* 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 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium chloride In dimethyl sulfoxide at 160℃; for 24 h; Schlenk technique
Silak reaction tube equipped with a magnetic stirrer was charged with 6.2 mg of silver sulfate,36.3 mg of copper acetate, 12.5 mg of 2,9-dimethyl-1,10-o-phenanthroline,36.2 mg of 2-nitro-4-methylbenzoic acid and 17.5 mg of sodium chloride4 mL of dimethyl sulfoxide.The reaction was heated at 160 ° C for 24 hours in the presence of oxygen.After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases are concentrated,17.5 mg of 2-nitro-4-methylchlorobenzene was obtained,The yield is 51percent.
Reference：
[1] Patent: CN107325002, 2017, A, . Location in patent: Paragraph 0091
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 30, p. 5416 - 5421
[3] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2794 - 2803
2
[ 89-62-3 ]
[ 89-60-1 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 1, p. 44 - 51
[2] Journal of the Society of Dyers and Colourists, vol. 41, p. 329[3] Chem. Zentralbl., 1926, vol. 97, # II, p. 1526
[4] Chemische Berichte, 1885, vol. 18, p. 2603
[5] Journal of Organic Chemistry, 1977, vol. 42, p. 2426 - 2431
[6] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1976, vol. 30, p. 141 - 149
[7] Patent: US2007/27178, 2007, A1, . Location in patent: Page/Page column 22
3
[ 106-43-4 ]
[ 89-59-8 ]
[ 89-60-1 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 19, p. 2385 - 2389
[2] Journal of the Indian Chemical Society, 1988, vol. 65, p. 415 - 416
[3] Journal of the Indian Chemical Society, 1988, vol. 65, p. 415 - 416
[4] Journal of the Society of Dyers and Colourists, vol. 41, p. 329[5] Chem. Zentralbl., 1926, vol. 97, # II, p. 1526
[6] Journal of the Chemical Society, 1924, vol. 125, p. 2195
[7] Chemische Berichte, 1886, vol. 19, p. 2443[8] Chemische Berichte, 1887, vol. 20, p. 199
[9] Chemische Berichte, 1874, vol. 7, p. 797
[10] Chemische Berichte, 1886, vol. 19, p. 2443[11] Chemische Berichte, 1887, vol. 20, p. 199
[12] Chemische Berichte, 1874, vol. 7, p. 797
4
[ 106-43-4 ]
[ 119-33-5 ]
[ 89-59-8 ]
[ 89-60-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, # 11, p. 1793 - 1802
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, # 11, p. 1793 - 1802
5
[ 106-43-4 ]
[ 89-60-1 ]
Reference：
[1] Helvetica Chimica Acta, 1929, vol. 12, p. 932
[2] Journal of the Society of Dyers and Colourists, vol. 41, p. 329[3] Chem. Zentralbl., 1926, vol. 97, # II, p. 1526
[4] Journal of the Chemical Society, 1924, vol. 125, p. 2195
[5] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, # 11, p. 1793 - 1802
[6] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, # 11, p. 1793 - 1802
6
[ 75508-74-6 ]
[ 89-59-8 ]
[ 89-60-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, # 11, p. 1793 - 1802
7
[ 106-43-4 ]
[ 89-59-8 ]
[ 75508-74-6 ]
[ 89-60-1 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1980, # 11, p. 513 - 514
8
[ 75508-74-6 ]
[ 106-43-4 ]
[ 89-59-8 ]
[ 89-60-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, # 11, p. 1793 - 1802
9
[ 75508-74-6 ]
[ 106-43-4 ]
[ 89-60-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, # 11, p. 1793 - 1802
10
[ 75508-74-6 ]
[ 86297-37-2 ]
[ 89-59-8 ]
[ 89-60-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, # 11, p. 1793 - 1802
11
[ 106-43-4 ]
[ 108-24-7 ]
[ 89-59-8 ]
[ 75508-74-6 ]
[ 89-60-1 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1980, # 11, p. 513 - 514
12
[ 108-88-3 ]
[ 89-60-1 ]
Reference：
[1] Helvetica Chimica Acta, 1929, vol. 12, p. 932
13
[ 106-43-4 ]
[ 108-24-7 ]
[ 89-59-8 ]
[ 89-60-1 ]
[ 75508-74-6 ]
Reference：
[1] Canadian Journal of Chemistry, 1986, vol. 64, p. 1764 - 1770
[2] Canadian Journal of Chemistry, 1986, vol. 64, p. 1764 - 1770
14
[ 75508-74-6 ]
[ 119-33-5 ]
[ 106-43-4 ]
[ 5306-98-9 ]
