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CAS No. : | 88-19-7 | MDL No. : | MFCD00007934 |
Formula : | C7H9NO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YCMLQMDWSXFTIF-UHFFFAOYSA-N |
M.W : | 171.22 | Pubchem ID : | 6924 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 42.4 |
TPSA : | 68.54 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.75 cm/s |
Log Po/w (iLOGP) : | 1.11 |
Log Po/w (XLOGP3) : | 0.84 |
Log Po/w (WLOGP) : | 1.72 |
Log Po/w (MLOGP) : | 0.63 |
Log Po/w (SILICOS-IT) : | 0.4 |
Consensus Log Po/w : | 0.94 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.77 |
Solubility : | 2.92 mg/ml ; 0.017 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.86 |
Solubility : | 2.35 mg/ml ; 0.0137 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.35 |
Solubility : | 0.774 mg/ml ; 0.00452 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.62 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H319 | Packing Group: | N/A |
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 |
---|---|---|
18% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 18 h; | 3-[2-Methoxy-4-(toluene-2-sulfonylaminocarbonyl)-benzyl]-1-methyl-1H-indol-5-yl)carbamic acid cyclopentyl ester: Under a nitrogen atmosphere, a mixture of 4-(5-cyclolpentyloxycarbonylamino-1-methyl-1H-indol-3-ylmethyl)-3-methoxy-benzoic acid (800 mg, 1.9 mmol), toluene-2-sulfonamide (341 mg, 2 mmol), 4-(dimethylamino)pyridine (244 mg, 2 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (384 mg, 2 mmol) was dissolved in dichloromethane (30 mL). The mixture was stirred at ambient temperature for about 18 hours, and then poured into 1 M hydrochloric acid (100 mL). Following standard extractive workup with chloroform, the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=2/1, v/v, elution) to afford the title compound (200 mg, 18percent). 1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.29 (d, 1H, J=8.1 Hz), 7.55-7.22 (m, 9H), 6.81 (s, 1H), 6.50 (s, 1H), 5.23 (s, 1H), 4.08 (s, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 2.71 (s, 3H), 1.96-1.76 (m, 8H); LC-MS: m/z=576 (MH)+; HPLC: 99percent (Purity). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; water | ||
With ammonia aus p-Toluolsulfochlorid enthaltendem Edukt1 mit gasfoermigem oder fluessigem Edukt2 und Entfernen aus dem Rohamid des Chlorammoniums durch wenig kaltes Wasser; | ||
With ammonium hydroxide; sodium hydroxide In water | 3 Preparation of Toluenesulfonamide from Crude Unrefined Chlorosulfonation Reaction Product Using Sodium Hydroxide to Neutralize Acids EXAMPLE 3 Preparation of Toluenesulfonamide from Crude Unrefined Chlorosulfonation Reaction Product Using Sodium Hydroxide to Neutralize Acids A 1160.4 gms portion of the crude chlorosulfonation reaction product of Example 1 was added to a stirred solution of 303 gms of ammonium hydroxide (28-30% ammonia), 100 g of 50% NaOH and 750 ml of water at 50°-55° C. until the pH reached 9, and then more 50% NaOH was added simultaneously, keeping the pH at 9.0-9.5, during the remainder of the chlorosulfonation addition. The amidation reaction mixture was warmed at 50°-55° C. with the pH at 9.0 for 0.5 hour, and then it was cooled to 20° C., filtered, and the solid was washed and dried as in Example 2, giving 313.3 gms of toluenesulfonamide mixture having a proton NMR and GC analysis essentially identical to the product obtained by the ammonia neutralization process of Example 2. |
With ammonium hydroxide In acetonitrile at 0 - 20℃; for 1h; Inert atmosphere; | Compound 11: General procedure for sulfonamide preparation General procedure: In a 50 ml RB flask, sulfonyl chloride (500 mg) was taken in acetonitrile (5 ml) and the solution was cooled to 0 deg. Cel. To this aqueous ammonia solution (1.5 ml) was added dropwise. RM was then stirred at RT for 1 hr. RM was evaporated to dryness and the residue was then trichirated with minimum water and suspension was filtered and solid was dried to get the sulfonamide as solid. | |
Multi-step reaction with 2 steps 1: sodium hydroxide 2: copper(II) oxide; oxygen / dimethyl sulfoxide / 8 h / 100 °C | ||
With ammonium hydroxide In acetone at 20℃; for 0.5h; | 230A Methylbenzenesulfonamide [00325] To a solution of 2-methylbenzene-l-sulfonyl chloride (1.0 g, 5.5 mmol) and in acetone (10 mL) was added ammonium hydroxide (2 mL). The reaction mixture was stirred at room temperature for 30 min. After concentration, the reddish residue was dissolved in DCM, washed with saturated NaHC03 and brine, dried over MgS04 and concentrated to obtain a reddish solid | |
With ammonium hydroxide In water for 1h; Reflux; | ||
With ammonia | ||
With hydroxylamine In acetonitrile at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25 - 35℃; | |
69% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 18h; | |
18% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 18h; | 1.8 3-[2-Methoxy-4-(toluene-2-sulfonylaminocarbonyl)-benzyl]-1-methyl-1H-indol-5-yl)carbamic acid cyclopentyl ester: Under a nitrogen atmosphere, a mixture of 4-(5-cyclolpentyloxycarbonylamino-1-methyl-1H-indol-3-ylmethyl)-3-methoxy-benzoic acid (800 mg, 1.9 mmol), toluene-2-sulfonamide (341 mg, 2 mmol), 4-(dimethylamino)pyridine (244 mg, 2 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (384 mg, 2 mmol) was dissolved in dichloromethane (30 mL). The mixture was stirred at ambient temperature for about 18 hours, and then poured into 1 M hydrochloric acid (100 mL). Following standard extractive workup with chloroform, the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=2/1, v/v, elution) to afford the title compound (200 mg, 18%). 1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.29 (d, 1H, J=8.1 Hz), 7.55-7.22 (m, 9H), 6.81 (s, 1H), 6.50 (s, 1H), 5.23 (s, 1H), 4.08 (s, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 2.71 (s, 3H), 1.96-1.76 (m, 8H); LC-MS: m/z=576 (MH)+; HPLC: 99% (Purity). |
With dmap; dicyclohexyl-carbodiimide In methanol; dichloromethane at 30℃; for 4h; | 9 Preparation Zafirlukast Acetonitrile Solvate (Formula IA) {3-[2-methoxy-4-carboxy-benzyl]-1-methyl-1H-indol-5-yl}-carbamic acid cyclopentyl ester (7 kg), dimethyl amino pyridine (2.5 kg), dicyclohexyl carbodiimide (3.9 kg), and dichloromethane (70 L) are charged and stirred for about 15 minutes. O-toluene sulphonamide (3.4 kg) is added at 30° C. and the reaction solution is stirred for about 4 hours at 30° C. The unwanted separated solid is filtered and the reaction solution is washed with dichloromethane (2×12 L). The obtained organic layer is washed with dilute hydrochloric acid and water and separated. The obtained organic solution is distilled off completely under vacuum below 45° C. Acetonitrile (14 L) is added and distilled off completely under vacuum. The obtained crude is cooled to 30° C., acetonitrile (35 L) is added and heated to 85° C., and stirred for about 40 minutes. The resultant reaction solution is cooled to 35° C. and stirred for about 55 minutes. The separated solid is filtered, washed with acetonitrile (7 mL), and suction dried for about 30 minutes. The obtained wet compound is again charged into a reactor containing methanol (84 L), heated to about 60° C., and stirred for about 30 minutes. The reaction solution is cooled to 30° C. and stirred for about 50 minutes for solid separation. The obtained solid is filtered, washed with methanol (7 L), and suction dried for 30 minutes. The solid is dried under vacuum at 70° C. for about 4 hours to afford the title compound.HPLC Purity: 97.5% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-sulfinyl-O-(tert-butyl)hydroxylamine In tetrahydrofuran at -78 - 20℃; for 18h; Inert atmosphere; | |
(i) SO2Cl2, (ii) aq. NH3; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In water at 150℃; for 0.5h; Microwave irradiation; | |
89% | With p-toluenesulfonic acid monohydrate In toluene at 20 - 100℃; for 0.5h; Inert atmosphere; | |
88% | With trifluorormethanesulfonic acid In dichloromethane at 20℃; for 2h; |
87% | With montmorillonite K-10 at 100℃; for 0.05h; microwave irradiation; | |
With acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With dmap; triethylamine In dichloromethane for 4h; | |
75% | With dmap; triethylamine In dichloromethane at 20℃; | |
With dmap; triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere; |
7.0 g (88%) | With dmap; sodium monohydrogen sulfate; triethylamine In dichloromethane | 19.A A. A. Preparation of N-t-butoxycarbonyl-2-methylbenzenesulfonamide: To a solution of 5.0 g (29.2 mmol) of 2-methylbenzenesulfonamide, 3.2 g (32.1 mmol) of triethylamine, and 0.35 g (2.9 mmol) of 4-dimethylaminopyridine in 100 mL of dichloromethane was added 7.0 g (32.1 mmol) of di-tert-butyl dicarbonate. The reaction was stirred at ambient temperature for 18 hours and was then washed with a 50 mL of a 10% aqueous solution of sodium hydrogen sulfate and 50 mL of brine. The organic layer was removed and dried over magnesium sulfate, filtered, and concentrated under vacuo to afford 7.0 g (88%) of the title compound. Negative ion electrospray mass spectrum: [M-H]-=270. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: 2,5-dimethylbenzoic acid With lithium diisopropyl amide In tetrahydrofuran at 0℃; Stage #2: methyl 2-(aminosulfonyl)benzoate In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With zinc(II) chloride at 23℃; | |
