* 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.
With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In water; toluene at 20℃; for 3 h;
A solution of benzenesulfonyl chloride (1.92 mL, 15.0 mmol) in toluene (15.0 mL) was added over a period of 15 min to a mixture of pyrrole (0.69 mL, 10.0 mmol), tetrabutylammonium bisulfate (0.34 g, 1.0 mmol), and 50percent aqueous sodium hydroxide (10.0 mL) in toluene (30.0 mL). The mixture was stirred at room temperature, and the reaction was monitored by thin layer chromatography. After stirring at room temperature for 3 h, TLC showed that the reaction was completed. The layers were separated, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 30percent CH2Cl2/hexane) to yield 1.81 g (87percent) of a white solid. M. p. 86-87 C ; lH NMR (300 MHz, CDC13) 8 6.30 (m, 2H), 7.17 (m, 2H), 7.50 (m, 2H), 7.57 (m, 1H), 7.84 (m, 1H), 7.87 (m, 1H).
60%
Stage #1: With sodium hydroxide In dichloromethane at 0℃; for 0.166667 h; Stage #2: at 0 - 20℃;
Example 30: 2-Chloro-5-(1 H-pyrrole-3-carbonyl)-benzenesulfonamide; 1-Benzenesulfonyl-1H-pyrrole; To a well-agitated suspension of sodium hydroxide (4.46 g, 111 mmol) in methylene chloride (26 ml_) at 0 0C is added pyrrole (2.5 g, 0.37 mmol), and the reaction mixture is stirred for 10 min, following which a solution of benzenesulfonyl chloride (7.86 g, 0.44 mmol) in methylene chloride (5.15 mL) is slowly added, allowed to warm to room temperature and stirred overnight. The reaction is quenched by pouring into water (100 mL). The organic layer is separated, and the aqueous layer is extracted with methylene chloride three times. The combined organic extracts are water, dried with sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (10percent ethyl acetate-hexane) provides 4.6 g (60percent) of the title compound as a white solid. 1H NMR (CDCI3): δ 7.80 (m, 2H), 7.50 (m, 3H), 7.25 (m, 2H), 6.30 (m, 2H).
Reference：
[1] Synthesis, 2004, # 12, p. 1951 - 1954
[2] Tetrahedron, 2006, vol. 62, # 8, p. 1699 - 1707
[3] Tetrahedron, 1998, vol. 54, # 46, p. 13915 - 13928
[4] Patent: WO2005/82343, 2005, A2, . Location in patent: Page/Page column 111
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[6] Patent: US6620841, 2003, B1,
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[8] Journal of Medicinal Chemistry, 2011, vol. 54, # 15, p. 5296 - 5306
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[11] Patent: WO2009/118292, 2009, A1, . Location in patent: Page/Page column 66
[12] Bulletin of the Chemical Society of Japan, 1984, vol. 57, # 11, p. 3488 - 3493
[13] Tetrahedron Letters, 1981, vol. 22, # 49, p. 4899 - 4900
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[21] Patent: US2015/51395, 2015, A1, . Location in patent: Paragraph 0888-0889
With manganese(IV) oxide In dichloromethane at 40℃; for 18 h;
Under a nitrogen atmosphere, N,N-diallylbenzene sulfonamide 2221 (660 mg, 2.78 mmol, 1 equiv) was dissolved in DCM (30 mL). Grubbs catalyst 1 (69.5 mg, 0.084 mmol, 3.0 mol percent) was added and the reaction was stirred at room temperature for 3 h. MnO2 (6.09 g, 70.0 mmol, 25 equiv) was then added to the reaction flask and heated to reflux with stirring for 18 h. On cooling the contents of the reaction were filtered through Celite® and washed with DCM (2*20 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (c-Hex-EtOAc; 6:1) which gave 26 (426 mg, 74percent) as a pale yellow solid. Mp=86-88 °C (lit.25 mp=87-88 °C); Rf=0.50 (c-Hex-EtOAc; 6:1); 1H NMR (400 MHz, CDCl3) 7.87-7.84 (2H, m, CH) 7.61-7.57 (1H, m, CH), 7.52-7.48 (2H, m, CH), 7.17-7.16 (2H, m, CH), 6.31-629 (2H, m, CH), ppm; 13C NMR (100 MHz, CDCl3) 139.1, 133.7, 129.3, 126.7, 120.8, 113.6 ppm; Anal. found (Calcd) for C10H9NO2S: C, 57.76percent (57.95percent); H, 4.07percent (4.38percent); N, 6.91percent (6.76percent).
