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CAS No. : | 637-88-7 | MDL No. : | MFCD00001606 |
Formula : | C6H8O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DCZFGQYXRKMVFG-UHFFFAOYSA-N |
M.W : | 112.13 | Pubchem ID : | 12511 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 29.24 |
TPSA : | 34.14 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.44 cm/s |
Log Po/w (iLOGP) : | 0.95 |
Log Po/w (XLOGP3) : | -0.64 |
Log Po/w (WLOGP) : | 0.7 |
Log Po/w (MLOGP) : | -0.04 |
Log Po/w (SILICOS-IT) : | 1.8 |
Consensus Log Po/w : | 0.55 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.13 |
Solubility : | 82.7 mg/ml ; 0.738 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.4 |
Solubility : | 279.0 mg/ml ; 2.49 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -1.26 |
Solubility : | 6.09 mg/ml ; 0.0543 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.29 |
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% | Stage #1: With sodium hydride In tetrahydrofuran at 0 - 5℃; for 1 h; Stage #2: at 20℃; for 16 h; |
Step 1: (1,4-Dioxa-spiro[4.5]dec-8-ylidene)-acetic acid ethyl ester Triethyl phosphonoacetate (1.14 ml, 7.04 mmol) was dissolved in 15 ml THF and cooled to 0-5° C. Sodium hydride (310 mg, 7.04 mmol, 55percent) was added and the reaction mixture stirred for 1 hour at 0-5° C. 1,4-Cyclohexanedione (1.0 g, 6.40 mmol) dissolved in 10 ml THF was added drop wise and stirred for 16 hours at room temperature. The reaction mixture was quenched with saturated NaHCO3-solution and extracted two times with ethyl acetate. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10-->0:100 gradient). The desired compound was obtained as a colourless liquid (1.10 g, 76percent), MS: m/e=227.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With 1-methyl-1H-imidazole; selenium(IV) oxide; dihydrogen peroxide In ethyl acetate | Example 31 Into a 50 ml flask equipped with a magnetic stirrer and a reflux condenser, 110 mg of selenium dioxide, 500 mg of N-methylimidazole and 1.06 g of 42percent by weight aqueous tetrafluoroboric acid solution were charged and the resulting mixture was stirred at room temperature for 10 minutes to obtain a homogeneous solution containing a selenium-containing oxidation catalyst composition. To the homogeneous solution, 1.13 g of 30percent by weight aqueous hydrogen peroxide solution and 1.12 g of 1,4-cyclohexanedione were charged and the reaction was conducted at an inner temperature of 60°C for 1 hour. After competition of the reaction, 10 g of ethyl acetate was added to the reaction mixture to separate to an aqueous layer containing the selenium-containing oxidation catalyst composition and an ethyl acetate layer containing oxygen-containing compounds. The aqueous layer containing the selenium-containing oxidation catalyst composition was extracted twice with ethyl acetate to obtain an organic layer and an aqueous layer containing the selenium-containing oxidation catalyst composition. The organic layer obtained was mixed with the ethyl acetate layer obtained before to obtain an ethyl acetate layer containing 3-oxocyclopentanecarboxylic acid. Yield: 44percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5% | With sulfuric acid In water at 90℃; | Example 1; 3,3-Dimethyl-l,5-dioxaspiro[5.5]undecan-9-one.; A continuous extraction apparatus is assembled. A 500 mL extraction solvent pot is charged with 250 mLπ-hexane and 5.00 g sodium bicarbonate. An oil bath is heated to 90°C. A 500 mL reaction pot is charged with 82.5 g (0.792 mol, 2.33 equiv) neopentyl glycol, 338 mLH20, 0.79 mL (1.45 g, 14.8 mmol, 4.35 molpercent) of 98percent sulfuric acid, and 38.08 g (0.340 mol) of 1,4-cyclohexanedione. π-Hexane (85 mL) is then added to bring the pot volume to the extractor return sidearm. The extraction pot is immediately immersed in the oil bath and the reaction mixture stir rate is increased to the point where there is efficient mixing in the lower (aqueous) phase but not in the upper (π-hexane) phase in the extractor. The extraction is continued for 99 