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CAS No. : | 93-35-6 | MDL No. : | MFCD00006878 |
Formula : | C9H6O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ORHBXUUXSCNDEV-UHFFFAOYSA-N |
M.W : | 162.14 | Pubchem ID : | 5281426 |
Synonyms : |
7-Hydroxycoumarin;Hydrangin;7-Hydroxycoumarin, 7 Hydroxycoumarin, 7Hydroxycoumarin, Hydrangin, Skimmetin, Umbelliferone;beta-umbelliferone;skimmetine;hydrangine;NSC 19790
|
Chemical Name : | 7-Hydroxy-2H-chromen-2-one |
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 44.51 |
TPSA : | 50.44 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) : | -6.17 cm/s |
Log Po/w (iLOGP) : | 1.44 |
Log Po/w (XLOGP3) : | 1.58 |
Log Po/w (WLOGP) : | 1.5 |
Log Po/w (MLOGP) : | 1.04 |
Log Po/w (SILICOS-IT) : | 1.97 |
Consensus Log Po/w : | 1.51 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.46 |
Solubility : | 0.566 mg/ml ; 0.00349 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.25 |
Solubility : | 0.912 mg/ml ; 0.00562 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.03 |
Solubility : | 0.153 mg/ml ; 0.000942 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.56 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
76% | With potassium carbonate In N,N-dimethyl-formamide for 3 h; Inert atmosphere; Reflux | Aurapten (5). Geranyl bromide (159 l, 0.80 mmol) was added to a stirred mixture of umbelliferone (2) (100 mg, 0.62 mmol) and K2CO3 (171 mg, 1.24 mmol) in dry DMF (5 ml) under argon. The reaction mixture was stirred under reflux for 3 h. The reaction mixture was neutralised by addition of aq. HCl (1M). The resulting brown residue was added in DCM (20 ml), washed with water (2 .x. 20 ml), brine (30 ml) and dried Na2SO4). Removal of solvent yielded a brown oil, which was purified by flash column chromatography, eluting with diethylether-hexane (1:1) to give a white powder 5 (181 mg, 76percent): 1H NMR (CDCl3, 700 MHz) 7.64 (1H, d, J = 9.5 Hz, H-4), 7.36 (1H, d, J = 8.6 Hz, H-5), 6.86 (1H, dd, J = 8.4, 2.4 Hz, H-6), 6.82 (1H, d, J = 2.4 Hz, H-8), 6.25 (1H, d, J = 9.5 Hz, H-3), 5.47 (1H, tq, J = 6.6, 1.4 Hz, H-2'), 5.08 (2H, m, H-1'), 4.61 (2H, d, J = 6.6 Hz, H-1'), 2.13 (2H, m, H-5'), 2.09 (2H, m, H-4'), 1.76 (3H, brs, H-9'), 1.67 (3H, brs, H-8'), 1.60 (3H, brs, H-10'); 13C NMR (CDCl3, 175 MHz) 162.2 (C, C-7), 161.3 (C, C-2), 155.9 (C, C-8a), 143.4 (CH, C-4), 142.4 (C-3'), 131.9 (C, C-7'), 128.7 (CH, C-5), 123.6 (CH, C-6'), 118.4 (CH, C-2'), 113.2 (CH, C-6), 112.9 (CH, C-3), 112.4 (C, C-4a), 101.6 (CH, C-8), 65.5 (CH2, C-1'), 39.5 (CH2, C-4'), 26.2 (CH2, C-5'), 25.6 (CH3, C-8'), 17.7 (CH3, C-10'), 16.7 (CH3, C-9'); HR-FABMS (pos) m/z 299.3877 [M + H]+ (calcd. for C19H23O3, 299.3860). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate at 120℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In acetone for 72h; Heating; | |
95% | With potassium carbonate In acetone for 4h; Inert atmosphere; Reflux; | |
91% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone for 0.25h; Inert atmosphere; Reflux; Stage #2: benzyl bromide In acetone Inert atmosphere; Reflux; | General procedure for the synthesis of 7-O-alkylumbelliferone (1a-j): General procedure: In a 50 mL two necked round-bottomed flask equipped with a magnetic stirrer, a condenser, and a nitrogen inlet,umbelliferone (1 equiv.), K2CO3 (3 equiv.) and 10 mL of anhydrous acetone were added. The mixture was heated underreflux for 15 min under nitrogen atmosphere and cooledto room temperature before the dropwise addition of alkylbromide (1.5 equiv.). The resulting mixture was heated underreflux for another 2-6 h. The reaction was quenched withwater (10 mL), followed by extraction with EtOAc (2×50 mL)and washed with brine solution. After drying (Na2SO4) andremoval of the solvent, the residue was purified by columnchromatography using hexane/EtOAc as mobile phase (gradientelution), to afford the corresponding compounds 1aj14.All the derivatives were characterized by 1H, 13C NMRand mass data. |
82% | With potassium carbonate In acetone Heating; | |
78% | With caesium carbonate | 7-(benzyloxy)-2H-chromen-2-one (CBn) 7-(benzyloxy)-2H-chromen-2-one (CBn) 7-Hydroxycoumarin (0.65 g, 4.0 mmol) was dissolved in 20 mL of MeCN. To this was added Cs2CO3 (2.61 g, 8.0 mmol) followed by benzyl bromide (1.0 mL, 8.0 mmol). The reaction was heated to 80° C. under nitrogen for 18 h. The mixture was then cooled to room temperature, filtered, and rinsed with CH2Cl2. The solvent was removed and the resulting residue was purified by silica gel chromatography eluting with 20-50% EtOAc in hexanes to afford the purified product in 78% yield (0.78 g, 3.1 mmol). 1H NMR (400 MHz, CDCl3): δ=7.62 (d, J=9.6 Hz, 2H), 7.44-7.35 (m, 6H), 6.91 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 5.12 (s, 2H). 13C NMR (100 MHz, CDCl3): δ=162.1, 161.4, 156.0, 143.6, 136.0, 129.1, 129.0, 128.6, 127.8, 113.5, 113.4, 112.9, 102.1, 70.7. ESI-MS (+): m/z 253.03 [M+H]+, 269.72 [M+NH4]+. |
56% | With potassium carbonate In ethanol at 60 - 80℃; | 1 4.2. General procedure for the synthesis of compounds 1-13 General procedure: The appropriate commercially available 7-hydroxylcoumarin (1 mmol, 1a-5a) and K2CO3 (1.1 mmol) were dissolved in 10 ml ethanol. To the mixture, benzyl bromide (1 mmol for compounds 1-4) or the appropriate bromobenzyl derivative (1 mmol for compounds 5-13) was added depending on the compound to be synthesised. The mixture was stirred under reflux conditions until the reaction reached completion (monitored by TLC, mobile phase = EtOAc). Once the reaction was complete, 20 ml of distilled water was added and the mixture was allowed to cool to room temperature. This resulted in the formation of a precipitate that was filtered of and allowed to dry overnight in a fume cupboard rendering the pure 7-(benzyloxy)coumarin derivatives (1-13) asoff-white amorphous solids. 4.2.1. 7-(Benzyloxy)-2H-chromen-2-one (1)Yield: 56% mp: 155 °C; 1H NMR: (400 MHz, CDCl3) dH: 7.64-7.60 (d, 1H, J = 9.2 Hz), 7.42-7.35 (m, 5H), 6.92-6.87 (m, 2H), 6.26-6.22 (d, 1H, J = 9.2 Hz), 5.11 (s, 2 H); 13C NMR (100 MHz, CDCl3): 161.84, 161.13, 155.78, 143.33, 135.72, 128.72, 128.35, 127.47, 113.21, 112.69, 101.88, 70.48; IR (ATR, cm-1): 1707, 1110, 693; MS (EI, 70 eV) m/z: 253.10 [M+H]+; HR-ESI [M+H]+: calcd. 259.0859, found. 259.0862. |
With potassium carbonate; acetone | ||
With potassium carbonate In ethanol Heating; | ||
Stage #1: 7-hydroxy-2H-chromen-2-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.416667h; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | Synthesis of 7-((2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyloxy)-2H-chromen-2-one (9) General procedure: To an oven dried 50-mL round-bottom flask equipped with a magnetic stirring bar, rubber septa and a nitrogen inlet,umbelliferone (1) (19.3 mg, 0.12 mmol) and 10 mL of anhydrous DMF were added. The solution was cooled to 0 °C and sodium hydride (4.2 mg of 60% mineral oil suspension) was added. The reaction mixture was allowed to stir for 25 min at 0 °C, and the crude geranylgeranyl bromide from the previous step was dissolved anhydrous DMF (2 mL) and added dropwise to the reaction flask via syringe. The reaction was allowed to slowly warm to room temperature and was stirred overnight. The desired compound was isolated via preparative thin layer chromatography using 3:7 ethyl acetate:hexanes solvent system. | |
With potassium carbonate for 12h; Inert atmosphere; | ||
With potassium carbonate In acetone at 80℃; for 1h; | ||
With potassium carbonate In acetone at 80℃; for 1h; | ||
In acetone at 80℃; for 1h; | ||
With potassium carbonate In acetone for 4h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.4% | With potassium carbonate; potassium iodide In acetone Reflux; Large scale reaction; | |
85% | With potassium carbonate In acetone at 56℃; Inert atmosphere; | 2 7-Benzyloxycoumarin (4a): To a solution of 7-hydroxy-2H-chromen-2-one (4.86 g, 30.00 mmol) and K2CO3 (10.35 g, 75.00 mmol) in acetone (200 mL) was added benzyl chloride (6.90 mL, 60.00 mmol). The resulting was heated to 56 C under N2 overnight. After filtration to remove K2CO3, the filtrate was concentrated in vacuo. The residue was diluted with distd H2O (100 mL) and then extracted with EtOAc (50 mL x 3). The organic layer was dried (Na2S04), filtered and the solvent removed in vacuo. The residue was purified by silica gel chromatography (EtOAc: -Hexane= 1 :4) to give 4a (6.43 g, 85%) as a white solid: mp: 135-140 °C; XH NMR (500 MHz, CDCb): δ= 7.62 (d, J=9.5 Hz, 1H), 7.42 (m, 3H), 7.37 (d, J=8.7 Hz, 1H), 7.34 (m, 2H), 6.91 (d, J=8.7 Hz, 1H), 6.89 (s, 1H), 6.25 (d, J=9.5 Hz, 1H), 5.13 ppm (s, 2H); MS (EI, 70 ev) m/z: 252 [M]+. |
With potassium carbonate; acetone |
With potassium hydroxide; potassium iodide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 7-hydroxy-2H-chromen-2-one With manganese(II) iodide; naphthalene; lithium In tetrahydrofuran at 20℃; for 0.166667h; Inert atmosphere; Stage #2: benzoyl chloride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; | Phenyl 3-Chlorobenzoate (1c); Typical Procedure General procedure: A 25 mL flask was charged with lithium (0.07 g, 9.68 mmol),naphthalene (0.19 g, 1.48 mmol), anhyd MnI2 (1.45 g, 4.71 mmol), and freshly distilled THF (10 mL) under argon pressure,and the mixture was stirred for 1 h at r.t. To the resultingslurry, containing 2.5 mmol of highly active manganese, wasadded PhOH (0.47 g, 5.0 mmol) and the resulting mixture wasstirred at r.t. for 10 min. Neat 3-chlorobenzoyl chloride (0.88 g,5.0 mmol) was then added to the flask, and the mixture wasstirred at r.t. for 30 min. The reaction was then quenched with3 M aq HCl, and the mixture was extracted with Et2O (3 × 10 mL).The organic layers were combined and washed with sat. aqNaHCO3 (3 × 10 mL), sat. aq Na2S2O3 (3 × 10 mL), and brine (3 ×10 mL), then dried (MgSO4). Column chromatography (silica gel,1% EtOAc-hexanes) gave a pale-yellow solid.yield: 0.96 g (83%). |
78% | With triethylamine In dichloromethane at 20℃; for 48h; | 4.1.7 Preparation of 5, 11 and 17 (Scheme 1e) General procedure: 0.4g of SM1 (2.2mmol), SM2 (2.4mmol) and SM3 (2.2mmol), respectively, were stirred in 2mL of CH2Cl2. After that, 2.5 molar equivalents of Et3N, and 5 molar equivalents of benzoyl chloride were added to the mixture. Reaction was agitated for 2 days and 12h for compounds 5, 11 and 17, respectively. After reactions were completed (analyzed by TLC), the solid was filtered off and dried to afford the corresponding compounds 5 (2-oxo-2H-chromen-7-yl benzoate), 11 (2-oxo-2H-chromene-7-yl benzoate) 17. (4-methyl-2-oxo-2H-chromene-7-yl benzoate) 17. |
34% | With sodium hydride In tetrahydrofuran at 25℃; for 2h; |
With pyridine | ||
With triethylamine In tetrahydrofuran at 20℃; for 16h; Inert atmosphere; | ||
With triethylamine In dichloromethane at 20℃; | 1 4.1.2. General procedures for the synthesis of benzoates 11-13 General procedure: To a well-stirred solution of compounds 1, 2 or 7 (1mmol) in DCM (2mL), Et3N (2.5 molar equivalents) and benzoyl chloride (5 molar equivalents) were added. The mixture was stirred until the end of the reaction (monitored by TLC) at room temperature and then cooled into ice. The solid in suspension was filtered off and recrystallized from the suitable solvent to give esters 11-13. Chemical and spectral data for 11-12 are in good agreement with literature [35]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In acetone for 5h; Heating; | |
100% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone at 20℃; for 0.0833333h; Stage #2: allyl bromide In acetone for 3h; Reflux; | 1 6.1.1 7-(Allyloxy)-2H-chromen-2-one (1c) In a typical procedure, 1b (0.50 g, 3.08 mmol) was dissolved in dry acetone (20 mL). K2CO3 (4.26 g, 30.85 mmol) was added and the reaction mixture stirred for 5 min at ambient temperature. 1a (0.44 g, 3.70 mmol) was charged to the above reaction mixture and the reaction mixture allowed to reflux for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was allowed to attain room temperature, filtered and the filtrate concentrated under vacuum to afford 1c in pure form (100%). 1H NMR (500 MHz, CDCl3): δ 4.61 (d, 2H, J = 5.27 Hz), 5.31-5.37 (m, 1H), 5.40-5.49 (m, 1H), 5.96-6.12 (m, 1H), 6.26 (d, 1H, J = 9.48 Hz), 6.86 (d, 1H, J = 9.58 Hz), 6.89 (s, 1H), 7.38 (d, 1H, J = 8.36 Hz), 7.64 (d, 1H, J = 9.49 Hz); Mass (ESI-MS): 224.8 (M+ + Na); C, H analysis for C12H10O3: Calculated C, 71.28; H, 4.98. Found C, 71.24; H, 4.93. |
98.6% | With potassium carbonate In acetone at 70℃; for 12h; |
97% | With potassium carbonate In acetone for 4h; Reflux; Inert atmosphere; | |
97% | With potassium carbonate In acetone Reflux; | |
96% | With potassium carbonate In acetone Heating; | |
95% | With potassium carbonate | |
92% | With potassium carbonate In acetone for 5h; Heating; | |
90% | With potassium carbonate In acetone for 5h; Reflux; | |
90% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone for 0.25h; Inert atmosphere; Reflux; Stage #2: allyl bromide In acetone Inert atmosphere; Reflux; | General procedure for the synthesis of 7-O-alkylumbelliferone (1a-j): General procedure: In a 50 mL two necked round-bottomed flask equipped with a magnetic stirrer, a condenser, and a nitrogen inlet,umbelliferone (1 equiv.), K2CO3 (3 equiv.) and 10 mL of anhydrous acetone were added. The mixture was heated underreflux for 15 min under nitrogen atmosphere and cooledto room temperature before the dropwise addition of alkylbromide (1.5 equiv.). The resulting mixture was heated underreflux for another 2-6 h. The reaction was quenched withwater (10 mL), followed by extraction with EtOAc (2×50 mL)and washed with brine solution. After drying (Na2SO4) andremoval of the solvent, the residue was purified by columnchromatography using hexane/EtOAc as mobile phase (gradientelution), to afford the corresponding compounds 1aj14.All the derivatives were characterized by 1H, 13C NMRand mass data. |
86% | With potassium carbonate In acetone for 16h; Heating; | |
85% | With potassium carbonate In acetone for 18h; Heating; | |
85% | With caesium carbonate In N,N-dimethyl-formamide at 60℃; | 4.1.4. Synthesis of allyloxycoumarines 5a-c General procedure: Hydroxycoumarin (1.0 g, 1.0 equiv), Cs2CO3 (3.0 equiv) and allylbromide (3.0 equiv) were dissolved in dry DMF (30 ml) and the mixture was stirred at 60 °C O.N. The reaction was quenched with slush and extracted with DCM (3 × 20 ml). The combined organic layers were washed with brine (3 × 20 ml), H2O (5 × 20 ml), dried over Na2SO4, filtered and concentrated under vacuo to give a residue that was crystallized from MeOH/H2O. |
84% | With potassium carbonate In acetone for 8h; Reflux; | |
83% | With potassium carbonate In acetone for 5h; Heating; | |
82% | With sodium hydroxide; tetra-(n-butyl)ammonium iodide; potassium iodide In dichloromethane; water at 20℃; for 2h; | |
80% | With potassium carbonate In ethanol at 70℃; for 10h; regioselective reaction; | General procedure for the selective synthesis of O-allyl phenolic derivatives (3a-i) using MMZCu(I)Y General procedure: 100 mg of MMZCu(I)Y was taken in a reaction tube containing ethanol (3 mL) as a solvent and K2CO3 (1 mmol) as base. A mixture of equimolar (1 mmol) phenol (1a) and allylbromide (2a) were added simultaneously to the reaction tube. The reaction mixture was allowed to stir for 10 hrs at 70°C and the proceedings of the reaction was constantly monitored by TLC. After 10 hrs, products were extracted from MMZCu(I)Y using excess amount of solvent. The organic layer was separated, dried and concentrated in vacuo and the residue was subjected to column Chromatography over silica gel [60-120 mesh, petether: ethylacetate, (8:2)]. The isolated products were characterized by 1H and 13C-NMR spectra on Bruker Instrument (300 MHz and 75 MHz respectively) in CDCl3. GC-MS spectrum recorded in Agilent GC 7820A and MS 5977E Model using DB-5 Column and the new products also by HR-MS spectrums |
70% | Stage #1: 7-hydroxy-2H-chromen-2-one; allyl bromide With sodium hydride In N,N-dimethyl-formamide at 20℃; for 24h; Stage #2: In N,N-dimethyl-formamide at 153℃; for 0.25h; Stage #3: In N,N-dimethyl-formamide at 20℃; for 24h; | General procedure for coumarin derivatives synthesis General procedure: 150 mg (0.926 mMol) of 6-hydroxy (1), 7-hydroxy (2), or4-hydroxycoumarin (3) separately were dissolved in 4 ml of DMF, with 36 mg (1.5 Eq) of NaH and 2 Eq. of 4-penten, 3-buten, trans-crotyl, allyl or γ,γ-dimethylallyl bromide. Similarly, 2 Eq. of 1-bromide-3-methyl butane were employed with 150 mg (0.926 mMol) of 7-hydroxycoumarin with 36 mg (1.5 Eq) of NaH. The reaction mixture was stirred at 0 °C for 15 min, then brought to a temperature below the boiling point of the DMF (153 °C) for another 15 min, and finally stirred at room temperature for 24 h, in order to favor the displacement of kinetic and thermodynamic equilibrium towards product formation. The crude reaction product was then partitioned with diethylether, a saturated solution of NaCl (brine) at room temperature and two washes with water at 5 °C. The organic layer was washed several times with distilled water and then dried with anhydrous Na2SO4. The vacuum evaporation residue was purified by silica gel column chromatography, using distillated n-Hexane/AcOEt mixtures at increasing polarities. The isolated compounds were analyzed by HRMS, ESI-MS 1H-NMR, 13C-NMR and bidimensional experiments like DEPT, H,H-COSY and HETCOR. |
42% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 1h; Inert atmosphere; | |
With potassium carbonate; acetone | ||
With potassium carbonate In acetone | ||
2 g | With potassium carbonate In acetone for 20h; Heating; | |
1.7 g | With potassium carbonate In acetone for 2h; Heating; | |
With potassium carbonate In acetone for 6h; Heating; | ||
With potassium carbonate | In an embodiment, the syn-ht-7-allyloxycoumarin photodimer (Scheme 1, RH2CCH-CH2-) was obtained from Lewis acid-catalyzed (BF3-OEt2) photodimerization of 7-allyloxycoumar synthesized from 7-hydroxycoumarin (Scheme 1, RH) and allyl bromide in the presence of potassium carbonate. | |
With potassium carbonate In acetone at 56℃; for 15h; | ||
With potassium carbonate In acetone for 2h; Reflux; | ||
With potassium carbonate In acetone | ||
With potassium carbonate In acetone for 12h; Inert atmosphere; Reflux; | ||
With potassium carbonate In acetone at 80℃; for 1h; | ||
With potassium carbonate In acetone at 57℃; for 10h; Inert atmosphere; Darkness; | ||
In acetone at 80℃; for 1h; | ||
at 70℃; for 14h; | ||
3.35 g | With potassium carbonate In acetone at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In dichloromethane at 0 - 20℃; for 6h; | |
85% | With triethylamine In dichloromethane at -5 - 20℃; for 6h; | 1 Preparation of umbelliferone chloroacetyl derivative A mixture of 7-hydroxycoumarin (compound of formula 1, 0.01 mol) and triethylamine (0.01 mol) dissolved in anhydrous dichloromethane (25 mL) was cooled in an ice salt mixture to 0-5 C .To the reaction mixture was added dropwise chloroacetyl chloride (0.01 mol) in dry dichloromethane while maintaining the above temperature, and stirring was continued for 1 hour. The reaction mixture was then further stirred at room temperature for 5 hours, then washed with 5% HCl, 5% sodium hydroxide and finally with brine solution. Subsequently, the organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to obtain a umbelliferone chloroacetyl derivative of the formula 2. (white solid, reaction time: 6 hours, yield: 85% 164 [deg.] C, Rf 0.64 (n-hexane: ethyl acetate 2: 1)). |
83.4% | With triethylamine In dichloromethane; chloroform at -10℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | General procedure: 0.4g of SM1 (2.2mmol), SM2 (2.4mmol) and SM3 (2.2mmol), respectively, were dissolved with CH3CN (2.0mL). After that, solid KOH (1.5 or 3 equivalents) was added, and stirred during thirty minutes. 2.1 equivalents of dimethyl sulfate (Me2SO4) were added to the mixture and heating for 48h at 40C. Finally, when reaction was completed (monitored by TLC analysis), the solid was filtered off and dried to afford the corresponding compounds 1 (6,7-dimethoxy-2H-chromen-2-one), 7 (7-methoxy-2H-chromen-2-one) and 13 (7-methoxy-4-methyl-2H-chromen-2-one), respectively. | |
90.2% | With potassium carbonate; potassium iodide; In acetone; at 20℃; for 5h; | General procedure: As an example, to a solution of 7-hydroxycoumarin (1.16 g, 7.15 mmol) in acetone (50 mL) was added K2CO3 (2.01 g, 14.55 mmol) and KI (4.38 g, 26.39 mmol) at room temperature. After stirring at room temperature for 10 min, 3-chloropropene (0.90 mL, 11.05 mmol) was added to the reaction mixture, and whole was refluxed at 60 C for 22 h. The solid was separated from the mixture, washed with acetone. Then the mixture was filtered, and the filtrate was washed by acetone (50 mL) three times. Acetone phase was combined, and then evaporated under reduced pressure. The residue was recrystallized in Petroleum ether-ethyl acetate (1:1, V/V) to produce a white needle shaped crystallite (1.31 g). Yield 90.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In acetone; at 25℃; for 5h;Inert atmosphere; | K2CO3 (2.0 g, 14.5 mmol) and MeI (3.42 g, 24.1 mmol) were added to a solution of 7-hydroxyl coumarin (6) (2.0 g, 12.3 mmol) in acetone (100 mL) and the mixture was reacted for 5 h. After filtration and dilution with EtOAc, the resulting solution was washed with brine and dried over anhydrous Na2SO4. The solvent was removed to afford compound 10 (2.1 g, 97%) as a crystalline solid. 1H NMR (400 MHz, CDCl3) delta 7.95 (d, J = 16.1 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 6.53-6.48 (m, 2H), 6.38 (s, 1H), 3.81 (s, 3H). |
73% | The 7-hydroxy-coumarin (1g, 6.2mmol) with 30 ml acetone dissolved, adding anhydrous potassium carbonate (1.7g, 12 . 35mmol), stirring the mixture at room temperature for 10 min. Add iodomethane (1.05g, 7 . 41mmol), heating reflux reaction 5h, stop heating, hot filtering, the filtrate is turns on lathe does, ethanol re-crystallization of the white crystal 0.8g, yield 73%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.5% | With N-chloro-succinimide; copper(II) chloride monohydrate; zinc(II) chloride In acetonitrile at 20℃; for 0.0833333h; regioselective reaction; | 2. The general synthetic procedure General procedure: To a 50 mL flask, the coumarin (1 mmol), appropriate amount of NXS, the Lewisacid catalyst and 20 mL anhydrous solvent were added in. The mixture was heated toreflux with a condenser under the protection of a drying tube. The reaction progresswas monitored by TLC. When the reaction was completed, the mixture was cooled toroom temperature. The solvent was removed by vacuum rotary evaporation, and theresidue was dispensed in 25 mL 5% sodium hydrogen sulfite (NaHSO3) aqueoussolution and then extracted with 25 mL ethyl acetate (EtOAc) for three times. Theorganic layer was combined, washed with 10 mL water and dried over anhydroussodium sulphate (Na2SO4). After the solvent was removed, the crude product waspurified by silica gel (300-400 mesh) column chromatograph. |
