* 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 tin(ll) chloride In N,N-dimethyl-formamide for 1 h;
Preparation 1; 3 ,5 -dichloro-4-methylaniline; Dissolve 1, 3 -dichloro-2-methyl-5 -nitrobenzene (0.50 g, 2.43 mmol) in DMF and treat with tin (II) chloride dihydrate (2.74 g, 12.1 mmol) in a single portion. Stir the reaction for 1 hour and dilute with ethyl acetate and filter through celite. Wash the filtrate four times with water and twice with brine, dry over MgSO4, filter and concentrate to a dark oil. Purify the residue by silica gel chromatography eluting with a gradient of 5percent to 10percent ethyl acetate in hexanes to give 342 mg (80percent) of the titled product as white flakes.
80%
With tin(ll) chloride In N,N-dimethyl-formamide for 1 h;
Preparation 8; 3 ,5 -dichloro-4-methylaniline; Dissolve l,3-dichloro-2-methyl-5-nitrobenzene (0.50 g, 2.43 mmol) in DMF and treat with tin (II) chloride dihydrate (2.74 g, 12.1 mmol) in a single portion. Stir the reaction for 1 hour, dilute with ethyl acetate, and filter through celite. Wash the filtrate four times with water and twice with brine, dry over MgSO4, filter and concentrate to a dark oil. Purify the residue by silica gel chromatography eluting with a gradient of 5percent to 10percent ethyl acetate in hexanes to give 342 mg (80percent) of the titled product as white flakes.
0.28 g
With iron; ammonium chloride In methanol; water at 20℃; Inert atmosphere; Reflux
Purged a 50-mL round-bottomed flask with argon. Charged l,3-dichloro-2-methyl-5- nitrobenzene (500 mg, 2.43 mmol, Eq: 1.00; from Maybridge), iron (678 mg, 12.1 mmol, Eq: 5.0), ammonium chloride (1.3 g, 24.3 mmol, Eq: 10.0), methanol (10 mL), and water (5 mL) while purging with argon. Fitted the reaction flask with a condenser, then sealed under a positive pressure of argon. Heated at reflux for 2 h, then cooled to room temperature. Stirred over weekend at room temperature. HPLC showed the reaction was complete. Filtered the reaction mixture through a bed of celite, rinsing with methanol. Concentrated filtrate. Added water and ethyl acetate, then added solid sodium bicarbonate. Transferred the mixture to a separatory funnel and added more ethyl acetate. Split layers and washed the organic layer with saturated sodium chloride solution. Dried over magnesium sulfate, filtered, and concentrated. Obtained 0.28 g (65.5percent) of 3,5-dichloro-4-methylaniline as a yellow solid. The FontWeight="Bold" FontSize="10" H NMR showed a second, unknown component. Carried to the isothiocyanate
Reference：
[1] Gazzetta Chimica Italiana, 1996, vol. 126, # 3, p. 179 - 185
[2] Tetrahedron, 1998, vol. 54, # 12, p. 2953 - 2966
[3] Patent: WO2007/127763, 2007, A2, . Location in patent: Page/Page column 37
[4] Patent: WO2007/127726, 2007, A2, . Location in patent: Page/Page column 40
[5] Journal of the Chemical Society, 1931, p. 79,81
[6] Journal of the Chemical Society, 1922, vol. 121, p. 814
[7] Patent: US2010/222345, 2010, A1, . Location in patent: Page/Page column 94
[8] Patent: WO2014/6066, 2014, A1, . Location in patent: Paragraph 0256
2
[ 121-86-8 ]
[ 54730-35-7 ]
Reference：
[1] Journal of the Chemical Society, 1922, vol. 121, p. 814
3
[ 99-99-0 ]
[ 54730-35-7 ]
Reference：
[1] Journal of the Chemical Society, 1931, p. 79,81
4
[ 54730-35-7 ]
[ 204930-37-0 ]
Yield
Reaction Conditions
Operation in experiment
45%
Stage #1: With hydrogen bromide In water at 0 - 20℃; Heating / reflux Stage #2: With sodium nitrite In water at 0℃; for 0.25 h; Stage #3: With hydrogen bromide; copper(I) bromide In water at 50℃; for 1 h;
Preparation 2; 5-bromo- 1 ,3-dichloro-2-methylbenzene; Suspend the 3,5-dichloro-4-methylaniline in 48percent HBr (5 mL) and water (5 mL) and heat with a heat gun until the mixture is near the boiling point. Cool the slurry to room temperature and then cool to 00C with an ice/brine bath. Add a solution of sodium nitrite (109 mg, 1.58 mmol) in water (2 mL) dropwise. After the addition is complete, stir <n="39"/>the reaction an additional 15 min in the cold bath. Add a solution of CuBr (1.08 g, 7.53 mmol) in 48percent HBr (2 mL) and heat the rapidly stirring reaction to 500C for 1 hour. Cool the reaction to room temperature, dilute the reaction with ethyl acetate and discard the aqueous layer. Wash the organic layer with water and brine, dry with MgSO4, filter through celite and concentrate to an orange residue. Purify the residue by silica gel chromatography eluting with hexanes to afford 164 mg (45percent) of the product as a yellow solid.
