Versatile and mild HCl-catalyzed cationic imino Diels-Alder reaction for the synthesis of new tetrahydroquinoline derivatives

A simple, inexpensive, and mild one-pot methodology for the synthesis of novel 4-aryl-3-methyl-1,2,3,4-tetrahydroquinolines derivatives using aqueous HCl as catalyst has been developed. The key step involves the formal inverse-electron-demand [4π⁺ + 2π] cycloaddition reaction of in situ–generated cationic 2-azadienes with arylpropenes (isoeugenol and trans-anethole). Iminium ion intermediates are generated through the condensation between N-benzylanilines and formalin. The products are obtained with good to excellent yields and high trans-diastereoselectivity. Further catalytic hydrogenation (Pd/C) allowed debenzylation to successfully obtain the respective 4-aryl-3-methyl-N-H-tetrahydroquinolines of interest. Recent reports suggest that these compounds could serve as interesting models in pharmacological studies against parasites that cause the most common tropical diseases.     

Experimental and Theoretical Approaches in the Study of Phenanthroline-Tetrahydroquinolines for Alzheimer's Disease

The imino-Diels-Alder reaction is one of the most common strategies in organic chemistry and is an important tool for providing a broad spectrum of biologically active heterocyclic systems. A combined theoretical and experimental study of the imino-Diels-Alder reaction is described. The new phenanthroline-tetrahydroquinolines were evaluated as cholinesterase inhibitors. Their cytotoxicity in human neuroblastoma SH-SY5Y cells was also evaluated. The theoretical results suggest that compounds formation in stages can be explained by endo cycloadducts under the established reaction conditions, thereby confirming experimental results obtained for percentage yield. These results allowed us to establish that pyridine substituent remarkably influences activation energy and reaction yield, as well as in acetylcholinesterase (AChE) activity. Among these derivatives, compounds with 4-pyridyl and 4-nitrophenyl showed favorable AChE activity and proved to be non-cytotoxic.     

Catalytic Asymmetric Intramolecular Hydroarylations of ω‐Aryloxy‐ and Arylamino‐Tethered α,β‐Unsaturated Aldehydes

Economical approach : The first organocatalytic asymmetric intramolecular hydroarylation of phenol‐ and aniline‐derived enals offers one of the most straightforward and atom‐economic approaches to enantioriched chromans and tetrahydroquinolines (up to 96 % ee; see scheme).

     

Aryl Radical Cyclization: Regioselective Synthesis of 6a,7,8,12b‐Tetrahydro‐6H‐chromeno[3,4‐c]quinolin‐6‐one

Regioselective synthesis of 6a,7,8,12b‐tetrahydro‐6H‐chromeno[3,4‐c]quinolin‐6‐ones 4 in good to excellent yields from 3‐(2‐bromoanilinomethyl)coumarins 3 by aryl radical cyclization is described. The cyclization precursors 3 were prepared by the reaction of 3‐chloromethyl coumarin with different 2‐bromoaniline.     

Thiourea-catalyzed 1,5-hydride transfer and ring closure sequences of o-dialkylamino-substituted nitrostyrenes: Synthesis of ring-fused tetrahydroquinoline derivatives

Thiourea-catalytic synthesis of tetrahydroquinolines has been achieved through a 1,5-hydride transfer/ring closure sequence. The feature of this research is a direct transformation of o-dialkylamino-substituted nitrostyrene derivatives into tetrahydroquinolines using a nitroalkene moiety as hydride acceptor in internal redox reactions.     

Asymmetric synthesis of tetrahydroquinolines with quaternary stereocenters through the Povarov reaction

The asymmetric Povarov reaction with α-alkyl styrenes as dienophiles was catalyzed by an N,N'-dioxide L4-Sc(OTf)(3) complex. Enantiopure tetrahydroquinoline derivatives with a quaternary stereocenter at the C4 position were synthesized for the first time. A wide variety of α-alkyl styrenes and N-aryl aldimines were tolerated in the reaction, to give excellent diastereo- (up to 99:1 d.r.) and enantioselectivities (92 to >99% ee). In addition, the reaction could be performed on the gram scale without any loss of yield, diastereoselectivity, or enantioselectivity. An intermolecular hydrogen-shift reaction was found to be a side reaction, which offered a method to synthesize the corresponding quinoline derivatives with chiral quaternary sterocenters.