* 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.
Reference Example 2 5-Bromo-1,3-benzoxazol-2(3H)-one To a solution of 2-amino-4-bromophenol (3.50 g, 18.6 mmol) in tetrahydrofuran (100 mL) is added 1,1'-carbonyldiimidazole (3.62 g, 22.3 mmol) at 20-25°C, and the mixture is refluxed for 1.5 hour. After the reaction, the reaction solution is cooled to 20-25°C, and thereto is added a 2N aqueous hydrochloric acid solution, and the mixture is extracted with ethyl acetate. The resulting organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried over anhydrous sodium sulfate. The resultant is filtered, and the solvent is evaporated under reduced pressure to give 5-bromo-1,3-benzoxazol-2(3H)-one (3.89 g, quantitative). IR (cm-1): 960, 1149, 1474, 1622, 1751
95%
for 2 h; Reflux
To a solution of 2-amino-4-phenylphenol (6.10 g, 32.9 mmol) in THF (150 mL) was added 1,1'-carbonyldiimidaziole (6.41 g, 39.5 mml) at room temperature. The mixture was stirred at reflux for 2 h and cooled to room temperature. The reaction was then quenched by adding 2 M HCl solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to give 11 (6.89 g, 99percent) as a white solid
95%
at 20℃; for 2 h; Inert atmosphere
1,1′-Carbonyldiimidazole (46.5 g, 287 mmol) was added to a solutionof bromophenol 2 (49.0 g, 261 mmol) in THF (300 mL) at r.t.,and the mixture was stirred at r.t. for 2 h. The reaction was then quenched with 2 M aq HCl (700 mL), and the mixture was extracted with EtOAc (2 × 500 mL). The organic layers were combined, washed with brine (500 mL), dried (NaSO4), filtered, and concentrated in vacuo to give a brown solid; yield: 53.2 g (95percent).
91%
at 120℃; for 3 h;
a. A mixture of 2-amino-4-bromophenol (6.0 g, 31.9 mmol) and 1 ,1'- carbonyldiimidazole (6.2 g, 38.3 mmol) in p-dioxane (30 mL) was heated at 120 °C for 3 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid (3 20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in hexanes/diethyl ether (1 :1 v/v, 50 mL) and washed with hexanes (20 mL) to afford 5- bromobenzo[d]oxazol-2(3H)-one in 91 percent yield (6.2 g) as a beige solid: 1H NMR (300 MHz, DMSO-d6) £ 11.85 (br s, 1 H), 7.28-7.25 (m, 3H); MS (ES+) m/z 212.0 (M + 1), 214.0 (M + 1).
63%
at 80℃; for 17 h; Inert atmosphere
To a solution of 14 (1.50 g. 7.98 mmol) in 1,4-dioxane (100 mL) was added Ι, Γ-carbonyldiimidazoie (1.55 g, 9.58 mmol). The reaction was heated at 80 "C for 17 h under nitrogen. The mixture was cooied to room temperature and 2N aq. HCI (40 mL) was added. The solution was diluted with ethyl acetate (200 mL) and washed with brine (2χ50 mL). The organic iayer was dried over sodium suifate, filtered and concentrated. Purification by chromatography (silica gel, 0-50percent ethyl acetate/hexanes) afforded 15 (1.08 g, 63percent) as an orange solid:XH M (5Q0 M Hz, DMSO-c/e) δ 11.81 (s, 1H), 7.27-7.25 (m, 3 H).
Reference：
[1] Patent: EP1719761, 2006, A1, . Location in patent: Page/Page column 26
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 18, p. 5568 - 5582
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 20, p. 8191 - 8195
[4] Synthesis (Germany), 2013, vol. 45, # 23, p. 3269 - 3275
[5] Patent: WO2013/64984, 2013, A1, . Location in patent: Page/Page column 125
[6] Patent: WO2015/2754, 2015, A2, . Location in patent: Paragraph 0198
[7] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9258 - 9272
[8] RSC Advances, 2016, vol. 6, # 115, p. 114491 - 114499
[9] Patent: WO2016/198400, 2016, A1, . Location in patent: Page/Page column 61
[10] Patent: WO2018/148745, 2018, A1, . Location in patent: Page/Page column 82, 83
2
[ 1450-75-5 ]
[ 14733-73-4 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 18, p. 3591 - 3596
3
[ 3889-13-2 ]
[ 14733-73-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1967, vol. 10, p. 408 - 410
With potassium carbonate; In dimethyl sulfoxide; at 20℃;
At room temperature, 154 methyl iodide (795 mg, 4.80 mmol) was added dropwise to 150 <strong>[14733-73-4]5-bromobenzo[d]oxazole-2(3H)-one</strong> (1.00 g, 4.67 mmol) and 56 potassium carbonate (1.29 g, 9.34 mmol) in anhydrous 29 DMSO (20 mL), and the reaction was reacted at room temperature overnight. The reaction was quenched by adding 48 water, extracted with ethyl acetate (50 mL×3), the combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the filtrate was separated on column chromatography to afford 910 mg of a brown-yellow solid, yield was 85.5%. LC-MS(APCI): m/z=228.0 (M-1).