94% | With zinc(II) chloride at 20℃; | |
82% | With zinc(II) chloride at 50℃; |
60% | With pyridine; dmap at 25℃; for 6h; | |
With zinc(II) chloride at 23℃; Inert atmosphere; Schlenk technique; | ||
With zinc(II) chloride at 20℃; | ||
With zinc(II) chloride at 23℃; | ||
With zinc(II) chloride at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyrrolidine In chloroform at 60℃; for 24h; Molecular sieve; | |
83% | Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyrrolidine In chloroform at 60℃; for 24h; Molecular sieve; | |
61% | Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl 2-(aminosulfonyl)benzoate; 4-[4-(5-methoxypyridin-2-yl)phenylamino]methyl}-5-methylfuran-2-carboxylic acid hydrochloride With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 16h; Stage #2: With triethylamine In tetrahydrofuran for 18h; | 39.e A suspension of 4-[4-(5-methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carboxylic acid hydrochloride salt (166) (30mg, 0.08mmoles) in tetrahydrofuran (5ml) was treated with toluene-2-sulphonamide (41mg, 0.24mmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34mg, 0.176mmoles) and 4-(N,N-dimethylamino)-pyridine (10mg, 0.08mmoles) and the mixture stirred at room temperature for 16 hours. Triethylamine (24.3mg, 0.24mmoles) was added and the mixture was stirred for a further 18 hours. The reaction mixture was concentrated and the residue was purified by HPLC to afford compound 167 as a yellow glass (1.1mg)). LC/MS System A ; Rt = 2.72mins, m/z (ES+) = 492 (M+H for C26H25N3O5S) and m/z (ES-) = 490 (M-H for C26H25N3O5S). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; acetonitrile at 20℃; for 18h; | 41.c A stirred solution of 4-[(4'-difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylic acid (176) (21mg, 0.054mmoles), 2-methyl-benzenesulphonamide (19mg, 0.108mmoles) and 4-(N,N-dimethylamino)-pyridine (1mg) in a mixture of dichloromethane (8ml) and acetonitrile (2ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.4mg, 0.060mmoles). The mixture was stirred at room temperature for 18 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 177 (2.9mg) as a solid. LC/MS System D; Rt = 11.21mins, m/z (ES+)-541 (M+H for C28H26F2N2O5S). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1.5h; | 12 o-Tolylsulfonamide (51 mg, 0.30 mmd), DMAP (22 mg, 0.18 mmd), and EDCI (58 mg, 0.30 mmol) were added to a mixture of (4S)-4-[4-Methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-2-pyrrolidone-l -acetic acid (50 mg, 0.15 mmol) in DMF (3 mL). After stirring for 90 minutes at room temperature the reaction was diluted with ethyl acetate (60 mL) and washed with IM HCl, water (30 mL) and brine (30 mL). The organic solvent was dried over sodium sulfate and evaporated to provide 92 mg of an amber oil. The oil was purified by HPLC using a Cl 8 column (5 um; 30x100 mm) and a gradient of 20-80% acetonitrile/water (0.1% formic acid) over 6 minutes. The fraction at 4 minutes was collected and concentrated to afford 25 mg (35%) of (45)-4-(4-methoxy-3- (3i?)-tetrahydrofuranyloxyphenyl)- 1 - [N-(2-methylpheny l)sulfony laminocarbonylmethyl] - 2-pyrrolidone as a white solid. 1H NMR (CDCl3; 300 MHz) 9.6 (br s, IH); 8.2 (d, IH); 7.5 (t, IH); 7.2-7.4 (m, 2H); 6.7-6.9 (m, 3H); 5.0 (br s, IH); 3.8-4.1 (m, 9H); 5.5-3.7 (m, 2H); 2,9 (m,2H); 2.5-2.7 (m, 4H); 2.2 (m,2H). MS [M+H] = 489. |
35% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20℃; for 1.5h; | 12 (4S)-4- [4-METHOXY-3- (3R)-TETRAHYDROFURANYLOXYPHENYL]-2-PYRROLIDONE-1-ACETIC acid (50 mg; 0.15 mmol) was stirred in DMF (3 mL) followed by addition OF O- tolylsulfonamide (51 mg; 0.30 MMOL), DMAP (22 mg; 0. 18 mmol), and EDCI (58 mg; 0.30 mmol). After stirring for 90 minutes at room temperature the reaction was diluted with ethyl acetate (60 ML) and washed with 1M HCl, 30 ML of water and 30 mL of brine. The organic solvent was dried over sodium sulfate and evaporated to provide 92 mg of an amber oil. The compound was purified by hplc using a C 18 column (5 um; 30X100 MM) and a gradient of 20-80% acetonitrile/water (0. 1% formic acid) over 6 minutes. A fraction at 4 minutes was concentrated to afford 25 mg (35% yield) of (4S)-4- (4-METHOXY-3-(3R)-TETRAHYDROFURANYLOXYPHENYL)-1-[N-(2- methylphenyl) sulfonylaminocarbonylmethyl]-2-pyrrolidone as a white SOLID. 1H NMR (CDC13 ; 300 MHz) 9.6 (br s, 1H) ; 8.2 (d, 1H) ; 7.5 (t, 1H) ; 7.2-7. 4 (m, 2H); 6.7-6. 9 (M, 3H); 5.0 (br s, 1H); 3.8-4. 1 (m, 9H); 5.5-3. 7 (m, 2H); 2,9 (m, 2H); 2.5-2. 7 (m, 4H); 2.2 (m, 2H). MS [M+H] =489. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With dmap; ammonium chloride In dichloromethane | 102.1 N-[1-benzhydryl-3-([(2-methylphenyl)sulfonyl]amino}carbonyl)-1H-indol-5-yl]cyclopentanecarboxamide Step 1: The acid chloride (1.0 eq) synthesised in step 1, Example 101, was weighed into a flask along with o-tolylsulfonamide (1.5 eq), DMAP (0.1 eq) and taken up in dichloromethane (0.1M) under nitrogen and then triethylamine (1.5 eq) was added and the resulting mixture was stirred for 12 hours and then worked up by the addition of 1/2 saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried and concentrated and purified via chromatography to yield the desired acylsulfonamide in 52% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap In dichloromethane | 28 4-(1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl-3-methoxy-N-o-tolylsulfonylbenzamide An analytical sample was attained by recrystallization from ethyl acetate/hexanes. To a solution of 4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (1.10 grams, 2.37 mmol), 4-dimethylaminopyridine (0.44 grams, 3.63 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1,2-dichloroethane) (0.70 grams, 3.64 mmol) in methylene chloride (100 mL) was added o-tolylsulfonamide (0.41 grams, 2.42 mmol). The resulting solution was stirred for 16 hours at room temperature. The solution was diluted with methylene chloride and washed with 1 M hydrochloric acid (ag) and brine. The organics were dried over sodium sulfate and concentrated. Chromatography on silica gel (5% methanol/methylene chloride gave 4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide (1.10 grams, 76% yield). HRMS calcd. for C31 H31 N3 O6 F2 S: 611.1902. Found: 611.1924. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With Wilkinson's catalyst; potassium carbonate at 120℃; for 12h; Sealed tube; | |
92% | With potassium carbonate; benzaldehyde at 135℃; for 18h; Schlenk technique; Green chemistry; | |
86% | With tris(triphenylphosphine)rhodium(l) chloride; potassium carbonate at 135℃; for 36h; |
86% | With [Mn(HN(C2H4PiPr2)2)(CO)2Br]; potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene at 150℃; for 24h; Sealed tube; | |
84% | With palladium diacetate; potassium carbonate In neat (no solvent) at 135℃; for 24h; Sealed tube; | |
83% | With [(η5-C5Me5)Ir(6,6'-dihydroxy-2,2'-bipyridine)(H2O)]OTf2; caesium carbonate In water at 120℃; for 15h; Inert atmosphere; Schlenk technique; | |
83% | With [(η5-C5Me5)Ir(6,6'-dihydroxy-2,2'-bipyridine)(H2O)]OTf2; caesium carbonate In water at 120℃; for 15h; Schlenk technique; | 20 Example 20: N- benzyl-2-methyl-benzenesulfonamide 2-methyl-benzenesulfonamide (171mg, 1mmol), catalyst A (8.3mg, 0.01mmol, 1mol%), cesium carbonate (33mg, 0.1mmol, 0.1equiv.), Benzyl alcohol (130mg, 1.2mmol) and water (1ml) were successively added to the reaction flask 25mlSchlenk.After the reaction mixture was reacted at 120 15 hours, cooled to room temperature.The solvent was removed by filtration, and then purified by column chromatography (developing solvent: ethyl acetate / petroleum ether) to give pure title compound Yield: 83% |
80% | With [(η5-pentamethylcyclopentadienyl)Ir(2,2'-biimidazole)(H2O)][OTf]2; caesium carbonate In water at 130℃; for 2h; Microwave irradiation; Inert atmosphere; Sealed tube; | |
80% | With [(η5-pentamethylcyclopentadienyl)Ir(2,2'-biimidazole)(H2O)][OTf]2; caesium carbonate In water at 130℃; for 2h; | 15 N-benzyl-2-methylbenzenesulfonamide Combine 2-methylbenzenesulfonamide (171mg, 1mmol),Catalyst (7.7mg, 0.01mmol, 1mol%),Cesium carbonate (33mg, 0.1mmol, 0.1equiv.),Benzyl alcohol (130mg, 1.2mmol)Water (1ml) was sequentially added to the microwave tube.After the reaction mixture was reacted at 130°C for 2 hours,Cool to room temperature.Rotary evaporation to remove the solvent,Then through column chromatography (developer:Petroleum ether/ethyl acetate) to obtain pure target compound,Yield: 80%. |
