Catalytic C-X-Bond Metathesis through Arylation

The present invention refers to a process for a catalytic aryl transfer to rearrange the backbone of aromatic C-X bonds.

The alkene metathesis reaction has had a transformative impact on chemistry by offering an alternative approach to olefin synthesis that is complementary in scope and reactivity to traditional olefination reactions, such as the Wittig reaction. Due to its versatility, alkene metathesis has consequently found applications in very diverse areas, including polymer chemistry, biomass valorization and drug synthesis due to the ubiquity of alkenes as starting materials, synthetic intermediates and final products. The isodesmic nature of the reaction enables the transformation of one alkene into another in a mild process, leading to an overall exchange of the alkene group substituents (Figure 1A). This feature facilitates the rapid generation of new molecular architectures while conserving the important olefin functionality. In light of the established synthetic power of alkene metathesis, it can be expected that the metathesis of other important bonds including single bonds would have a beneficial impact on the molecular sciences. Carbon-heteroatom bonds composed of heavy main group elements are commonly encountered in a wide range of applications (Figure 1 B). In particular, C(sp ² )-S and C(sp ² )-P bonds are essential in materials and medicinal sciences. Aromatic thioethers are key motifs in drug development and can also be found in many organic materials and polymers - for example, the thermoplastic polyphenylene sulfide (PPS, 1 ) is produced yearly on a 80,000 ton scale. Aromatic phosphines are commonly used as ligands and catalysts, both on laboratory scale and industrial processes. They are further employed in the area of organic materials, with applications ranging from sensors to organic light emitting diodes. There are rare examples of single C-X bond metathesis only, including transamidation processes. The metathesis of aromatic C-X bonds, however, has been virtually unexplored. It is an object of the present invention therefore to provide a carbon-heteroatom bond metathesis reactions, wherein compounds containing at least one C(sp ² )- heteroatom bond could effectively swap their substituents in a manner analogous to alkene metathesis. The challenge in developing catalytic metathesis reactions employing C-X bonds is to identify a mechanistic pathway in which the breakage of a C-X bond and subsequent ligand exchange can be realized. The reaction conditions wherein the oxidative addition and reductive elimination of common C- X bonds, including C-S or C-P bonds, and exchange of the resulting thiolate or phosphine ligand could be achieved to unlock novel catalytic C-X bond metathesis reactions should be identified. It is also an object to identify a general mechanistic manifold, proceeding through transfer arylation, to perform unprecedented catalytic C(sp ² )-X bond metathesis with several different main group elements (Figure 1 C). It has now been found that the above-mentioned disadvantages can be dealt with by a process for a catalytic aryl transfer wherein an aryl-compound (I) is reacted with an hydrocarbon (II) in the presence of a Pd- or Ni-catalyst coordinated by electron rich ligands and in the presence of a base in an organic solvent, as represented in the following reaction scheme:

Ar-X ¹ R ¹ + R ² X ² -R ³ ► Ar-X ¹ R ² + R ¹ X ² -R ³

(I) (ii) (ill) (IV)

wherein

- Ar is aryl, heteroaryl or vinyl, each being optionally substituted by one or more groups selected from straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, ether, acetal, silyl ether or amine, or by a heterosubstituent;

- X ¹ and X ² may be the same or different and are each S or Se, preferably S,

- R ¹ is H or methyl, a straight chain or branched C2-Ci6-alkyl, or aryl, each optionally being substituted by one or more groups selected from straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, ether, acetal, silyl ether or amine, or by a heterosubstituent;

- R ² is an primary, secondary or tertiary alkyl or aryl, each being optionally being substituted by one or more groups selected from straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or by a heterosubstituent;

- R ³ is H,

- the Pd- or Ni-catalyst coordinated by electron rich ligands is selected from the group consisting of Pd(OAc) ₂ , Pd ₂ (dba) ₃ , PdCI ₂ , PdCI ₂ (MeCN) ₂ , Ni(COD) ₂ .

- the electron rich ligands is selected from the group consisting of IPENT( 1 ,3- Bis(2,6-bis(1 -ethylpropyl)phenyl)imidazol-2-ylidene), SIPr (1 ,3-Bis(2,6- diisopropylphenyl)imidazolidene), ICy (1 ,3-bis-(cyclohexyl)imidazol-2-ylidene), or IPr (1 ,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene).

- the base is selected from the group consisting of LiHMDS, KHMDS, NaHDMS, LiOiBu, KOiBu, NaOiBu.

Such a process represents a powerful companion to traditional cross-coupling processes. This strategy is particularly useful for the rapid discovery and derivatization of functional molecules to prepare compound libraries that are essential for structure activity relationship (SAR) studies. Additionally, the process parallel the alkene metathesis reaction in providing an extremely flexible tool for the construction and deconstruction of organic molecules with potential applications in waste recycling and polymerization. A further attractive feature of this reaction is the possibility, at higher temperatures, to directly use, for example, an unprotected thiophenol as an electrophile through C-S bond cleavage (Figure 2B). This is notable, since previous examples of such reactivity are extremely rare due to catalyst poisoning, and only two thiophenol substrates have been reported to undergo C-S bond cleavage, using Grignard reagents under Ni-catalysis. Homodimerization of thiophenol, which could potentially have plagued the efficiency of a chemoselective coupling process, does not interfere with the inventive reaction when a more nucleophilic alkyl thiol is employed. However, if no cross-metathesis partner is present in the reaction mixture, homodimerization of thiophenol leads to the formation of diphenyl sulfide (44). Another chalcogen element, selenium, can also participate in this reaction and the homodimerization of selenophenol gave high yields of the corresponding diphenylselenide (45).

In one embodiment, a Pd-NHC (N-heterocyclic carbene) complex, preferably a [(NHC)Pd(dimethylbenzylamine)CI] complex is used as catalyst. Such a catalyst efficiently promotes the oxidative addition of Ar-X and its microscopic reverse, reductive elimination, to enable a facile X-R ³ group exchange to take place. According to the present invention, the Pd- or Ni- catalyst is present in an amount in the range of of 0.05 mol% to 1 mol% of the aryl-compound (I), preferably in the range of 0.2 mol% to 0.6 mol% of the aryl-compound (I).

In a preferred embodiment, the base used in the process of the present invention is a lithium base, sodium base or potassium base, preferably a lithium base, more preferably LiHMDS (lithium bis(trimethylsilyl)amide). Use of a lithium base proved clearly superior to sodium or potassium bases, reflecting the importance of solubilities in this reaction. The decreased solubility of the side-product, for example MeSLi when Ar-XR ¹ is a methyl aromatic thioether, when compared to the larger lithium thiolate salt generated from the thiol reagent and the base, efficiently drives the equilibrium of the reaction to completion.

Preferably, the base is present in an amount in the range of 1 equivalent to 6 equivalents, preferably in the range of 1 .5 equivalent to 4 equivalents of the reaction partners.

In a preferred embodiment, the aryl-compound (I) is reacted with the hydrocarbon (II) at a temperature in the range of 25°C to 250°C, preferably in the range of 80°C to 200°C, for 4 h to 20 h, preferably 8 h to 16 h.

The organic solvent used for reacting the aryl-compound (I) with the hydrocarbon (II) is not critical and can be selected amongst those which are commonly used for such kind of catalyzed reactions. Preferably, an aromatic solvent or an aliphatic hydrocarbon solvent, more preferably toluene, benzene, xylene, cumene, chlorobenzene or dichlorobenzene is used.

In a preferred embodiment, Ar is phenyl, 4-methylphenyl or naphtyl, each optionally being substituted by one or more groups selected from straight chain or branched chain alkyl, ether, acetal, silyl ether or amine, preferably being substituted by methyl, ketals, methoxy, MOMO, TIPSO, OCF ₃ , OBn, CF ₃ , F, TMS, ΝΜβ ₂ , CN, pyridyl, pyrazinyl, benzothiazyl, phenylvinyl, t-butyl or 5-phenyl- benzothiazyl.

In a preferred embodiment, Ar or Ar-X is a component of a polymer. The process of the present invention provides the possibility to depolymerize polymers, preferably, thermoplastic polymers, in particular PPS (1 ) to obtain simple chemical building blocks (Figure 3B).

In a preferred embodiment, X is S.

In a further embodiment, R ¹ is H, methyl, phenyl or 4-methoxyphenyl. In one embodiment, R ² is cyclohexyl, cyclopentyl, 2-methylbutyl, 1 -methyl-propyl, nCi ₂ H ₂₅ , adamantyl, 2-phenylethyl, 1 -methyl-5-dimethyl-bicyclo[4.1 .0]heptyl-, nC ₈ H ₁₇ , benzyl, optionally substituted steroid residue, 2-amantadyl-ethyl or C ₈ H ₁₇ .

In a preferred embodiment, the hydrocarbon (II) is present an amount in the range of 0.5 equivalents to 6 equivalents of the aryl-compound (I), preferably in the range of 1 .5 equivalent to 4 equivalents of the aryl-compound (I).

In a further embodiment, the process of the present invention is used to enable a sequence of arylation/retro-arylation to take place and equilibrate a simple reaction mixture (Figure 3C). Such a thioether cross-metathesis, in case X is S, leads to the same ratio of starting materials to products in the forward and reverse direction. In such an process, R ² X-R ³ is used as a co-catalytic amount in the range of 5 to 15%, preferably in the range of 7,5 to 12,5% of the total amount of the at least one Ar-X-R ¹ compound.

Accordingly, the present invention also provides an aryl-compound produced by the process of the present invention.

Definition for the substituents as described herein are given in the following.

A heterosubstituent according to the invention is to be understood as a substituent including heteroatoms, preferentially selected from O, N, S, Si and halogens. It can be preferentially selected from, =O, -OH, -F, -CI, -Br, -I, -CN, -N ₃ , -NO2, - SO3H, NCO, NCS, OP(O)(OR ^s1 )(OR ^S2 ), OP(OR ^s1 )(OR ^S2 ), a monohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethyl group, -CF(CF ₃ )2, -SF ₅ , - NR ^S1 2, -OR ^s1 , -OOR ^s1 , -OSiR ^s1 R ^S2 R ^S3 , -OSi(OR ^s1 )R ^S2 R ^S3 , -OSi(OR ^s1 )(OR ^S2 )R ^S3 , - OSi(OR ^s1 )(OR ^S2 )(OR ^S3 ), -OSO ₂ R ^s1 , -SR ^S1 , -SSR ^S1 , -S(O)R ^s1 , -S(O) ₂ R ^s1 , - C(O)OR ^s1 , -C(O)NR ^s1 R ^S2 , -NR ^s1 C(O)R ^S2 , -C(O)-R ^s1 , -COOM, wherein M may be a metal such as Na, K or Cs.

