Part I
Chapter 1
Synthesis of alk-1-enyl sulfones and
sulfoxides: state of the art
1.1 Introduction
In the past few decades unsaturated sulfones and sulfoxides have been widely employed as useful intermediates in organic synthesis. Sulfones display their synthetic potential in a wide range of transformations,3,4,5,23,24,25,26,27,28,29,30,31 which are particularly useful due to the large stereoelectronic control this functional group can exert.32,33,34,35,36,37,38,39 These characteristics have led to the description of sulfones as chemical chameleons,40 are due to their ability to stabilize adjacent carbanions and to be displaced by nucleophiles.
The chemistry of unsaturated sulfoxides is characterized by diverse and interesting reactivity,41,42,43 and these compounds have proven to be extremely valuable intermediates in organic synthesis. Polarization of the unsaturated bond by the sulfone and the sulfoxide functional group allows a large number of chemical transformations. Moreover, sulfoxides show their full potential in the field of asymmetric synthesis. It is well known that chiral sulfoxides can exert a great level of stereochemical control on adjacent transformations.44,45 This feature has contributed to their use as chiral building blocks in the synthesis of natural and bioactive compounds.21 A great deal of attention has been paid to the development of efficient synthetic approaches to sulfones and sulfoxides: the most widespread methodologies will be discussed later in this chapter. Given the scope
of this thesis work, the analysis of the literature focus on the synthesis of achiral compounds.
1.2 Synthesis of alk-1-enyl sulfones
As stated in the introduction to this chapter, synthesis of unsaturated sulfones has been widely investigated and reviewed2,46 during the past few decades. Due to the chemical versatility of the sulfone moiety, different synthetic approaches have been developed, depending on the particular feature to be considered. The possible pathways will be here divided in four main cathegories, depending on the reaction site considered:
1. Synthesis from other sulfur derivatives (including oxidative routes) 2. Formation of new C-S bonds
3. Elimination of good leaving groups in position β to the sulfur atom (including addition/elimination sequences)
4. Condensation reactions
It will be clear from the following sections that the first approach does not provide a general approach to sulfones, because different sulfur derivatives, (e.g. sulfides or acetylenic sulfoxides) which are necessary for those synthesis, are difficult to prepare with broad generality and regioselectivity. On the other hand, many of the reported approaches often presents remarkable stereoselectivity problems and are useful in the synthesis of sulfones from conformationally fixed alkenes. As it will be shown, one of the most promising and versatile fields in the synthesis of sulfones is the direct formation of the C-S bond, which will be the topic of this thesis work.
1.2.1 Synthesis from other sulfur derivatives
In this section attention will be focused on the synthesis of sulfones which do not involve formation of new C-S bonds, and can be roughly divided into two classes: oxidative routes starting from sulfides and non-oxidative routes, most of which employ alkynyl sulfones as starting materials. Due to their importance, a significant part of this section will deal with oxidative routes, whereas approaches starting from different sulfones will be discussed in the last part; particular attention will be devoted to the partial reduction of acetylenic sulfones.
Oxidative routes to sulfones
Oxidation of sulfides and sulfoxides represents the most general and widely employed synthetic pathway for the synthesis of sulfones,47 and much work48,49 has been done to provide efficient and selective protocols amenable to the synthesis of unsaturated sulfones. The main problem with this strategy, as long as alk-1-enyl sulfones are concerned, is the possibility of oxidation of the double bond. Sulfoxides are intermediates in the oxidation process of sulfides to sulfones; for this reason, oxidations to sulfoxides and sulfones are usually studied toghether. It is often sufficient to add just one molar equivalent of oxidizing agent to a sulfide in order to obtain the sulfoxide in high yields; as reported in Section 1.3.1, many oxidizing systems used are the same both for sulfones and sulfoxides.50
It has been known for a long time51 that acetylenic sulfides can be efficiently and simply oxidized to the corresponding sulfones in good yields by treatment with hydrogen peroxide in acetic acid. Many common oxidizing agents, such m-chloroperbenzoic acid (MCPBA), have been successfully employed in the oxidation of acetylenic sulfides to sulfones.52,53 Perbenzoic acid54, Oxone™55 and other oxidizing agents50 are widely employed in the preparation of acetylenic sulfones; the same protocol is applicable to vinyl sulfides. As reported in Scheme 1.1, fluorinated vinyl sulfides react smoothly with MCPBA56 affording difluoro alk-1-enyl sulfones, in good yields (77-88%) under mild reaction conditions. S S O O MCPBA, CH2Cl2, r.t. 77-88% F R F
R= Me, Et, n-Pr, c-Hex, Ph
R F F
Scheme 1.1: Oxidation of alk-1-enyl sulfides to sulfones with MCPBA
Recent oxidative approaches to sulfones have sought to find more chemoselective or more environmentally friendly systems. The periodic acid/CrO3
couple was shown to be superior to other systems in the preparation of sulfones, for what concerns selectivity and handling.57 Oxidations processes performed whith these reagents tolerate a wide range of functionalities (e.g. alcohols, aldehydes, nitriles), and are very valuable for the synthesis of functionalyzed unsaturated sulfones. Oxidation with Oxone™, described for the first time in 1981,58 has been later modified by using tetrabutylammonium-Oxone™ system
(TBA-Oxone™)59. Contrarily to the original procedure, the improved procedure does not require the use of water or ethanol and affords alk-1-enyl sulfones in good yields under anhydrous conditions. This protocol appears to be very chemoselective, and although slower than the corresponding oxidation with Oxone™,55 it constitutes a valuable oxidizing system.
S R S R O O R=H, Ph H2O2 (2 equiv.), EtOH r.t., 15min F20TPPFe (0.1-0.25%) F20TPPFe=iron tetrakis-(pentafluorophenyl)porphyrin 93-94%
Scheme 1.2: Oxidation of alk-1-enyl sulfides to the corresponding sulfones using H2O2 and F20TPPFe as catalyst
The long-time known oxidation with hydrogen peroxide has been extensively studied, and a new catalyst based on a Fe-porphyrine complex has been recently60 introduced (Scheme 1.2). The reaction is fast, high-yielding, and affords sulfones or sulfoxides nearly selectively depending on the stoichiometric ratio between H2O2 and the sulfide. Conjugated or isolated double bonds are unaffected.
MMPP OMe BnO S OH O p-Tol MeOH, r.t., 2-3h OMe BnO S OH O p-Tol O O OMe BnO O MsCl, Py 0 oC, 12-24h S O O Tol-p
Scheme 1.3: Oxidation of sulfides to the corresponding sulfones in the synthesis of vinyl sulfone-modified pent-2-enofuranosides
Magnesium monoperoxyphtalate (MMPP) has been recently61 reported to oxidize sulfides to sulfones in the synthesis of anomerically pure vinyl sulfone-modified pent-2-enofuranosides and hex-2-enopyranosides, without degradation of the other functional groups present in the molecule. The β-hydroxy sulfone affords the vinyl derivative after mesylation and base-induced elimination. This reaction pathway is reported in Scheme 1.3.
