* 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.
With pyridine In N,N-dimethyl-formamide; 3-bromo-5-fluorobenzonitrile
3-Bromo-2-methylbenzonitrile. This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35percent) of 3-bromo-2-methylbenzonitrile.
35%
With pyridine In N,N-dimethyl-formamide; 3-bromo-5-fluorobenzonitrile
3-Bromo-2-methylbenzonitrile This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35percent) of 3-bromo-2-methylbenzonitrile.
35%
With pyridine In N,N-dimethyl-formamide; 3-bromo-5-fluorobenzonitrile
3-Bromo-2-methylbenzonitrile. This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35percent) of 3-bromo-2-methylbenzonitrile.
35 %
With pyridine In N,N-dimethyl-formamide; 3-bromo-5-fluorobenzonitrile
EXAMPLE 178 6-(3-cyano-2-methylphenyl)-1,2-dihydro-2,2,4-trimethylquinoline (Compound 278, structure 4 of Scheme II, where R1 =3-cyano-2-methylphenyl) 3-Bromo-2-methylbenzonitrile. This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35 percent) of 3-bromo-2-methylbenzonitrile.
Reference：
[1] Patent: US5688810, 1997, A,
[2] Patent: US5693646, 1997, A,
[3] Patent: US5693647, 1997, A,
[4] Patent: US5696127, 1997, A,
[5] Patent: US5696130, 1997, A,
[6] Patent: US5696133, 1997, A,
5
[ 124-38-9 ]
[ 69321-60-4 ]
[ 76006-33-2 ]
Yield
Reaction Conditions
Operation in experiment
63.4%
With tert.-butyl lithium In tetrahydrofuran; pentane at -80 - -76℃;
Example 27 3-Bromo-2-methylbenzoic acid To a solution of 1,3-dibromo-2-methylbenzene (6.57 g) in dry THF (100 mL), t-BuLi solution (1.5 M in pentane, 17 mL) was added dropwise at -80° C. Then reaction mixture was stirred between -76~-78° C. for 2 h. Then the mixture was cooled to below -80° C. and dry ice was added after which the mixture was warmed to room temperature naturally. Solvent was removed, 5percent NaOH solution (40 mL) added and the aqueous solution was washed with CH2Cl2 (10 mL*2). Then the aqueous layer was acidified with concentrated HCl to pH=1 and extracted with EtOAc (100 mL*2). The combined organic extracts were dried over anhydrous Na2SO4. After removing the solvent, the residue was purified by silica column chomatography, (eluted with petrol. ether: EtOAc=8:1 to 1:1), to obtain 3.58 g of the product. Yield: 63.4percent. 1H NMR (400 MHz, CDCl3) δ 2.73 (s, 3H), 7.15 (t, J=8.0 Hz, 1H), 7.77 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.94 (dd, J=8.0 Hz, J=1.2 Hz, 1H).
63.4%
Stage #1: With tert.-butyl lithium In tetrahydrofuran; pentane at -80 - -76℃; Stage #2: at -80 - 20℃;
Example 27 3-Bromo-2-methylbenzoic Acid To a solution of 1,3-dibromo-2-methylbenzene (6.57 g) in dry THF (100 mL), t-BuLi solution (1.5 M in pentane, 17 mL) was added dropwise at -80° C. Then reaction mixture was stirred between -76~-78° C. for 2 h. Then the mixture was cooled to below -80° C. and dry ice was added after which the mixture was warmed to room temperature naturally. Solvent was removed, 5percent NaOH solution (40 mL) added and the aqueous solution was washed with CH2Cl2 (10 mL*2). Then the aqueous layer was acidified with concentrated HCl to pH=1 and extracted with EtOAc (100 mL*2). The combined organic extracts were dried over anhydrous Na2SO4. After removing the solvent, the residue was purified by silica column chomatography, (eluted with petrol. ether: EtOAc=8:1 to 1:1), to obtain 3.58 g of the product. Yield: 63.4percent. 1H NMR (400 MHz, CDCl3) δ 2.73 (s, 3H), 7.15 (t, J=8.0 Hz, 1H), 7.77 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.94 (dd, J=8.0 Hz, J=1.2 Hz, 1H).
63.4%
Stage #1: With tert.-butyl lithium In tetrahydrofuran; pentane at -80 - -76℃; Stage #2: at -80 - 20℃;
Example 30 3-Bromo-2-methylbenzoic Acid To a solution of 1,3-dibromo-2-methylbenzene (6.57 g) in dry THF (100 mL), t-BuLi solution (1.5 M in pentane, 17 mL) was added dropwise at -80° C. After addition, the reaction mixture was stirred between -76~-78° C. for 2 h. After the mixture was cooled to below -80° C., dry ice was added, and then warmed to room temperature naturally. Solvent was removed, 5percent NaOH solution (40 mL) was added, washed with CH2Cl2 (10 mL*2). Then the aqueous layer was acidified with concentrated HCl to pH=1, extracted with EtOAc (100 mL*2). The combined organic phase was dried over anhydrous Na2SO4. After removing the solvent, the residue was purified by silica column chromatography, (eluted with petrol ether:EtOAc=8:1 to 1:1), to obtain 3.58 g of the product. Yield: 63.4percent. 1H NMR (400 MHz, CDCl3): δ 2.73 (s, 3H), 7.15 (t, J=8.0 Hz, 1H), 7.77 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.94 (dd, J=8.0 Hz, J=1.2 Hz, 1H).
63.4%
Stage #1: With tert.-butyl lithium In tetrahydrofuran; pentane at -80 - -76℃; for 2 h; Stage #2: at -80℃; Stage #3: With hydrogenchloride In water
Example 27 3-Bromo-2-methylbenzoic acidTo a solution of l,3-dibromo-2-methylbenzene (6.57 g) in dry THF (100 mL), t-BuLi solution (1.5 M in pentane, 17 mL) was added dropwise at -80 C. Then reaction mixture was <n="131"/>stirred between -76 - 78 C for 2 h. Then the mixture was cooled to below -80 C and dry ice was added after which the mixture was warmed to room temperature naturally. Solvent was removed, 5percent NaOH solution (40 mL) added and the the aqueous solution was washed with CH2Cl2 (10 mL x 2). Then the aqueous layer was acidified with concentrated HCl to pH=l and extracted with EtOAc (100 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4. After removing the solvent, the residue was purified by silica column chomatography, (eluted with petrol, ether: EtOAc=8: l to 1 : 1), to obtain 3.58 g of the product. Yield: 63.4percent. 1H NMR (400 MHz, CDCl3) δ 2.73 (s, 3 H), 7.15 (t, J=8.0 Hz, 1 H), 7.77 (dd, J=8.0 Hz, ./=1.2 Hz, 1 H), 7.94 (dd, J=8.0 Hz, J=1.2 Hz, I H).
Reference：
[1] Tetrahedron, 2008, vol. 64, # 13, p. 2938 - 2950
[2] Journal of the Chemical Society, 1914, vol. 105, p. 514
[3] Chem. Zentralbl., 1913, vol. 84, # I, p. 393
[4] Chemische Berichte, 1935, vol. 68, p. 1505,1508
[5] European Journal of Organic Chemistry, 2001, # 2, p. 293 - 302
9
[ 594-27-4 ]
[ 69321-60-4 ]
Reference：
[1] Synthesis, 2008, # 3, p. 474 - 478
10
[ 101581-06-0 ]
[ 69321-60-4 ]
Reference：
[1] Organic Letters, 2005, vol. 7, # 5, p. 755 - 758
[2] Bulletin de la Societe Chimique de France, 1958, p. 496,498
[3] Chemische Berichte, 1880, vol. 13, p. 963[4] Chemische Berichte, 1881, vol. 14, p. 417
[5] Polyhedron, 2015, vol. 86, p. 125 - 132
[6] Patent: WO2009/100169, 2009, A1,
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 1 - 8
13
[ 98-51-1 ]
[ 69321-60-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 1 - 8
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 1 - 8
14
[ 4162-89-4 ]
[ 69321-60-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 1 - 8
15
[ 98840-42-7 ]
[ 69321-60-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 1 - 8
16
[ 108-36-1 ]
[ 74-88-4 ]
[ 69321-60-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9441 - 9456
17
[ 80948-78-3 ]
[ 69321-60-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[2] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
[3] Recueil des Travaux Chimiques des Pays-Bas, 1926, vol. 45, p. 303
18
[ 55289-35-5 ]
[ 69321-60-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 2, p. 293 - 302
19
[ 90914-81-1 ]
[ 69321-60-4 ]
Reference：
[1] Chemische Berichte, 1880, vol. 13, p. 963[2] Chemische Berichte, 1881, vol. 14, p. 417
20
[ 827-32-7 ]
[ 69321-60-4 ]
Reference：
[1] Chemische Berichte, 1880, vol. 13, p. 963[2] Chemische Berichte, 1881, vol. 14, p. 417
21
[ 69321-60-4 ]
[ 67713-23-9 ]
Reference：
[1] Chemische Berichte, 1935, vol. 68, p. 1505,1508
[2] European Journal of Organic Chemistry, 2001, # 2, p. 293 - 302
22
[ 69321-60-4 ]
[ 7726-95-6 ]
[ 601-84-3 ]
[ 67713-23-9 ]
Reference：
[1] Chemische Berichte, 1935, vol. 68, p. 1505,1508
23
[ 7677-24-9 ]
[ 69321-60-4 ]
[ 67197-53-9 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 2054 - 2060
24
[ 69321-60-4 ]
[ 68-12-2 ]
[ 83647-40-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere Stage #2: for 0.5 h;
n-BuLi (1.6M in hexanes, 28.5 mL, 45.6 mmol) was added dropwise to a solution of 1,3-dibromo-2-methylbenzene (9.50 g, 38.0 mmol) in THF (119 mL) at -78° C. and the reaction was maintained at this temperature for 30 minutes. N,N-Dimethylformamide (4.41 mL, 57.0 mmol) was added and the reaction was stirred for a further 30 min, before being allowed to warm to 0° C. over 1 hour. The reaction was quenched by addition of water, then was extracted with EtOAc. The organic phase was dried over magnesium sulfate and concentrated to dryness to afford 3-bromo-2-methylbenzaldehyde (7.19 g, 95percent) as a straw coloured oil. 1H NMR (500 MHz, CDCl3, 27° C.) 2.75 (3H, s), 7.18-7.37 (1H, m), 7.78 (2H, ddd), 10.26 (1H, s).
