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CAS No. : | 491-37-2 | MDL No. : | MFCD00006840 |
Formula : | C9H8O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MSTDXOZUKAQDRL-UHFFFAOYSA-N |
M.W : | 148.16 | Pubchem ID : | 68110 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 41.01 |
TPSA : | 26.3 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) : | -6.22 cm/s |
Log Po/w (iLOGP) : | 1.76 |
Log Po/w (XLOGP3) : | 1.38 |
Log Po/w (WLOGP) : | 1.65 |
Log Po/w (MLOGP) : | 1.05 |
Log Po/w (SILICOS-IT) : | 2.46 |
Consensus Log Po/w : | 1.66 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.03 |
Solubility : | 1.38 mg/ml ; 0.0093 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.54 |
Solubility : | 4.32 mg/ml ; 0.0291 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.84 |
Solubility : | 0.216 mg/ml ; 0.00146 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.81 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319 | 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 |
---|---|---|
62% | Stage #1: at 20℃; for 0.166667 h; Stage #2: at 0 - 80℃; for 0.333333 h; |
To mechanically stirred neat aluminum trichloride (18.0 g, 135 mmol, 2.50 equiv) was added 4-chromanone (8.00 g, 54.0 mmol) portionwise at room temperature. The resulting brown oil was stirred for 10 minutes and bromine (3.34 mL, 65.8 mmol, 1.20 equiv) was added portionwise. The mixture was stirred for 10 minutes, heated to 80 C for 10 minutes, cooled to 0 C and quenched with careful addition of ice. The mixture was then diluted with ether and water, the organic layer was washed with 1M hydrochloric acid (3x), brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified on a 40M Biotage column (0 to 10percent ethyl acetate in hexanes over 30 minutes) to give 7.61 g of 6-BROMO-CHROMAN-4-ONE (Yield: 62percent). The isolated product contains 21percent DIBROMIDE. HL NMR (400 MHz, CDC13) : 8 2.80 (t, 2H), 4.53 (t, 2H), 6.85 (d, 1H), 7.53 (dd, 1H), 7.98 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | at 0℃; for 2 h; | /V-(3,4-Dihydro-2W-chromen-6-yl)acetamide (228). A solution of KNO3 (2.25 g, 22.3 mmol) in CH2SO4 (10 mL) was added dropwise to a stirred solution of 4-chromanone (225) (3.0 g, 20.2 mmol) in CH2SO4 (50 mL) at 0 0C and the mixture stirred at 0 0C for 2 h. The mixture was poured into ice/water (500 mL), stirred 30 min and the precipitate filtered. The solid was washed with water (3 x 10 mL) and dried. The solid was purified by chromatography, eluting with 20percent EtOAc/pet. ether, to give (i) 8-nitro-2,3-dihydro-4/-/- chromen-4-one (226) (369 mg, 9percent) as a white solid: mp (EtOAc/pet. ether) 120-121 0C; 1H NMR δ 8.17 (dd, J = 7.8, 1.8 Hz, 1 H, H-7), 8.10 (dd, J = 8.0, 1.8 Hz, 1 H, H-5), 7.12 (dd, J = 8.0, 7.8 Hz, 1 H, H-6), 4.73 (dd, J = 6.5, 6.4 Hz, 2 H, H-2), 2.95 (br t, J = 6.5 Hz, 2 H, H-3). Anal, calcd for C9H7NO4: C, 56.0; H, 3.7; N, 7.3. Found: C, 56.1; H, 3.7; N, 7.3percent; and (ii) 6-nitro-2,3-dihydro-4/-/-chromen-4-one (227) (3.17 g, 81percent) as a white solid: mp (EtOAc/pet. ether) 169-171 0C; 1H NMR δ 8.78 (d, J = 2.8 Hz, 1 H, H-5), 8.32 (dd, J = 9.1, 2.8 Hz, 1 H, H-7), 7.11 (d, J = 9.1 Hz, 1 H, H-8), 4.67 (dd, J = 6.6, 6.4 Hz, 2 H, H-2), 2.91 (dd, J = 6.6, 6.4 Hz, 2 H, H-3); 13C NMR δ 189.4, 165.7, 142.1, 130.3, 123.7, 120.8, 119.3, 67.6, 37.1. Anal, calcd for C9H7NO4: C, 56.0; H, 3.7; N, 7.3. Found: C, 56.1; H, 3.7; N, 7.4percent.A mixture of nitrochromanone 227 (2.0 g, 13.4 mmol) and Pd/C (5percent, 100 mg) in EtOH/EtOAc (4:1, 150 mL), water (10 mL), and cHCI (1 mL) was stirred under H2 (60 psi) for 16 h. The mixture was filtered through celite, washed with EtOH (3 x 25 mL) and the solvent evaporated. The residue was partitioned between dilute aqueous NH3 solution and DCM, the organic fraction dried, and the solvent evaporated. The residue was dissolved in dry dioxane (100 mL) and Ac2O (2.8 mL, 29.4 mmol) added dropwise. The solution was stirred at 20 0C for 16 h, diluted with water and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (50-100percent) of EtOAc/pet. ether, to give acetamide 228 (2.09 g, 70percent) as a white solid: mp 111-113 0C [lit. (Hach, V. Coll. Czech. Chem. Commun. 1959, 24, 3136-3140) mp (EtOH) 118 0C]; 1H NMR δ 7.28 (d, J = 2.2 Hz, 1 H, H-5), 7.02 (dd, J = 8.6, 2.2 Hz, 1 H, H-7), 6.72 (d, J = 8.6 Hz, 1 H, H-8), 4.15 (br dd, J = 5.2, 5.0 Hz, 2 H, H-2), 2.77 (br t, J = 6.5 Hz, 2 H, H-4), 2.13 (s, 3 H, CH3), 1.95- 2.02 (m, 2 H, H-3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.2% | Stage #1: at 50 - 200℃; for 0.333333 h; Stage #2: at 0℃; for 0.5 h; |
37.0 g (278 mmol) of aluminum chloride was mixed with 3.70 g (61.3 mmol) of sodium chloride, the mixture was dissolved at 150C under heating, 6.40 g (43.2 mmol) of commercially available 2,3-dihydro-4H-chromen-4-one dissolved by heating (50C) was added to the mixture and the resulting mixture was stirred at 200C for 20 minutes. The reaction mixture (gum state) was cooled, and added to ice-cold hydrochloric acid (100 ml of conc. hydrochloric acid and ice were combined to make them 200 ml) little by little and stirred for 30 minutes. Methylene chloride was added to the mixture and the mixture was separated. The aqueous layer was filtered, and the filtrate was extracted with methylene chloride. The organic layers were combined, washed successively with water and brine, and dried over sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) to obtain 4.82 g (32.6 mmol, Yield: 75.2percent) of 7-hydroxy-1-indanone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: With titanium(IV) isopropylate; ammonia In ethanol at 20℃; for 6 h; Stage #2: With sodium tetrahydroborate In ethanol at 0 - 20℃; for 3.16 h; |
Chroman-4-amine :; Chroman-4-one (3 g, 20.1 mmol), titanium(IV) isopropoxide (12.0 niL, 40.2 mmol) and2 M solution of ammonia in ethanol (60.6 mL, 121.2 mmol) were stirred at room temperature for 6 h. The reaction was cooled to 0 °C and sodium borohydride was added portionwise during 10 min. (1.14 g, 30.2 mmol); the resultant mixture was stirred at rt for an additional 3 h. The reaction was quenched by pouring it into ammonium hydroxide (2 M, 60 mL), the precipitate that formed was filtered off and washed with ethyl acetate (15 mL x 3). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (15 mL x 2). The combined organic extracts were washed with 1 M HCl (25 mL). The acidic aqueous extracts were washed with ethyl acetate (50 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10-12, and extracted with ethyl acetate (40 mL x 3). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo to affordChroman-4-amine as an oil (2.61 g, 87 percent yield). 1H NMR (400 MHz, CDCl3) δ 7.31 (d, IH), 7.23 (m, IH), 6.94 (m, IH), 6.82 (d, IH), 4. 38 (m, 2H), 4.12 (m, IH), 2.19 (m, 2H), 1.82 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: for 0.283333 h; Stage #2: at 20℃; for 1 h; |
7-Bromo-4-chromanone. Into a round bottom flask kept at 0° C., AlCl3 (0.533 g, 3.99 mmol) and, 5 mL of CH2Cl2 was added. The reaction system was put under nitrogen and stirred for about 7 minutes before adding 10 mL of a CH2Cl2 solution of 4-chromanone (0.296 g, 1.99 mmol). After the reaction mixture was stirred for 10 minutes, 10 mL of Br2 (0.352 g, 2.20 mmol) was added and, the reaction mixture was stirred at room temperature for an hour. At the end of this period of time, the reaction mixture was poured into 30 mL of ice-water and, the product was extracted 3 times from the aqueous phase with EtOAc. The resultant organic phase was washed once with brine and dried under Na2SO4. After the solvent was evaporated, the solid formed was filtered and dried to obtain 0.361 g (1.51 mmol) of the product (93percent pure) in a 74percent yield. 1H NMR (300 MHz, CDCl3, δ): 7.90 (dd, J=2.6, 0.3 ArH, 1H,), 7.47 (dd, J=8.8, 2.5, Ar, 1H,), 6.82 (dd, J=8.8, 0.2, Ar, 1H), 4.48 (t, J=6.5, C2, 2H), 2.75 (t, J=6.5, C2, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrogenchloride In acetic acid at 0℃; for 24h; | |
90% | With piperidine at 100℃; for 2h; | General Procedure for Preparation of (3E)- 3-Benzylidene-2,3-dihydro-4H-1-benzopyran-4-one Derivatives(3-20) General procedure: A mixture of the corresponding 4-chromanone (1,1.0 mmol), substituted benzaldehyde (2, 1.2 mmol) and piperidine(1.2 mmol) was heated at 100°C until complete disappearanceof 4-chromanone. After the reaction mixture wasdiluted with ice-water and acidified with conc. HCl, the wholewas extracted with AcOEt. The combined organic layer waswashed with brine. The organic layer was dried over Na2SO4and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane-AcOEt system) to give the corresponding (3E)-3-benzylidene-2,3-dihydro-4H-1-benzopyran-4-one derivatives. (3E)-2,3-Dihydro-3-(phenylmetylene)-4H-1-benzopyran-4-one (3)Yield 90%. Colorless crystal. mp 110°C (lit. 111°C22)).1H-NMR (CDCl3, 400 MHz) δ: 8.03 (1H, dd, J=7.9, 1.8 Hz,H-5), 7.88 (1H, br s, CH), 7.49 (1H, ddd, J=8.4, 7.2, 1.8 Hz,H-7), 7.47-7.40 (3H, m, Ph), 7.33-7.30 (2H, m, Ph), 7.07 (1H,ddd, J=7.9, 7.2, 1.0 Hz, H-6), 6.97 (1H, dd, J=8.4, 1.0 Hz,H-8), 5.36 (2H, d, J=1.9 Hz, H-2). MS (EI) m/z: 236 [M]+. The1H-NMR spectrum was similar to that previously reported.22) |
89% | With aluminum oxide for 0.0666667h; Microwave irradiation; neat (no solvent); |
89% | With barium(II) hydroxide at 20℃; for 0.166667h; | |
85% | With sulfuric acid In acetic acid at 20℃; for 0.333333h; | |
85% | With piperidine at 130℃; for 5h; | 3.2. Synthesis of (E)-3-(4-methoxybenzylidene)-2-phenylchroman-4-one (1) General procedure: Amixture of 0.01 mol (2.243 g) 2-phenylchroman-4-one, 0.01 mol (1.362 g) 4-methoxy-benzaldehydeand five drops of piperidine were heated in oil bath with mechanical stirring at 130 °C for five hours.The progress of the reaction was tested by TLC (toluene:methanol 9:1). The mixture was left to coolat room temperature and dissolved in methanol. After 24 h, the compound was precipitated andthen purified by crystallization from methanol. The compound 1 was obtained as a white powder. |
82% | With sulfuric acid; acetic acid at 20℃; Inert atmosphere; | |
79% | With hydrogenchloride In methanol; water for 24h; Reflux; | 4.2. General procedure for the synthesis of 3-benzylidene-4-chromanones derivatives General procedure: A round-bottom flask was charged with the 4-chromanone (3.4 mmol) and aromatic-aldehyde (3.6 mmol). This was dissolved in methanol (20 mL), and concentrated hydrochloride (10 mL). The mixture was refluxed for 24 h and then diluted with water. Filtration afforded the crude product, which was crystallized from methanol to give the pure product. |
78% | With hydrogenchloride In ethanol for 4h; Heating; | |
76.2% | With 1-butyl-3-methylimidazolium trifluoroacetate In ethanol for 0.0666667h; Microwave irradiation; | |
73.1% | With hydrogenchloride In ethanol for 0.25h; | |
70% | With sulfuric acid In acetic acid for 24h; | |
70% | With sulfuric acid In acetic acid for 24h; Ambient temperature; | |
With potassium acetate at 120℃; | ||
With hydrogenchloride; ethanol Erhitzen des Reaktionsprodukts bis zum Schmelzpunkt; | ||
With hydrogenchloride; ethanol Behandeln des Reaktionsprodukts mit wss.-aethanol. Natronlauge; | ||
With potassium alcoholate In ethanol | ||
With phosphoric acid In water at 80℃; for 6h; | ||
With sodium hydroxide In ethanol; water at 0℃; for 0.5h; | ||
With piperidine at 150℃; | ||
With piperidine at 140℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogenchloride In acetic acid at 0℃; for 24h; | |
88% | With sulfuric acid In acetic acid at 20℃; for 0.333333h; | |
85% | With aluminum oxide for 0.0833333h; Microwave irradiation; neat (no solvent); |
81% | With hydrogenchloride In methanol; water for 24h; Reflux; | |
80% | With piperidine at 100℃; for 2h; | General Procedure for Preparation of (3E)- 3-Benzylidene-2,3-dihydro-4H-1-benzopyran-4-one Derivatives(3-20) General procedure: A mixture of the corresponding 4-chromanone (1,1.0 mmol), substituted benzaldehyde (2, 1.2 mmol) and piperidine(1.2 mmol) was heated at 100°C until complete disappearanceof 4-chromanone. After the reaction mixture wasdiluted with ice-water and acidified with conc. HCl, the wholewas extracted with AcOEt. The combined organic layer waswashed with brine. The organic layer was dried over Na2SO4and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane-AcOEt system) to give the corresponding (3E)-3-benzylidene-2,3-dihydro-4H-1-benzopyran-4-one derivatives. |
80% | With potassium hydroxide In methanol at 20℃; Cooling with ice; | |
72% | With piperidine | |
72.1% | With 1-butyl-3-methylimidazolium trifluoroacetate In ethanol for 0.0666667h; Microwave irradiation; | |
71.8% | With hydrogenchloride In ethanol for 24h; Ambient temperature; | |
71.8% | With hydrogenchloride In ethanol for 0.25h; | |
69% | With hydrogenchloride In methanol; water for 24h; Reflux; | 4.2. General procedure for the synthesis of 3-benzylidene-4-chromanones derivatives General procedure: A round-bottom flask was charged with the 4-chromanone (3.4 mmol) and aromatic-aldehyde (3.6 mmol). This was dissolved in methanol (20 mL), and concentrated hydrochloride (10 mL). The mixture was refluxed for 24 h and then diluted with water. Filtration afforded the crude product, which was crystallized from methanol to give the pure product. |
55% | With piperidine at 150℃; for 4h; | 3.4. Synthesis of (E)-3-(4-methoxybenzylidene)chroman-4-one (3) A mechanically-stirred mixture of 0.01 mol (1.481 g) of chroman-4-one, 0.01 mol (1.362 g) ofp-methoxybenzaldehyde and five drops of piperidine were heated at 150 °C in an oil bath for fourhours. After cooling, the reaction mixture was left for 24 h at room temperature. The solidified productwas filtered and crystallized from methanol. Compound 3 was obtained as a cream-colored powder.Yield: 55% m.p: 133.8-134.85 °C. MS (ESI+): m/z 267.5 C17H14O3 [M + H]+. IR (KBr) ν(cm1): 3038,3000 (C-H aromat.), 2958, 2866 (C-H aliph.), 1665 (C=O), 1603, 1568, 1510, 1477,1463 (C=C), 1146(C-O-C), 1112 (C-O). 1H-NMR (CDCl3) δ (ppm): 1.58 (3H, s, OCH3), 3.87 (1H, s, =CH), 5.38 (2H, d,JAB = 16.60 Hz C2-H), 6.96-8.03 (8H, m, C-H aromat.) (see Figure S6). 13C-NMR (CDCl3) δ (ppm):55.5 (OCH3), 67.8 (CH2), 114.3, 117.9, 127.0, 127.9, 128.9 (CHarom, =CH), 121.9, 132.1, 135.7, 137.4,160.1(Carom), 182.3 (C=O) (see Figure S6a). Anal. Calc. For C17H14O3 (M = 366.30 g/mol) %C: 76.67;%H: 5.25. Found %C: 76.68; %H: 5.20. |
33% | With sodium hydroxide In ethanol; water at 20℃; for 10h; Inert atmosphere; | |
With hydrogenchloride; ethanol | ||
With piperidine at 105℃; for 1h; | ||
With hydrogenchloride Reflux; | ||
With piperidine at 150℃; | ||
With piperidine at 140℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sulfuric acid In acetic acid at 20℃; for 0.333333h; | |
65% | With piperidine at 100℃; for 2h; | General Procedure for Preparation of (3E)- 3-Benzylidene-2,3-dihydro-4H-1-benzopyran-4-one Derivatives(3-20) General procedure: A mixture of the corresponding 4-chromanone (1,1.0 mmol), substituted benzaldehyde (2, 1.2 mmol) and piperidine(1.2 mmol) was heated at 100°C until complete disappearanceof 4-chromanone. After the reaction mixture wasdiluted with ice-water and acidified with conc. HCl, the wholewas extracted with AcOEt. The combined organic layer waswashed with brine. The organic layer was dried over Na2SO4and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane-AcOEt system) to give the corresponding (3E)-3-benzylidene-2,3-dihydro-4H-1-benzopyran-4-one derivatives. |
59.6% | With hydrogenchloride In ethanol for 24h; Ambient temperature; |
59.6% | With hydrogenchloride In ethanol for 0.25h; | |
With hydrogenchloride; ethanol | ||
With hydrogenchloride Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; Stage #2: iodomethane In tetrahydrofuran at -78 - 0℃; Further stages.; | |
70% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; for 0.333333h; Stage #2: iodomethane In tetrahydrofuran at 20℃; for 6h; Further stages.; | |
45% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -40℃; for 2h; Inert atmosphere; Stage #2: iodomethane In tetrahydrofuran at -40 - 20℃; Inert atmosphere; |
30% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.666667h; Inert atmosphere; Stage #2: iodomethane In tetrahydrofuran at -78 - 20℃; for 1h; Inert atmosphere; | 15.1 Step 1 Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,3-dihydro-1-benzopyran-4-one (15.0 g, 101.24 mmol, 1.00 equiv) and THF (200.0 mL). This was followed by the addition of LiHMDS (121.5 mL, 121.48 mmol, 1.20 equiv) dropwise with stirring at -78 °C. The resulting solution was stirred for 40 min at -78 °C. To this was added a solution of MeI (17.2 g, 121.49 mmol, 1.20 equiv) in THF (10 mL) dropwise with stirring at -78 °C. The resulting solution was allowed to react, with stirring, for an additional 1 h at 25 °C. The reaction was then quenched by the addition of 150 mL of Sat. NH4Cl. The resulting solution was extracted with 2x150 mL of EtOAc, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 5 g (30%) of 3-methyl-2,3-dihydro-1- benzopyran-4-one as light yellow oil. |
30% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.666667h; Inert atmosphere; Stage #2: iodomethane In tetrahydrofuran at -78 - 20℃; for 1h; Inert atmosphere; | 15.1 Step 1 Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,3-dihydro-1-benzopyran-4-one (15.0 g, 101.24 mmol, 1.00 equiv) and THF (200.0 mL). This was followed by the addition of LiHMDS (121.5 mL, 121.48 mmol, 1.20 equiv) dropwise with stirring at -78 °C. The resulting solution was stirred for 40 min at -78 °C. To this was added a solution of MeI (17.2 g, 121.49 mmol, 1.20 equiv) in THF (10 mL) dropwise with stirring at -78 °C. The resulting solution was allowed to react, with stirring, for an additional 1 h at 25 °C. The reaction was then quenched by the addition of 150 mL of Sat. NH4Cl. The resulting solution was extracted with 2x150 mL of EtOAc, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 5 g (30%) of 3-methyl-2,3-dihydro-1- benzopyran-4-one as light yellow oil. |
30% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.666667h; Inert atmosphere; Stage #2: iodomethane In tetrahydrofuran at -78 - 20℃; for 1h; Inert atmosphere; | 15.1 Step 1 Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,3-dihydro-1-benzopyran-4-one (15.0 g, 101.24 mmol, 1.00 equiv) and THF (200.0 mL). This was followed by the addition of LiHMDS (121.5 mL, 121.48 mmol, 1.20 equiv) dropwise with stirring at -78 °C. The resulting solution was stirred for 40 min at -78 °C. To this was added a solution of MeI (17.2 g, 121.49 mmol, 1.20 equiv) in THF (10 mL) dropwise with stirring at -78 °C. The resulting solution was allowed to react, with stirring, for an additional 1 h at 25 °C. The reaction was then quenched by the addition of 150 mL of Sat. NH4Cl. The resulting solution was extracted with 2x150 mL of EtOAc, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 5 g (30%) of 3-methyl-2,3-dihydro-1- benzopyran-4-one as light yellow oil. |
25% | With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; | |
With diethyl ether; sodium tert-pentylate; xylene | ||
Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.666667h; Inert atmosphere; Stage #2: iodomethane In tetrahydrofuran at -78 - 25℃; for 1h; Inert atmosphere; | 65.1 Example 65:(E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide Step 1: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,3-dihydro-1-benzopyran-4-one (15.00 g, 101.24 mmol, 1.00 equiv) and THF (200 mL). This was followed by the addition of LiHMDS (1 M inTHF, 1.20 equiv) dropwise with stirring at -78. The resulting solution was stirred for 40 min at -78. To this was added a solution of MeI (17.24 g, 121.49 mmol, 1.20 equiv) in THF (10 mL) dropwise with stirring at -78. The resulting solution was allowed to react, with stirring, for an additional 40 min at -78. Then stirred for an additional 1 h at 25. The reaction was then quenched by the addition of 150 mL of NH4Cl. The resulting solution was extracted with 2x150 mL of ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 5 g (30% yield) of 3-methyl-2,3-dihydro-1-benzopyran-4-one as a light yellow oil. | |
Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.666667h; Inert atmosphere; Stage #2: iodomethane In tetrahydrofuran at -78 - 25℃; for 1h; Inert atmosphere; | 65.1 Example 65:(E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide Step 1: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,3-dihydro-1-benzopyran-4-one (15.00 g, 101.24 mmol, 1.00 equiv) and THF (200 mL). This was followed by the addition of LiHMDS (1 M inTHF, 1.20 equiv) dropwise with stirring at -78. The resulting solution was stirred for 40 min at -78. To this was added a solution of MeI (17.24 g, 121.49 mmol, 1.20 equiv) in THF (10 mL) dropwise with stirring at -78. The resulting solution was allowed to react, with stirring, for an additional 40 min at -78. Then stirred for an additional 1 h at 25. The reaction was then quenched by the addition of 150 mL of NH4Cl. The resulting solution was extracted with 2x150 mL of ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 5 g (30% yield) of 3-methyl-2,3-dihydro-1-benzopyran-4-one as a light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 2-chloroanthracene-9,10-dione; cobalt(II) diacetate tetrahydrate; butane-2,3-dione dioxime In 1,2-dichloro-ethane at 20 - 30℃; for 36h; Irradiation; Schlenk technique; Sealed tube; Inert atmosphere; | |
96% | With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide In decane; water at 80℃; Green chemistry; | General procedure for the synthesisof 4H-chromen-4-one General procedure: An oven-dried 50 cm3 round bottom flask equipped witha magnetic stir bar was charged with chromanone 1a(0.7 mmol), n-Bu4NI [33, 34] (30 mol %), and aqueous solutionof TBHP (5-6 M in decane, 4 equiv.) at room temperature.The reaction mixture was then refluxed at 80 °C for 5 h.The progress of the reaction was monitored by TLC. Afterthe completion of the reaction, the reaction mixture wasadmixed with ethyl acetate and transferred into a separating funnel. The ethyl acetate layer was sequentially washed with5% solution of sodium bicarbonate and brine solution. Thecombined organic layer was dried over anhydrous Na2SO4,filtered and concentrated in vacuum. The resulting residuewas purified over a column of silica gel (100-200 mesh) togive 2a-2s with petroleum ether/ethyl acetate as the eluent. |
94% | With sulfuric acid; iodine; dimethyl sulfoxide at 100℃; for 1h; or without H2SO4; |
94% | With sulfuric acid; iodine; dimethyl sulfoxide at 100℃; for 1h; or without H2SO4; oxidation of other chromanones; | |
92% | With iron(III) chloride; 1,10-Phenanthroline; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In chlorobenzene at 120℃; for 24h; Inert atmosphere; Schlenk technique; | |
90% | With thallium(III) toluene-p-sulfonate In acetonitrile for 1h; Heating; | |
84% | With hydroxy(tosyloxy)iodobenzene; toluene-4-sulfonic acid In acetonitrile at 45℃; for 0.166667h; Irradiation; | |
84% | With [2,2]bipyridinyl; palladium(II) trifluoroacetate; oxygen; trifluoroacetic acid In 1,4-dioxane; dimethyl sulfoxide for 16h; | |
80% | With palladium(II) trifluoroacetate; oxygen; acetic acid; dimethyl sulfoxide at 100℃; for 48h; | |
75% | With 2,3-dicyano-5,6-dichloro-p-benzoquinone In 1,4-dioxane for 8h; Heating; | |
68% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In fluorobenzene; dimethyl sulfoxide at 80℃; for 48h; | |
68% | With oxygen; palladium diacetate; trifluoroacetic acid In dimethyl sulfoxide at 80℃; for 12h; Sealed tube; | |
65% | With iodine; dimethyl sulfoxide; potassium iodide at 130℃; for 16h; Schlenk technique; Inert atmosphere; Glovebox; | |
48% | With potassium hydroxide; iodine In methanol at 0 - 5℃; | |
22% | With manganese(IV) oxide In benzene for 24h; Heating; | |
With phosphorus pentachloride; benzene Erhitzen des Reaktionsprodukts mit Wasser; | ||
Multi-step reaction with 3 steps 1: 83 percent / NaH / ethanol; diethyl ether / 0 °C 2: 72 percent / TsN3, Et3N / CH2Cl2 / Ambient temperature 3: 95 percent / BF3*Et2O / CH2Cl2 / 1.5 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: p-toluenesulphonic acid / Heating 2: 4 percent / hexane / 6 h / Irradiation | ||
97 %Chromat. | With oxygen; lithium bromide In 1,4-dioxane; water at 80℃; for 8h; | |
Multi-step reaction with 2 steps 1: copper(ll) bromide 2: acetonitrile / Photolysis | ||
Multi-step reaction with 2 steps 1: copper(ll) bromide 2: N-Bromosuccinimide / acetonitrile / Inert atmosphere; Irradiation | ||
Multi-step reaction with 2 steps 1: pyridinium hydrobromide perbromide / dichloromethane / 25 °C 2: palladium diacetate; triphenylphosphine; triethylamine / dimethyl sulfoxide / 25 °C / Inert atmosphere | ||
84 %Chromat. | With oxygen In N,N-dimethyl acetamide at 70℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.2% | 37.0 g (278 mmol) of aluminum chloride was mixed with 3.70 g (61.3 mmol) of sodium chloride, the mixture was dissolved at 150C under heating, 6.40 g (43.2 mmol) of commercially available 2,3-dihydro-4H-chromen-4-one dissolved by heating (50C) was added to the mixture and the resulting mixture was stirred at 200C for 20 minutes. The reaction mixture (gum state) was cooled, and added to ice-cold hydrochloric acid (100 ml of conc. hydrochloric acid and ice were combined to make them 200 ml) little by little and stirred for 30 minutes. Methylene chloride was added to the mixture and the mixture was separated. The aqueous layer was filtered, and the filtrate was extracted with methylene chloride. The organic layers were combined, washed successively with water and brine, and dried over sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) to obtain 4.82 g (32.6 mmol, Yield: 75.2%) of 7-hydroxy-1-indanone. | |
With aluminum (III) chloride; sodium chloride; at 150 - 180℃; for 0.5h; | Step 1: To a mixture of aluminum chloride (37.0 g, 278 mmol) and sodium chloride (3.7 g, 61.3 mmol) was added chroman-4-one (S13-SM, 6.4 g, 43.2 mmol) at 150 C. After being allowed to stir at 180 C for 30 mins, the mixture was cooled to 160C and poured into ice-cold hydrochloric acid (100 mL) carefully and stirred for 30 mins. The mixture was extracted withmethylene chloride and the organic phases were combined and washed with brine. The organicphase was separated, dried with anhydrous Na2SO4, filtered and concentrated to give a residue,which was purified by column chromatography to afford S13-1. ?H NMR (300 MHz, CDC13) oe2.68-2.73 (m, 2H), 3.08-3.12 (m, 2H), 6.72 -6.75 (d, J= 8.1 Hz, 1H), 6.91 -6.93 (d, J= 7.2Hz, 1H), 7.42 - 7.47 (m, 1H), 9.04 (s, 1H); LC-MS: (M+H) 149. | |
With aluminum (III) chloride; sodium chloride; at 150 - 180℃; for 0.5h; | Step 1 : To a mixture of aluminum chloride (37.0 g, 278 mmol) and sodium chloride (3.7 g, 61.3 mmol) was added chroman-4-one (S13-SM, 6.4 g, 43.2 mmol) at 150 C. After being allowed to stir at 180 C for 30 mins, the mixture was cooled to 160 C and poured into ice-cold hydrochloric acid (100 mL) carefully and stirred for 30 mins. The mixture was extracted with methylene chloride and the organic phases were combined and washed with brine. The organic phase was separated, dried with anhydrous Na2S04, filtered and concentrated to give a residue, which was purified by column chromatography to afford S13-1. 1H NMR (300 MHz, CDCI3) delta 2.68 - 2.73 (m, 2H), 3.08 - 3.12 (m, 2H), 6.72 - 6.75 (d, / = 8.1 Hz, 1H), 6.91 - 6.93 (d, / = 7.2 Hz, 1H), 7.42 - 7.47 (m, 1H), 9.04 (s, 1H); LC-MS: (M+H)+ 149. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With trifluoroacetic acid; trifluoroacetic anhydride; at 20℃; for 12h;Inert atmosphere; | A 10 mL glass vial with a screw cap was charged with <strong>[7170-38-9]3-<strong>[7170-38-9]phenoxypropanoic acid</strong></strong> 5a (0.75 mmol, 1.0 equiv), TFAA (2.25 mmol, 3 equiv) and TFA (0.8 mL). The reaction mixture was stirred at room temperature for 12 h and monitored by TLC or GC-MS. Upon completion, the solvent was removed under reduced pressure and the residue was subjected to silica gel flash column chromatography (hexanes : AcOEt) to give ketone product 6a. |
With PPA; | EXAMPLE 3 4-Chromanone (III; R1, R2, R3, R4 and R17 = H and X = O) A mixture of beta-phenoxypropionic acid (34.7 g, 0.209 mole, described in Example 1) and polyphosphoric acid (285 g) is stirred at 100 C for 15 min. The red solution is poured on crushed ice and the mixture is extracted with ether. The organic phase is washed with aqueous sodium bicarbonate solution, saturated sodium chloride solution, dried and evaporated to give the title compound as an oil, numaxCHCl3; 1690 cm-1. Reported m.p. for this compound is 38 C, see S. G. Powell, cited above. In the same manner but replacing beta-phenoxypronic acid with an equivalent amount of beta-(phenylthio)proponic acid (described in Example 1) or beta-(phenylthio)butyric acid (described in Example 2) and replacing polyphosphoric acid with concentrated sulfuric acid, 4-thiochromanone, numaxCHCl3; 1680 cm-1 (reported m.p. for this compound is 29-30 C, see F. Krollpfeiffer and H. Schultze, cited above) and 2-methyl-4-thiochromanone, numax CHCl3; 1675 cm-1, are obtained, respectively. | |
With sulfuric acid; at 2 - 20℃; for 2h; | General procedure: To a mixture of acrylic acid (700 mL, 720 mg, 10 mmol)and thiophenol or phenol (15 mmol), I2 (20% mol, 760 mg,3 mmol) was added, and the mixture was stirred at 50 C for24 h. After the completion of the reaction (monitored byTLC), a cold saturated sodium thiosulfate solution (30 mL)was added and extracted with dichloromethane (2 × 25 mL).The combined organic layers were mixed with a saturatedsolution of sodium bicarbonate and extracted to remove theunreacted starting material layer, which was acidified with10% HCl and extracted with dichloromethane (3 × 50 mL).The combined organic layers were dried over Na2SO4, andthe evaporation of the solvent under reduced pressureafforded 64-66% of the desired additional product. Theproduct was cooled down to 2 C in an ice bath, 3 mL ofconcentrated sulfuric acid was added, and the reactionmixture was allowed to warm to room temperature for 2 h,with magnetic stirring. The reaction was quenched with ice,and the mixture was extracted with dichloromethane (3 ×50 mL). The combined organic layers were washed oncewith water, and then with saturated NaHCO3 solution. Thecombined organic layers were washed with brine, dried overNa2SO4, and concentrated under reduced pressure. Theresidue was purified by column chromatography over silicagel using hexane/EtOAc (9:1), as an eluent, to obtainthiochroman-4-one or 4-chromanone, as a white solid(90-85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium azide; sulfuric acid In toluene at 0 - 20℃; | |
78% | With sodium azide; sulfuric acid In water at 0 - 20℃; for 5h; regioselective reaction; | 3,4-Dihydro-1,4-benzoxazepin-5(2H)-one (rac-8a): To a stirred solution of chroman-4-one (7a) (10.0 g,67.49 mmol) in water and sulfuric acid 1:1 (100 mL), sodium azide (6.6 g, 101.5 mmol) was added in two equal portions at 0 C and stirred at room temperature. The reaction was monitored byTLC,visualized under a UV lamp and developed by phosphomolybdic acid solution. After 5 h, the reaction mixture was neutralized with sodium hydroxide solution and the aqueous layer was extracted with dichloromethane (5 50 mL). The combined organic layers were washed with water(50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product wa spurified by column chromatography on silica (EtOAc/hexane 2:5) to aord the rac-8a product as whitesolid [8.60 g, 52.71 mmol, 78%, mp 109-110 oC (lit. [52] mp 115-116 oC)]. 1H NMR (400 MHz, CDCl3): δ= 3.50 (dd, J = 9.6 Hz and 5.2 Hz, 3-H, 2 H), 4.39 (m, J = 9.6 Hz and 5.2 Hz, 2-H, 2 H), 7.03 (d, J = 8.0Hz, 9-H, 1 H), 7.10 (m, 7-H, 1 H), 7.4 (m, 8-H, 1 H), 7.9 (dd, J = 8.0 Hz and 1.6 Hz, 6-H, 1 H), 8.2 (br s,4-H, 1 H). 13C NMR (100 MHz, CDCl3): δ= 41.3 (C-3), 73.2 (C-2), 121.3 (C-9), 122.8 (C-7), 123.9 (C-5a), 131.6 (C-6), 133.3 (C-8), 155.3 (C-9a), 170.9 (C-5). IR (KBr): 1661, 3060, 3183, 3287 cm1. HRMS-ESI(m/z): [M + Na]+ calc’d for C9H9NO2Na, 186.053; found: 186.053. |
73% | With sodium azide; sulfuric acid at 10℃; |
64% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With sodium azide; sulfuric acid at 0 - 20℃; Stage #2: With sodium hydroxide In water at 0℃; | 22.A A. 3,4-Dihydro-2H-benzo[f][1,4]oxazepin-5-one. To a 0° C. solution of chroman-4-one (2.0 g, 0.014 mol) in concentrated H2SO4 (10 mL) was added NaN3 (1.1 g, 0.018 mol) in portions. The resulting mixture was stirred at 0° C. for 30 min, then was warmed to room temperature and stirred overnight. The reaction mixture was poured onto ice, basified to pH ~10 with 1 M NaOH, and extracted with EtOAc (3*). The combined organic layers were dried over MgSO4, filtered, and concentrated, to provide the title compound (1.40 g, 64%). HPLC (reverse phase): RT=6.40 min. 1H NMR (500 MHz, CDCl3): 7.98 (dd, J=8.0, 1.8 Hz, 1H), 7.45-7.42 (m, 1H), 7.16-7.12 (m, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.68 (br s, 1H), 4.40 (t, J=4.7 Hz, 2H), 3.51 (q, J=5.3 Hz, 2H). |
61% | With sodium azide; sulfuric acid for 2h; Ambient temperature; | |
54% | With sodium azide; sulfuric acid; acetic acid at 0℃; for 4h; Heating / reflux; | 9.ii 4-Chromanone (25 g, 169 mmol) and sodium azide (33.2 g, 510 mmol) were dissolved in acetic acid (335 ml). The solution was cooled to 0°C and concentrated sulfuric acid (50 ml) was added dropwise. The mixture was heated at reflux for 4 h and then cooled to RT. The mixture was poured onto ice (500 ml) and concentrated ammonium hydroxide was added until basic pH was reached. The mixture was stirred at ambient temperature for 20 h and the solid formed was collected by filtration to give the title compound (15 g, 54%). MS ESI m/z M+H+ 164. |
54% | With sodium azide; sulfuric acid; acetic acid at 0℃; for 4h; Heating / reflux; | 3.ii 4-Chromanone (25 g, 169 mmol) and sodium azide (33.2 g, 510 mmol) were dissolved in acetic acid (335 ml). The solution was cooled to O0C and concentrated sulfuric acid (50 ml) 5 was added dropwise. The mixture was heated at reflux for 4 h and then cooled to RT. The mixture was poured onto ice (500 ml) and concentrated ammonium hydroxide was added until basic pH was reached. The mixture was stirred at ambient temperature for 20 h and the solid formed was collected by filtration to give the title compound (15 g, 54%). MS ESI m/z M+H+ 164. |
45% | With sodium azide; sulfuric acid at 0 - 20℃; | 226.1 Step 1: 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (442) The chroman-4-one (5.0 g, 33.8 mmol) was dissolved in sulfuric acid (10 mL) and the mixture was cooled at 0° C. Sodium azide (2.88 g, 44.3 mmol) was added portionwise followed by some sulfuric acid (5 mL). The reaction mixture was stirred at room temperature over night. The mixture was then pour into ice-water and basified to pH=7 with potassium hydroxide pellets. This aqueous layer was extracted with ether (twice). (0679) The combined organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude was purified by flash chromatography (50% to 100% ethyl acetate in hexanes) to afford title compound 442 (2.47 g, 45%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 8.33 (s, 1H), 7.76 (dd, J=7.8, 2.0 Hz, 1H), 7.45 (ddd, J=7.6, 7.2, 2.0 Hz, 1H), 7.12 (ddd, J=7.8, 7.2, 1.2 Hz, 1H), 7.01 (dd, J=8.3, 1.1 Hz, 1H), 4.27 (dd, J=5.4, 4.4 Hz, 2H), 3.30 (dd, J=9.5, 5.5 Hz, 2H). MS (m/z): 164.0 (M+H). |
(i) P2O5, H2SO4, CHCl3, (ii) HN3; Multistep reaction; | ||
With sodium azide; sulfuric acid | ||
With sodium azide; PPA at 65 - 70℃; | ||
With sodium azide; sulfuric acid In benzene | ||
