* 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：
[1] Advanced Synthesis and Catalysis, 2015, vol. 357, # 10, p. 2311 - 2316
[2] Chemistry - A European Journal, 2017, vol. 23, # 42, p. 9996 - 10000
[3] Journal of the American Chemical Society, 2008, vol. 130, # 2, p. 472 - 480
2
[ 5344-78-5 ]
[ 59557-92-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
With iron; ammonium chloride In ethanol; water for 2 h; Reflux
1-Bromo-4-methoxy-2-nitrobenzene (1.71g, 7.2 mmol, 1 equiv.) was dissolved in EtOH (7 mL) and H2O (5 mL). Iron powder (2.00 g,35.7 mmol, 5 equiv.) and NH4Cl (1.53 g, 28.6 mmol, 4 equiv.) were added to the solution. The solution was heated to reflux for 2 h. The black organic phase was washed with diethyl ether(4 x 100 mL). This yielded 2-bromo-5-methoxyaniline (95percent) as a green substance, with data as reported.7 At 0 °C a solution of the crude 2-bromo-5-methoxyaniline (1.50 g, 7.4 mmol, 1equiv.) in conc. HCl (7 mL) was treated dropwise with aq. NaNO2 (0.5 g, 7.2 mmol, 1 equiv.)in deionized H2O (5 mL). Stirring was continued at 0 °C for 5 h resulting in the formation ofthe diazonium salt. In a separate flask, at 0 °C, H2O (8 mL) was treated with thionyl chloride(2.2 mL, 30.3 mmol, 4 equiv.). Stirring continued at 0 °C for 1 h. The aqueous phase was washed with ethylacetate (6 x 50 mL). The combined phases were dried over MgSO4. Solvent removal followed by column chromatography (c-Hex-EtOAc; 5:1) yielded S5 (1.50 g, 46percent) asa yellow oil. Rf = 0.3 (c-Hex-EtOAc; 5:1) with data as reported.8
91%
at 50℃; for 3.5 h;
Step i :To a 1 L flask equipped with a mechanical stirrer is added 55a (30 g, 129 mmo.) in acetic acid (300 ml_). To this mixture is added iron powder (14.4 g, 258 mmol) slowly in aliquots. The mixture is heated at 500C for 2 h before an additional 7.2 g (129 mmol) of iron powder is slowly added. After 1.5 h at 500C, the conversion to the aniline is complete. The solution is cooled to RT and diluted with 500 ml_ of EtOAc before being filtered through Celite. The filtrate is concentrated and the crude product is partitioned between EtOAc (1 L) and 200 mL of water. The mixture is vigorously shaken and the organic phase is washed with 200 mL of brine, dried over MgSO4, filtered and concentrated to give aniline 55b (23.7 g, 91 percent) as a brown oil which is used directly in the next step.
86%
With hydrogen In ethanol at 20℃; for 4 h;
A mixture of 1-bromo-4-methoxy-2-nitro-benzene (10 g, 43 mmol) and Raney Ni (5 g) in ethanol (100 mL) was stirred under H2 (1 atm) for 4 h at room temperature. Raney Ni was filtered off and the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography to give 2-bromo-5-methoxy-phenylamine (7.5 g, 86percent).
86%
With hydrogen In ethanol at 20℃; for 4 h;
A mixture of 1-bromo-4-methoxy-2-nitro-benzene (10 g, 43 mmol) and Raney Ni (5 g) in ethanol (100 mL) was stirred under H2 atm) for 4 h at room temperature. Raney Ni was filtered off and the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography to give 2-bromo-5-methoxy-phenylamine (7.5 g, 86percent).
52%
Stage #1: at 20℃; for 2 h; Stage #2: With potassium carbonate In water
Example I-XIPreparation of Compound 314General Procedure I-CSA mixture of 4-bromo-3-nitroanisole (5 g, 21.6 mmol) and Fe (9.7 g, 0.17 mol) in 30 mL of acetic acid was stirred at r.t for 2 h. After removal of the solvent under reduced pressure, the brown residue was taken up in 100 mL of water and treated with 10percent of aq. K2CO3 until pH 10. The mixture was extracted with EtOAc (150 mL.x.2) and the combined organic extracts were separated, dried over MgSO4, and concentrated to afford compound I-XIa (3 g, yield: 52percent). MS (ESI) m/z (M+H)+ 203.
48%
With acetic acid; zinc In ethanol at 20℃;
To a suspension of Zn (3.92 g, 60.3 mmol) in EtOH (80 mL) was added HOAc (3 mL), followed by solution of compound 5-1 (2.0 g, 8.6 mmol) in EtOH (20 mL) at rt. After stirring at rt overnight, the reaction mixture was filtered. The filtrate was concentrated and the residue was diluted with EtOAc (150 mL). The mixture was washed with water (200 mL) and brine (100 mL) and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether /EtOAc = 19/1 (v/v)) to give compound 5-2 (1.15 g, 48percent yield) as a yellow oil. LC-MS (ESI): mlz 202 [M+H]+.
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 42, p. 9996 - 10000
[2] Journal of Medicinal Chemistry, 1995, vol. 38, # 6, p. 950 - 957
[3] Organic Letters, 2015, vol. 17, # 4, p. 802 - 805
[4] Tetrahedron Letters, 2017, vol. 58, # 48, p. 4559 - 4562
[5] Journal of the American Chemical Society, 1994, vol. 116, # 26, p. 11797 - 11810
[6] Patent: WO2009/62285, 2009, A1, . Location in patent: Page/Page column 116
[7] Angewandte Chemie - International Edition, 2014, vol. 53, # 28, p. 7349 - 7353
[8] Tetrahedron, 2009, vol. 65, # 41, p. 8542 - 8555
[9] Patent: US2011/98311, 2011, A1,
[10] Patent: US2012/309758, 2012, A1,
[11] Patent: US2012/309758, 2012, A1, . Location in patent: Page/Page column 61
[12] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 0355
[13] Organic Letters, 2010, vol. 12, # 10, p. 2258 - 2261
[14] Patent: US2011/152246, 2011, A1, . Location in patent: Page/Page column 156-158
[15] Patent: WO2012/58125, 2012, A1, . Location in patent: Page/Page column 124
[16] Journal of the American Chemical Society, 2008, vol. 130, # 2, p. 472 - 480
[17] Journal of the Chemical Society, 1935, p. 946
[18] Journal of the American Chemical Society, 1948, vol. 70, p. 2314,2317
[19] J. Gen. Chem. USSR (Engl. Transl.), 1962, vol. 32, p. 2325 - 2331[20] Zhurnal Obshchei Khimii, 1962, vol. 32, # 7, p. 2358 - 2365
[21] Journal of Organic Chemistry, 1989, vol. 54, # 25, p. 5856 - 5866
[22] Journal of Organic Chemistry, 1992, vol. 57, # 24, p. 6380 - 6382
[23] Tetrahedron Letters, 2006, vol. 47, # 16, p. 2739 - 2742
[24] Tetrahedron, 2010, vol. 66, # 52, p. 9779 - 9784
[25] Journal of the American Chemical Society, 2011, vol. 133, # 15, p. 6061 - 6071
[26] Journal of the American Chemical Society, 2011, vol. 133, # 16, p. 6166 - 6169
[27] Patent: US9408907, 2016, B2, . Location in patent: Page/Page column 61
[28] Patent: WO2009/111337, 2009, A1, . Location in patent: Page/Page column 167
[29] Patent: WO2010/130842, 2010, A1, . Location in patent: Page/Page column 236-237
3
[ 536-90-3 ]
[ 59557-92-5 ]
[ 19056-40-7 ]
[ 35736-52-8 ]
Yield
Reaction Conditions
Operation in experiment
23%