[ 86297-37-2 ]
[ 89-59-8 ]
[ 89-60-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, # 11, p. 1793 - 1802
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, # 11, p. 1793 - 1802
15
[ 106-43-4 ]
[ 7697-37-2 ]
[ 89-59-8 ]
[ 89-60-1 ]
Reference：
[1] Journal of the Chemical Society, 1932, p. 1884,1885, 1888
[2] Recueil des Travaux Chimiques des Pays-Bas, 1909, vol. 28, p. 421,496
16
[ 106-43-4 ]
[ 7664-93-9 ]
[ 89-59-8 ]
[ 89-60-1 ]
Reference：
[1] Journal of the Society of Dyers and Colourists, vol. 41, p. 329[2] Chem. Zentralbl., 1926, vol. 97, # II, p. 1526
[3] Journal of the Chemical Society, 1924, vol. 125, p. 2195
17
[ 89-60-1 ]
[ 21303-50-4 ]
Reference：
[1] Patent: US5451594, 1995, A,
18
[ 89-60-1 ]
[ 39860-12-3 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 78, p. 35 - 42
19
[ 89-60-1 ]
[ 95-81-8 ]
Reference：
[1] Chemische Berichte, 1885, vol. 18, p. 2603
[2] Chemische Berichte, 1885, vol. 18, p. 2603
[3] Chemische Berichte, 1886, vol. 19, p. 2443[4] Chemische Berichte, 1887, vol. 20, p. 199
[5] Chemische Berichte, 1874, vol. 7, p. 797
[6] Journal of the American Chemical Society, 1933, vol. 55, p. 1212,1215
[7] Helvetica Chimica Acta, 1938, vol. 21, p. 1240,1247
[8] Journal of Applied Chemistry, 1957, vol. 7, p. 440,443
[9] Chemische Berichte, 1916, vol. 49, p. 2507
[10] Bulletin de la Societe Chimique de France, 1966, p. 1848 - 1858
[11] Chemische Berichte, 1979, vol. 112, p. 3490 - 3514
[12] Patent: US2007/27178, 2007, A1, . Location in patent: Page/Page column 22
[13] Patent: US2012/108583, 2012, A1, . Location in patent: Page/Page column 30
[14] European Journal of Organic Chemistry, 2018, vol. 2018, # 26, p. 3416 - 3425
[15] ChemCatChem, 2018, vol. 10, # 20, p. 4569 - 4577
20
[ 6819-41-6 ]
[ 89-60-1 ]
[ 95-81-8 ]
Reference：
[1] Journal of the American Chemical Society, 1931, vol. 53, p. 2357,2361
21
[ 6819-41-6 ]
[ 89-60-1 ]
[ 71-43-2 ]
[ 95-81-8 ]
Reference：
[1] Journal of the American Chemical Society, 1931, vol. 53, p. 2357,2361
22
[ 89-60-1 ]
[ 27329-27-7 ]
[ 98-88-4 ]
Reference：
[1] Patent: US4781750, 1988, A,
23
[ 544-92-3 ]
[ 89-60-1 ]
[ 27329-27-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 12, p. 3807 - 3815
A solution of sodium thiophenolate (3.96 g, 30 mmol) in 60 mL of DMF was heated at 50 0C with <strong>[89-60-1]4-chloro-3-nitrotoluene</strong> (2.65 mL, 20 mmol) with stirring for 2 days. Cooled to room temperature and diluted with CH2Cl2. Washed with water and dried the organic layer over Na2 SO4. Filtered and concentrated under vacuum giving the title compound (4.29 g, 87%) 1H NMR (300 MHz, <n="58"/>CDCl3) delta ppm: 2.36 (s, 3 H) 6.76 (d, J=8.09 Hz, 1 H) 7.16 (d, J=8.46 Hz, IH) 7.45 (m, 3 H) 7.58 (m, 2 H) 8.03 (s, 1 H).
Step B.; A 50 C. solution of tin(II)chloride (7.5 g, 39.5 mmol) in EtOH (12 mL) was added to 1-chloro-4-methyl-2-nitrobenzene (1.4 g, 7.9 mmol) followed by the addition of 12N HCl (11.9 mL, 142.2 mmol). The reaction mixture was stirred at 60 C. for 70 min. EtOH was removed under vacuum, the residue was basified via 1N NaOH to pH>12, and was extracted with CHCl3 The combined organic solution was washed with brine and dried over MgSO4, filtered and concentrated in vacuo to give 2-chloro-5-methylbenzenamine (0.95 g, 6.7 mmol).
Step 1 -Preparation of 2-chloro-5-methylaniline To a solution of 1-chloro-4-methyl-2-nitrobenzene (10.0 g, 0.058 mol) in methanol (50 mL), iron powder (3.0 g, 0.055 mol) and conc. HCl (10 mL) were added. The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and basified with NaHCO3 solution and extracted with DCM. The organic layer was separated and dried over anhydrous sodium sulphate and concentrated to afford 5.0 g of the desired compound. 1HNMR (CDCl3): delta 2.23 (s, 3H), 3.94 (s, 2H), 6.50 (d, J=7.8 Hz, 1H), 6.57 (s, 1H), 7.10 (d, J=7.8 Hz, 1H); MS [M+H]+: 142.25.
