketones of cyclohexanedione series.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 5. [1]Benzothieno[2,3-c]naphtho[2,1-f]-quinoline and [1]benzothieno[2,3-c]naphtho[1,2-g]quinoline

Two previously unknown heterocyclic ring systems, namely, [1]benzothieno[2,3-c]naphtho[2,1-f]quinoline ( 4 ) and [1]benzothieno[2,3-c]naphtho[1,2-g]quinoline ( 5 ) were synthesized via photocyclization of 3-chloro-N-(2-phenanthryl)benzo[b]thiophene-2-carboxamide ( 8 ) followed by chlorination and dechlorination. The total assignment of their ¹H- and ¹³C-nmr spectra was determined by utilizing inverse-detected HMQC and HMBC two-dimensional nmr spectroscopic methods.     

Synthesis of Benzo[a]phenanthridine Derivatives by Condensation of N-Arylmethylene-2-naphthylamines with 5-Phenyl- and 5-(p-Methoxyphenyl)-1,3-cyclohexanediones

Condensation of N-arylmethylene-2-naphthylamines with 5-phenyl- and 5-(p-methoxyphenyl)-1,3-cyclohexanediones in various solvents gave new hexahydrobenzo[a]phenanthridin-4-one derivatives. Three-component condensation of 2-naphthylamine, appropriate aldehyde, and 5-(p-methoxyphenyl)-1,3-cyclohexanedione was also studied.     

Thermal cyclization of N-[2-(2-propenyl)-1-naphthyl] ketenimines: intramolecular Diels-Alder reaction versus [1,5] hydrogen migration. Synthesis of dibenz[b,h]acridines and benzo[h]quinolines

The thermal treatment of N-(2-propenyl)-1-naphthylamines provided the expected aza-Claisen rearranged products, 2-(2-propenyl)-1-naphthylamines and benz[g]indoles, these last derived from an intramolecular hydroamination reaction on those primary products. The 2-(2-propenyl)-1-naphthylamines were converted into their triphenylphosphazene derivatives, which by aza-Wittig reaction with disubstituted ketenes yielded N-[2-(2-propenyl)-1-naphthyl] ketenimines. The heating of these ketenimines in boiling toluene induced their cyclization either via an intramolecular Diels-Alder reaction, to afford dibenz[b,h]acridines, or via [1,5] hydrogen migration from the sp³ carbon atom of the propenyl substituent to the central carbon atom of the ketenimine fragment, followed by a 6π electrocyclic ring closure, to give benzo[h]quinolines.     

4,5-Dihydroxyimidazolidin-2-ones in an α-ureidoalkylation reaction of N-(carboxyalkyl)-, N-(hydroxyalkyl)-, and N-(aminoalkyl)ureas 3. α-Ureidoalkylation of N-[2-(dimethylamino)ethyl]urea

α-Ureidoalkylation of N-[2-(dimethylamino)ethyl]urea with 1,3-unsubstituted, 1,3-dialkyl-, and 1,3-dimethyl-4,5-diphenyl-4,5-dihydroxyimidazolidin-2-ones(thiones) was systematically studied. Hitherto unknown N-[2-(dimethylamino)ethyl]glycolurils and their hydrochlorides were synthesized. The yields of the target glycoluril hydrochlorides decreased on going from 1,3-H₂- to 1,3-dialkyl-4,5-dihydroxyimidazolidin-2-ones and increased with the introduction of phenyl groups at the positions 4 and 5 of the starting 4,5-dihydroxyimidazolidin-2-one. X-ray diffraction study showed that 2-[2-(dimethylamino)ethyl]glycoluril crystallizes in the form of a conglomerate.     

Reactions of 1,2,4-triazole derivatives with a “model” thiirane

Reactions of 3-mono- and 3,5-disubstituted 1,2,4-triazoles with a “model” thiirane, 8-bromo-1,3-dimethyl-7-(thiiran-2-ylmethyl)-3,7-dihydro-1H-purine-2,6-diones proceed at the positions N¹ and N² of the triazole ring and yield 7-(5-R-3-R′-1,2,4-triazol-1-yl)methyl- and/or 7-(5-R′-3-R-1,2,4-triazol-1-yl)methyl-1,3-dimethyl-6,7-dihydro[1,3]thiazolo[2,3-f]-purine-2,4-(1H,3H)-diones. 3-Methylsulfonyl-1,2,4-triazole reacted regiospecifically at the position N¹ forming 1,3-dimethyl-7-[(3-methyl-sulfonyl-1,2,4-triazole-1-yl)-methyl]-6,7-dihydro[1,3]thiazolo-[2,3-f]purine-2,4(1H,3H)-dione.     