With N-Bromosuccinimide In chloroform at 5 - 20℃;
m-Anisidine (5.00 g, 40.6 mmol) was dissolved in chloroform (40 mL) and the solution was chilled to 5 °C. N-Bromosuccinimide (7.23 g, 40.6 mmol) was added portionwise to the chilled solution over a 1 h period and the mixture was then stirred for another 4 h in an ice bath at 5-10 °C. The reaction mixture was allowed to warm at room temperature and stirring was continued overnight. The mixture was washed with sodium hydroxide (2 M, 50 mL), followed by water (60 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated to afford a dark brown viscous liquid. The crude material was chromatographed (silica gel, dichloromethane/hexane 2:1) to afford a mixture of 2-bromo-5-methoxyaniline and 2,4-dibromo-5-methoxyaniline as the first major band eluted. Subsequently, another major band was eluted to afford 4-bromo-3-methoxyaniline (860 mg, 10percent) as peach coloured crystals: mp 97-98 °C (lit.65 93-94 °C); 1H NMR (400 MHz, CDCl3) δ 3.70 (br s, 2H, NH2), 3.80 (s, 3H, OCH3), 6.16 (dd, J 2.5, 8.4 Hz, 1H, ArH), 6.23 (d, J 2.5 Hz, 1H, ArH), 7.23 (d, J 8.4 Hz, 1H, ArH). The data are in agreement with those reported in the literature.65 The first major band was evaporated to dryness and rechromatographed (silica gel, ethyl acetate/hexane 1:2) to afford 2-bromo-5-methoxyaniline (830 mg, 10percent) as an orange liquid. 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H, OCH3), 4.07 (br s, 2H, NH2), 6.21 (dd J 2.9, 8.8 Hz, 1H, ArH), 6.30 (d, J 2.9 Hz, 1H, ArH), 7.25 (d, J 8.8 Hz, 1H, ArH). The data are in agreement with those reported in the literature.65 This was followed by the elution of a second band that afforded 2,4-dibromo-5-methoxyaniline (2.66 g, 23percent) as a brown liquid. Rf (80percent EtOAc/CH2Cl2) 0.87; IR (neat) νmax 3420, 3295, 3176, 2965, 2934, 1620, 1582, 1503, 1278, 1207, 1018, 805 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H, OCH3), 4.10 (br s, 2H, NH2), 6.31 (s, 1H, ArH), 7.49 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 56.1, 99.3, 99.3, 99.7, 135.1, 144.3, 155.8; Anal. Calcd for C7H7Br2NO: C, 29.93; H, 2.51; N, 4.99. Found: C 30.29; H 2.24; N 4.95percent.
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2870 - 2873
[2] Tetrahedron, 2011, vol. 67, # 32, p. 5798 - 5805
4
[ 5344-78-5 ]
[ 7439-89-6 ]
[ 59557-92-5 ]
Yield
Reaction Conditions
Operation in experiment
57%
With acetic acid In water
(i) Preparation of 2-bromo-5-methoxyaniline 4-Bromo-3-nitroanisole (10 g, 43 mmol) and iron powder (21.72 g, 385 mmol) were stirred in a mixture of water (10 mL) and acetic acid (100 mL) for 1.5 h. The solvent was removed in vacuo, the brown residue was taken up in water (200 mL) and treated with 10percent aq K2CO3 until pH 10. The mixture was extracted with EtOAc (4*150 mL) and the combined organic extracts were dried (MgSO4) and evaporated to give the desired aniline (5.0 g, 57percent) as a brown oil; δH (CDCl3, 400 MHz) 3.72 (3H, s), 4.05 (2H, br), 6.22 (1H, dd), 6.32 (1H, d), 7.26 (1H, d); MS m/z (TS+) 202, 204 (MH+).
Reference：
[1] Patent: US2003/207857, 2003, A1,
5
[ 5344-78-5 ]
[ 59557-92-5 ]
[ 536-90-3 ]
Reference：
[1] Patent: US5576324, 1996, A,
6
[ 96-96-8 ]
[ 59557-92-5 ]
Reference：
[1] Tetrahedron Letters, 2006, vol. 47, # 16, p. 2739 - 2742
[2] Journal of Organic Chemistry, 1989, vol. 54, # 25, p. 5856 - 5866
[3] Journal of the Chemical Society, 1935, p. 946
[4] J. Gen. Chem. USSR (Engl. Transl.), 1962, vol. 32, p. 2325 - 2331[5] Zhurnal Obshchei Khimii, 1962, vol. 32, # 7, p. 2358 - 2365
[6] Journal of the American Chemical Society, 2011, vol. 133, # 15, p. 6061 - 6071
7
[ 5344-78-5 ]
[ 7646-78-8 ]
[ 59557-92-5 ]
Reference：
[1] Patent: US2003/69239, 2003, A1,
8
[ 536-90-3 ]
[ 59557-92-5 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 40, p. 13147 - 13150
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1962, vol. 32, p. 2325 - 2331[2] Zhurnal Obshchei Khimii, 1962, vol. 32, # 7, p. 2358 - 2365
11
[ 51-66-1 ]
[ 59557-92-5 ]
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1962, vol. 32, p. 2325 - 2331[2] Zhurnal Obshchei Khimii, 1962, vol. 32, # 7, p. 2358 - 2365
12
[ 536-90-3 ]
[ 59557-92-5 ]
[ 19056-40-7 ]
[ 35736-52-8 ]
Yield
Reaction Conditions
Operation in experiment
23%
With N-Bromosuccinimide In chloroform at 5 - 20℃;
m-Anisidine (5.00 g, 40.6 mmol) was dissolved in chloroform (40 mL) and the solution was chilled to 5 °C. N-Bromosuccinimide (7.23 g, 40.6 mmol) was added portionwise to the chilled solution over a 1 h period and the mixture was then stirred for another 4 h in an ice bath at 5-10 °C. The reaction mixture was allowed to warm at room temperature and stirring was continued overnight. The mixture was washed with sodium hydroxide (2 M, 50 mL), followed by water (60 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated to afford a dark brown viscous liquid. The crude material was chromatographed (silica gel, dichloromethane/hexane 2:1) to afford a mixture of 2-bromo-5-methoxyaniline and 2,4-dibromo-5-methoxyaniline as the first major band eluted. Subsequently, another major band was eluted to afford 4-bromo-3-methoxyaniline (860 mg, 10percent) as peach coloured crystals: mp 97-98 °C (lit.65 93-94 °C); 1H NMR (400 MHz, CDCl3) δ 3.70 (br s, 2H, NH2), 3.80 (s, 3H, OCH3), 6.16 (dd, J 2.5, 8.4 Hz, 1H, ArH), 6.23 (d, J 2.5 Hz, 1H, ArH), 7.23 (d, J 8.4 Hz, 1H, ArH). The data are in agreement with those reported in the literature.65 The first major band was evaporated to dryness and rechromatographed (silica gel, ethyl acetate/hexane 1:2) to afford 2-bromo-5-methoxyaniline (830 mg, 10percent) as an orange liquid. 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H, OCH3), 4.07 (br s, 2H, NH2), 6.21 (dd J 2.9, 8.8 Hz, 1H, ArH), 6.30 (d, J 2.9 Hz, 1H, ArH), 7.25 (d, J 8.8 Hz, 1H, ArH). The data are in agreement with those reported in the literature.65 This was followed by the elution of a second band that afforded 2,4-dibromo-5-methoxyaniline (2.66 g, 23percent) as a brown liquid. Rf (80percent EtOAc/CH2Cl2) 0.87; IR (neat) νmax 3420, 3295, 3176, 2965, 2934, 1620, 1582, 1503, 1278, 1207, 1018, 805 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H, OCH3), 4.10 (br s, 2H, NH2), 6.31 (s, 1H, ArH), 7.49 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 56.1, 99.3, 99.3, 99.7, 135.1, 144.3, 155.8; Anal. Calcd for C7H7Br2NO: C, 29.93; H, 2.51; N, 4.99. Found: C 30.29; H 2.24; N 4.95percent.
