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Review

Organocatalytic Transformations from Sulfur Ylides

by
Marcio Hayashi
* and
Antonio C. B. Burtoloso
*
São Carlos Institute of Chemistry, University of São Paulo, São Carlos 13563-120, Brazil
*
Authors to whom correspondence should be addressed.
Catalysts 2023, 13(4), 689; https://doi.org/10.3390/catal13040689
Submission received: 28 February 2023 / Revised: 22 March 2023 / Accepted: 29 March 2023 / Published: 31 March 2023
(This article belongs to the Special Issue Organocatalysis in the Chemical Transformations)
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Abstract

:
Sulfur ylides are an important class of organic compounds due to their ability to perform many different transformations that can give diverse and interesting products with a high degree of complexity. Although metal-catalyzed transformations are frequent in this class of compounds, organocatalyzed transformations remain scarce. From initial works, this review aims to show organocatalyzed transformations from sulfur ylides, involving cyclopropanation and formal N–H, S–H, and C–H insertion reactions, including enantioselective versions. The proposed mechanisms and the modes of activation of these organocatalysts will be covered. Furthermore, advances in this area and potential challenges to be circumvented in the near future will also be discussed.

Graphical Abstract

1. Introduction

Organocatalysis, a term coined in 2003, by List and MacMillan independently, emerged as a powerful strategy to achieve complex compounds using small molecules as catalysts, with recognition for both researchers in the 2021 Nobel Prize in Chemistry [1]. From the synthesis of complex small molecules to total synthesis, the exponential rise of organocatalysis in organic synthesis showcases its importance [2,3,4,5,6,7]. The main advantage of organocatalysis, compared to metal catalysis and biocatalysis, is generally the use of small, stable molecules as catalysts. Using chiral pool strategies, for instance, can be accomplished in a few steps. Moreover, the stability of such molecules enables a desired reaction to be run under moisture and air [8].
Sulfur ylides, introduced by Ingold and Jessop in 1930 [9] and initially applied in organic synthesis by Johnson, in 1961 [10], and Corey and Chaykovsky, in 1965 [11,12,13], are versatile compounds with several possible applications since they can be synthesized through small rings, Stevens rearrangement, and metal carbene formation [14,15]. This versatility makes them surrogates of diazo compounds, especially considering their higher stability and similar reactivity. Electron-withdrawing groups in the α position to a sulfur ylide enhance their thermal stability, to a point where these compounds can be handled at larger-scale reactions [16].
Sulfonium and sulfoxonium ylides have an interesting reactivity: the ylidic carbon is nucleophilic but becomes electrophilic after the reaction with an electrophile. In this latter case releasing a sulfide and a sulfoxide, respectively. The difference in the nucleophilicity of these ylides resides in the oxidation state of the sulfur atom, where sulfonium ylides are more nucleophilic at the carbon atom than sulfoxonium ylides [17,18]. This difference in oxidation state results in divergent preferences in reactions, which will be discussed further (Scheme 1).
Even though sulfur ylide has been utilized for a long time in metal catalysis due to its ability to produce metal carbenes, it has not been utilized much in organocatalysis despite its ability to produce complex molecules in one step [14,19]. This review will discuss the advances in the organocatalyzed reactions from sulfur ylides, such as Corey–Chaykovsky cyclopropanations, formal C–H, C–X, and X–H insertion reactions, and cycloadditions (Scheme 2). Asymmetric transformations involving chiral and enantioenriched sulfur ylides as reactants will not be covered in this review [20,21,22].

