Enamines, cyclization

By annulation onto the seven-membered ring 2.5.2.1 Enamine cyclization (Scheme 45)... 

Similar enamine cyclization processes occur in several other successful heterocycle syntheses, e.g. in the Fischer indole synthesis. In this case, however, a labile N—N bond of a l-aryl-2-vinylhydrazine is cleaved in a [3,3]-sigmatropic rearrangement, followed by cyclization and elimination of ammonia to yield the indole (B. Robinson, 1963, 1969 R. J. Sundberg, 1970). Regioselectivity is only observed if R2 contains no enolizable hydrogen, otherwise two structurally isomeric indoles are obtained. Other related cyclization reactions are found in the Pechmann synthesis of triazoles (T.L. Gilchrist, 1974) and in G. Bredereck s (1939) imidazole synthesis (M.R. Grimmett, 1970). 

The enamine cyclization reaction has not been utilized in organic synthesis to the same extent as the corresponding enamide reaction. Schultz and Chiu have utilized this reaction in an approach to the synthesis of the aspidosperma alkaloids21. Irradiation of compound 37 produces tetracyclic compound 38 in 71% yield (equation 11). 

This reaction forms the required pyrrole in one step First, the oxime is reduced to an amine then the amino group forms an imine with the most reactive carbonyl group (the ketone) in the keto-diester. Finally, the very easily formed enamine cyclizes on to the other ketone. 

In the presence of a base various enamines cyclize with 4-chloropyridazine-3-carbonyl chloride to give pyrido[3,2-c]pyridazin-8(577)-ones 8.24... 

There are several ways to synthesize these alkaloids. The way developed in the author s laboratory, an intramolecular enamine cyclization, not only allows the synthesis of the naturally occurring stereoisomers but also the others by variation of the starting materials and/or reaction conditions, and, by the same procedure, the alkaloids of the gephyrotoxin class may also be obtained (refs. 17, 18, 19). Results on the antimicrobial activity of the gephyrotoxins are,however, not yet available. 

An intramolecular application of this type of catalysis was included in his first publication on this process, whereby the SOMO activated enamine cyclized onto an unactivated alkene using catalyst 103 (Scheme 1.26). 

Designof enamine-enamine cascades Examples of enamine-enamine and enamine-enamine cyclization cascades... 

We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode, although an iminium mode might be involved in the following steps. In this regard, several catalytic cascade sequences, including enamine-enamine, enamine-iminium, and enamine cyclization, are discussed here. 

Design of Enamine-Enamine Cascades Three possible active sites (e.g., carbonyl group, nucleophilic a- and Y-positions) of enamine catalysis product 4 or 6 (Figure 1.1) can be further functionalized via a second enamine process in a cascade manner. Taking advantage of the electrophilic carbonyl in 4 and 6, intermolecular enamine-enamine (Scheme 1.3a) and enamine-enamine cyclization (Scheme 1.3b) cascades could be possible. In addition, the a-position of the same (Scheme 1.3c) or different (Scheme 1.3d, e.g., Robinson annulation) carbonyl group can be subjected to a second enamine process. 

Examples of Enamine—Enamine and Enamine-Enamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)-catalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23... 

The closely related enamine cyclization process has also been applied to the synthesis of gambirtannine derivatives by Atta-ur-Rahman (Scheme 3.67) (72, 73). Condensation of 6-methoxyharmalane (391) with 392 afforded a separable mixture of the enamines 393 and 394. Irradiation of 393 afforded 11,16-dimethoxy-16-des(methoxycarbonyl) gambirtannine (395) in good yield. Under the same conditions, enamine 394 yielded ll,16-dimethoxy-14-(13-methoxybenzyl)-6-des(methoxycarbonyl) gambirtannine (396). 

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