R ^S1 R ^S2 and R ^S3 each individually represent H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, sulfonyl, silyl, each being optionally substituted by one or more alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aralkyl, heteroaralkyl, sulfonyl or heterosubstituent.

For the reaction system in more detail, alkyl may be Ci-C2o-Alkyl which can be straight chain or branched or cyclic and has 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Alkyl might particularly be CrC ₆ -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, likewise pentyl, 1 -, 2- or 3-methylpropyl, 1 ,1 -, 1 ,2- or 2,2-dimethylpropyl, 1 - ethylpropyl, hexyl, 1 -, 2-, 3- or 4-methylpentyl, 1 ,1 -, 1 ,2-, 1 ,3-, 2,2-, 2,3- or 3,3- dimethylbutyl, 1 - or 2-ethylbutyl, 1 -ethyl-1 -methylpropyl, 1 -ethyl-2-methylpropyl, 1 ,1 ,2- or 1 ,2,2-trimethylpropyl. Cycloalkyi may be a cyclic alkyl group forming a 3 to 20 membered ring and might be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

HeterocycloalkyI may be a cycloalkyi forming a 3 to 10 membered ring and incorporating one or more heteroatoms selected from N, O and S within the cycle. In particular, heterocycloalkyls can be preferentially selected from 2,3-dihydro-2-, - 3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1 ,3- dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl, 1 -, 2- or 3-pyrrolidinyl, tetrahydro-1 -, -2- or -4-imidazolyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1 -, -3- or -4- pyrazolyl, 1 ,4-dihydro-1 -, -2-, -3- or -4-pyridyl, 1 ,2,3,4-tetrahydro-1 -, -2-, -3-, -4- , -5- or -6-pyridyl, 1 -, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -

3- or -4-pyranyl, 1 ,4-dioxanyl, 1 ,3-dioxan-2-, -4- or -5-yl, hexahydro-1 -, -3- or -4- pyridazinyl, hexahydro-1 -, -2-, -4- or -5-pyrimidinyl, 1 -, 2- or 3-piperazinyl, 1 ,2,3,4- tetrahydro-1 -, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1 ,2,3,4-tetrahydro-1 -, -2-, -3-, -

4- , -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1 ,4- oxazinyl.

Halogen is F, CI, Br or I.

Aryl might be phenyl, naphthyl or biphenyl and substituted derivatives thereof. Aralkyl might be benzyl, naphthylmethyl and substituted derivatives thereof. Heteroaryl may have one or more heteroatoms selected from N, O,S and Si and is preferably 2- or 3-furyl, 2- or 3-thienyl, 1 -, 2- or 3-pyrrolyl, 1 -, 2-, 4- or 5-imidazolyl, 1 -, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5- thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, also preferably 1 ,2,3-triazol-1 -, -4- or -5-yl, 1 ,2,4-triazol-1 -, -3- or -5-yl, 1 - or 5-tetrazolyl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,3,4-thiadiazol-2- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl, 1 ,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1 -, 2-, 3-, 4-, 5-, 6- or 7-lndolyl, 4- or 5-isoindolyl, 1 -, 2-, 4- or 5-benz- imidazolyl, 1 -, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4- , 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7- benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1 ,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8- quinolyl, 1 -, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-,

5- , 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1 ,4- oxazinyl, also preferably 1 ,3-benzodioxol-5-yl, 1 ,4-benzodioxan-6-yl, 2,1 ,3- benzothiadiazol-4- or -5-yl or 2,1 ,3-benzoxadiazol-5-yl.

Heteroaralkyl might be any of the aforementioned heteroaryl bound to an alkyl group, such as pyridinylmethyl.

Optionally substituted means unsubstituted or monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or even further substituted on the respective group. The invention is further illustrated in the attached figures and the following experimental section below.

In the attached drawings:

Figure 1 illustrates the:

(A) Alkene metathesis.

(B) Selected applications of heavy main group elements bound to C(sp ² ).

(C) The process of the present invention showing a single-bond metathesis through arylation.

Figure 2 illustrates the:

(A) Products obtained by the process of the present invention using

aromatic thioethers as Ar-XR ¹ educt.

(B) Products obtained by the process of the present invention using

thiophenols as Ar-XR ¹ educt.

Figure 3 illustrates the synthetic potential of the C-S bond metathesis reaction of the present invention, in particular Figure 3 shows the:

(A) Late stage generation of a drug library using Thioridazine as Ar-XR ¹ starting material.

(B) Depolymerization of a commercial plastic. Experimental Section

Preparation Examples

General procedure for the catalytic aryl transfer with aryl ethers

SingaCycle A1 (0.4 mol%)

□HMDS (2.6 equiv) primary

secondary

Toluene, 100 °C, 12 h tertiary

0.

In the glovebox, aryl methyl sulfane (0.5 mmol), alkyl thiol (2.0 equiv, 1 .0 mmol), LiHMDS (1 .3 ml, 1 .0 M in toluene), and SingaCycle A1 (0.4 mol%, 0.4 ml, 0.005 M in toluene) were added into an oven-dried 8 ml vial with a magnetic stirring bar, followed by addition of toluene (0.3 ml). The vial was sealed and removed out of the glovebox and heated to 100 °C. After 12 h, the vial was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with saturated NaOH solution. The aqueous phase was extracted with ethyl acetate 3 times. The collected organic phases were dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give the desired product. Example 1

c clohexyl(p-tolyl)sulfane

Prepared by general procedure A; isolated as a colorless liquid using pentane/ethyl acetate (100:1 ) as eluent (94.2 mg, 92%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.31 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 3.12-2.94 (m, 1 H), 2.33 (s, 3H), 2.06-1 .91 (m, 2H), 1 .84-1 .71 (m, 2H), 1 .66-1 .57 (m, 1 H), 1 .44- 1 .15 (m, 5H). ¹³ C NMR (75 MHz, CDCI ₃ ) δ 136.8, 132.7, 131 .2, 129.5, 47.1 , 33.4, 26.1 , 25.8, 21 .0. HRMS Ci ₃ H ₁₈ S [M] ⁺ ; calculated 206.1 123, found: 206.1 126. The spectral data are consistent with those reported in the literature. Example 2

c clohexyl(m-tolyl)sulfane

Prepared by general procedure A; isolated as a colorless liquid using pentane/ethyl acetate (100:1) as eluent (95 mg, 93%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.25-7.12 (m, 3H), 7.03 (s, 1H), 3.23-3.01 (m, 1H), 2.33 (s, 3H), 2.05-1.93 (m, 2H), 1.77 (q, J= 5.4, 4.4 Hz, 2H), 1.66-1.58 (m, 1H), 1.45-1.20 (m, 5H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 138.5, 134.9, 132.5, 128.8, 128.6, 127.5, 46.6, 33.4, 26.1, 25.8, 21.3. HRMS Ci ₃ Hi ₈ S [M] ⁺ ; calculated 206.1123, found: 206.1125. The spectral data are consistent with those reported in the literature.

Example 3

c clopentyl(naphthalen-2-yl)sulfane

Prepared by general procedure A; isolated as a pale yellow liquid using pentane/ethyl acetate (100:1) as eluent (102.3 mg, 90%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.87-7.73 (m, 4H), 7.57-7.38 (m, 3H), 3.96-3.65 (m, 1H), 2.24- 2.03 (m, 2H), 1.92-1.60 (m, 6H). ¹³ C NMR (75 MHz, CDCI ₃ ) δ 134.8, 133.7, 131.7, 128.1, 128.0, 127.64, 127.63, 127.0, 126.4, 125.5, 45.8 , 33.5, 24.8. HRMS Ci ₅ H ₁₆ S [M] ⁺ ; calculated 228.0967, found: 228.0968.

Example 4

cyclopentyl(naphthalen-1-yl)sulfane

Prepared by general procedure A; isolated as a pale yellow liquid using pentane/ethyl acetate (100:1) as eluent (103 mg, 91%). ¹ H NMR (300 MHz, Chloroform-d) δ 8.55-8.42 (m, 1H), 7.92-7.82 (m, 1H), 7.81-7.71 (m, 1H), 7.65 (dd, J= 7.2, 1.2 Hz, 1H), 7.58-7.52 (m, 2H), 7.43 (dd, J= 8.2, 7.2 Hz, 1H), 3.68 (td, J =6.3, 5.7, 1.4 Hz, 1H), 2.19-1.96 (m, 2H), 1.92-1.80 (m, 2H), 1.78-1.58 (m, 4H). ¹³ C NMR (75 MHz, CDCI ₃ ) δ 134.3, 133.9, 133.3, 129.2, 128.4, 127.2, 126.2, 126.1, 125.5, 125.3, 46.5, 33.6, 24.7. HRMS Ci ₅ Hi ₆ S [M] ⁺ ; calculated 228.0967, found: 228.0969.

Example 5

-trimethyl-2-(4-((2-methylbutyl)thio)phenyl)-1,3-dioxane

Prepared by general procedure A at 80 °C; isolated as a yellow liquid using pentane/ethyl acetate (30:1) as eluent (109 mg, 71%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.36-7.27 (m, 4H), 3.45-3.32 (m, 4H), 2.97 (dd, J= 12.4, 5.8 Hz, 1H), 2.78 (dd, J= 12.4, 7.4 Hz, 1H), 1.79-1.64 (m, 1H), 1.60-1.53 (m, 1H), 1.51 (s, 3H), 1.34-1.27 (m, 1H), 1.26 (s, 3H), 1.04 (d, J= 6.7 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.58 (s, 3H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 138.1, 137.1, 128.4, 127.3, 100.0, 71.7, 40.4, 34.5, 31.9, 29.9, 28.8, 22.9, 21.9, 19.0, 11.3. HRMS Ci ₈ H ₂ 8O ₂ S [M] ⁺ ; calculated 308.1810, found: 308.1809.

