* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Materials Chemistry C, 2014, vol. 2, # 40, p. 8515 - 8524
2
[ 601-87-6 ]
[ 2687-25-4 ]
Reference：
[1] Journal of Materials Chemistry C, 2014, vol. 2, # 40, p. 8515 - 8524
[2] Chemische Berichte, 1891, vol. 24, p. 564
[3] Synthetic Communications, 2007, vol. 37, # 19, p. 3455 - 3470
3
[ 601-87-6 ]
[ 611-05-2 ]
[ 578-46-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1987, p. 1767 - 1772
4
[ 60310-07-8 ]
[ 601-87-6 ]
Yield
Reaction Conditions
Operation in experiment
90%
With bromine; sodium hydroxide In water at 0 - 80℃; for 2 h;
3-Methyl-2-nitroaniline To a mixture of NaOH (2.220 g, 55.5 mmol) in water (12 mL), Br2(0.322 mL, 6.26 mmol) was added at 0 °C. Then 3-methyl-2-nitrobenzamide (1 g, 5.55 mmol) was added in one portion, and the mixture is warmed slowly in a water bath. The material soon darkens in color, and at 50-55° C (internal temperature) oil droplets begin to separate. The temperature is raised gradually to 70° and maintained at this point for 1 h. A solution of 0.7 g. of NaOH in 4 cc. of water was added slowly and the temperature is increased to 80 °C for an additional hour. The reaction was cooled to RT and extracted with EtOAc (3x50 ml_). The combined organic layer was dried and concentrated to give 0.7 g (90percent) of the title compound. LC-MS m/z 153.1 (M+H)+, 1.65 (ret. time).
90%
With bromine; sodium hydroxide In water at 0 - 80℃; for 2 h;
3-Methyl-2-nitroaniline To a mixture of NaOH (2.220 g, 55.5 mmol) in water (12 mL), Br2 (0.322 mL, 6.26 mmol) was added at 0°C. Then 3-methyl-2-nitrobenzamide (1 g, 5.55 mmol) was added in one portion, and the mixture is warmed slowly in a water bath. The material soon darkens in color, and at 50-55° C (internal temperature) oil droplets begin to separate. The temperature is raised gradually to 70 °C and maintained at this point for one hour. A solution of 0.7 g of sodium hydroxide in 4 cc. of water was added slowly and the temperature is increased to 80°C for an additional hour. The reaction was cooled to ambient temperature and extracted with ethyl acetate (3x50mL). The combined organic layer was dried and concentrated to give 0.7 g (90percent) of the title compound. LC-MS m/z 153.1 (M+H)+, 1 .65 min (ret. time).
90%
With bromine; sodium hydroxide In water at 0 - 80℃; for 2 h;
To a mixture of NaOH (2.220 g, 55.5 mmol) in water (12 mL), Br2 (0.322 mL, 6.26 mmol) was added at 0 C. Then 3-methyl-2-nitrobenzamide (1 g, 5.55 mmol) was added in one portion, and the mixture is warmed slowly in a water bath. The material soon darkens in color, and at 50-55 00 (internal temperature) oil droplets begin to separate. The temperature is raised gradually to 70° and maintained at this point for one hour. A solution of 0.7 g. of NaOH in 4 mL.of water was added slowly and the temperature is increased to 80°C for an additional hour. The reaction was cooled to ambient temperature and extracted with EtOAc (3x5OmL). Thecombined organic layer was dried and concentrated to give of the title compound (0.7 g, 90percent). LC-MS m/z 153.1 (M+H), 1 .65 mm (ret. time).
90%
With bromine; sodium hydroxide In water at 0 - 80℃; for 2 h;
To a mixture of NaOH (2.220 g, 55.5 mmol) in water (12 mL), Br2 (0.322 mL, 6.26 mmol) was added at 0 C. Then 3-methyl-2-nitrobenzamide (1 g, 5.55 mmol) was added in one portion, and the mixture is warmed slowly in a water bath. The material soon darkens in color, and at 50-55 °C (internal temperature) oil droplets begin to separate. The temperature is raised gradually to 70° and maintained at this point for one hour. A solution of 0.7 g. of NaOH in 4 mL. of water was added slowly and the temperature is increased to 80°C for an additional hour. The reaction was cooled to ambient temperature and extracted with EtOAc (3x50mL). The combined organic layer was dried and concentrated to give of the title compound (0.7 g, 90percent). LC-MS m/z 153.1 (M+H)+, 1.65 min (ret. time).
