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CAS No. : | 79722-21-7 | MDL No. : | MFCD00191873 |
Formula : | C12H17NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MZNBNPWFHGWAGH-UHFFFAOYSA-N |
M.W : | 223.27 | Pubchem ID : | 736159 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.42 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 61.04 |
TPSA : | 47.56 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.91 cm/s |
Log Po/w (iLOGP) : | 2.51 |
Log Po/w (XLOGP3) : | 2.47 |
Log Po/w (WLOGP) : | 2.49 |
Log Po/w (MLOGP) : | 2.34 |
Log Po/w (SILICOS-IT) : | 1.59 |
Consensus Log Po/w : | 2.28 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.66 |
Solubility : | 0.486 mg/ml ; 0.00218 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.11 |
Solubility : | 0.172 mg/ml ; 0.000771 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.5 |
Solubility : | 0.0704 mg/ml ; 0.000316 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.48 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
69% | Stage #1: With sodium carbonate In dichloromethane for 1 h; Stage #2: at 0 - 25℃; for 17 h; |
Intermediate 153: tert-butyl benzyloxycarbamate To a solution of O-benzylhydroxylamine hydrochloride (225 g, 1.44 mol) in dichloromethane (300 mL) was added a solution of sodium bicarbonate (261 g, 3.11 mol, 300ml). After 1 hour the di-tert-butyl dicarbonate (375 g, 1.72 mol) was added at 0 °C. The resulting solution was stirred for 60 min at 0 °C in a water/ice bath and then the reaction was stirred for 16 h at room temperature. The reaction was then quenched by the addition of 300 mL of aqueous sodium bicarbonate. The aqueous phase was extracted with 3 x 500 mL of dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. Flash chromatograph on silica gel (PE: EA=10: 1) afforded 220 g (69percent) of the title compound as a yellow oil. 1H MR (300MHz. COCh) δ: 1.43 (9H, s), 4.85 (2H, s), 7.19-7.21 (1H, brs), 7.30-7.40 (5H, m). |
50% | With dmap; triethylamine In dichloromethane at 20℃; | O-Benzyl-hydroxylamine hydrochloride (300 mg, 1.89 mmol) was dissolved in DCM (5 mL). Triethylamine (1.05 mL, 7.56 mmol), DMAP (catalytic amount) and di-tert-butyldicarbonate (617 mg, 2.83 mmol) were added and the mixture was stirred at room temperature overnight. Water and DCM were then added. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by preparative TLC on silica gel (DCM/MeOH 99/1) to give compound (116a) (210 mg, 0.94 mmol, 50percent). |
91% | With triethanolamine In tetrahydrofuran; water; ethyl acetate | Nα -tert-Butyloxycarbonyl-O-benzylhydroxylamine (28) O-Benzyl hydroxylamine hydrochloride (15.9 g, 100 mmol) was suspended in THF (150 ml) and water (50 ml) mixture. To this stirred mixture was added TEA (15.15 g, 150 mmol) followed by di-tert-butyldicarbonate (23.98 g, 110 mmol). The reaction mixture was stirred at room temperature for 12 h and evaporated to dryness. The residue was partitioned between EtOAc (250 ml) and water (200 ml), and extracted in EtOAc. The EtOAc extract was washed with potassium hydrogen sulfate (100 ml) and brine (100 ml), dried and evaporated to dryness to give 15 g (91percent) of clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 20℃; for 20 h; | ieri-butyl benzyloxycarbamate (150): /V-hydroxybenzyl-amine (1 equivalent, 1 .62 g) was dissolved in 30 ml of THF. Boc20 (1 equivalent, 2.87 g) was added and the reaction mixture is stirred for 20 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with 10percent citric acid and brine then dried over Na2S04, filtered and concentrated to afford 150 as an oil (2.92 g, 99percent). H NMR (CDCI3): δ 1 .42 (s, 9H), 4.73 (s, 2H), 7.37 (m, 5H), 10.03 (s, 1 H). |
100% | With sodium hydroxide In tetrahydrofuran; water | EXAMPLE 4 t-Butyl-N-benzyloxycarbamate To a stirred solution of O-benzylhydroxylamine (16.0 g; 0.13 mol) and di-t-butyldicarbonate (28.4 g; 0.13 mol) in a mixture of water (150 ml) and tetrahydrofuran (150 ml) 2N NaOH solution was added dropwise to adjust the pH to 8-9 and this pH was maintained for an additional 2 hours by occasional addition of 2N NaOH. After extraction with ethylacetate the combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo to leave an oil which was used in the next example without any further purification; yield 29 g (100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydride; sodium iodide In N,N-dimethyl-formamide | |
92% | Stage #1: tert-butyl N-(benzyloxy)carbamate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: δ-chlorovaleronitrile With sodium iodide In N,N-dimethyl-formamide at 70℃; for 18h; Inert atmosphere; | |
91% | With sodium hydride; sodium iodide In N,N-dimethyl-formamide |
With sodium hydride; sodium iodide 1.) DMF, 15 min, 2.) DMF, 80 - 85 deg C, 4 h; Yield given. Multistep reaction; | ||
With sodium hydride; potassium iodide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | To a solution of N-benzyloxy-N-tert-butoxycarbonylamino (480 mg, 2.04 mmol) in dimethylformamide (5 ml) at 0C was added sodium hydride (60% mineral oil dispersion, 72.5 mg, 3.0 mmol). Solution was stirred for about 30 min till no more gas evolved. Ethyl-4-bromobutyrate (200 mg, 0.97 mmol) was then added and reaction mixture was stirred overnight at 40C. The solvent was removed under pressure and the remaining oil was purified by column chromatography on silica gel with 20% EtOAc/ hexane to give colorless oil (242 mg, 70%). 1H NMR (500 M Hz, CD3OD) delta 4.14- 4.10 (m, 2H), 3.50 (t, J = 6.5 Hz, 2H), 2.35 (t, J = 7.0 Hz, 2H), 1.91-1.86 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H), 1.46 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In tetrahydrofuran; at 20℃; for 20h; | ieri-butyl benzyloxycarbamate (150): /V-hydroxybenzyl-amine (1 equivalent, 1 .62 g) was dissolved in 30 ml of THF. Boc20 (1 equivalent, 2.87 g) was added and the reaction mixture is stirred for 20 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with 10% citric acid and brine then dried over Na2S04, filtered and concentrated to afford 150 as an oil (2.92 g, 99%). H NMR (CDCI3): delta 1 .42 (s, 9H), 4.73 (s, 2H), 7.37 (m, 5H), 10.03 (s, 1 H). |
With sodium hydroxide; In tetrahydrofuran; water; | 5. t-Butyl-N-benzyloxycarbamate To a stirred solution of O-benzylhydroxylamine (16.0 g, 0.13 mol) and di-t-butyldicarbonate (28.4 g, 0.13 mol) in a mixture of water (150 mL) and tetrahydrofuran (150 mL) 2N sodium hydroxide solution was added dropwise to adjust the pH to 8-9 and this pH was maintained for an additional two hours by occasional addition of 2N sodium hydroxide. After extraction with ethylacetate the combined organic layers were washed with brine, dried (Magnesium sulfate) and evaporated in vacuo to leave an oil which was used in the next step without any further purification. Yield 29 g (100%). | |