h.The suspension is cooled to 25°C and the precipitate is suction filtered, washed with 50 niLπ-hexane, and air dried 2 h at 25°C to afford 10.71 g of crude bisketal as a colorless solid. The bulk of the π-hexane is distilled from the combined mother liquors and the resulting suspension is cooled (95 g). Methanol (250 mL) is added and 163 mL of a mixture of the methanol-hexane azeotrope (28:72) and methanol are distilled to a head temperature of 60°C (bath 90°C). The suspension (168 g) is cooled to 25°C and water (100 mL) is added dropwise over 10 min. After stirring overnight, the precipitate is suction filtered, and air dried several h at 25°C to afford 7.22 g of additional crude bisketal as a colorless solid.The mother liquors are concentrated by distillation (dry ice-acetone cold finger condenser) at 30-35°C and 40-45 mm Hg ( 146 mL distillate collected) . The resulting suspension is cooled to 0-5°C and stirred for 90 min. The precipitate is suction filtered (mother liquors are used to complete the transfer) and air dried 24 h at 25°C to afford 50.17 g (74.5percent) of the monoketal 54 as a colorless solid.The combined crude bisketal crops ( 17.62 g) are resuspended in 200 mL water and stirred for I h. The insoluble material is suction filtered and air dried 6 h at 25°C to afford 13.06 g of bisketal as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydroxide; ethanol; water; at 28 - 47℃; for 4h; | Preparatory Example 1; Preparation of pentacene-6,13-dione.; A solution of 62.7 grams (0.559 mmoles, 1.0 equivalents) of cyclohexan-1,4-dione and 150 grams of o-phthalaldehyde (1.12 mmoles, 2.0 equivalents) in 2000 mL of ethanol was heat to 28 C. To this solution was added 220 mL of a 1M aqueous solution of sodium hydroxide. The reaction temperature increased to 47 C. during the addition. The mixture was then heated at 40 C. for 4 hours. The mixture was cooled and a yellow solid precipitate was collected. The solid was stirred in 2000 mL of N,N-dimethylformamide and heated to 50 C. for 2 hours. The mixture was cooled to room temperature (i.e., 20 C. to 25 C.) and the yellow solid was collected and washed with N,N-dimethylformamide, then with acetone and dried to give 108.3 grams (62 mole percent yield) of a bright yellow solid. |
With potassium hydroxide; In ethanol; at 0 - 60℃; for 2h; | A mixture of 1,4- cyclohexanedione (33.0 mmol) and potassium hydroxide (132 mmol) were dissolved in ethanol and solution was cooled to 0 C. Then o-phthalaldehyde (66.0 mmol) was added to the solution. The reaction mixture was stirred for 1 h at 0 C, and for an additional 1 h refluxed at 60 C. The product was filtered and washed thoroughly with water and ethanol [34] (Fig. 3). H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylmethylammonium chloride; at 50℃; for 1h; | Take 19.7 g of methyltriethylammonium chloride,Add 62g of ethylene glycol,Heat to 50 C,A colorless, transparent liquid is obtained. 11.2 g of 1,4-cyclohexanedione was weighed and added to the colorless transparent liquid, and reacted at 50 C for 1 h. After the reaction was completed, the temperature was lowered to room temperature, and 56 g of diethyl ether was added thereto to extract, the lower layer solution was taken, and the solvent was evaporated to give a white solid (15.6 g).The content of 1,4-cyclohexanedione monoethylene glycol ketal was 96.1%, and the yield was 96.0%. |
toluene-4-sulfonic acid; In toluene;Reflux; | The synthesis of 2-(4-ammo-l-(34-hydroxycyclohexyl)-lH-pyrazolo [3, 4-d]py?midm-3- yl)-lH-mdol-5-ol (Compound 14-9) is described m Scheme 14. 