92% | With N-Bromosuccinimide at 20℃; for 2h; regioselective reaction; | |
83% | With γ-picolinium bromochromate In acetonitrile at 90℃; for 1.66667h; regioselective reaction; |
82% | With N-Bromosuccinimide; montmorillonite K-10; tetrabutylammomium bromide for 0.1h; microwave irradiation; | |
76% | With bromine In acetic acid for 48h; | |
75% | With N-Bromosuccinimide In methanol; acetonitrile at 20℃; for 2h; | |
72% | With iodine(I) bromide; acetic acid for 0.0833333h; Heating; microwave irradiation; | |
68% | With phenyl-trimethyl-ammonium perbromide In 1,4-dioxane Ambient temperature; | |
60% | With aluminum oxide; copper(ll) bromide In various solvent(s) for 25h; Heating; | |
With bromine; acetic acid | ||
Multi-step reaction with 3 steps 1: sodium hydride / N,N-dimethyl-formamide / 4 h / 20 °C 2: N-Bromosuccinimide; sodium acetate / acetonitrile / 20 °C 3: boron tribromide / dichloromethane / 12 h / 0 °C / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sulfuric acid for 0.0583333h; Microwave irradiation; | |
74.2% | With sulfuric acid at 100℃; for 2.5h; | Synthesis of coumarin intermediates 2. General procedure: 7-Hydroxy coumarin 2a was synthesized according to the reported literature.20 Resorcinol (11.0 g, 0.1 mol) and 2-hydroxysuccinic acid (20.1 g, 0.15 mol) were added to a stirred solution of concentrated sulfuric acid (200 mL) in a reaction flask equipped with a thermometer and addition funnel. The reaction mixture was maintained at 100 oC for 2.5 h and poured into crushed ice under vigorous stirring. The off-white precipitate was filtered and purified by recrystallization from ethanol to give the product 2a. Another coumarin intermediate 7-hydroxy-4-methyl-2H-chromen-2-one 2b was prepared under relatively mild conditions by condensing resorcinol with ethyl acetoacetate in the presence of a catalytic amount of concentrated sulfuric acid in 1,4-dioxane at 60 oC for 4 h. (see Supplementary file.) |
71% | With sulfuric acid at 20 - 100℃; for 3h; | 1.1 4.1.1 7-Hydroxy-2H-chromen-2-one (2a) A mixture of resorcinol (1.4g, 12.7mmol), 2-hydroxysuccinic acid (1.9g, 14.0mmol) and conc. H2SO4 (5mL) was stirred at room temperature for 0.5h. The above mixture was heated to 100°C and stirred for another 2.5h. After cooling to room temperature, ice water was added to the mixture and stirred for 30min. The reaction mixture was filtered and dried to afford 2a as white solid. Yield 71%, mp 234-236°C; IR (KBr) ν 3157, 2828, 1706, 1679, 1603, 1567, 1408, 1323, 1235, 1136, 989, 902, 850, 835cm-1; 1H NMR (500MHz, CD3OD) δ 7.87 (d, 1H, J=9.5Hz), 7.48 (d, 1H, J=8.5Hz), 6.82 (dd, 1H, J=8.5Hz, J=2.0Hz), 6.73 (d, 1H, J=2.0Hz), 6.21 (d, 1H, J=9.5Hz); ESI-MS m/z: 163.0 [M+H]+. |
71% | With sulfuric acid at 20 - 100℃; for 3h; | 7-Hydroxy-2H-chromen-2-one (2) A mixture of resorcinol (1.4 g, 12.7 mmol), 2-hydroxysuccinic acid (1.9 g, 14.0mmol) and conc. H2SO4 (5 mL) was stirred at room temperature for 0.5 h. The above mixture was heated to 100 °C and stirred for another 2.5 h. After cooling to room temperature, ice water was added to the mixture and stirred for 30 min. The reaction mixture was filtered and dried to afford 2 as white solid. |
67% | Stage #1: malic acid With sulfuric acid at 20℃; for 0.166667h; Stage #2: recorcinol at 20 - 120℃; for 2h; | General procedure for the synthesis of hydroxycoumarins. General procedure: In around bottom flask equipped with a magnetic bar and condenser, 2equivalents of DL-malic acid were suspended in 15 mL of concentratedsulphuric acid. The slurry was stirred for 10 min at room temperatureafter which 1 equivalent of resorcinol was added and the resultingmixture was stirred at room temperature for another 10 min, then themixture was heated at 120 C for 2 h. After that time, the reactionreached room temperature and quenched with 20.00 g of ice (water).The crude product was filtered and crystallized from methanol-waterproducing the corresponding coumarins.7-hydroxycoumarin (1) [33]. Orange solid, 67% yield, m.p.204-206 C (204-206 C, lit). 1H NMR (DMSO-d6) : 7.86 (d, 1H, J =9.5, H-4), 7.51 (d, 1H, J = 8.5, H-5), 6.84 (dd, 1H, J = 8.5, 2.4, H-6).6.75 (d, 1H, J = 2.4, H-8), 6.16 (d, 1H, J = 9.5, H-3). 13C NMR : 162.2(C2), 161.7 (C7), 155.8 (C8a), 144.6 (C4), 129.2 (C5), 113.1 (C3), 111.7(C6), 110.9 (C4a), 101.9 (C8). |
60.8% | With perchloric acid at 90℃; for 4h; | 1.1 Example 1: 7-(4-(4-(3-(6-fluoro-benzisoxazole)-1-piperidyl)-n-butoxy))-2H-benzopyran-2-one (1) Example 1: 7-(4-(4-(3-(6-fluoro-benzisoxazole)-1-piperidyl)-n-butoxy))-2H-benzopyran-2-one (1) [0038] The target compound was synthesized according to Scheme 1. 1) 5.5 g of resorcinol and 6.7 g of d,l-malic acid were added to 50 ml of 70% HClO4, and the solution was heated to 90°C for reaction. The solution became clear slowly, and the reaction was completed after 4 hours. The reaction mixture was cooled to room temperature, and the reaction liquid was poured into an ice-water mixture. A large amount of solid was precipitated, which were filtrated. The cake was washed with water. Recrystallization with 95% ethanol gave 4.5 g of white crystal. Melting point: 226-228°C, Yield: 60.8%. |
60.8% | With perchloric acid In water at 90℃; for 4h; | 1.1 Example 1: 7-(4-(4-(3-(6-fluoro-benzisoxazole)-1-piperidyl)-n-butoxy))-2H-benzopyran-2-one (1) 1) 5.5 g of resorcinol and 6.7 g of d,l-malic acid were added to 50 ml of 70% HClO4, and the solution was heated to 90° C. for reaction. The solution became clear slowly, and the reaction was completed after 4 hours. The reaction mixture was cooled to room temperature, and the reaction liquid was poured into an ice-water mixture. A large amount of solid was precipitated, which were filtrated. The cake was washed with water. Recrystallization with 95% ethanol gave 4.5 g of white crystal. Melting point: 226-228° C., Yield: 60.8%. |
57% | With sulfuric acid for 0.0666667h; microwave irradiation; | |
43% | With sulfuric acid at 20 - 100℃; for 3h; | 1 Production of Umbelliferone Resorcinol (1.0 g, 9.08 mmol) was added to a 50 mL eggplant flask,Malic acid (1.34 g, 9.99 mmol, 1.1 eq.) Was added,Concentrated sulfuric acid was added as a solvent.After stirring at room temperature for 30 minutes,And the mixture was stirred at 100 ° C. for 2.5 hours.Thereafter, the reaction solution was cooled to room temperature,Ice was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes.Extracted three times with diethyl ether,The organic layer was washed with saturated brine.It was dried over anhydrous sodium sulfate,Filtered and concentrated.The residue was recrystallized from a hexane / ethyl acetate mixed solvent,633.2 mg (43%) of umbelliferone as a beige solid was obtained. |
With zirconium phosphate at 120℃; | ||
With sulfuric acid | ||
With titanium(IV) pyrophosphate at 120℃; | ||
With sulfuric acid | ||
With sulfuric acid for 1h; Heating; | ||
With sulfuric acid at 20 - 130℃; for 3h; | ||
With sulfuric acid at 120℃; for 2h; | ||
With sulfuric acid Microwave irradiation; | ||
With sulfuric acid In 1,4-dioxane at 100℃; for 2.5h; | 1.3 Synthesis and characterization of 7-hydroxy coumarin 5b To a flask containing resorcinol (1.0 g, 9.1 mmol) was added dropwise concentrated sulfuric acid (5ml), followed by 2-hydroxysuccinic acid (1.3 g, 10.0 mmol). The mixture was stirred at room temperature for 0.5 h and then was heated to 100 oC for another 2.5 h. After that, the mixture was poured into crude ice cautiously and the further white precipitate was filtered, dried under reduced pressure to afford compound of 5b. 7-hydroxy-2H-chromen-2-one (5b) 1H NMR (600 MHz, DMSO) δ: 10.55 (s, 1H), 7.92 (d, J = 9.3 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 6.77 (s, 1H), 6.69 (d, J = 8.5 Hz, 1H), 6.19 (d, J = 9.3 Hz, 1H). | |
With sulfuric acid at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.13% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: 1-bromo-butane In acetone at 65℃; for 24h; | 15.6. Procedure for synthesis of coumarin derivatives A21-A25 General procedure: The synthetic route is shown in Scheme 2. For example, to a stirred solution of 7-hydroxycoumarin (0.16 g, 1 mmol) in 20 mL acetone were added anhydrous K2CO3 (0.28 g, 2 mmol) at room temperature. After stirring at room temperature for 30 min, bromopropane (0.21 g, 1.5 mmol) was added to the reaction mixture, and whole was refluxed at 65°C for 24 h. The precipitate was filtered off and washed with acetone (4 × 30 mL). The solvent was evaporated under reduced pressure, and the residue was treated with water (50 mL) and extracted with ethyl acetate (4 × 30 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography with mixed petroleum ether and ethyl acetate (3:1, v/v) as eluent to give compounds A21-A25 as solid. |
67% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone for 0.25h; Inert atmosphere; Reflux; Stage #2: 1-bromo-butane In acetone Inert atmosphere; Reflux; | General procedure for the synthesis of 7-O-alkylumbelliferone (1a-j): General procedure: In a 50 mL two necked round-bottomed flask equipped with a magnetic stirrer, a condenser, and a nitrogen inlet,umbelliferone (1 equiv.), K2CO3 (3 equiv.) and 10 mL of anhydrous acetone were added. The mixture was heated underreflux for 15 min under nitrogen atmosphere and cooledto room temperature before the dropwise addition of alkylbromide (1.5 equiv.). The resulting mixture was heated underreflux for another 2-6 h. The reaction was quenched withwater (10 mL), followed by extraction with EtOAc (2×50 mL)and washed with brine solution. After drying (Na2SO4) andremoval of the solvent, the residue was purified by columnchromatography using hexane/EtOAc as mobile phase (gradientelution), to afford the corresponding compounds 1aj14.All the derivatives were characterized by 1H, 13C NMRand mass data. |
60% | With potassium carbonate In acetone for 30h; Heating; |
With potassium carbonate In acetone for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With copper(II) choride dihydrate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 10h; | 1.1 1. Add 0.30 g (1.85 mmol) of 7-hydroxycoumarin to a 10 mL round bottom flask.3 mL of acetonitrile 0.31 mL (2.04 mmol) DBU and 0.32 mg (0.00185 mmol) of copper chloride dihydrate were added in sequence.0.22 mL (1.94 mmol) of 2-methyl-3-butyn-1-ol was slowly added at 0 ° C, and reacted at room temperature for 10 h, and the reaction of the starting material was monitored by TLC.The reaction solution was poured into a saturated aqueous solution of NaHCO3 and extracted with ethyl acetate.Dry over anhydrous MgSO4, filtered, concentrated under reduced pressure and purified by column chromatography (eluent: EA/PE = 1:3).Compound I was obtained (0.37 g, yield 90%, white solid,Mp: 253-255 ° C), |
80% | With potassium carbonate; potassium iodide In water; acetone Heating; | |
76% | With potassium carbonate In acetone for 8h; Heating; |
68% | With potassium carbonate; potassium iodide In water; acetone for 21h; Heating; | |
60% | With copper(II) choride dihydrate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0℃; for 18h; | |
52% | With copper(II) choride dihydrate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0 - 20℃; | |
With copper(II) choride dihydrate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0 - 20℃; | ||
Alkaline conditions; | 1 EXAMPLE-1 EXAMPLE-1 Preparation of (+-) Marmesin, Columbianetin, Dihydroxanthyletin, Seselin and Coumarin Derivatives: The synthetic (+-) Marmesin and columbianetin were prepared starting from 7-Hydroxy coumarin (Umbelliferone). Condensation of 7-hydroxy coumarin with 2-chloro-2-methyl but-3-yne in the presence of base gave propargylether. The obtained ether on catalytic hydrogenation afforded alkene. The alkene on claisen rearrangement gave two isomeric products. Oxidation of 7-Hydroxy-6-Prenyl coumarin with m-chloroperbenzoic acid in ethyl acetate solvent gave (+/-) Marmesin. Oxidation of 7-Hydroxy-8-Prenyl coumarin with m-chloroperbenzoic acid in ethyl acetate solvent gave columbianetin. 7-Hydroxy-6-Prenyl coumarin on oxidation with m-chloroperbenzoic acid in chloroform solvent gave dihydroxanthyletin. (Tetrahedron, 27, 1247, 1971, Tetrahedron, 27, 4901, 1971). The synthetic seselin was prepared starting from 7-Hydroxy coumarin (Umbelliferone). Condensation of 7-hydroxy coumarin with 2-chloro-2-methyl but-3-yne in the presence of base gave propargylether. The propargylether on heating at 200° C. with N,N-dimethyl aniline gave seselin. (Tetrahedron, 27, 1247, 1971, Tetrahedron, 27, 4901, 1971). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate In acetone Heating; | |
90% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone for 0.25h; Inert atmosphere; Reflux; Stage #2: prenyl bromide In acetone Inert atmosphere; Reflux; | General procedure for the synthesis of 7-O-alkylumbelliferone (1a-j): General procedure: In a 50 mL two necked round-bottomed flask equipped with a magnetic stirrer, a condenser, and a nitrogen inlet,umbelliferone (1 equiv.), K2CO3 (3 equiv.) and 10 mL of anhydrous acetone were added. The mixture was heated underreflux for 15 min under nitrogen atmosphere and cooledto room temperature before the dropwise addition of alkylbromide (1.5 equiv.). The resulting mixture was heated underreflux for another 2-6 h. The reaction was quenched withwater (10 mL), followed by extraction with EtOAc (2×50 mL)and washed with brine solution. After drying (Na2SO4) andremoval of the solvent, the residue was purified by columnchromatography using hexane/EtOAc as mobile phase (gradientelution), to afford the corresponding compounds 1aj14.All the derivatives were characterized by 1H, 13C NMRand mass data. |
89% | With potassium carbonate In acetone Heating; |
84% | Stage #1: 7-hydroxy-2H-chromen-2-one; prenyl bromide With sodium hydride In N,N-dimethyl-formamide at 20℃; for 24h; Stage #2: In N,N-dimethyl-formamide at 153℃; for 0.25h; Stage #3: In N,N-dimethyl-formamide at 20℃; for 24h; | General procedure for coumarin derivatives synthesis General procedure: 150 mg (0.926 mMol) of 6-hydroxy (1), 7-hydroxy (2), or4-hydroxycoumarin (3) separately were dissolved in 4 ml of DMF, with 36 mg (1.5 Eq) of NaH and 2 Eq. of 4-penten, 3-buten, trans-crotyl, allyl or γ,γ-dimethylallyl bromide. Similarly, 2 Eq. of 1-bromide-3-methyl butane were employed with 150 mg (0.926 mMol) of 7-hydroxycoumarin with 36 mg (1.5 Eq) of NaH. The reaction mixture was stirred at 0 °C for 15 min, then brought to a temperature below the boiling point of the DMF (153 °C) for another 15 min, and finally stirred at room temperature for 24 h, in order to favor the displacement of kinetic and thermodynamic equilibrium towards product formation. The crude reaction product was then partitioned with diethylether, a saturated solution of NaCl (brine) at room temperature and two washes with water at 5 °C. The organic layer was washed several times with distilled water and then dried with anhydrous Na2SO4. The vacuum evaporation residue was purified by silica gel column chromatography, using distillated n-Hexane/AcOEt mixtures at increasing polarities. The isolated compounds were analyzed by HRMS, ESI-MS 1H-NMR, 13C-NMR and bidimensional experiments like DEPT, H,H-COSY and HETCOR. |
83% | With potassium carbonate In N,N-dimethyl-formamide for 3h; Reflux; | 7-Prenyloxycoumarin (4). 1-Bromo-3-methyl-2-butene (93 l, 0.80 mmol) was added to a stirred mixture of umbelliferone (2) (100 mg, 0.62 mmol) and K2CO3 (171 mg, 1.24 mmol) in dry DMF (5 ml) under argon. The reaction mixture was stirred under reflux for 3 h. The reaction mixture was neutralised by addition of aq. HCl (1M). The resulting brown residue was added in DCM (20 ml), washed with water (2 × 20 ml), brine (30 ml) and dried Na2SO4). Removal of solvent yielded a brown oil, which was purified by flash column chromatography, eluting with diethylether-hexane (1:1) to give a white powder 4 (118 mg, 83%): 1H NMR (CDCl3, 500 MHz) 7.64 (1H, d, J = 9.5 Hz, H-4), 7.36 (1H, d, J = 8.6 Hz, H-5), 6.85 (1H, dd, J = 8.6, 2.3 Hz, H-6), 6.82 (1H, d, J = 2.3 Hz, H-8), 6.25 (1H, d, J = 9.5 Hz, H-3), 5.48 (1H, m, H-2'), 4.58 (2H, d, J = 6.9 Hz, H-1'), 1.81 (3H, brs, H-4'), 1.77 (3H, brs, H-5'); 13C NMR (CDCl3, 125 MHz) 162.1 (C, C-7), 161.3 (C, C-2), 155.8 (C, C-8a), 143.5 (CH, C-4), 139.3 (C-3'), 128.7 (CH, C-5), 118.6 (CH, C-2'), 113.2 (CH, C-6), 112.9 (CH, C-3), 112.4 (C, C-4a), 101.5 (CH, C-8), 65.4 (CH2, C-1'), 25.8 (CH3, C-4'), 18.3 (CH3, C-5'); HR-FABMS (pos) m/z 231.2668 [M + H]+ (calcd. for C14H15O3, 231.2685). |
80% | With potassium carbonate In acetone for 8h; Heating; | |
67% | With tetra(n-butyl)ammonium hydroxide In dichloromethane at 20℃; for 2h; | |
65% | With potassium carbonate In acetone for 6h; Reflux; | |
With potassium carbonate In acetone at 70℃; for 1h; | ||
With potassium carbonate In acetone for 5h; Heating; | ||
Stage #1: 7-hydroxy-2H-chromen-2-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.416667h; Stage #2: prenyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | Synthesis of 7-((2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyloxy)-2H-chromen-2-one (9) General procedure: To an oven dried 50-mL round-bottom flask equipped with a magnetic stirring bar, rubber septa and a nitrogen inlet,umbelliferone (1) (19.3 mg, 0.12 mmol) and 10 mL of anhydrous DMF were added. The solution was cooled to 0 °C and sodium hydride (4.2 mg of 60% mineral oil suspension) was added. The reaction mixture was allowed to stir for 25 min at 0 °C, and the crude geranylgeranyl bromide from the previous step was dissolved anhydrous DMF (2 mL) and added dropwise to the reaction flask via syringe. The reaction was allowed to slowly warm to room temperature and was stirred overnight. The desired compound was isolated via preparative thin layer chromatography using 3:7 ethyl acetate:hexanes solvent system. | |
With potassium carbonate In acetone for 12h; Reflux; | General procedure for preparation of prenyloxycoumarin General procedure: A mixture of hydroxycoumarins 4a-f (5 mmol), prenyl bromide (6 mmol) and anhydrous potassium carbonate (0.70 g; 5 mmol) in dry acetone (3 mL) was refluxed for 12 h and then cooled. The mixture was diluted with water (10 mL) and then extracted with ether (2 * 20 mL). The combined extracts were washed with NaOH 10% (2 * 10 mL) and dried with anhydrous sodium carbonate. After removal of the solvent the products were purified by crystallization from methanol or by column chromatography (silicagel 60; 230-400; heptane). | |
Stage #1: 7-hydroxy-2H-chromen-2-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: prenyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 14h; Inert atmosphere; | Synthesis of 6-(((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)oxy)-2H-chromen-2-one (6) General procedure: An oven-dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (114 mg, 0.7 mmol) and 4 mL of anhydrous N,N-dimethylformamide (DMF) were added to the round bottom flask. The solution was stirred and cooled to 0 °C in a salt-ice bath. Sodium hydride (28 mg of 60% mineral oil suspension, 0.7 mmol) was added to the flask at which point the solution turned color from yellow to dark red. The solution was kept stirring at 0 °C for 30 minutes. Farnesyl bromide (450 μL, 1.66 mmol) in 1 mL of anhydrous DMF was cooled to 0 °C and added dropwise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen with warming to room temperature over 14 hours and concentrated in vacuo. The desired product was obtained by column chromatography using a solvent system of 100 % Hexanes, 20:1 Hexanes:Ethyl acetate, 15:1 Hexanes:Ethyl acetate, 10:1 Hexanes:Ethyl acetate, 7:3 Hexanes:Ethyl acetate, and 2:1 Hexanes:Ethyl acetate. The progress of the column was monitored by TLC, and the desired product was isolated. The identity of the purified product was verified by NMR spectroscopy (1H-NMR, 13C-NMR) and high-resolution mass spectrometry (HRMS). | |
With potassium carbonate In acetone at 80℃; for 1h; | ||
In acetone at 80℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In N,N-dimethyl-formamide; for 3h;Inert atmosphere; Reflux; | Aurapten (5). Geranyl bromide (159 l, 0.80 mmol) was added to a stirred mixture of umbelliferone (2) (100 mg, 0.62 mmol) and K2CO3 (171 mg, 1.24 mmol) in dry DMF (5 ml) under argon. The reaction mixture was stirred under reflux for 3 h. The reaction mixture was neutralised by addition of aq. HCl (1M). The resulting brown residue was added in DCM (20 ml), washed with water (2 × 20 ml), brine (30 ml) and dried Na2SO4). Removal of solvent yielded a brown oil, which was purified by flash column chromatography, eluting with diethylether-hexane (1:1) to give a white powder 5 (181 mg, 76%): 1H NMR (CDCl3, 700 MHz) 7.64 (1H, d, J = 9.5 Hz, H-4), 7.36 (1H, d, J = 8.6 Hz, H-5), 6.86 (1H, dd, J = 8.4, 2.4 Hz, H-6), 6.82 (1H, d, J = 2.4 Hz, H-8), 6.25 (1H, d, J = 9.5 Hz, H-3), 5.47 (1H, tq, J = 6.6, 1.4 Hz, H-2'), 5.08 (2H, m, H-1'), 4.61 (2H, d, J = 6.6 Hz, H-1'), 2.13 (2H, m, H-5'), 2.09 (2H, m, H-4'), 1.76 (3H, brs, H-9'), 1.67 (3H, brs, H-8'), 1.60 (3H, brs, H-10'); 13C NMR (CDCl3, 175 MHz) 162.2 (C, C-7), 161.3 (C, C-2), 155.9 (C, C-8a), 143.4 (CH, C-4), 142.4 (C-3'), 131.9 (C, C-7'), 128.7 (CH, C-5), 123.6 (CH, C-6'), 118.4 (CH, C-2'), 113.2 (CH, C-6), 112.9 (CH, C-3), 112.4 (C, C-4a), 101.6 (CH, C-8), 65.5 (CH2, C-1'), 39.5 (CH2, C-4'), 26.2 (CH2, C-5'), 25.6 (CH3, C-8'), 17.7 (CH3, C-10'), 16.7 (CH3, C-9'); HR-FABMS (pos) m/z 299.3877 [M + H]+ (calcd. for C19H23O3, 299.3860). |
General procedure: To an oven dried 50-mL round-bottom flask equipped with a magnetic stirring bar, rubber septa and a nitrogen inlet,umbelliferone (1) (19.3 mg, 0.12 mmol) and 10 mL of anhydrous DMF were added. The solution was cooled to 0 C and sodium hydride (4.2 mg of 60% mineral oil suspension) was added. The reaction mixture was allowed to stir for 25 min at 0 C, and the crude geranylgeranyl bromide from the previous step was dissolved anhydrous DMF (2 mL) and added dropwise to the reaction flask via syringe. The reaction was allowed to slowly warm to room temperature and was stirred overnight. The desired compound was isolated via preparative thin layer chromatography using 3:7 ethyl acetate:hexanes solvent system. | ||
