Investigation of the regioselectivity of alkylation of 3-nitropyridin-2(1H)-ones

Alkylation of 3-nitropyridin-2(1H)-ones in the presence of bases affords N-alkylated products and sometimes O-alkylated products. The yields and relative amounts of N- and O-alkylated products depend substantially on the size of the substituent at the C(6) atom of pyridone.     

Chiral phosphine-catalyzed asymmetric allylic alkylation of 3-substituted benzofuran-2(3H)-ones or oxindoles with Morita-Baylis-Hillman carbonates

An efficient chiral phosphine-catalyzed asymmetric substitution reaction of MBH carbonates with 3-substituted benzofuran-2(3H)-ones or 3-substituted oxindoles has been described in this context, giving the corresponding allylic alkylation products bearing adjacent quaternary and tertiary stereogenic centers in high yields, moderate diastereoselectivities and high enantioselectivities under mild conditions.     

Chiral biscinchona alkaloid promoted asymmetric allylic alkylation of 3-substituted benzofuran-2(3H)-ones with Morita-Baylis-Hillman carbonates

A highly diastereo- and enantioselective asymmetric allylic alkylation reaction with respect to prochiral 3-substituted benzofuran-2(3H)-ones and MBH carbonate by a chiral biscinchona alkaloid catalyst was investigated. The corresponding adducts, containing a quaternary center at the C3-position of the benzofuran-2(3H)-one as well as a vicinal tertiary center, were generally obtained in high yields (up to 97%) with very good diastereo- (up to 98:2 dr) and enantioselectivities (up to 95% ee).     

Synthesis of 3-S-hetaryl-substituted pyridin-2(1H)-ones and 5,6-dihydropyridin-2(1H)-ones*

A method has been developed for the synthesis of 3-S-hetaryl-substituted pyridin-2(1H)-ones and 5,6-dihydropyridin-2(1H)-ones based on the base catalyzed cyclization of N-(3-oxoalkyl)- and N-(3-oxoalkenyl)amides which contain a divalent sulfur atom in an α-position to a carbamoyl group and bound to the heterocycle.     

Synthesis of (hetero)arylated pyridazin-3(2H)-ones via Negishi reaction involving zincated pyridazin-3(2H)-ones

Zincated pyridazin-3(2H)-ones generated via bromine-magnesium exchange followed by transmetalation using ZnCl(2) or via lactam-directed ortho C4-H zincation with TMPZnCl·LiCl have been synthesized. These in situ created organometallics can be used in Negishi reactions with iodo(hetero)arenes delivering a new approach toward (hetero)arylpyridazin-3(2H)-ones.     

Improved Method for Preparation of 3-(1H-Indol-3-yl)benzofuran-2(3H)-ones

3-(1H-Indol-3-yl)benzofuran-2(3H)-ones were efficiently accessed via polyphosphoric acid-mediated condensation of 3-(2-nitrovinyl)-1H-indoles with phenols.     

Synthesis of regioisomeric N- and O-alkylated 3-polyfluoroalkyl-1,2-dihydroquinoxalin-2-ones

3-Polyfluoroalkyl-1,2-dihydroquinoxalin-2-ones react with 4-bromobutyl acetate to furnish 1-(4-acetoxybutyl)quinoxalin-2-ones and 2-(4-acetoxybutoxy)quinoxalines in the ratio 2: 1. Deacylation of these compounds under acidic conditions gives the corresponding 1-(4-hydroxybutyl)- and 2-(4-hydroxybutoxy)-substituted quinoxalines. The structures of compounds synthesized were established by X-ray crystallography, IR spectroscopy, ¹H and ¹⁹F NMR spectroscopy, GLC-MS.     

Synthesis of 2-Acyl- and 2-Sulfonylbenzisoselenazol-3(2H)-ones

Synthesis of two new groups of organoselenium compounds: 2-acyl-and sulfonylbenzisoselenazol-3(2H)-ones (3, 4), potential immunostimulants, in two alternative ways was elaborated. One of them was based on the reaction of 2-chlorobenzoyl chloride (2) with primary amides while the second one involved N-acylation or N-sulfonylation of benzisoselenazol-3(2H)-one (5) with acid chlorides. Two exceptions from general reaction of dichloride 2 with amides were observed. Thioacetamide produced 2,1-benzothiaselenophenone (6), and urea gave 6,7-benzo-2,4-diaza-1-selenacyclohepta-3,5-dione (7).     

Azo coupling of 5-substituted furan-2(3H)-ones and 1H-pyrrol-2(3H)-ones with arene(hetarene)diazonium salts

5-Substituted furan-2(3H)-ones and 1-phenyl-1H-pyrrol-2(3H)-ones reacted with diazonium salts derived from substituted anilines and 1H-1,2,4-triazol-5-amine to give azo coupling products at the methylene group in the heteroring. The products were found to exist as hydrazone tautomers.     

Molecular oxygen-mediated selective hydroxyalkylation and alkylation of quinoxalin-2(1H)-ones with alkylboronic acids

Herein, an efficient molecular oxygen-mediated method for the selective hydroxyalkylation and alkylation of quinoxalin-2(1H)-ones with alkylboronic acids under transition-metal free conditions has been developed. This strategy demonstrates a broad scope of quinoxalin-2(1H)-ones and alkylboronic acids, giving 3-hydroxyalkylquinoxalin-2(1H)-ones and 3-alkylquinoxalin-2(1H)-ones in moderate-to-good yield. Control experiments reveal that a radical pathway is involved.     

