Hydrogenation of enamides

Ligand Substrate SIC ratio Reaction conditions Percent ee of product (confign.) References 

Hydrogenation of a series of /Z-isomeric mixtures of a-arylenamides with a MOM-protected /3-hydroxyl group catalyzed by a BICP-Rh complex or an Me-DuPhos complex leads to the formation of chiral /3-amino alcohol derivatives with excellent enantioselectivities.70b A 1,4-diphosphane 26 with a rigid 1,4-dioxane backbone is also very effective for this transformation (Equation (28)).76 DIOP -Rh72a and Me-DuPhos-Rh219 catalysts are also effective for this transformation. 

Compared with 3-alkyl-3-(acylamino)acrylic acid derivatives, much less success has been obtained in the asymmetric hydrogenation of 3-aryl-3-(acylamino)acrylic acid derivatives. An Et-FerroTANE-Rh catalyst has provided up to 99% ee for the hydrogenation of a series of (E)-3-aryl-3-(acylamino)acrylates.95 Since (E)-3-aryl-3-(acylamino)-acrylic acid derivatives are difficult to obtain in large scales compared to (Z)-3-aryl-3-(acylamino)acrylic acid 

Recently, high enantioselectivity was obtained in the rhodium-catalyzed hydrogenation of a-aryl enamides and E/Z-isomeric mixtures of y9-substituted enamides. Tab. 1.3 lists some examples for the hydrogenation of a-phenylenamide and the /Z-isomeric mixture of yS-methyl-a-phenylenamide. A P-chiral ligand, TangPhos, proved to be particularly efficient for the rhodium-catalyzed hydrogenation of enamides, given the excellent enantioselectivity and reactivity, with up to 10000 turnovers. 

Ligand Substrate S/C ratio Reaction conditions % ee (config.) Ref. 

3 Applications of Chiral Phosphorous Ligands in Rhodium-Catalyzed Asymmetric Hydrogenation 15 

The hydrogenation of a series of T/Z-isomeric mixtures of a-arylenamides containing a MOM-protected /9-hydroxyl group, using BICP-Rh and Me-DuPhos-Rh catalysts, affords the /9-amino alcohol derivatives with excellent enantioselectivity [41c]. A 1,4-di-phosphane, T-Phos, with a rigid 1,4-dioxane backbone is also a very effective Hgand for this transformation (Eq. 11) [45]. 

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Scheme 8.15 Hydrogenations of enamides with dithiourea ligands.

Scheme 8.24 Hydrogenations of enamides with sulfonated diphosphines.

Scheme 9.27 Problems with hydrogenations of enamides bearing an aryl nitrile group.

Asymmetry in metal-alkene coordination plays a critical role in asymmetric catalysis, with implications far beyond the scope of the present treatment. An instructive example is provided by catalytic asymmetric hydrogenation of enamides,... 

Gridnev et al. studied the mechanism of the enantioselective hydrogenation of enamides with Rh-BisP" and Rh-MiniPHOS catalysts [22]. 

Enol esters have a similar structure as enamides. However, in contrast to many highly enantioselective examples on enantioselective hydrogenation of enamides, only a few successful results have been reported for the hydrogenation of... 

Wink reported the use of bisphosphite ligands in the asymmetric hydrogenation of enamides (2-10% ee) [114]. In 1998, Selke synthesized a series of analogues based on 98a. Of these compounds, 147 (Fig. 27.14) was selected as ligand for the Rh-catalyzed hydrogenation of methyl (Z)-2-ace tamidocinnamate, though it induced only low enantioselectivity (13% ee) [115]. 

Uemura developed a water-soluble phosphine-phosphinite ligand (derived from a,a-trehalose) (166) for the Rh-catalyzed hydrogenation of enamide derivatives this induced only moderate enantioselectivity [129]. 

Rhodium-catalyzed hydrogenation of enamides has been successfully performed using monodentate phosphites 17, with enantioselectivities of up to 95% being obtained [53]. The rate of hydrogenation is low in order to reach full conversion with a SCR of 500, hydrogenation is performed at a pressure of 60 bar for 20 h. The use of ligand 17 am in the rhodium-catalyzed hydrogenation of aromatic enamides resulted in ee-values of up to 95%. 

Fig. 31.15 Mechanism of the enantioselective hydrogenation of enamides by Ru BINAP, giving the opposite stereochemical course to the corresponding Rh catalyst. Note the heterolytic nature of the addition process with one of the two hydrogens arising from solvent.

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]. 

Fig. 41.5 En antiomeric hydrogenation of enamides catalyzed by Rh-MeDuPHOS complex heterogenized in [BMIM][PF6],...

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