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CAS No. : | 826-73-3 | MDL No. : | MFCD00004144 |
Formula : | C11H12O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KWHUHTFXMNQHAA-UHFFFAOYSA-N |
M.W : | 160.21 | Pubchem ID : | 70003 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.36 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 49.1 |
TPSA : | 17.07 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.46 cm/s |
Log Po/w (iLOGP) : | 2.02 |
Log Po/w (XLOGP3) : | 2.56 |
Log Po/w (WLOGP) : | 2.6 |
Log Po/w (MLOGP) : | 2.3 |
Log Po/w (SILICOS-IT) : | 3.3 |
Consensus Log Po/w : | 2.55 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.82 |
Solubility : | 0.245 mg/ml ; 0.00153 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.57 |
Solubility : | 0.435 mg/ml ; 0.00272 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.66 |
Solubility : | 0.0349 mg/ml ; 0.000218 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.69 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium <i>tert</i>-butylate In tetrahydrofuran; diethyl ether at 20℃; Inert atmosphere | General procedure: To a stirred suspension of methyltriphenylphosphonium bromide (1.5 equiv.) in diethylether(25-45 mL) under argon was added dropwise a solution of potassium-tert-butoxide 1M in THF (1.5 equiv.). The reaction mixture was immediately turned to yellow. After refluxing for 1 hour, the corresponding ketone (1.0 equiv.) was added in portions. The mixture was stirred at room temperature overnight. After completion, the reaction mixture was then hydrolyzed by water (5-8mL). The organic phase was separated and aqueous phase was extracted by diethyl ether (2 x 10mL). The combined organic phases were washed with water (20mLx2), brine (20mLx1), dried over anhydrous MgSO4 and concentrated under reduced pressure to yield crude product. Purification of this crude product by a suitable method afforded the corresponding alkene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With trifluorormethanesulfonic acid at 5 - 20℃; for 2h; | |
83% | With Nafion-H In various solvent(s) at 180℃; | |
With PPA |
With phosphorus pentoxide; benzene | ||
(cyclization); | ||
With PPA | ||
Multi-step reaction with 2 steps 1: Et3N / ethyl acetate / 0.5 h / 0 °C 2: AlCl3 / CS2 / 3 h / Heating | ||
Multi-step reaction with 2 steps 1: SOCl2 / Heating 2: AlCl3 / CS2 / Heating | ||
8 % Chromat. | With H-Beta zeolite HSZ-940HOA In 1,2-dichloro-benzene at 220℃; for 0.166667h; microwave irradiation; | |
With polyphosphoric acid at 85℃; for 2h; | ||
With polyphosphoric acid at 80℃; for 3h; | ||
With polyphosphoric acid at 90℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.2% | With triethylsilane; trifluoroacetic acid; at 60℃; for 4h; | (1) Weigh 6,7,8,9 tetrahydro-5H-benzo[7]l-en-5-one (200 mg, 1.25 mmol),Triethylsilane(434 mg, 3.75 mmol) was added to a reaction flask and 10 mL of dry trifluoroacetic acid (TFA) was added. Stir at 60 C for 4 h under nitrogen, add the appropriate amount of ethyl acetate and water to dilute the reaction solution.The liquid phase was separated, and the aqueous phase was extracted with ethyl acetate.Wash with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn,Drying over anhydrous sodium sulfate, concentration under reduced pressure, crude column chromatography(100% petroleum ether) gave a colorless oil (compound of formula II-3) 150 mg,Yield: 82.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-Bromosuccinimide; tetrachlorosilane; In acetonitrile; at 20℃; for 7h; | General procedure: To a mixture of NXS and substrate (1 or 6) in CH3CN at room temperature was added SiCl4 and the mixture left to stir until TLC showed the disappearance of the starting material. The reaction was then poured onto H2O and the mixture extracted with CH2Cl2. The extracts were combined, dried over MgSO4 and evaporated. The residue was purified by recrystallization (pet. ether-Et2O, 3:1) to give pure 2b-2g, 3b, or by silica gel column chromatography (hexane-EtOAc 10:1 or 30:1) to give pure 2a,h,i, 3a-5 or 7-9, respectively |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; In tetrahydrofuran; at 0℃; for 0.5h; | General procedure: 4.2.1 General procedures (A) for the enantioselective reduction of ketones (3-5) To a solution of (R)-(+)-2-methyl-CBS-oxazaborolidine or (S)-(-)-2-methyl-CBS-oxazaborolidine (0.2equiv) in THF (1mL/0.21mmol ketone) at 0C was added a 2.0 M solution of borane dimethyl sulfide in THF (1.2equiv). The mixture was stirred for 15min then a solution of ketone (1.0equiv) in THF (1mL/0.21mmol ketone) was cannulated dropwise into the reaction mixture. After stirring for 30 min, the reaction was quenched by the addition of MeOH (1mL/0.75mmol of BH3·SMe2), then concentrated under reduced pressure to afford colorless oils that solidified overnight at -20C. The (R)-CBS reagent produced the (S)-alcohols (6a-8a) and the (S)-CBS produced the (R)-alcohols (6b-8b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With trichlorophosphate; at 0 - 80℃; for 3.25h; | General procedure: Phosphorus oxychloride (8.3mmol) was added to a round bottom flask containing N,N-dimethylformamide (12.1mmol) in an ice bath at 0C and stirred for 10min, benzosuberone (6.2mmol) was added and stirred for 15min. The ice bath was replaced and stirred for an additional 3h at 80C. The reaction mixture was poured on crushed ice and stirred for 10min and neutralized with 20% sodium bicarbonate solution. After extraction with diethyl ether (3×100mL), the combined organic extracts were washed with brine solution (2×50mL) and water (3×100mL). The organic layer was dried over Na2SO4 and concentrated on reduced pressure to yield a red liquid. The product was purified by column chromatography (hexane/EtOAc). |
84.4% | With trichlorophosphate; at 0 - 80℃; for 4h; | General procedure: Phosphorus oxychloride (0.9g, 8.1mmol) was added to a ask containing N, N-dimethylformamide (5mL) in an ice bath and stirred for 10min. The ice bath was replaced with an ambient temperature water bath and stirred for an additional 10-15min. The substituted benzosuberone (1.0g, 6.2mmol) was added and stirred for 15min. The reaction mixture was heated to 80C and stirred for an additional 3h. The orange solution was diluted with ice water and neutralised with 20% sodium acetate solution and with diethyl ether (3×10-20mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (50mL), brine 50mL, and water (3×50mL). The organic layer was dried with sodium sulphate, and concentrated in vacuum to yield a red liquid. The product was purified by column chromatography using 60-120 mesh silica gel (hexane/EtOAc). |
