WO2007064869A2 - Catalysts for aryl sulfide synthesis and method of producing aryl sulfides - Google Patents

Abstract

The present invention relates to the formation of aryl sulfides and aryl thiols from aryl halides and thiols, thiolates or thiolate equivalents. The present invention provides a catalyst for the coupling of aryl halides with alkyl or aryl thiols or a hydrogen sulfide equivalent to form aryl alkyl, aryl silyl or diaryl sulfides. The reaction encompasses bromoarenes and other similar compounds containing leaving groups as well as nitrile, ester, keto, free hydroxyl, free amino, free carboxylic acid and other common functionalities. The invention can be used to prepare pharmaceutical compounds, especially including their intermediates, agricultural agents and aryl sulfide polymers.

Description

Catalysts for Aryl Sulfide Synthesis and Method of Producing Aryl Sulfides

Field of the Invention

The present invention relates to the formation of aryl sulfides and aryl thiols from aryl halides and thiols, thiolates or thiolate equivalents. The present invention provides a catalyst for the coupling of aryl halides with alkyl or aryl thiols or a hydrogen sulfide equivalent to form aryl alkyl, aryl silyl or diaryl sulfides with turnover numbers in excess of 1000 for the coupling of chloroarenes and typically and typically in the range of 10,000 for the coupling of bromo and iodoarenes. The reaction encompasses bromoarenes containing nitrile, ester, keto, free hydroxyl, free amino, free carboxylic acid and other common functionalities. The invention can be used to prepare pharmaceutical compounds, especially including their intermediates, agricultural agents and aryl sulfide polymers.

Related Applications and Government Support

This application claims the benefit of priority of provisional application US60/741,305 filed December 1, 2005, the entire contents of which are incorporated by reference herein.

This invention was made with support from the United States government NIH- NIGMS grant number GM-55382. Consequently, the government retains certain rights in this invention.

Background of the Invention

Aryl sulfides'-^1" are valuable intermediates in organic synthesis of biologically and pharmaceutically active molecules, of organic materials, or intermediates to these molecules. A number of aryl sulfides have shown potential clinical applications. These applications include the treatment of inflammation by acting as antagonists of the interaction between leukocyte function-associated antigen- 1 and both intracellular adhesion molecule- 1 (LFA- 1/ICAM-l)^13"41 and vascular cell adhesion molecule-1 (VCAM-1).^[5] The applications of aryl sulfides also include treatment of Alzheimer's and Parkinson's diseases by acting as muscarinic^ or nicotinic¹-⁷¹ receptor antagonists, treatment of asthma and obstructive pulmonary disease by acting as a 5 -lipoxygenase inhibitor,¹-⁸-¹ treatment of human immunodeficiency virus (HIV) by inhibiting HIV-I protease (an enzyme involved in the virus maduration)^[9J and treatment of cancer as tubulin polymerization inhibitors.¹-^10"11] Palladium-catalyzed cross-coupling reactions that form carbon-heteroatom bonds have recently emerged as an extremely powerful synthetic organic method. ^[12"19] In particular, the synthesis of aromatic amines and ethers from aryl halides or pseudohalides has been extensively studied and developed into practical methodology. In contrast, the analogous synthesis of aryl sulfides has received less attention. ^[20]

In 1978 and 1980 Migita and co-workers first reported the coupling of iodo and bromoarenes with thiols in the presence of Pd(PPh₃)₄ as catalyst. ^[21"22] In the last decade, more efficient catalyst systems containing bidentate phosphines or dialkylphosphine oxides ligands have been described for this reaction. ^[23'29] Nevertheless, these protocols display three major drawbacks that reduce their ability to form biologically active sulfides or precursors of biologically active compounds in a practical fashion. First, the published catalysts have short lifetimes; low turnover numbers (TON < 50) are typically achieved. Second, the coupling of thiols with aryl chlorides is undeveloped, and aryl chlorides are the most useful of the haloarenes because of their wider availability and lower cost.^[30] Third, the previous couplings to form sulfides have occurred with narrow scope. The demonstrated tolerance of the reactions to potentially reactive functional groups has been limited to haloarenes containing nitriles and esters. ^[23'27]

Nickel- and copper-catalyzed coupling of thiols with aryl halides has also been reported.^[31"32] However, these processes require either high temperatures or high catalyst loadings. Further, these reactions have typically been conducted with aryl iodides.^[33"34]

Palladium thiolates form easily and undergo relatively fast reductive eliminations with aryl groups.^[35"37] Thus, the current limitations on the aromatic thiation could result from the notorious sensitivity of late metal catalysts to substrates containing reactive sulfur functionality. The lifetime and concentrations of the catalysts used for the coupling of haloarenes with thiols is likely to be limited by factors such as displacement of dative ligands by thiolates to form anionic thiolate complexes I or the formation of bridging thiolate complexes II that undergo slow reductive elimination (Figure 1).^[36] Therefore, a more reactive catalyst for the coupling of thiolates might contain a bisphosphine that binds the metal strongly enough to prevent formation of anionic or bridging thiolate complexes I and II, while simultaneously promoting oxidative addition and reductive elimination.

Based on this hypothesis, we considered that the restricted backbone conformation, steric hindrance, and strong electron donation of the Josiphos ligand CyPF-t-Bu (1- dicyclohexylphosphino-2-di-t-butylphosphinoethylferroceno, 1 in Table 1)^[38] might create practical catalysts for the coupling of thiols with aryl halides. Herein, we describe the scope and limitations of the coupling of aryl chlorides with thiols using this catalyst system. In addition, we report an evaluation of other common ligands, as well as a preformed catalyst precursor (CyPF-J-Bu)PdCl₂, under conditions of low catalyst loading.

Brief Description of the Figures

Figure 1 shows the general mechanism for the palladium-catalyzed C-S bond forming reactions.

Figure 2 shows the effect of ligand on the coupling of aryl chlorides with thiols at 0.1 mol % catalyst loading. Reaction conditions: 4-chloroanisole (1 mmol), RSH (1 mmol), Pd(OAc)₂/Ligand (0.1 mol %), NaOtBu (1.1 mmol) in DME (1.5 niL) at 110⁰C for 24 hours.

Brief Description of the Invention

The present invention is directed to compounds which are catalysts or pre-catalysts according to the chemical structure:

Where R¹ and R² are each independently H or an optionally substituted C₁-C₁₀ hydrocarbyl group, preferably a C₁-C₆ alkyl group, an optionally substituted heterocyclic group, preferably an optionally substituted heteroaryl group, or said optionally substituted hydrocarbyl or optionally substituted heterocyclic group is bound to the benzylic carbon through carbon, oxygen, nitrogen, sulfur or phosphorus, and said group is preferably an optionally substituted C₁-C₁₀ hydrocarbyl group, more preferably a C₁-C₆ alkyl group; Y is M or a PR⁵R⁶ group;

R³, R⁴, R⁵ and R⁶ are each independently an optionally substituted C₁-C₁₀ hydrocarbyl group or an optionally substituted 3-14 membered heterocyclic group bound to phosphorus through carbon, oxygen, nitrogen, or sulfur; more preferably an optionally substituted aryl group, an optionally substituted C₁-C₆ alkyl group, an optionally substituted Ci-C₆ (preferably C₁-C₃) alkoxy group, an optionally substituted phenoxy group, an amino group which is optionally substituted with one or two C₁-C₆ alkyl or alkanol groups; an optionally substituted C₁-Ci₀ vinyl group, an optionally substituted 3 to 14 membered heterocyclic group, or a heteroaryl group; most preferably an optionally substituted C₁-C₆ alkyl group;

M is Pd, Ni or Pt, and M is substituted with X and L or X and a PHR⁵R⁶ group and is linked through a bond to PR³R⁴ or is M a PR⁵R⁶-M^! group where M¹ is Pd, Ni or Pt, M¹ is substituted with two X groups and is linked through a bond to PR³R⁴; X is a formally anionic 2-electron donor ligand;

L is a formally neutral 2-electronic donor ligand; and

CpFe is a cyclopentadienyl iron (ferrous) group.

Compounds according to the prevent invention are preferably represented by the following chemical structures: ,

Where each of R¹, R², R³, R⁴, R⁵, R⁶, X, L₅ M₅ M¹ and CpFe are the same as set forth above.

hi additional aspects of the present invention a catalyst comprises a compound according to the formula:

and a source of palladium (Pd), nickel (Ni) or platinum (Pt); Wherein R¹, R², R³, R⁴, R⁵ and R⁶ and CpFe are the same as set forth above.

In another aspect of the present invention, a catalyst comprises a compound according to the formula:

a secondary phosphine PHR⁵R⁶ Wherein R¹, R², R³, R⁴, R⁵, R⁶ L, X, M and CpFe are the same as set forth above. Preferably, M is Pd.

In a further aspect of the invention, a catalyst comprises a compound according to the formula:

Wherein R¹, R², R³, R⁴, R⁵, R⁶, X₅ M and CpFe are the same as set forth above. Preferably, M is Pd.

In a further aspect of the invention, a catalyst comprises a compound according to the formula:

Wherein R¹, R², R³, R⁴, R⁵, R⁶, X, M¹ and CpFe are the same as set forth above. Preferably, M¹ is Pd.

Any of compounds 1-6 of figure 2. Note that Cy in the figure represents a cyclohexyl group.

In various aspects of the present invention, R and R are preferably a C₁-C₄ hydrocarbyl group, more preferably a methyl, ethyl or propyl or a t-butyl group or a phenyl, a 3,5-xylyl, a 2,4-xylyl, p-tolyl or a 3,5-bis-trifluoromethylphenyl. R³, R⁴, R⁵ and R⁶ are preferably a C₁-C₈ hydrocarbyl group, more preferably a t-butyl group, a cyclohexyl group, or a phenyl, a 3,5-xylyl, a 2,4-xylyl, p-tolyl or a 3,5-bis-trifluoromethylphenyl group, a heteroaryl selected from the group consisting of a pyridyl (2, 3, or 4-pyridyl), a 2- or 3- thienyl group or a 2- or 3-furyl group, a methoxy, ethoxy, isopropoxy, or phenoxy group, or a dimethylamino group.

In a method aspect of the invention, an aryl C-S bond or olefmic C-S bond is formed by reacting an aryl or olefmic compound containing a leaving group (e.g., a halogen such as Cl, Br, I or a sulfonate group such as tosyl (toluenesulfonyl), triflic (trifluoromethylsulfonyl) or a related sulfonate leaving group) with a thiol-containing compound (HSR)in the presence of a pre-catalyst or catalyst according to the present invention and optionally, a secondary phosphine compound or a metal or metal-containing compound containing Pd, Ni, or Pt to produce an aryl or olefin compound containing an S-R group in a solvent at ambient temperature or a temperature above or below ambient temperature.

The following reactions are representative of the present invention:

HSR/ catalyst hydrogen

sulfide solvent

equivalent _temp

Where Ar is an aryl group, which term includes a heteroaryl group and fused bicyclic or polycyclic aryl or heteroaryl groups;

Each R' is a substituent on the aryl group, which may be the same or different and is an optionally substituted C₁-C₁₂ hydrocarbyl group, optionally substituted alkyl or aryl alkoxides (preferably, unsubstituted or substituted C₁-C₆ alkoxides or phenoxides), optionally substituted keto, ester or carboxylic acid groups, nitro, nitrile (CN), amines, which may be unsubstituted or substituted with one or two substituents otherwise disclosed herein (preferably including C₁-C₃ alkyl groups or alkanol groups), halogens (F, Br, Cl, I), mono- and dialkylamido groups, mono- and diarylamido groups, amidates (preferably unsubstituted or substituted alkyl or aryl amidates), carboxylic acid groups, hydroxyl groups, among numerous others, including optionally substituted 3-14 membered heterocyclic groups. Exemplary preferred substituents include unsubstituted or substituted C₁-C₆ alkyl groups or aryl groups (especially halogenated alkyl groups such as fluoro-substituted alkyl groups), preferably phenyl groups, alkoxide groups, keto groups, keto esters, carboxyl groups or amino groups, which substituents, within context, may be attached to a further substituent in context, through carbon, oxygen, nitrogen or sulfur atoms. Note that the term substituent subsumes or incorporates O, S or N atoms within alkyl or alkylene chains or in aryl groups (heteroaryl); n is from 0 to 5, preferably 0 to 3;

X¹ is a leaving group, preferably a halogen selected from Cl, Br or I or a sulfonate group such as a tosylate, mesylate or triflate (trifluoromethylsulfonate) group; and

R is an optionally substituted C₁-C₁₂ hydrocarbyl group, an optionally substituted 3- 14 membered heterocyclic group or a Si-containing group -SiR₁R₂R₃ group where R₁, R₂ and R3 are the same or different and are selected from H or a C1-C6 hydrocarbyl group which is optionally substituted with a halogen group or with at least one C₁-C₃ alkyl group with the proviso that not more than two OfR₁, R₂ and R₃ is H and preferably none are H.

In an alternative embodiment, reactions to introduce C-S bonds onto olefins occur by the following reaction wherein a thiol-containing compound is reacted with an olefinic group having a leaving group (halogen or sulfonate, preferably Cl, Br, I or tosylate, mesylate or triflate group):

HSR/ catalyst hydrogen sulfide solvent

equivalent temp

Where X¹ is a leaving group such as a halogen or sulfonate leaving group (Cl, Br, I, tosylate, mesylate or triflate);

R⁷, R⁸ and R⁹ are each independently selected from H, an optionally substituted C₁- C₁₂ hydrocarbyl group, an optionally substituted alkyl or aryl alkoxide (preferably, unsubstituted or substituted C₁-C₆ alkoxides or phenoxides), optionally substituted keto, ester or carboxylic acid groups, nitro, nitrile (CN), amines, which may be unsubstituted or substituted with one or two substituents otherwise disclosed herein (preferably including C₁- C₃ alkyl groups or alkanol groups), halogens (F, Br, Cl, I), mono- and dialkylamido groups, mono- and diarylamido groups, amidates (preferably unsubstituted or substituted alkyl or aryl amidates), carboxylic acid groups, hydroxyl groups, among numerous others, including optionally substituted 3-14 membered heterocyclic groups. Exemplary preferred substituents include unsubstituted or substituted C₁-C₆ alkyl groups or aryl groups (especially halogenated alkyl groups such as fluoro-substituted alkyl groups), preferably phenyl groups, alkoxide groups, keto groups, keto esters, carboxyl groups or amino groups, which substituents, within context, may be attached to a further substituent in context, through carbon, oxygen, nitrogen or sulfur atoms. Note that the term substituent subsumes or incorporates O₅ S or N atoms within alkyl or alkylene chains or in aryl groups (heteroaryl).

The present invention provides a catalyst for the coupling of aromatic compounds which have halogen or sulfonate leaving groups with alkyl or aryl thiols or hydrogen sulfide equivalent to form aryl, alkyl or diaryl sulfides with turnover numbers in excess of 1000 for the coupling of chloroarenes and typically in the range of 10,000 for the coupling of bromo and iodoarenes. The reaction encompasses an aryl group containing a leaving group with potentially a huge number of substituents including, for example, nitrile, ester, keto, hydroxyl, amino, carboxylic acid and other common functionality in many instances without the necessity of using protecting groups.

Detailed Description of the Invention

The following terms shall be used to describe the present invention.

The term "compound" is used to describe any chemical compound or ligand, including a pre-catalyst or catalyst, which is used in the present invention and in context may refer to a purified or substantially pure compound or a less than pure compound or a compound complexed to a metal and coordinating ligand in a catalyst complex, hi addition, compounds according to the present invention may refer to all optical (including enantiomeric and diastereomeric) isomers, regioisomers and/or stereoisomers within the context of use or synthesis and may include racemic mixtures and/or enantiomerically enriched compounds, individually or as mixtures. Purified and isolated compounds according to the present invention are preferred in numerous embodiments.

