Example Solvent selection in the reduction of an enamine

The reduction of the morpholine enamine from camphor by the reaction with formic acid was discussed in Chapter 5. In the example below, this reaction was applied to the reduction of the corresponding pyrrolidine enamine. The reaction was conducted without any solvent present, i.e. by adding formic acid dropwise to the hot enamine, and afforded an almost quantitative conversion to the corresponding bornyl pyrrolidine. However, the reaction was not stereoselective and a mixture of endo and exo isomers was formed. The proportions were endo isomer (85 %), exo isomer (15 %). This was regarded as a promising result. 

The reaction showed promising stereoselectivity when it was run without any solvent. As the reaction might involve charged species, it was quite natural to examine whether or not the selectivity could be increased in the presence of a solvent. The solvents used to investigate this were selected according to a maximum spread design in their principal properties, see Fig. 16.2. 

However, no improved stereoselectivity was found in any of the solvents examined. The proportion of the endo isomer was 85—87 %, and of the exo isomer 13—15 %. This was the same result as was obtained without any solvent. The tested solvents span a large range in properties. It can, of course, not be excluded that some solvent might have unique properties for giving an improved selectivity in this reaction. In view of the results obtained, the probability of finding such a solvent must, however, be considered extremely small. The attempts to find a suitable solvent was therefore abandoned, and a method to separate the isomers was developed instead.[l] 

By experiment with deuterated formic acid, it was later found that the reaction proceeds in two steps. The first step is a rapid and reversible protonation to yield an iminium formate, followed by a slow hydride transfer from the formate ion.[l] 

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