Asymmetric transfer hydrogenation of aromatic ketones with the ruthenium(II) catalyst derived from C2 symmetric N,N′-bis[(1S)-1-benzyl-2-O-(diphenylphosphinite)ethyl]ethanediamide

Asymmetric transfer hydrogenation of ketones with chiral molecular catalysts is realized to be one of the most magnificent tools to access chiral alcohols in organic synthesis. A new chiral phosphinite compound N,N′-bis[(1S)-1-benzyl-2-O-(diphenylphosphinite)ethyl]ethanediamide (1), has been synthesized by the reaction of chlorodiphenylphosphine with N,N′-bis[(1S)-1-benzyl-2-hydroxyethyl]ethanediamide under argon atmosphere. The oxidation of 1 with aqueous hydrogen peroxide, elemental sulfur or grey selenium in toluene gave the corresponding oxide 1a, sulfide 1b and selenide 1c, respectively. Pd, Pt and Ru complexes were obtained by the reaction of 1 with [MCl₂(cod)] (M: Pd 1d, Pt 1e) and [Ru(p-cymene)Cl₂]₂1f, respectively. All these new complexes were characterized by using NMR, FT-IR spectroscopies and microanalysis. Additionally, as a demonstration of their catalytic reactivity, the ruthenium complex 1f was tested as catalyst in the asymmetric transfer hydrogenation reactions of acetophenone derivatives with iPrOH was also investigated.     

Asymmetric transfer hydrogenation of acetophenone derivatives with novel chiral phosphinite based η-p-cymene/ruthenium(II) catalysts

Enantioselective reduction of prochiral ketones to optically active secondary alcohols is an important subject in synthetic organic chemistry because the resulting chiral alcohols are extremely useful, biologically active compounds. The new chiral ligands (2R)-2-[benzyl{(2-((diphenylphosphanyl)oxy)ethyl)}amino]butyldiphenylphosphinite, 1 and (2R)-2-[benzyl{(2-((dicyclohexylphosphanyl)oxy)ethyl)}amino]butyldicyclohexylphosphinite, 2 and the corresponding ruthenium(II) complexes 3 and 4 have been prepared. The structures of these complexes have been elucidated by a combination of multinuclear NMR spectroscopy, IR spectroscopy and elemental analysis. ³¹P-{¹H} NMR, DEPT, ¹H-¹³C HETCOR or ¹H-¹H COSY correlation experiments were used to confirm the spectral assignments. These ruthenium(II)-phosphinite complexes have been used as catalysts for the asymmetric transfer hydrogenation of acetophenone derivatives. Under optimized conditions, aromatic ketones were reduced in good conversions and in moderate to good enantioselectivities (up to 85% ee).     

Synthesis,characterization, and reactivity of ruthenium(II) complexes containing η6-arene-η1-pyrazole ligands

New ruthenium(II) complexes containing η⁶-arene-η¹-pyrazole ligands were synthesized and characterized by elemental analysis and spectroscopic methods. In addition, the molecular structure of dichloro-3,5-dimethyl-1-(pentamethylbenzyl)-pyrazole–ruthenium(II), [Ru]L_3b, was determined by X-ray diffraction studies. These complexes were applied in the transfer hydrogenation of acetophenone by isopropanol in the presence of potassium hydroxide. The activities of the catalysts were monitored by NMR.     

New C2-symmetric chiral phosphinite ligands based on amino alcohol scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones

Asymmetric transfer hydrogenation processes of ketones with chiral molecular catalysts are attracting increasing interest from synthetic chemists due to their operational simplicity. C₂-symmetric catalysts have also received much attention and been used in many reactions. A series of new chiral C₂-symmetric bis(phosphinite) ligands has been prepared from corresponding amino acid derivated amino alcohols or (R)-2-amino-1-butanol through a three- or four-step procedure. Their structures have been elucidated by a combination of multinuclear NMR spectroscopy, IR spectroscopy and elemental analysis. ¹H-³¹P NMR, DEPT, ¹H-¹³C HETCOR or ¹H-¹H COSY correlation experiments were used to confirm the spectral assignments. In situ prepared ruthenium catalytic systems were successfully applied to ruthenium-catalyzed asymmetric transfer hydrogenation of acetophenone derivatives by iso-PrOH. Under optimized conditions, these chiral ruthenium catalyst systems serve as catalyst precursors for the asymmetric transfer hydrogenation of acetophenone derivatives in iso-PrOH and act as good catalysts, giving the corresponding optical secondary alcohols in 99% yield and up to 79% ee.     

