* 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.
Stage #1: With hydrogenchloride; sodium azide In water at 0 - 20℃; for 17.5 h; Stage #2: With potassium carbonate In water at 0℃;
2.72 g (41.8 mmol) of sodium azide were added in portions to a solution of 6.11 g (41.8 mmol) of 3,4-dihydronaphthalen-1(2H)-one in conc. hydrochloric acid (75 ml) at 0° C. over a period of 1 h. Then stirring was performed for another 30 min at 0° C. and thereafter heating to RT over a period of 16 h. The reaction solution was poured into ice water and made basic (pH 9) with potassium carbonate. Then extraction was carried out with DCM. The organic phase was dried over MgSO4, filtered and evaporated under a vacuum. The residue was crystallised from hexane. CC (SiO2, hexane/EA 1:2) was performed with the resultant residue, 1.8 g (11.1 mmol, 27percent) of 2,3,4,5-tetrahydrobenzo[c]azepin-1-one being obtained.
25%
Stage #1: With hydrogenchloride; sodium azide In water at 0 - 20℃; Stage #2: With sodium hydroxide In water at 0℃;
A. 2,3,4,5-Tetrahydrobenzo[c]azepin-1-one. To an ice-cold solution of 3,4-dihydro-2H-naphthalen-1-one (4.44 g, 30.4 mol) in concentrated HCl (60 mL) was added NaN3 (2.02 g, 30.4 mol) in portions. The resulting mixture was allowed to stir at 0° C. for 30 min, then was warmed to room temperature and stirred overnight. The reaction mixture was poured onto ice, brought to pH ~10 with 1 M NaOH, and extracted with DCM (3*). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified by flash chromatography (hexanes/EtOAc) to provide the title compound (1.23 g, 25percent). HPLC (reverse phase): RT=6.92 min. 1H NMR (500 MHz, CDCl3): 7.71 (dd, J=7.6 Hz, 1.3 Hz, 1H), 7.42-7.39 (m, 1H), 7.36-7.32 (m, 1H), 7.20-7.19 (m, 1H), 3.15-3.11 (m, 2H), 2.87 (t, J=7.1 Hz, 2H), 2.05-2.00 (m, 2H), (NH not observed).
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 38, p. 12347 - 12351[2] Angew. Chem., 2018, vol. 130, # 38, p. 12527 - 12531,5
[3] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 11, p. 914 - 919
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307
[5] Angewandte Chemie - International Edition, 2017, vol. 56, # 13, p. 3655 - 3659[6] Angew. Chem., 2017, vol. 129, # 13, p. 3709 - 3713,5
[7] Patent: US2009/75978, 2009, A1, . Location in patent: Page/Page column 35
[8] Patent: US2005/38032, 2005, A1, . Location in patent: Page/Page column 18
[9] Patent: EP2168966, 2010, A1, . Location in patent: Page/Page column 54-55
[10] Australian Journal of Chemistry, 2010, vol. 63, # 2, p. 211 - 226
2
[ 529-34-0 ]
[ 6729-50-6 ]
[ 4424-80-0 ]
Reference：
[1] ChemMedChem, 2010, vol. 5, # 8, p. 1300 - 1317
[2] Australian Journal of Chemistry, 2010, vol. 63, # 2, p. 211 - 226
[3] Tetrahedron, 1993, vol. 49, # 9, p. 1807 - 1820
[4] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 6, p. 1773 - 1778
3
[ 529-34-0 ]
[ 6729-50-6 ]
[ 94216-24-7 ]
Reference：
[1] Australian Journal of Chemistry, 2010, vol. 63, # 2, p. 211 - 226
4
[ 529-34-0 ]
[ 6729-50-6 ]
[ 4424-80-0 ]
[ 94216-24-7 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 6, p. 1609 - 1617
[2] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 6, p. 1609 - 1617
[3] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 6, p. 1609 - 1617
[4] Journal of Medicinal Chemistry, 1996, vol. 39, # 18, p. 3539 - 3546
[5] Journal of Medicinal Chemistry, 1996, vol. 39, # 18, p. 3539 - 3546
5
[ 529-34-0 ]
[ 583-53-9 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 15, p. 5431 - 5435
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 4, p. 1184 - 1187
[2] Patent: CN108727416, 2018, A,
8
[ 529-34-0 ]
[ 40353-34-2 ]
Yield
Reaction Conditions
Operation in experiment
81%
at 15℃; for 1 h;
Concentrated sulfuric acid (60 ml) was cooled to 0°C in an ice bath. A-TETRALONE (8g, 54.7 mmol) was added with stirring, then potassium nitrate (6g, 59.3 mmol, 1.08 equiv. ) dissolved in concentrated sulfuric acid (18 ml) was added dropwise via a dropping funnel, making sure that the temperature of the solution did not rise above 15°C. After addition, the solution was stirred for 1 h and then poured into crushed ice. The precipitate was filtered and washed with distilled water and then left to dry. Recrystallisation from a ETHANOL/WATER (1: 1) yielded 8 as a slightly yellow solid (8.5 g, 81percent), m. p. 104-106°C ; I. R. (FILM)/CM~L 1675,1500, 1340 ; 1H NMR (400 MHz, CDC13) 2.18-2. 25 (2H, m, CH2), 2.75 (2H, t, J 6.8, CH2), 3.10 (2H, t, J 6. 1, CH2), 7. 45 (1H, d, J 8.4, ArH), 8. 30 (1H, dd, J 2. 4, 8. 4, ArH), 8. 86 (1H, d, J 2. 4, ArH).
65%
at -20℃; for 0.75 h;
7-Nitrotetralone was synthesized by nitration of commercially available 1-tetralone following the method previously described, and its spectroscopic data were consistent with those of the Literature [16] . Yield: 65percent. Mp 106-108 °C (Hexane). IR: 1355, 1519, 1607, 1681, 3085. 1H NMR (CDC13): δ 2.13-2.30 (m, 2H, H3); 2.66-2.81 (m, 2H, H4); 3.10 (t, J = 6.0 Hz, 2H, H2); 7.50 (d, J = 8.4 Hz, 1H, H5); 8.30 (dd, J = 2.5 Hz, J = 8.4 Hz, 1H, H6); 8.80 (d, J = 2.5 Hz, 1H, H8). 13C NMR (CDCl3): δ 22.4 (C3); 29.6 (C4); 38.4 (C2); 122.1 (C8); 126.9 (C6); 130.2 (C5); 133.2 (C8a); 146.8 (C7); 150.9 (C4a); 195.9 (C1). MS (CI): m/z = 192.0 (MH+, 100percent), 162.1 (29).
5.2 g
With sulfuric acid; nitric acid In water at 0 - 20℃; for 1.5 h;
Method 17 8-Amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one 5 g of alpha-tetralone are added to 18.2 ml of sulfuric acid cooled to 0° C., while maintaining the temperature <10° C. A mixture of 1.87 ml of nitric acid at 70percent in water and of 3.65 ml of sulfuric acid is added while maintaining the temperature <10° C. The reaction medium is stirred for 30 minutes at a temperature <10° C. and then stirred for one hour at ambient temperature. The reaction medium is poured into ice-cold water (250 ml). The insoluble material is filtered off under vacuum and dried, so as to give 5.2 g of 7-nitro-3,4-dihydronaphthalen-1(2H)-one in the form of a beige solid.
5.2 g
With sulfuric acid; nitric acid In water at 0 - 20℃; for 1.5 h;
5 g of alpha-tetralone are added to 18.2 ml of sulfuric acid cooled to O 'C, while maintaining the temperature < l O'C. A mixture of 1 .87 ml of nitric acid at 70percent in water and of 3.65 ml of sulfuric acid is added while maintaining the temperature < l O'C. The reaction medium is stirred for 30 minutes at a temperature < l O'C and then stirred for one hour at ambient temperature. The reaction medium is poured into ice-cold water (250 ml). The insoluble material is filtered off under vacuum and dried, so as to give 5.2 g of 7-nitro- 3,4-dihydronaphthalen-1 (2H)-one in the form of a beige solid
Reference：
[1] Patent: WO2004/87124, 2004, A1, . Location in patent: Page/Page column 47-48
[2] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 237 - 249
[3] Tetrahedron Letters, 1994, vol. 35, # 38, p. 7061 - 7064
[4] Justus Liebigs Annalen der Chemie, 1927, vol. 451, p. 53
[5] Journal of the Chemical Society. Perkin transactions 1, 1969, vol. 10, p. 1376 - 1378
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2649 - 2655
[7] Patent: US5216148, 1993, A,
[8] Patent: US6235789, 2001, B1,
[9] Patent: US2013/261106, 2013, A1, . Location in patent: Paragraph 0563
[10] Patent: WO2013/150036, 2013, A1, . Location in patent: Page/Page column 110
[11] Patent: US6087399, 2000, A,
9
[ 529-34-0 ]
[ 40353-34-2 ]
[ 51114-73-9 ]
Yield
Reaction Conditions
Operation in experiment
16%
at 0℃; for 1 h;
Λ/-(5,6,7,8-Tetrahydro-2-naphthalenyl)acetamide (166). fHNO3 (8.6 mL, 144 mmol) in CH2SO4 (50 mL) was added dropwise to a stirred solution of α-tetralone (165) (20 g, 137 mmol) in CH2SO4 (300 mL) at 0 0C and the solution stirred for 1 h. The solution was poured into ice/water (2 L), stirred for 30 min, filtered and washed with water. The solid was dried and purified by chromatography, eluting with 20percent EtOAc/pet. ether, to give (i) 5-nitro-3,4-dihydro-1(2H)-naphthalenone (4.1 g, 16percent) as a white solid: 1H NMR δ 8.35 (dd, J = 7.8, 1.4 Hz, 1 H, H-6), 8.09 (dd, J = 8.0, 1.4 Hz, 1 H, H-8), 7.48 (br t, J = 7.9 Hz, 1 H, H-7), 3.22 (t, J = 6.1 Hz, 2 H, H-4), 2.74 (dd, J = 6.8, 6.4 Hz, 2 H, H-2), 2.13-2.21 (m, 2 H, H-3); and (ii) 7-nitro-3,4-dihydro-1(2H)-naphthalenone (20.1 g, 77percent) as a white solid: 1H NMR δ 8.86 (d, J = 2.5 Hz, 1 H, H-4), 8.30 (dd, J = 8.4, 2.5 Hz, 1 H, H-6), 7.46 (d, J = 8.4 Hz, 1 H, H-5), 3.09 (t, J = 6.1 Hz, 2 H, H-4), 2.74 (dd, J = 7.0, 6.2 Hz, 2 H, H-2), 2.17- 2.25 (m, 2 H, H-3).A solution of 7-nitro-3,4-dihydro-1 (2H)-naphthalenone (1.67 g, 8.7 mmol) in EtOAc/EtOH (1 :1, 150 mL), water (15 mL) and cHCI (2 mL) with Pd/C (5percent, 500 mg) was stirred vigorously under H2 (60 psi) for 16 h. The suspension was filtered through Celite, washed with EtOH (4 x 10 mL) and the organic solvent evaporated. The aqueous residue was partitioned between DCM and dilute aqueous NH3 solution and the organic fraction dried and the solvent evaporated. The residue was dissolved in dioxane (20 mL), and Ac2O (1.8 mL, 19.2 mmol) was added dropwise to the solution at 0 0C. The solution was stirred at 20 0C for 16 h, diluted with water (50 mL), and partitioned between EtOAc and dilute aqueous NH3 solution. The organic fraction was washed with water (3 \\ 20 mL), dried and the solvent evaporated to give Λ/-(5,6,7,8-tetrahydro-2-naphthalenyl)acetamide 166 (1.57 g, 95percent) as a white solid: 1H NMR δ 7.18-7.25 (m, 2 H, H-1, NH), 7.15 (dd, J = 8.2, 2.1 Hz, 1 H, H-3), 7.00 (d, J = 8.2 Hz, 1 H, H-4), 2.69-2.77 (m, 4 H, 2 x CH2), 2.15 (s, 3 H, CH3), 1.74-1.80 (m, 4 H, 2 x CH2). The procedure was repeated a number of times to give N- (5,6,7, 8-tetrahydro-2-naphthalenyl)acetamide 166 (10.21 g, 88percent overall).
