Atropic acid, hydrogenation

Atropic acid hydrogenated with an optically active diphosphine-rhodium(I) catalyst and triethylamine in 1 2 benzene-ethanol (S)-hydratropic acid. Y ca. 100% optical purity 63%. - Similarly a-Acetaminocinnamic acid (R)-N-... 

The bis-DIOP complex HRh[(+)-DIOP]2 has been used under mild conditions for catalytic asymmetric hydrogenation of several prochiral olefinic carboxylic acids (273-275). Optical yields for reduction of N-acetamidoacrylic acid (56% ee) and atropic acid (37% ee) are much lower than those obtained using the mono-DIOP catalysts (10, II, 225). The rates in the bis-DIOP systems, however, are much slower, and the hydrogenations are complicated by slow formation of the cationic complex Rh(DIOP)2+ (271, 273, 274) through reaction of the starting hydride with protons from the substrate under H2 the cationic dihydride is maintained [cf. Eq. (25)] ... 

Under this aspect, the group of Jessop [102] investigated the influence of the ionic liquid used on enantioselectivity in the hydrogenation of atropic acid as an example... 

Styrene and its derivatives, such as a-methylstyrene, atropic acid, cinnamic acid, and cinnamyl alcohol, were readily reduced (acids were added as their salts), yielding the corresponding dihydro derivatives (Table I). However, propenyl-benzene, tmst/m-diphenylethylene, and stilbene absorbed no hydrogen. 

The diop system is the most effective of the Ru(II) chiral phosphine complexes that we have found for asymmetric hydrogenation (25, 26). The hydrogenation rates are about V50 as large as those using HRuCl(PPh3)3 under corresponding conditions (32) but are reasonably efficient nevertheless. For example, 1M solutions of atropic acid are converted quantitatively to 2-phen-ylpropionic acid (40% enantiomeric excess (ee)) in one day with 10 2 M catalyst at 1 atm H2. 

Wilkinson s (I) discovery that the soluble rhodium(I) phosphine complex, [Rh(PPh3)3Cl], was capable of homogeneous catalytic hydrogenation of olefins immediately set off efforts at modifying the system for asymmetric synthesis. This was made possible by the parallel development of synthetic methods for obtaining chiral tertiary phosphines by Horner (2) and Mislow (3,4, 5). Almost simultaneously, Knowles (6) and Horner (7) published their results on the reduction of atropic acid (6), itaconic acid (6), a-ethylstyrene (7) and a-methoxystyrene (7). Both used chiral methylphenyl-n-propyl-phosphine coordinated to rhodium(I) as the catalyst. The optical yields were modest, ranging from 3 to 15%. 

The first examples of asymmetric hydrogenation based on this principle were reported by Knowles and co-workers (the Monsanto group) in 1968 (12). Rhodium complexes of the type RhL3Cl3 (where L was a chiral phosphine) were used in the hydrogenation of a-phenylacrylic acid (atropic acid) and itaconic acid under the conditions indicated in Fig. 3. When L was (R)-( )-methylphenyl-n-propylphosphine,3 15% optically pure (S)-(+)-a-phenyl-pro-pionic acid and 3% optically pure methylsuccinic acid (configuration unreported) were obtained. 

A number of experiments indicated that the observed effects were related to the formation of a phosphobetaine by the reaction of atropic acid with any ligand in excess of 2 equivalents per equivalent of rhodium. In the presence of the phosphobetaine, atropic acid was hydrogenated rapidly to chiral a-phenyl-propionic acid. It was concluded that the phosphobetaine influenced the rate and optical yield only because it converted the substrate to the carboxylate anion (Fig. 7). This conclusion was supported by an experiment using L/Rh = 2 and the triethylamine salt of atropic acid in which a thirty-fold rate increase, compared to the rate at L/Rh = 2 in the absence of triethylamine, and also increased optical purity (28% ee) were obtained (15). 

The insolubilized DIOP catalyst (34) was found to be rather ineffective for the asymmetric hydrogenation of oleflnic substrates the hydrogenation of a-ethyl-styrene proceeded readily but gave (-)-R-2-phenylbutane with an optical purity of only 1.5%. Methyl atropate was hydrogenated to (+)-S-methylhydratropate (2.5% ee). The soluble DIOP catalyst gave 15 and 17% ee, respectively, for the same reductions. The optical purity of the products was lower when recovered insolubilized catalyst was used. There was no reduction of a-acetamidocinnamic acid in ethanol-benzene with the insolubilized catalyst, presumably due to the hydrophobic nature of the polymer support causing it to shrink in hydroxylic solvents. 

Enantioselective Hydrogenation. (R,5 )-CAMPHOS has been employed in combination with rhodium(I) to reduce alkene carbon-carbon double bonds. Thus, the Rh(I) complex formed from (R,5 )-CAMPHOS and [Rh(cyclooctene)2Cl]2 in toluene-EtOH-EtsN solution catalyzes the hydrogenation (1 atm H2, 20 °C) of atropic acid and of ct-acetamidocinnamic acid. The... 