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2870 - 2873
[2] Tetrahedron, 2011, vol. 67, # 32, p. 5798 - 5805
13
[ 536-90-3 ]
[ 59557-92-5 ]
[ 19056-40-7 ]
[ 35736-52-8 ]
Yield
Reaction Conditions
Operation in experiment
23%
With N-Bromosuccinimide In chloroform at 5 - 20℃;
m-Anisidine (5.00 g, 40.6 mmol) was dissolved in chloroform (40 mL) and the solution was chilled to 5 °C. N-Bromosuccinimide (7.23 g, 40.6 mmol) was added portionwise to the chilled solution over a 1 h period and the mixture was then stirred for another 4 h in an ice bath at 5-10 °C. The reaction mixture was allowed to warm at room temperature and stirring was continued overnight. The mixture was washed with sodium hydroxide (2 M, 50 mL), followed by water (60 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated to afford a dark brown viscous liquid. The crude material was chromatographed (silica gel, dichloromethane/hexane 2:1) to afford a mixture of 2-bromo-5-methoxyaniline and 2,4-dibromo-5-methoxyaniline as the first major band eluted. Subsequently, another major band was eluted to afford 4-bromo-3-methoxyaniline (860 mg, 10percent) as peach coloured crystals: mp 97-98 °C (lit.65 93-94 °C); 1H NMR (400 MHz, CDCl3) δ 3.70 (br s, 2H, NH2), 3.80 (s, 3H, OCH3), 6.16 (dd, J 2.5, 8.4 Hz, 1H, ArH), 6.23 (d, J 2.5 Hz, 1H, ArH), 7.23 (d, J 8.4 Hz, 1H, ArH). The data are in agreement with those reported in the literature.65 The first major band was evaporated to dryness and rechromatographed (silica gel, ethyl acetate/hexane 1:2) to afford 2-bromo-5-methoxyaniline (830 mg, 10percent) as an orange liquid. 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H, OCH3), 4.07 (br s, 2H, NH2), 6.21 (dd J 2.9, 8.8 Hz, 1H, ArH), 6.30 (d, J 2.9 Hz, 1H, ArH), 7.25 (d, J 8.8 Hz, 1H, ArH). The data are in agreement with those reported in the literature.65 This was followed by the elution of a second band that afforded 2,4-dibromo-5-methoxyaniline (2.66 g, 23percent) as a brown liquid. Rf (80percent EtOAc/CH2Cl2) 0.87; IR (neat) νmax 3420, 3295, 3176, 2965, 2934, 1620, 1582, 1503, 1278, 1207, 1018, 805 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H, OCH3), 4.10 (br s, 2H, NH2), 6.31 (s, 1H, ArH), 7.49 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 56.1, 99.3, 99.3, 99.7, 135.1, 144.3, 155.8; Anal. Calcd for C7H7Br2NO: C, 29.93; H, 2.51; N, 4.99. Found: C 30.29; H 2.24; N 4.95percent.
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2870 - 2873
[2] Tetrahedron, 2011, vol. 67, # 32, p. 5798 - 5805
14
[ 59557-92-5 ]
[ 107-14-2 ]
[ 107-06-2 ]
[ 81224-16-0 ]
Yield
Reaction Conditions
Operation in experiment
24%
With hydrogenchloride; sodium borohydrid; boron trichloride In 1,4-dioxane; dichloromethane; water
(a) 4-Methoxy-7-bromoindole. 2-Bromo-5-methoxy-aniline (4.4 g, 21.8 mmol) was added dropwise to a solution of boron trichloride in methylene chloride (1.0 M, 24 mL, 24 mmol) cooled with ice water. The reaction mixture was warmed to room temperature, stirred for 30 min, and chloroacetonitrile (4.01 mL, 26.2 mmol) and aluminum chloride (4.01 g, 24.0 mmol) were added, followed by 1,2-dichloroethane (28.5 mL). The reaction mixture was heated to 70° C. to distill off methylene chloride, and then heated to reflux for 24 hrs. After cooling to 0-5° C., the mixture was treated with 2.5 M HCl (38.4 mL) carefully, and then heated to 80° C. for 1 h until all solids dissolved. The aqueous layer was separated, extracted with methylene chloride and the combined extracts washed with water and brine, dried (sodium sulfate) and evaporated to a yellow solid, which was used without further purification. The crude product was taken into dioxane (37 mL) and water (4.2 mL), and treated with sodium borohydride (0.91 g, 24.0 mmol) in portions. After stirring at room temperature for 30 min, all the starting material was consumed and the reaction mixture was then heated to reflux for 14 hrs. After cooling to room temperature, the mixture was treated with concentrated HCl, and extracted with ethyl acetate. The organic extract was washed with water and brine; dried (sodium sulfate), and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) gave 4-methoxyl-7-bromoindole (1.2 g, 24percent). 1H NMR (400 MHz, CDCl3) 3.94 (s, 3H), 6.44 (d, J=8.21 Hz, 1H), 6.73 (m, 1H), 7.17 (t, J=2.74 Hz, 1H), 7.22~7.26 (m, 1H), 8.32 (br, 1H); MS (ES, m/z): C9H8BrNO: 227.99 (M+(79Br)+1), 230.0(M+(81Br)+1).