29 g (100%) | With sodium hydroxide; In tetrahydrofuran; water; | EXAMPLE 4 t-Butyl-N-benzyloxycarbamate To a stirred solution of O-benzylhydroxylamine (16.0 g; 0.13 mol) and di-t-butyldicarbonate (28.4 g; 0.13 mol) in a mixture of water (150 ml) and tetrahydrofuran (150 ml) 2N NaOH solution was added dropwise to adjust the pH to 8-9 and this pH was maintained for an additional 2 hours by occasional addition of 2N NaOH. After extraction with ethylacetate the combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo to leave an oil which was used in the next example without any further purification; yield 29 g (100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In tetrahydrofuran; 1,4-dioxane; water; at 20℃; for 2.5h; | To a stirred solution of 0- benzylhydroxylamine hydrochloride (9.6 g, 60 mmol, 1 eq) and triethylamine (9.0 mL, 66 mmol, 1.1 eq) in a 1:1 mixture of THF/H20 (100 mL), was added di-tert-butyl dicarbonate (30% in dioxane, 43.7 mL, 60 mmol, 1 eq). The reaction mixture was stirred at room temperature for 2.5 h, and then concentrated under reduced pressure to eliminate THF. The residue was extracted with EtOAc (3 x 50 mL), the combined organic layers were washed with 0.5 M citric acid (aq, 2 x 50 mL) and H20 (50 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude solid. The crude solid was then recrystallized in hexanes to afford the title compound as a white solid (12 g, 90%). ?H NIVIR (400 IVIFIz, CDC13) 7.97-7.29 (m, 5H), 5.28 (s, 2H), 1.90 (s, 9H). ?3C NIVIR (101 IVIHz, CDC13) 156.7, 135.7, 129.1, 128.5,81.7, 78.4, 28.2. LC-MS (ESI): 245.9 m/z [M+Na], 460.0 m/z [2M+Na]. |
69% | Intermediate 153: tert-butyl benzyloxycarbamate To a solution of O-benzylhydroxylamine hydrochloride (225 g, 1.44 mol) in dichloromethane (300 mL) was added a solution of sodium bicarbonate (261 g, 3.11 mol, 300ml). After 1 hour the di-tert-butyl dicarbonate (375 g, 1.72 mol) was added at 0 C. The resulting solution was stirred for 60 min at 0 C in a water/ice bath and then the reaction was stirred for 16 h at room temperature. The reaction was then quenched by the addition of 300 mL of aqueous sodium bicarbonate. The aqueous phase was extracted with 3 x 500 mL of dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. Flash chromatograph on silica gel (PE: EA=10: 1) afforded 220 g (69%) of the title compound as a yellow oil. 1H MR (300MHz. COCh) delta: 1.43 (9H, s), 4.85 (2H, s), 7.19-7.21 (1H, brs), 7.30-7.40 (5H, m). | |
50% | With dmap; triethylamine; In dichloromethane; at 20℃; | O-Benzyl-hydroxylamine hydrochloride (300 mg, 1.89 mmol) was dissolved in DCM (5 mL). Triethylamine (1.05 mL, 7.56 mmol), DMAP (catalytic amount) and di-tert-butyldicarbonate (617 mg, 2.83 mmol) were added and the mixture was stirred at room temperature overnight. Water and DCM were then added. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by preparative TLC on silica gel (DCM/MeOH 99/1) to give compound (116a) (210 mg, 0.94 mmol, 50%). |
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; | N--t-B utoxycarbonyl-O-benzylhydroxylamine To a stirred solution at 0 C. of O-benzylhydroxylamine hydrochloride in THF was added diisopropylethylamine (2.5 equiv.) and di-t-butyldicarbonate (1.2 equiv.). Reaction stirred one hour at 0 C. and overnight at ambient temperature. Reaction concentrated in vacuo. Residue taken up in EtOAc and washed with water, 1.0M NaHCO3, 1N H3PO4, and brine. Organic layer dried with Na2SO4, filtered, and evaporated. | |
15 g (91%) | With triethanolamine; In tetrahydrofuran; water; ethyl acetate; | Nalpha -tert-Butyloxycarbonyl-O-benzylhydroxylamine (28) O-Benzyl hydroxylamine hydrochloride (15.9 g, 100 mmol) was suspended in THF (150 ml) and water (50 ml) mixture. To this stirred mixture was added TEA (15.15 g, 150 mmol) followed by di-tert-butyldicarbonate (23.98 g, 110 mmol). The reaction mixture was stirred at room temperature for 12 h and evaporated to dryness. The residue was partitioned between EtOAc (250 ml) and water (200 ml), and extracted in EtOAc. The EtOAc extract was washed with potassium hydrogen sulfate (100 ml) and brine (100 ml), dried and evaporated to dryness to give 15 g (91%) of clear oil. |
A suspension of O-benzylhydroxylamine hydrochloride (30 g, 188 mmol) in acetonitrile (150 mL) was added triethylamine (29 mL). The thick suspension was stirred for 60 minutes at room temperature and filtered. The precipitate was washed with acetonitrile (100 mL) on the filter. The combined filtrates were added to a cooled (0C) solution of Boc20 (45 g, 207 mmol) in acetonitrile (150 ml), over 20 minutes. The reaction mixture was stirred at 0C, and allowed slowly to warm up to room temperature. The reaction mixture was left with stirring at room temperature overnight, when 1H-NMR indicated complete conversion of O-benzylhydroxylamine into N-BOC-O-benzylhydroxylamine. The reaction mixture was added a solution of BOC20 (6.7 g, 310 mmol) in acetonitrile (150 mL), followed by a solution of DMAP (2 g, 16.4 mmol) in acetonitrile (30 mL). The reaction mixture was then stirred at 40C until TLC (EtOAc:PE60/80 = 1: 5) indicated complete conversion of the intermediate N-Boc-O-benzylhydroxylamine (approx. 2 hours). The reaction mixture was evaporated to dryness and re-dissolved in EtOAc (200 mL). The organic phase was washed with a mixture of 1 M phosphate buffer pH = 7 (100 mL) and NACI (aq., sat.) (50 mL). The organic phase was dried with Na2SO4, filtered and evaporated to dryness to give an oil, which precipitated upon trituration by PE40/60 (20 mL). The precipitated was isolated by filtration to give 56 g (92%) of N,N-diBoc-O-benzylhydroxylamine as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium hydride In N,N-dimethyl-formamide at 25℃; for 1h; | |
Stage #1: tert-butyl N-(benzyloxy)carbamate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: ethylene dibromide With sodium iodide In tetrahydrofuran at 70℃; for 18h; Inert atmosphere; | ||
