Subbu Perumal

L-Proline-catalysed sequential four-component “on water” protocol for the synthesis of structurally complex heterocyclic ortho-quinones

The L-proline-catalyzed synthesis of 7-(aryl)-8-methyl-10-phenyl-5H-benzo[h]pyrazolo-[3,4-b]quinoline-5,6(10H)-diones via the four-component sequential reaction of phenylhydrazine, 3-aminocrotononitrile, substituted benzaldehydes and 2-hydroxynaphthalene-1,4-dione is described. This “on water” protocol proceeds in high atom economy and leads to the generation of two rings, together with two C–C, one C–N and two CN bonds in a single operation. The environmental advantages of the method include short reaction time, excellent yield, easy work-up, and the absence of extraction and chromatographic purification steps.

A microwave-assisted facile regioselective Fischer indole synthesis and antitubercular evaluation of novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles

A series of novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles has been synthesised regioselectively in good yields from the reaction of 5-aryldihydro-3(2H)-thiophenones and arylhydrazine hydrochloride. This reaction is found to be assisted by microwaves. The thieno[3,2-b]indoles were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among 22 compounds screened, [2-(2,4-dichlorophenyl)-7-fluoro-3,4-dihydro-2H-thieno[3,2-b]indole] (6t) was found to the most active compound with MIC of 0.4 microg/mL against MTB and MDR-TB.

Synthesis and discovery of novel piperidone-grafted mono- and bis-spirooxindole-hexahydropyrrolizines as potent cholinesterase inhibitors

Three-component reaction of a series of 1-acryloyl-3,5-bisbenzylidenepiperidin-4-ones with isatin and L-proline in 1:1:1 and 1:2:2 molar ratios in methanol afforded, respectively the piperidone-grafted novel mono- and bisspiro heterocyclic hybrids comprising functionalized piperidine, pyrrolizine and oxindole ring systems in good yields. The in vitro evaluation of cholinesterase enzymes inhibitory activity of these cycloadducts disclosed that monospiripyrrolizines (8a-k), are more active with IC50 ranging from 3.36 to 20.07 μM than either the dipolarophiles (5a-k) or bisspiropyrrolizines (9a-k). The compounds, 8i and 8e with IC50 values of 3.36 and 3.50 μM, respectively showed the maximum inhibition of acethylcholinesterase (AChE) and butrylylcholinestrase (BuChE). Molecular modeling simulation, disclosed the binding interactions of the most active compounds to the active site residues of their respective enzymes. The docking results were in accordance with the IC50 values obtained from in vitro cholinesterase assay.

Chemodivergent, multicomponent domino reactions in aqueous media: L-proline-catalyzed assembly of densely functionalized 4H-pyrano[2,3-c]pyrazoles and bispyrazolyl propanoates from simple, acyclic starting materials

A library of 4H-pyrano[2,3-c]pyrazol-6-amines was synthesized in excellent yield employing an L-proline-catalyzed, on-water four-component domino reaction from hydrazines, β-dicarbonyl compounds, nitriles and dialkyl acetylenedicarboxylates that generates two rings by the creation of C–C (two), C–N, CN and C–O bonds and presumably involves a sequence of hydrazone formation, cyclocondensation, Michael, [1,3]-hydrogen shift, Michael addition and 6-exo-dig annulation steps. When alkyl propiolates were employed, a three-component reaction took place furnishing alkyl 3,3-bis(5-hydroxy-1H-pyrazol-4-yl)propanoates via a double Michael domino process.

Antimycobacterial activity of spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrids obtained by a three-component regio- and stereoselective 1,3-dipolar cycloaddition

Spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrid compounds were obtained in excellent yields from the regio- and stereoselective reaction between β-nitrostyrenes and non-stabilized azomethine ylides, generated in situ from isatin and phenylglycine/proline/thiaproline. These compounds were evaluated for their in vitro activity against Mycobacterium tuberculosisH37Rv (MTB). Eleven compounds were more active than pyrazinamide and one of them, namely 6′-(3-nitrophenyl)-7′-nitro-3′,6′,7′,7a′-tetrahydro-1′H-spiro-[indoline-3,5′-pyrrolo-[1,2-c]thiazol]-2-one, displayed a 7.6 μM MIC value, which represents a potency similar to that of the first-line anti-TB drug ethambutol and 6.7 times higher than that of pyrazinamide.

