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CAS No. : | 15084-51-2 | MDL No. : | MFCD00007449 |
Formula : | C10H13ClO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YEZADZMMVHWFIY-UHFFFAOYSA-N |
M.W : | 232.73 | Pubchem ID : | 139882 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 58.8 |
TPSA : | 42.52 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.15 cm/s |
Log Po/w (iLOGP) : | 2.43 |
Log Po/w (XLOGP3) : | 3.62 |
Log Po/w (WLOGP) : | 3.99 |
Log Po/w (MLOGP) : | 2.76 |
Log Po/w (SILICOS-IT) : | 2.47 |
Consensus Log Po/w : | 3.05 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.75 |
Solubility : | 0.0415 mg/ml ; 0.000178 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.2 |
Solubility : | 0.0147 mg/ml ; 0.000063 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.16 |
Solubility : | 0.0162 mg/ml ; 0.0000698 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 1.68 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3261 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With ammonia In dichloromethane; water at 0 - 20℃; for 20 h; | [0362] To a 500-mL round-bottomed flask was added (4-tert-butylphenyl) sulfonyl chloride (2.30 g, 10.0 mmol) in 100 mL CH2Cl2 at 0° C. and then concentrated NH4OH (50 mL, 100 mmol, 10 equiv). The mixture was allowed to warm to rt and stirred for 20 h. The solvent was evaporated under diminished pressure and the remaining slurry was filtered by Buechner funnel, giving 1.60 g (75percent) of Compound A as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.7% | With hydrogenchloride; chlorosulfonic acid; sodium sulfide; iron; triphenylphosphine; In water; at 200℃; for 4h; | 60.0 g of p-tert-butylbenzenesulfonyl chloride, 250 ml of water and 150 ml of chlorosulfonic acid were added to the reaction vessel, mechanically stirred, and 1.3 g of triphenylphosphine, 5.7 g of iron and 34 g of sodium sulfide were added, and reacted at 200 C for 4 hours.TLC tracking monitoring.Allow to stand, separate the water layer, adjust the pH to 1.0, and concentrate the organic phase after extraction.Distillation under reduced pressure gave 40.3 g of p-tert-butylthiophenol in a yield of 93.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With ammonia; In dichloromethane; water; at 0 - 20℃; for 20h; | [0362] To a 500-mL round-bottomed flask was added (4-tert-butylphenyl) sulfonyl chloride (2.30 g, 10.0 mmol) in 100 mL CH2Cl2 at 0 C. and then concentrated NH4OH (50 mL, 100 mmol, 10 equiv). The mixture was allowed to warm to rt and stirred for 20 h. The solvent was evaporated under diminished pressure and the remaining slurry was filtered by Buechner funnel, giving 1.60 g (75%) of Compound A as a white solid. |
With ammonium hydroxide; at 100℃; for 1h; | General procedure: Substituted arylsulfonylchlorides was suspended in 3 mL ammonia water, and thenthe solution was refluxed at 100 C for 1 h. The mixture was cooleddown to room temperature. Substituted arylsulfamides wereobtained by filtration, washing with water and were then driedin vacuo (excepted for the commercially available 4-methylbenzenesulfonamide). | |
With ammonia; In water; at 20℃; | General procedure: To a ice cooled ammonia solution (10 ml, 25% in water) was added a solution of sulfonylchloride in portion or dropwise. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was quenched with water (10 ml), extracted with chloroform (3x50 ml), the organic layer was washed with 1N HCl (50 ml), then with water (50 ml), dried over Na2SO4, concentrated in rota-vap to give desired sulfonamide. No further purification was required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In tetrahydrofuran at 25 - 70℃; for 13h; Schlenk technique; | |
72% | With triethylamine In tetrahydrofuran at 20℃; | Phenylendiamine derivatives General procedure: The reactions were performed in analogy to a procedure described in the literature [5]. However, instead of CH2Cl2, THF was used as the solvent. A solution of 4-tert.-butylbenzenesulfonylchloride (2 mmol) in dry THF (7 mL) was added dropwise to a solution of the 1,2-phenylendiamine derivative (2 mmol) and triethylamine (4 mmol) in 10 mL of dry THF and the mixture was stirred at room temperature until the starting material was consumed as determined by TLC. Then, the solvent was removed under reduced pressure, the residue thus obtained was solved in dichloromethane and the organic phase was washed with water and brine, and dried over anhydrous sodium sulfate. After removing the solvent, the raw product was purified as described below. Compound 5 (N-(2-aminophenyl)- 4-(tert.-butyl)-benzenesulfonamide, CAS 500357-83-5) Recrystallization from isopropanol/diisopropyl ether yielded 72 % of light beige-colored crystals, mp 180-183 °C (ref[6], 135-136 °C) (ref[7] 180-182 °C). IR 3465, 3385, 3206, 1321, 1152. 1H-NMR (DMSO-d6) 9.20 (s br, 1H, NH), 7.66-7.62 (m, 2H, phenyl-H), 7.56-7.52 (m, 2H, phenyl-H), 4.95 (s br, 2H, NH2), 1.27 (s, 9H, C(CH3)3). Anal. Calcd. for C16H20N2O2S (304.41): C, 63.13; H, 6.62; N, 9.20; S, 10.53. Found: C, 63.10; H, 6.68; N, 9.23; S, 10.47. |
47% | With pyridine for 8h; |
Stage #1: 4-tert-butylbenzenesulfonyl chloride With triethylamine In tetrahydrofuran at 20℃; for 0.166667h; Schlenk technique; Stage #2: 1,2-diamino-benzene In tetrahydrofuran at 20℃; for 12h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With hydrazine hydrate monohydrate In tetrahydrofuran at 0 - 20℃; | 2 4.1.2.2 4-(tert-Butyl)benzenesulfonohydrazide (5j) General procedure: To solution of 1 mmol of arylsulfonyl chloride 4i-w in 10 ml of THF, 1.1 mmol of hydrazine-hydrate in 10 ml THF were added drop wise at 0-5 8C with stirring. After stirring 1-2 h at rt 20 ml of water were added, the precipitate was filtered, dried and crystallized from benzene or hexane. HPLC analysis revealed single peaks for all tested compounds. Yield 97%, m.p. 72-75 °C. 1H NMR (DMSO-d6): δ 1.34 (s, 9H, CH3C), 7.60 (d, 1H, JHH = 8.6 Hz, HAr), 7.84 (d, 1H, JHH = 8.6 Hz, HAr), 8.50 (s, 1H, NH). EI-MS (m/z): 229 [M+1]+. Anal. calcd. for C10H16N2O2S: C, 52.61; H, 7.06; N, 12.27; O, 14.02; S, 14.04; found: C, 52.82; H, 6.96; N, 12.38. |
77% | With hydrazine monohydrate In tetrahydrofuran at 5℃; | |
77% | With hydrazine hydrate monohydrate In tetrahydrofuran at -8℃; for 0.5h; | General Procedure for Sulfonylhydrazide Synthesis (2a-h) General procedure: To a solution of 80% hydrazine hydrate (0.1 ml, 2.1 mmol, 2.1 eq) in THF (10 ml) was slowly added sulfonylchloride (1 mmol, 1 eq). The mixture was stirred at -8°C for 30 min. The mixture was extracted with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel 60 (Merck; CHCl3/CH3OH, 9.4:0.6) to give sulfonylhydrazides. |
77% | With hydrazine hydrate monohydrate In tetrahydrofuran at -80℃; for 0.5h; | 2.1.1. General Procedure for Sulfonylhydrazide Synthesis (2a-d) General procedure: Hydrazine monohydrate 80% (2.1 mmol, 2.1 eq) wasadded to THF (10 ml). To this solution, a solution of respectivesulfonyl chloride (1 mmol, 1 eq) in THF was added dropwise. The mixture was further stirred at -8C for 30 min.The mixture was extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate and filtered. Theorganic extract was concentrated under reduced pressure,and the resulting residue was purified by column chromatographyon silica gel 60 (Merck; CHCl3/CH3OH, 9.4:0.6) toprovide the desired product. |
76% | With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | |
76% | With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | |
With hydrazine In dichloromethane for 0.25h; | ||
With lithium hydroxide monohydrate; hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at -30℃; for 0.5h; Inert atmosphere; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at -10℃; for 0.5h; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Schlenk technique; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.416667h; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran; lithium hydroxide monohydrate at 0℃; for 0.5h; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Schlenk technique; | ||
With hydrazine monohydrate In tetrahydrofuran; lithium hydroxide monohydrate at 0 - 20℃; for 0.5h; | ||
With hydrazine monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at 0 - 20℃; for 2h; | ||
