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Structure of 603-83-8 * Storage: {[proInfo.prStorage]}
* 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] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3177 - 3180
3
[ 603-83-8 ]
[ 2942-40-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
With sodium nitrite In water; acetic acid
A. Preparation of 4-Nitroindazole from 2-Methyl-3-Nitro-Aniline Sodium nitrite (20 grams, 0.29 mol) was dissolved in 50 mL water. This solution was added all at once to 2-methyl-3-nitroaniline (20 grams, 0.13 moles) in glacial acetic acid near zero degrees C. The reaction was stirred vigorously with an overhead stirrer. An immediate precipitate occurred upon addition of sodium nitrite solution. The reaction was allowed to reach room temperature and stirred overnight. The precipitate was filtered off and the filtrate was concentrated in vacuo. The dark orange solid was suspended in water, filtered, and dried yielding 14-21 grams of a dark orange solid (99percent yield).
90%
With acetic acid; sodium nitrite In water at 0 - 20℃;
Sodium nitrite (20 grams, 0.29 mol) was dissolved in 50 mL water. This solution was added all at once to 2-methyl-3-nitroaniline (20 grams, 0.13 moles) in glacial acetic acid near zero degrees C. The reaction was stirred vigorously with an overhead stirrer. An immediate precipitate occurred upon addition of sodium nitrite solution. The reaction was allowed to reach room temperature and stirred overnight. The precipitate was filtered off and the filtrate was concentrated in vacuo. The dark orange solid was suspended in water, filtered, and dried yielding 14-21 grams dark orange solid (99percent yield).
90.3%
With sodium nitrite In water; acetic acid at 20℃; for 24 h;
General procedure: Take compound 7 (5.00g, 32.9mmol), was dissolved in glacial acetic acid (235 mL), under stirring, was added at once sodium nitrite (2.50g, 36.2mmol) in water (6mL)solution, keeping the internal temperature not higher than 20 deg. C, the reaction was stirred for 24h, the system under reduced pressure rotary evaporated to remove most of the glacial acetic acid, was added a lot of water, a lot of solid precipitation, after which the resulting solid was suction filtered, washed with water and dried in vacuo to give the title compound, using this method the synthesis of compounds 8a-8d.
84%
With acetic acid; sodium nitrite In water at 0 - 20℃; for 48 h;
To a solution of 2-methyl-3-nitroaniline (50 g, 328 mmol) in AcOH (700 mL), a solution of NaN02 (45.4 g, 657 mmol) in water (100 mL) was added at 0 °C. The reaction was stirred at rt for 48h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was poured onto ice water and filtered. The filtrate was washed with water and dried under vacuum to afford 45 g of 4-nitro-1 H-indazole a1. Yield: 84percent. 1H NMR (400 MHz, DMSO-cfe) δ 8.53 (s, 1 H), 8.15 (d, J = 8.03 Hz, 1 H), 8.09 (d, J = 8.03 Hz, 1 H), 7.60 (t, J = 8.03 Hz, 2H).
81%
for 2 h;
Reference Example 5: Indazole-4-Boronate Ester (70): Route 1 EPO <DP n="34"/> (70) (69)To a solution of 2-methyl-3-nitroaniline (2.27g, 14.91mmol) in acetic acid (6OmL) was added a solution of sodium nitrite (1.13g, 1.1 eq.) in water (5mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole (67) (1.98g, 81percent).A mixture of 4-nitro-lH-indazole (760mg, 4.68mmol), palladium on charcoal (10percent, cat.) and ethanol (3OmL) was stirred under a balloon of hydrogen for 4 h. The reaction mixture was then filtered through celite, and the solvent removed in vacuo to yield lH-indazol-4-ylamine (68) (63 lmg, 100percent).An aqueous solution of sodium nitrite (337mg, 4.89mmol) in water (2mL) was added dropwise to a suspension of lH-indazol-4-ylamine (63 lmg, 4.74mmol) in 6M hydrochloric acid (7.2mL) at below O0C. After stirring for 30 minutes, sodium tetrafluorobrate (724mg) was added to the reaction mixture. A viscous solution resulted, which was filtered and washed briefly with water to yield lH-indazole-4- diazonium tetrafluoroborate salt (69) (218mg, 20percent) as a deep red solid.Dry MeOH (4mL) was purged with argon for 5 minutes. To this was added lH-indazole-4-diazonium tetrafluoroborate salt (218mg, 0.94mmol), bis-pinacolato EPO <DP n="35"/>diboron (239mg, l.Oeq.) and [l,r-bis(diphenylphosphino)ferrocene]palladium (II) chloride (20mg). The reaction mixture was stirred for 5 h and then filtered through celite. The residue was purified using flash chromatography to yield the desired title compound (70), (117mg).
81%
With acetic acid; sodium nitrite In water for 2 h;
Reference Example 4:; Indazole-4-Boronate Ester:; (Route 1); (70) (69) EPO <DP n="35"/>To a solution of 2-methyl-3-nitro aniline (2.27g, 14.91mmol) in acetic acid (6OmL) was added a solution of sodium nitrite (1.13g, l.leq.) in water (5mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole (67) (1.98g, 81percent).
81%
With acetic acid; sodium nitrite In water for 2 h;
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/water and the resulting precipitate collected by filtration to yield 4-nitro-1H-indazole (67) (1.98 g, 81percent).
81%
With sodium nitrite In water for 2 h;
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 hours, the deep red solution was poured onto ice/water and the precipitate collected by filtration to yield 4-nitro-1H-indazole (1.98 g, 81percent).
81%
With sodium nitrite In water; acetic acid for 2 h;
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4- nitro-lH-indazole C (1.98 g, 81percent).
81%
With acetic acid; sodium nitrite In water for 2 h;
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/water and the resulting precipitate collected by filtration to yield 4-nitro-1H-indazole C (1.98 g, 81percent).
81%
With acetic acid; sodium nitrite In water for 2 h;
Example 5 4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indazole7 -route 2 <n="140"/>[00280] To a solution of 2-methyl-3-nitroaniline (2.27g, 14.91mmol) in acetic acid(6OmL) was added a solution of sodium nitrite (1.13g, 1.1 eq.) in water (5mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole C (1.98g, 81percent).
81%
With sodium nitrite In water; acetic acid for 2 h;
To a solution of 2-methyl-3-nitroaniline (2.27g, 14.91mmol) in acetic acid(6OmL) was added a solution of sodium nitrite ( 1.13 g, 1.1 eq.) in water (5mL). After 2 hours, the deep red solution was poured onto ice/ water and the precipitate collected by filtration to yield 4-nitro-lH-indazole (1.98g, 81percent).A mixture of 4-nitro-lH-indazole (760mg, 4.68 mmol), palladium on charcoal (10percent, cat.) and ethanol (3OmL) was stirred under a balloon of hydrogen for 4 hours. The reaction mixture was then filtered through celite, and the solvent removed in vacuo to yield lH-indazol-4-ylamine (631mg, 100percent).An aqueous solution of sodium nitrite (337mg, 4.89mmol) in water (2mL) was added dropwise to a suspension of lH-indazol-4-ylamine (631mg, 4.74mmol) in 6M <n="43"/>hydrochloric acid (7.2mL) at below 0°C. After stirring for 30 minutes sodium tetrafluorobrate (724mg) was added. The reaction mixture became very thick and was filtered and washed briefly with water to yield lH-indazole-4-diazonium, tetrafluoroborate salt (218mg, 20percent) as a deep red solid.Dry methanol (4mL) was purged with argon for 5 minutes. To this was added lH-indazole-4-diazonium, tetrafluoroborate salt (218mg, 0.94mmol), bis-pinacolato diboron (239mg, l.Oeq.) and [l,r-bis(diphenylphosphino)ferrocene]palladium (II) chloride (20mg). The reaction mixture was stirred for 5 hours and then filtered through celite. The residue was purified using flash chromatography to yield the desired title compound (117mg).
81%
With acetic acid; sodium nitrite In water for 2 h;
Example 3 4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indazole24 - route 2 [0189] To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid(60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, <n="66"/>the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole C (1.98 g, 81percent).
