* 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] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 215,225
[2] Recueil des Travaux Chimiques des Pays-Bas, 1926, vol. 45, p. 531
[3] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 215,225
[4] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 215,225
4
[ 573-54-6 ]
[ 116529-60-3 ]
Reference：
[1] Journal of the American Chemical Society, 1938, vol. 60, p. 1411,1413
5
[ 67-56-1 ]
[ 573-54-6 ]
[ 5337-09-7 ]
Yield
Reaction Conditions
Operation in experiment
95.4%
for 12 h; Reflux
General procedure: By refluxing 2-bromo-3-nitrobenzoic acid and trimethylsilyl chloride (TMSCI) in a methanol solvent for 12 hours, 2-bromo-nitrobenzoic acid methylester was prepared. The compound prepared according to a representative synthetic method in Example 3-1 may include: Yield: 95.4percent White solid 1H-NMR (400 MHz, CDCl3) δ 7.85(dd, J=7.9, 1.6 Hz, 1H), 7.76(d, J=7.9, J=1.6 Hz, 1H), 7.52(dd, J=7.9, 7.9 Hz, 1H), 3.98(s, 3H)
89.5%
With hydrogenchloride In water for 24 h; Reflux; Inert atmosphere
Example 4 Methyl 2-bromo-3-nitrobenzoate 100 g (406 mmol) of 2-bromo-3-nitrobenzoic acid, 22 g (609 mmol) of conc. HCl and 1 l of methanol are heated under reflux for 24 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is recrystallised from ethanol. Yield: 94.6 g (363 mmol), 89.5percent of theory.
With sodium carbonate In N,N-dimethyl-formamide at 60℃; for 4 h;
(a) methyl 2-bromo-3-nitrobenzoate To a solution of 2-bromo-3-nitrobenzoic acid (33.9 g, 138 mmol) in DMF (240 mL) were added Na2C03 (58.5 g, 552 mmol) and iodomethane (34 mL, 544 mmol). The reaction mixture was heated at 60 °C for 4 h. The reaction mixture was diluted with water (1.5 L) and extracted with Et20 (2 x 750 mL). The combined organic layers were washed with brine (500 mL) and concentrated to afford methyl 2-bromo-3-nitrobenzoate (36.78 g, 137 mmol, 100percent yield) as a yellow solid. LC-MS (ES) m/z = 259.9, 261.9 [M+H]+.
99%
With sodium carbonate In N,N-dimethyl-formamide at 60℃; for 8 h;
[01392] Step 1 : Synthesis of methyl 2-bromo-3-nitrobenzoate[01393] To a stirred solution of 2-bromo-3-nitrobenzoic acid (3 g, 12.19 mmol) in DMF (30 mL), sodium carbonate (5.1 6 g, 48.6 mmol) and methyl iodide (6.92 g, 48.7 mmol) were added. Resulting reaction mixture was heated at 60 °C for 8 h. On completion, solid precipitated was filtered, residue washed with ethyl acetate (5 times). Combined organic layers were dried, concentrated under reduced pressure giving desired crude 2-bromo-3-nitrobenzoate (4 g, 99percent) which was used without further purification.
96%
With potassium carbonate In water; N,N-dimethyl-formamide
a) Methyl 2-bromo-3-nitrobenzoate A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM), and potassium carbonate (19.0 g, 137.4 mM) in 100 mL DMF was stirred at room temperature for 72 hours. The mixture was poured into 1.5 liters of H2O. The resultant precipitate was collected by filtration and dried in vacuoto afford 28.79 g (96percent) of methyl 2-bromo-3-nitrobenzoate as a white solid. 1H NMR (DMSO-d6) δ 8.3 (dd, 1H, J=1 and 8 Hz), 7.9 (dd, 1H, J=1 and 8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm-1) 2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e 259, 261.
96%
With potassium carbonate In <i>N</i>-methyl-acetamide; water
a) Methyl 2-bromo-3-nitrobenzoate A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM), and potassium carbonate (19.0 g, 137.4 mM) in 100 mL dimethylformamide was stirred at room temperature for 72 hours. The mixture was poured into 1.5 liters of water. The resultant precipitate was collected by filtration and dried in vacuo to afford 28.79 g (96percent) of methyl 2-bromo-3-nitrobenzoate as a white solid. 1H NMR (DMSO-d6) δ 8.3 (dd, 1H, J=1 and 8 Hz), 7.9 (dd, 1H, J=1 and 8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm-1) 2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e 259, 261. Elemental Analyses for C8H6NO4Br: Calculated: C, 36.95; H, 2.33; N, 5.39. Found: C, 37.14; H, 2.37; N, 5.45.
96%
With potassium carbonate In water; N,N-dimethyl-formamide
a) Methyl 2-bromo-3-nitrobenzoate A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM), and potassium carbonate (19.0 g, 137.4 mM) in 100 mL DMF was stirred at room temperature for 72 hours. The mixture was poured into 1.5 liters of H2O. The resultant precipitate was collected by filtration and dried in vacuo to afford 28.79 g (96percent) of methyl 2-bromo-3-nitrobenzoate as a white solid. 1H NMR (DMSO-d6) δ 8.3 (dd, 1H, J=1 and 8 Hz), 7.9 (dd, 1H, J=1 and 8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm-1) 2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e 259, 261. Elemental Analyses for C8H6NO4Br: Calculated: C, 36.95; H, 2.33; N, 5.39. Found: C, 37.14; H, 2.37; N, 5.45.