2. Organocatalytic Corey–Chaykovsky Reaction

Cyclopropanes are a class of molecules that are widely present in nature, with their corresponding natural products containing this structure [23]. Because of its potential as a bioisostere of double bonds, the efficient synthesis of natural and pharmaceutical products containing a cyclopropane moiety is being explored by several research groups and industries [24,25]. Some cyclopropanation reactions, such as the Simmons–Smith reaction, employ metal catalysis with the intermediacy of carbenes [26]. On the other hand, Corey and Chaykovsky published a metal-free cyclopropanation reaction involving electron-poor olefins and sulfonium ylides in 1965 [13]. Since then, enantioselective cyclopropanation has remained exclusive to metal catalysis in the Simmons–Smith reaction (use of chiral auxiliary and metal carbenes) [20,21,22,27].
The first contribution of an organocatalytic Corey–Chaykovsky cyclopropanation came from MacMillan and coworkers in 2005, where they used sulfonium ylides 2, α,β-unsaturated aldehydes 5, and a chiral dehydroindole organocatalyst (indole-cat 6). Cyclopropanes 7 (9 examples) were achieved in good yields (up to 85%) with excellent diastereoselectivities (up to 72:1) and enantioselectivities (up to 96% ee). The authors proposed a mode of activation that involved a directed electrostatic activation from the carboxylate and sulfonium functions, via intermediate A. The iminium Z isomer was suggested considering the minimization of the Van der Walls interaction between the aryl hydrogen and olefin (Scheme 3) [28].
In 2007, Arvidsson and colleagues improved the enantioselective Corey–Chaykovsky cyclopropanation protocol, modifying the organocatalyst indole-cat 6, using tetrazolic acid as a substitute for carboxylic acid. Compared to Macmillan’s work, Arvidsson showed that the designed organocatalyst 8 improved the yields (up to 93%), diastereoselectivities (up to 98% de), and enantioselectivities (up to 99% ee) of cyclopropanes 7 (7 examples). The tetrazolic acid, which has a larger group than carboxylic acid, imposed a steric hindrance on the nucleophilic attack step of the sulfonium ylide. This improves the enantioselectivity (Scheme 4) [29].
In the same year, Arvidsson and coworkers reported more modifications of organocatalysts using a sulfonamide group, which shared the same dehydroindole core with 6 and 8. A comparison with their and MacMillan’s work showed that the new organocatalysts 9 and 10 furnish the cyclopropanes 7a–7e, 7a′–e′, with high selectivity (up to 98% de and 99% ee), although at lower yields (up to 58%) (Scheme 5) [30].
In 2011, Chen, Xiao, and coworkers reported asymmetric cyclopropanation of β,γ-unsaturated-α-keto-esters 11 with sulfoxonium ylides 2, catalyzed by chiral urea (urea-cat 12), which afforded 1,2,3-trisubstituted cyclopropanes 13 (21 examples) in good yields (up to 86%) and moderate to good selectivities (up to 16:1 dr and up to 90:10 er). The use of toluene as solvent at a low temperature (−40 °C) for 72 h provided the optimal condition (Scheme 6) [31]. The authors proposed a catalytic cycle starting with the coordination of urea-cat 12 with sulfonium ylide 2, followed by the coordination of β,γ-unsaturated-α-keto-ester 11. The chiral environment in intermediate 15 leads to an enantioselective Michael addition, followed by alkylation, giving complex 17. This regenerates the organocatalyst, furnishing the cyclopropane 13 (Scheme 7) [31,32].