79%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 0.5h;
Commercially available <strong>[14733-73-4]5-bromobenzo[d]oxazol-2(3H)-one</strong> (1.00 g, 4.67 mmol) was dissolved in DMF (23 mL), and the mixture was stirred at room temperature for 30 minutes after adding potassium carbonate (3.87 g, 28.0 mmol) and methyl iodide (0.87 mL, 14.0 mmol). Water was added to the mixture, and the mixture was stirred. The precipitated solid was filtered off and dried to give 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (839 mg, 79%). ESI-MS: m/z 228, 230 [M + H]+.
With potassium carbonate; In dimethyl sulfoxide; at 20℃;
A mixture of 5-Bromo-3-hydro-3H-benzooxazoi-2-one {500 mg, 2.3 rnmoi), iodomethane {291 uL, 663 mg, 4.67 mmol), K2CO3 (807 mg, 5,84 mmoi) in DMSO (10 ml) was stirred at room temperature for overnight. After concentration under reduced pressure, the residue was purified by flash column and yielded colorless solid (440 mg}. 1HNMR (CDCi3, 400.342 MHz): delta 3.38 (S, 3H), 7.07 (d, J - 8 Hz, 1H), 7.10 (d, J ~ 1.9 Hz, 1 H), 7.24 (dd, J = 8, 1.9 Hz, 1H).
With potassium carbonate; In N,N-dimethyl-formamide; acetone; at 20 - 25℃; for 3h;
Reference Example 3 tert-Butyl (5-bromo-2-oxo-1,3-benzoxazol-3(2H)-yl)acetate To a solution of <strong>[14733-73-4]5-bromo-1,3-benzoxazol-2(3H)-one</strong> (47.8 g, 223 mmol) in acetone (400 mL)/dimethylformamide (40 mL) are added potassium carbonate (3.28 g, 23.7 mmol), tert-butyl bromoacetate (36.3 mL, 246 mmol) at 20-25C, and the mixture is stirred at 20-25C for 3 hours. After filtration, the solvent is evaporated under reduced pressure, and the obtained residue is washed with hexane to give tert-butyl (5-bromo-2-oxo-1,3-benzoxazol-3(2H)-yl)acetate (71.5 g, 98 %). IR (cm-1): 1151, 1242, 1485, 1736, 1782
92%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;Cooling with ice;
To a suspension of 46 (250 mg, 1.18 mmol) and K2CO3 (245 mg, 1.78 mmol) in DMF (5.0 mL) was added tert-butyl bromoacetate (0.192 mL, 1.30 mmol) with cooling in an ice bath. The reaction mixture was stirred at 60 C for 2 h and cooled to room temperature. Water was then added, and the mixture was extracted with a mixture of toluene and EtOAc (1:1). The organic layer was washed with H2O and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was recrystallized from hexane/EtOAc to give 47 (269 mg, 70%) as a white solid
92%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;Cooling with ice; Inert atmosphere;
t-BuO2CCH2Br (38.4 mL, 260 mmol) was added to a suspension of benzoxazolone 3 (53.0 g, 248 mmol) and K2CO3 (51.3 g, 371 mmol)in DMF (500 mL) cooled in an ice bath. The mixture was warmed to r.t. and stirred for 3 h. H2O (1000 mL) was added, and the mixture was extracted with 1:1 toluene- EtOAc (2 × 500 mL). The organic layer was separated, washed with H2O (2 × 500 mL) and brine (500mL), dried (NaSO4), filtered, and concentrated in vacuo. The residue was triturated with hexane (200 mL) to give a solid that was recovered by filtration and washed with hexane (100 mL) to give abeige solid; yield: 75.2 g (92%).
