* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With iron; ammonium chloride In methanol; water at 70℃; for 2 h;
INTERMEDIATE Bl2-Methyl- 1 ,3-benzoxazol-6-amine To a heated suspension (70 0C) of 6-nitro-2-methyl-benzoxazole (4.00 g, 22.4 mmol) in MeOH (60 mL) was added a solution of ammonium chloride (12.1 g, 0.227 mol) in water (40 mL) followed by iron powder (4.52 g, 80.1 mmol). The mixture was stirred for 2 h at 70 0C and then filtered through Celite and washed with MeOH. The filtrate was concentrated and the residue was partitioned between water and EtOAc. The organic layers were combined and the solvent was removed under reduced pressure to give the title compound. Yield 2.83 g (85percent). Analytical HPLC: purity 100percent (System A); LRESIMS (ESI+) m/z = 149 (M+H)+.
Reference：
[1] Patent: WO2009/150144, 2009, A1, . Location in patent: Page/Page column 137
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 28, p. 5082 - 5088
[3] Journal of the Chemical Society, 1928, p. 121
[4] Journal of the Chemical Society, 1930, p. 2685,2687
[5] DRP/DRBP Org.Chem.,
[6] Patent: US2326497, 1938, ,
[7] J. Gen. Chem. USSR (Engl. Transl.), 1960, vol. 30, p. 2640 - 2646[8] Zhurnal Obshchei Khimii, 1960, vol. 30, # 8, p. 2658 - 2664
[9] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, # 2, p. 268 - 275
[10] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, # 3, p. 371 - 380
[11] Tetrahedron Letters, 1999, vol. 40, # 46, p. 8085 - 8088
[12] Patent: US2014/274933, 2014, A1, . Location in patent: Paragraph 0081; 0082
[13] Chemical Communications, 2015, vol. 51, # 91, p. 16312 - 16315
[14] Journal of Photochemistry and Photobiology A: Chemistry, 2018, vol. 361, p. 62 - 66
[15] Patent: US2326497, 1939, ,
2
[ 5683-43-2 ]
[ 110-54-3 ]
[ 7439-89-6 ]
[ 5676-60-8 ]
Yield
Reaction Conditions
Operation in experiment
83%
With sodium carbonate In dichloromethane; water; acetic acid; ethyl acetate
A. 2-Methyl-6-aminobenzoxazole (479A) To a solution of 2-methyl-6-nitrobenzoxazole (100 mg, 0.560 mmol) in AcOH (2 mL) was added iron powder (325 mesh, 63.0 mg, 1.12 mmol) at 70° C. in a single portion. After 15 min at 70° C. additional iron powder (325 mesh, 63.0 mg, 1.12 mmol) was added and stirring was continued for 15 min. The mixture was cooled and concentrated under reduced pressure. The resulting residue was taken up into EtOAc and washed with sat. Na2CO3 followed by H2O. The organic layer was dried over MgSO4, concentrated under reduced pressure and purified by flash chromatography on silica gel eluding with a gradient of 0 to 25percent EtOAc in CH2Cl2 to yield 69 mg (83percent) of compound 479A as a solid. HPLC: 97percent at 0.24 min (retention time) (YMC S5 ODS column, 4.6*50 mm Ballistic, 10-90percent aqueous methanol over 4 min containing 0.2percent H3PO4, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 149.2 [M+H]+.
