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DOI: 10.1055/s-0039-1690714
Recent Advances in Difluoromethylthiolation
We thank the National Natural Science Foundation (21421002, 21672242), Key Research Program of Frontier Sciences, Chinese Academy of Sciences (QYZDJSSW-SLH049), and National Basic Research Program of China (2015CB931903), Hunan Graduate Science and Technology Innovation Projects (CX2018B585), the Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study (0223-0007-000004), the Undergraduate Research Learning and Innovative Experiment Project, University of South China (2019-100, 2018XJXZ188, 2018XJXZ350, 2018XJXZ194, 2018XJXZ351), the Guiding Project Of Hengyang Science and Technology Department (S2018F9031015299), Program for Innovative Talent Team of Hengyang (2017-1), the Key Project of Hengyang Science and Technology Department (2017KJ166) for financial support.
Publication History
Received: 10 July 2019
Accepted after revision: 26 September 2019
Publication Date:
21 October 2019 (online)
§ These authors contributed equally to this work.
Abstract
The difluoromethylthio group (HCF2S), which has been identified as a valuable functionality in drug and agrochemical discovery, has received increased attention recently. Two strategies, difluoromethylation and direct difluoromethylthiolation, have been well established for HCF2S incorporation. The former strategy suffers from the need to prepare sulfur-containing substrates. In contrast, direct difluoromethylthiolation is straightforward and step-economic. This short review covers the recent advances in direct difluoromethylthiolation, including electrophilic, radical, and transition-metal-catalyzed or -promoted reactions.
1 Introduction
2 Electrophilic Difluoromethylthiolation
3 Radical Difluoromethylthiolation
4 Transition-Metal-Catalyzed or -Promoted Difluoromethylthiolation
5 Conclusions and Perspectives
# 1
Introduction
Fluorine, which has been called ‘a magic atom’,[1] ‘fabulous fluorine’,[2] and ‘a small atom with a big ego’,[3] exhibits unique properties such as high electronegativity, low polarizability, and small atomic radius. The incorporation of fluorinated groups into organic molecules would lead to profound changes in the latter’s physicochemical properties.[4] Therefore, fluorine-containing compounds have found widespread application in various research areas, including pharmaceutical chemistry, agrochemistry, and material sciences.[4] [5] Since the first approval of the steroid fludrocortisone in 1955 by the FDA (US Food and Drug Administration), a large number of fluorinated drugs have been developed. It was estimated in 2006 that approximately 20% of pharmaceuticals (over 150 drugs) and 30% of agrochemicals contain a fluorinated substituent.[2] The percentages have been increasing since then.[5c]
Many fluorinated substituents have been identified as valuable functionalities in drug and agrochemical discovery, and the difluoromethylthio group (HCF2S) has received increasing attention recently[6] due to its intermediate lipophilicity (Hansch lipophilicity parameter π = 0.68),[7] electron-withdrawing nature (Hammett constants σp = 0.37, σm = 0.33),[8] and hydrogen bonding ability,[9] and also because of the possibility for further transformation of the HCF2S group. Some HCF2S-containing pharmaceuticals and agrochemicals have appeared (Scheme [1]), such as flomoxef sodium,[10] pyriprole,[11] triafamone,[12] pyrimisulfan,[13] and SSH-108.[14] Consequently, significant efforts have been devoted to the development of efficient approaches for the incorporation of the HCF2S into organic molecules.
Two strategies have been well-established for the installation of the HCF2S group, difluoromethylation of sulfur-containing compounds and direct difluoromethylthiolation.[6] The difluoromethylation strategy suffers from a limited substrate scope and the need to prepare the sulfur-containing substrates. In contrast, direct difluoromethylthiolation is straightforward and step-economic, and thus has become an active research area in organofluorine chemistry. A variety of difluoromethylthiolation reagents (Scheme [2]) and difluoromethylthiolation approaches have been developed over the past few years. The only example of a nucleophilic reagent is the Ag-SCF2H type reagent R1 developed by the Shen group,[15] and the other reagents exhibit good electrophilicity. The installation of the HCF2S group was reviewed by Besset and co-workers in 2016,[6] but studies prior to 2016 were focused on difluoromethylation strategies and most difluoromethylthiolation approaches were developed subsequent to the publication of this review. In this review, we will discuss the recent advances in direct difluoromethylthiolation. The reactions are classified into three categories, electrophilic, radical, and transition-metal-catalyzed or -promoted reactions.