Non-oxidative routes to sulfones
Many interesting approaches to structurally complex alkenyl sulfones hinge on the chemistry of unsaturated sulfones themselves. In this context, vinyl and acetylenic sulfones are versatile building blocks; furthermore vinyl sulfones,
whose preparation is rather trivial, are often commercially available, whereas acetylenic sulfones are readily prepared, as discussed later in this chapter.
Cross-metathesis has recently been used in the synthesis of sulfones, starting from vinyl sulfone and the appropriate alkenes.62 The reaction shows a good functional group tolerance and complete E stereoselectivity. The major drawback is the incompatibility of many metathesis catalysts with the sulfone functional group. Moreover it seems that there is no general catalyst suitable for all substrates, and choice of the appropriate catalyst is then rather empirical. An example that illustrates the synthetic potential of the reaction is shown in Scheme 1.4. Ph S O O + R Ph "Ru" CH2Cl2, rfx., 3-24h Ph S O O Ph R R= OH, OTBS 53-71%
Scheme 1.4: Synthesis of alk-1-enyl sulfones by cross-methathesis reaction between vinyl sulfone and alkenes
This protocol is not amenable to the synthesis of alk-1-enyl sulfoxides; it has been reported that the sulfoxide functional group poisons the catalyst.
Arylboronic acids easily react with vinyl sulfones in a Mizoroki–Heck type reaction with Pd(OAc)2 as catalyst. The reaction proceeds in good yields only in
the presence of oxygen.63 Vinyl and alkyl boronic acids are completely unreactive. This method is interesting because it makes it possible to transfer β-aryl substituted alkenyl chains, regardless of the nature of substituents on the aromatic ring; on the other hand, the reaction fails when an alkyl-substituted alkenyl chain is transferred. The reaction is shown in Scheme 1.5.
Ph S O O + Pd(OAc)2 (10 mol%) Na2CO3 (2 equiv.) DMF, O2, 60 oC S Ph O O Ar
Ar= p-Tol, m-NO2Ph, p-BrPh, p-MeOPh
70-84% Ar B(OH)2
Scheme 1.5: Synthesis of alk-1-enyl sulfones by reaction of a vinyl sulfone with arylboronic acids
The triple bond of aryl sulfonyl acetylenes is susceptible to the attack of carbon nucleophiles. Depending on the nature of the organometallic reagent and on the stoichiometric ratio between reagents, it is possible to obtain alkenyl or alkyl
sulfones. With appropriate choice of the organometallic system, it is possible to transfer a wide range of residues.
Many organometallic reagents have been used in the preparation of alkenyl sulfones by this approach: cuprates give the most interesting results. Addition of organocopper derivatives can be stereoselective depending on the nature of the reagent.64 Grignard reagents in the presence of CuBr (Scheme 1.6, reaction a)65 easily react with alkynyl sulfoxides, affording the addition products in low stereoselectivity; cuprates (Scheme 1.6, reactions b and c)64,66,67 and dialkyl zinc, in the presence of copper salts (Scheme 1.6, reaction d),67 give the desired products in variable yields and stereochemical purities. Grignard reagents and organolithium compounds, in the absence of catalysts, often react by a different pathway displacing the sulfonyl group.68
Ph S O O + CuBr, THF-78 oC Ph S O O Me 80% EtMgBr + 1) Et2O, -70 oC, 30min 2) MeOH Ph S O O Et R= i-Pr, t-Bu, α-Fur
82% ZnEt2 Me Me Ph S O O + Ph S O O R' 41-70% R' R Me3SiO Cu(BF4)2 CH2Cl2, 25 oC, 2-3h
H2O (1.5 equiv.), DMAD (1 equiv.)
R''= CH3, CH(OH)CH(CH3) Ph S O O Ph S O O Ph 90% Ph Me3Si
1) (Me3SiCH2)2CuMgCl
2) Allyl bromide Ph S O O Me R O Cu(BF4)2 a) b) c) d) Me
Scheme 1.6: Addition of organometallic derivatives to acetylenic sulfones
Cp2Zr(H)Cl (Schwartz’s reagent) reacts with the triple bond of acetylenic
sulfones, affording the (Z)-alkenyl zirconium derivatives in excellent yields and nearly complete regio- and stereoselectivity; the resulting intermediates have proven to be valuable in the synthesis of new sulfur-containing compounds. Hydrolysis of the alkenyl zirconium derivative leads to the (E)-alk-1-enyl sulfone.
When electrophiles other than water are added, substituted alkenyl sulfones can be obtained69 (Scheme 1.7). The stereoselectivity of the hydrozirconation process is complete for aryl-substituted alkynyl sulfones affording the (E)-isomer, whereas alkyl substituted sulfones often give poorer results, leading to mixtures of E and Z isomer. 2) E+ Ar S O O Ph 51-70% Ar S O O Ph 1) Cp2Zr(H)Cl, r.t., 5min E
Scheme 1.7: Addition of Schwartz’s reagent to acetylenic sulfones and products arising after quenching with electrophiles
The β-zirconyl sulfone intermediate can also react with different reaction partners, usually in the presence of copper halides or other transition metal catalysts; this feature can be used in the synthesis of more synthetically interesting compounds,70 as reported in Scheme 1.8. The reactivity of alkenyl zirconium intermediates opens a practical route to sulfonyl enynes, which are obtained by coupling with alkynyl halides in the presence of copper chloride.
Ph S O O Ph 51% Ph S O O Ph Cp2Zr(H)Cl Ph S O O Ph Cp2ClZr Allyl bromide Pd(PPh3)4 O Cl R CuBr Ph S O O Ph 65-70% R O Br R 62-70% Ph S Ph O O R r.t., 5min CuCl
Scheme 1.8: Reactions of β-zirconyl sulfone derivatives
Addition of Mg phenylselenate to acetylenic sulfones provides very versatile intermediates which can further react with carbonyl compounds (Scheme 1.9). The reported reactions are typical of organomagnesium derivatives.71,72
Unfortunately, formation of the bimetallic alkenyl sulfur derivative is not stereoselective, leading to a mixture of E and Z products. Furthermore, the two
isomers tend to equilibrate quickly to a 1/1 ratio. This leads, upon addition of an aldehyde, to the formation of a mixture of stereoisomers.
76% Ph S O O Ph PhSeMgBr Ph S O O Ph PhSe H2O 75% -20 oC, 5min MgBr Ph S O O Ph PhSe HO Cl Ph S O O Ph PhSe H Cl H O
Scheme 1.9: Addition of PhSeMgBr to acetylenic sulfones and subsequent reactions
The protocol has been improved by mixing the aldehyde and the acetylenic sulfone in the presence of Mg phenylselenate. Under these conditions, the aldehyde efficiently traps the organomagnesium intermediate and gives the (Z)-isomer of the secondary alcohol as the sole product (Scheme 1.10).
