* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Bulletin de la Societe Chimique de France, 1939, vol. <5> 6, p. 1025,1033
2
[ 14804-31-0 ]
[ 2362-12-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With boron tribromide In dichloromethane at -78 - 0℃; for 6 h; Stage #2: With water; sodium hydrogencarbonate In dichloromethane
Example 83: Preparation of the compound 83.; (1) Preparation of the intermediate 83(1).; Boron tribromide (2.0 ml, 21.116 mmol) was added dropwise to a solution of 5-bromo-2-methoxytoluene (2.108 g, 10.486 mmol) in dichloromethane (20 ml) at -78 °C, and the mixture was stirred at 0 °C for 6 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane : ethyl acetate = 15 : 1) to give the title compound (1.942 g, 99 percent) as a white solid. 1H-NMR (CDCl3) δ: 2.22 (3H, s), 4.83 (1H, s), 6.65 (1H, d, J = 8.4 Hz), 7.16 (1H, dd, J = 2.4, 8.4 Hz), 7.23 (1H, d, J = 2.4 Hz).
Reference：
[1] Patent: EP2272817, 2011, A1, . Location in patent: Page/Page column 271
[2] Journal of the American Chemical Society, 2001, vol. 123, # 28, p. 6809 - 6818
[3] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 10, p. 1162 - 1166
General procedure: 1 mL [Bmim]NO3, 0.5 mmolsubstrate and 0.25 mmol Br2 were added to a dried 45 mL tube equipped witha magnetic stirring (note: the air in the tube was not removed). Then thereaction tube was sealed to perform the reaction at 80 C for 24 h. Once thereaction time was reached, the mixture was cooled to room temperature and3 mL water was added. Then the desired product was extracted with CH2Cl2(3 10 mL). GC analysis of the mixture provided the GC yield of the product.The product in another parallel experiment was purified by columnchromatography, and identified by 1H NMR and 13C NMR.
Reference：
[1] Helvetica Chimica Acta, 1983, vol. 66, # 4, p. 1068 - 1077
[2] Helvetica Chimica Acta, 1983, vol. 66, # 4, p. 1068 - 1077
[3] Synthetic Communications, 2007, vol. 37, # 2, p. 323 - 328
[4] Chemistry - A European Journal, 2015, vol. 21, # 34, p. 11976 - 11979
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1999, vol. 38, # 5, p. 603 - 604
[6] Synthetic Communications, 1998, vol. 28, # 8, p. 1463 - 1470
[7] Russian Journal of Organic Chemistry, 2007, vol. 43, # 9, p. 1282 - 1284
[8] Journal of Organic Chemistry, 1995, vol. 60, # 16, p. 5328 - 5331
[9] Journal of Chemical Research - Part S, 1998, # 10, p. 662 - 663
[10] Organic Letters, 2006, vol. 8, # 18, p. 3987 - 3990
[11] Journal of the Serbian Chemical Society, 2011, vol. 76, # 5, p. 685 - 692
[12] Polyhedron, 2013, vol. 52, p. 246 - 254
[13] Australian Journal of Chemistry, 2015, vol. 68, # 3, p. 513 - 517
[14] Green Chemistry, 2018, vol. 20, # 19, p. 4448 - 4452
[15] Tetrahedron Letters, 2000, vol. 41, # 8, p. 1151 - 1154
[16] Tetrahedron Letters, 2003, vol. 44, # 49, p. 8781 - 8785
[17] Tetrahedron Letters, 2003, vol. 44, # 9, p. 1815 - 1817
[18] Synthetic Communications, 2005, vol. 35, # 14, p. 1947 - 1952
[19] Synthetic Communications, 2008, vol. 38, # 16, p. 2814 - 2819
[20] Organic Letters, 2017, vol. 19, # 16, p. 4243 - 4246
[21] Synthetic Communications, 1993, vol. 23, # 6, p. 779 - 788
[22] Chemistry - A European Journal, 2017, vol. 23, # 5, p. 1044 - 1047
[23] Journal of Organic Chemistry, 1997, vol. 62, # 13, p. 4321 - 4326
[24] Chemistry - A European Journal, 2004, vol. 10, # 20, p. 5233 - 5242
[25] Monatshefte fur Chemie, 2013, vol. 144, # 2, p. 179 - 181
[26] Dalton Transactions, 2017, vol. 46, # 20, p. 6553 - 6569
[27] Tetrahedron Letters, 2015, vol. 56, # 46, p. 6452 - 6455