The term "effective" is used to describe an amount of a compound or component which is used or included within the context of its use to provide an intended result. An effective amount may range quite broadly, within context, depending upon a number of factors, conditions, components and/or additives and the role that they play within the context of their use. One of ordinary skill will be able to determine an effective amount by routine experimentation, where such amount is not explicitly described.

The term "hydrocarbyl" shall mean a saturated or unsaturated (containing at least one unsaturated) group containing carbon atoms and hydrogen atoms and includes alkyl groups, alkene groups, alkyne groups and aromatic groups (pheny, naphthyl, phenanthryl, anthracenyl).

The term "alkyl" is used herein to refer to a fully saturated, monovalent radical containing carbon and hydrogen, and which may be a straight chain, branched or cyclic. Examples of preferred alkyl groups include C₁-C₇ alkyl groups such as methyl, ethyl, n- butyl, n-pentyl, n-heptyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl and cyclohexyl.

The term "aromatic" or "aryl" refers to a substituted or unsubstituted monovalent aromatic radical having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl, anthracene, phenanthrene, etc.). The term aromatic or aryl includes heteroaromatic or heteroaryl radicals with nitrogen, oxygen or sulfur or a combination of these atoms in the ring system. These "heteroaryl" groups have one or more nitrogen, oxygen, or sulfur atoms in the ring, such as imidazole, furyl, pyrrole, pyridyl, indole and fused ring systems such as indole and the like, among others, which may be substituted or unsubstituted.

The term "heterocycle" or "heterocyclic" shall mean an optionally substituted moiety which is cyclic and contains at least one atom other than a carbon atom, such as a nitrogen, sulfur, oxygen or other atom and contains from 3 to 14 atoms in the ring or fused-ring system (3 to 14-membered heterocyclic group). A heterocyclic ring shall contain up to four atoms other than carbon selected from nitrogen, sulfur and oxygen. These rings may be saturated or have unsaturated bonds and if fully unsaturated are heteroaryl groups. Fused rings are also contemplated by the present invention. A heterocycle according to the present invention is an optionally substituted imidazole, furan, pyrrole, imidazole, thiazole, oxazole, isoxazole, a piperazine (including piperazinone), piperidine group, all optionally substituted, among numerous others. Depending upon its use in context, a heterocyclic ring may be saturated and/or unsaturated. In instances where a heterocyclic ring is fully unsaturated, there is overlap with the term "heteroaryF'or "aryl" as defined above.

The term "substituted" is used to describe a substituent which in context may be incorporated onto a group of the precatalyst or catalyst according to the present invention, or the reactants according to the present invention. Exemplary substituents which may be used in the present invention include C₁-C₁₂ hydrocarbon groups such as alkyl, alkenyl or aryl (aromatic or heteroaromatic) groups, which themselves may be unsubstituted or substituted, alkyl or aryl alkoxides (preferably, unsubstituted or substituted C₁-C₆ alkoxides or phenoxides), keto, ester or carboxylic acid groups, nitro, nitrile (CN), amines, which may be unsubstituted or substituted with one or two substituents otherwise disclosed herein (including C₁-C₃ alkyl groups or alkanol groups), halogens (F, Br, Cl, I), mono- and dialkylamido groups, mono- and diarylamido groups, amidates (preferably unsubstituted or substituted alkyl or aryl amidates), carboxylic acid groups, hydroxyl groups, among numerous others. Exemplary preferred substituents include unsubstituted or substituted C₁- C₆ alkyl groups or aryl groups (especially halogenated alkyl groups such as fluoro-substituted alkyl groups), preferably phenyl groups, alkoxide groups, keto groups, keto esters, carboxyl groups or amino groups, which substituents, within context, may be attached to a further substituent in context, through carbon, oxygen, nitrogen or sulfur atoms. Note that the term substituent subsumes or incorporates O, S or N atoms within alkyl or alkylene chains or in aryl groups (heteroaryl), many of which may be bound to phorphorous. Substituents may also include heterocyclic groups (which may or may not be aromatic) containing one or more fused rings, which themselves may also be substituted. The present invention is particularly useful in that most of the substituent groups may be maintained in the molecule throughout the reaction without protection.

The term "olefin" is used throughout the specification to describe certain reactants, which are used in C-S forming reactions according to the present invention. An olefin is any compound with a carbon-carbon double bond containing a leaving group which can participate in C-S forming (thiolation) reactions according to the present invention, and includes terminal and internal alkenes (especially vinyl), vinylarenes, dienes, eneynes, and alpha-beta-unsaturated carbonyl compounds. The term "solvent" shall mean any solvent used in methods according to the present invention consistent with producing pre-catalyst, catalyst or with introducing C-S bonds into aromatic and olefin groups in the present invention. Exemplary solvents include toluene, benzene, chloroform, methylene chloride, dimethoxyethane (DME), tetrahydrofuran (THF), 1,4-dioxane, dimethylacetamide (DMA), dimethylformamide (DMF), acetonitrile, among numerous others. DME and toluene are preferred solvents for use in the present invention.

The term "base" is used to describe a chemical species that donates electrons or hydroxide ions or that accepts protons. In preferred aspects of the present invention, a base is generally a strong base which is capable of extracting a proton (accepts protons) within the context of the reaction in which the base is used. Exemplary bases for use in the present invention include stronger bases such as alkoxide bases, such as sodium or potassium t- butoxide (Na^{+ "}Ot-Bu or K^{+ "}Ot-Bu), NaHMDS (NaN(SiMe₃)₂), among others, or weaker bases including a carbonate base such as Na₂CO₃, K₂CO₃, or Cs₂CO₃ base.

The term temperature shall mean at ambient temperature (i.e., at the temperature of the room at which a reaction is conducted), or above or below ambient temperature. In many instances in the present invention, the temperature is elevated to above ambient temperature and preferably less than about 125 C.

The term "source of Pd, Ni or Pt" or "source of metal" shall mean a compound which contains palladium, nickel or platinum in a form which may be used in the present invention to produce a catalyst for introducing thiol-containing groups into aryl or olefin compounds. Such source may be palladium metal (powder), nickel metal (powder) or platinum metal (powder) or palladium, nickel and platinum compounds such as Pd(OAc)₂, Pd(dba)₂ (palladium dibenzylideneacetone), PdCl₂, (CH₃CN)₂PdCl₂, Ni(OAc)₂, Nickel acetonylacetonate, NiCl₂, Pt(OAc)₂, PtCl₂, among others.

The term "formally anionic 2-electron donor ligand" is used to describe a ligand bonded to a metal in a pre-catalyst or catalyst compound according to the present invention that donates two electrons to the metal center, and when these electrons are attributed to the ligand, the ligand is anionic. Common examples of 2-electronic anionic ligands include, for example, Cl, Br, I, OTf (triflate), OTs (tosylate), OAc (acetate), trifluoroacetate, among others.

The term "formally neutral 2-electron donor ligand" is used to describe a ligand bonded to a metal in a pre-catalyst or catalyst compound according to the present invention that donates two electrons to the metal center and when these electrons are attributed to the ligand, the ligand is neutral. Examples of these ligands include phosphines (PR"₃, where each R" is independently a C₁-C₁₀ optionally substituted hydrocarbyl group, preferably methyl, ethyl, isopropyl, phenyl, p-tolyl, xylyl, mono- or bis-trifluoromethylphenyl, etc.), olefins (preferably, C₂-C₁₀), amines (including mono- and di-alkyl or di-alkanol substituted amines) and ethers (preferably, C₂-C₁₀), among others.

The term "thiol", "thiolate" or "thiolate equivalent" is used to describe nucleophilic compounds containing sulfur nucleophiles or groups which are modified to obtain or create sulfur nucleophiles which, when reacted with compounds containing a leaving group according to the present invention in the presence of pre-catalysts and/or catalysts according to the present invention, produce C-S bonds in aryl compounds and olefins.

Thiolation reactions according to the present invention may be run in numerous solvents, including toluene, dimethoxyethane (DME), tetrahydrofuran (THF), 1,4-dioxane, dimethylacetamide (DMA), dimethylformamide, acetonitrile, among numerous others. The reactions may be run at ambient temperature or above or below ambient temperature. The precatalyst, catalyst and metal are used in catalytic amounts, generally ranging from about 0.001% to about 5 mol %, preferably about O.Olmol % to about 3 mol % the amount of aromatic reactant (containing leaving group) used in the reaction.

Development of the Catalyst and Reaction

In developing the present invention, it was considered that the restricted backbone conformation, steric hindrance, and strong electron donation of the Josiphos ligand CyPF-^- Bu (l-dicyclohexylphosphino-2-di-t-butylphosphinoethylferroceno, 1 in Table 1)^[38] might create practical catalysts for the coupling of thiols with aryl halides. Previously, the inventors showed that complexes generated from this ligand couple a broad range of thiols with aryl halides and pseudohalides and that reactions conducted with the Josiphos ligand occur with turnover numbers and tolerance of functional groups that far surpass those of previous catalysts. ^[39] hi contrast, the present application relates to the coupling of aryl chlorides and related compounds with thiols, thiolates and equivalents using this catalyst system, as well as preformed catalyst precursors including (CyPF-t-Bu)PdCl₂, under conditions of low catalyst loading.

Results and discussion

Establishment of reaction conditions. We initially selected the coupling of electron- rich 4-chloroanisole with 1-octanethiol as model system to assess the catalyst activity and to determine the optimum reaction conditions. The experiments were conducted using equimolecular amounts of 0.1 mol % Pd(OAc)₂ and CyPF-t-Bu ligand 1 and several bases (1.1 equivalents), solvents and reaction temperatures (Table 1). Reactions containing different bases were conducted at 100 ⁰C in DME (1,2-Dimethoxyethane),^[40] and the formation of aryl sulfide was measured by GC after 18 h. Reactions conducted with NaOtBu, KOtBu and NaHMDS (NaN(SiMeS)₂) occurred with moderate to good conversions (Table 1, entries 1-3), while reactions with weaker carbonate, phosphate and amine bases (not listed in Table 1) occurred to <5% conversion and formed large amounts of dioctyldisulfide.

Reactions at 110 °C occurred to higher conversions. Reactions at this temperature conducted with NaOtBu as base occurred to full conversion in less than 4 h and with an excellent yield of sulfide (Table 1, entry 4). In contrast, reactions conducted with KOtBu base proceeded to 94% conversion and 87% isolated yield after 18 h (Table 1, entry 5). Reactions conducted with NaOtBu in 1,4-dioxane occurred in high yield after similar times as the reactions with NaOtBu in DME (Table 1, entry 6), while reactions in other solvents, such as toluene, DMF or DMSO, formed only traces of the desired aryl sulfide.

Further studies were also conducted to fine-tune the catalyst loading and palladium precursor. These studies revealed that a decrease in the catalyst loading to 0.05% in certain instances resulted in incomplete conversion of this electron-rich chloroarene even at extended reaction times (Table 1, entry 7). However, reactions of electron-neutral and electron-poor chloroarenes described later hi the present application do occur with lower loadings These studies also showed that the catalyst system derived from Pd(dba)₂ and the one derived from Pd(OAc)₂ are similar, but that the one derived from Pd(dba)₂ reacts slightly slower (Table 1, entry 8).

Table 1. Optimization of Palladium-catalyzed coupling reaction of 4- chloroanisole with 1-octanethiol using CyPF-t-Bu ligand (l)^[a]

₂ HSOctyl + Base

CyPF-f-Bu (1)

Entry Base Solvent T[⁰C] Ib] t[h] Conversion[%](yield)^[c]

1 NaOtBu DME 100 18 84

2 KOtBu DME 100 18 80 3 NaHMDS DME 100 18 57 4 NaOtBu DME 110 <4 100 (98) 5 KOtBu DME 110 18 94 (87)

6 NaOtBu 1,4-Dioxane 110 5 100 (94)

₇M NaOtBu DME 110 48 93 (85) g[e] NaOtBu DME 110 7 100 (96)

^M All the experiments were conducted with a 1:1 ratio of metal to ligand, 1 mmol of both 4-chloroanisole and 1-octanethiol, and 1.1 equiv of base in 1.5 mL of solvent. ^M Bath temperature. ^[c] Determined by GC analysis. Isolated yields are indicated in parentheses. ^£d] 0.05% catalyst loading employed. ^[e] Pd(dba)₂ used as palladium precursor.

Ligand influence on the thiation of aryl chlorides at low catalyst loadings. After having established conditions for the coupling of chloroarenes with alkyl thiols using the combination OfPd(OAc)₂ and CyPF-t-Bu as catalyst, we surveyed palladium complexes of a series of ligands for these reactions at low catalyst loadings. The structures of these ligands and a summary of the results of this study are shown in Figure 2. Each reaction was conducted at 110 ⁰C for 24 h with 0.1 mol % of ligand and Pd(O Ach, and conversions to the desired sulfide were measured by GC.

Reactions were conducted with several members of the Josiphos family of ligands (1-6) as well as bidentate phosphines 7-12 that were previously reported for couplings of aryl halides with thiols. Among the Josiphos family of ligands, CyPF-t-Bu 1 clearly generated the most active catalyst, affording full conversion to the aryl sulfide in less than 4 h. Reactions catalyzed by complexes of Josiphos-type ligands 2 and 5, which are less rigid and less electron donating than 1, occurred to moderate conversions (ca 50%), even after 24 h. Reactions conducted with the less sterically demanding analogs 3, 4 and 6 formed moderate to small amounts of the desired sulfide. Catalysts based on BINAP, tol-BINAP or DPPF were completely ineffective for this coupling. Catalysts based on DPEphos, Xantphos and even DiPPF₅ which were reported to promote thiations of unactivated chloroarenes under similar reaction conditions but with higher catalyst loading, ^[25] afforded conversions up less than 30% when used in 0.1 mol % quantities.

A parallel study of the coupling of 4-chloroanisole with thiophenol was conducted. The reactions of thiophenol conducted with the Josiphos ligands 1-6 occurred in a similar fashion to the reactions of 1-octanethiol. Also similar to the reactions of the alkane thiol, reactions of thiophenol catalyzed by complexes of the other bisphosphines, including DPEphos, Xantphos and DiPPF, occurred hi low yield. Thus, CyPF-t-Bu 1 clearly generated the most active catalyst for the coupling of thiophenol.

Under the standard conditions developed, however, 4-methoxyphenyl phenyl sulfide A was formed with significant amounts of undesired symmetrical sulfides B and C (Scheme 1). Formation of these byproducts was first described for a nickel-catalyzed C-S bond- forming reaction, and a tentative mechanism for the aryl-aryl scrambling was proposed. ^[41] The amount of symmetrical sulfides formed from reactions of electron-deficient aryl halides and/or electron donating aromatic thiols is lower than the amount of these side products formed from reactions of electron-rich or electron-neutral aryl halides. For example, large amounts of these symmetrical byproducts were observed from the coupling of unactivated chloroarenes with an electron-rich aromatic thiol in the presence of the combination of Pd(OAc) and DiPPF as catalyst. The formation of these byproducts was suppressed by the use OfNEt₃ as solvent. ^[25]

Scheme 1: Byproducts formed from the coupling of 4-chloroanisole with thiophenol.

To prevent the formation of the symmetrical diaryl sulfides we determined the effect of base, solvent, and catalyst loading for the reaction of 4-chloroanisole with thiophenol. These results are summarized in Table 2. A significant dependence of the amount of side product on the nature of the base and its counterion was observed. The quantity of symmetrical sulfides was only 2% when the reaction was conducted with KOtBu as base, rather than 9% when it was conducted with NaOtBu (Table 2, entries 1 and 2); significant amounts of B and C were formed from reactions conducted with NaHMDS and LiHMDS as base (Table 2, entries 3-4). Reactions conducted with other bases such as NaOH, carbonates and amines gave low conversions to products.

