* 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] Journal of Organic Chemistry, 1980, vol. 45, # 8, p. 1546 - 1547
2
[ 53078-85-6 ]
[ 149-30-4 ]
[ 21303-50-4 ]
Reference：
[1] Patent: US2003/139390, 2003, A1,
3
[ 53078-85-6 ]
[ 2305-36-4 ]
Yield
Reaction Conditions
Operation in experiment
59%
With tert.-butyl lithium In hydrogenchloride; diethyl ether; water; pentane
a. 2-Amino-4-methylbenzoic acid To a cold (-78° C.) stirred solution of 2-bromo-5-methylaniline (10.0 g, 53.7 mM) in anhydrous ethyl ether (500 mL) under a nitrogen atmosphere was added t-butyllithium (127 mL of 1.7M solution, 214.8 mM) in pentane over a 15 min period during which time the temperature of the reaction was not allowed to exceed -65° C. After stirring at -78° C. for an additional 1.5 hr, the reaction mixture was quenched with an excess of crushed Dry Ice (solid CO2). After the Dry Ice had evaporated, water was added to the reaction mixture and the organic layer was separated and discarded. The aqueous layer was acidified with iN hydrochloric acid and then extracted with two portions of ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to provide the title amino acid (4.8 g, 59percent) as a tan crystalline solid; MS(CI): 152 (M+H).
Reference：
[1] Patent: US5599814, 1997, A,
4
[ 53078-85-6 ]
[ 7697-23-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
5
[ 53078-85-6 ]
[ 60956-23-2 ]
Reference：
[1] Journal of the Chemical Society, 1914, vol. 105, p. 514
6
[ 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
7
[ 5326-34-1 ]
[ 7439-89-6 ]
[ 53078-85-6 ]
Reference：
[1] Patent: US5202356, 1993, A,
8
[ 89-62-3 ]
[ 53078-85-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1942, vol. 550, p. 67,83
[2] Journal of the American Chemical Society, 1933, vol. 55, p. 1212,1215
[3] Justus Liebigs Annalen der Chemie, 1939, vol. 541, p. 283,290
[4] Journal of the American Chemical Society, 2011, vol. 133, # 16, p. 6166 - 6169
Stage #1: 2-bromo-5-methylaniline With hydrogenchloride; sodium nitrite In water at -10 - -5℃; for 1.16667h;
Stage #2: With potassium ethyl xanthogenate In water at 60℃; for 0.833333h;
Stage #3: With potassium hydroxide In ethanol for 18h; Reflux;
1.A Step A: Preparation of 2-bromo-5-methylbenzenethiol
To a suspension of 2-bromo-5-methylaniline (9.76 g, 52.5 mmol) in 8 mL of water was added 8.8 mL of concentrated HCl. The reaction mixture was cooled in an ice/NaCl bath (approximately -5 to -10 °C). Approximately 8 g of ice was added to the reaction mixture. A solution of NaNO2 (3.60 g, 52.3 mmol) in 16.2 mL of water was added slowly over 40 minutes. The solution was then stirred for an additional 30 minutes with cooling. Separately, a solution of potassium ethyl xanthogenate (10.1 g, 63.0 mmol) in 54 mL of water was prepared and heated to 60 °C. The cold solution of diazonium salt was then added slowly over 20 minutes to the solution of potassium ethyl xanthogenate. The reaction mixture was stirred for an additional 30 minutes at 60 °C, and then cooled to ambient temperature. It was then poured into a saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic extracts were washed with saturated brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. To this residue was added a solution of 1.8 M KOH/EtOH, and the reaction mixture was heated to reflux for 18 hours. The reaction mixture was then cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in water and extracted with diethyl ether. The aqueous phase was then acidified with concentrated HCl and extracted three times with dichloromethane. The combined organic extracts were dried over anhydrous MgSO4, filtered, concentrated, and purified by silica gel chromatography using 0-5% ethyl acetate/hexanes as eluent to provide 8.26 g (78%) of the title Compound as a pale yellow oil. 1H NMR (500 MHz, CDCl3( ^ ggd: 2.25-2.28 (m, 3H) 3.96 (s, 1H) 6.81 (d, J=8.03 Hz, 1H) 7.18 (d, J=1.89 Hz, 1H) 7.40 (d, J=8.20 Hz, 1H).
