Sulfoxides, unsaturated sulfides

A final, rather different example which fits in appropriately here, in that it involves hydrogen exchange, is the measurement of equilibrium and rate constants for the base-catalyzed isomerization of unsaturated sulfides, sulfoxides and sulfones193 ... 

Reaction of the cyclic sulfoxide 1176 with trimethylchlorosilane (TCS) 14 in CH2CI2 affords the unsaturated sulfide 1177, in 86% yield, and HCl and HMDSO 7 whereas the ester 1178 gives rise to 72% 1179, 16% isomer 1180, and, via 1181, the chloro compounds 1182 and the ring contracted 1183 in 7% yield [17, 18] (Scheme 8.5). 

Sila-Pummerer reaction of the /1-ketosulfoxide 1257 with the enol silyl ether of acetophenone 653 in the presence of BSA 22 a and stannous triflate affords the C-substituted sulfide 1258 in 82% yield and HMDSO 7 [52]. The allylic sulfoxide 1259 reacts with 653 in the presence of TMSOTf 20/DIPEA to give the unsaturated sulfide 1260 in 62% yield or, with the enol silyl ether of cyclohexanone 107a , the unsaturated sulfide 1261 in 63% yield and HMDSO 7 [53] (Scheme 8.21). 

Electrochemically, the reduction of activated sulfoxides (unsaturated or aromatic) in protic media exhibits a specific step leading to corresponding sulfides. However, in acidic solutions of sulfoxides a hydrogen reduction wave can be seen [223, 224] because of the reduction of their pro-tonated form. On the contrary, in the absence of electrophiles (in aprotic DMF), the reduction of aromatic sulfoxides was reported to afford [225] a complex between the reduced form and the substrate (the process therefore would be analogous to... 

As already mentioned above, sulfides are oxidized to the corresponding sulfoxides with alkyl hydroperoxides in the presence of various metal catalysts like Mo, W, Ti and V. In the presence of excess hydroperoxide further oxidation to the sulfone occurs. Sulfides are generally oxidized much faster than alkenes, which is reflected in the selective oxidation of unsaturated sulfides exclusively at the sulfur atom. During the last years many asymmetric versions of this reaction have been developed and can be mainly divided... 

Other types of reduction catalyzed by non-microsomal enzymes have also been described for xenobiotics. Thus, reduction of aldehydes and ketones may be carried out either by alcohol dehydrogenase or NADPH-dependent cytosolic reductases present in the liver. Sulfoxides and sulfides may be reduced by cytosolic enzymes, in the latter case involving glutathione and glutathione reductase. Double bonds in unsaturated compounds and epoxides may also be reduced. Metals, such as pentavalent arsenic, can also be reduced. 

This chapter is devoted exclusively to the alkylation of the above mentioned organometallic reagents with alkyl halides, epoxides and oxetanes. It includes a large variety of organosulfur- and organoselen-ium-stabilized carbanions derived from saturated and unsaturated sulfides, selenides, sulfoxides, selen-oxides and sulfones as well as those carbanions bearing another heteroatomic moiety. The chapter excludes, however, those organometallics which can be viewed as a-thio and a-seleno enolates. 

UNSATURATED SULFIDES, SULFOXIDES, SULFONES Ben-zeneselenenyl chloride. 

Scheme 20.6 Alternative synthesis of unsaturated sulfides and sulfoxides.

The phase transfer Wittig-Horner-Emmons reaction has been used to prepare examples of o, i3-unsaturated sulfides, sulfoxides, and sulfones [19]. Although these reactions are discussed in Sect. 14.3, we have summarized in Table 13.7 the results of transformations according to equation 13.10. Note that this reaction yields sulfur compounds on condensation with aldehydes only if the starting phosphonate is sulfur substituted. 

The kinetics of formation and hydrolysis of /-C H OCl have been investigated (262). The chemistry of alkyl hypochlorites, /-C H OCl in particular, has been extensively explored (247). /-Butyl hypochlorite reacts with a variety of olefins via a photoinduced radical chain process to give good yields of aUyflc chlorides (263). Steroid alcohols can be oxidized and chlorinated with /-C H OCl to give good yields of ketosteroids and chlorosteroids (264) (see Steroids). /-Butyl hypochlorite is a more satisfactory reagent than HOCl for /V-chlorination of amines (265). Sulfides are oxidized in excellent yields to sulfoxides without concomitant formation of sulfones (266). 2-Amino-1, 4-quinones are rapidly chlorinated at room temperature chlorination occurs specifically at the position adjacent to the amino group (267). Anhydropenicillin is converted almost quantitatively to its 6-methoxy derivative by /-C H OCl in methanol (268). Reaction of unsaturated hydroperoxides with /-C H OCl provides monocyclic and bicycHc chloroalkyl 1,2-dioxolanes. 