Structure–Reactivity Relationships in the Hydrogenation of Carbon Dioxide with Ruthenium Complexes Bearing Pyridinylazolato Ligands

Pyridinylazolato (N–N′) ruthenium(II) complexes of the type [(N–N′)RuCl(PMe₃)₃] have been obtained in high yields by treating the corresponding functionalised azolylpyridines with [RuCl₂(PMe₃)₄] in the presence of a base. ¹⁵N NMR spectroscopy was used to elucidate the electronic influence of the substituents attached to the azolyl ring. The findings are in agreement with slight differences in the bond lengths of the ruthenium complexes. Furthermore, the electronic nature of the azolate moiety modulates the catalytic activity of the ruthenium complexes in the hydrogenation of carbon dioxide under supercritical conditions and in the transfer hydrogenation of acetophenone. DFT calculations were performed to shed light on the mechanism of the hydrogenation of carbon dioxide and to clarify the impact of the electronic nature of the pyridinylazolate ligands.     

New functional chiral P-based ligands and application in ruthenium-catalyzed enantioselective transfer hydrogenation of ketones

Metal-catalyzed asymmetric transfer hydrogenation is a powerful and practical method for the reduction of ketones to produce the corresponding secondary alcohols, which are valuable building blocks in the pharmaceutical, perfume, and agrochemical industries. Hence, a series of novel chiral β-amino alcohols were synthesized by chiral amines with regioselective ring opening of (S)-propylene oxide or reaction with (S)-(+)-2-hydroxypropyl p-toluenesulfonate by a straightforward method. The chiral ruthenium catalytic systems generated from [Ru(arene)(μ-Cl)Cl]₂ complexes and chiral phosphinite ligands based on amino alcohol derivatives were employed in asymmetric transfer hydrogenation of ketones to give the corresponding optically active alcohols; (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]amino}propan-2-yldiphenylphosphinitobis[dichol-oro(η⁶-benzene)ruthenium(II)] acts an excellent catalyst in the reduction of α-naphthyl methyl ketone, giving the corresponding alcohol with up to 99% ee. The substituents on the backbone of the ligands were found to have a remarkable effect on both the conversion and enantioselectivity of the catalysts. Furthermore, this transfer hydrogenation is characterized by low reversibility under these conditions.     

Enantiomerically pure chiral pyridino-crown ethers: synthesis and enantioselectivity toward the enantiomers of α-(1-naphthyl)ethylammonium perchlorate

Seven new enantiomerically pure chiral pyridino-crown ethers (S,S)-4–(R,R)-10 were prepared. Three of them [(S,S)-4, (S,S)-7 and (R,R)-10] contain one, and two of them [(S,S)-5 and (S,S)-8] contain two linker chains with a terminal double bond. These linker chains were connected to the carbon atom at position 9 (opposite the pyridine moiety) of the macrocycle. The terminal double bond of the linker makes it possible to attach these ligands to silica gel to obtain chiral stationary phases (CSPs). The enantioselectivity of the new ligands toward the enantiomers of α-(1-naphthyl)ethylammonium perchlorate (NEA) was also determined by a titration ¹H NMR method.     

Ruthenium-catalyzed transfer hydrogenation of aromatic ketones with aminophosphine or bis(phosphino)amine ligands derived from isopropyl substituted anilines

A series of new highly active Ru(II) complexes with two new (N-diphenylphosphino)isopropylanilines, having an isopropyl substituent at carbon 2- (1) or 2,6- (2) and two new bis(diphenylphosphino)isopropylanilines, having an isopropyl substituent at carbon atom 2- (3) or 4- (4), were prepared starting from the dimeric complex [Ru(η⁶-p-cymene)(μ-Cl)Cl]₂. All the compounds have been fully characterized by microanalysis, IR, ³¹P{1H} NMR, ¹H NMR and ¹³C NMR spectroscopies. Following activation by NaOH, complexes 5–8 were tested in the transfer hydrogenation of acetophenone derivatives with iso-PrOH as the hydrogen source. Catalytic studies showed that the complexes are excellent catalytic precursors for the transfer hydrogenation of acetophenone derivatives.     