In water at 150℃; for 0.5h; Microwave irradiation;
93%
With montmorillonite K-10 at 100℃; for 0.05h; microwave irradiation;
90%
With iron(III) chloride heptahydrate In water at 60℃; for 2h;
73%
With p-toluenesulfonic acid monohydrate In toluene at 20 - 100℃; for 0.5h; Inert atmosphere;
70%
With Oxone In acetonitrile at 110℃; for 0.316667h; Microwave irradiation;
General procedure for the synthesis of 1-substituted aryl-pyrroles (3a-h)
General procedure: Oxone (0.09 g, 0.30 mmol) was added to a solution of the aromatic primary amines (2.5 mmol) and 2,5-dimethoxytetrahydrofuron (3.0 mmol) in a solvent (5 mL) was further added (Scheme1). The reaction mixture was heated under microwave irradiation for 10 min at 110 ± 10 °C. The reaction mixture was irradiated until total consumption of the amine was verified by TLC. Water was added and the products were extracted with EtOAc (3x20 mL). The organic phasewas dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The product was purified on a silica gel column chromatography eluted with mixture of ethylacetate/hexane (1:4) to afford the product.
98 % Chromat.
With trifluorormethanesulfonic acid In dichloromethane at 20℃; for 2h;
In water at 140℃; for 0.416667h; Microwave irradiation;
34.1
Example 34. 5-[4-([4-isopropyI-l-(phenylsulfonyl)-l//-indol-3- yl]sulfonyl}amino)piperidin-l-yl]-5-oxopentanoic acid[0219] Step 1. l-(Phenylsulfonyl)-lH-pyrrole[0220] To a solution of 2,5-dimethoxytetrahydrofuran (8.7 mL, 67 mmol) in water (30 mL) was added portion wise benzene sulfonamide (7.0 g, 45 mmol). The solution was heated with stirring using microwave irradiation (1400C) for 25 minutes. After cooling to room temperature the reaction was filtered and the crude product was taken up in dichloromethane and filtered through a plug of silica gel to give l-(phenylsulfonyl)-lH-pyrrole (9.6 g).
(122-1) Under nitrogen atmosphere, a solution of <strong>[768-66-1]2,2,6,6-tetramethyl-piperidine</strong> (1.87 g) in THF (30 mL) was cooled to -78 C., and thereto was added dropwise a 1.5N solution of n-BuLi in n-hexane (8.85 mL), and the mixture was stirred at -78 C. for 5 minutes, and stirred at -30 C. for 5 minutes. Then, the mixture was cooled to -78 C., and thereto was added dropwise a solution of 1-(phenylsulfonyl)pyrrole (2.50 g) in THF (20 mL). The mixture was stirred at -78 C. for 45 minutes, and thereto was added dropwise a solution of methyl telephthalaldehyde (2.38 g) in THF (20 mL), and the mixture was further stirred at -78 C. for 1.5 hour. To the mixture was added drowpise aqueous NH4Cl solution, and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate, and the organic layer was washed with a 2.5N aqueous hydrochloric acid solution and NaHCO3, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=4/1?3/1) to give methyl 4-{hydroxy[1-(phenylsulfonyl)-1H-pyrrol-2-yl]methyl}-benzoate (3.67 g, 82%). 1H NMR (CDCl3, 400 MHz) delta 7.94 (d, 2H, J=8.4 Hz), 7.73 (d, 2H, J=8.4 Hz), 7.63 (m, 1H), 7.49 (m, 2H), 7.34 (dd, 1H, J=3.3, 1.8 Hz), 7.31 (d, 2H, J=8.4 Hz), 6.21 (dd, 1H, J=3.3, 3.3 Hz), 6.11 (d, 1H, J=4.6 Hz), 5.77 (m, 1H), 3.92 (s, 3H), 3.33 (d, 1H, J=4.6 Hz).
