N-Acylenamines

Prior to the beginning of our work on sitagliptin, there had been some reports in the literature of catalytic asymmetric hydrogenation of enamines to access chiral secondary amines [19]. The synthesis of P-amino acids had also been established by catalytic asymmetric hydrogenation of enamides [20]. All these reports relied on N-acylenamines as substrates, since it was believed that the N-acyl group was required in order to achieve good reactivity and selectivity [21]. 

This reactivity of N-acylenamines 1 has opened up new possibilities for the use of enamides. in photochemical rearrangements2 as well as in acid-catalyzed cyclizations3,4, which lead to a variety of complex nitrogen-containing heterocycles from readily available simple precursors. These reactions have also been used to form a wide variety of natural products and polyfunctional compounds. Enamides can be also used as electrophilic reagents for amidoalkylation5,6, which can occur under certain conditions as a [4 + 2] cycloaddition to form 1,3-oxazinium heterocycles7. 

Synthesis of N-acylenamines from carbonyl compounds and nitriles 1451... 

The first observation was N— C acyl migration on irradiation of N-acylenamines (4-10). However, when A-benzoylenamines were irradiated, a new photocyclization reaction was discovered (9,10), and since has been developed for use as a synthetic tool with general applicability to the synthesis of various alkaloids. As a result, it is now firmly established as enamide photocyclization. 

A-Formylated 1,4-oxazines, including morpholine, can be oxidized anodically in metha-nolic solution to 3-methoxy derivatives, which under acidic conditions lose methanol to N-acylenamines these are of potential synthetic interest [280]. Other acylated secondary amines, such as those from pyrrolidine, piperidine, and tetrahydroisoquinoline, behave similarly (Chapter 24) [281]. 

Eisner and Sadeghi described the isomerization of dihydropyridine with RhClj-PhjP complex in benzene. Isomerization of l-alkyl-4-acyl-1,2,5,6-tetra-hydropyridines into l-alkyl-4-acyl-l,4,5,6-tetrahydropyridines has been observed. Pd/C-catalysed rearrangement of iV-acyl-l,2,3,6-tetrahydropyridines to N-acylenamines is described . Besselievre, Beugelmans and Husson reported the photochemical isomerization of cyclic allylaminc 79 to enamine 80. An equilibrium favouring 81 over 82 by 93 7 was established by treating 81 with t-BuOK-DMSO at 90°C. 

Reaction of 2-(/3-cyanoethyl)cyclohexanone benzylimide with carboxylic acid chlorides RCOCl (R = Me, Et, Pr, i-Pr, Bu, Mc2CHCH2) in benzene containing pyridine gave 47-81% N-acylenamines with high regiospecificity . ... 

Acylynamines a- and P-Alkoxy-a,p-ethylenenitriles Amidium salts, vinylogous p-Ammonio-a, p-ethylene-aldehydes Enacylamines N-Acylenamines 20 Eneformylamines Enaminones P-Amino-a,p-ethylene-ketones Enisocyanates... 

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