1, 4 cyclohexyldione is selectively monoketahzed, then the remaining ketone is reduced with sodium borohydride to yield compound 14-3. The hydroxyl is converted to the tosylate (compound 14-4), which is then reacted with pyrazolopy?midme iodide 1-3, to produce compound 14-5. The ketone of the cyclohexyl moiety is unmasked with acid treatment and reduced to hydroxy compound 14-7. Palladium catalyzed coupling with mdolyl boronic acid and subsequent deprotection affords compound 14-9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With Candida parapsilosis ATCC 7330 whole cells; In ethanol; water; at 25℃; for 8h;pH 6.8;Microbiological reaction; | General procedure: At first, 10 g of wet cells of Candida parapsilosis ATCC 7330 suspendedin 10 mL of water, and 40 mg (0.2 mmol) of benzil 1a dissolvedin 1 mL of dioxane (for other diketones ethanol was used) asa cosolvent were added into the cell suspension and incubated at25 C, 200 rpm for 8 h in a water bath shaker. The reaction was carriedout in triplicate. Control experiments were carried out in parallel without the whole cells and with heat treated cells underidentical conditions. In order to determine the isolated chemicalyield, the asymmetric reduction of 1a was carried out with80 mg of the substrate, wet cells and cosolvent were taken accordingly. After completion of the reaction the product 2a was extracted with ethyl acetate (3 10 mL) and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product obtained was purified by column chromatographyusing hexane/ethyl acetate (75:25) as the mobile phase to give 2a in 75% yield as a colourless solid. The ee was foundto be 98%, as determined by HPLC OD-H column using 9:1 hexane/isopropanol mixture. The specific rotation of 2a [a]D25 = +71.2 (c0.25, acetone) for 98% ee} was compared with the literature value to assign the absolute configuration, and it was found be (S). The same procedure was followed for the remaining diketones 1b-1j. The spectroscopic data of 2a, 2b, 2c, 2d, 2e, 2g and2h were in accordance with the literature values. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium hydroxide; In ethanol; water; at 20℃; for 3h;Reflux; | 2,3,9,10-Tetrachloro-6,13-pentacenequinone 4,5-Dichlorobenzene-1,2-dicarbaldehyde (2.0 g, 9.90 mmol) and 1,4-cyclohexanedione (0.62 g, 5.53 mmol) were stirred in 60 mL ethanol. To this was added dropwise with stirring, 10 mL of 5% aq potassium hydroxide. Upon addition of first drop, solution became black, brown, and then solids precipitate. Reaction mixture was stirred at RT for 1 h and refluxed for 2 h. Reaction mixture was cooled to RT, solids filtered, washed with water, dried to give 2,3,9,10-tetrachloro-6,13-pentacenequinone as brown solids in good yields (1.73 g, 70%). LDI-MS m/z: 446 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
hydrogenchloride; In water; acetonitrile; at 5℃; | Solution of allylic alcohol 1b (1 g, 6.75 mmol) and methylene blue (30 mg) in acetonitrile (100 ml) maintained at 0 C., was irradiated with 500 W tungsten-halogen lamp while oxygen was bubbled slowly into reaction mixture for 4 h <strong>[637-88-7]1,4-Cyclohexanedione</strong> (1.15 g, 10.13 mmol) and concd HCl (5 drops) were added and the reaction mixture was left at 5 C. overnight. Reaction mixture was concentrated under reduced pressure and residue taken up in ether (100 ml) was washed with sat. aq NaHCO3 (30 ml). The aqueous layer was extracted with ether (2*75 ml), combined ether layer dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using EtOAc-hexane (5:95) as eluant to furnish trioxane 3b (0.65 g, 42% yield, based on allylic alcohol 1b used), m.p. 104-105 C. | |
hydrogenchloride; In water; acetonitrile; at 5℃; | A solution of allylic alcohol Ib (1 g, 6.75 mmol) and methylene blue (30 mg) in acetonitrile (100 ml) maintained at 0C, was irradiated with a 500 W tungsten-halogen lamp while oxygen was bubbled slowly into the reaction mixture for 4 h. <strong>[637-88-7]1,4-Cyclohexanedione</strong> (1.15 g, 10.13 mmol) and coned HCl (5 drops) were added and the reaction mixture was left at 5C overnight. Reaction mixture was concentrated under reduced pressure and residue taken up in ether (100 ml) was washed with sat. aq NaHCO3 (30 ml). The aqueous layer was extracted with ether (2 x 75 ml), combined ether layer dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using EtOAc-hexane (5:95) as eluant to furnish trioxane 3b (0.65 g, 42 % yield, based on allylic alcohol Ib used), m.p. 104-1050C. | |
