* 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.
Preparation of 52A suspension 51 (O. lg, 0.43mmol) in unstabilized 57 percent HI (1.3 mL) was heated at 90°C for 5h. Reaction mixture was cooled, diluted with EtOAc (5 mL) and washed with saturated aq Na2S20s and brine. The organic layer was dried over anhydrous MgS04, filtered and concentrated. The crude product was further purified by silica-gel column chromatography to 52 (0.07 g, 80 percent).
80%
at 90℃; for 5 h;
[0584] Preparation of 52 [0585] A suspension 51 (0.1 g, 0.43 mmol) in unstabilized 57percent Hl (1.3 mL) was heated at 90° C. for 5 h. Reaction mixture was cooled, diluted with EtOAc (5 mL) and washed with saturated aq Na2S2O3 and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The crude product was further purified by silica-gel column chromatography to 52 (0.07 g, 80percent).
67%
Stage #1: With tin(ll) chloride In ethanol at 70℃; for 2 h; Stage #2: With sodium hydroxide In water
Stannous chloride (96.839 g, 5.0 eq.) was added to a solution of 2-bromo-4-nitroanisole (23.7 g, 1.0 eq.) in ethanol (250 mL) and the mixture was stirred at 70° C. for 2 h, partitioned between ethyl acetate and sodium bicarbonate solution 10percent. The pH was adjusted to 9 with 1N sodium hydroxide solution and the aqueous layer was extracted twice with ethyl acetate. The combined organic fractions were washed with water and brine, dried over magnesium sulfate, filtered, evaporated to dryness and purified on silica gel, eluding with hexane/ethyl acetate 1:1, to yield 13.82 g (67percent) from the desired product as light brown solid. MS (m/e): 204.1 (MH+, 100percent).
2.02 g
With tin(II) chloride dihdyrate In water at 20℃; for 3 h;
2-Bromo-1-methoxy-4-nitrobenzene (2.50 g, 10.8 mmol), SnCl2.2H2O (12.2 g, 53.9 mmol), and MeOH (30 mL) were combined and allowed to stir for 3 h at ambient temperature. To the mixture was added H2O (100 mL) and EtOAc (100 mL) resulting in the formation of a thick emulsion. To this was added sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3*30 mL). The organics were combined and dried over MgSO4 before being filtered. Concentration of the filtrate in vacuo gave 2.02 g of an off-white solid. This material was used without further purification.
Reference：
[1] ACS Catalysis, 2015, vol. 5, # 3, p. 1526 - 1529
[2] Patent: WO2011/98776, 2011, A1, . Location in patent: Page/Page column 60
[3] Patent: US2013/53372, 2013, A1, . Location in patent: Paragraph 0584; 0585
[4] Patent: US2007/123515, 2007, A1, . Location in patent: Page/Page column 24
[5] Justus Liebigs Annalen der Chemie, 1883, vol. 217, p. 44
[6] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 832 - 834
[7] Patent: US2008/9524, 2008, A1, . Location in patent: Page/Page column 387
[8] Patent: US2003/229058, 2003, A1, . Location in patent: Page 57
[9] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 1, p. 513 - 523
[10] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 1145
[11] Patent: US2017/73353, 2017, A1, . Location in patent: Paragraph 0514
2
[ 5197-28-4 ]
[ 7439-89-6 ]
[ 19056-41-8 ]
Reference：
[1] Patent: US5877191, 1999, A,
[2] Patent: US5929094, 1999, A,
3
[ 10025-69-1 ]
[ 5197-28-4 ]
[ 19056-41-8 ]
Reference：
[1] Patent: US2011/98311, 2011, A1,
4
[ 5197-28-4 ]
[ 636-93-1 ]
[ 17332-12-6 ]
[ 5847-59-6 ]
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1925 - 1934
5
[ 5197-28-4 ]
[ 25016-02-8 ]
Reference：
[1] Patent: WO2018/13774, 2018, A1,
6
[ 100-17-4 ]
[ 5197-28-4 ]
Yield
Reaction Conditions
Operation in experiment
86%
With N-Bromosuccinimide In neat (no solvent) at 20℃; for 1.5 h; Milling; Green chemistry
General procedure: 1-Methoxy-3,5-dimethylbenzene (100mg, 0.73 mmol), N-Bromosuccinimide (NBS,260 mg,1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reactionwas monitored by TLC/1H NMR.[1]After completion, the reaction mixture was transferred into 30 mL ethyl acetateand cooled at 0 °C. The product was isolated as filtrate upon paper filtrationand waste succinimide as precipitate. The resulting filtrate were concentrated in vacuoto isolate 250 mg (yield: 85percent) of 2bas colourless powder. To test the efficiency in largescale, the reaction was also performed for the mono-bromination of1-methoxy-3,5-dimethylbenzene in 1.3 g scale for 1 h and the product wasisolated in 87percent yield.[1] Themilling apparatus was stopped and small portion of the sample was collectedfrom the reaction jar to study either TLC/ proton NMR. Following, the reaction was started again andthis operation time was excluded for reporting the reaction timing.