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6853 - 6865
[2] Patent: WO2006/104406, 2006, A1, . Location in patent: Page/Page column 126
[3] Journal of the American Chemical Society, 1994, vol. 116, # 11, p. 4852 - 4857
[4] Journal of Medicinal Chemistry, 1989, vol. 32, # 9, p. 2128 - 2134
[5] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 466
10
[ 7697-37-2 ]
[ 529-34-0 ]
[ 40353-34-2 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1927, vol. 451, p. 53
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 466
11
[ 7697-37-2 ]
[ 529-34-0 ]
[ 40353-34-2 ]
[ 51114-73-9 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 466
12
[ 529-34-0 ]
[ 52927-23-8 ]
[ 91270-69-8 ]
Reference：
[1] Patent: US2003/225281, 2003, A1,
13
[ 529-34-0 ]
[ 109-77-3 ]
[ 2510-03-4 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 4, p. 852 - 860
[2] European Journal of Organic Chemistry, 2006, # 16, p. 3767 - 3770
[3] Journal of Organic Chemistry, 2005, vol. 70, # 9, p. 3584 - 3591
[4] European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4119 - 4130
[5] Angewandte Chemie - International Edition, 2016, vol. 55, # 51, p. 15792 - 15796[6] Angew. Chem., 2016, vol. 128, # 51, p. 16024 - 16028,5
[7] Russian Chemical Bulletin, 2003, vol. 52, # 10, p. 2235 - 2240
[8] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2014, vol. 69, # 5, p. 509 - 518
[9] Organic Letters, 2013, vol. 15, # 20, p. 5298 - 5301
[10] Journal of the American Chemical Society, 1945, vol. 67, p. 1050
[11] Journal of Organic Chemistry, 1966, vol. 31, p. 2784 - 2789
[12] Phosphorus, Sulfur and Silicon and the Related Elements, 1993, vol. 82, # 1-4, p. 91 - 98
[13] Journal of Medicinal Chemistry, 2005, vol. 48, # 19, p. 6066 - 6083
[14] Organic and Biomolecular Chemistry, 2006, vol. 4, # 1, p. 63 - 70
[15] Tetrahedron Letters, 2008, vol. 49, # 37, p. 5389 - 5392
[16] Advanced Synthesis and Catalysis, 2008, vol. 350, # 11-12, p. 1781 - 1784
[17] Synthetic Communications, 2011, vol. 41, # 10, p. 1410 - 1420
[18] Journal of Organic Chemistry, 2013, vol. 78, # 14, p. 7154 - 7168
[19] European Journal of Medicinal Chemistry, 2014, vol. 85, p. 450 - 457
[20] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 109, p. 170 - 177
[21] Organic Letters, 2016, vol. 18, # 3, p. 428 - 431
Reference：
[1] Tetrahedron Letters, 1996, vol. 37, # 12, p. 2063 - 2066
[2] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 11, p. 2429 - 2434
16
[ 119-64-2 ]
[ 21032-12-2 ]
[ 529-33-9 ]
[ 529-34-0 ]
Reference：
[1] Chemical and pharmaceutical bulletin, 2002, vol. 50, # 6, p. 744 - 748
17
[ 529-34-0 ]
[ 21032-12-2 ]
Reference：
[1] Journal of the American Chemical Society, 1989, vol. 111, # 1, p. 410 - 411
[2] Chemistry - A European Journal, 2016, vol. 22, # 41, p. 14567 - 14575
[3] ChemCatChem, 2018, vol. 10, # 14, p. 2962 - 2968
With toluene-4-sulfonic acid In toluene at 60℃; for 6 h;
2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-1-(2H)-one (12.0 g, 0.0.034 mol) was charged in a reactor equipped with overhead stirrer, reflux condenser and thermo-pocket. Toluene (200 mL) was added to suspend the material and p-toluene sulfonic acid (0.3 g, 2.5 mol percent) was added to the reaction mass which was then heated to 60 °C and stirred for 6 h. Progress of reaction was monitored on TLC. After completion of reaction, reaction mass was cooled to RT and solvent was evaporated under pressure to obtain residue. To the residue, was added ethyl acetate (150 mL) and washed with sat. NaHC03 soln. and brine followed by evaporation of solvent to give crude product which was further recrystallised from methanol to afford white solid compound (5.3 g, 50 percent yield). The mother liquor obtained after re-crystallisation was subjected to GC analysis wherein both a-tetralone and 4-(4-chlorophenyl) cyclohexanone were identified to be present in approx. 1 : 1 ratio (by respective retention times and AUCs in the mother liquor) and in 50 percent yield. GC retention time: a-tetralone (XII): 17.21 min (Area percent : 46)
Reference：
[1] Chemistry - A European Journal, 2002, vol. 8, # 22, p. 5204 - 5210
22
[ 529-34-0 ]
[ 26673-30-3 ]
Reference：
[1] Patent: WO2017/106624, 2017, A1,
23
[ 4619-18-5 ]
[ 26673-32-5 ]
[ 529-34-0 ]
Reference：
[1] Patent: US5492905, 1996, A,
[2] Patent: US5502048, 1996, A,
24
[ 529-34-0 ]
[ 26673-32-5 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1983, vol. 20, # 3, p. 663 - 666
[2] Justus Liebigs Annalen der Chemie, 1927, vol. 451, p. 53
25
[ 3984-34-7 ]
[ 26673-32-5 ]
[ 529-34-0 ]
Reference：
[1] Patent: US5502048, 1996, A,
26
[ 529-34-0 ]
[ 3349-64-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water
Step A: 1-Tetralone oxime To 4.6 L of water at room temperature in a 4-neck 50 L flask sitting in a steam bath apparatus equipped with an overhead stirrer, a temperature probe and reflux condenser was added 3.72 Kg (27.36 mol) of sodium acetate with stirring, followed by 1.9 Kg of hydroxylamine hydrochloride (27.36 mol). To this slurry at room temperature, 12 L of ethanol was added followed by 1.994 Kg (13.68 mol) of 1-tetralone. Additional ethanol (1.7 L) was used to rinse off the funnel and added to the reaction mixture. The resulting light orange slurry was heated to 75° C. over 40 minutes and maintained at 75°-85° C. for another 75 minutes. The reaction mixture was cooled with the aid of ice packed around the flask. When the internal temperature reached 32° C., the reaction mixture was pumped over 15 minutes into 60 L of ice contained in a 200 L vessel. The reaction vessel was washed with an additional 2 L of water which was added to the 200 L vessel. When the ice melted, the mixture was filtered through a filter pad and the wet cake washed with 4 L of water. The wet cake was suction dried for 1 hour then transferred to two trays and dried under vacuum at 40° C. for 2 days to give 2.094 Kg (13.01 mol,95percent) of product. 1 H NMR (250 MHz,CDCl3): 1.90 (m,2H), 2.80 (t,6 Hz,2H), 2.88 (t,6 Hz,2H), 7.15-7.35 (m,3H), 7.90 (d,8 Hz,1H), 8.9 (br s,1H).
95%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water
Step A: 1-Tetralone oxime To 4.6 L of water at room temperature in a 4-neck 50 L flask sitting in a steam bath apparatus equipped with an overhead stirrer, a temperature probe and reflux condenser was added 3.72 Kg (27.36 mol) of sodium acetate with stirring, followed by 1.9 Kg of hydroxylamine hydrochloride (27.36 mol). To this slurry at room temperature, 12 L of ethanol was added followed by 1.994 Kg (13.68 mol) of 1-tetralone. Additional ethanol (1.7 L) was used to rinse off the funnel and added to the reaction mixture. The resulting light orange slurry was heated to 75° C. over 40 minutes and maintained at 75°-85° C. for another 75 minutes. The reaction mixture was cooled with the aid of ice packed around the flask. When the internal temperature reached 32° C., the reaction mixture was pumped over 15 minutes into 60 L of ice contained in a 200 L vessel. The reaction vessel was washed with an additional 2 L of water which was added to the 200 L vessel. When the ice melted, the mixture was filtered through a filter pad and the wet cake washed with 4 L of water. The wet cake was suction dried for 1 hour then transferred to two trays and dried under vacuum at 40° C. for 2 days to give 2.094 Kg (13.01 mol, 95percent) of product. 1 H NMR (250 MHz, CDCl3): 1.90 (m, 2H), 2.80 (t, 6 Hz, 2H), 2.88 (t, 6 Hz, 2H), 7.15-7.35 (m, 3H), 7.90 (d, 8 Hz, 1H), 8.9 (br s, 1H).
