Synthesis of organosulfides using transition-metal-catalyzed ... - Core

Tetrahedron Letters 55 (2014) 3391–3399

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Synthesis of organosulfides using transition-metal-catalyzed substitution reactions: to construct exergonic reactions employing metal inorganic and organic co-substrate/co-product methods Mieko Arisawa ⇑ Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai 980-8578, Japan

a r t i c l e

i n f o

Article history: Received 21 March 2014 Revised 22 April 2014 Accepted 22 April 2014 Available online 30 April 2014 Keywords: Synthesis of organosulfides Organic co-substrate/co-product Metal inorganic co-substrate/co-product Exergonic reactions Catalytic substitution reaction

a b s t r a c t A catalyst changes the course of a reaction without affecting the relative thermodynamic stability of substrates and products, and a catalytic reaction must be exergonic in order to obtain high yields of the product and to attain reasonable reaction rates. In the case that the desired reaction is in equilibrium or is endergonic, devices for making products thermodynamically more stable than substrates are needed. In this review, the transition-metal-catalyzed synthesis of organosulfides using a substitution reaction is summarized, where metal inorganic and organic co-substrate/co-product methods are used in developing exergonic reactions. Ó 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/3.0/).

Contents Introduction: Catalytic reaction and chemical energy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Exergonic reactions using metal inorganic co-substrate/co-product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Exergonic reactions using organic co-substrates/co-products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Example of catalytic synthesis using organic co-substrate/co-product method: Synthesis of a-alkyl/arylthionitroalkanes . . . . . . . . . . . . . . . . . Transition-metal-catalyzed synthesis of organosulfides using metal inorganic co-substrate/co-product method . . . . . . . . . . . . . . . . . . . . . . . . . 1. Organothiolation of aryl/heteroaryl halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Organothiolation of heteroarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transition-metal-catalyzed synthesis of organosulfur compounds using organic co-substrate/co-product method . . . . . . . . . . . . . . . . . . . . . . . 1. Rhodium-catalyzed synthesis of symmetrical and unsymmetrical aryl sulfides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Rhodium-catalyzed organothiolation of various organic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction: Catalytic reaction and chemical energy A catalyst changes the course of a reaction without affecting the relative thermodynamic stability of the substrate S and the product P, and catalytic reactions must be exergonic, energetically downhill reactions, to obtain high P yields and to attain reasonable reaction rates (Fig. 1). When the relative thermodynamic stabilities of S and P are close, the reaction reaches equilibrium; in the case that S ⇑ Tel.: +81 22 795 6814; fax: +81 22 795 6811. E-mail address: [email protected]

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is thermodynamically unfavorable compared with P, a catalyst appears to be useless. When the desired reaction is in equilibrium or is endergonic, devices for making P thermodynamically more stable than S are needed. Exergonic reactions using metal inorganic co-substrate/coproduct A metal inorganic co-substrate MX is frequently used for the above purpose, which employs the chemical energy to convert

http://dx.doi.org/10.1016/j.tetlet.2014.04.081 0040-4039/Ó 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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M. Arisawa / Tetrahedron Letters 55 (2014) 3391–3399

Figure 1. Relative thermodynamic stability of substrates S and products P in catalytic reactions.

