* 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] Organic and Biomolecular Chemistry, 2016, vol. 14, # 44, p. 10511 - 10515
[2] Patent: CN106631968, 2017, A,
2
[ 5326-34-1 ]
[ 56341-38-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 44, p. 10511 - 10515
[2] Patent: CN106631968, 2017, A,
3
[ 5326-34-1 ]
[ 118-97-8 ]
Reference：
[1] American Chemical Journal, 1897, vol. 19, p. 14
4
[ 5326-34-1 ]
[ 7697-23-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
5
[ 99-08-1 ]
[ 7149-70-4 ]
[ 5326-34-1 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1885, vol. 231, p. 187
6
[ 27329-27-7 ]
[ 5326-34-1 ]
Yield
Reaction Conditions
Operation in experiment
69%
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium bromide In dimethyl sulfoxide at 160℃; for 24 h; Schlenk technique
Silak reaction tube equipped with a magnetic stirrer was charged with 6.2 mg of silver sulfate,36.3 mg of copper acetate, 12.5 mg of 2,9-dimethyl-1,10-o-phenanthroline,36.2 mg of 2-nitro-4-methylbenzoic acid and 30.9 mg of sodium bromide4 mL of dimethyl sulfoxide.The reaction was heated at 160 ° C for 24 hours in the presence of oxygen.After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases are concentrated,29.8 mg of 2-nitro-4-methylbromobenzene was obtained in a yield of 69percent.
Reference：
[1] Patent: CN107325002, 2017, A, . Location in patent: Paragraph 0091
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 30, p. 5416 - 5421
[3] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2794 - 2803
7
[ 89-62-3 ]
[ 5326-34-1 ]
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
[2] Justus Liebigs Annalen der Chemie, 1871, vol. 158, p. 344
[3] Justus Liebigs Annalen der Chemie, 1939, vol. 541, p. 283,290
[4] Justus Liebigs Annalen der Chemie, 1942, vol. 550, p. 67,83
[5] Journal of the American Chemical Society, 1933, vol. 55, p. 1212,1215
[6] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1976, vol. 30, p. 141 - 149
[7] Journal of the Chemical Society, 1929, p. 1255
[8] Journal of Organic Chemistry, 1977, vol. 42, p. 2426 - 2431
[9] Canadian Journal of Chemistry, 2005, vol. 83, # 3, p. 213 - 219
[10] Journal of the American Chemical Society, 2011, vol. 133, # 16, p. 6166 - 6169
8
[ 106-38-7 ]
[ 5326-34-1 ]
[ 60956-26-5 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1980, # 11, p. 513 - 514
9
[ 99-08-1 ]
[ 7149-70-4 ]
[ 5326-34-1 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1885, vol. 231, p. 187
10
[ 106-38-7 ]
[ 5326-34-1 ]
[ 60956-26-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[2] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
[3] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[4] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
[5] Journal of the American Chemical Society, 1953, vol. 75, p. 3275
11
[ 106-38-7 ]
[ 108-24-7 ]
[ 5326-34-1 ]
[ 60956-26-5 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1980, # 11, p. 513 - 514
12
[ 106-38-7 ]
[ 5326-34-1 ]
Reference：
[1] Australian Journal of Chemistry, 1977, vol. 30, p. 113 - 121
13
[ 612-45-3 ]
[ 5326-34-1 ]
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
14
[ 106-38-7 ]
[ 5326-34-1 ]
[ 60956-26-5 ]
[ 75508-75-7 ]
Reference：
[1] Canadian Journal of Chemistry, 1986, vol. 64, p. 2382 - 2387
15
[ 106-38-7 ]
[ 108-24-7 ]
[ 5326-34-1 ]
[ 60956-26-5 ]
[ 75508-75-7 ]
Reference：
[1] Canadian Journal of Chemistry, 1986, vol. 64, p. 2382 - 2387
16
[ 106-38-7 ]
[ 7697-37-2 ]
[ 5326-34-1 ]
[ 60956-26-5 ]
Reference：
[1] Journal of the Chemical Society, 1932, p. 1884,1885, 1888
17
[ 5326-34-1 ]
[ 6319-40-0 ]
Yield
Reaction Conditions
Operation in experiment
48.6%
With pyridine; hydrogenchloride; potassium permanganate In water