90%
at 0 - 80℃; for 2 h;
To a mixture of NaOH (2.220 g, 55.5 mmol) in water (12 mL), Br2 (0.322 mL, 6.26 mmol) was added at 0°C. Then 3-methyl-2-nitrobenzamide (ig, 5.55 mmol) was added inportion, and the mixture was warmed slowly in a water bath. The material soon turnedin color, and at 50-55 C (internal temperature) oil droplets began to separate. Thetemperature was raised gradually to 70° and maintained at this point for one hour. A solution of 0.7g. of sodium hydroxide in 4 mL. of water was added slowly and the temperature was increased to 80°C for an additional hour. The reaction was cooled to ambient temperature and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried and concentrated to give 0.7 g (90percent) of the title compound. LC-MS m/z 153.1 (M+H), 1.65 (ret. time).
Reference：
[1] Patent: WO2015/92713, 2015, A1, . Location in patent: Page/Page column 73; 74
[2] Patent: WO2016/203400, 2016, A1, . Location in patent: Page/Page column 49
[3] Patent: WO2016/203401, 2016, A1, . Location in patent: Page/Page column 60; 61
[4] Patent: WO2016/202253, 2016, A1, . Location in patent: Page/Page column 126; 127
[5] Patent: WO2018/104766, 2018, A1, . Location in patent: Page/Page column 60-61
[6] Patent: WO2018/109648, 2018, A1, . Location in patent: Page/Page column 52; 53
[7] Recueil des Travaux Chimiques des Pays-Bas, 1934, vol. 53, p. 1011,1016, 1025
[8] Helvetica Chimica Acta, 1976, vol. 59, p. 379 - 387
[9] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 3, p. 367 - 369
5
[ 5437-38-7 ]
[ 601-87-6 ]
Reference：
[1] Journal of Organic Chemistry, 1976, vol. 41, # 21, p. 3356 - 3359
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 3, p. 367 - 369
[3] Helvetica Chimica Acta, 1976, vol. 59, p. 379 - 387
[4] Patent: US4329518, 1982, A,
[5] Patent: US4402973, 1983, A,
[6] Patent: WO2015/92713, 2015, A1,
[7] Patent: WO2016/203400, 2016, A1,
[8] Patent: WO2016/202253, 2016, A1,
[9] Patent: WO2018/109648, 2018, A1,
Reference：
[1] Journal of the Chemical Society, 1920, vol. 117, p. 856
[2] Journal of the Chemical Society, 1921, vol. 119, p. 1052
[3] Journal of the Chemical Society, 1960, p. 672 - 676
8
[ 5367-26-0 ]
[ 601-87-6 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 1052
9
[ 50424-93-6 ]
[ 601-87-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 3, p. 367 - 369
[2] Recueil des Travaux Chimiques des Pays-Bas, 1934, vol. 53, p. 1011,1016, 1025
[3] Helvetica Chimica Acta, 1976, vol. 59, p. 379 - 387
Reference：
[1] Journal of the Chemical Society, 1960, p. 672 - 676
12
[ 70343-09-8 ]
[ 601-87-6 ]
Reference：
[1] Journal of the Chemical Society, 1960, p. 672 - 676
13
[ 5367-26-0 ]
[ 7664-41-7 ]
[ 601-87-6 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 1052
14
[ 601-87-6 ]
[ 52414-97-8 ]
Yield
Reaction Conditions
Operation in experiment
57%
With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 65℃; for 0.25 h; Heating / reflux
A mixture of copper(II) bromide (3.52 g, 15.7 mmol) in 20 mL dry acetonitrile was heated to 65° C. under an N2 atmosphere. t-Butyl nitrite (2.35 mL, 2.03 g, 19.7 mmol) was added all at once. A solution of 3-methyl-2-nitroaniline (lb; 2.00 g, 13.1 mmol; J. Org Chem. 1976 41(21):3357) in 15 mL acetonitrile was added to the above solution at a rate to sufficient to maintain gentle reflux. After addition the mixture was heated at a gentle reflux for an additional 15 min. The reaction mixture was cooled to rt and partitioned between 6N HCl solution (150 mL) and ether (150 mL). The ethereal solution was separated and washed with brine, then dried over MgSO4. Evaporation of the solvent afforded 2.76 g of impure material, which was flash chromatographed on SiO2 and eluted with 10percent acetone in hexane which afforded 1.62 g (57percent) of lc as a pale yellow-green liquid.