In 2012, Studer and coworkers reported an oxidative NHC-catalyzed Corey–Chaykovsky cyclopropanation of α,β-unsaturated aldehydes 19 with sulfonium ylides 18. Chiral NHC-catalyst (NHC-cat 20), DABCO, benzoquinone-derivative 21, and iPrOH were used in toluene at rt to afford cyclopropanes 22 (22 examples) in good yields (up to 74%) and excellent ee (up to 99%) (Scheme 8) [33]. The authors proposed a catalytic cycle involving the addition of NHC-cat 20 to aldehyde 19 to form a Breslow intermediate, which is oxidized by quinone to form intermediate 23. 1,4-addition of sulfonium ylide B, which was formed in situ from sulfonium salt 18, to intermediate 23 gives enolate 25, followed by cyclopropanation to furnish intermediate 26. Next, alcoholysis releases product 22, regenerating the NHC-cat (Scheme 9) [33,34,35].
In 2013, Liu, Feng, and coworkers reported an asymmetric Corey–Chaykovsky cyclopropanation of α,β-unsaturated ketones 27 with sulfonium ylides 2, catalyzed by chiral amine 28. Furthermore, benzoic acid, CHCl3, and 5 Å MS were used at 30 °C to furnish cyclopropanes 29 (20 examples) in good yields (up to 68%) and excellent ee and dr (up to 93% ee and >95:5 dr), with an improvement in ee after a single recrystallization (up to 99% ee) (Scheme 10). The authors have proposed that the mechanism starts with the formation of iminium 30 from the reaction of amine-cat 28 and unsaturated ketone 27, mediated by benzoic acid. Next, the secondary amine group from intermediate 30 coordinates with sulfonium ylide 2 via hydrogen bonding. This was followed by 1,4-addition and cyclopropanation by enamine attack to furnish the desired product 29 (after hydrolysis) and the amine-cat 28 (Scheme 11) [36].
In 2022, Fochi, Bernardi, and coworkers reported a Corey–Chaykoyvsky-type cyclopropanation using sulfoxonium ylides 1, 2-hydroxy-cinnamaldehydes 33, NaOAc, and Jørgensen–Hayashi proline 34 as an organocatalyst (JH-cat). Subsequently, the Wittig reaction was employed via a one-pot procedure to afford substituted cyclopropanes 36 (15 examples) in moderate to good yields (up to 70%) and excellent ee (up to 97%) (Scheme 12). Their initial proposed catalytic cycle starts with the formation of iminium 37 from JH-cat 34 and 2-hydroxy-cinnamaldehyde 33, which is in equilibrium with the hemiaminal 37′ form, the latter being unreactive and more stable. The sulfoxonium ylide 1 selectively attacks the olefin, followed by the enamine 38 attack to displace DMSO, yielding the cyclopropane 39. The iminium is then hydrolyzed to recover the catalyst, furnishing the aldehyde 40 (which epimerizes to 41 and cyclizes to the more stable hemiacetal 41a′) (Scheme 13). After optimization, the authors found that the basic condition (NaOAc) provided the best results. This shows that the phenol moiety is sufficiently acidic to form the iminium intermediate for the next step. In this case, the base is necessary to remove any acidic species that could be harmful to the sulfoxonium ylide [37].
Epoxides are a versatile class of compounds in organic synthesis, with extensive applications in the total synthesis of natural products and pharmaceuticals. In this scenario, the Corey–Chaykovsky epoxidation reaction is an interesting strategy for the synthesis of epoxides due to the use of aldehydes and trimethylsulfonium iodide as starting materials in mild conditions [38].
In 2008, Connon and coworkers reported urea-organocatalyzed Corey–Chaykovsky epoxidation using aldehydes 42, trimethylsulfonium iodide 4, and aqueous NaOH in CH2Cl2 at rt to furnish epoxides 44 (9 examples) in excellent yields (up to 96%). The purpose of the urea-cat 43 was to accelerate the attack of the sulfonium methylide on the carbonyl group of 42, which is the rate-determining step in this reaction (Scheme 14) [39].

