* 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] Yakugaku Zasshi, 1928, vol. 48, p. 74[2] Chem. Zentralbl., 1928, vol. 99, # II, p. 53
[3] Patent: WO2011/67272, 2011, A1, . Location in patent: Page/Page column 81
[4] Patent: US2012/238517, 2012, A1, . Location in patent: Page/Page column 38
[5] Journal of Organic Chemistry, 2014, vol. 79, # 11, p. 5379 - 5385
[6] Chemistry - A European Journal, 2016, vol. 22, # 32, p. 11165 - 11169
[7] Organic Letters, 2017, vol. 19, # 8, p. 2086 - 2089
2
[ 39478-78-9 ]
[ 51436-99-8 ]
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
3
[ 39478-78-9 ]
[ 31543-75-6 ]
Reference：
[1] Chemische Berichte, 1880, vol. 13, p. 963[2] Chemische Berichte, 1881, vol. 14, p. 417
[3] Journal of the Chemical Society, 1914, vol. 105, p. 514
[4] Chemische Berichte, 1880, vol. 13, p. 963[5] Chemische Berichte, 1881, vol. 14, p. 417
4
[ 39478-78-9 ]
[ 20776-50-5 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1935, vol. 7, p. 436,443
5
[ 39478-78-9 ]
[ 36138-76-8 ]
Yield
Reaction Conditions
Operation in experiment
51%
Stage #1: With sulfuric acid In water at 90℃; for 4.5 h; Stage #2: With sulfuric acid; sodium nitrite In water at 0 - 90℃; for 1 h;
5-Bromo-2-methylphenol; A solution of concentrated sulphuric acid (6 mL) in distilled water (75 mL) was added to 5-bromo-2-methylaniline (1 g, 5.38 mmol). The resultant suspension was heated to 90° C. and stirred for 4.5 h. The reaction mixture was then cooled using an ice bath and a solution of sodium nitrite (384 mg, 5.57 mmol) in water (5 mL) was added to the reaction mixture at 0° C. The reaction was then allowed to warm to ambient temperature. The reaction mixture was then added to a solution of concentrated sulphuric acid (6 mL) in water (75 mL) which had been preheated to 90° C. The reaction mixture was stirred for 1 h at 90° C. and allowed to cool, on standing, overnight. A precipitate was observed in the reaction mixture. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to afford 5-bromo-2-methylphenol as a brown solid (510 mg, 2.73 mmol, 51percent). M.S. (ESI) (m/z) 185, 187[M-H]-
51%
Stage #1: at 90℃; for 4.5 h; Stage #2: at 0 - 90℃;
A solution of concentrated sulphuric acid (6ml_) in distilled water (75ml_) was added to 5- bromo-2-methylaniline (1g, 5.38mmol). The resultant suspension was heated to 9O0C and stirred for 4.5h. The reaction mixture was then cooled using an ice bath and a solution of sodium nitrite (384mg, 5.57mmol) in water (5ml_) was added to the reaction mixture at O0C. The reaction was then allowed to warm to ambient temperature. The reaction mixture was then added to a solution of concentrated sulphuric acid (6ml_) in water (75ml_) which had been preheated to 9O0C. The reaction mixture was stirred for 1 h at 9O0C and allowed to cool, on standing, overnight. A precipitate was observed in the reaction mixture. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to afford 5-bromo-2-methylphenol as a brown solid (510mg, 2.73mmol, 51 percent). M.S. (ESI) (m/z) 185, 187[M-H]-
Reference：
[1] Patent: US2007/185156, 2007, A1, . Location in patent: Page/Page column 8-9
[2] Patent: WO2007/63071, 2007, A1, . Location in patent: Page/Page column 19
[3] Justus Liebigs Annalen der Chemie, 1913, vol. 398, p. 366
[4] Dissertation <Marburg 1912>, S. 21,
[5] Journal of the Chemical Society, 1926, p. 2038
[6] Molecules, 2011, vol. 16, # 9, p. 8053 - 8061
6
[ 39478-78-9 ]
[ 350-28-7 ]
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
7
[ 39478-78-9 ]
[ 260558-15-4 ]
Yield
Reaction Conditions
Operation in experiment
67%
at 0 - 80℃; for 0.5 h;
Intermediate 64-Bromo-2-iodo-1-methylbenzene; The synthesis of Intermediates 6 is shown in Scheme 4 and full experimental details are shown below.Stage 1-4-bromo-2-iodo-1-methylbenzeneTo a solution of 2-methyl-5-bromo aniline (1.5 g, 8.06 mmol) in di-iodo methane (3.4 ml) at 0° C. was slowly added tert-butyl nitrite (1.6 ml, 12.1 mmol). The ice bath was removed and the reaction was stirred at RT then heated at 80° C. for 30 minutes. The solvent was removed under reduced pressure and the residue purified by column chromatography (EtOAc/Heptane) to afford the title compound (1.6 g, 67percent yield).LCMS: m/z 297 [M+H]+. 1H NMR (300 MHz, CDCl3) δ: 7.96 (1H, s), 7.42-7.35 (1H, m), 7.12 (1H, d, J=8.1 Hz), 2.40 (3H, s).
67%
at 0 - 80℃;
Stage 1- 4-bromo-2-iodo-1-methylbenzeneTo a solution of 2-methyl-5-bromo aniline (1.5 g, 8.06 mmol) in di-iodo methane (3.4 ml) at 00C was slowly added tert-butyl nitrite (1.6 ml, 12.1 mmol). The ice bath was removed and the reaction was stirred at RT then heated at 800C for 30 minutes. The solvent was removed under reduced pressure and the residue purified by column chromatography (EtOAc/ Heptane) to afford the title compound (1.6 g, 67percent yield). LCMS: m/z 297 [M+H]+. 1H NMR (300 MHz, CDCI3) δ: 7.96 (1 H, s), 7.42-7.35 (1 H, m), 7.12 (1 H, d, J=8.1 Hz), 2.40 (3H, s).
45%
Stage #1: With sulfuric acid; sodium nitrite In water at 0℃; for 0.75 h; Stage #2: With sodium iodide In water at 20℃; for 1 h;
4-bromo-2-amino-toluene (10.0g, 53 . 7mmol) suspended in 30percent sulfuric acid (100 ml) in addition added dropwise sodium nitrite (3.89g, 56 . 4mmol) the aqueous solution (15 ml) Stirring at 0 °C for 45 minutes , then the sodium iodide (12.1g, 80 . 6mmol) dissolved in water (50 ml) in, in the aqueous solution of the above-mentioned diazonium salt solution is added. Further stirring at room temperature 1 hour, the ethyl ester of acetic acid 3 times after extraction, the saturated salt water to the acetic acid ethyl ester level to 1 times of cleaning, by means of magnesium sulfate to dry, reducing concentrated. Subsequently, by means of silica gel column purification (hexane) to obtain the target compound (9.0g, 45percent).
Reference：
[1] Patent: US2011/39920, 2011, A1, . Location in patent: Page/Page column 10
[2] Patent: WO2009/130434, 2009, A1, . Location in patent: Page/Page column 21
[3] Patent: TW2016/9616, 2016, A, . Location in patent: Paragraph 0161
8
[ 60956-26-5 ]
[ 39478-78-9 ]
Yield
Reaction Conditions
Operation in experiment
93%
With stannous chloride hydrate In ethyl acetate at 30℃;
First, into a 250-mL round-bottom flask, was placed 4-bromo-1-methyl-2-nitrobenzene (5 g, 23.14 mmol, 1.00 equiv), ethyl acetate (100 mL), SnCl2.H2O (20 g). The resulting solution was stirred overnight at 30° C. The pH value of the solution was adjusted to 10 with sodium hydroxide (5 mol/L). The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×50 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 4 g (93percent) of 5-bromo-2-methylaniline as brown oil.
92%
With iron; ammonium chloride In water for 48.5 h; Heating / reflux
The mixture of iron powder (9. 31g, 167 mmol) and [NH4C1] (2.48g, 46.3 mmol) in water (50 mL) was refluxed for 30 minutes. To this hot mixture was added 4-bromo-2-nitrotoluene (10 g, 46.3 mmol) slowly and then the reaction mixture was refluxed for 48 hours. The mixture was cooled to room temperature and extracted with EtOAc (3 x 100 mL). The organic solution was washed with [H20] (3 x 200 mL) and brine (200 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, 15percent EtOAc in hexanes) to give 7.9g (92percent) of title compound as a pale yellow [OIL.APOS;H] nuclear magnetic resonance (NMR) [(CDC13)] : 300 MHz [6] 6.88 (m, [1H),] 6.81 (m, 2H), 3.63 (bs, 2H), 2.09 (s, 3H).
80.7%
With tin(ll) chloride In ethyl acetate at 0 - 80℃; for 4.16667 h;
Example 1 5-BROMO-8-METHYL-1-PROPYL-3, 4-DIHYDRO-LH-BENZOTHIENO [2, 3-CLPYRAN-1- yl] acetic acid 5-BROMO-2-METHYLANILINE [0082] 4-bromo-2-nitrotoluene (25.0 g, 0.1157 mol) in EtOAc (250 mL) was cooled to 0°C. Tin (IN chloride dihydrate (87.76 g, 0.4623 mol) was then added portionwise over 10 min while stirring. The reaction mixture was allowed to come to room temperature and then refluxed at 80°C for 4 h. The mixture was cooled to 0°C and neutralized with 5 N NAOH while stirring. EtOAc layer was filtered and remaining portions were extracted with EtOAc. The organic solution was washed with brine, dried with Na2SO4, and concentrated. The residue was purified by flash chromatography (silica, 10percent ETOAC in hexanes) to give 17. 367 g (80.7percent) of the ANILINE.
