Novel Use of SelectfluorTM for the Synthesis of cis-Fused Pyrano- and Furanotetrahydroquinolines

Aryl imines formed in situ from aryl aldehydes and aromatic amines undergo smooth [4+2] cycloaddition reactions with cyclic enol ethers such as 3,4-dihydro-2H-pyran and 2,3-dihydrofuran in the presence of 10 mol % Selectfluor^TM in acetonitrile at room temperature to afford pyrano- and furanotetrahydroquinoline derivatives in excellent yields with high endo-selectivity.     

Bandgap Engineering of Conjugated Nanoporous Poly‐benzobisthiadiazoles via Copolymerization for Enhanced Photocatalytic 1,2,3,4‐Tetrahydroquinoline Synthesis under Visible Light

Conveniently combining properties such as high interfacial surface area, excellent visible light absorption and semiconductor‐range bandgap, conjugated nanoporous polymer networks are promising candidates as pure organic, metal‐free, visible light‐responsive and heterogeneous photocatalysts. Here, a facile yet precise bandgap engineering strategy to achieve fine justification of the valence and conduction band positions of a series of nanoporous polymers to optimally bracket the redox potential of the targeted individual photoredox reaction via copolymerization of the electron‐withdrawing benzobisthiadiazole moieties into the polymer network backbone is presented. The enhanced photocatalytic activity of the nanoporous polymer networks was demonstrated in the synthesis of 1,2,3,4‐tetrahydroquinoline, an important motif in pharmaceutical compounds, via photooxidative cyclization of N,N‐dimethylanilines with maleimides.

     

Organocatalytic Enantioselective Cascade Aza‐Michael/Michael Addition for the Synthesis of Highly Functionalized Tetrahydroquinolines and Tetrahydrochromanoquinolines

An efficient organocatalytic highly asymmetric cascade aza‐Michael/Michael addition reaction for the synthesis of tetrahydroquinolines and tetrahydrochromanoquinolines has been developed. This cascade reaction proceeds well at low catalyst loading with a broad substrate scope, furnishing the desired products in excellent yields with excellent diastereoselectivities and enantioselectivities (up to >99:1 dr, 99% ee) under mild conditions. Importantly, it is the first catalytic asymmetric method for tetrahydrochromanoquinolines. This protocol provides a straightforward entry to highly functionalized chiral tetrahydroquinoline and tetrahydrochromanoquinoline derivatives from simple starting materials.

     

Mild Metal‐Free Intramolecular Oxidative Alkylation of a Csp3?H Bond Adjacent to a Nitrogen Atom: A Versatile Approach to Ring‐Fused Tetrahydroquinolines

A metal‐free intramolecular oxidative cross‐coupling reaction for the constructing C_sp3 C_sp3 bonds mediated by 2,3‐dichloro‐5,6‐dicyanobenzoquinone (DDQ) under mild conditions was realized for the first time. This novel strategy provides a simple, efficient, and environmentally friendly access to diverse ring‐fused tetrahydroquinoline derivatives.     

Highly Enantioselective Synthesis of Chiral Tetrahydroquinolines and Tetrahydroisoquinolines by Ruthenium‐Catalyzed Asymmetric Hydrogenation in Ionic Liquid

Asymmetric hydrogenation reactions of quinolines and 3,4‐dihydroisoquinolines using the chiral cationic ruthenium complex Ru(TsDPEN) [TsDPEN=N‐(p‐toluenesulfonyl)‐1,2‐diphenylethylenediamine] as catalyst in neat imidazolium ionic liquids have been investigated. The catalytic performance was influenced by the anion of the ionic liquids for both substrate classes. A range of 2‐alkyl‐substituted 1,2,3,4‐tetrahydroquinolines and 1‐alkyl‐substituted 1,2,3,4‐tetrahydroisoquinolines was obtained in high yields with up to >99% ee. Interestingly, the hydrogenation of quinoline derivatives bearing a carbonyl group was selective for the CN (quinoline) over the CO (ketone) bonds, while such a unique chemoselectivity was not observed in methanol. Furthermore, the ruthenium catalysts could be easily recycled at least 5 times in the asymmetric hydrogenation of 3,4‐dihydroisoquinoline by solvent extraction. To further facilitate the recovery of catalyst and reduce the use of organic solvent, a thin film of ionic liquid containing Ru(TsDPEN) was supported on silica gels. This supported ionic liquid‐phase catalyst was effective in the asymmetric hydrogenation of quinoline, and could be recycled at least 6 times by simple filtration.