The solvent also affected the amount of the side products B and C. Reactions in 1,4- dioxane and toluene formed lower amounts of B and C. Even with NaOtBu as base, only 4% of these materials were formed in these two solvents. Ultimately, the highest isolated yield and selectivity were achieved when the reactions were conducted in toluene in the presence of KOtBu as base (Table 2, entries 5-8). Reactions in toluene with KOtBu as base in the presence of only 0.1 mol % catalyst afforded the coupled product after 6 h at 110 °C in high yields with less than 1% of the side products (Table 2, entry 9).

The palladium source also affected the amount of side product. Reactions conducted with Pd(dba)₂ and Josiphos ligand 1 as catalyst generated only traces (<0.5%) of byproduct (Table 2, entry 10). Reactions conducted with only 0.1 mol % of Pd(dba)₂ and Josiphos ligand 1 occurred in high yield in less than 4 h to form the desired diaryl sulfide in essentially quantitative yield (Table 2, entry 11).

Table 2. Optimization of Palladium-catalyzed coupling reaction of 4- chloroanisole with thiophenol using CyPF-Z-Bu ligand (l)^[a]

Loading Entry Base Solvent Pd source 7[h] A:B:C[%]^[b]

1 NaOtBu DME Pd(OAc)₂ 0.5 12 91:4:5

2 KOtBu DME Pd(OAc)₂ 0.5 12 98(93):1:1

3 NaHMDS DME Pd(OAc)₂ 0.5 12 71:15:14

4 LiHMDS DME Pd(OAc)₂ 0.5 12 56:24:20

5 NaOtBu 1,4-Dioxane Pd(OAc)₂ 0.5 12 96:2:2

6 KOtBu 1,4-Dioxane Pd(OAc)₂ 0.5 12 97(87):2:1

7 NaOtBu Toluene Pd(OAc)₂ 0.5 12 98(93):1:1

8 KOtBu Toluene Pd(OAc)₂ 0.5 12 >98(97):1:<1

9 KOtBu Toluene Pd(OAc)₂ 0.1 6 >98(95):<1:<1

10 KOtBu Toluene Pd(dba)₂ 0.5 12 >99.5(98):<0.5:-

11 KOtBu Toluene Pd(dba)₂ 0.1 <4 >99.5(98):<0.5:-

^LaJ All the experiments were conducted with a 1 :1 ratio of metal to ligand, 1 mmol of both 4-chloroanisole and thiophenol, and 1.1 equiv of base at 110⁰C in 1.5 mL of solvent. ^[b] Distribution of sulfides determined by GC. Isolated yield of desired sulfide A is indicated in parentheses. Thus, our studies on reaction conditions showed that the combination of Pd(OAc)₂/CyPF-t-Bu/NaOtBu/DME was most effective for the coupling of aryl chlorides with aliphatic thiols and that the combination of Pd(dba)₂/CyPF-t-Bu/KOtBu/toluene was most effective for reactions of aromatic thiols. Reactions under the standard conditions, but without catalyst, formed mostly disulfides. Less than 5% of the aryl sulfide was formed.

Scope of the reaction: Coupling of unactivated aryl chlorides. Reactions of a series of aryl chlorides with aliphatic and aromatic thiols were conducted under the optimized reaction conditions with the combination of palladium and Josiphos ligand 1 as catalyst; the results are summarized in Tables 3 and 4.

Reactions of aliphatic thiols with chloroarenes are summarized in Table 3. These data show that primary, secondary, and tertiary aliphatic thiols reacted to form the corresponding sulfides in excellent yields within short reaction times. Reactions were conducted with catalyst loadings in the range of 0.01 to 0.1 mol %. These loadings are one or two orders of magnitude lower than those in previous studies of this reaction (Table 3, entries 1-7, 9-10, 12- 16). For instance, the coupling of chlorobenzene with 1-octanethiol occurred in 85% yield with only 100 ppm of catalyst, corresponding to a turnover number of 8500 (Table 3, entry 4). This value is more than two orders of magnitude higher than that for the analogous coupling of an unactivated chloroarene with a primary thiol catalyzed by the combination of Pd(OAc)₂ and DiPPF (48 turnovers).^[25] Further attempts to decrease the catalyst loading of reactions conducted with the Josiphos ligand by increasing the temperature to 140 °C in a sealed reaction vessel or by changing the solvent to diethylene glycol diethyl ether (b.p. = 188 °C) led to incomplete conversions and formation of disulfide side product.

Table 3. Palladium-catalyzed coupling of aryl chlorides with alkyl thiols using

CyPF-f-Bu ligand^[a]

0.01-3 mol % Pd(OAc)₂

^M AU experiments were conducted with a 1 :1 ratio of metal to ligand, 1 mmol of both chloroarene and alkylthiol, and NaOtBu (1.1 equiv) in DME (1.5 mL) for 2-24 h at 110 ⁰C. ^m Isolated yield of an average of two runs. ^M Reactions performed without using a drybox. ^[d] 5 mmol scale. ^[e] Reaction performed at 70⁰C. ^[f] 82% conversion after 36 h.

Sterically demanding ortto-substituted chloroarenes coupled in high yield using catalyst loadings up to 0.5 mol % (Table 3, entries 13 and 18-21). Even a di-ort/zo-substituted chloroarene reacted with a hindered tertiary thiol, although a higher catalyst loading and long reaction time were necessary to achieve good yield and conversion in this case (Table 3, entry 22). Reactions could also be conducted at lower temperatures (70 °C) by simply increasing the amount of catalyst to 2.0 mol % and increasing reaction times to 24 hours (Table 3, entries 8, 11 and 17). Although a majority of the reactions were assembled in a drybox, identical catalyst activity was observed for reactions performed under inert atmosphere using common Schlenk techniques (Table 3, compare entries 3 and 5). Using these techniques, the coupling reaction was conducted with 5 mmol of chlorobenzene without a decrease in yield or catalyst efficiency (Table 3, entry 6).

Studies on the scope of the coupling of arene thiols are summarized in Table 4. Again, very high yields in short reaction times were obtained using one or two orders of magnitude less catalyst loading than was needed for analogous couplings with prior systems. In contrast to prior reactions that occurred in high yields with the combination of unactivated chloroarenes and electron-rich arenethiols or electron-defficient chloroarenes with electron- neutral aromatic thiols,¹²⁵¹ the current system coupled either electron-rich, electron-neutral or electron-defficient chloroarenes with electron-rich or electron-neutral aromatic thiols.

Unhindered chloroarenes reacted with aromatic thiols without formation of side products in the presence of 0.05-0.5 mol % catalyst (Table 4, entries 1-3, 5-12). No significant increase in the loading was necessary for the coupling of sterically demanding aromatic thiols, even when electron-rich aryl chlorides were used (Table 4, entries 13-14).

Table 4. Palladium-catalyzed coupling of aryl chlorides with aryl thiols using CyPF-f-Bu ligand^[a]

^M AU experiments were conducted with a 1:1 ratio of metal to ligand, 1 mmol of both chloroarene and aryl thiol, and KOtBu (1.1 equiv) in toluene (1.5 ml), requiring 2-24 h of heating at 110 ⁰C to complete. ^[b] Isolated yield of an average of two runs. ^[c] Reaction conducted at 70 ⁰C and stopped after 48 h at 90% conversion. ^[d] 1.1 equiv of LiHMDS were used as base. ^ ~10% of symmetrical sulfides were observed. ^ Reaction conducted at 90 ⁰C. ^~20% of symmetrical sulfides were observed.

Reactions conducted at lower temperature (70 °C) produced high conversion and in good yield after 48 h in the presence of 3.0 mol % catalyst (Table 4, entry 4).

Reactions of ortho-substituted chloroarenes also occurred, but some of these couplings were accompanied by formation of symmetrical diaryl sulfide side products. The reactions of electron-rich thiols with ortho-substituted chloroarenes and the reaction of 2- chloroanisole with thiophenol occurred in high yields without formation of side products (Table 4, entries 17-18). The reaction of 1-chloronaphthalene with thiophenol in the presence of only 0.1 mol% catalyst formed the coupled product in good yield, but 10% of the undesired symmetrical sulfides also formed. This side product was eliminated by conducting the reaction at the lower temperature of 90 °C (3 mol % catalyst). The reactions of 2- chlorotoluene with thiophenol and with 2-isopropylbenzenthiol did not occur at the lower temperature, and reactions at 110 ⁰C in the presence of 0.25-0.5 mol% catalyst formed the coupled products in 70% yield with about 20% of side products (Table 4, entries 19-20). Further, the reaction of 2,6-dimethyl chloroarene with thiophenol did not occur (Table 4, entry 21).

Coupling of functionalized aryl chlorides. The efficiency of the present catalyst system prompted us to evaluate the tolerance of this process to the presence of functional groups that might be expected to poison the catalyst or to react with thiolate nucleophiles. The coupling of a wide range of functionalized aryl chlorides with aliphatic thiols is summarized in Table 5. Chloroarenes bearing a nitrile, ketone, carboxylic acid, amide, protected or free amino groups, and aromatic or aliphatic hydroxyl groups coupled under the standard conditions to form the corresponding aryl sulfide in good to excellent yields (Table 5, entries 1-8 and 12-18). The catalyst loading for some of these reactions are extremely low, and even reactions of electron-rich and hindered substrates occurred with loadings at or below 2.0 mol %.

Reactions of aryl chlorides with ester or aldehyde functionalities that occur in modest yield or are incompatible with nucleophilic alkoxide bases occurred in high yield in the presence of the weaker Cs₂CO₃ base (Table 5, entries 9-11). However, couplings of chloroarenes possessing enolizable keto functionality were unsuccessful, even with weaker bases (not included in Table 5). Although both the rate and the yield of the formation of sulfides from chloroarenes containing electron- withdrawing groups in the para- and ortho- positions were higher in the presence of our catalyst system than in the absence of catalyst, uncatalyzed processes did occur in good yields and conversions after longer times (24-48 h vs <4 h with the palladium catalyst) at 110 ⁰C (Table 5, entries 21,23,25 vs 22,24,26).

The reaction of l-chloro-2-fluorobenzene with 1-octanethiol gave a mixture of the expected diarylsulfide product and a small amount (8%) of or^o-chlorophenyl sulfide from reaction at the C-F bond (Table 5, entry 19). Nevertheless, the analogous reaction with a secondary thiol in the presence of 0.25 mol % of catalyst afforded the expected ortho- fluorophenyl sulfide with only traces of product from thiation of both carbon-halogen bonds (Table 5, entry 20). We envisioned that the minor side product could be formed by an uncatalyzed nucleophilic substitution at the activated C-F bond. Indeed, reaction of 1-chloro- 2-fluorobenzene with 1-octanethiol in the absence of catalyst afforded 75% conversion to the product from substitution at the fluoride, and the C-Cl bond remained intact, as shown in Scheme 2. In contrast to these results with electron-poor aryl fluorides, no C-S bond formation was detected from reaction of unactivated aryl fluorides, such as l-fluoro-4- methylbenzene, in the presence of catalyst (Scheme 2).

Table 5. Palladium-catalyzed coupling of functionalized aryl chlorides with aliphatic thiols using CyPF-f-Bu ligand¹"¹

0.01-2 mol % Pd(OAc)₂

^M All experiments were conducted with a 1 : 1 ratio of metal to ligand, 1 rmnol of both chloroarene and alkyl thiol, and 2.4 equiv of NaOtBu₅ unless otherwise stated, in DME (1.5 mL), requiring 2-6 h of heating at 110 ⁰C to complete. ^M Isolated yield of an average of two runs. Conversions in incomplete reactions indicated in parentheses. ^[c] 1.1 equiv of NaOtBu were employed. ^[d] 1.02 equiv. of NaOtBu were used. ^[e] Reaction performed using 1.1 equiv OfCsCO₃ as base. ^M Estimated by ¹H-NMR (400 MHz) of a mixture with the related aryl sulfide from the reaction at C-F bond (8% yield). ^[gl Traces of dithiolation product were observed. ^M Uncatalyzed reaction.

75% conversion

1 mol % Pd(OAc)₂

Scheme 2. Nucleophilic aromatic substitution of activated fluoroarenes.

The scope of reactions of functionalized aryl chlorides with aromatic thiols is summarized in Table 6. In contrast with the couplings of less functionalized chloroarenes, no symmetrical sulfides were detected from reaction of the chloroarenes in Table 6 under the standard conditions involving Pd(OAc)₂ and ligand 1 as catalyst, NaOtBu as base and DME as solvent. Like the reactions of aliphatic thiols, the coupling reactions following this protocol were tolerant of nitrile, ketone, carboxylic acid, amide, protected and free amino groups, and aromatic hydroxyl groups (Table 6, entries 1-4 and 6-8). These reactions occurred in good to excellent yield with 0.10 to 2.0 mol % catalyst. Even l-chloro-2- fluorobenzene coupled with thiophenol in excellent yield without a competitive background reaction at the C-F bond. However, the uncatalyzed reaction of 2-chlorobenzonitrile furnished the corresponding sulfide in good yield (Table 6, entries 9-11).

The coupling of aromatic thiols conducted with the weaker carbonate base were generally unsuccessful. As a result, the coupling of aromatic thiols did not occur in the presence of aldehyde groups, and reactions with 3-chloro methylbenzoate formed 80% of the desired sulfide with 10-15% of the product from transesterification (Table 6, entry 5). Use of a different base in the reaction (generally, a stronger base) represents an alternative consideration in certain reactions. Table 6. Palladium-Catalyzed Coupling of Functionalized Arylchlorides with Arylthiols using CyPF-*-Bu ligand^[al

^[a] AU experiments were conducted with a 1 : 1 ratio of metal to ligand, 1 mmol of both ArCl and thiol, and 2.4 equiv of NaOtBu₅ unless otherwise stated, in DME (1.5 mL), requiring 2-5 h of heating at 110 ⁰C to complete. ^[b] Isolated yield. ^ 1.1 equiv of NaOtBu were employed. ^[d] Reaction performed using 1.1 equiv of KOtBu and toluene as solvent. ^[e] 10-15% of transesterification compound were also isolated. ^ra No catalyzed reaction.

(CyPF-^-Bu)PdCb as catalyst precursor. The methodology developed revealed that an equimolecular combination of metal to ligand is adequate to promote the coupling of chloroarenes with both aliphatic and aromatic thiols. Thus, a palladium complex containing a single CyPF-t-Bu ligand would be an alternative catalyst precursor for the C-S bond-forming reactions. The use of such a compound would alleviate the need to generate the metal-ligand complex in situ. As expected, (CyPF-t-Bu)PdCl₂ forms in high yield from (CH₃CN)₂PdCl₂ and Josiphos ligand 1 (Scheme 3). Studies on reactions catalyzed by this complex are presented in this section. We studied reactions of this compound because it is more stable over the long-term than the complex formed from ligand 1 and Pd(OAc)₂.

CH₂CI₂ / RT (CH₃CN)₂PdCI₂ + CyPF-f-Bu *- (CyPF-f-Bu)PdCI₂

30 min __no/ . . .

90% yield

Scheme 3. Synthesis of (CyPF-Z-Bu)PdCl₂.

Representative experiments were performed with the new Pd(II) complex using the combination of solvent and base developed for the different thiols. As shown in Table 7, the yields, reaction times and catalyst loadings for the coupling of aliphatic thiols catalyzed by (CyPF-A-Bu)PdCl₂ were comparable to those catalyzed by the combination OfPd(OAc)₂ and ligand 1 (Table 7 entries 1-3,5-6 vs Table 3 entries 1,3,14,16,21). The reaction of aromatic thiols catalyzed by (CyPF-t-Bu)PdCl₂ was also efficient (Table 7 entries 7-12). Only one example in this set of reactions required a slight increase in the catalyst loading (0.25 mol % for Table 7 entry 7 vs 0.1 mol % for Table 4 entry 7). Reactions catalyzed by (CyPF-t-

Bu)PdCl₂ also occurred with remarkable functional group tolerance. For instance, reactions of aryl chlorides bearing nitrile, ketone, amide and free amino and aromatic hydroxyl groups occurred in high yields under conditions similar to those of the couplings catalyzed by Pd(OAc)₂ and ligand 1 (Table 7 entries 13-17).