Enantiopure poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate): a new material for supported catalytic asymmetric hydrogen transfer reduction

A novel copolymer containing chiral epoxy residues was prepared. Free radical initiated suspension copolymerization of (R)- or (S)-glycidyl methacrylate with ethylene glycol dimethacrylate afforded crosslinked copolymer 1 in high yield. Optically active polymers containing amino alcohol functionalities were then formed from 1 through epoxide ring opening with a number of achiral and homochiral amines. It was shown that ruthenium complexes based on these new polymeric amino alcohol ligands were effective catalysts for the asymmetric hydrogen transfer reduction of acetophenone.     

Chiral memory effects in catalytic hydrogenations with dynamically chiral ligands

The low barrier for interconversion of chiral conformations of the dynamically chiral 2,2′-biphenyl ligand NMe₂C₆H₄C₆H₄PCy₂ is raised upon coordination. The individual enantiomers of the planar chiral arene-tethered complex Ru(η⁶:η¹- NMe₂C₆H₄C₆H₄PCy₂)Cl₂ (1), however, do not undergo racemization readily. A second source of chirality, such as a chiral diamine, can be included by conversion of 1 into a dicationic analogue [Ru(η⁶:η¹-NMe₂C₆H₄C₆H₄PCy₂)((1S,2S)-DPEN)](SbF₆)₂ (2), which is a catalyst precursor for the hydrogenation of aryl ketones. Two epimers of 2, R_Ar,S,S and S_Ar,S,S, are formed when starting from racemic 1; this 1:1 mixture of diastereomers catalyzed the asymmetric hydrogenation of acetophenone. The enantiomerically pure diastereomers were obtained from resolved 1 and used separately to catalyze the reaction. Each diastereomer showed different selectivity, with S_Ar,S,S-2 being the more selective (61% ee for the hydrogenation of acetophenone). Our studies suggest that ruthenium hydride formation is accompanied by a decrease in hapticity of the η⁶-arene and probable detachment of the ring from the metal. Nevertheless, the original conformational chirality of the biphenyl ligand appears to be at least partially retained during the catalysis.     

Optically active transition metal complexes. Part 117:Synthesis,crystal structure and properties of chiral (η6-arene)ruthenium complexes with N,O- and N,N-ligands

The complexes [(η⁶-p-ⁱPrC₆H₄Me)Ru(NO₂pesa)Cl] 2, [(η⁶-p-ⁱPrC₆H₄Me)Ru(oxazsa)Cl] 3 and [(η⁶-p-ⁱPrC₆H₄Me)Ru(pepy)Cl] 4, chiral in the chelate ligand and chiral at the ruthenium atom, have been prepared by reaction of [(η⁶-p-ⁱPrC₆H₄Me)RuCl₂]₂ with the anions of the (S)-configured bidentate N,O- and N,N-ligands. [(η⁶-p-ⁱPrC₆H₄Me)Ru(pesa)I] 5 was synthesized by halide exchange. The diastereomer ratios of compounds 2–4 with respect to the stereogenic ruthenium atom are in CDCl₃ 2a:2b=81:19, 3a:3b=77:23 and 4a:4b=61:39. Compound 5 is obtained diastereomerically pure. An X-ray structure analysis of 3 shows (R_Ru,S_C)-configuration     

Enantiomerically pure cyclopalladated diazaphospholidine

Enantiomerically pure (S)-2-(anilinomethyl)pyrrolidine (S)-2 was obtained from (S)-proline using a modified four-step procedure in a total yield of 56%. Diamine (S)-2 was converted to diazaphospholidine (S)-1 using ^oTolP(NMe₂)₂. The enantiomeric purity of ligand (S)-1 and diamine (S)-2 was determined by ³¹P and ¹H NMR spectroscopy, respectively, using a CN-palladacycle for their chiral derivatization. Direct cyclopalladation of (S)-1, using Pd(OAc)₂ in toluene under mild conditions regioselectively afforded the cyclopalladated complex with the (sp²)C–Pd bond. The aromatic C–H bond activation was confirmed by NMR spectral data and X-ray diffraction study of the PPh₃ derivative of the new P¹,C¹,N¹-chiral phosphapalladacycle.     

