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With titanium(IV) tetraethanolate; In tetrahydrofuran; for 2.5h;Reflux;
<strong>[127413-59-6]1-(3-Bromo-5-nitro-phenyl)-ethanone</strong> (11.6 g, 47.5 mmol), (R)-(+)-tert-butanesulfinamide (6.34 g, 52.3 mmol) and Ti(OEt)4 (24.64 ml, 119 mmol) were mixed in 62 ml THF and refluxed for 2.5 hrs. The reaction was cooled and carefully quenched by addition of ice and water. The white precipitate was filtered off and the aqueous mixture was extracted with ethyl acetate. The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure. The crude product was purified by automated column chromatography (cyclohexane/ethyl acetate) yielding the title compound as yellow oil. 1H-NMR (500 MHz, DMSO-d6): 8.58 (s, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 2.79 (s, 3H), 1.24 (s, 9H); MS: 347 [(M+H)+]; [alpha]D=+54.5 (c=0.481% in chloroform).
With caesium carbonate; In dichloromethane; at 20℃; for 1h;
Intermediate 15 A. (5',E)-N-((4-Chloro-3-fluoropyridin-2-yl)methylene)-2- methylpropane-2-sulfinamide: A solution of (i?)-2-methylpropane-2-sulfinamide (0.540 g, 4.32 mmol), <strong>[1260878-78-1]4-chloro-3-fluoropicolinaldehyde</strong> (0.627 g, 3.93 mmol) and Cs2C03 (1.921 g, 5.89 mmol) in DCM (20 mL) was stirred for 1 h at rt. The reaction mixture was diluted with EtOAc and washed with brine (3x20 mL). The organic layer was dried over MgS04, filtered and concentrated in vacuo to provide the desired product (1.1 g, 100%). MS (ESI) m/z: 263.0 (M+H)+.
(R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With copper(II) sulfate; In 1,2-dichloro-ethane; at 60℃; for 18h;
StepiTo a round bottom flask with stir bar was added <strong>[357405-75-5]4-bromo-2,5-difluorobenzaldehyde</strong> (5.3 g, 24.0 mmol), (R)-2-methylpropane-2-sulfinamide (3.2 g, 26.4 mmol) and DOE (80 mL). To this mixture was then added copper (II) sulfate (5.74 g, 36.0 mmol). The reaction mixture was heated in a preheated oil bath at 60 00 for i8 hours. The reaction mixture was filtered througha pad celite, washing the solids with DOE. The filtrate was concentrated to afford a viscous green oil of (R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (7.2 g,22.2 mmol, 93 percent yield). Material was taken onto next step without further purification. LOMS m/z 326.0 (M + H), Rt i .04 mm.
93%
With copper(II) sulfate; at 60℃; for 18h;
StepiTo a round bottom flask with stir bar was added <strong>[357405-75-5]4-bromo-2,5-difluorobenzaldehyde</strong> (5.3 g, 24.0 mmol), (R)-2-methylpropane-2-sulfinamide (3.2 g, 26.4 mmol) and DOE (80 mL). To this mixture was then added copper (II) sulfate (5.74 g, 36.0 mmol). The reaction mixture was heated in a preheated oil bath at 60 00 for i8 hours. The reaction mixture was filtered througha pad celite, washing the solids with DOE. The filtrate was concentrated to afford a viscous green oil of (R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (7.2 g,22.2 mmol, 93 percent yield). Material was taken onto next step without further purification. LOMS m/z 326.0 (M + H), Rt 1.04 mm.
(R,E)-N-((6-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With caesium carbonate; In dichloromethane; at 20℃; for 5h;
To a stirred suspension of (R)-2-methylpropane-2-sulfinamide (l.Og, 8.25 mmol) and Cs2C03 (4.03 g, 12.38 mmol) in DCM (15 mL) was added a solution of 6- methoxypicolinaldehyde (1.092 mL, 9.08 mmol) in DCM (2 mL) dropwise. The solution was then stirred at rt for 5 h. The solid was filtered and solvent was removed. The crude product was purified by normal phase chromatography to provide VI-3a as clear colorless oil (1.91 g, 96percent). LC-MS (ESI) m/z: 241.0 [M+H]+; 'H NMR (400MHZ, CDCI3) delta 8.59 (s, 1H), 7.72 - 7.58 (m, 2H), 6.85 (dd, J=7.9, 1.1 Hz, 1H), 3.99 (s, 3H), 1.29 (s, 9H).
(R)-N-((6-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With caesium carbonate; In dichloromethane; at 20℃; for 5h;
To a stirred suspension of (R)-2-methylpropane-2-sulfinamide (1.0 g, 8.3 mmol) and CS2CO3 (4.0 g, 12 mmol) in DCM (15 mL), was added a solution of 6- methoxypicolinaldehyde in DCM (1.1 mL, 9.1 mmol, in 3 mL DCM) dropwise. The solution was then stirred at rt for 5 h. The solid was filtered off, and the solvent was removed. The crude product was purified by normal phase chromatography to afford Intermediate 11A (1.9 g, 96percent) as a clear colorless oil. LC-MS (ESI) m/z: 241.0 [M+H]+; XH NMR (400MHz, CDC13) delta 8.59 (s, 1H), 7.72 - 7.58 (m, 2H), 6.85 (dd, J= 7.9, 1.1 Hz, 1H), 3.99 (s, 3H), 1.29 (s, 9H).