# 2
Electrophilic Difluoromethylthiolation
After the development of N-SCF3-type trifluoromethylthiolation reagents (NBS analogues),[16] in 2017 Shen, Lu, and co-workers developed a new N-SCF2H-type reagent R2.[17] This reagent is shelf-stable and easy-to-handle, but its preparation requires a four-step procedure and the use of Cl2 gas. It was found to be quite electrophilic, and was able to directly difluoromethylthiolate amines and thiols to give the corresponding products 1 and 2 (Scheme [3]). The presence of a base allowed for the difluoromethylthiolation of β-keto esters to give 3. The Lewis acid, TMSCl, could activate reagent R2 and heteroarenes would then undergo direct difluoromethylthiolation to give 4. The difluoromethylthiolation of boronic acids and terminal alkynes catalyzed by a copper source also proceeded smoothly giving 5 and 6, respectively.
On the basis of the reliable practicability of the N-SCF2H-type reagent R2, in 2017 Shen, Lu, and co-workers further designed a fluoroalkylthiolation reagent, R8.[18] It could be prepared either via sulfuration of phthalimide or via a substitution by potassium phthalimide. This reagent is also quite electrophilic and the difluoroalkylthiolation of heteroarenes and thiols was observed in the presence of a Lewis acid to give [(ethoxycarbonyl)difluoromethyl]thio derivatives 7 and 8, respectively (Scheme [4]). For active ketones, the α-positions were highly reactive towards this transformation using potassium carbonate as a base to give products such as 9. The CO2Et is a versatile functionality and could be transformed into other groups. Although a wide substrate scope was observed, the use of Cl2 gas is also necessary for the preparation of reagent R8, which is a disadvantage of this difluoromethylthiolation protocol.
In 2018, Xie, Zhu, and co-workers used the N-SCF2H-type reagent R2 to achieve an umpolung difluoromethylthiolation of tertiary ethers (Scheme [5]).[19] As shown in the proposed mechanism, two catalytic cycles are involved. Interestingly, even if a weaker benzylic C–H bond (BDE ≈ 90 kcal mol–1) is present in the substrates, the selective abstraction of a hydrogen from the stronger C–H bond in the ether group (BDE ≈ 93 kcal mol–1) by the RS• radical was observed to generate intermediate Int1. This phenomenon was ascribed to a polarity-matching effect, i.e., an electrophilic radical should undergo selective hydrogen abstraction at the most hydridic C–H bond, owing to a lower kinetic barrier.[20] The homolytic cleavage of the C–O bond in Int1 produces radical Int2, which is then converted into the desired product via an abstraction of the HCF2S moiety from Phth-SCF2H or [Phth-SCF2H]•–.
The successful development of efficient electrophilic ArN-SCF3-type trifluoromethylthiolation reagents R13 [21] prompted Billard and co-workers in 2016 to further develop PhNH-SCF2(SO2Ph) electrophilic difluoromethylthiolation reagent R4,[22] in which the SO2Ph group is an auxiliary. For the preparation of this reagent, a good yield (60%) was obtained on a gram scale (10 g), but the use of a hazardous reagent, DAST (diethylaminosulfur trifluoride), is required. An acid such as TsOH or BF3·Et2O could increase the electrophilicity of reagent R4 and therefore alkynes, alkenes, or arenes were well converted into the desired products such as 13 and 14 (Scheme [6]). Many functional groups could be tolerated, such as hydroxyl or amino groups and carboxylic acids, and a wide substrate scope was observed. Reduction conditions led to the removal of the auxiliary SO2Ph to give difluoromethylthiolated product 15.
