An efficient HCCP-mediated direct amination of quinazolin-4(3H)-ones

An efficient direct amination of quinazolin-4(3H)-ones has been developed. Treatment of quinazolin-4(3H)-ones with HCCP, DIPEA, and N-contained nucleophiles in acetonitrile could be able to form the corresponding 4-aminoquinazoline derivatives. Under the optimal reaction conditions, the amination products were achieved in good yields.     

Gallium(III) triflate-catalyzed one-pot selective synthesis of 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones

A series of 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones have been synthesized in good to excellent yields and high selectivity by one-pot reaction using isatoic anhydride, ammonium acetate (or amines), and aldehydes in ethanol or in DMSO under mild conditions, respectively. The reaction was efficiently promoted by 1 mol % Ga(OTf)₃ and the catalyst could be recovered easily after the reactions and reused without evident loss of reactivity.     

A new approach to the facile synthesis of mono- and disubstituted quinazolin-4(3H)-ones under solvent-free conditions

Quinazolin-4(3H)-one derivatives were synthesized successfully via a one-pot, three component reaction of isatoic anhydride and an orthoester with ammonium acetate or a primary amine catalyzed by silica sulfuric acid under solvent-free conditions. This is the first report on the synthesis of 2-substituted quinazolin-4(3H)-ones by this procedure.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Synthesis of substituted 3-(3-chloro-1H-pyrazol-5-yl)quinoxalin-2(1H)ones

Synthetic strategies to gain access to all four isomers of 3-(3-chloro-1H-pyrazol-5-yl)quinoxalin-2(1H)ones with monosubstituted benzo core (i.e., compounds 8a–d) are described. Preparation of these heterocyclic compounds succeeded starting from only two different substituted 2-nitroanilines (i.e., 3-methoxy- and 4-methoxy-2-nitroaniline) in three or five steps, respectively.     

Single step synthesis of 2,3-dialkyl-6-nitro-quinazolin-4(3H)-imines and 3,5-dialkyl-9-nitro-imidazo[1,2-c]quinazolin-2(3H)-ones

A single step synthesis of 2,3-dialkyl-6-nitro-quinazolin-4(3H)-imines and 3,5-dialkyl-9-nitro-imidazo-[1,2-c]-quinazolin-2(3H)-ones from simple carbonyl compounds, primary amines or amino acid methyl esters and 2-azido-5-nitro-benzonitrile was developed. Key intermediates were N,N′-disubstituted amidines obtained by rearrangement of 4,5-dihydrotriazoles; the new heterocyclic rings were formed by spontaneous intramolecular reaction of the amino and cyano groups which are present in the intermediates.     

CuO nanoparticles catalyzed simple and efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones under ultrasound irradiation in aqueous ethanol under ultrasound irradiation in aqueous ethanol

A CuO nanoparticle-catalyzed one-pot process has engineered for the preparation of diverse quinazolinones from the readily available isatoic anhydride, aldehydes and amine or ammonium. For amine substrates the reactions afford 2,3-dihydroquinazolin-4(1H)-ones in aqueous ethanol promoted by ultrasound irradiation. However, the ammonium substrates undergo intramolecular electron transfer and rearrangement yielding quinazolin-4(3H)-ones. The catalyst is recyclable four times without loss of substantial activity. Other remarkable features include the wide range of functional group tolerance (46 quinazolinones are synthesized and 9 of them are reported firstly), and providing moderate to excellent yield of the products under mild conditions.     

Spirooxindoles: reaction of 2,6-diaminopyrimidin-4(3H)-one and isatins

A simple and efficient cyclocondensation reaction of 2,6-diaminopyrimidin-4(3H)-one and isatins for the synthesis of spiro[pyrimido[4,5-b]quinoline-5,5′-pyrrolo[2,3-d]pyrimidine] and spiro[indoline-pyrido[2,3-d:6,5-d′]dipyrimidine] derivatives is reported.     

Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α-protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.     