96%
With potassium carbonate In water; N,N-dimethyl-formamide
a) Methyl 2-bromo-3-nitrobenzoate A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM), and potassium carbonate (19.0 g, 137.4 mM) in 100 mL DMF was stirred at room temperature for 72 hours. The mixture was poured into 1.5 liters of H2O. The resultant precipitate was collected by filtration and dried in vacuo to afford 28.79 g (96percent) of methyl 2-bromo-3-nitrobenzoate as a white solid. 1H NMR (DMSO-d6) δ 8.3 (dd, 1H, J=1 and 8 Hz), 7.9 (dd, 1H, J=1 and 8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm-1) 2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e 259, 261. Elemental Analyses for C8H6NO4Br: Calculated: C, 36.95; H, 2.33; N, 5.39. Found: C, 37.14; H, 2.37; N, 5.45.
Reference：
[1] Chemistry - An Asian Journal, 2011, vol. 6, # 6, p. 1431 - 1442
[2] Journal of the American Chemical Society, 1932, vol. 54, p. 4426,4428
[3] Journal of the American Chemical Society, 1934, vol. 56, p. 2123,2124
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 2, p. 746 - 751
[5] Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 434 - 444
Reference：
[1] Tetrahedron, 2000, vol. 56, # 2, p. 165 - 173
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 3, p. 385 - 390
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 3, p. 385 - 390
General procedure: A mixture of various carboxylic acids (1.0mmol), an excess of thionyl chrolide (5mL) was refluxed for 2h and concentrated in vacuo to give corresponding acyl chloride (quant).
With thionyl chloride; for 4h;Heating / reflux;
. [N- (6, 7-METHYLENEDIOXYQUINOLIN-4-YL)-N- (N, N-DIMETHYLAMINOETHYL)-2-] [BROMO-3-NITROBENZAMIDE] (8d). To a solution of compound 7 (259 mg, [1.] 0 mmol) and triethylamine (0.5 mL) in dry [CH2C12] (20 mL) was added a solution of <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> chloride in 20 mL of CH2C12 (which was prepared by refluxing of 295 mg, 1.2 mmol of <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> in 10 mL of thionyl chloride for 4 h). The reaction mixture was heated to reflux for 6 h. The reaction mixture was allowed to cool and then washed with saturated [NAHCO3] solution, water and brine and dried over [NA2S04.] Solvent was removed in vacuo to give 360 mg of a yellow solid (73.9%) ; mp [96-97 C] ; [1 H] NMR (CDC13) [8] 2.30 (s, 6H), 2.62 (t, 2H, [J=] 6.6), 3.59-3. 69 (m, [1H),] 4.53-4. 67 (m, 1H), 6. 18 (d, 2H, J= 5.2), 7.05 (d, 1H, J= 7.8), 7.14 (d, 1H, [J=] 7.4) 7.28- 7.36 (m, [3H)] 7.50 (dd, 1H, [J= 1.] 2,7. 8), 8.55 (d, [1H,] J= 3.8) ; 13C NMR [(CDC13)] 8 45.4, 46.5, 56.4, 97.8, 102.3, 106.7, 112.2, 119.5, 122.6, 125.2, 127.7, 129.7, 140.8, 144.6, 148.3, 148.5, 149.5, 151.4, 166.9
363 parts (81.7%)
With thionyl chloride; In hexane; toluene;
a) To a stirred suspension of 414 parts of <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> in 653 parts of methylbenzene there were added 440 parts of thionyl chloride. The whole was refluxed for 6 hours, cooled and left overnight. The reaction mixture was treated with activated charcoal, filtered over diatomaceous earth and evaporated. The residual oil was triturated with 396 parts of hexane (2*). The product was filtered off, washed with hexane and dried, yielding 363 parts (81.7%) of 2-bromo-3-nitrobenzoyl chloride (interm. 3).
With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 100℃; for 1h;
Example 13 : N-r2-ethyl-4-(l,2,2,3,3,3-hexafluoro-l-trifluoromethylpropyl)-6-methyl- phenyl. -2-bromo-3 -nitrobenzamidepyridine; To a suspension of <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (2.870 g, 0.0117 mol) in toluene (29 ml) was added Lambda/,Lambda/-dimethylformamide (90 mul) at ambient temperature, followed by slow addition of thionyl chloride (1.69 ml, 0.02332 mol). The reaction mixture was stirred for 1 hour at 1000C. The reaction mixture was allowed to cool to ambient temperature and the toluene was evaporated. The appropriate amount of acyl chloride was dissolved in THF and use without extra purification. To a solution of 2-ethyl-4-(l,2,2,3,3,3-hexafluoro-l-trifluoromethylpropyl)-6- methylaniline (preparation as described in WO 08/074427) (106 mg, 0.3 mmol) in tetrahydrofuran (0.5 ml) was added pyridine (72.6 mul, 0.9 mmol) at 0 to 5C. A solution of <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> chloride (87 mg, 0.33 mmol) in tetrahydrofuran (0.5 ml) was added. The reaction mixture was stirred at ambient temperature for 3 hours, then at reflux for 15 hours. After 15 hours, the reaction was not complete so JV,iV-dimethylacetamide("DMA") (0.1 equivalents) and more <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> chloride (0.2 equivalents) were added. The reaction mixture was stirred at ambient temperature for 41 hours. After 41 hours, the reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (10 ml) and the mixture extracted twice with ethyl acetate (2x 20 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 6: 1) to give jV-[2-ethyl-4-(l, 2,2, 3,3, 3-hexafluoro-l -trifluoromethylpropyl)-6-methylphenyl]-2- bromo-3 -nitrobenzamide (0.133 g, 76% yield).1H NMR (CDCl3, 400 MHz): 7.78 (dd, IH), 7.72 (dd, IH), 7.53 (t, IH), 7.32 (s, 2H), 7.17 (bs, IH), 2.71 (q, 2H), 2.40 (s, 3H), 1.19 (t, 3H).
