An Efficient Lewis Acid Catalyzed Povarov Reaction for the One-Pot Stereocontrolled Synthesis of Polyfunctionalized Tetrahydroquinolines­

Abstract

An easy and efficient synthetic methodology for the one-pot stereocontrolled synthesis of tetrahydroquinolines through Lewis acid activated Povarov reaction is described. The protocol takes advantage of the very cheap, easy to handle, and environmentally friendly cerium trichloride as catalyst and allows to obtain either the anti- or the syn-isomer of the final tetrahydroquinoline with good selectivity, by performing the reaction in solvent or solventless conditions. The scope of the reaction is expanded to the one-pot synthesis of N-alkyltetrahydroquinolines through a very efficient iminium-Povarov approach. A deeper insight on the reaction system was provided by the study on the side reactions occurring in the reaction conditions and on the nature of the stereoselectivity.

Progress in the Chemistry of Tetrahydroquinolines

“…For instance, 25 mol% of GdCl 3 triggered the three-component reaction to deliver excellent yields of the corresponding THQs 516 and 517 with good diastereoselectivity (Scheme ). In addition, Sc­(OTf) 3 , BF 3 ·OEt 2 , NbCl 5 , , Sm­(OTf) 3 , ceric ammonium nitrate (CAN), CeCl 3 ·7H 2 O/NaI, and Al­(OTf) 3 were also employed as catalysts for the same reaction. This chemistry was applied to the synthesis of hexahydro 2 H -pyrano­[3,2- c ]­quinolines as selective σ 1 receptor ligands .…”

Micellar Brønsted Acid Mediated Synthesis of DNA-Tagged Heterocycles

“…Tetrahydroquinolines are frequently occurring scaffolds among bioactive molecules. They can be found as central structures in natural products, a very recently disclosed inhibitor of CRISPR-Cas9, and clinical candidates ( 4 – 6 , Figure a). − The Povarov reaction, a formal aza-Diels–Alder reaction, affords in one-pot diverse tetrahydroquinolines 11 from readily available aldehydes 7 , anilines 8 , and electron-rich olefins 10 (Figure b). − …”

“…The Lewis acids Yb­(III), Sc­(III), Ceric ammonium nitrate (CAN), and Ce­(III) were previously shown to catalyze the Povarov reaction, but also failed under several tested reaction conditions to yield the DNA-coupled heterocycle (Table S3, Figures S9–12). − Thus, none of the evaluated homogeneous reactions based on Brønsted acid or Lewis acid catalysis met the requirements for encodable chemistry to afford the target product at high yields and preserve DNA integrity at the same time. These results prompted us to explore whether we could harness the aforementioned attractive features of micellar catalysis to enable the Povarov reaction on DNA-linked substrates.…”

The Povarov Reaction: A Versatile Method to Synthesize Tetrahydroquinolines, Quinolines and Julolidines

“…83 Moreover, mixed catalytic systems may be employed, such as Ca(OTf) 2 /Bu 4 NPF 6 84 and CeCl 3 /NaI. 85 Biocatalysis was also described by the use of bovine pancreas α-chemotrypsin in aqueous acetonitrile 86 with a strong preference towards the trans diastereoisomers, whereas other enzymes such as papain, lipases, and amylases failed to provide the THQ. Concerning the reaction medium, polar solvents such as acetonitrile 34 37 41 45 47 51 54 and alcohols 53 65 87 88 were the most typical, but not a requirement since apolar solvents including dichloromethane, 35 74 89 dichloroethane 28 60 90 and toluene 78 91 92 were also well represented in the literature.…”