* 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] Chemical Communications, 2011, vol. 47, # 23, p. 6635 - 6637
5
[ 174265-12-4 ]
[ 3970-52-3 ]
[ 3970-51-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 16013 - 16017[2] Angew. Chem., 2017, vol. 129, p. 16229 - 16233,5
6
[ 174265-12-4 ]
[ 935-99-9 ]
Reference：
[1] Organic Letters, 2015, vol. 17, # 22, p. 5566 - 5569
[2] Journal of the American Chemical Society, 2016, vol. 138, # 42, p. 13830 - 13833
[3] Tetrahedron Letters, 2017, vol. 58, # 4, p. 285 - 288
[4] Journal of Organic Chemistry, 2017, vol. 82, # 21, p. 11585 - 11593
[5] Chemistry - An Asian Journal, 2018, vol. 13, # 15, p. 1897 - 1901
7
[ 174265-12-4 ]
[ 60666-70-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium tetrahydroborate In methanol at 0 - 20℃; for 1 h;
Step 1: (2-Bromo-5-chlorophenyl)methanol To a stirred suspension of 2-bromo-5-chlorobenzaldehyde (4.48 g, 20.4 mmol) in MeOH (50 mL) was added NaBH4(1.16 g, 30.7 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min, then allowed to warm to room temperature and stirred for an additional 30 min. TLC analysis indicated complete consumption of starting material. The solvent was removed and then NH4C1 (aq. satd., 30 mL) was added to quench the reaction. The mixture was extracted with CH2CI2(3x50 mL). The combined organic phases were washed with NaCl (aq. satd.,100 mL) and dried over Na2S04. The solvent was concentrated to yield the title compound as an oil (4.55 g, quant.) which was used in the next step without further purification. 1H NMR (500 MHz, acetone-6) δ ppm 4.64 (br. s, 1H), 4.65 (s, 2H), 7.24 (dd, J=8.4, 2.7 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.62 (d, J=2.5 Hz, 1H)
95%
With sodium hydride In methanol at 20℃;
PREPARATION 172 (2-Bromo-5-chlorophenyl)methanol Sodium borohydride (0.17 g, 4.56 mmol) was suspended in 15 ml methanol. 2-Bromo- 5-chlorobenzaldehyde (1 g, 4.56 mmol) dissolved in 10 ml methanol was added drop- wise and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was re-dissolved in ethyl acetate. The organics were washed sequentially with water and brine. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure to give 0.97 g (4.34 mmol, 95percent) of the title compound as a white solid. Purity 99percent. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .98 (t, J=5.67 Hz, 1 H), 4.73 (d, J=5.47 Hz, 2 H), 7.15 (dd, J=8.60, 2.74 Hz, 1 H), 7.47 (d, J=8.60 Hz, 1 H), 7.53 (d, J=2.34 Hz, 1 H). UPLC/MS (3 min) retention time 1 .55 min. LRMS: m/z Molecular ion not detected.
94%
With sodium borohydrid In methanol; water; acetone
Example 73 Synthesis of 2-bromo-5-chlorobenzyl alcohol 2-Bromo-5-chlorobenzaldehyde (20.5 g) from Example 72 was dissolved with dry methanol (200 ml), followed by sodium borohydride (1.06 g) at 0° C., and the mixture was stirred for 30 minutes. After addition of acetone, the solvent was removed under reduced pressure, water was added the obtained residue, and then extracted with ether. The organic layer was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, to give the title compound (19.5 g; 94percent)
Reference：
[1] Patent: WO2016/25932, 2016, A1, . Location in patent: Page/Page column 183
[2] Patent: WO2013/10880, 2013, A1, . Location in patent: Page/Page column 164
[3] Patent: US5587392, 1996, A,
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 19, p. 6108 - 6115
[5] Tetrahedron, 2015, vol. 71, # 42, p. 8172 - 8177
8
[ 174265-12-4 ]
[ 57381-37-0 ]
Reference：
[1] Tetrahedron Letters, 2018, vol. 59, # 29, p. 2844 - 2847
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 42, p. 7959 - 7963
9
[ 60666-70-8 ]
[ 174265-12-4 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 55℃; for 1 h; Microwave irradiation
General procedure: The benzyl alcohols substrates (1a–1p) (0.2mmol), FeCl3·6H2O (0.002mmol, 5.4mg) and triphenylmethanol 2 (0.2mmol, 52mg) were mixed in a dried vessel. Then the reaction was irradiated under the microwave at 55°C for 1h. The crude mixture was purified by a flash column chromatography to afford the benzaldehydes (4a–4p).