With N-ethylmorpholine;; copper; copper(I) bromide; In methanol; for 16h;Reflux;
To a solution of <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (6, 1.01 g, 4.06 mmol) and 2,6-difluoroaniline (34, 1.05 g, 6.10 mmol) in methanol (50 mL) was added copper powder (13.0 mg, 0.20 mmol), copper (I) bromide (58.3 mg, 0.41 mmol) and N-ethyl morpholine (1.00 mL, 8.12 mmol). The reaction mixture was heated at reflux for 16 h, diluted with aqueous ammonium hydroxide (0.1 N, 12 mL) and filtered over celite. The solvent concentrated to half its volume under vacuum and then acidified to pH 2 using hydrochloric acid (1 N). The formed yellow precipitate was filtered, and dried under vacuum to afford 2-((2,6-difluorophenyl)amino)-3-nitrobenzoic acid as yellow solid (800 mg, 60%). To a solution of 2-((2,6-difluorophenyl)amino)-3-nitrobenzoic acid (650 mg, 2.21 mmol) in aqueous sodium hydroxide (2 N, 50 mL) was added sodium borohydride (336 mg, 8.84 mmol), and the reaction mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temperature, and acidified to pH 2 using hydrochloric acid (1 N). The formed precipitated was filtered, washed with water (2 x 20 mL) and dried under vacuum to afford 9-fluorophenazine-1-carboxylic acid 35, as yellow solid (224 mg, 31%); mp: 233-235 C. IR (KBr) 3047, 1728, 1515, 1458, 1246, 894, 763 cm-1; 1H NMR (500 MHz, CDCl3): delta 15.17 (s, 1 H), 9.02 (d, J = 7.0 Hz, 1 H), 8.54 (d, J = 9.0 Hz, 1 H), 8.16 (d, J = 9.0 Hz, 1 H), 8.09 (t, J = 9 Hz, 1 H), 7.95-7.91 (m, 1 H), 7.69 (t, J = 8.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3): 165.4, 144.4, 143.8, 138.1, 135.0, 131.2, 130.8, 130.8, 125.9, 125.8, 125.3, 115.5, 115.3; 19F NMR (470 MHz, CDCl3): delta -123.7; HRESIMS calcd for C13H7N2O2F 242.0492 (MH+), found 242.9999 (MH+).
With N-ethylmorpholine;; copper; copper(l) chloride; at 70℃; for 15h;
The intermediate 1 was prepared by the methods reported previously (Rewcastle et al. 1987). A 100 mL round bottom flask was charged with <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (40 mmol), p-toluidine (60 mmol), cuprous chloride (4.8 mmol), copper powder (0.15 mmol), N-ethylmorpholine (15 mL) and 2,3-butanediol (25 mL). The mixture was stirred at 70C for 15 h until the reaction was complete (monitored by TLC). Then, 0.1 mol/L NH4OH aqueous solution (100 mL) was added to the obtained solution, and filtered over celite. 2 mol/L HCl was added to the filtrate until a yellow solid precipitated. Then filtered and dried to obtain intermediate 1.
With N-ethylmorpholine;; copper; copper(l) chloride; at 70℃; for 4h;
To a 250 ml reaction flask are sequentially added <strong>[573-54-6]2-bromo-3-nitro benzoic acid</strong> (5.0g, 20.3 mmol), aniline (2.8 g, 30.5 mmol), copper powder (50 mg, 1%), cuprous chloride (250 mg, 5%), 2,3-butanediol (25 ml) and N-ethyl morpholine (15 ml), the temperature is increased to 70 C reaction, 4 hours after the end of reaction, cooling to room temperature, by adding 400 ml of 5% ammonia water solution of, filtration, then the filtrate slowly poured into dilute hydrochloric acid solution, with yellow solid is separated out, filtering, to get the yellow solid after drying 4.2 g, yield: 80.2%.
73%
With N-ethylmorpholine;; copper; copper(l) chloride; 2.3-butanediol; at 70℃; for 16h;Inert atmosphere;
In a round bottom flask were sequentially added <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (845 mg 3.43 mmol), copper(I) chloride (34 mg, 0.34 mmol), copper powder (11 mg, 0.17 mmol), aniline (0.470 mL, 5.15 mmol), N-ethylmorpholine (0.87 mL, 6.86 mmol), and 2,3-butanediol (2.14 mL). The reaction mixture was then heated to 70 C, stirred for 16 hours, diluted with 18 mL 0.1 N ammonium hydroxide solution, and filtered over CELITE. The filtrate waspoured slowly into 5 mL 2 N aqueous hydrochloric acid, and the yellow precipitate was filtered to yield the crude product which was recrystallized from toluene to afforded 886 mg (73% yield) of 3-nitro-2-(phenylamino)benzoic acid 28 as an amorphous yellow solid. [00307] lH NMR (400 MHz, J6-DMSO): delta 13.80 (br s, 1H), 9.88 (s, 1H), 8.21 (dd, J = 7.8, 1.7 Hz, 1H), 8.07 (dd, J = 8.2, 1.8 Hz, 1H), 7.24 (t, J = 1.9 Hz, 2H), 7.10 (t, J = 8.0 Hz, 1H), 6.99 (t, J = 1.4 Hz, 1H), 6.91 (d, J = 7.8 Hz, 2 H). [00308] 13C NMR (100 MHz, J6-DMSO): delta 168.6, 141.4, 139.9, 138.8, 136.7, 130.8, 129.2, 123.1, 120.5, 119.0, 118.1. [00309] HMRS (DART): m/z calc. for C13HnN204 [M+H]+: 259.0713, found: 259.0719
With N-ethylmorpholine;; copper; copper(l) chloride;
Aniline is coupled with <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> under copper catalysis,And then ring-forming under the action of sodium borohydride to obtain 1-carboxyphenazine,Finally, the carboxyl group is converted into an amino group under the action of diphenylphosphoryl azide to obtain 1-aminophenazine.
