* 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 boron tribromide In dichloromethane at 0 - 25℃; for 3 h;
To a mixture of 2-bromo-5-methoxybenzaldehyde (2000.0 mg, 9.3 mmol) indichioromethane (10 mL) was added boron tribromide (2M in DCM; 4.65 mL, 9.3 mmol) slowly at 0 °C. The reaction was warmed up to 25 °C and stirred for 3 h. The reaction was quenched with water (10 mL) at 0°C and extracted with EtOAc (50 mL). The organic layer was washed with water (50 mL x 2) and brine (50 mL), dried over Mg504 and concentrated. The residue was purified by flash column chromatography (petroleum ether) to afford 2-bromo-5-hydroxybenzaldehyde (1.7 g, 90.9percent yield) as a colorless oil.
Reference：
[1] Patent: WO2017/84630, 2017, A1, . Location in patent: Paragraph 00976
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 4, p. 599 - 608
[3] Patent: WO2005/123668, 2005, A1, . Location in patent: Page/Page column 46
[4] Patent: WO2005/123668, 2005, A1, . Location in patent: Page/Page column 47
3
[ 7507-86-0 ]
[ 6342-63-8 ]
Reference：
[1] Australian Journal of Chemistry, 2006, vol. 59, # 7, p. 445 - 456
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1979, p. 829 - 837
[3] Organic and Biomolecular Chemistry, 2011, vol. 9, # 22, p. 7836 - 7848
[4] Organic Letters, 2012, vol. 14, # 2, p. 628 - 631
[5] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 7, p. 550 - 554
[6] Organic Letters, 2012, vol. 14, # 12, p. 3230 - 3232
[7] Journal of Organic Chemistry, 2014, vol. 79, # 5, p. 2059 - 2074
[8] Organic Letters, 2015, vol. 17, # 22, p. 5566 - 5569
[9] Tetrahedron Letters, 2017, vol. 58, # 4, p. 285 - 288
[10] Journal of Organic Chemistry, 2017, vol. 82, # 21, p. 11585 - 11593
[11] Patent: WO2013/22740, 2013, A2,
4
[ 591-31-1 ]
[ 7507-86-0 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 25℃; for 36 h; Inert atmosphere
A/e/ -anisaldehyde (6.06 g, 44.6 mmol, 1.0 equiv) was dissolved in AcOH (10 mL), Br2 (2.75 mL, 53.6 mmol, 1.2 equiv) was then added dropwise, and the resultant solution was stirred for 36 h at 25 °C. Upon completion, the reaction contents were quenched with saturated Na2S03 (50 mL), poured into water (20 mL), and extracted with Et20 (5 x 30 mL). The combined organic layers were then washed with water (3 x 25 mL) and brine (30 mL), dried (MgS04), and concentrated to give the desired aldehyde 12 (9.49 g, 99percent yield) as a dark yellow solid. Alternatively, this aldehyde 12 can be purchased commercially. Next, 63aldehyde 12 (9.49 g, 44.2 mmol, 1.0 equiv) was dissolved in CH3CN (200 mL) and then this solution was added to a stirred solution of phosphonate 13 (14.9 g, 44.2 mmol, 1.0 equiv), LiCl (2.44 g, 57.4 mmol, 1.3 equiv), and DBU (6.59 mL, 44.2 mmol, 1.0 equiv) at 25 °C. The resultant dark yellow solution was stirred for 12 h at 25 °C. Upon completion, the reaction contents were quenched by the addition of saturated NH CI (100 mL) and the organic solvent was concentrated. The contents were redissolved in EtOAc (50 mL), poured into water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried (MgSOi), and concentrated to give diester 14 ( 17.5 g, 99percent yield) as a yellow oil. 14: R/= 0.57 (silica gel, hexanes/EtOAc, 4/1); IR (film) 2979, 2936, 1724, 1643, 1590, 1569, 1465, 1285, 1238, 1194, 1156, 1097, 1019; NMR (400 MHz, CDC13) δ 7.80 (s, 1 H), 7.47 (d. J = 8.8 Hz, 1 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.77 (dd, J = 8.8, 2.8 Hz, 1 H), 4.29 (q, J = 7.2 Hz, 2 H), 3.76 (s, 3 H), 3.33 (s, 2 H), 1.45 (s, 9 H), 1.35 (t, J = 7.2 Hz, 3 H); ,3C NMR (75 MHz, CDCI3) δ 170.2, 166.9, 158.7, 140.6, 136.3, 133.3. 128.3 116.5, 1 15.0, 114.3, 81.1, 61.2, 55.5 35.2, 28.0, 14.2; HRMS (MALDI-FTMS) calcd for C , 8H23Br05+ [M+| 398.0729, found 398.0746.
97.87%
With N-Bromosuccinimide In N,N-dimethyl-formamide for 3 h;
After the N- bromosuccinimide (749 g) dissolved in dimethylformamide (2 L), it was added dropwise a m- anisaldehyde (m-anisaldehyde) 334.2 g.The reaction mixture was stirred for 3 hours and then poured into ice water (2 L) was produced a yellow solid.The reaction mixture was filtered and the resulting solid was dissolved in ethyl acetate.The resulting solution was washed in turn with water and aqueous NaCl solution and, MgSO4over dried, and concentrated to give the title compound 517.72 g as a white solid.(Yield: 97.87percent)
93.5%
With bromine In acetic acid
The compound was made according to a literature method (Tetrahedron 1999, 10120). The following optional recrystallization was developed. To a 1 L round-bottom flask equipped with overhead stirring, reflux condenser and thermocouple was charged 2-bromo-5- methoxybenzaldehyde (50.0 g) and 250 mL 2-propanol. The slurry was warmed to 45°C to give a clear, faint yellow solution. Water (250 mL) was then added via addition funnel over the course of 10 minutes while maintaining the internaltemperature above 42 °C. Note : A slurry forms upon addition of the first approximately 1/3 of the water charge. Once the addition was complete, heating was turned off and the slurry was cooled to ambient temperature (21 °C) over 1.5 h. After 2 h the slurry was filtered and the cake was subsequently washed with 2: 1 water:2- propanol (65 mL). After air drying for 0.5 h, the solid (57 g) was dried in a vacuum oven (35 °C, 4 mbar) for 16 h. 2-Bromo-5-methoxybenzaldehyde (46.77 g, 93.5 percent yield) was obtained as a white solid.
