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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Synonyms: (R)-2-Methylpropane-2-sulfinamide
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CAS No. : | 196929-78-9 |
Formula : | C4H11NOS |
M.W : | 121.20 |
SMILES Code : | CC([S@](N)=O)(C)C |
Synonyms : |
(R)-2-Methylpropane-2-sulfinamide
|
MDL No. : | MFCD05861479 |
InChI Key : | CESUXLKAADQNTB-SSDOTTSWSA-N |
Pubchem ID : | 10964479 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
* 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 |
---|---|---|
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 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)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With titanium(IV) isopropylate; at 85℃; for 24h;Inert atmosphere; Microwave irradiation; Sealed tube; | 1-(1-Methyl-1H-pyrazol-4-yl)-1-ethanone (1.05 g, 8.46 mmol), (R)-2-methyl-2-propanesulfinamide (0.96 g, 7.9 mmol) and Ti(OiPr)4 (9.1 g, 9.57 mL, 32 mmol) were mixed in a high pressure tube, sealed and irradiated in a microwave reactor at 85 C (50 W) for 24 h. The progress of the reaction was monitored by 1H NMR. After disappearance of the sulfinamide signals, the reaction mixture was diluted with THF (30 mL) and poured into water (70 mL). After 20 min of stirring, the suspension was filtered through a pad of Super Cel, and the precipitate was washed two times with DCM. The filtrate was diluted with water (100 mL) and extracted with DCM (20 mL * 3). The combined extracts were dried over K2CO3 and evaporated under reduced pressure. The residue was recrystallized from diethyl ether to afford 2e (1.59 g, 88%) as a beige crystalline solid. Rf: 0.26 (EtOAc). = -73.7 (c 1, CHCl3). Mp 88-89 C (Et2O). 1H NMR (400 MHz, CDCl3): delta 7.84 (s, 1H, CHpyr), 7.81 (s, 1H, CHpyr), 3.93 (s, 3H, NMe), 2.60 (s, 3H, MeC=N), 1.27 (s, 9H, tBu). 13C NMR (100 MHz, CDCl3): delta 171.19, 139.40, 130.98, 124.47, 56.74, 39.36, 22.26 3C, 20.87. MS (70 eV, EI): m/z (%) = 228 (12) [MH]+, 211 (2), 172 (12), 171 (100), 170 (12), 130 (51), 123 (36), 108 (72), 107 (18), 89 (12), 82 (34), 81 (10). C10H17N3OS (227.3): calcd C 52.83, H 7.54, N 18.48, S 14.11; found C 52.80, H 7.55, N 18.35, S 13.97. |
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. |
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). |
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.79 g | A solution of fer?-butyl l-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5.24 g, 21.9 mmol), titanium(IV) isopropoxide (16.2 mL, 54.7 mmol), and (R)-2-methylpropane- 2-sulfinamide (3.45 g, 28.5 mmol) in THF (99 mL) was stirred for 12 h at 65 C. After cooling to -78 C, MeOH (9.9 mL) was added followed by lithium borohydride (1.43 g, 65.7 mmol). The resulting mixture was stirred at -78 C for 3 h and at RT for 1 h. MeOH was slowly added to quench the excess of borohydride followed by addition of brine. The resulting mixture was stirred for 15 min and then filtered through Celite. The aqueous mixture was extracted with EtOAc (3 x 20 mL). The organic phases were dried over MgS04, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0 to 50% gradient of EtO Ac/heptane to give (5)-?er?-butyl l-((R)-l,l-dimethylethylsulfinamido)-7- azaspiro[3.5]nonane-7-carboxylate (4.79 g. 13.90 mmol) as a white solid. MS m/z 345.3 (M+H)+. | |