86%
With caesium carbonate; In N,N-dimethyl-formamide; at 55℃; for 16h;
To a mixture of 5-bromo-3H-l,3-benzoxazol-2-one (500 mg, 2.34 mmol) and CS2CO3 (1.52 g, 4.67 mmol) in DMF (lOmL) was added tert-butyl 2-bromoacetate (911.36 mg, 4.67 mmol). The reaction mixture was stirred at 55 C for 16 hours to give a mixture. After cooling to r.t, the mixture was diluted with H20 (20 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated to give the crude product. The crude product was triturated from PE (5 mL) to give the product (660 mg, 2.01 mmol, 86% yield) as a solid.. 1H NMR (DMSO-c 400MHz) deltaH = 7.66 (d, 1H), 7.41 - 7.27 (m, 2H), 4.65 (s, 2H), 1.42 (s, 9H).
In tetrahydrofuran; at 20 - 25℃; for 1.5h;Heating / reflux;
Reference Example 2 5-Bromo-1,3-benzoxazol-2(3H)-one To a solution of 2-amino-4-bromophenol (3.50 g, 18.6 mmol) in tetrahydrofuran (100 mL) is added 1,1'-carbonyldiimidazole (3.62 g, 22.3 mmol) at 20-25C, and the mixture is refluxed for 1.5 hour. After the reaction, the reaction solution is cooled to 20-25C, and thereto is added a 2N aqueous hydrochloric acid solution, and the mixture is extracted with ethyl acetate. The resulting organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried over anhydrous sodium sulfate. The resultant is filtered, and the solvent is evaporated under reduced pressure to give 5-bromo-1,3-benzoxazol-2(3H)-one (3.89 g, quantitative). IR (cm-1): 960, 1149, 1474, 1622, 1751
100%
In tetrahydrofuran; at 85℃; for 2h;
At room temperature, 76 CDI (1.95 g, 12.00 mmol) was added into 151 2-amino-4-bromophenol (1.88 g, 10.00 mmol) in anhydrous 22 THF (50 mL), and the reaction was refluxed at 85 C. for 2 hrs. After cooling to room temperature, the reaction was quenched with 2 N diluted hydrochloric acid, extracted with ethyl acetate (50 mL×3), the combined organic layer was washed with saturated solution of 52 sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 2.15 g of a brown-yellow solid, yield was 100%. LC-MS(APCI): m/z=212 (M-1).
95%
In tetrahydrofuran; for 2h;Reflux;
To a solution of 2-amino-4-phenylphenol (6.10 g, 32.9 mmol) in THF (150 mL) was added 1,1'-carbonyldiimidaziole (6.41 g, 39.5 mml) at room temperature. The mixture was stirred at reflux for 2 h and cooled to room temperature. The reaction was then quenched by adding 2 M HCl solution, and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to give 11 (6.89 g, 99%) as a white solid
95%
In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere;
1,1?-Carbonyldiimidazole (46.5 g, 287 mmol) was added to a solutionof bromophenol 2 (49.0 g, 261 mmol) in THF (300 mL) at r.t.,and the mixture was stirred at r.t. for 2 h. The reaction was then quenched with 2 M aq HCl (700 mL), and the mixture was extracted with EtOAc (2 × 500 mL). The organic layers were combined, washed with brine (500 mL), dried (NaSO4), filtered, and concentrated in vacuo to give a brown solid; yield: 53.2 g (95%).
91%
In 1,4-dioxane; at 120℃; for 3h;
a. A mixture of 2-amino-4-bromophenol (6.0 g, 31.9 mmol) and 1 ,1'- carbonyldiimidazole (6.2 g, 38.3 mmol) in p-dioxane (30 mL) was heated at 120 C for 3 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid (3 20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in hexanes/diethyl ether (1 :1 v/v, 50 mL) and washed with hexanes (20 mL) to afford 5- bromobenzo[d]oxazol-2(3H)-one in 91 % yield (6.2 g) as a beige solid: 1H NMR (300 MHz, DMSO-d6) £ 11.85 (br s, 1 H), 7.28-7.25 (m, 3H); MS (ES+) m/z 212.0 (M + 1), 214.0 (M + 1).
