The Ramberg-Bäcklund Reaction allows a base-mediated conversion of α-halosulfones into E or Z alkenes. Z alkenes are often observed with weak bases, whereas strong bases give predominantly E alkenes. Myers' modification and newer synthetic protocols allow an in situ generation of α-halosulfones, so that the readily available sulfones can be used directly without performing a specific and more problematic halogenation step.
Mechanism of the Ramberg-Bäcklund Reaction
The Ramberg-Bäcklund Reaction is a convenient procedure for preparing alkenes, due to the accessibility of sulfones, the clearly defined location of the double bond as alkene rearrangements do not occur under basic conditions, and the broad range of substitution patterns that can be prepared including fully substituted alkenes, cyclobutenes and polyenes. Even polyfunctional molecules can be converted as long as base-sensitive groups are absent.
The anionic mechanism for the Ramberg-Bäcklund Reaction is generally accepted. A rapid deprotonation is followed by a slow cyclization to generate a thiirane dioxide intermediate. In this step, α-iodosulfones react faster than bromo- and chlorosulfones.
Formation of the thiirane dioxide is followed by extrusion of SO2. Here, a concerted, linear cheletropic loss is symmetry forbidden, so the occurrence of dipolar and diradical stepwise mechanisms have been suggested. As the rate of reaction is influenced by the concentration of base, the formation of a hypervalent intermediate is generally accepted, but the question, whether the subsequent decomposition involves a rotationally hindered diradical or a concerted symmetry-allowed non-linear cheletropic pathway has not yet been answered.
The stereoselectivity for weak base and most substrates is well-defined, leading to Z alkenes. Moreover, cis-substituted thiirane dioxides, which have been prepared to elucidate the mechanism, selectively lead to Z alkenes if heated or treated with KOH.
In the reaction with KOH, the selectivity is already well-defined in the cyclization step. There is no epimerization during the formation of the alkene from a pure cis-subsituted thiirane dioxide. The formation of the cis-substituted thiirane dioxides seems to be favored, possibly due to diastereomeric carbanion formation, or attractive dispersion, or steric attraction. However, there is also an epimerization from the cis- to the trans-substituted thiirane dioxide when strong bases are used, as shown for the conversion of the cis-substituted thiirane dioxide. So the overall conversion can be summarized as:
As mentioned above, some substrates give E-substituted alkenes. For example, in α-chlorobenzyl benzyl sulfone, the presence of phenyl as acidifying substituent favors epimerization and leads to the energetically more stable trans-substituted thiirane dioxide:
The same diastereoselectivity can also be observed for the Myers' modification, exemplified by the conversion of dibenzyl sulfone:
However, a recent publication by Taylor shows unexpected Z-stereoselectivity in the Ramberg-Bäcklund reaction of diarylsulfones leading to cis-stilbenes, so the situation is somewhat more complicated for substituted arenes.
For the preparation of α-halosulfones, sulfides can be first chlorinated and then oxidized (first example), or the readily available sulfones can be used, in which an α-position can be deprotonated (for example using BuLi) and subsequently halogenated using an electrophilic halogenating reagent such NCS or NBS. The second example shows a convenient alternative using an alanate as intermediate:
Myers' modification circumvents this often problematic synthetic step by using an in situ halogenation-Ramberg-Bäcklund sequence in the presence of CCl4 as both solvent and halogenating reagent. After halogenation by the solvent, the product undergoes cyclization and olefin formation as know from the unmodified Ramberg-Bäcklund reaction.
One drawback is the production of the highly reactive dichlorocarbene that can undergo addition to electron rich alkenes producing gem-dichlorocyclopropane adducts, which limits the synthetic scope.
As a solution, either phenol or an additional alkene can be added as a carbene scavenger, or some recently reported alternative halogenation reagents can be used. For example, with highly substituted substrates producing electron-rich alkenes, a recent modification by Chan is more suitable with CBr2F2 instead of CCl4, as the produced carbene :CF2 is not as reactive as :CCl2.
For a review of the Ramberg-Bäcklund Reaction covering a multitude of examples and synthetic options such as non-halide leaving groups please refer to the recent publication by Taylor and Casy (Org. React. 2003, 62, 357. DOI).
1,2-Dibromotetrachloroethane: An Ozone-Friendly Reagent for the in Situ Ramberg-Bäcklund Rearrangement and Its Use in the Formal Synthesis of E-Resveratrol
S. C. Söderman, A. L. Schwan, J. Org. Chem., 2012, 77, 10978-10984.
Unexpected Z-stereoselectivity in the Ramberg-Bäcklund reaction of diarylsulfones leading to cis-stilbenes: the effect of aryl substituents and application in the synthesis of the integrastatin nucleus
J. S. Foot, G. M. P. Giblin, A. C. Whitwood, R. J. K. Taylor, Org. Biomol. Chem., 2005, 3, 756-763.