4.79 g | A solution of teri-butyl l-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5.24 g, 21.9 mmol), titanium(IV) isopropoxide (16.2 mL, 54.7 mmol), and (R)-2- methylpropane-2-sulfinamide (3.45 g, 28.5 mmol) in THF (99 mL) was stirred for 12 h at 65 C. After cooling to -78 C, MeOH (9.9 mL) was added followed by lithium borohydride (1.43 g, 65.7 mmol). The resulting mixture was stirred at -78 C for 3 h and at room temperature for 1 h. MeOH was slowly added to quench the excess of borohydride followed by addition of brine. The resulting mixture was stirred for 15 min and then filtered through Celite. The aqueous mixture was extracted with EtOAc (3 x 20 mL). The organic phases were dried over MgS04, filtered, and concentrated. The resulting residue was purified by silica chromatography (0-50% EtO Ac/heptane eluent) to provide (5)-teri-butyl 1 -((/?)- 1 , 1- dimethylethylsulfinamido)-7-azaspiro[3.5]nonane-7-carboxylate (4.79 g. 13.90 mmol) as a white solid. LCMS: m/z 345.3 (M+H)+. | |
4.79 g | A solution of <strong>[849203-60-7]tert-butyl 1-oxo-7-azaspiro[3.5]nonane-7-carboxylate</strong> (5.24 g, 21.9 mmol), titanium(IV) isopropoxide (16.2 mE, 54.7 mmol), and (R)-2-methylpro- pane-2-sulfinamide (3.45 g, 28.5 mmol) in THF (99 mE) was stirred for 12 h at 65 C. Afier cooling to -78 C., MeOH (9.9 mE) was added followed by lithium borohydride (1.43 g, 65.7 mmol). The resulting mixture was stirred at-78 C. for 3 h and at RT for 1 h. MeOH was slowly added to quench the excess of borohydride followed by addition of brine. The resulting mixture was stirred for 15 mm and then filtered through Celite. The aqueous mixture was extracted with EtOAc (3x20 mE). The organic phases were dried over Mg504, filtered, and the volatiles were removed under reduced pressure. The resulting residue was purified by silica chromatography (0 to 50% gradient of EtOAc/heptane to give (5)-tert-butyl 1 -((R)- 1,1 -dimethylethylsulfinamido)7-azaspiro[3 .5]nonane-7-carboxylate (4.79 g. 13.90 mmol) as a white solid. MS mlz 345.3 (M+H). |
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.7% | With titanium(IV) tetraethanolate; at 105℃; for 4h;Inert atmosphere; | Step b: A flask containing tert-butyl 1 -oxo-8-azaspiro [4.Sjdecane-8- carboxylate (238 g, 939 mmol) was charged with (R)-(+)-2-methyl-2-propanesulfinamide (171 g, 1409 mmol) under N2 atmosphere. Titanium(IV)ethoxide (985 mL, 4.70 mol) was added and the mixture was then heated to 105 C for 4 h. The heating mantle was removed and the mixture was vacuum transferred, under a stream of N2, with EtOAc (6 L) via a FEP tubing cannula to a 10 L, 4-necked flask equipped with a mechanical overhead stirrer and a 250 mL addition funnel with an N2 inlet adapter that was cooled in a cold water bath. Water (288 mL) was added dropwise via theaddition funnel over 30-45 mm, resulting in the precipitation of a large volume of light yellow salts. The suspension was aged for 15 minutes with the bath removed before filtering the entire mixture through Celite, washing with EtOAc (2 x 1 L). The filtrate was then washed with water (3 x 1 L) and concentrated under reduced pressure. Upon concentration and back-addition of heptane (2 L), the water was azeotroped off, which led to the precipitation of a cloudy, white film of salts on the interior wall of the flask. The light brown mixture was filtered through a medium sintered glass funnel (rinsed with EtOAc and heptane). The filtrate was further concentrated until most of the EtOAc was removed, and additional heptane was added (1 L). The mixture was concentrated further under reduced pressure to produce a precipitate, and additional heptane (500 mL) was added to keep the mixture mobile. The mixture was stirred at RT, then cooled with an ice bath before isolating the solids by vacuum filtration. The solid was washed three times with ice-cold heptane. The solid was dried under reduced pressure to give (R,E)-tert-butyl 1-((tert- butylsulfinyl)imino)-8-azaspiro[4.Sjdecane-8-carboxylate as a cream solid (408.9 g, 66.7% yield). ?H NMR (400 MHz, Chloroform-d) oe ppm 3.93 (m, 2 H), 3.05 (m, 3 H), 2.71 (dt, J=19.6, 7.2 Hz, 1 H), 1.96-1.71 (m, 6 H), 1.49 (s, 9 H), 1.42 (m, 2 H), 1.27 (s, 9 H). |