88%
With bromine In water; acetic acid
Step 1 Production of 2-bromo-5-methoxybenzaldehyde 3-Methoxybenzaldehyde (15 g) was dissolved in acetic acid (75 ml), and a solution of bromine (5.7 ml) dissolved in acetic acid (15 ml) was added dropwise. The mixture was stirred overnight at room temperature and water (150 ml) was added to the reaction mixture. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give the title compound (21 g, yield 88percent). 1H-NMR (300 MHz, CDCl3): 10.31 (1H, s), 7.52 (1H, d, J=8.8 Hz), 7.41 (1H, d, J=3.3 Hz), 7.03 (1H, dd, J=8.8, 3.3 Hz), 3.48 (3H, s).
87%
With bromine In acetic acid at 0 - 20℃;
Stage A 50 g of 3-methoxy-benzaldehyde is dissolved in 245 ml of acetic acid. At 0° C., 22 ml of bromine is added dropwise, followed by agitation at ambient temperature for 4 hours, then leaving overnight at ambient temperature. 300 ml of water is added to the solution and the expected product crystallizes. After filtration and washing with water and drying, 68 g of 2-bromo-5-methoxy-benzaldehyde, of molecular formula C8H7Br.O2 is obtained (M=114 g). The corresponding yield is 87percent.
87%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃;
To a solution of m-anisaldehyde (55.4 g, 0.41 mol) in DMF (400 mL) was added a solution of N-bromosuccinimide (124.0 g, 0.69 mol) dropwise at room temperature. After the addition, the reaction solution was stirred at room temperature for 12 h, then poured into a mixture of ice and water and stirred for 10 min. The precipitate was collected by filtration and dissolved in ethyl acetate. The resulting <n="44"/>solution was washed with water (2x) and brine, dried over sodium sulfate and concentrated in vacuo to give compound 19 (76.4 g, 87percent) as an off-white solid: 'H NMR (CDCl35 500 MHz) 10.32 (s, IH), 7.53 (d, J = 8.5 Hz, IH), 7.42 (d, J = 3.5 Hz,IH), 7.04 (dd, J = 9.0, 3.0 Hz, IH), 3.85 (s, 3H).
87%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 12 h;
To a solution of m-anisaldehyde (55.4 g, 0.41 mol) in DMF (400 mL) was added a solution of N-bromosuccinimide (124.0 g, 0.69 mol) dropwise at room temperature. After the addition, the reaction solution was stirred at room temperature for 12 h, then poured into a mixture of ice and water and stirred for 10 min. The precipitate was collected by filtration and dissolved in ethyl acetate. The resulting solution was washed with water (2×) and brine, dried over sodium sulfate and concentrated in vacuo to give compound 19 (76.4 g, 87percent) as an off-white solid: 1H NMR (CDCl3, 500 MHz) 10.32 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.42 (d, J=3.5 Hz, 1H), 7.04 (dd, J=9.0, 3.0 Hz, 1H), 3.85 (s, 3H)
84%
With bromine In acetic acid at 20℃; for 24 h;
Bromine (2.75 mL, 8.58 g, 53.6 mmol) was added dropwise to a stirred solution of m-anisaldehyde(6.06 g, 44.6 mmol) in AcOH (10 mL) in 3 minutes to bring the solution to gentle reflux. After 24 hours the reaction mixture was poured into water (130 mL). The precipitate was filtered, washed with water and dissolved in EtOAc (60 mL). This solution was washed with water (50 mL), brine (50 mL), dried over Na2SO4 and concentrated on a rotary evaporator. The yellow residue was recrystallized from hexane to give bromobenzaldehyde SI-1c (8.05 g, 37.4 mmol, 84percent) as beige solid.
83%
at 20℃; for 36 h;
To the solution of meta-anisaldehyde (3.03 g,22.3 mmol) in AcOH (5.0 mL), Br2 (1.4 mL, 26.8 mmol, 1.2 eq.) was drop wisely added, andthe reaction mixture was stirred for 36 h at room temperature. Upon completion, the reactionwas quenched with a saturated solution of Na2SO3 (25 mL), then poured into water (10 mL),and extracted with EtOAc (3×25 mL). The combined organic layers were washed with water(3×20 mL) and brine (15 mL), dried (Na2SO4), and concentrated to give the desired 2-bromo--5-methoxybenzaldehyde (21, 3.99 g, 83 percent).
80%
at 20℃; for 48 h;
(Z)-2-(2-Iodethenyl)-4-methoxybrombenzol (III):; 1. 2-Brom-5-methoxybenzaldehyde: Bromine (5.72 mL, l l l mmol) was added at room temperature to a solution of 3-methoxybenzaldehyde (11.8 mL, 97.0 mmol). After stirring for 48 h, the mixture was poured into water (650 mL) and the precipitated product was filtered of and extensively washed with water. After drying in vacuo aldehyde (16.7 g, 80 percent) was obtained as white solid. IH NMR (200 MHz, CDC13): δ = 3.85 (s, 3 H, 5- OCH3), 7.04 (dd, J = 8.8 Hz, 3.2 Hz, 1 H, 4-H), 7.42 (d, J = 3.2 Hz, 1 H, 6-H), 7.53 (d, J = 8.8 Hz, I H, 3-H), 10.32 (s, I H, 1-CHO); MS (7O eV, EI): m/z (percent):214.1/216.1 (100/87) [M+].
78%
With bromine In dichloromethaneInert atmosphere
Prepared according to the literature [1], starting with 3-methoxybenzaldehyde (61 mL, 0.5 mol) and bromine (26 mL, 0.5 mol) in CH2Cl2 (400 mL), yielding 83.9 g (78.0percent) of 3a, colourless needles, mp 76-78°C (n-hexane). Chemical formula: C8H7BrO2. Molecular weight: 215.04. Elemental analysis: Calculated: C, 44.68; H, 3.28; found: C, 44.88; H, 3.09. 1H-NMR (400 MHz; CDCl3): 3.83 (s, 3H, OCH3), 7.03 (dd, 1H, 3J 8.6 Hz, 4J 3.3 Hz, C4-H), 7.41 (d, 1H, 4J 3.3 Hz, C6-H), 7.51 (d, 1H, 3J 8.6 Hz, C3-H), 10.30 (s, 1H, CHO). 13C-{1H}-NMR (100 MHz; CDCl3): 55.7, 112.6, 117.9, 123.1, 133.9, 134.5, 159.2, 191.8.