95%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water
Step A: 1-Tetralone oxime To 4.6L of water at room temperature in a 4-neck 50 L flask sitting in a steam bath apparatus equipped with an overhead stirrer, a temperature probe and reflux condenser was added 3.72 Kg (27.36 mol) of sodium acetate with stirring, followed by 1.9 Kg of hydroxylamine hydrochloride (27.36 mol). To this slurry at room temperature, 12 L of ethanol was added followed by 1.994 Kg (13.68 mol) of 1-tetralone. Additional ethanol (1.7 L) was used to rinse off the funnel and added to the reaction mixture. The resulting light orange slurry was heated to 75° C. over 40 minutes and maintained at 75°-85° C. for another 75 minutes. The reaction mixture was cooled with the aid of ice packed around the flask. When the internal temperature reached 32° C., the reaction mixture was pumped over 15 minutes into 60 L of ice contained in a 200 L vessel. The reaction vessel was washed with an additional 2 L of water which was added to the 200 L vessel. When the ice melted, the mixture was filtered through a filter pad and the wet cake washed with 4 L of water. The wet cake was suction dried for 1 hour then transferred to two trays and dried under vacuum at a40° C. for 2 days to give 2.094 Kg (13.01 mol, 95percent) of product. 1 H NMR (250 MHz, CDCl3): 1.90 (m,2 H), 2.80 (t,6 Hz,2H), 2.88 (t,6 Hz,2H), 7.15-7.35 (m,3H), 7.90 (d,8 Hz,1H), 8.9 (br s,1H).
95%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water
Step A 1-Tetralone oxime To 4.6 L of water at room temperature in a 4-neck 50 L flask sitting in a steam bath apparatus equipped with an overhead stirrer, a temperature probe and reflux condenser was added 3.72 Kg (27.36 mol) of sodium acetate with stirring, followed by 1.9 Kg of hydroxylamine hydrochloride (27.36 mol). To this slurry at room temperature, 12 L of ethanol was added followed by 1.994 Kg (13.68 mol) of 1-tetralone. Additional ethanol (1.7 L) was used to rinse off the funnel and added to the reaction mixture. The resulting light orange slurry was heated to 75° C. over 40 minutes and maintained at 75°-85° C. for another 75 minutes. The reaction mixture was cooled with the aid of ice packed around the flask. When the internal temperature reached 32° C., the reaction mixture was pumped over 15 minutes into 60 L of ice contained in a 200 L vessel. The reaction vessel was washed with an additional 2 L of water which was added to the 200 L vessel. When the ice melted, the mixture was filtered through a filter pad and the wet cake washed with 4 L of water. The wet cake was suction dried for 1 hour then transferred to two trays and dried under vacuum at 40° C. for 2 days to give 2.094 Kg (13.01 mol, 95percent) of product. 1 H NMR (250 MHz, CDCl3): 1.90 (m,2H), 2.80 (t,6 Hz,2H), 2.88 (t,6 Hz,2H), 7.15-7.35 (m,3H), 7.90 (d,8 Hz,1H), 8.9 (br s,1H).
95%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water
Step A 1-Tetralone oxime To 4.6 L of water at room temperature in a 4-neck 50 L flask sitting in a steam bath apparatus equipped with an overhead stirrer, a temperature probe and reflux condenser was added 3.72 Kg (27.36 mol) of sodium acetate with stirring, followed by 1.9 Kg of hydroxylamine hydrochloride (27.36 mol). To this slurry at room temperature, 12 L of ethanol was added followed by 1.994 Kg (13.68 mol) of 1-tetralone. Additional ethanol (1.7 L) was used to rinse off the funnel and added to the reaction mixture. The resulting light orange slurry was heated to 75° C. over 40 minutes and maintained at 75°-85° C. for another 75 minutes. The reaction mixture was cooled with the aid of ice packed around the flask. When the internal temperature reached 32° C., the reaction mixture was pumped over 15 minutes into 60 L of ice contained in a 200 L vessel. The reaction vessel was washed with an additional 2 L of water which was added to the 200 L vessel. When the ice melted, the mixture was filtered through a filter pad and the wet cake washed with 4 L of water. The wet cake was suction dried for 1 hour then transferred to two trays and dried under vacuum at 40° C. for 2 days to give 2.094 Kg (13.01 mol, 95percent) of product, 1 H NMR (250 MHz, CDCl3): 1.90 (m, 2H), 2.80 (t, 6 Hz, 2H), 2.88 (t, 6 Hz, 2H), 7.15-7.35 (m, 3H), 7.90 (d, 8 Hz, 1H), 8.9 (br s, 1H).
95%
With hydroxylamine hydrochloride; sodium acetate In ethanol; water
Step A 1-Tetralone oxime To 4.6 L of water at room temperature in a 4-neck 50 L flask sitting in a steam bath apparatus equipped with an overhead stirrer, a temperature probe and reflux condenser was added 3.72 Kg (27.36 mol) of sodium acetate with stirring, followed by 1.9 Kg of hydroxylamine hydrochloride (27.36 mol). To this slurry at room temperature, 12 L of ethanol was added followed by 1.994 Kg (13.68 mol) of 1-tetralone. Additional ethanol (1.7 L) was used to rinse off the funnel and added to the reaction mixture. The resulting light orange slurry was heated to 75° C. over 40 minutes and maintained at 75°-85° C. for another 75 minutes. The reaction mixture was cooled with the aid of ice packed around the flask. When the internal temperature reached 32° C., the reaction mixture was pumped over 15 minutes into 60 L of ice contained in a 200 L vessel. The reaction vessel was washed with an additional 2 L of water which was added to the 200 L vessel. When the ice melted, the mixture was filtered through a filter pad and the wet cake washed with 4 L of water. The wet cake was suction dried for 1 hour then transferred to two trays and dried under vacuum at 40° C. for 2 days to give 2.094 Kg (13.01 mol, 95percent) of product. 1 H NMR (250 MHz, CDCl3): δ 1.90 (m, 2H), 2.80 (t, 6 Hz, 2H), 2.88 (t, 6 Hz, 2H), 7.15-7.35 (m, 3H), 7.90 (d, 8 Hz, 1H), 8.9 (br s, 1H).
75%
With hydroxylamine hydrochloride In pyridine; methanol for 16 h; Heating / reflux
To a solution of 3,4-dihydro-2H-naphthalen-1-one (30 g, 20.5 mmol) in 1:1 MeOH/pyridine (100 mL) was added hydroxylamine hydrochloride (1.88 g, 31 mmol) and the resulting mixture was heated at reflux for 16 h. The solvent was evaporated to give a brown solid that was dissolved in CH2Cl2 and washed with 0.5 N HCl. After trituation from EtOAc, 1A was obtained as a brown solid (24.8 g, 75percent). LC/MS m/z 162.0 (M+H)+.
63%
With hydroxylamine hydrochloride In methanol for 2 h; Heating / reflux
Preparation 17l 4,5, 6,7-Tetrahydroazepino [3,2, 1-hi] indole; 3, 4-Dihydro-2H-naphthalen-1-one oxime; Add hydroxylamine hydrochloride (71.0 g, 1.03 mol) to a solution of a-tetralone (100.0 g, 0.68 mol) in 300 mL of methanol and stir the resulting solution at reflux for 2 hours. Cool the mixture to 20-24°C and concentrate under reduced pressure. Dilute the residue with 1 L of water and extract with dichloromethane. Wash the organic layer with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure. Crystallize the residue from isopropanol to provide the desired compound as an off-white solid (70.0 g, 63percent). MS (FIA, m/z) CloHllNO (M++1) = 162.4.
63%
With hydroxylamine hydrochloride In methanol for 2 h; Heating / reflux
Preparation X 4,5,6,7-Tetrahydroazepino[3,2,1-hi]indole [0185] 3,4-Dihydro-2H-naphthalen-1-one Oxime [0186] To a solution of α-tetralone (100.0 g, 0.68 mol) in 300 mL of methanol was added hydroxylamine hydrochloride (71.0 g, 1.03 mol) and the resulting solution was stirred at reflux for 2 hours. The mixture was allowed to cool to 20-24° C. and was concentrated under reduced pressure. The resulting mixture was diluted with 1 L of water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from isopropanol to provide 70.0 g (63percent) of the desired compound as an off-white solid. [0187] MS (FIA, m/z) C10H11NO (M++1)=162.4. [0188] 1,3,4,5-Tetrahydrobenzo[b]azepin-2-one [0189] A 1L 3-neck round bottom flask equipped with a mechanical stirrer was charged with neat polyphosphoric acid (100 g) and the acid heated to 125° C. while being stirred under nitrogen. 3,4-Dihydro-2H-naphthalen-1-one oxime (15.0 g, 93 mmol) was added carefully to control exotherm, keeping the temperature below 175° C. Following 10 minutes of heating the mixture was cooled to 20-24° C. and the reaction quenched with ice and water to generate a precipitate. The aqueous suspension was filtered and the precipitate washed with water until the filtrate became neutral. The filtered solid was dried under vacuum to provide 12.8 g (85percent) of the desired compound as an off-white solid. [0190] MS (ES, m/z) C10H11NO (M++1)=161.9 [0191] 2,3,4,5-Tetrahydro-1H-benzo[b]azepine [0192] To a solution of 1,3,4,5-tetrahydrobenzo[b]azepin-2-one (12.9 g, 80.0 mmol) in 720 mL of tetrahydrofuran was added 80 mL of lithium aluminum hydride (1 M solution in tetrahydrofuran). The reaction mixture was stirred at reflux for 3 hours and cooled to 0° C. The reaction was quenched by the sequential addition of 3 mL of water, 3 mL of 15percent sodium hydroxide, and 9 mL of water. The mixture was filtered through Celite and the filter cake rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to provide 10.0 g (85percent) of the desired compound as an orange solid. [0193] MS (FIA, m/z) C10H13N (M++1)=148.2. [0194] 2-Oxo-3-(2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-propionic acid ethyl ester [0195] To a 0° C. suspension of 60percent sodium hydride (3.0 g, 0.12 mol) in 300 mL of dimethylformamide was added 2,3,4,5-tetrahydro-1H-benzo[b]azepine in small portions. Upon complete addition of the amine, the ice bath was removed and the reaction stirred at 20-24° C. for 40 minutes. Ethyl bromopyruvate (22.6 mL, 0.16 mol) was then added and the resulting mixture stirred at 20-24° C. for 6 hours. An additional 5 mL of ethyl bromopyruvate was added and the mixture stirred for 1 hour. The reaction was quenched by the addition of 50 mL of water followed by dilution with 1.5 L of dichloromethane. The layers were separated and the organic layer was washed with water (2.x.500 mL) and saturated aqueous sodium chloride (500 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure at 60° C. The residual brown oil was dissolved in ethyl acetate (500 mL) and was washed 3 times with water (100 mL) and once with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5-10percent EtOAc/hexanes to provide 7.0 g (40percent) of the desired compound as an off white solid. [0196] MS (FID, m/z) C15H19NO3 (M+)=261.13. [0197] 4,5,6,7-Tetrahydroazepino[3,2,1-hi]indole-1-carboxylic acid ethyl ester [0198] Magnesium chloride (2.55 g, 26.8 mmol) was added to 30 mL of 2-methoxyethanol and the mixture heated to reflux. A solution of 2-oxo-3-(2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-propionic acid ethyl ester (7-0.0 g, 26.8 mmol) in 2-methoxyethanol (20 mL) was slowly added to the MgCl2 mixture over 1 hour. The resulting mixture was stirred for 6 hours at reflux, cooled to 20-24° C. and concentrated under reduced pressure. The residue was diluted with 400 mL of dichloromethane and washed with 2 N hydrochloric acid (100 mL), followed by saturated aqueous sodium bicarbonate (100 mL) and finally saturated aqueous sodium chloride (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. This residue was subjected to silica gel chromatography, eluting with 20percent EtOAc/Hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 3.1 g (48percent) of the desired compound as a yellow oil. [0199] MS (FIA, m/z) C15H17NO2 (M++1)=244.4. [0200] 4,5,6,7-Tetrahydroazepino[3,2,1-hi]indole-1-carboxylic Acid [0201] To a solution of 4,5,6,7-tetrahydroazepino[3,2,1-hi]indole-1-carboxylic acid ethyl ester (2.0 g, 8.22 mmol) in ethanol (13 mL) and water (9 mL) was added powdered sodium hydroxide (0.71 g, 17.8 mmol) and the resulting mixture stirred at reflux for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and washed with dichloromethane (2.x.50 mL). The layers were separated and the aqueous layer was filtered through Celite and the filtrate was acidified with concentrated hydrochloric acid. The suspension was filtered and the recovered solid washed with water and dried under reduced pressure to provide 1.59 g (90percent) of the desired compound as a white solid. [0202] MS (FIA, m/z) C13HL3NO2 (M++1)=216.3 [0203] Decarboxylation [0204] To a solution of 4,5,6,7-tetrahydroazepino[3,2,1-hi]indole-1-carboxylic acid (1.4 g, 6.5 mmol) in 7.5 mL of quinoline was added copper chromite (0.55 g, 1.77 mmol). The resulting mixture was stirred at 185° C. for 4 hours and then cooled to room temperature, diluted with dichloromethane and filtered through Celite. The filtrate was washed with 2 N hydrochloric acid (2.x.25 mL) followed by 2 N sodium hydroxide (25 mL). The organic layer was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 5percent EtOAc/Hexane to provide 0.85 g (76percent) of the title compound as an orange solid. [0205] MS (EI, m/z) C12H13N (M+)=171.4
4.4 g
With hydroxylamine hydrochloride; sodium acetate In methanol for 1 h; Reflux
1-tetralone (4.00 g, 27.40 mmol), sodium acetate (2.64 g, 32.20 mmol), hydroxylamine hydrochloride (2.42 g, 32.2 mmol) and methanol (12.00 mL) were stirred under reflux for 1 h, then, ethyl acetate (50.00 mL) and 2M NaOH solution (50 mL) were added and the organic phase was extracted and concentrated by reduced pressure. After this, water (40.00 mL), ethyl acetate (80.00 mL) and saturated NaCl solution (50.00 mL) were added to the resultant mixture. The organic phase was extracted, dried over MgSO4 and concentrated under reduced pressure furnishing 4.40 g (27.40 mmol) of a white solid without futher purification.
