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Structure of 2973-59-3 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
2-bromo-5-hydroxy-4-methoxybenzaldehyde and then a 2 g (8.70 mmol) under a nitrogen condition dissolved in N, N- dimethylformamide, 87 mL (0.1 M), 1.8 g of potassium carbonate at 0oC (13.1 mmol), benzyl bromide 1.77 g (10.4 mmol) were added sequentially. .After the reaction temperature raised to 25 ° C, and reacted for 5 hours. It was added to 100 mL of ammonium chloride aqueous solution to terminate the reaction and extracted with EtOAc (3 × 30 mL). Washing the organic layer with brine (brine, 10 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound 5- (benzyloxy) -2-bromo-4-methoxybenzaldehyde 2.73 g (8.53 mmol, 98percent).
83%
With potassium carbonate In acetonitrile at 50℃; for 20 h;
2-Bromo-5-hydroxy-4-methoxybenzaldehyde (25 g, 0.108 mol) and K2CO3 (30 g, 0.216 mol) were added to acetonitrile (250 mL) and flushed with Ar. Benzyl bromide (20 g, 0.12 mol) was added and the mixture was heated under Ar for 20 h at 50° C. After cooling, the mixture was poured into water (200 ml) and extracted with CH2Cl2 (300 mL). The CH2Cl2 was washed with water (3*100 mL), dried and concentrated. Recrystallization with isopropanol: water (3:1) gave 28.8 g (83percent) of 2 as a light brown solid. 1H-NMR (400 MHz, CDCl3) dH 3.96 (3H, s, OCH3), 5.16 (2H, s, CH2Ph), 7.07-7.48 (7H, m, ArH+CH2Ph), 10.16 (1H, s, CHO).
67.9%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
To a solution 2-bromo-5-hydroxy-4-methoxybenzaldehyde (1c) (120 g, 520 mmol) in DMF (1000 mL) was added potassium carbonate (79 g, 572 mmol) and benzyl bromide (68 mL, 572 mmol). The reaction mixture was stirred at room temperature overnight and quenched with water (3000 mL). The solid obtained was collected by filtration, washed with ether and dried under vacuum to furnish 5-(benzyloxy)-2-bromo-4-methoxybenzaldehyde (1d) (113.19 g, 67.9percent) as a white solid, MP 144 °C; 1HNMR (300 MHz, DMSO-c/6): δ 10.06 (s, 1H), 7.47- 7.34 (m, 7H), 5.17 (s, 2H), 3.92 (s, 3H); IR (KBr) 2898, 2851 , 1673, 1592, 1502, 1437, 1402, 1264, 1210, 1158, 1017, 754 cm"1; Analysis calculated for C 5H13Br03: C, 56.10; H, 4.08; Found: C, 55.44; H, 4.08.
With potassium carbonate In acetonitrile at 80℃; for 15 h;
To a solution of 2-bromo-5-hydroxy-4-methoxy-benzaldehyde (25 g, 108 mmol) in MeCN (500 mL) was added (chloromethyl)benzene (13.7 g, 108 mmol) and potassium carbonate (29.9 g, 216 mmol). The mixture was heated at 80 °C with stirring for 15 hours. After being cooledrt, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residuewas partitioned between brine and DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 5 -(benzyloxy)-2-bromo-4-methoxy- benzaldehyde (34.2 g, 96.9 mmol) which was used in the next step without further purification.
Reference：
[1] Heterocycles, 1990, vol. 31, # 6, p. 1067 - 1076
[2] Journal of the American Chemical Society, 2014, vol. 136, # 6, p. 2583 - 2591
[3] Journal of Organic Chemistry, 2004, vol. 69, # 9, p. 2920 - 2928
[4] Patent: WO2017/17043, 2017, A1, . Location in patent: Page/Page column 27; 28
Reference：
[1] Journal of the Chemical Society, 1930, p. 2279,2287
[2] Journal of Organic Chemistry, 1940, vol. 5, p. 204,208
11
[ 621-59-0 ]
[ 7726-95-6 ]
[ 64-19-7 ]
[ 2973-59-3 ]
[ 2973-58-2 ]
Reference：
[1] Journal of the Chemical Society, 1930, p. 2279,2287
[2] Journal of Organic Chemistry, 1940, vol. 5, p. 204,208
12
[ 2973-59-3 ]
[ 121936-68-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: With aminosulfonic acid In water; ethyl acetate Stage #2: With sodium chlorite In water; ethyl acetate at -10 - 20℃; for 1 h;
Example 3; 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13); 1 Kg of 2-bromo-5-hydroxy-4-methoxy benzaldehyde (B2) and 1.255 Kg of sulfamic acid were added with stirring into a mixture of 4.473 Kg of EtOAc and 8 L of water. The reaction mixture was stirred until all of the solid had dissolved. The reaction mixture was cooled to between -10 and 0° C. An aqueous solution of sodium chlorite was prepared by dissolving 505 g of sodium chlorite in 3 L of water. The sodium chlorite solution was added to the pre-cooled B2 solution at a rate that maintained the reaction temperature under 5° C. After the complete addition of sodium chlorite solution, the reaction mixture was stirred for another hour at 0° C. and was then allowed to warm up to room temperature. The reaction was monitored by TLC. After the TLC analysis showed completion of the reaction, the aqueous layer was separated. The aqueous layer was extracted with EtOAc (1.789 Kg) and the combined organic layer was transferred to another flask and EtOAc was removed by vacuum distillation at 40° C. 6.92 Kg of toluene was added at between 30 to 40° C., the slurry was cooled to between -10 to 0° C. and the precipitate was collected by filtration to give about 950 g (89percent (wt?)yield) of 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13). 1H NMR (CDCl3) δ 3.95 (3H, s, CH3), 7.22 (1H, s, CH), 7.46 (1H, s, CH).
