| 90% |
With thionyl chloride; N,N-dimethyl-formamide In toluene at 70℃; for 4h; |
1.1 1) Chlorination reaction:
Mix 421 g (1.37 mol) of 2,2'-dithiodibenzoic acid, 1.15 L (10.83 mol) of toluene, 212 mL (3 mol) of thionyl chloride, and 10.6 mL (0.14 mol) of DMF, and carry out acid chloride at 70°C Reaction for 4 hours,Add 2L n-hexane (15mol), lower the temperature to 10°C, crystallize, filter, wash the filter cake twice with 250mL n-hexane, and dry to obtain 2,2'-dithiodibenzoyl chloride 425g (1.24mol) , The yield is 90%. |
| 89% |
With thionyl chloride In N,N-dimethyl-formamide; toluene at 80℃; |
1f
Step If. 2,2Dithiosalicylic acid dichloride (Compound 108)2,2'-dithiosalicylic acid 107 (3.22 g, 10.5 mmol) was dissolved in toluene (30 niL) and thionyl chloride (2 rnL) and DMF (0.2 rnL) were added. The mixture was stirred at 80 0C overnight. Solvents were evaporated to obtain compound 108 as a yellow solid (3.2 g, 89% yield). |
| 89% |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20 - 50℃; for 42h; |
58 Production of 2,2’-dithiosalicylic dichloride
Oxalyl chloride (25 mL, 291.5 mmol) and N,N-dimethylformamide (150 mL, 1.94 mmol) were added to a solutionof 2,2’-dithiosalicylic acid (25.0 g, 81.6 mmol) in dichloromethane (220 mL), and stirred at room temperature for 18 hours.The resulting solution was further stirred at 50°C for 24 hours, and then the solvent was distilled away under a reducedpressure. The resulting solid was washed with hexane at 0°C and dried to obtain the title compound (24.9 g, 89%) asa pale yellow solid.1H NMR (400 MHz, CDCl3) δ 8.40 (2H, dd, J = 8.0, 1.4 Hz), 7.77 (2H, dd, J = 8.0, 1.1 Hz), 7.55 (2H, td, J = 8.0, 1.4 Hz),7.24 (2H, td, J = 8.0, 1.1 Hz) |
| 89% |
Stage #1: 2,2'-dithiobenzoic acid With N,N-dimethyl-formamide In 1,2-dichloro-ethane at 30 - 40℃; for 0.5h;
Stage #2: With trichloromethyl chloroformate In 1,2-dichloro-ethane |
15
Add o-dithiodibenzoic acid (61.3g, 0.20mol), 150mL of dichloroethane and a catalytic amount of N,N-dimethylformamide into the reaction flask, increase the temperature to 30-40°C, and continue to stir 0.5 hThen, add dropwise a solution prepared by trichloromethyl chloroformate (43.5g, 0.22mol) and 130mL dichloroethane, keep the reaction warm, after all the raw materials are converted (about 2~3h), cool down, concentrate under reduced pressure, and crystallize , Vacuum drying, 61.1g o-dithiodibenzoyl chloride, yield 89%. |
| 84% |
With thionyl chloride for 24h; Heating; |
|
| 83% |
With thionyl chloride; N,N-dimethyl-formamide In toluene at 35 - 75℃; for 16h; Large scale; |
|
| 80% |
With thionyl chloride for 48h; Reflux; |
Preparation of compound 1.
