Download PDF
Synthesis 2022; 54(18): 3928-3940
DOI: 10.1055/s-0041-1737493
short review

Recent Advances in Thianthrenation/Phenoxathiination Enabled Site-Selective Functionalization of Arenes

Xiao-Yue Chen
a   State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS 345 Lingling Road, Shanghai 200032, P. R. of China
,
Yichen Wu
a   State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS 345 Lingling Road, Shanghai 200032, P. R. of China
,
Peng Wang  ∗
a   State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS 345 Lingling Road, Shanghai 200032, P. R. of China
b   CAS Key Laboratory of Energy Regulation Materials, Shanghai Institute of Organic Chemistry, CAS 345 Lingling Road, Shanghai 200032, P. R. of China
c   School of Chemistry and Material Sciences, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, P. R. of China
› Author Affiliations

We gratefully acknowledge National Natural Science Foundation of China (22101291, 22171277, 21821002), Shanghai Rising-Star Program (20QA1411400), Shanghai Institute of Organic Chemistry, and State Key Laboratory of Organometallic Chemistry for financial support.
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Abstract

Site-selective functionalization of simple arenes remains a paramount challenge due to the similarity of multiple C–H bonds in the same molecule with similar steric environment and electronic properties. Recently, the site-selective thianthrenation/phenoxathiination of arenes has become an attractive solution to reach this challenging goal and it has been applied in the late-stage functionalization of various bioactive molecules. This short review aims to summarize recent advances in the site-selective C–H functionalization of arenes via aryl thianthrenium salts, as well as mechanistic insights in the remarkable site-selectivity obtained in thianthrenation step.

1 Introduction

2 Site-Selective Thianthrenation of Arenes and Mechanistic Insight

3 Thianthrenation-Enabled Site-Selective Functionalization of Arenes

3.1 Thianthrenation-Enabled C(sp 2)–C Bond Formation Reaction

3.2 Thianthrenation-Enabled C(sp 2)–X Bond Formation Reaction

4 Conclusion and Outlook


#

Key words

thianthrenation - phenoxathiination - arene - sulfonium salts - C–H functionalization
1

Introduction

Zoom Image
Xiao-Yue Chen was born in Sichuan, China (1993). He obtained his B.S. degree from Sichuan University (SCU) in 2017. After that, he continued his research experience as a graduate student in both Shanghai Institute of Organic Chemistry (SIOC), CAS and East China Normal University under the co-supervision of Prof. Dr. Peng Wang and Prof. Dr. Jian Zhou. His current research interest focuses on thianthrenation enabled site-selective C–H functionalization. Yichen Wu received her Ph.D. degree from the Institute of Chemical Research of Catalonia (ICIQ), Spain in 2017 under the supervision of Prof. Alexandr Shafir. From 2018, she joined Prof. Wang’s group at the Shanghai Institute of Organic Chemistry (SIOC) first as a postdoctoral researcher and now as an assistant professor. Her current research interest focuses on organosilicon chemistry. Peng Wang received his B.S. degree from Tianjin University in 2007, and completed his Ph.D. under the supervision of Prof. Yong Tang at Shanghai Institute of Organic Chemistry (SIOC) in 2013. He joined SIOC as a full professor in early 2018 after carrying postdoctoral research with Prof. Jin-Quan Yu at the Scripps Research Institute (TRSI). His research group focuses on transition metal catalysis and main group chemistry.

Direct nondirected C–H functionalization of arenes has been considered as an effective and powerful tool for the construction of carbon–carbon and carbon–heteroatom bonds due to the wide availability of aromatics as the raw materials and fundamental microstructure ubiquitous in numerous organic compounds.[1] [2] The rapid development of the nondirected C–H bond functionalization of arenes could not only convert simple aromatic raw materials into high-value products, but also provide an efficient approach to enrich molecular complexity via late-stage functionalization that could greatly increase the efficiency of the drug discovery and material development process.[3] Two major well-known challenges remain in the nondirected C–H functionalization of simple arenes: (1) low reactivity of simple arenes, which requires an excess or solvent amount of arenes; and (2) insufficient site-selectivity caused by multiple C–H bonds with similar electronic and steric properties existing in the same molecule. To data, a variety of innovative strategies have been applied to the site-selective C–H diversification of arenes, including electronic control in electrophilic aromatic substitution,[4] directing group approach,[2] [5] steric modulation with transition metal catalysis,[6] and radical functionalization,[7] etc. However, these approaches still suffer from insufficient site-selectivity, arene scope, and functional group tolerance. A more general approach that features high reactivity, remarkable site-selectivity, and good functional group tolerance is still high desired as the late-stage functionalization of drug molecules and bioactive molecules requires the tolerance of complex motifs containing heterocycles and myriad other functionalities.

