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CAS No. : | 493-08-3 | MDL No. : | MFCD00138123 |
Formula : | C9H10O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VZWXIQHBIQLMPN-UHFFFAOYSA-N |
M.W : | 134.18 | Pubchem ID : | 136319 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 40.59 |
TPSA : | 9.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.34 cm/s |
Log Po/w (iLOGP) : | 2.07 |
Log Po/w (XLOGP3) : | 2.5 |
Log Po/w (WLOGP) : | 2.01 |
Log Po/w (MLOGP) : | 2.06 |
Log Po/w (SILICOS-IT) : | 2.84 |
Consensus Log Po/w : | 2.3 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.69 |
Solubility : | 0.273 mg/ml ; 0.00204 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.34 |
Solubility : | 0.614 mg/ml ; 0.00458 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.93 |
Solubility : | 0.156 mg/ml ; 0.00116 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.68 |
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 |
---|---|---|
55.1% | With trichlorophosphate In 1,2-dichloro-ethane at 50 - 85℃; for 12.5 h; | To a solution of chromane (LVI) (3 g, 22.4 mmol, 1.0 eq) and DMF (3.3 g, 45.2 mmol, 2 eq) in DCE (20 mL) was added phosphorus oxychloride (3.4 g, 45.2 mmol, 2 eq) dropwise over 30 min below 50° C. The mixture was stirred at 85° C. for 12 h. The reaction was quenched by water and extracted with EtOAc (3×300 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE:EtOAc=8:1) to give chromane-6-carbaldehyde (LVII) as yellow oil. (2.0 g, 12.3 mmol, 55.1percent yield). 1H NMR (CDCl3, 400 MHz) δ ppm 2.01 (q, J=45.8 Hz, 2H), 2.82 (t, J=6.4 Hz, 2H), 4.24 (t, J=5.2 Hz, 2H), 6.85 (d, J=8.4 Hz, 1H), 7.52-7.64 (m, 2H), 9.79 (s, 1H); ESIMS found C10H10O2 m/z 163.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With n-butyllithium In tetrahydrofuran; <i>N</i>-methyl-acetamide | 8-Chromanylacetic acid can be prepared in three stages from chroman, with an overall yield of 60percent, as illustrated by Synth. Comm., 12, 763-70 (1982). On treatment with n-butyllithium and then with dimethylformamide in tetrahydrofuran, chroman results in 8-chromanal, which is then treated with trimethylsilyl cyanide in the presence of zinc iodide in dichloromethane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium acetate In N,N-dimethyl-formamide at 95℃; for 5 h; | A solution of the 6-iodochroman 11c (1.0 g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for an additional 5 min before being heated to 950C for 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With hydrogen In chloroform at 20℃; for 12h; ambient pressure; | |
With palladium on activated charcoal; acetic acid Hydrogenation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: chromane; acetyl chloride With Ethyl oxalyl chloride In dichloromethane at -10℃; Stage #2: With hydrogenchloride In water at 20℃; for 2h; | 49.1 Step 1 : Preparation of intermediate 1 -(3,4-dihydro-2/-/-1 -benzopyran-6-yl)ethan-1 -one (49a)Aluminium chloride (1 .19 g, 8.9 mmol) was added portionwise to a stirred solution of acetyl chloride (1 .21 mL, 17.0 mmol) in dry dichloromethane (20 mL), previously cooled to -10°C, until homogeneous (5 min). The solution was added, via cannula, to a solution of 3,4-dihydro-2H-1 -benzopyran (9a) (1 .20 g, 8.9 mmol) in dry dichloromethane (17mL) at -10°C. The mixture was stirred at the same temperature for 30 minutes before being poured into ice/concentrated hydrochloric acid (5:1 , v/v, 126 mL). The stirring was maintained at room temperature for 2 hours and the solution was extracted with dichloromethane (3 x 50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 1 -(3,4-dihydro-2H-1 - benzopyran-6-yl)ethan-1 -one (49a) (1 .55 g, 8.8 mmol, 99%) which was used without further purification.1H NMR (300 MHz, CDCI3) 1 .97-2.07 (m, 2H), 2.53 (s, 3H), 2.82 (t, J =6.4 Hz, 2H), 4.24 (t, J = 5.2 Hz, 2H), 6.81 (d, J =9.2 Hz, 1 H), 7.67-7.74 (m, 2H).MS m/z ([M+H]+) 177. |
88% | With aluminium trichloride In 1,2-dichloro-ethane at 0℃; for 1h; | |
85% | Stage #1: acetyl chloride With aluminum (III) chloride In dichloromethane at -10℃; for 0.166667h; Stage #2: chromane In dichloromethane at -10℃; for 1h; |
80% | Stage #1: acetyl chloride With aluminum (III) chloride In dichloromethane at -10℃; for 0.25h; Stage #2: chromane In dichloromethane at -10℃; for 0.5h; | |
70% | In dichloromethane at -30 - -15℃; for 0.833333h; Inert atmosphere; | 148.B Chromane (4.64 g, 29.4 mmol) is dissolved in 30 mL of anhydrous dichloromethane (DCM) under a nitrogen atmosphere. The reaction medium is cooled to -300C, and then a cold solution (-100C) of ethanoyl chloride (4.75 mL, 67 mmol) in 20 mL of anhydrous DCM is added within 5 minutes. The mixture is stirred for 45 min at -15°C, and then poured over a mixture of 100 g of ice and 50 mL of concentrated HCl and extracted three times with DCM. The organic phases are combined, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The thereby obtained residue is purified on a column of 120 g of silica (gradient of 0% to 20% EtOAc in heptane in 60 minutes), in order to obtain two batches of compound 148B (70%) .Batch 1: 2.25 g; HPLC: RT = 4.09 min, 96.6%.1H NMR, dmso-dβ,δ (ppm) : 1.93 (q, 2H); 2.49 (s, 3H); 2.79 (t, 2H); 4.21 (t, 2H); 6.81 (d, IH); 7.65-7.75 (m, 2H) .Mass spectrum (ESI+ ) : m/z 177 (MH+, 100%) .Batch 2: 1.79 g; HPLC: RT = 4.09 min, 81%. |
65% | With aluminium trichloride In dichloromethane for 1h; | |
64% | With aluminium trichloride In dichloromethane at -10℃; for 0.5h; | |
With carbon disulfide; aluminium trichloride | ||
With aluminium trichloride In 1,2-dichloro-ethane at 5℃; | ||
4.0 g (64%) | With aluminium trichloride In dichloromethane | 14 N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]chromane-6-carboxamide-fumarate To a stirred solution of acetyl chloride (4.78 mL, 67.1 mmol) in dry CH2Cl2 (20 mL) in a -10° C. bath is added aluminum trichloride (4.76 g, 35.7 mmol) in small portions. The mixture is stirred for 15 min until the solution became homogeneous. The solution is added via canula to a separate solution of chromane (4,79 g, 35.7 mmol) in CH2Cl2 (30 mL) all at -10° C. After complete addition, the solution is stirred at -10° C. for 30 min. The solution is poured over a mixture of crushed ice and concentrated HCl. The mixture is extracted with CH2Cl2. The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The remaining residue is purified via crystallization from hexanes to give 4.0 g (64%) of 1-(3,4-dihydro-2H-chromen-6-yl)ethanone as a white solid. 1H NMR (400 MHz, CDCl3) δ7.76-7.73, 6.75, 4.27, 2.86, 2.57, 2.09-2.03. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.1% | With trichlorophosphate In 1,2-dichloro-ethane at 50 - 85℃; for 12.5h; | 2 Preparation of chromane-6-carbaldehyde (LVII) To a solution of chromane (LVI) (3 g, 22.4 mmol, 1.0 eq) and DMF (3.3 g, 45.2 mmol, 2 eq) in DCE (20 mL) was added phosphorus oxychloride (3.4 g, 45.2 mmol, 2 eq) dropwise over 30 min below 50° C. The mixture was stirred at 85° C. for 12 h. The reaction was quenched by water and extracted with EtOAc (3×300 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE:EtOAc=8:1) to give chromane-6-carbaldehyde (LVII) as yellow oil. (2.0 g, 12.3 mmol, 55.1% yield). 1H NMR (CDCl3, 400 MHz) δ ppm 2.01 (q, J=45.8 Hz, 2H), 2.82 (t, J=6.4 Hz, 2H), 4.24 (t, J=5.2 Hz, 2H), 6.85 (d, J=8.4 Hz, 1H), 7.52-7.64 (m, 2H), 9.79 (s, 1H); ESIMS found C10H10O2 m/z 163.1 (M+H). |
35% | With trichlorophosphate In 1,2-dichloro-ethane at 85℃; for 12h; | 3,4-dihydro-2H-1-benzopyran-6-carbaldehyde To a solution of 3,4-dihydro-2H-1-benzopyran (27.0 g, 201 mmol) in 1,2-dichloroethane (270 ml) were added N,N-dimethylformamide (31 ml, 400 mmol) and phosphorus oxychloride (38 ml, 400 mmol) at room temperature. The reaction mixture was heated to 85 °C and stirred at 85 °C for 12 hours. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate. The organic layer was evaporated under reduced pressure to give a residue. The residue was purified by chromatography (1000 mesh, petroluem ether: ethyl acetate = 100: 1, then 50: 1, then 20: 1) to give chromane-6-carbaldehyde (11.5 g, 35 % yield) as a colorless oil. (2353) 1H NMR (400 MHz, DMSO-d6) d [ppm] = 9.80 (s, 1H), 7.67-7.55 (m, 2H), 6.90 (d, 1H), 4.23 (t, 2H), 2.81 (t, 2H), 1.98-1.91 (m, 2H). |
