Modified Julia Olefination
The Modified Julia Olefination enables the preparation of alkenes from benzothiazol-2-yl sulfones and aldehydes in a single step:
The Julia-Kochienski Olefination - a further refinement of the Modified Julia Olefination - offers very good E-selectivity.
Mechanisms of Modified Julia Olefinations
The initial addition of the sulfonyl anion to the aldehyde is not reversible:
Whether the anti or syn intermediate is generated can be influenced to some extent by the choice of reaction conditions:
|A chelate will form with small counterions (Li) and in apolar solvents, leading to a closed transition state.|
|With larger counterions (K) and polar solvents, an open transition state becomes possible.|
The intermediates that form react further to give E- and Z-isomers of the alkene:
A mechanistically related nucleophilic addition of the sulfonyl carbanion to a second equivalent of the BT sulfone leads to a side product.
Since the reaction with the aldehyde occurs faster, it is best to carry out this reaction under “Barbier-like conditions”: in general, the base is added to a mixture of the aldehyde and sulfone.
The benzothiazolyl group (BT) can play several roles: in one, it enables a more or less strongly pronounced complexation that influences the selectivity; on the other hand, it can also undergo nucleophilic substitution at the carbon attached to the sulfonyl group, which then becomes a leaving group. Other (hetero)cyclic substituents can assume these roles, and offer somewhat different selectivity:
Specifically, the pyridinyl sulfone exhibits high Z-selectivity, while the 1-phenyl-1H-tetrazol-5-yl sulfone (PT-SO2R) gives somewhat better E-selectivity than the BT sulfones. The reason for this is the sterically demanding phenyl group, which favors the following transition state:
The 1-phenyl-1H-tetrazol-5-yl sulfones do not have a tendency to self-condense, so they can first be deprotonated with base and then reacted with the aldehyde. This makes possible a far milder reaction process, including reactions with base-sensitive aldehydes.
The following table shows the selectivity and yields for BT and PT sulfones in various solvents, where they are first metalated with various bases and then reacted with an aldehyde.
In contrast to the classical Julia Olefination, the Modified Julia Olefination offers the possibility of saving one or two synthesis steps. In addition, there are fewer problems with scale-up than with the classical variant. The E/Z-selectivity can be controlled by varying the sulfonyl group, solvent and base.
A Stereoselective Synthesis of trans-1,2-Disubstituted Alkenes Based on the Condensation of Aldehydes with Metallated 1-Phenyl-1H-tetrazol-5-yl Sulfones
P. R. Blakemore, W. J. Cole, P. J. Kocienski, A. Morley, Synlett, 1998, 26-28.
Ethyl (benzothiazol-2-ylsulfonyl)acetate: a new reagent for the stereoselective synthesis of α,β-unsaturated esters from aldehydes
P. R. Blakemore, D. K. H. Ho, W. M. Nap, Org. Biomol. Chem., 2005, 3, 1365-1368.