The known compound 1 was prepared using a published protocol.1 A mixture of 2,2'-dithio-dibenzoic acid (3.0 g, 9.8 mmol) and SOCl2 (25 mL) was heated under reflux for 48 h, and the solvent was removed by distillation followed by evaporation in vacuo. The residue was triturated with hexanes, quickly filtered, and washed with hexanes and dried under vacuum to afford compound 1 (2.69 g, 80%) as a yellow solid: 1H NMR (400 MHz, CDCl3, Fig. S1, which matches the lit.1) δ8.37 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz,2H). |
| 80% |
With thionyl chloride Reflux; |
4.2.1. Preparation of ebsulfurs 1a-o following procedure A
General procedure: 2-(Chlorosulfanyl)benzoyl chloride (b) has been obtained by 2,2′-disulfanediyldibenzoic acid (a) react with SOCl2 according to the procedure described [22]. To a stirred and ice-cooled mixture of primary amine (3mmol) and 75 Et3N (0.45mL, 3.2mmol) in anhydrous CH2Cl2 (40mL), 2, 2′-dithiobenzoyl chloride (b, 0.50g, 1.5mmol) in anhydrous CH2Cl2 (20mL) was added dropwise over 20min. The reaction mixture was warmed-up to RT, stirred for 12h, and washed with aq. sat. NaHCO3 (30mL) and H2O (30mL). The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo, and the resulting residue was purified by flash column chromatography (SiO2, EtOAc:hexane/1:2) to afford the final compounds 1a-o [25]. |
| 78% |
With thionyl chloride Reflux; |
|
| 71% |
With thionyl chloride In N,N-dimethyl-formamide; toluene at 75℃; for 18h; |
|
| 70% |
With thionyl chloride; N,N-dimethyl-formamide In toluene at 0 - 75℃; for 18h; Inert atmosphere; |
|
| 68% |
With thionyl chloride for 14h; Heating; |
|
| 68% |
With thionyl chloride for 12h; Heating / reflux; |
A
Example A; Synthesis of bis-[2-(2-oxazolyl)-phenyl]-disulfide (2OPD); A mixture of 20 g of 2,2'-dithio-bis-(benzoic acid) (65 mmol) in 28.6 mL thionylchloride (390 mmol) was refluxed for 12 hours and then filtered. The filtrate was dried using a rotary evaporator and 15.0 g of 2,2'-dithio-bis-(benzoyl chloride) powder (44 mmol) was collected. Yield for this reaction was 68%. |
| 68% |
With thionyl chloride at 80℃; for 0.166667h; Microwave irradiation; |
Microwave-assisted Method
2,2'-Dithiodibenzoic acid (1.0000 g,3.26 mmol) and thionyl chloride (1.6000 g, 13.50 mmol) was takenin a round bottom flask in StartSYNTH-Microwave Synthesis Labstationsystem.(MW, E1000 W, 80 C, 10 min, yield [68%). M.p.75e76 C; FT-IR (g cm1) 746, 786, 1109, 1160, 1242, 1350, 1450,1560, 1600, 1725, 3080; 1HNMR (CDCl3, 100 MHz) d 7.30e7.60 (m,4H), 7.75 (d, 2H, J 8.0 Hz), 8.40 (d, 2H, J 8.0 Hz). LS-MS (m/z) 342(M), 340, 338, 303, 233, 201, 179, 169, 167, 148, 133, 118, 102, 94 |
| 68% |
With thionyl chloride for 1h; Microwave irradiation; Reflux; |
2.2.1. 2,2’-Dithiodibenzoyl dichloride (A)
The synthesis of 2,20-dithiodibenzoyl dichloride was carriedout according to the literature (Abd El-Hady et al., 2013;Bruening et al., 1991; Calisir & Cicek, 2017; Seyedi et al.,2005). 7.00 g (22.85 mmol) of 2,20-dithiodibenzoic acid wastaken into a 100 mL reaction flask. It was heated with microwavesynthesis device (1000 W) under reflux for 1 hour byadding 25 mL of thionyl chloride. Reaction was followed byTLC. Excess thionyl chloride was removed under low temperatureby evaporator. Brown solid product was obtained. Itwas used directly in the next step without further purification(M.P.: 75-76 C, yield: 68%). FT-IR (c cm1): 3071 CH(sp2) stretch, 1717OC-Cl stretch, 1580 asymmetric strain ofbenzene ring, 1554 benzene ring symmetric strain, 1435-1320-1294-1263-1208-1194-1134-1039872 C-Cl bends,689 C-Cl bends. |