73%
With bromine In dichloromethane at 0℃; for 2.5 h;
Example 13: Scheme ClO; Br2 (1 equiv., 22 mmol, 1.1 ml) in dichloro methane (5 ml) was added dropwise over a period of 2.5 h to a stirred solution of m-anisaldehyde ClO.l (1 equiv., 22 mmol, 3.0 g) in dichloromethane (25 ml) at 00C. The reaction mixture was allowed to reach room temperature overnight. The solvent was evaporated and the residue was purified column chromatography on silica gel (heptane / ethyl acetate 99:1) to give C 10.2 (4.7 g, yield = 73percent). 1H-NMR (δ , CDCl3): 3.85 (3H, s), 7.04 (IH, dd, J = 8.8, 3.2 Hz), 7.42 (IH, d, J = 3.2 Hz), 7.53 (IH, d, J = 8.8 Hz), 10.32 (IH, s) ppm
56%
With N-Bromosuccinimide In acetonitrile at 70 - 90℃; for 29 h; Inert atmosphere
4.4.1 Preparation of 2-bromo-5-methoxybenzaldehyde A solution of m-anisaldehyde (3.66 mL, 30 mmol) and N-bromosuccinimide (5.874 g, 33 mmol) in acetonitrile (90 mL) was heated at 90 °C for 11 h then at 70 °C for 18 h. After cooling, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (3*100 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography (cyclohexane/ethyl acetate, 90:10) to afford a first fraction (2.80 g, white solid). The second fraction (1.60 g) was further purified by flash chromatography (cyclohexane/ethyl acetate, 97.5:2.5) to give another fraction (0.82 g, white solid). These two fractions were collected to give the title compound (2.80+0.82=3.62 g, 56percent) as a white solid; mp 78-79 °C (lit. 45 78-80 °C). 1H NMR (300 MHz, CDCl3): δ=3.84 (s, 3H), 7.04 (dd, J=8.7-3.0 Hz, 1H), 7.42 (d, J=3.6 Hz, 1H), 7.53 (d, J=9.3 Hz, 1H), 10.32 (s, 1H). Spectral data were in agreement to those reported in the literature. 45
Reference：
[1] Angewandte Chemie - International Edition, 2010, vol. 49, # 30, p. 5146 - 5150
[2] Patent: WO2011/103442, 2011, A2, . Location in patent: Page/Page column 62-63
[3] Patent: KR2015/107357, 2015, A, . Location in patent: Paragraph 0063-0065
[4] Tetrahedron Letters, 2010, vol. 51, # 10, p. 1383 - 1385
[5] Heterocycles, 1986, vol. 24, # 2, p. 297 - 302
[6] European Journal of Organic Chemistry, 2003, # 24, p. 4731 - 4736
[7] Patent: WO2014/14885, 2014, A1, . Location in patent: Page/Page column 16; 17
[8] European Journal of Organic Chemistry, 2011, # 17, p. 3165 - 3170
[9] Patent: US2003/50320, 2003, A1,
[10] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1538 - 1552
[11] Patent: US2005/245505, 2005, A1, . Location in patent: Page/Page column 50-51
[12] Patent: WO2009/149258, 2009, A2, . Location in patent: Page/Page column 22; 42-43
[13] Patent: US2014/275101, 2014, A1, . Location in patent: Paragraph 0072; 0129; 0130
[14] Organic Process Research and Development, 2018, vol. 22, # 10, p. 1393 - 1408
[15] Tetrahedron Letters, 2004, vol. 45, # 37, p. 6941 - 6945
[16] Tetrahedron Letters, 2016, vol. 57, # 1, p. 11 - 14
[17] Chemistry - A European Journal, 2007, vol. 13, # 30, p. 8543 - 8563
[18] Journal of the Serbian Chemical Society, 2015, vol. 80, # 7, p. 839 - 852
[19] Journal of Fluorine Chemistry, 2009, vol. 130, # 2, p. 216 - 224
[20] Canadian Journal of Chemistry, 2009, vol. 87, # 2, p. 440 - 447
[21] Molecules, 2014, vol. 19, # 3, p. 3401 - 3416
[22] Tetrahedron, 1995, vol. 51, # 37, p. 10115 - 10124
[23] Chemistry - A European Journal, 2008, vol. 14, # 5, p. 1541 - 1551
[24] Patent: WO2009/33499, 2009, A1, . Location in patent: Page/Page column 25
[25] Organic Letters, 2010, vol. 12, # 24, p. 5772 - 5775
[26] Journal of Organic Chemistry, 1999, vol. 64, # 10, p. 3650 - 3654
[27] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 3, p. 814 - 823
[28] Journal of Medicinal Chemistry, 1998, vol. 41, # 15, p. 2745 - 2753
[29] Journal of the American Chemical Society, 2006, vol. 128, # 29, p. 9340 - 9341
[30] Patent: WO2008/37784, 2008, A1, . Location in patent: Page/Page column 46
[31] Journal of Organic Chemistry, 2007, vol. 72, # 25, p. 9786 - 9789
[32] Canadian Journal of Chemistry, 1997, vol. 75, # 6, p. 817 - 824
[33] Tetrahedron, 2013, vol. 69, # 10, p. 2336 - 2347
[34] Justus Liebigs Annalen der Chemie, 1912, vol. 391, p. 44
[35] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1979, p. 829 - 837
[36] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 6, p. 484 - 486
[37] Tetrahedron Letters, 1999, vol. 40, # 1, p. 105 - 108
[38] Molecules, 2000, vol. 5, # 3, p. 493 - 494
[39] Australian Journal of Chemistry, 2006, vol. 59, # 7, p. 445 - 456
[40] Patent: US5571506, 1996, A,
[41] Patent: US6211234, 2001, B1,
[42] Tetrahedron, 2012, vol. 68, # 6, p. 1745 - 1749
[43] Journal of the American Chemical Society, 2012, vol. 134, # 39, p. 16131 - 16134,4
5
[ 150192-39-5 ]
[ 7507-86-0 ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline In 1,4-dioxane at 80℃; Schlenk technique
General procedure: In an oven dried Schlenk tube, were added alcohol 1 (69.0–199.5 mg, 0.5 mmol), CuI (10 molpercent)and 1,10-Phenanthroline (20 molpercent) and K3PO4 (2 mmol) followed by the addition of dioxane (2mL) at room temperature under a nitrogen atmosphere. The stirred reaction mixture was heatedin an oil bath at 80 C for 24–48 h. Progress of the reaction was monitored by TLC till thereaction is completed. Then, the reaction mixture was cooled to room temperature, quenchedwith aqueous NH4Cl solution and then extracted with CH2Cl2 (3 10 mL). The organic layerwas washed with saturated NaCl solution, dried (Na2SO4), and filtered. Evaporation of thesolvent under reduced pressure and purification of the crude material by silica gel columnchromatography (petroleum ether/ethyl acetate) furnished the aldehyde/ketone 2 (58–92percent).