Also in 2016, Besset and co-workers developed a similar reagent R5 and disclosed an effective method for the incorporation of the SCF2PO(OEt)2 group into molecules (Scheme [7]).[23] R5 could be prepared without the use of a hazardous reagent. The activation of R5 by a Lewis acid was necessary to facilitate the difluoromethylthiolation of various nucleophiles, including ketones (16), electron-rich arenes and heteroarenes (17), aniline derivatives (18), and thiols (19). Hydrolysis of the SCF2PO(OEt)2-containing product by NaOH gave a difluoromethylthiolated product. The strong basic conditions for hydrolysis indicate that this protocol may not be quite suitable for the synthesis of functionalized HCF2S-molecules.
The Shibata group found, in 2017, that the HCF2SO2Na/Ph2PCl (R7) system could act as an efficient electrophilic difluoromethylthiolation reagent (Scheme [8]).[24] They propose that HCF2SO2Na first reacts with Ph2PCl to generate intermediate Int3, which is in fast equilibrium with Int4. Intermediate Int4 is reduced by a second Ph2PCl to generate reactive species Int5. The electrophilicity of Int5 is not high enough and therefore the activation by a Lewis acid is required. Final difluoromethylthiolation gives the desired products 20 or 21. Interestingly, the reagent system could be used for the late-stage direct difluoromethylthiolation of a number of natural products and pharmaceutically attractive molecules, demonstrating the synthetic utility of this approach.
Zhang, Yi, and co-workers described, in 2017, the difluoromethylthiolation of heteroarenes and electron-rich arenes with the HCF2SO2Na/(EtO)2P(O)H (R9) system (Scheme [9]).[25] Like Ph2PCl,[24] (EtO)2P(O)H could also convert HCF2SO2Na into active HCF2S species for electrophilic difluoromethylthiolation. Due to the high affinity of phosphorus towards oxygen, (EtO)2P(O)H would abstract oxygen from HCF2SO2Na to release HCF2S(O)H (Int6), which is in equilibrium with HCF2SOH (Int7). Although HCF2SSCF2H could also be generated, they found that this species cannot difluoromethylthiolate electron-rich arenes such as indoles. Therefore, they propose that it is HCF2SOH that generates HCF2S+ species via the activation of S–OH bond by TMSCl, allowing for the final difluoromethylthiolation to give products 20. Compared with Shibata’s method using Ph2PCl, which is moisture sensitive,[24] this approach may be relatively more operationally convenient since (EtO)2P(O)H is not so sensitive to moisture.
Besides HCF2SO2Na, HCF2SO2Cl can also be considered as a HCF2S+ source. Yi and co-workers found that difluoromethylthiolation of indoles or pyrroles with HCF2SO2Cl (R10) proceeded smoothly by using (EtO)2P(O)H as a reducing agent (Scheme [10]).[26] They proposed that HCF2SO2Cl is reduced to HCF2S-Cl, which is the active difluoromethylthiolation species. Compared with the HCF2SO2Na/Ph2PCl (R7) or HCF2SO2Na/(EtO)2P(O)H (R9) systems, the HCF2SO2Cl/(EtO)2P(O)H system could effectively difluoromethylthiolate the substrates without the need for a Lewis acid. However, the high volatility of HCF2SO2Cl (bp 95–99 °C) and the necessity of the toxic Cl2 gas for its preparation[27] are disadvantages of this difluoromethylthiolation approach.