Ph S O O Ph PhSeMgBr 75% -20 oC, 5min Ph S O O Ph PhSe HO Cl Cl H O + + THF/CH2Cl2
Scheme 1.10: Addition of PhSeMgBr to acetylenic sulfones in the presence of aldehydes
Hydrogenation of acetylenic sulfones with the Lindlar catalyst gives (Z)-alk-1-enyl sulfones or unreacted starting material, depending on reaction conditions.73,74 Dry hydrogen bromide and chloride add chemo- and regioselectively to sulfonyl acetylenes, in the presence of copper halides, affording β-halo alkenyl sulfones in good yields (Scheme 1.11).50
Ph S O O HX, CuX Ph S O O X H X= Cl, Br
Scheme 1.11: Addition of dry hydrogen halides to benzenesulfonyl acetylene
β-Iodo triflones, obtained by reaction of lithium iodide in glacial acetic acid with benzenesulfonyl acetylene, have been further modified to dienyl triflones75
by Stille coupling. The ability of alkynyl sulfones to easily undergo radical additions opens a synthetically useful route to alk-1-enyl sulfones. In addition, it was reported that in the presence of the Lewis acid Cl2AlEt, alkenes and alkynyl
sulfones undergo an ene reaction to yield alkenyl sulfones76 (Scheme 1.12). The reaction is reported to be quite general for cylic and acyclic alkenes, although highly variable yields (20-89%) are obtained.
Ph S O O Et2AlCl Ph S O O H + 66%
Scheme 1.12: Ene reaction of alkenes with acetylenic sulfone in the presence of Lewis acids
1.2.2 Sulfones
via formation of new C-S bonds
Formation of sulfones via direct formation of C-S bonds is a powerful tool in the synthesis of alk-1-enyl sulfones, although somewhat less employed than the methods described in the previous section. The interesting feature of this approach is the possibility to obtain target products with a limited number of synthetic steps, starting from commercially available reagents. Moreover, in many approaches the double bond stereochemistry of the starting reagents is already defined, and high degrees of stereospecificity can be achieved. It is possible to classify the methodologies resulting in the formation of C-S bonds into two main groups:
1. Nucleophilic substitution at sulfonyl sulfur by alkenyl derivatives 2. Addition of sulfur derivatives onto alkynes
The first approach involves the use of organometallic reagents, which react either in the presence of transition metal catalysts or by radical mechanism, whereas the second one mostly involves radical reactions of sulfur derivatives. The analysis of synthetic methods will be divided into two parts according to the above classification.
Nucleophilic substitution at sulfonyl sulfur with alkenyl derivatives
The formation of new C-S bonds to obtain unsaturated sulfones has been widely studied. It was claimed that aryl sulfonyl chlorides undergo a cross-coupling reaction with alkenyl stannanes in the presence of palladium complexes as catalysts.77 The reaction (Scheme 1.13) seems to be general for many aryl
sulfonyl chlorides and alkenyl stannanes. Evidence for the presence of a radical mechanism78 is provided by the otherwise inexplicable lack of reactivity of tributyl vinyl stannane, which is rationalized with the poor stability of the vinyl radical. R S Cl O O R=Ar, Me n-Bu3Sn R' + Pd(PPh3)4 70 oC, 15min R S O O R' + n-Bu3SnCl 60-90%
Scheme 1.13: Reaction between alkenyl stannanes and sulfonyl chlorides in the presence of palladium catalyst
Moreover, it was recently reported79,80 that sulfonyl chlorides oxidatively add
to palladium or nickel catalysts and the resulting species undergo desulfonylation by SO2 elimination.81
Whatever mechanism is involved, the reaction is interesting in consideration of the wide availability of sulfonyl chlorides, as well as the simple synthetic procedure and good yields. The need for preparing alkenyl stannanes constitutes a limitation for this procedure.
Alkenyl zirconium derivatives have been claimed82 to react with aryl or alkyl sulfonyl chlorides in the absence of catalyst, affording alkenyl sulfones under mild reaction conditions and short reaction times. As shown in Scheme 1.14, hydrozirconation and the subsequent coupling reaction are both stereoselective, and the pure (E)-isomer is recovered in satisfactory to good yields. Alkenylzirconium derivatives are compatible with a large number of functional groups, and this feature makes the reported method suitable for the preparation of functionalized sulfones. R Cp2Zr(H)Cl, THF 30min-1h, r.t. ClCp 2Zr R R'SO 2Cl 1h30min-3h, 40 oC R' S O O R
R=Ar, Alk R'=Ar, Alk
50-78%
Scheme 1.14: Alk-1-enyl sulfones starting from organozirconium derivatives and sulfonyl chlorides
The drawback of this synthetic approach is the fact that zirconium derivatives are highly expensive, and their use is thus confined to the preparation of sulfones on a small scale.
A recent approach reported by Fuchs et al.75 allows the synthesis of triflones by nucleophilic attack of acetylides on triflic anhydride. Addition of lithium acetylides to triflic anhydride provides the triflone in very good yields (75-87%). The addition of triflic anhydride to the acetylide causes the formation of substantial amounts of diacetylenic byproducts, arising from the substitution of the triflone moiety by the organometallic reagents. This method, shown in Scheme 1.15, gives easy access to a diverse group of alkynyl triflones. Further reaction with lithium iodide and acetic acid in THF, under mild conditions, affords β-iodo alkenyl triflones in very good yields.
75-87% CF3 S O O R I Li R +(CF3SO2)2O -78 oC, 30minEt2O S CF3 O O R LiI, AcOH THF, 0 oC, 15min 93-95%
Scheme 1.15: Synthesis of alkynyl triflones starting from triflic anhydride and lithium acetylides
Palladium-catalyzed reactions can be used in the synthesis of alkenyl sulfones from alkenyl triflates and sodium sulfinates. According to the proposed mechanism, the triflate adds oxidatively to the palladium catalyst. Sodium aryl sulfinate substitutes the triflate ligand on the palladium center. Reductive elimination affords the alkenyl sulfone. This method has been succesfully applied to the synthesis of many cyclic aryl alkenyl sulfones in moderate to good yields;83 an example is reported in Scheme 1.16.
