Catalyst- and solvent-free coupling of 2-methyl quinazolinones and 3-(trifluoroacetyl)coumarins: An environmentally benign access of quinazolinone derivatives

An environmentally benign highly atom-economic protocol for the construction of the CC bond has been developed under catalyst- and solvent-free conditions. This protocol involves the efficient coupling of 2-methyl quinazolinones with 3-(trifluoroacetyl)coumarins for the access of quinazolinone derivatives in excellent yields (up to 90 %). The crystal structure of compound 3di was investigated by X-ray diffraction analysis. The biological activities, such as in vitro antifungal activity of the quinazolinone derivatives against Fusarium graminearum, Fusarium moniliforme, Fusarium oxysporum, Phytophthora parasitica var nicotianae, and Rhizoctonia solani Kuhn, were investigated. The bioassay results indicated that most of the target products exhibited promising fungicidal activities, and compound 3 cl exhibited 95 % fungicidal activity against R. solani, with an EC₅₀ value of 10.6 μg/mL.     

Evidence for involvement of cationic intermediate in epoxidation of chiral allylic alcohols and unfunctionalised alkenes catalysed by MnIII(quinazolinone) complexes

A pair of Mn^III(quinazolinone) complexes was prepared and evaluated in the catalytic epoxidation of the chiral allylic alcohols and unfunctionalised alkenes with iodosylbenzene. Epoxidation of chiral allylic alcohols with 1,3-allylic strain proceeded chemo- and diastereoselectively to give threo-epoxy alcohol (up to 99% d.r). Epoxidation of unfunctionalised alkenes by the proposed catalyst system proceeded nonselectively, as evidenced by the formation of isomerization and rearrangement products in the epoxidation of (Z)-stilbene. A three-step pathway involving a cationic intermediate is proposed for the formation of isomerization and rearrangement products. The fact that only products resulting from the cationic intermediate were detected in the oxidation of a mechanistic probe, (2-methoxy-3-vinylcyclopropyl)benzene, with Mn^III(quinazolinone) and PhIO substantiated the cationic oxygen transfer mechanism.     

Synthesis of some new pyrazoloquinazolinone and quinazolinone derivatives

The benzoxazinone derivative 2‐(6,8‐dibromo‐4‐oxo‐4H‐benzo[d]‐1,3‐oxazin‐2‐yl)‐3‐(4‐methoxyphenyl) acrylonitrile ( 1 ) has been used as a starting material for preparation of the hitherto unknown pyrazoloquinazolinone and quinazolinone derivatives. Under different conditions the benzoxazinone ( 1 ) was reacted with hydrazine hydrate to provide the pyrazolocarbonitrile derivative ( 2 ) and the azine derivative ( 3 ) and/or the pyrazoloquinazoline derivative ( 4 ). When ( 4 ) was conducted to react either with EAA (ethyl acetoacetate) or Ac₂O/AcOH (acetic anhydride/acetic acid) mixture or phthalic anhydride/acetic acid mixture, the pyrazoloquinazoline carbonitrile ( 5 ), pyrazolo‐quinazoline acetic acid ( 6 ) or the pyrazoloquinazolinone derivative ( 7 ) were formed respectively. When ( 1 ) was reacted with phenylhydrazine, a mixture of the quinazolinone derivative ( 8 ) and the hydrazone derivative ( 9 ) were obtained. The benzoxazinone derivative ( 1 ) was found also to react with benzylamine in ethanol or without solvent to give the quinazolinone derivative ( 10 ) or the quinazolindione ( 11 ) respectively. Fusion of ( 1 ) with ammonium acetate yielded the quinazolinone ( 12 ), which was methylated to give ( 13 ) and thiated to the thioxyquinazoline derivative ( 14 ), while reaction of ( 1 ) with formamide gave the N‐formylquinazoline derivative ( 15 ).     