| 68% |
With thionyl chloride for 1h; Microwave irradiation; Reflux; |
2.2.1. 2,2’-Dithiodibenzoyl dichloride (A)
The synthesis of 2,20-dithiodibenzoyl dichloride was carriedout according to the literature (Abd El-Hady et al., 2013;Bruening et al., 1991; Calisir & Cicek, 2017; Seyedi et al.,2005). 7.00 g (22.85 mmol) of 2,20-dithiodibenzoic acid wastaken into a 100 mL reaction flask. It was heated with microwavesynthesis device (1000 W) under reflux for 1 hour byadding 25 mL of thionyl chloride. Reaction was followed byTLC. Excess thionyl chloride was removed under low temperatureby evaporator. Brown solid product was obtained. Itwas used directly in the next step without further purification(M.P.: 75-76 C, yield: 68%). FT-IR (c cm1): 3071 CH(sp2) stretch, 1717OC-Cl stretch, 1580 asymmetric strain ofbenzene ring, 1554 benzene ring symmetric strain, 1435-1320-1294-1263-1208-1194-1134-1039872 C-Cl bends,689 C-Cl bends. |
| 67% |
With thionyl chloride for 24h; Heating; |
|
| 47% |
With thionyl chloride; N,N-dimethyl-formamide for 0.5h; Heating; |
|
| 42% |
With thionyl chloride In benzene Heating; |
|
|
With phosphorus pentachloride |
|
|
With thionyl chloride |
|
|
With thionyl chloride |
|
|
With pyridine; thionyl chloride In benzene Heating; |
|
|
With pyridine; thionyl chloride In toluene Heating; |
|
|
With thionyl chloride Heating; |
|
|
With thionyl chloride; N,N-dimethyl-formamide In toluene at 75 - 80℃; |
|
|
With oxalyl dichloride |
|
|
With thionyl chloride Heating; |
|
|
With thionyl chloride for 1.5h; Heating; |
|
|
With thionyl chloride at 80℃; |
|
|
With thionyl chloride for 18h; Heating; |
|
|
With thionyl chloride for 1h; Heating; |
|
|
With thionyl chloride In benzene for 3h; Heating; |
|
|
|
7
Example 7 Compounds of formula I Synthesis of 128. 2-(5-Fluoro-1H-indol-3-ylsulfanyl)-benzylamine; 4.50 g NaBH4 (119 mmol) was added in portions to 7.50 g allyl bromide (62. 0 mmol) and 8.35 g 2,2'-dithiodibenzamide (27.4 mmol, prepared from 2, 2'-dithiodibenzoic acid via 2,2'- dithiodibenzoic acid chloride) in 80 mL methanol at 0°C. The reaction mixture was stirred 1 hour at room temperature. 50 mL 1N HC1 was added and stirring was continued 1 hour. Methanol was removed in vacuo. The residue was extracted with ethyl acetate. The organic phase was washed with brine, dried with MgSO4 and concentrated in i) actio to give 10.0 g 2- allylsulfanyl-benzamide (51.7 mmol, 94%). 2.1 g LiAlH4 (55 mmol) was added to 6.0 g 2- allylsulfanyl-benzamide (31 mmol) in 50 mL dry THF at 0°C. The reaction mixture was stirred for 16 hours at room temperature. The reaction was quenched with 4 mL water and 3 mL 2N NaOH. The reaction mixture was stirred for 1 hour, then 9 mL water was added and stirring was continued for another hour. The mixture was filtered, dried with MgSO4 and concentrated ift vaczto to give 5.05 g 2-allylsulfanyl-benzylamine (28. 2 mmol, 91%). 2.05 g Di-tert-butyl dicarbonate (9.37 mmol) was added to 1.40 g 2-allylsulfanyl-benzylamine (7. 81 mmol) and a catalytic amount of N, N-dimethyl-4-amino pyridine in 20 mL THF. The reaction mixture was stirred for 15 minutes at room temperature. 10 mL 20% citric acid was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate, the two phases were separated and the organic phase was washed with brine, dried with MgSO4 and concentrated ira vaczro to give (2-allylsulfanyl- benzyl) -carbamic acid te} t-butyl ester in quantitative yield. 