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27
[ 529-34-0 ]
[ 3349-64-2 ]
Reference：
[1] Patent: US5324725, 1994, A,
28
[ 529-34-0 ]
[ 40353-34-2 ]
[ 51114-73-9 ]
Yield
Reaction Conditions
Operation in experiment
16%
at 0℃; for 1 h;
Λ/-(5,6,7,8-Tetrahydro-2-naphthalenyl)acetamide (166). fHNO3 (8.6 mL, 144 mmol) in CH2SO4 (50 mL) was added dropwise to a stirred solution of α-tetralone (165) (20 g, 137 mmol) in CH2SO4 (300 mL) at 0 0C and the solution stirred for 1 h. The solution was poured into ice/water (2 L), stirred for 30 min, filtered and washed with water. The solid was dried and purified by chromatography, eluting with 20percent EtOAc/pet. ether, to give (i) 5-nitro-3,4-dihydro-1(2H)-naphthalenone (4.1 g, 16percent) as a white solid: 1H NMR δ 8.35 (dd, J = 7.8, 1.4 Hz, 1 H, H-6), 8.09 (dd, J = 8.0, 1.4 Hz, 1 H, H-8), 7.48 (br t, J = 7.9 Hz, 1 H, H-7), 3.22 (t, J = 6.1 Hz, 2 H, H-4), 2.74 (dd, J = 6.8, 6.4 Hz, 2 H, H-2), 2.13-2.21 (m, 2 H, H-3); and (ii) 7-nitro-3,4-dihydro-1(2H)-naphthalenone (20.1 g, 77percent) as a white solid: 1H NMR δ 8.86 (d, J = 2.5 Hz, 1 H, H-4), 8.30 (dd, J = 8.4, 2.5 Hz, 1 H, H-6), 7.46 (d, J = 8.4 Hz, 1 H, H-5), 3.09 (t, J = 6.1 Hz, 2 H, H-4), 2.74 (dd, J = 7.0, 6.2 Hz, 2 H, H-2), 2.17- 2.25 (m, 2 H, H-3).A solution of 7-nitro-3,4-dihydro-1 (2H)-naphthalenone (1.67 g, 8.7 mmol) in EtOAc/EtOH (1 :1, 150 mL), water (15 mL) and cHCI (2 mL) with Pd/C (5percent, 500 mg) was stirred vigorously under H2 (60 psi) for 16 h. The suspension was filtered through Celite, washed with EtOH (4 x 10 mL) and the organic solvent evaporated. The aqueous residue was partitioned between DCM and dilute aqueous NH3 solution and the organic fraction dried and the solvent evaporated. The residue was dissolved in dioxane (20 mL), and Ac2O (1.8 mL, 19.2 mmol) was added dropwise to the solution at 0 0C. The solution was stirred at 20 0C for 16 h, diluted with water (50 mL), and partitioned between EtOAc and dilute aqueous NH3 solution. The organic fraction was washed with water (3 \\ 20 mL), dried and the solvent evaporated to give Λ/-(5,6,7,8-tetrahydro-2-naphthalenyl)acetamide 166 (1.57 g, 95percent) as a white solid: 1H NMR δ 7.18-7.25 (m, 2 H, H-1, NH), 7.15 (dd, J = 8.2, 2.1 Hz, 1 H, H-3), 7.00 (d, J = 8.2 Hz, 1 H, H-4), 2.69-2.77 (m, 4 H, 2 x CH2), 2.15 (s, 3 H, CH3), 1.74-1.80 (m, 4 H, 2 x CH2). The procedure was repeated a number of times to give N- (5,6,7, 8-tetrahydro-2-naphthalenyl)acetamide 166 (10.21 g, 88percent overall).
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6853 - 6865
[2] Patent: WO2006/104406, 2006, A1, . Location in patent: Page/Page column 126
[3] Journal of the American Chemical Society, 1994, vol. 116, # 11, p. 4852 - 4857
[4] Journal of Medicinal Chemistry, 1989, vol. 32, # 9, p. 2128 - 2134
[5] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 466
29
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Yield
Reaction Conditions
Operation in experiment
15.7%
at 0 - 5℃; for 1 h;
[00139] To the solution of 3,4-dihydronaphthalen-l(2H)-one (20 g, 137 mmol) in con. H2SO4 (300 mL), the solution of HNO3 (8.6 mL, 144 mmol, 63percent) in con. H2SO4 (50 mL) was dropped in while the reaction maintaining below 5 °C, and the solution was stirred at 0 °C for 1 hour. And then the solution was poured into ice- water (2L), and the mixture was stirred at room temperature for 30 mins. After filtration, the solid afforded was washed with water, and dried in vacuo. After purification with silica gel chromatography (Hex-EtOAc as a gradient eluent), white solid (4.1 g, 15.7percent) was afforded as an off-white solid.
Example 1; Preparation of 7-Bromo-l-tetralone; 7-bromo-1-tetralone was prepared according to the procedure described in Cornelius, L. A. M.; Combs, D. W. Synthetic Communications 1994,24, 2777-2788. The above isomers were separated using silica gel flash chromatography (Biotage Flash 75, elution solvent 20/1 hexanes: MTBE) to yield 5-bromo-1-tetralone (11.59 g, 51percent) and 7-bromo-1-tetralone (9.45 g, 42percent).
42%
at 75 - 80℃; for 0.55 h;
A 500 mL three-necked flask fitted with an addition funnel, reflux condenser and thermometer was charged with aluminum chloride (33.34 g, 250 mmol) and heated to 75-80 °C. 1- Tetralone (14.6 g, 13.3 ML, 100 mmol) was added dropwise over 10 min. The resulting brown slurry was stirred for 3 min before dropwise addition of bromine (19.21 g, 6.15 ml, 120 mmol) over 15 min. The mixture was stirred for 5 min and then poured into a mixture of ice (300 g) and 12N HC1 (40 mL). The mixture was stirred until the aluminum chloride was dissolved and then diluted with water (200 mL). The mixture was extracted with diethyl ether (3 X 300 mL) and the combined organics were washed with water (2 X 300 mL), dried (sodium sulfate), filtered and evaporated in vacuo to give a dark brown mixture of 5-and 7- BROMO-1-TETRALONE. The isomers were separated using silica gel flash chromatography (Biotage Flash 75, elution solvent 20/1 hexanes: MTBE) to yield 5-BROMO-1-TETRALONE (11.59 g, 51percent) and 7- BROMO-1-TETRALONE (9.45 g, 42percent).
42%
Stage #1: at 75 - 80℃; for 0.216667 h; Stage #2: for 0.333333 h;
A 500 mL three-necked flask fitted with an addition funnel, reflux condenser and thermometer was charged with aluminum chloride (33.-34 g, 250 mmol) and heated to 75-80 °C. 1- Tetralone (14.6 g, 13.3 mL, 100 mmol) was added dropwise over 10 MIN. THE resulting brown slurry was stirred for 3 min before dropwise addition of bromine (19.21 g, 6.15 ml, 120 mmol) over 15 min. The mixture was stirred for 5 min and then poured into a mixture of ice (300 g) and 12N HC1 (40 mL). The mixture was stirred until the aluminum chloride was dissolved and then diluted with water (200 mL). The mixture was extracted with diethyl ether (3 X 300 mL) and the combined organics were washed with water (2 X 300 mL), dried (sodium sulfate), filtered and evaporated in vacuo to give a dark brown mixture of 5-and 7- BROMO-1-TETRALONE. The isomers were separated using silica gel flash chromatography (Biotage Flash 75, elution solvent 20/1 hexanes: MTBE) to yield 5-BROMO-1-TETRALONE (11.59 g, 51percent) and 7- BROMO-1-TETRALONE (9.45 g, 42percent). [Note 1. Procedure: Cornelius, L. A. M.; Combs, D. W. Synthetic Communications 1994,24, 2777-2788].
