Bond-Forming and -Breaking Reactions at Sulfur(IV): Sulfoxides, Sulfonium Salts, Sulfur Ylides, and Sulfinate Salts

Organosulfur compounds have long played a vital role in organic chemistry and in the development of novel chemical structures and architectures. Prominent among these organosulfur compounds are those involving a sulfur(IV) center, which have been the subject of countless investigations over more than a hundred years. In addition to a long list of textbook sulfur-based reactions, there has been a sustained interest in the chemistry of organosulfur(IV) compounds in recent years. Of particular interest within organosulfur chemistry is the ease with which the synthetic chemist can effect a wide range of transformations through either bond formation or bond cleavage at sulfur. This review aims to cover the developments of the past decade in the chemistry of organic sulfur(IV) molecules and provide insight into both the wide range of reactions which critically rely on this versatile element and the diverse scaffolds that can thereby be synthesized.


INTRODUCTION
Since the early days of synthetic organic chemistry, organosulfur reactivity has occupied a prominent role. Its impact on the discipline can be highlighted by the sheer number of named reactions based on the rich chemistry of this element. Apart from the range of sulfide-and sulfone-based reactions (not covered in this review article), the chemistry of sulfur at the oxidation state +IV has been extensively studied. This research has led to the development of a variety of highly useful transformations, including (but not limited to) venerable reactions such as the Pummerer rearrangement, 1−5 the Mislow−Braverman−Evans rearrangement, 6,7 the suite of Swern-and Kornblum-type oxidation reactions, 8−11 the Johnson−Corey−Chaykovsky epoxidation and cyclopropanation, 12−14 the Stevens rearrangement, 15 and the Gassman indole synthesis. 16 Focusing on the four major groups of organosulfur(IV) compounds carrying S−C and S−O bonds, namely sulfoxides, sulfonium salts, sulfur ylides, and sulfinate salts, this review article aims to provide an overview of a decade of research up to October 2018 that has led to the development of novel reactions and the enhancement of pre-existing protocols and textbook transformations. We center our attention on reactions that involve either bond formation or bond cleavage at sulfur, thereby excluding sulfoxide-based ligands and auxiliaries (both previously reviewed: refs 17, 18, and 19 as well as 20 and 21, respectively). Additional classes of sulfur species carrying bonds to other elements (such as the S−N of sulfylimines) are not covered.
The presentation chosen focuses on new reactivity and highlights methods for the formation of C−C and C−S bonds, the synthesis of a wide range of heterocycles and, where applicable, research that has led to the development of stereoselective processes and their application in natural product synthesis.
Owing to the diverse nature of the functional groups discussed within this review, each section is accompanied by an individual brief introduction, providing context and setting the scene for the modern organosulfur(IV) chemistry presented therein.

Pummerer Reactions
The venerable Pummerer rearrangement is perhaps the most well-known reaction of sulfoxides and has been the subject of several reviews in the past. 1−5 Since its discovery, it has inspired and intrigued many chemists and led to the development of numerous extensions, applications, and different modifications. Depending on the substrate substitution, different pathways are available upon activation of the sulfoxide with a suitable electrophile; these are summarized in Scheme 1. In the classical Pummerer reaction, a proton αto the sulfur of sulfonium species 1 is abstracted and nucleophilic attack leads to α-substituted sulfides. As the nucleophile attacks a position which was previously nucleophilic in the sulfoxide starting material, this can also be considered an Umpolung process. If instead nucleophilic attack on 1 occurs directly on sulfur, an interrupted Pummerer reaction is observed and numerous applications have emerged from the resulting intermediate. Similarly, attack on the adjacent carbon in S N 1 or S N 2 fashion leads to the Pummerer fragmentation pathway.
Aromatic sulfoxides can be further substituted by means of the aromatic Pummerer reaction. With an acidic hydrogen on a substituent, nucleophilic attack will occur in meta-position to the sulfoxide, whereas otherwise ortho-or para-substitution is observed.
As is the case for alkyl sulfoxides, activated vinyl sulfoxides offer several pathways for attack of a nucleophile. Deprotonation of the γ-position and consequent nucleophilic addition to the same carbon is referred to as the vinylogous Pummerer reaction. Alternatively, direct nucleophilic attack on the double bond leads to the pathway of the extended Pummerer reaction. If a second nucleophilic addition occurs at the α-position of this intermediate (often with the same nucleophile), the reaction is also called additive Pummerer reaction.
The following sections will discuss the more recent applications and developments of the Pummerer reaction.
2.1.1. Classical Pummerer and Pummerer Fragmentation Reactions. Sulfoxides display tetrahedral geometry with one lone pair located on sulfur, and, providing that the two moieties on sulfur are different, are chiral compounds. In the classical Pummerer reaction, the activation of chiral sulfoxides with acetic anhydride (acetate thereby serving as the subsequent nucleophile) usually affords racemic αacetoxysulfides. However, work by Nagao and co-workers showed that modification of the reaction conditions allowed for the reaction to be performed in a stereoselective fashion (Scheme 2). 22 Key to obtaining products in high enantioselectivities was the use of an electrophilic activator such as TMSOTf as well as an amide as additive or solvent. To gain additional insight into the origin of stereoselectivity, the mechanism was later investigated by Thiel et al., employing computational studies. 23 The electrophilic activator was found to have great influence by lowering the energy barrier for the acylation of the sulfoxide in the rate determining step. Equally as important is its role in trapping the forming acetate, thus preventing the formation of achiral sulfurane 6 preserving the chirality on sulfur. A concerted cyclic acetate transfer is responsible for the observed chirality preservation and yields the α-acetoxysulfides 5. It was suggested that the amide additive modulates the Lewis acidity of TMSOTf and prevents extensive racemization of the products rather than being involved in the rate-determining step itself.
Marzorati and co-workers compared the use of thioesters and sulfones to commonly used esters, as adjacent electronwithdrawing substituents, in the intermolecular Pummerermediated arylation with arenes (Scheme 3a). 24 Consistent with literature precendent, the reaction rate was found to be much higher for thioesters. However, the yields and ratios obtained remain similar to those observed when esters are employed. In the first reaction step, 10 is formed rapidly upon exposure of 8 to trifluoroacetic anhydride. Addition of a Lewis acid then facilitates the formation of the thionium ion prior to electrophilic aromatic substitution (S E Ar) to afford 9.
In their synthesis of albomycin derivatives, aiming at the development of novel potent antimicrobial agents, He and co-Scheme 1. Pummerer Reaction Types Depending on the Sulfoxide Substituent Scheme 2. Stereoselective Pummerer Reaction Studied Computationally by Thiel and Co-workers 23 workers recently used the classical Pummerer reaction to introduce the DNA-base uracil into the thioribose structure. (Scheme 3b). 25 In this case, the silylating agent TMSOTf was used for electrophilic activation of the sulfoxide, conditions commonly used in combination with nucleobases. 26,27 Competitive nucleophilic addition of triethylamine was observed, motivating the use of the more hindered Hunig's base (DIPEA).
The use of azides as nucleophiles in the Pummerer reaction was established in a direct fashion by the group of Jiao (Scheme 4a). 28 The authors employed diphenylphosphoryl azide (DPPA, 15) as a single reagent serving both as the electrophilic activator of the sulfoxide and as the azide source. In a one-pot procedure, the transiently formed α-azidosulfides were subjected to a 1,3-dipolar cycloaddition with alkynes (under inert conditions) or alkenes (under an oxidative atmosphere), leading to triazole products (16). Later, Matsugi et al. used a more electrophilic DPPA derivate (18) to broaden the scope of sulfoxides that could be employed (Scheme 4b). 29 A number of azidomethylsulfides (19) were successfully formed, while a range of unsuccessful substrates provided deeper understanding of the limitations of the method.
Another application of the Pummerer reaction was presented by the group of Gamba-Sańchez, accessing heterocycles. 30 They reported the synthesis of oxazolines (21) from β-amidosulfoxides (20), using oxalyl chloride (Scheme 5). In this reaction, the initially formed α-chlorosulfides readily undergo cyclization upon addition of aqueous ammonia to afford oxazolines in good to excellent yields.
The addition of 2-fluoropyridine to an S-methylthionium intermediate has been shown to yield 2-pyridones (24) (Scheme 6a). 31 Interestingly, upon changing the alkyl substituent of the sulfoxide to a benzyl moiety, the Pummerer fragmentation became more favorable and direct nucleophilic displacement after activation led to desulfurated alkylation products (25). With 2-chloropyridines, the respective pyridinium salts could be isolated (not shown). A similar Pummerer fragmentation of a sulfonium species was reported by Adamo and co-workers. 32 In their work, a sulfur(IV) species was displaced by chloride after the treatment of phenyl sulfides with (dichloroiodo)benzene (Scheme 6b). A broad number of secondary and tertiary sulfides underwent nucleophilic substitution and the chloride products (28 and 29) could be isolated in good yields, even in instances where different electron-withdrawing groups would otherwise threaten elimination.
Another example of displacement of the sulfoxide group was described by Yorimitsu and co-workers during their work with 1,3-dithiane 1-oxide deriviatives (Scheme 7). 33 When 30 was treated with TFAA at 0°C, clean cyclization of the carbamate onto the thionium intermediate 32 and subsequent elimination of cyclic disulfide 33 led to the protected indole product 31 in 92% yield.
2.1.2. Alternative Activation Strategies. Over the last decades, many different reaction conditions have been developed for the suite of Pummerer reactions, relying on a broad range of activating agents. Most commonly, acid anhydrides such as TFAA are used for electrophilic activation, but many other electrophiles, such as Brønsted or Lewis acids or even silylating agents 26, 27 can be used to initiate the reaction. In some cases, the reaction conditions can be crucial for the success of the reaction, as was shown by Kuhakarn and co-workers in their synthesis of indolizidines (Scheme 8a). 34 On the basis of conditions developed in Kita's pioneering work on the synthesis on lactams, 35 O-silyated ketene acetals and catalytic amounts of zinc diiodide proved superior to other Pummerer conditions to form the cyclized product. An example that a slight change of the conditions can lead to different regioselectivity was presented by Aucagne and coworkers. 36 In their work on sulfinylmethyl C-glycosides 37, they were able to show that, by using either TFAA or the ketene acetal, opposite regioselectivities were observed, favoring attack on the methylene or methyl moieties of the sulfoxide, respectively (Scheme 8b).
Arguably, one limitation of Pummerer-type reactions is the requirement for strong electrophilic activators to generate the electrophilic thionium intermediate, which in turn limits the scope of tolerated nucleophiles. Mendoza and co-workers recently developed a base-promoted Pummerer reaction which is even compatible with Grignard reagents as nucleophiles. 37 On the basis of seminal work by Kobayashi et al., 38 magnesium amides 41 were found to be ideal bases for the conversion of sulfoxides 40 into Pummerer-derived products with only small amounts of dimerization and essentially no sulfoxide− magnesium exchange (for more detail on this process, see section 2.4) as the competing side reaction (Scheme 9a).
The nature of the amide base as well as the ratio of Mg to Li were found to be crucial. Deuterium-labeling studies revealed that the base does not deprotonate the sulfoxide in the absence of the Grignard reagent (Scheme 9b). A large variety of aryl, alkenyl, alkynyl, or alkyl nucleophiles including bulky teriary alkyl substituents were successfully introduced to the αposition (Scheme 9c). Interestingly, when an optically enriched chiral sulfoxide (44) was used, the product 46 was obtained with 40% enantiomeric excess, suggesting the intermediacy of a closed ion pair as well as hinting at possible future more enantioselective processes (Scheme 9d). Later, the same group developed a one-pot oxidation-base promoted Pummerer reaction protocol (Scheme 10). 39 The authors were able to demonstrate that simple evaporation was perfectly suited as the workup for the first step, and as little as 1.05 equiv of the respective Grignard reagent sufficed to obtain yields of 48 comparable with those of a two-step protocol. Although the yields were only moderate, a conceptually intriguing iterative process that progressively builds up the alkyl substituent of a given sulfide of interest was expounded.
In an alternative approach, Pappo et al. demonstrated that the Pummerer reaction of β-ketosulfoxides 49 can be promoted by catalytic amounts of Cu(OTf) 2 . 40 In nitromethane at elevated temperatures, the formed thionium intermediate could be condensed with β-ketoesters (50) and phenol derivatives or reacted with tetraallylsilane (Scheme 11). The proposed mechanism involves the formation of triflic acid to activate the sulfoxide, and the elimination of water, forming the key thionium ion intermediate.