45%
Stage #1: With hydrogen bromide In waterHeating / reflux Stage #2: With sodium nitrite In water at 0℃; for 0.25 h; Stage #3: With hydrogen bromide; copper(I) bromide In water at 50℃; for 1 h;
Preparation 9; 5-bromo-l,3-dichloro-2-methylbenzene; Suspend 3, 5 -dichloro-4-methylaniline in 48percent HBr (5 mL) and water (5 mL) and heat with a heat gun until the mixture is near the boiling point. Cool the slurry to room temperature and then cool to 00C with an ice/brine bath. Add dropwise a solution of sodium nitrite (109 mg, 1.58 mmol) in water (2 mL). After the addition is complete, stir the reaction an additional 15 min in the cold bath. Add a solution of CuBr (1.08 g, 7.53 mmol) in 48percent HBr (2 mL) and heat the rapidly stirring reaction to 500C for 1 hour. Cool the reaction to room temperature, dilute with EtOAc and discard the aqueous layer. Wash the organic layer with water and brine, dry with MgSO4, filter through celite and concentrate to an orange residue. Purify the residue by silica gel chromatography eluting with hexanes to afford 164 mg (45percent) of the product as a yellow solid.
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 2, 2000, # 4, p. 871 - 877
[2] Patent: WO2007/127763, 2007, A2, . Location in patent: Page/Page column 37-38
[3] Patent: WO2007/127726, 2007, A2, . Location in patent: Page/Page column 40
[4] Tetrahedron, 1998, vol. 54, # 12, p. 2953 - 2966
[5] Patent: US2010/222345, 2010, A1, . Location in patent: Page/Page column 94
5
[ 54730-35-7 ]
[ 111829-72-2 ]
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 2, 2000, # 4, p. 871 - 877
With tin(ll) chloride; In N,N-dimethyl-formamide; for 1h;
Preparation 1; 3 ,5 -dichloro-4-methylaniline; Dissolve 1, 3 -dichloro-2-methyl-5 -nitrobenzene (0.50 g, 2.43 mmol) in DMF and treat with tin (II) chloride dihydrate (2.74 g, 12.1 mmol) in a single portion. Stir the reaction for 1 hour and dilute with ethyl acetate and filter through celite. Wash the filtrate four times with water and twice with brine, dry over MgSO4, filter and concentrate to a dark oil. Purify the residue by silica gel chromatography eluting with a gradient of 5% to 10% ethyl acetate in hexanes to give 342 mg (80%) of the titled product as white flakes.
80%
With tin(ll) chloride; In N,N-dimethyl-formamide; for 1h;
Preparation 8; 3 ,5 -dichloro-4-methylaniline; Dissolve l,3-dichloro-2-methyl-5-nitrobenzene (0.50 g, 2.43 mmol) in DMF and treat with tin (II) chloride dihydrate (2.74 g, 12.1 mmol) in a single portion. Stir the reaction for 1 hour, dilute with ethyl acetate, and filter through celite. Wash the filtrate four times with water and twice with brine, dry over MgSO4, filter and concentrate to a dark oil. Purify the residue by silica gel chromatography eluting with a gradient of 5% to 10% ethyl acetate in hexanes to give 342 mg (80%) of the titled product as white flakes.
With tin(II) chloride dihdyrate; In ethanol; for 2h;Reflux;
A mixture of 1,3-dichloro-2-methyl-5-nitrobenzene (5.0 g, 24.3 mmol) and tin(II) chloride dihydrate (21.9 g, 97.1 mmol) in ethanol (80 mL) was heated at reflux for 2 h. The reaction was allowed to cool, then was quenched with water and saturated aq. sodium bicarbonate until slightly basic. (Addition of sodium bicarbonate caused vigorous gas emission) The thick mixture was extracted with ethyl acetate (3×) and the combined extracts were dried over sodium sulfate and concentrated in vacuo. Chromatography (20% ethyl acetate/hexanes) provided the product, 3,5-dichloro-4-methylaniline. 1H NMR (400 MHz, CDCl3) delta 2.29 (s, 3H), 2.35 (br s, 2H), 6.66 (s, 2H).