84% | Phosphorus oxychloride (9.6 mmol) was added to a round bottom ask containing N,N-dimethylformamide (11.7 mmol) in an ice bath at 0 oC and stirred for 10 min.The ice bath was replaced with an ambient temperature water bath and stirred for an additional 8 min.The mixture was cooled to 0 oC and benzosuberone (5.34 mmol) was added and stirred for 15 min. The ice bath was replaced with an ambient temerature water bath and stirred for an additional 15 min. The reaction mixture was poured on crushed ice and stirred for 10 min and neutralized with 20 % sodium bicarbonate solution. After extraction with diethyl ether (3×100 mL), the combined organic extracts were washed with brine solution (2 x 50 mL) and water (3×100 mL). The organic layer was dried over Na2SO4 and concentrated on reduced pressure to yield a red liquid. The product was purified by flash chromatography (hexane/EtOAc).9-chloro-6,7-dihydro-5H-benzo[7]annulene-8-carbaldehyde (2a): Brown liquid in a yield of 84%, IR(NEAT, v cm-1): 2936, 2860, 1671, 1580,1448, 1262, 919, 750, 1H NMR (300 MHz, CDCl3): d 2.03-2.09 (m, 4H, 2CH2), 2.61-2.65 (t, J= 6.5 Hz, 2H, CH2), 7.29-7.32 (m, 1H, Ar-H), 7.33-7.40 (m, 2H, Ar-H), 7.43-7.46 ( m, 1H, Ar-H), 10.32 (s, 1H, CHO); 13CNMR (75 MHz, CDCl3): d 22.4, 31.8, 33.7, 126.5, 128.2, 128.9, 129.0,130.4,136.1,137.6140.7,190.3, ESI-MS: m/z = 207 [M+H] +, 229 [M +Na] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With triphenylmethyl perchlorate In acetic acid for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 32% 2: 30% | With aluminium trichloride; bromine at 80℃; for 5h; | |
With aluminum (III) chloride; bromine at 75℃; | 28.1 PREPARATIVE EXAMPLE 28; Step i; 28A 28B; A 3-neck round bottom flask fitted with a condenser was charged with AICb (41.6 g, 0.31 mol) and then heated to 75 0C. 1-Benzosuberone (20 g, 0.13 mol) was added dropwise to the hot AICI3. To the resulting brown slurry was added Br2 (24 g, 0.15 mol) dropwise. The reaction mixture was stirred for 5 min before it was cooled to 0 0C. The reaction mixture was quenched with ice chips. Concentrated HCI was added slowing with stirring to get the mixture into solution. The mixture was diluted with H2O and extracted the organic layer with Et20 (2X). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give a mixture of 6- bromocyclohepta-1-one 28A and 8- bromocyclohepta-1-one 28B (in a 1:2 ratio) | |
Stage #1: 1-Benzosuberone With aluminum (III) chloride at 20℃; for 0.5h; Inert atmosphere; Stage #2: With bromine at 80℃; for 0.0833333h; | 12.1 Step 1: 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (8 g, 50 mmol) was added to a flask containing A1C13 (16.6 g, 125 mmol) dropwise under N2 and the mixture was stirred at r.t. for 30 minutes, and then Br2 (3 mL, 60 mmol) was added dropwise and the mixture was heated to 80 °C for another 5 minutes. Then the mixture was poured into a mixture of cone. HCl (20 mL) and ice (200 g) and stirred for 10 minutes. Then the mixture was extracted with MTBE and the organic layer was washed with aq. NaHC03 and brine, dried, filtered and concentrated. The residue was purified by silica gel chromatography to give l-bromo-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-one (6 g, crude) and 3-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (4 g, crude), which were used for next step directly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium tert-butylate; In tetrahydrofuran; diethyl ether; at 20℃;Inert atmosphere; | General procedure: To a stirred suspension of methyltriphenylphosphonium bromide (1.5 equiv.) in diethylether(25-45 mL) under argon was added dropwise a solution of potassium-tert-butoxide 1M in THF (1.5 equiv.). The reaction mixture was immediately turned to yellow. After refluxing for 1 hour, the corresponding ketone (1.0 equiv.) was added in portions. The mixture was stirred at room temperature overnight. After completion, the reaction mixture was then hydrolyzed by water (5-8mL). The organic phase was separated and aqueous phase was extracted by diethyl ether (2 x 10mL). The combined organic phases were washed with water (20mLx2), brine (20mLx1), dried over anhydrous MgSO4 and concentrated under reduced pressure to yield crude product. Purification of this crude product by a suitable method afforded the corresponding alkene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sulfuric acid; Selectfluor; at 50℃; for 16h;Inert atmosphere; | General procedure: To 1-tetralone (1.33 mL, 10.0 mmol) and Selectfluor (4.25 g, 12.0 mmol) in MeOH (5.0 mL), was treated concd H2SO4 (53 muL, 1.00 mmol). The mixture was stirred under N2 at 50 C overnight, filtered and the solvent was removed in vacuo. Ether was added and washed with water and brine and dried over MgSO4. The crude product was purified by flash chromatography (10% of EtOAc in hexane) to afford fluorotetralone 3a (1.44 g, 93%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at 0 - 40℃; for 24h;Sealed tube; Inert atmosphere; | General procedure: To an oven dried 25 mL round-bottomed flask was added 1-tetralone (600 mg, 4.1 mmol, 1equiv). The flask was sealed and purged with N2 before addition of CH2Cl2 (16.5 mL, 0.25M) and Et3N (0.86 mL, 6.2 mmol, 1.5 equiv). The reaction mixture was cooled to 0 C andtrifluoromethanesulfonic anhydride (1 mL, 6.2 mmol, 1.5 equiv) was added dropwise undernitrogen before it was heated to 40 C and maintained at this temperature with stirring for 24h. Upon completion of the reaction, the solution was washed with water (2 x 20 mL) and theorganics passed through a hydrophobic frit and concentrated under reduced pressure to give abrown oil, which was purified by flash chromatography (silica gel, 0-5% Et2O in petroleumether) to afford the title compound as a yellow oil (1.15 g, quant.). |