Table 7. Palladium-catalyzed coupling of aryl chlorides with thiols using (CyPF- J-Bu)PdCl₂ complex'⁸¹

^[a] Experiments were conducted with 1 mmol of both ArCl and thiol, and 1.1 equiv of NaOtBu at 110 ⁰C in DME (1.5 mL). Reactions with unfunctionalized chloroarenes were carried out in toluene (1.5 mL) in the presence of 1.1 equiv of KOtBu. ^ Isolated yield. ^[c] Reaction performed using 1.1 equiv of LiHMDS. ^M 18% of symmetrical sulfides were also observed. ^[e] 2.4 equiv of NaOtBu were employed. Conclusion. In summary, we have shown that palladium complexes generated from the Josiphos ligand CyPF-Z-Bu are general, highly efficient catalysts for the coupling of chloroarenes with thiols. Reactions catalyzed by the complexes generated in situ from Pd(OAc)₂ or Pd(dba)₂ and ligand 1 and reactions catalyzed by (CyPF-Z-Bu)PdCl₂ occur with turnover numbers that are typically two orders of magnitude higher than those of related couplings by previous catalysts. The ability to conduct reactions with low catalyst loadings illustrates that the CyPF-Z-Bu ligand resists deactivation processes that could occur by displacement of dative ligands with thiolates. The process exhibits a broad scope and a high tolerance for functionality, such as fluoro, cyano, keto, free carboxylate, amido, carboalkoxy, carboxaldehyde, aromatic and aliphatic hydroxyl and amino functionalities. Only reactions of hindered aryl chlorides with aromatic thiols and reactions of aromatic thiols with chloroarenes containing carboxaldehyde functionality proceed to partial conversion or form significant amounts of side products. Related thiations of more reactive bromo- and iodoarenes, which overcome these few limitations of the reactions of chloroarenes, as well as studies of the mechanism of the coupling process are in progress.

Examples

Experimental

General Considerations: All reactions were assembled under an inert atmosphere. Reactions were conducted in 4 mL vials sealed with a cap containing a PTFE septum. All glassware was oven-dried, evacuated and purged with nitrogen immediately prior to use. All reaction temperatures refer to bath temperatures. All common reagents as well as Pd(OAc)₂ and bisphosphine ligands 7-12 were obtained from commercial suppliers and used without further purification. CyPF-Z-Bu (l-dicyclohexylphosphino-2-di-Z- butylphosphinoethylferroceno) as well as the other commercial available Josiphos-type ligands 3-6 were obtained from Solvias AG and Strem Chemicals and used without purification. Pd(dba)₂ was prepared according to literature procedures.¹^⁴²-¹ Toluene was degassed by purging with nitrogen for 45 min and dried with a solvent purification system containing a i m column of activated alumina. 1,2-Dimethoxyethane (DME, 99.9% purity, HPLC grade) was used without further purification, but was stored under nitrogen. Other solvents were dried by standard methods. Reactions performed at 110 °C in DME (b.p. = 85 °C) were conducted using the standard vials and caps cited above; no loss of solvent was observed. ¹H, ¹³C and ³¹P(¹H)NMR spectra were recorded in CDCl₃ on 400 MHz or 500 MHz spectrometers with tetramethylsilane or residual protiated solvent used as a reference. Abbreviations for ¹H NMR splitting patterns are: s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; sept, septet; oct, octet; dd, doublet of doublets; dt, doublet of triplets; td, triplet of doublets; tt, triplet of triplets; m, multiple! The coupling constants are reported in hertz (Hz). Flash column chromatography was carried out on silica gel (230-240 mesh). The yields of the coupled products included in all tables refer to isolated yields and are the average of two runs. Products that had been reported previously were isolated in greater than 95% purity, as determined by ¹H NMR spectroscopy and capillary gas chromatography (GC). GC analyses were obtained with a DB-1301 narrow bore column suitable for use with a fast temperature ramp (max 120 °C/min). Elemental Analyses were performed by Atlantic Microlab, Inc., Norcross, Georgia 30071.

Synthesis of Josiphos type ligand 2 (l-dicyclohexyIphosphino-2-di-f- butylphosphinomethylferroceno): This bisphosphine was prepared according to literature procedures for related ferrocenyl ligands.^[43] 95% yield. Yellow solid. ¹H NMR (CD₂Cl₂): δ = 4.67 (bs, 1 H), 4.16 (m, IH), 4.10 (s, 5H), 4.09-4.05 (m, IH), 2.70 (m, 2H), 2.28-2.22 (m, IH), 2.14-2.05 (m, 2H), 1.87-1.60 (m, 13H), 1.47-1.36 (m, 4H), 1.27-1.01 (m, 2H), 1.21 (d, J = 10.8 Hz, 9H), 1.07 (d, J= 10.8 Hz, 9H). ³¹P(¹H) NMR (CD₂Cl₂): δ = 26.0 (s), 11.8 (s). Anal. Calc'd for C₃₁H₅₀P₂Fe: C, 68.88; H, 9.32. Found: C, 68.85; H, 9.47.

Preparation of stock solution A (1.0 x 10^"2 M): DME (1.0 mL) was added to a mixture of Pd(OAc)₂ (2.2 mg) and CyPF-t-Bu (5.5 mg). The resulting orange solution was stirred at room temperature for 1 min before using.

General procedure for the palladium-catalyzed coupling of aryl chlorides with aliphatic thiols: The appropriate quantity of stock solution A was added to a 4 mL vial containing the aryl chloride (1.00 mmol) and sodium tert-butoxide (106 mg, 1.10 mmol) in 1.5 mL of DME. The aliphatic thiol (1.00 mmol) was then added, and the vial sealed with a cap containing a PTFE septum. The mixture was heated at 110⁰C until the chloroarene was consumed, as determined by GC. Silica gel (0.5 g) was added, and the solvents were evaporated under reduced pressure. The crude residue was purified by column chromatography on silica gel using hexane or a mixture of hexane and ethyl acetate as eluent. Aryl sulfides were isolated in the yields reported in Table 3. 4-Methoxyphenyl octyl sulfide (Table 3, entry 1).^[33] 100 μL of stock solution A were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 98% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.25 (d, J= 8.6 Hz, 2H)₅ 6.76 (d, J= 8.6 Hz, 2H), 3.71 (s, 3H), 2.73 (t, J= 7.4 Hz, 2H), 1.50 (quint, J= 7.4 Hz, 2H), 1.30 (quint, J= 7.4 Hz, 2H)₅ 1.22-1.14 (m, 8H)₅ 0.80 (t, J= 7.1 Hz₅ 3H). ¹³C NMR (CDCl₃): δ = 158.6, 132.8 (2C), 126.9, 114.4 (2C)₅ 55.2, 35.7, 31.7, 29.3, 29.09, 29.06, 28.6, 22.6, 14.0.

Octyl phenyl sulfide (Table 3, entry 2).^[44] 100 μL of stock solution A were used. Hexane was used as chromatography eluent. 91% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.25-7.23 (m, 2H), 7.21-7.16 (m, 2H), 7.09-7.06 (m, IH), 2.83 (t, J= 7.4 Hz, 2H), 1.57 (quint, J= 7.4 Hz, 2H), 1.34 (quint, J= 7.4 Hz, 2H), 1.21-1.18 (m, 8H), 0.80 (t, J= 7.1 Hz, 3H). ¹³C NMR (CDCl₃): δ 137.0, 128.7 (4C), 125.5, 33.5, 31.7, 29.09, 29.06 (2C), 28.8, 22.6, 14.0.

Octyl phenyl sulfide (Table 3, entry 3). 50 μL of stock solution A were used. 91% yield.

Octyl phenyl sulfide (Table 3, entry 4). 10 μL of stock solution A were used. 85% yield.

Preparation of stock solution B (1.0 x 10^~2 M): Pd(OAc)₂ (2.2 mg) and CyPF-t-Bu (5.5 mg) were added in air to a 4 mL vial. The flask was sealed with a cap containing a PTFE septum and then evacuated and backfilled with N₂. DME (1.0 mL) was then added to the vial by syringe, and the resulting orange solution was stirred at room temperature for 1 min before using.

Representative procedure without using a drybox. A. 1 mmol scale (Table 3, entry 5): An oven-dried test tube with a screw cap containing a PTFE-lined septum was evacuated and backfilled with N₂. To the flask was added NaOtBu (106 mg, 1.10 mmol) and a stir bar. The flask was evacuated and heated to remove the moisture present in the base; then evacuated and backfilled with N₂ three times. To the flask was then added chlorobenzene (102 L, 1.00 mmol), DME (2.0 mL), 50 μL of stock solution B₅ and 1- octanethiol (173 μL, 1.00 mmol), which were stored and handled under an inert atmosphere. The resulting mixture was stirred for 6 h at 110 °C until the chlorobenzene was consumed, as determined by GC. Silica gel (0.5 g) was then added, and solvents were evaporated under reduced pressure. The crude residue was purified by column chromatography on silica gel using hexane as eluent to give 205 mg (92% yield) of octyl phenyl sulfide as a colorless liquid.

B. 5 mmol scale. (Table 3, entry 6): NaOtBu (0.53 g, 5.50 mmol), chlorobenzene (0.51 mL, 5.00 mmol), DME (10.0 mL), 250 μL of stock solution B₅ and 1-octanethiol (0.87 mL, 5.00 mmol) were used following the same procedure described above to give, after 18 h, 1.03 g (93% yield) of octyl phenyl sulfide as a colorless liquid.

4-Methylphenyl octyl sulfide (Table 3, entry 7).^[33] 50 μL of stock solution A were used. Hexane and a 50:1 mixture of hexane/ethyl acetate were used as successive chromatography eluents. 97% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.10 (d, J = 8.1 Hz₃ 2H)₃ 6.95 (d, J= 8.1 Hz, 2H)₃ 2.73 (t, J= 7.4 Hz₅ 2H)₅ 2.17 (s, 3H)₅ 1.48 (quint, J= 7.4 Hz₃ 2H)₃ 1.26 (quint, J= 7.4 Hz₅ 2H), 1.17-1.08 (m, 8H), 0.74 (t, J= 6.9 Hz₅ 3H). ¹³C NMR (CDCl₃): δ = 135.7, 133.1, 129.7 (2C), 129.5 (2C), 34.3, 31.7, 29.2, 29.10, 29.06, 28.7, 22.6, 20.9, 14.0.

4-Methylphenyl octyl sulfide (Table 3, entry 8). A solution of Pd(OAc)₂ (4.4 mg) and CyPF-t-Bu (11 mg) in DME (1 mL) was used as catalyst; the reaction was conducted at 70 ⁰C. 97% yield.

2-Methylbutyl phenyl sulfide (Table 3, entry 9).^[45] 50 DL of stock solution A were used. Hexane was used as chromatography eluent. 95% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.25-7.22 (m, 2H), 7.20-7.15 (m, 2H), 7.08-7.04 (m, IH), 2.86 (dd, J= 6.0 Hz and 12.6 Hz₅ IH), 2.66 (dd, J= 7.6 Hz and 12.6 Hz, IH), 1.57 (m, IH), 1.45 (m, IH)₅ 1.18 (m, 1 H), 0.94 (d, J= 6.6 Hz₃ 3H)₃ 0.82 (t, J= 7.4 Hz₅ 3H). ¹³C NMR (CDCl₃): δ = 137.5, 128.7 (2C), 128.6 (2C), 125.4, 40.6, 34.4, 28.7, 18.8, 11.2.

1-Methylpropyl phenyl sulfide (Table 3, entry 10).^[44] 50 μL of stock solution A were used. Hexane was used as chromatography eluent. 91% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.32-7.29 (m, 2H), 7.20-7.16 (m, 2H)₃ 7.13-7.09 (m, IH), 3.07 (sext, J= 6.6 Hz, IH), 1.57 (m, IH), 1.45 (m, IH), 1.18 (d, J= 6.6 Hz, 3H), 0.92 (t, J= 7.4 Hz₅ 3H). ¹³C NMR (CDCl₃): δ = 135.4, 131.7 (2C), 128.6 (2C), 126.4, 44.7, 29.4, 20.4, 11.4. 1-Methylpropyl phenyl sulfide (Table 3, entry 11). A solution OfPd(OAc)₂ (4.4 mg) and CyPF-Z-Bu (11 mg) in DME (1 niL) was used as catalyst; the reaction was conducted at 70 ⁰C. 89% yield.

2-Methyl-2-propyl 4-trifluoromethylphenyI sulfide (Table 3, entry 12). 100 μL of stock solution A were used. Hexane was used as chromatography eluent. 82% yield.

Colorless liquid. ¹H NMR (CDCl₃): δ = 7.56 (d, J= 7.9 Hz, 2H), 7.50 (d, J= 7.9 Hz, 2H), 1.23 (s, 9H). ¹³C NMR (CDCl₃): δ = 137.6, 137.3 (2C)₅ 130.5 (q, ²J_C._F= 32.6 Hz), 125.2 (q, ⁵Jc-F= 3.8 Hz), 124.5 (q, ¹J₀-F= 272.5 Hz), 46.6, 30.9 (3C). Anal. Calc'd for C₁₁H₁₃F₃S: C, 56.39; H, 5.59. Found: C, 56.59; H, 5.60.

1-Naphthalenyl octyl sulfide (Table 3, entry 13).^[46] 50 μL of stock solution A were used. Hexane was used as chromatography eluent. 92% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 8.45 (d, J= 8.8 Hz, IH), 7.86 (d, J= 8.2 Hz, IH), 7.74 (d, J= 8.2 Hz₅ IH), 7.60-7.52 (m, 3H)₅ 7.43 (t, J= 8.2 Hz₅ IH)₅ 3.0 (t, J= 7.5 Hz₅ 2H), 1.71 (quint, J= 7.5 Hz, 2H)₅ 1.49-1.45 (m, 2H), 1.30 (bs, 8H)₅ 0.92 (t, J= 7.6 Hz, 3H). ¹³C NMR (CDCl₃): δ = 134.2, 133.8, 132.8, 128.4, 127.3, 126.7, 126.1, 126.0, 125.5, 124.9, 34.1, 31.7, 29.1 (3C), 28.8, 22.6, 14.0.

Octyl 2-thiophenyl sulfide (Table 3, entry 14).^[47] 50 μL of stock solution A were used. Hexane was used as chromatography eluent. 96% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.23 (dd, J= 5.4 Hz and 1.3 Hz, IH), 7.02 (dd, J= 3.5 Hz and 1.3 Hz, IH), 6.88 (dd, J= 5.4 Hz and 3.5 Hz, IH)₅ 2.70 (t, J= 7.3 Hz, 2H), 1.53 (quint, J= 7.3 Hz, 2H), 1.33- 1.27 (m, 2H), 1.20 (bs, 8H)₅ 0.80 (t, J= 6.9 Hz, 3H). ¹³C NMR (CDCl₃): δ = 134.9, 133.1, 128.7, 127.3, 38.9, 31.7, 29.3, 29.1, 29.0, 28.3, 22.6, 14.0.