Reference：
[1] Patent: WO2005/95326, 2005, A2, . Location in patent: Page/Page column 110-111
[2] Patent: WO2004/94384, 2004, A2, . Location in patent: Page 63-64
[3] Patent: WO2004/94413, 2004, A1, . Location in patent: Page 63-64
[4] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 1, p. 29 - 35
[5] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 16, p. 4405 - 4409
[6] Synthetic Communications, 1994, vol. 24, # 19, p. 2777 - 2788
[7] Gazzetta Chimica Italiana, 1988, vol. 118, # 5, p. 369 - 374
[8] Patent: US5753655, 1998, A,
[9] Patent: US2004/6229, 2004, A1, . Location in patent: Page/Page column 13-14
[10] Organic and Biomolecular Chemistry, 2017, vol. 15, # 6, p. 1381 - 1392
[11] Patent: US2003/225281, 2003, A1, . Location in patent: Page 12
43
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[ 68449-30-9 ]
Yield
Reaction Conditions
Operation in experiment
44%
Stage #1: at 0 - 90℃; for 0.916667 h; Stage #2: at 90℃; for 1 h;
Example III Synthesis of Tetrahydronaphthalene Derivatives 5-Bromo-1-tetralone. (Cornelius, L. A. H.; Combs, D. W. Synthetic Communications 1994, 24(19), 2777-2788) Into a round bottom flask kept at 0° C., AlCl3 (19.6 g, 146.8 mmol) was added and the reaction system was put under nitrogen. 8 mL of tetralone (8.62 g, 58.9 mmol) were added during a 10-minute period, at which point, the reaction mixture was heated in an oil bath at 90° C. for about 45 minutes before adding 3.6 mL of Br2 (11.2 g, 70.1 mmol). The reaction mixture was stirred at 90° C. for an hour before 30 mL of ice-water and 20 mL of NaHCO3 were added. The product was extracted twice from the aqueous phase with Et2O and, the resultant organic phase was washed once with NaHCO3, once with brine and dried under Na2SO4. The crude reaction mixture was purified by flash chromatography (2.5percent EtOAc/97.5percent hex) which afforded 5.87 g (26.1 mmol) of the product in a 44percent yield. 1H NMR (300 MHz, CDCl3, δ): 8.01 (dd, J=7.8, 1.3, Ar, 1H), 7.73 (dd, J=7.9, 1.3, Ar, 1H), 7.18 (tt, J=7.9, 0.6, Ar, 1H), 3.01 (t, J=6.2, C2, 2H), 2.64 (dd, J=6.7, 5.6, C2, 2H), 2.15 (td, J=13.0, 6.5, C2, 2H). 13C NMR (75 MHz, CDCl3): δ 197.5, 143.4, 137.3, 134.9, 127.7, 126.5, 124.8, 38.2, 30.0, 22.3. Dept 135 NMR (75 MHz, CDCl3): δ 137.3 (H), 127.7 (H), 126.5 (H), 38.2 (H2), 30.0 (H2), 22.3 (CH2). EIMS: m/z (percent rel. intensity) 226 (M++2, 93), 224 (M+, 93), 211 (25), 209 (25), 198(100), 196 (100), 170 (50), 168 (50), 145 (25), 115 (45), 89 (60), 63 (28).
27%
Stage #1: at 70℃; Stage #2: at 20 - 80℃; for 0.416667 h; Stage #3: at 0℃;
To prepare this compound, 1-tetralone (10.2 g, 70 mmol) was added dropwise to a slurry of aluminum trichloride (23.3 g, 175 mmol) heated to 70 °C in a 3-neck flask with an outlet tube connected to a 2 M sodium carbonate solution. The slurry was stirred with a spatula. After the addition of 1-tetralone, the slurry was removed from heat and allowed to cool to room temperature. Bromine (12.3 g, 77 mmol) was added dropwise over 15 minutes. After that addition was complete, the slurry was heated at 80 °C for 10 minutes, then it was poured into a mixture of 200 grams of ice and 25 mL concentrated HC1. The 3-neck flask was rinsed with water and that rinse water was also added to the ice and slurry solution. That solution was extracted twice with ether (200 mL each) and those two extracts were combined. The combined ether extract was washed sequentially with water (50 mL), saturated sodium bicarbonate (25 mL), and brine (100 mL), and then was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil. The oil was subjected to flash chromatography (12percent THF/hexanes), and the resultant product was recrystallized from hexanes to afford 4.4 g (27percent) of 5-bromo-3,4-dihydro-2No.-naphthalen-l-one. XH NMR (500 MHz, CDC13) 5 8.03 (dd, J = 7.7, 1.2, 1H), 7.75 (dd, J = 7.7,1.2, 1H), 7.20 (t, J = 7.8,1H), 3.03 (t, J = 6.2, 2H), 2.66 (t, J = 6.5, 2H), 2.15-2.20 (m, 2H).
Reference：
[1] Patent: US2009/76076, 2009, A1, . Location in patent: Page/Page column 20
[2] Journal of the American Chemical Society, 2018, vol. 140, # 12, p. 4317 - 4326
[3] Patent: WO2006/23158, 2006, A2, . Location in patent: Page/Page column 54
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[5] Patent: WO2015/179366, 2015, A1, . Location in patent: Paragraph 00172
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[ 32281-97-3 ]
[ 68449-30-9 ]
Yield
Reaction Conditions
Operation in experiment
28.3%
Stage #1: Under N2 Stage #2: at 80℃; for 0.0833333 h;
Anhydrous AlCl3 (66.67 g, 0.50 mol, 99.99percent) under N2 was stirred vigorously as 1-tetralone (29.83 g, 0.20 mol) was added dropwise over 7 min. The evolved HCl gas was scrubbed through 5 N NaOH. The resulting mixture was a dark brown oil that exothermed to 75° C. When the temperature had cooled to 50° C., Br2 was added dropwise over 15 min. The mixture, which had cooled further to 40° C., was heated to 80° C. for 5 min, then poured into a mixture of ice (600 g) and 12 N HCl (80 mL). All the ice melted, leaving a cool dark mixture which was diluted with H2O (200 mL) and extracted with CH2Cl2 (200 mL, 100 mL). The combined extracts were dried with MgSO4 and concentrated in vacuo (30-60° C.) to a dark brown oil (45.6 g; theory=45.02 g).[0085] Chromatography over silica gel 60 with 8:1 heptane:THF did not prove effective, but two passes through the Biotage radially pressured silica gel cartridges using 9:1 heptane:MTBE as eluent produced acceptably pure fractions. [0086] 5-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as an orange oil (12.27 g, 28.3percent). HPLC showed an apparent wide divergence in absorbances at 230 nm for the two regioisomers, and was therefore not reliable for a potency check. TLC on silica gel (4:1 heptane:MTBE) confirmed modest contamination with 7-bromo-3,4-dihydro-1(2H)-naphthalenone. [0087] 7-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as a yellowish-white solid (15.48 g, 35.8percent); mp 69.5-75° C. (lit 74-75° C.). 1H NMR (CDCl3) corresponded to the literature description, plus a trace of heptane and an undefined by-product. TLC showed it to be cleaner than 5-bromo-3,4-dihydro-1(2H)-naphthalenone. [0088] A third fraction of orange oil (9.06 g, 20.9percent) was isolated. TLC showed it to be a nearly 1:1 ratio of 5-bromo-3,4-dihydro-1(2H)-naphthalenone, and 7-bromo-3,4-dihydro-1(2H)-naphthalenone.
With sodium hydride In methanol; mineral oil at 80℃; for 3 h; Inert atmosphere
Under nitrogen atmo-sphere, α-tetralone (25.0 mmol, 3.33 mL), dimethyl carbonate (300 mmol, 25.0 mL), sodium hydride (60percent in mineral oil, 50.0 mmol, 2.00 g) and dry methanol (0.1 mL) are heated to 80 °C and stirred for 3 hours. After cooling, hydrochloric acid (3 N, 30.0 mL) is added, the mixture is extracted with ethyl acetate and the combined organic phases are dried over sodium sulphate. After removing the solvent, 4 (5.06 g, 100percent) is obtained as a red-brown liquid.
92%
Inert atmosphere; Reflux
General procedure: A solution of α-tetralone (10 mmol) in dimethyl carbonate(5 mL) was added to a stirred suspension of NaH (60percent dispersion,15 mmol) in dimethyl carbonate (10 mL) under argon atmosphere.The solution was refluxed and once the reaction was judged completeafter a TLC test the solvent was evaporated. The resultant solid was dissolved in hydrochloric acid (2 M) and the phases were separated. The aqueous phase was extracted with ethyl acetate(35 mL). The organic extracts were dried (MgSO4) and evaporated to dryness. Flash chromatography (EtOAc/hexane 10percent) afforded the pure products. 4.2.1. Methyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate(5a).33 Yield 92percent; brown solid; mp66e68 C; Rf 0.35 (hexane/EtOAc 10/1). IR (KBr) (cm1): 2946; 2897; 1728; 1677; 1598; 1451;1372; 1313; 1156; 949; 900; 732; 1H NMR (CDCl3, 400 MHz) dH:12.41 (s, 1H), 8.04 (d, J7.9 Hz, 1H), 7.78 (d, J7.6 Hz, 1H), 7.47e7.43(m, 1H), 7.30e7.23 (m, 3H), 7.21 (d, J7.6 Hz, 1H), 7.13 (d, J7.1 Hz),3.79 (s, 3H), 3.75 (s, 3H), 3.59 (dd, J10.5, 4.7 Hz, 1H), 3.04e2.92 (m,2H), 2.77 (dd, J10.8, 4.6 Hz, 2H), 2.57e2.51 (m, 2H), 2.49e2.42 (m,1H), 2.34e2.29 (m, 1H); 13C NMR (CDCl3, 100 MHz) dC: 193.3, 173.2,170.7, 165.2, 143.8, 139.5, 134.0, 131.8, 130.6, 130.0, 128.9, 127.8,127.5, 127.0, 126.7, 124.4, 96.9, 54.5, 52.5, 51.8, 27.8, 27.7, 26.5, 20.6;MS (EI) m/z (percent): 204 (M), 189, 172, 144, 127, 118, 115, 90, 77, 63, 51.
