2-(3-ethyl-2,2-dimethylcyclobutyl-methyl)-4(3H)-quinazolinones

Anthranilic acid and its 5-bromo and 4-chloro derivatives react with pinanoic and pinonoic acid chlorides to give the corresponding N-acyl derivatives. The pinanoyl derivatives give the corresponding 2-(3-ethyl-2,2-dimethyl-cyclobutylmethyl)-4-(3H)-quinazolinones when refluxed in formamide. Pinanoylanthranilic acid reacts with dicyclohexylcarbodiimide to give 2-(3-ethyl-2,2-dimethylcyclobutylmethyl)benz-3,1-oxazin-4(H)-one and subsequently with hydrazine hydrate to give 3-amino-2-(3-ethyl-2,2-dimethylcyclobutylmethyl)-4(3H)-quinazolinone. Refluxing of the pinanoyl- and pinonoylanthranilic acids with acetic anhydride gives acetylanthranilic acid, and pinonoylanthranilic acid gives 4(3H)-quinazolinone with formamide.Riga Technical University, Riga LV-1658, Latvia; e-mail: marina@osi.lanet.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 811–817, June, 1999.     

A facile synthesis of new 3-(2-benzimidazolyl)-2-alkyl-4-(3H)-quinazolinones under microwave irradiation

Preparation of 2-amino-N-(1-H-benzimidazol-2-yl)benzamide and a variety of new 3-(2-benzimidazolyl)-2-alkyl-4-(3H)-quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters under microwave irradiation are described.     

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.     

2-(3-Acetylamino-2,2-dimethylcyclobutyl)-methyl-4(3H)-quinazolinones

Beckmann rearrangement of N-[3-(1-hydroxyimino)ethyl-2,2-dimethylcyclobutyl]acetylanthranilic acid, and its 5-bromo and 4-chloro derivatives gives the corresponding N-(3-acetylamino-2,2-dimethylcyclobutyl)acetylanthranilic acids. Treatment of these acylanthranilic acids with formamide gives 2-(3-acetylamino-2,2-dimethylcyclobutyl)methyl-4(3H)-quinazoline and its 6-bromo and 7-chloro derivatives.     

Synthesis and anticonvulsant activity of 3-alkyl-3,4-dihydro-2(1H)-quinazolinones

Previously we reported the potent anticonvulsant activity of 3-dimethylamino-3,4-dihydro-2(1H)-quinazolinone. In this report, a series of 3-alkyl-3,4-dihydro-2(1H)-quinazolinones was synthesized in three steps from isatoic anhydrides or an anthranilic acid. Structure/activity investigations revealed optimal activity for the 3-isopropyl and 3-cyciohexyl analogs. These compounds were effective against seizures induced by maximal electroshock.     

Novel and efficient one-pot tandem synthesis of 2-styryl-substituted 4(3H)-quinazolinones

A novel one-pot tandem synthesis of 2-styryl-4(3 H)-quinazolinones in an acidic ionic liquid is reported. In this procedure isatoic anhydride, a primary aniline or ammonium acetate, and triethylorthoacetate are reacted in the presence of imidazolium trifluoroacetate [Hmim]TFA. Subsequently an aromatic aldehyde is added to the mixture to afford the title compounds in high to excellent yields.     

Lithiation of 2-Alkyl-3-amino- and 2-Alkyl-3-(methylamino)-4(3H)-quinazolinones(1)

3-Amino-2-methyl-4(3H)-quinazolinone has been doubly lithiated, on nitrogen and in the 2-methyl group, with n-butyllithium. The lithium reagent thus obtained reacts with a variety of electrophiles (D(2)O, benzophenone, cyclohexanone, cyclopentanone, acetophenone, benzaldehyde, tetraisopropylthiuram disulfide (TITD)) to give the corresponding 2-substituted derivatives in very good yields. Reactions of the dilithio reagent with 2 molar equiv of methyl iodide or phenyl isocyanate give disubstituted derivatives. Double lithiation of the 2-ethyl and 2-propyl analogues have been achieved using LDA, and subsequent reactions with most electophiles are then similar. In the reaction of the dianion of the 2-ethyl compound with TITD, deamination from position 3 takes place with the formation of the 2-substituted derivative. In reactions with prochiral ketones, the dianion of the 2-ethyl compound gives very high diastereoselectivity. Lithiation and subsequent reactions of 3-(methylamino) analogues take place in a similar manner, thus providing access to a range of substituted 3-(methylamino)-2-alkyl-4(3H)-quinazolinones by a general procedure. Lithiation of 3-(dimethylamino)-2-ethyl-4(3H)-quinazolinone did not take place under similar conditions. Lithiation of 3-amino-2-unsubstituted-4(3H)-quinazolinone was also unsuccessful.     

