* 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 potassium carbonate In acetone for 6 h; Reflux
General procedure: 6-Hydroxy-1-tetralone (0.3 g, 1.85 mmol) was suspended in acetone (15 mL) containing K2CO3 (3.70 mmol). The reaction was treated with an appropriately substituted arylalkyl bromide (2.035 mmol) and heated under reflux for 6 h. The reaction progress was monitored using silica gel TLC with ethyl acetate:petroleum ether (1:2) as mobile phase. Upon completion, the reaction was filtered through a pad of celite and concentrated in vacuo. The crude thus obtained was purified by recrystallization from cyclohexane.
97%
With potassium carbonate In acetone for 6 h; Reflux
General procedure: 6-Hydroxy-1-tetralone (0.3 g, 1.85 mmol) was suspended in acetone (15 mL) containing K2CO3 (3.70mmol). The reaction was treated with an appropriately substituted arylalkyl bromide (2.035 mmol) and heated under reflux for 6 h. The reaction progress was monitored using silica gel TLC with ethyl acetate:petroleum ether (1:2) as mobile phase. Upon completion, the reaction was filtered through a pad of celite and concentrated in vacuo. The crude thus obtained was purified by recrystallization from cyclohexane. 6-(Benzyloxy)-3,4-dihydronaphthalen-1(2H)-one (6a) The title compound was prepared in a yield of 97percent: mp 100.9–102.1 °C (cyclohexane). 1H NMR (BrukerAvance III 600, CDCl3) δ 2.09 (p, J = 6.5 Hz, 2H), 2.56 – 2.61 (m, 2H), 2.90 (t, J = 6.1 Hz, 2H), 5.09 (s,2H), 6.77 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 8.7, 2.6 Hz, 1H), 7.30 – 7.36 (m, 1H), 7.36 – 7.43 (m, 4H),8.00 (d, J = 8.7 Hz, 1H); 13C NMR (Bruker Avance III 600, CDCl3) δ 23.29, 30.10, 38.85, 69.20, 113.53,113.58, 122.11, 126.64, 128.99, 129.67, 131.78, 135.20, 146.94, 162.30, 197.08; APCI-HRMS m/z: calcdfor C17H17O2 (MH+), 253.1223, found 253.1220.
94%
With potassium carbonate In acetonitrile at 50℃; for 2 h;
Step 1: Preparation of 6-benzyloxytetralin-1-one To a solution of 6-hydroxytetralin-l-one (100 g, 616.56 mmol, 1.00 eq) in acetonitrile (1000 mL) was added potassium carbonate (170.43 g, 1.23 mol, 2.00 eq) and benzyl bromide (126.54 g, 739.87 mmol, 88 mL, 1.20 eq). The reaction mixture was stirred at 50° C. for 2 hours. TLC (petroleum ether:ethyl acetate=5:1) showed most of the starting material was consumed. Water (1000 mL) was added to the mixture, the resulting mixture was extracted with ethyl acetate (600 mL*3). The combined organic phase was washed with brine (800 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was triturated with petroleum ether and ethyl acetate (303 mL, petroleum ether:ethyl acetate=100:1, V:V). The mixture was filtered and the filter cake was washed with petroleum ether (50 mL*2), dried in vacuum to give 6-benzyloxytetralin-1-one (146 g, 578.65 mmol, 94percent yield) as a brown solid. 1H-NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.8 Hz, 1H), 7.45-7.34 (m, 5H), 6.91 (dd, J=8.8, 2.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 5.12 (s, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.62 (t, J=6.4 Hz, 2H), 2.15-2.09 (m, 2H).