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 19, p. 3116 - 3127
[2] Patent: US2015/366198, 2015, A1, . Location in patent: Paragraph 0132
[3] Journal of Medicinal Chemistry, 2004, vol. 47, # 26, p. 6603 - 6608
[4] Patent: WO2003/99824, 2003, A1, . Location in patent: Page 23
[5] Patent: US6337351, 2002, B1, . Location in patent: Example 14
[6] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
[7] Patent: WO2005/16932, 2005, A1, . Location in patent: Page/Page column 33
[8] Journal of Chemical Research - Part S, 2000, # 6, p. 290 - 291
[9] Synlett, 1998, # 9, p. 1028 - 1028
[10] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 9, p. 955 - 977
[11] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1869, vol. 69, p. 477[12] Zeitschrift fuer Chemie, 1869, p. 636
[13] Justus Liebigs Annalen der Chemie, 1870, vol. 154, p. 294
[14] Justus Liebigs Annalen der Chemie, 1871, vol. 158, p. 340
[15] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[16] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
[17] Collection of Czechoslovak Chemical Communications, 1935, vol. 7, p. 436,443
[18] Helvetica Chimica Acta, 1946, vol. 29, p. 872,876
[19] Patent: US2008/200471, 2008, A1, . Location in patent: Page/Page column 34
[20] ChemMedChem, 2016, vol. 11, # 23, p. 2607 - 2620
[21] Patent: WO2018/52903, 2018, A1, . Location in patent: Page/Page column 81
Reference：
[1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
12
[ 39478-78-9 ]
[ 60710-80-7 ]
Yield
Reaction Conditions
Operation in experiment
75%
With 2-(2-methoxyphenyl)-1-methyl-3-(diphenylphosphino)-1H-indole; potassium <i>tert</i>-butylate; triethylamine; bis(dibenzylideneacetone)-palladium(0) In dichloromethane; water; acetonitrile at 50℃; for 24 h; Inert atmosphere
General procedure: An oven-dried Schlenk tube with the presence of magnetic stir bar which is Teflon-coated was charged with Pd(dba)2 (11.5 mg, 0.02 mmol, 2 molpercent) and ligand L4 (8.4 mg, 0.02 mmol, 2 molpercent). The flask was evacuated and backfilled with nitrogen (3 cycles). Pre-complexation of palladium and ligand was initiated by injecting freshly distilled dry dichloromethane (2.0 mL) and Et3N (0.1 mL) into the tube. The solution was stirred and warmed with hair drier till the solvent condensed on the tube wall. The solvent was removed under vacuum. Aryl bromide (1.0 mmol), KOt-Bu (0.25 mmol), and potassium hexacyanoferrate(II) trihydrate (0.23 mmol) were charged successively to the tube followed by another 3 evacuation-nitrogen refill cycles. Water (1.0 mL) and acetonitrile (1.0 mL) were used as a solvent mixture. The tube was immersed into a preheated 50 °C oil bath for 24 hours. The reaction was quenched by cooling to ambient temperature and added with EtOAc and water. The organic supernatant was analyzed by GC. The organic layer was separated and the remained aqua medium was further extracted with EtOAc (10 mL .x. 3). The combined organic phases were concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (230-400 mesh). The pure fractions were collected, dried under vacuum, and followed by proton (1H) and carbon (13C) NMR characterization
With stannous chloride hydrate; In ethyl acetate; at 30℃;
First, into a 250-mL round-bottom flask, was placed 4-bromo-1-methyl-2-nitrobenzene (5 g, 23.14 mmol, 1.00 equiv), ethyl acetate (100 mL), SnCl2.H2O (20 g). The resulting solution was stirred overnight at 30 C. The pH value of the solution was adjusted to 10 with sodium hydroxide (5 mol/L). The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×50 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 4 g (93%) of 5-bromo-2-methylaniline as brown oil.
92%
With iron; ammonium chloride; In water; for 48.5h;Heating / reflux;
The mixture of iron powder (9. 31g, 167 mmol) and [NH4C1] (2.48g, 46.3 mmol) in water (50 mL) was refluxed for 30 minutes. To this hot mixture was added 4-bromo-2-nitrotoluene (10 g, 46.3 mmol) slowly and then the reaction mixture was refluxed for 48 hours. The mixture was cooled to room temperature and extracted with EtOAc (3 x 100 mL). The organic solution was washed with [H20] (3 x 200 mL) and brine (200 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, 15% EtOAc in hexanes) to give 7.9g (92%) of title compound as a pale yellow [OIL.'H] nuclear magnetic resonance (NMR) [(CDC13)] : 300 MHz [6] 6.88 (m, [1H),] 6.81 (m, 2H), 3.63 (bs, 2H), 2.09 (s, 3H).
80.7%
With tin(ll) chloride; In ethyl acetate; at 0 - 80℃; for 4.16667h;
Example 1 5-BROMO-8-METHYL-1-PROPYL-3, 4-DIHYDRO-LH-BENZOTHIENO [2, 3-CLPYRAN-1- yl] acetic acid 5-BROMO-2-METHYLANILINE [0082] 4-bromo-2-nitrotoluene (25.0 g, 0.1157 mol) in EtOAc (250 mL) was cooled to 0C. Tin (IN chloride dihydrate (87.76 g, 0.4623 mol) was then added portionwise over 10 min while stirring. The reaction mixture was allowed to come to room temperature and then refluxed at 80C for 4 h. The mixture was cooled to 0C and neutralized with 5 N NAOH while stirring. EtOAc layer was filtered and remaining portions were extracted with EtOAc. The organic solution was washed with brine, dried with Na2SO4, and concentrated. The residue was purified by flash chromatography (silica, 10% ETOAC in hexanes) to give 17. 367 g (80.7%) of the ANILINE.
With ammonium chloride; acetic acid; zinc; In ethanol; water; at 60℃; for 2h;
Synthesis of 5-bromo-2-methylbenzenamine Into a 1000 mL round-bottom flask, was placed 4-bromo-1-methyl-2-nitrobenzene (40 g, 185.19 mmol). To this was added ammonium chloride (199 g, 3.69 mol). Addition of zinc (120 g, 1.85 mol) was next. This was followed by the addition of a solution of EtOH (500 g) in H2O (100 mL). To the mixture was added acetic acid (40 mL). The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at 60 C. in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). A filtration was performed. The filtrate was concentrated by evaporation. A filtration was performed again. This resulted in 20 g (58%) of 5-bromo-2-methylbenzenamine as a brown solid.
With iron; ammonium chloride; In ethanol; water; at 80℃; for 2h;
Step 1 : To the solution of 4-bromo-2-riitrotoiuene (8.00 g, 37.03mmol) in 100 mL of ethanol and 100 mL of H20 were added NhUCi (19.8 g, 370.3 mmol) and Fe (14.4 g, 259.2 mmol). The reaction was stirred at 80 "C for 2h. The completion of the reaction was monitored by HPLC. Upon completion, the reaction mixture was filtered over Celite. The cake was washed with MeOH and the filtrated was concentrated in vacuo. To the crude residue was added H2O and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous aHCOs, brine and dried over ajSO . Filtration and removal of the solvent in vacuo provided 5-brorno-2-rnethyfanil.ine as a light yellow oil, which was used without further purification; 1H NMR (400 MHz, CDCia) delta = 6-99 - 6,82 (m, 3 H), 4.47 (br. s., 2 H), 2, 15 (s, 3 H).
5-Bromo-2-methylphenol; A solution of concentrated sulphuric acid (6 mL) in distilled water (75 mL) was added to 5-bromo-2-methylaniline (1 g, 5.38 mmol). The resultant suspension was heated to 90 C. and stirred for 4.5 h. The reaction mixture was then cooled using an ice bath and a solution of sodium nitrite (384 mg, 5.57 mmol) in water (5 mL) was added to the reaction mixture at 0 C. The reaction was then allowed to warm to ambient temperature. The reaction mixture was then added to a solution of concentrated sulphuric acid (6 mL) in water (75 mL) which had been preheated to 90 C. The reaction mixture was stirred for 1 h at 90 C. and allowed to cool, on standing, overnight. A precipitate was observed in the reaction mixture. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to afford 5-bromo-2-methylphenol as a brown solid (510 mg, 2.73 mmol, 51%). M.S. (ESI) (m/z) 185, 187[M-H]-
51%
A solution of concentrated sulphuric acid (6ml_) in distilled water (75ml_) was added to 5- bromo-2-methylaniline (1g, 5.38mmol). The resultant suspension was heated to 9O0C and stirred for 4.5h. The reaction mixture was then cooled using an ice bath and a solution of sodium nitrite (384mg, 5.57mmol) in water (5ml_) was added to the reaction mixture at O0C. The reaction was then allowed to warm to ambient temperature. The reaction mixture was then added to a solution of concentrated sulphuric acid (6ml_) in water (75ml_) which had been preheated to 9O0C. The reaction mixture was stirred for 1 h at 9O0C and allowed to cool, on standing, overnight. A precipitate was observed in the reaction mixture. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to afford 5-bromo-2-methylphenol as a brown solid (510mg, 2.73mmol, 51 %). M.S. (ESI) (m/z) 185, 187[M-H]-
With sulfuric acid; In nitrobenzene; at 150℃; for 3h;
A solution of <strong>[39478-78-9]5-Bromo-2-methylaniline</strong> (7.44 g), glycerol (7.4 g), nitrobenzene (4.9 g) in 15 75% sulfuric acid (20 ml) was heated at 150C for 3 hrs. The solution was cooled to 0C then carefully neutralized with aqueous sodium hydroxide. The reaction mixture became a dark gum and was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, then dried with sodium sulphate and the solvent removed in vacuo. The crude product was purified by column20 chromatography (dichloromethane) to afford the title compound as a solid (6g). 1H-NMR (CDC13, 400 MHz) 8.91 (m, 1H), 8.51 (m, 1H), 7.7 (m, 1H), 7.50 (m, 1H), 7.4 (m, 1H), 2.72 (s, 3H).