A microwave-assisted and heteropolyacids-catalysed cyclocondensation reaction for the synthesis of 4(3H)-quinazolinones

We have investigated a microwave-assisted synthesis of 4(3H)-quinazolinones by condensation of anthranilic acid, orthoesters (or formic acid) and substituted anilines,using Keggin-type heteropolyacids (H(3)PW(12)O(40).13H(2)O, H(4)SiW(12)O(40).13H(2)O,H(4)SiMo(12)O(40).13H(2)O or H(3)PMo(12)O(40).13H(2)O) as catalysts. We found that the the use of H(3)PW(12)O(40).13H(2)O acid coupled to microwave irradiation allows a solvent-free, rapid (approximately 13min) and high-yielding reaction.     

Concise synthesis of 2-amino-4(3H)-quinazolinones from simple (Hetero)aromatic amines

A novel and simple method of preparation of 2-alkylaminoquinazolin-4-ones with fused heteroaromatic rings from easily accessible (hetero)aromatic amines is described. The method is very efficient, and the 2-alkylaminoquinazolinone derivatives are obtained in three steps without chromatographic purification. The key step is the ring closure of the N-protected guanidine intermediates by intramolecular Friedel-Craft's type substitution.     

NMR studies of 4(3H)-quinazolinones and 4(3H)-quinazolinethiones

Summary Unambiguous¹H and¹³C NMR assignments for 4(3H)-quinazolinones1–6 and their corresponding 4-thiones7–12 have been made. This resulted in the revision of the previous assignments for the two benzenoid carbons (C-5 and C-8) of quinazolinones1,2,4, and5. Thionation of the nucleophilic amides1–6 has been found to cause a distinct change in the¹³C chemical shift of particularly C-4, but also of those of C-4a, C-5, and C-8a. One-bond and several long range heteronuclear coupling constants for the compounds have also been measured.

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Kernresonanzspektroskopie von 4(3H)-Chinazolinonen und 4(3H)-Chinazolinthionen

Zusammenfassung Die¹H- und¹³C-NMR-Spektren der 4(3H)-Chinazolinone1–6 und ihrer entsprechenden 4-Thione7–12 wurden zugeordnet. Dabei zeigte sich, daß eine frühere Zuordnung der beiden benzoiden Kohlenstoffe (C-5 und C-8) der Chinazolinone1,2,4 und5 falsch war. Ersatz des Sauerstoffs durch Schwefel in den nukleophilen Amiden1–6 führt insbesondere für C-4, aber auch für C-4a, C-5 und C-8a zu einer deutlichen Änderung der chemischen Verschiebung. Heteronukleare Kopplungskonstanten über eine und über mehrere Bindungen wurden bestimmt.

     

Efficient synthesis of 4(3H)-quinazolinones using a soluble polymeric support

4(3H)-Quinazolinones have been synthesized from poly(ethylene glycol)(PEG)supported aza-Wiuig reaction.2-Dialkylamino- 4(3H)-quinazolinones 6 were synthesized efficiently by reaction of secondary amine with PEG-supported carbodiimides 4,which were obtained from aza-Wittig reaction of PEG-supported iminophosphoranes 3 with isocyanates.     

A convenient preparation of 2-thioxo-4(3H)-quinazolinones

A simple method is described for the preparation of 3-aryl-2-thioxo-4(3H)-quinazolinones (4) by the reaction of anthranilic acids and ammonium or triethylammonium N-aryl-dithiocarbamates in ethanol. The method is also applicable to the preparation of 3-ethyl-2-thioxo-4(3H)-quinazolinone.     