85%
at 140℃; for 1 h; Microwave irradiation
General procedure: To 10 mL of a microwave tube was added benzyl alcohol (0.5 mmol, 61.2 mg) and triphenylmethanol (0.5 mmol,(0.015 mmol, 11 mg) was added, the reaction mixture was heated to 120 ° C with a microwave reactor, and the reaction was stirred for 60 minutes. After completion of the reaction, the reaction product was separated by flash column chromatography to obtain the desired product I, 92percent.Substitution of 37.0 mg of Ph3PAuNTf2 for 11 mg of Ph3PAuNTf2,In the same manner as in Example 1,The target compound I,Yield 96percent.2-bromo-5-chlorobenzyl alcohol was used in place of 2-bromo-5-fluorobenzyl alcohol,In the same manner as in Example 4,The target compound V,Yield 85percent.
Reference：
[1] Chemical Communications, 2018, vol. 54, # 20, p. 2467 - 2470
[2] Tetrahedron, 2015, vol. 71, # 38, p. 6744 - 6748
[3] Patent: CN104817441, 2017, B, . Location in patent: Paragraph 0034-0037; 0041; 0055-0057
[4] Journal of the American Chemical Society, 2011, vol. 133, # 20, p. 7916 - 7925
[5] Patent: US9540357, 2017, B1, . Location in patent: Page/Page column 68
10
[ 66192-24-3 ]
[ 174265-12-4 ]
Yield
Reaction Conditions
Operation in experiment
92%
With 4-methylmorpholine N-oxide In acetonitrile at 0℃; for 2 h; Molecular sieve
Step 2: 2-bromo-5-chlorobenzaldehyde; 2-bromo-5-chlorobenzaldehyde was prepared according to literature precedent (/. Am. Chem. Soc. 2002, 124 (7), 1354): a mixture of activated powdered 4A molecular sieves (800 mg/mmol substrate), N- methylmorpholine-N-oxide (2 eq) and 2-bromomethyl-5-chlorobenzaldehyde (1 eq) in MeCN (0.16 M) was stirred at 0 0C for 2 h. The reaction was then filtered through a pad of celite and concentrated in vacuo to afford the title compound (92 percent)
Reference：
[1] Patent: WO2006/46030, 2006, A2, . Location in patent: Page/Page column 28
[2] Journal of the American Chemical Society, 2002, vol. 124, # 7, p. 1354 - 1363
11
[ 587-04-2 ]
[ 174265-12-4 ]
Yield
Reaction Conditions
Operation in experiment
90.1%
at 10 - 25℃; for 3 h;
Concentrated sulfuric acid (mass fraction 98percent, 150mL) was added to the reactor to reduce the temperature.The temperature of the system is ≤ 10°C, the compound A liquid (3-chlorobenzaldehyde, 0.5 mol) is slowly added dropwise, and after addition, an appropriate amount of catalyst I2 (0.236-2.36 mmol, 30 mg in this example) is added.When 3-chlorobenzaldehyde and catalyst 12 were added, there was a clear exothermic phenomenon and the reaction temperature of the system was controlled to be ≤ 10°C; System temperature control ≤15°C, add in batches 5-10 timesNBS (N-bromosuccinimide, 0.5 mol); Insulation reaction for 2h, slowly rise to 25 °C, and stir the reaction for 1h,GC detection of raw materials 3_ chlorobenzaldehyde content ≤ 1 percent,The reaction solution was purified by post-treatment to obtain an acicular off-white solid compound (98 g, purity 98.0percent, yield 90.1 percent).
Reference：
[1] Patent: CN107879918, 2018, A, . Location in patent: Paragraph 0034-0037; 0058-0065; 0070-0085
[2] Journal of the American Chemical Society, 2017, vol. 139, # 2, p. 888 - 896
[3] Journal of Organic Chemistry, 2011, vol. 76, # 15, p. 6414 - 6420
12
[ 882772-93-2 ]
[ 174265-12-4 ]
Yield
Reaction Conditions
Operation in experiment
83%
With sulfuric acid In methanol; water for 0.5 h; Reflux
(2-Bromo-5-chlorophenyl)methanediyl diacetate(1.5 g, 4.7 mmol) was refluxed in MeOH–H2O (15 mL, 1/1 V/V) containing H2SO4 (1.6 mL)for 30 min. The reaction mixture was then diluted with H2O (15 mL) and extracted withEtOAc (3×20 mL). The combined organic layers were washed with H2O (20 mL) and brine(20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue and 1 Mhydrochloric acid (4.0 mL) were heated for 3 h in THF (15 mL) under reflux. The solvent wasremoved under reduced pressure. The residue was purified by column chromatography (SiO2,hexane/EtOAc = 95/5). Yield: 0.84 g, 83 percent.