92%
Inert atmosphere; Reflux
General procedure: A solution of the α-tetralone (10 mmol) in dimethyl carbonate (5 mL) was added to a stirred suspension of NaH (60percent dispersion, 15 mmol) in dimethyl carbonate (10 mL) under an atmosphere of argon. The solution was refluxed; when the reaction was complete (TLC monitoring) the solvent was evaporated. The resultant solid was dissolved in 2 M HCl and the phases were separated. The aqueous phase was extracted with EtOAc (3 × 15 mL). The organic extracts were dried (MgSO4) and evaporated to dryness. Flash chromatography (10percent EtOAc/hexane) afforded the pure products.
80%
Stage #1: With sodium hydride In mineral oil at 90℃; for 0.0833333 h; Stage #2: at 115℃; for 6 h;
Example 1 Preparation of Compound 1; IPrOH Step A - Synthesis of Compound 1 bTo Me2COe (9mL) was added NaH (60percent dispersion in oil, 2.52g, 1.51mmol) and the solution was heated to 9O0C for 5min. To the solution α- tetralone (4.0Og, 27.4mmol) in Me2COa (9mL) was added and the solution was stirred at 1150C for 6h. Allowed to cool, added MeOH (0.9mL), added 3M HCI (93mL), transferred to sep funnel, extracted with ether, washed with sat. aq. NaHCψ3, washed with H2O, washed with brine, dried (MgSO4), filtered, and concentrated. Crude product was purified by flash column chromatography to yield compound 1b (4.5g, 80percent).
64%
at 80℃; for 0.333333 h;
Methyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate Sodium hydride (1.26 g, 36.75 mmol, 0.73 equiv, 70percent) was added in several batches to a mixture of 3,4-dihydronaphthalen-1(2H)-one (7.3 g, 50.00 mmol, 1.00 equiv) and dimethyl carbonate (50 mL). The resulting solution was stirred for 20 min at 80° C. The reaction was quenched by the addition of 150 mL of water/ice, then extracted with 3*100 mL of ether.The organic layers were combined and washed with 1*50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether. This provided 6.5 g (64percent) of methyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate as a white solid. LC-MS: (ES, m/z): 205 [M+H]+ 1H-NMR (300 MHz, CDCl3, ppm): 12.40 (s, 0.5H), 8.07-7.16 (m, 4H), 3.83-3.78 (m, 3H), 3.66-3.61 (m, 0.5H), 3.07-2.79 (m, 2H), 2.60-2.37 (m, 2H)
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46
[ 17640-15-2 ]
[ 529-34-0 ]
[ 7442-52-6 ]
Reference：
[1] Organic Syntheses, 1992, vol. 70, p. 256 - 256
[2] Journal of Medicinal Chemistry, 1995, vol. 38, # 4, p. 617 - 628
alpha-Tetralone (14.6 g, 100 mmol) and 1-naphthylhydrazinium chloride (19.5 g, 100 mmol) were put in ethanol together with 2-3 drops of acetic acid, followed by boiling and stirring. After boiling for 3 hours, water was added and the resulting solid was filtered and dried to give a brown solid (24 g, 85%).
Example 1.2: Preparation of 6',6'-dimethyl-2',3',4',4a',5',6'-hexahydro-l'/ -spiro[cyclopropane- l,7'-naphtho[l,8-cd]azepine] (Compound 102) Step A: Preparation of 2,2-dimethyl-3,4-dihydronaphthalen-l(2/ )-one To a suspension of 60% sodium hydride dispersion (4 g, 100.0 mmol) in 180 mL THF, a solution of 3,4-dihydronaphthalen-l(2 )-one (5.1 g, 34.89 mmol) in 20 mL THF was added slowly. After stirring at room temperature for 10 min, flask was placed into an ice/water-bath and iodomethane (6.5 mL, 104.2 mmol) was added. The mixture was allowed to slowly warm to room temperature. After stirring overnight, the mixture was quenched by the slow addition of water, partly concentrated, an extracted with water and AcOEt. Organic phase was dried over MgS04, filtered, and concentrated. The residue was purified by biotage column chromatography (S1O2, hexane/ AcOEt gradient) to give 2,2- dimethyl-3,4-dihydronaphthalen-l(2 )-one (5.5 g, 91 %) as a colorless liquid. NMR (400 MHz, CDCI3) delta 1.22 (s, 6H), 1.99 (t, J = 6.4 Hz, 2H), 2.99 (t, J = 6.4, 2H), 7.20-7.23 (m, 1H), 7.28-7.32 (m, 1H), 7.43-7.47 (m, 1H), 8.04 (dd, J, = 8.0 Hz, J2 = 1.3 Hz, 1H).
83%
To a suspension of NaH (8.2 gm, 343 mmol) in THF (250 mL) in a one-liter round bottomed flask, 1-tetralone [11] (10.0 gm, 69 mmol) dissolved in dry THF (25 mL) was added. After stirring the mixture for 10 minutes at RT, methyl iodide (11.1 ml, 178 mmol) was added via a syringe. The mixture was heated on an oil bath to 40C for 30 minutes, and stirring continued at RT until the starting material disappeared. The reaction was monitored by TLC using ethyl acetate: hexane (1: 6) solvent mixture. The reaction was quenched by addition of water (slowly and dropwise) to destroy excess sodium hydride. The mixture was extracted with ethyl acetate, washed with water and dried over sodium sulphate. Evaporation of the solvent yielded a brown oil. Column chromatography using silica gel with EtOAc: Hexane (1:6) afforded clean 2,2-dimethyl-1-tetralone [12] (10.8 g, 83%). FTIR (lambdamax) : 2956,1682,1601 cm-1. 1H NMR (500 MHz, CDCl3); 1.20 (s, 6H, 2 x CH3), 1.97 (t, 2H, J=6.5 Hz, 2 H-3), 2.97 (t, 2H, J=6.5 Hz, 2 H-4), 7.21 (d, 1H, J=7.5 Hz, ArH-5), 7.28 (t, 1H, J=7.5 Hz, ArH- 6), 7.45 (t, 1H, J=7.5 Hz, ArH-7) and 8.03 (d, 1H, J=7.5 Hz, ArH-8). HRMS: Calculated for C12H14O, 174.1045, Found: 174.1031.
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 1h;
a) Acetic acid 2,2-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl ester; <n="91"/>To a suspension of 60% NaH in an oil dispersion (20 g, 500 mmol) in THF (600 mL) at 0 0C is added a solution of alpha-tetralone (24.8 g, 166.5 mmol) in THF (40 mL) via cannula, followed by iodomethane (119 g, 833 mmol). The reaction is permitted to warm to room temperature and after one hour is quenched with 1 M aqueous sodium bisulfate. The reaction mixture is partitioned between water and ethyl acetate and the organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting residue is then dissolved in methanol (600 mL) and dichloromethane (100 mL). Sodium borohydride (37.8 g, 262 mmol) is then added in five portions over 20 minutes. After one hour the reaction is diluted with water, and the organic solvents are then evaporated in vacuo. The resulting mixture is extracted with ethyl acetate, and the organic extract is dried with magnesium sulfate, filtered and concentrated. The resulting residue is then dissolved in dichloromethane (300 mL). To the resulting solution is added triethylamine (50 g, 490 mmol) and 4-dimethylaminopyridine (4 g, 33 mmol). The reaction is cooled to 0 0C and charged with acetic anhydride (42 g, 408 mmol). The reaction is permitted to stir for 10 minutes, then is diluted with ethyl acetate, and washed with 1 M aqueous NaHSO4, followed by saturated aqueous NaHCO3. The organic phase is dried with magnesium sulfate, filtered, and concentrated. The resulting oil is then purified by distillation (110 0C at 0.2 torr) to furnish acetic acid 2,2-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl ester; 1H NMR (400 MHz, CDCI3) delta ppm 0.95 (s, 3 H), 1.01 (s, 3 H), 1.50 - 1.63 (m, 1 H), 1.84 - 1.99 (m, 1 H), 2.10 (s, 3 H), 2.76 - 2.94 (m, 2 H), 5.74 (s, 1 H), 7.08 - 7.31 (m, 4 H).
Example 1; Preparation of 7-Bromo-l-tetralone; 7-bromo-1-tetralone was prepared according to the procedure described in Cornelius, L. A. M.; Combs, D. W. Synthetic Communications 1994,24, 2777-2788. The above isomers were separated using silica gel flash chromatography (Biotage Flash 75, elution solvent 20/1 hexanes: MTBE) to yield 5-bromo-1-tetralone (11.59 g, 51%) and 7-bromo-1-tetralone (9.45 g, 42%).
42%; 51%
With aluminum (III) chloride; bromine; at 75 - 80℃; for 0.55h;
A 500 mL three-necked flask fitted with an addition funnel, reflux condenser and thermometer was charged with aluminum chloride (33.34 g, 250 mmol) and heated to 75-80 C. 1- Tetralone (14.6 g, 13.3 ML, 100 mmol) was added dropwise over 10 min. The resulting brown slurry was stirred for 3 min before dropwise addition of bromine (19.21 g, 6.15 ml, 120 mmol) over 15 min. The mixture was stirred for 5 min and then poured into a mixture of ice (300 g) and 12N HC1 (40 mL). The mixture was stirred until the aluminum chloride was dissolved and then diluted with water (200 mL). The mixture was extracted with diethyl ether (3 X 300 mL) and the combined organics were washed with water (2 X 300 mL), dried (sodium sulfate), filtered and evaporated in vacuo to give a dark brown mixture of 5-and 7- BROMO-1-TETRALONE. The isomers were separated using silica gel flash chromatography (Biotage Flash 75, elution solvent 20/1 hexanes: MTBE) to yield 5-BROMO-1-TETRALONE (11.59 g, 51%) and 7- BROMO-1-TETRALONE (9.45 g, 42%).
42%; 51%
A 500 mL three-necked flask fitted with an addition funnel, reflux condenser and thermometer was charged with aluminum chloride (33.-34 g, 250 mmol) and heated to 75-80 C. 1- Tetralone (14.6 g, 13.3 mL, 100 mmol) was added dropwise over 10 MIN. THE resulting brown slurry was stirred for 3 min before dropwise addition of bromine (19.21 g, 6.15 ml, 120 mmol) over 15 min. The mixture was stirred for 5 min and then poured into a mixture of ice (300 g) and 12N HC1 (40 mL). The mixture was stirred until the aluminum chloride was dissolved and then diluted with water (200 mL). The mixture was extracted with diethyl ether (3 X 300 mL) and the combined organics were washed with water (2 X 300 mL), dried (sodium sulfate), filtered and evaporated in vacuo to give a dark brown mixture of 5-and 7- BROMO-1-TETRALONE. The isomers were separated using silica gel flash chromatography (Biotage Flash 75, elution solvent 20/1 hexanes: MTBE) to yield 5-BROMO-1-TETRALONE (11.59 g, 51%) and 7- BROMO-1-TETRALONE (9.45 g, 42%). [Note 1. Procedure: Cornelius, L. A. M.; Combs, D. W. Synthetic Communications 1994,24, 2777-2788].