Triphenylphosphine could also activate HCF2SO2Cl (R10) for difluoromethylthiolation. In 2017, Lu and co-workers reported the difluoromethylthiolation of thiols[28] and electron-rich aromatics[29] with the HCF2SO2Cl (R10)/Ph3P system in the presence of an iodide anion. The iodide anion would react with HCF2SO2Cl/Ph3P to produce molecular iodine, which could be trapped by Ph3P to generate iodophophonium salt Int8 (Scheme [11]). Int8 is an electrophilic species and would be attacked by the oxygen lone pair electrons in HCF2SO2Cl to afford Int9. The strong P=O bond drives the cleavage of S–O bond to give Int10. A second similar sequence affords difluoromethanesulfenyl chloride (HCF2SCl).
The HCF2SO2Cl (R10)/Ph3P system can be used to achieve not only difluoromethylthiolation,[28] [29] but also chloro-difluoromethylthiolation.[30] Zhang, Yi, and co-workers disclosed the chloro-difluoromethylthiolation of alkenes and alkynes with this reagent system (Scheme [12]).[30] Interestingly, iodide anion was not necessary in this conversion, and the regioselectivity depends on whether the unsaturated bond is conjugated with an aromatic ring or not. They propose that HCF2SCl could be directly produced from HCF2SO2Cl via reduction by Ph3P. HCF2SO3H, which is formed from HCF2SO2Cl by hydrolysis, serves as a catalyst for electrophilic addition. The conjugation of the double bond with a phenyl ring would favor the formation of Markovnikov products 22 via the generation of intermediate Int12. In the case of non-styrene-type alkenes, the steric hindrance of the R group is the dominant factor to control the regioselectivity, and therefore anti-Markovnikov adducts 23 would be formed.
HCF2SO2Cl (R10) has to be activated by a reducing reagent, such as (EtO)2P(O)H or Ph3P, for difluoromethylthiolation. In contrast, HCF2SOCl (R11) could directly difluoromethylthiolate electron-rich substrates without the need for a reductant. Zhang, Yi, and co-workers found that difluoromethylthiolation of indoles or ketones with HCF2SOCl occurred smoothly under heating conditions (Scheme [13]).[31] They proposed that HCF2SOCl could react with indole to generate Int14, which is reduced by HCF2SOCl to afford the final product. HCF2SOCl may also undergo disproportionation to form HCF2SO2Cl and HCF2SCl, and the subsequent difluoromethylthiolation delivers the expected product.
Our group has previously shown that the phosphobetaine salt (Ph3P+CF2CO2 –) R12 could rapidly react with elemental sulfur (S8) to generate thiocarbonyl fluoride (CF2=S), a process which was used to achieve trifluoromethylthiolation and 18F-trifluoromethylthiolation.[32] CF2=S is an electrophilic species and would be readily trapped by nucleophiles. The use of vicinal hydroxyl (or amino) arylamines as nucleophiles could efficiently give difluoromethylthiolated heterocycles 20 (Scheme [14]).[33] We propose that substrates undergo cyclization with CF2=S to deliver thiourea Int17 via the formation of phenylcarbamothioic fluoride Int15 or isothiocyanate Int16; Int17 is in equilibrium with thiol Int18. The insertion of difluorocarbene generated from phosphobetaine salt (Ph3P+CF2CO2 –)[34] into Int18 affords the final products.
# 3
Radical Difluoromethylthiolation
PhSO2SCF2H (R3), developed by Shen, Lu, and co-workers in 2016, is a mild electrophilic difluoromethylthiolation reagent which could be prepared by a two-step procedure.[35] It was found that the AgNO3/K2S2O8 system can promote the reaction of boronic acids and alkanoic acids with PhSO2SCF2H to give difluoromethylthiolation products 24 and 25, respectively (Scheme [15]).[35] In the case of alkenes, phenylsulfonyl-difluoromethylthio difunctionalization was observed to give 26. The mechanistic investigations revealed that a radical mechanism may be operative. PhSO2SCF2H is a very efficient difluoromethylthiolation reagent, and has been used by other groups for radical reactions.