63%
In 1,4-dioxane; at 80℃; for 17h;Inert atmosphere;
To a solution of 14 (1.50 g. 7.98 mmol) in 1,4-dioxane (100 mL) was added Iota, Gamma-carbonyldiimidazoie (1.55 g, 9.58 mmol). The reaction was heated at 80 "C for 17 h under nitrogen. The mixture was cooied to room temperature and 2N aq. HCI (40 mL) was added. The solution was diluted with ethyl acetate (200 mL) and washed with brine (2chi50 mL). The organic iayer was dried over sodium suifate, filtered and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/hexanes) afforded 15 (1.08 g, 63%) as an orange solid:XH M (5Q0 M Hz, DMSO-c/e) delta 11.81 (s, 1H), 7.27-7.25 (m, 3 H).
In tetrahydrofuran; for 2h;Reflux;
A solution of 2-amino-4-bromophenol (50.1 g, 266 mmol) and Iota, -carbonyl- diimidazole (51.9 g, 320 mmol) in THF (1 L) was stirred at reflux for 2 h. After cooling to r.t., the mixture was diluted with aqueous HC1 (2M) and extracted with EtOAc. The organic layer was washed with saturated aqueous NaHC03 solution and brine, then dried (Na2S04) and evaporated in vacuo. The residue was triturated from a mixture of EtOAc (30 mL) and heptane (3 mL) to afford a first crop of the title compound (32.5 g, 56%). Concentration of the mother liquor afforded a second crop of the title compound (24.5 g, 41%). deltaEta (300 MHz, DMSO-de) 11.84 (s, 1H), 7.26 (s, 3H). LCMS [M-H]" 212/214, RT 2.603 minutes
In tetrahydrofuran; at 20℃; for 1.5h;
To a solution of A-1 (5 g, 26.59 mmol, 1 eq) in THF (50 mL) was added CDI (5.17 g, 31.91 mmol, 1.2 eq), and the mixture was stirred at 20 C for 1.5 hours. The mixture was poured into water (50 mL), acidized with 1 N HC1 (40 mL), extracted with EtOAc (50 mL x 2). The combined organic phase was washed with sat. Na2C03 (40 mL) and brine (10 mL), dried over Na2S04, filtered and concentrated to afford A-2 (6 g, crude) as a solid. *H NMR (OMSO-d6 400MHz) deltaH = 7.43 - 7.00 (m, 3H)
In tetrahydrofuran; for 2h;Reflux;
To a solution of 4-bromo-2-aminophenol (500.0 mg,2.66 mmol) in 150 mL of THF, 1,10-carbonyldiimidazole(518.0 mg, 3.19 mmol) was added. The mixturewas refl uxed with stirring for 2 h. The reaction mixturewas quenched by adding 2 m HCl solution after coolingto room temperature. EtOAc was used for the extraction.The organic phase was washed with brine, driedover anhydrous sodium sulfate, and fi ltered. Thereafter,the solvent was removed in vacuo to get the productas white solid. MS (ESI), m/z: 211.7 [M-H]+; calculatedm/z: 211.9 [M-H]+. 1H NMR (DMSO, 600 MHz):7.20-7.28 m (3H). 13C NMR (DMSO, 150 MHz): 111.7,112.9, 115.8, 124.8, 132.5, 143.0, 154.6.
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 18h;
Step A; Commercially available 5-Bromo-3H-benzooxazol-2-one (1 g) was dissolved in DMF (15 ml) and Zn(CN)2 (1.09 g) added. The mixture was sonicated for 5 Min while a stream of nitrogen was bubbled through the solution. After the addition of Pd[P(Ph)3]4 (0.54 g), the mixture was heated at 100 0C oil bath temperature for 18 h. The solvents were evaporated and the residue purified by chromatography on silica using EtOAc/cyclohexane (20:80 -> 50:50) to afford the title compound as white solid (674 mg; 91 %; MH+ = 161).
[00272] To a solution of commercially available 5-bromo-3H-benzooxaol-2-one (l .Og, 4.6 mmol) in dry THF (28 mL) at -78 0C under nitrogen was added BuLi (1.6 M in hexanes, 8.8 mL) dropwise, the reaction mixture was stirred -40 0C for 1 hour and trimethyl borate (2.13 mL) was added. The reaction mixture was allowed to warm up to rt and stirred overnight. IN HCl (50 mL) was added and stirred for 30 min, then extracted with EtOAc. The organic layer was dried and concentrated to give 2-oxo-2,3-dihydrobenzo[d]oxazol-6-ylboronic acid as a solid, which was dried and used for the next step.
