Olefin metathesis reactions of sulfur-containing alkenes and dienes

The olefin metathesis reaction of sulfur-containing olefins is a challenging transformation. However, these molecules are valuable in organic synthesis. In this article the reactivity of sulfides, sulfones and sulfoxides in olefin metathesis reactions is discussed.


Introduction
Since 1995, when the first well-defined ruthenium carbene complexes such as 1a were introduced by Grubbs (Figure 1), olefin metathesis has become a routine process in the manipulation of C-C double bonds. 1 Further improvements of ruthenium pre-catalysts structure, 2 namely the exchange of the one phosphine ligand with an N-heterocyclic carbene, leads to the so-called 'second generation' complexes 1b and 1c. 3 Subsequently, a second generation phosphine free ruthenium complex 4a was independently synthesized by Blechert and Hoveyda 1d. 4 Afterwards, highly active counterparts of complex 1d were synthesized by Blechert 1e (activated via steric interactions) 5a and Grela 1f (activated via electronic interactions).5b,c Nowadays, olefin metathesis has emerged as a versatile and powerful tool for target oriented organic synthesis as well as in material science. 1 Ruthenium-based pre-catalysts display a high functional group tolerance and satisfactory to excellent air and thermodynamic stability (Figure 1).However, further research aimed at developing of new catalysts of improved stability and/or activity is of vital importance.Besides evolutionary improvements of the catalyst structure, research aimed at finding some new reaction conditions that allow more optimal use of known catalysts can be considered as a complementary approach. 6Cross-metathesis (CM), 7 ring closing metathesis (RCM), 1 enyne metathesis and their combinations are commonly used reactions to form C-C double bonds of highly sophisticated molecules. 1