Example 6

c clopentyl(4-methoxyphenyl)sulfane

Prepared by general procedure A; isolated as a colorless liquid using pentane/ethyl acetate (50:1) as eluent (95.9 mg, 93%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.37 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 3.48-3.38 (m, 1H), 2.01-1.89 (m, 2H), 1.81-1.73 (m, 2H), 1.63-1.50 (m, 4H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 159.0, 134.1, 127.0, 114.4, 55.3, 48.0, 33.4, 24.6. HRMS Ci ₂ Hi ₆ SO [M] ⁺ ; calculated 208.0916, found: 208.0919. The spectral data are consistent with those reported in the literature. Example 7

sec-butyl(4-(methoxymethoxy)phenyl)sulfane

Prepared by general procedure A; isolated as a colorless liquid using pentane/ethyl acetate (30:1 ) as eluent (1 10.3 mg, 98%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.43-7.32 (m, 2H), 7.03-6.87 (m, 2H), 5.16 (s, 2H), 3.48 (s, 3H), 2.99 (td, J = 6.9, 6.1 Hz, 1 H), 1 .62-1 .38 (m, 2H), 1 .23 (d, J = 6.7 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H). ¹³ C NMR (75 MHz, Chloroform-d) δ 156.8, 135.2, 126.9, 1 16.6, 94.4, 56.0, 46.1 , 29.4, 20.5, 1 1 .5. HRMS Ci ₂ Hi ₈ O ₂ S [M+H] ⁺ ; calculated 227.1 100, found: 227.1 102.

Example 8

triisopropyl(4-((2-methylbutyl)thio)phenoxy)silane

Prepared by general procedure A; isolated as a colorless liquid using pentane/ethyl acetate (50:1 ) as eluent (136.1 mg, 78%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.35-7.19 (m, 2H), 6.89-6.76 (m, 2H), 2.87 (dd, J = 12.6, 5.7 Hz, 1 H), 2.68 (dd, J = 12.6, 7.4 Hz, 1 H), 1 .72-1 .45 (m, 2H), 1 .26 (dd, J = 14.8, 6.8 Hz, 4H), 1 .19-1 .06 (m, 18H), 1 .01 (d, J = 6.6 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H). ¹³ C NMR (75 MHz, CDCI ₃ ) δ 155.0, 132.3, 128.0, 120.4, 42.8, 34.6, 28.7, 18.8, 17.9, 12.6, 1 1 .2. HRMS C ₂₀ H ₃ 6OSSi [M] ⁺ ; calculated 352.2251 , found: 352.2249.

Example 9

-methylbutyl)(4-(trifluoromethoxy)phenyl)sulfane

Prepared by general procedure A for 7 h; isolated as a pale yellow liquid using pentane/ethyl acetate (50:1 ) as eluent (1 17 mg, 89%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.38-7.31 (m, 2H), 7.19-7.11 (m, 2H), 2.96 (dd, J= 12.5, 5.8 Hz, 1H), 2.77 (dd, J= 12.5, 7.4 Hz, 1H), 1.76-1.48 (m, 2H), 1.37-1.23 (m, 1H), 1.05 (d, J= 6.6 Hz, 3H), 0.93 (t, J= 7.4 Hz, 3H). ¹⁹ F NMR (282 MHz, Chloroform-d) δ - 58.0. ¹³ C NMR (75 MHz, Chloroform- d) δ 147.1 (q, J = 1.9 Hz), 136.4, 129.9, 121.4, 120.4 (q, J= 257.0 Hz), 41.0, 34.4, 28.7, 18.9, 11.2. HRMS Ci ₂ Hi ₅ SOF ₃ [M] ⁺ ; calculated 264.0790, found: 264.0792.

Example 10

-(benzyloxy)phenyl)(sec-butyl)sulfane

Prepared by general procedure A; isolated as a pale yellow liquid using pentane/ethyl acetate (50:1) as eluent (113.3 mg, 83%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.48-7.30 (m, 7H), 6.92 (d, J= 8.8 Hz, 2H), 5.05 (s, 2H), 2.97 (td, J= 6.9, 6.1 Hz, 1H), 1.70-1.39 (m, 2H), 1.22 (d, J= 6.8 Hz, 3H), 1.00 (t, J= 7.4 Hz, 3H). ¹³ C NMR (75 MHz, Chloroform-d) δ 158.5, 136.8, 135.5, 128.6, 128.0, 127.5, 125.6, 115.2, 70.1, 46.2, 29.4, 20.5, 11.5. HRMS Ci ₇ H ₂₀ OS [M] ⁺ ; calculated 272.1229, found: 272.1232.

Example 11

-methylbutyl)(4-(trifluoromethyl)phenyl)sulfane

Prepared by general procedure A for 1 h; isolated as a pale yellow liquid using pentane/ethyl acetate (80:1) as eluent (100.1 mg, 81%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.52 (dt, J = 8.3, 0.7 Hz, 2H), 7.41-7.34 (m, 2H), 3.01 (dd, J = 12.5, 5.8 Hz, 1H), 2.82 (dd, J= 12.5, 7.5 Hz, 1H), 1.79-1.69 (m, 1H), 1.62-1.51 (m, 1H), 1.34 (dd, J= 14.3, 6.7 Hz, 1H), 1.07 (d, J= 6.6 Hz, 3H), 0.95 (t, J= 7.4 Hz, 3H). ¹⁹ F NMR (282 MHz, Chloroform-d) δ -62.4. ¹³ C NMR (126 MHz, Chloroform-d) δ 143.2, 127.1, 127.0 (q, J= 32.4 Hz), 125.5 (q, J = 3.8 Hz), 124.2 (q, J = 271 .6 Hz), 39.5, 34.4, 28.8, 19.0, 1 1 .2. HRMS Ci ₂ H ₁₅ SF ₃ [M] ⁺ ; calculated 248.0841 , found: 248.0843.

Example 12

c clohexyl(4-fluorophenyl)sulfane

Prepared by general procedure A; isolated as a colorless liquid using pentane/ethyl acetate (100:1 ) as eluent (78.5 mg, 75%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.42 (dd, J = 8.8, 5.3 Hz, 2H), 7.01 (t, J = 8.7 Hz, 2H), 3.00 (ddt, J = 10.3, 7.2, 3.8 Hz, 1 H), 1 .99-1 .90 (m, 2H), 1 .85-1 .71 (m, 2H), 1 .66-1 .56 (m, 1 H), 1 .44-1 .09 (m, 5H). ¹⁹ F NMR (282 MHz, Chloroform-d) δ -1 14.9. ¹³ C NMR (75 MHz, Chloroform-d) δ 162.2 (d, J = 246.8 Hz), 134.9 (d, J = 8.1 Hz), 129.8 (d, J = 3.4 Hz), 1 15.7 (d, J = 21 .6 Hz), 47.5, 33.3, 26.0, 25.7. HRMS Ci ₂ Hi ₅ FS [M] ⁺ ; calculated 210.0873, found: 210.0872. The spectral data are consistent with those reported in the literature.

Example 13

4-(cyclopentylthio)phenyl)trimethylsilane

Prepared by general procedure A; isolated as a colorless liquid using pentane as eluent (109.7 mg, 88%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.42 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 3.62 (ddt, J = 7.0, 3.4, 1 .6 Hz, 1 H), 2.23-2.00 (m, 2H), 1 .88-1 .72 (m, 2H), 1 .72-1 .56 (m, 4H), 0.25 (s, 9H). ¹³ C NMR (126 MHz, CDCIs) δ 139.5, 138.4, 134.8, 129.6, 46.4, 34.7, 26.0, 0.0. HRMS Ci ₄ H ₂₂ SSi [M] ⁺ ; calculated 250.1206, found: 250.1204.

Example 14

4-(sec-butylthio)-N,N-dimethyl

Prepared by general procedure A; isolated as a pale yellow liquid using pentane/ethyl acetate (50:1 ) as eluent (91 .8 mg, 88%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.41-7.30 (m, 2H), 6.79-6.55 (m, 2H), 2.96 (s, 6H), 2.89 (q, J = 6.7 Hz, 1 H), 1 .69-1 .37 (m, 2H), 1 .21 (d, J = 6.7 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H). ¹³ C NMR (126 MHz, Chloroform-d) δ 136.0 (2C), 1 12.6 (2C), 46.4, 40.5, 29.4, 20.5, 1 1 .6. HRMS d ₂ H ₁₉ NS [M+H] ⁺ ; calculated 210.131 1 , found: 210.1308.

Example 15

4- cyclopentylthio)benzonitrile

Prepared by general procedure A for 5 h at 80 °C; isolated as a pale yellow liquid using pentane/ethyl acetate (50:1 ) as eluent (49 mg, 44%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.49-7.39 (m, 2H), 7.28-7.21 (m, 2H), 3.74-3.53 (m, 1 H), 2.08 (dddd, J = 9.4, 4.8, 2.5, 1 .0 Hz, 2H), 1 .73 (d, J = 1 .4 Hz, 2H), 1 .66-1 .47 (m, 4H). ¹³ C NMR (75 MHz, Chloroform-d) δ 145.8, 132.0, 127.2, 1 18.9, 107.7, 44.0, 33.3, 24.9. HRMS C12H13NS [M+Na] ⁺ ; calculated 226.0661 , found: 226.0661 .

Example 16

-(cyclopentylthio)benzo[d]thiazole

Prepared by general procedure A for 5 h; isolated as a yellow liquid using pentane/ethyl acetate (30:1 ) as eluent (75.2 mg, 64%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.88 (dd, J = 8.2, 1 .0 Hz, 1 H), 7.76 (dd, J = 7.9, 1 .1 Hz, 1 H), 7.41 (ddd, J = 8.3, 7.2, 1 .2 Hz, 1 H), 7.32-7.27 (m, 1 H), 4.20-4.07 (m, 1 H), 2.34-2.23 (m, 2H), 1 .90-1 .64 (m, 6H). ¹³ C NMR (75 MHz, Chloroform-d) δ 167.5, 153.4, 135.2, 126.0, 124.1 , 121 .5, 120.8, 46.7, 33.8, 24.9. HRMS Ci ₂ H ₁₃ NS ₂ [M+Na] ⁺ ; calculated 258.0382, found: 258.0379. The spectral data are consistent with those reported in the literature.