94 %Chromat. | With manganese(IV) oxide; potassium carbonate at 135℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With trifluorormethanesulfonic acid; silica gel In water; toluene at 85℃; for 20h; | Typical procedure for the hydroamination of alkenes with sulfonamides catalyzed by the in situ silica gel adsorbed TfOH General procedure: The toluene (2 mL) suspension of silica gel (200-300 mesh, 0.1 g), TfOH (7.7 mg, 0.05 mmol) and water (20 μL) was stirred in a test-tube at room temperature for 30 min. Then alkene (2 mmol or 4 mmol) and sulfonamide (1 mmol) were added to the suspension and the reaction mixture was stirred at 70 oC (or 85 oC). The course of the reaction was monitored by TLC. After the completion of the reaction, the mixture was cooled to room temperature and the reactor was centrifuged (2000 r/min) for 2 min and the solution was removed by syringe. The catalyst was then washed with toluene (1 mL) twice with the same procedure and a new reaction was carried out by adding the new batch of alkene (2 mmol), sulfonamide (1 mmol) and toluene (2 mL) to the recovered catalyst. The solution containing the product was purified through a silica gel flash column to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With trifluorormethanesulfonic acid; silica gel In water; toluene at 85℃; for 20h; | Typical procedure for the hydroamination of alkenes with sulfonamides catalyzed by the in situ silica gel adsorbed TfOH General procedure: The toluene (2 mL) suspension of silica gel (200-300 mesh, 0.1 g), TfOH (7.7 mg, 0.05 mmol) and water (20 μL) was stirred in a test-tube at room temperature for 30 min. Then alkene (2 mmol or 4 mmol) and sulfonamide (1 mmol) were added to the suspension and the reaction mixture was stirred at 70 oC (or 85 oC). The course of the reaction was monitored by TLC. After the completion of the reaction, the mixture was cooled to room temperature and the reactor was centrifuged (2000 r/min) for 2 min and the solution was removed by syringe. The catalyst was then washed with toluene (1 mL) twice with the same procedure and a new reaction was carried out by adding the new batch of alkene (2 mmol), sulfonamide (1 mmol) and toluene (2 mL) to the recovered catalyst. The solution containing the product was purified through a silica gel flash column to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With silica gel supported triflic acid In toluene at 85℃; for 20h; | Typical procedure for the hydroamination of alkenes with sulfonamides catalyzed by the prepared TfOH-SiO2 General procedure: The prepared TfOH-SiO2 (60 mg, containing 0.05 mmol TfOH) was added to the toluene (2 mL) solution of alkene (2 mmol or 4 mmol) and sulfonamide (1 mmol) and the reaction mixture was stirred at 70 oC (or 85 oC). The course of the reaction was monitored by TLC. After the completion of the reaction, the mixture was cooled to room temperature and the reactor was centrifuged (2000 r/min) for 2 min and the solution was removed by syringe. The catalyst was then washed with toluene (1 mL) twice with the same procedure and a new reaction was carried out by adding the new batch of alkene (2 mmol), sulfonamide (1 mmol) and toluene (2 mL) to the recovered catalyst. The solution containing the product was purified through a silica gel flash column to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With silica gel supported triflic acid In toluene at 85℃; for 20h; | Typical procedure for the hydroamination of alkenes with sulfonamides catalyzed by the prepared TfOH-SiO2 General procedure: The prepared TfOH-SiO2 (60 mg, containing 0.05 mmol TfOH) was added to the toluene (2 mL) solution of alkene (2 mmol or 4 mmol) and sulfonamide (1 mmol) and the reaction mixture was stirred at 70 oC (or 85 oC). The course of the reaction was monitored by TLC. After the completion of the reaction, the mixture was cooled to room temperature and the reactor was centrifuged (2000 r/min) for 2 min and the solution was removed by syringe. The catalyst was then washed with toluene (1 mL) twice with the same procedure and a new reaction was carried out by adding the new batch of alkene (2 mmol), sulfonamide (1 mmol) and toluene (2 mL) to the recovered catalyst. The solution containing the product was purified through a silica gel flash column to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With silica gel supported triflic acid In toluene at 85℃; for 20h; | Typical procedure for the hydroamination of alkenes with sulfonamides catalyzed by the prepared TfOH-SiO2 General procedure: The prepared TfOH-SiO2 (60 mg, containing 0.05 mmol TfOH) was added to the toluene (2 mL) solution of alkene (2 mmol or 4 mmol) and sulfonamide (1 mmol) and the reaction mixture was stirred at 70 oC (or 85 oC). The course of the reaction was monitored by TLC. After the completion of the reaction, the mixture was cooled to room temperature and the reactor was centrifuged (2000 r/min) for 2 min and the solution was removed by syringe. The catalyst was then washed with toluene (1 mL) twice with the same procedure and a new reaction was carried out by adding the new batch of alkene (2 mmol), sulfonamide (1 mmol) and toluene (2 mL) to the recovered catalyst. The solution containing the product was purified through a silica gel flash column to afford the product. |
59% | With iron(III) chloride; silver hexafluoroantimonate In 1,2-dichloro-ethane at 40℃; for 18h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With tert.-butylhydroperoxide; sodium iodide In water at 90℃; for 3h; | |
87% | With N-Bromosuccinimide; water at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine In acetonitrile at 70℃; for 14h; Inert atmosphere; | General procedure General procedure: Inside a N2 filled glovebox, benzenesulfonamide (250 mg, 1.590 mmol) and copper(I) iodide (15.14 mg, 0.080 mmol), 4-toluene bromide (326mg, 1.91 mmol), potassium carbonate (550 mg, 3.98 mmol), Acetonitrile (4 mL), and N1,N2dimethylethane-1,2-diamine (70.1 mg, 0.795 mmol) was charged into a vial. The vial was then heated to 70 oC for 8hr, LC indicated >97% conversion of benzenesulfonamide. The reaction mixture was then cooled to room temperature. 2N HCl (4mL) was added slowly, followed by EtOAc extraction (5mL x 3). The organic layers were combined, concentrated, and flash chromatographed (SiO2, 20:1--> 3:1 Heptane:EtOAc) to give N(p-tolyl) benzene sulfonamide as white solids (380 mg, 97%). |
> 95 %Chromat. | With (PhPAd-DalPhos)NiCl(o-tol); sodium t-butanolate In tetrahydrofuran at 80℃; for 18h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 1.16667h; regioselective reaction; | 2 4.2 N-(1,1,1-Trifluoro-3-(phenylprop-2-ynyloxy)propan-2-yl)toluenesulfonamide (4a) General procedure: A 25 mL two-necked flask equipped with a magnetic stir bar, a stopcock, and a three-way stopcock, was charged with 3-phenyl-2-propyn-1-ol 2a (26.0 mL, 0.21 mmol) and tBuOK (23.4 mg, 0.21 mmol) in DMSO (1 mL). After stirring for 10 min, to this mixture was added 2-CF3-N-Ts-aziridine 1 (50.8 mg, 0.19 mmol) and the mixture was stirred for 1 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution. The aqueous layer was extracted with hexane/EtOAc=3/1. An additional extraction was repeated twice. The combined organic solution was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting oily residue was purified by column chromatography (silica gel, hexane/EtOAc=3/1) to give 4a as a white solid (61.1 mg, 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 4-(1-methyl-5-nitro-indol-3-yl-methyl)-3-methoxy-benzoic acid With benzoic acid anhydride; zinc(II) chloride In dichloromethane at 20℃; for 0.166667h; Inert atmosphere; Stage #2: methyl 2-(aminosulfonyl)benzoate In dichloromethane at 20℃; for 2h; Inert atmosphere; | 12 3-Methoxy-4-(1-methyl-5-nitro-1H-indole-3-carbonyl)-N-(o-tolylsulfonyl) benzamide (IIe) To a stirred solution of anhydrous ZnCl2 (2 mg, 30 mol%) in anhydrous dichloromethane (2 ml), carboxylic acid compound of formula Hie (300 mg, 0.88 mmol) was added followed by the addition of benzoic anhydride (0.12 ml, 1.05 mmol) under a nitrogen atmosphere at room temperature. After 10 min, a solution of sulphonamide (16 mg, 0.88 mmol) in CH2Cl2 ( 1 ml) was added dropwise and the resulting reaction mixture was stirred at room temperature for 2 h. After completion, the reaction quenched with water (5 ml) and the mixture was extracted with CHCl3 (2 x 10 mL) then the organic layer was washed with brine and the combined organic layer were dried over sodium sulphate and evaporated under reduced pressure. The crude compound was purified by column chromatography to afford compound of formula II (406 mg, 92%,) as a yellow solid.Rf = 0.5 (silica, EtOAc: hexane = 8:2); IR (neat): 3479, 2925, 2850, 1723, 1622, 1582, 1435, 1293, 1108, 767, 671 cm-1; M.P. = 152-156 °C; 1H NMR (400 MHz, CDCI3): d 9.43 (s, 1H), 8.51 (d, 7 = 2.2 Hz, 1H), 8.25 (dd, J = 8.0, 1.1 Hz, 1H), 8.10 (dd, J = 9.1, 2.2 Hz, 1H), 7.52 (td, / = 7.5, 1.2 Hz, 1H), 7.40 (dd, / = 13.9, 5.9 Hz, 2H), 7.31 - 7.26 (m, 3H), 7.14 (d, / = 7.8 Hz, 1H), 6.92 (s, 1H), 4.10 (s, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 2.68 (s, 3H); 13C NMR (100 MHz, CDCI3): d 164.2, 157.7, 141.4, 140.0, 138.0, 137.0, 136.0, 134.2, 133.0, 132.0, 130.5, 130.4, 130.1, 127.2, 127.0, 120.0, 117.5, 117.0, 116.0, 110.1, 109.3, 56.2; HRMS (m/z): [M + Na] + calcd. for C25H23N306S+ 516.1988, found 516.1975. |