The 3,4-dimethoxy-2-bromobenzaldehyde (100 g, 0.408 mol) obtained in Step 1 was added to 260 mL of 98% by mass concentrated sulfuric acid at 85-90 C for 4 hours; After the reaction was completed, it was added to 1.0 kg of cold water at about 5 C, Stirred for 0.5 hours, Suction filtration, 78g crude product dried; To the crude product was added 800 mL of toluene and heated to reflux for 1 hour; The solution is then cooled to 80-90 C, Add 15g activated carbon, Stirred for 1 hour, Hot air filtration, The filtrate was distilled under reduced pressure to about 300g of toluene, Gradually cooled to 0-5 deg C, Continue stirring for 2 hours, Suction filtration, The filter cake was washed with 2 * 15 mL of frozen toluene, Dried to give 58 g of 5-hydroxy-4-methoxy-2-bromobenzaldehyde represented by the following formula 3 as an off-white solid, Yield 61.7%.
With bromine; sodium acetate; acetic acid;iron; at 20℃; for 0.75h;
Isovanillin (5 gm, 0.033 mol) was dissolved in glacial acetic acid (30 ml). Anhydrous sodium acetate (5.4 gm) was added to the above solution followed by powdered iron (0.15 gm). The system was flushed thoroughly with nitrogen. A solution of bromine (5.79 gm, 0.0362 mol) in glacial acetic acid (10 ml) was added to the above stirred suspension at room temperature over a period of 15 min. The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was poured into aqueous 2% sodium bisulfite (200 ml) and stirred for 10 min. The precipitate was filtered washed with water (100 ml), and dried to obtain 3.5 gm of 2-bromoisovanillin as white powder mp: (200-202C). IR (KBr) 3233,2990, 2891,2844, 1669,1593, 1564,1494, 1463,1286, 1238,1205, 1019, 987,805, 786 cm-1. 'H NMR (300 MHz, CDC13) 8 3.99 (s, 3H), 6.13 (s, 1H), 6.89 (d, 1H, J= 8. 4 Hz), 7.55 (d, 1H, J= 8. 4 Hz), 10.23 (s, 1H).
With N-Bromosuccinimide; In acetonitrile; for 8h;Reflux;
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
With potassium tert-butylate; In methanol; dimethyl sulfoxide; at 50℃; for 1.45h;Large scale;
A solution of potassium terf-butoxide (10.7 kg, 95.36 mol) in DMSO (49 L) was stirred at 50 C for 30 min. Methanol (49 L) was added slowly over a period of 4.25 h and stirred at 50 C for 30 min. 6-Bromobenzo[1 ,3]dioxole-5-carbaldehyde (1 b) (9.91 kg, 43.27 mol) was added to the reaction mixture in small portions over a period of 45 min and stirred at 50 C for 1 h. The reaction mixture was cooled to room temperature and split into two equal portions. Each portion was quenched with water (50.9 L) and basified with 50% aqueous NaOH solution (2.4 L). Each portion was extracted with MTBE (4 x 36 L) to remove impurities. The aqueous layer was acidified with cone. HCI to pH ~ 3 to obtain product as a yellow solid. The solid was collected by filtration using a centrifuge, washed with water (2 x 35 L) and air-dried to afford 2-Bromo-5-hydroxy-4-methoxy-benzaldehyde (1c) (4.37 kg, 40.7%, contains 7 % water); Mp: 100-102C; 1HNMR (300MHz, DMSO-d6): delta 10.00 (s, 1 H), 9.92 (s,1 H), 7.27 (s, 1 H), 7.26 (s, 1 H), 3.93 (s, 3H).
With potassium carbonate; In acetonitrile; at 80℃; for 15h;
To a solution of <strong>[2973-59-3]2-bromo-5-hydroxy-4-methoxy-benzaldehyde</strong> (25 g, 108 mmol) in MeCN (500 mL) was added (chloromethyl)benzene (13.7 g, 108 mmol) and potassium carbonate (29.9 g, 216 mmol). The mixture was heated at 80 C with stirring for 15 hours. After being cooledrt, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residuewas partitioned between brine and DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 5 -(benzyloxy)-2-bromo-4-methoxy- benzaldehyde (34.2 g, 96.9 mmol) which was used in the next step without further purification.
With pyridine; aluminium(III) iodide; In acetonitrile; at 80℃; for 18h;
General procedure: To a solution of AlI3 (36.6 mmol, 1.1 equiv) in MeCN (100 mL)was added dropwise a solution of pyridine (12.2 g, 154.2 mmol,4.6 equiv) and eugenol (5.4 g, 33.0 mmol). The mixture wasstirred at 80 C for 18 h. After cooling to room temperature, themixture was quenched with aq HCl (2 mol/L, 50 mL), and wasextracted with EtOAc (4 × 50 mL). The combined organic phaseswere washed with brine and dried by MgSO4. After evaporationof solvents by a rotary evaporator, the residue was purifiedthrough flash column chromatography to afford 5 as a whitesolid (4.9 g, 99%).
