Imine complexes asymmetric transfer hydrogenation

Noyori and coworkers reported well-defined ruthenium(II) catalyst systems of the type RuH( 76-arene)(NH2CHPhCHPhNTs) for the asymmetric transfer hydrogenation of ketones and imines [94]. These also act via an outer-sphere hydride transfer mechanism shown in Scheme 3.12. The hydride transfer from ruthenium and proton transfer from the amino group to the C=0 bond of a ketone or C=N bond of an imine produces the alcohol or amine product, respectively. The amido complex that is produced is unreactive to H2 (except at high pressures), but readily reacts with iPrOH or formate to regenerate the hydride catalyst. 

Asymmetric transfer hydrogenation of imines catalyzed by chiral arene-Ru complexes achieves high enantioselectivity (Figure 1.34). Formic acid in aprotic dipolar solvent should be used as a hydride source. The reaction proceeds through the metal-ligand bifunctional mechanism as shown in the carbonyl reduction (Figure 1.24). 

Figure 1.34. Asymmetric transfer hydrogenation of imines catalyzed by chiral Ru complexes.

A water-soluble, recyclable ruthenium(II) complex including a chiral diamine ligand has been used for asymmetric transfer hydrogenation of cyclic imines and iminiums in water, with yields and ee up to 99%.49... 

Anomalous concentration dependence observed in the asymmetric transfer hydrogenation of imines with formic acid, catalysed by chiral rhodium-diamine complexes, has been attributed to the participation of both reactant and product in the formation of formate salt. The probable resting state of the catalyst is a rhodium hydride species.373... 

Chan et al. synthesized first- and second-generation dendrimers containing up to 12 chiral diamines at the periphery (Fig. 8) [29]. Their ruthe-nium(II) complexes displayed high catalytic activity and enantioselectivity in the asymmetric transfer hydrogenation of ketones and imines. Quantitative yields, and in some cases a slightly higher enantioselectivity compared to those of the monomeric systems (up to 98.7% ee), were obtained. 

One place to look for good alcohol racemization catalysts is in the pool of catalysts that are used for hydrogen transfer reduction of ketones. One class of complexes that are excellent catalysts for the asymmetric transfer hydrogenation comprises the ruthenium complexes of mono sulfonamides of chiral diamines developed by Noyori and coworkers [20, 21]. These catalysts have been used for the asymmetric transfer hydrogenation of ketones [20] and imines [21] (Fig. 9.9). 

The Noyori asymmetric transfer hydrogenation was utilized in the synthesis of the chiral 1,2,3,4-tetrahydroisoquinolines by R.A. Sheldon et al. These compounds are important intermediates in the Rice and Beyerman routes to morphine. The "Rice imine" was exposed to a series of chiral Ru " complexes, which was prepared from r -arene-Ru " chloride dimeric complexes and A/-sulfonated 1,2-diphenylethylenediamines along with the azeotropic mixture of HCOOH/NEts. With the best catalyst the desired tetrahydroisoquinoline was isolated in 73% yield and the enantiomeric excess was 99%. 

In order to facilitate recycling of the multiple TsDPEN-functionalized dendrimer catalysts, the same group recently reported the synthesis of a novel form of hybrid dendrimer ligands by coupling polyether dendrons with peripherally TsDPEN-functionahzed Newkome-type poly(ether-amide) dendrimer (Figure 4.28) [90]. The solubility of these hybrid dendrimers was found to be affected by the generation of the polyether dendron. The ruthenium complexes produced were applied in the asymmetric transfer hydrogenation of ketones, enones, imines and activated... 

Another useful reduction process is asymmetric transfer hydrogenation (ATH) where the hydrogen is transferred from the solvent, often isopropanol, to the ketone or imine function to produce the enantiopure alcohol or amine. For example, Baratta et alP made ruthenium complexes containing the (/ ,S)-Xyliphos ligand to reduce a simple ketone to (5)-l-(3-trifluoromethylphenyl)ethanol, used in the synthesis of the fungicide (5)-MA20565 (Scheme 3). 