With hydrazine monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | 2.2 General procedure for synthesis of sulfonyl hydrazides General procedure: Hydrazine hydrate (12.5 mmol) was added dropwise to a solution of sulfonyl chloride(5.0 mmol) in dry THF (25 mL) at 0°C under N2. After vigorous stirring for 30 min at0°C, ethyl acetate (60 mL) was added, and the mixture was washed repeatedly withice-cold 10% aqueous sodium chloride solution (3 × 20 mL). The organic layer wasdried over sodium sulfate, filtered, and added slowly to stirred hexane (40 mL) over 5min. Sulfonyl hydrazide precipitated within 10 min as an off-white solid and wascollected by vacuum filtration. The filter cake was washed with hexanes (2 × 50 mL)and then was dried in vacuum to give corresponding sulfonyl hydrazides in 60-80%yields. | |
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran; lithium hydroxide monohydrate at 0℃; for 0.5h; | 2.1 The synthesis of arylsulfonyl hydrazides [S1]. General procedure: Hydrazine monohydrate (80%) (275 mg, 4.4 mmol) was added water (260 mg) and was cooled to 0 °C. To this solution was added dropwise a solution of arylsulfonyl chloride (2.0 mmol) in THF (10 mL) at 0 °C. The mixture was further stirred at 0 °C for 30 min., followed by addition of diethyl ether (10 mL). The mixture was extracted with saturated brine (3 × 10 mL). The organic layer was dried over sodium sulfate, filtered through Celite. The combined organic extracts were concentrated and the resulting residue was purified by column chromatography on silica gel to provide the desired product. | |
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | 2. Preparation of sulfonyl hydrazides1 General procedure: A 100 mL round-bottom flask, which was equipped with a magnetic stir bar and charged with sulfonyl chloride (2.0 mmol) was evacuated and backfilled with nitrogen. After THF (1.0 mL) was added, the solution was cooled to 0°C . Then, hydrazine monohydrate (2.5 equiv, 5 mmol) was added dropwise. The reaction mixture was stirred for 0.5 h at 0°C . The mixture was diluted by adding EtOAc and washed with saturated brine. The organic layer was dried over MgSO4, filtered, and concentrated on rotary evaporator. The residue was purified by recrystallization using EtOAc and hexane. | |
With hydrazine monohydrate In tetrahydrofuran at 0 - 20℃; for 1h; | Sulfonyl Hydrazides 1; General Procedure General procedure: To a stirred solution of the corresponding sulfonyl chloride (10 mmol, 1.0 equiv) in THF (20 mL) at 0 °C, hydrazine hydrate (11 mmol, 1.1 equiv) was added slowly. The reaction mixture was allowed to warm to ambient temperature and was stirred for over 1 h, with the progress monitored by TLC analysis. After the sulfonyl chloride had been completely consumed, the residue was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with H2O (2 × 10 mL) and brine (2 × 5 mL) and then dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give the corresponding sulfonyl hydrazide 1. | |
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; Inert atmosphere; | 2 Experimental Procedure for Compounds 1 General procedure: Eighty percent hydrazine hydrate (50 mmol) was added dropwise to a solution ofarenesulfonyl chlorides (20 mmol) in tetrahydrofuran (20 mL) surrounded by anice-water bath. The mixture was stirred for 0.5-1h under a nitrogen atmosphere(detected by TLC). After the mixture was diluted with ethyl acetate, the solution waswashed with saturated brine and the organic layer was dried with anhydrousmagnesium sulfate. Then filtering the inorganic salt, and added slowly to stirredpetroleum ether (25 mL) over 6 min. After being stirred for 15 min, the mixture wasfiltered, and the collected solid was dried in vacuum. The yields for the formation ofarylsulfonyl hydrazides range from 70% to 97%. | |
With hydrazine hydrate monohydrate In tetrahydrofuran at 0 - 20℃; for 0.5h; | ||
With hydrazine monohydrate In tetrahydrofuran at 0℃; Inert atmosphere; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Sealed tube; | 2.1 Preparation of Sulfonyl Hydrazides General procedure: Sulfonyl hydrazides 1b-o were prepared according to the literature procedure.1 Hydrazine monohydrate(1.8 ml, 30 mmol) was added dropwise to a solution of an sulfonyl chloride (10.0 mmol) intetrahyrdofuran (15 mL) under argon at 0 °C. During the addition the mixture became brown and awhite precipitate of hydrazine hydrochloride was deposited. The mixture was stirred at 0 °C for 30 min,added ethyl acetate (60 mL), and washed with saturated brine (3 x 30 mL). The organic layer was driedover sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash columnchromatography on silica gel to give the desired product in 30% to 91% yields. | |
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; | ||
With hydrazine hydrate monohydrate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; | 2. Synthesis of sulfonyl hydrazides 4 General procedure: The hydrazinemonohydrate F (30 mmol) was added dropwise into the solution of sulfonylchloride E (10 mmol) in THF (50 mL) under nitrogen at 0 °C. Subsequently, the mixture wasfurther stirred at 0 °C for 30minutes. After the completion of the reaction, the solvent wasremoved by evaporation, and the residue was extracted with dichloromethane (3 x 20 mL), andthe combined organic layer was washed with water, and brine, and dried over Na2SO4. Thesolvent was removed under vacuum and the residue was subjected to column chromatographyon SiO2 with PE-EtOAc as an eluent to give the desired product 4 | |
With hydrazine hydrate monohydrate In tetrahydrofuran at 0 - 5℃; for 0.5h; | ||
With hydrazine monohydrochloride; sodium hydroxide In tetrahydrofuran; lithium hydroxide monohydrate at 0℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | In tetrahydrofuran; methanol; water; mineral oil; | EXAMPLE 39 4-tert-Butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide A solution of <strong>[33084-49-0]5-amino-4-bromo-3-methylisoxazole</strong> (354 mg, 2.0 mmol) in dry THF (1 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0-5 C. After stirring at 0-5 C. for 10 min., the reaction was warmed to room temperature for 10 min. to complete the reaction. The reaction mixture was re-cooled to 0 C. and 4-tert-butylbenzenesulfonyl chloride (512 mg, 2.2 mmol) was added slowly. Stirring was continued for 20 min. at 0-5 C. Excess sodium hydride was decomposed by addition of methanol (0.4 ml) followed by water (0.5 ml). The mixture was acidified with hydrochloric acid and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give a crude product, which was purified by recrystallization from ethyl acetate/hexanes to give a white solid in 21% yield, m.p. 170 C. (dec.). |
21% | In tetrahydrofuran; methanol; water; mineral oil; | EXAMPLE 5 4-tert-Butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide A solution of <strong>[33084-49-0]5-amino-4-bromo-3-methylisoxazole</strong> (354 mg, 2.0 mmol) in dry THF (1 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 188 mg, 4.4 mmol)in dry THF (1 ml) at 0-5 C. After stirring at 0-5 C. for 10 min., the reaction was warmed to room temperature for 10 min. to complete the reaction. The reaction mixture was re-cooled to 0 C. and 4-tert-butylbenzenesulfonyl chloride (512 mg, 2.2 mmol) was added slowly. Stirring was continued for 20 min. at 0-5 C. Excess sodium hydride was decomposed by addition of methanol (0.4 ml) followed by water (0.5 ml). The mixture was acidified with hydrochloric acid and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give a crude product, which was purified by recrystallization from ethyl acetate/hexanes to give a white solid in 21% yield, m.p. 170 C. (dec.). |
21% | In tetrahydrofuran; methanol; water; mineral oil; | EXAMPLE 39 4-tert-Butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide A solution of <strong>[33084-49-0]5-amino-4-bromo-3-methylisoxazole</strong> (354 mg, 2.0 mmol) in dry THF (1 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0-5 C. After stirring at 0-5 C. for 10 min., the reaction was warmed to room temperature for 10 min. to complete the reaction. The reaction mixture was re-cooled to 0 C. and 4-tert-butylbenzenesulfonyl chloride (512 mg, 2.2 mmol) was added slowly. Stirring was continued for 20 min. at 0-5 C. Excess sodium hydride was decomposed by addition of methanol (0.4 ml) followed by water (0.5 ml). The mixture was acidified with hydrochloric acid and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give a crude product, which was purified by recrystallization from ethyl acetate/hexanes to give a white solid in 21% yield, m.p. 170 C. (dec.). |
