| 94% |
With 1,2,3,4-tetrahydroquinolin-8-ol; potassium carbonate; copper(I) bromide In dimethyl sulfoxide at 80℃; for 24h; Inert atmosphere; |
|
| 92% |
With 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride; potassium <i>tert</i>-butylate; nickel diacetate In N,N-dimethyl-formamide at 70℃; for 12h; Glovebox; Inert atmosphere; |
General procedure for the coupling reaction of aryl halides with phenyl sulfide ;4-Acetylphenyl phenyl sulfide
General procedure: In a typical run, a 5 mL vial equipped with a magnetic bar was charged with a mixture of aryl halide (1 mmol), thiol (1 mmol), Ni(OAc)2 (0.1 mmol), NHC (0.05 mmol) and KOtBu (1.5 mmol) in glove box, 2 mL of DMF was injected, the mixture was stirred at 70 °C for 12 h. After cooling to room temperature, brine was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane for three times. The combined organic layers were dried with Mg2SO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to afford the desired products. |
| 92% |
With caesium carbonate In dimethyl sulfoxide at 25℃; for 4h; Irradiation; Inert atmosphere; |
|
| 92% |
With potassium carbonate In water; N,N-dimethyl-formamide at 90℃; for 9h; |
1.3.General procedure for the S-arylation coupling reaction
General procedure: Aryl halide (1.0 mmol), thiol (1.2 mmol), K2CO3 (2.0 mmol) and catalyst (0.4 mol% Cu) in DMF/H2O (v/v = 2:1, 1.5 mL) were stirred at 90 C for the appropriate time. The progress of the reaction was monitored by TLC using n-hexane-EtOAc (30:1) as eluent. After completion of the reaction, EtOAc (5 mL) was added to the mixture and filtered. The organic phase was separated and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The organic layer drying (MgSO4) and evaporation of the solvent provided a residue which was purified on preparative TLC (silica gel). All the products have been previously reported, and their identities were confirmed by comparison of their 1H and 13C NMR spectral data with the values of authentic samples. |
| 92% |
With caesium carbonate In dimethyl sulfoxide at 25℃; for 4h; Inert atmosphere; UV-irradiation; |
2; 9 1-(4-(Phenylthio)phenyl)ethan-1-one (3a)
A 25 mL storage flask was charged with a stir bar, flame dried under vacuum and back filled with nitrogen three times. The flask was then charged with Cs2CO3 (97.7 mg, 0.3 mmol, 1.5 eq.), 4'-Bromoacetophenone (39.8 mg, 0.2 mmol, 1.00 eq.), benzenethiol (33.0 mg, 0.3 mmol, 1.5 eq.) and 1.5 mL DMSO. The reaction mixture was evacuated and purged with inert gas (N2) three times. The reaction mixture was then placed into an LED-lined beaker and stirred with an air gas tube for cooling. After stirred for 4 hours, the reaction mixture was washed with water, extracted with EtOA and concentrated in vacuum. The product was isolated by flash chromatography (1:6 EtOAc:hexanes) as white solid (X=Br, 43 mg, 92%). Physical State: white solid; Rf=0.5 (silica gel, 1:6 EtOAc:hexanes); 1H NMR (300 MHz, CDCl3) δ 7.84 (dt, J=8.7, 2.1 Hz, 2H), 7.54-7.49 (m, 2H), 7.44-7.41 (m, 3H), 7.23 (dt, J=8.7, 2.1 Hz, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 197.1, 144.9, 134.5, 133.8, 132.1, 129.7, 128.9, 128.8, 127.5, 26.44; HRMS (ESI-TOF): m/z calcd. for C14H12OS ([M+H]+) 229.0687, found 229.0685. |
| 91% |
With pyridine; zinc In acetonitrile at 80℃; for 10h; |
|
| 90% |
With N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane for 6h; Heating; |
|
| 90% |
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane for 6h; Heating / reflux; |
|
| 90% |
With potassium hydroxide In dimethyl sulfoxide at 80℃; for 1h; |
2.6. General procedure for the S-arylation coupling reaction Thiol
General procedure: Thiol (1.2 mmol), aryl halide (1 mmol), KOH (1.5 mmol) and the supported palladium catalyst (Fe3O4SiO2C22-Pd(II), 0.5 mol%)in DMSO (2 mL) were stirred at 80 °C for an appropriate time. The progress of the reaction was monitored by TLC, using n-hexane as eluent. After the completion and magnetic separation of the catalyst, the reaction mixture was treated with ethyl acetate (10 mL) and water (3 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic solution was washed with brine (3 × 5 mL). Drying(Na2SO4) and evaporation of the solvent provided a residue which was purified on preparative TLC (silica gel), using hexane. All of the products have been previously reported, and their identities have been confirmed by comparing their1H and13C NMR spectral data with the values of the authentic samples. |
