Enamides thermal cyclization

As knowledge of the reactivity of enamides accumulated during the course of a 10-year study on enamides, attention was focused on the cyclizability of enamides also under thermal conditions. It was first thought that electron deficiency in the aromatic ring of enamides caused by the introduction of an electron-withdrawing factor would bring about nucleophilic attack from the enamine portion of the molecule, therefore giving rise to the cyclized product, even under thermal conditions as described in Scheme 23. 

By applying this facile thermal cyclization of enamides, nauclefine (29) was synthesized (Scheme 27) 69,71,72). 

In the course of study on thermal cyclization of enamides of iV-nicotinoy-lenamine type (27), the cyclizability of enamides under various conditions was investigated (73). The results are summarized in Table II. 

The photocyclization of enamides has been the subject of detailed study and provides a valuable approach to the synthesis of alkaloids. A comprehensive review has been published.31 A variety of reaction types has been reported. The N-benzoylenamine 33, for example, is converted on irradiation to the trans-lactam 34 by a process involving conrotatory photocyclization followed by a thermally allowed [l,5]-suprafacial hydrogen migration.32 The influence of substituents on this transformation has been studied.33 The enacylamine 35 undergoes an analogous cyclization to give a mixture of cis- and trans-lactams 36, the ratio of which is solvent... 

Enamides can even undergo cyclization under thermal and acylating conditions, depending on the structure of enamide. 

As expected, it has been shown that some enamides having an electron deficiency in their aromatic moiety can undergo cyclization under thermal... 

Based on the above result, a newly isolated alkaloid alamarine (33, structure, see p. 240) was synthesized by the route involving enamide cyclization under both thermal and photochemical conditions, giving predominantly the desired lactam (32) (Scheme 28) (73). 

Recently, Mujumdar and Martin (74) and Atta-ur-Rahman and Ghazala (75) independently reported thermal cyclization of the enamides of A-nico-tinoylenamine type. 

One of the major areas of research in enamide chemistry has been the application of enamide cyclization to the synthesis of natural alkaloids and related heterocyclic compounds. Ever since Ninomiya and co-workers discovered nonoxidative photocyclization of the A-benzoylenamine-type ena-mides in 1969 (9), several types of alkaloids have been synthesized, starting from enamides of rather simple structures, by applying enamide cyclization under both photochemical and thermal conditions. 

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. 

The cyclization of l-methylene-2-nicotinoylisoquinolines 27 under three different conditions, photochemical, thermal, and acylating conditions, are compared (73). Starting from the above enamide (27), Ninomiya et al. (73) synthesized 10-azaberbine as the major product by simple heating at 195-200°C, whereas 12-azaberbine was the major product under acylating condition as shown in Table II. Further, total synthesis of alamarine (33), the only alkaloid having an azaberbine structure, was synthesized via the route involving enamide cyclization under both thermal and photochemical conditions (73) as shown in Scheme 71. 

However, it was demonstrated that either acylation or alkylation of the pyridine nitrogen of the enamide 201 brought about a regioselective thermal cyclization to give the cyclized lactam 204 or the quaternary salt 205. The... 

The structure of alamarine [( )-58], a typical member of this benzopyri-doquinolizine family, was confirmed by its synthesis featuring thermal or photochemical cyclization of the enamide 134 (1,116). Chowdhury (227) synthesized isoalamarine (59) from the isomeric enamide 135 via a parallel route. For the syntheses of ( )-alangimaridine [( )-61] and alangimarine... 

Scheme 193). On heating the mixture, preferably in the absence of triethylamine, the hexahydro-a-quinolone 185 was obtained directly, together with the enamide 184 and amide 186. Since the enamide could not be cyclized to the hexahydro-a-quinalone under thermal or acid-catalysed conditions, then clearly the enamide is not an intermediate in the formation of the heterocycle which must therefore arise by. /V-acylation of the enamine tautomer, followed by a [3,3]sigmatropic rearrangement and cyclization of the ketene intermediate (Scheme 194). Significantly vide infra), when the imine of 2-methylcyclohexanone was used, the rearrangement to the ketene occurred at the more substituted Cj position. 

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