21% | In tetrahydrofuran; methanol; water; mineral oil; | EXAMPLE 45 4-tert-Butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide A solution of <strong>[33084-49-0]5-amino-4-bromo-3-methylisoxazole</strong> (354 mg, 2.0 mmol) in dry THF (1 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0-5 C. After stirring at 0-5 C. for 10 min., the reaction was warmed to room temperature for 10 min. to complete the reaction. The reaction mixture was re-cooled to 0 C. and 4-tert-butylbenzenesulfonyl chloride (512 mg, 2.2 mmol) was added slowly. Stirring was continued for 20 min. at 0-5 C. Excess sodium hydride was decomposed by addition of methanol (0.4 ml) followed by water (0.5 ml). The mixture was acidified with hydrochloric acid and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give a crude product, which was purified by recrystallization from ethyl acetate/hexanes to give a white solid in 21% yield, m.p. 170 C. (dec.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Example 45: N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tenVbutyl-N-methoxymethyl- benzenesulfonamide; [00436] A 200 mL round-bottom flask was charged with 2-bromo-5-chloro- pyridin-3-ylamine (10.4 g, 50.0 mmol), 4-tert-butyl-benzenesulfonyl chloride (20.0 g, 85.0 mmol), and pyridine (38 mL). The resultant solution was heated to 70 C and stirred overnight. The following day, the pyridine was removed by removed in vacuo and THF (30 mL) and 4.0 N NaOH (100 mL) were added and the reaction was stirred at 60 C overnight. The organics were subsequently removed in vacuo and the residues were diluted with water (400 mL). The small quantity of insoluble solid was removed by filtration and the pH was adjusted to 6-7 with concentrated HCI. The resultant aqueous solution was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford the diarylsulfonamide (13.4 g) in 66 % yield. To a solution of the crude sulfonamide (12.0 g, 35.0 mmol) and K2CO3 (24.0 g, 170 mmol) in anhydrous THF (80 mL) was added chloromethyl methyl ether (4.0 mL, 52.7 mmol). The resultant heterogeneous solution was stirred for 60 min at ambient temperature and the solids were subsequently removed via filtration. The filtrate was then removed in vacuo and the residue was dissolved in EtOAc. The organics were washed with saturated Na2CO3, dried over MgSO4, and evaporated in vacuo to generate a brownish oil. The oil was triturated with hexanes and the resultant solid filtered to produce the desired product as a light yellowish solid (11.5 g, 86% yield). | |
66% | Example; N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-benzenesulfonamide; A 200 mL round-bottom flask was charged with <strong>[90902-83-3]2-bromo-5-chloro-pyridin-3-ylamine</strong> (10.4 g, 50.0 mmol), 4-tert-butyl-benzenesulfonyl chloride (20.0 g, 85.0 mmol), and pyridine (38 mL). The resultant solution was heated to 70 C. and stirred overnight. The following day, the pyridine was removed by removed in vacuo and 30 mL THF (tetrahydrofuran) and 100 mL 4.0 N NaOH were added and the reaction was stirred at 60 C. overnight. The organics were subsequently removed in vacuo and the residues were diluted with 400 mL water. The small quantity of insoluble solid was removed by filtration and the pH was adjusted to 6-7 with concentrated HCl. The resultant aqueous solution was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford the desired sulfonamide (13.4 g) in 66% yield: MS (ES) M+H expected 403.0, found 403.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyridine In acetonitrile | S.11 11-1 Synthesis of 8-(4-tert-Butylbenzenesulfonylamino)quinoline 11-1 Synthesis of 8-(4-tert-Butylbenzenesulfonylamino)quinoline 8-Aminoquinoline (50.8 g) (0.352 mol) was dissolved in 300 ml of acetonitrile, and 29.0 ml (0.359 mol) of pyridine was added to the above solution at 0° C. under the nitrogen atmosphere. Then, a solution of 250 ml of acetonitrile containing 67.9 g (0.356 mol) of 4-tert-butylbenzenesulfonyl chloride was dropwise added thereto slowly while maintaining the reaction temperature at 5° C. or less. After completion of the dropwise addition, the temperature was gradually raised and the reaction was continued for 5 hours at room temperature. The reaction solution was then poured into a chilled dilute aqueous hydrochloric acid. The solids precipitated were filtered out, washed with water, and the solids obtained were recrystallized with acetonitrile, thereby 96.7 g of the objective compound was obtained. Yield: 92%. |
91% | With pyridine at 130℃; for 0.05h; Microwave irradiation; Inert atmosphere; | |
91% | With pyridine at 130℃; for 0.05h; Microwave irradiation; |
85% | With triethylamine In tetrahydrofuran at 20℃; for 12h; Schlenk technique; | |
80% | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
78% | With triethylamine In acetone at 0 - 20℃; for 8.5h; | |
73% | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
72% | With triethylamine In dichloromethane at 0 - 20℃; | |
47% | With triethylamine In dichloromethane at 0 - 20℃; | |
With triethylamine In dichloromethane at 0 - 20℃; Sealed tube; Inert atmosphere; | ||
With triethylamine In tetrahydrofuran at 20℃; for 12h; | ||
With triethylamine In tetrahydrofuran for 12h; | ||
With pyridine at 130℃; for 0.5h; | ||
Stage #1: 8-amino quinoline With triethylamine In dichloromethane at 0℃; Stage #2: 4-tert-butylbenzenesulfonyl chloride In dichloromethane at 0 - 20℃; for 16h; | General procedure: The hydroxyquinoline or aminoquinoline (2mmol) was stirred with triethylamine (3mmol) in dichloromethane (10mL) for 10-30min at 0°C, then sulfonyl chloride (3mmol) was added dropwise over 10min. The reaction mixture was further stirred for about 16h at room temperature, upon complete consumption of the sulfonyl chloride (monitored by TLC), diluted with ethyl acetate, washed with 0.5M HCl and brine, and the resulting organic layer was dried over MgSO4, the solvent was completely removed under reduced pressure. The crude product was purified by chromatography on silica gel (ethyl acetate/hexanes) or recrystallization from chloroform/diethyl ether to give the target products. The compounds synthesized were characterized by 1H and 13C NMR and confirmed by HRMS. | |
Stage #1: 8-amino quinoline With triethylamine In dichloromethane at 0℃; Stage #2: 4-tert-butylbenzenesulfonyl chloride In dichloromethane at 0 - 20℃; for 16h; | General procedure: The hydroxyquinoline or aminoquinoline (2mmol) was stirred with triethylamine (3mmol) in dichloromethane (10mL) for 10-30min at 0°C, then sulfonyl chloride (3mmol) was added dropwise over 10min. The reaction mixture was further stirred for about 16h at room temperature, upon complete consumption of the sulfonyl chloride (monitored by TLC), diluted with ethyl acetate, washed with 0.5M HCl and brine, and the resulting organic layer was dried over MgSO4, the solvent was completely removed under reduced pressure. The crude product was purified by chromatography on silica gel (ethyl acetate/hexanes) or recrystallization from chloroform/diethyl ether to give the target products. The compounds synthesized were characterized by 1H and 13C NMR and confirmed by HRMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine; at 20℃; | To a solution of <strong>[861673-68-9]2-(2-tert-butylphenoxy)pyridin-3-amine</strong> (1a) (20 mg, 0.083 mmol) in pyridine (0.75 ml) was added 4-tert-butylbenzene-1-sulfonyl chloride (20 mg, 0.086 mmol). The reaction was allowed to set at rt overnight. Solvent was removed under vacuum. Purification by Prep. HPLC (C18 28 mm×100 mm, 20-100% solvent B, 10 min. gradient, 4 min. hold, 25 ml/min: solvent A=10% MeOH/Water+0.1% TFA, solvent B=90% MeOH/Water+0.1% TFA) provided Example 30 (16.3 mg, 0.037 mmol). (M+H)+=439.28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine; In ethanol; at 40℃; for 3h; | Then, 4-t-butylphenyl sulfonyl chloride (9.7g, 0.04 mol) was dissolved in ethanol. To the solution, triethylamine (5.0g, 0.05 mol) was added dropwise and 1.3 equivalent weight of 4-(lH-imidazol-l-yl)aniline (8.0g, 0.05 mol) dissolved in ethanol (20 mi) was slowly added dropwise. The solution was stirred further for 3 hours at 40 C . After completion of the reaction, the reaction was filtered, concentrated, dissolved in dichloromethane (250 mi) and washed with distilled water (100 mi). Next, the solution was dried with anhydrous manganese (10Og), filtered, concentrated, crystallized with hexane and filtered to obtain 12.2 g of [4-t-butyl phenyl]-N-(4-imidazol- 1-yl phenyl) sulfonamide (yield = 82%). TLC (ethyl acetate :hexane = 10:1); Rf = 0.591H NMR (DMSO^6): 10.44(s, IH), 8.24(s, IH), 7.62(m, 7H), 7.18(d, 2H), 7.08(s, IH), 1.21(s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h; | 1b) 5-(4-tert-Butyl-phenylsulfonylamino 1H-indole-2-carboxylic acid ethyl ester 5.18 ml of ethyldiisopropylamine