Racemization of secondary alcohols catalyzed by cyclopentadienylruthenium complexes: evidence for an alkoxide pathway by fast beta-hydride elimination-readdition

The racemization of sec-alcohols catalyzed by pentaphenylcyclopentadienyl-ruthenium complex 3a has been investigated. The mechanism involves ruthenium-alkoxide intermediates: reaction of tert-butoxide ruthenium complex 4 with a series of sec-alcohols with different electronic properties gave ruthenium complexes bearing a secondary alkoxide as a ligand. The characterization of these alkoxide complexes by NMR spectroscopy together with a study of the reaction using in situ IR spectroscopy is consistent with a mechanism in which the alkoxide substitution step and the beta-hydride elimination step occur without CO dissociation. The alkoxide substitution reaction is proposed to begin with hydrogen bonding of the incoming alcohol to the active ruthenium-alkoxide intermediate. Subsequent alkoxide exchange can occur via two pathways: i) an associative pathway involving a eta3-CpRu intermediate; or ii) a dissociative pathway within the solvent cage. Racemization at room temperature of a 1:1 mixture of (S)-1-phenylethanol and (S)-1-phenyl-[D4]-ethanol gave only rac-1-phenylethanol, and rac-1-phenyl-[D4]-ethanol, providing strong support for a mechanism in which the substrate stays coordinated to the metal center throughout the racemization, and does not leave the coordination sphere. Furthermore, racemization of a sec-alcohol bearing a ketone moiety within the same molecule does not result in any reduction of the original ketone, which rules out a mechanism where the intermediate ketone is trapped within the solvent cage. These results are consistent with a mechanism where eta3-Ph(5)C(5)-ruthenium intermediates are involved. Competitive racemization on nondeuterated and alpha-deuterated alpha-phenylethanols was used to determine the kinetic isotope effect kH/kD for the ruthenium-catalyzed racemization. The kinetic isotope effect kH/kD for p- X-C(6)H(4)CH(OH)CH(3) was 1.08, 1.27 and 1.45 for X=OMe, H, and CF3, respectively.     

均相苯乙酮加氢反应研究

合成了一种新的钌膦配合物[RuCl2(Dmpp)2en](Dmpp=4-(2，6-二甲氧吡啶基)二苯基膦，en=乙二胺)，对其结构进行了表征．系统研究了反应温度，氢气压力，底物和催化剂的比例，碱和催化剂的比例等反应条件对[RuCl2(Dmpp)2en]催化的芳香酮加氢反应活性的影响，证明其在苯乙酮加氢反应中具有很好的催化活性．     

Novel Pd/C-catalyzed redox reactions between aliphatic secondary alcohols and ketones under hydrogenation conditions: application to H-D exchange reaction and the mechanistic study

A liquid-phase redox system between secondary alcohols and ketones is described. Deuteration of either secondary alcohols or ketones using the Pd/C-H2-D2O system gave a mixture of deuterium-labeled secondary alcohols and ketones. The results indicated that the secondary alcohol was oxidized to the corresponding ketone without oxidants under the hydrogenation conditions and the hydrogenation of the aliphatic ketone to the corresponding secondary alcohol simultaneously proceeded. Detailed mechanistic studies on the redox system as well as the H-D exchange reaction are discussed.     

Chiral Modification of Platinum by Co‐Adsorbed Cinchonidine and Trifluoroacetic Acid: Origin of Enhanced Stereocontrol in the Hydrogenation of Trifluoroacetophenone