Nonsulfoxide Thionium Chemistry. A pivotal intermediate in several
Pummerer-type reactions is the thionium ion, which is usually formed upon deprotonation of the α-carbon of the activated sulfoxide. The consideration of alternative means to access that thionium intermediate broadens the scope of Pummerer-type reactions considerably. Examples involve the condensation of an aldehyde and a thiol (Scheme 12, pathway A), ionization of dithioketals (pathway B) or oxidative pathways including hydride-abstraction from sulfides or oxidation and elimination (pathway C). Even though these reactions do not strictly include the involvement of sulfur(IV) species, they are closely related to the Pummerer chemistries presented herein and will be briefly discussed in the following section.
In cases where the thionium ion is accessed from an aldehyde, the process is often referred to as connective Pummerer reaction, by virtue of it forming two new bonds at the expense of a carbonyl group. Procter et al. have played a crucial role in developing this approach, using particularly electrophilic aldehydes such as 54 to afford cyclized products bearing a new sulfide moiety (Scheme 13). 41 The authors found that superstoichiometric amounts of both anhydride and Lewis acid were necessary to obtain significant product yields. Later, the protocol could be improved by the use of either catalytic amounts of Sc(OTf) 3 or 1.5 equiv of zinc chloride to promote dehydration of the hemithioacetal. 42 Another example of the connective Pummerer reaction was developed by Pappo and co-workers, employing Cu(OTf) 2 as the catalyst (Scheme 14a). 43 Addition of three equivalents of ethanethiol to a mixture of a ketone (60) and an aldehyde (61) in highly polar solvents effected a Pummerer-aldol reaction. The proposed mechanism involves simultaneous vinyl sulfide/thionium ion formation and combination, followed by hydrolysis, proceeding successfully for a number of aliphatic and aromatic aldehydes. Later, this reaction was extended toward arenes as the corresponding nuclephiles, affording either the α-aryl sulfides 63 (Scheme 14b) or, if a silane was added after the reaction in one-pot fashion, desulfurated Friedel−Crafts alkylation products (not shown). 44 Alternatively, the thionium intermediate can be accessed by treating a dithioketal with a soft electrophilic activator. This strategy has been successfully used as the key C−C bond forming event for Trost's total synthesis of asteriscunolide D, 45 as well as an approach to the core of nakadomarin A. 46 In the former account, an effective 11-membered ring macrocyclization with very high levels of diastereoselectivity was realized, affording moderate yields of 65 (Scheme 15). In both of the mentioned reports, dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) was used to ionize the dithioketal at low temperatures.
In an interesting study on the ring expansion of cyclic dithioketals, Terada and co-workers uncovered surprising enantioselectivity using chiral phosphoric acid derivatives (67) (Scheme 16). 47 In contrast to the intuitive assumption that the addition of a nucleophile to the thionium intermediate is the enantiodetermining step, it was demonstrated that enantioselectivity is actually induced during the concerted 1,2sulfur migration (66 → 69). Diastereospecific nucleophilic addition to the contact ion pair then furnishes the ring expanded products 68 with moderate to high levels of enantiomeric excess.
Reactions that start from a sulfide to directly access the thionium species are referred to as oxidative Pummerer-type reactions. Common reagents used for oxidative Pummerer reactions are hypervalent iodine reagents that act as both the oxidant and the leaving group. Following seminal work by Tamura et al., 48 the reaction was applied to a number of sulfides, often bearing acidic hydrogens (such as αketosulfides). Recently, the groups of Wang and Chen showed that the use of ionic liquids allowed the oxidative Pummerer reaction to proceed at lower temperatures and with higher yields (Scheme 17a). 49 Other examples include Oda and coworkers' oxidative Pummerer rearrangement utilizing Koser's reagent to prepare thio-nucleosides 50 as well as reactions shown in Schemes 6b, 22b, and 28b. Alternatively, Singh and co-workers have developed a copper-catalyzed process, shown in Scheme 17b. 51 Under an atmosphere of air, the sulfides 74 were sequentially oxidized to the corresponding thionium species and hydrolyzed to deliver α-ketoester products (75). Recently, Toste et al. developed the first catalytic, asymmetric Pummerer-type reaction using a chiral-anion phase-transfer catalyst 77 (Scheme 17c). 52 Therein, the insoluble oxidant 78 is brought into solution by anion exchange with catalytic amounts of 77. This highly electrophilic species can achieve hydride abstraction adjacent to sulfur, triggering an intramolecular cyclization to form N,S-acetal products (79). The stereoselectivity is governed by the chiral environment provided by the anion. An alternative mechanism via sulfide oxidation was ruled out by mechanistic studies.
2.1.4. Aromatic Pummerer Reactions. With an aromatic system adjacent to the activated sulfoxide, nucleophiles can attack the aromatic ring to lead to substituted aryl sulfides. Alternatively, similarly to the classical Pummerer reaction in which activated sulfoxides undergo α-deprotonation on the alkyl moiety, aryl sulfoxides carrying substituents with acidic hydrogen atoms can undergo (remote) deprotonation, leading to quinone-type intermediates. These reactions allow for the nucleophilic functionalization of the aromatic ring in a manner that is conceptually opposite to the more common electrophilic aromatic substitution. Such transformations are commonly referred to as aromatic Pummerer reactions, which were pioneered by Kita and co-workers at the beginning of this century. 53−56 Recently, Zhou and co-workers have employed p-aniline sulfoxide derivatives (80) as substrates for the aromatic Pummerer reaction (Scheme 18a). 57 Using ammonium halide (Cl/Br) salts as the corresponding nucleophiles, addition selectively took place meta-to the sulfur substituent. Additionally, aqueous sodium bicarbonate and thiols were also employed and led to facile introduction of hydroxyl-or thiosubstituents, respectively. Importantly, alkyl aryl sulfoxides also afforded moderate to good yields of the products of aromatic Pummerer reaction with only low amounts of classical Pummerer-type products being detected.
Aromatic sulfoxides carrying C−H acidic substituents are also viable substrates for this process, as shown by the same group shortly after their first report (Scheme 18b). 58 The reaction allowed the introduction of a broad range of nucleophiles in remote positions. However, this variant of the transformation was limited to diaryl sulfoxides (82).
In 2017, the group of Yorimitsu reported an aromatic additive Pummerer-type reaction relying on sulfoxide activation in the presence of sulfides (Scheme 19). 59 Following nucleophilic addition (preferentially in para-relationship to the sulfoxide), the resulting sulfonium salts could either be directly dealkylated by the addition of ethanolamine or isolated and used for a sequential cross-coupling (for a description of the latter process, see section 3.2).
2.1.5. Vinylogous and Extended Pummerer Reactions. As in the case of aryl sulfoxides, if vinyl sulfoxides are subjected to Pummerer reaction conditions, new reaction pathways become feasible due to influence of the conjugated system. After activation of the sulfoxide, nucleophilic addition at the β-position leads to what is referred to as an extended Pummerer reaction pathway, whereas deprotonation and functionalization in the γ-position leads to reactions of the vinylogous Pummerer type. Predicting the regioselectivity of the nucleophilic attack between αand γ-addition can be difficult and highly dependent on the reaction conditions (Scheme 20a). Yoshimura and co-workers studied this selectivity for their thioglycosylation reaction and found that nucleophilic attack can be reversible and that the kinetic αaddition product was converted to the thermodynamically more favorable γ-addition product under the reaction conditions (Scheme 20b). 60 The vinylogous Pummerer reaction has also found application in several natural product syntheses. In their route toward hyperforin, reported in 2010, Kanai, Shibasaki, and co-workers turned to a vinylogous Pummerer reaction to install a hydroxyl group in the γposition, forming 92 (Scheme 20c). 61 In the model studies, the ratio of classic and vinylogous Pummerer products was found to be highly dependent on the base, with bulky pyridines such as 2,6-di-t-butylpyridine, giving the best results with yields between 70 and 80% for the vinylogous product (the real substrate yielded 65% of the desired product with an inconsequential dr > 33:1). One year later, Fukuyama et al. made use of a complex vinyl sulfoxide (93) in their total synthesis of (+)-lyconadin A (Scheme 20d). 62 With an excess of acetic anhydride and stoichiometric amounts of camphorsulfonic acid to protonate the basic nitrogen, the vinylogous Pummerer reaction afforded the desired product 94 in a high yield.
An unexpected remote functionalization was reported by Satyam and co-workers during their attempted esterification of carboxylic acid 95 with oxalyl chloride (Scheme 21). 63 In that event, the authors were surprised to obtain a lactone with a reduced sulfide substitutent (96). The formation of 96 can be explained by activation of the sulfoxide with oxalyl chloride, deprotonation in α-position to the carboxylic acid group, and cyclization of the carboxylate onto the ring. Thus, the reaction is best described as a "long-distance" vinylogous Pummerer type reaction.
Vinyl sulfoxides have also found use in the synthesis of thioribonucleosides by Haraguchi et al. 64 Additive Pummerer reaction of the dihydrothiophene oxide derivative 97 led to the stereoselective introduction of two new acetoxy substituents (Scheme 22a). When TMSOTf was employed instead of TMSOAc, substantial amounts of the β-triflated product were observed. After optimization, a higher stoichiometry of reagents afforded the desired product 98 in 62% yield.
Extending the Pummerer chemistry, the group of Feldman reported several studies on additive and vinylogous Pummerertype reactions during their synthetic efforts toward dibromoagelaspongin and dibromopalau'amine. 65−68 A representative example of an oxidative vinylogous Pummerer type cyclization is shown in Scheme 22b. 69 Treatment of sulfide 99 with an oxidant such as the Stang reagent leads to activated species 101, which undergoes deprotonation and attack by the tethered amide, followed by a second cyclization of the pyrrole unit to yield the polycycle 100 in 55% yield and as a single diasteromer.
Important work further extending the chemistry of the extended Pummerer reaction was reported by Yorimitsu et al. in 2008. 70 Therein, direct arylation of vinyl sulfoxides 104 in the β-position was reported to occur after treatment with triflic anhydride (Scheme 23). The aryl substituent R 1 played an important role in directing the electrophilic aromatic substitution to the β-position, leading to the 1,1-diaryl motif. Additional substitution on the aryl moieties led to lower yields, and strongly electron-withdrawing groups (such as p-CF 3 ) led to complex mixtures and no product formation. With an intramolecular aryl tether 108, the only product obtained was phenanthrene 109, being formed after an additional 1,2-carbon shift in intermediate 110.
In 2013, the same group reported this reaction with thioalkynes and ynamides as nucleophiles (Scheme 24). 71 Interestingly, copper bromide was used as the activating agent to enhance the electrophilicity of the vinyl sulfoxide toward nucleophilic attack. An intramolecular sulfur-to-carbon oxygen transfer was proposed to lead to copper enolate 118, which affords the ketene dithioacetals 119 after proton transfer. One equivalent of water proved beneficial when thioalkynes were used as nucleophiles, increasing the yield substantially. The reaction was successful for both methyl-and aryl-substituted vinyl sulfoxide, however, more bulky groups such as cyclohexyl shut down the reaction completely. This reaction is mechanistically related to the family of reactions discussed in section 2.2.1, which involve [3,3]-sigmatropic rearrangements.
2.1.6. Interrupted Pummerer Reactions. The interrupted Pummerer reaction, perhaps the most versatile of the Pummerer-type reactions, is initiated when a nucleophile directly attacks the activated sulfoxide intermediate at sulfur. This reaction has been used in a variety of contexts, and the following segment will cover the most recent applications and developments. Interrupted Pummerer-initiated rearrangements and alkene functionalizations will be described in the subsequent section.
In 2009, Kobayashi et al. utilized interrupted Pummerer reactions to access a range of substituted benzothiophene derivatives from the corresponding sulfoxide precursors (Scheme 25a). 72,73 Herein, activation of the sulfoxide leads to an attack of the olefin on sulfur followed by deprotonation, with subsequent dealkylation affording the heterocycles. Shortly after, the same group reported the use of an intramolecular 1,3-dicarbonyl tethered sulfoxide 124 in which cyclization through the enol form leads to benzothiophenes (125) after subsequent acylation at oxygen under the reaction conditions (Scheme 25b). 74 In 2015, Wan et al. reported the use of an interrupted Pummerer reaction in the context of carbohydrate chemistry (Scheme 26). 75 Therein, sugar derivative 126 was introduced as a bench-stable glycosyl acceptor bearing a carefully disposed sulfoxide as a "remote silent activator", that could be switched on by the use of triflic anhydride (Scheme 26, bottom). The activated sulfoxide triggers the expulsion of sulfonium species 130 and forms the active electrophile 129 which can be attacked by a variety of alcohols, most importantly diverse sugar derivatives in glycosyl transfer reactions. Importantly, hydroxysulfoxide 131 can be recovered after the reaction in 92% yield and can thereafter be recycled. Later, a detailed optimization of the sulfoxide unit and more applications of this reaction were reported, 76,77 and recently the use of sulfoxides in carbohydrate synthesis has been reviewed. 78,79 Several groups have used the interrupted Pummerer reaction for the sulfanylation of arenes. In 2015, Groombridge et al. reported the formation of novel tricyclic structures by intramolecular sulfanylation of pyrrole derivatives based on reports by Bates and co-workers (Scheme 27a). 80,81 Both pyridine-and pyrimidine-derived sulfoxides were annulated under strongly acidic conditions (TFA as the solvent) to afford a variety of heterocycles.
In an intermolecular sense, Procter and co-workers demonstrated the conversion of methyl sulfoxides 93 into aryl sulfides through activation, electrophilic aromatic substitution and, finally, a demethylation step effected by addition of an amine such as DBU (Scheme 27b). 82 A broad range of sulfoxides was employed in combination with either electronneutral or -rich arenes in a regioselective manner. With phenolic substrates, the reaction leads to the concomitant formation of new C−S and C−O bonds, as was reported by Huang et al. in 2017 (Scheme 28a). 83 Initially, the interrupted Pummerer reaction leads to the formation of the corresponding sulfonium salts 139. By heating the reaction in water in the presence of micellar macromolecules, an intramolecular transfer of the R 1 substituent from sulfur to oxygen is triggered, likely occurring via a Smiles-like rearrangement.
The reaction could be performed directly using sulfide starting materials 141, as was also shown by Huang and coworkers (Scheme 28b). 84 Using ZnCl 2 as the Lewis acid and PIFA as the stoichiometric oxidant, a variety of electron-rich arenes could thereby be sulfanylated. The reaction mechanism was proposed to proceed via single-electron transfer (SET) of the arene partner, however, oxidative activation of the sulfide in an interrupted Pummerer fashion could not be ruled out.
Recently, the Procter group utilized the intermediary sulfonium salts that are obtained via interrupted Pummerer reactions as transient leaving groups for an in situ nickelcatalyzed Negishi-type cross coupling in a one-pot manner (Scheme 29, for more information on the cross coupling of sulfonium salts, see section 3.2). 85 A broad scope of organozinc reagents was employed, and the reaction could be expanded to aryl-and alkynylsulfonium salts as well as to domino C−C bond formation employing suitable tethers.

Sigmatropic Rearrangements of Activated Sulfoxides
The activation of aryl and alkenyl sulfoxides with electrophilic reagents can lead to intermediates diverging in reactivity from classical Pummerer chemistry, undergoing structural reorganization through charge-accelerated sigmatropic rearrangements. 3,86−91 In this context, [3,3]-and [2,3]-sigmatropic rearrangements can be instigated by the formation of either unsaturated sulfonium intermediates or allylic sulfoxides and sulfur ylides. 6 (146) to afford the allylated ketene dithioacetal 149 (Scheme 30a). 95 The authors postulated the transformation to proceed via a [3,3]-sigmatropic thio-Claisen rearrangement involving the sulfonium intermediate 148. Identical reactivities were observed for the interactions of similar activated dithiane monoxides with both ketones 96 and phenols, 97,98 the latter leading to the formation of benzofurans (154) through subsequent condensation. While the reaction of aryl sulfoxides that have been activated by addition of strong electrophiles with electron-rich aromatics is also known to proceed via carbon attack on sulfur, ultimately forming aryl ethers or thioethers, 59,99 Yorimitsu and co-workers were able to show that O-nucleophilic attack of phenols onto activated aryl sulfoxides can be followed by [3,3]-sigmatropic rearrangement to elegantly afford biaryls (157) after rearomatization (Scheme 30b). 100 The treatment of aryl sulfoxides with electrophilic activators such as triflic anhydride (Tf 2 O) or trifluoroacetic anhydride (TFAA) has also featured prominently in recent ortho-arene and -heteroarene C−H functionalization chemistry (Scheme 31). In resemblance to the mechanism of sulfoxide activation in Yorimitsu et al.'s early work, 96 in 2011, Maulide and coworkers were able to show that the initial O-nucleophilic addition of β-ketoesters to activated aryl sulfoxides can lead to intermediates of type 160 (Scheme 31a), prone to chargeaccelerated [3,3]-sigmatropic rearrangement, affording αarylated ketones (161) as the reaction products. 101,102 Shortly thereafter, Procter and co-workers demonstrated that the reaction of activated aryl sulfoxides with allylsilanes also leads to the formation of sulfonium intermediates poised for thio-Claisen rearrangement involving the arene, ultimately affording ortho-allylated aryl sulfides (163) (Scheme 31b). 103 The following years saw elaboration of this protocol to the allylation of various heterocycles 104 as well as the use of propargyl silanes to afford propargylated arenes via the intermediacy of allenyl aryl sulfonium ions 164 and a corresponding allenyl thio-Claisen rearrangement (Scheme 31c). 105−107 Recently, heteroaromatic S-oxides have been employed in C−H functionalization reactions, leading to C2or C3-arylated, -allylated, and -propargylated benzothiophenes (168−173, Scheme 31c). 108,109 Utilizing allyl sulfoxides, Procter and co-workers have also achieved the dual vicinal functionalization of related indoles (and other heteroaromatics) via a remarkable sequence of S E Ar/[3,3]-sigmatropic rearrangement (Scheme 31d). 110 In 2016, Procter and co-workers were able to exploit the nucleophilicity of unactivated alkynes for a formal C−H addition to aryl sulfoxides activated with triflic anhydride (Scheme 32). 111 In this mechanistically elegant transformation, an intermediate enol trilate (179) undergoes base-promoted isomerization to afford sulfur-ylide 180, which rearranges to form the desired propargyl arene products 181 after [3,3]sigmatropic rearrangement, rearomatization, and triflate elimination. One year later, expanding the reactivity to the incorporation of nitriles, Peng and co-workers were able to provide detailed mechanistic insight into this family of reactions, 112 Magnier et al. having reported a similar transformation of aryl perfluoroalkyl sulfoxides some years earlier. 113 The group of Peng was further able to extend the scope of sulfoxides by employing α-stannyl nitriles, thereby allowing for far milder reaction conditions. 114 While the methods detailed above hinge on the treatment of a sulfoxide-oxygen with an electrophilic activator, an alternative approach engages the sulfoxide in the trapping of a second, activated reaction partner (Scheme 33). In this context, the use of aryl sulfoxides as nucleophilic reagents for the capture of activated π-systems, followed by sigmatropic rearrangement affords α-arylated carbonyl compounds in a redox-neutral manner, whereby the carbonyl oxygen of the final products originates from the sulfoxide reagent itself. The earliest reports of this type of reactivity by the groups of Zhang, Toste, and Grainger focused on the gold-mediated activation of alkynes, followed by intramolecular sulfoxide capture (Scheme 33a), 115−117 and were only shown several years later to in fact proceed via sigmatropic rearrangement. 118 The first intermolecular variants of this transformation were reported by the Liu and Asensio groups, providing access to acyclic αaryl ketones (187) (Scheme 33b). 119,120 In lieu of catalytic activation using gold, alkyne derivatives can also be competently activated by simple Brønsted acids to afford electrophilic intermediates suited for sulfoxide attack (Scheme 34). In 2014, Maulide and co-workers reported the formation of arylated amide derivatives (191) through transient formation of keteniminium ions (190) from ynamides (Scheme 34a). 121 In analogy to this transformation, proceeding via addition of an aryl sulfoxide to the electrophilic position at the center of the keteniminium ion and subsequent [3,3]-sigmatropic rearrangement, the group also reported the α-arylation of amides. 122 Pivotal to this chemistry was the electrophilic activation of the amide substrate prior to sulfoxide addition, ensuring keteniminium ion formation over more readily occurring sulfoxide activation (Scheme 34a). The breadth of application of these redox-neutral arylations was further extended by the groups of Zhu and Maulide, employing ynol ethers, thioalkynes, unactivated alkynes, and propargyl alcohols (the latter leading to the formation of α-arylated α,βunsaturated carbonyl compounds (194) in an interrupted Meyer−Schuster rearrangement) as the substrates (Scheme 34b). 123−125 Notably, recent studies have shown divergence in terms of regioselectivity. With increasing electron-donating ability of substituents ortho-to sulfur, or additional bias in the arene substitution pattern, rearrangement into the metaposition becomes more favored with ratios of up to 10:1. Computational analysis revealed the new product to arise from an initial [3,3]-sigmatropic rearrangement onto the substituted ortho-carbon atom and a subsequent 1,2-alkyl shift, followed by rearomatization (Scheme 34c). 126 Owing to the chirality (stereogenic sulfur) of unsymmetrically substituted sulfoxides and their facile preparation, great interest has been placed in the use of such enantiopure reagents for enantioselective carbon−carbon bond formation. 127,128 In 2017, Maulide and co-workers were able to report an asymmetric variant of the sulfoxide-mediated arylation of ynamides and thioalkynes employing enantioenriched sulfoxides (Scheme 35a). 129 Herein, careful adjustments of the transition state by choice of the counteranion enabled the synthesis of a wide array of enantioenriched α-arylated carbonyl derivatives resulting from 1,4-chirality transfer from sulfur to carbon during the key [3,3]-sigmatropic rearrangement. Importantly, similar chirality transfer using enantioenriched sulfoxides in the sulfoxide-activation mode was shown to be less efficient, leading to racemic products. Chirality transfer was high but not perfect (on average 88% for ynamides and 85% for thioalkynes), a fact that can be ascribed to the competition between dearomatizing [3,3]-sigmatropic rearrangement and potential racemization of the intermediate itself. Most recently, this chirality transfer phenomenon was considerably enhanced for vinyl sulfoxides in the synthesis of 1,4-dicarbonyl compounds (203) by Maulide and co-workers (Scheme 35b). 130 All four possible stereoisomers could be obtained selectively by fine-tuning the chiral center at sulfur (responsible for absolute stereocontrol) and double-bond geometry (responsible for relative stereocontrol). In this intriguing transformation, a chairlike transition state reminiscent of those proposed for the allylboration of aldehydes was postulated to account for the stereochemical outcome. The reaction is further amenable to the construction of quaternary centers with high stereoselectivity. It is noteworthy that the presumably lower barrier for a [3,3]-sigmatropic rearrangement event not paying the energetic penalty of dearomatiza-tion allows complete chirality transfer without loss of enantiopurity from the reagents to the products.
De la Pradilla and co-workers have exploited the suprafacial nature of this reaction in their syntheses of pseudoconhydrine (212) as well as the core-structures of ent-dysiherbaine and deoxymalayamicin A (213) (Scheme 37a). 131,132 The Chida group reported a racemic application of the Mislow− Braverman−Evans rearrangement in their total synthesis of angelastatin. 133 In contrast to these applications, Manthorpe and co-workers observed an unwanted degradative [2,3]sigmatropic rearrangement of vinyl bissulfoxide intermediates 216 en route to (9R,10S)-dihydrosterulic acid (Scheme 37b). 134 In addition, the groups of Fukuyama, 135 in the synthesis of stemofoline cores, and Raghavan, in their approach to brefeldin A, 136 and phoslactomycin B (applying a propargyl Mislow−Evans rearrangement, Scheme 37c), 137 have shown the synthetic utility of this textbook transformation.
De la Pradilla and co-workers have furthermore exploited the stereoretentive nature of [2,3]-sigmatropic rearrangements for the construction of allylic stereocenters following conjugate addition to enantiopure vinyl sulfoxide derivatives (Scheme 38). 138,139 A related approach (not shown) was chosen by Zard and co-workers for the synthesis of α-keto vinyl carbinols. 140 At the beginning of this decade, the groups of Poli and Norrby investigated the synthesis of diaryl sulfoxides from allyl aryl sulfoxides (Scheme 39). 141,142 This transformation also hinges on an allylic sulfoxide−allyl sulfenate rearrangement. The resulting sulfenate ester 231 can, when attacked by a palladium catalyst, undergo oxidative addition to form a Pd−πallyl complex (233) and an aryl sulfenate anion (232). 232, in turn, can subsequently undergo palladium-catalyzed cross couplings with additional aryl iodides to afford unsymmetrical diaryl sulfoxides 235.
The addition of thioethers to metal carbenes leads to the formation of sulfur ylides (Scheme 40). When allyl sulfides are employed in this addition, the resulting intermediate 238 is prone to [2,3]-sigmatropic rearrangement in what is known as the Doyle−Kirmse reaction. Recent developments in sigmatropic rearrangements of sulfur ylides not derived from sulfoxides are covered in section 4.4.1.
Li and co-workers have reported a series of metal-free [2,3]sigmatropic rearrangements of related sulfur ylides, resulting in elegant allylic and propargylic C−H functionalization reactions (Scheme 41). 143,144 Mechanistically resembling Procter's arene-propargylation discussed in the previous section, 111 these transformations hinge on the nucleophilicity of the πsystem, furnishing intermediate allyl (242) and allenyl (244) sulfonium ylides. Their respective formations set the stage for the pivotal [2,3]-sigmatropic rearrangements to afford the products of C−H alkylation.
Scheme 42 shows a brief summary of sigmatropic rearrangements based on the reactivity of sulfoxides. [3,3]-Sigmatropic rearrangements can occur after formation of intermediate 249, which can be formed either by addition of a nucleophilic moiety (248) to an activated sulfoxide or by trapping an activated species such as 252 with a sulfoxide (Scheme 42a). In contrast, [2,3]-sigmatropic rearrangements as shown in Scheme 42b generally do not require activating agents and rely on thermal activation of allylic sulfoxides alone. The allyl sulfenates (208) formed thereby can either undergo S−O bond cleavage, affording allylic alcohols, or can be attacked by a suitable nucleophile to extrude the sulfenate, as shown by the formation of 233.

