Solid-phase synthesis of 3-alkyl-8-arylamino-1H-imidazo[4,5-g]quinazolin-2(3H)-thiones and 3-alkyl-8-arylamino-1H-imidazo[4,5-g]quinazolin-2(3H)-ones

An efficient approach for the synthesis of 3-alkyl-8-arylamino-1H-imidazo[4,5-g]quinazolin-2(3H)-thiones and 3-alkyl-8-arylamino-1H-imidazo[4,5-g]quinazolin-2(3H)-ones on solid phase has been developed. The reaction conditions were readily amenable and the products were obtained in good yields and purities after their cleavage from the resin.     

Iodine-catalyzed synthesis of 2-arylpyrazolo[5,1-b]quinazolin-9(3H)-one derivatives in ionic liquids via domino reaction

The domino reaction of (E)-2-amino-N′-(1-arylethylidene)benzohydrazide and triethyl orthoformate in ionic liquids catalyzed by 10 mol % iodine gave 3a,4-dihydro-2-arylpyrazolo[5,1-b]quinazolin-9(3H)-one derivatives unexpectedly. In the presence of K₂S₂O₈, it could be oxidized to aromatized products in good yields.     

One-pot synthesis of quinazolin-4(3H)-ones and fused quinazolinones by a palladium-catalyzed domino process

An efficient one-pot synthesis of quinazolin-4(3H)-ones, benzoimidazo[2,1-b]quinazolin-12(6H)-ones and imidazo[2,1-b]quinazolin-5(1H)-ones via a palladium-catalyzed domino process has been developed. The Pd-catalyzed reactions of 2-azidobenzamides 1 with isocyanides 2 produced quinazolin-4(3H)-ones 4 at room temperature by a domino Pd-catalyzed cross-coupling/carbodiimide-mediated cyclization. However, as 2-azido-N-(2-bromophenyl)benzamides 1 were used under heating condition in the presence of Cs₂CO₃, the benzoimidazo[2,1-b]quinazolin-12(6H)-ones 5 were directly obtained by twice Pd-catalyzed domino cyclization. A domino reogioselective 5-exo-dig intramolecular cyclization reaction of alkynyl-containing azides 6 with isocyanides 2 generated imidazo[2,1-b]quinazolin-5(1H)-ones 9 in 74–93% yields in the presence of catalyst Pd(PPh₃)₄ and K₂CO₃.     

Novel series of 8H-quinazolino[4,3-b]quinazolin-8-ones via two Niementowski condensations

Efficient microwave-assisted multi-step synthesis of 8H-quinazolino[4,3-b]quinazolin-8-one was investigated. The synthesis involved two Niementowski condensations from anthranilic acids. Homogeneous or heterogeneous conditions were studied with the aim to develop convenient syntheses of the desired compounds.     

Copper(I)-catalyzed synthesis of 1-arylpyrazolo[5,1-b]quinazolin-9(1H)-one via intramolecular alkyne hydroamination

The 1-arylpyrazolo[5,1-b]quinazolin-9(1H)-one derivatives were obtained via intramolecular alkyne hydroamination reaction of 2-amino-N′-arylbenzohydrazide and alkynal diethyl acetal in the presence of CuBr and Cs₂CO₃. This new procedure provides an efficient method to construct fused tricyclic heterocycle containing both pyrazole and quinazoline analogues.     

Reactions of 2-aminothiobenzamide with isocyanates: A new synthesis of 2, 3-dihydroimidazo[1, 2-c]quinazolin-5(6H)-one and 3, 4-Dihydro-2H-pyrimido[1, 2-c]quinazolin-6(7H)-one

2-(2-Chloroethylureido)- and 2-(3-chloropropylureido)thiobenzamides 5a, b were prepared in good yields by treating 2-aminothiobenzamide with 2-chloroethyl and 3-chloropropyl isocyanates respectively. Subsequent treatment of compound 5a and 5b either with alkali or mineral acid led to the formation of 2, 3-dihydro-imidazo[1, 2-c]quinazolin-5(6H)-one 7a and 3, 4-Dihydro-2H-pyrimido[1, 2-c]quinazolin-6(7H)-one 7b .     