Rapid and Efficient Synthesis of 3,3-Di(1H-indol-3-yl)indolin-2-ones and 2,2-Di(1H-indol-3-yl)-2H-acenaphthen-1-ones Catalyzed by p-TSA

An efficient synthesis of 3,3-di(1H-indol-3-yl)indolin-2-ones and 2,2-di(1H-indol-3-yl)-2H-acenaphthen-1-ones via a reaction of various isatins or acenaphthenequinone with indoles in the presence of p-methylbenzene sulfonic acid (p-TSA) in CH₂Cl₂ at room temperature is described. The advantages of this method include good reaction yield, simple workup procedure, and mild reaction condition.     

Thioureidoquinazolin-4(3H)-ones

3-(N′, N′-Dialkylthioureido)quinazolin-4(3H)-ones prepared by the reaction of 3-aminoquinazolin-4(3H)-one with thiuram disulfides undergo the previously, unknown acid-induced recyclization to give the corresponding 5-(2-aminophenyl)-2-dialkylamino-1,3,4-thiadiazoles. The structures of the products obtained were confirmed by IR and¹H and¹³C NMR data. A plausible mechanism of the recyclization is discussed.     

Solid-phase syntheses of 6-arylpyridazin-3(2H)-ones

The 3-chloropyridazine moiety was immobilized on a Wang resin, using two different methodologies. The first of these involved direct nucleophilic substitution of 3,6-dichloropyridazine with the alcoholate of Wang resin. The experimental conditions were optimized. The second method involved a Mitsunobu reaction between the Wang resin and 6-chloropyridazin-3-ol during which a problem of regioselectivity was observed. The so-obtained chloropyridazine-containing resins were subsequently reacted with various arylboronic acids under Suzuki conditions. Acid cleavage yielded 6-arylpyridazin-3(2H)-ones with high chemical purity.     

Palladium-catalyzed carbonylative annulation reaction of 2-(1-alkynyl)benzenamines: selective synthesis of 3-(halomethylene)indolin-2-ones

A novel and selective palladium-catalyzed carbonylative annulation process for the synthesis of 3-(halomethylene)indolin-2-ones was demonstrated. In the presence of PdX2 and CuX2, 3-(halomethylene)indolin-2-ones were selectively obtained from the carbonylative annulations of 2-(1-alkynyl)benzenamines with CO in moderate to good yields.     

Structural assignment of regioisomeric 3-[2- or 5-anilino-2-(alkylamino)phenyl]propanoic acids, 2H-1,4-benzothiazin-3(4H)-ones and 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones by 1D NOE and gHMBC NMR techniques

The 1H and 13C NMR spectra of compounds 1-11 and 16-22 in CDCl3 and DMSO-d6 solutions allowed structural assignment to regioisomers 1/5 and 2/6 and their regioselective cyclization products 16-18 utilizing one- and two-dimensional NMR techniques (APT, DEPT, NOE difference, COSY, NOESY, HETCOR and gHMQC, gHMBC). Temperature-dependent 1H NMR spectra of 8-anilino-5-(4-methyl-2-pentyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (18) indicated a free energy of activation (deltaG++) of ca 17 kcal mol(-1) for interconversion between rotamers. The 1H and 13C NMR spectra of 20 and 22 containing two chiral centers exhibit duplication of several signals, indicating the existence of two diastereomeric forms. The structure of 4 was unambiguously confirmed by x-ray crystallography.     

Electron ionization mass spectra of some 4β-phenyl-substituted cycloalkane-cis-fused 1,3-oxazin-2(3H)-ones, -2(3H)-thiones and 1,4-oxazepin-3(4H)-ones

The 70 eV mass spectra of 4β-phenyl-substituted cyclopentane- and cyclohexane cis-fused 1,3-oxazin-2(3H)-ones, the two related 2-thiones, 6,7-cis-trimethylene-5β-phenyl-1,4-oxazepin-3(4H)-one and its 2β-methyl derivative were recorded and their fragmentations examined by means of metastable ion analysis, collision induced dissociation technique and exact mass measurement. The fragmentation patterns of the 1,3-oxazin-2(3H)-ones were relatively simple: the favored formation of cycloalkene ions implied that a considerable proportion of the molecular ions might possess an enol structure. Changes in the size of the fused cycloalkane ring had little or no effect on the fragmentations. Instead, small changes in the heterocyclic part of the molecule caused remarkable effects on the fragmentation behavior. Compared to 1,3-oxazin-2(3H)-ones studied, both 1,3-oxazine-2(3H)-thiones and 1,4-oxazepin-3(4H)-ones showed much more complicated fragmentation patterns.     

Green chemistry approach to the synthesis of 3-substituted-quinazolin-4(3H)-ones and 2-methyl-3-substituted-quinazolin-4(3H)-ones and biological evaluation

ABSTRACT

A synthesis of two series of 3-substituted quinazolinones was performed utilizing a green chemistry approach, deep eutectic solvents and microwaves, namely. 2-Methyl-3-substituted-quinazolin-4(3H)-one derivatives were synthesized in a two-step reaction, using choline chloride:urea deep eutectic solvent (DES). 3-Substituted-quinazolin-4(3H)-ones were synthesized in one-pot one-step reaction of anthranilic acid, amines and orthoester in a microwave reactor. For the synthesis of 2-methyl-3-substituted-quinazolin-4(3H)-ones, first conventional synthesis of benzoxazinone, as an intermediate, was performed. Further, benzoxazinone in reaction with corresponding amines, in choline choline:urea deep eutectic solvent, furnished desired compounds. These procedures are based on green principles with the aim of developing synthetic routes for the potential antitumor agents. All compounds were characterized by LC/MS, ¹H NMR and ¹³C NMR spectral techniques. Compound 1 bearing trifluoromethoxyphenyl group showed promising activity against HuT-78 cell line with IC₅₀ of 51.4?±?5.1?µM.