0.28 g
With iron; ammonium chloride; In methanol; water; at 20℃; under 760.051 Torr;Inert atmosphere; Reflux;
Purged a 50-mL round-bottomed flask with argon. Charged l,3-dichloro-2-methyl-5- nitrobenzene (500 mg, 2.43 mmol, Eq: 1.00; from Maybridge), iron (678 mg, 12.1 mmol, Eq: 5.0), ammonium chloride (1.3 g, 24.3 mmol, Eq: 10.0), methanol (10 mL), and water (5 mL) while purging with argon. Fitted the reaction flask with a condenser, then sealed under a positive pressure of argon. Heated at reflux for 2 h, then cooled to room temperature. Stirred over weekend at room temperature. HPLC showed the reaction was complete. Filtered the reaction mixture through a bed of celite, rinsing with methanol. Concentrated filtrate. Added water and ethyl acetate, then added solid sodium bicarbonate. Transferred the mixture to a separatory funnel and added more ethyl acetate. Split layers and washed the organic layer with saturated sodium chloride solution. Dried over magnesium sulfate, filtered, and concentrated. Obtained 0.28 g (65.5%) of 3,5-dichloro-4-methylaniline as a yellow solid. The FontWeight="Bold" FontSize="10" H NMR showed a second, unknown component. Carried to the isothiocyanate
Preparation 2; 5-bromo- 1 ,3-dichloro-2-methylbenzene; Suspend the 3,5-dichloro-4-methylaniline in 48percent HBr (5 mL) and water (5 mL) and heat with a heat gun until the mixture is near the boiling point. Cool the slurry to room temperature and then cool to 00C with an ice/brine bath. Add a solution of sodium nitrite (109 mg, 1.58 mmol) in water (2 mL) dropwise. After the addition is complete, stir <n="39"/>the reaction an additional 15 min in the cold bath. Add a solution of CuBr (1.08 g, 7.53 mmol) in 48percent HBr (2 mL) and heat the rapidly stirring reaction to 500C for 1 hour. Cool the reaction to room temperature, dilute the reaction with ethyl acetate and discard the aqueous layer. Wash the organic layer with water and brine, dry with MgSO4, filter through celite and concentrate to an orange residue. Purify the residue by silica gel chromatography eluting with hexanes to afford 164 mg (45percent) of the product as a yellow solid.
45%
Preparation 9; 5-bromo-l,3-dichloro-2-methylbenzene; Suspend 3, 5 -dichloro-4-methylaniline in 48percent HBr (5 mL) and water (5 mL) and heat with a heat gun until the mixture is near the boiling point. Cool the slurry to room temperature and then cool to 00C with an ice/brine bath. Add dropwise a solution of sodium nitrite (109 mg, 1.58 mmol) in water (2 mL). After the addition is complete, stir the reaction an additional 15 min in the cold bath. Add a solution of CuBr (1.08 g, 7.53 mmol) in 48percent HBr (2 mL) and heat the rapidly stirring reaction to 500C for 1 hour. Cool the reaction to room temperature, dilute with EtOAc and discard the aqueous layer. Wash the organic layer with water and brine, dry with MgSO4, filter through celite and concentrate to an orange residue. Purify the residue by silica gel chromatography eluting with hexanes to afford 164 mg (45percent) of the product as a yellow solid.
To a solution of HBr (40percent in water, 3.4 mL) in water (3 mL) was added 3,5-dichloro-4-methylaniline (2.0 g, 11.4 mmol). The suspension was heated to dissolve as much of the solid as possible, then the mixture was cooled to 0 degrees C. and a solution of sodium nitrite (0.83 g, 12.0 mmol) in water (2 mL) was added dropwise (temperature was maintained <5 degrees C.). After 10 min., the diazonium salt mixture was poured into a mixture of CuBr (8.2 g, 57.0 mmol) in 40percent aq. HBr (13 mL) at room temperature. The resulting mixture was heated at 50 degrees C. for 45 min., then cooled to room temperature. The mixture was diluted with water and extracted with dichloromethane (3.x.). The combined organics were filtered through Celite and dried over sodium sulfate, then concentrated in vacuo to provide the product, 5-bromo-1,3-dichloro-2-methylbenzene, as an orange solid. 1H NMR (400 MHz, CDCl3) delta 2.40 (s, 3H), 7.43 (s, 2H).
1-(3,5-dichloro-4-methylphenyl)-piperazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In butan-1-ol;
EXAMPLE 6 1-(3,5-Dichloro-4-methylphenyl) piperazine A mixture of <strong>[54730-35-7]3,5-dichloro-4-methylaniline</strong> (6g, prepared by the method of W. Davies, J. Chem. Soc. 1922, 806) and bis-2-chloroethylamine hydrochloride (6.05g) in n-butanol (25 ml) was stirred under reflux for 24 hr. Anhydrous potassium carbonate (4.69g) was added and the mixture was stirred under reflux for a further 48 hr. then filtered and allowed to cool. The resulting solid was removed by filtration and crystallized from ethanol-ether to give 1-(3,5-dichloro-4-methylphenyl) piperazine hydrochloride (0.82g) m.p. 280-287.
In dichloromethane; at 20℃; under 760.051 Torr;Inert atmosphere;
Transferred <strong>[54730-35-7]3,5-dichloro-4-methylaniline</strong> (0.28 g, 1.59 mmol, Eq: 1.00) to a 50-mL round-bottomed flask using dichoromethane (10 mL). Added Iota,Gamma-thiocarbonyldiimidazole (429 mg, 2.41 mmol, Eq: 1.51) and stirred overnight at room temperature. HPLC showed no starting material remaining. Concentrated the reaction mixture onto silica. Purified using a 12 g silica column on an Intelliflash 280; collected peaks only in 9 mL fraction at 32 mL/min; equilibrated with heptane; dry loaded; eluted 1 min with heptane; increased from 0 - 10%> dichloromethane/heptane over 5 min. Obtained 226 mg (65%) of l,3-dichloro-5-isothiocyanato- 2-methylbenzene as a yellow solid.
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