Step A: 5-Bromo-8-methyl-quinoline A solution of <strong>[39478-78-9]5-Bromo-2-methylaniline</strong> (7.44 g), glycerol (7.4 g), nitrobenzene (4.9 g) in 75% sulfuric acid (20 ml) was heated at 150 C. for 3 hrs. The solution was cooled to 0 C. then carefully neutralized with aqueous sodium hydroxide. The reaction mixture became a dark gum and was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, then dried with sodium sulphate and the solvent removed in vacuo. The crude product was purified by column chromatography (dichloromethane) to afford the title compound as a solid (6 g). 1H-NMR (CDCl3, 400 MHz) 8.91 (m, 1H), 8.51 (m, 1H), 7.7 (m, 1H), 7.50 (m, 1H), 7.4 (m, 1H), 2.72 (s, 3H).
Step A: N-(5-bromo-2-methylphenyl)-3,3-dimethylbutanamide 3,3-Dimethylbutanoyl chloride (1.0 g, 5.4 mmol) was added to a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (0.796 g, 5.9 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to yield the title compound (0.9 g, 60%) as a white powder.
5-bromo-2-methyl-phenylhydrazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
To a suspension [OF 5-BROMO-2-METHYLANILINE] (4.80g, 25.8 mmol) in concentrated [HCL] (16 mL) was added dropwise a solution of sodium nitrite (1.96 g, 28.4 mmol) in water (10 mL) over 30 minutes at [0C.] To the mixture was added dropwise a solution [OF SNCL2W2H2O] (17.46g, 77.4 mmol) in concentrated [HCL] (15 mL) over 50 minutes. After stirring for 1 hour at [0C,] the reaction mixture was basified with 50% NaOH (30 mL). The mixture was further diluted with water (20 mL) and treated with another [50% NAOH] (10 mL) and then crushed ice (100 g). The reaction mixture was extracted with ether (3 x 100 mL) and the combined organic phases were washed with brine, dried over [NA2SO4,] and filtered. The filtrate was acidified by adding an anhydrous solution of [HC1] in ether [(1] N in ether, 31 mL, 31 mmol). The precipitate was collected and dried under reduced pressure to give 4.57 g (75%) of title compound as a white amorphous solid. 'H NMR (DMSO): 300MHz510. 31 (bs, 3H), 8.11 (bs, 1H), 7.12 (s, [IH),] 7.06 [(M,] 2H), 2.14 (s, 3H).
To a solution of 3-BROMO-6-METHYLANILINE (1.00 g, 5.37 mmol) in pyridine (8 ML) was added acetyl chloride (0.76 mL, 10.7 mmol) at 0 C. The reaction mixture was stirred at room temperature for 1 hour and concentrated. The residue was extracted with EtOAc, washed with 5% citric acid, dried over MgS04, concentrated, and triturated with ether to give 0.750 g (61%) of the desired product as off-white crystal. MS (DCI/NH3) m/z : 227. 9 (M+H) +, 229. 9 (M+2+H) +; 1H NMR (300 MHz, CDC13) o 2.21 (s, 6 H), 6.90 (m, 1 H), 7. Q4 (d, J=8. 14 Hz, 1 H), 7. 20 (d, J=7. 80 Hz, 1 H), 8. 06 (s, 1 H).
To a suspension of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (14.85 g, 79.8 mmol) in 15.5 mL of water was added 13.3 mL of concentrated HCl. The reaction mixture was cooled in an ice/NaCl bath (approximately -5 to -10 C). Approximately 15 g of ice was added to the reaction mixture. A solution of NaNO2 (5.51 g, 79.82 mmol) in 16.2 mL of water was added slowly over 10 minutes. The solution was stirred for an additional 30 minutes with cooling. Separately, a solution of potassium ethyl xanthate (15.4 g, 95.8 mmol) in 25 mL of water was prepared and heated to 65 C. The cold solution of diazonium salt was then added slowly over 20 minutes to the warmed solution of potassium ethyl xanthogenate. The reaction mixture was stirred for an additional 30 minutes at 65 C and then cooled to ambient temperature. It was then poured into saturated NaHCO3, extracted thrice with diethyl ether. The combined organic extracts were washed with saturated brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. A solution of 1.8M KOH/EtOH was added to the residue and the mixture was heated to reflux for 18 hours. It was then cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in water and extracted with diethyl ether. The aqeuous was then acidified with concentrated HCl and extracted thrice with diethyl ether. The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated to give 11.8 g (73 %) of the title Compound as a dark oil.1H NMR (500 MHz, CHLOROFORM-d( ^ ggd 1-15 'j+ 3 H) 3.34 (s, 1 H) 6.98 - 7.03 (m, 1 H) 7.15 - 7.20 (m, 1 H) 7.38 - 7.43 (m, 1 H).
72.7%
5-Bromo-2-methylbenzenethiol [0083] A solution of sodium nitrite (6.42 g, 0. 0930 mol) in water (18 mL) was added over 30 min to an ice cooled solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (17.302 g, 0.0930 mol) in 35% HC1 (14.2 mL, 0.1860 mol) containing ice, while potassium ethyl xanthate was prepared by rapid stirring of a mixture OF KOH (6.26 g, 0.1116 mol), ethanol (13.0 mL), water (23.3 mL), and carbon disulfide (12.75 g, 0.1674 mol) for 2.5 h. The prepared potassium ethyl xanthate was slowly added to the solution of 5-bromo-2-methylbenzenediazonium salt at 0C. After the addition, the mixture was heated at 50-55C for 30 min, cooled, and then extracted with ether. The organic phase was dried with NA2S04 and concentrated. The residue was refluxed with KOH (27.9 g, 0.4976 mol) in ethanol for 10 h, neutralized with 10% HCI, and extracted with ether. The organic phase was dried with NA2S04, concentrated, and the residue was purified by flash chromatography (silica, 100% hexanes) to give 13.75 g (72.7%) of the 5- bromo-2-methylbenzenethiol.
5-bromo-2-methylphenyldiazonium tetrafluoroborate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of sodium nitrite (4.08 g, 53.7 mmol, 1.10 equiv) in water (40 mL) was added slowly to a pre-cooled (-10 C) mixture of finely powdered <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (6-1, 10.0 g, 54.5 mmol, 1 equiv) and concentrated aqueous hydrochloric acid solution (12 M, 13.4 mL, 161 mmol, 3.00 equiv) in water (70 mL) at a rate that kept the reaction mixture temperature below 0 C. Following the addition, the reaction mixture was stirred at -5 C for 30 min, then filtered. A solution of sodium tetrafluoroborate (17.7 g, 161 mmol, 3.00 equiv) in water (50 mL) was immediately added to the cold filtrate. The precipitate was filtered and washed with ice-cold water (30 mL). The remaining solid was air-dried to give 5-bromo-2-methylbenzenediazonium tetrafluoroborate as a white solid. A suspension of this product (15.0 g, 52.7 mmol, 1 equiv), potassium acetate (12.9 g, 132 mmol, 2.50 equiv) and 18- crown-6 (1.39 g, 5.27 mmol, 0.100 equiv) in chloroform (300 mL) was stirred at 23 C for 20 h. The reaction mixture was filtered and concentrated. The residue was partitioned between water and EtOAc (500 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 6-bromo-1H-indazole (6-2) as a tan solid. 1H NMR (300 MHz, CDCl3) delta 10.20 (br s, 1H), 8.06 (br s, 1H), 7.70 (s, 1H), 7.63 (d, 1H, J = 8.5 Hz), 7.29 (dd, 1H, J = 8.5, 1.5 Hz).
1.90 g
With tetrafluoroboric acid; sodium nitrite; In water; at 0 - 20℃; for 0.5h;
[0409] Sodium nitrite (0.56 g) in water(2.0 mL) was slowly added to a mixture of <strong>[39478-78-9]2-methyl-5-bromoaniline</strong> (1.50g) intetrafluoroboric acid (6.0 mL) and water (4.0 mL) at 0-5 C. After addition, the reaction was stirred at room temperaturefor 30 min. The mixture was cooled to 0 C, filtered, washed with cold water, cold methanol and ether. The mixture wasthen dried to provide the product 5-bromo-2-methylphenyldiazonium tetrafluroborate (1.90 g).