With 2,6-di-tert-butyl-4-methylpyridine; In 1,2-dichloro-ethane; at 20℃;Inert atmosphere; | To a round-bottom flask containing 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- one (3 g) in DCE (70 mL) under N2 atmosphere, Tf20 (4.1 mL) and 2,6-di-tert-butyl-4- methylpyridine (6.3 g) was added. The mixture was stirred at rt overnight. Then hexane (200 mL) was added. The mixture was filtered and the filtrate was concentrated on a rotary evaporator to give ZBC90. To a round-bottom flask containing Pd(dppf)Cl2 (1.7 g), dppf (1.2 g), KOAc (3.1 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (5.4 g) in dioxane (100 mL) under N2 atmosphere, ZBC90 in dioxane (50 mL) was added. The reaction mixture was heated at 100 C overnight. The mixture was filtered and the filtrate was concentrated on a rotary evaporator. The residues were purified by flash column chromatography on silica gel to afford ZBC92 in 1.3g. ESI- MS calculated for Ci7H24B02 [M+H]+ = 271.18; Observed: 271.32. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With trifluoromethylsulfonic anhydride In 1,2-dichloro-benzene at 20 - 120℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 3,3-dimethyl-butan-2-one; carbonyl bis(hydrido)tris(triphenylphosphine)ruthenium(II) for 1h; Heating; | |
92% | With carbonyl bis(hydrido)tris(triphenylphosphine)ruthenium(II) In 3,3-dimethyl-butan-2-one for 1h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With nitric acid; at -17 - -10℃; for 1h; | Fuming nitric acid (29.5 mL, 703 mmol) was poured into a three necked flask. 1-Benzo-suberone (8) (9.3 mL, 62.42 mmol) was added dropwise under vigorous stirring and cooling to -10 to -17 C by acetone and dry ice. After complete addition of 2 the mixture was stirred for 1 h at < -10 C. The mixture was poured on ice and stirred till the ice was molten. The solid residue was filtered off in vacuo and washed several times with ice cold water. The crude product was purified by recrystallization from EtOH 96% to form a light yellow solid, mp 92-93 C, yield 11.2 g (87%). C11H11NO3 (205.2). TLC (petroleum ether: ethyl acetate = 8:2): Rf = 0.29. 1H NMR (CDCl3): delta [ppm] = 1.82-1.90 (m, 2H, 7-H), 1.91-1.99 (m, 2H, 8-H), 2.83-2.87 (m, 2H, 6-H), 3.02-3.07 (m, 2H, 9-H), 7.40 (d, 3J = 8.4Hz, 1H, 1-H), 8.26 (dd, 3J = 8.3 Hz, 4J = 2.5 Hz, 1H, 2-H), 8.56 (d, 4J = 2.5 Hz, 1H, 4-H). 13C NMR (CDCl3): delta [ppm] = 20.8 (1C, C-7), 25.0 (1C, C-8), 32.7 (1C, C-9), 40.7 (1C, C-6), 124.1 (1C, C-4), 126.4 (1C, C-2), 131.2 (1C, C-1), 140.0 (1C, C-4a), 148.2 (1C, C-3), 152.9 (1C, C-9a), 203.6 (1C, C-5). Exact mass (APCI): m/z = 206.0829 (calcd. 206.0812 for C11H12NO3 [MH]+). IR (neat): ? [cm-1] = 2951 (w, nuC-H), 1670 (s, nuC = O aryl), 1604 (m, nuC=C arom.), 1519 (s, nuN=O), 1342 (s, nuN=O konj.). Purity (HPLC): tR = 17.43 min, purity 97.4%. |
78% | With sulfuric acid; potassium nitrate; at 15℃; for 1h; | Concentrated sulfuric acid (55 ml) was cooled to 0C in an ice bath. 1-BENZOSUBERONE (8 g, 49.9 mmol) was added with stirring, then potassium nitrate (5.55g, 54.9 mmol) dissolved in concentrated sulfuric acid (15 ml) was added dropwise via a dropping funnel, making sure that the temperature of the solution did not rise above 15C. 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 ethanol/water 1: 1 yielded nitro derivative 12 as a pale yellow solid (7.98 g, 78%), m. p. 91-93C (lit. m. p. 92-93C) ; 13C NMR (100.61 MHz, CDC13) 25.1 (t), 31.5 (t), 32.1 (t), 38.9 (t), 123.6 (d), 127.9 (d), 129.1 (d), 138.2 (s), 145.6 (s), 146.1 (s), 197.6 (s). |
72% | With sulfuric acid; potassium nitrate; at 0℃; for 1.5h;Cooling with ice; | A solution ofKN03 (2.8 g, 27.7 mmol) in concentrated H2S04 (7.5 mL) wasadded dropwise to a mixture ofbenzosuberone ( 4.0 g, 25 mmol) in concentrated H2S04 (28mL) at 0 oc in 30 min. The mixture was stirred for 1 hat 0 C, and then the poured intocrushed ice. The precipitate was filtered, rinsed with water and dried. The crude product waspurified by column chromatography on silica gel (EtOAc/hexane, 1 :4) to afford the pure nitroproduct 4 (3.69 g, 72%). CuHuN03; white needles, mp 90-92 oc (lit.s1 mp 89-90 C)(Murineddu, G., et al. J Med. Chem. 2005, 48, 7351.); TLC (EtOAc/hexane, 1 :4) R1= 0.31;1H NMR (600 MHz, CDCb) 8 8.53 (1 H, d, J = 2.5 Hz), 8.22 (1 H, dd, J = 8.3, 2.5 Hz), 7.37(1 H, d, J= 8.3 Hz), 3.01 (2 H, t, J= 6.4 Hz), 2.77 (2 H, t, J= 6.1 Hz), 1.94-1.90 (2 H, m),1.85-1.81 (2 H, m); 13C NMR (150 MHz, CDCb) 8 203.4, 148.0, 147.0, 139.8, 131.0, 126.2,123.9, 40.4, 32.4, 24.7, 20.5. |
72% | With sulfuric acid; potassium nitrate; at 0℃; for 1.5h; | 3-Nitro-6, 7,8,9-tetrahvdrobenzocyclohepten-5-one (A). [00198] A solution of <strong>[826-73-3]1-benzosuberone</strong> (4.0 g, 25 mmol) in concentrated H2S04 (28 mL) was cooled at 0 C, and a solution of KappaNu03 (2.8 g, 27.7 mmol) in concentrated H2S04 (7.5 mL) was added dropwise over a period of 30 min. The mixture was stirred for additional 1 h at 0 C, and then poured into crushed ice. The precipitate was filtered, washed with water and air-dried to yield a yellow solid. The crude product was purified by column chromatography on silica gel (EtOAc/hexane, 1 :4) to afford the pure nitro product A (3.69 g, 72%). CnHiiN03, white needles, mp 90-92 C (lit.S2 mp 89-90 C); TLC (EtOAc/hexane, 1:4) Rf= 0.31 ; NMR (600 MHz, CDCI3) delta 8.53 (1 H, d, J= 2.5 Hz), 8.22 (1 H, dd, J= 8.3, 2.5 Hz), 7.37 (1 H, d, J= 8.3 Hz), 3.01 (2 H, t, J= 6.4 Hz), 2.77 (2 H, t, J= 6.1 Hz), 1.94-1.90 (2 H, m), 1.85-1.81 (2 H, m); 13C NMR (150 MHz, CDC13) delta 203.4, 148.0, 147.0, 139.8, 131.0, 126.2, 123.9, 40.4, 32.4, 24.7, 20.5; HRMS calcd for CnHi2N03: 206.0812, found: m/z 206.0814 [M + H]+. |