84%
With potassium carbonate In acetonitrile at 15℃; for 3 h;
Step 1: 6-(Benzyloxy)-3,4-dihydronaphthalen-1(2H)-one 129a To a mixture of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one 101f (20.0 g, 123.31 mmol) and benzyl bromide (20 mL, 246.62 mmol) in MeCN (70 mL) was added K2CO3 (33.2 g, 240.21 mmol) at 15° C. and the resulting mixture was stirred for 3 hours. The mixture was filtered, concentrated and the residue was purified by flash column chromatography eluted with 0-10percent EtOAc in petroleum ether to afford 129a (26 g, 84percent yield) as brown oil. 1H NMR (400 MHz, CDCl3) δ 8.06-7.98 (m, 1H), 7.46-7.32 (m, 5H), 6.90 (d, J=8.8 Hz, 1H), 6.80 (s, 1H), 5.16-5.08 (m, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.62 (t, J=6.4 Hz, 2H), 2.17-2.06 (m, 2H).
80%
With potassium carbonate In acetoneInert atmosphere of nitrogen; Heating; Reflux
The mixture of 6-hydroxy-3,4-dihydro-2H-naphthalen-l-one (30.74 g, 0.1895 mol), benzyl bromide (27.0 mL, 0.227 mol) and potassium carbonate (39.3 g, 0.284 mol) in acetone (250 mL, 3.4 mol) was heated to reflux under an atmosphere of nitrogen for 3 hours. The mixture was cooled to 10 °C with an ice bath, filtered and washed with small amount of acetone. The filtrate was concentrated in rotavap. The resulting crystals were collected by filtration and washed with EtOAc-hexane then hexane to give a pale yellow solid product as the first crop. The mother liquid was concentrated in rotavapor and the residue was purified by chromatograph with EtOAc:hexane (0:100 to 20:80) to give the second crop of solid product (38.07g, 80percent). 1H NMR (CHLOROFORM-d) δ: 8.02 (d, J = 8.6 Hz, IH), 7.32 - 7.51 (m, 5H), 6.91 (dd, J = 8.8, 2.3 Hz, IH), 6.80 (s, IH), 5.13 (s, 2H), 2.93 (t, J = 6.1 Hz, 2H), 2.56 - 2.68 (m, 2H), 2.12 (quin, J = 6.3 Hz5 2H). MS (M+l): 253.0.
34.5g
With potassium carbonate In acetone at 40℃; for 3.5 h;
To a solution of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (CAS registry number: 3470-50-6) (24.3 g) inacetone (160 mL), benzyl bromide (29.4 mL) and potassium carbonate (31.1 g) were added at room temperature andthe mixture was stirred at 40°C for 3.5 hours. After insoluble matters were filtered off, the mixture was concentrated andwashed with a mixed solvent of tert-butyl methyl ether (MTBE)-hexane (1 : 4) to give the title compound (34.5 g) havingthe following physical property.TLC: Rf 0.38 (hexane : ethyl acetate = 3 : 1).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2758 - 2763
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2758 - 2763
[3] Patent: US2018/155322, 2018, A1, . Location in patent: Paragraph 1502; 1503
[4] European Journal of Organic Chemistry, 2003, # 15, p. 2799 - 2812
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 144 - 148
[6] Patent: US2017/129855, 2017, A1, . Location in patent: Paragraph 0243
[7] Patent: WO2010/51031, 2010, A1, . Location in patent: Page/Page column 64-65
[8] Patent: US6359138, 2002, B1, . Location in patent: Page column 34
[9] ChemMedChem, 2010, vol. 5, # 9, p. 1577 - 1593
[10] Journal of Medicinal Chemistry, 1996, vol. 39, # 26, p. 5035 - 5046
[11] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 99 - 102
[12] Patent: EP1577288, 2005, A1, . Location in patent: Page/Page column 165
[13] Patent: WO2006/64757, 2006, A1, . Location in patent: Page/Page column 80
