Rhodium-Catalyzed Synthesis of Organosulfur Compounds Involving S-S Bond Cleavage of Disulﬁdes and Sulfur

molecules

Review Rhodium-Catalyzed Synthesis of Organosulfur Compounds Involving S-S Bond Cleavage of Disulﬁdes and Sulfur

Mieko Arisawa * and Masahiko Yamaguchi

Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai 980-8578, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-22-795-6814

Academic Editor: Bartolo Gabriele Received: 17 July 2020; Accepted: 5 August 2020; Published: 7 August 2020

Abstract: Organosulfur compounds are widely used for the manufacture of drugs and materials, and their synthesis in general conventionally employs nucleophilic substitution reactions of thiolate anions formed from thiols and bases. To synthesize advanced functional organosulfur compounds, development of novel synthetic methods is an important task. We have been studying the synthesis of organosulfur compounds by transition-metal catalysis using disulﬁdes and sulfur, which are easier to handle and less odiferous than thiols. In this article, we describe our development that rhodium complexes eﬃciently catalyze the cleavage of S-S bonds and transfer organothio groups to organic compounds, which provide diverse organosulfur compounds. The synthesis does not require use of bases or organometallic reagents; furthermore, it is reversible, involving chemical equilibria and interconversion reactions.

Keywords: rhodium; catalysis; synthesis; organosulfur compounds; S-S bond cleavage; chemical equilibrium; reversible reaction

1. Introduction

1.1. Structure and Reactivity of Organic Disulfides Organosulfur compounds containing C-S bonds are widely used for the manufacture of drugs and materials. Compared with organic compounds containing oxygen, which is another group 16(6A) element, different properties appear owing to the large size and polarizability of sulfur atoms. A characteristic feature of inorganic and organic sulfur compounds is the involvement of different oxidation states (between 2 and +6) of sulfur atoms, which give rise to diverse sulfur functional − groups [1]. Thiols (RSH) and sulfonic acids (RSO3H) are organosulfur compounds with low and high oxidation states, respectively. Sulfenic acids (RSOH) and sulfinic acids (RSO2H) exhibit intermediate oxidation states. These sulfur acids can form ester and amide derivatives. Elemental sulfur in the oxidation state of 0 is a convenient source of organosulfur compounds. Among organic functional groups containing sulfur, disulfides (RS-SR) with S-S bonds are of interest. In contrast to peroxides (RO-OR) with O-O bonds, disulfides are stable and exhibit significantly 1 different reactivities. The bond energy of S-S bonds is 226 kJ mol− (for S8)[2–5], which is the highest 1 1 among the X-X bonds of the group 16 elements: O-O, 142 kJ mol− ; Se-Se, 172 kJ mol− ; and Te-Te, 1 150 kJ mol− . Disulfides have a molecular structure with a dihedral angle of C-S-S-C of approximately 90◦ in the most stable conformation. Proteins and peptides contain disulfides that form their three-dimensional structures [6–9] Disulfides in proteins are found predominantly in secreted extracellular proteins, and thiols are

Molecules 2020, 25, 3595; doi:10.3390/molecules25163595 www.mdpi.com/journal/molecules Molecules 2020, 25, 3595 2 of 35 Molecules 2020, 25, x FOR PEER REVIEW 2 of 35 preserved in the cytosol in a reductive environment. It is is known known that that the the functions functions of of proteins proteins can be switchedswitched via via the cleavage or formation of disulfides disulfides is known [10,11]. [10,11]. Disulfides Disulfides are are found in some smallsmall molecules that are biologically active natural products [[12].12]. Sulfides,Sulfides, disulfides, disulfides, and and polysulfides polysulfides are are important important functional functional groups groups in in synthetic synthetic rubber rubber [13]. [13]. Natural rubberrubber isis treated treated with with sulfur sulfur to convertto convert it into it materialsinto materials witha with large a range large of range hardness, of hardness, elasticity, elasticity,and mechanical and mechanical durability, indurability, which sulfur in which atoms sulfur form cross-linking atoms form bridgescross-linking between bridges polymer between chains polymerin a process chains called in a vulcanization. process called vulcanization. An important important reversible reaction of disulfides disulfides is their reduction to thiols, which may may be be oxidized oxidized toto disulfides disulfides (Figure (Figure 11).). SuchSuch reactivityreactivity hashas beenbeen utilizedutilized inin biologicalbiological systemssystems andand alsoalso inin syntheticsynthetic systemssystems for for molecular molecular switching switching [14]. [14]. Various Various reacti reactionsons have have been been reported reported for for the the interconversion. interconversion. The exchange reaction of S-S bonds between disulf disulfidesides is another important reversible reaction (Scheme 1) 1) [15,16]. [15,16]. The The reaction reaction of oftwo two different different disulfides disulfides produces produces a statistical a statistical 1:1:2 1:1:2 mixture mixture of two of symmetrictwo symmetric disulfides disulfides and andan anunsymmetric unsymmetric disulfide disulfide under under chemical chemical equilibrium equilibrium when when their thermodynamicthermodynamic stabilities are comparable.

Figure 1.1.Interconversion Interconversion reactions reactions of disulﬁdes of disulfides/thiols/thiols by reduction by reduction/oxidation/oxidation and chemical and equilibrium chemical equilibriumunder disulﬁde under exchange. disulfide exchange.

Both reduction/oxidation and exchange reactions of disulfides can be used for a molecular switching Both reduction/oxidation and exchange reactions of disulfides can be used for a molecular function. A characteristic aspect of disulfide exchange reactions compared with reduction/oxidation switching function. A characteristic aspect of disulfide exchange reactions compared with reactions is that direct one-step interconversion proceeds without forming thiols. This makes procedures reduction/oxidation reactions is that direct one-step interconversion proceeds without forming thiols. simple, and various transformations that are incompatible in the presence of thiols can be conducted. This makes procedures simple, and various transformations that are incompatible in the presence of Basic conditions are often employed for disulfide exchange reactions, which involve the nucleophilic thiols can be conducted. Basic conditions are often employed for disulfide exchange reactions, which attack of thiolate anions on S-S bonds via an SN2 mechanism. Photoirradiation is effective for the involve the nucleophilic attack of thiolate anions on S-S bonds via an SN2 mechanism. exchange reaction of aromatic disulfides, which involves the homolytic cleavage of S-S bonds generating Photoirradiation is effective for the exchange reaction of aromatic disulfides, which involves the thiyl radicals. Acidic conditions can also be employed. The reactivity of disulfides depends on their homolytic cleavage of S-S bonds generating thiyl radicals. Acidic conditions can also be employed. substituents. Aromatic disulfides are easier to dissociate than aliphatic disulfides, which reflects the The reactivity of disulfides depends on their substituents. Aromatic disulfides are easier to dissociate relative dissociation energies of PhS-SPh (230 kJ mol 1) and MeS-SMe (309 kJ mol 1)[3]. than aliphatic disulfides, which reflects the relative −dissociation energies of PhS-SPh− (230 kJ mol−1) −1 and1.2. SynthesisMeS-SMe of (309 Organosulfur kJ mol ) [3]. Compounds Using Disulfides

1.2. SynthesisSynthesis of ofOrganosulfur organosulfur Compounds compounds Using has Disulfides generally been conducted using thiols, and a typical method is a substitution reaction with organohalogen compounds in the presence of a base [17–20]. Synthesis of organosulfur compounds has generally been conducted using thiols, and a typical The roles of bases are to form highly reactive thiolate anions and to neutralize hydrogen halides formed method is a substitution reaction with organohalogen compounds in the presence of a base [17–20]. as byproducts. The neutralization reaction is significantly exothermic and promotes the reaction The roles of bases are to form highly reactive thiolate anions and to neutralize hydrogen halides according to the Bell–Evans–Polanyi principle [17]. formed as byproducts. The neutralization reaction is significantly exothermic and promotes the The use of disulfides in the substitution reaction of organohalogen compounds has been rare. reaction according to the Bell–Evans–Polanyi principle [17]. This is because disulfides are neutral compounds and are less reactive than thiolate anions. Consider a The use of disulfides in the substitution reaction of organohalogen compounds has been rare. hypothetical substitution reaction of an organohalogen compound and a disulfide to provide a sulfide This is because disulfides are neutral compounds and are less reactive than thiolate anions. Consider containing a C-S bond. Formally, the reaction is accompanied by the formation of a sulfenyl halide, a hypothetical substitution reaction of an organohalogen compound and a disulfide to provide a which is thermodynamically unstable and makes the reaction thermodynamically unfavorable. The use sulfide containing a C-S bond. Formally, the reaction is accompanied by the formation of a sulfenyl of disulfides in organic synthesis, however, can have several advantages over the use of thiolate anions: halide, which is thermodynamically unstable and makes the reaction thermodynamically (1) disulfides are stable and easy to handle; (2) they are less odiferous; (3) they can be activated by unfavorable. The use of disulfides in organic synthesis, however, can have several advantages over various methods, including the use of acids, bases, radicals, metals, and photoirradiation; and (4) they the use of thiolate anions: (1) disulfides are stable and easy to handle; (2) they are less odiferous; (3) do not form metal halide byproducts. In addition, characteristic reactivities of disulfides can appear, they can be activated by various methods, including the use of acids, bases, radicals, metals, and photoirradiation; and (4) they do not form metal halide byproducts. In addition, characteristic reactivities of disulfides can appear, which thiols do not have. As such, special methods are needed

Molecules 2020, 25, 3595 3 of 35 Molecules 2020, 25, x FOR PEER REVIEW 3 of 35 whichto utilize thiols disulfides do not have.in the Assynthesis such, special of organosulfur methods are compounds. needed to An utilize example disulfides was inreported the synthesis in the oxidation–reductionof organosulfur compounds. condensation An exampleof bi(2-pyridyl) was reported disulfide in and the a oxidation–reduction carboxylic acid in the condensation presence of triphenylphosphineof bi(2-pyridyl) disulfide to provide and a carboxylica 2-pyridylthio acid in ester the presence[21]. The of reaction triphenylphosphine is thermodynamically to provide favorablea 2-pyridylthio because ester of the [21 ].exothermic The reaction oxidation is thermodynamically reaction of triphenylphosphine favorable because to the of thecorresponding exothermic oxide.oxidation Thus, reaction it is reasonable of triphenylphosphine to consider that to the disulfides corresponding can be oxide.used as Thus, substrates it is reasonable in organic to synthesis consider andthat that disulfides the reactions can be usedcan proceed as substrates in the in absence organic of synthesis bases. and that the reactions can proceed in the absence of bases. 1.3. Rhodium-Catalyzed Synthesis of Organosulfur Compounds Using Disulfides 1.3. Rhodium-Catalyzed Synthesis of Organosulfur Compounds Using Disulfides Transition-metal catalysis for the synthesis of organosulfur compounds has attracted interest; however,Transition-metal this interest has catalysis been limited. for the synthesisIn particular, of organosulfur the use of disulfides compounds has been has rare, attracted with the interest; only exceptionshowever, this of addition interest reactions has been to limited. alkenes In and particular, alkynes originally the use of reported disulfides by hasOgawa been [22], rare, Beletskaya with the [23],only and exceptions Mitsudo of [24]. addition The lack reactions of such tosynthetic alkenes methods and alkynes for organosulfur originally reportedcompounds by Ogawais due to [ 22the], strongBeletskaya bonding [23], andbetween Mitsudo transition [24]. The metals lack of and such su syntheticlfur atoms, methods which for does organosulfur not readily compounds allow the is liberationdue to the of strong the metals bonding and between products; transition as a result, metals the and catalyst sulfur cannot atoms, be which regenerated. does not readilyMethods allow are requiredthe liberation to overcome of the metals the relatively and products; unreactive as a result, natu there of catalyst neutral cannot disulfides be regenerated. and to prevent Methods catalyst are deactivationrequired to overcome by (1) the the development relatively unreactive of highly nature active of catalysts neutral disulfidesand (2) the and judicious to prevent choice catalyst of substratesdeactivation and by products (1) the development that produce of exothermic highly active reactions. catalysts and (2) the judicious choice of substrates and productsWe have thatfound produce that rhodium exothermic complexes reactions. catalyze various substitution and insertion reactions usingWe disulfides, have found which that rhodium indicates complexes that sulfur catalyze ligands various on substitutionrhodium atoms and insertion liberate reactions organosulfur using compoundsdisulfides, which with indicatesregeneration that sulfurof the ligandsrhodium on catalyst. rhodium In atoms this liberatearticle, a organosulfur substitutioncompounds reaction is withdefined regeneration as the transformation of the rhodium of a S-S catalyst. bond and In this an X-Y article, single a substitutionbond to form reaction a S-X bond; is defined an insertion as the reactiontransformation is defined of aas S-S the bond transformation and an X-Y of single a S-S bond bond to and form an aX=Y S-X multiple bond; an bond insertion to form reaction a S-X-S is subunitdefined with as the one transformation atom of X inserted of a S-S or bond a S-X-Y-S and an subunit X=Y multiple with two bond atoms to of form X-Y a inserted S-X-S subunit (Figure with 2). Weone describe atom of Xin inserted this article or a that S-X-Y-S rhodium-catalyzed subunit with two activation atoms of of X-Y S-S inserted bonds can (Figure be applied2). We describe to a broad in rangethis article of chemical that rhodium-catalyzed transformations activationwith different of S-S or bondsganic compounds can be applied containing to a broad S-S, range Se-Se, of Te-Te, chemical P- P,transformations and P-S heteroatom with diff erentbonds, organic along compounds with C-S, containingC-P, C-F, C-N, S-S, Se-Se, C-O, Te-Te,C-H, P-P,C-C, and and P-S H-H heteroatom bonds. Unsaturatedbonds, along C=O, with C-S,C≡C, C-P, and C-F, C=N C-N, bonds C-O, can C-H, also C-C, participate and H-H in bonds. the rhodium-catalyzed Unsaturated C=O, reactions C C, and of ≡ S-SC= Nbonds. bonds can also participate in the rhodium-catalyzed reactions of S-S bonds.

Figure 2. Diverse reactivity of substitution and insertion reactions of the S-S bond in disulfides with Figure 2. Diverse reactivity of substitution and insertion reactions of the S-S bond in disulfides with various other chemical bonds. various other chemical bonds. A characteristic feature of rhodium catalysis is its capability to activate C-H bonds [25], which is utilizedA characteristic here for C-S bondfeature formation of rhodium of 1-alkynes, catalysis is nitroalkanes, its capability malonates, to activateα C-H-phenylketones, bonds [25], which ketones, is utilizedaldehydes, here and for heteroaromaticC-S bond formation compounds. of 1-alkynes, Activation nitroalkanes, of C-C malonates, bonds in ketonesα-phenylketones, and H-H bondsketones, in aldehydes,hydrogen is and also heteroaromatic shown. compounds. Activation of C-C bonds in ketones and H-H bonds in hydrogenAnother is also notable shown. property of rhodium-catalyzed synthesis using disulfides is its applicability to reactionsAnother in water. notable Peptides property and of proteinsrhodium-catalyzed containing synthesis the cysteine using moiety disulfides can be is modifiedits applicability in water to reactions in water. Peptides and proteins containing the cysteine moiety can be modified in water without protecting groups (Schemes 2, 3, and 16). These results indicate a high tolerance of functional

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Molecules 2020, 25, x FOR PEER REVIEW 4 of 35 without protecting groups (Schemes 2, 3, and 16). These results indicate a high tolerance of functional groupsgroups in rhodium catalysis, whichwhich selectivelyselectively activatesactivates disulfides disulfides in in the the presence presence of of a largea large number number of ofoxygen- oxygen- and and nitrogen-containing nitrogen-containing functional functional groups. groups. 8 TheThe most most stable stable form form of of elemental elemental sulfur sulfur is is the the eight-membered S S8 ringring containing containing S-S S-S bonds, bonds, whichwhich is is produced by desulfurization of petroleum. Sulfur Sulfur exhibits exhibits chemical chemical reactivities reactivities similar similar to to thosethose of of disulfides, disulfides, but but different different chemical chemical reactiviti reactivitieses also also appear. appear. This This is is because because disulfides disulfides contain contain sulfursulfur atoms atoms bonded to one sulfursulfur atomatom andand oneone organic organic group; group; sulfur sulfur contains contains sulfur sulfur atoms atoms bonded bonded to totwo two sulfur sulfur atoms. atoms. Although Although organic organic synthesis synthesis using using sulfur sulfur has attracted has attracted attention attention [26], it has [26], generally it has generallybeen conducted been conducted by thermal by reactions thermal involving reactions sulfur involving radicals sulfur and byradicals nucleophilic and by reactions nucleophilic using reactionshighly reactive using mainhighly group reactive metal main reagents. group Inmetal this study,reagents. synthesis In this ofstudy, organosulfur synthesis compounds of organosulfur using compoundsdisulfides under using rhodium disulfides catalysis under rhodium is extended cataly to synthesessis is extended using to sulfur. syntheses using sulfur. AlongAlong withwith the the development development of rhodium-catalyzedof rhodium-catalyzed synthesis synthesis of organosulfur of organosulfur compounds compounds involving involvingS-S bond cleavage,S-S bondwe cleavage, have studied we have the synthesisstudied the of organophosphorussynthesis of organophosphorus compounds involving compounds P-P involvingbond cleavage. P-P bond This comparativecleavage. This study comparative of organoheteroatom study of compoundsorganoheteroatom with elements compounds adjacent with on elementsthe periodic adjacent table ison a the novel period approach.ic table is a novel approach.

1.4.1.4. Reversible Reversible Nature Nature of of Rhodium- Rhodium-CatalyzedCatalyzed Reactions Reactions of of Disulfides Disulfides Transition-metal-catalyzedTransition-metal-catalyzed reactions using disulfides disulfides to to provide provide organosulfur organosulfur compounds compounds often often reachreach chemical chemical equilibria equilibria and and are are reversible. reversible. This This behavior behavior implies implies that that the the relative relative thermodynamic thermodynamic stabilitiesstabilities ofof substrates substrates and and products products are similarare similar and the and energy the barrier energy is lowbarrier (Figure is 3lowa). Consequently,(Figure 3a). Consequently,shifting the chemical shifting equilibriumthe chemical toward equilibrium the desired toward product the desired is critical product to is obtaining critical to high obtaining yields. highIn this yields. study, In this we study, developed we developed several methods several meth for thatods for purpose: that purpose: (1) structures (1) structures of substrates of substrates and andproducts products are selectedare selected to provideto provide exothermic exothermic reactions; reactions; (2) (2) chemical chemical equilibrium equilibrium is is shifted shifted using using a alarger larger amount amount ofof one substrate; (3) (3) chemical chemical equilibrium equilibrium is isshifted, shifted, removing removing a volatile a volatile product; product; (4) appropriate(4) appropriate combinations combinations of cosubstrates of cosubstrates and and co coproductsproducts are are developed developed to to provide provide exothermic reactions;reactions; (5) (5) a product isis convertedconverted toto thermodynamicallythermodynamically stable stable form; form; and and (6) (6) the the desired desired product product is isremoved removed from from an an equilibrium equilibrium mixture mixture by silicaby silica nanoparticle nanoparticle precipitation. precipitation. In this In way,this way, the nature the nature of the ofsynthetic the synthetic reactions reactions for organosulfur for organosulfur compounds, compou presentednds, presented herein, isherein, significantly is significantly different fromdifferent that fromof conventional that of conventional irreversible reactionsirreversible using reacti thiolateons anions,using whichthiolate involve anions, strong which exothermic involve reactions strong exothermicusing bases reactions (Figure3b). using bases (Figure 3b).

FigureFigure 3. 3. (a(a) )Chemical Chemical equilibrium equilibrium of of rhodium-catalyzed rhodium-catalyzed re reactionsactions using using disulfides disulﬁdes and and a a cosubstrate; cosubstrate; ((bb)) highly highly exothermic exothermic irreversible irreversible reaction reaction using metal thiolates.

It is thought that chemical equilibrium is not favorable in organic synthesis because chemical It is thought that chemical equilibrium is not favorable in organic synthesis because chemical yields are governed by the relative thermodynamic stability of substrates and products. We show in this yields are governed by the relative thermodynamic stability of substrates and products. We show in article that the use of chemical equilibrium has intrinsic synthetic advantages: (1) chemical equilibrium this article that the use of chemical equilibrium has intrinsic synthetic advantages: (1) chemical is energy-saving because it does not require a strong exothermic reaction and it involves a small energy equilibrium is energy-saving because it does not require a strong exothermic reaction and it involves barrier; (2) chemical equilibrium can provide diﬀerent products by shifting the equilibrium through a small energy barrier; (2) chemical equilibrium can provide different products by shifting the the control of reaction conditions; (3) regeneration of substrates from products is easy; (4) catalysis equilibrium through the control of reaction conditions; (3) regeneration of substrates from products is eﬀective for both forward and backward reactions, which can be used to promote the reaction; is easy; (4) catalysis is effective for both forward and backward reactions, which can be used to promote the reaction; (5) chemical equilibria generally do not form inorganic byproducts, which is

