Functionalization of Quinazolin‐4‐Ones Part 2#: Reactivity of 2‐Amino‐3, 4, 5, or 6‐Nitrobenzoic Acids with Triphenylphosphine Thiocyanate,Alkyl Isothiocyanates,and Further Derivatization Reactions

2‐amino‐3, 4, 5, or 6‐nitrobenzoic acids were reacted with PPh₃(SCN)₂ and alkyl isothiocyanates to give 5, 6, 7, or 8‐nitro‐2‐thioxo‐3‐substituted quinazolin‐4‐ones, respectively. The position of the nitro group was found to have significant influence on the outcome of the reactions. Similarly, the nature of the substituent at position 8 (NO₂, NH₂, NH(C═O)CH₃) in 8‐substituted‐2‐methylthio quinazolin‐4‐ones was also found to significantly influence their reactivity towards morpholine. A selection of the products were also tested for in vitro antibacterial activity but little activity was observed.     

Facile synthesis of 2‐alkylthio‐3‐amino‐4 H‐imidazol‐4‐ones and 2H‐imidazo[2,1‐b]‐1,3,4‐thiadiazin‐6(7H)‐ones via N‐vinylic iminophosphorane

2‐Alkylthio‐3‐amino‐4H‐imidazol‐4‐ ones 5 were synthesized by S‐alkylation of 2‐thioxo‐3‐amino‐4‐imidazolidinones 4 , which were obtained via cyclization of isothiocyanates 2 with hydrazine hydrate. 5l–n reacted with Ph₃P, C₂Cl₆, and NEt₃ to give 2H‐imidazo[2,1‐b]‐1,3,4‐thiadiazin‐ 6(7H)‐ones 7a–c in good yields. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:76–80, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20069     

Simple and Efficient Synthesis of Novel 3‐Substituted 2‐Thioxo‐2,3‐dihydro‐1H‐benzo[g]quinazolin‐4‐ones and Their Reactions with Alkyl Halides and α‐Glycopyranosyl Bromides

A series of 3‐substituted 2‐thioxo‐2,3‐dihydro‐1H‐benzo[g]quinazolin‐4‐ones 4a – e were synthesized from the reaction of 3‐aminonaphthalene‐2‐carboxylic acid 1 with isothiocyanate derivatives 2a – e . The alkylation of 4a – e with alkyl halides gave 3‐substituted 2‐alkylsulfanyl‐2,3‐dihydro‐1H‐benzo[g]quinazolin‐4‐ones 5a – o . S‐Glycosylation was carried out via the reaction of 4a – e with glycopyranosyl bromides 7a and 7b under anhydrous alkaline conditions. The structure of the compounds was established as S‐nucleoside and not N‐nucleoside. Conformational analysis has been studied by homonuclear and heteronuclear two‐dimensional NMR methods (2D DFQ‐COSY, heteronuclear multiple quantum coherence, and heteronuclear multiple bond correlation). The S site of alkylation and glycosylation was determined from the ¹H and ¹³C heteronuclear multiple quantum coherence experiments.     

2,5‐Disubstituted Pyrazolo[4,3‐c]cinnolin‐3‐ones

Complementary strategies to 2,5‐disubstituted pyrazolo[4,3‐c ]cinnolin‐3‐ones are reported herein, providing late stage substituent introduction at either the 2‐ or the 5‐position. Treating a readily prepared 4‐thiocinnoline ester with substituted hydrazines afforded late stage access to the 2‐position, while late stage substituent introduction at the 5‐position was achieved via two different strategies: alkylation of 4‐hydrazonopyrazol‐3‐ones, followed by a ring‐closing intramolecular S_NAr tactic and direct reaction of 5‐(2‐fluorophenyl)‐2,4‐dihydro‐3H‐pyrazol‐3‐ones with aryl diazonium salts, followed by cyclization. The strategies described herein provide practical and general methods to prepare 2,5‐disubstituted pyrazolo[4,3‐c ]cinnolin‐3‐ones.     

Synthesis,Characterization and Crystal Structure of Some Novel 1‐Aryl‐2‐Thioxo‐2,3‐Dihydro‐1H‐Quinazolin‐4‐Ones

The base catalyzed intramolecular nucleophilic cyclization of 1‐(2‐haloaroyl)‐3‐aryl thioureas ( 1a‐i ), in the presence of DMF afforded the 1‐aryl‐2‐thioxo‐2,3‐dihydro‐1H‐quinazolin‐4‐ones ( 2a‐i ). The structures were confirmed by spectroscopic data, elemental analyses and in case of the 2c by single crystal X‐ray diffraction data. The mechanistic studies support an intramolecular nucleophilic substitution (S_NAr mechanism) rather than intramolecular aromatic substitution (S_RN1 mechanism).     

