Rh/DUPHOS catalyst

It is well known that acrylates undergo transition metal catalyzed reductive aldol reaction, the silanes R3SiH first reacting in a 1,4 manner and the enolsilanes then participating in the actual aldol addition.57,58 A catalytic diastereoselective version was discovered by arrayed catalyst evaluation in which 192 independent catalytic systems were screened on 96-well microtiter plates.59 Conventional GC was used as the assay. A Rh-DuPhos catalyst turned out to be highly diastereoselective, but enantioselectivity was poor.59... 

Less-common types of C=N derivatives can also be reduced enantioselectively. An interesting example is the hydrogenation of the aromatic N-acyl hydrazones 13 with the Rh-duphos catalyst (Table 34.6 entry 6.1). This reaction was devel-... 

Dow/Chirotech [35, 36], Topcro Pharma [37] as well as by Solvias [38] using Rh-DuPhos catalysts (Fig. 37.6). Besides these successful examples, a process using Rh-DuPhos was abandoned because of reproducibility problems due to impurities carried over from the preceding step, and because of concerns about the toxicity of 2-nitropropane, even though ee-values of 99% were achieved [39]. 

The hydrogenation of enamides and enol acetates without acid function is often more demanding, and at present is not applied widely. Besides a bench-scale application by Roche with a Ru-biphep catalyst [55], two examples are of interest a pilot process for a cyclic enol acetate by Roche [55], and a feasibility study by Bristol-Myers Squibb [56], both using Rh-DuPhos catalysts (Fig. 37.11). In the latter case, despite very good ee-values, a chiral pool route was finally chosen. Chiral Quests Rh-f-KetalPhos (see Fig. 37.9) has been shown to hydrogenate a variety of substituted aryl enamide model substrates at r.t., 1 bar, with very promising catalyst performance (ee 98-99%, TON 10000) [47]. 

The hydrogenation was carried out on 12-kg scale for Pfizer by Dow/Chirotech, using a cationic Rh-DuPhos catalyst [79] and on 250-kg scale by PPG-Sipsy with a Ru-biphep complex [80]. Both catalysts achieved very high enantioselectivities and medium activities. 

We calculate only a 0.7 kcal/mol difference between R-DIHY-B and S-DIHY-B, with nearly identical migratory insertion barriers, so we would predict only modest enantioselectivity if a DuPHOS-ligated catalyst reacted along the hydride route. However, we are not aware of any evidence that a solvated Rh-DuPHOS catalyst reacts with hydrogen to form dihydrides. 

Rh-Catalyzed Hydrogenation of C=C (ChiroTech, PPG-Sipsy). This hydrogenation process for an intermediate for candoxatril was developed and carried out for Pfizer by both by ChiroTech, using a cationic Rh/duphos catalyst (71a) and by PPG-Sipsy with a Ru-MeObiphep catalyst system (71b). 

Remarkable is the striking difference in the sense of enantioselec-tion observed in the Rh-catalyzed asymmetric hydrogenation of a-phenyl (13) and a-f-butyl (16)-substituted enamides with Rh-DuPhos catalyst (Scheme 1.25). ° Later, similar results were obtained with the use of Rh-f-BuBisP Rh-BenzP Rh-QuinoxP and Rh-DioxyBenzP complexes. Thus, with Rh-f-BuBisP the corresponding hydrogenation products (85 and 86) were obtained with 99% ee each, but with different configuration R in case of 85 and S in case of 86.3 ... 

Based upon the above-mentioned assumptions, the reaction scheme in Figure 3.1 is reduced to the scheme shown in Figure 3.2A. It should be noted that active catalyst is used in the reaction scheme in Figure 3.1 while most asymmetric hydrogenation processes use a pre-catalyst (11). Hence, the relationship between the precatalyst and active catalyst needs to be established for the kinetic model. The precatalyst used in this study is [Et-Rh(DuPhos)(COD)]BF4 where COD is cyclooctadiene. The active catalyst (Xq) in Figure 3.2A is formed by removal of COD via hydrogenation, which is irreversible. We assume that the precatalyst is completely converted to the active catalyst Xq before the start of catalytic reaction. Hence, the kinetic model derived here does not include the formation of the active catalyst from precatalyst. 

Using unmodified Ru-BINAP and Rh-Et-DUPHOS catalysts Jacobs et al. performed hydrogenation reactions of dimethylitaconate (DMI) and methyl-2-acetamidoacrylate (MAA), respectively. [11,47] The continuous hydrogenation reaction was performed in a 100 mL stirred autoclave containing an MPF-60 membrane at the bottom, which also acts as a dead-end membrane reactor. The hydrogenation reactions will be discussed in paragraph 4.6.1. 