Application of subcritical gaseous CO2 to an organic liquid causes the liquid phase to expand noticeably, due to extensive dissolution of the CO2 into the liquid phase (131). This expansion is accompanied by a reduction in the liquid phase viscosity, an increase in the solubility of H2 in the liquid, and an increase in the mass transfer rates from the gas to liquid phase. There is evidence that this can affect the enantioselectivity of reactions in viscous liquids. The enantioselectivity of asymmetric hydrogenation of unsaturated carboxylic acids in a viscous ionic liquid was shown to be strongly affected by CO2 expansion of the liquid, the enantioselectively being improved for one substrate (atropic acid) and decreased for another (tiglic acid). The results were explained in terms of the solubility and rate of transfer of H2 gas into the expanded ionic liquid (23). The same effect was not observed in expanded methanol. 

The unsaturated nature of the monobasic acid, atropic acid, which results from the dehydration of tropic acid, is readily established by the ease with which it absorbs two atoms of bromine (14) or hydrogen (sodium amalgam) (18). From the oxidation of atropic acid to benzoic acid it may be characterized as an unsaturated Cg-monocarboxylic acid with one phenyl group as a substituent. Only two structures (II and III) account for these facts. The isolation of formic acid and phenylacetic acid from the alkaline... 

The addition of hydrogen chloride to atropic acid, followed by the replacement of the chlorine atom (Na2C03) by a hydroxyl group (213), or the addition of hypochlorous acid to the unsaturated acid followed by the reductive elimination of the chlorine (Zn-Fe + NaOH) (82) completed the synthesis of tropic acid but gave no clear insight into the position of the hydroxyl in the tropic acid molecule (V or VI). Although both V and VI... 

Apoatropine results from the dehydration (27) (nitric acid, sulfuric acid, acetic or benxoic anhydrides, or phosphorus pentoxide) of atropine. It was proved to be atropyltropeine, for it results from the repeated evapo-ratiiHi of a hydrochloric acid solution of tropine wdth atropic acid (22) or by the action of tropine with o(-phenyl-/3-chloropropionyl chloride and elimination of hydrogen chloride from the primary tropeine (158). 

Atropic acid ethyl ester Hydrogen chloride... 

There are known to be some limitations to asymmetric hydrogenation of certain substrates. Asymmetric hydrogenation of tiglic acid requires alow H2 concentration, or low H2 pressure and mass transfer rates, which is obtained in viscous ionic liquids. On the other hand, the hydrogenation of atropic acid is more enantioselective when... 

A rhodium(i) complex with the optically active phosphine (26) is an efficient catalyst for asymmetric hydrogenation atropic acid is reduced to (5)-hydratropic acid in an optical yield of 63 % this method has been extended to the preparation of optically active amino-acids. 

Asymmetric hydrogenation can be achieved by the use of rhodium complexes of chiral phosphines as catalysts. The chiral diphosphine species Rh (Cl)(diphosphine)(solvent), generated in situ from [RhCl(cyclo-octene)2]2 and the diphosphine (95), is a stereoselective catalyst a-acetamidocinnamic acid (96) is reduced with an optical purity yield of 72%, atropic acid (97) is reduced with 63% optical purity. These results... 

Asymmetric hydrogenation has been achieved with dissolved Wilkinson type catalysts (A. J. Birch, 1976 D. Valentine, Jr., 1978 H.B. Kagan, 1978). The (R)- and (S)-[l,l -binaph-thalene]-2,2 -diylblsCdiphenylphosphine] (= binap ) complexes of ruthenium (A. Miyashita, 1980) and rhodium (A. Miyashita, 1984 R. Noyori, 1987) have been prepared as pure atrop-isomers and used for the stereoselective Noyori hydrogenation of a-(acylamino) acrylic acids and, more significantly, -keto carboxylic esters. In the latter reaction enantiomeric excesses of more than 99% are often achieved (see also M. Nakatsuka, 1990, p. 5586). 

The aluminium salt obtained is acidified and dehydrated to give the unsaturated (atropic type) acid precursor. This can be asymmetrically hydrogenated in methanol under 7 bar of H2 with an enantiomeric excess of 98.5%. A turnover of 3000 was most efficient. The reaction scheme is shown in Fig. 6.31. 

The insoluble, polymer-supported, optically-active rhodium complex prepared by Dumont et al. (1973) was used for asymmetric reduction of alkenes, leading to optically active hydrocarbons. Thus, 2-phenylbutene produced (R)-2-phenyl butane in 1.5% optical purity. The catalyst also hydrogenated methyl atropate to (5)-(-i-) methyl hydroatropate with an optical yield 2.5%. With a-acetamidocinnamic acid there was no reduc-... 

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