Reference Example 34 4-Bromo-3-nitrotoluene (25.3 g, 0.117 mol) was added to a mixed solution of pyridine and water (1:1, 300 mL), and potassium permanganate (36.9 g, 0.234 mol) was added thereto over 5 hours while the solution was stirred under heat at 50°C. Then, excess potassium permanganate was quenched with methanol. The reaction mixture was concentrated under reduced pressure; the residue obtained was washed with ether and dissolved in water; and aqueous 4 N hydrochloric acid solution was added thereto until the solution becomes acidic, allowing precipitation of solid. The crude product was recrystallized from methanol and water, to obtain 4-bromo-3-nitrobenzoic acid (14.0 g, 48.6percent) as pale yellow needle crystals. 1H-NMR(CDCl3) δ:7.89(1H,d,J=8.3Hz),B.12(1H,dd,J=8.3,2.0Hz), 8.53(1H,d,J=1.95Hz)ppm FABMS:247(M+1)
Reference：
[1] Patent: EP1820799, 2007, A1,
[2] Patent: WO2006/51851, 2006, A1, . Location in patent: Page/Page column 59
[3] Chemistry - A European Journal, 2012, vol. 18, # 3, p. 880 - 886
[4] Justus Liebigs Annalen der Chemie, 1867, vol. 143, p. 241
18
[ 5326-34-1 ]
[ 53078-85-6 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 100℃; for 12.3333 h;
Production Example 1 Synthesis of 2-bromo-5-methylaniline 4-Bromo-3-nitrotoluene (60.35 g, 279 mmol), 5percent by weight platinum carbon (1.09 g, 0.28 mmol) and triethylamine (112.93 g, 1116 mmol) were stirred under heating at 100° C., to which formic acid (99percent) (42.39 g, 921 mmol) was added dropwise over 20 minutes. After stirring for 12 hours, it was brought back to room temperature, and then 100 ml of ethyl acetate and 100 ml of water were added thereto. After stirring well, it was filtered through celite to remove platinum carbon. By further adding 200 ml of ethyl acetate and 100 ml of water, it was extracted, the organic phase was washed with water (300 ml*3 times), and dried on magnesium sulfate. The solvent was evaporated to obtain 2-bromo-5-methylaniline (51.30 g, 276 mmol). The yield was 99percent. 1H-NMR (270 MHz, CDCl3) δ(ppm): 7.260 (1H, d), 6.583 (1h
97.5%
With hydrogenchloride; sodium hydroxide; stannous chloride In ethanol
Reference Example 36 A conc. hydrochloric acid solution (45 mL) containing stannous chloride (21.6 g, 114 mmol) was added to an ethanol solution (60 mL) containing 4-bromo-3-nitrotoluene (5 g, 23.1 mmol) while the mixture was cooled on an ice bath. The reaction solution was stirred at 60°C for 0.5 hour. After the reaction was completed, ethanol was evaporated under reduced pressure, and 12 N aqueous sodium hydroxide solution was added to the aqueous solution until pH 12 or more. The aqueous solution was extracted with ether; the organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, to obtain 2-bromo-5-methylaniline (4.21 g, 97.5percent) as a pale yellow solid. 1H-NMR (CDCl3) δ: 2.22 (3H, s), 2.73-4.79 (2H,br), 6.44 (1H, dd, J=8.06, 2.2Hz), 6.59 (1H, d, J=1.5Hz), 7.23-7.29(1H,m) ppm FABMS:187(M+1)
97.4%
With hydrazine hydrate In methanol at 20℃; for 2 h;
Example 123[0328] (S)-2-(2-(3-ethyl-2,4-dimethyl- lH-indol- 1 -yl)acetamido)-N-(6-methoxypyridin-3- yl)-N-methyl-3-phenylpropanamideExample 123A. Preparation of 2-bromo-5-methylbenzenamine[0329] To a solution of bromo-4-methyl-2-nitrobenzene (5 g, 23.3 mmol, 1.0 eq) in MeOH, was added Ranney Nickel (2 mL). The mixture was stirred for 15 minutes, and hydrazine hydrate (2.33 g, 46.6 mmol, 2 eq) was added dropwise. The resulting mixture was stirred for 2 hours at room temperature Then the reaction mixture was filtered, the filtrate was concentrated under vacuum. The residue was washed with H20 (2x30 mL), extracted with EtOAc (2x20 mL). The combined organic extracts were evaporated to afford 2-bromo- 5-methylbenzenamine (4.2 g, 22.7 mmol, yield: 97.4percent), LC/MS: m/z M++l = 186.