77%
With acetic acid; sodium nitrite In water for 24 h;
2-Methyl-3-nitroaniline (4.023 g, 26.44 mmol) was dissolved inglacial acetic acid (200 mL). Afterwards,a solution of NaNO2 (2.26 g,30.27 mmol) in water (10 mL) was added dropwise. This led to the precipitationof the diazonium salt. After re-dissolution of the precipitate (after 24 h) themixture was concentrated under reduced pressure. Afterwards, hot water (500 mL)was added to yield an orange solid. The mixture was filtered, washed with waterand dried to yield 4-nitro-1H-indazole (3.33g, 77percent). Rf =0.34 (toluene/ethyl acetate, 3:2). 1H NMR(400 MHz, CDCl3) δ: 7.55 (dd,3J6,5 = 8.4 Hz,3J6,7 = 7.7 Hz,1H, H‑6), 7.89 (d, 3J6,5= 8.4 Hz, 1H, H-5), 8.19 (d, 3J7,6= 7.7 Hz, 1H, H-7), 8.74 (s, 1H, H-3)
74%
With sodium nitrite In water; acetic acid at 20℃;
To a solution of 2 -methyl- 3 -nitro aniline (500 mg, 3.29 mmol) in AcOH (10 mL) was added a solution of sodium nitrite (250 mg, 3.62 mmol) in H20 (1 mL). the reaction was stirred at r.t. overnight. The mixture was poured into ice-water and the precipitate was collected by filtration. The filtrate was treated with aq. NaOH (I ) and adjusted to pH=9 and filtrated again. The precipitate was dried under vacuum to afford the desired product (400 mg, 74percent yield). MS: 164.0 (M+l)+.
74%
With sodium nitrite In water
Step A: 4-Nitro-1H-indazole To a solution of 2-methyl-3-nitroaniline (500 mg, 3.29 mmol) in AcOH (10 mL) was added a solution of sodium nitrite (250 mg, 3.62 mmol) in H2O (1 mL). the reaction was stirred at r.t. overnight. The mixture was poured into ice-water and the precipitate was collected by filtration. The filtrate was treated with aq. NaOH (1 N) and adjusted to pH=9 and filtrated again. The precipitate was dried under vacuum to afford the desired product (400 mg, 74percent yield). MS: 164.0 (M+1)+.
70%
With acetic acid; sodium nitrite In water at 15 - 30℃; for 2 - 3.5 h;
Example 6; 4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indazole 1 - route 2[00239] To a solution of 2-methyl-3-nitroaniline (2.27g, 14.91mmol) in acetic acid(6OmL) was added a solution of sodium nitrite (1.13g, 1.1 eq.) in water (5mL). After 2 h, the <n="72"/>deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole C (1.98g, 81percent). Example 11 1 -(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1 ,3,2 dioxaborolan-2-yl)-lH-indazole 62 (Route B)[00256] Step A: Preparation of 4-nitro-lH-indazole: A mixture of 2-methyl-3-nitro aniline <n="77"/>(200 g, 1.315 moles), acetic acid (8000 ml) was cooled to 15-20° C and a solution of sodium nitrite (90.6 g, 1.315 moles) in water (200 ml) was slowly added over 30 min. After the addition, the reaction temp, was increased to 25-30° C and the reaction was stirred at this temp for 2-3 h. Reaction progress was monitored by TLC and after completion of reaction product was filtered and residue was washed with acetic acid (1000 ml). Acetic acid was distilled under vacuum (550 mm of Hg) below 80 °C and water (8000 ml) was added, cooled to 25-30 °C and stirred for 30 min. The slurry was filtered and washed with water (1000 ml). Crude product was dried under heating at 70-80 °C for 2 hours, then was taken in 5percent ethyl acetate/n-hexane (100:2000 ml) solution and stirred for 1-1.5 h at ambient temperature. The suspension was filtered and washed with 5percent ethyl acetate/n-hexane mixture (25:475 ml). The product obtained was dried under vacuum at below 80 °C for 10 -12 h to give 4-nitro-lH-indazole as a brown solid (150 g, 70percent): mp: 200-203 °C; 1U NMR (200 MHz, CDCl3) δ 13.4 (br, IH), 8.6 (s, IH), 8.2-7.95 (dd, 2H), 7.4 (m, IH). ESMS m/z 164 (M+l). Purity: 95percent (HPLC)
70%
With acetic acid; sodium nitrite In water at 15 - 30℃; for 2 - 3.5 h;
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole C (1.98 g, 81percent).; Preparation of 4-nitro-lH-indazole: A mixture of 2-methyl-3-nitro aniline(200 g, 1.315 moles), acetic acid (8000 ml) was cooled to 15-20° C and a solution of sodium nitrite (90.6 g, 1.315 moles) in water (200 ml) was slowly added over 30 min. After the addition, the reaction temp, was increased to 25-30° C and the reaction was stirred at this temp for 2-3 h. Reaction progress was monitored by TLC and after completion of reaction product was filtered and residue was washed with acetic acid (1000 ml). Acetic acid was distilled under vacuum (550 mm of Hg) below 80 °C and water (8000 ml) was added, cooled to 25-30 °C and stirred for 30 min. The slurry was filtered and washed with water (1000 ml). Crude product was dried under heating at 70-80 °C for 2 hours, then was taken in 5percent ethyl acetate/n-hexane (100:2000 ml) solution and stirred for 1-1.5 h at ambient temperature. The suspension was filtered and washed with 5percent ethyl acetate/n-hexane mixture (25:475 ml). The product obtained was dried under <n="73"/>vacuum at below 80 °C for 10 -12 h to give 4-nitro-l//-indazole as a brown solid (150 g, 70percent): mp: 200-203 °C; 1H NMR (200 MHz, CDCl3) δ 13.4 (br, IH), 8.6 (s, IH), 8.2-7.95 (dd, 2H), 7.4 (m, IH). ESMS m/z 164 (M+l). Purity: 95percent (HPLC)
70%
With sodium nitrite In water; acetic acid at 15 - 30℃;
Step A: Preparation of 4-nitro-1H-indazole: A mixture of 2-methyl-3-nitro aniline (200 g, 1.315 moles), acetic acid (8000 ml) was cooled to 15-20° C and a solution of sodium nitrite (90.6 g, 1.315 moles) in water (200 ml) was slowly added over 30 min. After the addition, the reaction temp, was increased to 25-30° C and the reaction was stirred at this temp for 2-3 h. Reaction progress was monitored by TLC and after completion of reaction product was filtered and residue was washed with acetic acid (1000 ml). Acetic acid was distilled under vacuum (550 mm of Hg) below 80 °C and water (8000 ml) was added, cooled to 25-30 °C and stirred for 30 min. The slurry was filtered and washed with water (1000 ml). Crude product was dried under heating at 70-80 °C for 2 hours, then was taken in 5percent ethyl acetate/n-hexane (100:2000 ml) solution and stirred for 1-1.5 h at ambient temperature. The suspension was filtered and washed with 5percent ethyl acetate/n-hexane mixture (25:475 ml). The product obtained was dried under vacuum at below 80 °C for 10 -12 h to give 4-nitro-lH-indazole as a brown solid (150 g, 70percent): mp: 200-203 °C; 1H NMR (200 MHz, CDCI3) δ 13.4 (br, 1H), 8.6 (s, 1H), 8.2-7.95 (dd, 2H), 7.4 (m, 1H). ESMS m/z 164 (M+1). Purity: 95percent (HPLC)
68%
With acetic acid; sodium nitrite In water at 20℃; for 0.75 h;
2-methyl-3-nit.ro aniline (1O g, 0.005 mol) was taken in acetic acid (100 ml, 10 times) and cooled to 2O0C. A solution of sodium nitrite (1Og, 0.14 mol, 2.25 eq) in water (25 ml) was added drop wise for 15 min at 2O0C. The overall reaction mixture was stirred for 30 min at 2O0C and later stirred for 2 hrs at rt. Progress of the reaction was monitored by TLC (15percent ethyl acetate/hexane, Rf-0.2). On completion of the reaction, acetic acid was distilled off completely and the residue obtained was taken in cold water (200 ml). Solid thrown out was filtered and dried to yield the required product as an yellow colored solid (8.5 g, 68percent yield).
67.8%
With acetic acid; sodium nitrite In water at 0 - 20℃; for 4.25 h;
A solution of 2-methyl-3-nitτo-phenylamine (5.5 g, 36.15 mmol) in glacial acetic acid (250 ml) was stirred at 0° C. Sodium nitrite (2.5 g, 36.15 mmol) dissolved in water (6 ml) was added to the stirred solution all at once and the stirring continued for 15 min. Yellow precipitate was removed by filtration and discarded and the solution stirred at ambient temperature for 4 hr. Solvent was removed in vacuo and water (20 ml) was added. The precipitate was separated by filtration and dried to afford the crude product. Chromatographic purification on silica gel (eluent, hexane:ethyl acetate, 70:30 to 50:50) afforded the title compound (4.0 g, 67.8 percent).
