Hydrogenation high substrate/catalyst ratios

We report here a number of examples of the use of this anchored catalyst for the hydrogenation of different substrates at moderate to high substrate/catalyst ratios along with a direct comparison of these results with those obtained using the homogeneous Wilkinson under the same conditions. Also presented will be some examples of the use of the anchored catalyst in long term continuous reactions. Reaction rates, selectivities and the extent of metal loss will be presented where appropriate. 

Most recently, these BlNAP-cored dendrimers were further employed in the Ir-catalyzed asymmetric hydrogenation of quinolines by Fan et al. (Scheme 4.3) [33]. Unlike the asymmetric hydrogenation of prochiral olefins, ketones and imines, the hydrogenation of heteroaroniatic compounds proved to be rather difficult [34—37]. All four generations of dendrimer catalysts generated in situ from BlNAP-cored dendrimers and [lr(COD)Cl]2 were found to be effective, even at an extremely high substrate catalyst ratio in the asymmetric hydrogenation of quinaldine with... 

Several new, water-soluble atropisomeric diphosphines in the biphenyl series, such as (S)-(+)- and (R)-(—)-MeO-BIPHEP tetrasulfonate (32), were prepared and used as components of Ru(II)- and Rh(I)-based hydrogenation catalysts [98]. Several C=C unsaturated substrates (enamides, unsaturated acids) could be hydrogenated biphasically with high rates and enantioselectivities (Eqs. 33 and 34). In some cases high substrate/catalyst ratios could be used (up to 10000 1), a strong requirement for practical applications [99]. 

Allylic alcohols, such as gcraniol (42) and nerol (43), can be converted to citronellol (44) with high efficiency and excellent enantioselectivity by hydrogenation using ruthenium BINAP complexes108 or related catalysts76. Enantiomeric excesses between 96-98%, essentially quantitative yields, and very high substrate/catalyst ratios (up to 50000 1) are attractive attributes of... 

Since most transfer hydrogenation catalysts employ precious metals, a high number of turnovers are required in order to make their use economic. As the ligands are simply made they are generally of low cost. In our experience, for the average pharmaceutical intermediate, a substrate catalyst ratio (SCR) of about 1000 1 is sufficient for the catalysts contribution to the product cost to be minor. These SCRs are regularly achieved, and so from an economic standpoint there has been little incentive to recover and recycle the catalyst, unless a low-cost product is required. The recovery of precious metals from waste streams provides another way in which costs can be minimized. 

The mantiosdcctivity, expressed as enantiomeric excess (ee, %) of a catalyst should be >99% for pharmaceuticals if no purification is possible. This case is quite rare, and ee-values >90% are often acceptable. Chemosdectivity (or functional group tolerance) will be very important when multifunctional substrates are involved. The catalyst productivity, given as turnover number (TON mol product per mol catalyst) or as substrate catalyst ratio (SCR), determines catalyst costs. For hydrogenation reactions, TONs should be >1000 for high-value products and >50000 for large-scale or less-expensive products (catalyst re-use increases the productivity). 

R)-BINAP/l,2-diphenylethylenediamine ruthenium(II) complexes covalently attached to polystyrene (Scheme 4.32) promote the asymmetric hydrogenation of aromatic ketones and of a, yS-unsaturated ketones [125]. The catalysts (52) and (53) were reused at high substrate/catalyst molar ratio (S/C) of 2470 in 14 experiments. Remarkably, the enantiopurity of the products remained high after each run, constantly being in the range of 97 to 98% ee. 

Low-loaded, organophilic Pd-montmorillonites were shown to exhibit high cis-selectivity in the hydrogenation of 1-phenyl-1-alkynes working with high (=5000) substrate catalyst ratio.402 Studies with respect to the use palladium membrane catalysts403 105 and polymeric hollow fiber reactors406"408 were reported. 

Homogeneous catalytic hydrogenation has recently been achieved with high TOFs of up to ca 3900 h-1 and substrate catalyst ratios of 1000 1 (see Section 12.3). 

In addition to the high enantioselectivity, the rate of the hydrogenation using Rh(7 -SpirOP) catalyst is also very fast. When a substrate/catalyst ratio of 10000 was used and when the reaction was carried out at ambient temperature under 200 psi H2, >99.9% conversion of 2-acetamidoacrylic acid to 2-acetamidopropionic acid (96.8% ee) was observed in 1 h. The detailed results are shown in Table 3. 

In the presence of a BINAP-Ru complex (Structures 10 and 11), geraniol (7) or nerol (9) is hydrogenated selectively at the C(2)-C(3) double bond to give citronellol (8) quantitatively (Scheme 2) [19]. This hydrogenation is effected in methanol with a substrate catalyst ratio as high as 50000 1 to give either natural or unnatural compounds in up to 99 % enantiomeric purity. 

MPa of hydrogen with a high substrate/catalyst molar ratio, up to 100 000, and with a high substrate concentration. The catalyst system is notable for its excellent chemoselectivity of the carbonyl group over olefinic or acetylenic bonds. Under identical conditions benzalacetone (41) is converted into the (5)-allyl alcohol 42 in 97 % ee [43c]. 

The nature of the substituent directly attached to the N-atom influences the properties (basicity, reduction potential, etc.) of the C=N function more than the nature of the substituents at the carbon atom. For example, it was found that the Ti-ebthi catalyst (Fig. 1) can hydrogenate only hf-alkylimines but not N-arylimines [6]. Oximes and other C=N-X compounds show even a more pronounced variation in their reactivity. The following sections give a short summary of the results obtained for different classes of C=N groups. Only catalysts with synthetically useful selectivities or otherwise of interest were included in Tables 2, 3, 4, 5, and 6 (s/c substrate/catalyst ratio, tof turnover frequency at high conversion). 

High enantioselectivities in the hydrogenation of 2-phenyl-l-butene have been achieved using chiral samarium complexes such as 55 (96% ee at — 80°C, 64-80% cc at 25°C)129. The reaction was carried out in heptane at 1 bar of H2 using a substrate/catalyst ratio of 200 1, and quantitative conversion and high turnover frequencies were observed under these conditions. The same catalyst gave 72% ee in the deuteration of styrene with D2 at 25 "C. Substantial enantiomeric excesses in the hydrogenation of 1,1-disubstituted olefins have also been obtained with the chiral bis(cyclopentadienyl)titanium complex 5690. 

Fluorophenylacetic acid was transformed into the unsaturated acid 48 by reaction with 2 mol equiv. of i-PrMgCl, followed by acetone addition, dehydration, and crystallization. The tetra-substituted double bond was then hydrogenated under high pressure in an ad hoc designed continuous-stirred tank reactor system and in the presence of the Ru complex 49 (substrate/catalyst ratio =1000) to afford (.5)-acid 50 in 93.5% e.e. Crystallization of its sodium salt upgraded the e.e. to 98%. 

The mechanism of the catalysis (Scheme 20.8) is quite unlike that of the rhodium-DuPhos catalysis of prochiral olefins described above, since the ketone substrate does not bind to the metal (ruthenium) atom. When a substrate binds the metal, as in the rho-dium-DuPhos systems, there are opportnnities for unwanted pathways that terminate the catalysis. On the other hand, a conseqnence of the metal being protected by its ligands in the Noyori-Ikariya catalysis in principle rednces the likelihood of catalyst deactivation and increases the expectation for achieving very high catalyst utilization (substrate/catalyst ratios). Thus, in the asymmetric hydrogenation of acetophenone to (i )-l-phenylethanol, Noyori et al. reported an astounding molar snbstrate/catalyst ratio of 2,400,000 1. ... 

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