Zoom Image
Scheme 1 Thianthrenation/phenoxathiination enabled site-selective functionalization of arenes

Recently, the site-selective thianthrenation of arenes has become an attractive solution for the late-stage C–H functionalization of simple arenes (Scheme [1]). In particular, isolated or in situ generated sulfonium salts[8] [9] can be site-selectively formed from simple arenes with tetrafluorothianthrene S-oxide (TFTSO), thianthrene S-oxide (TTSO), and phenoxathiin 10-oxide (POSO) under acidic conditions. For instance, the Ritter group[10] determined that the site-selectivity of the formation of sulfonium salts for ethylbenzene with tetrafluorothianthrene S-oxide in the presence of trifluoroacetic anhydride and HBF4·Et2O in CH3CN and a catalytic amount of tetrafluorothianthrene (TFT) is 500/2.5/1 (para/meta/ortho) measured by 1H NMR spectroscopy (Scheme [2a]). The Wang group[11] reported that the thianthrenation of toluene with thianthrene S-oxide provides a selectivity of 95/1.0 (para/ortho) measured by 1H NMR spectroscopy in the presence of trifluoromethanesulfonic anhydride in DCM; the phenoxathiination of toluene with phenoxathiin 10-oxide leads to a selectivity of 77/1.0 (para/ortho) under the same conditions (Scheme [2b]). Generally, the thianthrenation process presents remarkable para-selectivity for electron-rich and electron-neutral arenes; the thianthrenation normally occurs at the most electron-rich site of the aromatic ring for multiple substituted arenes. The thianthrenation was also compatible with chlorobenzene and fluorobenzene, albeit more electron-deficient arenes and heteroarenes were not tolerated. The high site-selectivity for the most electron-rich site of the arene allows compounds to be selectively functionalized via further transformations, and thus paves the way for a new, efficient C–H functionalization of arenes. This thianthrenation strategy has attracted tremendous attention in synthetic chemistry, and diverse late-stage functionalizations of undirected arenes in a site-selective manner have been developed. This review summarizes recent advances in the thianthrenation/phenoxathiination-enabled C–H functionalization of arenes utilizing site-selective thianthrenation as the key process, including the various transformations for C(sp 2)–C and C(sp 2)–X bond construction, and the mechanistic causes for the remarkable site-selectivity obtained in the thianthrenation step.

Zoom Image
Scheme 2 Remarkable site-selectivity in thianthrenation and phenoxathiination of arenes

# 2

Site-Selective Thianthrenation of Arenes and Mechanistic Insight

Although the utilization of thianthrenation as a strategy in the site-selective C–H functionalization of undirected arenes has been developed recently, the phenomenon of the para-selective thianthrenation of electron-rich monosubstituted arene (such as anisole) was observed in the 1970s in work pioneered by Shine. In 1971, the reaction of thianthrenium perchlorate 1, a stable thianthrenium radical cation,[12] with electron-rich arenes (anisole and toluene) was reported during an exploration of the reactivity of the thianthrene radical cation intermediate by the Shine group.[13] The reaction does not happen with benzene and electron-deficient arenes, including chlorobenzene and nitrobenzene. A series of experiments with anisole as the model substrate (the anisylation reaction) were carried out to explore the reaction mechanistically (Scheme [3]). The kinetic data showed the second order in the thianthrene cation radical and an experiment of the addition of excess thianthrene slowed down the reaction. These results were in line with the disproportionation mechanism, in which the dication intermediate TT++ (Int I) was proposed as the reactive intermediate (pathway A), slowly generated from disproportionation of the cation radical. Another pathway, which is analogous to that generally proposed in electrophilic substitution, was also mentioned (pathway B). However, the contradiction that electron-transfer step should be either the rate-determining step to fit the kinetic behavior or reversible so that retardation could occur when excess thianthrene was added made it less possible.

Zoom Image
Scheme 3 The reaction of thianthrene perchlorate and anisole

In 1974, the Shine group further studied the reaction of thianthrene cation radical perchlorate 1 with phenol or acetanilide, they found the kinetic behaviors under certain conditions were quite different from that of anisole, which challenged the disproportionation mechanism.[14] In 1975, the anisylation was reinvestigated by Parker and co-workers.[15] This time, the thianthrene cation radical was generated via thianthrene in the DCM-TFA-TFAA or MeCN-TFAA solvent system at constant current. The experimental data, including the observation that the rate law changed when using different cation radical concentrations, were quite different from the ones predicted by the disproportionation mechanism. Therefore, the mechanism defined as half regeneration was established (Scheme [4]). The thianthrene radical cation reacts with anisole to give a more easily oxidized species, followed by electron transfer to form the thianthrene dication–anisole intermediate which loses a proton together with bond formation to afford the product.