Cyclohexyl 3-methylphenyl sulfide (Table 3, entry 15).^[48] 50 μL of stock solution A were used. Hexane and a 50:1 mixture of hexane/ethyl acetate were used as successive chromatography eluents. 98% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.14-7.07 (m, 3H), 6.95-6.93 (m, IH), 3.02 (tt, J= 10.4 Hz and 3.7 Hz, IH), 2.24 (s, 3H)₅ 1.92-1.89 (m, 2H), 1.71-1.67 (m, 2 H), 1.55-1.51 (m, IH)₅ 1.33-1.13 (m, 5 H). ¹³C NMR (CDCl₃): δ = 138.4, 134.8, 132.4, 128.8, 128.5, 127.4, 46.4, 33.3 (2C), 26.0, 25.7 (2C), 21.2.

Cyclohexyl 4-methylphenyl sulfide (Table 3, entry 16).^[48] 50 μL of stock solution A were used. Hexane and a 50:1 mixture of hexane/ethyl acetate were used as successive chromatography eluents. 97% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.23 (d, J= 8.0 Hz₅ 2H)₅ 7.01 (d, J= 8.0 Hz, 2H), 2.93 (tt, J= 10.5 Hz and 3.8 Hz, IH)₅ 2.24 (s, 3H)₅ 1.89- 1.86 (m, 2H)₅ 1.69-1.66 (m, 2 H)₅ 1.53-1.49 (m, IH)₅ 1.30-1.11 (m, 5H). ¹³C NMR (CDCl₃): δ = 136.7, 132.7 (2C), 131.1, 129.4 (2C), 47.0, 33.3 (2C), 26.0, 25.7 (2C)₅ 21.0.

Cyclohexyl 4-niethylphenyl sulfide (Table 3, entry 17). A solution of Pd(OAc)₂

(4.4 mg) and CyPF-t-Bu (11 mg) in DME (1 mL) was used as catalyst; the reaction was conducted at 70 ⁰C. 91% yield.

Cyclohexyl 2-methyIphenyl sulfide (Table 3, entry 18).^[48] 250 μL of stock solution A were used. Hexane was used as chromatography eluent. 90% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.41-7.39 (m, IH)₅ 7.22-7.20 (m, IH), 7.18-7.13 (m, 2H)₅ 3.12 (tt, J= 10.4 Hz and 3.7 Hz₅ IH)₅ 2.43 (s, 3H)₅ 2.02-2.00 (m, 2H)₅ 1.82-1.79 (m, 2 H), 1.66-1.64 (m, IH), 1.47-1.28 (m, 5 H). ¹³C NMR (CDCl₃): δ = 139.3, 134.5, 131.2, 130.1, 126.3, 126.1, 45.8, 33.3 (2C), 26.0, 25.7 (2C), 20.7.

2-Methylphenyl octyl sulfide (Table 3, entry 19). 250 μL of stock solution A were used. Hexane was used as chromatography eluent. 95% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.15 (d, J= 8.2 Hz, IH), 7.06-7.03 (m, 2H)₅ 6.98-6.95 (m, IH)₅ 2.79 (t₅ J= 7.4 Hz₅ 2H)₅ 2.27 (s, 3H), 1.57 (quint, J= 7.5 Hz, 2H), 1.38-1.32 (m, 2H)₅ 1.19 (bs₅ 8H)₅ 0.80 (t, J= 6.9 Hz, 3H). ¹³C NMR (CDCl₃): δ = 137.0, 136.4, 129.9, 127.1, 126.2, 125.1, 32.7, 31.7, 29.1 (2C)₅ 28.9 (2C), 22.6, 20.2, 14.0. Anal. Calcd for C₁₅H₂₄S: C, 76.20; H, 10.23. Found: C, 76.41; H, 10.17.

2-Methoxyphenyl octyl sulfide (Table 3, entry 20). 250 μL of stock solution A were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 97% yield. Colorless liquid. ¹HNMR (CDCl₃): δ = 7.23 (dd, J= 7.6 Hz and 1.6 Hz₅ IH)₅ 7.15-7.12 (m, IH)₅ 6.90 (td₅ J= 7.6 Hz and 1.3 Hz₅ IH)₅ 6.82 (dd, J= 8.0 Hz and 1.3 Hz₅ IH), 3.86 (s, 3H), 2.87 (t, J= 7.6 Hz, 2H)₅ 1.65 (quint, J= 7.6 Hz, 2H), 1.43 (m, 2H), 1.31-1.22 (m, 8 H), 0.87 (t, J= 6.9 Hz, 3H). ¹³C NMR (CDCl₃): δ = 156.9, 128.4, 126.4, 125.1, 120.8, 110.1, 55.5, 31.7, 31.6, 29.0 (2C), 28.8, 28.7, 22.5, 13.9. Anal. Calcd for C₂₂H₃₁O₂S: C₅ 73.49; H₅ 8.69. Found: C₅ 73.76; H, 8.82.

2,5-Dimethylphenyl 2-methyl-2-propyl sulfide (Table 3, entry 21).^[25] 500 μL of stock solution A were used. Hexane was used as chromatography eluent. 89% yield. Colorless liquid. ¹HNMR (CDCl₃): δ = 7.26 (s, IH), 7.06 (d, J= 7.9 Hz₅ IH)₅ 6.96 (d, J= 7.9 Hz₅ IH)₅ 2.38 (s₅ 3H), 2.21 (s, 3H), 1.20 (s, 9H). ¹³C NMR (CDCl₃): δ = 140.5, 139.4, 135.0, 131.7, 130.0, 129.6, 46.9, 31.0 (3C), 21.2, 20.6.

2,6-Dimethylphenyl 2-methyl-2-propyl sulfide (Table 3, entry 22).^[25] A solution of Pd(OAc)₂ (6.6 mg) and CyPF-t-Bu (16.5 mg) in DME (1 mL) was used as catalyst. Hexane was used as chromatography eluent. 77% yield (82% conversion) after 36 h of reaction. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.04 (bs, 3H), 2.49 (s, 6H)₅ 1.21 (s, 9H). ¹³C NMR . (CDCl₃): δ = 145.2 (2C)₅ 132.1, 128.2, 127.9 (2C), 49.1, 31.5 (3C), 23.0 (2C). t

Preparation of stock solution C (1.0 x 10^~2 M): Toluene (1.0 mL) was added to a mixture of Pd(dba)₂ (2.2 mg) and CyPF-MBu (5.5 mg). The resulting purple solution was stirred at room temperature for 1 min before using.

General procedure for the palladium-catalyzed coupling of aryl chlorides with aromatic thiols: The appropriate quantity of stock solution C was added to a 4 mL vial containing the aryl chloride (1.00 mmol) and potasium terf-butoxide (123 mg, 1.10 mmol) in 1.5 mL of toluene. The aromatic thiol (1.00 mmol) was then added, and the vial sealed with a cap containing a PTFE septum. The mixture was heated at 110 ⁰C until the chloroarene was consumed, as determined by GC. Silica gel (0.5 g) was then added, and solvents were evaporated under reduced pressure. The crude residue was purified by column chromatography on silica gel using hexane or a mixture of hexane and ethyl acetate as eluent. Aryl sulfides were isolated in the yields reported in Table 4.

4-Methoxyphenyl phenyl sulfide (Table 4, entry 1).^[49] 100 μL of stock solution C were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 98% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.23 (d, J= 8.8 Hz₅ 2H), 7.06-7.02 (m, 2H), 7.00-6.93 (m, 3H), 6.71 (d, J= 8.8 Hz₅ 2H)₅ 3.62 (s, 3H). ¹³C NMR (CDCl₃): δ = 159.7, 138.5, 135.3 (2C), 128.8 (2C), 128.1 (2C), 125.7, 124.2, 114.9 (2C)₅ 55.3.

Diphenyl sulfide (Table 4, entry 2).^t49] 100 μL of stock solution C were used. Hexane was used as chromatography eluent. 95% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.26-7.24 (m, 4H), 7.21-7.18 (m, 4H)₅ 7.16-7.13 (m, 2H). ¹³C NMR (CDCl₃): δ = 135.7 (2C), 130.9 (4C), 129.1 (4C), 126.9 (2C). 4-MethyIphenyl phenyl sulfide (Table 4, entry 3).^[49] 100 μL of stock solution C were used. Hexane was used as chromatography eluent. 95% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.21 (d, J= 8.0 Hz₅ 2H)₅ 7.19-7.14 (m, 4H)₅ 7.11-7.05 (m, IH)₅ 7.03 (d, J= 8.0 Hz, 2H)₅ 2.25 (s₅ 3H). ¹³C NMR (CDCl₃): δ = 137.5, 137.0, 132.2 (2C)₅ 131.2, 130.0 (2C)₅ 129.7 (2C)₅ 128.9 (2C), 126.3, 21.0.

4-Methylphenyl phenyl sulfide (Table 4, entry 4). A solution of Pd(dba)₂ (6.6 mg) and CyPF-t-Bu (16.5 mg) in toluene (1.0 niL) was used as catalyst; the reaction was heated at 70 °C until no further reaction was observed (93% conversion). 83% yield.

3-Methylphenyl phenyl sulfide (Table 4, entry 5).^[50] 100 μL of stock solution C were used. Hexane was used as chromatography eluent. 98% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.22-7.20 (m, 2H)₅ 7.17-7.14 (m, 2H)₅ 7.11-7.03 (m, 4H), 6.92 (m₅ IH)₅ 2.18 (s, 3H). ¹³C NMR (CDCl₃): D = 138.9, 136.0, 135.1, 131.7, 130.6 (2C)₅ 129.0 (2C)₅ 128.9, 128.2, 127.9, 126.7, 21.2.

3-Methylphenyl phenyl sulfide (Table 4, entry 6). 50 μL of stock solution C were used. 86% yield.

4-Methylphenyl 4-methoxyphenyl sulfide (Table 4, entry 7).^[51] 100 μL of stock solution C were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 95% yield. White solid. ¹H NMR (CDCl₃): δ = 7.47 (d, J= 8.8 Hz, 2H), 7.25 (d, J= 8.0 Hz, 2H), 7.16 (d, J= 8.0 Hz, 2H), 6.96 (d, J= 8.8 Hz, 2H), 3.87 (s, 3H), 2.40 (s, 3H). ¹³C NMR (CDCl₃): δ = 159.3, 135.9, 134.21 (2C)₅ 134.15, 129.6 (2C), 129.2 (2C), 125.4, 114.7 (2C), 55.1, 20.8.

3-Methylphenyl 4-Methylphenyl sulfide (Table 4, entry 8).^[52] 100 μL of stock solution C and LiHMDS (184 mg, 1.10 mmol) were used. Hexane was used as chromatography eluent. 93% yield. Colorless liquid. ¹HNMR (CDCl₃): δ = 7.28-7.25 (m, 2H)₅ 7.16-7.07 (m, 5H), 6.97 (d, J= 7.3 Hz₅ IH)₅ 2.31 (s, 3H), 2.26 (s, 3H). ¹³C NMR

(CDCl₃): δ = 138.7, 137.2, 136.5, 131.9 (2C), 131.5, 130.5, 129.9 (2C)₅ 128.8, 127.3, 127.0, 21.2, 21.0.

4-Methylphenyl phenyl sulfide (Table 4, entry 9). 250 μL of stock solution C and LiHMDS (184 mg₅ 1.10 mmol) were used. Hexane was used as chromatography eluent. 98% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.21 (d, J= 8.0 Hz, 2H), 7.19-7.14 (m, 4H), 7.11-7.05 (m, IH), 7.03 (d, J= 8.0 Hz, 2H), 2.25 (s, 3H). ¹³C NMR (CDCl₃): δ = 137.5, 137.0, 132.2 (2C), 131.2, 130.0 (2C), 129.7 (2C), 128.9 (2C), 126.3, 21.0.

Di-4-methoxyphenyl sulfide (Table 4, entry 10).^[28] 250 μL of stock solution C were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 99% yield. White solid. ¹H NMR (CDCl₃): δ = 7.26 (d, J= 8.8 Hz, 4H), 6.81 (d, J= 8.8 Hz, 4H), 3.76 (s, 6H). ¹³C NMR (CDCl₃): δ = 158.8 (2C), 132.6 (4C), 127.3 (2C), 114.6 (4C), 55.2 (2C).

3-MethylphenyI 4-methoxyphenyl sulfide (Table 4, entry 11). 250 μL of stock solution C were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 97% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.38 (d, J= 8.8 Hz, 2H), 7.09 (t, J = 7.8 Hz, IH), 7.01 (s, IH), 6.96-6.91 (m, 2H), 6.85 (d, J= 8.8 Hz, 2H). ¹³C NMR (CDCl₃): δ = 159.6, 138.6, 138.1, 135.0 (2C), 128.8, 128.7, 126.6, 125.3, 124.4, 114.8 (2C), 55.1, 21.2. Anal. Calc'd for C₁₄H₁₄OS: C, 73.01; H, 6.13. Found: C, 73.27; H, 6.57.

Phenyl 4-trifluoromethylphenyl sulfide (Table 4, entry 12).^[53] 500 μL of stock solution C were used. Hexane was used as chromatography eluent. 89% yield. Colorless liquid. ¹HNMR (CDCl₃): δ = 7.47-7.45 (m, 4H), 7.39-7.35 (m, 3H), 7.28-7.24 (m, 2H). ¹³C NMR (CDCl₃): δ = 142.8, 133.5 (2C), 132.4, 129.6 (2C), 128.6, 128.2 (2C), 128.1 (q, ²Jc-_F= 32.6 Hz), 125.7 (d, ⁵Jc-F= 3.8 Hz), 124.0 (q, ¹Jc-_F= 271.6 Hz).

2-Isopropylphenyl 4-methoxyphenyl sulfide (Table 4, entry 13).^[54] 250 μL of stock solution C were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 94% yield. White solid. ¹H NMR (CDCl₃): δ = 7.44 (d, J= 8.8 Hz, 2H), 7.41 (d, J= 7.8 Hz, IH), 7.31-7.27 (m, IH), 7.17-7.13 (m, 2H), 6.99 (d, J= 8.8 Hz, 2H), 3.88 (s, 3H), 3.68 (sept, J= 6.9 Hz, IH), 1.38 (d, J= 6.9 Hz, 6H). ¹³C NMR (CDCl₃): δ = 159.2, 147.5, 135.6, 134.2 (2C), 130.0, 126.6, 126.2, 125.4, 125.3, 114.8 (2C), 55.1, 30.2, 23.2 (2C).

2-Isopropylphenyl 4-methylphenyl sulfide (Table 4, entry 14). 250 μL of stock solution C were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 97% yield. Colorless liquid. ¹HNMR (CDCl₃): δ = 7.32 (dd, J= 7.7 Hz and 1.4 Hz, IH), 7.26-7.14 (m, 4H), 7.11-7.06 (m, 3H), 3.54 (sept, J= 6.8 Hz, IH), 2.32 (s, 3H), 1.22 (d, J= 6.8 Hz, 6H). ¹³C NMR (CDCl₃): δ = 149.2, 136.4, 133.8, 132.7, 132.3, 130.6 (2C), 129.8 (2C)₅ 127.6, 126.4, 125.7, 30.4, 23.4 (2C), 20.9. Anal. Calc'd for C₁₆H₁₈S: C, 79.29; H, 7.49. Found: C, 78.99; H, 7.57.

1-Naphthalenyl phenyl sulfide (Table 4, entry 15).^[46] 100 μL of stock solution C were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 84% yield. 10% of symmetrical sulfides were also formed. Colorless liquid. ¹H NMR (CDCl₃): δ = 8.26 (s, IH), 7.71-7.53 (m, 3H), 7.37-7.0 (m, 8H). ¹³C NMR (CDCl₃): δ = 136.8, 134.1, 133.5, 132.4, 131.1, 129.1, 129.0 (2C), 128.9 (2C), 128.5, 126.8, 126.3, 126.0, 125.7, 125.5.