Reference：
[1] Journal of the Serbian Chemical Society, 2015, vol. 80, # 7, p. 839 - 852
[2] Journal of Agricultural and Food Chemistry, 2008, vol. 56, # 13, p. 5247 - 5253
13
[ 14495-51-3 ]
[ 1333-82-0 ]
[ 174265-12-4 ]
Yield
Reaction Conditions
Operation in experiment
77%
With sulfuric acid In ethanol; water; acetic anhydride
Example 72 Synthesis of 2-bromo-5-chlorobenzaldehyde To the solution of 2-bromo-5-chlorotoluene (25 g) in acetic anhydride (100 ml) and sulfuric acid (20 ml) was added dropwise chromium(VI) oxide (36.5 g) in acetic anhydride (200 ml) for 3 hours at -15° C. The mixture was stirred for 1 hour at -5° C. and then poured into ice-cooled water, and extracted with ether. The organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was suspended in ethanol (100 ml) and 3N-HCl (200 ml) and refluxed for 1 hour. After removal of the solvent, water was added to the residue, and extracted with ether. The organic layer was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by chromatography on a silica gel column (hexane:methylene chloride=4:1) to give the title compound (20.5 g; 77percent).
Reference：
[1] Patent: US5587392, 1996, A,
14
[ 7775-19-1 ]
[ 174265-12-4 ]
Reference：
[1] Patent: US2012/261615, 2012, A1,
15
[ 1313762-49-0 ]
[ 174265-12-4 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 23, p. 6635 - 6637
16
[ 13780-71-7 ]
[ 174265-12-4 ]
Reference：
[1] Patent: US2012/313083, 2012, A1,
17
[ 14495-51-3 ]
[ 174265-12-4 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 23, p. 6635 - 6637
[2] Journal of the Serbian Chemical Society, 2015, vol. 80, # 7, p. 839 - 852
18
[ 21739-93-5 ]
[ 174265-12-4 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 20, p. 7916 - 7925
[2] Chemical Communications, 2018, vol. 54, # 20, p. 2467 - 2470
19
[ 33499-36-4 ]
[ 174265-12-4 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 15, p. 6414 - 6420
20
[ 174265-12-4 ]
[ 536-74-3 ]
[ 1186603-47-3 ]
Reference：
[1] Organic Letters, 2011, vol. 13, # 9, p. 2228 - 2231
[2] Organic and Biomolecular Chemistry, 2012, vol. 10, # 9, p. 1922 - 1930
[3] Chemistry - A European Journal, 2015, vol. 21, # 50, p. 18122 - 18127
[4] Advanced Synthesis and Catalysis, 2013, vol. 355, # 2-3, p. 559 - 568
[5] Chemical Communications, 2013, vol. 49, # 96, p. 11320 - 11322
[6] Journal of the American Chemical Society, 2015, vol. 137, # 3, p. 1165 - 1180
[7] Journal of Organic Chemistry, 2015, vol. 80, # 15, p. 7635 - 7641
[8] Organic Letters, 2015, vol. 17, # 16, p. 4018 - 4021
[9] Journal of Organic Chemistry, 2014, vol. 79, # 21, p. 10674 - 10681
[10] Chemistry - A European Journal, 2016, vol. 22, # 27, p. 9125 - 9129
[11] Patent: CN105330663, 2016, A, . Location in patent: Paragraph 0038; 0039; 0040
[12] Chemical Communications, 2017, vol. 53, # 85, p. 11666 - 11669
[13] Organic Letters, 2017, vol. 19, # 19, p. 5070 - 5073
[14] Organic Letters, 2017, vol. 19, # 21, p. 5856 - 5859
[15] Angewandte Chemie - International Edition, 2017, vol. 56, # 49, p. 15570 - 15574[16] Angew. Chem., 2017, vol. 129, p. 15776 - 15780,5
[17] Advanced Synthesis and Catalysis, 2018, vol. 360, # 15, p. 2825 - 2830
With sulfuric acid; In ethanol; water; acetic anhydride;
Example 72 Synthesis of 2-bromo-5-chlorobenzaldehyde To the solution of <strong>[14495-51-3]2-bromo-5-chlorotoluene</strong> (25 g) in acetic anhydride (100 ml) and sulfuric acid (20 ml) was added dropwise chromium(VI) oxide (36.5 g) in acetic anhydride (200 ml) for 3 hours at -15 C. The mixture was stirred for 1 hour at -5 C. and then poured into ice-cooled water, and extracted with ether. The organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was suspended in ethanol (100 ml) and 3N-HCl (200 ml) and refluxed for 1 hour. After removal of the solvent, water was added to the residue, and extracted with ether. The organic layer was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by chromatography on a silica gel column (hexane:methylene chloride=4:1) to give the title compound (20.5 g; 77%).