3. Organocatalytic Formal C–H, N–H, and S–H Insertion

The chemistry of sulfur ylides has recently gained more attention due to their ability to provide a formal insertion bond leading to α-substituted carbonyl compounds [17,18]. One of the seminal works comes from Baldwin and coworkers in 1993, where they treated β-lactams with trimethylsulfoxonium iodide, and upon exposure to diverse reagents and catalysts, several products of N–H, O–H, Cl–H, and Br–H insertion reactions were obtained [40,41]. Specifically in the N–H insertion reaction, the discovery of the carbene pathway has made sulfur ylides surrogates of diazo compounds [41]. Additionally, one of the most important applications comes from the N–H insertion reaction of key intermediates in the pharmaceutical industry. In 2011, Mangion and coworkers at Merck developed the synthesis of MK-7655, a β-lactamase inhibitor, via iridium-catalyzed N–H insertion. In 2012, Molinaro and colleagues at Merck reported the three different synthetic routes to MK-7246, a selective CRTH2 antagonist for the treatment of respiratory diseases. The final route, or manufacturing route, used the intramolecular N–H insertion of sulfoxonium ylide, catalyzed by iridium. In 2022, Ruck and coworkers at Merck reported the synthesis of MK-1029, a CRTH2 antagonist, via intramolecular N–H insertion of sulfoxonium ylide with indole, catalyzed by iridium [42,43,44].
As an alternative to metal-catalyzed X–H insertions from carbonyl sulfur ylides, capable of generating a stereogenic center at the α-carbonyl position, the use of organocatalyzed reactions is another way to obtain such compounds in mild conditions. In this case, a prerequisite to achieving enantioselectivity is the use of “pro-chiral” sulfoxonium ylides. Two methods to prepare these more complex sulfur ylides (without passing through diazo compounds as intermediates) have been described independently by the research groups of Burtoloso and Aïssa. The former developed an aryne approach to coupling with sulfoxonium ylides, while the latter reported a palladium-catalyzed coupling of aryl halides with sulfoxonium ylides [45,46,47].
In 2020, Mattson, Burtoloso, and coworkers reported the first enantioselective formal S–H insertion reaction of pro-chiral sulfoxonium ylides 45. Besides the ylide, an aromatic thiol 46 and thiourea organocatalyst (TU-cat 47) in CHCl3 were used. The reaction was carried out at a lower temperature (–28 °C) and afforded α-thiol ester 48 (31 examples) in excellent yields (up to 97%) and with excellent enantioselectivity (up to 95% ee) (Scheme 15). The proposed mechanism, supported by 1H NMR and DFT calculations, indicates that the first step is the formation of a hydrogen bond between the TU-cat and the S=O bond of the sulfoxonium ylide to yield the intermediate 49. The next step is the protonation of 49 with H–SPh, which is both a rate-determing and enantiodeterming step, leading to 50. The SN2 reaction of thiolate with 50 then furnishes the desired product 48 and regenerates the organocatalyst 47 (Scheme 16) [48,49].
In 2021, Mattson, Burtoloso, and coworkers developed a formal C–H insertion reaction of indoles 51 into sulfoxonium ylide esters 45, using a chiral phosphoric acid (S)-TRIP 52 in CHCl3 at low temperature (−5 °C), providing the C–C bond adducts 53 (29 examples) in moderate yields (up to 50%) and good to excellent enantioselectivity (up to 93% ee). It is noteworthy that no indole protection is required (Scheme 17). The mechanism proposed by the authors involves the protonation of sulfoxonium ylide with (S)-TRIP, forming complex 54, with charged species in protonated ylide and organocatalyst. Subsequently, indole performs an electrophilic aromatic substitution reaction, leading to the intermediate 55, which undergoes a rearomatization of the indole ring via proton abstraction from (S)-TRIP, yielding the product 53, and regenerating the organocatalyst 52 (Scheme 18) [50].
In 2020, Li, Sun, and coworkers reported an organocatalytic formal N–H insertion reaction using sulfonium ylides 56 and anilines 57, catalyzed by chiral phosphoric acid (CPA-cat). In the majority of examples (EDG and slightly EWG), a two-step procedure involving the formal N–H insertion reaction catalyzed by CPA-A1-cat 58, followed by a Cu(OAc)2-mediated oxidation, was employed. α-amino ketones 60 (17 examples) were obtained with excellent enantioselectivities (up to 99%). For secondary amines and alkyl groups (R2) in sulfonium ylides, CPA-A2-cat 59 allowed the products 60 (6 examples) and 60′ (7 examples), respectively, in excellent selectivities (up to 96% ee and 98% ee, respectively), without any additional operation (Scheme 19 and Scheme 20). In the case of α-amino esters 60″, with the Me group at R2, CPA-A3-cat 61 was employed, leading to products with very good selectivities (up to 86% ee). However, with longer alkyl groups, the SPINOL catalyst (CPA-A4-cat 62) provided the α-amino esters 60″ in excellent ee (up to 95%; Scheme 20). The authors proposed a mechanism starting with the protonation of the sulfonium ylide by CPA-cat, leading to the intermediate 63, which was epimerized to 63′ in equilibrium. The attack of aniline in preferred face furnished product 60, via dynamic kinetic resolution, with extrusion of Ph2S and regeneration of the organocatalyst. If the applied aniline is not reactive, the deprotonated CPA-cat will dispose of the Ph2S, leading to an inactive subproduct 64 (Scheme 21) [51].
In 2021, Sun, Huang, and coworkers reported an organocatalytic N–H insertion using esters of sulfoxonium ylides 45, unprotected amines 57, and chiral phosphoric acid catalyst (CPA-A1-cat 59) in CH2Cl2 at low temperature to enable enantioenriched α-aryl glycines 65 (36 examples) with excellent yields (up to 99%) and enantioselectivities (up to 97% ee; Scheme 22). Compared to Burtoloso’s N–H insertion work, which used a copper/squaramide co-catalyzed system, this report used a metal-free approach [52,53]. The mechanism proposed by the authors involves protonation of the sulfoxonium ylide with CPA-A1-cat 59 in an equilibrium favoring intermediate 66. The nucleophilic attack of the amine 57 is rate the determing step, providing the product 65 and regenerating the organocatalyst 59 (Scheme 23) [54].
In 2022, Guo, Sun, and collaborators reported an organocatalyzed azidation of sulfoxonium ylides 1 to afford chiral tertiary azides 68 (18 examples) in excellent yields (up to 96%) and enantioselectivities (up to 96% ee). In this reaction, pro-chiral sulfoxonium ylides were employed, and a squaramide organocatalyst (SQ-cat 67), TMSN3, and PhCO2H were used as reactants to obtain HN3 in situ. Although acid was involved in the reaction, mechanistic studies showed that no epimerization occurred. The choice of CHCl3 as the solvent and the lower temperature proved to be crucial in obtaining higher enantioselectivity (Scheme 24). The authors proposed a mechanism involving the first hydrogen bonding of SQ-cat 67 to sulfoxonium ylide 1, yielding intermediate 70, followed by protonation with HN3. In this case, the step provides two epimerizable intermediates 71 and 71′, in reversible protonation. The next step, rate determing and enantiodeterming, involves the SN2 reaction of azide with intermediate 71, via dynamic kinetic resolution, providing the product 68 and the SQ-cat 67, capable of coordinating with DMSO (SQ-cat•DMSO 69) (Scheme 25) [55].