With sulfuric acid In acetic acid | 3.a a a 2,3,4,5-Tetrahydro-1,4-benzoxazepin-5-one To 4-chromanone (50 g, 340 mmol) in acetic acid (670 ml) was added sodium azide (66.31 g, 1.02 mol) and conc. sulfuric acid (100 ml) dropwise at 0° C. The mixture was heated to 50° C. for 4 h and then cooled to room temperature. The mixture was poured onto ice (1 l) and basified with conc. ammonium hydroxide. The mixture was stirred for 24 h and the solids were collected by filtration (30.43 g, 55%), MSm/z 164 [M+H]+. | |
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium acetate / ethanol / 2 h / Reflux 2: polyphosphoric acid / 2 h / 95 °C | ||
With sodium azide; sulfuric acid at 0 - 20℃; for 12h; | 147.147-1 Example 147-1 Synthesis of 3,4-dihydro-2H-1,4-benzoxazepin-5-one Chroman-4-one (2.0 g, 14 mmol) was dissolved in 10 mL of concentrated sulfuric acid, and sodium azide (1.1 g, 18 mmol) was slowly added thereto at 0° C. The reaction mixture was slowly heated to room temperature and stirred for 12 hours. The reaction mixture was maintained at 0° C. under an ice bath, and 1 M sodium hydroxide aqueous solution was slowly added thereto. After basifying the reaction solution to pH 10 or more, ethyl acetate was added and extracted 3 times. The combined organic layers were dried over anhydrous magnesium sulfate, the solvent was removed by evaporating under reduced pressure, and recrystallized with dichloromethane and hexane to obtain the title compound as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With pyrrolidine In methanol at 20℃; | 5 4.1.2. General procedure for the synthesis of (E)-3-heteroarylidenechroman-4-ones (1a-r) General procedure: METHOD A: Pyrrolidine (10 mmol) was added to a mixture of the appropriate chroman-4-one (6.7 mmol) and heteroaryl aldehyde (10 mmol) in dry MeOH (15 mL for 1a, 1b, 1e, 1h, 1k-r and 30mL for 1c, 1d, 1i, 1j). The reaction mixture was stirred at room temperature for 1-24 h (1h for 1f, 3h for 1l-q, 24h for 1a-c, 1h-j, 1n, and 1o). The mixture was diluted with ice-water, and the precipitate was filtered off and washed with water. The crude solid was purified by column chromatography on silica gel, eluting with a mixture of AcOEt and CHCl3 (3:1) (1a-g and 1i-r) or CHCl3 (1h) and crystallized from n-hexane. METHOD B: (synthesis of 1f and 1g) A mixture of chroman-4-one (6.7 mmol), the appropriate pyridinecarbaldehyde (10 mmol) and pyrrolidine (10 mmol) was heated at 120 °C under stirring for 1 h. After cooling, the mixture was diluted with ice-water, and the precipitate was filtered off and washed with water. The crude solid was purified by column chromatography on silica gel, eluting with a mixture of AcOEt and CHCl3 (3:1), and crystallized from n-hexane. 4.1.2.5 (E)-3-[(Pyridin-2-yl)methylene]chroman-4-one (1e) Yield: 77%, mp = 139-140 °C (lit. 142 °C) [17] . IR (KBr): 1673 cm-1. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.65 (d, 1H, H3', J3'-4' = 8.0 Hz), 8.02 (dd, 1H, H5, J5-6 = 8.0 Hz, J5-7 = 1.6 Hz), 7.74 (dt, 1H, H7, J7-6 = J7-8 = 8.0 Hz, J5-7 = 1.6 Hz), 7.71 (t, 1H, =CH, Jall = 2.0 Hz), 7.51-7.47 (m, 2H, H5', H6'), 7.26-7.23 (m, 1H, H4'), 7.05 (t, 1H, H6, J5-6 = J7-6 = 8.0 Hz), 6.99 (d, 1H, H8, J7-8 = 8.0 Hz), 5.92 (d, 2H, H2, Jall = 2.4 Hz). 13C NMR (CDCl3, 100 MHz): δ (ppm) 182.26, 161.72, 154.18, 149.66, 136.54, 135.94, 134.33, 133.27, 127.95, 127.84, 123.15, 121.83, 121.63, 118.07, 68.41. Anal. Calcd. for C15H11NO2: C, 75.94; H, 4.67; N, 5.90. Found: C, 76.16; H, 4.69; N, 5.85. |
51% | With potassium alcoholate In ethanol for 2h; Ambient temperature; | |
With potassium alcoholate In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With zinc(II) iodide In dichloromethane at 0 - 20℃; | |
96% | In dichloromethane at 20℃; for 52h; Heating / reflux; | 57 Chroman-4-one (4.44 g, 0.03 moles) and zinc iodide (100 mg) were dissolved in CH2Cl2 at room temp under nitrogen atmosphere. To this mixture was added drop wise trimethylsilylcyanide (3.2 g, 0.0315 moles) and stirred at room temp for two days. Added additional trimethylsilylcyanide (2.2 g) to the reaction mixture and refluxed for 4 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography using 15 % ethyl acetate / hexane to afford the title compound as yellow viscous oil (7.2 g, 96 % yield). 1H NMR (400 MHz, CDCl3) 7.6 (IH, d), 7.25 (IH, t), 7.0 (IH, t), 6.85 (IH, d), 4.35 (2H, m), 2.4 (2H, m), 0.2 (9H, s). |
45% | With zinc(II) iodide In dichloromethane at 0 - 20℃; Inert atmosphere; | 25.1 Step 1. 4-(trimeth lsilyloxy)chroman-4-carbonitrile Into a 250-mL round-bottom flask, was placed 3,4-dihydro-2H-l-benzopyran-4-one (2 g, 13.50 mmol, 1.00 equiv), Znl2 (8.6 g, 26.94 mmol, 2.00 equiv), dichloromethane (40 mL). This was followed by the addition of TMSCN (2 g, 20.20 mmol, 1.50 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred overnight at room temperature. The resulting mixture was washed with sat. NaHCCb (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. This resulted in 1.5 g (45%) of 4- (trimethylsilyloxy)chroman-4-carbonitrile as a yellow solid. |
With zinc(II) iodide In dichloromethane at 50 - 55℃; for 5h; | ||
With Lewis acid catalyst Ambient temperature; | ||
With zinc(II) iodide In dichloromethane at 25℃; for 24h; | ||
With copper(II) bis(trifluoromethanesulfonate) In dichloromethane at 20℃; for 48h; Inert atmosphere; | 4.1. Synthesis of cyanohydrins (+/-)-2a-c General procedure: To a stirred solution of ketone 1a-c (3.4 mmol) in dry dichloromethane (5 mL), TMSCN (1.2 mL, 8.9 mmol) and Cu(OTf)2 (124 mg, 0.3 mmol) were added under an N2 atmosphere. The resulting mixture was stirred for 48 h at rt. After this time, 1 M HCl (2 mL) and acetonitrile (2 mL) were added and the resulting mixture was stirred for 1 h at rt. Then, the reaction mixture was quenched with water (6 mL) and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with brine separated and dried over Na2SO4; the solvent was removed under reduced pressure to give a brown oil as a crude residue in 88-95% yield, which was used for the acylation without further purification. | |
32 g | With zinc(II) iodide In dichloromethane at 20℃; for 20h; | Intermediate 743: To a solution of commercial 2,3-dihydro-4H-chromen-4-one (20 g, 135 mmoles) in methylene chloride (400 mL) there are added ZnI2 (0.8 g) and TMSCN (20 g, 201 mmoles). The reaction mixture is stirred at ambient temperature for 20 hours, and then the organic phase is washed with an aqueous NaHCO3 solution (400 mL), dried over MgSO4, filtered and concentrated in vacuo. Intermediate 743 is obtained (32 g) in the form of an oil, which is used in the following step.1H NMR (400 MHz, CDCl3): 7.47 (dd, 1H), 7.18 (dd, 1H), 6.88 (td, 1H), 6.75 (dd, 1H), 4.25 (m, 2H), 2.30 (m, 2H), 0.08 (s, 9H) |
In dichloromethane at 20℃; for 5h; | 29.29A To a solution of 4-chromanone (2.96 g, 20 mmol) in CH2C12 (25 mL) at 0 °C was added trimethylsilyl cyanide (3.97 g, 40 mmol) as a solution in CH2C12 (10 mL) dropwise. The cold bath was removed and the reaction stirred at RT for 5 h. The reaction was diluted with additional CH2C12 (20 mL) and the mixture washed successively with saturated NaHC03 and brine. The organic layer was dried (Na2S04) and concentrated to give the crude target compound (4.79 g, 97%) as a light yellow oil which was used in the next step without further purification. | |
With zinc(II) iodide In dichloromethane at 20℃; for 8h; | 165.A Example 165. Synthesis of 1-(chroman-4-ylmethyl)-4-(4-fluorophenoxy)piperidine A. To a solution of chroman-4-one (2 g, 13.5 mmol) in DCM (30 mL) was added trimethylsilanecarbonitrile (2.01 g, 20.25 mmol) and zinc(II) iodide (4.31 g, 13.5 mmol). The reaction was stirred at ambient temperature for 8 h. Water (40 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the org/aq phase was extracted with DCM (3 x 200 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 1.9 g of crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.3% | With sodium hydroxide In ethanol; water at 20℃; for 1h; | 3 General procedure: To the solution of 4-chromanone 3 (0.9 g, 6.0 mmol, 1.0 equiv.)and 2-chlorobenzaldehyde 1d (1.0 mL, 9.0 mmol, 1.5 equiv.) in ethanol (6 mL), 5% aqueous NaOH solution (4 mL) was added dropwise which resulted precipitation. The mixture was stirred for 1 hat room temperature. The precipitate was isolated by filtration and washed with cold ethanol to obtain 4-chromanone intermediate 5d (1.27 g, 78.2%, 4.7 mmol) as a white solid. |
With hydrogenchloride In ethanol at 0℃; | ||
With sodium hydroxide In ethanol; water at 20℃; for 2h; |
With sodium hydroxide In ethanol; water at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuric acid In acetic acid at 20℃; for 0.333333h; | |
91% | With aluminum oxide for 0.0583333h; Microwave irradiation; neat (no solvent); | |
90% | With hydrogenchloride In acetic acid at 0℃; for 24h; |
81.3% | With hydrogenchloride In ethanol for 24h; Ambient temperature; | |
81.3% | With hydrogenchloride In ethanol for 0.25h; | |
80% | With sulfuric acid In acetic acid for 24h; | |
80% | With sulfuric acid In acetic acid for 24h; Ambient temperature; | |
77% | With hydrogenchloride In ethanol | |
73% | With piperidine | |
70% | With hydrogenchloride In methanol; water for 24h; Reflux; | 4.2. General procedure for the synthesis of 3-benzylidene-4-chromanones derivatives General procedure: A round-bottom flask was charged with the 4-chromanone (3.4 mmol) and aromatic-aldehyde (3.6 mmol). This was dissolved in methanol (20 mL), and concentrated hydrochloride (10 mL). The mixture was refluxed for 24 h and then diluted with water. Filtration afforded the crude product, which was crystallized from methanol to give the pure product. |
70% | With piperidine at 100℃; for 2h; | General Procedure for Preparation of (3E)- 3-Benzylidene-2,3-dihydro-4H-1-benzopyran-4-one Derivatives(3-20) General procedure: A mixture of the corresponding 4-chromanone (1,1.0 mmol), substituted benzaldehyde (2, 1.2 mmol) and piperidine(1.2 mmol) was heated at 100°C until complete disappearanceof 4-chromanone. After the reaction mixture wasdiluted with ice-water and acidified with conc. HCl, the wholewas extracted with AcOEt. The combined organic layer waswashed with brine. The organic layer was dried over Na2SO4and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane-AcOEt system) to give the corresponding (3E)-3-benzylidene-2,3-dihydro-4H-1-benzopyran-4-one derivatives. |
With phosphoric acid In water at 80℃; for 6h; | ||
With piperidine at 105℃; for 1h; | ||
With sodium hydroxide In ethanol; water at 0℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With trichlorophosphate | |
96% | Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 2,3-dihydro-4H-1-benzopyran-4-one at 0 - 60℃; for 22h; Inert atmosphere; | |
90% | With trichlorophosphate at 20℃; for 3.5h; Cooling with ice; | 46 Synthesis of 3-formyl-4-chloro-2H-chromanene (11) Under ice bath conditions, phosphorus oxychloride (4.76 ml, 50.7 mmol) was added to the anhydrous DMF solution of compound 10 (5 g, 33.8 mmol), and the reaction was carried out for 0.5 h under ice bath. Then it was moved to room temperature and reacted for 3h, TLC monitored the raw material reaction to be complete. The system was poured into crushed ice, stirred until the ice cubes were completely melted, and filtered with suction to obtain a yellow solid 11 (5.8 g, 90%). |
87% | With trichlorophosphate In dichloromethane at 80℃; for 4h; Inert atmosphere; | |
80% | With trichlorophosphate In dichloromethane at 20℃; Inert atmosphere; Reflux; | A1 Intermediate Al: 4-chloro-2H-chromene-3-carbaldehyde Chroman-4-one (2 g, 13.50 mmol) was dissolved in DCM (45 ml) and of DMF (1.6 ml, 20.25 mmol), then POCb (3.77 ml, 40.5 mmol) was added drop wise under nitrogen and the mixture heated at reflux for 6 h and RT overnight. The reaction was diluted with DCM, washed with water, with saturated NaClaq, dried over Na2S04 and evaporated to dryness. The crude was chromatographed on silica gel with HexaneYEtOAc mixtures to give the title compound (2.1 g, 80% yield) as a yellow solid. UPLC-MS: 1.99 min, 194.8 [M+H]+, method 1. |
With anhydrous Sodium acetate; trichlorophosphate 1.) CHCl=CCl2, 65 deg C, 3 h; Yield given. Multistep reaction; | ||
With trichlorophosphate at 5 - 60℃; for 2h; | ||
With trichlorophosphate at 0 - 5℃; | ||
With trichlorophosphate | ||
With oxalyl dichloride | ||
With oxalyl dichloride at 0 - 80℃; for 3h; | 1.4. General procedure for the preparation of 4-chloro-2-oxo-2H-chromene-3-carbaldehydes (7a-h) General procedure: Dry DMF (5 mmol) was added dropwise to oxalyl chloride (5 mmol) at 0 oC for 10-15 min and the temperature was maintained for another 30 min (VH reaction). 4-Chromanone 6a (1 mmol) in dry DMF was added to the reaction mixture and stirred at room temperature for 1 h. The reaction mixture was heated at 70-80 °C for 2 h. After completion of the reaction (TLC), the reaction mixture was poured onto crushed ice and the reaction mixture was extracted with ethyl acetate (3×50ml). The combined organic extracts were washed with H2O, layers were separated and organic layer was dried over anhyd. Na2SO4. The solvent was removed under reduced pressure and purified by column chromatography using silica gel (60-120 mesh, hexane) to afford the pure product 7a. Similarly, carbaldehydes 7b-h were prepared from the corresponding 4-chromanones 6b-h under our optimized VH conditions. The compounds 7a-b and 7f-h are known and compared with the literature data. The compounds 7c-e are unknown and characterized by spectral data. | |
With trichlorophosphate at 0 - 20℃; | ||
With trichlorophosphate at 0 - 20℃; | ||
Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0 - 20℃; for 2h; Stage #2: 2,3-dihydro-4H-1-benzopyran-4-one at 0 - 80℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydroxyamino hydrochloride; triethylamine In methanol at 20℃; for 16h; | 2.K To a solution of 4-chromanone (10 g, 67.6 mmol) in methanol (150 ml_) was added triethylamine (15 ml_, 108.1 mmol) and hydroxylamine hydrochloride (7.5g, 108.1 mmol). The mixture was stirred at rt for 16 hrs. The solvent was evaporated giving a residue which was dissolved in ethyl acetate and extracted with water. The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation of the filtrate afforded chroman-4-one oxime (16.1g, 100%) as a white crystalline solid. MS: 164.0 (M+H)+; tR = 1.99 min (method 1 ). |
99% | With hydroxyamino hydrochloride; anhydrous Sodium acetate In methanol at 60℃; for 4h; | |
96% | With hydroxyamino hydrochloride; anhydrous Sodium acetate In ethanol; water monomer at 60℃; for 1.5h; Heating / reflux; | A2.a Example A2; 2-Amino-4-[(4R)4-chromanylamino]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine (Table 1, Compound number 1.20); a. chroman-4-one oxime A mixture of sodium acetate (41.53 g, 0.506 mol) in water at 60° C. was combined with a stirred mixture of chroman-4-one (25 g, 0.169 mol) and hydroxylamine hydrochloride (20.0 g, 0.287 mol) in ethanol at 60° C. The resulting mixture was heated at reflux for 90 minutes, cooled and filtered. The crude solid was washed with water to give chroman-4-one oxime (27.9 g, yield 96%), mp. 114-117° C., purity 95%. |
94% | With pyridine; hydroxyamino hydrochloride In methanol at 70℃; for 4h; | |
90% | With sodium hydroxide; hydroxyamino hydrochloride In ethanol; water monomer for 2h; Reflux; | |
90% | With hydroxyamino hydrochloride; anhydrous Sodium acetate In methanol at 20℃; for 12h; | |
86% | With pyridine; hydroxyamino hydrochloride at 20℃; for 3h; | 4.1.3. General produce for the preparation of 2,3,4,5-tetrahydro-1Hbenzo[b]azepine by reductive ring expansion General procedure: Hydroxylamine hydrochloride (2 equiv) was added to a stirredsolution of 3,4-dihydronaphthalen-1(2H)-one in pyridine (1 equiv).After the mixture was stirred for 3 h at room temperature, pyridinewas removed under reduced pressure. Then the products wereisolated following recrystallizations from aqueous ethanol. Moreover, the mixture could be extracted by EtOAc and purified bycolumn chromatography (PE/EA 5/1) to yield corresponding 3,4-dihydronaphthalen-1(2H)-one oxime.DIBALH (1Min n-hexane, 6 equiv)was added to a stirred solutionof 3,4-dihydronaphthalen-1(2H)-one oxime inCH2Cl2 drop by drop at0 C. Then the mixture was transferred to room temperature andstirred for another 2 h. The reaction was quenched carefully byaddition of NaF (12 equiv) and water at 0 C. The aluminum saltprecipitated out as colloid. Then the mixture was stirred at roomtemperature for another 2 h, and aluminumsaltwas filtered as sandlikesolid. The filtrate was dried over Na2SO4 and concentrated invacuo. The crude product was purified by column chromatography(Al2O3, PE/EA 5:1) to give 2,3,4,5-tetrahydro-1H-benzo[b]azepine.Then the designed compounds were obtained as methodsabove.Chroman-4-one oxime (26a): 9.5 g, 86%, white solid; 1H NMR(400 MHz, DMSO-d6) d 2.83 (t, J 6.2 Hz, 2H), 4.18 (t, J 6.2 Hz, 2H),6.85e6.99 (m, 2H), 7.25 (ddd, J 8.2, 7.2, 1.7 Hz, 1H), 7.78 (dd,J 7.9, 1.7 Hz, 1H), 11.24 (s, 1H). |
80% | With pyridine; hydroxyamino hydrochloride at 20℃; | |
With hydroxyamino hydrochloride; potassium carbonate In ethanol | ||
With hydroxyamino hydrochloride; anhydrous Sodium acetate In methanol at 60℃; for 2h; | ||
With hydroxyamino hydrochloride; anhydrous Sodium acetate In ethanol; water monomer for 2h; Heating / reflux; | XXI To a mixture of 4-chromanone (10.00 g, 67.50 mmol) and hydroxylamine hydrochloride (7.04 g, 101 mmol) in EtOH (100 ml) was added a solution of NaOAc (16.61 g, 202.5 mmol) in H2O (30 mL). The reaction was heated to reflux for 2 h. The mixture was cooled to RT and concentrated in vacuo. The residue was diluted with H2O and acidified with 1N HCl. The aqueous was extracted with EtOAc until tlc analysis showed no evidence of title compound in the aqueous layer. The combined organics were dried with MgSO4 and concentrated in vacuo to furnish the crude title compound which was used without further purification. MS (APCI pos) 164 (M+H). | |
With hydroxyamino hydrochloride; anhydrous Sodium acetate In ethanol at 25℃; | ||