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1h;
Step 1: (2-Bromo-5-chlorophenyl)methanol To a stirred suspension of 2-bromo-5-chlorobenzaldehyde (4.48 g, 20.4 mmol) in MeOH (50 mL) was added NaBH4(1.16 g, 30.7 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min, then allowed to warm to room temperature and stirred for an additional 30 min. TLC analysis indicated complete consumption of starting material. The solvent was removed and then NH4C1 (aq. satd., 30 mL) was added to quench the reaction. The mixture was extracted with CH2CI2(3x50 mL). The combined organic phases were washed with NaCl (aq. satd.,100 mL) and dried over Na2S04. The solvent was concentrated to yield the title compound as an oil (4.55 g, quant.) which was used in the next step without further purification. 1H NMR (500 MHz, acetone-6) delta ppm 4.64 (br. s, 1H), 4.65 (s, 2H), 7.24 (dd, J=8.4, 2.7 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.62 (d, J=2.5 Hz, 1H)
95%
With sodium hydride; In methanol; at 20℃;
PREPARATION 172 (2-Bromo-5-chlorophenyl)methanol Sodium borohydride (0.17 g, 4.56 mmol) was suspended in 15 ml methanol. 2-Bromo- 5-chlorobenzaldehyde (1 g, 4.56 mmol) dissolved in 10 ml methanol was added drop- wise and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was re-dissolved in ethyl acetate. The organics were washed sequentially with water and brine. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure to give 0.97 g (4.34 mmol, 95percent) of the title compound as a white solid. Purity 99percent. 1 H NMR (400 MHz, CHLOROFORM-d) delta ppm 1 .98 (t, J=5.67 Hz, 1 H), 4.73 (d, J=5.47 Hz, 2 H), 7.15 (dd, J=8.60, 2.74 Hz, 1 H), 7.47 (d, J=8.60 Hz, 1 H), 7.53 (d, J=2.34 Hz, 1 H). UPLC/MS (3 min) retention time 1 .55 min. LRMS: m/z Molecular ion not detected.
94%
With sodium borohydrid; In methanol; water; acetone;
Example 73 Synthesis of 2-bromo-5-chlorobenzyl alcohol 2-Bromo-5-chlorobenzaldehyde (20.5 g) from Example 72 was dissolved with dry methanol (200 ml), followed by sodium borohydride (1.06 g) at 0° C., and the mixture was stirred for 30 minutes. After addition of acetone, the solvent was removed under reduced pressure, water was added the obtained residue, and then extracted with ether. The organic layer was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, to give the title compound (19.5 g; 94percent)
With palladium diacetate; Cs2CO3; triphenylphosphine In tetrahydrofuran; lithium hydroxide monohydrate at 70℃;
86%
With palladium diacetate; Cs2CO3; triphenylphosphine In tetrahydrofuran; lithium hydroxide monohydrate at 70℃; for 16h; Inert atmosphere;
81%
With Cs2CO3; triphenylphosphine; palladium (II) chloride In tetrahydrofuran; lithium hydroxide monohydrate at 85℃; for 22h; sealed tube; Inert atmosphere;
80%
With Cs2CO3; triphenylphosphine; palladium (II) chloride In tetrahydrofuran; lithium hydroxide monohydrate at 85℃; for 6h; Sealed tube;
5-Chloro-2-vinylbenzaldehyde (MDW-1-75)
According to a literature procedure, a resealable tube was charged with 2-bromo-5-chlorobenzaldehyde (1.800 g, 27.34 mmol), potassium vinyltrifluoroborate (1.428 g, 10.66 mmol), PdC12 (0.117 g, 0.660 mmol),triphenylphosphine (0.517 g, 1.97 mmol), and cesium carbonate (8.022 g, 24.62 mmol).’ A solution of degassed THF/water (20.5 mL, 9:1) was added to the tube, whereupon it was sealed and stirred at 85 °C for 6 h. The reaction mixture was allowed to cool to room temperature, diluted with water (30 mL), and extracted using Et20 (3 x 30 mL). The organic layer was washed with brine (1 x 30 mL), dried (Na2SO4), and concentrated under reduced pressure toprovide an orange oil. The crude residue was purified via flash chromatography (Si02), eluting with 1 hexanes/EtOAc (99:1) affording 1.091 g (80%) of MDW-1-75 as a pale yellow solid. ‘H NMR consistent with those reported in literature
80%
With Cs2CO3; triphenylphosphine; palladium (II) chloride In tetrahydrofuran; lithium hydroxide monohydrate
With palladium diacetate; Cs2CO3; triphenylphosphine In tetrahydrofuran; lithium hydroxide monohydrate at 20 - 90℃;
With palladium diacetate; Cs2CO3; triphenylphosphine In tetrahydrofuran; lithium hydroxide monohydrate at 70℃; for 4h;
With palladium diacetate; Cs2CO3; triphenylphosphine In tetrahydrofuran; lithium hydroxide monohydrate at 70℃; for 4h; Inert atmosphere;
With triphenylmethyl alcohol; iron(III) chloride hexahydrate; at 55℃; for 1h;Microwave irradiation;
General procedure: The benzyl alcohols substrates (1a?1p) (0.2mmol), FeCl3·6H2O (0.002mmol, 5.4mg) and triphenylmethanol 2 (0.2mmol, 52mg) were mixed in a dried vessel. Then the reaction was irradiated under the microwave at 55°C for 1h. The crude mixture was purified by a flash column chromatography to afford the benzaldehydes (4a?4p).