4. Cyclization

In addition to the Corey–Chaykoysky reaction, formal cyclizations have emerged as powerful methods for obtaining enantioenriched 5- to 6-membered cyclic products using organocatalytic cascade transformations of sulfur ylides [14].
In 2008, Xiao and coworkers reported a urea catalyzed (4 + 1)/rearrangement cascade reaction of sulfonium ylides 2 with nitroolefins 72 that furnished 4,5-disubstituted oxazolidinones 74 (19 examples) in excellent yields (up to 96%) and with excellent diastereoselectivity (up to >99:1 dr). It was important to use 2-CTU 73 and DMAP as additives because both promoted the complex formation and rearrangement steps, respectively. This method proved to be tolerant to a wide range of nitroolefins and sulfonium ylides, although substitution at the α-carbonyl position of the sulfonium ylide resulted in lower yields (Scheme 26). Their proposed catalytic cycle, supported by NMR and labeling studies, starts with the coordination of 2-CTU-cat 73 with nitroolefin to obtain the intermediate 75. Michael’s addition of sulfonium ylide led to Michael adduct 76, and subsequent intramolecular O-alkylation afforded intermediate 77, in equilibrium with bicycle 78. The deprotonation of 78 by DMAP, followed by ring opening, furnishes intermediate 79 and oxazirene 80, respectively. Ring opening by strain release of the three-membered ring leads to the formation of nitrene 81, followed by Hofmann rearrangement, yielding isocyanate 82. The ring-closing reaction and protonation give intermediate 83 and oxazolidinone 74, respectively (Scheme 27) [56].
In 2009, as an application of the formal (4 + 1)/(3 + 2) cycloaddition cascade of sulfonium ylide 2 and nitroolefin 84, Xiao and coworkers employed chiral urea organocatalyst (Urea-cat-12) in xylene at low temperature to deliver the desired product 85 in 80% yield, 95:5 dr and 90:10 er (with an increase to 99:1 after one recrystallization). In this reaction, five stereocenters were obtained in one step, and at the time it represented the first successful example of a chiral Brønsted acid catalyzed reaction involving sulfur ylides (Scheme 28) [57].
In 2012, the same group reported a chiral urea-catalyzed (4 + 1)/rearrangement cascade reaction of sulfonium ylide 2 with nitro olefin 72, affording 4,5-disubstituted oxazolidinones 74 (21 examples) in excellent yields and enantiomeric/diastereomeric ratios. In all cases, 95:5 of the anti diastereoisomer was obtained. Temperature control was crucial (Scheme 29). Based on their mechanistic studies, the proposed catalytic cycle involves the formation of a complex between the organocatalyst and sulfonium ylide 14 through strong hydrogen bonding, followed by coordination with nitroolefin 72. This intermediate 86 undergoes a dual activation by a direct Lewis acid activation of the urea catalyst with nitroolefin and a direct Lewis base activation by sulfur ylide. The next step involves a Michael addition of sulfur ylide to the nitro olefin, leading to the Michael adduct 87 in an enantiodeterming step (followed by intramolecular O-alkylation to give complex 88). The release of the nitronate intermediate with coordination of the unreacted sulfur ylide 2 regenerates the organocatalyst. Increasing the temperature favors the Hoffmann rearrangement, providing the desired product 74 (Scheme 30) [58].
In 2017, Yang and coworkers reported an asymmetric dihydrobenzofuran synthesis from sulfonium ylides 2 and ortho-quinone methide (o-QM) generated in situ from halides 89. A chiral urea organocatalyst (Urea-cat 90) was used to induce stereoselectivity, CsF was used to promote the o-QM formation, and 18-crown-6 to enhance fluorine reactivity in toluene at low temperatures. The desired product 91 (19 examples) was obtained with excellent yields (up to 98%) and good selectivity (up to 89:11 er; Scheme 31). The authors have proposed a catalytic cycle involving the coordination of urea-cat with sulfonium ylide, leading to intermediate 92, followed by the coordination of o-QM 93, which is formed in situ by treating 89 with CsF, to form complex 94. The Michael addition, which is the stereoselective step, furnishes intermediate 95, with subsequent intramolecular O-alkylation and SMe2 extrusion. This leads to the dihydrobenzofuran product 91 and regenerates the urea-cat (Scheme 32) [59].
In 2012, Tong and coworkers developed an amine-catalyzed formal (3 + 3) cycloaddition of 2-(acetoxymethyl)buta-2,3-dienoate 97 with sulfonium ylides 2 to provide 4H-pyrans 98 in yields up to 96%. The allene moiety proved to be critical in this reaction, as cyclization did not occur when olefin 98f was used instead of allene 97 (Scheme 33). The authors have proposed a mechanism involving an attack of DABCO on allene 97 via SN2′, followed by 1,4-addition with sulfonium ylide 2, leading to intermediates 99 and 100, respectively. Instead of the Corey–Chaykovsky cyclopropanation, an 1,2-elimination regenerates the DABCO, and the allene intermediate 101 is obtained. Nucleophilic attack (Br– or AcO−) on sulfonium 101 provided sulfide 102 via the S–Me cleavage. Subsequent oxa-Michael addition leads to 4H-pyran 98 (Scheme 34) [60].
In 2021, Bernardi and coworkers reported a catalyst- and substrate-dependent chemodivergent reaction between sulfoxonium ylides 1 and salicylaldehydes 103, yielding 2H-chromenes 105 (for EDG and H in 16 examples) and dihydrobenzofurans 106 (for EWG in 3 examples). In the former case, Brønsted-acid organocatalyst (PA-cat 104) led to 2H-chromenes 105 with good yields (up to 81%). In the latter case, without the use of a catalyst, dihydrobenzofurans 106 were obtained in good yields (up to 85%) (Scheme 35). In these two cases, the proposed mechanism was explained after some control experiments. For EDG and H substituents, the catalytic cycle involves the coordination of PA-cat 104 with salicylaldehyde via intermediate 107, followed by an attack of sulfoxonium ylide 1, leading to intermediate 108. The attack of the second ylide 1 yields the second intermediate 109 with the extrusion of DMSO. The nucleophilic attack of phenol 110 leads to the formation of chromane 111, which is dehydrated to furnish 2H-chromene 105 (Scheme 36; Pathway a). For EWG, sulfoxonium ylide 1 directly attacks salicylaldehyde 103. Proton transfer to intermediate 113, followed by dehydration, yields o-QM 114 in situ. A formal (4 + 1) of the o-QM intermediate 114 with another equivalent of sulfoxonium ylide 1 led to the formation of dihydrobenzofuran 106 (Scheme 36; Pathway b) [61].