Results and Discussion
Sulfides and thiols.Several sulfur-containing alkenes have been applied as substrates in olefin metathesis reactions.The 'first generation' ruthenium pre-catalysts, such as 1a are known to be poorly or not reactive in the RCM of α,ω-dienes containing sulfide and disulfide moieties, 8a-c whereas Schrock's molybdenum complex 1j was found to be more compatible with these substrates.8d-f Later, Nolan and Mioskowski et al., have published an elegant study to show that the 'second generation' pre-catalyst 1c acts in such transformations extremely well, and can be successfully employed in RCM and CM of allyl substituted sulfides 2a (equation 1), disulfides 3a (equation 1), and dithianes, and even in the self-cross metathesis reaction of thiols 4a (equation 2).9a Allyl sulfides participate in olefin metathesis reaction catalyzed by ruthenium based complexes, and thus have found applications in the site selective modification of proteins via CM reactions performed in water.9b On the other hand, vinyl sulfides are electron rich alkenes that usually do not participate in olefin metathesis reactions due to the formation of Fischer type carbenes.1a We tested the CM reaction of phenyl vinyl sulfide 5a with our standard CM reaction partner (5-hexenyl tertbutyldimethylsilyl ether) in the presence of the very active ruthenium catalyst 1f.Despite many attempts, we found that this reaction indeed does not proceed (equation 3).This result was quite surprising, because we had observed previously that vinyl sulfides participate in CM reactions with vinyl halides (equation 4).CM of 5a performed in neat (E)-1,2-dichloroethene catalyzed by 5 mol% of the highly active complex 1f lead to the desired sulfide 5b with excellent (Z)diastereocontrol (equation 4). 10 It is worth to mention that the use of (Z)-1,2-dichloroethene, instead of the (E) isomer, causes a drop in selectivity and isolated yield.10a The reaction works perfectly well when the catalyst is added portion-wise via a syringe pump over 5 h (95% isolated yield of 5b).Recently vinyl sulfides were used in ring-opening/cross-metathesis sequence 10 (equation 5).In this reaction the ring strain of 7-azanorbornene derivative 6a is a driving force for the reaction with 5a, which proceeds in very high yield (equation 5). 11Ring-opening/crossmetathesis reaction and ring rearrangement metathesis have been intensely studied in the Blechert laboratories.1e An excellent review, presenting many outstanding target-oriented syntheses in this area, was recently published by Blechert et al. 12 These results show that while vinyl sulfides can actually participate in some CM reactions, their use is rather limited.
The sulfone moiety is an important functionality in organic synthesis.Sulfones are useful substrates in many reactions, such as the Julia-Kocienski olefination and Ramberg-Bäcklund reactions.13a Moreover, sulfones are present in some bioactive compounds, for instance vinyl sulfones are well-known covalent inhibitors of Falcipain-2, 14 and were reported to inactivate the enzyme by irreversible addition to the thiol group of an active cysteine site to the electrophilic vinyl sulfone moiety.The CM reaction can be a reasonable method for the synthesis of sulfonecontaining alkenes, completing other approaches known in classical organic synthesis.
The compatibility of remote sulfone moiety with ruthenium and molybdenum-based metathesis catalysts is well established. 13,15The first CM of allyl sulfones catalyzed by ruthenium complexes has been reported by Grubbs. 13b,c Recently, Yao has published a very elegant method for the preparation of cyclic sulfones by RCM or enyne metathesis of various diallyl 7a and 8a (equations 6 and 7) and homoallyl sulfones.13a Yao also presented preparation of α,ω-unsaturated sultams and sultones from unsaturated sulfonamides and sulfonates.13a On the other hand, we previously described that CM of vinyl sulfones is more challenging comparing to allyl sulfones but still possible using commercially available 'second generation' ruthenium complexes (equations 8 and 9). 15Vinyl sulfones are electron poor olefin that are type III alkenes in CM reactions.7a The CM of vinyl sulfones have been than applied in a number of syntheses of natural and biologically active compounds. 14ulfoxides are important intermediates in organic synthesis, especially if containing an asymmetric sulfur atom.To the best of our knowledge, only a few examples of the application of unsaturated sulfoxides in olefin metathesis reactions have been described. 16Liras et al. published an example, where the RCM reaction of a substituted vinyl sulfoxide with a stoichiometric amount of catalyst 1a was employed as the key cyclisation step en route to (±)-securinine, an important member of the Securinega family of alkaloids.16a Bates et al. recently successfully employed RCM of allyl sulfoxide derivatives catalyzed by 1b (10 mol%) in the synthesis of thiazocine-2-acetic acid derivatives.16b Colbert et al. showed an example of CM reaction of a molecule containing a chiral sulfoxide moiety (asymmetric 5-pentene-sulfinyl derivative) in the synthesis of a α-tocopherol derivative.This transformation was forced by use of 20 mol% of the very active complex 1h (using microwave irradiation heating), but only 50% of the desired product was obtained.16c Previously, we had studied CM reactions of vinyl and allyl sulfoxides and found that these compounds were inactive in olefin metathesis using 'classical' reaction conditions. 15While CM of allyl and vinyl sulfones is generally straightforward (equations 8 and 9), we found that when vinyl 11a and allyl sulfoxide 12a were used in the same model reaction only starting material was recovered (equations 10 and 11).Inability of sulfoxides to participate in the CM reaction was initially explained by redox catalyst degradation, as it is known that Fishertype carbenes can be oxidized by sulfoxides. 17Moreover, the sulfoxide moiety could also form stable chelates with ruthenium, thus 'arresting' the active propagating species and slowing down the productive metathesis process. 18Interestingly, Szadkowska et al. reported that the sulfoxide moiety can be actually present in the ruthenium complex 1g, without destroying its catalytic activity in olefin metathesis. 19Having in mind this divergence in the literature, we decided to reinvestigate selected representative CM and RCM reactions of vinyl and allyl sulfoxides.
Comparison between vinyl sulfone 10a and sulfoxide 11a shows that under identical reaction conditions the first was quantitatively converted into the corresponding sulfone 10b, while in the latter case only the starting material was recovered.15b Similarly, in our model CM reaction, promoted by the 'first generation' complex 1a, allyl sulfone 9a was transformed into the desired product 9b (equation 8).In contrast, allyl sulfoxide 12a was practically inert, even when the more active 'second generation' pre-catalyst 1b was used (equation 11).
To our surprise diallyl sulfoxide 13a was quantitatively transformed into desired product 13b in the RCM reaction using only 0.5 mol% of 1b (equation 12) under otherwise the same conditions as used in the previous reaction (equation 11).Having such solid evidence that the sulfoxide group is indeed compatible with ruthenium catalysts, we returned to the CM of allyl sulfoxides that failed previously (equation 13).In a hope to 'force' this reaction, we tested a number of conditions (elevated temperature, concentration, solvents etc), 6 to find that even addition of a Lewis acid (10 mol% of triphenyl borate) was rather ineffective (TON = 1). 18Next, we decided to use fluorinated aromatic hydrocarbons (FAH), the highly activating solvents which were independently developed in Blechert's and Grela's groups. 20It has been proven that FAH solvents can increase the efficiency of the 'second generation' ruthenium catalysts in many olefin metathesis reactions. 20Unfortunately, in the present model reaction of allyl sulfoxide carried out in C6F6 and catalyzed by 10 mol% of 1b only 31 % of desired product was isolated (TON = 3) under these conditions.The vinyl sulfoxide 11a was again completely inert (equation 10), even in the highly-promoting reaction conditions using aromatic fluorinated solvents. 20e present results force us to conclude that while the sulfoxide moiety is in general compatible with ruthenium catalysts, and the RCM of allylic sulfoxides is actually very easy, the related CM reactions of allyl and vinyl sulfoxides are either very difficult or impossible.This is in distinct contrast with the analogous reactions of vinyl and allyl sulfones, which are generally quite straightforward.This difference between sulfones and sulfoxides was also clearly apparent in reactions conducted with more advanced substrates, such as compound 15a studied by us in our current project devoted to steroid side-chain modifications via CM (equation 14).While the reaction of 10a with 15a gave the expected product 15b in a satisfactory isolated yield (55% of (E) isomer exclusively), the analogous CM reaction between 15a and allyl sulfoxide 14a gave a complicated reaction mixture.© ARKAT-USA, Inc.