With iron; ammonium chloride; In ethanol; water; for 2h;Reflux;
1-Bromo-4-methoxy-2-nitrobenzene (1.71g, 7.2 mmol, 1 equiv.) was dissolved in EtOH (7 mL) and H2O (5 mL). Iron powder (2.00 g,35.7 mmol, 5 equiv.) and NH4Cl (1.53 g, 28.6 mmol, 4 equiv.) were added to the solution. The solution was heated to reflux for 2 h. The black organic phase was washed with diethyl ether(4 x 100 mL). This yielded 2-bromo-5-methoxyaniline (95%) as a green substance, with data as reported.7 At 0 C a solution of the crude 2-bromo-5-methoxyaniline (1.50 g, 7.4 mmol, 1equiv.) in conc. HCl (7 mL) was treated dropwise with aq. NaNO2 (0.5 g, 7.2 mmol, 1 equiv.)in deionized H2O (5 mL). Stirring was continued at 0 C for 5 h resulting in the formation ofthe diazonium salt. In a separate flask, at 0 C, H2O (8 mL) was treated with thionyl chloride(2.2 mL, 30.3 mmol, 4 equiv.). Stirring continued at 0 C for 1 h. The aqueous phase was washed with ethylacetate (6 x 50 mL). The combined phases were dried over MgSO4. Solvent removal followed by column chromatography (c-Hex-EtOAc; 5:1) yielded S5 (1.50 g, 46%) asa yellow oil. Rf = 0.3 (c-Hex-EtOAc; 5:1) with data as reported.8
91%
With iron; acetic acid; at 50℃; for 3.5h;
Step i :To a 1 L flask equipped with a mechanical stirrer is added 55a (30 g, 129 mmo.) in acetic acid (300 ml_). To this mixture is added iron powder (14.4 g, 258 mmol) slowly in aliquots. The mixture is heated at 500C for 2 h before an additional 7.2 g (129 mmol) of iron powder is slowly added. After 1.5 h at 500C, the conversion to the aniline is complete. The solution is cooled to RT and diluted with 500 ml_ of EtOAc before being filtered through Celite. The filtrate is concentrated and the crude product is partitioned between EtOAc (1 L) and 200 mL of water. The mixture is vigorously shaken and the organic phase is washed with 200 mL of brine, dried over MgSO4, filtered and concentrated to give aniline 55b (23.7 g, 91 %) as a brown oil which is used directly in the next step.
86%
In ethanol;
Example 2 2-Bromo-5-methoxy-phenylamine A mixture of 1-bromo-4-methoxy-2-nitro-benzene (10 g, 43 mmol) and Raney Ni (5 g) in ethanol (100 mL) was stirred under H2 (1 atm) for 4 h at room temperature. Raney Ni was filtered off and the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography to give 2-bromo-5-methoxy-phenylamine (7.5 g, 86%).
86%
With hydrogen;Raney Ni; In ethanol; at 20℃; for 4h;
A mixture of 1-bromo-4-methoxy-2-nitro-benzene (10 g, 43 mmol) and Raney Ni (5 g) in ethanol (100 mL) was stirred under H2 (1 atm) for 4 h at room temperature. Raney Ni was filtered off and the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography to give 2-bromo-5-methoxy-phenylamine (7.5 g, 86%).
86%
With hydrogen; In ethanol; at 20℃; for 4h;
A mixture of 1-bromo-4-methoxy-2-nitro-benzene (10 g, 43 mmol) and Raney Ni (5 g) in ethanol (100 mL) was stirred under H2 atm) for 4 h at room temperature. Raney Ni was filtered off and the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography to give 2-bromo-5-methoxy-phenylamine (7.5 g, 86%).
52%
Example I-XIPreparation of Compound 314General Procedure I-CSA mixture of 4-bromo-3-nitroanisole (5 g, 21.6 mmol) and Fe (9.7 g, 0.17 mol) in 30 mL of acetic acid was stirred at r.t for 2 h. After removal of the solvent under reduced pressure, the brown residue was taken up in 100 mL of water and treated with 10% of aq. K2CO3 until pH 10. The mixture was extracted with EtOAc (150 mL×2) and the combined organic extracts were separated, dried over MgSO4, and concentrated to afford compound I-XIa (3 g, yield: 52%). MS (ESI) m/z (M+H)+ 203.
48%
With acetic acid; zinc; In ethanol; at 20℃;
To a suspension of Zn (3.92 g, 60.3 mmol) in EtOH (80 mL) was added HOAc (3 mL), followed by solution of compound 5-1 (2.0 g, 8.6 mmol) in EtOH (20 mL) at rt. After stirring at rt overnight, the reaction mixture was filtered. The filtrate was concentrated and the residue was diluted with EtOAc (150 mL). The mixture was washed with water (200 mL) and brine (100 mL) and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether /EtOAc = 19/1 (v/v)) to give compound 5-2 (1.15 g, 48% yield) as a yellow oil. LC-MS (ESI): mlz 202 [M+H]+.
With hydrogenchloride; iron; In ethanol; for 24h;Reflux;
A solution of 1-bromo-4-methoxy-2-nitrobenzene (1.0 eq.), iron powder (3.0 eq.), and concentrated HCl (1.04 eq.) were mixed together in ethanol (0.64 M) and heated to reflux. The reaction was stirred for 24 hours, and the solvent was evaporated. The resulting residue was diluted with ethyl acetate and saturated aqueous ammonium chloride solution. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water, brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-15% ethyl acetate in hexane to give the product as oil.
With hydrogenchloride; iron; In ethanol; water; for 24h;Reflux;
A solution of l-bromo-4-methoxy-2-nitrobenzene (1.0 eq.), iron powder (3.0 eq.), and concentrated HCl (1.04 eq.) were mixed together in ethanol (0.64 M) and heated to reflux. The reaction was stirred for 24 hours, and the solvent was evaporated. The resulting residue was diluted with ethyl acetate and saturated aqueous ammonium chloride solution. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water, brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-15% ethyl acetate in hexane to give the product as oil.
Step 2 :A mixture of 1 -bromo-4-methoxy-2-nitrobenzene (10 g; 43.1 mmol), ethanol (100 ml), acetic acid (100 ml) and iron powder (9,63 g; 172 mmol) was heated at 100cC for 2 h. The mixture was cooled to room temperature and diluted with water (300 ml). The suspension was neutralized with solid potassium carbonate. The mixture was filtered on a plug of celite and extracted with dichloromethane. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure to afford 2-bromo-5-methoxyaniline, which was used in the next step without further purification.NMR (1H, DMSO-de) delta 7,27 (d, J = 8,6 Hz, 1 H, Harom.); 6,32 (d, J = 2,7 Hz, 1 H, Harom.); 6,22 (dd, J1 = 8,7 Hz, J2 = 2,8 Hz, 1 H, Harom.); 4,07(bs, 2 H, NH2); 3,74 (s, 3 H, OCH3).
A mixture of 2-bromo-5-methoxy-phenylamine (540 mg, 2.64 mmol) and diethyl 2-(ethoxymethylene)malonate (600 mg, 2.7 mmol) was stirred at 100 C. for 2 h. After cooling, the reaction mixture was recrystallized from methanol (10 mL) to give 2-[(2-bromo-5-methoxy-phenylamino)-methylene]-malonic acid diethyl ester as a yellow solid (0.8 g, 81%).
81%
at 100℃; for 2h;
A mixture of 2-bromo-5-methoxy-phenylamine (540 mg, 2.64 mmol) and diethyl 2-(ethoxymethylene)malonate (600 mg, 2.7 mmol) was stirred at 100 C. for 2 h. After cooling, the reaction mixture was recrystallized from methanol (10 mL) to give 2-[(2-bromo-5-methoxy-phenylamino)-methylene]-malonic acid diethyl ester as a yellow solid (0.8 g, 81%).
2-[(2-Bromo-5-methoxy-phenylamino)-methylene]-malonic acid diethyl ester A mixture of 2-bromo-5-methoxy-phenylamine (540 mg, 2.64 mmol) and diethyl 2-(ethoxymethylene)malonate (600 mg, 2.7 mmol) was stirred at 100 C. for 2 h. After cooling, the reaction mixture was recrystallized from methanol (10 mL) to give 2-[(2-bromo-5-methoxy-phenylamino)-methylene]-malonic acid diethyl ester as a yellow solid (0.8 g, 81%).