2,6-bis-[1-(5-bromo-2-methylphenylimino)-ethyl]-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
toluene-4-sulfonic acid; In toluene; for 72h;Heating / reflux;
1-(6-Acetyl-pyridin-2-yl)ethanone [8.33 g (0.051 mol)], 20.0 g (0.107 mol) of 5-bromo-2-methyl-pheny.amine and 200 ml of dry toluene with a few crystals of para-toluenesulfonic acid were refluxed under the flow of the nitrogen using a Dean-Stark trap for 3 d until the calculated <n="20"/>amount of the water was separated (1.84 mi). The solvent was removed in a rotary evaporator and the resultant reaction mixture was recrystallized from 50 ml of ethanol. The yield of 26 was 19.88 g (78%) as a pale yellow solid. 1H NMR (500 MHz, C6D6, TMS): delta 1.90 (s, 6 H, Me), 2.12 (s, 6 H, Me), 6.50 (m, 2H, Arom-H), 7.20 (m, 4H, Arom-H), 7.30 (t, 3JHH=7.8 HZ, 1 H1 Py-H), 8.40 (d, 3JHH=7.8 HZ, 2H, Py-H). 13C NMR (500 MHz, C6D6, (selected signals)): delta 167.4 (C=N). Anal. Calculated for C23H2IBr2N3 (MoI. Wi: 499.24): C, 55.33; H, 4.24; N, 8.42. Found: C, 55.48; H, 4.45; N, 8.53.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 24h;Heating / reflux;
Tetrakis(triphenylphosphine)palladium (0) (3.7 g, 0.003 mol) and 4-chlorophenylboronic acid (20.2 g, 0.13mol) are added to a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (20 g, 0.1 mol) in 1 ,2- dimethoxyethane (200 ml). After stirring the reaction mixture for 15 minutes at 2O0C, a solution of 20% aqueous sodium carbonate (300ml) is added to the mixture, and the resulting mixture is heated at reflux for 24 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 3-amino-4'-chloro-4-methylbiphenyl (21.0 g).
Example 1; Preparation of (1RS.2SR.6RS.7Sf?)-4-(4'-chloro-4-methylbiphen-3-yl)-10- oxatricyclof5.2.1.02'6ldec-8-ene-3.5-dione.; Step 1 : Preparation of 3-amino-4'-chloro-4-methylbiphenyl.; Tetrakis(triphenylphosphine)palladium (0) (3.7 g, 3 mmol) and 4-chlorophenylboronic acid (20.2 g, 0.13 mol) are added to a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (20 g, 0.1 mol) in 1 ,2-dimethoxy- ethane (200 ml). After stirring the reaction mixture for 15 minutes at 20 0C, a solution of 20% aqueous sodium carbonate (300 ml) is added to the mixture, and the resulting mixture is refluxed for 24 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue is further purified by column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 3-amino- 4'-chloro-4-methylbiphenyl.
Step 14-Chlorophenylboronic acid (20.2 g, 0.13mol) and tetrakis(triphenylphosphine)palladium (0) (3.7g, 0.003 mol) are added to a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (20 g, 0.1 mol) in 1 ,2- dimethoxyethane (200 ml). After stirring the reaction mixture for 15 minutes at 2O0C, a solution of 20% aqueous sodium carbonate (300ml) is added to the mixture, and the resulting mixture is refluxed for 24 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 5-(4- chlorophenyl)-2-methylaniline (21.0 g).
4-Chlorophenylboronic acid (20.2 g, 0.13mol) and tetrakis(triphenylphosphine)palladium (0) (3.7g, 0.003 mol) are added to a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (20 g, 0.1 mol) in 1 ,2- dimethoxyethane (200 ml). After stirring the reaction mixture for 15 minutes at 200C, a solution of 20% aqueous sodium carbonate (300ml) is added to the mixture, and the resulting mixture is <n="71"/>refluxed for 24 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 5-(4- chlorophenyl)-2-methylaniline (21.0 g).
Step 14-Chlorophenylboronic acid (20.2 g, 0.13mol) and tetrakis(triphenylphosphine)palladium (0) (3.7g, 0.003 mol) are added to a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (20 g, 0.1 mol) in 1 ,2- dimethoxyethane (200 ml). After stirring the reaction mixture for 15 minutes at 20C, a solution of 20% aqueous sodium carbonate (300ml) is added to the mixture, and the resulting mixture is refluxed for 24 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 5-(4- chlorophenyl)-2-methylaniline (21.0 g).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 20℃; for 0.404167h;Heating / reflux;
Step 1 Preparation of 3-amiotano-4'-chloro-4-methylbiotaphenylTeirakiotas(triotapnenylphosphiotane)palladiotaum (0) (3 7 g, 0 003 mol) and 4-chlorophenylboroniotac acid (20 2 g, 0 13mol) are added to a solution of 5-bromo-2-methylaniotaliotane (20 g, 0 1 mol) in 1 ,2- dimethoxyethane (200 ml) After stirring the reaction mixture for 15 minutes at 2O0C, a solution of 20% aqueous sodium carbonate (300ml) is added to the mixture, and the resulting mixture is <n="49"/>heated at reflux for 24 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 3-amino-4'-chloro-4-methylbiphenyl (21.0 g).
Tetrakis(triphenylphosphine)palladium (0) (3.7 g, 0.003 mol) and 4-chlorophenylboronic acid (20.2 g, 0.13mol) are added to a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (20 g, 0.1 mol) in 1 ,2- dimethoxyethane (200 ml). After stirring the reaction mixture for 15 minutes at 200C, a solution of 20% aqueous sodium carbonate (300ml) is added to the mixture, and the resulting mixture is heated at reflux for 24 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 3-amino-4'-chloro-4-methylbiphenyl (21.0 g).
In a 500-mL round-bottomed flask was placed <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (9 g, 0.048 mol), copper(I) iodide (0.92 g, 0.005 mol), and TEA (50 mL) in DMF (50 mL). Nitrogen was bubbled in for 5 min. To the mixture was added Pd(PPh3 )4 (5.6 g, 0.005 mol). The reaction was stirred at 80 DC overnight. Concentration in vacuo removed solvents, and to the residue was added THF (100 mL). After filtration, the filtrate was concentrated to give the crude product, which was purified by ISCO MPLC (EtOAc and hexane) to afford the title compound. 1U NMR (CDCl3) delta 2.18 (s, 3 H), 3.03 (s, 1 H), 3.63 (s, 2 H), 6.82 (s, 1 H), 6.90 (d, 1 H), 7.00 (d, 1 H).
2. Synthesis of 1-(6-bromo-1H-indazol-1-yl)ethanone Into a 500 mL round-bottom flask, was placed a solution of 5-bromo-2-methylbenzenamine (25 g, 134.41 mmol) in CHCl3 (60 mL). To the above was added acetic anhydride (27.97 g, 273.95 mmol) dropwise with stirring, while cooling to a temperature of 0 C. over a time period of 1 hour. The resulting solution was allowed to react, with stirring, for 3 hours while the temperature was maintained at 0-5 C. in a bath of H2O/ice. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:5). Addition of isoamylnitrite (37.35 g, 319.23 mmol) was next. This was followed by the addition of KOAc (4.39 g, 44.80 mmol). To the mixture was added acetic anhydride (47.6 g, 466.21 mmol). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:5). The mixture was concentrated by evaporation under vacuum using a rotary evaporator. Adjustment of the pH to 7 was accomplished by the addition of NaHCO3 (50%). The resulting solution was extracted three times with 600 mL of ethyl acetate and concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluding through a column with a 1:100 ethyl acetate/petroleum ether solvent system. This resulted in 26 g (81%) of 1-(6-bromo-1H-indazol-1-yl)ethanone as a orange solid.
With potassium phosphate;copper(l) iodide; L-proline; In dimethyl sulfoxide; at 120℃; for 6h;
2-Methyl-5-(4-morpholinyl)aniline was prepared in the following manner: Potassium phosphate (8500 mg, 40.0 mmol), L-proline (461 mg, 4.00 mmol) & copper(l) iodide (381 mg, 2.002 mmol) were added to a solution of 5-bromo-2- methylaniline (2.5 ml, 20.02 mmol) and morpholine (2.62 ml, 30.0 mmol) in Dimethyl Sulfoxide (DMSO) (15 ml) under Argon and stirred at 120 0C overnight. <n="73"/>Reaction stirred at 120 0C for a further 6 hours. Reaction allowed to cool and diluted with water (-4OmL), extracted with EtOAc (x3) organic layer seperated and washed with water (x2) which was back extracted with EtOAc (x2). Combined organics dried over Na2SO4, filtered and reduced under vacuum to leave a brown oil. Purified bySP4 chromatography to leave a light brown solid. 512mg. Taken onto next step without further purification.
With potassium phosphate; copper(l) iodide; L-proline; In dimethyl sulfoxide; at 120℃;Inert atmosphere;
Potassium phosphate (8.50 g, 40.0 mmol), L-proline (0.46 g, 4.00 mmol) and copper(l) iodide (0.38 g, 2.00 mmol) were added to a solution of 5-bromo-2- methylaniline (2.5 ml, 20.0 mmol) and morpholine (2.62 ml, 30.0 mmol) in dimethyl sulfoxide (15 ml). The reaction was heated to 120 0C under argon overnight. The reaction was then stirred at 120 0C for a further 6 hours. The reaction was allowed to cool before being diluted with water (-40 ml). The mixture was extracted with ethyl acetate (x3), the organic layer separated and washed with water (x2). The aqueous phase was then back extracted with ethyl acetate (x2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash-silica gel chromatography to give crude 2-methyl-5-(4- morpholinyl)aniline (0.51 g), which was used without further purification.
