Some Transformations of 2-(Chloromethyl)-5,5-dimethyl-5,6-dihydrobenzo[<Emphasis Type="Italic">h</Emphasis>]quinazolin-4(3<Emphasis Type="Italic">H</Emphasis>)-one

The condensation of 1-amino-3,3-dimethyl-3,4-dihydronaphthalene-2-carbonitrile with chloroacetyl chloride afforded chloro-N-(2-cyano-3,3-dimethyl-3,4-dihydronaphthalen-1-yl)acetamide which underwent cyclization to 2-(chloromethyl)-5,5-dimethyl-5,6-dihydrobenzo[h]quinazolin-4(3H)-one. The latter reacted with various nucleophiles (alkali metal alkoxides, piperazine, 2-sulfanylethanol) to give 2-(alkoxymethyl)-, 2-(piperazin-1-ylmethyl)-, and 2-{[(2-hydroxyethyl)sulfanyl]methyl}-5,5-dimethyl-5,6-dihydrobenzo[h]quinazolin- 4(3H)-ones. The condensation of 2-(chloromethyl)benzo[h]quinazoline with 2-thioxo derivatives of quinazoline and benzo[h]quinazolines led to the formation of bis-quinazolines in which 5,5-dimethyl-5,6- dihydrobenzo[h]quinazolin-4(3H)-one fragment is linked to quinazoline or benzo[h]quinazoline system through a CH₂S bridge.     

Synthesis of tetra- and pentaaza heterocyclic systems and benzimidazo[1,2-c]quinazoline derivatives

5,6-Dihydropyrimido[5′,4′: 5,6]pyrido[1,2-a]benzimidazole and pyrimido[4′,5′: 4,5]pyrimido[1,6-a]-benzimidazole derivatives were synthesized starting from 3-[4-hydroxy-6-methyl(hydroxy)-2-phenylpyrimidin-5-yl]propanoic and 4-hydroxy-2-phenylpyrimidine-5-carboxylic acids. New 6-sulfanyl-substituted benzimidazo-[1,2-c]quinazolines were also prepared.     

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.     

Palladium-catalyzed carbonylative synthesis of indoloisoindoloquinazolinone derivatives by using CO as a carbonyl source

An efficient synthesis of indolo[1,2-c]isoindolo[2,1-a]quinazolin-5(16aH)-one derivatives through palladium-catalyzed cyclocarbonylation reaction of 6-(2-bromoaryl)-5,6-dihydroindolo[1,2-c]quinazolines with the use of CO as a carbonyl source under atmospheric pressure has been disclosed. More intriguingly, the above-mentioned products can also be obtained directly from a one-pot two-step tandem reaction of 2-(1H-indol-2-yl)anilines and 2-bromobenzaldehydes, which are the precursors of 6-(2-bromoaryl)-5,6-dihydroindolo[1,2-c]quinazolines, under an atmospheric CO pressure in modest yields.     

2-Oxobenzo[h]chromene: a novel entry for the synthesis of functionalized angular polycyclic azaarenes

An efficient and short synthesis of (5,6-dihydrobenzo[h]pyrido[2,1-b]quinazolin-2-ylidene)acetonitriles, (5,6-dihydrobenzo[h]pyrazino[2,1-b]quinazolin-2-ylidene)acetonitriles and (5,6-dihydrobenzimidazo[1,2-b]benzo[f]isoquinolin-7-yl)acetonitriles in good yields is delineated through base catalyzed ring transformation of 4-(piperidin-1-yl)-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with 2-amino-pyridine, 2-aminopyrazine and (imidazo-2-yl)acetonitrile.     

Polycyclic N-heterocyclic compounds. XLV. Synthesis of 4-substituted 5,6-dihydrobenzo[h]quinazolines and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidines and their inhibitory activity on platelet aggregation

The synthesis of 4-substituted 5,6-dihydrobenzo[h]quinazolines and 6,7-dihydro-5H-benzo[6,7]cyclohepta-[1,2-d]pyrimidines with substituents which are an electron-attracting group such as a nitrite, an amide, a thione, or a carboxyl group is described. Their inhibitory activity against collagen-induced platelet aggregation was also investigated.     