Example 17

2-cyclohexylthio)pyridine

Prepared by general procedure A for 2 h at 70 °C; isolated as a pale yellow liquid using pentane/ethyl acetate (20:1) as eluent (83 mg, 86%). ¹ H NMR (300 MHz, Chloroform-d) δ 8.42 (dt, J =4.8, 1.5 Hz, 1H), 7.45 (ddd, J = 8.0, 7.3, 1.9 Hz, 1H), 7.18-7.12 (m, 1H), 6.95 (ddd, J = 7.4, 4.9, 1.1 Hz, 1H), 3.82 (ddd, J = 10.1 , 6.2, 3.7 Hz, 1H), 2.13-2.01 (m, 2H), 1.85-1.69 (m, 2H), 1.69-1.59 (m, 1H), 1.54-1.22 (m, 5H). ¹³ C NMR (75 MHz, Chloroform-d) δ 159.2, 149.3, 136.0, 123.0, 119.3, 43.0, 33.3, 26.0, 25.8. HRMS C11H15NS [M+H] ⁺ ; calculated 194.0997, found: 194.0998. The spectral data are consistent with those reported in the literature.

Example 18

2-cyclohexylthio)pyrazine

Prepared by general procedure A for 2 h at 80 °C; isolated as a pale yellow liquid using pentane/ethyl acetate (50:1) as eluent (77.6 mg, 80%). ¹ H NMR (300 MHz, Chloroform-d) δ 8.42 (d, J = 1.6 Hz, 1H), 8.37 (dd, J =2.7, 1.6 Hz, 1H), 8.19 (d, J = 2.7 Hz, 1 H), 3.93-3.78 (m, 1 H), 2.18-2.04 (m, 2H), 1.87-1.73 (m, 2H), 1.67 (ddt, J= 9.6, 6.3, 2.4 Hz, 1H), 1.58-1.29 (m, 5H). ¹³ C NMR (75 MHz, Chloroform-d) δ 157.3, 144.2, 143.9, 139.2, 42.9, 33.1, 25.9, 25.7. HRMS Ci ₀ H ₁₄ N ₂ S [M+H] ⁺ ; calculated 195.0950, found: 195.0950.

Example 19

dodecyl(4-methoxyphenyl)sulfane

Prepared by general procedure A; isolated as a pale yellow liquid using pentane/ethyl acetate (50:1 ) as eluent (135 mg, 88%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.35 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.84 (br, 2H), 1 .72-1 .50 (m, 2H), 1 .43-1 .28 (m, 18H), 0.98-0.82 (m, 3H). ¹³ C NMR (126 MHz, CDCIs) δ 158.7, 132.9, 1 14.8, 1 14.5, 55.3, 35.8, 31 .9, 29.7, 29.63, 29.59, 29.5, 29.40, 29.35, 29.2, 28.7, 22.7, 14.1 . HRMS C19H32OS [M] ⁺ ; calculated 308.2168, found: 308.2167. The spectral data are consistent with those reported in the literature.

Example 20

-adamantan-1-yl)(phenyl)sulfane

Prepared by general procedure A; isolated as a white solid using pentane as eluent (95 mg, 78%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.56-7.48 (m, 2H),

7.39-7.29 (m, 3H), 2.06-1 .95 (m, 3H), 1 .82 (d, J = 2.9 Hz, 6H), 1 .70-1 .56 (m, 6H).

¹³ C NMR (126 MHz, CDCI ₃ ) δ 137.7, 130.5, 128.6, 128.3, 47.8, 43.6, 36.2, 30.0.

HRMS Ci ₆ H ₂₀ S [M] ⁺ ; calculated 244.1280, found: 244.1280.

Example 21

henethyl(phenyl)sulfane

Prepared by general procedure A; isolated as a colorless liquid using pentane/ethyl acetate (100:1 ) as eluent (60.5 mg, 57%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.21-7.15 (m, 2H), 7.1 1 (td, J = 7.7, 3.1 Hz, 4H), 7.07-6.96 (m, 4H), 3.04-2.93 (m, 2H), 2.80-2.69 (m, 2H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 140.2, 136.4, 129.2, 128.9, 128.6, 128.5, 126.5, 126.0, 35.7, 35.1 . HRMS Ci ₄ H ₁₄ S [M] ⁺ ; calculated 214.0816, found: 214.0816. The spectral data are consistent with those reported in the literature. Example 22

,5R)-2,6,6-trimethylbicyclo[3.1.1 ]heptan-2-yl)sulfane

Prepared by general procedure A; isolated as a colorless liquid using pentane/ethyl acetate (100:1) as eluent (114 mg, 93%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.41-7.32 (m, 2H), 7.32-7.27 (m, 2H), 7.24-7.13 (m, 1H), 3.19- 2.79 (m, 2H), 2.46-2.24 (m, 2H), 2.14-1.82 (m, 5H), 1.74-1.53 (m, 1H), 1.22 (s, 3H), 1.06 (s, 3H), 0.91 (d, J= 9.7 Hz, 1H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 137.3, 128.9, 128.8, 125.6, 45.6, 41.3, 40.8, 40.6, 38.7, 33.3, 28.0, 26.2, 23.3, 22.1. HRMS Ci ₆ H ₂₂ S [M] ⁺ ; calculated 246.1436, found: 246.1437.

Example 23

oct l(phenyl)sulfane

Prepared by general procedure A; isolated as a colorless liquid using pentane as eluent (102 mg, 92%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.15 (dd, J= 8.6, 1.4 Hz, 2H), 7.09 (dd, J = 8.6, 6.9 Hz, 2H), 7.01-6.94 (m, 1H), 2.82-2.69 (m, 2H), 1.63-1.40 (m, 2H), 1.33-1.20 (m, 2H), 1.16-1.03 (m, 8H), 0.71 (t, J= 7.0 Hz, 3H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 137.1, 128.84, 128.81, 125.6, 33.6, 31.9, 29.23, 29.20, 29.19, 28.9, 22.7, 14.1. HRMS Ci ₄ H ₂₂ S [M] ⁺ ; calculated 222.1442, found: 222.1441. The spectral data are consistent with those reported in the literature.

Example 24

benzyl(phenyl)sulfane Prepared by general procedure A for 1 h; isolated as a colorless liquid using pentane as eluent (76.6 mg, 77%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.37-7.26 (m, 9H), 7.25-7.19 (m, 1 H), 4.16 (s, 2H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 137.5, 136.4, 129.8, 128.9, 128.8, 128.5, 127.2, 126.4, 39.1 . HRMS C13H12S [M] ⁺ ; calculated 200.0654, found: 200.0654. The spectral data are consistent with those reported in the literature (45).

Example 25

1 3-bis(cyclohexylthio)benzene

Prepared by general procedure A (0.2 mmol scale); isolated as a pale yellow liquid using pentane/ethyl acetate (100:1 ) as eluent (53.9 mg, 88%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.41 (s, 1 H), 7.24-7.15 (m, 3H), 3.30-3.00 (m, 2H), 2.07-1 .91 (m, 4H), 1 .84-1 .74 (m, 4H), 1 .69-1 .59 (m, 2H), 1 .44-1 .17 (m, 10H). ¹³ C NMR (126 MHz, CDCIs) δ 135.9, 134.2, 129.7, 128.9, 46.5, 33.3, 26.0, 25.8. HRMS Ci ₈ H ₂ 6S ₂ [M] ⁺ ; calculated 306.1476, found: 306.1478.

Example 26

((3S,10R,13R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)- 2,3,4,7,8,9,10,11 ,12,13,14,15,16,17-tetradecahydro-1 H- cyclopenta[a]phenanthren-3-yl)(phenyl)sulfane

Prepared by general procedure A (0.2 mmol scale); isolated as a white solid using pentane as eluent (66.6mg, 70%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.42 (dd, J = 8.2, 1 .3 Hz, 2H), 7.31 (dd, J = 8.2, 6.8 Hz, 2H), 7.28-7.20 (m, 1 H), 5.34 (dd, J = 5.1 , 1 .7 Hz, 1 H), 3.17-2.95 (m, 1 H), 2.35 (d, J = 8.2 Hz, 2H), 2.08-1 .95 (m, 2H), 1 .92 (dt, J = 9.5, 3.7 Hz, 2H), 1 .90-1 .80 (m, 1 H), 1 .69-1 .44 (m, 12H), 1 .45-1 .05 (m, 9H), 1.02 (s, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 2.2 Hz, 3H), 0.89 (d, J = 2.2 Hz, 3H), 0.70 (s, 3H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 141.7, 134.9, 131.8, 128.8, 126.6, 121.2, 56.8, 56.2, 50.3, 47.4, 42.3, 39.8, 39.7, 39.5, 36.9, 36.2, 35.8, 31.9, 31.8, 29.5, 28.2, 28.0, 24.3, 23.9, 22.8, 22.6, 20.9, 19.4, 18.7, 11.9. [a] _D ²⁵ = - 37.7 (c= 0.52, CH ₂ CI ₂ ). HRMS C33H ₅ 0S [M] ⁺ ; calculated 478.3633, found: 478.3634.

Example 27

c clohexyl(phenyl)sulfane

Prepared by general procedure A; isolated as a colorless liquid using pentane as eluent (86.2 mg, 90%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.41-7.38 (m, 2H), 7.30-7.26 (m, 2H), 7.23-7.18 (m, 1H), 3.17-3.01 (m, 1H), 2.02-1.95 (m, 2H), 1.82-1.73 (m, 2H), 1.66-1.58 (m, 1H), 1.44-1.24 (m, 5H). ¹³ C NMR (125 MHz, CDCI ₃ ) δ 135.2, 131.9, 128.7, 126.6, 46.6, 33.4, 26.1, 25.8. HRMS d ₂ H ₁₆ S [M] ⁺ ; calculated 192.0967, found: 192.0969. The spectral data are consistent with those reported in the literature.