Zoom Image
Scheme 4 The proposed mechanism for the reaction of thianthrene perchlorate and anisole

In the case of the reaction with phenol, the presence of TFA was found to affect the kinetic behavior and a high kinetic isotope effect was observed. Thus, the above half regeneration mechanism was modified, where uncharged radical Int II was formed via the interaction between the phenol and thianthrene radical cation (Scheme [5]).[16]

Zoom Image
Scheme 5 The proposed mechanism for thianthrene perchlorate and phenol

In 1982, Tinker and Bard investigated this anisylation in liquid sulfur dioxide in an electrochemical manner (Scheme [6]).[17] These nucleophile-free solvent conditions can inhibit the reaction between the thianthrene and solvent or impurity (such as water), which is generally proposed to have occurred under the previous reported conditions. The phenomenon that the thianthrene dication species rapidly reacted with anisole, while barely any reaction occurred with its radical cation, was observed by cyclic voltammetry and coulometry, indicating that dication TT++ was the reactive intermediate under such conditions.

Zoom Image
Scheme 6 The thianthrenation of aromatics in liquid sulfur dioxide

The early studies on the mechanism of this thianthrenation process mainly focused on distinguishing the reactive electrophile species. The origin of the high site-selectivity in the thianthrenation of arenes had not previously been elucidated. In 2019, the Ritter group published a site-selective thianthrenation of a broad range of arenes including drug molecules (Scheme [7]). The thianthrenium salts were formed in the presence of tetrafluorothianthrene S-oxide, trifluoroacetic anhydride, and HBF4·Et2O.[10] With newly designed TFTSO as the reagent, the thianthrenation reaction features broad substrate scope, and tolerated an electron-deficient chlorobenzene (86% yield). The reaction generally has high efficiency and was complete within 3 hours. This reaction provides a charming opportunity for the development of the thianthrene-mediated C–H functionalization of arenes. The proposed the mechanism is via radical cation intermediate Int III, which was observed by EPR (electron paramagnetic resonance spectroscopy). The radical cation Int III reacts with the arene to give the Wheland intermediate Int IV, which is supported by the Hammett analysis data (ρ = –11). Deprotonation of Wheland intermediate Int IV gives the aryl thianthrenium salts (Scheme [7]).

Zoom Image
Scheme 7 The proposed mechanism for the thianthrenation of arenes

The Wang group was simultaneously working on a transient mediator approach for the para-selective functionalization of undirected arenes, and found thianthrene S-oxide and phenoxathiin 10-oxide to be the most selective mediators in comparison to other organosulfur S-oxides.[11] Although the radical cation intermediate was detected by the EPR, it was found that the reaction did not proceed at low concentrations even though the thianthrene radical cation is generated rapidly in situ. These observations led to detailed mechanistic experiments and DFT calculations. The mechanistic studies and DFT calculations indicate that although the thianthrene or phenoxathiin cation radical is detected under the reported reaction conditions, highly electrophilic thianthrene or phenoxathiin dication species Int I is the key to the high regioselectivity. The remarkable regioselectivity obtained in the thianthrenation step might originate from subtle electronic differences at the para- and ortho-positions and the highly electrophilic nature of the dication intermediates. Moreover, the dication species, under their reaction conditions according to the DFT calculation, is generated via heterolysis of the sulfide ditriflate (Scheme [8]).[18]

Zoom Image
Scheme 8 The proposed mechanism for thianthrenation of arenes

In 2021, the Ritter and Houk groups explored the nature of the high site-selectivity of C–H thianthrenation under their previous reported conditions.[19] Using systematic experimental and computational studies, they elucidated the mechanism with TT+-TFA as the key intermediate, which was characterized by 1H NMR. This intermediate then affords the dication species Int I via S–O dissociation. Both species (TT+-TFA and Int I) can be involved in electrophilic addition depending on the reaction conditions (acidic or basic conditions) and the substrate (nucleophilicity and electron density of the aromatics). After reversible radical recombination, the subsequent irreversible deprotonation was addressed as the selectivity determining step, which was supported by the result of the kinetic isotope effect study in the intermolecular competition experiments (KIE = 1.9) and the DFT calculation of the lowest energy barrier during deprotonation of Wheland intermediates when the substituent on the arene was para to thianthrene (Scheme [9]). The outcome of the remarkable para-selectivity in thianthrenation is the combination of a polar contribution (para/meta selectivity) and steric effect (para/ortho selectivity) in the reversible interconversion between different constitutional Wheland isomer intermediates.