[14] Patent: EP1760071, 2007, A1, . Location in patent: Page/Page column 49
[15] Journal of Organic Chemistry, 2013, vol. 78, # 5, p. 1718 - 1729
[16] Patent: US2014/100195, 2014, A1, . Location in patent: Page/Page column
[17] Patent: EP3228615, 2017, A1, . Location in patent: Paragraph 0104
[18] Patent: EP1661881, 2006, A2, . Location in patent: Page/Page column 122-123
2
[ 3470-50-6 ]
[ 100-44-7 ]
[ 32263-70-0 ]
Reference：
[1] Canadian Journal of Chemistry, 1988, vol. 66, # 3, p. 517-527
[2] Archiv der Pharmazie (Weinheim, Germany), 1994, vol. 327, # 2, p. 99 - 104
3
[ 3470-50-6 ]
[ 100-39-0 ]
[ 32263-70-0 ]
Reference：
[1] Patent: EP1826197, 2007, A1,
4
[ 1078-19-9 ]
[ 32263-70-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 99 - 102
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2758 - 2763
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2758 - 2763
Add bromine (107 mL, 2.08 mol) into a solution of 6-benzyloxy-3, 4-dihydro-2H- naphthalen-1-one (250 g, 0.99 mol) in chloroform (2 L) at 5 C over 1.5 hours. Add sodium thiosulfate solution (250 mL) to quench the reaction at 0 C. Add ethyl acetate (1 L) and separate layers. Extract the aqueous layer with CH2Cl2 (500 mL) and combine the organic layers, wash with aqueous sodium bicarbonate solution and brine. Dry with sodium sulfate and concentrate in vacuo. Triturate the residue by adding 10% ethyl acetate in hexane (600 mL) to obtain a solid. Filter and dry the solid to get 405 g (100 %) of 6-benzyloxy-2,2-dibromo-3, 4-dihydro-2H-naphthalen-1-one. Add 1M sodium methoxide (215 mL, 0.99 mol) into a solution of 6-benzyloxy- 2,2-dibromo-3, 4-dihydro-2H-naphthalen-l-one (205 g, 0.5 mol) in methanol (1.3 L). Heat the suspension to dissolution. Cool the reaction mixture to 0 C and add IN HCl (540 mL). Add H20 (3 L) and cool to 3 C to obtain a solid. Filter and dry the solid to obtain 152 g (92 %) of 6-benzyloxy-2-bromo-naphthalen-1-ol. Add sodium hydride (24 g, 0.6 mmol) portionwise to a solution of 6-benzyloxy-2-bromo-naphthalen-1-ol (179 g, 0.54 mol) in THF (3.0 L) at 0 C. Add methanesulfonyl chloride (47 mL, 0.61 mol) over 45 minutes and stir the reaction for 1.5 hours at 10 C. Add sodium bicarbonate solution (500 mL) and water (500 ml). Separate the layers and extact the aqueous layer with ethyl acetate (500 mL x2). Combine the organic layers and wash with brine (200 mL). Dry with magnesium sulfate, filter and concentrate in vacuo. Triturate the residue by adding 20% ethyl acetate in hexane (1 L) to obtain a solid. Filter, wash the solid with toluene (200 mL x 2) and dry the solid to get 176 g (80 %) of methanesulfonic acid 6-benzyloxy-2-bromo-naphthalen-1-yl ester. Combine methanesulfonic acid 6-benzyloxy-2-bromo-naphthalen-1-yl ester (10.0 g, 24.4 mmol), 4-fluorophenylboronic acid (10.2 g, 72.9 mmol), sodium carbonate (7.8 g, 73.6 mmol) and tetrakistriphenylphosphine palladium (2.8 g, 2.4 mmol) in a mixture of toluene (300 mL), ethanol (60 mL) and water (40 mL). Heat the mixture at 100 C for 12 hours. Cool and filter the suspension through a pad of celite. Evaporate the solvent in vacuo. Wash the residue with sodium bicarbonate solution and brine. Dry with magnesium sulfate and concentrate in vacuo. Purify the residue over silica gel, eluting the material with a step gradient of methanol/dichloromethane (0 to 10%), to obtain 10.1 g (98%) of methanesulfonic acid 6-benzyloxy-2- (4-fluoro-phenyl)-naphthalen-1-yl ester. Dissolve methanesulfonic acid 6-benzyloxy-2- (4-fluoro-phenyl)-naphthalen-1-yl ester (5.2 g, 12.3 mmol) in 5M sodium hydroxide (12 mL, 60 mmol), THF (86 mL) and MeOH (86 mL). Heat to 50 C for 1 hour. Cool and add ethyl acetate (100 mL). Wash the organic layer with IN HC1, saturated sodium bicarbonate solution and brine. Dry with magnesium sulfate and concentrate in vacuo to obtain 3.4 g (89%) of 6-benzyloxy-2- (4- fluoro-phenyl)-naphthalen-1-ol. Add sodium hydride (400 mg, 10 mmol) into a solution of 6-benzyloxy-2- (4- fluoro-phenyl)-naphthalen-l-ol in NMP (40 mL). Add the above alkoxide suspension into a solution of 4-fluorobenzaldehyde (2 mL, 19 mmol) in NMP (30 mL) at 165 C. Heat at 165 C for 1 hour. Cool and add buffer solution (pH=7,10 mL). Add diethyl ether (1 L). Separate the layers and wash the aqueous layer with diethyl ether (2 x 200 mL). Combine the organic layers, dry with magnesium sulfate and concentrate in vacuo. Chromatograph the residue on a biotage column eluting the material with a step gradient of methanol/ dichloromethane (0 to 10%) to obtain 2.9 g (70%) of 4- [6-benzyloxy-2- (4-fluoro-phenyl)- naphthalen-1-yloxy]-benzaldehyde. Add 18M H2S04 (1 mL, 16.8 mmol) dropwise into a solution of H202 (1 mL, 9.7 mmol) and 4- [6-benzyloxy-2- (4-fluoro-phenyl)-naphthalen-1-yloxy]-benzaldehyde at 0 C and stir at room temperature for 12 hours. Add H20 (20 mL) and CH2Cl2 (100 mL). Separate layers and extract the aqueous layer with CH2C12 (2 x 50 mL). Combine the organic layers, dry with magnesium sulfate and concentrate in vacuo to obtain 1.88 g (73%) of the title compound: mass spectrum (ion spray) m/z=435. 1 (M-H).
With copper(ll) bromide; In chloroform; ethyl acetate;Inert atmosphere; Reflux;
Copper(II) bromide (43.1 g, 0.193 mol) was heated to reflux in ethyl acetate (150 mL, 1.5 mol). 6-Benzyloxy-3,4-dihydro-2H-naphthalen-l-one (24.35 g, 0.09651 mol) in chloroform (150 mL, 1.9 mol) was slowly added and the mixture was refluxed overnight. The mixture was cooled to r.t., filtered. The filtrate was decolorized with activated carbon, and filtered throgh Celite. The filtrate was concentrated and dried in high vacuum pump to give an oily product (32.9g, 97%). 1H NMR (CHLOROFORM-d) delta: 8.08 (d, J = 9.1 Hz, IH), 7.30 - 7.50 (m, 5H), 6.96 (dd, J = 8.8, 2.3 Hz, IH), 6.82 (s, IH), 5.14 (s, 2H), 4.70 (t, J = 4.0 Hz, IH), 3.29 (dt, J = 11.0, 5.4 Hz, IH), 2.87 (dt, J = 16.9, 4.2 Hz, IH), 2.36 - 2.59 (m, 2H). MS (M+l): 332.0
97%
In chloroform; ethyl acetate;
Example 105 6-(Benzyloxy)-2-bromo-3,4-dihydronaphthalen-1(2H)-one Copper(II) bromide (43.1 g, 0.193 mol) was heated to reflux in ethyl acetate (150 mL, 1.5 mol). 6-Benzyloxy-3,4-dihydro-2H-naphthalen-1-one (24.35 g, 0.09651 mol) in chloroform (150 mL, 1.9 mol) was slowly added and the mixture was refluxed overnight. The mixture was cooled to r.t., filtered. The filtrate was decolorized with activated carbon, and filtered through Celite. The filtrate was concentrated and dried in high vacuum pump to give an oily product (32.9 g, 97%). 1H NMR (CHLOROFORM-d) delta: 8.08 (d, J=9.1 Hz, 1H), 7.30-7.50 (m, 5H), 6.96 (dd, J=8.8, 2.3 Hz, 1H), 6.82 (s, 1H), 5.14 (s, 2H), 4.70 (t, J=4.0 Hz, 1H), 3.29 (dt, J=11.0, 5.4 Hz, 1H), 2.87 (dt, J=16.9, 4.2 Hz, 1H), 2.36-2.59 (m, 2H). MS (M+1): 332.0
With bromine; In diethyl ether; at 0 - 20℃;
The title compound was synthesized by referring to J. Org. Chem., 1984, 49 (22), 4226. To a suspension of <strong>[32263-70-0]6-benzyloxy-3,4-dihydro-2H-naphthalen-1-one</strong> (200 g) in diethyl ether (2 1) was added dropwise bromine (60 ml) on an ice bath, and the solution was stirred overnight at room temperature. The reaction mixture was poured into ice water, extracted with diethyl ether, then sequentially washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, then filtered through NH silica gel, the solvent was evaporated in vacuo. To the resulting 6-benzyloxy-2-bromo-3,4-dihydro-2H-naphthalen-1-one (250 g) was added ethanol (2.5 1), the solution was stirred, sodium borohydride (25 g) was added thereto on an ice bath followed by stirring overnight at room temperature. The reaction mixture was poured into ice water, and the resulting solid was washed with water to provide 6-benzyloxy-2-bromo-1,2,3,4-tetrahydronaphthalen-1-ol (290 g). To a suspension of this compound (260 g) in toluene (800 ml) was added p-toluenesulfonic acid monohydrate (6.0 g), and the solution was refluxed for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then filtered through NH silica gel, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (34 g).1H-NMR (400MHz, CDCl3); delta (ppm): 2.73 (t, 2H), 2.92 (t, 2H), 5.04 (s, 2H), 6.72-6.76 (m, 3H), 6.90 (d, 1H), 7.30-7.44 (m, 5H).
Example 2 7-(benzyloxy)-4-methyl-1,2-dihydronaphthalene To a solution of the compound (34.5 g) prepared in Example 1 in tetrahydrofuran (300 mL), methylmagnesiumbromide (3 mol/L diethyl ether solution, 55 mL) was added at 0C, followed stirring at room temperature for 1 hours. The reaction mixture was cooled to 0C and poured into ice-saturated aqueous ammonium chloride solution. After adding 2 mol/L hydrochloric acid, the mixture was stirred at room temperature for 3 hours. Then, the resultant was extracted with ethyl acetate and the organic layer was successively washed with water and a brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), to thereby obtain the title compound (24.8 g) having the following physical properties. TLC: Rf 0.57 (hexane:ethyl acetate = 15: 1)
Procedure (2): To a solution of the obtained 6-(benzyloxy)-3,4-dihydronaphtalen-1(2H)-one (34.5 g) in tetrahydrofuran (300 mL), methyl magnesium bromide (3M diethyl ether solution, 55 mL) was added at 0C, followed by stirring at room temperature for 1 hour. The reaction mixture was cooled to 0C and poured into ice-saturated aqueous ammonium chloride solution. After adding 2N hydrochloric acid, the mixture was stirred at room temperature for 3 hours. Then, the resultant was extracted with ethyl acetate and the organic layer was successively washed with water and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10:1) to thereby give the title compound (24.8 g) having the following physical properties. TLC: Rf 0.71 (hexane:ethyl acetate = 3:1); ESI-MS: 251 (M+H)+; NMR (CDCl3): delta 7.26-7.49 (m, 5H), 7.09-7.21 (m, 1H), 6.67-6.90 (m, 2H), 5.60-5.81 (m, 1H), 5.07 (s, 2H), 2.74 (t, J = 7.96 Hz, 2H), 2.17-2.31 (m, 2H), 1.94-2.08 (m, 3H).
24.8 g
In tetrahydrofuran; diethyl ether; at 0 - 20℃; for 1h;
To a solution of the compound (34.5 g) prepared in Example 1 in tetrahydrofuran (THF) (300 mL), methylmag-nesium bromide (3 mol/L solution in diethyl ether, 55 mL) was added at 0C, and the mixture was stirred at roomtemperature for 1 hour. The reaction liquid was cooled to 0C and was poured to ice-saturated ammonium chlorideaqueous solution, and 2 mol/L hydrochloric acid was added to the mixture, and the mixture was stirred at room temperaturefor 3 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with waterand saturated saline, was dried and then was concentrated. The obtained residue was purified by silica gel columnchromatography (hexane: ethyl acetate = 10 : 1) to give the title compound (24.8 g) having the following physical property.TLC: Rf 0.57 (hexane : ethyl acetate = 15 : 1).
To a solution of the compound (34.5 g) prepared in Reference Example 01 in tetrahydrofuran (300 mL), methyl magnesium bromide (3 M diethyl ether solution, 55 mL) was added at 0C, followed by stirring at room temperature for 1 hour. Then, the reaction mixture was cooled to 0C and poured into ice-saturated aqueous ammonium chloride. After adding 2 N hydrochloric acid, the mixture was stirred at room temperature for 3 hours. Then, the mixture was extracted with ethyl acetate and the organic layer was successively washed with water and a saturated aqueous sodium chloride solution, dried and concentrated. The residue thus obtained was purified by silica gel column chromatography (hexane : ethyl acetate = 10 : 1) to thereby give the title compound (24.8 g) having the following physical properties. TLC: Rf 0.57 (hexane : ethyl acetate = 15 : 1).
5,6,7,8-Tetrahydro-5-oxo-6-[2-(4-phenyl-1-piperidinyl)ethyl]-2-naphthalenecarboxylic acid, methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34 g (81%)
With hydrogenchloride; lithium hexamethyldisilazane; In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; ethyl acetate;
Example 138 5,6,7,8-Tetrahydro-5-oxo-6-[2-(4-phenyl-1-piperidinyl)ethyl]-2-naphthalenecarboxylic acid, methyl ester STR152 A. 3,4-Dihydro-2-(2-propenyl)-6-(phenylmethoxy)-1(2H)naphthalenone Lithium bis(trimethylsilyl)amide (1 M in THF, 150 mL, 0.15 mol) was added over 20 minutes to a solution of <strong>[32263-70-0]6-benzyloxytetralone</strong> (37 g, 0.14 mol) in dry THF (580 mL) stirring at -78 C. under argon in a flame dried flask. HMPA (26 mL, 0.15 mol) was added and then the -78 C. bath was replaced with a 0 C. bath. After 10 minutes, allyl bromide (49 mL, 0.58 mol) was added quickly in one portion. After stirring at ambient temperature for 45 minutes, the reaction was quenched with water (56 mL). The reaction was transferred to a separatory funnel with ether/1 N HCl. Extraction with ether (2*600 mL), washing the combined organic layers with water, saturated NaHCO3, water, and brine, and drying over MgSO4 afforded 48 g of crude product. A series of 4 flash chromatographies (silica, 75 mm dia., 10% EtOAc/hexane) afforded 34 g (81%) of the title compound. Rf (silica, 25% EtOAc/hexane)=0.50.
With potassium tert-butylate; In tetrahydrofuran; water;
8.1. 3.8 g of potassium tert-butylate (0.0338 mol) were added portionwise at -78 C. to a solution of 5.0 g of 6-benzyloxy-1,2,3,4-tetrahydro-naphthalen-1-one (0.0198 mol) in 50 ml of THF while gassing with argon. The mixture was stirred at -78 C. for 2 hrs. and then a solution of 4.7 ml of 1,4-dibromobutane (8.55 g, 0.0396 mol) in 50 ml of THF was added dropwise. The cooling bath was removed and the mixture was stirred at RT for 16 hrs. Water was added, the mixture was extracted with ether, the organic phase was washed with a saturated aqueous sodium chloride solution, dried over MgSO4, filtered off, concentrated and the residue was chromatographed over silica gel with toluene. The product was recrystallized from hexane/ether and dried in vacuo. Yield: 2.0 g (33%) of 6'-benzyloxy-3'4'-dihydro-spiro-[cyclopentane-1,2'(1'H)naphthalen]-1'-one as white crystals; m.p. 79-81 C.
EXAMPLE F 3,4-Dihydro-6-(phenylmethoxy)-1(2H)-naphthalenone The title compound (1.30 g, m.p. 95-97 C.) was prepared in a similar manner to that demonstrated in the preparation of 2,3-dihydro-6-(phenylmethoxy)-1H-inden-1-one (Example E) using the following: 6-hydroxytetralone (1.20 g, 7.40 mmol, benzyl alcohol (0.77 mL, 7.40 mmol), triphenylphosphine (2.90 g, 11.0 mmol), diethylazodicarboxylate (1.70 mL, 11.0 mmol), THF (20.0 mL).
46
[ 32263-70-0 ]
[ 51145-58-5 ]
C30H28N2O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
acetic acid; In ethanol; for 3h;Heating / reflux;
A solution consisting of 4-benzyloxyphenylhydrazide 18 (8 g, 37.3 mmol), 4-bezyloxytetralone 17 (11.3 g, 44.8 mmol), AcOH (5 drops) in EtOH (100 mL) was heated to reflux for 3 hours during which time all of the reactants went into solution. The reaction was cooled to 0C and the product precipitated out and was filtered out. The product 20 (9.5 g) was isolated as a white solid: mp 102 - 104C. We found that the product was best used immediately because the products sitting out at room temperature results in discoloration.
A. Synthesis of 6-benzyloxy-1-oxo-1,2,3,4-tetrahydronaphtho-2-glyoxylic acid methyl ester 6-Benzyloxy-1-oxo-1,2,3,4-tetrahydronaphthalene was treated in the same manner as in the step C of Example 1 to obtain the desired compound. Melting point: 80-81 C.; 1H-NMR (CDCl3): delta 7.98 (d, J=8.6, 1H), 7.50-7.25 (m, 5H), 6.93 (dd, J=2.4, 8.6, 1H), 6.79 (d, J=2.4, 1H), 5.12 (s, 2H), 3.90 (s, 3H), 3.10-2.70 (m, 4H).
Example 1 6-(benzyloxy)-3,4-dihydronaphthalene-1(2H)-one To a solution of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (24.3 g) in acetone (160 mL), benzyl bromide (29.4 mL) and potassium carbonate (31.1 g) were added at room temperature, followed by stirring at 40C for 3.5 hours. After filtering off the insoluble matters and concentrating the filtrate, the resultant was washed with a mixed solvent of tert-butyl methyl ether-hexane (1:4), to thereby obtain the title compound (34.5 g) having the following physical properties. TLC: Rf 0.38 (hexane:ethyl acetate = 3:1)
To a suspension of NaH (816 mg, 60 % in oil, 2 eq, 20. 42 mmol) in 40 mL dry THF, diethylcarbonate (3.7 mL, 3 eq, 30.64 mmol) was added, and the mixture was heated at 60 C. To that a solution of 6- (benzyloxy) tetralone (2.57 g, 1 eq, 10.21 mmol) in 10 mL THF was added and the heating was continued for another 4 hours. Reaction mixture was condensed and diluted with ethyl acetate (100 mL) and washed with water. Organic layer was dried (Na2SO4), condensed, and the residue was chromatographed using ethyl acetate and hexane to obtain the title compound as thick liquid (2.58 g, 78 % yield). TLC as well as'H-NMR indicates that the compound is a mixture keto/enol tautomers of 70: 30 ratio. For clarification, lH-NMR data is given here for the keto form. IH NMR (CDC13, 400 MHz) 5 : 1.28 (t, J=7 Hz, 3H); 2.30-3. 10 (m, 4H); 3.54 (dd, J= 10,4. 5 Hz, 1H); 4.23 (q, J= 7 Hz, 2H); 5.11 (s, 2H); 6.77-6. 92 (aromatics, 2H); 7.32-7. 44 (aromatics, 5 H); 8.02 (d, J= 8.6 Hz, 1H). IR (neat) cm 1 : 2936,1737, 1677, and 1600. Mass m/z (CI) : 325 [M+1].
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