70% | With sulfuric acid; potassium nitrate; at -5 - 0℃; for 1h; | Prepared according to a literature procedure.2 Benzosuberone (1.0 g, 6.24 mmol, 1.0 equiv.) was dissolved in cold concentrated 98 % H2SO4 (5 mL). The solution was cooled to -5 C and the temperature was monitored by an internal thermometer. KNO3 (700 mg, 6.87 mmol, 1.1 equiv) was dissolved in concentrated 95 % H2SO4 (2 mL) and cooled to 0 C. The KNO3 solution obtained above was added dropwise over 30 min to the reaction mixture while stirring vigorously. After additional 30 min, ice-water mixture was added and the mixture extracted with Et2O (3 × 40 mL). The organic layer was washed with NaHCO3 solution (20 mL), dried over Na2SO4 and concentrated. Purification of the residue by flash chromatography (EtOAc/Hexane 10:90) furnished the desired 8-NO2 product 10 as a white solid (900 mg, 70 %). mp: 88.2-91.2 C; Rf (EtOAc/Hexane 20:80) = 0.3; IR (film, cm-1): 2946, 1686, 1608, 1524 1342, 1093; 1H NMR (300 MHz, CDCl3) delta: 8.4 (d, 1H, J = 2.5 Hz), 8.24 (dd, 1H, J = 8.3, 2.5 Hz), 7.39 (app. d, 1H, J = 8.3 Hz), 3.04 (t, 2H, J = 6.2 Hz), 2.80 (app. t., 2H, J = 6.1 Hz), 1.95 (pent., 2H, J = 2.0 Hz), 1.86 (distorted pent., 2H, J = 6.1 Hz); 13C NMR (125 MHz, CDCl3) delta: 203.6, 148.2, 147.2, 140.6, 131.2, 126.4, 124.1, 40.7, 32.7, 25.0, 20.8; HRMS (ESI+): m/z [M+Na] calcd for C11H11NO3Na]+ 228.0631, found 228.0602, Delta = 2.9 mDa. |
58% | With sulfuric acid; nitric acid; at 0℃; for 0.5h; | Example 135 T^^IO-Tetrahydro-betaW-cycloheptatgHi^^benzotriazin-S-amine 1-0xide (186). 3-Nitro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-amine (185). A solution of fHNO3 (7.5 mL) in CH2SO4 (50 ml.) was added dropwise to a stirred suspension of 1- benzosuberone (181) (20 g, 124.8 mmol) in CH2SO4 (400 mL) at 0 0C. The mixture was stirred a further 30 min and poured into ice/water. The slurry was extracted with ether (2 x 200 mL), the combined organic fraction dried, and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-30%) of EtOAc/pet. ether, to give 3-nitro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (14.75 g, 58%) as a tan powder: mp (EtOAc/pet. ether) 81-82 0C; 1H NMR delta 8.56 (d, J = 2.5 Hz, 1 H, H-4), 8.26 (dd, J = 8.3, 2.5 Hz, 1 H, H-2), 7.40 (d, J = 8.3 Hz, 1 H, H-1), 3.02-3.08 (m, 2 H, H-9), 2.78-2.82 (m, 2 H, H-6), 1.92-1.99 (m, 2 H, H-8), 1.83-1.90 (m, 2 H, H-7). A solution of ketone (14.7 g, 71.6 mmol) in EtOAc/EtOH (1:1 , 100 mL) and 20% HCI (50 mL) was stirred vigorously under H2 (60 psi) for 5 days. The suspension was filtered through Celite, washed with EtOH (4 x 20 mL) and the solvent evaporated. The residue was dissolved in DCM, washed with dilute NH3, dried, and the solvent evaporated. The residue was dissolved in dioxane (300 mL), cooled to 0 0C, and Ac2O (13.5 mL, 143.2 mmol) added dropwise. The solution was stirred at 20 0C for 16 h, diluted with water (500 mL) and the suspension filtered. The filtrate was extracted with EtOAc (2 x 100 mL); the combined organic fraction washed with water (50 mL) and dilute aqueous NH3 solution (2 x 50 mL), dried, and the solvent evaporated. The combined solids were purified by chromatography, eluting with 50% EtOAc/pet. ether, to give Lambda/-(6,7,8,9-tetrahydro-5AV-benzo[a]cyclohepten- 2-yl)acetamide (10.89 g, 75%) as a tan powder: mp 112-114 0C; 1H NMR delta 7.20 (d, J = 2.2 Hz, 1 H, H-1), 7.15-7.21 (m, 2 H, H-3, NH), 7.02 (d, J = 8.0 Hz, 1 H, H-4), 2.71-2.77 (m, 4 H, H-5, H-9), 2.15 (s, 3 H, CH3), 1.78-1.86 (m, 2 H, H-7), 1.56-1.66 (m, 4 H, H-6, H- 8). A solution of KNO3 (5.96 g, 58.9 mmol) in CH2SO4 (25 mL) was added dropwise to a stirred suspension of amide (10.89 g, 53.6 mmol) in CH2SO4 (160 mL) at 0 0C and the mixture stirred at 0-5 0C for 2 h. The mixture was poured into ice/water, stirred 30 min, EPO <DP n="134"/>filtered, washed with water (3 x 30 mL) and dried. The solid was purified by chromatography, eluting with a gradient (20-50%) of EtOAc/pet. ether, to give (i) /V-(3- nitro-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl)acetamide (182) (2.62 g, 20%) as a white solid: 1H NMR delta 10.32 (br s, 1 H, NH), 8.52 (s, 1 H, H-4), 7.94 (s, 1 H, H-1), 2.84- 2.88 (m, 2 H, H-5), 2.78-2.82 (m, 2 H, H-9), 2.27 (s, 3 H, CH3), 1.80-1.87 (m, 2 H, H-7), 1.61-1.69 (m, 4 H, H-6, H-8); (ii) /V-(1-nitro-6,7,8,9-tetrahydro-5H-ben?o[a]cyclohepten-2- yl)acetamide (183) (0.85 g, 6%) as a white solid: 1H NMR delta 7.81 (br d, J = 8.4 Hz, 1 H, H- 4), 7.77 (br s, 1 H, NH), 7.23 (d, J = 8.4 Hz, 1 H, H-3), 2.82-2.86 (m, 2 H, H-5), 2.65-2.69 (m, 2 H, H-9), 2.27 (s, 3 H, CH3), 1.80-1.88 (m, 2 H, H-7), 1.61-1.73 (m, 4 H, H-6, H-8); and (iii) Lambda/-(4-nitro-6,7,8,9-tetrahydro-5/-/-benzo[a]cyclohepten-2-yl)acetamide (184) (6.91 g, 52%) as a white solid: 1H NMR delta 7.69 (br d, J = 1.9 Hz, 1 H, H-3), 7.45 (d, J = 1.9 Hz, 1 H, H-1), 7.24 (br s, 1 H, NH), 2.84-2.88 (m, 2 H, H-5), 2.78-2.81 (m, 2 H, H-9), 2.19 (s, 3 H, CH3), 1.81-1.87 (m, 2 H, H-7), 1.61-1.72 (m, 4 H, H-6, H-8). A suspension of 3-nitroacetamide 182 (2.62 g, 10.6 mmol) in 5 M HCI (100 mL) was stirred at reflux temperature for 16 h. The suspension was cooled, diluted with water (100 mL), filtered, washed with water (3 x 10 mL) and dried to give nitroaniline 185 (1.96 g, 90%) as a yellow powder, mp 137-139 0C; 1H NMR delta 7.83 (s, 1 H, H-4), 6.55 (s, 1 H, H- 1), 5.96 (br s, 2 H, NH2), 2.67-2.73 (m, 4 H, H-5, H-9), 1.76-1.81 (m, 2 H, H-7), 1.59-1.67 (m, 4 H, H-6, H-8); 13C NMR delta 153.1 , 143.2, 133.0, 129.8, 125.1 , 118.5, 36.6, 35.4, 32.1 , 28.8, 28.2. Anal, calcd for C11H14N2O2: C, 64.1 ; H, 6.8; N, 13.6. Found: C, 64.0; H, 6.5; N, 13.5%. |
55.8% | With sulfuric acid; nitric acid; at 0℃; for 0.5h; | 1-BENZOSUBERONE (175.0 g, 1.09 mol) was dissolved in concentrated sulfuric acid (3.5 L) and cooled to 0 C. To this mixture was added drop wise, a solution of fuming nitric acid (65.03 ml, 1.13 mol) in sulfuric acid (425 ml) and after the addition was complete, the reaction mixture was stirred at 0 C for 30 min. The reaction mixture was poured into ice water and extracted with diethyl ether (3 X 2.0 L). The organic extracts are pooled, washed with brine, dried over anhydrous NA2S04, filtered and evaporated under vacuum. The residue obtained was triturated with hexane (3 X 1.0 L), filtered and dried to give the title compound. Yield: 125. 0g (55.8%), mp. 88-89 C |