Stage #1: 2-bromo-5-methylaniline; glycerol With sulfuric acid; nitrobenzene In water at 150℃; for 3h;
Stage #2: With sodium hydroxide In water
36.2
Step 2:A mixture of compound 36b (3.3 g, 17.7 mmol), glycerin (3.3 g, 35.5 mmol), nitrobenzene (2.2 g, 17.7 mmol) and 75% aqueous sulfuric acid (10 mL, 138 mmol) is stirred at 1500C for 3 h (mixture turns black and viscous). The reaction mixture is cooled down, poured into ice-water (200 mL) and 10 N aqueous NaOH is added (30 mL, 300 mmol). The black mixture is then shaken with EtOAc (100 mL) and is centrifuged in 50 mL portions. The upper EtOAc layers are combined and the bottom aqueous layers containing the black tar are shaken with EtOAc and re-centrifuged. All EtOAc extracts are combined, washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give 4.8 g of a brown-red oil. This material is chromatographed on 80 g silica gel column (CombiFlash Companion apparatus, hexanes-EtOAc gradient). The fractions containing the compound are concentrated under vacuum to afford compound 36c as a white solid (3.26 g, 83% yield).
83%
Stage #1: 2-bromo-5-methylaniline; glycerol With sulfuric acid; nitrobenzene In water at 150℃; for 3h;
Stage #2: With sodium hydroxide In water at 0℃;
36.2
A mixture of compound 36b (3.3 g, 17.7 mmol), glycerin (3.3 g, 35.5 mmol), nitrobenzene (2.2 g, 17.7 mmol) and 75% aqueous sulfuric acid (10 ml_, 138 mmol) is stirred at 1500C for 3 h (mixture turns black and viscous). The reaction mixture is cooled down, poured into 200 ml. ice-water and 10 N aqueous NaOH is added (30 ml_, 300 mmol). The black mixture is then shaken with 100 ml. EtOAc and is centrifuged in 50 ml_ portions. The upper EtOAc layers are combined and the bottom aqueous layers containing the black tar are shaken with EtOAc and re-centrifuged. All EtOAc extracts are combined, washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give 4.8 g of a brown-red oil. This material is chromatographed on 80 g silica gel column (CombiFlash Companion apparatus, hexanes-EtOAc gradient). The fractions containing the compound are concentrated under vacuum to afford compound 36c as a white solid (3.26 g, 83% yield).
83%
Stage #1: 2-bromo-5-methylaniline; glycerol With sulfuric acid; nitrobenzene In water at 150℃; for 3h;
Stage #2: With sodium hydroxide In water at 0℃;
36.2
A mixture of compound 36b (3 3 g, 17 7 mmol), glycerin (3 3 g, 35 5 mmol), nitrobenzene (2 2 g, 17 7 mmol) and 75% aqueous sulfuric acid (10 mL, 138 mmol) is stirred at 15O0C for 3 h (mixture turns black and viscous) The reaction mixture is cooled down, poured into ice-water (200 mL) and 10 N aqueous NaOH is added (30 mL, 300 mmol) The black mixture is then shaken with EtOAc (100 mL) and is centrifuged in 50 mL portions The upper EtOAc layers are combined and the bottom aqueous layers containing the black tar are shaken with EtOAc and re-centϖfuged All EtOAc extracts are combined, washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give 4.8 g of a brown-red oil. This material is chromatographed on 80 g silica gel column (CombiFlash Companion apparatus, hexanes/EtOAc gradient). The fractions containing the compound are concentrated under vacuum to afford compound 36c as a white solid (3.26 g, 83% yield).
83%
Stage #1: 2-bromo-5-methylaniline; glycerol With sulfuric acid; nitrobenzene In water at 150℃; for 3h;
Stage #2: With sodium hydroxide In water
36.2
A mixture of compound 36b (3.3 g, 17.7 mmol), glycerin (3.3 g, 35.5 mmol), nitrobenzene (2.2 g, 17.7 mmol) and 75% aqueous sulfuric acid (10 ml_, 138 mmol) is stirred at 1500C for 3 h (mixture turns black and viscous). The reaction mixture is cooled down, poured into ice-water (200 ml.) and 10 N aqueous NaOH is added (30 ml_, 300 mmol). The black mixture is then shaken with EtOAc (100 ml.) and is centrifuged in 50 mL portions. The upper EtOAc layers are combined and the bottom aqueous layers containing the black tar are shaken with EtOAc and re-centrifuged. All EtOAc extracts are combined, washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give a brown-red oil. This material is chromatographed on 80 g silica gel column (CombiFlash Companion apparatus, hexane-EtOAc gradient). The fractions containing the compound are concentrated under vacuum to afford compound 36c as a white solid (3.26 g, 83% yield).
