Tianli Wang

Highly Enantioselective Hydrogenation of Quinolines Using Phosphine-Free Chiral Cationic Ruthenium Catalysts: Scope, Mechanism, and Origin of Enantioselectivity

Asymmetric hydrogenation of quinolines catalyzed by chiral cationic η(6)-arene-N-tosylethylenediamine-Ru(II) complexes have been investigated. A wide range of quinoline derivatives, including 2-alkylquinolines, 2-arylquinolines, and 2-functionalized and 2,3-disubstituted quinoline derivatives, were efficiently hydrogenated to give 1,2,3,4-tetrahydroquinolines with up to >99% ee and full conversions. This catalytic protocol is applicable to the gram-scale synthesis of some biologically active tetrahydroquinolines, such as (-)-angustureine, and 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, a key intermediate for the preparation of the antibacterial agent (S)-flumequine. The catalytic pathway of this reaction has been investigated in detail using a combination of stoichiometric reaction, intermediate characterization, and isotope labeling patterns. The evidence obtained from these experiments revealed that quinoline is reduced via an ionic and cascade reaction pathway, including 1,4-hydride addition, isomerization, and 1,2-hydride addition, and hydrogen addition undergoes a stepwise H(+)/H(-) transfer process outside the coordination sphere rather than a concerted mechanism. In addition, DFT calculations indicate that the enantioselectivity originates from the CH/π attraction between the η(6)-arene ligand in the Ru-complex and the fused phenyl ring of dihydroquinoline via a 10-membered ring transition state with the participation of TfO(-) anion.

Hydrogenation of Quinolines Using a Recyclable Phosphine‐Free Chiral Cationic Ruthenium Catalyst: Enhancement of Catalyst Stability and Selectivity in an Ionic Liquid

Room-temperature ionic liquids (RTILs) have recently received a great deal of attention as alternative reaction media. Numerous catalytic reactions have proven feasible in a variety of ionic liquids, with many reactions displaying enhanced reactivities and selectivities, and some of which were not possible in common organic solvents. Furthermore, RTILs have served as a promising means to immobilize a catalyst, therefore facilitating product isolation and offering an opportunity to reuse the catalyst. However, the use of RTILs in asymmetric catalytic reactions is still limited. The recycling and reuse of chiral catalysts in ionic liquids have often been problematic because of the instability and/or leaching of the catalysts. From a practical standpoint, development of highly effective and recyclable catalysts in ionic liquids for use in asymmetric hydrogenation remains a challenge: in particular for heteroaromatic substrates which are difficult to hydrogenate. Although a variety of chiral Rh, Ru, and Ir complexes have been efficient and enantioselective reagents for the hydrogenation of prochiral olefins, ketones, and imines, most of these catalysts failed to give satisfactory results in the asymmetric hydrogenation of heteroaromatic compounds. A few successful examples for the asymmetric hydrogenation of quinolines have recently been reported. However, all catalysts for such reactions have at least one phosphine ligand around the metal center and are often air sensitive. From the viewpoints of both scientific interest and practical application, it is highly desirable to develop recyclable and phosphine-free chiral catalysts for the highly enantioselective hydrogenation of quinolines. Few examples of phosphine-free homogeneous catalysts capable of activating molecular hydrogen have been reported. Recently, Noyori and co-workers reported that chiral h-arene/Ntosylethylenediamine–Ru complexes (which are known as excellent catalysts for asymmetric transfer hydrogenation, for example Ru/Ts-dpen) can be used for the asymmetric hydrogenation of prochiral ketones under slightly acidic conditions. Inspired by this important breakthrough and following our continued pursuit of developing effective and environmentally benign catalyst systems for asymmetric hydrogenations, herein we report a practical and efficient catalyst system of Ru/Ts-dpen in [BMIM]PF6 (BMIM = 1-nbutyl-3-methylimidazolium) for the enantioselective hydrogenation of quinolines (Scheme 1).

Air-Stable and Phosphine-Free Iridium Catalysts for Highly Enantioselective Hydrogenation of Quinoline Derivatives†

Enantioselective hydrogenation of quinoline derivatives catalyzed by phosphine-free chiral cationic Cp*Ir(OTf)(CF 3TsDPEN) complex (CF 3TsDPEN = N-(p-trifluoromethylbenzenesulfonyl)-1,2-diphenylethylene-diamine) afforded the 1,2,3,4-tetrahydroquinoline derivatives in up to 99% ee. The reaction could be carried out with a substrate-to-catalyst molar ratio as high as 1000 in undegassed methanol and with no need for inert gas protection.