With potassium carbonate; In acetonitrile; at 60℃; for 16h;
a) 5-Bromo-3-(2-methoxyethyl)benzo[<i]oxazol-2(3H)-oneA mixture of <strong>[14733-73-4]5-bromobenzo[d]oxazol-2(3H)-one</strong> (2.06 g), l-bromo-2-methoxyethane (1.085 mL) and potassium carbonate (3.99 g) in acetonitrile (15 mL) was heated at 60 0C for 16 h. Water was added and the mixture was extracted with ethyl acetate (3 times). The organic layers were dried over magnesium sulfate, evaporated and purified by flash silica chromatography eluting with 5 : 1 isohexane / acetone to give the subtitle compound (1.359 g).1 H NMR (300 MHz, CDCl3) delta 7.28 - 7.18 (m, 2H), 7.06 (d, J= 16.1 Hz, IH), 3.97 (t, J= 5.1 Hz, 2H), 3.69 (t, J= 5.1 Hz, 2H), 3.36 (s, 3H).
With potassium carbonate; In acetonitrile; at 60℃; for 16h;
A mixture of <strong>[14733-73-4]5-bromobenzo[d]oxazol-2(3H)-one</strong> (2.06 g), l-bromo-2-methoxy ethane (1.085 rnL) and potassium carbonate (3.99 g) in acetonitrile (15 mL) was heated at 60 0C for 16 h. Water was added and the mixture was extracted with ethyl acetate (3 times). The organic layers were dried over magnesium sulfate, evaporated and purified by flash silica chromatography eluting with 5 : 1 isohexane / acetone to give the subtitled compound (1.359 g)- 1H NMR (300 MHz, CDCl3) delta 7.28 - 7.18 (m, 2H), 7.06 (d, IH), 3.97 (t, 2H), 3.69 (t, 2H), 3.36 (s, 3H).
With potassium acetate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In water; acetonitrile; for 50h;Inert atmosphere of nitrogen; Heating; Reflux;
To a mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3.09 g), 5- bromobenzo[d]oxazol-2(3H)-one (2 g) and potassium acetate (2.75 g) in acetonitrile (20 mL) and water (15 mL), under a nitrogen atmosphere was added 1,1 bis{-tert- butylphosphino)ferrocene palladium dichloride (61 mg) and the mixture stirred and heated under reflux for 5O h. The cooled reaction mixture was concentrated under vacuum and the residue partitioned between water (100 mL) and diethyl ether (200 mL). The layers were separated and the organic extract was dried over magnesium sulfate and concentrated to dryness to afford a viscus oil. The crude product was purified by chromatography on silica eluting with ethyl acetate / ohexane (20:80) to afford the sub-titled compound (1.1 g).1H NMR (399.824 MHz, CDCl3) delta 9.03 (s, IH), 7.61 (dd, IH), 7.53 (s, IH), 7.21 (d, IH), 1.35 (s, 12H).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In tetrahydrofuran; at 80℃; for 72h;Inert atmosphere;
10. Preparation of 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)- one 5-Bromo-2-benzoxazolinone (200 mg, 0.935 mmol),bis(pinacole)diborane (309 mg, 1.215 mmol), potassium acetate (275mg, 2.80 mmol) and Pd(dppf)C12.CH2CI2 (153 mg, 0.187 mmol) were loaded in a microwave vial. The capped vial was evacuated using high vacuum and purged with nitrogen (each three times). Dry THE (4 mL) was added and the mixture was degassed again by using the high vacuum and purged with nitrogen again (each threetimes). The mixture was heated conventional at 80 C for 3 days before it was filtered over Celite and the residue was washed with CHCI3IMeOH. The filtrate was concentrated in vacuum and the resulting brown oil was purified by chromatography on silica gel (biotage, DCM/EtOH) to give the product (40 mg, 16%, purity 76%) as a light yellow sticky solid containing bis(pinacole)diborane. 1H-NMR (500 MHz, CDCI3) ppm = 7.99 (bs,1H).7.62 (dd, J=8.0, 1.0, IH), 7.50 (s, IH), 7.22 (d, J=8.0, 1H), 1.36 (s, 12H). HRMS m/z(ESl) [M+H] C13H16BN04, calc 261.1281, found 261.1284, Rt = 2.89 mm (HPLC methodE).