1-Naphthalenyl phenyl sulfide (Table 4, entry 16). A solution of Pd(dba)₂ (6.6 mg) and CyPF-t-Bu (16.5 mg) in toluene (1.0 niL) was used as catalyst; the reaction was heated at 90 ⁰C until reaction was complete (48 h). 95% yield.

2,5-Dimethylphenyl 4-methoxyphenyl sulfide (Table 4, entry 17).^[25] 1000 μL of stock solution C were used. 50:1 and 20:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 92% yield. Colorless liquid. ¹HNMR (CDCl₃): δ = 7.27 (d, J= 8.8 Hz, 2H), 7.03 (d, J= 7.6 Hz, IH), 6.89 (d, J= 7.6 Hz, IH), 6.86-6.82 (m, 3H), 3.75 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H). ¹³C NMR (CDCl₃): δ = 159.2, 136.1, 135.9, 134.3, 133.8 (2C), 130.1, 130.0, 127.1, 124.9, 114.8 (2C), 55.1, 20.8, 19.7.

2-Methoxyphenyl phenyl sulfide (Table 4, entry 18).^[49] 1000 μL of stock solution C were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 97% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.42-7.40 (m, 2H), 7.36 (t, J= 7.4 Hz, 2H), 7.32-7.27 (m, 2H), 7.14 (dt, J= 7.8 Hz and 1.7 Hz, IH), 6.96-6.90 (m, 2H), 3.91 (s, 3H). ¹³C NMR (CDCl₃): δ = 157.1, 134.3, 131.4, 131.3 (2C), 129.0 (2C), 128.2, 126.9, 123.9, 121.1, 110.7, 55.7.

2-Methylphenyl phenyl sulfide (Table 4, entry 19).^[49] 500 μL of stock solution C were used. Hexane was used as chromatography eluent. 70% yield. -20% of symmetrical sulfides were also formed. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.47-7.19 (m, 9H), 2.50 (s, 3H). ¹³C NMR (CDCl₃): δ = 136.0, 133.6, 132.9, 130.9, 130.5, 129.5 (2C), 129.0 (2C), 127.8, 126.6, 126.2, 20.5.

2-Isopropylphenyl 2-methylphenyl sulfide (Table 4, entry 20).^[54] 250 μL of stock solution C were used. Hexane was used as chromatography eluent. 70% yield. ~20% of symmetrical sulfides were also formed. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.26 (d, J= 7.6 Hz₅ IH), 7.19-7.14 (m, 2H), 7.07 (t, J= 7.3 Hz, IH), 7.02-6.99 (m, 3H), 6.95 (d, J= 7.6 Hz, IH), 3.43 (sept, J= 6.7 Hz, IH), 2.31 (s, 3H), 1.17 (d, J= 6.7 Hz, 6H). ¹³CNMR (CDCl₃): δ = 149.3, 138.3, 135.3, 132.9, 131.9, 130.9, 130.3, 127.6, 126.7, 126.54, 126.49, 125.8, 30.5, 23.4 (2C), 20.3.

General procedure for the palladium-catalyzed coupling of functionalized aryl chlorides with aliphatic and aromatic thiols: The appropriate quantity of stock solution A was added to a 4 mL vial containing the aryl chloride (1.00 mmol) and NaOtBu (230 mg, 2.40 mmol), unless otherwise stated, in 1.5 mL of DME. The thiol (1.00 mmol) was then added, and the vial sealed with a cap containing a PTFE septum. The mixture was heated at 110 ⁰C until the chloroarene was consumed, as determined by GC. Silica gel (0.5 g) was added, and the solvents were evaporated under reduced pressure. The crude residue was purified by column chromatography on silica gel using hexane or mixtures of hexane and ethyl acetate as eluent. Aryl sulfides were isolated in the yields reported in Tables 5 and 6.

3-Cyanophenyl 2-methyl-2-propyl sulfide (Table 5, entry 1). 50 μL of stock solution A and NaOtBu (106 mg, 1.10 mmol) were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 90% yield. White solid. ¹H NMR (CDCl₃): δ = 7.82 (s, IH), 7.76 (d, J= 7.8 Hz, IH), 7.65 (d, J= 7.8 Hz, IH), 7.45 (t, J= 7.8 Hz, IH), 1.30 (s, 9H). ¹³C NMR (CDCl₃): δ = 141.5, 140.2, 134.7, 132.0, 129.1, 118.1, 112.6, 46.7, 30.8 (3C). Anal. Calc'd for C₁₁H₁₃NS: C, 69.07; H, 6.85; N, 7.32. Found: C, 69.25; H, 6.78; N, 7.25.

3-Cyanophenyl 2-methyl-2-propyl sulfide (Table 5, entry 2). 10 μL of stock solution A and NaOtBu (106 mg, 1.10 mmol) were used. 79% yield.

3-Benzoylphenyl cyclohexyl sulfide (Table 5, entry 3). 50 μL of stock solution A and NaOtBu (106 mg, 1.10 mmol) were used. 50:1 and 20:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 86% yield. Colorless oil. ¹H NMR (CDCl₃): δ = 7.90-7.78 (m, 3H), 7.62-7.56 (m, 3H), 7.47 (t, J= 7.9 Hz, 2H), 7.38 (t, J= 7.8 Hz, IH), 3.16 (tt, J= 10.4 Hz and 3.7 Hz, IH), 2.0-1.96 (m, 2H), 1.78-1.75 (m, 2H), 1.62-1.59 (m, IH), 1.42-1.21 (m, 5H). ¹³C NMR (CDCl₃): δ = 195.9, 138.0, 137.2, 136.0, 134.9, 132.4, 132.2, 129.9 (2C), 128.5, 128.1 (2C), 127.8, 46.2, 33.0 (2C), 25.8, 25.5 (2C). Anal. Calc'd for C₁₉H₂₀OS: C, 76.98; H, 6.80. Found: C, 76.95; H, 6.79. 3-(l-Methylpropylsulfanyl)benzoic acid (Table 5, entry 4). 100 μL of stock solution A were used. 5:1 and 3:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 76% yield. Pale yellow oil. ¹H NMR (CDCl₃): δ = 11.92 (bs, IH), 8.12 (s, IH)₅ 7.95 (d, J= 7.9 Hz₅ IH)₅ 7.61 (d, J= 7.9 Hz₅ IH)₅ 7.39 (t, J= 7.9 Hz, IH)₅ 3.25 (sext, J= 6.6 Hz₅ IH), 1.73-1.64 (m, IH)₅ 1.62-1.53 (m, IH)₅ 1.31 (d, J= 6.6 Hz₅ 3H)₅ 1.03 (t, J= 7.4 Hz₅ 3H). ¹³C NMR (CDCl₃): δ = 171.9, 136.8, 136.5, 132.5, 129.8, 128.8, 128.1, 44.7, 29.4, 20.4, 11.3. Anal. Calc'd for C₁₁H₁₄O₂S: C, 62.83; H, 6.71. Found: C, 62.87; H, 6.80.

3-(2-Methyl-2-propylsulfanyl)benzoic acid (Table 5, entry 5).^[55] 50 μL of stock solution A were used. 5:1 and 3:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 67% yield. White solid. ¹H NMR (CDCl₃): δ = 12.01 (bs, IH), 8.30 (s, IH), 8.12 (d, J= 7.8 Hz, IH), 7.78 (d, J= 7.8 Hz, IH), 7.46 (t, J= 7.8 Hz, IH), 1.31 (s, 3H). ¹³C NMR (CDCl₃): δ = 171.8, 142.6, 138.7, 133.6, 130.3, 129.6, 128.6, 46.3, 30.9 (3C).

3-(2-Methyl-2-propylsulfanyl)benzoic acid (Table 5, entry 6). 10 μL of stock solution A were used. 71% yield.

3-(2-Methyl-2-propylsulfanyl)benzamide (Table 5, entry 7). 50 μL of stock solution A were used. A 1:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 98% yield. White solid. ¹HNMR (CDCl₃): δ = 7.99 (t, J= 1.7 Hz₅ IH)₅ 7.85 (dt, J= 7.8 Hz and 1.4 Hz₅ IH)₅ 7.68 (td, J= 7.8 Hz and 1.7 Hz, IH), 7.41 (t, J= 7.8 Hz₅ IH)₅ 6.70- 6.48 (m, 2H), 1.29 (s, 9H). ¹³C NMR (CDCl₃): δ = 169.2, 140.6, 135.9, 133.7, 133.4, 128.6, 127.7, 46.2, 30.8 (3C). Anal. Calc'd for C₁₁H₁₅NOS: C, 63.12; H, 7.22; N, 6.69. Found: C, 62.92; H, 7.19; N, 6.57.

3-(2-Methyl-2-propylsulfanyl)benzamide (Table 5, entry 8). 10 μL of stock solution A were used. 91% yield.

Methyl 3-cyclohexylsulfanylbenzoate (Table 5, entry 9).^[25] 100 μL of stock solution A and NaOtBu (98 mg, 1.02 mmol) were used. A 50: 1 mixture of hexane/ethyl acetate was used as chromatography eluent. 56% yield. Pale yellow oil. ¹H NMR (CDCl₃): δ = 7.97 (s, IH)₅ 7.78 (d, J= 7.9 Hz₅ IH)₅ 7.48 (d, J= 7.9 Hz, IH), 7.28-7.24 (m, IH), 3.83 (s, 3H), 3.10-3.05 (m, IH), 1.90-1.86 (m, 2H)₅ 1.69-1.67 (m, 2H), 1.54-1.51 (m, IH), 1.33-1.15 (m, 5H). ¹³C NMR (CDCl₃): δ = 166.5, 136.0, 135.8, 132.3, 130.6, 128.6, 127.5, 52.0, 46.4, 33.1 (2C), 25.8, 25.6 (2C). Methyl 3-cycIohexyIsulfanyIbenzoate (Table 5, entry 10). 500 μL of stock solution A and Cs₂CO₃ (359 mg, 1.10 mmol) were used. 72% yield.

3-(2-MethyI-2-propylsulfanyl)benzaIdehyde (Table 5, entry 11). 250 μL of stock solution A and Cs₂CO₃ (359 mg, 1.10 mmol) were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 91% yield. Colorless oil. ¹H NMR (CDCl₃): δ = 10.03 (s, IH), 8.02 (t, J= 1.6 Hz, IH), 7.88 (dt, J= 7.6 Hz and 1.6 Hz, IH), 7.79 (dt, J= 7.6 Hz and 1.6 Hz, IH), 7.51 (t, J= 7.6 Hz, IH), 1.31 (s, 9H). ¹³C NMR (CDCl₃): δ = 191.5, 143.0, 138.2, 136.5, 134.2, 129.4, 128.9, 46.2, 30.7 (3C). Anal. Calc'd for C₁₁H₁₄OS: C, 68.00; H, 7.26. Found: C, 67.88; H, 7.45.

N-(3-(2-MethylbutyIsulfanyl)phenyl) acetamide (Table 5, entry 12). 250 μL of stock solution A were used. 3:1 and 1:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 99% yield. White solid. ¹H NMR (CDCl₃): δ = 8.45 (bs, IH), 7.58 (s, IH), 7.27 (d, J= 7.9 Hz, IH), 7.16 (t, J= 7.9 Hz, IH), 7.01 (d, J= 7.9 Hz, IH), 2.89 (dd, J= 6.0 Hz and 12.6 Hz, IH), 2.70 (dd, J= 7.6 Hz and 12.6 Hz, IH), 2.14 (s, 3H), 1.63 (oct, J= 6.6 Hz, IH), 1.54-1.46 (m, IH), 1.27-1.19 (m, IH), 0.98 (d, J= 6.6 Hz, 3H), 0.87 (t, J= 6.8 Hz, 3H). ¹³C NMR (CDCl₃): δ = 169.0, 138.4, 138.3, 128.9, 123.9, 119.6, 117.0, 40.2, 34.2, 28.5, 24.2, 18.7, 11.0. Anal. Calc'd for C₁₃H₁₉NOS: C, 65.78; H, 8.07; N, 5.90. Found: C, 65.54; H, 8.12; N, 5.89.

3-(2-Methyl-2-propylsulfanyl)aniline (Table 5, entry 13). 250 μL of stock solution A and NaOtBu (106 mg, 1.10 mmol) were used. 20:1 and 5:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 96% yield. Yellow oil. ¹H NMR (CDCl₃): δ = 7.10 (t, J= 7.8 Hz, IH), 6.93 (d, J= 7.6 Hz, IH), 6.87 (s, IH), 6.67 (dd, J= 7.8 Hz and 2.5 Hz, IH), 3.71 (bs, 2H), 1.29 (s, 9H). ¹³C NMR (CDCl₃): δ = 146.1, 133.2, 129.0, 127.5, 123.7, 115.4, 45.6, 30.9 (3C). Anal. Calc'd for C₁₀H₁₅NS: C, 66.25; H, 8.34; N, 7.73. Found: C, 66.16; H, 8.34; N, 7.76.

4-(2-Methyl-2-propylsulfanyl)phenol (Table 5, entry 14).^[56] 1000 μL of stock solution A were used. 5:1 and 3:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 91% yield. White solid. ¹HNMR (CDCl₃): δ = 7.39 (d, J= 8.5 Hz, 2H), 6.80 (d, J= 8.5 Hz, 2H), 5.62 (bs, 1 H), 1.26 (s, 9H). ¹³C NMR (CDCl₃): δ = 156.3, 139.0 (2C), 123.4, 115.5 (2C), 45.6, 30.6 (3C). 3-(2-Methylbutylsulfanyl)phenol (Table 5, entry 15). 500 μL of stock solution A were used. A 20:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 85% yield. Yellow oil. ¹H NMR (CDCl₃): δ = 7.04 (t, J= 7.9 Hz, IH), 6.80 (m, IH), 6.72 (t, J= 2.1 Hz, IH), 6.53 (m, IH), 5.90-4.20 (bs, IH), 2.84 (dd, J= 12.3 Hz and 5.7 Hz, IH), 2.65 (dd, J= 12.3 Hz and 7.6 Hz, IH), 1.58 (oct, J= 6.6 Hz, IH)₅ 1.49-1.40 (m, IH), 1.22-1.13 (m, IH), 0.93 (d, J= 6.6 Hz, 3H), 0.82 (d, J= 7.4 Hz, 3H). ¹³C NMR (CDCl₃): δ = 155.6, 139.1, 129.8, 120.7, 115.0, 112.5, 40.2, 34.3, 28.7, 18.8, 11.1. Anal. Calc'd for C₁₁H₁₆OS: C, 67.30; H, 8.22. Found: C, 67.52; H, 8.27.

2-Octylsulfanylphenol (Table 5, entry 16).^[57] A solution OfPd(OAc)₂ (4.4 mg) and CyPF-Z-Bu (11 mg) in DME (1 mL) as catalyst was used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 97% yield. Yellow liquid. ¹H NMR (CDCl₃): δ = 7.38 (dd, J= 7.6 Hz and 1.5 Hz, IH), 7.17 (dt, J= 7.6 Hz and 1.5 Hz, IH), 6.90 (d, J= 8.1 Hz, IH), 6.80-6.76 (m, IH), 6.70 (bs, 1 H), 2.60 (t, J= 7.5 Hz, 2H), 1.50-1.43 (m, 2H), 1.31- 1.17 (m, 10H), 0.79 (t, J= 6.8 Hz, 3H). ¹³C NMR (CDCl₃): δ = 156.8, 135.8, 130.8, 120.6, 119.1, 114.6, 36.7, 31.7, 29.5, 29.04, 28.98, 28.5, 22.5, 14.0.