Example 28

c clohexyl(styryl)sulfane

Prepared from the corresponding starting material (E/Z 5:1) by general procedure A at 160 °C; isolated as a pale yellow liquid using pentane/ethyl acetate (100:1) as eluent (89 mg, 82%, E/Z = 5:1). E isomer: ¹ H NMR (500 MHz, Chloroform-d) δ 7.35-7.30 (m, 4H), 7.25-7.19 (m, 1H), 6.80 (d, J = 15.6 Hz, 1H), 6.61 (d, J = 15.6 Hz, 1H), 3.05-3.01 (m, 1H), 2.20-2.03 (m, 2H), 1.92-1.78 (m, 2H), 1.73-1.64 (m, 1H), 1.55-1.07 (m, 6H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 137.2, 128.6, 128.6, 126.9, 125.6, 124.1, 45.3, 33.6, 26.0, 25.7. Z isomer: ¹ H NMR (500 MHz, Chloroform-d) δ 7.58-7.49 (m, 2H), 7.38 (t, J= 7.8 Hz, 2H), 7.24 (s, 1H), 6.47 (d, J= 11.0 Hz, 1H), 6.37 (d, J = 11.0 Hz, OH), 2.97-2.88 (m, 1H), 2.09-2.07 (m, 2H), 1.85-1.82 (m, 2H), 1.69-1.66 (m, 1H), 1.58-1.28 (m, 6H). ¹³ C NMR (126 MHz, CDCI3, characteristic peak) 137.2, 128.2, 126.5, 125.9, 125.0, 47.8, 33.7, 25.6. HRMS Ci ₄ H ₁₈ S [M] ⁺ ; calculated 218.1 129, found: 218.1 129. The spectral data are consistent with those reported in the literature.

General procedure for the catalytic aryl transfer with thiophenols

Sin aC cle A1 0.4 mol%

0.2 mmol scale 2.0 equiv

In the glovebox, aryl thiol (0.2 mmol), alkyl thiol (2.0 equiv, 0.4 mmol), LiHMDS (3.9 equiv, 135 mg), and SingaCycle A1 (0.4 mol%, 0.2 ml, 0.005 M in o-xylene) were added into the oven-dried 8 ml vial with a magnetic stirring bar, followed by addition of o-xylene (1 .8 ml). The vial was sealed and removed out of the glovebox and heated to 160 °C. After 12 h, the vial was cooled to room temperature. The reaction was diluted with ethyl acetate and washed by saturated NaOH solution. The aqueous phase was extracted with ethyl acetate 3 times. The collected organic phases were dried over anhydrous Na ₂ SO _. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give the desired product.

Example 29

4-methoxyphenyl)(octyl)sulfane

Prepared by general procedure B; isolated as a pale yellow liquid using pentane/ethyl acetate (50:1 ) as eluent (38 mg, 76%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.34 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 2.99-2.71 (m, 2H), 1 .65-1 .50 (m, 2H), 1 .45-1 .17 (m, 10H), 0.97-0.75 (m, 3H). ¹³ C NMR (75 MHz, CDCI ₃ ) δ 158.7, 132.8, 127.0, 1 14.4, 55.3, 35.8, 31 .8, 29.3, 29.1 , 29.0, 28.7, 22.6, 14.1 . HRMS Ci ₅ H ₂₄ SO [M] ⁺ ; calculated 252.1542, found: 252.1544. The spectral data are consistent with those reported in the literature.

Example 30 cyclohexyl(p-tolyl)sulfane

Prepared by general procedure B; isolated as a colorless liquid using pentane/ethyl acetate (100:1 ) as eluent (30.5 mg, 75%). See above for experimental data.

Example 31

cyclopentyl(o-tolyl)sulfane

Prepared by general procedure B; isolated as a colorless liquid using pentane/ethyl acetate (100:1 ) as eluent (29.3 mg, 77%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.39-7.29 (m, 1 H), 7.15 (t, J = 7.7 Hz, 2H), 7.1 1-7.06 (m, 1 H), 3.71-3.49 (m, 1 H), 2.37 (s, 3H), 2.17-2.03 (m, 2H), 1 .84-1 .75 (m, 2H), 1 .72-1 .56 (m, 4H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 137.5, 136.8, 130.0, 128.8, 126.2, 125.4, 44.9, 33.6, 24.9, 20.5. HRMS Ci ₂ Hi ₆ S [M] ⁺ ; calculated 192.0973, found: 192.0970. The spectral data are consistent with those reported in the literature.

Example 32

c clohexyl(phenyl)sulfane

Prepared by general procedure B; isolated as a colorless liquid using pentane eluent (32.3 mg, 85%). See above for experimental data.

Example 33

(4-(tert-butyl)phenyl)(2-methylbutyl)sulfane Prepared by general procedure B; isolated as a colorless liquid using pentane/ethyl acetate (100:1) as eluent (42.6 mg, 91%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.44-7.27 (m, 4H), 2.97 (dd, J= 12.5, 5.9 Hz, 1H), 2.77 (dd, J = 12.5, 7.5 Hz, 1H), 1.87-1.66 (m, 1H), 1.63-1.51 (m, 1H), 1.34 (s, 9H), 1.32-1.24 (m, 1H), 1.06 (d, J = 6.7 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). ¹³ C NMR (126 MHz, CDCIs) δ 148.8, 133.9, 128.9, 125.8, 41.2, 34.6, 34.4, 31.3, 28.8, 18.9, 11.3. HRMS Ci ₅ H ₂₄ S [M] ⁺ ; calculated 236.1599, found: 236.1599.

Example 34

-(cyclohexylthio)pyrid

Prepared by general procedure B; isolated as a colorless liquid using pentane/ethyl acetate (20:1) as eluent (18 mg, 47%). ¹ H NMR (500 MHz, Chloroform-d) δ 8.37 (d, J= 6.3 Hz, 2H), 7.11 (d, J = 6.3 Hz, 2H), 3.48-3.25 (m, 1H), 2.10-1.95 (m, 2H), 1.86-1.74 (m, 2H), 1.68-1.64 (m, 1H), 1.54-1.35 (m, 5H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 149.1, 148.8, 121.7, 43.4, 32.9, 25.8, 25.6. HRMS C11H15NS [M+H] ⁺ ; calculated 194.0997, found: 194.0997. The spectral data are consistent with those reported in the literature. Example 35

-dimethylphenyl)(2-methylbutyl)sulfane

Prepared by general procedure B; isolated as a colorless liquid using pentane/ethyl acetate (100:1) as eluent (37.6 mg, 91%). ¹ H NMR (500 MHz, Chloroform-d) δ 6.98 (s, 2H), 6.82 (s, 1H), 2.97 (dd, J = 12.4, 5.8 Hz, 1H), 2.77 (dd, J= 12.4, 7.5 Hz, 1H), 2.32 (s, 6H), 1.78-1.65 (m, 1H), 1.63-1.54 (m, 1H), 1.31 (dt, J= 13.5, 7.5 Hz, 1H), 1.06 (d, J= 6.6 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 138.4, 137.1, 127.4, 126.4, 40.6, 34.6, 28.8, 21.3, 19.0, 11.3. HRMS Ci ₃ H ₂₀ S [M] ⁺ ; calculated 208.1286, found spectral data are consistent with those reported in the literature.

Example 36

-methoxyphenyl)(2-methylbutyl)sulfane

Prepared by general procedure B; isolated as a pale yellow liquid using pentane/ethyl acetate (40:1) as eluent (33.9 mg, 81%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.41-7.27 (m, 2H), 6.91-6.78 (m, 2H), 3.79 (s, 3H), 2.85 (dd, J = 12.6, 5.7 Hz, 1H), 2.66 (dd, J= 12.6, 7.4 Hz, 1H), 1.68-1.45 (m, 2H), 1.35-1.17 (m, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). ¹³ C NMR (75 MHz, CDCIs) δ 158.6, 132.6, 127.6, 114.5, 55.3, 43.0, 34.5, 28.6, 18.8, 11.2. HRMS Ci ₂ Hi ₈ SO [M] ⁺ ; calculated 210.1078, found: 210.1079. Example 37

-((2-methylbutyl)thio)-5-phenylbenzo[d]thiazole

Prepared by general procedure B; isolated as a pink solid using pentane/ethyl acetate (50:1) as eluent (23 mg, 37%). ¹ H NMR (300 MHz, Chloroform-d) δ 8.08 (s, 1 H), 7.80 (d, J = 8.3 Hz, 1 H), 7.66 (d, J = 7.5 Hz, 2H), 7.55-7.37 (m, 4H), 3.44 (dd, J= 12.7, 5.9 Hz, 1H), 3.24 (dd, J= 12.7, 7.4 Hz, 1H), 1.97-1.76 (m, 1H), 1.71-1.52 (m, 1H), 1.39-1.30 (m, 1H), 1.08 (d, J= 6.7 Hz, 3H), 0.97 (t, J= 7.4 Hz, 3H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 168.5, 154.0, 140.8, 139.6, 134.1, 128.9, 127.4, 127.3, 123.5, 121.0, 119.8, 40.4, 34.9, 28.7, 18.9, 11.3. HRMS Ci ₈ Hi ₉ S ₂ N [M] ⁺ ; calculated 314.1032, found: 314.1033.

Example 38

cyclohexyl(naphthalen-1-yl)sulfane

Prepared by general procedure B; isolated as a colorless liquid using pentane/ethyl acetate (100:1) as eluent (33.5 mg, 70%). ¹ H NMR (300 MHz, Chloroform-d) δ 8.63-8.49 (m, 1H), 7.89-7.75 (m, 2H), 7.71 (dd, J= 7.2, 1.2 Hz, 1H), 7.55 (ddd, J= 10.5, 7.9, 1.4 Hz, 2H), 7.42 (dd, J= 8.2, 7.2 Hz, 1H), 3.31-3.04 (m, 1H), 2.06-1.92 (m, 2H), 1.82-1.73 (m, 2H), 1.65-1.57 (m, 1H), 1.52-1.12 (m, 5H). ¹³ C NMR (75 MHz, CDCI ₃ ) δ 134.4, 134.0, 132.3, 131.8, 128.4, 128.1, 126.3, 126.0, 125.9, 125.4, 47.2, 33.5, 26.0, 25.8. HRMS Ci ₆ Hi ₈ S [M] ⁺ ; calculated 242.1124, found: 242.1123.