With potassium carbonate; In acetonitrile; at 70℃; for 3h;
R6 (530 mg, 2.48 mmol), R7 (473 mg, 2.81 mmol) and K2CO3 (1 g, 7.24 mmol) in acetonitrile (10 mL) are heated to 70 C for 3 h. The cool reaction mixture is diluted with EA and water, the aqueous layer extracted three times with EA, the combined organic layers are washed with brine, dried and concentrated. The residue is purified via column chromatography (cyclohexane / EA = 3:1). Yield 30% m/z 286/288 [M+H]+, rt 0.66 min, LC-MS Method b.
With potassium carbonate; In acetonitrile; at 70℃; for 16h;
A mixture of <strong>[14733-73-4]5-bromobenzo[d]oxazol-2(3H)-one</strong> (1.1 g), 3-methoxypropyl methanesulfonate (1.297 g) and potassium carbonate (2.131 g) in acetonitrile (25 mL) was heated at 70 0C for 16h. Water was added and the mixture was extracted with ethyl acetate (3 times). The organic layers were dried (MgSO4), evaporated and purified by flash chromatography (silica, isohexane - acetone (5:1) as eluent) to give the sub-titled compound (1.50 g) as an oil.m/e (APCI+) 286/288 [M+Eta]+
With potassium carbonate; In acetonitrile; at 70℃; for 16h;
i) 5-Bromo-3-(3-methoxypropyl)benzo [d] oxazol-2(3H)-oneA mixture of <strong>[14733-73-4]5-bromobenzo[d]oxazol-2(3H)-one</strong> (1.1 g), 3-methoxypropyl methanesulfonate (1.297 g) and potassium carbonate (2.131 g) in acetonitrile (25 mL) was heated at 700C for 16h. Water was added and the mixture was extracted with ethyl acetate (3 times). The combined organic layers were dried with magnesium sulfate, evaporated and purified by flash silica chromatography eluting with ohexane - acetone (5:1) to give the sub-titled compound as an oil (1.5 g).m/e (APCI+) 286/288 [M+Eta]4
With potassium carbonate; In acetonitrile; at 70℃; for 3h;
R6 (530 mg, 2.48 mmol), R7 (473 mg, 2.81 mmol) and K2CO3 (1 g, 7.24 mmol) in acetonitrile (10 mL) are heated to 70 C. for 3 h. The cool reaction mixture is diluted with EA and water, the aqueous layer extracted three times with EA, the combined organic layers are washed with brine, dried and concentrated. The residue is purified via column chromatography (cyclohexane/EA=3:1). Yield 30% m/z 286/288 [M+H]+, rt 0.66 min, LC-MS Method b.
A 100 ml round-bottomed flask was charged with 5-brorno-2-benzoxazlinone (0.750 g, 3.50 mrnol), n-propy. iodide (0.684 ml, 7.01 mmoi), potassium carbonate (1.211 g, 8.78 mmol} and Dioxane (5 mL). The reaction mixture was stirred at room temperature for overnight. The reaction was quenched with water. Colorless precipitate was collected through ftiiration and 5-Bromo-3-propyl-3H-bbetanzooxazoi-2-one was obtained. ESI-JVIS: m/z 258.2(M+H)"
With potassium tert-butylate;5-(di-tert-butylphosphino)-1?, 3?, 5?-triphenyl-1?H-[1,4?]bipyrazole; tris-(dibenzylideneacetone)dipalladium(0); In tert-Amyl alcohol; at 60℃;
Potassium t-butoxide (88 mg, 0.79 mmol) was added to a solution of <strong>[14733-73-4]5-bromo-2-benzoxazolinone</strong> (28 mg, 0.15 mmol), (2R,5R)-2-methyl-5-phenylmorpholine (Preparation 2, 27 mg, 0.15 mmol), Tris(dibenzylideneacetone) dipalladium(0) (7 mg, 0.008 mmol) and 5-(di-tert-butylphosphino)-1', 3',5'-triphenyl-1H-[1,4]bipyrazole (7 mg, 0.015 mmol) in t-amyl alcohol (0.5 mL). The reaction mixture was stirred at 60 C. overnight. The reaction was cooled to room temperature and extracted with ethyl acetate and saturated aqueous ammonium chloride. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in dimethylsulfoxide and purified by preparative HPLC Method A. Gradient: 85% water/acetonitrile linear gradient to 100% acetonitrile in 8.5 min. Analytical LCMS Method A: retention time 2.84 minutes; LCMS (ES+): 311.14 (M+H).