Eco-friendly synthesis of 2-substituted-2,3-dihydro-4(1H)-quinazolinones in water

2-Substituted-2,3-dihydro-4(1H)-quinazolinones were synthesized in high yield by condensation of 2-anthranilamide with aromatic aldehydes or ketones in refluxing water without catalyst.This protocol has advantages of high yield,simple work-up and environmental friendly procedure.     

Facile and efficient synthesis of 2-substituted-N1-carbethoxy-2, 3-dihydro-4(1H)-quinazolinones in fluorous solvent

A facile, efficient and novel approach to access 2-substituted-N1-carbethoxy-2,3-dihydro-4(1H)-quinazolinones was developedby condensation of substituted N-carbethoxyanthranilamide with alkyl, aromatic or heteroaromatic aldehydes in the refluxing 2,2,2-trifluoroethanol or hexafluoroisopropanol using p-toluenesulfonic acid as catalyst.? 2008 Bai Ling Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.     

The use of aliphatic aldehydes for the synthesis of 4-alkyl-6-amino- 3,5-dicyanopyridine-2(1H)-thiones

The condensation of aliphatic aldehydes with malononitrile and cyanothioacetamide gives 4-alkyl-2,6-diamino-3,5-dicyano-4H-thiopyrans which recyclize into 4-alkyl-6-amino3,5-dicyanopyridine-2(IH)-thiones. The latter are easily S-alkylated with -haloacetonitriles and -haloacetophenones.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 938–942, April, 1996     

Synthesis of 4(3H)-quinazolinones from derivatives of methyl 2-isothiocyanatobenzoate

Ethyl N-(2-methoxycarbonylphenyl)thiocarbamate ( 2), N -(2-ethoxycarbonylphenyl)-4-methoxythiobenz-amide ( 3b ), and 2-(4-methoxyphenyl)-4H-3,1-benzothiazin-4-one ( 4a ), react with nucleophilic reagents containing at least one primary amino group to yield a variety of 2-substituted and 2,4-disubstituted 4(3H)quinazolinones, as well as some tricyclic and tetracyclic products.     

Synthesis and anticonvulsant activity of 3-amino-4(3H)-quinazolinones

Several 3-amino-4(3H)-quinazolinones were prepared from o-aminobenzoylhydrazines and triethyl orthoformate or from isatoic anhydrides, hydrazines and triethyl orthoformate. o-Aminobenzoylhydrazine intermediates were obtained by reaction of isatoic anhydrides with hydrazines. Some of the aminoquinazolinones displayed anticonvulsant activity in mice.     

Lithiation of 3-(Acylamino)-2-unsubstituted-, 3-(Acylamino)-2-ethyl-, and 3-(Acylamino)-2-propyl-4(3H)-quinazolinones: Convenient Syntheses of More Complex Quinazolinones(1)

3-(Pivaloylamino)- and 3-(acetylamino)-4(3H)-quinazolinones react with alkyllithium reagents to give 1,2-addition products in very good yields. Lithiation takes place with LDA and is regioselective at position 2. The lithium reagents thus obtained react with a variety of electrophiles to give the corresponding substituted derivatives in very good yields. Reactions of the lithium reagents with iodine give oxidatively dimerized cyclic structures. 3-(Pivaloylamino)- and 3-(acetylamino)-2-ethyl-4(3H)-quinazolinones and 3-(pivaloylamino)- and 3-(acetylamino)-2-propyl-4(3H)-quinazolinones are lithiated at the benzylic position with LDA. The lithium reagents so produced also react with a variety of electrophiles to give the corresponding 2-substituted-4(3H)-quinazolinone derivatives in very good yields. However, lithiation of 3-(acylamino)-2-(1-methylethyl)-4(3H)-quinazolinones was unsuccessful, as were lithiations of compounds having a diacetylamino group at position 3. The amide groups have been cleaved in good yield under basic or acidic conditions from some of the products to provide access to the free amino compounds.