OTf + NaO2S Me Pd2(dba)3 Xantphos Cs2CO3 toluene 60 oC S Me O O
Scheme 1.16: Synthesis of alkenyl sulfones from alkenyl triflates and sodium sulfinates using a Pd catalyst
Copper(II) sulfinates can be prepared from sulfinic acids and copper carbonate, or used in situ, reacting smoothly under sonochemical conditions with alkynyl halides, and affording alkynyl sulfones in moderate to good yields. Acetylenic iodides give very good yields of the sulfone, whereas the use of bromides leads to substantial amounts of byproducts; as a consequence, the yields of the sulfone drastically drop. Yields are also dependent on the nature of the acetylenic system used. In particular, phenylacetylene gives the best results, whereas
alkyl-substituted acetylenes react in poor yields.84 The reaction is shown in Scheme 1.17. I Ar' S O O Ar (Ar'SO2)2Cu + THF Sonication Ar 49-94%
Scheme 1.17: Synthesis of alkynyl sulfones from alkynyl iodides and copper sulfinates under sonochemical conditions
Although not widely used, alkenyl mercury halides react with sulfinates under photochemical conditions85 affording the corresponding alkenyl sulfones in moderate to good yields, with complete stereospecificity. The reaction works well with both aryl and alkyl sulfinates, and substitution on the alkene is tolerated. Vinyl mercurials which are sterically hindered at the α position to the metal atom (R’’’, Scheme 1.18) fail to afford the coupling products. Aryl and alkyl mercury halides do not give any product with this process.
31-85% R SO2Na R' R''' R'' HgX hv 15-40h R S R'' R' R''' O O +
Scheme 1.18: Synthesis of alkenyl sulfones by photoinduced reaction between alkenyl mercury halides and sodium sulfinates
Addition of sulfur derivatives onto alkynes
This approach is based on the tendency of sulfur derivatives to react under radical conditions. Sulfonyl radicals, generated by photoinduced reaction starting from aryl sulfonyl iodides, stereoselectively add to alkynes,86 affording (E)-β-iodo alkenyl sulfones in good yields (Scheme 1.19).
69-87% + S Me I O O R' R hv Et2O S O O I R Me R'
Scheme 1.19: Synthesis of β-iodo alkenyl sulfones by photoinduced reaction of sulfonyl iodides and alkynes
Addition of sulfonyl chlorides and bromides to acetylenes in the presence of copper (II) chloride affords α-chloro alkenyl sulfones. This reaction gives mixtures of cis and trans products via a radical pathway;87,88 studies have been performed to improve the stereoselectivity.89,90 In the absence of light, sulfonyl
bromides selectively afford the trans product.91
Sulfonyl chlorides add to terminal and internal alkynes, in the presence of cuprous chloride, affording β-chloro vinyl sulfones.92 Yields are, however, modest
and variable (10-58%), and the reaction is not completely stereoselective, affording E/Z mixtures where the major isomer depends on the polarity of the solvent.
Free-radical selenosulfonylation of acetylenes is a useful synthetic route to β-selenosubstituted vinyl sulfones,93,94,95 which are in turn readily susceptible to
further transformations.96 An example of the applicability of selenosulfonylation followed by substitution and applied to the synthesis of alkenyl sulfones is reported in Scheme 1.20. 52-94% + Ar S SePh O O R' R AIBN Ar S O O PhSe R R' R''CuSePhLi 52-94% Ar S O O R'' R R'
Scheme 1.20: Selenosulfonation of acetylenes under radical conditions and substitution of selenide with copper reagents
Subsequent extensions have been performed on enynes.97 The competition between 1,2 and 1,4 addition causes a remarkable variability of yields, which strongly depend on the nature of the enyne employed; moreover stereoselectivity is, in most cases, incomplete.
60-92% SeR2 Ph Ph S O O RO PhSO2Na R'OH 3h Ph 76-79% Ph S O O R2Se PhSO2H 3h Ph i-PrOH Li R 73-86% Ph S O O Ph R a) b) Ph S O O R2Se Ph 1 2 3 H RO
-Scheme 1.21: Addition of sulfinyl derivatives to alkynyl selenonium salts and further modification of the selenonium intermediate.
Use of organoselenium species in the synthesis of alk-1-enylsulfones is not limited to the above reported reactions. Organoselenium species have been used98 in the synthesis of β-functionalyzed vinyl sulfones. In this process, it has been shown that alkynyl selenonium salt can react with sodium benzenesulfinate. Intermediate 1 (Scheme 1.21, path a) is formed in protic solvents, and subsequent addition of alkoxide stereoselectively affords the β-alkoxy substituted alkenyl sulfones. When sulfinic acid is used in the first step, intermediate 2 is formed, which can be reacted with different nucleophiles (Scheme 1.21, path b). In the latter case, the use of alkynyllithium derivatives leads to enyne sulfones 3 in good yield (73-86%).
1.2.3 Sulfones
via addition-elimination of good leaving groups
This approach represents one of the best known methods for the synthesis of alk-1-enyl sulfones, and has been reviewed in the case of cycloalkenyl sulfones.2
The most common strategies are chlorosulfenylation/oxidation/elimination99,100 or
chlorosulfonylation/elimination sequences, whose general pathways are depicted in Scheme 1.22.
R R' ArSX R R' RCO 3H X SAr R R' X SO2Ar elim R R' SO2Ar ArSO2X X= Hal,OR
Scheme 1.22: Common strategies for the synthesis of alkenyl sulfones from stereodefined olefins
These approaches have remarkable synthetic applicability when the starting alkene is conformationally fixed and hence the stereochemistry of the resulting sulfone is defined. This feature makes the reported approach the method of choice for the synthesis of cycloalkenyl sulfones, whereas its applicability decreases when applied to acyclic alkenes: in this case E/Z mixtures are often produced.
Additions of sulfonyl chlorides to conformationally defined alkenes,101102 dienes103 and trienes in the presence of copper chloride as catalyst opens up a new route to alkenyl, dienyl and trienyl sulfones, which can be obtained from the addition products by simple treatment with triethylamine at room temperature (Scheme 1.23); yields are modest.90 As reported, this strategy has been applied to the synthesis of acyclic dienyl sulfones, but stereochemical problems arise and complex E/Z mixtures are formed.102
+ p-Tol S Cl O O CuCl S Cl Tol-p O O Et3N 44% C6H6, r.t., 2h S Tol-p O O 94%
Scheme 1.23: Copper-catalyzed addition of sulfonyl chlorides to dienes followed by elimination
Addition of sulfonyl chlorides to the double bond in the presence of copper (I) or (II) salts as catalysts occurs when silyl ethylene is used.88 In this case elimination of hydrochloric acid with triethylamine affords the pure (E)-isomer in acceptable yields (70-74%). β-Acetoxy alkyl sulfones are interesting starting materials for the synthesis of alkenyl sulfones by means of elimination reactions.25
Radical addition/elimination sequences are valuable, considering ability of the sulfur atom to stabilize adjacent radicals. As reported in Section 1.2.2 addition to acetylenes can be exploited in a direct synthesis of alkenyl sulfones. Differently from what observed in the reaction with acetylenes, sulfonyl iodides are completely unreactive towards alkenes. Addition of a catalytic amount of copper (II) chloride causes the rapid formation of the β-iodo alkyl sulfone, as shown in Scheme 1.24. Upon basic treatment these intermediates can evolve to alkenyl sulfones which are isolated in good yields (50-75%).104 Given the fact that sulfonyl iodides are rather unstable, these intermediates are prepeared immediately prior to their use or stored for short times at low temperature.