5. Conclusions

Organocatalytic transformations from sulfur ylides have proven to be an essential strategy to obtain enantioenriched products, for example, cyclopropanes, 5- or 6-membered cycles, or even gem-disubstituted carbonyl compounds. However, there are potential challenges to be faced. For instance, sulfonium ylides were predominant in cyclization reactions, and sulfoxonium ylides were the best substrates for formal bond insertion reactions. To distinguish the reactivity of sulfur ylides and to expand the scope of methodologies, studies of sulfonium ylides in formal insertion reactions and sulfoxonium ylides in cyclization are required.
Although examples of enantioselective formal X–H insertion reactions were described, asymmetric insertions in X–Y bonds (dihalogenation or fluoration-azidation, for example) are desired. By using different sources of nucleophiles and electrophiles, this type of difunctionalization can increase the degree of functionalization and provide interesting gem-difunctionalized carbonyl compounds in a single step [62].
This review [63] has covered organocatalytic transformations of sulfur ylides, indicating the mechanism and the corresponding modes of activation. We intend to inspire the reader to explore this exciting area by developing novel methodologies in organic synthesis with this fascinating class of organic compounds, either by developing new sulfur ylides or organocatalysts with divergent modes of activation.

Author Contributions

Conceptualization, A.C.B.B. and M.H.; writing—original draft preparation, M.H.; writing—review and editing, A.C.B.B.; visualization, A.C.B.B.; supervision, A.C.B.B.; project administration, A.C.B.B.; funding acquisition, A.C.B.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by FAPESP, grant number 2020/07147-0.

Data Availability Statement

Not applicable.

Acknowledgments

We thank the Coordination for the Improvement of Higher Education Personnel (CAPES) for a fellowship grant (88887.668991/2022-00) to M.H.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

18-crown-61,4,7,10,13,16-hexaoxacyclooctadecane
AcOacetyl
ÅAngstrom
aqaqueous
Araryl
Bnbenzyl
Bubutyl
catcatalyst
DABCO1,4-diazabicyclo[2.2.2]octane
Decdecanyl
DMAPN,N-4-dimethylaminopyridine
DMSOdimethylsulfoxide
dediastereomeric excess
drdiastereomeric ratio
EDGelectron directing group
eeenantiomeric excess
eqequivalent
erenatiomeric ratio
Etethyl
EWGelectron withdrawing group
iiso
mmili
Mmolar (mol·L−1)
Memethyl
MSmolecular sieves
nnormal
NHCN-heterocyclic carbene
oortho
Phphenyl
Prpropyl
QMquinone methide
rtroom temperature
ttert
TBStert-butyldimethylsilyl
TMStrimethylsilyl
yyield

