* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 2 mol% Pd/C; sodium carbonate In N,N-dimethyl-formamide at 140℃; for 144 h; Inert atmosphere
aryl bromide (1 mmol), alkyne (3 mmol), Na2CO3 (3 mmol), Pd/C (2 mo lpercent) and DMF (2 mL) were introduced in a sealed tube. The reactor was placed under stirring in a preheated oil bath at 120 °C or 140 °C after being flushed by argon. The reaction completion was monitored by GC. After cooling to room temperature, the reaction mixture was filtered through a celite pad, which was washed with EtOAc (100 mL). The resulting organic layer was then washed with Na2CO3 (2 .x. 40 mL) and brine (40 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. If necessary (for the silylated compounds), the crude product could be fully deprotected by treatment with HCl 1 M before being purified by flash chromatography on silica.
Reference：
[1] Chemistry - A European Journal, 2008, vol. 14, # 4, p. 1351 - 1356
3
[ 873-38-1 ]
[ 98-80-6 ]
[ 73006-78-7 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 23, p. 14588 - 14599
[2] Patent: WO2006/37982, 2006, A2, . Location in patent: Page/Page column 23
[3] Journal of the American Chemical Society, 2011, vol. 133, # 15, p. 5996 - 6005
[4] Advanced Synthesis and Catalysis, 2012, vol. 354, # 13, p. 2473 - 2483,11
[5] Advanced Synthesis and Catalysis, 2012, vol. 354, # 13, p. 2473 - 2483
[6] Organic Letters, 2015, vol. 17, # 6, p. 1597 - 1600
[7] Organic Letters, 2017, vol. 19, # 15, p. 4134 - 4137
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[10] Organic Letters, 2013, vol. 15, # 7, p. 1468 - 1471
[11] Organic Letters, 2013, vol. 15, # 15, p. 3990 - 3993
[12] Advanced Synthesis and Catalysis, 2016, vol. 358, # 22, p. 3642 - 3648
[13] Angewandte Chemie - International Edition, 2013, vol. 52, # 41, p. 10792 - 10795[14] Angew. Chem., 2013, vol. 125, # 41, p. 10992 - 10995,4
[15] Organic Letters, 2014, vol. 16, # 4, p. 1260 - 1263
[16] Organic Letters, 2014, vol. 16, # 9, p. 2546 - 2549
[17] Organic Letters, 2015, vol. 17, # 5, p. 1232 - 1235
[18] Chemical Communications, 2016, vol. 52, # 8, p. 1598 - 1601
[19] Journal of Organic Chemistry, 2016, vol. 81, # 15, p. 6672 - 6676
[20] European Journal of Organic Chemistry, 2016, vol. 2016, # 34, p. 5611 - 5615
[21] Chemical Communications, 2017, vol. 53, # 11, p. 1908 - 1911
[22] European Journal of Organic Chemistry, 2017, vol. 2017, # 22, p. 3145 - 3151
[23] European Journal of Organic Chemistry, 2017, vol. 2017, # 39, p. 5892 - 5895
[24] Green Chemistry, 2018, vol. 20, # 6, p. 1362 - 1366
[25] Journal of Organic Chemistry, 2018, vol. 83, # 7, p. 3840 - 3856
4
[ 75-15-0 ]
[ 873-38-1 ]
[ 51618-29-2 ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodiumsulfide nonahydrate In N,N-dimethyl-formamide at 110℃; for 15 h; Sealed tube; Inert atmosphere
General procedure: A sealed tube (50 mL) was charged with 2-haloaniline 1a (2mmol), CS2 (10 mmol), Na2S (4mmol) and DMF (2 mL) at room temperature under an argon gas atmosphere and the tube was flushed with argon for three times and sealed. Then the mixture was stirred electromagnetically at 110 °C for 12 hours. The reaction process was monitored by TLC on silica gel. After the reaction was completed, the reaction mixture was cooled to room temperature, 2 mL HCl (3 mol/L) was added and stirred for 30 minutes. Then the reaction mixture solution was extracted by dichloromethane (3*20 mL). Subsequently, the combined organic solution were dried by anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel colum chromatography (eluent: petroleum ether / ethyl acetate) give the corresponding pure product 2a.
Stage #1: With hydrogenchloride; sodium nitrite In water at -15 - 0℃; for 0.833333 h; Stage #2: With potassium iodide In water at 20℃; for 6.17 h;
[Production Example 4]; The following Indenopyrene Compound D was produced through the following synthesis route. [Show Image] Synthesis of Intermediate D1; 2-Bromo-4-chloroaniline (10 g, 48 mmoles) was suspended in hydrochloric acid water (50 mL of concentrated hydrochloric acid and 35 mL of water), and the suspension was cooled on a dry ice/methanol bath at -15°C. A sodium nitrite aqueous solution (3.6 g, 52 mmoles, 1. 1 eq. /20 mL) was gradually added dropwise thereto over 20 minutes, and the mixture was stirred at from -15°C to 0°C for 30 minutes, thereby preparing a diazonium salt. The reaction solution was gradually added dropwise to a potassium iodide aqueous solution (73 g, 0.44 moles, 9 eq. /220 mL) at room temperature over 10 minutes. The reaction mixture was stirred at room temperature for 6 hours and then allowed to stand overnight. Dichloromethane (200 mL) was added to the reaction mixture, and subsequently, sodium hydrogensulfite (2 g) was added, thereby deactivating generated iodine. An organic layer was aliquoted, washed with a 10percent sodium hydrogensulfite aqueous solution (100 mL) and saturated salt water (30 mL) and dried over anhydrous magnesium sulfate, and the solvent was then distilled off to obtain a red liquid. This was purified by means of column chromatography (silica gel/hexane) to obtain a white needle crystal (12.4 g, 81percent). 1H-NMR (400 MHz, CDCl3, TMS): δ6.98 (1H, dd, J = 8 Hz, 2 Hz), 7.61 (1H, d, J = 2 Hz), 7.74 (1H, d, J = 8 Hz)
16.4 g
With hydrogenchloride; potassium iodide; sodium nitrite In water at -15 - 20℃; for 18.5 h;
To a solution of 2-bromo-4-chloroaniline (15 g) in concentrated hydrochloric acid (85 ml_) is added at -15°C a solution of NaNO2 (5.5 g) in water (10 ml_) and the mixture is stirred for 30 minutes. Then the mixture is added at room temperature to a solution of Kl (109 g) in water (200 ml_). After stirring for 18 hours the mixture is partitioned between dichloromethane and 10percent aqueous Na2S2O3 solution. The organic phase is washed with 10percent aqueous Na2S2O3 solution and brine and concentrated to give the title compund. Yield: 16.4 g; Mass spectrum (El): m/z = 316 [M]+.
Reference：
[1] Patent: EP2316816, 2011, A1, . Location in patent: Page/Page column 21
[2] Chemistry - A European Journal, 2018, vol. 24, # 55, p. 14622 - 14626
[3] Angewandte Chemie - International Edition, 2008, vol. 47, # 5, p. 888 - 890
[4] Angewandte Chemie - International Edition, 2008, vol. 47, # 9, p. 1726 - 1728
[5] Journal of Organic Chemistry, 1987, vol. 52, # 5, p. 748 - 753
[6] Angewandte Chemie - International Edition, 2012, vol. 51, # 8, p. 1958 - 1961
[7] Patent: WO2013/144098, 2013, A1, . Location in patent: Page/Page column 122
[8] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 1494 - 1502
8
[ 873-38-1 ]
[ 1435-50-3 ]
Reference：
[1] Journal of the Chemical Society, 1901, vol. 79, p. 1297
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1913, vol. <5> 22 I, p. 823[2] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1914, vol. <5> 23 I, p. 283 Anm.