67%
With sulfuric acid; nitrobenzene at 150℃; for 3h;
52%
With nitrobenzene In sulfuric acid at 140℃; for 3h;
2.1 Step 1. 8-Bromo-5-methylquinoline
Step 1. 8-Bromo-5-methylquinoline: A suspension of 2-bromo-5-methylaniline (500 g, 2.69 mol), glycerin (519 g, 5.64mo1), and nitrobenzene (350. g, 2.85 mol) in sulfuric acid (1230 mL, 75%), split into two batches, was stirred at 140 °C for 3 h. After cooling to rt, the two batches were combined and poured into a solution of NaOH (7.5 L,10 M) in ice-water; the mixture was allowed to stand at rt overnight. The undissolved solids were then collected by filtration and dissolved in EtOAc (10 L). The resulting solution was washed with water (10 L) and brine (10 L), dried over Na2SO4, and evaporated. The obtained crude product was purified by column chromatography (EtOAc gradient in PE from 0% to 50%) to afford 8-bromo-5-methylquinoline as a whitesolid (640 g, 52%).
With sulfuric acid In water; nitrobenzene at 150℃; for 3h;
101 Synthesis of 8-bromo-5-methylquinoline (101 A) :
To a stirred solution of 2-bromo-5- methyl aniline (1200 g, 6.45 mol) in nitrobenzene (660 ml_) and 75% H2SO4 (3.6 L) was added glycerol (1180 g, 6.45 mol) at RT and then slowly heated to 150 °C for 3 h. Caution: highly exothermic reaction. The mixture was cooled to RT and poured into ice- water while maintaining the temperature below 10 °C. The pH was adjusted ~10 with aq. 10N NaOH and the product was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under vacuum to afford crude material. This material was dissolved in DCM/hexanes (5:1) and stirred for 30 minutes. The solid was filtered off and the filtrate was evaporated under reduced pressure to afford 101 A.
With sulfuric acid In nitrobenzene at 20 - 150℃; for 3h;
1 Example 1
Synthesis of 8-bromo-5-methylquinoline (1A): To a stirred solution of 2-bromo-5- methyl aniline (1200 g, 6.45 mol) in nitrobenzene (660 ml_) and 75% H2SO4 (3.6 L) was added glycerol (1180 g, 6.45 mol) at RT and then slowly heated to 150 °C for 3 h. The mixture was cooled to RT and poured into ice-water while maintaining the temperature below 10 °C. The pH was adjusted ~10 with aqueous 10N NaOH and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under vacuum to afford material that was dissolved in DCM/hexanes (5:1) and stirred for 30 minutes. The solid was filtered off and the filtrate was evaporated under reduced pressure to afford 1A. NBS, Benzene
General Procedure for Preparation of 2-Haloarylamides
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 triethylamine In tetrahydrofuran at 0 - 20℃; for 0.666667h;
2.2 General procedure for the preparation of N-(2-bromophenyl)-N-methylacylamides
General procedure: The procedure consists of two steps. First, to a stirred, cooled (0-5°C) solution of 2-bromoaniline (2.190g, 10mmol) and Et3N (1.113g, 1.55ml, 11mmol) in 20ml of dry THF, a solution of an appropriate acyl chloride (10mmol) in 5ml of dry THF was added dropwise within 10min. Then the ice bath was removed and the mixture was stirred vigorously for 30min at room temperature. Then, solid Et3NHCl was filtered off and washed with THF (3×5ml). The resulting organic fractions were combined and THF was removed under reduced pressure to yield crude amides. Recrystallization from hexane/CHCl3 and drying in vacuum afforded the analytically pure intermediate compounds: N-(2-bromophenyl)acylamides. In the second step, to a stirred suspension of NaH (0.132g; 5.5mmol) in 5ml of dry THF at 0°C the respective amide (5mmol) dissolved in 10ml of THF was added dropwise within 10min. The reaction mixture was stirred until the solution became clear (30min, hydrogen gas evolved), and the solution of MeI (0.923g; 0.405ml; 6.5mmol) in 5ml of THF was added dropwise within 10min. The solution was warmed up to room temperature and stirred for 3-8h. Then, the reaction mixture was quenched with water (30ml). The resulting solution was extracted with ethyl acetate (3×20ml). Combined organic layers were washed with brine (1×20ml) and dried over Na2SO4. Ethyl acetate was removed under reduced pressure to give crude 1a-r. Recrystallization from hexane and drying in vacuum afforded analytically pure compounds 1a-r. In the case of (1n) and (1o), the same procedure was conducted but instead of MeI, ethyl bromide and benzyl bromide were respectively used. In the case of (1p), 2-bromopyridin-3-amine was used instead of 2 bromoaniline. In the case of (1a-Cl) and (1a-I), the same procedure was conducted but instead 2-bromoaniline, 2-chloro- and 2-iodoaniline were respectively used.