With hydrogenchloride; In dichloromethane; water; acetonitrile; at 0℃; for 18h; | Allylic alcohol 1b was prepared according to the reported procedure (Singh, C.; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1N02/00093, dated Mar. 28, 2002). A solution of allylic alcohol of 1b (1 g) and methylene blue (10 mg) in CH2Cl2: MeCN (1:4, 50 mL) was photooxygenated at -10 C. to 0 C. for 4 h to give beta-hydroxyhydroperoxide 2b which was reacted in situ with 1,4-cyclohexanedione (1 g) in presence of concd HCl (5 drops) for 18 h at 0 C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3b (0.65 g, 42% yield, based on allylic alcohol 1b used), m.p. 104-105 C. |
hydrogenchloride; In dichloromethane; water; acetonitrile; at 0℃; for 18h; | Allylic alcohol 1b was prepared according to the reported procedure (Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT/1 N02/00093, dated 28.3.2002). A solution of allylic alcohol of 1b (1g) and methylene blue (10 mg) in CH2CI2 : MeCN (1 :4, 50 mL) was photooxygenated at -1O0C to O0C for 4h to give beta- hydroxyhydroperoxide 2b which was reacted in situ with 1 ,4-cyclohexanedione (1g) in presence of coned HCI (5 drops) for 18h at 0C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3b (0.65 g, 42% yield, based on allylic alcohol 1b used), m.p. 104-105C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With ozone; In dichloromethane; pentane; at 0 - 20℃;Inert atmosphere; | General procedure: Trioxolanes were prepared by coupling O-methyl-2-adamantanone oxime (2) with a cyclohexanone derivative, through ozonolysis.Ozone, produced with an ozone generator Sander Labor-Ozonizator 301.7 (0.5 L/min O2, 140 V), was passed through a solution of dichloromethane at -78C and flushed into a solution of O-methyl ketone oxime and a ketone, in pentane/dichloromethane (6:4) at 0C. After completion, the solution was flushed with nitrogen for 5 min and concentrated under reduced pressure at room temperature to give a crude material that was purified by column chromatography. |
29% | With ozone; In dichloromethane; pentane; at 0℃; for 1h; | O-methyl 2-adamantanone oxime (4.5 g, 25 mmol) and 1 ,4 cyclohexanedione (5.6 g, 50 mmol) were dissolved in a solvent mixture of pentane: dichloromethane (1 :1.5). The flask was cooled to 0 0C and ozone gas was bubbled through the reaction mixture for 1 hr. The reaction was monitored using TLC (10 % ethyl acetate:hexane). After completion the solvent was evaporated and the residue purified immediately using silica gel chromatography (10 % ethyl acetate:hexane) to afford the title compound as a white solid. Yield: 2.0 g (29%). MS (m/z): (M+ Na+) = 301. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; at 20℃; for 3h; | To a solution of thiophene-2,3--dicarboxaideliyde (2.0 g, 17.2 mmol) in 200 mL of EtOH was stirred at room temperature followed by addition of 1,4-cyciohexane dione (0,96 g, 8.6 mmoi). Afterwards, a solution of 15% KOhl was added to the reaction mixture to form brown precipitate. The resulting reaction mixture was stirred for an additional 3h and then filtered to obtain a pale yellow powder in quantitative yield. Compounds 4 and 6 could not he charactenzed due to their poor soiubhty in common organic solvents. HR-mass spectroscopy confirmed formation of the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
hydrogenchloride; In water; acetonitrile; at 5℃; | Solution of allylic alcohol 1e (1 g, 6.16 mmol) ad methylene blue (30 mg) in acetonitrile (100 ml) maintained at 0 C. was irradiated with a 500 W tungsten-halogen lamp while oxygen was bubbled slowly into reaction mixture for 4 h. <strong>[637-88-7]1,4-Cyclohexanedione</strong> (1.15 g, 10.13 mmol) and concd HCl (5 drops) were added and reaction mixture was left at 5 C. overnight. Reaction mixture was concentrated under reduced pressure and residue taken up in ether (100 ml) was washed with sat. aq NaHCO3 (30 ml). The aqueous layer was extracted with ether (2*75 ml), combined ether layer dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using EtOAc-hexane (5:95) as eluant to furnish trioxane 3e (0.58 g, 32.7% yield, based on allylic alcohol 1e used), m.p. 66-68 C. | |