Synthesis and some properties of N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]pyrazinones

Reactions of methyl 2-(2-formyl-1H-pyrrol-1-yl)alkanoates with unsubstituted aliphatic 1,2-, 1,3-, and 1,4-diamines gave N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]-pyrazinones. Some of them show ring-chain tautomerism. Transformations of these compounds led to a number of novel heterocyclic systems: 2,10-dihydro-3H,5H-imidazo[1,2-a]-pyrrolo[1,2-d]pyrazines, 2,3,4,11-tetrahydro-6H-pyrrolo[1??,2??:4,5]pyrazino[1,2-a]pyrimidines, 1,2,3,5,6,10b-hexahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazines, 1,3,4,6,7,11b-hexahydro-2H-pyrrolo[2??,1??:3,4]pyrazino[1,2-a]pyrimidines, and 2,3,4,5,6,7-hexahydro-1H-pyrrolo[2,1-c]-[1,4,7]triazacycloundecin-8(9H)-one.     

Synthesis of amino derivatives of triazolopyrimidine

Heterocyclization of 1-(4,6-dimethylpyrimidin-2-yl)-4-R-thiosemicarbazides by the action of methyl iodide in ethanol in the presence of sodium acetate is accompanied by Dimroth rearrangement leading to the formation of 5,7-dimethyl-2-R-amino[1,2,4]triazolo[1,5-a]pyrimidines. Analogous heterocyclization of 4-aryl-1-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thiosemicarbazides gives 3-arylamino-7-methyl-5-oxo-[1,2,4]triazolo[4,3-a]pyrimidines. The presence in the pyrimidine ring of a carbonyl group capable of forming hydrogen bond with protons of the amino group stabilizes the molecule, thus hampering the Dimroth rearrangement.     

Preparation of imidazo[2,1-b]quinazolin-5(3H)-ones and related tricyclic systems using a novel,double displacement reaction

New methodology is described for the construction of tricyclic heterocycles. Thus, a double displacement reaction of l-(2-fluorobenzoyl)-2-methylthio-2-imidazoline ( 8a ) with 1,1-dialkylhydrazines gave 10-substituted 2,10-dihydroimidazo[2,1-b]quinazolin-5(3H)-ones in good yield. The corresponding 1-(2-nitrobenzoyl)-2-meth-ylthio-2-imidazolines also underwent double displacement reactions with hydrazines. Other tricyclics made using double displacement reactions were pyrimido[2,1-b]quinazolines, imidazo[1,2-a]pyrido[2,3-d]pyrimidines, and imidazo[1,2-a]pyrazolo[3,4-d]pyrimidines. Treatment of 8a with hydrazine hydrate or methylhydrazine gave products resulting from displacement, but did not afford fused benzotriazepinones.     

Regioselective synthesis of fused pyrazolo[1,5-a]pyrimidines by reaction of 5-amino-1H-pyrazoles and β-dicarbonyl compounds containing five-membered rings

Reactions of 3-substituted-5-amino-1H-pyrazoles with 2-acetylcyclopentanone or 2-ethoxycarbo-nylcyclopentanone lead to the regioselective formation of a new series of cyclopentapyrazolo[1,5-a]pyrimidines in good yields. When 2-acetylbutyrolactone was used, the reaction provided 6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidinone and/or the intermediate (3Z)-3-{1-[(5-R-1H-pyrazol-3-yl)amino]ethylidene}-4,5-dihydrofuranone. This indicates that the cyclization proceeds with butyrolactone ring opening as the last step. Several aspects of this regioselective reaction, including mechanistic and structural studies, are considered.     

Synthesis of pyrazolo[1,5‐a]‐, 1,2,4‐triazolo[1,5‐a]‐ and imidazo[1,2‐a]pyrimidines related to zaleplon,a new drug for the treatment of insomnia

This paper describes the preparation of some pyrazolo[1,5‐a]‐, 1,2,4‐triazolo[1,5‐a]‐ and imidazo[1,2‐a]‐pyrimidines substituted on the pyrimidine moiety by a 4‐[(N‐acetyl‐N‐ethyl)amino]phenyl group. A new synthesis of related benzo[h]pyrazolo[1,5‐a]‐, benzo[h]pyrazolo[5,1‐b]‐ and benzo[h]1,2,4‐triazolo[1,5‐a]‐quinazolines is also reported.     