With potassium carbonate; In acetone; for 12h;Reflux; | General procedure: A mixture of hydroxycoumarins 4a-f (5 mmol), prenyl bromide (6 mmol) and anhydrous potassium carbonate (0.70 g; 5 mmol) in dry acetone (3 mL) was refluxed for 12 h and then cooled. The mixture was diluted with water (10 mL) and then extracted with ether (2 * 20 mL). The combined extracts were washed with NaOH 10% (2 * 10 mL) and dried with anhydrous sodium carbonate. After removal of the solvent the products were purified by crystallization from methanol or by column chromatography (silicagel 60; 230-400; heptane). |
General procedure: An oven-dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (114 mg, 0.7 mmol) and 4 mL of anhydrous N,N-dimethylformamide (DMF) were added to the round bottom flask. The solution was stirred and cooled to 0 C in a salt-ice bath. Sodium hydride (28 mg of 60% mineral oil suspension, 0.7 mmol) was added to the flask at which point the solution turned color from yellow to dark red. The solution was kept stirring at 0 C for 30 minutes. Farnesyl bromide (450 muL, 1.66 mmol) in 1 mL of anhydrous DMF was cooled to 0 C and added dropwise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen with warming to room temperature over 14 hours and concentrated in vacuo. The desired product was obtained by column chromatography using a solvent system of 100 % Hexanes, 20:1 Hexanes:Ethyl acetate, 15:1 Hexanes:Ethyl acetate, 10:1 Hexanes:Ethyl acetate, 7:3 Hexanes:Ethyl acetate, and 2:1 Hexanes:Ethyl acetate. The progress of the column was monitored by TLC, and the desired product was isolated. The identity of the purified product was verified by NMR spectroscopy (1H-NMR, 13C-NMR) and high-resolution mass spectrometry (HRMS). | ||
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20 - 60℃; for 5.25h; | General procedure: DBU (1.0 mmol) and corresponding bromide 12a-e (0.75 mmol) were added to compound 4 (0.5mmol) in dry DMF (5mL) at r.t. under stirring. The reaction mixture was stirred at r.t. for 15 minutes, and then heated at 60C for 5h. H2O (15ml) was added and the product was extracted with ethyl acetate. The extracts were washed with brine, dried with Na2SO4 and evaporated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydride In tetrahydrofuran; dimethyl sulfoxide for 2h; Heating; | |
83% | With potassium carbonate In acetone at 20℃; for 12h; | |
80% | With potassium carbonate In acetone for 6h; Reflux; |
74% | With potassium carbonate In acetone at 80℃; for 1h; | 1 Example 1 : Synthesis of umbelliprenin A mixture of 7-hydroxy-oxycoumarin (5.0 mmol), trans-trans farnesyl bromide (4.8 mmol) and dry potassium carbonate (6.0 mmol) dissolved in acetone (10 ml) was heated at 80 °C for 1 hour under magnetic stirring, cooled and then poured into water (100 ml). The resulting solution was extracted with n-hexane (3 x 20 ml). The combined organic phases were dried over anhydrous sodium sulphate, filtered and concentrated to dryness under vacuum. The resulting brownish solid was purified by crystallization (MeOH) affording umbelliprenin as a white solid in 74 % yield. Melting point: 61 -63 °C 1 H NMR (200 MHz, CDCI3) δ 7.60 (d, J = 9.45 Hz, 1 H), 7.32 (d, J = 8.52 Hz, 1 H), 6.84 (dd, J, = 8.52 Hz, J2 = 2.03 Hz, 1 H), 6.77 (d, J = 2.03 Hz, 1 H), 6.24 (d, J = 9.5 Hz, 1 H), 5.42 (d, J = 7.02 Hz, 1 H), 5.08-5.05 (m, 2H), 4.56 (d, J = 7.02 Hz, 2H), 2.09-2.06 (m, 4H), 2.04-2.01 (M, 2H), 1 .95 (t, J = 8.04 Hz, 2H), 1 .77 (s, 3H), 1 .64 (s, 3H), 1 .56 (s, 3H) 13C NMR (50.1 MHz, CDCI3) δ 162.0, 161 .0, 155.6, 143.3, 142.3, 135.7, 131.0, 128.5, 124.3, 123.6, 1 18.4, 1 13.0, 1 12.7, 1 12.2, 101 .3, 65.4, 39.4, 26.5, 26.0, 25.8, 17.5, 16.8, 15.9. EIMS m/z 366 [C24H3o03]+ (4.6) |
With tetrabutylammomium bromide; sodium hydride In N,N-dimethyl-formamide | ||
With potassium carbonate In acetone | ||
With potassium carbonate In acetone for 12h; Reflux; | General procedure for preparation of prenyloxycoumarin General procedure: A mixture of hydroxycoumarins 4a-f (5 mmol), prenyl bromide (6 mmol) and anhydrous potassium carbonate (0.70 g; 5 mmol) in dry acetone (3 mL) was refluxed for 12 h and then cooled. The mixture was diluted with water (10 mL) and then extracted with ether (2 * 20 mL). The combined extracts were washed with NaOH 10% (2 * 10 mL) and dried with anhydrous sodium carbonate. After removal of the solvent the products were purified by crystallization from methanol or by column chromatography (silicagel 60; 230-400; heptane). | |
Stage #1: 7-hydroxy-2H-chromen-2-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: farnesyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 14h; Inert atmosphere; | Synthesis of 6-(((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)oxy)-2H-chromen-2-one (6) General procedure: An oven-dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (114 mg, 0.7 mmol) and 4 mL of anhydrous N,N-dimethylformamide (DMF) were added to the round bottom flask. The solution was stirred and cooled to 0 °C in a salt-ice bath. Sodium hydride (28 mg of 60% mineral oil suspension, 0.7 mmol) was added to the flask at which point the solution turned color from yellow to dark red. The solution was kept stirring at 0 °C for 30 minutes. Farnesyl bromide (450 μL, 1.66 mmol) in 1 mL of anhydrous DMF was cooled to 0 °C and added dropwise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen with warming to room temperature over 14 hours and concentrated in vacuo. The desired product was obtained by column chromatography using a solvent system of 100 % Hexanes, 20:1 Hexanes:Ethyl acetate, 15:1 Hexanes:Ethyl acetate, 10:1 Hexanes:Ethyl acetate, 7:3 Hexanes:Ethyl acetate, and 2:1 Hexanes:Ethyl acetate. The progress of the column was monitored by TLC, and the desired product was isolated. The identity of the purified product was verified by NMR spectroscopy (1H-NMR, 13C-NMR) and high-resolution mass spectrometry (HRMS). | |
In acetone at 80℃; for 1h; | ||
With potassium carbonate In acetone for 12h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In pyridine; dichloromethane for 0.25h; | |
99% | With SiO2-supported Co(II) Salen complex catalyst at 50℃; for 0.75h; | |
99% | With pyridine In ethyl acetate at 20℃; for 1.5h; Inert atmosphere; |
98% | With pyridine at 20℃; for 24h; | |
98% | With aluminum triflate at 20℃; for 0.00833333h; | |
97% | With pyridine In dichloromethane at 20℃; for 24h; | |
97% | With pyridine In dichloromethane at 20℃; | |
97% | With pyridine In dichloromethane at 20℃; | 2.1 1. Synthesis of compound B1 1. Synthesis of compound B1n 100 ml round-bottom flask, the 7-hydroxy-coumarin (3.1g, 19 . 1mmol) is added to the 50 ml dichloromethane, to form a suspension, add 2 ml acetic anhydride and a drop of pyridine. The above-mentioned reaction solution stirring the mixture at room temperature for overnight to obtain flaxen clear solution. turns on lathe does the solvent dichloromethane under reduced pressure, the crude product may be strawcoloured of the solid. Then its added to the 100 ml water, extraction with ethyl acetate, obtaining the organic layer, the water layer removed, anhydrous sodium sulfate to ethyl acetate after drying is removed by rotating the evaporimeter, to obtain yellow solid. The chromatographic separation column chromatography (petroleum ether: ethyl acetate = 2 the [...] 1, (v/v)), get 3.8g (yield 97%) of white solid. |
96% | With pyridine In dichloromethane at 20℃; for 16h; Inert atmosphere; | |
95.4% | With piperidine In dichloromethane for 12h; Inert atmosphere; Reflux; | 1.1 1. Under the protection of N2, add 120 mL of dichloromethane to a 250 mL three-necked flask.7-hydroxycoumarin (9.3 g, 57.3 mmol),Stir and dissolve,Additional acetic anhydride (11.7 g, 114.6 mmol) was added.Piperazine 7 to 8 drops (0.3, g), reflux at room temperature,Reaction 12h,After completion of the reaction, the solvent was distilled off under reduced pressure, and water was added and then extracted with ethyl acetate.The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered and evaporated.Crude product column chromatography separation,The eluent is chloroform.The white product 7-acetoxycoumarin was 11.16 g, and the yield was 95.4%. 1H NMR(400MHz,CDCl3)δ(ppm): 2.36 (s,3H,CH3), 6.41(d,1H,J9.6Hz,ArH), 7.07(d,1H,J8.4Hz,ArH), 7.14(s,1H,ArH), 7.50(d,1H,J8.4Hz,ArH), 7.71(d,1H,J9.6Hz,ArH) |
93% | With sodium hydroxide for 0.05h; Irradiation; | |
93.4% | With triethylamine In tetrahydrofuran at 20℃; for 0.5h; | |
90% | for 1.5h; Heating; | |
90% | With iron oxide nanoparticles supported on porous silicates SBA-15 In neat (no solvent) at 40℃; for 0.25h; | 2.3 General procedure for the acetylation of alcohols and phenols General procedure: To a solution of substrate (1 mmol) and acetic anhydride (1.5 mmol) was added supported iron catalyst (Fe/SBA-15) (0.005 mmol, 0.085 g) and the mixture was stirred at 40 °C. After completion of the reaction (TLC), the reaction mixture was filtered and the catalyst rinsed with ethyl acetate and heated at 70 °C prior to its reuse in the next reaction. The organic layer was washed with saturated NaHCO3 and water, and dried over anhydrous sodium sulfate. The product was obtained after removal of the solvent. |
90% | With sulfuric acid; triethylamine at 20℃; for 0.166667h; Cooling with ice; | 4.1.6 Preparation of 4, 10 and 16 (Scheme 1d) General procedure: 0.4g of SM1 (2.2mmol), SM2 (2.4mmol) and SM3 (2.2mmol), respectively, were stirred with 4 molar equivalents of acetic anhydride and two drops of H2SO4 (as catalyst) under ice bath. After that, 2.5 molar equivalents of Et3N were added to the mixture and agitated for 2 days, 10min and 30min, respectively, at room temperature. After reactions were completed (analyzed by TLC), the solid was filtered off and dried to afford the corresponding compounds 4 (2-oxo-2H-chromene-6,7-diyl diacetate), 10 (2-oxo-2H-chromen-7-yl acetate) and 16 (4-methyl-2-oxo-2H-chromen-7-yl acetate), respectively. |
90% | With pyridine In dichloromethane at 25℃; for 16h; | |
88% | for 5h; Reflux; | |
87% | With pyridine In dichloromethane; chloroform for 10h; | 2.1 Synthesis of 7-hydroxy-8-aldehyde coumarin (Compound 2) Add 50 mmol of 7-hydroxycoumarin to the reaction flask. Into it was added dropwise 100 mL of dichloromethane to dissolve it; Then 100 mmol acetic anhydride and 25 mmol pyridine is added dropwise to Compound 1 dissolved in chloroform 10 hours, A clear yellow solution is obtained and rotovaped. column chromatography afforded a white solid compound 2. The eluent was petroleum ether:dichloromethane=1:4 with a yield of 87%. The hydrogen spectrum data of the obtained compound 2 are as follows |
85% | With pyridine at 20℃; for 10h; | Synthesis of compound 3 (7-Acetoxycoumarin) Acetic anhydride (2 mL) and pyridine (0.1 mL) were added to a solution of dichloromethane (50 mL) containing 7-hydroxycoumarin (3.1 g, 19.1 mmol) [1]. After the reaction mixture was stirred at room temperature for 10 h, the volatiles were evaporated under reduced pressure. The residue was purified by column chromatography (petroleum: ethyl acetate= 2: 1) to afford 3 (3.3 g, yield: 85%). |
83% | With pyridine In dichloromethane at 30℃; for 60h; | |
81% | Stage #1: 7-hydroxy-2H-chromen-2-one With manganese(II) iodide; naphthalene; lithium In tetrahydrofuran at 20℃; for 0.166667h; Inert atmosphere; Stage #2: acetic anhydride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; | Phenyl 3-Chlorobenzoate (1c); Typical Procedure General procedure: A 25 mL flask was charged with lithium (0.07 g, 9.68 mmol),naphthalene (0.19 g, 1.48 mmol), anhyd MnI2 (1.45 g, 4.71 mmol), and freshly distilled THF (10 mL) under argon pressure,and the mixture was stirred for 1 h at r.t. To the resultingslurry, containing 2.5 mmol of highly active manganese, wasadded PhOH (0.47 g, 5.0 mmol) and the resulting mixture wasstirred at r.t. for 10 min. Neat 3-chlorobenzoyl chloride (0.88 g,5.0 mmol) was then added to the flask, and the mixture wasstirred at r.t. for 30 min. The reaction was then quenched with3 M aq HCl, and the mixture was extracted with Et2O (3 × 10 mL).The organic layers were combined and washed with sat. aqNaHCO3 (3 × 10 mL), sat. aq Na2S2O3 (3 × 10 mL), and brine (3 ×10 mL), then dried (MgSO4). Column chromatography (silica gel,1% EtOAc-hexanes) gave a pale-yellow solid.yield: 0.96 g (83%). |
80% | With pyridine In dichloromethane at 20℃; for 16h; Inert atmosphere; | |
80% | Stage #1: 7-hydroxy-2H-chromen-2-one; acetic anhydride In dichloromethane at 25℃; for 0.5h; Stage #2: With piperidine In dichloromethane for 1h; | 1.1 Example 1: Synthesis of CMPV 1. Dissolve 3g (18.5mmol) of 7-hydroxycoumarin and 5mL of acetic anhydride in 25mL of dichloromethane, activate at 25°C for half an hour, then add 0.1mL of piperidine to continue the reaction for 1 hour; after the reaction, add ice water to wash , Suction filtration to obtain Intermediate 1, which is a white solid, 3.02 g, with a yield of 80%. |
With pyridine for 24h; | ||
In pyridine | ||
for 5h; Heating; | ||
In pyridine at 0 - 20℃; for 3h; | 1 Example 1 Synthesis of 7-acetoxycoumarin (7AC) [0217] The following example illustrates the preparation of a preferred HDAC substrate provided according to the present inventive subject matter. [0218] To an ice cold solution of 20% acetic anhydride in pyridine (60 ml) was added 25 mmol of 7-hydroxycoumarin (Aldrich) with stirring so the temperature did not rise above 4° C. The reaction immediately darkened, stirring was continued at 0° C. for 30 min, the reaction was allowed to warn to room temperature, and stirred an additional 2.5 h. The reaction mixture was rotary evaporated to dryness and the residue was taken up in 100 ml EtOAc and washed with 10% citric acid (5×100 ml), brine (5×100 ml) dried with MgSO4 and evaporated to dryness. The resulting solid was recrystallized two times from EtOAc/hexanes to provide the title compound as a white solid: m.p. 135-137° C.; 1H NMR d(ppm) 2.3 (s, 3H, CH3), 6.4 (d, 1H, J=9.5 Hz, H2'), 7.1 (dd, 2H, J=1.5 Hz, J=8.5 Hz, H3', H2) 7.2 (d, 2H, J=1.5 Hz, H-2) 7.7 (d, 2H, J=9 Hz, H-5), 8.0 ppm (d, 2H, J=9.5 Hz, H-6); 13C NMRδ=20.721, 109.969, 115.395, 116.512, 118.504, 129.188, 143.647, 152.777, 153.967, 159.588, 168.670 ppm. | |
for 5h; Reflux; | ||
With pyridine In dichloromethane at 20℃; for 12h; | ||
for 5h; Reflux; | ||
Reflux; | ||
for 5h; Reflux; | ||
With pyridine In dichloromethane | ||
With sulfuric acid; triethylamine at 20℃; Cooling with ice; | 1 4.1.1 General procedures for the synthesis of acetates 8-10 General procedure: The compounds 1, 2 or 7 (respectively 1.2, 1.1mmol and 1.1) were stirred with acetic anhydride (3mL) in ice bath and a catalytic amount of 96% sulfuric acid was added dropwise. After that, 2.5 molar equivalents of Et3N were added to the mixture and agitated until the disappereance of starting compounds (analyzed by TLC). After reaction was completed it was cooled into ice and the solid was filtered off and dried to afford the corresponding compounds 8-10. Chemical and spectral data for 8-9 are in good agreement with literature [35]. | |
at 140℃; | ||
With pyridine at 90℃; | 4.1. Acetylation of UMB In a typical acetylation experiment, UMB (Sigma-Aldrich, St. Louis, MA, USA) was dissolvedin acetic anhydride (Samchun Chemical Co., Ltd., Seoul, Korea), and then pyridine (Junsei ChemicalCo., Ltd., Tokyo, Japan) was added. The solution was kept overnight at 90 C under magnetic stirring.After cooling slowly, the mixture was thoroughly washed with ethanol and acetone to remove theunreacted acetic anhydride and acetic acid by product. The final product was then dried at 40 C for1 h under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydroxide; methyltrialkyl(C8-C10)ammonium chloride (Adogen 464) In dichloromethane for 2h; | |
89.2% | Stage #1: 7-hydroxy-2H-chromen-2-one With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 3h; Inert atmosphere; Stage #2: chloromethyl methyl ether In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; for 17h; Inert atmosphere; | 1 (1) Synthesis of 7-methyl ether oxycoumarin, the reaction formula is as follows: 56.75g (0.35mol) of 7-hydroxycoumarin was dissolved in dry tetrahydrofuran-dimethylformamide (380mL, 5:3, v/v), and 14g (0.35mol) of 60% sodium hydride was dissolved in dry tetrahydrofuran -In dimethylformamide (570mL, 5:1, v/v), under the protection of nitrogen with magnetic stirring, the 7-hydroxycoumarin solution was added dropwise to the sodium hydride solution, and the temperature was controlled at 0°C. The reaction mixture was stirred at room temperature for 3 hours, then 28.18 g (0.35 mol) of chloromethyl methyl ether was added dropwise at 0° C., and the mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure, and then 1000 mL of water was added. The solid was obtained by suction filtration, washed with a small amount of water, and dried in a vacuum dryer. Recrystallization from methanol gave the product (64.38 g, yield 89.20%),colorless needle-like crystals, melting point 104-105°C. |
With sodium hydride 1.) THF, DMF, RT, 3 h, 2.) THF, DMF, RT, 17 h; Yield given. Multistep reaction; |
With N-isopropylethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 4h; | 12 Reference Example 12 7-methoxymethoxycoumarine: Under an atmosphere of argon, to a solution of 7-hydroxycoumarine (100 g), isopropylethylamine (161 mL) in anhydrous DMF (500 mL), methoxymethyl chloride (70.3 mL) was dropped at 0°C. The mixture was stirred for 4 hours at room temperature. To the reaction mixture, a mixture of hexane / ethyl acetate (2/1), and a saturated aqueous solution of sodium bicarbonate were added, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (74.1 g) having the following physical data. TLC: Rf 0.50 (hexane: ethyl acetate = 3: 2); NMR (300 MHz, CDCl3):δ 7.64 (d, J = 9.6 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.7, 2.4 Hz, 1H), 6.28 (d, J = 9.6 Hz, 1H), 5.24 (s, 2H), 3.49 (s, 3H). | |
With N-isopropylethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 4h; | 8 7-methoxymethoxycoumarine: Example 8 7-methoxymethoxycoumarine: Under an atmosphere of argon, to a solution of 7-hydroxycoumarine (100 g), isopropylethylamine (161 mL) in anhydrous DMF (500 mL), methoxymethyl chloride (70.3 mL) was added dropwise at 0°C. The mixture was stirred for 4 hours at room temperature. To the reaction mixture, a mixture of hexane / ethyl acetate (2/1), and a saturated aqueous solution of sodium bicarbonate were added, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (74.1 g) having the following physical data. TLC: Rf 0.50 (hexane: ethyl acetate = 3: 2); NNIR (300MHz, CDCl3): δ 7.64, 7.39, 7.01, 6.96, 6.28, 5.24, 3.49. | |
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | ||
With potassium carbonate In acetone | MOM Derivatives; Selected Procedure for 1 General procedure: To the mixture (vanillin, 6.5mmol and K2CO3, 8mmol, inacetone), methoxymethyl chloride (8.1 mmol) was added andstirred for 1-2 hr. After completion of the reaction, (monitoredby TLC; solvent system-7:3 hexane and ethyl acetate)reaction mass filtered and the product (>95% yield) was obtainedon removal of the solvent. | |
With N-isopropylethylamine In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 4h; | 41 Reference Example 41; 7-methoxymethoxycoumarin To a solution of 7-hydroxycoumarin (100 g) and isopropylethylamine (161 ml) in anhydrous dimethylformamide (DMF; 500 ml) was added dropwise methoxymethylchloride (70.3 ml) at 0 °C under an atmosphere of argon. The mixture was stirred at room temperature for 4 hours. To the reaction mixture were added hexane / ethyl acetate (2/1, 1000 ml) and a saturated aqueous solution of sodium bicarbonate (1000 ml) and the mixture was extracted twice with ethyl acetate. The organic layer was washewd with water (twice) and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (74.1 g) having the following physical data. The obtained crude product was used to the next step without further purification. TLC: Rf 0.50 (hexane : ethyl acetate = 3 : 2); NMR (300 MHz, CDCl3): δ 7.64 (d, J = 9.6 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.7, 2.4 Hz, 1H), 6.28 (d, J = 9.6 Hz, 1H), 5.24 (s, 2H), 3.49 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 2h; | |
97% | With potassium carbonate In acetone for 8h; Reflux; | |
95% | With potassium carbonate In acetone at 50℃; for 18h; |
95% | With potassium carbonate In acetone at 50℃; for 18h; | |
95% | With potassium carbonate In acetone at 50℃; for 12h; | General Procedure for the Synthesis of Propargyloxycoumarins (15d-g) and Naphthalenes (15h-i) General procedure: To a solution of coumarins 17d-g/naphthols 17h-i (100 mmol) in dry acetone (10 mL), anhydrous potassium carbonate (150 mmol), and propargyl bromide 18 (150 mmol) were added. The resultant mixture was stirred and refluxed at 50 °C for 12 hours, then the mixture was cooled and filtered, and the solvent was removed under reduced pressure. The residue was treated with 15 mL of water and extracted with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuum. The crude product thus obtained was purified by crystallization from ethyl acetate/hexane mixture to give propargyloxycoumarins 15d-g and propargyloxynaphthalenes 15h-i in 81%-95%yield. |
92% | With potassium carbonate In acetone; toluene at 60℃; | |
90% | With potassium carbonate In acetonitrile at 60℃; for 12h; Inert atmosphere; | |
87% | With potassium carbonate In acetone; toluene | |
86% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃; for 4h; | |
82% | With potassium carbonate In acetone for 3h; Heating; | |
82% | With sodium hydroxide In acetone for 6h; Reflux; | 4.2. General procedure to synthesize alkyne intermediates13a~13m and target compounds 19a~19o General procedure: To a solution of hydroxy compounds, sulfhydryl compounds oramino compounds (1.0 eq) and propargyl bromide (1.2 eq) inacetone (20 ml) was added NaOH (1.5 eq), the mixturewas refluxedfor about 6 h. Upon completion, the residue was purified withcolumn chromatography (hexane:EtOAc 7:1) to obtain analogue13a~13m. Sulfonyl chlorides (1.0 eq) and propynylamine (1.2 eq) inCH2Cl2 (20 ml) was added Et3N (1.5 eq), the mixture was stirred atroom temperature for about 6 h. Upon completion, the residue waspurified with column chromatography (hexane:EtOAc 9:1) toobtain analogue 13n~13o. |
82% | With potassium carbonate In acetone at 50℃; for 24h; Inert atmosphere; | |
78% | With potassium carbonate In acetone | |
77% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | |
77.8% | With potassium carbonate; potassium iodide In acetone at 80℃; for 24h; | |
75% | With potassium carbonate In acetone at 65℃; for 24h; Reflux; | Preparation of Propargylated Coumarin Derivatives (4) General procedure: 7-Hydroxycoumarin derivatives (10.0 mmol), K2CO3 (1.38 g, 10.0 mmol) and anhydrousacetone (30 mL) were put into a 100 mL three-necked flask. Propargyl bromide(1.18 g, 10.0 mmol) was added under stirring at room temperature. The reaction mixturewas refluxed at 65C for 24 h. This process was monitored by TLC (thin-layer chromatography).After the reaction was finished, the solution was cooled to room temperature. The solvent was removed by rotary evaporation. Then water (30 mL) was added, and the resultingmixture was extracted with dichloromethane (3 × 30 mL). The combined organic phasewas dried over Na2SO4, filtered, and evaporated under vacuum, and the crude compoundwas purified by column chromatography on silica gel with methanol as eluent to give pure4a-4g. |
73% | With potassium carbonate In acetone at 50℃; for 36h; Inert atmosphere; Schlenk technique; | |
73% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; | 1 4.3.1.1 Synthesis 7-prop-2-ynyloxy-chromen-2-one 2 General procedure: 7-Prop-2-ynyloxy-chromen-2-one 2 was obtained according the general procedure 2 reported earlier. 25 The reaction mixture was stirred at rt for 2 h, quenched with H2O and extracted with EtOAc to give the titled compound 2 as a white powder. |
73% | With potassium carbonate In N,N-dimethyl-formamide; toluene at 100℃; for 5h; Inert atmosphere; | |
71% | With potassium carbonate; potassium iodide In acetone at 80℃; | |
62% | With potassium carbonate In acetone at 50℃; for 24h; | Synthesis of 7-(prop-2-yn-1-yloxy)-2H-chromen-2-one (3) The propynyloxy coumarin 3 was synthesized according tothe literature procedure [35]. To a solution of 7-hydroxycoumarin (1.00 g, 6 mmol) in acetone (30 mL), anhydrouspotassium carbonate (0.30 g, 2 mmol) and propargyl bromide(3.14 g, 2 mL, 26 mmol) were added. The resultingmixture was stirred at 50 °C for 24 h, then the mixture wascooled and the solvent was removed under reduced pressure.The residue was treated with water and extracted withethyl acetate. The combined organic phases were washedwith water and evaporated in vacuum. The crude productwas purified by crystallization from an ethyl acetate-hexanemixture to give 7-(prop-2-yn-1-yloxy)-2H-chromen-2-oneas light yellow crystals (0.76 g, 62.0%). M.p.: 100-105 °C.1H NMR (400 MHz, DMSO-d6, Fig. S5) δ(ppm): 3.66(1H, OCH2CCH,t, J = 2.4 Hz), 4.94 (2H, OCH2CCH,d,J = 2.4 Hz), 6.32 (1H, ArH, d, J = 9.6 Hz), 6.99 (1H, ArH,dd, J = 2.5 Hz, J = 8.5 Hz), 7.05 (1H, ArH, d, J = 2.5 Hz),7.66 (1H, ArH, d, J = 8.5 Hz), 8.00 (1H, ArH, d, J = 9.6 Hz).13C NMR (100 MHz, DMSO-d6, Fig. S6) δ(ppm): 56.6,78.9, 79.4, 102.3, 113.3, 113.4, 113.6, 129.9, 144.7, 155.6,160.7, 160.9. |
49% | With potassium carbonate In acetone for 3h; Heating; | |
26% | With potassium carbonate In acetone at 20 - 50℃; | General procedure for the preparation of propargyloxy substituted coumarins 8a-c General procedure: To a stirred solution of coumarin derivative (0.60mmol, 1.0eq) and K2CO3 (0.90mmol, 1.5eq) in acetone (3mL) was added propargyl bromide (0.72mmol, 1.2eq) at room temperature, and then the mixture was kept at 50°C for 4-10h. Upon completion, K2CO3 was filtered and the solvent was removed under vacuum to give the residue, which was recrystallized from EtOAc to give the corresponding product. Compounds 8a-c are known compounds [45-47] and therefore the spectra data of compound 8a is only given here. White solid, yield: 26%, m. p.: 119.1-120.5°C, Rf=0.12 (petroleum ether/ethyl acetate=6/1). 1H NMR (400MHz, CDCl3) δ 7.67 (d, J=9.5Hz, 1H), 7.43 (d, J=8.5Hz, 1H), 7.03-6.86 (m, 2H), 6.31 (d, J=9.5Hz, 1H), 4.79 (d, J=2.4Hz, 2H), 2.60 (t, J=2.4Hz, 1H).13C NMR (100MHz, CDCl3) δ 161.02, 160.55, 155.67, 143.28, 128.84, 113.70, 113.20, 113.09, 102.15, 76.58, 56.22 |
With potassium carbonate In acetone for 7h; Heating; | ||
With sodium iodide; potassium hydroxide In acetone at 25℃; for 8h; | ||
With potassium carbonate In acetone for 2h; Reflux; | 4.4. General procedure for the synthesis of propynyloxy derivatives (8a-b) General procedure: A propargyl bromide (2.4 mmol) was added to a suspension of an appropriate coumarin (2 mmol) and potassium carbonate (4 mmol) in acetone (15 mL). The suspension was heated under reflux for 2 h. The reaction was allowed to cool and then concentrated under reduced pressure. Water (30 mL) was added and extracted with EtOAc (3 30 mL). The organic extracts were combined and washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography. | |
With potassium carbonate In acetone for 2h; Reflux; | 4.4. General procedure for the synthesis of propynyloxy derivatives (8a-b) General procedure: A propargyl bromide (2.4 mmol) was added to a suspension of an appropriate coumarin (2 mmol) and potassium carbonate (4 mmol) in acetone (15 mL). The suspension was heated under reflux for 2 h. The reaction was allowed to cool and then concentrated under reduced pressure. Water (30 mL) was added and extracted with EtOAc (3 x 30 mL). The organic extracts were combined and washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography. | |
Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone for 0.166667h; Inert atmosphere; Schlenk technique; Stage #2: propargyl bromide In acetone at 20℃; for 5h; Inert atmosphere; Schlenk technique; | ||
With potassium carbonate In acetone at 50℃; | ||
Stage #1: 7-hydroxy-2H-chromen-2-one With caesium carbonate In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 0 - 20℃; for 2h; | 3.3.2. Experimental procedure for the preparation of alkyne partners (4a-4j) General procedure: To a solution of amine or alcohol in DMF, Cs2CO3 was added at 0 °C, and the reaction mixturewas stirred for 30 min at the same temperature. Propargyl bromide was added slowlyto the reaction mixture at 0 °C and it was stirred at RT for 2 h. The progress of the reactionwas monitored by TLC; it indicated the consumption of the reactants on TLC. The reactionmixture was poured into ice cold water (15 ml) and then it was extracted with ethyl acetate(10 ml × 3). The organic layers were combined, washed with saturated sodium bicarbonatesolution (10 ml × 3) and brine (10 ml × 3), then it was dried over anhydrous sodium sulfate, and the combined organic layers were concentrated under reduced pressure. The resultingcrude residue was purified using silica gel column chromatography (60:120 silica gel mesh).The product was eluted (Hexane: Ethyl acetate = 92:8) to afford the product. | |
With potassium carbonate In acetone Reflux; Inert atmosphere; | ||
With potassium carbonate In acetone at 50℃; for 3h; | ||
With potassium carbonate In N,N-dimethyl-formamide at 80℃; | General procedures General procedure: Propargyl bromide 2 (1 mmol) was added to a solution of K2CO3 (2 mmol) and 7-hydroxy coumarin (1 mmol) 1 inDMF (5 mL). The mixture was kept at 80 °C for 10-16 h. When the reaction was completed (monitored by TLC), thereaction mixture was diluted with ethyl acetate (EtOAc,25 mL) and water (25 mL). The organic layer was separatedand the aqueous phase was extracted with EtOAc (2 ×25 mL). The organic extracts were combined and dried overanhydrous Na2SO4. Removal of the solvent under reducedpressure afforded the desired propargylated compounds 3 inquantitative yield and sufficient purity (as indicated byTLC) to be directly used in the next reaction without anyfurther purification. Next, a solution of benzyl halide derivative4 (1.5 mmol), Et3N (0.3 mmol), NaN3 (1.5 mmol) inH2O/t-BuOH (10 mL, 1:1) was stirred at room temperaturefor 1-2 h. After that, the mixture of 3 (1 mmol), sodiumascorbate (0.2 mmol), and CuSO4.5H2O (0.1 mmol) wasadded to the latter mixture and the reaction was continuedfor 24 h. After completion of the reaction, the product wasextracted with ethyl acetate (2 × 20 mL) and then dried overNa2SO4 and concentrated. The product was separated andpurified by column chromatography on silica gel using anethyl acetate/petroleum ether mixture (1/1) as the eluent toafford pure products. | |
With potassium carbonate In acetone Reflux; | ||
With potassium carbonate In acetone | ||
With potassium carbonate In acetone for 8h; Reflux; | 4.2.1 4.2.1 4-methyl-/7-(prop-2-yn-1-yloxy)-2H-chromen-2-one (2a-b) General procedure: To a solution of 7-hydroxycoumarin or 4-methyl-7-hydroxycoumarin (1.00g, 6.17mmol) in acetone (40mL), propargyl bromide (0.88g, 7.40mmol) and anhydrous K2CO3 (1.00g) were added. The mixture was refluxed for 8h, and then it was hot filtered and concentrated under reduced pressure. The crude was crystallized with petroleum ether, affording (95-97%) of 2a-b [37]. | |
With potassium carbonate In acetone for 2h; Reflux; | ||
Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: propargyl bromide With potassium iodide In acetone for 3h; Reflux; | 2.2.1. Synthesis of O-propargylated Coumarins 4 or 5 General procedure: A suspension of coumarin derivative 1 or 2 (1 mmol) andK2CO3 (2 mmol) in acetone (5 ml) was stirred at room temperature for 30 min. Then, it was added to a suspension of propargyl bromide 3 (1.2 mmol) and KI in acetone (5 ml) dropwise and the reaction mixture was stirred at reflux for 3h. After that, the solvent was evaporated under reduced pressure,the precipitate was dissolved in ethyl acetate (30 ml),the organic phase was washed with water (4 × 10 ml) andbrine (2 × 10 ml), and dried over Na2SO4. The solvent wasevaporated under vacuum and the residue was recrystallizedfrom EtOH to obtain pure O-propargylated coumarins 4 or 5. | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; | 4.2. General procedure for the preparation of propargyloxycoumarins 2b and 16b 7-Hydroxycoumarin or 4-hydroxycoumarin (2a or 16a, 1.0 eq.)were added to a stirring mixture of K2CO3 (1.2 eq.) in DMF, followed by adding propargyl bromide (1.2 eq.). The reaction mixture wasstirred at room temperature for 12 h. After completion of the reaction,water (30 mL) was added and the resulting mixture wasextracted using ethyl acetate/n-hexane (4:1). The organic layerswere washed with saturated brine and the volatile solvents wereevaporated under reduced pressure. The obtained product (2b and16b) was used for the next step without further purification. | |
Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: propargyl bromide With potassium iodide In acetone for 3h; Reflux; | ||
Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In N,N-dimethyl-formamide at 20℃; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃; | 2.1.1. General procedure for the synthesis of 4-(prop-2-ynyloxy)-2H-chromen-2-one General procedure: 4- hydroxy coumarin (1 equiv) was dissolved in DMF used as a solvent and then potassium carbonate (K 2 CO 3 ) (1.5 equiv) was added to the reaction mixture. The reaction mixture was stirred at room temperature for about 15-20 min. After the scheduled time, propargyl bromide (1.5 equiv) was added dropwise to the re- action mixture and was allowed to stir at room temperature. The completion of the reaction was monitored by analytical thin layer chromatography (TLC). After the completion of reaction, the reac- tion mixture was poured on to the crushed ice and the mixture was kept aside for a few minutes. The mixture was then filtered and dried to get pure 4-(prop-2-ynyloxy) -2H-chromen-2-one un- der vacuum system. The similar procedure was followed for the propargylation of 7-hydroxy coumarin. | |
Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone for 0.5h; Reflux; Stage #2: propargyl bromide In acetone Reflux; | General procedure for the synthesis of terminalalkynes 3a, 3b General procedure: 7-Hydroxy-2H-chromen-2-one (1a)/4-hydroxy-2Hchromen-2-one (1b) (1.0 mmol) was taken in 20 cm3acetonein a round-bottomed flask. To this, anhydrous potassium carbonate(1.5 mmol) was added and the resulting suspensionwas refluxed for 30 min. Propargyl bromide (1.5 mmol) wasadded slowly to the reaction mixture and the reaction mixturewas further refluxed for 7-8 h. Progress of the reactionwas monitored by TLC. After the completion of reaction,reaction content was poured into crushed ice, the separatedsolid was filtered and recrystallized using ethyl acetate to getthe desired alkynes 3a, 3b [74]. | |
With potassium carbonate In acetone at 50℃; | ||
With potassium carbonate In acetone for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In acetone for 12h; Reflux; | |
86.9% | With potassium carbonate In acetonitrile Reflux; | 2 4.1.5 General procedure for the synthesis of compound 9a-9c General procedure: A mixture of coumarin derivative (1 eq), dibromoalkane (3 eq) and K2CO3 (6 eq) in 50mL acetonitrile was refluxed overnight. After the completion of reaction, excess K2CO3 was removed by filtration of celite and the filtrate was concentrated, washed with DCM and dried with Na2SO4. The residue was purified by column chromatography (EA: DCM: HEX=1:25:25) to afford the white solid. |
79% | With potassium carbonate In acetone Reflux; | 4.1.1 General procedures for the preparation of compounds 2a-c General procedure: To a solution of 7-hydroxy-2H-chromen-2-one 1 (4mmol) and powdered K2CO3 (8mmol) in acetone (20mL), corresponding α,ω-dibromoalkane (24mmol) was added. The reaction mixture was refluxed for 10-12h. Upon completion, K2CO3 was removed by filtration and the solvent was concentrated under vacuum, the residue was purified on silica gel chromatography with petroleum ether/ethyl acetate (7:1, v/v) as elution solvent to give the desired product 2a-c [18,38]. |
78% | Stage #1: 1,3-dibromo-propane With potassium carbonate In acetone for 0.166667h; Inert atmosphere; Reflux; Stage #2: 7-hydroxy-2H-chromen-2-one In acetone for 2h; Reflux; Inert atmosphere; | |
78% | With potassium carbonate In acetone for 2h; Reflux; Inert atmosphere; | 7-(3-Azidopropyloxy)coumarin (1).1 A mixture of potassium carbonate (30.8 g, 222 mmol) and 1,3-dibromopropane (30.8 g, 154 mmol) was mixed in acetone (50 mL) and stirred under reflux during 10 min. To this resulting mixture was slowly added 7-hydroxycoumarin (2.50 g, 15.4 mmol) and the reaction was stirred for 2 h under reflux. Acetone was removed under reduced pressure and the crude was diluted in CH2Cl2 (50 mL) and water (50 mL). The organic layer was separated, the water phase was extracted twice with CH2Cl2 (100 mL) and the combined organic layers were dried over MgSO4. The crude product was purified by flash chromatography on silica gel (100% petroleum ether, then 100% CH2Cl2) to give 7-(3-bromopropyloxy)coumarin as a white solid (3.21 g, 78% yield). A solution of 7-(3-bromopropyloxy)coumarin (2.10 g, 7.35 mmol) and sodium azide (1.75 g, 26.3 mmol) in DMF (30 mL) was stirred at 60 °C for 1 h. The mixture was cooled to room temperature and diluted with diethyl ether (50 mL). The organic phase was washed with 5% aqueous LiCl (3 x 20 mL), the organic extract was dried over MgSO4 and evaporated to give 1 as a yellow solid (1.69 g, 100%). mp = 82 °C. 1H NMR (400 MHz, CDCl3, ppm): δH 7.63 (d, 1H, J = 9.5 Hz), 7.37 (d, 1H, J = 8.5 Hz), 6.80-6.85 (m, 2H), 6.25 (d, 1H, J = 9.5 Hz), 4.10 (t, 2H, J = 5.9 Hz), 3.53 (t, 2H, J = 6.6 Hz), 2.08 (q, 2H, J = 6.2 Hz). 13C NMR (100 MHz, CDCl3, ppm): δC 161.8, 161.1, 155.8, 143.3, 128.8, 113.2, 112.7, 112.7, 101.4, 65.1, 48.4, 48.0, 28.5. HRMS (ESI) calcd for C12H11N3O3Na [M+Na]+ 268.0698; found: 268.0709. |
71% | With potassium carbonate In acetone for 4h; Reflux; | 1 4.1.6 General procedures for the preparation of compounds 3a-t General procedure: A mixture of 2a-c/2e (5.0mmol) with suitable α,ω-dibromoalkanes (50mmol) and anhydrous K2CO3 (1.4g, 10mmol) in acetone (15mL) was refluxed under stirring for 4h. After cooling, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography with hexane/acetone (20:1) as eluent to give compounds 3a-t as white solid. |
71% | With potassium carbonate In acetonitrile for 2h; Reflux; | 4.2.2. General procedure for the synthesis of 3a-h General procedure: K2CO3(12mmol) and dibromide derivatives (6mmol) were added to a solution of 1a(2mmol) in CH3CN (20mL). The reaction mixture was refluxed for 2h. Upon completion, K2CO3 was removed by filtration and the solvent was concentrated under vacuum, the residue was dissolved in CH2Cl2, washed with water, brine, dried over anhydrous Na2SO4and concentrated under vacuum to give compounds 3a-h and purification coloumn chromatograph (Eluent; Hexane-EtOAc; 4:1) [38]. |
64% | With potassium carbonate In acetonitrile at 60℃; | 4.3.1. Synthesis of 7-Bromoalkoxy-2H-chromen-2-ones (14) and 4-Bromoalkoxy-2H-chromen-2-ones (16) General procedure: Compound 13 or 15 (3.08 mmol, 1 equiv.) was dissolved in acetonitrile(2 mL) followed by addition of anhydrous K2CO3 (6 equiv.).Then an appropriate alkyl halide (9.25 mmol, 3 equiv.) was addeddropwise to the stirred reaction mixture. The stirring was continued for4-5 h at 60 °C. The reaction mixture was extracted with CH2Cl2(80 mL), the organic extracts were washed with water (100 mL), driedover anhydrous Na2SO4, filtered and the solvent was removed in vacuo.The crude mixture was purified by column chromatography on silicagel using hexane:ethyl acetate as eluent to obtain the pure compounds(14 or 16) [24]. |
57.14% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: 1,3-dibromo-propane In acetone at 60℃; for 24h; | The procedure for the synthesis of intermediate coumarin bromides A1-A6 General procedure: For example, to a solution of 7-hydroxycoumarin (5.0 g, 31.0 mmol) in acetone (60.0 mL) was added anhydrous K2CO3 (6.9 g, 50.0 mmol) and triethylamine (1.0 mL) at room temperature. After stirring at room temperature for 30 min, 1, 2-dibromoethane (12.6 g, 62.0 mmol) was added to the reaction mixture, and the whole was refluxed at 60°C for 24 h. Then the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was treated with water (200.0 mL) and extracted with dichloromethane (4×200.0 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography with mixed petroleum ether and ethyl acetate (5:1, v/v) as eluent, and resulted in a white solid. |
57.14% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: 1,3-dibromo-propane In acetone at 60℃; for 24h; | 15.1. Procedure for synthesis of intermediate coumarin bromides A1-A5 General procedure: The intermediate coumarin bromides A1-A5 were synthesized as reported in a previous study. The synthetic route is illustrated in Scheme 1. For example, anhydrous K2CO3 (13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature were added to a solution of 7-hydroxycoumarin (10.0 g, 62 mmol) in acetone (120 mL). After stirring at room temperature for 30 min, 1, 2-dibromoethane (23.3 g, 124 mmol) was added to the reaction mixture, which was then refluxed at 60°C for 24 h. The precipitate was filtered and washed with acetone (4 × 100 mL). The solvent was evaporated under reduced pressure, and the residue was treated with water (200 mL) and extracted with dichloromethane (4 × 250 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography with a mixture of petroleum ether and ethyl acetate (5:1, v/v) as the eluent, yielding in a white solid. |
51% | With potassium carbonate In acetone | |
50.66% | With potassium carbonate In dichloromethane Reflux; | |
With potassium carbonate In acetone for 4h; Reflux; | ||
With potassium carbonate In acetone for 4h; Reflux; | 4.1.4 General procedure for the preparation of bromoalkoxy intermediate 2 General procedure: A mixture of substituted 7-hydroxycoumarin (5mmol), appropriate dibromoalkane (50mmol) and anhydrous K2CO3 (1.4g, 10mmol) was refluxed in acetone (15mL) for 4h. After cooling, the reaction mixture was filtered and the organic phase was evaporated under reduced pressure. The obtained residue was triturated with n-hexane to give the product 2 as white solid [39]. | |
With potassium carbonate In acetonitrile Reflux; | ||
With potassium carbonate In acetone at 60℃; Sealed tube; | ||
With potassium carbonate In acetonitrile for 2h; Reflux; | ||
Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.25h; Stage #2: 1,3-dibromo-propane In N,N-dimethyl-formamide at 25℃; | 2.1.4. General procedure for the synthesis of 4-(2-bromoalkoxy)-2H-chromen-2-ones. General procedure: 4-hydroxy coumarin (1 equiv) was dissolved in DMF and K2CO3 (1.5 equiv) was added to it. The mixture so obtained was allowed to stir for 15 mins. After 15 mins, dibromobutane (1 equiv) was added in the reaction mixture and was allowed to stir at room temperature until it was completed (monitored by analytical TLC). As the reaction completed, the reaction mixture was poured on crushed ice and set aside for a while (until the ice was completely converted into water), filtered and dried. The obtained crude product was purified using column chromatography using hexane: ethyl acetate (9.5: 0.5) to get pure 4-(4-bromobutoxy)-2H-chromen-2-one. | |
With potassium carbonate In acetone for 4h; Reflux; | 2.1. Synthesis of bromopropoxycoumarin derivatives General procedure: Coumarin derivatives (1 mmol), excess of 1,3-dibromopropane (10 mmol), and anhydrous K 2 CO 3 (2 equiv.) were mixed in ace- tone (5 mL) and stirred at reflux for 4 h. Reaction progress was monitored using thin layer chromatography (TLC). When reaction was completed, the resulting mixture was filtered, and solvent was evaporated under vacuum. The obtained residue was purified by silica gel chromatography with ethyl acetate/hexane (1:2) as elu- ent. The purity of isolated bromopropoxycoumarin derivatives was confirmed by NMR spectroscopy and LC-MS spectrometry (Supple- mentary material). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With ammonium hydroxide; iodine; potassium iodide In water for 1.5h; | Synthesis of 7-hydroxy-8-iodo-2H-chromen-2-one (2) Umbelliferone (1) (200 mg, 1.23 mmol) was dissolved in a 20% NH4OH solution (5 mL) to which a solution of I2 (313 mg, 1.23 mmol) dissolved in aqueous KI (5%, 10 mL) was added dropwise. After 1.5 h, the reaction was quenched with 2.5 NH2SO4 until acidic and precipitation occurred. The solid was filtered and purified with silica gel column chromatography using 5:95 ethyl acetate:dichloromethane to afford the desired product as a yellow solid (318 mg, 90%). |
85% | With ammonium peroxydisulfate; potassium iodide In methanol; water at 20℃; | |
84% | With iodine; potassium iodide In ammonium hydroxide for 2.5h; |
72% | With ammonia; iodine; potassium iodide In 1,4-dioxane; water at 0℃; for 1.5h; | |