85%
With N-Bromosuccinimide In neat (no solvent) at 20℃; for 1.5 h; Milling; Green chemistry
General procedure: 1-Methoxy-3,5-dimethylbenzene(100mg, 0.73 mmol), N-Bromosuccinimide (NBS,260 mg,1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reaction was monitored by TLC/1H NMR.[1]After completion, the reaction mixture was transferred into 30 mL ethyl acetate and cooled at 0 °C. The product was isolated as filtrate upon paper filtration and waste succinimide as precipitate. The resulting filtrate were concentrated in vacuo to isolate 250 mg (yield: 85percent) of 2b as colourless powder. To test the efficiency in large scale, the reaction was also performed for the mono-bromination of 1-methoxy-3,5-dimethylbenzene in 1.3 g scale for 1 h and the product was isolated in 87percent yield.[1] The milling apparatus was stopped and small portion of the sample was collected from the reaction jar to study either TLC/ proton NMR. Following, the reaction was started again andthis operation time was excluded for reporting the reaction timing.
Reference：
[1] Tetrahedron Letters, 2015, vol. 55, # 13, p. 2154 - 2156
[2] Tetrahedron Letters, 2014, vol. 55, # 13, p. 2154 - 2156
[3] Applied Catalysis A: General, 2010, vol. 384, # 1-2, p. 18 - 26
[4] International Journal of Chemical Kinetics, 2016, vol. 48, # 2, p. 98 - 105
[5] Journal of the Indian Chemical Society, 1983, vol. 60, p. 953 - 957
[6] Journal of the Indian Chemical Society, 1983, vol. 60, p. 1106 - 1107
[7] Monatshefte fuer Chemie, 1927, vol. 48, p. 610
[8] Journal of the Chemical Society, 1928, p. 2935
[9] Catalysis Letters, 2010, vol. 137, # 3-4, p. 190 - 201
[10] Organic Letters, 2013, vol. 15, # 9, p. 2108 - 2111
7
[ 99-59-2 ]
[ 5197-28-4 ]
Reference：
[1] Journal of the Chemical Society, 1867, vol. 20, p. 94[2] Journal fuer Praktische Chemie (Leipzig), 1867, vol. <1> 101, p. 91
[3] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 832 - 834
[4] Canadian Journal of Chemistry, 2005, vol. 83, # 3, p. 213 - 219
8
[ 104-92-7 ]
[ 100-17-4 ]
[ 21702-84-1 ]
[ 33696-00-3 ]
[ 5197-28-4 ]
Reference：
[1] Canadian Journal of Chemistry, 1989, vol. 67, p. 1472 - 1479
9
[ 578-57-4 ]
[ 5197-28-4 ]
[ 98775-19-0 ]
Reference：
[1] Journal of the American Chemical Society, 1934, vol. 56, p. 1787,1790
10
[ 18771-85-2 ]
[ 5197-28-4 ]
Reference：
[1] Journal of Organic Chemistry, 1964, vol. 29, p. 2605 - 2609
11
[ 186581-53-3 ]
[ 5847-59-6 ]
[ 5197-28-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1981, p. 2456 - 2463
12
[ 5847-59-6 ]
[ 74-88-4 ]
[ 5197-28-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1994, vol. 67, # 10, p. 2639 - 2646
13
[ 21678-94-4 ]
[ 5197-28-4 ]
Reference：
[1] Journal of Organic Chemistry, 1964, vol. 29, p. 2605 - 2609
14
[ 578-57-4 ]
[ 5197-28-4 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1897, vol. <3> 17, p. 115
[2] Chemische Berichte, 1896, vol. 29, p. 2598[3] Chemische Berichte, 1899, vol. 32, p. 161 Anm.