78%
Stage #1: With tin(ll) chloride In ethyl acetate at 70 - 100℃; for 2 h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
Step 1 :4-bromo-3-nitrotoluene 36a (5.0 g, 22.9 mmol) is dissolved in 50 ml_ ethyl acetate and solid tin(ll) chloride dihydrate (20.0 g, 86.9 mmol) is added. The mixture is heated under nitrogen atmosphere at 7O0C for 2 h (note: temporary overheating to 1000C is observed. Caution should be exercised.). The mixture is cooled down and is poured into 200 ml. of ice-water. 50 ml. of 5percent aqueous NaHCO3 solution is <n="91"/>added (rapid foaming.), followed by 10 N aqueous NaOH to bring the pH ~ 7-8. Large volume of gelatinous yellowish precipitate is formed. This heterogeneous mixture is shaken with EtOAc (200 ml_) and the mixture is centrifuged in 50 mL portions, resulting in good separation of a yellowish solid. The clear supernatant is decanted and is extracted with EtOAc. Combined organic phase is washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum to give an orange oily residue. This residue is re-dissolved in 100 mL of ether and the solution is washed with 10percent Na2CO3 (20 mL) followed by 2.5 M aqueous NaOH (20 mL). The dark brown organic solution is then stirred with MgSO4 and active charcoal and filtered to give a light yellow solution, which darkened rapidly on standing in open flask. The solvent is removed under vacuum to give the desired compound 36b as a brown-red oil which is used in the next step without further purification (3.31 g, 78percent yield).
78%
With water; tin(ll) chloride In ethyl acetate at 70℃; for 2 h;
4-bromo-3-nitrotoluene 36a (5.0 g, 22.9 mmol) is dissolved in 50 mL ethyl acetate and solid tin(ll) chloride dihydrate (20.0 g, 86.9 mmol) is added. The mixture is heated under nitrogen atmosphere at 700C for about 2 h (note: temporary overheating to 1000C is observed. Caution should be exercised.). The mixture is cooled down and is poured into 200 mL of ice-water. 50 mL of 5percent aqueous NaHCO3 solution is added (rapid foaming.), followed by 10 N aqueous NaOH to bring the pH to about 7-8. Large volume of gelatinous yellowish precipitate is formed. This heterogeneous mixture is shaken with 200 mL EtOAc and the mixture is centrifuged in 50 mL portions, resulting in good separation of a yellowish solid. The clear supernatant is decanted and is extracted with EtOAc. Combined organic phase is washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum to give an orange oily residue. This residue is re-dissolved in 100 mL of ether and the solution is washed with 10percent Na2CO3 (20 mL) followed by 2.5 M aqueous NaOH (20 mL). The dark brown organic solution is then stirred with MgSO4 and active charcoal and filtered to give a light yellow solution, which <n="101"/>13-152darkened rapidly on standing in open flask. The solvent is removed under vacuum to give the desired compound 36b as a brown-red oil which is used in the next step without further purification (3.31 g, 78percent yield).
78%
Stage #1: With tin(ll) chloride In ethyl acetate at 70 - 100℃; for 2 h; Stage #2: With sodium hydroxide; water; sodium hydrogencarbonate In ethyl acetate