| 87% |
With copper(II) ferrite; potassium <i>tert</i>-butylate In 1,4-dioxane for 24h; Reflux; Inert atmosphere; |
|
| 85% |
In 1,4-dioxane at 110℃; for 12h; |
18
[0138] 1.35 g (6.7 mmol) of p-bromoacetophenone, 0.75 g (6.7 mmol) of thiophenol, 1.8 g (13.5 mmol) of potassium carbonate and 380 mg (0.7 mmol) of the catalyst from Example 3 are stirred in 50 ml of dioxane under an argon atmosphere at 110° C. for 12 h. The reaction solution is subsequently admixed with 20 ml of aqueous ammonia and extracted with ethyl acetate, and the combined organic extracts are dried under reduced pressure. After workup by column chromatography (hexane), 1.3 g (85%) of product are obtained. |
| 85% |
With copper(l) iodide; 2,2',2''-triaminotriethylamine; caesium carbonate In 1,4-dioxane at 110℃; for 21h; |
|
| 85% |
With fac-tris[2-phenylpyridinato-C2,N]iridium(III); caesium carbonate In N,N-dimethyl-formamide at 25℃; for 9h; Schlenk technique; Inert atmosphere; Irradiation; |
|
| 84% |
Stage #1: para-bromoacetophenone; thiophenol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: In N,N-dimethyl-formamide at 110℃; for 10h; |
|
| 84% |
With CuMoO4; caesium carbonate In dimethyl sulfoxide at 30℃; for 10h; Inert atmosphere; |
|
| 81% |
With copper(II) oxide; potassium hydroxide In N,N-dimethyl acetamide at 27℃; for 15h; Inert atmosphere; Sealed tube; |
Procedure for C-O/C-S cross coupling
General procedure: A magnetic stirring bar, nanocrystalline CuO (10 mg, 3 mol %), KOH (112 mg, 2 mmol) and phenol/substituted phenol/ thiophenol (1.2 mmol) were added into an oven-dried flask (25 mL). The flask was sealed with a septum, followed by three cycles of evacuation and filling with dry nitrogen. Then aryl halide (1 mmol) and N,N-dimethyl acetamide (DMAc) (4 mL) were injected through a syringe. The flask was sealed and stirred under nitrogen until the completion of the reaction (as monitored by TLC or GC). The catalyst was recovered from the reaction mixture and washed several times with ethyl acetate. The catalyst-free reaction mixture was quenched with brine solution and the product was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate, 80/20) to afford the product with high purity. |
| 78% |
With 1,4-diaza-bicyclo[2.2.2]octane; copper(l) iodide; potassium carbonate In 1,2-dimethoxyethane at 120℃; for 12h; Sealed tube; Inert atmosphere; chemoselective reaction; |
General procedure
General procedure: A mixture of thiol (0.5 mmol), aryl halide (0.6mmol), CuI (5 mol%, 4 mg), DABCO (10 mol%, 5.6 mg) K2CO3(2 equiv, 138 mg) and DME (3 ml) were added to an oven-dried sealed tube equipped with a stirring bar under nitrogen. The sealed tube was stirred in a preheated oil bath at 120 oC for 12 h. After being cooled to room temperature, the mixture was diluted with ethyl acetate(30 ml) and washed with saturated aqueous NaCl solution (3 x 15 ml).The organic phase was dried with anhydrous Na2SO4,filtered, and the solvent was removed under vacuum. The crude residue was purified by column chromatography on silica gel using ethyl acetate/hexanes as the eluent to give the desired sulphides. |
| 78% |
With 1,4-diaza-bicyclo[2.2.2]octane; copper(l) iodide; potassium carbonate In 1,2-dimethoxyethane at 120℃; for 12h; Sealed tube; Inert atmosphere; chemoselective reaction; |
2. General reaction procedure
General procedure: A mixture of thiol (0.5 mmol), aryl halide (0.6 mmol), CuI (5 mol%, 4 mg), DABCO (10 mol%, 5.6 mg) K2CO3 (2 equiv., 138 mg) and DME (3 ml) were added to an oven-dried sealed tube equipped with a stirring bar under nitrogen. The above mixture was taken in a sealed tube and was stirred in a preheated oil bath at 120 oC for 12 h. It is then cooled to room temperature. The cooled mixture was diluted with ethyl acetate (30 ml) and washed with saturated aqueous NaCl solution (3 x 15 ml). Any moisture content if present was removed by drying with anhydrous Na2SO4. The dried mixture is filtered and the solvent was removed under vacuum. The crude residue was purified by column chromatography on silica gel using ethyl acetate/hexanes as the eluent to give the desired sulphides. |