With trichlorophosphate anschliessendes Behandeln mit Wasser; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With nitric acid at 0 - 20℃; | |
21% | With nitric acid at -10℃; for 1h; Cooling with ice; | 61.2 Step 2: Synthesis of 6-nitro-3,4-dihydro-1H-benzopyran Under the ice-salt bath,(7.50 g, 55.90 mmol) was slowly added to HNO3 (63%, 13 mL).After adding,Stir at -10°C for 1 h.The reaction solution was slowly poured into ice water (20mL),Sodium hydroxide aqueous solution (1N) is adjusted to weakly alkaline,DCM extraction (50mL*2),Combine the organic phases,Wash with saturated brine (40mL*2),Dry with anhydrous sodium sulfate,concentrate,The crude product was subjected to silica gel column chromatography to obtain a yellow solid (2.1 g, yield 21%). |
19% | With nitric acid at -10℃; for 1h; | 4.1.7.3. 6-Nitrochroman (6). To chroman 4 (4.88 g) was added dropwise a solution of HNO3 (8.5 mL, 63%) at -10°C for 1 h. After the reaction was completed, the mixture was basified with a 10% solution of NaOH and extracted with dichloromethane (3100 mL). The combined organic extracts were washed with water (350 mL) and brine, dried over MgSO4, and purified by chromatography on a silica gel column (EtOAc/n-hexane gradient) to give 6 (1.35 g, 19%) as a yellow solid. |
With nitric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With Amberlist 15 In toluene for 3h; Heating; | |
82% | With phosphoric acid at 147℃; for 0.416667h; | |
49% | With di-isopropyl azodicarboxylate; triphenylphosphine |
With phosphoric acid at 150℃; | ||
With hydrogenchloride at 150℃; | ||
With phosphorus tribromide; benzene erwaermen des Reaktionsgemisches mit wss.Natronlauge; | ||
With triphenylphosphine; diethylazodicarboxylate In 1,4-dioxane Yield given; | ||
With zinc(II) chloride at 298 - 463℃; | ||
With phosphoric acid | ||
Multi-step reaction with 2 steps 1: 12 percent / EDCI; 4-(dimethylamino)pyridine / CH2Cl2 / 3 h / 20 °C 2: 50 percent / mercury(II) trifluoromethanesulfonate / CH2Cl2 / 12 h / 20 °C | ||
Multi-step reaction with 2 steps 1: pyridine / 0 °C 2: aq. NaOH / propan-2-ol / 5 h / 70 - 80 °C | ||
Multi-step reaction with 2 steps 1: CH2Cl2 / 0.58 h 2: Et3N / CH2Cl2 / 19 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With aluminium trichloride In 1,2-dichloro-ethane for 1h; below 5 deg C; | |
34% | With aluminum (III) chloride In dichloromethane at 0℃; for 0.5h; Inert atmosphere; | 19.1 Step 1 : Preparation of intermediate 2-bromo-1 -(3,4-dihydro-2/-/-1 -benzopyran-6- yl)ethan-1 -one (19a)To a solution of 3,4-dihydro-2/-/-1 -benzopyran (9a) (0.70 g, 5.22 mmol) in anhydrous dichloromethane (10 mL) under nitrogen atmosphere were added at 0°C aluminium trichloride (2.09 g, 15.6 mmol) and bromoacetyl chloride (0.73 mL, 8.76 mmol). The mixture was stirred at 0°C for 30 minutes and poured in ice (50 mL). The aqueous layer was extracted with ethyl acetate (2x20 mL). The organic layers were successively washed with a saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20) to provide a 80/20 mixture of 2-bromo-1 -(3,4-dihydro-2/-/-1 -benzopyran-6-yl)etha-1 -none (19a) and 2-bromo-1 -(3,4-dihydro-2/-/-1 -benzopyran-8-yl)ethan-1 -one (0.45 g, 1 .76 mmol, 34%) as yellow oil.1H NMR (300 MHz, CDCI3) 1 .99-2.1 1 (m, 2H), 2.81 -2.85 (m, 2H), 4.24-4.27 (m, 2H), 4.37 (s, 2H), 6.84 (d, J = 9.3 Hz, 1 H), 7.72-7.74 (m, 2H).MS m/z ([M+H]+) 255, 257. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With aluminium trichloride In dichloromethane at 15℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With aluminium trichloride In dichloromethane at 15℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With aluminium trichloride In dichloromethane at 15℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With aluminium trichloride In dichloromethane at 15℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With aluminium trichloride In dichloromethane at 15℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With aluminium trichloride In dichloromethane at 15℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With aluminium trichloride In dichloromethane at 15℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In cyclohexane at 120℃; for 5h; Yield given; | ||
With hydrogen In cyclohexane at 120℃; for 5h; Yield given. Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sulfur trioxide In nitromethane at 0℃; for 3600h; other reagent; other time; other temp; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In dichloromethane Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With n-butyllithium In tetrahydrofuran; hexane at -100℃; for 0.5h; | |
79% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 1.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With Raney nickel W 4 In ethanol for 1.5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With palladium on activated charcoal; hydrogen In acetic acid at 18 - 25℃; for 12h; | 3,4-dihydro-2H-1-benzopyran To a solution 2,3-dihydro-4H-1-benzopyran-4-one (30.0 g, 202 mmol) in acetic acid (300 ml) was added palladium on carbon (2.15 g, 20.2 mmol) at room temperature. After stirring at room temperature for 12 hours under hydrogen (50 psi) atmosphere, the reaction mixture was filtered through celite. The filtrate was evaporated under reduced pressure to give chromane (27.0 g, 99% yield) as yellow oil. (2350) 1H NMR (400 MHz, DMSO-d6) d [ppm] = 7.07-6.99 (m, 2H), 6.79 (td, 1H), 6.74-6.67 (m, 1H), 4.11 (t, 2H), 2.72 (t, 2H), 1.96-1.83 (m, 2H). |
95% | With acetic acid; zinc at 100℃; | 11.1 Step 1 :Commercially available chromanone 11a (9.78 g, 66.0 mmol) dissolved in AcOH (20 mL) is added to a suspension of zinc dust (108 g, 1.65 mol) in AcOH (150 mL). The mixture is heated to 1000C and is stirred mechanically overnight. The mixture is then filtered through Celite (washed with EtOAc, 10OmL), diluted with PhMe (300 mL) and the solution is evaporated to give chroman intermediate 11b (8.45 g, 95% yield). |
95% | With acetic acid; zinc at 100℃; | 11.1 Commercially available chromanone 11a (9.78 g, 66.0 mmol) dissolved in AcOH (20 ml_) is added to a suspension of zinc dust (108 g, 1.65 mol) in AcOH (150 ml_). The mixture is heated to 1000C and is stirred mechanically overnight. The mixture is then filtered through Celite (washed with EtOAc, 10OmL), diluted with PhMe (300 ml_) and the solution is evaporated to give chroman intermediate 11b (8.45 g, 95% yield). |
95% | With acetic acid; zinc at 100℃; | 11.1 Commercially available chromanone 11a (9 78 g, 66 0 mmol) dissolved in AcOH (20 mL) is added to a suspension of zinc dust (108 g, 1 65 mol) in AcOH (150 mL) The mixture is heated to 100°C and is stirred mechanically overnight The mixture is then filtered through Celite (washed with EtOAc 10OmL), diluted with PhMe (300 mL) and the solution is evaporated to give chroman intermediate 11b (8 45 g, 95% yield) |
95% | With acetic acid; zinc at 100℃; | 11.1 Commercially available chromanone 11a (9.78 g, 66.0 mmol) dissolved in AcOH (20 mL) is added to a suspension of zinc dust (108 g, 1.65 mol) in AcOH (150 mL). The mixture is heated to 1000C and is stirred mechanically overnight. The mixture is then filtered through Celite (washed with EtOAc, 10OmL), diluted with PhMe (300 mL) and the solution is evaporated to give chroman intermediate 11b (8.45 g, 95% yield). |
94% | With molybdenum trisulfide; hydrogen In octane at 240℃; for 1.5h; | |
92% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With iron(III) chloride In methanol at 20℃; for 0.05h; Stage #2: In methanol at 20℃; for 0.166667h; chemoselective reaction; | |
92% | With palladium 10% on activated carbon In methanol; chlorobenzene at 25℃; for 2h; Sealed tube; | |
91% | With zinc In acetic acid at 100℃; for 4h; | |
88% | With acetic acid; zinc at 100℃; for 16h; | |
88.7% | With acetic acid; zinc at 110℃; for 6h; | 1 To a suspension of zinc dust (100 g, 1.56 mol) in HOAc (300 mL) was added chroman-4-one (LV) (10 g, 67.6 mol). The mixture was stifled at 110° C. for 6 h. Then the mixture was cooled and filtrated. The filtrate was poured into water (500 mL) and extracted with EtOAc (3×100 mL). The organic layer was concentrated to give chromane (LVI) as colorless oil. (8.05 g, 60.0 mmol, 88.7% yield). 1H NMR (CDCl3, 400 MHz) δ ppm 2.04 (q, J=4.3 Hz, 2H), 2.81 (t, J=6.6 Hz, 2H), 4.21 (t, J=5.2 Hz, 2H), 6.72-6.92 (m, 2H), 7.00-7.17 (m, 2H); ESIMS found C9H10O m/z 135.0 (M+H). |
88% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With acetic acid; zinc at 100℃; for 16h; Stage #2: With sodium hydroxide In water | 162 Alternative Preparation of Λ/-(3,4-Dihydro-2/Y-chromen-6-yl)acetamide (228). A solution of 4-chromanone (225) (14.82 g, 0.1 mol) in HOAc (50 mL) was added to a stirred suspension of Zn dust (10 eq. w/w, 148 g) in HOAc (200 mL) and the mixture stirred at 100 0C for 16 h. The mixture was cooled, filtered, washed with HOAc (3 x 100 mL) and the solvent from the combined filtrate evaporated. The residue was suspended in water (200 mL) and the suspension made basic with NaOH1 extracted with EtOAc (3 x 100 mL), the combined extracts dried and the solvent evaporated to give chroman (229) (11.83 g, 88%) as a white solid. AICI3 (11.8 g, 88.2 mmol) was added in small portions to a stirred solution of AcCI (11.9 mL, 167.5 mmol) in dry DCM (250 mL) at -10 0C and the mixture stirred until homogeneous (15 min). The solution was added, via a cannula, to a stirred solution of chroman (229) (11.8 g, 88.2 mmol) in dry DCM (200 mL) at -10 0C and the solution stirred for 30 min at -10 °C and then poured into ice/cHCI (5:1 v/v, 1.5 L). The mixture was stirred for 2 h, extracted with DCM (3 x 100 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-20%) of EtOAc/pet. ether, to give 1-(3,4-dihydro-2f/-chromen-6-yl)ethanone (230) (12.45 g, 80%) as a white solid: 1H NMR δ 7.68-7.22 (m, 2 H, H-5, H-7), 6.82 (d, J = 9.2 Hz, 1 H, H-8), 4.24 (br dd, J = 5.3, 5.2 Hz, 2 H, H 2), 2.83 (br t, J = 6.5 Hz, 2 H, H-4), 2.53 (s, 3 H, CH3), 2.00-2.06 (m, 2 H, H-3). Hydroxylamine HCI (2.9 g, 41.9 mmol) was added to a stirred solution of ketone 230 (6.15 g, 34.9 mmol) and pyridine (3.7 mL, 45.4 mmol) in MeOH (30 mL) and the mixture stirred at 20 0C for 16 h. The solvent was evaporated and the residue partitioned between brine and EtOAc. The organic fraction was dried and the solvent evaporated to give crude 1- (3,4-dihydro-2/7-chromen-6-yl)ethanone oxime (6.3 g, 94%). HCI gas was bubbled through a solution of oxime (6.3 g, 32.5 mmol) in Ac2O (6.1 mL, 65 mmol) and HOAc (40 mL, 650 mmol), and the solution stood at 20 0C for 24 h. The precipitate was poured into ice/water, stirred for 2 h, the solid filtered and washed with water and dried. The aqueous fraction was extracted with DCM (2 x 50 mL), the combined extract dried and the solvent evaporated. The slurry was treated with water (20 mL) and evaporated several times to remove Ac2O. The combined solids were purified by chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 228 (3.74 g, 59%) as a white solid: spectroscopically identical to the sample prepared above. |
83% | With aluminum (III) chloride; lithium aluminium tetrahydride In tetrahydrofuran at 40℃; for 2.5h; Inert atmosphere; Cooling with ice; | 61.1 Step 1: Synthesis of 3,4-dihydro-1H-benzopyran Under nitrogen protection,2,3-Dihydrobenzopyran-4-one (10.0g, 67.49mmol)Dissolved in anhydrous tetrahydrofuran (120mL),Cooled in an ice bath,Slowly add anhydrous aluminum trichloride (31.5g, 236.2mmol) in batchesAnd tetrahydroaluminum lithium (4.35g, 114.6mmol),Gaby,Continue stirring for 0.5h under ice bath,Warm up to 40°C and stir for 2h.The reaction liquid was cooled to room temperature,Slowly add water (4.5mL) to quench the reaction,Continue to add saturated ammonium chloride aqueous solution (20mL),Stir water (50mL) and anhydrous sodium sulfate (20g) for 0.5h,filter,The filter cake was washed with ethyl acetate,Combine the organic phases,Wash with saturated brine (50mL*2),Dry with anhydrous sodium sulfate,concentrate,The crude product was subjected to silica gel column chromatography to obtain a colorless oil (7.5 g, yield 83%). |
77% | With triethylsilane; trifluoroacetic acid at 65℃; | |
77% | With acetic acid; zinc at 100℃; | |
72% | With acetic acid; zinc at 100℃; | |
61% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With boron trifluoride diethyl etherate; sodium cyanoborohydride In tetrahydrofuran at 20 - 65℃; Inert atmosphere; Stage #2: With water In tetrahydrofuran | 148.A 4-chromanone (5.0 g, 33.7 mmol) is dissolved in 102 mL of THF under a nitrogen atmosphere. BF3. OEt2 (12.8 mL, 101 mmol) is added at room temperature and sodium cyanoborohydride (4.33 g, 67.4 mmol) is added slowly (violent reaction) . The thereby obtained white suspension is heated to 65°C of 18 hours, and then neutralized with water. The reaction mixture is extracted twice with ethyl acetate. The organic phases are combined, successively washed with a saturated NaHCO3 solution and a saturated NaCl solution, and then dried on magnesium sulfate, filtered and concentrated under reduced pressure. The thereby obtained residue is purified on silica (gradient of 0% to 50% dichloromethane in heptane, and then 10% ethyl acetate in heptane) , in order to obtain the partly purified compound 148A (3.34 g, 61%) .HPLC: RT = 4.56 min, 83%1H NMR, dmso-de, δ (ppm) : 1.91 (q, 2H); 2.72 (t, 2H); 4.11 (t, 2H); 6.70 (d, IH); 6.80 (t, IH); 7.0-7.05 (m, 2H) |
59% | With acetic acid; zinc at 100℃; for 18h; | |
54% | With aluminum (III) chloride; lithium aluminium tetrahydride In diethyl ether at 0℃; Reflux; | 4.1.7.1. Chroman (4). To a solution of chroman-4-one (10 g, 1 equiv) in diethyl ether was slowly added aluminum chloride (31.5 g, 3.5 equiv) at 0°C, followed by lithium aluminium hydride (4.35 g, 1.75 equiv) added portionwise. The reaction mixture was stirred for 1 h at boiling temperature. The reaction was cooled, and a solution of NH4HCO3 was added slowly, after which the solution was filtered through a plug of Celite and extracted with ethylacetate (3200 mL). The combined organic extracts were washed with water (3100 mL), and brine (100 mL), dried over MgSO4, and purified by chromatography on a silica gel column (EA/n-hexane = 1:9) to give 4 (4.88 g, 54%) as a light yellow oil |
In aluminum nickel | 11.8 Preparation of 2-(dimethoxymethyl)-6-hydroxy-2,5,7,8-tetramethyl-chroman (for the formula, cf. Example 8) 0.50 g (1.7 mmoles) of the chromanone obtained as described in Example 2 was hydrogenated under 250 bar and at 180° C. in the presence of 1 g of Raney nickel over 2 hours. Purification of the crude product by chromatography gave the above chroman whose properties agreed with those of the product of Example 8. | |
With acetic acid; zinc at 100℃; for 4h; | A.4.5 A solution of 4-chromanone (19.6 mmol) in HOAc (30 mL) is added to a suspension of zinc powder (445 mmol) in HOAc (60 mL). The mixture is stirred at 1000C for 4h, cooled to RT, filtered through celite and concentrated in vacuo. EtOAc and aq. NaOH solution (1.0 M) are added, the layers are separated and the aq. layer is extracted twice with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification. 1H-NMR (CDCI3): δ = 2.04 (m, 2H); 2.82 (m, 2H); 4.21 (m, 2H); 6.80-6.89 (m, 2H); 7.04-7.14 (m, 2H). | |
With acetic acid; zinc at 100℃; for 4h; | 9; A.5.5 A solution of 4-chromanone (19.6 mmol) in HOAc (30 niL) is added to a suspension of zinc powder (445 mmol) in HOAc (60 mL). The mixture is stirred at 1000C for 4h, cooled to RT, filtered through celite and concentrated in vacuo. EtOAc and aq. NaOH solution (1.0 M) are added, the layers are separated and the aq. layer is extracted twice with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification. 1H-NMR (CDCl3): δ = 2.04 (m, 2H); 2.82 (m, 2H); 4.21 (m, 2H); 6.80-6.89 (m, 2H); 7.04-7.14 (m, 2H). | |
With acetic acid; zinc at 100℃; for 4h; | A.3.5 A solution of 4-chromanone (19.6 mmol) in HOAc (30 mL) is added to a suspension of zinc powder (445 mmol) in HOAc (60 mL). The mixture is stirred at 100° C. for 4 h, cooled to RT, filtered through celite and concentrated in vacuo. EtOAc and aq. NaOH solution (1.0 M) are added, the layers are separated and the aq. layer is extracted twice with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification. 1H-NMR (CDCl3): δ=2.04 (m, 2H); 2.82 (m, 2H); 4.21 (m, 2H); 6.80-6.89 (m, 2H); 7.04-7.14 (m, 2H). | |