Stage #1: tert-butyl N-(benzyloxy)carbamate With sodium hydride In N,N-dimethyl-formamide for 0.5h; Stage #2: ethylene dibromide In N,N-dimethyl-formamide at 60℃; for 11.5h; | 64.1 Step 1: synthesis of compound WX064-2 Compound WX064-1 (20 g) was dissolved in DMF (300 ml) at room temperature, and then sodium hydride (4.30 g, 60% purity) was added. After the mixture was stirred for 0.5 hour, 1,2-dibromoethane (100.97 g) was added rapidly, and then the mixture was heated to 60 °C and stirred for 11.5 hours. The mixture was cooled to room temperature, the reaction was quenched with saturated brine (600 ml), and ethyl acetate (200 ml × 3) was added for extraction. The organic phases were combined, washed with water (600 ml) and saturated saline (600 ml) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1-50/1) to give compound WX064-2. MS-ESI m/z: 231.8[M-100+2+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.544 g | With potassium tert-butylate; at 60℃; for 4h; | EXAMPLE 5 [0083] This example demonstrates the synthesis of N-allyl-O-benzylhydroxylamine 5 (Figure 5) in an embodiment of the invention. [0084] N-Boc-O-benzylhydroxylamine (2.203 g, 9.87 mmol) was melted by heating at 60 C and, after cooling, allyl bromide (1.7 mL, 19.74 mmol) was added, followed by potassium tert-butoxide (1.383 g, 12.34 mmol). After heating at 60 C for 4 h, the mixture was cooled to rt, water was added and the product was extracted by CH2C12, dried over MgS04, filtered and concentrated in vacuo resulting in an oily residue. Purification by flash chromatography using hexane/acetone (95/5) afforded a colorless oil (2.554 g). To this oil was added TFA (4.53 mL, 59.2 mmol) and the mixture was stirred at rt for 4 h. It was then diluted with CH2C12 (150 mL) and water (75 mL). Solid Na2C03 was added until pH = 10-11 , The organic layer was dried over MgS04, filtered and concentrated in vacuo to afford compound 5 as a colorless liquid (2.09 g, 95%). 1H NMR (CDC13, 300 MHz, ppm): delta 3.55 (d, 2H, J= 6.3 Hz), 4.72 (s, 2H), 5.20 (m, 2H), 5.55 (s, 1H), 5.94 (m, 1H), 7.35 (m, 5H). I3C NMR (CDCI3, 75 MHz, ppm): S 55.2, 76.4, 1 18.1 , 128.0, 128.6(2), 134.5, 138.1. ESI-MS: m/z = 164.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Compound (116a) (210 mg, 0.94 mmol) was dissolved in DMF (2 mL). Sodium hydride 60% in mineral oil (42 mg, 1.04 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Iodomethane (146 mg, 1.04 mmol) was added and the mixture was stirred at room temperature overnight. Water and brine were added. The middle was extracted with EtOAc. Organic layer was dried over sodium sulfate, filtered and concentrated. Residue was purified by preparative TLC on silica gel (Cyclohexane/EtOAc 8/2) to give compound (116b) (165 mg, 0.696 mmol, 75%) as a yellow oil. 1H NMR (400 MHz, CDCl3) delta 1.49 (s, 9H), 3.05 (s, 3H), 4.02 (s, 2H), 7.31-7.43 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To carbamate 67 (42.5mmol, 1 equivalent) in DMF (0.4M) under nitrogen atmosphere at rt is added the unwashed sodium hydride slowly (2.2g in oil, 1.3 equivalents, added in about 3 equal portions) then stirred for 10 minutes. Bubbling and foaming result, with a milky white mixture resulting. Sodium iodide (213mmol, 5 equivalents) followed by the nitrile 66(42.5mmol, 1 equivalent) is added and the mixture is maintained at 80 C for 6 hours, then cooled, followed by quenching any remaining sodium hydride with water dropwise.Extracted out product with ethyl acetate thrice, combined organic layers, dried and concentrated in vacuo. Flash chromatographed using a gradient method (10-30% EtOAc in Hexanes) is used to produce pure product 68 in quantitative yield (42.5mmol). Nitrile 68 is suspended in approximately 145mL of 4M HC1 in dioxane and stirred at rt for 3 hours until deemed complete, then concentrated in vacuo to afford a solid precipitate, which is further washed with ethyl ether to produce clean cyclized product 69. Product 69 is redissolved in methanol and subjected to hydrogenation conditions (lg of 10% Pd on charcoal, under a hydrogen atmosphere at atmospheric pressure) for 6 hours. The catalyst is filtered off through celite, and the filtrate concentrated. The resulting solid is washed with Et20 and collected to afford almost quantitative product 70 (42.4mmol). Dimethyl acetyenedicarboxylate (1 equivalent) is added to a stirred solution of prepared amidoxime 70 (42.4 mmol) in chloroform (0.335M) containing 1.5 equivalents of triethylamine and maintained at reflux for 75 minutes to 4 hours until deemed complete. Note, temperature variations are dependent on amidoxime (i.e 6 membered cyclic amidoxime requires temperature modification). Upon cooling and evaporation of the solvent, the crude mixture is charged with xylenes (0.335M) and heated to 140 C for 8 hours more before cooling slowly to rt. The resulting heavy precipitate is collected, washed with ethyl ether, then dried under vacuum to afford desired l,2-cyclic-5,6-dihydroxypyrimidines-4-carboxyester (i.e 71) in yields ranging from 30-70%. Spectral comparison to referenced compounds confirmed desired starting intermediates given by this procedure. | |
70% | To a stirred solution of tert-butyl benzyloxycarbamate (5.00 g, 22.4 mmol) and sodium iodide (0.168 g,1.12 mmol) in dimethylformamide (80 mL) was added sodium hydride (60% dispersion in paraffin liquid, 1.22 g, 30.5mmol) at 0 C. After 15 min, 4-chlorobutyronitrile (9) (2.78 g, 26.9 mmol) was added to the reaction mixture, and the temperature was elevated to 85 C, where the stirring continued for 3 hr. After cooling, the reaction was quenched with water (200 mL), and the resulting mixture was extracted with ethyl ether (150 mL × 3). The combined organic layerswere washed with brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The crude residue was purified by flash column chromatography (SiO2, hexanes: ethyl acetate = 9:1) to afford the desired product 10 (4.60 g, 15.7 mmol) in 70% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: tert-butyl N-(benzyloxy)carbamate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: 1-Bromo-2-butyne In N,N-dimethyl-formamide | |
92% | Stage #1: tert-butyl N-(benzyloxy)carbamate With sodium hydride In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: 1-Bromo-2-butyne In tetrahydrofuran at 20℃; for 12h; | |