Cinchonidine (CD) adsorbed onto a platinum metal catalyst leads to rate acceleration and induces strong stereocontrol in the asymmetric hydrogenation of trifluoroacetophenone. Addition of catalytic amounts of trifluoroacetic acid (TFA) significantly enhances the enantiomeric excess from 50 to 92 %. The origin of the enantioselectivity bestowed by co‐adsorbed CD and TFA is investigated by using in situ attenuated total reflection infrared spectroscopy and modulation excitation spectroscopy. Molecular interactions between the chiral modifier (CD), acid additive (TFA) and the trifluoro‐activated substrate at the solid–liquid interface are elucidated under conditions relevant to catalytic hydrogenations, that is, on a technical Pt/Al₂O₃ catalyst in the presence of H₂ and solvent. Monitoring of the unmodified and modified surface during the hydrogenation provides an insight into the phenomenon of rate enhancement and the crucial interactions of CD with the ketone, corresponding product alcohol, and TFA. Comparison of the diastereomeric interactions occurring on the modified surface and in the liquid solution shows a striking difference for the chiral preferences of CD. The spectroscopic data, in combination with calculations of molecular structures and energies, sheds light on the reaction mechanism of the heterogeneous asymmetric hydrogenation of trifluoromethyl ketones and the involvement of TFA in the diastereomeric intermediate surface complex: the quinuclidine N atom of the adsorbed CD forms an N?H?O‐type hydrogen‐bonding interaction not only with the trifluoro‐activated ketone but also with the corresponding alcohol and the acid additive. Strong evidence is provided that it is a monodentate acid/base adduct in which the carboxylate of TFA resides at the quinuclidine N‐atom of CD, which imparts a better stereochemical control.     

Mechanism of asymmetric hydrogenation of ketones catalyzed by BINAP/1,2-diamine-rutheniumII complexes

Asymmetric hydrogenation of acetophenone with trans-RuH(eta(1)-BH(4))[(S)-tolbinap][(S,S)-dpen] (TolBINAP = 2,2'-bis(di-4-tolylphosphino)-1,1'-binaphthyl; DPEN = 1,2-diphenylethylenediamine) in 2-propanol gives (R)-phenylethanol in 82% ee. The reaction proceeds smoothly even at an atmospheric pressure of H(2) at room temperature and is further accelerated by addition of an alkaline base or a strong organic base. Most importantly, the hydrogenation rate is initially increased to a great extent with an increase in base molarity but subsequently decreases. Without a base, the rate is independent of H(2) pressure in the range of 1-16 atm, while in the presence of a base, the reaction is accelerated with increasing H(2) pressure. The extent of enantioselection is unaffected by hydrogen pressure, the presence or absence of base, the kind of base and coexisting metallic or organic cations, the nature of the solvent, or the substrate concentrations. The reaction with H(2)/(CH(3))(2)CHOH proceeds 50 times faster than that with D(2)/(CD(3))(2)CDOD in the absence of base, but the rate differs only by a factor of 2 in the presence of KO-t-C(4)H(9). These findings indicate that dual mechanisms are in operation, both of which are dependent on reaction conditions and involve heterolytic cleavage of H(2) to form a common reactive intermediate. The key [RuH(diphosphine)(diamine)](+) and its solvate complex have been detected by ESI-TOFMS and NMR spectroscopy. The hydrogenation of ketones is proposed to occur via a nonclassical metal-ligand bifunctional mechanism involving a chiral RuH(2)(diphosphine)(diamine), where a hydride on Ru and a proton of the NH(2) ligand are simultaneously transferred to the C=O function via a six-membered pericyclic transition state. The NH(2) unit in the diamine ligand plays a pivotal role in the catalysis. The reaction occurs in the outer coordination sphere of the 18e RuH(2) complex without C=O/metal interaction. The enantiofaces of prochiral aromatic ketones are kinetically differentiated on the molecular surface of the coordinatively saturated chiral RuH(2) intermediate rather than in a coordinatively unsaturated Ru template.     

pH-Dependent isotope exchange and hydrogenation catalysed by water-soluble NiRu complexes as functional models for [NiFe]hydrogenases

The pH-dependent hydrogen isotope exchange reaction between gaseous isotopes and medium isotopes and hydrogenation of the carbonyl compounds have been investigated with water-soluble bis(mu-thiolate)(mu-hydride)NiRu complexes, Ni(II)(mu-SR)(2)(mu-H)Ru(II) {(mu-SR)(2) = N,N'-dimethyl-N,N'-bis(2-mercaptoethyl)-1,3-propanediamine}, as functional models for [NiFe]hydrogenases. In acidic media (at pH 4-6), the mu-H ligand of the Ni(II)(mu-SR)(2)(mu-H)Ru(II) complexes has H(+) properties, and the complexes catalyse the hydrogen isotope exchange reaction between gaseous isotopes and medium isotopes. A mechanism of the hydrogen isotope exchange reaction between gaseous isotopes and medium isotopes through a low-valent Ni(I)(mu-SR)(2)Ru(I) complex is proposed. In contrast, in neutral-basic media (at pH 7-10), the mu-H ligand of the Ni(II)(mu-SR)(2)(mu-H)Ru(II) complexes acts as H(-), and the complexes catalyse the hydrogenation of carbonyl compounds.     