In 2018, Shen and co-workers further used the AgNO3/ K2S2O8-promoted strategy to achieve ring-opening difluoromethylthiolation of cycloalkanols 27 with PhSO2SCF2H (R3) to deliver HCF2S-containing ketones 28 (Scheme [16]).[36] Various cycloalkanols, including cyclopropanols, cyclobutanols, cyclopentanols, cyclohexanols, and cycloheptanols, were all suitable for this conversion. Initial mechanistic studies indicate that a cycloalkoxy radical intermediate Int19 is generated. The ring-opening of the alkoxy radical forms an alkyl radical Int20, which abstracts the HCF2S group from PhSO2SCF2H to afford the final products 28. This is a very effective method for the synthesis of HCF2S-substituted ketones.
Most difluoromethylthiolation methods focus on the synthesis of difluoromethyl thioethers. Difluoromethyl thioesters should also receive attention because they would predictably lead to new bioactive molecules, as indirectly demonstrated by the anti-inflammatory monofluoromethyl thioester drug fluticasone and its derivative fluticasone propionate.[37] Shen, Wang, and co-workers found that the NaN3/PhI(OAc)2 system was also a suitable radical initiator to enable the difluoromethylthiolation of aldehydes with PhSO2SCF2H (R3) at room temperature to give S-difluoromethyl thioesters (Scheme [17]).[38] Experimental evidence supports a radical pathway. The oxidation of NaN3 by PhI(OAc)2 generates an azide radical. The abstraction of H atom from an aldehyde by this azide radical forms a carbonyl radical, which reacts with PhSO2SCF2H to provide the desired S-difluoromethyl thioester 29.
The Wang group also reported a radical difluoromethylthiolation of aldehydes with PhSO2SCF2H (R3) (Scheme [18]).[39] Various aryl, heteroaryl, alkyl, and alkenyl aldehydes could all be converted into the expected products, demonstrating a wide substrate scope. They proposed that t-BuOOH could directly abstract a hydrogen atom from aldehydes to generate a carbonyl radical. In the NaN3/PhI(OAc)2-promoted method,[38] room temperature was the reaction temperature but hazardous NaN3 has to be used. In this method,[39] the operations are relatively more convenient, but a higher reaction temperature is necessary.
Although hydro-fluoroalkyl(thiol)ation of multiple bonds has proved to be effective methods for the incorporation of fluoroalkyl or fluoroalkylthio groups into organic molecules,[40] hydro-difluoromethylthiolation has not been reported until recently. In 2019, Shen, Lu, and co-workers described a Co-catalyzed radical hydro-difluoromethylthiolation of unactivated alkenes with PhSO2SCF2H (R3) at room temperature (Scheme [19]).[41] They proposed that hydro-metalation followed by a homolytic cleavage of the Co–C bond generates an alkyl radical Int23, which is trapped by PhSO2SCF2H to afford the final product.
Visible-light-promoted reactions, a valuable synthetic tool for functionalization, usually proceed via the generation of radical intermediates.[42] Recently, the Li group developed a visible-light-promoted radical difluoromethylthiolation of arenes with PhSO2SCF2H (R3) (Scheme [20]).[43] Under CFL (compact fluorescent lamp) irradiation, a difluoromethylthio radical (HCF2S•) is generated from PhSO2SCF2H either by the homolysis of the S–SCF2H bond or by the photoinduced electron transfer reaction between PhSO2SCF2H and iodide. The capture of the HCF2S• radical by an arene produces radical intermediate Int24, and the subsequent hydrogen atom abstraction by the PhSO2 • radical furnishes the target compound. Interestingly, irrespective of whether Bu4NI was used or not, high yields could be obtained. Only electron-rich (hetero)arenes are suitable for this conversion.
Visible-light catalysis could also enable the radical difluoromethylthiolation of arenediazonium salts with PhSO2SCF2H (R3) (Scheme [21]).[44] In contrast to Li’s case,[43] the visible light catalytic conditions generated an Ar• radical rather than the HCF2S• radical. Both an oxidative quenching pathway and a reductive quenching pathway are proposed. The [Ru2+]* complex, generated from [Ru2+] by photoexcitation, reduces [ArN2 + BF4 –] to generate an Ar• radical (oxidative quenching), which is trapped by PhSO2SCF2H to furnish the final products 20. The [Ru2+]* complex could also be reduced by sodium ascorbate to [Ru+] (reductive quenching), by which [ArN2 + BF4 –] is reduced to produce the Ar• radical. A wide substrate scope was observed, but the prefunctionalization of substrates is required.