Abbott and coworkers229 found that nucleophilic addition of amines to a, p-unsaturated sulfoxide gave asymmetrically induced adducts. For example, treatment of (R)-(—)-cis-propenyl p-tolyl sulfoxide 184 with piperidine in methanol gave a quantitative mixture of the diastereomeric adduct 185. Reduction of this mixture gave (Rs)-(Sc)-2-piperidinopropyl p-tolyl sulfide 186 in 74% optical yield, suggesting that the amines attack from the opposite side of the bulky aryl group at the transition state, as shown above (Figure 6). 

In the presence of Znl2 in acetonitrile the saturated sulfoxide 1262 is converted by the O-trimefhylsilylketene acetal 663 into the sulfide 1263 in 55% yield and HMDSO 7 [54] whereas the unsaturated sulfoxide 1264 affords with excess O-silyl-ketene acetal 663 the bis-addition product 1265 in 45% yield [55, 56] (Scheme 8.22). 

A novel, unprecedented sulfoxide-directed borane reduction of the a,P-unsaturated sulfoxide to the saturated sulfide was discovered. 

Sodium sulfide or hydrosulfide can be used in double Michael additions thus the bridged thiopyran (11) is formed from 2,7-cyclooctadienone (12),12 and dihydrodithiin oxides (13) and related compounds are similarly produced from unsaturated sulfoxides (14).13... 

Bromination of the enol ether product with two equivalents of bromine followed by dehydrobromination afforded the Z-bromoenol ether (Eq. 79) which could be converted to the zinc reagent and cross-coupled with aryl halides [242]. Dehydrobromination in the presence of thiophenol followed by bromination/dehydrobromination affords an enol thioether [243]. Oxidation to the sulfone, followed by exposure to triethylamine in ether, resulted in dehydrobromination to the unstable alkynyl sulfone which could be trapped with dienes in situ. Alternatively, dehydrobromination of the sulfide in the presence of allylic alcohols results in the formation of allyl vinyl ethers which undergo Claisen rearrangements [244]. Further oxidation followed by sulfoxide elimination results in highly unsaturated trifluoromethyl ketonic products (Eq. 80). 

Unsaturated 1,5-dicarbonyl compounds. The phenylthioalkylation of silyl enol ethers of carbonyl compounds (9, 521-522) can be extended to the synthesis of unsaturated 1,5-dicarbonyl compounds. In a typical reaction the enol silyl ether of a ketone is alkylated with the unsaturated chloride 1 under ZnBr2 catalysis to give a homoallyl sulfide. Ozonolysis of the methylene group is accompanied by oxidation of the phenylthio group sulfoxide elimination results in an unsaturated 1,5-aldehydo ketone (equation I). Alkylation with 2 results in a methyl ketone (equation II). 

The rhodium-catalyzed hydroboration has opened the way to cyclization reactions starting from dienes [92], For instance, rhodium-catalyzed hydroboration of the terminal alkenyl group of an os/f-unsaturated lactone followed by reaction with the PTOC-OMe chain transfer reagent afforded the bicyclic a-S-pyridyl lactone in 63% yield (Scheme 39). After oxidation of the sulfide with m-CPBA, thermal elimination of the sulfoxide afforded the corresponding a-methylene lactone in 65% yield. Interestingly, such bicyclic a -methylenelactones are substructures that can be found in many natural products such as mirabolide [93]. 

The Pummerer rearrangement of sulfoxides with acid anhydrides has been extensively utilized as a method for the synthesis of a-substituted sulfides. When a,(3-unsaturated sulfoxides are used, the initial formed oxysulfonium ion may undergo two different pathways the additive Pummerer reaction or the vinylogous Pummerer reaction. The following sections will consider examples from both pathways. 

For the intramolecular vinylogous Pummerer reaction pathway, an electrophilic thionium ion intermediate (222) is formed by y-proton loss from 221 followed by sulfoxide S-O bond scission. This unsaturated thionium ion (222) is then intercepted by a nucleophile at the y-position to yield a vinyl sulfide product (223) (Fig. 11). 

A few examples of additive Pummerer leairangements arc known involving direct conversion of a, -unsaturated sulfoxides into a, -disubstitutBd sulfide. 4 4. 63 Scheme 4 illustrates two gomal pathways for such processes and specific exanqiles of each are known. For example, alk-l-oiyl j oiyl sulfoxiite... 

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