87%
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).
Reference：
[1] Dalton Transactions, 2013, vol. 42, # 2, p. 355 - 358
[2] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 149 - 162
[3] Journal of the American Chemical Society, 2005, vol. 127, # 29, p. 10124 - 10125
[4] Journal of Organic Chemistry, 1993, vol. 58, # 17, p. 4579 - 4583
[5] Synthetic Communications, 2014, vol. 44, # 14, p. 2076 - 2087
[6] Tetrahedron, 2015, vol. 71, # 38, p. 6744 - 6748
[7] Journal of the American Chemical Society, 2011, vol. 133, # 20, p. 7916 - 7925
[8] Chemistry - An Asian Journal, 2018, vol. 13, # 17, p. 2401 - 2404
6
[ 2973-80-0 ]
[ 74-88-4 ]
[ 7507-86-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 60 h;
To a solution of 2-bromo-5-hydroxybenzaldehyde (1000.0 mg, 4.975 mmol) in DMF (20 mL) were added methyl iodide (0.31 mL, 5.000 mmol) and potassium carbonate (1036.6 mg, 7.500 mmol). The reaction mixture was stirred at rt for 2.5 days. Water was added and the reaction mixture was extracted with hexanes-ether (1:1) solvent system. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum to yield 2-bromo-5-methoxybenzaldehyde (1069.8 mg, 100percent) as colorless oil. LC-MS (M+H)+=215.11. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H). 7.70 (d, J=10 Hz, 1H) 7.35 (d, J=3 Hz, 1H) 7.23 (dt, J1=7.0 Hz, J2=2.0 Hz, 1H) 3.83 (s, 3H).
Reference：
[1] Patent: US2008/194535, 2008, A1, . Location in patent: Page/Page column 30
[2] Organic letters, 2002, vol. 4, # 16, p. 2711 - 2714
[3] Journal of the Chemical Society, 1951, p. 181,184
7
[ 22921-68-2 ]
[ 7507-86-0 ]
Reference：
[1] Journal of the American Chemical Society, 2002, vol. 124, # 7, p. 1354 - 1363
[2] Journal of Organic Chemistry, 1993, vol. 58, # 17, p. 4579 - 4583
[3] Journal of the American Chemical Society, 2011, vol. 133, # 20, p. 7916 - 7925
[4] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 149 - 162
[5] Chemistry - An Asian Journal, 2018, vol. 13, # 17, p. 2401 - 2404
8
[ 591-31-1 ]
[ 7507-86-0 ]
Yield
Reaction Conditions
Operation in experiment
83%
With iodine pentoxide; potassium bromide In water at 20℃; for 23 h;
General procedure: A mixture of arene (0.5 mmol), I2O5 (334 mg, 1.0 mmol), and KBr (148 mg, 1.25 mmol) was dissolved in 2mL of H2O. The reaction was complete after stirring for the indicated time at room temperature. The mixture was extracted by ethyl acetate and concentrated under reduced pressure, and the mixture was purified by flash column chromatography (silica gel) to afford the desired product.
Reference：
[1] Organic Letters, 2010, vol. 12, # 5, p. 940 - 943
[2] Journal of the American Chemical Society, 2005, vol. 127, # 29, p. 10124 - 10125
[3] Synlett, 2009, # 11, p. 1852 - 1858
[4] European Journal of Organic Chemistry, 2010, # 35, p. 6760 - 6778
10
[ 27060-75-9 ]
[ 7507-86-0 ]
Reference：
[1] Journal of the American Chemical Society, 2005, vol. 127, # 29, p. 10124 - 10125
[2] Journal of Organic Chemistry, 2004, vol. 69, # 6, p. 2084 - 2093
[3] European Journal of Organic Chemistry, 2010, # 35, p. 6760 - 6778
11
[ 6971-51-3 ]
[ 7507-86-0 ]
[ 591-31-1 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1991, vol. 64, # 3, p. 796 - 800
12
[ 150192-39-5 ]
[ 7507-86-0 ]
Reference：
[1] Patent: US6514964, 2003, B1,
13
[ 100-83-4 ]
[ 7507-86-0 ]
Reference：
[1] Organic letters, 2002, vol. 4, # 16, p. 2711 - 2714
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 6, p. 484 - 486
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 5, p. 2059 - 2074
19
[ 7507-86-0 ]
[ 150192-39-5 ]
Reference：
[1] Chemical Communications (Cambridge, United Kingdom), 2018, vol. 54, # 83, p. 11805 - 11808
[2] Journal of the American Chemical Society, 1941, vol. 63, p. 2279
[3] Journal of the American Chemical Society, 1941, vol. 63, p. 2279
[4] Tetrahedron Letters, 1999, vol. 40, # 1, p. 105 - 108
[5] Heterocycles, 2001, vol. 54, # 1, p. 259 - 274
[6] Tetrahedron Letters, 2004, vol. 45, # 37, p. 6941 - 6945
[7] Journal of Organic Chemistry, 2010, vol. 75, # 3, p. 897 - 901
[8] Tetrahedron Letters, 2012, vol. 53, # 42, p. 5635 - 5640
[9] Tetrahedron, 2013, vol. 69, # 47, p. 10098 - 10107
[10] Advanced Synthesis and Catalysis, 2014, vol. 356, # 16, p. 3415 - 3421
[11] Tetrahedron, 2015, vol. 71, # 42, p. 8172 - 8177
[12] Angewandte Chemie - International Edition, 2016, vol. 55, # 5, p. 1777 - 1781[13] Angew. Chem., 2016, vol. 128, # 5, p. 1809 - 1813
[14] Organic and Biomolecular Chemistry, 2017, vol. 15, # 1, p. 69 - 75
[15] Chemical Communications, 2017, vol. 53, # 57, p. 8042 - 8045
[16] Organic Letters, 2019, vol. 21, # 1, p. 170 - 174
20
[ 7507-86-0 ]
[ 140860-51-1 ]
Reference：
[1] Synlett, 2000, # 8, p. 1169 - 1171
21
[ 7507-86-0 ]
[ 75534-35-9 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 20, p. 7916 - 7925
22
[ 7507-86-0 ]
[ 85604-06-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 4, p. 599 - 608
23
[ 7507-86-0 ]
[ 887581-09-1 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With tert-butyldimethylsilane; methyl carbamate; trifluoroacetic acid In acetonitrile at 80℃; for 6 h; Stage #2: With water; lithium hydroxide In tetrahydrofuran; methanol at 80℃; for 16 h;