95%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78 - 0℃; for 1.5 h;
Preparation of 3-bromo-2-methylbenzaldehvde w-BuLi in hexanes (1.6M; 28.5 mL, 45.6 mmol) was added dropwise to a solution of 1,3- dibromo-2-methylbenzene (9.50 g, 38.0 mmol) in THF (119 mL) at -78 °C and the reaction was maintained at this temperature for 30 minutes. N,N-Dimethylformamide (4.41 mL, 57.0 mmol) was added and the reaction was stirred for a further 30 minutes before being allowed to warm to 0 °C over 1 hour. The reaction was quenched by addition of water and then was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to afford 3-bromo-2-methylbenzaldehyde (7.19 g, 95percent) as a light yellow oil. lH NMR (500 MHz, CDC13, 27 °C) 2.75 (3H, s), 7.18 - 7.37 (1H, m), 7.78 (2H, ddd), 10.26 (1H, s).
Example 26 1,3-Dibromo-2-methylbenzene A solution of (3,5-dibromo-4-methylphenyl)amine dissolved in water (80 mL) and concentrated HCl (7.5 mL) stirring for 20 min, then the mixture was cooled to 0~5 C., and a solution of NaNO2 (3.4 g/40 mL H2O) was added. The reaction mixture was stirred for 2 h at 0~5 C., then the suspension was added to a solution of hypophosphorous acid (50%, 27.9 g), and the mixture was cooled to 0 C. The mixture was stirred at room temperature overnight. Then it was extracted with CH2Cl2 (100 mL*2). The organic layer was washed with brine (30 mL) and dried over Na2SO4. After silica column chomatography, (eluted with petroleum ether), 3.57 g product was obtained, as a colorless liquid. 1H NMR (400 MHz, CDCl3) delta 2.57 (s, 3H), 6.89 (t, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H).
Example 29 1,3-Dibromo-2-methylbenzene A solution of (3,5-dibromo-4-methylphenyl)amine dissolved in water (80 mL) and concentrated HCl (7.5 mL) stirring for 20 min, then the mixture was cooled to 0~5 C., and the solution of NaNO2 (3.4 g/30 mL H2O) was added. The reaction mixture was stirred for 2 h at 0~5 C., then the suspension was added to hypophosphorous acid solution (50%, 27.9 g), which was cooled to 0 C. The mixture was stirred at room temperature overnight. Then it was extracted with CH2Cl2 (100 mL*2) and the combined organic layers were washed with brine (30 mL) and dried over Na2SO4. After silica column chromatography, (eluted with petroleum ether), 3.57 g product was obtained, as colorless liquid. 1H NMR (400 MHz, CDCl3): delta 2.57 (s, 3H), 6.89 (t, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H).
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 14h;Inert atmosphere;
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was purged with nitrogen and charged with <strong>[69321-60-4]2,6-dibromotoluene</strong> (2.50 g, 10.0 mmol), N-bromosuccinimide (1.78 g, 10.0 mmol) and carbon tetrachloride (40 iriL). The solution was heated to 80 C (oil bath temperature), and 2,2'-azobisisobutyronitrile (164 mg, 1.00 mmol) was added. The resulting mixture was refluxed for 14 h. After that time, the mixture was cooled to room temperature and filtered. The filter cake was washed with carbon tetrachloride (2 x 20 iriL). The filtrate was diluted with ethyl acetate (200 iriL) and washed with water (40 mL), saturated aqueous sodium bicarbonate (40 iriL) and brine (40 iriL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford a quantative yield (3.28 g) of l,3-dibromo-2-(bromomethyl)benzene as a yellow solid: mp 77-78 C; ]H NMR (300 MHz, CDC13) delta 7.55 (d, 2H, / = 8.1 Hz), 7.07 (t, IH, 7 = 8.1 Hz), 4.83 (s, 2H)
100%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 14h;Reflux; Inert atmosphere;
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was purged with nitrogen and charged with <strong>[69321-60-4]2,6-dibromotoluene</strong> (2.50 g, 10.0 mmol), N-bromosuccinimide (1.78 g, 10.0 mmol) and carbon tetrachloride (40 mL). The solution was heated to 80 C (oil bath temperature), and 2,2'-azobisisobutyronitrile (164 mg, 1.00 mmol) was added. The resulting mixture was refluxed for 14 h. After that time, the mixture was cooled to room temperature and filtered. The filter cake was washed with carbon tetrachloride (2 x 20 mL). The filtrate was diluted with ethyl acetate (200 mL) and washed with water (40 mL), saturated aqueous sodium bicarbonate (40 mL) and brine (40 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford a quantative yield (3.28 g) of l,3-dibromo-2-(bromomethyl)benzene as a yellow solid: mp 77-78 C; ]H NMR (300 MHz, CDC13) delta 7.55 (d, 2H, / = 8.1 Hz), 7.07 (t, 1H, J = 8.1 Hz), 4.83 (s, 2H).
100%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 14h;Inert atmosphere;
Example 103d 2,6-Dibromobenzyl Acetate (2d l,3-Dibromo-2-(bromomethyl)benzene 103dA 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was purged with nitrogen and charged with <strong>[69321-60-4]2,6-dibromotoluene</strong> (2.50 g, 10.0 mmol), N-bromosuccinimide (1.78 g, 10.0 mmol) and carbon tetrachloride (40 mL). The solution was heated to 80 C (oil bath temperature), and 2,2' -azobisisobutyronitrile (164 mg, 1.00 mmol) was added. The resulting mixture was refluxed for 14 h. After that time, the mixture was cooled to room temperature and filtered. The filter cake was washed with carbon tetrachloride (2 x 20 mL). The filtrate was diluted with ethyl acetate (200 mL) and washed with water (40 mL), saturated aqueous sodium bicarbonate (40 mL) and brine (40 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford a quantative yield (3.28 g) of l,3-dibromo-2-(bromomethyl)benzene as a yellow solid: mp 77-78 C; ]H NMR (300 MHz, CDC13) delta 7.55 (d, 2H, / = 8.1 Hz), 7.07 (t, 1H, / = 8.1 Hz), 4.83 (s, 2H).
99.7%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃;Inert atmosphere;
To a mixture of 1, 3 -dibromo-2-m ethylbenzene (500 mg, 2 mmol) in CCl4 (20 mL) was added NBS (365mg, 2 mmol) and AIBN (33 mg, 0.2 mmol). The resulting mixture was stirred at 80 C under nitrogen atmosphere overnight. Solvent was removed and the residue was purified by silica gel column chromatography (PE) to give l,3-dibromo-2-(bromomethyl)benzene (650 mg, yield: 99.7 %) as a white solid. 1H NMR (300 MHz, CDCl3): d = 7.57-7.53 (m, 2H), 7.04-6.98 (m, 1H), 4.82 (s, 2H).
98%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 85℃; for 16h;
1,3-Dibromo-2-(bromomethyl)benzene. A mixture of <strong>[69321-60-4]2,6-dibromotoluene</strong> (22.9 g, 92 mmol), N-bromosuccinimide (NBS) (15 g, 84 mmol), CCl4 (250 mL) and benzoyl peroxide (0.03 eq) was stirred at 85 C. (hot oil bath temperature) for 16 h, cooled to RT, filtered, washed with aq. NaHSO3, dried (Na2SO4), filtered, and evaporated to give 29.5 g (yield of 98%) of title product as a white solid. This solid contained 10% unreacted starting material but was successfully used without further purification. 1H NMR (300 MHz, CDCl3) delta 4.81 (s, 2H), 7.01 (t, 1H), 7.53 (d, 2H).