With hydroxyamino hydrochloride; anhydrous Sodium acetate In methanol at 60℃; Inert atmosphere; | ||
With hydroxyamino hydrochloride; anhydrous Sodium acetate In methanol at 60℃; for 2h; | ||
With hydroxyamino hydrochloride; anhydrous Sodium acetate In methanol for 2h; Reflux; Inert atmosphere; | ||
With hydroxyamino hydrochloride; anhydrous Sodium acetate In ethanol; water monomer at 95℃; for 2h; | ||
With hydroxyamino hydrochloride; anhydrous Sodium acetate In ethanol; water monomer at 95℃; for 2h; | 2.1 General procedure for the synthesis of enamides General procedure: To a solution of ketone S 1 (10 mmol, 1.0 equiv) in EtOH/H 2 O (7.5/22.5 mL) was added hydroxylamine hydrochloride (1.04 g, 15 mmol, 1.5 equiv) and NaOAc (2.05 g, 25 mmol, 2.5 equiv). After stirring at 95 o C in oil bath for 2 h, the mixture was concentrated in vacuo and the residue was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na 2 SO 4 and concentrated to give the crude product S 2 . | |
With hydroxyamino hydrochloride; anhydrous Sodium acetate In ethanol; water monomer at 95℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium formate In methanol at 50℃; for 9h; Inert atmosphere; | 7 Working Examples 8-13; The reaction was performed to synthesize (R)-4-chromanol under a similar conditions to those of Working Example 1 at 50° C. and for 24 hours, except using RuCl[(R,R)-Tsdpen] (p-cymene) to perform the reaction at a higher S/C, or changing the catalyst to be used. The results are summarized in Table 2. Note that, in Working Example 9, the reaction solvent was a mixed solvent of 4 mL methanol and 2 mL water.; Working Example 1; A ruthenium complex RuCl[(R,R)-Tsdpen] (p-cymene) (6.4 mg, 0.01 mmol), potassium formate (1.0 g, 12 mmol) and 4-chromanone (1.48 g, 10 mmol, substrate/catalyst ratio=1,000) were set in a 20 mL glass Schlenk-type reaction tube under an argon atmosphere. Methanol (6 mL) was added thereto and stirred at 50° C. After reacting for 3 hours, the yield of (R)-4-chromanol was 99%, and the optical purity was 99% ee. The reaction was allowed to further continue to give, after 6 hours, a yield of 100% and optical purity of 99% ee. After 24 hours, (R)-4-chromanol was produced at 100% yield and 99% ee optical purity.This confirmed that the racemization of (R)-4-chromanol did not proceed over time in this reaction system. |
100% | With formic acid; C38H40ClN2O3RhS; triethylamine In neat (no solvent) at 24 - 30℃; for 4h; Inert atmosphere; enantioselective reaction; | |
99% | With C28H31BrMnN2O2P; potassium <i>tert</i>-butylate; hydrogen In methanol at 20℃; for 16h; Glovebox; Autoclave; enantioselective reaction; |
97% | With formic acid; [RhCl2(p-cymene)]2; syn-(3R)-3-[(S)-α-aminobenzyl]-1,1-dioxo-1,2-benzothiazolidine; triethylamine In 1,2-dichloro-ethane at 40℃; for 12h; Inert atmosphere; enantioselective reaction; | |
95% | With hydrogen; C43H45ClN4Ru; sodium t-butanolate In isopropyl alcohol at 22℃; for 24h; Autoclave; enantioselective reaction; | |
90% | With (p-cymene)ruthenium(II) chloride; sodium formate; (S)-N-Benzylpyrrolidine-2-carboxyamide In water at 30℃; for 72h; enantioselective reaction; | |
82% | With (S)-2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]pyrrolidine; dimethylsulfide borane complex In tetrahydrofuran at 25℃; for 4h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | |
78% | With formic acid; N-((R,R)-2-((4′-methoxy-[1,1′-biphenyl]-2-ylmethyl)amino)-1,2-diphenylethyl)-4-methylbenzenesulfonamide ruthenium(II) chloride; triethylamine at 60℃; for 24h; Inert atmosphere; | |
76% | With potassium hydroxide; (-)-(1R,2S)-ephedrine hemisulfate In isopropyl alcohol at 20℃; | |
75% | With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; sodium formate In water at 30℃; for 24h; Inert atmosphere; Schlenk technique; enantioselective reaction; | 2.3. General procedure for the catalytic reductions General procedure: In a schlenk tube, the chiral ligand (0.05 mmol) and the metallicprecursor (0.025 mmol) are dissolved in the water (4 mL). After 1 hof stirring at 30 °C, the sodium formate (10 mmol) and the ketone (1 mmol) were added to the aqueous solution. The biphasic solution was stirred at 30 for the indicated time and follow by TLC untilthe total reduction of ketone. The formed alcohol was separated from the catalyst by simple extraction with pentane (2 8 mL) and the organic layer was dried over MgSO4 and concentrated in vacuo.The crude residue was distilled in order to purify the alcohol. |
59% | With sodium hydroxide; (R)-2-Boc-amino-N-((R)-2-hydroxy-propyl)-propionamide; isopropyl alcohol at 20℃; for 3h; | |
58% | With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; N-(tert-butoxycarbonyl)-L-valine-(6-O-benzoyl-1-O-benzyl-5-deoxy-2,3-O-isopropylidene-5-thioamido-α-D-mannofuranose); potassium <i>tert</i>-butylate; lithium chloride In tetrahydrofuran; isopropyl alcohol at 20℃; for 3h; enantioselective reaction; | |
57% | With Almag CRED A161; NADP; glucose dehydrogenase In water; dimethyl sulfoxide; isopropyl alcohol at 20℃; Enzymatic reaction; | 4.4_B General procedure: Almac CRED (200 mg) and NADP or NAD (10 mg)were charged into a 100 mL round bottomed flask and dissolvedin 0.1 M potassium phosphate buffer (pH 7, ca. 50 mL). Next, IPA(7 mL) was added, followed by a solution of ketone (900-1700 mg) in DMSO (2.5-5 mL, depending on solubility). This was shaken at room temperature overnight and the reaction progresswas checked by 1H NMR. If not complete, additional CRED (100-200 mg) and NADP or NAD (10 mg) were added and shaking wascontinued. This was repeated until the reaction reached completion.If the reaction appeared to stall or proceed very slowly, experimentalmethod C was used. |
54% | With hydrogen In methanol at 50℃; for 15h; | 21 Synthesis of (R)-4-chromanol by Hydrogenation Reaction of 4-chromanone Example 21 Synthesis of (R)-4-chromanol by Hydrogenation Reaction of 4-chromanone In a stainless steel autoclave, Ru(OTf)[(R,R)-Tsdpen](p-cymene) (2.4 mg, 3.3 μmol) and 4-chromanone (1.48 g, 10 mmol) were charged, followed by purging with argon. Then, 0.5 ml of methanol was added, and the autoclave was pressurized with hydrogen, followed by ten times of purging. Then, hydrogen was charged to 15 atm to initiate reaction. After stirring at 50° C. for 15 hours, the reaction pressure was returned to normal pressure. 1H-NMR and HPLC analysis of the product showed that (R)-4-chromanol with 83% ee was produced in a yield of 54%. |
44% | With potassium formate In water; toluene at 50℃; for 24h; | F.6 The reaction was performed under the same conditions as those in Example F-1-1, except that 0.887 mg (1.6 μmol) of Cp*IrCl[(R,R)-MsCYDN] was used as the catalyst. HPLC analysis of the reactant confirmed that 4-chromanol with optical purity of 94% ee was produced in 44% yield, demonstrating that the combination of the Cp*IrCl[(R,R)-MsCYDN] complex with a potassium formate solution exhibits a moderate level of catalytic activity. |
With dimethylsulfide borane complex In tetrahydrofuran at 25℃; Yield given; | ||
With borane Ν,Ν-diethylaniline complex; Trimethyl borate; chiral 2-(diphenylhydroxymethyl)pyrrolidine In toluene at 23℃; | ||
Multi-step reaction with 2 steps 1: [Rh(cod)Cl]2; asymmetric tetraphenyl-tetraoxa-phosphazulene derivative / toluene / 24 h / 0 °C 2: 1 percent p-TsOH / methanol | ||
With [RhCl2(p-cymene)]2; 5-[(2S,4R)-4-(tert-butyldiphenylsilyloxy)pyrrolidin-2-yl]-1H-1,2,3-triazole; potassium hydroxide In isopropyl alcohol at 20℃; for 4h; Inert atmosphere; optical yield given as %ee; | ||
With hydrogen In methanol at 60℃; for 23h; autoclave; Inert atmosphere; | 8 7.0 mg (11.9 mmol) of RuCl[(R,R)-Msdpen] (TMS-toluene) was added into a 100-ml autoclave, and the autoclave was purged with nitrogen. Subsequently, 0.89 g (6.0 mmol) of 4-chromanone and 20 ml of methanol were added thereto, the pressure was increased to 1.5 MPa with hydrogen, and then the mixture was stirred for 23 hours at 60° C. The reaction mixture was analyzed by GC, and as a result, (R)-4-chromanol was found to be produced at a conversion rate of 84% and an optical purity of 97.0% ee | |
With formic acid; C31H33ClN2O3RuS; triethylamine at 60℃; for 5h; Inert atmosphere; enantioselective reaction; | ||
With (2S)-N-{(1S,2S)-2-[(S)-pyrrolidine-2-carboxamido]-1,2-diphenylethyl}pyrrolidine-2-carboxamide; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; sodium formate In water at 60℃; for 24h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | ||
99.1 % ee | With hydrogen In methanol at 60℃; for 18h; Autoclave; Inert atmosphere; | 20 Asymmetric hydrogenation of 4-chromanoneIn a 50-ml autoclave, 3.3 mg (0.005 mmol, S/C=1000) of RuCl((R,R)-0-HT-Tsdpen) was placed, and the autoclave was purged with nitrogen. Subsequently, 0.74 g (5.0 mmol) of 4-chromanone and 4.4 ml of methanol were added thereto, and the pressure was raised with hydrogen up to 3.0 MPa. Subsequently, the mixture was stirred for 18 hours at 60°C. The reaction liquid was subjected to a GC analysis, and as a result, (R)-4-chromanol was obtained at a conversion rate of 98.6% with an optical purity of 99.1% ee. |
99 % ee | With N-[(1R,2R)-1,2-diphenyl-2-(3-phenylpropylamino)ethyl]-4-methylbenzene sulfonamide ammonium chloride ruthenium; hydrogen In methanol at 60℃; for 24h; enantioselective reaction; | |
91 % ee | With dodecacarbonyl-triangulo-triruthenium; (R,R)-N-(1-benzyl-1,2,3-triazole-4-ylmethyl)-N’-4-toluenesulphonyl-1,2-diphenylethylenediamine; isopropyl alcohol at 80℃; for 20h; Inert atmosphere; | |
90 % ee | With dodecacarbonyl-triangulo-triruthenium; (S,S)-N-{1,2-diphenyl-2-[(pyridin-2-ylmethyl)amino]ethyl}-4-methylbenzenesulfonamide In isopropyl alcohol at 80℃; for 48h; Inert atmosphere; Schlenk technique; enantioselective reaction; | General procedure for asymmetric transfer hydrogenation of ketones: General procedure: A mixture of catalyst (2 mol%) and Ru3 (CO)12 (0.67 mol%) in IPA (10 cm3) was stirred at 80 °C under an inert atmosphere in a schlenk tube for 30 min. To this solution, ketone (1 mmol) was added and the resulting mixture was stirred at 80 °Cfor 48 h. The reaction mixture was filtered through a short column of silica using (EtOAc:hexane 1:1), a small amount of the filtrate was dilluted in EtOAc and then injected on the GC to determine the conversion and enantiomeric excess. |
99.2 % ee | With formic acid; N-{(1R,2R)-2-[3-(4-methoxyphenyl)propylamino]-1,2-diphenylethyl}-4-methylbenzenesulfonamide ruthenium chloride; triethylamine at 60℃; for 3h; Inert atmosphere; | |
Multi-step reaction with 3 steps 1: sodium tetrahydroborate 2: Burkholderia cepacia Amano-PS lipase; immobilized on diatomaceous earth / tert-butyl methyl ether / 14 h / 23 °C / Resolution of racemate; Enzymatic reaction 3: potassium carbonate; methanol / 3 h / 23 °C | ||
99 % ee | With N-{(1R,2R)-2-[3-(4-methoxyphenyl)propylamino]-1,2-diphenylethyl}-4-methylbenzenesulfonamide ruthenium chloride; hydrogen In methanol at 60℃; for 24h; Inert atmosphere; | |
260 mg | With formic acid; (S)-chloro[(1,2,3,4,5-η)-pentamethyl-2,4-cyclopentadien-1-yl](2-pyrrolidinecarboxamidato-kN1,kN2)iridium (III); triethylamine In methanol at -20℃; for 48h; | 4 <Example 4> [0098] In 40 ml of methanol, 296 mg of 4-chromanone was dissolved, and 38 mg of (S)-chloro[(1,2,3,4,5-η)-pentamethyl-2,4-cyclopentadien-1-y 1](2-pyrrolidinecarboxamidato-κN1, κN2)iridium(III) was added. After the solution was cooled to -20°C, 4.0 ml of a mixture of formic acid/triethylamine (molar ratio: 5/2) was added dropwise, and the resulting mixture was continuously stirred at the same temperature for 2 days. Then, the reaction was completed. The reaction mixture was concentrated in vacuo and extracted with methylene chloride. After the extract was basified with an aqueous sodium carbonate solution, the resulting layers were separated. The organic layer was washed with water and concentrated. The resulting oil was purified by silica gel column chromatography to give 260 mg of a colorless crystal. [0099] By the analysis of this product using a chiral column (CHIRALPAK IB; manufactured by Daicel Chemical Industries, Ltd. , n-hexane/2-propanol = 95/5), the optical purity was found to be 99.0%ee. This product was (R)-4-chromanol. [0100] Specific rotation: [α]D20 72.7 (c = 0.5, EtOH) 1H-NMR (200 MHz, CDCl3): δ 1.93-2.19 (3H, m, 3-H2 and OH), 4.19-4.33 (2H, m, 2-H2), 4.75 (1H, br t, J = 3.9 Hz, 4-H), 6.83 (1H, dd, J = 8.2, 1.3 Hz, 8-H), 6.91 (1H, td, J = 7.5, 1.3 Hz, 6-H), 7.20 (1H, ddd, J = 8.2, 7.5, 1.6 Hz, 7-H), 7.30 (1H, dd, J = 7.5, 1.6 Hz, 5-H). 13C-NMR (50.3 MHz, CDCl3): δ 30.8 (3-C), 61.9 (2-C), 63.2 (4-C), 117.1 (ArCH), 120.6 (ArCH), 124.3 (quaternary ArC), 129.6 (overlapped, 2 x ArCH), 154.6 (quaternary ArC). |
> 98 % ee | With formic acid; Noyori's catalyst; triethylamine at 20℃; for 120h; Inert atmosphere; | |
96 % ee | With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; water; sodium formate; (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine for 0.333333h; Milling; enantioselective reaction; |
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 |
---|---|---|
65% | With Calcium tetrakis(pentafluorophenyl)borate; dihydrogen peroxide; oxalic acid In water; 1,2-dichloro-ethane at 70℃; for 24h; | 61 As shown in Tables 5 and 6, the Baeyer-Villiger oxidation reaction was investigated using various reactive substrates. As the catalyst, a borate salt of Li or Ca was used. In general, although the catalytic activity of a Ca borate salt was higher, since a Li borate salt was a commercially available product, and the amount thereof to be used was small due to its low molecular weight, the Li borate salt was first used (Examples 57, 58, 66 to 71, and 73). However, when the Li borate salt was not sufficient depending on the reactive substrate, and the chemical yield of the product was low, the Ca borate salt was used as the catalyst (Examples 59 to 65, 72, and 74 to 76). In Example 61, when 4-chromanone was used as the reactive substrate, a produced lactone was hydrolyzed, and a corresponding hydroxycarboxylic acid was obtained.Product of Example 61: White solid. TLC, Rf=0.4 (EtOAc only); 1H NMR (CDCl3, 400 MHz) δ 2.90 (t, J=6.0 Hz, 2H), 4.28 (t, J=6.0 Hz, 2H), 6.15 (brs, 1H), 6.81-6.86 (m, 1H), 6.92-6.97 (m, 3H); 13C NMR (CD3CN, 100 MHz) δ 34.5, 66.2, 115.5, 116.2, 120.9, 123.3, 147.0, 147.9, 174.0. |
With perchloric acid; dihydrogen peroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tris(triphenylphosphine)ruthenium(II) chloride; formaldehyd; water; potassium carbonate In toluene at 110℃; for 18h; Inert atmosphere; Sealed tube; chemoselective reaction; | |
80% | With triethylsilane; 1,1,1,3',3',3'-hexafluoro-propanol; tris(pentafluorophenyl)borate at 40℃; for 1h; chemoselective reaction; | |
75% | With ammonia; calcium In tetrahydrofuran at -33℃; for 2h; |
75% | With N,N-dicyclohexyl-2-methyl-1-propanamine; Trichloro(trifluoromethylsulfonyloxy)silane In dichloromethane at -40℃; for 0.5h; Inert atmosphere; | |
74% | With sodium tetrahydroborate; nickel dichloride In methanol; water at 20℃; for 4.5h; | |
66% | With hydrogen; N-ethyl-N,N-diisopropylamine In toluene at 20℃; for 8h; Autoclave; | |
58% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; tetrahydroxydiboron; water; triethylamine In tetrahydrofuran at 30℃; for 12h; Schlenk technique; Inert atmosphere; | |
46.2% | With Wilkinson's catalyst; hydrogen In dichloromethane for 24h; | |
40% | With phenylsilane; iron(III) acetylacetonate In ethanol at 40℃; for 5h; | |
33% | Stage #1: 1-benzopyran-4(4H)-one With bis-(1,2-dimethylpropyl)borane In tetrahydrofuran at 20℃; Stage #2: With sodium hydroxide; dihydrogen peroxide In tetrahydrofuran; water at 20℃; for 6h; | |
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane; 4,4'-di-tert-butyl-2,2'-bipyridine In tetrahydrofuran at 80℃; for 4h; | General hydroborylation-bromination procedure General procedure: To [Ir(COD)OMe]2 (7.3 mg, 11 μmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (7.0 mg, 26 μmol) in a flame-dried vial under nitrogen were added THF (0.7 mL), pinacolborane (0.18 mL, 1.24 mmol) and 1,4-dimethoxynaphthalene (7) (188 mg, 1.0 mmol). The mixture was stirred at 80 °C for 24 h then filtered through Celite and concentrated in vacuo to afford crude pinacol ester 13 (100% conversion by 1H NMR) that was used directly in the next step. | |
41 %Chromat. | With aluminum (III) chloride In ethanol; water; acetonitrile at 20℃; for 12h; Irradiation; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With piperidine In ethanol for 4h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: N,N-dimethyl-formamide With phosphorus tribromide In chloroform at 20℃; for 0.666667h; Inert atmosphere; Cooling with ice; Stage #2: 2,3-dihydro-4H-1-benzopyran-4-one In chloroform at 20℃; for 12h; Inert atmosphere; | General procedure for the synthesis of β-bromo-α,β-unsaturated aldehyde General procedure: A solution of dimethylformamide (5 mmol) inanhydrous chloroform was cooled in ice bath. Phosphorous tribromide (2mmol) was added drop-wise over a period of 10 min. The resulting whitesuspension was warmed to room temperature and stirred for additional 30 min. Asolution of carbonyl compound (1 mmol) in chloroform was added drop-wise and stirred for 12 h at room temperature. The reaction mixture was then poured in icewater. Solid sodium bicarbonate was carefully added to neutralize the acids and the mixture was extracted several times with dichloromethane. The organic partwas then washed with cold water thoroughly, dried with sodium sulphate and evaporated. Purification of the residue was done by silica gel (60-120 mesh)column chromatography to get pure β-bromo-α,β-unsaturated aldehyde |
80% | Stage #1: N,N-dimethyl-formamide With phosphorus tribromide In chloroform at 0 - 20℃; for 0.666667h; Stage #2: 2,3-dihydro-4H-1-benzopyran-4-one In chloroform at 20℃; for 12h; | |
With phosphorus tribromide 1.) CHCl3, r.t., 1 h, 2.) CHCl3, 50-55 deg C, 1 h; Yield given; Multistep reaction; |