     

Scandium‐Catalyzed Cascade Cyclization to Produce Cyclobutane‐Fused Tetrahydroquinoline,Chromane, Thiochromane,and Tetrahydronaphthalene Derivatives

We have succeeded in the highly diastereoselective synthesis of cyclobutane‐fused multi‐cyclic compounds using a scandium‐catalyzed cascade cyclization. Using 3–10 mol% of scandium(III) triflate [Sc(OTf)₃], various cyclobutane‐fused tetrahydroquinoline derivatives as well as its chromane, thiochromane, and tetrahydronaphthalene analogues were obtained in good to excellent yields. Derivatizations of the reaction products, as well as the plausible reaction mechanism, are also discussed.

     

Lead Evaluation of Tetrahydroquinolines as Nonsteroidal Selective Androgen Receptor Modulators for the Treatment of Osteoporosis

Tetrahydroquinoline (THQ) was deemed to be a suitable scaffold for our nonsteroidal selective androgen receptor modulator (SARM) concept. We adapted the strategy of switching the antagonist function of cyano‐group‐containing THQ (CN‐THQ) to the agonist function and optimized CN‐THQ as an orally available drug candidate with suitable pharmacological and ADME profiles. Based on binding mode analyses and synthetic accessibility, we designed and synthesized a compound that possesses a para‐substituted aromatic ring attached through an amide linker. The long‐tail THQ derivative 6‐acetamido‐N‐(2‐(8‐cyano‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinolin‐4‐yl)‐2‐methylpropyl)nicotinamide ( 1 d ), which bears a para‐acetamide‐substituted aromatic group, showed an appropriate in vitro biological profile, as expected. We considered that the large conformational change at Trp741 of the androgen receptor (AR) and the hydrogen bond between 1 d and helix 12 of the AR could maintain the structure of the AR in its agonist form; indeed, 1 d displays strong AR agonistic activity. Furthermore, 1 d showed an appropriate in vivo profile for use as an orally available SARM, displaying clear tissue selectivity, with a separation between its desirable osteoanabolic effect on femoral bone mineral density and its undesirable virilizing effects on the uterus and clitoral gland in a female osteoporosis model.     

Asymmetric Synthesis of Tetrahydroquinolines via 1,5‐Hydride Transfer/Cyclization Catalyzed by Chiral Primary Amine Catalysts

Chiral primary amine‐catalyzed asymmetric C H functionalization has been achieved. In this process, enantiotopic Csp³ H functionalization at the α‐position to the nitrogen atom of 4‐[ortho‐(dialkylamino)phenyl]but‐3‐en‐2‐one is activated by chiral 9‐amino(9‐deoxy)‐epi‐quinine to afford tetrahydroquinine derivatives with high enantioselectivities (up to 97% ee).

     

The Reaction of Tertiary Anilines with Maleimides under Visible Light Redox Catalysis

Tertiary anilines can be prompted to react with N‐aryl‐ and N‐benzylmaleimides to form tetrahydroquinoline products under photocatalysis using visible light irradiation, the ruthenium or iridium complexes Ru(bpy)₃Cl₂ or Ir(ppy)₂(dtbbpy)PF₆ as catalyst, and air as terminal oxidant.     

Efficient preparation of substituted 5,6,7,8-tetrahydroquinolines and octahydroacridine derivatives

The reaction of the enamine 4 with different β-amino ketone hydrochlorides 3a – e affords the diketones 5a – e which can be cyclized to the corresponding mono- and disubstituted tetrahydroquinolines 6a – e . Furthermore the preparation of the octahydroacridines 8f and 8g by using a straightforward multi step sequence is described.