87%
To a 100 ml eggplant flask were added iodine (2.101 g), aluminum powder (0.385 g) and acetonitrile (40 ml), heated toReflux, stir for 2 hours to the purple red of iodine disappears. Pyridine (1.787 g) and <strong>[2973-59-3]2-bromo-5-hydroxy-4-methoxybenzaldehyde</strong> were added(1.161 g) and the reaction was continued for 18 hours. After stirring and cooling to room temperature, 2 mol / L dilute hydrochloric acid (10 ml) was added to the reaction solution,Acidified and extracted with ethyl acetate (50 ml x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration, the filtrate with rotary evaporationThe residue was purified by flash column chromatography (mobile phase ethyl acetate: petroleum ether = 1: 3, by volume) to give 2-Bromo-4,5-dihydroxybenzaldehyde (yellow solid, 0.946 g, 87% yield).
84%
With aluminium(III) iodide; In Dimethyl ether; acetonitrile; at 80℃; for 18h;
To a 100 ml eggplant-shaped flask, aluminum triiodide (2.240 g, 5.5 mmol), acetonitrile (40 ml) and DMSO (0.430 g, 5.5 mmol) were added, and the mixture was heated to 80 C with stirring, and kept under stirring for 0.5 hour, followed by stirring for 0.5 hour. Add <strong>[2973-59-3]2-bromo-4-methoxy-5-hydroxybenzaldehyde</strong> (1.155 g, 5.0 mmol), continue to incubate (80 C) to stir the reaction, stop the reaction after 18 hours, cool to room temperature and then into the eggplant bottle The mixture was acidified with EtOAc (EtOAc (EtOAc) (EtOAc) Dry over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness eluted with EtOAc EtOAc (EtOAc) -4,5-dihydroxybenzaldehyde (yellow solid, yield 84%).
84%
With aluminium(III) iodide; dimethyl sulfoxide; In acetonitrile; at 80℃; for 18h;
General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in MeCN was added anhyd DMSO (0.430 g, 5.5 mmol, 1.1 equiv). After stirring for 0.5 h at 80 C, the selected substrate (5 mmol) was added in one portion. The mixture was stirred overnight (18 h) at that temperature before quenching with aq 2 M HCl (10 mL). After extraction with EtOAc (3 50 mL), the organic phases were combined, washed with sat. aq Na2S2O3 and brine, and dried (MgSO4). The solvents were removed on a rotary evaporator, and the residue was purified by column chromatography to give the relevant catechol or phenol.
61%
With aluminium(III) iodide; diisopropyl-carbodiimide; In acetonitrile; at 80℃; for 18h;
To a 100 ml eggplant flask were added aluminum triiodide (2.250 g), acetonitrile (40 ml) DIC (0.378 g) and <strong>[2973-59-3]2-bromo-5-hydroxy-4-methoxybenzaldehyde</strong> (1.156 g), heated to 80 C, After stirring for 18 hours, the mixture was stirred, cooled to room temperature and then acidified with 2 mol / L dilute hydrochloric acid (10 ml) Extracted with ethyl acetate (50 ml X), the combined organic phases were washed with saturated aqueous sodium thiosulfate solution (10 ml) Washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness with a rotary evaporator, The residue was purified by flash column chromatography (eluent: ethyl acetate / petroleum ether = 1: 4, volume ratio) To give 0.666 g of 2-bromo-4,5-dihydroxybenzaldehyde (yellow solid in 61% yield)
42%
With boron tribromide; In dichloromethane; at 0 - 20℃; for 16h;
To a solution of 141 (30 g, 130 rnmoi) in DCM (500 mL) is added boron tribrornide (65.3 g, 261 rnmoi) dropwise at 0 C. After stirring at room temperature for 16 hours. MeOH (100 mL) is added and the mixture is concentrated and purified by silica gel column chromatography (MeOH :DCM = 1:15) to give 142 as a solid (12 g, 42% yield), (MS:[M+HJ 218.2)
With dmap; triethylamine; In dichloromethane; at 20℃;
(0036) To a stirred solution of 2-bromo-4-hydroxy-5-methoxybenzaldehyde (0.30 g, 1.30 mmol) in CH2Cl2 (13mL) at room temperature was added acetic anhydride (0.25mL, 2.60mmol), DMAP (0.16g, 1.30mmol) and Et3N (0.18mL, 1.30mmol). The reaction mixture was stirred until all of the starting material was consumed as monitored by TLC. Water (5mL) and CH2Cl2 (5mL) were added, and the two phases were separated. The aqueous layer was extracted with CH2Cl2 (10mL×2). The combined organic layers were washed with brine (10mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. Following purification by column chromatography on silica (40% EtOAc/hexanes), the product was obtained as a pale brown solid (0.35g, 1.27mmol, 98%) mp 95-96C. Rf (EtOAc/hexane) 0.53. IR (UATR): numax 1013, 1135, 1182, 1217, 1271, 1369, 1497, 1595, 1679, 1751cm-1. 1H NMR (300MHz, CDCl3): delta 2.31 (s, 3H), 3.92 (s, 3H), 7.17 (s, 1H), 7.62 (s, 1H), 10.17 (s, 1H). 13C NMR (75MHz, CDCl3): delta 20.4, 56.5, 116.8, 123.7, 125.6, 126.8, 139.6, 156.3, 168.3, 189.9. LRMS (EI) m/z (rel intensity) 232 (M[81Br]-OAc+H+, 99), 230 (M[79Br]-OAc+H+, 100), 229 (53). TOF-HRMS calcd for C10H1081BrO4 (M[81Br]+H+) 274.9738, found 274.9737; for C10H1079BrO4 (M[79Br]+H+) 272.9757, found 272.9748.