72.8% | With iodine; potassium carbonate; potassium iodide In water at 30℃; for 6h; | 1 Example 1 Synthesis of Compound 1 Weigh I2 (8.82g, 34.72mmol) with KI (8.65g, 52.08mmol) in water (70ml) to dissolve, and compound 7-hydroxycoumarin (5g, 30.86mmol) with K2CO3 (11.98g, 86.8mmol) of water (70 ml) was dissolved. Then use a constant pressure dropping funnel to add the KI solution of I2 to the 7-hydroxycoumarin dissolved in the K2CO3 aqueous solution. After the addition, transfer to 30 ° C for 6 hours. TLC detection; 3 mol / L sulfuric acid was added to adjust the pH to neutral, and all solids were precipitated. The precipitated solids were filtered and dried under vacuum to obtain 6.49 g of light yellow powder solid, namely Intermediate 1. The yield was 72.8%. |
48% | With ammonium hydroxide; iodine; potassium iodide at 20℃; | |
46% | With iodine; periodic acid In ethanol for 2h; Ambient temperature; | |
42% | With ammonium hydroxide; iodine; potassium iodide at 20℃; for 1h; | |
41% | With ammonium hydroxide; iodine; potassium iodide | |
37% | With ammonia; iodine; potassium iodide In water at 20℃; for 25h; | |
21% | With iodine; potassium iodide In water | |
With ammonium hydroxide; iodine; potassium iodide In water for 24.5h; | ||
With ammonium hydroxide; iodine; potassium iodide In water at 20℃; for 25.25h; | ||
With iodine; potassium carbonate; potassium iodide In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen In acetic acid | |
99% | With palladium 10% on activated carbon; hydrogen In acetic acid at 20℃; for 12h; Inert atmosphere; | |
96.5% | With palladium 10% on activated carbon; hydrogen; acetic acid at 50℃; for 17h; | 1 Preparation of Intermediate 7-hydroxyDihydrocoumarin In a 100 mL single neck flask, 7-hydroxycoumarin (5.0 mmol), 10%? (1 / (:( 0.158) and acetic acid25 mL, stirred until the solid was completely dissolved, filled with hydrogen (3.4 bar), and the reaction was stirred at 50 ° C for 17 h. After completion of the reaction,The filter cake was washed with acetic acid solution and the filtrate was evaporated under reduced pressure to give compound 2 in a yield of 96.5%. |
95% | With hydrogen In ethanol for 24h; | |
94% | With hydrogen In acetic acid at 20℃; for 10h; | |
90% | With palladium on activated charcoal; hydrogen; acetic acid at 50℃; for 17h; | 4.2 General procedures for the preparation of compound 4 Compound 2 was synthesized based on the reported method [26]. The commercial 7-hydroxy-coumarin (1) was dissolved in acetic acid, and a catalytic amount of Pd/C was added to the mixture. The solution was stirred at 50°C in H2 atmosphere for 17h. After the reaction was completed, the catalyst was eliminated by filtering to get a crude product, which was recrystallized for further purification and obtained the desired in a yield of 90%. |
61% | With hydrogen In ethanol for 24h; | |
With hydrogen; toluene-4-sulfonic acid 1.) ethanol, 60 deg C, 40 psi, 2.) toluene, reflux, 45 min; Yield given. Multistep reaction; | ||
6.2 mmol | With hydrogen In acetic acid for 24h; | |
Multi-step reaction with 2 steps 1: palladium/charcoal; aq.-ethanolic NaOH-solution / Hydrogenation 2: 130 °C | ||
With hydrogen In tetrahydrofuran; ethanol at 0 - 65℃; for 30h; | 1 Reference Example 1; 7-Hydroxycroman-2-one Reference Example 1 7-Hydroxycroman-2-one A mixture of 100 g of 7-hydroxycromen-2-one, 10 g of 10% palladium on carbon, 500 mL of tetrahydrofuran and 800 mL of ethanol was stirred under a hydrogen atmosphere at 65°C for 15 hours. To the reaction mixture were added a suspension of 10 g of 10%palladium on carbon in 200 mL of ethanol under ice-cooling, and the mixture was stirred under a hydrogen atmosphere at 65°C for 15 hours. The reaction mixture was filtered through a diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 106.5 g of colorless 7-hydroxy-croman-2-one. 1H-NMR (CDCl3) δ ppm: 2.75-2.96 (4H, m), 5.81 (1H, br s), 6.59-6.66 (2H, m), 7.04 (1H, d, J=7.9Hz) | |
In ethanol; water | 5 Synthesis of the Formula V Compound Example 5 Synthesis of the Formula V Compound The compound represented by Formula V (2,4-dihydroxyphenylpropionyldiaminobutane): STR16 was synthesised according to the following procedure: A solution of 7-hydroxycoumarin (5.0 g, 0.031 mol; Aldrich Chemical Company) in absolute ethanol (200 mL) was hydrogenated under pressure in a Parr apparatus over 10% Pd/C (Catalyst; 500 mg, 50% water; Kodak, Inc., Rochester, N.Y.) for 24 hours at 55° C. Thin layer chromatography (TLC; Silica gel: EtOAc/hexane: 1:1) showed completion of the reaction. The reaction mixture was then filtered over a bed of Celite (Rohm and Haas Co., Philadelphia, Pa.) and evaporated in vacuo to provide the crude product (4.5 g). A portion (2.5 g) of this material was recrystallized from toluene and dried under vacuum to provide 7-hydroxydihydrocoumarin. Yield: 1.83 g; melting point 133°-135.5° C.; 1 H NMR (CD3 CN) 300 MHz δ7.01 (d, J=8.3 Hz, 1H, C5), δ6.55 (d of d, J=4.1, 2.4 Hz, 1H, C6), δ6.48 (d, J=2.4 Hz, 1H, C8), δ2.847 (t, J=7.2 Hz, 2H, C3), δ2.685 (d of d, J=7.7, 6.0 Hz, 2H, C6). 13 C NMR (CD3 CN) 75.47 (J Modulatd spin echo method) δ169.85 (C2, +ve intensity), δ157.57 (C7, +ve intensity), δ157.57 (C10, +ve intensity), δ112.21 (C6, -ve intensity), δ104.42 (C8, -ve intensity), δ30.01 (C3, +ve intensity), δ23.35 (C4, +ve intensity). | |
With 10% Pd/C; hydrogen In tetrahydrofuran; ethanol at 65℃; | ||
With hydrogen In tetrahydrofuran; ethanol at 65℃; for 30h; | 1.1 Reference Example 1; Crystalline form A of n-butyl [4-[2-[2-hydroxy-5-(N-hydroxy carbamimidoyl)benzenesulfonylamino]ethyl]-2'-methanesulfonyl-3-yloxy]acetate hydrochloride; (Step 1); 7-Hydroxycroman-2-one (Step 1) 7-Hydroxycroman-2-one A mixture of 100 g of 7-hydroxycromen-2-one, 10 g of 10% palladium on carbon, 500 mL of tetrahydrofuran and 800 mL of ethanol was stirred under a hydrogen atmosphere at 65° C for 15 hours. To the reaction mixture was added a suspension of 10 g of 10% palladium on carbon in 200 mL of ethanol under ice-cooling, and the mixture was stirred under a hydrogen atmosphere at 65° C for 15 hours. The reaction mixture was filtered through a diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 106.5 g of colorless 7-hydroxycroman-2-one. 1H-NMR (CDCl3) δppm: 2.75-2.96 (4H, m), 5.81 (1H, brs), 6.59-6.66 (2H, m), 7.04 (1H, d, J=7.9Hz) | |
With hydrogen In tetrahydrofuran at 20℃; for 2h; | 1.1 Synthesis of 7-hydroxychroman-2-one (Intermediate 1) A solution of hydroxycoumarin (2.0 g, TCI) in anhydrous THF (50 ml) was added with 10% palladium hydroxide/activated carbon (1.0 g, WAKO), and stirred at room temperature for 2 hours under hydrogen atmosphere. The atmosphere was replaced with nitrogen gas, and then the insoluble matters were removed by filtration through Celite. The solvent was evaporated under reduced pressure to obtain the title compound (2.0 g).(LCMS: 163.0 (MH-), Retention time: 3.03 minutes, LCMS condition: A) | |
With palladium on activated charcoal; hydrogen; acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With ytterbium(III) trifluoromethanesulfonate hydrate at 80℃; for 0.0333333h; Microwave irradiation; | General procedure for coumarin synthesis by MW irradiation General procedure: An open reaction vessel containing a mixture of the phenol (1.0 mmol), propiolic acid (1.1 mmol), and Yb(OTf)3 hydrate (0.1 mmol) was put in the MW apparatus and irradiated at 200 W (80 °C) for 2 min. The reaction was monitored by TLC (eluent CH2Cl2 / MeOH 99:1). The crude solid obtained was diluted with Et2O and the resulting suspension filtered under vacuum to separate the catalyst, the precipitate washed several times with Et2O. The filtrate was washed twice with a 5% NaHCO3 solution (10 mL) dried over MgSO4 and evaporated to dryness under vacuum yielding the desired product. |
60% | With para-chlorotoluene at 150℃; for 20h; | |
60% | With H-BEA In various solvent(s) at 150℃; for 20h; |
59% | With iron(III) chloride; silver trifluoromethanesulfonate; trifluoroacetic acid In 1,2-dichloro-ethane at 30℃; for 15h; | |
55% | With iron(III) chloride; silver trifluoromethanesulfonate In 1,2-dichloro-ethane; trifluoroacetic acid at 30℃; | 46.a (a) Synthesis of 7-hydroxy-2H-1-benzopyran-2-one Dissolve resorcinol (1g, 9.08mmol), propiolic acid (318mg, 4.54mmol), ferric chloride (147mg, 0.91mmol), and silver trifluoromethanesulfonate (700mg, 2.72mmol) in trifluoroacetic acid In a mixed solution (1:1, 3 mL) with 1,2-dichloroethane, the reaction mixture was stirred overnight at 30°C. Appropriate amount of ethyl acetate was added to the system, washed with water and saturated brine in turn, the organic layer was dried and concentrated over anhydrous Na2SO4, and the residue was subjected to column chromatography to obtain a white solid; yield: 55% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With bromine; <i>tert</i>-butylamine In toluene | |
68% | With 2,4,4,6-Tetrabromo-2,5-cyclohexadien-1-one In acetonitrile for 8h; Reflux; regioselective reaction; | |
68% | With flavin reductase enzyme from E. Coli; radicicol halogenase from Chaetomium chiversii D456E/T501S mutant; β-nicotinamide adenine dinucleotide reduced; riboflavin adenine dinucleotide; potassium bromide In aq. phosphate buffer; ethanol at 30℃; for 2h; Enzymatic reaction; regioselective reaction; |
56% | With hydrogen bromide; dihydrogen peroxide In methanol; water; dimethyl sulfoxide at -10 - 0℃; for 0.75h; | Synthesis of 8-bromo-umbelliferone (10b): To a stirred solution of umbelliferone (1) (1.62 g, 10.0 mmol) in MeOH/DMSO (1/1 (v/v), 25 mL) at -10 °C was added 48% HBr (1.7 mL, 10.0 mmol), followed by the dropwise addition of hydrogen peroxide (30% aq sol’n, 1.1 mL, 10.0 mmol) over 15 mins.The reaction mixture was warmed to 0 °C and 48% HBr (0.85 mL, 5 mmol) was added more. After stirring at the same temperature for 30 mins, distilled water was added to make the solid which was filtrated, to give 2.1 g of crude product. The crude solid was recrystallized (acetone/MeOH = 3/1) to furnish the desired 8-bromo-umbelliferone (10b) (1.36 g,56%). 1H NMR (500 MHz, CDCl3) δ 7.63 (d, 1H,J = 9.6 Hz), 7.36 (d, 1H, J = 8.7 Hz), 6.99 (d, 1H, J = 8.7 Hz), 6.29 (d, 1H, J = 9.6 Hz), 6.12 (s, 1H). |
35% | With bromine; <i>tert</i>-butylamine In toluene for 2h; Heating; | |
34% | With 2,6-dimethylpyridine; sodium dihydrogenphosphate; 6,6'-((1R,2R)-cyclohexane-1,2-diyl)bis(2-((3,5-bis(trifluoromethyl)phenyl)amino)-9-dodecylthiazolo[5',4':5,6]benzo[1,2-g]pteridine-8,10(6H,9H)-dione); oxalic acid; lithium bromide In dichloromethane for 2h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In acetone for 4h; Heating; | |
98% | With potassium carbonate In acetone for 5h; Heating; | |
96% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone for 0.5h; Stage #2: ethyl bromoacetate In ethyl acetate at 20℃; for 6h; | 4.1.Preparation of 6, 12 and 18 (Scheme 1f) General procedure: 0.4g of SM1 (2.2mmol), SM2 (2.4mmol) and SM3 (2.2mmol), respectively, were dissolved in acetone (2.0mL) and 1.75 or 3.5 molar equivalents of K2CO3 was add, and stirred during thirty min. After that, it was added drop wise 1.75 molar equivalents of ethyl bromoacetate. The mixture was reacted at room temperature during 6h for compounds 6 and 12, and 8h for 18. After reactions were completed (analyzed by TLC), the solid was filtered off and dried to afford the corresponding compounds 6 ethyl [6-(2-ethoxy-2-oxoethoxy)-2-oxo-2H-chromen-7-yl]oxy}acetate, 12 [ethyl 2-(2-oxo-2H-chromen-7-yloxy)acetate] and 18 [ethyl 2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetate]. |
89% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone at 20℃; for 0.25h; Stage #2: ethyl bromoacetate In acetone at 58℃; for 6h; | Ethyl 2-((2-oxo-2H-chromen-7-yl)oxy)acetate 47 To a solution of 7-hydroxy-2H-chromen-2-one (240 mg, 0.97 mmol) in 8 mL of acetone, K2CO3(228 mg, 1.63 mmol) was added. The mixture was stirred at room temperature for 15 min, and then ethyl bromoacetate (0.18 mL, 1.63 mmol) dissolved in 6 mL acetone was added dropwise. The reaction mixture was heated at 58 °C for 6 h and, after cooling, water (10 mL) was added. The suspension was filtered under vacuum and the solid obtained was dried under vacuum. The title compound was obtained as a white solid. Yield: 89%, mp 107-110 °C.1H-NMR (400 MHz, CDCl3) δ: 7.64 (d,J= 9.6 Hz, 1H, CH); 7.40 (d,J= 8.4 Hz, 1H, CH); 6.89 (dd,J= 8.4, 2.2 Hz, 1H, CH); 6.78 (d,J= 2.2 Hz, 1H, CH); 6.28 (d,J= 9.6 Hz, 1H, CH); 4.68 (s, 2H, OCH2); 4.30 (q,J= 7.2 Hz, 2H, OCH2); 1.32 (t,J= 7.2 Hz, 3H, CH3) ppm. |
86.4% | With potassium carbonate In acetone for 6h; Reflux; | 1 Example One:Ethyl 2 - ((2-oxo -2H--chromen-7-yl) oxy) acetatePreparation The 7-hydroxycoumarin (1.62g, 10mmol), ethyl bromoacetate (1.84g, 11mmol), potassium carbonate (4.15g, 30mmol) placed in a round bottom flask and acetone was added 100mL, the reaction was refluxed for 6 hours, TLC shows the reaction is complete, the reaction was stopped, cooled to room temperature, potassium carbonate was removed by filtration, the filtrate was spin-dried, recrystallized from ethanol to give a white solid powder, yield 86.4%. |
86.4% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone for 1h; Reflux; Stage #2: ethyl bromoacetate In acetone for 6h; Reflux; | |
82% | With potassium carbonate In acetone for 12h; Reflux; | |
81% | With potassium carbonate In acetone for 16h; Reflux; Inert atmosphere; | |
76% | With potassium carbonate In acetone for 12h; Reflux; | |
With sodium hydride In N,N-dimethyl-formamide | ||
With potassium carbonate In acetone at 65℃; for 5h; Inert atmosphere; Cooling with ice; | 7-Carboxyl methoxycoumarin (COU-COOH) was synthesized according to a previously reported method. 7-Hydroxycoumarin (1.00g, 6.17mmol) and K2CO3 (1.25g, 9.00mmol) were dissolved in acetone (20mL) in a round-bottomed flask. The reaction vessel was consecutively evacuated and refilled with nitrogen for three times. Ethyl bromoacetate (1.24g, 7.42mmol) was added dropwise under stirring. The reaction flask was lowered into an ice bath for 2h and then submerged in a 65°C oil bath for another 3h. The reaction was terminated and the precipitate was removed. The solution was concentrated under reduced pressure, ethanol (50ml) was added to the concentrated solution, the mixture was placed in refrigerator at 4°C for recrystallization. White needle crystal of 7-ethoxy carbonyl methoxycoumarin was obtained after filtration. | |
With potassium carbonate In acetone at 20℃; Inert atmosphere; Reflux; | 1 5.1. General procedure for the synthesis of compounds 3a-c General procedure: A mixture of 7-hydroxycoumarin (1a) or 4-methyl-7-hydroxycoumarin (1b) (5.0 mmol) and potassium carbonate (5.5 mmol) in acetone (5 ml) was stirred at room temperature for several minutes. Then, ethyl 2-bromoacetate or ethyl 4-bromobutanoate (5.2 mmol) was added dropwise to the mixture under argon atmosphere and the mixture was refluxed for 7-9 h. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The precipitated product 2 was collected by filtration and washed with water, and used without further purification. The crude product 2a-c was dissolved in aqueous 10% NaOH (25 ml) and the solution was refluxed for 4 h. The reaction mixture was cooled and acidified with aqueous 6% HCl. The precipitated white solid was filtered off and subsequently washed with water to give compound 3. | |
Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: ethyl bromoacetate In N,N-dimethyl-formamide at 90℃; for 5h; | Synthesis of coumarin esters (2a-i); general procedure General procedure: The appropriate hydroxycoumarin derivative (5 mmol) and potassium carbonate (5.5 mmol) were dissolved in DMF (5 mL). The solution was stirred at room temperature for 20 min and then ethyl bromoacetate,or ethyl 2-bromopropionate or ethyl 4-bromobutanoate (5.2 mmol) was added dropwise to the mixture. The solution was heated at 90 °C for5 h. Upon completion, determined by thin layer chromatography, the mixture was cooled and diluted with ice. The resultant precipitate was filtered, washed and used without further purifications. | |
With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyridine In dichloromethane at 0 - 20℃; for 0.5h; | 24.A Step A: Step A: Into a suspension of 7-hydroxycoumarin (16.2 g, 100 mmol) in pyridine (16.3 mL, 200 mmol) and CH2CI2 (250 mL) at 0 °C was added dropwise a solution of triflic anhydride (20.2 mL, 120 mmol) in CH2CI2 (50 mL). The mixture warmed to room temperature over 30 min. The mixture was washed with dilute aqueous HC1, water, brine, and then dried over NaS04 and concentrated to give a solid 2-oxo-2H-chromen-7-yl trifluoromethanesulfonate (28.5 g, 97%) as a tan solid. MS m/z 295.0 [M+H]+. |
97% | With pyridine In dichloromethane at 0 - 20℃; for 0.5h; | |
97% | With pyridine In dichloromethane at 0 - 20℃; | 24.A Step A: Into a suspension of 7-hydroxycoumarin (16.2 g, 100 mmol) in pyridine (16.3 mL, 200 mmol) and CH2Cl2 (250 mL) at 0° C. was added dropwise a solution of triflic anhydride (20.2 mL, 120 mmol) in CH2Cl2 (50 mL). The mixture warmed to room temperature over 30 min. The mixture was washed with dilute aqueous HCl, water, brine, and then dried over NaSO4 and concentrated to give a solid 2-oxo-2H-chromen-7-yl trifluoromethanesulfonate (28.5 g, 97%) as a tan solid. MS m/z 295.0 [M+H]+. |
96% | With pyridine at 0 - 20℃; for 24.5h; | Synthesis of 2-oxo-2H-chromen-7yl trifluoromethanesulfonate (1) Trifluoromethanesulfonic anhydride (20 ml, 119 mmol) was added to a solution of umbelliferon(21.35 g, 132 mmol) in pyridine (500 ml) at 0 °C. The mixture was stirred at 0 °C for5 minutes and then at room temperature for 24 hours. The reaction mixture was poured intowater (400 ml) and extracted with toluene (400 ml). The organic extracts were washed with10%HCl solution (100ml) and then with saturated NaCl solution (100ml). The organic layerwas dried over Na2SO4, filtered and evaporated to dryness to give 33.8 g (96%) in a whitesolid.1H NMR (400 MHz, CDCl3): δ 7.73 - 7.71 (d, 1H), 7.60 - 7.58 (d, 1H), 7.27 - 7.20 (m,2H), 6.48 (d, 1H). Anal. Calcd. for C10H5F3O5S (294.2 g/mol): C, 40.82%; H, 1.71%. Found:C, 40.74%; H, 1.82%. |
95% | With pyridine In dichloromethane at 0℃; for 0.25h; | |
91% | With pyridine for 4h; ice cooling; | |
91% | With dmap In dichloromethane at 20℃; | |
88% | With pyridine In dichloromethane at -10℃; for 1h; Inert atmosphere; | |
88% | With pyridine at 20℃; for 5h; Inert atmosphere; Cooling with ice; | 1-1 Synthesis of 2-Oxo-2H-chromen-7-yl trifluoromethanesulfonate Under an argon atmosphere, 4-Methylumbelliferone (100 mg, 617 μmol) of pyridine (6 mL)Ice-Cooled Dissolved.Trifluoromethanesulfonic Anhydride (114 MyuL, 679 Myumol) Was Added DropwiseIt was.The Mixture Was Then Stirred At Room Temperature For 5 Hours.After Completion Of The Reaction, And Extracted With Ethyl Acetate, Washed With Saturated Brinedid.Organic Layer Was The Dried Over Anhydrous Sodium Sulfate And The Solvent Was Distilled Off.Purification Silica Gel Column (SiOTwo. At 20 g), to give a white solid compound (160 mg, 88%) |
86.5% | With 4-methyl-morpholine In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; | |
85% | With pyridine at 0 - 20℃; for 2.83333h; | Synthesis of 2-oxo-2H-chromen-7-yltrifluoromethanesulfonate (9) A solution of 7-hydroxycoumarin (8) (1.0 g, 6.17 mmol) inpyridine (5 mL) was cooled to 0 °C and treated with triflicanhydride (2.1 mL, 12.34 mmol, 20 min addition). Thereaction mixture was allowed to warm to room temperatureand stirred for an additional 2.5 h. The crude mixture waspartitioned between saturated aqueous CuSO4 and ethylacetate. After separation of the fractions, the organic fractionwas dried (Na2SO4) and concentrated under reducedpressure. The crude product was purified by column chromatographyover silica gel. Elution with a mixture ofhexane-ethyl acetate (8:2 ratio) afforded compound 9 in85% yield (1.54 mg, 85% yield). M.p. 78-80 °C; IR (KBr, cm-1): νmax 1720 (C=O),1421 y 1220 S(=O)2, 1130 (CF3), 1294 (C-O-C), 1110((C=O)-O), 748-979 (C-O-S). 1H NMR (CDCl3,300 MHz): δ 6.53 (H3, d, J = 9.7 Hz), 7.25 (H6, dd, J = 2.3,8.6 Hz), 7.31 (H8, d, J = 2.3 Hz), 7.62 (H5, d, J = 8.6 Hz),7.76 (H4, d, J = 9.7 Hz). 13C NMR (CDCl3, 75MHz): δ110.60 (C8), 117.81 (C3, C6), 118.66 (-SO3CF3, q, JC-F =321 Hz), 118.80 (C4a), 129.48 (C5), 142.18 (C4), 150.84(C7), 154.57 (C8a), 159.35 (C=O). EIMS: m/z 294.9880 [M+ H]+, (calculated for [C10H6F3O5S]+: 294.9884). |
82% | With pyridine at 20℃; for 25h; | 7 To a solution of 7-hydroxy-benzopyran-2-one (3.20 g, 20.0 mmol)Pyridine (30.0 mL)Triflic anhydride (5.00 mL, 30.0 mmol) was added slowly to the solution.After stirring for 5 minutes, the temperature was raised to room temperature and the reaction was stirred for 25 hours.The reaction system was quenched by adding water (10 mL)Extract with ether (20.0 mL).The extract was washed with water (50 mL), 10%Aqueous hydrochloric acid (100 mL), water (50 mL) and saturated brine, the organic phase was dried over anhydrous magnesium sulfate and evaporated under reduced pressureAfter flashing solvent, flash column chromatography (eluent PE: EA = 3: 1, Rf = 0.40)A white solid (5.33 g, 82%) was obtained, |
81% | With pyridine In dichloromethane at 0 - 20℃; | |
80% | With pyridine In dichloromethane at 20℃; for 2h; | |
64% | With pyridine In dichloromethane at 0 - 20℃; for 1h; | |
With triethylamine In dichloromethane at 0℃; | 1 2.5 Synthesis of 7-trifluoromethylsulfonyloxycoumarins (5a-c) General procedure: The coumarins (5a-c) were synthesized by the reaction of 7-hydroxycoumarins (4a-c) (0.56mmol) and trifluoromethanesulfonic anhydride (0.72mmol) in the presence of Et3N (0.74mmol) as reported in the literature [40]. The spectral data of known compounds (5a-b) are found to be in good agreement with the reported data [41,42] whereas the characterization data of unknown compound 5c are given below. | |
With pyridine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.9% | With potassium carbonate In acetone for 12h; Reflux; | |