82%
With n-butyllithium; In tetrahydrofuran; hexane;
(122-1) Under nitrogen atmosphere, a solution of <strong>[768-66-1]2,2,6,6-tetramethylpiperidin</strong>e (1.87 g) in THF (30 mL) was cooled to -78C, and thereto was added dropwise a 1.5N solution of n-BuLi in n-hexane (8.85 mL), and the mixture was stirred at -78C for 5 minutes, and stirred at -30C for 5 minutes. Then, the mixture was cooled to -78C, and thereto was added dropwise a solution of 1-(phenylsulfonyl)pyrrole (2.50 g) in THF (20 mL). The mixture was stirred at -78C for 45 minutes, and thereto was added dropwise a solution of methyl telephthalaldehyde (2.38 g) in THF (20 mL), and the mixture was further stirred at -78C for 1.5 hour. To the mixture was added drowpise aqueous NH4Cl solution, and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate, and the organic layer was washed with a 2.5N aqueous hydrochloric acid solution and NaHCO3, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate = 4/1? 3/1) to give methyl 4-{hydroxy[1-(phenylsulfonyl)-1H-pyrrol-2-yl]methyl}benzoate (3.67 g, 82 %). 1H NMR (CDCl3, 400MHz) delta 7.94 (d, 2H, J=8.4Hz), 7.73 (d, 2H, J=8.4Hz), 7.63 (m, 1H), 7.49 (m, 2H), 7.34 (dd, 1H, J=3.3, 1.8Hz), 7.31 (d, 2H, J=8.4Hz), 6.21 (dd, 1H, J=3.3, 3.3Hz), 6.11 (d, 1H, J=4.6Hz), 5.77 (m, 1H), 3.92 (s, 3H), 3.33 (d, 1H, J=4.6Hz).
Stage #1: 3-(aminosulfonyl)-4-chlorobenzoyl chloride In dichloromethane at 20℃; for 0.166667h;
Stage #2: N-phenylsulfonylpyrrole In dichloromethane at 20℃;
30
5-(1 -Benzenesulfonyl-1 H-pyrrole-3-carbonyl)-2-chloro-benzenesulfonamide; To a suspension of aluminum chloride (1.89 g, 14 mmol) in methylene chloride (10 mL) is added 4-chloro-3-sulfamoyl-benzoyl chloride (2 g, 7.9 mmol). The reaction mixture is stirred at room temperature for 10 minutes then a solution of 1 -benzenesulfonyl-1 H-pyrrole (1.13 g, 5.45 mmol) in methylene chloride (3.3 mL) is added. After stirring at room temperature overnight, the reaction is quenched with 6 N HCI and extracted with ethyl 52419A acetate three times. The combined organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate/hexane: 2:8) provides 0.6 g (26%) of the title compound as a yellow solid. 1H NMR (DMSO): δ 8.30 (s, 1 H), 8.15 (m, 2H), 8.05 (m, 2H), 7.80 (m, 4H), 7.70 (m, 2H), 7.40 (m, 1 H), 6.70 (m, 1 H).
To a solution of N-benzenesulfonylpyrrole (25 g, 121 mmol) in acetic acid (300 mL) at rt was added bromine (20.24 g, 127 mmol) in acetic acid (100 mL) dropwise over 30 min. The solution was heated to reflux for 2 hrs, then stirred the weekend at rt. The solution was concentrated, saturated sodium bicarbonate was added, extracted with DCM, dried over MgSO4 and concentrated. Purification by flash chromatography (400 g column) eluting with 5 to 15% EA/heptane gives 3-bromo-1-(phenylsulfonyl)-1H-pyrrole (27.07 g, 78%). 1H NMR (CHLOROFORM-d) δ: 7.81-7.92 (m, 2H), 7.45-7.71 (m, 3H), 7.14-7.21 (m, 1H), 7.09 (t, J=2.8 Hz, 1H), 6.26-6.34 (m, 1H).
70%
With bromine; acetic acid at 20℃; Reflux;
70%
With bromine; acetic acid for 2h; Reflux;
68%
With bromine; acetic acid for 2h; Reflux;
7.69 g
With bromine; acetic acid for 1h; Reflux; regioselective reaction;
With trifluorormethanesulfonic acid; at 20℃; for 0.0833333h;Neat (no solvent);
General procedure: 430 muL of anisyl acetate (2.5 mmol, 1 equiv) and 2.2 mL of anisole (12.25 mmol, 5 equiv) were placed into a 10 mL round-bottom flask equipped with a magnetic stir-bar. Then 11 muL 5% of pure triflic acid (0.125 mmol) was added and the solution was stirred for 20 min. The crude was analyzed by 1H NMR and GC-MS. Purification by column chromatography gave 484 mg (85% yield) of bis(4-methoxyphenyl)methane, which was identical to an authentic sample.