Stage #1: N,N-dimethyl-formamide With phosphorus tribromide In dichloromethane at 0℃; for 2h; Inert atmosphere; Schlenk technique; Stage #2: 2,3-dihydro-4H-1-benzopyran-4-one In dichloromethane at 40℃; for 12h; Inert atmosphere; Schlenk technique; | ||
Stage #1: N,N-dimethyl-formamide With phosphorus tribromide In chloroform at 20℃; for 0.666667h; Stage #2: 2,3-dihydro-4H-1-benzopyran-4-one In chloroform at 20℃; for 12h; Stage #3: Cooling with ice; | β-Bromo α,β-Unsaturated Aldehydes 1 General procedure: A mixture of DMF (5 mmol) and anhyd CHCl3 was cooled in an ice bath, and PBr3 (2 mmol) was added dropwise over 10 min. The resulting white suspension was warmed to r.t. and stirred for another 30 min. A solution of the appropriate carbonyl compound (1 mmol) in CHCl3 (7 mL) was added dropwise and the mixture was stirred for 12 h at r.t. The mixture was then poured into ice-water. Solid NaHCO3 was carefully added to neutralize the acids and the mixture was extracted with CH2Cl2 (3 × 10 mL). The organic phases were combined, washed with cold H2O (2 × 10 mL), dried (Na2SO4), and concentrated. The residue was purified by column chromatography [silica gel (60-120 mesh)] | |
Stage #1: N,N-dimethyl-formamide With phosphorus tribromide In chloroform at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: 2,3-dihydro-4H-1-benzopyran-4-one In chloroform for 2h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hypochlorite; tetrabutylammomium bromide In ethyl acetate at 20℃; for 3.51667h; | |
99% | With Merrifield's resin-bound N-aminoimidazolium chlorochromate In dichloromethane for 3h; Heating; | |
98% | Stage #1: 4-hydroxychroman With copper(I) bromide In acetonitrile at 20℃; for 0.05h; Inert atmosphere; Stage #2: With N,N'-di-tert-butyldiaziridinone In acetonitrile at 20℃; for 12h; |
89% | With tert.-butylhydroperoxide In ethanol; water at 20℃; for 12h; Inert atmosphere; Irradiation; | |
88% | With ammonium nitrate; hydrogenchloride; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen In water; acetonitrile at 60℃; for 18h; Green chemistry; | |
88% | With manganese(II) triflate; 1-Adamantanecarboxylic acid; C32H38N4O2; dihydrogen peroxide In water; acetonitrile at 0℃; for 2h; chemoselective reaction; | |
88% | With ammonium nitrate; hydrogenchloride; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In acetonitrile at 60℃; for 18h; Green chemistry; chemoselective reaction; | |
87% | With C29H35Cl2IrN2O2; sodium acetate In 2,2,2-trifluoroethanol for 20h; Inert atmosphere; Reflux; Schlenk technique; | |
87% | With potassium carbonate In n-heptane at 80℃; for 24h; | S4. Procedure for the synthesis of aldehydes and ketones General procedure: A magnetic stir bar, 0.5 mmol alcohol and 3 mL n-heptane solvent were added to 20 mL glass tube. Then, 35mg catalyst and 10 mol% of K2CO3 were added. The glass tube containing reaction mixture was f itted withseptum and connected to a balloon containing one bar of air. Then the glass tube was placed into a preheatedaluminum block at 85°C. Temperature inside the reaction tube was measured to be 80 oC and this temperaturehas been taken as the reaction temperature. The reaction was allowed to progress under continuous stirringfor the required time at 80 °C. Af ter completion of the reaction, the glass tube was cooled down to roomtemperature. Afterwards, the catalyst was f iltered-off and washed with ethyl acetate. The solvent f rom thef iltrate containing the reaction products was removed in vacuum and the corresponding aldehyde/ketone waspurif ied by column chromatography. All products were analyzed by GC-MS and NMR spectroscopy analysis.In the case of yields determined the by GC, 100 μL n-hexadecane was added to the reaction vial containingthe products and diluted with ethyl acetate. Then, the reaction mixture containing catalyst and products wasf iltered through a plug of silica and the filtrate containing product was analyzed by GC. |
84% | With 9-fluorenone In dimethyl sulfoxide at 20℃; Irradiation; | |
82% | With 1,2-dimethyl-3-[3-(methylsulfinyl)propyl]-1H-imidazolium triflate; oxalyl dichloride; triethylamine In dichloromethane; acetonitrile at -78 - 20℃; | |
82% | With Langlois reagent In acetonitrile at 25℃; for 12h; Irradiation; Sealed tube; | |
80% | With chlorine-triphenylphosphine; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; for 3.25h; | |
79% | With dimethyl sulfoxide; triethylamine In dichloromethane at -40 - 20℃; for 8h; | |
71% | With bromopentacarbonylmanganese(I); N-methyl-N,N-di(2-pyridylmethyl)amine; acetone; sodium t-butanolate In toluene at 90℃; for 24h; Inert atmosphere; Schlenk technique; Darkness; | |
63% | With trimethylamine-N-oxide; C18H26O4RuSi2 In water; acetone for 18h; Reflux; Inert atmosphere; | |
54% | With [bis({2‐[bis(propan‐2‐yl)phosphanyl]ethyl})amine](borohydride)(carbonyl)(hydride)iron(II); potassium <i>tert</i>-butylate; acetone In n-heptane at 80℃; for 24h; Schlenk technique; Inert atmosphere; | |
52% | With sodium hypochlorite In water; ethyl acetate Inert atmosphere; | |
With tert.-butylhydroperoxide; tetrabutyl-ammonium chloride; 2,2′‐biquinoline‐4,4′‐dicarboxylic acid dipotassium salt In water at 20℃; for 24h; | ||
With 2,6-dichloropyridine N-oxide; trifluoromethylcyclohexane In hexane; benzene at 55℃; for 0.25h; | ||
With trimethylaluminum In toluene at 20℃; for 1h; | ||
Multi-step reaction with 3 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 3: 5 percent / Pseudomonas putida UV4 / 18 h | ||
With oxygen; 1-(tert-butylsulfonyl)-2-iodylbenzene at 70℃; for 14h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sulfuric acid; Selectfluor In methanol at 50℃; Inert atmosphere; | |
89% | With sulfuric acid; Selectfluor In methanol at 50℃; Inert atmosphere; | |
83% | With 1-methyl-3-(propyl-3-sulfonyl)imidazolium trifluoromethanesulfonate; 1-butyl-3-ethylimidazolium hexafluorophosphate; Selectfluor at 80℃; for 12h; Inert atmosphere; Schlenk technique; | Typical procedure for fluorination of carbonyl compounds: General procedure: The carbonyl compound (0.25mmol) and Selectfluor (0.25mmol) were added to [BMIM][PF6] (25equiv) in a Schlenk tube, and [PMIM(SO3H)][OTf] (∼0.5mmol) was introduced at rt with stirring under a nitrogen atmosphere. The reaction mixture was stirred at 80°C for the specified period of time (see Tables). After completion of the reaction (TLC monitoring), the reaction mixture was extracted several times with diethyl ether (4×10mL), and the combined organic extracts were washed with aqueous saturated NaHCO3 followed by water, dried (MgSO4), and the solvent was evaporated under vacuum. The crude product was purified by silica gel column chromatography using 3-6% diethyl ether in hexane as eluent. |
79% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2,2,2]octane-1,4-bis(tetrafluoroborate) In methanol for 1.16667h; Heating; Stage #2: With hydrogenchloride In acetonitrile | |
64% | With Selectfluor In methanol Reflux; | |
With Selectfluor In methanol Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sulfuric acid In acetic acid at 20℃; for 0.333333h; | |
88% | With aluminum oxide for 0.0666667h; Microwave irradiation; neat (no solvent); | |
80% | With hydrogenchloride In acetic acid at 0℃; for 24h; |
75% | With piperidine | |
75% | With hydrogenchloride In methanol; water for 24h; Reflux; | 4.2. General procedure for the synthesis of 3-benzylidene-4-chromanones derivatives General procedure: A round-bottom flask was charged with the 4-chromanone (3.4 mmol) and aromatic-aldehyde (3.6 mmol). This was dissolved in methanol (20 mL), and concentrated hydrochloride (10 mL). The mixture was refluxed for 24 h and then diluted with water. Filtration afforded the crude product, which was crystallized from methanol to give the pure product. |
With piperidine at 105℃; for 1h; | ||
With piperidine at 140℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With chloro-trimethyl-silane; sodium iodide In acetonitrile at 20℃; for 0.833333h; | |
82% | With trimethylsilyl bromide; iron(III) chloride hexahydrate In acetonitrile at 90℃; for 2h; Microwave irradiation; Sealed tube; Inert atmosphere; | 3.3. General Procedure for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones (6) General procedure: A high-pressure microwave vessel (capacity 10 mL) was loaded with ketones (0.5 mmol),benzaldehydes (0.5 mmol), urea (0.75 mmol), FeCl36H2O (0.05 mmol) and TMSBr (0.5 mmol) in CH3CN (3.0 mL). The vessel was degassed, refilled with nitrogen, and sealed. Then the mixture was heated to 90 °C for 2 h under microwave irradiation using a CEM Discover (fixed power, 30 W). Aftercooling, the solids which had precipitated out were separated by filtration, and the solids obtained were washed with CH3CN to give the desired products 6. |
81% | With chloro-trimethyl-silane In acetonitrile for 12h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen In methanol at 30℃; for 23h; | 45 An example of synthesizing optically active 4-chromanol by hydrogenation of chromanone is described below. A 50 mL stainless steel autoclave was charged with RuCl[(S,S)-Tsdpen](mesitylene) (1.0 mg, 0.0016 mmol) under argon. Then 4-chromanone (474 mg, 3.2 mmol) and methanol (6.4 mL) were added thereto. After pressurization with hydrogen, substitution was conducted five times. Hydrogen was charged to 50 atm to initiate reaction. After stirring for 23 hours at 30°C, the reaction pressure was reduced to normal. The product was analyzed by 1H-NMR and HPLC reporting synthesis of (S)-4-chromanol in 91% ee and 100% yield. |
99% | With formic acid; dichloro(hexamethylbenzene)ruthenium(II) dimer; (S)-2-piperidinemethanethiol hydrochloride; triethylamine at 30℃; for 24h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | |
99% | With Cp*Ir(OTf)(Msdpen); hydrogen In methanol at 60℃; for 24h; optical yield given as %ee; enantioselective reaction; |
99% | With formic acid; dichloro(hexamethylbenzene)ruthenium(II) dimer; (S)-2-piperidinemethanethiol hydrochloride; triethylamine at 30℃; for 24h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | |
98% | With hydrogen In methanol at 50℃; for 15h; | 17 In a stainless steel autoclave, Ru(OTf)[(S,S)-Tsdpen](p-cymene) (2.4 mg, 3.3 μmol), Yb(OTf)3 (0.62 mg, 1 μmol), and 4-chromanone (1.48 g, 10 mmol) were charged, followed by purging with argon. Then, 0.7 ml of methanol was added, and the autoclave was pressurized with hydrogen, followed by ten times of purging. Then, hydrogen was charged to 15 atm to initiate reaction. After stirring at 50° C. for 15 hours, the reaction pressure was returned to normal pressure. 1HNMR and HPLC analysis of the product showed that (S)-4-chromanol with 97% ee was produced in a yield of 98%. |
98% | With hydrogen In methanol at 50℃; for 15h; | 23 Synthesis of (S)-4-chromanol by Hydrogenation Reaction of 4-chromanone Example 23 Synthesis of (S)-4-chromanol by Hydrogenation Reaction of 4-chromanone In a stainless steel autoclave, Ru(OSO2CH3) [(S,S)-Tsdpen](p-cymene) (1.4 mg, 2 μmol) and 4-chromanone (300 mg, 2 mmol) were charged, followed by purging with argon. Then, 0.1 ml of methanol was added, and the autoclave was pressurized with hydrogen, followed by ten times of purging. Then, hydrogen was charged to 15 atm to initiate reaction. After stirring at 50° C. for 15 hours, the reaction pressure was returned to normal pressure. 1H-NMR and HPLC analysis of the product showed that (S)-4-chromanol with 95% ee was produced in a yield of 98%. |
97% | With formic acid; C29H38N3O2RuS; triethylamine at 60℃; for 30h; Inert atmosphere; enantioselective reaction; | |
96% | With potassium methylate In water monomer; toluene at 50℃; for 24h; | F.1.2; F.1.3 The reaction was performed under the same conditions as those in Example F-1-1, except that 32 mg (100 μmol) of tetrabutylammonium bromide as the phase-transfer catalyst was added. HPLC analysis of the reactant confirmed that 4-chromanol with optical purity of 97% ee was produced in 99% yield, demonstrating that the activity and enantioselectivity of the main catalyst is improved by the addition of a phase-transfer catalyst.; Example F-1-3; Asymmetric Reduction of 4-chromanone Using Cp*IrCl[(S,S)-MsDPEN] Catalyst with Addition of Phase-Transfer Catalyst and Potassium Formate Solution as Hydrogen Source (Reaction at S/C=10,000); 2.02 g (24.0 mmol) of HCOOK as the hydrogen source, 1.305 mg (2.0 μmol) of Cp*IrCl[(S,S)-MsDPEN] as the catalyst, 64.5 mg (0.20 mmol) of tetrabutylammonium bromide as the phase-transfer catalyst, and 2.96 g (20.0 mmol) of 4-chromanone were introduced in a 20 mL Schlenk tube, and the mixture was subjected to argon substitution. 4 mL of water and 2 ml of toluene were added and the resulting mixture was maintained at 50° C. for 24 hr while stirring. The organic phase was washed three times with 5 mL of water, and the toluene was distilled off under reduced pressure to give an optically-active alcohol. HPLC analysis of the reactant confirmed that 4-chromanol with optical purity of 98% ee was produced in 96% yield, demonstrating that the use of a potassium formate solution as the hydrogen source and the catalyst system in which Cp*IrCl[(S,S)-MsDPEN] catalyst is combined with tetrabutylammonium bromide exhibits high efficiency. |
95% | With hydrogen In methanol at 50℃; for 15h; | 15; 16; 18; 19; 20 Synthesis of (S)-4-chromanol by Hydrogenation Reaction of 4-chromanone Example 15 Synthesis of (S)-4-chromanol by Hydrogenation Reaction of 4-chromanone In a stainless steel autoclave, Ru(OTf)[(S,S)-Tsdpen](p-cymene) (2.4 mg, 3.3 μmol) and 4-chromanone (1.48 g, 10 mmol) were charged, followed by purging with argon. Then, 0.5 ml of methanol was added, and the autoclave was pressurized with hydrogen, followed by ten times of purging. Then, hydrogen was charged to 15 atm to initiate reaction. After stirring at 50° C. for 15 hours, the reaction pressure was returned to normal pressure. 1H-NMR and HPLC analysis of the product showed that (S)-4-chromanol with 91% ee was produced in a yield of 100%. The spectral data of the resultant alcohol compound was as follows: 1H-NMR (400 MHz, CDCl3) δ 1.99 (m, 1H, CHCHOH), 2.08 (m, 1H, CHCHOH), 2.31 (br, 1H, OH), 4.23 (m, 2H, C2OC), 4.74 (m, 1H, COH), 6.81-6.92 (m, 2H, aromatic H), 7.17-7.30 (m, 2H, aromatic H); HPLC (CHIRALCEL OJ-H; solvent, hexane/2-propanol=99/1; flow rate, 1.5 ml/min; temperature, 35°; UV wavelength, 220 nm); tR of (S)-4-chromanol, 26.7 minutes; tR of (R)-4-chromanol, 30.8 minutes; tR of 4-chromanone, 11.8 minutes; specific rotatory power [α]25D-72° (c0.5, C2H5OH); document value, [α]25D+80.40 (c0.5, C2H5OH), 100% ee (R), J. Am. Chem. Soc., 1993, 115, 3318. Example 16Synthesis of (S)-4-chromanol by Hydrogenation Reaction of 4-chromanoneIn a stainless steel autoclave, Ru(OTf)[(S,S)-Tsdpen](p-cymene) (2.4 mg, 3.3 μmol) and 4-chromanone (1.48 g, 10 mmol) were charged, followed by purging with argon. Then, 0.7 ml of methanol was added, and the autoclave was pressurized with hydrogen, followed by ten times of purging. Then, hydrogen was charged to 15 atm to initiate reaction. After stirring at 50° C. for 15 hours, the reaction pressure was returned to normal pressure. 1HNMR and HPLC analysis of the product showed that (S)-4-chromanol with 93% ee was produced in a yield of 100%.; Examples 18 to 20(S)-4-chromanol was synthesized by reaction under the same conditions as in Example 15 except that the substrate/catalyst ratio and the hydrogen pressure were changed. The results are summarized in Table 3. |
95% | With hydrogen In methanol at 50℃; for 15h; | 24 Synthesis of (S)-4-chromanol by Hydrogenation Reaction of 4-chromanone In a stainless steel autoclave, Cp*Ir(OTf)[(S,S)-Tsdpen] (1.6 mg, 2 μmol) and 4-chromanone (300 mg, 2 mmol) were charged, followed by purging with argon. Then, 0.4 ml of methanol was added, and the autoclave was pressurized with hydrogen, followed by ten times of purging. Then, hydrogen was charged to 30 atm to initiate reaction. After stirring at 50° C. for 15 hours, the reaction pressure was returned to normal pressure. 1HNMR and HPLC analysis of the product showed that (S)-4-chromanol with 95% ee was produced in a yield of 95%. |
95% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With 1-((1R,2R)-2-(benzylamino)cyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea; benzo[1,3,2]dioxaborole In toluene at -46℃; for 24h; Molecular sieve; Inert atmosphere; Stage #2: With methanol; sodium hydroxide In toluene at -46 - 20℃; optical yield given as %ee; enantioselective reaction; | |
93% | With hydrogen In methanol at 60℃; for 15h; | |
93% | With anhydrous sodium perchlorate; hydrogen In methanol at 30℃; for 23h; | 47 An example of synthesizing optically active 4-chromanol by hydrogenation of chromanone is described below. A 50 mL stainless steel autoclave was charged with RuCl[(S,S)-Tsdpen](p-cymene) (1.0 mg, 0.0016 mmol) and NaClO4 (10 mg, 0.08 mmol) under argon. Then 4-chromanone (1185 mg, 8.0 mmol) and methanol (16 mL) were added thereto. After pressurization with hydrogen, substitution was conducted five times. Hydrogen was charged to 50 atm to initiate reaction. After stirring for 23 hours at 30°C, the reaction pressure was reduced to normal. The product was analyzed by 1H-NMR and HPLC reporting synthesis of (S)-4-chromanol in 97% ee and 93% yield. |
89% | With potassium methylate In water monomer; toluene at 50℃; for 24h; | F.1.1 3.36 g (40.0 mmol) of HCOOK as the hydrogen source, 1.044 mg (1.6 μmol) of Cp*IrCl[(S,S)-MsDPEN] as the catalyst, and 1.185 g (8.0 mmol) of 4-chromanone were introduced in a 20 mL Schlenk tube, and the mixture was subjected to argon substitution. 2 mL of water and 2 ml of toluene were added and the resulting mixture was maintained at 50° C. for 24 hr while stirring. The organic phase was washed three times with 3 mL of water, and the toluene was distilled off under reduced pressure to give an optically-active alcohol. HPLC analysis of the reactant confirmed that 4-chromanol with optical purity of 95% ee was produced in 89% yield. |