MX into a metal inorganic co-product MY, typically metal halides. Organometallic reagents are also used. Chemical energy is stored in the chemical bonds of MX; it is released in a chemical reaction producing MY, which is accompanied by heat formation. Equilibrium and endergonic reactions are converted to exergonic reactions using the chemical energy of the metal inorganic co-substrate/ co-product MX/MY. In this review, co-substrates are defined as all the stoichiometric reagents used in the reaction other than the organic substrate, and co-products are defined as all the stoichiometric byproducts other than the desired product. It was not considered whether a co-substrate is incorporated in the product or not. The term of the co-substrates/co-products is used here in a broad sense in order to make the following discussions simple. To analyze the energetic aspect on the use of the metal inorganic co-substrate/co-product MX/MY, a gas phase reaction of chlorobenzene and hydrogen sulfide giving diphenyl sulfide (Fig. 2, reaction 1) is treated as a model. The following discussions focus on the thermodynamic aspects of this hypothetical reaction using the reaction enthalpy DH. Although the Gibbs free energy DG should be discussed with regard to the equilibrium constant, DH was treated here, because standard DS is not always available, and DH can be used for comparative analysis. Reaction 1 is exothermic with an enthalpy of reaction DH = 36 kJ/mol, as calculated using the following standard enthalpies of formation: PhCl (g), +52 kJ/mol; H2S (g), 21 kJ/ mol; Ph2S (g), +231 kJ/mol; and HCl (g), 92 kJ/mol.1 Under the conditions, the reaction may not effectively proceed, because of the low reaction enthalpy and the possibly large activation energy. Therefore, it is necessary to make the reaction largely exothermic. When a stoichiometric amount of NaOH is added, the reaction gives thermodynamically stable NaCl and water as inorganic coproducts (reaction 2). Reaction 2 is largely exothermic with DH = 306 kJ/mol, which is calculated from the following standard enthalpies of formation: NaOH (c), 426 kJ/mol; NaCl (c), 411 kJ/ mol; and H2O (g), 242 kJ/mol. The use of NaOH converts reaction 1 with DH = 36 kJ/mol to reaction 2 with DH = 306 kJ/mol, and likely reduces the activation energy, which will accelerate the reaction and improve the yield. The effect of a base can also be considered in terms of energy, and the use of a strong base provides a large chemical energy. When ammonia is used in place of NaOH in the above reaction, the reaction enthalpy decreases to DH = 388 kJ/mol (reaction 3). The use of a weaker base provides less exergonic reactions: The reaction enthalpy increases to DH = 179 kJ/mol using Na2CO3 (reaction 4) and to DH = 44 kJ/mol using NaHCO3 (reaction 5).

Figure 2. Hypothetical synthesis of diphenyl sulfide using metal inorganic cosubstrate/co-product method.

The use of strong bases implies the supply of a large chemical energy to the reaction system. Catalysts can then be developed for exergonic reactions using metal inorganic co-substrate/co-product method. The method, however, supplies an excessively large chemical energy and forms metal salts as waste materials. Note that a large energy is required to recover the metal inorganic co-product MY and regenerate the metal inorganic substrate MX. Thus, it may be conceivable to consider the synthesis of NaOH by NaCl electrolysis in water. Exergonic reactions using organic co-substrates/co-products With the above background, it was then considered attractive to develop a catalytic reaction, that uses a designed combination of the organic co-substrate/organic co-product S0 /P0 . The equilibrium between S and P can be shifted to P in the presence of S0 forming P0 , when the relative thermodynamic stability of the P/P0 system is higher than that of the S/S0 system (Fig. 1). When ethylene is used as the organic co-substrate in reaction 1 between chlorobenzene and hydrogen sulfide, diphenyl sulfide is obtained along with ethyl chloride as an organic co-product (Fig. 3, reaction 6). Reaction 6 is exothermic with DH = 180 kJ/ mol, which is calculated using the following standard enthalpies of formation: H2C = CH2 (g), +52 kJ/mol; CH3CH2Cl (g), 112 kJ/ mol. By using the organic co-substrate/co-product S0 /P0 , instead of metal inorganic co-substrate/co-product MX/MY, the reaction can be conducted using a smaller chemical energy. Also note that metal waste is not formed. One advantage of the organic co-substrate/co-product S0 /P0 method is that the reaction can be fine-tuned using various combinations of S0 and P0 . In order to discuss the effect of such combinations, a gas phase reaction of benzene to give diphenyl sulfide is treated as a model (Fig. 4). When sulfur reacts, the reaction is endothermic with DH = +52 kJ/mol, as calculated using the standard enthalpies of formation: PhH (g), 83 kJ/mol; S8 (g), 101 kJ/ mol; and Ph2S (g), 231 kJ/mol (reaction 7). In principle, the reaction


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Figure 3. Hypothetical exergonic synthesis of diphenyl sulfide using ethylene as organic co-substrate.

Figure 5. Hypothetical exergonic synthesis of diphenyl sulfide using ethylene as organic co-substrate.

Figure 6. Reversible reaction system using organic co-substrate/co-product method.