New amidophosphine-phosphinites (tLANOPs) as chiral ligands for asymmetric hydrogenation reactions

The new amidophosphine-phosphinite (AMPP) ligands 4a–g (called tLANOP ligands) derived from the chiral hydroxy amide (R)- or (S)-2-hydroxy-3,3,N-trimethylbutyramide have been prepared in 48–83% yield. The crystal structures of the square planar complexes [(SP-4-3)-Pd((R)-dmphea)((S)-4a)]BF₄ and [Rh((R)-4a)(COD)]BF₄ have allowed the absolute configurations of the ligands to be assigned. In both complexes the 7-membered chelating ring of 4a has virtually the same twist-boat conformation. With this class of ligands the rhodium catalyzed asymmetric hydrogenation of 4-oxoisophorone enol acetate gave (S)-phorenol acetate in up to 71% ee. The iridium catalyzed asymmetric hydrogenation of the cyclic iminium salts 16a and 16b afforded after work-up the corresponding cyclic secondary amine (S)-17 in up to 86% ee, when bulky groups were present on the phenyl substituents on the two phosphorus atoms.     

Cationic and neutral ruthenium(II) complexes containing both arene or Cp* and functionalized aminophosphines. Application to hydrogenation of aromatic ketones

Hydrogen transfer reduction processes are attracting increasing interest from synthetic chemists in view of their operational simplicity. For this aim, a series of novel Ru(II) complexes with the P-N-P ligands were synthesized starting from the complex [Ru(η⁶-p-cymene)(μ-Cl)Cl]₂ or [RuCp*Cl(COD)]. The complexes were fully characterized by analytical and spectroscopic methods. ³¹P-{¹H} NMR, DEPT, ¹H-¹³C HETCOR or ¹H-¹H COSY correlation experiments were used to confirm the spectral assignments. Complexes 5, 6 and 7 catalyze the transfer hydrogenation of acetophenone derivatives to 1-phenylethanol derivatives in the presence of iso-PrOH as the hydrogen source. Catalytic studies showed that all complexes are excellent catalytic precursors for the transfer hydrogenation of acetophenone derivatives in 0.1 M iso-PrOH solution. Notably 5 acts as an excellent catalyst giving the corresponding alcohols in excellent conversions up to 99% (TOF ≤ 492 h⁻¹).     

Determination of the absolute stereochemistry and the activation barriers of thermally interconvertible heterocyclic compounds bearing a naphthyl substituent

The enantiotopic methyl signals of the compounds studied were resolved in the presence of the optically active chiral auxiliary (S)-(+)-2,2,2-trifluoroanthryl ethanol, [(S)-TFAE] via complex formation between (S)-TFAE and the respective compounds. Two different solvation models were proposed for both M and P conformations leading to the assignments of the ¹H NMR signals and thus absolute conformations. The solvation models proposed also explained the strong temperature dependence of the ¹H NMR signals upon cooling. The activation barriers for interconversion between the enantiomers of the compounds studied have been determined by either temperature dependent NMR or enantioresolution on a chiral sorbent via HPLC.     

Ferrocene based chiral binuclear η6‐benzene‐Ru(II)‐phosphinite complexes: Synthesis,characterization and catalytic activity in asymmetric reduction of ketones

In the present study, a series of chiral C₂‐symmetric ferrocenyl based binuclear η⁶‐benzene‐Ru(II) complexes bearing diphenylphosphinite and diisopropylphosphinite moieties have been synthesised. The new binuclear η⁶‐benzene‐Ru(II)‐phosphinite complexes were characterised based on nuclear magnetic resonance (¹H, ¹³C, ³¹P–NMR), FT‐IR spectroscopy and elemental analysis. Then, these complexes have been screened as catalytic precursors in the transfer hydrogenation of acetophenone with 2‐propanol as both the hydrogen source and solvent in the presence of KOH. The corresponding optically active secondary alcohols were obtained in excellent conversion rates between 96 and 99% and moderate to good enantioselectivities (up to 78% ee). The complex 5 was the most efficient catalyst among the four new complexes investigated herein.     