11
[ 873-38-1 ]
[ 63860-31-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6224 - 6229
[2] Advanced Synthesis and Catalysis, 2007, vol. 349, # 14-15, p. 2286 - 2300
12
[ 106-47-8 ]
[ 873-38-1 ]
Yield
Reaction Conditions
Operation in experiment
90%
With 1,2-ethanediylbis(triphenylphosphonium) ditribromide In methanol; dichloromethane at 20℃; for 0.0833333 h;
General procedure: To a mixture of anilines or phenols (0.7 mmol) the brominatingagent (1) (0.72 g, 0.7 mmol) in dichloromethane(30 ml)-methanol (15 ml) was added. The reactionmixture was stirred at room temperature until decolorizationof the orange solution took place. The progress of thereaction was monitored by TLC (eluent: n-hexane/ethylacetate, 7:3). After completion of the reaction, the solventwas evaporated and diethyl ether (10 ml) was added to theresidue. The supernatant was decanted and the insolubleresidue was washed by ether (3 × 10 ml). The combinedether extracts were dried on magnesium sulfate and also evaporated under vacuum to afford monobromo anilines ormonobromo phenols which was purified by flash columnchromatography over silica gel (n-hexane/ethyl acetate,7:3).
90%
With o-xylylene bis(triethylammonium tribromide) In acetonitrile at 20℃; for 0.0833333 h;
General procedure: To a magnetic solution of aromatic compound (1 mmol)in acetonitrile (5 mL), OXBTEATB (0.233 g, 0.5 mmol) wasadded and stirred at room temperature for the appropriatetime (Table 1). The reaction was monitored by TLC (eluent:n-hexane/ethyl acetate: 5/1). The reaction mixture was transferredinto a separatory funnel after filtration of OXBTEABand was extracted with water (15 mL) and dichloromethane(20 mL). The organic layer was dried over anhydrousNa2SO4, and the solvent was concentrated in a rotary evaporator.The crude product was purified by passing it over acolumn of silica gel using a mixture of n-hexane and ethylacetate as the eluent. In order to regenerate the reagent, whitesolid was treated with liquid bromine. All the product structureswere confirmed by comparison of melting point or 1HNMR spectra with ones reported in the literature [29a-29e].
77%
With acetic acid; potassium bromide In water at 30℃; for 1 h;
A solution of 254 mg (2 mmol) of p-chloroaniline and 143 mg (1.2 mmol) of potassium bromide was added to a 50 ml three-necked flask, Into the AcOH: H2O = 9: 1 10ml solvent, transferred to the constant temperature magnetic stirring water bath, control the temperature of 30 stirring reactionOne hour, 1.8 g (1.8 mmol) of ZnAl-BrO3-LDHs was added slowly in portions 15 minutes before the reaction. After the reaction, use two The reaction mixture was extracted with methyl chloride and the organic phases were combined. Two syrups of silica gel (200-300 mesh) were added to the dichloromethane phase and Dichloromethane was distilled off under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 10: 1 as eluent) To a pure product of 317 mg. The material was a gray solid with a yield of 77percent.
Reference：
[1] Synthetic Communications, 2009, vol. 39, # 2, p. 215 - 219
[2] Tetrahedron Letters, 2006, vol. 47, # 49, p. 8693 - 8697
[3] Canadian Journal of Chemistry, 2005, vol. 83, # 2, p. 146 - 149
[4] Synthetic Communications, 2010, vol. 40, # 5, p. 647 - 653
[5] Tetrahedron Letters, 2005, vol. 46, # 51, p. 8959 - 8963
[6] Tetrahedron Letters, 2009, vol. 50, # 9, p. 1007 - 1009
[7] Tetrahedron, 2015, vol. 71, # 49, p. 9346 - 9356
[8] Journal of Organic Chemistry, 1980, vol. 45, # 13, p. 2570 - 2575
[9] Russian Journal of Applied Chemistry, 2009, vol. 82, # 9, p. 1570 - 1576
[10] Journal of the Chilean Chemical Society, 2011, vol. 56, # 4, p. 863 - 865
[11] RSC Advances, 2013, vol. 3, # 30, p. 12091 - 12095
[12] Journal of the Iranian Chemical Society, 2016, vol. 13, # 11, p. 2019 - 2028
[13] Letters in Organic Chemistry, 2018, vol. 15, # 8, p. 682 - 687
[14] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 3, p. 496 - 501
[15] Monatshefte fur Chemie, 2013, vol. 144, # 2, p. 179 - 181
[16] Synthetic Communications, 2004, vol. 34, # 12, p. 2143 - 2152
[17] Synthetic Communications, 2010, vol. 40, # 6, p. 868 - 876
[18] Chinese Chemical Letters, 2012, vol. 23, # 4, p. 387 - 390
[19] Journal of the Iranian Chemical Society, 2012, vol. 9, # 3, p. 321 - 326
[20] Tetrahedron Letters, 2007, vol. 48, # 7, p. 1255 - 1259
[21] Patent: CN107089919, 2017, A, . Location in patent: Paragraph 0048; 0049; 0050; 0051
[22] Journal of Chemical Research, Synopses, 1995, # 11, p. 457
[23] Angewandte Chemie - International Edition, 2012, vol. 51, # 12, p. 2925 - 2929
[24] Tetrahedron Letters, 2008, vol. 49, # 1, p. 189 - 194
[25] Journal of the American Chemical Society, 2011, vol. 133, # 18, p. 6868 - 6870
[26] Tetrahedron Letters, 2011, vol. 52, # 52, p. 7064 - 7066
[27] Chemistry - A European Journal, 2011, vol. 17, # 49, p. 13665 - 13669
[28] Tetrahedron Letters, 2012, vol. 53, # 2, p. 127 - 131
[29] Angewandte Chemie - International Edition, 2012, vol. 51, # 8, p. 1958 - 1961
[30] Journal of Molecular Catalysis A: Chemical, 2012, vol. 358, p. 38 - 48
[31] Catalysis Letters, 2013, vol. 143, # 2, p. 225 - 233
[32] Synthesis (Germany), 2013, vol. 45, # 11, p. 1497 - 1504
[33] Journal of Organometallic Chemistry, 2014, vol. 761, p. 169 - 178
[34] Tetrahedron Letters, 2014, vol. 55, # 38, p. 5338 - 5341
[35] Journal of the American Chemical Society, 2016, vol. 138, # 40, p. 13147 - 13150
[36] Chinese Journal of Chemistry, 2018, vol. 36, # 9, p. 815 - 818
13
[ 823-86-9 ]
[ 873-38-1 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1921, vol. 424, p. 300[2] Justus Liebigs Annalen der Chemie, 1925, vol. 441, p. 303
[Production Example 4]; The following Indenopyrene Compound D was produced through the following synthesis route. [Show Image] Synthesis of Intermediate D1; 2-Bromo-4-chloroaniline (10 g, 48 mmoles) was suspended in hydrochloric acid water (50 mL of concentrated hydrochloric acid and 35 mL of water), and the suspension was cooled on a dry ice/methanol bath at -15C. A sodium nitrite aqueous solution (3.6 g, 52 mmoles, 1. 1 eq. /20 mL) was gradually added dropwise thereto over 20 minutes, and the mixture was stirred at from -15C to 0C for 30 minutes, thereby preparing a diazonium salt. The reaction solution was gradually added dropwise to a potassium iodide aqueous solution (73 g, 0.44 moles, 9 eq. /220 mL) at room temperature over 10 minutes. The reaction mixture was stirred at room temperature for 6 hours and then allowed to stand overnight. Dichloromethane (200 mL) was added to the reaction mixture, and subsequently, sodium hydrogensulfite (2 g) was added, thereby deactivating generated iodine. An organic layer was aliquoted, washed with a 10% sodium hydrogensulfite aqueous solution (100 mL) and saturated salt water (30 mL) and dried over anhydrous magnesium sulfate, and the solvent was then distilled off to obtain a red liquid. This was purified by means of column chromatography (silica gel/hexane) to obtain a white needle crystal (12.4 g, 81%). 1H-NMR (400 MHz, CDCl3, TMS): delta6.98 (1H, dd, J = 8 Hz, 2 Hz), 7.61 (1H, d, J = 2 Hz), 7.74 (1H, d, J = 8 Hz)
67%
General procedure: Compound 15 (67.5 g, 0.355 mol) was added to the 300 mL 15 % aq. HCl. A resulting suspension was stirred for 1 h at 80 oC, then cooled to -5 C and NaNO2 (26.0 g, 0.365 mol) in H2O (50 mL) was slowly added. The mixture was stirred for 1.5 h at -5 C and then the excess of HNO2 was neutralized with urea. The solution of KI (57.2 g, 0.0355 mol) in 50 mL H2O was added dropwise at 0 oC (caution, the fast evolution of N2 was observed). The mixture was warmed to room temperature and stirred for 40 h. After this time CHCl3 was added, water phase was extracted with CHCl3 (3 × 100 mL), joined organic phases were washed with saturated solution of NaHCO3 (200 mL), 5% solution of Na2S2O3 (200mL) and5% solution of Na2S2O5 (200mL). Organic phase was dried over MgSO4 and concentrated under reduced pressure. The obtained crude product was distilled under reduced pressure (b.p. 90-91 oC, 2 Tr) affording 17 as viscous oil (69.1 g, 64%).