4-(l-HydroxyethyI)phenyI 2-methyl-2-propyl sulfide (Table 5, entry 17). 500 μL of stock solution A and NaOtBu (98 mg, 1.02 mmol) were used. 20:1 and 5:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 93% yield. Colorless oil. ¹H NMR (CDCl₃): δ = 7.50 (d, J= 8.0 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H), 4.91 (q, J= 6.6 Hz, IH), 1.95 (bs, IH), 1.50 (d, J= 6.6 Hz, 3H), 1.28 (s, 9H). ¹³C NMR (CDCl₃): δ = 146.3, 137.5 (2C), 131.5, 125.4 (2C), 70.0, 45.8, 30.9 (3C), 25.1. Anal. Calc'd for Ci₂H₁₈OS: C, 68.52; H, 8.63. Found: C, 68.49; H, 8.63.

4-(l-Hydroxyethyl)phenyI 2-methyl-2-propyl sulfide (Table 5, entry 18). 500 μL of stock solution A and Cs₂CO₃ (359 mg, 1.10 mmol) were used. 67% yield.

2-Fluorophenyl octyl sulfide (Table 5, entry 19). 100 μL of stock solution A were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 78% yield. It could not be separated of the corresponding aryl sulfide from the reaction at C-F bond (8% yield). The following spectroscopic data were obtained from the mixture. ¹H NMR (CDCl₃): δ = 7.28-7.24 (m, IH), 7.11-7.06 (m, IH), 7.00-6.92 (m, 2H), 2.80 (t, J= 7.3 Hz, 2H), 1.53 (quint, J= 7.6 Hz, 2H), 1.40-1.27 (m, 2H), 1.18 (bs, 8H), 0.79 (t, J= 6.8 Hz, 3H). ¹³C NMR (CDCl₃): δ = 161.2 (d, ¹Jc-F= 244.6 Hz), 131.4, 127.7 (d, ³J₀-_F= 7.7 Hz), 124.2 (d, ³J_C._F= 3.9 Hz)₅ 123.7 (d, ²Jc-F= 27.6 Hz), 115.4 (d, ²Jc-F= 23.0 Hz), 33.1, 31.7, 29.1 (2C), 29.0, 28.6, 22.5, 14.0.

2-Fluorophenyl 1-methylpropyl sulfide (Table 5, entry 20). 250 μL of stock solution A were used. Hexane was used as chromatography eluent. 98% yield. Colorless liquid. Traces of the product of dithiolation were observed and could not be separated. ¹H NMR (CDCl₃): δ = 7.42 (td, J= 7.6 Hz and 1.8 Hz, IH), 7.26-7.21 (m, IH), 7.09-7.03 (m, 2H), 3.22 (sext, J= 6.6 Hz, IH), 1.70-1.61 (m, IH), 1.59-1.47 (m, IH), 1.25 (d, J= 6.6 Hz, 3H), 1.00 (t, J= 7.4 Hz, 3H). ¹³C NMR (CDCl₃): δ = 162.3 (d, ¹J₀-F= 245.4 Hz), 134.7, 128.9 (d, ³Jc-F== 8.4 Hz), 124.1 (d, ³J₀-F= 3.8 Hz), 122.1 (d, ²Jc-_F= 17.6 Hz), 115.6 (d, ²Jc_-F= 13.8 Hz), 44.3, 29.5, 20.3, 11.2.

Benzyl 4-benzoylphenyl sulfide (Table 5, entry 21).^[58] 10 μL of stock solution A and NaOtBu (106 mg, 1.10 mmol) were used. 20:1 and 5:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 93% yield. White solid. ¹H NMR (CDCl₃): δ = 7.75 (d, J= 8.3 Hz, 2H), 7.71 (d, J= 8.3 Hz, 2H), 7.59-7.55 (m, IH), 7.47 (t, J= 7.6 Hz, 2H), 7.38 (d, J= 7.6 Hz, 2H), 7.35-7.25 (m, 5H), 4.23 (s, 2H). ¹³C NMR (CDCl₃): δ = 195.6, 143.4, 137.6, 136.2, 134.3, 132.1, 130.5 (2C), 129.7 (2C), 128.62 (2C), 128.55 (2C), 128.1 (2C), 127.4, 126.6 (2C), 37.1.

Benzyl 4-benzoylphenyl sulfide (Table 5, entry 22). No catalyzed reaction. NaOtBu (106 mg, 1.10 mmol) were used. 86% yield.

4-Cyanophenyl cyclohexyl sulfide (Table 5, entry 23).^[48] 10 μL of stock solution A and NaOtBu (106 mg, 1.10 mmol) were used. A 20:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 90% yield. White solid. ¹H NMR (CDCl₃): δ = 7.53 (d, J= 8.8 Hz, 2H), 7.35 (d, J= 8.8 Hz, 2H), 3.32 (tt, J= 10.2 Hz and 3.5 Hz, IH), 2.06-2.03 (m, 2H), 1.84-1.80 (m, 2H), 1.69-1.65 (m, IH), 1.49-1.27 (m, 5H). ¹³C NMR (CDCl₃): δ = 143.9, 132.1 (2C), 128.4 (2C), 118.8, 108.3, 44.8, 32.8 (2C), 25.8, 25.5 (2C).

4-Cyanophenyl cyclohexyl sulfide (Table 5, entry 24). No catalyzed reaction. NaOtBu (106 mg, 1.10 mmol) were used and the reaction heated for 48 h. 79% yield (91% conversion). 2-Cyanophenyl 2-methyl-2-propyl sulfide (Table 5, entry 25).^[59] 250 μL of stock solution A and NaOtBu (106 mg, 1.10 mmol) were used. 50:1 and 20:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 80% yield. Yellow liquid. ¹HNMR (CDCl₃): δ = 7.73 (dd, J= 7.6 Hz and 1.5 Hz, IH), 7.71-7.69 (m, IH), 7.58 (td, J= 7.6 Hz and 1.5 Hz, IH), 7.49 (td, J= 7.5 Hz and 1.2 Hz, IH), 1.36 (s, 9H). ¹³C NMR (CDCl₃): δ = 138.7, 136.4, 133.5, 132.1, 129.1, 121.1, 118.0, 48.7, 30.8 (3C).

2-Cyanophenyl 2-methyl-2-propyl sulfide (Table 5, entry 26). No catalyzed reaction. NaOtBu (106 mg, 1.10 mmol) and the reaction heated for 24 h. 77% yield.

3-Cyanophenyl phenyl sulfide (Table 6, entry 1).^[54] 100 μL of stock solution A and NaOtBu (106 mg, 1.10 mmol) were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 93% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.46-7.31 (m, 9H). ¹³C NMR (CDCl₃): δ = 139.8, 133.2 (2C), 132.7, 132.0, 131.5, 129.7 (2C), 129.5, 129.4, 128.7, 118.1, 113.2.

3-Benzoylphenyl phenyl sulfide (Table 6, entry 2). 100 μL of stock solution A and NaOtBu (106 mg, 1.10 mmol) were used. 50:1 and 20:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 95% yield. Colorless oil. ¹H NMR (CDCl₃): δ = 7.75- 7.71 (m, 3H), 7.62 (dt, J= 7.6 Hz and 1.3 Hz, IH), 7.57-7.53 (m, IH), 7.48-7.23 (m, 9H). ¹³C NMR (CDCl₃): δ = 195.7, 138.3, 137.2, 136.9, 134.1, 133.6, 132.5, 131.9 (2C), 131.2, 129.9 (2C), 129.3 (2C), 128.9, 128.2 (2C), 128.1, 127.7. Anal. Calc'd for C₁₉H₁₄OS: C, 78.59; H, 4.86. Found: C, 78.65; H, 4.87.

3-(4-Methoxyphenylsulfanyl)benzoic acid (Table 6, entry 3).^[54] 250 μL of stock solution A were used. 3:1 and 1:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 74% yield. White solid. ¹H NMR (CDCl₃): δ = 7.90 (bs, IH), 7.86- 7.83 (m, IH), 7.45 (d, J= 9.0 Hz, 2H), 7.36-7.31 (m, 2H), 6.92 (d, J= 9.0 Hz, 2H), 3.83 (s, 3H). ¹³C NMR (CDCl₃): δ = 171.8, 160.1, 140.1, 135.9 (2C), 132.6, 129.9, 129.0, 128.9, 127.2, 122.8, 115.2 (2C), 55.3.

3-Phenylsulfanylbenzamide (Table 6, entry 4).^[60] 250 μL of stock solution A were used. A 1:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 70% yield. White solid. ¹H NMR (CDCl₃): δ = 7.75 (t, J= 1.8 Hz, IH), 7.65 (dt, J= 7.6 Hz and 1.3 Hz, IH), 7.43-7.26 (m, 7H), 6.40-6.18 (m, 2H). ¹³C NMR (CDCl₃): δ = 168.9, 137.4, 134.3, 134.2, 133.5, 131.8 (2C), 129.4 (2C)₅ 129.3, 128.9, 127.7, 125.6.

Methyl 3-phenylsulfanylbenzoate (Table 6, entry 5).^[41] 250 μL of stock solution C and KOtBu (123 mg, 1.10 mmol) were used; the reaction was conducted in toluene (1.5 niL). 50:1 and 20:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 80% yield (10-15% of tert-butyl ester derivative was also observed). Colorless liquid. ¹H NMR (CDCl₃): δ = 8.01 (t, J= 1.8 Hz, IH), 7.88 (dt, J= 7.9 Hz and 1.3 Hz, IH), 7.46 (m, IH), 7.38-7.25 (m, 6H), 3.89 (s, 3H). ¹³C NMR (CDCl₃): δ = 166.4, 137.0, 134.6, 134.5, 131.6 (2C)₅ 131.3, 131.1 (2C)₅ 129.3, 129.1, 127.9, 127.6, 52.2.

iV-(3-PhenyIsulfanyl)phenyl acetamide (Tabla 6, entry 6). 250 μL of stock solution

A were used. A 1:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 99% yield. Colorless oil. ¹H NMR (CDCl₃): δ = 7.80 (bs, IH), 7.46 (d, J= 8.1 Hz₅ IH), 7.39 (t, J= 1.8 Hz, IH), 7.36-7.19 (m, 6H), 7.02 (d, J= 7.8 Hz₅ IH)₅ 2.09 (s, 3H). ¹³C NMR (CDCl₃): δ = 168.7, 138.6, 136.8, 134.9, 131.5 (2C)₅ 129.5, 129.1 (2C), 127.3, 126.1, 121.4, 118.4, 24.4. Anal. Calc'd for C₁₄H₁₃NOS: C, 69.11; H, 5.39; N₅ 5.76. Found: C, 69.04; H₅ 5.37; N, 5.77.

3-Phenylsulfanylaniline (Table 6, entry 7).^[61] 250 μL of stock solution A were used. A 5:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 91% yield. Yellow oil. ¹H NMR (CDCl₃): δ = 7.35-7.32 (m, 2H), 7.29-7.20 (m, 3H), 7.05 (t, J= 8.1 Hz, IH), 6.73-6.68 (m, IH)₅ 6.61-6.09 (m, IH)₅ 6.53-6.50 (m, IH)₅ 3.60 (bs, 2H). ¹³C NMR (CDCl₃): δ = 147.0, 136.3, 135.6, 130.9 (2C), 129.8, 129.0 (2C)₅ 126.8, 120.8, 116.9, 113.8.

4-(2-Isopropylphenylsulfanyl)phenol (Table 6, entry 8). A solution OfPd(OAc)₂ (4.4 mg) and CyPF-t-Bu (11 mg) in DME (1 mL) was used as catalyst. 20:1 and 5:1 mixtures of hexane/ethyl acetate were used as successive chromatography eluents. 91% yield. Pale yellow oil. ¹HNMR (CDCl₃): δ = 7.22-7.16 (m, 3H), 7.13-7.08 (m, IH), 7.00-6.93 (m, 2H), 6.74-6.70 (m, 2H), 5.28 (bs, 1 H)₅ 3.43 (m, IH)₅ 1.16 (dd₅ J= 6.8 Hz and 1.8 Hz₅ 6H). ¹³C NMR (CDCl₃): δ = 155.3, 147.7, 135.5, 134.4 (2C)₅ 130.1, 126.7, 126.3, 125.6, 125.5, 116.4 (2C)₅ 30.2, 23.2 (2C). Anal. Calc'd for C₁₅H₁₆OS: C, 73.73; H, 6.60. Found: C, 73.45; H, 6.64.

2-Fluorophenyl phenyl sulfide (Table 6, entry 9).^[62] 1000 μL of stock solution C and KOtBu (123 mg, 1.10 mmol) were used; the reaction was conducted in toluene (1.5 mL). Hexane was used as chromatography eluent. 96% yield. Colorless liquid. ¹H NMR (CDCI3): δ = 7.18-7.05 (m, 7H)₅ 6.94-6.86 (m, 2H). ¹³C NMR (CDCl₃): δ = 161.0 (d, ¹J₀-_F= 246.9 Hz), 134.0, 133.3, 130.8 (2C), 129.3, 129.2 (2C), 127.2, 124.6 (d, ³J_C._F= 10.7 Hz), 122.6 (d, ²J₀-F = 17.6 Hz), 115.8 (d, ²J₀-F= 22.23 Hz).

2-Cyanophenyl phenyl sulfide (Table 6, entry 10).^[59] 250 μL of stock solution A and NaOtBu (106 mg, 1.10 mmol) were used. A 20:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 99% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.54 (d, J = 8.0 Hz, IH), 7.39-7.37 (m, 2H), 7.34-7.29 (m, 4H), 7.19-7.15 (m, IH), 7.03 (d, J= 8.0 Hz, IH). ¹³C NMR (CDCl₃): δ = 142.1, 133.5, 133.4 (2C), 132.9, 131.6, 129.7, 129.6 (2C), 128.8, 126.3, 116.8, 112.6.

2-Cyanophenyl phenyl sulfide (Table 6, entry 11). No catalyzed reaction. NaOtBu (106 mg, 1.10 mmol) and the reaction heated for 24 h. 87% yield.

Synthesis of (CyPF-Z-Bu)PdCl₂. Josiphos CyPF-t-Bu (55 mg, 0.10 mmol) was added to a solution Of(CH₃CN)₂PdCl₂ (26 mg, 0.10 mmol) in CH₂Cl₂ (5.0 mL) and the resulting mixture was stirred for 30 minutes at room temperature. The reaction mixture was filtered through celite and the resulting solution concentrated under vacuum to approximately 1.0 mL. Red needle crystals (65 mg, 90% yield) were obtained by layering with hexane and cooling at -10 °C. ¹H NMR (CDCl₃): δ = 4.85 (s, 1 H), 4.55 (s, 1 H), 4.53 (s, 1 H), 4.25 (s, 5 H), 3.60-3.75 (m, 1 H), 3.00-3.10 (m, 1 H), 2.50-2.60 (m, 1 H), 2.27-2.90 (m, 1 H), 2.13-2.25 (m, 2 H), 2.00-2.10 (m, 1 H), 1.97 (dd, J= 9.0, 7.5 Hz, 3 H), 1.70-1.95 (m, 4 H), 1.20-1.30 (m, 8 H), 1.63 (d, J= 13.0 Hz, 9 H), 1.30-1.45 (m, 4 H), 1.23 (d, J= 14.5 Hz, 9 H). ¹³C NMR (CDCl₃) δ = 96.5 (dd, J= 13.3 and 5.5 Hz), 71.9 (d, J= 2.5 Hz), 69.9 (d, J= 9.1 Hz), 69.8 (5C), 69.6 (d, J= 9.2 Hz), 69.3 (t, J= 5.7 Hz), 41.60 (d, J= 35.5 Hz), 41.57 (d, J= 8.2 Hz), 40.6 (d, J= 11.2 Hz), 37.6 (d, J= 35.5 Hz), 34.5 (t, J= 9.1 Hz), 32.0 (d, J= 1.9 Hz, 3C), 31.1 (d, J= 1.9 Hz, 3C), 30.0, 29.2, 28.1, 27.6 (d, J= 6.8 Hz), 27.3 (d, J= 10.2 Hz), 27.0 (d, J= 12.6 Hz), 26.9 (d, J= 5.2 Hz), 26.8 (d, J= 3.8 Hz), 26.1 (d, J= 1.9 Hz), 25.6, 18.0 (d, J= 6.7 Hz). Anal. Calc'd for C₃₂H₅₂Cl₂FeP₂Pd: C, 52.51; H, 7.16. Found: C, 52.72; H, 7.38.