Nickel boride mediated reductive desulfurization of 2‐thioxo‐4(3H)‐quinazolinones: A new synthesis of quinazolin‐4(3H)‐ones and 2,3‐dihydro‐4(1H)‐quinazolinones

A novel one‐pot approach for the synthesis of aryl substituted quinazolin‐4(3H)‐ones and 2,3‐dihydro‐4(1H)‐quinazolinones has been reported based on the reductive desulfurization of 3‐aryl‐2‐thioxo‐4(3H)‐quinazolinones with nickel boride in dry methanol at ambient temperature.     

6‐Methoxy‐2‐oxo‐1,2‐dihydroquinoline‐3,4‐dicarbonitriles,A Red Compound Class with Solvent and pH Independent Green Fluorescence Maxima

The sodium p‐toluenesulfinate mediated reaction of potassium cyanide with 4‐chlorocarbostyrils 8 , 16 , 18 , and 23 gave in all cases the highly fluorescent and stable 6‐methoxy‐2‐oxoquinoline‐3,4‐dicarbonitrile 9 (λ_exc 460 nm and λ_em 545 nm). This is remarkable, because starting carbostyrils 8 , 16 , 18 , and 23 had a chloro substituent, a nitro substituent, an acetylamino substituent, or a piperidinyl substituent in position 3. Hence, we observed not only a substitution of the 4‐chloro and expected 3‐chloro substituents by the cyanide nucleophile but also an exchange of a nitro substituent, an acetylamino substituent, and a piperidinyl substituent in position 3. The multistep insertion of substituents leading to 8 , 16 , 18 , and 23 started from 4‐hydroxy‐6‐methoxyquinolone 4 , easily obtained from p‐anisidine and malonic acid. Substitutions in position 3 gave 4‐hydroxy‐3‐nitro and 3‐chloro intermediates, which were converted to 3,4‐dichlorocarbostyril 8 and 4‐chloro‐3‐nitrocarbostyril 16 . Reduction of the 3‐nitro intermediate led to the 3‐acetylamino analog and subsequent chlorination led to 3‐acetylamino‐4‐chlorocarbostyril 18 . 4‐Chloro‐3‐piperidinylcarbostyril 23 was obtained from intermediate 3,3‐dichloroquinolinedione by subsequent amination, reduction and chlorination. Further, 3‐acetylamino‐4‐chlorocarbostyril 18 gave with lithium p‐toluenesulfinate highly fluorescent 3‐amino‐6‐methoxy‐4‐p‐tolylsulfonylquinolone 19 .     

Facile synthesis of 2‐alkylthio‐5‐phenylmethylene‐4H‐imidazol‐4‐ones

2‐Alkylthio‐5‐phenylmethylidene‐4H‐imidazol‐4‐ones 4 were synthesized by S‐alkylation of 2‐thioxo‐3‐alkyl(aryl)‐4‐imidazolidinones 3 , which were obtained via cyclization of isothiocyanates 2 with aliphatic(aromatic) primary amines. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:348–351, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10160     

Design and Synthesis of Novel 3‐(Phenyl)‐2‐(3‐substituted propylthio) Quinazolin‐4‐(3H)‐ones as a New Class of H1‐Antihistaminic Agents

A series of novel 3‐(phenyl)‐2‐(3‐substituted propylthio) quinazolin‐4‐(3H)‐ones were synthesized by the reaction of 2‐(3‐bromopropylthio)‐3‐(phenyl) quinazolin‐4‐(3H)‐one with various amines. The starting material, 2‐(3‐bromopropylthio)‐3‐(phenyl) quinazolin‐4‐(3H)‐one was synthesized from aniline. When tested for their in vivo H₁‐antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from histamine‐induced bronchospasm significantly. Compound 2‐(3‐(4‐methylpiperazin‐1‐yl) propylthiothio)‐3‐(phenyl) quinazolin‐4(3H)‐one ( Ph5 ) emerged as the most active compound (73.23% protection) of the series when compared with the reference standard chlorpheniramine maleate (70.09% protection). Compound Ph5 shows negligible sedation (5.01 %) compared with chlorpheniramine maleate (29.58%). Therefore, compound Ph5 can serve as the leading molecule for further development into a new class of H₁‐antihistaminic agents.     