63%
Stage #1: With tetrafluoroboric acid; sodium nitrite In water at 0 - 20℃; for 3 h; Stage #2: With 18-crown-6 ether; potassium acetate In chloroform at 20℃; for 2 h;
General procedure: To a cooled solution of the chosen 2-methylaniline dissolved in HBF4 (50percent solution in water; 15–30 mL) was added at 0 °C dropwise a cooled aqueous solution of NaNO2 (1 equiv in the minimum of water). After the end of the addition, the mixture was stirred 1 h at 0 °C and 2 h at room temperature. Then, the resulting precipitate was filtered, washed with Et2O (3 × 100 mL) and dried to obtain the corresponding 2-methylphenyldiazonium tetrafluoroborate salts which were directly added in one portion under nitrogen to a stirred mixture of KOAc (2 equiv) and 18-crown-6 (0.05 equiv) in dry CHCl3 (350–700 mL). After 2 h at room temperature, the mixture was filtered, washed with CHCl3 (3 × 100 mL) and the organic filtrate was finally concentrated in vacuo. The residual gum was purified by column chromatography on silica gel (EtOAc/cyclohexane 1:3) to give the desired indazoles 1 and 2a.
62%
With sodium nitrite In water; acetic acid at 20℃; for 2 h;
Step 1Compound [65] (15.0 g, 0.099 mol) was dissolved in 375 ml glacial acetic acid in a 500 ml round bottom flask. An aqueous solution of sodium nitrite (8.16 g, 0.12 mol, in 35 ml of water) was added to it. The reaction mixture was stirred for 2 hrs at RT. TLC monitoring showed complete consumption of starting material. Reaction was ceased by the addition of ice-cold water, solid thus formed was filtered and dried well to afford yellowish solid [66] (10.0 g, 62 percent).
62%
With acetic acid; sodium nitrite In water at 20℃; for 2 h;
Step 1 Compound [65] ( 15.0 g, 0.099 mol) was dissolved in 375 ml glacial acetic acid in a 500 ml round bottom flask. An aqueous solution of sodium nitrite (8. 16 g, 0. 12 mol, in 35 ml of water) was added to the reaction mixture. The reaction mixture was stirred for 2 hrs at RT. TLC monitoring showed complete consumption of starting material. Reaction was ceased by the addition, of ice-cold water, solid thus formed was filtered and dried well to afford yellowish solid [66] ( 10.0 g, 62 percent).
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[22] Chemistry Letters, 2008, vol. 37, # 9, p. 974 - 975
[23] Green Chemistry, 2014, vol. 16, # 9, p. 4162 - 4169
[24] International Journal of Chemical Kinetics, 2018, vol. 50, # 1, p. 15 - 30
6
[ 19406-51-0 ]
[ 603-83-8 ]
Reference：
[1] Journal of the American Chemical Society, 1960, vol. 82, p. 99 - 104
7
[ 606-20-2 ]
[ 823-40-5 ]
[ 603-83-8 ]
Reference：
[1] Environmental Science and Technology, 2001, vol. 35, # 2, p. 406 - 410
8
[ 2464-33-7 ]
[ 7664-41-7 ]
[ 603-83-8 ]
[ 99-55-8 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1884, vol. 225, p. 385
9
[ 7664-93-9 ]
[ 95-53-4 ]
[ 603-83-8 ]
[ 99-52-5 ]
[ 99-55-8 ]
Reference：
[1] Journal of the Chemical Society, 1891, vol. 59, p. 1017
10
[ 603-83-8 ]
[ 41252-98-6 ]
Yield
Reaction Conditions
Operation in experiment
85%
With sulfuric acid; sodium nitrite In water at 0 - 5℃; for 1 h;
4.1.10. 2-Methyl-3-nitro-iodobenzene (26).33 Concentrated sulfuricacid (8 mL) was added to a solution of 2-methyl-3-nitroaniline (25)(5.00 g, 32.9 mmol) in water (50 mL). The mixture was cooled to0 C, and a solution of sodium nitrite (2.49 g, 36.2 mmol) in water(5 mL) added dropwise. The mixture was stirred for 1 h, and a solutionof potassium iodide (8.18 g, 49.3 mmol) in water (20 mL)added dropwise. The mixture was stirred for 1 h, and extractedwith dichloromethane (330 mL). The combined organic extractswerewashed with saturated aqueous sodium thiosulfate (Na2S2O3),dried (Na2SO4), and the solvents removed under reduced pressureto yield a crude oil. The residue was purified by column chromatographyusing ethyl acetate/petroleum ether (1:10) to afford theproduct as a yellow solid (7.43 g, 85percent); mp 36e37 C; nmax (film)/cm1 3082, 1591, 1519, 1443, 1348, 1273, 1204, 1087, 1001, 860, 794,735, 696; 1H NMR (400 MHz, CDCl3): d 2.52 (3H, s, CH3), 6.96 (1H, t,J8.0 Hz, CH arom., H5), 7.64 (1H, dd, J8.0, 1.2 Hz, CH arom., H6),7.80 (1H, dd, J8.0, 1.2 Hz, CH arom., H4); 13C NMR (100 MHz,CDCl3): d 25.0 (CH3, ArCH3), 103.6 (C quat., arom., C1), 123.9 (CHarom., C4), 128.0 (CH arom., C5), 135.0 (C quat., arom., C2), 143.1 (CHarom., C6), 150.4 (C quat., arom., C3); m/z (EI) 262.9439; C7H6INO2(M) requires 262.9443.
81.7%
Stage #1: With hydrogenchloride In water at 0 - 5℃; Stage #2: With nitric acid In water Stage #3: With potassium iodide In water at 0 - 5℃;
Step 1 1-Iodo-2-methyl-3-nitro-benzene 2-Methyl-3-nitro-phenylamine 74a (21.28 g, 0.14 mol) was dissolved in 70 ml of concentrated hydrochloric acid in an ice-water bath, added with water (40 ml), stirred at 0~5° C. and yellow-green precipitates were formed. The reaction mixture was added dropwise with nitric acid solution (40 ml, 3.6 M), stirred for 15 minutes and filtered. The filtrate was added dropwise to potassium iodide solution (280 ml, 5.25 M) at 0~5° C. Upon completion of the addition, the reaction mixture was stirred for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was dissolved in ethyl acetate, and washed with aqueous sodium hydroxide solution (10percent), water, sodium thiosulfate (5percent), saturated brine. The organic phase was dried over anhydrous magnesium sulfate to obtain the brown oil (34.4 g). The crude product was purified by silica gel column chromatography to obtain the title compound 1-iodo-2-methyl-3-nitro-benzene 74b (30.1 g, yield 81.7percent) as a white solid.
81.7%
Stage #1: With hydrogenchloride In water at 0 - 5℃; Cooling Stage #2: With nitric acid In water for 0.25 h; Stage #3: With potassium iodide In water at 0 - 5℃;
2-Methyl-3-nitro-phenylamine 74a (21.28 g, 0.14 mol) was dissolved in 70 ml of concentrated hydrochloric acid in an ice-water bath, added with water (40 ml), stirred at 0.similar.5°C and yellow-green precipitates were formed. The reaction mixture was added dropwise with nitric acid solution (40 ml, 3.6 M), stirred for 15 minutes and filtered. The filtrate was added dropwise to potassium iodide solution (280 ml, 5.25 M) at 0.similar.5°C. Upon completion of the addition, the reaction mixture was stirred for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was dissolved in ethyl acetate, and washed with aqueous sodium hydroxide solution (10percent), water, sodium thiosulfate (5percent), saturated brine. The organic phase was dried over anhydrous magnesium sulfate to obtain the brown oil (34.4 g). The crude product was purified by silica gel column chromatography to obtain the title compound 1-iodo-2-methyl-3-nitro-benzene 74b (30.1 g, yield 81.7percent) as a white solid.