16.4 g
With hydrogenchloride; potassium iodide; sodium nitrite; In water; at -15 - 20℃; for 18.5h;
To a solution of <strong>[873-38-1]2-bromo-4-chloroaniline</strong> (15 g) in concentrated hydrochloric acid (85 ml_) is added at -15C a solution of NaNO2 (5.5 g) in water (10 ml_) and the mixture is stirred for 30 minutes. Then the mixture is added at room temperature to a solution of Kl (109 g) in water (200 ml_). After stirring for 18 hours the mixture is partitioned between dichloromethane and 10% aqueous Na2S2O3 solution. The organic phase is washed with 10% aqueous Na2S2O3 solution and brine and concentrated to give the title compund. Yield: 16.4 g; Mass spectrum (El): m/z = 316 [M]+.
To a stirred mixture of <strong>[873-38-1]2-bromo-4-chloroaniline</strong> (5 g, 24 mmol) and catalytic DMAP in CH2Cl2 (15 mL) was add acetic anhydride (2.3 mL, 24 mmol) at room temperature. The reaction mixture was stirred overnight then washed with saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried (MgSO4), filtered, concentrated in vacuo. The crude material was triturated with Hexane/Et2O and the solid filtered and dried in vacuo to give N-(2-bromo-4-chloro-phenyl)-acetamide (5.2 g, 86%). HPLC: Rt=2.26 min. m/z=248 M+H+).
at 20℃; for 1.5h;
A solution of <strong>[873-38-1]2-bromo-4-chloroaniline</strong> (1 g, 4.84 mmol) in acetic anhydride (5 ml, 4.84 mmol) was stirred at RT for 1.5 hrs. The resulting suspension was collected by filtration and dried on a vacuum line to give the title compound as a white solid. (0532) LC-MS: Rt 0.90 mins; MS m/z 250.0 [M+H]+; Method 2minLowpH (0533) 1H NMR (400 MHz, DMSO-d6) delta 9.51 (1H, s), 7.78 (1H, d), 7.62 (1H, d), 7.44 (1H, dd), 2.08 (3H, s).
With 1,2-ethanediylbis(triphenylphosphonium) ditribromide; In methanol; dichloromethane; at 20℃; for 0.0833333h;Catalytic behavior;
General procedure: To a mixture of anilines or phenols (0.7 mmol) the brominatingagent (1) (0.72 g, 0.7 mmol) in dichloromethane(30 ml)-methanol (15 ml) was added. The reactionmixture was stirred at room temperature until decolorizationof the orange solution took place. The progress of thereaction was monitored by TLC (eluent: n-hexane/ethylacetate, 7:3). After completion of the reaction, the solventwas evaporated and diethyl ether (10 ml) was added to theresidue. The supernatant was decanted and the insolubleresidue was washed by ether (3 × 10 ml). The combinedether extracts were dried on magnesium sulfate and also evaporated under vacuum to afford monobromo anilines ormonobromo phenols which was purified by flash columnchromatography over silica gel (n-hexane/ethyl acetate,7:3).
90%
With o-xylylene bis(triethylammonium tribromide); In acetonitrile; at 20℃; for 0.0833333h;
General procedure: To a magnetic solution of aromatic compound (1 mmol)in acetonitrile (5 mL), OXBTEATB (0.233 g, 0.5 mmol) wasadded and stirred at room temperature for the appropriatetime (Table 1). The reaction was monitored by TLC (eluent:n-hexane/ethyl acetate: 5/1). The reaction mixture was transferredinto a separatory funnel after filtration of OXBTEABand was extracted with water (15 mL) and dichloromethane(20 mL). The organic layer was dried over anhydrousNa2SO4, and the solvent was concentrated in a rotary evaporator.The crude product was purified by passing it over acolumn of silica gel using a mixture of n-hexane and ethylacetate as the eluent. In order to regenerate the reagent, whitesolid was treated with liquid bromine. All the product structureswere confirmed by comparison of melting point or 1HNMR spectra with ones reported in the literature [29a-29e].
80%
With cetyl-trimethylammonium tribromide; In water; at 90℃; for 0.0666667h;Microwave irradiation; Green chemistry;
General procedure: A homogenous mixture of the reagent CTMATB (2 mmol) and substrate 1-9 (2 mmol) were taken in 1:1 ratio in a 50 mL round bottomed flask equipped with reflux condenser in the microwave reactor. 10 mL H2O was added to the mixture and stirred thoroughly. The reaction mixture was placed inside the microwave reactor. The reactor was switched on and kept at a controlled power of P-7 which corresponds to 595 W. Reaction temperature was recorded using the flexible temperature probe attached to the microwave reactor, immediately after the completion of the reaction, and was found to be 90 C. The progress of the reaction was monitored by TLC on silica gel HF254 using ethyl acetate-hexane solvent system (volume ratio varied for different substrates). After completion of the reaction, the product was extracted with 10 mL (2×) ethyl acetate and washed with 5 mL (2×) sodium bicarbonate solution. The crude product thus obtained was subjected to column chromatography over a pad of silica gel using ethyl acetate-hexane solvent system (volume ratio varied for different substrates) to obtain the desired products 1a-9a.
77%
With acetic acid; potassium bromide; In water; at 30℃; for 1h;
A solution of 254 mg (2 mmol) of p-chloroaniline and 143 mg (1.2 mmol) of potassium bromide was added to a 50 ml three-necked flask, Into the AcOH: H2O = 9: 1 10ml solvent, transferred to the constant temperature magnetic stirring water bath, control the temperature of 30 stirring reactionOne hour, 1.8 g (1.8 mmol) of ZnAl-BrO3-LDHs was added slowly in portions 15 minutes before the reaction. After the reaction, use two The reaction mixture was extracted with methyl chloride and the organic phases were combined. Two syrups of silica gel (200-300 mesh) were added to the dichloromethane phase and Dichloromethane was distilled off under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 10: 1 as eluent) To a pure product of 317 mg. The material was a gray solid with a yield of 77%.