With pyridine In 5,5-dimethyl-1,3-cyclohexadiene at 0 - 20℃; for 2 h;
The synthetic route for 1 was outlined in Scheme 1, and the detailed procedures were presented as follows: (a) To a solution of 2-amino-5-nitrophenol (7.70g, 50.0mmol) and pyridine (3.96g, 50.0mmol) in dry xylene (150mL) at 0°C was added dropwise acetyl chloride (4.32g, 55.0mmol). The solution was stirred at ambient temperature for 2h. To above solution was added p-toluenesulfonic acid (1.72g, 10.0mmol), the solution was refluxed till no water was discharged. After cooling to room temperature, the solution was washed with water (100mL×3) and a saturated solution of NaCl (50.0mL), respectively. The organic solution was collected and dried over Na2SO4, after evaporation of the solvent, the crude 2-methyl-6-nitrobenzoxazole (pale solid, 8.80g, 95percent yield) was obtained for next step without purification. (b) To a solution of 13 2-methyl-6-nitrobenzoxazole (3.92g, 22.0mmol) in 14 methanol (60.0mL) at 70°C was added 15 NH4Cl (11.77g, 220mmol) in 16 H2O (40.0mL) and Fe (4.48g, 80.0mmol). The mixture solution was stirred at 70°C for 4h till the starting material disappeared (TLC detection). The mixture solution was cooled to ambient temperature and filtered, the solution was extracted with ethyl acetate (30.0mL×3). The combined organic solution was dried over Na2SO4, after evaporation of the solvent, the crude 17 2-methylbenzoxazol-6-amine (2.77g, 85percent yield) was obtained for next step reaction without purification. (c) To a solution of 2-methylbenzoxazol-6-amine (2.66g, 18.0mmol) in methanol (30.0mL) was added 18 formaldehyde (37percent, 12mL, 144mmol) and 19 NaBH3CN (2.27g, 36.0mmol). The solution was stirred at ambient temperature for 36h till the starting material disappeared (TLC detection). The solution was poured into H2O (30.0mL), and the mixture solution was extracted with ethyl acetate (30.0mL×3). The combined organic solution was dried over Na2SO4, the solution is concentrated and 20 2-methyl-6-(N, N-dimethylamino) benzoxazole (2.50g, 79percent yield) is obtained by flash column chromatography (elute: petroleum ether / ethyl acetate=10 / 1, v/v, Rf =0.11).
Reference：
[1] Journal of Photochemistry and Photobiology A: Chemistry, 2018, vol. 361, p. 62 - 66
4
[ 25351-89-7 ]
[ 5683-43-2 ]
Yield
Reaction Conditions
Operation in experiment
85%
With Amberlyst-15 In water at 90℃; for 1 h; Irradiation
General procedure: To a mixture of N-acyl or benzoy lderivative (6, 1 mmol) in water (5 mL) was added amberlyst-15 (10percent, w/w) and the mixture was irradiated with ultrasound (40 KHz) continuously at 90 °C till the completion of the reaction (monitored by TLC) as indicated in Table 4. The solid separated was filtered, washed with diethyl ether (2 x 5 mL), dried and treated with EtOAc (15 mL). After stirring for 10 min the mixture was filtered to remove the insoluble catalyst. The filtrate was collected and concentrated under vacuum. The solid obtained was purified by recrystallization (column chromatography in few cases) to afford the desired products 7, 8 or 9.
With iron; ammonium chloride; In methanol; water; at 70℃; for 2h;
INTERMEDIATE Bl2-Methyl- 1 ,3-benzoxazol-6-amine To a heated suspension (70 0C) of <strong>[5683-43-2]6-nitro-2-methyl-benzoxazole</strong> (4.00 g, 22.4 mmol) in MeOH (60 mL) was added a solution of ammonium chloride (12.1 g, 0.227 mol) in water (40 mL) followed by iron powder (4.52 g, 80.1 mmol). The mixture was stirred for 2 h at 70 0C and then filtered through Celite and washed with MeOH. The filtrate was concentrated and the residue was partitioned between water and EtOAc. The organic layers were combined and the solvent was removed under reduced pressure to give the title compound. Yield 2.83 g (85%). Analytical HPLC: purity 100% (System A); LRESIMS (ESI+) m/z = 149 (M+H)+.
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 16h;
2-methylbenzo[d]oxazol-6-amine 2-Methyl-6-nitrobenzoxazole (10.0 g, 56 mmol) and 10% Pd/C (3.4 g) in MeOH (10 mL) were hydrogenated at rt for 16 h. The reaction mixture was filtered through Celite and wash with MeOH (100 mL). The filtrate was concentrated under vacuum to obtained crude 2-methylbenzo[d]oxazol-6-amine (8.4 g), (MS: ESI +ve, 149.07 [M+H]); 1H NMR: (400 MHz, DMSO) delta: 2.47 (s, 3H), 5.24 (s, 2H), 6.56-6.53 (dd, J=2, 1H), 6.70-6.70 (d, J=1.6, 1H), 7.25-7.23 (d, J=8.4, 1H).
