Weijun Tang

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 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.

Cooperative Catalysis through Noncovalent Interactions

Noncovalent interactions, such as hydrogen bonding, electrostatic, p–p, CH–p, and hydrophobic forces, play an essential role in the action of nature s catalysts, enzymes. In the last decade these interactions have been successfully exploited in organocatalysis with small organic molecules. In contrast, such interactions have rarely been studied in the wellestablished area of organometallic catalysis, where electronic interactions through covalent bonding and steric effects imposed by bound ligands dictate the activity and selectivity of a metal catalyst. An interesting question is: What happens when an organocatalyst meets an organometallic catalyst? This unification has already created an exciting new space for both fields: cooperative catalysis, where reactants are activated simultaneously by both types of catalyst, thereby enabling reactivity and selectivity patterns inaccessible within each field alone. However, the mechanisms by which the two catalysts cooperatively effect the catalysis remain to be delineated. We recently found that combining an achiral iridium catalyst with a chiral phosphoric acid allows for highly enantioselective hydrogenation of imines (Scheme 1). To gain insight into the mechanism of this metal–organo cooperative catalysis, we studied the catalytic system with a range of techniques, including high pressure 2D-NMR spectroscopy, diffusion measurements, and NOEconstrained computation. Herein we report our findings. To evaluate the mechanism, a simplified achiral complex C was used, which leads to [C][A ] upon mixing, in situ or ex situ, with the chiral phosphoric acid HA through protonation at the amido nitrogen (Scheme 1). In the asymmetric hydrogenation of the model ketimine 1a, [C][A ] afforded 95% ee and full conversion. On the basis of related studies, the hydrogenation can be broadly explained by the catalytic cycle shown in Scheme 1, that is, [C][A ] activates H2 to give the hydride D and protonated 1a, which forms an ion pair with the phosphate affording [1a][A ]; hydride transfer furnishes the amine product 2a while regenerating [C][A ]. Questions pertinent to possible iridium–phosphate cooperation then arise: 1) How does the chiral phosphoric acid induce asymmetry in the hydrogenation? and 2) Does the enantioselectivity result from D being formed enantioselectively from [C][A ], from the phosphate salt [1a][A ], or from interactions involving all three components? We looked first at how the formation of hydride D and its transfer into the substrate are influenced by the chiral acid HA. The studies were carried out in CH2Cl2 or CD2Cl2 owing to the low solubility of the various metal complexes in toluene. The catalytic hydrogenation is feasible in both solvents, giving a 95% ee in toluene and 85 % ee in CH2Cl2 in the case of hydrogenation of 1a with C and HA under the conditions given in Scheme 1. The solution NMR studies show that the ionic complex [C][A ] is formed instantly on protonation of C (0.05 mmol) with one equivalent HA in CD2Cl2 (0.5 mL). Under H2 pressure (> 1 bar), proton transfer from a [C]–H2 dihydrogen intermediate (not observed) to 1a converts [C] into the hydride D and affords the salt [1a] [A ]. Formation of D took place instantly even at 78 8C, and it is observed during catalytic turnover, thus indicating that the hydrogenation is rate-limited by the hydride transfer step. Scheme 1. Hydrogenation of imine with achiral C and chiral acid HA (PMP = p-methoxyphenyl, Ar= 2,4,6-triisopropylphenyl, Ts = tosyl, Bn = benzyl).

Highly efficient chemoselective construction of 2,2-dimethyl-6-substituted 4-piperidones via multi-component tandem Mannich reaction in ionic liquids

The room temperature ionic liquid [bmim][PF6] has been demonstrated to be an efficient and recyclable medium for highly chemoselective synthesis of 2,2-dimethyl-6-substituted 4-piperidones via a L-proline catalyzed tandem Mannich reaction of ammonia, aldehydes and acetone, and good yields were achieved for aryl and alkyl aldehydes.

The Remarkable Effect of a Simple Ion: Iodide‐Promoted Transfer Hydrogenation of Heteroaromatics