With sulfuric acid; potassium nitrate; In water; at 5℃; for 2.5h;Cooling with ice;
To a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (5.0 g, 27 mmol) in conc.H2S04 (40 mL) was added KN03 (2.7 g, 27 mmol) in portions and kept the internal temperature below 5 C. The resulting mixture stirred for 2 hrs under ice bath. The resulting mixture was poured into icewater and stirred for 10 mm. The mixture was filtered and the cake was washed with water(100 mL). The cake was purified by column chromatography (PE: EtOAc from 20: ito 10: 1)to give the title compound (3.1 g, yield 50%).0421 1H NMR (300 MHz, CDCI3): oe 7.88 (s, IH), 6.91 (s, 1H), 4.25 (brs, 2H), 2.16 (s, 3H).
50%
With sulfuric acid; potassium nitrate; at 5℃; for 2h;
To a stirred solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (5.0 g, 27 mmol) in conc.H2S04 (40 ml) was added KNO3 (2.7 g, 27 mmol) in portions and kept the internal temperature below 5C. The resulting mixture was stirred for 2 hours under ice bath. The resulting mixture was pouredinto ice water and stirred for 10 mm. The mixture was filtered and the filter cake was washedwith water (100 ml). The filter cake was purified by column chromatography (PE:EtOAc from20:1 to 10:1) to give the title compound (3.1 g, yield: 50%).1H NMR (300 MHz, CDCI3) 67.88 (s, IH), 6.91 (s, IH), 4.25 (br, 2H), 2.16 (s, 3H).
Step A: N-(5-Bromo-2-methylphenyl)-2,2,2-trifluoroacetamide To a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (10 g, 54 mmol) in DCM (500 mL) was added TEA (11 mL, 81 mmol) and TFAA (9 mL, 65 mmol). After 1 h, the reaction was diluted with water. The organic phase was washed two times with water, dried over MgSO4 and concentrated to give the desired product (15 g, 99%) as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) delta 11.02 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.43 (dd, J=8.0 and 2.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 2.13 (s, 3H) ppm.
76%
In dichloromethane; at 0℃; for 1h;
Next, into a 100-mL round-bottom flask, was placed <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (2 g, 10.75 mmol, 1.00 equiv), dichloromethane (40 mL), trifluoroacetyl 2,2,2-trifluoroacetate (2.7 g, 12.86 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at 0 C. The resulting mixture was concentrated under vacuum. This resulted in 2.3 g (76%) of N-(5-bromo-2-methylphenyl)-2,2,2-trifluoroacetamide as a light brown solid.
In dichloromethane; at 20℃; for 1h;
Step 2: To the solution of 5-bromo-2-methyianiii.ne in 200 ml of DCM was added trifiuoroacetic anhydride (6,18 mL, 44.43 mmol). The reaction was stirred at room tem erature for in. The completion of the reaction was monitored by HPLC. Upon completion, removal of volatile in vacuo provided 9.30g (89% yield over 2 steps) of the title compound as a light yellow solid, which was used without further purification; H NMR (400 MHz, CDCI3) delta = 7.99 (s, 1 H), 7.76 (br. s.s 1 H), 7,33 (dd, J - 2.0, 8,1 Hz, 1 H), 7.12 (d, J 8.1 Hz, 1 H), 2.25 (s, 3 H).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 25℃; for 15h;
A. tert-Butyl 2-(5-bromo-2-methylphenylamino)-2- oxoethyl(methyl)carbamate. To a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (0.744 g, 4 mmol), DMAP (0.538 g, 4.40 mmol) and 2-(tert-butoxycarbonyl(methyl)amino)acetic acid (0.833 g, 4.40 mmol) in DMF (10 mL) was added EDC (0.843 g, 4.40 mmol). The reaction mixture was stirred at 250C for 15 h, concentrated, and purified by silica gel chromatography (15% ethylacetate in hexanes). Fractions containing product were concentrated to give the title compound as a white solid (1.318 g, 3.69 mmol, 92% yield); MS (ESI) MS (ESI) m/z 359.1 [M+ 1]+.
With tert.-butylnitrite; diiodomethane; at 0 - 80℃; for 0.5h;
Intermediate 64-Bromo-2-iodo-1-methylbenzene; The synthesis of Intermediates 6 is shown in Scheme 4 and full experimental details are shown below.Stage 1-4-bromo-2-iodo-1-methylbenzeneTo a solution of 2-methyl-5-bromo aniline (1.5 g, 8.06 mmol) in di-iodo methane (3.4 ml) at 0 C. was slowly added tert-butyl nitrite (1.6 ml, 12.1 mmol). The ice bath was removed and the reaction was stirred at RT then heated at 80 C. for 30 minutes. The solvent was removed under reduced pressure and the residue purified by column chromatography (EtOAc/Heptane) to afford the title compound (1.6 g, 67% yield).LCMS: m/z 297 [M+H]+. 1H NMR (300 MHz, CDCl3) delta: 7.96 (1H, s), 7.42-7.35 (1H, m), 7.12 (1H, d, J=8.1 Hz), 2.40 (3H, s).
67%
With tert.-butylnitrite; diiodomethane; at 0 - 80℃;
Stage 1- 4-bromo-2-iodo-1-methylbenzeneTo a solution of 2-methyl-5-bromo aniline (1.5 g, 8.06 mmol) in di-iodo methane (3.4 ml) at 00C was slowly added tert-butyl nitrite (1.6 ml, 12.1 mmol). The ice bath was removed and the reaction was stirred at RT then heated at 800C for 30 minutes. The solvent was removed under reduced pressure and the residue purified by column chromatography (EtOAc/ Heptane) to afford the title compound (1.6 g, 67% yield). LCMS: m/z 297 [M+H]+. 1H NMR (300 MHz, CDCI3) delta: 7.96 (1 H, s), 7.42-7.35 (1 H, m), 7.12 (1 H, d, J=8.1 Hz), 2.40 (3H, s).
45%
4-bromo-2-amino-toluene (10.0g, 53 . 7mmol) suspended in 30% sulfuric acid (100 ml) in addition added dropwise sodium nitrite (3.89g, 56 . 4mmol) the aqueous solution (15 ml) Stirring at 0 C for 45 minutes , then the sodium iodide (12.1g, 80 . 6mmol) dissolved in water (50 ml) in, in the aqueous solution of the above-mentioned diazonium salt solution is added. Further stirring at room temperature 1 hour, the ethyl ester of acetic acid 3 times after extraction, the saturated salt water to the acetic acid ethyl ester level to 1 times of cleaning, by means of magnesium sulfate to dry, reducing concentrated. Subsequently, by means of silica gel column purification (hexane) to obtain the target compound (9.0g, 45%).
With hydrogenchloride; In dichloromethane; for 3h;
Example 1.Preparation of 2-methyl-5-bromophenylguanidine nitrate of the Formula 3; Preparation of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> hydrochlorideA 5-L reactor has been charged with 812.3 g of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (4.36 mol. 1.0 eq), and 3.7 kg of methylene chloride. After cooling the obtained clear solution to 1O0C, 190.7 g of dry hydrogen chloride gas was added from a bottle over a period of 2.5 h. The resulting mixture was stirred for ca. 30 minutes, whereafter the obtained crystalline product was filtered off on a filter funnel. The precipitate was washed on a filter funnel with two portions of methylene chloride (200 g each). The product was dried at room temperature for 3 days to yield 976.4 g of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> hydrochloride (100%) having an HPLC purity of 99.6%.
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 70℃; for 22h;
(i) 5-Bromo-2-methyl-N-(2-methylpropyl)aniline 7.44 g (40.0 mmol) of <strong>[39478-78-9]5-bromo-2-methylaniline</strong>, 8.22 g (60.0 mmol) of 1-bromo-2-methyl propane, 8.99 g (60.0 mmol) of sodium iodide and 8.29 g (60.0 mmol) of potassium carbonate were stirred in a DMF solvent at 70C for 22 hours. To the reaction mixture was added water and extracted with ethyl acetate. The organic layer was separated, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography to give 5.92 g of 5-bromo-2-methyl-N-(2-methylpropyl)aniline (yield: 61%). 1H-NMR (CDCl3) delta: 1.00 (6H, d, J = 6.8 Hz), 1.80-2.05 (1H, m), 2.07 (3H, s), 2.94 (2H, dd, J= 6.8, 5.7 Hz), 3.58 (1H, br), 6.65-6.75 (2H, m), 6.83-6.93 (1H, m).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 7h;Reflux;
(i) N-(3'-amino-4'-methylbiphenyl-4-yl)acetamido; 0.60 g (3.20 mmol) of 5-bromo-2-methylaniline and 1.01 g (4.87 mmol) of 4-acetamidophenylboronic acid pinacol ester were dissolved in 15 mL of DME. Next, 5 mL of a 2M aqueous sodium carbonate solution, and then 369 mg (0.32 mmol) of tetrakis (triphenyl phosphine)palladium (0) were added and heated under reflux for 7 hours. After completion of the reaction, ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Filtration was then carried out, and the filtrate was condensed. The resulting crude product was separated and purified using silica gel column chromatography to give N-(3'-amino-4'-methylbiphenyl-4-yl)acetamido (yield: 66%). 1H-NMR (CDCl3) delta: 2.19 (3H, s), 2.20 (3H, s), 3.68 (2H, br), 6.88-6.94 (2H, m), 7.10 (1H, d, J = 7.4 Hz), 7.29-7.32 (1H, m), 7.48-7.55 (4H, m).