4-bromo-3-nιtrotoluene 36a (5 0 g, 22 9 mmol) is dissolved in ethyl acetate (50 mL) and solid tιn(ll) chloride dihydrate (20 0 g, 86 9 mmol) is added The mixture is heated under nitrogen atmosphere at 700C for 2 h (note temporary overheating to 1000C is observed) The mixture is cooled down and is poured into ice-water (200 mL) 5percent aqueous NaHCO3 (50 mL) solution is added (rapid foaming), followed by 10 N aqueous NaOH to bring the pH ~ 7-8 Large volume of gelatinous yellowish precipitate is formed This heterogeneous mixture is shaken with EtOAc (200 mL) and the mixture is centrifuged in 50 mL portions, resulting in good separation of a yellowish solid The clear supernatant is decanted and is extracted with EtOAc Combined organic phase is washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum to give an orange oily residue This residue is re- dissolved in 100 mL of ether and the solution is washed with 10percent Na2CO3 (20 mL) followed by 2 5 M aqueous NaOH (20 mL) The dark brown organic solution is then stirred with MgSO4 and active charcoal and filtered to give a light yellow solution, which darkened rapidly on standing in open flask The solvent is removed under vacuum to give the desired compound 36b as a brown-red oil which is used in the next step without further purification (3 31 g, 78percent yield)
78%
Stage #1: With tin(ll) chloride In ethyl acetate at 70℃; for 2 h; Stage #2: With sodium hydroxide; sodium hydrogencarbonate In water; ethyl acetate
4-bromo-3-nitrotoluene 36a (5.0 g, 22.9 mmol) is dissolved in 50 ml. ethyl acetate and solid tin(ll) chloride dihydrate (20.0 g, 86.9 mmol) is added. The mixture is heated under nitrogen atmosphere at 7O0C for 2 h (note: temporary overheating to 1000C is observed. Caution should be exercised.). The mixture is cooled down and is poured into 200 ml_ of ice-water. 5percent aqueous NaHCO3 (50 ml.) solution is added (rapid foaming.), followed by 10 N aqueous NaOH to bring the pH ~ 7-8. Large volume of gelatinous yellowish precipitate is formed. This heterogeneous mixture is shaken with EtOAc (200 ml_) and the mixture is centrifuged in 50 ml. portions, resulting in good separation of a yellowish solid. The clear supernatant is decanted and is extracted with EtOAc. Combined organic phase is washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum to give an orange oily residue. This residue is re-dissolved in 100 mL of ether and the solution is washed with 10percent Na2CO3 (20 mL) followed by 2.5 M aqueous NaOH (20 mL). The dark brown organic solution is then stirred with MgSO4 and active charcoal and filtered to give a light yellow solution, which darkened rapidly on standing in open flask. The <n="104"/>solvent is removed under vacuum to give the desired compound 36b as a brown-red oil which is used in the next step without further purification (3.31 g, 78percent yield).
77%
With ammonium chloride; zinc In 1,4-dioxane; water at 20℃; for 3 h;
2-bromo-5-methylaniline (1): To a solution of l-bromo-4-methyl-2-nitrobenzene (3.0 g, 13.8 mmol) in dioxane/water (1 : 1; 60 mL), zinc dust (9 g, 138.8 mmol) was added followed by the addition of ammonium chloride (7.3 g, 138.8 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2 (2 g, 77percent) as a pale yellow liquid. 1H NMR (400 MHz, DMSO-d6): δ 2.12 (s, 3H), 5.14 (s, 2H), 6.28 (dd, J = 1.7, 8.0 Hz, 1H), 6.58 (s, 1H), .16 (d, J = 8.0 Hz, 1H). MS m/z (M+H): 186.3
68%
With hydrogenchloride; iron In methanol; water at 20℃; for 168 h; Heating / reflux
Add iron powder (7.75 g, 138 mmol), concentrated HC1 (1 mL) and water (10 mL) to a solution of commercially available 4- bromo-3-nitrotoluene (10 g, 46 mmol) in methanol (200 mL) at room temperature under nitrogen and heat the mixture at reflux for 168 h. Remove the solvents under reduced pressure, suspend the residue in 0.1 N NAOH (350 mL) and extract with chloroform (3 x 300 mL). Dry the combined organic extracts over MGS04 and remove the solvents under reduced pressure to afford to afford 2-bromo-5- methylphenylamine (Step 1) as an amber oil (5.87 g, 68percent): 1H NMR (CDC13) 5 2.20 (s, 3H), 4.00 (br s, 2H), 6.40 (d, 1H), 6.60 (s, 1H), 7.20 (d, 1H).