Multisite Solid Catalyst for Cascade Reactions: The Direct Synthesis of Benzodiazepines from Nitro Compounds

Substituted 1,5‐benzodiazepines are selectively synthesized in one pot from substituted nitroaromatics and ketones. The reaction is performed in the presence of hydrogen and in the absence of solvent by using a bifunctional solid catalyst with a chemoselective hydrogenation functional group capable of reducing the nitro group to a diamino group and an acid functional group, which catalyzes the cyclocondensation of the amino group with the ketone.     

Role of the NH2 functionality and solvent in terdentate CNN alkoxide ruthenium complexes for the fast transfer hydrogenation of ketones in 2-propanol

The reaction of [RuCl(CNN)(dppb)] (1; HCNN=6-(4-methylphenyl)-2-pyridylmethylamine) with NaOiPr in 2-propanol/C6D6 affords the alcohol adduct alkoxide [Ru(OiPr)(CNN)(dppb)].n iPrOH (5), containing the Ru-NH2 linkage. The alkoxide [Ru(OiPr)(CNN)(dppb)] (4) is formed by treatment of the hydride [Ru(H)(CNN)(dppb)] (2) with acetone in C6D6. Complex 5 in 2-propanol/C6D6 equilibrates quickly with hydride 2 and acetone with an exchange rate of (5.4+/-0.2) s(-1) at 25 degrees C, higher than that found between 4 and 2 ((2.9+/-0.4) s(-1)). This fast process, involving a beta-hydrogen elimination versus ketone insertion into the Ru-H bond, occurs within a hydrogen-bonding network favored by the Ru-NH2 motif. The cationic alcohol complex [Ru(CNN)(dppb)(iPrOH)](BAr(f)4) (6; Ar(f)=3,5-C6H3(CF3)2), obtained from 1, Na[BAr(f)4], and 2-propanol, reacts with NaOiPr to afford 5. Complex 5 reacts with either 4,4'-difluorobenzophenone through hydride 2 or with 4,4'-difluorobenzhydrol through protonation, affording the alkoxide [Ru(OCH(4-C6H4F)2)(CNN)(dppb)] (7) in 90 and 85 % yield of the isolated product. The chiral CNN-ruthenium compound [RuCl(CNN)((S,S)-Skewphos)] (8), obtained by the reaction of [RuCl2(PPh3)3] with (S,S)-Skewphos and orthometalation of HCNN in the presence of NEt3, is a highly active catalyst for the enantioselective transfer hydrogenation of methylaryl ketones (turnover frequencies (TOFs) of up to 1.4 x 10(6) h(-1) at reflux were obtained) with up to 89% ee. Also the ketone CF3CO(4-C6H4F), containing the strong electron-withdrawing CF3 group, is reduced to the R alcohol with 64% ee and a TOF of 1.5 x 10(4) h(-1). The chiral alkoxide [Ru(OiPr)(CNN)((S,S)-Skewphos)]n iPrOH (9), obtained from 8 and NaOiPr in the presence of 2-propanol, reacts with CF3CO(4-C6H4F) to afford a mixture of the diastereomer alkoxides [Ru(OCH(CF3)(4-C6H4F))(CNN)((S,S)-Skewphos)] (10/11; 74% yield) with 67% de. This value is very close to the enantiomeric excess of the alcohol (R)-CF3CH(OH)(4-C6H4F) formed in catalysis, thus suggesting that diastereoisomeric alkoxides with the Ru-NH2 linkage are key species in the catalytic asymmetric transfer hydrogenation reaction.     