67%
Stage #1: With sulfuric acid; sodium nitrite In water at 0℃; Stage #2: With potassium iodide In water at 20℃; for 1 h;
General procedure: 1-Iodo-2-methyl-3-nitrobenzene (22): 2-Methyl-3-nitroaniline (21, 4.85 g, 31.88 mmol, 1.0 equiv) was suspended in H2O (33 mL) and a mixture of H2SO4 (6.7 mL) and H2O (33 mL) was added. The solution was cooled to 0 °C. A solution ofS17NaNO2 (2.31 g, 33.48 mmol, 1.1 equiv) in H2O (33 mL) was added (the temperature had to be kept constantly below 5 °C). After stirring for 1 h there was still solid material left. Further addition of H2SO4 (6.7 mL) in H2O (33 mL) and NaNO2 (1.10 g, 15.94 mmol, 0.5 equiv) in H2O (17 mL) was necessary to give the desired clear solution of the diazonium salt. KI (7.94 g, 47.82 mmol, 1.5 equiv) in H2O (33 mL) was added dropwise and evolution of gas could be observed. After complete addition the solution was stirred for 1 h and warmed to rt. The reaction mixture was extracted four times with CH2Cl2 (50 mL each). The organic phase was washed with aqueous Na2S2O3 and brine (100 mL each), dried with MgSO4, and filtered. After evaporation of the solvent, the crude product was subjected to column chromatography on silica gel with PE/EA (30:1) to give a yellow solid (5.61 g, 21.33 mmol, 67percent).
Reference：
[1] Chemical & Pharmaceutical Bulletin, 1986, vol. 34, # 9, p. 3971 - 3973
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3177 - 3180
[3] Chemical Communications, 2015, vol. 51, # 6, p. 1070 - 1073
[4] Tetrahedron, 2013, vol. 69, # 2, p. 758 - 769
[5] Patent: US2010/75952, 2010, A1, . Location in patent: Page/Page column 89
[6] Patent: EP2157093, 2010, A1, . Location in patent: Page/Page column 98
[7] Organic Letters, 2016, vol. 18, # 17, p. 4166 - 4169
[8] Journal of the American Chemical Society, 2005, vol. 127, # 38, p. 13148 - 13149
[9] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 1700 - 1706
[10] Chemische Berichte, 1904, vol. 37, p. 1021
Reference：
[1] Journal of the Chemical Society, 1901, vol. 79, p. 1130[2] Journal of the Chemical Society, 1902, vol. 81, p. 1347
[3] P. Ch. S., p. 154
16
[ 603-83-8 ]
[ 443-84-5 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1960, vol. 69, p. 312 - 322
17
[ 603-83-8 ]
[ 5460-31-1 ]
Reference：
[1] Chemistry - A European Journal, 2009, vol. 15, # 12, p. 2742 - 2746
[2] Chemische Berichte, 1884, vol. 17, p. 1959
[3] Chemische Berichte, 1904, vol. 37, p. 1021
[4] Tetrahedron, 1968, vol. 24, p. 6093 - 6109
18
[ 7664-93-9 ]
[ 603-83-8 ]
[ 5460-31-1 ]
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 1959
19
[ 603-83-8 ]
[ 606-20-2 ]
Yield
Reaction Conditions
Operation in experiment
63%
With 3-chloro-benzenecarboperoxoic acid In 1,2-dichloro-ethane for 10 h; Reflux
General procedure: m-CPBA(1.7 g, 8.0 mmol, 85percent) was dissolved in 1,2-dichloroethane (15.0 mL) in a threeneckflask equipped with a condenser and heated to reflux (at rt in case of 1b).Then, the substrate aromatic amine (2.0 mmol) dissolved in 1,2-dichloroethane(5.0 mL) was added dropwise to the refluxing peracid solution. After 10 h, themixture was cooled to rt and quenched with saturated aqueous Na2S2O3. Thesolvent was removed under reduced pressure and the residue was treated with10percent NaOH solution followed by extraction with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous Na2SO4. Removal of thesolvent under vacuum afforded the crude product, which was purified bycolumn chromatography using hexane/ethyl acetate as eluant.
Reference：
[1] Bulletin des Societes Chimiques Belges, 1960, vol. 69, p. 312 - 322
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3177 - 3180
[3] Journal of the American Chemical Society, 1960, vol. 82, p. 99 - 104
21
[ 603-83-8 ]
[ 58579-54-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1996, p. 1699 - 1704
[2] Journal of Organic Chemistry, 1984, vol. 49, # 14, p. 2658 - 2662
22
[ 603-83-8 ]
[ 4837-88-1 ]
Reference：
[1] Tetrahedron, 1968, vol. 24, p. 6093 - 6109
Reference：
[1] Archiv der Pharmazie, 2015, vol. 348, # 4, p. 266 - 274
[2] European Journal of Organic Chemistry, 2018, vol. 2018, # 17, p. 2013 - 2021
25
[ 603-83-8 ]
[ 769-10-8 ]
Reference：
[1] Chemische Berichte, 1896, vol. 29, p. 841
[2] Bulletin des Societes Chimiques Belges, 1960, vol. 69, p. 312 - 322
[3] Journal of the American Chemical Society, 1960, vol. 82, p. 99 - 104
[4] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3177 - 3180
26
[ 603-83-8 ]
[ 697-73-4 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1960, vol. 69, p. 312 - 322
27
[ 603-83-8 ]
[ 7766-23-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2018, vol. 2018, # 17, p. 2013 - 2021
28
[ 603-83-8 ]
[ 55289-35-5 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: With hydrogen bromide In water for 0.166667 h; Reflux Stage #2: With sodium nitrite In water at 0 - 5℃; for 0.5 h; Stage #3: With copper(I) bromide In water at 20 - 70℃; for 1.5 h;
2-Methyl-3-nitrobenzenamine (45.6 g, 0.3 mol) was suspended in water (200 mL) and HBr (100 mL, 40percent aq.) and the mixture was heated to reflux for 10 min. Then the mixture was cooled to 0 °C and NaNO2 (20.7 g, 0.3 mol) in water (100 mL) was added dropwise at such a rate that the temperature did not exceed 5 °C. The diazonium solution was stirred for a further 30 min at 0-5 °C and then added slowly to a stirred mixture of CuBr (43.1 g, 0.3 mol) in HBr (150 mL) and water (150 mL) at room temperature. The mixture was stirred at room temperature for 30 min and then heated to 70°C for 1h. The mixture was poured onto ice and extracted with CH2Cl2 (400 mL.x.3), and washed with sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography with petroleum ether as eluent to give a pale yellow solid (58 g, 89percent)The mixture of 1-bromo-2-methyl-3-nitrobenzene (37.0 g, 0.17 mol), NBS (61 g, 0.34 mol) and AIBN (0.7 g, 4.2 mmol) in CCl4 (500 mL) was refluxed overnight. The mixture was filtered and the filtrate was concentrated to give a red liquid (53 g) as a crude product which was used in the next step without any purification.1-Bromo-2-(bromomethyl)-3-nitrobenzene (53 g) and NaOAc (32.8 g, 0.4 mol) in DMF (300 mL) was stirred at 70 °C overnight. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography with petroleum ether/ethyl acetate = 2 0/1 eluent to give a white solid (24.0 g, 51percent over two steps).To 2-bromo-6-nitrobenzyl acetate (24.5 g, 0.089 mol) in 1,4-Dioxane (500 mL) was bubbled nitrogen in the solution for 20 min. Potassium acetate (38.4 g, 0.358mol), Pd(dppf)Cl2 (3.65 g, 4.5 mmol) and bis(pinacolato)diboron (34.1 g, 0.13 mol) were added and the reaction mixture was stirred under nitrogen at 95 °C for 20 h. The reaction mixture was then cooled and was evaporated under vacuum. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography with petroleum ether/ethyl acetate = 20/1 as eluent to give a white solid (11.0 g, 38percent). LC-MS (ESI) m/z 322 [M+1]+, (calcd MS 321.1).To a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-nitrobenzyl acetate (11.0 g, 0.034 mol) in methanol (350 mL) was added 5 N NaOH (17 mL, 0.085 mol). The reaction mixture was stirred and refluxed under nitrogen for 24h. The reaction mixture was then concentrated under vacuum and was dissolved in 200 mL of tetrahydrofuran (THF). HCl (5 N, 60 mL, 0.3 mol) was added and the reaction mixture was stirred and heated at 40 °C for 16h. The reaction mixture was cooled, diluted with EtOAc and poured into brine. The separated organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized in the mixture of ethyl acetate and petroleum ether to give a yellow solid (5.0 g, 81percent). LC-MS (ESI) m/z 180 [M+1]+, (calcd MS 179.0). 1H NMR (300 MHz, DMSO-d6): δ 9.59 (s, 1H), 8.33 (d, 1H), 8.14 (d, 1H), 7.71 (t, 1H), 5.37 (s, 2H).4-Nitrobenzo[c][1,2]oxaborol-1(3H)-ol (2.7 g, 0.015 mol) in methanol (150 mL) was added Pd/C (1.0 g) and the hydrogenation was conducted at one atmosphere and room temperature overnight to provide the desired product 2f as a yellow solid (1.5 g, 66percent). LC-MS (ESI) m/z 150 [M+1]+, (calcd MS 149.1). 1H NMR (300 MHz, DMSO-d6): δ 8.92 (s, 1H), 7.02 (t, 1H), 6.90 (d, 1H), 6.62 (d, 1H), 4.99(s, 2H), 4.77(s, 2H).