Step 1 2-Bromo-4-methoxy-5-(1-methylethoxy)benzaldehyde 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (100.0 g, 433 mmol), 2-bromopropane (160.0 g, 1.30 mol) and potassium carbonate (300 g, 2.16 mol, anhydrous, freshly ground) are stirred in acetonitrile (1200 ml) for 48 hours at 60 C. The reaction mixture is filtered, the solvent is distilled off in a rotary evaporator, and the residue is dispersed between water (800 ml) and ether (800 ml). The aqueous phase is extracted with ether (2*300 ml), the combined organic phases are washed with water (2*500 ml) and saturated common salt solution (1*500 ml), dried (sodium sulfate/activated carbon), filtered, and the residue that is obtained after the solvent was distilled off is recrystallized from methanol (500 ml). In this way, the product is obtained in the form of pale rose-colored crystals (98.1 g, 83%). Melting point: 75-76 C.; TLC: Petroleum ether:ethyl acetate=3:1, Rf=0.75; 1H NMR (CDCl3) delta 10.13 (s, 1H), 7.40 (s, 1H), 7.03 (s, 1H), 4.61 (septet, J=6.4 Hz, 1H), 3.92 (s, 3H), 1.38 (d, J=6.4 Hz 6H); 13C NMR (CDCl3): delta 190.8 (d), 15.6 (s), 147.1 (s), 126.4 (s), 120.0 (s), 115.8 (d), 113.7 (d), 71.5 (d), 56.4 (q), 21.8 (q).
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
In N,N-dimethyl-formamide; at 25℃; for 5h;Inert atmosphere;
<strong>[2973-59-3]2-bromo-5-hydroxy-4-methoxybenzaldehyde</strong> and then a 2 g (8.70 mmol) under a nitrogen condition dissolved in N, N- dimethylformamide, 87 mL (0.1 M), 1.8 g of potassium carbonate at 0oC (13.1 mmol), benzyl bromide 1.77 g (10.4 mmol) were added sequentially. .After the reaction temperature raised to 25 C, and reacted for 5 hours. It was added to 100 mL of ammonium chloride aqueous solution to terminate the reaction and extracted with EtOAc (3 × 30 mL). Washing the organic layer with brine (brine, 10 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound 5- (benzyloxy) -2-bromo-4-methoxybenzaldehyde 2.73 g (8.53 mmol, 98%).
83%
With potassium carbonate; In acetonitrile; at 50℃; for 20h;
2-Bromo-5-hydroxy-4-methoxybenzaldehyde (25 g, 0.108 mol) and K2CO3 (30 g, 0.216 mol) were added to acetonitrile (250 mL) and flushed with Ar. Benzyl bromide (20 g, 0.12 mol) was added and the mixture was heated under Ar for 20 h at 50 C. After cooling, the mixture was poured into water (200 ml) and extracted with CH2Cl2 (300 mL). The CH2Cl2 was washed with water (3*100 mL), dried and concentrated. Recrystallization with isopropanol: water (3:1) gave 28.8 g (83%) of 2 as a light brown solid. 1H-NMR (400 MHz, CDCl3) dH 3.96 (3H, s, OCH3), 5.16 (2H, s, CH2Ph), 7.07-7.48 (7H, m, ArH+CH2Ph), 10.16 (1H, s, CHO).
67.9%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution <strong>[2973-59-3]2-bromo-5-hydroxy-4-methoxybenzaldehyde</strong> (1c) (120 g, 520 mmol) in DMF (1000 mL) was added potassium carbonate (79 g, 572 mmol) and benzyl bromide (68 mL, 572 mmol). The reaction mixture was stirred at room temperature overnight and quenched with water (3000 mL). The solid obtained was collected by filtration, washed with ether and dried under vacuum to furnish 5-(benzyloxy)-2-bromo-4-methoxybenzaldehyde (1d) (113.19 g, 67.9%) as a white solid, MP 144 C; 1HNMR (300 MHz, DMSO-c/6): delta 10.06 (s, 1H), 7.47- 7.34 (m, 7H), 5.17 (s, 2H), 3.92 (s, 3H); IR (KBr) 2898, 2851 , 1673, 1592, 1502, 1437, 1402, 1264, 1210, 1158, 1017, 754 cm"1; Analysis calculated for C 5H13Br03: C, 56.10; H, 4.08; Found: C, 55.44; H, 4.08.
50%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
Compound 97: Compound 96 (1 g, 4.32 mmol) was dissolved in DMF (5 mL). K2CO3 (900 mg, 6.52 mmol) and benzyl bromide (940 mg, 5.50 mmol) were added. The reaction mixture was stirred at room temperature overnight; neutralized by the addition of sat. aq. K2RO4; and extracted with ethyl acetate. The organic extract was washed with water; dried with MgS04, filtered and concentrated to give compound 97 (695 mg, 50% yield) as a solid. m/z = 321, 323 (M+l).