85% | With hydrogen In methanol at 30℃; for 23h; | 46 An example of synthesizing optically active 4-chromanol by hydrogenation of chromanone is described below. A 50 mL stainless steel autoclave was charged with RuCl[(S,S)-Tsdpen](p-cymene) (1.0mg, 0.0016 mmol) under argon. Then 4-chromanone (474 mg, 3.2 mmol) and methanol (6.4 mL) were added thereto. After pressurization with hydrogen, substitution was conducted five times. Hydrogen was charged to 50 atm to initiate reaction. After stirring for 23 hours at 30°C, the reaction pressure was reduced to normal. The product was analyzed by 1H-NMR and HPLC reporting synthesis of (S)-4-chromanol in 97% ee and 85% yield. |
83% | With borane-N,N-diethylaniline complex; (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c]-[1,3,2]oxazaborole In toluene at 25℃; for 4h; Inert atmosphere; optical yield given as %ee; | |
80% | With 1,4-butenediol; Wills catalyst; potassium hydroxide In tetrahydrofuran at -10℃; for 4h; Inert atmosphere; enantioselective reaction; | |
77% | With hydrogen In methanol at 50℃; for 15h; | 22 Synthesis of (S)-4-chromanol by Hydrogenation Reaction of 4-chromanone Example 22 Synthesis of (S)-4-chromanol by Hydrogenation Reaction of 4-chromanone In a stainless steel autoclave, Ru[OSO2(p-NO2Ph)][(S,S)-Tsdpen](p-cymene) (2.6 mg, 3.3 μmol) and 4-chromanone (1.48 g, 10 mmol) were charged, followed by purging with argon. Then, 0.5 ml of methanol was added, and the autoclave was pressurized with hydrogen, followed by ten times of purging. Then, hydrogen was charged to 15 atm to initiate reaction. After stirring at 50° C. for 15 hours, the reaction pressure was returned to normal pressure. 1H-NMR and HPLC analysis of the product showed that (S)-4-chromanol with 91% ee was produced in a yield of 77%. |
70% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With dichloro(p-cymene)ruthenium(II) dimer; isopropanol; lithium chloride; Boc-L-alanine(2S)-hydroxypropylamide In tetrahydrofuran at 30℃; for 0.25h; Inert atmosphere; Stage #2: With sodium isopropanolate In tetrahydrofuran at 30℃; for 0.5h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | |
70% | With di-μ-chlorobis-[(η6-p-cymene)chlororuthenium(II)]; N-(tert-butoxycarbonyl)-L-valine-(6-amido-1-O-benzyl-6-deoxy-2,3-O-isopropylidene-α-D-mannofuranose); potassium-t-butoxide; lithium chloride In tetrahydrofuran; isopropanol at 20℃; for 3h; enantioselective reaction; | |
44% | With Almag CRED A131; NADP; glucose dehydrogenase In water monomer; dimethyl sulfoxide at 30℃; Enzymatic reaction; | 4.4 General procedure: Almac CRED (200 mg),NADP or NAD (10 mg), GDH (20 mg) and glucose (1.5 equiv) weremeasured into a 100 mL round bottomed flask then dissolved in0.1 M potassium phosphate buffer (pH 7, ca. 50 mL) and stirredat 30 C. Next, a solution of ketone (900-1700 mg) in DMSO(2.5-5 mL, depending on solubility) was added to the reactionand this was allowed to stir overnight under pH-stat control (pH7.0, adjusted with 1 M NaOH solution). The following day, reactionprogress was checked by 1H NMR. If not complete, additional CRED(100-200 mg), NADP or NAD (10 mg) and GDH (10 mg) wereadded and stirring was continued. This was repeated until the reactionreached completion or had stalled and would not go any further. |
39% | With potassium hydroxide; (+)-Norephedrine In isopropanol at 20℃; | |
19% | With potassium methylate In water monomer; toluene at 50℃; for 24h; | F.9 The reaction was performed under the same conditions as those in Example F-1-1, except that 1.165 mg (1.6 μmol) of Cp*IrCl[(S,S)-TsDPEN] was used as the catalyst. HPLC analysis of the reactant confirmed that 4-chromanol with optical purity of 94% ee was produced in 19% yield. Comparison with Example F-1-1 demonstrated that it is superior to have a methyl group as the substituent on the sulfonyl group. |
10% | With formic acid; triethylamine at 50℃; for 24h; | F.2.1; F.2.2 A formic acid-triethylamine mixture (molar ratio of HCOOH:Et3N:substrate=3.1:2.6:1) as the hydrogen source, 1.044 mg (1.6 μmol) of Cp*IrCl[(S,S)-MsDPEN] as the catalyst, and 1.185 g (8.0 mmol) of 4-chromanone were introduced in a 20 mL Schlenk tube, and the mixture was subjected to argon substitution, then maintained at 50° C. for 24 hr while stirring. HPLC analysis of the reactant confirmed that 4-chromanol with optical purity of 88% ee was produced in 10% yield.; Example F-2-2; Asymmetric Reduction of 4-chromanone Using Cp*IrCl[(S,S)-MsDPEN] Catalyst and Formic Acid-Triethylamine Mixture as Hydrogen Source; The reaction was performed under the same conditions as those in Example F-2-1, except that the amount of the catalyst was 2.610 mg (4.0 μmol). HPLC analysis of the reactant confirmed that 4-chromanol with optical purity of 95% ee was produced in 89% yield. |
7% | With hydrogen In methanol at 50℃; for 15h; | 1 In a stainless steel autoclave, Ru[(S,S)-Tsdpen](p-cymene) (1.2 mg, 2 μmol) and 4-chromanone (0.3 g, 2 mmol) were charged, followed by purging with argon. Then, 2 ml of methanol was added, and the autoclave was pressurized with hydrogen, followed by ten times of purging. Then, hydrogen was charged to 30 atm to initiate reaction. After stirring at 50° C. for 15 hours, the reaction pressure was returned to normal pressure. 1HNMR and HPLC analysis of the product showed that (S)-4-chromanol with 86% ee was produced in a yield of 7%. As a result, it was found that the sulfonate catalyst of the present invention exhibits excellent activity as compared with a conventional well-known ruthenium complex. |
With borane N,N-diethylaniline complex; Trimethyl borate; chiral 2-(diphenylhydroxymethyl)pyrrolidine In toluene at 23℃; | ||
With sodium isopropanolate; isopropanol; Boc-L-alanine(2S)-hydroxypropylamide at 20℃; for 1h; | ||
Multi-step reaction with 2 steps 1: [Rh(cod)Cl]2; asymmetric tetraphenyl-tetraoxa-phosphazulene derivative / toluene / 24 h / 0 °C 2: 1 percent p-TsOH / methanol | ||
With N,N-diethylaniline borane; (R)-(+)-α,α-diphenyl-2-pyrrolidinemethanol In tert-butyl methyl ether at 45℃; for 1.5h; | ||
97.9 % ee | With (S,S)-RuCl(η6-CH3C6H4CH2CH2CH2CH2NHCH(C6H5)CH(C6H5)NSO2Ts); C32H35ClN2O2RuS; hydrogen In methanol at 60℃; for 19h; Inert atmosphere; Autoclave; enantiospecific reaction; | 39 Asymmetric hydrogenation of 4-chromanone using RuCl(Tol-C4-teth-(S,S)-Tsdpen) Example 39 Asymmetric hydrogenation of 4-chromanone using RuCl(Tol-C4-teth-(S,S)-Tsdpen) In a 100-ml autoclave, 3.1 mg (0.00478 mmol, S/C=1000) of RuCl(Tol-C4-teth-(S,S)-Tsdpen) was placed, followed by purging with nitrogen. Subsequently, 0.72 g (5.0 mmol) of 4-chromanone and 4.4 ml of methanol were added thereto, and hydrogen was introduced to a pressure of 3.0 MPa, followed by stirring at 60° C. for 19 hours. The result of GC analysis of the reaction liquid showed that (S)-4-chromanol was obtained with a conversion of 100% and an optical purity of 97.9% ee.; Example 40 Asymmetric hydrogenation of 4-chromanone using RuCl(Tol-C4-teth-(S,S)-Msdpen) In a 100-ml autoclave, 2.8 mg (0.00489 mmol, S/C=1000) of RuCl(Tol-C4-teth-(S,S)-Msdpen) was placed, followed by purging with nitrogen. Subsequently, 0.72 g (5.0 mmol) of 4-chromanone and 4.4 ml of methanol were added thereto, and hydrogen was introduced to a pressure of 3.0 MPa, followed by stirring at 60° C. for 19 hours. The result of GC analysis of the reaction liquid showed that (S)-4-chromanol was obtained with a conversion of 100% and an optical purity of 97.6% ee. |
Multi-step reaction with 2 steps 1: sodium tetrahydridoborate 2: Burkholderia cepacia Amano-PS lipase; immobilized on diatomaceous earth / tert-butyl methyl ether / 14 h / 23 °C / Resolution of racemate; Enzymatic reaction | ||
96 % ee | With di-μ-chlorobis-[(η6-p-cymene)chlororuthenium(II)]; anhydrous sodium formate; chitosan In water monomer; isopropanol at 20℃; for 46h; Green chemistry; enantioselective reaction; | |
96 % ee | With di-μ-chlorobis-[(η6-p-cymene)chlororuthenium(II)]; anhydrous sodium formate; chitosan In water monomer; isopropanol at 23℃; for 46h; Sealed tube; enantioselective reaction; | |
Multi-step reaction with 3 steps 1: sodium tetrahydridoborate; methanol / 0.67 h / 0 - 20 °C / Inert atmosphere 2: (OC-6-23)-[2-[6-[(amino-κN)methyl]-2-pyridinyl-κN]-5-methylphenyl-κC][1,1'-(1,4-butanediyl)bis[1,1-diphenylphosphine-κP]]chlororuthenium(II); copper chloride (I); sodium tertiary butoxide; 1,2-bis((2R,5R)-2,5-diphenylphospholan-1-yl)ethane / toluene / 14 h / 20 °C / Glovebox; Inert atmosphere 3: N,N,N-tributylbutan-1-aminium fluoride / tetrahydrofuran / 0.5 h / 20 °C / Inert atmosphere | ||
96 % ee | With di-μ-chlorobis-[(η6-p-cymene)chlororuthenium(II)]; anhydrous sodium formate; chitosan In water monomer; isopropanol at 20℃; for 24h; enantioselective reaction; | |
99 % ee | With di-μ-chlorobis-[(η6-p-cymene)chlororuthenium(II)]; anhydrous sodium formate In water monomer; isopropanol at 50℃; for 5h; |
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 |
---|---|---|
100% | With potassium-t-butoxide In tetrahydrofuran at -78 - 20℃; | |
100% | With potassium-t-butoxide In tetrahydrofuran at -78 - 60℃; for 24h; | 4 Preparation of 3,3-dimethyl-2,3-dihydro-4H-chromen-4-one, Compound 3 Preparation of 3,3-dimethyl-2,3-dihydro-4H-chromen-4-one, Compound 3 To a cooled (-78° C. bath temperature) solution of 2,3-dihydro-4H-chromen-4-one (25 grams, 0.169 mole) and iodomethane (120 grams, 53 ml, 0.945 mole) in anhydrous tetrahydrofuran (1000 ml) was added portion-wise potassium tertiary butoxide (94.5 grams, 0.945 mole) over a period of 1 hour under an argon atmosphere. During this process, the reaction temperature was kept at -78° C. to avoid exothermic reaction. The cooling bath was removed, and the resulting mixture was warmed to room temperature over a period of 4 hours. The white viscous mixture was heated at 60° C. (bath temperature) for 4 hours, cooled to room temperature, and stirred at room temperature for 15 hours. The resulting mixture was poured into a mixture of diethyl ether and water. The organic layer was separated, and the aqueous layer was extracted with diethyl ether. The combined extracts were washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The residue was chromatographed (silica gel, elution by methylene chloride) to give 30 grams (100%) of 3,3-dimethyl-2,3-dihydro-4H-chromen-4-one as a clear pale yellow oil. Physical properties of the product were the same as those described in Example 3. |
89% | With potassium-t-butoxide In tetrahydrofuran at -78 - 20℃; Inert atmosphere; |
85% | With potassium-t-butoxide In tetrahydrofuran at -78 - 20℃; for 18.5h; Inert atmosphere; | |
69.1% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one In tetrahydrofuran at 0℃; Stage #2: iodomethane With potassium-t-butoxide In tetrahydrofuran at 0 - 10℃; for 0.916667h; | 5.1 (1) The first step: the preparation of 3,3-dimethylchroman-4-one (3,3-dimethylchroman-4-one) To a 100 mL three-necked flask, add tetrahydrofuran (40 mL, 12 V), stir to dissolve, replace with nitrogen three times, and lower the internal temperature to 0°C in an ice-water bath.2,3-Dihydrobenzopyran-4-one tetrahydrofuran solution (5g, dissolved in 20ml THF, 4V) was added dropwise, and the system was a colorless and transparent solution.The internal temperature was controlled to 0-15° C., 50% iodomethane tetrahydrofuran solution (95.6 g, 10 eq) was added dropwise with no obvious exotherm, and the mixture was stirred for 10 min.Potassium tert-butoxide (9.46g, 2.5eq) was added in batches under the control of the internal temperature at 0-10°C, and the system gradually changed from a colorless and transparent solution to an orange-yellow suspension.After 45 minutes, the addition was completed, and the internal temperature was controlled at 0-5 °C and stirred for 1 hour. TLC spot plate, the raw material has not reacted completely.The internal temperature was controlled to 0-5°C, potassium tert-butoxide (1.89g, 0.5eq) was added, and the reaction was stirred for 1h.TLC monitoring showed that the main impurities were reduced (presumed to be monomethyl impurities), and the raw materials remained.After post-treatment, add water (15ml, 3V) under temperature control at 5-20°C, the temperature did not rise significantly, after stirring for 10min,1M dilute hydrochloric acid was added to adjust pH=5, the system gradually turned into a yellow clear solution, and stirred for 30min. Extract with EA (100ml×4), combine the organic phases, dry with anhydrous sodium sulfate,It was concentrated under reduced pressure at 35° C. until no droplets were observed to obtain 6.1 g of yellow oil, which was purified by column chromatography to obtain 4.1 g of pure 3,3-dimethylchroman-4-one. Yield 69.1%. |
63% | With potassium-t-butoxide In tetrahydrofuran at -70℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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85% | With pyrrolidine In methanol at 20℃; for 3h; | 17 4.1.2. General procedure for the synthesis of (E)-3-heteroarylidenechroman-4-ones (1a-r) General procedure: METHOD A: Pyrrolidine (10 mmol) was added to a mixture of the appropriate chroman-4-one (6.7 mmol) and heteroaryl aldehyde (10 mmol) in dry MeOH (15 mL for 1a, 1b, 1e, 1h, 1k-r and 30mL for 1c, 1d, 1i, 1j). The reaction mixture was stirred at room temperature for 1-24 h (1h for 1f, 3h for 1l-q, 24h for 1a-c, 1h-j, 1n, and 1o). The mixture was diluted with ice-water, and the precipitate was filtered off and washed with water. The crude solid was purified by column chromatography on silica gel, eluting with a mixture of AcOEt and CHCl3 (3:1) (1a-g and 1i-r) or CHCl3 (1h) and crystallized from n-hexane. METHOD B: (synthesis of 1f and 1g) A mixture of chroman-4-one (6.7 mmol), the appropriate pyridinecarbaldehyde (10 mmol) and pyrrolidine (10 mmol) was heated at 120 °C under stirring for 1 h. After cooling, the mixture was diluted with ice-water, and the precipitate was filtered off and washed with water. The crude solid was purified by column chromatography on silica gel, eluting with a mixture of AcOEt and CHCl3 (3:1), and crystallized from n-hexane. 4.1.2.17 (E)-3-[(Thiophen-2-yl)methylene]chroman-4-one (1q) Yield: 85%, mp = 126-127 °C (lit. 125-126 °C) [16] . IR (KBr): 1661 cm-1. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.01 (d, 1H, H5, J5-6 = 7.2 Hz), 7.98 (s, 1H, =CH), 7.59 (d, 1H, H3', J3'-4' = 4.4 Hz), 7.48 (t, 1H, H7, J7-8 = J7-6 = 7.2 Hz), 7.34 (d, 1H, H5', J4'-5' = 4.4 Hz), 7.16 (t, 1H, H4', J3'-4' = J4'-5' = 4.4 Hz), 7.06 (t, 1H, H6, J5-6 = J7-6 7.2 Hz), 6.98 (d, 1H, H8, J7-8 = 7.2 Hz), 5.46 (d, 2H, H2, Jall = 1.2 Hz). 13C NMR (CDCl3, 100 MHz): δ (ppm) 181.24, 161.02, 137.67, 135.69, 133.88, 130.94, 128.70, 128.20, 127.87, 127.28, 121.95, 121.89, 117.83, 67.81. Anal. Calcd. for C14H10O2S: C, 69.40; H, 4.16; S, 13.23. Found: C, 69.26; H, 4.16; S, 13.28. |
84% | With hydrogenchloride In acetic acid at 0℃; for 24h; | |
With hydrogenchloride Reflux; |
Yield | Reaction Conditions | Operation in experiment |
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62% | To mechanically stirred neat aluminum trichloride (18.0 g, 135 mmol, 2.50 equiv) was added 4-chromanone (8.00 g, 54.0 mmol) portionwise at room temperature. The resulting brown oil was stirred for 10 minutes and bromine (3.34 mL, 65.8 mmol, 1.20 equiv) was added portionwise. The mixture was stirred for 10 minutes, heated to 80 C for 10 minutes, cooled to 0 C and quenched with careful addition of ice. The mixture was then diluted with ether and water, the organic layer was washed with 1M hydrochloric acid (3x), brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified on a 40M Biotage column (0 to 10% ethyl acetate in hexanes over 30 minutes) to give 7.61 g of 6-BROMO-CHROMAN-4-ONE (Yield: 62%). The isolated product contains 21% DIBROMIDE. HL NMR (400 MHz, CDC13) : 8 2.80 (t, 2H), 4.53 (t, 2H), 6.85 (d, 1H), 7.53 (dd, 1H), 7.98 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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Preparation Example 7 By the reaction and treatment in the same manner as in Preparation Example 5 using 4-chromanone (5.1 g) as a starting material, chroman-4-carboxylic acid (4.1 g) was obtained. melting point: 94.3ØC |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Chroman-4-amine :; Chroman-4-one (3 g, 20.1 mmol), titanium(IV) isopropoxide (12.0 niL, 40.2 mmol) and2 M solution of ammonia in ethanol (60.6 mL, 121.2 mmol) were stirred at room temperature for 6 h. The reaction was cooled to 0 C and sodium borohydride was added portionwise during 10 min. (1.14 g, 30.2 mmol); the resultant mixture was stirred at rt for an additional 3 h. The reaction was quenched by pouring it into ammonium hydroxide (2 M, 60 mL), the precipitate that formed was filtered off and washed with ethyl acetate (15 mL x 3). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (15 mL x 2). The combined organic extracts were washed with 1 M HCl (25 mL). The acidic aqueous extracts were washed with ethyl acetate (50 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10-12, and extracted with ethyl acetate (40 mL x 3). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo to affordChroman-4-amine as an oil (2.61 g, 87 % yield). 1H NMR (400 MHz, CDCl3) delta 7.31 (d, IH), 7.23 (m, IH), 6.94 (m, IH), 6.82 (d, IH), 4. 38 (m, 2H), 4.12 (m, IH), 2.19 (m, 2H), 1.82 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With trifluoromethanesulfonic acid anhydride; In hexane; dichloromethane; | (34a) Trifluoromethanesulfonic anhydride (1.2 mL, 7.4 mmol)was added drop wise to a stirring solution of chroman-4-one (1.0 g, 6.7 mmol), 2,6-di-t-butyl-4-methyl pyridine (1.59 g, 7.7 mmol) in dichloromethane (40 mL), under nitrogen atmosphere. The reaction was heated to reflux for 2 h, allowed to cool to room temperature and was concentrated in vacuo to give a semi solid residue. This was treated with hexane and the solids were filtered off. The filtrate was concentrated to give 4-[(trifluoromethyl)sulfonyl]-2H-chromene (1.78 g, 94percent) as an orange oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium bicarbonate; In nitric acid; | Step 1 6-Nitrochroman-4-one At -35 C., 60 g of 4-chromanone are added in small portions to 385 ml of 90% nitric acid. The whole is poured onto ice and then extracted with dichloromethane. The organic phase is washed with a saturated solution of sodium hydrogen carbonate and dried over magnesium sulphate and then the solvent is evaporated off. | |