Stage #1: 2-(2-nitrophenyl)acetic acid With oxalyl dichloride In 1,2-dichloro-ethane for 0.5h; Inert atmosphere;
Stage #2: N-phenylsulfonylpyrrole With aluminum (III) chloride In 1,2-dichloro-ethane at 0℃; for 0.416667h;
Stage #3: With hydrogenchloride; water Cooling;
1.7
Example 1.7: 2-(2-Nitrophenyl)-1-[1-(phenylsulfonil)-1H- pyrrol-3-yl]ethan-1-one.Oxalyl chloride (2.46 g, 1.64 mL, 0.019 mol) and a catalytic amount of DMF are added to 2-nitrophenylacetic acid (3.52 g, 0.019 mol) in anhydrous 1 ,2-dichloroethane (88 mL) under argon. After 30 min, 1-(phenylsulfonil)-1H-pyrrole (4.04 g, 0.00019 mol) and anhydrous aluminium chloride (2.59 g, 0.0019 mol) and the reaction mixture is stirred at 0°C for 25 min. After cooling the reaction is blocked by pouring in 1 N HCI acidified ground ice and extracted with chloroform. The organic layer is washed with water and dried. After solvent removal the obtained residue is purified by column chromatography (silica gel, acetone:n-hexane 1 :2 as eluent) to give 2-(2-nitrophenyl)-1-[1- (phenylsulfonil)-1H-pyrrol-3-yl]ethan-1-one (0.7 g, 10%), melting point 135°C (after ethanol crystallization). 1H NMR (DMSO-d6): δ 4.45 (s, 2H), 6.41-6.43 (m, 1 H), 7.25-7.30 (m, 2H), 7.45-7.60 (m, 5H), 7.85-7.86 (m, 1 H), 7.90-7.92 (m, 2H), 8.06 ppm (dd, J = 1.2 and 8.18 Hz, 1 H). IR: v 1680 cm-1. Anal. (C18H14N205S (370.38)) C, H, N, S.
10%
Stage #1: 2-(2-nitrophenyl)acetic acid With oxalyl dichloride In 1,2-dichloro-ethane; N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere;
Stage #2: N-phenylsulfonylpyrrole With aluminum (III) chloride In 1,2-dichloro-ethane; N,N-dimethyl-formamide at 0℃; for 0.416667h; Inert atmosphere;
5-oxo-5-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]pentanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With aluminum (III) chloride In dichloromethane at 20℃; for 1h;
1 General procedure for the preparation of 5-[1 H-pyrrol-3-yl]-5-oxo-pentanoic acid (5a, b).
A suspension of AICI3 (12 g, 90 mmol) and glutaric anhydride (3.40 g, 30 mmol) in anhydrous dichloromethane (60 ml_) was stirred at room temperature for 1 h. Then a solution of 4a,b (15 mmol) in anhydrous dichloromethane (30 ml_) was added and the reaction mixture was stirred at room temperature for 1.5 h. Ice and water were added (80 ml_) and the two phases were separated. Then the aqueous phase was extracted with ethyl acetate (3 x 60 ml_). The organic layer was dried (Na2S04) and the solvent was removed under reduced pressure. The crude product was purified by chromatography column (dichloromethane/ethyl acetate 1 : 1). 5-Oxo-5-[1 -(phenylsulfonyl)-1 H-pyrrol-3-yl]pentanoic acid (5a). This compound was obtained from reaction of 5a. Yield: 80%, light brown solid; m.p. : 1 1 1 .6 - 1 1 1.8 °C; I R: 3550 (OH), 1706 (CO), 1675 (CO) cm"1 ; 1 H NMR (DMSO-de) (ppm): 1 .72 - 1.83 (2H, m, CH2), 2.26 (2H, t, J = 1.2, Hz, CH2), 2.85 (2H, t, J = 7.3 Hz, CH2), 6.67 (1 H, dd, J = 3.3, 1.8 Hz, H-4), 7.45 (1 H, dd, J = 3.3, 1.8 Hz, H-5), 7.64 - 7.86 (3H, m, H-3', H-4'and H-5'), 8.06 - 8.13 (2H, m, H-2'and H-6'), 8.21 (1 H, s, H-2), 12.07 (1 H, s, OH); 13C NMR (DMSO-d6) (ppm): 19.2 (t), 32.8 (t), 38.0 (t), 1 12.0 (d), 122.2 (d), 125.4 (d), 127.2 (d x 2), 128.6 (s), 130.1 (d x 2), 135.1 (d), 137.3 (s), 174.1 (s), 194.7 (s). Anal calcd for C15H15N05S (321 .35): C, 56.06; H, 4.70; N, 4.36. Found: C, 56.18; H, 4.89; N, 4.15