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
With potassium carbonate; In acetonitrile; at 80℃; for 4h;
Add <strong>[2973-59-3]2-bromo-5-hydroxy-4-methoxybenzaldehyde</strong> (20 g, 86.56 mmol), acetonitrile (200 mL), potassium carbonate (24 g, 173.1 mmol), and benzyl bromide (10.8 mL, 90.9 mmol) to the reaction bottle in this order. ), Warmed to 80 C and stirred for 4h.Post-treatment: suction filtration while hot, washing the filter residue (200mL × 3) with ethyl acetate, spin-drying the filtrate, adding methanol (80mL), stirring and pulping for 1h, suction filtration, washing the filter cake (10mL × 2) with methanol, collecting the filter cake The title compound was obtained as a white solid by spin-drying and used directly in the next reaction.
With potassium carbonate; In acetonitrile; at 80℃; for 4h;
To the reaction flask were added <strong>[2973-59-3]2-bromo-5-hydroxy-4-methoxybenzaldehyde</strong> (20 g, 86.56 mmol) , acetonitrile (200 mL) , potassium carbonate (24 g, 173.1 mmol) and benzyl bromide (10.8 mL, 90.9 mmol) in turn. The mixture was warmed to 80 and stirred for 4 h. Post processing: The reaction solution was filtered and the filter residue was washed with with ethyl acetate (200 mL × 3) . The filtrate was concentrated in vacuo. The residue was stirred with methanol (80 mL) for 1 h, and then filtered. The filter cake was washed with methanol (10 mL × 2) and dried to give the title compound as a white solid for the next step reaction. MS (ESI, pos. ion) m/z: 321.1, 323.1 [M+H]+
With potassium fluoride; In dimethyl sulfoxide; at 140℃; for 4h;
To a stirred suspension of potassium fluoride (1.89 gm, 0.0326 mol) in dry DMSO (10 ml) was added a solution of <strong>[2973-59-3]2-bromoisovanillin</strong> (5.0 gm, 0.0217 mol) in DMSO (10 ml). A solution of 4-fluoronitrobenzene (5.0 gm, 0.0260 mol) in DMSO (5 ml) was added to the above suspension and the reaction mixture was stirred at 140C for 4 h. The reaction mixture was cooled to room temperature and the contents were poured into water (150 ml) and extracted with ethyl acetate (50 ml x 3). The organic extracts were combined and washed with IN sodium hydroxide (25 ml x 2), water and brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated in vacuo and the residue was purified by silica-gel column chromatography using 20% ethyl acetate-petroleum ether as the eluent to give 2-BROMO-3- (P-NITROPHENOXY)-4-METHOXY benzaldehyde as a pale yellow solid (5.0 gm) mp: 132-140C. IR (KBr) 3084,2874, 1689,1584, 1506,1486, 1348,1285, 1253,1234, 1114,1025, 848, 815, 747 cm-1. 'H NMR (300 MHz, CDC13) 8 3.86 (s, 3H), 6.89 (d, 2H, J= 7.2 Hz), 7.07 (d, 1H, J= 9.0 Hz), 7.92 (d, 1H, J= 8. 4 Hz), 8.17 (d, 2H, J= 9. 0 Hz), 10.24 (s, 1H).
With cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In methanol; 1,2-dimethoxyethane; at 70℃;
A mixture of <strong>[2973-59-3]2-bromo-5-hydroxy-4-methoxy-benzaldehyde</strong> (1.00 g, 4.32 mmol), 4- bromophenyl boronic acid (1.04 g, 5. 18 mmol), Pd (PPh3)4 (0.250 g), and CsF (1.97 g, 12. 6 mmol) in DME/MEOH (1: 1,65 mL) was heated at 70 C overnight. The mixture was diluted with CH2C12 and washed with water. The organic layer was dried over MGS04, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography eluting with HEXANE/CH2CLZ (1: 9) to give 0. 809G (60%) of the desired product which was carried into the next step without further purification. MS (DCI/NH3) m/z: 307.4 (M+H) +.
With ammonium acetate; In methanol; nitromethane; water;
Step 1: 4-Bromo-2-methoxy-5-(2-nitroethenyl)-phenol 40.0 g (173 mmol) of <strong>[2973-59-3]2-bromo-5-hydroxy-4-methoxybenzaldehyde</strong> and 13.3 g (173 mmol) of ammonium acetate are refluxed in 400 ml of nitromethane for 15 minutes. The reaction mixture is evaporated to the dry state, the residue is digested in about 70 ml of methanol and then suctioned off. To obtain a second fraction of the product, the methanol solution is concentrated by evaporation to about 30 ml and then poured onto 500 ml of water. The precipitated solid is filtered off by suction, washed with about 100 ml of water and dried together with the first fraction at 50 C./50 mbar, by which a total of 43.6 g (92% of theory) of yellow crystals is obtained on 4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol with a melting point of 152-154 C. TLC: CH2Cl2:MeOH=9:1; 1H-NMR (CDCl3; delta (ppm): 3.85 (s, 3H, OCH3); 7.30 (s, 1H, H-6); 7.38 (s, 1H, H-3); 8.03 (d, 3JHH=13.41 Hz, 1H, ArCH=); 8.16 (d, 3JHH=13.41 Hz, 1H, =CHNO2); 13C-NMR (CDCl3; delta (ppm): 56.3 (q, OCH3); 114.7 (d, C-6); 116.1 (d, C-3); 116.6 (s, C-2); 121.4 (s, C-1); 136.8 (d, ArCH=); 137.6 (d, =CHNO2); 146.5 (s, C-5); 152.2 (s, C-4)
Example 3; 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13); 1 Kg of 2-bromo-5-hydroxy-4-methoxy benzaldehyde (B2) and 1.255 Kg of sulfamic acid were added with stirring into a mixture of 4.473 Kg of EtOAc and 8 L of water. The reaction mixture was stirred until all of the solid had dissolved. The reaction mixture was cooled to between -10 and 0 C. An aqueous solution of sodium chlorite was prepared by dissolving 505 g of sodium chlorite in 3 L of water. The sodium chlorite solution was added to the pre-cooled B2 solution at a rate that maintained the reaction temperature under 5 C. After the complete addition of sodium chlorite solution, the reaction mixture was stirred for another hour at 0 C. and was then allowed to warm up to room temperature. The reaction was monitored by TLC. After the TLC analysis showed completion of the reaction, the aqueous layer was separated. The aqueous layer was extracted with EtOAc (1.789 Kg) and the combined organic layer was transferred to another flask and EtOAc was removed by vacuum distillation at 40 C. 6.92 Kg of toluene was added at between 30 to 40 C., the slurry was cooled to between -10 to 0 C. and the precipitate was collected by filtration to give about 950 g (89% (wt?)yield) of 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13). 1H NMR (CDCl3) delta 3.95 (3H, s, CH3), 7.22 (1H, s, CH), 7.46 (1H, s, CH).