General procedure: To a solution of o-haloaniline (4.63 mmol) in dry DCM (20 mL) at room temperature was dropped acyl chloride (5.09 mmol). The reaction mixture was stirred for 24 hours then poured into water, extracted with DCM, washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated. The product was carried on to next step without any further purification in most cases.
With N-Bromosuccinimide; In chloroform; at 5 - 20℃;
m-Anisidine (5.00 g, 40.6 mmol) was dissolved in chloroform (40 mL) and the solution was chilled to 5 C. N-Bromosuccinimide (7.23 g, 40.6 mmol) was added portionwise to the chilled solution over a 1 h period and the mixture was then stirred for another 4 h in an ice bath at 5-10 C. The reaction mixture was allowed to warm at room temperature and stirring was continued overnight. The mixture was washed with sodium hydroxide (2 M, 50 mL), followed by water (60 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated to afford a dark brown viscous liquid. The crude material was chromatographed (silica gel, dichloromethane/hexane 2:1) to afford a mixture of 2-bromo-5-methoxyaniline and 2,4-dibromo-5-methoxyaniline as the first major band eluted. Subsequently, another major band was eluted to afford 4-bromo-3-methoxyaniline (860 mg, 10%) as peach coloured crystals: mp 97-98 C (lit.65 93-94 C); 1H NMR (400 MHz, CDCl3) delta 3.70 (br s, 2H, NH2), 3.80 (s, 3H, OCH3), 6.16 (dd, J 2.5, 8.4 Hz, 1H, ArH), 6.23 (d, J 2.5 Hz, 1H, ArH), 7.23 (d, J 8.4 Hz, 1H, ArH). The data are in agreement with those reported in the literature.65 The first major band was evaporated to dryness and rechromatographed (silica gel, ethyl acetate/hexane 1:2) to afford 2-bromo-5-methoxyaniline (830 mg, 10%) as an orange liquid. 1H NMR (400 MHz, CDCl3) delta 3.72 (s, 3H, OCH3), 4.07 (br s, 2H, NH2), 6.21 (dd J 2.9, 8.8 Hz, 1H, ArH), 6.30 (d, J 2.9 Hz, 1H, ArH), 7.25 (d, J 8.8 Hz, 1H, ArH). The data are in agreement with those reported in the literature.65 This was followed by the elution of a second band that afforded 2,4-dibromo-5-methoxyaniline (2.66 g, 23%) as a brown liquid. Rf (80% EtOAc/CH2Cl2) 0.87; IR (neat) numax 3420, 3295, 3176, 2965, 2934, 1620, 1582, 1503, 1278, 1207, 1018, 805 cm-1; 1H NMR (400 MHz, CDCl3) delta 3.80 (s, 3H, OCH3), 4.10 (br s, 2H, NH2), 6.31 (s, 1H, ArH), 7.49 (s, 1H, ArH); 13C NMR (100 MHz, CDCl3) delta 56.1, 99.3, 99.3, 99.7, 135.1, 144.3, 155.8; Anal. Calcd for C7H7Br2NO: C, 29.93; H, 2.51; N, 4.99. Found: C 30.29; H 2.24; N 4.95%.
A solution [OF 2-BROMO-5-METHOXY-PHENYLAMINE (16. 1G,] 80 mmol), 2,2-dimethyl- [[1,] 3] dioxane-4,6-dione [(MELDRUM'S] acid) (13.7g, 95 mmol) and triethyl orthoformate [(14.] [1G,] 95 mmol) in ethanol (82 ml) was heated to reflux for 2 hours then allowed to cool to room temperature. Filtration and drying in vacuo afforded a white solid (25.7g, [91%)] MS (APCI-) [IIILZ] 354 (M-H)
N-(2-Bromo-5-methoxyphenyl)-3-fluoro-4-(2-piperidin-1-ylethoxy)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A mixture of 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (4.0 g), thionyl chloride (8 ml) and toluene (10 ml) was refluxed for 30 minutes. To the residue obtained by concentrating the reaction mixture in vacuo, were added <strong>[59557-92-5]2-bromo-5-methoxyaniline</strong> (2.0 g) and pyridine (10 ml) on an ice bath, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.9 g).1H-NMR (400MHz, CDCl3); delta (ppm): 1.40-1.49 (m, 2H), 1.60-1.63 (m, 4H), 2.50-2.58 (m, 4H), 2.82 (t, 2H), 3.82 (s, 3H), 4.25 (t, 2H), 6.60 (d, 1H), 7.08 (t, 1H), 7.42 (d, 1H), 7.61-7.70 (m, 2H) 8.21 (d, 1H), 8.39 (brs, 1H).
With potassium carbonate; triphenylphosphine;palladium diacetate; In N,N-dimethyl acetamide;
(Step A) Synthesis of 2-tert-Butyl-6-methoxy-3-methyl-1H-indole 2-Bromo-5-methoxyaniline (1.01 g; synthesised according to the process reported by J. H. Tidwell et al., J. Am. Chem. Soc., vol. 116, pp. 11797-11810 (1994)), 2,2-dimethyl-3-pentyne (480 mg; mfd. by Chemsampco), palladium acetate (28.1 mg), tetra-n-butylammonium chloride (1.39 g; mfd. by TOKYO KASEI), potassium carbonate (3.45 g) and triphenylphosphine (65.6 mg) were dissolved in N,N-dimethylacetamide (50 mL). After stirring at 100 C. for 20 hours, the reaction mixture was diluted with water and extracted with ether. The organic layer was washed with a saturated aqueous ammonium chloride solution and water, and then dried. The solvent was distilled off under reduced pressure. The residue was purified twice by silica gel column chromatography (5:1 hexane/ethyl acetate) to yield the title compound (202 mg). 1H-NMR (CDCl3): delta (ppm) 1.38 (9H, s), 2.27 (3H, s), 3.72 (3H, s), 6.57 (1H, dd, J=2.2, 8.5), 6.78 (1H, d, J=2.2), 7.23 (1H, d, J=8.5), 10.19 (1H, brs).
(i) Preparation of 2-bromo-5-methoxyaniline 4-Bromo-3-nitroanisole (10 g, 43 mmol) and iron powder (21.72 g, 385 mmol) were stirred in a mixture of water (10 mL) and acetic acid (100 mL) for 1.5 h. The solvent was removed in vacuo, the brown residue was taken up in water (200 mL) and treated with 10% aq K2CO3 until pH 10. The mixture was extracted with EtOAc (4*150 mL) and the combined organic extracts were dried (MgSO4) and evaporated to give the desired aniline (5.0 g, 57%) as a brown oil; deltaH (CDCl3, 400 MHz) 3.72 (3H, s), 4.05 (2H, br), 6.22 (1H, dd), 6.32 (1H, d), 7.26 (1H, d); MS m/z (TS+) 202, 204 (MH+).
Reference Example 71 6-Bromo-3-methoxyaniline 4-Bromo-3-nitroanisole (19.8 g, 85.1 mmol) was dissolved in methanol (150 ml). Conc. HCl (40 ml) was added to the resultant solution, and the mixture was stirred while cooling. During stirring, reduced iron (14.3 g) was added to the mixture by small portions, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was condensed under reduced pressure. 2N-Caustic soda solution (100 ml) was added to the condensate, and the insoluble matter was filtered off. The filtrate was extracted with chloroform. The organic phase was dried and condensed under reduced pressure to obtain 16.0 g of the title compound, 3-methoxyaniline, as a brown oil (93.0%). IR(KBr): 3444, 3363, 1610, 1489, 1460, 1299, 1262, 1207, 1169, 1045, 1008, 825, 601 cm-1. 1 H-NMR(CDCl3)delta: 7.29(1H,d,J=8.8 Hz), 6.34(1H,d,J=2.5 Hz), 6.25(1H,dd,J=2.5,8.8 Hz), 4.16-3.95(2H,br), 3.76(3H,s).