With N-Bromosuccinimide; dibenzoyl peroxide; In benzene;Heating / reflux;
To a solution of <strong>[69321-60-4]2,6-dibromotoluene</strong> (5.38 g, 21.53 mmol) in benzene (1.54 M) was added N-bromosuccinimide (4.21 g, 23.68 mmol) and benzoyl peroxide (0.52 g, 2.15 mmol). The mixture was then heated to reflux overnight. The mixture was cooled to rt, diluted with H2O and extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4 and concentrated to afford 7.65 g of the benzyl bromide, a brown solid. 1 H NMR (400 MHz, CDCI3) delta 4.83 (s, 2 H), 7.01 (t, J=8.0 Hz, 1 H), 7.55 (d, J=8.1 Hz, 2 H).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 1.5h;Reflux;
<strong>[69321-60-4]2,6-dibromotoluene</strong> (2.5Og, lO.Ommol) was dissolved in 20 mL carbontetrachloride. N-bromo- succinimide (1.87g, 10.5mmol) was added followed by benzoyl peroxide (73mg, 0.30mmol). The resulting mixture was heated at reflux for 90 minutes. 50 mL petroleum ether was added. This was filtered and concentrated in vacuo to yield l,3-Dibromo-2-bromomethyl-benzene (3.52g, 10.7mmol). 1HNMR (300MHz, CDCl3) delta 4.83 (s, 3H), 7.02 (t, J= 8 Hz, IH), and 7.55 (d, J= 8 Hz, 2H).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 1.5h;Reflux;
<strong>[69321-60-4]2,6-dibromotoluene</strong> (2.50 g, 10.0 mmol) was dissolved in 20 mL carbontetrachloride. N-bromosuccinimide (1.87 g, 10.5 mmol) was added followed by benzoyl peroxide (73 mg, 0.30 mmol). The resulting mixture was heated at reflux for 90 minutes. 50 mL petroleum ether was added. This was filtered and concentrated in vacuo to yield 1,3-Dibromo-2-bromomethyl-benzene (3.52 g, 10.7 mmol). 1H-NMR (300 MHz, CDCl3) delta 4.83 (s, 3H), 7.02 (t, J=8 Hz, 1H), and 7.55 (d, J=8 Hz, 2H).
With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; for 20h;Reflux;
To the solution of <strong>[69321-60-4]2,6-dibromotoluene</strong> (55.5 g, 222.1 mmol) and NBS (43.5 g, 244.3 mmol) in carbon tetrachloride (300 mL) was added benzoyl peroxide (5.37 g, 22.2 mmol). The reaction mixture was refluxed for 20 h, cooled to room temperature, washed with water (300 mL×3) and brine (300 mL) and dried over anhydrous sodium sulfate. The solution was filtered and evaporated to give 1,3-dibromo-2-bromomethylbenzene as a yellow power (71 g). This material was used for next step without further purification.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 16h;Heating;
A mixture of <strong>[69321-60-4]2,6-dibromotoluene</strong> (22.9 g, 92 mmol), N-bromosuccinimide (NBS) (15 g, 84 mmol), CC14 (250 mL) and benzoyl peroxide (0.03 eq) was stirred at 85C (hot oil bath temperature) for 16 h, cooled to RT, filtered, washed with aq. NaHS03, dried (Na2S04), filtered, and evaporated to give 29.5 g (yield of 98%>) of title product as a white solid. This solid contained 10% unreacted starting material but was successfully used without further purification. 1H NMR (300 MHz, CDC13) delta 4.81 (s, 2 H), 7.01 (t, 1 H), 7.53 (d, 2 H).
With nitric acid In (2S)-N-methyl-1-phenylpropan-2-amine hydrate
PREPARATION OF 2,6-DIBROMO-3-NITROTOLUENE
PREPARATION OF 2,6-DIBROMO-3-NITROTOLUENE To 38 g of 2,6-dibromotoluene (0.152 mol) was added dropwise with stirring, over a period of thirty minutes, 76 ml of 70% nitric acid. An exothermic reaction was observed. The resulting mixture was stirred for an additional sixty minutes, after which time the mixture was poured into 1500 ml of ice water. The solids which separated were collected by filtration and dried to yield 44.62 g of 2,6-dibromo-3-nitrotoluene. Recrystallization of the reaction product from ethyl alcohol-water yielded material melting at 47°-48° C.
With 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate;copper(l) chloride; In 1-methyl-pyrrolidin-2-one; at 120℃; for 17h;Heating;
Example 67 3- {4- [3- (4-Cliloro-2-phenoxy-phenoxy)-2-methyl-phenoxy]-2-methyl-phenyl}-propionic acid Step A 3- [4- (3-Bromo-2-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester A mixture of 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (2.0 g, 10.3 mmol), <strong>[69321-60-4]2,6-dibromotoluene</strong> (7.72 g, 30.9 mmol), cesium carbonate (4.03 g, 12.4 mmol), and 2,2, 6,6-tetramethyl-3, 5-heptanedione (0.47 g, 2.55 mmol) in 1-methyl-2- pyrrolidinone (20 mL) is purged with N2, and then copper (I) chloride (0.51 g, 5.15 mmol) is added. The reaction is heated to 120 C for 17 hours under N2, and then cooled and quenched with 1 N HCl (50 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 2.92 g (78%) of the title compound. Rf= 0.35 (4/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calculated for C18H19O3Br 362, found 363 and 365 (M +1 and M + 3,100%).
With pyridine; In N,N-dimethyl-formamide; 3-bromo-5-fluorobenzonitrile;
3-Bromo-2-methylbenzonitrile. This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35%) of 3-bromo-2-methylbenzonitrile.
50 mg (35%)
With pyridine; In N,N-dimethyl-formamide; 3-bromo-5-fluorobenzonitrile;
3-Bromo-2-methylbenzonitrile This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35%) of 3-bromo-2-methylbenzonitrile.
50 mg (35%)
With pyridine; In N,N-dimethyl-formamide; 3-bromo-5-fluorobenzonitrile;
3-Bromo-2-methylbenzonitrile. This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35%) of 3-bromo-2-methylbenzonitrile.
50 mg (35%)
With pyridine; In N,N-dimethyl-formamide; 3-bromo-5-fluorobenzonitrile;
EXAMPLE 178 6-(3-cyano-2-methylphenyl)-1,2-dihydro-2,2,4-trimethylquinoline (Compound 278, structure 4 of Scheme II, where R1 =3-cyano-2-methylphenyl) 3-Bromo-2-methylbenzonitrile. This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35 %) of 3-bromo-2-methylbenzonitrile.
With tert.-butyl lithium; In tetrahydrofuran; pentane; at -80 - -76℃;
Example 27 3-Bromo-2-methylbenzoic acid To a solution of <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (6.57 g) in dry THF (100 mL), t-BuLi solution (1.5 M in pentane, 17 mL) was added dropwise at -80 C. Then reaction mixture was stirred between -76~-78 C. for 2 h. Then the mixture was cooled to below -80 C. and dry ice was added after which the mixture was warmed to room temperature naturally. Solvent was removed, 5% NaOH solution (40 mL) added and the aqueous solution was washed with CH2Cl2 (10 mL*2). Then the aqueous layer was acidified with concentrated HCl to pH=1 and extracted with EtOAc (100 mL*2). The combined organic extracts were dried over anhydrous Na2SO4. After removing the solvent, the residue was purified by silica column chomatography, (eluted with petrol. ether: EtOAc=8:1 to 1:1), to obtain 3.58 g of the product. Yield: 63.4%. 1H NMR (400 MHz, CDCl3) delta 2.73 (s, 3H), 7.15 (t, J=8.0 Hz, 1H), 7.77 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.94 (dd, J=8.0 Hz, J=1.2 Hz, 1H).
63.4%
Example 27 3-Bromo-2-methylbenzoic Acid To a solution of <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (6.57 g) in dry THF (100 mL), t-BuLi solution (1.5 M in pentane, 17 mL) was added dropwise at -80 C. Then reaction mixture was stirred between -76~-78 C. for 2 h. Then the mixture was cooled to below -80 C. and dry ice was added after which the mixture was warmed to room temperature naturally. Solvent was removed, 5% NaOH solution (40 mL) added and the aqueous solution was washed with CH2Cl2 (10 mL*2). Then the aqueous layer was acidified with concentrated HCl to pH=1 and extracted with EtOAc (100 mL*2). The combined organic extracts were dried over anhydrous Na2SO4. After removing the solvent, the residue was purified by silica column chomatography, (eluted with petrol. ether: EtOAc=8:1 to 1:1), to obtain 3.58 g of the product. Yield: 63.4%. 1H NMR (400 MHz, CDCl3) delta 2.73 (s, 3H), 7.15 (t, J=8.0 Hz, 1H), 7.77 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.94 (dd, J=8.0 Hz, J=1.2 Hz, 1H).
63.4%
Example 30 3-Bromo-2-methylbenzoic Acid To a solution of <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (6.57 g) in dry THF (100 mL), t-BuLi solution (1.5 M in pentane, 17 mL) was added dropwise at -80 C. After addition, the reaction mixture was stirred between -76~-78 C. for 2 h. After the mixture was cooled to below -80 C., dry ice was added, and then warmed to room temperature naturally. Solvent was removed, 5% NaOH solution (40 mL) was added, washed with CH2Cl2 (10 mL*2). Then the aqueous layer was acidified with concentrated HCl to pH=1, extracted with EtOAc (100 mL*2). The combined organic phase was dried over anhydrous Na2SO4. After removing the solvent, the residue was purified by silica column chromatography, (eluted with petrol ether:EtOAc=8:1 to 1:1), to obtain 3.58 g of the product. Yield: 63.4%. 1H NMR (400 MHz, CDCl3): delta 2.73 (s, 3H), 7.15 (t, J=8.0 Hz, 1H), 7.77 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.94 (dd, J=8.0 Hz, J=1.2 Hz, 1H).
63.4%
Example 27 3-Bromo-2-methylbenzoic acidTo a solution of l,3-dibromo-2-methylbenzene (6.57 g) in dry THF (100 mL), t-BuLi solution (1.5 M in pentane, 17 mL) was added dropwise at -80 C. Then reaction mixture was <n="131"/>stirred between -76 - 78 C for 2 h. Then the mixture was cooled to below -80 C and dry ice was added after which the mixture was warmed to room temperature naturally. Solvent was removed, 5% NaOH solution (40 mL) added and the the aqueous solution was washed with CH2Cl2 (10 mL x 2). Then the aqueous layer was acidified with concentrated HCl to pH=l and extracted with EtOAc (100 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4. After removing the solvent, the residue was purified by silica column chomatography, (eluted with petrol, ether: EtOAc=8: l to 1 : 1), to obtain 3.58 g of the product. Yield: 63.4%. 1H NMR (400 MHz, CDCl3) delta 2.73 (s, 3 H), 7.15 (t, J=8.0 Hz, 1 H), 7.77 (dd, J=8.0 Hz, ./=1.2 Hz, 1 H), 7.94 (dd, J=8.0 Hz, J=1.2 Hz, I H).