With tert.-butylnitrite; copper dichloride; In acetonitrile; at 20 - 65℃; for 16h;
Example 18 6-Chloro-9-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride Step A.; To a solution of 4-methyl-2-nitrobenzenamine (1.2 g, 7.9 mmol) in acetonitrile (5 mL) was added a solution of tert-butyl nitrite (1.2 g, 11.8 mmol) and cupric (II) chloride (1.3 g, 9.5 mmol) in acetonitrile (11 mL) dropwise via syringe pump at 20 C. over a 1 h period. The-reaction mixture was stirred at 65 C. for 15 h, brought to 20 C.; poured over 6N HCl (60 ml) and extracted with diethyl ether. The combined organic solution was dried-over MgSO4, filtered and concentrated in vacuo to give-1-chloro-4-methyl-2-nitrobenzene (1.35g, 7.9 mmol).
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane;Inert atmosphere; Reflux;
General procedure: To a stirred solution of 2-fluoro-5-methyl-3-nitropyridine 4a (3.0 g, 19.22 mmol) in carbon tetrachloride (80 mL) were added azodiisobutyronitrile (316 mg, 1.90 mmol) and N-bromosuccinimide (3.76 g, 21.14 mmol). The reaction mixture was heated at reflux for 48 h under an argon atmosphere and then the contents were cooled to room temperature. The insoluble solid was removed by filtration, the filtrate was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate (30 mL×4) and brine (20 mL×2), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/dichloromethane/ ethyl acetate = 15:1:1) to give the title compound 5a (1.8 g, 35.5%). White solid; mp 73-75 C; 1H NMR (400 MHz, CDCl3) delta (ppm): 8.56 (d, J = 8.4 Hz, 1H), 8.50 (s, 1H), 4.52 (s, 2H)
PREPARATION 94(1) 4-Chloro-3-nitrobenzyl bromide (7.90 g) was obtained as orange oil from <strong>[89-60-1]4-chloro-3-nitrotoluene</strong> (5.00 g) in a manner similar to Preparation 9 1 (2). NMR (CDCl3, delta): 4.47 (2H, s), 7.54 (2H, s), 7.92 (1H, s).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;
General procedure: Corresponding 2-chloro-methylphenyl compounds (1 mmol) and PBO (0.1 mmol ) were dissolved in 5 mL CCl4, then NBS (1.1 mmol) was added slowly. The reaction was stirred at room temperature and monitored by TLC and cooled to room temperature upon completion of the reaction. The precipitated solid was filtrated and the filtrate was concentrated to give an oily liquid, which was directly subjected to a further reaction with Cs2CO3 (1.5 mmol) in 5 mL of CH3CN, and corresponding Schiff base (1 mmol) in dissolved CH3CN was added dropwise at room temperature. The solution was stirred at room temperature and monitored by TLC. Upon completion of the reaction, CH3CN was distilled off under reduced pressure and the residue was extracted CH2Cl2 (203 mL). Organic layer was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified by silica gel column to give the targeted compound.
With sodium iodide; sodium carbonate; In cyclohexane; water; ethyl acetate; cyclohexanol;
Step 1: A mixture of 69 g of 4-chloro-3-nitro-toluene, 50 g of ethyl 4-amino-1-piperidinecarboxylate, 24 g of sodium carbonate, 0.1 g of sodium iodide and 120 mL of cyclohexanol was heated to 150 C. for 72 h. After cooling the cyclohexanol was distilled off under reduced pressure and the residue partitioned between 1 L of ethyl acetate and 1 L of water. The organic extract was dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel, eluding with 20% ethyl acetate in cyclohexane gave 38.5 g (42.3%) of ethyl 4-(4-methyl-2-nitroanilino)-1-piperidinecarboxylate as an orange crystalline solid. 1 H NMR (400 MHz, CDCl3) 8.0 (s, 1H), 7.27 (t, J=9 Hz, 1H), 6.8 (d, J=9 Hz, 1H), 4.15 (q, J=7 Hz, 2H), 4.05 (br m, 2H), 3.67 (br m, 1H), 3.10 (br t, J=11 Hz, 2H), 2.27 (s, 3H), 2.06 (br d, J=11 Hz, 2H), 1.6 (m, 2H), 1.27 (t, J=7 Hz, 4H).
38.5 g (42.3%)
With sodium iodide; sodium carbonate; In cyclohexane; water; ethyl acetate; cyclohexanol;
Step 1: A mixture of 69 g of 4-chloro-3-nitro-toluene, 50 g of ethyl 4-amino-1-piperidinecarboxylate, 24 g of sodium carbonate, 0.1 g of sodium iodide and 120 ml of cyclohexanol was heated to 150 C. for 72 h. After cooling the cyclohexanol was distilled off under reduced pressure and the residue partitioned between 1 L of ethyl acetate and 1 L of water. The organic extract was dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel, eluding with 20% ethyl acetate in cyclohexane gave 38.5 g (42.3%) of ethyl 4-(4-methyl-2-nitroanilino)-1-piperidinecarboxylate as an orange crystalline solid. 1 H NMR (400 MHz, CDCl3) 8.0 (s, 1H), 7.27 (t, J=9 Hz, 1H), 6.8 (d, J=9 Hz, 1H), 4.15 (q, J=7 Hz, 2H), 4.05 (br m, 2H), 3.67 (br m, 1H), 3.10 (br t, J=11 Hz, 2H), 2.27 (s, 3H), 2.06 (br d, J=11 Hz, 2H), 1.6 (m, 2H), 1.27 (t, J=7 Hz, 4H).