hydrogenchloride; In water; acetonitrile; at 5℃; | A solution of allylic alcohol Ie (1 g, 6.16 mmol) and methylene blue (30 mg) in acetonitrile (100 ml) maintained at O0C was irradiated with a 500 W tungsten-halogen lamp while oxygen was bubbled slowly into the reaction mixture for 4 h. <strong>[637-88-7]1,4-Cyclohexanedione</strong>(1.15 g, 10.13 mmol) and coned HCl (5 drops) were added and the reaction mixture was left EPO <DP n="20"/>at 5C overnight. Reaction mixture was concentrated under reduced pressure and residue taken up in ether (100 ml) was washed with sat. aq NaHCO3 (30 ml). The aqueous layer was extracted with ether (2 x 75 ml), combined ether layer dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using EtOAc-hexane (5:95) as eluant to furnish trioxane 3e (0.58 g, 32.7 % yield, based on allylic alcohol Ie used), m.p. 66-680C. | |
With hydrogenchloride; In water; acetonitrile; at 0℃; for 18h; | Allylic alcohol 1e was prepared according to the reported procedure (Singh, C. Tetrahedron Lett. 1990, 31, 6901). A solution of allylic alcohol of 1e (1 g) and methylene blue (10 mg) in MeCN (50 mL) was photooxygenated at -10 C. to 0 C. for 4 h to give beta-hydroxyhydroperoxide 2e which was reacted in situ with 1,4-cyclohexanedione (1.38 g) in presence of concd HCl (5 drops) for 18 h at 0 C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3e (0.58 g, 32.7% yield, based on allylic alcohol 1e used), m.p. 66-68 C. |
hydrogenchloride; In water; acetonitrile; at 0℃; for 18h; | Allylic alcohol 1e was prepared according to the reported procedure (Singh, C. Tetrahedron Lett. 1990, 31, 6901). A solution of allylic alcohol of 1e (1 g) and methylene blue (10 mg) in MeCN (50 mL) was photooxygenated at -1O0C to O0C for 4h to give beta-hydroxyhydroperoxide 2e which was reacted in situ with 1 ,4- cyclohexanedione (1.38 g) in presence of coned HCI (5 drops) for 18h at O0C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3e (0.58 g, 32.7% yield, based on allylic alcohol 1e used), m.p. 66-68C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
hydrogenchloride; In water; acetonitrile; at 5℃; | Solution of allylic alcohol 1c (1 g, 5.47 mmol) and methylene blue (30 mg) in acetonitrile (100 ml) maintained at 0 C., was irradiated with 500 W tungsten-halogen lamp while oxygen was bubbled slowly into reaction mixture for 4 h. <strong>[637-88-7]1,4-Cyclohexanedione</strong> (1.22 g, 10.95 mmol) and concd HCl (5 drops) were added and the reaction mixture was left at 5 C. overnight. Reaction mixture was concentrated under reduced pressure and residue taken up in ether (100 ml) was washed with sat. aq NaHCO3 (30 ml). The aqueous layer was extracted with ether (2*75 ml), combined ether layer dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using EtOAc-hexane (5:95) as eluant to furnish trioxane 3c (0.64 g, 38% yield, based on allylic alcohol 1c used), m.p. 72-74 C. | |
hydrogenchloride; In water; acetonitrile; at 5℃; | A solution of allylic alcohol Ic (1 g, 5.47 mmol) and methylene blue (30 mg) in acetonitrile (100 ml) maintained at 00C, was irradiated with a 500 W tungsten-halogen lamp while oxygen was bubbled slowly into the reaction mixture for 4 h. <strong>[637-88-7]1,4-Cyclohexanedione</strong> (1.22 g, 10.95 mmol) and coned HCl (5 drops) were added and the reaction mixture was left at 5C overnight. Reaction mixture was concentrated under reduced pressure and residue taken up in ether (100 ml) was washed with sat. aq NaHCO3 (30 ml). The aqueous layer was extracted with ether (2 x 75 ml), combined ether layer dried over anhyd. Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel using EtOAc-hexane (5:95) as eluant to furnish trioxane 3c (0.64 g, 38 % yield, based on allylic alcohol Ic used), m.p. 72-740C | |