66-95% + S I O O R CH 3CN R' CuCl2, Et3NI 0-40 oC, 2-4h Ar R R' I S Ar O O Et3N C6H6, r.t. 76-90% R R' S Ar O O
Scheme 1.24: Synthesis of alk-1-enyl sulfones by addition of sulfonyl iodide to alkenes followed by base-induced elimination
A closely related radical addition-elimination sequence, which affords unsaturated sulfones in good yields, has been recently reported.105 In this sequence (Scheme 1.25) styrenes react with sodium sulfinate, cerium ammonium nitrate (CAN) and sodium iodide, giving the products in good yields. Linear alkenes afford vinyl sulfones in similar yields, while cyclic alkenes give poor results. The proposed mechanism involves the addition of the sulfinyl radical to the alkene, followed by reaction with iodine and subsequent in situ HI elimination to give the unsaturated sulfone; CAN may have the role of radical initiator.
+ SO2Na R CH3CN CAN, NaI 0 oC, 45min p-Tol 63-87% R S Tol-p O O
Scheme 1.25: Synthesis of alk-1-enyl sulfones by CAN-mediated reaction of sodium sulfinate with alkenes
β-Sulfonyl acetals undergo stereospecific elimination in the presence of n-butyllithium, to afford intermediate 4 (Scheme 1.26). In the presence of two molar equivalents of n-butyllithium, compound 4 is regioselectively lithiated at the α-position vs. the sulfonyl group. Further reaction with suitable electrophiles can give a variety of vinyl sulfones in acceptable to good yields (Scheme 1.26).106
56-87% OMe S Ph O O OMe n-BuLi OMe S Ph O O 1) n-BuLi OMe S Ph O O E 2) E+ 4
Scheme 1.26: Synthesis of trisubstituted alkenyl sulfones by reaction of β-sulfonyl acetal with
n-butyllithium and electrophiles
β-Hydroxy sulfones are useful precursors to alkenyl sulfones. Treatment with MsCl and pyridine affords the alkenyl sulfones under mild conditions. This approach has been employed in the synthesis of enantiomerically pure γ-hydroxy vinyl sulfones.107 The necessary β keto sulfones can be easily obtained by reaction of α-lithiated alkyl sulfones with N-acyl-benzotriazoles.108
Selenosulfonation of alkenes has been studied in order to achieve regio- and stereospecific approaches to alk-1-enyl sulfones. It was found109,110,111 that selenosulfonates add to olefins at room temperature in the presence of boron trifluoride or, at higher temperatures, in absence of catalyst. The resulting β-seleno sulfones can be converted to alk-1-enyl sulfones by simple treatment with MCPBA followed by spontaneous selenoxide fragmentation, which affords products in very good yields and excellent stereochemical purities. The whole transformation is illustrated in Scheme 1.27.
62-89% + S SePh O O R CH 2Cl2 R' BF3 OEt2 r.t., 18-27h R PhSe R' R'' S Ar O O MCPBA CH2Cl2, r.t. 77-100% R R' S Ar O O R''
.
R R''Scheme 1.27: Addition/elimination sequence of selenosulfonates and alkenes
Analogously to the selenosulfonation of alkenes, formation of sulfonyl mercury compounds, followed by elimination, represents a good method for obtaining alkenyl sulfones. It was reported112 that sodium sulfinate adds stereoselectively trans to alkenes in the presence of mercury (II) chloride. The reaction proceeds in water at room temperature, and the resulting sulfonyl mercury derivatives 5 give alkenyl sulfones via reaction with bromine and then with excess of triethylamine.
73-96% + H2O, r.t. S Ar O O ClHg R R' 1) Br2, C6H6, r.t. 59-84% Ar S O O R R' R R' ArSO2Na HgCl2+ 24-46h 2) Et3N (3 equiv.) 5
Scheme 1.28: Synthesis of alkenyl sulfones through sulfonyl mercury intermediates
The process is shown in Scheme 1.28; overall yields in sulfones are acceptable. Stereoselectivity is good only when the reaction is carried out on cyclic alkenes. The extreme toxicity of organomercury compounds is a strong limitation to this method.
1.2.4 Sulfones
via condensation reactions
Condensation reactions are a widely employed and high-yielding pathway to alk-1-enyl sulfones. In the past few decades attention was directed towards the use of the Horner-Wittig reaction and the Knoevenagel condensation of aldehydes with alkyl sulfones. The Horner-Wittig approach, starting from sulfonomethyl phosphonates, was proposed as a practical route to alkenyl sulfones. The starting material is lithiated at low temperatures and the resulting anion is then added to the appropriate carbonyl derivative (Scheme 1.29). Unsaturated sulfones are thus obtained, usually with excellent (E) stereochemical purities when aldehydes are employed,113 while the use of ketones often leads to isomeric mixtures.
S Ph (EtO)2P O O O 1) BuLi 2) R1 R2 S O Ph O 72-97% O R2 R1
Scheme 1.29: Horner-Wittig approach to unsaturated sulfones starting from sulfonomethyl phosphonates
The need to separately prepare alkyl sulfonyl phosphonates, which requires an additional synthetic step, represents the main drawback of this approach. Efforts have been devoted to the development of a one-pot Horner-Wittig reaction. Two examples among the many procedures available will be briefly described here. Sulfonyl fluorides had been used for the synthesis of sulfonyl-stabilized methylenetriphenylphosphoranes.114 Recently it has been reported that it is possible to achieve, with an analogous process, the one-pot synthesis of alkenyl sulfones.115 Addition of the appropriate aldehyde to the anionic intermediate 6 (Scheme 1.30) leads to the desired product in reasonable yield; the stereochemistry of products is usually E.