Among a variety of heteroaromatics, 1,2,3,4-tetrahydroquinolines, -isoquinolines and -quinoxalines are three significant substructures in many bioactive compounds and have attracted a great deal of attention in research concerning pharmaceuticals, agrochemicals, dyes and fragrances, as well as hydrogen-storage materials. They can be directly accessed by hydrogenation from commercially available quinolines, isoquinolines and quinoxalines. Traditionally, stoichiometric metal hydrides and reactive metals are used as reducing reagents. Apart from producing copious waste and using often hazardous reagents, these methods suffer from limited substrate scope, incompatibility with functionality and poor chemoselectivity. A more attractive method is to use catalytic hydrogenation. Over the past several decades, a number of homogeneous and heterogeneous catalysts have been applied to the hydrogenation of heteroaromatics, including the asymmetric version. The need for high H2 pressure, high reaction temperature or high catalyst loading is typical of metal-catalysed hydrogenation. Obviating the need for hydrogen gas, transfer hydrogenation (TH) offers an alternative. However, only a few catalysts have been reported thus far that allow for the TH of heteroaromatics, and in all cases the catalyst loading is relatively high ( 0.5 %). Furthermore, in either hydrogenation or TH, there appears to be no catalyst capable of reducing all three classes of heteroaromatics: quinolines, isoquinolines and quinoxalines. Herein, we disclose a highly effective catalyst system, enabled by a simple ion, I , which shows unprecedented activity in the reduction of these heteroaromtics under mild conditions. We recently reported the first example of asymmetric transfer hydrogenation (ATH) of quinolines in water with formate as the hydrogen source. Excellent enantioselectivities were obtained with a Rh–Ts-dpen catalyst, [Cp*RhCl(Ts-dpen-H)] (Ts-dpen =N-(p-toluenesulfonyl)1,2-diphenylethylenediamine). Following this success, we attempted the ATH of quaternary quinoline salts, aiming to directly obtain chiral N-substituted 1,2,3,4-tetrahydroquinolines. We chose the N-methyl-2-methylquinoline iodide salt as a benchmark substrate and Rh–Ts-dpen as the catalyst (1 mol%). There was little reduction using sodium formate as the reductant in water at 40 8C in 24 h, under which quinolines were readily reduced. Somewhat surprisingly, changing the aqueous formate to the azeotropic HCO2H/ NEt3 mixture led to an excellent isolated yield of 95 % but a very low enantiomeric excess (ee) value of 5 % for the tetrahydro product. Interestingly, similar conversion was also observed under identical conditions with [(Cp*RhCl2)2] as catalyst, without adding the Ts-dpen ligand. Thus, the low ee value might result from the diamine ligand in Rh–Ts-dpen being replaced by the iodide anion in the salt during the reaction. Bearing in mind the unusual effects of iodide documented in catalysis and the scarcity of effective catalysts for TH of heteroaromatics, we thought it would be interesting to explore whether [(Cp*RhCl2)2] in combination with the iodide ion would lead to a simple but active catalyst. Choosing 2-methylquinoline 1 a (pKa 5.4) as a model substrate, which is expected to be protonated when using formic acid (pKa 3.6) as the reductant, the TH was first carried out with 0.05 mol % [(Cp*RhCl2)2] in the azeotropic HCO2H/NEt3 at 40 8C. The reduction was insignificant, with the conversion of 1 a being only 6 % (Table 1, entry 2), indicating that iodide might indeed be necessary. To our delight, in the presence of 1 or even 0.1 equivalent of an iodide salt, tetrabutylammonium iodide (TBAI), full conversion was observed (Table 1, entries 3 and 4). In contrast, the analogous bromide salt TBAB is much less effective (Table 1, entry 5) and the chloride TBAC is ineffective (entry 6). The cheaper KI was equally effective, showing that it is the iodide ion that promotes the catalysis (Table 1, entry 7). Remarkably, in the presence of KI, the metal loading could be decreased to 0.01 mol % without affecting the conversion (Table 1, entry 8). At an even a lower loading of 0.001 mol % of rhodium with 0.5 equivalent of KI added, a moderate conversion of 71 % was still obtained, albeit in a longer reaction [a] J. Wu, Dr. W. Tang, Prof. J. Xiao Department of Chemistry, University of Liverpool Liverpool L69 7ZD (UK) E-mail : j.xiao@liv.ac.uk [b] Dr. C. Wang School of Chemistry & Chemical Engineering Shaanxi Normal University, Xi an 710062 (P.R. China) [c] Dr. A. Pettman Chemical R & D, Global Research & Development, Pfizer Sandwich, Kent CT13 9NJ (UK) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201201517.

Cooperative Catalysis: Combining an Achiral Metal Catalyst with a Chiral Brønsted Acid Enables Highly Enantioselective Hydrogenation of Imines

Asymmetric hydrogenation of imines leads directly to chiral amines, one of the most important structural units in chemical products, from pharmaceuticals to materials. However, highly effective catalysts are rare. This article reveals that combining an achiral pentamethylcyclopentadienyl (Cp*)-iridium complex with a chiral phosphoric acid affords a catalyst that allows for highly enantioselective hydrogenation of imines derived from aryl ketones, as well as those derived from aliphatic ones, with ee values varying from 81 to 98 %. A range of achiral iridium complexes containing diamine ligands were examined, for which the ligands were shown to have a profound effect on the reaction rate, enantioselectivity and catalyst deactivation. The chiral phosphoric acid is no less important, inducing enantioselection in the hydrogenation. The induction occurs, however, at the expense of the reaction rate.

Direct synthesis of 8-aryl tetrahydroquinolines via pd-catalyzed ortho-arylation of aryl ureas in water

An efficient protocol for the direct synthesis of 8-arylated tetrahydroquinolines via Pd-catalyzed ortho-arylation of aryl ureas with aryl iodides was developed. The reaction proceeded smoothly in water under ligand-free and surfactant-free conditions, providing the desired products in high yields with remarkable functional group tolerance.

The preparation of 2,6-disubstituted pyridinyl phosphine oxides as novel anti-cancer agents

A series of 2,6-dimethoxylpyridinyl phosphine oxides have been synthesized and examined for their antitumor activity. 2,6-Dimethoxy-3-phenyl-4-diphenylphosphinoylpyridine 2 has been employed as the lead compound for this study. We found out that the presence of phosphine oxide on the 2,6-dimethoxylpyridine ring is important for the antitumor activity; the presence of bromine on this core leads to a further enhancement of its antitumor activity. This is the first reported work on the antitumor activity of the 2,6-dimethoxy-3,5-dibromopyridinyl phosphine oxide 5b towards MDAMB-231 breast cancer and SKHep-1 hepatoma cell lines.

Pd-catalyzed ligand-free Suzuki reaction of β-substituted allylic halides with arylboronic acids in water

The catalyst system consisting of Pd(TFA)2 and KOH allows for a wide range of β-substituted allylic halides to react efficiently with various arylboronic acids in neat water under ligand-free conditions, affording the allylated arenes in high yields with broad functional group tolerance and up to 7.4 × 105 TON and 15416 h−1 TOF.

Phase selectively soluble dendrimer-bound osmium complex: a highly effective and easily recyclable catalyst for olefin dihydroxylation.

A new switched biphasic catalysis system for highly effective olefin dihydroxylation has been described, in which the dendritic osmium catalyst preferred to dissolve in the non-polar organic layer and could be easily separated from the polar diol products through phase separation induced by addition of water at the end of the reaction.