With acetic acid; zinc at 100℃; | 27.A A solution of chroman-4-one (10 g, 67.5 mmol) in acetic acid (20 mL) was added to a suspension of zinc dust (1 10g, 1687 mmol) in acetic acid (150 mL). The mixture was heated to 100 °C overnight with mechanical stirring. 1 H NMR indicated complete conversion to the desired product. Then the reaction mixture was cooled to ambient temperature, filtered through a pad of Celite and washed with a mixture of 200mL ethyl acetate and 600mL toluene. The filtrate was concentrated and dried in vacuo to afford crude chroman which was used without further purification. 1H NMR (400MHz, CHLOROFORM-d) δ ppm 6.82 (d, J = 12.3 Hz, 4 H), 4.29 - 4.09 (m, 2 H), 2.80 (t, J = 6.5Hz, 2 H), 2.08 - 1.94 (m, 2 H), 2.08 - 1.94 (m, 2 H). A solution of crude chroman in MeOH (200 mL) was treated with AgN03 (12.84g, 76 mmol) and l2(15.42g, 60.7 mmol) . After one hour, the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous Na2S203, water and brine, dried over Na2S04, filtered and concentrated. The residue was purified on silica gel (0%~30% EA-hexane) to afford 6-iodocharoman (13.8 g, 53.1 mmol, 79% yield) as a yellow oil. 1 H NMR (400MHz, CHLOROFORM-d) δ ppm 7.52 - 7.30 (m, 2 H), 6.65 - 6.51 (m, 1 H), 4.20 - 4.16 (m, 2 H), 2.76 (t, J = 6.5 Hz, 2 H), 2.02 - 1 .97 (m, 2 H). | |
Multi-step reaction with 2 steps 1: methanol / 60 °C / Inert atmosphere 2: potassium carbonate; methanol; hydrogen; palladium 10% on activated carbon / 24 h / 65 °C / 760.05 Torr | ||
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; methanol / 2 h / 0 - 25 °C 2: triethylsilane; trifluoroacetic acid / dichloromethane / 12.5 h / 0 - 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 21% 2: 3% | With oxygen for 6h; Irradiation; further conditions, also without O2, further allylbenzene derivative; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 31% 2: 24% | Stage #1: 1-benzopyran-4(4H)-one With 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran at 20℃; Stage #2: With sodium hydroxide; dihydrogen peroxide In tetrahydrofuran; water at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl; palladium diacetate; caesium carbonate In toluene at 65℃; for 21h; | |
87% | With racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl; palladium diacetate; caesium carbonate In toluene at 65℃; for 21h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 1-iodo-2-(3'-iodopropyloxy)benzene With isopropylmagnesium chloride In tetrahydrofuran at -30℃; for 1h; Stage #2: In tetrahydrofuran at 25℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: chromane With 4,4'-di-tert-butylbiphenyl; lithium In tetrahydrofuran at 20℃; for 3h; Stage #2: furfural In tetrahydrofuran at -78℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: chromane With 4,4'-di-tert-butylbiphenyl; lithium In tetrahydrofuran at 20℃; for 3h; Stage #2: benzophenone In tetrahydrofuran at -78℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: chromane With 4,4'-di-tert-butylbiphenyl; lithium In tetrahydrofuran at 20℃; for 3h; Stage #2: dipentyl ketone In tetrahydrofuran at -78℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: chromane With 4,4'-di-tert-butylbiphenyl; lithium In tetrahydrofuran at 20℃; for 3h; Stage #2: (2R,5S)-menthone In tetrahydrofuran at -78℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | Stage #1: chromane With 4,4'-di-tert-butylbiphenyl; lithium In tetrahydrofuran at 20℃; for 3h; Stage #2: cyclohexanone In tetrahydrofuran at -78℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: chromane With 4,4'-di-tert-butylbiphenyl; lithium In tetrahydrofuran at 20℃; for 3h; Stage #2: benzaldehyde In tetrahydrofuran at -78℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 42% 2: 10% | Stage #1: chromane With 4,4'-di-tert-butylbiphenyl; lithium In tetrahydrofuran at 20℃; for 3h; Stage #2: pivalaldehyde In tetrahydrofuran at -78℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: chromane With 4,4'-di-tert-butylbiphenyl; lithium In tetrahydrofuran at 20℃; for 3h; Stage #2: With water In tetrahydrofuran at -78℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With gold(III) chloride; silver trifluoromethanesulfonate In 1,2-dichloro-ethane at 120℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With gold(III) chloride; silver trifluoromethanesulfonate In 1,2-dichloro-ethane at 120℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tert.-butylhydroperoxide; sodium hydrogencarbonate In decane; 1,2-dichloro-ethane at 40℃; for 16h; | |
91% | With N-hydroxyphthalimide; 6-((cobalt(II) 4,9,16,23-tetraaminephthalocyanin-4-yl))cellulose; oxygen; potassium hydroxide In o-xylene for 11h; Reflux; Green chemistry; | Typical procedure for the oxidation of tetraline General procedure: N-Hydroxyphthalimide (0.01 g, 0.06 mmol) was added to a two-necked flask equipped with a gas bubbling tube containing colloidal of CoPcCell (0.05 g), tetraline (0.13 g, 1.00 mmol) and KOH (0.25 mmol) in o-xylene (5 mL). The mixture was stirred under reflux conditions in O2 atmosphere provided with a balloon. The reaction temperature was raised to refluxing o-xylene. The progress of the reaction was followed by TLC. Upon completion, CoPcCell was separated by filtration and washed with acetone (5 mL). Tetralone was isolated from the mixture using column chromatography with n-hexane:ethyl acetate (10:1) in 88% yield. |
75% | With tert.-butylhydroperoxide; C56H53ClN3P2Ru(1+)*F6P(1-) In benzene at 25℃; for 18h; Inert atmosphere; Schlenk technique; |
54% | With pyridine; tert.-butylhydroperoxide; iron(III) chloride at 82℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With boron trifluoride diethyl etherate In dichloromethane at 25℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With mercury(II) trifluoromethanesulfonate In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 50 percent / baker's yeast; aq. D-glucose / ethanol / 48 h / 35 - 38 °C 2: LiAlH4 / diethyl ether / 5 h / Heating 3: pyridine / 0 °C 4: aq. NaOH / propan-2-ol / 5 h / 70 - 80 °C | ||
Multi-step reaction with 2 steps 1: Lawesson's reagent / toluene / Heating 2: Raney nickel / diethyl ether / 1.) -15 deg C, 2.) -10 deg C, 2 min | ||
Multi-step reaction with 2 steps 1: sodium; alcohol 2: alcoholic hydrochloric acid / 150 °C |
Multi-step reaction with 2 steps 1: ethanol; copper oxide-chromium oxide / 250 °C / 73550.8 - 147102 Torr / Hydrogenation 2: phosphorus (III)-bromide; benzene / erwaermen des Reaktionsgemisches mit wss.Natronlauge | ||
Multi-step reaction with 3 steps 1: LiBH4; diethyl ether / 20 °C 2: Erhitzen unter vermindertem Druck 3: palladium/charcoal; acetic acid / Hydrogenation | ||
Multi-step reaction with 2 steps 1: triethylsilane; indium tribromide; allyl-trimethyl-silane / toluene / 24 h / 70 °C 2: triethylsilane; indium tribromide / toluene | ||
Multi-step reaction with 2 steps 1: triethylsilane; indium tribromide; allyl-trimethyl-silane / toluene / 24 h / 70 °C 2: indium tribromide / chloroform |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylsilane; indium tribromide In toluene | |
89% | With acetic acid; zinc at 100℃; for 15h; | 9.1 Step 1 : Preparation of intermediate 3,4-dihydro-2/-/-1 -benzopyran (9a)A suspension of chromanone (1 g, 6.75 mmol) and zinc powder (3.07 g, 47 mmol) in acetic acid (15 mL) was warmed at 100°C for 15 hours. Residue of zinc was then removed by filtration on celite. The filtrate was concentrated under vacuum by co- evaporation with toluene to give the desired product (9a) without further purification (810 mg, 6.03 mmol, 89%).1H NMR (300 MHz, CDCI3) 1 .96-2.07 (m, 2H), 2.80 (t, J = 6.5 Hz, 2H), 4.16-4.22 (m, 2H), 6.78-6.86 (m, 2H), 7.03-7.20 (m, 2H). |
Multi-step reaction with 3 steps 1: LiAlH4 / diethyl ether / 5 h / Heating 2: pyridine / 0 °C 3: aq. NaOH / propan-2-ol / 5 h / 70 - 80 °C |
Multi-step reaction with 3 steps 1: 99 percent / i-Bu2AlH / toluene / 0.33 h / 20 °C 2: CH2Cl2 / 0.58 h 3: Et3N / CH2Cl2 / 19 h / Heating | ||
Multi-step reaction with 2 steps 1: diisobutylaluminium hydride / toluene / 49.9 °C 2: ZnCl2 / 298 - 463 °C | ||