With hydrogenchloride; bromine;aluminium trichloride; In tetrahydrofuran; hexane;
7-Bromo-1-tetralone (IXa) and 5-bromo-1-tetralone (IXb) STR10 1-Tetralone (VII) (7.3 g, 0.05 mol) was added dropwise to anhydrous aluminum chloride (16.6 g, 0.125 mol) with vigorous stirring over 3 minutes. Bromine (3.71 mL, 0.06 mol) was added to the resulting slurry over 10 minutes. The mixture was heated to 80 C. for 5 minutes after the addition of bromine was complete and the still molten mixture was poured into 150 g of crushed ice containing 20 ml of 12N HCl. Following the same work up as for example 1, 10.85 g of a brown oil was obtained. The oil was chromatographed on a silica gel column (45*10 cm) using hexane:THF (8:1). The separated isomers were each recrystallized from hexane to give 4.2 g of 7-bromo-1-tetralone (IXa) and 4.5 g of 5-bromo-1-tetralone (IXb).
Preparation 1 [0086] Preparation of 1-Bromo-5-methoxy-naphthalene. [CHEMMOL-00020] [0087] Preparation of 5-Bromo-3,4-dihydro-1(2H)-naphthalenone and 7-bromo-3,4-dihydro-1(2H)-naphthalenone. [0088] Anhydrous AlCl3 (66.67 g, 0.50 mol, 99.99%) under N2 was stirred vigorously as 1-tetralone (29.83 g, 0.20 mol) was added dropwise over 7 min. The evolved HCl gas was scrubbed through 5 N NaOH. The resulting mixture was a dark brown oil that exothermed to 75 C. When the temperature had cooled to 50 C., Br2 was added dropwise over 15 min. The mixture, which had cooled further to 40 C., was heated to 80 C. for 5 min, then poured into a mixture of ice (600 g) and 12 N HCl (80 mL). All the ice melted, leaving a cool dark mixture which was diluted with H2O (200 mL) and extracted with CH2Cl2 (200 mL, 100 mL). The combined extracts were dried with MgSO4 and concentrated in vacuo (30-60 C.) to a dark brown oil (45.6 g; theory=45.02 g). [0089] Chromatography over silica gel 60 with 8:1 heptane:THF did not prove effective, but two passes through the Biotage radially pressured silica gel cartridges using 9:1 heptane:MTBE as eluent produced acceptably pure fractions. [0090] 5-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as an orange oil (12.27 g, 28.3%). HPLC showed an apparent wide divergence in absorbances at 230 nm for the two regioisomers, and was therefore not reliable for a potency check. TLC on silica gel (4:1 heptane:MTBE) confirmed modest contamination with 7-bromo-3,4-dihydro-1(2H)-naphthalenone. [0091] 7-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as a yellowish-white solid (15.48 g, 35.8%); mp 69.5-75 C. (lit 74-75 C.). 1H NMR (CDCl3) corresponded to the literature description, plus a trace of heptane and an undefined by-product. TLC showed it to be cleaner than 5-bromo-3,4-dihydro-1(2H)-naphthalenone. [0092] A third fraction of orange oil (9.06 g, 20.9%) was isolated. TLC showed it to be a nearly 1:1 ratio of 5-bromo-3,4-dihydro-1(2H)-naphthalenone, and 7-bromo-3,4-dihydro-1(2H)-naphthalenone.
Anhydrous AlCl3 (66.67 g, 0.50 mol, 99.99%) under N2 was stirred vigorously as 1-tetralone (29.83 g, 0.20 mol) was added dropwise over -7 min. The evolved HCl gas was scrubbed through 5 N NaOH. The resulting mixture was a dark brown oil that exothermed to 75 C. When the temperature had cooled to 50 C., Br2 was added dropwise over 15 min. The mixture, which had cooled further to 40 C., was heated to 80 C. for 5 min, then poured into a mixture of ice (600 g) and 12 N HCl (80 mL). All the ice melted, leaving a cool dark mixture which was diluted with H2O (200 mL) and extracted with CH2Cl2 (200 mL, 100 mL). The combined extracts were dried with MgSO4 and concentrated in vacuo (30-60 C.) to a dark brown oil (45.6 g; theory=45.02 g). Chromatography over silica gel 60 with 8:1 heptane:THF did not prove effective, but two passes through the Biotage radially pressured silica gel cartridges using 9:1 heptane:MTBE as eluent produced acceptably pure fractions. 5-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as an orange oil (12.27 g, 28.3%). HPLC showed an apparent wide divergence in absorbances at 230 nm for the two regioisomers, and was therefore not reliable for a potency check. TLC on silica gel (4:1 heptane:MTBE) confirmed modest contamination with 7-bromo-3,4-dihydro-1(2H)-naphthalenone. 7-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as a yellowish-white solid (15.48 g, 35.8%); mp 69.5-75 C. (lit 74-75 C.). 1H NMR (CDCl3) corresponded to the literature description, plus a trace of heptane and an undefined by-product. TLC showed it to be cleaner than 5-bromo-3,4-dihydro-1 (2H)-naphthalenone. A third fraction of orange oil (9.06 g, 20.9%) was isolated. TLC showed it to be a nearly 1:1 ratio of 5-bromo-3,4-dihydro-1(2H)-Naphthalenone, and 7-bromo-3,4-dihydro-1(2H)-Naphthalenone.
With N-Bromosuccinimide; dibenzoyl peroxide; In benzene; for 4h;Reflux; Inert atmosphere;
General procedure: A benzene suspension (30 mL) of 1-tetralone 4, 11, 16 (1.0 equiv), N-bromosuccinimide (NBS) (2.2 equiv) and (PhCOO)2 (5 mol percent) was refluxed under Argon atmosphere for 4 h and then cooled to 20 °C. To the reaction mixture was added triethylamine (1 mL) and the solvent was removed in vacuo. The reaction mixture was diluted with water and extracted with CH2Cl2 (3.x.25 mL). The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, heptane/EtOAc) to give 5, 12 and 17.
59%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In benzene; for 4h;Reflux; Inert atmosphere;
A benzene suspension (30 mL) of 1-tetralone (1.8mL, 13.7 mmol), N-bromosuccinimide (NBS) (4.9 g, 27.5 mmol), and AIBN (0.1 g, 5 molpercent) was refluxed under argon atmosphere for 4 h, and then cooled to 20 . To the reaction mixture was added triethylamine (2 mL) and the solvent was removed in vacuo, added by water and extracted with CH3Cl. The organic layer was dried over MgSO4 and concentrated in vacuo. The product was purified by flash column chromatography using hexane and EtOAc to give 2-bromo-1-naphthol as white solid (1.8 g, 59percent), 1H NMR (300MHz, CDCl3) d 8.24?8.21 (m, 1H), 7.77?7.73 (m, 1H),7.51?7.43(m, 3H), 7.28 (d, J = 8.8 Hz, 1H),5.96 (s, 1H); 13C NMR (75 MHz, CDCl3) d 148.1, 133.7,128.3, 127.5, 126.8, 126.1, 124.3, 122.2, 121.3, 103.9; GC-MS m/z 222, 224 (M+).
2-(N-benzylmethylamino)methyl-6-fluoro-3,4-dihydro-2H-naphthalene-1-one hydrochloride[ No CAS ]
[ 529-34-0 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; paraformaldehyde; In ethanol; water;
Step D 2-(N-Benzylmethylamino)methyl-6-fluoro-3,4-dihydro-2H-naphthalene-1-one hydrochloride To an ice-cooled solution of N-benzylmethylamine (5.67 cm3) in ethyl alcohol (60 cm3) was added hydrochloric acid (5 M, 10 cm3). <strong>[703-67-3]6-Fluoro-3,4-dihydro-2H-naphthalene-1-one</strong> (6.00 g) and paraformaldehyde (1.32 g) were then added and the resulting mixture was stirred and heated to reflux for 4 h. Upon cooling, the alcohol was removed under reduced pressure and water (100 cm3) was added. The remaining tetralone was extracted into diethyl ether (100 cm3) and the aqueous mixture was then extracted further with dichloromethane (2*100 cm3). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. Trituration with diethyl ether and filtration provided the title compound (3.18 g) as a white solid.
b. 7-Chloro-1-tetralone. 4-(4-Chlorophenyl)butyric acid (26.62 g) was added to 150 g of hot polyphosphoric acid (90 C.); the mixture was maintained at 90-95 C. for 0.33 hour. After cooling to room temperature, the reaction mixture was added to 400 mL of ice-cold stirred water. The solution was allowed to warm to room temperature; and the resulting precipitate was filtered, washed (water) and air dried to give a pale yellow solid (22.3 g). The solid was recrystallized from toluene (50 mL) at -10 C. The crystals were collected and washed with cold toluene and then hexanes to give the tetralone as pale yellow crystals (18.18 g); mp 100.3-101.1 C.
With PPA; In water;
b. 7-Chloro-1-tetralone. 4-(4-Chlorophenyl)butyric acid (26.62 g) was added to 150 g of hot polyphosphoric acid (90 C.); the mixture was maintained at 90-95 C. for 0.33 hour. After cooling to room temperature, the reaction mixture was added to 400 mL of ice-cold stirred water. The solution was allowed to warm to room temperature; and the resulting precipitate was filtered, washed (water) and air dried to give a pale yellow solid (22.3 g). The solid was recrystallized from toluene (50 mL) at -10 C. The crystals were collected and washed with cold toluene and then hexanes to give the tetralone as pale yellow crystals (18.18 g); mp 100.3-101.1 C.