Zoom Image
Scheme 9 The proposed mechanism for thianthrenation of arenes

# 3

Thianthrenation-Enabled Site-Selective Functionalization of Arenes

Since 2019, the thianthrenation-enabled site-selective functionalization of arenes has become an efficient late-stage functionalization strategy for decorating bioactive molecules. A series of carbon–carbon and carbon–heteroatom bond forming reactions have been developed via aryl thianthrenium salts, and the chemistry of aryl thianthrenium salts has been largely explored by Ritter, Wang, and others. In 2019, the Ritter group showcased the transformations of pyriproxyfen-derived thianthrenium salt 3 under transition metal catalysis or photocatalysis conditions to construct pyriproxyfen derivatives with diverse functional groups, which indicates that late-stage functionalization of the complex molecules from the parent C(sp 2)–H compounds is feasible (Scheme [10]).[10]

Zoom Image
Scheme 10 The formation of pyriproxyfen-derived thianthrenium salts and their transformation

Around the same time, the Wang group reported the thianthrene-enabled para-selective borylation of monosubstituted aromatics via the in situ para-selective thianthrenation of arenes.[11] Different sulfoxides were evaluated to identify the most suitable as the transient mediator for the thianthrenation of monosubstituted arenes, which were phenoxathiin S-oxide and thianthrene S-oxide that gave the product in a remarkably para-selective manner. All other dialkyl and diaryl sulfur oxides led to insufficient regioselectivity (Scheme [11]). Unlike Ritter’s stepwise process, the borylation was conducted in one-pot and generated the aryl thianthrenium salt efficiently in situ with trifluoromethanesulfonic anhydride (within 1.0 h); the aryl thianthrenium salt underwent further photocatalyzed borylation to give various arylboronic esters 5 in good yields.

Zoom Image
Scheme 11 para-Selective borylation of monosubstituted arenes

There have since been a number of reports on the site-selective C–H functionalization of arenes via thianthrenation. Various functionalities have been site-selectively installed in arenes via C–C and C–X (X = N, O, F, Si, B, etc.) formation reaction.

3.1

Thianthrenation-Enabled C(sp 2)–C Bond Formation Reaction

In 2020, the Wang group applied this strategy to the construction of various para-arylated and alkenylated monosubstituted arenes 4 by combining in situ para-selective thianthrenation and Pd-catalyzed thio-Suzuki–Miyaura coupling (Scheme [12]).[20] Notably, this reaction features simple manipulation and high efficiency. The solvent and acid in the first thianthrenation step were tolerated in the second step, the thio-Suzuki–Miyaura coupling which used a palladium catalyst with phosphine ligand in the presence of an excess amount of base. It is worth noting that some pharmaceuticals, such as LJ570, were synthesized from commercially available, cheap, simple starting materials by a shortened synthetic route.

Zoom Image
Scheme 12 para-Arylation and alkenylation of arenes

In addition, several examples of the regioselective insertion of heteroarenes into arenes have been reported. 2-(Hetero)aryl-azoles 8 were produced by the Zhang group via Pd/Cu catalyzed cross-coupling with isolated aryl thianthrenium salts (Scheme [13]).[21] The protocol used a wide range of substrates, and it had good functional group tolerance. Moreover, a one-pot process using toluene as the starting material gave 8a in comparable yield. This strategy was applied to the synthesis of Febuxostat and gave the targeted drug with high efficiency.

Zoom Image
Scheme 13 Regioselective insertion of heteroarenes into arenes under transition-metal-catalytic conditions

Arylsulfonium salts are good aryl radical precursors. For example, the Procter group reported the photoredox-catalyzed cross-coupling between in situ generated 5-aryldibenzothiophenium salts and heteroarenes in 2020.[9f] In 2021, the Ritter group developed a methodology for heteroarylation using aryl thianthrenium salts as radical precursors via a radical addition process (Scheme [14]).[22] Here, the C–S bond is activated with α-aminoalkyl radicals. The reaction proceeds under simple and air-moisture tolerant conditions with Na2S2O8 and a tertiary amine, no light or photoredox catalyst was required in this system. Other transformations via this radical activation mode, including borylation, iodination and allylation, were also showcased.