Sulfoxide-Mediated Oxidative Functionalization Reactions
The following chapters aim to provide an overview of recent developments in oxidative functionalization based on the use of a sulfoxide as either the reactant or the oxidant. The use of the simplest sulfoxide, DMSO, as a synthon and reagent in organic chemistry has been previously expertly reviewed by the groups of Magolan 145 and Wu, 146 and these works should be sought out for additional detail on historic transformations and developments preceding the scope of this review.
2.3.1. Allylic and Benzylic Functionalization. In contrast to the transformations depicted in Scheme 41, the treatment of allyl benzenes (251) with activated diphenyl sulfoxide in the presence of alkylamines was shown by Li and co-workers to afford the rearranged products of allylic functionalization (256 and 257) (Scheme 43). 147 A variety of cationic and dicationic intermediates were proposed to account for the divergence of the reaction, hinting at the versatility of sulfur(IV)-intermediates in the functionalization of allylic or benzylic positions, as well as alkenes, alkynes, and arenes (vide infra).
A recent addition to allylic functionalization using activated DMSO was reported by Zografos and co-workers, 148 providing a direct path to allylic chlorides (Scheme 44a). This transformation is based on an ene-type allylic chlorination of electron-rich alkenes, critically attacking the chlorosulfonium ion 259 at chlorine rather than sulfur. Interestingly, the converse unusual attack of a benzylic enolate on the sulfur atom of DMSO enables a base-mediated benzylic oxidation, as disclosed by Ravikumar and co-workers (Scheme 44b). 149 Intermediate 262, formed after this initial attack, undergoes [1,2]-sigmatropic rearrangement to afford an alkoxide, which in turn is further oxidized following a second attack on DMSO and E1cb-elimination.
Employing sulfoxides for the oxidative functionalization of tetrahydrocarbazoles (and other 2-substituted indole derivatives), Kawasaki and co-workers have reported a range of nucleophilic additions to sulfonium-activated intermediates (Scheme 45). 150 151 Intermediate 270, formed upon the second sulfoxide addition, can easily undergo Kornblum-type oxidation to form the corresponding benzylic ketone 271.
A similar strategy was employed by the same group in the oxidative dimerization of trypatime, affording homo-or heterodimeric pyrroloindolines at will. 152 2.3.2. Arene Functionalization. Moving away from electronically privileged allylic and benzylic positions, sulfoxide-mediated arene functionalization has also seen considerable synthetic efforts in the past decade. Recent additions to this class of transformation have focused predominantly on methyl-and alkylthiolation reactions, both in the absence and presence of transition metal catalysts (Scheme 46). In the context of metal-free methylthiolations, Roychowdhury and co-workers have reported the conversion of indoles, imidazopyridines, and other imidazo-fused heterocyclic compounds using a combination of DMSO and POCl 3 for the formation of chlorodimethylsulfonium ion 259 (Scheme 46a). 153 Notably, trace amounts of the corresponding chlorinated heterocycles were detected, reflecting the presence of a second electrophilic site in 259. Disulfides 154 and other dichalcogenides 155 have been employed for the functionalization of indoles and arylboronic acids, using DMSO as the stoichiometric oxidant for the regeneration of molecular iodine (Scheme 46b). Magolan and co-workers have, in turn, employed DMSO in the methylthiolation of electron-deficient aryl fluorides via S N Ar with dimethyl sulfide formed in situ (Scheme 46c). 156 A number of alternative, copper-based approaches to the methylthiolation of arenes have been reported in recent years, ranging from ortho-directed methylthiolation of arylpyridines proceeding via concerted metalation−deprotonation (CMD) 157,158 to the methylthiolation of aryl halides (Scheme 46d) 159−161 and heterocycles. 162 Similarly, Pan and co-workers reported the formation of 2-(phenylthiol)phenols (279) by tandem C−S coupling/C−H functionalization of aryl halides, aryl sulfides, and DMSO, via the proposed intermediate 280 (Scheme 46e). 163 Combining DMSO and hydrogen halides, Jiao and coworkers have developed a scalable procedure for the halogenation of arenes (Scheme 47). 164 This process, performed on up to kilogram scale, proceeds via the in situ formation of X 2 , the slow release of which is crucial for the regioselectivity of the process.
The inherent charge separation of DMSO (and indeed sulfoxides in general), rendering it both nucleophilic (at oxygen) and electrophilic (at sulfur) has led to its deployment in the functionalization of arynes (Scheme 48a). The groups of Xiao and Wang have shown that the addition of DMSO to aryne moieties can afford oxathietane intermediates 287, prone to undergo ring-opening to cyclohexadienone−sulfur ylides (288), themselves amenable to further in situ functionalization with electrophiles. 165,166 A range of further developments has shown that arynes, 167 electron-deficient arenes, 168 or tethered enoates 169 can engage in reactions with 288, functionalizing the intermediate phenolate. Also utilizing the reaction of arynes with sulfoxides, Li and co-workers developed a trifunctionalization reaction (Scheme 48b). 170 Herein, the use of an allyl sulfoxide leads to the formation of an oxathietane capable of undergoing an S-to-O allyl migration, followed by an oxonium Claisen rearrangement, affording a new carbon−carbon bond. A single intriguing example of aryne formation with subsequent capture with a sulfoxide was reported by the same group shortly thereafter (Scheme 48c). 171 Employing 3-triflyloxyarynes in [2 + 2]-cycloadditions, the authors were able to form benzocyclobutanes 294, which were readily opened via Grob fragmentation to afford new arynes. Apart from several other nucleophiles, the reaction with a sulfoxide was also reported, affording 296 as a single regioisomer.
When alkyl aryl sulfoxides are employed to capture arynes, deprotonation α to sulfur leads to the formation of an ylide that can be engaged in a range of Corey−Chaykovsky-type epoxidations (Scheme 49). 13,172 2.3.3. Alkene and Alkyne Functionalization. The combination of DMSO and a hydrogen halide, in this case HBr, enabled Magolan and co-workers to achieve the Br 2 -free dibromination of olefins (Scheme 50a, left). 173 The authors propose bromodimethylsulfonium ion 303 as the active reagent, leading to intermediate bromonium ion formation, followed by opening with a further equivalent of bromide. In contrast to Magolan's method, Jiao and co-workers have reported the formation of bromohydrins 304 (observed only in some cases by Magolan) from styrene derivatives/benzylic bromides under similar reaction conditions, employing DMSO both as the oxidant and the nucleophile for the opening of the intermediate bromonium ion (Scheme 50a, right). 174 Notably, rather than undergoing Kornblum-type oxidation to form the α-bromo ketone, intermediate 305 is presumably attacked at sulfur by bromide, furnishing the alcohol and reforming 303.
While for all intents and purposes relying on a similar combination of reagents, work by Li, Yuan and co-workers reporting the oxysulfenylation of styrenes is presumed to proceed via a radical mechanism instead (Scheme 50b). 175 There, the thermal homolytic cleavage of molecular iodine leads to the formation of both thiyl (308) and alkoxy (309) radicals that add across the reactive double bond.
In 2012, Maulide and co-workers disclosed the sulfoxidemediated umpolung of alkali halide salts, enabling halogenation of alkenes (through halolactonization) and enols (Scheme 50c). 176 Herein, Lewis acid activation of a sulfoxide enables the addition of a halide, forming tetrahedral intermediate 311.
This electrophilic species undergoes attack by the alkene in a halonium-type fashion.
Apart from halonium equivalents, other electrophilic reagents have also found application in the sulfoxide-mediated functionalization of alkenes (Scheme 51). In 2010, Danishefsky and co-workers described an intriguing process of epoxidation mediated by a tethered sulfoxide. 177 Herein, treatment of sulfoxide 314 with trifluoroacetic anhydride led to the formation of an electrophilic intermediate 315 (Scheme 51a). Subsequent attack of the tetrasubstituted double bond on the positively charged sulfur atom and interception of the resulting carbenium ion by the trifluoroacetate counteranion was shown to afford the stable salt 316. Final hydrolytic cleavage of the trifluoroacetate ester and 3-exo-tet epoxide formation concluded the highly diastereoselective oxidation sequence.
Akita and co-workers have reported the use of electrophilic Togni's reagent as a precursor for the photoredox-catalytic formation of a CF 3 -radical (Scheme 51b). 178 Following addition of said radical to a suitable olefinic coupling partner, single-electron oxidation by virtue of the photocatalyst was proposed to afford a cation (318), the interception of which with DMSO afforded an alkoxysulfonium intermediate (319). Structures of type 319 have been well-known for several decades, as they represent crucial intermediates in all DMSOmediated carbonyl formations (vide supra). Recently, Ye and co-workers have extended this approach to the oxo-alkylation of styrenes with alkyl radicals derived from redox-active esters using photoredox-catalysis. 179 Anodic oxidation was employed by Yoshida and co-workers for the functionalization and oxidation of both alkenes and benzylic positions (Scheme 52). Initially focusing on the direct oxidation of the substrate followed by interception of the resulting carbenium ion with DMSO (Scheme 52a), 180,181 the group later showed the potential of forming electrophilic halogens (325) and chalcogens through anodic oxidation (Scheme 52b). 182 Nucleophilic attack of an olefin onto 325, followed by interception of the resulting carbocation with DMSO once more led to the formation of intermediate 326, prone to Kornblum-type oxidation and resulting in formation of α-halogenated carbonyls (327).
An alternative pathway for the formation of cationic species susceptible to interception with sulfoxides was described previously (section 2.2.1). In addition to the transformations presented there, which incorporate the sulfenyl moiety through sigmatropic rearrangement, the groups of Liu, 120 as well as Maulide and Niggemann, 183 have shown differing reactivity in specialized cases (Scheme 53). While Liu's work on the goldcatalyzed addition of diphenyl sulfoxide to cyclobutylalkyne 328 was shown to instigate the [3,3]-sigmatropic rearrangement pathway described previously (Scheme 53a), direct fragmentation of intermediate 331 (resulting from addition of diphenyl sulfoxide to activated cyclopropylalkyne 330), accompanied by loss of diphenyl sulfide, was reported to lead to the formation of cyclobutenyl ketone 332 through ringexpansion. A related oxidative rearrangement, hinging on suppression of the sigmatropic shift through steric crowding of the reactive center, was recently disclosed jointly by the groups of Niggemann and Maulide (Scheme 53b). 183 Following capture of vinyl cation 334 with diphenyl sulfoxide, cleavage of the S−O bond leads to the formation of an α-carbonyl cation which readily undergoes a 1,2-hydride-or Wagner−Meerweintype carbon shift to afford 337 after terminating deprotonation. The use of Kornblum-or Swern-type processes for the formation of carbonyl compounds from π-unsaturated compounds, alluded to in the descriptions of several of the above transformations, has, in recent years, found application predominantly in the synthesis of α-ketoamides (Scheme 54). Starting from either styrenes (Scheme 54a, left) or phenylacetylenes (Scheme 54a, right), Shah and co-workers have shown that a combination of iodine and DMSO can lead to the formation of α-iodo ketones (342), 184,185 which are directly formed from ketones in works reported by the groups of Ahmed and Vishwakarma (Scheme 54b). 186,187 The formation of α-carbonyliminium ion 343 from 342 is common to all processes depicted in Scheme 54 and is followed by nucleophilic addition of DMSO and subsequent Kornblumtype oxidation to furnish the amide carbonyl.
2.3.4. Kornblum-Type Oxidations. Among the most common oxidation reactions in organic chemistry, the suite of Kornblum-and Swern-type oxidation reactions developed to date is countless, and much of recent research has focused on rendering known processes more economical and environmentally friendly. Owing to these circumstances, we urge the interested reader to turn to refs 8−11 for further and in-depth information.
As described above, the α-halogenation of ketones mediated by the combination of DMSO and a halide has been a prime source for recent developments in the area of Kornblum-type oxidations (Scheme 55). In this regard, and in addition to the previously mentioned examples, the groups of Cao and Deng have developed further protocols for the α-oxidation of ketones with DMSO and HBr. 188,189 Similar results were obtained by Jiao and co-workers, achieving selective αhydroxylation of linear and α-branched ketones (347), using substoichiometric amounts of iodine and a large excess of DMSO (Scheme 55a). 190 In situ 1,2-dicarbonyl formation was additionally exploited in Wu and co-workers' oxazole synthesis, as shown in Scheme 55b. 191

Metal−Sulfoxide Exchange
Organometallic reagents have long been employed as strong bases and highly reactive nucleophiles in organic synthesis. They are classically generated through the addition of a suitable metal (most often lithium or magnesium) to a halogenated precursor, often forming a metal salt as a byproduct. While this remains the method of choice in the generation of simple organometallic reagents, access to more complex structures usually requires a more subtle approach. The halogen−metal exchange, popularized by Gilman and Wittig in the late 1930s, 192−195 represents such an option. The formal metathesis reaction between an organolithium and an organic halide operates under thermodynamic control, affording the more stable organometallic reagent. A prime example of this control would be the reaction of an alkyl lithium species with a haloarene to generate an aryl lithium species. Analogous reactivity has since been demonstrated whereby, instead of halide-containing precursors, sulfoxides are the substrates of choice. As demonstrated in Scheme 56, an organometallic reagent is thought to have the ability to add reversibly to the electrophilic sulfur center, forming what is known as an σ-sulfurane (354). This metastable, hypervalent intermediate could then expel one ligand to generate the most stable organometallic reagent, and a sulfoxide that represents the formal product of nucleophilic substitution at the sulfur center (355). The precise mechanism of this process is Regardless of the mechanism, this method can be used for either for the stereospecific synthesis of chiral sulfoxides (section 2.4.1) or for the selective preparation of complex organometallic reagents (as will be discussed in section 2.4.2).
2.4.1. Metal−Sulfoxide Exchange for Sulfoxide Synthesis. The synthesis of chiral alkyl aryl sulfoxides has long been reliably achieved through the use of Andersen's reagent (356), a menthol-derived sulfonate ester, pioneered in 1962 (Scheme 57a). 196 Reaction of the aryl sulfinate ester with an alkyl organometallic reagent forms a sulfoxide (357) and metal mentholate salt. The reaction is generally stereospecific, the While this stereospecificity has been observed over a wide range of aryl-derived sulfinate esters, the reliability tails off notably for alkyl sulfinate esters. As a result, alternative methods for the synthesis of dialkyl sulfoxides have been sought. Indeed, one of the very first synthetic methodologies to employ metal−sulfoxide exchange involved a lithium− sulfoxide exchange between an alkyl aryl sulfoxide and an alkyllithium species, generating a dialkyl sulfoxide with inversion of configuration. 197 More recently, Friedel−Craftstype reactivity has been shown with racemic sulfinate salts to achieve the sulfinylation of electron-rich arenes. 198 A recent development in this field was reported by the group of Bruckner in 2015, involving the desymmetrization of symmetric diaryl sulfoxides by a chiral organometallic reagent, generated through the combination of a dialkylmagnesium with a Li 2 -(S)-BINOLate salt (360) (Scheme 57b). 199 High selectivities were observed over a broad range of substrates in what represents the first example of an enantioselective metal− sulfoxide exchange. Because symmetrical aryl sulfoxides are easily synthesized, this methodology has the potential for practical applications.
2.4.2. Metal−Sulfoxide Exchange for the Generation of Organometallic Species. While the above developments have contributed to the synthesis of enantioenriched sulfoxides, the major applications in recent years have predominantly been in the field of sulfoxides as organometallic precursors. When compared with halogen−metal exchange, the advantages of metal−sulfoxide exchange are not limited to selectivity and functional group tolerance. The chiral nature of sulfoxides allows for the facile synthesis of diastereomerically pure substrates, which can then easily be converted into enantiopure organometallic reagents, useful for asymmetric synthesis.
Remaining for the present outside the arena of asymmetric synthesis, metal−sulfoxide exchange reactions have been shown in recent years to be of use in the preparation of high-energy intermediates such as benzynes and cycloalkynes.
Benzyne in particular has long been employed in organic synthesis, allowing for the rapid multifunctionalization of aromatic rings, either through a difunctionalization approach or cycloaddition chemistry. 200 The use of Grignard reagents to generate arynes through metal−sulfoxide exchange followed by β-elimination is orthogonal and complementary to the use of the classical Kobayashi precursors, relying on the fluoridepromoted elimination from an ortho-silyl aryl triflate (as briefly shown in section 2.3.2). Originally reported in 1987, 201 employing halide-based precursors, the methodology has recently been improved upon by the group of Hosoya by exchanging the halide leaving group for a triflate. 202 Shortly afterward the same laboratory demonstrated that a similar approach could be employed for the in situ synthesis of strained cycloalkynes. 203 The authors detail the preparation of seven-and eight-membered cycloalkynes, the latter being stable enough to isolate but the former requiring in situ preparation. These cycloalkynes generate a wide range of interesting products through either (3 + 2)-or [4 + 2]cycloaddition reactions at 0°C in short reaction times (Scheme 58).
In a series of publications, Knochel et al. combined a sulfoxide-directed ortho-metalation/functionalization reaction with a magnesium−sulfoxide exchange for the difunctionalization of arenes. 204−207 In these reports, they employ a "Turbo-Hauser base" (370) for selective ortho-metalation, and a "Turbo-Grignard reagent" for the magnesium−sulfoxide exchange (Scheme 59a), with each generated intermediate able to react with a range of electrophiles. The high functional group tolerance allows for the generation of a wide range of 1,2,4-trisubstituted arenes in addition to 1,2-disubstituted heterocycles.
In addition to simple capture with electrophiles, intermediates generated through metal−sulfoxide exchange can also be functionalized through catalytic cross-coupling reactions. A prime example of this is the synthesis of highly substituted aziridines (375) through a magnesium−sulfoxide exchange/ cross-coupling sequence reported by Bull et al. in 2013 (Scheme 59b). 208 A range of highly functionalized sulfinyl aziridines 373, easily accessed through a Darzens-type process between an α-halosulfoxide and PMP-imine underwent the reaction efficiently in a stereoretentive manner. The stability of the generated aziridinyl Grignard reagent 374 (and subsequent aziridinyl zinc) was a key point of interest in the investigation, with reaction yields seen to diminish when delays were introduced prior to the addition of the catalyst mixture due to degradation of the intermediate. As previously discussed, the chiral nature of sulfoxides allows for metal−sulfoxide exchange processes to be used in asymmetric synthesis. In what is by far the most common use of metal−sulfoxide exchange in the academic literature of the past decade, chiral sulfoxides can readily serve as precursors to lithium/magnesium carbenoids, typically used for the homologation of boronic esters (Scheme 60). A slew of papers detailing the use of α-halo sulfoxides have been released from the group of Blakemore over the past 10 years. 209−215 A number of deleterious side reactions were sometimes observed when these precursors are employed and, as a result, investigations by O'Brien 216 and Aggarwal 217 focused on the use of α-sulfinyl carbonates and benzoates, respectively. O'Brien's synthesis relied on a double induction strategy involving a chiral base and Andersen's sulfinate to generate the key sulfoxides. In contrast, Aggarwal and co-workers preferred to use an achiral base and separate the two diastereomers formed, allowing access to either carbenoid epimer. It was additionally possible to diastereoselectively alkylate these chiral α-sulfinyl benzoates, allowing for the generation of quaternary centers.
Once generated, these diastereomeric α-sulfinyl benzoates Despite the rich breadth of metal−sulfoxide exchange chemistry, there are of course potential difficulties when it comes to controlling the reaction outcome. Not only can the organometallic reagents potentially react with other more reactive centers, but even in the event of interaction with the sulfoxide, the reaction path can be unpredictable. Often the identities of the sulfoxide substituents are the key to this selectivity. For instance, in Knochel's arene difunctionalization chemistry, 207 the formation of the more electron-poor Grignard reagent (Ar is either p-anisyl or p-dimethylaminophenyl) is key to the method.
Despite several years of study, not much is known of the precise mechanism, with various theories propounded. In addition to an ill-defined radical pathway, an interesting proposal (as detailed in the introduction of this section 2.4) involves a reversible addition of the organometallic reagent to the sulfur center forming a metastable σ-sulfurane 386 (Scheme 61). The latter, in addition to expelling a leaving group as a new Grignard reagent, can also theoretically undergo a reductive elimination-type pathway to generate a magnesium sulfenate 388 in addition to a C−C cross coupling product. This process, first observed by Oae in the late 1980s 218 (see also Oae and Trost's ligand coupling reactions involving sulfonium salts), 219,220 was studied in great detail to try to ascertain the mechanism. However, synthetic applications have remained limited. The scope of the reaction, and the potential for accessing chiral Csp 2 −Csp 3 coupled products (without resort to transition metal catalysis) was assessed in a 2016 publication by the laboratory of Stockman (Scheme 61). 221 Among other results, Stockman showed that the ligandcoupling reaction could occur with faithful retention of stereochemistry at any carbon-based stereogenic centers, which can (as has been seen above) be generated by the diastereoselective functionalization of a chiral sulfoxide. While the scope of C−C coupling products is largely limited to 1,1diarylalkanes, the reaction remains intriguing for its insight into the potential mechanism of metal−sulfoxide exchange.