With N-ethylmorpholine;; copper; copper(l) chloride; at 70℃; for 15h;
Add aniline and <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> to 2,3-butanediol, add CuCl, Cu powder and N-ethylmorpholine, and heat and stir at 70 C for 15h.Wash with 0.1M ammonia, filter,The resulting solution was slowly poured into 2M HCl to obtain the intermediate 3-nitro-2-phenylaminobenzoic acid;Add it and NaBH4 to a solution in 2M NaOH, reflux for 5h, and cool in an ice bath.Acidified with dilute hydrochloric acid to obtain phenazine-1-carboxylic acid;Under ice-bath conditions, phenazine-1-carboxylic acid was dissolved in dichloromethane, and oxalyl chloride and N, N-dimethylformamide were added dropwise under the protection of nitrogen. After stirring at room temperature for 16 hours,Remove the volatiles in vacuo and cool to 0 C.Add ammonia dropwise and stir for half an hour,The reaction was filtered to give a solid,After drying, it was recrystallized from ethyl acetate.Phenazine-1-carboxamide is obtained;The mixture with 1,3-dichloroacetone was heated at 130 C for 1 h, and after cooling to room temperature,It was quenched by adding water, and the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered,Concentrated under reduced pressure,Column chromatography gave 2- (1-phenazine) -4-chloromethyloxazole.Yellow liquid, 68% yield.
With N-ethylmorpholine;; copper; copper(l) chloride; 2.3-butanediol; at 70℃; for 16h;Inert atmosphere;
In a round bottom flask were sequentially added <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (1.00 g, 4.06 mmol), copper(I) chloride (40 mg, 0.40 mmol), copper powder (13 mg, 0.20 mmol), 2- chloroaniline (0.640 mL, 6.09 mmol), N-ethylmorpholine (1.03 mL, 8.12 mmol), and 2,3-butanediol (2.5 mL). The mixture was heated to 70 C with stirring for 16 hours, diluted with 25 mL 0.1 N aqueous ammonium hydroxide, and filtered over CELITE. The filtrate was poured slowly into 5 mL 2 N aqueous hydrochloric acid, and the resulting yellow precipitate was filtered to yield the crude product which was recrystallized from toluene to afforded 712 mg (60% yield) of 2-((2-chlorophenyl)amino)-3-nitrobenzoic acid 31 as an amorphous yellow solid. This product appeared to be [00346] lH NMR (400 MHz, J6-DMSO): delta 10.06 (br s, 1H), 8.26 (d, J = 7.7 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.19 - 7.07 (m, 2H), 7.01 (t, J = 7.3 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H). [00347] 13C NMR (100 MHz, d6-DMSO): delta 168.7, 139.6, 138.3, 138.1, 136.9, 131.0, 130.0, 127.6, 124.3 (2), 120.6, 119.7, 117.1. [00348] HRMS (DART): m/z calc. for C13Hi0N2O4Cl [M+H]+: 293.0324, found: 293.0332.
With N-ethylmorpholine;; copper; copper(I) bromide; In ethanol; for 16h;Reflux;
General procedure: To a solution of <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (6, 1.01 g, 4.06 mmol) and 3-bromoaniline (14, 1.05 g, 6.10 mmol) in ethanol (50 mL) was added copper powder (13.0 mg, 0.20 mmol), copper(I) bromide (58.3 mg, 0.41 mmol) and N-ethyl morpholine (1.00 mL, 8.12 mmol). The reaction mixture was heated at reflux for 16 h, diluted with aqueous ammonium hydroxide (0.1 N, 12 mL) and filtered over celite. The filtrate was acidified to pH 2 using hydrochloric acid (1 N) and the solvent concentrated to half. The formed yellow precipitate was filtered, and dried under vacuum to afford 2-((3-bromophenyl)amino)-3-nitrobenzoic acid as yellow solid (800 mg, 60%), which was used without further purification. To a solution of 2-((3-bromophenyl)amino)-3-nitrobenzoic acid (800 mg, 2.37 mmol) in aqueous sodium hydroxide (2 N, 50 mL) was added sodium borohydride (359 mg, 9.50 mmol), and the reaction mixture was heated to 100 C for 12 h. The reaction mixture was cooled to room temperature, and acidified to pH 2 using hydrochloric acid (1 N). The formed precipitated was filtered, washed with water (2 x 20 mL) and dried under vacuum to afford 6-bromophenazine-1-carboxylic acid, 18, as yellow solid (450 mg, 62%)
With N-ethylmorpholine;; copper; copper(I) bromide; In ethanol; for 16h;Reflux;
General procedure: To a solution of <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (6, 1.01 g, 4.06 mmol) and 3-bromoaniline (14, 1.05 g, 6.10 mmol) in ethanol (50 mL) was added copper powder (13.0 mg, 0.20 mmol), copper(I) bromide (58.3 mg, 0.41 mmol) and N-ethyl morpholine (1.00 mL, 8.12 mmol). The reaction mixture was heated at reflux for 16 h, diluted with aqueous ammonium hydroxide (0.1 N, 12 mL) and filtered over celite. The filtrate was acidified to pH 2 using hydrochloric acid (1 N) and the solvent concentrated to half. The formed yellow precipitate was filtered, and dried under vacuum to afford 2-((3-bromophenyl)amino)-3-nitrobenzoic acid as yellow solid (800 mg, 60%), which was used without further purification. To a solution of 2-((3-bromophenyl)amino)-3-nitrobenzoic acid (800 mg, 2.37 mmol) in aqueous sodium hydroxide (2 N, 50 mL) was added sodium borohydride (359 mg, 9.50 mmol), and the reaction mixture was heated to 100 C for 12 h. The reaction mixture was cooled to room temperature, and acidified to pH 2 using hydrochloric acid (1 N). The formed precipitated was filtered, washed with water (2 x 20 mL) and dried under vacuum to afford 6-bromophenazine-1-carboxylic acid, 18, as yellow solid (450 mg, 62%)
General procedure: By refluxing 2-bromo-3-nitrobenzoic acid and trimethylsilyl chloride (TMSCI) in a methanol solvent for 12 hours, 2-bromo-nitrobenzoic acid methylester was prepared. The compound prepared according to a representative synthetic method in Example 3-1 may include: Yield: 95.4% White solid 1H-NMR (400 MHz, CDCl3) delta 7.85(dd, J=7.9, 1.6 Hz, 1H), 7.76(d, J=7.9, J=1.6 Hz, 1H), 7.52(dd, J=7.9, 7.9 Hz, 1H), 3.98(s, 3H)
89.5%
With hydrogenchloride; In water; for 24h;Reflux; Inert atmosphere;
Example 4 Methyl 2-bromo-3-nitrobenzoate 100 g (406 mmol) of 2-bromo-3-nitrobenzoic acid, 22 g (609 mmol) of conc. HCl and 1 l of methanol are heated under reflux for 24 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is recrystallised from ethanol. Yield: 94.6 g (363 mmol), 89.5% of theory.