To a stirred solution of bromobenzaldehyde 1b (1.0 g, 4.6 mmol) and methyl carbamate (524 mg, 7.0 mmol) in acetonitrile (12 mL), were added sequentially TFA (0.71 mL, 9.3 mmol) and tert-butyldiemthylsilane (TBDMSH) (1.53 mL, 9.3 mmol) and the resulting solution was stirred at 80 °C for 6 h. The reaction mixture was concentrated in vacuo and the residue dissolved in a mixture of THF, MeOH and aq. LiOH [1.95 g, 46.5 mmol in H2O (5 mL)] (1:1:1, total 15 mL) and heated at 80 °C for 16 h. The reaction mixture was cooled to RT and then treated with aqueous NaOH [700 mg in H2O (10 mL)] and the mixture was extracted with ethyl acetate (3 .x. 20 mL). The combined organic layers were washed with saturated NaCl solution, dried (Na2SO4), and filtered. Evaporation of the solvent and purification of the crude material by flash chromatography (short column, ethyl acetate/hexane, 1:1 to 100percent ethyl acetate, then 5:95 methanol/ethyl acetate to 10:90 methanol/ethyl acetate) furnished the benzylamine 3b (960 mg, 95percent) as pale yellowish viscous liquid. 1H NMR (400 MHz, CDCl3): = 7.40 (d, J = 8.6 Hz, 1H, Ar-H), 6.93 (d, J = 3.0 Hz, 1H, Ar-H), 6.67 (dd, J = 8.6, 3.0 Hz, 1H, Ar-H), 3.86 (s, 2H, CH2NH2), 3.78 (s, 3H, OCH3), 2.12 (br. s, 2H, CH2NH2); 13C NMR (100 MHz, CDCl3): = 159.3 (C), 142.5 (C), 133.4 (CH), 114.8 (CH), 114.1 (CH), 113.7 (C), 55.4 (OCH3), 46.8 (CH2NH2); HRMS (ESI) calcd for C8H11BrNO [M+H]+ 216.0018, found 216.0017.
With sodium tetrahydroborate; In methanol; at 20℃; for 1h;Inert atmosphere;
General procedure: To an ice cold, magnetically stirred solution of a bromobenzaldehyde 7 (500 mg, 1.56-2.70 mmol) in methanol (15-20 mL), was added sodium borohydride (2.73-4.05 mmol). Then the reaction mixture was allowed to attain room temperature and stirred for 1 h. Solvent was removed under reduced pressure, treated with aqueous NH4Cl solution and extracted with ethyl acetate (3 ´ 15 mL). The organic layer was washed with saturated NaCl solution, dried (Na2SO4), and filtered. Evaporation of the filtrate under reduced pressure and purification of the crude material by silica gel column chromatography (petroleum ether/ethyl acetate) furnished the alcohol 1 (77-98%).
With sodium chlorite; sodium dihydrogenphosphate; 2-methyl-but-2-ene; In tetrahydrofuran; water; tert-butyl alcohol; at 20℃; for 1.16667h;
). 2-Bromo-5-methoxybenzaldehyde (548 mg, 2.5 mmol), tert-butyl alcohol (30 mL), 2-methyl-2-butene (6 mL), and THF (30 mL) were addedto a round-bottom flask. NaClO2 (811 mg, 7.1 mmol) and NaH2PO4(2.14 g, 14 mmol) dissolved in water were gradually added over a period of 10min and the resulting mixture was stirred for 1.0 hr at room temperature. Afterthe removal of tert-butyl alcohol, 2-methyl-2-butene, and THF under reduced pressure, 2M HCl was added to the reaction mixture to acidify it (pH 2). The solution was thenextracted with ethyl acetate. The organic phase was washed with brine and driedover anhydrous Na2SO4. The solvent was removed underreduced pressure. The white solid (616 mg, quantitative yield) was identifiedas 2-bromo-5-methoxybenzoic acid (4a) on the basis of 1H-NMRand mass spectra. 1H-NMR (400 MHz, CDCl3): d 3.84 (s, -OCH3, 3H), 6.95 (dd, J=8.8 Hz, 3.0 Hz, 1H), 7.50 (d, J=3.0 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H); MS (ESI): m/z[M-H+2]- 231, [M-H]- 229.
72%
With potassium permanganate; In water; at 75℃; for 2h;
Commercially available 2-bromo-5-methoxybenzaldehyde (4.65mmol) was dissolved in 20mL of water. KMnO4 (6.51mmol, 1.4 eq.) was dissolved in 15mL of water and added dropwise to the reaction mixture. The reaction mixture was stirred at 75C for 2h, then a solution of KOH at 20% was added to obtain a strongly basic pH. The reaction mixture was filtered through a pleated filter, the filter washed with hot water and the aqueous filtrates were cooled to rt and filtered again to remove aldehyde residues. When the aqueous filtrates were acidified with HCl 37% the 2-bromo-5-methoxybenzoic acid 2b precipitated as white solid that was collected by filtration under reduced pressure (Yield: 72%, 773mg). No further purification was necessary. 1H NMR (300MHz, CDCl3): delta=7.58 (d, J=8.8Hz, 1H, arom.), 7.52 (d, J=3.1Hz, 1H, arom.), 6.95 (dd, J=8.8, 3.1Hz, 1H, arom.), 3.84 (s, 3H, -CH3). These data are in good agreement with literature values [27].
With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline; In 1,4-dioxane; at 80℃;Schlenk technique;
General procedure: In an oven dried Schlenk tube, were added alcohol 1 (69.0-199.5 mg, 0.5 mmol), CuI (10 mol%)and 1,10-Phenanthroline (20 mol%) and K3PO4 (2 mmol) followed by the addition of dioxane (2mL) at room temperature under a nitrogen atmosphere. The stirred reaction mixture was heatedin an oil bath at 80 C for 24-48 h. Progress of the reaction was monitored by TLC till thereaction is completed. Then, the reaction mixture was cooled to room temperature, quenchedwith aqueous NH4Cl solution and then extracted with CH2Cl2 (3 10 mL). The organic layerwas washed with saturated NaCl solution, dried (Na2SO4), and filtered. Evaporation of thesolvent under reduced pressure and purification of the crude material by silica gel columnchromatography (petroleum ether/ethyl acetate) furnished the aldehyde/ketone 2 (58-92%).
87%
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 55C for 1h. The crude mixture was purified by a flash column chromatography to afford the benzaldehydes (4a-4p).