[28] Bulletin de la Societe Chimique de France, 1981, vol. 1, # 1-2, p. 42 - 48
[29] Am. Perfumer, 1930, vol. 25, p. 19,75
[30] Journal of the American Chemical Society, 1930, vol. 52, p. 4087,4090
[31] Journal of the Chemical Society, 1923, vol. 123, p. 1992
[32] Tetrahedron, 1967, vol. 23, p. 2253 - 2264
[33] Journal of the Indian Chemical Society, 1963, vol. 40, # 5, p. 327 - 338
[34] Synthetic Communications, 1992, vol. 22, # 17, p. 2571 - 2578
[35] Journal of the American Chemical Society, 2001, vol. 123, # 28, p. 6809 - 6818
[36] Patent: US5214046, 1993, A,
[37] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 10, p. 1162 - 1166
Reference：
[1] Chemical Science, 2018, vol. 9, # 15, p. 3860 - 3865
7
[ 2362-12-1 ]
[ 77-78-1 ]
[ 14804-31-0 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 1, p. 1 - 5
[2] Bulletin de la Societe Chimique de France, 1961, p. 1900 - 1905
[3] Journal of the American Chemical Society, 1925, vol. 47, p. 2025
[4] Journal of Medicinal Chemistry, 1996, vol. 39, # 9, p. 1846 - 1856
Reference：
[1] Bulletin de la Societe Chimique de France, 1939, vol. <5> 6, p. 1025,1033
[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1932, vol. 195, p. 155[3] Bulletin de la Societe Chimique de France, 1934, vol. <5> 1, p. 539,541
10
[ 104-92-7 ]
[ 14804-31-0 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1932, vol. 195, p. 155[2] Bulletin de la Societe Chimique de France, 1934, vol. <5> 1, p. 539,541
[3] Bulletin de la Societe Chimique de France, 1939, vol. <5> 6, p. 1025,1033
11
[ 95-48-7 ]
[ 77-78-1 ]
[ 14804-31-0 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 20, p. 9889 - 9899
12
[ 2362-12-1 ]
[ 14804-31-0 ]
Reference：
[1] Journal of the Chemical Society, 1960, p. 959 - 963
13
[ 7017-52-9 ]
[ 925-90-6 ]
[ 14804-31-0 ]
[ 178363-65-0 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1934, vol. 198, p. 2107[2] Bulletin de la Societe Chimique de France, 1934, vol. <5> 1, p. 539,541
14
[ 46202-40-8 ]
[ 7726-95-6 ]
[ 14804-31-0 ]
Reference：
[1] Journal of the Chemical Society, 1923, vol. 123, p. 1992
15
[ 578-58-5 ]
[ 7726-95-6 ]
[ 64-19-7 ]
[ 14804-31-0 ]
Reference：
[1] Journal of the Chemical Society, 1923, vol. 123, p. 1992
16
[ 124-38-9 ]
[ 14804-31-0 ]
[ 6880-04-2 ]
Reference：
[1] Organic Letters, 2006, vol. 8, # 18, p. 3987 - 3990
[2] Chemistry - A European Journal, 2004, vol. 10, # 20, p. 5233 - 5242
Reference：
[1] European Journal of Organic Chemistry, 2014, vol. 2014, # 19, p. 4115 - 4122
[2] Organic Letters, 2013, vol. 15, # 16, p. 4194 - 4197
21
[ 14804-31-0 ]
[ 175883-62-2 ]
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 36, p. 10977 - 10996
[2] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 6, p. 588 - 598
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 5, p. 2324 - 2341
22
[ 14804-31-0 ]
[ 184970-28-3 ]
Reference：
[1] Organic Letters, 2013, vol. 15, # 16, p. 4194 - 4197
[2] European Journal of Organic Chemistry, 2014, vol. 2014, # 16, p. 3402 - 3410
[3] Patent: US2018/155298, 2018, A1, . Location in patent: Paragraph 1052; 1053
A mixture of bis(pinacolato)diborane (10.7 g, 42.1 mmol), 4-bromo-1-methoxy-2-methylbenzene (7.70 g, 38.3 mmol) and KOAc (10.9 g, 114 mmol) in DMSO (200 mL) was degassed with argon for 10 min. PdCl2dppf (1:1 complex with CH2Cl2, 2.50 g, 3.06 mmol) was next added and the reaction mixture was heated to 80 C. for 24 h. The reaction mixture was diluted with water and extracted with C6H6 (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 95:5) to yield the title compound (5.1 g, 54% yield) as a colorless oil.