55.8% | With sulfuric acid; nitric acid; at 0℃; for 0.5h; | <strong>[826-73-3]1-Benzosuberone</strong> (175.0 g, 1.09 mol) was dissolved in concentrated sulfuric acid (3.5 L) and cooled to 0 C. To this mixture was added drop wise, a solution of fuming nitric acid (65.03 mL, 1.13 mol) in sulfuric acid (425 mL) and after the addition was complete, the reaction mixture was stirred at 0 C for 30 minutes. The reaction mixture was poured into ice water and extracted with diethyl ether (3 X 2.0 L). The organic extracts were pooled, washed with brine, dried over anhydrous NA2S04, filtered and evaporated under vacuum. The residue obtained was triturated with hexane (3 X 1. 0 L), filtered and dried to give the title compound. Yield: 125.0 g (55.8%), mp. 88-89 C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: KNO3; H2SO4 2: H2 / Pd/C | ||
Multi-step reaction with 3 steps 1: nitric acid / 1 h / -17 - -10 °C 2: sodium tetrahydroborate / methanol / 0.5 h / 20 °C / Inert atmosphere 3: hydrogen; palladium 10% on activated carbon / methanol / 20 °C / 3000.3 Torr | ||
Multi-step reaction with 2 steps 1: potassium nitrate; sulfuric acid / 2 h / 0 °C 2: sodium tetrahydroborate; copper diacetate / ethanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With ammonium acetate; sodium cyanoborohydride In ethanol at 130℃; for 0.0333333h; | 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine (54) To a solution of 1-benzosuberone (0.62 mmol, 1.0 eq.) in ethanol (1.3 mL) were successively added ammonium acetate (721 mg, 0.93 mmol, 15.0 eq.) and sodium cyanoborohydride (47 mg, 0.75 mmol, 1.2 eq.). The mixture was brought to 130° C. under microwave radiation for 2 minutes, then concentrated in vacuo. a 2 N sodium hydroxide solution was added until pH >10 was obtained, after which the product was extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo to give the title product 54 (119 mg, quantitative) in the form of a yellow oil. |
88% | With ammonium acetate; sodium cyanoborohydride In ethanol at 130℃; for 0.0333333h; Microwave irradiation; | |
Multi-step reaction with 2 steps 1: formic acid / 1 h / Heating 2: aq. HCl / 1 h / Heating |
Multi-step reaction with 2 steps 1: amberlyst A-21; NH2OH*HCl / ethanol / 24 h / 20 °C 2: H2 / Pd/C / ethanol / 72 h | ||
With ammonium acetate; sodium cyanoborohydride; isopropyl alcohol at 20℃; Reflux; | H.265.1 Step 1: 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine A round bottomed flask was charged with 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1 ml, 6.68 mmol), isopropanol (70 mL), sodium cyanoborohydride (2.94 g, 46.8 mmol), and ammonium acetate (15.46 g, 201 mmol). The mixture was stirred at room temperature for 4 h and then heated to reflux overnight. After cooling, the reaction was quenched with 1 N sodium hydroxide (100 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with water, dried with sodium sulfate, and concentrated under reduced pressure to give a crude residue that contained 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine. This material was used directly in the following amide bond formation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 68 percent / KNO3; H2SO4 / 3 h / -5 °C 2: 84 percent / Sn; aq. HCl / ethanol / 0.5 h / Heating | ||
Multi-step reaction with 2 steps 1: potassium nitrate; sulfuric acid / 1.5 h / 0 °C / Cooling with ice 2: hydrogenchloride; tin / ethanol / 0.83 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid; potassium nitrate / 1.5 h / 0 °C 2: tin; hydrogenchloride / ethanol / 0.83 h / Reflux |
Multi-step reaction with 2 steps 1: nitric acid / 1 h / -17 - -10 °C 2: hydrogen; palladium 10% on activated carbon / methanol / 44 h / 20 °C / 2250.23 Torr | ||
Multi-step reaction with 2 steps 1: sulfuric acid; potassium nitrate / 0 °C 2: tin; hydrogenchloride / ethanol / 0.83 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 80 percent / NaOH / ethanol 2: 84 percent / KOH / ethanol / 8 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Stage #1: 1-Benzosuberone With aluminum (III) chloride at 75℃; for 0.333333h; Inert atmosphere; Stage #2: With bromine at 75℃; for 0.333333h; Stage #3: With hydrogenchloride In water for 0.5h; Cooling with ice; | A1 Step Al . 3-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-oneA 3 -neck 250mL flask fitted with a condenser was charged with aluminum trichloride (45.0 g, 337 mmol) which was then heated to 75 °C under nitrogen. 6,7,8,9-Tetrahydro- 5H-benzo[7]annulen-5-one (20.0 g, 125 mmol) was added slowly dropwise via additional funnel. After complete addition, a dark brown slurry was formed. After stirring for 20 min, bromine (8.36 ml, 162 mmol) was added dropwise very slowly at 75 °C, and the reaction mixture was stirred at 75 °C for an additional 20 min. The hot mixture was slowly poured into 400 g of ice and 30 mL of concentrated HC1. The resulting mixture was stirred for 30 min, then extracted with diethyl ether (3x400 mL). The ethereal extract was concentrated and the residue was purified using silica gel column chromatography (hexanes-10% EtOAc) to afford 3-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (8.3 g, 28%). XH NMR (500 MHz, chloroform-if) δ 7.86 (d, J=2.1 Hz, IH), 7.54 (dd, J=8.2, 2.1 Hz, IH), 7.10 (d, J=8.2 Hz, IH), 2.94 - 2.88 (m, 2H), 2.80 - 2.72 (m, 2H), 1.94 - 1.80 (m, 4H). |
21% | With aluminum (III) chloride; bromine at 20 - 80℃; for 0.333333h; | 2.A.A To the vigorously stirred aluminum chloride was added 1-benzosuberone. After 10 minutes, bromine was added slowly and the reaction mixture was stirred at room temperature for 5 minutes and then heated to 80 C for 5 minutes. The reaction was then quenched by slowly adding a mixture of crushed ice and 1N hydrochloric acid. After the addition, the reaction mixture was slowly cooled to room temperature and ether was added. The resulting mixture was stirred until the residue had dissolved. The layers were then separated and the aqueous layer extracted once with diethyl ether. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to a residue, which was purified by column chromatography. (21% yield). H1 NMR (400 MHz, CDC13) : 6 1.83 (m, 4H), 2.71 (apparent triplet, 2H), 2. 87 (apparent triplet, 1H), 7.07 (d, J = 7. 9 HZ, 1H), 7.51 (d, d, J = 8. 3,2. 5 HZ, 1H), 7.82, (d, J = 2. 8 HZ, 1H). |
Multi-step reaction with 2 steps 1: Br2 2: H2, NaOAc / Pd-C / acetic acid |