Example 39

c clohexyl(naphthalen-2-yl)sulfane

Prepared by general procedure B; isolated as a colorless liquid using pentane/ethyl acetate (100:1) as eluent (40 mg, 83%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.87 (d, J = 1.8 Hz, 1H), 7.79 (ddd, J = 12.7, 7.9, 2.4 Hz, 3H), 7.56-7.41 (m, 3H), 3.37-3.17 (m, 1H), 2.19-1.99 (m, 2H), 1.85-1.73 (m, 2H), 1.71-1.59 (m, 1H), 1.52-1.20 (m, 5H). ¹³ C NMR (75 MHz, CDCI ₃ ) δ 133.6, 132.6, 132.0, 130.1, 129.6, 128.2, 127.6, 127.2, 126.3, 125.8, 46.5, 33.3, 26.0, 25.8. HRMS Ci ₆ Hi ₈ S [M] ⁺ ; calculated 242.1124, found: 242.1123.

Example 40

-adamantan-1-yl)(phenyl)sulfane

Prepared by general procedure B; isolated as a white solid using pentane as eluent (34.1 mg, 70%). See above for experimental data. Example 41

,5R)-2,6,6-trimethylbicyclo[3.1.1 ]heptan-2-yl)sulfane

Prepared by general procedure B; isolated as a colorless liquid using pentane/ethyl acetate (100:1 ) as eluent (45 mg, 92%). See above for experimental data.

Example 42

N N-dimethyl-2-(phenylthio)ethan-1 -amine

Prepared by general procedure B; isolated as a pale yellow liquid using acetone as eluent (21 .6 mg, 60%). ¹ H NMR (300 MHz, Chloroform-d) δ 7.41-7.34 (m, 2H), 7.33-7.26 (m, 2H), 7.23-7.15 (m, 1 H), 3.20-2.93 (m, 2H), 2.83-2.52 (m, 2H), 2.30 (s, 6H). ¹³ C NMR (75 MHz, CDCI ₃ ) δ 136.4, 128.9, 128.8, 125.8, 58.5, 45.3, 31 .4. HRMS C10H1 ₅ SN [M+H] ⁺ ; calculated 182.0998, found: 182.0999.

Example 43

-((3r,5r,7r)-adamantan-1-yl)ethyl)(phenyl)sulfane

Prepared by general procedure B; isolated as a colorless liquid using pentane/ethyl acetate (100:1 ) as eluent (39.3 mg, 73%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.39-7.27 (m, 4H), 7.24-7.14 (m, 1 H), 3.05-2.76 (m, 2H), 1 .99 (q, J = 3.0 Hz, 3H), 1 .82-1 .71 (m, 3H), 1 .70-1 .63 (m, 3H), 1 .55 (d, J = 3.0 Hz, 6H), 1 .52-1 .37 (m, 2H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 137.2, 128.8, 128.4, 125.5, 43.6, 42.2, 37.1 , 32.8, 28.6, 27.5. HRMS Ci ₈ H ₂₄ S [M] ⁺ ; calculated 272.1599, found: 272.1597.

Example 44

henethyl(phenyl)sulfane

Prepared by general procedure B; isolated as a colorless liquid using pentane/ethyl acetate (100:1 ) as eluent (30.2 mg, 71 %). See above for experimental data.

Example 45

diphenylsulfane

SingaCycle A1 (0.4 mol%)

In the glovebox, phenyl thiol (0.2 mmol), LiHMDS (1 .5 equiv, 51 .6 mg), and SingaCycle A1 (0.4 mol%) were added into an oven-dried 8 ml vial with a magnetic stirring bar, followed by addition of o-xylene (2 ml). The vial was sealed and removed out of the glovebox and heated to 160 °C. After 12 h, the vial was cooled to room temperature. The reaction was diluted with ethyl acetate and washed by saturated NaOH solution. The aqueous phase was extracted with ethyl acetate 3 times. The collected organic phases were dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (pentane) to give the title product (14.1 mg, 76%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.41-7.36 (m, 4H), 7.36-7.31 (m, 4H), 7.30- 7.25 (m, 2H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 135.8, 131 .1 , 129.2, 127.0. HRMS C ₁₂ H ₁ 0S [M] ⁺ ; calculated 186.0497, found: 186.0498. The spectral data are consistent with those reported in the literature.

Example 46

Diphenylselane

In the glovebox, phenyl selenol (0.2 mmol), LiHMDS (1 .5 equiv, 51 .6 mg), and SingaCycle A1 (0.4 mol%) were added into an oven-dried 8 ml vial with a magnetic stirring bar, followed by addition of o-xylene (2 ml). The vial was sealed and removed out of the glovebox and heated to 160 °C. After 12 h, the vial was cooled to room temperature. The reaction was diluted with ethyl acetate and washed by saturated NaOH solution. The aqueous phase was extracted with ethyl acetate 3 times. The collected organic phases were dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (pentane) to give the title product (22.3 mg, 96%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.53 (dq, J = 7.7, 3.5 Hz, 4H), 7.31 (dq, J = 5.7, 3.0 Hz, 6H). ¹³ C NMR (126 MHz, Chloroform-d) δ 133.1 (d, J = 3.0 Hz), 131 .2 (d, J = 4.3 Hz), 129.4 (d, J = 3.8 Hz), 127.4 (d, J = 2.1 Hz). HRMS Ci ₂ H ₁₀ Se [M] ⁺ ; calculated 233.9947, found: 233.9948. The spectral data are consistent with those reported in the literature.

Procedure for late-staqe derivatization

Example 47

-(cyclohexylthio)-10-(2-(1 -methylpiperidin-2-yl)ethyl)-1 OH-phenothiazine

In the glovebox, thioridazine (0.2 mmol), cyclohexyl thiol (2.0 equiv, 0.4 mmol), LiHMDS (3.6 equiv), and SingaCycle A1 (0.4 mol%) were added into an oven- dried 8 ml vial with a magnetic stirring bar, followed by addition of o-xylene (1 .0 ml). The vial was sealed and removed out of the glovebox and heated to 160 °C. After 12 h, the vial was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with NaOH solution. The aqueous phase was extracted with ethyl acetate 3 times. The collected organic phases were dried over anhydrous Na ₂ SO _. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (0-5% MeOH in DCM) to give the title product. Isolated as syrup like liquid (54.3 mg, 62%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.21-7.1 1 (m, 2H), 7.05 (d, J = 7.9 Hz, 1 H), 6.98 (dd, J = 7.9, 1 .7 Hz, 1 H), 6.93 (dd, J = 1 1 .5, 1 .7 Hz, 2H), 6.89 (dd, J = 7.9, 1 .1 Hz, 1 H), 4.09-3.92 (m, 1 H), 3.86 (dt, J = 14.2, 7.4 Hz, 1 H), 3.14-2.99 (m, 1 H), 2.97-2.86 (m, 1 H), 2.27-2.23 (m, 6H), 2.04-1 .88 (m, 3H), 1 .83-1 .55 (m, 7H), 1 .49-1 .12 (m, 7H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 145.4, 144.9, 134.1 , 127.6, 127.5, 127.4, 126.5, 125.4, 124.5, 122.8, 1 19.7, 1 15.9, 62.3, 56.7, 47.2, 43.8, 42.4, 33.3, 30.2, 29.3, 26.0, 25.7, 24.9, 23.6. HRMS C26H ₃ S ₂ N2 [M+H] ⁺ ; calculated 439.2236, found: 439.2239.

Example 48

1 -(2-(1-methylpiperidin-2-yl)ethyl)-2-(octylthio)-10H-phenoth iazine

Thioridazine

In the glovebox, thioridazine (0.2 mmol), 1 -octanethiol (2.0 equiv, 0.4 mmol), LiHMDS (3.6 equiv), and SingaCycle A1 (0.4 mol%) were added into an oven- dried 8 ml vial with a magnetic stirring bar, followed by addition of o-xylene (1 .0 ml). Then the vial was sealed and removed out of the glovebox and heated to 160 °C. After 12 h, the vial was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with NaOH solution. The aqueous phase was extracted with ethyl acetate 3 times. The collected organic phases were dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (0-5% MeOH in DCM) to give the title product. Isolated as orange oil (46 mg, 49%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.20-7.09 (m, 2H), 7.04 (d, J = 7.9 Hz, 1 H), 6.97-6.81 (m, 4H), 3.96 (ddd, J = 13.8, 8.5, 5.3 Hz, 1 H), 3.84 (ddd, J = 13.8, 8.7, 6.1 Hz, 1 H), 2.93- 2.81 (m, 3H), 2.24 (s, 3H), 2.15 (qt, J = 9.8, 7.2, 3.3 Hz, 3H), 1.89 (dtd, J= 13.8, 8.0, 4.8 Hz, 1H), 1.77-1.69 (m, 2H), 1.66-1.57 (m, 4H), 1.55-1.43 (m, 1H), 1.43- 1.35 (m, 2H), 1.35-1.19 (m, 9H), 0.87 (t, J = 6.9 Hz, 3H). ¹³ C NMR (126 MHz, CDCIs) δ 145.8, 145.1, 136.2, 127.7, 127.6, 127.4, 125.5, 123.4, 123.2, 122.8, 117.0, 115.9, 62.4, 57.0, 44.0, 43.0, 34.4, 31.9, 30.7, 29.8, 29.3, 29.3, 29.3, 29.0, 25.5, 24.1, 22.8, 14.2. HRMS C ₂ 8H ₄ oS ₂ N2 [M+H] ⁺ ; calculated 469.2705, found: 469.2709.