Aryl radical cyclizations of N-(2-halobenzoyl)-cyclic ketene-N,S-acetals

2-Ethylthiazolines react with 2-halobenzoyl chlorides to form N-(2-halobenzoyl)-cyclic ketene-N,S-acetals, which undergo stereo-controlled radical cyclizations to afford (R,S,S)-3-alkyl-10-methyl-2,3,10,10a-tetrahydrothiazolo[3,2-b]isoquinolin-5-one and (R,R,S)-3-alkyl-10-methyl-2,3,10,10a-tetrahydrothiazolo[3,2-b]isoquinolin-5-one.     

Studies on quinazolinones. 2. Synthesis of 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-oxazolo[2,3–6]quinazolin-5-one and -2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one

To search for novel antihypertensive heterocycles in the condensed quinazoline series, two representative compounds were synthesized via a suitable reaction sequences. Treating anthranilonitrile with allyl isocyanate gave 2-(allylureido)benzonitrile ( 10 ) in a quantitative yield. Compound 10 was cyclized to 3-allylquinazoline-2(1H, 4(3H)-dione ( 11 ). Bromination of 11 in carbon tetrachloride converted it into the corresponding 3-(2,3-dibromopropyl) derivative ( 12 ) in 92% yield. Ring closure of 12 was effected by the action of alkali to afford 2-bromomethyl-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one ( 13 ). The title compound, 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one ( 7 ) could be obtained by a reaction of either 12 or 13 with 1-benzylpiperazine respectively. Starting from the readily available 3-allyl-2H-thioxoquinazolin-4(3H)-one ( 16 ) via the analogous reactions gave the 2-bromomethyl-2,3-dihydro-5H-thiazolo[2,3-b]-quinazolin-5-one ( 19 ) in good yield. However, the reaction of 19 with 1-benzylpiperazine provided another target compound, 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one ( 8 ) only in poor yield (8%). As major product, the dehydrobrominated compound, 2-methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one ( 22 ) was isolated. A preliminary pharmacological evaluation revealed that both compounds 7 and 8 are devoid of the antihypertensive activity.     

Convenient synthesis of 6,7-dihydroazolo[5,1-b]quinazolin-8(5H)-one derivatives

Three-component condensation of 3(5)-aminoazoles with benzaldehydes and dimedone in acetonitrile in the presence of montmorillonite KSF as heterogeneous catalyst regioselectively afforded 5,6,7,9-tetrahydroazolo[5,1-b]quinazolin-8(4H)-one derivatives in good yields. Oxidation of the condensation products with ceric ammonium nitrate in acetone gave the corresponding 6,7-dihydroazolo[5,1-b]quinazolin-8(5H)-ones.     

Preparation of novel heterocyclic systems from isatoic anhydrides

Isatoic anhydride ( 1a ) and 5-chloroisatoic anhydride ( 1b ) were treated with 2-(1-methylhydrazino)ethanol ( 2 ) to produce 2-aminobenzoic acid 2-(2-hydroxyethyl)-2-methylhydrazide ( 3a ) and its 5-chloro analog 3b , respectively. Treatment of 3a and 3b with carbon disulfide gave, respectively, 2,3-dihydro-3-[(2-hydroxyethyl)methylamino]-2-thioxo-4-(1H)quinazolinone ( 4a ) and its 6-chloro analog 4b . Compounds 4a and 4b afforded 5,6-dihydro-5-methyl-2-thioxo-4H,8H-[1,3,5,6]oxathiadiazocino[4,5-b]quinazolin-8-one ( 5a ) and its 10-chloro analog 5b , respectively, upon treatment with thiophosgene. Compound 5a could be produced directly from 3a and thiophosgene. Treatment of 4a and 4b with trifluoroacetic anhydride followed by potassium carbonate gave 3,4-dihydro-4-methyl-2H,6H-[1,3,4]thiadiazino[2,3-b]quinazolin-6-one ( 7a ) and its 8-chloro analog 7b , respectively. Treatment of 4a with thionyl chloride also gave 7a , but 4b and thionyl chloride afforded a mixture of 7b and 8-chloro-3,4-dihydro-4-methyl-2H,6H-[1,3,4]oxadiazino[2,3-b]quinazolin-6-one ( 10 ). The dimethyl analogs of 4a and 4b ( 13a and 13b ) upon treatment with thiophosgene afforded 3,4-dihydro-2,2,4-trimethyl-2H,6H-[1,3,4]oxadiazino[2,3-b]quinazolin-6-one ( 14a ) and its 8-chloro analog 14b , respectively.     