Multi-step reaction with 2 steps 1: LiAlH4; diethyl ether 2: phosphoric acid / 150 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 4-hydroxychroman With acetic anhydride In acetic acid for 3h; Heating / reflux; Stage #2: With hydrogen | 4 Chroman To a stirred solution of 4-hydroxychroman (10.14 g, 67.5 mmol) in acetic acid (150 mL) under Ar was added acetic anhydride (12.7 mL, 135 mmol) and the mixture was heated at reflux for 3 h, then allowed to cool to ambient temperature. Palladium on carbon (10 wt %; 1.8 g, 2.5 mol %) was added and the mixture was shaken in a Parr hydrogenator under a 42 psi atmosphere of hydrogen overnight. The reaction mixture was filtered, the solvent was removed in vacuo and the residue was taken-up in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate solution, brine, dried (magnesium sulfate) and concentrated in vacuo to afford the product (7.73 g, 85%) as a pale yellow liquid: IR νmax (film)/cm-1 2937, 2863, 1737, 1609, 1582, 1490, 1456, 1304, 1267, 1228, 1189, 1116, 1065, 1008 and 754; NMR (400 MHz, CDCl3) δH 2.00 (2H, m), 2.78 (2H, t, J 6.5 Hz), 4.17 (2H, t, J 7 Hz), 6.81 (2H, m) and 7.05 (2H, m). |
Multi-step reaction with 2 steps 1: 74 percent / p-TsOH; hydroquinone / benzene / 2 h / Heating 2: 67 percent / H2 / 10percent Pd/C / CHCl3 / 12 h / 20 °C / ambient pressure | ||
With triethylsilane; trifluoroacetic acid In dichloromethane at 0 - 25℃; for 12.5h; | 1.2 Step 2 The chroman-4-alcohol was dissolved in methylene chloride, and triethylsilane and trifluoroacetic acid were added successively at 0°C and the reaction was heated at 10°C for 0.5 hours. The chroman-4-ol and tris The molar ratio of ethyl silane and trifluoroacetic acid was 1:1.5:6, followed by a temperature rise and room temperature reaction for 12 hours to produce an intermediate chroman. The reaction solution was diluted with water and then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by column to give intermediate chroman. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 85 percent / tetrabutylammonium chloride; sodium bicarbonate; palladium acetate / dimethylformamide / 22 h / 45 °C 2: 98 percent / sodium borohydride / methanol / 20 °C 3: 87 percent / Pd(OAc)2; Cs2CO3; 2-(di-tert-butylphosphanyl)-1,1'-binaphthyl / toluene / 21 h / 65 °C | ||
Multi-step reaction with 3 steps 1: 85 percent / tetrabutylammonium chloride; sodium bicarbonate; palladium acetate / dimethylformamide / 22 h / 45 °C 2: 98 percent / sodium borohydride / methanol / 20 °C 3: 87 percent / Pd(OAc)2; di-tert-butyl-[2-(1,1'-binaphthyl)]phosphine; Cs2CO3 / toluene / 21 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 71 percent / diethyl ether / 0 - 20 °C 2: 87 percent / Pd(OAc)2; Cs2CO3; 2-(di-tert-butylphosphanyl)-1,1'-binaphthyl / toluene / 21 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 51 percent / pyridinium chlorochromate / CH2Cl2 / 1.5 h / 20 °C 2: 71 percent / diethyl ether / 0 - 20 °C 3: 87 percent / Pd(OAc)2; Cs2CO3; 2-(di-tert-butylphosphanyl)-1,1'-binaphthyl / toluene / 21 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 98 percent / sodium borohydride / methanol / 20 °C 2: 87 percent / Pd(OAc)2; Cs2CO3; 2-(di-tert-butylphosphanyl)-1,1'-binaphthyl / toluene / 21 h / 65 °C | ||
Multi-step reaction with 2 steps 1: 98 percent / sodium borohydride / methanol / 20 °C 2: 87 percent / Pd(OAc)2; di-tert-butyl-[2-(1,1'-binaphthyl)]phosphine; Cs2CO3 / toluene / 21 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 79 percent / HNO3 / 0 - 20 °C 2: 91 percent / hydrogen / Raney nickel / ethanol / 3 h | ||
Multi-step reaction with 2 steps 1: aqueous nitric acid 2: Raney nickel; ethanol / Hydrogenation | ||
Multi-step reaction with 2 steps 1: nitric acid / 1 h / -10 °C 2: palladium 10% on activated carbon; hydrogen / methanol; tetrahydrofuran / 2 h / 20 °C |
Multi-step reaction with 2 steps 1: nitric acid / 1 h / -10 °C / Cooling with ice 2: iron; ammonium chloride / ethanol; water / 1 h / 80 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 92 percent / 3.4 M sodium bis(2-methoxyethoxy)aluminum / toluene / 0.17 h / Heating 2: 82 percent / 85percent H3PO4 / 0.42 h / 147 °C | ||
Multi-step reaction with 2 steps 1: LiAlH4 / diethyl ether 2: phosphoric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.00 g (98%) | In acetic acid | 14 N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]chromane-6-carboxamide-fumarate EXAMPLE 14 N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]chromane-6-carboxamide-fumarate A mixture of chromene (see: Chatterjea, J. Indian Chem. Soc. 1959, 35, 78.) (5.00 g, 37.8 mmol) and 10% palladium on activated carbon (250 mg) in glacial acetic acid (100 mL) is placed in a Parr bottle. The mixture is shaken under an atmosphere of hydrogen (45 psi) for 3 h at rt. The mixture is filtered through Celite and the filtrate is concentrated in vacuo to afford 5.00 g (98%) of chromane as light yellow oil: 1H NMR (400 MHz, CDCl3) δ7.15-7.05, 6.89, 6.80, 4.23, 2.84, 2.08-2.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With n-butyllithium; In tetrahydrofuran; N-methyl-acetamide; | 8-Chromanylacetic acid can be prepared in three stages from chroman, with an overall yield of 60%, as illustrated by Synth. Comm., 12, 763-70 (1982). On treatment with n-butyllithium and then with dimethylformamide in tetrahydrofuran, chroman results in 8-chromanal, which is then treated with trimethylsilyl cyanide in the presence of zinc iodide in dichloromethane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With H2 In acetic acid; ethyl acetate | 1.B B. B. Preparation of Ethyl 3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate In a pressure bottle, the chromone (12.07 g, 0.044 mol) was dissolved in 210 mL of acetic acid. 10% Pd/C (7.2 g) catalyst was added to this solution and the bottle was pressurized with 52 psi of H2 gas. The reaction was agitated for 23 hours. The catalyst was removed by filtration through a celite pad in a sintered glass funnel. The catalyst was washed with EtOAc. The solvent was removed from the filtrate and the resulting oil was azeotroped with toluene providing 12 g of brown oil. The material was purified on a Waters Prep 500 HPLC, equipped with silica gel cartridges, running a 5% to 40% EtOAc/Hexane gradient over 50 min at a flow rate of 250 mL/min and collecting 500 mL fractions. The purified chroman was obtained as a pink oil (10 g, 86%). TLC: Rf=0.50 (40% EtOAc/Hexane). 1H NMR (CDCl3) δ6.73 (d, 1, J=8.20 Hz), 6.37 (d, 1, J=8.20 Hz), 4.78 (s(br), 1), 4.75 (m, 1), 4.25 (m, 2), 2.68 (m, 4), 2.16 (m, 2), 1.60 (m, 2), 1.29 (t, 3, J=7.07 Hz), 0.99 (t, 3, J=7.34 Hz). |
86% | With H2 In acetic acid; ethyl acetate | 10.G F. G. Preparation of Ethyl 3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate. In a parr bottle, chromone (12.07 g, 0.044 mol) was dissolved in 210 mL of acetic Acid. 10% Pd/C (7.2 g) catalyst was added to this solution and the bottle was pressurized with 52 psi of H2 gas. The reaction was agitated for 23 h. The catalyst was removed by filtration through a celite pad in a sintered glass funnel. The catalyst was washed with EtOAc. The solvent was removed from the filtrate and the resulting oil was azeotroped with toluene providing 12 g of brown oil. The material was purified on a Waters Prep 500 HPLC, equiped with silica gel cartridges, running a 5% to 40% EtOAc/Hexane gradient over 50 min at a flow rate of 250 mL/min and collecting 500 mL fractions. The purified chroman was obtained as a pink oil (10 g, 86%). TLC: Rf=0.50 (40% EtOAc/Hexane). 1 H NMR (CDCl3)δ6.73 (d,1,J=8.20 Hz), 6.37 (d,1,J=8.20 Hz), 4.78 (s(br), 1), 4.75 (m,1), 4.25 (m,2), 2.68 (m, 4), 2.16 (m,2), 1.60 (m,2), 1.29 (t,3,J=7.07 Hz), 0.99 (t,3,J=7.34 Hz). |
86% | With H2 In acetic acid; ethyl acetate | 9.C B. C. Preparation of Ethyl 3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate. In a parr bottle, chromone (12.07 g, 0.044 mol) was dissolved in 210 mL of acetic acid. 10% Pd/C (7.2 g) catalyst was added to this solution and the bottle was pressurized with 52 psi of H2 gas. The reaction was agitated for 23 h. The catalyst was removed by filtration through a celite pad in a sintered glass funnel. The catalyst was washed with EtOAc. The solvent was removed from the filtrate and the resulting oil was azeotroped with toluene providing 12 g of brown oil. The material was purified on a Waters Prep 500 HPLC, equiped with silica gel cartridges, running a 5% to 40% EtOAc/Hexane gradient over 50 min at a flow rate of 250 mL/min and collecting 500 mL fractions. The purified chroman was obtained as a pink oil (10 g, 86%). TLC: Rf=0.50 (40% EtOAc/Hexane). 1H NMR (CDCl3)δ6.73 (d,1 J=8.20 Hz) 6.37 (d,1,J=8.20 Hz), 4.78 (s(br), 1), 4.75 (m,1), 4.25 (m,2), 2.68 (m, 4), 2.16 (m,2), 1.60 (m,2), 1.29 (t,3,J=7.07 Hz), 0.99 (t,3,J=7.34 Hz). |