Molecules 2020, 25, 3595 5 of 35

(5) chemical equilibria generally do not form inorganic byproducts, which is inevitable in exothermic reactions using bases. It should also be noted that the recovery of bases from inorganic byproducts is tedious and energy-consuming. A novel concept is derived from the reversible nature of the rhodium-catalyzed synthesis of organosulfur compounds under chemical equilibrium. Catalysts can cleave C-S bonds of products, which implies that, in the presence of suitable acceptors, products can be converted to other organosulfur compounds: rhodium complexes can activate S-X bonds in the products and convert then into compounds with S-Z bonds (Figure2). Such examples are described for the reactions of 1-thioalkynes and thioesters in Section7. Our working hypothesis on the mechanisms of rhodium-catalyzed reactions of disulfides is the involvement of oxidative addition of low-valent rhodium to form S-Rh-S species, which is followed by substitution or insertion by other organic groups. Chemical equilibrium indicates that all processes are reversible. Organosulfur compounds can be used as alkylating reagents analogous to organohalogen 1 compounds. This concept is inferred from the bond energy of C-S (272 kJ mol− ), which is comparable 1 to that of C-Br (285 kJ mol− )[1]. Organothio groups can be used as leaving groups in substitution reactions, and they can exhibit different properties from halogen groups. Sulfur leaving groups have divalent sulfur atoms, whereas halogen leaving groups have monovalent atoms, and the properties of the sulfur leaving groups can be tuned by the organic groups. In addition, substitution reactions using sulfur leaving groups are reversible under rhodium catalysis; such examples are described in Section7. It should be noted that the bond energy of C-S is comparable to that of C-P (264 kJ mol 1) and that − organosulfur and organophosphorus compounds are interconvertible (Schemes 14, 18, and 33). The above describes the reversibility of reactions under chemical equilibrium between X and Y in a closed system, in which no matter is exchanged with the surroundings but energy is exchanged (Figure4a). Such reactions are indicated in this article by two straight arrows pointing in opposite directions. A reversible reaction in an open system can also be considered, in which both matter and energy are exchanged. Substrate X and product Y are interconverted by the addition of reagents A and C, which provide the X + A Y + B and Y + C X + D reactions, respectively (Figure4b). → → Addition of A and C makes these reactions exothermic, and catalysis reduces the energy barrier, which accelerates these reactions. Such reactions are called interconversion reactions in this article and are expressed by curved arrows pointing in opposite directions. Many of the reactions described in this article are reversible and involve catalysis either under chemical equilibria or interconversion reactions. Reversibility in synthetic reactions provides a novel concept in chemistry that has some similarity with biological systems. The model of interconversion reactions in an open system between X and Y provides another interesting aspect in the development of synthetic reactions (Figure4b). When the model is analyzed in terms of input and output, the A + C B + D reaction can be considered. Such reactions can be → developed, as shown in this article (Schemes 5, 7, and 14). X and Y can be used as catalysts for the A + X B + Y and Y + C X + D reactions proceeding under the same conditions. → → One of our purposes in the study of transition-metal-catalyzed synthesis of organosulfur compounds is the development of biologically active compounds. Heteroatoms are essential for biological functions, as shown by the huge amounts of nitrogen and oxygen atoms used by living things. In contrast, the use of sulfur is limited mostly to amino acids, and the development of biologically active organosulfur compounds, which exhibit exotic properties for living things, is an interesting subject. The transition-metal-catalyzed synthetic method discussed herein has indeed provided biologically active organosulfur compounds [26,27]. Our previous review articles on the transition-metal-catalyzed synthesis of organosulfur compounds focused on the development of exothermic reactions [28,29], the synthesis and properties of bis(heteroaryl) compounds [26,27], the use of elemental sulfur [30], and the P-P bond cleavage reactions [31]. The present article describes an overview of our studies that began in the early 2000s and involve classification of the chemical reactions with S-S bond cleavage and organothio transfer. Molecules 2020, 25, x FOR PEER REVIEW 5 of 35

inevitable in exothermic reactions using bases. It should also be noted that the recovery of bases from inorganic byproducts is tedious and energy-consuming. A novel concept is derived from the reversible nature of the rhodium-catalyzed synthesis of organosulfur compounds under chemical equilibrium. Catalysts can cleave C-S bonds of products, which implies that, in the presence of suitable acceptors, products can be converted to other organosulfur compounds: rhodium complexes can activate S-X bonds in the products and convert then into compounds with S-Z bonds (Figure 2). Such examples are described for the reactions of 1- thioalkynes and thioesters in Section 7. Our working hypothesis on the mechanisms of rhodium- catalyzed reactions of disulfides is the involvement of oxidative addition of low-valent rhodium to form S-Rh-S species, which is followed by substitution or insertion by other organic groups. Chemical equilibrium indicates that all processes are reversible. Organosulfur compounds can be used as alkylating reagents analogous to organohalogen compounds. This concept is inferred from the bond energy of C-S (272 kJ mol−1), which is comparable to that of C-Br (285 kJ mol−1) [1]. Organothio groups can be used as leaving groups in substitution reactions, and they can exhibit different properties from halogen groups. Sulfur leaving groups have divalent sulfur atoms, whereas halogen leaving groups have monovalent atoms, and the properties of the sulfur leaving groups can be tuned by the organic groups. In addition, substitution reactions using sulfur leaving groups are reversible under rhodium catalysis; such examples are described in Section 7. It should be noted that the bond energy of C-S is comparable to that of C-P (264 kJ mol−1) and that organosulfur and organophosphorus compounds are interconvertible (Schemes 14, 18, and 33). The above describes the reversibility of reactions under chemical equilibrium between X and Y in a closed system, in which no matter is exchanged with the surroundings but energy is exchanged (Figure 4a). Such reactions are indicated in this article by two straight arrows pointing in opposite directions. A reversible reaction in an open system can also be considered, in which both matter and energy are exchanged. Substrate X and product Y are interconverted by the addition of reagents A and C, which provide the X + A → Y + B and Y + C → X + D reactions, respectively (Figure 4b). Addition of A and C makes these reactions exothermic, and catalysis reduces the energy barrier, Moleculeswhich2020 accelerates, 25, 3595 these reactions. Such reactions are called interconversion reactions in this article6 of 35 and are expressed by curved arrows pointing in opposite directions. Many of the reactions described in this article are reversible and involve catalysis either under chemical equilibria or interconversion In addition, emphasized herein are the chemical equilibria and interconversion reactions provided by reactions.Molecules 2020 Reversibility, 25, x FOR PEER in REVIEW synthetic reactions provides a novel concept in chemistry that has some6 of 35 thesimilarity reversible with nature biological of the systems. rhodium-catalyzed synthesis. The model of interconversion reactions in an open system between X and Y provides another interesting aspect in the development of synthetic reactions (Figure 4b). When the model is analyzed in terms of input and output, the A + C → B + D reaction can be considered. Such reactions can be developed, as shown in this article (Schemes 5, 7, and 14). X and Y can be used as catalysts for the A + X → B + Y and Y + C → X + D reactions proceeding under the same conditions. One of our purposes in the study of transition-metal-catalyzed synthesis of organosulfur compounds is the development of biologically active compounds. Heteroatoms are essential for biological functions, as shown by the huge amounts of nitrogen and oxygen atoms used by living things. In contrast, the use of sulfur is limited mostly to amino acids, and the development of biologically active organosulfur compounds, which exhibit exotic properties for living things, is an interesting subject. The transition-metal-catalyzed synthetic method discussed herein has indeed provided biologically active organosulfur compounds [26,27]. Our previous review articles on the transition-metal-catalyzed synthesis of organosulfur compounds focused on the development of exothermic reactions [28,29], the synthesis and properties of bis(heteroaryl) compounds [26,27], the use of elemental sulfur [30], and the P-P bond cleavage reactionsFigure 4.[31].(a) ChemicalThe present equilibrium article describes in a closed an systemoverview between of ourX studiesand Y.( thatb) Interconversion began in the early reaction 2000s Figure 4. (a) Chemical equilibrium in a closed system between X and Y. (b) Interconversion reaction andin involve an open classification system between of Xtheand chemicalY, in which reactions the relative with S-S thermodynamic bond cleavage stability and organothio of substrates transfer. and in an open system between X and Y, in which the relative thermodynamic stability of substrates and In productsaddition, is emphasized inverted and herein induces areX +theA chemicalY + B and equilibriaY + C andX + interconversionD reactions. reactions provided products is inverted and induces X + A →→ Y + B and Y + C →→ X + D reactions. by the reversible nature of the rhodium-catalyzed synthesis. 2. Rhodium-Catalyzed Exchange Reactions of Disulﬁdes

2. DisulfidesRhodium-Catalyzed can exchange Exchange organothio Reactions groups of Disulfides under acidic or basic conditions and when exposed to heatDisulfides or photoirradiation. can exchange We organothio found that groups disulfide under exchange acidic or basic reactions conditions proceed and ewhenfficiently exposed in the presenceto heat of or a photoirradiation. rhodium complex We [32 found]. A mixture that disulfide of RhH(PPh exchange3)4, sulfonic reactions acid, proceed and phosphine efficiently promotes in the catalysispresence of of the a rhodium disulfide complex exchange [32]. reaction, A mixture which of RhH(PPh proceeds3)4 rapidly, sulfonic under acid, and acetone phosphine reflux promotes (Scheme1 ). Dibutylcatalysis disulfide of the disulfide and bis(2-benzoyloxyethyl) exchange reaction, whic disulfideh proceeds were rapidly reacted under in acetone refluxing reflux acetone (Scheme in 1). the presenceDibutyl of disulfide RhH(PPh and3)4 (3bis(2-benzoyloxyethyl) mol%), trifluoromethanesulfonic disulfide were acid reacted (6 mol%), in refluxing and (p-tol) acetone3P (12 in mol%), the andpresence 2-benzoyloxyethyl of RhH(PPh3 butyl)4 (3 mol%), disulfide trifluoromethanesulfonic was obtained in 49% yield.acid (6 Themol%), reaction and ( isp-tol) applicable3P (12 mol%), to both aliphaticand 2-benzoyloxyethyl and aromatic disulfides, butyl disulfide and it proceeds was obtained at a much in 49% lower yield. temperature The reaction than is applicable in the conventional to both heatingaliphatic method. and aromatic A chemical disulfides, equilibrium and it was proceeds rapidly at reached a much within lower 15 temperature min, which than included in the two symmetricconventional disulfides heating and method. one asymmetric A chemical disulfide equilibrium at a was statistical rapidly 1:1:2 reached ratio. within Chemical 15 min, equilibrium which wasincluded confirmed two bysymmetric the reverse disulfides reaction and of one an unsymmetricasymmetric disulfide disulfide. at a Thestatistical method 1:1:2 is ratio. applicable Chemical to the equilibrium was confirmed by the reverse reaction of an unsymmetric disulfide. The method is exchange of disulfides, diselenides/ditellurides, and other heteroatom compounds of group 16 elements. applicable to the exchange of disulfides, diselenides/ditellurides, and other heteroatom compounds The proposed mechanism involves the initial oxidative addition of a low-valent rhodium complex of group 16 elements. The proposed mechanism involves the initial oxidative addition of a low-valent and a disulfide. The subsequent oxidative addition of another disulfide or ligand exchange of the rhodium complex and a disulfide. The subsequent oxidative addition of another disulfide or ligand organothio group occurs, and the disulfide is liberated by reductive elimination with the regeneration exchange of the organothio group occurs, and the disulfide is liberated by reductive elimination with of the regeneration catalyst. of the catalyst.

SchemeScheme 1. 1. DisulﬁdeDisulfide exchange reaction. reaction.

WhenWhen one one product product is is removed removed from from thethe solutionsolution of the disulfide disulfide exchange exchange reaction, reaction, the the chemical chemical equilibriumequilibrium can can be be shifted shifted (Figure (Figure5 a)5a) [ [33].33]. WeWe developed a a silica silica nanoparticle nanoparticle precipitation precipitation method, method, inin which which nanoparticles nanoparticles precipitated precipitated fromfrom solutionsolution withwith concomitant molecular molecular recognition recognition and and adsorptionadsorption of of molecules. molecules. Silica Silica ( P(P)-nanoparticles)-nanoparticles of 70 nm mean mean diameter diameter grafted grafted with with (P ()-heliceneP)-helicene werewere employed. employed. When When butyl butyl (R)-(hydroxyphenylmethyl) (R)-(hydroxyphenylmethyl) disulfide disulfide (R)-45 was(R)- treated45 was with treated RhH(PPh with3 )4 (20RhH(PPh mol%), trifluoromethanesulfonic3)4 (20 mol%), trifluoromethanesulfonic acid (40 mol%), andacid ( p(40-tol) 3mol%),P (80 mol%) and ( inp-tol) chlorobenzene3P (80 mol%) for in 24 h chlorobenzene for 24 h in the presence of silica (P)-nanoparticles, precipitates containing (R,R)-

Molecules 2020, 25, 3595 7 of 35 Molecules 2020, 25, x FOR PEER REVIEW 7 of 35 inbis(hydroxyphenylmethyl) the presence of silica (P)-nanoparticles, disulfide (R, R)- precipitates43 (27%) and containing (R)-45 (3%) (R, Rwere)-bis(hydroxyphenylmethyl) formed (Figure 5b). The disulfidehigh preference (R, R)-43 for(27%) (R, R)- and43 is (R notable,)-45 (3%) and were no formed dibutyl (Figure disulfide5b). 44 The was high contained preference in the for precipitates. ( R, R)-43 is notable,The solution and phase no dibutyl contained disulfide (R, R44)-43was (6%), contained (R)-45 (30%), in the and precipitates. 44 (33%). The solutioncomposition phase of containeddisulfides (inR ,theR)- 43precipitates(6%), (R)- 45deviates(30%), andconsiderably44 (33%). from The compositionthat of the initial of disulfides chemical in equilibrium the precipitates with deviates (R, R)- considerably43:(R)-45:44 = from1:2:1. thatIt should of the also initial be chemicalnoted that equilibrium most of the withbutylthio (R, R )-group43:(R )-remained45:44 = 1:2:1. in solution. It should also be noted that most of the butylthio group remained in solution.

(a)

(b)

Figure 5. ((aa)) Equilibrium Equilibrium shift shift in in disulfide disulﬁde exchange exchange reacti reactionon induced induced by bythe theprecipitation precipitation of silica of silica (P)- (nanoparticles.P)-nanoparticles. (b) Equilibrium (b) Equilibrium shift shift in the in thereaction reaction of (R of, R (R)-,43R)-, 4344, 44and, and (R)- (45R)-. 45.

The disulfidedisulfide exchangeexchange reactionreaction ofof hydrophilichydrophilic disulfidesdisulfides occursoccurs inin waterwater whenwhen usingusing thethe RhClRhCl33 catalyst (Scheme2 2))[ [34].34]. When glutathione disulfide disulfide and glycolic acid disulfide disulfide (4 equivalents) were treatedtreated with RhCl RhCl33 (10(10 mol%) mol%) in in water water at at 40 40 °C◦C for for 1 1h, h, methylthiolated methylthiolated glutathione glutathione was was obtained obtained in in81% 81% yield. yield. The The reverse reverse reaction reaction confirmed confirmed the theinvo involvementlvement of chemical of chemical equilibrium. equilibrium. In addition, In addition, the thecomposition composition under under chemical chemical equilibrium equilibrium could could be bechanged changed by by the the addition addition of of a a disulfide, disulfide, whichwhich indicatedindicated that catalysis catalysis occurred occurred after after reaching reaching chem chemicalical equilibrium. equilibrium. This This method method can can be be applied applied to tothe the reaction reaction of ofdimethyl dimethyl disulfide, disulfide, which which is is not not water-soluble. water-soluble. A A two-phas two-phasee system system of glutathione 3 disulfidedisulfide in water and excess dimethyl disulfidedisulfide was treated with RhCl3 (10(10 mol%) mol%) at at 40 40 °C◦C for for 1 h, and methylthiolated glutathioneglutathione waswas obtainedobtained inin 40%40% yield.yield.

Scheme 2. Disulﬁde exchange reaction of glutathione in water. Scheme 2. Disulfide exchange reaction of glutathione in water.

Molecules 2020, 25, 3595 8 of 35

Molecules 2020, 25, x FOR PEER REVIEW 8 of 35 Molecules 2020, 25, x FOR PEER REVIEW 8 of 35 The RhCl3-catalyzed method was applied to insulin containing three S-S bonds, and the reaction The RhCl3-catalyzed method was applied to insulin containing three S-S bonds, and the reaction with excess thioglycolic acid preferentially exchanged the disulﬁde at the 7 positions in both A and withThe excess RhCl thioglycolic3-catalyzed acid method preferentially was applied exchanged to insulin the containing disulfide three at the S-S 7 positionsbonds, and in the both reaction A and B chains (Scheme3)[ 35]. The product was obtained in 30% yield at room temperature for 1 h using withB chains excess (Scheme thioglycolic 3) [35]. acid The preferentially product was exchangedobtained in the 30% disulfide yield at atroom the 7temperature positions in for both 1 h A using and RhCl (300 mol%) with recovery of insulin in 70% yield. The rhodium-catalyzed method in water BRhCl 3chains3 (300 (Scheme mol%) 3) with [35]. recovery The product of insulin was obtained in 70% yield.in 30% The yield rhodium-catalyzed at room temperature method for 1 inh usingwater toleratesRhCltolerates3 various (300 various mol%) functional withfunctional recovery groups, grou of includingps, insulin including in amides, 70% amides, yield. amines, Theamines, carboxylicrhodium-catalyzed carboxylic acids, acids, alcohols, method alcohols, andin water phenols,and becausetoleratesphenols, of the becausevarious higher offunctional atheﬃnity higher ofgrou affi rhodiumps,nity including of forrhodium sulfur amides, for atoms sulfur amines, in atoms the carboxylic presencein the presence ofacids, nitrogen of alcohols, nitrogen and and oxygenand functionalphenols,oxygen groups. functional because of groups. the higher affinity of rhodium for sulfur atoms in the presence of nitrogen and oxygen functional groups.

SchemeScheme 3. 3.Disulfide Disulfide exchangeexchange reaction reaction of of insulin. insulin. Scheme 3. Disulfide exchange reaction of insulin. 3. Rhodium-Catalyzed3. Rhodium-Catalyzed Substitution Substitution Reactions Reactions UsingUsing Disulfides Disulfides 3. Rhodium-Catalyzed Substitution Reactions Using Disulfides TheThe S-S S-S bonds bonds of disulfidesof disulfides are are reversibly reversibly cleavedcleaved under rhodium rhodium catalysis, catalysis, as asindicated indicated by the by the disulfidedisulfideThe exchange S-S exchange bonds reaction. of reaction. disulfides Rhodium Rhodium are reversibly complexes complexes cleave also cleavedalso under cleave C-S rhodium and C-S C-H catalysis,and bonds C-H inasbonds organicindicated in compounds,organic by the anddisulfidecompounds, combinations exchange and of these combinationsreaction. bond Rhodium cleavage of these reactionscomplexes bond provide cleavagealso cleavevarious reactions C-S chemical and provide C-H transformations bondsvarious in chemicalorganic for the synthesiscompounds,transformations of organosulfur and for combinations the compounds,synthesis ofof organosulfur includingthese bond thioesters, compounds, cleavageα -thioketones,reactions including providethioesters, 1-thioalkynes, various α-thioketones, chemical aryl sulfides, 1- andtransformationsthioalkynes, dithiophosphinates. aryl for sulfides, the synthesis and dithiophosphinates. of organosulfur compounds, including thioesters, α-thioketones, 1- thioalkynes, aryl sulfides, and dithiophosphinates. 3.1. Substitution3.1. Substitution Reactions Reactions of of Thioesters Thioesters 3.1. Substitution Reactions of Thioesters ThioestersThioesters are are excellent excellent substrates substrates forfor rhodium-catalyzedrhodium-catalyzed reactions reactions and and provide provide various various acyl acyl derivativesderivativesThioesters by theirby theirare reactions excellent reactions withsubstrates with di differentfferent for rhodiu substrates. substrm-catalyzedates. Organothio Organothio reactions exchange exchange and providereaction reaction variousof thioesters of thioesters acyl derivativesoccurs with by disulfides their reactions (Scheme with 4) different [36]. S-Octyl substr benzothioateates. Organothio and exchangebis(2-ethoxyethyl) reaction ofdisulfide thioesters (4 occurs with disulfides (Scheme4)[ 36]. S-Octyl benzothioate and bis(2-ethoxyethyl) disulfide occursequivalents) with disulfideswere reacted (Scheme in the presence4) [36]. S of-Octyl RhCl(PPh benzothioate3)3 (2.5 mol%) and bis(at 3-pentanone2-ethoxyethyl) reflux disulfide for 1.5 (4h, (4 equivalents) were reacted in the presence of RhCl(PPh3)3 (2.5 mol%) at 3-pentanone reflux for 1.5 h, equivalents)and S-(2-ethoxyethyl) were reacted benzothioate in the presence was of obtainedRhCl(PPh 3in)3 (2.587% mol%) yield. at 3-pentanoneChemical equilibrium reflux for 1.5 was h, andanddeterminedS-(2-ethoxyethyl) S-(2-ethoxyethyl) by the reverse benzothioate benzothioate reaction was and obtainedwas formation obtained in of 87% a statisticalin yield. 87% Chemical1:2:1yield. mixture Chemical equilibrium employing equilibrium was 1 equivalent determined was by thedeterminedof reversedisulfides. reaction by theIt was reverse and also formation reaction observed and of athatformation statistical the reaction of1:2:1 a statistical mixtureof S-methyl 1:2:1 employing mixture thioesters employing 1 equivalent and disulfides1 equivalent of disulfides. (4 It wasofequivalents) alsodisulfides. observed gave It was thathigher also the yields reactionobserved of the of thatSexchange-methyl the reaction products thioesters of under andS-methyl disulfides1,2-dichlorobenzene thioesters (4 equivalents) and refluxdisulfides gavebecause higher(4 yieldsequivalents)of ofthe the removal exchange gave of highervolatile products yields dimethyl under of the disulfide 1,2-dichlorobenzeneexchange from products the reaction under reflux mixture. 1,2-dichlorobenzene because These of results the removal reflux indicate because of facile volatile dimethylofcleavage the removal disulfide of C-S of bonds from volatile thein thioestersdimethyl reaction disulfideby mixture. rhodium from These catalysis. the results reaction indicate mixture. facile These cleavage results indicate of C-S facile bonds in thioesterscleavage by of rhodium C-S bonds catalysis. in thioesters by rhodium catalysis.

Scheme 4. Organothio exchange reaction of thioesters. SchemeScheme 4. 4.Organothio Organothio exchange reaction reaction of of thioesters. thioesters. Acid fluorides show high reactivity under rhodium-catalyzed conditions (Scheme 5) [37]. When benzoylAcidAcid fluorides fluoride, fluorides show bis( showp high-tolyl) high reactivity reactivitydisulfide, under underand triphenylphosphine rhodium-catalyzed conditionswere conditions reacted (Scheme(Scheme in the 5) presence [37].5)[ 37 When]. Whenof benzoylbenzoylRhH(PPh fluoride, fluoride,3)4 (1 mol%) bis( bis(p-tolyl) andp-tolyl) 1,2-diphenylphosphinoethane disulfide, disulfide, andand triphenylphosphine (dppe) (2 mol%)were were reacted in reacted refluxing in the in THF thepresence for presence 2 h, ofS- of RhH(PPhRhH(PPh(p-tolyl)3)4 benzothioate3(1)4 (1 mol%) mol%) and and was 1,2-diphenylphosphinoethane1,2-diphenylphosphinoethane obtained in 100% yield. Formally, (dppe) (dppe) the (2 reaction mol%) (2 mol%) inprovides refluxing in refluxing unstable THF for THF sulfenyl 2 h, for S- 2 h, S-(p-tolyl)(fluoridep-tolyl) benzothioate benzothioatewith disulfide waswas regeneration. obtainedobtained in in 100%The 100% role yield. yield. of Formally,triphenylphosphine Formally, the the reaction reaction is provides to provides trap fluoridesunstable unstable sulfenylto form sulfenyl fluoridefluoride with with disulfide disulfide regeneration. regeneration. The role of of triphenylphosphine triphenylphosphine is isto totrap trap fluorides fluorides to form to form phosphine difluoride with disulfide regeneration, which results in an exothermic reaction suitable for catalysis. Molecules 2020, 25, x FOR PEER REVIEW 9 of 35

Moleculesphosphine2020, 25, 3595difluoride with disulfide regeneration, which results in an exothermic reaction suitable9 of 35 for catalysis.

Molecules 2020, 25, x FOR PEER REVIEW 9 of 35

phosphine difluoride with disulfide regeneration, which results in an exothermic reaction suitable for catalysis.

SchemeScheme 5. 5.Interconversion Interconversion betweenbetween acid acid fluorides ﬂuorides and and thioesters. thioesters.

TheThe rhodium-catalyzed rhodium-catalyzedScheme method 5.method Interconversion waswas alsoalso between employed acid fluorides in in the the andsynthesis synthesis thioesters. of acid of acid fluorides fluorides from from thioestersthioesters (Scheme (Scheme5)[ 5)37 [37].].When When SS-(-(pp-tolyl)-tolyl) benzothioate benzothioate and andhexafluorobenzene hexafluorobenzene were reacted were in reacted the in presenceThe ofrhodium-catalyzed RhH(PPh3)4 (2.5 mol%) method and was dppe also (5 mol%)employed in refl inuxing the synthesischlorobenzene, of acid benzoyl fluorides fluoride from the presence of RhH(PPh3)4 (2.5 mol%) and dppe (5 mol%) in refluxing chlorobenzene, benzoyl wasthioesters obtained (Scheme in 94% 5) [37]. yield When in addition S-(p-tolyl) to benzothioate1,4-di(p-tolylthio)-2,3,5,6-tetrafluorobenzene. and hexafluorobenzene were reacted This in is the a fluoride was obtained in 94% yield in addition to 1,4-di(p-tolylthio)-2,3,5,6-tetrafluorobenzene. This is noteworthypresence of fluorinatingRhH(PPh3)4 (2.5reaction mol%) using and stable dppe neutral(5 mol%) aromatic in refluxing fluorides. chlorobenzene, Chemical equilibriumbenzoyl fluoride also a noteworthy fluorinating reaction using stable neutral aromatic fluorides. Chemical equilibrium also occurswas obtained between in an 94% acid yieldfluoride in andaddition a thioeste to 1,4-di(r in a pclosed-tolylthio)-2,3,5,6-tetrafluorobenzene. system under rhodium catalysis. This is a occursnoteworthy betweenThe above anfluorinating acidresults fluoride indicate reaction and involvement using a thioester stable of neutralinterconversion in a closed aromatic system reactionsfluorides. under in Chemical rhodiuman open systemequilibrium catalysis. between also Thethioesteroccurs above between and results acid an acidfluoride indicate fluoride catalyzed involvement and a thioesteby rhodium: ofr interconversion in a closedAcid fluoridessystem reactions under are converted rhodium in an open catalysis. to thioesters system between by thioesteradding andThe disulfides, acidabove fluoride results and thioestersindicate catalyzed involvement are by converted rhodium: of interconversionto Acid acid fluoridesfluorides reactions by are adding converted in hexafluorobenzene.an open to thioesters system between by The adding disulfides,additionthioester and ofand thioesters external acid fluoride reagents are converted catalyzed inverts to bythe acid rhodium: rela fluoridestive Acidthermodynamic by fluorides adding hexafluorobenzene.are stability converted and to promotes thioesters The additionthe by of externalinterconversionadding reagents disulfides, reactions inverts and thioesters (Figure the relative 4).are It converted was thermodynamic considered to acid that fluorides stability a R’SSR’ by and +adding ArF promotes → hexafluorobenzene. Ar-SR’ the+ R’S-F interconversion reaction The reactionsmayaddition also (Figure occur;of 4external). this It was reaction reagents considered is described inverts that thelater a R’SSR’ rela (Schemetive+ ArFthermodynamic 12). Ar-SR’ + stabilityR’S-F reaction and promotes may also the occur; → this reactioninterconversionRhodium-catalyzed is described reactions later reaction (Figure (Schemes 4). of Itdisulfides 12). was considered can be appliedthat a R’SSR’ to diselenides + ArF → Ar-SR’(Scheme + R’S-F6) [38]. reaction Bis(2- pyridyl)may also diselenide occur; this and reaction 1-adamantanecarbonyl is described later (Scheme fluoride 12).were reacted in the presence of RhH(PPh3)4 Rhodium-catalyzed reactions of disulfides can be applied to diselenides (Scheme6)[ 38]. (2.5 mol%)Rhodium-catalyzed and dppe (5reaction mol%)s of in disulfides refluxing can chlorobenzene, be applied to diselenides and 1-adamantanecarbonyl (Scheme 6) [38]. Bis(2- 2- Bis(2-pyridyl) diselenide and 1-adamantanecarbonyl fluoride were reacted in the presence of pyridylselenoesterpyridyl) diselenide was and obtained 1-adamantanecarbonyl in 88% yield. This fluoride method were was reacted used forin thethe presencesynthesis of of RhH(PPh heteroaryl3)4 RhH(PPhselenoesters,(2.5 3mol%))4 (2.5 which mol%)and dppe are and generally (5 dppe mol%) (5 less mol%) in stable refluxing in than refluxing aryl chlorobenzene, thioesters. chlorobenzene, The and heteroaryl 1-adamantanecarbonyl and 1-adamantanecarbonyl compounds can be2- 2-pyridylselenoesterusedpyridylselenoester for the synthesis was was of obtained obtained novel organoselenium inin 88%88% yield. Thiscompounds. This method method was was used used for for the the synthesis synthesis of heteroaryl of heteroaryl selenoesters,selenoesters, which which are are generally generally less less stable stable than than arylaryl thioesters. The The heteroaryl heteroaryl compounds compounds can be can be usedused for the for synthesis the synthesis of novelof novel organoselenium organoselenium compounds. compounds.