Example 26 1,3-Dibromo-2-methylbenzene A solution of (3,5-dibromo-4-methylphenyl)amine dissolved in water (80 mL) and concentrated HCl (7.5 mL) stirring for 20 min, then the mixture was cooled to 0~5 C., and a solution of NaNO2 (3.4 g/40 mL H2O) was added. The reaction mixture was stirred for 2 h at 0~5 C., then the suspension was added to a solution of hypophosphorous acid (50%, 27.9 g), and the mixture was cooled to 0 C. The mixture was stirred at room temperature overnight. Then it was extracted with CH2Cl2 (100 mL*2). The organic layer was washed with brine (30 mL) and dried over Na2SO4. After silica column chomatography, (eluted with petroleum ether), 3.57 g product was obtained, as a colorless liquid. 1H NMR (400 MHz, CDCl3) delta 2.57 (s, 3H), 6.89 (t, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H).
Example 26 l,3-Dibromo-2-methylbenzeneA solution of (3,5-dibromo-4-methylphenyl)amine dissolved in water (80 mL) and concentrated HCl (7.5 mL) stirring for 20 min, then the mixture was cooled to 0-5 C, and a solution OfNaNO2 (3.4 g/ 40 mL H2O) was added. The reaction mixture was stirred for 2 h at 0-5 C, then the suspension was added to a solution of hypophosphorous acid (50%, 27.9 g), and the mixture was cooled to 0 C. The mixture was stirred at room temperature overnight. Then it was extracted with CH2Cl2 (100 mL x 2). The organic layer was washed with brine (30 mL) and dried over Na2SOphi After silica column chomatography, (eluted with petroleum ether), 3.57 g product was obtained, as a colorless liquid. 1H NMR (400 MHz, CDCl3) delta 2.57 (s, 3 H), 6.89 (t, J=8.0 Hz, 1 H), 7.50 (d, J=8.0 Hz, 2 H).
With N-ethyl-N,N-diisopropylamine;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Inert atmosphere;
24.1) 1-Benzylsulfanyl-3-bromo-2-methyl-benzene (Intermediate 83): <strong>[69321-60-4]2,6-dibromotoluene</strong> (20 g, 100 mmol) in dioxane (160 ml) was stirred under argon. Then, DIPEA (30.9 ml, 160 mmol), xantphos (2.77g, 4.8 mmol) and Pd2(dba)3 (2.4 g, 2.4 mmol) were added and the reaction was heated to 1000C. Phenyl-methanethiol (9.4 ml, 80 mmol) was slowly added and the reaction stirred for 6 h. The reaction was quenched by the addition of 150 ml of H2O. After extraction (three times) with ethyl acetate, the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the product was purified by silica gel chromatography. Yield: 17g, 72 %
32.1) 2-(3-Bromo-2-methyl-phenyl)-pyridine (intermediate 101): A solution of i-PrMgCI (27.49 ml_, 2M in THF, 55 mmol.) was added dropwise to commercially available 1 ,3-dibromo-2-methyl-benzene ( 12.5 g, 50 mmol) at RT under argon and then heated at 65C for 1.5 h. The mixture was added via syringe to a suspension of dry ZnCb (6.83 g, 50 mmol.) in dry THF (20 ml) and cooled to 00C under argon. The resulting suspension was stirred at RT for 30 min. Then 2-bromo-pyridine (4.78 ml, 50 mmol.) and PdCI2*dppf (2.03 g) were added and the mixture was refluxed for 2 h. The reaction mixture was then quenched by the addition of a 5% solution of citric acid (200 ml) and extracted with ethyl acetate (2x 250ml). The combined organic layers were consecutively washed with a 5% solution of citric acid (150ml) and brine (150 ml), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was chromatographed on silica gel. Yield: 7.7 g, 78 %.
With potassium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 150℃; for 48h;Inert atmosphere;
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-l-one (150mg, 0.789mmol), cuprous iodide (30mg, O.lbetammol) and potassium carbonate (109mg, 0.789mmol) were deposited in a sealed vessel. 3 mL DMSO and <strong>[69321-60-4]2,6-dibromotoluene</strong> (395mg, 1.58mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 1500C for 24 hours. Cuprous iodide (30mg, O.lbetammol) was added and the mixture was heated at 1500C for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between DCM and 5% aq. ammonium hydroxide. The DCM layer was washed with brine. The combined aqueous layers were washed with DCM. The <n="60"/>combined DCM layers were dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-l-one (181mg, 0.504mmol). MS (ESI) 361.1 (M+H)+.
With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 150℃;Inert atmosphere of argon;
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (150 mg, 0.789 mmol), cuprous iodide (30 mg, 0.16 mmol) and potassium carbonate (109 mg, 0.789 mmol) were deposited in a sealed vessel. 3 mL DMSO and <strong>[69321-60-4]2,6-dibromotoluene</strong> (395 mg, 1.58 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150 C. for 24 hours. Cuprous iodide (30 mg, 0.16 mmol) was added and the mixture was heated at 150 C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was washed with brine. The combined aqueous layers were washed with dichloromethane. The combined dichloromethane layers were dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (181 mg, 0.504 mmol). MS (ESI) 361.1 (M+H)+.
With potassium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 150℃; for 5h;Inert atmosphere;
6-Dimethylamino-2H-isoquinolin-l-one (50mg, 0.27mmol), cuprous iodide (lOmg, 0.053mmol), and potassium carbonate (37mg, 0.27mmol) were deposited in sealed vessel. 3mL DMSO and <strong>[69321-60-4]2,6-dibromotoluene</strong> (133mg, 0.532mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 1500C for 5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (30% ethyl acetate/hexanes) to yield 2-(3-Bromo-2-methyl-phenyl)-6-dimethyl- amino-2H-isoquinolin-l-one (43mg, 0.12mmol). MS (ESI) 357 (M+H)+.
With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 150℃; for 5h;sealed vessel; Inert atmosphere;
Example 35 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one 6-Dimethylamino-2H-isoquinolin-1-one (50 mg, 0.27 mmol), cuprous iodide (10 mg, 0.053 mmol), and potassium carbonate (37 mg, 0.27 mmol) were deposited in sealed vessel. 3 mL DMSO and <strong>[69321-60-4]2,6-dibromotoluene</strong> (133 mg, 0.532 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150 C. for 5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (30% ethyl acetate/hexanes) to yield 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (43 mg, 0.12 mmol). MS (ESI) 357 (M+H)+.
With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 150℃;Inert atmosphere of argon;
6-Dimethylamino-2H-isoquinolin-1-one (50 mg, 0.27 mmol), cuprous iodide (10 mg, 0.053 mmol), and potassium carbonate (37 mg, 0.27 mmol) were deposited in sealed vessel. 3 mL DMSO and <strong>[69321-60-4]2,6-dibromotoluene</strong> (133 mg, 0.532 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150 C. for 5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (30% ethyl acetate/hexanes) to yield 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (43 mg, 0.12 mmol). MS (ESI) 357 (M+H)+.
Example 22 5'-[(te/f-butoxycarbonyl-ethyl-amino)-methyl]-4'-methyl-[2,3']bipyridinyl-4-carboxylic acid methyl esterStep 1 : 2,6-Dibromotoluene (9.8 g, 39 mmol) in THF (300 ml.) was stirred under N2 and was then cooled to -100 0C (ether/liquid N2). n-BuLi (16.4 mL, 41 mmol, 2.5 M in hexane) was then added drop wise and after stirring for 5 minutes DMF (4.5 mL, 58.6 mmol) was added. The reaction was stirred for a further 20 minutes and then for an hour at -78 0C. The reaction was quenched with saturated aqueous NH4CI and allowed to warm up to room temperature. The reaction was diluted with water and the pH adjusted to pH 7-8 with sat. aqueous NaHCO3. The mixture was evaporated in vacuo to remove the THF, and the product was then extracted with Et2O (x3). The combined organic layers were washed with brine and dried (MgSO4). The product was filtered and evaporated on vacuo to give delta-bromo^-methyl-pyridine-S-carbaldehyde as a colourless solid which was used without further purification.
n-BuLi (1.6M in hexanes, 28.5 mL, 45.6 mmol) was added dropwise to a solution of <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (9.50 g, 38.0 mmol) in THF (119 mL) at -78 C. and the reaction was maintained at this temperature for 30 minutes. N,N-Dimethylformamide (4.41 mL, 57.0 mmol) was added and the reaction was stirred for a further 30 min, before being allowed to warm to 0 C. over 1 hour. The reaction was quenched by addition of water, then was extracted with EtOAc. The organic phase was dried over magnesium sulfate and concentrated to dryness to afford 3-bromo-2-methylbenzaldehyde (7.19 g, 95%) as a straw coloured oil. 1H NMR (500 MHz, CDCl3, 27 C.) 2.75 (3H, s), 7.18-7.37 (1H, m), 7.78 (2H, ddd), 10.26 (1H, s).