benzyl 2-cyano-2-(2-nitro-4-methylphenyl)ethanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 24h;
benzyl cyanoacetate (3.50 g; 20 mmol) is added to a suspension of potassium carbonate (6.08 g; 44 mmol) in 5 mL of DMF. The carbonate is washed with 2 mL of DMF. A solution of <strong>[89-60-1]3-nitro-4-chlorotoluene</strong> (3.41 g, 20 mmol) in 5 mL of DMF is added and the resulting reaction mixture is stirred at 70 C. for 24 hours. After cooling down to ambient temperature, it is treated with a 5N aqueous solution of HCl (12.5 mL). The mixture is divided between ether (100 mL) and water (50 mL) then the organic phase is re-extracted with ether. The ethereal phases are washed with water, dried over anhydrous MgSO4, filtered under vacuum and evaporated. The residue is purified by chromatography on silica gel (eluent: CH2Cl2/pentane, 1/1) in order to produce benzyl 2-cyano-2-(2-nitro-4-methylphenyl)ethanoate with a yield of 75%.
With potassium carbonate; In dimethyl sulfoxide; at 150℃;
INTERMEDIATE: (3,7-Dimethyl-quinoxalin-2-yl)-hydrazine (Ilj). 4-Chloro-3-nitrotoluene (19 mL) was dissolved in DMSO (300 mL). Racemic alanine (45 g) and K2C03 (20 g) were added, and the mixture was stirred overnight at 150 C. The crude mixture was poured into water (300 mL) and acidified with 37% aq HC1. The product was extracted into EtOAc. The organic layer was washed with brine and concentrated in vacuo. The residue was refluxed for 0.5h in a mixture of methanol (300 mL) and 96% sulfuric acid (20 mL). The volatiles were removed in vacuo. The residue was partitioned between water and EtOAc after basification with NaOH. The organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo. The residue was dissolved in a mixture of ethanol (500 mL), THF (100 mL) and 2M aq sulfuric acid (35 mL). The mixture was degassed with Ar. 10% Palladium on charcoal (1 g) was added, and the mixture was treated with hydrogen gas (3 bar) using a Parr shaker for 3 h. More 10% palladium on charcoal (1 g) was added and the mixture was treated with hydrogen gas (3 bar) using a Parr shaker overnight. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was partitioned between water and EtOAc. The aq layer was basified with 28% aq NaOH and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO i, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (eluent: heptanes? EtOAc) to afford 3,7-dimethyl-3,4-dihydro-lH-quinoxalin-2-one (6.12 g) as a pale brown solid that was used directly in the next step. A suspension of this material (5.98 g) and 10% palladium on charcoal (0.60 g) in 1,2-dimethylbenzene (200 mL) refluxed overnight. The crude mixture was cooled to 50 C and diluted with THF (200 mL) before it was filtered through a plug of celite. The filtrate was concentrated in vacuo to yield 3,7-dimethylquinoxalin-2(lH)-one (5.9 g) as a brown solid that was used in the next step. A portion of this material (1.08 g) was added to an ice-cold mixture of phosphoryl chloride (20 mL) and DIPEA (2.16 mL). The mixture was heated at 100 C for 2h. The volatiles were removed in vacuo. The residue was diluted with DCM (50 mL) and poured carefully onto ice (200 mL) to quench excess phosphoryl chloride. The aq layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO i, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (eluent: heptanes? EtOAc) to afford 3-chloro-2,6-dimethyl-quinoxaline (879 mg) sufficiently pure for the next step. A larger portion of this material (3.31 g) prepared in a similar manner was dissolved in ethanol (100 mL). Hydrazine hydrate (3.2 mL) was added, and the mixture was refluxed for 8h before the heat was turned off and the mixture was allowed to stand at ambient temperature overnight. Next morning, hydrazine hydrate (1 mL) added and the mixture was refluxed for 8h. The mixture was allowed to cool to ambient temperature. The volatiles were removed in vacuo. The residual solid was washed with water and heptanes before it was dried to afford Ilj (2.57 g) as a slightly red solid sufficiently pure for the next step.
EXAMPLE 32 4-Chloro-3-(1,5-dimethyl-1H-benzoimidazol-2-yl)-phenylamine A pressure bottle was charged with 40% methylamine in water (40 ml), ethanol (40 ml), and <strong>[89-60-1]1-chloro-4-methyl-2-nitro-benzene</strong> (3.44 g, 20 mmol). The bottle was sealed and heated at 95-100 C. for 48 hours. After cooling to room temperature, the solid was filtered, washed with water (2*10 ml), and dried under vacuum to provide methyl-(4-methyl-2-nitro-phenyl)-amine (3.1 g, 93% yield) as a red powder.