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Catalysts 13 00689 sch001 550
Scheme 1. Sulfur ylides and their stability and nucleophilicity at carbon.
Scheme 1. Sulfur ylides and their stability and nucleophilicity at carbon.
Catalysts 13 00689 sch001
Catalysts 13 00689 sch002 550
Scheme 2. Organocatalyzed reactions from sulfur ylides.
Scheme 2. Organocatalyzed reactions from sulfur ylides.
Catalysts 13 00689 sch002
Catalysts 13 00689 sch003 550
Scheme 3. Indole-organocatalyst catalyzed cyclopropanation, with selected examples.
Scheme 3. Indole-organocatalyst catalyzed cyclopropanation, with selected examples.
Catalysts 13 00689 sch003
Catalysts 13 00689 sch004 550
Scheme 4. Tetrazole-organocatalyst catalyzed cyclopropanation, with selected examples.
Scheme 4. Tetrazole-organocatalyst catalyzed cyclopropanation, with selected examples.
Catalysts 13 00689 sch004
Catalysts 13 00689 sch005 550
Scheme 5. Sulfonamide-organocatalyst catalyzed cyclopropanation, with selected examples.
Scheme 5. Sulfonamide-organocatalyst catalyzed cyclopropanation, with selected examples.
Catalysts 13 00689 sch005
Catalysts 13 00689 sch006 550
Scheme 6. Urea-organocatalyst catalyzed cyclopropanation, with selected examples.
Scheme 6. Urea-organocatalyst catalyzed cyclopropanation, with selected examples.
Catalysts 13 00689 sch006
Catalysts 13 00689 sch007 550
Scheme 7. Proposed catalytic cycle of urea-catalyzed cyclopropanation of β,γ-unsaturated-α-keto-ester.
Scheme 7. Proposed catalytic cycle of urea-catalyzed cyclopropanation of β,γ-unsaturated-α-keto-ester.
Catalysts 13 00689 sch007
Catalysts 13 00689 sch008 550
Scheme 8. Oxidative NHC-catalyzed cyclopropanation of unsaturated aldehydes with selected examples.
Scheme 8. Oxidative NHC-catalyzed cyclopropanation of unsaturated aldehydes with selected examples.
Catalysts 13 00689 sch008
Catalysts 13 00689 sch009 550
Scheme 9. Proposed catalytic cycle of NHC-catalyzed cyclopropanation of α,β-unsaturated aldehyde.
Scheme 9. Proposed catalytic cycle of NHC-catalyzed cyclopropanation of α,β-unsaturated aldehyde.
Catalysts 13 00689 sch009
Catalysts 13 00689 sch010 550
Scheme 10. Amine-catalyzed cyclopropanation of unsaturated ketones with selected examples (in parentheses yield and ee after recrystallization).
Scheme 10. Amine-catalyzed cyclopropanation of unsaturated ketones with selected examples (in parentheses yield and ee after recrystallization).
Catalysts 13 00689 sch010
Catalysts 13 00689 sch011 550
Scheme 11. Proposed catalytic cycle of amine-catalyzed cyclopropanation of α,β-unsaturated ketone by dual activation.
Scheme 11. Proposed catalytic cycle of amine-catalyzed cyclopropanation of α,β-unsaturated ketone by dual activation.
Catalysts 13 00689 sch011
Catalysts 13 00689 sch012 550
Scheme 12. (1) Proline-derivative catalyzed cyclopropanation of aldehydes and sulfoxonium ylides, followed by (2) Wittig reaction, with selected examples.
Scheme 12. (1) Proline-derivative catalyzed cyclopropanation of aldehydes and sulfoxonium ylides, followed by (2) Wittig reaction, with selected examples.
Catalysts 13 00689 sch012
Catalysts 13 00689 sch013 550
Scheme 13. Proposed catalytic cycle of cyclopropanation via iminium/enamine sequence.
Scheme 13. Proposed catalytic cycle of cyclopropanation via iminium/enamine sequence.
Catalysts 13 00689 sch013
Catalysts 13 00689 sch014 550
Scheme 14. Urea-catalyzed epoxidation of aldehydes with selected examples.
Scheme 14. Urea-catalyzed epoxidation of aldehydes with selected examples.
Catalysts 13 00689 sch014
Catalysts 13 00689 sch015 550
Scheme 15. Thiourea-catalyzed S–H insertion of sulfoxonium ylides by aryl thiol with selected examples.
Scheme 15. Thiourea-catalyzed S–H insertion of sulfoxonium ylides by aryl thiol with selected examples.
Catalysts 13 00689 sch015
Catalysts 13 00689 sch016 550
Scheme 16. Proposed catalytic cycle of enantioselective S–H insertion.
Scheme 16. Proposed catalytic cycle of enantioselective S–H insertion.
Catalysts 13 00689 sch016
Catalysts 13 00689 sch017 550
Scheme 17. (S)-TRIP-catalyzed C–H insertion of sulfoxonium ylides by indoles with selected examples.
Scheme 17. (S)-TRIP-catalyzed C–H insertion of sulfoxonium ylides by indoles with selected examples.
Catalysts 13 00689 sch017
Catalysts 13 00689 sch018 550
Scheme 18. Proposed catalytic cycle of enantioselective C–H insertion.
Scheme 18. Proposed catalytic cycle of enantioselective C–H insertion.
Catalysts 13 00689 sch018
Catalysts 13 00689 sch019 550
Scheme 19. Chiral Phosphoric Acid-catalyzed N–H insertion of sulfonium ylides by anilines, with selected examples.
Scheme 19. Chiral Phosphoric Acid-catalyzed N–H insertion of sulfonium ylides by anilines, with selected examples.
Catalysts 13 00689 sch019
Catalysts 13 00689 sch020 550
Scheme 20. Chiral phosphoric acid-catalyzed N–H insertion of sulfonium ylides by anilines, with selected examples and catalysts.