and 4.69 g of 4-tert-butyl-phenylsulfonyl chloride are added to a solution of 4.12 g of the amine, produced in Example 1a), in 195 ml of DMF at 0 C., and it is stirred for two hours at room temperature. The solvent is removed under reduced pressure, and the residue is purified by chromatography on silica gel with hexane/0-80% ethyl acetate. In this way, 7.56 g of the title compound is obtained. NMR (300 MHz, DMSO-d6): delta=1.20 (9H), 1.27 (3H), 4.27 (2H), 6.97-7.03 (2H), 7.25 (1H), 7.31 (1H), 7.48 (2H), 7.59 (2H), 9.93 (1H), 11.80 (1H). | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h; | 5.18 ml of ethyldiisopropylamine and 4.69 g of 4-tert-butyl-phenylsulfonyl chloride are added to a solution of 4.12 g of the amine, produced in Example 1a), in 195 ml of DMF at 0 C., and it is stirred for two hours at room temperature. The solvent is removed under reduced pressure, and the residue is purified by chromatography on silica gel with hexane/0-80% ethyl acetate. In this way, 7.56 g of the title compound is obtained. NMR (300 MHz, DMSO-d6): delta=1.20 (9H), 1.27 (3H), 4.27 (2H), 6.97-7.03 (2H), 7.25 (1H), 7.31 (1H), 7.48 (2H), 7.59 (2H), 9.93 (1H), 11.80 (1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 48h; | To a solution of (1S,4S)-2-BOC-2,5-diazabicyclo[2.2.1]heptane (1.0 g, 5.04 mmol) in 50 ml_ dichloromethane was added diisopropylethyl amine (2.63 mL, 15.12 mmol) followed by 4-tert-butyl-sulfonyl chloride (1.76 g, 7.56 mmol). The reaction was stirred at room temperature for 48 h after which it was concentrated and purified by column chromatography (5% MeOH in dichloromethane) to afford the desired sulfonamide Compound 25 (2.0 g, 99% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 20℃; for 36h; | I. Methyl 3-(4-tert-butylphenylsulfonamido)benzo[b]thiophene-2-carboxylate (88)To a solution methyl 3-aminobenzo[b]thiophene-2-carboxylate (0.207 g; 1 mmol) in pyridine (1 mL) was added 4-tert-butylbenzenesulfonyl chloride (0.256 g; 1.1 mmol). The resulting mixture was stirred at room temperature for 36 hours and then partitioned between dichloromethane and aqueous hydrochloric acid (2N). The organic layer was separated, dried over sodium sulfate, filtered through a pad of silica gel, and concentrated under reduced pressure to give the desired product as a yellow solid (120 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: benzoimidazole With pyridine In dichloromethane at 25℃; for 1h; Inert atmosphere; Stage #2: 4-tert-butylbenzenesulfonyl chloride In dichloromethane for 1h; Inert atmosphere; | 4.2 General synthetic procedure General procedure: A mixture of the benzimidazole (3mmol), 1.5mL of anhydrous pyridine and methylene chloride (15mL) was stirred at room temperature for 1h, after which the corresponding arylsulfonyl chloride (3.2mmol) was added. The mixture was stirred for 1h and the completion of the reaction was tested by TLC using hexane:acetone (7:3) or chloroform:methanol:acetone (8:1:1) as the mobile phase. The sulfonylation time was around 1h, after which the reaction was stopped by the addition of HCl 10% (30mL). The resulting immiscible phases were separated, with the organic phase being extracted by sequentially adding HCl 10% (1×30mL), a saturated Na2CO3 solution (1×30mL) and brine (1×30mL). The resulting organic phase was dried over anhydrous MgSO4, filtered and concentrated to dryness under vacuum to isolate the reaction products as solids. End-products were purified by crystallisation from ethanol, n-hexane or mixtures of them. |
76% | With triethylamine In acetone at 20℃; for 4h; | |
With triethylamine |
With potassium hydroxide In acetonitrile at 80℃; for 48h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine In acetone at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With triethylamine; In tetrahydrofuran; water; at 0℃; | Example 15: (S)-3-(4'-rei*i-ButyIbenzenesulfonyIamino)-azepan-2-one; ((S)-3-amino-azepan-2-one hydrochloride (2.35 g, 9.18 mmoles) was dissolved in H20 (20 mL) and cooled to 0C. 4-tButylbenzenesulfonyl chloride (1.92 g, 8.25) in THF (40 mL) was added and triethylamine (3.5 mL, 25 mmoles) and the reaction was stirred over night. The THF was removed in vacuo and the product was dissolved in ethyl acetate and washed with pH 2 buffer (3 x 20 mL) and reduced in vacuo. The product was purified by silica column chromatography (petroleum etherrethyl acetate 50:50:0 to 0:80:20) to give the product as a white solid 0.67 g (25 %); mp 189-190 0 C; deltaEta (400 MHz, CDCI3) 7.74 (d, 2H, J 8.5, CH-C-lBu), 7.47 (d, 2H, J 8.5, CH-C-SO2), 6.27 (br.t, 1H, J 6.5, NH-C1), 6.19 (d, 1H, J4.5, NH-CH), 3.88-3.81 (m, 1H, CH-C4), 3.21-3.12 (m, 1Eta, HI), 3.05 (ddd, 1H, J 14.5, 11.5, 5, HI), 2.19-2.13 (m, 1H, H4), 2.02-1.96 (m, 1H, H3), 1.81-1.74 (m, 1H, H2), 1.71-1.54 (m, 2H, H3 & H4), 1.33-1.29 (m, 1H, H2) and 1.31 (s, 3H, C(CH3)3); 6C (100 MHz, CDC13) 175.5 (C=0), 156.4 (C- C(CH3)3), 137.0 (C-C=0), 126.8, 126.1 (CH phenyl), 55.4 (CH-NH), 42.3 (CI), 35.2 (C(CH3)3), 33.5 (C4), 31.1 (C(CH3)3) and 28.7 (C2), 28.0 (C3); vm mA : 3219 (NH indole), 2968 (C-H), 1668 (amide C=0), 1594 (aromatic), 1361 (S02) and 1159 (S02); ESI m/z 100 %, 347.1 (MNa+) and 26 %, 670.6 (M2Na+); HR ESI m/z (C,6H24N203SH+ requires 325.1580) found 325.1580; [ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 4h; | |
96% | With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 4h; | |
85% | With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 15h; | a) A solution of sodium bicarbonate (1.44g, 17.2mmol) and sodium sulfite (2.16 g, 17.2mmol) in water (9 ml) was heated to 80 °C for 3h, then 4-tert-butylphenylsulfonyl chloride (2 g, 8.59 mmol) was added in two portions and again heated to 80 °C for 1h. The mixture was cooled to room temperature, allowed to stand for 2h, and the solids collected by filtration then dried on high vacuum to obtain 4-tert-butylbenzene sulfinic acid sodium salt (1.61 g, 85%) as a white solid. |
85% | With Sodium hydrogenocarbonate; anhydrous sodium sulphite at 80℃; for 1h; | 56.a a) A solution of sodium bicarbonate (1.44g, 17.2mmol) and sodium sulfite (2.16 g, 17.2mmol) in water (9 ml) was heated to 80 °C for 3h, then 4-tert-butylphenylsulfonyl chloride (2 g, 8.59 mmol) was added in two portions and again heated to 80 °C for lh. The mixture was cooled to room temperature, allowed to stand for 2h, and the solids collected by filtration then dried on high vacuum to obtain 4-tert-butylbenzene sulfinic acid sodium salt (1.61 g, 85%>) as a white solid. |
65% | With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 70 - 80℃; for 4h; | |
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 70 - 80℃; for 4h; Inert atmosphere; | General Procedure for the Preparation of Sodium Sulfinates (1c-1e, 1h) [1] General procedure: 4-Methoxybenzenesulfinic acid sodium salt (1c) was prepared by heating 2.5 g of sodium sulfite,2.06 g of 4-methoxybenzenesulphonyl chloride, and 1.68 g of sodium bicarbonate in 9.6 mL ofwater at 70-80 °C for 4 h. After cooling to room temperature, water was removed under vacuumand the residue was extracted by ethanol, recrystallization as a white solid, the yield was 67%(1.34 g). Similarly, other sodium arenesulfinates (1d, 1e, 1h) was prepared from theircorresponding sulphonyl chlorides. | |
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 8h; | ||
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer for 3h; Reflux; | ||
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 70 - 80℃; for 4h; | General procedure for the preparation of sodium sulfinates General procedure: 4-Methoxybenzenesulfinic acid sodium salt (1j) was prepared by heating 2.5 g of sodium sulfite, 2.06 g of 4-methoxybenzenesulphonyl chloride, and 1.68 g of sodium bicarbonate in 9.6 mL of water at 70-80 °C for 4 h. After cooling to room temperature, water was removed under vacuum and the residue was extracted by ethanol, recrystallization as a white solid, the yield was 67% (1.34 g). Similarly, other sodium arenesulfinates were prepared from their corresponding sulphonyl chlorides. | |
With water monomer; Sodium hydrogenocarbonate; anhydrous sodium sulphite at 80℃; for 4h; | ||
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 8h; | ||
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 4h; | ||
With sodium dihydrosulfite; Sodium hydrogenocarbonate In water monomer at 80℃; for 4h; | 5.1.4 General procedure for the preparation of sodium aryl sulfinates 4a-l General procedure: Sodium sulfite 3a-l (0.02mol), aryl sulfonyl chloride (0.01mmol), and sodium bicarbonate (0.02mol) were dissolved in distilled water (9.6mL). The reaction mixture was stirred at 80°C for 4 hand then cooled to room temperature. Water was removed under vacuum and the residue was extracted by ethanol (25mL) to afford the desired aryl sulfinate with yield of 20%-80%. | |