In the early 1990s, Burk introduced a new series of efficient chiral bisphospholane ligands BPE and DuPhos.55,55a-55c The invention of these ligands has expanded the scope of substrates in Rh-catalyzed enantioselective hydrogenation. For example, with Rh-DuPhos or Rh-BPE as catalysts, extremely high efficiencies have been observed in the asymmetric hydrogenation of a-(acylamino)acrylic acids, enamides, enol acetates, /3-keto esters, unsaturated carboxylic acids, and itaconic acids. 

In the case of cyclopentenyl carbamate in which a directive group is present at the homoallyl position, the cationic rhodium [Rh(diphos-4)]+ or iridium [Ir(PCy3)(py)(nbd)]+ catalyst cannot interact with the carbamate carbonyl, and thus approaches the double bond from the less-hindered side. This affords a cis-product preferentially, whereas with the chiral rhodium-duphos catalyst, directivity of the carbamate unit is observed (Table 21.7, entry 7). The presence of a hydroxyl group at the allyl position induced hydroxy-directive hydrogenation, and higher diastereoselectivity was obtained (entry 8) [44]. 

The effects of temperature on enantioselectivities have been examined using a Rh-Et-DuPhos catalyst in both MeOH [56d] and THF [144]. With /5-dehydro-amino acid derivative 73 in MeOH, an increase in temperature was found to have a slight beneficial effect for both ( ) and (Z)-isomers over a 70°C range, with maximum values being observed between 0°C and 25°C. In THF, however, the effect is much more pronounced, especially for the (Z)-isomer which varies in selectivity from 65% ee at 10 °C to 86% ee at 25 °C. Interestingly, when substrate 72 was reduced with a Rh-Et-BPE catalyst in THF, this temperature dependence on enantioselectivity for the (Z)-isomer was most apparent, the se-lectivities varying from 43% ee (10°C) to 90% ee (40°C). Examination of these results also seemed to indicate that the hydrogenation of /9-dehydroamino acid derivatives follows an unsaturated pathway (vide supra) [144]. 

Catalyst performance was far superior to the corresponding BINAP or Me-Du-Phos systems, with both conversions and selectivities being higher. The hydrogenation of enol ethers using Rh-PennPhos catalysts has been reported in a patent by Zhang [67d]. Under mild conditions, high enantioselectivities were obtained (73-94% ee) for 1-aryl-l-methoxy-ethene derivatives 121, compared to Me-DuPhos (40-73% ee) and BINAP (46-48% ee). 

Until now, only a few effective ligands of this type have been identified (Fig. 25.4). Kagan and co-workers [5] prepared one of the few chiral diphosphines with only planar chirality and obtained 95% ee for the hydrogenation of DM IT with LI (Table 25.1, entry 1.1.), but enantioselectivities for several enamide derivatives were below 82% ee (the best results were with the cyclohexyl analogue of LI). For the reactions with DM IT or MAC, the cationic Rh-kephos complex showed comparable or better performance than corresponding duphos catalysts. 

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

Rhodium diphosphine catalysts can be easily prepared from [Rh(nbd)Cl]2 and a chiral diphosphine, and are suitable for the hydrogenation of imines and N-acyl hydrazones. However, with most imine substrates they exhibit lower activities than the analogous Ir catalysts. The most selective diphosphine ligand is bdppsuif, which is not easily available. Rh-duphos is very selective for the hydrogenation of N-acyl hydrazones and with TOFs up to 1000 h-1 would be active enough for a technical application. Rh-josiphos complexes are the catalysts of choice for the hydrogenation of phosphinyl imines. Recently developed (penta-methylcyclopentyl) Rh-tosylated diamine or amino alcohol complexes are active for the transfer hydrogenation for a variety of C = N functions, and can be an attractive alternative for specific applications. 

Allylic alcohol derivatives are quite useful in organic synthesis, so the asymmetric synthesis of such compounds via asymmetric hydrogenation of dienyl (especially enynyl) esters is desirable. The olefin functionality preserves diverse synthetic potential by either direct or remote functionalization. Boaz33 reported that enynyl ester and dienyl ester were preferred substrates for asymmetric hydrogenation using Rh-(Me-DuPhos) catalyst [Rh(I)-(R,R)-14], and products with extremely high enantioselectivity (>97%) were obtained (Schemes 6-11 and 6-12). 

Cationic Rh(I) catalysts containing (/ ,/ )-i-Pr-DuPHOS promote asymmetric intramolecular hydrosilylation of certain a-siloxy ketones with high selectivity (Scheme 8) (25). Reaction of 4-dimethylsiloxy-2-butanone produces an (/ )-l,3-[Pg.74]

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