Design,synthesis, biological activity evaluation and mechanism of action of myricetin derivatives containing thioether quinazolinone

Plant bacteria and viruses have a huge negative impact on food crops in the world. Therefore, it is important to create new and efficient green pesticides. In this paper, a series of myricetin derivatives containing quinazolinone sulfide were introduced. Good antibacterial and antiviral activities of the drug molecules 2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-6-fluoro-3-phenylquinazolin-4(3H)-one (T5) and 2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-6-methyl-3-phenylquinazolin-4(3H)-one (T15) respectively were found by biological activity screening. The value of dissociation constant (K_d) of compound T15 to TMV CP was 0.024 ± 0.006 μM, determined by Microscale thermophoresis (MST), which was far less than the value of 8.491 ± 2.027 μM of commercial drug ningnanmycin (NNM). The interaction between compound T15 and TMV CP was further verified by molecular docking. Compound T15 formed strong hydrogen bonds with residues SER:49 and SER:15 (1.92 Å, 2.20 Å, respectively), which were superior to the traditional hydrogen bonds formed by NNM with residue SER:215 (3.64 Å). In addition, the effects of compound T15 on the contents of chlorophyll and peroxidase (POD) in tobacco were studied, and the results indicated that compound T15 could enhance the disease resistance of tobacco plants to a certain extent.     

Synthesis of new azetidinonyl/thiazolidinonyl quinazolinone derivatives as antiparkinsonian agents

Several 3-amantadinyl-2-[(2-substituted benzylidenehydrazinyl)methyl]-quinazolin-4(3H)-ones (5a–5l) were prepared by the reaction of 3-amantadinyl-2-hydrazinylmethyl substituted quinazolin-4(3H)-ones (4a–4b) with various substituted aromatic aldehydes. Cycloaddition of compounds (5a–5l) with thioglycolic acid in the presence of anhydrous zinc chloride yielded 3-amantadinyl-2-[((substitutedphenyl)-4-oxo-thiazolidin-3-yl)methylamino]-quinazolin-4(3H)-ones (6a–6l). Compounds 5a–5l on further reaction with chloro acetyl chloride in the presence of triethylamine gave 3-amantadinyl-2-[((substitutedphenyl)-3-chloro-2-oxo-azetidin-1-yl)methylamino]-quinazolin-4(3H)-ones (7a–7l). The compounds 5a–5l, 6a–6l and 7a–7l were screened for their antiparkinsonian activity. The most active compound was 6g i.e. 3-amantadinyl-6-bromo-2-[((3,4-dimethoxyphenyl)-4-oxo-thiazolidin-3-yl)methylamino]-quinazolin-4(3H)-ones. Structures of the newly synthesized compounds were established on the basis of elemental and spectral (IR, ¹H NMR and mass) analysis.     

An efficient synthesis of 4-alkyl-2(1H)-quinazolinones and 4-alkyl-2-chloroquinazolines from 1-(2-alkynylphenyl)ureas

An efficient synthesis of 4-alkyl-2(1H)-quinazolinones has been achieved by cyclization of 1-(2-alkynylphenyl)ureas (2 R₂ = alkyl) in dichloroethane catalyzed by TfOH. In the case of aryl substitution (2 R₂ = aryl), a mixture of quinazolinone tautomers is obtained in dichloroethane with TFA as co-solvent. Chlorination of the resulting mixture affords 4-alkyl-2-chloro-quinazolines as sole products.     

Quinazolinone derivatives. Kinetics of the reaction of 2-chloromethyl-3-hydroxy-4-(3H)quinazolinone with nucleophiles

Reaction of 2-Chloromethyl-3-hydroxy-4(3H)quinazolinone ( 1 ) with aliphatic amines and hydroxide follows two different routes affording substituted methyl quinazolinones and a dimer 2 derived from 1 . The former were formed by S_N² reactions while the latter was formed by an inter-molecular nucleophilic displacement. Second-order and third-order rate constants, respectively, were determined, and the kinetic factors influencing both parallel reactions were analysed.     

Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids

Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids has been developed for the preparation of vasicinone and deoxyvasicinone by two approaches. The derivative of polymer-supported p-nitrophenyl carbonate was attached to anthranilic acid and then coupled with various bromo-lactams. This resin-linked bromo intermediate upon acetylation, hydrolysis and resin cleavage gave the cyclized [2,1-b]quinazolinones (vasicinone). Alternatively, resin-linked azido-benzoic acids were coupled with bromo-substituted lactams followed by cyclization in an aza-Wittig reductive cyclization process giving the bromo-substituted quinazolinone intermediates, with subsequent acetylation, hydrolysis and resin cleavage affording the fused [2,1-b]quinazolinones.     