Reference：
[1] Patent: US2004/110815, 2004, A1, . Location in patent: Page/Page column 18
[2] Recueil des Travaux Chimiques des Pays-Bas, 1934, vol. 53, p. 1011,1016, 1025
15
[ 540-80-7 ]
[ 601-87-6 ]
[ 52414-97-8 ]
Yield
Reaction Conditions
Operation in experiment
57%
With copper(I) bromide In acetonitrile at 65℃; for 0.25 h; Heating / reflux
EXAMPLE 1 7-Bromo-2H-indazole step 1 3-Bromo-2-nitrotoluene (Scheme 1 ; IC)-A mixture of copper (II) bromide (3.52g, 15.7 mol) in 20 mL dry acetonitrile was heated to 65 °C under an N2 atmosphere. t-Butyl nitrite (2.35 mL, 2.03 g, 19.7 mmol) was added all at once. A solution of 3-methyl-2- nitroaniline (LB ; 2. 00g, 13.1 mmol; J. ORG CHEM. 1976 41 (21): 3357) in 15 mL acetonitrile was added to the above solution at a rate to sufficient to maintain gentle reflux. After addition the mixture was heated at a gentle reflux for an additional 15 M. The reaction mixture was cooled to rt and partitioned between 6N HC1 solution (150 mL) and ether (150 mL). The ethereal solution was separated and washed with brine, then dried over MGS04. Evaporation of the solvent afforded 2.76g of impure material, which was flash chromatographed on Si02 and eluted with 10percent acetone in hexane which afforded 1.62g (57percent) of lc as a pale yellow-green liquid.
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 65℃; for 0.25h;Heating / reflux;
A mixture of copper(II) bromide (3.52 g, 15.7 mmol) in 20 mL dry acetonitrile was heated to 65 C. under an N2 atmosphere. t-Butyl nitrite (2.35 mL, 2.03 g, 19.7 mmol) was added all at once. A solution of 3-methyl-2-nitroaniline (lb; 2.00 g, 13.1 mmol; J. Org Chem. 1976 41(21):3357) in 15 mL acetonitrile was added to the above solution at a rate to sufficient to maintain gentle reflux. After addition the mixture was heated at a gentle reflux for an additional 15 min. The reaction mixture was cooled to rt and partitioned between 6N HCl solution (150 mL) and ether (150 mL). The ethereal solution was separated and washed with brine, then dried over MgSO4. Evaporation of the solvent afforded 2.76 g of impure material, which was flash chromatographed on SiO2 and eluted with 10% acetone in hexane which afforded 1.62 g (57%) of lc as a pale yellow-green liquid.
Stage #1: 3-methyl-2-nitroaniline With sulfuric acid; sodium nitrite In water cooling;
Stage #2: With copper; potassium iodide In water at 80℃; for 0.5h;
Diazotieren und Behandeln mit Kaliumjodid Loesung;
With copper(I) bromide; In acetonitrile; at 65℃; for 0.25h;Heating / reflux;
EXAMPLE 1 7-Bromo-2H-indazole step 1 3-Bromo-2-nitrotoluene (Scheme 1 ; IC)-A mixture of copper (II) bromide (3.52g, 15.7 mol) in 20 mL dry acetonitrile was heated to 65 C under an N2 atmosphere. t-Butyl nitrite (2.35 mL, 2.03 g, 19.7 mmol) was added all at once. A solution of 3-methyl-2- nitroaniline (LB ; 2. 00g, 13.1 mmol; J. ORG CHEM. 1976 41 (21): 3357) in 15 mL acetonitrile was added to the above solution at a rate to sufficient to maintain gentle reflux. After addition the mixture was heated at a gentle reflux for an additional 15 M. The reaction mixture was cooled to rt and partitioned between 6N HC1 solution (150 mL) and ether (150 mL). The ethereal solution was separated and washed with brine, then dried over MGS04. Evaporation of the solvent afforded 2.76g of impure material, which was flash chromatographed on Si02 and eluted with 10% acetone in hexane which afforded 1.62g (57%) of lc as a pale yellow-green liquid.
With ammonium hydroxide In ethanol; water at 0 - 80℃; for 24h; Sealed tube;
3-methyl-2-nitroaniline
To a stirred solution of l-fluoro-3-methyl-2-nitrobenzene (1 g, 6.45 mmol) in ethanol (10 mL) was added aqueous ammonium hydroxide (30%, 10 mL) in a sealed tube at 0 °C. The reaction mixture was heated to 80 °C and stirred for 24 h. After consumption of starting material (by TLC), the reaction mixture was diluted with water (40 mL) and extracted with Et20 (2 x 40 mL). The combined organic extracts were dried over anhydrous NaiSCL and concentrated under reduced pressure to afford 3-methyl-2-nitroaniline (1.2 g) as a pale yellow solid. The crude material was taken to the next step without further purification. (0419) LC-MS: m/z 153.0 [M+H]+ at 2.15 RT (36.85% purity)
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