Reactions of Bisazomethines of the Naphtalene Series with 1,3-Diketones

Bisazomethines prepared from aromatic dialdehydes and 2-naphthylamine were for the first time reacted with the following diketones: 1,3-cyclohexanedione, 5,5-dimethyl-1,3-cyclohexanedione, 5-phenyl-1,3-cyclohexanedione, indandione, and 2,2-dimethyl-1,3-dioxane-4,6-dione was studied. The reactions with 1,3-diketones of the cyclohexane series yield benzophenanthridine derivatives. The reactions with indandione, depending on conditions, give either bisarylideneindandiones or bisdihydrobenzo[f]indenoquinoline. As evidenced by the ^13C NMR and IR spectra, in the case of biphenyl-4,4'-dicarbaldehyde bis[N-(2-naphthyl)imine] and 2,2-dimethyl-1,3-dioxane-4,6-dione, 4,4'-bis(3-oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-1-yl)biphenyl is formed.     

The reaction of tetralones with nitriles: a simple approach to the synthesis of new substituted benzo[h]quinazolines, benzo[f]quinazolines and dibenzo[a,i]phenanthridines

The one-pot reaction of 1-tetralone with nitriles in the presence of triflic anhydride affords in good yields 2,4-disubstituted 5,6-dihydrobenzo[h]quinazolines, which oxidation with DDQ leads to the corresponding benzo[h]quinazolines. 2-Tetralone undergoes identical process forming 1,3-disubstituted 5,6-dihydrobenzo[f]quinazolines. However, when the reaction of 2-tetralone is carried out with methylthiocyanate as nitrile, 5-methylthiotetrahydrodibenzo[a,i]phenanthridines are isolated in good yields. Easy transformations of the methylthio group offer possible access to a variety of substituted dibenzo[a,i]phenanthridines.     

Synthese von [1,2,4]Triazolo [1,5-a]chinazolinen. Ableitung der Konformation von Substituenten mit Hilfe der 13C-NMR.-Spektroskopie

Synthesis of [1,2,4]Triazolo[1,5-a]quinazolines. Assignment of the Conformation of Substituents with the Aid of ¹³C-NMR. Spectroscopy The synthesis of [1,2,4]triazolo[1,5-a]quinazolines by condensation of 2-hydrazinobenzoic acid with N-cyano-imidates is reported. The preferred conformation of substituents at C (5), e.g. N (CH₃)₂, N (CH₃)NH₂, N (CH₃)OH, relative to the aromatic system is deduced with the aid of ¹³C-NMR. chemical shifts and proton nuclear Overhauser effect experiments.     

2-Allyl-N-benzyl substituted α-naphthylamines as building blocks in heterocyclic synthesis. New and efficient syntheses of benz[e]naphtho[1,2-b]azepine and naphtho[1,2-b]azepine derivatives

A new series of 13-acetyl-7,12-dihydro-7-ethylbenz[e]naphtho[1,2-b]azepine (4a-d) and 2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepine derivatives (6a-d) have been synthesized from N-allyl-N-benzyl substituted α-naphthylamines (1a-d) by utilizing aromatic amino-Claisen rearrangement, intramolecular Friedel-Crafts alkylation and intramolecular dipolar 1,3-cycloaddition nitrone-olefin reactions.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 23 . Naphtho[2′,1′:4,5]thieno‐[2,3‐c]naphtho[2,1‐f]quinoline

A previously unknown heterocyclic ring system, naphtho[2′,1′:4,5]thieno[2,3‐c]naphtho[2,1‐f]quinoline ( 14 ), was synthesized via oxidative photocyclization of 3‐chloro‐N‐(2‐phenanthryl)naphtho[1,2‐b]‐thiophene‐2‐carboxamide ( 9 ). Further elaboration of the lactam 10 yielded the unsubstituted ring system 14 . Structural confirmation of compound 14 was accomplished by a total assignment of its ¹H and ¹³C nmr spectra utilizing the concerted two‐dimensional nmr spectroscopic methods.     

Synthesis and Structure Elucidation of Pyrimidobenzimidazoles and Fused Derivatives II [1]. Dodecahydrobenzimidazo-[2,1-b]quinazolines and Decahydrobenzimidazo-[2,1-b]benzo[h]quinazolines [2]