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 3h; | 2) Typical procedure of the preparation for sodium arylsulfinates General procedure: The 4-cyanobenzenesulfonyl chloride (15 mmol, 1.0 equiv, 3.0 g) was dissolved in water (50 mL). Sodium sulfite (30 mmol, 2.0 equiv, 3.8 g) and sodium bicarbonate (30 mmol, 2.0 equiv, 2.5 g) were added, and the reaction mixture was reacted at 80 oC for 3 h. The solvent was evaporated and ethanol (150 mL) was added to the residue. The suspension was heated to 80 oC for 10 min, refluxed and filtered. The filtrate was evaporated, and then ethanol (100 mL) was added and heated to 80 oC for 10 min, refluxed and filtered at the second time. The solvent was evaporated under vacuum to give sodium 4-cyanobenzenesulfinate (1h, 1.99 g, 71%) as white powders. | |
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 8h; | ||
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 70 - 80℃; for 4h; Inert atmosphere; | 3.2. General Procedure for the Preparation of Sodium Sulfinates General procedure: 4-Methoxybenzenesulfinic acid sodium salt (2e) was prepared by heating 2.5 g of sodium sulfite,2.06 g of 4-methoxybenzenesulphonyl chloride, and 1.68 g of sodium bicarbonate in 9.6 mL of waterat 70-80 C for 4 h. After cooling to room temperature, water was removed under vacuum and theresidue was extracted by ethanol, recrystallization as a white solid, the yield was 67% (1.34 g). Similarly,other sodium arenesulfinates were prepared from their corresponding sulfonyl chlorides. | |
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 4h; | ||
With sodium hydrogen sulphite; anhydrous sodium sulphite In water monomer at 80℃; for 4h; | ||
With anhydrous sodium sulphite | ||
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 4h; | ||
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; | ||
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 10h; | ||
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 3h; | 2) Typical procedure of the preparation for sodium arylsulfinates General procedure: The ethyl 4-(chlorosulfonyl)benzoate (20 mmol, 1.0 equiv, 4.98 g) was dissolved in water (50 mL). Sodium sulfite (40 mmol, 2.0 equiv, 5.04 g) and sodium bicarbonate(40 mmol, 2.0 equiv, 3.4 g) were added, and the reaction mixture was stirred at 80 oCfor 3 h. The solvent was evaporated and ethanol (100 mL) was added to the residue.The suspension was heated to 80 oC for 10 min, refluxed and filtered. The filtrate wasevaporated, and then ethanol (100 mL) was added and heated to 80 oC for 10 min,refluxed and filtered at the second time. The solvent was evaporated under vacuum togive sodium 4-(ethoxycarbonyl)benzenesulfinate (1c, 2.7 g, 58%) as white powders. | |
With Sodium hydrogenocarbonate; anhydrous sodium sulphite In water monomer at 80℃; for 12h; | ||
With Sodium hydrogenocarbonate In water monomer at 80℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine; In dichloromethane; at 0 - 20℃; | General procedure: To a stirred solution of <strong>[837-52-5]7-chloro-4-piperazin-1-yl-quinoline</strong> (2) (0.25 g, 1 mmol) in 8-10 mL of DCM at 0 C was added triethylamine (0.12 mL, 1.26 mmol). Different aryl sulfonyl chlorides (1 mmol) were added dropwise/portion wise and the resulting solution was stirred further for 15 min at 0 C and then stirred at room temperature for different time intervals. On reaction completion (TLC), the reaction mix was diluted with 20 mL water and 20 mL DCM and partitioned in separating funnel, where the organic layer was washed with water (3 × 20 mL) before being separated and dried over sodium sulfate to yield compound 3 in which was recrystallized in DCM:Hexane to yield pure products in 85-95% yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.2% | With hydrogenchloride In 1,4-dioxane | 54.a a) a) Preparation of N-p-t-butyl-benzenesulfonyl-D-leucine D-leucine (1.4 g) was dissolved in 1.5N sodium hydroxide solution (10 ml), dioxane (10 ml) was added, and cooled down to control the temperature between 0 and 5° C.; p-t-butyl benzenesulfonyl chloride (2.3 g) and 1.5N sodium hydroxide solution were added slowly dropwisely to maintain the pH at 9-10; the resulting mixture was allowed to react at 0° C. for 2 h and warm up naturally to room temperature to react for 2 h. Upon cooled, dilute hydrochloric acid was added dropwisely to adjust pH to 3, and the resulting mixture was concentrated under reduced pressure to remove dioxane, and the water phase was extracted with ethyl acetate (20 ml*3), the resulting organic phase was washed with acid, base and water until to be neutral, dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified on a column to give a white solid (3 g, 83.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In dichloromethane; at 0 - 20℃; for 6h; | General procedure: 2-(Piperazin-1-yl)benzazolyl derivatives 8a-d (1 equivalent) and triethylamine (1.5 equivalents) were dissolved in 25 ml dry CH2Cl2 and cooled to 0C in an ice salt bath. Then the required phenylsulfonyl chloride (1.1 equivalents) dissolved in 20 ml dry CH2Cl2 was added dropwise. After the addition, the reaction mixture was stirred at 0C for a further 1h and then allowed to warm to room temperature and the course of the reaction followed by TLC. After completion, the mixture was diluted with additional 50 ml of CH2Cl2 and extracted with 10% NaHCO3 solution (3 x 50 ml). The organic phase was washed with dist. H2O, sat. NaCl solution, dried over anhyd. Na2SO4, filtered and evaporated to dryness. The product was recrystallised from the appropriate solvent, the precipitate formed was filtered under suction and dried at 60C under high vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.2% | With sodium hydroxide In 1,4-dioxane at 0 - 20℃; for 4h; | 54.a Example 54: N-p-t-butyl-benzenesulfonyl-D-leucyl-L-prolyl- [(4-amidinophenyl) methyl] amide hydrochloride a) Preparation of N-p-t-butyl-benzenesulfonyl-D-leucine[0217] D- leucine (1.4g) was dissolved in 1.5N sodium hydroxide solution (10ml) , dioxane (10ml) was added, and cooled down to control the temperature between 0 and 5°C; p- t- butyl benzenesulfonyl chloride (2.3g) and 1.5N sodiumhydroxide solution were added slowly dropwisely to maintain the pH at 9- 10; the resulting mixture was allowed to reactat 0°C for 2h and warm up naturally to room temperature to react for 2h. Upon cooled, dilute hydrochloric acid was addeddropwisely to adjust pH to 3, and the resulting mixture was concentrated under reduced pressue to remove dioxane,and the water phase was extracted with ethyl acetate (20ml33) , the resulting organic phase was washed with acid,base and water until to be neutral, dried over anhydrous sodium sulfate, and the filtrate was concentrated and purifiedon a column to give a white solid (3g, 83.2%) .Rf = 0.8Developer: n- butyl alcohol: water: acetic acid: ethyl acetate = 1: 1: 1: 1Color development: iodine and 1% ninhydrin solution |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine In acetone at 20℃; for 4h; Cooling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine at 80℃; for 4h; | General Procedure for the synthesis of arylsulfonamides (1-8) General procedure: A solution of sulfonylchloride and amine in pyridine (2 ml) was stirred at 80 for 4 hours. The reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (30 ml), washed with water (3 x 5 ml) and brine (5 ml) dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel using an appropriate mixture of ethyl acetate/hexane as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine In dichloromethane at 20℃; for 6h; | 16 Example 16 Add 1.40g (6mmol) of p-tert-butylbenzenesulfonyl chloride and 10mL of dichloromethane to a dry reaction flask, stir to dissolve at room temperature, and slowly add dropwise 10mL containing 0.54g (5mmol) of 2-aminomethylpyridine and 0.76g ( 7.5 mmol) a dichloromethane solution of triethylamine, the addition is complete, and the reaction is stirred at room temperature for 6 hours. After the reaction is completed, the reaction liquid is concentrated by rotary evaporation to obtain a paste. In an ice water bath, the paste was fully washed with deionized water, and it solidified into a solid, filtered, and dried to obtain 1.43 g of white powder with a yield of 94% and an HPLC purity of 99%. |
79.5% | In tetrahydrofuran for 4h; | |