Zoom Image
Scheme 14 Regioselective insertion the heteroarenes into the aromatics under metal-free conditions

In 2021, the Patureau group reported a photoinduced heteroarylation using isolated aryl thianthrenium salts 10 as substrates (Scheme [15]).[23] Under UV-light (254 nm, 144 W), the isolated thianthrenium salts 10 reacted with heterocycles smoothly giving the corresponding products 11 with high regioselectivities in good yields. In this catalyst-free reaction, the C–S bond was disrupted under UV-light to initiate the aryl radicals.

Zoom Image
Scheme 15 Regioselective insertion the heteroarenes into the aromatics via the photoinduced process

The Liang and Niu group, in 2020, reported the photoinduced Sonogashira coupling (Scheme [16]).[24] The isolated aryl thianthrenium tetrafluoroborate 10 was coupled with terminal alkynes in the presence of CuCl catalyst under blue LEDs to give the alkynylated arenes 12 with high chemoselectivities. Functional groups, such as halogen, alkenyl, heterocycle, could be tolerated under the reported conditions.

In 2021, the Ritter group demonstrated a C(sp 2)–C(sp 3) reductive cross-coupling between aryl thianthrenium salts 10 and readily available alkyl iodides by employing a Pd catalyst in the presence of the reductant (Zn) (Scheme [17]).[25] A variety of alkyl motifs containing different functional groups were regioselectively introduced to the arene. Moreover, two complex building blocks were also cross-linked via this process. The mechanistic studies results favor the Negishi-type alkylation where the zinc reagent is formed in situ.

Zoom Image
Scheme 16 The photoinduced Sonogashira coupling
Zoom Image
Scheme 17 Site-selective alkylation of arenes via thianthrenation and Pd-catalyzed Negishi-type alkylation

α-Arylation of carbonyl compounds with simple arenes is synthetically useful and attracts great attention. The Wang group utilized a strategy using the in situ generation of aryl thianthrenium salts to realize the formal α-arylation of carbonyl compounds with simple arenes 7 to give α-aryl carbonyl compounds 14 (Scheme [18]).[26] A series of ketones and phenylacetate derivatives were used in this reaction and produced the corresponding α-arylated products with high efficiency. Notably, this procedure also tolerated heterocycle-containing acetophenones and phenylacetate. In comparison with normal aryl halides and other arylsulfonium salts, the aryl thianthrenium salt showed the highest reactivity.

Zoom Image
Scheme 18 α-Arylation of carbonyl compounds with simple arenes

α-Amino-azine motifs, which widely exist in pharmaceuticals and ligands, have also been constructed via this thianthrenation chemistry. In this reported protocol, the photocatalyzed hydroarylation of azine-substituted enamides was carried out with in situ generated aryl thianthrenium salts to afford various α-amino-azine derivatives 15, including α-aminopyridine decorated drugs (Scheme [19]).[27]

Zoom Image
Scheme 19 Photocatalyzed hydroarylation of azine-substituted enamides

The incorporation of the trifluoromethyl group into pharmaceutical molecules often enhances their properties, including permeability, lipophilicity, and metabolic stability. Therefore, the development of a strategy for trifluoromethylation, especially a site-selective one, is highly in demand. In 2019, the Ritter group applied thianthrenium chemistry to site-selective arene trifluoromethylation (Scheme [20]).[28] The isolated aryl thianthrenium salts 10 containing diverse functional groups reacted efficiently with in situ generated Cu(I)–CF3 species under the photoredox-catalyzed conditions. Furthermore, this approach was also utilized for the insertion of other fluoro-containing functional groups, such as difluoromethyl or pentafluoroethyl group.

Zoom Image
Scheme 20 Site-selective trifluoromethylation of aromatics

# 3.2

Thianthrenation-Enabled C(sp 2)–X Bond Formation Reaction

In addition to C–C bond formation, C–X (X = N, F, Si etc.) bond-forming reactions enabled by the site-selective thianthrenation of simple arenes have also been demonstrated with transition metal catalysis or photoredox catalysis. For instance, in 2019 the Ritter group realized the C(sp2 )–N cross-coupling of aryl thianthrenium salts with various N-nucleophiles, including primary and secondary alkylamines, arylamines, NH-heterocycles, and amides, etc. (Scheme [21]).[29] Diverse reaction conditions (Pd catalysis or photocatalysis) were utilized for the different N-nucleophiles, producing a broad range of N-arylated products 17. This approach was also applied to late-stage diversification, giving nitrogen-containing Flurbiprofen derivatives in good yields. This method opens a new avenue for the construction of N-arylated molecules that are ubiquitous in natural products and FDA-approved pharmaceuticals.

