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Mannich bases (b-aminoketones) and their derivatives are important synthetic intermediates, particularly in the preparation of biologically active molecules.  The traditional method for their preparation is the Mannich reaction, however, this method has many drawbacks such as long reaction times, poor regioselectivity, no enantioselectivity, and competition from unwanted side reactions.

We are developing new methods for the preparation of Mannich bases from 2-acylaziridines through intermediary proximal b-amino silyl enol ethers.  These functionalized silyl enol ethers should react with a variety of electrophiles to provide Mannich bases of varied structural complexity.

During the first two years of this project, we have focused on developing two separate but related methods for the stereo- and regioselective preparation of the Mannich bases and proximal b-amino silyl enol ethers, respectively.  The central reaction common to both methods is the reaction of a 2-acylaziridine with a silyllithium reagent, which triggers a Brook rearrangement with concomitant opening of the adjacent aziridine ring.

For the direct formation of simple Mannich bases, an excess of silyllithium reagent is used and conditions have been adjusted to promote the in situ cleavage of the intermediate silyl enol ether, which provides the Mannich base on work up. 

Optimization studies were performed using N-acetyl-2-benzoyl-3-methylaziridine and 2-acetyl-3,3-dimethyl-N-tosylaziridine as representative aryl and alkyl ketones substrates, respectively.  As anticipated, it was found that solvents such as THF that strongly bind to lithium ions gave the highest yield of Mannich base.  Use of nonpolar solvents such as ether or toluene retarded the necessary desilylation, resulting in lower yields of the desired Mannich base.  The most commonly encountered silyllithium reagent, dimethylphenylsilyllithium, was found to efficiently effect the reaction of the aryl ketone substrate, N-acetyl-2-benzoyl-3-methylaziridine. However, reaction of the alkyl ketone substrate, 2-acetyl-3,3-dimethyl-N-tosylaziridine, required the use of methyldiphenylsilyllithium to achieve an acceptable yield of Mannich base.  The lack of an electron-withdrawing group at the reaction site of the alkyl ketone necessitated additional electron withdrawal from the incorporation of a second phenyl substituent on the silyl group.  Overall, the combination of excess methyldiphenylsilyllithium in THF at -40 °C proved to be a convenient system that gave the desired Mannich base in good yield from either the alkyl or aryl substituted substrate.  Several differentially substituted 2-acylaziridine substrates have been prepared and reacted using these optimized conditions to determine the scope of the method.  Both aryl and alkyl 2-acylaziridines reacted to give the corresponding Mannich bases in good to excellent yields.  The method is compatible with amide, carbamate and sulfonamide protecting groups on the aziridine nitrogen, but ineffective for use with an unprotected nitrogen.

Substantial progress has also been made on the second method of the project, the preparation of proximal b-amino silyl enol ethers.  Initial optimization studies have been performed using N-acetyl-2-benzoyl-3-methylaziridine as an investigative substrate. Use of nonpolar solvents such as ether or toluene retarded the desilylation providing mixtures of Mannich base and the desired b-amino silyl enol ether.  Variations on the silyllithium reagent have also been investigated.  Reaction of N-acetyl-2-benzoyl-3-methylaziridine with dimethylphenylsilyllithium provided the desired b-amino silyl enol ether in low yield.  Use of methyldiphenylsilyllithium resulted in a substantially higher yield of the silyl enol ether, but was accompanied by a substantial amount of undesired Mannich base.  Increasing the steric bulk of the silyl group was investigated as a potential means to retard the undesired desilylation of the silyl enol ether. Use of t-butyldiphenylsilyllithium was found to completely suppress the cleavage of the silyl enol ether.

Future work on the direct preparation of Mannich bases will include the reaction of additional substrates to further demonstrate the generality of the method.  For the preparation of b-amino silyl enol ethers, additional optimization studies will be performed.  A variety of N-protecting groups will be investigated to determine the group's influence on the suppression of the desilylation.  We will also investigate whether the use of t-butyldiphenylsilyllithium can prevent cleavage of the sily enol ether even in solvents such as THF which typically promote desilylation but which also promote the Brook rearrangement.  This may be crucial for the successful reaction of alkyl 2-acylaziridines, which are expected to undergo Brook rearrangement much more slowly than the aryl 2-acylaziridines investigated so far.