Example 245 2-Mercapto -5-Methyl-benzothiazole (245) The title compound was prepared using the method of Example 239, starting with 2-bromo-5-methyl-phenylamine (244) (4.48 g, 24.0 mmol), O-ethylxanthic acid, potassium salt (Lancaster, 8.70 g, 54 mmol) in DMF (35 mL). The mercaptobenzothiazole 245 was obtained as an pale brown solid (2.31 g, 53%). 1H NMR (DMSO-d6) delta 13.70 (br s, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.15-7.10 (m, 2H), 2.38 (s, 3H). MS (M-H) 180.
N-Acetylation; General Procedure
General procedure: In a 50-mL, round-bottom flask, aniline (5.0 mmol, 1.0 equiv) was dissolved in CHCl3 (20 mL), followed by addition of DMAP (0.031 g, 0.25 mmol, 5 mol%). Ac2O (0.51 g, 5.0 mmol, 1.0 equiv) was added dropwise, and the mixture was stirred at reflux temperature (TLC monitoring) until completion. The mixture was cooled to r.t. and washed with distilled water. The organic layer was dried (anhyd MgSO4), followed by removal of solvent under reduced pressure to obtain the crude product, which was purified by flash chromatography (EtOAc/n-hexane).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 24h;Inert atmosphere; Reflux;
To a degassed solution of Pd2(dba)3 (21.7 mg, 1 mol %) and XANTPHOS (29.8 mg, 2.1 mol %) in dry dioxane (10 mL), Cs2CO3 (1.08 g, 3.31 mmol), <strong>[3964-04-3]4-bromoquinoline</strong> (500 mg, 2.40 mmol) and 2-bromo-5-methylaniline (490 mg, 2.63 mmol) were added. The flask was flushed with nitrogen and the mixture refluxed for 24 h under nitrogen. After cooling, the reaction mixture was filtered through Celite, washing with DCM (120 mL). The solvent was removed in vacuo and the residue purified by flash column chromatography eluting with DCM and EtOAc (50:50 increasing to 20:80). Off-white solid; yield 76% (572 mg). Mp 155-156 C. 1H NMR (600 MHz, CDCl3): delta 2.33 (3H, s, CH3), 6.84 (1H, dd, J = 8.4, 2.4 Hz, H-4'), 7.02 (1H, d, J = 5.4 Hz, H-3), 7.34 (1H, d, J = 2.4 Hz, H-6'), 7.52 (1H, d, J = 7.8 Hz, H-3'), 7.54 (1H, ddd, J = 8.4, 7.2, 1.2 Hz, H-6), 7.71 (1H, ddd, J = 8.4, 7.2, 1.2 Hz, H-7), 8.01 (1H, d, J = 8.4 Hz, H-8), 8.09 (1H, d, J = 8.4 Hz, H-5), 8.63 (1H, d, J = 4.8 Hz, H-2). 13C NMR (100 MHz, CDCl3): delta 21.3, 102.8, 114.5, 119.8, 120.8, 124.2, 126.3, 127.1, 128.3, 130.5, 133.3, 137.4, 139.0, 147.1, 148.4, 148.9. MS (EI): 218 (31), 231 (15), 232 (23), 233 (100), 234 (18), 312 (27), 314 (28). HRMS (EI): 312.0263 (C16H13N2Br [M]+ requires 312.0262).