86% | With hydrogen In acetic acid; ethyl acetate | 12.G F. G. Preparation of Ethyl 3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate. In a Parr bottle, chromone (12.07 g, 0.044 mole) was dissolved in 210 ml of acetic acid. A catalyst (10% palladium/activated carbon) (7.2 g) was added to this solution and the bottle was pressurized with 52 psi of hydrogen gas. The reaction was agitated for 23 hours. The catalyst was removed by filtration through a Celite pad in a sintered glass funnel. The catalyst was washed with ethyl acetate. The solvent was removed from the filtrate and the resulting oil was azeotroped with toluene providing 12 g of brown oil. The material was purified on a Waters Prep 500 HPLC, equipped with silica gel cartridges, running a 5% to 40% ethyl acetate/hexane gradient over 50 minutes at a flow rate of 250 ml/min and collecting 500 ml fractions. The purified chroman was obtained as a pink oil (10 g, 86%). TLC: Rf=0.50 (40% EtOAc/Hexane). 1 H NMR (CDCl3) δ6.73 (d, 1, J=8.20 Hz), 6.37 (d, 1, J=8.20 Hz), 4.78 (s(br), 1), 4.75 (m, 1), 4.25 (m, 2), 2.68 (m, 4), 2.16 (m, 2), 1.60 (m, 2), 1.29 (t, 3, J=7.07 Hz), 0.99 (t, 3, J=7.34 Hz). |
86% | With H2 In acetic acid; ethyl acetate | 13.B Preparation of 7-[3-(4-acetyl-2-ethyl-5-hydroxyphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid. STR18 B. Preparation of Ethyl 3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate. In a pressure bottle, the chromone (12.07 g, 0.044 mole) was dissolved in 210 ml of acetic acid. 10% palladium on activated carbon (7.2 g) catalyst was added to this solution and the bottle was pressurized with 52 psi of H2 gas. The reaction was agitated for 23 hours. The catalyst was removed by filtration through a Celite pad in a sintered glass funnel. The catalyst was washed with ethyl acetate. The solvent was removed from the filtrate and the resulting oil was azeotroped with toluene providing 12 g of brown oil. The material was purified on a Waters Prep 500 HPLC, equiped with silica gel cartridges, running a 5% to 40% ethyl acetate/hexane gradient over 50 minutes at a flow rate of 250 ml/minutes and collecting 500 ml fractions. The purified chroman was obtained as a pink oil (10 g, 86%). TLC: Rf=0.50 (40% ethyl acetate/hexane). 1 H NMR (CDCl3) δ6.73 (d, 1, J=8.20 Hz), 6.37 (d, 1, J=8.20 Hz), 4.78 (s(br), 1), 4.75 (m, 1), 4.25 (m, 2), 2.68 (m, 4), 2.16 (m, 2), 1.60 (m, 2), 1.29 (t, 3, J=7.07 Hz), 0.99 (t, 3, J=7.34 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: acetyl chloride With aluminum (III) chloride In dichloromethane at -10℃; for 0.25h; Stage #2: chromane In dichloromethane at -10℃; for 0.5h; Stage #3: With hydrogenchloride In dichloromethane; water at 0℃; for 2h; | 162 Alternative Preparation of Λ/-(3,4-Dihydro-2/Y-chromen-6-yl)acetamide (228). A solution of 4-chromanone (225) (14.82 g, 0.1 mol) in HOAc (50 mL) was added to a stirred suspension of Zn dust (10 eq. w/w, 148 g) in HOAc (200 mL) and the mixture stirred at 100 0C for 16 h. The mixture was cooled, filtered, washed with HOAc (3 x 100 mL) and the solvent from the combined filtrate evaporated. The residue was suspended in water (200 mL) and the suspension made basic with NaOH1 extracted with EtOAc (3 x 100 mL), the combined extracts dried and the solvent evaporated to give chroman (229) (11.83 g, 88%) as a white solid. AICI3 (11.8 g, 88.2 mmol) was added in small portions to a stirred solution of AcCI (11.9 mL, 167.5 mmol) in dry DCM (250 mL) at -10 0C and the mixture stirred until homogeneous (15 min). The solution was added, via a cannula, to a stirred solution of chroman (229) (11.8 g, 88.2 mmol) in dry DCM (200 mL) at -10 0C and the solution stirred for 30 min at -10 °C and then poured into ice/cHCI (5:1 v/v, 1.5 L). The mixture was stirred for 2 h, extracted with DCM (3 x 100 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-20%) of EtOAc/pet. ether, to give 1-(3,4-dihydro-2f/-chromen-6-yl)ethanone (230) (12.45 g, 80%) as a white solid: 1H NMR δ 7.68-7.22 (m, 2 H, H-5, H-7), 6.82 (d, J = 9.2 Hz, 1 H, H-8), 4.24 (br dd, J = 5.3, 5.2 Hz, 2 H, H 2), 2.83 (br t, J = 6.5 Hz, 2 H, H-4), 2.53 (s, 3 H, CH3), 2.00-2.06 (m, 2 H, H-3). Hydroxylamine HCI (2.9 g, 41.9 mmol) was added to a stirred solution of ketone 230 (6.15 g, 34.9 mmol) and pyridine (3.7 mL, 45.4 mmol) in MeOH (30 mL) and the mixture stirred at 20 0C for 16 h. The solvent was evaporated and the residue partitioned between brine and EtOAc. The organic fraction was dried and the solvent evaporated to give crude 1- (3,4-dihydro-2/7-chromen-6-yl)ethanone oxime (6.3 g, 94%). HCI gas was bubbled through a solution of oxime (6.3 g, 32.5 mmol) in Ac2O (6.1 mL, 65 mmol) and HOAc (40 mL, 650 mmol), and the solution stood at 20 0C for 24 h. The precipitate was poured into ice/water, stirred for 2 h, the solid filtered and washed with water and dried. The aqueous fraction was extracted with DCM (2 x 50 mL), the combined extract dried and the solvent evaporated. The slurry was treated with water (20 mL) and evaporated several times to remove Ac2O. The combined solids were purified by chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 228 (3.74 g, 59%) as a white solid: spectroscopically identical to the sample prepared above. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate In water; pentane; benzene | 2 Synthesis of 6,7-methylenedioxy-2,2-dimethyl chromene EXAMPLE 2 Synthesis of 6,7-methylenedioxy-2,2-dimethyl chromene 5.1 gm of 3-methyl-1-bromo-2-butene was combined with 4 gm of 3,4-methylenedioxyphenol and dissolved in 50 ml. of pentane and 50 ml. benzene. 2 gm of anhydrous ZnCl2 was added and the reaction mixture refluxed for 1 hour and cooled. The mixture was extracted with ether and washed successively with 100 ml. of water, 100 ml. 5% sodium carbonate and 100 ml. of saturated salt solution. After drying the extract over anhydrous sodium sulfate, the solvent was removed in vacuo leaving 7.4 g of crude chromane. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate In formic acid; water | 3 Synthesis of 6,7-dimethoxy-2-methyl-2-ethyl chromene Thus, 2 g of 3,4-dimethoxy phenol and 1.9 g of 3-methyl-1-pentene-3-ol were combined in 10 ml. formic acid with stirring at room temperature for 18 hours. Formic acid was removed in vacuo. The residue dissolved in ether was washed successively with 100 ml. of water, 100 ml. 5% sodium carbonate and 100 ml. saturated salt solution. The ether solution was dried over anhydrous sodium sulfate and gave 3.5 gm of crude product on removal of the ether in vacuo. Chromatography over Florisil gave 2.5 g of pure chromane. |
Yield | Reaction Conditions | Operation in experiment |
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With chloranil In 5,5-dimethyl-1,3-cyclohexadiene; benzene | 1 Synthesis of 6,7-dimethoxy-2,2-dimethyl-3-chromene The chromane is treated with a dehydrogenating agent such as chloranil or DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) in a suitable solvent such as benzene or xylene to introduce the double bond and give the corresponding chromene. |
Yield | Reaction Conditions | Operation in experiment |
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57% | In water; toluene | 7 2,2-Dimethyl-7-dimethylaminoethyloxy-4-(2-thienyl)chroman hydrochloride EXAMPLE 7 2,2-Dimethyl-7-dimethylaminoethyloxy-4-(2-thienyl)chroman hydrochloride Sodium hydride (0.2 g of a 60% dispersion in oil) was added to 2,2-dimethyl-4-(2-thienyl) chroman -ol (0.1 g) in dry toluene (20 ml). The solution was stirred for 10 minutes. Dimethylaminoethyl chloride (0.5 g) was added and the solution was refluxed for 3 hr. The solvent was evaporated under reduced pressure. The oil was taken up in water and ether, the aqueous layer extracted with ether and the organic layers dried over magnesium sulphate. Removal of the solvent under reduced pressure gave a yellow oil. Dissolution in dry ether and passage of dry hydrogen chloride through the solution gave the required chroman as the hydrochloride salt (0.8 g, 57%), m.p. 120°-123° C., (ethyl acetate). |