With triethylamine In tetrahydrofuran at 25℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium hydrogen difluoride In water monomer; acetonitrile at 20℃; for 21h; | Sulfonyl Fluorides 1b, 1c, 1g, and 1i; General Procedure General procedure: A round-bottomed flask was charged with KHF2 (15.6 g, 200 mmol)and H2O (40.17 g) and the mixture was stirred at r.t. for 1 h. Then, asolution of the required sulfonyl chloride (100 mmol) in MeCN (45mL) was added, and the mixture was vigorously stirred for 20 h. Then,the mixture was transferred to a separatory funnel, extracted withDCM (2 × 100 mL), and the combined organic phases were dried(MgSO4). The mixture was filtered, evaporated, and dried in vacuo toobtain the desired sulfonyl fluoride. The crude products 1b, 1c, 1g,and 1i were analytically pure. |
Multi-step reaction with 2 steps 1: anhydrous sodium sulphite; water monomer / 5 h / 70 - 80 °C 2: 3,4,7,8-tetramethyl-1,10-phenanthroline; tetrakis(acetonitrile)palladium(II) tetrafluoroborate; N-fluorobis(benzenesulfon)imide / tetrahydrofuran / 0.5 h / Inert atmosphere; Schlenk technique | ||
With potassium hydrogen difluoride In water monomer; acetonitrile at 20℃; |
With potassium hydrogen difluoride In water monomer; acetonitrile at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine; In chloroform; at 0 - 90℃; for 12h; | To a stirred solution of compound LXIV (5 g, 24.10 mmol) in chloroform (25 ml) was added pyridine (100 ml) at 0C followed by addition of 4-tert-butylbenzenesulfonyl chloride (XI, 6.71 g, 28.41 mmol). The reaction mixture was heated at 90C for 12 h, cooled to room temperature and concentrated under reduced pressure. The crude mass was diluted withsaturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine solution and dried over anhydrous Na2504, filtered and evaporated under reduced pressure to afford N-(6-bromo-5 -chloropyridin-2-yl)-4-(tert-butyl)benzenesulfonamide (LXV; 7.7 g, 79 % yield). ?H NMR (400 MHz, CDC13) oe 7.82-7.80 (d, J 8.4 Hz, 2H), 7.64- 7.62 (d, J 8.4 Hz, 1H), 7.5 1-7.49 (d, J8.4 Hz, 2H), 7.34-7.32 (d, J= 8.4 Hz, 1H), 1.37 (s,9H). MS (M+1): 404.89 (LCMS Purity 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With pyridine; In chloroform; at 0 - 100℃; for 12.0h; | To a stirred solution of compound LXVIII (3 g, 21.12 mmol) in chloroform (60 ml) was addedpyridine (15 ml) at 0C followed by addition of 4-tert-butylbenzenesulfonyl chloride (XI, 5.89g, 25.34 mmol). The reaction mixture was heated at 100C for 12 h, cooled to room temperature and concentrated under reduced pressure. The crude material was diluted with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and evaporated under reducedpressure to afford 4-(tert-butyl)-N-(5 -chloro-6-methylpyridin-2-yl)benzenesulfonamide(LXIX; 6 g, 84% yield). ?H NMR (400 MHz, DMSO-d6) oe 11.11 (bs, 1H), 7.86-7.84 (d, J8.4 Hz, 2H), 7.72-7.70 (d, J 8.8 Hz, 1H), 7.60-7.58 (d, J 8.4 Hz, 2H), 6.94-6.93 (d, J= 7.6Hz, 1H), 2.36 (s, 3H), 1.27 (s, 9H). MS (M+1): 339.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With pyridine; In chloroform; at 0 - 100℃; for 4h; | To a stirred solution of compound LXXX (200 g, 1.07 mol) in chloroform (1 L) was added pyridine (600 ml) at 0C followed by addition of 4-tert-butylbenzenesulphonyl chloride (Xl,299 g, 1.28 mol). The reaction mixture was heated at 100C for 4 h, cooled to room temperature and concentrated under reduced pressure. The crude mass was diluted with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and evaporated under reducedpressure to afford N-(5 -bromo-6-methylpyridin-2-yl)-4-(tert-butyl)benzenesulfonamide (LXXXI, 320 g, 78% yield). ?HNMR(400 MHz, DMSO-d6) oe 11.14 (bs, 1H), 7.86-7.82 (m, 3H), 7.60-7.58 (d, J= 8.4 Hz, 2H), 6.87-6.85 (d, J= 10.4 Hz, 1H), 2.39 (s, 3H), 1.27 (s, 9H). MS (M+1): 383.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pyridine; In chloroform; at 0 - 100℃; for 12.0h; | To a stirred solution of compound CXXI (5 g, 26.88 mmol) in chloroform (60 ml) was added pyridine (20 ml) at 0C followed by addition of 4-tert-butylbenzenesulfonyl chloride (XI, 12.4 g, 53.76 mmol). The reaction mixture was heated at 100C for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude mass was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. Anorganic layer was washed with brine solution, dried over anhydrous Na2504 and evaporated under reduced pressure to afford N-(3 -bromo-6-methylpyridin-2-yl)-4-(tert- butyl)benzenesulfonamide (CXXII; 9 g, 90 % yield). ?H NMR (400 MHz, DMSO-d6) oe 11.18 (bs, 1H), 7.86-7.83 (m, 2H), 7.60-7.58 (d, J= 8.4 Hz, 2H), 6.88-6.86 (d, J 8.4 Hz, 2H), 2.39 (s, 3H), 1.27 (s, 9H). MS (M+1): 381.22. (LCMS Purity 97.01%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 90℃; for 12h; | 3 Synthesis of Compound 58 (4-(tert-butyl)-N-(6-cyanopyrazolo [1 .5-aj pyrimidin-7- yl)benzenesulfonamide’): To a stirred solution 7-aminopyrazolo[1,5-a]pyrimidine-6-carbonitrile (XVI; 0.5 g; 3.14 mmol)in acetonitrile (10 mL) was added DIPEA (1.21 g; 9.43 mmol) and 4-tertbutylphenylsulfonylchloride (XI; 0.87 g; 3.77 mmol) at 0°C. The reaction mixture was then heated at 90°C for 12 hours. The reaction mixture was concentrated at reduced pressure, diluted with cold water and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2504, filtered and concentrated under vacuum. The crude compound waspurified through a Combiflash column using 3% MeOH-DCM as an eluent to afford the titlecompound, 4-(tert-butyl)-N-(6-cyanopyrazolo [1,5 -a]pyrimidin-7-yl)benzenesulfonamide, as awhite solid (58; 0.050 g, 4% yield). ‘H NMR (400 MHz, DMSO-d6): ö 8.58 (s, 1H), 8.09 (d, J= 2.0 Hz, 1H), 7.87-7.84 (d, J = 8.4 Hz, 2H), 7.58-7.56 (d, J = 8.4 Hz, 2H), 6.48 (d, J = 2.0Hz, 1H), 1.29 (s, 9H). MS (M+1): 356.09. (LCMS purity 97.26%, 4.87 mm) (1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine In toluene at 100℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; sodium carbonate In 1,4-dioxane at 70℃; for 12h; Schlenk technique; Inert atmosphere; regioselective reaction; | |
77% | With copper(l) iodide; potassium carbonate; silver carbonate In 1,4-dioxane at 110℃; for 32h; Sealed tube; regioselective reaction; | Typical procedure for the synthesis of sulfonylazoquinolines: General procedure: N-(Quinolin-8-yl)benzamide (1a) (24.8 mg, 0.1 mmol), K2CO3 (27.6 mg, 0.2 mmol), Ag2CO3(27.6 mg, 0.1 mmol), CuI (1.9 mg, 0.01 mmol), p-tolylsulfonylchloride (2a) (57.2 mg, 0.3 mmol), and 1,4-dioxane (2 mL) were successively added to a sealed tube. The mixture was stirred at 110 °C (oil bath temperature) under air for 12 h. After cooling to ambient temperature, the resulting mixture was filtered through a pad of tripolite and washed with 5 mL dichloromethane. The filtrate was concentrated under vacuum and separated on a silica gel column using ethyl acetate/petroleum ether (1:8, v/v) as eluent to give the product 3aa as a white solid (29.0 mg, 72%). |
76% | With copper(l) iodide; potassium carbonate at 100℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h; | 8 Synthesis of the target sulfonate compounds 1a-i General procedure: A solution of compound 4a,b (0.456 mmol) in dry THF (10 mL)was cooled to 0 C, and triethylamine (0.25 mL, 2.47 mmol) wasadded thereto. A solution of the appropriate sulfonyl chloride(0.90 mmol) in dry THF (3 mL) was added dropwise to the reactionmixture at the same temperature. The reaction mixture was stirredat room temperature for 2 h. After reaction completion, the mixturewas quenched with ethyl acetate (10 mL) and water (10 mL).The organic layer was separated, and the aqueous layer wasextracted with ethyl acetate (3 5 mL). The combined organiclayer extract were washed with saline (3 10 mL), and dried overanhydrous sodium sulfate. The organic solvent was evaporatedunder reduced pressure, and the crude residue was purified by columnchromatography (silica gel, appropriate ratio of hexane/ethylacetate) to obtain the pure product. |
85% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h; | 4.2. General method for synthesis of the target sulfonate derivatives 1a-hand 1l-z [13,14] General procedure: was cooled to 0 °C, and triethylamine (0.25 mL, 2.47 mmol) was addedthereto. The appropriate sulfonyl chloride (0.90 mmol) was dissolved indry THF (3 mL), and the solution was added dropwise to the reactionmixture at 0 °C. The reaction mixture was stirred at ambient temperaturefor 2 h. The mixture was quenched with ethyl acetate (10 mL) andwater (10 mL). The organic layer was separated, and the aqueous layerwas extracted with ethyl acetate (3 × 5 mL). The combined organicextracts were washed with saturated saline (3×10 mL), and dried overanhydrous sodium sulfate. The organic solvent was evaporated underreduced pressure, and the crude residue was purified by normal phasecolumn chromatography (silica gel, an appropriate ratio of hexane :ethyl acetate) to isolate pure product. The yield percentages and thespectral data are provided in the supplementary file. |