SchemeScheme 6. 6.Synthesis Synthesis of selenoesters. selenoesters.

3.2. Substitution Reactions of 1-Alkynes Rhodium complexes can activate C-H bonds of organic molecules, and this reaction is employed here for thiolation reactions using disulfides [30]. The reaction of a S-S bond in a disulfide and a C-H bond in an organic compound formally provides an organosulfur compound with a C-S bond and a

Molecules 2020, 25, 3595 10 of 35

3.2. Substitution Reactions of 1-Alkynes Molecules 2020, 25, x FOR PEER REVIEW 10 of 35 Rhodium complexes can activate C-H bonds of organic molecules, and this reaction is employed thiolhere forwith thiolation a S-H bond. reactions The thiol using can disulfides be oxidized [30]. to The a disulfide reaction ofin athe S-S presence bond in aof disulfide oxygen, anda reaction a C-H bond in an organic compound formally provides an organosulfur compound with a C-S bond and a that isMolecules also catalyzed 2020, 25, x FOR by PEER rhodium REVIEW complexes. 10 of 35 thiol with a S-H bond. The thiol can be oxidized to a disulfide in the presence of oxygen, a reaction When 1-(triethylsilyl)-acetylene was treated with dibutyl disulfide in the presence of RhH(PPh3)4 (2that mol%) isthiol also andwith catalyzed diphenylphosphinoferrocenea S-H bond. by rhodium The thiol complexes.can be oxidized (dppf) to (3 a mol%)disulfide for in 1the h inpresence refluxing of oxygen, acetone, a reaction1-butylthio- that is also catalyzed by rhodium complexes. 2-triethylsilylacetyleneWhen 1-(triethylsilyl)-acetylene was obtained wasin 80% treated yield, with which dibutyl was accompanied disulfide in the by presence a thiol (Scheme of RhH(PPh 7) [39].3)4 When 1-(triethylsilyl)-acetylene was treated with dibutyl disulfide in the presence of RhH(PPh3)4 The(2 mol%) reaction and of diphenylphosphinoferrocene a thiol and a 1-thioacetylene (dppf) formed (3 mol%)the original for 1 h1-alkyne in refluxing under acetone, argon 1-butylthio-2-atmosphere. (2 mol%) and diphenylphosphinoferrocene (dppf) (3 mol%) for 1 h in refluxing acetone, 1-butylthio- 1-Alkynes/disulfidestriethylsilylacetylene wasand obtained1-thioalkyne/thiols in 80% yield, are which under was chemical accompanied equilibrium by a thiol in the (Scheme presence7)[ 39of]. The reaction2-triethylsilylacetylene of a thiol and was a1-thioacetylene obtained in 80% yield, formed which the was original accompanied 1-alkyne by undera thiol (Scheme argon atmosphere. 7) [39]. rhodiumThe reactioncatalysis. of aThe thiol rhodium and a 1-thioacetylene complex also formed rapidly the oxidizes original 1-alkynethiols to under disulfides argon andatmosphere. water in the 1-Alkynes/disulfides and 1-thioalkyne/thiols are under chemical equilibrium in the presence of rhodium presence1-Alkynes/disulfides of a trace amount and of 1-thioalkyne/thiols oxygen (Schemes are 7 and under 23). chemicalIn combination equilibrium with in the the oxidation presence reaction of undercatalysis.rhodium air, Thethe catalysis. rhodiumthiolation The complex reactionrhodium also complexof rapidly1-alkynes also oxidizes rapidly proceeds oxidizes thiols in toan thiols disulfides energetically to disulfides and waterdownhill and water in the mannerin presencethe to provideof a tracepresence 1-thioalkynes amount of a trace of oxygen amount in higher (Schemeof oxygenyields.7 (Schemes Theand interc Scheme 7 onversionand 23). 23). In combinationreactions proceed with with the between the oxidation oxidation 1-alkynes reaction reaction and 1-thioalkynes.underunder air, air, the the thiolation thiolation reaction reaction of of 1-alkynes1-alkynes proceeds in in an an energetically energetically downhill downhill manner manner to to provideprovide 1-thioalkynes 1-thioalkynes in in higher higher yields. The The interc interconversiononversion reactions reactions proceed proceed between between 1-alkynes 1-alkynes and and 1-thioalkynes.1-thioalkynes.

SchemeScheme 7. 7. OrganothiolationOrganothiolation Organothiolation reactionreaction of of 1-alkynes. 1-alkynes.

A rhodium rhodiumA rhodium complex complex complex catalyzes catalyzes catalyzes the the the organothio organothioorganothio exchange exchange reaction reaction reaction of of1-thioalkynes of 1-thioalkynes 1-thioalkynes with with withdisulfides, disulfides, disulfides, thethe observation observationthe observation of of which of which which confirmed confirmed confirmed the the C-S C-S C-S bondbond bond clcleavageeavage cleavage by by rhodium by rhodium rhodium catalysis catalysis catalysis (Scheme (Scheme (Scheme 8) [39]. 8) 8[39].In)[ 39 In]. principle,In principle,principle, diverse diverse diverse 1-thialkynes 1-thialkynes1-thialkynes can can can be be beobtained obtained obtained byby bythisthis this method method method using using using different different diff erentdisulfides. disulfides. disulfides.

Scheme 8. Organothio exchange reaction of 1-thioalkyne. Scheme 8. Organothio exchange reaction of 1-thioalkyne. Scheme 8. Organothio exchange reaction of 1-thioalkyne. 3.3. Substitution3.3. Substitution Reactions Reactions of of Active Active Methylene Methylene Compounds 3.3. SubstitutionActive methyleneReactions ofcompounds, Active Methylene which include Compounds nitroalkanes, malonate, and benzyl ketones, with Active methylene compounds, which include nitroalkanes, malonate, and benzyl ketones, acidic hydrogen atoms are thiolated with disulfides under rhodium catalysis (Scheme 9) [40]. When withActive acidic methylene hydrogen atomscompounds, are thiolated which withinclude disulfides nitroalkanes, under malonate, rhodium and catalysis benzyl (Scheme ketones,9)[ with40]. 1-nitropentane was treated with bis(p-chlorophenyl) disulfide in N, N-dimethylacetamide (DMA) in acidicWhen hydrogen 1-nitropentane atoms wasare thiolated treated with with bis(disulfidp-chlorophenyl)es under rhodium disulfide catalysis in N, (SchemeN-dimethylacetamide 9) [40]. When air at room temperature for 3 h in the presence of RhH(PPh3)4 (5 mol%) and dppe (10 mol%), 2-(p- 1-nitropentane was treated with bis(p-chlorophenyl) disulfide in N, N-dimethylacetamide (DMA) in (DMA)chlorophenyl) in air at roomnitropentane temperature was produced for 3 hin in50% the yield. presence The reaction of RhH(PPh without air3)4 is(5 under mol%) chemical and dppe air(10 at mol%),equilibrium, room 2-(temperaturep-chlorophenyl) and α-thiolated for 3 h nitropentane innitroalkanes the presence wasare of produced thermodyRhH(PPhnamically in3)4 50%(5 mol%) yield. unfavorable. and The dppe reaction Accordingly, (10 mol%), without 2-( airp- chlorophenyl)is undertreatment chemical ofnitropentane an equilibrium,α-thiolated was nitroalkane andproducedα-thiolated with in a50% thiol nitroalkanes yi quantitivelyeld. The reaction are provided thermodynamically without the original air is nitroalkane.under unfavorable. chemical equilibrium,Accordingly,Air/oxygen treatmentand converts α-thiolated thiols of an toα -thiolated disulfidesnitroalkanes and nitroalkane waterare inthermody an with exothermic a thiolnamically quantitively reaction. unfavorable. Diethyl provided malonate Accordingly, the and original treatmentnitroalkane.1,2-diphenyl-1-ethanone of an Air α/oxygen-thiolated converts were nitroalkane also thiols reacted with to with disulfides a thiolaromatic quantitively and disulfides water ininprovided anair to exothermic provide the original organothiolated reaction. nitroalkane. Diethyl Air/oxygenmalonatecompounds. and converts 1,2-diphenyl-1-ethanone thiols to disulfides wereand water also reacted in an exothermic with aromatic reaction. disulfides Diethyl in malonate air to provide and 1,2-diphenyl-1-ethanoneorganothiolated compounds. were also reacted with aromatic disulfides in air to provide organothiolated compounds.

Molecules 2020, 25, x FOR PEER REVIEW 11 of 35

3.3. Substitution Reactions of Active Methylene Compounds Active methylene compounds, which include nitroalkanes, malonate, and benzyl ketones, with acidic hydrogen atoms are thiolated with disulfides under rhodium catalysis (Scheme 9) [40]. When 1-nitropentane was treated with bis(p-chlorophenyl) disulfide in N, N-dimethylacetamide (DMA) in air at room temperature for 3 h in the presence of RhH(PPh3)4 (5 mol%) and dppe (10 mol%), 2-(p- chlorophenyl) nitropentane was produced in 50% yield. The reaction without air is under chemical equilibrium, and α-thiolated nitroalkanes are thermodynamically unfavorable. Accordingly, treatment of an α-thiolated nitroalkane with a thiol quantitively provided the original nitroalkane. Air/oxygen converts thiols to disulfides and water in an exothermic reaction. Diethyl malonate and 1,2-diphenyl-1-ethanone were also reacted with aromatic disulfides in air to provide organothiolated Molecules 2020, 25, x 3595 FOR PEER REVIEW 11 of 35 compounds.

Scheme 9. Organothiolation reactions of active methylene compounds.

3.4. Substitution ReactionsSchemeScheme 9.of 9. OrganothiolationKetonesOrganothiolation and Heteroarenes reactions reactions of of active active methylene methylene compounds. compounds. 3.4. Substitution Reactions of Ketones and Heteroarenes 3.4. Substitutionα-Thioketones Reactions efficiently of Ketones undergo and Heteroarenes C-S substitu tion reactions in the presence of rhodium catalysts.α-Thioketones In combination efficiently with undergo the C-H C-S substitutioncleavage reaction reactions catalyzed in the presence by rhodium of rhodium complexes, catalysts. α-Thioketones efficiently undergo C-S substitution reactions in the presence of rhodium organothiolationIn combination with of various the C-H or cleavageganic compounds, reaction catalyzed including by ketones rhodium and complexes, heteroarenes, organothiolation occurs. of catalysts. In combination with the C-H cleavage reaction catalyzed by rhodium complexes, variousIt was organic determined compounds, that including organothio ketones exchange and heteroarenes, reactions of occurs. α-thioketones with disulfides organothiolation of various organic compounds, including ketones and heteroarenes, occurs. proceededIt was with determined the involvement that organothio of C-S exchange bond cleava reactionsge by ofrhodiumα-thioketones catalysis with (Scheme disulfides 10) [41]. proceeded When It was determined that organothio exchange reactions of α-thioketones with disulfides withan α-phenylthioacetophenone the involvement of C-S was bond treated cleavage with bis(3-me by rhodiumthoxypropyl) catalysis disulfide (Scheme (3 10 equivalents))[41]. When in the an proceeded with the involvement of C-S bond cleavage by rhodium catalysis (Scheme 10) [41]. When presenceα-phenylthioacetophenone of RhH(PPh3)4 (1 mol%) was treatedand dppe with (2 mol%) bis(3-methoxypropyl) in refluxing THF disulfidefor 1–2 h, (3α-(3-methoxypropyl) equivalents) in the an α-phenylthioacetophenone was treated with bis(3-methoxypropyl) disulfide (3 equivalents) in the presenceacetophenone of RhH(PPh was obtained3)4 (1 mol%) in 82% and yield. dppe The (2 mol%)reverse in reaction refluxing under THF forthe 1–2same h, αconditions-(3-methoxypropyl) indicated presence of RhH(PPh3)4 (1 mol%) and dppe (2 mol%) in refluxing THF for 1–2 h, α-(3-methoxypropyl) theacetophenone involvement was of obtained chemical in 82%equilibrium. yield. The The reverse exchange reaction reactions under theof sameorganothio conditions groups indicated using acetophenone was obtained in 82% yield. The reverse reaction under the same conditions indicated differentthe involvement disulfides of chemical under rhodium equilibrium. catalysis The exchangeprovide diverse reactions derivatives of organothio starting groups from using a single different α- the involvement of chemical equilibrium. The exchange reactions of organothio groups using thioketone.disulfides under rhodium catalysis provide diverse derivatives starting from a single α-thioketone. different disulfides under rhodium catalysis provide diverse derivatives starting from a single α- thioketone.

Scheme 10. Organothio exchange reaction of α-thioketones. Scheme 10. Organothio exchange reaction of α-thioketones. α-Thioketones can be used as organothiolating reagents of organic compounds via organorhodium intermediatesα-Thioketones with C-Rh-Scan be subunits used as (Scheme organothiola 11). Ating methylthio reagents transfer of organic reaction compounds occurs between via organorhodiumdifferent ketones intermediates at the α-position, with inC-Rh-S which subunits a catalytic (Scheme amount 11). of dimethylA methylthio disulfide transfer significantly reaction occurs between different ketones at the α-position, in which a catalytic amount of dimethyl disulfide

Molecules 2020, 25, 3595 12 of 35 Molecules 2020, 25, x FOR PEER REVIEW 12 of 35 significantlypromotes the reactionpromotes [42 ].th Whene reactionα-methylthio- [42]. Whenp-cyanoacetophenone α-methylthio-p-cyanoacetophenone and 1,2-diphenylethanone and were1,2- diphenylethanonereacted in reﬂuxing were THF forreacte 3 hd in in the refluxing presence THF of RhH(PPh for 3 h 3in)4 the(4 mol%), presence dppe of (8RhH(PPh mol%), and3)4 (4 dimethyl mol%), dppedisulﬁde (8 mol%), (12 mol%), and dimethyl 2-methylthio-1,2-diphenylethanone disulfide (12 mol%), 2-methylthio-1,2-diphenylethanone was obtained in 68% yield. The was methylthio obtained ingroup 68% moved yield. fromThe αmethylthio-methylthio- groupp-cyanoacetophenone moved from α-methylthio- to 1,2-diphenylethanonep-cyanoacetophenone under chemical to 1,2- diphenylethanoneequilibrium. This methodunder chemical is applied equilibrium. to cyclic α-phenyl This method ketones is withapplied acidic to cyclicα-protons. α-phenyl The reactionketones withof 2-phenylthio-4-( acidic α-protons.t-butyl) The cyclohexanonereaction of 2-phenylthio-4-( and α-methylthio-t-butyl)p-chloroacetophenone cyclohexanone and α gave-methylthio- a productp- chloroacetophenonewith an axial methylthio gave group,a product and thewith cleavage an axia ofl methylthio the phenylthio group, group and was the slowcleavage under of these the phenylthioconditions [group43]. was slow under these conditions [43].

SchemeScheme 11. 11. OrganothiolationOrganothiolation reactions reactions of of ketones ketones and and benzothiazole. benzothiazole. 2-Methylthio-1,2-diphenylethanone is effective in the α-methylthiolation reactions of ketones 2-Methylthio-1,2-diphenylethanone is effective in the α-methylthiolation reactions of ketones with less acidic α-protons compared with α-methylthio-p-cyanoacetophenone [44]. Reaction of with less acidic α-protons compared with α-methylthio-p-cyanoacetophenone [44]. Reaction of 2- 2-benzylcyclohexanone and 2-methylthio-1,2-diphenylethanone in the presence of RhH(PPh3)4 benzylcyclohexanone and 2-methylthio-1,2-diphenylethanone in the presence of RhH(PPh3)4 (4 (4 mol%), dppe (8 mol%), and dimethyl disulfide (12 mol%) in refluxing THF for 3 h gave mol%), dppe (8 mol%), and dimethyl disulfide (12 mol%) in refluxing THF for 3 h gave 2-benzyl-2- 2-benzyl-2-methylthiocyclohexanone in 47% yield. The regioselectivity indicated the important methylthiocyclohexanone in 47% yield. The regioselectivity indicated the important role of the enol role of the enol form of 2-methylcyclohexanone. The method is also applied to α-methylthiolation form of 2-methylcyclohexanone. The method is also applied to α-methylthiolation of aldehydes. In of aldehydes. In these α-thiolation reactions, disulfides alone did not give satisfactory results, and these α-thiolation reactions, disulfides alone did not give satisfactory results, and α-thioketones were α-thioketones were employed as the donors. A favorable chemical equilibrium may be involved employed as the donors. A favorable chemical equilibrium may be involved in forming ketones from in forming ketones from α-thioketones rather than forming thiols from disulfides. Possible roles α-thioketones rather than forming thiols from disulfides. Possible roles of dimethyl disulfide are the of dimethyl disulfide are the generation of reactive rhodium species with sulfur ligands and/or the generation of reactive rhodium species with sulfur ligands and/or the transient formation of α- transient formation of α-methylthio ketones. methylthio ketones. Phenylthiolation reactions of aromatic hydrogen atoms in benzo-fused heteroaromatic compounds Phenylthiolation reactions of aromatic hydrogen atoms in benzo-fused heteroaromatic were conducted using α-phenylthioisobutyrophenone, which provided higher yields of the products compounds were conducted using α-phenylthioisobutyrophenone, which provided higher yields of when compared with 2-methylthio-1,2-diphenylethanone [45]. This result may be due to the the products when compared with 2-methylthio-1,2-diphenylethanone [45]. This result may be due thermodynamically favorable nature of chemical equilibrium to form a ketone with a less acidic α-proton. to the thermodynamically favorable nature of chemical equilibrium to form a ketone with a less acidic 1,3-Benzothiazole and α-methylthioisobutyrophenone were reacted in chlorobenzene reflux for 3 h in the α-proton. 1,3-Benzothiazole and α-methylthioisobutyrophenone were reacted in chlorobenzene presence of RhH(PPh3)4 (4 mol%) and dppe (8 mol%), which provided 2-phenylthio-1,3-benzothiazole reflux for 3 h in the presence of RhH(PPh3)4 (4 mol%) and dppe (8 mol%), which provided 2- in 92% yield. The methylthiolation reaction of benzothiazole provided α-methythioisobutyrophenone phenylthio-1,3-benzothiazole in 92% yield. The methylthiolation reaction of benzothiazole provided in the presence of dimethyl disulfide, albeit in lower yields. α-methythioisobutyrophenone in the presence of dimethyl disulfide, albeit in lower yields.

MoleculesMolecules 20202020,, 2525,, x 3595 FOR PEER REVIEW 1313 of of 35 35 Molecules 2020, 25, x FOR PEER REVIEW 13 of 35 These results indicate that methylthio groups can hop between α-protons of ketones under rhodiumTheseThese catalysis resultsresults (Figure indicateindicate 6). that thatThis methylthio methylthiois analogous groupsgroups to thecan αcan-proton hophop between betweenexchange αα -protonsreactions-protons ofbetweenof ketonesketones ketones underunder underrhodiumrhodium acidic catalysis catalysis or basic (Figure (Figure conditions.6 ).6). This This is is analogous analogous to to the theα α-proton-proton exchange exchange reactions reactions between between ketones ketones underunder acidic acidic or or basic basic conditions. conditions.

Figure 6. Rhodium-catalyzed hopping of methylthio groups among ketones at α-positions. FigureFigure 6. 6.Rhodium-catalyzed Rhodium-catalyzed hoppinghopping ofof methylthiomethylthio groups groups among among ketones ketones at atα α-positions.-positions. 3.5. Substitution Reactions of Aromatic Fluorides 3.5.3.5. SubstitutionSubstitution ReactionsReactions ofof AromaticAromaticFluorides Fluorides Organofluorine compounds are highly reactive under rhodium catalysis, as noted in the reaction of acylOrganofluorineOrganofluorine fluorides to form compounds compounds thioesters are are (Scheme highly highly reactive reactive5). This under undebehaviorr rhodium rhodium may catalysis,be catalysis, due to as asthe noted noted high in inreactivity the thereaction reaction of rhodiumofof acylacyl fluoridesfluorides fluoride tointermediates,to form form thioesters thioesters which (Scheme(Scheme is consiste5 ).5). This Thntis with behavior behavior the notably may may be be high due due toreactivity to the the high high of reactivity RhF(PPhreactivity of3 )of3 [46].rhodiumrhodium Accordingly, fluoride fluoride intermediates, C-Fintermediates, bonds in which fluorobenzeneswhich is consistentis consiste were withnt with theconverted notablythe notably to high C-S high reactivity bonds reactivity via of RhF(PPh reaction of RhF(PPh3) 3with[463].) 3 disulfidesAccordingly,[46]. Accordingly, (Scheme C-F bonds C-F12). inbondsWhen fluorobenzenes in1-bromo-4-chloro-3-fluoroben fluorobenzenes were converted were converted to C-Szene bonds towas C-S viareacted bonds reaction withvia with reaction bis( disulfidesp-tolyl) with disulfide(Schemedisulfides 12and ).(Scheme Whentriphenylphosphine 1-bromo-4-chloro-3-fluorobenzene12). When 1-bromo-4-chloro-3-fluoroben in the presence wasof reactedRhH(PPhzene withwas3)4 bis((0.25reactedp-tolyl) mol%) with disulfide bis(andp -tolyl)1,2- and (diphenylphosphino)triphenylphosphinedisulfide and triphenylphosphine in benzene the presence (dppBz) of RhH(PPh in(0.5 the mol%) 3)presence4 (0.25 under mol%) chlorobenzeneof andRhH(PPh 1,2-(diphenylphosphino)3 )reflux4 (0.25 for mol%) 3 h, 5-bromo-2- and benzene 1,2- chlorophenyl(dppBz)(diphenylphosphino) (0.5 p mol%)-tolyl sulfide under benzene was chlorobenzene (dppBz)obtained (0.5 in 72% reflux mol%) yield for under [47]. 3 h, Thechlorobenzene 5-bromo-2-chlorophenyl reaction proceeded reflux for selectively 3p -tolylh, 5-bromo-2- sulfide at the fluoridewaschlorophenyl obtained atom without inp-tolyl 72% sulfide yieldaffecting [ 47was ].chloride obtained The reaction and in brom72% proceeded yieldide atoms. [47]. selectively The Triphenylphosphine reaction at theproceeded fluoride was selectively atom employed without at tothe trapafluorideffecting fluorides chlorideatom bywithout andforming bromide affecting phosphine atoms. chloride Triphenylphosphine difluoride, and brom whichide atoms. wasresulted employedTriphenylphosphine in an toexothermic trap fluorides was reaction. employed by forming The to reactionphosphinetrap fluorides of perfluorobenzenes difluoride, by forming which phosphine resultedshowed innotable difluoride, an exothermic select whichivity reaction. in resultedthe substitution The in reaction an exothermic reaction, of perfluorobenzenes and reaction. thiolation The occurredshowedreaction notableofat perfluorobenzenes the selectivity p-positions, in the showedwhich substitution notablewas named reaction,selectivity the and in thep thiolation-difluoride substitution occurred rule. reaction, The at the andreactionp-positions, thiolation of hexafluorobenzenewhichoccurred was namedat the theandp-positions,p-difluoride bis(p-tolyl) which rule. disulfide The was reaction gavenamed of1,4-bis( hexafluorobenzenethe pp-tolyl)-2,3,5,6-tetrafluorobenzene,-difluoride andrule. bis( Thep-tolyl) reaction disulfide inof whichgavehexafluorobenzene 1,4-bis( no monothiolatedp-tolyl)-2,3,5,6-tetrafluorobenzene, and product bis(p-tolyl) was detected.disulfide in gave which 1,4-bis( no monothiolatedp-tolyl)-2,3,5,6-tetrafluorobenzene, product was detected. in which no monothiolated product was detected.