Example 49

-(benzylthio)-10-(2-(1 -methylpiperidin-2-yl)ethyl)-1 OH-phenothiazine

Thioridazine

In the glovebox, thioridazine (0.2 mmol), benzyl thiol (2.0 equiv, 0.4 mmol), LiHMDS (3.6 equiv), and SingaCycle A1 (0.4 mol%) were added into an oven- dried 8 ml vial with a magnetic stirring bar, followed by addition of o-xylene (1.0 ml). The vial was sealed and removed out of the glovebox and heated to 160 °C. After 12 h, the vial was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with NaOH solution. The aqueous phase was extracted with ethyl acetate 3 times. The collected organic phases were dried over anhydrous Na2SO _4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (0-5% MeOH in DCM) to give the title product. Isolated as orange oil (49.7 mg, 56%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.22-7.12 (m, 5H), 7.10-7.01 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.87-6.77 (m, 2H), 6.76 (dd, J= 8.0, 1.2 Hz, 1H), 6.65 (d, J= 1.8 Hz, 1H), 3.98 (s, 2H), 3.79 (ddd, J= 13.1, 7.7, 5.0 Hz, 1H), 3.64 (dt, J= 14.3, 7.7 Hz, 1H), 2.89 (d, J = 11.8 Hz, 1H), 2.22-2.06 (m, 6H), 1.86-1.47 (m, 6H), 1.32-1.11 (m, 1H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 145.5, 144.6, 137.5, 135.4, 128.81, 128.80, 128.6, 127.6, 127.5, 127.3, 125.6, 124.4, 124.1, 122.9, 117.7, 116.0, 62.4, 56.5, 43.6, 42.0, 39.4, 29.7, 28.7, 24.4, 23.3. HRMS C27H30S2N2 [M+H] ⁺ ; calculated 447.1923, found: 447.1925.

Example 50

2-(sec-butylthio)-10-(2-(1 -methylpiperidin-2-yl)ethyl)-1 OH-phenothiazine

Thioridazine

In the glovebox, thioridazine (0.2 mmol), sec-butyl thiol (2.0 equiv, 0.4 mmol), LiHMDS (3.6 equiv), and SingaCycle A1 (0.4 mol%) were added into an oven- dried 8 ml vial with a magnetic stirring bar, followed by addition of o-xylene (1 .0 ml). The vial was sealed and removed out of the glovebox and heated to 160 °C. After 12 h, the vial was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with NaOH solution. The aqueous phase was extracted with ethyl acetate 3 times. The collected organic phases were dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (0-5% MeOH in DCM) to give the title product. Isolated as orange oil (58.3 mg, 71 %). ¹ H NMR (500 MHz, Chloroform-d) δ 7.19-7.10 (m, 2H), 7.04 (d, J = 7.9 Hz, 1 H), 6.96 (dd, J = 7.9, 1 .7 Hz, 1 H), 6.95-6.88 (m, 2H), 6.91-6.85 (m, 1 H), 3.96 (ddd, J = 13.8, 8.5, 5.3 Hz, 1 H), 3.85 (ddd, J = 13.8, 8.5, 6.3 Hz, 1 H), 3.10 (q, J = 6.3 Hz, 1 H), 2.88 (d, J = 1 1 .3 Hz, 1 H), 2.24 (s, 3H), 2.21-2.10 (m, 3H), 1 .89 (d, J = 8.5 Hz, 1 H), 1 .78-1 .69 (m, 2H), 1 .67-1 .58 (m, 3H), 1 .58-1 .47 (m, 2H), 1 .36-1 .26 (m, 1 H), 1 .25 (d, J = 6.3 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 145.4, 144.9, 134.4, 127.5, 127.43, 127.35, 126.3, 125.2, 124.3, 122.7, 1 19.6, 1 15.8, 62.2, 56.8, 45.5 (d, J = 1 .8 Hz), 43.9, 42.7, 30.5, 29.6, 29.5, 25.3, 23.9, 20.5, 1 1 .5. HRMS C ₂ H3 ₂ S ₂ N ₂ [M+H] ⁺ ; calculated 413.2079, found: 413.2083.

Example 51 2-(((1 s,3s)-adamantan-1 -yl)thio)-10-(2-(1 -methylpiperidin-2-yl)ethyl)-10H- phenothiazine

In the glovebox, thioridazine (0.2 mmol), 1-adamentanethiol (2.0 equiv, 0.4 mmol), LiHMDS (3.6 equiv), and SingaCycle A1 (0.4 mol%) were added into an oven- dried 8 ml vial with a magnetic stirring bar, followed by addition of o-xylene (1.0 ml). The vial was sealed and removed out of the glovebox and heated to 160 °C. After 12 h, the vial was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with NaOH solution. The aqueous phase was extracted with ethyl acetate 3 times. The collected organic phases were dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (0-5% MeOH in DCM) to give the title product. Isolated as syrup like liquid (59.4 mg, 61%). ¹ H NMR (500 MHz, Chloroform-d) δ 7.20-7.11 (m, 2H), 7.08-7.03 (m, 2H), 6.98 (d, J= 1.3 Hz, 1H), 6.97-6.87 (m, 2H), 3.98 (ddd, J= 13.6, 8.2, 5.2 Hz, 1H), 3.87 (ddd, J= 14.2, 8.2, 6.6 Hz, 1H), 3.00-2.82 (m, 1H), 2.52-2.18 (m, 6H), 2.07-1.98 (m, 3H), 1.97- 1.86 (m, 1H), 1.80 (d, J= 2.8 Hz, 6H), 1.74-1.71 (m, 2H), 1.69-1.52 (m, 8H), 1.54- 1.47 (m, 1H), 1.37-1.17 (m, 1H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 144.9, 131.7, 129.5, 127.6, 127.5, 127.4, 126.9, 126.6, 125.0, 124.4, 122.8, 115.8, 62.2, 56.7, 48.2 , 43.9, 43.7, 42.5, 36.1, 30.2, 30.0, 29.4 , 25.1, 23.7. HRMS C30H38S2N2 [M+H] ⁺ ; calculated 491.2549, found: 491.2552.

Example 52 - Procedure for depolyme zation

1 ,4-bis(cyclopentylthio)benzene

MW -10000 In the glovebox, poly(1 ,4-phenylene sulfide (MW-10000, 0.5 equiv, 0.1 mmol), 1 - octanethiol (2.0 equiv, 0.4 mmol), LiHMDS (3.9 equiv), and SingaCycle A1 (0.4 mol%) were added into an oven-dried 8 ml vial with a magnetic stirring bar, followed by addition of o-xylene (2.0 ml). The vial was sealed and removed out of the glovebox and heated to 160 °C. After 12 h, the vial was cooled to room temperature. The reaction was diluted with ethyl acetate and washed with NaOH solution. The aqueous phase was extracted with ethyl acetate 3 times. The collected organic phases were dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (pentane/ethyl acetate 40:1 ) to give the title product. Isolated as a pale yellow liquid (24.5 mg, 89 %). ¹ H NMR (500 MHz, Chloroform-d) δ 7.19 (d, J = 1 .3 Hz, 4H), 3.54-3.43 (m, 2H), 2.03-1 .92 (m, 4H), 1 .79-1 .66 (m, 4H), 1 .61-1 .48 (m, 8H). ¹³ C NMR (126 MHz, CDCI ₃ ) δ 134.9, 130.5, 46.2, 33.5, 24.8. HRMS C16H22S2 [M] ⁺ ; calculated 278.1 163, found: 278.1 166.

Preparation Examples for the Nickel catalyzed C/S bond metathesis by arylation

a SMe

2.5 equiv. 100°C, 16h

General procedure

In a glovebox, an oven-dried 8 mL vial was charged with Bis- (dicyclohexylphosphino)-ethan (10.57 mg, 0.025 mmol, 5 mol%), Bis-(1 ,5- cyclooctadien)-nickel(O) (6.88 mg, 0.025 mmol, 5 mol%), Lithium bis(trimethylsilyl)amide (209.16 mg, 1 .25 mmol, 2.5 equiv.), Methylthio arene (0.5 mmol, 1 equiv.), Alkylthiol (1 .25 mmol, 2.5 equiv.) and toluene (1 .25 mL, 0.4 mol/L). The reaction mixture was stirred at 100°C for 12h. The reaction mixture was allowed to cool to room temperature and was diluted with EtOAc and an aqueous solution of NaOH (1 mol/L). The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over anhydrous MgSO and concentrated to dryness. The residue was purified by FC (SiO ₂ , n-pentane to n-pentane:MTBE) to afford the title compound.

Example 53

Cyclohexyl(phenyl)sulfane (1a)

Following the general procedure using thioanisole (62.1 mg, 0.5 mmol) and cyclohexanethiol (145.3 mg, 1 .25 mmol). Purification by FC (S1O2, n-pentane to n- pentane:MTBE 100:1 ) to afford the title compound (85.6 mg, 89%) as a colorless liquid. ¹ H NMR (501 MHz, Chloroform-d) δ 7.42 - 7.37 (m, 2H), 7.31 - 7.26 (m, 2H), 7.24 - 7.19 (m, 1 H), 3.1 1 (tt, J = 10.5, 3.7 Hz, 1 H), 2.03 - 1 .95 (m, 2H), 1 .82 - 1 .72 (m, 2H), 1 .62 (dddd, J = 1 1 .6, 4.5, 2.7, 1 .4 Hz, 1 H), 1 .41 - 1 .21 (m, 5H). ¹³ C NMR (126 MHz, Chloroform-d) δ 135.32, 132.00, 128.88, 126.71 , 46.73, 33.50, 26.21 , 25.92.

Example 54

Cyclohexyl(4-methoxyphenyl)sulfane (1 b)

Following the general procedure using 4-(Methylmercapto)-anisol (77.1 mg, 0.5 mmol) and cyclohexanethiol (145.3 mg, 1 .25 mmol). Purification by FC (S1O2, n- pentane to n-pentane:MTBE 100:1 ) to afford the title compound (108.1 mg, 98%) as a slightly yellow oil. ¹ H NMR (501 MHz, Chloroform-d) δ 7.42 - 7.35 (m, 2H), 6.89 - 6.80 (m, 2H), 3.80 (s, 3H), 2.90 (tt, J = 10.6, 3.7 Hz, 1 H), 1 .97 - 1 .89 (m, 2H), 1 .79 - 1 .71 (m, 2H), 1 .65 - 1 .56 (m, 1 H), 1 .37 - 1 .15 (m, 5H). ¹³ C NMR (126 MHz, Chloroform-d) δ 159.44, 135.71 , 125.14, 1 14.41 , 55.44, 48.06, 33.52, 26.26, 25.92.