2. (Z)-2-(2-Iodethenyl)-4-methoxybrombenzol (III): KHMDS (0.500 M in toluene, 70 mL, 35.0 mmol) was added at room temperature to a suspension of iodmethyl- triphenylphosphonium iodide (10) (18.5 g, 34.9 mmol) in dry THF (200 mL). The mixture was stirred for 10 min at room temperature and then cooled to -78 C. A solution of the aldehyde of 1. (6.00 g, 27.9 mmol) in dry THF (20 mL) was added slowly and stirring was continued for 30 min at -78 C. The solution was then warmed to room temperature and poured into saturated aqueous NH4C1 (200 mL). The mixture was extracted with diethyl ether (3 x 150 mL), the combined organic layers were washed with saturated aqueous NaCl (100 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue was subjected to column chromatography (n-pentane). Vinyliodide 5 (7.51 g, 79 %) was obtained as yellow oil. Rf= 0.17 (n-pentane); IH NMR (300 MHz, CDC13): delta = 3.84 (s, 3 H, 4-OCH3), 6.74 (d, J = 8.5 Hz, 1 H, 2'-H), 6.78 (dd, J = 8.8 Hz, 3.0 Hz, 1 H, 5-H), 7.24 <n="27"/>- -(d, J = 3.0 Hz, 1 H, 3-H), 7.31 (d, J = 8.5 Hz, 1 H, l '-H), 7.47 (d, J = 8.8 Hz, 1 H, 6-H); 13C NMR (50.3 MHz, CDC13): delta = 55.54 (4-OCH3), 83.46 (C-2')> 113.9 (C-I), 115.3, 116.1 (C-3, C-5), 133.4 (C-6), 138.1 (C-2), 139.0 (C-I'), 158.5 (C-4); IR (FiIm): ? =2933, 1589, 1566, 1462, 1294, 1238, 1176, 1114, 1055, 1018, 860, 806, 722, 667 cm-l ; UV (CH3CN): /tmax (Ig epsilon) = 200.5 nm (4.3589). MS (70 eV, EI): m/z (%) = 338.0/340.0 (56/56) [M+], 132.1 (100) [M+ - Br - I].
With tetrakis(triphenylphosphine) palladium(0); potassium phosphate monohydrate; In 1,2-dimethoxyethane; at 150℃; for 1.5h;Microwave irradiation;
General procedure: To degassed solutions of 1 equiv of substituted 2-bromo-benzaldehydes 10, 13 or 14 in DME were added 1.5 equiv of boronic species, 3 equiv of K3PO4·H2O and 0.05 equiv of Pd(PPh3)4; the suspensions were heated under microwave irradiation (6 bars, 80-150 watts) for 1 h 30 min at 150 C. The resulting mixtures were filtered (washed with Et2O or EtOAc) and concentrated under reduced pressure. The crude products were then purified by flash chromatography.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; lithium chloride; In 1,2-dimethoxyethane; water;
Preparation of the cyclization precursor is directly analogous to that described with reference to Figure 2 inachieving compound 7a/Formula 1. As shown in Figure 3, in accordance with Scheme 3, biaryl 8 is obtained by Suzuki-Miyaura coupling and which has been made previously, is similarly subjected to reaction with vinylmagnesium bromide.The resultant alcohol (9) is then oxidized to ketone 10
With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 100℃; Inert atmosphere;
1.2.1. General procedure 1: Synthesis of (substituted) biphenyl-2-carboxaldehydes by Suzuki crosscoupling
General procedure: To a mixture of boronic acid 7 (1.5 equiv) and bromobenzaldehyde 6 (1.0 equiv) a solution of Pd(PPh3)4(0.050 equiv) in DMF/H2O 1:1 (10 mL per mmol bromobenzaldehyde) was added under N2 atmosphere,followed by an aqueous solution of Na2CO3 (0.3 M, 3.0 equiv). The resulting heterogeneous mixture wasrefluxed for 16 h before it was diluted with H2O and extracted with EtOAc. The combined organic layerswere separated, washed with brine, dried over MgSO4, and evaporated in vacuo. The crude product waspurified by FCC.
85%
With dicyclohexyl({2’,6’-dimethoxy-[1,1‘-biphenyl]-2-yl})phosphane; tripotassium phosphate tribasic; tris-(dibenzylideneacetone)dipalladium(0) In toluene for 10h; Inert atmosphere; Schlenk technique; Reflux;
With anhydrous sodium carbonate In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 25℃; for 12h;
With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In ethanol; toluene Reflux;
With palladium diacetate; anhydrous sodium carbonate In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 20℃;
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 110℃;
With palladium diacetate; anhydrous sodium carbonate at 20℃; Inert atmosphere;
4.2. Typical experimental procedure for the synthesis of the startingmaterials 2-arybenzaldehydes 1 (or 5-arylpyrazole-4-carbaldehydes 3)
General procedure: These compounds were synthesized according to the literature procedure.21 Typical procedure: 2-bromobenzaldehyde (0.92 g,5 mmol), phenylboronic acid (0.67 g, 5.5 mmol), sodium carbonate (0.53 g, 5 mmol), and Pd(OAc)2 (0.028 g, 0.125 mmol) were added to a flask (50 mL) equipped with a high-vacuum PTFE valve-to-glass seal. The flask was opened to the vacuum, pumped for 2-3 min and backfilled with an inert Ar gas. The reaction mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was diluted with CH2Cl2 (3 20 mL) and the organic layer was dried over Na2SO4, concentrated under the reduced pressure to give a dark brown oil, which was further purified via column chromatography on Silica gel (eluent: petroleum ether: EtOAc 20:1) to give 2-phenylbenzaldehyde 1a (0.86 g, 95%).