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 32, p. 10162 - 10173
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2048 - 2054
[3] Archiv der Pharmazie, 2015, vol. 348, # 4, p. 266 - 274
[4] European Journal of Organic Chemistry, 2018, vol. 2018, # 17, p. 2013 - 2021
[5] Recueil des Travaux Chimiques des Pays-Bas, 1934, vol. 53, p. 1011,1016, 1025
[6] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1974, p. 2435 - 2447
[7] Journal of Organic Chemistry, 1984, vol. 49, # 14, p. 2658 - 2662
[8] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 4, p. 1414 - 1418
[9] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 20, p. 2565 - 2580
[10] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1996, p. 1699 - 1704
29
[ 603-83-8 ]
[ 654-01-3 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1960, vol. 69, p. 312 - 322
30
[ 603-83-8 ]
[ 385-02-4 ]
Reference：
[1] Chemische Berichte, 1896, vol. 29, p. 841
31
[ 603-83-8 ]
[ 53222-92-7 ]
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 1959
[2] Chemische Berichte, 1904, vol. 37, p. 1021
32
[ 603-83-8 ]
[ 20876-37-3 ]
Reference：
[1] Tetrahedron, 1968, vol. 24, p. 6093 - 6109
33
[ 603-83-8 ]
[ 172681-47-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3177 - 3180
[2] Chemische Berichte, 1904, vol. 37, p. 1021
34
[ 603-83-8 ]
[ 106912-94-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 20, p. 2565 - 2580
35
[ 603-83-8 ]
[ 99365-48-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 4, p. 1414 - 1418
36
[ 603-83-8 ]
[ 85696-95-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 9, p. 3417 - 3427
With sulfuric acid; sodium nitrite; In water; at 0 - 5℃; for 1h;
4.1.10. 2-Methyl-3-nitro-iodobenzene (26).33 Concentrated sulfuricacid (8 mL) was added to a solution of 2-methyl-3-nitroaniline (25)(5.00 g, 32.9 mmol) in water (50 mL). The mixture was cooled to0 C, and a solution of sodium nitrite (2.49 g, 36.2 mmol) in water(5 mL) added dropwise. The mixture was stirred for 1 h, and a solutionof potassium iodide (8.18 g, 49.3 mmol) in water (20 mL)added dropwise. The mixture was stirred for 1 h, and extractedwith dichloromethane (330 mL). The combined organic extractswerewashed with saturated aqueous sodium thiosulfate (Na2S2O3),dried (Na2SO4), and the solvents removed under reduced pressureto yield a crude oil. The residue was purified by column chromatographyusing ethyl acetate/petroleum ether (1:10) to afford theproduct as a yellow solid (7.43 g, 85%); mp 36e37 C; nmax (film)/cm1 3082, 1591, 1519, 1443, 1348, 1273, 1204, 1087, 1001, 860, 794,735, 696; 1H NMR (400 MHz, CDCl3): d 2.52 (3H, s, CH3), 6.96 (1H, t,J8.0 Hz, CH arom., H5), 7.64 (1H, dd, J8.0, 1.2 Hz, CH arom., H6),7.80 (1H, dd, J8.0, 1.2 Hz, CH arom., H4); 13C NMR (100 MHz,CDCl3): d 25.0 (CH3, ArCH3), 103.6 (C quat., arom., C1), 123.9 (CHarom., C4), 128.0 (CH arom., C5), 135.0 (C quat., arom., C2), 143.1 (CHarom., C6), 150.4 (C quat., arom., C3); m/z (EI) 262.9439; C7H6INO2(M) requires 262.9443.
81.7%
Step 1 1-Iodo-2-methyl-3-nitro-benzene 2-Methyl-3-nitro-phenylamine 74a (21.28 g, 0.14 mol) was dissolved in 70 ml of concentrated hydrochloric acid in an ice-water bath, added with water (40 ml), stirred at 0~5 C. and yellow-green precipitates were formed. The reaction mixture was added dropwise with nitric acid solution (40 ml, 3.6 M), stirred for 15 minutes and filtered. The filtrate was added dropwise to potassium iodide solution (280 ml, 5.25 M) at 0~5 C. Upon completion of the addition, the reaction mixture was stirred for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was dissolved in ethyl acetate, and washed with aqueous sodium hydroxide solution (10%), water, sodium thiosulfate (5%), saturated brine. The organic phase was dried over anhydrous magnesium sulfate to obtain the brown oil (34.4 g). The crude product was purified by silica gel column chromatography to obtain the title compound 1-iodo-2-methyl-3-nitro-benzene 74b (30.1 g, yield 81.7%) as a white solid.
81.7%
2-Methyl-3-nitro-phenylamine 74a (21.28 g, 0.14 mol) was dissolved in 70 ml of concentrated hydrochloric acid in an ice-water bath, added with water (40 ml), stirred at 0?5C and yellow-green precipitates were formed. The reaction mixture was added dropwise with nitric acid solution (40 ml, 3.6 M), stirred for 15 minutes and filtered. The filtrate was added dropwise to potassium iodide solution (280 ml, 5.25 M) at 0?5C. Upon completion of the addition, the reaction mixture was stirred for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was dissolved in ethyl acetate, and washed with aqueous sodium hydroxide solution (10%), water, sodium thiosulfate (5%), saturated brine. The organic phase was dried over anhydrous magnesium sulfate to obtain the brown oil (34.4 g). The crude product was purified by silica gel column chromatography to obtain the title compound 1-iodo-2-methyl-3-nitro-benzene 74b (30.1 g, yield 81.7%) as a white solid.
67%
General procedure: 1-Iodo-2-methyl-3-nitrobenzene (22): 2-Methyl-3-nitroaniline (21, 4.85 g, 31.88 mmol, 1.0 equiv) was suspended in H2O (33 mL) and a mixture of H2SO4 (6.7 mL) and H2O (33 mL) was added. The solution was cooled to 0 C. A solution ofS17NaNO2 (2.31 g, 33.48 mmol, 1.1 equiv) in H2O (33 mL) was added (the temperature had to be kept constantly below 5 C). After stirring for 1 h there was still solid material left. Further addition of H2SO4 (6.7 mL) in H2O (33 mL) and NaNO2 (1.10 g, 15.94 mmol, 0.5 equiv) in H2O (17 mL) was necessary to give the desired clear solution of the diazonium salt. KI (7.94 g, 47.82 mmol, 1.5 equiv) in H2O (33 mL) was added dropwise and evolution of gas could be observed. After complete addition the solution was stirred for 1 h and warmed to rt. The reaction mixture was extracted four times with CH2Cl2 (50 mL each). The organic phase was washed with aqueous Na2S2O3 and brine (100 mL each), dried with MgSO4, and filtered. After evaporation of the solvent, the crude product was subjected to column chromatography on silica gel with PE/EA (30:1) to give a yellow solid (5.61 g, 21.33 mmol, 67%).
A. Preparation of 4-Nitroindazole from 2-Methyl-3-Nitro-Aniline Sodium nitrite (20 grams, 0.29 mol) was dissolved in 50 mL water. This solution was added all at once to 2-methyl-3-nitroaniline (20 grams, 0.13 moles) in glacial acetic acid near zero degrees C. The reaction was stirred vigorously with an overhead stirrer. An immediate precipitate occurred upon addition of sodium nitrite solution. The reaction was allowed to reach room temperature and stirred overnight. The precipitate was filtered off and the filtrate was concentrated in vacuo. The dark orange solid was suspended in water, filtered, and dried yielding 14-21 grams of a dark orange solid (99% yield).
90%
With acetic acid; sodium nitrite; In water; at 0 - 20℃;
Sodium nitrite (20 grams, 0.29 mol) was dissolved in 50 mL water. This solution was added all at once to 2-methyl-3-nitroaniline (20 grams, 0.13 moles) in glacial acetic acid near zero degrees C. The reaction was stirred vigorously with an overhead stirrer. An immediate precipitate occurred upon addition of sodium nitrite solution. The reaction was allowed to reach room temperature and stirred overnight. The precipitate was filtered off and the filtrate was concentrated in vacuo. The dark orange solid was suspended in water, filtered, and dried yielding 14-21 grams dark orange solid (99% yield).