With chlorosulfonic acid; In dichloromethane; at 18 - 25℃; for 18h;
Preparation of 5-Bromo-2-oxo-2,3-dihvdrobenzofd1oxazole-6-sulfonyl chloride (35-210258] To a mixture of commercially-available <strong>[14733-73-4]5-bromobenzo[d]oxazol-2(3H)-one</strong> (35-1, 500 mg, 2.336 mmol) in DCM (23 mLl) at RT was added chlorosulfonic acid (1565 ??, 23.36 mmol). The mixture became a solution that was stirred at RT. After 18 h, The solution was cooled to 0 C and carefully quenched with ice chips and then partitioned between water (15 mL) and EtOAc (150 mL). The aqueous layer was extracted with 3 x 30 mL DCM. The combined organics were dried over Na2S04, filtered, concentrated to give 35-2 as a white solid, which was carried forward without further purification.
b. To a cold (0 C) suspension of sodium hydride (0.589 g of a 60% w/w dispersion in mineral oil, 14.7 mmol) in /V,A/-dimethylformamide (50 mL) was added in portions 5-bromo-benzo[of]oxazol-2(3 - )-one (3.0 g, 14.0 mmol). The reaction mixture was stirred for 1 h at 0 C and benzhydryl bromide (3.81 g, 15.4 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. Further benzhydryl bromide (1.7 g. 6.9 mmol) was added and the reaction mixture was heated at 70 C for 16 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was suspended in ethyl acetate (300 mL), washed with water (2 20 mL) and brine (2 20 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 0-50% gradient of ethyl acetate in hexanes to afford 3-benzhydryl-5- bromobenzo[d]oxazol-2(3H)-one as an orange solid in 71% yield (3.87 g): 1H NMR (300 MHz, CDCI3) £7.41-7.34 (m, 6H), 7.27-7.21 (m, 4H), 7.19-7.14 (m, 1 H), 7.06 (d, J = 8.5 Hz, 1 H), 6.78 (s, 1H), 6.46 (s, 1 H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In N,N-dimethyl-formamide; at 110℃; for 1h;Microwave irradiation; Inert atmosphere; Sealed tube;
Under an atmosphere of nitrogen, a mixture of (4-(((tert- butoxycarbonyl)amino)methyl)phenyl)boronic acid (commercially available from for example Aldrich) (387 mg, 1.54 mmol), 5-bromobenzo[d]oxazol-2(3H)-one (commercially available from for example Aldrich) (300 mg, 1.40 mmol) and sodium carbonate (446 mg, 4.21 mmol) in DMF (4 mL) was treated with dicholoro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II) (commercially available from for example Aldrich) (72 mg, 0.098 mmol) then sealed and heated in a Biotage "Initiator" microwave at 110 C for 1 hr. The cooled product mixture was treated with dichloromethane (50 mL) and water (10 mL). The mixture was separated and the organic fraction was evaporated to dryness. The product was subjected to purification by mass-directed automated preparative HPLC (formic acid modifier) to afford the title compound (178 mg, 0.52 mmol, 37 % yield). LCMS RT= 1.03 min, ES+ve m/z 341 [M+H]+.
37%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In dichloromethane; water; N,N-dimethyl-formamide; at 110℃; for 1h;Inert atmosphere; Microwave irradiation;
Under an atmosphere of nitrogen, a mixture of <strong>[489446-42-6](4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid</strong> (commercially available from for example Aldrich) (387 mg, 1.54 mmol), 5-bromobenzo[d]oxazol-2(3H)-one (commercially available from for example Aldrich) (300 mg, 1.40 mmol) and sodium carbonate (446 mg, 4.21 mmol) in DMF (4 mL) was treated with dicholoro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (commercially available from for example Aldrich) (72 mg, 0.098 mmol) then sealed and heated in a Biotage "Initiator" microwave at 110 C. for 1 hr. The cooled product mixture was treated with dichloromethane (50 mL) and water (10 mL). The mixture was separated and the organic fraction was evaporated to dryness. The product was subjected to purification by mass-directed automated preparative HPLC (formic acid modifier) to afford the title compound (178 mg, 0.52 mmol, 37% yield). LCMS RT=1.03 min, ES+ve m/z 341 [M+H]+.