Example 55 4-(Cyclohexylthio)benzonitrile

Following the general procedure using 4-(Methylthio)-benzonitrile (74.6 mg, 0.5 mmol) and cyclohexanethiol (145.28 mg, 1 .25 mmol). Purification by FC (S1O ₂ , n- pentane to n-pentane:MTBE 20:1 ) to afford the title compound (64.4 mg, 59%) as a slightly yellow oil. ¹ H NMR (501 MHz, Chloroform-d) δ 7.55 - 7.48 (m, 2H), 7.37 - 7.30 (m, 2H), 3.29 (tt, J = 10.3, 3.7 Hz, 1 H), 2.07 - 1 .96 (m, 2H), 1 .84 - 1 .76 (m, 2H), 1 .66 (dddd, J = 12.9, 4.7, 3.0, 1 .4 Hz, 1 H), 1 .50 - 1 .23 (m, 5H). ¹³ C NMR (126 MHz, Chloroform-d) δ 144.1 1 , 132.33, 128.71 , 1 19.05, 108.58, 45.06, 33.09, 26.01 , 25.75.

Example 56

4-(Cyclohexylthio)-N,N-dimethylaniline

Following the general procedure using N,N-dimethyl-4-(methylthio)aniline (83.6 mg, 0.5 mmol) and cyclohexanethiol (145.28 mg, 1 .25 mmol). Purification by FC (S1O ₂ , n-pentane to n-pentane:MTBE 50:1 ) to afford the title compound (1 1 1 .8 mg, 95%) as an orange oil. ¹ H NMR (501 MHz, Chloroform-d) δ 7.38 - 7.30 (m, 2H), 6.69 - 6.61 (m, 2H), 2.96 (s, 6H), 2.82 (tt, J = 10.7, 3.7 Hz, 1 H), 2.01 - 1 .89 (m, 2H), 1 .74 (dt, J = 1 1 .9, 4.1 Hz, 2H), 1 .62 - 1 .53 (m, 1 H), 1 .40 - 1 .14 (m, 5H). ¹³ C NMR (126 MHz, Chloroform-d) δ 150.27, 136.18, 1 19.40, 1 12.61 , 48.35, 40.54, 33.57, 33.39, 26.33, 25.96.

Example 57

Cyclohexyl(naphthalen-2-yl)sulfane

Following the general procedure using 2-(Methylthio)-naphthalin (87.1 mg, 0.5 mmol) and cyclohexanethiol (145.3 mg, 1 .25 mmol). Purification by FC (SiO ₂ , n- pentane to n-pentane:MTBE 100:1 ) to afford the title compound (1 14.9 mg, 95%) as a colorless oil. ¹ H NMR (501 MHz, Chloroform-d) δ 7.86 (d, J = 1 .7 Hz, 1 H), 7.83 - 7.71 (m, 3H), 7.51 - 7.36 (m, 3H), 3.24 (tt, J = 10.6, 3.7 Hz, 1 H), 2.08 - 1 .99 (m, 2H), 1 .84 - 1 .74 (m, 2H), 1 .63 (dddd, J = 12.1 , 4.7, 2.9, 1 .4 Hz, 1 H), 1 .49 - 1 .21 (m, 5H). ^{l d} C NMR (126 MHz, Ch lore-form- d) δ 133.82, 132.80, 132.22, 130.32, 129.74, 128.34, 127.80, 127.40, 126.53, 125.97, 46.73, 33.52, 29.86, 26.21 , 25.93.

Example 58

(2-Methylbutyl)(naphthalen-2-yl)sulfane

Following the general procedure using 2-(Methylthio)-naphthalin (87.1 mg, 0.5 mmol) and 2-Methyl-1 -butanthiol (130.3 mg, 1 .25 mmol). Purification by FC (SiO ₂ , n-pentane to n-pentane:MTBE 50:1 ) to afford the title compound (1 12.9 mg, 98%) as a slightly brown oil. ¹ H NMR (501 MHz, Chloroform-d) δ 7.81 - 7.70 (m, 4H), 7.47 (ddd, J = 8.1 , 6.7, 1 .4 Hz, 1 H), 7.46 - 7.38 (m, 2H), 3.07 (dd, J = 12.5, 5.8 Hz, 1 H), 2.86 (dd, J = 12.5, 7.5 Hz, 1 H), 1 .79 - 1 .67 (m, 1 H), 1 .59 (dqd, J = 12.9, 7.4, 5.3 Hz, 1 H), 1 .38 - 1 .25 (m, 1 H), 1 .07 (d, J = 6.7 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H). ¹³ C NMR (126 MHz, Chloroform-d) δ 135.25, 133.95, 131 .69, 128.36, 127.83, 127.36, 127.08, 126.60, 126.25, 125.53, 40.70, 34.66, 29.86, 29.00, 19.15, 1 1 .44.

Example 59

Cyclopentyl(naphthalen-2-yl)sulfane

Following the general procedure using 2-(Methylthio)-naphthalin (87.1 mg, 0.5 mmol) and Cyclopentanthiol (127.8 mg, 1 .25 mmol). Purification by FC (S1O2, n- pentane to n-pentane:MTBE 100:1 ) to afford the title compound (98.7 mg, 86%) as a slightly yellow oil. ¹ H NMR (501 MHz, Chloroform-d) δ 7.82 - 7.71 (m, 4H), 7.51 - 7.36 (m, 3H), 3.73 (tt, J = 7.2, 6.0 Hz, 1 H), 2.17 - 2.04 (m, 2H), 1 .89 - 1 .75 (m, 2H), 1 .75 - 1 .58 (m, 3H). ¹³ C NMR (126 MHz, Chloroform-d) δ 135.01 , 133.91 , 131 .84, 128.29, 128.20, 127.82, 127.23, 126.55, 125.66, 45.94, 33.72, 29.86, 25.02.

Example 60

Naphthalen-2-yl((1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept an-2-yl)sulfane

Following the general procedure using 2-(Methylthio)-naphthalin (87.1 mg, 0.5 mmol) and 2-,3-,10-Mercaptopinane (212.9 mg, 1.25 mmol). Purification by FC (S1O2, n-pentane to n-pentane:MTBE 100:1) to afford the title compound (134.9 mg, 91%) as a pink oil. ¹ H NMR (501 MHz, Chloroform-d) δ 7.78 (dd, J= 7.9, 1.3 Hz, 1H), 7.77- 7.68 (m, 3H), 7.46 (ddd, J= 8.2, 6.8, 1.4 Hz, 1H), 7.42 (ddd, J = 8.3, 6.2, 1.6 Hz, 2H), 3.18 - 3.02 (m, 2H), 2.99 - 2.90 (m, 0.34H), 2.40 - 2.23 (m, 2H), 2.15 - 1.74 (m, 5H), 1.64 (dddd, J = 15.1, 10.8, 6.8, 5.6 Hz, 1H), 1.54 (s, 0.20H), 1.51 - 1.36 (m, 0.37H), 1.29 (s, 0.17H), 1.22 (d, J= 11.4 Hz, 3H), 1.06 (s, 2H), 0.88 (d, J= 9.7 Hz, 1H), 0.80 (s, 0.52H). ¹³ C NMR (126 MHz, Chloroform-d) δ 135.30, 134.91, 133.97, 133.95, 131.73, 131.68, 128.38, 128.33, 127.84, 127.43, 127.33, 127.10, 127.08, 126.59, 126.43, 126.11, 125.55, 125.51, 124.77, 45.78, 45.27, 41.42, 41.01 , 40.81 , 40.69, 40.05, 39.69, 39.59, 38.87, 34.86, 33.46, 29.86, 28.10, 27.71, 26.85, 26.39, 26.30, 24.45, 23.60, 23.47, 22.42, 22.27, 20.25, 19.83.

Example 61

(2-(Adamantan-1 -yl)ethyl)(4-methoxyphenyl)sulfane

Following the general procedure using 4-(Methylmercapto)-anisol (77.1 mg, 0.5 mmol) and 2-(1-Adamantyl)-ethanthiol (245.4 mg, 1.25 mmol). Purification by FC (S1O2, n-pentane to n-pentane:MTBE 50:1) to afford the title compound (146.7 mg, 97%) as a pink oil. ¹ H NMR (501 MHz, Chloroform-d) δ 7.35 - 7.26 (m, 2H), 6.88 - 6.81 (m, 2H), 3.80 (s, 3H), 2.84 - 2.76 (m, 2H), 1.94 (p, J= 3.1 Hz, 3H), 1.73 - 1.57 (m, 6H), 1.47 (d, J= 2.8 Hz, 6H), 1.41 - 1.34 (m, 2H). ¹³ C NMR (126 MHz, Chloroform-d) δ 158.73, 132.56, 127.27, 114.64, 55.48, 44.11, 42.35, 37.24, 32.88, 29.89, 28.77.

Example 62

2-(Adamantan-1 -ylthio)pyridine

Following the general procedure using 2-(Methylthio)-pyridin (62.6 mg, 0.5 mmol) and Tricyclo[3.3.1.13,7]decan-1 -thiol (210.4 mg, 1.25 mmol). Purification by FC (S1O2, n-pentane to n-pentane:MTBE 50:1) to afford the title compound (105.7 mg, 96%) as a beige solid. ¹ H NMR (501 MHz, Chloroform-d) δ 8.53 (ddd, J =4.9, 2.0, 0.9 Hz, 1H), 7.53 (td, J =7.7, 2.0 Hz, 1H), 7.38 (dt, J= 7.9, 1.1 Hz, 1H), 7.10 (ddd, J= 7.4, 4.8, 1.1 Hz, 1H), 2.10 - 2.02 (m, 9H), 1.69 (t, J= 3.0 Hz, 6H). ¹³ C NMR (126 MHz, Chloroform-d) δ 156.97, 149.73, 136.11, 129.11, 121.44, 50.19, 43.77, 36.43, 30.24.

Ligands investigation

(a) Reactions were performed on 0.2 mmol scale of thioanisole.

(b) Product yield was determined by GC analysis using dodecane as internal standard.