15
[ 5411-50-7 ]
[ 124-41-4 ]
[ 5197-28-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1937, vol. 56, p. 541,554, 863, 871
16
[ 90150-94-0 ]
[ 5197-28-4 ]
Reference：
[1] Journal of Organic Chemistry, 1964, vol. 29, p. 2605 - 2609
17
[ 100-17-4 ]
[ 7726-95-6 ]
[ 5197-28-4 ]
Reference：
[1] Monatshefte fuer Chemie, 1927, vol. 48, p. 610
18
[ 110-86-1 ]
[ 100-17-4 ]
[ 7726-95-6 ]
[ 5197-28-4 ]
Reference：
[1] Journal of the Chemical Society, 1928, p. 2935
19
[ 578-57-4 ]
[ 7697-37-2 ]
[ 64-19-7 ]
[ 5197-28-4 ]
Reference：
[1] Chemische Berichte, 1896, vol. 29, p. 2598[2] Chemische Berichte, 1899, vol. 32, p. 161 Anm.
20
[ 99-58-1 ]
[ 7697-37-2 ]
[ 5197-28-4 ]
[ 36324-64-8 ]
[ 954815-08-8 ]
Reference：
[1] Gazzetta Chimica Italiana, 1884, vol. 14, p. 235
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1925 - 1934
24
[ 578-57-4 ]
[ 5197-28-4 ]
[ 98775-19-0 ]
Reference：
[1] Journal of the American Chemical Society, 1934, vol. 56, p. 1787,1790
25
[ 99-58-1 ]
[ 7697-37-2 ]
[ 5197-28-4 ]
[ 36324-64-8 ]
[ 954815-08-8 ]
Reference：
[1] Gazzetta Chimica Italiana, 1884, vol. 14, p. 235
26
[ 5197-28-4 ]
[ 1826-67-1 ]
[ 90858-86-9 ]
Yield
Reaction Conditions
Operation in experiment
3%
at -40 - -20℃; for 0.5 h;
Example 12 Synthesis of 4-bromo-5-methoxyindole (XLVI) To a -40° C. solution of 2-bromo-4-nitro-anisole (1.16 g, 5 mmol) in THF (10 ml) was added vinylmagnesium bromide (1M in THF, 15 ml). The reaction mixture was stirred for 30 min while allowing the temperature to rise to -20° C. The reaction was quenched by addition of a saturated solution of NH4Cl, diluted with Et2O, and the aqueous layer was extracted twice with Et2O. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) to provide 4-bromo-5-methoxyindole XLVI (38 mg, 3percent yield) as an oil.
Preparation of 52A suspension 51 (O. lg, 0.43mmol) in unstabilized 57 % HI (1.3 mL) was heated at 90C for 5h. Reaction mixture was cooled, diluted with EtOAc (5 mL) and washed with saturated aq Na2S20s and brine. The organic layer was dried over anhydrous MgS04, filtered and concentrated. The crude product was further purified by silica-gel column chromatography to 52 (0.07 g, 80 %).