Scheme 12. Substitution reaction of aromatic fluorides. Scheme 12. Substitution reaction of aromatic fluorides. 3.6. Substitution Reactions ofScheme Organophosphorus 12. Substitution Compounds reaction of aromatic fluorides. 3.6. Substitution Reactions of Organophosphorus Compounds 3.6. SubstitutionOrganophosphorus Reactions compounds of Organophosphorus efficiently Compounds react with disulfides in rhodium-catalyzed substitution reactions,Organophosphorus owing to the strong compounds bonding ofefficiently sulfur and phosphorusreact with atoms.disulfides Cleavage in rhodium-catalyzed of the P-S bond was Organophosphorus compounds efficiently react with disulfides in rhodium-catalyzed substitutiondetermined reactions, by organothio owing exchange to the strong reactions bonding of dithiophosphinates of sulfur and phosphorus and disulfides atoms. (SchemeCleavage 13 of)[ the48]. substitution reactions, owing to the strong bonding of sulfur and phosphorus atoms. Cleavage of the P-SWhen bond phenyl was determined dimethyldithiophosphinate by organothio exchange and bis(4-methoxybutyl) reactions of dithiophosphinates disulfide were and reacted disulfides in the (SchemeP-S bond 13) was [48]. determined When phenyl by organothiodimethyldithiophos exchangephinate reactions and of bis(4-methoxybutyl) dithiophosphinates disulfide and disulfides were presence of RhH(PPh3)4 (2 mol%) and dppe (4 mol%) under acetone reflux for 0.5 h, the corresponding (Scheme 13) [48]. When phenyl dimethyldithiophosphinate and bis(4-methoxybutyl) disulfide were reacteddithiophosphinate in the presence was of obtained RhH(PPh in3 74%)4 (2 mol%) yield. and dppe (4 mol%) under acetone reflux for 0.5 h, the correspondingreacted in the dithiophosphinatepresence of RhH(PPh was3)4 obtained(2 mol%) inand 74% dppe yield. (4 mol%) under acetone reflux for 0.5 h, the corresponding dithiophosphinate was obtained in 74% yield.

Molecules 2020, 25, 3595 14 of 35 Molecules 2020,, 25,, xx FORFOR PEERPEER REVIEWREVIEW 14 of 35

Scheme 13. OrganothioOrganothio exchange exchange reaction reaction of dithiophosphinates. Reactions of acylphosphine sulfides and disulfides provided dithiophosphinates and thioesters, Reactions of acylphosphine sulfides and disulfides provided dithiophosphinates and thioesters, which involved the formation of C-S and P-S bonds from C-P and S-S bonds (Scheme 14)[49]. which involved the formation of C-S and P-S bonds from C-P and S-S bonds (Scheme 14) [49]. When When diethyl(p-dimethylaminobenzoyl) phosphine sulfide was reacted with di(undecyl) disulfide in diethyl(p-dimethylaminobenzoyl) phosphine sulfide was reacted with di(undecyl) disulfide in the the presence of RhH(PPh3 4 3)4 (2 mol%) and dppe (4 mol%) in refluxing THF for 3 h, the corresponding presence of RhH(PPh3)4 (2(2 mol%)mol%) andand dppedppe (4(4 mol%)mol%) inin refluxingrefluxing THFTHF forfor 33 h,h, thethe correspondingcorresponding thioester was obtained in 90% yield, along with dithiophosphonate. thioester was obtained in 90% yield, along with dithiophosphonate.

SchemeScheme 14. InterconversionInterconversion reactions reactions between between acylphosphine acylphosphine sulfides sulﬁdes and thioesters.

Thioesters were converted to acylphosphine sulfides sulfides by reacting with diphosphine sulfides sulfides (Scheme 14)14)[ [49].49]. When When S-(p S-(-tolyl)p-tolyl) p-methoxybenzothioatep-methoxybenzothioate and andtetraethyldiphosphine tetraethyldiphosphine disulfides disulfides were were reacted in refluxing chlorobenzene for 6 h in the presence of RhH(PPh3 4 ) (5 mol%) and reacted in refluxing chlorobenzene for 6 h in the presence of RhH(PPh3)4 (5(53 mol%)4mol%) andand 1,2-1,2- (diethylphosphino)1,2-(diethylphosphino) ethane ethane (depe) (depe) (10 mol%), (10 mol%), acylph acylphosphineosphine sulfide sulfide was obtained was obtained in 55% in yield. 55% Thus, yield. interconversionThus, interconversion reactions reactions in an inopen an opensystem system occur occur between between thioesters thioesters and andacylphosphines acylphosphines in the in presencethe presence of appropriate of appropriate reagents, reagents, which which are are cata catalyzedlyzed by by rhodium rhodium complexes; complexes; i.e., i.e., organosulfur compounds and organophosphorus compounds may be interconverted.interconverted. On the basis of analysis of interconversion reacti reactionsons in open systems, it was suggested that the treatmenttreatment of of diphosphine diphosphine disulfides disulfides and and disulfides disulfides provides provides dithiophosphinates dithiophosphinates via via the the exchange exchange of P-Pof P-P bonds bonds and and S-S S-S bonds bonds (Figure (Figure 4)4)[ [48].48]. When When dioctyl dioctyl disulfide disulfide and tetramethyldiphosphinetetramethyldiphosphine disulfide were reacted under acetone reflux for 0.5 h in the presence of RhH(PPh 3)4 (1.5 mol%) and disulfide were reacted under acetone reflux for 0.5 h in the presence of RhH(PPh33)4 (1.5(1.5 mol%)mol%) andand dppe (3 mol%), thiophosphinate was obtained in 97% yield (Scheme 15).15). The The reaction reaction is is irreversible, irreversible, owing to to the the formation formation of of strong strong P- P-SS bonds bonds from from weak weak P-P P-P bonds. bonds. The The reaction reaction is also is also applicable applicable to diselenides.to diselenides.

Molecules 2020, 25, x FOR PEER REVIEW 14 of 35

Scheme 13. Organothio exchange reaction of dithiophosphinates.

Reactions of acylphosphine sulfides and disulfides provided dithiophosphinates and thioesters, which involved the formation of C-S and P-S bonds from C-P and S-S bonds (Scheme 14) [49]. When diethyl(p-dimethylaminobenzoyl) phosphine sulfide was reacted with di(undecyl) disulfide in the presence of RhH(PPh3)4 (2 mol%) and dppe (4 mol%) in refluxing THF for 3 h, the corresponding thioester was obtained in 90% yield, along with dithiophosphonate.

Scheme 14. Interconversion reactions between acylphosphine sulfides and thioesters.

Thioesters were converted to acylphosphine sulfides by reacting with diphosphine sulfides (Scheme 14) [49]. When S-(p-tolyl) p-methoxybenzothioate and tetraethyldiphosphine disulfides were reacted in refluxing chlorobenzene for 6 h in the presence of RhH(PPh3)4 (5 mol%) and 1,2- (diethylphosphino) ethane (depe) (10 mol%), acylphosphine sulfide was obtained in 55% yield. Thus, interconversion reactions in an open system occur between thioesters and acylphosphines in the presence of appropriate reagents, which are catalyzed by rhodium complexes; i.e., organosulfur compounds and organophosphorus compounds may be interconverted. On the basis of analysis of interconversion reactions in open systems, it was suggested that the treatment of diphosphine disulfides and disulfides provides dithiophosphinates via the exchange of P-P bonds and S-S bonds (Figure 4) [48]. When dioctyl disulfide and tetramethyldiphosphine disulfide were reacted under acetone reflux for 0.5 h in the presence of RhH(PPh3)4 (1.5 mol%) and dppe (3 mol%), thiophosphinate was obtained in 97% yield (Scheme 15). The reaction is irreversible, Moleculesowing to2020 the, 25 formation, 3595 of strong P-S bonds from weak P-P bonds. The reaction is also applicable15 of 35to diselenides.

Molecules 2020,, 25,, xx FORFOR PEERPEER REVIEWREVIEW 15 of 35

Scheme 15. Exchange reaction of diphosphine disulfides and disulfides. Scheme 15. Exchange reaction of diphosphine disulﬁdes and disulﬁdes.

The reactionreaction of of hydrophilic hydrophilic disulﬁdes disulfides and diphosphonates,and diphosphonates, which which are also are water-soluble, also water-soluble, proceeds proceedsin water in in the water presence in the of presence RhCl3 (Scheme of RhCl 1633 (Scheme(Scheme)[50]. Glutathione 16)16) [50].[50]. GlutathioneGlutathione disulﬁde was disulfidedisulfide reacted waswas with reactedreacted tetramethyl withwith tetramethyldiphosphonatetetramethyl diphosphonatediphosphonate in water at in 40in waterwater◦C for atat 36 4040 h °C°C in theforfor presence3636 hh inin thethe of RhClpresencepresence3 (10 ofof mol%), RhClRhCl33 and(10(10 mol%),mol%), glutathione andand glutathionephosphonate phosphonate was obtained was in 77%obtained yield. in 77% yield.

SchemeScheme 16. 16. ExchangeExchange reaction reaction of of diphosphine diphosphine disulfides disulﬁdes and disulfides disulﬁdes in water.

Polyphosphines are are compounds containing containing ph phosphorusosphorus atoms atoms with with two two P-P bonds and one organic group, and they exhibit reactivities diff different from thosethose ofof diphosphines,diphosphines, which contain phosphorus atoms with one P-P bond and two two orga organicnic groups. Polyphosphines Polyphosphines undergoundergo substitutionsubstitution reactions with disulfides, disulfides, which which involve involve the the ex exchangechange of of P-P P-P and and S-S S-S bonds bonds (Scheme (Scheme 17)17)[ [51].51]. Pentaphenylcyclopentaphosphine was reacted with dihexyl disulfide in the presence of RhH(dppe) Pentaphenylcyclopentaphosphine was reacted with dihexyl disulfide in the presence of RhH(dppe)22 (5(5 mol%)mol%) mol%) inin in THFTHF THF refluxreflux reflux forfor for 1515 15min,min, min, whichwhich which producedproduced produced dihexyldihexyl dihexyl phenylphosphonodithionitephenylphosphonodithionite phenylphosphonodithionite inin 94%94% in yield.yield. 94% Whenyield. Whencyclic disulfides cyclic disulfides are employed, are employed, novel novelheterocyclic heterocyclic phosphonodithinites phosphonodithinites are obtained. are obtained. The intermediateTheintermediate intermediate formationformation formation ofof aa ofdiphosphene–rhodiumdiphosphene–rhodium a diphosphene–rhodium complexcomplex complex waswas wasshownshown shown byby spectroscopicspectroscopic by spectroscopic andand andMSMS analyses.MS analyses.

Scheme 17. ExchangeExchange reaction reaction of of cyclop cyclopentaphosphineentaphosphine and disulfides. disulﬁdes.

A rhodium rhodium catalyst catalyst promoted promoted the the cleavage cleavage of ofC-P C-P bonds bonds in heteroaryl in heteroarylphosphinephosphine sulfides sulfides and exchangeand exchange with disulfides with disulfides (Schem (Schemee 18) [52]. 18 When)[52 ].(2-benzothiazoly When (2-benzothiazolyl)l)l) dimethylphosphinedimethylphosphine dimethylphosphine sulfidesulfide waswas reactedsulfide waswith reacted dioctyl with disulfide dioctyl disulfide inin thethe in presencepresence the presence ofof ofRhH(PPhRhH(PPh RhH(PPh33))443 )4(10(10(10 mol%)mol%)mol%) andandand 1,2-bis 1,2-1,2- bis(dimethylphosphino)benzene(dimethylphosphino)benzene (dmppBz) (dmppBz)(dmppBz) (20 mol%)(20(20 mol%)mol%) in refluxing inin refluxingrefluxing chlorobenzene chlorobenzenechlorobenzene for 3 h, 2-(octylthio)forfor 33 h,h, 2-2- (octylthio)benzothiazole(octylthio) benzothiazolebenzothiazole was obtained waswas in obtainedobtained 46% yield. inin 46%46% yield.yield. The reverse reaction converts heteroaryl sulfides to heteroarylphosphine sulfides in the presence of diphosphine disulfides (Scheme 18)[52,53]. When 2-(p-tolylthio)-1,3-benzothiazole and tetraethyldiphosphine disulfides were reacted in refluxing chlorobenzene for 6 h in the presence of RhH(PPh3)4 (5 mol%) and 1,2-(diethylphosphino) ethane (depe) (10 mol%), 2-(diethylphosphino)-

Molecules 2020, 25, x FOR PEER REVIEW 15 of 35

Scheme 15. Exchange reaction of diphosphine disulfides and disulfides.

The reaction of hydrophilic disulfides and diphosphonates, which are also water-soluble, proceeds in water in the presence of RhCl3 (Scheme 16) [50]. Glutathione disulfide was reacted with tetramethyl diphosphonate in water at 40 °C for 36 h in the presence of RhCl3 (10 mol%), and glutathione phosphonate was obtained in 77% yield.

Scheme 16. Exchange reaction of diphosphine disulfides and disulfides in water.

Polyphosphines are compounds containing phosphorus atoms with two P-P bonds and one organic group, and they exhibit reactivities different from those of diphosphines, which contain phosphorus atoms with one P-P bond and two organic groups. Polyphosphines undergo substitution reactions with disulfides, which involve the exchange of P-P and S-S bonds (Scheme 17) [51]. Pentaphenylcyclopentaphosphine was reacted with dihexyl disulfide in the presence of RhH(dppe)2 (5 mol%) in THF reflux for 15 min, which produced dihexyl phenylphosphonodithionite in 94% yield. When cyclic disulfides are employed, novel heterocyclic phosphonodithinites are obtained. The intermediate formation of a diphosphene–rhodium complex was shown by spectroscopic and MS analyses.

Scheme 17. Exchange reaction of cyclopentaphosphine and disulfides.

MoleculesA rhodium2020, 25, 3595 catalyst promoted the cleavage of C-P bonds in heteroarylphosphine sulfides16 ofand 35 Molecules 2020, 25, x FOR PEER REVIEW 16 of 35 exchange with disulfides (Scheme 18) [52]. When (2-benzothiazolyl) dimethylphosphine sulfide was reacted with dioctyl disulfide in the presence of RhH(PPh3)4 (10 mol%) and 1,2- 1,3-benzothiazolebis(dimethylphosphino)benzene sulﬁde was obtained (dmppBz) in 49% yield. (20 mol%) This is anotherin refluxing example chlorobenzene of interconversion for reactions3 h, 2- in(octylthio) an open system,benzothiazole in which was organophosphorus obtained in 46% yield. and organosulfur compounds are interconverted.

MoleculesScheme 2020, 25 18., x Interconversion FOR PEER REVIEW reactions of heterocyclic phosphine sulfides and heterocyclic sulfides. 16 of 35

The reverse reaction converts heteroaryl sulfides to heteroarylphosphine sulfides in the presence of diphosphine disulfides (Scheme 18) [52,53]. When 2-(p-tolylthio)-1,3-benzothiazole and tetraethyldiphosphine disulfides were reacted in refluxing chlorobenzene for 6 h in the presence of RhH(PPh3)4 (5 mol%) and 1,2-(diethylphosphino) ethane (depe) (10 mol%), 2-(diethylphosphino)-1,3- benzothiazole sulfide was obtained in 49% yield. This is another example of interconversion reactions in an open system, in which organophosphorus and organosulfur compounds are interconverted.

4. Rhodium-Catalyzed Insertion Reactions Using Disulfides Insertion reactions of disulfides and alkynes/alkenes are generally exothermic, involving the conversion of high-energy unsaturated compounds to low-energy less unsaturated compounds. Previously reported palladium-catalyzed insertion reactions of disulfides with alkynes in general employed diaryl disulfidesSchemeScheme [21,23]. 19. 19. InsertionInsertion Rhodium-catalyzed reaction reaction of of di disulfidessulfides insertion and and 1-alkynes. 1-alkynes. of 1-akynes may be applied to aliphatic disulfides, which are less reactive than aromatic disulfides (Scheme 19) [54]. AWhenWhen mixture 1-octyne1-octyne of a disulfide andand diethyldiethyl and disulfide disulfidea diselenide were were predominantly reacted reacted in in refluxing refluxing provides acetone acetone 1-seleno-2-thioalkene, for for 10 10 h inh in the the presence presence which of isRhH(PPhof accompanied RhH(PPh3)43)(44 (4 mol%),by mol%), minor trifluoromethanesulfonic trifluoromethanesulfonic amounts of other insert acid ion products(4 (4 mol%), mol%), (Schemeand and (p-MeOC (p -MeOC20) [55].6H64H) 3WhenP4) (143P (14mol%), 1-octyne, mol%), 1,2- diphenyl1,2-bis(alkylthio)-1-alkenebis(alkylthio)-1-alkene disulfide, and withdiphenyl with the Z-configuration diselenide the Z-configuration were was reacted obtained was in obtainedrefluxing in 93% yield. inacetone 93% The for yield. proposed 4 h in The the mechanism proposedpresence ofmechanisminvolves RhH(PPh the3involves )oxidative4 (5 mol%) the addition oxidativeand 1,4-(diphenylphosphino) of low-valent addition of rhodium low-valent andbutane rhodiuma disulfide, (dppb) and followed(10 a disulfide,mol%), by 2-butylthio-1-the followed transfer byof butylseleno-1-octenethetwo transfer organothio of two groups organothio was to 1-alkyne.obtained groups in to 1-alkyne.72% yield. The reaction is also applicable to dialkyl disulfides/diselenides.A mixture of a disulfide The reaction and a diselenideis under chemic predominantlyal equilibrium provides of disulfide/diselenide 1-seleno-2-thioalkene, exchange, which is inaccompanied which selenosulfides by minor amountsare selectively of other transferred insertionproducts to 1-alkynes. (Scheme 20)[55]. When 1-octyne, diphenyl disulfide, and diphenyl diselenide were reacted in refluxing acetone for 4 h in the presence of RhH(PPh3)4 (5 mol%) and 1,4-(diphenylphosphino) butane (dppb) (10 mol%), 2-butylthio-1-butylseleno-1-octene was obtained in 72% yield. The reaction is also applicable to dialkyl disulfides/diselenides. The reaction is under chemical equilibrium of disulfide/diselenide exchange, in which selenosulfides are selectively Scheme 19. Insertion reaction of disulfides and 1-alkynes. transferred to 1-alkynes. A mixture of Schemea disulfide 20. Insertion and a diselenide reaction of predominantly disulfides/diselenides provides and 1-alkynes.1-seleno-2-thioalkene, which is accompanied by minor amounts of other insertion products (Scheme 20) [55]. When 1-octyne, diphenyl disulfide, and diphenyl diselenide were reacted in refluxing acetone for 4 h in the presence of RhH(PPh3)4 (5 mol%) and 1,4-(diphenylphosphino) butane (dppb) (10 mol%), 2-butylthio-1- butylseleno-1-octene was obtained in 72% yield. The reaction is also applicable to dialkyl disulfides/diselenides. The reaction is under chemical equilibrium of disulfide/diselenide exchange, in which selenosulfides are selectively transferred to 1-alkynes.

Scheme 20. Insertion reaction of disulfides/diselenides and 1-alkynes.

Molecules 2020, 25, x FOR PEER REVIEW 16 of 35

Scheme 18. Interconversion reactions of heterocyclic phosphine sulfides and heterocyclic sulfides.

Scheme 19. Insertion reaction of disulfides and 1-alkynes.

A mixture of a disulfide and a diselenide predominantly provides 1-seleno-2-thioalkene, which is accompanied by minor amounts of other insertion products (Scheme 20) [55]. When 1-octyne, diphenyl disulfide, and diphenyl diselenide were reacted in refluxing acetone for 4 h in the presence of RhH(PPh3)4 (5 mol%) and 1,4-(diphenylphosphino) butane (dppb) (10 mol%), 2-butylthio-1- butylseleno-1-octene was obtained in 72% yield. The reaction is also applicable to dialkyl disulfides/diselenides.Molecules 2020, 25, 3595 The reaction is under chemical equilibrium of disulfide/diselenide exchange,17 of 35 in which selenosulfides are selectively transferred to 1-alkynes.

MoleculesMolecules 2020 2020, 25, 25, x, xFOR FORSchemeScheme PEER PEER REVIEW REVIEW20. InsertionInsertion reaction reaction of of disulfides/diselenides disulﬁdes/diselenides and 1-alkynes. 1717 of of 35 35

TheTheThe reaction reaction reaction of of allene of allene allene in in place place in placeof of 1-alkyne 1-alkyne of 1-alkyne prov providesides provides a adifferent different a variety variety different of of products varietyproducts (Scheme of (Scheme products 21) 21) (Scheme 21)[56]. When 1,2-octadiene and dibutyl disulfide were reacted in refluxing acetone [56]. [56]. When When 1,2-octadiene 1,2-octadiene and and dibutyl dibutyl disulfide disulfide we werere reacted reacted in in refluxing refluxing acetone acetone for for 2 2h h in in the the for 2 h in the presence of RhH(PPh3)4 (3 mol%), trifluoromethanesulfonic acid (3 mol%), and (p-tol)3P presencepresence of of RhH(PPh RhH(PPh3)34) (34 (3 mol%), mol%), trifluoromethanesulfonic trifluoromethanesulfonic acid acid (3 (3 mol%), mol%), and and ( p(-tol)p-tol)3P3P (12 (12 mol%), mol%), 2- 2- (butylthio)-1,3-octadiene(12(butylthio)-1,3-octadiene mol%), 2-(butylthio)-1,3-octadiene and and (E(E)-2-(butylthio)-2-octene)-2-(butylthio)-2-octene and (E)-2-(butylthio)-2-octene werewere bothboth were obtainedobtained both obtainedin in 47%47% in yields.yields. 47% yields. TwoTwo organothioTwoorganothio organothio groups groups groups are are transferred transferred are transferred to to two two to allene allene two allenemolecules molecules molecules with with concomitant withconcomitant concomitant hydride hydride hydride transfer. transfer. transfer. This This reactionThisreaction reaction is is also also is applicable alsoapplicable applicable to to diselenides. diselenides. to diselenides.

SchemeSchemeScheme 21. 21.21. Insertion InsertionInsertion reaction reactionreaction of ofof allenes allenesallenes and andand disulfides. disulﬁdes.disulfides.

TheTheThe α αα-insertion-insertion-insertion reaction reactionreaction of ofof carbon carboncarbon monoxide monoxidemonoxide with withwith disulfide disulfidedisulfide occurred occurredoccurred to toto provide provideprovide dithiocarbonate dithiocarbonatedithiocarbonate (Scheme(Scheme(Scheme 22)22 22))[ [36].36 [36].]. WhenWhen When dibutyldibutyl dibutyl disulfide disulfide disulfide was was was treated treate treate withdd with with carbon carbon carbon monoxide monoxide monoxide at 30 at atmat 30 30 inatm atm toluene in in toluene toluene at 180 ◦at Cat 180for180 24°C °C h for infor the 24 24 presenceh h in in the the of presence RhH(PPhpresence 3of )of4 (10RhH(PPh RhH(PPh mol%)3 and)34) 4(10 (10 dppe mol%) mol%) (20 mol%), and and dppe dibutyldppe (20 (20S ,mol%), Smol%),’-dithiocarbonate dibutyl dibutyl S S, was,S S’-’- dithiocarbonateobtaineddithiocarbonate in 15% was yield.was obtained obtained This reaction in in 15% 15% is yield. underyield. This equilibriumThis re reactionaction and is is under favorsunder equilibrium disulfideequilibrium and and and carbon favors favors monoxide disulfide disulfide at andambientand carbon carbon pressure monoxide monoxide as well at at ambient asambient at 30 atm.pressure pressure Rhodium-catalyzed as as well well as as at at 30 30α -insertionatm. atm. Rhodium-catalyzed Rhodium-catalyzed reactions of carbenoids α α-insertion-insertion and reactionsdisulfidesreactions of of have carbenoids carbenoids been reported and and disulf disulf [57ides,58ides]. have have been been reported reported [57,58]. [57,58].