With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h; | 5.3. General procedure for synthesis of the target sulfonate compounds1a-zk General procedure: The appropriate phenolic intermediate 4a-f (0.456 mmol) was dissolved in dry THF (10 mL), and the mixture was cooled to 0 °C. Triethylamine (0.25 mL, 2.47 mmol) was added thereto. A solution of appropriate sulfonyl chloride (0.912 mmol) in dry THF (2 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 2 h until reaction completion. The mixture was quenched with ethyl acetate (10 mL) and water (10 mL).The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layer extract was washed with saline (3×10 mL) and dried over anhydrous Na2SO4. The organic solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography (silica gel, appropriateratio of hexane: ethyl acetate) to obtain the pure product. The spectral data of compounds 1b and 1f-m have been reported in our previous report48 and those for the other target compounds are reported herein in details |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With triethylamine; In tetrahydrofuran; at 20℃; for 12h; | General procedure: A mixture of sulfonyl chloride (1, 1 equiv), secondary amine (2, 1.5 equiv) and triethylamine (Et3N, 3 equiv) in anhydrous tetrahydrofuran (THF, 0.2 M) was stirred for 12 h at room temperature. Next, the reaction mixture was diluted and filtered with ethyl acetate (EtOAc). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on SiO2 (Hexane: EtOAc: Methylene chloride = 3: 2: 1) to yield sulfonamide analogues (3-25). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With triethylamine; In tetrahydrofuran; at 20℃; for 12h; | General procedure: A mixture of sulfonyl chloride (1, 1 equiv), secondary amine (2, 1.5 equiv) and triethylamine (Et3N, 3 equiv) in anhydrous tetrahydrofuran (THF, 0.2 M) was stirred for 12 h at room temperature. Next, the reaction mixture was diluted and filtered with ethyl acetate (EtOAc). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on SiO2 (Hexane: EtOAc: Methylene chloride = 3: 2: 1) to yield sulfonamide analogues (3-25). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine In dichloromethane at 0℃; | |
80% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; | Experimental procedure for the synthesis of piperazine linked thienopyrimidine derivatives: 13a-h General procedure: Equimolar amounts of intermediate 5 and piperazine ( 10 ,1mmol) was taken into RBF and add the quantity of 10 ml 2- proponal and refluxed for 10-12 h. On cooling intermediate 11 was obtained which was treated with different arylsulphonylchlorides ( 12a-h , 1 mmol) in the presence of DIPEA (1 mmol), DCM at room temperature to acquire 13a-h derivatives. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium carbonate; In water; at 20℃;pH 8;Green chemistry; | General procedure: To gabapentin (1eq, 1.2 mmol) in distilled water (10 ml)sulfonyl chloride, G2-G8 (1eq, 1.2 mmol) was added whilemaintaining the pH of the reaction mixture at 8 by using 3 %aqueous sodium carbonate solution. The consumption of thereactants was confirmed by TLC. Once the reaction wascompleted, the pH of the reaction mixture was adjusted to 3by using 3N HCl. The precipitates formed were washed withplenty of water, dried and crystallized from methanol: ethylacetate (50:50 % v/v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With dmap; triethylamine; In toluene; at 70℃; for 12h; | General procedure: A mixture of the appropriate arylsulfonyl chloride (11.2 mmol), the corresponding arylsulfonamide (12.3 mmol), DMAP (0.274 g, 2.24 mmol), and Et3N (1.95 mL, 14.0 mmol) in toluene (0.5 M) was kept at 70 °C for 12 h (monitored by TLC). The reaction was quenched with aq 2 M HCl (30 mL) to pH 1. The mixture was extracted with EtOAc (3 × 20 mL) and the combined organic layers were dried (anhydrous MgSO4). The solvent was evaporated, and the crude product mixture was purified by recrystallization using hot CHCl3/hexane to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With water; sodium carbonate; eosin y In acetonitrile at 100℃; for 20h; Schlenk technique; Irradiation; Inert atmosphere; | 2.2 Typical Experimental Procedure for the visible-light-mediated synthesis of3-sulfonylspiro[4,5]trienones from propiolamides and sulfonyl chlorides General procedure: To a Schlenk tube were added 1 (0.2 mmol), 2 (1.5 eqiuv, 0.3 mmol), Eosin Y (2mol %, 0.004 mmol), Na2CO3 (2 eqiuv, 0.4 mmol), H2O (4.0 equiv, 0.8 mmol) CH3CN (2 mL). Then the mixture was stirred at 100 °C (oil bath temperature) in argon atmosphere (1 atm) under 5 W blue LED light for 20 h until complete consumption of starting material as monitored by TLC and GC-MS analysis. After the reaction was finished, the reaction mixture was washed with brine. The aqueous phase was re-extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuum. The residue was purified by silica gel flash column chromatography (hexane/ethyl acetate = 3 : 1 to 1 : 1) to afford the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In methanol; at 20℃; | General procedure: Solutions of selected methyl ketones (2 mmol) in methanol(6 mL) were stirred and corresponding sulfonylchlorides (2.4 mmol) were added. Then, triethylamine(0.6 mL) was added dropwise. The mixtures were stirredovernight at room temperature. After completion of thereactions, mixtures were poured into iced water withstirring. In some cases (for our compounds 7f, 7g, 8e, 8f,8g, and 9g; see below), the formed precipitate was filteredand washed with cold diethyl ether. In other cases, whenno precipitate formed, the organic layer was extractedwith dichloromethane (3 × 50 mL), dried over anhydrousNa2SO4 and evaporated under vacuum. The residue waspurified by short column chromatography on silica gel,using dichloromethane as eluent. The oil obtained usuallycrystallized; if not, the oily residue was dissolved indiethyl ether from which products crystallized on standingin a deepfreeze. Crude products were washed with coldether, and 21 pure, mostly white crystals were obtained, asfollows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h; | 5.3. General procedure for synthesis of the target sulfonate compounds1a-zk General procedure: The appropriate phenolic intermediate 4a-f (0.456 mmol) was dissolved in dry THF (10 mL), and the mixture was cooled to 0 °C. Triethylamine (0.25 mL, 2.47 mmol) was added thereto. A solution of appropriate sulfonyl chloride (0.912 mmol) in dry THF (2 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 2 h until reaction completion. The mixture was quenched with ethyl acetate (10 mL) and water (10 mL).The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layer extract was washed with saline (3×10 mL) and dried over anhydrous Na2SO4. The organic solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography (silica gel, appropriateratio of hexane: ethyl acetate) to obtain the pure product. The spectral data of compounds 1b and 1f-m have been reported in our previous report48 and those for the other target compounds are reported herein in details |
76% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h; | 4.2. General method for synthesis of the target sulfonate derivatives 1a-hand 1l-z [13,14] General procedure: was cooled to 0 °C, and triethylamine (0.25 mL, 2.47 mmol) was addedthereto. The appropriate sulfonyl chloride (0.90 mmol) was dissolved indry THF (3 mL), and the solution was added dropwise to the reactionmixture at 0 °C. The reaction mixture was stirred at ambient temperaturefor 2 h. The mixture was quenched with ethyl acetate (10 mL) andwater (10 mL). The organic layer was separated, and the aqueous layerwas extracted with ethyl acetate (3 × 5 mL). The combined organicextracts were washed with saturated saline (3×10 mL), and dried overanhydrous sodium sulfate. The organic solvent was evaporated underreduced pressure, and the crude residue was purified by normal phasecolumn chromatography (silica gel, an appropriate ratio of hexane :ethyl acetate) to isolate pure product. The yield percentages and thespectral data are provided in the supplementary file. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h; | 5.3. General procedure for synthesis of the target sulfonate compounds1a-zk General procedure: The appropriate phenolic intermediate 4a-f (0.456 mmol) was dissolved in dry THF (10 mL), and the mixture was cooled to 0 °C. Triethylamine (0.25 mL, 2.47 mmol) was added thereto. A solution of appropriate sulfonyl chloride (0.912 mmol) in dry THF (2 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 2 h until reaction completion. The mixture was quenched with ethyl acetate (10 mL) and water (10 mL).The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layer extract was washed with saline (3×10 mL) and dried over anhydrous Na2SO4. The organic solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography (silica gel, appropriateratio of hexane: ethyl acetate) to obtain the pure product. The spectral data of compounds 1b and 1f-m have been reported in our previous report48 and those for the other target compounds are reported herein in details |
90% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h; | 4.2. General method for synthesis of the target sulfonate derivatives 1a-hand 1l-z [13,14] General procedure: was cooled to 0 °C, and triethylamine (0.25 mL, 2.47 mmol) was addedthereto. The appropriate sulfonyl chloride (0.90 mmol) was dissolved indry THF (3 mL), and the solution was added dropwise to the reactionmixture at 0 °C. The reaction mixture was stirred at ambient temperaturefor 2 h. The mixture was quenched with ethyl acetate (10 mL) andwater (10 mL). The organic layer was separated, and the aqueous layerwas extracted with ethyl acetate (3 × 5 mL). The combined organicextracts were washed with saturated saline (3×10 mL), and dried overanhydrous sodium sulfate. The organic solvent was evaporated underreduced pressure, and the crude residue was purified by normal phasecolumn chromatography (silica gel, an appropriate ratio of hexane :ethyl acetate) to isolate pure product. The yield percentages and thespectral data are provided in the supplementary file. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.9% | With triethylamine; In dichloromethane; at 25℃; for 4h; | General procedure: To a mechanically stirred suspension of suspension of 1 (0.21 g, 0.53 mmol) in 30 ml CH2Cl2 were added triethylamine (0.5 ml) and aromatic sulfonyl chloride (0.53 mmol) at 25 C for 4 h. The reaction process was detected by TLC method. Then, antagonized by dilute sodium hydroxide, extracted, and washed with ether and water, evaporated under vacuum. Finally, the mixture was recrys-tallizated from ethyl acetate , providing a total product yield of 65.4%-88.6 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In water; at 20℃; | General procedure: A suspension of amine A1-A3 (1 mmol) in water is takenin a round bottomed flask; to this sulphonyl chloride(1 mmol) was added. This was stirred at room temperature while monitoring the reaction. The product was filtered,recrystallised using methanol-water and column purified.The structures were confirmed by 1H NMR, 13C NMR, IRand mass spectral analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; triethylamine In dichloromethane at 20℃; for 1h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With palladium diacetate; lithium carbonate; In 1,4-dioxane; at 140℃; for 16h;Inert atmosphere; Schlenk technique; | General procedure: To a 25 mL oven dried Schlenk tube, benzenesulfonyl chloride (1.5 mmol), Methoxalen (0.216 g, 1 mmol), Li2CO3 (0.148 g, 2 mmol), 1,4-dioxane (2 mL) and Pd(OAc)2 (11.2 mg, 0.05 mmol) were successively added. The reaction mixture was evacuated by vacuum-argon cycles (5 times) and stirred at 140 C (oil bath temperature) for 16 hours. After cooling the reaction at room temperature and concentration, the crude mixture was purified by silica column chromatography to afford the C2-arylated Methoxalen. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triethylamine; In dichloromethane; at 20℃; for 6h; | General procedure: To a solution of <strong>[204255-11-8]oseltamivir phosphate</strong> (0.82 g, 2.0 mmol), 10 mLof triethylamine and 30 mL of acetonitrile or dichloromethane,arylsulfonyl chloridewas added (1.2 equiv.) The mixturewas stirredat room temperature for 6 h. After confirming the completion of thereaction by TLC, the solvent was evaporated under reduced pressure.Sodium chloride solution (30 mL) was added to the residueand extracted with ethyl acetate (3 40 mL). The combined organiclayer was washed twice with saturated sodium chloride (30 mL).And dried with anhydrous MgSO4, Then, filtered and the solventwas removed, the crude product was obtained, and purified bycolumn chromatography to obtain the corresponding intermediates16a-16g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine In dichloromethane at 20℃; | 3.2. General procedure for the synthesis of sulfonate derivatives of carvacroland thymol (3a-p and 4a-p) General procedure: To a solution of carvacrol/thymol (1/2, 1.0 mmol) and ethanesulfonyl chloride/arylsulfonylchloride (5, 1.2 mmol) in dry dichloromethane (CH2Cl2, 10 ml) at room temperature,a solution of triethylamine (Et3N) (1.5 mmol) in dry CH2Cl2 (5 ml) wasadded dropwise for 10 min. When the reaction was completed by TLC analysis, thereaction mixture was diluted with water (15 ml), and extracted with CH2Cl2 (30 ml 3). Subsequently, the combined organic phase was washed by saturated aq. brine(30 ml), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silicagel column chromatography to afford title compounds in 40-97% yields. The data for3a-p and 4a-p are shown as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | at 20℃; for 24h;Cooling with ice; Inert atmosphere; | General procedure: The acid or sulfonyl chloride (1.0-1.1 equiv.) was added in one go to an ice-cooled solution of the appropriate amine or amine hydrochloride (1.0-1.1 equiv.) and diisopropylethylamine, triethylamine or pyridine (2.0-3.0 equiv.) in CH2Cl2 or chloroform (0.1-0.2M) and stirred at RT. After 24h, the reaction was quenched with 1M HCl. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered and concentrated in vacuo, and column chromatography isolated the target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With palladium diacetate; silver(l) oxide; Trimethylacetic acid In 1,2-dichloro-ethane at 110℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0 - 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-chloro-succinimide In acetonitrile at 20℃; for 2h; | 4.2. General Procedure for Synthesis of Sulfonyl Chloride 3 or Sulfonyl Bromide 4 General procedure: N-Chlorosuccinimide 2a or N-bromosuccinimide 2b (0.6 mmol, 2.0 equiv) was addedto a solution of sulfonyl hydrazide 1 (0.3 mmol) in CH3CN (2 mL) in one portion. Themixture was stirred at room temperature for 2 h. The solvent was removed, and the residuewas purified by flash column chromatography (petroleum ether/ethyl acetate) to providethe corresponding sulfonyl chloride 3 or sulfonyl bromide 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine at 70℃; for 3h; | General Procedure for the preparation of compound 2 and 4: General procedure: To a solution of 3-iodopyridine-2-amine (6) (1.0 mmol) in pyridine (2.0 mmol) was added substituted benzenesulfonylchloride (7) (1.2 mmol) at 70 °C and the mixture was stirred for 3 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was neutralized with dil. H2SO4 (1.0 mmol), washed with cold water (20 mL) and then extracted with ethylacetate (3 x 15 mL). The organic layers were collected, combined, dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The residue obtained was washed with n-hexane to give desired product 2. | |
With pyridine at 70℃; for 3h; | General Procedure for the preparation of compound 2 and 4: General procedure: To a solution of 3-iodopyridine-2-amine (6) (1.0 mmol) in pyridine (2.0 mmol) was added substituted benzenesulfonylchloride (7) (1.2 mmol) at 70 °C and the mixture was stirred for 3 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was neutralized with dil. H2SO4 (1.0 mmol), washed with cold water (20 mL) and then extracted with ethylacetate (3 x 15 mL). The organic layers were collected, combined, dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The residue obtained was washed with n-hexane to give desired product 2. |
Tags: 15084-51-2 synthesis path| 15084-51-2 SDS| 15084-51-2 COA| 15084-51-2 purity| 15084-51-2 application| 15084-51-2 NMR| 15084-51-2 COA| 15084-51-2 structure
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P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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