Asymmetric transfer hydrogenation has become a practically useful tool in reduction chemistry in the last decade or so. This was largely triggered by the seminal work of Noyori and co-workers in the mid-1990s and is driven by its complementing chemistry to hydrogenation employing H2. This Focus Review attempts to present a “holistic” overview on the advances in the area, focusing on the achievements recorded around the last three years. These include more-efficient and “greener” metal catalysts, catalysts that enable hydrogenation as well as transfer hydrogenation, biomimetic and organocatalysts, and their applications in the reduction of CO, CN, and CC bonds. Also highlighted are efforts in the development of environmentally benign and reusable catalytic systems.

Broader, Greener, and More Efficient: Recent Advances in Asymmetric Transfer Hydrogenation

Recyclable stereoselective catalysts.

1,2,3,4-Tetrahydroquinolines exist as key structural elements in many natural products and have found broad commercial application. In particular, optically pure tetrahydroquinolines are commonly present in alkaloids and are required in pharmaceutical and agrochemical synthesis. Representative examples include the bioactive alkaloids (+)-galipinine and ( )-augustureine, 3] and the antibacterial drug (S)-flumequine.

pH-Regulated Asymmetric Transfer Hydrogenation of Quinolines in Water

The mechanism of aqueous-phase asymmetric transfer hydrogenation (ATH) of acetophenone (acp) with HCOONa catalyzed by Ru-TsDPEN has been investigated by stoichiometric reactions, NMR probing, kinetic and isotope effect measurements, DFT modeling, and X-ray structure analysis. The chloride [RuCl(TsDPEN)(p-cymene)] (1), hydride [RuH(TsDPEN)(p-cymene)] (3), and the 16-electorn species [Ru(TsDPEN-H)(p-cymene)] (4) were shown to be involved in the aqueous ATH, with 1 being the precatalyst, and 3 as the active catalyst detectable by NMR in both stoichiometric and catalytic reactions. The formato complex [Ru(OCOH)(TsDPEN)(p-cymene)] (2) was not observed; its existence, however, was demonstrated by its reversible decarboxylation to form 3. Both 1 and 3 were protonated under acidic conditions, leading to ring opening of the TsDPEN ligand. 4 reacted with water, affording a hydroxyl species. In a homogeneous DMF/H(2)O solvent, the ATH was found to be first order in the concentration of catalyst and acp, and inhibited by CO(2). In conjunction with the NMR results, this suggests that hydrogen transfer to ketone is the rate-determining step. The addition of water stabilized the ruthenium catalyst and accelerated the ATH reaction; it does so by participating in the catalytic cycle. DFT calculations revealed that water hydrogen bonds to the ketone oxygen at the transition state of hydrogen transfer, lowering the energy barrier by about 4 kcal mol(-1). The calculations also suggested that the hydrogen transfer is more step-wise in nature rather than concerted. This is supported to some degree by the kinetic isotope effects, which were obscured by extensive H/D scrambling.

A Multilateral Mechanistic Study into Asymmetric Transfer Hydrogenation in Water

Reductive amination of vari- ous ketones and aldehydes by transfer hydrogenation under aqueous condi- tions has been developed, by using cy- clometallated iridium complexes as cat- alysts and formate as hydrogen source. The pH value of the solution is shown to be critical for a high catalytic chemoA and activity, with the best pH value being 4.8. In comparison with that in organic solvents, the reduc- tive amination in an aqueous phase is faster, and the molar ratio of the sub- strate to the catalyst (S/C) can be set as high as 1 � 10 5 , the highest S/C value ever reported in reductive amination reactions. The catalyst is easy to access and the reaction is operationally simple, allowing a wide range of ke- tones and aldehydes to react with vari- ous amines in high yields. The protocol provides a practical and environmental friendly new method for the synthesis of amine compounds.

Fast Reductive Amination by Transfer Hydrogenation "on Water"

An enantiopure 1,2-diamine having two phenolic hydroxy groups was synthesized, and attached to chloromethylated poly(styrene) through a benzyl ether linkage. The polymer-supported Ru precatalysts were prepared from the polymeric chiral 1,2-diamine and RuCl 2 /BINAP complex. In the presence of t-BuOK the polymeric catalyst system worked well in asymmetric hydrogenation of aromatic ketones in a mixed solvent of 2-propanol and DMF. The insoluble polymeric catalyst was readily separated from the reaction mixture and reused at least several times without loss of the catalytic activity.