Figure 4. Hypothetical synthesis of diphenyl sulfide using organic co-substrate/coproduct method.

does not provide a product, and it is necessary to make the reaction exergonic. The use of a combination of the organic co-substrate/coproduct S0 /P0 can decrease the reaction enthalpy. When benzenethiol is used as S0 , the reaction provides diphenyl sulfide along with the co-product H2 and becomes less endothermic, DH = +36 kJ/mol (reaction 8). With thioanisole or diphenyl disulfide as S0 , the enthalpy decreased to DH = +28 and DH = +16 kJ/mol (reactions 9 and 10), respectively, which is calculated from the following standard enthalpies of formation: MeSH (g), 23 kJ/mol; PhSH (g), +112 kJ/mol. When diphenyl sulfide is used as S0 , the reaction enthalpy may be DH = ca. 0 kJ/mol (reactions 11), because of the ArS exchange nature of the reaction. The use of benzenesulfenic acid still decreases the reaction enthalpy to DH = 60 kJ/mol (reaction 12), which is calculated using the standard enthalpy of formation of PhSOH (g), 34 kJ/mol.2 Note that the inorganic metal cosubstrate/co-product method may not be applicable to this reaction, because the products are neutral compounds that have no halides. The method has another advantage in that the organic co-product S0 can undergo further chemical transformation to make the reaction energetically favorable. When oxygen is added to reaction 10, diphenyl sulfide and water are formed (Fig. 5, reaction 13). The reaction 10 + 13 = 14 is exothermic with DH = 95 kJ/mol, as calculated from the standard enthalpy of formation of H2O (g), 242 kJ/mol. The endothermic reaction with DH = +16 kJ/mol is converted to exothermic reaction 14 with DH = 95 kJ/mol by the oxidation of benzenethiol to diphenyl disulfide and water. Reaction 13 may be exergonic practically enough to induce the

reaction, and the transformation can take place efficiently using catalysis. Also note that water is the only co-product P0 for this reaction. There are other advantages of the use of the organic co-substrate/co-product method to develop exergonic reactions. The use of stoichiometric amounts of strong bases and organometallic reagents needs special care for manipulation, and often moisture and oxygen must strictly be removed. In contrast, because of the stable nature of organic co-substrates/co-products, their reactions are easier to carry out, and various functional groups are tolerated to give a diversity of products. In addition, when S0 with a simple structure and a low molecular weight is formed, it can readily be separated and deposited. Alternatively, the co-product P0 can be useful for other purposes. The organic co-substrate/co-product method can be used to revert the product P to the substrate S. Since the thermodynamic stabilities of the S/P and S0 /P0 systems are close, the use of an appropriate combination of P0 /S0 effectively transforms P to S (Fig. 6). The method may be employed for the reuse or recycle of organic compounds for resource conservation. Another issue related to further study is that the organic cosubstrate/co-product method can be used for developing consecutive reaction systems. Chemical equilibrium is used for biosynthesis, metabolism, and molecular transportation in living organisms, and a number of low-activation-energy reactions are organized consecutively. Such an energy-saving reaction system can be realized by reactions using organic co-substrates/co-products with a small chemical energy, but not by inorganic co-substrate reactions with a large chemical energy. The development of chemical reactions using the organic co-substrate/co-product method has significant implication in organic synthesis.

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Example of catalytic synthesis using organic co-substrate/coproduct method: Synthesis of a-alkyl/arylthionitroalkanes As part of our study to develop synthetic methods for organoheteroatom compounds, I found transition-metal catalysis to be useful for the transformation of organosulfur compounds. Various rhodium-catalyzed reactions involving the formation, cleavage, and rearrangement of CAH, CAS, CAP, CAF, CAN, SAS, PAP, and PAS bonds were developed.3 Such single bond substitution reactions are often in equilibrium or are endergonic. The thermodynamic control of the reactions to obtain the desired products with high efficiency has become critical, and the organic co-substrate/co-product method was examined. An example is provided here for the conversion of the thermodynamically unfavorable reaction to an exergonic reaction. The reaction of 1-nitroalkanes to form 1-arylthio-1-nitroalkanes was developed under rhodium catalysis.4 The treatment of 1-nitrohexane 1 and bis(p-chlorophenyl) disulfide 2 in the presence of a catalytic amount of RhH(PPh3)4 (5 mol %) and dppe (10 mol %) at rt for 3 h under air atmosphere gave 1-arylthio-1-nitrohexane 3 in 50% yield (Scheme 1). The yield of 3 decreased to 1% in argon atmosphere, which showed a critical role of oxygen. When equimolar amounts of 3 and p-chlorobenzenethiol 4 were treated with the catalyst at rt for 3 h in argon atmosphere, 1 and 2 were obtained in 95% and 86% yields, respectively. The reactions to form 3 from 1 and 2 turn out to be in equilibrium with the endergonic nature (Fig. 7, reaction 15). Thus 3 was obtained in air atmosphere due to the oxidation of the thiol 4 to the disulfide 2 and water under rhodium catalysis (reaction 16), by which an exergonic reaction developed to shift equilibrium to the product 3 (reaction 15 + 16 = 17). As noted in the model reaction to synthesize diphenyl sulfide from benzene and diphenyl disulfide (reaction 14), the