66.7% | With titanium(IV) tetraethanolate; at 105℃; for 4h;Inert atmosphere; | Step b: A flask containing ferf-butyl l-oxo-8-azaspiro[4.5]decane-8- carboxylate (238 g, 939 mmol) was charged with (R)-(+)-2-methyl-2-propanesulfinamide (171 g, 1409 mmol) under N2 atmosphere. Titanium(IV)ethoxide (985 mL, 4.70 mol) was added and the mixture was then heated to 105 C for 4 h. The heating mantle was removed and the mixture was vacuum transferred, under a stream of N2j with EtOAc (6 L) via a FEP tubing cannula to a 10 L, 4-necked flask equipped with a mechanical overhead stirrer and a 250 mL addition funnel with an N2 inlet adapter that was cooled in a cold water bath. Water (288 mL) was added dropwise via the addition funnel over 30-45 min, resulting in the precipitation of a large volume of light yellow salts. The suspension was aged for 15 minutes with the bath removed before filtering the entire mixture through Celite, washing with EtOAc (2 x 1 L). The filtrate was then washed with water (3 x 1 L) and concentrated under reduced pressure. Upon concentration and back-addition of heptane (2 L), the water was azeotroped off, which led to the precipitation of a cloudy, white film of salts on the interior wall of the flask. The light brown mixture was filtered through a medium sintered glass funnel (rinsed with EtOAc and heptane). The filtrate was further concentrated until most of the EtOAc was removed, and additional heptane was added (1 L). The mixture was concentrated further under reduced pressure to produce a precipitate, and additional heptane (500 mL) was added to keep the mixture mobile. The mixture was stirred at RT, then cooled with an ice bath before isolating the solids by vacuum filtration. The solid was washed three times with ice-cold heptane. The solid was dried under reduced pressure to give (R,E)-tert-butyl l-((tert- butylsulfinyl)imino)-8-azaspiro[4.5]decane-8-carboxylate as a cream solid (408.9 g, 66.7% yield). NMR (400 MHz, Chloroform- ) delta ppm 3.93 (m, 2 H), 3.05 (m, 3 H), 2.71 (dt, 7=19.6, 7.2 Hz, 1 H), 1.96-1.71 (m, 6 H), 1.49 (s, 9 H), 1.42 (m, 2 H), 1.27 (s, 9 H). |
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With titanium(IV) tetraethanolate; at 60℃; | To a 40 mL vial was added (R)-2-methylpropane-2-sulfinamide (1.83 g, 15.1 mmol), <strong>[10599-69-6]1-(5-methylfuran-2-yl)propan-1-one</strong> (2.0 mL, 15.1 mmol), and titanium ethoxide (7.8 mL). The reaction mixture was stirred at 60 C. overnight. The reaction was diluted with dichloromethane (100 mL) and quenched with sodium sulfate decahydrate (10.2 g). The reaction mixture was filtered through celite and rinsed with dichloromethane. Evaporation of the solvent gave the crude product which was purified by silica gel chromatography using a mixture of ethyl acetate and hexane as the eluent. | |
With titanium(IV) tetraethanolate; at 60℃; | [0165] Step a: To a 40 mL vial was added (i?)-2-methylpropane-2-sulfinamide (1.83 g, 15.1 mmol), l-(5-methylfuran-2-yl)propan-l-one (2.0 mL, 15.1 mmol), and titanium ethoxide (7.8 mL). The reaction mixture was stirred at 60 C overnight. The reaction was diluted with dichloromethane (100 mL) and quenched with sodium sulfate decahydrate (10.2 g). The reaction mixture was filtered through celite and rinsed with dichloromethane. Evaporation of the solvent gave the crude product which was purified by silica gel chromatography using a mixture of ethyl acetate and hexane as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With titanium(IV) tetraethanolate; In tetrahydrofuran; at 60 - 70℃; for 16h;Large scale; | (R)-(+)-2-Methyl-2-propanesulfinamide (400 g, 3.28 mmol), Intermediate 26 (500g, 2.73 mmol) and titanium(IV) ethoxide (1.55 kg, 5.45 mol) were stirred in THF (5 L) at60-70C for 16 h. Brine (1.5 L) was added, and the mixture was stirred at 25C for 30minutes, then filtered. The filter cake was washed with ethyl acetate (3 x 15 L), then the filtrate was washed with brine (500 mL) and dried over Na2SO4. The organic layer was concentrated. The crude residue was purified by silica gel chromatography (20:1 petroleum ether:ethyl acetate) to give the title compound (1.2 kg, 5 1%). 