Conclusions
In conclusion: the differences in reactivity of olefins containing sulfur atom on different oxidation states are presented. 21The most challenging transformations are cross-metathesis reactions with allyl and vinyl sulfoxides.We confirmed our recent observation that vinyl sulfoxides are unreactive, while allyl sulfoxides can react, but in general are very poor partners in CM reaction.In contrast, the RCM of dienes containing the sulfoxide group, as well as RCM and CM reactions of unsaturated sulfones, are straightforward.

Experimental Section
General.All reactions were carried out under argon atmosphere in pre-dried glassware using Schlenk techniques.The solvents: octafluorotoluene (FluoroChem), hexafluorobenzene (FluoroChem), toluene (Fluka), dichloromethane (Merck) and 1,2-dichloroethane (Aldrich) were dried by distillation over CaH2 under argon and stored under argon atmosphere.Commercially available ruthenium pre-catalysts were obtained from Sigma Aldrich 1a, 1b, 1d or Apeiron Catalysts 1f (www.apeiron-catalysts.com)and used as received.Analytical thin layer chromatography (TLC) was accomplished using Merck TLC aluminum sheets (silica gel 60 F254).Flash column chromatography was carried out on Merck silica gel (230-400 mesh).NMR spectra were recorded with Bruker (500 MHz) or Varian (200 or 400 MHz) machines in CDCl3; chemical shifts (δ) are given in ppm relative to TMS, coupling constants (J) are in Hz.Multiplicities are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br).MS (ESI) spectra were recorded on Mariner Perseptive Biosystems, Inc. MS (TOF MS FD) spectra were recorded on Waters GCT Premier.IR spectra were recorded on a Perkin-Elmer Spectrum One FTIR spectrometer with Diamond ATR accessory.Micro-analyses were provided by Institute of Organic Chemistry, PAS, Warsaw.