| 77% |
With 1-(2,6-diisopropylphenyl)-3-[2-(mesitylamino)-2-oxoethyl]-1H-imidazol-3-ium bromide; palladium diacetate; sodium hexamethyldisilazane In dimethyl sulfoxide at 80℃; for 12h; |
Typical experimental procedure:
General procedure: Pd(OAc)2 (6.7mg, 0.03mmol), ligand 1 or 2 (0.036mmol), aryl halides (3.0mmol), thiol (3.0mmol) and NaHMDS (825mg, 4.5mmol) or KOtBu (505mg, 4.5mmol) were combined with DMSO (10mL) in a small round-bottomed flask. The resulting mixture was stirred at 80°C for 12h. The reaction mixture was poured into water and extracted with EtOAc. The solvent was removed under vacuum, and the resulting crude product was purified by flash chromatography on silica gel to give the desired product. |
| 70% |
With 5%-palladium/activated carbon; potassium hydroxide In dimethyl sulfoxide at 110℃; for 9h; Inert atmosphere; |
|
| 65% |
With potassium carbonate In 1,4-dioxane at 110℃; for 12h; |
8
1.35 g (6.7 mmol) of p-bromoacetophenone, 0.75 g (6.7 mmol) of thiophenol, 1.8 g (13.5 mmol) of potassium carbonate and 300 mg (0.7 mmol) of the catalyst from example 1 are stirred in 50 ml of dioxane under an argon atmosphere at 110° C. for 12 h. The reaction solution is subsequently admixed with 20 ml of aqueous ammonia and extracted with ethyl acetate, and the combined organic extracts are dried under reduced pressure. After workup by column chromatography (hexane), 970 mg (65%) of product are obtained. [0126] GC-MS/EI: 228 (M) |
| 64% |
With pyridine; (1,2-dimethoxyethane)dichloronickel(II); 3,7-di([1,1′-biphenyl]-4-yl)-10-(naphthalen-1-yl)-10H-phenoxazine; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl acetamide at 20℃; for 24h; Inert atmosphere; Irradiation; Sealed tube; |
|
| 62% |
With copper(l) iodide; potassium phosphate tribasic trihydrate at 110℃; for 12h; |
|
| 61% |
With copper(I) oxide; caesium carbonate; ethyl 2-oxocyclohexane carboxylate In dimethyl sulfoxide at 80℃; for 24h; |
|
| 61% |
With iron(III) chloride hexahydrate; tetrabutylammomium bromide; <i>L</i>-proline; potassium hydroxide In water at 130℃; for 24h; Sealed tube; |
General procedure: A sealed tube was charged with 1.2 mmol (295 mg) of 4-iodoacetophenone, 20 mol% of L-proline (23 mg) and 2 equiv. of KOH (112 mg). To the above mixture were added 10 mol % of FeCl3.6H2O (27 mg), 1 equiv. of TBAB (322 mg) and 3 ml of distilled water followed by the addition of 1 mmol of thiophenol (0.101 ml). The sealed tube was heated in an oil bath which was preheated to 130 oC and the reaction mixture was stirred under the same conditions for 24 hours. The reaction mixture was then cooled, extracted with ethyl acetate (3 x 15 ml) and the ethyl acetate layer was washed with saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure in a rotary evaporator. The crude residue was purified by column chromatography using EtOAc-hexane (2: 98) as the eluent to get 217 mg (95 %) of the product as a colourless solid. All other products were synthesized by similar procedure |
| 60% |
With iron(III) chloride; potassium carbonate; <i>L</i>-proline In 1,2-dimethoxyethane at 120℃; for 24h; Sealed tube; Inert atmosphere; Green chemistry; |
Synthesis of 1-(4-phenylsulfanyl-phenyl)-ethanone (3a)
General procedure: A sealed tube was charged with 1 mmol of 4-iodoactophenone (0.246 mg), 20 mol% of l-proline (0.023 mg) and 2 equiv. of K2CO3 (0.276 mg) followed by the addition of 10 mol% FeCl3 (0.016 mg) and 3 ml of DME under nitrogen. 1.2 mmol of thiophenol (0.12 ml) was added to it and the sealed tube was then heated in an oil bath which was preheated to 120°C and the reaction mixture was stirred under the same conditions for 24 hours. The cooled reaction mixture was partitioned between saturated NaCl (10 ml) and EtOAc (20 ml). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 * 10 ml). The combined organic layer was dried using Na2SO4 and the solvent was evaporated in a rotary evaporator to get a residue. Purification of the residue by column chromatography using hexane-EtOAc as the eluent gave the desired product as a colourless solid (0.223 g, 98%); |