L-proline-catalyzed three-component domino [3+2+1] annulation for the regio- and diastereoselective synthesis of highly substituted thienothiopyrans containing three or four stereocenters.

L-proline-catalyzed three-component reactions of ethyl 2-[(2-oxo-2-arylethyl)sulfonyl]acetate or ethyl 2-[(2-ethoxy-2-oxoethyl)sulfonyl]acetate, aromatic aldehydes, and 5-aryltetrahydro-3-thiophenone furnished a variety of highly substituted thieno[3,2-c]thiopyran derivatives. This facile transformation presumably occurs via a one-pot domino sequence of enamine formation/aldol condensation/Michael addition/6-exo-trig cyclization/elimination and involves the creation in a single operation of three C-C bonds and the generation of three new stereocenters with complete diastereoselectivity in all cases and a fourth one in ca. 7:3 diastereomeric ratio when starting from a 5-substituted tetrahydro-3-thiophenone derivative.

A facile, three-component domino protocol for the microwave-assisted synthesis of functionalized naphtho[2,3-b]furan-4,9-diones in water

A three-component domino reaction of 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes and a pyridinium salt in the presence of ammonium acetate, under microwave irradiation and using water as solvent, furnished a library of novel 2-arylcarbonyl-3-aryl-4,9-dihydronaphtho[2,3-b]furan-4,9-diones in good yields, in a transformation that presumably proceeds via an α,β-unsaturated triketone generation/Michael addition/intramolecular cyclisation/air oxidation one-pot sequence.

Domino reactions in water: diastereoselective synthesis of densely functionalized indolyldihydrofuran derivatives†

A library of trans-5-aroyl-2-(indol-3-yl)-4-aryl-4,5-dihydrofuran-3-carbonitriles was diastereoselectively synthesized in excellent yields from the reaction of 2-(3-indolylcarbonyl)-3-aryl-2-propenenitriles with (2-aryl-2-oxoethyl)pyridinium bromides in the presence of triethylamine via a simple, user-friendly domino process carried out in water. Extraction and chromatographic steps were avoided, since the final products could be simply filtered from the aqueous reaction medium and recrystallized. This one-pot transformation generates one C–C and one C–O bond and presumably proceeds by a domino sequence involving the generation of a pyridinium ylide, a Michael addition and a final annulation via intramolecular nucleophilic substitution.

A facile four-component sequential protocol in the expedient synthesis of novel 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones in water and their antitubercular evaluation.

A series of 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones has been synthesized by one-pot, four-component sequential reactions of phenylhydrazine, methyl acetoacetate, aromatic aldehydes and β-naphthol in the presence of p-toluenesulphonic acid in water in good yields. These 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones were screened for in-vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Among the 15 compounds screened, 4-[(2,4-dichlorophenyl)(2-hydroxy-1-naphthyl)methyl]-2-(4-fluorophenyl)-5-methyl-2,3-dihydro-1H-3-pyrazolone displays the maximum potency with a minimum inhibitory concentration (MIC) of 1.6 μM against MTB, being 2.94 and 4.75 times more active than ciprofloxacin and ethambutol respectively.

A microwave-assisted, facile, regioselective Friedländer synthesis and antitubercular evaluation of 2,9-diaryl-2,3-dihydrothieno-[3,2-b]quinolines

A series of 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinolines have been synthesized regioselectively by Friedländer annulation of 5-aryldihydro-3(2H)-thiophenones and 2-aminobenzophenones in the presence of trifluoroacetic acid in good yields under microwave irradiation at 100 degrees C. The 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinolines were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among the 17 compounds screened, 7-chloro-2-(2,4-dichlorophenyl)-9-phenyl-2,3-dihydrothieno-[3,2-b]quinoline and 7-chloro-2-(3-nitrophenyl)-9-phenyl-2,3-dihydrothieno[3,2-b]quinoline display maximum activity with MIC of 0.90 and 0.95 muM against MTB and MDR-TB respectively.