Organocatalysis in heterocyclic synthesis: DABCO as a mild and efficient catalytic system for the synthesis of a novel class of quinazoline, thiazolo [3,2-a]quinazoline and thiazolo[2,3-b] quinazoline derivatives.
ABSTRACT: BACKGROUND: There are only limited publications devoted to the synthesis of especially thiazolo[3,2-a]quinazoline which involved reaction of 2-mercaptopropargyl quinazolin-4-one with various aryl iodides catalyzed by Pd-Cu or by condensation of 2-mercapto-4-oxoquinazoline with chloroacetic acid, inspite of this procedure was also reported in the literature to afford the thiazolo [2,3-b] quinazoline. So the multistep synthesis of the thiazolo[3,2-a]- quinazoline suffered from some flaws and in this study we have synthesized a novel class of thiazoloquinazolines by a simple and convenient method involving catalysis by 1,4-diazabicyclo[2.2.2]octane (DABCO). RESULTS: A new and convenient one-pot synthesis of a novel class of 2-arylidene-2H-thiazolo[3,2-a]quinazoline-1,5-diones 9a-i was established through the reaction between methyl-2-(2-thio-cyanatoacetamido)benzoate (4) and a variety of arylidene malononitriles 8a-i in the presence of DABCO as a mild and efficient catalytic system via a Michael type addition reaction and a mechanism for formation of the products observed is proposed. Moreover 4 was converted to ethyl-2-[(4-oxo-3,4-dihydroquinazolin-2-yl)thio]acetate (10) upon reflux in ethanol containing DABCO as catalyst. The latter was reacted with aromatic aldehydes and dimethylformamide dimethylacetal (DMF-DMA) to afford a mixture of two regioselectively products with identical percentage yield, these two products were identified as thiazolo[3,2-a]quinazoline 9,13 and thiazolo[2,3-b]quinazoline 11,12 derivatives respectively. The structure of the compounds prepared in this study was elucidated by different spectroscopic tools of analyses also the X-ray single crystal technique was employed in this study for structure elucidation, Z/E potential isomerism configuration determination and to determine the regioselectivity of the reactions. CONCLUSION: A simple and efficient one-pot synthesis of a novel class of 2-arylidene-2H-thiazolo[3,2-a]quinazoline-1,5-diones 9a-i was established through DABCO catalyzed Michael type addition reaction. In addition many fused quinazoline and quinazoline derivatives were synthesized which appeared as valuable precursors in synthetic and medicinal chemistry.
Project description:In our efforts to address the rising incidence of hepatocellular carcinoma (HCC), we have made a commitment to the synthesis of novel molecules to combat Hep-G2 cells. A facile and highly efficient one-pot, multicomponent reaction has been successfully devised utilizing a p-toluenesulfonic acid (p-TSA)-catalyzed domino Knoevenagel/Michael/intramolecular cyclization approach for the synthesis of novel 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2-a]pyrimidine analogs bearing a bridgehead nitrogen atom. This domino protocol constructed one new ring by the concomitant formation of multiple bonds (C-C, C-N, and C=N) involving multiple steps without the use of any metal catalysts in one-pot, with all reactants effi-ciently exploited. All the newly synthesized compounds were authenticated by means of Fourier transform infrared spectroscopy, liquid chromatography-mass spectrometry, proton nuclear magnetic resonance spectroscopy, and carbon-13 nuclear magnetic resonance spectroscopy, together with elemental analysis, and their antitumor activity was evaluated in vitro on a Hep-G2 human cancer cell line by sulforhodamine B assay. Computational molecular modeling studies were carried out on cancer-related targets, including interleukin-2, interleukin-6, Caspase-3, and Caspase-8. Two compounds (4A and 6A) showed growth inhibitory activity comparable to the positive control Adriamycin, with growth inhibition of 50% <10 ?g/mL. The results of the comprehensive structure-activity relationship study confirmed the assumption that two or more electronegative groups on the phenyl ring attached to the thiazolo[2,3-b]quinazoline system showed the optimum effect. The in silico simulations suggested crucial hydrogen bond and ?-? stacking interactions, with a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and molecular dynamics, in order to explore the molecular targets of HCC which were in complete agreement with the in vitro findings. Considering their significant anticancer activity, 4A and 6A are potential drug candidates for the management of HCC.
Project description:An effective and highly regio- and diastereoselective one-pot method for the synthesis of new polynuclear dispiroheterocyclic systems with five stereogenic centers (dispiro[imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-6,3'-pyrrolidine-2',3''-indoles]) comprising pyrrolidinyloxindole and imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine moieties has been developed. The method relies on a 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin derivatives and sarcosine to 6-benzylideneimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7-diones.
Project description:A series of 3(2)-phosphonylated thiazolo[3,2-a]oxopyrimidines was synthesized for the first time by the reactions of chloroethynylphosphonates with unsubstituted and 5(6)-substituted 2-thiouracils. The reaction of chloroethynylphosphonates with 6-substituted 2-thiouracils bearing electron-donor groups (CH3, Ph) proceeded with high regioselectivity involving the cyclization through the N3-nitrogen atom to form new 3-phosphonylated thiazolo[3,2-a]-5-oxopyrimidines with good yield. In the case of unsubstituted and 5-methyl-2-thiouracils, cyclization occurred predominantly through the N1 atom and partially via the N3-nitrogen atom to form a mixture of the corresponding thiazolo[3,2-a]-7- and 5-oxopyrimidines. A dramatic change in the reaction regioselectivity was observed in the case of 6-trifluoromethyl-2-thiouracil that afforded 2- and 3-phosphonylated 5-oxothiazolopyrimidines in a 1:1 ratio.