N-(4-methyl-2-nitrophenyl)-N',N'-dimethylethylenediamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In propan-1-ol; ethyl acetate;
EXAMPLE 5 STR38 A mixed solution of <strong>[89-60-1]4-chloro-3-nitrotoluene</strong> (1.30 g) and N,N-dimethylethylenediamine (1.34 g) in 1-propanol (20 ml) was refluxed for 24 hours and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and the solution was successively washed with water (*2) and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=30:1) to give 0.19 g of N-(4-methyl-2-nitrophenyl)-N',N'-dimethylethylenediamine. Mass spectrum (m/z): 224 (MH+). NMR (CDCl3 delta: 2.26 (3H, s), 2.30 (3H, s), 2.62 (2H, t, J=7 Hz), 3.25-3.44 (2H, m), 6.75 (1H, d, J=9 Hz), 7.27 (1H, dd, J=2 and 9 Hz), 7.97 (1H, d, J=2 Hz), 8.17 (1H, br s).
With sodium carbonate;
EXAMPLE 33 17.2 g. of <strong>[89-60-1]4-chloro-3-nitrotoluene</strong>, 9 g. of 2-dimethylaminoethylamine, and 21.5 g. of anhydrous sodium carbonate are agitated for 7 hours at 135 C. Excess starting material is removed by steam distillation. The distillation residue is extracted with chloroform, the chloroform solutions are dried, filtered, and concentrated under a vacuum. By distilling the residue at 0.05 mm Hg and 133-137 C., 10.5 g. of 3-nitro-4-(2-dimethylaminoethylamino)-toluene is obtained, m.p. 59 C. 3.5 g. of this compound is reduced as described in Example 27, and 3 g. of crude 3-amino-4-(2-dimethylaminoethylamino)-toluene is thus obtained.
Piperidine (660 mul, 6.66 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 1 ml) solution of <strong>[89-60-1]4-chloro-3-nitrotoluene</strong> (358 mg, 2.08 mmol, commercially available product). The resulting mixture was stirred at 100C for 17 hours. The mixture was cooled to room temperature, and then water was added thereto. The resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate = 50/1). Thus, 1-(4-methyl-2-nitrophenyl)piperidine (212 mg, 46.2%) was yielded as a colorless oily material. TLC Rf 0.54 (hexane/ethyl acetate = 10/1).
5-methyl-2-(2,2,2-trifluoroethoxy)aniline hydrochloride[ No CAS ]
[ 122142-15-8 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In N,N-dimethyl-formamide;
Step 1. Preparation of 5-Methyl-2-(2,2,2-trifluoroethoxy)aniline Hydrochloride 2,2,2-Trifluoroethanol (60 g, 0.6 mol) was added dropwise to a stirred mixture of sodium hydride (12 g of a 60% dispersion, 0.3 mol) in 500 mL of DMF. After stirring for 20 minutes, <strong>[89-60-1]4-chloro-3-nitrotoluene</strong> (51.3 g, 0.3 mol) was added and the reaction heated at 150 C. for 16 hours. The reaction was cooled, poured into ice cold 5% HCl. The resulting precipitate was collected by filtration, dried to give 64 g of 5-methyl-2-(2,2,2-trifluoroethoxy)nitrobenzene. 1 H NMR (CDCl3): delta 8.4 (bs, 1H), 7.7 (s, Harom), 7.4 (d, Harom, J=8 Hz), 7.03 (d, Harom, J=8 Hz), 4.48 (q, 2H, J=8 Hz), 2.4 (s, 3H)
With hydrogenchloride; sodium sulfite; In 5,5-dimethyl-1,3-cyclohexadiene; water;
EXAMPLE 4 514 Parts of 4-chloro-3-nitro-toluene and 300 parts of water were reacted in the same manner as described in Example 1 at from 90 to 95C with 1446 parts of a 36% aqueous sodium hydrogen sulfide solution while stirring. Then, the 4-chloro-3-amino-toluene which had formed as by-product was eliminated by steam distillation. After cooling to 20 - 30C, 1,210 parts of sodium sulfite (Na2 SO3. 7 H2 O) and 430 parts of xylene were successively added and the pH was adjusted at 6 at a temperature within the range of from 10 to 12C within from 2 to 3 hours with 565 parts of a 30% hydrochloric acid while stirring. For better separation of the phases, the mixture was heated at 25C and the mother liquor was stirred with 174 parts of xylene. The 4-methyl-2-amino-thiophenol was isolated from the organic phase by vacuum distillation. Yield: 60% of the theoretical amount, calculated on <strong>[89-60-1]4-chloro-3-nitrotoluene</strong>:
CuCN; In aq H2 SO4; benzonitrile; N,N-dimethyl-formamide;
EXAMPLE C Preparation of 2-Nitro-p-Toluic Acid A slurry of 100 g of <strong>[89-60-1]4-chloro-3-nitrotoluene</strong> and 80 g of copper (I) cyanide in 500 ml of DMF was refluxed for 12 hours. An additional 20 g of CuCN was added and the reaction refluxed another 4 hours. Ether was added and the ether phase decanted from the dark oil. The ether phase was dried with molecular sieves, filtered and the solvent removed under reduced pressure to yield an orange-brown semi-solid. The semi-solid product was triturated with hexane. The hexane was evaporated off under reduced pressure to yield 30.5 g of the desired product which was used without further purification. The benzonitrile (10 g) was refluxed for 90 min. in 50% aq H2 SO4. TLC indicated complete hydrolysis of the nitrile. The reaction was pured onto ice and extracted with ether. The ether phase was washed with saturated brine, dried over molecular sieves, filtered and the solvent removed under reduced pressure to yield 4.2 g of the desired product, IR (Nujol) 1695 (C=O--acid), NMR (CDCl3 /DMSO/TMS) 2.52 ppm, (S, 3H), 7.80 ppm, (M, 3H). This material was used without further purification in the preparation of the corresponding benzoyl chloride. IR (neat) 1775 cm-1 (C=O) acid halide.