R (EtO)2P O 1) LiHMDS (2 equiv.)-78 oC R' S O Ph O 52-75% 2)PhSO2F -78 oC to r.t. S (EtO)2P O R Ph O O O H R' -78 oC to r.t. 1) 2) H2O R 6
Scheme 1.30: Wittig-Horner approach to unsaturated sulfones by in situ formation of sulfonomethyl phosphonate
α-Functionalized unsaturated sulfones can be obtained in good yields starting from chloro- or methoxy-methyl phenyl sulfone (Scheme 1.31).116 In this case, when aromatic aldehydes are employed (R”=H), acetylenic sulfones can be obtained in good yields by treatment of the intermediate alkenyl sulfone with t-BuOK. Aliphatic aldehydes give complex mixtures of products under these conditions.117 R' S O Ph O 69-85% O R'' R' -78 oC to r.t. 1) 2) H2O X X S O Ph O 1) BuLi (2 equiv.) 2) (EtO)2P(O)Cl -78 oC, 30min S P(OEt)2 O Ph O O Li X R'' X=Cl,OMe S O Ph O O R'' R' -78 oC to r.t. 1) 2) t-BuOK R''=H R'
Scheme 1.31: Horner-Wittig approach to unsaturated sulfones by in situ formation of substituted sulfonomethyl phosphonates
It was reported118 that allyl sulfones can be lithiated and the resulting anion condensed with aldehydes. Treatment of intermediate 7 with alkyl halides gives β-alkoxy sulfones 8, which afford dienyl sulfones upon base-catalyzed elimination (Scheme 1.32). The choice of the conditions used for the base-promoted elimination of the ethoxy group greatly influences both yields and stereochemical purity of the dienyl sulfone. The elimination step proceeds in fairly good yields (60-70%), and the process represents a valid synthetic route to dienyl sulfones, which are usually obtained in remarkable stereoselectivity.
R 1)BuLi 2) R'CHO, THF, -35 oC S O PhO R R' LiO R''X SO PhO R R' RO Base SO PhO R R' S OO Ph 7 8
Scheme 1.32: Reaction of lithiated allyl sulfones with aldehydes, subsequent addition of alkyl halides and base-promoted formation of dienyl sulfones
Treatment of alkyl sulfones with EtMgBr, followed by reaction with prop-2-ynal, affords β keto sulfone 9 which, upon treatment with Tf2O-Hünig’s base,
gives the labile product 10 (Scheme 1.33).119
Ar S Me O O 1) EtMgBr, 0 oC H O R 2) PCC, CH2Cl2 R O SO2Ar 25-44% R SO2Ar EtN(i-Pr)2 (CF3SO2)2O -78 oC 62-98% 9 10
Scheme 1.33: Synthesis of sulfonyl diynes by condensation of sulfonyl carbanions with aldehydes and dehydration
1-Sulfonyl ethyl phosphonate has been recently reported to be a useful precursor for the synthesis of trifluoromethylated enynyl sulfones in good yields. The proposed synthesis involves deprotonation of the starting material with n-butyllithium, reaction with trifluoroacetic anhydride and addition of acetylides to the resulting carbonyl compound.
S Me Ph (EtO)2P O O O 1) BuLi 2) (CF3CO)2O S Ph (EtO)2P O O O Me O CF3 Li R MgBr R F3C Me S O Ph O R CF3 Me S O Ph O R 45-54% 57-76%
Scheme 1.34: Synthesis of (E) and (Z) trifluoromethylated sulfonyl enynes by reaction of organometallic derivatives with trifluoroacetylated sulfonyl phosphonates
The nature of the alkynylating agent (organolithium or Grignard reagents) influences the stereochemistry of the product (Scheme 1.34), making it possible to obtain stereoselectively (E) or (Z)-enynyl sulfones.120
Knoevenagel condensation of aryl aldehydes with sulfones has proven to be an effective method for the synthesis of alk-1-enyl sulfones. The reaction is shown in a general form in Scheme 1.35 and many different substrates were studied in order to explore its scope.
S R O O Y + O R1 R2 S Y R2 R1 R O O
Scheme 1.35: Synthesis of alkenyl sulfones by Knoevenagel condensation
The most widespread methods involve the presence of carbonyl compounds,121 carboxylic groups,122,123 or esters124 in the starting sulfone (Y in Scheme 1.35). The major problem in this approach is constituted by the variable stereochemistry of the products, which is dependent on the steric hindrance of the alkenes; furthermore, the yields are not excellent. Much effort has been expended in order to optimize this reaction, and recently a very effective catalyst, Na2CaP2O7, has
been reported;125 it allows the Knoevenagel reaction between 2-(phenylsulfonyl)acetonitrile and aromatic aldehydes, affording alkenyl sulfones in 50-94% yield.
1.3 Synthesis of alk-1-enyl sulfoxides
The synthesis of unsaturated sulfoxides, both in their racemic and optically active form, has been extensively reviewed.21,45,126 Synthetic pathways to sulfoxides are often similar to those examined for sulfones; due to this similarity the same classification will be employed.
1.3.1 Alk-1-enyl sulfoxides from other sulfur derivatives
Oxidative routes
Oxidation of sulfides as route to sulfoxides has been investigated starting from 1865, and still remains one of the most important approaches to sulfoxides. This methodology has been extensively studied, both for the synthesis of racemic49,127,128,129,130 and optically active131 sulfoxides, and many oxidizing
systems have been proposed, including hydrogen peroxide,132 organic peracids, chromic acid, nitric acid,133 halogens, iodosobenzene,134 sodium hypochlorite.135,136 The main problem involved in this method is the overoxidation to the corresponding sulfone, which depends on the oxidizing system used. In most cases, however, reaction conditions are mild enough to obtain sulfoxides in good yields, even when sensitive groups are present. It has been shown that sulfoxides are intermediates in the oxidation of sulfides to sulfones; for this reason, many oxidative approaches to unsaturated sulfones can be also used to prepare unsaturated sulfoxides.52,60 These methods have already been described in Section 1.2.1 and will not be discussed further.
The preparation of 1-vinyl alk-1’-ynyl sulfoxides starting from the corresponding sulfides has been reported (Scheme 1.36);137 both H2O2 or peracids
can be used as oxidants.
S R H2O2 or MCPBA CH3COOH or CH2Cl2 r.t., 40h S R O 67-84%
Scheme 1.36: Oxidation of alk-1-ynyl vinyl sulfides to sulfoxides with hydrogen peroxide
Organic peracids are known to be powerful oxidizing agents under mild conditions, and their ability to oxidize sulfides to sulfoxides can be efficiently employed in the synthesis of sulfoxides that are sensitive to bases.138 An example is reported in Scheme 1.37, where thiiranedialene is quantitatively oxidized at 0
oC using MCPBA.139
S
MCPBA S
O
Scheme 1.37: Oxidation of thiiranedialene with MCPBA
Sodium metaperiodate is a good oxidant for sulfides, and has been used for the synthesis of 1-butadienyl phenyl sulfoxide140 (Scheme 1.38).