75%
With N-Bromosuccinimide; In acetonitrile; at 0 - 60℃; for 13h;
General procedure: This compound was prepared according to the modified version of already published procedure [1]. NBS (89 g, 0.5 mol) was added in portions to the stirred solution of 4-fluoroaniline (55.5 g, 0.5 mol) in MeCN (500 mL) at 0 oC. During the addition, the mixture turned brown. After 1 hour of stirring it was warmed to 60 oC and then stirred for another 12 h. Then 1 L of H2O was added. The aqueous phase was separated followed by the extraction with CHCl3 (3 × 200 mL). The joined organic phases were washed with water and brine. Then organic phase was dried over MgSO4, filtrated and concentrated under reduced pressure. The obtained oily residue was subjected to fractional distillation giving 15 as a viscous oil (b.p. 87-88 C, 2 Tr), which crystalized after several days.
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; at 75℃; for 18h;Heating / reflux;
To a well-stirred mixture consisting of <strong>[873-38-1]2-bromo-4-chloroaniline</strong> (5.0 g, 24 mmol) in tetrahydrofuran (180 ML), diethyl-3-pyridyl borane (4.07 g, 28 MMOL), and bis (TRIPHENYLPHOSOPHINE) PALLADIUM (II) chloride (2.53 g, 3.6 mmol), a solution of sodium carbonate (12.72 g, 120 MMOL) in water (60 ML) was added. The reaction was then heated at 75C for 18 hours. The layers of the biphasic mixture were separated, and the aqueous phase was extracted with an equal volume of ethyl acetate. The combined original reaction organic phase and ethyl acetate extract were dried and concentrated in vacuo to afford an oil (9.4 g). Flash chromatography of the entire sample (silica gel ; initial elution with ethyl acetate/hexanes = 8: 2 in volume followed by elution with pure hexane) afforded the title compound as a colorless oil (3.64 g, 74% yield). TLC Rf (silica gel plates ; elution with ethyl acetate, UV detection): 0.46.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene;Inert atmosphere; Reflux;
500 mL under nitrogen stream<strong>[873-38-1]2-bromo-4-chloroaniline</strong> (25.0 g, 121.08 mmol) in flaskAnd phenyl boronic acid (17.72 g, 145.30 mmol),Potassium carbonate (33.47 g, 242.17 mmol),Tetrakis (triphenylphosphine) palladium (0) (4.20 g, 3.63 mmol),Toluene (300 mL), EtOH (80 mL) and H2O (80 mL)Was added and stirred to reflux.After completion of the reaction, the toluene layer was extracted using toluene and water. The extracted solution was treated with MgSO 4 to remove residual water, concentrated under reduced pressure, and purified by column chromatography to obtain 17.78 g of Compound 2-A in 72.1% yield.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,3-dioxane; for 48h;Heating / reflux;
A mixture of <strong>[873-38-1]2-bromo-4-chloroaniline</strong> (4g), sodium carbonate (6.Ig) phenylboronic acid (2.93g) and tetrakis(triphenylphosphine)palladium(0) (0.5g) in dioxane (30ml) was heated under reflux for 48h then cooled. The mixture was partitioned between ethyl acetate and water, the organic layer was washed with water, dried, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-10% ethyl acetate/isohexane, yield 0.99g. MS: APCI (+ve) 204/6
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 6h;Inert atmosphere; Schlenk technique;
General procedure: Taking 1d as an example: (A) Under a nitrogen atmosphere, a 100 mL Schlenk flask was charged with 2-bromoaniline (0.86 g, 5.0 mmol), 4-tert-butylphenylboronic acid (1.07 g, 6.0 mmol), Na2CO3 (1.33 g, 12.5 mmol), and a solvent mixture of toluene/EtOH/H2O (24 mL, 1:1:1 (v/v/v)) with stirring. Pd(PPh3)4 (0.29 g, 0.25 mmol) was added. Then, the mixture was stirred at 80 C for 6 h, cooled to room temperature, quenched with saturated NH4Cl, and extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of petroleum ether and ethyl acetate (10:1 (v/v)) as eluents to afford 4'-(tert-butyl)-[1,1'-biphenyl]-2-amine as a yellow oil (0.88 g, 78%).
With triethylamine; In dichloromethane; at 20℃; for 1h;
2-Bromo-4-chloroaniline (1.0 eq) was dissolved in CH2CI2 (0.25 M), then triethylamine and trifluoroacetyl anhydride (1.1 eq each) were added. The resulting mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by flash chromatography with CH2CI2 as eluent to give the amide in 97% yield. m/z(M-H)" 300.0.
97%
With triethylamine; In dichloromethane; at 20℃; for 1h;
2-Bromo-4-chloroaniline (1.0 eq) was dissolved in CH2Cl2(0.25M), then triethylamine and triflouroacetyl anhydride (1.1 eq each) were added. The resulting mixture was stirred at room temperature for 1 hour. Solvent was then stripped-off from the reaction mixture, and the residue was purified by flash chromatography with dichloromethane as eluent to give the described product in 97% yield. m/z(M-H) -300.0.
97%
With triethylamine; In dichloromethane; at 20℃; for 1h;
Step 1: 2-Bromo-4-chloroaniline (1.0 eq) was dissolved in CH2Cl2 (0.25 M), then triethylamine and trifluoroacetyl anhydride (1.1 eq each) were added. The resulting mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by flash chromatography with CH2Cl2 as eluent to give the amide in 97% yield. m/z(M-H)- 300.0
With pyridine; In dichloromethane; at 40℃; for 0.5h;
5-(3-aminopropyl)-8-chloro-3-methyl-3,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (1-4)N-(2-bromo-4-chlorophenyl)-1-methyl-1H-imidazole-5-carboxamide (1-2)A solution of 1-methyl-1H-imidazole-5-carboxylic acid (350 mg, 2.78 mmol, 1 equiv) in dichloromethane (5 mL) was added slowly to thionyl chloride (8.00 mL, 109 mmol, 39.5 equiv) precooled to 0 C. The reaction mixture was warmed to 23 C. and allowed to stir for 20 min. The reaction mixture was concentrated in vacuo and the residue was dissolved in a 1:1 mixture of CH2Cl2 and pyridine (10 mL). To the stirred solution was added 2-bromo-4-chloroaniline (1.15 g, 5.55 mmol, 2.0 equiv) and the resulting mixture was heated at 40 C. for 30 min. The reaction mixture was concentrated to dryness and the residue purified by reverse-phase liquid chromatography (H2O/CH3CN gradient w/0.05% NH4OH present) to yield N-(2-bromo-4-chlorophenyl)-1-methyl-1H-imidazole-5-carboxamide (1-2) as an off white solid. LRMS m/z (M+H) 316.5 found, 316.0 required.
With 2 mol% Pd/C; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;Inert atmosphere;
aryl bromide (1 mmol), alkyne (3 mmol), Na2CO3 (3 mmol), Pd/C (2 mo l%) and DMF (2 mL) were introduced in a sealed tube. The reactor was placed under stirring in a preheated oil bath at 120 C or 140 C after being flushed by argon. The reaction completion was monitored by GC. After cooling to room temperature, the reaction mixture was filtered through a celite pad, which was washed with EtOAc (100 mL). The resulting organic layer was then washed with Na2CO3 (2 × 40 mL) and brine (40 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. If necessary (for the silylated compounds), the crude product could be fully deprotected by treatment with HCl 1 M before being purified by flash chromatography on silica.