Unusual transformations of lithium enolate of ethyl 4,4,4-trifluoro-3-oxobutanoate

The present paper describes unusual reactions of lithium enolate of ethyl 4,4,4-trifluoro-3-oxobutanoate with ammonium acetate and 1-aminonaphthalene. These reactions produce 4-amino-2,6-bis(trifluoromethyl)pyridine and 4-trifluoromethyl-2-[(Z)-1,1,1-trifluoroprop-1-en-2-ol-1-yl]benzo[h]quinoline, respectively. The reaction of 1,1,7,7,7-hexafluoroheptane-2,4,6-trione hydrate with 1-naphthylamine gives a mixture of 4-trifluoromethyl-2-[(Z)-1,1,1-trifluoroprop-1-en-2-ol-1-yl]benzo[h]quinoline and N,N??-bis(naphth-1-yl)-2,6-bis(trifluoromethyl)pyridine-4(1H)-imine, respectively.     

A synthesis of 6-functionalized 4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines

6-Unsubstituted 7-R-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines (R = H or Me) were synthesized via two pathways: (a) deacylation of the corresponding 5-acetyl Biginelli-like precursors in KOH/H₂O and (b) reduction of the corresponding 1,2,4-triazolo[1,5-a]pyrimidines using LiAlH₄. The products could be easily formylated at position 6, which is promising for the further synthesis of functionalized 6-substituted derivatives of 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines. In contrast, 6-acetyl-7-(4-(N,N-dimethylaminophenyl))-5-methyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine undergoes a cascade process in KOH/H₂O, leading to the formation of a 4,5,8,9-tetrahydro[1,2,4]triazolo[5,1-b]quinazoline derivative.     

Synthesis of 5-thioxo-6H-imidazo[1,2-c]quinazolines and related compounds based on cyclocondensations of 2-isothiocyanatobenzonitrile (ITCB) with α-aminoketones

Pharmacologically relevant 5-thioxo-6H-imidazo[1,2-c]quinazolines and 5-oxo-6H-imidazo[1,2-c]quinazolines were prepared by sequential reactions of α-aminoketones with 2-isothiocyanatobenzonitrile (ITCB) and 2-isocyanatobenzonitrile (ICB), respectively. The functionalization of the thioxo moiety allowed the synthesis of 5-amino-6H-imidazo[1,2-c]quinazolines and of 1,2,4-triazolo[4,3-a]-imidazo[1,2-c]quinazolines.     

Strukturelle Abwandlungen an Nukleotiden,Nukleosiden und Nukleosidbasen mit β-Acylvinylphosphoniumsalzen

β-Acetylvinyl-triphenylphosphonium bromide1 reacts with CMP to form the 3,N⁴-etheno-derivative {[6-(5′-phosphoribofuranosyl)-2-methyl-5-oxo-imidazo [1.2-c]pyrimidin-3-yl]-methyl}triphenyl-phosphonium bromide (2). Guanine affords mainly the lin. condensation product [(6-methyl-9-oxo-imidazo[1.2-a]-purin-7-yl)-methyl]triphenylphosphonium bromide (3) and the angular tricyclic product [(6-methyl-9-oxo-imidazo[2.1-b]purin-5-yl)-methyl]-triphenylphosphonium bromide (4). For comparison we synthesized the angular condensed heterocycle5, (6.8-dimethyl-9-oxo-imidazo[2.1-b]purin-5-yl)-methyl]triphenylphosphonium bromide, by reaction of 1-methylguanine with1, and the corresponding linear derivative6 [(4.6-dimethyl-9-oxo-imidazo[1.2-a]purin-7-yl)-methyl]-triphenylphosphoniumbromide from 3-methylguanine and1. AHofmann-type degradation of3 with the anion of diethyl malonate led to7, diethyl (6-methyl-9-oxo-imidazo[1.2-a]purin-7-yl)-methylmalonate, a compound whose structure resembles some Y-bases in t-RNA.Wittig reaction of the silylated nucleoside derivative8 a {[2-methyl-5-oxo-6-(2′.3′.5′-tris-trimethylsilyl)-ribofuranosyl-imidazo[1.2-c]pyrimidin-3-yl]methyl}-triphenylphosphonium bromide, with C₆H₅CHO resulted in the 2-methyl-3(ω-styryl)-6[2′.3′.5′-tris-(trimethylsilyl)]ribofuranosyl-imidazo[1.2-c] pyrimidin-5-one (9).     

Novel Aspects of the Reaction of 3-(Benzimidazol-2-yl)-2-iminocoumarins with Aromatic Aldehydes

The reaction of 3-(benzimidazol-2-yl)-2-iminocoumarins with aromatic aldehydes has been studied. The condensation products 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines or 3-(benzimidazol-2-yl)coumarins are formed depending on the nature of the substituent in the starting 2-iminocoumarin and aldehyde. In DMF medium, 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines isomerize to the corresponding 7-aryl-14H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines. The effect of the substituent on the isomerization process has been studied and the reaction mechanisms are discussed.     