0.70g NaIO4 (3.3 mmol) in 20 mL water was added to 0. 75 g (2-allylsulfanyl-benzyl)-carbamic acid te) t-butyl ester (2, 7 mmol) in 20 mL methanol and stirred for 2 hours at room temperature. The reaction mixture was filtered and methanol was removed in vaciso. The residue was extracted with ethyl acetate. The organic phase was washed with brine, dried with MgSO4 and concentrated il7 vaczso. The residue was redissolved in 5 mL THF and added to 0. 50 g fluoro-lH-indole (3.7 mmol) and 0.65 g trichlor acetic acid (4.0 mmol) in 5 mL THF and stirred for 16 hours at 50°C. Sat. aqueous NaHCO3 and ethyl acetate was added, the two phases were separated and the organic phase was washed with brine, dried with MgSO4 and concentrated ill vaczso. The residue was purified by flash chromatography and 0.157g [2- (5-fluoro-lH-indol-3- ylsulfanyl) -benzyl] -carbamic acid tert-butyl ester (0. 42 mmol, 16%) was isolated after recrystallization from ethyl acetate/heptane. 8 mL diethyl ether saturated with HCl was added to 0.157g [2- (5-fluoro-lH-indol-3-ylsulfanyl)-benzyl]-carbamic acid test-butyl ester (0.42 mmol) in 8 mL methanol and stirred 16 hours. The reaction was neutralized with 2N NaOH and extracted with ethyl acetate. The organic phase was washed with brine, dried with MgSO4 and concentrated in vaczto to give 0. 112 g 2- (5-fluoro-lH-indol-3-ylsulfanyl)- benzylamine (98%). |
|
With thionyl chloride In <i>N</i>-methyl-acetamide; toluene |
R.7.1 Reference example 7
(1) 12.5 ml of thionylchloride are added dropwise to a solution of 25.0 g of 2,2'-dithiodibenzoic acid in a mixture of 120 ml of toluene and 0.5 ml of dimethylformamide at a room temperature. The mixture is warmed to a temperature of 70° to 80° C. and then stirred at the same temperature overnight. After 20 hours, the crystals are collected by filtration to obtain 14.9 g of 2,2'-dithiodibenzoyl chloride as colorless crystal. m.p.:140°-141° C. |
|
In thionyl chloride; hexane |
A 2,2'-Dithiobisbenzoyl chloride
PREPARATION A 2,2'-Dithiobisbenzoyl chloride A mixture of 2,2'-dithiobisbenzoic acid (25 g, 81.6 mmol) in 350 mL of thionyl chloride was heated at reflux for 18 hours. The resulting solution was cooled to about 30° C. and excess thionyl chloride was removed in vacuo. The crude solid was slurried in hexane and the title compound was recovered by filtration to yield 21.2 g. This compound was used without further purification, mp 150°-151° C.; NMR (CDCl3): δ8.4 (m, 2H), 7.7 (d, 2H), 7.5 (m, 2H), 7.3-7.4 (m, 2H). |
|
In thionyl chloride; hexane |
1 2,2'-Dithiobisbenzoyl chloride
PREPARATION 1 2,2'-Dithiobisbenzoyl chloride A mixture of 2,2'-dithiobisbenzoic acid (25 g, 81.6 mmol) in 350 mL of thionyl chloride was heated at reflux for 18 hours. The resulting solution was cooled and excess thionyl chloride was removed in vacuo. The crude solid was slurried in hexane and the title compound was recovered by filtration to yield 21.2 g mp 150°-151° C. This compound was used without further purification. |
| 1619 g (71%) |
With thionyl chloride In N,N-dimethyl-formamide; toluene |
1 1,2-Benzisothiazol-3(2H)-one (Method 1)