S Ph NaIO4 MeOH, 0 oC S Ph O 76%
Scheme 1.38: Oxidation of 1-butadienyl phenyl sulfide with sodium metaperiodate
Its use is not completely general, and in some cases no reaction is observed.141 Non-oxidative routes
Although non-oxidative routes to alk-1-enyl sulfoxides are less employed than oxidative ones, this field seems very promising, and has recently received considerable attention. As with oxidative routes, many approaches resemble very closely those already discussed for alk-1-enyl sulfones. Hydrozirconation of alkynyl sulfur derivatives,70,142 already discussed in Section 1.2.1, has recently attracted much attention, due to its stereoselectivity and the versatility of organozirconium intermediates, which are precursors to a host of more complex systems. The anti-stereoselectivity obtained in this procedure, which is likely to be due to the coordinating effect of the sulfoxide group, is not always complete and depends on the bulk of the substituent in the position β to the sulfoxide group (Scheme 1.39). Poor yields (23%) are obtained when aryl-substituted alkynyl sulfoxides are used as starting materials, and are in the range 39-47% when alkyl-substituted alkynyl sulfoxides are used.
Ar S O R Ar S O R Cp2Zr(H)Cl, r.t., 5min Cp2ClZr E+ Ar S O R E R=Pr, n-Alk E+=H+, NBS 39-47% (R=n-Alk) 23% (R=Ar)
Scheme 1.39: Hydrozirconation and trapping of alkynyl sulfoxides with electrophiles
In a recently reported synthesis of alkenyl disulfoxides, alkynyl sulfoxides have been used both as sulfinyl source and as acceptors; palladium-catalyzed sulfinyl zincation143 can afford alkenyl disulfoxides in good yields, (Scheme 1.40, path a). The mechanism involved is still uncertain, but presumably proceeds through the following steps: a) oxidative addition with insertion of the palladium catalyst in the (sp)C-S bond; b) substitution of the sulfinyl group by the ethyl group of diethylzinc; this leads to the formation of an ethylzinc sulfinate with regeneration of the catalyst; c) addition of ethylzinc sulfinate to the alkynyl
sulfoxide. This protocol presents an interesting feature, because it allows one to perform sulfinyl zincation on alkynes different from the alkynyl sulfoxide itself. This is due to the strong tendency of alkynyl sulfoxides to oxidatively add to palladium, which makes the oxidative addition step very selective. It is therefore possible to obtain highly functionalyzed alkenyl sulfoxides, as reported in Scheme 1.40, path b. A drawback of this process is the loss of the alkynyl chain present on the sulfoxide, which causes the whole reaction to suffer from low atom economy.
Ar S S Ar S R Pd(dba)3 CHCl3 R 82-97% Et2Zn (2 equiv.) THF -78 oC 1) 2) H3O+ Ar O O Tol-p S O t-Bu Pd(dba)3 CHCl 3 Et2Zn (2 equiv.) THF -78 oC 1) 2) H3O+ OR' R + O OR' C S R 48-98% p-Tol O O O a) b)
.
.
Scheme 1.40: Sulfinyl zincation of alkynyl sulfoxides in the presence of palladium catalysts
Organozinc derivatives144 add in good yields to alkynyl sulfoxides in the presence of catalytic amounts of copper salts. This route affords many structurally different products; the great functional group tolerance of organozinc derivatives makes this approach very valuable in the synthesis of alk-1-enyl sulfoxides (Scheme 1.41, path a).
Moreover, if a suitable electrophile is added to the reaction mixture before the hydrolysis, more complex derivatives can be obtained in good yields (Scheme 1.41, path b).
Ar S R' Ar S R Cu(OTf)2 R 70-94% THF -78 oC 1) 2) H3O+ O O a) b) R'ZnX Ar S Et Ar S R Cu salt R 40-88% THF -78 oC 1) 2) Allyl bromide O O Et2Zn
Scheme 1.41: Addition of organozinc derivatives to alkynyl sulfoxides in the presence of copper catalysts
Alkynyl sulfoxides afford cis or trans alkenyl sulfoxides by simple reduction with DIBAL-H (or LiAlH4) or H2/RhCl(PPh3)3 respectively; products are obtained
in excellent yields with complete stereoselectivity (Scheme 1.42).145 Stereochemistry of the hydroalumination is anti, due to the coordinating effect of sulfoxide group; this is in good agreement with what reported for analogous reactions performed on propargilic alcohols.
Ar S R Ar S R O O Al(Bu-i)2 Ar S 59-97% O R DIBAL-H, 15min THF or Toluene -90 oC or LiAlH4, 30min THF -90 oC H2 (1 atm) ClRh(PPh3)3 benzene r.t. Ar S R 84-95% O H H3O+
Scheme 1.42: Reduction of alkynyl sulfoxides to cis- or trans- alkenyl sulfoxides
Hydrostannylation of alkynyl sulfoxides can be performed with trialkyltin hydrides, and in this case a stable α-stannyl alkenyl sulfoxide is obtained.
Ar S Bu Ar S Bu 85% O O Ar S 87% O Bu3SnH, 18h hexane r.t. Pd(PPh3)4 benzene -78 oC SnBu3 E/Z=7.5/1 Bu3SnH SnBu3 NIS THF, r.t. S Ar O Bu 1) 2) SnBu3 R' Pd2(dba)3 5% AsPh3 20% BHT (1 equiv.) THF, r.t., 2h R' 70-81% Bu
Scheme 1.43: Reduction of alkynyl sulfoxides with tributyltin hydride and further modification to dienyl sulfoxides
This intermediate is useful for further modifications and, in particular, iodolysis has been successfully employed to afford β-iodo sulfoxides, which can be cross-coupled with alkenyl stannanes to give 2-dienyl sulfoxides in good yield (Scheme 1.43).146
The Michael addition of malonate ion to acetylenic sulfoxides, which affords the trans-addition products exclusively, is one of the oldest methods for the functionalization of alkynyl sulfoxides.147 It is also reported that addition of malonate ion to β-bromo alkenyl sulfoxides affords, after elimination of HBr, the corresponding alkenyl sulfoxides in good yields. Reaction of organocopper derivatives with alkynyl sulfoxides affords instead the cis addition product only;148,149 it is noteworthy that monoalkyl copper derivatives give good yields, while the more reactive dialkyl cuprates lead mainly to substitution products of the sulfinyl moiety.