Cross Coupling of Sulfoxides
Recently, the cross-coupling of organosulfur compounds as electrophiles has seen increased interest. These reactions focus mainly on the coupling of sulfonium salts, unactivated sulfides, and sulfones. 222 In stark contrast, cross-coupling reactions with sulfoxides have been far less investigated. Conceptually, two distinct approaches are known: desulfurylation reactions, proceeding under extrusion of a sulfenate as the byproduct, and sulfoxide syntheses, in which the sulfenate is engaged in metal-catalyzed coupling reactions and incorporated into the desired product. The recent advances on the cross-coupling of sulfoxides will be discussed in this section.
2.5.1. Desulfurylation Reactions. Seminal work by Wenkert and co-workers revealed the possibility of palladium-catalyzed coupling of aryl sulfoxides with methyl-and arylmagnesium reagents to obtain the corresponding desulfurized cross-coupling products. 223 In 2013, Enthaler reported a similar transformation, using nickel catalyst 390 (Scheme 62). 224 However, only three examples were reported with moderate yields.
In 2017, the group of Yorimitsu developed a Sonogashira− Hagihara-type coupling of diaryl sulfoxides with terminal alkynes using palladium−PEPPSI as a precatalyst, 225 and more recently, the same group reported a palladium−NHCcatalyzed Buchwald−Hartwig-type coupling with a variety of amines, affording aniline derivatives (Scheme 63). 226 In contrast to these palladium-catalyzed reactions of diaryl sulfoxides, in the case of nickel-catalyzed cross-coupling of the more readily accessible alkyl aryl sulfoxides with diarylzinc nucleophiles, the alkanesulfenate anions generated as leaving groups during the course of the reaction inhibit catalytic turnover. Oxidative homocoupling of the diarylzinc reagent (with concomitant reduction of the sulfenate anion to a thiolate) readily consumed the former species, resulting in an efficient catalytic reaction (Scheme 64). 227 The cross-coupling reactions afford biaryls 398 in good to excellent yields, albeit accompanied by an equimolar amount of the homocoupling byproduct, which can result in difficult purifications.
Carbon−heteroatom bond formations such as borylation 228,229 and phosphinylation 230 using aryl sulfoxides have also been reported, are, however, often low-yielding and limited in scope. 2.5.2. Sulfoxide Synthesis. Madec, Poli, and co-workers reported that sulfenate anions could also be employed as nucleophiles in palladium-catalyzed cross-coupling with aryl halides to yield diaryl sulfoxide products. β-Sulfinyl esters (400) could be used for the in situ generation of sulfenate anions through retro-Michael reaction (Scheme 65a). Subsequent arylation with aryl iodides afforded diaryl sulfoxides 195 in good yields but with only moderate substrate scope. 231 The reaction was also rendered enantioselective by replacing XantPhos with a chiral ligand. Josiphos was found to be the best ligand, affording the diaryl sulfoxides in good yields and moderate ee (not shown). 232 A more general and robust approach for the enantioselective arylation of general sulfenate anions was recently reported by Zhang and co-workers, using a XantPhos-derived PC-Phos ligand (Scheme 65b). 233 Additionally, Tan and co-workers disclosed an organocatalytic approach for the enantioselective alkylation of sulfenate anions generated from sulfoxides, using halogenated pentanidium salts as phasetransfer catalysts. 234 Other strategies to generate sulfenate anions in situ through Mislow−Evans rearrangement have been previously discussed (section 2.2.2, Scheme 39) and should be complemented at this point, although not involving sulfoxide formation, by Zhang's sulfinamide synthesis (Scheme 65c). 235 Herein, the sulfenate anion is engaged in a copper-catalyzed coupling with benzoylhydroxylamines (404) to afford the desired products 405 in moderate to excellent yields.
The group of Walsh reported that sulfenate anions can also be generated from aryl benzyl sulfoxides (406) (Scheme 66). 236 The process involves sulfoxide α-arylation, C−S bond cleavage to form the sulfenate anion and finally arylation. The diarylmethyl tert-butyl ether byproduct 408 of C−S bond cleavage could be isolated from the reaction mixture, corroborating the proposed mechanism.
This process was found to allow for the coupling of a wide variety of readily available aryl benzyl sulfoxides with several (hetero)aryl bromides in good to excellent yields. A catalytic

Chemical Reviews
Review asymmetric coupling was achieved with a JosiPhos derivative as the ligand, affording a wide range of diaryl sulfoxides that would be difficult to synthesize using classical enantioselective sulfide oxidation protocols with good to excellent enantioselectivities. 237 While not involving bond formation or cleavage at sulfur, the possibility of dynamic kinetic resolution of allyl 238 or vinyl sulfoxides 239 should be mentioned as an elegant means for obtaining enantioenriched sulfoxides.

SULFONIUM SALTS
Sulfonium ions are positively charged sulfur ions with three organic substituents and as such have been employed in a wide range of reaction types, exploiting their inherent electron deficiency. Compared to their oxygen analogues, the oxonium salts, they show increased stability and most sulfonium salts are easy to handle, bench-stable compounds. In general, the chemistry of sulfonium salts is dominated by their tendency to form an uncharged sulfide (Scheme 67). In this regard, they resemble organohalides displaying excellent nucleofugal properties, facile one-electron reduction and a propensity to undergo oxidative addition with transition metal catalysts. Sulfonium salts have thus shown to be highly versatile reagents in C−C and other bond-forming reactions and have seen a wide range of applications.
If combined with simple nucleophiles, sulfonium ions will undergo classical nucleophilic substitution reactions and have even been used as excellent leaving groups in S N Ar processes, where they display the added advantage of enabling reactivity on only moderately electron-poor aromatics due to their innate positive charge (Scheme 67a). In this context, arylsulfonium salts have found widespread application in the radiolabeling of medicinally relevant compounds with fluorine-18. 240−244 The addition of a single electron to a sulfonium ion leads to its fragmentation, forming a carbon-centered radical (Scheme 67b). This type of process has been of great interest in recent years, especially for the introduction of fluoroalkyl groups into organic substrates, the prototypical reagent for this application being Umemoto's reagent.
The abstraction of a proton α to the sulfonium moiety leads to the formation of sulfur ylides (Scheme 67c), a class of compounds displaying a rich and versatile chemistry which will be discussed in chapter 4.
Owing to the ease with which oxidative addition into the C− S bond of sulfonium ions can take place, these compounds have found application in transition metal-catalyzed crosscoupling reactions, mainly employing palladium and nickel catalysts (Scheme 67d).
Interestingly, the irradiation of sulfonium salts with UV light can also effect C−S bond cleavage affording radicals, the recombination of which is known to lead to the release of a proton (Scheme 67e). 245 This property has led to the use of sulfonium salts as photoacid generators, an application that has found widespread implementation in the synthesis of photoresponsive materials. Notably, recent developments have led to the synthesis of visible-light responsive sulfonium-based photoacid generators. 246 Vinylsulfonium salts constitute a privileged class of sulfonium ions, able undergo bond formation with nucleophiles at their β-position, forming sulfur ylides which themselves can form up to two new bonds (Scheme 67f).
Just as the wide variety of possible reactions of sulfonium ions mentioned above, the multifaceted reactivity of vinylsulfonium salts will be presented in this chapter, highlighting the most recent and compelling transformations.

Sulfonium Salts As Fluoroalkylating Agents
Increased interest in fluorinated organic molecules by medicinal chemists has led to the development of a myriad of approaches for the introduction of fluorine or fluorinated moieties. 247,248 In this context, many sulfur-based reagents that enable a wide range of approaches for the introduction of fluorine have been developed and heavily studied. Owing to the immense impact of organofluorine compounds in recent decades and the interconnected interest in methodological development, a number of excellent reviews on the topic of fluoroalkylation have been published and should be consulted for information complementing the survey presented below. 249−262 In this section, we aim to present a short overview of their reactivity and their most commonly found transformations: reaction with nucleophiles, photoredoxcatalyzed processes, and transition metal-catalyzed reactions that proceed through trifluoromethylated metal species.
Since their emergence toward the end of the last century, several fluoroalkylated sulfonium salts have been developed as electrophilic fluoroalkylating agents, the groups of Umemoto, 263 Shreeve, 264 Shibata, 265 Prakash, and Olah 266 and others making many contributions to the advancement of the field (Scheme 68a). All of these sulfonium-based reagents possess a similar aromatic core structure. In the process of studying derivatives of 409, it was found that the reactivity can be further enhanced by the introduction of electron-withdrawing groups; 260 moreover, sulfonate groups have been used to increase the reagents' solubility in water and thus simplify purification. 267 As shown in Scheme 68b, nucleophiles can be directly engaged in fluoroalkylation reactions in polar solvents and under mild conditions. However, the scope of suitable nucleophiles can vary immensely. This discrepancy in reactivity and generality has been attributed to a change of mechanism (that can vary between an ionic (CF 3 + ) and a radical (CF 3 • ) pathway) depending on the nature of the nucleophile, the properties of the fluoroalkylating agent and the reaction conditions. 268 For example, mechanistic investigations have suggested a radical pathway in the reaction with silyl enol ethers, 269 and in rare cases, a mechanism involving carbene formation is also observed. 270 With some nucleophiles, such as amines, sulfonium salts can form donor−acceptor complexes (EDA complexes), able to generate CF 3 -radicals which can be used for the trifluoromethylation of arenes. 271 More commonly, trifluoromethyl radical transformations with sulfonium salts can be performed using photoredox catalysis (Scheme 69). 261 A representative catalytic cycle is shown in Scheme 69a: upon photoexcitation, a range of common photoredox catalysts are able to reduce trifluoromethyl sulfonium salts (414) via single-electron reduction, leading to fragmentation with the formation of a trifluoromethyl radical (415). Addition of this radical to an alkene or an alkyne forms a new carbon-centered radical (416) which, in turn, can be oxidized to the corresponding carbocation (417) propargation mechanism involving single-electron transfer (SET) to the sulfonium salt is also feasible (not shown). 417 can be trapped by a number of nucleophiles, such as water, alcohols, carboxylates, nitriles, or halides, affording a wide range of products (Scheme 69b). As shown in Scheme 51b, using dimethyl sulfoxide as the solvent, α-trifluoromethyl ketones are obtained after Kornblum-type oxidation. 178 Direct hydrotrifluoromethylation has also been achieved using methanol as the terminal reducing agent. 272 Under similar conditions, internal alkynes can be functionalized with sulfonate nucleophiles to afford sulfonyloxy trifluoromethylated alkenes. 273 These vinyl triflate products can be subjected to palladium-catalyzed cross coupling, allowing stereoselective access to a range of tetrasubstituted alkenes bearing a trifluoromethyl group.
The combination of transition metals (such as copper or palladium) with Umemoto's and related reagents, leading to the formation of trifluoromethylated metal species, is another extremely versatile group of transformations for the incorporation of fluoroalkyl group in organic compounds. 252,253 Most commonly, these reactions involve the intermediacy of Cu I , Cu III , or Pd IV species (Scheme 70a). With elemental copper, trifluoromethyl sulfonium salts are readily reduced to form the highly versatile CuCF 3 species (after a second SET) under mild conditions. This facile process was applied to the cross coupling of aryl iodides, aryl boronic acids, and aniline derivatives, the latter reaction involving the in situ formation of the corresponding diazonium salt to form trifluoromethylted arenes (Scheme 70b). More recently, MacMillan and coworkers have been able to cross couple previously challenging aryl bromides and convert them into their trifluoromethylatedderivatives by employing a combination of photocatalysis and copper catalysis. 274 Moreover, the trifluoromethyl group can be directly be installed with the use of directing groups. 275,276 A combination of catalytic Pd(OAc) 2 and stoichiometric Cu(OAc) 2 can be used to introduce the trifluoromethyl group at the orthoposititon of a range of directing groups (Scheme 70c). This reaction is not limited to the trifluoromethyl group, also lending itself to a range of different alkyl groups that can be introduced, using the respective sulfonium salts. 277

Cross Coupling of Sulfonium Salts
While the cross coupling of sulfides and thioesters (both S(II) compounds and therefore not within the scope of this review) is well developed and has found many applications, 222,278,279 the use of sulfonium salts as coupling partners, pioneered by Liebeskind and co-workers toward the end of the last millennium, 280,281 offers significant advantages (Scheme 71). 90,222 Most notably, (hetero)aryl (as well as alkenyl or benzyl) sulfonium salts (426) promise to exhibit considerably increased tendency to undergo oxidative addition, owing to their inherent electron deficiency, and additionally, catalyst poisoning by the corresponding leaving group in sulfonium cross coupling (a thioether) is less likely than in the case of a thiolate leaving group. For these reasons, while laying dormant for several years, recent reports have highlighted the utility of transition metal-catalyzed cross-coupling reactions of sulfonium ions.
While the aforementioned traditional sulfonium crosscoupling reactions rely on activation of the S−C aryl bond, Lu, Shen, Lu, and co-workers reported the interesting selective cleavage of the S−C vinyl bond of 428 to afford styrenes (429) after Suzuki-type cross coupling (Scheme 72a). 282 Additional experiments highlighted the importance of the vinylogous trifluoromethyl group to ensure both the reactivity and the desired chemoselectivity. Apart from this report, all crosscoupling reactions of sulfonium ions rely on the activation and cleavage of the S−C aryl bond, affording a functionalized arene as the product.
In this context, in 2015, Yorimitsu and co-workers disclosed the facile transformation of dibenzothiophene (430) into triphenylenes (434), which relied on sequential double alkylation and cross coupling via alkylsulfonium salts 431 and 433 (Scheme 72b). 283,284 Following this transformation, Chemical Reviews Review the same group was able to develop a general palladiumcatalyzed cross coupling of arylsulfonium salts with sodium tetraarylborates (Scheme 72c), 285 a similar transformation, albeit on specialized substrates, having been reported in a metal-free variant a year prior by Huang and co-workers. 286 In 2016, Zhang and co-workers, as well as the groups of Cowper and Lewis reported Suzuki-type cross-coupling reactions of arylsulfonium salts with arylboronic acids and esters, enabling the syntheses of biphenyls, stilbenes, 287 and arylated azulene derivatives, respectively. 288 Moreover, the Zhang group also developed Mizoroki−Heck and Sonogashiratype coupling reactions of diarylsulfonium salts (Scheme 73a). 289,290 A similar approach was utilized by the Yorimitsu group, coupling monoaryldialkylsulfonium salts with enol ethers, affording the corresponding aryl ketones after hydrolysis (Scheme 73b). 291 Yorimitsu and co-workers were also able to show that arylsulfonium ions readily undergo cross-coupling with diboron reagents, affording arylboronic esters (Scheme 73c). 292 Notably, the authors established that this transformation can be carried out in a one-pot process starting from the aryl sulfide that is methylated in a first step, prior to cross coupling.
More intricate methods for the two-step conversion of sulfides into sulfonium ions, followed by transition metalcatalyzed cross couplings, have also been reported. While the Yorimitsu group showed that the reation of 84 with 85 and electrophilic activators could afford the sulfanylated coupling product 86 through aromatic additive Pummerer reaction (as previously seen in section 2.1.6, Scheme 19), 59 the same publication also highlighted that the intermediate sulfonium salt 445 (isolated by facile precipitation) could be employed in cross-coupling reactions with tetraarylborates (Scheme 74). The authors encountered low chemoselectivity in the case of acyclic diarylsulfonium salts but were able to overcome this challenge by employing cyclic sulfides (444), favoring subsequent cleavage of the exocyclic C−S bond. Moreover, Procter and co-workers have also established nickel-catalyzed Negishi-type cross-coupling reactions of vinylsulfonium salts as a facile means of carbon−carbon bond formation (see Scheme 29), thereby complementing the methods discussed above. 85