With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In ethanol; 2-methoxy-2-methylpropane; lithium hydroxide monohydrate at 90℃; for 6h; Inert atmosphere;
With palladium diacetate; anhydrous sodium carbonate In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 20℃; for 24h; Schlenk technique; Inert atmosphere;
Multi-step reaction with 2 steps
1.1: 89 percent / p-toluenesulfonic acid / toluene / 15 h / Heating
2.1: n-BuLi / diethyl ether; hexane / 0.75 h / -78 °C
2.2: B(OBu)3 / -78 - 20 °C
2.3: 81 percent / H2O; H+ / 2 h / 25 °C
Multi-step reaction with 2 steps
1.1: 100 percent / toluene-p-sulfonic acid / benzene / 20 h / Heating
2.1: n-BuLi / diethyl ether; hexane / 1 h / -75 °C
2.2: triisopropyl borate / diethyl ether; hexane / 2.5 h / 20 °C
2.3: 92.7 percent / aq. HCl / diethyl ether; hexane / 1.5 h / Heating
Multi-step reaction with 2 steps
1.1: tetra-N-butylammonium tribromide; orthoformic acid triethyl ester / 12 h / 65 °C
2.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C
2.2: -78 - 20 °C
2.3: 20 °C
Multi-step reaction with 3 steps
1: APTS / benzene
2: n-butyllithium / tetrahydrofuran
3: hydrogenchloride; water
Stage #1: 2-bromo-5-methoxy-benzaldehyde With toluene-4-sulfonic acid; ethylene glycol In toluene Reflux;
Stage #2: With n-butyllithium; Triisopropyl borate In diethyl ether at -78℃;
Stage #3: With hydrogenchloride In water
Multi-step reaction with 2 steps
1.1: potassium acetate / 1,4-dioxane / 8 h / 90 °C / Inert atmosphere
2.1: sodium periodate / tetrahydrofuran; water / 0.33 h / 20 °C
2.2: 2 h
Multi-step reaction with 2 steps
1.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 8 h / 80 °C / Inert atmosphere
2.1: sodium periodate / tetrahydrofuran; water / 0.33 h / 20 °C
2.2: 2 h / 20 °C
Multi-step reaction with 2 steps
1.1: montmorillonite K-10 / dichloromethane / 0.5 h / 20 °C
2.1: n-butyllithium / tetrahydrofuran; cyclohexane / 1 h / -78 °C
2.2: 1 h / -78 °C
2.3: -78 - 5 °C
Step C 2-Bromo-5-methoxybenzaldehyde Pyridinium Chlorochromate (1.2 eq) was added to a solution of <strong>[150192-39-5]2-bromo-5-methoxybenzyl alcohol</strong> (1 eq) and Celite (1.2 eq) in methylene chloride (0.30 M) at RT and the resulting mixture was stirred under nitrogen for 3 h. The mixture was filtered through a plug of silica rinsing with methylene chloride and concentrated in vacuo to give 2-bromo-5-methoxy benzaldehyde as a white solid. EI-MS m/z 232, 234 (M+NH4)+
With potassium carbonate In water; N,N-dimethyl-formamide at 20 - 120℃; Microwave irradiation;
13
To a solution of 2-bromo-5-methoxybenzaldehyde (200 mg, 0.93 mmol) in DMF (10 mL) and H20 (2 mL) are added 2,4-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3-thiazole (333 mg, 1.4 mmol), Pd(PPh3)4 (107 mg, 0.09 mmol) and K2C03 (257 mg, 1.9 mmol) at room temperature. The solution is heated to 120 °C for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and is filtered. The filtrate is washed with H20 (10 mL) and is extracted with EtOAc (3 x 10 mL). The combined organic layer is dried, (MgS04), filtered and is concentrated and the residue is purified by silica gel flash chromatography eluting with 50% EtOAc in heptane to afford 2-(2,4-Dimethyl-thiazol-5-yl)-5-methoxy-benzaldehyde (150 mg, 65%)as a white foam.
With caesium carbonate;copper(l) iodide; L-proline; In N,N-dimethyl-formamide; at 110℃; for 18h;
Embodiment 30 Preparation of compound 71 (6-methoxy-2-methylquinazoline) A mixture of 2-bromo-5-methoxybenaldehyde (0.50 g, 2.33 mmol), acetamidine hydrochloride (0.25 g, 2.56 mmol), L-proline (0.05 g, 0.47 mmol), cesium carbonate (2.28 g, 6.98 mmol) and cuprous iodide (0.05 g, 0.23 mmol) in DMF (20 mL) was heated to 110 C. for stirring for 18 hours. The reaction mixture was cooled and filtered through a pad of celite. The filtrate was evaporated under reduced pressure, and then extracted with EtOAc (20 mL*3). The combined extract was dried over MgSO4 and evaporated to give a residue that was purified by silica gel flash column chromatography (EtOAc:n-hexane=1:1) to afford compound 71 (41% yield).
To a stirred solution of bromobenzaldehyde 1b (1.0 g, 4.6 mmol) and methyl carbamate (524 mg, 7.0 mmol) in acetonitrile (12 mL), were added sequentially TFA (0.71 mL, 9.3 mmol) and tert-butyldiemthylsilane (TBDMSH) (1.53 mL, 9.3 mmol) and the resulting solution was stirred at 80 C for 6 h. The reaction mixture was concentrated in vacuo and the residue dissolved in a mixture of THF, MeOH and aq. LiOH [1.95 g, 46.5 mmol in H2O (5 mL)] (1:1:1, total 15 mL) and heated at 80 C for 16 h. The reaction mixture was cooled to RT and then treated with aqueous NaOH [700 mg in H2O (10 mL)] and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated NaCl solution, dried (Na2SO4), and filtered. Evaporation of the solvent and purification of the crude material by flash chromatography (short column, ethyl acetate/hexane, 1:1 to 100% ethyl acetate, then 5:95 methanol/ethyl acetate to 10:90 methanol/ethyl acetate) furnished the benzylamine 3b (960 mg, 95%) as pale yellowish viscous liquid. 1H NMR (400 MHz, CDCl3): = 7.40 (d, J = 8.6 Hz, 1H, Ar-H), 6.93 (d, J = 3.0 Hz, 1H, Ar-H), 6.67 (dd, J = 8.6, 3.0 Hz, 1H, Ar-H), 3.86 (s, 2H, CH2NH2), 3.78 (s, 3H, OCH3), 2.12 (br. s, 2H, CH2NH2); 13C NMR (100 MHz, CDCl3): = 159.3 (C), 142.5 (C), 133.4 (CH), 114.8 (CH), 114.1 (CH), 113.7 (C), 55.4 (OCH3), 46.8 (CH2NH2); HRMS (ESI) calcd for C8H11BrNO [M+H]+ 216.0018, found 216.0017.