With 2 mol% Pd/C; sodium carbonate; In N,N-dimethyl-formamide; at 140℃; for 144h;Inert atmosphere;
aryl bromide (1 mmol), alkyne (3 mmol), Na2CO3 (3 mmol), Pd/C (2 mo l%) and DMF (2 mL) were introduced in a sealed tube. The reactor was placed under stirring in a preheated oil bath at 120 C or 140 C after being flushed by argon. The reaction completion was monitored by GC. After cooling to room temperature, the reaction mixture was filtered through a celite pad, which was washed with EtOAc (100 mL). The resulting organic layer was then washed with Na2CO3 (2 × 40 mL) and brine (40 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. If necessary (for the silylated compounds), the crude product could be fully deprotected by treatment with HCl 1 M before being purified by flash chromatography on silica.
With N-ethyl-N,N-diisopropylamine In toluene for 24h; Reflux;
Synthesis of ethyl 2-(5-methyl-2-(pyrrolidin-1-yl)phenyl)-2-oxoacetate 1b as a representative example.
General procedure: To a solution of S3a[2] (1.43 g, 7.7 mmol) in toluene (40 mL) were successively added i-Pr2NEt (3 mL, 18.48 mmol), and 1,4-dibromobutane (1.65 mL, 13.8 mmol). After the reaction mixture was heated to reflux for 24 h, the salt was removed and the residue was concentrated in vacuo, purified by column chromatography (silica gel, petro ether) to give S4a (1.78 g). At this moment, the crude material S4a was mixed with 1,4-dibromobutane, but we used it for the next reaction without further purification.
With N-ethyl-N,N-diisopropylamine In toluene for 24h; Reflux;
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 80℃; for 22h;Inert atmosphere;
In a 20 ml microwave vial was added 2-bromo-4-chloroaniline (3 g, 14.53 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.53 g, 21.80 mmol), KOAc (3.66 g, 37.3 mmol), Pd(dppf)Cl2-CH2Cl2 adduct (0.32 g, 0.44 mmol) and DMSO (9 ml). The resulting suspension was purged with N2, capped and heated at 80 C for 22 h. The reaction was cooled to rt. Water was added to dissolve the salts, then the reaction was filtered. The remaining solid was suspended in DCM and the insoluble solid was filtered. The filtrate was concentrated and then purified by normal phase chromatography to give 4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.15 g, 86 % yield) as a white solid. MS (ESI) m/z:172.3 (M-C6H10+H)+.1H NMR (400MHz, CDCl3) delta 7.54 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 6.52 (d, J=8.6 Hz, 1H), 4.72 (br. s., 2H), 1.34 (s, 12H).
With bis-triphenylphosphine-palladium(II) chloride; triethylamine; In 1,4-dioxane; at 120℃; for 16h;Inert atmosphere;
Step 1 : 4-chloro-2-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)aniline To a solution of 2- bromo-4-chloroaniline (2.06 g, 9.98 mmol), Pd(PPh3)2Cl2 (0.20 g, 0.285 mmol) and TEA (5.60 mL, 40.2 mmol) in dioxane (100 mL) was added 4,4,5, 5-tetramethyl-l,3,2-dioxaborolane (4.33 mL, 29.90 mmol) and stirred at 120C for 16 hours under N2. LCMS showed the reaction was complete. The mixture was poured into aq. sat. H4C1 (100 mL) and extracted with DCM (200 mL). The organic layer was dried over Na2S04, concentrated in vacuo and purified by chromatography on silica gel (100-200 mesh) (24 g) (pet. Ether : EtOAc = 95 : 5) to give the title compound. MS (ESI) m/z 254.1 (M+H).
With tetrakis(triphenylphosphine) palladium(0); Aliquat 336; potassium carbonate; In 1,4-dioxane; water; for 24h;Inert atmosphere; Reflux;
2.00 g (6.07 mmol) of 23 were suspended in 15.0 ml of water. Then, 8.0 ml of concentrated hydrochloric acid were added under cooling. At a temperature of - 5 C, 7.0 ml of an aqueous solution containing 1.04 g (15.05 mmol) sodium nitrite were added drop- wise. During this procedure, the color of the reaction mixture changed from yellow to dark brown. Subsequently, 20.0 ml of an aqueous solution containing 10.19 g (60.79 mmol) potassium iodide were added dropwise while maintaining the temperature below 0 C. After the addition, the reaction was allowed to proceed for 1 h at room temperature. After extraction with DCM, treatment with an aqueous solution of sodium thiosul- fate and removal of the solvent under reduced pressure the crude product was purified by column chromatography (hexane/ethyl acetate = 8/2) to yield 1.40 g (3.55 mmol) of 24 in 42 % as a yellowish solid 1H NMR (300 MHz, CD2CI2): delta 7.91 (d, J = 8.5, 2H), 7.41 (s, 4H), 7.39 (d, J = 2.5, 2H), 7.08 (dd, J = 2.6, 8.5, 2H). 13C NMR (75 MHz, CD2CI2): delta 148.20, 143.29, 141.26, 135.03, 130.62, 129.65, 129.49, 96.09. MS (FD, 8kV): m/z (%) = 549.1 (100.0 %, M+), (calc. Ci8H10CI2l2 = 550.99 g/mol). Elemental Analysis: found 40.60 % C, 2.22 % H - calc. 39.24 % C, 1.83 % H.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 80℃; for 22h;Inert atmosphere;
In a 20 mL microwave vial was added 2-bromo-4-chloroaniline (3 g, 14.53 mmol), 4,4,5,5 -tetramethyl-2-(tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1,3 ,2-dioxaborolane (5.53 g, 21.80 mmol), KOAc (3.66 g, 37.3 mmol), Pd(dppf)C12-CH2C12 adduct (0.32 g,0.44 mmol) and DMSO (9 mL). The resulting suspension was purged with N2, capped and heated at 80 C for 22 h. The reaction was cooled to rt. Water was added to dissolve the salts, then the reaction was filtered. The remaining solid was suspended in DCM and the insoluble solid was filtered. The filtrate was concentrated and then purified by normal phase chromatography to give 4-chloro-2-(tetramethyl- 1,3 ,2-dioxaborolan-2-yl)aniline (3.15 g, 86% yield) as a white solid. MS(ESI) m/z:172.3 (M-C6H,o+H). ?H NMR (400MHz, CDC13) oe 7.54 (d, J2.6 Hz, 1H), 7.13 (dd, J8.8, 2.6 Hz, 1H), 6.52 (d, J8.6 Hz, 1H), 4.72 (br. s., 2H), 1.34 (s, 12H).
86%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 80℃; for 22h;Inert atmosphere; Sealed tube;
In a 20 ml microwave vial was added 2-bromo-4-chloroaniline (3 g, 14.53 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.53 g,21.80 mmol), KOAc (3.66 g, 37.3 mmol), Pd(dppf)C12-CH2C12 adduct (0.32 g, 0.44mmol) and DMSO (9 ml). The resulting suspension was purged with N2, capped and heated at 80 C for 22 h. The reaction was cooled to rt. Water was added to dissolve the salts, then the reaction was filtered. The remaining solid was suspended in DCM and the insoluble solid was filtered. The filtrate was concentrated and then purified by normal phase chromatography to give 4-chloro-2-(tetramethyl- 1,3 ,2-dioxaborolan- 2-yl)aniline(3.15 g, 86 % yield) as a white solid. MS (ESI) m/z. 172.3 (M-C6H,o+H)t ?H NIVIR (400MHz, CDC13) oe 7.54 (d, J2.6 Hz, 1H), 7.13 (dd, J8.8, 2.6 Hz, 1H), 6.52 (d, J8.6 Hz, 1H), 4.72 (br. s., 2H), 1.34 (s, 12H).