Reference：
[1] Patent: US2003/191325, 2003, A1, . Location in patent: Page/Page column 8
[2] Patent: EP1820799, 2007, A1,
[3] Patent: WO2006/51851, 2006, A1, . Location in patent: Page/Page column 59-60
[4] Patent: WO2012/65062, 2012, A1, . Location in patent: Page/Page column 89-90
[5] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
[6] Patent: WO2009/62285, 2009, A1, . Location in patent: Page/Page column 89-90
[7] Patent: WO2009/62308, 2009, A1, . Location in patent: Page/Page column 99-100
[8] Patent: WO2009/62288, 2009, A1, . Location in patent: Page/Page column 97
[9] Patent: WO2009/62289, 2009, A1, . Location in patent: Page/Page column 102-103
[10] Patent: WO2014/149164, 2014, A1, . Location in patent: Paragraph 001109
[11] Patent: WO2004/63155, 2004, A1, . Location in patent: Page 134-135
[12] Justus Liebigs Annalen der Chemie, 1939, vol. 541, p. 283,290
[13] Justus Liebigs Annalen der Chemie, 1942, vol. 550, p. 67,83
[14] Journal of the American Chemical Society, 1933, vol. 55, p. 1212,1215
[15] Chemische Berichte, 1880, vol. 13, p. 963[16] Chemische Berichte, 1881, vol. 14, p. 417
[17] Patent: US2003/139390, 2003, A1,
[18] Angewandte Chemie - International Edition, 2007, vol. 46, # 39, p. 7509 - 7512
[19] Journal of the American Chemical Society, 2011, vol. 133, # 16, p. 6166 - 6169
[20] Dalton Transactions, 2018, vol. 47, # 48, p. 17401 - 17411
19
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[ 7439-89-6 ]
[ 53078-85-6 ]
Reference：
[1] Patent: US5202356, 1993, A,
20
[ 106-38-7 ]
[ 5326-34-1 ]
[ 60956-26-5 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1980, # 11, p. 513 - 514
21
[ 106-38-7 ]
[ 5326-34-1 ]
[ 60956-26-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[2] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
[3] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[4] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
[5] Journal of the American Chemical Society, 1953, vol. 75, p. 3275
22
[ 106-38-7 ]
[ 108-24-7 ]
[ 5326-34-1 ]
[ 60956-26-5 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1980, # 11, p. 513 - 514
23
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[ 60956-26-5 ]
[ 75508-75-7 ]
Reference：
[1] Canadian Journal of Chemistry, 1986, vol. 64, p. 2382 - 2387
24
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[ 108-24-7 ]
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[ 60956-26-5 ]
[ 75508-75-7 ]
Reference：
[1] Canadian Journal of Chemistry, 1986, vol. 64, p. 2382 - 2387
25
[ 106-38-7 ]
[ 7697-37-2 ]
[ 5326-34-1 ]
[ 60956-26-5 ]
Reference：
[1] Journal of the Chemical Society, 1932, p. 1884,1885, 1888
26
[ 5326-34-1 ]
[ 452-74-4 ]
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
27
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[ 42872-83-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1939, vol. 541, p. 283,290
With potassium fluoride; copper(I) iodide In N,N-dimethyl-formamide
Step A 2-Nitro-4-methylbenzotrifluoride A mixture of 6.00 g (27.8 mmol) of 4-bromo-3-nitrotoluene, 5.86 mL (8.03 g, 55.6 mmol) of methyl chlorodifluoroacetate, 1.93 g (33.4 mmol) of potassium fluoride, 5.31 g (27.8 mmol) of cuprous iodide, and 25 mL of dry DMF was stirred at 110° C. for 2 days. The cooled material was diluted with aqueous citric acid and extracted 3* with ethyl acetate. The combined organic extracts were washed with H2 O, then with brine, and dried over anhydrous Na2 SO4. The residue obtained upon concentration of the filtered solution was flash chromatographed 3* on silica gel (elution with 100:1 and 25:1 hexane-EtOAc) to give 3.25 g (57percent) of the title compound as a yellow liquid; homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (EI) m/e 205 (M+). 400 MHz 1 H NMR (CDCl3) δ2.48 (s, 3H), 7.49 (d, J=8 Hz, 1H), 7.67 (s, 1H) overlapping 7.68 (d, J=8 Hz, 1H).
In tetrahydrofuran; at -60 - -30℃; for 1h;Inert atmosphere;
To a solution of 1-bromo-4-methyl-2-nitro-benzene (40.0 g, 185 mmol, 25.3 mL) in tetrahydrofuran (400 mL) was added bromo(vinyl)magnesium (1 M, 611 mL) at -60 OC under nitrogen gas atmosphere. The reaction mixture was then stirred at -30 OC for 1 hour. On completion, the reaction mixture was quenched with saturated ammonium chloride solution (150 mL), followed with water (100 mL). The mixture was concentrated in vacuo to remove the tetrahydrofuran. The residue was extracted with ethyl acetate (2×500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by column chromatography (petroleum ether:ethyl acetate=100:1) to give the title compound (18.0 g, 42% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) delta 11.27 (br s, 1H), 7.37 (t, J=2.8 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 6.75 (dd, J=0.8, 7.6 Hz, 1H), 6.57 (dd, J=1.6, 3.2 Hz, 1H), 2.44 (s, 3H).