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; for 8h;Reflux;
(i) 4'-Fluoro-4-methylbiphenyl-3-amine 5.0 g (22.5 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-fluorobenzene, 1.87 mL (15 mmol) of <strong>[39478-78-9]5-bromo-2-methylaniline</strong>, 1.73 g (1.5 mmol) of tetrakis(triphenyl phosphine)palladium (0), and 7.33 g (15 mmol) of cesium carbonate were heated under reflux for 8 hours in 150 mL of THF. After completion of the reaction, THF was distilled off under reduced pressure, and ethyl acetate was added to separate the solid by filtration. The organic layer was then washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography, thereby giving 4'-fluoro-4-methylbiphenyl-3-amine (yield: 43%). 1H-NMR (CDCl3) delta: 2.19 (3H, s), 3.66 (2H, br), 6.83-6.90 (2H, m), 7.03-7.13 (3H, m), 7.43-7.53 (2H, m).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 7h;Reflux;
(i) N-(3'-amino-4'-methylbiphenyl-3-yl)acetamido; 0.67 g (3.61 mmol) of 5-bromo-2-methylaniline and 1.14 g (4.37 mmol) of <strong>[480424-93-9]3-acetamidophenyl boronic acid pinacol ester</strong> were dissolved in 15 mL of DME. Subsequently, 5 mL of a 2M aqueous sodium carbonate solution, and then 417 mg (0.36 mmol) of tetrakis(triphenyl phosphine)palladium (0) were added to the mixture, and the mixture was heated under reflux for 7 hours. After completion of the reaction, ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Filtration was conducted, and the filtrate was condensed. The resulting crude product was separated and purified using silica gel column chromatography to give N-(3'-amino-4'-methylbiphenyl-3-yl)acetamido (yield: 74%). 1H-NMR (CDCl3) delta: 2.19 (3H, s), 2.20 (3H, s), 3.68 (2H, br), 6.88-6.94 (2H, m), 7.10 (1H, d, J = 7.4 Hz), 7.30-7.69 (5H, m).
hydrogenchloride; In ethanol; water; for 18h;Reflux;
To a solution <strong>[39478-78-9]5-bromo-2-methyl aniline</strong> (6.38 g, 36.74 mmol) in EtOH (30 ml) was added acetonyl acetone (5.0 ml, 42.62 mmol) and one drop of conc. aqueous HCl. The mixture was heated at reflux for 18 h and then cooled. Solvent was evaporated to dryness under reduced pressure and the residue was partitioned between water and EtOAc. The organic layer was separated and washed with water and brine dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/8:2) gave 5.8 g of 1-(5-bromo-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrole (60%) as a clear oil.
potassiumhexacyanoferrate(II) trihydrate[ No CAS ]
[ 39478-78-9 ]
[ 60710-80-7 ]
Yield
Reaction Conditions
Operation in experiment
75%
With 2-(2-methoxyphenyl)-1-methyl-3-(diphenylphosphino)-1H-indole; potassium tert-butylate; triethylamine; bis(dibenzylideneacetone)-palladium(0); In dichloromethane; water; acetonitrile; at 50℃; for 24h;Inert atmosphere;
General procedure: An oven-dried Schlenk tube with the presence of magnetic stir bar which is Teflon-coated was charged with Pd(dba)2 (11.5 mg, 0.02 mmol, 2 mol%) and ligand L4 (8.4 mg, 0.02 mmol, 2 mol%). The flask was evacuated and backfilled with nitrogen (3 cycles). Pre-complexation of palladium and ligand was initiated by injecting freshly distilled dry dichloromethane (2.0 mL) and Et3N (0.1 mL) into the tube. The solution was stirred and warmed with hair drier till the solvent condensed on the tube wall. The solvent was removed under vacuum. Aryl bromide (1.0 mmol), KOt-Bu (0.25 mmol), and potassium hexacyanoferrate(II) trihydrate (0.23 mmol) were charged successively to the tube followed by another 3 evacuation-nitrogen refill cycles. Water (1.0 mL) and acetonitrile (1.0 mL) were used as a solvent mixture. The tube was immersed into a preheated 50 C oil bath for 24 hours. The reaction was quenched by cooling to ambient temperature and added with EtOAc and water. The organic supernatant was analyzed by GC. The organic layer was separated and the remained aqua medium was further extracted with EtOAc (10 mL × 3). The combined organic phases were concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (230-400 mesh). The pure fractions were collected, dried under vacuum, and followed by proton (1H) and carbon (13C) NMR characterization
With potassium dihydrogenphosphate; tricyclohexylphosphine;palladium diacetate; In water; toluene; at 20 - 100℃; for 6h;Inert atmosphere;
Reference Example 355-Cyclopropyl-2-methylanilineAt room temperature, to a suspension of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (372 mg), cyclopropylboronic acid monohydrate (270 mg), tricyclohexylphosphine (56.0 mg), and potassium phosphate (1.49 g) in toluene (8.0 mL)-water (0.4 mL) was added palladium (II) acetate (22.4 mg), and the mixture was stirred under an argon gas atmosphere at 100 C. for 6 hours. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the organic layer was combined. The layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluting solvent: hexane-ethyl acetate) to obtain the title compound (256 mg).
2.25 g
With potassium phosphate monohydrate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 15h;
Reference Example 13 5-Cyclopropyl-2-methylaniline To a mixture of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (3.51 g), cyclopropylboronic acid monohydrate (2.55 g), tricyclohexylphosphine (about 0.6 mol/L toluene solution, 3.14 mL), tripotassium phosphate monohydrate (15.2 g), toluene (52.4 mL), and water (5.24 mL) was added palladium(II) acetate (212 mg), and this mixture was stirred at 100 C. for 15 hours. The reaction mixture was left to be cooled, and filtrated through a Celite (registered trademark) pad. The pad was washed with ethyl acetate (100 mL). The filtrate and the washing liquid were mixed, and washed with water/saturated brine (1/1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (2.25 g). 1H-NMR (CDCl3) delta ppm: 0.58-0.67 (2H, m), 0.83-0.93 (2H, m), 1.73-1.84 (1H, m), 2.12 (3H, s), 3.54 (2H, br s), 6.35-6.50 (2H, m), 6.93 (1H, d, J=7.5 Hz).
tert-butyl 5-bromo-2-methylphenylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h;
tert-butyl 5-bromo-2-methylphenylcarbamate (1): To a solution of 5-bromo-2- methylaniline (2.0 g, 10.7 mmol) in dichloromethane (15.0 mL), diisopropylethylamine (5.6 g, 43.0 mmol) and boc-anhydride (11.8 g, 53.5 mmol) were added. The reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, solvent was removed under reduced pressure. The resulting residue was diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was triturated with pentane to afford 1 (3.0 g, 98%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): delta 1.45 (s, 12H), 7.10 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 1.9, 8.1 Hz, 1H), 7.58 (s, 1H), 8.64 (s, 1H). MS m/z (M+H): 286.0
To dry DMF (5 ml) add NaH (132 mg, 3.30 mmol), cool to 0 C then add a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (558 mg, 3.00 mmol) in DMF (5 ml). Stir at 0 C for 25 minutes. Then at 0 C with stirring add di -tert-butyl di carbonate (0.696 ml, 3.00 mmol) and let warm to room temperature and then stir at 40 C for 22 hr. The reaction was followed by LCMS. To the crude reaction add 200 ml of ethyl acetate, wash with 5% NaOH soln (filter solid impurities off), water (2x), saturated salt solution, dry sodium sulfate, filter and concentrate to crude solid. The crude was purified by silica gel chromatography using 40g column eluting with 0%-15% ethyl acetate with heptane. The desired fractions were concentrated to constant mass, giving 320 mg of the titled compound as free base used without further purification. LCMS (m/z): 230.1/232.1(MH+) (loss of BOC t-butyl), rt = 1.12 mm. 1H NMR (300 MHz, DMSO-i/6, 25 C) delta ppm 1.45 (s, 9 H) 2.14 (s, 3 H) 7.07 - 7.14 (m, 1 H) 7.14 - 7.22 (m, 1 H) 7.58 (d, J=1.47 Hz, 1 H) 8.65 (s, 1 H)
With magnesium sulfate; acetic acid; In dichloromethane; at 20℃; for 18h;Inert atmosphere;
To a soln of benzaldehyde (2.45 g, 23.1 mmol) and <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (4.30 g, 23.1 mmol) in CH2Cl2 (30 mL) were added AcOH (0.3 mL) and MgSO4 (6 g) and the mixture was heated under reflux for 4 h. The suspension was filtered, the filtrate was washed with sat. aq NaHCO3 (10 mL) and dried (Na2SO4), and the solvent was removed. The crude product was recrystallized (EtOH) to give 5d as yellowish crystals; yield: 4.56 g (72%); mp 82.1-82.5 C; Rf = 0.48 (cyclohexane-EtOAc, 15:1).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -78 - 20℃;
N-(5-bromo-2-methylphenyl)acrylamide (1): To a solution of 5-bromo-2- methylaniline (2.0 g, 10.8 mmol) in dichloromethane (10 mL), diisopropylethylamine (4.18 g, 32.3 mmol) and acryloyl chloride (1.16 g, 12.8 mmol) were added at -78C. The resulting mixture was stirred at room temperature for 30 min. After completion of reaction, the reaction mixture was quenched with water and the aqueous solution was extracted with dichloromethane (2x40.0 mL). The organic layer was washed with water followed by brine solution. The organic layer was dried over anhydrous sodium sulfate and concentrated over reduced pressure. The residue was triturated with n-pentane to afford 1 (2.2 g, 85%) as an off white solid. 1H NMR (400 MHz, CDCls) delta 2.23 (s, 3H), 5.79-5.82 (dd, J = 1.1, 10.2 Hz, 1H), 6.23-6.30 (dd, J = 10.2, 16.8 Hz, 1H), 6.42 (dd, J = 1.1, 16.8 Hz, 1H), 6.99 (brs, 1H), 7.04 (d, J = 8.1 Hz, 1H), 7.20 (m, 1H), 8.20 (brs, 1H). MS m/z (M-H): 238.0
Stage #1: 2-sulfobenzoic acid cyclic anhydride; 5-bromo-2-methylaniline In tetrahydrofuran for 12h; Inert atmosphere; Reflux;
Stage #2: With thionyl chloride In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; Reflux; chemoselective reaction;
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; at 20℃; for 18h;
Example 86.2. Preparation of O-benzoyl-IX-103.O-Benzoyl-IX-103 was prepared according to procedures in Example 44.2, butusing DL-2-benzamido-3 -(4-(benzoyloxy)phenyl)propanoic acid (Example 86.1;160 mg; 0.41 mmol) and <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (76 mg; 0.41 mmol; Aldrich)in place of (1 H-indole-4-carbonyl)phenylalanine and o-methoxyaniline. Yield: 62 mg, 27%.MS (MALDI): calculated: m/z 557.44 (M); found: 557.17 (M), 581.16 (M+Na).