With pyridine; dmap; triethylamine; In dichloromethane; at 20℃; for 24h;
EXAMPLE 2 4-(2-Bromo-5-methoxy-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.9 g, 12.68 mmol) was dissolved in dry methylene chloride (19 mL) and dry pyridine (2.61 mL). To the reaction mixture was then added thionyl chloride (1.81 g, 15.22 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was then added successively, under nitrogen atmosphere, 2-bromo-5-methoxy-phenylamine (2.82 g, 13.95 mmol), dry triethylamine (4.49 g, 44.40 mmol), dry methylene chloride (23 mL), 4-(dimethylamino)pyridine (0.15 g, 1.26 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then partitioned with aqueous 2N HCl and tert-butyl methyl ether. The organic layer was washed with aqueous 2N HCl, aqueous NaHCO3, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (25% ethyl acetate/hexanes) to yield the title compound as a solid. 1H NMR (300 MHz, CDCl3) delta 8.09 (1H, bs), 7.71 (1H, bs), 7.39 (1H, d, J=8.9 Hz), 6.59-6.55 (1H, m), 4.19-4.11 (2H, m), 3.80 (3H, s), 2.86-2.78 (2H, m), 2.50-2.42 (1H, m), 1.98-1.94 (2H, m), 1.81-1.68 (2H, m), 1.47 (9H, s) MS (ES+) m/z 435.1 (M+H)+
With hydrogenchloride; sodium borohydrid; boron trichloride;aluminium trichloride; In 1,4-dioxane; dichloromethane; water;
(a) 4-Methoxy-7-bromoindole. 2-Bromo-5-methoxy-aniline (4.4 g, 21.8 mmol) was added dropwise to a solution of boron trichloride in methylene chloride (1.0 M, 24 mL, 24 mmol) cooled with ice water. The reaction mixture was warmed to room temperature, stirred for 30 min, and chloroacetonitrile (4.01 mL, 26.2 mmol) and aluminum chloride (4.01 g, 24.0 mmol) were added, followed by 1,2-dichloroethane (28.5 mL). The reaction mixture was heated to 70 C. to distill off methylene chloride, and then heated to reflux for 24 hrs. After cooling to 0-5 C., the mixture was treated with 2.5 M HCl (38.4 mL) carefully, and then heated to 80 C. for 1 h until all solids dissolved. The aqueous layer was separated, extracted with methylene chloride and the combined extracts washed with water and brine, dried (sodium sulfate) and evaporated to a yellow solid, which was used without further purification. The crude product was taken into dioxane (37 mL) and water (4.2 mL), and treated with sodium borohydride (0.91 g, 24.0 mmol) in portions. After stirring at room temperature for 30 min, all the starting material was consumed and the reaction mixture was then heated to reflux for 14 hrs. After cooling to room temperature, the mixture was treated with concentrated HCl, and extracted with ethyl acetate. The organic extract was washed with water and brine; dried (sodium sulfate), and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) gave 4-methoxyl-7-bromoindole (1.2 g, 24%). 1H NMR (400 MHz, CDCl3) 3.94 (s, 3H), 6.44 (d, J=8.21 Hz, 1H), 6.73 (m, 1H), 7.17 (t, J=2.74 Hz, 1H), 7.22~7.26 (m, 1H), 8.32 (br, 1H); MS (ES, m/z): C9H8BrNO: 227.99 (M+(79Br)+1), 230.0(M+(81Br)+1).
Step 2:To a stirred solution of aniline 49c (7.5 g, 44 mmol) in AcOH (50 mL) is added 49b (8.0 g, 40 mmol) portionwise. Following addition, the reaction mixture is warmed to 35C. After 2 h, the reaction mixture is cooled to room temperature and poured in ice/water (600 mL). The resulting precipitate is isolated by filtration, rinsed with water (100 mL) and dried under vacuum to give 49d (9.1 g, 61 % yield).
Step 2:Aniline 55b (600 mg, 3 mmol) is treated with 6N HCI (8 mL) and sonicated until a white suspension appears (HCI salt). This mixture is heated to 1000C before being treated with the vinyl ketone 55c (1.2 g, 5.9 mmol) which is prepared similarly to that reported (Ref: Bull. Korean Chem. Soc. 24 (2003) 1 , 13-14) but via the Weinreb amide. The reaction mixture is heated at reflux for 6 h, then stirred at RT for 16 h. The mixture is diluted with EtOAc and basified with 1ON NaOH. The organic phase is separated and the aqueous phase re-extracted with EtOAc. The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated. The material <n="118"/>is purified by Combiflash Companion (EtOAc/hexanes) to afford the desired alcohol 55d (330 mg, 37.5%) as a pale brown solid.
Step 3 :<strong>[59557-92-5]2-bromo-5-methoxyaniline</strong> (6 g; 29.7 mmol) was dissolved in acetic acid (33.7 ml) and 2,6-dioxo-3,6-dihydro-2/-/-pyran-4-yl acetate (4.59 g; 27.0 mmol) was added. The reaction was stirred at 35 0C in a sand bath for 2 h. The reaction was quenched by adding ice-water (250 ml), the precipitate formed was filtered, washed with water and dried over phosphorus pentoxide under reduced pressure to afford 8.98 g (71 %) of 1-(2-bromo-5- methoxyphenylamino)-1 ,5-dioxohex-3-en-3-yl acetate as a grey solid. ESI/APCI(+): 372-374 (M+H).
61%
In acetic acid; at 20 - 35℃; for 2h;
To a stirred solution of aniline 46c (7.5 g, 44 mmol) in AcOH (50 mL) is added 46b (8.0 g, 40 mmol) portionwise. Following addition, the reaction mixture is warmed to 35C. After 2 h, the reaction mixture is cooled to RT and poured in ice/water (600 mL). The resulting precipitate is isolated by filtration, rinsed with water (100 mL) and dried under vacuum to give 46d (9.1 g, 61% yield).
tert-butyl (2-bromo-5-methoxyphenyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of <strong>[59557-92-5]2-bromo-5-methoxyaniline</strong> (1.0 eq.) (from step 1) in tetrahydrofuran (0.2 M) at 0 C. under N2 atmosphere was added dropwise 1M NaHMDS (2.5 eq.). The reaction was stirred for 15 minutes at 0 C., and a solution of di-tert-butyl dicarbonate in tetrahydrofuran was added. The reaction was warmed to room temperature overnight. The solvent was evaporated, and the resulting residue was quenched with 0.1N HCl aqueous solution. The aqueous suspension was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-5% ethyl acetate in hexane to give product as light yellow oil.