With hydrogenchloride; In water; acetonitrile; at 0℃; for 18h; | Allylic alcohol 1c was prepared according to the reported procedure (Singh, C. Tetrahedron Lett. 1990, 31, 6901). A solution of allylic alcohol of 1c (1 g) and methylene blue (10 mg) in MeCN (50 mL) was photooxygenated at -10 C. to 0 C. for 4 h to.give beta-hydroxyhydroperoxide 2c which was reacted in situ with 1,4-cyclohexanedione (1.22 g) in presence of concd HCl (5 drops) for 18 h at 0 C. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography on silica gel to furnish trioxane 3c (0.64 g, 38% yield, based on allylic alcohol 1c used), m.p. 72-74 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Preparation of 7,8, 15 , 16-Tetraoxa-dispiro[5.2.5.2]hexadecan-3 -one 10; A solution of (0.12g, 2mmol) of cyclohexanone 6, (0.05g, 4mmol) of 30% H2O2 and (0.0005g, 0.002mmol) of methyltrioxorhenium (MTO) in 4ml of 2,2,2- trifluoroethanol (TFE) was stirred for 2 hours at room temperature. Into the solution, (0.4485g, 4mmol) of 1,4-cyclohexanedione 9 was added, followed by the addition of (0.095g, 2mmol) of 54% ethereal solution of tetrafluoroboric acid. The reaction mixture was left under stirring for an additional hour. Dichloromethane was added and the organic phases washed wish diluted NaHSO4, dried over MgSO4 and solvent evaporated under reduced pressure. Products were determined by NMR spectroscopy, isolated by column chromatography (SiO2, CH2Cl2: Hexane = 9:1) to give the tetraoxane in 38%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5% | With sulfuric acid; In water; at 90℃; | Example 1; 3,3-Dimethyl-l,5-dioxaspiro[5.5]undecan-9-one.; A continuous extraction apparatus is assembled. A 500 mL extraction solvent pot is charged with 250 mL?-hexane and 5.00 g sodium bicarbonate. An oil bath is heated to 90C. A 500 mL reaction pot is charged with 82.5 g (0.792 mol, 2.33 equiv) neopentyl glycol, 338 mLH20, 0.79 mL (1.45 g, 14.8 mmol, 4.35 mol%) of 98% sulfuric acid, and 38.08 g (0.340 mol) of 1,4-cyclohexanedione. ?-Hexane (85 mL) is then added to bring the pot volume to the extractor return sidearm. The extraction pot is immediately immersed in the oil bath and the reaction mixture stir rate is increased to the point where there is efficient mixing in the lower (aqueous) phase but not in the upper (?-hexane) phase in the extractor. The extraction is continued for 99 h.The suspension is cooled to 25C and the precipitate is suction filtered, washed with 50 niL?-hexane, and air dried 2 h at 25C to afford 10.71 g of crude bisketal as a colorless solid. The bulk of the ?-hexane is distilled from the combined mother liquors and the resulting suspension is cooled (95 g). Methanol (250 mL) is added and 163 mL of a mixture of the methanol-hexane azeotrope (28:72) and methanol are distilled to a head temperature of 60C (bath 90C). The suspension (168 g) is cooled to 25C and water (100 mL) is added dropwise over 10 min. After stirring overnight, the precipitate is suction filtered, and air dried several h at 25C to afford 7.22 g of additional crude bisketal as a colorless solid.The mother liquors are concentrated by distillation (dry ice-acetone cold finger condenser) at 30-35C and 40-45 mm Hg ( 146 mL distillate collected) . The resulting suspension is cooled to 0-5C and stirred for 90 min. The precipitate is suction filtered (mother liquors are used to complete the transfer) and air dried 24 h at 25C to afford 50.17 g (74.5%) of the monoketal 54 as a colorless solid.The combined crude bisketal crops ( 17.62 g) are resuspended in 200 mL water and stirred for I h. The insoluble material is suction filtered and air dried 6 h at 25C to afford 13.06 g of bisketal as a colorless solid. |