86%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 80℃; for 22h;Inert atmosphere;
In a 20 mL microwave vial was added 2-bromo-4-chloroaniline (3 g, 14.53mmol), 4,4,5,5 -tetramethyl-2-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 ,3,2-dioxaborolane(5.53 g, 21.80 mmol), KOAc (3.66 g, 37.3 mmol), Pd(dppf)C12-CH2C12 adduct (0.32 g, 0.44 mmol) and DMSO (9 mL). The resulting suspension was purged with N2, capped and heated at 80 C for 22 h. The reaction was cooled to rt. Water was added to dissolve the salts, then the reaction was filtered. The remaining solid was suspended in DCM andthe insoluble solid was filtered. The filtrate was concentrated and then purified by normalphase chromatography to give 4-chloro-2-(tetramethyl- 1 ,3,2-dioxaborolan- 2-yl)aniline(3.15 g, 86 % yield) as a white solid. MS (ESI) m/z: 172.3 (M-C6H1o+H). ?H NMR(400MHz, CDC13) 7.54 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 6.52 (d, J=8.6Hz, 1H), 4.72 (br. s., 2H), 1.34 (s, 12H).
86%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 80℃; for 22h;Inert atmosphere;
In a 20 mL microwave vial was added 2-bromo-4-chloroaniline (3 g, 14.53 mmol), 4,4,5, 5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (5.53 g, 21.80 mmol), KOAc (3.66 g, 37.3 mmol), Pd(dppf)Cl2-CH2Cl2adduct (0.32 g, 0.44 mmol) and DMSO (9 mL). The resulting suspension was purged with N2, capped and heated at 80 C for 22 h. The reaction was cooled to rt. Water was added to dissolve the salts, then the reaction was filtered. The remaining solid was suspended in DCM and the insoluble solid was filtered. The filtrate was concentrated and then purified by normal phasechromatography to give 4-chloro-2-(tetramethyl-l ,3,2-dioxaborolan- 2-yl)aniline (3.15 g, 86 % yield) as a white solid. MS (ESI) m/z: 172.3 (M-CeHio+H)+. NMR (400MHz, CDCh) delta 7.54 (d, J=2.6 Hz, IH), 7.13 (dd, J=8.8, 2.6 Hz, IH), 6.52 (d, J=8.6 Hz, IH), 4.72 (br. s., 2H), 1.34 (s, 12H).
79%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 24h;Inert atmosphere;
4-chloro-2-bromo-aniline (206 mg, 0.01 mmol) was dissolved in dimethylsulfoxide (20 mL). Under a nitrogen atmosphere, bis(pinacolato)diboron (3.8 g, 15 mmol), potassium acetate (2.5 g, 25.7 mmol) and [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium (218 mg, 0.3 mmol) were added thereto, and the temperature was raised to 80 C. to allow the reaction to proceed for 24 hours. Water (100 ml) was added to the reaction solution, which was extracted with ethyl acetate (80 ml×2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:100 to 1:30) to give the title compound 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2i) as a white solid (2.0 g, yield 79%). 1H NMR (400 MHz, CDC3) delta 7.54 (s, 1H), 7.19-7.08 (m, 1H), 6.55 (d, 1H), 4.86 (s. 2H), 1.34 (s, 12H). LCMS m/z=254.0 [M+1].
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 80℃;Inert atmosphere;
Example 237 (S)-1-(3-(4-chloro-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-2-methyl-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oic acid Intermediate 237a Into a 100-mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-4-chlorobenzenamine (10 g, 48.43 mmol, 1.00 equiv) in DMSO (30 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (18.5 g, 72.86 mmol, 1.50 equiv), potassium acetate (12.2 g, 124.36 mmol, 2.57 equiv), Pd(dppf)Cl2 (1.1 g, 1.50 mmol, 0.03 equiv). The resulting solution was stirred overnight at 80 C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 5 g (41%) of 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine as a white solid. LC-MS (ES, m/z): 254 [M+H]+ H-NMR (400 MHz, CDCl3, ppm): 1.51 (s, 12H), 6.53 (d, J=6.6 Hz, 1H), 7.15 (m, 1H), 7.73 (m, 1H).
With bromine In acetic acid at 20℃; for 3h; Cooling with ice;
2-Amino-4-bromo-6-chlorobenzo[d]thiazole (S1)
To an ice-cooled mixture of 2-bromo-4-chloroaniline (15.5 g, 75.1 mmol), ammonium thiocyanate (23.0 g, 0.302 mol) in acetic acid (100 mL) was added dropwise a solution of bromine (7.8 mL, 0.152 mol) in acetic acid (20 mL) over 1 h. After stirring at room temperature for 2 h, the yellow insoluble material was collected by filtration. The yellow cake was suspended in water, and the pH was adjusted to 11 by adding potassium carbonate. The insoluble material was collected again, and the cake was purified by flash column chromatography on silica gel (Hexane:AcOEt = 3:1) to give the title compound as a yellow solid (14.2 g, 70%). Mp 261-262 °C. 1H NMR (400 MHz, CDCl3) δ 7.49 (1H, d, J = 1.8 Hz), 7.81 (1H, d, J = 1.8 Hz), 7.96 (2H, brs). 13C NMR (100 MHz, DMSO-d6) δ 110.1, 120.1, 124.5, 127.9, 132.5, 149.9, 167.6. IR (ATR) nmax 3444, 3276, 3061, 1638, 1530, 1428, 1384, 1315, 1267, 1122, 1103 cm-1. MS (ESI) 262 (M+H)+. HRMS (ESI) calcd for C7H5BrClN2S (M+H)+ 262.90453, found 262.90410.
2-bromo-4-chlorobenzenediazonium tetrafluoroborate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With tert.-butylnitrite; In tetrahydrofuran; dichloromethane; at -20 - 0℃; for 0.583333h;
General procedure: To a stirred solution of 1 (22.8 mmol) in CH2Cl2 (65 mL) BF3·OEt2(6.81 g, 47.9 mmol, 2.1 equiv) was added. After stirring for 5 min, dryTHF (10 mL) was added to give clear solution followed by cooling to-20 C. t-Butyl nitrite (2.94 g, 22.8 mmol, 1.0 equiv) in CH2Cl2 (7 mL)was added and the reaction mixture was warmed to 0 C over 30 min.The formed precipitate was filtered, washed with Et2O (25 mL) anddried under reduced pressure affording pure 3
With tert.-butylnitrite; trimethylsilylazide; In acetonitrile; at 0 - 20℃; for 72h;
At 0C, 2.75 g (26.6 mmol) of tert-butyl nitrite were added dropwise to a solution of 5.00 g (24.2 mmol) of <strong>[873-38-1]2-bromo-4-chloroaniline</strong> and 3.35 g (29.1 mmol) of trimethylsilyl azide in 120.0 ml ofacetonitrile. The mixture was then brought to RT and stirred for another 72 hours, The mixture was then concentrated and the residue was purified by flash silica gel chromatography (dichioromethane). Yield: 5.60 g (99% of theory).?H-NMR (400 MHz, DMSO-d6): oe [ppm] = 7.80 (s, 1H), 7.58-7.52 (m, 1H), 7.47-7.44 (m, 1H).