90.3%
With sodium nitrite; In water; acetic acid; at 20℃; for 24h;
General procedure: Take compound 7 (5.00g, 32.9mmol), was dissolved in glacial acetic acid (235 mL), under stirring, was added at once sodium nitrite (2.50g, 36.2mmol) in water (6mL)solution, keeping the internal temperature not higher than 20 deg. C, the reaction was stirred for 24h, the system under reduced pressure rotary evaporated to remove most of the glacial acetic acid, was added a lot of water, a lot of solid precipitation, after which the resulting solid was suction filtered, washed with water and dried in vacuo to give the title compound, using this method the synthesis of compounds 8a-8d.
84%
With acetic acid; sodium nitrite; In water; at 0 - 20℃; for 48h;
To a solution of 2-methyl-3-nitroaniline (50 g, 328 mmol) in AcOH (700 mL), a solution of NaN02 (45.4 g, 657 mmol) in water (100 mL) was added at 0 C. The reaction was stirred at rt for 48h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was poured onto ice water and filtered. The filtrate was washed with water and dried under vacuum to afford 45 g of 4-nitro-1 H-indazole a1. Yield: 84%. 1H NMR (400 MHz, DMSO-cfe) delta 8.53 (s, 1 H), 8.15 (d, J = 8.03 Hz, 1 H), 8.09 (d, J = 8.03 Hz, 1 H), 7.60 (t, J = 8.03 Hz, 2H).
81%
With acetic acid; sodium nitrite; for 2h;
Reference Example 5: Indazole-4-Boronate Ester (70): Route 1 EPO <DP n="34"/> (70) (69)To a solution of 2-methyl-3-nitroaniline (2.27g, 14.91mmol) in acetic acid (6OmL) was added a solution of sodium nitrite (1.13g, 1.1 eq.) in water (5mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole (67) (1.98g, 81%).A mixture of 4-nitro-lH-indazole (760mg, 4.68mmol), palladium on charcoal (10%, cat.) and ethanol (3OmL) was stirred under a balloon of hydrogen for 4 h. The reaction mixture was then filtered through celite, and the solvent removed in vacuo to yield lH-indazol-4-ylamine (68) (63 lmg, 100%).An aqueous solution of sodium nitrite (337mg, 4.89mmol) in water (2mL) was added dropwise to a suspension of lH-indazol-4-ylamine (63 lmg, 4.74mmol) in 6M hydrochloric acid (7.2mL) at below O0C. After stirring for 30 minutes, sodium tetrafluorobrate (724mg) was added to the reaction mixture. A viscous solution resulted, which was filtered and washed briefly with water to yield lH-indazole-4- diazonium tetrafluoroborate salt (69) (218mg, 20%) as a deep red solid.Dry MeOH (4mL) was purged with argon for 5 minutes. To this was added lH-indazole-4-diazonium tetrafluoroborate salt (218mg, 0.94mmol), bis-pinacolato EPO <DP n="35"/>diboron (239mg, l.Oeq.) and [l,r-bis(diphenylphosphino)ferrocene]palladium (II) chloride (20mg). The reaction mixture was stirred for 5 h and then filtered through celite. The residue was purified using flash chromatography to yield the desired title compound (70), (117mg).
81%
With acetic acid; sodium nitrite; In water; for 2h;
Reference Example 4:; Indazole-4-Boronate Ester:; (Route 1); (70) (69) EPO <DP n="35"/>To a solution of 2-methyl-3-nitro aniline (2.27g, 14.91mmol) in acetic acid (6OmL) was added a solution of sodium nitrite (1.13g, l.leq.) in water (5mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole (67) (1.98g, 81%).
81%
With acetic acid; sodium nitrite; In water; for 2h;
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/water and the resulting precipitate collected by filtration to yield 4-nitro-1H-indazole (67) (1.98 g, 81%).
81%
With sodium nitrite; In water; for 2h;
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 hours, the deep red solution was poured onto ice/water and the precipitate collected by filtration to yield 4-nitro-1H-indazole (1.98 g, 81%).
81%
With sodium nitrite; In water; acetic acid; for 2h;
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4- nitro-lH-indazole C (1.98 g, 81%).
81%
With acetic acid; sodium nitrite; In water; for 2h;
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/water and the resulting precipitate collected by filtration to yield 4-nitro-1H-indazole C (1.98 g, 81%).
81%
With acetic acid; sodium nitrite; In water; for 2h;
Example 5 4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indazole7 -route 2 <n="140"/>[00280] To a solution of 2-methyl-3-nitroaniline (2.27g, 14.91mmol) in acetic acid(6OmL) was added a solution of sodium nitrite (1.13g, 1.1 eq.) in water (5mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole C (1.98g, 81%).
81%
With sodium nitrite; In water; acetic acid; for 2h;
To a solution of 2-methyl-3-nitroaniline (2.27g, 14.91mmol) in acetic acid(6OmL) was added a solution of sodium nitrite ( 1.13 g, 1.1 eq.) in water (5mL). After 2 hours, the deep red solution was poured onto ice/ water and the precipitate collected by filtration to yield 4-nitro-lH-indazole (1.98g, 81%).A mixture of 4-nitro-lH-indazole (760mg, 4.68 mmol), palladium on charcoal (10%, cat.) and ethanol (3OmL) was stirred under a balloon of hydrogen for 4 hours. The reaction mixture was then filtered through celite, and the solvent removed in vacuo to yield lH-indazol-4-ylamine (631mg, 100%).An aqueous solution of sodium nitrite (337mg, 4.89mmol) in water (2mL) was added dropwise to a suspension of lH-indazol-4-ylamine (631mg, 4.74mmol) in 6M <n="43"/>hydrochloric acid (7.2mL) at below 0C. After stirring for 30 minutes sodium tetrafluorobrate (724mg) was added. The reaction mixture became very thick and was filtered and washed briefly with water to yield lH-indazole-4-diazonium, tetrafluoroborate salt (218mg, 20%) as a deep red solid.Dry methanol (4mL) was purged with argon for 5 minutes. To this was added lH-indazole-4-diazonium, tetrafluoroborate salt (218mg, 0.94mmol), bis-pinacolato diboron (239mg, l.Oeq.) and [l,r-bis(diphenylphosphino)ferrocene]palladium (II) chloride (20mg). The reaction mixture was stirred for 5 hours and then filtered through celite. The residue was purified using flash chromatography to yield the desired title compound (117mg).
81%
With acetic acid; sodium nitrite; In water; for 2h;Product distribution / selectivity;
Example 3 4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indazole24 - route 2 [0189] To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid(60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, <n="66"/>the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole C (1.98 g, 81%).
77%
With acetic acid; sodium nitrite; In water; for 24h;
2-Methyl-3-nitroaniline (4.023 g, 26.44 mmol) was dissolved inglacial acetic acid (200 mL). Afterwards,a solution of NaNO2 (2.26 g,30.27 mmol) in water (10 mL) was added dropwise. This led to the precipitationof the diazonium salt. After re-dissolution of the precipitate (after 24 h) themixture was concentrated under reduced pressure. Afterwards, hot water (500 mL)was added to yield an orange solid. The mixture was filtered, washed with waterand dried to yield 4-nitro-1H-indazole (3.33g, 77%). Rf =0.34 (toluene/ethyl acetate, 3:2). 1H NMR(400 MHz, CDCl3) delta: 7.55 (dd,3J6,5 = 8.4 Hz,3J6,7 = 7.7 Hz,1H, H-6), 7.89 (d, 3J6,5= 8.4 Hz, 1H, H-5), 8.19 (d, 3J7,6= 7.7 Hz, 1H, H-7), 8.74 (s, 1H, H-3)
74%
With sodium nitrite; In water; acetic acid; at 20℃;
To a solution of 2 -methyl- 3 -nitro aniline (500 mg, 3.29 mmol) in AcOH (10 mL) was added a solution of sodium nitrite (250 mg, 3.62 mmol) in H20 (1 mL). the reaction was stirred at r.t. overnight. The mixture was poured into ice-water and the precipitate was collected by filtration. The filtrate was treated with aq. NaOH (I ) and adjusted to pH=9 and filtrated again. The precipitate was dried under vacuum to afford the desired product (400 mg, 74% yield). MS: 164.0 (M+l)+.
