Yan-Mei He

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 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.

Peripherally dimethyl isophthalate-functionalized poly(benzyl ether) dendrons: a new kind of unprecedented highly efficient organogelators.

A series of poly(benzyl ether) dendrons, up to the fourth generation, decorated in their periphery with dimethyl esters were divergently synthesized and fully characterized. These dendrons were found to be unprecedented highly efficient organogelators toward various aromatic and polar organic solvents with the critical gelator concentration (CGC) approaching 2.2 mg/mL. The gelation ability was found to be highly dependent on the nature of the peripheral groups, dendron generation, and the dendritic architecture. The large monodisperse dendron G(4) with a globular shape could also form stable gels in several aromatic solvents with relatively high CGCs. A number of experiments (SEM, TEM and AFM imaging, X-ray crystal structure analysis, concentration- and temperature-dependent (1)H NMR spectroscopy, fluorescence spectroscopy, and powder X-ray diffraction) confirmed the self-aggregation of these dendrons, despite the lack of any conventional gelating motifs such as amides, long alkyl side chains, and steroidal groups. The multiple strong pi-pi stacking interactions due to the peripheral dimethyl isophthalate rings and the internal benzyl rings are found to be the key contributor in forming the self-assembled gel.

Asymmetric hydrogenation of 2- and 2,3-substituted quinoxalines with chiral cationic ruthenium diamine catalysts.

The enantioselective hydrogenation of 2-alkyl- and 2-aryl-subsituted quinoxalines and 2,3-disubstituted quinoxalines was developed by using the cationic Ru(η(6)-cymene)(monosulfonylated diamine)(BArF) system in high yields with up to 99% ee. The counteranion was found to be critically important for the high enantioselectivity and/or diastereoselectivity.

Advances in transition metal-catalyzed asymmetric hydrogenation of heteroaromatic compounds.

Transition metal-catalyzed asymmetric hydrogenation of heteroaromatic compounds is undoubtedly a straightforward and environmentally friendly method for the synthesis of a wide range of optically active heterocyclic compounds, which are widespread and ubiquitous in naturally occurring and artificial bioactive molecules. Over the past decade, a number of transition metal (Ir, Rh, Ru, and Pd) catalysts bearing chiral phosphorus ligands, amine-tosylamine ligands, and N-heterocyclic carbene ligands have been developed for such challenging transformation. This review will describe the significant contributions concerning the transition metal-catalyzed asymmetric hydrogenation of N-, O-, and S-containing heteroaromatic compounds, with emphasis on the evolution of different chiral ligands, related catalyst immobilization, and mechanism investigations.

Asymmetric Hydrogenation in the Core of Dendrimers

The transition metal complexes containing chiral phosphorus ligands are the most widely and successfully used catalysts in asymmetric hydrogenation of unsaturated compounds. However, a major problem associated with these homogeneous catalytic systems is the separation and recycling of the often expensive and easily oxidized chiral catalysts. In addition, many hydrogenation reactions still lack efficient chiral catalysts, and the stereoselectivities in many hydrogenation reactions are substrate-dependent. Therefore, the development of highly effective and recyclable chiral phosphorus catalysts is highly desirable. Over the past few decades, a number of chiral catalysts have been successfully anchored onto different supports, such as cross-linked polymeric resins and inorganic materials. However, most of the classical supported chiral catalysts suffered from inferior catalytic properties to their homogeneous counterparts due to poor accessibility, random anchoring, and disturbed geometry of the active sites in the solid matrix. To overcome this drawback, dendrimers, which have well-defined and globular macromolecular architectures serve as a promising type of soluble catalyst support. The catalytic sites are generally located at the core or on the periphery of the dendrimer, and the resulting dendritic catalysts are designable. Incorporation of a chiral catalyst into a sterically demanding dendrimer will create a specific microenvironment around the catalytic site and thus influence the catalytic performance of the metal center, like an enzyme does. In this Account, we survey the development of core-functionalized chiral dendritic phosphorus ligands for asymmetric hydrogenation mainly by our research group. Several series of chiral dendritic phosphorus ligands, including diphosphines, monodentate phosphoramidites, and P,N-ligands, have been synthesized by attaching the corresponding chiral phosphorus units into the core or the focal point of Fréchet-type dendrons. Their transition metal (Ru, Rh, or Ir) complexes have been applied in the asymmetric hydrogenation of prochiral olefins and ketones, as well as some challenging imine-type substrates. All reactions were carried out in a homogeneous manner, and the structure-property relationships in some cases were established. The sterically demanding dendritic wedges were found to play important roles in catalytic properties, and better catalytic activities or enantioselectivities or both than those obtained from the corresponding monomeric catalysts were achieved in most cases. In addition, the dendritic catalysts could be readily recycled by means of solvent precipitation, water- or temperature-induced two-phase separation. Our study has thus demonstrated that dendrimer catalysis could combine the advantages of both classical heterogeneous and homogeneous catalysis.

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