1.3.2 Alk-1-enyl sulfoxides by nucleophilic substitution at the
sulfur atom
Nucleophilic substitution at sulfur by carbon nucleophiles is one of the most important approaches to racemic and optically active unsaturated sulfoxides. Sulfinic acid derivatives are known since 1926150 to be excellent substrates for reactions involving Grignard reagents, and organocopper derivatives have been shown to effectively alkylate sulfinyl esters.126 The Andersen protocol, developed in the 1960s,151 is one of the most important routes to the synthesis of
enantiomerically pure sulfoxides. This method allows alkylation of chiral sulfinates with organometallic reagents and affords the corresponding sulfoxides in good yields and optical purities with inversion of configuration at S.152 This approach has been widely applied to the synthesis of chiral alkenyl sulfoxides153,154 (Scheme 1.44). 74% R MgBr E/Z=70/30 Ph S O-(l)-Ment O + THF/benzene r.t. Ph S O R E/Z=70/30
Scheme 1.44: The Andersen protocol applied to the synthesis of optically active alkenyl sulfoxides
The same protocol has been successfully applied to the synthesis of enantiomerically pure alkynyl sulfoxides, precursors of cis or trans alkenyl sulfoxides, by one of the reduction methods described above (Section 1.3.1).154 Due to the great interest in the synthesis of enantiomerically pure sulfoxides, preparation of chiral sulfinates in satisfactory yields and optical purities is a task of great interest; as a consequence, much effort has been devoted to finding novel chiral sulfinates, which are able to overcome the limitations of the Andersen protocol regarding yield and easy access to both enantiomers.155,156,157
Sulfinyl chlorides are reported to react readily with alkenyl zirconium derivatives, affording the unsaturated sulfoxides in good yields.158 The reaction is
shown in Scheme 1.45 and is performed with α-stannyl vinyl zirconium complexes 11. α-Stannyl-substituted alkenyl sulfoxides can be obtained stereospecifically in good yields with this method. The presence of a stannyl substituent at the α-position of the sulfinyl group creates a handle for further reaction, e.g. by means of palladium-catalyzed cross coupling reactions.
R SnR3'Cp2Zr(H)Cl THF r.t., 5min R ZrCp2Cl SnR3' R''SOCl R S SnR3' R'' O 63-80% Ph2I+Cl -Pd(PPh3)4 CuI 2h R S Ph R'' O 75% 11
Scheme 1.45: Synthesis of alkenyl sulfoxides by reaction of α-stannyl zirconium complexes with sulfinyl chlorides
Alkynylation of sulfinyl chlorides with lithium acetylides has been reported to proceed in satisfactory yields.159 It has also been claimed that vinyl Grignard
(toluene, 0 oC) although in modest yields. The results, however, appear erratic depending on the substrate used, and it is reported that the starting sulfinyl chlorides present some stability problem.
1.3.3 Alk-1-enyl
sulfoxides
via condensation reactions
As already seen for sulfones, sulfoxides can also be obtained by condensation reactions; the remarkable acidity of protons bonded in α-position to sulfinyl functional group, makes this approach attractive.160 The classical Wittig-Horner approach (Scheme 1.46), relies on the deprotonation of arenesulfinyl methanephosphonates 12 and its subsequent reaction with aldehydes; this approach has been developed in the following years, by using phase-transfer catalysis.161 The main disadvantage of this approach is represented by the formation of E/Z isomers mixtures, whose composition strongly depends on the nature of the aldehyde employed,162 even though many attempts have been
reported to overcome these limitations.163,164
n-BuLi, THF -78 oC to 0 oC R S Me O 70% S (EtO)2P O Me O + R H O 12
Scheme 1.46: Synthesis of alkenyl sulfoxides by Wittig-Horner reaction of arenesulfinyl methanephosphonates anion with aldehydes
The necessary arenesulfinyl methanephosphonates can be obtained from the arenesulfenyl methanephosphonates by controlled oxidation at sulfur atom or by reaction of anions of dialkyl methanephosphonates with sulfinate esters. A significative improvement in the stereoselectivity of the Wittig-Horner reaction, applied to the synthesis of racemic and chiral sulfoxides, has been recently achieved with the use of α-sulfinyl phosphonium ylides, generated in situ from methyltriphenylphosphonium iodide, n-BuLi and methyl p-toluenesulfinate.165 It has also been reported that formation of sulfonyl phosphite and condensation with aldehydes can be performed in situ.166
2 Ph3P+CH3I- n-BuLi Ph3P H H R' SOMe O S R' O Ph3P 2 RCHO R' S R O E/Z=68/32-100/0 50-88%
Scheme 1.47: Synthesis of alkenyl sulfoxides by Wittig reaction of α sulfinyl phosphonium ylides
The reaction, illustrated in Scheme 1.47, often proceeds with nearly complete (E) stereoselectivity and, if p-methylphenyl menthyl sulfinate is employed, affords the alkenyl sulfoxides with excellent enantiomeric excesses.
In a similar approach, [(α-chloro)sulfinylmethyl]diphenylphosphine oxides are used in a Wittig synthesis of α-chloro alkenyl sulfoxides. The reaction is shown in Scheme 1.48 and the resulting products are obtained stereoselectively and in good yields.167,168 The starting phosphonates 13 are obtained in two steps starting from tosyloxymethyl triphenylphosphine oxide.
LDA, THF -50 oC to r.t. R' S R O 56-87% S (C6H5)2P O R O Cl -50 oC R'CHO 1) 2) Cl 13
Scheme 1.48: Synthesis of α-chloro alkenyl sulfoxides by Wittig reaction of [(α-chloro)-sulfinylmethyl]-diphenylphosphine oxides
The Knoevenagel condensation represents a useful route to unsaturated sulfoxides; this approach has been recently studied, and applications have resulted in one-pot sequencies to γ-keto and γ-hydroxy alk-1-enyl sulfoxides.169 Chiral
derivatives can be obtained when a chiral bis sulfoxide is employed in the condensation step.
Anions derived from deprotonation at the α position of the sulfinyl group add to aldehydes, forming β-hydroxy sulfoxides. Subsequent elimination170 or
mesylation-elimination171 sequences afford the desired products in good yields and complete stereoselectivity. This can be followed by an intramolecular Heck reaction, which affords cyclic dienyl sulfoxides (Scheme 1.49).171 Quenching of the alkoxide intermediate with acetyl chloride, followed by base-catalyzed elimination, also afford alk-1-enyl sulfoxides in good yields.172
I H O p-Tol S Me O THF, -78 LDA oC p-Tol S O OH I 1) 2) MsCl, Et3N CH2Cl2, r.t. p-Tol S O I 72% 60% S Tol-p O
Scheme 1.49: Synthesis of cyclic dienyl sulfoxides
Addition of carbanion of p-tolyl methyl sulfoxide to esters leads to the formation of β-keto sulfoxides. This reaction can be performed on unsaturated esters; enolization with LDA and quenching at low temperature with t-butyl dimethylsilyl triflate leads to the synthesis of stereochemically pure dienyl sulfoxides in high yields.173 Conservation of chiral information on the sulfur atom during deprotonation and alkylation processes constitutes an interesting and synthetically useful feature of this process.
R' S Ph O 66-87% S Me3Si Ph O Li + O R' R THF -70 oC R
Scheme 1.50: Synthesis of alkenyl sulfoxides starting from silyl sulfinyl derivatives
Sulfinyl silyl derivatives have been used in the synthesis of alk-1-enyl sulfoxides.174 The first step is the deprotonation of the sulfinyl silyl precursor, which after addition to an aldehyde, affords the alkenyl sulfoxide upon warming to room temperature (Scheme 1.50). Although the yields are usually quite good, the stereochemistry of the product is uncertain, even when aldehydes are employed.