Symmetrically bridged bis-N-heterocyclic carbene rhodium (I) complexes and their catalytic application for transfer hydrogenation reaction

Bridged rhodium(I) bis(NHC) complexes of the formula [bis-(NHC)Rh(I)PF₆] (1c-5c) were synthesized and applied as catalysts in the transfer hydrogenation of acetophenone in 2-propanol. The activity of the rhodium(I) complexes largely depends on the nature of the N-substituents and the applied bases. The synthesized compounds were characterized by elemental analysis, ¹H and ¹³C NMR-spectroscopy and mass spectrometry. The structure of complex 2c was exemplary determined by X-ray analysis.     

Chiral solvating properties of (S)-1-benzyl-6-methylpiperazine-2,5-dione

In CDCl₃ solution, enantiopure (S)-1-benzyl-6-methylpiperazine-2,5-dione (S)-1a formed diastereomeric CO⋯H–N hydrogen-bonded associates with racemic (RS,Z)-1-benzyl-3-[(dimethylamino)methylidene]piperazine-2,5-diones 2a and 2b, (RS)-tert-butyl pyroglutamate (RS)-2c and (RS)-N-benzoylalanine methyl ester (RS)-2d. This resulted in splitting (doubling) of the characteristic signals in the ¹H NMR and ¹³C spectra of racemic compounds 2a–d in the presence of 1 equiv of (S)-1a. The formation of hydrogen-bonded dimers in CDCl₃ solution was studied by ¹H NMR, ¹³C NMR and 2D NMR and confirmed by the intermolecular NOE observed between the hydrogen-bonded amide protons from each of the monomeric units, (S)-1a and 2a–c. On the other hand, a slightly different binding mode was proposed for association of (S)-1a with alaninamide (RS)-2d. Enantiomer compositions of known (weighed) mixtures of both enantiomers of tert-butyl pyroglutamate 2c were re-determined by ¹H NMR in the presence of (S)-1a in CDCl₃. The experimental values were in good agreement with the theoretical values, thus indicating the potential applicability of (S)-1a and related diketopiperazines as chiral solvating agents in NMR spectroscopy.     

Efficient alkylation of ketones with primary alcohols catalyzed by ruthenium(II)/P,N ligand complexes

An efficient catalytic system containing [RuCl₂(η⁶-p-cymene)]₂ and one P,N ligand, N-diphenylphosphino-2-aminopyridine (L1) was loaded in catalyzing the alkylation of ketones with primary alcohols for a diverse array of substrates. Other five P,N ligands based on pyridin-2-amine and pyrimidin-2-amine were also examined in this reaction to explore the influence of steric hindrance and electronic effects. Monitoring by ¹H NMR and ESI-MS reveals a stable cationic L1-coordinated ruthenium hydride intermediate, identified as [Ru(η⁶-p-cymene)(κ²-L1)H]⁺. Organic intermediates consistent with a three-step dehydrogenation, alkylation and hydrogenation pathway were also observed. The final step in this reaction, the ruthenium-catalysed transfer hydrogenation reduction of α,β-unsaturated ketone with benzyl alcohol was performed separately.     

Efficient transfer hydrogenation of ketones in the presence of ruthenium N-heterocyclic carbene catalysts

Novel ruthenium carbene complexes have been in situ generated and tested for the transfer hydrogenation of ketones. Applying Ru(cod)(methylallyl)₂ in the presence of imidazolium salts in 2-propanol and sodium-2-propanolate as base, turnover frequencies up to 346 h⁻¹ have been obtained for reduction of acetophenone. A comparative study involving ruthenium carbene and ruthenium phosphine complexes demonstrated the higher activity of ruthenium carbene complexes.