Regioselective synthesis of N(3)‐ and O‐acylmethyl derivatives of 2‐methylthio‐4(3H)‐quinazolinone

Reaction of 2‐methylthio‐4(3H)‐quinazolinone with chloroacetone, ω‐bromoacetophenone or ethyl bromoacetate in different solvents (methanol, acetonitrile, dimethylformamide and toluene) using sodium methoxide or potassium carbonate as a base were studied. Regioselective N₍₃₎‐alkylation took place in toluene using potassium carbonate, whereas in dimethylformamide O‐acylmethyl derivatives were obtained. However chloroacetone reacted with 2‐methylthio‐4(3H)‐quinazolinone under various conditions to give a mixture of N₍₃₎/O‐isomers.     

Synthesis and Antibacterial Activity of 2‐substitued‐(3‐pyridyl)‐quinazolinone Derivatives

A series of 2‐substitued‐(3‐pyridyl)‐quinazolinone derivatives were synthesized, characterized, and evaluated for bacteriostatic activity against three species of phytopathogenic bacteria (Xanthomonas oryzae pv. oryzae, Xoo, Ralstonia solanacearum, and Xanthomonas axonopodis pv. citri, Xac). Biological evaluation showed that compounds 4b , 4g , 4h , 4l , and 4m exhibited higher antibacterial activity than bismerthiazol, the positive control, under conditions. In particular, compounds 4l and 4m exhibited significant bacteriostatic activity against Xac.     

Polymorph‐Dependent Solid‐State Fluorescence and Selective Metal‐Ion‐Sensor Properties of 2‐(2‐Hydroxyphenyl)‐4(3H)‐quinazolinone

2‐(2‐Hydroxy‐phenyl)‐4(3H)‐quinazolinone (HPQ), an organic fluorescent material that exhibits fluorescence by the excited‐state intramolecular proton‐transfer (ESIPT) mechanism, forms two different polymorphs in tetrahydrofuran. The conformational twist between the phenyl and quinazolinone rings of HPQ leads to different molecular packing in the solid state, giving structures that show solid‐state fluorescence at 497 and 511 nm. HPQ also shows intense fluorescence in dimethyl formamide (DMF) solution and selectively detects Zn²⁺ and Cd²⁺ ions at micromolar concentrations in DMF. Importantly, HPQ not only detects Zn²⁺ and Cd²⁺ ions selectively, but it also distinguishes between the metal ions with a fluorescence λ_max that is blue‐shifted from 497 to 420 and 426 nm for Zn²⁺ and Cd²⁺ ions, respectively. Hence, tunable solid‐state fluorescence and selective metal‐ion‐sensor properties were demonstrated in a single organic material.     

Novel Four-Step Synthesis of Thioxo-quinazolino[3,4-a]quinazolinone Derivatives

A novel synthesis of thioxo-quinazolino[3,4-a]quinazolinone framework was developed through a four-step reaction starting from isatoic anhydride. The resulting 2-aminobenzamides from the reaction of isatoic anhydride and different amines underwent coupling–cyclization reaction with 2-nitrobenzaldehydes, reduction of nitro group, and then cyclization reaction with carbon disulfide (CS₂). All steps were carried out under easy and user-friendly conditions in a short time without using expensive catalysts or reagents.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

Kumada cross coupling reaction based synthesis,antimicrobial and computational studies of 6-aryl-2-phenyl-3-methylquinazolin-4(3<Emphasis Type="Italic">H</Emphasis>)-ones

Nickel catalyzed Kumada cross coupling reaction, a novel synthetic method for the synthesis of 6-aryl-2-phenyl-3-methylquinazolin-4(3H)-ones (6a–6i), was carried out by condensing 6-iodo-2-phenyl-3-methyl-quinazolin-4(3H)-one (4) with various 6-aryl/heteroaryl Grignard reagents. Molecular properties of compounds 4 and 6a–6i were studied using semiempirical PM3 computational method. The optimized geometry of the product 6 indicated that the aryl group at the position 6 was not coplanar with respect to either quinazolinone ring or phenyl group at 2 position. Compounds 6a–6i were screened for their activity against bacteria and fungi.     