80%
With hydrogen iodide; at 90℃; for 5h;
[0584] Preparation of 52 [0585] A suspension 51 (0.1 g, 0.43 mmol) in unstabilized 57% Hl (1.3 mL) was heated at 90 C. for 5 h. Reaction mixture was cooled, diluted with EtOAc (5 mL) and washed with saturated aq Na2S2O3 and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The crude product was further purified by silica-gel column chromatography to 52 (0.07 g, 80%).
67%
Stannous chloride (96.839 g, 5.0 eq.) was added to a solution of 2-bromo-4-nitroanisole (23.7 g, 1.0 eq.) in ethanol (250 mL) and the mixture was stirred at 70 C. for 2 h, partitioned between ethyl acetate and sodium bicarbonate solution 10%. The pH was adjusted to 9 with 1N sodium hydroxide solution and the aqueous layer was extracted twice with ethyl acetate. The combined organic fractions were washed with water and brine, dried over magnesium sulfate, filtered, evaporated to dryness and purified on silica gel, eluding with hexane/ethyl acetate 1:1, to yield 13.82 g (67%) from the desired product as light brown solid. MS (m/e): 204.1 (MH+, 100%).
With tin(ll) chloride; In methanol; at 20℃; for 3h;
Preparation 8 3-Bromo-4-methoxybenzenamine 2-Bromo-1-methoxy-4-nitrobenzene (2.50 g, 10.8 mmol), SnCl2.2H2O (12.2 g, 53.9 mmol), and MeOH (30 mL) were combined and allowed to stir for 3 h at ambient temperature. To the mixture was added H2O (100 mL) and EtOAc (100 mL) resulting in the formation of a thick emulsion. To this was added sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3*30 mL). The organics were combined and dried over MgSO4 before being filtered. Concentration of the filtrate in vacuo gave 2.02 g of an off-white solid. This material was used without further purification. In addition to bromo-anilines prepared according to preparation 8, non-limiting examples of commercially available bromo anilines and bromo nitrobenzenes are given in Table 3.
With hydrogenchloride; iron; In ethanol; water; for 0.333333h;Heating / reflux;
To a mixture of 2-bromo-4-nitroanisole (5.0 g, 21.5 mmol, Lancaster), ethanol (25 mL) and water (25 mL), was added powdered iron (4.8 g, 86 mmol) and 12 N HCl (0.5 mL). The solution was heated at reflux for 20 minutes. 1N NaOH (10 mL) was added and the reaction mixture was filtered through a pad of celite while still hot, and then rinsed with ethanol (2×50 mL). The ethanol was removed under reduced pressure and the residue extracted with dichloromethane (2×100 mL). The organic extracts were dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography on silica gel (75 g) eluting with dichloromethane, to give 4-amino-2-bromoanisole as a light tan solid.
2.02 g
With tin(II) chloride dihdyrate; In water; at 20℃; for 3h;
2-Bromo-1-methoxy-4-nitrobenzene (2.50 g, 10.8 mmol), SnCl2.2H2O (12.2 g, 53.9 mmol), and MeOH (30 mL) were combined and allowed to stir for 3 h at ambient temperature. To the mixture was added H2O (100 mL) and EtOAc (100 mL) resulting in the formation of a thick emulsion. To this was added sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3*30 mL). The organics were combined and dried over MgSO4 before being filtered. Concentration of the filtrate in vacuo gave 2.02 g of an off-white solid. This material was used without further purification.
With water; ammonium chloride; zinc; In ethanol; at 80℃; for 3h;
Step 1: 3-bromo-4-methoxyaniline To a solution of 2-bromo-1-methoxy-4-nitrobenzene (5 g, 21.55 mmol) in ethanol (40 mL) and H2O (20 mL) was added zinc (7.04 g, 108 mmol) and NH4Cl (5.76 g, 108 mmol). The resulting mixture was stirred at 80 C. for 3 hours. Then the hot reaction mixture was filtered, and the filtrate was concentrated. The aqueous phase was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give the titled compound (3.3 g, yield 76%) that was used for the next step without further purification. 1H NMR (400 MHz, methanol-d4) delta ppm 7.01 (s, 1H), 6.88-6.86 (d, J=8.0 Hz, 1H), 6.75-6.72 (d, J=12.0 Hz, 1H), 3.81 (s, 3H).
