The Griesbaum Coozonolysis allows the preparation of defined, tetrasubsituted ozonides (1,2,4-trioxolanes) by the reaction of O-methyl oximes with a carbonyl compound in the presence of ozone. In contrast to their traditional role as intermediates in oxidative alkene cleavage, 1,2,4-trioxolanes with bulky substituents are isolable and relatively stable compounds.
The selective synthesis of substituted 1,2,4-trioxolanes has drawn considerable interest following indications that this heterocycle confers potent pharmacologic activity such as in the antimalarial area.
Mechanism of the Griesbaum Coozonolysis
The unmodified ozonolysis of an unsymmetrical alkene produces the intermediate carbonyl compounds and carbonyl oxides nonselectively; these can then react with each other to give a statistical mixture of 1,2,4-trioxolanes.
A coozonolysis (two compounds in presence of ozone) is possible if one precursor generates the carbonyl oxide in situ that then reacts with the second compound - the carbonyl. N-Methyl oximes have been found to be ideal precursors, because they readily react as dipolarophiles in a 1,3-dipolar cycloaddition with ozone. A retro-1,3-dipolar cycloaddition then leads to the formation of the carbonyl oxide and methyl nitrite:
The 1,3-dipolar cycloaddition of the carbonyl oxide with the carbonyl compound gives tetrasubsituted ozonides:
If no carbonyl compound is added, 1,2,4,5-tetraoxanes might be isolated through dimerization of the carbonyl oxide:
Synthesis of Tetrasubstituted Ozonides by the Griesbaum Coozonolysis Reaction: Diastereoselectivity and Functional Group Transformations by Post-Ozonolysis Reactions
Y. Tang, Y. Dong, J. M. Karle, C. A. DiTusa, J. L. Vennerstrom, J. Org. Chem., 2004, 69, 6470-6473.