Scheme 1.

oxidation of a thiol to a disulfide makes the whole reaction exergonic. It was previously reported that the rhodium complex catalyzes the oxidation of thiols to disulfides and water.5 Also note that water is the only co-product of this reaction, which is derived from the initial co-product thiol. 1-Organothio-1-nitroalkanes are versatile intermediates in organic synthesis, and their conventional synthesis methods employed stoichiometric amounts of metal bases such as MeONa, NaOH, and t-BuOK,6 which may make the reaction exergonic through the chemical energy of inorganic cosubstrates/co-products. In the following part of this review, the transition-metal-catalyzed synthesis of organosulfur compounds is discussed with emphasis on organosulfides, and reactions using metal inorganic and organic co-substrates/co-products are described. The metal inorganic co-substrate/co-product method gives products in high yields at relatively rapid reaction rates using a large chemical energy. In contrast, the organic co-substrate/co-product method uses a smaller chemical energy, which has extensively been studied by my group. In such a reaction system, the reactions can be fine-tuned by using the structure design of the organic co-substrates/co-products. In addition, using the reversible nature of the reaction, both the synthesis of products and the regeneration of substrates are conducted. Transition-metal-catalyzed synthesis of organosulfides using metal inorganic co-substrate/co-product method Organosulfur compounds are widely used for drugs and materials, and it is necessary that efficient methods of synthesizing organosulfur compounds be developed. Sulfur is a third row element in the periodic table. Compared with oxygen in the second row, sulfur is larger and polarizable, moreover, various states of this element, such as thiols, sulfides, and disulfides, are available. The synthesis of organosulfur compounds uses different methods from that of organooxygen compounds.7 The formation of CAS bonds represents a key step in the synthesis of organosulfur compounds, and substitution and addition reactions are generally employed. Substitution reactions using transition-metal catalysis are described here, and the scope of methods using these reactions is discussed along with the energetic aspect. Refer to other reviews for catalytic addition reactions.8 1. Organothiolation of aryl/heteroaryl halides The transition-metal-catalyzed cross-coupling of aryl halides and thiols has been developed for CAS bond formation for organosulfide synthesis. The first reaction of this type was reported in 1978 by Kosugi et al.9 Diaryl and aryl alkyl sulfides were obtained by the reaction of thiols and aryl iodides/bromides in the presence of Pd(PPh3)4 and a stoichiometric amount of t-BuONa. The finding revealed that CAS bond formation can be conducted using transition-metal catalysis. The reaction is accompanied by the formation of sodium halides as co-products, and chemical energy is employed to convert sodium alkoxide to sodium halides (Scheme 2). Aryl CAS bond formation has recently been extended using new catalytic systems.10 Hartwig and co-workers used the Josiphos

Figure 7. Exergonic organothiolation of nitroalkanes using oxidation of thiol.

Scheme 2.

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Scheme 8.

Scheme 3.

nyl)-2-pyridines were synthesized using aryl thiols or dimethyl disulfide in the presence of a stoichiometric amount of copper.23,24 The catalytic CAS bond formation via cross-coupling provides functionalized aryl/heteroaryl sulfides in high yields. The reactions use stoichiometric amounts of metal inorganic co-substrates in order to make the reaction exergonic. Scheme 4.

Transition-metal-catalyzed synthesis of organosulfur compounds using organic co-substrate/co-product method

Scheme 5.