With sodium hydride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With di-tert-butyl dicarbonate;dmap; In acetonitrile; at 40℃; for 2h; | A suspension of O-benzylhydroxylamine hydrochloride (30 g, 188 mmol) in acetonitrile (150 mL) was added triethylamine (29 mL). The thick suspension was stirred for 60 minutes at room temperature and filtered. The precipitate was washed with acetonitrile (100 mL) on the filter. The combined filtrates were added to a cooled [(0C)] solution of Boc20 (45 g, 207 mmol) in acetonitrile (150 ml), over 20 minutes. The reaction mixture was stirred at 0C, and allowed slowly to warm up to room temperature. The reaction mixture was left with stirring at room temperature overnight, when 1H-NMR indicated complete conversion of O-benzylhydroxylamine into N-Boc-O- benzylhydroxylamine. The reaction mixture was added a solution of Boc20] (6.7 g, 310 mmol) in acetonitrile (150 mL), followed by a solution of DMAP (2 g, 16.4 mmol) in acetonitrile (30 mL). The reaction mixture was then stirred at 40C until TLC (EtOAc:PE60/80 = 1:5) indicated complete conversion of the intermediate N-Boc-O-benzylhydroxylamine (approx. 2 hours). The reaction mixture was evaporated to dryness and re-dissolved in EtOAc (200 mL). The organic phase was washed with a mixture of 1 M phosphate buffer pH = 7 (100 mL) and NACI (aq., sat.) (50 mL). The organic phase was dried with Na2SO4, filtered and evaporated to dryness to give an oil, which precipitated upon trituration by PE40/60 (20 mL). The precipitated was isolated by filtration to give 56 g (92%) of N, N-diBoc-O-benzylhydroxylamine as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.0 g (66%) | With NaH; In water; ethyl acetate; N,N-dimethyl-formamide; | N-tert-Butyloxycarbonyl-N-[(tetrahydropyranyl)oxy] ethyl-O-benzylhydroxylamine (30) To a stirred solution of N-tert-butyloxycarbonyl-O-benzylhydroxylamine 28 (5.79 g, 25.96 mmol) in dry DMF (50 ml) was added NaH (60%, 1.2 g, 30 mmol) slowly during 15 min period under argon atmosphere at 0 C. The reaction was allowed to stir at 0 C. for 30 min and at room temperature for 1 h. 1-Chloro-2-(tetrahydropyranyl)oxy-ethane 29 (4.95 g, 30 mmol) was added and the reaction mixture was heated at 80 C. for 12 h. The reaction was cooled and evaporated to dryness. The residue was suspended in water (50 ml), pH of the solution adjusted to 7 and extracted in EtOAc (150 ml). The EtOAc extract was washed with water and brine, dried and evaporated to dryness. The residue was purified by flash chromatography over silica gel using hexane?CH2 Cl2 as the eluent. The required fractions were collected and evaporated to give 6.0 g (66%) of an oily product. 1 H-NMR (CDCl3): delta1.48 (s, 9H, Boc), 1.49-1.84 (m, 6H, 3.CH2), 3.48-3.70 (m, 4H, 2.CH2), 3.86 (m, 2H, CH2), 4.60 (t, 1H, CH), 4.84 (s, 2H, CH2 Ph) and 7.32-7.42 (m, 5H, Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium hydroxide In toluene at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium hydroxide In toluene at 20℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium hydroxide In toluene at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium hydroxide In toluene at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium hydroxide In toluene at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium hydroxide In toluene at 20℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium hydroxide In toluene at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hydroxide In toluene at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hydroxide In toluene at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium hydroxide In toluene at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In tetrahydrofuran; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 9-amino-9-deoxy-epi-cinchonidine; trifluoroacetic acid In toluene at 20 - 40℃; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 9-epi-9-amino-9-deoxyquinine; trifluoroacetic acid In dichloromethane at 20℃; for 120h; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 9-epi-9-amino-9-deoxyquinine; trifluoroacetic acid In dichloromethane at 20℃; for 96h; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 9-epi-9-amino-9-deoxyquinine; trifluoroacetic acid In dichloromethane at 20℃; for 92h; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With trifluoroacetic acid; 9-amino-9-deoxyepicinchonine In dichloromethane at 20℃; for 160h; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 9-epi-9-amino-9-deoxyquinine; trifluoroacetic acid In dichloromethane at 20℃; for 162h; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With trifluoroacetic acid; 9-amino-9-deoxyepicinchonine In dichloromethane at 20℃; for 170h; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 9-epi-9-amino-9-deoxyquinine; trifluoroacetic acid In dichloromethane at 20℃; for 120h; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 9-epi-9-amino-9-deoxyquinine; trifluoroacetic acid In dichloromethane at 20℃; for 72h; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 9-amino-9-deoxy-epi-cinchonidine; trifluoroacetic acid In toluene at 20 - 40℃; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 9-epi-9-amino-9-deoxyquinine; trifluoroacetic acid In dichloromethane at 20℃; for 72h; optical yield given as %ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.7% | With potassium carbonate; In acetonitrile;Reflux; | General procedure: Potassium carbonate (0.304 g, 2.2 mmol) was added to a solution of 422 (0.086 g, 0.44 mmol) and 3-bromopropylphenyl sulfone (0.139 g, 0.53 mmol) in MeCN (4 mL) and the mixture was stirred at reflux overnight. The mixture was poured into water (60 mL) and extracted with CH2Cl2 (4×15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, and the solvent was removed in vacuo. The crude product was purified by radial chromatography (EtOAc/hexane=1:2-1:1) to give sulfone 2a as a colorless oil (0.15 g, 90.4%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | ieri-butyl benzyloxy(ethyl)carbamate (151): 150 (1 .66 g, 1 equivalent) was dissolved in 20 ml of DMF and this solution was cool to 0 C, then NaH (1 equivalent, 180 mg) was added in one portion. The reaction mixture was let at 0 for 5 min, then ethyl iodide was added (1 .2 equivalent, 1 .40 g) and the reaction mixture was let at room temperature overnight. 