Multi-step reaction with 3 steps 1: (i) Br2, AcOH, (ii) Py 2: Br2 3: H2, NaOAc / Pd-C / acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.0% | With sodium acetate; potassium carbonate; In ethanol; at 80℃; for 1.5h; | In a 3 liter-three-necked flask, 166.0 g (1036 mM) of 1-benzosuberone, 125.0 g (1141 mM) of <strong>[38945-21-0]O-allylhydroxylamine hydrochloride</strong>, 93.5 g (1140 mM) of sodium acetate, 158.0 g (1143 mM) of potassium carbonate and 1500 ml of ethanol were placed and heat-stirred for 1.5 hour at 80 C. The reaction product was cooled to room temperature and the solvent was removed under reduced pressure to obtain a residue. To the residue, 1500 ml of water was added, followed by extraction three times each with 500 ml of ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, followed by removal of the solvent under reduced pressure to obtain a pale brown liquid. The liquid was subjected to distillation under reduced pressure to obtain 221.8 g (Yield: 99.0 %) of 1-benzosuberone=oxime=O-allyl=ether (boiling point = 75 = 83 C (4.0 Pa)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | SYNTHETIC PREPARATION 4; Synthesis of ethyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetateCompound of formula (Db)To a mixture of <strong>[826-73-3]1-benzosuberone</strong> (5.0 g, 31.2 mmol, Aldrich) in dry tetrahydrofuran (THF) (20 mL) was added hexamethylphosphoramide (6.5 ml_, 37.5 mmol) (99%, Aldrich). The resulting mixture was stirred at ambient temperature for 10 min and then cooled to 0 0C with a ice-water bath, 1.0 M solution of lithium bis(trimethylsilyl)-amide in THF (32.7 mL, 32.7 mmol) was added dropwise in 30 min. After the addition, the reaction mixture was stirred at 0 0C for 30 min. Ethyl bromoacetate (8.7 mL, 78.1 mmol) was then added. After stirring for a further 10 min, the reaction mixture was warmed to ambient temperature and stirred for 2 h. Solvent was evaporated, the residue was diluted with ethyl acetate (EtOAc) (300 mL), and washed with water and brine. After being dried (MgSO4), filtered, and concentrated, the residue was purified by flash column chromatography eluting with hexanes-ethyl acetate 6:1 ? 4:1 ) to afford 6.6 g of the compound of formula (Db), ethyl 2-(5-oxo- 6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetate, as an orange oil (84%), 1H NMR (300 MHz, CDCI3) delta: 7.69-7.21 (m, 4H), 4.22-4.05 (m, 2H), 3.40-3.30 (m, 1 H), 3.12- 2.92 (m, 3H), 2.52-2.43 (m, 1 H), 2.20-1.58 (m, 4H), 1.28-1.21 (m, 3H); LC-MS: purity: 91.8%; MS (m/e): 247 (MH+). | |
84% | SYNTHETIC PREPARATION 7 Synthesis of ethyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetate Compound of formula (Db). To a mixture of <strong>[826-73-3]1-benzosuberone</strong> (5.0 g, 31.2 mmol, Aldrich) in dry tetrahydrofuran (THF) (20 ml.) was added hexamethylphosphoramide (6.5 ml_, 37.5 mmol) (99%, Aldrich). The resulting mixture was stirred at ambient temperature for 10 min and then cooled to 0 0C with a ice-water bath, 1.0 M solution of lithium bis(trimethylsilyl)-amide in THF (32.7 ml_, 32.7 mmol) was added dropwise in 30 min. After the addition, the reaction mixture was stirred at 0 0C for 30 min. Ethyl bromoacetate (8.7 ml_, 78.1 mmol) was then added. After stirring for a further 10 min, the reaction mixture was warmed to ambient temperature and stirred for 2 h. Solvent was evaporated, the residue was diluted with ethyl acetate (EtOAc) (300 ml_), and washed with water and brine. After being dried (MgSO4), filtered, and concentrated, the residue was purified by flash column chromatography eluting with hexanes-ethyl acetate 6:1 -? 4:1 ) to afford 6.6 g of the compound of formula (Db), ethyl 2-(5-oxo-6,7,8,9- tetrahydro-5H-benzo[7]annulen-6-yl)acetate, as an orange oil (84%), 1H NMR (300 MHz, CDCI3) delta: 7.69-7.21 (m, 4H), 4.22-4.05 (m, 2H), 3.40-3.30 (m, 1 H), 3.12-2.92 (m, 3H), 2.52-2.43 (m, 1 H), 2.20-1.58 (m, 4H), 1.28-1.21 (m, 3H); LC-MS: purity: 91.8%; MS (m/e): 247 (MH+). | |
84% | Synthetic Preparation 4; Compound of Formula (Db); To a mixture of <strong>[826-73-3]1-benzosuberone</strong> (5.0 g, 31.2 mmol, Aldrich) in dry tetrahydrofuran (?THF?) (20 mL) was added hexamethylphosphoramide (6.5 mL, 37.5 mmol) (99%, Aldrich). The resulting mixture was stirred at ambient temperature for 10 min and then cooled to 0 C. with a ice-water bath, 1.0 M solution of lithium bis(trimethylsilyl)-amide in THF (32.7 mL, 32.7 mmol) was added dropwise in 30 min. After the addition, the reaction mixture was stirred at 0 C. for 30 min. Ethyl bromoacetate (8.7 mL, 78.1 mmol) was then added. After stirring for a further 10 min, the reaction mixture was warmed to ambient temperature and stirred for 2 h. Solvent was evaporated, the residue was diluted with ethyl acetate (EtOAc) (300 mL), and washed with water and brine. After being dried (MgSO4), filtered, and concentrated, the residue was purified by flash column chromatography eluting with hexanes-ethyl acetate 6:1?4:1) to afford 6.6 g of the compound of formula (Db), ethyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetate, as an orange oil (84%), 1H NMR (300 MHz, CDCl3) delta: 7.69-7.21 (m, 4H), 4.22-4.05 (m, 2H), 3.40-3.30 (m, 1H), 3.12-2.92 (m, 3H), 2.52-2.43 (m, 1H), 2.20-1.58 (m, 4H), 1.28-1.21 (m, 3H); LC-MS: purity: 91.8%; MS (m/e): 247 (MH+). |
84% | To a mixture of <strong>[826-73-3]1-benzosuberone</strong> (5.0 g, 31.2 mmol, Aldrich) in dry tetrahydrofuran (THF) (20 ml_) was added hexamethylphosphoramide (6.5 mL, 37.5 mmol) (99%, Aldrich). The resulting mixture was stirred at ambient temperature for 10 min and then cooled to 0 C with a ice-water bath, 1.0 M solution of lithium bis(trimethylsilyl)-amide in THF (32.7 mL, 32.7 mmol) was added dropwise in 30 min. After the addition, the reaction mixture was stirred at 0 0C for 30 min. Ethyl bromoacetate (8.7 mL, 78.1 mmol) was then added. After stirring for a further 10 min, the reaction mixture was warmed to ambient temperature and stirred for 2 h. Solvent was evaporated, the residue was diluted with ethyl acetate (EtOAc) (300 mL), and washed with water and brine. After being dried (MgSO4), filtered, and concentrated, the residue was purified by flash column chromatography eluting with hexanes-ethyl acetate 6:1 ? 4:1 ) to afford 6.6 g of the compound of formula (Db), ethyl 2-(5-oxo-6, 7,8,9- tetrahydro-5H-benzo[7]annulene-6-yl)acetate, as an orange oil (84%), 1H NMR (300 MHz, CDCI3) delta: 7.69-7.21 (m, 4H), 4.22-4.05 (m, 2H), 3.40-3.30 (m, 1 H), 3.12-2.92 (m, 3H), 2.52-2.43 (m, 1 H), 2.20-1.58 (m, 4H)1 1.28-1.21 (m, 3H); LC-MS: purity: 91.8%; MS (m/e): 247 (MH+). | |
