Substituted enamides

Rh-catalyzed hydrogenation of simple enamides has attracted much attention recently. With the development of increasingly efficient chiral phosphorus ligands, extremely high ee-values can be obtained in the Rh-catalyzed hydrogenation of a-aryl enamides. E/Z-isomeric mixtures of -substituted enamides can also be hydrogenated, with excellent ee-values. Some efficient examples (>95% ee) of hydrogenation of a-phenylenamide and E/Z-isomeric mixtures of / -methyl-a-phenylenamide are listed in Table 26.3. 

Figure 12. ONIOM optimized geometries of diastereomers for ferf-Butyl substituted enamides.

Although understanding the effect of the a-substituent on relative alkyl hydride stabilities is straightforward, understanding the effect on the catalyst-enamide diastereomers is not. To clarify this matter we performed a series of calculations on a variety of substituted enamides [78], To eliminate the effect of the amide oxygen, we examined frontier orbitals of the [Rh(PH3)2(formamide)]+ fragment (15) and those of model enamides (16). 

The enantioselective ability of chiral ligands has often been evaluated by hydrogenation of a-hydroxycarbonyl- or ot-alkoxycarbonyl-substituted enamides. Figure 1.2... 

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. 

Recently, Mo(CO)6 was used as the CO-source in the palladium-catalyzed generation of 3-acylaminoindanones [40]. These target structures were prepared from o-bromoaryl-substituted enamides after 30 min of microwave heating (Scheme 5). 

It is assumed that the intermediate N-acyliminium ions formed from the Lewis acid-assisted ring opening of the isomiinchnone cycloadducts undergo rapid proton loss to produce tetra-substituted enamides. In the case of 65, this process is clearly evident as witnessed by the stereochemical outcome observed... 

Photocyclization of the enamide 80 and the o-methoxy-substituted enamide 85 under nonoxidative conditions afforded the trans lactams 81 (52%) and 86 (53%) and the dehydrolactams 82 (41%) and 87 (50%), respectively. Since dehydrogenation of the trans lactams 81 and 86 with 30% Pd/C gave lactams 83 and 88, although in low yields, the dehydrolactams (82) and (87) were used for ready dehydrogenation with the same reagent, followed by reduction to the desired alkaloids dihydroavicine (84) and dihydronitidine (89), natural alkaloids that had been converted already to nitidine and avicine, respectively (1,2) (Schemes 44 and 45). 

The enamides of TV-aroylenamine type (143-146), which contain an electron-deficient aromatic ring caused by the introduction of some electron-withdrawing factor, undergo a facile cyclization not only photochemi-cally but also thermally to afford the dehydrolactams (147-150) in good yields (53,67). The dinitro-substituted enamide (143) was thermally cyclized when refluxed in benzene to afford the corresponding dehydrolactam (147) in 95% yield. Compound 147 was also obtained from the 1-methylisoquino-... 

Based on the facile thermal cyclization of the nitro-substituted enamides, Naito and Ninomiya (6 7) have further developed thermal cyclization for the synthesis of azaberbines under acylating conditions. 

Regioselective photocyclization of the o-methoxy-substituted enamide 133 (32) or the obromoenamide 133 (29,30) gave only the dehydrolactam 156 in 85 or 80% yield, respectively. Reduction of the lactam 155 with LAH... 

By using the p-methoxy-substituted enamide (192), Ninomiya et al. (54) succeeded in a simple synthesis of alloyohimbone (196) via the unconjugated lactam 194, which has an enol ether structure. Lithium aluminum hydride reduction of the lactam 194, followed by hydrolysis with hydrochloric acid and subsequent catalytic hydrogenation over platinum dioxide, yielded alloyohimbone (196) stereoselectively in an overall yield of 59% from harmalane (54) this was the most convenient synthesis of alloyohimbone (196) so far reported (Scheme 75). 

Similarly, photocyclization of the /i-methoxy-substituted enamide 229, followed by two-step hydride reduction with LAH and sodium borohydride, furnished the depyrrole analog of agroclavine (55) (Scheme 87). 

Shortly thereafter, Zhou and coworkers independently reported the enantioselec tive F C reaction of indoles with a aryl substituted enamides catalyzed by chiral phosphoric acid catalyst lq (Scheme 3.22) [52], in which the quaternary stereogenic center bearing the nitrogen atom vas constructed in a highly enantioselective manner. 

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