To a suspension of <strong>[873-38-1]2-bromo-4-chloroaniline</strong> (5g, 24.22 mmol) in HCl (36.5%wt, 30 mL, 365 mmol) and water (100 mL) at -5C, a solution of sodium nitrite (1.838 g, 26.6 mmol) in water (10 mL) was added dropwise. The mixture was stirred at -5C for 1 h, and the suspension turn into a clear solution. A solution of sodium azide (1.732 g, 26.6 mmol) in water (10 mL) was added dropwise to the reaction. Solids precipitated out from the solution during the addition. It was stirred at -5C for 0.5 h. The mixture was extracted with ethyl acetate (70 mL x 3). The combined organic layers were washed with saturated aqueous sodium bicarbonate (20 mL), water (40 mL) and brine (50 mL) sequentially. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound.
3-bromo-5-chloro-N-(2-bromo-4-chlorophenyl)-2-nitroaniline[ No CAS ]
3-bromo-5-chloro-N-(2-bromo-4-chlorophenyl)-2-nitrosoaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%; 29%
With potassium tert-butylate; In N,N-dimethyl-formamide; at -65℃;
General procedure: To a cooled solution of t-BuOK (6 mmol, 672 mg) in DMF (12 mL) was added dropwise at 65 C a solution of aniline 1 (2 mmol), then nitroarene 2 (2 mmol) in DMF (2 mL each). The mixture was stirred at this temperature for 20-60 min or, in a few cases, the cooling bath was removed and the mixture was allowed to reach room temperature (see Table 1). The reaction mixture was then poured into a concentrated NH4Cl solution (ca. 50 mL) and extracted with EtOAc. The extract was washed thoroughly with water and brine, and dried with Na2SO4. After evaporation, the crude product was subjected to column chromatography (SiO2,hexane/AcOEt, hexane/CH2Cl2 or hexane/toluene) to isolate 3 and/or 4.
tert-butyl 4-methoxy-2-[5-methoxy-2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl]butanoate[ No CAS ]
tert-butyl 2-[4-(2-amino-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; at 80℃; for 72h;Inert atmosphere;
18 ml of dioxane were added to 350 mg (1.70 mmol) of <strong>[873-38-1]2-bromo-4-chloroaniline</strong>, 718 mg (1.70 mmol) of tert-butyl 4-methoxy-2-[5-methoxy-2-oxo-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-1 (2H)-yl]butanoate (racemate) and 703 mg (5.09 mmol) of potassium carbonate. For 5mm, argon was passed through the reaction mixture. 83.1 mg (102 rmo1) of [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex were then added, and the mixture was stirred at 80C for 3 days. The reaction mixture was filtered through kieselguhr, washing with dichloromethane and acetonitrile, and the filtrate was concentrated. The crnde product was purified by normal phase chromatography (mobile phase: cyclohexane/ethylacetate, 50-100%). Yield: 674 mg (89% pure, 84% of theory).LC/MS [Method 10]: R = 1,81 mm; MS (ESIpos): m/z = 423 (M+H).
With potassium tert-butylate; copper(I) bromide; In tetrahydrofuran; at 60℃; for 4h;Schlenk technique;
General procedure: A mixture of 2-iodoanilines (1.0 mmol), THF (3 mL), and t-BuOK (3 mmol) was stirred in a 10-mL sealed Schlenk tube for 5 min, and then dimethylthiocarbamoyl chloride (1.2 mmol) and CuBr (10 mol %) were added. The reaction mixture was heated at 60 C until completion as indicated by TLC. Then the mixture was cooled down to room temperature and quenched with sat. NH4Cl solution (5 mL). The aqueous phase was extracted with EtOAc (3 x10 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure. The obtained crude product was purified by flash column chromatography.
benzyl 4-(((2-bromo-4-chlorophenyl)amino)methyl)-4-hydroxypiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With lithium perchlorate; In acetonitrile; at 90℃; for 18h;
General procedure: A mixture of <strong>[77211-75-7]benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate</strong> (247 mg, 1.0 mmol), 2-bromo-4-methoxyaniline (303 mg, 1.5 mmol) and lithium perchlorate (190 mg, 1.7 mmol) were taken in acetonitrile (3.0 mL). The reaction mixture was heated to 90 C for 18 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the product was purified by column chromatography (silica gel, 50% EtOAc/hexanes) to provide benzyl 4-(((2-bromo-4-methoxyphenyl)amino)methyl)-4-hydroxypiperidine-1-carboxylate, 5c (358 mg, 80%) as a colourless syrup.
With sodiumsulfide nonahydrate; In N,N-dimethyl-formamide; at 110℃; for 15h;Sealed tube; Inert atmosphere;
General procedure: A sealed tube (50 mL) was charged with 2-haloaniline 1a (2mmol), CS2 (10 mmol), Na2S (4mmol) and DMF (2 mL) at room temperature under an argon gas atmosphere and the tube was flushed with argon for three times and sealed. Then the mixture was stirred electromagnetically at 110 C for 12 hours. The reaction process was monitored by TLC on silica gel. After the reaction was completed, the reaction mixture was cooled to room temperature, 2 mL HCl (3 mol/L) was added and stirred for 30 minutes. Then the reaction mixture solution was extracted by dichloromethane (3*20 mL). Subsequently, the combined organic solution were dried by anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel colum chromatography (eluent: petroleum ether / ethyl acetate) give the corresponding pure product 2a.
N-(2-bromo-4-chlorophenyl)-1-hydroxynaphthalene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With phosphorus trichloride; In chlorobenzene; at 130℃; for 0.25h;Microwave irradiation;
General procedure: 1-Hydroxynaphthalene-2-carboxylic acid (5.3 mmol) and the corresponding substituted aniline (5.3 mmol) were suspended in 30 mL of dry chlorobenzene. Phosphorous trichloride (2.65 mmol) was added dropwise, and the reacting mixture was heated in the microwave reactor at maximal allowed power 500 W and 130 C, using infrared flask-surface control of temperature, for 15 min. The solvent was evaporated under reduced pressure, the solid residue washed with 2 M HCl, and the crude product was recrystallized from aqueous ethanol. All the studied compounds are presented in Table 1.
With 4-(diphenylphosphino)morpholine; copper(II) bis(trifluoromethanesulfonate); acetic acid; bis-[(trifluoroacetoxy)iodo]benzene; isopentyl nitrite; In acetonitrile; at 50℃; for 8h;Inert atmosphere;
Under the protection of inert gas, the reactor was added 10ml volume ratio of 2: 1 acetic acid and acetonitrile mixed organic solution1 mmol of the compound of the above formula (I-2), 1.2 mmol of the compound of the formula (II-2), 0.1 mmol of the catalyst of copper trifluoromethanesulfonate, 0.1 mmol of the cocatalyst, 2 mmoll bis (trifluoroacetate) iodobenzene, and then 1.5 mmol of isoamyl nitrite were added to the reaction solution. The temperature was raised to 50 C with stirring, and the reaction was stirred at this temperature for 8 hours. After completion of the reaction, all the volatiles were removed in vacuo and the product was extracted with ethyl acetate. The organic phase was freed from the solvent and the resulting residue was subjected to silica gel column chromatography on 300-400 mesh. The elution solvent was a mixture of petroleum ether and acetic acid Ethyl ester, the compound of the above formula (III-3) was obtained in a yield of 91.6%.