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 150℃; for 24h;
Intermediate 14: 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbonitrile To a solution of 5-bromo benzoxazolinone (1 g, 4.7 mmol) in DMF (15 mL), were added Zn(CN)2 (1 g, 9.4 mmol) and Pd(PPh3)4. The reaction was stirred at 150 C. for 24 h. The reaction progress was monitored by TLC (100% EtOAc). The reaction was diluted with EtOAc (10 mL) and filtered through Celite brand filter agent. The organic layer was concentrated and purified by column chromatography (silica gel, 0-50% EtOAc in hexanes) to give the title compound. 1H NMR (400 MHz, CDCl3): delta 8.6 (br s, 1H), 7.5 (dd, J=1.8, 8.4 Hz, 1H), 7.3-7.4 (m, 2H).
A mixture of <strong>[14733-73-4]5-bromobenzo[d]oxazol-2(3H)-one</strong> (ig, 4.67mmol) and copper (I) cyanide (0.71g, 7.93mmol) in 3 ml DMF is heated at 150C under nitrogen atmosphere for 22 hr. After cooling to room temperature, a solution of 1.55 g (31.6 mmol) of sodium cyanide in 32 ml water is added followed by 1 hr stirring. The system is extracted thoroughly with ethyl acetate, washed with brine, dried and concentrated in vacuum to provide 1.04 of the crude mixture, which was carried out forward without further purification.LRMS (mlz): 161 (M+1)+
3-benzyl-5-bromobenzo[d]oxazol-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium carbonate; In acetonitrile; at 80℃; for 3h;
To a solution of 15 (150 mg, 0.701 rnmo) in acetonitrie (10 mL) was added benzyl bromide (180 mg, 1.05 mmol} and potassium carbonate (193 mg, 1.40 mmol). The reaction was heated at 80 C for 3 h. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) to afford 16 (195 mg, 92%) as an off-white solid:JH N R (500 M Hz, CDC13) 6 7.41-7.30 (m, 5H), 7.22 (dd, J = 8.5, 1.7 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.97 (d, J - 1.6 Hz, 1H), 4.97 (s, 2H).
3-[3-(N-benzyl-N-methylamino)propyl]-5-bromobenzoxazolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;
General procedure: One equivalent of appropriate heterocyclic derivative was dissolved in DMF. Three equivalents of potassium carbonate and 1.2 equivalent of the appropriate 3-chloropropan-1-amine derivative were added. The resulting mixture was heated at 70C until disappearance of the starting material. The reaction was monitored by TLC. After 24-96 h, the solvent was removed under reduced pressure, and water added to the residue. The crude product was extracted with dichloromethane. The combined organic fractions were washed with water and dried over magnesium sulphate. Purification by thick layer chromatography or column chromatography was performed.
5-bromo-3-(cyclopropylmethyl)-1,3-benzoxazol-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h;
Cesium carbonate (1.79 g, 5.5 mmol) was added to a solution of <strong>[14733-73-4]5-bromo-1,3-benzoxazol-2(3H)-one</strong> (1.07 g, 5.0 mmol) in DMF (10 mL). (Bromomethyl)cyclopropane (743 mg, 5.5 mmol) was added dropwise and the reaction stirred at rt for 24 h. The solvents were removed under reduced pressure and the resultant oil dissolved in EtOAc. The organic extract was washed with water, saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The resultant oil was purified by silica gel column chromatography eluting with a 1:2 ratio of DCM:iso-hexane to afford the subtitled compound as a white solid (918 mg, 68%). 1H NMR (400 MHz, CDCl3): delta 7.24 (dd, 1H), 7.17 (d, 1H), 7.13-7.04 (m, 1H), 3.68 (d, 2H), 1.29-1.17 (m, 1H), 0.69-0.54 (m, 2H), 0.51-0.41 (m, 2H).
68%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h;
Cesium carbonate (1.79 g, 5.5 mmol) was added to a solution of <strong>[14733-73-4]5-bromo-1,3-benzoxazol-2(3H)-one</strong> (1.07 g, 5.0 mmol) in DMF (10 mL). (Bromomethyl)cyclopropane (743 mg, 5.5 mmol) was added dropwise and the reaction stirred at rt for 24 h. The solvents were removed under reduced pressure and the resultant oil dissolved in EtOAc. The organic extract was washed with water, saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The resultant oil was purified by silica gel column chromatography eluting with a 1:2 ratio of DCM:iso-hexane to afford the subtitled compound as a white solid (918 mg, 68%). 1H NMR (400 MHz, CDCl3): delta 7.24 (dd, 1H), 7.17 (d, 1H), 7.13-7.04 (m, 1H), 3.68 (d, 2H), 1.29-1.17 (m, 1H), 0.69-0.54 (m, 2H), 0.51-0.41 (m, 2H).
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