Example III Synthesis of Tetrahydronaphthalene Derivatives 5-Bromo-1-tetralone. (Cornelius, L. A. H.; Combs, D. W. Synthetic Communications 1994, 24(19), 2777-2788) Into a round bottom flask kept at 0 C., AlCl3 (19.6 g, 146.8 mmol) was added and the reaction system was put under nitrogen. 8 mL of tetralone (8.62 g, 58.9 mmol) were added during a 10-minute period, at which point, the reaction mixture was heated in an oil bath at 90 C. for about 45 minutes before adding 3.6 mL of Br2 (11.2 g, 70.1 mmol). The reaction mixture was stirred at 90 C. for an hour before 30 mL of ice-water and 20 mL of NaHCO3 were added. The product was extracted twice from the aqueous phase with Et2O and, the resultant organic phase was washed once with NaHCO3, once with brine and dried under Na2SO4. The crude reaction mixture was purified by flash chromatography (2.5% EtOAc/97.5% hex) which afforded 5.87 g (26.1 mmol) of the product in a 44% yield. 1H NMR (300 MHz, CDCl3, delta): 8.01 (dd, J=7.8, 1.3, Ar, 1H), 7.73 (dd, J=7.9, 1.3, Ar, 1H), 7.18 (tt, J=7.9, 0.6, Ar, 1H), 3.01 (t, J=6.2, C2, 2H), 2.64 (dd, J=6.7, 5.6, C2, 2H), 2.15 (td, J=13.0, 6.5, C2, 2H). 13C NMR (75 MHz, CDCl3): delta 197.5, 143.4, 137.3, 134.9, 127.7, 126.5, 124.8, 38.2, 30.0, 22.3. Dept 135 NMR (75 MHz, CDCl3): delta 137.3 (H), 127.7 (H), 126.5 (H), 38.2 (H2), 30.0 (H2), 22.3 (CH2). EIMS: m/z (% rel. intensity) 226 (M++2, 93), 224 (M+, 93), 211 (25), 209 (25), 198(100), 196 (100), 170 (50), 168 (50), 145 (25), 115 (45), 89 (60), 63 (28).
27%
To prepare this compound, 1-tetralone (10.2 g, 70 mmol) was added dropwise to a slurry of aluminum trichloride (23.3 g, 175 mmol) heated to 70 C in a 3-neck flask with an outlet tube connected to a 2 M sodium carbonate solution. The slurry was stirred with a spatula. After the addition of 1-tetralone, the slurry was removed from heat and allowed to cool to room temperature. Bromine (12.3 g, 77 mmol) was added dropwise over 15 minutes. After that addition was complete, the slurry was heated at 80 C for 10 minutes, then it was poured into a mixture of 200 grams of ice and 25 mL concentrated HC1. The 3-neck flask was rinsed with water and that rinse water was also added to the ice and slurry solution. That solution was extracted twice with ether (200 mL each) and those two extracts were combined. The combined ether extract was washed sequentially with water (50 mL), saturated sodium bicarbonate (25 mL), and brine (100 mL), and then was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil. The oil was subjected to flash chromatography (12% THF/hexanes), and the resultant product was recrystallized from hexanes to afford 4.4 g (27%) of 5-bromo-3,4-dihydro-2No.-naphthalen-l-one. XH NMR (500 MHz, CDC13) 5 8.03 (dd, J = 7.7, 1.2, 1H), 7.75 (dd, J = 7.7,1.2, 1H), 7.20 (t, J = 7.8,1H), 3.03 (t, J = 6.2, 2H), 2.66 (t, J = 6.5, 2H), 2.15-2.20 (m, 2H).
With aluminum (III) chloride; bromine; at 80℃; for 0.166667h;
5.1 5-Bromo-3,4-dihydro-2H-naphth-1-one 2.21 g of AlCl3 are placed in a round-bottomed flask, to which 0.91 ml of 3,4-dihydro-2H-naphth-1-one is added over 10 min and 0.41 ml of Br2 is added over 5 min, and the mixture is heated at 80 C. for 10 min. It is allowed to return to ambient temperature and a solution comprising 20 g of ice and 2.7 ml of concentrated hydrochloric acid is added thereto. The mixture is then diluted with water and diethyl ether. The organic phase is subsequently separated, dried and concentrated under reduced pressure. The residue is purified by reverse phase preparative chromatography. 172 mg of compound are obtained. 1H NMR spectrum (d6-DMSO, delta in ppm): 2.1 (m, 2H); 2.65 (m, 2H); 2.95 (m, 2H); 7.35 (t, 1H); 7.9 (m, 2H). M+H=226.
With zirconium(IV) chloride; In toluene; at 20 - 50℃; for 2h;
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, was charged 2-(4-(4-chlorophenyl)-1-hydroxy cyclohexyl)-3,4-dihydronaphthalen-1-(2H)-one (5.0 g, 0.04 mol) and dissolved in toluene (50 mL) at room temperature. To the above solution was added ZrCl4 (0.33 g, 1.4 mmol) and the reaction mass was stirred at 50 °C for 2 h. The reaction mass showed complete conversion of starting material to a-tetralone and 4-(4- chlorophenyl) cyclohexanone in 1 :1 ratio and no olefin product could be identified and isolated.
With toluene-4-sulfonic acid; In toluene; at 60℃; for 6h;
2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-1-(2H)-one (12.0 g, 0.0.034 mol) was charged in a reactor equipped with overhead stirrer, reflux condenser and thermo-pocket. Toluene (200 mL) was added to suspend the material and p-toluene sulfonic acid (0.3 g, 2.5 mol percent) was added to the reaction mass which was then heated to 60 °C and stirred for 6 h. Progress of reaction was monitored on TLC. After completion of reaction, reaction mass was cooled to RT and solvent was evaporated under pressure to obtain residue. To the residue, was added ethyl acetate (150 mL) and washed with sat. NaHC03 soln. and brine followed by evaporation of solvent to give crude product which was further recrystallised from methanol to afford white solid compound (5.3 g, 50 percent yield). The mother liquor obtained after re-crystallisation was subjected to GC analysis wherein both a-tetralone and 4-(4-chlorophenyl) cyclohexanone were identified to be present in approx. 1 : 1 ratio (by respective retention times and AUCs in the mother liquor) and in 50 percent yield. GC retention time: a-tetralone (XII): 17.21 min (Area percent : 46)
General procedure: A solutionof carboxylic acid (1 mmol), ketone (1 mmol, if required) and TFAA (0.85 mL, 6 mmol) in dichloromethane (1 mL) was stirred for 15 min at rt. The required quantity of triflic acid (usually 44 muL, 0.5 mmol) was then added, and the resulting solution was stirred at rt for 1-4 h (24 h for 3v and 3w) under the conditions indicated in Scheme 1, Scheme 2, Table 1, and Table 2 (TLC monitoring). The reaction mixture was evaporated under reduced pressure, and after quenching with water, the residue was redissolved in dichloromethane (10 mL), washed with 5% NaHCO3 (2 × 3 mL), water (2 × 3 mL), and dried over MgSO4. The solvent was removed in vacuum, andthe crude reaction mixture was purified by silica gel chromatography (n-hexane/CH2Cl2/MeOH).
3,4-dihydronaphthalen-1(2H)-one (5-chloropyridin-2-yl)hydrazone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
In ethanol; for 0.5h;Reflux;
General procedure: A solution of the appropriateketone (4.0 mmol) in ethanol (7 ml) was added to asolution of hydrazine 1 (0.574 g, 4.0 mmol) in ethanol(5 ml), and the mixture was refluxed for 30 min. Thesolvent was removed by distillation until constant mass,producing the corresponding hydrazone 5a-p. Theobtained reaction residue was treated with polyphosphoricacid (5 g),12 stirred and heated to 160 (beginning of anexothermic reaction), and maintained at 160-180 untilthe foaming stopped (~5 min). After cooling to ~40, thereaction mixture was suspended in water (30 ml), cooled to0-5C, and adjusted with aqueous 25% NH3 solution to pH9-10. The precipitate that formed was filtered off, washedwith ice water (2×5 ml), methanol (1 ml, cooled to 0),and air-dried, then recrystallized. In the case if oilseparated the reaction mixture was extracted with CH2Cl2(3×20 ml), the extract was dried over anhydrous Na2SO4and evaporated to dryness. The obtained residue wasrecrystallized from methanol or ethyl acetate.
N-(5-fluoropyridin-3-yl)-3,4-dihydronaphthalen-1(2H)-imine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,2-dichloro-ethane; at 90℃; for 24h;Molecular sieve;
General procedure: To a solution of 1-indanone (264 mg, 2.0 mmol) and <strong>[210169-05-4]5-fluoropyridin-3-amine</strong> (235mg, 2.1 mmol) in 20 mL dichloroethane was added 20 g 4A molecular sieves, and the mixture was stirred at 90 C for 24 hours. The reaction was monitored by TLC. After consumption of indanone, the sieves were removes by filtration through celite, and the filtrate was evaporated to afford the imine product 4 which was used for next step without further purification.
General procedure: The reactions were carried out according to a literature method.2 A solution of i-Pr2NH (1.3 mL, 9.1 mmol) and n-BuLi (4.9 mL, 1.6 M in hexane) in THF (15 mL) was stirred at 0 C for 1.5 h. To this solution was added ketone (5 mmol) in THF (3 mL) at 0 C. After stirring for 1 h, Benzil (6.5 mmol) in THF (5 mL) was added at -78 C dropwise via syringe over 0.5 h. After 12 h, the reaction was quenched with saturated NH4Cl. Products were extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude mixture, which was purified by silica gel column chromatography (eluent: EtOAc / hexane = 1/20) to afford 1, 3 as white solid.
rac-(6aR,6bR,9aR,14cR)-5,6,6a,6b,8,9a,10,14c-octahydro-8-(4-hydroxyphenyl)naphtho[2,1-c]pyrrolo[3,4-a]carbazole-7,9-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%Spectr.
With toluene-4-sulfonic acid; In isopropyl alcohol; for 72h;Inert atmosphere; Reflux; Darkness;
General procedure: Compounds 8a-g and 10a-e were prepared as follows: isopropyl alcohol (20 mL) was added to a mixture of indole (4) (1.172 g, 10 mmol, 1 eq), 1-tetralone (5) (1.33 mL, 10 mmol, 1 eq), N-phenylmaleimide (7) (1.732 g, 10 mmol, 1 eq) and p-toluenesulfonic acid (0.380 g, 2 mmol, 0.2 eq). 9a-g were prepared similarly: isopropyl alcohol (20 mL) was added to a mixture of indole (4) (1.172 g, 10 mmol, 1 eq), 4-chromanone (6) (1.482 g, 10 mmol, 1 eq), N-phenylmaleimide (7) (1.732 g, 10 mmol, 1 eq) and p-TsOH (0.380 g, 2 mmol, 0.2 eq). The reaction mixture was heated at reflux for three days under a nitrogen atmosphere, and in the absence of light. Upon completion, a solid reaction mixture was cooled down and filtered with IPA (15 mL) and water (5 mL). The crude material was triturated with IPA (20 mL) three times in the absence of light to give a solid. If further purification was necessary, recrystallization with a mixture of dichloromethane and pentane was performed. In the case of 6 derivatives (9a-g) solubility was found to be very poor, and thus recrystallization was performed with a mixture of tetrahydrofuran and pentane. Using this procedure 8a-g, 9a-g, and 10a-e were synthesized.
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