85%
With triphenylmethyl alcohol; [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I); at 140℃; for 1h;Microwave irradiation;
General procedure: To 10 mL of a microwave tube was added benzyl alcohol (0.5 mmol, 61.2 mg) and triphenylmethanol (0.5 mmol,(0.015 mmol, 11 mg) was added, the reaction mixture was heated to 120 ° C with a microwave reactor, and the reaction was stirred for 60 minutes. After completion of the reaction, the reaction product was separated by flash column chromatography to obtain the desired product I, 92percent.Substitution of 37.0 mg of Ph3PAuNTf2 for 11 mg of Ph3PAuNTf2,In the same manner as in Example 1,The target compound I,Yield 96percent.<strong>[60666-70-8]2-bromo-5-chlorobenzyl alcohol</strong> was used in place of 2-bromo-5-fluorobenzyl alcohol,In the same manner as in Example 4,The target compound V,Yield 85percent.
Dimethyl sulfoxide (472 muL, 6.10 mmol) was added to a ?78° C. solution of oxalyl chloride (1.47 mL of a 2.0 M solution in CH2Cl2, 2.94 mmol) and CH2Cl2 (4 mL). After 30 min at ?78° C., a solution of <strong>[60666-70-8](2-bromo-5-chlorophenyl)methanol</strong> (500 mg, 2.26 mmol) in CH2Cl2 (2 mL) was added. After 5 min, triethylamine (2.52 mL, 18.0 mmol) was added and the mixture was allowed to warm to 0° C. After 1 hour, the mixture was allowed to warm to room temperature. After 3 hours, the reaction was quenched with saturated aqueous NaHCO3 (60 mL) and extracted with CH2Cl2 (3×50 mL). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford 400 mg of crude 2-bromo-5-chlorobenzaldehyde that was used in the next step without further purification.
With copper(l) iodide; bis(triphenylphosphine)palladium(II) chloride; triethylamine; In tetrahydrofuran;Inert atmosphere; Reflux;
General procedure: (1) intermediate compound 3a-3i synthesis:Taking 1mmol compound 1a-1c, compound 1mmol 2a-2c, 0 . 1mmol CuI of, 0.03mmol the Pd (PPh3)2Cl2and 2mmol triethylamine dissolved in 5 ml of tetrahydrofuran, under the protection of nitrogen, heating to reflux, TLC monitoring of the reaction process, the reaction is complete, the reactant is cooled to room temperature, by adding a proper amount of water, and then divide the liquid extraction, drying, then column chromatography, to obtain compound 3a-3i (the 1 to 2-bromophenylacetic formaldehyde or 2-bromo-5-methyl-phenyl-formaldehyde or 2-bromo-5-chlorobenzene formaldehyde, 2 for phenylacetylene or the methyl acetylene or to paradichlorbenzene acetylene, thus 1a-1c and 2a-2c intermediate obtained by reaction of a compound 9 a).
With N-Bromosuccinimide; sulfuric acid; iodine at 10 - 25℃; for 3h;
1 Example 1
Concentrated sulfuric acid (mass fraction 98%, 150mL) was added to the reactor to reduce the temperature.The temperature of the system is ≤ 10°C, the compound A liquid (3-chlorobenzaldehyde, 0.5 mol) is slowly added dropwise, and after addition, an appropriate amount of catalyst I2 (0.236-2.36 mmol, 30 mg in this example) is added.When 3-chlorobenzaldehyde and catalyst 12 were added, there was a clear exothermic phenomenon and the reaction temperature of the system was controlled to be ≤ 10°C; System temperature control ≤15°C, add in batches 5-10 timesNBS (N-bromosuccinimide, 0.5 mol); Insulation reaction for 2h, slowly rise to 25 °C, and stir the reaction for 1h,GC detection of raw materials 3_ chlorobenzaldehyde content ≤ 1 %,The reaction solution was purified by post-treatment to obtain an acicular off-white solid compound (98 g, purity 98.0%, yield 90.1 %).
88%
With N-Bromosuccinimide; 4-chloro-2-(trifluoromethyl)aniline; palladium diacetate In 1,2-dichloro-ethane; trifluoroacetic acid at 60℃; for 24h;
1.2 General procedure for the synthesis of 3a-3w
General procedure: Compound 1 (0.4 mol), N-bromosuccinimide (NBS) (0.48 mol, 85.4 mg), and Pd(OAc)2(10 mol%, 8.9 mg), 2-Amino-5-chlorobenzotrifluoride (20 mol%, 15.6 mg) were mixed withDCE (2.5 mL) and TFA (0.5 mL) solvent. The reaction mixture was stirred 24 h at 60 °C. Aftercompletion of the reaction, the solution was concentrated in vacuo and purified by columnchromatography on silica gel using PE/DCM/EtOAc as eluent to give the desired product.