Zoom Image
Scheme 21 Site-selective C(sp2 )–N bond formation

In 2020, the Ritter group reported a cine-substitution of electron-rich heteroarylsulfonium salts where various N-containing heterocycles were used as N-nucleophiles.[30] This cine-substitution goes through a novel reaction pathway elucidated in Scheme [22], that is, the sulfur ylide is formed after addition of the nucleophile to the heteroarylsulfonium salt, followed by the protonation and elimination to give the final product. It should be noted that in this chemistry, the sulfonium group showed distinguished leaving ability from other (pseudo)halides.

Zoom Image
Scheme 22 cine-Substitution of electron-rich heteroarylsulfonium salts

C(sp2 )–O Bond formation is another attractive issue in synthetic chemistry due to its wide appearance in natural products, pharmaceuticals, and materials. However, methods for forming the C–O bond in molecules, especially in a site-selective manner, are rare. Taking the advantage of the easy initiation of radicals from thianthrenium salts under photoredox conditions, the Ritter group combined the site-selective thianthrenation of arenes 7 with photocatalyzed oxygenation to transform a variety of arenes, including drug-like molecules, into phenols 19 or aryl ethers 20 when water or alcohol, respectively, were used as nucleophile (Scheme [23]).[31] The proposed reaction mechanism is by generation of the aryl radical by reduction of the aryl thianthrenium salt with Ir(II) species, followed by oxidative ligation to give Ar-Cu(III)-OH, which undergoes reductive elimination to form the C–O bond. In 2022, the Patureau group utilized a similar strategy to produce arylated phenols under metal-free conditions using TEMPO as the oxygen source.[32]

Zoom Image
Scheme 23 Site-selective C(sp2 )–O bond formation

Aryl thianthrenium salts generally show similar chemical behavior to aryl halides in transition-metal-catalyzed coupling reactions, which is quite different from that of organometal reagents. The conversion of aryl thianthrenium salts into the corresponding aryl-metal reagent will diversify the reaction pattern for further functionalization. In 2020, the Wang group reported the para-borylation of in situ generated sulfonium salts of monosubstituted aromatics 7 using thianthrene or phenoxathiin as the transient mediator.[11] The reaction was carried out using 4-CzIPN as the photocatalyst in one-pot without isolation and purification of the in situ formed sulfonium salts. However, this photoredox process cannot tolerate the solvent and the acidic conditions used in the first sulfonium salt forming step. Taking advantage of transition metal catalysis, the Wang group further reported a simplified procedure for the site-selective borylation of simple arenes.[33] With the new protocol, the extra manipulations for removal of the solvent and acids in the thianthrenation step are discarded, thus significantly increasing the practicality of the thianthrenation enabled site-selective borylation of arenes. Moreover, the transition metal catalysis showed better efficiency and reproducibility in comparison to that of photoredox catalysis. In both cases, remarkable regioselectivity was achieved with simple manipulations and they also demonstrated examples of the late-stage functionalization of pharmaceuticals and complex bioactive molecules (Scheme [24]).

Zoom Image
Scheme 24 Site-selective borylation of aromatics

Following the success of site-selective borylation reaction, the Wang group reported the site-selective silylation of arenes via aryl thianthrenium salts. A series of arylsilanes were synthesized in high yields by employing a thianthrenation/transition-metal-catalyzed silylation sequence (Scheme [25]).[34] Arenes containing various groups, including acid and aniline derivatives, were reacted smoothly using the Pd(OAc)2/PPh3 catalyst system to obtain silylated products 22 in a remarkable site-selective manner. Moreover, pharmaceuticals could also be efficiently decorated with the silyl group, which has potential to make a contribution to drug discovery via a ‘silicon–carbon switch strategy’.

Zoom Image
Scheme 25 Site-selective silylation of arenes
Zoom Image
Scheme 26 Site-selective C(sp2 )–Ge bond formation

In 2020, the Schoenebeck group reported methodology to obtain arylgermanes from arylsulfonium salts by utilizing their developed air/moisture-stable Pd(I) dimer as the pre-catalyst (Scheme [26]).[35] The tolerance of halide and OTf groups indicated that arylsulfonium salts were more reactive than (pseudo)halides under such conditions. Notably, the chemoselective transformation of arylsulfonium salts in the presence of aryl halides has been observed in the Pd-catalyzed Suzuki-type coupling reaction with 5-aryldibenzothiophenium salts.[9e]

In 2020, the challenging C–F bond formation was achieved under a Cu(III)-mediated photoredox catalysis system by the Ritter group (Scheme [27]).[36] The proposed mechanism is similar to that of C–O bond formation. Aryl radicals initiated by Ir(II) species underwent oxidation to afford Ar-Cu(III)-F complexes, followed by reductive elimination to form the final fluorinated arenes.