Preparation of Polymer‐Supported Chiral 1,2‐Diamine as an Efficient Ligand for Asymmetric Hydrogenation Catalyst

An enantiopure 1,2-diamine monomer possessing a p-vinylbenzyl group as a polymerizable group was synthesized from chiral 1,2-bis(p-hydroxyphenyl)-N,N′-bis(tert-butoxycarbonyl)-1,2-diaminoethane. The chiral monomer was copolymerized with styrene, and this was followed by the deprotection of the tert-butoxycarbonyl group, which yielded the polymer-supported chiral 1,2-diamine. The polymeric catalyst system was established with the polymeric chiral 1,2-diamine complexed with 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl/RuCl2. In the presence of potassium tert-butoxide (t-BuOK), the polymeric catalyst system worked well in the asymmetric hydrogenation of aromatic ketones. The corresponding chiral secondary alcohols were obtained in quantitative yields with a high level of enantioselectivity. The insolubility of the catalyst, caused by the crosslinked structure of the polymer, made it recyclable. The polymeric catalyst was reused several times without a loss of catalytic activity. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4556–4562, 2004

Preparation of the enantiopure 1,2‐diamine monomer and its polymerization: The efficient polymeric chiral ligand of an asymmetric hydrogenation catalyst

A novel chiral 1,2-diamine monomer (S,S)-12 has been synthesized and copolymerized with styrene to give cross-linked polymer. After deprotection of the tert-butoxycarbonyl groups, polymer-supported chiral 1,2-diamine (S,S)-P was obtained. The primary 1,2-diamine moieties on the polymer have been allowed to form the complex with RuCl2/(S)-BINAP. The polymeric chiral complex was used as a catalyst of asymmetric hydrogenation of aromatic ketones to yield the corresponding secondary alcohols in quantitative conversion with high level of enantioselectivity. The polymeric catalyst was recycled several times without any loss of the catalytic activity.

Synthesis of chiral 1,2-diamine immobilized on polystyrene and its application to asymmetric hydrogenation of aromatic ketones

Polymer-supported chiral 1,2-diamine derivatives have been prepared. The poly- mers containing free 1,2-diamine moiety were applied to enantioselective hydrogenation cat- alyst by combination with RuCl 2 -BINAP complex. Asymmetric hydrogenation of aromatic ketones was performed by means of the polymeric catalyst derived from these polymers to give the chiral secondary alcohols with high ee in quantitative conversion. The polymers con- taining 1,2-diamine monosulfonamide were applied to enantioselective transfer hydrogena- tion catalyst by combination with RuCl 2 -p-cymene complex. Asymmetric transfer hydro- genation of aromatic ketones was performed by means of the polymeric catalyst to afford the chiral secondary alcohols. A high level of enantioselectivities up to 99 % ee was attained in neat water by using the polymeric catalyst prepared from quaternary ammonium salt-type polymer support.

https://media.iupac.org/publications/pac/2007/pdf/7909x1471.pdf

Synthesis of polymers containing chiral 1,2-diamine derivatives and their application to asymmetric reactions*

Novel polymer-supported chiral 1,2-diamines have successfully synthesized by radical copolymerization of N-Boc protected enantiopure 1,2-diamine bearing two vinylphenyl moieties ((S,S)-5) with various achiral vinyl monomer including methyl methacrylate, 2-hydroxyethyl methacrylate, butyl acrylate, and N-isopropyl acrylamide, followed by deprotection of N-Boc moiety. Hydrogenation of acetophenone in 2-propanol/DMF mixed solvent was performed with use of polymeric catalyst system prepared from the polymer-supported chiral 1,2-diamine and RuCl2/(S)-BINAP. The reaction proceeded smoothly to give 1-phenylethanol in quantitative yield with high level of enantioselectivity. In addition, various other aromatic ketones could be asymmetrically hydrogenated by the polymeric catalyst system. Furthermore, the polymeric catalyst could be reused several times in hydrogenation of aromatic ketones without loss of the enantioselectivity.

Miyuki Takahashi

Papers

Preparation of Polymer‐Supported Chiral 1,2‐Diamine as an Efficient Ligand for Asymmetric Hydrogenation Catalyst

Preparation of the enantiopure 1,2‐diamine monomer and its polymerization: The efficient polymeric chiral ligand of an asymmetric hydrogenation catalyst

Synthesis of chiral 1,2-diamine immobilized on polystyrene and its application to asymmetric hydrogenation of aromatic ketones

Synthesis of polymers containing chiral 1,2-diamine derivatives and their application to asymmetric reactions*

Polymer‐Supported Chiral 1,2‐Diamines by Radical Copolymerization with Vinyl Monomer for Asymmetric Hydrogenation of Aromatic Ketones