With sodium sulfate; triethylamine; In tetrahydrofuran; at 80℃; for 3h;Microwave irradiation;
General procedure: In a 20 mL glass tube equipped with septa, the aldehyde, dry Na2SO4 (2.81 equiv) and triethylamine (2 equiv) were suspended in dry THF. Then, the hydroxylamine hydrochloride (2 equiv) was added. The mixture was stirred for 30 s, and then exposed to MWI (250 W) at 80 °C during the time indicated for each compound. When the reaction was over (TLC analysis), the reaction mixture was diluted with water, extracted with CH2Cl2, dried over anhydrous sodium sulphate, filtered and the solvent was evaporated. The resultant solid was purified by column chromatography to give pure compounds.
With sodium sulfate; triethylamine; In tetrahydrofuran; at 80℃; for 0.916667h;Microwave irradiation;
General procedure: In a 20 mL glass tube equipped with septa, the aldehyde, dry Na2SO4 (2.81 equiv) and triethylamine (2 equiv) were suspended in dry THF. Then, the hydroxylamine hydrochloride (2 equiv) was added. The mixture was stirred for 30 s, and then exposed to MWI (250 W) at 80 C during the time indicated for each compound. When the reaction was(TLC analysis), the reaction mixture was diluted with water, extracted with CH2Cl2, driedanhydrous sodium sulphate, filtered and the solvent was evaporated. The resultant solid was purified by column chromatography to give pure compounds.
General procedure: A mixture of 8 (1 mmol), aromatic aldehyde (1 mmol) and piperdine (2 equiv.) in isopropyl alcohol was refluxed for 4-5 h. After completion of the reaction as seen from the TLC, (eluent 7:3 /hexane:ethyl acetate) the mixture was allowed to cool to room temperature. Then the reaction mixture was poured onto ice-water and neutralized with dilute HCl. The precipitated solid was filtered, washed with water and dried under vacuum.
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).
A solution of potassium tert-butoxide (397 g, 3.36 mol) in DMSO (1.5 L) was heated at 50 C for 30 min. Methanol (1.5 L) was added to it and continued heating at 50 C for additional 30 min. To the hot reaction mixture was added 6-bromo-benzo[d][1,3]dioxole-5-carbaldehyde (1 b) (350g, 1.53 mol) and continued heating at 50 C for 30 min. The reaction mixture was cooled to room temperature and quenched with water (2.3 L) and sodium hydroxide (61.2 g, 1.53 mol). The reaction mixture was washed with ether (2 x 1.5 L), acidified to pH 2 using cone. HCI and extracted with ethyl acetate ( 1 L). The ethyl acetate layers were combined and concentrated under vacuum to dryness. The residue obtained was treated with water (1.5 L) and ethyl acetate (1 L). The solid obtained was collected by filtration to furnish 2-bromo-5-hydroxy-4-methoxybenzaldehyde (1c) (97 g, 27.5% as a first crop). The layers from the filtrate were separated and aqueous layer was extracted with ethyl acetate (200 ml_). The ethyl acetate layers were combined dried over MgS04 and concentrated under vacuum to dryness to furnish 2-bromo-5-hydroxy-4-methoxybenzaldehyde (1c) (192 g, 54.4%, second crop) as an orange solid, MP 108 C; 'HNMR (300MHz, DMSO-cfe): S 10.00 (s, 1 H), 9.92 (s,1 H), 7.27 (s, 1 H), 7.26 (s, 1 H), 3.93 (s, 3H); IR (KBr) 3477, 2967, 2917, 2837, 2767, 2740, 1657, 1595, 1428, 1270, 1210, 1164, 1022 cm"'; Analysis calculated for C8H7Br03.H20: C, 38.58; H, 3.64: Found: C, 38.60; H, 3.60.