74%
With sodium nitrite; In water;
Step A: 4-Nitro-1H-indazole To a solution of 2-methyl-3-nitroaniline (500 mg, 3.29 mmol) in AcOH (10 mL) was added a solution of sodium nitrite (250 mg, 3.62 mmol) in H2O (1 mL). the reaction was stirred at r.t. overnight. The mixture was poured into ice-water and the precipitate was collected by filtration. The filtrate was treated with aq. NaOH (1 N) and adjusted to pH=9 and filtrated again. The precipitate was dried under vacuum to afford the desired product (400 mg, 74% yield). MS: 164.0 (M+1)+.
70 - 81%
With acetic acid; sodium nitrite; In water; at 15 - 30℃; for 2 - 3.5h;Product distribution / selectivity;
Example 6; 4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indazole 1 - route 2[00239] To a solution of 2-methyl-3-nitroaniline (2.27g, 14.91mmol) in acetic acid(6OmL) was added a solution of sodium nitrite (1.13g, 1.1 eq.) in water (5mL). After 2 h, the <n="72"/>deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole C (1.98g, 81%). Example 11 1 -(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1 ,3,2 dioxaborolan-2-yl)-lH-indazole 62 (Route B)[00256] Step A: Preparation of 4-nitro-lH-indazole: A mixture of 2-methyl-3-nitro aniline <n="77"/>(200 g, 1.315 moles), acetic acid (8000 ml) was cooled to 15-20 C and a solution of sodium nitrite (90.6 g, 1.315 moles) in water (200 ml) was slowly added over 30 min. After the addition, the reaction temp, was increased to 25-30 C and the reaction was stirred at this temp for 2-3 h. Reaction progress was monitored by TLC and after completion of reaction product was filtered and residue was washed with acetic acid (1000 ml). Acetic acid was distilled under vacuum (550 mm of Hg) below 80 C and water (8000 ml) was added, cooled to 25-30 C and stirred for 30 min. The slurry was filtered and washed with water (1000 ml). Crude product was dried under heating at 70-80 C for 2 hours, then was taken in 5% ethyl acetate/n-hexane (100:2000 ml) solution and stirred for 1-1.5 h at ambient temperature. The suspension was filtered and washed with 5% ethyl acetate/n-hexane mixture (25:475 ml). The product obtained was dried under vacuum at below 80 C for 10 -12 h to give 4-nitro-lH-indazole as a brown solid (150 g, 70%): mp: 200-203 C; 1U NMR (200 MHz, CDCl3) delta 13.4 (br, IH), 8.6 (s, IH), 8.2-7.95 (dd, 2H), 7.4 (m, IH). ESMS m/z 164 (M+l). Purity: 95% (HPLC)
70 - 81%
With acetic acid; sodium nitrite; In water; at 15 - 30℃; for 2 - 3.5h;Product distribution / selectivity;
To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in acetic acid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) in water (5 mL). After 2 h, the deep red solution was poured onto ice/ water and the resulting precipitate collected by filtration to yield 4-nitro-lH-indazole C (1.98 g, 81%).; Preparation of 4-nitro-lH-indazole: A mixture of 2-methyl-3-nitro aniline(200 g, 1.315 moles), acetic acid (8000 ml) was cooled to 15-20 C and a solution of sodium nitrite (90.6 g, 1.315 moles) in water (200 ml) was slowly added over 30 min. After the addition, the reaction temp, was increased to 25-30 C and the reaction was stirred at this temp for 2-3 h. Reaction progress was monitored by TLC and after completion of reaction product was filtered and residue was washed with acetic acid (1000 ml). Acetic acid was distilled under vacuum (550 mm of Hg) below 80 C and water (8000 ml) was added, cooled to 25-30 C and stirred for 30 min. The slurry was filtered and washed with water (1000 ml). Crude product was dried under heating at 70-80 C for 2 hours, then was taken in 5% ethyl acetate/n-hexane (100:2000 ml) solution and stirred for 1-1.5 h at ambient temperature. The suspension was filtered and washed with 5% ethyl acetate/n-hexane mixture (25:475 ml). The product obtained was dried under <n="73"/>vacuum at below 80 C for 10 -12 h to give 4-nitro-l//-indazole as a brown solid (150 g, 70%): mp: 200-203 C; 1H NMR (200 MHz, CDCl3) delta 13.4 (br, IH), 8.6 (s, IH), 8.2-7.95 (dd, 2H), 7.4 (m, IH). ESMS m/z 164 (M+l). Purity: 95% (HPLC)
70%
With sodium nitrite; In water; acetic acid; at 15 - 30℃;
Step A: Preparation of 4-nitro-1H-indazole: A mixture of 2-methyl-3-nitro aniline (200 g, 1.315 moles), acetic acid (8000 ml) was cooled to 15-20 C and a solution of sodium nitrite (90.6 g, 1.315 moles) in water (200 ml) was slowly added over 30 min. After the addition, the reaction temp, was increased to 25-30 C and the reaction was stirred at this temp for 2-3 h. Reaction progress was monitored by TLC and after completion of reaction product was filtered and residue was washed with acetic acid (1000 ml). Acetic acid was distilled under vacuum (550 mm of Hg) below 80 C and water (8000 ml) was added, cooled to 25-30 C and stirred for 30 min. The slurry was filtered and washed with water (1000 ml). Crude product was dried under heating at 70-80 C for 2 hours, then was taken in 5% ethyl acetate/n-hexane (100:2000 ml) solution and stirred for 1-1.5 h at ambient temperature. The suspension was filtered and washed with 5% ethyl acetate/n-hexane mixture (25:475 ml). The product obtained was dried under vacuum at below 80 C for 10 -12 h to give 4-nitro-lH-indazole as a brown solid (150 g, 70%): mp: 200-203 C; 1H NMR (200 MHz, CDCI3) delta 13.4 (br, 1H), 8.6 (s, 1H), 8.2-7.95 (dd, 2H), 7.4 (m, 1H). ESMS m/z 164 (M+1). Purity: 95% (HPLC)
68%
With acetic acid; sodium nitrite; In water; at 20℃; for 0.75h;
2-methyl-3-nit.ro aniline (1O g, 0.005 mol) was taken in acetic acid (100 ml, 10 times) and cooled to 2O0C. A solution of sodium nitrite (1Og, 0.14 mol, 2.25 eq) in water (25 ml) was added drop wise for 15 min at 2O0C. The overall reaction mixture was stirred for 30 min at 2O0C and later stirred for 2 hrs at rt. Progress of the reaction was monitored by TLC (15% ethyl acetate/hexane, Rf-0.2). On completion of the reaction, acetic acid was distilled off completely and the residue obtained was taken in cold water (200 ml). Solid thrown out was filtered and dried to yield the required product as an yellow colored solid (8.5 g, 68% yield).
ethyl 2-[(2-methyl-3-nitrophenyl)hydrazono]propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: 3-nitro-o-tolylamine With hydrogenchloride; sodium nitrite In water; acetonitrile at -10 - -5℃; for 0.5h;
Stage #2: 2-acetylpropanoic acid ethyl ester With potassium hydroxide In ethanol; water; acetonitrile at -6 - 2℃; for 0.166667h;
Stage #3: With hydrogenchloride In ethanol; water; acetonitrile at 0℃; for 1h;
55
Reference Example 55 ethyl 2-[(2-methyl-3-nitrophenyl)hydrazono]propanoate 2-Methyl-3-nitroaniline (50.0 g) was suspended in a mixed solvent of acetonitrile (75 mL) and 2N aqueous hydrochloric acid solution (411 mL), and the mixture was cooled to -10°C. A solution of sodium nitrite (27.3 g) in water (50 mL) was added dropwise at an inside temperature of -5°C or below. After stirring at the same temperature for 30 min, the reaction mixture was filtered through celite. Ethyl 2-methylacetoacetate (46.6 mL) and potassium hydroxide (64.6 g) were dissolved in a mixed solvent of water (350 mL) and ethanol (350 mL), and the mixture was cooled to -6°C and the above-mentioned filtrate was added dropwise at an inside temperature of 2°C or below. After stirring at the same temperature for 10 min, 6N aqueous hydrochloric acid solution (100 mL) was added, and the mixture was stirred at 0°C for 1 hr. The resulting solid was collected by filtration, dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (76.7 g, yield 88%) as a red solid. 1H NMR (300 MHz, DMSO-d6) δ: 1.27 (3 H, t, J=7.0 Hz), 2.15 (3 H, s), 2.33 (3 H, s), 4.22 (2 H, q, J=7.0 Hz), 7.38 - 7.48 (2 H, m), 7.68 (1 H, dd, J=7.3, 2.1 Hz), 8.94 (1 H, s).