Scheme 6.

ligand CyPF-t-Bu to carry out the cross-coupling of aryl chlorides/ triflates and thiols (Scheme 3).11 The catalytic synthesis of diaryl sulfides containing a heteroarene is also interesting in relation to drugs development,12 which was conducted by the coupling of either heteroaryl thiols/aryl halides or aryl thiols/haloheteroarenes.13 A palladium-catalyzed reaction allows the coupling of aryl or alkyl thiols and 2-bromopyridine using a stoichiometric amount of t-BuONa (Scheme 4).14 The cross-coupling of 2-mercaptobenzothiazole and aryl iodides/bromides provided 2-arylthiobenzothiazolyl sulfides in the presence of a CuI catalyst and a stoichiometric amount of Na2 CO3 (Scheme 5).15 Symmetrical diaryl sulfides were synthesized from aryl halides and sulfur reagents such as thiourea,16 xanthate,17 thioacetate,18 thiocyanate,19 and metal sulfides20 in the presence of palladium or copper catalysts along with bases (Scheme 6).

We have been studying the development of a transition-metalcatalyzed synthesis process for organosulfur compounds, and examining substitution reactions involving the cleavage of various heteroatom bonds, which include the CAF, CAH, CAS, SAS, CAP, and CAO bonds, under rhodium catalysis.3,25 The reactions are often in equilibrium or are endergonic, and the demand for devices for producing the desired products with high efficiency has become critical. The method using organic co-substrates/co-products was employed. 1. Rhodium-catalyzed synthesis of symmetrical and unsymmetrical aryl sulfides It was found that aryl fluorides are excellent substrates for the rhodium-catalyzed substitution reaction with sulfur reagents. To develop an exergonic reaction, it is necessary to consider the thermodynamic stability of substrates and products, particularly the fate of fluoride. The rhodium-catalyzed reaction of aryl fluorides and diaryl disulfides gave diaryl sulfides in the presence of a stoichiometric amount of triphenylphosphine (Fig. 8).26 The reaction formally forms sulfenium fluoride R-SF, which is extremely unstable.27 In order to convert R-SF to a stable product and to carry out a thermodynamically favorable reaction, triphenylphosphine was added, which converted R-SF to triphenyl phosphine difluoride and disulfide. Under rhodium catalysis, fluoride substitution

2. Organothiolation of heteroarenes Another attractive method of synthesizing heteroaryl sulfides is the catalytic conversion of the CAH bond to the CAS bond. Fukuzawa developed the copper-catalyzed thiolation of benzoxazole using diaryl disulfides in the presence of Cs2CO3 in oxygen atmosphere (Scheme 7).21 The copper-catalyzed alkyl thiolation of azoles with alkyl thiols has been reported under oxidative conditions using CuO (Scheme 8).22 Its mechanism was suggested to entail the addition of copper thiolate to heteroarenes followed by oxidation.23 2-Organothiobenzothiazoles and (2-organothiophe-

Scheme 7.

Figure 8. Substitution triphenylphosphine.

reaction

of

aryl

fluorides

and

disulfides

using

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Scheme 9.

proceeded more readily than chloride and bromide substitutions (Scheme 9). The reaction of hexafluorobenzene and a diaryl disulfide gave 1,4-diarylthio-2,3,5,6-tetrafluorobenzene, 1,2,4,5-tetraarylthio-3,5-difluorobenzene, and hexaarylthiobenzene in a stepwise manner. The rhodium-catalyzed polyarylthiolation reaction of polyfluorobenzenes exhibited a strong tendency to form 1,4-difluorobenzenes.25a,b The method was extended to the reaction of sulfur, where tributylsilane was used to capture fluoride, thereby forming tributylsilyl fluoride. With regard to the fate of the hydrogen atom in silane, a small amount of oxygen present in the reaction was assumed to react with this atom giving a water co-product. Substituted pentafluorobenzenes reacted with sulfur to give bis(4-substituted2,3,5,6-tetrafluorophenyl) sulfides in the presence of a rhodium catalyst and a stoichiometric amount of tributylsilane (1 equiv) (Scheme 10).28 An organic trisulfide and a tetrasulfide were also examined, which exhibited different reactivities with sulfur: Di(t-butyl) tetrasulfide reacted with substituted pentafluorobenzenes and 2-fluorobenzothiazole; di-(t-butyl) trisulfide reacted with aryl monofluorides. Thus, diaryl sulfides were synthesized from aryl fluorides and sulfur reagents, where the reductive capture of fluoride atoms by triphenylphosphine or tributylsilane was critical for efficient reaction. Using the symmetrical diaryl sulfides obtained above (Scheme 10), unsymmetrical diaryl sulfides were synthesized by a rhodium-catalyzed arylthio exchange reaction (Fig. 9, reaction 21).29 Since the interconversion of diaryl sulfides is under equilib-

Figure 9. Aryl exchange triisopropylsilane.

reaction

of

symmetrical

diaryl

sulfides

using

Scheme 11.

