Methyl -a-acetamido cinnamate

For our initial studies we chose to evaluate the hydrogenation of two unsaturated carbonyl model prochiral substrates with rhodium complexes of chiral ferrocene diphosphine and tetraphosphine ligands using a standard set of conditions. The substrates screened were methyl a-acetamido cinnamate (MAC) and dimethyl iticonate (DIMI). The substrates, catalysts, conditions, and experimental results are shown in Table 1. 

Table 1. Hydrogenation of methyl a-acetamido cinnamate (MAC) and dimethyl itaconate (DMI) in MeOH.

Fig. 3 Conversion curves for the asymmetric hydrogenation of Z-methyl-a-acetamido-cinnamate for the different catalyst generations...

Fig. 20 Conversion curves for the Rh-catalyzed hydrogenation of Z-methyl-a-acetamido-cinnamate using ligands bearing the backfolded poly(aryl ether) dendrons displayed in Fig. 19. (B-Gx) compared with that of the third-generation catalyst displayed in Fig. 17 (G3) [48]...

Recently, Reek et al. published the synthesis of a 9H,9 H- [4,4 ]bicarbazole-3,3r-diol (BICOL)-based chiral monodentate phosphoramidite ligand, which was functionalized with two different third-generation carbosilane dendritic wedges (Fig. 26) [57]. As reference reaction in the catalytic study, the rhodium-catalyzed asymmetric hydrogenation of Z-methyl-a-acetamido-cinnamate was chosen. Using a ligand-to-rhodium ratio of 2.2 led to enantio-selectivities which were comparable to the results obtained using the parent BINOL-derived monodentate phosphoramidite MonoPhos. 

Rh (DIPHOS ) (Z-methyl-a-acetamidocinnamate ) ]BF4. A sample of 0.2 g of [Rh2(DIPHOS)2][BF4]2 and 0.1 g of Z-methyl-a-acetamido-cinnamate were stirred in ca. 10 mL of warm methanol until a clear red solution was obtained. After cooling to room temperature, diethyl ether was added slowly until the solution turned slightly cloudy, followed by addition of just enough methanol to clarify the solution. Red crystals of [Rh( DIPHOS) (Z-methyl-a-acetamidocinnamate)][BF4] were grown by diflFusing diethyl ether into the solution over a period of ca. 20 hr and subjected to x-ray structure analysis. 

As mentioned earlier, in the asymmetric hydrogenation of methyl a-acetamido cinnamate, in situ PHIP-NMR data suggest structure 335 for the dihydride intermediate. Computational energy calculations based on density functional theory (DFT) are also in agreement with such a structure. In this case, to keep the computational requirements to a manageable level, calculations were carried out on a model complex where PHANEPHOS was approximated by two PH3 ligands. 

In 2001, Engel and Gade [57] prepared a series of chiral phosphine-functionalized poly(propyleneimine) (PPI) dendrimers (29) by the reaction of carboxyl-linked C2-chiral pyrphos ligand (pyrphos, 3,4-bis(diphenylphosphino) pyrrolidine) with commercially available zero- to fourth-generation PPI. The subsequent metallation of multisite phosphines with [Rh(COD)2]-BF4 (COD, 1,5-cyclooctadiene) was in situ generated and carried out in the asymmetric hydrogenation of Z-methyl-a-acetamido cinnamate and dimethyl itaconate (Figure 4.28, Equation 1). In contrast... 

In asymmetric hydrogenation of olefins, the overwhelming majority of the papers and patents deal with hydrogenation of enamides or other appropriately substituted prochiral olefins. The reason is very simple hydrogenation of olefins with no coordination ability other than provided by the C=C double bond, usually gives racemic products. This is a common observation both in non-aqueous and aqueous systems. The most frequently used substrates are shown in Scheme 3.6. These are the same compounds which are used for similar studies in organic solvents salts and esters of Z-a-acetamido-cinnamic, a-acetamidoacrylic and itaconic (methylenesuccinic) acids, and related prochiral substrates. The free acids and the methyl esters usually show appreciable solubility in water only at higher temperatures, while in most cases the alkali metal salts are well soluble. 