80%
Stage #1: glutaric anhydride, With aluminum (III) chloride In dichloromethane at 20℃; for 1h;
Stage #2: N-phenylsulfonylpyrrole In dichloromethane at 20℃; for 1.5h;
5.1.1. Preparation of 5-oxo-5-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]pentanoic acid (6)
A suspension of AlCl3 (12 g, 90 mmol) and glutaric anhydride(3.40 g, 30 mmol) in anhydrous DCM (60 mL) was stirred at rt for1 h. Then a solution of 5 (15 mmol) in anhydrous dcm (30 mL) wasadded and the reaction mixturewas stirred at rt for 90 min. Ice andwater were added (80 mL) and the two phases were separated.Then the aqueous phase was extracted with EtOAc (3 x 60 mL). Theorganic layer was dried (Na2SO4) and the solvent was removedunder reduced pressure. The crude product was purified by flashchromatography eluting with DCM/EtOAc (6:4). Light brown solid;yield 80%. Spectroscopic data are in accordance with those previousreported [52]; Rf 0.55 (DCM/EtOAc, 6:4); m.p.: 111-112 °C; IRcm1: 3550 (OH), 1706 (CO), 1675 (CO); 1H NMR (DMSO-d6,200 MHz, ppm): δ 1.72-1.83 (2H, m, CH2), 2.26 (t, 2H, J 7.3 Hz,CH2CH2CH2COOH), 2.85 (t, 2H, J 7.3 Hz, CH2CH2CH2COOH), 6.67(dd, 1H, J4,5 3.3, J4,2 1.8 Hz, H-4), 7.45 (dd, 1H, J5,4 3.3,J5,2 1.8 Hz, H-5), 7.64-7.86 (m, 3H, H-3' , H-4' and H-5'), 8.06-8.13(m, 2H, H-2' and H-6'), 8.21 (s, 1H, H-2), 12.07 (s, 1H, OH); 13C NMR(DMSO-d6, 50 MHz, ppm): δ 19.2 (CH2CH2CH2COOH), 32.8(CH2CH2CH2COOH), 38.0 (CH2CH2CH2COOH), 112.0 (C-4), 122.2 (C-2), 125.4 (C-5), 127.2 (C-2', C-6'), 128.6 (C-3), 130.1 (C-3', C-5'), 135.1(C-4'), 137.3 (C-1'), 174.1 (COCH2CH2CH2COOH), 194.7(COCH2CH2CH2COOH). Anal calcd for C15H15NO5S (321.35): C,56.06; H, 4.70; N, 4.36, found: C, 56.18; H, 4.89; N, 4.15.
(3-fluorophenyl)(1H-pyrrol-3-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: 3-fluorobenzoyl chloride With aluminum (III) chloride In 1,2-dichloro-ethane at 20℃; for 0.25h; Inert atmosphere;
Stage #2: N-phenylsulfonylpyrrole In 1,2-dichloro-ethane at 20℃; for 1.5h; Inert atmosphere;
Stage #3: With sodium hydroxide In 1,4-dioxane at 20℃; for 16h;
4.1.1. General procedure A: Friedel-Crafts aroylation and alkalinehydrolysis (1d-g)
General procedure: To a suspension of AlCl3 (1.16 g, 8.68 mmol) in 1,2-dichloroethane (15 mL) under an inert atmosphere, the appropriatearoyl chloride (8.1 mmol)was added slowly and the resultingmixture was stirred at room temperature for 15 min. A solution of1-benzenesulfonyl-1H-pyrrole (1.5 g, 7.24 mmol) in 1,2-dichloroethane (3 mL) was added and the mixture was allowed tostir at room temperature for 90 min. The reaction mixture wasquenched with equal parts of ice and water over 30 min. Theaqueous phase was extracted with DCM (2 x 30 mL) and thecombined organic extracts werewashed with brine, dried over anh.Na2SO4 and concentrated under reduced pressure. The resultingresidue was dissolved in dioxane (30 mL) and to this a 5 N NaOHsolution (30 mL) was added. The reaction mixture was vigorouslystirred overnight at room temperature. The aqueous layer was thenextracted with EtOAc (3 30 mL) and the combined organic layers were washed with brine, dried over anh. Na2SO4 and concentratedunder reduced pressure. The residue was purified by silica gelcolumn chromatography (10e25% EtOAc in petroleum ether).
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