63% | With dmap; dicyclohexyl-carbodiimide In dichloromethane for 5h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With 1,10-Phenanthroline; palladium(II) trifluoroacetate; oxygen In toluene at 140℃; for 40h; | 2 2.2. General procedure: 4-methyl-N-phenylbenzenesulfonamide (3a) General procedure: 2.2 General procedure: 4-methyl-N-phenylbenzenesulfonamide (3a) A 25 mL oven-dried reaction vessel was charged with Pd(TFA)2 (2.3 mg, 0.01 mmol), 1,10-phenanthroline (3.6 mg, 0.02 mmol), p-toluene sulfonamide (1a, 34.2 mg, 0.2 mmol), cyclohexanone (2a, 32 μL, 0.3 mmol). The reaction vessel was flushed with oxygen three times and then sealed. Toluene (0.7 mL) was added by syringe and the resulting solution was stirred at 140 °C for 40 h. After cooling to room temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 4:1) to give the corresponding product 3a (39.9 mg) as white solid in 81% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With trifluorormethanesulfonic acid In toluene at 120℃; for 35h; | In a typical procedure General procedure: To a mixture of tolsulfonamide (0.5mmol) and THF (2mmol) in toluene (1mL), was added TfOH (40mol%). The resulting mixture was than sealed and stirred for 18h at 120°C. After quenching with satdaqNaHCO3, the reaction mixture was extracted three times with EtOAc, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography with PE and EtOAc (3:1) as the eluent to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With trifluorormethanesulfonic acid In toluene at 120℃; for 35h; | In a typical procedure General procedure: To a mixture of tolsulfonamide (0.5mmol) and THF (2mmol) in toluene (1mL), was added TfOH (40mol%). The resulting mixture was than sealed and stirred for 18h at 120°C. After quenching with satdaqNaHCO3, the reaction mixture was extracted three times with EtOAc, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography with PE and EtOAc (3:1) as the eluent to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20.0℃; for 4.0h;Inert atmosphere; | General procedure: In 25ml RB flask to a solution of Compound 9 (200 mg) in dry DMF (5ml), EDCI (250 mg, 1.25eq) and DMAP (130 mg,1eq) were added followed by addition of Sulfonamide (1eq). RM was stirred at RT for 4hrs. Solvent from the reaction mixture was evaporated. To the residue water was added and acidified with 6N HCl, solid precipitated out. Solid was filtered and dried. Crude solid was purified by flash chromatography eluating with 4-8% MeOH/DCM as solvent system to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; Sealed tube; Microwave irradiation; | 22 Representative Procedure 1: substitution of 2,3-dichloronaphthalene-1,4-diones with sulfonamides. General procedure: 2,3-Dichloronaphthalene-1,4-dione (1.0 equiv), the requisite sulfonamide(1.0 equiv) and Cs2CO3 (1.4 equiv) were stirred in DMF in a sealed microwave vial at rt for 5 h. 1 M aq HCl (50 mL) was added and the organic product extracted with EtOAc (3 20 mL). The organic washings were combined, washed with brine (3 20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product.4.1.22: N-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2'-methylbenzenesulfonamide (33) Following Representative Procedure 1, using 2,3-dichloronaphthalene-1,4-dione 7 (500 mg, 2.20 mmol), ortho-toluenesulfonamide (377 mg, 2.20 mmol) and Cs2CO3 (1000 mg, 3.08 mmol) in DMF (5 mL). Purification via column chromatography on silica gel (eluent pet ether/acetone 80:20) gave sulfonamide 33 as a yellow solid (555 mg, 70%). Mp 157-162 °C; νmax (neat) 3370 (N-H), 1666 (C=O), 1589 (C=O); δH (500 MHz, DMSO-d6) 2.65 (3H, s, Me), 7.39 (1H, app. t, J 7.4, H5'), 7.44 (1H, d, J 7.4, H3'), 7.56 (1H, app. td, J 7.4, 1.3, H4'), 7.84-7.93 (3H, m, H6, H7 and H6'), 7.95-7.98 (1H, m, H5 or H8), 8.04-8.08 (1H, m, H5 or H8); δC (125 MHz, DMSO-d6) 20.0, 125.9, 126.6, 126.7, 128.3, 130.4, 131.0, 132.2, 132.6, 134.5, 134.7, 136.2, 140.5, 141.1, 177.4, 178.8; m/z (ESI+) 384 ([M(35Cl)+Na]+, 100%); HRMS (ESI+) C17H13ClNNaO4S+ ([M(35Cl)+Na]+) requires 384.0068, found 384.0057. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 24h; | General procedure for title compound 6 and 7 General procedure: To a stirred solution of 3I-3III (10 mmol) and Et3N (12 mmol) in anhydrous acetonitrile was added sulfamide (4a-i and 5, 10 mmol) followed by addition EDCI (12 mmol) and DMAP (12 mmol). The mixture was stirred at r.t. for 24 h. The reaction mixture was concentrated, and the residue was dissolved in dichloromethane. The organic layer was washed with 1N HCl and water for 3 times respectively, dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was subjected to silica gel chromatography or crystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.2% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 20℃; for 24h; | General procedure: To a stirred solution of 3I-3III (10 mmol) and Et3N (12 mmol) in anhydrous acetonitrile was added sulfamide (4a-i and 5, 10 mmol) followed by addition EDCI (12 mmol) and DMAP (12 mmol). The mixture was stirred at r.t. for 24 h. The reaction mixture was concentrated, and the residue was dissolved in dichloromethane. The organic layer was washed with 1N HCl and water for 3 times respectively, dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was subjected to silica gel chromatography or crystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 24h; | General procedure for title compound 6 and 7 General procedure: To a stirred solution of 3I-3III (10 mmol) and Et3N (12 mmol) in anhydrous acetonitrile was added sulfamide (4a-i and 5, 10 mmol) followed by addition EDCI (12 mmol) and DMAP (12 mmol). The mixture was stirred at r.t. for 24 h. The reaction mixture was concentrated, and the residue was dissolved in dichloromethane. The organic layer was washed with 1N HCl and water for 3 times respectively, dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was subjected to silica gel chromatography or crystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With [(Cp*IrCl)2(4,4′,6,6′-tetrahydroxy-2,2′-bipyrimidine)][Cl]2; potassium hydroxide In water at 130℃; for 12h; | 4 N,2-dimethylbenzenesulfonamide Combine o-methylbenzenesulfonamide (85.6 mg, 0.5 mmol), iridium catalyst (5.1 mg, 0.005 mmol, 1 mol%), potassium hydroxide (28 mg, 0.5 mmol, 1 equiv), then methanol (0.3 mL) and water (0.9 mL) were added to the reaction vessel in sequence. After the reaction mixture was reacted at 130 ° C for 12 hours in a reaction vessel, it was cooled to room temperature. The solvent was removed by rotary evaporation, and then the purified target compound was obtained by column chromatography (developing solvent: petroleum ether / ethyl acetate), yield: 96%. |
92% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydroxide at 150℃; for 12h; Inert atmosphere; Schlenk technique; Green chemistry; | |
91% | With [(Cp*IrCl)2(4,4′,6,6′-tetrahydroxy-2,2′-bipyrimidine)][Cl]2; potassium hydroxide In water at 130℃; for 12h; Schlenk technique; |
90% | With [Cp*Ir(2-(1H-benzo[d]imidazol-2-yl)-1H-benzo[d]imidazole)Cl][Cl]; caesium carbonate at 120℃; for 12h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 73% 2: 16% | With boron trifluoride diethyl etherate In chloroform for 2h; Reflux; Green chemistry; | Mono- and Di-N-benzylated Sulfonamides 3 and 4; General Procedure General procedure: In a round-bottom flask, a benzyl alcohol 2 (1.0 mmol), a sulfonamide1 (1.8 mmol) and BF3·OEt2 (151 μL, 1.2 mmol) were dissolved in CHCl3 (2.0 mL). The mixture was stirred for 2 h under reflux in air atmosphere, then the solvent was removed under reduced pressure using a rotary evaporator. The product was isolated by column chromatography of the residue on silica gel (EtOAc-PE, 1:10 to 1:2, v/v) to give the desired mono- and di-N-benzylated products 3 and 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With trifluoromethylsulfonic anhydride In toluene at 120℃; for 48h; | General procedure for the reaction of sulfonamides with diols General procedure: To a mixture of sulfonamide (2 mmol) and diol (3 mmol) in toluene (3 mL) was added Tf2O (20 mol%). The mixture was then sealed and stirred at 120 °C until the reaction was completed as judged by TLC. After quenching with sat. aq. NaHCO3, the reaction mixture was extracted three times with EtOAc, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography with PE and EtOAc (3: 1) as the eluent to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With trifluoromethylsulfonic anhydride In 1,4-dioxane at 120℃; for 48h; | General procedure for the reaction of sulfonamides with alcohols General procedure: To a mixture of sulfonamide (2 mmol) and alcohol (10 mmol) in 1,4-dioxane (3 mL) was added Tf2O (2 mmol). The mixture was then sealed and stirred at 120 °C until the reaction was completed as judged by TLC. After quenching with satd. aq. NaHCO3, the reaction mixture was extracted three times with EtOAc, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography with PE and EtOAc (3: 1) as the eluent to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: methyl 2-(aminosulfonyl)benzoate; diosgenin acetate With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 8h; Inert atmosphere; Stage #2: In toluene Reflux; Dean-Stark; | Gerneral procedure: General procedure: To a solution of steroidal sapogenin (1 equiv) and RSO2NH2 (4 equiv)in freshly distilled dichloromethane (DCM, 0.1 M) was added BF3•Et2O (4 equiv) underargon at ambient temperature. The resulting yellow mixture was allowed to stand for eight toten hours until thin layer chromatography (TLC) showed full consumption of the startingmaterial. The dark red mixture was quenched by adding a saturated aqueous solution ofNaHCO3 and extracted with DCM for three times. The combined organic layers were washedwith brine, dried over Na2SO4, and concentrated under reduced pressure. The residue wasdissolved in toluene and heated to reflux with a Dean-Stark trap for five to eight hours.Removal of the solvent under reduced pressure and flash column chromatography of the crudeon silica gel afforded the product with indicated yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With oxygen; copper(II) oxide In dimethyl sulfoxide at 100℃; for 8h; | General procedure for primary aryl sulfonamides 2 General procedure: A mixture of aryl sulfonyl amino acid 1 (0.5 mmol), CuO (0.15 mmol), and DMSO (0.5 mL) was placed in a 25-mL, round-bottom flask. The mixture was stirred for 8 h at 100 °C under air. Then, the reaction mixture was cooled, diluted with ethyl acetate, filtered through celite, and concentrated in vacuo. The residue was purified by silica-gel column chromatography with ethyl acetate / petroleum ether to afford the desired product 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tert.-butylhydroperoxide; ammonium hydroxide; iodine In water; acetonitrile at 100℃; for 16h; | |
