Stereoselective addition reactions with chalcogen electrophiles

The addition of chalcogen electrophiles to alkenes is investigated using sulfur and tellurium electrophiles. These reagents have been prepared in analogy to the known and well-investigated selenium counterparts.


Introduction
Electrophilic addition reactions to alkenes are known for a long time as key transformations in organic chemistry.Halogen-as well as chalcogen-based methods are widely explored and are now very useful tools in the hands of synthetic chemists.
Before organoselenium reagents became important reagents it was discovered that electrophilic selenium compounds can add stereospecifically to alkenes. 1 Since that time this reaction has been an important tool in the portfolio of organic chemists and is now routinely used even for the synthesis of complex target compounds.Comprehensive reviews on this chemistry have appeared 2,3,4,5,6 and recently the synthesis of chiral selenium electrophiles and their application in asymmetric synthesis has emerged.Herein we describe the synthesis and use of enantiomerically pure sulfur-and tellurium-electrophiles and compare these reagents to the known chiral electrophilic selenium reagents.

Results and Discussion
The addition of chalcogen electrophiles to alkenes are usually stereospecific anti-additions.The additions proceed via the formation of a chalcogeniranium ion of type 1, which are opened in the presence of external nucleophiles to addition products 2. Internal nucleophiles can lead to cyclic products via an endo or via an exo pathway.
We have investigated various enantiomerically pure selenium electrophiles of the general structure 5 and employed these in stereoselective addition reactions of alkenes.Common precursor molecules are the corresponding diselenides 4 which are easily transferred into the aryl selenenyl halides or into other selenium electrophiles with exchanged counterions.Under certain reaction conditions selectivities of up to 98:2 can be obtained.The right choice of the heteroatom Y and of the counterion X -is important for obtaining high selectivities and some systematic studies of their influence have been published. 7,8The diselenides are usually obtained from the enantiomerically pure precursors 3 using either an ortho-metallation or a bromine -lithium exchange depending on the substitution pattern and on other functional groups R. The aryllithium compound is obtained for the subsequent reaction with elemental selenium to yield the diselenides 4 after oxidative work-up.An electron lone pair of the heteroatom Y coordinates to the σ* orbital of the selenium atom as shown in 5. 9  The synthetic route to the corresponding sulfur-and tellurium-electrophiles with a stereogenic center in a benzylic position is similar to the selenium electrophiles mentioned above.The bromine containing precursor 6 could be converted into the disulfide 7 using the method of Pfaltz et al., 11 but the main product in this reaction was the monosulfide 8.The ratio of 7:8 was 1:5 with 90% combined yield.The two compounds were separated by MPLC.Other methods 12 describing the addition of elemental sulfur to the aryllithium reagent at 0 ºC and not at -78 ºC were not successful in this reaction.The corresponding tellurium compound was obtained by ortho-deprotonation of (S)phenylethanol 9, but the ditelluride 10 was obtained in only 7% yield.This compound is lightsensitive and all operations have to be performed in the dark.An addition reaction using the tellurium electrophile generated from 10 was performed but the reaction mixture decomposed rapidly and no addition product could be isolated.The sulfur electrophile 11 was generated from disulfide 7 by reaction with sulfuryl chloride in THF.Reaction of 11 with alkenes 13 -15 yielded cyclization products 16 -18 as shown in Table 1.The yields of the cyclization products were much lower than using the corresponding selenium electrophile, although in the case of the unsaturated carboxylic acid 13 almost similar selectivities were obtained.The strong intramolecular coordination has been proven in the case of selenium electrophiles, its presence in the sulfur electrophiles such as 11 might also be a reason for the low yields in these cyclizations.Although the selectivity in the exo-cyclisation of 13 are almost identical for the sulfur electrophile 11 and the selenium electrophile 12, the results differ in the endo-cyclisation of 14, where a lower selectivitiy is observed with 11.Unoptimized reaction conditions might be one reason, but the smaller size of the sulfur atom versus the selenium atom might lead to a less efficient interaction of the oxygen lone-pair with the σ*orbital of the sulfur atom and, therefore, to lower selectivity as this interaction is crucial for an efficient stereoselective reaction.The intramolecular coordination of the hydroxy-group with the sulfur electrophile should be weakened by protecting the free hydroxy-group.In addition to disulfide 20, synthesized from the precursor 19 in 30% yield, we also prepared the nitrogen-based disulfide 22 starting from (R)-N,N-dimethyl-1-phenylethylamine 21 (9% yield). 12The synthesis yields the free thiols which have then been oxidized to the disulfides using sodium iodide and iron trichloride. 14fter generation of the sulfur electrophile using elemental bromine / silver triflate, only product mixtures were obtained with the alkenes 13 -15.Only the cyclisation of 4-pentenol led to the tetrahydrofuran derivative 23 although in only 10% yield but with a remarkable diasteromeric ratio of 65:35.The corresponding selenium electrophile only generates a 1:1 diastereomeric ratio with this type of substrate. 13he nitrogen based sulfur electrophile generated from 22 did, however, not react at all with the alkenes shown in Table 1 under the reaction conditions.The corresponding selenium electrophile has already been proven to be difficult to react. 15n conclusion, we have shown that disulfides and a ditelluride could be prepared in analogy to the diselenides investigated earlier.The generation of the corresponding electrophiles is possible using the disulfide precursors, although the reaction yields as well as the observed selectivities are disappointingly low.Optimization of reaction conditions and reagents is required to obtain higher yields and selectivities using sulfur-based electrophilic reagents of the structures mentioned above.

Table 1 .
Electrophilic cyclizations with electrophiles 11 and 12 a Determined by NMR.b Not determined.