100 ml of AcOEt was added to the reaction mixture. The organic phase are washed with 10% citric acid, saturated NaHC03 and brine then dried over Na2S04, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 1/9) to afford 151 as an oil (1 .67 g, 90%). H NMR (CDCI3): delta 1 .31 (t, 3H, J= 7.0 Hz), 1 .66 (s, 9H), 3.61 (q, 2H, J= 7.0 Hz), 4.99 (s, 2H), 7.50 (m, 3H), 7.57 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; caesium carbonate; In N,N-dimethyl-formamide; at 105℃; under 760.051 Torr; for 96h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; under 760.051 Torr; for 84h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr; for 16h;Schlenk tube; | General procedure: Nucleophile (1-3 mol equiv), tris-(dibenzylideneacetone)dipalladium (2.5 mol %), tris-(2-furyl)phosphine (10 mol %) and potassium carbonate (2 mol equiv) were added to a solution of the aryl halide (1 mmol) in dry dimethylformamide (10 mL) in a Schlenk tube. The reaction mixture was then degassed using the freeze, pump, thaw (F.P.T.) technique (one cycle). Allene gas was then introduced at the required pressure (1 atm) and the Schlenk tube contents stirred and heated at 80 C for 16 h. After cooling and venting, DCM (20 mL) was added and the mixture filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | To a solution of tert-butyl benzyloxycarbamate 2 (14.7 mmol, 3.27 g) in anhydrous DMF (30 mL) under N2 was added sodium hydride (60% in mineral oil, 15.2 mmol, 0.61 g) portionwise at 0 C. After evolution of hydrogen ceased, the contents were allowed to stir at room temperature for 1 h. Then was added diethyl (3-bromopropyl)phosphonate (15.2 mmol, 2.92 mL) at 0 C. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed on a rotavap at 60 C. Water was added to the crude residue and extracted with EtOAc (3*200 mL). The combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography using EtOAc/methanol (100:0 to 95:5) as eluent to obtain the desired product 3 (5.67 g, 96%) as a transparent thick oil, Rf (10% EtOAc/isohexane) 0.45; numax (neat) 2978, 1699, 1367, 1245, 1156 cm-1; deltaH (400 MHz, CDCl3) 7.42-7.32 (m, 5H, Ph), 4.83 (s, 2H, OCH2Ph), 4.15-4.00 (m, 4H, 2(OCH2Me)), 3.47 (t, J=6.8 Hz, 2H, CH2CH2N), 1.96-1.84 (m, 2H, PCH2CH2), 1.79-1.68 (m, 2H, CH2CH2CH2), 1.50 (s, 9H, OCMe3), 1.30 (t, J=7.0 Hz, 6H, 2(OCH2Me)); deltaC (101 MHz, CDCl3) 156.5, 135.5, 129.4, 128.5, 128.4, 81.5, 77.0, 61.5 (d, J=6.9 Hz), 49.9 (d, J=19.2 Hz), 28.3, 23.1 (d, J=142 Hz), 20.5 (d, J=4.6 Hz), 16.4 (d, J=6.1 Hz); MS (ESI) m/z 402 [M+H]+; HRMS m/z found [M+H]+ 402.2041, C19H33NO6P requires 402.2045. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | To a solution of tert-butyl benzyloxycarbamate 2 (15.0 mmol, 3.35 g) in anhydrous DMF (30 mL) under N2 was added sodium hydride (60% in mineral oil, 15.5 mmol, 0.62 g) portionwise at 0 C. After evolution of hydrogen ceased, the contents were allowed stir at room temperature for 1 h. Then was added 1,3-dibromopropane (60.0 mmol, 6 mL) once at 0 C. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed on a rotavap at 60 C. Water was added to the reaction mixture and extracted with EtOAc (3*200 mL). The combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography using isohexane/EtOAc (100:0 to 98:2) as eluent to obtain the desired product 7 (4.71 g, 91%) as a transparent oil, Rf (10% EtOAc/isohexane) 0.50; numax (neat) 2976, 1700, 1366, 1253, 1153 cm-1; deltaH (400 MHz, CDCl3) 7.35 (s, 5H, Ph), 4.84 (s, 2H, OCH2Ph), 3.56 (t, J=6.6 Hz, 2H, BrCH2CH2), 3.40 (t, J=6.5 Hz, 2H, CH2CH2N), 2.12 (quin, J=6.6 Hz, 2H, CH2CH2CH2), 1.51 (s, 9H, OCMe3); deltaC (101 MHz, CDCl3) 156.4, 135.4, 129.4, 128.6, 128.5, 81.6, 76.9, 48.1, 30.8, 30.4, 28.3; MS (ESI) m/z 344 [M+H]+; HRMS m/z found [M+H]+ 344.0859, C15H2379BrNO3 requires 344.0861. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Intermediate 154: (R)-tert-butyl benzyloxy(l-hvdroxybut-3-en-2-yl)carbamate In a 3 L RBF, a solution of tert-butyl benzyloxycarbamate (Intermediate 153, 86.9 g, 389.22 mmol), N,N(l S,2S)-cyclohexane-l,2-diyl)bis(2-(diphenylphosphino)-l-naphthamide) (18.5 g, 23.39 mmol), Pd2(dba)3-CHC13 (8.05 g, 7.78 mmol) and TBAB (150.5 g, 466.81 mmol) in acetonitrile (1.8 L) was bubbled with N2 for 30 minutes and the flask was closed with a rubber septum. The solution was then kept in a -20 C freezer for 2 hrs. 2-vinyloxirane (30 g, 428.02 mmol, 1.10 equiv) was added and the mixture was stirred in the freezer (-20-25 C) for 3 days. The mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel column eluted with EtOAc/hexane (0 - 40%) to give the title compound (106 g, 93%) as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | General procedure: EXAMPLE 1 [0067] This example demonstrates the synthesis of N-alkylated-JV-Boc-O- benzylhydroxylamines la-c (Figure 1) in an embodiment of the invention. [0068] N-Boc-O-benzylhydroxylamine (5.00 g, 22.4 mmol) under nitrogen atmosphere was dissolved in dry DMF (100 mL) and cooled in an ice bath. 60% sodium hydride (887 mg, 22.2 mmol) was added and the mixture was stirred until end of hydrogen evolution (~ 30 min). Ethyl-6-bromohexanoate (6.19 g, 28 mmol) was added and the mixture was heated for 14 h at 65 C. The DMF was then evaporated in vacuo, the residue was dissolved in AcOEt and washed twice with water. After drying the organic layer with MgS04, the oil obtained after filtration and concentration was purified by flash chromatography using hexane/acetone (9/1), affording la as a colorless oil (7.04 g, 86%). 1H NMR (CDC13, 300 MHz, ppm): delta 1.24 (t, 3H, J= 7.2 Hz), 1.31 (m, 2H), 1.50 (s, 9H), 1.61 (m, 4H), 2.28 (t, 2H, J= 7.5 Hz), 3.40 (t, 2H, J= 12 Hz), 4.1 1 (q, 2H, J= 7.2 Hz), 4.82 (s, 2H), 7.36 (m, 5H). I3C NMR (CDC13, 75 MHz, ppm): delta 14.4, 24.8, 26.5, 26.9, 28.5, 34.4, 49.6, 60.4, 77.1, 81.4, 128.6(2), 129.5, 135.9, 156.8, 173.8. ESI-MS: m/z = 266.2 [M+H]+. [0069] The same alkylation procedure using ethyl-7-bromoheptanoate provided lb as a colorless oil (91%). 1H NMR (CDC13, 300 MHz, ppm): delta 1.24 (t, 3H, J= 7.2), 1.31 (m, 4H), 1.50 (s, 9H), 1.60 (m, 4H), 2.27 (t, 2H, J= 7,5 Hz), 3.40 (t, 2H, J= 6.9 Hz), 4,1 1 (q, 2H, J = 6.9 H), 4.82 (s, 2H), 7.33 (m, 5H). I3C NMR (CDC13, 75 MHz, ppm): delta 14.3, 24.9, 26.5, 26.9, 28.4, 28.8, 34.3, 49.6, 60.2, 76.9, 81.1, 128.4, 128.5, 129.4, 135.8, 156.6, 173.7. ESI- MS: m/z = 402.2 [M+Na]+. | |