Project description:A series of 5H-thiazolo[3,2-a]pyrimidin-5-ones were synthesized by the cyclization reactions of S-alkylated derivatives in concentrated H?SO?. Upon treatment of S-alkylated derivatives at different temperatures, intramolecular cyclization to 7-(substituted phenylamino)-5H-thiazolo[3,2-a]pyrimidin-5-ones or sulfonation of cyclized products to sulfonic acid derivatives occurred. The structures of the target compounds were confirmed by IR, ¹H-NMR, (13)C-NMR and HRMS studies. The compounds were evaluated for their preliminary in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria and screened for antitubercular activity against Mycobacterium tuberculosis by the broth dilution assay method. Some compounds showed good antibacterial and antitubercular activities.
Project description:A novel series of thiazolo[3,2-a]benzimidazole derivatives containing benzofuran nucleus (5a-l) have been synthesized. The key intermediate, substituted benzimidazol-sulfanyl benzofuran ethanone (3a-d) was prepared by refluxing the mixture of substituted 2-acetyl benzofuran and substituted 2-mercaptobenzimidazole in acetic acid. The cyclisation of compounds (3a-d) using polyphosphoric acid furnished the corresponding 6-substituted benzofuran thiazolo[3,2-a]benzimidazoles (4a-d). Further, the cyclized compounds (4a-d) were subjected for Mannich reaction to give corresponding Mannich bases (5a-l). All newly synthesized compounds were screened for antifungal and anthelmintic activity. Amongst the tested compounds, 4b and 4d exhibited potential antifungal activity. From the anthelmintic activity data, it was found that the compounds 3a, 3b and 5i were found to be more effective against the tested earthworm Pheretima posthuma. In correlation to anthelmintic activity, the selected compounds were subjected for molecular docking studies and the compounds 3a and 5i have emerged as active anthelmintic agents with maximum binding affinity (-3.7 and -5.4 kcal/mol).
Project description:A novel three-component bicyclization for the efficient synthesis of densely functionalized pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidines has been established from readily accessible aryl aldehydes, ?-thiocyanate ketones and pyrazol-5-amines. The reaction pathway involves nucleophilic addition/5-exo-trig /6-endo-trig bicyclization sequence, resulting in continuous multiple bond-forming events including C-N and C-C bonds to rapidly a molecular complexity.
Project description:An effective method for transition-metal-free postfunctionalization of thiazolo[3,2-c][1,3,5,2]oxadiazaborinine dyes via direct lithiation of the 1,3-thiazole ring was developed. The reaction allows valuable regioselective C-H modification of these N,O-chelated organoboron chromophores incorporating different groups, including C-, Hal-, Si-, S-, Se-, and Sn-substituents. As a result, a library of novel fluorescent 1,3-thiazole-based organoboron complexes has been synthesized and characterized. The influence of the donor/acceptor strength of the substituent E on the photophysical properties has been established. The compound with a bulky lipophilic substituent (SnBu3) exhibits a relatively high solid-state photoluminescence quantum yield of 44%.
Project description:A series of 1,2,3-triazolyl 3-hydroxy-quinazoline-2,4(1H,3H)-diones was constructed utilizing Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) method. The biological significance of the novel synthesized quinazolines was highlighted by evaluating them in vitro for antiviral activity, wherein several compounds exhibited excellent activity specifically against vaccinia and adenovirus. Especially, 24b11 displayed the most potent inhibitory activity against vaccinia with an EC50 value of 1.7?M, which was 15 fold than that of the reference drug Cidofovir (EC50=25?M). 24b13 was the most potent compound against adenovirus-2 with an EC50 value of 6.2?M, which proved lower than all the reference drugs. Preliminary structure-activity relationships were also discussed. To the best of our knowledge, no data are present in the literature on antiviral activity of 3-hydroxy-quinazoline-2,4(1H,3H)-diones against DNA-viruses. Thus, these findings warrant further investigations (library expansion and compound refinement) on this novel class of antiviral agents.
Project description:?-Bromo-?,?-unsaturated aldehydes and 2-bromobenzaldehydes react with 4,7-dimethoxy-1H-benzo[d]imidazole-2-amine by microwave irradiation in dimethylformamide in the presence of a base to give the corresponding dimethoxy-substituted benzo[4,5]imidazo[1,2-a]pyrimidines and benzo[4,5]imidazo[1,2-a]quinazolines, respectively, in moderate to good yields. Oxidation of such N-fused hybrid scaffolds by aqueous ceric ammonium nitrate affords pyrimidine- and quinazoline-fused benzimidazole-4,7-diones in high yields.
Project description:The derivatization of resin-bound aminobenzimidazole toward the parallel solid-phase synthesis of aminobenzimidazole tethered pharmacologically important heterocycles such as quinazoline-2,4-diones, thioxoquinazolin-4-ones, benzodiazepine-2,3,5-triones, isoxazoles and isoxazolines is reported. All the compounds were tested for IKK inhibition. Only one compound elicited significant inhibition of IKK?, TBK-1 and IKK2.