To a solution of <strong>[59557-92-5]2-bromo-5-methoxyaniline</strong> (1.0 eq.) (from step 1) in tetrahydrofuran(0.2 M) at 00C under N2 atmosphere was added dropwise IM NaHMDS (2.5 eq.). The reaction was stirred for 15 minutes at 00C, and a solution of di-fer?-butyl dicarbonate in tetrahydrofuran was added. The reaction was warmed to room temperature overnight. The solvent was evaporated, and the resulting residue was quenched with 0.1N HCl aqueous solution. The aqueous suspension was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH system (ISCO) using 0-5% ethyl acetate in hexane to give product as light yellow oil.
With sulfuric acid; sodium 3-nitrobenzenesulfonate; at 140℃; for 3h;Inert atmosphere;
General Procedure I-CT3-Nitrobenzenesulfonic acid sodium salt (3.3 g, 15 mmol) was added to the mixture of compound I-XIa (3 g, 15 mmol) and propane-1,2,3-triol (3.6 g, 0.039 mol). Then 12 mL of conc. H2SO4 was added, and the reaction mixture was stirred at 140 C. for 3 h under N2 protection. After cooled to r.t, water (18 g) was added, and a grayish by product was filtered off. The filtrate was diluted with aq. NaOH (20 mL, 50%) and extracted with of CH2Cl2 (80 mL). The organic layer was separated, washed with brine (20 mL), dried over MgSO4, and concentrated. The residue was purified by column chromatography to afford compound I-XIb (600 mg, yield: 19%). MS (ESI) m/z (M+H)+ 238.
With pyridine; In dichloromethane; at 0 - 20℃; for 0.5h;
A solution of compound 5-2 (10.0 g, 49.8 mmol) in anhydrous pyridine (50 mL) was added MsCl (4.04 mL, 52.2 mmol) at 0 C. After stirring at rt for 30 min, the reaction mixture was diluted with EtOAc (200 mL). The mixture was washed with 1 N aq.HCl (100 mL x 3) and brine (100 mL) and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 10/1 (v/v)) to give compound 5-3 (9.3 g, 67% yield) as a white solid. LC-MS (ESI): m/z 280 [M+H]+.
With dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 12h;Inert atmosphere;
General procedure: To a stirred solution of commercially available or known bromoaniline compound (1.0 mmol) inCH2Cl2 (5 mL) and the corresponding propiolic acid (1.3 mmol, 1.3 equiv) was addeddicyclohexyl carbodimide (DCC, 1.3 mmol, 1.3 equiv) at 0 C. Then, the temperature wasgradually raised to 25 C over 30 min. The mixture was stirred at the same temperature for 12 h,and diluted with EtOAc (50 mL) and sat. aq. NH4Cl (30 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purifiedby column chromatography (silica gel, hexanes:EtOAc 8:1 or CH2Cl2 only) to affordpropiolamides 4-s, 6a-s~6e-s.
40%
With dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 25℃; for 12.5h;
General procedure: To a stirred solution of commercially available or known bromoaniline compound (1.0 mmol) inCH2Cl2 (5 mL) and the corresponding propiolic acid (1.3 mmol, 1.3 equiv) was addeddicyclohexyl carbodimide (DCC, 1.3 mmol, 1.3 equiv) at 0 C. Then, the temperature wasgradually raised to 25 C over 30 min. The mixture was stirred at the same temperature for 12 h,and diluted with EtOAc (50 mL) and sat. aq. NH4Cl (30 mL). The organic layer was separated,dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, hexanes:EtOAc 8:1 or CH2Cl2 only) to affordpropiolamides 4-s, 5-s, 8a-s, 8b-s, and 10-s.
General procedure: A mixture of <strong>[59557-92-5]2-bromo-5-methoxyaniline</strong> (10 mmol, 2.02 g), malonic acid (15 mmol) and POCl3 (25 mL) was refluxed for 16 h. The reaction mixture was slowly poured into water and extracted with DCM. The organic layers was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel, eluted with DCM, to afford the final product as a light yellow solid in 90% yield [8]. 1H-NMR (400 MHz, CDCl3): delta 7.96 (t, J = 8 Hz, 1H), 7.47 (s, 1H), 6.82 (t,J = 8 Hz, 1H), 3.96 (s, 3H). 13C-NMR (100 MHz, CDCl3): delta 156.2, 151.4, 144.2, 143.5, 138.0, 118.8,122.0, 114.6, 105.0, 56.2. ESI-MS (m/z, %): 303.8989 [M-H]-. Mp: 204-206 C.
40%
With trichlorophosphate; at 0℃;
To <strong>[59557-92-5]2-bromo-5-methoxyaniline</strong> (10.0 g, 494 mmol) and malonic acid (7.72 g, 74.23 mmol) was added drop wise at 0C POCl3 (100 ml). The resulting mixture was stirred under reflux overnight. Then, the reaction mixture was cooled, concentrated under reduced pressure and co-evapored twice with toluene (500 ml). The residue was then taken up with DCM (500 ml) and washed with cold water. The aqueous layer was extracted with DCM and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown solid (6.0 g, yield: 40%) corresponding to 2,4-dichloro-5-methoxy-8-bromoquinoline (12-1). HPLC-MS, Method C: tr =2.21 min, (ES+) C10H6BrCl2NO found 306 [M+required 305; H]. 1H NMR (400 MHz, CDCl3)
1-(2-amino-3-bromo-6-methoxyphenyl)-2-chloroethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
Synthesis of 1-(2-amino-3-bromo-6-methoxyphenyl)-2-chloroethanone (compound 2b) A dichloromethane (500 mL) solution of <strong>[59557-92-5]2-bromo-5-methoxyphenylamine</strong> (compound 2a) (100 g, 0.495 mol) was slowly dropped at 0C into a dichloromethane (540 mL) solution of boron trichloride (BCl3) (1M hexane solution, 540 mL, 0.540 mol). The resultant black reaction solution was stirred at 0C for 30 minutes, and chloroacetonitrile (76 mL, 1.2 mol) and aluminum chloride (AlCl3) (72 g, 0.54 mol) were added to the solution. The mixture was stirred at room temperature for 1 hour, and then heated to reflux overnight. After the reaction was completed, the mixture was ice-cooled to 0C, and hydrochloric acid (2 M, 100 mL) was added to the mixture. Then, hydrochloric acid (5 M, 200 mL) was further added to the mixture and stirred at room temperature for 1 hour. The organic layer was collected and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and thus 1-(2-amino-3-bromo-6-methoxyphenyl)-2-chloroethanone (compound 2b) (138 g, 0.495 mol, 100%) was obtained as a dark green solid. 1H NMR (400 MHz, CDCl3) delta 7.46 (d, J = 8.8 Hz, 1H), 6.74 (brs, 2H), 6.11 (d, J = 8.8 Hz, 1H), 4.75 (s, 2H), 3.88 (s, 3H)
100%
Synthesis of 1-(2-amino-3-bromo-6-methoxyphenyl)-2-chloroethanone (compound 2b) A dichloromethane (500 mL) solution of <strong>[59557-92-5]2-bromo-5-methoxyphenylamine</strong> (compound 2a) (100 g, 0.495 mol) was slowly dropped at 0 C. into a dichloromethane (540 mL) solution of boron trichloride (BCl3) (1M hexane solution, 540 mL, 0.540 mol). The resultant black reaction solution was stirred at 0 C. for 30 minutes, and chloroacetonitrile (76 mL, 1.2 mol) and aluminum chloride (AlCl3) (72 g, 0.54 mol) were added to the solution. The mixture was stirred at room temperature for 1 hour, and then heated to reflux overnight. After the reaction was completed, the mixture was ice-cooled to 0 C., and hydrochloric acid (2 M, 100 mL) was added to the mixture. Then, hydrochloric acid (5 M, 200 mL) was further added to the mixture and stirred at room temperature for 1 hour. The organic layer was collected and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and thus 1-(2-amino-3-bromo-6-methoxyphenyl)-2-chloroethanone (compound 2b) (138 g, 0.495 mol, 100%) was obtained as a dark green solid. 1H NMR (400 MHz, CDCl3) delta 7.46 (d, J=8.8 Hz, 1H), 6.74 (brs, 2H), 6.11 (d, J=8.8 Hz, 1H), 4.75 (s, 2H), 3.88 (s, 3H)
With 1,10-Phenanthroline; potassium carbonate; In acetonitrile; at 100℃; for 3h;Inert atmosphere; Sealed tube;
General procedure: o-Bromaniline (1a, 0.2 mmol), benzoyl chloride (2a, 1.2 eq), Cu NPs (1.3 mg, 10 mol%), 1,10-phen(4.0 mg, 10 mol%), K2CO3 (2.0 equiv), and 1.5 mL of MeCN were added into a 5-mL sealed tubeunder N2. The mixture was stirred at 90 for 1 hour. Then, the reaction was stopped, and the reactionmixture was purified by flash column chromatography on silica gel (hexanes/EtOAc 15:1). Compound4a was obtained in >99 % of yield.