A solution of tert-butyl-N-(benzyloxy)carbamate (4.00 g, 17.9 mmol) in DMF (20 mL) wasadded slowly to a suspension of sodium hydride (60% in mineral oil) (0.932 g; 23.3 mmol) inDMF (52 mL) at 0C. The reaction was stirred at 0C for 1 h, then ethyl 6-bromohexanoate (15.9 mL, 89.6 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with sat. ammonium chloride solution (130 ml) and the mixture was extracted with DCM (3x 200 ml). The combined organic layers were dried(Na2SO4), filtered and concentrated in vacuo. The obtained crude material (la) was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | To a solution of tert-butyl benzyloxycarbamate (4.02 g,18.0 mmol) in anhydrous DMF (60 mL) under N2 at 0C was added NaH (1.51 g, 37.8 mmol). The mixture was warmed to rt and stirred for 30 min. After cooling back to 0C , 6-bromohexanoic acid(3.86 g, 19.8 mmol) was added and the mixture was stirred at rt for1 h and then heated at 70C for 18 h. The reaction mixture was cooled and quenched with saturated NH4Cl (50 mL) and the aqueous layer acidied to pH 2 with conc. HCl. The product was extracted into ethyl acetate (350 mL), dried (Na2SO4) and the solvent was removed in vacuo. The crude product was dissolved in1M NaOH and impurities removed by extraction with ethyl acetate(220 mL). The aqueous later was then acidied with conc. HCl,and the product extracted into ethyl acetate (330 mL), dried(Na2SO4) and the solvent removed in vacuo to give acid 12 (4.27 g,70%) as an oil, which was used in the next step without further purication. A portion of 12 was puried by preparative chromatography for characterization: IR (lm) 2937, 1705 (C]O) cm1;1HNMR (300 MHz, CDCl3) d 11.2e10.85 (br s, 1H), 7.46e7.28 (m, 5H),4.82 (s, 2H), 3.40 (t, J7.1 Hz, 2H), 2.32 (t, J7.5 Hz, 2H), 1.73e1.54(m, 4H), 1.50 (s, 9H), 1.40e1.23 (m, 2H);13C NMR (75 MHz, CDCl3)d 179.7, 156.6, 135.7, 129.4, 128.5, 128.4, 81.3, 76.9, 49.4, 34.0, 28.3,26.7, 26.2, 24.4. HRMS (MNa) m/z calcd for C18H27NO5Na360.1781, found 360.1777. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Sodium hydride 60% dispersion in mineral oil (0.55 g, 13.7 mmol) was added portion- wise to a stirring solution of fe/f-Butyl /V-(benzyloxy)carbamate (2.05 g, 9.18 mmol) in DMF (15 mL) under a nitrogen atmosphere at ambient temperature. The reaction mixture was stirred for 15 min. 1 (3.00 g, 10.1 mmol) in DMF (10 mL) was added dropwise and the reaction mixture was stirred under a nitrogen atmosphere at ambient temperature overnight. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were pooled, washed with brine (100 mL), dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 1 :4 ethyl acetate/hexane to give a yellow oil (Yield: 1 .94 g, 37%). (0296) 1 H NMR (400 MHz, CDCI3): : delta 7.78 - 7.82 (m, 2H), 7.65 - 7.70 (m, 2H), 7.29 - 7.37 (m, 5H), 4.77 (s, 2H), 3.87 (t, J = 7.2 Hz, 2H), 3.69 (t, J = 7.2 Hz, 2H), 3.60 - 3.62 (m, 2H), 3.54 - 3.57 (m, 2H), 1.45 (s, 9H); 13C NMR (101 MHz, CDCI3): delta 168.3, 156.8, 135.8, 134.1 , 132.3, 129.6, 128.6, 128.5, 123.4, 81 .5, 77.1 , 67.7, 67.3, 49.8, 37.5, 28.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | To a solution of N-Boc-benzyloxyamine (2 · lg, 9.44 mmol, 1.2 eq) in DMAC (20 ml) was added potassium tert-butoxide (1.06 g, 9.44 mmo 1,1 · 2 eq) After 30 min, a solution of compound 8 (4 · Og, 7 · 87 mmo 1) in DMAC (20 ml) was added and the reaction was quenched at room temperature for 10 h. The reaction was quenched with saturated ammonium chloride solution (30 ml), concentrated, And the aqueous phase was extracted with ethyl acetate (50 ml * 2), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate and concentrated to give compound 9 (3.788, 95%). The 111 bandits 1? (4001 hold, 0) (: 13): 38.01 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | To a solution of 8 (1.2 g, 5.4 mmol, 1 eq) in dry THF (15 mL) under N2 at 0 Cwas added dropwise a suspension of NaH (60% in oil, 430 mg, 10.8 mmol, 2 eq) in dry THF (10 mL). This mixture was stirred at 0 C for 30 mm at which point 7 (2 g, 5.9 mmol, 1.1 eq) in dry THF (3 mL) was added as well as NaT (16 mg, 0.11 mmol, 0.02 eq) at 0 C. The reaction mixture was stirred at room temperature for 20 h, quenched with saturated NaHCO3 (aq, 30 mL), concentrated under reduced pressure to eliminate THF and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. Chromatographic separation on silica gel (EtOAc/CH2C12 = 2/1) gave the title compound as a light yellow oil (1.6 g, 77%). ?H NMR (400 IVIHz, CDC13) 7.39-7.31 (m, 5H), 6.69 (ddt, J= 22.4, 17.2, 5.3 Hz, 1H), 5.82 (ddt, J= 18.9, 17.2, 1.7 Hz, 1H), 4.83 (s, 2H), 4.12 -4.02 (m,6H), 1.49 (s, 9H), 1.31 - 1.27 (m, 6H). ?3C NIVIR (101 IVIHz, CDC13) 156.3, 146.4 (d, J= 5.3 Hz), 135.4, 129.3, 128.6, 128.4, 119.5 (d, J= 187.6 Hz), 82.0, 61.8 (d, J= 5.6 Hz),52.5 (d, J= 24.6 Hz), 28.2, 16.3 (d, J= 6.5 Hz). LC-MS (ESI): 799.2 m/z [2M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.3% | Dissolve BnONHBoc (5.8g) in DMAc (20mL) at 15-25 C.Added to a solution of potassium t-butoxide (2.91 g) in DMAc (40 mL),Keep the temperature at 15-25 , stir for 0.5h, and then turn into a slurry.Compound 7 (7.0 g) in Example 7 was dissolved in DMAc (20 mL) and added to the slurry.The mixture was heated to 40 C for 3.5h, and then reacted at 20 C for 12h. After the reaction is complete,Water (100 mL) and dichloromethane (100 mL × 3) were added for extraction. The dichloromethane phase was extracted with water,Wash with saturated sodium chloride solution and dry with anhydrous sodium sulfate,Concentrated to give oily compound 8(7.1 g, yield 74.3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With caesium carbonate; In N,N-dimethyl-formamide; at 65℃; for 4h;Inert atmosphere; | To a solution of acrylamide intermediate (250 mg, 0.58 mmol) and <strong>[79722-21-7]tert-butyl N-(benzyloxy)carbamate</strong> (569 mg, 1.16 mmol) in DMF is added Cs2CC>3 (569 mg, 1.75 mmol). The reaction mixture is stirred at 65C for 4 h (reaction monitored by LCMS), is then diluted with EtOAc (50 mL), is washed with water (20 mL) followed by brine (20 mL) and is dried over MgSCh. The organic solution is filtered, evaporated and purified by prep. HPLC (Prep-HPLC-1 conditions) to give tert-butyl (benzyloxy)(3-(3-((2-(difluoromethoxy)-6-methylpyridin-3- yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-3-oxopropyl)carbamate as a colorless wax (289 mg, 76% yield). 1H NMR (500 MHz, CDCh) <5: 8.54 (d, J = 8.1 Hz, 1 H), 7.49-7.43 (m, 2 H), 7.42-7.36 (m, 3 H), 7.34-7.30 (m, 3 H), 7.28 (s, 1 H), 7.26 (t, J = 72.6 Hz, 1 H), 7.22 (s, 1 H), 6.94 (d, J = 8.2 Hz, 1 H), 4.95-4.79 (m, 3 H), 4.71-4.60 (m, 1 H), 4.54-4.30 (m, 2 H), 3.80 (t, J = 7.3 Hz, 2 H), 2.47-2.42 (m, 2 H), 2.40-2.34 (m, 4 H), 1.50 (s, 9 H), 1.15 (d, J = 6.6 Hz, 3 H), 1.12 (d, J = 6.6 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With copper(I) oxide; potassium carbonate; 2,3-butane diamine In toluene at 80℃; for 16h; Molecular sieve; Sealed tube; Inert atmosphere; | Coupling of Iodopyridines with Functionalized Hydroxylamines General procedure: Hydroxamate (0.90 mmol), iodopyridine (1.34 mmol, 1.0-1.5 equiv), Cu2O (0.90 mmol), dry K2CO3 (1.79 mmol), and 3 Å molecular sieves (100% weight to the hydroxamate) were placed in a pressure tube. The tube was purged with argon three times. Degassed anhyd toluene (9.0 mL) and degassed DMEDA (0.18 mmol) were added to the flask. The vessel was sealed, and the mixture was stirred at 80 °C for 16 h. The mixture was cooled to r.t. and