Xu and co-workers described an atom-transfer radical addition of alkynes to give difunctionalized alkenes by the combination of visible-light photoredox catalysis and gold catalysis (Scheme [22]).[45] The E/Z stereoselectivity is a challenging issue for atom-transfer radical addition to alkynes due to the low activation barriers for E/Z isomerization of the vinyl radicals generated in situ. In this work, high E/Z selectivity was observed due to the stabilization of the vinyl radical by the Au catalyst. They proposed that the Au catalyst interacts with the vinyl radical to form intermediate Int25 or Int26. Radical Int25 can then react with PhSO2SCF2H to form the trans-difunctionalization product and regenerate a sulfonyl radical and the Au(I) catalyst. Intermediate Int26 might react with PhSO2SCF2H through single electron oxidation to generate the sulfonyl radical and a Au(III) intermediate Int27, the reductive elimination of which delivers the final product.
Organoboron compounds have served as valuable nucleophiles for a variety of reactions such as Suzuki coupling.[46] Recent studies (2010–2014) indicated that organoboron compounds can also act as radical precursors, but usually a photoredox catalyst or strong oxidant is required.[47] In 2018, the Li group reported a distinct strategy for generating both aryl and alkyl radicals from organotrifluoroborates through an SH2 (bimolecular homolytic substitution) process, and by using visible light as the energy input and diacetyl as the promoter in the absence of any metal catalyst or redox reagent.[48] This approach utilizes the triplet diacetyl to activate organotrifluoroborate and proceeds under mild reaction conditions. The use of PhSO2SCF2H (R3) as the radical trapping reagent led to the difluoromethylthiolation product (Scheme [23]).
In 2016, the Glorius group developed a visible-light-promoted decarboxylative difluoromethylthiolation of alkanoic acids with reagent R2 (Scheme [24]).[49] Two catalytic cycles may be involved in this transformation. Photoexcitation of the IrIII photocatalyst produces a strong oxidant, IrIII*, which could oxidize the carboxylic acid to generate the R• radical (photocatalytic cycle). The abstraction of the HCF2S group from R2 by the radical affords the final product and the and the phthalimidyl radical (Phth•). A redox reaction between IrII and Phth• regenerates the catalyst IrIII complex. Alternatively, the Phth• radical may also oxidize the carboxylic acid to form the R• radical (hole-catalyst chain). The cheap and abundant nature of alkanoic acids is an advantage of this protocol.
# 4
Transition-Metal-Catalyzed or -Promoted Difluoromethylthiolation
The nucleophilic difluoromethylthiolation reagent (SIPr)Ag(SCF2H) (R1) was developed by Shen and co-workers in 2015.[15] It was prepared from a nucleophilic difluoromethylation reagent R14, which was also developed by Shen and co-workers.[50] Cu-mediated Sandmeyer-type difluoromethylthiolation of arene- and heteroarenediazonium salts with reagent R1 occurred under mild reaction conditions and a variety of functional groups were compatible (Scheme [25]).[15] A practical one-pot protocol for the synthesis of HCF2S-substituted arenes from arylamines via direct diazotization followed by difluoromethylthiolation was developed. A series of biologically active HCF2S-containing molecules was prepared via this Sandmeyer reaction, further demonstrating the synthetic utility of the protocol. Despite its relatively high cost, reagent R1 shows wide applicability for various coupling reactions.