(R)-N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With caesium carbonate; In dichloromethane; at 20℃; for 18.5h;
To a stirred suspension of(R)-2-methylpropane-2-sulfinamide (13.03 g, 108 mmol) and Cs2CO3 (52.5 g, 161 mmol) in DCM (400 ml) was added 2-bromopyridine-4- carbaldehyde (20 g, 108 mmol) over 10 mm. The reaction mixture was then stirred for 18.5 h at rt. The reaction mixture was concentrated and the residue was diluted with EtOAc (50 ml) and washed with brine (3 x 20 ml). The organic layer was dried overMgSO4, filtered and the filtrate concentrated. The residue was purified by normal phase chromatography using hexanes and EtOAc as eluents to afford (R)-N-[(1E)-(2- bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide (27.2 g, 87percent) as a white solid. MS(ESI) m/z: 289-291.0 (M+H).
87%
With caesium carbonate; In dichloromethane; at 20℃; for 18.5h;
To a stirred suspension of (R)-2-methylpropane-2-sulfinamide (13.03 g, 108 mmol) and CS2CO3 (52.5 g, 161 mmol) in DCM (400 ml) was added 2-bromopyridine-4- carbaldehyde (20 g, 108 mmol) over 10 min. The reaction mixture was then stirred for 18.5 h at rt. The reaction mixture was concentrated and the residue was diluted with EtOAc (50 ml) and washed with brine (3 x 20 ml). The organic layer was dried over MgS04 and filtered and then the filtrate was concentrated. The residue was purified by normal phase chromatography using hexanes and EtOAc as eluents to afford (27.2 g, 87percent) of (R)-N-[(lE)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide as a white solid. MS(ESI) m/z: 289-291.0 (M+H)+.
59%
With titanium(IV) tetraethanolate; In dichloromethane; at 20℃;Inert atmosphere;
To a solution of 2?bromopyridine?4?carbaldehyde (7e, 1g,5.38 mmol) and Ti(OEt)4 (5.64 mL, 26.9 mmol) in CH2Cl2(10.75 mL) was added (R)-2-methylpropane-2-sulfinamide(0.717 g, 5.91 mmol). The reaction was stirred overnight at rt.The reaction mixture was poured into a rapidly stirred mixtureof brine. The resulting suspension was filtered through a plug ofCelite and the filter cake was washed with CH2Cl2 to give a biphasicfiltrate. The layers were separated. The organic layer waswashed with brine, dried over MgSO4, filtered and concentrated.Column chromatography on silica gel (gradient elution 0?30percent EtOAc/Hex) gave 0.92 g (59percent yield) of (R)?N?[(1E)?(2?bromopyridin?4?yl)methylidene]?2?methylpropane?2?sulfinamide as a yellowoil. LCMS: 288.9 (M+H)+ and 290.9 (M+2+H)+. 1H NMR(400 MHz, CDCl3) d: 8.56?8.52 (m, 2H), 7.89 (s, 1H), 7.64 (dd,J = 4.9, 1.6 Hz, 1H), 1.29 (s, 9H).
N-[1-(4-bromo-1,3-thiazol-2-yl)ethylidene]-(R)-2-methylpropane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With titanium(IV) tetraethanolate; In tetrahydrofuran; at 75℃; for 16h;
This experiment was carried out in two identical batches. Titanium(IV) ethoxide (321 g, 1 .41 mol) was added in one portion to a room temperature (-15 C) solution of 1 -(4-bromo-1 ,3-thiazol-2-yl)ethanone (145 g, 704 mmol) and (f?)-2-methylpropane-2- sulfinamide (128 g, 1 .06 mol) in tetrahydrofuran (2.0 L), and the reaction mixture was heated at 75 C for 16 hours. It was then cooled to room temperature (-15 C), quenched with water (500 mL), and filtered. The filter cake was washed with ethyl acetate (4 x 500 mL), and the combined filtrates were concentrated in vacuo. The residues from the two batches were combined and purified via silica gel chromatography (Gradient: 5% to 25% ethyl acetate in petroleum ether), providing the product as a yellow solid. Yield: 340 g, 1.10 mol, 78%.1H NMR (400 MHz, CDCI3) delta 7.42 (s, 1 H), 2.85 (s, 3H), 1.32 (s, 9H).
(R)-N-(2-chloro-4-methylbenzylidene)-2-methylpropane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
442 mg
With caesium carbonate; In dichloromethane; at 45℃;
To a stirred solution of 2-chloro-3-methyl-benzaldehyde (327 mg, 2.12 mmol) in dichloromethane (10 mL) was added (R)-(+)-2-methyl-2-propanesulfinidine (308 mg, 2.54 mmol) and cesium carbonate (993 mg, 3.05 mmol) at RT. The resulting mixture was stirred overnight at 45 C. The reaction mixture was filtered through celite bed and the bed was washedwith dichloromethane (5 mL x 2). The combined filtrates were concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 442 mg of the titled compound. ?H NMR (300 MHz, CDC13) oe 1.27 (s, 9H), 1.41 (s, 1H), 2.39 (s, 3H), 7.15 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 7.8 Hz, 1H), 8.99 (s, 1H); ESI-MS (m/z) 258 (M+H)+
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