Immobilization of Chiral Catalyst on Amorphous Al2O3 for the Selective Hydrogenation of Ethyl 1H-Indole-2-carboxylate

Ru-B/γ-Al2O3 catalyst was prepared by reductant impregnation method,which was applied in the selective hydrogenation of ethyl 1H-indole-2-carboxylate for producing ethyl 2,3,3a,7a-tetrahydro-1H-indole-2-carboxylate with hydrogen as reductant.Furthermore,we discussed the influences of substrate concentration,reaction solvent,hydrogenation temperature,initial hydrogen pressure and reaction time on the catalytic performance of the as-prepared catalyst.The obtained Ru-B/γ-Al2O3 catalyst showed a high-efficiency for the selective hydrogenation of ethyl 1H-indole-2-carboxylate（＞99％ conversion and selectivity） in i-propanol used as solvent at a concentration of 10％（mass fraction） of ethyl 1H-indole-2-carboxylate,a pressure of hydrogen of 6 MPa and a reaction temperature of 373 K.     

Effect of chelating ring size in catalytic ketone hydrogenation: facile synthesis of ruthenium(II) precatalysts containing an N-heterocyclic carbene with a primary amine donor for ketone hydrogenation and a DFT study of mechanisms

A half-sandwich ruthenium(II) complex, [Ru(η(6)-p-cymene)(C-NH(2))Cl]PF(6) (4·PF(6)), containing an N-heterocyclic carbene (NHC) with a primary amine donor (C-NH(2)) which chelates through the carbene carbon and the amine nitrogen to form a 6-membered ring was synthesized in a one-pot reaction starting from a primary-amine functionalized imidazolium salt 2. Complex 4·PF(6) catalyzed the hydrogenation of ketones using 2-propanol or H(2) as the reductant. A maximum turnover frequency of 1062 h(-1) and a turnover number of 1140 at 5 h were achieved for the transfer hydrogenation of 3'-chloroacetophenone in 2-propanol at 75 °C. A cationic hydride-amine complex 5, [Ru(η(6)-p-cymene)(C-NH(2))H]PF(6), was synthesized, and this reacted very slowly with acetophenone unless first activated by an alkoxide base. Computational studies by DFT methods suggested that the poor reactivity of the hydride-amine complex 5 was attributed to a large barrier for the transfer of its H(+)/H(-) couple to a ketone for bifunctional catalysis. An inner-sphere mechanism, which involves a decoordinated amine group of the C-NH(2) ligand, was computed to be a feasible energetic pathway in comparison to the computed outer-sphere bifunctional mechanism. This explains the catalytic activity and selectivity that is observed for the newly synthesized ruthenium(II) catalysts.     

Base-catalyzed hydrogenation: rationalizing the effects of catalyst and substrate structures and solvation

Ab initio molecular orbital calculations have been used to study the base-catalyzed hydrogenation of carbonyl compounds. It is found that these hydrogenation reactions share many common features with S(N)2 reactions. Both types of reactions are described by double-well energy profiles, with deep wells and a low or negative overall energy barrier in the gas phase, while the solution-phase profiles show very shallow wells and much higher barriers. For the hydrogenation reactions, the assembly of the highly ordered transition structure is found to be a major limiting factor to the rate of reaction. In the gas phase, the overall barriers for reactions catalyzed by Group I methoxides increase steadily down the group, due to the decreasing charge density on the metal. On the other hand, for Group II and Group III metals, the overall barriers decrease down the group, which is attributed to the increasing ionic character of the metal-oxygen bond. The reaction with B(OCH(3))(3) has an exceptionally high barrier, which is attributed to pi-electron donation from the oxygen lone pairs of the methoxy groups to the formally vacant p orbital on B, as well as to the high covalent character of the B-O bonds. In solution, these reactivity trends are generally the opposite of the corresponding gas-phase trends. While similar barriers are obtained for reactions catalyzed by methoxides and by tert-butoxides, reactions with benzyloxides have somewhat higher barriers. Aromatic ketones are found to be more reactive than purely aliphatic ketones. Moreover, comparison between catalytic hydrogenation of 2,2,5,5-tetramethylcyclopentanone and pivalophenone shows that factors such as steric effects may also be important in differentiating their reactivity. Solvation studies with a wide range of solvents indicate a steady decrease in barrier with decreasing solvent dielectric constant, with nonpolar solvents generally leading to considerably lower barriers than polar solvents. In practice, a good balance between polarity and catalyst solubility is required in selecting the most suitable solvent for the base-catalyzed hydrogenation reaction.     