(8-1) After cooling 40 ml of fuming nitric acid to -30 to -35 C., 5.8 g of 4-chromanone was added with stirring over about 30 minutes and further stirred for 30 minutes at the same temperature. The reaction mixture was successively poured into ice water and extracted with 500 ml of ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The crude product thus obtained was washed with a solvent mixture, n-hexane:ethyl acetate=1:1, to give 5.4 g of 6-nitro-4-chromanone. | ||
With nitric acid; | (3-1) Fuming nitric acid (200 ml) was cooled to from -30 to -35 C. and 4-chromanone (29.0 g) was added with stirring over 30 minutes. The mixture was further stirred for 30 minutes at the intact temperature and successively poured into ice water. The resulting mixture was extracted with ethyl acetate (2,500 ml). The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the crude product as a yellow solid. The crude product was washed with a solvent mixture, n-hexane:ethyl acetate=1:1, to obtain 6-nitro-4-chromanone (27.0 g). |
With nitric acid; | (3-1) Fuming nitric acid (200ml) was cooled to from -30 C to -35 C and 4-chromanone (29.0g) was added with stirring over 30 minutes. The mixture was further stirred for 30 minutes at the same temperature and successively poured into ice water. The resulting mixture was extracted with ethyl acetate (2,500ml). The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the crude product as a yellow solid. The crude product was washed with a solvent mixture, n-hexane: ethyl acetate = 1: 1, to obtain 6-nitro-4-chromanone (27.0g). | |
With nitric acid; at -30℃; for 3h; | To a cooled solution of 90% HN03 (20 mL) at -30 C, was added compound Bl (10 g, 67.5 mmol) portionwise over 30 min. The resulting mixture was stirred at -30C for 3 h and then slowly poured onto ice. To the mixture was added cold water. The solid product was isolated via filtration. The solid was then washed with water and dried under vacuum to afford B2. FontWeight="Bold" FontSize="10" H- NMR (CDC13, 400 MHz): 8.8.82 (d, J = 2.8 Hz, 1H), 8.36 (dd, J = 9.1, 2.8 Hz, 1H), 7.14 (d, J = 9.1 Hz, 1H), 4.69 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.5 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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81%; 9% | With sulfuric acid; potassium nitrate; at 0℃; for 2h; | /V-(3,4-Dihydro-2W-chromen-6-yl)acetamide (228). A solution of KNO3 (2.25 g, 22.3 mmol) in CH2SO4 (10 mL) was added dropwise to a stirred solution of 4-chromanone (225) (3.0 g, 20.2 mmol) in CH2SO4 (50 mL) at 0 0C and the mixture stirred at 0 0C for 2 h. The mixture was poured into ice/water (500 mL), stirred 30 min and the precipitate filtered. The solid was washed with water (3 x 10 mL) and dried. The solid was purified by chromatography, eluting with 20% EtOAc/pet. ether, to give (i) 8-nitro-2,3-dihydro-4/-/- chromen-4-one (226) (369 mg, 9%) as a white solid: mp (EtOAc/pet. ether) 120-121 0C; 1H NMR delta 8.17 (dd, J = 7.8, 1.8 Hz, 1 H, H-7), 8.10 (dd, J = 8.0, 1.8 Hz, 1 H, H-5), 7.12 (dd, J = 8.0, 7.8 Hz, 1 H, H-6), 4.73 (dd, J = 6.5, 6.4 Hz, 2 H, H-2), 2.95 (br t, J = 6.5 Hz, 2 H, H-3). Anal, calcd for C9H7NO4: C, 56.0; H, 3.7; N, 7.3. Found: C, 56.1; H, 3.7; N, 7.3%; and (ii) 6-nitro-2,3-dihydro-4/-/-chromen-4-one (227) (3.17 g, 81%) as a white solid: mp (EtOAc/pet. ether) 169-171 0C; 1H NMR delta 8.78 (d, J = 2.8 Hz, 1 H, H-5), 8.32 (dd, J = 9.1, 2.8 Hz, 1 H, H-7), 7.11 (d, J = 9.1 Hz, 1 H, H-8), 4.67 (dd, J = 6.6, 6.4 Hz, 2 H, H-2), 2.91 (dd, J = 6.6, 6.4 Hz, 2 H, H-3); 13C NMR delta 189.4, 165.7, 142.1, 130.3, 123.7, 120.8, 119.3, 67.6, 37.1. Anal, calcd for C9H7NO4: C, 56.0; H, 3.7; N, 7.3. Found: C, 56.1; H, 3.7; N, 7.4%.A mixture of nitrochromanone 227 (2.0 g, 13.4 mmol) and Pd/C (5%, 100 mg) in EtOH/EtOAc (4:1, 150 mL), water (10 mL), and cHCI (1 mL) was stirred under H2 (60 psi) for 16 h. The mixture was filtered through celite, washed with EtOH (3 x 25 mL) and the solvent evaporated. The residue was partitioned between dilute aqueous NH3 solution and DCM, the organic fraction dried, and the solvent evaporated. The residue was dissolved in dry dioxane (100 mL) and Ac2O (2.8 mL, 29.4 mmol) added dropwise. The solution was stirred at 20 0C for 16 h, diluted with water and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 228 (2.09 g, 70%) as a white solid: mp 111-113 0C [lit. (Hach, V. Coll. Czech. Chem. Commun. 1959, 24, 3136-3140) mp (EtOH) 118 0C]; 1H NMR delta 7.28 (d, J = 2.2 Hz, 1 H, H-5), 7.02 (dd, J = 8.6, 2.2 Hz, 1 H, H-7), 6.72 (d, J = 8.6 Hz, 1 H, H-8), 4.15 (br dd, J = 5.2, 5.0 Hz, 2 H, H-2), 2.77 (br t, J = 6.5 Hz, 2 H, H-4), 2.13 (s, 3 H, CH3), 1.95- 2.02 (m, 2 H, H-3). |
With sulfuric acid; potassium nitrate; at 0℃; for 3h; | StepTo a solution of chroman-4-one (5.0 g, 33.7 mmol) in concentrated H2S04 (50 mL), a solution of potassium nitrate (3.75 g, 37.1 mmol) in 30 mL concentrated H2S04 was added portion-wise at 00 C. The solution was stirred for 3 hours at 0 C. After completion of the reaction, the solution was poured slowly onto a water-ice mixture. The precipitate obtainedwas filtered, washed with water and air-dried, to obtain a crude mixture which contains 6- nitro-4-chromanone as the major isomer and 5-nitro-4-chromanone as a minor isomer. The crude mixture was recrystallized using ethyl acetate/hexane to obtain the pure compound.1H NMR (DMSO-cL5, 300 MHz): S ppm 8.80 (d, J=2.7Hz, 1H), 8.36 (dd, J=2.7 & 9.3Hz, 1H), 7.14 (d, J=9.3Hz, 1H), 4.70 (t, J=6.6 & 6.6Hz, 2H), 2.94 (t, J=6.6 & 6.6Hz, 2H); Mass(ESI): mlz 194 [M + H] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In ethanol; isopropyl alcohol; | EXAMPLE I 3-[(4-Chromanylidene)amino]-2-oxazolidinone A 62-g (0.61 mole) portion of <strong>[80-65-9]3-amino-2-oxazolidinone</strong> was charged in a 500-ml, 3-necked flask equipped with a thermometer, stirrer and reflux condenser, and treated successively with 92 ml of H2 O, 8 ml of 10% HCl and 42 g (0.28 mole) of 4-chromanone in 200 ml ethanol. The reaction mixture was refluxed for 36 hr, stripped in vacuo to one-half volume and cooled in the refrigerator overnight. The slurry was filtered and the white crystalline solid washed with 50 ml of isopropanol then 200 ml of ether and dried. M.p. 105-108. Yield: 44 g (68%). The filtrate was extracted with 250 ml of CHCl3, and the CHCl3 extract dried over MgSO4, filtered, and stripped in vacuo. | |
With hydrogenchloride; In ethanol; isopropyl alcohol; | A. 3-[(4-Chromanylidene)amino]-2-oxazolidinone A 62 g (0.61 mole) portion of <strong>[80-65-9]3-amino-2-oxazolidinone</strong> was charged in a 500 ml, 3-necked flask equipped with a thermometer, stirrer and reflux condenser, and treated successively with 92 ml of H2 O, 8 ml of 10% HCl and 42 g (0.28 mole) of 4-chromanone in 200 ml of ethanol. The reaction mixture was refluxed for 36 hrs., stripped in vacuo to one-half volume and cooled in the refrigerator overnight. The slurry was filtered and the white crystalline solid washed with 50 ml of isopropanol then 200 ml of ether and dried; m.p. 105-108. Yield: 44 g (68%). The filtrate was extracted with 250 ml of CHCl3, and the CHCl3 extract dried over MgSO4, filtered and stripped in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With pyridine; hydroxylamine hydrochloride for 1.5h; | (4E)-N-Hydroxy-2,3-dihydro-4H-chromen-4-imine (13): Hydroxylamine hydrochloride (2.81 g,40.44 mmol) was added to the stirred solution of chroman-4-one (7a, 3.0 g, 20.25 mmol) in pyridine (25 mL) and the mixture was stirred for 1.5 h. Cool water (100 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl-acetate (3 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel (hexane/EtOAc 3:1) to give 13 as white solid (3.1 g, 94%, mp140-141 oC). 1H NMR (360 MHz, CDCl3): δ= 3.01 (m, J = 6.1 Hz, 2 H, 3-H), 4.25 (m, J = 6.1 Hz, 2 H,2-H), 6.89-6.96 (m, 2 H, 6-H, 8-H), 7.25 (m, 1 H, 7-H), 7.81 (dd, J = 9.7 Hz and 1.8 Hz, 1 H, 5-H), 9.39(br s, 1 H, OH). 13C NMR (90 MHz, CDCl3): δ= 23.5 (C-3), 64.9 (C-2), 117.8 (C-8), 118.1 (C-5a), 121.5(C-6), 123.9 (C-5), 131.2 (C-7), 149.9 (C-4), 156.7 (C-8a). IR (KBr): 1046, 1253, 1454, 1603, 3263 cm-1.HRMS-ESI (m/z): [M + H]+ calc’d for C9H9NO2H, 164.071; found: 164.071. |
93% | With hydroxylamine hydrochloride; sodium acetate In ethanol at 80℃; for 16h; | Intermediate 36 (1-36)(4E)-2,3-Dihydro-4H-chromen-4-one oxime (1-36)Sodium acetate (503.852 mg, 6.14 mmol) was added to a stirred solution of4-chromanone ([CAS491-37-2], 700 mg, 4.73 mmol) and hydroxylamine hydrochloride ([CAS5470-11-1], 426.808 mg, 6.14 mmol) in EtOH (31 mL). The mixture was stirred at 80 °C for 16 h. The mixture was cooled to RT, diluted with EtOAc, and washed with water. The organic layer was separated, dried (Na2S04), filtered and concentrated in vacuo to yield 1-36 (727.7 mg, 93%) as a white solid, which was used in the next step without further purification. |
91% | With hydroxylamine hydrochloride; sodium carbonate In ethanol; water at 60 - 65℃; |
88% | With pyridine; hydroxylamine hydrochloride for 8h; Heating / reflux; | 5 Example 5; 6-(3-Fluoro-pyridin-4-yl)-3-methyl-2-((4aRS,10bRS)-trans-2,3,10,10a- tetrahydro-4aH-4,9-dioxa-l-aza-phenanthren-l-yl)-3H-pyrimidin-4-one (Compound No.B3l); Chroman-4-one oxime; Chroman-4-one (46.5 g, 314 mmol) was dissolved in pyridine (160 ml) and hydroxylamine hydrochloride (51 g, 734 mmol). was added to this solution. The solution was refluxed for 8 hours and then cooled to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between water and chloroform. The organic layer was washed with IN aqueous hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitate was filtered, washed with diisopropylether, and dried to afford chroman-4-one oxime (22.9 g, 275 mmol, 88 %) as white crystals. |
81% | With hydroxylamine hydrochloride; sodium hydroxide In ethanol; water for 1h; Reflux; | |
66% | With hydroxylamine hydrochloride; sodium acetate In ethanol for 2h; Reflux; | |
With hydroxylamine hydrochloride; sodium acetate In ethanol; water | 2 Preparation of 4-Chromanone Oxime Example 2 Preparation of 4-Chromanone Oxime A quantity (18.4 g.) of 4-chromanone was dissolved in 100 ml. ethanol with heating to the boiling temperature. To this hot solution was added 18.4 g. hydroxylamine hydrochloride and a hot aqueous solution of sodium acetate (36.8 g.) that had been dissolved in 50 ml. water heated on a steam bath. The reaction mixture was heated at the reflux temperature for 1.5 hrs. when a thin layer chromatogram indicated that the reaction was completed. After cooling the mixture to about 10° C., crystals formed. The crystals were collected on a filter, washed with water, and dried in air. There was thus obtained 18.63 g. of 4-chromanone oxime that had a melting point at 139° to 142° C. Recrystallization from methanol gave 16.5 g. of the compound having the same melting point (139° to 142° C.). Analysis: Calc'd. for C9 H9 NO2: C, 66.24; H, 5.56; N, 8.58. Found: C, 66.30; H, 5.75; N, 8.27. | |
With hydroxylamine hydrochloride; triethylamine In methanol at 20 - 80℃; for 2.75h; Large scale; |
Yield | Reaction Conditions | Operation in experiment |
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Example 57; (4-(3,4-Dihydro-naphthalen- 1-yl)- lH-imidazole; a) 2-(tert-Butyl-dimethyl-silanyl)-4-( 1-hydroxy- 1,2,3,4- tetrahydro-naphthalen- 1-yl)- imidazo Ie-I -sulfonic acid dimethylamide; 2-(tert-Butyl-dimethyl-silanyl)-4-( 1-hydroxy- 1,2,3,4- tetrahydro-naphthalen- 1-yl)- imidazole- 1-sulfonic acid dimethylamide was prepared from 2-(tert-butyl-dimethyl- silanyl)-imidazole-l-sulfonic acid dimethylamide and chroman-4-one in analogy to the <n="59"/>procedure published by S. Ohta et al., Synthesis 1990, 78: light brown viscous oil; MS(ISP): 438.5 ((M+H)+ ). |
Yield | Reaction Conditions | Operation in experiment |
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74% | 7-Bromo-4-chromanone. Into a round bottom flask kept at 0 C., AlCl3 (0.533 g, 3.99 mmol) and, 5 mL of CH2Cl2 was added. The reaction system was put under nitrogen and stirred for about 7 minutes before adding 10 mL of a CH2Cl2 solution of 4-chromanone (0.296 g, 1.99 mmol). After the reaction mixture was stirred for 10 minutes, 10 mL of Br2 (0.352 g, 2.20 mmol) was added and, the reaction mixture was stirred at room temperature for an hour. At the end of this period of time, the reaction mixture was poured into 30 mL of ice-water and, the product was extracted 3 times from the aqueous phase with EtOAc. The resultant organic phase was washed once with brine and dried under Na2SO4. After the solvent was evaporated, the solid formed was filtered and dried to obtain 0.361 g (1.51 mmol) of the product (93% pure) in a 74% yield. 1H NMR (300 MHz, CDCl3, delta): 7.90 (dd, J=2.6, 0.3 ArH, 1H,), 7.47 (dd, J=8.8, 2.5, Ar, 1H,), 6.82 (dd, J=8.8, 0.2, Ar, 1H), 4.48 (t, J=6.5, C2, 2H), 2.75 (t, J=6.5, C2, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With pyrrolidine In methanol at 20℃; for 3h; | 16 4.1.2. General procedure for the synthesis of (E)-3-heteroarylidenechroman-4-ones (1a-r) General procedure: METHOD A: Pyrrolidine (10 mmol) was added to a mixture of the appropriate chroman-4-one (6.7 mmol) and heteroaryl aldehyde (10 mmol) in dry MeOH (15 mL for 1a, 1b, 1e, 1h, 1k-r and 30mL for 1c, 1d, 1i, 1j). The reaction mixture was stirred at room temperature for 1-24 h (1h for 1f, 3h for 1l-q, 24h for 1a-c, 1h-j, 1n, and 1o). The mixture was diluted with ice-water, and the precipitate was filtered off and washed with water. The crude solid was purified by column chromatography on silica gel, eluting with a mixture of AcOEt and CHCl3 (3:1) (1a-g and 1i-r) or CHCl3 (1h) and crystallized from n-hexane. METHOD B: (synthesis of 1f and 1g) A mixture of chroman-4-one (6.7 mmol), the appropriate pyridinecarbaldehyde (10 mmol) and pyrrolidine (10 mmol) was heated at 120 °C under stirring for 1 h. After cooling, the mixture was diluted with ice-water, and the precipitate was filtered off and washed with water. The crude solid was purified by column chromatography on silica gel, eluting with a mixture of AcOEt and CHCl3 (3:1), and crystallized from n-hexane. 4.1.2.16 (E)-3-[(Furan-2-yl)methylene]chroman-4-one (1p) Yield: 87%, mp = 118-119 °C (lit. 105 °C) [19] . IR (KBr): 1668 cm-1. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.99 (d, 1H, H5, J5-6 = 8.0 Hz) 7.59 (s, 1H, =CH), 7.50 (s, 1H, H3'), 7.45 (t, 1H, H7, J7-8 = J7-6 = 8.0 Hz), 7.03 (t, 1H, H6, J5-6 = J7-6 = 8.0 Hz), 6.96 (d, 1H, H8, J7-8 = 8.0 Hz), 6.73 (s, 1H, H5'), 6.52 (s, 1H, H4'), 5.57 (s, 2H, H2). 13C NMR (CDCl3, 100 MHz): δ (ppm) 181.53, 161.43, 151.37, 145.61, 135.59, 127.82, 126.80, 122.02, 121.75, 121.71, 118.50, 117.88, 112.66, 67.98. Anal. Calcd. for C14H10O3: C, 74.33; H, 4.46. Found: C, 74.54; H, 4.47. |
81% | With aluminum oxide for 0.0833333h; Microwave irradiation; neat (no solvent); | |
69% | With sodium hydroxide In ethanol; water at 20℃; for 10h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 60℃; | |
92% | With Nafion NR50 In ethanol at 200℃; for 1h; Microwave irradiation; | Quinoline Derivatives 1, 5, and 6; General Procedure General procedure: A mixture of 2-aminobenzophenone 2 (1.0 mmol), ketone 3 or 4 (1.1 mmol), and Nafion NR50 (20 mol%) in ethanol (10 mL) was loaded into a dried 35 mL microwave vial at 25 °C. The mixture was subjected to microwave irradiation and stirred at 200 °C for 1 h. Consumption of the starting materials was confirmed by TLC. The mixture was cooled to 25 °C and then transferred to a 100 mL round-bottom flask; the solvent was concentrated under reduced pressure to afford crude product. The solid crude product was recrystallized (hexane-EtOAc, 5:1 to 2:1). The oily or gummy crude product was purified by column chromatography (silica gel, hexanes-EtOAc, 4:1 to 1:1). This afforded products 1a-ac, 5a-k, and 6a-p. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With palladium(II) trifluoroacetate; copper (II) trifluoroacetate hydrate; silver(I) acetate at 100℃; for 48h; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With piperidine at 110℃; for 1h; | |
56.6% | With boron trifluoride diethyl etherate In 1,4-dioxane at 20℃; for 24h; | 1.6 4.1.3. Synthesis of 3-(4-hydroxybenzylidene)chroman-4-one (5c) To a solution of 4-chromanone 3 (1.5 g, 10.0 mmol, 1.0 equiv.)and 4-hydroxybenzaldehyde 1c (1.2 g, 10.0 mmol, 1.0 equiv.) in dioxane (10 mL) was slowly added boron trifluoride diethyl etherate(2.1 mL, 15.0 mmol, 1.5 equiv.). The mixture was stirred for 24 h at room temperature. After the completion of reaction monitored by TLC, the mixture was diluted with ethyl acetate (100 mL) and washed with distilled water (40 mL, 4 times), and saturated NaCl (40 mL, 2 times). The organic layer was dried with anhydrous MgSO4 and filtered off. Silica gel column chromatography was used to purify the compound using ethyl acetate and n-hexane as eluent to afford 4-chromaonne intermediate 5c (1.43 g, 56.6%, 5.6 mmol)as a yellow solid.TLC (ethyl acetate/n-hexane = 1:2) Rf = 0.23, mp: 238.9-239.6 C.1H NMR (250 MHz, DMSO d6) d 10.18 (s, 1H, phenyl 4-OH), 7.85(dd, J = 7.82, 1.62 Hz, 1H, chromanone H-5), 7.66 (br s, 1H, ACHA),7.56 (td, J = 8.50, 1.67 Hz, 1H, chromanone H-7), 7.33 (d, J = 8.62Hz, 2H, phenyl H-2 and H-6), 7.10 (t, J = 7.37 Hz, 1H, chromanoneH-6), 7.03 (d, J = 8.25 Hz, 1H, chromanone H-8), 6.87 (d, J = 8.55Hz, 2H, phenyl H-3 and H-5), 5.41 (s, 2H, ACH2A). 13C NMR(62.5 MHz, DMSO d6) d 181.13, 160.52, 159.40, 137.06, 136.06,132.93 (2C), 127.65, 127.28, 124.87, 121.97, 121.71, 117.91,115.88 (2C), 67.65. |