4-(2-nitro-4-methylphenylamino)-1-benzylpiperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium iodide; sodium carbonate; In cyclohexanol;
(1) Production of 4-(2-nitro-4-methylphenylamino)-1-benzylpiperidine Sodium carbonate of 6.2 g and potassium iodide of 50 mg were added to a cyclohexanol 50 ml solution of 4-amino-1-benzylpiperidine of 11.0 g and <strong>[89-60-1]4-chloro-3-nitrotoluene</strong> of 10.0 g, and the solution was heated and stirred at 150 C. for 41 hours. The reaction solution was allowed to come down to a room temperature and diluted with ethyl acetate. It was washed with water and saturated brine and dried on anhydrous sodium sulfate. Then, the solvent was distilled off, and the resulting residue was separated and refined by means of silica gel column chromatography (ethyl acetate/hexane=1/3), whereby the captioned compound of 6.2 g was obtained in the form of a yellow oily substance.
Production Example 11 A solution of 5.21 g of <strong>[89-60-1]1-chloro-4-methyl-2-nitrobenzene</strong> in 150 mL of THF was cooled to -50C. To the solution was added 95 mL of 1 M vinylmagnesium bromide solution in THF while the inner temperature was kept at -30C or lower, and the resulting mixture was stirred at -50C for 2 hours. To the solution, 100 mL of the saturated aqueous ammonium chloride solution and 100 mL of 1 M hydrochloric acid were added, then the resulting mixture was warmed to room temperature and stirred for 15 minutes, and then extracted twice with 100 mL of ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane = 1:9) to obtain 2.69 g of 7-chloro-4-methylindole as a brown oil. Compounds listed in Table 3 were obtained by the method similar to that described in Production Example 11.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;
The title compound was prepared from l-Chloro-4-methyl-2-nitro-benzene (3.00 g,17.5 mmol), lH-[l,2,4]Triazole-3-thiol (1.94 g, 19.2 mmol), and K2CO3 (4.22 g, 30.6 mmol) heated in DMF at 100 0C for 16 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. Dried over Na2SOzI, filtered and concentrated under vacuum giving the title compound (1.1 g, 26 %).
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 12h;
A solution of 4-chloro-3-nitro-toluene (25 g, 145 mmol) in anhydrous DMF (200 ml) was treated with K2CO3 (40.29 g, 291 mmol) and 1 -propane thiol (12.2 g, 160 mmol). The reaction mixture was heated to70 0C for 12 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, diluted water and extracted with ethyl acetate (200 ml). The organic layer was washed with brine, dried over sodium sulphate and evaporated under reduced pressure, to give a crude which was purified by column chromatography (silica) using petroleum ether/ethyl acetate as eluent to afford the title compound (28 g, 91%) as a pale yellow solid. 1H NMR (300MHz, DMSO-d6) delta [ppm] 8.01 (s, 1 H), 7.37-7.35(d, 2H, J= 10Hz), 7.29- 7.27(dd, 1 H, J= 9.6Hz), 2.96-2.89 (m, 2H), 2.40(s, 3H), 1.81-1.17(m, 2H), 1.11 (s, 1 H).
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 12h;Inert atmosphere;
Step (lb): 4-Chloro-3-nitrotoluene (0.11 mol), diethylene glycol (0.05 mol), potassium carbonate (0.33 mol), and 200 ml of N,N-dimethylformamide were placed in a reactor equipped with a stirrer and a heater in a N2 atmosphere and allowed to react at 130 C. for 12 hours. DMF was then removed under reduced pressure. The resulting solid was dissolved in 200 ml of dichloromethane, followed by partitioning with 100 ml of water three times. The organic layer was dried over 5 g of sodium sulfate, and dichloromethane was removed under reduced pressure to give an intermediate product P (nitro compound).