95%
Preparation of 3-bromo-2-methylbenzaldehvde w-BuLi in hexanes (1.6M; 28.5 mL, 45.6 mmol) was added dropwise to a solution of 1,3- dibromo-2-methylbenzene (9.50 g, 38.0 mmol) in THF (119 mL) at -78 C and the reaction was maintained at this temperature for 30 minutes. N,N-Dimethylformamide (4.41 mL, 57.0 mmol) was added and the reaction was stirred for a further 30 minutes before being allowed to warm to 0 C over 1 hour. The reaction was quenched by addition of water and then was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to afford 3-bromo-2-methylbenzaldehyde (7.19 g, 95%) as a light yellow oil. lH NMR (500 MHz, CDC13, 27 C) 2.75 (3H, s), 7.18 - 7.37 (1H, m), 7.78 (2H, ddd), 10.26 (1H, s).
DESCRIPTION FOR D933-bromo-2-methylbenzaldehyde (D93)To a solution of <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (3 g, 12.00 mmol) in Tetrahydrofuran (THF) (100 mL) stirred under nitrogen at -78 C. was added BuLi (9.00 mL, 14.40 mmol) dropwise. The reaction mixture was stirred at -78 C. for 20 min. DMF (1.115 mL, 14.40 mmol) was added dropwise. The reaction mixture was continuously stirred for 2 hours. The reaction was quenched with sat. aq. ammonia chloride solution. The aqueous layers were separated and extracted by EA for 3 times. The combined organic layers were washed by brine, dried over anhydrous sodium sulfate. The dried solution was concentrated in vacuo to afford 3-bromo-2-methylbenzaldehyde (D93) (2.4 g), which was used for the next step without further purification. MS (ES): C8H7BrO requires 197.9. found 199 (M+H+)
To a solution of 1 , 3-dibromo-2-methylbenzene (3 g, 12.00 mmol) in Tetrahydrofuran (THF) (100 mL) stirred under nitrogen at -78 C was added BuLi (9.00 mL, 14.40 mmol) dropwise. The reaction mixture was stirred at -78 C for 20 min. DMF (1.1 15 mL, 14.40 mmol) was added dropwise. The reaction mixture was continuously stirred for 2 hours. The reaction was quenched with sat. aq. ammonia chloride solution. The aqueous layers were seperated and extracted by EA for 3 times. The combined organic layers were washed by brine, dried over anhydrous sodium sulfate. The dried solution was concentrated in vacuo to afford 3-bromo-2-methylbenzaldehyde (D93) (2.4g), which was used for the next step without further purification. MS (ES):C8H7BrO requires 197.9; found 199 (M+H+)
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 20 - 80℃; for 5h;Inert atmosphere;
In a 100-ml three-neck flask, 0.825 g (2.66 mmol) of compound a-8, 0.665 g (2.66 mmol) of compound a-13, 6.5 g of sodium carbonate, 30 ml of toluene, 10 ml of ethanol, and 20 ml of water were placed, and in a nitrogen atmosphere, under stirring at room temperature, 90.1 mg oftetrakis (triphenylphosphine) palladium (0 ) was added thereto. The resulting mixture was heated to 80C, and stirring was performed for 5 hours. After completion of the reaction, the organic layer was extracted with toluene and dried over anhydrous sodium sulfate, followed by purification by silica gel column chromatography (developing solvent:toluene/heptane mixture) to give 0.534 g (yield 57%) of intermediate a-14 (white solid) .
With caesium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 105℃; for 14h;Inert atmosphere;
A 100-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 102b (1.00 g, 5.37 mmol), (2.69 g, 10.7 mmol), cesium carbonate (3.49 g, 10.7 mmol), N,N'-dimethylethylenediamine (473 mg, 5.37 mmol) and 1 ,4-dioxane (45 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper iodide (510 mg, 2.69 mmol) was added, and the reaction mixture was heated at 105 C (oil bath temperature) for 14 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (200 mL) and water (40 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 62% yield (1.18 g) of 102c as an off-white solid: mp 178-180 C; ]H NMR (300 MHz, CDC13) delta 7.74 (dt, 1H, / = 8.2, 1.0 Hz), 7.58 (dd, 1H, / = 7.8, 1.2 Hz), 7.37 (m, 3H), 7.19 (m, 3H), 4.45 (m, 2H), 4.21 (m, 1H), 3.95 (m, 1H), 2.38 (s, 3H); MS (ESI+) m/z 355.0 (M+H).
With caesium carbonate;copper(l) iodide; N-methyl-ethane-1,2-diamine; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 117a (400 mg, 1.27 mmol), <strong>[69321-60-4]2,6-dibromotoluene</strong> (633 mg, 2.53 mmol), cesium carbonate (828 mg, 2.54 mmol), N-methylethylenediamine (112 mg, 1.27 mmol) and 1 ,4-dioxane (20 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper iodide (121 mg, 2.54 mmol) was added. A reflux condenser was attached to the flask, and the reaction mixture was heated at 100 C for 16 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column to afford 117b in 41% yield (251 mg) as a yellow oil: ]H NMR (500 MHz, CDC13) delta 7.71 (d, 1H, / = 8.0 Hz), 7.68 (d, 1H, / = 8.0 Hz), 7.63 (d, 1H, / = 8.0 Hz), 7.47 (t, 1H, / = 8.0 Hz), 7.32-7.28 (m, 2H), 7.21 (t, 1H, / = 8.0 Hz), 6.13 (s, 2H), 4.15 (m, 1H), 3.93 (m, 1H), 3.69 (m, 2H), 3.29 (m, 2H), 2.45 (s, 3H), 0.95 (t, 2H, / = 8.0 Hz), -0.07 (s, 9H).
With caesium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 105℃; for 14h;Inert atmosphere;
A 50-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with ethyl l-(2-aminoethyl)-4, 5,6,7- tetrahydro-lH-indole-2-carboxylate 101k (560 m g, 2.95 mmol), <strong>[69321-60-4]2,6-dibromotoluene</strong> (1.47 g, cesium carbonate (1.92 g, 5.90 mmol), N,N'-dimethylethylenediamine (260 mg, 2.95 mmol) and 1,4-dioxane (25 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper N,N'-dimethylethylenediamine (260 mg, 2.95 mmol) was added, and the reaction mixture was heated at 105 C (oil bath temperature) for 14 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (100 mL) and water (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by columnchromatography to afford a 57% yield (600 mg) of 2-(3-bromo-2-methylphenyl)-3,4,6,7,8,9- hexahydropyrazino[l,2-fl]indol-l(2H)-one 1011 as a white solid: mp 163-165 C; 'H NMR (500 MHz, DMSO-i¾ delta 7.57 (dd, 1H, J = 8.0, 0.5 Hz), 7.32 (d, 1H, J = 7.5 Hz), 7.21 (t, 1H, J = 8.0 Hz), 6.50 (s, 1H), 4.11 (m, 3H), 3.75 (m, 1H), 2.59 (m, 2H), 2.45 (m, 2H), 2.21 (s, 3H), 1.78 (m, 2H), 1.68 (m, 2H); (APCI+) m/z 358.6 (M+H)
With caesium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 105℃; for 16h;Inert atmosphere; Reflux;
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 107c (775 mg, 4.10 mmol), <strong>[69321-60-4]2,6-dibromotoluene</strong> (2.05 g, 8.19 mmol), cesium carbonate (2.67 g, 8.19 mmol), N,N'-dimethylethylenediamine (361 mg, 4.10 mmol) and 1,4-dioxane (15 rriL). After bubbling nitrogen through the resulting suspension for 30 min, copper iodide (390 mg, 2.05 mmol) was added. A reflux condenser was attached to the flask, and the reaction mixture was heated at 105 C for 16 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (100 rriL) and water (50 rriL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (50 rriL), and the combined organic layers were washed with brine (50 rriL) and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 80:20 hexanes/ethyl acetate) to afford 107d in 66% yield (972 mg) as an amorphous off-white solid: mp 120-122 C; ]H NMR (500 MHz, CDC13) delta 7.99 (d, 7 = 1.5 Hz, 1H), 7.68 (dd, 7 = 8.0, 1.5 Hz, 1H), 7.60 (dd, 7 = 8.0, 1.5 Hz, 1H), 7.46 (dd, 7 = 8.0, 0.5 Hz, 1H), 7.22 (dd, 7 = 8.0, 1.0 Hz, 1H), 7.14 (t, 7 = 8.0 Hz, 1H), 4.67 (s, 2H), 2.31 (s, 3H), 1.40 (s, 9H); MS (ESI+) mJz 358.1 (M+H).
(3-bromo-2-methyl-phenyl)-methyl-phenyl-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 72h;Inert atmosphere;
Example 156A (3-bromo-2-methyl-phenyl)-methyl-phenyl-amine 1,3-Dibromo-2-methylbenzene (5.01 g) and N-methylaniline (1.00 g) were added to toluene (65 mL). The solution was degassed and flushed with nitrogen three times. Cesium carbonate (9.12 g), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.872 g), and palladium (II) acetate (0.314 g) were added. The solution was degassed and flushed with nitrogen and then heated to 85 C. for 72 hours. The solution was cooled, added to 1 M aqueous HCl, and extracted with diethyl ether. The extract was washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified on silica gel using 2% ethyl acetate in hexanes.