SchemeSchemeScheme 22. 22.22. Insertion InsertionInsertion reaction reactionreaction of ofof carbon carboncarbon monoxide monoxidemonoxide and andand disulfide. disulfide.disulfide. 5. Rhodium-Catalyzed Reduction/Oxidation Reactions of Disulfides 5.5. Rhodium-Catalyzed Rhodium-Catalyzed Reduction/Oxidation Reduction/Oxidation Reactions Reactions of of Disulfides Disulfides Interconversion of a disulfide and two thiols is an important chemical reaction in organosulfur InterconversionInterconversion of of a adisulfide disulfide and and two two thiols thiols is is an an important important chemical chemical reaction reaction in in organosulfur organosulfur chemistry. Various methods have been reported for the reduction of disulfides to thiols using different chemistry.chemistry. Various Various methods methods have have been been reported reported for for the the reduction reduction of of disulfides disulfides to to thiols thiols using using reducing reagents. Hydrogenation may be the most convenient in terms of availability of reducing differentdifferent reducing reducing reagents. reagents. Hydrogenation Hydrogenation may may be be the the most most convenient convenient in in terms terms of of availability availability of of reagent and simple operations, which is also achieved by rhodium catalysis (Scheme 23). When di(octyl) reducingreducing reagent reagent and and simple simple operations, operations, which which is is also also achieved achieved by by rhodium rhodium catalysis catalysis (Scheme (Scheme 23). 23). disulfide was treated with hydrogen at 1 atm in the presence of RhH(PPh3)4 (0.5 mol%) in refluxing WhenWhen di(octyl) di(octyl) disulfide disulfide was was treated treated with with hydr hydrogenogen at at 1 1atm atm in in the the presence presence of of RhH(PPh RhH(PPh3)34) (0.54 (0.5 mol%) mol%) toluene for 0.5 h, 1-octanethiol was obtained in 90% yield [59]. Care to deactivate a rhodium complex inin refluxing refluxing toluene toluene for for 0.5 0.5 h, h, 1-octanethiol 1-octanethiol was was ob obtainedtained in in 90% 90% yield yield [59]. [59]. Care Care to to deactivate deactivate a a is critical during quenching of the reaction because thiols are rapidly converted to disulfide under air rhodiumrhodium complex complex is is critical critical during during quenching quenching of of the the reaction reaction because because thiols thiols are are rapidly rapidly converted converted to to in the presence of the rhodium complex. Metal-catalyzed hydrogenolysis of disulfides to thiols has disulfidedisulfide under under air air in in the the presence presence of of the the rhod rhodiumium complex. complex. Metal-catalyzed Metal-catalyzed hydrogenolysis hydrogenolysis of of been rare, which may be because of catalyst poisoning by thiols. disulfidesdisulfides to to thiols thiols has has been been rare, rare, which which may may be be because because of of catalyst catalyst poisoning poisoning by by thiols. thiols. The reverse reaction, oxidation of thiols to disulfides, is also catalyzed by the rhodium complex using oxygen as the oxidation reagent (Scheme 23)[59]. Treatment with 1-octanethiol under oxygen at 1 atm in methanol at 0 ◦C for 1 h in the presence of RhH(PPh3)4 (0.1 mol%) and 1,4-bis(diphenylphosphino)butane (dppb) (0.2 mol%) provided dioctyl disulfide in 93% yield.

SchemeScheme 23. 23. Interconversion Interconversion reactions reactions of of disulfides disulfides and and thiols. thiols.

TheThe reverse reverse reaction, reaction, oxidation oxidation of of thiols thiols to to disulfides, disulfides, is is also also catalyzed catalyzed by by the the rhodium rhodium complex complex usingusing oxygen oxygen as as the the oxidation oxidation reagent reagent (Scheme (Scheme 23) 23) [59]. [59]. Treatment Treatment with with 1-octanethiol 1-octanethiol under under oxygen oxygen

Molecules 2020, 25, x FOR PEER REVIEW 17 of 35

The reaction of allene in place of 1-alkyne provides a different variety of products (Scheme 21) [56]. When 1,2-octadiene and dibutyl disulfide were reacted in refluxing acetone for 2 h in the presence of RhH(PPh3)4 (3 mol%), trifluoromethanesulfonic acid (3 mol%), and (p-tol)3P (12 mol%), 2- (butylthio)-1,3-octadiene and (E)-2-(butylthio)-2-octene were both obtained in 47% yields. Two organothio groups are transferred to two allene molecules with concomitant hydride transfer. This reaction is also applicable to diselenides.

Scheme 21. Insertion reaction of allenes and disulfides.

The α-insertion reaction of carbon monoxide with disulfide occurred to provide dithiocarbonate (Scheme 22) [36]. When dibutyl disulfide was treated with carbon monoxide at 30 atm in toluene at 180 °C for 24 h in the presence of RhH(PPh3)4 (10 mol%) and dppe (20 mol%), dibutyl S, S’- dithiocarbonate was obtained in 15% yield. This reaction is under equilibrium and favors disulfide and carbon monoxide at ambient pressure as well as at 30 atm. Rhodium-catalyzed α-insertion reactions of carbenoids and disulfides have been reported [57,58].

Scheme 22. Insertion reaction of carbon monoxide and disulfide.

5. Rhodium-Catalyzed Reduction/Oxidation Reactions of Disulfides Interconversion of a disulfide and two thiols is an important chemical reaction in organosulfur chemistry. Various methods have been reported for the reduction of disulfides to thiols using different reducing reagents. Hydrogenation may be the most convenient in terms of availability of reducing reagent and simple operations, which is also achieved by rhodium catalysis (Scheme 23). Molecules 2020, 25, 3595 18 of 35 When di(octyl) disulfide was treated with hydrogen at 1 atm in the presence of RhH(PPh3)4 (0.5 mol%) in refluxing toluene for 0.5 h, 1-octanethiol was obtained in 90% yield [59]. Care to deactivate a rhodiumThese complex interconversion is critical reactions during quenching in open systems of the canreaction be a convenientbecause thiols method are rapidly for the developmentconverted to disulfideof molecular under switching air in functions,the presence which of employthe rhod hydrogenium complex. as the Metal-catalyzed reducing reagent hydrogenolysis and oxygen as theof disulfidesoxidizing reagent.to thiols has been rare, which may be because of catalyst poisoning by thiols.

Molecules 2020, 25, x FOR PEER REVIEW 18 of 35 at 1 atm in methanol at 0 °C for 1 h in the presence of RhH(PPh3)4 (0.1 mol%) and 1,4- bis(diphenylphosphino)butane (dppb) (0.2 mol%) provided dioctyl disulfide in 93% yield. These interconversion reactions in open systems can be a convenient method for the development of molecular switching functions, which employ hydrogen as the reducing reagent and oxygen as the oxidizing reagent. Scheme 23. InterconversionInterconversion reactions reactions of disulfides disulﬁdes and thiols.

6.6. Rhodium-Catalyzed Rhodium-Catalyzed Reactions Reactions of of Sulfur Sulfur The reverse reaction, oxidation of thiols to disulfides, is also catalyzed by the rhodium complex usingSulfurSulfur oxygen isis a as readilya thereadily oxidation available available reagent source source of(Scheme organosulfur of 23)or ganosulfur[59]. compounds Treatment compounds in with organic 1-octanethiol synthesis.in organic under Conventional synthesis. oxygen Conventionalmethods using methods sulfur generallyusing sulfur employ generally the formation employ the of thiylformation radicals, of thiyl which radicals, are generated which are by generated by heating above the melting point of sulfur (115 °C) [30]. Several previously reported heating above the melting point of sulfur (115 ◦C) [30]. Several previously reported metal-catalyzed metal-catalyzedmethods employ highmethods temperatures, employ high which temperatures, likely involve radical-which andlikely metal-catalyzed involve radical- mechanisms and metal- and catalyzedaccordingly mechanisms are not easy and to analyzeaccordingly and control.are not easy To secure to analyze the eff ectand of control. metal catalysis,To secure we the conducted effect of metalrhodium-catalyzed catalysis, we conducted reactions of rhodium-catalyzed sulfur well below reactions the melting of point.sulfur Thewell reactivitybelow the of melting sulfur canpoint. be Thedifferent reactivity from of disulfide, sulfur can and be Rh-S-S different intermediates from disulfide, formed and from Rh-S-S sulfur intermediates can exhibit formed different from reactivities sulfur canfrom exhibit Rh-S-C different intermediates reactivities formed from from Rh-S-C disulfides intermediates because offormed the presence from disulfides of the adjacent because weak of the S-S presencebonds in of the the latter. adjacent weak S-S bonds in the latter. IntroductionIntroduction of of sulfur sulfur atoms atoms between between S-S S-S bonds bonds in in disulfides disulfides provides provides polysulfides, polysulfides, and and such such reactionsreactions occur above the meltingmelting pointpoint andand involveinvolve radicalradical mechanisms.mechanisms. Rhodium-catalyzed reactions proceed at much lower temperatures [60]. In the presence of RhH(PPh3)4 (2.5 mol%) and reactions proceed at much lower temperatures [60]. In the presence of RhH(PPh3)4 (2.5 mol%) 1,2-bis(diphenylphosphino)etheneand 1,2-bis(diphenylphosphino)ethene (dppv) (dppv) (5 mol%), (5 mol%), dibutyl dibutyl trisulfide trisulfide and andsulfur sulfur were were reacted reacted in acetonein acetone at room at room temperature temperature for 5 for min, 5 min, and dibutyl and dibutyl tetrasulfide, tetrasulfide, pentasulfide, pentasulfide, and hexasulfide and hexasulfide were obtainedwere obtained in 39, in14, 39, and 14, 8% and yields, 8% yields, respectively, respectively, accompanied accompanied by higher by higher homologs homologs (Scheme (Scheme 24). The 24). reactionThe reaction occurred occurred rapidly rapidly and and provided provided a mixture a mixture of ofpolysulfides. polysulfides. Aliphatic Aliphatic disulfides disulfides were were not not reactivereactive underunder thesethese conditions. conditions. In In contrast, contrast, diaryl diaryl disulfides disulfides effectively effectively reacted reacted with sulfur with tosulfur provide to providepolysulfides, polysulfides, including including trisulfides, trisulfides, tetrasulfides, tetrasulfides, and pentasulfides. and pentasulfides.

Scheme 24. Insertion reaction of sulfur and disulfides. Scheme 24. Insertion reaction of sulfur and disulfides. Thioisonitriles were synthesized by sulfuration of isonitriles under rhodium-catalyzed conditions, Thioisonitriles were synthesized by sulfuration of isonitriles under rhodium-catalyzed which resulted in the 1,1-insertion of sulfur at the nitrogen atom of the C=N bond (Scheme 25)[61]. conditions, which resulted in the 1,1-insertion of sulfur at the nitrogen atom of the C=N bond (Scheme The reaction of cyclohexylisonitrile and sulfur under acetone reflux for 2 h in the presence of RhH(PPh3)4 25) [61]. The reaction of cyclohexylisonitrile and sulfur under acetone reflux for 2 h in the presence of (1 mol%) provided thioisonitrile in 91% yield in 2 h. The reaction is faster than the known molybdenum RhH(PPh3)4 (1 mol%) provided thioisonitrile in 91% yield in 2 h. The reaction is faster than the known method developed by Bargon [62]. Trisulfides and tetrasulfides can also react under rhodium catalysis. molybdenum method developed by Bargon [62]. Trisulfides and tetrasulfides can also react under An induction period was observed with an initially slow reaction for 40 min followed by a rapid rhodium catalysis. An induction period was observed with an initially slow reaction for 40 min followed by a rapid reaction completed in 100 min. The phenomenon was ascribed to the slow formation of active sulfur species because preheating sulfur in acetone for 1.5 h eliminated the induction period.

Scheme 25. Insertion reaction of sulfur and thioisonitriles.

6. Rhodium-Catalyzed Reactions of Sulfur Sulfur is a readily available source of organosulfur compounds in organic synthesis. Conventional methods using sulfur generally employ the formation of thiyl radicals, which are generated by heating above the melting point of sulfur (115 °C) [30]. Several previously reported metal-catalyzed methods employ high temperatures, which likely involve radical- and metal- catalyzed mechanisms and accordingly are not easy to analyze and control. To secure the effect of metal catalysis, we conducted rhodium-catalyzed reactions of sulfur well below the melting point. The reactivity of sulfur can be different from disulfide, and Rh-S-S intermediates formed from sulfur can exhibit different reactivities from Rh-S-C intermediates formed from disulfides because of the presence of the adjacent weak S-S bonds in the latter. Introduction of sulfur atoms between S-S bonds in disulfides provides polysulfides, and such reactions occur above the melting point and involve radical mechanisms. Rhodium-catalyzed reactions proceed at much lower temperatures [60]. In the presence of RhH(PPh3)4 (2.5 mol%) and 1,2-bis(diphenylphosphino)ethene (dppv) (5 mol%), dibutyl trisulfide and sulfur were reacted in acetone at room temperature for 5 min, and dibutyl tetrasulfide, pentasulfide, and hexasulfide were obtained in 39, 14, and 8% yields, respectively, accompanied by higher homologs (Scheme 24). The reaction occurred rapidly and provided a mixture of polysulfides. Aliphatic disulfides were not reactive under these conditions. In contrast, diaryl disulfides effectively reacted with sulfur to provide polysulfides, including trisulfides, tetrasulfides, and pentasulfides.

Scheme 24. Insertion reaction of sulfur and disulfides.

Thioisonitriles were synthesized by sulfuration of isonitriles under rhodium-catalyzed conditions, which resulted in the 1,1-insertion of sulfur at the nitrogen atom of the C=N bond (Scheme 25) [61]. The reaction of cyclohexylisonitrile and sulfur under acetone reflux for 2 h in the presence of RhH(PPh3)4 (1 mol%) provided thioisonitrile in 91% yield in 2 h. The reaction is faster than the known molybdenumMolecules 2020, 25 method, 3595 developed by Bargon [62]. Trisulfides and tetrasulfides can also react under19 of 35 rhodium catalysis. An induction period was observed with an initially slow reaction for 40 min followed by a rapid reaction completed in 100 min. The phenomenon was ascribed to the slow formationreaction completed of active insulfur 100min. species The because phenomenon prehea wasting ascribed sulfur toin theacetone slow formationfor 1.5 h eliminated of active sulfur the inductionspecies because period. preheating sulfur in acetone for 1.5 h eliminated the induction period.

Scheme 25. Insertion reaction of sulfur and thioisonitriles. Molecules 2020, 25, x FOR PEERScheme REVIEW 25. Insertion reaction of sulfur and thioisonitriles. 19 of 35 Symmetric diaryl sulfides are synthesized from perfluorobenzene and sulfur involving Symmetric diaryl sulfides are synthesized from perfluorobenzene and sulfur involving C-F bond C-F bond activation, which showed reactivity and the p-difluoride rule similar to disulfides activation, which showed reactivity and the p-difluoride rule similar to disulfides (Scheme 26) [63]. (Scheme 26)[63]. Treatment of 4-phenylthiopentafluorobenzene, sulfur, and tributylsilane in DMF Treatment of 4-phenylthiopentafluorobenzene, sulfur, and tributylsilane in DMF at room at room temperature in the presence of RhH(PPh3)4 (5 mol%) and dppBz (10 mol%) provided temperature in the presence of RhH(PPh3)4 (5 mol%) and dppBz (10 mol%) provided bis(4-cyano-2,3- bis(4-cyano-2,3-5,6-tetrafluorophenyl) sulfides in 77% yield. Fluorides were trapped by trialkylsilane 5,6-tetrafluorophenyl) sulfides in 77% yield. Fluorides were trapped by trialkylsilane giving silyl giving silyl fluoride. Aromatic fluorides in place of polyfluorobenzenes also reacted, provided that fluoride. Aromatic fluorides in place of polyfluorobenzenes also reacted, provided that electron- electron-withdrawing groups were attached. Trisulfide and tetrasulfide may also be used as the sulfur withdrawing groups were attached. Trisulfide and tetrasulfide may also be used as the sulfur source, source, but they exhibit reactivities different from those of sulfur. but they exhibit reactivities different from those of sulfur.

Scheme 26. InsertionInsertion reaction reaction of of sulfur sulfur and and aryl aryl fluorides. ﬂuorides.

Thiiranes are are three-membered heterocyclic ring compounds containing containing a a sulfur atom, and the insertioninsertion reaction reaction of of a sulfur a sulfur atom atom at the at alkene the alkene C=C bond C=C is bond a convenient is a convenient method for method their synthesis for their [64].synthesis The reaction [64]. The may reaction be efficiently may be econductedﬃciently conductedby rhodium by catalysis rhodium (Scheme catalysis 27) (Scheme [65]. When 27)[65 7-]. oxabenzonorbornene,When 7-oxabenzonorbornene, sulfur, and sulfur, p-tolylacetylene and p-tolylacetylene were werereacted reacted in the in presence the presence of RhH(PPh of RhH(PPh3)4 3(5)4 mol%)(5 mol%) and and dppe dppe (10 (10mol%) mol%) in refluxing in reﬂuxing acetone acetone for 3 for h, 3exo-thiirane h, exo-thiirane was wasobtained obtained in 91% in 91%yield. yield. The acetyleneThe acetylene added added stabilizes stabilizes the therhodium rhodium intermediates. intermediates. The The isolated isolated RhH(dppe) RhH(dppe)22 alsoalso exhibited catalytic activity.activity. The The reaction reaction is applicableis applicable to reactive to reactive alkenes, alkenes, including including bicyclo[2.2.1]heptenes, bicyclo[2.2.1]heptenes, allenes, allenes,and (Z)-cyclooctene. and (Z)-cyclooctene.

Scheme 27. InsertionInsertion reaction reaction of of sulfur sulfur and and alkene. alkene.

1,4-Dithiine isis a nonaromatica nonaromatic six-membered six-membered ring heterocyclicring heterocyclic compound compound with a nonplanarwith a nonplanar structure. structure.Dithiines Dithiines are synthesized are synthesized by the rhodium-catalyzed by the rhodium-catalyzed reaction reaction of reactive of reactive alkynes alkynes and sulfur, and sulfur, which whichinvolves involves an insertion an insertion reaction reaction of an alkyne of an betweenalkyne between a S-S bond a S-S of bond sulfur of (Scheme sulfur (Scheme 28)[66]. 28) The [66]. reaction The of cyclooctyne and sulfur in reﬂuxing 2-butanone for 3 h in the presence of RhH(PPh ) (5 mol%) and reaction of cyclooctyne and sulfur in refluxing 2-butanone for 3 h in the presence of3 4RhH(PPh3)4 (5 mol%)dppe (10 and mol%) dppe provided(10 mol%) tricyclic provided dithiine tricyclic in 53%dithii yield.ne in When53% yield. acetylenedicarboxylate When acetylenedicarboxylate was added, wasunsymmetric added, unsymmetric dithiine was dithiine selectively was obtained selectively without obtained the formation without ofthe a formation symmetric of dithiine. a symmetric dithiine.Rhodium-catalyzed synthesis of organosulfur compounds using sulfur has high potential in organic synthesis because it proceeds well below the melting point of sulfur. An interesting consideration is their application to less reactive substrates such as unstrained alkenes and alkynes, which may be developed employing thermodynamically favorable reaction systems.

Scheme 28. Insertion reaction of sulfur and alkyne.

Rhodium-catalyzed synthesis of organosulfur compounds using sulfur has high potential in organic synthesis because it proceeds well below the melting point of sulfur. An interesting consideration is their application to less reactive substrates such as unstrained alkenes and alkynes, which may be developed employing thermodynamically favorable reaction systems.

7. Reversible Nature of Rhodium-Catalyzed C-S Bond Formation

Molecules 2020, 25, x FOR PEER REVIEW 19 of 35

Symmetric diaryl sulfides are synthesized from perfluorobenzene and sulfur involving C-F bond activation, which showed reactivity and the p-difluoride rule similar to disulfides (Scheme 26) [63]. Treatment of 4-phenylthiopentafluorobenzene, sulfur, and tributylsilane in DMF at room temperature in the presence of RhH(PPh3)4 (5 mol%) and dppBz (10 mol%) provided bis(4-cyano-2,3- 5,6-tetrafluorophenyl) sulfides in 77% yield. Fluorides were trapped by trialkylsilane giving silyl fluoride. Aromatic fluorides in place of polyfluorobenzenes also reacted, provided that electron- withdrawing groups were attached. Trisulfide and tetrasulfide may also be used as the sulfur source, but they exhibit reactivities different from those of sulfur.

Scheme 26. Insertion reaction of sulfur and aryl fluorides.

Thiiranes are three-membered heterocyclic ring compounds containing a sulfur atom, and the insertion reaction of a sulfur atom at the alkene C=C bond is a convenient method for their synthesis [64]. The reaction may be efficiently conducted by rhodium catalysis (Scheme 27) [65]. When 7- oxabenzonorbornene, sulfur, and p-tolylacetylene were reacted in the presence of RhH(PPh3)4 (5 mol%) and dppe (10 mol%) in refluxing acetone for 3 h, exo-thiirane was obtained in 91% yield. The acetylene added stabilizes the rhodium intermediates. The isolated RhH(dppe)2 also exhibited catalytic activity. The reaction is applicable to reactive alkenes, including bicyclo[2.2.1]heptenes, allenes, and (Z)-cyclooctene.

Scheme 27. Insertion reaction of sulfur and alkene.

1,4-Dithiine is a nonaromatic six-membered ring heterocyclic compound with a nonplanar structure. Dithiines are synthesized by the rhodium-catalyzed reaction of reactive alkynes and sulfur, which involves an insertion reaction of an alkyne between a S-S bond of sulfur (Scheme 28) [66]. The reaction of cyclooctyne and sulfur in refluxing 2-butanone for 3 h in the presence of RhH(PPh3)4 (5 mol%) and dppe (10 mol%) provided tricyclic dithiine in 53% yield. When acetylenedicarboxylate wasMolecules added,2020 ,unsymmetric25, 3595 dithiine was selectively obtained without the formation of a symmetric20 of 35 dithiine.

SchemeScheme 28. 28. InsertionInsertion reaction reaction of of sulfur sulfur and and alkyne. alkyne.

Molecules7. ReversibleRhodium-catalyzed 2020, 25, Nature x FOR PEER of Rhodium-Catalyzedsynthesis REVIEW of organosulfur C-S Bond compounds Formation using sulfur has high potential20 of in 35 organicRhodium-catalyzed synthesis because reactions it proceeds of disulfides well below provide the melting various organosulfurpoint of sulfur. compounds An interesting by the Rhodium-catalyzed reactions of disulfides provide various organosulfur compounds by the considerationcleavage of RS-SR is their bonds application and the to formation less reactive of C-SR substrates bonds, such and theyas unstrained involve C-Rh-SR alkenes intermediatesand alkynes, cleavage of RS-SR bonds and the formation of C-SR bonds, and they involve C-Rh-SR intermediates which(Scheme may 29 be). developed Because C-SR employing bond formation thermodynamically reactions are favorable often reversible, reaction systems. C-Rh-SR intermediates (Scheme 29). Because C-SR bond formation reactions are often reversible, C-Rh-SR intermediates can can also be formed from products with C-SR bonds. The C-Rh-SR intermediates can undergo also be formed from products with C-SR bonds. The C-Rh-SR intermediates can undergo various 7.various Reversible substitution Nature of and Rhod insertionium-Catalyzed reactions C-S to provide Bond Formation organic compounds. Insertion reactions of substitution and insertion reactions to provide organic compounds. Insertion reactions of C-Rh-SR C-Rh-SR intermediates with X=Y bond compounds provide C-X-Y-SR compounds, which are generally intermediates with X=Y bond compounds provide C-X-Y-SR compounds, which are generally irreversible reactions. Substitution reactions with compounds containing X-Y bonds provide novel C-X irreversible reactions. Substitution reactions with compounds containing X-Y bonds provide novel bond compounds accompanied by compounds containing RS-Y bonds, and these reactions are often C-X bond compounds accompanied by compounds containing RS-Y bonds, and these reactions are reversible. This is a substitution reaction of C-SR compounds to C-X compounds, in which the role of often reversible. This is a substitution reaction of C-SR compounds to C-X compounds, in which the the SR group is that of a formal leaving group. The RS-Y bond compounds are organosulfur compounds role of the SR group is that of a formal leaving group. The RS-Y bond compounds are organosulfur that are easy to recover and use and can be converted to other organosulfur compounds. When C-Rh-SR compounds that are easy to recover and use and can be converted to other organosulfur compounds. intermediates undergo an organothio exchange with another disulfide R’S–SR’, the resulting C-Rh-SR’ When C-Rh-SR intermediates undergo an organothio exchange with another disulfide R’S–SR’, the intermediates also undergo various reactions. This is a chemical reaction network, which provides resulting C-Rh-SR’ intermediates also undergo various reactions. This is a chemical reaction network, diverse organosulfur compounds involving chemical equilibrium and interconversion reactions. In this which provides diverse organosulfur compounds involving chemical equilibrium and section, we describe the reactivities of organosulfur compounds synthesized by rhodium-catalyzed interconversion reactions. In this section, we describe the reactivities of organosulfur compounds reactions using disulfides. synthesized by rhodium-catalyzed reactions using disulfides.

