Pyrrolidine enamine dialkylation

C-Alkylation affords monoalkylated products as a result of the lower reactivity of the monoalkylated enamines. Enamine salts obtained by alkylation can afford new enamines capable of further alkylation only by the loss of a proton. In some cases, dialkylation can be achieved by the addition of the more basic ethyldicyclohexylamine. Monoalkylation of the pyrrolidine enamine of cyclohexanone is due to a considerable energy difference between the transition states caused... 

Various 1,5-disubstituted derivatives of bicyclo[3,3 l]nonane have been prepared from (662), the desulphurization by Raney-Nickel being the first step. Reactions of pyrrolidine enamines of dialkyl 4-oxocyclohexane-l,l dicarboxylates (663) with acryloyl chloride give alkyl 2,6-dioxobicyclo[3,3,l]nonane-l-carboxylates (666) rather than the expected alkyl 2,9-dioxobicyclo[3,3,l]nonane-7-carboxylate. However, the enamines (664) and (665) give rise to the normal products, and reasons for the change in reaction course are advanced. 

The choice of the secondary amine for formation of the enamine is not completely arbitrary even though it does not end up in the final alkylated product. Simple dialkyl amines can be used but cyclic amines such as pyrrolidine, piperidine, and morpholine are popular choices as the ring structure makes both the starting amine and the enamine more nucleophilic (the alkyl groups are tied back and can t get in the way). The higher boiling points of these amines allow the enamine to be formed by heating. 

Extension of the enamine-mediated carbonyl a-amination strategy to the generation of quaternary stereogenic centers at the a-position of a-branched aldehydes under catalysis by prohne 1 [8, 9], pyrrolidine tetrazole 3 [10, 11], or L-azetidin-2-carboxylic acid 4 [8] has also been explored (Table 11.1). The observed enantio-selectivities ranged from essentially none to >99%. Derivatives of 2-phenylpropanal gave better enantioselectivities than a,a-dialkyl substituted aldehydes. Erase and coworkers [11] employed microwave irradiation to accelerate the rate of proline-catalyzed amination, and found that yields as well as enantioselectivity can be somewhat improved with shorter reaction times. It appears that the pyrrolidine tetrazol 3 was a more effective catalyst than L-proline 1 for the amination of 2-phenylpropanal derivatives [10,11]. Subsequent reduction of adducts and cyclization could be carried out to afford the respective a-amino alcohols or the A-amino-oxazolidinones. 

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