| 58% |
With diethylzinc; <i>L</i>-proline; sodium t-butanolate In hexane; acetonitrile at 80℃; for 20h; Sealed tube; Inert atmosphere; Green chemistry; |
|
| 55% |
In 1,4-dioxane at 110℃; for 12h; |
7
[0119] 1.3 g (6.7 mmol) of p-bromoacetophenone, 0.75 g (6.7 mmol) of thiophenol, 1.8 g (13.5 mmol) of potassium carbonate and 500 mg (0.7 mmol) of the catalyst from Example 1 are stirred in 50 ml of dioxane under an argon atmosphere at 110° C. for 12 h. The reaction solution is subsequently admixed with 20 ml of aqueous ammonia and extracted with ethyl acetate, and the combined organic extracts are dried under reduced pressure. After workup by column chromatography (hexane), 840 mg (55%) of product are obtained. [0120] GC-MS/EI: 228 (M) |
| 54% |
In 1,4-dioxane at 110℃; for 12h; |
17
[0137] 1.35 g (6.7 mmol) of p-bromoacetophenone, 0.75 g (6.7 mmol) of thiophenol, 1.8 g (13.5 mmol) of potassium carbonate and 490 mg (0.7 mmol) of the catalyst from Example 2 are stirred in 50 ml of dioxane under an argon atmosphere at 110° C. for 12 h. The reaction solution is subsequently admixed with 20 ml of aqueous ammonia and extracted with ethyl acetate, and the combined organic extracts are dried under reduced pressure. After workup by column chromatography (hexane), 810 mg (54%) of product are obtained. |
|
With potassium carbonate In 1,4-dioxane at 110℃; for 12h; |
9
1.35 g (6.7 mmol) of p-bromoacetophenone, 0.75 g (6.7 mmol) of thiophenol, 1.8 g (13.5 mmol) of potassium carbonate and 360 mg (0.7 mmol) of the catalyst from example 2 are stirred in 50 ml of dioxane under an argon atmosphere at 110° C. for 12 h. The GC analysis of the crude product indicates product formation with 75% conversion. |
|
With i-Pr2NEt |
5 Production of 4-phenylsulfanylacetophenone:
Example 5 Production of 4-phenylsulfanylacetophenone: Heating and refluxing time: 6 hours. Aryl halide and its amount used: 4-Bromoacetophenone (398 mg, 2 mmol). Thiol compound and its amount used: Thiophenol (205 μL, 2 mmol). Amount of Pd2(dba)3 used: 46 mg, 0.05 mmol. Amount of Xantphos used: 58 mg, 0.1 mmol. Base and its amount used: i-Pr2NEt (700 μL, 4 mmol). Amount of 1,4-dioxane used: 8 mL. Property, yield and yield percentage of 4-phenylsulfanylacetophenone: White solid; yield 411 mg; yield percentage 90 %. Development solvent in flash column chromatography: Hexane/ethyl acetate = 10/1. Melting point: 66°C-67°C. 1H NMR (CDCl3, 500 MHz) δ ppm: 7.82 (dt, 2H, J = 1.8 Hz, 6.7 Hz), 7.50 (dt, 2H, J = 1.8 Hz, 7.8 Hz), 7.38-7.42 (m, 3H), 7.21 (dt, 2H, J = 1.8 Hz, 6.7 Hz), 2.55 (s, 3H). 13C NMR (CDCl3, 125 MHz) δ ppm: 197.13, 144, 92, 134.52, 133.87, 132.13, 129.69, 128.90, 128.80, 127.50, 26.47. |
| 99 %Chromat. |
With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 100℃; for 16h; |
4
The catalytic activity of Nl-plτn catalyst B was investigated in C-S coupling of aryl halides. Several solvents and bases were examined for the reaction of 4-chlorobenzotrifluoride and thiophenol over Ni-plm catalyst B (1.5 mol%) . Sulfide products were obtained in excellent yields (94%) in DMF/potassium terfc-butoxide (KOfcBu) system, but moderate or low yields were obtained in other solvents (toluene or THF) .Conversion of both activated and non-activated aryl halides to the corresponding sulfides was generally observed with good to excellent yields. However, only moderate or low yields were typically observed for deactivated aryl bromides and chlorides. Yields above 95% are considered excellent yields, yields from 80 to 95% are considered good yields, yields from 50 to 80% are considered moderate yields and yields less than 50% are considered low yields. Results from experiments conducted are presented in Table 1. |
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