With sodium thioethylate; In N,N-dimethyl-formamide; at 20 - 115℃; for 2h;
2-Bromo-4-nitrophenol 2-Bromo-4-nitroanisole (20 g, 0.086 mol) was dissolved in DMF (414 mL) at rt under N2. Sodium ethylthiolate (17.4 g, 0.207 mol) was added and the reaction mixture was warmed to 115 C. for 2 h. The reaction was cooled to rt and diluted with EtOAc (200 mL) and 1 M HCl (aq., 200 mL). The phases were separated, and the desired product was extracted into 1 M NaOH (aq, 150 mL*3). The basic aqueous extracts were combined and acidified using conc. HCl. The desired product was extracted from the acidic aqueous solution using EtOAc (250 mL*2). The combined organic layers were washed with brine and dried over sodium sulfate. The volatiles were removed in vacuo to afford a light brown semi-solid (9.8 g, 52% yield). 1H NMR (DMSO-d6) delta 8.33 (m, 1H); 8.09 (m, 1H); 7.07 (d, 1H).
52%
With sodium thioethylate; In DMF (N,N-dimethyl-formamide); at 115℃; for 2h;
2-Bromo-4-nitroanisole (20 g, 0.086 mol) was dissolved in DMF (414 mL) at rt under N2. Sodium ethylthiolate (17.4 g, 0.207 mol) was added and the reaction mixture was warmed to 115 C. for 2 h. The reaction was cooled to rt and diluted with EtOAc (200 mL) and 1 M HCl (aq., 200 mL). The phases were separated, and the desired product was extracted into 1 M NaOH (aq, 150 mL×3). The basic aqueous extracts were combined and acidified using conc. HCl. The desired product was extracted from the acidic aqueous solution using EtOAc (250 mL×2). The combined organic layers were washed with brine and dried over sodium sulfate. The volatiles were removed in vacuo to afford a light brown semi-solid (9.8 g, 52% yield). 1H NMR (DMSO-d6) delta 8.33 (m, 1H); 8.09 (m, 1H); 7.07 (d,1H).
52%
With sodium thioethylate; In N,N-dimethyl-formamide; at 20 - 115℃; for 2h;Inert atmosphere;
2-Bromo-4-nitroanisole (20 g, 0.086 mol) was dissolved in DMF (414 mL) at room temperature under N2. Sodium ethylthiolate (17.4 g, 0.207 mol) was added and the reaction mixture was warmed to 115 C. for 2 hours. The reaction was cooled to room temperature and diluted with EtOAc (200 mL) and 1 M HCl (aq., 200 mL). The phases were separated, and the desired product was extracted into 1 M NaOH (aq, 150 mL*3). The basic aqueous extracts were combined and acidified using conc. HCl. The desired product was extracted from the acidic aqueous solution using EtOAc (250 mL*2). The combined organic layers were washed with brine and dried over sodium sulfate. The volatiles were removed in vacuo to afford a light brown semi-solid (9.8 g, 52% yield). 1H NMR (DMSO-d6) delta 8.33 (m, 1H); 8.09 (m, 1H); 7.07 (d, 1H).