With potassium carbonate; In water; at 70℃; for 2h;Inert atmosphere;
General procedure: In a typical run, h-BN(at)Fur(at)Pd(OAc)2 (0.05 mmol) was added to a mixture of arylboronic acid 1 (1.0 mmol), aryl bromide 2 (1.5 mmol) and K2CO3 (1.5 mmol) in water (1 mL). The resulting mixture was stirred at 70 C under Ar protection, and the progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate was added to the reaction mixture and the catalyst was separated. The organic phase was washed with water, dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. Finally, the residue was isolated by chromatography on a column of silica gel to afford the corresponding product 3.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; for 5h;Reflux; Inert atmosphere;
(1-1) Synthesis of 2-Methyl-5-Phenylaniline A mixture of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (10.0 g), phenylboronic acid (8.52 g), tetrakis(triphenylphosphine)palladium (0) (1.86 g), a 2 M sodium carbonate aqueous solution (80.6 mL), and 1,2-dimethoxyethane (DME) (135 mL) was refluxed for 5 hours in an argon atmosphere. The resulting reaction mixture was cooled to room temperature, and extracted with dichloromethane. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude 2-methyl-5-phenylaniline was used directly for the subsequent step.
A solution of sodium nitrite (2.04 g, 29.57 mmol) in water (15 mL) was added dropwise to a solution of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (5.0 g, 26.88 mmol) in cone. aq. HCI (20 mL) at 0 C. The reaction mixture was stirred at 0 C for 1 h, and then stannous chloride monohydrate (18.19 g, 80.64 mmol) in cone. aq. HCI (20 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0 C for an additional 1 h. The reaction mixture was slowly made basic with 50% aq. NaOH and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated to obtain the title compound without the need for further purification. MS (ESI+) m/z 201 .1 (M(79Br)+H).
General procedure: A solution of sodium troponate, which was prepared from tropolone (262mg, 2.2mmol) and 10mL of a 10% aqueous solution of NaOH, was added at 0C, and the reaction mixture was stirred at room temperature overnight. The mixture was poured into 10% hydrochloric acid, and the thus obtained brown precipitate was collected, washed with water, and dried to afford 571mg (quantitative yield) of crude 1a, which was purified by recrystallization from AcOEt to afford 116mg (25% yield) of brown needles.
A mixture of the carboxylic acid ( (2-[4-chloro-2-(methoxycarbonyl)phenyl]amino}-2-oxoethoxy)acetic acid ) (6a)15 (5 g, 16.6 mmol), N,N-dimethylformamide (DMF) (cat. amount), oxalylchloride (19.9 mmol) in tetrahydrofuran (THF) (50 mL) was stirred at 0C for 30 min. After the mixturewas concentrated to dryness in vacuo, a solution of the amine (7a) (16.6 mmol) in N,N-dimethylacetamide(DMA) (50 mL) was added at 0C thereto. The mixture was stirred overnight at room temperature, dilutedwith an aqueous NaHCO3 solution and extracted with ethyl acetate (AcOEt). The organic layer wasseparated, washed with water, and dried over Na2SO4. After the solvent was distilled off under reducedpressure, the resulting crude product was purified by silica gel column chromatography to afford thecorresponding amide (9a) as a solid (7.17g, 92%).1H-NMR (200 MHz, CDCl3) delta: 2.27 (3H, s), 3.67 (3H, s), 4.28 (2H, s), 4.31 (2H, s),7.10 (1H, d, J = 8.2Hz), 7.27 (1H, dd, J = 8.2, 2.0 Hz), 7.54 (1H, dd, J = 9.1, 2.6 Hz), 7.84 (1H, d, J =2.0 Hz), 8.01 (1H, d, J =2.6 Hz), 8.73 (1H, brs),8.77 (1H, d, J = 9.1 Hz), 11.93 (1H, brs).
4-((5-bromo-2-methylphenyl) amino)-2-chlorobenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In acetonitrile; for 5h;Reflux;
Compound i (1054 mg, 4 mmol), <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (744 mg, 4 mmol),Cesium carbonate (3.25 g, 10 mmol), Pd2(dba)3 (183.2 mg, 0.2 mmol), 213697-53-1 (126 mg, 0.32 mmol) were placed in a flask.Acetonitrile (24 ml) was added, nitrogen was purged three times and refluxed for 5 h.Cool to room temperature, concentrate under reduced pressure, dilute with water, extract twice with ethyl acetate, and combine the organic phases.It was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column (PE:EA=10:1) to give 750 mg of pale yellow solid n. Yield: 59%.
With caesium carbonate; bis(dibenzylideneacetone)-palladium(0); DavePhos; In acetonitrile; for 5h;Inert atmosphere; Reflux;
General procedure: Under N2 atmosphere, a mixture of intermediate 12 (263.5 mg,1.0 mmol), 3-bromoaniline (172.0 mg, 1.0 mmol), Cs2CO3 (325.8 mg,1.0 mmol), Pd2(dba)3 (45.8 mg, 0.05 mmol) and Davephos (31.5 mg,0.08 mmol) in MeCN (6.0 ml) was heated to reflux for 5 h. The reactionmixture was cooled to room temperature and diluted withethyl acetate. The resulting mixturewas filtered off and the solutionwas concentrated under vacuum to give a crude product 16 thatwas purified by column chromatography on silica using a solvent of10% ethyl acetate in hexanes. The desired compound 16 was obtainedas a yellow solid (220.0 mg, yield 72%). For the synthesis ofintermediate 13-15, compound 12 or commercially available 11and corresponding aromatic amine were used respectivelyfollowing the procedure described for 16.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In acetonitrile; for 5h;Reflux;
Compound W (270 mg, 0.84 mmol), <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (93.3 mg, 0.5 mmol),Cesium carbonate (407.3,1.25mmol), Pd2 (dba) 3 (22.9mg, 0.025mmol),213697-53-1 (15.7 mg, 0.04 mmol) was placed in a flask, acetonitrile (3 ml) was added, nitrogen was purged three times, and refluxed for 5 h.Cooled to room temperature, concentrated under reduced pressure, diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with saturated brine.After drying over anhydrous sodium sulfate, it was concentrated and purified by silica gel column (PE:EA=1:1) to obtain 135 mg of pale yellow viscous compound K, yield: 71.6%.
N-(5-bromo-2-methylphenyl)propane-1-sulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With pyridine; dmap; In dichloromethane; at 20℃; for 40h;Inert atmosphere;
General procedure: To a solution of 3-bromo-5-methoxyaniline (11b) (150.0 mg, 0.74 mmol) and a catalyticamount of DMAP in anhydrous CH2Cl2 (8 mL) was added pyridine(0.08 mL, 0.55 mmol) and 2-propanesulfonyl chloride (0.09 mL,0.82 mmol) under an argon atmosphere. The mixturewas stirred atroom temperature for 40 h. After being quenched with 1 N HCl(aq)(0.5 mL) and water, CH2Cl2 were added, and the layers wereseparated. The combined organic phases were washed with brine,dried over anhydrous Na2SO4, filtered and concentrated. The residuewas purified by column chromatography on silica gel (EtOAc/hexane,10:90 to 20:80) to give 13e (67.8 mg, 30%) as a yellow oil.