With chloride derivative; at 0℃;Reflux;
General procedure: II, IV, and VIII: Thionyl chloride was added dropwise toa solution of benzoic acid derivative (I, III, and VII) in anhydrousmethyl alcohol at 0C. After this addition, the mixture was stirred atreflux for 8?12 hours. The reaction mixture was basified with 10%sodium bicarbonate, and ethyl acetate was added. The organic layerwas dried over anhydrous MgSO4, filtered, and the solvent wasevaporated to give the products II, IV, and VIII.
With sulfuric acid; at 80℃; for 18h;
Example 157: Synthesis of 3-[3-(benzylamino)prop-l-yn-l-yl]-2- phenylbenzoic acid Methyl 2-bromo-3-nitrobenzoate: To a stirring solution of 2-bromo-3- nitrobenzoic acid (500 mg, 2.04 mmol) in methanol (5 mL) was added concentrated sulfuric acid (0.5 mL). The resulting solution was heated at 80 C for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated at reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with IN aqueous sodium hydroxide solution (50 mL) and brine, dried (magnesium sulfate), filtered and concentrated at reduced pressure to give the desired product as a colorless oil which was used in the next step without further purification.
With N-ethylmorpholine;; copper; copper(l) chloride In ethylene glycol
R.1.R 2-Methoxy-benzo[a]phenazine-11-carboxylic Acid (II.33)
7-Methoxy-naphthalen-1-ylamine was treated with 2-bromo-3-nitro-benzoic acid according to the analogous procedure described by G. W. Rewcastle et al (J. Med. Chem. 1987, p843) to yield 2-(7-methoxy-naphthalen-1-ylamino)-3-nitro-benzoic acid.
With N-ethylmorpholine;; copper; copper(l) chloride; 2.3-butanediol; at 70℃; for 16h;Inert atmosphere;
In a round bottom flask were sequentially added <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (1.00 g, 4.06 mmol), copper(I) chloride (40 mg, 0.40 mmol), copper powder (13 mg, 0.20 mmol), 4- bromoaniline (1.05 g, 6.09 mmol), N-ethylmorpholine (1.03 mL, 8.12 mmol), and 2,3- butanediol (2.5 mL). The reaction mixture was then heated to 70 C with stirring for 16 hours before being diluted with 25 mL 0.1 Nu aqueous ammonium hydroxide and filtered over CELITE. The filtrate was poured slowly into 5 mL 2 Nu aqueous hydrochloric acid, and the yellow precipitate was filtered to give 491 mg (36% yield) of 2-((4-bromophenyl)amino)-3-nitrobenzoic acid 30 as an amorphous orange solid. [00338] lH NMR (400 MHz, J6-DMSO): delta 8.17 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 1.1 Hz, 2H), 7.18 (t, J = 1.9 Hz, 1H), 6.85 (d, J = 1.1 Hz, 2H). [00339] 1JC NMR (100 MHz, d6-DMSO): delta 168.1, 141.4, 140.6, 137.8, 136.4, 131.8, 130.3, 122.1, 120.0, 119.8, 114.0. [00340] HRMS (DART): m/z calc. for C13Hi0N2O4Br [M+H]+: 336.9818, found: 336.9821.
31%
Butane-2,3-diol (10 ml), <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (145) (Culhane, P. J., Organic Syntheses, Wiley, New York, 1944, Collect. VoI I, 125) (4.10 g, 16.7 mmol), cuprous chloride (206 mg) and copper powder (410 mg) are successively added to a solution of 4-bromoaniline (4.30 g, 24.5 mmol) in JV-ethylmorpholine (6 ml, 46.9 mmol). The solution is heated at 700C for 7.5 hours. Heating is halted and a 0.5M aqueous ammonia solution (140 ml) is added with stirring. The medium is then rapidly filtered through Celite 545. The Celite is washed with 0.5M aqueous ammonia solution (20 ml). The filtrate is poured, with vigorous stirring, onto a 2N aqueous hydrochloric acid solution (140 ml). After stirring for 10 minutes, the solution loses its colour and a pale yellow precipitate is formed. The solution is placed in a refrigerator overnight and the precipitate formed is filtered off and then dried in a desiccator, to result in the diphenylamine 146 (1.76 g, 5.22 mmol) Yield: 31%; melting point: 194-196 C; 1H NMR (400 MHz, J6-DMSO) d 6.86 (d, 2H, J= 9 Hz), 7.16 (t, IH, J= 8 Hz), 7.38 (d, 2H, J= 9 Hz), 8.09 (d, IH, J= 8 Hz), 8.18 (d, IH, J= 8 Hz), 9.69 (bs, IH); 13C NMR (100 MHz, CDCl3) d 114.1, 119.8 (2C), 120.0, 122.0, 130.4, 131.8 (2C), 136.5, 137.8, 140.5, 141.4, 168.1; IR (KBr) v cm"1: 1259, 1437, 1526, 1668, 3328; ESI-MS m/z 334.7 [M-H]+.