With copper; In water; at 100℃; for 8h;Sealed tube;
General procedure: A solution of 1-chloro-2-nitrobenzene (1.57g, 10mmol), 40% aqueous methylamine (4.3mL, 50mmol), and copper powder (31mg, 0.5mmol) was sealed in a 30mL screw-cap tube and stirred at 100C for 8h. The reaction mixture was then cooled-down to room temperature and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product 4 (1.4g, yield 95%) as oil. The crude product was used directly in next reaction step. 1H NMR (400MHz, CDCl3) delta 8.18 (d, J=8.0 Hz, 1H), 8.16 (NH, 1H), 7.45 (t, J=7.8Hz, 1H), 6.84 (d, J=8.0Hz, 1H), 6.65 (t, J=7.8Hz, 1H), 3.02 (d, J=5.2Hz, 3H); LC/MS (electrospray) m/z (M+H)+ 153.05.
With bis-triphenylphosphine-palladium(II) chloride; In 1,2-dichloro-ethane; at 120℃; for 0.75h;Microwave irradiation;
To <strong>[89-60-1]1-chloro-4-methyl-2-nitrobenzene</strong> (2.00 g, 11.7 mmol), allyltributylstannane (5.79 g, 17.5 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.818 g, 1.17 mmol) in two 25-mL reaction vials was added 1,2-dichloroethane (20 mL). The vials were capped and heated at 120 C. for 45 minutes in a Biotage Initiator microwave reactor with an external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was loaded onto a Celite cartridge. The crude material was purified by flash column chromatography using 0-50% ethyl acetate/hexanes as eluent followed by reverse-phase flash column chromatography using 0-100% acetonitrile/water as eluent. The combined acetonitrile/water fractions were concentrated, extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated, and dried in a vacuum oven to provide the title compound as a yellow liquid (1.76 g, 84%): 1H NMR (400 MHz, CDCl3) delta 7.73 (d, J=0.9 Hz, 1H), 7.34 (dd, J=7.8, 1.2 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 5.96 (ddt, J=16.6, 10.1, 6.4 Hz, 1H), 5.08 (ddq, J=18.5, 17.0, 1.5 Hz, 2H), 3.64 (d, J=6.4 Hz, 2H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) delta 149.09, 137.62, 135.35, 133.81, 131.81, 131.72, 124.94, 116.81, 36.62, 20.72; EIMS m/z 176 ([M]+).
84%
With bis-triphenylphosphine-palladium(II) chloride; In 1,2-dichloro-ethane; at 120℃; for 0.75h;Microwave irradiation;
To <strong>[89-60-1]1-chloro-4-methyl-2-nitrobenzene</strong> (2.00 g, 11.7 mmol), allyltributylstannane (5.79 g, 17.5 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.818 g, 1.17 mmol) in two 25-mL reaction vials was added 1,2-dichloroethane (20 mL) . The vials were capped and heated at 120 C for 45 minutes in a Biotage Initiator microwave reactor with an external IR-sensor temperature monitoring from the side of the vessel . The reaction mixture was loaded onto a Celite cartridge. The crude material was purified by flash column chromatography using 0-50% ethyl acetate/hexanes as eluent followed by reverse-phase flash column chromatography using 0-100% (0138) acetonitrile/water as eluent. The combined acetonitrile/water fractions were (0139) concentrated, extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated, and dried in a vacuum oven to provide the title compound as a yellow liquid (1.76 g, 84%) : 1H NMR (400 MHz, CDCI3) delta 7.73 (d, J = 0.9 Hz, 1 H), 7.34 (dd, J = 7.8, 1.2 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 5.96 (ddt, J = 16.6, 10.1, 6.4 Hz, 1H), 5.08 (ddq, J = 18.5, 17.0, 1.5 Hz, 2H), 3.64 (d, J = 6.4 Hz, 2H), 2.40 (s, 3H) ; 13C NM R (101 MHz, CDCI3) delta 149.09, 137.62, 135.35, 133.81, 131.81, 131.72, 124.94, 116.81, 36.62, 20.72; EIMS m/z 176 ([M]+) .
With sulfur; In neat (no solvent); at 130℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: A mixture of 2-chloronitrobenzene (1 mmol), amine (3 mmol), and elemental sulfur (2 mmol) was stirred in a sealed tube under nitrogen atmosphere at indicated temperature for 24 h (See Table 2). After being cooled to room temperature, the crude reaction mixture was triturated and dissolved in ethylacetate, then filtered and the filtrate was concentrated, and the residue was purified by column chromatography on silica gel to afford the desired product.
With sulfur; In neat (no solvent); at 130℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: A mixture of 2-chloronitrobenzene (1 mmol), amine (3 mmol), and elemental sulfur (2 mmol) was stirred in a sealed tube under nitrogen atmosphere at indicated temperature for 24 h (See Table 2). After being cooled to room temperature, the crude reaction mixture was triturated and dissolved in ethylacetate, then filtered and the filtrate was concentrated, and the residue was purified by column chromatography on silica gel to afford the desired product.