A solution of potassium tert-butoxide (10.7 kg, 95.36 mol) in DMSO (49 L) was stirred at 50 C for 30 min. methanol (49 L) was added slowly over a period of 4.25 h and stirred at 50 C for 30 min. 6-Bromobenzo[l,3]dioxole-5-carbaldehyde (lb) (9.91 kg, 43.27 mol) was added to the reaction mixture in small portions over a period of 45 min and stirred at 50 C for 1 h. The reaction mixture was cooled to room temperature and split into two equal portions. Each portion was quenched with water (50.9 L) and basified with 50% aqueous NaOH solution (2.4 L). Each portion was extracted with MTBE (4 x 36 L) to remove impurities. The aqueous layer was acidified with cone. HC1 to pH ~ 3 to obtain product as a yellow solid. The solid was collected by filtration using a centrifuge, washed with water (2 x 35 L) and air- dried to afford 2-Bromo-5-hydroxy-4-methoxy-benzaldehyde (lc) (4.37 kg, 40.7%, contains 7 % water); Mp: 100-102C; NMR (300MHz, OMSO-de): delta 10.00 (s, 1H), 9.92 (s, lH), 7.27 (s, 1H), 7.26 (s, 1H), 3.93 (s, 3H).
5-hydroxy-4-methoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.6%
With tetrakis(triphenylphosphine) palladium(0); potassium acetate; In toluene; at 90℃; for 10h;Dean-Stark; Reflux; Large scale;
Bromo-5-hydroxy-4-methoxy-benzaldehyde (1c) [1.3 kg (93%, 7% water content), 5.25 mol] was dissolved in toluene (13 L) in a reaction flask equipped with a Dean Stark apparatus. The solution was heated at reflux with stirring to distil off about 25% of the toluene along with water (90 ml_). The solution was cooled to 90 C then (0887) bis(pinacolato)diboron (1.5 kg, 5.82 mol), KOAc (772.6 g, 7.87 mol) and Pd(PPh3) (24.3 g, 0.02 mol) were added and the reaction mixture was heated at reflux for 10h. After confirming the completion of reaction by TLC (mobile phase: 100% DCM), the reaction mixture was cooled to room temperature and was kept standing overnight. The reaction mixture was filtered through celite and the celite cake was washed with toluene (4 L). The filtrate of this batch was mixed with the filtrate of another batch (batch size 1.3 kg obtained from an identical reaction). The mixed filtrate was washed with water (17.5 L), brine (17.5 L), dried over Na2S04, filtered and the solution was passed through a pad of silica gel (2 kg, mesh size 230-400). The silica gel pad was washed with toluene. The combined filtrate and washing was concentrated under reduced pressure and the residual crude product was stirred with n-hexane (23 L) for 1 h to obtain a solid product. The solid was collected by filtration, washed with n-hexane (5 L) and dried to afford 5- hydroxy-4-methoxy-2-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)benzaldehyde (4a) (2.47 kg, 84.6%). H NMR (300 MHz, CDCI3) delta 10.54 (s, 1 H), 7.57 (s, 1 H), 7.33 (s, 1 H), 5.89 (s, 1 H), 4.01 (s, 3H), 1.37 (s, 12H); 1H NMR (300 MHz, DMSO-d6) delta 10.35 (s, 1 H), 9.95 (s, 1 H), 7.33 (s, 1 H), 7.23 (s, 1 H), 3.87 (s, 3H), 1.33 (s, 12H); MS (ES+) 301.1 (M+Na); 579.1 (2M+Na); Analysis calculated for C14H19B05: C, 60.46; H, 6.89; Found: C, 60.60; H, 6.87
4-bromo-5-formyl-2-methoxyphenyl methyl carbonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With dmap; triethylamine; In dichloromethane; at 20℃;
(0037) To a stirred solution of 2-bromo-4-hydroxy-5-methoxybenzaldehyde (1.00g, 4.33mmol) in CH2Cl2 (40mL) at room temperature was added methyl chloroformate (0.40mL, 5.19mmol), DMAP (0.026g, 0.22mmol) and Et3N (0.60mL, 4.33mmol). The reaction mixture was stirred until all of the starting material was consumed as monitored by TLC. Water (20mL) and CH2Cl2 (10mL) were added, and the two phases were separated. The aqueous layer was extracted with CH2Cl2 (20mL×2). The combined organic layers were washed with brine (20mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. Following purification by column chromatography on silica (40% EtOAc/hexanes), the product was obtained as a white solid (1.25g, 4.32mmol, 99%). Rf (40% EtOAc/hexane) 0.58. IR (UATR): numax 1022, 1194, 1260, 1438, 1501, 1601, 1683, 1766, 2851, 2959cm-1. 1H NMR (300MHz, CDCl3): delta 3.92 (s, 3H), 3.95 (s, 3H), 7.19 (s, 1H), 7.72 (s, 1H), 10.18 (s, 1H). 13C NMR (75MHz, CDCl3): delta 55.9, 56.7, 110.0, 123.3, 125.8, 126.8, 139.9, 153.1, 156.3, 189.8. LRMS (EI) m/z (rel intensity) 290 (M[81Br]+H+, 63) 288 (M[79Br]+H+, 65), 243 (100), 94 (94). TOF-HRMS calcd for C10H981BrO5Na (M[81Br]+Na+) 312.9505, found 312.9540; for C10H979BrO5Na (M[79Br]+Na+) 310.9526, found 310.9524.