SchemeScheme 29. ReversibleReversible nature nature of of rhodium-ca rhodium-catalyzedtalyzed substitution reactions.

InIn organic synthesis, substitution reaction reactionss are generally conducted using organohalogen compounds; in in this this article, article, we we describe describe the the use use of of organosulfur organosulfur compounds compounds for for such such purpose. purpose. Halogens andand organothioorganothio groups groups are are leaving leaving groups, grou whichps, which can exhibit can exhibit diﬀerent di propertiesfferent properties of reactions. of reactions.For example, For organohalogensexample, organohalogens are involved are in involved irreversible in irreversible reactions, and reactions, organosulfurs and organosulfurs can be involved can bein reversibleinvolved reactions,in reversible which reactions, provide diversewhich organosulfurprovide diverse compounds organosulfur by slight compounds changes in by catalysts slight changesand/or reaction in catalysts conditions. and/or Thereaction organohalogen conditions. reactionsThe organohalogen form metal halides,reactions which form aremetal not halides, easy to whichrecover are and not reuse; easy theto recover organosulfur and reuse; reactions the orga providenosulfur organosulfur reactions provid compoundse organosulfur for coproducts, compounds which forcan coproducts, be used for which various can purposes. be used for various purposes.

7.1. Reactions Reactions of of 1-Thioalkynes 1-Thioalkynes As shown previously, previously, the C-S bonds in 1-thioalkynes are readily activated by rhodium catalysis (Schemes 77 andand8 8))[ [39],39], and then 1-thioalkynes can can be be used used for for substitution substitution and and insertion insertion reactions. reactions. Organothio groupsgroups can can be be exchanged exchanged between between diﬀerent different 1-thioalkynes, 1-thioalkynes, which conﬁrmedwhich confirmed the reversible the reversible cleavage of C-S bonds (Scheme 30) [67]. Two 1-thioalkynes in refluxing acetone in the presence of RhH(PPh3)4 (1 mol%) and bidentate dppf (2 mol%) provided a mixture containing comparable amounts of four possible 1-thioalkynes under chemical equilibrium. This is referred to as C-S/C-S to C-S/C-S metathesis.

Scheme 30. Organothio exchange reaction between 1-thioalkynes.

Molecules 2020, 25, x FOR PEER REVIEW 20 of 35

Rhodium-catalyzed reactions of disulfides provide various organosulfur compounds by the cleavage of RS-SR bonds and the formation of C-SR bonds, and they involve C-Rh-SR intermediates (Scheme 29). Because C-SR bond formation reactions are often reversible, C-Rh-SR intermediates can also be formed from products with C-SR bonds. The C-Rh-SR intermediates can undergo various substitution and insertion reactions to provide organic compounds. Insertion reactions of C-Rh-SR intermediates with X=Y bond compounds provide C-X-Y-SR compounds, which are generally irreversible reactions. Substitution reactions with compounds containing X-Y bonds provide novel C-X bond compounds accompanied by compounds containing RS-Y bonds, and these reactions are often reversible. This is a substitution reaction of C-SR compounds to C-X compounds, in which the role of the SR group is that of a formal leaving group. The RS-Y bond compounds are organosulfur compounds that are easy to recover and use and can be converted to other organosulfur compounds. When C-Rh-SR intermediates undergo an organothio exchange with another disulfide R’S–SR’, the resulting C-Rh-SR’ intermediates also undergo various reactions. This is a chemical reaction network, which provides diverse organosulfur compounds involving chemical equilibrium and interconversion reactions. In this section, we describe the reactivities of organosulfur compounds synthesized by rhodium-catalyzed reactions using disulfides.

Scheme 29. Reversible nature of rhodium-catalyzed substitution reactions.

In organic synthesis, substitution reactions are generally conducted using organohalogen compounds; in this article, we describe the use of organosulfur compounds for such purpose. Halogens and organothio groups are leaving groups, which can exhibit different properties of reactions. For example, organohalogens are involved in irreversible reactions, and organosulfurs can be involved in reversible reactions, which provide diverse organosulfur compounds by slight changes in catalysts and/or reaction conditions. The organohalogen reactions form metal halides, which are not easy to recover and reuse; the organosulfur reactions provide organosulfur compounds for coproducts, which can be used for various purposes.

7.1. Reactions of 1-Thioalkynes

MoleculesAs 2020shown, 25, 3595previously, the C-S bonds in 1-thioalkynes are readily activated by rhodium catalysis21 of 35 (Schemes 7 and 8) [39], and then 1-thioalkynes can be used for substitution and insertion reactions. Organothio groups can be exchanged between different 1-thioalkynes, which confirmed the reversiblecleavage ofcleavage C-S bonds of C-S (Scheme bonds 30 (Scheme)[67]. Two30) [67]. 1-thioalkynes Two 1-thioalkynes in reﬂuxing in refluxing acetone inacetone the presence in the presenceof RhH(PPh of 3RhH(PPh)4 (1 mol%)3)4 (1 and mol%) bidentate and dppfbidentate (2 mol%) dppf provided(2 mol%) a provided mixture containing a mixture comparablecontaining comparableamounts of fouramounts possible of four 1-thioalkynes possible 1-thioalkynes under chemical under equilibrium. chemical equilibrium. This is referred This to is as referred C-S/C-S to to asC-S C-S/C-S/C-S metathesis. to C-S/C-S metathesis.

Molecules 2020, 25, x FOR PEER REVIEW 21 of 35 Scheme 30. Organothio exchange reaction between 1-thioalkynes. MoleculesThe 2020 ligand, 25, x FOReffect SchemePEER was REVIEW substantial 30. Organothio in theexchange reaction reactis ofon 1-thioalkynes, between 1-thioalkynes. and the coupling reaction21 of 35of 1-thioalkynes occurred in the presence of a monodentate ligand (Scheme 31). The reaction of 1- The ligand effect effect was was substantial substantial in in the the reaction reactionss of of 1-thioalkynes, 1-thioalkynes, and and th thee coupling coupling reaction reaction of (triethylsilyl)-2-butylthioalkyne in refluxing acetone for 2 h in the presence of RhH(PPh3)4 (1 mol%) of1-thioalkynes 1-thioalkynes occurred occurred in inthe the presence presence of ofa mono a monodentatedentate ligand ligand (Scheme (Scheme 31). 31 The). The reaction reaction of of1- and a monodentate ligand (p-MeOC6H4)3P (3 mol%) gave 1,3-diyne in 74% yield and disulfide. This 1-(triethylsilyl)-2-butylthioalkyne(triethylsilyl)-2-butylthioalkyne in in refluxing refluxing acetone acetone for for 2 2 h h in in the the presence of RhH(PPh33)4 (1(1 mol%) mol%) oxidative coupling reaction is referred to as C-S/C-S to C-C/S-S metathesis, which is in contrast to the and a monodentatemonodentate ligandligand ((pp-MeOC-MeOC66H4))3PP (3 (3 mol%) mol%) gave gave 1,3-diyne in 74% yield and disulfide.disulfide. This above C-S/C-S to C-S/C-S metathesis (Scheme 30). oxidative coupling reaction is referred to as C-SC-S/C-S/C-S to C-CC-C/S-S/S-S metathesis, whichwhich is in contrast to the above C-SC-S/C-S/C-S toto C-SC-S/C-S/C-S metathesismetathesis (Scheme(Scheme 3030).).

Scheme 31. Oxidative coupling reaction of 1-thioalkynes. Scheme 31. Oxidative coupling reaction of 1-thioalkynes. The insertion reaction of 1-thioalkynes and unsaturated compounds provides novel organosulfur compounds, and 1,3-butadiyne is used as a substrate (Scheme 32) [68]. The reaction of The insertioninsertion reaction reaction of 1-thioalkynesof 1-thioalkynes and unsaturated and unsaturated compounds compounds provides novel provides organosulfur novel 1-butylthio-2-triethylsilyletyne and 1,4-(p-methoxyphenyl)-1,3-butadiyne in N, N- compounds,organosulfur andcompounds, 1,3-butadiyne and 1,3-butadiyne is used as a substrate is used as (Scheme a substrate 32) [68 (Scheme]. The reaction32) [68]. ofThe 1-butylthio-2- reaction of dimethylimodazolinone (DMI) at 135 °C for 6 h in the presence of RhH(PPh3)4 (5 mol%) and Me2PhP triethylsilyletyne1-butylthio-2-triethylsilyletyne and 1,4-(p-methoxyphenyl)-1,3-butadiyne and 1,4-(p-methoxyphenyl)-1,3-butadiyne in N, N-dimethylimodazolinone in N, (DMI)N- (10 mol%) gave 1-butylthio-2-ethynyl-1,3-buten-yne in 66% yield, which is a highly unsaturated atdimethylimodazolinone 135 ◦C for 6 h in the presence (DMI) at of 135 RhH(PPh °C for 63 )h4 (5in mol%)the presence and Me of2 RhH(PPhPhP (10 mol%)3)4 (5 mol%) gave 1-butylthio-2- and Me2PhP organosulfur compound. ethynyl-1,3-buten-yne(10 mol%) gave 1-butylthio-2-ethynyl-1,3-buten-yne in 66% yield, which is a highly unsaturated in 66% yield, organosulfur which is compound. a highly unsaturated organosulfur compound.

Scheme 32. Insertion reaction of 1-thioalkynes and alkynes. Scheme 32. Insertion reaction of 1-thioalkynes and alkynes. The conversion ofScheme 1-thioalkynes 32. Insertion to organophosphorus reaction of 1-thioalkynes compounds and alkynes. proceeds under rhodium The conversion of 1-thioalkynes to organophosphorus compounds proceeds under rhodium catalysis by reacting with diphosphine disulfides (Scheme 33)[53]. When 1-hexylthio-2-(2,4,6- catalysis by reacting with diphosphine disulfides (Scheme 33) [53]. When 1-hexylthio-2-(2,4,6- trimethylphenyl)The conversion acetylene of 1-thioalkynes and tetramethyldiphosphine to organophosphorus disulfidecompounds were proceeds reacted under in refluxingrhodium trimethylphenyl) acetylene and tetramethyldiphosphine disulfide were reacted in refluxing chlorobenzenecatalysis by reacting for 12 hwith in the diphosphine presence of RhH(PPhdisulfides3 )(Scheme4 (2 mol%) 33) and [53]. 1,2-(diethylphosphino) When 1-hexylthio-2-(2,4,6- ethane chlorobenzene for 12 h in the presence of RhH(PPh3)4 (2 mol%) and 1,2-(diethylphosphino) ethane (depe)trimethylphenyl) (4 mol%), 1-alkynylphosphine acetylene and tetramethyldipho sulfide was obtainedsphine in 88%disulfide yield. 1-Thioalkyneswere reacted under in refluxing rhodium (depe) (4 mol%), 1-alkynylphosphine sulfide was obtained in 88% yield. 1-Thioalkynes under catalysischlorobenzene exhibit for di 12fferent h in reactivitiesthe presence from of RhH(PPh 1-alkynes3)4 and(2 mol%) 1-haloalkynes; and 1,2-(diethylphosphino) for example, nobase ethane or rhodium catalysis exhibit different reactivities from 1-alkynes and 1-haloalkynes; for example, no organometallic(depe) (4 mol%), reagents 1-alkynylphos are used inphine these sulfide reactions. was obtained in 88% yield. 1-Thioalkynes under base or organometallic reagents are used in these reactions. rhodium catalysis exhibit different reactivities from 1-alkynes and 1-haloalkynes; for example, no base or organometallic reagents are used in these reactions.

Scheme 33. Exchange reaction of diphosphine disulfide and 1-thioalkynes. Scheme 33. Exchange reaction of diphosphine disulfide and 1-thioalkynes. 7.2. Reactions of Thioesters 7.2. ReactionsThioesters of Thioestersare reactive substrates in rhodium-catalyzed reactions and undergo various chemical transformations that are not observed with acyl halides. The reversible cleavage of C-S bonds was Thioesters are reactive substrates in rhodium-catalyzed reactions and undergo various chemical transformations that are not observed with acyl halides. The reversible cleavage of C-S bonds was

Molecules 2020, 25, x FOR PEER REVIEW 21 of 35

The ligand effect was substantial in the reactions of 1-thioalkynes, and the coupling reaction of 1-thioalkynes occurred in the presence of a monodentate ligand (Scheme 31). The reaction of 1- (triethylsilyl)-2-butylthioalkyne in refluxing acetone for 2 h in the presence of RhH(PPh3)4 (1 mol%) and a monodentate ligand (p-MeOC6H4)3P (3 mol%) gave 1,3-diyne in 74% yield and disulfide. This oxidative coupling reaction is referred to as C-S/C-S to C-C/S-S metathesis, which is in contrast to the above C-S/C-S to C-S/C-S metathesis (Scheme 30).

Scheme 31. Oxidative coupling reaction of 1-thioalkynes.

The insertion reaction of 1-thioalkynes and unsaturated compounds provides novel organosulfur compounds, and 1,3-butadiyne is used as a substrate (Scheme 32) [68]. The reaction of 1-butylthio-2-triethylsilyletyne and 1,4-(p-methoxyphenyl)-1,3-butadiyne in N, N- dimethylimodazolinone (DMI) at 135 °C for 6 h in the presence of RhH(PPh3)4 (5 mol%) and Me2PhP (10 mol%) gave 1-butylthio-2-ethynyl-1,3-buten-yne in 66% yield, which is a highly unsaturated organosulfur compound.

Scheme 32. Insertion reaction of 1-thioalkynes and alkynes.

The conversion of 1-thioalkynes to organophosphorus compounds proceeds under rhodium catalysis by reacting with diphosphine disulfides (Scheme 33) [53]. When 1-hexylthio-2-(2,4,6- trimethylphenyl) acetylene and tetramethyldiphosphine disulfide were reacted in refluxing chlorobenzene for 12 h in the presence of RhH(PPh3)4 (2 mol%) and 1,2-(diethylphosphino) ethane (depe) (4 mol%), 1-alkynylphosphine sulfide was obtained in 88% yield. 1-Thioalkynes under

Moleculesrhodium2020 catalysis, 25, 3595 exhibit different reactivities from 1-alkynes and 1-haloalkynes; for example,22 of no 35 base or organometallic reagents are used in these reactions.

Scheme 33. Exchange reaction of diphosph diphosphineine disulfidedisulfide and 1-thioalkynes. 7.2. Reactions of Thioesters MoleculesMolecules7.2. Reactions 2020 2020, ,25 25 of, ,x x ThioestersFOR FOR PEER PEER REVIEW REVIEW 2222 of of 35 35 Thioesters are reactive substrates in rhodium-catalyzed reactions and undergo various chemical Thioesters are reactive substrates in rhodium-catalyzed reactions and undergo various chemical determinedtransformations in studies that areof reactions not observed of thioesters with acyl and halides. disulfides The (Scheme reversible 4). cleavageThioesters of were C-S bondsapplied was to determinedtransformations in studies that are of reactionsnot observed of thioesters with acyl an had disulfideslides. The (Schemereversible 4). cleavage Thioesters of wereC-S bonds applied was to acylationdeterminedacylation reactions, reactions, in studies forming forming of reactions C-S, C-S, C-P, C-P, of thioestersC-N, C-N, and and andC-C C-C disulfidesbonds. bonds. (Scheme4). Thioesters were applied to acylation ThioestersThioesters reactions, reactreact forming withwith C-S,NN-organothioacylamides-organothioacylamides C-P, C-N, and C-C bonds. toto provideprovide acylimidesacylimides withwith concomitantconcomitant formationformationThioesters ofof disulfides,disulfides, react with whichwhichN-organothioacylamides isis aa novelnovel acylationacylation to reactionreaction provide atat acylimides anan amideamide nitrogen withnitrogen concomitant atomatom (Scheme(Scheme formation 34)34) [69].of[69]. disulfides, SS-(-(pp-Tolyl)-Tolyl) which benzothioatebenzothioate is a novel acylation andand NN-( reaction-(pp-tolylthio)--tolylthio)- at anN amideN-butylbenzamide-butylbenzamide nitrogen atom werewere (Scheme reactedreacted 34)[ 69 inin]. Srefluxingrefluxing-(p-Tolyl) chlorobenzenebenzothioatechlorobenzene and forforN 66-( hhp -tolylthio)- inin thethe presencepresenceN-butylbenzamide ofof RhH(dppBz)RhH(dppBz) were22 (5(5 reacted mol%),mol%), in andand refluxing NN-benzoyl--benzoyl- chlorobenzeneNN-butylbenzamide-butylbenzamide for 6 h in wasthewas presence obtainedobtained of inin RhH(dppBz) 79%79% yield.yield. This2This(5 mol%), isis aa novelnovel and metal-catalyzedNmetal-catalyzed-benzoyl-N-butylbenzamide couplingcoupling reactionreaction was obtainedinvolvinginvolving in N-CN-C 79% bondbond yield. formationThisformation is a novel with with metal-catalyzedcleavage cleavage of of C-S C-S and and coupling S-N S-N bonds bonds reaction in in two two involving organosulfur organosulfur N-C bond compounds compounds formation followed followed with cleavage by by oxidative oxidative of C-S eliminationandelimination S-N bonds of of disulfides. disulfides. in two organosulfur compounds followed by oxidative elimination of disulfides.

SchemeScheme 34. 34. Oxidative Oxidative coupling coupling reaction reaction of of thioester thioester and and N N-thioamides.-thioamides.

ArylAryl methyl methyl methyl ethers ethers ethers are are cleaved cleaved are cleaved with with thioesters thioesters with thioesters under under rhodium-catalyzed rhodium-catalyzed under rhodium-catalyzed conditions conditions (Scheme (Scheme conditions 35) 35) [70].(Scheme[70]. The The reaction 35reaction)[70]. of Theof m m-dimethoxybenzene reaction-dimethoxybenzene of m-dimethoxybenzene and and S S-(-(pp-tolyl)-tolyl) and p p-dimethylaminobenzothioate-dimethylaminobenzothioateS-(p-tolyl) p-dimethylaminobenzothioate at at 130 130 °C °C for for at 130 C for 12 h without a solvent in the presence of RhH(CO)(PPh3 3 ) (8 mol%) and dppe (16 mol%) 1212 h h without without◦ a a solvent solvent in in the the presence presence of of RhH(CO)(PPh RhH(CO)(PPh3))3 (8 (8 mol%) mol%) and and3 3 dppe dppe (16 (16 mol%) mol%) provided provided m m-- methoxyphenylprovidedmethoxyphenylm-methoxyphenyl benzoate benzoate in in 91% 91% benzoate yield yield along inalong 91% with with yield p p-tolyl-tolyl along methyl methyl with p sulfide. -tolylsulfide. methyl This This cleavage cleavage sulﬁde. reaction Thisreaction cleavage of of an an arylreactionaryl methylmethyl of an etherether aryl toto methyl provideprovide ether anan aryl toaryl provide esterester proceeprocee an aryldsds ester underunder proceeds neutralneutral under conditionsconditions neutral withoutwithout conditions usingusing without strongstrong nucleophilesusingnucleophiles strong or nucleophilesor Lewis Lewis acids. acids. or Lewis acids.

Scheme 35. Substitution reaction of thioester and aryl methyl ethers. SchemeScheme 35. 35. Substitution Substitution reaction reaction of of thioester thioester and and aryl aryl methyl methyl ethers. ethers. Heteroaryl aryl ethers are reacted with aryl thioesters to provide unsymmetric bis(heteroaryl) HeteroarylHeteroaryl arylaryl ethersethers areare reactedreacted withwith arylaryl thioestersthioesters toto provideprovide unsymmetricunsymmetric bis(heteroaryl)bis(heteroaryl) sulfides (Scheme 36)[71]. S-(3-Pyridyl) benzothioate and 2-benzothiazolyl 4-chlorophenyl ether were sulfidessulfides (Scheme (Scheme 36) 36) [71]. [71]. S S-(3-Pyridyl)-(3-Pyridyl) benzothioate benzothioate and and 2-benz 2-benzothiazolylothiazolyl 4-chlorophenyl 4-chlorophenyl ether ether were were reacted in refluxing chlorobenzene for 5 h in the presence of RhH(PPh3)4 (5 mol%) and dppBz (10 mol%) reactedreacted inin refluxingrefluxing chlorobenzenechlorobenzene forfor 55 hh inin thethe presencepresence ofof RhH(PPhRhH(PPh33))44 (5(5 mol%)mol%) andand dppBzdppBz (10(10 and provided 3-pyridyl 2-benzothiazolyl sulfide in 95% yield. The other reaction pathway to form an mol%)mol%) andand providedprovided 3-pyridyl3-pyridyl 2-benz2-benzothiazolylothiazolyl sulfidesulfide inin 95%95% yield.yield. TheThe otherother reactionreaction pathwaypathway toto aryl sulfide and a heteroaryl ester did not proceed. Very few unsymmetric bis(heteroaryl) sulfides formform anan arylaryl sulfidesulfide andand aa heteroarylheteroaryl esterester diddid notnot proceed.proceed. VeryVery fewfew unsymmetricunsymmetric bis(heteroaryl)bis(heteroaryl) were previously known, and this method provides novel multiple heteroatom compounds, some of sulfidessulfides werewere previouslypreviously known,known, andand thisthis methodmethod providesprovides novelnovel multiplemultiple heteroatomheteroatom compounds,compounds, which show interesting biological activities. somesome of of which which show show interesting interesting biological biological activities. activities.

SchemeScheme 36. 36. Substitution Substitution reaction reaction of of thioester thioester and and diaryl diaryl ethers. ethers.

ThisThis reaction reaction is is applicable applicable to to the the synthesis synthesis of of sulfides sulfides with with aliphatic aliphatic cyclic cyclic groups groups and and heteroaryl heteroaryl groupsgroups [72].[72]. Specifically,Specifically, thethe reactionreaction ofof aa stersteroidaloidal benzothioatebenzothioate providedprovided steroidalsteroidal heteroarylheteroaryl sulfidessulfides (Scheme(Scheme 37).37). ThisThis isis anan interestinginteresting synthesisynthesiss ofof alkylalkyl arylaryl sulfidessulfides thatthat doesdoes notnot requirerequire thethe useuse of of bases. bases.

Molecules 2020, 25, x FOR PEER REVIEW 22 of 35 determined in studies of reactions of thioesters and disulfides (Scheme 4). Thioesters were applied to acylation reactions, forming C-S, C-P, C-N, and C-C bonds. Thioesters react with N-organothioacylamides to provide acylimides with concomitant formation of disulfides, which is a novel acylation reaction at an amide nitrogen atom (Scheme 34) [69]. S-(p-Tolyl) benzothioate and N-(p-tolylthio)-N-butylbenzamide were reacted in refluxing chlorobenzene for 6 h in the presence of RhH(dppBz)2 (5 mol%), and N-benzoyl-N-butylbenzamide was obtained in 79% yield. This is a novel metal-catalyzed coupling reaction involving N-C bond formation with cleavage of C-S and S-N bonds in two organosulfur compounds followed by oxidative elimination of disulfides.

Scheme 34. Oxidative coupling reaction of thioester and N-thioamides.

