Design Bromination of an enamine

Synthesis of bromomethyl ketones can be accomplished by treating the morpholine enamine from the parent ketone with elemental bromine followed by hydrolysis. 

When this procedure was applied to the enamine derived from methyl neopentyl ketone, poor yields ( 60 %) were obtained. This was unexpected, since a variety of other ketones had afforded good yields ( 85 %) by the same procedure. The problem was to determine (7) Why the enamine from methyl neopentyl ketone did not work in this procedure, and (2) what to do about it. 

The procedure involved two steps, bromination and hydrolysis. The poor yield might depend on either or both of these steps Due to steric hindrance, the bromination reaction might not have gone to completion when water was introduced, and/or the hydrolysis was slow and was not completed when the mixture was worked up. To clarify this, the important variables must be identified. It was known from other similar reaction, that the bromination must be effected at low temperature to suppress side reactions, and that the hydrolysis should be carried out not above room temperature. During the hydrolysis step, bromomethyl ketones are susceptible to acid catalyzed rearrangements to the isomeric 3-bromoketone. With these limitations taken into account, the following experimental variables were considered to be able to influence the result. 

Xj the concentration of bromine might possibly have an influence on the rate of the first step. 

The low levels of the variables correspond to the conditions used with other enamine substrates. Under these conditions, the yield of bromomethyl neopentyl ketone was 45 %. To see whether or not the experimental domain is sufficiently large to give an observable variation in the experimental result, the next experiment to be run was with all variables set to their high levels. This afforded a 63 % yield, which is a considerable improvement. To be able to detect which variable(s) was/were critical, the remaining experiments aimed at giving a complete two-level factorial design were run. The results are summarized in Table 5.9. 

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