57% | In water; toluene | 7 2,2-Dimethyl-7-dimethylaminoethyloxy-4-(2-thienyl)chroman hydrochloride EXAMPLE 7 2,2-Dimethyl-7-dimethylaminoethyloxy-4-(2-thienyl)chroman hydrochloride Sodium hydride (0.2g of a 60% dispersion in oil) was added to 2,2-dimethyl-4-(2-thienyl) chroman -ol (0.1g) in dry toluene (20 ml). The solution was stirred for 10 minutes. Dimethylaminoethyl chloride (0.5g) was added and the solution was refluxed for 3 hr. The solvent was evaporated under reduced pressure. The oil was taken up in water and ether, the aqueous layer extracted with ether and the organic layers dried over magnesium sulphate. Removal of the solvent under reduced pressure gave a yellow oil. Dissolution in dry ether and passage of dry hydrogen chloride through the solution gave the required chroman as the hydrochloride salt (0.8g, 57%), m.p. 120°-123° C, (ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
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64% | In <i>N</i>-methyl-acetamide; n-heptane; water | 9 Preparation of 6-benzyloxy-2-(dimethoxymethyl)-2,5,7,8-tetramethyl-chroman STR25 EXAMPLE 9 Preparation of 6-benzyloxy-2-(dimethoxymethyl)-2,5,7,8-tetramethyl-chroman STR25 1.47 g (5.25 mmoles) of the chroman obtained in Example 8 were heated at 100° C. with 3.2 g of benzyl bromide, 1.5 g of Na2 CO3 and 7 ml of dimethylformamide for 13 hours, and water was then added. This mixture was extracted with heptane, after which the crude product obtained from the extract phase was chromatographed on 50 g of silica gel using a mixture of 1 part by volume of ether and 2 parts by volume of heptane. The following fractions were obtained: F1=1.28 g; F2 (mixed fraction)=0.13 g; F3 (starting material)=0.23 g. Fractions F1 and F2 were chromatographed again on 100 g of silica gel, the above product being obtained, in 64% yield, as white crystals of melting point 46°-48° C. |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: chromane With n-butyllithium In diethyl ether; hexane at 20℃; for 2.66667h; Heating / reflux; Stage #2: carbon dioxide In diethyl ether; hexane at 20℃; | A.4.6 At RT a solution of chroman (17.7 mmol) in ether (15 mL) is added over 10 min to a solution of n-BuLi (19.5 mmol) in a mixture of hexane (12.2 mL) and ether (15 mL). The mixture is stirred at reflux for 150 min, allowed to reach RT and poured into a mixture of dry ice and ether. Ice water is added and the layers are separated. The aq. layer is made acidic and extracted with a mixture of ether and EtOAc. The combined organic layers are washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude product which is purified by CC (heptane/EtOAc 9/1 to EtOAc). LC-MS: tR = 0.76 min; [M+CH3CN+H]+ = 220.1. | |
Stage #1: chromane With n-butyllithium In diethyl ether; hexane at 20℃; for 2.66667h; Heating / reflux; Stage #2: carbon dioxide With water In diethyl ether; hexane | 9; A.5.6 At RT a solution of chroman (17.7 mmol) in ether (15 mL) is added over 10 min to a solution of n-BuLi (19.5 mmol) in a mixture of hexane (12.2 mL) and ether (15 mL). The mixture is stirred at reflux for 150 min, allowed to reach RT and poured into a mixture of dry ice and ether. Ice water is added and the layers are separated. The aq. layer is made acidic and extracted with a mixture of ether and EtOAc. The combined organic layers are washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude product which is purified by FC (heptane/EtOAc 9/1 to EtOAc). LC-MS: tR = 0.76 min; [M+CH3CN+H]+ = 220.1. | |
Stage #1: chromane With n-butyllithium In diethyl ether; hexane at 20℃; Reflux; Stage #2: carbon dioxide With water In diethyl ether; hexane Cooling with ice; | A.3.6 At RT a solution of chroman (17.7 mmol) in ether (15 mL) is added over 10 min to a solution of n-BuLi (19.5 mmol) in a mixture of hexane (12.2 mL) and ether (15 mL). The mixture is stirred at reflux for 150 min, allowed to reach RT and poured into a mixture of dry ice and ether. Ice water is added and the layers are separated. The aq. layer is made acidic and extracted with a mixture of ether and EtOAc. The combined organic layers are washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude product which is purified by CC (heptane/EtOAc 9/1 to EtOAc). LC-MS: tR=0.76 min; [M+CH3CN+H]+=220.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With iodine; silver nitrate In methanol for 1h; | 11.2 Step 2:AgNO3 (12.0 g, 70.6 mmol) and I2 (15.8 g, 62.3 mmol) are added sequentially to a solution of 11b (8.45 g, 63.0 mmol) dissolved in MeOH (225 mL). The reaction is allowed to stir for 1 h, filtered on Celite and the filtrate concentrated under reduced pressure. The crude mixture is diluted with EtOAc (250 mL) and washed with saturated sodium thiosulfate (250 mL). The organic layer is washed with water (200 mL) and then dried over Na2SO4, filtered and concentrated. The crude mixture is further purified by CombiFlash Companion to give 6-iodochroman 11c (12.1 g, 74% yield). |
74% | With iodine; silver nitrate In methanol for 1h; | 11.2 AgNO3 (12.0 g, 70.6 mmol) and I2.(15.8 g, 62.3 mmol) are added sequentially to a solution of 11b (8.45 g, 63.0 mmol) dissolved in MeOH (225 ml_). The reaction is allowed to stir for about 1 h, filtered on Celite and the filtrate concentrated under reduced pressure. The crude mixture is diluted with EtOAc (250 mL) and washed with saturated sodium thiosulfate (250 mL). The organic layer is washed with water (200 mL) and then dried over Na2SO4, filtered and concentrated. The crude mixture is further purified by CombiFlash Companion to give 6-iodochroman 11c (12.1 g, 74% yield). |
74% | With iodine; silver nitrate In methanol for 1h; | 11.2 AgNO3 (12 0 g, 70 6 mmol) and I2 (15 8 g, 62 3 mmol) are added sequentially to a solution of 11b (8 45 g, 63 0 mmol) dissolved in MeOH (225 mL) The reaction is allowed to stir for 1 h, filtered on Celite and the filtrate concentrated under reduced pressure The crude mixture is diluted with EtOAc (250 mL) and washed with saturated sodium thiosulfate (250 mL) The organic layer is washed with water (200 mL) and then dried over Na2SO4, filtered and concentrated The crude mixture is further purified by CombiFlash Companion to give 6-ιodochroman 11c (12 1 g, 74% yield) |
74% | With iodine; silver nitrate In methanol for 1h; | 11.2 AgNO3 (12.0 g, 70.6 mmol) and I2 (15.8 g, 62.3 mmol) are added sequentially to a solution of 11b (8.45 g, 63.0 mmol) dissolved in MeOH (225 mL). The reaction is allowed to stir for 1 h, filtered on Celite and the filtrate concentrated under reduced pressure. The crude mixture is diluted with EtOAc (250 mL) and washed with saturated sodium thiosulfate (250 mL). The organic layer is washed with water (200 mL) and then dried over Na2SO4, filtered and concentrated. The crude mixture is further purified by CombiFlash Companion to give 6-iodochroman 11c (12.1 g, 74% yield). |
With iodine; silver nitrate In methanol for 1h; | 27.A A solution of chroman-4-one (10 g, 67.5 mmol) in acetic acid (20 mL) was added to a suspension of zinc dust (1 10g, 1687 mmol) in acetic acid (150 mL). The mixture was heated to 100 °C overnight with mechanical stirring. 1 H NMR indicated complete conversion to the desired product. Then the reaction mixture was cooled to ambient temperature, filtered through a pad of Celite and washed with a mixture of 200mL ethyl acetate and 600mL toluene. The filtrate was concentrated and dried in vacuo to afford crude chroman which was used without further purification. 1H NMR (400MHz, CHLOROFORM-d) δ ppm 6.82 (d, J = 12.3 Hz, 4 H), 4.29 - 4.09 (m, 2 H), 2.80 (t, J = 6.5Hz, 2 H), 2.08 - 1.94 (m, 2 H), 2.08 - 1.94 (m, 2 H). A solution of crude chroman in MeOH (200 mL) was treated with AgN03 (12.84g, 76 mmol) and l2(15.42g, 60.7 mmol) . After one hour, the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous Na2S203, water and brine, dried over Na2S04, filtered and concentrated. The residue was purified on silica gel (0%~30% EA-hexane) to afford 6-iodocharoman (13.8 g, 53.1 mmol, 79% yield) as a yellow oil. 1 H NMR (400MHz, CHLOROFORM-d) δ ppm 7.52 - 7.30 (m, 2 H), 6.65 - 6.51 (m, 1 H), 4.20 - 4.16 (m, 2 H), 2.76 (t, J = 6.5 Hz, 2 H), 2.02 - 1 .97 (m, 2 H). | |
Multi-step reaction with 2 steps 1: 0.67 h / 0 °C / Inert atmosphere 2: potassium iodide / 1,2-dichloro-ethane / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
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82% | With sodium hydride In N,N-dimethyl-formamide at 80℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