With N-ethylmorpholine;; copper; copper(I) bromide; In ethanol; for 16h;Reflux;
General procedure: To a solution of <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (6, 1.01 g, 4.06 mmol) and 3-bromoaniline (14, 1.05 g, 6.10 mmol) in ethanol (50 mL) was added copper powder (13.0 mg, 0.20 mmol), copper(I) bromide (58.3 mg, 0.41 mmol) and N-ethyl morpholine (1.00 mL, 8.12 mmol). The reaction mixture was heated at reflux for 16 h, diluted with aqueous ammonium hydroxide (0.1 N, 12 mL) and filtered over celite. The filtrate was acidified to pH 2 using hydrochloric acid (1 N) and the solvent concentrated to half. The formed yellow precipitate was filtered, and dried under vacuum to afford 2-((3-bromophenyl)amino)-3-nitrobenzoic acid as yellow solid (800 mg, 60%), which was used without further purification. To a solution of 2-((3-bromophenyl)amino)-3-nitrobenzoic acid (800 mg, 2.37 mmol) in aqueous sodium hydroxide (2 N, 50 mL) was added sodium borohydride (359 mg, 9.50 mmol), and the reaction mixture was heated to 100 C for 12 h. The reaction mixture was cooled to room temperature, and acidified to pH 2 using hydrochloric acid (1 N). The formed precipitated was filtered, washed with water (2 x 20 mL) and dried under vacuum to afford 6-bromophenazine-1-carboxylic acid, 18, as yellow solid (450 mg, 62%)
With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4h;
(a) methyl 2-bromo-3-nitrobenzoate To a solution of 2-bromo-3-nitrobenzoic acid (33.9 g, 138 mmol) in DMF (240 mL) were added Na2C03 (58.5 g, 552 mmol) and iodomethane (34 mL, 544 mmol). The reaction mixture was heated at 60 C for 4 h. The reaction mixture was diluted with water (1.5 L) and extracted with Et20 (2 x 750 mL). The combined organic layers were washed with brine (500 mL) and concentrated to afford methyl 2-bromo-3-nitrobenzoate (36.78 g, 137 mmol, 100% yield) as a yellow solid. LC-MS (ES) m/z = 259.9, 261.9 [M+H]+.
99%
With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;Product distribution / selectivity;
[01392] Step 1 : Synthesis of methyl 2-bromo-3-nitrobenzoate[01393] To a stirred solution of 2-bromo-3-nitrobenzoic acid (3 g, 12.19 mmol) in DMF (30 mL), sodium carbonate (5.1 6 g, 48.6 mmol) and methyl iodide (6.92 g, 48.7 mmol) were added. Resulting reaction mixture was heated at 60 C for 8 h. On completion, solid precipitated was filtered, residue washed with ethyl acetate (5 times). Combined organic layers were dried, concentrated under reduced pressure giving desired crude 2-bromo-3-nitrobenzoate (4 g, 99%) which was used without further purification.
28.79 g (96%)
With potassium carbonate; In water; N,N-dimethyl-formamide;
a) Methyl 2-bromo-3-nitrobenzoate A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM), and potassium carbonate (19.0 g, 137.4 mM) in 100 mL DMF was stirred at room temperature for 72 hours. The mixture was poured into 1.5 liters of H2O. The resultant precipitate was collected by filtration and dried in vacuoto afford 28.79 g (96%) of methyl 2-bromo-3-nitrobenzoate as a white solid. 1H NMR (DMSO-d6) delta 8.3 (dd, 1H, J=1 and 8 Hz), 7.9 (dd, 1H, J=1 and 8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm-1) 2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e 259, 261.
28.79 g (96%)
With potassium carbonate; In N-methyl-acetamide; water;
a) Methyl 2-bromo-3-nitrobenzoate A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM), and potassium carbonate (19.0 g, 137.4 mM) in 100 mL dimethylformamide was stirred at room temperature for 72 hours. The mixture was poured into 1.5 liters of water. The resultant precipitate was collected by filtration and dried in vacuo to afford 28.79 g (96%) of methyl 2-bromo-3-nitrobenzoate as a white solid. 1H NMR (DMSO-d6) delta 8.3 (dd, 1H, J=1 and 8 Hz), 7.9 (dd, 1H, J=1 and 8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm-1) 2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e 259, 261. Elemental Analyses for C8H6NO4Br: Calculated: C, 36.95; H, 2.33; N, 5.39. Found: C, 37.14; H, 2.37; N, 5.45.
28.79 g (96%)
With potassium carbonate; In water; N,N-dimethyl-formamide;
a) Methyl 2-bromo-3-nitrobenzoate A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM), and potassium carbonate (19.0 g, 137.4 mM) in 100 mL DMF was stirred at room temperature for 72 hours. The mixture was poured into 1.5 liters of H2O. The resultant precipitate was collected by filtration and dried in vacuo to afford 28.79 g (96%) of methyl 2-bromo-3-nitrobenzoate as a white solid. 1H NMR (DMSO-d6) delta 8.3 (dd, 1H, J=1 and 8 Hz), 7.9 (dd, 1H, J=1 and 8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm-1) 2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e 259, 261. Elemental Analyses for C8H6NO4Br: Calculated: C, 36.95; H, 2.33; N, 5.39. Found: C, 37.14; H, 2.37; N, 5.45.