Asymmetric hydrogenation of dimethyl itaconate and methyl (Z)-a-acetamido cinnamate with in situ formed rhodium(I)-diphosphinite catalyst system gave the desired products with high activity and enantioselectivity (Table 2.1). The asymmetric hydrogenation may be applied to a wide range of substrates. 

In the case of methyl (Z)-a-acetamido cinnamate (B) the reaction mixture was passed through a short silicagel column to remove the catalyst. The ee was determined on CP-CHIRASIL-L-VAL column [25 m, internal diameter 0.25 mm, film thickness 0.12 pm, carrier gas 100 kPa nitrogen, FID detector the retention times of the enantiomers are 32.5 min (R), 34.2 min (5)]. 

Racemic diphosphines may be resolved by using transition metal complexes that contain optically active olefinic substrates (Scheme 11) (24). When racemic CHIRAPHOS is mixed with an enantiomerically pure Ir(I) complex that has two ( —)-menthyl (Z)-a-(acetam-ido)cinnamate ligands, (S,5)-CHIRAPHOS forms the Ir complex selectively and leaves the R,R enantiomer uncomplexed in solution. Addition of 0.8 equiv of [Rh(norbomadiene)2]BF4 forms a catalyst system for the enantioselective hydrogenation of methyl (Z)-a-(acetamido)cinnamate to produce the S amino ester with 87% ee. Use of the enantiomerically pure CHIRAPHOS-Rh complex produces the hydrogenation product in 90% ee. These data indicate that, in the solution containing both (S,S)-CHIRAPHOS-Ir and (/ ,/ )-CHIRAPHOS-Rh complexes, hydrogenation is catalyzed by the Rh complex only. 

In another example de Souza and Dupont studied the asymmetric hydrogenation of a-acetamido cinnamic acid and the kinetic resolution of ( )-methyl-3-hydroxy-2-methylenebutanoate with chiral Rh(I) and Ru(ii) complexes in [BMIM][BF4] and [BMIM][PFs] [106]. A special focus oftheir work was on the influence of H2 pressure on conversion. They determined the hydrogen solubility in the ionic liquid using... 

One of the most thoroughly studied such substrates is the ester, methyl (Z)-a-(acetamido)cinnamate, MAC, whose Rh catalyzed hydrogenation is described in Scheme 5.30. In several reports. Wiles and Bergens used a solvated (BINAP)Ru precatalyst and low temperature NMR to study the (BINAP)Ru-MAC system largely under stoichiometric conditions. Their observations are summarized in the following Scheme ... 

In the asymmetric hydrogenation of the methyl ester of a-acetamido cinnamic acid, 3.24 cannot be observed by conventional NMR techniques. In situ PHIP-NMR studies in contrast do show two hydride signals at -19 and -2 ppm. Using a C-enriched substrate, the coupling between the asterisk-labeled carbon and the hydride at -2 ppm can also be observed. Based on the NMR data, the actual structure is concluded to be more like 3.25 than 3.24. 

Zhang reported two new (S)-BINOL based ligands phosphine-phosphite (S,R)-o-BINAPHOS 163 and phosphine-phosphinite (S)-o-BIPNITE 164 [128]. Applications of these ligands in the Rh-catalyzed hydrogenation of methyl N-2-acetamido-cinnamate and methyl N-2-acetamidoacrylate induced very high enantioselectiv-ities (>99% ee), and with a wide range of substrates. 

The mechanism of hydrogenation of methyl (Z)-2-(acetamido)cinnamate catalyzed by a CHIRAPHOS- or DIPAMP-Rh complex have been exhaustively... 

Table 2.1 Asymmetric hydrogenation of dimethyl itaconate (A) and methyl (Z)-ot-acetamido cinnamate (B)...

Table 2.9 Rhodium-catalyzed hydrogenation of methyl a-(Z)-N-acetamido cinnamate (8) and dimethyl itaconate (9). ...

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