sulfuric acid; In dichloromethane; at 10 - 20℃; | [0030] 1,4 cyclohexane dione (20.0 grams) and neopentyl glycol (18.6 grams) were dissolved in dichloromethane (160 ml). Then sulfuric acid (3.2 grams) was added to the reaction solution at an ambient temperature and stirred till the reaction substantially completes, accompanied by cooling the reaction mixture to 10-20 C. The resulting reaction mixture was washed with saturated aqueous sodium bicarbonate solution (80 ml) and separated the organic layer from the resulting biphasic mixture. The solvent was distilled off from organic layer till substantial completion under reduced pressure. Hexane (200 ml) was added to the resulting residual mass and followed by cooling the reaction mass to a temperature of 0-5 C. to filter the by-products. Then the solvent from the filtrate was distilled off till the substantial completion under vacuum to yield the desired 1,4 cyclohexanedione mono-2,2-dimethyl trimethylene ketal. [0031] (Weight: 22.9 grams) EXAMPLE 3 [0034] 1,4 cyclohexane dione (25.0 grams) and neopentyl glycol (23.5 grams) were dissolved in dichloromethane (200 ml). Then sulfuric acid (4.0 grams) was added to the reaction solution at an ambient temperature and stirred till the reaction substantially completes, accompanied by cooling the reaction mixture to 10-20 C. The resulting reaction mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) and separated the organic layer from the resulting biphasic mixture. The solvent was distilled off from organic layer till substantial completion under reduced pressure. n-Heptane (250 ml) was added to the resulting residual mass and followed by cooling the reaction mass to a temperature of 0-5 C. to filter the by-products. Then the solvent from the filtrate was distilled off till the substantial completion under vacuum to yield the desired 1,4 cyclohexanedione mono-2,2-dimethyl trimethylene ketal. [0035] (Weight: 30.0 grams). | |
sulfuric acid; In chloroform; at 10 - 20℃; | [0032] 1,4 cyclohexane dione (25.0 grams) and neopentyl glycol (23.5 grams) were dissolved in chloroform (200 ml). Then sulfuric acid (4.0 grams) was added to the reaction solution at an ambient temperature and stirred till the reaction substantially completes, accompanied by cooling the reaction mixture to 10-20 C. The resulting reaction mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) and separated the organic layer from the resulting biphasic mixture. The solvent was distilled off from organic layer till substantial completion under reduced pressure. Hexane (250 ml) was added to the resulting residual mass and followed by cooling the reaction mass to a temperature of 0-5 C. to filter the by-products. Then the solvent from the filtrate was distilled off till the substantial completion under vacuum to yield the desired 1,4 cyclohexanedione mono-2,2-dimethyl trimethylene ketal. [0033] (Weight: 29.0 grams) |
With sulfuric acid; In dichloromethane; | Reference example- 1:Preparation of 4-Methylaminocyclohexanone (2',2'-dimethyltrimethylene) ketal hydrochloride:1,4 cyclohexane dione (200 grams) was dissolved in MDC. To this con sulfuric acid was added followed by the addition of neopentyl glycol in dichloromethane. After completion of the reaction, sodium bicarbonate was added and stirred. Organic layer was filtered and the filtrate was distilled under vacuum then work up carried out using petroleum ether to filter the by-products. To the reaction mass methanol was added and un-dissolved material was filtered. To the filtrate, methanol was added followed by the addition of methanolic methylamine. This solution was charged with Pd/C and was hydrogenated. The reaction mass filtered and to the filtrate IPA was added, it was distilled to reach 2V. To this IPA was added followed by the addition of IPA.HC1. The product obtained was filtered and washed with IPA then dried. The dried product was slurried with THF at 25-35 for 30-45 min. The solid obtained was filtered and washed with THF then suck dried to yield the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.5% | palladium/active carbon; In ethanol; at 50 - 60℃; for 8h; | 1.00 g of 1-methylpiperadine, 1.68 g of 1,4- cyclohexanedione and 40 mg of 10% palladium-carbon were heated with stirring in 40 ml of ethanol at 50C to 60C and reacted for 8 hours under air bubbling. During the reaction, ethanol was added as needed. After the completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resultant was purified by silica gel column chromatography (ethyl acetate: methanol = 3: 1) and 1. 26 g of 1- (4- hydroxyphenyl)-4-methylpiperadine was obtained (yield 65. 5%). 1H-NMR (300 MHz, CDCl3) bppm : 2.37 (3H, s), 2.64 (4H, t-like, J = 5.1 Hz, J = 4.8 Hz), 3.10 (4H, t-like, J = 5.1 Hz, J = 4. 9 Hz), 6.78 (2H, d, J = 9.0 Hz), 6. 84 (2H, d, J = 9. 0 Hz). |