Vinylsulfonium Salts
Vinylsulfonium salts are versatile reagents in organic synthesis. Their reactivity mostly relies on the transient formation of a sulfonium ylide upon conjugate addition. Depending on the further reaction pathways adopted by this ylide, a wide range of synthetic processes are available (Scheme 75), rendering these species very appealing as building blocks for synthesis. A recently published review by Kerrigan and co-workers offers a comprehensive overview of products that can be obtained from vinylsulfonium and vinylsulfoxonium salts. 293 3.3.1. Forming One New Bond. In the simplest reaction pathway, the vinylsulfonium species acts as a vinyl cation synthon. Addition of a nucleophile with subsequent protonation and elimination of the corresponding sulfide leads overall to a vinyl transfer from sulfur to a heteroatom. This reaction is usually observed as a competing pathway in reactions with vinylsulfonium salts when a projected second nucleophile acts as a base instead, triggering elimination. In 2011, Aggarwal et al. studied the influence of the electron withdrawing substituent carried by a nitrogen nucleophile on the reaction pathway, specifically comparing sulfonamides and carbamates. 294 The latter led, after intramolecular cyclization, to the formation of vinyl carbamates (449) rather than morpholine derivatives by attack on the carbonyl carbon (Scheme 76a).
More recently, Qian and co-workers used vinylsulfonium salts for the N-vinylation of indoles (Scheme 76b). 295 Several αand β-arylvinylsulfonium salts (450) could be transferred to heterocyclic nitrogen atoms in high yields. Interestingly, pnitrophenyl and pyrimidine substituted vinylsulfonium salts reversed the regioselectivity of the vinylation and led to the Edouble bond isomer (456) instead of the expected 1,1disubstituted vinylation product akin to 454. The authors reasoned that the strong electron withdrawing ability overrides the directing effect of the sulfonium group, leading to initial nucleophilic addition to the sulfonium-substituted carbon.
The reactivity of vinylsulfonium salts was also exploited for transformations in biological systems. In a study by Zhou and co-workers on the enzyme thiopurine methyltransferase, Svinyl adenosylvinthionine 458 was synthesized which, instead of the natural S-methylsulfonium, bears a vinyl substituent. With suitable thiol substrates, sulfonium sulfide adducts 459 are formed which are strong inhibitors of the enzyme and thus allow only a single turnover (Scheme 77). 296  the authors could identify potential enzyme substrates and develop strong specific inhibitors.

Forming Two New Bonds.
Vinylsulfonium reagents can be used to link two nucleophiles together via a two-carbon unit, enabling annulation reactions to form cyclic products of various ring sizes.
During the past decade, several contributions have greatly advanced this chemistry. In 2008, the Aggarwal group recognized the potential of using vinylsulfonium salts (448) with substrates bearing two heteroatom nucleophiles, leading to a number of valuable building blocks from the morpholine, thiomorpholine, and piperazine family (Scheme 78a). 297 Excellent yields were generally obtained with sulfonamides as well as free amines.
Shortly thereafter, the same group demonstrated the feasibility of using bromoethylsulfonium salt 464 as an easyto-handle, bench-stable alternative to the oily vinylsulfonium salts (Scheme 78b). 298 Under the basic reaction conditions, the vinylsulfonium salt is generated in situ and reacts directly to afford the functionalized products. Among other sixmembered rings, this enabled the synthesis of pharmacologically relevant seven-membered 1,4-benzoxazepines and 1,4benzodiazepines (466).
In an attempt to access heterocycles with more substituents, an investigation into phenyl-substituted vinylsulfonium salts was also undertaken (Scheme 78c). 299 Using β-arylvinylsulfonium salts, however, only poor stereoselectivities and moderate yields were observed. Fortunately, switching to the geminally substituted isomer α-phenyl vinylsulfonium (468), high stereocontrol and regioselectivity were observed for a range of aminoalcohols and protected diamines.
In 2011, Xiao et al. employed the standard vinylsulfonium salt to provide access to a library of fused indole heterocycles (472 and 473) (Scheme 79a). 300 Interestingly, the use of the β-phenyl vinysulfonium salt led exclusively to N-vinylation.
Shortly thereafter, the group of Aggarwal investigated the sulfinyl moiety as a possible nitrogen protecting group alternative to the commonly used tosylamides, which are not always easy to remove. 301 To this end, the p-tolylsulfinyl p-tolyl sulfone 475 was used to install the sulfinamide group, which proved competent in the subsequent annulation (Scheme 79b). Facile removal under acidic conditions was demonstrated in high yields, using hydrogen chloride in ether. Inconveniently, sulfinamides generate diastereomeric mixtures due to the additional stereocenter at sulfur, leading to a more complex analysis (especially when other isomeric compounds can be expected to coexist in the reaction/crude mixtures).
Various heterocycles can also be obtained by using carboxylic acid derivatives in combination with vinylsulfonium salts. Recent additions include work by Xie and co-workers, who used simple carbamates to obtain various N-substituted oxazolidinones (480) (Scheme 80a). 302 In a similar fashion, Aggarwal et al. used formamidines (481) for the synthesis of imidazolinium ions (482) (Scheme 80b), 303 providing access to a range of symmetrical and unsymmetrical potential NHC precursors.
Extending possible modes of cyclization, Xie and co-workers used secondary amides to form γ-lactams (485) (Scheme 81a). 304 The reaction appears to be rather limited as the authors demonstrated that without the R 1 -substituent cyclopropanation is observed and without an additional electronwithdrawing group N,O-alkylation and subsequent hydrolysis leads to linear amino esters. In the case of N-alkyl malonyl amides the corresponding γ-lactones are formed due to preferred O-alkylation and hydrolysis (Scheme 81a). The synthesis of challenging substituted azetidines (490) was accomplished by Aggarwal and co-workers via the deployment of N-protected α-amino esters (Scheme 81b). 305 When malonates were employed, the process could also be extended to the synthesis of oxetanes in good yields.

Chemical Reviews
The group of Lin investigated the cyclopropanation of aminoketones using substituted vinylsulfonium salts 492, with high cis-selectivity observed for β-phenyl-substituted vinyl moieties (Scheme 82a). 306 In a related study, Chandrasekaran et al. investigated the scope of cyclopropanation using substituted 2-bromosulfonium salts (395) (Scheme 82b). 307 The use of unsymmetrical active methylene nucleophiles led to very good diastereomeric ratios, however, with higher substituted homologues, both reactivity and diastereoselectivty decreased significantly.
To assess how rhodium-catalyzed cyclopropanation using diazonium salts compares to the cyclopropanation of malonates with aryl substituted sulfonium salts, Yakura and co-workers set out to study both reactions on the same substrates (Scheme 83a). 308 In all cases studied, the yield of the sulfonium salt-mediated cyclopropanation was almost 2fold higher than the rhodium-catalyzed alternative. Recently, Qian and co-workers investigated the cyclopropanation of oxindoles (502) (Scheme 83b). 309 These are classically challenging substrates, as with unprotected oxindoles competitive N-vinylation, is commonly observed. In the event, the authors were able to show that the use of zinc triflate as an additive improves both reactivity and selectivity.
Another recent example of an annulation with carbon nucleophiles was published in 2018 by Yan et al. (Scheme 83c). 310 Therein, the annulation of naphthols and 4hydroxycoumarins to form a range of dihydrofurans was accomplished in good yields. In this case, the authors propose an electrophilic aromatic substitution as the first step; subsequent cyclization affords dihydrofurans, which can be oxidized by DDQ to the respective furan derivatives.
3.3.3. Forming Three New Bonds. If, after nucleophilic attack onto the vinylsulfonium species, the transiently formed sulfonium ylide engages in a Johnson−Corey−Chaykovskytype reaction, up to three new bonds can be formed in a single domino reaction. After Jimenez et al. showed the use of a vinylsulfonium salt in their synthesis of the mitomycin skeleton, 311,312 Aggarwal and co-workers generalized the reaction toward a number of fused nucleophiles bearing a carbonyl derivative (Scheme 84). 313 A number of epoxides fused to nitrogen heterocycles could be prepared with the use of achiral vinylsulfonium salts 448 in good yield yields. Furthermore, through the use of a chiral vinylsulfonium salt 509, the products could be obtained in high enantiomeric purity and the reaction was successfully applied in the formal synthesis of (−)-balanol (514).
The reaction can also be carried out in an intermolecular fashion, leading to epoxides or aziridines, respectively, as was shown shortly after by the same group (Scheme 85a). 314 A number of nucleophiles were used in the three-component reaction, albeit with modest diastereoselectivity in some cases. Interestingly, several specific substrates displayed a particular preference for either the cis-or trans-aziridine.
In an interesting extension, Aggarwal and co-workers took a closer look at substrates bearing chiral centers in combination with achiral and chiral vinylsulfonium salts (Scheme 85b). 315 Strong matched and mismatched effects were observed in the case of the chiral sulfonium salt 509. With a slight change of conditions, from using sodium hydride to employing DBU as a base, potentially epimerizable substrates such as 516 could also be used with no observable racemization.
During these investigations, formation of seven-membered rings (519) from γ-aminoaldehydes (518) was generally challenging as they preferentially exist in the cyclic aminal form, leading to a low concentration of nucleophile in solution (Scheme 86a). 316 Stereocontrol in the reaction leading to azepines was studied in more detail by Aggarwal et al. For substrates bearing a stereogenic center, a high dependency on the solvent was observed.
In 2012, Aggarwal and co-workers investigated the use of a more accessible chiral vinylsulfonium equivalent in the form of salt 521 (Scheme 86b). 317 In most cases however, lower enantiomeric ratios were observed when compared to previously studied derivative 509. Ley and co-workers compared vinylsulfonium and vinylphosphonium salts in their reaction with chiral β-hydroxyaldehydes (524) (Scheme 87a). 318 As expected, the two reagents both behave as conjugate electrophiles in a first step, eventually diverging toward epoxidation and olefination, respectively.
While tethered carbonyls afford three-membered epoxides, tethered Michael acceptors lead to cyclopropane derivatives. The group of Aggarwal employed ω-amino-unsaturated carbonyls, extending the applicability of vinylsulfonium salts to the synthesis of fused cyclopropyl pyrrolidines in a 2013 study (Scheme 87b). 319 With unsaturated ketone 531, epoxidation outcompeted cyclopropanation, while small amounts of the Michel addition product were also observed.
To access additional substitution on the fused heterocyclic systems, Aggarwal et al. studied aryl-substituted vinylsulfonium salts 536 in combination with α-aminoketones (Scheme 88). 320 Several tetrasubstituted epoxides were thus formed in good yields and, with Michael acceptors, high diasteromeric ratios were observed in favor of the exo-product.
Recently, Wu and co-workers used acceptor-substituted vinylsulfonium salts in a formal (3 + 2)-cycloaddition with sodium azide (Scheme 89a). 321 Interestingly, the vinylsulfonium salt could be generated in situ by nucleophilic substitution followed by aldol condensation with an aldehyde using catalytic L-proline. These acceptor-substituted vinylsulfonium species then engage the azide anion, leading to a range of triazoles (540). A large substrate scope and high yields add to the appeal of this method.
Another example of a formal cycloaddition of vinyl sulfonium salts was reported by Xiao et al., using stabilized isoquinolinium N-ylides (Scheme 89b). 322 In this case, the isoquinolinium salt (541) is deprotonated in situ and subsequently adds to the vinylsulfonium salt. The intermediate ylide cyclizes, followed by extrusion of diphenylsulfide, initially leading to a pyrroline derivative. Terminal oxidation delivers the fused pyrrole systems (542) in moderate to good yields.
3.3.4. Fluorinated Vinylsulfonium Salts. Fluorinated organic compounds play an increasingly important role in pharmaceutical chemistry. Because of its small steric, yet large electronic influence on the properties of molecules, as well as its contribution to increased metabolic stability, fluorine has gained a prevalent role in the structure of a large number of pharmaceuticals. With their wide applicability to form variously substituted heterocycles, vinylsulfonium salts have great potential to introduce fluorine atoms into readily available building blocks. Trifluoromethylated vinylsulfonium salt 543 was first prepared in 2010 by Hanamoto et al., who could show its use for the formation of trifluoromethylated aziridines (544) from primary amines, and as an N-and P-vinylation agent (Scheme 90). 323 Lu and co-workers developed the cyclopropanation of malonate derivatives with trifluoromethyl-substituted vinylsulfonium salts (Scheme 91). 324 Interestingly, three different products could be obtained simply by varying the reaction conditions. The expected cyclopropanation readily took place using DBU as the base, leading to a number of trifluoromethyl substituted cyclopropanes with good to excellent diastereomeric ratios (Scheme 91a). When sodium hydride was used, an isomeric product was formed which was shown to be cyclopropane 547 (Scheme 91b). The authors reasoned that the nucleophilic adduct would readily form a cyclobutene intermediate in the presence of sodium as the counterion. Retro-Aldol opening and subsequent displacement of diphenyl sulfide led to a new cyclopropane featuring both electron withdrawing substituents on adjacent carbons. Pleasingly, moderate to high yields and high diastereoselectivities were observed. Performing the reaction at low temperature, and using sodium hydride as the base, O-nucleophilic attack of the Shortly thereafter, an improved protocol by Hanamoto expanded the scope of cyclopropanation, again affording high yields and diastereoselectivities (Scheme 92a). 325 Importantly, amino alcohols only underwent vinylation of one of the heteroatoms, a challenge that could be partially circumvented by using a nonfluorinated vinylsulfonium salt for the formation of heterocycles with fluorinated substates (Scheme 92b). 326 Starting from fluorinated aziridine, trifluoromethylated piperazine (550) derivatives were obtained in a two-step one-pot manner.
In 2012, Aggarwal et al. successfully applied the trifluoromethylated vinylsulfonium salt 543 to make fused heterobicyclic systems (Scheme 92c). 327 It is important to note that the CF 3 group implemented a strong conformational fixation during the reaction, leading to virtually all substrates being formed as single diastereomers.
In 2015, Hanamoto and co-workers also demonstrated the synthesis and use of difluoromethyl vinylsulfonium salt 554 as a reagent for the synthesis of fluorinated building blocks (Scheme 93). 328,329 Aziridination (Scheme 93a) as well as cyclopropanation (Scheme 93b) could be carried out in very high yields using only a slight excess of the sulfonium reagent.

Propargylsulfonium Salts
Key to the reactivity of propargylsulfonium salts (559) is their facile isomerization to allenylsulfonium salts (560) under basic conditions (Scheme 95). These highly electrophilic inter-mediates can react in various, not always productive, manners, which explains the fact that their use in organic synthesis remained scarce for a long time.
Recently, the group of Huang has found several new domino reactions using propargylsulfonium salts, developing a synthesis of hydroindol-5-ones (563) in 2017 (Scheme 96). 331 After 5-exo-trig cyclization of the sulfonium ylide intermediate, double-bond migration and demethylation by attack of the bromide led to the methylthio substituted products in good yields. The authors demonstrated the dealkylation event using the cyclic sulfonium salt 565 (Scheme 96, bottom).
Later that year, the same group developed a route to hexahydropyrrolo [3,2- 332 Through a sequence of nucleophilic attack, cyclization, and displacement by a second nucleophile, the products are formed in good to excellent yields. This domino reaction leads to two new five-membered cycles and an exocyclic double bond that can serve as a reactive handle for further derivatization.
Propargylsulfonium salts were also successfully used in combination with sulfonyl amides tethered to a Michael acceptor, leading to bicylic enamides possessing a fused cyclopropane ring (571) (Scheme 97b). 333 The proposed mechanism is analogous to the case previously discussed for vinylsulfonium salts (see Scheme 87b). The products were found to hydrolyze over time or under acidic conditions to afford monocyclic aminoketones (572), a process that could be accelerated by simple addition of hydrochloric acid to the crude reaction mixture.
Most recently, Huang and co-workers reported the reaction of propargylsulfonium salts with indolo-phenolic substrates (573) (Scheme 98). 334 After isomerization to the allenylsulfonium salt, 2-fold nucleophilic addition with consequent protonation led to key intermediate 576, which afforded the sulfide 577 as a product of (5 + 1) annulation after final demethylation.

SULFUR YLIDES
Sulfur ylides are zwitterionic compounds defined by a carbanion and a neighboring, positively charged sulfur atom. They are known as a family of versatile reagents and have been widely applied as one-carbon synthons in a number of classical transformations, many of which have become textbook knowledge. The addition of sulfur ylides to electron-poor πsystems with subsequent elimination of the sulfonium moiety (generally in the context of epoxidation, aziridination and cyclopropanation reactions), as well as several rearrangement reactions, are the most representative examples (Scheme 99).
While reactions with unstabilized sulfonium ylides are known, most modern processes utilize stabilized versions, in which the negative charge is delocalized into one or more electron withdrawing groups. This added stability means that sulfur ylides can be used as practical, bench-stable reagents, and enables the development of reactions with increased complexity. Several classical reviews have been written to summarize the advances achieved during different periods. 335−339 Our discussion will focus on reactions of stabilized sulfur ylides in recent developments over the last 10 years.