80%
With N-Bromosuccinimide; palladium diacetate; silver trifluoroacetate; toluene-4-sulfonic acid; trifluoroacetic acid; 4-Nitroanthranilic acid In 1,2-dichloro-ethane at 90℃; for 24h; Sealed tube;
Multi-step reaction with 3 steps
1: pyridine / dichloromethane / 1 h / 20 °C
2: N-Bromosuccinimide; Ag(1-)*C2F3O2(1-); palladium diacetate / 1,2-dichloro-ethane / 24 h / 120 °C
3: formaldehyd; toluene-4-sulfonic acid / tetrahydrofuran; water / 0.25 h / 100 °C / Microwave irradiation
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 11h;Reflux;
In a four-necked 200 mL round bottomed flask, intermediate A1 (3.6 g, 12 mmol), 2-bromo-5-chlorobenzaldehyde (2.4 g, 11 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol) were placed, and dissolved in dimethoxyethane (40 mL). 20 mL of an aqueous solution of sodium carbonate (3.8 g, 36 mmol) was added to the reaction solution, and the resulting mixture was heated under reflux for 11 hours. After completion of the reaction, water was added. The solid obtained was filtered and washed with water and methanol. The resulting crude product was purified by column chromatography, whereby intermediate A2 was obtained (3.4 g, yield 98%).The intermediate A2 was identified by 1H-NHR (400 MHz, CDCl3). The results are shown below.δ 10.03 (s, 1H), 8.50 (s, 1H), 8.48 (s, 1H), 8.12 (d, J=9 Hz, 1H), 8.06-8.03 (m, 3H), 7.95 (s, 1H), 7.66 (dd, J=8.2 Hz, 1H), 7.57 (d, J=8 Hz, 1H), 7.53-7.47 (m, 3H)
With copper(l) iodide; potassium carbonate; ethylenediamine In N,N-dimethyl-formamide at 110℃; for 3h;
General procedure: To a solution of 2-bromobenzaldehyde (1a, 1 mmol) and 1H-pyrazol-5-amine (2a, 1.2 mmol) in DMF (5 mL) were added K2CO3 (2 mmol), CuI (0.2 mmol) and ethylenediamine(0.2 mmol). The mixture was stirred at 110 °C until a complete conversion as indicated by TLC. It was cooled to room temperature and added with saturated brine, then extracted with ethyl acetate. The combined organic phase was concentrated under vacuum. The crude product was purified by columnchromatography eluting with petroleum ether/ethyl acetate (10:1) to give the desired product 3a. Products 3b-3ll were obtained in a similar manner.
With copper(l) iodide; potassium carbonate; ethylenediamine In N,N-dimethyl-formamide at 110℃; for 5h;
General procedure: To a solution of 2-bromobenzaldehyde (1a, 1 mmol) and 1H-pyrazol-5-amine (2a, 1.2 mmol) in DMF (5 mL) were added K2CO3 (2 mmol), CuI (0.2 mmol) and ethylenediamine(0.2 mmol). The mixture was stirred at 110 °C until a complete conversion as indicated by TLC. It was cooled to room temperature and added with saturated brine, then extracted with ethyl acetate. The combined organic phase was concentrated under vacuum. The crude product was purified by columnchromatography eluting with petroleum ether/ethyl acetate (10:1) to give the desired product 3a. Products 3b-3ll were obtained in a similar manner.
3-chloro-12,12-dimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 10h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
85%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; for 10h;Reflux;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
3-chloro-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
83%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; for 15h;Reflux;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0 mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0 mmol), and DMSO (10 mL). The mixture was stirred at reflux until completion (TLC monitoring). The solid was filtered off, and the filtrate was distilled under reduced pressure to recover the solvent; the residue was purified by chromatography (silica gel, EtOAc-petroleum ether, 1:2) to give 4.
3-chloro-7,12,12-trimethyl-12,13-dihydropyrazolo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With copper(l) iodide; caesium carbonate; In dimethyl sulfoxide; at 100℃; for 16.0h;
General procedure: A 25-mL flask was charged with o-halogenated benzaldehyde 1 (1.0mmol), 1H-indazol-6-amine 2 (133 mg, 1.0 mmol), cyclohexane-1,3-dione 3 (1.0 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (652 mg, 2.0mmol), and DMSO (10 mL). The mixture was stirred at reflux untilcompletion (TLC monitoring). The solid was filtered off, and the filtratewas distilled under reduced pressure to recover the solvent; theresidue was purified by chromatography (silica gel, EtOAc-petroleumether, 1:2) to give 4.
(E)-9-(2-bromo-5-chlorophenyl)-8-[(hydroxyimino)(phenyl)methyl]-8,9-dihydro-1H-pyrazolo[3,4-f]quinolin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
In ethanol at 80℃; for 11h;
8,9-Dihydro-1H-pyrazolo[3,4-f]quinolin-7(6H)-ones 5; General Procedure
General procedure: A dry 25-mL flask was charged with an aromatic aldehyde 1 (1.0 mmol), 1H-indazol-6-amine (2a; 133 mg, 1.0 mmol), a 3-phenylisoxazol-5(4H)-one 3 (1.0 mmol) and EtOH (10.0 mL). The reaction mixture was stirred under reflux for 8-11 h until all the reactant amine was consumed (monitored by TLC). Then, the mixture was allowed to cool to r.t., and the product 5 was collected by filtration without further purification.