2-Methoxy-5-bromo-α,α-dimethylbenzyl cyanide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49 g (92%)
With bromine; dibenzoyl peroxide; In water; N,N-dimethyl-formamide;
(a) 2-Methoxy-5-bromo-alpha,alpha-dimethylbenzylcyanide 2-Methoxy-5-bromobenzyl cyanide (prepared by reaction of 2-methyl-4-bromoanisole, benzoyl peroxide and bromine, followed by reaction with sodium cyanide) (47 g, 0.208 mole) in dimethyl formamide (100 ml) was added cautiously to a cooled, stirred mixture of sodium hydride 10 g (0.416 mole) and dry dimethyl formamide (500 ml). After 15 minutes, methyl iodide (59 g, 0.416 mole) was added dropwise at 15-20 C. (external cooling) and the mixture stirred at room temperature for 21/2 hours. Water was then added very cautiously until no further reaction occurred. Addition to a large excess of ice and filtration gave after drying 49 g (92%) buff solid which was shown to be the title product by NMR.
Stage #1: 2-methyl-4-bromoanisole With potassium acetate In DMF (N,N-dimethyl-formamide) at 80℃; for 24h;
Stage #2: 2-(4-bromophenyl)-acetic acid With sodium carbonate In water at 25 - 80℃; for 12h;
3b
Step b: To a degassed (argon) solution of 3b (10.0 g, 49.7 [MMOL)] in DMF (310 mL) was added bis (pinacolato) diborane (13.9 g, 54.7 [MMOL), KOAC] (14.2 g, 149 [MMOL)] and [PDCL2DPPF] (1: 1 complex with [CH2CI2,] 4.87 g, 5.96 [MMOL).] The reaction mixture was heated to 80 C for 24 h then was cooled to 25 [C.] 4-Bromobenzeneacetic acid (21.4 g, 99.5 [MMOL),] aqueous 2 M [NA2CO3 SOLUTION] (124 mL, 248 [MMOL)] and additional [PDCI2DPPF] (1: 1 complex with [CH2CI2,] 4.87 g, 5.96 [MMOL)] were added to the mixture. The reaction mixture was heated to [80 C] for 12 h. The cooled mixture was acidified with aqueous 4 N HCI solution and extracted with EtOAc (3 x). The combined organic layers were successively washed with water (2 x) and brine, dried [(MGS04),] filtered and concentrated under reduced pressure. The crude resulting acid was dissolved in [ET2O] and was treated with excess ethereal [CH2N2] solution (ca. 0.6 M). The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc, 19/1) to give 3c (4.25 g, 32% yield) as a pale yellow solid.
(RS)-1-(3-Bromo-5-fluorophenyl)-1-(4-methoxy-3-methylphenyl)-ethanol Magnesium turnings (627 mg) and a crystal of iodine were suspended in tetrahydrofuran (10 mL) at room temperature. To this was added ~5 mL of a solution of 4-bromo-2-methylanisole (4.54 g) in tetrahydrofuran (50 mL). The mixture was then heated to reflux until initiation (colour change from brown to colourless ~15-30 min) after which time the heat was removed. The remaining 4-bromo-2-methylanisole solution was added dropwise to maintain a gentle reflux and then heated at reflux for 2 h. Upon cooling to room temperature, a solution of <strong>[105515-20-6]1-(3-bromo-5-fluorophenyl)-ethanone</strong> (4.67 g) in tetrahydrofuran (50 mL) was added dropwise, again maintaining a gentle reflux. This was then heated at reflux for 2 h before being allowed to cool to room temperature, poured onto ice-water (400 mL), and the solvent removed by evaporation. The product was extracted with ethyl acetate (3*100 mL), dried over sodium sulfate and the solvent removed by evaporation to yield a yellow oil. Purification by flash chromatography on silica (20:1-5:1 hexane/ethyl acetate) yielded the alcohol as a yellow oil (4.4 g, 60%). 1H NMR (CDCl3): 1.88 (3H, s, ArCH3), 2.19 (3H, s, ArCH3), 3.81 (3H, s, ArOCH3), 6.76 (1H, d, Ar), 7.00-7.20 (4H, m, Ar), 7.34 (1H, t, Ar).