2-(4-chlorophenyl)-5-methylbenzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With sulfur; In neat (no solvent); at 130℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: A mixture of 2-chloronitrobenzene (1 mmol), amine (3 mmol), and elemental sulfur (2 mmol) was stirred in a sealed tube under nitrogen atmosphere at indicated temperature for 24 h (See Table 2). After being cooled to room temperature, the crude reaction mixture was triturated and dissolved in ethylacetate, then filtered and the filtrate was concentrated, and the residue was purified by column chromatography on silica gel to afford the desired product.
With sulfur; In neat (no solvent); at 130℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: A mixture of 2-chloronitrobenzene (1 mmol), amine (3 mmol), and elemental sulfur (2 mmol) was stirred in a sealed tube under nitrogen atmosphere at indicated temperature for 24 h (See Table 2). After being cooled to room temperature, the crude reaction mixture was triturated and dissolved in ethylacetate, then filtered and the filtrate was concentrated, and the residue was purified by column chromatography on silica gel to afford the desired product.
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium chloride; In dimethyl sulfoxide; at 160℃; for 24h;Schlenk technique;
Silak reaction tube equipped with a magnetic stirrer was charged with 6.2 mg of silver sulfate,36.3 mg of copper acetate, 12.5 mg of 2,9-dimethyl-1,10-o-phenanthroline,36.2 mg of 2-nitro-4-methylbenzoic acid and 17.5 mg of sodium chloride4 mL of dimethyl sulfoxide.The reaction was heated at 160 C for 24 hours in the presence of oxygen.After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases are concentrated,17.5 mg of 2-nitro-4-methylchlorobenzene was obtained,The yield is 51%.
With sodium carbonate; In dimethyl sulfoxide; at 60 - 130℃; for 6h;
17.2 parts of <strong>[89-60-1]4-chloro-3-nitrotoluene</strong>,28.0 parts of sodium 3-mercaptopropanesulfonate,And 60 parts of dimethylsulfoxide were added,Under stirring,Heat to 60 C,To this was added 16.5 parts of sodium carbonate.The reaction solution was heated to 120 to 130 C.,The mixture was reacted at the same temperature for 6 hours.The reaction solution was cooled to room temperature,330 parts of 2-propanol,The precipitated solid was separated by filtration,And washed with 100 parts of 2-propanol.The obtained solid was added to 200 parts of water,The pH of the solution was adjusted to 7.0 to 7.5 with 35% hydrochloric acid,Sodium chloride was added to salting out,By separating the precipitated solid by filtration,74.3 parts of a wet cake containing a compound represented by the following formula (46) was obtained. The total amount of the wet cake containing the compound represented by the formula (46)1.8 parts of activated carbon, and 0.4 part of anhydrous ferric chloride were added to 120 parts of water,The solution was heated to 70 to 80 C.,15 parts of 80% hydrazine monohydrate was added dropwise over a period of about 30 minutes. The reaction solution was heated to 85 to 95 C. and reacted for 3 hours,Cooled to room temperature.After insoluble matter was filtered off,The precipitated solid obtained by adding 50% sulfuric acid to the filtrate and acid precipitationFiltered off,A compound represented by the following formula (47)47.9 parts of a wet cake containingObtained.
With N-methylcyclohexylamine; sulfur; at 110℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: A mixture of o-chloronitrobenzene (0.5 mmol), benzyl chloride (1.0 mmol), elemental sulfur (1.5 mmol) and N-methylpiperidine (1.5 mL) was placed in a sealed pressure vessel (25 mL) containing a magnetic stirring bar. The The tube was purged with nitrogen three times, and then capped and stirred in a preheated oil bath at 110 C for 24 h. After the mixture was cooled to room temperature, concentrated in vacuum and purified by silica gel column chromatography by using petroleum ether and ethyl acetate (PE:EA=1:500) as eluent.
4-bromo-N-(4-methyl-2-nitrophenyl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 0.2h;Microwave irradiation;
General procedure: A mixture of benzenesulfonamides (1, 1.0 mmol), halogenated nitrobenzene(2, 1.0 mmol) and K2CO3 (1.1 mmol) were dissolved in DMF in a microwave tube. Then, the reaction mixture was irradiated in a microwave apparatus at 140 C for 12 minutes. After the reaction mixture was cooled to ambient temperature, the product was concentrated, and the crude mixture was purified by column chromatography on silica gel to the desired products 3.
5-methyl-2-phenylbenzo[d][1,3]selenazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With N-methylcyclohexylamine; selenium; at 130℃; for 24h;Inert atmosphere; Sealed tube;
General procedure: A mixture of o-chloronitrobenzene (1.0 mmol), arylacetic acid (1.5 mmol), selenium powder (1.5 mmol) and NMP (3 mmol) was placed in a sealed pressure vessel (10 mL) containing a magnetic stirring bar and then capped and stirred at 130 C for 24 h under argon atmosphere. After the reaction was completed (TLC), the mixture was cooled to room temperature, diluted with dichloromethane (10 mL), evaporated in vacuum and purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluent.
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