2-chloro-12,12-dimethyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 12h;Reflux;
General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature.
2-chloro-12-methyl-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 12h;Reflux;
General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature.
2'-formyl-4,4"-di(2-pyridyl)-1,1':4',1"-terphenyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.3%
With potassium phosphate; palladium diacetate; XPhos; In 1,4-dioxane; at 80℃; for 4h;Inert atmosphere;
Under an argon stream, 1.50 g (6.83 mmol) of 2-bromo-5-chloro-benzoic acid,3.40 g (17.1 mmol) of 4- (2-pyridyl) phenylboronic acid,Palladium acetate 76.7 mg (0.342 mmol),326 mg (0.683 mmol) of 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl,And 32.8 mL (32.8 mmol) of 1M tripotassium phosphate aqueous solution were dissolved in 90 mL of dioxane, and the mixture was heated and stirred at 80 C. for 4 hours. After cooling to room temperature, 900 mL of pure water was added and the mixture was separated and extracted with chloroform. After distilling off the solvent under reduced pressure, the resulting crude product was purified by silica gel column chromatography (developing solvent: chloroform: ethyl acetate = 9: 1) to obtain the desired 2'-formyl-4,4 "-di -pyridyl) -1,1 ': 4', 1 "-terphenyl as a white solid (yield 1.98 g, yield 70.3%).
In dimethyl sulfoxide; at 70℃; for 10h;Inert atmosphere; Schlenk technique;
General procedure: To a schlenk tube (15 mL) containing a solution of <strong>[32566-01-1]2-(1H-indol-2-yl)aniline</strong> 3a (0.4 mmol) in DMSO (2 mL) was added 2-bromobenzaldehyde 4 (0.44 mmol) under nitrogen atmosphere.Then, the reaction mixture was stirred at 70C for 10 h until <strong>[32566-01-1]2-(1H-indol-2-yl)aniline</strong> 3a was consumed completely. Next, Pd(PPh3)2Cl2(0.02 mmol), [(t-Bu)3PH]BF4 (0.06 mmol) and Et3N (1.2 mmol) wereadded into the above reaction system under CO (1 atm) atmo-sphere. After being stirred at 120C for 5 h, the resulting mixturewas quenched with NH4Cl and extracted with ethyl acetate. Thecombined organic layer was washed with H2O and brine, and thendried over anhydrous Na2SO4. The solvent was removed underreduced pressure and the residue was puried by column chro-matography on silica gel (petroleum ether/ethyl acetate 5:1) toafford the corresponding indolo[1,2-c]isoindolo[2,1-a]quinazolin-5(16aH)-one 2.
Add 2-ester benzimidazole (0.5 mmol) and 5-chloro-2-bromobenzaldehyde (0.6 mmol) to the dry Schlenk tube, evacuate nitrogen, and add piperidine (0.05 mmol), 1, 4-Dioxane (2 ml), and the reaction was stirred at room temperature for 3 hours. At room temperature, CuI (0.05 mmol) K2CO3 (1 mmol) and 1,10-phenanthroline (0.1 mmol) were added to the reaction system, and then the mixture was heated to 90 C. and stirred for 8 hours. After stopping the reaction, 15 ml of CH2Cl2 was added to the reaction system, filtered through a sand funnel, and washed with CH2Cl2 three times. The filtrate and washing solution were combined, dried over anhydrous Na2SO4, and concentrated and separated by silica gel column chromatography (eluent: ethyl acetate). Ester: dichloromethane = 30: 1) to obtain the pure product. The material was a yellow solid with a yield of 37%.
With palladium diacetate; sodium carbonate In water; acetone at 20℃; for 12h;
1 Synthesis of compound 71
2-Benzoflanylboronic acid in a round bottom flask(2-Benzofuranylboronic acid) 21.95 g (135.53 mmol),2-Bromo-5-chlorobenzaldehyde (2-bromo-5-chlorobenzaldehyde) 26.77 g (121.98 mmol), Pd (OAc) 2 2.74 g (12.20 mmol), Na2CO3 25.86 g (243.96 mmol) acetoneAfter suspending in 200 ml of (Acetone) and 220 ml of distilled water, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, it is concentrated and extracted with methylene chloride (Methylene Chloride).The organic layer was subjected to a silica gel column (Silicagel colimm) to obtain 21.4 g (Yield 68%) of the target compound, Compound A.
68%
With palladium diacetate; sodium carbonate In water; acetone at 20℃; for 12h;
21.1 1st Step: Synthesis of Int-33
21.95 g (135.53 mmol) of 2-benzofuranylboronic acid, 26.77 g (121.98 mmol) of 2-bromo-5-chlorobenzaldehyde, 2.74 g (12.20 mmol) of Pd(OAc)2, and 25.86 g (243.96 mmol) of Na2CO3 were suspended in 200 ml of acetone/220 ml of distilled water in a round-bottomed flask and then, stirred for 12 hours at ambient temperature. When a reaction was completed, the resultant was concentrated and extracted with methylene chloride, and an organic layer therefrom was silica gel-columned to obtain 21.4 g (Yield: 68%) of Int-33.