EXAMPLE 1 1,2-Benzisothiazol-3(2H)-one (Method 1) A slurry of 2,2'-dithiosalicylic acid (2017 g, 6.584 moles), thionyl chloride (1645 g, 13.826 moles), toluene (10 liter) and N,N-dimethylformamide (40 mL) was heated at about 75° for 18 hours. At this point all solid had dissolved and the resulting dark solution was cooled to 8°. The reaction product crystallized and was isolated by filtration and washed on the filter with about 1 liter of cold Skelly F. Drying yielded 1619 g (71%) of 2,2'-dithio-bis-benzoyl chloride, m.p. 154°-156° (Lit. m.p. 155°-156°; cf: I. R. Douglass and B. S. Farrah, J. Org. Chem., 26, 351-354 (1961)). |
|
With thionyl chloride; N,N-dimethyl-formamide for 3h; Heating / reflux; |
1.1.1
1.1 : Dithiodibenzoic acid - dimethylester 25 g (81.6 mmol) of dithiodibenzoic acid is refluxed in 60 ml of SOCI2 and 1.5 ml of dimethylformamide (DMF) for 3 hrs. Then the excess of SOCI2 is distilled off, and the residue is dissolved in CHCI3 and added dropwise to a solution of methanol (50 ml) and triethylamine (0.204 mol) in CHCI3 (300 I). After standing over night the reaction mixture is shaked with water and saturated K2CO3 solution. After drying the organic layer the solvent is evaporated and methanol is added to the residue (oil). 13.6 g (50%) of solid product is obtained. |
|
With thionyl chloride for 3h; Heating / reflux; |
|
|
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane |
|
|
With thionyl chloride for 8h; Reflux; |
|
|
With oxalyl dichloride In N,N-dimethyl-formamide at 0℃; |
4.2.1. Synthesis of para- and ortho-substituted aromatic ethylene glycol disulfide polymers57 (general procedure using polymer 20 as an example)
General procedure: 4,4'-Dithiobenzoic acid (11) [23], [58] and [59] (0.213 g, 0.696 mmol) was dissolved in 4 mL of THF, and then DMF (10 μL) was added. The solution was cooled to 0 °C, and oxalyl chloride (13) (0.883 g, 6.96 mmol) was slowly added into the solution via syringe. The solution was stirred for 3 h and then reduced under vacuum to give a yellow oil. The yellow oil was dissolved in 6 mL of CH2Cl2 and then transferred to a flask containing triethylene glycol disulfide (17) (0.981 g, 2.98 mmol), Et3N (0.77 mL, 5.57 mmol), and 46 mL of CH2Cl2 at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and gradually warmed to room temperature, and then stirring continued overnight. The reaction mixture was dissolved in 50 mL of CH2Cl2 and then washed with 50 mL of 0.1 N HCl. The organic layer was then washed with water (2 × 50 mL), dried (MgSO4), filtered, and reduced under vacuum to provide 0.81 g of polymer 20. |
|
With thionyl chloride for 24h; Reflux; |
|
|
With thionyl chloride Reflux; |
|
|
With thionyl chloride at 80℃; for 24h; Reflux; |
Typical experimental procedure
Various benzisothiazolones (1.1 to 1.31) were synthesized starting from commercially available dithiodibenzoic acid (2). Dithiodibenzoic acid (2 g) was refluxed with thionyl chloride (10 mL) for 24 h at 80 oC. Excess thionyl chloride was removed by distillation and chased-up with dry benzene to get dithiodibenzoyl chloride as a pale brown solid 2.2 g (crude). To a stirred solution of dithiodibenzoyl chloride (2.2 g, 6.41 mmol) in dry DCM (20 mL) was added bromine (0.66 mL, 12.8 mmol) and the mixture was refluxed for 12 h. Dichloromethane and excess bromine were distilled off and the residue was chased with dry benzene (2 x 5 mL) to get 3.2 g of 2-bromosulfenylbenzoyl chloride (3) as a brown solid which was directly subjected to next step without further purification. |
|
With oxalyl dichloride In dichloromethane for 3h; Inert atmosphere; Cooling with ice; |
1 Preparation of a compound formula 1