Scheme 12.

rium, a device is required to shift the equilibrium to the desired product. Substituted fluorobenzenes were reacted with a symmetrical diaryl sulfide in the presence of triisopropylsilane, where one of the aryl groups in the symmetrical diaryl sulfide was reduced to unreactive hydrogenated product with the concomitant formation of silyl fluoride (reaction 22). Various unsymmetrical polyfluorinated diaryl sulfides were synthesized from symmetrical polyfluorinated diaryl sulfides by aryl exchange (Scheme 11). Overall, symmetrical and unsymmetrical diaryl sulfides are synthesized from sulfur and aryl fluorides without using metal inorganic cosubstrates (Schemes 10 and 11). The copper-catalyzed synthesis of diaryl sulfides by the reaction of aryl iodides and carbon disulfide was reported using DBU (Scheme 12).30 2. Rhodium-catalyzed organothiolation of various organic compounds

Scheme 10.

A method for the rhodium-catalyzed conversion of the CAH bond to the CAS bond was developed for the synthesis of organosulfides using the organic co-substrate/co-product method. This type of reaction was examined using proton acidity as the reactivity index: The reactions of acidic substrates were initially examined, which were extended to reactions of less acidic substrates.

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In studies of the rhodium-catalyzed synthesis of organosulfur compounds, a reaction to convert 1-alkynes to 1-alkylthio/arylthio-1-alkynes was developed. The reaction exchanges CAH/SAS bonds to CAS/SAH bonds (Scheme 13).31 Aryl, alkyl, and silyl 1alkynes were reacted with dialkyl/diaryl disulfides under rhodium catalysis, and 1-alkyl/arylthio-1-alkynes were obtained with the concomitant formation of thiol. The reaction turned out to be in equilibrium, which suggested that the catalytic conversion of various organic compounds to organosulfides can proceed without supplying a large chemical energy. The a-organothiation reaction of nitroalkanes (pKa 16–18)32 using disulfides was mentioned above (Scheme 1), in which the endergonic reaction was converted to an exergonic reaction by the air oxidation of thiols to disulfides. Diethyl malonate (pKa 16)33 and 1,2-diphenyl-1-ethanone 1 (pKa 18)34 with similar acidic protons were also a-organothiolated using a disulfide in air atmosphere (Fig. 10).4 It was confirmed that the yield of 2 decreased in argon atmosphere. The reversible nature of the above reaction suggested that the organothio group of organosulfur compounds can be transferred to other organic compounds. Such a reaction may be useful for the sequential synthesis of organosulfur compounds via the rearrangement of the organothio group. In argon atmosphere, the amethylthiolation reaction of 1 was conducted using a-methylthio-p-cyanoacetophenone 3 as the co-substrate (Fig. 10).35 The methylthio group was effectively transferred from 3 to 1, and 2methylthio-1,2-diphenyl-1-ethanone 4 was obtained with the concomitant formation of p-cyanoacetophenone 5. It shows that an organothiation reaction of organic compounds can be developed using an organosulfur compound as the co-substrate. Organothiolation reactions using disulfides and organosulfur compounds are complimentary (Fig. 10), and can be used for various substrates. Unactivated ketones with less acidic a-protons were methylthiolated using 4 as the co-substrate, which was obtained by the above reaction. The reaction of propiophenone 6 (pKa 24)36 and 4 gave a-methylthiopropiophenone 7 (Scheme 14).37 It was noted