With ammonium chloride; In tetrahydrofuran; ethyl acetate;
Production Example 7 7-Bromo-4-methyl-1H-indole To 300 ml of a solution of 65.0 g (301 mmol) of 2-bromo-5-methylnitrobenzene in tetrahydrofuran was added 1 liter of a 1.0M solution of vinyl magnesium bromide (1 mol) in tetrahydrofuran at -60 C. in a nitrogen atmosphere under stirring during 1 hour. To the reaction mixed solution were added a saturated aqueous solution of ammonium chloride and ethyl acetate, and the resulting insoluble matters were filtered off. The resulting filtrate was dried over magnesium sulfate, concentrated, and then the resulting residue was purified by a silica gel column chromatography to give 35.5 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm); 2.42(3H,s), 6.55(1H,s) 6.73(1H,d,J=7.6 Hz), 7.16(1H,d,J=7.6 Hz), 7.35(1H,s), 1 11.24(1H,brs)
With ammonium chloride; In tetrahydrofuran; ethyl acetate;
PRODUCTION EXAMPLE 7 7-Bromo-4-methyl-1H-indole 1 l (1 mol) of a tetrahydrofuran solution containing 1.0 M vinylmagnesium bromide was added to a tetrahydrofuran solution (300 ml) containing 65.0 g (301 mmol) of 2-bromo-5-methylnitrobenzene at -60 C. under stirring for one hour in nitrogen atmosphere. An aqueous saturated ammonium chloride and ethyl acetate were added to the reaction mixture solution, and the insoluble matters were filtered off. The filtrate was dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel column chromatography, to give 35.5 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm): 2.42(3H, s), 6.55(1H, s), 6.73(1H, d, J=7.6 Hz), 7.16(1H, d, J=7.6 Hz), 7.35(1H, s), 11.24(1H, br s)
In tetrahydrofuran; at -50℃; for 1.5h;
(4-methyl-1 H-indol-7-yl)(phenyl)methanamine - To a solution of 1 -bromo-4-methyl-2-nitrobenzene (2.0 g, 9.26 mmol) in THF was added vinyl magnesium bromide 1 M in THF (27.8 ml_, 27.77 mmol) at - 50C. The reaction was finished after 1 h30. The reaction was quenched with sat. NH4CI. The aqueous layer was extracted with a non-water miscible organic solvent. The combined organic layers were dried over MgS04, filtered and the solution was concentrated to dryness. The crude material was purified on silica gel column chromatography usinf hexanes/EtOAc (9:1 ) as eluent. A solution of the freshly synthesized 7-bromo-4-methyl-1 H-indole (1 .1 g, 5.24 mmol), zinc cyanide (860 mg, 7.32 mmol) and Pd(PPh3)4 (0.03 eq.) in DMF Ex.97 was heated under microwave irradiation at 170C for 1 h. After cooling, water was added to quench the reaction. The aqueous layer was extracted with a non-water miscible organic solvent. The combined organic layers were dried over MgS04, filtered and the solution was concentrated under reduced pressure. The crude material was purified on silica gel column chromatography using hexanes/EtOAc (12:1 to 4:1 ) as eluent. The titled compound was then obtained following the modified procedure described in WO2006035157 (Protocol A) - Yield: 2% ; appearance: pale brown solid ; 1 H NMR, d (ppm) (Methanol d4) : 2.49 (s, 3H); 5.51 (s, 1 H); 6.47 (d, 1 H, J=3.2Hz); 6.81 (dd, 1 H, J=0.6Hz , J=7.3Hz); 7.01 (d, 1 H, J=7.3Hz); 7.17-7.22 (m, 2H); 7.25-7.31 (m, 2H); 7.39- 7.43 (m, 2H)
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane;Inert atmosphere; Reflux;
General procedure: To a stirred solution of 2-fluoro-5-methyl-3-nitropyridine 4a (3.0 g, 19.22 mmol) in carbon tetrachloride (80 mL) were added azodiisobutyronitrile (316 mg, 1.90 mmol) and N-bromosuccinimide (3.76 g, 21.14 mmol). The reaction mixture was heated at reflux for 48 h under an argon atmosphere and then the contents were cooled to room temperature. The insoluble solid was removed by filtration, the filtrate was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate (30 mL×4) and brine (20 mL×2), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/dichloromethane/ ethyl acetate = 15:1:1) to give the title compound 5a (1.8 g, 35.5%). White solid; mp 73-75 C; 1H NMR (400 MHz, CDCl3) delta (ppm): 8.56 (d, J = 8.4 Hz, 1H), 8.50 (s, 1H), 4.52 (s, 2H)