4-[1-(3-Bromo-4-fluoro-phenyl)-vinyl]-1-methoxy-2-methyl-benzene 8 mL of a solution of 4-bromo-2-methylanisole (5.22 g, 26 mmol, 1.1 eq) in 40 mL of dry diethyl ether was added dropwise to a mixture of magnesium turnings (700 mg, 28.8 mmol, 1.2 eq) in 5 mL of dry diethyl ether under an inert atmosphere. A drop of bromine was added to initiate the reaction and gas evolution was observed. The remaining solution of 4-bromo-2-methylanisole (32 mL) was added and the reaction was stirred for 4 h at room temperature. The solution was then cooled to 0 C. and a solution of <strong>[1007-15-4]4-fluoro-3-bromoacetophenone</strong> in 40 mL of dry diethyl ether was added; the mixture was stirred while warming to room temperature for 2 h. The solution was examined by TLC (cyclohexane/ethyl acetate 6%) which showed consumption of starting material. The solution was quenched with water, until gas evolution ceased, and then 1N HCl was added to reach a pH=5. The two phases formed were separated; the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude (tertiary alcohol) and a catalytic amount of p-toluene sulfonic acid were dissolved in 100 mL toluene (Dean-Stark apparatus) and the mixture was heated to reflux for 3 h. The solution was examined by TLC (cyclohexane/ethyl acetate 6%) which showed consumption of starting material but many side products formed. Solvent was evaporated under reduced pressure and the crude residue was purified by flash chromatography eluding with a gradient (cyclohexane/ethyl acetate 0-4%). 1.65 g of product was obtained as liquid (20%). Mass (calculated) C16H14BrFO [321] M-H+ not observed LC Rt=3.15, (5 min method) 1H-NMR (CDCl3): 2.21 (s, 3H); 3.85 (s, 3H); 5.29 (s, 1H), 5.38 (s, 1H), 6.79 (m, 1H), 6.84 (m, 1H), 7.09 (m, 2H), 7.24 (m, 1H); 7.55 (m, 1H) 90%
Stage #1: 2-methyl-4-bromoanisole With iodine; magnesium In tetrahydrofuran at 20℃; Heating; Reflux;
Stage #2: 3-bromo-4-methylacetophenone In tetrahydrofuran at 20℃; Heating; Reflux;
AN 2-Bromo-4-[1-(4-methoxy-3-methylphenyl)-vinyl]-1-methyl-benzene
2-Bromo-4-[1-(4-methoxy-3-methylphenyl)-vinyl]-1-methyl-benzene Magnesium turnings (342 mg) and a crystal of iodine were suspended in tetrahydrofuran (5 mL) at room temperature. To this was added ~5 mL of a solution of 4-bromo-2-methylanisole (2.48 g) in tetrahydrofuran (25 mL). The mixture was then heated to reflux until initiation (colour change from brown to colourless ~15-30 mins) after which time the heat was removed. The remaining 4-bromo-2-methylanisole solution was added dropwise to maintain a gentle reflux and the mixture was then heated to reflux for 2 hours. On cooling to room temperature, a solution of 4-methyl-3-bromoacteophenone (2.5 g) in tetrahydrofuran (25 mL) was added dropwise, again maintaining a gentle reflux. This was then heated to reflux for 2 hours before being cooled to room temperature and the solvent removed under vacuum. The reaction was quenched with 2 M HCl (20 mL) and the product extracted with ethyl acetate (3*20 mL). The organic layers were combined, dried over sodium sulfate and the solvent removed under vacuum to yield a yellow oil. Purification by dry flash chromatography (hexane) yielded 2-bromo-4-[1-(4-methoxy-3-methylphenyl)-vinyl]-1-methyl-benzene as a colourless oil which solidified upon standing (2.19 g, 59%), mp 48-51° C. 1H NMR (CDCl3): 2.20 (3H, s, ArCH3), 2.41 (3H, s, ArCH3), 3.85 (3H, s, ArOCH3), 5.30 and 5.35 (each 1H, s, Ar2C=CH2), 6.79 (1H, d, Ar), 7.09-7.17 (4H, m, Ar), 7.53 (1H, s, Ar)
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 95℃; for 3h;
A mixture of 4-bromo-1-methoxy-2-methylbenzene (1.0 eq) in CCl4 (0.3M), NBS (1.1 eq), and AIBN (0.2 eq) was stirred at 95 C. for 3 h. Then the mixture was filtered and the filtration was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on a silica gel (eluent: PE) to give the title compound as a white solid.