Under argon atmosphere, 2,2'-dithiodibenzoic acid (1.53 g, 5 mmol) and oxalyl chloride (2.96 g, 23.3 mmol) were reacted in 100 ml of methylene chloride under ice-cooling for 3 hours. The solvent was evaporated to dryness stand-by. Under ice-water bath, the cyanine fluorophore (500mg, 1.08mmol) was dissolved in methylene chloride, and then 2,2'-dithiodibenzoyl chloride was added dropwise. After reacting for 1 hour in ice bath, The mixture was then extracted with dichloromethane (100ml X 3). After evaporation of the solvent, the crude product was dissolved in 50ml of ethanol and sodium borohydride (g, mol) was added dropwise in ice-water bath. The reaction was continued for 15 minutes with dilute hydrochloric acid (10%) To neutrality, then extracted with dichloromethane (100 ml X 3), dried over sodium sulfate, and the solvent was evaporated to dryness. The residue was separated by silica gel column chromatography (200-300 mesh). The eluent was dichloromethane and petroleum ether (1: 1 / V / V). The yellow component was collected and the product was evaporated to dryness to yield 0.51 g. Yield: 75%. |
|
With phosphorus pentachloride |
|
|
With thionyl chloride In N,N-dimethyl-formamide for 4h; Reflux; |
Procedure for synthesis of compound 11
After 2,2’-dithiosalicylic acid 10 (1.1 g, 3 mmol, 1 equiv) was dissolved in thionylchloride (0.7 mL, 9.6 mmol, 3 equiv), DMF (10 mL) was added to the reaction mixture. The reaction mixture was stirred at refluxing for 4 h, then cooled down to room temperature, concentrated in a vacuum, and then recrystallized in n-hexane. The solid residue was filtered and dried in a vacuum to provide 2,2’-dithiosalicylic aciddichloride 10a. To a solution of the intermediate 10a (654.8 mg, 2 mmol, 1 equiv) in THF (2 mL) was added 8-Aminoquinoline (576.7 mg, 4 mmol, 2 equiv) at 0 °C for over 1 h until the PH value was stable between 9 and 10. The reaction mixture was then allowed to stir at room temperature for another 10 h. The reaction mixture was poured into water and the slurry was filtered. The white solid was obtained after washing with water and dried in a vacuum to provide 10b. The intermediate 10b (1.4 g, 2 mmol, 1 equiv) was dissolved in THF (4 mL). After the solution was cooled down to 0 °C, sodium borohydride (302.6 mg, 8 mmol, 4 equiv) was added in potions over 4 h. In this period, the temperature was controlled below 30 °C. After the reaction was complete, water and acetic acid were added to quench the reaction. Then ethyl acetate (4x500mL) was used to extract the product. The organic phase was combined, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography (eluent: petroleum ether :ethylacetate = 4 : 1) to afford the final product 11 as a yellow solid (343.3 mg, 61%). |
|
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 4h; Reflux; |
|
|
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; |
|
|
With oxalyl dichloride In N,N-dimethyl-formamide at 0 - 20℃; for 3.5h; |
4
DMF (0.15 ml, cat.) was added to a suspension of bis(2-carboxyphenyl) disulfide (2.94 g, 9.6 mmol, 1.0 eq.) in THF (60 ml). Oxalyl chloride (8.23 ml, 12.19 g, 96.0 mmol, 10.0 eq.) was added dropwise to the reaction mixture at 0° C. and the mixture was stirred at this temperature for 30 min. The resulting yellow solution was then stirred at RT for a further 3 h. The solvent and excess oxalyl chloride were then distilled off. A yellow solid was isolated that was used for the next synthesis step without further analysis or purification (on account of its reactivity). |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