83% | With ammonium hydroxide; manganese(IV) oxide; oxygen In water; N,N-dimethyl-formamide at 90℃; for 40h; Autoclave; | |
83% | With ammonium hydroxide; manganese (IV) dioxide; oxygen In water; N,N-dimethyl-formamide at 90℃; for 40h; Autoclave; | 2.1 (1) Sulfonamide Synthesis Reaction Oxidation reaction was carried out using an autoclave reaction vessel having a 13 mL Teflon (registered trademark) container. Typical sulfonamide synthesis reaction was carried out in accordance with the following procedure. Into the autoclave reaction vessel, benzenethiol (1.0 mmol), MnO2 (0.1 g), a 28% NH3 aqueous solution (5.0 mmol), DMF/H2O (0.6/0.4 mL), and O2 (1 MPa) were introduced, and they were allowed to react at 90° C. for 20 hours. After the reaction, the catalyst was separated by filtration, and isolation and collection of a product in the filtrate were carried out using an elution position control automated setup medium pressure preparative liquid chromatograph (EPCLC-AI-580S, manufactured by Yamazen Corporation). |
78% | With [bis(acetoxy)iodo]benzene; ammonium carbamate In methanol at 25℃; for 24h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | With 2-chloro-1,3-dimethylimidazolinium chloride; triethylamine In 1,2-dichloro-ethane at 20℃; for 10h; | 1 Example 2 The 4 - (1-methyl-5-cyclopentyl acyl amino indole-3-yl methyl) - 3-methoxybenzoic acid (42.2 g, 0.1 mole) of the 2-methyl benzene sulfonamide (17.1 g, 0.1 mole), chloropivaloyl 1,3-dimethyl-2-chlorotrifluoromethylbenzene imidazoline (13.7 g, 0 . 12 mol), dissolved in 1,2-dichloroethane in (200 ml), triethylamine dropped under stirring (15.2 g, 0 . 15 mol), the reaction at room temperature 12 hours. Adding water (100 ml), with 5% sodium hydroxide adjusting pH=9-10, water is washed to neutral, drying. Concentration to obtain pale yellow solid product, recrystallization anhydrous ethanol, to obtain white crystalline product 51.8 g (liquid chromatography measuring the purity of 99.51%,), yield 90.1% ; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With titanium tetrachloride; triethylamine In dichloromethane for 0.5h; | |
67% | With pyrrolidine In chloroform at 60℃; for 24h; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In acetonitrile; at 75.0℃; for 4.0h; | -(Bromomethyl)benzenesulfonamide [00326] A mixture of 230A (780 mg, 4.6 mmol), NBS (940 mg, 5.3 mmol) and AIBN (230 mg, 1.4 mmol) in acetonitrile (5 mL) was stirred at 75 C for 4 h. The reaction mixture was diluted with EtOAc, washed with saturated NaHCC^ and brine, dried over MgS04 and then concentrated to obtain a brown solid. MS(ESI) m/z 250/252 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 72h; | |
32% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 72h; | 4 Example 4: L-pyroglutamic acid (0.65 g, 5.0 mmol) and o-methylbenzenesulfonamide (1.03 g, 6.0 mmol) were dissolved in lOmL dichlorMethane, 4-dimethylaminopyridine (DMAP, 0.18 g, 1.5 mmo 1) and 1-ethyl- (3-dimethylaminoPropyl) carbodiimide hydrochloride (EDCI, 1.08 g, 6.0 mmol). After stirring at room temperature for 72 hours, the reaction mixture was added100 mL of ethyl acetate and 15 mL of 1 M hydrochloric acid. The organic phase was washed with half-saturated brine (3X 30 mL) and then with noDried over sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed on silica gel eluting with methanol-dichloromethane (1: 99-5: 95)Gradient elution to give a white solid, 45 g, in 32% yield. Melting point 111-112 ° C. [a] D2Q = -39 • 7 (c = 0 • 5in(400 MHz), IR (KBr) ν3423,1634,1466,1338,1186,899,848,760 cm-1;(S, lH), 7.56-7.68 (m, 1 H), 7.41-7.45 (m, 1 H), 7.46 (s,(S, 3H), 2.27-2.36 (m, 1 Hz), 1.97-2.12 (m, 2 H), 1.721.80(m, lH); 13C NMR (100 MHz, DMS0-d6)? 177.5, 172.2, 137.8, 137.4, 134.1, 132.9, 130.7,HRMS (T0F-ES +) m / z: [M + Na] + calcd for C12H14N2O4S & lt; RTI ID = 0.0 & gt;305.0572, found 305.0580. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With oxygen; copper diacetate In chlorobenzene at 90℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With [bis(acetoxy)iodo]benzene; triphenylphosphine In acetonitrile at 80℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 2-chloro-6-[3-(1-trifluoromethylcyclobutylmethoxy)pyrazole-1-yl]nicotinic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h; Stage #2: methyl 2-(aminosulfonyl)benzoate With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 2h; | 56.A Step A: 2-Chloro-N-(o-tolylsulfonyl)-6-[3-[[l-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl]pyridine-3-carboxamide 2-Chloro-6-[3-[[l-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl]pyridine-3-carboxylic acid (150 mg, 0.3992 mmol) and carbonyl diimidazole (approximately 81.69 mg, 0.5038 mmol) were combined in THF (1.339 mL) and stirred for 2 h. At this point, 2-methylbenzenesulfonamide (approximately 71.77 mg, 0.4192 mmol) was added, followed by DBU (approximately 202.6 mg, 199.0 , 1.331 mmoμl)L and the reaction was stirred for an additional 2 h at room temperature. The reaction was diluted with ethyl acetate and washed with a 1 M citric acid solution, followed by brine. The organics were separated, dried over sodium sulfate, and evaporated to give 2-chloro-N-(o-tolylsulfonyl)-6-[3-[[l-(trifluoromethyl)cyclobutyl]methoxy]pyrazol-l-yl]pyridine-3-carboxamide (208 mg, 99%) ESI-MS m/z calc. 528.0846, found 529.0 (M+l) + ; Retention time: 0.77 minutes |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 2-chloro-6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h; Stage #2: methyl 2-(aminosulfonyl)benzoate With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 16h; | 23.A Step A: 2-Chloro-N-(o-tolylsulfonyl)-6-[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridine-3-carboxamide 2-Chloro-6-[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridine-3-carboxylic acid (200 mg, 0.5529 mmol) and CDI (approximately 107.6 mg, 0.6635 mmol) were combined in THF (960 ) and stiμrrLed at room temperature for 2 hours. 2-methylbenzenesulfonamide (approximately 123.1 mg, 0.7188 mmol) was added followed by DBU (approximately 101.0 mg, 99.21 , 0.6635 mμLmol) and the reaction was stirred for an additional 16 h at room temperature. A IM citric acid solution (1 mL) was added and the reaction was stirred for 20 min. The resulting solid was collected by vacuum filtration (washing with water) and dried under vacuum to give a white powder, which was used in the next step without further purification. 2-chloro-N-(o4olylsulfonyl)-6-[3-[[l-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-l-yl]pyridine-3-carboxamide (280 mg, 98%) ESI-MS m/z calc. 514.1, found 515.1 (M+l)+; Retention time: 0.73 minutes. lH NMR (400 MHz, DMSO) δ d 13.56 - 12.55 (s, 1H), 8.42 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 6.23 (d, J = 2.9 Hz, 1H), 4.39 (s, 2H), 2.64 (s, 3H), 1.12 - 1.06 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 2-chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-1-yl]pyridine-3-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1.5h; Stage #2: methyl 2-(aminosulfonyl)benzoate With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 1.5h; | 15.E Step E: 2-Chloro-N-(o-tolylsulfonyl)-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridine-3-carboxamide 2-Chloro-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridine-3-carboxylic acid (150 mg 0.429 mmol) and was dissolved/suspended in THF (2 mL), and carbonyl dhmidazole (64.2 mg, 0.396 mmol) was added. The suspension was allowed to stir at room temperature for 1.5 hours. 2-Methylbenzenesulfonamide (73.4 mg, 0.429 mmol) was then added followed by DBU (59.2 μL, 0.396 mmol). The resulting solution was then stirred for another 1.5 hours. Volatiles were evaporated. The remaining residue was taken up in dichloromethane (2 mL) and washed with aqueous 1 M citric acid (1 x 2 mL). The organic layer was injected onto a silica gel column for chromatography: 12 gram silica gel column, 0-10% MeOH/DCM gradient. 2-chloro-N-(o-tolylsulfonyl)-6-[3-[(2,2,3,3-tetramethylcyclopropyl)methoxy]pyrazol-l-yl]pyridine-3-carboxamide (115 mg, 53%) was obtained. ESI-MS m/z calc. 502.14417, found 503.0 (M+l)+; Retention time: 2.25 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; silver(I) acetate; silver(I) triflimide In dichloromethane at 60℃; for 24h; | 14 Example 14 (1) 0.0040g iridium catalyst [Cp * IrCl2] 2,0.0076 g silver salt bis(trifluoromethanesulfonyl)imide silver,0.825g oxidant silver acetate,31.4 μL acetophenone-O-methyl oxime and 0.0684 g o-toluene sulfonamide were placed in a reaction tube.Add 2mL of dichloromethane as a solvent,Heating and stirring reaction,The temperature of heating and stirring is 60°C.Reaction time 24h.(2) After the reaction is over,Separation by column chromatography (300-400 column chromatography silica gel column packing,Eluent: ethyl acetate: petroleum ether = 12:100 v/v),Can get the productN-[2-(1-methoxyimino)ethyl]phenyl-2-methylbenzenesulfonamide.The yield was 82%. |
82% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; silver(I) acetate; silver(I) triflimide In dichloromethane at 60℃; for 24h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dichloro bis(acetonitrile) palladium(II); silver(I) acetate In 1,4-dioxane; dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; Schlenk technique; | General procedure for the synthesis of 3 General procedure: Under the argon atmosphere, a Schlenk tube (15 mL) equipped with a magnetic bar was loaded with the sulfonamide 1 (0.5 mmol), sodium arylsulfinates 2 (0.6 mmol, 1.2 equiv.), Pd(MeCN)2Cl2 (6.5 mg, 5 mol%) and AgOAc (166.9 mg, 1.0 mmol) in one portion. Then, the mixture of 1,4-dioxane/DMSO (3.5 mL in a 9:1 ratio) was added to obtain a clear solution and the reaction mixture was allowed to stir at 120 °C for 24 h. After cooling to room temperature, the mixture was filtered through a short celite pad and washed with dichloromethane (15 mL 3). The filtrate was concentrated and the oily crude product was purified by column chromatography using silica gel (200-300 mesh) as stationary phase and a petroleum ether and ethyl acetate (3/1) as eluent to give the N-aryl sulfonamides 3 in noted yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | cyclopentyl N-[1-methyl-3-({4-[(2-methylbenzenesulfonyl)carbamoyl]phenyl}methyl)-1H-indol-5-yl]carbamate (2): General procedure: Carboxylicacid (1 eq.), DMAP (1.5 eq.), EDC (1.2 eq.), and amine/sulfonamide(1.2 eq.) were added to DCM (10 mL/mmol of carboxylic acid) inthat order. The reaction was stirred at room temperature for 16 h 2M HCl was added to the reaction. Organic layer was extracted 3 EtOAc. Combined organic layers were washed with brine. Organiclayer was dried with Mg2SO4 and rotovapped. Product was purifiedby column chromatography. Grey solid; 69%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | Cyclopentyl N-[1-methyl-3-({4-[(2-methylbenzenesulfonyl)carbamoyl]phenyl}methyl)-1H-indol-5-yl]carbamate (2): General procedure: Carboxylicacid (1 eq.), DMAP (1.5 eq.), EDC (1.2 eq.), and amine/sulfonamide(1.2 eq.) were added to DCM (10 mL/mmol of carboxylic acid) inthat order. The reaction was stirred at room temperature for 16 h 2M HCl was added to the reaction. Organic layer was extracted 3 EtOAc. Combined organic layers were washed with brine. Organiclayer was dried with Mg2SO4 and rotovapped. Product was purifiedby column chromatography. Grey solid; 69%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | cyclopentyl N-[1-methyl-3-({4-[(2-methylbenzenesulfonyl)carbamoyl]phenyl}methyl)-1H-indol-5-yl]carbamate (2): General procedure: Carboxylicacid (1 eq.), DMAP (1.5 eq.), EDC (1.2 eq.), and amine/sulfonamide(1.2 eq.) were added to DCM (10 mL/mmol of carboxylic acid) inthat order. The reaction was stirred at room temperature for 16 h 2M HCl was added to the reaction. Organic layer was extracted 3 EtOAc. Combined organic layers were washed with brine. Organiclayer was dried with Mg2SO4 and rotovapped. Product was purifiedby column chromatography. Grey solid; 69%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | cyclopentyl N-[1-methyl-3-({4-[(2-methylbenzenesulfonyl)carbamoyl]phenyl}methyl)-1H-indol-5-yl]carbamate (2): General procedure: Carboxylicacid (1 eq.), DMAP (1.5 eq.), EDC (1.2 eq.), and amine/sulfonamide(1.2 eq.) were added to DCM (10 mL/mmol of carboxylic acid) inthat order. The reaction was stirred at room temperature for 16 h 2M HCl was added to the reaction. Organic layer was extracted 3 EtOAc. Combined organic layers were washed with brine. Organiclayer was dried with Mg2SO4 and rotovapped. Product was purifiedby column chromatography. Grey solid; 69%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | cyclopentyl N-[1-methyl-3-({4-[(2-methylbenzenesulfonyl)carbamoyl]phenyl}methyl)-1H-indol-5-yl]carbamate (2): General procedure: Carboxylicacid (1 eq.), DMAP (1.5 eq.), EDC (1.2 eq.), and amine/sulfonamide(1.2 eq.) were added to DCM (10 mL/mmol of carboxylic acid) inthat order. The reaction was stirred at room temperature for 16 h 2M HCl was added to the reaction. Organic layer was extracted 3 EtOAc. Combined organic layers were washed with brine. Organiclayer was dried with Mg2SO4 and rotovapped. Product was purifiedby column chromatography. Grey solid; 69%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | |
59% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | Synthesis of Compound 4b. A mixture of compound 3 (100 mg, 0.34 mmol), o-toluenesulfonamide (64 mg, 0.37 mmol), EDC.HCl (84 mg, 0.44 mmol), and DMAP (62 mg, 0.51 mmol) in anhydrous CH2Cl2 (10 mL) was stirred at room temperature overnight. After completion of the reaction, the solvents were removed and the crude product obtained was bycolumn chromatography (SiO2 gel, pure Hexanes to Hexanes:EtOAc/1:1, Rf 0.47 in CH2C2:MeOH/19:1) followed by recrystallization in EtOH to afford compound 4b (90 mg, 59%) as an off-white solid: 1H NMR (400 MHz, (CD3)2CO) δ 10.94 (s, 1H, O═CNH), 8.16 (dd, J1=8.0 Hz, J2=1.2 Hz, 1H, aromatic), 7.56 (td, J1=J2=7.6 Hz, J3=1.2 Hz, 1H, aromatic), 7.48 (s, 1H, aromatic), 7.49 (d, J=8.4 Hz, 1H, aromatic), 7.44 (td, J1=J2=7.6 Hz, J3=1.2 Hz, 1H, aromatic), 7.43 (dd, J1=8.0 Hz, J2=1.2 Hz, 1H, aromatic), 7.38 (d, J=7.6 Hz, 1H, aromatic), 7.32 (d, J=8.4 Hz, 1H, aromatic), 7.18 (d, J=7.6 Hz, 1H, aromatic), 7.12 (t, J=8.0 Hz, 1H, aromatic), 7.01 (s, 1H, aromatic), 6.97 (t, J=8.0 Hz, 1H, aromatic), 4.07 (s, 2H, CH2Ar), 3.92 (s, 3H, OCH3), 3.75 (s, 3H, NCH3), 2.64 (s, 3H, ArCH3); 13C NMR (100 MHz, (CD3)2CO) δ 164.4, 157.3, 137.9, 137.5, 136.0, 133.5, 132.3, 131.2, 130.6, 129.7, 127.9, 127.6, 127.3, 126.0, 121.2, 120.2, 118.7, 118.5, 112.0, 109.7, 109.2, 55.1, 31.7, 24.9, 19.4; m/z calcd for C25H24N2O4S 448.2; found 449.1 [M+H]+. Purity of the compound was further confirmed by RP-HPLC by using method B: Rt=25.35 min (96%). |
50% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | Cyclopentyl N-[1-methyl-3-({4-[(2-methylbenzenesulfonyl)carbamoyl]phenyl}methyl)-1H-indol-5-yl]carbamate (2): General procedure: Carboxylicacid (1 eq.), DMAP (1.5 eq.), EDC (1.2 eq.), and amine/sulfonamide(1.2 eq.) were added to DCM (10 mL/mmol of carboxylic acid) inthat order. The reaction was stirred at room temperature for 16 h 2M HCl was added to the reaction. Organic layer was extracted 3 EtOAc. Combined organic layers were washed with brine. Organiclayer was dried with Mg2SO4 and rotovapped. Product was purifiedby column chromatography. Grey solid; 69%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | Cyclopentyl N-[1-methyl-3-({4-[(2-methylbenzenesulfonyl)carbamoyl]phenyl}methyl)-1H-indol-5-yl]carbamate (2): General procedure: Carboxylicacid (1 eq.), DMAP (1.5 eq.), EDC (1.2 eq.), and amine/sulfonamide(1.2 eq.) were added to DCM (10 mL/mmol of carboxylic acid) inthat order. The reaction was stirred at room temperature for 16 h 2M HCl was added to the reaction. Organic layer was extracted 3 EtOAc. Combined organic layers were washed with brine. Organiclayer was dried with Mg2SO4 and rotovapped. Product was purifiedby column chromatography. Grey solid; 69%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With copper(II) bis(trifluoromethanesulfonate) at 80℃; for 2h; | 10 Example ten The reaction flask was charged sequentially Compound 1j (0.5 mmol, 85.6 mg), Compound 3a (3 mmol, 316 μL), Cu(OTf)2 (0.01 mmol, 3.6 mg) and compound 2a (2 mL). The system is then heated in air at 80 °C for about 2 hours. Quenched with saturated sodium sulfite solution, extract with ethyl acetate (10 mL × 3), Remove the solvent with a rotary evaporator, silica gel adsorption, the product 4j was obtained by simple column chromatography in a yield of 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium metabisulfite; sodium azide; tetrabutylammomium bromide; triphenylphosphine In water; acetonitrile at 80℃; for 12h; Inert atmosphere; | |
70% | With sodium metabisulfite; sodium azide; tetrabutylammomium bromide; triphenylphosphine In water; acetonitrile at 80℃; for 12h; Inert atmosphere; Schlenk technique; | 14 Synthesis of compound 2n: Under nitrogen protection,Diazonium salt 1n (257.4 mg, 1.25 mmol), NaN3 (32.5 mg, 0.5 mmol), PPh3 (157.4 mg, 0.6 mmol), Na2S2O5 (190.1 mg, 1.0 mmol), TBAB (241.7 mg, 0.75 mmol) and MeCN /H2O=2/1 (1 mL) was added to the Schlenk reaction tube. After the reaction was stirred at 80 ° C for 12 h,Reduce to room temperature, add 10mL water to the system to dilute,Extracted with ethyl acetate (10 mL*3), dried over anhydrous sodiumColumn chromatography gave 2n (70%) as a colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With pyrrolidine In chloroform at 60℃; for 24h; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tert.-butylhydroperoxide; copper acetylacetonate; caesium carbonate In water; acetonitrile at 100℃; for 12h; Schlenk technique; | 5. General procedure towards N-aryl sulfonamides 5 General procedure: Under the air atmosphere, a Schlenk tube (35 mL) equipped with a magnetic bar was loaded with the sulfonamide 4 (0.5 mmol), Cu(acac)2 (20 mol%), TBHP (70% in water, 2.0 equiv.), Cs2CO3 (2.0equiv.) in dry solvent MeCN (4.0 mL). Then the reaction mixture was allowed to stir at 60C for 12 h. After the completion of the reaction, as monitored by TLC analysis, the mixture was filtered through a short celite pad and washed with dichloromethane (15 mL x 3). The filtrate was concentrated, and the oily crude product was puried by column chromatography using silica gel (200-300 mesh) as stationary phase and a mixture of n-hexane and ethyl acetate (2:1) as eluent to give the corresponding arylated products 5 (Rf = ca.0.3 otherwise noted). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | |
100% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | Synthesis of Compound 11b A mixture of compound 9 (40 mg, 0.16 mmol), o-toluenesulfonamide (30 mg, 0.18 mmol EDC.HCl (40 mg, 0.21 mmol), and DMAP (29 mg,0.24 mmol) in anhydrous CH2Cl2 (5 mL) was stirred at room temperature overnight. Upon completion, the reaction mixture was purified by column chromatography (SiO2 gel, CH2Cl2:MeOH/49:1, Rf 0.46 in CH2Cl2:MeOH/19:1) to afford compound 11b (67 mg, quant.) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H, O═CNH), 8.24 (d, J=8.0 Hz, 1H, aromatic), 8.08 (s, 1H, NH), 7.67 (d, J=8.0 Hz, 2H, aromatic), 7.48 (t, J=7.6 Hz, 1H, aromatic), 7.38 (t, J=7.6 Hz, 2H, aromatic), 7.34 (d, J=7.6 Hz, 1H, aromatic), 7.30-7.24 (m, 3H, aromatic), 7.16 (t, J=7.6 Hz, 1H, aromatic), 7.04 (t, J=7.6 Hz, 1H, aromatic), 6.89 (s, 1H, aromatic), 4.10 (s, 2H, CH2Ar), 2.66 (s, 3H, ArCH3); 13C NMR (100 MHz, CDCl3) δ 164.2, 147.8, 137.6, 136.5, 136.4, 134.0, 132.5, 131.5, 129.2 (2 carbons), 128.5, 128.0 (2 carbons), 127.1, 126.4, 122.6, 122.2, 119.5, 118.8, 114.1, 111.3, 31.6, 20.4; m/z calcd for C23H20N2O3S 404.1; found 403.1 [M-H]-. Purity of the compound was further confirmed by RP-HPLC by using method B: Rt=23.58 min (97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | |
95% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | Synthesis of Compound 21b. A mixture of compound 18 (50 mg, 0.18 mmol), o-toluenesulfonamide (33 mg, 0.20 mmol), EDC.HCl (44 mg, 0.23 mmol), and DMAP (33 mg, 0.27 mmol) in anhydrous CH2Cl2 (10 mL) was stirred at room temperature overnight. Upon completion, the reaction mixture was purified by column chromatography (SiO2 gel, CH2Cl2:MeOH/49:1, Rf 0.50 in Hexanes:EtOAc/1:1) to afford compound 21b (73 mg, 95%) as an off-white solid: 1H NMR (400 MHz, (CD3)2CO) δ 10.60 (s, 1H, NHSO2), 10.01 (s, 1H, NH), 8.14 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H, aromatic), 7.73 (d, J=2.0 Hz, 1H, aromatic), 7.54 (td, J1=8.0 Hz, J2=1.6 Hz, 1H, aromatic), 7.51 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H, aromatic), 7.44-7.35 (m, 3H, aromatic), 7.34 (dd, J1=8.4 Hz, J2=0.8 Hz, 1H, aromatic), 7.13 (d, J=2.4 Hz, 1H, aromatic), 7.12 (d, J=8.4 Hz, 1H, aromatic), 7.04 (app. t, J1 7.2 Hz, 1H, aromatic), 6.91 (app. t, J=7.2 Hz, 1H, aromatic), 4.054 (s, 2H, CH2Ar), 4.048 (s, 3H, OCH3), 2.66 (s, 3H, ArCH3); 13C NMR (100 MHz, (CD3)2CO) δ 162.4, 156.1, 137.7, 137.5, 137.0, 135.1, 134.8, 133.6, 132.3, 131.2, 131.1, 127.2, 126.0, 122.9, 121.3, 119.2, 118.6, 118.5, 114.2, 112.2, 111.3, 56.1, 30.0, 19.3; m/z calcd for C24H22N2O4S 434.1; found 435.1 [M+H]+. Purity of the compound was further confirmed by RP-HPLC by using method A: Rt=20.50 min (98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | |
89% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | Synthesis of Compound 22b. A mixture of compound 19 (30 mg, 0.10 mmol), o-toluenesulfonamide (21 mg, 0.12 mmol), EDC.HCl (31 mg, 0.16 mmol), and DMAP (22 mg,0.18 mmol) in anhydrous CH2Cl2 (5 mL) was stirred at room temperature overnight. Upon completion, the reaction mixture was diluted with H2O and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, pure Hexanes to Hexanes:EtOAc/1:1, Rf 0.47 in Hexanes:EtOAc/1:1) to afford compound 22b (41 mg, 89%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H, NH), 8.24 (dd, J1=8.0 Hz, J2=2.4 Hz, 1H, aromatic), 7.95 (d, J=2.4 Hz, 1H, aromatic), 7.46 (td, J1=7.2 Hz, J2=1.2 Hz, 1H, aromatic), 7.40 (d, J=2.8 Hz, 1H, aromatic), 7.38-7.35 (m, 2H, aromatic), 7.26-7.22 (m, 2H, aromatic), 7.16 (td, J1=7.2 Hz, J2=1.2 Hz, 1H, aromatic), 6.99 (td, J1=8.0 Hz, J2=1.2 Hz, 1H, aromatic), 6.88 (d, J=8.8 Hz, 1H, aromatic), 6.72 (s, 1H, aromatic), 4.00 (s, 3H, ArOCH3), 3.98 (s, 2H, CH2Ar), 3.68 (s, 3H, NCH3), 2.66 (s, 3H, ArCH3); 13C NMR (100 MHz, CDCl3) δ 162.4, 156.1, 137.4, 137.2, 137.0, 135.3, 135.2, 133.7, 132.5, 132.7, 132.5, 132.4, 132.3, 131.4, 128.1, 127.4, 127.1, 126.3, 126.2, 121.6, 118.9, 118.8, 118.4, 113.4, 111.8, 109.2, 56.5, 32.6, 30.4, 20.2; m/z calcd for C25H24N2O4S 448.2; found 449.1 [M+H]+. Purity of the compound was further confirmed by RP-HPLC by using method B: Rt=25.71 min (95%). |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | |
72% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | Synthesis of Compound 23b. A mixture of compound 20 (25 mg, 0.073 mmol), o-toluenesulfonamide (15 mg, 0.088 mmol), EDC.HCl (22 mg, 0.11 mmol), and DMAP (16 mg, 0.13 mmol) in anhydrous CH2Cl2 (5 mL) was stirred at room temperature overnight. Upon completion, the reaction mixture was diluted with H2O and extracted with CH2Cl2 (3*). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product obtained was purified by column chromatography (SiO2 gel, CH2C2:MeOH/49:1, Rf 0.66 in CH2Cl2:MeOH/19:1) to afford compound 23b (26 mg, 72%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H, NH), 8.30 (d, J=2.4 Hz, 1H, aromatic), 8.21 (dd, J1=8.0 Hz, J2=1.2 Hz, 1H, aromatic), 8.06 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H, aromatic), 7.86 (d, J=2.4 Hz, 1H, aromatic), 7.47-7.41 (m, 2H, aromatic), 7.35 (t, J=7.2 Hz, 1H, aromatic), 7.24 (d, J=8.8 Hz, 2H, aromatic), 6.95 (d, J=8.4 Hz, 1H, aromatic), 6.85 (s, 1H, aromatic), 4.03 (s, 3H, ArOCH3), 4.00 (s, 2H, CH2Ar), 3.74 (s, 3H, NCH3), 2.65 (s, 3H, ArCH3); 13C NMR (100 MHz, CDCl3) δ 162.2, 156.3, 141.1, 139.9, 137.4, 137.0, 135.1, 134.0, 133.8, 132.4, 132.3, 131.4, 130.3, 126.7, 126.3, 118.7, 117.4, 116.4, 116.3, 112.0, 109.2, 56.6, 33.1, 30.0, 20.1; m/z calcd for C25H23N3O6S 493.1; found 494.0 [M+H]+. Purity of the compound was further confirmed by RP-HPLC by using method B: Rt=25.04 min (98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With (PhPAd-DalPhos)NiCl(o-tol); sodium t-butanolate In tetrahydrofuran at 80℃; for 18h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With (PhPAd-DalPhos)NiCl(o-tol); sodium t-butanolate In tetrahydrofuran at 80℃; for 18h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With (PhPAd-DalPhos)NiCl(o-tol); sodium t-butanolate In 1,4-dioxane at 110℃; for 18h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With (PhPAd-DalPhos)NiCl(o-tol); sodium t-butanolate In 1,4-dioxane at 110℃; for 18h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87 % ee | With copper(II) bis(trifluoromethanesulfonate); (1R,2R)-(+)-N,N'-dimethyl-1,2-diphenyl-ethylenediamine; sodium phosphate In 1,2-dichloro-ethane at 20℃; for 15h; Schlenk technique; Inert atmosphere; Overall yield = 94 percent; Overall yield = 129 mg; enantioselective reaction; | II. General Procedure for the Asymmetric Intermolecular N-monoarylation General procedure: The diaryliodonium salt 1 (0.25 mmol, 1.0 equiv), sulfonamide 2a (0.30 mmol, 1.2 equiv) ,catalyst (0.025 mmol, 10 mol%), ligand L1 (0.0375 mmol, 15 mol%) and base (0.5 mmol, 2.0 equiv)were added to a 10 mL oven-dried Schlenk tube, followed by addition of anhydrous 1,2-dichloroethane (1.5 mL) under argon atmosphere. The mixture was stirred at room temperaturefor 15 hours. Then the reaction mixture was poured into water (1.5mL) and extracted withdichloromethane (3 × 5 mL). The combined organic phase dried over anhydrous Na2SO4 andconcentrated under reduced pressure. The crude product was purified by flash chromategraphy(silica gel, petroleum ether/ethyl acetate = 5:1) to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 130℃; for 24h; | General Procedure for the Cross Coupling Reaction. General procedure: The N-nucleophile (0.4e0.8 mmol), CuI (0.004e0.04 mmol), Cs2CO3 (0.8-1.6 mmol), N,N-dibenzyl-4-iodobenzenesulfonamide (0.6-1.2 mmol) and dimethylformamide (DMF) (0.2e0.4 mL) were added to a reaction vial and a screw cap was fitted to it. The reaction mixture was stirred under air in a closed system at 130 °C for 24 h. After cooling to room temperature, the mixture was diluted with dichloromethane and filtered through a pad of Celite. The combined organic extracts were dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude productwas purified by silica-gel column chromatography to afford the N-arylated product. The identity and purity of the products was confirmed by 1H, 13C NMR spectroscopic analysis and elemental analysis or mass spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: 5-chloro-2-(2-chlorophenyl)-1-methyl-1H-imidazole-4-carboxylic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Stage #2: methyl 2-(aminosulfonyl)benzoate In dichloromethane at 20℃; for 48h; | Preparation of 5-chloro-2-(2-chlorophenyl)-1-methyl-N-[(2-methylphenyl)sulphonyl]-1 Himidazole-4-carboxamide Preparation of 5-chloro-2-(2-chlorophenyl)-1-methyl-N-[(2-methylphenyl)sulphonyl]-1 Himidazole-4-carboxamide 