Scheme 20. Chiral phosphoric acid-catalyzed N–H insertion of sulfonium ylides by anilines, with selected examples and catalysts.
Catalysts 13 00689 sch020
Catalysts 13 00689 sch021 550
Scheme 21. Proposed catalytic cycle of enantioselective N–H insertion of sulfonium ylide.
Scheme 21. Proposed catalytic cycle of enantioselective N–H insertion of sulfonium ylide.
Catalysts 13 00689 sch021
Catalysts 13 00689 sch022 550
Scheme 22. Chiral phosphoric acid-catalyzed N–H insertion of sulfoxonium ylides by anilines, with selected examples.
Scheme 22. Chiral phosphoric acid-catalyzed N–H insertion of sulfoxonium ylides by anilines, with selected examples.
Catalysts 13 00689 sch022
Catalysts 13 00689 sch023 550
Scheme 23. Proposed catalytic cycle of enantioselective N–H insertion of sulfoxonium ylide.
Scheme 23. Proposed catalytic cycle of enantioselective N–H insertion of sulfoxonium ylide.
Catalysts 13 00689 sch023
Catalysts 13 00689 sch024 550
Scheme 24. Squaramide-catalyzed N–H insertion of sulfoxonium ylides by azides, with selected examples.
Scheme 24. Squaramide-catalyzed N–H insertion of sulfoxonium ylides by azides, with selected examples.
Catalysts 13 00689 sch024
Catalysts 13 00689 sch025 550
Scheme 25. Proposed catalytic cycle of enantioselective N–H azidation of sulfoxonium ylide.
Scheme 25. Proposed catalytic cycle of enantioselective N–H azidation of sulfoxonium ylide.
Catalysts 13 00689 sch025
Catalysts 13 00689 sch026 550
Scheme 26. Thiourea-catalyzed (4 + 1) cyclization/rearrangement cascade reaction with selected examples.
Scheme 26. Thiourea-catalyzed (4 + 1) cyclization/rearrangement cascade reaction with selected examples.
Catalysts 13 00689 sch026
Catalysts 13 00689 sch027 550
Scheme 27. Proposed mechanism of (4 + 1) cyclization/rearrangement cascade reaction.
Scheme 27. Proposed mechanism of (4 + 1) cyclization/rearrangement cascade reaction.
Catalysts 13 00689 sch027
Catalysts 13 00689 sch028 550
Scheme 28. Enantioselective (4 + 1)/(3 + 2) cycloaddition cascade of sulfonium ylide and nitroolefin.
Scheme 28. Enantioselective (4 + 1)/(3 + 2) cycloaddition cascade of sulfonium ylide and nitroolefin.
Catalysts 13 00689 sch028
Catalysts 13 00689 sch029 550
Scheme 29. Urea-catalyzed enantioselective (4 + 1) cyclization/rearrangement cascade reaction with selected examples.
Scheme 29. Urea-catalyzed enantioselective (4 + 1) cyclization/rearrangement cascade reaction with selected examples.
Catalysts 13 00689 sch029
Catalysts 13 00689 sch030 550
Scheme 30. Proposed mechanism of enantioselective (4 + 1) cyclization/rearrangement cascade reaction.
Scheme 30. Proposed mechanism of enantioselective (4 + 1) cyclization/rearrangement cascade reaction.
Catalysts 13 00689 sch030
Catalysts 13 00689 sch031 550
Scheme 31. Urea-catalyzed enantioselective (4 + 1) formal cyclization of sulfonium ylides and in situ generated o-QM.
Scheme 31. Urea-catalyzed enantioselective (4 + 1) formal cyclization of sulfonium ylides and in situ generated o-QM.
Catalysts 13 00689 sch031
Catalysts 13 00689 sch032 550
Scheme 32. Proposed mechanism of enantioselective (4 + 1) cyclization reaction.
Scheme 32. Proposed mechanism of enantioselective (4 + 1) cyclization reaction.
Catalysts 13 00689 sch032
Catalysts 13 00689 sch033 550
Scheme 33. DABCO-catalyzed formal (3 + 3) cycloaddition with selected examples.
Scheme 33. DABCO-catalyzed formal (3 + 3) cycloaddition with selected examples.
Catalysts 13 00689 sch033
Catalysts 13 00689 sch034 550
Scheme 34. Proposed mechanism of formal (3 + 3) cycloaddition.
Scheme 34. Proposed mechanism of formal (3 + 3) cycloaddition.
Catalysts 13 00689 sch034
Catalysts 13 00689 sch035 550
Scheme 35. Phosphoric acid-catalyzed chemodivergent annulations between sulfoxonium ylides and salicylaldehydes.
Scheme 35. Phosphoric acid-catalyzed chemodivergent annulations between sulfoxonium ylides and salicylaldehydes.
Catalysts 13 00689 sch035
Catalysts 13 00689 sch036 550
Scheme 36. Proposed mechanisms of (a) 2H-chromene synthesis catalyzed by PA-cat; (b) dihydrobenzofuran synthesis.
Scheme 36. Proposed mechanisms of (a) 2H-chromene synthesis catalyzed by PA-cat; (b) dihydrobenzofuran synthesis.
Catalysts 13 00689 sch036
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Hayashi, M.; Burtoloso, A.C.B. Organocatalytic Transformations from Sulfur Ylides. Catalysts 2023, 13, 689. https://doi.org/10.3390/catal13040689

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Hayashi M, Burtoloso ACB. Organocatalytic Transformations from Sulfur Ylides. Catalysts. 2023; 13(4):689. https://doi.org/10.3390/catal13040689

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Hayashi, Marcio, and Antonio C. B. Burtoloso. 2023. "Organocatalytic Transformations from Sulfur Ylides" Catalysts 13, no. 4: 689. https://doi.org/10.3390/catal13040689

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