Syntheses,Characterization and X‐ray Structure of the First Silver(I) Complexes with 4‐Amino‐3‐thioxo‐3,4‐dihydro‐1,2,4‐triazin‐5(2H)‐one

Reaction of thiocarbohydrazide with glyoxolic acid monohydrate led to 4‐amino‐3‐thioxo‐3,4‐dihydro‐1,2,4‐triazin‐5(2H)‐one (AHTTO, 1 ). Treatment of 1 with AgNO₃ and PPh₃ gave thecomplexes [(PPh₃)₂Ag₂(μ‐N,S‐AHTTO)₂](NO₃)₂ ( 2 ) and [(PPh₃)₂Ag(AHTTO)]NO₃ · MeOH ( 3 ) was obtained under different conditions. All the compounds have been characterized by elemental analyses, IR spectroscopy and X‐ray diffraction studies.     

A General and Facile Synthesis of Novel Polysubstituted Quinazolin‐4(3H)‐ones

A simple and efficient approach to synthesize novel polysubstituted quinazolin‐4(3H)‐ones has been developed, and the key step is a sequential procedure involved iron‐mediated reduction and acid‐catalytic cyclization. The present method provides a convenient and practical strategy for the synthesis of quinazolin‐4(3H)‐one derivatives.     

Functionalization of Quinazolin‐4‐ones Part 3: Synthesis,Structures Elucidation,DNA‐PK,PI3K,and Cytotoxicity of Novel 8‐Aryl‐2‐morpholino‐quinazolin‐4‐ones

A series of novel 8‐aryl‐2‐morpholino quinazolines ( 11a – n , 12a – d , 14a – f , and 15 ) were synthesized from the precursor 2‐thioxo quinazolin‐4‐ones 8 . The 8‐aryl‐2‐morpholino quinazolines compounds were assayed for DNA‐PK and PI3K. All compounds showed low DNA‐PK % inhibition activity at 10 μM compound concertation, and the most active was 8‐(dibenzo[b,d]thiophen‐4‐yl) 12d with 38% inhibition. Similar pattern of PI3K α, β, γ, and δ isoforms inhibition activity at 10 μM were observed. The most active isoform was PI3K δ of 41% inhibition for 8‐(dibenzo[b,d]furan‐4‐yl) compound 11 . Most compounds were less active than expected in spite of the strong structural resemblance to known inhibitors ( NU7441 , 3 , 4 , and 6 ). Loss of activity could be attributed to the tautomerization to the aromatic enol (4‐OH), which could specify that the important functional group for the activity is the 4‐carbonyl (C=O) group. Alternatively, the aromatization of the pyrimidine heterocyclic ring could alter the conformation, and thus binding site, of the 2‐morpholine ring, which could reduce the compound‐receptor hydrogen bonding to the morpholine 4‐oxygen. Selected compounds displayed appreciable cytotoxicity with 6‐chloro‐8‐(dibenzo[b,d]thiophen‐4‐yl)‐2‐morpholinoquinazolin‐4(1H)‐one 11j exhibiting the greatest activity with an IC₅₀ of 9.95 μM. Therefore, the mechanism of the cytotoxicity of compound 11j were not through DNA‐PK or PI3K inhibition activity.     

Synthesis of N4‐substituted[1,3,4]oxadiazinan‐2‐ones derived from norephedrine

[1,3,4]‐Oxadiazinan‐2‐ones bearing substitution at the N₄‐position have been synthesized from norephedrine in good yield via N‐alkylation, nitrosation, reduction and cyclization.     

Cu‐free Sonogashira Type Cross‐Coupling of 6‐Halo‐2‐cyclopropyl‐3‐(pyridyl‐3‐ylmethyl) Quinazolin‐4(3H)‐ones as Potential Antimicrobial Agents

C(sp)–C(sp2) bond formation via Sonogashira cross‐coupling reactions on 6‐halo‐2‐cyclopropyl‐3‐(pyridyl‐3‐ylmethyl)quinazolin‐4(3H )‐ones with appropriate alkynes was explored. Optimization of reaction conditions with various catalysts, ligands, bases, and solvents was conducted. The combination of PdCl₂(MeCN)₂ with X‐Phos proved to be the best metal–ligand system for this conversion in the presence of triethylamine (Et₃N) in tetrahydrofuran at room temperature for iodosubstrates, at 80°C for the bromosubstrates in 8 h, and also for the chlorosubstrates in 16 h. We also demonstrated synthesis of a successful diversity‐oriented synthesis library of highly functionalized quinazolinones via Cu‐free Sonogashira coupling of diverse aryl halides and azido‐alkyne (“click”) ligation reactions with substituted azides. The library exhibited significant antimicrobial activity when screened against several microorganisms.     