Palladium-catalyzed Suzuki-Miyaura couplings of potassium aryl trifluoroborates with 4-tosyloxycoumarins or 4-tosyloxyquinolin-2(1H)-one

Pd(PPh₃)₄ catalyzed Suzuki-Miyaura cross-coupling reactions of 4-tosyloxycoumarins or 4-tosyloxyquinolin-2(1H)-one with various potassium aryl trifluoroborates afforded the corresponding 4-substituted coumarins or 4-substituted quinolin-2(1H)-ones in good to excellent yield.     

Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol-4(1H)-ones

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′,3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.     

Synthesis and properties of 4,9-methanoundecafulvenes and their transformation to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones: photo-induced autorecycling oxidizing reaction toward amines

The synthesis and properties of 4,9-methanoundecafulvene [5-(4,9-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-trione] derivatives 8a,b were studied. Their structural characteristics were investigated on the basis of the ¹H and ¹³C NMR and UV-vis spectra. The rotational barrier (ΔG^‡) around the exocyclic double bond of 8a was found to be 12.55 kcal mol⁻¹ by the variable temperature ¹H NMR measurement. The electrochemical properties of 8a,b were also studied by CV measurement. Furthermore, the transformation of 8a,b to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones 16a,b was accomplished by oxidative cyclization using DDQ and subsequent ring-opening and ring-closure. The structural details and chemical properties of 16a,b were clarified. Reaction of 16a with deuteride afforded C13-adduct 19 as the single product, and thus, the methano-bridge controls the nucleophilic attack to prefer endo-selectivity. The photo-induced oxidation reaction of 16a and a vinylogous compound, 3-methylcyclohepta[4,5]furo[2,3-d]pyrimidine-2,4(3H)-dione 2a, toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling number of 6.1-64.0 (for 16a) and 2.7-17.2 (for 2a), respectively.     

Solid-phase synthesis of 2,6- and 2,7-diamino-4(3H)-quinazolinones via palladium-catalyzed amination

A new procedure for the solid-phase synthesis of 2,6- and 2,7-diamino-4(3H)-quinazolinones is described. The method involves coupling of 2,4,6- and 2,4,7-trichloroquinazoline to a solid support via benzyl alcohol type linkers, subsequent displacement of chlorine at C-2 then at the C-6 or C-7 positions by amines (Fig. 1) and the cleavage of the products from the resin. The palladium-catalyzed amination of C-6 and C-7 positions with a representative set of amines in the presence of 2-(di-t-butylphosphino)biphenyl (DTBPBP), P(t-Bu)₃ and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) ligands has been investigated. This method should prove to be a useful tool for constructing combinatorial libraries containing the 4(3H)-quinazolinone moiety.     

A facile synthesis and fungicidal activities of novel fluorine-containing pyrido[4,3-d]pyrimidin-4(3H)-ones

Sixteen novel 2-substituted-5,8,9-trimethyl-3-(4-fluoro-substituted)phenyl-thieno[3′,2′-5,6] pyrido[4,3-d]pyrimidin-4(3H)-ones 5a-5p were designed and have been successfully synthesized via tandem aza-Wittig and annulation reactions of the corresponding iminophosphorances 1, para-fluoro phenyl isocyanate, and substituted phenols or amines in 73-90% isolated yields. Their structures were clearly verified by IR, ¹H NMR, EI-MS spectroscopy and elemental analysis, and in the case of compound 5a, analyzed by single-crystal X-ray diffraction further. The results of preliminary bioassay indicated that some compounds possess inhibition activities against Rhizoctonia solani and Botrytis cinereapers at a dosage of 50 mg/L.     