8-cyclopropyl-3,4-dihydro-2H-1,4-benzoxazepin-5-one[ No CAS ]
[ 69321-60-4 ]
4-(3-bromo-2-methylphenyl)-8-cyclopropyl-2,3-dihydro-1,4-benzoxazepin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
Intermedite VIII- 1: 4-(3-bromo-2-methyl-phenyl)-8-cycIopropyl-2,3-dihydro-l,4- benzoxazepin-5-one Step-I: Argon was purged through a solution of VII-1 (9 g, 44.33 mmol), 2, 6-dibromo toluene ( 16.6 g, 66.5 mmol), N,N- dimethylcyclohexane- l ,2-diamine (2.52 g, 1 7.7 mmol) and K3PO4 (18.8 g, 88.66 mmol) in dioxane for 30 min and then cuprous iodide (3.37 g, 3.37 mmol) was added. The resulting reaction mixture was then heated at 100 C for 16 h. After completion of reaction (monitored by TLC), the solid was filtered off and the filtrate was diluted using EtOAc (150 mL). The organic layer was washed with water ( 100 mL), brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product so obtained was purified by silica gel column chromatography (using 20% EtOAc in hexane) to afford title compound VIII- 1 (7 g, 44%); LCMS: m/z 372 (M+l )+. NMR (CDC13, 400 MHz) delta 0.74-0.78 (m, 2H); 1.02- 1.06 (m, 2H); 1 .80-1.93 (m, l H); 2.36 (s, 3H); 3.80-3.82 (m, 2H); 4.42-4.44 (m, 2H); 6.75 (s, 1H); 6.90 (d, J = 8.0 Hz, 1 H); 7.1 1 -7.19 (aromatics, 2H); 7.55 (d, J= 8.0 Hz, 1H); 7.76 (d, J = 8.0 Hz, 1 H).
44%
Argon was purged through a solution of VII-1 (9 g, 44.33 mmol), 2,6-dibromo toluene (16.6 g, 66.5 mmol), N,N-dimethylcyclohexane-1,2-diamine (2.52 g, 17.7 mmol) and K3PO4 (18.8 g, 88.66 mmol) in dioxane for 30 min and then cuprous iodide (3.37 g, 3.37 mmol) was added. The resulting reaction mixture was then heated at 100 C. for 16 h. After completion of reaction (monitored by TLC), the solid was filtered off and the filtrate was diluted using EtOAc (150 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product so obtained was purified by silica gel column chromatography (using 20% EtOAc in hexane) to afford title compound VIII-1 (7 g, 44%); LCMS: m/z 372 (M+1)+. 1H NMR (CDCl3, 400 MHz) delta 0.74-0.78 (m, 2H); 1.02-1.06 (m, 2H); 1.80-1.93 (m, 1H); 2.36 (s, 3H); 3.80-3.82 (m, 2H); 4.42-4.44 (m, 2H); 6.75 (s, 1H); 6.90 (d, J=8.0 Hz, 1H); 7.11-7.19 (aromatics, 2H); 7.55 (d, J=8.0 Hz, 1H); 7.76 (d, J=8.0 Hz, 1H).
2-(3-bromo-2-methylphenyl)-6-cyclopropylphthalazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17 mg
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 150℃; for 18h;Inert atmosphere;
6-Cyclopropylphthalazin-1(2H)-one (56 mg, 0.30 mmol), <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (150 mg, 0.60 mmol), cesium carbonate (195 mg, 0.60 mmol) and copper (I) iodide (11 mg, 0.06 mmol) were dissolved in DMSO (2 mL). The reaction vessel was filled with nitrogen during a period of 5 min, and then stirred at 150 C for 18 h. Cooled to ambient temperature, the reaction mixture was poured into cold water, and extracted with ethyl acetate for 2 times. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by chromatography on silica gel, eluted with hexane/ethyl acetate to afford 2-(3-bromo-2-methylphenyl)-6-cyclopropylphthalazin -1(2H)-one (17 mg). 1H NMR (400 MHz, DMSO-d6) delta 11.23 - 10.60 (m, 1H), 7.69 - 7.63 (m, 2H), 7.50 - 7.45 (m, 1H), 7.45 - 7.33 (m, 1H), 7.21 - 7.08 (m, 1H), 6.95 - 6.83 (m, 1H), 2.23 - 2.12 (m, 4H), 1.13 - 1.06 (m, 2H), 0.90 - 0.84 (m, 2H).; LCMS (m/z): 355.1, 357.1 [M+H]+.
2-(3-bromo-2-methylphenyl)-3,4-dihydroisoquinolin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 160℃; for 4h;Inert atmosphere;
A mixture of 3,4-dihydroisoquinolin-1(2H)-one (3.5 g, 13.6 mmol), <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (17.5 g, 70.5 mmol) and K2C03 (9.85 g, 71.3 mmol) in DMSO (40 mL) was purged with N2, treated with CuT (1.75 g, 9 mmol) and heated to about 160 C for about 4 h. The reaction mixture was diluted with DCM and filtered through Celite. The filtrate was washed with 5% ammonia hydroxide, dried and concentrated. The residue was purified by column chromatography on silica gel to provide 2-(3- bromo-2-methylphenyl)-3,4-dihydroisoquinolin-](2H)-one (6 g, 80%): ?H NMR (CDC13) 3 8.16-8.14 (d, 1H), 7.56-7.54 (d, 2H), 7.49-7.41 (t, 1H), 7.26 (d, 1H), 7.25-7.18 (d, 1H), 7. 15-7.13 (d, 1H), 3.98- 3.92 (m, 1H), 3.76-3.70 (m, 1H), 3.30-3.22 (m, 1H), 3.13-3.07(m, 1H) 2.36 (s, 3H).
With tetrakis(triphenylphosphine) palladium(0); sodium hydroxide; In 1,4-dioxane; water; for 16h;Inert atmosphere; Schlenk technique; Reflux;
To a solution of <strong>[69321-60-4]2,6-dibromotoluene</strong> (15 mg, 0.06 mmol) in distilled 1,4-dioxane (0.08 mL) under argon, were added a 3 M aqueous solution of NaOH (0.11 mL), ferroceneboronic acid (90 mg, 0.4 mmol), and Pd(PPh3)4 (13 mg, 0.011 mmol). The reaction was stirred for 16 h. H2O (15 mL) was added to the resulting suspension and extracted with dichloromethane (10 mL). The organic layer was washed successively with 1 M NaOH (10 mL), brine (10 mL), and H2O (10 mL), dried with anhydrous MgSO4, filtered and evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography using 15% dichloromethane in hexanes as eluent to give 2,6-bisferrocenyltoluene as a red-orange solid (78%, Rf=0.25): m.p. 139.5-141.0 C (decomposition at 205 C); 1H NMR (500 MHz, CDCl3) delta 2.27 (3 H, s), 4.22 (10 H, s), 4.26 (4H, J=1.8 Hz, t), 4.42 (4H, J=1.9 Hz, t), 7.21 (1H, J=7.7 Hz, t), 7.73 (2H, J=7.6 Hz, d); 13C NMR delta 13.14, 67.54, 69.49, 70.59, 89.03, 124.59, 124.59, 129.50, 134.63, 137.98; IR: 1413, 1542, 2857, 2959 cm-1; HRMS (m/z): Calcd for C27H24Fe2, 460.0576; Found: 460.05687.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene; at 90℃; for 5h;Inert atmosphere;
The reaction vessel was a nitrogen gas atmosphere, the compound L4a (50 g), the compound L4b (75 g), toluene (500 mL), deionized water (500 mL), tetrakis (triphenylphosphine) palladium (0) (1.2 g) and sodium carbonate (85 g) was added and stirred for 5 hours at 90 C.. After cooling to room temperature, the resulting reaction solution was filtered using Celite, and the resulting filtrate was washed with deionized water. The resulting organic layer activated carbon (5 g) was added, after stirring for 1 hour at room temperature, filtered through celite, the resulting filtrate was concentrated under reduced pressure. The resulting concentrate was purified by crystallization using a mixed solvent of toluene and methanol and then dried under reduced pressure to give Compound L4c (65g, 91% yield) as a white solid. HPLC area percentage value of the compound L4c was 99.5% or more.
2-(3-bromo-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.362 g <strong>[69321-60-4]2,6-dibromo-toluene</strong> (9.45 mmol) was dissolved in 10 mL dry THF under N2 atmosphere and the mixture was cooled to -78 C. Then 5.2 mL nBuLi (2.OM in pentane,10.4 mmol) was added dropwise and the mixture was stirred for 15 minutes. Then 2.31 mL2-isopropoxy-4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolane (11.3 mmo 1) was added dropwise and the mixture was allowed to warm up to r.t.. It was stirred until no further conversion was observed. Then the mixture was quenched with aqueous NH4C1 solution, then extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and thefiltrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Preparation B7. 1H NMR(400 MHz, CDC13) oe: 7.67 (d, 1H), 7.62 (d, 1H), 7.10 (t, 1H), 2.53 (s, 3H), 1.29 (s, 12H)
(2R)-1-(3-bromo-2-methylphenyl)propan-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
n-BuLi (26.1 mL, 41.8 mmol) was added dropwise to a solution of <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (9.95 g, 39.8 mmol) in THF (100 mL) at -78 C. After stirring for 30 minutes, (R)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (10.39 g, 43.8 mmol) was added in portions and the reaction was stirred for a further 30 minutes before being allowed to warm to 0 C. over 30 minutes. 1N citric acid was added and the mixture was stirred for 5 minutes before it was extracted with EtOAc (*2). The combined organic phases were evaporated. The residue was stirred in 4M HCl in dioxane (69.7 mL, 278.7 mmol) at room temperature for 1 hour, then the volatiles were evaporated. The residue was suspended in diethyl ether, and extracted with water (*2). The combined aqueous phases were basified by addition of 2N Na2CO3, then extracted with DCM (*3). The combined organics phases were dried over MgSO4 and concentrated to afford (R)-1-(3-bromo-2-methylphenyl)propan-2-amine (7.55 g, 83%) as a yellow oil. 1H NMR (400 MHz, CDCl3, 27 C.) 1.13 (3H, d), 1.43 (2H, s), 2.40 (3H, s), 2.61 (1H, dd), 2.77 (1H, dd), 3.14 (1H, dq), 6.97 (1H, t), 7.08 (1H, d), 7.43 (1H, d). m/z (ES+), [M+H]+=228.