4-Bromo-1-methoxy-2-methylbenzene (3.134 mg, 15.6 mmol), sodium tert- butoxide (3.053 g, 32 mmol), Palladium(ll) acetate (69 mg, 0.3 mmol), 1 ,1'- bis(diphenylphosphino)ferrocene (DPPF) (169 mg, 0.3 mmol) are dissolved in toluene (10 ml) in a 4-neck flask with condenser. The reaction mixture is stirred under N2 flow for 5 minutes, then 4-methoxy-3-methylphenylaniline (2.064 g, 15.0 mmol) and 40 ml_ of toluene are added. The mixture is heated to 120 C for 21 h. After the reaction, the reaction mixture is filtered. After concentration by rotary evaporator and purification by flash column chromatography over silica gel (hexane/EtOAc 2 % -> 20 %) the product is obtained as an orange viscous oil. This oil is recrystallized by hexane thermally, to obtain bis(4-methoxy-3-methylphenyl)amine as white solid [2.725 g, 10.6 mmol, yield 70.4 %]. C16H19N02, MW 257.33, Exact MS 257, GC-MS 257[M]+).
In nitrogen atmosphere, to a 500 ml three-neck flask, 16.2 g (80.6 mmol) of 4-bromo-2-methylanisole, and 200 ml of dehydrated diethyl ether were added. While the mixture was cooled in a methanol/dry ice bath, 51.6 ml (84.6 mmol) of a n-butyllithium/hexane solution (1.64 M) was gradually added. While the temperature was gradually elevated to room temperature, the mixture was stirred for 15 hours. While the mixture was cooled in an ice bath, a solution composed of 5.06 g (32.2 mmol) of N-carboethoxypiperidine and 50 ml of dehydrated diethyl ether was gradually added with a dropping funnel over a period of 20 minutes. The mixture was stirred for 1 hour at room temperature, and stirred for 2 hours under heating to reflux. While the mixture was cooled in an ice bath, 100 ml of 2N hydrochloric acid was gradually added. The resultant two-layer solution was transferred to a 500 ml separating funnel, and was shaken several times. Thereafter, the aqueous layer was removed. Subsequently, the organic layer was washed two times with 100 ml of water, one time with 100 ml of a saturated aqueous sodium bicarbonate solution, and one time with 100 ml of a saturated saline solution, and dried over anhydrous magnesium sulfate for 30 minutes. After the solvent was distilled off under reduced pressure, a small amount of hexane was added to perform recrystallization. The resultant solid was dried under reduced pressure. As a result, 7.57 g (28.0 mmol, 87.0%) of 4,4'-dimethoxy-3,3'-dimethylbenzophenone was obtained as a white solid. 4,4'-Dimethoxy-3,3'-dimethylbenzophenone was identified by 1H NMR spectrum. Measured values thereof are shown below. 1H NMR spectrum (270 MHz, CDCl3): delta/ppm 7.63-7.60 (m, 4H), 6.86-6.83 (m, 2H), 3.89 (s, 6H), 2.24 (s, 6H)
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 80℃; for 16h;
A mixture of 4-bromo-1-methoxy-2-methylbenzene (1.0 eq) in DMF (1M), Zn(CN)2 (1.5 eq), Pd2(dba)3 (0.02 eq) and S-phos (0.05 eq) was stirred at 80 C. for 16 h. The resulting mixture was concentrated and purified by column chromatography on silica gel (eluent PE/EA=100:1?20:1) to give the title compound.