With iron; ammonium chloride; In methanol; water; at 70℃; for 4h;
The synthetic route for 1 was outlined in Scheme 1, and the detailed procedures were presented as follows: (a) To a solution of 2-amino-5-nitrophenol (7.70g, 50.0mmol) and pyridine (3.96g, 50.0mmol) in dry xylene (150mL) at 0C was added dropwise acetyl chloride (4.32g, 55.0mmol). The solution was stirred at ambient temperature for 2h. To above solution was added p-toluenesulfonic acid (1.72g, 10.0mmol), the solution was refluxed till no water was discharged. After cooling to room temperature, the solution was washed with water (100mL×3) and a saturated solution of NaCl (50.0mL), respectively. The organic solution was collected and dried over Na2SO4, after evaporation of the solvent, the crude <strong>[5683-43-2]2-methyl-6-nitrobenzoxazole</strong> (pale solid, 8.80g, 95% yield) was obtained for next step without purification. (b) To a solution of 13 <strong>[5683-43-2]2-methyl-6-nitrobenzoxazole</strong> (3.92g, 22.0mmol) in 14 methanol (60.0mL) at 70C was added 15 NH4Cl (11.77g, 220mmol) in 16 H2O (40.0mL) and Fe (4.48g, 80.0mmol). The mixture solution was stirred at 70C for 4h till the starting material disappeared (TLC detection). The mixture solution was cooled to ambient temperature and filtered, the solution was extracted with ethyl acetate (30.0mL×3). The combined organic solution was dried over Na2SO4, after evaporation of the solvent, the crude 17 2-methylbenzoxazol-6-amine (2.77g, 85% yield) was obtained for next step reaction without purification. (c) To a solution of 2-methylbenzoxazol-6-amine (2.66g, 18.0mmol) in methanol (30.0mL) was added 18 formaldehyde (37%, 12mL, 144mmol) and 19 NaBH3CN (2.27g, 36.0mmol). The solution was stirred at ambient temperature for 36h till the starting material disappeared (TLC detection). The solution was poured into H2O (30.0mL), and the mixture solution was extracted with ethyl acetate (30.0mL×3). The combined organic solution was dried over Na2SO4, the solution is concentrated and 20 2-methyl-6-(N, N-dimethylamino) benzoxazole (2.50g, 79% yield) is obtained by flash column chromatography (elute: petroleum ether / ethyl acetate=10 / 1, v/v, Rf =0.11).
Example 11; 2-Phenyl-pyrimidine-5-carboxylic acid r2-(2-pyrrolidin-l-yl-ethyl)-benzooxazol-6-yl1 -amide; Step 1; A solution of <strong>[5683-43-2]2-methyl-6-nitro-benzoxazole</strong> (30 mmol), dimethyl formamide dimethyl acetal (60 mmol) and pyrrolidine (60 mmol) in DMF (45 mL) is stirred at 1000C for 16 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with water and brine, dried (Na2SO4) and filtered. The filtrate is concentrated. The residue is washed with cooled EtOAc to afford 6-nitro-2-f 2-pyrrolidin- 1 -yl-vinyl Vbenzooxazole as a solid. 1H NMR (300 MHz, CDCl3): delta 1.80-2.25 (broad, 4H), 3.10-3.80 (broad, 4H), 5.06 (d, H), 7.44 (d, H), 7.96 (d, H), 8.21 (m, 2H).