75% | With potassium carbonate In acetone Reflux; | 4.1.1 General procedures for the preparation of compounds 2a-c General procedure: To a solution of 7-hydroxy-2H-chromen-2-one 1 (4mmol) and powdered K2CO3 (8mmol) in acetone (20mL), corresponding α,ω-dibromoalkane (24mmol) was added. The reaction mixture was refluxed for 10-12h. Upon completion, K2CO3 was removed by filtration and the solvent was concentrated under vacuum, the residue was purified on silica gel chromatography with petroleum ether/ethyl acetate (7:1, v/v) as elution solvent to give the desired product 2a-c [18,38] 4.1.1.1 7-(2-bromoethoxy)-2H-chromen-2-one (2a) The general procedure described for 2a-c was used, starting from 1, 1,2-dibromoethane and powdered K2CO3, and 2a was obtained as a White solid (yield 75%); 1H NMR (500MHz, DMSO) δ 8.00 (d, J=9.5Hz, 1H, H4-coumarin), 7.65 (d, J=8.6Hz, 1H, H5-coumarin), 7.03 (d, J=2.4Hz, 1H, H8-coumarin), 6.99 (dd, J=8.6, 2.5Hz, 1H, H7-coumarin), 6.31 (d, J=9.5Hz, 1H, H3-coumarin), 4.45 (t, J=5.3Hz, 2H,O-CH2-), 3.84 (t, J=5.3Hz, 2H, CH2Br). Analytical data of 2a were conform to the literature [18,38]. |
69% | With potassium carbonate In acetonitrile at 60℃; | 4.3.1. Synthesis of 7-Bromoalkoxy-2H-chromen-2-ones (14) and 4-Bromoalkoxy-2H-chromen-2-ones (16) General procedure: Compound 13 or 15 (3.08 mmol, 1 equiv.) was dissolved in acetonitrile(2 mL) followed by addition of anhydrous K2CO3 (6 equiv.).Then an appropriate alkyl halide (9.25 mmol, 3 equiv.) was addeddropwise to the stirred reaction mixture. The stirring was continued for4-5 h at 60 °C. The reaction mixture was extracted with CH2Cl2(80 mL), the organic extracts were washed with water (100 mL), driedover anhydrous Na2SO4, filtered and the solvent was removed in vacuo.The crude mixture was purified by column chromatography on silicagel using hexane:ethyl acetate as eluent to obtain the pure compounds(14 or 16) [24]. |
65% | With potassium carbonate In acetone for 4h; Reflux; | 1 4.1.6 General procedures for the preparation of compounds 3a-t General procedure: A mixture of 2a-c/2e (5.0mmol) with suitable α,ω-dibromoalkanes (50mmol) and anhydrous K2CO3 (1.4g, 10mmol) in acetone (15mL) was refluxed under stirring for 4h. After cooling, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography with hexane/acetone (20:1) as eluent to give compounds 3a-t as white solid. |
56.32% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: ethylene dibromide In acetone at 60℃; for 24h; | The procedure for the synthesis of intermediate coumarin bromides A1-A6 General procedure: For example, to a solution of 7-hydroxycoumarin (5.0 g, 31.0 mmol) in acetone (60.0 mL) was added anhydrous K2CO3 (6.9 g, 50.0 mmol) and triethylamine (1.0 mL) at room temperature. After stirring at room temperature for 30 min, 1, 2-dibromoethane (12.6 g, 62.0 mmol) was added to the reaction mixture, and the whole was refluxed at 60°C for 24 h. Then the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was treated with water (200.0 mL) and extracted with dichloromethane (4×200.0 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography with mixed petroleum ether and ethyl acetate (5:1, v/v) as eluent, and resulted in a white solid.Compound A1. Yield 56.32%. 1H NMR (500 MHz, CDCl3) δ 7.64-7.63 (d, 1H, J = 9.5 Hz), 7.40-7.39 (d, 1H, J = 8.6 Hz), 6.88-6.86 (dd, 1H, J = 8.6, 2.4 Hz), 6.82-6.81 (d, 1H, J = 2.4 Hz) 6.28-6.27 (d, 1H, J = 9.5 Hz), 4.36-4.34 (t, 2H), 3.69-3.66 (t, 2H). 13C NMR (126 MHz, CDCl3) δ 161.31, 161.15, 155.90, 143.40, 129.09, 113.71, 113.21, 112.97, 101.84, 68.12, 28.54. ESI-MS (m/z): 269.15 ([M]+). |
55.18% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: ethylene dibromide In acetone at 60℃; | 1.1.1.The procedure for the synthesis of intermediate coumarin bromides1-4 The intermediate coumarin bromides 1-4 were synthesized as reported in aprevious study.45 The synthetic route is shown in Scheme 1. For example, to a solution of 7-hydroxycoumarin(10.0 g, 62 mmol) in acetone (120 mL) was added anhydrous K2CO3(13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature. After stirringat room temperature for 30 min, 1, 2-dibromoethane (23.29 g, 124 mmol) wasadded to the reaction mixture, and whole was refluxed at 60 °C for 24 h. The precipitate was filtered off and washed withacetone (4×100 mL). The solvent was evaporated under reducedpressure, and the residue was treated with water (100 mL) and extracted withdichloromethane (4×200 mL). The organic layer werecombined, dried with anhydrous Na2SO4, and concentratedunder reduced pressure. The crude product was purified via silicagel column chromatography with mixed petroleum ether and ethyl acetate (5:1,v/v) as eluent, and resulted in a white solid. Compound1.Yield 55.18%. 1H NMR(500 MHz, CDCl3) δ 7.65-7.64(d, 1H, H-4, J=9.5 Hz), 7.41-7.39 (d,1H,H-5, J=8.6 Hz), 6.89-6.86(dd,1H,H-8, J=8.6, 2.4 Hz), 6.82-6.81(d,1H,H-6, J= 2.4 Hz) 6.28-6.27(d,1H,H-3, J=9.5 Hz), 4.37- 4.34(t,2H,H-1’),3.69-3.66(t,2H,H-2’). 13C NMR (126 MHz, CDCl3) δ 161.32,161.13, 155.91, 143.40, 129.09, 113.71, 113.21, 112.97, 101.84, 68.34, 28.54.ESI-MS m/z: 269.15 ([M]+). |
55.18% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: ethylene dibromide In acetone at 60℃; for 24h; | 1.1.2. The procedure for the synthesis of intermediatecoumarin bromides1-5 The intermediate coumarin bromides1-5were synthesized as reported in a previous study. The synthetic route is shown in Scheme 1.For example,to a solution of 7-hydroxycoumarin (10.0 g, 62 mmol) in acetone (120 mL) was added anhydrous K2CO3(13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature. After stirring at room temperature for 30 min, 1, 2-dibromoethane (23.29 g, 124 mmol) was added to the reaction mixture, and whole was refluxed at 60°Cfor 24 h. The precipitate was filtered off and washed with acetone (4×100 mL).The solvent was evaporated under reduced pressure, and the residue was treated with water (100 mL) and extracted with dichloromethane (4×200 mL).The organic layer were combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure.The crude product was purified via silica gel column chromatography with mixed petroleum ether and ethyl acetate (5:1, v/v) as eluent, and resulted in a white solid.Compound 1.Yield55.18%.1H NMR (500 MHz, CDCl3) δ 7.65-7.64 (d, 1H, H-4,J= 9.5 Hz), 7.41-7.39 (d, 1H, H-5,J= 8.6 Hz), 6.89-6.86 (dd, 1H, H-8,J= 8.6, 2.4 Hz), 6.82-6.81 (d, 1H, H-6,J= 2.4 Hz) 6.28-6.27 (d, 1H, H-3,J= 9.5 Hz), 4.37- 4.34 (t, 2H, H-1’), 3.69-3.66 (t, 2H, H-2’).13C NMR (126 MHz, CDCl3) δ 161.32, 161.13, 155.91, 143.40, 129.09, 113.71, 113.21, 112.97, 101.84, 68.34, 28.54. ESI-MS m/z: 269.15 ([M]+). |
55.18% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: ethylene dibromide In acetone at 60℃; for 24h; | 15.1. Procedure for synthesis of intermediate coumarin bromides A1-A5 General procedure: The intermediate coumarin bromides A1-A5 were synthesized as reported in a previous study. The synthetic route is illustrated in Scheme 1. For example, anhydrous K2CO3 (13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature were added to a solution of 7-hydroxycoumarin (10.0 g, 62 mmol) in acetone (120 mL). After stirring at room temperature for 30 min, 1, 2-dibromoethane (23.3 g, 124 mmol) was added to the reaction mixture, which was then refluxed at 60°C for 24 h. The precipitate was filtered and washed with acetone (4 × 100 mL). The solvent was evaporated under reduced pressure, and the residue was treated with water (200 mL) and extracted with dichloromethane (4 × 250 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography with a mixture of petroleum ether and ethyl acetate (5:1, v/v) as the eluent, yielding in a white solid. |
50% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 96h; | |
42% | With potassium carbonate In acetonitrile for 2h; Reflux; | 4.2.2. General procedure for the synthesis of 3a-h General procedure: K2CO3(12mmol) and dibromide derivatives (6mmol) were added to a solution of 1a(2mmol) in CH3CN (20mL). The reaction mixture was refluxed for 2h. Upon completion, K2CO3 was removed by filtration and the solvent was concentrated under vacuum, the residue was dissolved in CH2Cl2, washed with water, brine, dried over anhydrous Na2SO4and concentrated under vacuum to give compounds 3a-h and purification coloumn chromatograph (Eluent; Hexane-EtOAc; 4:1) [38]. 7-(2-bromoethoxy)-2H-chromen-2-one (3a). White powder, 42% yield; IR: 3081, 1727, 1711, 1605, 1556, 1508, 1393, 1353, 1268, 1226, 1202, 1122, 1096, 1010, 990, 891, 831, 806, 760, 615, 572, 546, 483, 461cm-1; 1H NMR (DMSO-d6, 300MHz) δ/ppm: 3.84 (2H, s, br), 4.40 (2H, s, br), 6.31 (1H, dd, J=2.6Hz, 9.3Hz), 6.97-7.04 (2H, m), 7.64 (1H, d, J=8.4Hz), 8.0 (1H, dd, J=2.0Hz, 9.6Hz); 13C NMR (DMSO-d6, 75MHz) δ/ppm: 31.7, 69.0, 102.1, 112.9, 113.4, 130.3, 144.9, 156.0, 160.9, 161.6, 162.6. |
39.7% | With potassium carbonate In acetonitrile Reflux; | 1 4.1.5 General procedure for the synthesis of compound 9a-9c General procedure: A mixture of coumarin derivative (1 eq), dibromoalkane (3 eq) and K2CO3 (6 eq) in 50mL acetonitrile was refluxed overnight. After the completion of reaction, excess K2CO3 was removed by filtration of celite and the filtrate was concentrated, washed with DCM and dried with Na2SO4. The residue was purified by column chromatography (EA: DCM: HEX=1:25:25) to afford the white solid. 4.1.5.1 87 7-(2-bromoethoxy)-2H-chromen-2-one (9a) (0029) Yield: 39.7%. 1H NMR (400MHz, DMSO-d6): δ 8.00 (1H, dd, J=9.5, 0.6Hz, C=CH), 7.64 (1H, d, J=8.6Hz, ArH), 7.03 (1H, d, J=2.4Hz, ArH), 6.98 (1H, dd, J=8.6, 2.5Hz, ArH), 6.30 (1H, d, J=9.5Hz, C=CH), 4.47-4.39 (2H, m, CH2), 3.88-3.79 (2H, m, CH2) ppm. 13C NMR (100MHz, DMSO-d6): 161.46, 160.67, 155.79, 144.71, 130.06, 113.25, 113.22, 113.19, 101.93, 68.85, 31.49ppm. |
With potassium carbonate In acetonitrile for 2h; Reflux; | 4.7 General procedure for the synthesis of compounds 11a-b General procedure: K2CO3 (1.66 g, 12 mmol) and 1,2-dibromoethane (1.12 g, 6 mmol) were added to a solution of 10a or 10b (2 mmol) in CH3CN (20 mL). The reaction mixture was refluxed for 2 h. Upon completion, K2CO3 was removed by filtration and the solvent was concentrated under vacuum, the residue was dissolved in CH2Cl2, washed with water, brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give compounds 11a-b, which were used in the next reaction without further purification. | |
With potassium carbonate In acetone for 4h; Reflux; | ||
With potassium carbonate In acetone at 60℃; for 4h; | ||
With potassium carbonate In acetone at 60℃; Sealed tube; | ||
Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.25h; Stage #2: ethylene dibromide In N,N-dimethyl-formamide at 25℃; | 2.1.4. General procedure for the synthesis of 4-(2-bromoalkoxy)-2H-chromen-2-ones. General procedure: 4-hydroxy coumarin (1 equiv) was dissolved in DMF and K2CO3 (1.5 equiv) was added to it. The mixture so obtained was allowed to stir for 15 mins. After 15 mins, dibromobutane (1 equiv) was added in the reaction mixture and was allowed to stir at room temperature until it was completed (monitored by analytical TLC). As the reaction completed, the reaction mixture was poured on crushed ice and set aside for a while (until the ice was completely converted into water), filtered and dried. The obtained crude product was purified using column chromatography using hexane: ethyl acetate (9.5: 0.5) to get pure 4-(4-bromobutoxy)-2H-chromen-2-one. | |
With caesium carbonate; 4-methyl-2-pentanone at 110℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.6% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone at 20℃; for 2h; Stage #2: 1 ,6-dibromohexane In acetone at 60℃; for 24h; | 1.1 (1) Preparation of 7-(6-bromohexyloxy)coumarin (Compound 1) See Figure 2. 4.86g (30mmol) of purchased 7-hydroxycoumarin, 13.8g anhydrous K2CO3(100mmol) and 120 ml anhydrous acetone was added to a 250 ml round-bottom flask. After stirring at room temperature for 2h. To the said round-bottom flask was then added 22g (90mmol) 1,6-dibromohexane. At 60 °C reflux reaction for 24h. Reducing pressure and evaporating anhydrous acetone in the reaction system (45 °C, 0 . 05 MPa negative pressure), to the circular bottom flask is added in 100 ml distilled water, to be mixed, mixed solution with chloroform extraction (150 ml × 4), merging the lower organic phase; adding the organic phase 20-30g anhydrous sodium sulfate standstill sleepovers, filtering to remove the solid sodium sulfate, concentrated under reduced pressure (45 °C, 0 . 05 MPa negative pressure) to get the solid compound crude product. Crude product by silica gel column chromatography (Vpetroleum ether: Vethyl acetate= 4:1) separation and purification, TLC detection collection contains part of the elution of a target compound, removing the elution reagent concentrated under reduced pressure (55 °C, 0 . 05 MPa negative pressure), shall be 6.63g white needle-like solid. |
68.6% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone at 20℃; for 2h; Stage #2: 1 ,6-dibromohexane In acetone at 60 - 65℃; for 24h; | 1.1 (1) Preparation of 7-(6-bromohexyloxy)coumarin (intermediate compound) Referring to Figure 2, 4.86 g (30 mmol) of the commercially available 7-hydroxycoumarin,13.8 g of anhydrous K2CO3 (100 mmol) and 120 mL of acetone were added to a 250 mL round bottom flask and stirred at room temperature for 2 h.Further, 22 g (90 mmol) of 1,6-dibromohexane was added to the round bottom flask, and the mixture was refluxed at 60 ° C for 24 hours. Evaporating the acetone in the reaction system under reduced pressure (45 ° C, 0.05 MPa negative pressure),To the round bottom flask was added 100 mL of distilled water and extracted with chloroform (150 mL × 4), and the lower organic phase was combined;Add 20-30 g of anhydrous sodium sulfate to the organic phase and let stand overnight.The sodium sulfate solid was removed by filtration, and concentrated under reduced pressure (45 ° C, 0.05 MPa under pressure) to give a crude solid compound.The crude product was separated and purified by silica gel column chromatography (V petroleum ether: V ethyl acetate = 4:1), and the eluted fraction containing the intermediate compound was collected by TLC.Concentrated under reduced pressure to remove the elution reagent (55 ° C, 0.05 MPa negative pressure),6.63 g of a white acicular solid was obtained. |
65% | With potassium carbonate In acetone for 24h; Reflux; |
65.56% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: 1 ,6-dibromohexane In acetone at 60℃; for 24h; | The procedure for the synthesis of intermediate coumarin bromides A1-A6 General procedure: For example, to a solution of 7-hydroxycoumarin (5.0 g, 31.0 mmol) in acetone (60.0 mL) was added anhydrous K2CO3 (6.9 g, 50.0 mmol) and triethylamine (1.0 mL) at room temperature. After stirring at room temperature for 30 min, 1, 2-dibromoethane (12.6 g, 62.0 mmol) was added to the reaction mixture, and the whole was refluxed at 60°C for 24 h. Then the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was treated with water (200.0 mL) and extracted with dichloromethane (4×200.0 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography with mixed petroleum ether and ethyl acetate (5:1, v/v) as eluent, and resulted in a white solid. |
62.46% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: 1 ,6-dibromohexane In acetone at 60℃; | 1.1.1.The procedure for the synthesis of intermediate coumarin bromides1-4 General procedure: The intermediate coumarin bromides 1-4 were synthesized as reported in aprevious study.45 The synthetic route is shown in Scheme 1. For example, to a solution of 7-hydroxycoumarin(10.0 g, 62 mmol) in acetone (120 mL) was added anhydrous K2CO3(13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature. After stirringat room temperature for 30 min, 1, 2-dibromoethane (23.29 g, 124 mmol) wasadded to the reaction mixture, and whole was refluxed at 60 °C for 24 h. The precipitate was filtered off and washed withacetone (4×100 mL). The solvent was evaporated under reducedpressure, and the residue was treated with water (100 mL) and extracted withdichloromethane (4×200 mL). The organic layer werecombined, dried with anhydrous Na2SO4, and concentratedunder reduced pressure. The crude product was purified via silicagel column chromatography with mixed petroleum ether and ethyl acetate (5:1,v/v) as eluent, and resulted in a white solid. |
62.46% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: 1 ,6-dibromohexane In acetone at 60℃; | 1.1.2. The procedure for the synthesis of intermediatecoumarin bromides1-5 General procedure: The intermediate coumarin bromides1-5were synthesized as reported in a previous study. The synthetic route is shown in Scheme 1.For example,to a solution of 7-hydroxycoumarin (10.0 g, 62 mmol) in acetone (120 mL) was added anhydrous K2CO3(13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature. After stirring at room temperature for 30 min, 1, 2-dibromoethane (23.29 g, 124 mmol) was added to the reaction mixture, and whole was refluxed at 60°Cfor 24 h. The precipitate was filtered off and washed with acetone (4×100 mL).The solvent was evaporated under reduced pressure, and the residue was treated with water (100 mL) and extracted with dichloromethane (4×200 mL).The organic layer were combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure.The crude product was purified via silica gel column chromatography with mixed petroleum ether and ethyl acetate (5:1, v/v) as eluent, and resulted in a white solid. |
62.46% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: 1 ,6-dibromohexane In acetone at 60℃; for 24h; | 15.1. Procedure for synthesis of intermediate coumarin bromides A1-A5 General procedure: The intermediate coumarin bromides A1-A5 were synthesized as reported in a previous study. The synthetic route is illustrated in Scheme 1. For example, anhydrous K2CO3 (13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature were added to a solution of 7-hydroxycoumarin (10.0 g, 62 mmol) in acetone (120 mL). After stirring at room temperature for 30 min, 1, 2-dibromoethane (23.3 g, 124 mmol) was added to the reaction mixture, which was then refluxed at 60°C for 24 h. The precipitate was filtered and washed with acetone (4 × 100 mL). The solvent was evaporated under reduced pressure, and the residue was treated with water (200 mL) and extracted with dichloromethane (4 × 250 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography with a mixture of petroleum ether and ethyl acetate (5:1, v/v) as the eluent, yielding in a white solid. |
60% | With potassium carbonate In acetone for 4h; Reflux; | 1 4.1.6 General procedures for the preparation of compounds 3a-t General procedure: A mixture of 2a-c/2e (5.0mmol) with suitable α,ω-dibromoalkanes (50mmol) and anhydrous K2CO3 (1.4g, 10mmol) in acetone (15mL) was refluxed under stirring for 4h. After cooling, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography with hexane/acetone (20:1) as eluent to give compounds 3a-t as white solid. |
60.1% | With potassium carbonate In acetone for 12h; Reflux; | |
60% | With potassium carbonate In acetonitrile for 2h; Reflux; | 4.2.2. General procedure for the synthesis of 3a-h General procedure: K2CO3(12mmol) and dibromide derivatives (6mmol) were added to a solution of 1a(2mmol) in CH3CN (20mL). The reaction mixture was refluxed for 2h. Upon completion, K2CO3 was removed by filtration and the solvent was concentrated under vacuum, the residue was dissolved in CH2Cl2, washed with water, brine, dried over anhydrous Na2SO4and concentrated under vacuum to give compounds 3a-h and purification coloumn chromatograph (Eluent; Hexane-EtOAc; 4:1) [38]. |
36% | With potassium carbonate In acetone Reflux; | Synthesis of 7-(6-bromohexyl-1-oxy)-2H-chromen-2-one(1) A mixture of 7-hydroxycoumarin (5.35 g, 33.0 mmol),1,6-dibromohexane (8.05 g, 33.0 mmol) and potassium carbonateanhydrous (6.84 g, 49.5mmol) in 150 ml dried acetonewas refluxed overnight. The solvent was removed under vacuum.The crude product was washed with water and extractedwith dichloromethane. The organic layer was dried over anhydrousmagnesiumsulphate and excess solvent was removedunder vacuum. The crude was further purified over a silica gelcolumn chromatograph with 1:1 chloroform-hexane eluent toafford 3.7 g (36 % yield) of a white solid. Rf=0.71 (1:1hexane:ethyl acetate), m.p.: 53-55 °C. 1H NMR (400 MHz,CDCl3): δ 7.6 (d, J=9.5 Hz, ArH, 1H) 7.3 (d, J=8.6 Hz, ArH,1H), 6.8 (dd, J=6.4 Hz, ArH, 1H), 6.7 (d, J=2.2 Hz, ArH,1H), 6.2 (d, J=9.3 Hz, ArH 1H), 3.9 (t, J=6.3 Hz, CH2O,2H), 3.4 (t, J=6.8 Hz, CH2Br, 2H) 1.2-1.9 (m, CH2, 8H). 13CNMR (400 MHz, CDCl3): 162.3, 161.2, 155.9, 143.4, 128.7,114.9, 112.9, 112.6, 101.3, 68.4, 33.7, 32.6, 28.8, 27.9, 25.4.FTIR (cm-1): 2943(s), 2864 (s), 1706 (s), 1613(s), 1468(s),1131 (s). A. |
With potassium carbonate In acetone for 7h; Heating; | ||
With potassium carbonate In acetone | ||
With potassium carbonate; triethylamine In acetone at 60℃; | ||
Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.25h; Stage #2: 1 ,6-dibromohexane In N,N-dimethyl-formamide at 25℃; | 2.1.4. General procedure for the synthesis of 4-(2-bromoalkoxy)-2H-chromen-2-ones. General procedure: 4-hydroxy coumarin (1 equiv) was dissolved in DMF and K2CO3 (1.5 equiv) was added to it. The mixture so obtained was allowed to stir for 15 mins. After 15 mins, dibromobutane (1 equiv) was added in the reaction mixture and was allowed to stir at room temperature until it was completed (monitored by analytical TLC). As the reaction completed, the reaction mixture was poured on crushed ice and set aside for a while (until the ice was completely converted into water), filtered and dried. The obtained crude product was purified using column chromatography using hexane: ethyl acetate (9.5: 0.5) to get pure 4-(4-bromobutoxy)-2H-chromen-2-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; potassium iodide In acetone for 30h; Reflux; | 7-[(6-Hydroxyhexyl)oxy]coumarin (1c) 6-Bromohexan-1-ol (1.57 ml; 12 mmol) was added to a mixture of 7-hydroxycoumarin (1a, 12 mmol), anhydrous potassium carbonate (5.5 g; 40 mmol) and a catalytic amount of potassium iodide in a round-bottomed flask with freshly distilled acetone (75 mL). The mixture was heated at reflux for 30 h. The solid was filtered off and the solvent was evaporated to dryness under vacuum. The crude product was purified by column chromatography on silica gel (hexane-ethyl acetate, 4:6)to afford 1c as an oil after solvent evaporation; yield 89%. 1H-NMR (500 MHz, CDCl3): δ 1.2-1.95(m, 8H, -CH2CH2CH2CH2-), 3.7 (t, 2H, -CH2OH), 4.00 (t, 2H, -CH2-OAr), 6.2 (d, 1H, =CH-C(O)-),6.81 (m, 2H, Ar-H), 7.4 (d, 1H, Ar-H), 7.6 (d, 1H, Ar-H). |
With potassium carbonate In acetone for 7h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium hydride In tetrahydrofuran at 25℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 110℃; | |
88% | With potassium carbonate In N,N-dimethyl-formamide Reflux; | |
72% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 60℃; for 5h; | 4.1.6. Synthesis of 7-(2'-hydroxyethoxy)-2H-chromen-2-one (7) A mixture of 7-hydroxy-2H-chromen-2-one (0.5 g, 1.0 equiv), K2CO3 (5.0 equiv), KI (1.0 equiv) and chloroethanol (1.0 equiv) in DMF dry (10 ml) was stirred at 60 °C for 5 h. The reaction mixture was cooled down to 0 °C, quenched with 6 M aqueous hydrochloric acid (50 ml) and extracted with ethyl acetate (3 × 20 ml). The combined organic layers were washed several timed with H2O, dried over Na2SO4, filtered-off and concentrated under vacuo to afford a residue that was purified by silica gel column chromatography eluting with 50% ethyl acetate/ n-hexane v/v. |
72% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 60℃; for 5h; | 3.2 A mixture of 7-hydroxy-2H-chromen-2-one (0.5g, 1.0 eq), K2C03 (5.0 eq), Kl (1.0 eq) and chloroethanol (1.0 eq) in DMF dry (10 ml) was stirred at 60°C for 5 h. The reaction mixture was cooled down to 0°C, quenched with 6M aqueous hydrochloric acid (50 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed several timed with H20, dried over Na2S04, filtered-off and concentrated under vacuo to afford a residue that was purified by silica gel column chromatography eluting with 50 % ethyl acetate/ n- hexane v/v. |
50% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 90℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; diethylazodicarboxylate; In 1,4-dioxane; at 20 - 40℃; for 19h; | Method B; 7-(1,2,2,6,6-Pentamethyl-piperidin-4-yloxy)-chromen-2-one hydrochloric acid salt; 5 A mixture of triphenylphosphine (9.4 g, 36 mmol) and dioxane (100 ml) was stirred at room temperature where diethylazodicarboxylate (5.6 ml, 36 mmol) was added slowly. 4-Hydroxy-1 ,2,2,6,6-pentamethyl-piperidine (5.1 g, 30 mmol) (prepared from 1 ,2,2,6,6- pentamethyl-piperidine-4-one by reduction with sodium borohydride) and 7-hydroxy- coumarine (5.2 g, 32 mmol) was added and the reaction mixture was allowed to stir for10 15 h at room temperature, followed by stirring at 40C for 4 h . Aqueous sodium hydroxide (100 ml, 1 M) was added and the mixture was extracted with diethyl ether (2 x 50 ml). The diethyl ether phase was washed with water (50 ml). The volume of the ether phase was reduced to 30 ml and the crystaline triphenyl-phosphine oxide was filtered off. The filtrate was mixed with hydrochloric acid (30 ml, 1 M) and was washed15 twice with diethyl ether (2 X 50 ml). The aqueous mixture was made alkaline by adding concentrated ammonia. The product precipitated as the free base and was collected by filtration. The free base was solved in ethyl acetate (40 ml) and hydrochloric acid (2 ml, 3 M) was added. The product precipitated as the hydrochloric acid salt and filtered. The product was recrystalised from isopropanol (50 ml). Yield 1.05 g (10 %).20 Mp 273C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | A reaction flask was charged a suspension of 60% sodium hydride 0.84 g (washed with petroleum ether), and then 30 ml of dry N,N-dimethylformamide (DMF) was added, the mixture was stirred at room temperature for 30 minutes. To this agitated suspension, 1.7 g of 7-hydroxycoumarin was added, the mixture was agitated continuously till to no gas emerging. 3.0g of methyl (E)-alpha-[2-(bromomethyl)phenyl]-beta-methoxyacrylate was added to the reaction mixture and they were agitated continuously for 3 hours at room temperature. The reaction mixture was poured into ice water, extracted with ethyl acetate 3 times. The combined extracts were washed with brine 3 times, dried, filtered and concentrated under vacuum, to obtain the crude oil product 5g. This was subjected to column chromatography to obtain 2.8 g of compound 1 as a faint red-yellow oily substance in 76.5% yield. 1HNMR(300MHz, internal standard=TMS, CDCl3): deltappm 3.69(3H, s), 3.88(3H, s), 5.04(2H, s), 6.19-6.23(1H, d), 6.77(1H, s), 6.83-6.87(1H, d), 7.18-7.20(1H, m), 7.26-7.34(4H, m), 7.48-7.64(2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 20h; | 1 Example 1 (Scheme 4) 324.28 mg (2 mmol) of 7-hydroxycoumarin and 2472 mg (20 mmol) of dimethylaminothiocarbonyl chloride were dissolved in dichloromethane and 2586 mg (20 mmol) of DIPEA was added and stirred at room temperature for 20 h, using a dichloromethane system. Perform column chromatography separation,Obtained 370 mg of a yellow solid.The yield was 88.0%. |
81% | Stage #1: 7-hydroxy-2H-chromen-2-one With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: N,N-Dimethylthiocarbamoyl chloride In tetrahydrofuran; mineral oil at 60℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 5-Nitro-1,10-phenanthroline; oxygen; palladium diacetate In N,N-dimethyl-formamide at 80℃; for 24h; chemoselective reaction; | |
68% | Stage #1: 7-hydroxy-2H-chromen-2-one With 1,10-Phenanthroline; oxygen; palladium diacetate In N,N-dimethyl-formamide for 0.0833333h; Stage #2: phenylboronic acid In N,N-dimethyl-formamide at 100℃; for 24h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.26% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: propyl bromide In acetone at 65℃; for 24h; | 15.6. Procedure for synthesis of coumarin derivatives A21-A25 General procedure: The synthetic route is shown in Scheme 2. For example, to a stirred solution of 7-hydroxycoumarin (0.16 g, 1 mmol) in 20 mL acetone were added anhydrous K2CO3 (0.28 g, 2 mmol) at room temperature. After stirring at room temperature for 30 min, bromopropane (0.21 g, 1.5 mmol) was added to the reaction mixture, and whole was refluxed at 65°C for 24 h. The precipitate was filtered off and washed with acetone (4 × 30 mL). The solvent was evaporated under reduced pressure, and the residue was treated with water (50 mL) and extracted with ethyl acetate (4 × 30 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography with mixed petroleum ether and ethyl acetate (3:1, v/v) as eluent to give compounds A21-A25 as solid. |
27% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone for 0.5h; Stage #2: propyl bromide With triethylamine In [(2)H6]acetone at 40℃; for 60h; | 4.1. Preparation of 3, 9 and 15 (Scheme 1c) General procedure: 0.4g of SM1 (2.2mmol), SM2 (2.4mmol) and SM3 (2.2mmol), respectively, were dissolved with 2mL of acetone (for compound 9 and 15) and DMF (for compound 3). After that, solid K2CO3 (4 molar equivalent) was added and stirred during thirty minutes. Then 3 equivalents of triethylamine (Et3N) and 3 equivalents of n-propyl bromide were added. All of three reactions were heating for 2, 2.5 and 5 days at 40°C, respectively. After reactions were completed (analyzed by TLC), the solid was filtered off and dried to afford the corresponding compounds 3 (6,7-dipropoxy-2H-chromen-2-one), 9 (7-propoxy-2H-chromen-2-one) and 15 (4-methyl-7-propoxy-2H-chromen-2-one). |
With potassium carbonate In acetone for 12h; Inert atmosphere; |
With potassium carbonate In acetone at 80℃; for 1h; | ||
In acetone at 80℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.2% | With potassium carbonate In propan-2-one for 4h; Reflux; | |
83% | With potassium carbonate In propan-2-one Reflux; | 4.1.1 General procedures for the preparation of compounds 2a-c General procedure: To a solution of 7-hydroxy-2H-chromen-2-one 1 (4mmol) and powdered K2CO3 (8mmol) in acetone (20mL), corresponding α,ω-dibromoalkane (24mmol) was added. The reaction mixture was refluxed for 10-12h. Upon completion, K2CO3 was removed by filtration and the solvent was concentrated under vacuum, the residue was purified on silica gel chromatography with petroleum ether/ethyl acetate (7:1, v/v) as elution solvent to give the desired product 2a-c [18,38]. |
70.6% | With potassium carbonate In acetonitrile Reflux; | 3 4.1.5 General procedure for the synthesis of compound 9a-9c General procedure: A mixture of coumarin derivative (1 eq), dibromoalkane (3 eq) and K2CO3 (6 eq) in 50mL acetonitrile was refluxed overnight. After the completion of reaction, excess K2CO3 was removed by filtration of celite and the filtrate was concentrated, washed with DCM and dried with Na2SO4. The residue was purified by column chromatography (EA: DCM: HEX=1:25:25) to afford the white solid. |
65% | With potassium carbonate In propan-2-one for 4h; Reflux; | 1 4.1.6 General procedures for the preparation of compounds 3a-t General procedure: A mixture of 2a-c/2e (5.0mmol) with suitable α,ω-dibromoalkanes (50mmol) and anhydrous K2CO3 (1.4g, 10mmol) in acetone (15mL) was refluxed under stirring for 4h. After cooling, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography with hexane/acetone (20:1) as eluent to give compounds 3a-t as white solid. |
61.34% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In propan-2-one at 20℃; for 0.5h; Stage #2: 1,4-dibromo-butane In propan-2-one at 60℃; for 24h; | The procedure for the synthesis of intermediate coumarin bromides A1-A6 General procedure: For example, to a solution of 7-hydroxycoumarin (5.0 g, 31.0 mmol) in acetone (60.0 mL) was added anhydrous K2CO3 (6.9 g, 50.0 mmol) and triethylamine (1.0 mL) at room temperature. After stirring at room temperature for 30 min, 1, 2-dibromoethane (12.6 g, 62.0 mmol) was added to the reaction mixture, and the whole was refluxed at 60°C for 24 h. Then the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was treated with water (200.0 mL) and extracted with dichloromethane (4×200.0 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography with mixed petroleum ether and ethyl acetate (5:1, v/v) as eluent, and resulted in a white solid. |
60.7% | With potassium carbonate In propan-2-one for 6h; Reflux; | 1.2 Example 1: 7-(4-(4-(3-(6-fluoro-benzisoxazole)-1-piperidyl)-n-butoxy))-2H-benzopyran-2-one (1) 2) 5 g of product of step 1), 6 g of anhydrous potassium carbonate, 50 ml of acetone and 8.2 g of 1,4-dibromobutane were heated under reflux for 6 hours. Then the mixture was cooled to room temperature and filtrated. The solvent was distilled to give yellowish oil, which was passed through a column to give 5.4 g of white solid. Melting point: 55-57°C, Yield:60.7%. |
60.7% | With potassium carbonate In propan-2-one for 6h; Reflux; | 1.2 Example 1: 7-(4-(4-(3-(6-fluoro-benzisoxazole)-1-piperidyl)-n-butoxy))-2H-benzopyran-2-one (1) 2) 5 g of product of step 1), 6 g of anhydrous potassium carbonate, 50 ml of acetone and 8.2 g of 1,4-dibromobutane were heated under reflux for 6 hours. Then the mixture was cooled to room temperature and filtrated. The solvent was distilled to give yellowish oil, which was passed through a column to give 5.4 g of white solid. Melting point: 55-57° C., Yield: 60.7%. |
60.04% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In propan-2-one at 20℃; for 0.5h; Stage #2: 1,4-dibromo-butane In propan-2-one at 60℃; | 1.1.1.The procedure for the synthesis of intermediate coumarin bromides1-4 General procedure: The intermediate coumarin bromides 1-4 were synthesized as reported in aprevious study.45 The synthetic route is shown in Scheme 1. For example, to a solution of 7-hydroxycoumarin(10.0 g, 62 mmol) in acetone (120 mL) was added anhydrous K2CO3(13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature. After stirringat room temperature for 30 min, 1, 2-dibromoethane (23.29 g, 124 mmol) wasadded to the reaction mixture, and whole was refluxed at 60 °C for 24 h. The precipitate was filtered off and washed withacetone (4×100 mL). The solvent was evaporated under reducedpressure, and the residue was treated with water (100 mL) and extracted withdichloromethane (4×200 mL). The organic layer werecombined, dried with anhydrous Na2SO4, and concentratedunder reduced pressure. The crude product was purified via silicagel column chromatography with mixed petroleum ether and ethyl acetate (5:1,v/v) as eluent, and resulted in a white solid. |
60.04% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In propan-2-one at 20℃; for 0.5h; Stage #2: 1,4-dibromo-butane In propan-2-one at 60℃; | 1.1.2. The procedure for the synthesis of intermediatecoumarin bromides1-5 General procedure: The intermediate coumarin bromides1-5were synthesized as reported in a previous study. The synthetic route is shown in Scheme 1.For example,to a solution of 7-hydroxycoumarin (10.0 g, 62 mmol) in acetone (120 mL) was added anhydrous K2CO3(13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature. After stirring at room temperature for 30 min, 1, 2-dibromoethane (23.29 g, 124 mmol) was added to the reaction mixture, and whole was refluxed at 60°Cfor 24 h. The precipitate was filtered off and washed with acetone (4×100 mL).The solvent was evaporated under reduced pressure, and the residue was treated with water (100 mL) and extracted with dichloromethane (4×200 mL).The organic layer were combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure.The crude product was purified via silica gel column chromatography with mixed petroleum ether and ethyl acetate (5:1, v/v) as eluent, and resulted in a white solid. |
60.04% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In propan-2-one at 20℃; for 0.5h; Stage #2: 1,4-dibromo-butane In propan-2-one at 60℃; for 24h; | 15.1. Procedure for synthesis of intermediate coumarin bromides A1-A5 General procedure: The intermediate coumarin bromides A1-A5 were synthesized as reported in a previous study. The synthetic route is illustrated in Scheme 1. For example, anhydrous K2CO3 (13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature were added to a solution of 7-hydroxycoumarin (10.0 g, 62 mmol) in acetone (120 mL). After stirring at room temperature for 30 min, 1, 2-dibromoethane (23.3 g, 124 mmol) was added to the reaction mixture, which was then refluxed at 60°C for 24 h. The precipitate was filtered and washed with acetone (4 × 100 mL). The solvent was evaporated under reduced pressure, and the residue was treated with water (200 mL) and extracted with dichloromethane (4 × 250 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography with a mixture of petroleum ether and ethyl acetate (5:1, v/v) as the eluent, yielding in a white solid. |
54% | With potassium carbonate In acetonitrile for 2h; Reflux; | 4.2.2. General procedure for the synthesis of 3a-h General procedure: K2CO3(12mmol) and dibromide derivatives (6mmol) were added to a solution of 1a(2mmol) in CH3CN (20mL). The reaction mixture was refluxed for 2h. Upon completion, K2CO3 was removed by filtration and the solvent was concentrated under vacuum, the residue was dissolved in CH2Cl2, washed with water, brine, dried over anhydrous Na2SO4and concentrated under vacuum to give compounds 3a-h and purification coloumn chromatograph (Eluent; Hexane-EtOAc; 4:1) [38]. |
With potassium carbonate In acetonitrile Reflux; | ||
With potassium carbonate In propan-2-one for 24h; Reflux; | ||
With potassium carbonate In propan-2-one for 4h; Reflux; | 4.1.4 General procedure for the preparation of bromoalkoxy intermediate 2 General procedure: A mixture of substituted 7-hydroxycoumarin (5mmol), appropriate dibromoalkane (50mmol) and anhydrous K2CO3 (1.4g, 10mmol) was refluxed in acetone (15mL) for 4h. After cooling, the reaction mixture was filtered and the organic phase was evaporated under reduced pressure. The obtained residue was triturated with n-hexane to give the product 2 as white solid [39]. | |
With potassium carbonate In propan-2-one for 6h; Reflux; | 1.8 Synthesis and characterization of 6a-n General procedure: The corresponding coumarin derivatives (4.21mmol) 5a-k and potassium carbonate (0.872 g, 6.31 mmol) were suspended in dry acetone, and then the corresponding dibromoalkyl derivative (84.12 mmol) was added. The mixture was refluxed for 6 h. After cooling to room temperature, the solid was filtered and washed with acetone. The filtrate was concentrated under reduced pressure and purified by column chromatography using petroleum ether/ethy actate (5 : 1 to 8:1) as eluent to get the intermediates of 6a-n | |
With potassium carbonate In acetonitrile Reflux; | ||
With potassium carbonate In propan-2-one at 60℃; Sealed tube; | ||
With potassium carbonate; potassium iodide In propan-2-one Heating; | ||
Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.25h; Stage #2: 1,4-dibromo-butane In N,N-dimethyl-formamide at 25℃; | 2.1.4. General procedure for the synthesis of 4-(2-bromoalkoxy)-2H-chromen-2-ones. General procedure: 4-hydroxy coumarin (1 equiv) was dissolved in DMF and K2CO3 (1.5 equiv) was added to it. The mixture so obtained was allowed to stir for 15 mins. After 15 mins, dibromobutane (1 equiv) was added in the reaction mixture and was allowed to stir at room temperature until it was completed (monitored by analytical TLC). As the reaction completed, the reaction mixture was poured on crushed ice and set aside for a while (until the ice was completely converted into water), filtered and dried. The obtained crude product was purified using column chromatography using hexane: ethyl acetate (9.5: 0.5) to get pure 4-(4-bromobutoxy)-2H-chromen-2-one. | |
With Cs2CO3 In acetonitrile at 80℃; for 5h; Inert atmosphere; | 2.1 (1) Preparation of Intermediate 2-2 50ml of acetonitrile was added to the three-necked flask, then 2.5g of compound 1-2, 14.5g of compound 1,4-dibromobutane, and 10g of cesium carbonate were added in sequence, and the reaction was refluxed for 5h at 80°C under an argon atmosphere. Cool to room temperature and filter the mixture. The solvent of the reaction mixture was removed with a rotary evaporator, the remaining liquid was added dropwise to petroleum ether, filtered and dried to obtain compound 2-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With di-isopropyl azodicarboxylate; triethylamine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | Step A: Diisopropyl azodicarboxylate (5.5 mL, 28 mmol) was added dropwise to a mixture of 7-hydroxycoumarin (4.6 g, 28 mmol), (R)-tert-butyl 3-hydroxypyrrolidine-l- carboxylate (6.0 g, 31 mmol), triphenylphosphine (7.4 g, 28 mmol) and triethylamine (3.9 mL, 28 mmol) in THF (28 mL) at 0 C. The mixture was stirred at room temperature overnight. The solids were removed by filtration and washed with cold THF. The solid was dissolved in EtOAc. The solution was washed with aqueous HC1 (0.5 N), dried over NaS04, then filtered and concentrated to give (S)-tert-butyl 3-(2-oxo-2H-chromen-7-yloxy)pyrrolidine-l-carboxylate (4.85 g, 52%) as a pale yellow solid. MS m/z 232.2 [M-Boc+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine In ethanol at 20℃; | Preparation of 1. NBD-Cl (0.24 g, 1.2 mmol) was addedto a solution of 7-hydroxycoumarin (0.19 g, 1.2 mmol) and triethylamine (0.36 g, 3.6 mmol) in ethanol(10 mL). The reaction mixture was stirred at room temperature for overnight,and the resulting brown precipitates were filtered and washed with ethanol. Thecrude product was crystallized from a mixture of dichloromethane/acetone (1:1,v/v) solution and dried under vacuum to afford compound 1 (72% yield) as brown crystals; mp: 263 °C. 1H NMR (600 MHz, DMSO-d6) δ 8.66 (d, J= 8.3 Hz, 1H), 8.15 (d, J = 9.5 Hz, 1H), 7.93 (d, J = 8.5 Hz,1H), 7.56 (d, J = 2.4 Hz, 1H), 7.42 (dd, J = 8.5, 2.4 Hz, 1H),7.01 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 9.5 Hz, 1H); 13C NMR (150 MHz, DMSO-d6)δ 160.0, 156.1, 155.2, 152.2, 145.9, 144.9, 144.2, 135.6, 131.6, 131.1, 117.7,117.4, 116.3, 112.3, 109.1; HRMS: (EI+); m/z calcd for C15H7N3O6[M]+: 325.0335, found 325.0332. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | A suspension of <strong>[629-09-4]1,6-diiodohexane</strong> (24.9 g, 73.6 mmol) and K2CO3 (5.10 g, 36.8 mmol) in DMF (23 mL) was heated to 60 C. To the resulting suspension was added an orange solution of umbelliferone (1.20 g, 74.0 mmol) in DMF (23 mL) dropwise over 15 min via syringe. After 35 min of stirring, the completion of the reaction was confirmed by TLC analysis and the suspension was concentrated in vacuo to a small volume. The resulting suspension was diluted with CH2Cl2, filtered through a filter paper, and evaporated to give the crude product as a yellow viscous liquid. Purification by silica gel column chromatography (225 g, eluent: 20% ethyl acetate/hexane) afforded the title compound as a yellow viscous liquid, which turned solid while drying under 0.5 Torr (2.18 g, 79% yield): IR (powder) 3065, 2941, 2864, 2362, 2339, 1729, 1621, 1556, 1509, 1471, 1401, 1293, 1239, 1193, 1127, 1096, 1023, 999, 891, 757, 722 cm-1; 1H NMR (400 MHz, CDCl3) delta 1.50 (m, 4H), 1.85 (m, 4H), 3.21 (t, J = 7.0 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 6.25 (d, J = 9.4 Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 6.84 (dd, J = 2.5, 8.6Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 9.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) delta 6.97 (CH2), 24.97 (CH2), 28.77 (CH2), 30.16 (CH2), 30.95 (CH), 33.27 (CH2), 68.35 (CH2), 101.29 (CH), 112.41, 112.93 (CH), 128.74 (CH), 143.47 (CH), 155.88, 161.26, 162.28; Anal Calcd for C15H17O3I: C, 48.33; H, 4.65. Found C, 48.41; H, 4.60. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With Di-tert-butyl acetylenedicarboxylate; In neat (no solvent); at 100℃; for 0.0833333h;Microwave irradiation; Green chemistry; | General procedure: In a 10-mL reaction vial, a mixture of N-methylimidazole (3, 0.26 g, 2.0 mmol) and dimethyl acetylenedicarboxylate (2a, 0.24 mL, 2.0 mmol) under solvent-free condition was stirred for 1 min. Subsequently, 4-hydroxycoumarin (1a, 0.32 g, 2.0 mmol) was added to the reaction mixture, and the reaction vial was capped and pre-stirred for 20 s. The mixture was subjected to microwave irradiation at a power of 600 W for 6 min at 100 C. Upon completion, monitored by TLC, the reaction mixture was cooled to room temperature. The resulting precipitate was separated by filtration and recrystallized from diethyl ether (Et2O) to afford the pure compound 4a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 1-methyl-1H-imidazole; In neat (no solvent); at 100℃; for 0.0666667h;Microwave irradiation; Green chemistry; | General procedure: In a 10-mL reaction vial, a mixture of N-methylimidazole (3, 0.26 g, 2.0 mmol) and dimethyl acetylenedicarboxylate (2a, 0.24 mL, 2.0 mmol) under solvent-free condition was stirred for 1 min. Subsequently, 4-hydroxycoumarin (1a, 0.32 g, 2.0 mmol) was added to the reaction mixture, and the reaction vial was capped and pre-stirred for 20 s. The mixture was subjected to microwave irradiation at a power of 600 W for 6 min at 100 C. Upon completion, monitored by TLC, the reaction mixture was cooled to room temperature. The resulting precipitate was separated by filtration and recrystallized from diethyl ether (Et2O) to afford the pure compound 4a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | NaI (46.2 mg, 0.308 mmol), <strong>[112-26-5]1,2-bis(2-chloroethoxy)ethane</strong> (48 muL, 0.308 mmol) and Cs2CO3 (100 mg, 0.308 mmol) were mixed in DMF (1.0 mL) at rt. The mixture was protected from light, and heated to 100 C for 15 min, after which time, 7-hydroxy-2H-chromen-2-one (50 mg, 0.308 mmol) was added. The reaction was heated for 75 min more, then cooled to rt. The mixture was quenched with 1 N HCl, and extracted with EtOAc (3 x 4 mL). The combined organic layers were evaporated to dryness. The crude material was purified by flash column chromatography (silica gel, solvent gradient 0-50% EtOAc in heptane) to give 32% yield of intermediate chloride SI-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-Bromo-2'-acetonaphthone In N,N-dimethyl-formamide at 20℃; for 24h; | 5 3-[2-(Naphthalen-2-yl)-2-oxoethoxy]-2H-chromen-2-one (9e) General procedure: 3-Hydroxycoumarin (1, 1.55 g, 5 mmol), K2CO3 (0.69 g, 5 mmol), and dry DMF (50 mL) were stirred at room temperature (r.t.) for 30 min. To this solution was added 2-(bromoacetyl)naphthalene (1.25 g, 5 mmol) in DMF (10 mL) in one portion. The resulting mixture was stirred continuously at r.t. for 24 h (TLC monitoring) and then poured into ice-water (100 mL). The white solid thus obtained was collected and crystallized from Et2O to give 9e (1.55 g, 94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | In ethanol Reflux; | 3.2 General method for Mannich bases 3a-d, 4, 5, 6 General procedure: To 20.0mmol of 7-hydroxycoumarin (or 4-methyl-7-hydroxycoumarin) dissolved in 20mL of ethanol, 10.0mmol of the suitable amine (A) and 2.0mL of 40% formaldehyde were added. The resulting mixture was refluxed for 4-6h. After cooling, the solvent was evaporated under reduced pressure. The pale yellow oil obtained was treated with cool acetone, leaving a white solid crystallized from a suitable solvent (B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.34% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: 1,8-dibromooctane In acetone at 60℃; for 24h; | The procedure for the synthesis of intermediate coumarin bromides A1-A6 General procedure: For example, to a solution of 7-hydroxycoumarin (5.0 g, 31.0 mmol) in acetone (60.0 mL) was added anhydrous K2CO3 (6.9 g, 50.0 mmol) and triethylamine (1.0 mL) at room temperature. After stirring at room temperature for 30 min, 1, 2-dibromoethane (12.6 g, 62.0 mmol) was added to the reaction mixture, and the whole was refluxed at 60°C for 24 h. Then the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was treated with water (200.0 mL) and extracted with dichloromethane (4×200.0 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography with mixed petroleum ether and ethyl acetate (5:1, v/v) as eluent, and resulted in a white solid. |