Chemical Reviews
Review relied on the use of stoichiometric chiral sulfur ylides. In 2012, Bolm and co-workers reported a metal-triggered formal (4 + 1)-cycloaddition of sulfur ylides, which allowed for a remarkable catalytic and enantioselective version of this transformation. 340 By deprotonation of α-halo hydrazones (583) by action of Na 2 CO 3 , highly reactive azoalkene 586 was generated in situ (Scheme 100). This intermediate, further activated by coordination to a chiral BINAP−copper complex, can undergo subsequent enantioselective addition of a stabilized sulfur ylide (584) to afford a variety of enantioenriched dihydropyrazoles (585) in good yields with moderate to good enantioselectivities. Interestingly, stabilized sulfur ylides proved to be the best substrates for this reaction. While for many classical ylide transformations these compounds are usually considered as somewhat unreactive, this precise feature renders them easier to control in metalmediated processes.
The following years would usher in major developments in the generation of 1,4-dipoles from readily available starting materials. In 2014, the group of Xiao reported a palladiumcatalyzed decarboxylation/cycloaddition sequence with vinyl carbamates 587 as 1,4-dipole precursors. 341 This transformation allows the synthesis of a wide range of trans-2acyl-3-vinylindolines (590) with excellent diastereo-and enantioselectivity (Scheme 101). This was the first time the enantioselective capture of Pd-stabilized allylic zwitterionic intermediates by sulfur ylides was achieved. Both the aromatic moiety and the ylide-stabilizing group can be modified without significant loss of enantioselectivity. The optically active indoline products constitute valuable building blocks and offer straightforward access to complex chiral targets.
In 2016, the same reaction was reported with an Fe catalyst, 342 the group of Xiao showing that nucleophilic iron complexes provide similar reactivity with a reduced ecological footprint (Scheme 102). This was the first iron-catalyzed cycloaddition reaction of sulfur ylides. Although the reaction was not performed in an enantioselective manner, antidisubstituted indolines (592) were obtained with good yields and excellent diastereoselectivities.
Thereafter, the same group further applied asymmetric copper catalysis to a decarboxylative formal (4 + 1)cycloaddition reaction, changing the vinyl benzoxazinanone functionality to a propargyl benzoxazinanone (593) (Scheme 103). 343 Copper−allenylidene intermediates were proposed as reactive 1,4-dipoles, with initial studies identifying chiral PyBOX ligands (L3) as the most efficient in delivering the products in good yields with moderate enantiomeric excess. However, the enantioselectivity was drastically improved when the ylide was generated in situ by deprotonation of the corresponding sulfonium salt with an excess of DIPEA. Observed nonlinear effects strongly suggest the participation of a multinuclear complex in the enantio-determining step of the reaction. Other, related allenylidene-based reactions indicate that the presence of DIPEA could help the formation of such multinuclear species. 344 This could explain the remarkable enhancement of enantioselectivity observed when the reaction was performed with an excess of base. Despite the significant potential of these decarboxylative formal (4 + 1)-cycloadditions, the diversity of benzoxazinanones is strongly limited to vinyl or alkynyl substituted compounds. Very recently, the groups of Gouverneur and Shibata showed in a collaborative paper that this could be extended to CF 3 -substituted benzoxazinanones (597) (Scheme 104). 345 The CF 3 group is responsible for a strongly electrondeficient benzylic carbon, resulting in a highly electrophilic palladium-π-benzyl zwitterionic intermediate by oxidative addition to Pd(0) and enabling access to CF 3 -indolines, albeit in racemic fashion.
In 2017, Doyle and co-workers reported an elegant enantioselective copper-catalyzed synthesis of cyclobutenes (Scheme 105). 346 The reported strategy relies on a formal (3 + 1)-cycloaddition between sulfonium ylides and enoldiazo compounds as 1,3-dipole precursors. A wide range of cyclobutenes containing one or two stereogenic centers (600) were obtained in diastereoselective manner, with a bulky bisoxazoline ligand ensuring good to excellent levels of enantioselectivity.
The proposed mechanism is depicted in Scheme 105. In the first step, metal carbenoid 601 is formed by decomposition of the enoldiazo compound (598) in the presence of the copper catalyst. This intermediate 601 is assumed to be in equilibrium with donor−acceptor cyclopropene 602. This assumption was supported by the finding that independently prepared 602 also afforded the cyclobutene product in similar yield and selectivity when exposed to the reaction conditions. Sulfur ylides can add to 601 in nucleophilic fashion, followed by cyclization and decomplexation to afford the desired cyclobutenes, releasing the catalyst.

Transition
Metal-Catalytic Activation of Alkenes and Alkynes. The tremendous development of π-acid catalysis has enabled the activation of previously unreactive πsystems toward nucleophilic attack from a wide range of nucleophiles. This has inspired several groups to envisage transition metal-catalyzed cycloadditions of such π-electrophiles with sulfur ylides. In 2012, the groups of Maulide 348 and Skrydstrup 349 independently reported syntheses of furans based on this strategy. In both cases, a cationic gold complex allowed the activation of an alkyne and promoted a formal (3 + 2)-cycloaddition with a stabilized sulfur ylide. Maulide focused on intramolecular cyclizations of doubly stabilized sulfonium ylides (608), prepared via direct ylide transfer, 350,351 to afford bicyclic furans (609) (Scheme 107a). On the other hand, an intermolecular approach developed by Skrydstrup and coworkers led to a range of 2,4-disubstituted furans (611) in good yields (Scheme 107b). Analogously to the Skrydstrup procedure, the group of Maulide also reported the reaction of doubly stabilized sulfur ylides in an intermolecular context. Because of the lower reactivity of the starting materials, higher temperatures and a bulkier, electron-rich ligand were needed to ensure efficient formation of 2,3,4-trisubstituted furans (613) (Scheme 107c). 348 The cyclization step was then thought to proceed concomitantly with the extrusion of diphenylsulfide, delivering oxocarbenium ion 619, which is analogous to 616. Neither route has been conclusively disproven; nevertheless, the computational studies performed by Maulide and colleagues could not locate an energy minimum corresponding to a carbene or carbenoid intermediate.
During the development of the intermolecular furan synthesis with allyl ester substrates, the group of Maulide recognized a side product that did not incorporate the alkyne partner. Removal of the alkyne from the reaction mixture revealed that allyl ester-derived sulfur ylides are directly converted into cyclopropanes under gold catalysis. This intramolecular gold-catalyzed cyclopropanation proved to be remarkably efficient, proceeding in good yields, with excellent diastereoselectivity and tolerating a broad range of functional groups. 352 An interesting feature of the process was observed when investigating substituted substrates. Starting from either the "linear" or "branched" isomer of the starting material (620 and 621, respectively), the position of substituent R 2 in the cyclopropane products is identical (Scheme 109). This unexpected result suggested a complex underlying mechanism and motivated further mechanistic investigations, 353 which ultimately led to the development of an enantioselective version of this reaction. 354 A cationic gold complex supported by a dimeric TADDOL-based phosphoramidite ligand (L5) promoted asymmetric cyclopropanation with high degrees of enantioselectivity and diastereoselectivity. Strikingly, "branched" and "linear" isomers of the starting materials led to the same lactone-fused cyclopropanes (622) with high yields and optical purities.
Recently, the group of Maulide also reported the cyclopropanation of sulfur ylides with S-tethered olefins. 355 The cyclopropanation of sulfur ylide 623, carrying two olefins, showed high selectivity for the S-tethered olefin, affording product 624 in 75% yield (Scheme 110). Interestingly, the authors describe a catalyst-dependent cyclization, where other π-acidic catalysts such as Pd(II) and Pt(II) salts selectively afforded dihydrofuran 625 in moderate to excellent yields. Mechanistic experiments and computational studies have shown that palladium unlocks an oxidative addition/reductive elimination catalytic cycle that is not accessible with gold.
Interestingly, this novel approach for synthesizing threemembered rings (Scheme 110, top) allows new opportunities for diazo-free cyclopropanations. The process, however, proved difficult to extend to an intermolecular variant. Only the cyclopropanation of electron rich allenamide derivatives 627 turned out to be feasible thus far. 356 In the presence of doubly stabilized ylides and a cationic gold complex, smooth conversion to the methylenecyclopropane (628) was observed at room temperature (Scheme 111). Computational studies provided mechanistic insight, helping to explain both the regioand stereoselectivity of the reaction: The most electron rich double bond coordinates to the gold catalyst, while In most cases, variations of the substituents on the sulfonium group are of little interest because the corresponding sulfide is eliminated. In 2016, however, the Maulide group disclosed the results of their investigations into vinyl-substituted sulfur ylides 629. When treated with a gold(I) catalyst, these compounds were shown to efficiently undergo S-to-O vinyl transfers (Scheme 112). 357 The reaction resembles a Smiles rearrangement and was proposed to occur in two steps. An initial 5-exotrig cyclization through the attack of the carbonyl oxygen atom onto the activated vinyl substituent, followed by elimination to generate the final product. Alternative mechanistic pathways were ruled out through isotope labeling experiments. The products were in turn used as substrates for photocatalytic transformations.

Metal−Carbene Precursors.
In the previous section it was shown how sulfur-based ylides have been used as one-carbon synthons in a number of examples. One of the most ubiquitous methods of introducing such synthons is through metal carbene intermediates (also known as metal alkylidenes), generated from diazocompounds and metal complexes. Typical reactions include cyclopropanation and insertion into C−H and X−H (X = N, O, S, P, Se) bonds. 358−362 While diazocompounds are highly efficient and often used, their large-scale applications have significant drawbacks due to concerns of both safety and operational simplicity. The use of sulfur ylides as alternative reagents has therefore been actively investigated. 337,363 Intriguingly, the results of these investigations have shown a huge divergence in reactivity between sulfonium ylides, demonstrated as suitable substrates for cyclopropanation reactions, and sulfoxonium ylides (sulfur(VI), and therefore beyond the scope of this review), which are most suitable for X−H insertion reactions. 364−367 Neither examples of X−H insertion reactions employing sulfonium ylides, nor cyclo-propanations with sulfoxonium ylides have been reported to date.
The use of sulfonium ylides for catalytic cyclopropanation dates back to a publication of 1966 by Trost, 365 however, the process remains underdeveloped. Recent advances include the use of an iron porphyrin catalyst to decompose sulfonium ylides. Gu and co-workers reported the cyclopropanation of styrenes using the fluorinated ylide generated from sulfonium salt 631 (Scheme 113). 368 Good trans-selectivity was observed across a broad range of styrenes, although no alkyl-substituted or 1,2-disubstituted alkenes were tolerated. Key to this novel cyclopropanation was the use of the (TPP)FeCl catalyst (632), which significantly outperformed other catalyst systems, with Cu(acac) 2 able to achieve only 16% yield, and copper sulfate and rhodium diacetate completely inactive.
In 2017, the same group reported the synthesis of difluoromethyl cyclopropanes using the same catalyst system. 369 In this case, 20 mol % of Zn dust was added to assist the reduction of Fe(III) to Fe(II), which is believed to be the active catalyst in solution.
As shown in this section, transition-metal catalysis can be employed for a wide range of transformations of sulfur ylides, hinging on their reactivity as one-carbon synthons. In this context, the reaction with activated extended π-systems has enabled the efficient development of asymmetric (4 + 1)cycloaddition reactions, as well as some examples affording ring sizes other than five. Activation of alkenes and alkynes with transition metal catalysts has shown sulfur ylides to also be versatile reagents for formal (3 + 2)-or (2 + 1)cycloadditions, depending either on the choice of substrate or catalyst. A different approach toward the formation of cyclopropanes lies in the use of sulfur ylides as carbene precursors.

Asymmetric (Organocatalytic) Reactions
Organocatalysis has gained considerable notoriety over the past 20 years. 378 In this context, the deployment of sulfurbased ylides in organocatalytic annulation reactions based on various activation modes shall be presented in the following subsection. When organocatalysts without a carboxylic acid moiety were used, no product formation was observed. Attractive electrostatic interactions between the sulfonium cation and the carboxylate in the iminium complex were postulated, which could increase the nucleophilicity of the ylide and direct the nucleophilic attack. The reaction with L-proline as the organocatalyst afforded the product in a similar yield, but lower enantioselectivity due to the lack of E/Z control of the iminium configuration.
Inspired by this work, Arvidsson and co-workers developed two new organocatalysts (leading to slightly improved selectivities) by replacing the carboxylic acid functionality with either a tetrazole or aryl sulfonamide group. 380,381 The cyclopropanation of α,β-unsaturated ketones with sulfur ylides was first reported in 2013 by Feng and co-workers. 382 In the presence of chiral diamine 639, the reaction provided trisubstituted cyclopropanes (640) in moderate yields but with good enantioselectivities (Scheme 115).
4.2.2. Asymmetric Nucleophilic Catalysis. Organocatalysis with N-heterocyclic carbenes (NHCs) is recognized as a powerful tool in modern organic chemistry. In 2005, Studer and co-workers reported a classical example of asymmetric nucleophilic catalysis for the cyclopropanation of α,β-unsaturated aldehydes with sulfonium ylides, employing catalytic amounts of 642 (Scheme 116). 383 The reaction provided a wide range of trisubstituted cyclopropanes in moderate yields but with good diastereo-and enantioselectivities.

Asymmetric H-Bonding Catalysis. Cheng and
Xiao reported the cyclopropanation of β,γ-unsaturated αketoesters with sulfur ylides, catalyzed by an H-bonding urea catalyst (650) (Scheme 118). A range of cyclopropanes could be synthesized in moderate to good yields with enantioselectivities up to 80% ee. 385

Review
In 2008, the group of Xiao developed a formal (4 + 1)cycloaddition of nitrostyrenes with sulfur ylides, followed by a DMAP-catalyzed rearrangement reaction (Scheme 119). 386 This transformation affords a range of oxazolidinones (655) in moderate to good yields with good to excellent diastereoselectivities. The same group also reported an enantioselective variant of this reaction, using the same chiral urea catalyst 650 as shown before (cf Scheme 118). Despite the high enantioselectivities, the high catalyst loading (50 mol %) required to achieve good yields was a slight drawback of this process. 387 Recently, the same group disclosed an asymmetric formal (4 + 1)-cycloaddition of TBS-protected phenols with sulfur ylides (Scheme 120). The reaction proceeds through in situ generated ortho-quinone methides 659 and affords enantioenriched 2,3-dihydrobenzofurans (658) in good yields, but with moderate ee's. 388 4.2.4. Use of Enantioenriched Sulfur Ylides. In 2013, Aggarwal, McGarrigle and co-workers reported in-depth studies of sulfur ylide-mediated asymmetric epoxidations and aziridinations using a chiral sulfide 662 (Scheme 121). 389 This compound, later shown to be readily available on 25 gram scale, 390 was easily converted into the corresponding bench stable sulfonium salt 663 through alkylation (Scheme 121a). Subsequent in situ ylide formation was shown to enable diastereo-and enantioselective epoxidations and aziridinations on a wide range of substrates (Scheme 121b), with high amounts of the chiral reagent being easily recovered. In addition to exploring the scope of the transformation, extensive efforts were undertaken to determine the limitations of the reagent as well as rationalizations for the observed selectivities.
Another type of chiral sulfonium salt, reminiscent of 521 (cf Scheme 86), was applied to the Aggarwal group's synthesis of the cyclopiazonic acid family, employing 667 (Scheme 122). 391 Herein, the bromoisoxazole ensures semistabilization of the ylide generated in situ, rendering betaine formation the enantiodetermining step and leading to high levels of enantiomeric excess and good diastereocontrol. The resulting aziridine 668 was subsequently converted into cyclopiazonic acids 669 and 670 in only four further steps.
This section has shown that, in the absence of chiral metal complexes, asymmetry can be induced in a wide range of different manners. Many of the approaches for enantioselective cyclization reactions of suflur ylides rely on classical organocatalytic approaches, such as the condensation of chiral amines with carbonyl moieties or the transient addition of nucleophiles such as N-heterocyclic carbenes. Moreover, the use of (thio)urea catalysts for hydrogen-bonding catalysis and the use of chiral, enantioenriched sulfur ylides themselves has enabled a plethora of enantioselective transformations.