The Hydrogenation/Transfer Hydrogenation Network in Asymmetric Reduction of Ketones Catalyzed by [RuCl2(binap)(pica)] Complexes

Chiral binap/pica‐Ru^II complexes (binap=(S)‐ or (R)‐2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl; pica=α‐picolylamine) catalyze both asymmetric hydrogenation (AH) of ketones using H₂ and asymmetric transfer hydrogenation (ATH) using non‐tertiary alcohols under basic conditions. The AH and ATH catalytic cycles are linked by the metal–ligand bifunctional mechanism. Asymmetric reduction of pinacolone is best achieved in ethanol containing the Ru catalyst and base under an H₂ atmosphere at ambient temperature, giving the chiral alcohol in 97–98 % ee. The reaction utilizes only H₂ as a hydride source with alcohol acting as a proton source. On the other hand, asymmetric reduction of acetophenone is attained with both H₂ (ambient temperature) and 2‐propanol (>60 °C) with relatively low enantioselectivity. The degree of contribution of the AH and ATH cycles is highly dependent on the ketone substrates, solvent, and reaction parameters (H₂ pressure, temperature, basicity, substrate concentration, H/D difference, etc.).     

Computational study of the factors controlling enantioselectivity in ruthenium(II) hydrogenation catalysts

The reduction of prochiral ketones catalyzed by Ru(diphosphine)(diamine) complexes has been studied at the DFT-PBE level of theory. Calculations have been conducted on real size systems [trans-Ru(H)2(S, S-dpen)(S-xylbinap) + acetophenone], [trans-Ru(H)2(S, S-dpen)(S-tolbinap) + acetophenone] and [trans-Ru(H)2(S, S-dpen)(S-xylbinap) + cyclohexyl methyl ketone] with the aim of identifying the factors controlling the enantioselectivity in Ru(diphosphine)(diamine) catalysts. The high enantiomeric excess (99%) in the hydrogenation of acetophenone catalyzed by trans-Ru(H)2(S, S-dpen)(S-xylbinap) has been explained in terms of the existence of a stable intermediate along the reaction pathway associated with the (R)-alcohol. The formation of this intermediate is hindered with the competitive pathways, which consequently increases the activation energy for the hydrogen transfer acetophenone/(S)-phenylethanol reaction. For the [trans-Ru(H)2(S, S-dpen)(S-tolbinap) + acetophenone] system, the lower enantioselectivity (i.e. 80%) is rationalized by the smaller differences in the activation energy between the competitive pathways which differentiate between the two diastereomeric approaches of the prochiral ketone. The DFT-PBE results suggest that this reaction is driven to the (R)-product only by the process of binding the acetophenone to the active site of the trans-Ru(H) 2(S, S-dpen)(S-tolbinap) catalyst. For the hydrogenation of cyclohexyl methyl ketone catalyzed by trans-Ru(H)2(S, S-dpen)(S-xylbinap), the low performance in the enantioselective hydrogenation of the dialkyl ketone (i.e. 37%) is again explained by the small differences in the activation and binding energies which are the factors which could effectively differentiate between the two alkyl groups.     

Direct observation of aldehyde insertion into rhodium-aryl and -alkoxide complexes

Several organorhodium(I) complexes of the general formula (PPh(3))(2)(CO)RhR (R = p-tolyl, o-tolyl, Me) were isolated and were shown to insert aryl aldehydes into the aryl-rhodium(I) bond. Under nonaqueous conditions, these reactions provided ketones in good yield. The stability of the arylrhodium(I) complexes allowed these reactions to be run also in mixtures of THF and water. In this solvent system, diarylmethanols were generated exclusively. Mechanistic studies support the formation of ketone and diarylmethanol by insertion of aldehyde into the rhodium-aryl bond and subsequent beta-hydride elimination or hydrolysis to form diaryl ketone or diarylmethanol products. Kinetic isotope effects and the formation of diarylmethanols in THF/water mixtures are inconsistent with oxidative addition of the acyl carbon-hydrogen bond and reductive elimination to form ketone. Moreover, the intermediate rhodium diarylmethoxide formed from insertion of aldehyde was observed directly during the reaction. Its structure was confirmed by independent synthesis. This complex undergoes beta-hydrogen elimination to form a ketone. This alkoxide also reacts with a second aldehyde to form esters by insertion and subsequent beta-hydrogen elimination. Thus, reactions of arylrhodium complexes with an excess of aldehyde formed esters by a double insertion and beta-hydrogen elimination sequence.     