A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.     

Synthesis,in silico and in vitro Evaluation of Novel Oxazolopyrimidines as Promising Anticancer Agents

New potential bioactive oxazolopyrimidines have been synthesized using two main approaches: the pyrimidine ring annulation on a functionalized oxazole and the benzoyl bromide trimerization followed by rearrangement and formation of the oxazolo[5,4-d]pyrimidine scaffold. The docking analyzes have shown that 7-piperazine substituted oxazolo[4,5-d]pyrimidines 8a – 8c could be potential VEGFR2 inhibitors with high free energy of ligand–protein complex formation (ΔG: −10.1, −9.6, −9.8 kcal/mol, respectively). In vitro antitumor assays confirmed theoretical predictions that oxazolo[4,5-d]pyrimidines 8a – 8c containing positively charged piperazine moiety should demonstrate significantly higher cytotoxic effects. 4-[5-(4-Chlorophenyl)-2-phenyl[1,3]oxazolo[4,5-d]pyrimidin-7-yl]piperazin-1-ium trifluoroacetate ( 8c ) exhibited a slightly higher antiproliferative effect (IC₅₀=0.21 μm ) than doxorubicin (IC₅₀=0.36 μm ) on MDA-MB-231 cell line and has relatively good results on OVCAR-3 (IC₅₀=1.7 μm ) and HCT-116 (IC₅₀=0.24 μm ) cells.     

Synthetic transformations of isoquinoline alkaloids. Synthesis of N′-substituted 1-alkynyl-7α,8α-(2,5-dioxopyrrolidino)-[3,4-h]-6,14-endo-ethenotetrahydrothebaines and their transformations

The iodination of N??-substituted (2,5-dioxopyrrolidino)[3,4-h]-6,14-endo-ethenotetrahydrothebaines with N-iodosuccinimide in trifluoroacetic acid afforded depending on the excess of the reagent either 1-iodo- or 1,2-diiodoendo-ethenotetrahydrothebaines. The Sonogashira reaction of 1-iodo-6,14-endo-ethenotetrahydrothebaines with trimethylsilylacetylene led to the formation of N??-substituted 1-(trimethylsilylethynyl)-(2,5-dioxopyrrolidino)-[3,4-h]-6,14-endo-ethenotetrahydrothebaines whose desilylation cleanly furnished the corresponding 1-ethynylendo-ethenotetrahydrothebaines. The Mannich reaction of the acetylene derivatives of tetrahydrothebaine with amines and formaldehyde catalyzed by compounds of Cu(I) provided 1-[3-(morpholin-4-yl)propynyl]-, 1-[3-(4-methylpiperazin-1-yl)propynyl]-, and 1-[3-(4-tert-butoxycarbonylpiperazin-1-yl)propynyl]-(2,5-dioxopyrrolidino)[3,4-h]-6,14-endo-ethenotetrahydrothebaines.     

Synthese von 2,4-Diamino-thieno[2,3-d]pyrimidin-Derivaten

Synthesis of 2,4-Diamino-thieno[2,3-d]pyrimidines Condensation of 2-aminothiophene-3-carbonitrile ( 4 ) with guanidine or sequential addition of CS₂ and NH₃ to 4 provides 2,4-diaminothieno[2,3-d]pyrimidine ( 7 ). This compound yields, after sequential addition of sec-BuLi and either [3-(trifluoromethyl)benzene]sulfenyl chloride ( 8 ) or the corresponding disulfide 9 , followed by acidic work up, 2,4-diamino-6-{[3-(trifluoromethyl)phenyl]thio}thieno[2,3-d]pyrimidine ( 10 ). In another approach, 2-amino-5-{[3-(trifluoromethyl)phenyl]thio}thiophene-3-carbonitrile ( 11 ) obtained from 4 and 8 is transformed to 10 by condensation with guanidine. Corresponding to the second route, 2,4-diamino-6-[(naphth-2-yl)thio]thieno-[2,3-d]pyrimidine ( 16 ) is synthesized. Oxidation of 10 with m-chloroperbenzoic acid gives 2,4-diamino-6-{[3-(tri-fluoromethyl)phenyl]sulfinyl}thieno[2,3-d]pyrimidine ( 13 ).