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; at 75℃; for 18h;Heating / reflux;
To a well-stirred mixture consisting of 4-bromo-3-nitrotoluene (4.0 g, 18.5 MMOL) in tetrahydrofuran (145 ML), diethyl-3-pyridylborane (3.12 g, 21 mmol), and bis (TRIPHENYLPHOSPHINE) PALLADIUM (II) CHLORIDE (1.94 g, 2.8 mmol), a solution of sodium carbonate (9.8 g, 92.5 MMOL) in water (50 ML) was added. The reaction mixture was heated to 75C for 18 hours. The organic layer of the biphasic mixture was dried (anhydrous sodium sulfate), and the solvent was removed in vacuo to afford an oil (7.0 g). Flash chromatography of the entire sample (silica gel, 47-61 micron mesh; elution with ethyl acetate/hexanes = 1 : 1 in volume) afforded the title compound (2.58 g, 65% yield) as a light yellow foam. TLC Rf (silica gel plates ; elution with ethyl acetate/hexanes = 1 : 1 in volume, UV detection): 0.51. MS m/z 215 (M+1).13C NMR (125 MHz, CDCI3) delta 148. 4,147. 9,140. 3,136. 4,134. 3,133. 9,132. 1,130. 1, 125.2, 123.6, 21.1 ppm
With potassium fluoride; copper(I) iodide; In N,N-dimethyl-formamide;
Step A 2-Nitro-4-methylbenzotrifluoride A mixture of 6.00 g (27.8 mmol) of 4-bromo-3-nitrotoluene, 5.86 mL (8.03 g, 55.6 mmol) of methyl chlorodifluoroacetate, 1.93 g (33.4 mmol) of potassium fluoride, 5.31 g (27.8 mmol) of cuprous iodide, and 25 mL of dry DMF was stirred at 110 C. for 2 days. The cooled material was diluted with aqueous citric acid and extracted 3* with ethyl acetate. The combined organic extracts were washed with H2 O, then with brine, and dried over anhydrous Na2 SO4. The residue obtained upon concentration of the filtered solution was flash chromatographed 3* on silica gel (elution with 100:1 and 25:1 hexane-EtOAc) to give 3.25 g (57%) of the title compound as a yellow liquid; homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (EI) m/e 205 (M+). 400 MHz 1 H NMR (CDCl3) delta2.48 (s, 3H), 7.49 (d, J=8 Hz, 1H), 7.67 (s, 1H) overlapping 7.68 (d, J=8 Hz, 1H).
With palladium(II) trifluoroacetate; caesium carbonate; tricyclohexylphosphine In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 15h; Schlenk technique; Sealed tube; Inert atmosphere;
With palladium(II) trifluoroacetate; caesium carbonate; tricyclohexylphosphine In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 15h; Schlenk technique; Inert atmosphere; chemoselective reaction;
With palladium(II) trifluoroacetate; caesium carbonate; tricyclohexylphosphine In 5,5-dimethyl-1,3-cyclohexadiene at 110℃; for 15h; Inert atmosphere;
9.1
trifluoroacetic acid palladium (0.025mmol, 8 mg), three-ring hexyl phosphine (0.05mmol, 14 mg, cesium carbonate (0.75mmol, 244 mg) and 1b (0.5mmol, 108 mg) is put into the 25 ml reaction tube, sufficient vacuum, nitrogen (three times). Under the protection of nitrogen injected through the syringe 2b (1.5mmol, 219 mg), xylene 3 ml. In 110 °C pot oil bath stirring 15h, after cooling to room temperature the temperature of the reaction system by adding 20 ml water, add 25 ml ethyl acetate extraction, grass-roots takes has saturated salt water for washing, for Na2 SO4 Drying, then adding a small amount of silica gel turns on lathe the main column chromatography.
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium bromide; In dimethyl sulfoxide; at 160℃; for 24h;Schlenk technique;
Silak reaction tube equipped with a magnetic stirrer was charged with 6.2 mg of silver sulfate,36.3 mg of copper acetate, 12.5 mg of 2,9-dimethyl-1,10-o-phenanthroline,36.2 mg of <strong>[27329-27-7]2-nitro-4-methylbenzoic acid</strong> and 30.9 mg of sodium bromide4 mL of dimethyl sulfoxide.The reaction was heated at 160 C for 24 hours in the presence of oxygen.After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases are concentrated,29.8 mg of 2-nitro-4-methylbromobenzene was obtained in a yield of 69%.
