Aza Ene Type Reactions

Scheme 27 Vinylogous Mannich reaction of silyl dienolates 2.3.5 Aza-Ene-Type Reaction...

Two years later, Terada and coworkers described an asymmetric organocatalytic aza-ene-type reaction (Scheme 28) [50], BINOL phosphate (7 )-3m (0.1 mol%, R = 9-anthryl) bearing 9-anthryl substituents mediated the reaction of A-benzoylated aldimines 32 with enecarbamate 76 derived from acetophenone. Subsequent hydrolysis led to the formation of P-amino ketones 77 in good yields (53-97%) and excellent enantioselectivities (92-98% ee). A substrate/catalyst ratio of 1,000 1 has rarely been achieved in asymmetric Brpnsted acid catalysis before. 

In 2007, Terada et al. extended their previously described chiral phosphoric acid-catalyzed aza-ene-type reaction of M-acyl aldimines with disubstituted enecarbamates (Scheme 28) to a tandem aza-ene-type reaction/cyclization cascade as a one-pot entry to enantioenriched piperidines 121 (Scheme 48). The sequential process was rendered possible by using monosubstituted 122 instead of a disubstituted enecarbamate 76 to produce a reactive aldimine intermediate 123, which is prone to undergo a further aza-ene-type reaction with a second enecarbamate equivalent. Subsequent intramolecular cychzation of intermediate 124 terminates the sequence. The optimal chiral BINOL phosphate (R)-3h (2-5 mol%, R = 4-Ph-C H ) provided the 2,4,6-sub-stituted M-Boc-protected piperidines 121 in good to exceUent yields (68 to > 99%) and accomplished the formation of three stereogenic centers with high diastereo- and exceUent enantiocontrol (7.3 1 to 19 1 transicis, 97 to > 99% ee(trans)) [72]. 

Scheme 48 Tandem aza-ene-type reaction/cyclization cascade scope and reaction intermediates...

Scheme 55 Aza-ene-type reaction between ethyl glyoxylate and various enecarbamates...

In related studies, Terada described the synthesis of optically pure piperidines via a tandem aza-ene-type reaction/cyclization sequence (Scheme 5.18) [32]. The reaction of a monosubstituted enecarbamate and an N-acyl aldimine affords aza-ene-type intermediate 5, which reacts with a second equivalent of enecarbamate to give aldimine 6. Subsequent intramolecular cyclization terminates the aze-ene-type reaction sequence to furnish trans-piperidine 7 in high enantio- and diasterio-selectivities. 

Terada et al. successfully applied the aza ene type reaction to the cascade trans formation by taking advantage ofthe formation of imine products (Scheme 3.30) [69]. They employed monosubstituted enecarbamates [70] instead of the disubstituted versions and as a result, piperidine derivatives with multiple stereogenic centers were obtained in high stereoselectivities. The acid catalyzed aza ene type reaction of the initial aldimines with monosubstituted enecarbamates afforded aza ene type... 

Scheme 3.29 Enantioselective aza ene type reaction under low catalyst load.

Blechert, Thomas, and co-workers developed a microporous recyclable heterogeneous catalyst 155 based on chiral phosphoric acid, which has been utilized in transfer hydrogenation, aza-ene-type reaction, and AFC alkylation of pyrrole. In the presence of 5 mol% polymer-supported catalyst 155, the AFC alkylation of pyrrole with nitroalkene occurred smoothly to afford the desired product in 91% yield with 96% ee (Scheme 6.71). 

Shortly later, within 2 months, a similar reaction, the enantioselective cascade aza-ene-type cyclization reactions of a,p-unsaturated aldehydes 28 and enamide 154, was also reported by Wang et al. In addition, the reaction product hemiaminal 157 was converted to ketoaldehyde 158, pyridine 159 and enamide 160, Scheme 3.51 [67]. Similarity, the reaction mechanism started from a nucleophilic attack of enamide (an aza-ene-type reaction), followed by reversible enamine-iminium transformation and hydrolysis to provide the hemiaminal. 

Scheme 3.51 Organocatalytic cascade aza-ene-type reactions of a, 3-unsaturated aldehydes with enamides and the subsequent transformations.

An efficient enantioselective reductive amination of a-branched aldehydes (90) via d5namic kinetic resolution catalyzed by (89) has been described (Scheme 26). Reductive coupling of 1,3-enynes to heterocyclic aromatic aldehydes use an achiral rhodium-catalyst with a chiral Bronsted acid (89) as co-catalyst (Scheme 27). A highly efficient enantioselective aza-ene-type reaction of N-benzoylimines (91) with enecarbamates (92) has been achieved. The reaction can be performed at extremely low loading of the catalyst (93) without notable loss of enantioselectivity of P-aminoimines obtained (Scheme 28). ... 

Terada, M. Soga, K. Momiyama, N. Enantioselective Activation of Aldehydes by Chiral Phosphoric Acid Catalysts in an Aza-Ene-Type Reaction between Glyoxate and Enecarbamate. Angew. Chem. Int. Ed. 2008, 47, 4122-4175. 

The area of reactions of phosphate derivatives has been dominated by highly stereoselective reactions in which the latter were used as chiral catalysts or achiral reagents. Among this group of reactions, it is worthy to note several asymmetric reactions ring opening of w 50-aziridinium and episulfonium ions, addition of alcohols to imines, 1,3-dipolar addition of aldehydes, amino esters and dipolarophiles, protonation of silyl enol ethers, epoxidation of a,p-unsaturated aldehydes, aza-ene-type reactions as well as asymmetric versions of named reactions Mannich, Friedel-Crafts, Kabachnik-Fields, aza-Darzens and aza-Henry. 

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