Qing-Hua Fan

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).

A pH‐Triggered, Fast‐Responding DNA Hydrogel

A fast, pH-responsive DNA hydrogel (see picture; right) was prepared by a three-armed DNA nanostructure (left) assembling together through the formation of intermolecular i-motif structures (middle). The hydrogel can be switched to the non-gel state in minutes by simply using environmental pH changes.

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.

Asymmetric Hydrogenation of Quinoxalines with Diphosphinite Ligands: A Practical Synthesis of Enantioenriched, Substituted Tetrahydroquinoxalines†

The 1,2,3,4-tetrahydroquinoxaline ring system is an important structural unit in many bioactive compounds. Optically pure tetrahydroquinoxaline derivatives have shown great potential for pharmaceutical applications. For example, chiral compound A has been pursued as a potent vasopressin V2 receptor antagonists, and optically pure compound B is a promising inhibitor of cholesteryl ester transfer protein. In both cases, the chirality of the compounds was found to play a very important role in the relevant bioactivity of these compounds. The most convenient and straightforward route to chiral tetrahydroquinoxalines is the asymmetric hydrogenation of quinoxalines. Although several kinds of heteroaromatic compounds, such as quinolines, indoles, furans, pyridines, and pyrazines have been successfully hydrogenated with good to excellent enantioselectivities and yields in the presence of chiral transition-metal catalysts, the enantioselective hydrogenation of substituted quinoxaline derivatives has been less extensively studied. In 1987, Murata et al. first reported the rhodium-catalyzed asymmetric hydrogenation of 2-methylquinoxaline with only 3% ee. Later Bianchini et al. enantioselectively hydrogenated 2-methylquinoxaline with an orthomelated dihydride iridium complex to produce the product with up to 90% ee, but the reduction suffered from lower conversions. The performance of [RuCl2(diphosphine)(diamine)] complexes [3d,e] and Ir/PQphos (PQ-phos = (R)-[6,6-(2S,3S-butadioxy)]-(2,2’)-bis(diphenylphosphino)-(1,1’)-biphenyl) was also investigated, but only gave medium to low ee values. Given the importance of chiral tetrahydroquinoxalines and in view of the lack of efficient methods for the preparation of these compounds, the development of a practical and highly efficient catalytic asymmetric synthetic method appeared to be of great importance. Herein we describe the asymmetric hydrogenation of quinoxalines with an easily accessible Ir/diphosphinite catalyst. Good to excellent enantioselectivity (up to 98 % ee), unprecedented high catalytic activity (TOF up to 5620 h ), and productivity (TON up to 18 140) were observed for a wide range of substrates. Recently, the combination of transition metals and chiral phosphinite ligands has led to efficient catalysts for the asymmetric hydrogenation of prochiral olefins. In comparison with diphosphines, diphosphinites offer the advantages of easy preparation and derivatization. Recently, we have demonstrated that the easily accessible chiral diphosphinite ligands derived from (R)-H8-binol (binol = (1,1’-bi-2-naphthyl)) and (R)-1,1-spirobiindane-7,7-diol provided excellent catalytic activity and/or enantioselectivity in the Ir-catalyzed asymmetric hydrogenation of quinolines. Based on our previously optimized reaction conditions, we first investigated the performance of the [{IrCl(cod)}2] (cod = 1,5-cyclooctadiene)/(R)-H8-binapo or the (R)-sdpo/I2 catalyst system in THF for the asymmetric hydrogenation of 2-methylquinoxaline (1 a). To our delight, both catalysts worked efficiently with full conversions and good enantioselectivities (Table 1, entries 1 and 2), and (R)-H8-binapo gave the desired product in somewhat better enantiomeric excess. In sharp contrast to [*] Dr. W. Tang, J. Wang, Dr. B. Fan, Prof. Z. Zhou, Dr. K.-h. Lam, Prof. A. S. C. Chan Department of Applied Biology and Chemical Technology and Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis The Hong Kong Polytechnic University, Hong Kong (China) E-mail: bcachan@polyu.edu.hk

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.

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.

Donor-acceptor-donor triads incorporating tetrathiafulvalene and perylene diimide units: synthesis, electrochemical and spectroscopic studies

Abstract Three donor–acceptor–donor triads 1–3 consisting of tetrathiafulvalene units attached to perylene diimides by flexible and rigid spacers were synthesized and characterized. UV/vis spectroscopic and cyclic voltammetric results indicate that they all show negligible intramolecular charge transfer interaction in their ground states. As compared to the reference compound 21 , triads 1–3 display reduced fluorescence and their fluorescence lifetimes are shortened, which is probably owing to the photoinduced electron transfer interactions between the PI units and TTF units. The different photophysical behaviors between 1 and 2 (and 3 ) might be due to their difference in the spatial separation of TTF and PI units. It is preliminarily found that the steric hindrance of the groups attached to TTF units can affect their photostability.