28.79 g (96%)
With potassium carbonate; In water; N,N-dimethyl-formamide;
a) Methyl 2-bromo-3-nitrobenzoate A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM), and potassium carbonate (19.0 g, 137.4 mM) in 100 mL DMF was stirred at room temperature for 72 hours. The mixture was poured into 1.5 liters of H2O. The resultant precipitate was collected by filtration and dried in vacuo to afford 28.79 g (96%) of methyl 2-bromo-3-nitrobenzoate as a white solid. 1H NMR (DMSO-d6) delta 8.3 (dd, 1H, J=1 and 8 Hz), 7.9 (dd, 1H, J=1 and 8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm-1) 2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e 259, 261. Elemental Analyses for C8H6NO4Br: Calculated: C, 36.95; H, 2.33; N, 5.39. Found: C, 37.14; H, 2.37; N, 5.45.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 2h;
20
To a solution of 2-bromo-3-nitrobenzoic acid (0.974 g, 3.96 mmol) in DMF (3 mL) was added methylamine, 2.0m solution in tetrahydrofuran (2.97 mL, 5.94 mmol), 1,1'-dimethyltriethylamine (1.38 mL, 7.92 mmol) and (1H-benzo[d]-[1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (2.47 g, 4.75 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel column using DCM/EtOAc-DCM (1:1) as eluent to give 2-bromo-N-methyl-3-nitrobenzamide: LC-MS (ESI) m/z 261.0 [M+H]+.
With potassium phosphate; tricyclohexylphosphine;palladium diacetate; In water; toluene; at 100℃; for 6h;
A solution of 2- bromo-3-nitrobenzoic acid (1.17 g, 4.28 mmol), Pd(OAc)2 (0.048 g, 0.21 mmol), P(Cy)3 (0.132 g, 0.471 mmol), K3P04 (3.18 g, 15.0 mmol) and cyclopropylboronic acid (0.735 g, 8.56 mmol) in toluene (4 mL) and water (1 mL) was stirred at 100 C for 6 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The aqueous layer was separated and acidified with saturated potassium hydrogen sulfate to about pH 3-4. The resulting solid was collected by filtration to give 2-cyclopropyl-3-nitrobenzoic acid (0.63 g, 71.0%) as a solid.
5-nitro-3-(4-trifluoromethylphenyl)isocoumarin[ No CAS ]
[ 709-63-7 ]
[ 583-02-8 ]
Yield
Reaction Conditions
Operation in experiment
5%; 11%; 6%
With sodium ethanolate; copper; for 16h;Reflux;
Compound 1034 (2.5g, 10mmol) and Cu powder (220mg, 3.5mmol) were added to 11a40 (3.5g, 15mol) and NaOEt (1.6g, 23mmol) in EtOH (35mL). The mixture was boiled under reflux for 16h, then poured into H2O and acidified with aq HCl (2M). Extraction (Et2O), evaporation and chromatography (hexane/EtOAc 4:1) gave 12a (160mg, 5%) as yellow crystals, with data as below. Further elution gave 13 (210mg, 11%) as a colourless oil (lit.41 oil): 1H NMR (CDCl3) delta 2.56 (3H, s, Me), 7.55 (2H, d, J=8.2Hz, Ph 3,5-H2), 8.14 (2H, d, J=8.2Hz, Ph 2,6-H2). Further elution gave 14 (130mg, 6%) as a colourless oil (lit.42 oil): 1H NMR (CDCl3) delta 1.41 (3H, t, J=7.2Hz, Me), 4.41 (2H, q, J=7.2Hz, CH2), 7.75 (2H, d, J=8.2Hz, 3,5-H2), 8.16 (2H, d, J=8.2Hz, 2,6-H2).
With potassium tert-butylate; copper; In tert-butyl alcohol; for 16h;Reflux;
Compound 1034 (5.0g, 20mmol) and Cu powder (150mg, 2.4mmol) were added to 17b (22.9g, 102mmol) and KOBut (4.6g, 41mmol) in ButOH (100mL). The mixture was boiled under reflux for 16h, then poured into water and acidified with aq HCl (2M). This suspension was extracted (Et2O). Evaporation and chromatography (hexane/EtOAc 10:1) gave 12b (4.2g, 78%) as yellow crystals, with data as above.
78%
With potassium tert-butylate; copper; In tert-butyl alcohol; for 16h;Reflux;
5-Nitro-3-phenylisocoumarin (3c). 1 ,3-Diphenylpropane-1 ,3-dione (22.9 g, 102 mmol) was boiled under reflux with <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> 285 (4.5 g, 20 mmol), potassium f-butoxide (4.6 g, 41 mmol) and copper powder (150 mg, 2.4 mmol) in 2- methylpropan-2-ol (100 mL) for 16 h. The mixture was poured into water (350 mL) and the mixture was acidified by addition of aqueous hydrochloric acid (2 M). The solution was extracted with diethyl ether. The solvent was evaporated from the extract and chromatography (hexane / ethyl acetate 10:1) gave 5-nitro-3-phenylisocoumarin 3c (4.2 g, 78%) as yellow crystals: mp 142-143C; IR vmax (KBr) 1739, 1626, 1525, 1341 cm"1; 1H NMR (CDCI3) delta 7.50-7.53 (3 H, m, Ph 3,4,5-H3), 7.62 (1 H, t, J = 7.8 Hz, 7-H), 7.89 (1 H, d, J = 0.8 Hz, 4-H), 7.93-7.97 (2 H, m, Ph 2,6-H2), 8.51 (1 H, dd, J = 8.2, 1.2 Hz, 6-H), 8.65 (1 H, ddd, J = 8.2, 1.2, 0.8 Hz, 8-H); 13C NMR (CDCI3) delta 117.18 4-C, 121.01 , 125.61 , 127.59, 127.90, 128.28, 128.77, 129.83, 131.18, 135.44, 148.42, 157.06, 165.07 (C=0); MS (electron impact) m/z 267.0532 (M)+ (C15H9N04 requires 267.0532).