Summary.  The cyclization reactions of trans-3a-hexahydro-2-benzimidazolamine with 2-alkylidene- and 2-benzylidenecyclohexanones and α-tetralones, respectively, yield mixtures of two isomeric condensates each. Thorough high resolution NMR analyses (¹H and ¹³C NMR, HH-COSY, gs-HSQC, gs-HMBC, 1D TOCSY, and 1D NOE difference spectra) revealed that the corresponding isomers are in all cases linearly fused diastereomeric 12α- and 12β-substituted trans-6aα-dodecahydrobenzimidazo[2,1-b]quinazolines and 7α-substituted trans-8aβ- and trans-8aα-decahydrobenzimidazo[2,1-b]benzo[h]quinazolines, respectively. The formation of corresponding angularly fused regioisomers was not observed so far. The stereochemistry and the tautomerism of some bases and their hydrochlorides as well as the regiospecific course of the cyclization reactions are discussed. Biological tests showed that the novel compounds don’t exert remarkable antibacterial and antimycotic effects. Received November 3, 1999. Accepted November 30, 1999     

Facile synthesis of novel 3-quinoxalinyl-1,5-benzodiazepines via ring transformation. Stable tautomers in the 1,5-benzodiazepin-2-one ring system

Novel 3-quinoxalinyl-1,5-benzodiazepines 4, 5, 6, 9, 10 were synthesized via the ring transformation of 3-(N,N-dimethylcarbamoyl)furo[2,3-b]quinoxaline hydrochloride ( 1 ). The 3-quinoxalinyl- 1 ,5-benzodiazepine hydrochlorides 4 and 6 are the tautomers of the N^1′-H (or N⁵-H) form and the C³-H form, respectively, which are stable in solid and solution. However, 4 (NH form) was found to be converted into 6 (C³-H form) by refluxing in acetic acid. The individual spectral evidences and different reactivity of these tautomers are described.     

Synthetic studies on indoles and related compounds. XXXI. Chemical confirmation of the synthetic route for the benz[f]indole skeleton and its application

To confirm the structure of ethyl 9-methoxybenz[f]indole ( 8a ) prepared from ethyl pyrrole-2-carboxylate ( 4 ) via a new synthetic route, the following chemical correlation work was performed. Ethyl 9-methoxybenz[f]in-dole ( 8a ) was converted to 1-benzyl-3-methyl-5,6,7,8-tetrahydrobenz[f]indole ( 25 ), which was alternatively and authentically synthesized from ethyl 3-methylpyrrole-2-carboxylate ( 11 ). On the basis of the established route to the benz[f]indole nucleus, two representative benz[f]indoles, benz[f]indole ( 1 ) and 4,9-dioxobenz[f]indole ( 26 ) were synthesized.     

Synthesis of Some New 3-Oxo-2-[(Z)-1-phenylmethylidene]-5H-[1,3]thiazolo[3,2-a]-and N-Acetylated Pyrimidines

3-Oxo-2-[(Z)-1-phenylmethylidene]-5H-[1,3]thiazolo[3,2-a] pyrimidine derivatives 2a–f were synthesized by the reaction of an appropriate 3,4-dihydro-2(H)-pyrimidone 1 , chloroacetic acid, sodium acetate and benzaldehyde. Reaction of 1 with acetic anhydride under heating afforded only 3-N-acetylated 3,4-dihydro-2(H)-pyrimidines 3a–f . The yields of the products after recrystallization from ethanol were of the order of 60–92 %. IR, ¹ H NMR spectroscopy, and elemental analysis were used for the identification of these compounds.     

Synthesis of benzo[<Emphasis Type="Italic">f</Emphasis>]quinoline derivatives by condensation of <Emphasis Type="Italic">N</Emphasis>-arylmethylene-2-naphthylamines with acetylcyclohexane and 1-acetylcyclohexene

N-Arylmethylene-2-naphthylamines react with acetylcyclohexane and 1-acetylcyclohexene under mild conditions to afford 2-aryl-2-(2-naphthylamino)ethyl cyclohexyl and 1-cyclohexenyl ketones, respectively. Under more severe conditions (110°C), the reaction is accompanied by cyclization with formation of 3-aryl-1-cyclohexyl(or 1-cyclohexenyl)benzo[f]quinolines. Proper choice of the amount of catalyst, temperature, and reaction time allows isolation of intermediate 3-aryl-1-cyclohexyl(or 1-cyclohexenyl)-3,4-dihydrobenzo[f]quinolines.Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 11, 2004, pp. 1878–1883.Original Russian Text Copyright © 2004 by Grachek.This revised version was published online in April 2005 with a corrected cover date.     

The first iodine improved 1,3-dipolar cycloaddition: facile and novel synthesis of 2-substituted benzo[f]isoindole-4,9-diones

The first novel protocol of the synthesis of 2-substituted benzo[f]isoindole-4,9-dione framework via the one-pot, 1,3-dipolar cycloaddition of quinones, paraformaldehyde and N-substituted amino ester hydrochlorides in the present of iodine at refluxing acetonitrile was reported. All these reactions proceed with good to excellent yields. The promising results obtained 1,3-dipolar cycloaddition will have the potential application in natural product exhibiting important biological activities.