Investigation towards an efficient synthesis of benzo[g]isoquinoline-1,5,10(2H)-triones

As part of our research on 2-aza analogues of pentalongin, the active principle of Pentas longiflora Oliv., the first synthesis of 2,3-disubstituted benzo[g]isoquinoline-1,5,10(2H)-triones via 3,4-disubstituted 6-hydroxybenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-diones as the key intermediates is reported. The latter compounds have been prepared by treating 2-methoxycarbonyl-1,4-naphthoquinone with N-substituted enaminoesters under acidic conditions. These reagents are easily accessible from readily available 1,4-dihydroxy-2-naphthoic acid, β-ketoesters and primary amines. Finally, a short synthesis of substituted benzo[g]isoquinoline-1,5,10(2H)-triones is achieved by an oxidative addition of N-substituted enaminoesters onto methyl 1,4-dihydroxynaphthalene-2-carboxylate.     

Copper-catalyzed one-pot synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones from ortho-bromobenzamides and isothiocyanates

Copper-catalyzed tandem reaction of ortho-bromobenzamides and isothiocyanates is described, which provides an efficient and practical route for the synthesis of 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones. The optimal condition involved the following parameters: CuI as precatalyst, Cs₂CO₃ as base, N,N′-dimethylethane-1,2-diamine as ligand, and toluene as solvent, with reaction temperature at 120 °C.     

Synthesis and ring transformations of 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-ones

Heating 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolinium chloride in the presence of hydrazine bishydrate produces regioselectively the five-membered heterocycle 1-amino-1,2,3,9a-tetrahydro-9,9,9a-trimethylimidazo[1,2-a]indol-2(9H)-one. The assignment of the structure is based on extensive ¹H, ¹³C and ¹⁵N NMR spectroscopic studies. No ring-chain tautomerism of the 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-one was observed to open-chain hydrazides or the corresponding six-membered 1,2,10,10a-tetrahydro[1,2,4]triazino[4,3-a]indol-3(4H)-one. Further transformations of 1-amino-1,2,3,9a-tetrahydroimidazo[1,2-a]indol-2(9H)-one were performed by treatment with aromatic aldehydes, acid chlorides and isocyanates giving access to 40 novel hydrazones, N,N′-diacylhydrazines, N-acyl-N′-carbamoylhydrazines and 1,3,4-oxadiazoles.     

Synthesis of zwitterionic 4-hydroxy-2(1H)-quinolinone derivatives

Zwitterionic 4-hydroxy-2(1H)-quinolinone derivatives were synthesized through a unique reaction of 4-hydroxy-2(1H)-quinolinone with p-benzoquinone and N-heterocyclic aromatics. The zwitterions possessed astropisomeric nature. A possible mechanism of the reaction was presented.     

Synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-ones via Pd-catalyzed regioselective cross-coupling reaction and cyclization

An efficient and novel route for the synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 via palladium-catalyzed site-selective cross-coupling reaction and cyclization process was described. Reaction of 3-bromo-4-trifloxy-quinolin-2(1H)-one 3 with arylboronic acid catalyzed by PdCl₂(PPh₃)₂ afforded 3-bromo-4-aryl-quinolin-2(1H)-one 4, which then reacted with 2-ethynylaniline 5 via Pd-catalyzed Sonogashira coupling and CuI-mediated cyclization leading to the desired 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 in good yields.     

First straightforward synthesis of 2,4-disubstituted benz[g]isoquinoline-3,5,10(2H)-triones, 1,2,3,5-substituted naphtho[3,2,1-de]isoquinoline-4,7-diones, and 6-substituted benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-diones

Structural modifications to the benz[g]isoquinoline skeleton of N-substituted benz[g]isoquinoline-3,5,10(2H)-triones were envisaged in order to make future SAR studies possible for this type of bioactive compounds. Several N-substituted benz[g]isoquinoline-3,5,10(2H)-triones were converted to novel 2,4-substituted benz[g]isoquinoline-3,5,10(2H)-triones, new tetracyclic 1,2,3,5-substituted naphtho[3,2,1-de]isoquinoline-4,7-diones, and 6-substituted benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-diones. All the synthesized target compounds represent new heterocyclic systems, which were previously undescribed in the literature.