54.1% | With boron trifluoride diethyl etherate In 1,4-dioxane at 20℃; for 18h; Inert atmosphere; | General method for preparation of 3-(4-hydroxybenzylidene)chroman-4-one (9) To a solution of 5 (4.00 g, 26.99 mmol, 1.00 equiv) and 4-hydroxybenzaldehyde8 (3.29 g, 26.99 mmol, 1.00 equiv) in dioxane(10 mL) BF3Et2O (5.08 mL, 40.49 mmol, 1.50 equiv) was addedslowly and reaction mixture was stirred for 18 h at room temperatureunder N2 gas. The precipitate obtained was filtered andwashed with H2O to give red solid, which was purified by silicagel column chromatography using ethyl acetate and n-hexane aseluents to yield 3.68 g (54.1%, 14.58 mmol) of 9 as a yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyrrolidine In ethanol for 24h; Inert atmosphere; Reflux; | |
78% | With piperidine In ethanol at 20℃; for 12h; | 2.1 Preparation of substrates 1 General procedure: Ester compound thus obtained was dissolved in EtOH (6 mL) followed by addition of benzaldehyde (2.0 mmol, 1.0 equiv). After that, piperidine (0.1 mmol, 20 mmol %) was added to the above ethanol solution. The resulting mixture was stirred at ambient temperature for about 12 h. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (EtOAc/PE = 5/95) to give the desired compounds 1. |
With pyrrolidine In ethanol Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: sodium azide; sulfuric acid / 10 °C 2: aluminum (III) chloride; bromine / dichloromethane / 0 - 20 °C 3: butyl magnesium bromide; lithium aluminium tetrahydride; magnesium chloride / tetrahydrofuran 4: sodium hydroxide; di-<i>tert</i>-butyl dicarbonate / water 5: n-butyllithium; butyl magnesium bromide / tetrahydrofuran; hexane / 1.25 h / 2 °C / Inert atmosphere; Large scale 6: tetrahydrofuran; hexane / -10 - -8 °C / Inert atmosphere; Large scale 7: hydrogenchloride / water; tetrahydrofuran; hexane / 20 °C / Inert atmosphere; Large scale 8: potassium carbonate; bis-triphenylphosphine-palladium(II) chloride / water; tetrahydrofuran; hexane / 65 °C / Inert atmosphere; Large scale 9: hydrogenchloride / water; tetrahydrofuran / 34 - 36 °C / Large scale 10: potassium carbonate / water; dichloromethane; N,N-dimethyl-formamide / 18 h / 15 °C / Inert atmosphere; Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 2: triethylamine; trifluoromethylsulfonic anhydride / dichloromethane 3: triphenylphosphine / toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.6% | With sodium hydroxide In methanol; water at 20℃; for 24h; | 1.1 To the mixture of 2-hydroxybenzaldehyde 1a (1.6 mL, 15.0mmol, 1.0 equiv.) and DIPEA (7.8 mL, 45.0 mmol, 3.0 equiv.) in CH2Cl2 (25 mL) was added MOM-Cl (1.7 mL, 22.5 mmol, 1.5equiv.). The mixture was stirred for 3 h at room temperature. After the completion of reaction monitored by TLC, H2O (150 mL) was added and extracted with CH2Cl2 (50 mL, 3 times). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo at 60 C and dried under high vacuum to give a yellowish brown oil. Silica gel column chromatography was used to purify the compound using ethyl acetate and n-hexane as eluents to yield 2a (2.40 g, 96.5%, 14.5 mmol) as a light yellow oil. In a further step,to the solution of 2a (2.4 g, 14.5 mmol, 1.0 equiv.) and 4-chromanone 3 (2.7 g, 16.2 mmol, 1.0 equiv.) in methanol (30 mL) was added aqueous NaOH (0.8 g in 11 mL H2O) dropwise and stirred for 24 h at room temperature. The mixture was evaporated,extracted with ethyl acetate (200 mL), and washed with distilled water (50 mL, 5 times) followed by saturated NaCl solution (50mL, 2 times). The organic layer was dried with anhydrous MgSO4 and filtered off. Purification was performed by silica gel column chromatography using ethyl acetate and n-hexane as eluents to obtain 4a (4.59 g, 95.6%, 15.5 mmol) as a yellow solid. Finally,deprotection of 4a was achieved by refluxing 4a (4.6 g, 15.5 mmol,1.0 equiv.) with aqueous 2 M HCl (11.7 mL, 1.5 equiv.) in ethanol (60 mL) for 1 h at 80 C. The mixture was evaporated and extracted with ethyl acetate (200 mL), washed with distilled water (50 mL, 4 times), and saturated NaCl solution (50 mL). The organic layer was dried over anhydrous MgSO4 and filtered off. Further purification was performed using silica gel column chromatography by elution of ethyl acetate and n-hexane to give 4-chromanone intermediate 5a (1.96 g, 50.2%, 7.8 mmol) as a yellow solid. |
78.6% | With sodium hydroxide In methanol; water at 20℃; for 24h; | General method for preparation of 3-(2-hydroxybenzylidene)chroman-4-one (7a) To a solution of 2-hydroxybenzaldehyde 3a (1.00 g, 8.18 mmol,1.00 equiv), in CH2Cl2 (25 mL) DIPEA (4.27 mL, 24.56 mmol,3.00 equiv) was added followed by MOM-Cl (0.93 mL, 12.28 mmol,1.50 equiv) at room temperature. The reaction mixture was stirredfor 2.5 h at room temperature. H2O (100 mL) was added and reactionmixture was extracted with CH2Cl2 (50 mL 3), dried overMgSO4 (1 spatula), filtered and concentrated to give light yellowoil. It was further purified by column chromatography using ethylacetate and n-hexane as eluents to yield 1.27 g (93.3%, 7.64 mmol)of 4a as a light yellow oil. To a solution of 5 (1.13 g, 7.64 mmol,1.00 equiv) and 4a (1.27 g, 7.64 mmol, 1.00 equiv) in MeOH(15 mL), aqueous NaOH was added (0.36 g in 5 mL) at room temperature.The reaction mixture was stirred for 24 h at room temperature.MeOH was evaporated. The reaction mixture wasextracted with EtOAc (100 mL), washed with H2O (50 mL 3), saturatedNaCl (30 mL), dried over MgSO4 (1 spatula) and filtered. Theorganic solvent was evaporated to yield a yellow viscous compound.It was further purified by silica gel column chromatographyusing EtOAc and n-hexane as eluents to yield 1.78 g (78.6%,6.00 mmol) of 6a as a yellow solid. Finally, 6a (1.78 g, 6.00 mmol,1.00 equiv) was deprotected using 2 M HCl (4.5 mL, 1.50 equiv)in EtOH (50 mL). The reaction mixture was refluxed at 85 C for1.5 h and EtOH evaporated. The reaction mixture was extractedwith ethyl acetate (100 mL), washed with H2O (50 mL 3), satd.NaCl (30 mL), dried over MgSO4 (1 spatula) and filtered. After filtration,it was concentrated to give dark red viscous compound.It was further purified using ethyl acetate and n-hexane as eluentsto yield 1.04 g (68.7%, 4.12 mmol) of 7a as a yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With palladium(II) trifluoroacetate; 5-Nitro-1,10-phenanthroline; oxygen In dimethyl sulfoxide at 100℃; for 48h; | |
70% | With palladium(II) trifluoroacetate; 5-Nitro-1,10-phenanthroline; oxygen In dimethyl sulfoxide at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With palladium(II) trifluoroacetate; 5-Nitro-1,10-phenanthroline; oxygen In dimethyl sulfoxide at 100℃; for 48h; | |
27% | With palladium(II) trifluoroacetate; 5-Nitro-1,10-phenanthroline; oxygen In dimethyl sulfoxide at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With n-butyllithium; 1,1,1,3,3,3-hexamethyl-disilazane In tetrahydrofuran; hexane at -78℃; for 1.5h; Inert atmosphere; Stage #2: methyl cyanoformate In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; | |
85% | Stage #1: 2,3-dihydro-4H-1-benzopyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: methyl cyanoformate In tetrahydrofuran at -78℃; for 1h; | Methyl 4-oxochromane-3-carboxylate (1aa)[5] To a solution of 4-chromanone (5 mmol, 1.0 equiv) in THF (10 mL) stirred at -78 °C was added a solution of LiHMDS (1 M in THF, 7.5 mL, 7.5 mmol, 1.5 equiv) dropwise and the mixture was stirred for 30 minutes. Methyl cyanoformate (10 mmol, 2.0 equiv) in THF (10 mL) was added dropwise and the reaction was stirred at -78 °C for 1 hour. The mixture was allowed to warm to room temperature and was quenched by the addition of aq. NH4Cl (25 mL) and H2O (25 mL). The mixture was extracted with EtOAc (3 x 25 mL). The combined organic phases were washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo. Flash column chromatography (ethyl acetate/ petroleum ether = 1:15) afforded the product as a colorness oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With pyrrolidine; In methanol; at 20℃; for 24h; | General procedure: METHOD A: Pyrrolidine (10 mmol) was added to a mixture of the appropriate chroman-4-one (6.7 mmol) and heteroaryl aldehyde (10 mmol) in dry MeOH (15 mL for 1a, 1b, 1e, 1h, 1k-r and 30mL for 1c, 1d, 1i, 1j). The reaction mixture was stirred at room temperature for 1-24 h (1h for 1f, 3h for 1l-q, 24h for 1a-c, 1h-j, 1n, and 1o). The mixture was diluted with ice-water, and the precipitate was filtered off and washed with water. The crude solid was purified by column chromatography on silica gel, eluting with a mixture of AcOEt and CHCl3 (3:1) (1a-g and 1i-r) or CHCl3 (1h) and crystallized from n-hexane. METHOD B: (synthesis of 1f and 1g) A mixture of chroman-4-one (6.7 mmol), the appropriate pyridinecarbaldehyde (10 mmol) and pyrrolidine (10 mmol) was heated at 120 C under stirring for 1 h. After cooling, the mixture was diluted with ice-water, and the precipitate was filtered off and washed with water. The crude solid was purified by column chromatography on silica gel, eluting with a mixture of AcOEt and CHCl3 (3:1), and crystallized from n-hexane. 4.1.2.8 (E)-3-[(6-Aminopyrimidin-3-yl)methylene]chroman-4-one (1h) Yield: 84%, mp = 186-187 C. IR (KBr): 3387, 3117, 1657 cm-1. 1H NMR (DMSO-d6, 400 MHz): delta (ppm) 8.11 (s, 1H, =CH), 7.86 (d, 1H, H5, J5-6 = 8.0 Hz), 7.59-7.53 (m, 3H, H2', H6', H7), 7.11 (t, 1H, H6, J5-6 = J7.6 = 7.2 Hz), 7.04 (d, 1H, H8, J7-8 = 8.4 Hz), 6.69 (s, 2H, NH2), 6.53 (d, 1H, H5', J5'-6' = 8.4 Hz), 5.43 (s, 2H, H2). 13C NMR (DMSO-d6, 100 MHz): delta (ppm) 180.52, 160.32, 160.27, 152.40, 138.60, 135.63, 134.72, 127.04, 126.11, 121.69, 121.63, 118.19, 117.63, 107.73, 67.64. Anal. Calcd. for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C, 71.52; H, 4.83; N, 11.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyrrolidine; In methanol; at 20℃; for 24h; | General procedure: METHOD A: Pyrrolidine (10 mmol) was added to a mixture of the appropriate chroman-4-one (6.7 mmol) and heteroaryl aldehyde (10 mmol) in dry MeOH (15 mL for 1a, 1b, 1e, 1h, 1k-r and 30mL for 1c, 1d, 1i, 1j). The reaction mixture was stirred at room temperature for 1-24 h (1h for 1f, 3h for 1l-q, 24h for 1a-c, 1h-j, 1n, and 1o). The mixture was diluted with ice-water, and the precipitate was filtered off and washed with water. The crude solid was purified by column chromatography on silica gel, eluting with a mixture of AcOEt and CHCl3 (3:1) (1a-g and 1i-r) or CHCl3 (1h) and crystallized from n-hexane. METHOD B: (synthesis of 1f and 1g) A mixture of chroman-4-one (6.7 mmol), the appropriate pyridinecarbaldehyde (10 mmol) and pyrrolidine (10 mmol) was heated at 120 C under stirring for 1 h. After cooling, the mixture was diluted with ice-water, and the precipitate was filtered off and washed with water. The crude solid was purified by column chromatography on silica gel, eluting with a mixture of AcOEt and CHCl3 (3:1), and crystallized from n-hexane. 4.1.2.1 (E)-3-[(2-Aminopyrimidin-5-yl)methylene]chroman-4-one (1a) Yield: 97%, mp = 260-261 C. IR (KBr): 3304, 3160, 1670 cm-1. 1H NMR (DMSO-d6, 400 MHz): delta (ppm) 8.43 (s, 2H, H2', H6'), 7.87 (d, 1H, H5, J5-6 = 7.6 Hz), 7.60-7.56 (m, 2H, =CH, H7), 7.34 (s, 2H, NH2), 7.12 (t, 1H, H6, J5-6 = J7.6 = 7.6 Hz), 7.05 (d, 1H, H8, J7-8 = 8.0 Hz), 5.43 (s, 2H, H2). 13C NMR (DMSO-d6, 100 MHz): delta (ppm) 180.43, 162.83, 160.43, 160.20, 135.88, 131.50, 127.67, 127.10, 121.78, 121.42, 117.18, 116.79, 67.57. Anal. Calcd. for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found: C, 66.59; H, 4.29; N, 16.68. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine In dichloromethane at 0℃; for 21h; Inert atmosphere; Reflux; | 2.1. General Procedure A: Triflation of tetralones General procedure: For example, the preparation of 6-methoxy-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (1a)-6-Methoxy-1-tetralone (2.00 g, 11.35 mmol, 1 equiv) was weighed into an oven-dried flask.The flask was sealed and purged with N2 before the addition of CH2Cl2 (45 mL, 0.25 M). The reaction was cooled to 0 °C and triflic anhydride (3.8 mL, 22.7 mmol, 2 equiv) and Et3N (3.2mL, 22.7 mmol, 2 equiv) were added dropwise via syringe sequentially. The reaction mixture was then heated to reflux for 22 h with stirring. After the reaction was complete, the reaction was allowed to cool to room temperature and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% EtOAc in petroleum ether)to afford the desired product as a yellow oil (2.41 g, 69%). |
43% | With sodium carbonate In dichloromethane at 0 - 20℃; for 6h; Inert atmosphere; | |
With 2,6-di-tert-butyl-4-methylpyridine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; triethylamine / methanol / 16 h / 20 °C 2: 1 h / 130 °C 3: borane-THF / tetrahydrofuran / 4 h / 70 °C | ||
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; pyridine / 1.5 h 2: diisobutylaluminium hydride / hexane; dichloromethane / 24 h / 5 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: hydroxylamine hydrochloride; pyridine / 3 h / 20 °C 2.1: diisobutylaluminium hydride / hexane; dichloromethane / 2 h / 0 - 20 °C 2.2: 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 80.0℃; for 16.0h; | General procedure: A mixture of 2 (50mg, 0.23mmol) and hydrazine (36muL, 5 equiv) in EtOH (1mL) was stirred at 80C for 3h. After being concentrated under reduced pressure, the crude residue (acylhydrazide) was redissolved in EtOH (1mL) and 2-methoxybenzaldehyde (36.5mg, 1.2 equiv) was added at rt. After being stirred at 80C for 16h, the resulting precipitated product was collected by filtration and dried to give 3 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With toluene-4-sulfonic acid; In isopropyl alcohol; for 72h;Inert atmosphere; Reflux; Darkness; | General procedure: Compounds 8a-g and 10a-e were prepared as follows: isopropyl alcohol (20 mL) was added to a mixture of indole (4) (1.172 g, 10 mmol, 1 eq), 1-tetralone (5) (1.33 mL, 10 mmol, 1 eq), N-phenylmaleimide (7) (1.732 g, 10 mmol, 1 eq) and p-toluenesulfonic acid (0.380 g, 2 mmol, 0.2 eq). 9a-g were prepared similarly: isopropyl alcohol (20 mL) was added to a mixture of indole (4) (1.172 g, 10 mmol, 1 eq), 4-chromanone (6) (1.482 g, 10 mmol, 1 eq), N-phenylmaleimide (7) (1.732 g, 10 mmol, 1 eq) and p-TsOH (0.380 g, 2 mmol, 0.2 eq). The reaction mixture was heated at reflux for three days under a nitrogen atmosphere, and in the absence of light. Upon completion, a solid reaction mixture was cooled down and filtered with IPA (15 mL) and water (5 mL). The crude material was triturated with IPA (20 mL) three times in the absence of light to give a solid. If further purification was necessary, recrystallization with a mixture of dichloromethane and pentane was performed. In the case of 6 derivatives (9a-g) solubility was found to be very poor, and thus recrystallization was performed with a mixture of tetrahydrofuran and pentane. Using this procedure 8a-g, 9a-g, and 10a-e were synthesized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With hydrogenchloride; In methanol; water; at 60 - 80℃; for 6h; | General procedure: To a solution of (7) 1-(<strong>[4649-09-6]1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde</strong> (0.300g, 2.053mmol) in 32% aqueous HCl/methanol (1.5:1 v/v) (4.5ml/3 ml) was added a selected bicyclic scaffold (tetralone, indanone, 3-coumaranone, 4-chromanone and thiochroman-4-one) (2.053mmol) and the reaction was refluxed for at least 6h at 60-80C. The progress of the reaction was monitored by silica gel TLC with ethyl acetate as mobile phase. When the reaction reached completion, the target products were isolated by precipitation with ice-cold water, after which they were purified by recrystallisation with ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydroxide In ethanol; water at 20℃; for 1h; | Experimental The title molecule was synthesized by the base catalyst Claisen-Schmidt condensation reaction method.[21] During the synthesis process, an aqueous solution of NaOH (10%,10mL) was added to a mixture of 2,3-dihydro-4H-1-benzopyran-4-one and (2,4,5-trimethoxy phenyl) methylidene in 95% ethanol. The reaction mixture is stirred for 1 h and is left overnight. A dark yellow colored product is obtained after filtering and is washed with ice-cold water and then recrystallized by using ethanol as solvent at ambient temperature. A diffraction quality yellow colored crystals were obtained after seven days (Yield: 85%; MP: 70 C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1,4-diaza-bicyclo[2.2.2]octane In lithium hydroxide monohydrate at 30℃; for 0.0833333h; Sonication; | 2.2. Synthesis of Knoevenagel Condensation Products (5a-d, 8a-d, 10a,b, 12a,b, 14a-d, and 16a,b) General procedure: To a mixture of appropriate active methylene (1.0 mmol) in IL-H2O-DABCO (60-40%-1.0 mmol), 1.0 mmol of carbonyl compounds (3, 13, and 15) was added. The resultingsolution was sonicated at 30 °C for 5 min (TLC). After cooling to room temperature, theobtained crystals were filtered off, dried, and crystallized from a proper solvent. |
Tags: 491-37-2 synthesis path| 491-37-2 SDS| 491-37-2 COA| 491-37-2 purity| 491-37-2 application| 491-37-2 NMR| 491-37-2 COA| 491-37-2 structure
[ 98232-51-0 ]
8-Methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one
Similarity: 0.92
[ 35212-22-7 ]
7-Isopropoxy-3-phenyl-4H-chromen-4-one
Similarity: 0.88
[ 41118-21-2 ]
Methyl 4-oxochroman-7-carboxylate
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[ 98232-51-0 ]
8-Methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one
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P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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