0H (400 MHz,DMSO-d6) 8.24-8.20 (m, 1H), 8.01-7.94 (m, 1H), 7.52-7.48 (m, 1H), 2.68 (d, J 1.2 Hz,3H), 1.19 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With titanium(IV) isopropylate; In toluene; at 110℃; for 16h;Inert atmosphere; | To a mixture of (R)-2-methylpropane-2-sulfinamide (2.58 g, 21.27 mmol) and <strong>[37687-18-6]1-(1-methyl-1H-pyrazol-4-yl)ethanone</strong> (2.2 g, 17.72 mmol) in toluene (35 mL) was added titanium(IV) isopropoxide (10.49 mL, 35.44 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 110 C for 16 h. Sat. aq. NaHCO3 (10 mL) was added and filtered through a short pad of anhydrous Na2SO4, washed with EtOAc (20 mL x 3). The combined organic layers were concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc =2 : 3) to give the title compound (2.5 g, 62%) as a yellow solid. 1H NMR(400 MHz, CDCl3) delta 7.85 (s, 1H), 7.81 (s, 1H), 3.93 (s, 3H), 2.61 (s, 3H), 1.27 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With titanium(IV) tetraethanolate; In tetrahydrofuran; at 70℃; for 16h; | (R)- (+)-2-Methyl-2-propanesulfinamide (400 g, 3.28 mol), 1 -(2-fluoro-3-nitro-phenyl)ethanone (500 g, 2.73 mol) and titanium(IV) ethoxide (1550 g, 8.4 mol) in THF(5.0 L) were stuffed at 70C for 16 h. The mixture was washed with water and filtered.The filter cake was washed with ethyl acetate (15 L), then the filtrate was washed with brine (5 L) and dried over Na2504. The organic layer was concentrated. The crude residue was purified by column chromatography (silica, 100-200 mesh, 5% EtOAc in petroleum ether) to afford the title compound (398 g, 5 1%). oH (400 MHz, DMSO-d6)8.24-8.20 (m, 1H), 8.01-7.94 (m, 1H), 7.52-7.48 (m, 1H), 2.68 (d, J 1.2 Hz, 3H), 1.19 (s,9H). |
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)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dichloromethane; at 20℃;Inert atmosphere; | A flask (equipped with a nitrogen inlet, overhead stirring, and thermocouple) was charged with DCM (3 L, 10 vol). The mixture was agitated, and the mixture was deoxygenated with subsurface nitrogen for 1 h. Next 5-fluoro-2- methoxynicotinaldehyde (1) (300 g, 1934 mmol) and (R)-2-methylpropane-2-sulfinamide (246 g, 2031 mmol) were charged. The CS2CO3 (441 g, 1354 mmol) was charged in portions, with agitation, over several minutes . The reaction was agitated overnight at ambient temperature under nitrogen. The reaction was sampled and analyzed by HPLC for reaction completion. A 15 wt% solution of the citric acid (in water) was prepared (using 1.5 eq of citric acid based on the CS2CO3 input). This solution was charged into the reactor with the reaction mixture, using an addition funnel. The charge was done in portions. The biphasic mixture was transferred to a separatory funnel, and the lower DCM layer was removed. The upper aqueous layer was removed and discarded. The DCM layer was transferred back into the separatory funnel, and washed with saturated brine (2 L). Again, the lower DCM layer was removed, and the upper aqueous layer was discarded. The DCM layer was concentrated under vacuum (rotovap) to give the desired product. | |
