Trapti Aggarwal

Iodine-Mediated Solvent-Controlled Selective Electrophilic Cyclization and Oxidative Esterification of o-Alkynyl Aldehydes: An Easy Access to Pyranoquinolines, Pyranoquinolinones, and Isocumarins

Chemoselective behavior of iodine in different solvents in the electrophilic iodocyclization of o-alkynyl aldehydes is described. o-Alkynyl aldehydes 3a-t on reaction with I2 in CH2Cl2 with appropriate nucleophiles provides pyrano[4,3-b]quinolines 4a-f, via formation of cyclic iodonium intermediate Q; however, using alcohols as a solvent as well as nucleophile, o-alkynyl esters 5a-y were obtained selectively in good to excellent yields via formation of hypoiodide intermediate R. Subsequently, o-alkynyl esters were converted in to pyranoquinolinones 6a-i and isocoumarin 6j by electrophilic iodocyclization. This developed oxidative esterification provides a novel access for the chemoselective synthesis of esters 5q-u from aldehydes 3n-p without oxidizing primary alcohol present in the substrate.

Highly efficient Ag(I)-catalyzed regioselective tandem synthesis of diversely substituted quinoxalines and benzimidazoles in water

A green and operationally simple approach for the diverse synthesis of fused quinoxalines and benzimidazoles from o-alkynylaldehydes and amines having an N-tethered nucleophile using Ag(I) as the catalyst in water, is described. The X-ray crystallographic studies confirmed the proposed mechanistic pathway and the cyclized product.

Palladium-catalyzed regioselective [3 + 2] annulation of internal alkynes and iodo-pyranoquinolines with concomitant ring opening.

A regioselective tandem synthesis of highly functionalized pyrrolo[1,2-a]quinolines has been developed through a novel strategy by palladium-catalyzed [3 + 2] annulation of iodo-pyranoquinolines and internal alkynes with subsequent ring opening. Pyranoquinoline with n-alkyl substitution at the 3-position leads to the formation of pyrrolo-acridones via [3 + 2] annulations/ring opening and successive intramolecular cross-aldol condensation.

Site-selective electrophilic cyclization and subsequent ring-opening: a synthetic route to pyrrolo[1,2-a]quinolines and indolizines.

An efficient strategy for the synthesis of pyrrolo[1,2-a]quinolines and indolizines from pyranoquinolines via site-selective electrophilic cyclization and subsequent opening of pyran ring using silver/iodine under mild reaction conditions is described. This approach involves the preferential attack of the pyridyl nitrogen over aryl ring and leads to the formation of 5-endo-dig cyclized products. Quantum chemical calculations between C-N (ΔE(a) = 9.01 kcal/mol) and C-C (ΔE(a) = 31.31 kcal/mol) bond formation were performed in order to rationalize the observed site selectivity. Structure of the products were confirmed by the X-ray crystallographic studies. Iodo-substituted compounds generated by the electrophilic iodocyclization were further diversified via Pd-catalyzed cross-coupling reactions.

Pyrano(4,3-b)quinolines Library Generation via Iodocyclization and Palladium-Catalyzed Coupling Reactions

Synthesis of a 80-member library of novel pyrano[4,3-b]quinolines in solution-phase is reported. The key intermediate, 4-iodopyrano[4,3-b]quinolines were synthesized by the electrophilic iodocyclization of corresponding ortho-alkynyl aldehydes in good to excellent yields under mild reaction conditions. Subsequently a diverse set of libraries was generated by employing palladium-catalyzed Suzuki-Miyaura, Heck, and Sonogashira coupling reactions on 4-iodopyrano[4,3-b]quinolines. In this way, a series of structurally different and biologically interesting molecules were obtained. Some of the selected compounds were screened against 3D7 strains of Plasmodium falciparum for antimalarial activity. Suzuki coupling products 6{3} and 6{21} and Heck coupling product 8{12} exhibit promising antimalarial activity.

Tandem Synthesis of Pyrroloacridones via [3 + 2] Alkyne Annulation/Ring-Opening with Concomitant Intramolecular Aldol Condensation

An efficient cascade strategy for the direct synthesis of pyrrolo[3,2,1-de]acridones 4a-v, 5a-h from iodo-pyranoquinolines 2a-i by the palladium-catalyzed regioselective [3 + 2] alkyne annulation/ring-opening followed by intramolecular aldol condensation under microwave irradiation is described. The chemistry involves the in situ formation of pyrroloquinolines Y, via palladium-catalyzed selective [3 + 2] annulation of iodopyranoquinolines and internal akynes with ring-opening and successive intramolecular cross-aldol condensation. Both the symmetrical and unsymmetrical internal alkynes were reacted smoothly to provide the desired pyrroloacridones in good yields. This methodology provides the facile conversion of easily accessble iodopyranoquinoline into highly functionalized biologically important pyrroloacridones in a single process.

Palladium meets copper: one-pot tandem synthesis of pyrido fused heterocycles via Sonogashira conjoined electrophilic cyclization

An efficient step-economical tandem approach for the direct synthesis of pyrido fused indole, quinoline, benzofuran and benzothiophene derivatives using a bimetallic Pd/Cu catalytic system has been described. The three component reaction of o-halo aldehydes, alkynes and tert-butylamine leads to the synthesis of biologically active polyheterocycles. The present strategy involves the dual role of tert-butylamine and copper(i) in Sonogashira coupling followed by electrophilic cyclization through imine formation. The chemistry has been validated by X-ray crystallographic studies.

Chemoselective Azidation of o-Alkynylaldehydes over [3 + 2] Cycloaddition and Subsequent Staudinger Reaction: Access to Benzonaphthyridines/Naphthyridines

An efficient tandem approach for the chemoselective synthesis of functionalized azido-pyranoquinolines and azido-iodo-pyranoquinolines via electrophilic cyclization of o-alkynylaldehydes in the presence of sodium azide under mild reaction conditions is described. Mechanistic studies confirm the formation of azido-pyranoquinolines through nucleophilic attack of azide on pyrilium intermediate over [3 + 2] cycloaddition of the azide on the alkyne. The synthesized azido-pyranoquinolines were transformed into benzonaphthyridines via Staudinger reaction. The mechanistic pathway was supported by deuterium labeling experiment and X-ray crystallographic studies.