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84% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 95℃; for 5h; | A solution of the 6-iodochroman 11c (1.0 g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for an additional 5 min before being heated to 950C for 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84% yield). |
Yield | Reaction Conditions | Operation in experiment |
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1: 53% 2: 11% | With 1,3-Diiodo-5,5-dimethyl-2,4-imidazolidinedione In ethyl acetate at 40℃; for 9h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
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With aluminum (III) chloride In dichloromethane at 0 - 20℃; | 54-56.I To a stirred solution of 2-bromo-5-iodobenzoic acid (1.0 g, 3.06 mmol) in DCM (5 mL) was added DMF (0.2 mL) and oxalyl chloride (0.44 mL, 4.59 mmol) at 0 °C. After complete addition, the reaction mixture was stirred at room temperature for 3h. The volatiles were evaporated under reduced pressure, and the crude product was dissolved in DCM (4 mL) and added to chroman (488 mg, 3.67 mmol) which had been cooled to 0°C. To this mixture was added aluminum chloride (488 mg, 3.67 mmol) in portions. After stirring for 4 h, the reaction was quenched by pouring it into crushed ice. This was extracted with dichloromethane (50 mL X 2). The dichloromethane layers were combined and washed with water (20 mL), saturated aqueous sodium bicarbonate solution (20 mL X 2), and brine (20 mL), then dried over sodium sulfate, andconcentrated. The crude product was purified by column chromatography to furnish (2- bromo-5-iodo-phenyl)-chroman-6-yl-methanone (1.2 g). |
Yield | Reaction Conditions | Operation in experiment |
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Examples 54-56; Step I. To a stirred solution of <strong>[25252-00-0]2-bromo-5-iodobenzoic acid</strong> (1.0 g, 3.06 mmol) in DCM (5 mL) was added DMF (0.2 mL) and oxalyl chloride (0.44 mL, 4.59 mmol) at 0 C. After complete addition, the reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure, and the crude product was dissolved in DCM (4 mL) and added to chroman (488 mg, 3.67 mmol) which had been cooled to 0 C. To this mixture was added aluminum chloride (488 mg, 3.67 mmol) in portions. After stirring for 4 h, the reaction was quenched by pouring it into crushed ice. This was extracted with dichloromethane (50 mL×2): The dichloromethane layers were combined and washed with water (20 mL), saturated aqueous sodium bicarbonate solution (20 mL×2), and brine (20 mL), then dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to furnish (2-bromo-5-iodo-phenyl)-chroman-6-yl-methanone (1.2 g). |
Yield | Reaction Conditions | Operation in experiment |
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35% | In dichloromethane for 3h; | 9.2 Step 2: Preparation of intermediate 2-chloro-1 -(3,4-dihydro-2/-/-1 -benzopyran-6- yl)ethan-1 -one (9b)Aluminium chloride (III) (1 .9 g, 14.25 mmol) was added portion wise at 0°C to a solution of 3,4-dihydro-2H-1 -benzopyran (9a) (450 mg, 3.35 mmol) and 2-chloroacetyl chloride (270 μΙ_, 3.4 mmol) in dichloromethane (10 mL). After 3 hours, the mixture was quenched by a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/cyclohexane 40/60) to afford the desired product (9b) as a white yellow oil (250 mg, 1 .19 mmol, 35%). 1H NMR (400 MHz, CDCI3) 2.00-2.08 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 4.23-4.29 (m, 2H), 6.84 (d, J = 9 Hz, 1 H), 7.68-7.73 (m, 2H).MS m/z ([M+H]+) 21 1 . |
Yield | Reaction Conditions | Operation in experiment |
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With methanol; palladium 10% on activated carbon; hydrogen; potassium carbonate at 65℃; for 24h; | 4 4.2. General procedure for the N-tosylhydrazine mediated reductive deoxygenation of aldehydes and ketones with Pd/C-H2. General procedure: The aldehyde or ketone (0.5mmol), N-tosylhydrazine (98mg, 1.05equiv), and MeOH (10mL) were placed in a 50mL two-necked round bottle equipped with magnetic stirring bar and condenser. The reaction was heated at 60°C until aldehyde or ketone was completely consumed. (For diarylmethanones, the preparation of corresponding N-tosylhydrazones often need 1mol% TsOH·H2O as catalyst.) After cooling to the room temperature, 10% w/w of Pd/C (26.5mg, 5mol%) and K2CO3 (276mg, 4equiv) were added. The mixture was degassed by ‘pump-freeze-thaw’ cycles (×3) and flushed with hydrogen. The resulting solution was heated at 65°C for 24h under 1atm of hydrogen atmosphere. Resulting product mixture was filtered through a short path of silica gel, eluting with ethyl acetate. The volatile compounds were removed in vacuo and the crude residue was purified by column chromatography (SiO2, hexane) or analyzed by GC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With palladium on activated charcoal; hydrogen In methanol at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With Co(dmgBF<SUB>2</SUB>)<SUB>2</SUB>(CH<SUB>3</SUB>CN)<SUB>2</SUB>; 3-cyano-N-methyl-quinolinium perchlorate In acetonitrile at 20℃; Sealed tube; Inert atmosphere; Irradiation; High pressure; | |
Multi-step reaction with 2 steps 1: 100 °C 2: fac-tris(2-phenylpyridinato-N,C2')iridium(III); pyridine / acetonitrile / 1 h / 30 °C / Inert atmosphere; Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chlorosulfonic acid In chloroform at 0℃; for 1h; | 1.3 Step 3 The chroman was mixed with chloroform and chlorosulfuric acid was added at 0° C., the chroman to chlorosulphonic acid molar ratio was 1:2, and the temperature was reacted for 1 hour to produce chroman- 6-sulfonyl chloride. The reaction solution was diluted with ice water and then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by column to give product chroman-6-sulfonyl chloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: chromane With tellurium tetrachloride at 120℃; for 0.5h; Inert atmosphere; Stage #2: With sodium tetrahydroborate In ethanol at 20℃; Stage #3: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With trimethylsilylazide; copper diacetate; (S,S)-4,4'-bis(phenylmethyl)-2,2',5,5'-tetrahydro-2,2'-bioxazole; N-fluorobis(benzenesulfon)imide In nitromethane at 30℃; for 24h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With C18H26Br2N2Ni; zinc In toluene at 80℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With palladium on activated charcoal; hydrogen In methanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35 %Spectr. | With diisopropyl hydrogenphosphonate; copper (I) acetate; 4,4′,5,5′-Tetrahydro-2,2′-bioxazole; N-fluorobis(benzenesulfon)imide In acetonitrile at 30℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With 9‑mesityl-10-methylacridinium perchlorate In dichloromethane at 20℃; for 5h; Irradiation; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% ee | With tetrakis(acetonitrile)copper(I)tetrafluoroborate; N-(tert-butyl)-N-fluoro-4-(trifluoromethyl)benzenesulfonamide; N-(2-((3aR,8aS)-3a,8a-dihydro-8H-indeno[1,2-d]oxazol-2-yl)-3-(trifluoromethyl)phenyl)-2-(diphenylphosphanyl)benzamide; caesium carbonate In chlorobenzene at 0℃; Schlenk technique; Inert atmosphere; Overall yield = 59 percent; Overall yield = 15.5 mg; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nickel(II) bromide dimethoxyethane; (3aR,3a’R,8aS,8a’S)-2,2’-(cyclopropane-1,1-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]-oxazole); [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; potassium carbonate In ethyl acetate at 15℃; for 24h; Irradiation; | ||
With nickel(II) bromide dimethoxyethane; (3aR,3a’R,8aS,8a’S)-2,2’-(cyclopropane-1,1-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]-oxazole); [Ir(dF(CF3)ppy)2(dtbbpy)]Cl; potassium carbonate In 1,4-dioxane at 25℃; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nickel(II) bromide dimethoxyethane; (3aR,3a’R,8aS,8a’S)-2,2’-(cyclopropane-1,1-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]-oxazole); [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; potassium carbonate In ethyl acetate at 15℃; for 24h; Irradiation; |
Tags: 493-08-3 synthesis path| 493-08-3 SDS| 493-08-3 COA| 493-08-3 purity| 493-08-3 application| 493-08-3 NMR| 493-08-3 COA| 493-08-3 structure
[ 32337-93-2 ]
2,3,4,5-Tetrahydrobenzo[b]oxepin-7-ol
Similarity: 0.93
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