Enamide hydrogenation conditions

The asymmetric reduction of enamides using hydrogenation conditions is a well documented reaction with a number of groups reporting excellent results [14]. Syn delivery of hydrogen from the same face of the molecule ensures that the enamide geometry defines the relative stereochemistry obtained, and a range of chiral catalysts have been developed to control the absolute stereochemistry. However, a... 

With all other pieces of the synthesis in place our attention now focused on the final piece in the jigsaw-the asymmetric hydrogenation of the amide enamide 42. Screening of hydrogenation conditions rapidly led to identification of a number of conditions which allowed the desired hydrogenation to proceed at low catalyst loadings and in non-chlorinated solvents (Table 9.9). 

Enamide 88 proved to be unreactive under homogeneous hydrogenation conditions using either Wilkinson s or Crabtree s catalysts even at high temperature and pressure suggesting that the trisubstituted double bond was too hindered to participate in such a process. 

Various catalyst, pressure, and solvent systems were investigated in an attempt to maximize the stereoselectivity of the enamide hydrogenation. In contrast to the results obtained on the more straightforward derivatives 150 and 151, a mixture of C-4 epimers was obtained under all of the conditions tried. The results obtained are summarized in Scheme 71 and Table 18 below. (Note Solvents/solvent mixtures were chosen with as low a polarity as possible in an attempt to maximize coordination of the substrate to the heterogeneous catalyst.80) Overall yields in all cases where reduction occurred were essentially quantitative. 

Hydrogenation of Itaconic Acid. Compared to the hydrogenation of amidoacylic acids, enols, and enamides, the Rh(/ -SpirOP)+ catalyzed hydrogenation of itaconic acid was less successful. After optimizing the hydrogenation conditions, 76.8% ee of the corresponding product was obtained in isopropanol at ambient temperature under 100 psi H2 for 2 h (eq 3). 

In 1986, Noyori reported a hexa coordinate BINAP Ru(II) complex that can efficiently catalyze the asymmetric hydrogenation of (Z) N acyl 1 alkylidenete tra hydroisoquinolines (70) in the presence of 0.5 1 mol% of the catalyst loadings in a 5 1 mixture of ethanol and dichloromethane under 1 4 atm of hydrogen at 23 °C (Scheme 9.18) [63]. However, the corresponding E enamide substrates were inert to this catalytic system under the same hydrogenation conditions. 

Typical square-planar rhodium-olefin complexes such as acetylacetonates (48) have a stoichiometry of two coordinated olefins per metal-atom. Since chelating olefins are bidentate in their cationic rhodium biphosphine complexes, it would be surprising if bis-olefin complexes were never found under hydrogenation conditions. It seems clear, in fact, that they can be the major coordinated species under certain conditions. Thus examples of 2 1 rhodium enamide complexes with biz-diphenyl-phosphinopropane have been observed (49), although the majority of cases involve a8-unsaturated acids co-complexed with DIOP. 

Alternate Crosslinking Modes. In addition to the crosslinking modes previously described, (co)polymers containing 1 and 2 may be cured by other means. For example, under appropriate acidic conditions with limited availability of active hydrogen species cyclic hemiamidals 2 will lose ROH to form the enamide 9 (Scheme 5). This has been demonstrated on model systems, e.g., 2 where vinyl is replaced by methyl ). The product, N-acetylpyrroline, has in turn been converted to nonvolatile products (oligomers) under free radical catalysis. These systems may thus be considered for application in the UV/EB or catalyzed free radical cure field. 

Unlike the Rh-based hydrogenation of a-(acylamino)acrylates, the corresponding Ru chemistry has not been studied extensively. Ru complexes of (S)-BINAP and (S,S)-CHIRAPHOS catalyze the hydrogenation of (Z)-a-(acylamino)cinnamates to give the protected ( -phenylalanine with 92% ee [74] and 97% ee [75], respectively. It is interesting that the Rh and Ru complexes with the same chiral diphosphines exhibit an opposite sense of asymmetric induction (Scheme 1.6) [13,15,56,74,75]. This condition is due primarily to the difference in the mechanisms the Rh-catalyzed hydrogenation proceeds via Rh dihydride species [76], whereas the Ru-catalyzed reaction takes place via Ru monohydride intermediate [77]. The Rh-catalyzed reaction has been studied in more detail by kinetic measurement [78], isotope tracer experiments [79], NMR studies [80], and MO calculations [81]. The stereochemical outcome is understandable by considering the thermodynamic stability and reactivity of the catalyst-enamide complexes. 

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