84% | Synthetic Preparation 7 Synthesis of ethyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetate Compound of Formula (Db) To a mixture of <strong>[826-73-3]1-benzosuberone</strong> (5.0 g, 31.2 mmol, Aldrich) in dry tetrahydrofuran (THF) (20 mL) was added hexamethylphosphoramide (6.5 mL, 37.5 mmol) (99%, Aldrich). The resulting mixture was stirred at ambient temperature for 10 min and then cooled to 0 C. with a ice-water bath, 1.0 M solution of lithium bis(trimethylsilyl)-amide in THF (32.7 mL, 32.7 mmol) was added dropwise in 30 min. After the addition, the reaction mixture was stirred at 0 C. for 30 min. Ethyl bromoacetate (8.7 mL, 78.1 mmol) was then added. After stirring for a further 10 min, the reaction mixture was warmed to ambient temperature and stirred for 2 h. Solvent was evaporated, the residue was diluted with ethyl acetate (EtOAc) (300 mL), and washed with water and brine. After being dried (MgSO4), filtered, and concentrated, the residue was purified by flash column chromatography eluting with hexanes-ethyl acetate 6:1-4:1) to afford 6.6 g of the compound of formula (Db), ethyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetate, as an orange oil (84%), 1H NMR (300 MHz, CDCl3) delta: 7.69-7.21 (m, 4H), 4.22-4.05 (m, 2H), 3.40-3.30 (m, 1H), 3.12-2.92 (m, 3H), 2.52-2.43 (m, 1H), 2.20-1.58 (m, 4H), 1.28-1.21 (m, 3H); LC-MS: purity: 91.8%; MS (m/e): 247 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Example 1; Synthesis of 2-((lambda)-2-methyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)- piperazin-l-yl)acetic acid <n="71"/>Step 1A mixture of 1 -benzosuberone (0.803 ml, 5.01 mmol), (/?)-2-methylpiperazine (1.505 g, 15 mmol) in titanium (4+) isopropoxide (4.399 ml, 15 mmol) was heated at 800C overnight. After cooling to RT, the reaction mixture was diluted with 30 mL of MeOH and sodium borohydride (0.529 ml, 15 mmol) was slowly added. After stirring at rt for 20 min, the solvent was evaporated to dryness. The residue was redissolved in 50 mL of EtOAc and to this solution was added 1O g OfNaHCO3 and 0.5 mL of water to generate a white slurry. After stirring at rt for 2 h, the mixture was filtered with the help of excess EtOAc and the filtrate was evaporated to dryness. Column chromatography (SiO2, DCM/MeOH = 100:5 to 100:10 to 100:15 to 100:20) gave (3lambda)-3-methyl-l-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- yl)piperazine (860 mg, 70percent yield) as an off white gum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | (1) Ethyl (6,7,8,9-tetrahydro-5-benzocycloheptenylidene)acetate [Show Image] A suspension of sodium hydride (60%, 2.25 g) in anhydrous benzene (100 ml) was slowly added with a solution of diethyl phosphonoacetate (14.0 g) in anhydrous benzene (20 ml) at 0C, and the mixture was stirred at 0C for 15 minutes. The mixture was added with a solution of <strong>[826-73-3]1-benzosuberone</strong> (5.00 g) in anhydrous benzene (30 ml), and the mixture was stirred at 0C for 15 minutes, and then refluxed overnight by heating. The reaction mixture was left to cool and then added with saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane = 1:200) to quantitatively obtain the title compound. | |
100% | 1) Ethyl (6,7,8,9-tetrahydro-5-benzocycloheptenylidene)acetate A suspension of sodium hydride (60%, 2.25 g) in anhydrous benzene (100 ml) was slowly added with a solution of diethyl phosphonoacetate (14.0 g) in anhydrous benzene (20 ml) at 0C, and the mixture was stirred at 0C for 15 minutes. The mixture was added with a solution of <strong>[826-73-3]1-benzosuberone</strong> (5.00 g) in anhydrous benzene (30 ml), and the mixture was stirred at 0C for 15 minutes, and then refluxed overnight by heating. The reaction mixture was left to cool and then added with saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane = 1:200) to quantitatively obtain the title compound. | |
100% | To a cooled (0C) suspension of NaH (60% in mineral oil, 2.25g, 56.3 mmol) in benzene (100 ml) was added dropwise a solutionof ethyl diethylphosphonoacetate (14.0 g, 62.4 mmol) in benzene(20 ml) and the mixture was stirred at 0C for 15 min. To this mixture was slowly added dropwise asolution of <strong>[826-73-3]1-benzosuberone</strong> (5.00 g, 31.2 mmol) in benzene (30 ml). The reaction mixture was stirred at ambient temperature for 15 min and then refluxed overnight, cooled, poured into saturated aqueous NH4Cl and extracted with AcOEt. Usual work-up gave a residue, which was purified bysilica gel column chromatography (AcOEt/n-hexane=1:200) to afford ethyl (6,7,8,9-tetrahydro-5-benzocycloheptenylidene)acetate (7.19 g, quant.). To a solution of ethyl (6,7,8,9-tetrahydro-5-benzocycloheptenylidene)acetate (0.550 g, 2.39 mmol) in AcOEt (10 ml) was added 10% Pd/C(0.055 g). The reaction mixture was vigorously stirred under a hydrogen atmosphere for 3 h, thenfiltered through Celite, and the filtrate was evaporated to afford ethyl (6,7,8,9-tetrahydro-5H-5-benzocycloheptenyl)acetate (0.551 g, 99%). This was used for the next reaction without furtherpurification. To a cooled (-78C) solution of ethyl (6,7,8,9-tetrahydro-5H-5-benzocycloheptenyl)acetate (0.550 g, 2.37 mmol) in toluene (10 ml) was added dropwise DIBAL-H (0.93 M solution inn-hexane, 2.8 ml, 2.60 mmol) and the mixture was stirred ambient temperature for 1 h. Then MeOH(3 ml) and 2 M aqueous HCl were added to it and the resultant mixture was extracted with AcOEt.Usual work-up gave a residue, which was purified by silica gel column chromatography(AcOEt/n-hexane=1:300) to afford (6,7,8,9-tetrahydro-5H-5-benzocycloheptenyl)acetaldehyde(0.432 g, 97% from <strong>[826-73-3]1-benzosuberone</strong>). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With boron trifluoride diethyl etherate; lead(IV) tetraacetate In toluene at 20℃; for 22h; | 12.A Step A: (+/-)-Ethyl 1 ,2,3,4-Tetrahydronaphthalene-1-carboxylate; A solution of 1- benzosuberone (3.3 g, 21 mmol) and BF3-Et20 (15 mL, 120 mmol) in EtOH (20 ml, anhydrous) was added to a suspension of Pb(OAc)4 (9.3 g, 20 mmol) in benzene (100. mL). The reaction mixture, which turned yellow, was stirred for 22 hours at room temperature. Subsequently, the reaction was quenched with cold water (250 mL). The aq. layer was isolated and extracted with EtOAc (2x60 mL). The combined organic layers were washed sequentially with sat. aq. NaHC03 and water, dried over MgS04, and concentrated to dryness by rotary evaporation. The residue was purified by repeated MPLC (gradient from pure heptane to ca. 9:1 1 EtOAc/heptane) to afford the title compound (200 mg, 4.9 % yield) as an impure oil, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With aluminum (III) chloride; bromine at 80℃; Inert atmosphere; | The titled compound was prepared using conditions similar to those described in Cornelius, L. A. M. and Combs, D. W. Synth. Commun. 1994, 24, 2777-2788.Aluminum chloride (17.18 g, 0.129 mol) was placed in a 250 mL, three-necked round-bottomed flask under argon. The flask was fitted with a condenser, overhead stirrer, and rubber septum; and 1-benzosuberone (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; approx. 7.6 mL; approx. 0.05 mol) was added slowly over 3 min. The mixture was stirred for 5 min, and then bromine (approx. 3.1 mL, approx. 0.06 mol) was added slowly over 9 min. The reaction vessel was placed in an oil bath at 80° C. and stirred for 5 min. The reaction mixture was then poured over a mixture of ice (100 g) and HCl (20 mL). Vigorous gas evolution occurred. The flask was rinsed with water and the combined rinsings and diluted reaction mixture were stirred for about 7 min. The mixture was extracted twice with ether. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and evaporated to give 12.71 g of crude material. Unsuccessful attempts were made to purify this material by chromatography (using a mixture of THF and hexanes as eluent) and also by distillation. The material was finally purified in two batches (of 6 g and 4.9 g) by supercritical fluid chromatography using a Daicel AD 5×25 cm column, and eluting with 20% MeOH/CO2. The cycle time was 8.2 min, and the material was purified using 500 mg injections. 12 runs were made to purify the 6 g batch, and 10 runs were used to purify the 4.9 g batch.Purification of the 6 g batch gave 2.77 g of 1-bromo-6,7,8,9-tetrahydro-benzocyclohepten-5-one as an orange oil [1H NMR (300 MHz, DMSO-d6) δ: 7.79 (dd, J=8.0, 1.1 Hz, 1H), 7.46 (dd, J=7.5, 0.9 Hz, 1H), 7.17-7.32 (m, 1H), 3.03 (t, J=6.3 Hz, 2H), 2.60-2.72 (m, 2H), 1.54-1.83 (m, 4H)]; 2.17 g of 3-bromo-6,7,8,9-tetrahydro-benzocyclohepten-5-one [1H NMR (300 MHz, DMSO-d6) δ: 7.62-7.69 (m, 2H), 7.27 (d, J=8.2 Hz, 1H), 2.88 (t, J=6.2 Hz, 2 H), 2.64-2.72 (m, 2H), 1.61-1.82 (m, 4H)]; and 0.44 g of 1,3-dibromo-6,7,8,9-tetrahydro-benzocyclohepten-5-one [1H NMR (300 MHz, DMSO-d6) δ: 8.05 (d, J=2.1 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 2.99 (t, J=6.2 Hz, 2H), 2.60-2.72 (m, 2H), 1.57-1.80 (m, 4H)].Purification of the 4.9 g batch gave 1.19 g of 1-bromo-6,7,8,9-tetrahydro-benzocyclohepten-5-one [1H NMR (300 MHz, DMSO-d6) δ: 7.79 (dd, J=7.8, 0.9 Hz, 1H), 7.46 (dd, J=7.7, 1.1 Hz, 1H), 7.20-7.30 (m, 1H), 2.94-3.15 (m, 2H), 2.56-2.79 (m, 2H), 1.50-1.86 (m, 4H)]; 2.10 g of 3-bromo-6,7,8,9-tetrahydro-benzocyclohepten-5-one [1H NMR (300 MHz, DMSO-d6) δ: 7.62-7.68 (m, 2H), 7.27 (d, J=7.8 Hz, 1H), 2.88 (t, J=6.0 Hz, 2H), 2.65-2.71 (m, 2H), 1.62-1.81 (m, 4H)]; and 1.38 g of 1,3-dibromo-6,7,8,9-tetrahydro-benzocyclohepten-5-one [1H NMR (300 MHz, DMSO-d6) δ: 8.05 (d, J=2.1 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 2.99 (t, J=6.2 Hz, 2H), 2.63-2.69 (m, 2H), 1.56-1.80 (m, 4H)].The total yield of 1-bromo-6,7,8,9-tetrahydro-benzocyclohepten-5-one was 3.96 g (approx. 33%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With carbonyl bis(hydrido)tris(triphenylphosphine)ruthenium(II); caesium carbonate In neat (no solvent) at 150℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With manganese(IV) oxide; ammonium hydroxide; oxygen; chlorobenzene; In N,N-dimethyl-formamide; at 100℃; under 15001.5 Torr; for 24h;Autoclave; Green chemistry; | General procedure: 0.01g of MnO2 catalyst, 0.5mmol of 1-indanone, 0.2g of ammonia water (25wt%) and 2g of chlorobenzene were added to a stainless steel autoclave with a polytetrafluoroethylene inner liner.The temperature was raised to 110 by automatic temperature controller, 0.6MPa oxygen was added and the reaction was continued for 4h. The pressure was kept constant during the reaction.The reaction product was analyzed using GC-MS with a phthalamide yield of 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: N-acetyl-3-trifluoromethylbenzenamine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Schlenk technique; Stage #2: 1-Benzosuberone In tetrahydrofuran; hexane at 20℃; for 12h; Inert atmosphere; Schlenk technique; | |
With n-butyllithium In tetrahydrofuran at -78 - 23℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: n-butyllithium / tetrahydrofuran / -78 - 23 °C 2: tetrabutylammonium tetrafluoroborate / acetonitrile; water / 4.5 h / 23 °C / Electrolysis; Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydride In 1-methyl-pyrrolidin-2-one at 120℃; for 24h; | Compounds 8a-8j and 9a-9d; General Procedure General procedure: All reactions were carried out on 0.5-mmol scale. A reaction tube wascharged with NaH (3.0 equiv), carbonyl compound (1.0 equiv) andNMP (3 mL) were added followed by addition of trialkyl phosphate(3.0 equiv). Then, this reaction mixture was heated to 120 °C for 24 h.After that, the reaction mixture was diluted with Et2O, washed withwater and extracted with Et2O. The organic layer was dried overNa2SO4 and concentrated to obtain crude product which was purifiedby column chromatography (EtOAc/hexane) to afford the desiredproduct 8 and 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: hydrogenchloride; sodium azide / water / 24 h / 20 °C 2: lithium diisopropyl amide / tetrahydrofuran / 16 h / 0 - 70 °C |
Tags: 826-73-3 synthesis path| 826-73-3 SDS| 826-73-3 COA| 826-73-3 purity| 826-73-3 application| 826-73-3 NMR| 826-73-3 COA| 826-73-3 structure
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