With caesium carbonate; In dichloromethane; at 20℃;Inert atmosphere; | A flask (equipped with a nitrogen inlet, overhead stirring, and thermocouple) was charged with DCM (3 L, 10 vol). The mixture was agitated, and the mixture was deoxygenated with subsurface nitrogen for 1 h. Next 5-fluoro-2- methoxynicotinaldehyde (1) (300 g, 1934 mmol) and (R)-2-methylpropane-2-sulfinamide (246 g, 2031 mmol) were charged. The CS2CO3 (441 g, 1354 mmol) was charged in portions, with agitation, over several minutes. The reaction was agitated overnight at ambient temperature under nitrogen. The reaction was sampled and analyzed by HPLC for reaction completion. A 15 wt% solution of the citric acid (in water) was prepared (using 1.5 eq of citric acid based on the CS2CO3 input). This solution was charged into the reactor with the reaction mixture, using an addition funnel. The charge was done in portions. The biphasic mixture was transferred to a separatory funnel, and the lower DCM layer was removed. The upper aqueous layer was removed and discarded. The DCM layer was transferred back into the separatory funnel, and washed with saturated brine (2 L). Again, the lower DCM layer was removed, and the upper aqueous layer was discarded. The DCM layer was concentrated under vacuum (rotovap) to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.5 g | With caesium carbonate; In dichloromethane; at 30℃; for 4h;Inert atmosphere; | Dissolve 5-fluoro-2-methoxypyridine-3-formaldehyde 4a (10.00 g, 64.5 mmol) in dichloromethane (120 mL), Add cesium carbonate (42.00 g, 129.00 mmol) and (R)-2-methylpropane-2-sulfinamide (8.26 g, 67.70 mmol) in this order, and react at 30 C for 4 hours after the addition. After the reaction, the solution was filtered, and the filtrate was directly spin-dried to obtain (R)-N-((5-fluoro-2-methoxypyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide 4b. (17.50 g, yellow oil), directly into the next step without further purification; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With titanium(IV) tetraethanolate; In tetrahydrofuran; at 20 - 35℃; for 1h; | To a mixture of <strong>[1280786-80-2]5-bromo-3-chloro-2-fluorobenzaldehyde</strong> (10.0 g, 42.2 mmol, 1.00 eq) and (R)-2-methylpropane-2-sulfinamide (5.6 g, 46.4 mmol, 1.1 eq) in anhydrous THF (100 mL) under nitrogen atmosphere was added Ti(OEt)4 (14.4 g, 63.3 mmol, 1.50 eq) dropwise at room temperature and the temperature maintained below 30oC. The reaction mixture was warmed to 35 C and stirred for 1 hour. LCMS showed that the reaction was completed. Water (100 mL) and EtOAc (100 mL) were added into the mixture and stirred at room temperature for 5 mins. The mixture was filtered and washed with EtOAc (50 mL). The filtrate was separated. The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 4:1) to provide (R, E)-N-(5-bromo-3-chloro-2- fluorobenzylidene)-2-methylpropane-2-sulfinamide as a yellow oil (14.0 g). Yield 98% (ESI 341.9 (M+H)+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18%; 72% | A mixture of the thiochromanone (10g, 60.9 mmol, 1.0 eq), (R)-2-methylpropane-2-sulfinamide (7.38 g, 60.9 mmol, 1.0 eq) and titanium tetraethoxide (27.8g,1.0eq) was stirred under nitrogen at 70C for 30 min .The mixture, cooled to r.t., was diluted with ethyl acetate (250 mL) and lOmL of brine. The mixture was stirred vigorously for 10 min. The mixture was filtered through celite and the filter cake was washed with ethyl acetate (300 mL). The solvents were removed under vacuum and the crude was solubilized in THF (0.3M) containing 2% water and cooled down to -50C. Sodium borohydride (3.0eq, 4.2 g) was added (3.0 eq) and the mixture was stirred at -50C for lh then at 23C for 2 hours. The solvents were removed under vacuum and the crude was purified by