(2R)-1-(3-bromo-2-methylphenyl)propan-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
n-BuLi (26.1 mL, 41.8 mmol) was added dropwise to a solution of <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (9.95 g, 39.8 mmol) in THF (100 mL) at -78 C. After stirring for 30 minutes, (R)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (10.39 g, 43.8 mmol) was added in portions and the reaction was stirred for a further 30 minutes before being allowed to warm to 0 C. over 30 minutes. 1N citric acid was added and the mixture was stirred for 5 minutes before it was extracted with EtOAc (*2). The combined organic phases were evaporated. The residue was stirred in 4M HCl in dioxane (69.7 mL, 278.7 mmol) at room temperature for 1 hour, then the volatiles were evaporated. The residue was suspended in diethyl ether, and extracted with water (*2). The combined aqueous phases were basified by addition of 2N Na2CO3, then extracted with DCM (*3). The combined organics phases were dried over MgSO4 and concentrated to afford (R)-1-(3-bromo-2-methylphenyl)propan-2-amine (7.55 g, 83%) as a yellow oil. 1H NMR (400 MHz, CDCl3, 27 C.) 1.13 (3H, d), 1.43 (2H, s), 2.40 (3H, s), 2.61 (1H, dd), 2.77 (1H, dd), 3.14 (1H, dq), 6.97 (1H, t), 7.08 (1H, d), 7.43 (1H, d). m/z (ES+), [M+H]+=228.
60%
n-BuLi in hexanes (2.5 M; 8.1 mL, 20 mmol) was added dropwise to a solution of <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (4.8 g, 19 mmol) in THF (50 mL) at -78 C. at such a rate as to keep the internal reaction temperature below -60 C. After stirring for 30 minutes, tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5.01 g, 21.1 mmol) was added in portions, and the reaction was stirred for a further 30 minutes before being allowed to warm to 0 C. over 2 hours. Aqueous citric acid (1N; 40 mL) was added at 0 C., and the mixture was stirred for 15 min before it was extracted with EtOAc (2*100 mL). The combined organic layers were concentrated under reduced pressure. The residue was stirred in HCl in dioxane (4N; 30 mL) at room temperature for 1 hour and then concentrated. The resulting residue was dissolved in water (100 mL) and extracted with diethyl ether (2*60 mL). The aqueous layer was then basified by addition of Na2CO3 and extracted with DCM (3*100 mL). The combined DCM extracts were dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Product fractions were concentrated to dryness to afford (R)-1-(3-bromo-2-methylphenyl)propan-2-amine (2.6 g, 60%) as a brown oil. 1H NMR (500 MHz, DMSO-d6, 27 C.) 1.1 (3H, d) 2.34 (3H, s) 2.64 (1H, dd) 2.77 (1H, dd) 3.08 (1H, ddd) 7.05 (1H, t) 7.15 (1H, d) 7.45 (1H, d). NH2 was not observed. m/z: ES+ [M+H]+ 228.
(2R)-l-(3-bromo-2-methyl-phenyl)propan-2-amine w-BuLi (1.6M in hexanes) (67.6 mL, 108.10 mmol) was added dropwise to a solution of l,3-dibromo-2-methylbenzene (25.73 g, 102.95 mmol) in THF (250 mL) at -78 C at such a rate as to keep the internal reaction temperature below -60 C. After stirring for 30 min, tert-butyl (4R)-4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (26.9 g, 113.24 mmol) was added in portions and the reaction was stirred for a further 30 min before being allowed to warm to 0 C over 2 hours. IN Citric acid (200 mL) was added (at 0 C) and the mixture was stirred for 15 min before it was extracted with EtOAc (2 x 250 mL). The combined organic layers were evaporated. The residue was stirred in 4N HC1 in dioxane (100 mL) at room temperature for 1 hour and then concentrated. The residue was dissolved in water (200 mL) and extracted with diethyl ether (2 x 200 mL). The aqueous was then basified by addition of Na2C03 and extracted with DCM (3 x 250 mL). The combined DCM extracts were dried (MgS04) and concentrated to afford (2R)-l-(3-bromo-2-methyl- phenyl)propan-2-amine (14.36 g, 61%) as a yellow oil. lH NMR (400 MHz, CDC13, 30 C) 1.13 (3H, d), 2.40 (3H, s), 2.62 (1H, dd), 2.77 (1H, dd), 3.16 (1H, ddd), 6.97 (1H, t), 7.09(1H, dd), 7.43 (1H, dd). NH2 was not observed, m/z: ES+ [M+H]+ 228/230.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere;
Embodiment 5 (E)-2-((2,6-Dimethoxy-4-(2-(2-methylbiphenyl-3-yl)vinyl)benzyl)amino)pro pane-1,3-diol 5 Synthetic route Synthesis of compound 5-c Phenylboronic acid (1.626g, 13.34mmol) and <strong>[69321-60-4]2,6-dibromotoluene</strong> (5.0g, 20.0mmol) were dissolved in a mixed solvent of 1,4-dioxane (60mL) and water (3mL), followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.154g, 1.334mmol) and sodium carbonate (3.535g, 33.35mmol). After the reaction system was purged with nitrogen three times, the reaction solution was heated to 80C and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100mL), washed successively with water (100mL x 3) and saturated brine (100mL). The obtained organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give compound 5-c (1.9g, yield 57.2%). 1H NMR (400 MHz, CDCl3) delta: 7.56-7.54 (m, 1H), 7.44-7.35 (m, 3H), 7.28-7.25 (m, 2H), 7.17-7.15 (m, 1H), 7.08 (t, J = 8Hz, 1H), 2.31 (s, 3H) ppm.
4.7 g
With potassium carbonate; In 1,4-dioxane; water; at 20℃;
A mixture of <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (6.0 g, 24 mmol), phenylboronic acid(2.9 g, 24 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1: 1) (817 mg, 1. 0 mmol) and potassium carbonate (1 0 g, 725 mmol) in 1,4-dioxane (100 mL) and water (70 mL) was stirred at room temperatureovernight. The reaction was quenched with water, and extracted with ethyl acetate (3x 150mL). The combined organic layers were washed with brine, dried over Na2S04, filtered andconcentrated under reduced pressure. The residue was purified by chromatography on silicagel, eluting with 0-5% EtOAc/hexanes, to give the desired product (4.7 g).
tert-butyl 2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate[ No CAS ]
tert-butyl 2-(3'-bromo-2,2'-dimethylbiphenyl-3-yl)-4H-pyrrolo[3,4-d]thiazole-5(6H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
210 mg
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃;
A mixture of <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (Combi Blocks catOT-1437: 339 mg, 1.356 mmol), tert-butyl 2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylate (200.0 mg, 0.452 mmol), sodium carbonate (96 mg, 0.904 mmol) and tetrakis(triphenylphosphine)palladium(0) (52.2 mg, 0.045 mmol) in dioxane (3.00 mL)/ water (1.0 mL) was heated at 90 C. overnight. The reaction was then cooled to room temperature, diluted with saturated aqueous NH4Cl, and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel, eluting with 0-40% EtOAc/hexanes, to give the desired product (210 mg). LC-MS calculated for C24H26BrN2O2S (M+H)+: m/z=485.1/487.1; found 485.0/487.0.
tert-butyl 4-((3-bromo-2-methylphenyl)ethynyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In 1,4-dioxane; at 90℃; for 3h;Inert atmosphere;
A mixture of <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (Combi-Blocks catOT-1437: 143 mg, 0.573 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (ArkPharm catalog AK-34528: 60 mg, 0.287 mmol), copper(I) iodide (4.37 mg, 0.023 mmol), dichlorobis(triphenylphosphine)-palladium( II) (26.8 mg, 0.038 mmol), and triethylamine (0.080 ml, 0.573 mmol) in 1,4-Dioxane (3.0 ml) was flushed with N2. The resulting slurry was stirred at 90 C. for 3 h. The reaction was then quenched with water, extracted with EtOAc (3×15 mL). The organic layers were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel, eluting with 0-35% ethyl acetate/hexanes, to give the desired product. LC-MS calculated for C15H17BrNO2 (M+H-tBu)+: m/z=322.0; found 322.0.
tert-butyl 5-(3-bromo-2-methylphenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium diacetate; caesium carbonate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In 1,4-dioxane; at 90.0℃;Inert atmosphere;
A mixture of <strong>[1147422-00-1]tert-butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate</strong> (Combi-Blocks catalog ST-7254: 60 mg, 0.265 mmol), 1,3-dibromo-2-methylbenzene (Combi-Blocks cat OT-1437: 199 mg, 0.795 mmol), palladium(II) acetate (5.95 mg, 0.027 mmol), (R)-(+)-2,2?-bis(diphenylphosphino)-1,1?-binaphthyl (16.51 mg, 0.027 mmol), and cesium carbonate (173 mg, 0.530 mmol) in 1,4-Dioxane (5.0 ml) was flushed with N2. The resulting slurry was stirred at 90 C. overnight. After being cooled to room temperature, the reaction mixture was quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel, eluting with ethyl acetate in hexanes (0-50%) to afford the desired product. LC-MS calculated for C19H28BrN2O2 (M+H)+: m/z=395.1; found 395.1.