that 7 was not obtained using 3 in place of 4, which showed a critical role of the co-substrate for efficient methylthio transfer reaction. The phenomenon was ascribed to the weaker CAS bond of 3 than of 4. a,a-Disubstituted aldehydes and cyclohexanone (pKa 26)38 were also converted using 4 to their corresponding a-methylthiolated products in high yields (Scheme 15). The organothiolation of benzothiazole 8 with the less acidic proton (pKa 27)34 was conducted using (a-phenylthio)isobutyrophenone 9 as the co-substrate, giving 2-phenylthiobenzothiazole 10 in 92% yield (Scheme 16).39 The effects of the co-substrate under the same conditions are as follows: 2-methylthio-1,2-diphenylethanone 4 gave no methylthiolated product 12; methylthiopropiophenone 7 gave 12 in 13% yield; a(methylthio)isobutyrophenone improved the yield of 12 to 43%. These results suggested the use of organosulfur co-substrates with a stronger CAS bond for less acidic substrates. Various heteroarenes such as benzothiazoles and benzoxazoles, 3-cyanobenzothiophene, and N-methyl tetrazole were converted to their corresponding arylthiolated products in high yields using 9. This shows the advantage of the organic co-substrate/co-product method, in which the combination can be fine-tuned to improve the product yield. Also note that the reaction proceeds without using metal bases or oxidants and is likely to entail the CAH activation of heteroarenes. A series of rhodium-catalyzed organothiolation reactions were developed for the synthesis of organosulfides, which employ substrates with pKa values 16–27.40 All the reactions are in equilibrium, which was shifted to the desired products using the organic co-substrate/co-product method (Fig. 11): Relatively acidic compounds (pKa values 16–18) reacted with diaryl disulfides in the presence of O2; 1-alkynes with a relatively acidic proton (pKa 21) reacted with disulfides; less acidic alkyl ketones and heteroarenes (pKa ca. 27) were reacted with organosulfur compounds by CAH/ CAS exchange. Recently, Nishihara developed the palladium/copper-catalyzed thiolation reaction of arenes bearing a 2-pyridyl directing group

Scheme 13.

Scheme 14.

Scheme 15.

Figure 10. Organothiolation of 1,2-diphenyl-1-ethanone.

Scheme 16.

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groups were transformed between thioesters, acylphosphine sulfides, aryl esters, acid fluorides, benzyl ketones, and acyl phthalimides. These reactions are in equilibrium and efficiently proceed using the organic co-substrate/co-product method, giving acyl derivatives in high yield (Fig. 12).26a,c,d,43 The use of rhodium-catalysis and the organic co-substrate/coproduct method provided various organosulfides. Substitution reactions often reach equilibrium, and the desired products are efficiently obtained by the fine-tuning of the co-substrate structure. Considering the thermodynamic stability of organic co-substrate/co-product systems, organosulfide synthesis can be conducted using a small chemical energy. Summary

Figure 11. Rhodium-catalyzed organothiolation reaction using organic co-substrate/co-product method.

Scheme 17.

It is necessary to develop exergonic reactions for conducting efficient catalytic reactions. Thus, metal inorganic co-substrates/ co-products and organic co-substrates/co-products are discussed. The former reactions are promoted by the formation of thermodynamically stable inorganic salts from metal inorganic co-substrates and can give the desired products within a short reaction time in high yield. Although the reactions are relatively easy to control, a large chemical energy is employed, which is accompanied by metal waste formation. In contrast, the organic co-substrate/co-product method can promote reactions using smaller chemical energy. In addition, the method has advantages in that the reversible reaction can be conducted and that the reactions can be fine-tuned using various combinations of co-substrates/co-products. However, unlike the inorganic co-substrate/co-product method, the thermodynamic stability of substrates and products needs to be well designed, and such a principle is not yet well established. From the viewpoint of energy conservation, and the synthesis and reuse of useful organic compounds, the organic co-substrate/co-product method is an attractive. Acknowledgments

Scheme 18.

This work was supported by a Grant-in-Aid for the Scientific Research (Nos. 22689001 and 25109503) and Asahi Glass Foundation. References and notes

Figure 12. Rhodium-catalyzed acyl transfer reactions using organic co-substrate/ co-product method.

with disulfides (Scheme 17).41 The energetic aspect of this reaction seems to be close to the reaction 14 (Fig. 5), although DMSO is noted for the oxidant of thiols. The copper-catalyzed thiolation of xanthine derivatives with disulfides has been conducted under oxygen atmosphere (Scheme 18).42 In addition to organic sulfides, thioesters are excellent substrates for the rhodium-catalyzed substitution reaction. Acyl

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