Aryl methyl ethers are cleaved with thioesters under rhodium-catalyzed conditions (Scheme 35) [70]. The reaction of m-dimethoxybenzene and S-(p-tolyl) p-dimethylaminobenzothioate at 130 °C for 12 h without a solvent in the presence of RhH(CO)(PPh3)3 (8 mol%) and dppe (16 mol%) provided m- methoxyphenyl benzoate in 91% yield along with p-tolyl methyl sulfide. This cleavage reaction of an aryl methyl ether to provide an aryl ester proceeds under neutral conditions without using strong nucleophiles or Lewis acids.

Scheme 35. Substitution reaction of thioester and aryl methyl ethers.

Heteroaryl aryl ethers are reacted with aryl thioesters to provide unsymmetric bis(heteroaryl) sulfides (Scheme 36) [71]. S-(3-Pyridyl) benzothioate and 2-benzothiazolyl 4-chlorophenyl ether were reacted in refluxing chlorobenzene for 5 h in the presence of RhH(PPh3)4 (5 mol%) and dppBz (10 mol%) and provided 3-pyridyl 2-benzothiazolyl sulfide in 95% yield. The other reaction pathway to form an aryl sulfide and a heteroaryl ester did not proceed. Very few unsymmetric bis(heteroaryl) sulfidesMolecules 2020were, 25 previously, 3595 known, and this method provides novel multiple heteroatom compounds,23 of 35 some of which show interesting biological activities.

SchemeScheme 36. 36. SubstitutionSubstitution reaction reaction of of thioester thioester and and diaryl diaryl ethers. ethers.

ThisThis reaction reaction is is applicable applicable to to the the synthesis synthesis of of sulfides sulfides with with aliphatic aliphatic cyclic cyclic groups groups and and heteroaryl heteroaryl groupsgroups [[72].72]. Specifically,Specifically, the the reaction reaction of aof steroidal a steroidal benzothioate benzothioate provided provided steroidal steroidal heteroaryl heteroaryl sulfides Molecules 2020, 25, x FOR PEER REVIEW 23 of 35 sulfides(Scheme (Scheme 37). This 37). is an This interesting is an interesting synthesis synthesi of alkyl aryls of alkyl sulfides aryl that sulfides does not that require does not the userequire of bases. the use of bases.

SchemeScheme 37. 37. SubstitutionSubstitution reaction reaction of of thioes thioesterter and and aryl aryl heteroaryl heteroaryl ethers.

RhodiumRhodium catalysts catalysts cleave cleave C-C C-C bonds bonds of of benzyl ke ketones,tones, which which then then reac reactt with thioesters and estersesters [73[73].]. WhenWhen S-methyl S-methyl benzothioate benzothioate was reactedwas reacted with 2-(2-thienyl)-1-( with 2-(2-thienyl)-1-(p-cyanophenyl)-1-ethanonep-cyanophenyl)-1- ethanonein DMI at in 150 DMI◦C at for 150 12 °C h infor the 12 presenceh in the presence of RhH(CO)(PPh of RhH(CO)(PPh3)3 (10 mol%)3)3 (10 andmol%) dppBz and (20dppBz mol%), (20 mol%),a benzyl-exchanged a benzyl-exchanged ketone wasketone obtained was obtained in 76% yield.in 76% The yield. benzyl The group benzyl was group transferred was transferred between betweendifferent different thioesters thioesters by the cleavage by the ofcleavage a C-C bond of a underC-C bond chemical under equilibrium. chemical equilibrium. The other pathway The other of pathwaythe bond of exchange the bond reaction exchange providing reaction benzyl providing sulfide benzyl and 1,2-diketones sulfide and 1,2-diketones did not occur, did which not may occur, be whichdue to may thermodynamic be due to thermodynamic reasons involving reasons the substrates involving and the products. substrates The and use products. of an aryl The ester use in of place an arylof the ester thioester in place also of givesthe thioester benzyl-exchanged also gives benzyl-exchanged products. products. TheseThese results indicate that the rhodium complex catalytically cleaves C-C bonds of unstrained benzylbenzyl ketones. The The reaction reaction of of aryl aryl ethers ethers in in pl placeace of of thioesters/esters thioesters/esters provided provided a a route route to to form diarylmethanesdiarylmethanes [74]. [74]. The The reaction reaction of of 2-( 2-(p-chlorophenoxy)-5-acetylfuranp-chlorophenoxy)-5-acetylfuran and and 2-(1,3-benzoxazolyl)-1- 2-(1,3-benzoxazolyl)- phenyl-1-ethanone1-phenyl-1-ethanone in in refluxing refluxing chlorobenz chlorobenzeneene for for 6 6h h in in the the presence presence of of RhH(PPh 3))44 (10(10 mol%) mol%) and and dppBzdppBz (20(20 mol%)mol%) provided provided (1,3-benzoxazolyl) (1,3-benzoxazolyl) (5-acetylfuryl) (5-acetylfuryl) methane methane in 53% in yield53% alongyield withalong phenyl with phenylbenzoate. benzoate. The synthesis The issynthesis applicable tois theapplicable production to of variousthe production unsymmetric of bis(heteroaryl)methanesvarious unsymmetric bis(heteroaryl)methanesthat were previously not that known. were In previously addition, diarylmethanesnot known. In addition, are obtained diarylmethanes from neutral are compounds obtained fromby the neutral cleavage compounds and formation by the of C-C cleavage bonds and without formation using basesof C-C or organometallicbonds without reagents. using bases or organometallicThe reactions reagents. in Schemes 38 and 39 are notable examples of rhodium-catalyzed cleavage of C-C bondsThe in reactions benzyl ketones, in Schemes in which 38 and di ff39erent are notable types of examples reactions of proceed rhodium-catalyzed depending on cleavage the substrates of C-C 2 bondsused (Schemein benzyl 40 ketones,). The benzylin which exchange different reaction types of ofreactions esters and proceed thioesters depending proceeds on the by substrates CO-OAr usedbond (Scheme cleavage, 40). which The benzyl is under exchange chemical reaction equilibrium; of esters the and substitution thioesters proceeds reaction ofby ethers CO-OAr provided2 bond 2 cleavage,diarylmethane which and is estersunder by chemical O-Ar bond equilibrium; cleavage. the substitution reaction of ethers provided diarylmethaneRhodium-catalyzed and esters by insertion O-Ar2 bond reactions cleavage. of thioesters occur with 1-alkynes (Scheme 41)[49]. When S-butyl p-cyanobenzothioate was reacted with 1-decyne in DMSO at 100 ◦C for 12 h in the presence of RhH(PPh3)4 (5 mol%) and Et2PhP (15 mol%), a conjugated enone was obtained in 49% yield. The benzoyl group was attached at the terminal carbon atom of the 1-alkyne and the organothio group at the internal carbon atom.

Scheme 38. Substitution reaction of thioester/esters and arylmethyl ketones.

Scheme 39. Substitution reaction of diaryl ethers and arylmethyl ketones.

Molecules 2020, 25, x FOR PEER REVIEW 23 of 35 Molecules 2020, 25, x FOR PEER REVIEW 23 of 35

Scheme 37. Substitution reaction of thioester and aryl heteroaryl ethers. Scheme 37. Substitution reaction of thioester and aryl heteroaryl ethers. Rhodium catalysts cleave C-C bonds of benzyl ketones, which then react with thioesters and estersRhodium [73]. When catalysts S-methyl cleave C-Cbenzothioate bonds of benzylwas reacted ketones, with which 2-(2-thienyl)-1-( then react withp-cyanophenyl)-1- thioesters and estersethanone [73]. in WhenDMI at S-methyl 150 °C for benzothioate 12 h in the presencewas reacted of RhH(CO)(PPh with 2-(2-thienyl)-1-(3)3 (10 mol%)p-cyanophenyl)-1- and dppBz (20 ethanonemol%), a inbenzyl-exchanged DMI at 150 °C for ketone 12 h wasin the obtained presence in of76% RhH(CO)(PPh yield. The benzyl3)3 (10 mol%)group wasand transferreddppBz (20 mol%),between a differentbenzyl-exchanged thioesters ketoneby the wascleavage obtained of a C-Cin 76% bond yield. under The chemical benzyl groupequilibrium. was transferred The other betweenpathway different of the bond thioesters exchange by thereaction cleavage providing of a C-C benzyl bond sulfide under chemicaland 1,2-diketones equilibrium. did Thenot occur,other pathwaywhich may of thebe due bond to exchangethermodynamic reaction reasons providing involv benzyling the sulfide substrates and 1,2-diketonesand products. did The not use occur, of an whicharyl ester may in be place due ofto the thermodynamic thioester also reasonsgives benzyl-exchanged involving the substrates products. and products. The use of an aryl esterThese in resultsplace of indicate the thioester that the also rhodium gives benzyl-exchanged complex catalytically products. cleaves C-C bonds of unstrained benzylThese ketones. results The indicate reaction that of the aryl rhodium ethers complexin place catalyticallyof thioesters/esters cleaves providedC-C bonds a ofroute unstrained to form benzyldiarylmethanes ketones. The[74]. reactionThe reaction of aryl of 2-(ethersp-chlorophenoxy)-5-acetylfuran in place of thioesters/esters andprovided 2-(1,3-benzoxazolyl)-1- a route to form diarylmethanesphenyl-1-ethanone [74]. in The refluxing reaction chlorobenz of 2-(p-chlorophenoxy)-5-acetylfuranene for 6 h in the presence of and RhH(PPh 2-(1,3-benzoxazolyl)-1-3)4 (10 mol%) and phenyl-1-ethanonedppBz (20 mol%) inprovided refluxing (1,3-benzoxazolyl) chlorobenzene for (5-acetylfuryl) 6 h in the presence methane of RhH(PPh in 53% 3yield)4 (10 mol%)along withand dppBzphenyl (20benzoate. mol%) providedThe synthesis (1,3-benzoxazolyl) is applicable (5-acetylfuryl) to the production methane ofin 53%various yield unsymmetric along with phenylbis(heteroaryl)methanes benzoate. The thatsynthesis were previouslyis applicable not known.to the Inproduction addition, diarylmethanes of various unsymmetric are obtained bis(heteroaryl)methanesfrom neutral compounds that by were the previouslycleavage and not foknown.rmation In ofaddition, C-C bonds diarylmethanes without using are obtainedbases or fromorganometallic neutral compounds reagents. by the cleavage and formation of C-C bonds without using bases or organometallicThe reactions reagents. in Schemes 38 and 39 are notable examples of rhodium-catalyzed cleavage of C-C bondsThe in reactions benzyl ketones, in Schemes in which 38 and different 39 are notable types of examples reactions of proceed rhodium-catalyzed depending on cleavage the substrates of C-C bondsused (Scheme in benzyl 40). ketones, The benzyl in which exchange different reaction types of of esters reactions and thioestersproceed depending proceeds byon CO-OArthe substrates2 bond usedcleavage, (Scheme which 40). Theis under benzyl chemical exchange equilibrium; reaction of esters the substitutionand thioesters reaction proceeds of by ethers CO-OAr provided2 bond cleavage,Moleculesdiarylmethane2020 which, 25, 3595and is estersunder by chemical O-Ar2 bond equilibrium; cleavage. the substitution reaction of ethers provided24 of 35 diarylmethane and esters by O-Ar2 bond cleavage.

Scheme 38. Substitution reaction of thioester/esters and arylmethyl ketones. Scheme 38. Substitution reaction of thioester/esters and arylmethyl ketones. MoleculesMolecules 2020 2020, ,25 25, ,x Schemex FOR FOR PEER PEER 38. REVIEW REVIEWSubstitution reaction of thioester/esters and arylmethyl ketones. 2424 of of 35 35

Molecules 2020, 25, x FORScheme PEER 39. REVIEWSubstitution reaction of diaryl ethers and arylmethyl ketones. 24 of 35 Scheme 39. Substitution reaction of diaryl ethers and arylmethyl ketones. Scheme 39. Substitution reaction of diaryl ethers and arylmethyl ketones.

SchemeScheme 40. 40. Comparison Comparison of of substitution substitution reactions reactions of of aryl arylmethylmethyl ketones ketones and and aryl aryl esters/aryl esters/aryl ethers. ethers.

Rhodium-catalyzedRhodium-catalyzed insertioninsertion reactionsreactions ofof thioestersthioesters occuroccur withwith 1-alkynes1-alkynes (Scheme(Scheme 41)41) [49].[49]. WhenWhen S S-butyl-butyl p p-cyanobenzothioate-cyanobenzothioate was was reacted reacted with with 1-decy 1-decynene in in DMSO DMSO at at 100 100 °C °C for for 12 12 h h in in the the presencepresence of of RhH(PPh RhH(PPh3)34) 4(5 (5 mol%) mol%) and and Et Et2PhP2PhP (15 (15 mol%), mol%), a a conjugated conjugated enone enone was was obtained obtained in in 49% 49% yield.yield. The The benzoyl benzoyl group group was was attached attached at at the the terminal terminal carbon carbon atom atom of of the the 1-alkyne 1-alkyne and and the the organothio organothio group at the internal carbon atom. groupScheme at the internal 40. Comparison carbon atom. of substitution reactions of arylmethyl ketones and aryl esters/aryl ethers. Scheme 40. Comparison of substitution reactions of arylmethyl ketones and aryl esters/aryl ethers.

Rhodium-catalyzed insertion reactions of thioesters occur with 1-alkynes (Scheme 41) [49]. When S-butyl p-cyanobenzothioate was reacted with 1-decyne in DMSO at 100 °C for 12 h in the presence of RhH(PPh3)4 (5 mol%) and Et2PhP (15 mol%), a conjugated enone was obtained in 49% yield. The benzoyl group was attached at the terminal carbon atom of the 1-alkyne and the organothio

group at the internal carbon atom. SchemeSchemeScheme 41. 41. Insertion InsertionInsertion reaction reactionreaction of ofof thioesters thioestersthioesters and andand 1-alkyne. 1-alkyne.1-alkyne.

Insertion reactions of thioesters occur with strained alkenes (Scheme 42)[75]. The reaction of InsertionInsertion reactions reactions of of thioesters thioesters occur occur with with stra strainedined alkenes alkenes (Scheme (Scheme 42) 42) [75]. [75]. The The reaction reaction of of S S-- S-(p-tolyl) benzothioate and norbornadiene under THF reﬂux for 6 h in the presence of Pd2(dba)3 (p(p-tolyl)-tolyl) benzothioate benzothioate and and norbornadiene norbornadiene under under THF THF reflux reflux for for 6 6 h h in in the the presence presence of of Pd Pd2(dba)2(dba)3 3(dba (dba (dba = dibenzylideneacetone) (5 mol%) and (2,4,6-(MeO)3C6H2)3P (20 mol%) gave the acylated adduct == dibenzylideneacetone) dibenzylideneacetone) (5 (5 mol%) mol%) and and (2,4,6-(MeO) (2,4,6-(MeO)3C3C6H6H2)23)P3P (20 (20 mol%) mol%) gave gave the the acylated acylated adduct adduct with with with trans conﬁguration, in which an acyl group is attached in the endo position. The initial bond transtrans configuration,configuration, inin whichwhich anan acylacyl groupgroup isis attachedattached inin thethe endoendo position.position. TheThe initialinitial bondbond formation is considered to involve acylation, which is followed by thiolation. formationformation is is considered considered to to involve involve acylat acylation,ion, which which is is followed followed by by thiolation. thiolation. Scheme 41. Insertion reaction of thioesters and 1-alkyne.

Insertion reactions of thioesters occur with strained alkenes (Scheme 42) [75]. The reaction of S- (p-tolyl) benzothioate and norbornadiene under THF reflux for 6 h in the presence of Pd2(dba)3 (dba = dibenzylideneacetone) (5 mol%) and (2,4,6-(MeO)3C6H2)3P (20 mol%) gave the acylated adduct with trans configuration, in which an acyl group is attached in the endo position. The initial bond formation is considered to involve acylation, which is followed by thiolation.

SchemeSchemeScheme 42. 42. Insertion InsertionInsertion reaction reactionreaction of ofof thioesters thioestersthioesters and andand alkene. alkene.alkene.

7.3.7.3. Reactions Reactions of of α α-Thioketone-Thioketone TheThe C-S C-S bonds bonds in in α α-thioketones-thioketones are are activated activated by by rhodium rhodium catalysts catalysts to to form form oxidative oxidative addition addition intermediatesintermediates with with S-Rh-C S-Rh-C subunits, subunits, which which react react with with C-H C-H bonds bonds in in organi organicc compounds compounds (Scheme (Scheme 11) 11) [43,44]. The activation of α-thioketones can be used for the coupling reaction to form C-C bonds at [43,44]. The activation of α-thioketones can be used for the coupling reaction to form C-C bonds at thethe ketoneketone αα-position-position (Scheme(Scheme 43)43) [76].[76]. TheThe reactireactionon ofof 1,2-diphenyl-1-ethanone1,2-diphenyl-1-ethanone andand Scheme 42. Insertion reaction of thioesters and alkene. methylthiomethylmethylthiomethyl t -butylt-butyl ketone ketone in in refluxing refluxing chlorobenzen chlorobenzenee for for 6 6 h h in in the the presence presence of of RhH(PPh RhH(PPh3)34) 4(10 (10 mol%) and dppBz (20 mol%) gave a dimeric ketone at the α-position in 67% yield. The reaction is mol%)7.3. Reactions and dppBz of α-Thioketone (20 mol%) gave a dimeric ketone at the α-position in 67% yield. The reaction is consideredconsidered to to involve involve the the initial initial transfer transfer of of the the methylthio methylthio group group to to 1,2-diphenyl-1-ethanone 1,2-diphenyl-1-ethanone followed followed byby coupling couplingThe C-S to to bonds form form diketone indiketone α-thioketones along along with with are dimethyl activateddimethyl disulfide. bydisulfide. rhodium The The catalysts mechanism mechanism to form was was oxidativedetermined determined addition from from theintermediatesthe reactionreaction betweenbetween with S-Rh-C αα-methylthiolated-methylthiolated subunits, which 1,2-diphenyl-1-ethanone1,2-diphenyl-1-ethanone react with C-H bonds in and organiand 1,2-diphenyl-1-ethanone1,2-diphenyl-1-ethanonec compounds (Scheme 11) toto provide[43,44].provide The thethe couplingactivationcoupling product. product.of α-thioketones ItIt shouldshould can bebe be notednoted used that thatfor the oxidativeoxidative coupling dimerizationdimerization reaction to offormof ketonesketones C-C bonds cancan be beat conductedtheconducted ketone under under α-position rhodium rhodium catalysis (Schemecatalysis using using43) α α[76].-thioketones-thioketones The reacti as as oxidation oxidationon of reagents. reagents.1,2-diphenyl-1-ethanone and methylthiomethyl t-butyl ketone in refluxing chlorobenzene for 6 h in the presence of RhH(PPh3)4 (10

mol%) and dppBz (20 mol%) gave a dimeric ketone at the α-position in 67% yield. The reaction is considered to involve the initial transfer of the methylthio group to 1,2-diphenyl-1-ethanone followed by coupling to form diketone along with dimethyl disulfide. The mechanism was determined from the reaction between α-methylthiolated 1,2-diphenyl-1-ethanone and 1,2-diphenyl-1-ethanone to provide the coupling product. It should be noted that oxidative dimerization of ketones can be conducted under rhodium catalysis using α-thioketones as oxidation reagents.

Molecules 2020, 25, 3595 25 of 35

7.3. Reactions of α-Thioketone The C-S bonds in α-thioketones are activated by rhodium catalysts to form oxidative addition intermediates with S-Rh-C subunits, which react with C-H bonds in organic compounds (Scheme 11)[43,44]. The activation of α-thioketones can be used for the coupling reaction to form C-C bonds at the ketone α-position (Scheme 43)[76]. The reaction of 1,2-diphenyl-1-ethanone and methylthiomethyl t-butyl ketone in reﬂuxing chlorobenzene for 6 h in the presence of RhH(PPh3)4 (10 mol%) and dppBz (20 mol%) gave a dimeric ketone at the α-position in 67% yield. The reaction is considered to involve the initial transfer of the methylthio group to 1,2-diphenyl-1-ethanone followed by coupling to form diketone along with dimethyl disulﬁde. The mechanism was determined from the reaction between α-methylthiolated 1,2-diphenyl-1-ethanone and 1,2-diphenyl-1-ethanone to provide the coupling product. It should be noted that oxidative dimerization of ketones can be conducted Molecules 2020, 25, x FOR PEER REVIEW 25 of 35 underMolecules rhodium 2020, 25, x catalysis FOR PEER using REVIEWα-thioketones as oxidation reagents. 25 of 35

Scheme 43. Oxidative coupling reaction of ketones. Scheme 43.43. Oxidative coupling reaction of ketones. 7.4. Reactions of Aryl/Heteroaryl Aryl/Heteroaryl SulfidesSulfides 7.4. Reactions of Aryl/Heteroaryl Sulfides The rhodium-catalyzed C-S bond cl cleavageeavage of aryl sulfides sulfides provided other aryl sulfides sulfides by the The rhodium-catalyzed C-S bond cleavage of aryl sulfides provided other aryl sulfides by the exchange of arylthio groups [[77].77]. Polyfluorophenyl Polyfluorophenyl and heteroaryl derivatives are highly reactive exchange of arylthio groups [77]. Polyfluorophenyl and heteroaryl derivatives are highly reactive substrates for the cleavage and formation of C-S bonds, and symmetric diaryl sulfides sulfides can be substrates for the cleavage and formation of C-S bonds, and symmetric diaryl sulfides can be converted into unsymmetric diaryl sulfides sulfides (Scheme (Scheme 44).44). Perfluorinated Perfluorinated bis( bis(pp-benzoylphenyl)-benzoylphenyl) sulfide, sulfide, converted into unsymmetric diaryl sulfides (Scheme 44). Perfluorinated bis(p-benzoylphenyl) sulfide, 3 4 (phenylthiol)pentafluorobenzene,(phenylthiol)pentafluorobenzene, andand triisopropylsilanetriisopropylsilane werewere reactedreacted inin thethe presencepresence ofof RhH(PPhRhH(PPh3))4 (phenylthiol)pentafluorobenzene, and triisopropylsilane were reacted in the presence of RhH(PPh3)4 (5 mol%) and dppBz (10 mol%) in refluxing refluxing THF for 6 h and provided unsymmetric diaryl sulfide sulfide in (5 mol%) and dppBz (10 mol%) in refluxing THF for 6 h and provided unsymmetric diaryl sulfide in 51% yield. Silane Silane was was added to to trap fluoride fluoride by th thee formation of silyl fluoride, fluoride, which resulted in an 51% yield. Silane was added to trap fluoride by the formation of silyl fluoride, which resulted in an exothermic reaction. The reaction is under chemic chemicalal equilibrium without silane, and the unsymmetric exothermic reaction. The reaction is under chemical equilibrium without silane, and the unsymmetric diaryl sulfide sulfide can also undergo the aryl exchange reaction. Combined with the synthesis of symmetric diaryl sulfide can also undergo the aryl exchange reaction. Combined with the synthesis of symmetric diaryl sulfides sulfides from polyfluorobenzene polyfluorobenzene and sulfur (Scheme 26),26), various unsy unsymmetricmmetric diaryl sulfides sulfides diaryl sulfides from polyfluorobenzene and sulfur (Scheme 26), various unsymmetric diaryl sulfides can be synthesized using sulfur. can be synthesized using sulfur.

Scheme 44. ExchangeExchange reaction of diaryl sulfides sulfides and aryl fluorides. fluorides. Scheme 44. Exchange reaction of diaryl sulfides and aryl fluorides. Benzo-fused heteroarenes are thiolated under rhodium-catalyzed conditions using Benzo-fused heteroarenes are thiolated under rhodium-catalyzed conditions using α- α-phenylthioisobutyrophenone (Scheme 11), and nonbenzo-fused heteroarenes are thiolated using phenylthioisobutyrophenoneBenzo-fused heteroarenes (Scheme are thiolated11), and nonbunderenzo-fused rhodium-catalyzed heteroarenes areconditions thiolated using using α2-- 2-methylthiothiazole (Scheme 45)[78]. The former thiolating reagent is more reactive than methylthiothiazolephenylthioisobutyrophenone (Scheme 45) (Scheme [78]. The 11), former and nonb thioenzo-fusedlating reagent heteroarenes is more reactive are thiolated than disulfides using 2- disulfides and α-thioketones because the less acidic nature of the 2-proton of 2-(methylthio)thiazole andmethylthiothiazole α-thioketones because (Scheme the 45) less [78]. acidic The natureformer of thio thelating 2-proton reagent of 2-(methylthio)thiazole is more reactive than causesdisulfides the causes the chemical equilibrium to favor the formation of thiolated nonbenzo-fused heteroarenes. chemicaland α-thioketones equilibrium because to favor the the less formation acidic nature of th ofiolated the 2-proton nonbenzo-fused of 2-(methylthio)thiazole heteroarenes. The causes reaction the chemical equilibrium to favor the formation of thiolated nonbenzo-fused heteroarenes. The reaction of 3-phenylthiazole and 2-(methylthio) benzothiazole (3 equivalents) in the presence of RhH(PPh3)4 (10of 3-phenylthiazole mol%) and 1,3-(dicyclohexylphosphino)-1,3-propane and 2-(methylthio) benzothiazole (3 equivalents) (dcypp) (20in the mol%) presence in refluxingof RhH(PPh 1,2-3)4 dichlorobenzene(10 mol%) and for1,3-(dicyclohexylphosphino)-1,3-propane 3 h gave 2-methylthio-3-phenylthiazole (dcypp) in 74% (20yield. mol%) This reactionin refluxing is under 1,2- chemicaldichlorobenzene equilibrium, for 3 and h gave removal 2-methylthio-3-phenylt of volatile thiazole increasedhiazole in the 74% yield. yield. The This reaction reaction is applicable is under tochemical various equilibrium, substituted thiazolesand removal and ofoxazoles. volatile thiazole increased the yield. The reaction is applicable to various substituted thiazoles and oxazoles.