A multilateral mechanistic study into asymmetric transfer hydrogenation 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.     

Coupling-isomerization synthesis of chalcones

The Sonogashira coupling of electron-deficient (hetero)aryl halides 1 and (hetero)aryl or alkenyl 1-propargyl alcohols 2 does not terminate at the stage of the expected internal propargyl alcohols, but rather gives rise to the formation of alpha,beta-unsaturated ketones 3 with a variety of acceptor substituents. This new domino reaction, a coupling-isomerization reaction (CIR), can be rationalized as a sequence of rapid Pd/Cu-catalyzed alkynylation followed by a slow amine-base-catalyzed propargyl alcohol-enone isomerization. Performing the CIR in deuterated protic solvents or with a selectively deuterated propargyl alcohol revealed that the base-catalyzed isomerization step proceeds through a formal 1,3-H shift with minimal H/D exchange with the surrounding solvent. Additionally, 19F NMR kinetic measurements on the isomerization step with the fluorinated propargyl alcohol 4 r support the mechanistic rationale.     

Asymmetric Catalysis by Architectural and Functional Molecular Engineering: Practical Chemo- and Stereoselective Hydrogenation of Ketones

Hydrogenation is a core technology in chemical synthesis. High rates and selectivities are attainable only by the coordination of structurally well-designed catalysts and suitable reaction conditions. The newly devised [RuCl(2)(phosphane)(2)(1,2-diamine)] complexes are excellent precatalysts for homogeneous hydrogenation of simple ketones which lack any functionality capable of interacting with the metal center. This catalyst system allows for the preferential reduction of a C=O function over a coexisting C=C linkage in a 2-propanol solution containing an alkaline base. The hydrogenation tolerates many substituents including F, Cl, Br, I, CF(3), OCH(3), OCH(2)C(6)H(5), COOCH(CH(3))(2), NO(2), NH(2), and NRCOR as well as various electron-rich and -deficient heterocycles. Furthermore, stereoselectivity is easily controlled by the electronic and steric properties (bulkiness and chirality) of the ligands as well as the reaction conditions. Diastereoselectivities observed in the catalytic hydrogenation of cyclic and acyclic ketones with the standard triphenylphosphane/ethylenediamine combination compare well with the best conventional hydride reductions. The use of appropriate chiral diphosphanes, particularly BINAP compounds, and chiral diamines results in rapid and productive asymmetric hydrogenation of a range of aromatic and heteroaromatic ketones and gives a consistently high enantioselectivity. Certain amino and alkoxy ketones can be used as substrates. Cyclic and acyclic alpha,beta-unsaturated ketones can be converted into chiral allyl alcohols of high enantiomeric purity. Hydrogenation of configurationally labile ketones allows for the dynamic kinetic discrimination of diastereomers, epimers, and enantiomers. This new method shows promise in the practical synthesis of a wide variety of chiral alcohols from achiral and chiral ketone substrates. Its versatility is manifested by the asymmetric synthesis of some biologically significant chiral compounds. The high rate and carbonyl selectivity are based on nonclassical metal-ligand bifunctional catalysis involving an 18-electron amino ruthenium hydride complex and a 16-electron amido ruthenium species.     