Pyridopyrimidines. X. Synthesis of 3‐Substituted 2‐Thioxo‐5,7‐dimethylpyrido[2,3‐d] pyrimidin‐4(3H)‐ones and their S‐Alkylation Under Phase Transfer Conditions

2‐Thioxo‐5,7‐dimethylpyrido[2,3‐d]pyrimidin‐4(3H)‐ones 3 were synthesized by the cyclocondensation of 2‐amino‐3‐carbethoxy‐4,6‐dimethylpyridine 1 with methyl‐N‐aryldithiocarbamates 2 and compared with the condensation between 1 and aryl isothiocyanates 4. When a comparative study of N vs S alkylation of ambident 2‐thioxo‐5,7‐dimethylpyrido[2,3‐d]pyrimidin‐4(3H)‐ones 3 was carried out under liquid‐liquid and solid‐liquid phase transfer conditions using various alkylating agents 5 , the S‐alkylated products 6 were obtained exclusively and selectively.     

Synthesis and Pharmacological Evaluation of 3‐propyl‐2‐substitutedamino‐3H‐quinazolin‐4‐ones as Analgesic and Anti‐Inflammatory Agents

A variety of novel 3‐propyl‐2‐substitutedamino‐quinazolin‐4(3H)‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐propyl quinazolin‐4(3H)‐one with a variety of aldehydes and ketones. The starting material 2‐hydrazino‐3‐propyl quinazolin‐4(3H)‐one was synthesized from propylamine. The title compounds were investigated for analgesic and anti‐inflammatory activities. The compound 2‐(1‐ethylpropylidene‐hydrazino)‐3‐propyl‐quinazolin‐4(3H)‐one ( SR2 ) emerged as the most active compound of the series, and it is more potent in its analgesic and anti‐inflammatory activities when compared with the reference standard diclofenac sodium.     

Synthesis of Novel 2‐Amino‐(2‐thioxo‐3‐alkyl‐4‐methyl‐3H‐thiazol‐5‐yl)‐[1,3,4]thiadiazole Derivatives and Their Growth Stimulant Activity

On the base of synthesized 2‐amino and 2‐ethylamino‐(2‐thioxo‐3‐alkyl‐4‐methyl‐3H‐thiazol‐5‐yl)‐[1,3,4]thiadiazoles, their alkyl, acetyl, and alkylacetylamino derivatives are obtained. The alkylation of 2‐ethylamino derivatives can occur at both exo and endo nitrogen atoms of amidine group, and the acetylation takes place exclusively at the exocyclic nitrogen atom. At acetylation of 2‐amino‐[1,3,4]thiadiazoles, only exo substitution is observed. At the further alkylation of these products, a mixture of exo‐ and endo‐substituted forms is obtained. At preliminary screening, the synthesized compounds have shown expressed growth stimulant properties. The activity of the most active derivatives was in the range of 65–100%, compared with that of heteroauxin.     

CuBr/Et3N‐Promoted Reactions of 2‐Aminobenzamides and Isothiocyanates: Efficient Synthesis of Novel Quinazolin‐4(3H)‐ones

A series of novel quinazolin‐4(3H)‐one derivatives were efficiently synthesized starting from isatoic anhydride. First, reaction of isatoic anhydride and amines in H₂O at room temperature afforded 2‐aminobenzamides. Then, CuBr/Et₃N promoted reaction of 2‐aminobenzamides and different aryl isothiocyanates in DMF at 80° afforded the title compounds in good yield.     

Palladium‐Catalyzed Aza‐Wittig‐Type Condensation of Isoxazol‐5(4H)‐ones with Aldehydes

This paper describes the development of a palladium‐catalyzed decarboxylative inter‐ and intramolecular condensation reaction of isoxazol‐5(4 H)‐ones with carbonyl compounds in the presence of PPh₃, giving various 2‐azabuta‐1,3‐dienes or pyrroles in moderate to high yields.     

Synthesis and Antioxidant Evaluation of Quinoxalino[2′,3′:5,6][1,3,4]thiadiazino[2,3‐b]quinazolin‐15‐ones: Derivatives of a Novel Ring System

Quinoxalino[2′,3′:5,6][1,3,4]thiadiazino[2,3‐b]quinazolin‐15‐one, a novel fused heterocyclic system, was synthesized from a one‐pot condensation reaction of 2,3‐dichloroquinoxaline and 3‐amino‐2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐one under mild condition. Derivatization was performed on treatment of the titled compound with several alkyl bromides. In vitro antioxidant activity of the synthesized compounds was evaluated.