5-Chloro-2-(2-chlorophenyl)-1-methyl-1H-imidazole-4-carboxylic acid (163 mg; 0.60 mmol; 1 eq.) was dissolved in 10 ml of dichloromethane. After addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (345 mg, 1.8 mmol, 3 eq.) and DMAP (220 mg, 1.8 mmol, 3 eq.), the mixture was stirred at room temperature for 1 h. 2-Methylbenzenesulphonamide (103 mg; 0.6 mmol, 1 eq.) was then added, and the mixture was subsequently stirred at room temperature for 48 h. The solvent was removed on a rotary evaporator and the residue was purified chromatographically (reversed phase; mobile phase: acetonitrile, H2O). This gave 134 mg (52%) of the desired product. log P (acidic): 3.17; MH+: 424; 1H-NMR (400 MHz, D6-DMSO) δ ppm: 8.04 (d, 1H); 7.65-7.52 (m, 5H), 7.46-7.38 (m, 2H), 3.41 (s, 3H); 2.61 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With iron(III) sulfate; potassium hydrogensulfate In cyclohexane at 90℃; for 24h; | 18 Example 18 Add amide (0.5 mmol), sulfonamide (0.75 mmol), iron sulfate (20% mmol), potassium hydrogen sulfate (2.0 eq) to the test tube, then add cyclohexane (2 mL), and finally add ethyl diazoacetate EDA (3.0 mmol), the mixture was reacted at 90°C in an oil bath under an air atmosphere for 24 hours. After the reaction is completed, it is quenched with saturated sodium chloride solution, extracted with ethyl acetate, the organic phases are combined and dried over anhydrous magnesium sulfate, and the solvent is spin-dried under reduced pressure. The product can be obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether with a yield of 53%. The main test data of the prepared product are as follows. Through analysis, it can be known that the actual synthesized product is consistent with the theoretical analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With Isobutyronitrile; copper(II) bis(trifluoromethanesulfonate); sodium phosphate In dichloromethane at 20℃; for 24h; Irradiation; Inert atmosphere; Sealed tube; | General procedure for sulfonamidation General procedure: An oven-dried 6-ml vial equipped witha stir bar was placed in a nitrogen-filled glovebox and charged with Cu(OTf)2 (180.8 mg, 2.5 equiv., 0.50 mmol), Na3PO4 (98.2 mg, 3.0 equiv., 0.60 mmol), the sulfonamide nucleophile (1.5-3.0 equiv.), carboxylic acid (1.0 equiv., 0.20 mmol), methylene chloride (2.0 ml, 0.10 M) and isobutyronitrile (100 μl, 5.5 equiv.,1.1 mmol). The vial was sealed with a screwcap bearing a Teflon septum, removed from the glovebox and placed on a stir plate. The vial was irradiated at 427 nm with two 40-W Kessil PR160 lamps at a distance of 10 cm with stirring at 800 r.p.m. A fan was used to maintain the vial at room temperature. After 24 h, the crude reaction mixture was diluted with 1.5 ml of EtOAc and adsorbed directly on diatomaceous earth (Celite). The product was purified by flash chromatography on silica gel, eluting with mixtures of ethyl acetate and hexanes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; | 4.1.1. general procedure for the synthesis of compounds 3a-3s General procedure: 4.1.1.1. 2-(4-Methoxyphenoxy)-N-tosylacetamide (3a). To a solution of4-methoxyphenoxyacetic acid (182 mg, 1 mmol) in 10 mL anhydrousTHF at room temperature, N, N-diisopropylethylamine (494 μL, 3 mmol)and isobutyl chloroformate (194 μL, 1.5 mmol) were added. Then, afterstirred for 3 h, the solution of p-toluenesulfonamide (188 mg, 1.1 mmol)in THF, which was pretreated aforehand with NaH (120 mg, 3 mmol) for3 h at 0 C, was added dropwise. The reaction mixture was allowed towarm slowly to room temperature and stirred overnight. Then, thesolvent was evaporated off in vacuum. The resulting residue wasneutralized by 1 M HCl solution and extracted with EtOAc, then theorganic phase was washed by 0.5 M citric acid solution and brine anddried by MgSO4. The crude was purified by column chromatography (PE/EA = 2:1) to generate compound 3a, a white powder. Yield: 65%,1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 7.81 (d, J = 8.1 Hz, 2H),7.43 (d, J = 8.1 Hz, 2H), 6.80 (d, J = 9.1 Hz, 2H), 6.73 (d, J = 9.1 Hz,2H), 4.54 (s, 2H), 3.68 (s, 3H), 2.40 (s, 3H). 13C NMR (101 MHz,Chloroform-d) δ 166.5, 155.2, 150.5, 145.5, 135.2, 129.7, 128.6, 115.8,114.9, 68.1, 55.7, 21.7. HRMS (ESI) m/z: calculated for C16H18NO5S [M+ H]+ 336.0900, found 336.0897. | |
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; | 4.1.1. general procedure for the synthesis of compounds 3a-3s General procedure: 4.1.1.1. 2-(4-Methoxyphenoxy)-N-tosylacetamide (3a). To a solution of4-methoxyphenoxyacetic acid (182 mg, 1 mmol) in 10 mL anhydrousTHF at room temperature, N, N-diisopropylethylamine (494 μL, 3 mmol)and isobutyl chloroformate (194 μL, 1.5 mmol) were added. Then, afterstirred for 3 h, the solution of p-toluenesulfonamide (188 mg, 1.1 mmol)in THF, which was pretreated aforehand with NaH (120 mg, 3 mmol) for3 h at 0 C, was added dropwise. The reaction mixture was allowed towarm slowly to room temperature and stirred overnight. Then, thesolvent was evaporated off in vacuum. The resulting residue wasneutralized by 1 M HCl solution and extracted with EtOAc, then theorganic phase was washed by 0.5 M citric acid solution and brine anddried by MgSO4. The crude was purified by column chromatography (PE/EA = 2:1) to generate compound 3a, a white powder. Yield: 65%,1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 7.81 (d, J = 8.1 Hz, 2H),7.43 (d, J = 8.1 Hz, 2H), 6.80 (d, J = 9.1 Hz, 2H), 6.73 (d, J = 9.1 Hz,2H), 4.54 (s, 2H), 3.68 (s, 3H), 2.40 (s, 3H). 13C NMR (101 MHz,Chloroform-d) δ 166.5, 155.2, 150.5, 145.5, 135.2, 129.7, 128.6, 115.8,114.9, 68.1, 55.7, 21.7. HRMS (ESI) m/z: calculated for C16H18NO5S [M+ H]+ 336.0900, found 336.0897. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | Stage #1: 1-(4-(difluoromethoxy)benzyl)-1H-indole-3-carboxylic acid With thionyl chloride at 20℃; for 0.0833333h; Stage #2: methyl 2-(aminosulfonyl)benzoate With dmap; triethylamine In dichloromethane for 2h; | 14.14-3 Step 14-3.1-(4-(difluoromethoxy)benzyl)-N-(o-tolylsulfonyl)-1H-indole-3- 10 carboxamide (Compound 312) To a 50-mL round bottom flask containing 1-(4-(difluoromethoxy)benzyl)-1H- indole-3-carboxylic acid, (INT-14B), (50 mg, 1.0 equiv., 0.16 mmol) was added SOCl2 (5 mL) and stirred at rt for 5 min. Volatile was removed under vacuo, and the residue was 15 added 2-methylbenzenesulfonamide (30 mg, 1.1 equiv., 0.17 mmol), DMAP (21 mg, 1.1 equiv., 0.17 mmol), and anhydrous DCM (5 mL). At 1 h, 2-methylbenzenesulfonamide (30 mg, 1 equiv., 0.17 mmol) was added followed by Et3N (50 µmol). After an additional 1 h, solvents were removed under vacuo. The residue was diluted with EtOAc (50 mL) and washed consecutive with 1 M HCl (aq., 30 mL), 1 M NaOH (aq., 30 mL), saturated 20 NaHCO3 (aq., 30 mL), and brine (aq., 30 mL), dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography260 using ISCO eluting with 0-100% EtOAc/hexanes. Product fractions were combined, concentrated and the residue was dissolved in CH3CN/H2O and lyophilized to yield 26 mg (36%) of 1-(4-(difluoromethoxy)benzyl)-N-(o-tolylsulfonyl)-1H-indole-3- carboxamide (Compound 312) as a solid. LCMS (m/z) calculated for C24H20F2N2O4S: 5 470.11; found 471.4 [M+H] +, tR = 11.81 min (method 3).1H NMR (400 MHz, DMSO- d6) δ 12.12 (s, 1H), 8.56 (s, 1H), 8.06 (d, J = 8 Hz, 1H), 7.96 (d, J = 8 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.46 (t, J = 8 Hz, 1H), 7.41 - 7.03 (m, 8H), 5.50 (s, 2H), 2.65 (s, 3H). |
36% | Stage #1: 1-(4-(difluoromethoxy)benzyl)-1H-indole-3-carboxylic acid With thionyl chloride at 20℃; for 0.0833333h; Stage #2: methyl 2-(aminosulfonyl)benzoate With dmap; triethylamine In dichloromethane for 2h; | 14.14-3 Step 14-3.1-(4-(difluoromethoxy)benzyl)-N-(o-tolylsulfonyl)-1H-indole-3- 10 carboxamide (Compound 312) To a 50-mL round bottom flask containing 1-(4-(difluoromethoxy)benzyl)-1H- indole-3-carboxylic acid, (INT-14B), (50 mg, 1.0 equiv., 0.16 mmol) was added SOCl2 (5 mL) and stirred at rt for 5 min. Volatile was removed under vacuo, and the residue was 15 added 2-methylbenzenesulfonamide (30 mg, 1.1 equiv., 0.17 mmol), DMAP (21 mg, 1.1 equiv., 0.17 mmol), and anhydrous DCM (5 mL). At 1 h, 2-methylbenzenesulfonamide (30 mg, 1 equiv., 0.17 mmol) was added followed by Et3N (50 µmol). After an additional 1 h, solvents were removed under vacuo. The residue was diluted with EtOAc (50 mL) and washed consecutive with 1 M HCl (aq., 30 mL), 1 M NaOH (aq., 30 mL), saturated 20 NaHCO3 (aq., 30 mL), and brine (aq., 30 mL), dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography260 using ISCO eluting with 0-100% EtOAc/hexanes. Product fractions were combined, concentrated and the residue was dissolved in CH3CN/H2O and lyophilized to yield 26 mg (36%) of 1-(4-(difluoromethoxy)benzyl)-N-(o-tolylsulfonyl)-1H-indole-3- carboxamide (Compound 312) as a solid. LCMS (m/z) calculated for C24H20F2N2O4S: 5 470.11; found 471.4 [M+H] +, tR = 11.81 min (method 3).1H NMR (400 MHz, DMSO- d6) δ 12.12 (s, 1H), 8.56 (s, 1H), 8.06 (d, J = 8 Hz, 1H), 7.96 (d, J = 8 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.46 (t, J = 8 Hz, 1H), 7.41 - 7.03 (m, 8H), 5.50 (s, 2H), 2.65 (s, 3H). |
Tags: 88-19-7 synthesis path| 88-19-7 SDS| 88-19-7 COA| 88-19-7 purity| 88-19-7 application| 88-19-7 NMR| 88-19-7 COA| 88-19-7 structure
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