52%
With sodium thioethylate; In N,N-dimethyl-formamide; at 20 - 115℃; for 2h;
Preparation of 2-Bromo-4-nitrophenol 2-Bromo-4-nitroanisole (20 g, 0.086 mol) was dissolved in DMF (414 mL) at room temperature under N2. Sodium ethylthiolate (17.4 g, 0.207 mol) was added and the reaction mixture was warmed to 115C for 2 hours. The reaction was cooled to room temperature and diluted with EtOAc (200 mL) and 1 M HCI (aq. , 200 mL). The phases were separated, and the desired product was extracted into 1 M NaOH (aq, 150 mL X 3). The basic aqueous extracts were combined and acidified using conc. HCI. The desired product was extracted from the acidic aqueous solution using EtOAc (250 mL X 2). The combined organic layers were washed with brine and dried over sodium sulfate. The volatiles were removed in vacuo to afford a light brown semi- solid (9.8 g, 52% yield).
a 2-Bromo-4-aminoanisole A mixture of 670 mg (2.9 mmol) of 2-bromo-4-nitroanisole and 1.20 g (21.1. mmol) of iron powder in 10 mL of 1:1 v/v HOAc/H2 O was heated at 80 C. for 1.5 h. The mixture was cooled and filtered onto a pad of Celite. The flask and filtered solids were rinsed with 100 mL of EtOAc and 100 mL of H2 O. The filtrate was transferred to a separatory funnel and the layers were separated. The organic layer was washed with 50 mL of sat'd NaHCO3, 50 mL sat'd NaCl, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 25 g of silica gel using 3:2 v/v hexanes/ether as the eluant afforded 504 mg (86%) of the title compound as an oil. 1 H NMR (500 MHz, CDCl3): delta 3.54 (br s, 2H), 3.81 (s, 3H), 6.60 (dd, J=8.5, 2.5, 1H), 6.74 (d, J=8.5, 1H), 6.93 (d, J=2.5, 1H).
504 mg (86%)
In water; acetic acid; ethyl acetate;
a 2-Bromo-4-aminoanisole A mixture of 670 mg (2.9 mmol) of 2-bromo-4-nitroanisole and 1.20 g (21.1. mmol) of iron powder in 10 mL of 1:1 v/v HOAc/H2 O was heated at 80 C. for 1.5 h. The mixture was cooled and filtered onto a pad of Celite. The flask and filtered solids were rinsed with 100 mL of EtOAc and 100 mL of H2 O. The filtrate was transfered to a separatory fumel and the layers were separated. The organic layer was washed with 50 mL of sat'd NaHCO3, 50 mL sat'd NaCl, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 25 g of silica gel using 3:2 v/v hexanes/ether as the eluant afforded 504 mg (86%) of the title compound as an oil. 1 H NMR (500 MHz, CDCl3): delta 3.54 (br s, 2H), 3.81 (s, 3H), 6.60 (dd, J=8.5, 2.5, 1H), 6.74 (d, J=8.5, 1H), 6.93 (d, J=2.5, 1H).
Example 12 Synthesis of 4-bromo-5-methoxyindole (XLVI) To a -40° C. solution of 2-bromo-4-nitro-anisole (1.16 g, 5 mmol) in THF (10 ml) was added vinylmagnesium bromide (1M in THF, 15 ml). The reaction mixture was stirred for 30 min while allowing the temperature to rise to -20° C. The reaction was quenched by addition of a saturated solution of NH4Cl, diluted with Et2O, and the aqueous layer was extracted twice with Et2O. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) to provide 4-bromo-5-methoxyindole XLVI (38 mg, 3percent yield) as an oil.
(a) Preparation of 2-Bromo-4-nitrophenol 2-Bromo-4-nitroanisole (20 g, 0.086 mol) was dissolved in DMF (414 mL) at room temperature under N2. Sodium ethylthiolate (17.4 g, 0.207 mol) was added and the reaction mixture was warmed to 115 C. for 2 hours. The reaction was cooled to room temperature and diluted with EtOAc (200 mL) and 1 M HCl (aq., 200 mL). The phases were separated, and the desired product was extracted into 1 M NaOH (aq, 150 mL X 3). The basic aqueous extracts were combined and acidified using conc. HCl. The desired product was extracted from the acidic aqueous solution using EtOAc (250 mL*2). The combined organic layers were washed with brine and dried over sodium sulfate. The volatiles were removed in vacuo to afford a light brown semi-solid (9.8 g, 52% yield). 1H NMR (DMSO-d6) delta 8.33 (m, 1H); 8.09 (m, 1H); 7.07 (d, 1H).
