An efficient, greener, and solvent-free one-pot multicomponent synthesis of 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones

Herein, we report an efficient, greener, and solvent-free novel method for the synthesis of 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones in a one-pot sequence using methyl anthranilate or 2-aminothiophene-3-carboxylate with N,N′-dimethyl formamide dimethyl acetal and various anilines. The driving force for this reaction is the removal of N,N′-dimethylamine by various anilines resulting in 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones.     

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.     

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.     

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.     

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.     

New 5-(2-ethenylsubstituted)-3(2H)-furanones with in vitro antiproliferative activity

A convenient route to new 3(2H)-furanones is described through hydrogenolysis and subsequent acidic hydrolysis of isoxazoles. The antiproliferative activity of title compounds were evaluated against leukemia-, carcinoma-, neuroblastoma-, and sarcoma-derived human cell lines in comparison to the natural compound geiparvarin. The structure activity relationship indicated that the maximum in vitro antiproliferative activity correlates with the presence of a heterocyclic ring on the ethenyl moiety.     

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.     

Ring-closing metathesis for the synthesis of 2H- and 4H-chromenes

Six 4H-chromenes were synthesized from substituted phenols using vinylstannylation and ring-closing metathesis (RCM) as key steps. In addition, a different approach involving amongst other steps, an aryl allyl isomerization and RCM afforded a set of seven 2H-chromenes from phenolic precursors.     

Synthesis of substituted 4-(1H-indol-6-yl)-1H-indazoles as potential PDK1 inhibitors

The development of a preparative route to a series of novel 4-(1H-indol-6-yl)-1H-indazole compounds as potential PDK1 inhibitors is described. The synthetic strategy centres on the late-stage Suzuki cross-coupling of N-unprotected indazole and indole fragments. The use of a monoligated palladium catalyst system was found to be highly beneficial in the cross-coupling reaction. The indazole and indole fragments were constructed by diazotisation/cyclisation and S_NAr/reductive cyclisation sequences, respectively.     

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.     

Chemoselective synthesis of 3H-pyrrolo[2,3-c]quinolin-4(5H)-one derivatives from 3-phenacylideneoxindoles and substituted tosylmethyl isocyanide (TosMIC)

A simple and convenient synthetic approach to access of 3H-pyrrolo[2,3-c]quinolin-4(5H)-one derivatives by the reaction of (Z)-3-(2-oxo-2-ethylidene)indolin-2-one derivatives 1 with functionalized TosMICs under basic conditions has been reported. The desired products were obtained in good to excellent yields (82–94%). The easy accessibility of the starting materials, simple and mild reaction conditions, short reaction time, and good to excellent chemical yields make this methodology highly efficient.     

Facile synthesis of 4-phenylquinolin-2(1H)-one derivatives from N-acyl-o-aminobenzophenones

An efficient synthesis of 4-phenylquinolin-2(1H)-one derivatives has been achieved in a one-pot reaction from N-acyl-o-aminobenzophenones 1a-c (a: acyl=acetyl; b: acyl=propanoyl; c: acyl=heptanoyl) using NaH as a base. Treatment of 1 with NaH provided the quinolones 2a-c with 62-83% yields, whereas the reaction in the presence of alkyl iodide (alkyl=methyl, ethyl, n-octyl) gave the corresponding N-alkylated quinolones 3a-g in 75-95% yields. The alkylation reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl halide gave a mixture of N-alkylated and O-alkylated products. Comparison of IR and NMR data of the N-alkylated and O-alkylated compounds with those of 2a-c indicated that 2a-c exist as the lactam form.     

Synthesis of 2-diphenylphosphinoyl-3,5-(diaryl)-3,4-dihydro-2H-thiopyrans by the reaction of a bis[(diphenylphosphinoyl)methyl]sulfide with chalcones

The NaH-promoted tandem Michael addition/intramolecular Horner-Wittig reaction of bis(diphenylphosphinoylmethyl)sulfide with chalcones afforded 3,4-dihydro-2H-thiopyrans 3a-l in 78-88% yield.     

Efficient synthesis and fluorescence properties of highly functionalized 2-aryl-quinazolin-4(3H)-ones

Three different methodologies for the preparation of highly substituted 2-aryl-quinazolin-4(3H)-ones including short and high-yielding reaction sequences are described. The 2-aryl-substituent of most of the target compounds bears three functional groups. The fluorescence properties of these compounds are presented and potential correlations between structure and optical properties are discussed.     

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.     

Tri-component reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones: synthesis of 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino-[4,5-b:4,5-e]-4H-thiopyran-1,6-dione and 2-(4-cyanophenoxy) pyrimidine

Reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones with p-cyanophenol and 2-mercaptopyrimidine in the presence of base gave 2,4,5-trisubstituted-pyridazin-3(2H)-ones 4-9, 2-(4-cyanophenoxy)pyrimidine (10) and 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-e]-4H-thiopyran-1,6-diones 11 as a novel heterocycle.     

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.     

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.     

Solvent-free microwave synthesis of 4-hydroxy-3-phenylquinolin-2(1H)-ones and variants using activated arylmalonates

The disclosure herein describes the rapid synthesis of 4-hydroxy-3-phenylquinolin-2(1H)-ones and variants via a solvent-free microwave cyclocondensation reaction using di-(2,4,6-trichlorophenyl)-2-phenylmalonate, which improves the general scope of this reaction.