filtered. The filtrate was collected and eluted through a small silica plug, then concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel using a gradient of 0-20% EtOAc/CH2Cl2 to yield the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 55% 2: 30 mg | With copper(I) oxide; potassium carbonate; 2,3-butane diamine In toluene at 80℃; for 16h; Molecular sieve; Sealed tube; Inert atmosphere; | Coupling of Iodopyridines with Functionalized Hydroxylamines General procedure: Hydroxamate (0.90 mmol), iodopyridine (1.34 mmol, 1.0-1.5 equiv), Cu2O (0.90 mmol), dry K2CO3 (1.79 mmol), and 3 Å molecular sieves (100% weight to the hydroxamate) were placed in a pressure tube. The tube was purged with argon three times. Degassed anhyd toluene (9.0 mL) and degassed DMEDA (0.18 mmol) were added to the flask. The vessel was sealed, and the mixture was stirred at 80 °C for 16 h. The mixture was cooled to r.t. and filtered. The filtrate was collected and eluted through a small silica plug, then concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel using a gradient of 0-20% EtOAc/CH2Cl2 to yield the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: tert-butyl N-(benzyloxy)carbamate In toluene at 20℃; for 0.5h; Inert atmosphere; Alkaline conditions; Sealed tube; Stage #2: (E)-4,4,4-trifluoro-1-phenylbut-2-en-1-one In toluene at 20℃; for 12h; Inert atmosphere; Sealed tube; Alkaline conditions; | 1 Add mesitylene-substituted indanol-derived triazole carbene catalyst (0.02mmol, 0.2equiv.) into a dry 10mL test tube, 0.6mL anhydrous toluene, replaced with argon three times, After adding alkali (0.02mmol, 0.2eq), the reaction tube was sealed and stirred at room temperature for 30min. The nucleophile tert-butyl carbamate (0.12mmol, 1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 hours. The corresponding β-trifluoromethyl ketene (0.1 mmol, 1.0 equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction, The reaction solution was filtered through a glass dropper containing silica gel, washed with ether, and the filtrate was spin-dried. Column chromatography separation to obtain the target product precursor, Colorless oily liquid, The yield is 95%, 92%ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: tert-butyl N-(benzyloxy)carbamate In toluene at 20℃; for 0.5h; Inert atmosphere; Alkaline conditions; Sealed tube; Stage #2: C7H4F3NOS In toluene at 20℃; for 12h; Inert atmosphere; Sealed tube; Alkaline conditions; | 3 In a dry 10mL test tube, add mesitylene-substituted indanol-derived triazole carbene catalyst (0.02mmol, 0.2equiv.), 0.6mL anhydrous toluene, replace with argon three times, add alkali (0.02mmol, 0.2eq) to react After the test tube was sealed, it was stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol, 1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 hours. The corresponding β-trifluoromethyl ketene (0.1 mmol, 1.0 equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction is completed, the reaction solution is filtered through a glass dropper containing silica gel, washed with ether, the filtrate is spin-dried, and column chromatography is separated to obtain the target product precursor, a colorless oily liquid, with a yield of 93% and 98% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: tert-butyl N-(benzyloxy)carbamate In toluene at 20℃; for 0.5h; Inert atmosphere; Alkaline conditions; Sealed tube; Stage #2: C8H5F3N2O In toluene at 20℃; for 12h; Inert atmosphere; Sealed tube; Alkaline conditions; | 4 In a dry 10mL test tube, add mesitylene-substituted indanol-derived triazole carbene catalyst (0.02mmol, 0.2equiv.), 0.6mL anhydrous toluene, replace with argon three times, add alkali (0.02mmol, 0.2eq) to react After the test tube was sealed, it was stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol, 1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 hours. The corresponding β-trifluoromethyl ketene (0.1 mmol, 1.0 equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the completion of the reaction, the reaction solution was filtered through a glass dropper containing silica gel, washed with ether, the filtrate was spin-dried and separated by column chromatography to obtain the target product precursor, a white solid, with a yield of 92% and 94% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: tert-butyl N-(benzyloxy)carbamate In toluene at 20℃; for 0.5h; Inert atmosphere; Alkaline conditions; Sealed tube; Stage #2: C11H7F5O In toluene at 20℃; for 12h; Inert atmosphere; Sealed tube; Alkaline conditions; | 5 In a dry 10mL test tube, add mesitylene-substituted indanol-derived triazole carbene catalyst (0.02mmol, 0.2equiv.), 0.6mL anhydrous toluene, replace with argon three times, add alkali (0.02mmol, 0.2eq) to react After the test tube was sealed, it was stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol, 1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 hours. The corresponding β-pentafluoroethyl ketene (0.1 mmol, 1.0 equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the completion of the reaction, the reaction solution was filtered through a glass dropper containing silica gel, washed with ether, the filtrate was spin-dried and separated by column chromatography to obtain the target product precursor, a colorless oily liquid, with a yield of 91% and 95% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: tert-butyl N-(benzyloxy)carbamate In toluene at 20℃; for 0.5h; Inert atmosphere; Alkaline conditions; Sealed tube; Stage #2: (E)-4,4-Difluoro-1-phenyl-but-2-en-1-one In toluene at 20℃; for 12h; Inert atmosphere; Sealed tube; Alkaline conditions; | 6 In a dry 10mL test tube, add mesitylene-substituted indanol-derived triazole carbene catalyst (0.02mmol, 0.2equiv.), 0.6mL anhydrous toluene, replace with argon three times, add alkali (0.02mmol, 0.2eq) to react After the test tube was sealed, it was stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol, 1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 hours. The corresponding β-difluoromethyl ketene (0.1 mmol, 1.0 equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction is completed, the reaction solution is filtered through a glass dropper containing silica gel, washed with ether, the filtrate is spin-dried, and column chromatography is separated to obtain the target product precursor, a colorless oily liquid, with a yield of 92% and 95% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: tert-butyl N-(benzyloxy)carbamate In toluene at 20℃; for 0.5h; Inert atmosphere; Alkaline conditions; Sealed