Preparation 8 3-Bromo-4-methoxybenzenamine 2-Bromo-1-methoxy-4-nitrobenzene (2.50 g, 10.8 mmol), SnCl2.2H2O (12.2 g, 53.9 mmol), and MeOH (30 mL) were combined and allowed to stir for 3 h at ambient temperature. To the mixture was added H2O (100 mL) and EtOAc (100 mL) resulting in the formation of a thick emulsion. To this was added sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3*30 mL). The organics were combined and dried over MgSO4 before being filtered. Concentration of the filtrate in vacuo gave 2.02 g of an off-white solid. This material was used without further purification. In addition to bromo-anilines prepared according to preparation 8, non-limiting examples of commercially available bromo anilines and bromo nitrobenzenes are given in Table II.B-3.
With zinc; In N,N-dimethyl-formamide; at 90℃; for 22.0h;Inert atmosphere; Sealed tube;
To a vessel charged with 2-bromo-1-methoxy-4-nitrobenzene (lg, 4.31 mmol), zinc cyanide (0.506 g, 4.31 mmol), zinc (0.028 g, 0.43 1 mmol) and palladium tetrakis (0.174 g, 0.15 1 mmol) was added DMF (14.37 ml), and the mixture was sparged withargon for 20 mm. The vial was sealed and heated to 90 C overnight. After 22 h, the black solution was diluted with water and EtOAc. The organic phase was extracted, washed with brine, concentrated and purified by ISCO (80g, 0-100% EtOAc/Hexanes, 28 mm. Product at 50%) to provide Intermediate 3 12A (520mg, 2.92 mmol, 67.7 % yield) as an off-white solid. LC-MS. Method H, RT = 0.78 mm, MS (ESI) m/z: None Observed(M+H). ?H NIVIR (4001V11{z, CHLOROFORM-d) 8.49 (d, J=2.6 Hz, 1H), 8.48-8.43 (m, 1H), 7.10 (d, J=9.2 Hz, 1H), 4.08 (s, 3H).
tert-butyl ((1r,4r)-4-((2-methoxy-5-nitrophenyl)amino)cyclohexyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 120℃; for 16h;Sealed tube; Inert atmosphere;
To a stirred solution of 2-bromo-1-methoxy-4-nitrobenzene (2) (1.20 g, 5.60 mmol, 1.2 eq) in toluene (18 mL) in a sealed tube was added tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (Compound 114-01) (1.0 g, 4.67 mmol, 1.0 eq) and sodium tert-butoxide (672 mg, 7.0 mmol, 1.5 eq). The reaction mixture was degassed with argon for 20 min and then added Pd2(dba)3 (428 mg, 0.46 mmol, 0.1 eq) followed by BINAP (582 mg, 0.93 mmol, 0.2 eq) and heated at 120 C. for 16 h. After completion of reaction by TLC, the reaction mixture was filtered through Celite bed and the filtrate was concentrated to obtain crude product. The crude was purified by Grace flash chromatography [gradient elution with 20% Ethyl acetate/Hexane] to afford tert-butyl ((1r,4r)-4-((2-methoxy-5-nitrophenyl)amino)cyclohexyl)carbamate (Compound 114-02) (900 mg, yield: 53%). TLC system: EtOAc:Hexane (30:70), Rf value: ?0.5; LCMS (m/z): 366.2 (M+H)+; 1H NMR (400 MHz, CDCl3) delta 7.59 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 4.44 (brs, 1H), 4.28 (d, J=8.0 Hz, 1H), 3.94 (s, 3H), 3.50 (brs, 1H), 3.31-3.28 (m, 1H), 2.18-2.16 (m, 2H), 2.10-2.09 (m, 2H), 1.46 (s, 9H), 1.32-1.28 (m, 4H).
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