Ru(II)-SDP-complex-catalyzed asymmetric hydrogenation of ketones. Effect of the alkali metal cation in the reaction

The Ru(II) complexes of SDP and DPEN combined with t-BuOK in 2-propanol formed a very effective catalyst for the hydrogenation of simple aromatic ketones with high activity and enantioselectivity. The racemic alpha-arylcycloalkanones can also be hydrogenated by this system, providing alpha-arylcycloalkanols in excellent cis/trans stereoselectivity (>99:1) and enantioselectivity (up to 99.9%) for the cis isomer. In the study of the effect of the alkali metal cation in the hydrogenation of acetophenone using RuCl(2)(Tol-SDP)(DPEN) and RuCl(2)(Xyl-SDP)(DPEN) catalysts, we found that t-BuONa provided a faster reaction than t-BuOK, which indicated that the sterically hindered diphosphine ligands preferred the base with the smaller metal cation.     

The importance of alkali cations in the [{RuCl2(p-cymene)}2]-pseudo-dipeptide-catalyzed enantioselective transfer hydrogenation of ketones

We studied the role of alkali cations in the [{RuCl2(p-cymene)}2]-pseudo-dipeptide-catalyzed enantioselective transfer hydrogenation of ketones with isopropanol. Lithium salts were shown to increase the enantioselectivity of the reaction when iPrONa or iPrOK was used as the base. Similar transfer-hydrogenation systems that employ chiral amino alcohol or monotosylated diamine ligands are not affected by the addition of lithium salts. These observations have led us to propose that an alternative reaction mechanism operates in pseudo-dipeptide-based systems, in which the alkali cation is an important player in the ligand-assisted hydrogen-transfer step. DFT calculations of the proposed transition-state (TS) models involving different cations (Li+, Na+, and K+) confirm a considerable loosening of the TS with larger cations. This loosening may be responsible for the fewer interactions between the substrate and the catalytic complex, leading to lower enantiodifferentiation. This mechanistic hypothesis has found additional experimental support; the low ee obtained with [BnNMe3]OH (a large cation) as base can be dramatically improved by introducing lithium cations into the system. Also, the complexation of Na+, K+, and Li+ cations by the addition of [15]crown-5 and [18]crown-6 ethers and cryptand 2.1.1 (which selectively bind to these cations and, thus, increase their bulkiness), respectively, to the reaction mixture led to a significant drop in the enantioselectivity of the reaction. The lithium effect has proved useful for enhancing the reduction of different aromatic and heteroaromatic ketones.     

CNN Pincer Ruthenium Catalysts for Hydrogenation and Transfer Hydrogenation of Ketones: Experimental and Computational Studies

Reaction of [RuCl(CNN)(dppb)] ( 1‐Cl ) (HCNN=2‐aminomethyl‐6‐(4‐methylphenyl)pyridine; dppb=Ph₂P(CH₂)₄PPh₂) with NaOCH₂CF₃ leads to the amine‐alkoxide [Ru(CNN)(OCH₂CF₃)(dppb)] ( 1‐OCH₂CF₃ ), whose neutron diffraction study reveals a short RuO ??? HN bond length. Treatment of 1‐Cl with NaOEt and EtOH affords the alkoxide [Ru(CNN)(OEt)(dppb)] ? (EtOH)_n ( 1‐OEt?n EtOH ), which equilibrates with the hydride [RuH(CNN)(dppb)] ( 1‐H ) and acetaldehyde. Compound 1‐OEt?n EtOH reacts reversibly with H₂ leading to 1‐H and EtOH through dihydrogen splitting. NMR spectroscopic studies on 1‐OEt?n EtOH and 1‐H reveal hydrogen bond interactions and exchange processes. The chloride 1‐Cl catalyzes the hydrogenation (5 atm of H₂) of ketones to alcohols (turnover frequency (TOF) up to 6.5×10⁴ h^?1, 40 °C). DFT calculations were performed on the reaction of [RuH(CNN′)(dmpb)] ( 2‐H ) (HCNN′=2‐aminomethyl‐6‐(phenyl)pyridine; dmpb=Me₂P(CH₂)₄PMe₂) with acetone and with one molecule of 2‐propanol, in alcohol, with the alkoxide complex being the most stable species. In the first step, the Ru‐hydride transfers one hydrogen atom to the carbon of the ketone, whereas the second hydrogen transfer from NH₂ is mediated by the alcohol and leads to the key “amide” intermediate. Regeneration of the hydride complex may occur by reaction with 2‐propanol or with H₂; both pathways have low barriers and are alcohol assisted.