With potassium tert-butylate; copper; In tert-butyl alcohol; for 16h;Reflux;
Compound 1034 was treated with 17h,45 Cu and KOBut in ButOH, as for the synthesis of 12b (Method B) to give 12h (36%) as a pale yellow oil, with data as above.
36%
With potassium tert-butylate; copper; In tert-butyl alcohol; for 16h;Reflux;
-Nitro-3-pentylisocoumarin (3b). Tridecane-6,8-dione (31.8 g, 150 mmol) was boiled under reflux with <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> 285 (7.4 g, 30 mmol), potassium f-butoxide (6.8 g, 61 mmol) and copper powder (190 mg, 3.0 mmol) in 2-methyl-2- propanol (100 mL) for 16 h. The mixture was poured into water (350 mL) and the mixture was acidified by addition of aqueous hydrochloric acid (2 M). The solution was extracted with diethyl ether. The solvent was evaporated from the extract and chromatography (hexane / ethyl acetate 4:1) gave 5-nitro-3-pentylisocoumarin 3b (2.8 g, 36%) as a yellow oil: IR vmax (film) 1736, 1646, 1530, 1344 cm"1; 1H NMR (CDCI3) delta 0.92 (3 H, m, pentyl 5-H3), 1.35-1.40 (4 H, m, pentyl 3,4-H4), 1.70-1.78 (2 H, m, pentyl 2-H2), 2.59 (2 H, t, J = 7.8 Hz, pentyl 1 -H2), 7.12 (1 H, d, J = 0.8 Hz, 4-H), 7.55 (1 H, t, J = 7.8 Hz, 7-H), 8.41 (1 H, dd, J = 7.8, 1.6 Hz, 6-H), 8.56 (1 H, ddd, J = 7.8, 1.6, 0.8 Hz, 8-H); 13C NMR (CDCI3) delta 13.96 (pentyl 5-C), 22.37 (CH2), 26.61 (CH2), 31.18 (CH2), 34.20 (CH2), 97.69 (4-C), 122.08, 126.83, 131.34, 131.85, 135.71 , 143.82, 160.99, 162.36 (C=0); MS m/z 261.1002 (electron impact) (M)+ (C14H15N04 requires 261.1001).
3-(4-methoxyphenyl)-5-nitro-1H-isochromen-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With potassium tert-butylate; copper; In tert-butyl alcohol; for 16h;Reflux;
Compound 1034 was treated with 17d,43 Cu and KOBut in ButOH, as for the synthesis of 12b (Method B) (chromatographic eluent: hexane/EtOAc 4:1) to give 12d (61%) as yellow crystals, with data as above.
60%
With potassium tert-butylate; copper; In tert-butyl alcohol; for 16h;Reflux;
3-(4-Methoxyphenyl)-5-nitroisocoumarin (3e). 1 ,3-Di(4-methoxyphenyl)-1 ,3- propanedione87 (10.0 g, 35 mmol) was boiled under reflux with <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> 285 (2.5 g, 10 mmol), potassium i-butoxide (2.3 g, 20 mmol) and copper powder (63 mg, 1.0 mmol) in 2-methylpropan-2-ol (50 mL) for 16 h. The mixture was poured into water (350 mL) and the mixture was acidified by addition of aqueous hydrochloric acid (2 M). The solution was extracted with diethyl ether. The solvent was evaporated from the extract and chromatography (hexane / ethyl acetate 4:1) gave 3-(4- methoxyphenyl)-5-nitroisocoumarin 3e (180 mg, 60%) as yellow crystals: mp 241- 242C; IR vmax (KBr) 1738, 1620, 1511 , 1346 cm-1: 1H NMR (CDCI3) delta 3.88 (3 H, s, Me), 6.99 (2 H, d, J = 9.0 Hz, Ph 3,5-H2), 7.54 (1 H, t, J = 8.2 Hz, 7-H), 7.76 (1 H, s, 4-H), 7.88 (2 H, d, J = 9.0 Hz, Ph 2,6-H2), 8.46 (1 H, dd, J = 8.2, 1.2 Hz, 6-H), 8.59 (1 H, dd, J = 8.2, 1.2 Hz, 8-H); 13C NMR (CDCI3) delta 55.56 (Me), 94.74 (4-C), 1 14.52), 126.56, 127.73, 131.71 , 135.92; MS m/z (electron impact) 297.0639 (M)+ (C^HnNOs requires 297.0637).
2-((2-bromophenyl)amino)-3-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With N-ethylmorpholine;; copper; copper(I) bromide; In ethanol; for 16h;Reflux;
To a solution of <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (6, 2.0 g, 8.1 mmol) and 2-bromoaniline (7, 2.1g, 12 mmol) in ethanol (100 mL) was added copper powder (26 mg, 0.4 mmol), copper (I) bromide (117 mg, 0.81 mmol) and N-ethyl morpholine (2.0 mL, 16 mmol). The reaction mixture was heated to reflux for 16 h, diluted with aqueous ammonium hydroxide solution (0.1 N, 25 mL) and filtered over celite. The filtrate was acidified to pH 2 using hydrochloric acid (1 N), and the solvent removed by filtration. The obtained yellow precipitate was dried under vacuum to afford 2-((2-bromophenyl)amino)-3-nitrobenzoic acid 8 as yellow solid (1.6 g, 60%, yield). Which was used for the next step without further purification.
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