Although a reductive-elimination step may be problematic for the Pd-catalyzed difluoromethylthiolation of heteroaryl halides due to the electron-withdrawing nature of the HCF2S group, Shen and co-workers found that Pd-catalyzed reactions by using (SIPr)Ag(SCF2H) (R1) as the difluoromethylthiolation reagent proceeded smoothly (Scheme [26]).[51] A variety of heteroaryl iodides, bromides and triflates could all be converted into HCF2S-substituted heteroarenes. Likewise, aryl iodides were transformed into the desired products in high yields. Medicinally important compounds were prepared by this Pd-catalyzed difluoromethylthiolation reaction, demonstrating the applicability of this protocol.
Apparently, the C–Cl bond is much stronger than C–I and C–Br bonds, and therefore it would be more difficult to achieve the Pd-catalyzed coupling reaction of aryl chlorides with (SIPr)Ag(SCF2H) (R1). However, Shen and co-workers disclosed that the use of an electron-rich and sterically bulky alkylphosphine as a ligand could enable the coupling reaction (Scheme [27]).[52] Besides aryl chlorides, both aryl bromides and aryl triflates could also be converted smoothly. The functionalization of biologically active molecules and material molecules were achieved by this Pd-catalyzed coupling reaction.
In 2013, the Shibata group developed an effective trifluoromethanesulfonyl hypervalent iodonium ylide reagent R15 for trifluoromethylthiolation.[53] On the basis of this work, they further developed (2016) difluoromethanesulfonyl hypervalent iodonium ylide reagents R6.[54] These reagents were very effective for the Cu-catalyzed difluoromethylthiolation of a variety of nucleophiles, such as enamines, indoles, β-keto esters, silyl enol ethers, and pyrroles (Scheme [28]). The difluoromethylthiolation of enamines is particularly effective with wide generality, and a series of HCF2S-containing cyclic and acyclic β-keto esters, and 1,3-diketones could be synthesized by this approach. They propose that the copper source is a catalyst for the generation of the carbene intermediate Int28. The subsequent formation of oxathiirene 2-oxide Int29, rearrangement to sulfoxide Int30, and the further collapse produces thioperoxoate Int31. Intermediate Int31 is likely to be the real species for the difluoromethylthiolation of nucleophiles.
In 2018, the Shibata group further used reagents Phth-SF2H (R2) and R6 to synthesize racemic α-SCF2H-β-keto-substituted allyl esters 21 (Scheme [29]).[55] Interestingly, a Pd-catalyzed Tsuji decarboxylative asymmetric allylation of racemic β-keto allyl esters 21 gave chiral α-allyl-α-SCF2H ketones 34 with high enantiopurity. The electron-withdrawing properties of the HCF2S group presumably accelerate the decarboxylation process by stabilizing the resulting anion. This is the first report of the construction of a HCF2S-containing tetrasubstituted stereogenic center.
Intensive research efforts have been devoted to the development of difluoromethylthiolation methods, but asymmetric difluoromethylthiolation remains challenging. Although the above work provides a method for constructing HCF2S-containing stereogenic centers,[55] a tedious two-step procedure is required. In 2019, the Shibata group further used their reagent R6b to achieve the asymmetric difluoromethylthiolation of indanone-based β-keto esters to deliver chiral HCF2S-containing β-keto esters 35 (Scheme [30]).[56] In this reaction, high enantioselectivity was obtained, but stoichiometric chiral amines have to be used as chiral auxiliaries.
# 5
Conclusions and Perspectives
As emphasized in this review, the incorporation of the HCF2S group into organic compounds can drastically change their biological and physicochemical properties. The emergence of HCF2S-containing pharmaceuticals and agrochemicals have prompted research into the development of efficient approaches for direct difluoromethylthiolation, including electrophilic, radical, and transition-metal-catalyzed or -promoted reactions. Although significant accomplishments have been made in the past two years, further developments are still necessary. The C–H difluoromethylthiolation and asymmetric catalyzed difluoromethylthiolation have rarely been reported. It is our hope that this review will encourage organic chemists to develop new and exciting methods for direct difluoromethylthiolation.
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