With hydrogenchloride; sodium nitrite Multistep reaction;
2.1. N-(2-Methyl-3-nitro-phenyl)-acetimidic acid ethyl ester (310)
In a tow-necked flask equipped with a Claisen condenser were placed commercial 2-methyl-3-nitroaniline (6.00 g, 39.4 mmol), p-toluenesulfonic acid (0.032 g, 0.2 mmol) and anhydrous triethyl-ortoformate (10 mL, d = 0.885, 54.7 mmol); the mixture was heated at 120 °C until all the ethanol had distilled off. Then, following vacuum distillation at 150 °C and 0.6 mmHg, the imidate ester (6.97 g) was collected. Yellow oily liquid; yield 92%; rf 0.80 (ethyl acetate/n-hexane 1:1); 1H NMR (DMSO-d6) δ 1.29 (t, 3H, J = 7.05 Hz, CH3), 1.77 (s, 3H, CH3), 2.15 (s, 3H, CH3), 4.23 (q, 2H, J = 7.05 Hz, CH2), 7.04 (dd, 1H, J6,5 = 8.01 Hz, J6,4 = 0.96 Hz, 6-H), 7.34 (dd, 1H, J5,6 = 8.01 Hz, J5,4 = 8.01 Hz, 5-H), 7.55 (dd, 1H, J4,5 = 8.01 Hz, J4,6 = 0.96, 4-H).
73%
With toluene-4-sulfonic acid at 120℃; for 1h;
With toluene-4-sulfonic acid at 120℃; for 1h;
34
Reference Example 34 Ethyl N-(2-methyl-3-nitrophenyl)acetimidate 2-methyl-3-nitroaniline (5.1 g) was dissolved in triethyl orthoacetate (33.3 mL), p-toluenesulfonic acid monohydrate (316 mg) was added, and the mixture was stirred at 120°C for 1 hour. The reaction mixture was returned to room temperature, and concentrated under reduced pressure, and the resulting residue was then crystallized with cooled n-hexane. The resulting crystal was filtered, and dissolved again in n-hexane, and the solvent was then concentrated under reduced pressure to obtain the title compound (7.1 g). 1H NMR (CDCl3) δ (ppm): 1.37(3H,t), 1.78(3H,s), 2.26(3H,s), 4.28(2H,q), 6.88(1H,d), 7.22(1H,dd), 7.52(1H,d).
Stage #1: 3-nitro-o-tolylamine With tetrafluoroboric acid; sodium nitrite In water
Stage #2: furfural With copper dichloride In acetone at 20℃; for 48h; Further stages.;
2-methyl-1-nitro-3-propylsulfanylbenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With n-Butyl nitrite; copper In chloroform at 70 - 80℃; for 5.16667h;
I.1.1.1.1
1.1 : 2-Methyl-1-nitro-3-propylsulfanylbenzene;:400 g (2.63 mol) of 2-methyl-3-nitroaniline, 655 g (4.35 mol) of dipropyl disulfide, 30 g (0.47 mol) of copper powder were suspended in 1000 ml of chloroform and heated to 70 to 75°C. Then, over the course of 70 min, 339 g (3.28 mol) of n-butyl nitrite were added dropwise. The mixture was stirred at 75 to 80°C for 4 h. The reaction mixture was cooled to room temperature and then washed three times with 1000 ml of concen¬ trated hydrochloric acid, twice with 20% strength aqueous sodium hydroxide solution and once with saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was distilled off in vacuo. The result was a dark oil which was purified by vacuum distillation (b.p. 127°C/1.2 mbar). Yield: 267 g (48% of theory) of the desired product.1H NMR (in CDCI3): δ = 1.05 ppm (t, 3H, aliph. Me), 1.7 ppm (m, 2H, aliph. CH2),2.9 ppm (t, 2H, S CH2), 7.3 ppm (m, 1H, arom. H), 7.45 ppm (d, 1 H, arom. H), 7.5 ppm(d, 1H, arom. H).
Example 14; 3-(3-Methoxyphenyl)-6-nitro-2,7-dimethyl-1H-indole (Compound 118, Structure 8 of Scheme III, where Rl = nitro, R2 = R6 = Me, R4 = R5 = H, R7 = 3- methoxyphenyl); 0. 5 g (3. 3 mmol) of 2-methyl-3-nitroaniline was dissolved in 15 mL of concentrated hydrochloric acid with stirring at 0 C. Sodium nitrite (1. 6 g, 1. 2 eq) in 5 mL water was then added dropwise. Thirty minutes later, tin chloride dihydrate (1. 6 g, 2. 1 eq) in 7 mL concentrated HCl was added. The reaction was stirred for 1 hour and then 7 mL of ethanol was added followed by 3- methoxyphenylacetone (1. 3 mL, 2. 5 eq). The reaction mixture was heated in a 100 C oil bath. After 12 hours, the reaction was cooled, added to 50 mL of water, extracted into ethyl acetate (3x50 mL), dried and then concentrated. Chromatography (silica, 15-25% ethyl acetate/hexanes) afforded the title compound 0. 132 g (15% yield) as a light yellow powder. 1H NMR (500MHz, CDC13) No. 8. 28 (s, 1H) ; 7. 87 (d, J=8. 8 Hz, 1H) ; 7. 53 (d, J=8. 8 Hz, 1H) ; 7. 41 (dd, J=8. 3, 7. 6 Hz, 1H) ; 7. 05 (ddd, J=7. 6, 1. 6, 1. 0 Hz, 1H) ; 7. 00 (dd, J=2. 6, 1. 6 Hz, 1H) ; 6. 91 (ddd, J=8. 3, 2. 6, 1. 0 Hz, 1H) ; 3. 87 (s, 3H) ; 2. 80 (s, 3H) ; 2. 59 (s, 3H).
Stage #1: 3-nitro-o-tolylamine With hydrogenchloride; sodium nitrite In water; acetonitrile at -20℃; for 0.5h;
Stage #2: ethyl 2-ethyl-3-oxobutanoate With potassium hydroxide In ethanol; water at -20℃; for 0.166667h;
Stage #3: With hydrogenchloride In ethanol; water at 0℃; for 1h;
76
Reference Example 76 ethyl 2-[(2-methyl-3-nitrophenyl)hydrazono]butanoate 2-Methyl-3-nitroaniline (24.0 g) was suspended in a mixed solvent of acetonitrile (36 mL) and 2N aqueous hydrochloric acid solution (139 mL), and the mixture was cooled to -20°C. Sodium nitrite (13.1 g) was dissolved in water (24 mL), and added dropwise thereto at the same temperature. After stirring for 30 min, the mixture was filtered through celite. Ethyl 2-ethylacetoacetate (25.0 g) and potassium hydroxide (25.0 g) were dissolved in a mixed solvent of water (168 mL) and ethanol (168 mL), and the above-mentioned filtrate was added dropwise at -20°C. The mixture was stirred at the same temperature for 10 min, 6N aqueous hydrochloric acid solution (50 mL) was added, and the mixture was stirred at 0°C for 1 hr. The resulting solid was collected by filtration, dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (20.8 g, yield 47%) as a red solid. 1H NMR (300 MHz, DMSO-d6) δ: 1.02 - 1.35 (6 H, m), 2.24 (1.5 H, s), 2.33 (1.5 H, s), 2.48 - 2.75 (2 H, m), 4.08 - 4.35 (3 H, m), 7.36 - 7.80 (3H, m), 9.15 (0.5 H, s), 12.12 (0.5 H, s).
Multi-step reaction with 3 steps
1.1: glacial acetic acid; NaNO2 / water monomer / 2 h / 20 °C
2.1: triethylamine / dichloromethane / 6 h / 20 °C
3.1: zinc powder / methanol / 0.17 h / Cooling with ice
3.2: 5 h / 0 - 20 °C
Multi-step reaction with 3 steps
1.1: glacial acetic acid; NaNO2 / water monomer / 2 h / 20 °C
2.1: triethylamine / 6 h / 20 °C
3.1: zinc powder / methanol / 0.17 h / 20 °C
3.2: 5.5 h / 20 °C
With N-Bromosuccinimide In acetonitrile at 0℃; for 0.5h;
A.d.1
Dissolve compound C1 (2.0g, 13.2mmol) in acetonitrile, cool to 0°C, add NBS (2.57g, 14.5mmol) in batches, add and stir at the same temperature for 30min, the reaction is complete, spin dry, and purified by column chromatography to a bright yellow solid (2.68g, 11.6mmol), the yield is 88%.
With N-Bromosuccinimide In acetonitrile at 0 - 20℃; for 0.5h; Inert atmosphere;
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