Photocatalytic Reactions of Sulfur Ylides
Radical reactions offer a complementary approach to ionic chemistry, 392−394 as reactive intermediates with an unpaired valence electron typically display reactivity inaccessible to twoelectron manifolds. The recent years have seen a revival of radical chemistry in organic synthesis due to the advent of photoredox catalysis. These reactions rely on the ability of an appropriate catalyst to trigger single electron transfer (SET) processes upon visible light irradiation. 395,396 In 2016, Xiao et al. reported a photocatalytic reaction in which doubly stabilized sulfur ylides (671) underwent a SET process, thus initiating a formal C−H insertion (Scheme 123). 397 The reaction occurs in the presence of 2 mol % of a cationic Ir(III) complex that can be excited by blue light irradiation. The resulting excited complex is a strong oxidant, capable of removing an electron from the sulfur ylide to form radical cation 673. Formation of five-membered intermediate 674 occurs more rapidly than decomposition of the ylide to form the free carbene. 365,398 Termination through either pathway a or b affords oxindoles in moderate to good yields.
Recently, the group of Xiao also reported a photoinduced formal (4 + 1) cyclization of sulfur ylides with N-tosyl vinylaniline 675 and a radical precursor (Scheme 124). The reaction is promoted by blue light and the use of Ru(phen) 3 Cl 2 as a photocatalyst to generate 2,3-disubstituted indoles in moderate to excellent yields. Interestingly, using Umemoto's reagent resulted in a remarkable catalyst-free procedure. 399 In contrast to the previous example in this section, the sulfur ylide is not directly involved in the SET process. The proposed mechanism (Scheme 124, bottom) involves addition of the initially formed radical R • to the styrene moiety of 675, followed by oxidation to the benzylic carbocation. The resulting ortho-quinone methide 678 is then captured by the sulfur ylide in a classical cycloaddition process. Sigmatropic rearrangements are a powerful tool for the efficient formation of C−C bonds, and [2,3]-sigmatropic rearrangements are no exception. Significant accelerations are observed when one or more bonds in the system are polarized; the fastest rearrangements take place when an atom bears a formal charge. In this context, it is not surprising that sulfur ylides are useful substrates for such transformations. The in situ formation of sulfur ylides through metal-catalyzed decomposition of diazo compounds followed by rearrangement has emerged as a synthetically appealing approach. The reaction of allyl or propargyl sulfides with metal carbenoids, followed by spontaneous [2,3]-sigmatropic rearrangement of the zwitterionic intermediate 680 is known as the Doyle−Kirmse reaction (Scheme 125, as alluded to in section 2.2.2.). This transformation has been studied extensively and offers a unique approach for the construction of S-substituted quaternary centers. 400,401 As for many classical diazo decomposition reactions, the Doyle−Kirmse reaction has been extensively studied with copper and rhodium catalysts, as they do not require complex ligand architectures. Nonetheless, the reaction has also been studied with catalysts based on other metals such as Co, 402 Ag, 403 Pd, 404 Ru, 405 The exploration of iron catalysts has led to the identification of highly efficient catalyst 684 that can be used in loadings as low as 0.2 mol % (Scheme 126). 412,413 Typically, allyl sulfides and propargyl sulfides are converted to homoallyl (685) and homoallenyl (686) sulfides, respectively, at room temperature in very short reaction times. Another compelling aspect of the Doyle−Kirmse reaction is its high functional group tolerance. Reactions can be chemoselectively performed in the presence of allyl ethers, boronates, disulfides, secondary anilines, and even free alcohols. 414 The [2,3]-sigmatropic rearrangement can also occur with an aromatic ring as the π-component and is then known as the Sommelet−Hauser rearrangement. The first example of a thia-Sommelet−Hauser reaction was described by Wang et al. in 2008 and relies on the in situ formation of sulfur ylides from diazo(aryl)acetates (687) and aryl sulfides under rhodium catalysis (Scheme 127). Despite the required dearomatization step, the reactions proceed smoothly at ambient temperature and deliver a range of di-and trisubstituted arenes in moderate to good yields. Interestingly, the mechanism involves an unusual ylide transposition (to form 689) prior to [2,3]sigmatropic rearrangement. 415 The group of Wang, employing a modified Gassman indole synthesis, applied this strategy for the synthesis of oxindoles (Scheme 128). Rhodium-catalyzed decomposition of diazo compounds in the presence of sulfenamides, followed by [2,3]sigmatropic rearrangement allowed for a one-step preparation of oxindoles bearing quarternary centers. 416 The development of an enantioselective variant of the Doyle−Kirmse reaction would be highly appealing, as it would enable the simultaneous stereocontrolled formation of a C−S and a C−C bond to the same carbon atom. This endeavor has been a major topic in the last two decades, and research has mainly focused on the use of chiral metal catalysts. For a long time, the best enantioselectivities were obtained through the use of both a chiral metal complex and Oppolzer's chiral auxiliary in an approach developed by Wang. 417 Only recently it has become possible to achieve good enantioselectivities in purely catalyst-controlled systems. 418 In 2017, the Wang group was the first to report high levels of enantioselectivity for the Doyle−Kirmse reaction without the need for a chiral auxiliary (Scheme 129). The combination of a new set of ligands (L6) and highly electron-poor trifluoromethyl sulfides (695 and 696) allowed for high enantiocontrol over a wide range of alkenyl-, aryl-, and heteroarylsubstituted diazoacetate derivatives. Despite this success, low diastereoselectivities were obtained when internal olefins were used. Notably, these catalysts led to the formation of nearly racemic products when diallyl sulfide was employed. These observations support previous proposals of ligand decoordination from the metal complex prior to the [2,3]-sigmatropic event. 419 In 2018, the group of Feng reported another breakthrough in asymmetric Doyle−Kirmse reactions, using a chiral nickel(II) catalyst and pyrazoleamide-derived diazocompounds (Scheme 130). The introduction of a pyrazole unit to the diazo reactant (701) allows the chiral catalyst to remain bound to the sulfur ylide intermediate, affording excellent yields and high enantioselectivities. Control experiments using diazo compounds that did not include the pyrazole afforded nearly racemic products under otherwise similar reaction conditions. The reaction with the pyrazole moiety and diallyl sulfide affords enantioenriched products up to 92% ee, proving that the catalyst remains bound to the substrate during the [2,3]shift. 420 Despite the fact that diazo compounds are often excellent metal carbene precursors and can react under mild conditions with good chemoselectivity, major drawbacks arise from their hazardous and potentially explosive nature, which limit their applicability for large-scale reactions. Therefore, several alternatives have been developed that avoid the direct use of diazo compounds, including the generation of diazo intermediates in situ and the access to metal carbenoids from unsaturated C−C bonds in the presence of π-acid catalysts.
In this framework, tosylhydrazones are valuable precursors of unstabilized diazo compounds through the Bamford− Stevens reaction. In the presence of base, allyl sulfides, and catalytic Rh 2 (OAc) 4 , tosylhydrazones smoothly undergo the Doyle−Kirmse reaction. 421 This approach also obviates the requirement for an electron-withdrawing group, which is usually necessary to stabilize the diazo starting material.
Another method for the in situ generation of diazo compounds is the slow addition of sodium nitrite to a primary amine. In 2017, Koenigs and co-workers applied this approach in an iron-catalyzed Doyle−Kirmse reaction. 422 Despite improvement in safety and scalability, these procedures do not yet offer as wide a scope as the Bamford−Stevens reaction.
Murakami and co-workers were the first to report the use of 1-sulfonyl-1,2,3-triazoles (703) as masked diazoimines in combination with the [2,3]-rearrangement of allylsulfonium ylides. 423 The authors propose a domino process, starting with a copper-catalyzed (3 + 2)-cycloaddition between alkynes and tosylazides to form a triazole intermediate (Scheme 131). Rhodium-catalyzed decomposition of the diazoimine tautomer 704 affords an electrophilic metal carbene complex that can react with the allyl sulfide, followed by [2,3]-sigmatropic rearrangement. The resulting α-sulfenylated imines (706) can be either hydrolyzed to the corresponding aldehydes or reduced with LiAlH 4 to afford tosylamines. Especially considering the complexity of this sequence, remarkably high yields and chemoselectivities were observed. The group of Anbarasan reported a similar strategy on the rhodiumcatalyzed denitrogenative synthesis of α-sulfenylated imines. 424 While the in situ generation of diazo compounds represents an improvement from the perspective of safety and operational simplicity, other developments have been made in the generation of metal carbenoids without the need for nitrogen gas extrusion. Propargyl carbonates can also function as carbenoid precursors through migration of the acyl unit under π-acid catalysis. In 2008, Davies and co-workers used this approach in a Doyle−Kirmse reaction using gold catalysis. Notably, the expected homoallyl sulfides were not obtained, but the isolated products bore structure 710 (Scheme 132). 425 The precise mechanism of this transformation remains unclear, but [3,3]-sigmatropic rearrangement of the expected Doyle− Kirmse products would provide a plausible explanation.
In 2009, the same authors proposed a similar strategy using sulfoxides. 426 On the basis of the works of Toste 427 and Zhang, 428 alkyne oxidation was achieved through the intramolecular addition of a sulfoxide moiety, promoted by the πacidic catalyst (Scheme 133). Following S−O bond cleavage, the resulting carbenoid and sulfide were proposed to react intramolecularly, forming ylide 714. A final [2,3]-sigmatropic rearrangement afforded the heterocyclic products. Optimization of the reaction conditions revealed PtCl 2 to be the optimal catalyst for the reaction with terminal alkynes, whereas internal alkynes required dichloro(pyridine-2-carboxylato)gold(III) 183 for the efficient synthesis of cyclic sulfides bearing a quaternary stereocenter. Ester-and aryl-substituted internal alkynes were well tolerated, while highly substituted allyl sulfoxides afforded the desired product but only with low levels of diastereoselectivity.
More recent methodologies using the intermolecular oxidation of alkynes that employ stoichiometric amounts of N-oxides have also been reported. These procedures have the advantage of not having to use highly specialized substrates. As regioselectivity presents an added problem in intermolecular processes, polarized alkynes (e.g., ynamides) were used to control the reaction outcome. 429 In 2014, the group of Zhang addressed this issue efficiently by employing syringe pump addition of the oxidizing reagent (8-methylqunoline-N-oxide) and, more importantly, P,Sbidentate supporting ligands (L8) in order to decrease the electrophilicity of the α-oxo gold carbene intermediate (Scheme 134). Starting from terminal alkynes, a threecomponent synthesis of α-aryl(alkyl)thio-γ,δ-unsaturated ketones (717) was achieved in good yields, but low diastereoselectivities were obtained with substituted allyl sulfides. 430 Recent developments employ the release of the ring-strain of cyclopropenes for the generation of carbenoids. Treatment of cyclopropene 718 with catalytic amounts of Rh 2 (OAc) 4  431 This section has so far detailed that sulfur ylides containing a pendant π-system (in form of either an alkene, an alkyne or an arene) readily undergo [2,3]-sigmatropic rearrangement reactions. The metal-catalyzed Doyle−Kirmse reaction of sulfides with diazo compounds stands out in terms of the number of reports. However, the central metal−carbenoids can also be elegantly generated in situ using π-acid catalysis or the decomposition of cyclopropenes.
Metal-free sulfur ylide formation followed by [2,3]sigmatropic rearrangement was reported independently by the groups of Biju 432 and Tan. 433 Both groups showed that allyl and propargyl thioethers can react with arynes to form sulfur ylides in situ (Scheme 136). These intermediates can then quickly undergo [2,3]-sigmatropic rearrangement to afford homoallyl sulfides (723). While the work of Tan and co-workers mainly focuses on symmetrical thioethers, the group of Biju incorporated an electron-withdrawing group in the R 1 -position, thereby enabling the reactions to proceed at considerably lower temperatures (typically room temperature). Moreover, the formation of quatenary carbon centers was shown, increasing the procedure's synthetic value. However, in contrast to transition-metal catalyzed processes, monosubstituted benzyne derivatives were shown to afford mixtures of regioisomeric products.
4.4.2. [1,2]-Rearrangements. Direct 1,2-migration of alkyl substituents from the cationic to the anionic center of an ylide are collectively known as the Stevens rearrangement. These reactions have been extensively studied in systems based on oxonium and ammonium ylides, but the sulfur-equivalent, i.e., thia-Stevens rearrangement, has not received nearly as much attention. Despite being underdeveloped, the reaction has still proven to be a powerful tool for C−C (and C−N 434 ) bond formation and the synthesis of quaternary centers. Mechanistically, the (thia-)Stevens rearrangement displays retention of configuration; this is in disagreement with a concerted reaction, which would require an antarafacial shift. Therefore, a homolytic cleavage within the solvent cage and subsequent recombination seem highly likely (Scheme 137). 335 When combined with the power of in situ transition metalcatalyzed ylide formation, the synthetic potential of this strategy is greatly improved. In particular, such processes have most commonly been used for the synthesis of sulfur containing heterocycles through ring-expanding 1,2-shifts.
In this context, such a process was reported by Zakarian et al. for the synthesis of tetrahydrothiophenes from thietanes (727), 435 which was applied to the synthesis of a complex structure akin to the nuphar thioalkaloids' thiolane core (731) (Scheme 138). 436 Further application of this strategy in natural product synthesis can be found in a report by West and co-workers, who used the thia-Stevens rearrangement of a monothioacetalderived ylide as a key step in their formal synthesis of (+)-laurencin (734). 437 Medium-sized cyclic thioether 733 was obtained in 60% yield from this copper-catalyzed step (Scheme 139). Importantly, the α-stereogenic center was perfectly conserved during the 1,2-migration with stereochemical fidelity comparable to the ammonium ylide variants.
In 2009, Tang and co-workers reported a catalytic enantioselective Stevens rearrangement through the action of a chiral bisoxazoline (737/738)/copper complex (Scheme 140). 438 They were able to synthesize a number of sixmembered 1,4-oxathianes (739) from diazomalonates and Interestingly, sulfur ylides with allylic functionality, shown to be good substrates for 2,3-sigmatropic shifts in section 4.4.1, exclusively underwent the 1,2-shift in this system.
Competition studies undertaken by Pan and co-workers to probe the selectivity for either 1,2-or 2,3-shift showed that the preferred pathway strongly depends on the reaction conditions and the electronic properties of the substrate. 439 Hemincatalyzed formation and rearrangement of benzyl sulfonium ylides led to the formation of different products, dependent on both the nature of the solvent and the electronics of the substrate's aromatic ring (Scheme 141). The authors established that electron-withdrawing substituents on the benzyl unit significantly enhance the [2,3]-Sommelet−Hauser rearrangement (leading to 742), whereas electron-rich aromatics exclusively lead to [1,2]-Stevens rearrangement (leading to 741). Protic solvents were also found to favor the Sommelet−Hauser rearrangement. Metal-free ylide formation followed by Stevens rearrangement was achieved by employing benzyne intermediates (Scheme 142). 440 He and co-workers showed that simple monosubstituted β-keto thioethers can add to benzynes generated in situ, forming sulfur ylides. These intermediates (745) undergo smooth [1,2]-rearrangement to afford substituted β-keto thioethers. The methodology could be advantageous to make quaternary carbons. However, in this paper, only one successful example was described with moderate yield. 4.4.3. In Situ Generated Sulfur Ylides through Nucleophilic Substitution/Deprotonation. In addition to their versatile use in transition metal-catalyzed in situ ylide formation, sulfides are competent S N 2 nucleophiles toward activated halides. Recently, the group of Huang used this reactivity to generate sulfur ylides in situ in a base-mediated process, without the need for transition metal catalysis. 441 The corresponding ylides were employed in a coupling reaction with arylboronic acids (747) to generate diarylmethanes using catalytic amounts of the sulfide 748 (Scheme 143). The proposed mechanism involves ylide formation and reaction with 747 to generate a boronate complex, followed by 1,2metalate shift and protodeboronation. The reaction represents a complementary approach to Suzuki cross couplings due to its high selectivity for benzyl chlorides over aryl halides.

(3 + 2)-Cycloaddition Reactions of Thiocarbonyl Ylides.
Most of the ylide reactions discussed so far involve the anionic functionality of the ylide acting as a nucleophile, followed by expulsion of a sulfide, and alternative ylide structures can lead to alternative reactivity. One example of such alternative reactivity is the 1,3-dipolar behavior of thiocarbonyl ylides. While azomethine ylides, 442,443 and indeed carbonyl ylides, 444 have been extensively studied, the corresponding thiocarbonyl ylides are mostly known for being transient intermediates in the Barton−Kellogg olefination. 445 Once formed, the ylide undergoes a rapid electrocyclization, forming a thiirane (751), which proceeds to extrude sulfur, affording a tetrasubstituted olefin (Scheme 144a). Attempts to access 1,3-dipolar functionality have mostly focused on the use of a narrow range of ylides, normally under cryogenic conditions. 446 In 2018, the Maulide group demonstrated that by using thiouronium ylides, in which the cationic functionality is stabilized, it was possible to achieve (3 + 2)-cycloadditions at room temperature under very mild conditions, generating dihydrothiophenes (755) following elimination of an amine (Scheme 144b). 447 Alternative approaches have been employed in natural product syntheses by Trauner (Scheme 144c) 448 and Magauer (Scheme 144d), 449 as a strategy for syn-dialkylation of alkenes, because the generated tetrahydrothiophenes can be desulfurized through the use of Raney Ni. The latter example makes use of high pressure conditions to promote productive reactivity, and both examples employ highly polar solvents.
4.4.5. Formation of Sulfur Ylides through Reaction of Sulfides with Arynes. As seen in the previous sections, sulfides can add to arynes to afford sulfur ylides in situ. The general mechanism for this process can be seen in Scheme 145. The reaction of benzyne with an alkyl sulfide leads to the formation of zwitterionic intermediate 766, and the following intramolecular 1,4-proton shift leads to the formation of a sulfur ylide (767).
This chemistry was mainly studied between 1960 and 1990 450,451 but has seen increased interest lately due to a 2014 report by Xu and co-workers. 452 Therein, the group reported a one-pot sulfur ylide formation, followed by epoxidation of isatins (Scheme 146). The reaction involves trapping of two reactive intermediates under mild conditions and the corresponding products could be isolated in moderate to good yields, albeit with low diastereoselecitivty.
The group of Hoye showed an interesting three-component coupling of arynes with cyclic sulfides and protic nucleophiles (Scheme 147). 453 Notably, these reactions do not proceed through sulfur ylide formation, but the indermediate 775 is protonated by the protic nucleophile. Arynes were not generated through classical methods, but rather by thermal cycloisomerization of tethered triynes. Interesting selectivity is observed in these reactions, where the addition of sulfides to arynes outcompetes the direct addition of the protic nucleophile to the aryne. However, the regioselectivity of this addition is not always perfect, leading to a mixture of constitutional isomers.
In 2016, the group of Studer showed that the trapping of arynes with vinyl sulfides leads to the formation of benzanullated sulfur ylides via (3 + 2) cycloaddition (Scheme 148). 454 Quenching of this intermediate with water led to protonation and subsequent β-elimination of the sulfonium salt to afford a wide range of di-and trisubstituted alkenes, however, in moderate yield.
In 2018, the group of Mhaske reported the direct reaction of arynes with sulfur ylides (Scheme 149). 455 The proposed mechanism proceeds through a [2 + 2]-cycloaddion, followed by nucleophilic opening of the resulting four-membered ring. The reaction affords difunctionalized arenes, however, the yields are only moderate in most cases. Reagent 779 has also been employed in the synthesis of benzofurans from arynes, incorporating the oxygen from the solvent DMF. 456

SULFINATE SALTS AND DERIVATIVES
No discussion of sulfur(IV) compounds would be complete without acknowledging the importance of sulfinate salts. Historically synthesized through the addition of organometallic reagents to SO 2 gas, or by a controlled oxidation of thiols, sulfinate salts (781) have long been utilized in a number of roles, both as synthetic intermediates (Scheme 150) and as protecting groups (e.g., for highly reactive imines). Despite, or perhaps as a result of this rich history, the chemistry of sulfinate salts has enjoyed a renaissance in the past 10 years, predominantly as a result of the development of SO 2 surrogates: bench stable, crystalline compounds that can either release SO 2 in situ or react directly as SO 2 equivalents (Scheme 150). 457,458 Predominant among these new reagents are DABSO 459,460 (a charge transfer complex between DABCO and two molecules of SO 2 ) and inorganic sulfur containing salts (e.g., potassium metabisulfite 461 and sodium sulfite 462 ). As this field is so broad, with new developments reported with an astonishing regularity, it is beyond the scope of this section to conduct an exhaustive review. Readers are directed to the excellent review by Hamze. 463 As depicted in Scheme 150, there are a number of routes for the synthesis of sulfinate salts, including catalytic methods as well as derivatizations. Their rich reactivity includes direct addition to electrophiles as well as desulfinative processes and shall be discussed below.