With toluene-4-sulfonic acid; In toluene; for 3h;Reflux; Dean-Stark;
General procedure: Mixture of <strong>[1215071-17-2]tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate</strong> (200 mg, 0.85 mmol), 2-bromo anilines (2.33 mmol) and catalytic amount of para toluenesulfonic acid in toluene (20 mL) were reflux and the water was removed azeotropically using a Dean-Stark apparatus for 3 h. After completion of the reaction (TLC), the reaction mixture was concentrated in vacuo at nitrogen to give the product as a yellow liquid of (E)-tert-butyl 3,3-difluoro-4-(phenylimino)piperidine-1-carboxylate derivatives (8a-h). Each derivative (8a-h) was taken in seal tube with pyridine (10 mL) as solvent under nitrogen atmosphere, to this diisopropylethylamine (439.5 mg, 3.4 mmol) and bis(triphenylphosphine) palladium(II) dichloride (59.67 mg, 0.085 mmol) were added, and then the mixture was degassed with nitrogen and heated to 120 C for 16 h. The completion of the reaction was monitored by TLC and after being cooled to room temperature, the reaction mixture was concentrated in vacuo to give the crude product which was purified by column chromatography over silica gel (60-120 mesh) using 10-20% ethyl acetate and hexane as eluent to get pure product (9a-h).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In dimethyl sulfoxide at 110℃; for 6h;
2 5-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2):
5-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2): A solution of 2-bromo-5-methylani fine (1.5 g, 8.0 mmol) in dimethyl sulfoxide (20.0 mL) was treated with bis-pinacolatodiborane(2.4 g, 9.7mmol), potassium acetate (2.4 g, 24 mmol), and [1,1 'Bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (329 mg, 0.04 mmol) at 110 °C for 6 h. After completion of the reaction, the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to afford 2 (320 mg, 17%) as a pale yellow liquid. 1H NMR (400 MHz, DMSO-d6): δ 1.26 (s, 12H), 2.13 (s, 3H), 5.37 (s, 2H), 6.29 (d, J = 7.5 Hz, 1H), 6.37 (s, 1H), 7.23 (d, J = 7.5 Hz, 1H). MS m/z (M+H): 234.2
Stage #1: 2-bromo-5-methyl-phenylamine With hydrogenchloride In lithium hydroxide monohydrate at 25℃; for 0.333333h; Inert atmosphere;
Stage #2: With NaNO2 In lithium hydroxide monohydrate at -5℃; for 1h; Inert atmosphere;
Stage #3: bis(cyclopentadienyl) iron(II) With aminosulfonic acid; anhydrous Sodium acetate In dichloromethane; lithium hydroxide monohydrate at 25℃; for 12h; Inert atmosphere; Schlenk technique;
2. Synthesis of 2-Bromoarylferrocene1-5
General procedure: Step 1: 2-Bromoaniline (1.03 g, 6 mmol; 1 equiv.) was dissolved in 25 mL distilled water at room temperature and 12 M hydrogen chloride (8 mL, 96 mmol; 16 equiv.) was dropwise over 20 minutes to the mixture. The resulting reaction mixture was cooled down to -5 °C using an ice bath. Sodium nitrite (0.49 g, 7.2 mmol; 1.2 equiv.) was dissolved in 1.5 mL water and cooled down to -5 °C, which was added dropwise to the main reaction mixture. The resulting mixture was stirred for 1.0 hours at -5°C. Finally, sulfamic acid (0.69 g, 7.2 mmol; 1.2 equiv.) and dichloromethane (30 mL) were added to the reaction mixture sequentially at room temperature. Step 2: To another dried 250 mL Schlenk flask equipped with a stirring bar was charged with ferrocene (1.12 g, 6 mmol; 1 equiv.) and sodium acetate (0.98 g, 7.2 mmol; 1.2 equiv.). This flask was closed with a plug, evacuated, back-filled with nitrogen. Next, The reaction mixture of Step 1 was added to the mixture of ferrocene and sodium acetate. The resulting mixture was stirred at room temperature overnight. The reaction was extracted with dichloromethane. The combined organic phase was washed with brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the crude product was obtained purified by column chromatography (PE) to give the 2-bromophenylferrocene 1a as orange solid.
Stage #1: 2-bromo-5-methyl-phenylamine With hydrogenchloride; lithium hydroxide monohydrate; NaNO2 at -5 - 20℃; for 1h; Inert atmosphere;
Stage #2: bis(cyclopentadienyl) iron(II) With aminosulfonic acid; anhydrous Sodium acetate In dichloromethane at 20℃; for 12h; Inert atmosphere;
Stage #1: 2-bromo-5-methyl-phenylamine With hydrogenchloride; NaNO2 In lithium hydroxide monohydrate at -5 - 20℃; Inert atmosphere;
Stage #2: bis(cyclopentadienyl) iron(II) With sulfur trioxide * ammonia; anhydrous Sodium acetate In dichloromethane; lithium hydroxide monohydrate at 20℃; Inert atmosphere;
5-methyl-N,N-dimethyl-2-benzothiazolamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium <i>tert</i>-butylate; copper(I) bromide In tetrahydrofuran at 60℃; for 4h; Schlenk technique;
General procedure for synthesis of 2-aminobenzothiazoles derivatives (3a-i)
General procedure: A mixture of 2-iodoanilines (1.0 mmol), THF (3 mL), and t-BuOK (3 mmol) was stirred in a 10-mL sealed Schlenk tube for 5 min, and then dimethylthiocarbamoyl chloride (1.2 mmol) and CuBr (10 mol %) were added. The reaction mixture was heated at 60 °C until completion as indicated by TLC. Then the mixture was cooled down to room temperature and quenched with sat. NH4Cl solution (5 mL). The aqueous phase was extracted with EtOAc (3 x10 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure. The obtained crude product was purified by flash column chromatography.
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