With sodium carbonate; In dichloromethane; water; acetic acid; ethyl acetate;
A. 2-Methyl-6-aminobenzoxazole (479A) To a solution of <strong>[5683-43-2]2-methyl-6-nitrobenzoxazole</strong> (100 mg, 0.560 mmol) in AcOH (2 mL) was added iron powder (325 mesh, 63.0 mg, 1.12 mmol) at 70 C. in a single portion. After 15 min at 70 C. additional iron powder (325 mesh, 63.0 mg, 1.12 mmol) was added and stirring was continued for 15 min. The mixture was cooled and concentrated under reduced pressure. The resulting residue was taken up into EtOAc and washed with sat. Na2CO3 followed by H2O. The organic layer was dried over MgSO4, concentrated under reduced pressure and purified by flash chromatography on silica gel eluding with a gradient of 0 to 25% EtOAc in CH2Cl2 to yield 69 mg (83%) of compound 479A as a solid. HPLC: 97% at 0.24 min (retention time) (YMC S5 ODS column, 4.6*50 mm Ballistic, 10-90% aqueous methanol over 4 min containing 0.2% H3PO4, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 149.2 [M+H]+.
With Amberlyst-15; In water; at 90℃; for 1.0h;Irradiation;
General procedure: To a mixture of N-acyl or benzoy lderivative (6, 1 mmol) in water (5 mL) was added amberlyst-15 (10%, w/w) and the mixture was irradiated with ultrasound (40 KHz) continuously at 90 C till the completion of the reaction (monitored by TLC) as indicated in Table 4. The solid separated was filtered, washed with diethyl ether (2 x 5 mL), dried and treated with EtOAc (15 mL). After stirring for 10 min the mixture was filtered to remove the insoluble catalyst. The filtrate was collected and concentrated under vacuum. The solid obtained was purified by recrystallization (column chromatography in few cases) to afford the desired products 7, 8 or 9.
With pyridine; In 5,5-dimethyl-1,3-cyclohexadiene; at 0 - 20℃; for 2.0h;
The synthetic route for 1 was outlined in Scheme 1, and the detailed procedures were presented as follows: (a) To a solution of 2-amino-5-nitrophenol (7.70g, 50.0mmol) and pyridine (3.96g, 50.0mmol) in dry xylene (150mL) at 0C was added dropwise acetyl chloride (4.32g, 55.0mmol). The solution was stirred at ambient temperature for 2h. To above solution was added p-toluenesulfonic acid (1.72g, 10.0mmol), the solution was refluxed till no water was discharged. After cooling to room temperature, the solution was washed with water (100mL×3) and a saturated solution of NaCl (50.0mL), respectively. The organic solution was collected and dried over Na2SO4, after evaporation of the solvent, the crude 2-methyl-6-nitrobenzoxazole (pale solid, 8.80g, 95% yield) was obtained for next step without purification. (b) To a solution of 13 2-methyl-6-nitrobenzoxazole (3.92g, 22.0mmol) in 14 methanol (60.0mL) at 70C was added 15 NH4Cl (11.77g, 220mmol) in 16 H2O (40.0mL) and Fe (4.48g, 80.0mmol). The mixture solution was stirred at 70C for 4h till the starting material disappeared (TLC detection). The mixture solution was cooled to ambient temperature and filtered, the solution was extracted with ethyl acetate (30.0mL×3). The combined organic solution was dried over Na2SO4, after evaporation of the solvent, the crude 17 2-methylbenzoxazol-6-amine (2.77g, 85% yield) was obtained for next step reaction without purification. (c) To a solution of 2-methylbenzoxazol-6-amine (2.66g, 18.0mmol) in methanol (30.0mL) was added 18 formaldehyde (37%, 12mL, 144mmol) and 19 NaBH3CN (2.27g, 36.0mmol). The solution was stirred at ambient temperature for 36h till the starting material disappeared (TLC detection). The solution was poured into H2O (30.0mL), and the mixture solution was extracted with ethyl acetate (30.0mL×3). The combined organic solution was dried over Na2SO4, the solution is concentrated and 20 2-methyl-6-(N, N-dimethylamino) benzoxazole (2.50g, 79% yield) is obtained by flash column chromatography (elute: petroleum ether / ethyl acetate=10 / 1, v/v, Rf =0.11).
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