Asymmetric Transfer Hydrogenation of Ketones. The first reports on asymmetric transfer hydrogenation (ATH) reactions catalyzed by chiral metallic compounds were published at the end of the seventies. Prochiral ketones were reduced using alcohols as the hydrogen source, and Ru (274,275) or Ir (276) complexes were used as catalysts. Since then, many chiral catalytic systems for homogeneous ATH of ketones, imines, and olefins have been developed (37,38,256,257,277-289). The catalytic systems are usually based on ruthenium, rhodium, or iridium, and the ATH of aryl ketones is by far the most studied. Because of the reversibility of this reaction, at high conversions, a gradual erosion of the ee of the product has been frequently reported. An azeotropic 5 2 mixture of formic acid/triethylamine can be used to overcome this limitation. 

The amino acid complexes [(q -arene)Ru(aa)Cl], where aa = N,0-chelated amino acid, undergo rapid epimerization even at temperatures below 0 °C [66,67]. Similar lability and epimerization has been found for sahcylaldiminato complexes [68]. In contrast, [(ri -p-cymene)Ru(imine)Cl] complexes are configurationally stable unless heated to high temperatures in polar solvents [69]. Configurationally-stable half sandwich Ru(If) arene complexes are ofmuch interest as potential asymmetric catalysts (e.g. for Diels-Alder and Mukaiyama reactions) [63]. The chloride ligand is usually removed in order to allow the complex to act as a Lewis add catalyst and exchange ofcoordinated water on [(r -l,3,5-trimethylbenzene)Ru(pyridyloxazoline-N,N )(H20)] is slow on the NMR timescale in acetone-water [70]. Chiral chloro arene Ru(II) catalysts for asymmetric transfer hydrogenation can be activated in situ by treatment with KOH in 2-propanol [71]. 

Fig. 1 Asymmetric transfer hydrogenation of imines using Ru/TsDPEN complexes...

F. 41 Asymmetric transfer hydrogenation of a [ o hinoyl imine using iron complex 14... 

Mao, J. Baker, D. C. A chiral rhodium complex for rapid asymmetric transfer hydrogenation of imines with high enantioselectivity. Org. Lett. 1999,1, 841-843. 

Noyori Asymmetric Transfer Hydrogenation Noyori s well-designed chiral Ru -arene complexes catalyze the asymmetric transfer hydrogenation of ketones and imines (not shown) with stable organic hydrogen donors such as 2-propanol [69]. The reaction is reversible, and the involved chiral ruthenium species and the proposed transition state are depicted in Scheme 2.140. 

Au(l)/Br0nsted Acid System Han et al. developed an unprecedented protocol to synthesize tetrahydroquinolines 332 directly from 2-(2-propynyl)aniline derivatives 365 in one pot under relay catalysis of an achiral Au complex 368 and a chiral phosphoric acid 5j [131]. The Au -catalyzed intramolecular hydroamination of 2-(2-propynyl)aniline provided the 1,4-dihydroquinolines 366, followed by isomerization into imine-like 3,4-dihydroquinoliniums 367 with 5j. This active intermediate then underwent asymmetric transfer hydrogenation with Hantzsch ester to produce enantioenriched tetrahydroquinoUne products (Scheme 2.97). 

Asymmetric transfer hydrogenation of imines using HC02H/Et3N as a hydrogen donor and catalyzed by suitably designed chiral Ru(II)-complexes was developed by Noyori et al., and since then, it has become the method of choice in enantioselective reduction of cyclic imines. Using this protocol, several asymmetric syntheses of... 

Several approaches toward the syntheses of quinolacta-cins were published. ° In 2008, Silva Santos and coworkers applied Noyori asymmetric transfer hydrogenation of cyclic imine 218 to the total synthesis of (5)-(—)-quinolactacin B, which showed activity against mmor necrosis factor production. The hydrogenation of imine 218 was accomplished with the (/ ,/ )-Ts-DPEN-Ru(ll) complex in DMF and a HC02H/Et3N mixture to obtain amine (5)-(—)-219 in 89% yield and >90% ee (Scheme 30.43). 

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