With hydrogenchloride; In water; at 110℃; for 16h;Inert atmosphere;
5-bromo-8-methylquinoline To a mixture of <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (980 mg, 5.27 mmol) in HCl solution (2 M, 30 mL) was added 3,3-diethoxyprop-1-ene (1.67 g, 12.80 mmol) at room temperature. The resulting mixture was stirred for 16 h at 110 C. When the reaction was done, the pH value of the reaction mixture was adjusted to 7-8 with sodium bicarbonate solution (4 M). The resulting mixture was extracted with DCM (100 mL*3). The organic phases were combined, washed with brine and dried over Na2SO4. The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 70% gradient) to yield 5-bromo-8-methylquinoline as yellow solid (360 mg, 30%). MS: m/z=223.9 [M+H]+.
5-(3,5-dimethylisoxazole-4-yl)-2-methylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere;
Pd (pph3) 4 (900mg, 0.8mmol), 3,5-dimethylisoxazole-4-boronic acid pinacolate (5g, 22.5mmol), Na2CO3 (4.74g, 45mmol) and 5-bromo-2- Methylaniline (2.79g, 15mmol) was added to the flask at the same time, and then H2O (20ml) and 1,4-dioxane (37ml) were added to pump nitrogen 3 times, heated to 90 C and stirred overnight.Cooled to room temperature, diluted with water, extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, purified by silica gel column (PE: EA = 2: 1) to obtain 2g of light yellow solid, namely intermediate 5- ( 3,5-Dimethylisoxazole-4-)-2-methylaniline, yield: 66.0%.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 6h;
General procedure: Under N2 atmosphere, a mixture of 6 (100.0 mg, 0.26 mmol),Pd(pph3)4 (30.0 mg, 0.026 mmol), 2.0M aq Na2CO3 (0.29 ml,0.78 mmol) and 1-Methyl-1H-pyrazole-5-boronic acid pinacolester (108.2 mg, 0.52 mmol) in 1,4-Dioxane (0.65 ml) was heated to90 C and stirred for 6 h. The reaction mixture was cooled, dilutedwith ethyl acetate, washed with water, dried over anhydrousNa2SO4, filtered and concentrated under vacuum. Purification onsilica using a solvent gradient of 10-30% ethyl acetate in hexanesyielded the desired compound 1j (77.0 mg, 77.5%). Compounds 1akwere prepared according to general procedure as described forcompound 1j using corresponding aryl bromide 2-4 and theappropriate boronic acid or boronic acid pinacol ester. The characterizationdata for compounds 1a-k were provided below.
With caesium carbonate; bis(dibenzylideneacetone)-palladium(0); DavePhos; In acetonitrile; for 5h;Inert atmosphere; Reflux;
General procedure: Under N2 atmosphere, a mixture of intermediate 12 (263.5 mg,1.0 mmol), 3-bromoaniline (172.0 mg, 1.0 mmol), Cs2CO3 (325.8 mg,1.0 mmol), Pd2(dba)3 (45.8 mg, 0.05 mmol) and Davephos (31.5 mg,0.08 mmol) in MeCN (6.0 ml) was heated to reflux for 5 h. The reactionmixture was cooled to room temperature and diluted withethyl acetate. The resulting mixturewas filtered off and the solutionwas concentrated under vacuum to give a crude product 16 thatwas purified by column chromatography on silica using a solvent of10% ethyl acetate in hexanes. The desired compound 16 was obtainedas a yellow solid (220.0 mg, yield 72%). For the synthesis ofintermediate 13-15, compound 12 or commercially available 11and corresponding aromatic amine were used respectivelyfollowing the procedure described for 16.
With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 12h;Inert atmosphere;
5-(1H-imidazol-1-yl)-2-methylaniline (S2):Take a 250ml reaction tube and put in a magnet.The reaction was added <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (920 mg, 5.0 mmol).Imidazole (510 mg, 7.5 mmol),Transfer the reaction tube to a nitrogen atmosphere,CuI (190 mg, 1 mmol), Cs2CO3 (3.26 g, 10 mmol),Finally, the solvent N,N-dimethylformamide (20 mL) was added.The reaction was carried out at 110 C for 12 h.After the reaction is completed, the reaction is cooled to room temperature.30 ml of ethyl acetate was added, and the reaction solution (30 mL x 3) was washed with water. The organic phase is dried over anhydrous NaSO4.The solvent was removed using a rotary evaporator.Finally, the product is separated by a chromatography column.The chromatographic conditions were: n-hexane / EtOAc (1:1 v/v).The product is a white solid.The yield was 70%.
<strong>[39478-78-9]2-methyl-5-bromoaniline</strong> in N-methylpyrrolidone (20 mL)(4.33 g,23.3 mmol), compound 1 (3.0 g, 15.5 mmol,(See WO2011020749 for the synthesis method), and the mixture was stirred at 120 C for 24 hours.The reaction was poured into water (200 mL) and stirred at room temperature for 30 minutes.The precipitated solid was collected by filtration and washed with water.The obtained solid was washed with diisopropyl ether and dried under reduced pressure to give Compound 2 (4.58 g, yield 94.8%).
3-(5-bromo-2-methyl-phenylimino)-1,3-dihydro-indol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With acetic acid; In ethanol; at 180℃; for 2h;Microwave irradiation; Green chemistry;
General procedure: An equimolar mixture of isatin/5-bromoisatin and an aromatic primary amine were introduced into an Erlenmeyer flask. Ethanol (1 mL) and a few drops of acetic acid were added. The Erlenmeyer flask was placed in an ultrasonic bath filled with water (80 Hz,100%), the temperature was adjusted at 40C. At the end of the reaction (monitored by TLC), the product obtained by filtration was recrystallized from ethanol. For the reactions carried out in microwave Biotage, the reagents in 4 mL of ethanol were put in a magnetic stir bar for 2-5 mL vial and the temperature was set at 150C, 160C then 180C.
5-bromo-3-(5-bromo-2-methyl-phenylimino)-1,3-dihydroindol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With acetic acid; In ethanol; at 180℃; for 2h;Microwave irradiation; Green chemistry;
General procedure: An equimolar mixture of isatin/5-bromoisatin and an aromatic primary amine were introduced into an Erlenmeyer flask. Ethanol (1 mL) and a few drops of acetic acid were added. The Erlenmeyer flask was placed in an ultrasonic bath filled with water (80 Hz,100%), the temperature was adjusted at 40C. At the end of the reaction (monitored by TLC), the product obtained by filtration was recrystallized from ethanol. For the reactions carried out in microwave Biotage, the reagents in 4 mL of ethanol were put in a magnetic stir bar for 2-5 mL vial and the temperature was set at 150C, 160C then 180C.
7-chloro-2-morpholino-N-(pyridin-2-ylmethyl)quinazolin-4-amine[ No CAS ]
7-(3-amino-4-methylphenyl)-2-morpholino-N-(pyridin-2-ylmethyl)quinazolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
General procedure: To a solution of freshly activated magnesium turnings (2.00 eq, 20.0 mmol) in THF (10 mL)at room temperature, under N2 atmosphere was added catalytic amount of 1,2-dibromoethane fallowed with Aryl bromides (1.00 eq, 10.0 mmol) in THF (5 mL) over aperiod of 5 min. During the addition, Grignard generation initiated and temperature increased to 60C to 80C. The reaction was further refluxed for 15 min and then cooled to room temperature. The reagent was transferred to an addition funnel under nitrogen atmosphere. This solution was used for the next step. A suspension of 7-chloro-2-morpholino-N-(pyridin-2-ylmethyl)quinazolin-4-amine(2) (1.00 eq, 10 mmol) and Nickel catalyst (0.05 eq, 0.5mmol) in THF (10 mL) was stirred at room temperature under N2 atmosphere. Then, freshly prepared above Grignard reagent was slowly added to reaction at room temperature over a period of 5 min. The mixture was refluxed for 2-5h. The TLC showed complete reaction. The reaction was cooled to 0-5C and quenched slowly by the addition of 1 N HCl (50 mL), diluted with EtOAc(100 mL). The organic layer was separated and aqueous layer extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude product was recrystallized in EtOH and MTBE to obtain compounds 3a-3t with 85-96% yield.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere;
Take compound 1-1 (1.86g, 10mmol), compound 2-1 (3.17g, 12mmol), Pd (dppf) Cl2 (5mmol%), potassium carbonate (2.76g, 20mmol),50 mL of a mixed solvent of 1,4-dioxane and water (volume ratio 4:1) was added, and the reaction was performed at 100C for 6 hours after replacement with N2.The reaction was monitored by TLC. After the reaction was completed, the reaction solution was distilled off under reduced pressure.The residue was dissolved in a mixed solvent of methylene chloride and methanol, and filtered through celite,After the filtrate was concentrated, column chromatography (PE:EA=2:1) gave intermediate I-1 (light yellow solid, 73%),
With N-ethyl-N,N-diisopropylamine; at 100℃; for 15h;
The compound <strong>[39478-78-9]5-bromo-2-methylaniline</strong> (3.0g, 16.1mmol),Alpha-bromocyclopropanone (2.9 g, 17.7 mmol) and N,N-diisopropylethylamine (4.2 g, 32.2 mmol) were dissolved in 100 ml of toluene and reacted at 100C for 15 hours.After the reaction is over, the reaction solution is concentrated,The residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 1:30) to obtain 3.37g of product,The yield was 78.4%.
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