5-(4-chloro-2-bromophenyl)furan-2-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
General procedure: Method A: To a solution of 3a (150 mg, 0.47 mmol) in a mixture of dry DME (3 mL) and dry EtOH (3 mL), bis(triphenylphosphine)palladium(II) dichloride (17 mg, 0.02 mmol) was added. After 30 min, a solution of sodium carbonate (299 mg, 2.82 mmol) in H2O(2 mL) and a solution of 5-formyl-2-furanylboronic acid 4 (93 mg,0.66 mmol) in dry EtOH (1.5 mL) were added in this order. The reaction was heated under reflux for 12 h. After this time, H2O (4 mL)was added at 25 C and the organic phase was extracted with EtOAc(3 5 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (2% EtOAc in petroleum ether) to give 5a as orange solid(79 mg, 60%). Method B: To a suspension of 16a (1.0 g, 4.8 mmol) in H2O (20 mL), HCl (37%, 2 mL) was added. The resulting solution was cooled at 0 C and a solution of sodium nitrite (397 mg, 5.76 mmol) in H2O (2 mL) was added dropwise. After 1 h, a solution of 17(400 mL, 4.8 mmol) in acetone (2 mL) and solid copper(II) chloride(128 mg, 0.96 mmol) were added. The mixture kept at 25 C for 12 h. EtOAc was added (3 10 mL) and the organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (2% EtOAc in petroleum ether) to give 5a as orange solid (1.23 g, 90%).
4-((2-bromo-4-chlorophenyl)amino)-2-butanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With iodine; In dimethyl sulfoxide; at 20℃; for 8h;Inert atmosphere;
Adding magnetons in sequence in a 25 mL reaction flask,0.1 mmol I2, 1 mmol 4-hydroxy-2-butanone,1mmol <strong>[873-38-1]4-chloro-2-bromoaniline</strong> and 2mL dimethyl sulfoxide,The reaction system was reacted in a nitrogen atmosphere at room temperature for 8 h.The reaction solution was extracted with water, and the organic layer was combined and washed three times with saturated brine, dried over anhydrous sodium sulfate, and evaporated and evaporated.Ethyl ester / petroleum ether = 1:4) gave 4-((2-bromo-4-chlorophenyl)amino)-2-butanone as a yellow oil, yield 76% (209.7mg)
76%
With iodine; In dimethyl sulfoxide; at 20℃; for 8h;
General procedure: A 25 mL RBF was subsequently charged with 1.0 mmol aromatic amines, 1.0 mmol 4-hydroxybutan-2-one, 10 mol% I2 (25.4 mg), 2mL DMSO. The resulting mixture was performed at room temperature for 8 h. After reaction was complete, the resulting mixturewas poured into water (20 mL) and extracted with ethyl acetate (3 x10 mL). The combined organic extracts were washed with brine (3 5 mL), then dried over Na2SO4 and concentrated in vacuum. The resulting residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether 1:20-1:4) to afford the desired products.
With toluene-4-sulfonic acid; In neat (no solvent); at 50℃; for 48h;Sealed tube;
General procedure: beta-Ketoester (1 equiv), 2-bromo-4-chloroaniline (1.2 equiv) and p-TSA (0.1 equiv) were stirred in a sealed reaction vessel at 50 C forapproximately 48 h. The mixture was transferred to a flask and refluxedbriefly in cyclohexane. The solid was filtered off and the solvent wasevaporated. The residue was dissolved in diphenyl ether (5 mL) and thesolution was heated in a microwave reactor at 250 C for 45 min. Excesshexane was added and the product was collected the next day by filtration.The compounds were recrystallized from chloroform/hexane toremove traces of diphenyl ether.
In N,N-dimethyl acetamide at 150℃; for 0.0833333h; Microwave irradiation;
General procedure: In a 20mL microwave reaction vial (Biotage), a mixture of substituted 2-halogeno-aniline (1 equiv, 500 mg), O-isopropylxanthic acid potassium salt (PIX) (2 equiv), and DMAC (8 mL) was added. The vial was irradiated at 150 °C for 5 min in a Biotage microwave reactor. The mixture was cooled to room temperature. Then it was poured into cold H2O and adjusted to pH 3 by HCl 1N. The precipitate was filtered and washed (5 times) with H2O to afford products without additional purification.
1-(2-bromo-4-chlorophenyl)-5-(3-(trifluoromethyl)phenyl)-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With potassium carbonate In methanol Reflux;
77%
Stage #1: 3-Trifluoromethylbenzaldehyde; 4-chloro-2-bromoaniline In methanol at 20℃; for 1h;
Stage #2: [(p-methylphenyl)sulfonylmethyl]isonitrile With potassium carbonate In methanol at 60℃; for 7h;
1.1; 6.1 Example 6
(1) Add aryl aldehyde (2mmol) and o-bromo or o-iodoaniline (2mmol) to a 50mL flask containing anhydrous methanol (10mL), stir at room temperature for 1h, and then add TosMIC isonitrile reagent (3mmol), K2CO3(3mmol), react in an oil bath at 60°C for 7h; after the reaction is completed, the solvent is distilled off under reduced pressure, and then purified by column chromatography (the eluent is a mixed solvent of ethyl acetate and petroleum ether, ethyl acetate and petroleum ether The volume ratio is 1:9) to obtain the intermediate compound A-5, which is a light yellow liquid, the yield is 0.616 g, and the yield is 77%. The compound structure detection result is:
(Z)-2-((Z)-(2-bromo-4-chlorophenyl)diazenyl)-2-nitroethen-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: 4-chloro-2-bromoaniline With hydrogenchloride; sodium nitrite In water at 0℃; for 1h;
Stage #2: (E)-N,N-dimethyl-2-nitroethenamine In acetonitrile at 0 - 20℃; for 16h;
Step 1 &2. To a solution of 2-bromo-4-chloroaniline (4.85 g,23.5 mmol) in 4.0M HCl (23.5 mL) was added a 4 mL H 2O solution of NaNO 2(1.62 g,23.5 mmol) slowly at 0 . The mixture was stirred at 0 for 1 hour. And then a solution of (E)-N,N-dimethyl-2-nitroethen-1-amine (3.00 g,25.9 mmol) in acetonitrile (15 mL) was added at 0 . The reaction mixture was allowed to warm to r.t. and stirred for 16 h. The reaction mixture was diluted with water (100 mL) . The resulting suspension was filtered. The filter cake was washed with cold Et 2O (50 mL) and dried to give (Z)-2-((Z)-(2-bromo-4-chlorophenyl)diazenyl)-2-nitroethen-1-ol (5.40 g, 17.7 mmol, 75.0 %) as an orange solid. 1H NMR (400 MHz, DMSO-d 6) : δ 13.7(br s, 1H) , 11.1 (s, 1H) , 7.97(d, J = 2.0 Hz, 1H) , 7.75(d, J = 8.8 Hz, 1H) , 7.66 -7.63 (m,2H) .
With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 110℃; for 4h;
36 Preparation of Compound 197-1
After dissolving Compound 148-2 (20 g, 60.4 mmol) in 1,4-dioxane and H2O, 2-bromo-4-chloroaniline (12.4 g, 1 eq.), Pd(PPh3)4 (4.1 g, 0.05 eq.) and K2CO3 (30.8 g, 3.0 eq.) were added thereto, and the mixture was stirred for 4 hours at 110° C. After the reaction was completed, the result was cooled to room temperature, and then extracted with distilled water and EA. After drying the organic layer with anhydrous MgSO4, the solvent was removed using a rotary evaporator, and the result was purified by column chromatography using ethyl acetate and dichloromethane as a developing solvent to obtain target Compound 197-1 (14.9 g, 75%).
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