Scheme 45. Organothio exchange reaction of thiazoles. Scheme 45. Organothio exchange reaction of thiazoles.

Molecules 2020, 25, x FOR PEER REVIEW 25 of 35

Scheme 43. Oxidative coupling reaction of ketones.

7.4. Reactions of Aryl/Heteroaryl Sulfides The rhodium-catalyzed C-S bond cleavage of aryl sulfides provided other aryl sulfides by the exchange of arylthio groups [77]. Polyfluorophenyl and heteroaryl derivatives are highly reactive substrates for the cleavage and formation of C-S bonds, and symmetric diaryl sulfides can be converted into unsymmetric diaryl sulfides (Scheme 44). Perfluorinated bis(p-benzoylphenyl) sulfide, (phenylthiol)pentafluorobenzene, and triisopropylsilane were reacted in the presence of RhH(PPh3)4 (5 mol%) and dppBz (10 mol%) in refluxing THF for 6 h and provided unsymmetric diaryl sulfide in 51% yield. Silane was added to trap fluoride by the formation of silyl fluoride, which resulted in an exothermic reaction. The reaction is under chemical equilibrium without silane, and the unsymmetric diaryl sulfide can also undergo the aryl exchange reaction. Combined with the synthesis of symmetric diaryl sulfides from polyfluorobenzene and sulfur (Scheme 26), various unsymmetric diaryl sulfides can be synthesized using sulfur.

Scheme 44. Exchange reaction of diaryl sulfides and aryl fluorides.

Benzo-fused heteroarenes are thiolated under rhodium-catalyzed conditions using α- phenylthioisobutyrophenone (Scheme 11), and nonbenzo-fused heteroarenes are thiolated using 2- methylthiothiazole (Scheme 45) [78]. The former thiolating reagent is more reactive than disulfides Moleculesand α-thioketones2020, 25, 3595 because the less acidic nature of the 2-proton of 2-(methylthio)thiazole causes26 ofthe 35 chemical equilibrium to favor the formation of thiolated nonbenzo-fused heteroarenes. The reaction Theof 3-phenylthiazole reaction of 3-phenylthiazole and 2-(methy andlthio) 2-(methylthio) benzothiazole benzothiazole (3 equivalents) (3 equivalents)in the presence inthe of RhH(PPh presence3 of)4 (10 mol%) and 1,3-(dicyclohexylphosphino)-1,3-propane (dcypp) (20 mol%) in refluxing 1,2- RhH(PPh3)4 (10 mol%) and 1,3-(dicyclohexylphosphino)-1,3-propane (dcypp) (20 mol%) in reﬂuxing 1,2-dichlorobenzenedichlorobenzene for for3 h 3 gave h gave 2-methylthio-3-phenylt 2-methylthio-3-phenylthiazolehiazole in in74% 74% yield. yield. This This reaction reaction is is under chemical equilibrium,equilibrium, andand removalremoval of of volatile volatile thiazole thiazole increased increased the the yield. yield. The The reaction reaction is applicableis applicable to variousto various substituted substituted thiazoles thiazoles and and oxazoles. oxazoles.

Molecules 2020, 25, x FOR PEER SchemeREVIEW 45. Organothio exchange reaction of thiazoles. 26 of 35

Rhodium-catalyzed organothiolationorganothiolation reactions of heteroarenes and relatedrelated compoundscompounds usingusing disulfidesdisulfides [[79–89]79–89] andand sulfursulfur [[90]90] have recently beenbeen reported.reported. These methods employ stoichiometric or substoichiometric amounts amounts of of copper(II) copper(II) or or silver(I) silver(I) salts. salts. The The strong strong metal metal oxidizing oxidizing reagents reagents are areconsidered considered to regenerate to regenerate higher higher oxidation oxidation states states of rhodium of rhodium complexes complexes and produce and produce copper(I) copper(I) salts saltsor copper/silver or copper/silver metals metals as byproducts. as byproducts. The Thepresent present reaction reaction is characterized is characterized by bysimple simple transfer transfer of oforganothio organothio groups groups without without using using such such metal metal reagen reagents,ts, which which is is achieved achieved by by judicious choice ofof organothio donor. A A strong strong metal metal oxidizing oxidizing reagent reagent is an is anequivalent equivalent of a of large a large amount amount of energy, of energy, and anda related a related discussion discussion will will be provided be provided in inSection Section 8 8on on the the use use of of the the strong metal basebase ofof sodiumsodium hydroxide (Scheme(Scheme 47).47). 2,5-Disubstituted 1,4-dithiines undergoundergo rearrangement to provide 2,6-disubstituted derivatives, whichwhich involvesinvolves the the cleavage cleavage of twoof two C-S bondsC-S bonds (Scheme (Scheme 46)[91 46)]. The [91]. reaction The reaction requires requires rhodium rhodium catalysis andcatalysis is under and chemical is under equilibrium. chemical equilibrium. When 2,5-di( Whent-butyl)-1,4-dithiine 2,5-di(t-butyl)-1,4-dithiine was treated withwas treated RhH(dppe) with2 (10RhH(dppe) mol%) and2 (10 dimethyl mol%) and acetylenedicarboxylate dimethyl acetylenedicarboxylate (DMAD) (3 equivalents)(DMAD) (3 equivalents) in refluxing in toluene refluxing for 24toluene h, 1,6-di( for t-butyl)-1,4-dithiine24 h, 1,6-di(t-butyl)-1,4-dithiine was obtained was in 48% obtained yield, alongin 48% with yield, the startingalong with material the starting in 51% recoverymaterial yield.in 51% The recovery role of acetyleneyield. The was role to stabilizeof acetylene the intermediate was to stabilize rhodium the complex.intermediate Under rhodium forced conditionscomplex. Under of 150 ◦forcedC without conditions a solvent, of one150 of°C the without olefin moietiesa solvent, in one the startingof the olefin material moieties is exchanged in the withstarting DMAD. material The formationis exchanged of a with rhodacycle DMAD. intermediate The formation and theof involvementa rhodacycle of intermediate the thio-Diels–Alder and the reactioninvolvement are proposed of the thio-Diels–Alder to occur. reaction are proposed to occur.

Scheme 46.46. Exchange reaction of 1,4-dithiines.

Organosulfur compounds can be transformed into other organosulfur compounds and related Organosulfur compounds can be transformed into other organosulfur compounds and related organic compounds by the rhodium-catalyzed method owing to the reversible nature of the reactions. organic compounds by the rhodium-catalyzed method owing to the reversible nature of the reactions. Such manipulation provides a diversity of derivatives starting from a single organosulfur compound Such manipulation provides a diversity of derivatives starting from a single organosulfur compound by changing their cosubstrates. by changing their cosubstrates. 8. Conclusions 8. Conclusion 8.1. Mechanisms of Rhodium-Catalyzed Substitution and Insertion Reactions of Disulfides 8.1. Mechanisms of Rhodium-Catalyzed Substitution and Insertion Reactions of Disulfides Rhodium complexes catalyze the cleavage of disulfide S-S bonds and transfer of organothio groupsRhodium to other complexes organic compounds, catalyze the which cleavage provides of disulfide various organosulfurS-S bonds and compounds. transfer of Mechanistic organothio modelsgroups ofto substitutionother organic reactions compounds, and insertion which provid reactionses various are shown organosulfur below (Figure compounds.7). A low-valent Mechanistic Rh(I) complexmodels of undergoes substitution oxidative reactions addition and insertion with a disulfide reactions to are provide shown a S-Rh(III)-Sbelow (Figure complex 7). A (Figurelow-valent7a). Rh(I) complex undergoes oxidative addition with a disulfide to provide a S-Rh(III)-S complex (Figure 7a). Such oxidative addition reactions of disulfides are known [92–94]. Formation of dithiorhodacycles by reactions of rhodium complexes and sulfur has also been reported [65,95]. Then, ligand exchange proceeds with a molecule possessing an X-Y bond to form an X-Rh(III)-S complex, and reductive elimination provides a product possessing a S-X bond with the regeneration of the Rh(I) complex. Alternatively, formation of a Rh(V) complex can be considered by subsequent oxidative addition of the S-Rh(III)-S complex with a molecule possessing an X-Y bond.

Molecules 2020, 25, 3595 27 of 35

Such oxidative addition reactions of disulﬁdes are known [92–94]. Formation of dithiorhodacycles by reactions of rhodium complexes and sulfur has also been reported [65,95]. Then, ligand exchange proceeds with a molecule possessing an X-Y bond to form an X-Rh(III)-S complex, and reductive elimination provides a product possessing a S-X bond with the regeneration of the Rh(I) complex. Alternatively, formation of a Rh(V) complex can be considered by subsequent oxidative addition of the

S-Rh(III)-SMolecules 2020 complex, 25, x FORwith PEER aREVIEW molecule possessing an X-Y bond. 27 of 35

Figure 7. Mechanistic models of rhodium-catalyzed (a) substitution reactions and (b) insertion reactions Figure 7. Mechanistic models of rhodium-catalyzed (a) substitution reactions and (b) insertion with disulfides. reactions with disulfides. Two reductive eliminations then provide two molecules containing X-S and Y-S bonds, which Two reductive eliminations then provide two molecules containing X-S and Y-S bonds, which are accompanied by regeneration of the Rh(I) complex. Formation of Rh(V) complexes has been are accompanied by regeneration of the Rh(I) complex. Formation of Rh(V) complexes has been reported [96–99]. A mechanistic model of the insertion reaction can also involve oxidative addition reported [96–99]. A mechanistic model of the insertion reaction can also involve oxidative addition of a Rh(I) complex and a disulfide, which is followed by the transfer of two organothio groups to an of a Rh(I) complex and a disulfide, which is followed by the transfer of two organothio groups to an unsaturated molecule possessing an X=Y bond to form a product possessing a S-X-Y-S group with the unsaturated molecule possessing an X=Y bond to form a product possessing a S-X-Y-S group with regeneration of the Rh(I) complex (Figure7b). the regeneration of the Rh(I) complex (Figure 7b). Involvement of chemical equilibria is a notable feature of the present rhodium-catalyzed Involvement of chemical equilibria is a notable feature of the present rhodium-catalyzed substitution reactions using disulfides. The above mechanistic model shows reversible nature substitution reactions using disulfides. The above mechanistic model shows reversible nature in the in the oxidative addition of a rhodium(I) complex and a disulfide (Figure7a). In addition, ligand oxidative addition of a rhodium(I) complex and a disulfide (Figure 7a). In addition, ligand exchange exchange of a S-Rh(III)-S complex possessing an X-Y molecule is reversible; reductive elimination of a S-Rh(III)-S complex possessing an X-Y molecule is reversible; reductive elimination of an X- of an X-Rh(III)-S complex to provide a product with a S-X bond may be reversible. Such a sequence Rh(III)-S complex to provide a product with a S-X bond may be reversible. Such a sequence of of reversible reactions involving organosulfur–rhodium complexes provides a chemical equilibrium. reversible reactions involving organosulfur–rhodium complexes provides a chemical equilibrium. Disulfide exchange reactions described in Section2 support the reversible mechanistic model. Disulfide exchange reactions described in Section 2 support the reversible mechanistic model. Insertion reactions can also involve reversible oxidative addition of a Rh(I) complex and a disulfide Insertion reactions can also involve reversible oxidative addition of a Rh(I) complex and a (Figure7b). Subsequent insertion of an X =Y molecule may be irreversible because reactions of disulfide (Figure 7b). Subsequent insertion of an X=Y molecule may be irreversible because reactions unsaturated compounds to form saturated compounds are generally exothermic. of unsaturated compounds to form saturated compounds are generally exothermic. It should be noted that the formation of Rh-S bonds can be reversible, which may be a basis for the It should be noted that the formation of Rh-S bonds can be reversible, which may be a basis for rhodium-catalyzed synthesis of organosulfur compounds described in this article. This is in contrast to the rhodium-catalyzed synthesis of organosulfur compounds described in this article. This is in contrast to a general thought that chemical bonds between transition metals and sulfur atoms are very strong and make such catalysis difficult.

8.2. Rhodium-Catalyzed Synthesis of Diverse Organosulfur Compounds The rhodium-catalyzed synthetic method developed in this study provides organosulfur compounds with diverse structures; the development of highly active catalysts and design of exothermic reactions have been critical for this method. The synthesis employs disulfides and sulfur

Molecules 2020, 25, 3595 28 of 35 a general thought that chemical bonds between transition metals and sulfur atoms are very strong and make such catalysis diﬃcult.

8.2. Rhodium-Catalyzed Synthesis of Diverse Organosulfur Compounds The rhodium-catalyzed synthetic method developed in this study provides organosulfur Moleculescompounds 2020, with25, x FOR diverse PEER structures; REVIEW the development of highly active catalysts and design of exothermic28 of 35 reactions have been critical for this method. The synthesis employs disulﬁdes and sulfur possessing possessingS-S bonds, whichS-S bonds, are stable which and are readily stable available.and readil Rhodiumy available. complexes Rhodium cleave complexes S-S bonds cleave and S-S promote bonds andsubstitution promote and substitution insertion and reactions insertion with reac varioustions organicwith various compounds. organic compounds. None of these these reactions reactions employ employ bases bases or or organometa organometallicllic reagent. reagent. This This feature feature is in is incontrast contrast to conventionalto conventional syntheses syntheses of oforganosulfur organosulfur compou compoundsnds using using thiolate thiolate anions anions and and organohalogen compounds, whichwhich rely rely on on the the exothermic exothermic nature nature of reactions of reactions owing toow theing neutralization to the neutralization of hydrogen of hydrogenhalides. Such halides. a reaction Such involving a reaction rhodium involving catalysis rhodium was also catalysis reported was [100 also]. In reported this context, [100]. the In role this of context,a base is the considered, role of a for base example, is considered, in a reaction for exam generatingple, in hydrogena reaction chloride,generating which hydrogen is a substitution chloride, whichreaction is ofa substitution an alkyl chloride reaction and of a thiol.an alkyl Neutralization chloride and of a hydrogenthiol. Neutralization chloride with of hydrogen sodium hydroxide chloride withto form sodium sodium hydroxide chloride isto stronglyform sodium exothermic, chloride∆H is= strongly285.8 kJ exothermic, mol 1, as calculated ΔH = −285.8 from kJ the mol heat−1, as of − − calculatedformation (Schemefrom the 47 heat). The of regenerationformation (Scheme of sodium 47). hydroxide The regeneration from sodium of sodium chloride hydroxide by electrolysis from 1 −1 sodiumrequires chloride a large amount by electrolysis of energy: requires∆H = +a271.4 large kJ amount mol− . of No energy: base is Δ incorporatedH = +271.4 kJ in mol the product,. No base and is incorporatedthe neutralization–regeneration in the product, and cycle the neutralizati consumes energyon–regeneration to make the cycle reaction consumes exothermic. energy Metal to make halides the reactionare not easy exothermic. to recover Metal and halides reuse, andare tonot do easy so requiresto recover a largeand reuse, amount and of to energy. do so Arequires strong a base large is amountan equivalent of energy. of a largeA strong amount base of is energy; an equivalent for example, of a thelarge production amount of of energy; sodium for hydroxide example, from the productionsodium chloride of sodium (1 10 hydroxide10 kWh in from 2017) sodium [101] consumes chloride 1%(1 × of 10 all10 kWh electricity in 2017) in Japan [101] (8consumes1011 kWh 1% of in × × all2015) electricity [102]. The in Japan atom (8 economy × 1011 kWh is often in 2015) employed [102]. The to analyze atom economy the eﬃciency is often of employed a synthetic to chemical analyze thereaction efficiency [103]. of The a synthetic formation chemical of metal reaction halides can[103]. provide The formation a favorable of atommetal economy halides can because provide their a favorablemolecular atom weights economy are small. because However, their molecular it is also critical weights to are consider small. energy, However, and it the is reusealso critical of metal to considerhalides requires energy, aand vast the amount reuse of energy.metal halides requires a vast amount of energy.

Scheme 47. Thermodynamic analysis of the use of sodium hydroxide. Scheme 47. Thermodynamic analysis of the use of sodium hydroxide. Another notable aspect of the syntheses presented herein is the provision of diverse organic Another notable aspect of the syntheses presented herein is the provision of diverse organic compounds that are structurally related. This feature is derived from the use of disulﬁdes (RS-SR) compounds that are structurally related. This feature is derived from the use of disulfides (RS-SR) and sequential substitution reactions (Figure8). When a rhodium-catalyzed reaction converts one and sequential substitution reactions (Figure 8). When a rhodium-catalyzed reaction converts one SR SR group with A, a series of products RS-A1, RS-A2, RS-A3, RS-A4, ... are produced. Then, the group with A, a series of products RS-A1, RS-A2, RS-A3, RS-A4, … are produced. Then, the rhodiumrhodium-catalyzed organothio exchange reaction of RS-A1 provides diverse organosulfur compounds catalyzed organothio exchange reaction of RS-A1 provides diverse organosulfur compounds R1S-A1, R1S-A1,R2S-A1,R3S-A1, ... , as described in Sections2,3 and6. Using the reversible nature of R2S-A1, R3S-A1, …, as described in Sections 2, 3, and 6. Using the reversible nature of the rhodium- the rhodium-catalyzed reactions, we can substitute the RS group in RS-A1 with B1, which provides catalyzed reactions, we can substitute the RS group in RS-A1 with B1, which provides coupling coupling products B1-A1, B1-A2, B1-A3, ... . Rhodium catalysis then provides other coupling products products B1-A1, B1-A2, B1-A3, …. Rhodium catalysis then provides other coupling products B2-A1, B2- B2-A1, B2-A2, B2-A3, ... , as described in Section7. Thus, organothio groups derived from disulﬁdes A2, B2-A3, …, as described in Section 7. Thus, organothio groups derived from disulfides RS-SR have RS-SR have dual roles. One is as a part of organosulfur compounds RnS-Am; the other is as a leaving dual roles. One is as a part of organosulfur compounds RnS-Am; the other is as a leaving group to group to provide coupling products Bn-Am. This chemistry provides a systematic method to construct provide coupling products Bn-Am. This chemistry provides a systematic method to construct a library a library of compounds in an energy-saving manner. of compounds in an energy-saving manner.

Molecules 2020, 25, 3595 29 of 35 Molecules 2020, 25, x FOR PEER REVIEW 29 of 35

FigureFigure 8. 8.Synthesis Synthesis ofof diversediverse organosulfurorganosulfur compoundscompounds and and couplingcoupling products products by by rhodium-catalyzed rhodium-catalyzed reactionsreactions of of disulﬁdes. disulfides.

8.3.8.3. ChemicalChemical ReactionReaction NetworkNetwork SystemSystem TheThe rhodium-catalyzedrhodium-catalyzed synthesissynthesis ofof organosulfurorganosulfur compoundscompounds involvesinvolves reversiblereversible reactions,reactions, whichwhich are are chemical chemical equilibria equilibria and and interconversion interconversion reactions reactions (Figure (Figure9). Chemical 9). Chemical equilibrium equilibrium in closed in systemsclosed systems involves involves a comparable a comparable thermodynamic thermodynamic stability of stability substrates of andsubstrates products, and along products, with aalong low energywith a barrierlow energy (Figure barrier4). Such (Figure reactions 4). Such are reactions shown by are straight shown arrows by straight pointing arrows in oppositepointing directions.in opposite Interconversiondirections. Interconversion reactions in openreactions systems in open involve syst theems addition involve ofthe appropriate addition of organic appropriate cosubstrates organic andcosubstrates the formation and the of coproducts, formation of which coproducts, inverts thewhic relativeh inverts thermodynamic the relative thermodynamic stability of substrates stability and of products.substrates The and reactions products. can The then reactions proceed can in eitherthen pr direction,oceed in aseither shown direction, by curved as shown arrows by pointing curved inarrows opposite pointing directions. in opposite The summary directions. of this The work summary provides of athis chemical work provides reaction networka chemical with reaction many reversiblenetwork with reactions, many in reversible which substrates reactions, and in products which substrates are mutually and relatedproducts (Figure are 9mutually). The product related of(Figure a reaction 9). The can product be a substrate of a reaction in the nextcan be or a distantly substrate located in the chemicalnext or distantly reactions. located This chemicalchemical reactionreactions. network, This chemical however, reaction is a simplified network, model however, based is on athe simplified reactions model of disulfide based andon the sulfur, reactions and the of realdisulfide network and is sulfur, multidimensional. and the real Asnetwork examples is mult of suchidimensional. networks, As we examples have previously of such networks, proposed anwe acylationhave previously reaction proposed network [an49] acylation and a C-H reaction thiolation network reaction [49] network and a C-H [29 ].thiolation reaction network [29].Biological systems employ complex chemical reaction networks with energy-saving characteristics. ChemicalBiological equilibria systems can be controlledemploy bycomplex flow systems chemical in biological reaction cells, networks and interconversion with energy-saving reactions cancharacteristics. be controlled Chemical by external equilibria energy using can ATPbe cont androlled ADP toby produce flow systems exothermic in biological reactions. Biologicalcells, and reactioninterconversion networks reactions are further can controlled be controlled by enzymatic by external catalysis energy [6, 7using]. The ATP chemical and reactionADP to networkproduce hereinexothermic can be reactions. a model of Biological biological reaction systems networ involvingks manyare further chemical controlled equilibria by andenzymatic interconversion catalysis reactions,[6,104]. The although chemical biological reaction systems network are herein much can more be well-organizeda model of biological and functional. systems involving many chemical equilibria and interconversion reactions, although biological systems are much more well- organized and functional.

Molecules 2020, 25, 3595 30 of 35 Molecules 2020, 25, x FOR PEER REVIEW 30 of 35

FigureFigure 9.9. SchematicSchematic presentationpresentation ofof aa rhodium-catalyzedrhodium-catalyzed chemicalchemical reactionreaction networknetwork usingusing disulﬁdedisulfide andand sulfur.sulfur. Straight Straight arrows arrows pointing in opposite directions show chemical equilibriaequilibria inin closedclosed systems,systems, andand curvedcurved arrowsarrows pointingpointing inin oppositeopposite directionsdirections showshow interconversioninterconversion reactionsreactions inin openopen systems.systems. Red Red R letters are derivedderived fromfrom organicorganic groupsgroups inin disulﬁdes.disulfides. SquaresSquares containcontain importantimportant syntheticsynthetic intermediates.intermediates.

Author Contributions: Writing, M.A. and M.Y. All authors have read and agreed to the published version of Author Contributions: Writing, M.A. and M.Y. All authors have read and agreed to the published version of the manuscript. the manuscript. Funding:Funding: This research waswas supportedsupported by thethe JapanJapan AgencyAgency forfor MedicalMedical ResearchResearch andand DevelopmentDevelopment (AMED), PlatformPlatform ProjectProject forfor SupportingSupporting DrugDrug DiscoveryDiscovery and LifeLife ScienceScience ResearchResearch (Grant(Grant NumberNumber JP19 am0101100),am0101100), NagaseNagase ScienceScience and Technology Foundation,Foundation, KobayashiKobayashi Foundation,Foundation, and Tohoku UniversityUniversity CenterCenter forfor GenderGender EqualityEquality PromotionPromotion (TUMUG).(TUMUG). Conﬂicts of Interest: The authors declare no conﬂict of interest. Conflicts of Interest: The authors declare no conflict of interest.

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