Zoom Image
Scheme 27 Site-selective fluorination of aromatics
Zoom Image
Scheme 28 Site-selective C(sp2 )–S bond formation via a hydroxymethyl sulfone

Also in 2020, the Ritter group realized the formation of arylsulfonates via this thianthrenation process (Scheme [28]).[37] Compared to the former sulfination of arenes, normally via electrophilic aromatic substitution with chlorosulfuric acid as an electrophile, this protocol demonstrates remarkable site-selectivity and good functional group tolerance. Arylsulfonium salts 10 were transformed into the corresponding hydroxymethyl sulfone efficiently using Rongalite (sodium hydroxymethylsulfinate) as the SO2 2– source, and they could be further converted into other sulfone derivatives.

In 2022, Molander and co-workers demonstrated the thioetherification of thianthrenium salts.[38] Various sulfides 26 containing different functional groups, such as acid and aldehyde, were constructed under photoinduced conditions. In this protocol, the formation of the EDA complex is crucial, and this undergoes a SET step to generate an aryl radical for further transformation (Scheme [29]).

Zoom Image
Scheme 29 Site-selective C(sp2 )–S bond formation via an EDA complex
Zoom Image
Scheme 30 Site-selective C(sp2 )–P bond formation

In 2021, Huang and co-workers reported the construction of a C–P bond via the cross-coupling of aryl thianthrenium salts and diarylphosphines (Scheme [30]).[39] The C–S bond in the thianthrenium salt was cleaved differently depending on the conditions used and whether palladium catalysis was involved. In the absence of the palladacycle catalyst Pd-1, the endocyclic C–S bond was broken to give product 27 exclusively, otherwise, the cleavage of exocyclic C–S bond occurred to afford 28 with good selectivity.

Tritium (3H) labelled compounds have widespread applications in drug discovery processes. For example, compounds containing the 3H isotope are a powerful diagnostic tool in drug adsorption, distribution, metabolism, and excretion (ADME) studies. In 2021, the Ritter group successfully incorporated tritium into arenes by Pd-catalyzed hydrogenolysis under a sub-atmospheric pressure of tritium gas (Scheme [31]).[40] The tritiation proceeded smoothly under air/moisture tolerant conditions to give the target products 29 with tritium incorporation to the predicted site. This protocol was also applied to the deuteration of thianthrenium salts, affording the corresponding products 30 with high isotopic purity.

Zoom Image
Scheme 31 Tritiation and deuteration of aryl thianthrenium salts

#
# 4

Conclusion and Outlook

This short review summarizes recent advances in the functionalization of arenes with diverse functional groups via the thianthrenation/phenoxathiination process. The history of thianthrenation of aromatics and detailed mechanism are also discussed. By using this strategy, a variety of chemical bonds, such as C–C, C–N, C–O, C–F bond, have been efficiently constructed in a site-selective manner, which opens a new avenue for the late-stage functionalization.

Although elegant progress has been made in this field, challenges still remain. The substrate scope reported is limited to the electron-neutral and electron-rich aromatics. Moreover, using a stoichiometric amount of thianthrene S-oxide and its derivatives, almost quantitative yield of the side product thianthrene or its analogues is formed after functionalization, which is contrary to green chemistry rules in terms of atom-economy. In order to keep progress in this field, further effects could be made include but not limited to the following directions: (1) Consideration of the limitations in the scope of the aromatic substrate and exploration of the functionalization of electron-deficient aromatics, including pyridine, is desired, which will largely expand the application of this strategy in organic synthetic chemistry and medicinal chemistry. (2) The fact that the quantitative recovery of thianthrene could be converted into thianthrene S-oxide under oxidative conditions for further transformations indicates the potential in developing this strategy with substoichiometric or catalytic amounts of thianthrene. (3) Further mechanistic studies for clarifying the principles of this site-selective thianthrenation will enlighten the other transient mediator development for site-selective C–H functionalization. (4) The novel reactivities of aryl thianthrenium salts in comparison with aryl halides need to be largely explored, which will further enrich the diversity of thianthrene enabled C–H functionalization of arenes and the synthetic toolbox in organic synthesis. Undoubtedly, the thianthrenation enabled site-selective functionalization of arenes will find wide synthetic applications in both academia and industry. In addition, more fundamentally novel reactions based on the sulfonium salts flourish in the near future encouraged by these discoveries.