2-(4-chlorophenyl)-5-methoxybenzo[d]oxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With 1,10-Phenanthroline; potassium carbonate; In acetonitrile; at 100℃; for 3h;Inert atmosphere; Sealed tube;
General procedure: o-Bromaniline (1a, 0.2 mmol), benzoyl chloride (2a, 1.2 eq), Cu NPs (1.3 mg, 10 mol%), 1,10-phen(4.0 mg, 10 mol%), K2CO3 (2.0 equiv), and 1.5 mL of MeCN were added into a 5-mL sealed tubeunder N2. The mixture was stirred at 90 for 1 hour. Then, the reaction was stopped, and the reactionmixture was purified by flash column chromatography on silica gel (hexanes/EtOAc 15:1). Compound4a was obtained in >99 % of yield.
With 1,10-Phenanthroline; potassium carbonate; In acetonitrile; at 100℃; for 3h;Inert atmosphere; Sealed tube;
General procedure: o-Bromaniline (1a, 0.2 mmol), benzoyl chloride (2a, 1.2 eq), Cu NPs (1.3 mg, 10 mol%), 1,10-phen(4.0 mg, 10 mol%), K2CO3 (2.0 equiv), and 1.5 mL of MeCN were added into a 5-mL sealed tubeunder N2. The mixture was stirred at 90 for 1 hour. Then, the reaction was stopped, and the reactionmixture was purified by flash column chromatography on silica gel (hexanes/EtOAc 15:1). Compound4a was obtained in >99 % of yield.
1-Bromo-4-methoxy-2-nitrobenzene (1.71g, 7.2 mmol, 1 equiv.) was dissolved in EtOH (7 mL) and H2O (5 mL). Iron powder (2.00 g,35.7 mmol, 5 equiv.) and NH4Cl (1.53 g, 28.6 mmol, 4 equiv.) were added to the solution. The solution was heated to reflux for 2 h. The black organic phase was washed with diethyl ether(4 x 100 mL). This yielded <strong>[59557-92-5]2-bromo-5-methoxyaniline</strong> (95%) as a green substance, with data as reported.7 At 0 C a solution of the crude <strong>[59557-92-5]2-bromo-5-methoxyaniline</strong> (1.50 g, 7.4 mmol, 1equiv.) in conc. HCl (7 mL) was treated dropwise with aq. NaNO2 (0.5 g, 7.2 mmol, 1 equiv.)in deionized H2O (5 mL). Stirring was continued at 0 C for 5 h resulting in the formation ofthe diazonium salt. In a separate flask, at 0 C, H2O (8 mL) was treated with thionyl chloride(2.2 mL, 30.3 mmol, 4 equiv.). Stirring continued at 0 C for 1 h. The aqueous phase was washed with ethylacetate (6 x 50 mL). The combined phases were dried over MgSO4. Solvent removal followed by column chromatography (c-Hex-EtOAc; 5:1) yielded S5 (1.50 g, 46%) asa yellow oil. Rf = 0.3 (c-Hex-EtOAc; 5:1) with data as reported.8
With dmap; triethylamine; In dichloromethane; at 0 - 20℃;
General procedure: A solution of the substituted 2-iodoaniline or 2-bromoaniline (1.0 equiv), DMAP (0.05 equiv) and NEt3 (2.0 equiv) was prepared in CH2Cl2 (2mL) and cooled to 0 C. The acyl chloride solution was added dropwise into the solution. After 5 minutes, the reaction was allowed to warm to room temperature and was stirred overnight. The reaction was quenched with a saturated NaHCO3 solution and extracted with CH2Cl2 twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting crude amide was used in next step without further purification.
With boron tribromide; In dichloromethane; at 0 - 20℃; for 24h;
General procedure: A solution of BBr3 in dichloromethane (1.0 M, 12 mL,12 mmol) was added slowly to a solution of 4-bromo-3-methoxyaniline (800 mg, 3.96 mmol) in methylene chloride(15 mL) at 0C. The resulting brown solution was warmed toroom temperature and stirred for 24 h. After saturated aqueousNaHCO3 (30 mL) was added at 0C, the solution was extractedwith EtOAc (20 mL × 3). The combined organic layer wasdried with anhydrous Na2SO4, filtered and concentrated invacuum. The residue was purified by flash chromatographyover silica gel (petroleum-EtOAc = 2 : 1) to give 5-amino-2-bromophenol (665 mg, 88%). To a solution of 5-amino-2-bromophenol (55 mg, 0.29 mmol)and triethylamine (53 muL, 0.38 mmol) in tetrahydrofuran (THF)(3 mL) was added slowly benzoyl chloride (0.32 mmol) at 0C.The reaction mixture was then stirred at room temperature for30 min. After the reaction was quenched with water (10 mL),the solution was extracted with EtOAc (10 mL × 2). The combinedorganic layer was dried over anhydrous Na2SO4, filteredand concentrated in vacuum. The residue was purified bycolumn chromatography to afford the product 3 (74 mg, 87%).
2-bromo-N- (2-bromo-6-nitrophenyl)-5-methoxyaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
In a suspension of sodium hydride (7.92 g, 198 mmol) in THF (200 mL) at room temperature, 2-bromo-5-methoxyaniline (20.0 g, 99.0 mmol)Was added in portions over 5 minutes. The mixture was stirred at room temperature for 1.5 hours.Then a solution of <strong>[58534-94-4]1-bromo-2-fluoro-3-nitrobenzene</strong> (25.0 g, 114 mmol) in dry THF (100 mL) was added dropwise over 5 minutes,The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with ice water (450 mL), The mixture was extracted with DCM (2 × 600 mL). The combined organic extracts were dried (MgSO 4), filtered and concentrated in vacuo.The crude material was purified by chromatography on silica gel (0-30% MTBE / isohexane),2-Bromo-N- (2-bromo-6-nitrophenyl) -5-methoxyaniline (29.2 g, 73%) was obtained as an orange solid.
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