64.68% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: 1,8-dibromooctane In acetone at 60℃; | 1.1.1.The procedure for the synthesis of intermediate coumarin bromides1-4 General procedure: The intermediate coumarin bromides 1-4 were synthesized as reported in aprevious study.45 The synthetic route is shown in Scheme 1. For example, to a solution of 7-hydroxycoumarin(10.0 g, 62 mmol) in acetone (120 mL) was added anhydrous K2CO3(13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature. After stirringat room temperature for 30 min, 1, 2-dibromoethane (23.29 g, 124 mmol) wasadded to the reaction mixture, and whole was refluxed at 60 °C for 24 h. The precipitate was filtered off and washed withacetone (4×100 mL). The solvent was evaporated under reducedpressure, and the residue was treated with water (100 mL) and extracted withdichloromethane (4×200 mL). The organic layer werecombined, dried with anhydrous Na2SO4, and concentratedunder reduced pressure. The crude product was purified via silicagel column chromatography with mixed petroleum ether and ethyl acetate (5:1,v/v) as eluent, and resulted in a white solid. |
64.68% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: 1,8-dibromooctane In acetone at 60℃; | 1.1.2. The procedure for the synthesis of intermediatecoumarin bromides1-5 General procedure: The intermediate coumarin bromides1-5were synthesized as reported in a previous study. The synthetic route is shown in Scheme 1.For example,to a solution of 7-hydroxycoumarin (10.0 g, 62 mmol) in acetone (120 mL) was added anhydrous K2CO3(13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature. After stirring at room temperature for 30 min, 1, 2-dibromoethane (23.29 g, 124 mmol) was added to the reaction mixture, and whole was refluxed at 60°Cfor 24 h. The precipitate was filtered off and washed with acetone (4×100 mL).The solvent was evaporated under reduced pressure, and the residue was treated with water (100 mL) and extracted with dichloromethane (4×200 mL).The organic layer were combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure.The crude product was purified via silica gel column chromatography with mixed petroleum ether and ethyl acetate (5:1, v/v) as eluent, and resulted in a white solid. |
64.68% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate; triethylamine In acetone at 20℃; for 0.5h; Stage #2: 1,8-dibromooctane In acetone at 60℃; for 24h; | 15.1. Procedure for synthesis of intermediate coumarin bromides A1-A5 General procedure: The intermediate coumarin bromides A1-A5 were synthesized as reported in a previous study. The synthetic route is illustrated in Scheme 1. For example, anhydrous K2CO3 (13.8 g, 100 mmol) and triethylamine (2 mL) at room temperature were added to a solution of 7-hydroxycoumarin (10.0 g, 62 mmol) in acetone (120 mL). After stirring at room temperature for 30 min, 1, 2-dibromoethane (23.3 g, 124 mmol) was added to the reaction mixture, which was then refluxed at 60°C for 24 h. The precipitate was filtered and washed with acetone (4 × 100 mL). The solvent was evaporated under reduced pressure, and the residue was treated with water (200 mL) and extracted with dichloromethane (4 × 250 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography with a mixture of petroleum ether and ethyl acetate (5:1, v/v) as the eluent, yielding in a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With [(4-acetamidophenyl)(fluorosulfonyl)amino]sulfonyl fluoride; 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 0.166667h; | |
85% | With fluorosulfonyl fluoride; N-ethyl-N,N-diisopropylamine In dichloromethane; water at 20℃; for 5h; | 2 preparation of 2-oxo-2H-chromen-7-yl sulfurofluoridate Diisopropylethylamine (DIPEA) (0.87 mL, 5 mmol) was added after dissolving Umbelliferone (0.162 g, 1.0 mmol) in a mixed solvent of dichloromethane: water (3: 2) Was added. The reaction flask was closed with a stopper, the air in the flask was removed, and the mixture was stirred at room temperature for 5 hours under a balloon of sulfuric fluoride gas (SO2F2). The solvent was concentrated under reduced pressure, diluted with 1N hydrochloric acid aqueous solution, and extracted with dichloromethane. The organic layer was concentrated in vacuo to give the desired product, 2-oxo-2H-chromen-7-ylsulfofluoridate (0.21 g, 85% yield) as a white solid. |
84% | With [(4-acetamidophenyl)(fluorosulfonyl)amino]sulfonyl fluoride; potassium carbonate In dimethyl sulfoxide at 20℃; for 1h; | 29 Example 29. 2-Oxo-2H-chromen-7-yl sulfurofluoridate To a 2-dram vial containing 7-hydroxy-2H-chromen-2-one (50 mg, 0.31 mmol) and (4-acetamidophenyl)(fluorosulfonyl)sulfamoyl fluoride (116 mg, 0.37 mmol) in dimethyl sulfoxide (4 mL), potassium carbonate (128 mg, 0.925 mmol) was added and the reaction solution was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (2*10 ml) and washed with brine (10 ml). The organic fraction was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (4 g silica, 15% ethyl acetate in petroleum ether) to get product as a white solid (63 mg, 84% yield). 1H NMR: (400 MHz, DMSO) δ 8.13 (d, J=9.6 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.86 (d, J=2.3 Hz, 1H), 7.66-7.59 (m, 1H), 6.61 (d, J=9.6 Hz, 1H). 13C NMR: (101 MHz, DMSO) δ 159.10 (s, 1H), 154.09 (s, 1H), 150.56 (s, 1H), 143.15 (s, 3H), 130.63 (s, 3H), 119.46 (s, 1H), 117.40 (d, J=9.6 Hz, 6H), 110.11 (s, 3H). 19F NMR: (376 MHz, DMSO) δ 39.76 (s, 1H). |
72% | With fluorosulfonyl fluoride; triethylamine In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With di-isopropyl azodicarboxylate; triethylamine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16h; | Step A: Diisopropyl azodicarboxylate (5.5 mL, 28 mmol) was added dropwise to a mixture of 7-hydroxycoumarin (4.6 g, 28 mmol), <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (6.0 g, 31 mmol), triphenylphosphine (7.4 g, 28 mmol) and triethylamine (3.9 mL, 28 mmol) in THF (28 mL) at 0 C. The mixture was stirred at room temperature overnight. The solids were removed by filtration and washed with cold THF. The solid was dissolved in EtOAc. The solution was washed with aqueous HCl (0.5 N), dried over NaSO4, then filtered and concentrated to give (S)-tert-butyl 3-(2-oxo-2H-chromen-7-yloxy)pyrrolidine-1-carboxylate (4.85 g, 52%) as a pale yellow solid. MS m/z 232.2 [M-Boc+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone for 0.25h; Inert atmosphere; Reflux; Stage #2: methyl bromide In acetone Inert atmosphere; Reflux; | General procedure for the synthesis of 7-O-alkylumbelliferone (1a-j): General procedure: In a 50 mL two necked round-bottomed flask equipped with a magnetic stirrer, a condenser, and a nitrogen inlet,umbelliferone (1 equiv.), K2CO3 (3 equiv.) and 10 mL of anhydrous acetone were added. The mixture was heated underreflux for 15 min under nitrogen atmosphere and cooledto room temperature before the dropwise addition of alkylbromide (1.5 equiv.). The resulting mixture was heated underreflux for another 2-6 h. The reaction was quenched withwater (10 mL), followed by extraction with EtOAc (2×50 mL)and washed with brine solution. After drying (Na2SO4) andremoval of the solvent, the residue was purified by columnchromatography using hexane/EtOAc as mobile phase (gradientelution), to afford the corresponding compounds 1aj14.All the derivatives were characterized by 1H, 13C NMRand mass data. |
69.56% | Stage #1: 7-hydroxy-2H-chromen-2-one With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: methyl bromide In acetone at 65℃; for 24h; | 15.6. Procedure for synthesis of coumarin derivatives A21-A25 General procedure: The synthetic route is shown in Scheme 2. For example, to a stirred solution of 7-hydroxycoumarin (0.16 g, 1 mmol) in 20 mL acetone were added anhydrous K2CO3 (0.28 g, 2 mmol) at room temperature. After stirring at room temperature for 30 min, bromopropane (0.21 g, 1.5 mmol) was added to the reaction mixture, and whole was refluxed at 65°C for 24 h. The precipitate was filtered off and washed with acetone (4 × 30 mL). The solvent was evaporated under reduced pressure, and the residue was treated with water (50 mL) and extracted with ethyl acetate (4 × 30 mL). The organic layer was combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography with mixed petroleum ether and ethyl acetate (3:1, v/v) as eluent to give compounds A21-A25 as solid. Compound A21. Yield 69.56%.1H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 9.5 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 6.87 - 6.78 (m, 2H), 6.23 (d, J = 9.4 Hz, 1H), 3.86 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 162.97, 161.29, 156.04, 143.52, 128.88, 113.22, 112.69, 112.66, 100.98, 55.89. ESI-MS m/z: 199.0382 ([M+Na]+). |
With potassium carbonate In acetone at 80℃; for 1h; |
In acetone at 80℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 2.2 Preparation and Characterization of the YQ-1 Synthesis of probe (YQ-1) is summarized in Scheme 1. 2,2′-Dithiosalicylic acid (210mg, 1.0mmol), 4-dimethylaminopyridine (40mg, 0.3mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC, 400mg, 2.1mmol) and 7-hydroxycoumarin (370mg, 2.1mmol) were mixed in 30mL anhydrous dichloromethane. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The resulting residue was further purified by column chromatography on silica gel using petroleum: dichloromethane: ethyl acetate (5:1:1, v/v/v) as eluent to give the target as off-white solids (445mg, 75%). 1H NMR (DMSO-d6, 600MHz): δ (ppm): 8.36 (d, J=7.7Hz, 2H), 8.13 (d, J=9.4Hz, 2H), 7.87 (d, J=8.0Hz, 2H), 7.77 (t, J=8.9Hz, 2H), 7.74 (d, J=7.7Hz, 2H), 7.56 (s, 2H), 7.51 (s, 2H), 7.41 (d, J=8.3Hz, 2H), 6.53 (d, J=9.6Hz, 2H). 13C NMR (DMSO-d6, 150MHz): δ (ppm): 163.2, 159.1, 153.5, 152.0, 143.2, 139.1, 134.0, 131.9, 128.9, 126.0, 125.2, 124.9, 118.2, 116.4, 115.2, 109.8 (Fig. S1). ESI-MS m/z: [probe +H]+ Calcd. For 595.0443, Found 595.0542 (Fig. S2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: Nerol With pyridine; phosphorus tribromide In diethyl ether for 0.5h; Inert atmosphere; Cooling with ice; Stage #2: 7-hydroxy-2H-chromen-2-one With potassium carbonate; potassium iodide In diethyl ether; acetone at 20℃; | The synthesis of 2'-Z auraptene (1) 2'-Z auraptene (1) was synthesized as the following methods (Tsangarakis et al. 2007). A mixture of nerol(1.36 g, 10.0 mmol), PBr3 (1.35 g, 10.0 mmol), and appropriate pyridine in diethyl ether was placed in ice water bath with a nitrogen atmosphere. After 0.5 h stirring,ice water was added to terminate reaction, and subsequently the mixture was extracted by diethyl ether to afford the rude intermediation used in the next step without further purification. Then, a mixture of the intermediation obtained from above, 7-hydroxycoumarin (1.62 g,10.0 mmol), K2CO3 (1.38 g, 10.0 mmol), and KI (catalytic)in acetone were stirred at room temperature for 2-3 h. Subsequently, the obtained crude mixture was purified by silica gel chromatography, eluting with petroleum ether- ethyl acetate (20:1, v/v).Compound 1 was obtained as colorless solid (1.19 g,80% yield) and identified by spectroscopic methods. NMR data of 1 was conform to that of published data for (Z)-7-((3', 7'-dimethylocta-2', 6'-dien-1'-yl)oxy)coumarin(Coates and Melvin 1970), so we identified compound 1 as(Z)-7-((3',7'-dimethylocta-2',6'-dien-1'-yl)oxy)-2H- chromen-2-one, and named it as cis-auraptene in our study |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With sodium carbonate In water at 80℃; for 18h; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate; triethylamine In N,N-dimethyl-formamide at 70℃; for 72h; | 6.1.8. General procedure for the synthesis of substituted tert-butyl4-[(2-oxo-2H-chromen-7-yl)oxy]alkyl}piperidine-1-carboxylate(7b-e) and tert-outyl 3-[(2-oxo-2H-chromen-7-yl)oxy]methyl}piperidine-1-carboxylate (7g) General procedure: By following a previously reported method [28], a mixture of theappropriate 7-hydroxycoumarin (7.0 mmol), the suitable mesylateester (6.7 mmol), triethylamine (2.8 mL, 20 mmol) and cesiumcarbonate (2.3 g, 7.0 mmol) were heated in dry DMF (15 mL) at70 C for 72 h. Then the mixture was poured onto crushed ice. Thefiltratewas collected and washed with abundant water yielding the desired Boc-protected intermediates 7b-e, 7g that were deprotectedwithout further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; potassium iodide; In acetone; at 130℃; for 0.5h;Microwave irradiation; | General procedure: The appropriate 7-hydroxycoumarin 1a-g (2.0 mmol for 2a-gand 2i-r; 3.0 mmol for 1h) was suspended in anhydrous acetone(10 mL) before adding potassium carbonate (for 2a-g and 2i-r: 0.83 g, 6.0 mmol; for 1h: 1.2 g, 9.0 mmol), the suitable monohalide(for 1h: 2-[4-(bromomethyl)phenyl]ethanol, 3.0 mmol) or dihalide(for 2a-g and 2i-r: 6.0 mmol of alpha,alpha'-dibromo(chloro)-xylenes or trans-1,4-dibromo-2-butene; 10 mmol of 1,omega-dibromoalkanes) anda catalytic amount of KI in a Pyrex vessel charged with a magnetic stirring bar and aWeflon bar. The vessel was placed in a microwave apparatus and irradiated at 130 C for 30 min. After cooling to room temperature, the inorganic residue was filtered off after thorough washing with CH2Cl2. The solutionwas concentrated to dryness andthe resulting crude was purified as detailed below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate; In acetone; at 80℃; for 1h; | General procedure: To a solution of 7-hydroxycoumarin (1.0 mmol) in acetone (5 mL),dry K2CO3 (1.3 mmol) and alkyl bromide (iodide) (1.05 mmol) wereadded and the resulting suspension was stirred at 80 C for 1 h. Thewarm solution was poured into icy water (50 mL) and the resultingprecipitate collected by filtration under vacuum yielding the desiredadduct. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | Adding NaI to a suspension of Compound 1 (4.86 g, 10 mmol) and acetone (110 mL)15 g, 100 mmol, 10 equivalents). Stir at room temperature for 2 hours,A substitution reaction takes place and the solvent is removed in vacuo. The crude mixture was partitioned between H 2 O (100 mL) and organic solvent (100 mL). The aqueous layer was extracted with the same organic solvent (2×100 ml), and then the combined organic layer was washed with 5% Nas.The organic layer was dried over a dry pad, filtered and concentrated in vacuo.The crude product was dissolved in acetonitrile (150 mL), 7-hydroxy coumarin (3.24 g, 20 mmol, 2 eq.) and potassium carbonate (5.52 g, 40 mmol, 4 eq.).A substitution reaction occurs. The reaction mixture was stirred at room temperature for 12 hours.The solvent was evaporated in vacuo to give the crude mixture in water (100 ml) and organic solvent (100 ml)Allocated. After separating the layers, the aqueous layer was extracted with the same organic solvent (2×100 ml).The combined organic layers were then washed with 5% aqueous Na 2 O 3 (2 100 mL) and brine (100 mL). The organic layer was dried over a dry pad, filtered and concentrated in vacuo.The crude product was purified by column chromatography ( petroleum ether / ethyl acetate, 1:1).Compound 2 (2.4 g, 39%) was obtained as a light brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.9% | With potassium carbonate; In acetonitrile; at 60℃; | In a 50 mL round-bottomed flask, 7-hydroxycoumarin (720 mg, 4.4 mmol), potassium carbonate (670 mg, 4.88 mmol) and intermediate III (1.0 g, 4.9 mmol) were added, and acetonitrile (25 mL) was used as a solvent at 60 C. The reaction was stirred under stirring, followed by thin layer chromatography to the end of the reaction, cooled to room temperature, and subjected to post-treatment such as column chromatography separation and drying to obtain intermediate IV (700 mg), yield 54.9%; white solid; melting point: 179-180 C, Among them, 7-hydroxycoumarin was obtained by resorcinol as starting material through Pechmann reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetone at 80℃; | Synthesis of target compounds 4-11, 13-20, and 22-28 General procedure: 7-Hydroxy-2H-chromen-2-one/4-hydroxy-2H-chromen-2- one/7-hydroxy-3,4-dihydroquinolin-2(1H)-one (10.0 mmol), K2CO3 (10.0 mmol), and 50 ml acetone were combined in a 100 ml round-bottomed flask, and the resulting mixture was stirred for 6-12 h at 80 C. After the reaction was completed (TLC), the mixture was poured into water (50 ml), and then extracted with CH2Cl2. The combined organic extracts were washed with water, dried (MgSO4), and concentrated to dryness in vacuum. The residue was purified by chromatography on silica gel, eluting with CH2Cl2, to extract target compounds 4-11, 13-20, and 22-28. Half of the compounds thus obtained were novel compounds (Compounds 4, 5 and 6 are reported by reference [17]; Compounds 7, 13 and 16 are reported by reference [18]; Compounds 10 and 17 are reported by reference [19]; Compounds 22, 25 and 27 are reported by reference [20]). The spectral data of the synthesized known compounds were consistent with the previously described papers [17-20]. The yield, melting point, and nuclear magnetic data of the new target compounds are shown below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium carbonate In acetone at 80℃; | Synthesis of target compounds 4-11, 13-20, and 22-28 General procedure: 7-Hydroxy-2H-chromen-2-one/4-hydroxy-2H-chromen-2- one/7-hydroxy-3,4-dihydroquinolin-2(1H)-one (10.0 mmol), K2CO3 (10.0 mmol), and 50 ml acetone were combined in a 100 ml round-bottomed flask, and the resulting mixture was stirred for 6-12 h at 80 C. After the reaction was completed (TLC), the mixture was poured into water (50 ml), and then extracted with CH2Cl2. The combined organic extracts were washed with water, dried (MgSO4), and concentrated to dryness in vacuum. The residue was purified by chromatography on silica gel, eluting with CH2Cl2, to extract target compounds 4-11, 13-20, and 22-28. Half of the compounds thus obtained were novel compounds (Compounds 4, 5 and 6 are reported by reference [17]; Compounds 7, 13 and 16 are reported by reference [18]; Compounds 10 and 17 are reported by reference [19]; Compounds 22, 25 and 27 are reported by reference [20]). The spectral data of the synthesized known compounds were consistent with the previously described papers [17-20]. The yield, melting point, and nuclear magnetic data of the new target compounds are shown below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | EDCI (2.0 eq) was added to a solution of 1-carboxymethyl 5-fluorouracil 2 (0.2 g, 1.0 eq) and DMAP (0.03 eq) in dry DMF(2 ml) under a nitrogen atmosphere and the reaction mixture wasstirred at r.t. until the consumption of the starting material (TLCmonitoring). Thereafter 7-hydroxycoumarin 11b (1.5 eq)was addedto the reaction mixture, that was stirred at r.t. until the disappearanceof the 1-carboxymethyl 5-fluorouracil was observed (TLCmonitoring) and then quenched with ice and sodium bicarbonate.The collected, water-washed precipitate triturated with ethylacetateto afford the pure titled compound 12b as a powder. 15%yield; m.p. 270e272 C; silica gel TLC Rf 0.45 (MeOH/CH2Cl2 20% v/v); dH (400 MHz, DMSO-d6): 12.08 (s, 1H, exchange with D2O,CONHCO), 8.17 (d, J 6.7 Hz, 1H, AreH), 8.09 (d, J 9.6 Hz, 1H,AreH), 7.80 (dd, J 17.8, 8.5 Hz, 1H, AreH), 7.30 (s, 1H, AreH), 7.21(dd, J 8.5, 2.2 Hz, 1H, AreH), 6.51 (d, J 9.6 Hz, 1H, AreH), 4.78 (d,J 32.0 Hz, 2H, CH2); dC (100 MHz, DMSO-d6): 167.62, 160.66,158.47 (d, J2 CF 25.8 Hz),155.16,153.26,150.77,144.80,140.57 (d, J2CF 230.2 Hz), 131.21 (d, J2 CF 34.7 Hz), 130.69, 119.25, 118.16,116.95, 110.76, 49.85; dF (376 MHz, DMSO-d6): 169.21; m/z (ESInegative) calcd for C15H8FN2O6 [M H]- 331.0, found 331.0. |
Tags: 93-35-6 synthesis path| 93-35-6 SDS| 93-35-6 COA| 93-35-6 purity| 93-35-6 application| 93-35-6 NMR| 93-35-6 COA| 93-35-6 structure
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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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