<Reaction Scheme 1> In the reaction vessel, <strong>[69321-60-4]2,6-dibromotoluene</strong> (1.00 g, 4.00 mmol), 20 ml of tetrahydrofuran was added and the mixture was stirred at -78 C. Thereafter, 1.6 M n-butyl lithium (n-BuLi) hexane solution (2.53 ml, 4.00 mmol) was added dropwise, After further stirring for 1 hour, 3,5-diphenyl-1-chlorotriazine was added, 3 hours at room temperature, Followed by stirring. After completion of the reaction, water was added to the reaction mixture, The mixture was extracted with chloroform, and the organic layer was concentrated. after that, Tetrahydrofuran was added to and dissolved in the obtained residue, Purification was carried out by reprecipitation twice using methanol to obtain Compound A.
tert-butyl ((3’-bromo-2’-methyl-[1,1‘-biphenyl]-4-yl)methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;
<strong>[489446-42-6](4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid</strong> (1 g, 4 mmol), 1,3-dibromo-2- methylbenzene (2 g, 8 mmol), Pd(dppf)C12CH2C12 (0.32 g, 0.4 mmol) and potassium carbonate (1.6 g, 12mmol) were suspended in 10 mL dioxane and 1 mL water. The mixture was sparged for 5 mm withargon and heated to 90 C in a heating block for 4 h. After cooling to room temperature, the reaction was diluted with EtOAc and brine. The organic layer was separated, dried with Na2SO4 and concentrated.Purified by silica gel chromatography (eluting with EtOAc-Hex) to provide tert-butyl ((3?-bromo-2?- methyl-[ 1,1 ?-biphenyll -4-yl)methyl)carbamate.
(R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ol[ No CAS ]
(R)-4-(3-bromo-2-methylphenyl)-2,3-dihydro-1H-inden-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere;
(R)-4-(4,4,5,5 -tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2,3 -dihydro- 1H-inden- 1-01 (2 g, 7.7 mmol),<strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (3.8 g, 15.4 mmol), Pd(dppf)C12CH2C12 (0.44 g, 0.77 mmol) and potassium carbonate (2.1 g, 15.4 mmol) were suspended in 20 mL dioxane and 2 mL water. The mixture was sparged for 10 mm with argon and heated to 90 C in a heating block for 4 h. After cooling to room temperature, the reaction was diluted with EtOAc and brine. The organic layer was separated, dried withNa2SO4 and concentrated. Purified by silica gel chromatography (eluting with EtOAc-Hex) to provide (R)-4-(3-bromo-2-methylphenyl)-2,3 -dihydro- 1H-inden- 1 -ol.
2’-methyl-3‘-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1‘-biphenyl]-4-carbaldehyde[ No CAS ]
3”-bromo-2’,2”-dimethyl[1,1’:3,1“-terphenyl]-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;
2?-methyl-3 ?-(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- [1,1 ?-biphenyll -4-carbaldehyde (1 g,3.1 mmol), <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (1.57 g, 6.2 mmol), Pd(dppf)C12CH2C12 (0.178 g, 0.22 mmol)and potassium carbonate (1.3 g, 9.3 mmol) were suspended in 10 mL dioxane and 1 mL water. The mixture was sparged for 10 mm with argon and heated to 90 C in a heating block for 4 h. After cooling to room temperature, the reaction was diluted with EtOAc and brine. The organic layer was separated, dried with Na2SO4 and concentrated. Purified by silica gel chromatography (eluting with EtOAc-Hex) to provide 0.72 g (63%) of 3?-bromo-2?,2?-dimethyl-[ 1,1?: 3,1 ?-terphenylj-4-carbaldehyde.
2.3-dihydro-1,4-benzodioxin-6-ylboronic acid[ No CAS ]
C15H13BrO2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere;
Embodiment 15 (S,E)-1-(4-(3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylstyryl)-2,6-dim ethoxybenzyl)pyrrolidin-2-yl)methanol 15 Synthesis of compound 15-c 1,4-Dioxane-6-benzeneboronic acid (3.60g, 20mmol) and <strong>[69321-60-4]2,6-dibromotoluene</strong> (7.50g, 30mmol) were dissolved in a mixed solvent of 1,4-dioxane (100mL) and water (15mL), followed by addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (817mg, 1mmol) and sodium carbonate (6.38g, 60mmol). After the reaction system was purged three times with nitrogen, the reaction solution was heated to 80C and stirred for 16 hours. Then the reaction solution was cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give compound 15-c (2.70g, yield 44%).
2,4-dibromo-3-methylbenzenesulfonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With chlorosulfonic acid; In 1,2-dichloro-ethane; at 20℃; for 72h;
To a solution of <strong>[69321-60-4]2,6-dibromotoluene</strong> (10.0 g, 40 mmol) in 1,2-dichloroethane (40 mL) was added drop wise chlorosufonic acid (4.66 g, 40 mmol, 1 eq). The reaction mixture was stirred at room temperature for 3 days, and monitored by TLC and LC-MS. After concentrated to about 20 mL, solid precipitated out. The solid was filtered and washed with hexane, and dried in vacuo to yield 2,4-dibromo-3-methylbenzenesulfonic acid (3.65 g, 28%) as pale white solid. LC-MS: 328.7 [M-H]"; NMR (300 MHz, CD3OD): delta 7.83 (d, J= 9.0 Hz, 1 H), 7.62 (d, J = 9.0 Hz, 1 H), 2.66 (s, 3 H).
4,4,5,5-tetramethyl-2-(thianthren-2-yl)-1,3,2-dioxaborolane[ No CAS ]
[ 69321-60-4 ]
4,4,5,5-tetramethyl-2-(phenoxathiin-3-yl)-1,3,2-dioxaborolane[ No CAS ]
C31H20OS3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 85℃; for 18h;
Intermediate 1 (3.25 mmol, 1.11 g),Intermediate 3 (3.25 mmol, 1.06 g),1,3-dibromo-2 toluene(3.25mmol, 750mg), potassium carbonate (20mmol, 2.76g), Pd(PPh3)4 (150mg), toluene 90mL, ethanol 40mLAfter entering the reactor and passing nitrogen for 15 min, the reaction was heated at 85 C for 18 h. After the reaction is over, the system is returned to room temperature, using twoThe organic phase was extracted by extracting methyl chloride and saturated brine, and the solvent was evaporated under reduced pressure. The crude product is separated and purified by column chromatography.The eluent was petroleum ether/dichloromethane 3:1 to give the product of structure (15) with a yield of 88%.
4,4,5,5-tetramethyl-2-(thianthren-2-yl)-1,3,2-dioxaborolane[ No CAS ]
[ 69321-60-4 ]
C31H20S4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 85℃; for 18h;
Intermediate 1 (3.25 mmol, 1.11 g),1,3-dibromo-2 toluene (1.62 mmol, 383 mg),Potassium carbonate (10 mmol, 1.38 g),Pd(PPh3)4 (100mg),Toluene 90mL,40 mL of ethanol was sequentially added to the reactor, and after passing nitrogen for 15 minutes,The reaction was heated at 85 C for 18 h.After completion of the reaction, the system was returned to room temperature, extracted with dichloromethane and brine, and the organic phase was recovered.The crude product was purified by column chromatography eluting with petroleum ether/dichloromethane 3:1 to afford product (11).
tert-butyl N-[5-(3-bromo-2-methylphenyl)indan-2-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 95℃; for 2h; Inert atmosphere;
41 tert- Butyl N-[5-(3-bromo-2-methyl-phenyl)indan-2-yl] carbamate:
To a solution of fe/V-butyl N-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indan-2- yljcarbamate (0.50 g, 1.39 mmol) and l,3-dibromo-2-methyl-benzene (0.35 g, 1.39 mmol) in degassed dioxane (5 mL) were added a solution of potassium carbonate (0.58 g, 4.18 mmol) in degassed H2O (1 mL) and Pd(PPh3)4 (0.16 g, 0.14 mmol) and the mixture was stirred at 95 °C for 2 hours under N2(g). After cooling to rt and workup, the residue was purified by flash column chromatography using ethyl acetate in hexanes as eluent (0 to 20% gradient). 'H NMR (400 MHz, Chloroform-d): d 7.54 (dd, J= 8.0, 1.4 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.16 - 7.10 (m, 2H), 7.10 - 7.04 (m, 2H), 4.85 (s, 1H), 4.53 (s, 1H), 3.41 - 3.26 (m, 2H), 2.84 (dt, J = 16.1, 4.9 Hz, 2H), 2.32 (s, 3H), 1.47 (s, 9H).
With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In tetrahydrofuran; water monomer for 12h; Reflux; Inert atmosphere;
4
General procedure: Under nitrogen protection, in a dry 2L three-necked flask, add M1 (30g, 0.1mol), 9-([1,1'-biphenyl]-4-yl)-3-bromo-9H-carbazole (39.8, 0.1 mol) and tetrahydrofuran 500mL, add potassium carbonate 27g, deionized water 100mL, tetrakis(triphenylphosphine)palladium 1.1g, turn on stirring, heat to reflux, and react for 12h. After the reaction, the organic phase was separated, extracted, dried, subjected to column chromatography, and the solvent was spin-dried to obtain 43.7 g of product M1 with a yield of 76%.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