Benzologs of allopurinol: Synthesis of pyrazolo [4,3-g] and [3,4-f] quinazolinones

Convenient syntheses of pyrazolo [4,3-g]quinazolin-5 (6H) -one (3), its xanthine oxidase metabolite 4 and the [3,4-f] analog 5 have been developed, involving anellation of the pyrimidine ring onto aminoindazolcarboxylic acids 9 and 18, or attachment of the pyrazol portion onto quinazolinone 22 via intramolecular azo coupling.     

A facile total synthesis of rutaecarpine

The indoloquinazoline alkaloid rutaecarpine has been synthesized efficiently by employing 9,10,11,12-tetrahydro-4H-pyrido[2,1-b]quinazoline-4,9-dione (4) as a key intermediate, which was prepared by adapting a Dieckmann condensation-decarboxylation sequence from quinazolinone diester 6.     

Sartorymensin,a new indole alkaloid,and new analogues of tryptoquivaline and fiscalins produced by Neosartorya siamensis (KUFC 6349)

Seven new indole alkaloids including a new indoloazepinone derivative (2), two new quinazolinone derivatives (7, 8) and four new pyrazinoquinazolinone derivatives: epi-fiscalin C (10), epi-fiscalin A (12), neofiscalin A (13), epi-neofiscalin A (14) were isolated, together with 4-dihydroxy-3-methylacetophenone (1), tryptoquivaline (3), tryptoquivalines L (4), H (5), F (6) as well as fiscalins A (11) and C (9), from the culture of the fungus Neosartorya siamensis (KUFC 6349). The absolute configuration of the stereogenic carbons of the previously reported tryptoquivalines F, H, L was revised using the data obtained from an X-ray analysis of tryptoquivaline l and the NOESY correlations. The structures of the new pyrazinoquinazolinone derivatives (10, 12, 13, 14) were established based on 1D and 2D NMR spectral analysis, and the absolute configuration of their stereogenic carbons was determined by an X-ray crystallographic analysis of fiscalin C (9) and a new compound epi-fiscalin C (10), in conjunction with the correlations observed in their NOESY and long range COSY spectra. Compounds 2–8 and 12 were evaluated for their in vitro growth inhibitory activity on the human U373 and Hs683 glioblastoma, the A549 non-small cell lung cancer, the MCF-7 breast cancer and the SKMEL-28 melanoma cell lines by MTT colorimetric assay.     

Copper‐Catalyzed Coupling Reaction of 2‐Thioxo‐4‐quinazolinone and Thieno[3,2‐d]pyrimidin‐4‐one Methane Sulphonamide with Aryl Iodides: Preparation of Potential COX‐2 Selective Inhibitors

Thio‐aryl methane sulfonamide derivatives of 4‐quinazolinone and thieno[2,3‐d]pyrimidin‐4‐one were synthesized using powdery copper/copper(I) iodide as catalyst; their structural elucidation is also reported. These derivatives were planned as sulfur bioisosteres of selective COX‐2 inhibitor drugs.     

Efficient and selective microwave-assisted copper-catalyzed synthesis of quinazolinone derivatives in aqueous

Microwave-assisted copper-catalyzed cascade reactions between 2-halobenzoic acids and amidines to synthesize quinazolinone derivatives in water are reported. A variety of target products were obtained in good to excellent yields up to 94%. Its application was performed by the synthesis of 4-(1H-benzo[d]imidazol-2-ylthio)-6-methoxypteridine, which displayed significant anti-proliferation effect.     

Utilization of isatoic anhydride in the syntheses of various types of quinazoline and quinazolinone derivatives

Isatoic anhydride has attracted a great deal of attention in recent decades. A review of the methods of preparation of all known quinazoline and quinazolinone derivatives is given herein. Isatoic anhydrides react with some nitrogen nucleophiles, followed by cyclocondensation by electrophiles, to produce several quinazoline and quinazolinone derivatives. These compounds find use as medicinal and pharmacological substances.     

Synthesis of Some Novel 1,3,4‐Oxadiazol‐2‐yl‐4(3H)‐quinazolinones

N‐1‐Aroyl‐2‐{[(3‐methyl‐4(3H)‐quinazolinone‐2‐yl)methyl]anilino} ethano hydrazides (4), prepared from 2‐phenylaminomethyl‐3‐methyl‐4(3H)‐quinazolinone (1), underwent PPA‐catalyzed cyclization the to title compounds 5 in 51–67% yield.