ethyl 4-hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
Stage #1: 2-methyl-4-bromoanisole With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h;
Stage #2: ethyl 4-oxocyclohexane-1-carboxylate In tetrahydrofuran at -78℃; for 2h;
1 Step 1: Ethyl 4-hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate
n-Butyllithium (2.5 M in hexanes, 60 mL, 150.0 mmol) was added dropwise to a solution of 4-bromo-1-methoxy-2-methylbenzene (27.78 g, 138.2 mmol) in THF (300 mL) at-78 °C. The mixture was stirred at -78 °C for 1 h and then added dropwise to a solution of ethyl 4-oxocyclohexanecarboxylate (22.34 g, 131.3 mmol) in THF (300 mL) at -78 °C. The mixture was stirred at -78 °C for 2 h, added to sat’d NH4C1 (600 mL) and then extracted with EtOAc (2x600 mL). The combined organic extracts were washed with water (400 mL), washed with brine (400 mL), dried (Na2504), filtered, concentrated, and purified by silica gel chromatography (petroleum ether/EtOAc = 10/1) to give ethyl 4-hydroxy-4-(4-methoxy-3 - methylphenyl)cyclohexanecarboxylate (18.9 g, 45%) as a yellow oil. ‘H NIVIR (400 MHz, DMSO): 7.11-7.26 (m, 2H), 6.75-6.84 (m, 1H), 4.59-4.64 (m, 1H), 3.98-4.11 (m, 2H), 3.72 (s, 3H), 2.25-2.39 (m, 1H), 2.07-2.13 (s, 3H), 1.77-1.93 (m, 3H), 1.42-1.75 (m, 5H), 1.11- 1.23 (m, 3H); LCMS: 275.2 [M-OH].
45%
Stage #1: 2-methyl-4-bromoanisole With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h;
Stage #2: ethyl 4-oxocyclohexane-1-carboxylate In tetrahydrofuran; hexane at -78℃; for 2h;
1 Step 1: Ethyl 4-hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate
-Butyllithium (2.5 M in hexanes, 60 mL, 150.0 mmol) was added dropwise to a solution of 4-bromo-l-m ethoxy-2 -m ethylbenzene (27.78 g, 138.2 mmol) in THF (300 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h and then added dropwise to a solution of ethyl 4-oxocyclohexanecarboxylate (22.34 g, 131.3 mmol) and THF (300 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 2 h, added to saturated NH4Cl (600 mL) and then extracted with EtOAc (2x600 mL). The combined organic extracts were washed (400 mL water and then 400 mL brine), dried (Na2S04), filtered, and concentrated. The crude was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1) to give ethyl 4- hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (18.9 g, 45%) as a yellow oil. 1H NMR (400 MHz, DMSO-i): d 7.11-7.26 (m, 2H), 6.75-6.84 (m, 1H), 4.59-4.64 (m, 1H), 3.98-4.11 (m, 2H), 3.72 (s, 3H), 2.25-2.39 (m, 1H), 2.07-2.13 (s, 3H), 1.77-1.93 (m, 3H), 1.42-1.75 (m, 5H), 1.11-1.23 (m, 3H); LCMS: 275.2 [M-OH]+.
45%
Stage #1: 2-methyl-4-bromoanisole With n-butyllithium In tetrahydrofuran; 2-Methylpentane at -78℃; for 1h;
Stage #2: ethyl 4-oxocyclohexane-1-carboxylate In tetrahydrofuran; hexane at -78℃; for 2h;
Step 1: Ethyl 4-hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate
n-Butyllithium (2.5 M in hexanes, 60 mL, 150.0 mmol) was added dropwise to a solution of 4-bromo-1-methoxy-2-methylbenzene (27.78 g, 138.2 mmol) in THF (300 mL) at -78° C. The mixture was stirred at -78° C. for 1 h and then added dropwise to a solution of ethyl 4-oxocyclohexanecarboxylate (22.34 g, 131.3 mmol) and THF (300 mL) at -78° C. The reaction mixture was stirred at -78° C. for 2 h, added to saturated NH4Cl (600 mL) and then extracted with EtOAc (2×600 mL). The combined organic extracts were washed (400 mL water and then 400 mL brine), dried (Na2SO4), filtered, and concentrated. The crude was purified by silica gel chromatography (petroleum ether/EtOAc=10/1) to give ethyl 4-hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (18.9 g, 45%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 7.11-7.26 (m, 2H), 6.75-6.84 (m, 1H), 4.59-4.64 (m, 1H), 3.98-4.11 (m, 2H), 3.72 (s, 3H), 2.25-2.39 (m, 1H), 2.07-2.13 (s, 3H), 1.77-1.93 (m, 3H), 1.42-1.75 (m, 5H), 1.11-1.23 (m, 3H); LCMS: 275.2 [M-OH]+.