#
#

Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Peng Wang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry
CAS 345 Lingling Road, Shanghai 200032
P. R. of China   

Publication History

Received: 08 April 2022

Accepted after revision: 02 May 2022

Article published online:
28 June 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Xiao-Yue Chen was born in Sichuan, China (1993). He obtained his B.S. degree from Sichuan University (SCU) in 2017. After that, he continued his research experience as a graduate student in both Shanghai Institute of Organic Chemistry (SIOC), CAS and East China Normal University under the co-supervision of Prof. Dr. Peng Wang and Prof. Dr. Jian Zhou. His current research interest focuses on thianthrenation enabled site-selective C–H functionalization. Yichen Wu received her Ph.D. degree from the Institute of Chemical Research of Catalonia (ICIQ), Spain in 2017 under the supervision of Prof. Alexandr Shafir. From 2018, she joined Prof. Wang’s group at the Shanghai Institute of Organic Chemistry (SIOC) first as a postdoctoral researcher and now as an assistant professor. Her current research interest focuses on organosilicon chemistry. Peng Wang received his B.S. degree from Tianjin University in 2007, and completed his Ph.D. under the supervision of Prof. Yong Tang at Shanghai Institute of Organic Chemistry (SIOC) in 2013. He joined SIOC as a full professor in early 2018 after carrying postdoctoral research with Prof. Jin-Quan Yu at the Scripps Research Institute (TRSI). His research group focuses on transition metal catalysis and main group chemistry.
Zoom Image
Scheme 1 Thianthrenation/phenoxathiination enabled site-selective functionalization of arenes
Zoom Image
Scheme 2 Remarkable site-selectivity in thianthrenation and phenoxathiination of arenes
Zoom Image
Scheme 3 The reaction of thianthrene perchlorate and anisole
Zoom Image
Scheme 4 The proposed mechanism for the reaction of thianthrene perchlorate and anisole
Zoom Image
Scheme 5 The proposed mechanism for thianthrene perchlorate and phenol
Zoom Image
Scheme 6 The thianthrenation of aromatics in liquid sulfur dioxide
Zoom Image
Scheme 7 The proposed mechanism for the thianthrenation of arenes
Zoom Image
Scheme 8 The proposed mechanism for thianthrenation of arenes
Zoom Image
Scheme 9 The proposed mechanism for thianthrenation of arenes
Zoom Image
Scheme 10 The formation of pyriproxyfen-derived thianthrenium salts and their transformation
Zoom Image
Scheme 11 para-Selective borylation of monosubstituted arenes
Zoom Image
Scheme 12 para-Arylation and alkenylation of arenes
Zoom Image
Scheme 13 Regioselective insertion of heteroarenes into arenes under transition-metal-catalytic conditions
Zoom Image
Scheme 14 Regioselective insertion the heteroarenes into the aromatics under metal-free conditions
Zoom Image
Scheme 15 Regioselective insertion the heteroarenes into the aromatics via the photoinduced process
Zoom Image
Scheme 16 The photoinduced Sonogashira coupling
Zoom Image
Scheme 17 Site-selective alkylation of arenes via thianthrenation and Pd-catalyzed Negishi-type alkylation
Zoom Image
Scheme 18 α-Arylation of carbonyl compounds with simple arenes
Zoom Image
Scheme 19 Photocatalyzed hydroarylation of azine-substituted enamides
Zoom Image
Scheme 20 Site-selective trifluoromethylation of aromatics
Zoom Image
Scheme 21 Site-selective C(sp2 )–N bond formation
Zoom Image
Scheme 22 cine-Substitution of electron-rich heteroarylsulfonium salts
Zoom Image
Scheme 23 Site-selective C(sp2 )–O bond formation
Zoom Image
Scheme 24 Site-selective borylation of aromatics
Zoom Image
Scheme 25 Site-selective silylation of arenes
Zoom Image
Scheme 26 Site-selective C(sp2 )–Ge bond formation
Zoom Image
Scheme 27 Site-selective fluorination of aromatics
Zoom Image
Scheme 28 Site-selective C(sp2 )–S bond formation via a hydroxymethyl sulfone
Zoom Image
Scheme 29 Site-selective C(sp2 )–S bond formation via an EDA complex
Zoom Image
Scheme 30 Site-selective C(sp2 )–P bond formation
Zoom Image
Scheme 31 Tritiation and deuteration of aryl thianthrenium salts