With sulfuric acid; at 50 - 65℃; for 4h;Large scale;
To the reactor D, 1830 kg of concentrated sulfuric acid was added, and 572 kg of the compound II obtained in the step was added with stirring,Heating to 50 ~ 55 insulation reaction 1h, and then heated to 60 ~ 65 incubation reaction 3h.After the reaction of the material into the water containing 6,600 kg of ice-water tank, cooled to 40 C below the discharge centrifugal, filter cakeWashed to pH = 6 ~ 7, 6 - bromoiso-vanillin crude.6-bromoiso-vanillin crude 10 times in turn followed by toluene dissolved, activated clay decolorization, hot filter, the filtrate cooled to the stirring0 C crystallization, filtration, filter cake by 60 C drying, get 385.3kg pale yellow solid powder 6-bromoiso-vanillin refined products, yield(In terms of compound II) of 75.5%
With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 8h;
To a solution of 141 (231 mg. 1.0 mrnoi) and 222 (200 mg, 1.2 mmol) in DMF (15 mL) is added potassium iert-buioxide (135 mg. 1.2 mmoi). After stirring al 100 C for 8hours, the mixture is concentrated and purified by silica gel column chromatography (EA:PE 1:3) to give CB9 as a cHow solid (175 mg. 54%). (MS: [M+Hr 383.2)
5-tert-butyldiphenylsilyloxy-4-methoxy-2-bromobenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
5-Hydroxy-4-methoxy-2-bromobenzaldehyde (150 g, 0.649 mol) prepared in Step 2 Was dissolved in 800 mL of tetrahydrofuran (moisture = 0.08%), 60% NaH (28.6 g, 0.714 mol) was added in 3 portions, Add 9.5g each batch, Plus warming to reflux, Then continue stirring for 1 hour, To this was added tert-butyldiphenylchlorosilane (214.5 g, 0.780 mol) Drop end to continue reflux reaction 16 hours, Cooled to room temperature, Add 600mL water, Liquid separation, The organic phase was distilled off until the basic no longer drip, To the residue was added 800 mL of 95% ethanol, Stirring at room temperature to precipitate a large amount of solid, Cooling to 0 deg C or so, Continue stirring for 2 hours, Suction filtration, The filter cake was washed with 2 * 40 mL of ice-cold 90% ethanol, Drying to obtain 288 g of 5-t-butyldiphenylsiloxy-4-methoxy-2-bromobenzaldehyde shown by the following formula 4 as a white solid, Yield 94%.
2-bromo-4-methoxy-5-(3-methoxypropoxy)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1h;
To a solution of 1OA (10 g, 43 mmol) in DMF (40 ml) was added K2C03 (12 g, 87mmol) followed by dropwise addition of 1-bromo-3-methoxypropane (7.3 g, 48mmol). The reaction mixture was heated to 50 C for lh. The reaction was then pouredonto ice and water and the resulting solid was collected by filtration. The solid waswashed with water and dried. ?H NMR (400 MHz, Chloroform-d) oe 10.17 (s, 1H), 7.43(s, 1H), 7.04 (s, 1H), 4.14 (t, J= 6.5 Hz, 3H), 3.93 (s, 3H), 3.54 (t, J = 6.1 Hz, 3H), 3.34(s, 3H), 2.10 (p, J= 6.3 Hz, 3H).
The synthesis route is as follows:The synthesis method is: a multi-function reactor of a 4-liter four-necked flask, four connected to a dropping funnel, a thermometer, and a condensation tube, respectively;Blender. A certain amount of acetonitrile-methanol mixed solvent was added to the reactor and a certain amount of 6-bromoisovanillin was added. Start stirringMix the device at a speed of 100 r/min and stir for about 20 minutes until 6-bromoisovanillin is completely dissolved. Start heating to about 50C,Add 0.1mol/L ethanol solution of n-hexylamine in a suitable amount, and control the flow rate to 1.0-1.5mLmin, and control the reaction temperature.About 80 C. After the addition was completed, the reaction was carried out at this temperature for 6-7 hours; the solution turned from colorless to yellow-brown and the condensation was complete.The product is filtered and dried: After the reactor is cooled, the reactants are taken out, filtered and dried to obtain 6-bromoisovanillin.Chain organic amine Schiff base.Solvent recovery: Part of the solvent is evaporated. Part of the target product dissolved in the solvent is further precipitated, filtered, dried and collected.Target product.The target product was a pale yellow crystalline solid, melting point 140-141C.Ratio of reaction raw materials, the ratio of the amount of 6-bromoisovanillin to n-hexylamine is 1:1.1; n-hexylamine is slightly overAmount to ensure complete conversion of 6-bromoisovanillin.
5-(allyloxy)-2-bromo-4-methoxybenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
General procedure: NBS (180 mg, 1.0 mmol) was added to a stirred solution of isovanillin (1; 152 mg, 1.0 mmol) in MeCN (10 mL) at r.t. and stirred for 10 min. The mixture was then stirred at reflux for 8 h. The reaction was monitored by TLC until 1 was consumed. Then, K2CO3 (276 mg, 2.0 mmol) was added to a stirred solution of the resulting product in MeCN (10 mL) at r.t. and stirred for 10 min. The corresponding alkyl halide (RX, for 3a-g and 3i-m, 1.2 mmol; 1,6-dibromohexane for 3h, 134 mg, 0.55 mmol) was added at r.t. and the mixture was stirred at reflux for 8 h. The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product 2. Without further purification, freshly prepared phenylallylboronic pinacol ester (365 mg, 1.5 mmol), Pd(OAc)2 (45 mg, 20 mol %), PPh3 (130 mg, 0.5 mmol), and Na2CO3 (110 mg, 1.0 mmol) were added sequentially to a solution of the bromide 2 in EtOH (15 mL) at r.t. The reaction mixture was stirred at reflux for 8 h (the reaction was monitored by TLC). The mixture was cooled to r.t., concentrated, and extracted with EtOAc (3 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the crude product. Purification on silica gel (hexanes/EtOAc 8:1 to 4:1) afforded the desired 3a-m.
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