General procedure: To a solution of compound 1a-e (10.0 mmol,1.0 eq) in anhydrousTHF (20 mL) was slowly added n-BuLi (6 mL of 2.5 M solution inhexane, 15.0 mmol, 1.5 eq) at 78 C. The mixture was stirred for1 h and triisopropyl borate (50.0 mmol, 5.0 eq) was added by syringe.The solutionwas stirred for another 1 h and allowed towarmto 25 C overnight. The reactionwas cooled to 0 C, followed by thesequential addition ofwater (5 mL) and 2N HCl (5 mL). After 10 min,an additional 35 mL of 2N HCl was added and the mixture wasfurther stirred for 30 min. The mixture was extracted with ethylacetate (20 mL * 3) and the combined organic layers wereconcentrated to a thick oil under reduced pressure. Crystallizationwith cold hexane yielded a white solid.
8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With n-butyllithium In hexane at -60℃; for 1h; Inert atmosphere; Large scale;
1 Step 1: 8-(4-Methoxy-3-methylphenyl)-l,4-dioxaspiro[4.5]decan-8-ol
3 batches were run in parallel: -BuLi (762 mL, 1.90 mol, 2.5 M in -hexane) was added dropwise over 1 h to a solution of 4-bromo-l-methoxy-2-m ethylbenzene (333 g, 1.66 mol) and dry THF (2 L) at -60 °C under N2. The reaction was stirred at -60 °C for 1 h, and then a solution of l,4-dioxaspiro[4.5]decan-8-one (284.53 g, 1.82 mol) and dry THF (1 L) was added dropwise over 45 min. The reaction was stirred at -60 °C for 1 h, and then the 3 batches were poured into sat. aq. NH4Cl (3 L). This mixture was extracted with EtOAc (5 L c 2). The combined organic layers were washed with brine (5 L), dried over Na2S04, filtered, concentrated, and then triturated in -hexane (1.2 L) at rt overnight. The mixture was filtered, and the filter cake was washed with cool n-hexane (200 mL c 2) and then dried under vacuum to give 8-(4-methoxy-3-methylphenyl)-l,4-dioxaspiro[4.5]decan-8-ol (1100 g, 82%) as a white solid. 1H NMR (400MHz, CDCl3): 57.30-7.20 (m, 2H), 6.74 (d, 1H), 4.02-3.87 (m, 4H), 3.78 (s, 3H), 2.18 (s, 3H), 2.15-2.00 (m, 4H), 1.82-1.73 (m, 2H), 1.68-1.60 (m, 2H), 1.48 (s, 1H).
82%
Stage #1: 2-methyl-4-bromoanisole With n-butyllithium In tetrahydrofuran; hexane at -60℃; for 1h; Inert atmosphere; Large scale;
Stage #2: cyclohexanedione monoethylene ketal In tetrahydrofuran; hexane at -60℃; for 1.75h; Large scale;
Step 1: 8-(4-Methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol
3 batches were run in parallel: n-BuLi (762 mL, 1.90 mol, 2.5 M in n-hexane) was added dropwise over 1 h to a solution of 4-bromo-1-methoxy-2-methylbenzene (333 g, 1.66 mol) and dry THF (2 L) at -60° C. under N2. The reaction was stirred at -60° C. for 1 h, and then a solution of 1,4-dioxaspiro[4.5]decan-8-one (284.53 g, 1.82 mol) and dry THF (1 L) was added dropwise over 45 min. The reaction was stirred at -60° C. for 1 h, and then the 3 batches were poured into sat. aq. NH4Cl (3 L). This mixture was extracted with EtOAc (5 L×2). The combined organic layers were washed with brine (5 L), dried over Na2SO4, filtered, concentrated, and then triturated in n-hexane (1.2 L) at rt overnight. The mixture was filtered, and the filter cake was washed with cool n-hexane (200 mL×2) and then dried under vacuum to give 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol (1100 g, 82%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.30-7.20 (m, 2H), 6.74 (d, 1H), 4.02-3.87 (m, 4H), 3.78 (s, 3H), 2.18 (s, 3H), 2.15-2.00 (m, 4H), 1.82-1.73 (m, 2H), 1.68-1.60 (m, 2H), 1.48 (s, 1H).
82%
Stage #1: 2-methyl-4-bromoanisole With n-butyllithium In tetrahydrofuran; hexane at -60℃; for 1h; Inert atmosphere; Large scale;
Stage #2: cyclohexanedione monoethylene ketal In tetrahydrofuran; hexane at -60℃; for 1.75h; Inert atmosphere; Large scale;
1.1 Step 1: 8-(4-Methoxy-3-methylphenyl)-l,4-dioxaspiro[4.5]decan-8-ol
3 batches were run in parallel: -BuLi (762 mL, 1.90 mol, 2.5 M in -hexane) was added dropwise over 1 h to a solution of 4-bromo-l-m ethoxy -2-methylbenzene (333 g, 1.66 mol) and dry THF (2 L) at -60 °C under N2. The reaction was stirred at -60 °C for 1 h, and then a solution of l,4-dioxaspiro[4.5]decan-8-one (284.53 g, 1.82 mol) and dry THF (1 L) was added dropwise over 45 min. The reaction was stirred at -60 °C for 1 h, and then the 3 batches were poured into sat. aq. NH4CI (3 L). This mixture was extracted with EtOAc (5 L x 2). The combined organic layers were washed with brine (5 L), dried over Na2SCri, filtered, concentrated, and then triturated in -hexane (1.2 L) at rt overnight. The mixture was filtered, and the filter cake was washed with cool n-hexane (200 mL x 2) and then dried under vacuum to give 8-(4-m ethoxy-3 - methylphenyl)-l,4-dioxaspiro[4.5]decan-8-ol (1100 g, 82%) as a white solid.1H NMR (400MHz,CDCh): 57.30-7.20 (m, 2H), 6.74 (d, 1H), 4.02-3.87 (m, 4H), 3.78 (s, 3H), 2.18 (s, 3H), 2.15-2.00 (m, 4H), 1.82-1.73 (m, 2H), 1.68-1.60 (m, 2H), 1.48 (s, 1H).
82%
Stage #1: 2-methyl-4-bromoanisole With n-butyllithium In tetrahydrofuran; hexane at -60℃; for 1h; Inert atmosphere; Large scale;
Stage #2: cyclohexanedione monoethylene ketal In tetrahydrofuran; hexane at -60℃; for 1.75h; Inert atmosphere; Large scale;
1.1 Step 1: 8-(4-Methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol
3 batches were run in parallel: -BuLi (762 mL, 1.90 mol, 2.5 M in w-hexane) was added dropwise over 1 h to a solution of 4-bromo-1-m ethoxy -2-methylbenzene (333 g, 1.66 mol) and dry THF (2 L) at -60 °C under N2 The reaction was stirred at -60 °C for 1 h, and then a solution of l,4-dioxaspiro[4.5]decan-8-one (284.53 g, 1.82 mol) and dry THF (1 L) was added dropwise over 45 min. The reaction was stirred at -60 °C for 1 h, and then the 3 batches were poured into sat. aq. NH4CI (3 L). This mixture was extracted with EtOAc (5 L x 2). The combined organic layers were washed with brine (5 L), dried over Na2SO4, filtered, concentrated, and then triturated in -hexane (1.2 L) at rt overnight. The mixture was filtered, and the filter cake was washed with cool n-hexane (200 mL x 2) and then dried under vacuum to give 8-(4-m ethoxy-3 - methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol (1100 g, 82%) as a white solid. 1H NMR (400MHz, CDCl3): δ7.30-7.20 (m, 2H), 6.74 (d, 1H), 4.02-3.87 (m, 4H), 3.78 (s, 3H), 2.18 (s, 3H), 2.15- 2.00 (m, 4H), 1.82-1.73 (m, 2H), 1.68-1.60 (m, 2H), 1.48 (s, 1H).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