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.     

Reactions of o-aminonitriles with isocyanates. 1. A two-step synthesis of 2,6-dihydroimidazo[1,2-c]quinazolin-5-(3H)one

The reaction of anthranilonitrile with 2-chloroethyl isocyanate yields 2-[3-(2-chloroethyl)ureido]benzo-nitrile ( 6 ) which, upon heating, or treatment with base, undergoes a double cyclization to form 2,6-dihydroimidazo[1,2-c]quinazolin-5-(3H) one ( 8 ) in excellent yield. When heated with hydrochloric acid, 6 is converted initially into 2-(2-chloroethylamino)-4H-[3,1]benzoxazin-4-one ( 18 ) and further into 3-(2-chloroethyl)-2,4-(1H,3H)quinazolinedione ( 15 ). The acid-catalyzed reaction of 2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one ( 14 ) with nucleophilic reagents yields 3-substituted 2,4-(1H,3H)quinazolinediones.     

Microwave synthesis,characterization and antimicrobial study of new pyrazolyl-oxopropyl-quinazolin-4(3H)-one derivatives

Heterocyclic compounds containing pyrazolyl-oxopropyl-quinazolin-4(3H)-one are reported to possess significant biological activity. Syntheses of 6-bromo-2-(3-chloro-2-oxopropyl)-3-(4-fluorophenyl)quinazolin-4(3H)-one 2 6-bromo-3-(4-fluorophenyl)-2-(3-hydrazinyl-2-oxopropyl)quinazolin-4(3H)-one 3 and 6-bromo-2-(3-(3-(4-(1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneamino)phenyl)-5-(substituted phenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxopropyl)-3-(4-fluorophenyl)quinazolin-4(3H)-one 5a–j using microwave irradiation have been described. These compounds have been characterized on the basis of the UV, IR, ¹H NMR, ¹³C NMR, Mass and elemental analysis. Compounds have been evaluated for their antimicrobial activity.     

Metaboliten der 1,5-Dihydroimidazo[2,1-b]chinazolin-2(3H)-one. Synthese und Reaktionen einiger 1,5-Dihydro-3-hydroxyimidazo[2,1-b]chinazolin-2(3H)-one

Metabolites of 1,5-Dihydroimidazo[2,1-b ]quinazolin-2(3H)-ones. Preparation and Reactions of Some 1,5-Dihydro-3-hydroxyimidazo[2,1-b]quinazolin-2(3H)-ones Hydroxylated 1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-ones 2–4 and 6 were isolated as metabolites of imidazoquinazolinones 1a and 1b , respectively. The synthesis of 1,5-dihydro-3-hydroxy-3-methylimidazo[2,1-b]quinazolin-2(3H)-ones 3 , 4 , and 6 , and the preparation of some derivatives thereof is described.     

Some Transformations of 2-(Chloromethyl)-5,5-dimethyl-5,6-dihydrobenzo[<Emphasis Type="Italic">h</Emphasis>]quinazolin-4(3<Emphasis Type="Italic">H</Emphasis>)-one

The condensation of 1-amino-3,3-dimethyl-3,4-dihydronaphthalene-2-carbonitrile with chloroacetyl chloride afforded chloro-N-(2-cyano-3,3-dimethyl-3,4-dihydronaphthalen-1-yl)acetamide which underwent cyclization to 2-(chloromethyl)-5,5-dimethyl-5,6-dihydrobenzo[h]quinazolin-4(3H)-one. The latter reacted with various nucleophiles (alkali metal alkoxides, piperazine, 2-sulfanylethanol) to give 2-(alkoxymethyl)-, 2-(piperazin-1-ylmethyl)-, and 2-{[(2-hydroxyethyl)sulfanyl]methyl}-5,5-dimethyl-5,6-dihydrobenzo[h]quinazolin- 4(3H)-ones. The condensation of 2-(chloromethyl)benzo[h]quinazoline with 2-thioxo derivatives of quinazoline and benzo[h]quinazolines led to the formation of bis-quinazolines in which 5,5-dimethyl-5,6- dihydrobenzo[h]quinazolin-4(3H)-one fragment is linked to quinazoline or benzo[h]quinazoline system through a CH₂S bridge.     