Preparation of stock solution D (1.0 x 10 ² M): (CyPF-t-Bu)PdCl₂ (7.3 mg) was diluted in THF (1.0 mL) and the resulting orange solution was stirred at room temperature for 1 min before using. General procedure for the palladium-catalyzed coupling of aryl chlorides with thiols using (CyPF-J-Bu)PdCh complex: The appropriate quantity of stock solution D was added to a 4 mL vial containing the aryl chloride (1.00 mmol) and base (1.10 mmol) in 1.5 mL of solvent (NaOtBu and DME for aliphatic thiols, KOtBu and toluene for aromatic thiols, unless otherwise stated). The thiol (1.00 mmol) was then added, and the vial sealed with a cap containing a PTFE septum. The mixture was heated at 110 ⁰C until the chloroarene was consumed, as determined by GC. Silica gel (0.5 g) was added, and the solvents were evaporated under reduced pressure. The crude residue was purified by column chromatography on silica gel using hexane or a mixture of hexane and ethyl acetate as eluent. Aryl sulfides were isolated in the yields reported in Table 7.

4-Methoxyphenyl octyl sulfide (Table 7, entry 1). 100 μL of stock solution D were used. 97% yield.

Octyl phenyl sulfide (Table 7, entry 2). 50 μL of stock solution D were used. 97% yield.

Cyclohexyl 4-methylphenyl sulfide (Table 7, entry 3). 50 μL of stock solution D were used. 94% yield.

2-Methylbutyl 3-methoxyphenyl sulfide (Table 7, entry 4). 50 μL of stock solution D were used. A 50:1 mixture of hexane/ethyl acetate was used as chromatography eluent. 98% yield. Colorless liquid. ¹H NMR (CDCl₃): δ = 7.07 (t, J= 7.9 Hz, IH), 6.80-6.76 (m, 2H), 6.59-6.56 (m, IH), 3.67 (s, 3H), 2.84 (dd, J= 12.5 Hz and 5.9 Hz, IH), 2.64 (dd, J= 12.5 Hz and 7.6 Hz, IH), 1.60-1.52 (m, IH), 1.49-1.39 (m, IH), 1.22-1.11 (m, IH), 0.91 (d, J = 6.6 Hz, 3H), 0.81 (t, J= 7.1 Hz, 3H). ¹³C NMR (CDCl₃): δ = 159.6, 138.8, 129.4, 120.5, 113.7, 110.9, 55.0, 40.2, 34.3, 28.7, 18.8, 11.1. Anal. Calc'd for C₁₂H₁₈OS: C, 68.52; H, 8.63. Found: C, 68.32; H, 8.68.

Octyl 2-thiophenyl sulfide (Table 7, entry 5). 50 μL of sto+ck solution D were used. 93% yield.

2,5-Dimethylphenyl 2-methyl-2-propyl sulfide (Table 7, entry 6). 3.7 mg of

(CyPF-t-Bu)PdCl₂ were used. 96% yield. 4-MethylphenyI 4-methoxyphenyl sulfide (Table 7, entry 7). 250 μL of stock solution D were used. 88% yield.

4-Methylphenyl phenyl sulfide (Table 7, entry 8). 250 μL of stock solution D and LiHMDS (184 mg, 1.10 mmol) were used. 97% yield.

Phenyl 4-trifluoromethylphenyl sulfide (Table 7, entry 9). 3.7 mg of

(CyPF-J-Bu)PdCl₂ were used. 90% yield.

2-Isopropylphenyl 4-methoxyphenyl sulfide (Table 7, entry 10). 250 μL of stock solution D were used. 94% yield.

1-Naphthalenyl phenyl sulfide (Table 7, entry 11). 100 μL of stock solution D were used.98% yield. <2% of symmetrical sulfides were detected.

2-Methylphenyl phenyl sulfide (Table 7, entry 12). 3.7 mg of (CyPF-t- Bu)PdCl₂ were used.77% yield. 18% of symmetrical sulfides were also formed.

3-CyanophenyI 2-methyl-2-propyl sulfide (Table 7, entry 13). 50 μL of stock solution D were used. 91% yield.

3-Benzoylphenyl cyclohexyl sulfide (Table 7, entry 14). 100 μL of stock solution D were used. 80% yield.

3-Phenylsulfanylbenzamide (Table 7, entry 15). 3.7 mg of (CyPF-t- Bu)PdCl₂ and NaOtBu (230 mg, 2.40 mmol) were used. 66% yield.

3-Phenylsulfanylaniline (Table 7, entry 16). 3.7 mg of (CyPF-t-Bu)PdCl₂ and NaOtBu (230 mg, 2.40 mmol) were used. 92% yield.

3-(2-Methylbutylsulfanyl)phenol (Table 7, entry 17). 3.7 mg of (CyPF-t- Bu)PdCl₂ and NaOtBu (230 mg, 2.40 mmol) were used. 96% yield.

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Claims

Claims:

A compound according to the chemical structure:

Where R and R are each independently H, an optionally substituted C₁-C₁₀ hydrocarbyl group or an optionally substituted heterocyclic group, wherein each of said C₁-C₁₀ hydrocarbyl group or heterocyclic group is optionally bound to phosphorus at the exocyclic carbon through carbon, oxygen, nitrogen, or sulfur;

Y is M or a PR⁵R⁶ group;

R³, R⁴, R⁵ and R⁶ are each independently an optionally substituted C₁-C₁₀ hydrocarbyl group or an optionally substituted 3-14 membered heterocyclic group bound to phosphorus through carbon, oxygen, nitrogen, or sulfur; M is Pd, Ni or Pt, and M is substituted with X and L or X and a PHR⁵R⁶ group and is linked through a bond to PR³R⁴ or is M a PR^-M¹ group where M¹ is Pd, Ni or Pt, M¹ is substituted with two X groups and is linked through a bond to PR³R⁴; X is a formally anionic 2-electron donor ligand; L is a formally neutral 2-electronic donor ligand; and CpFe is a cyclopentadienyl iron (ferrous) group.

2. The compound according to claim 1 wherein R¹ and R² are each independently an optionally substituted hydrocarbyl or an optionally substituted heteroaryl group bound to the beiLzylic carbon through carbon, oxygen, nitrogen, sulfur or phosphorus.

3. The compound according to claim 1 or 2 wherein R¹ and R² are each independently an optionally substituted C₁-C₁₀ hydrocarbyl group.

4. The compound according to any of claims 1-3 wherein R and R are each independently a C₁-C₆ alkyl group.

5. The compound according to any of claims 1-4 wherein any one or more of R³, R⁴, R⁵ and R⁶ groups are optionally substituted aryl groups.

6. The compound according to any of claims 1 -4 wherein any one or more of R³, R⁴,

R⁵ and R⁶ groups are optionally substituted C₁-C₆ alkyl groups.

7. The compound according to any of claims 1-4 wherein any one or more of R , R , R⁵ and R⁶ groups are optionally substituted C₁-C₃ alkyl groups.

8. The compound according to any of claims 1 -4 wherein any one or more of R³, R⁴, R⁵ and R⁶ groups are optionally substituted C₁-C₆ alkoxy groups.

9. The compound according to any of claims 1-4 wherein any one or more of R³, R⁴, R⁵ and R⁶ groups are optionally substituted C₁-C₃ alkoxy groups.

10. The compound according to any of claims 1-4 wherein any one or more of R³, R⁴, R⁵ and R⁶ groups are optionally substituted phenoxy groups.

11. The compound according to any of claims 1 -4 wherein any one or more of R³, R⁴,

R⁵ and R⁶ groups are optionally substituted C₁-C₁₀ vinyl groups.

12. The compound according to any of claims 1-4 wherein any one or more of R³, R⁴, R⁵ and R⁶ groups are optionally substituted 3-14 membered heterocyclic groups.

13. The compound according to any of claims 1-4 and 12 wherein any one or more of R³, R⁴, R⁵ and R⁶ groups are optionally substituted heteroaryl groups.

14. The compound according to any of claims 1-13 wherein M or M¹ is Pd.

15. The compound according to any of claims 1-14 wherein each X is independently Cl, Br, I, OTf (triflate), OTs (tosylate), OAc (acetate) or trifluoroacetate.

16. The compound according to any of claims 1-15 wherein L is an optionally substituted C₂-C₁₀ olefin, an optionally substituted amine an optionally substituted C₂-C_1O ether, or a PR"₃ group, wherein each R" is a C₁-C_1O optionally substituted hydrocarbyl group.

17. The compound according to claim 16 wherein each R" is independently methyl, ethyl, isopropyl, phenyl, p-tolyl, xylyl, or mono- or bis-trifluoromethylphenyl.

18. The compound according to claim 16 where in said amine group is a mono- di- (C₁-C₃) alkylamine or a C₁-C₃ mono- or di-alkanol substituted amine.

19. The compound according to any of claims 1-18 wherein any one or more of R³, R R⁴⁴,, RR⁵⁵ aanndd RR⁶⁶ ggrroouuppss iiss aann ooppttiioonnaallllyy ssuubbssttiittuutteedd 33--1144 membered heterocyclic groups bound to the exocyclic carbon through phosphorous.

20. The compound according to any of claims 1-18 wherein any one or more of R³, R⁴, R⁵ and R⁶ groups is an optionally substituted C₁-C_1O hydrocarbyl group bound to the exocyclic carbon through phosphorous.

21. A compound of claim 1 according to the chemical structure:

Wherein R¹, R², R³, R⁴, R⁵, R⁶, X, L, M₅ M¹ and CpFe are the same as set forth in claim 1.

22. A composition comprising: a compound according to the formula:

and a source of palladium (Pd), nickel (Ni) or platinum (Pt); Wherein R¹, R², R³, R⁴, R⁵ and R⁶ and CpFe are the same as set forth in claim 1.

23. A composition comprising: a compound according to the formula:

a secondary phosphine PHR⁵R⁶

Wherein each of R¹, R², R³, R⁴, R⁵, R⁶ L, X, M and CpFe is the same as set forth in claim 1.

24. The composition according to claim 23 wherein M is Pd.

25. A composition comprising: a compound according to the formula:

Wherein R¹, R², R³, R⁴, R⁵, R⁶, X₅ M and CpFe are the same as set forth in claim 1.

26. The composition according to claim 25 wherein M is Pd.

27. A composition comprising a compound according to the formula:

Wherein R¹, R², R³, R⁴, R⁵, R⁶, X₅ M¹ and CpFe are the same as set forth in claim 1.

28. The composition according to claim 27 wherein M¹ is Pd.

29. Any of compounds 1-6 of figure 2.

30. A method of forming an aryl or olefin C-S bond comprising reacting an aryl or olefmic compound containing a leaving group with a thiol-containing compound, a thiolate-containing compound or a compound containing a thiolate equivalent in the presence of a compound according to claim 1 and optionally a secondary phosphine compound or a metal selected from the group consisting of Pd, Ni or Pt or a metal- containing compound comprising Pd, Ni or Pt in a solvent at ambient temperature or a temperature above or below ambient temperature to produce an aryl or olefin compound containing a C-S group.

31. The method according to claim 30 wherein said leaving group is selected from the group consisting of a halogen or a sulfonate leaving group.

32. The method according to claim 31 wherein said halogen is Cl.

33. The method according to claim 31 wherein said sulfonate leaving group is a toluensulfonyl or trifluoromethylsulfonyl group.

34. The method according to any of claims 30-33 which forms an aryl C-S bond.

35. A method of producing an aryl compound containing a C-S bond comprising reacting a compound according to the chemical structure:

Wherein Ar is an aryl group; Each R' is a substituent on the aryl group; n is from 0 to 5, preferably 0 to 3; and X is a leaving group; With a compound H-SR, S-R or a thiolate equivalent compound containing an R group where R is an optionally substituted C₁-C₁₂ hydrocarbyl group, an optionally substituted 3-14 membered heterocyclic group or a Si-containing group -SiR₁R₂R₃ group where R₁, R₂ and R₃ are the same or different and are selected from H or a C₁- C₆ hydrocarbyl group which is optionally substituted with a halogen group or with at least one C₁-C₃ alkyl group with the proviso that not more than two OfR₁, R₂ and R₃ is H;

In the presence of a pre-catalyst or catalyst compound according to claim 1 and optionally a secondary phosphine compound or a metal selected from the group consisting of Pd, Ni or Pt or a metal-containing compound comprising Pd, Ni or Pt in a solvent at ambient temperature or a temperature above or below ambient temperature to produce a compound according to the chemical structure:

36. The method according to claim 35 wherein R' is the same or different and is H, an optionally substituted C₁-C₁₂ hydrocarbyl group, a nitro group, a nitrile (CN) group, an amine, which may be unsubstituted or substituted with one or two C₁-C₆ alkyl groups or alkanol groups, a halogen, a mono- or dialkylamido groups, a mono- or diarylamido group, an optionally substituted alkyl or aryl amidate group, a hydroxyl groups or an optionally substituted 3 to 14 membered heterocyclic group.

37. The method according to claim 35 or 36 wherein R' is an optionally substituted alkyl or aryl alkoxide.

38. The method according to any of claims 35-37 wherein said leaving group is Cl,

Br, I, a toluenesulfonyl (tosyl) group or a trifluoromethylsulfonyl (trifate) group.

39. The method according to any of claims 35-38 wherein said metal is Pd or said metal-containing compound comprises Pd.

40. The method according to any of claims 35-39 wherein said pre-catalyst or catalyst is a compound according to any of compounds 1-6 of figure 2.

41. A method of producing an olefϊnic compound containing a C-S bond comprising reacting a compound according to the chemical structure:

Wherein X¹ is a leaving group;

R , R and R are each independently selected from H, an optionally substituted C₁- C₁₂ hydrocarbyl group, a nitro group, a nitrile (CN) group, an amine, which may be unsubstituted or substituted with one or two C₁-C₃ alkyl groups or alkanol groups, a halogen, a mono- or dialkylamido groups, a mono- or diarylamido group, an optionally substituted alkyl or aryl amidate group, a hydroxyl groups or an optionally substituted 3 to 14-membered heterocyclic group, With a compound H-SR, S-R or a thiolate equivalent compound containing an R group where R is an optionally substituted C₁-C₁₂ hydrocarbyl group, an optionally substituted 3-14 membered heterocyclic group or a Si-containing group -SiR₁R₂R₃ where R₁, R₂ and R₃ are the same or different and are selected from H or a C₁-C₆ hydrocarbyl group which is optionally substituted with a halogen group or with at least one C₁-C₃ alkyl group with the proviso that not more than two of R₁, R₂ and R₃ is H; In the presence of a pre-catalyst or catalyst compound according to claim 1 and optionally a secondary phosphine compound or a metal selected from the group consisting of Pd, Ni or Pt or a metal-containing compound comprising Pd₅ Ni or Pt in a solvent at ambient temperature or a temperature above or below ambient temperature to produce a compound according to the chemical structure:

42. The method according to claim 41 wherein said leaving group is Cl, Br₅ 1₅ a toluenesulfonyl (tosyl) group or a trifluoromethylsulfonyl (trifate) group.

43. The method according to claim 41 or 42 wherein said metal is Pd or said metal- containing compound comprises Pd.

44. The method according to any of claims 40-43 wherein said pre-catalyst or catalyst is a compound according to any of compounds 1-6 of figure 2.