Sulfinate Salt Formation
One of the classical syntheses of metal sulfinate salts is the addition of organometallic reagents to SO 2 gas. However, while an efficient process, the use of SO 2 gas has a number of significant disadvantages. First, and most obviously, the gaseous nature of SO 2 means that reactions need to be designed in such a way as to disperse the gas in solution. More problematically, SO 2 is highly toxic and the large-scale application of a toxic, gaseous reagent poses technical problems of its own.
The addition of organometallic reagents to SO 2 surrogates is a straightforward solution to these problems, enabling simpler and safer protocols. Crucially, it also offers a more accurate control of stoichiometry, a potentially key issue for transition metal-catalyzed processes. The addition of organometallic reagents to DABSO (usually followed by further derivatization) has been demonstrated for the synthesis of lithium, 464 magnesium, 460 zinc, 465 and sodium 466 sulfinate salts.
While the use of SO 2 surrogates to develop safer alternatives to classical transformations is certainly a worthy goal, the true potential of these developments can be seen in the arena of transition metal catalysis. The ability to generate sulfinate salts without the use of highly reactive organometallic species has clear operational advantages. Such a process was demonstrated in two independent reports in late 2013/early 2014 describing the palladium-catalyzed synthesis of metal sulfinates from aryl halides using K 2 S 2 O 5 467 and the palladium-catalyzed synthesis of ammonium sulfinates from iodoarenes employing DABSO 468 (Scheme 151a) (bromoarenes were successfully converted using a modified system reported more recently). 469 The former method utilized sodium formate as a stoichiometric reductant, whereas the latter was able to rely on the reductive properties of the iPrOH solvent. In both publications, the sulfinates thus generated were subjected to a range of derivatizations.
As well as the above reductive processes, redox-neutral methods involving the metal-catalyzed sulfinylation of boronic acids (782) have been achieved. A DABSO-based phosphinefree palladium-catalyzed process was developed in 2016, in which the generated sulfinic acids were subsequently deprotonated to the desired salt prior to derivatization (Scheme 151b). 470 As well as palladium(II) catalysis, similar reactivity has been demonstrated when combining boronic acids with either copper(I) 471 or gold(I) 472 complexes, as well as processes that combine aryl silanes with either copper(I) 473 or cobalt(II). 474  Besides transition metal-catalyzed sulfinylation, Lewis acids have been used to activate DABSO in order to unlock simple S E Ar reactivity, resulting in a formal C−H sulfinylation, affording sodium sulfinates (following the addition of a sodium base). 475 While each of the above examples builds up sulfinate salts from an SO 2 source and a nucleophilic/electrophilic reactant, a number of methods have also been developed that rely on the degradation of larger momlecular entities. One such example is the base-promoted elimination of sodium sulfinate salts from fully substituted N-aminosulfonamides (785) (Scheme 152a), 476 themselves easily synthesized through a palladium catalyzed reaction (see section 5.2.3). 459,477 This method was used to prepare a number of sulfone derivatives. When treated with base, thiosulfonates can similarly degrade to sulfinate salts. 478 The Baran laboratory has demonstrated that sulfinates are ideal precursors for radical based C−H functionalization reactions (see section 5.2.2) and have developed a number of routes for their synthesis. As depicted, the reduction of commercially available sulfonyl chlorides (788) with dissolving zinc metal affords the corresponding zinc sulfinate (Scheme 52b), 479 while S N Ar-type processes can be used to synthesize fluorinated sodium sulfinates (791) (Scheme 152c). 480 5.2. Sulfinate Salt Derivatization 5.2.1. Sulfone Synthesis. In general, the broadest synthetic use of sulfinates is the synthesis of sulfones. While organic chemists may tend to represent sulfinates analogously to a carboxylate, with oxygen-centered anionic character, in reality both the sulfur and oxygen centers are strongly nucleophilic. This ambident nature of sulfinates theoretically introduces selectivity problems as well as opportunities. In practice, however, most carbon-based electrophiles selectively undergo S-alkylation, resulting in the formation of sulfones, as opposed to the sulfinate esters that would result from Oalkylation. Thus, it is unsurprising that the majority of publications on sulfinate preparation demonstrates their use in sulfone synthesis as the archetypical application. 464 The vast majority of the above sulfone syntheses rely on sulfinate alkylation, and even the iodonium-promoted arylation is restricted by the availability of aryl iodonium salts. As a result, the arylation of metal sulfinates (e.g., for the synthesis of diaryl sulfones) represents a separate challenge for which the solution can be found in the realm of transition metal-catalyzed cross-coupling chemistry. Employing metal or ammonium sulfinates, Pd-catalyzed coupling with aryl halides has been shown to furnish diaryl sulfones in excellent yields (Scheme 153a, bottom right). 464 Furthermore, the addition of sulfinate salts to arynes has also proven a viable pathway for the synthesis of aryl sulfones (Scheme 153a, bottom middle). 485−487 In keeping with recent trends, it has also been demonstrated that photoredox catalysis can be suitable for the coupling of metal sulfinates with arenes. 488,489 While the majority of alkylating agents are selective for Salkylation, O-alkylation would generate sulfinate esters, long known to be useful reagents for the synthesis of sulfoxides through the addition of organometallic reagents (see the use of Andersen's sulfinate, section 2.4.1). The Willis laboratory has reported that silylating agents are O-selective due to the large Si−O bond energy and have exploited this for a DABSO-based sulfoxide synthesis, in which DABSO formally acts as a sulfinyl dication (Scheme 153b). 490 5.2.2. Sulfinate Halogenation. Another highly flexible method for sulfinate derivatization relies on their conversion into sulfonyl halides. These highly reactive species can be reacted with a variety of nucleophiles to form a range of sulfur(VI) species, most commonly sulfonic esters and sulfonamides. Sulfuryl chloride (SO 2 Cl 2 ) has for many years been used for the in situ formation of sulfonyl chlorides from classically generated sulfinates (Scheme 154a). This chemistry works equally well with DABSO-derived sulfinates and has been applied to sulfonamide and sulfamide synthesis. 460 Halogenation using molecular iodine has similarly been used for the formation of sulfonic esters via the sulfonyl iodide. 491 In addition to the highly reactive sulfonyl chlorides and iodides, interest has recently increased in the synthesis of the more stable sulfonyl fluorides (such as 800). The fine balance between reactivity and stability allows molecules containing the −SO 2 F moiety to be used for applications ranging from biological probes to deoxyfluorination. Treatment of ammonium sulfinates with either NFSI 469 or SelectFluor 492 has been demonstrated to be an effective protocol for their synthesis (Scheme 154b). 5.2.3. Sulfonamide Synthesis. As mentioned above, the in situ formation of sulfonyl chlorides from sulfinates has long been used as a key step in sulfonamide synthesis (see Scheme 154a). While efficient and achievable in a one-pot manner, such a process necessarily represents a three-step synthesis, which leaves room for improvement in terms of operational ease. Although the two steps required from sulfinate to sulfonamide cannot be combined, a single-step reaction between sulfinate salts and an electrophilic nitrogen source has been demonstrated to be an effective method. N-Chloroamines, generated in situ by the combination of bleach with the appropriate amines, have been used for the one-pot, two-step synthesis of sulfonamides (801), through the intermediacy of either metal 493  In addition to the methods mentioned above, several further protocols for sulfonamide formation from sodium sulfinates have been reported in recent years. Common to these approaches, relying either on molecular iodine, 498−501 or the oxidation of iodide, 502−504 is the putative formation of a sulfonyl iodide intermediate.

Desulfinylative
Methods. The use of sulfinate salts as nucleophilic coupling partners in cross-coupling reactions has been presented above in the synthesis of sulfones and/or sulfonamides. In addition to being used to afford these key sulfonyl-incorporating substrates, sulfinate salts have long been used in desulf inylative coupling reactions. While boronic acids are perhaps the archetypical stable organometallic reagent, stability to moisture and aerobic conditions is actually notoriously better for sulfinate salts. Often this increased stability makes little difference, which is why sulfinate salts have not supplanted boronic acids. However, there are key substrate areas where this additional stability becomes a distinct advantage. A range of desulfinylative couplings have been reported using simple aryl sulfinate salts, 505 including Suzuki−Miyaura 506 and (oxidative) Mizoroki−Heck couplings. 507 It is however in the coupling of heterocyclic fragments where the use of sulfinate salts comes into its own. In particular, reactions employing pyridyl boronic acids have long been plagued with difficulties, mostly stemming from the extreme instability of the pyridyl−boron bond to, among other things, protodeboronation. Only in recent years has the development of 2-pyridyl MIDA-boronates by Burke and coworkers begun to alleviate this problem. 508 The Willis laboratory has demonstrated that a wide range of 2-, 3-, and 4-pyridyl sulfinate salts can be coupled to aryl bromides and chlorides in excellent yields through the use of a simple palladium catalyst (Scheme 156a). 509 Further work expanded this concept to an extensive, functional group-tolerant scope of fiveand six-membered heteroaryl sulfinates. 510 In addition to transition metal-catalyzed desulfinylative couplings, a number of uncatalyzed reactions warrant discussion. As alluded to at the end of section 5.1, the Baran laboratory have in recent years reported desulfinylative Minisci-type reactions, in which a radical formed under oxidative conditions is trapped through reaction with an electron-poor heterocycle (Scheme 156b). 479

Langlois' Reagent
When talking about fluoroalkyl radicals generated from sulfinate salts, discussion of the Langlois reagent (sodium triflinate, 806) 514 is inevitable; for a discussion of other sulfurbased trifluoromethylating reagents such as Umemoto's reagent, see section 3.1. Owing to the myriad of reports on the reactivity of Langlois' reagent published in the past decade, and the publication of expert reviews in recent years, 515−519 our aim is it provide an overview of general reactivity trends, illustrated by appropriate seminal examples.
The one-electron oxidation of the inexpensive and benchstable solid sodium triflinate, for which several approaches are known, leads to the initial formation of a sulfonyl radical (807), which readily decomposes to the trifluoromethyl radical 415 under loss of SO 2 (Scheme 157a). The formation and use of 415 has experienced a resurgence in recent years and has found application in a wide range of transformations that shall be exemplified below.
Owing to the electrophilicity of 415, several protocols for the radical trifluoromethylation of alkenes have been developed, such as the oxytrifluoromethylation and hydrotrifluoromethylation of simple alkenes. In 2013, the Maiti group's oxytrifluoromethylation of alkenes was shown to proceed through silver-catalyzed oxidative decomposition of the triflinate anion, affording 807, which was confirmed by Xray photoelectron spectroscopy (Scheme 157b). 520 Subsequent addition to the alkene was proposed to afford an alkyl radical, trapping of which with dioxygen was shown to lead to formation of 809, as shown by isotopic labeling with 18  range of related procedures were reported in addition to this method.
Following an early, but low-yielding electrochemical report of hydrotrifluoromethylation of alkenes by Langlois, 521 in 2013, Nicewicz and co-workers reported this reaction in the context of photoredox catalysis (Scheme 157c). 522 Herein, Nmethyl-9-mesitylacridinium tetrafluoroborate (812) serves to both oxidize the triflinate and reduce the thiyl radical generated during hydrogen-atom transfer to the intermediate alkyl radical.
In the context of carbotrifluoromethylation, a suite of cyclization reactions has also been reported using Langlois' reagent. Most prominent among these transformations is the trifluoromethylative cyclization of an aryl moiety onto a double bond, as shown by the reaction of N-aryl acrylamides to form oxindoles (Scheme 158). 557−559 In addition to these templates, products of radical additions of 415 to ynamides and isonitriles are also known to be trapped by arenes, 560−562 as are cyclizations of alkynes onto the intermittent radicals. 563−565 In addition to the reaction with alkenes, sodium triflinate has also been used extensively for the trifluoromethylation of arenes and heteroarenes (Scheme 159a). Following Baran's early reports on the trifluoromethylation of heterocycles (see Scheme 156b), 511−513 a plethora of further protocols for the sodium triflinate-mediated protocols were developed, enabling the trifluoromethylations of a wide range of functionalized (hetero)arenes. Initial work exploited the reactivity of arylboronic acids (Scheme 159b), 566,567 whereas later work showed the tendency of electron-rich aromatics to undergo addition of trifluoromethyl radicals (Scheme 159c). 568−571 Other examples of arene−trifluoromethylation rely on metal-catalysis in combination with directing groups, 572−574 light-mediated transformations, 575,576 or the addition of 415 to heteroarenes. 577−580 Further applications of Langlois' reagent in recent years have included the trifluoromethylation of imines, 581,582 as well as applications in the ring opening of cyclopropanols 583 and the trifluoromethylations of nitrosoarenes 584 as well as alkynyltrifluoroborates. 585

One-Step Sulfonylative Multicomponent Reactions (MCRs)
Although most of the sulfinate syntheses described at the beginning of this chapter are often compatible with derivatization conditions allowing for a multistep, one-pot protocol, the development of single-step processes has clear advantages from the viewpoint of operational simplicity, especially when working on scale or for combinatorial chemistry. A number of such transformations have been discussed in earlier sections, namely those involving transition metal-catalyzed sulfinate formation in the presence of an electrophile and many reactions involving Langlois' reagent. The electrophiles required for sulfone synthesis (typically activated alkyl bromides) do not tend to interfere with the initial steps and capture the transition metal-sulfinate to close the catalytic cycle. Generally, these processes are redox-neutral, employing arylsilanes or boronic acids as nucleophilic components. 471−474 While it has been demonstrated that sulfonamide synthesis can be achieved in either a one-pot three-step protocol (sulfinate formation, chlorination, and then addition of amine) or a one-pot two-step protocol (sulfinate formation, then oxidative amination), simple one-step processes have remained elusive until recently. A far easier transformation is Naminosulfonylation (Scheme 160a). The very first transformation to utilize DABSO as an SO 2 surrogate in 2010, as well as the first transition metal-catalyzed sulfonylative coupling, 459 relies on the high nucleophilicity of the hydrazine coupling partners, as simple amines are not competent substrates under the developed conditions. 477 Alternative conditions employing other SO 2 surrogates, 459 starting materials, 586 and metals 587 have been developed. A handful of sulfonamide syntheses involving radical mechanisms (see below) have been reported, however, it was not until 2018 that a direct one-step aminosulfonylation reaction employing amines and readily available carbon synthons was developed by the Willis group (Scheme 160b). 588 The exact mechanism of the transformation is yet to be elucidated, however, mechanistic experiments ruled out the intermediacy of a sulfinate salt.
Intramolecular reactions forming sultams 589 and benzothiophene dioxides (823) 590 are other examples of transition metal-catalyzed one-step sulfonylative processes (Scheme 160c). Interested readers are directed to more focused reviews for further examples. 591 As mentioned previously, the major alternatives to purely transition metal-catalyzed sulfonylative MCRs are those that invoke radical mechanisms. A comprehensive review of this field has recently been published 592 and covers the area in great detail. While in discussing the combination of DABSO and transition metal catalysts the work of the Willis laboratory dominates, the lion's share of publications employing radical mechanisms have been reported by the Wu laboratory. The very first such process was an N-aminosulfonamide synthesis (Scheme 161a), with products analogous to the previously described Pd-catalyzed process (see Scheme 160a), employing diazonium salts (824) in the absence of a metal catalyst. 593 The authors propose that the release of nitrogen from the diazonium salt is mediated by a SO 2 −hydrazine complex. However, the Maulide group have demonstrated subsequently that hydrazines are competent catalysts for the degradation of diazonium salts for Meerwein-type processes without the need for SO 2 . 594 Generation of the key radical species (that is rapidly sulfonylated to afford a sulfinate radical) in this way is conceptually very attractive. Nevertheless, other methods include transition metal-catalyzed radical generation (as seen with the Mizoroki−Heck-type functionalization of styrenes in Scheme 161b), 595 and light-promoted processes, be they direct irradiation with UV light 596 or through photoredox catalysis (Scheme 161c). 597 Recently, Jiang and co-workers have added to the suite of metal-free sulfonylative MCRs by employing sodium metabisulfite as the reducing agent (Scheme 162). 598 Herein, triphenylphosphine and sodium azide serve as the oxidant and nitrogen source, respectively, affording sulfonamides with impressive functional group tolerance.
A multitude of publications over the past five years have exploited the ease at which radicals can be sulfonylated, 592 and the rate of novel developments shows no signs of abating.

SUMMARY AND CONCLUSIONS
This review article has shown the wide range of chemical transformations of organic sulfur(IV) compounds that involve either bond formation or bond cleavage at sulfur. Focusing on transformations pioneered or developed over the past decade, novel reactions as well as further developments of textbook organic transformations have been presented. The breadth of reactivity exhibited by organic compounds bearing sulfur(IV) moieties spreads over several classes of functional groups. Specifically, sulfoxides, diverse types of sulfonium salts, and sulfur ylides as well as sulfinate salts and their derivatives have been at the forefront of organosulfur research and have therefore formed the core of this article.
Sulfoxides have been shown to be amenable to a broad range of Pummerer-type reactions, enabling carbon−carbon and carbon−heteroatom bond formation in the α-position of the sulfoxide starting materials, often through sigmatropic rearrangements. Importantly, several protocols for arylation or the functionalization of arenes have also been developed using sulfoxide-activation chemistry. In addition to this, following in the footsteps of the ubiquitous Swern oxidation, activated sulfoxides have continued to show great versatility in a variety of oxidation reactions of alkenes, arenes, and alcohols alike. Furthermore, metal−sulfoxide exchange has been demonstrated to be a practical alternative to the metalation of halide-containing precursors and has thus found application in the selective synthesis of organometallic reagents.
Sulfonium salts have shown remarkable reactions in the arenas of fluoroalkylation and transition metal-catalyzed crosscoupling reactions. Among this general class, vinyl-and propargylsulfonium salts stand out in terms of versatility, allowing for the formation of up to three new bonds across a simple C 2 unit. Specifically, in this context, the number of heterocycles and strained rings synthesized by virtue of the multiple reactive sites of sulfonium salts seems to know no bounds and has been shown to proceed with high levels of diastereo-and even enantioselectivity.
Sulfur ylides are arguably the most versatile class of organosulfur(IV) compounds, finding widespread application as one-carbon synthons, ranging from simple nucleophilic epoxidation, aziridination, and cyclopropanation to a wide variety of more complex (n + 1)-cycloadditions and transition metal-catalyzed reactions with π-systems, both of which have led to the development of a large number of novel protocols for the formation of heterocycles. Additionally, sulfur ylides have been shown to engage in a series of asymmetric transformations, either promoted by organocatalysts or by virtue of a chiral sulfur ylide itself. Furthermore, with the emergence of photoredox catalysis, sulfur ylides have recently started being employed in photocatalytic transformations. Sulfur ylides are also highly useful substrates for sigmatropic rearrangements, as the inherent charge leads to significant acceleration of the pericyclic reaction. In this regard, the further development of the Doyle−Kirmse reaction has provided several intriguing transformations, forming new carbon−sulfur bonds through the decomposition of diazo compounds in the presence of simple sulfides.
Sulfinate salts boast a long history in the context of organic chemistry. Recent developments have allowed for more facile protocols for the formation of sulfinates by utilizing benchstable SO 2 equivalents in lieu of the notoriously toxic gas. The facilitated access to this structural motif has inspired a variety of sulfone syntheses through coupling reactions, as well as desulfinylative couplings and one-step sulfinylative multicomponent reactions, affording structurally diverse and valuable products.
Although sulfur(IV) compounds enjoy a rich and fruitful history in the context of organic synthesis, this review has aimed to show that their chemical reactivity and potential utility for synthetic chemists is far from being exhausted and the various sulfur(IV) functional groups promise to provide chemical research with many more exciting discoveries and developments.

Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Notes
The authors declare no competing financial interest.

ACKNOWLEDGMENTS
We are grateful to the University of Vienna for continued support of our research programs. Funding by the FWF (P30226), the Austrian Academy of Sciences (DOC fellowships to D.K. and I.K.) and the ERC (CoG 682002) is gratefully acknowledged. N.M. is a recipient of the Lieben Prize of the Austrian Academy of Sciences.