Highly enantioselective hydrogenation of quinolines under solvent-free or highly concentrated conditions

The phosphine-free chiral cationic Ru(OTf)(TsDPEN)(η6-cymene) complex was found to be an efficient catalyst for the enantioselective hydrogenation of quinolines under more environmentally friendly solvent-free or highly concentrated conditions. Excellent yields and enantioselectivities (up to 97% ee) were obtained at only 0.02–0.10 mol% catalyst loading.

Highly efficient and enantioselective hydrogenation of quinolines and pyridines with Ir-Difluorphos catalyst

The combination of the readily available chiral bisphosphine ligand Difluorphos with [Ir(COD)Cl](2) in THF resulted in a highly efficient catalyst system for asymmetric hydrogenation of quinolines at quite low catalyst loadings (0.05-0.002 mol%), affording the corresponding products with high enantioselectivities (up to 96%), excellent catalytic activities (TOF up to 3510 h(-1)) and productivities (TON up to 43000). The same catalyst was also successfully applied to the asymmetric hydrogenation of trisubstituted pyridines with nearly quantitative yields and up to 98% ee. In these two reactions, the addition of I(2) additive is indispensable; but the amount of I(2) has a different effect on catalytic performance.

Highly Effective Asymmetric Hydrogenation of Cyclic N-Alkyl Imines with Chiral Cationic Ru-MsDPEN Catalysts

A range of cyclic N-alkyl imines were efficiently hydrogenated by using a chiral cationic Ru(η(6)-cymene)(MsDPEN)(BArF) complex (MsDPEN = N-(methanesulfonyl)-1,2-diphenylethylenediamine) in high yields and up to 98% ee. A one-pot synthesis of chiral 2-phenylpyrrolidine via reductive amination was also developed.

Asymmetric ruthenium-catalyzed hydrogenation of 2- and 2,9-substituted 1,10-phenanthrolines.

Asymmetric hydrogenation of heteroaromatic compounds has captured considerable attention because it offers straightforward and environmentally benign routes to optically active compounds with chiral heterocyclic skeletons. Recently, various heteroarenes such as quinolines, isoquinolines, quinoxalines, indoles, pyrroles, (benzo)furans, pyridines, imidazoles, and (benzo)thiophenes have been successfully hydrogenated with high enantiomeric excesses. However, despite achievements made in this field, many challenges still remain and polycyclic heteroarenes (containing more than one heterocycle) are particularly difficult substrates. 1,10-Phenanthroline (Phen; 1) and its derivatives containing two pyridyl rings are one of the most versatile bidentate ligands for transition-metal catalysis. Much less attention has been directed toward the partially reduced 1,2,3,4-tetrahydroand 1,2,3,4,7,8,9,10-octahydro-1,10-phenanthroline [TPhen (2) and OPhen (3), respectively] derivatives, which are two kinds of heterocycle-containing compounds with potential bioactivity and can also be used as new ligands such as vicinal diamines and benzimidazole-based N-heterocyclic carbenes. So far, few reports have focused upon heterogeneous metal-catalyzed hydrogenation or reduction with stoichiometric reducing agents of 1,10-phenanthroline and its derivatives, and all these methods suffered from low stereoselectivities and poor reaction yields. Moreover, as far as we know, homogeneous transition-metal catalyzed hydrogenation of such substrates has never been reported, probably because of the aromaticity, as well as the strong coordination and poisoning ability of the substrate or the reduced product. For example, the cationic half-sandwich ruthenium complex 4 containing a 1,10-phenanthroline ligand was found to be an effective catalyst for the transfer hydrogenation of ketones. Expectedly, it is more challenging to realize the asymmetric reduction of substituted 1,10-phenanthrolines to selectively provide chiral TPhen and OPhen (Scheme 1). To the best of our knowledge, only one example of asymmetric transfer hydrogenation of 2and 2,9substituted 1,10-phenanthrolines catalyzed by chiral Bronsted acid has been reported. However, several obvious limitations remain, such as low reactivity or selectivity, and