With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 110℃; Inert atmosphere;
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 80℃; for 2h; Inert atmosphere;
114.1; 116.1 Step 1:
The title compound was prepared by using the scheme and procedures shown below: [00719] Step 1: To a solution of 2-bromo-5-chlorobenzaldehyde (2.2 g, 10 mmol) and (Bpin)2 (3.8 g 15 mmol) in dioxane (30 mL) was added AcOK (2.94 g, 30.0 mmol) and Pd(dppf)Cl2 (816 mg, 1 mmol) at room temperature under N2 atmosphere. The mixture was then heated to 80 °C for 2h. LCMS indicated the reaction was completed. The mixture was cooled to room temperature, diluted with EtOAc (20 mL), and filtered through a pad of CELITE. The filtrate was concentrated in vacuo and purified by silica chromatography eluting with PE/EtOAc (100:0 to 100:10) to give 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzaldehyde (2.1 g, yield 79%) as a white solid. 1HNMR (400 MHz, CDCl3): δ 10.59 (d, J = 1.0 Hz, 1H), 7.98-7.89 (m, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.60-7.50 (m, 1H), 1.39 (s, 12H) ppm.
79%
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 80℃; for 2h; Inert atmosphere;
114.1; 116.1 Step 1:
The title compound was prepared by using the scheme and procedures shown below: [00719] Step 1: To a solution of 2-bromo-5-chlorobenzaldehyde (2.2 g, 10 mmol) and (Bpin)2 (3.8 g 15 mmol) in dioxane (30 mL) was added AcOK (2.94 g, 30.0 mmol) and Pd(dppf)Cl2 (816 mg, 1 mmol) at room temperature under N2 atmosphere. The mixture was then heated to 80 °C for 2h. LCMS indicated the reaction was completed. The mixture was cooled to room temperature, diluted with EtOAc (20 mL), and filtered through a pad of CELITE. The filtrate was concentrated in vacuo and purified by silica chromatography eluting with PE/EtOAc (100:0 to 100:10) to give 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzaldehyde (2.1 g, yield 79%) as a white solid. 1HNMR (400 MHz, CDCl3): δ 10.59 (d, J = 1.0 Hz, 1H), 7.98-7.89 (m, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.60-7.50 (m, 1H), 1.39 (s, 12H) ppm.
With anhydrous potassium acetate In 1,4-dioxane at 90℃; for 8h; Inert atmosphere;
General procedure: To a round bottom flask was added bis(pinacolato)diboron (1.22 g, 4.8 mmol, 1.2 equiv.), substituted 2-bromo benzaldehyde 1a -1h (4.0 mmol, 1.0 equiv.), PdCl2(dppf) (88 mg, 0.12 mmol, 3 mol %) and KOAc (1.18 g, 12 mmol, 3.0 equiv.). The mixture was closed by a septum, purged by argon gas for several times then the dry 1,4-dioxane (15 mL) was then added into the reaction mixture and kept stirring at 90 °C for 8 h. The crude reaction mixture was diluted with EA, extracted by sat. NaCl. The combined organic layer was collected, dried over the Na2SO4 and concentrated in vacuo. The crude products 4a- 4h were subsequently used in the next step. To a solution of 4a -4h (4.0 mol, 1.0 equiv.) in THF: H2O = 10:1 (32 mL), was added NaIO4 (6.0 mmol, 1.5 equiv). The mixture was stirred at room temperature for 20 minutes until homogeneous. HCl (1.0 M in water, 10 mL) was then added, and the mixture was stirred for additional 2 h. After the starting material 4a -4h was consumed as indicated by TLC, The resulting mixture was extracted with DCM (3×50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified through flash column chromatography by using petroleum ether and ethyl acetate as eluent to give compounds 5a -5h (42-60% yields for two steps).
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 80℃; for 8h; Inert atmosphere;
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 20℃; for 12h;
1.a a) Synthesis of Intermediate H-1-1
In a round-bottomed flask, 50.00 g (135.41 mmol) of 9-phenyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9H-carbazole, 29.72 g (135.41 mmol) of 2-bromo-5-chloro-benzaldehyde, 4.69 g (4.06 mmol) of Pd(PPh3) 4, and 37.43 g (270.81 mmol) of K 2CO 3 were suspended in a mixed solvent of 400 mL of THF/220 mL of distilled water and then stirred for 12 hours at room temperature. When a reaction was complete, the resultant was concentrated, extracted with methylene chloride, and an organic layer therefrom was silica gel columned to obtain 45.0 g (Yield of 87%) of a target compound, Intermediate H-1-1.
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