De Kimpe Aziridine Synthesis
The De Kimpe Azirdine Synthesis allows the generation of various aziridines by the reaction of α-chloroimines with nucleophiles such as hydride, cyanide, or Grignard reagents.
Mechanism of the De Kimpe Aziridine Synthesis
Aziridines are formed by nucleophilic addition to the imino carbon and subsequent intramolecular nucleophilic substitution:
Normally, the intermediate open form cannot be isolated. However, if R''' stabilizes anions, such as in the later mentioned N-(tert-butanesulfinyl)-imines, aziridines can only be formed, if more forcing conditions are applied, for example, with additional base under reflux conditions.
The De Kimpe Azridine Synthesis is suitable for the conversion of both aldimines and ketimines. A synthesis of a simple aziridine is shown, with hydride as the nucleophile:
N. De Kimpe, R. Verhé, L. De Buyck, N. Schamp, Recl. Trav. Chim. Pays-Bas, 1977, 96, 242-246.
However, for certain substrates, for example ketimines in which R' is not equal to R, only mixtures of cis- and trans-substituted aziridines are available with isomer ratios in the range of from 1:1 to 2:3 depending on reaction temperature, rate of addition of the reagents and the scale. However, there are remarkable exceptions of diastereoselective transformations, such as the formation of cis-aziridines from α,α-dichloroarylketimines in the presence of lithium aluminum hydride. Here, the mechanism involves the formation of an azirinium chloride as an intermediate:
The intermediate azirinium chloride is attacked by hydride from the more accessible side.
The use of α-chlorinated N-(tert-butanesulfinyl)-imines enables a diastereoselective synthesis of chiral aziridines. The tert-butanesulfinyl group can later be removed with hydrogen chloride in dioxane:
The situation in these reactions is slightly more complicated, as both the chlorine atom as well as the tert-butanesulfinyl group can form complexes with the nucleophilic reagents used. Typical chelation-controlled transition states look like this: