* 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.
a) Preparation of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene Aluminium trichloride (0.60 g, 4.49 mmol) is weighed into a 100 ml three-necked flask fitted with a condenser, a magnetic stirrer and a thermometer. 20 ml of anhydrous benzene is added and then a solution of 2,5-dichloro-2,5-dimethylhexane (3.00 g, 16.38 mmol) in 10 ml of anhydrous benzene is added through a bromine ampoule. The reaction medium is heated to reflux for 4 hours. There is a large release of HCl and the reaction medium becomes dark red. After cooling the reaction medium, this is poured over ar ice/water mixture (100 ml), extracted with ether (3*50 ml), washed with a saturated solution of NaHCO3 (2*100 ml) and the ether phase dried with MgSO4, filtered and evaporated. The raw product is purified by flash chromatography on silica (eluent petroleum ether). 1.95 g (yield=63percent) of a colourless liquid, 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene is obtained. b.pt.=74° C. under 0.5 mm Hg]. NMR1H 80 MHz (CDCl3): 1.28 (s, 12H, 1,4-Me); 1.68 (s, 4H, -CH2-); 7.05-7.40 (m, 4H, ArH).
Reference：
[1] Patent: US6265423, 2001, B1,
[2] Patent: US5344959, 1994, A,
[3] Patent: US5475022, 1995, A,
[4] Patent: US5130335, 1992, A,
[5] Patent: US5149705, 1992, A,
2
[ 6223-78-5 ]
[ 71-43-2 ]
[ 6683-46-1 ]
Yield
Reaction Conditions
Operation in experiment
91%
for 16 h; Reflux
l,l,4,4-tetramethyl-l,2,3,4-tetrahydronaphth.alene (18): 2,5-dichloro-2,5- dimethylhexane (300 mg, 1.64 mmol, 1 eq) was dissolved in dry benzene (25 mL). A1C13 (22.0 mg, 0.164 mmol, 0.1 eq) was added to the solution, which was stirred at reflux for 16 hours. The reaction was quenched with 3M HC1 (5 mL) and extracted with hexanes (10 mL x 3). The combined organic layer was washed with brine, dried with Na2S04, filtered, and concentrated in vacuo. The crude was purified by flash chromatography (100percent hexanes) to give 18 (309 mg, 91percent yield) as a colourless oil. Characterization data for 18: <5H (500MHz, CDC13) 1.33 (s, 12H), 1.74 (s, 4H), 7.16-7.19 (m, 2H), 7.34-7.36 (m, 2H, J 2 Hz and 8.4 Hz).<5c (500MHz, CDC13) 31.9, 34.2, 35.1, 125.5, 126.5, 144.8.
88%
for 16 h; Reflux; Inert atmosphere
In a 250 mL round-bottomed flask was weighed T-1 (11.0 g, 60 mmol). Dry benzene (240 mL) was added and then AICI3 (1.0 g, 7.5 mmol, 1.25 equiv) in portions. A resulting mixture was refluxed under argon for 16 h. The mixture was cooled to room temperature, and then poured on ice-water (500 mL). An organic layer was separated and an aqueous layer was extracted with Et.20 (2 x 200 mL). Organics were combined, dried with MgS04, and solvent was evaporated under reduced pressure. A crude product residue was distilled under reduced pressure to afford the title compound T-2 as a colorless oil (10.0 g, 88percent yield). The analytical data matches those reported in the literature.
82%
Reflux; Inert atmosphere
To a solution of 2,5-dichloro-2,5-dimethyl hexane 20(2.0 mmol) in benzene 21 (2 mL mmol-1), AlCl3 (0.2 mmol)was added and the reaction mixture was stirred under refluxin nitrogen atmosphere for 64 h. Excess benzene 21 wasdistilled off and the resulting mixture was poured intodistilled water. The mixture was extracted with ethyl acetateand the organic phase was dried over MgSO4. The solventwas removed under vacuum. The residue was purified bydistillation at low pressure (0.5 mm Hg), and the product 22was collected between 90 and 120 °C as a colorless oil in82percent yield. 1H NMR (300 MHz, CDCl3) δ 1.30 (s, 12H,3CH3), 1.71 (s, 4H, 2CH2), 7.15 (m, 2H, Ar-H), 7.33 (m,2H, Ar-H); 13C NMR (75 MHz, CDCl3) δ 31.88, 34.19,35.10, 125.52, 126.45, 144.74.
Reference：
[1] Patent: WO2015/188015, 2015, A1, . Location in patent: Page/Page column 31
[2] Patent: WO2018/107289, 2018, A1, . Location in patent: Page/Page column 17
[3] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 1, p. 109 - 124
[4] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2182 - 2192
[5] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 6, p. 1948 - 1959
[6] Patent: WO2007/5568, 2007, A1, . Location in patent: Page/Page column 10
[7] Journal of the American Chemical Society, 1940, vol. 62, p. 36,43
[8] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 9, p. 2352 - 2356
[9] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4740 - 4746
[10] European Journal of Medicinal Chemistry, 2012, vol. 58, p. 346 - 354
[11] Letters in Drug Design and Discovery, 2016, vol. 13, # 8, p. 729 - 733
[12] Patent: US2018/207156, 2018, A1, . Location in patent: Paragraph 0195; 0196
[13] Patent: US2198374, 1938, ,
3
[ 110-03-2 ]
[ 6683-46-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2182 - 2192
[2] Journal of the American Chemical Society, 1940, vol. 62, p. 36,43
[3] European Journal of Medicinal Chemistry, 2012, vol. 58, p. 346 - 354
[4] Letters in Drug Design and Discovery, 2016, vol. 13, # 8, p. 729 - 733
[5] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 1, p. 109 - 124
[6] Patent: WO2018/107289, 2018, A1,
[7] Patent: US2018/207156, 2018, A1,
4
[ 97595-53-4 ]
[ 6683-46-1 ]
Reference：
[1] Journal of the American Chemical Society, 1963, vol. 85, p. 173 - 180
5
[ 110-03-2 ]
[ 71-43-2 ]
[ 6683-46-1 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 1997, vol. 39, # 6, p. 501 - 507
6
[ 51510-58-8 ]
[ 6683-46-1 ]
Reference：
[1] Helvetica Chimica Acta, 1973, vol. 56, # 5, p. 1775 - 1779
[2] Journal of Organic Chemistry, 1963, vol. 28, p. 2248 - 2255
7
[ 7446-70-0 ]
[ 6223-78-5 ]
[ 71-43-2 ]
[ 6683-46-1 ]
Reference：
[1] Journal of the American Chemical Society, 1940, vol. 62, p. 36,43
8
[ 7446-70-0 ]
[ 110-03-2 ]
[ 71-43-2 ]
[ 6683-46-1 ]
[ 22306-30-5 ]
Reference：
[1] Doklady Akademii Nauk SSSR, 1951, vol. 80, p. 369,371[2] Chem.Abstr., 1952, p. 5022
Reference：
[1] Doklady Akademii Nauk SSSR, 1951, vol. 80, p. 369,371[2] Chem.Abstr., 1952, p. 5022
11
[ 6683-46-1 ]
[ 92050-16-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 9, p. 2352 - 2356
[2] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2182 - 2192
[3] Patent: US4703110, 1987, A,
[4] Heterocycles, 2010, vol. 81, # 11, p. 2465 - 2470
[5] Organic Letters, 2013, vol. 15, # 6, p. 1378 - 1381
[6] Letters in Drug Design and Discovery, 2016, vol. 13, # 8, p. 729 - 733
12
[ 6683-46-1 ]
[ 92050-16-3 ]
Reference：
[1] Patent: US2003/125383, 2003, A1,
13
[ 6683-46-1 ]
[ 92050-16-3 ]
[ 102121-55-1 ]
Reference：
[1] Patent: US5087743, 1992, A,
[2] Patent: US5128479, 1992, A,
14
[ 6683-46-1 ]
[ 94497-51-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2182 - 2192
[2] Letters in Drug Design and Discovery, 2016, vol. 13, # 8, p. 729 - 733
15
[ 6683-46-1 ]
[ 27452-17-1 ]
Yield
Reaction Conditions
Operation in experiment
92%
With boron trifluoride-tetrahydrofuran complex; bromine In dichloromethane at 0 - 20℃; for 2 h; Inert atmosphere
In a 50 mL round-bottomed flask was weighed T-2 (1.88 g, 10 mmol). Dry CH2CI2 (12 mL) was added and then the resulting solution was cooled to 0°C. Br2 (0.95 mL, 18.5 mmol, 1.8 equiv) was added dropwise. Then BF3*THF complex (1.2 mL, 11 mmol, 1.1 equiv) dissolved in 2 mL CH2CI2 was added dropwise. The mixture was stirred at room temperature under argon for 2 h, and then the reaction was quenched by the addition of water (10 mL). An organic layer was separated and an aqueous layer was extracted with CH2CI2 (2 x 20 mL). The organics were combined, dried with MgS04 and the solvent was evaporated under reduced pressure. A crude product residue was purified via column chromatography to afford compound T-3 (2.5 g, 92percent).
79%
With N-Bromosuccinimide; toluene-4-sulfonic acid In methanol at 55℃; for 48 h; Inert atmosphere
To a solution of tetrahydronaphthalene 22 (20.0 mmol)in MeOH (2.5 mL mmol-1), under nitrogen atmosphere, NBS(1.5 mmol) and TsOH (0.15 mmol) were added. The reactionmixture was refluxed at 55 °C for 48 h, then poured into saturated NaHCO3 solution and extracted with ethyl acetate(3 × 30 mL). The organic phase was dried over MgSO4 andthe solvent removed under vacuum. The product was purifiedby distillation at low pressure (0.5 mm Hg) at temperaturesbetween 90 and 145 °C. The product 23 was obtained ascolorless oil in 79percent yield. 1H NMR (300 MHz, CDCl3)37 δ 1.25 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3), 1.66 (s, 4H, 2CH2),7.16 (d, 1H, J 8.5 Hz, Ar-H), 7.23 (dd, 1H, J 8.5, 2.1 Hz,Ar-H), 7.40 (d, 1H, J 2.1 Hz, Ar-H); 13C NMR (75 MHz,CDCl3) δ 31.72, 31.88, 34.06, 34.46, 34.83, 34.86, 119.40,128.44, 128.65, 129.42, 143.82, 147.36.
Reference：
[1] Patent: WO2018/107289, 2018, A1, . Location in patent: Page/Page column 17
[2] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 1, p. 109 - 124
[3] Organic and Biomolecular Chemistry, 2008, vol. 6, # 19, p. 3497 - 3507
[4] Journal of Medicinal Chemistry, 1995, vol. 38, # 17, p. 3368 - 3383
[5] Patent: US8293803, 2012, B2,
6
1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-naphthalene 5 (2.0 g, 10.6 mmol) was dissolved in dichloromethane (4 mL). The solution was frozen at 0°C, and aluminium trichloride (1.56 g, 11.7 mmol) was added. The mixture was stirred at 0°C under nitrogen atmosphere. Methyl oxalyl chloride (1.08 mL, 11.7 mmol) was added via syringe. The black mixture was stirred at 0 °C for 2 h. While stirring at room temperature, ice (20 g) was added then slowly concentrated HCl (2 mL). The product was extracted with CH2Cl2 (5 x 50 mL). The organic layer was washed with brine (3 x 20 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by chromatography on silica using as eluent cyclohexane:EtOAc = 98:02. Methyl 2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)-2-oxoacetate14 (2.05 g, 71 % yield) was obtained as a yellow oil. [] MW: 274.35; Yield: 71 %; Yellow Oil.Rf: 0.35 (cyclohexane:EtOAc = 98:02).1H-NMR (CDCl3,δ): 1.30 (s, 6H, 2xCH3), 1.31 (s, 6H, 2xCH3), 1.71 (s, 4H, 2xCH2), 3.97 (s, 3H, OMe), 7.43 (d, 1H, J = 8.3 Hz, ArH), 7.71 ( dd, 1H, J = 8.3 Hz, J = 1.9 Hz, ArH), 8.00 (d, 1H, J = 1.9 Hz, ArH)13C-NMR (CDCl3,δ): 183.70, 162.12, 151.00, 143.71, 127.64, 126.30, 125.01, 124.99, 50.27, 32.70, 32.41, 32.31, 32.19, 29.44.MS-ESI m/z (rel. int.): 297 ([M+Na]+, 5), 215 (100).HPLC: Method A, detection UV 254 nm, RT = 7.45 min, peak area 93.78 %.
With boron trifluoride-tetrahydrofuran complex; bromine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
In a 50 mL round-bottomed flask was weighed T-2 (1.88 g, 10 mmol). Dry CH2CI2 (12 mL) was added and then the resulting solution was cooled to 0C. Br2 (0.95 mL, 18.5 mmol, 1.8 equiv) was added dropwise. Then BF3*THF complex (1.2 mL, 11 mmol, 1.1 equiv) dissolved in 2 mL CH2CI2 was added dropwise. The mixture was stirred at room temperature under argon for 2 h, and then the reaction was quenched by the addition of water (10 mL). An organic layer was separated and an aqueous layer was extracted with CH2CI2 (2 x 20 mL). The organics were combined, dried with MgS04 and the solvent was evaporated under reduced pressure. A crude product residue was purified via column chromatography to afford compound T-3 (2.5 g, 92%).
79%
With N-Bromosuccinimide; toluene-4-sulfonic acid; In methanol; at 55℃; for 48h;Inert atmosphere;
To a solution of tetrahydronaphthalene 22 (20.0 mmol)in MeOH (2.5 mL mmol-1), under nitrogen atmosphere, NBS(1.5 mmol) and TsOH (0.15 mmol) were added. The reactionmixture was refluxed at 55 C for 48 h, then poured into saturated NaHCO3 solution and extracted with ethyl acetate(3 × 30 mL). The organic phase was dried over MgSO4 andthe solvent removed under vacuum. The product was purifiedby distillation at low pressure (0.5 mm Hg) at temperaturesbetween 90 and 145 C. The product 23 was obtained ascolorless oil in 79% yield. 1H NMR (300 MHz, CDCl3)37 delta 1.25 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3), 1.66 (s, 4H, 2CH2),7.16 (d, 1H, J 8.5 Hz, Ar-H), 7.23 (dd, 1H, J 8.5, 2.1 Hz,Ar-H), 7.40 (d, 1H, J 2.1 Hz, Ar-H); 13C NMR (75 MHz,CDCl3) delta 31.72, 31.88, 34.06, 34.46, 34.83, 34.86, 119.40,128.44, 128.65, 129.42, 143.82, 147.36.
With BF3.Et2O; bromine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
Intermediate 7a: 6-Bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene To a solution of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene 1a (10.0 g, 53.0 mmol) in DCM (60 cm3) at 0 C. under N2 was added Br2 (15.58 g, 97.5 mmol). BF3.Et2O (8.27 g, 58.3 mmol) in DCM (10 cm3) was added dropwise over 2 h. The reaction mixture was diluted with 40/60 EtOAc/hexane (150 cm3) and washed with saturated Na2SO3 solution (100 cm3), saturated NaHCO3 solution (100 cm3), and H2O (100 cm3). The organic layer was dried over MgSO4, filtered and the solvents removed in vacuo to give a dark brown oil. Kugelrohr distillation (120 C., 8*10-3 mbar) gave 7a as pale yellow crystals (11.02 g, 77.8%); M.p. 43 C.
EXAMPLE 3 The nitration of 1.2 g of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene with nitric acid/sulfuric acid mixture in sulfuric acid gave a 2-nitro derivative having a melting point of 71-72 C. (0.9 g, recrystallized from methanol). The reduction of the obtained nitro derivative with Pd-C as catalyst in alcohol gave 2-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene having a melting point of 72-73 C. (recrystallized from hexane).
6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene[ No CAS ]
[ 6683-46-1 ]
[ 92050-16-3 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; nitric acid; acetic acid;palladium-carbon; In ethanol; acetic anhydride;
Example 1 Synthesis of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (20.0 g, 106.2 mmole) in 85 ml of acetic anhydride at 0 C. was treated with 12.2 mL of acetic acid followed by 11.1 mL of nitric acid (70%) and was allowed to warm to room temperature. After 24 hours the reaction mixture was poured onto 300 mL ice-water and extracted with three 150 mL portions of ether. The combined organic extracts were washed with four 100 mL portions of 15% aqueous sodium hydroxide solution, two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried, filtered and concentrated in vacuo, giving 23.93 g (97%) of 6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (3) as a pale yellow solid. 1.4 g of Pd/C (10%) was added to a solution of 6-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (3) (23.93 g, 102.6 mmole) in 1 L of ethanol. The resulting suspension was maintained under 1 atmosphere for 15 hours. The mixture was filtered over Celite (2*) and concentrated in vacuo. The residue was taken up in 200 mL ether and dried over MgSO4. Filtration and concentration in vacuo gave a light brown solid, which was purified by flash chromatography (SiO2, 5%-20%, ethyl acetate/hexanes), providing 17.641 g (85%) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) as a pale yellow solid. M.P.: 68-69 C.
With nitric acid; acetic anhydride; In acetic acid;
EXAMPLE B 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine 77.2 ml of glacial acetic acid and 20.8 ml of nitric acid (98% strength) were mixed while cooling and then added dropwise within 2 hours to a solution of 65.8 g (0.35 mol) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 154 ml of glacial acetic acid and 257 ml of acetic anhydride in a salt/ice bath. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The solution was then poured into water, and the precipitate was filtered off with suction, washed with water and dried. 79.7 g of crude 2-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene of melting point 46-50 C. were obtained.
With nitric acid; acetic anhydride; In acetic acid;
Example H 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine 77.2 ml of glacial acetic acid and 20.8 ml of nitric acid (98% strength) were mixed while cooling and then added dropwise within 2 hours to a solution of 65.8 g (0.35 mol) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 154 ml of glacial acetic acid and 257 ml of acetic anhydride in a salt/ice bath. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. The solution was then poured into water, and the precipitate was filtered off with suction, washed with water and dried. 79.7 g of crude 2-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene of melting point 46-50 C. were obtained.
With aluminum (III) chloride; sodium hydroxide; In 1,2-dichloro-benzene; at 70.0℃; for 7.5h;Inert atmosphere; Cooling with ice;
A polymerization catalyst is prepared similar to Comparative Example 1 but with the catalyst compound of Formula VI. A new metallocene compound representative of Formula VI is prepared by the following procedure: Outside of the glovebox, a 500 mL two-necked round bottomed flask equipped with a magnetic stir bar, a powder addition funnel containing aluminum chloride (26.6 g, 199 mmol), a nitrogen inlet, and an outlet which purges to a NaOH scrubber is flushed with dry nitrogen gas. The vessel is charged with anhydrous o-dichlorobenzene (250 mL) followed by 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (25.00 g, 132.8 mmol) and acryloyl chloride (12.02 g, 132.8 mmol) and then cooled using an ice water bath. Aluminum chloride is added over 30 min via the powder addition funnel, then the vessel is warmed to room temperature. After stirring 1 hr at room temperature, the dark red solution is heated to 70 C. and allowed to react for 6 hours. The solution is then cooled to room temperature and poured over ice (?300 g) containing conc. HCl (15 mL). The biphasic mixture is transferred to a separatory funnel; the layers are separated, and the aqueous layer extracted with dichloromethane (300 mL) then ethyl acetate (300 mL). Combined organic fractions are washed with water (200 mL) and brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. Reaction solvent is removed by distillation under high vacuum, leaving a viscous, sticky, red residue. Hexane is added, and the resultant yellow precipitate collected by filtration and chromatographed (SiO2, hexanes?5% hexanes in EtOAc). then purified further by vacuum sublimation (100 C., 0.1 torr) to give 5,5,8,8-tetramethyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-1-one as a white solid (6.86 g, 21.3%).
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