column chromatography (15-75% ethyl acetate in hexanes, the R enantiomer is the first to elute) to afford the pure (R)-2-methyl-N-((R)-thiochroman-4- yl)propane-2-sulfinamide [12g, 72%yield, NMR (400 MHz, CDCL) d 7.32 (d, 1H), 7.16 - 7.08 (m, 2H), 7.07 - 7.01 (m, 1H), 4.61 (q, 1H), 3.26 (td, 1H), 3.18 (s, 1H), 2.80 (dt, 1H), 2.49 - 2.37 (m, 1H), 2.07 - 1.94 (m, 1H), 1.21 (s, 9H), 13C NMR (400 MHz, CDCL) d 133.76, 132.69, 131.45, 128.50, 126.85, 124.75, 55.66, 50.99, 28.25, 22.70, 21.18] and the pure (R)-2-methyl-N-((S)- thiochroman-4-yl)propane-2-sulfinamide [3g, 18% yield, NMR (400 MHz, CDCL) d 7.31 (ddt, 1H), 7.15 - 7.08 (m, 2H), 7.05 - 7.00 (m, 1H), 4.51 (ddd, 1H), 3.53 (d, 1H), 3.16 (ddd, 1H), 3.03 - 2.95 (m, 1H), 2.44 (dtd, 1H), 2.35 (ddt, 1H), 1.22 (s, 9H). The pure (R)-2-methyl-N-((R)- thiochroman-4-yl)propane-2-sulfinamide (2g, 1 eq) was then solubilized in dioxane (1M) and 4 M HC1 in dioxane (10 eq) was added slowly. The mixture was stirred for 14 hours at 23C. Diethyl ether (to reach 0.1M) was added and the precipitate was fdtrated, washed with diethyl ether (30 mL), collected and lyophilized in dioxane. 0.5g (40% yield, white powder). NMR (400 MHz, CD3OD) d 7.35 (ddd, 1H), 7.25 (ddd, 1H), 7.20 - 7.16 (m, 1H), 7.14 (td, 1H), 4.56 (t, 1H), 3.19 (ddd, 1H), 3.04 (ddd, 1H), 2.53 - 2.44 (m, 1H), 2.38 - 2.28 (m, 1H). 13C NMR (101 MHz, CD3OD) d 135.19, 131.29, 130.43, 128.77, 128.21, 125.64, 27.74, 21.90. LC-MS m/z: 163.80 (calcd: 164.05 [M-H]+). | |
18%; 72% | A mixture of the thiochromanone (10g, 60.9 mmol, 1.0 eq), (R)-2-methylpropane-2-sulfinamide (7.38 g, 60.9 mmol, 1.0 eq) and titanium tetraethoxide (27.8g,1.0eq) was stirred under nitrogen at 70C for 30 min .The mixture, cooled to r.t., was diluted with ethyl acetate (250 mL) and lOmL of brine. The mixture was stirred vigorously for 10 min. The mixture was filtered through celite and the filter cake was washed with ethyl acetate (300 mL). The solvents were removed under vacuum and the crude was solubilized in THF (0.3M) containing 2% water and cooled down to -50C. Sodium borohydride (3.0eq, 4.2 g) was added (3.0 eq) and the mixture was stirred at -50C for lh then at 23C for 2 hours. The solvents were removed under vacuum and the crude was purified by column chromatography (15-75% ethyl acetate in hexanes, the R enantiomer is the first to elute) to afford the pure (R)-2-methyl-N-((R)-thiochroman-4- yl)propane-2-sulfinamide [12g, 72%yield, NMR (400 MHz, CDCL) d 7.32 (d, 1H), 7.16 - 7.08 (m, 2H), 7.07 - 7.01 (m, 1H), 4.61 (q, 1H), 3.26 (td, 1H), 3.18 (s, 1H), 2.80 (dt, 1H), 2.49 - 2.37 (m, 1H), 2.07 - 1.94 (m, 1H), 1.21 (s, 9H), 13C NMR (400 MHz, CDCL) d 133.76, 132.69, 131.45, 128.50, 126.85, 124.75, 55.66, 50.99, 28.25, 22.70, 21.18] and the pure (R)-2-methyl-N-((S)- thiochroman-4-yl)propane-2-sulfinamide [3g, 18% yield, NMR (400 MHz, CDCL) d 7.31 (ddt, 1H), 7.15 - 7.08 (m, 2H), 7.05 - 7.00 (m, 1H), 4.51 (ddd, 1H), 3.53 (d, 1H), 3.16 (ddd, 1H), 3.03 - 2.95 (m, 1H), 2.44 (dtd, 1H), 2.35 (ddt, 1H), 1.22 (s, 9H). The pure (R)-2-methyl-N-((R)- thiochroman-4-yl)propane-2-sulfinamide (2g, 1 eq) was then solubilized in dioxane (1M) and 4 M HC1 in dioxane (10 eq) was added slowly. The mixture was stirred for 14 hours at 23C. Diethyl ether (to reach 0.1M) was added and the precipitate was fdtrated, washed with diethyl ether (30 mL), collected and lyophilized in dioxane. 0.5g (40% yield, white powder). NMR (400 MHz, CD3OD) d 7.35 (ddd, 1H), 7.25 (ddd, 1H), 7.20 - 7.16 (m, 1H), 7.14 (td, 1H), 4.56 (t, 1H), 3.19 (ddd, 1H), 3.04 (ddd, 1H), 2.53 - 2.44 (m, 1H), 2.38 - 2.28 (m, 1H). 13C NMR (101 MHz, CD3OD) d 135.19, 131.29, 130.43, 128.77, 128.21, 125.64, 27.74, 21.90. LC-MS m/z: 163.80 (calcd: 164.05 [M-H]+). |