tube; Stage #2: C13H10O3S In toluene at 20℃; for 12h; Inert atmosphere; Sealed tube; Alkaline conditions; | 7 In a dry 10mL test tube, add mesitylene-substituted indanol-derived triazole carbene catalyst (0.02mmol, 0.2equiv.), 0.6mL anhydrous toluene, replace with argon three times, add alkali (0.02mmol, 0.2eq) to react After the test tube was sealed, it was stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol, 1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 hours. The corresponding β-methyl ketene (0.1 mmol, 1.0 equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction is completed, the reaction solution is filtered through a glass dropper containing silica gel, washed with ether, the filtrate is spin-dried, and column chromatography is separated to obtain the target product precursor, a colorless oily liquid, with a yield of 96% and 90% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: tert-butyl N-(benzyloxy)carbamate In toluene at 20℃; for 0.5h; Inert atmosphere; Alkaline conditions; Sealed tube; Stage #2: C39H52O3S In toluene at 20℃; for 12h; Inert atmosphere; Sealed tube; Alkaline conditions; | 8 In a dry 10mL test tube, add mesitylene-substituted indanol-derived triazole carbene catalyst (0.02mmol, 0.2equiv.), 0.6mL anhydrous toluene, replace with argon three times, add alkali (0.02mmol, 0.2eq) to react After the test tube was sealed, it was stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol, 1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 hours. The corresponding β-ethyl ketene (0.1 mmol, 1.0 equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the completion of the reaction, the reaction solution was filtered through a glass dropper containing silica gel, washed with ether, the filtrate was spin-dried and separated by column chromatography to obtain the target product precursor, a white solid, with a yield of 87% and 92% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: tert-butyl N-(benzyloxy)carbamate In toluene at 20℃; for 0.5h; Stage #2: C9H8F2O2S In toluene at 20℃; for 12h; | 4 Add mesitylene-substituted indanol-derived triazole carbene catalyst (0.02mmol, 0.2equiv.) into a dry 10mL test tube,0.6mL anhydrous toluene, replaced with argon three times,After adding alkali (0.02mmol, 0.2eq), the reaction tube was sealed and stirred at room temperature for 30min.The nucleophile tert-butyl carbamate (0.12mmol, 1.2eq) was slowly added to the reaction system,Stir at room temperature for 0.5 hour.The corresponding β-difluoromethyl unsaturated sulfone compound (0.1mmol, 1.0equiv.) was slowly added to the reaction system,The resulting mixture was stirred at room temperature for 12 hours.After the reaction is completed, the reaction liquid is filtered through a glass dropper containing silica gel,After rinsing with ether, the filtrate was spin-dried and separated by column chromatography.Obtain the target product precursor, a colorless oily liquid,The yield was 82%, 90%ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: tert-butyl N-(benzyloxy)carbamate In toluene at 20℃; for 0.5h; Stage #2: 1,1,1-trifluoro-3-phenylsulfonyl-2-propene In toluene at 20℃; for 12h; | 1 Add mesitylene-substituted indanol-derived triazole carbene catalyst (0.02mmol, 0.2equiv.), 0.6mL anhydrous toluene, argon replacement three times, add alkali (0.02mmol, 0.2eq) to the dry 10mL test tube. After the test tube was sealed, it was stirred at room temperature for 30 min. The nucleophile tert-butyl carbamate (0.12mmol, 1.2eq) was slowly added to the reaction system and stirred at room temperature for 0.5 hours. The corresponding β-trifluoromethyl unsaturated sulfone compound (0.1 mmol, 1.0 equiv.) was slowly added to the reaction system, and the resulting mixture was stirred at room temperature for 12 hours. After the completion of the reaction, the reaction solution was filtered through a glass dropper containing silica gel, washed with ether, the filtrate was spin-dried and separated by column chromatography to obtain the target product precursor, a colorless oily liquid, with a yield of 88% and 94% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: tert-butyl N-(benzyloxy)carbamate In toluene at 20℃; for 0.5h; Stage #2: C8H6F3NO2S In toluene at 20℃; for 12h; | 2 Add mesitylene-substituted indanol-derived triazole carbene catalyst (0.02mmol, 0.2equiv.) into a dry 10mL test tube,0.6mL anhydrous toluene,Replace with argon three times,After adding alkali (0.02mmol, 0.2eq), the reaction tube was sealed and stirred at room temperature for 30min.The nucleophile tert-butyl carbamate (0.12mmol, 1.2eq) was slowly added to the reaction system,Stir at room temperature for 0.5 hour.The corresponding β-trifluoromethyl unsaturated sulfone compound (0.1mmol, 1.0equiv.) was slowly added to the reaction system,The resulting mixture was stirred at room temperature for 12 hours.After the reaction is completed, the reaction liquid is filtered through a glass dropper containing silica gel,After rinsing with ether, the filtrate was spin-dried and separated by column chromatography.Obtain the target product precursor, a colorless oily liquid,The yield is 95%, 94%ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: tert-butyl N-(benzyloxy)carbamate In toluene at 20℃; for 0.5h; Stage #2: C10H7F5O2S In toluene at 20℃; for 12h; | 3 Add mesitylene-substituted indanol-derived triazole carbene catalyst (0.02mmol, 0.2equiv.) into a dry 10mL test tube,0.6mL anhydrous toluene, replaced with argon three times,After adding alkali (0.02mmol, 0.2eq), the reaction tube was sealed and stirred at room temperature for 30min.The nucleophile tert-butyl carbamate (0.12mmol, 1.2eq) was slowly added to the reaction system,Stir at room temperature for 0.5 hour.The corresponding β-pentafluoroethyl unsaturated sulfone compound (0.1mmol, 1.0equiv.) was slowly added to the reaction system,The resulting mixture was stirred at room temperature for 12 hours.After the reaction is completed, the reaction liquid is filtered through a glass dropper containing silica gel,After rinsing with ether, the filtrate was spin-dried and separated by column chromatography.Obtain the target product precursor, a colorless oily liquid,The yield is 80%, 94%ee. |
Tags: 79722-21-7 synthesis path| 79722-21-7 SDS| 79722-21-7 COA| 79722-21-7 purity| 79722-21-7 application| 79722-21-7 NMR| 79722-21-7 COA| 79722-21-7 structure
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P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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