(S)-1-(2-bromo-5-methoxyphenyl)-3-buten-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: A mixture of AgF (32.9 mg, 0.26 mmol) and (R)-BINAP·AgF (99.6 mg, 0.16 mmol) was dissolved in anhydrous methanol (3 ml) under nitrogen atmosphere with exclusion of direct light, and it was stirred at room temperature for 10 min. To the resulting solution were added dropwise 2-bromobenzaldehyde (264 muL, 2.6 mmol) and <strong>[2551-83-9]allyltrimethoxysilane</strong> (791 muL, 4.7 mmol) at -20 C. The mixture was stirred for 4 h at this temperature, and then treated with a mixture of 1 N HCl (13 ml) and solid KF (1.3 g) at room temperature for 30 min. The resulting precipitate was filtered off, dried over Na2SO4, and concentrated in vacuo. The residual crude product was purified by column chromatography on silica gel with ethyl acetate/hexane (1:6) as eluent to afford the chiral homoallylic alcohol (469 mg, 2 mmol, 80% yield) as a colorless oil.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; for 23h;Reflux;
To a degassed solution of 2-bromo-5-methoxybenzaldehyde (1.5 g, 7.04 mmol, Fluorochem) and trimethylboroxine (0.98 mL, 7.04 mmol) in 1,4-dioxane (80 mL) was added potassium carbonate (2.91 g, 21.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.813 g, 0.70 mmol). The mixture was heated under reflux for about 20 h, then more tetrakis(triphenylphosphine)palladium(0) (0.200 g, 0.17 mmol) and trimethylboroxine (0.25 mL, 1.8 mmol) were added and the mixture was heated under reflux for about another 3 h. After cooling to rt the mixture was filtered over diatomaceous earth and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:3) to give 5-methoxy-2-methyl-benzaldehyde (0.97 g, 92%) as a colorless liquid. 1H-NMR (CDCl3, Bruker 400 MHz) 2.60 (3H, s); 3.83 (3H, s); 7.04 (1H, dd, J=8.5 Hz, 2.4 Hz); 7.16 (1H, d, J=8.5 Hz); 7.33 (1H, d, J=2.4 Hz); 10.2 (1H, s).
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.
2-(2-bromo-5-methoxyphenyl)-2-methoxyacetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
Stage #1: Trimethylmethoxysilane; 2-bromo-5-methoxy-benzaldehyde With iron(III) chloride In dichloromethane at 0℃; for 3h; Inert atmosphere;
Stage #2: trimethylsilyl cyanide In dichloromethane at 0℃; for 1h; Inert atmosphere;
4,5'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarbaldehyde[ No CAS ]
[ 132901-31-6 ]
Yield
Reaction Conditions
Operation in experiment
36%
With copper(I) thiophene-2-carboxylate; copper; In dimethyl sulfoxide; at 65 - 70℃;
General procedure: (0013) A mixture of aryl halide (1 equiv), Cu(0) powder (10 equiv), and CuTC (2 equiv) in DMSO (0.2 mL/mmol of aryl halide) was stirred at 65-70 C for 15-72 h. Water and EtOAc were added, and the two phases were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by preparative TLC (EtOAc/hexanes) to furnish the desired product.
2-methoxy-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 18h;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.
With tetrakis-(triphenylphosphine)-palladium; anhydrous potassium acetate In toluene at 110℃; for 16h; Inert atmosphere;
11.11a Step 11a: 5-Methoxy-2-pinacolatoboronic acid benzaldehyde (5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde ) (Compound 0104-31) Preparation:
Under nitrogen protection,Combine the compound 2-bromo-5-methoxybenzaldehyde (1 g, 4.65 mmol, 1 eq),Bispinacolato borate (1.77 g, 6.975 mmol, 1.5 eq),Potassium acetate (1.37 g, 3 equivalents),Tetratriphenylphosphine palladium (538 mg, 0.465 mmol, 0.1 eq.)Mix in 10 ml of toluene,The reaction was stirred at 110 °C for 16 hours.After the reaction is completed, cool to room temperature, filter, and concentrate the filtrate under reduced pressure.The product, 5-methoxy-2-pinacolatoboronic acid benzaldehyde (1.5 g, crude), was obtained as a black oil and used directly in the next reaction.
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 10H-phenothiazine; Cs2CO3 In acetonitrile at 20℃; Irradiation;
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere;
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate In 1,4-dioxane at 90℃; for 12h; Schlenk technique; Inert atmosphere;
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-methoxy-2-bromobenzaldehyde (0.6 mmol) to the dry Schlenk tube, evacuate nitrogen, add piperidine (0.05 mmol), 1,4-dioxane (2 ml), and the reaction was stirred at room temperature for 3 hours. CuI (0.05 mmol) K2CO3 (1 mmol) and 1,10-phenanthroline (0.1 mmol) were added to the reaction system at room temperature, and then the mixture was heated to 90 C. and stirred for 8 hours. After stopping the reaction, add 15 ml of CH2Cl2 to the reaction system, filter with a sand funnel, wash CH2Cl2 three times, combine the filtrate and the washing solution, dry over anhydrous Na2SO4, and concentrate after separation with silica gel column chromatography (eluent is acetic acid Ethyl acetate: dichloromethane = 30: 1) to obtain the pure product. The material was a yellow solid with a yield of 20%.
(E)-2-(2-cyclopropylvinyl)-5-methoxybenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate In tetrahydrofuran; water at 90℃; for 12h; Inert atmosphere; Schlenk technique;
5-methoxy-2-(2-methoxyphenyl)benzo[b]thiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With potassium carbonate; sulfur; In N,N-dimethyl-formamide; at 110℃; for 16h;Inert atmosphere;
A mixture of 36 (1.0mmol), 2-bromo-5-methoxybenzaldehyde (1.5mmol), K2CO3 (3.0mmol), S (4.0mmol) were dissolved in 3mL of dimethylformamide and stirred for 16hat 110C under nitrogen. The mixture was filtered and the filtrate was evaporated to remove solvent. The residue was purified by flash chromatography using silica gel to give product. Yield 43%; red oil. 1H NMR (400MHz, CDCl3) δ 7.72-7.65 (m, 3H), 7.34-7.27 (m, 1H), 7.24 (d, J=2.1Hz, 1H), 7.05-6.98 (m, 2H), 6.95 (dd, J=8.8, 2.5Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H).
With tris-(dibenzylideneacetone)dipalladium(0); potassium fluoride dihydrate; tri-tert-butylphosphonium hydrogen tetrafluoroborate In tetrahydrofuran at 20℃; for 12h; Schlenk technique; Inert atmosphere;
69%
Stage #1: 2-(dihydroxyboryl)-5-methoxybenzaldehyde With tris-(dibenzylideneacetone)dipalladium(0); potassium fluoride dihydrate; tri-tert-butylphosphonium hydrogen tetrafluoroborate for 0.05h; Inert atmosphere; Sealed tube;
Stage #2: 2-bromo-5-methoxy-benzaldehyde In tetrahydrofuran at 25 - 60℃; Inert atmosphere; Sealed tube;
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110K+ Compounds
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