Preparation of 6-aminoquinazolin-4(3H)-ones via direct SNAr on the quinazoline ring

The preparation of 6-aminoquinazolin-4(3H)-ones requires the use of platinum–metal group catalysis on the corresponding C-6-iodo or 6-bromo precursors. Herein, we report to our knowledge the first successful S_NAr reaction directly at the unactivated C-6 position of the quinazolin-4(3H)-one nucleus.     

Methyl 3,3,3-trifluoro-2-(thiazol-2-ylimino)propionate in cycloaddition and cyclocondensation reactions

The behavior of methyl 3,3,3-trifluoro-2-(thiazol-2-ylimino)propionate (1) in cycloaddition and cyclocondensation reactions was studied. Cycloaddition of dimethylcyanamide to imine 1 gave a thiazolo[3,2-a][1,3,5]triazine derivative. Cyclocondensations of imine 1 with 2-aminothiazoline, N-cyclohexylbenzamidine, methyl (Z)-3-aminobut-2-enoate, and 6-amino-1-benzyluracil yielded dihydroimidazo[2,1-b]thiazol-5(6H)-one, 4,5-dihydroimidazol-5-one, 4,5-dihydro-1H-pyrrol-5-one, and dihydro-1H-pyrrolo[2,3-d]pyrimidine-2,4,6-trione derivatives, respectively.     

Synthesis and heterocyclization of 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}pyrimidin-4(3<Emphasis Type="Italic">h</Emphasis>)-ones

Alkylation of sodium 4(5)-alkyl-6-oxo-1,6-dihydropyrimidine-2-thiolates with 2-bromo-1-(4-bromophenyl)ethan-1-one afforded 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}pyrimidin-4(3H)-ones. Analogous reaction with sodium 4-trifluoromethyl-6-oxo-1,6-dihydropyrimidine-2-thiolate gave a mixture of 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}-4-(trifluoromethyl)pyrimidin-4(3H)-one and its intramolecular cyclization product, 3-(4-bromophenyl)-3-hydroxy-7-trifluoromethyl-2,3-dihydro[1,3]thiazolo[3,2-a]-pyrimidin-5-one.     

Transition metal-free synthesis of quinolino[2′,3′:3,4]pyrazolo[5,1-<Emphasis Type="Italic">b</Emphasis>]quinazolin-8(6<Emphasis Type="Italic">H</Emphasis>)-ones via cascade dehydrogenation and intramolecular <Emphasis Type="Italic">N</Emphasis>-arylation

2-(2-Chloroquinolin-3-yl)-3-(arylamino)-2,3-dihydroquinazolin-4(1H)-one was converted to quinolino[2′,3′:3,4]pyrazolo[5,1-b]quinazolin-8(6H)-ones in the presence of KOtBu in DMSO at room temperature. The present method has the advantages of easy conditions, construction of highly novel five heterocycles, transition metal-free conditions, cascade dehydrogenation and intramolecular N-arylation and good to high yield of products.     

Directed regiospecificity of 1,3-dipolar cycloaddition of 2-diazopropane to 4- and 5-substituted pyridazin-3(2H)-ones

6-Methoxy-2-methylpyridazin-3(2H)-one ( 1 ) gave with 2-diazopropane ( 8 ) a mixture of 3H-pyrazolo[3,4-d]-pyridazin-4(5H)-one derivative 12 , as the main product, and -7(6H)-one derivative 10 , as the minor product. On the other hand, 4-substituted pyridazin-3(2H)-ones 2, 3 , and 4 gave 3H-pyrazolo[3,4-d]pyridazin-7(6H)-one 10 , exclusively, while 5-substituted pyridazin-3(2H)-ones 5, 6 , and 7 produced only the isomeric 3H-pyrazolo[3,4-H]pyridazin-4(5H)-one 12 . The 5-phenylsulfonyl derivative 13 gave with 8 by elimination of a molecule of nitrogen, followed by rearrangement, 1,2-diazepine derivative 15 and with an excess of 8 3H-pyrazolo[3,4-d][1,2]diazepine derivative 16. 1 ,2-Dimethylpyridazine-3,6-(1H,2H)-dione and its derivatives 18 and 19 produced 3H-pyrazolo[3,4-d]pyridazine-4,7(5H,6H)-dione derivative 23 , while from 17 and 1-diazoindane ( 24 ) the spiro compound 27 was obtained. The 1,2-dihydro and 3a,7a-dihydro intermediates 21 and 25 were isolated.