5-methoxy-2-(4-methyl-2-nitrophenylthio)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.1 g
Stage #1: 2-Amino-5-methoxybenzoic acid With hydrogenchloride; sodium hydroxide; sodium nitrite In water at -10℃; for 1h; Inert atmosphere;
Stage #2: With potassium ethyl xanthogenate In water at 80℃; for 0.5h; Inert atmosphere;
Stage #3: 4-Bromo-3-nitrotoluene With sodium ethanolate In ethanol for 16h; Reflux; Inert atmosphere;
4.1.8. 5-Methoxy-2-(4-methyl-2-nitrophenylthio)benzoic acid (11)
To a solution of 2-amino-5-methoxybenzoic acid (4.0 g, 24 mmol) in50% aqueous sodium hydroxide (2.6 mL, 47 mmol) was added a solutionof NaNO2 (1.6 g, 24 mmol) in water (1.5 mL). The resulting mixturewas poured into a solution of HCl (concd, 8.2 mL, 94 mmol) at-10 °C. The reaction was stirred under N2 for 1 h and then neutralizedby addition of potassium acetate to pH = 5-6. The mixture was carefullyadded to a solution of potassium O-ethyl dithiocarbonate(KS2COEt, 11.5 g, 72.0 mmol,) in water (50 mL) and stirred at 80 °Cunder N2 for 30 min. The solution was acidified by concd HCl to pH = 2-3, extracted with IPA/EtOAc (1/7, 400 mL × 3) and the organiclayer was evaporated. Toluene was added to the crude mixture forazeotropic removal of residual water and a brown solid was obtained.To the solution of the brown solid in EtOH (115 mL), a solution ofEtONa (52.2 mmol) in ethanol (55 mL) and 1-bromo-4-methyl-2-nitrobenzene(6.22 g, 28.8 mmol) were added in sequence. The mixturewas refluxed under N2 for 16 h. After cooled to rt, the solvent wasevaporated and then water (400 mL) was added to the crude residue.The resulting mixture was acidified by concd HCl in a ice bath, and thenextracted with IPA/EtOAc (1/7, 400 mL × 3). The organic layer waswashed with brine, dried over MgSO4, filtered, and evaporated. Theresidue was chromatographed (silica gel, HOAc/EtOAc/n-hexane = 1/50/50) to afford 11 (4.1 g, 54%) as a yellow solid. 1H NMR (200 MHz,DMSO-d6) δ 2.35 (s, 3H), 3.80 (s, 3H), 6.84 (d, J = 8.3 Hz, 1H), 7.17(dd, J = 8.6, 2.9 Hz, 1H), 7.36-7.52 (m, 3H), 8.01-8.02 (m, 1H), 13.33(bs, 1H, eCOOH); 13C NMR (50 MHz, DMSO-d6) δ19.9, 55.7, 115.3,118.1, 121.3, 125.2, 130.0, 133.5, 135.0, 136.7, 137.6, 138.2, 146.0,160.0, 167.5; ESIHRMS calcd for C15H12NNa2O5S [M-H + 2Na]+,364.0232; found, 364.0231.
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium carbonate In ethylene glycol dimethyl ether; ethanol; lithium hydroxide monohydrate for 8h; Inert atmosphere; Reflux;
4.2.21 5-(4-methyl-2-nitrophenyl)furan-2-carbaldehyde (13a)
General procedure: 1-bromo-4-methyl-2-nitrobenzene (200mg, 926μmol) and (5-formylfuran-2-yl)boronic acid (155mg, 1.11mmol) were mixed in 2mL dimethoxyethane, 1mL ethanol and 1mL water followed by the addition of Pd(PPh3)2Cl2 (65mg, 92.6μmol) and K2CO3 (256mg, 1.85mmol). The mixture was heated at reflux under the protection of nitrogen for 8h and then cooled to room temperature. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic phase was dried over anhydrous Na2SO4 and concentrated to give a crude product, which was purified by silica gel column chromatography to get 82mg, yield: 38.3%.
38.3%
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium carbonate In ethylene glycol dimethyl ether; ethanol; lithium hydroxide monohydrate for 8h; Inert atmosphere; Reflux;
4.2.21 5-(4-methyl-2-nitrophenyl)furan-2-carbaldehyde (13a)
General procedure: 1-bromo-4-methyl-2-nitrobenzene (200mg, 926μmol) and (5-formylfuran-2-yl)boronic acid (155mg, 1.11mmol) were mixed in 2mL dimethoxyethane, 1mL ethanol and 1mL water followed by the addition of Pd(PPh3)2Cl2 (65mg, 92.6μmol) and K2CO3 (256mg, 1.85mmol). The mixture was heated at reflux under the protection of nitrogen for 8h and then cooled to room temperature. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic phase was dried over anhydrous Na2SO4 and concentrated to give a crude product, which was purified by silica gel column chromatography to get 82mg, yield: 38.3%.
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