33.9% | In ethanol; at 50 - 60℃; for 8h; | 1. 00 g of 1-methylpiperadine and 2.24 g of 1,4-cyclohexanedione were heated with stirring in 15 ml of ethanol at 50C to 60C and reacted in air for 8 hours. During the reaction, ethanol was added as needed. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resultant was purified by silica gel column chromatography (ethyl acetate: methanol = 3: 1) and 0.65 g of 1- (4-hydroxyphenyl)-4-methylpiperadine was obtained (yield 33. 9%)- 1H-NMR (300 MHz, CDCl3) bppm : 2.37 (3H, s), 2.63 (4H, t-like, J = 5.1 Hz, J = 4. 9 Hz), 3.10 (4H, t-like, J = 5.1 Hz, J = 4.9 Hz), 6.74 (2H, d, J = 8.9 Hz), 6. 84 (2H, d, J = 9. 0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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27.4% | With triethylamine; In ethanol; at 50 - 60℃; for 8h; | 0.93 g of aniline, 2.24 g of 1, 4- cyclohexanedione and 1.4 ml of triethylamine were heated with stirring in 15 ml of ethanol at 50C to 60C and reacted in air for 8 hours. During the reaction, ethanol was added as needed. After concentrating the reaction mixture under reduced pressure, the resultant was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) and 0.50 g of N- (4-hydroxyphenyl) aniline was obtained (yield 27. 4%). 1H-NMR (300 MHz, CDCl3) bppm : 4.70 (1H, br), 5. 48 (1H, br), 6. 76-6. 87 (1H, m), 6.79 (2H, d, J = 9.0 Hz), 6.88-6. 92 (2H, m), 7.00-7. 06 (1H, m), 7. 03 (2H, d, J = 8. 7 Hz), 7. 18-7. 28 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
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89% | palladium/active carbon; In ethanol; at 70 - 80℃; for 9h; | 261 mg of 4- (4- trifluoromethoxyphenoxy) piperidine, 224 mg of 1,4- cyclohexanedione and 4 mg of 10% palladium-carbon were heated in ethanol and reacted at 70C to 80C for 9 hours. After the completion of the reaction, the resultant was separated by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) and 315 mg of 1- (4-hydroxyphenyl)-4- (4- trifluoromethoxyphenoxy) piperidine was obtained (yield 89%). 1H-NMR (300 MHz, CDCl3) 8ppm : 1.91-2. 01 (2H, m), 2.07-2. 15 (2H, m), 2.94-3. 02 (m, 2H), 3.32-3. 39 (2H, m), 4.37-4. 45 (1H, m), 4.7 (1H, br), 6.74-6. 79 (2H, m), 6.87-6. 94 (4H, m), 7.11-7. 17 (2H, m). |
43.8% | In ethanol; for 7h;Heating / reflux; | 261 mg of 4- (4- trifluoromethoxyphenoxy) piperidine and 224 mg of 1,4- cyclohexanedione were heated under reflux in 5 ml of ethanol and reacted for 7 hours. After concentrating the reaction mixture under reduced pressure, the resultant was separated by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) and 154.9 mg of 1- (4-hydroxyphenyl)-4- (4- trifluoromethoxyphenoxy) piperidine was obtained (yield 43. 8%). H-NMR (300 MHz, CDCl3) 8ppm : 1.91-2. 01 (2H, m), 2.07-2. 15 (2H, m), 2.94-3. 02 (m, 2H), 3.32-3. 39 (2H, m), 4.37-4. 45 (1H, m), 4.7 (1H, br), 6.74-6. 79 (2H, m), 6.87-6. 94 (4H, m), 7.11-7. 17 (2H, m). |
With triethylamine; In ethanol; at 50 - 60℃; for 6h;Product distribution / selectivity; | Reference Example 44- [4- (4-trifluoromethoxyphenoxy)piperidin-1- yljphenol-paratoluenesulfonic acid salt 4- (4-trifluoromethoxyphenoxy) piperidine (4.0 g) , 1,4- cyclohexanedione (2.575 g) and triethylamine (2.16 mL) were dissolved in ethanol (60 mL) , and the obtained mixture was heated at 50 to 60C, and reacted for 6 hours under air bubbling. After the reaction, the solvent was distilled off under reduced pressure; ethyl acetate (20 mL) and paratoluenesulfonic acid monohydrate (4.'37 g) were added to the obtained residue; the obtained mixture was cooled, and stirred for 1 hour. The precipitated crystal was filtered, and washed with a small amount of ethyl acetate, and then dried at room temperature to obtain a target compound as a light yellow powder crystal. The yield amount was 4.465 g (55.5%) . Melting point: 211 to 214C (decomposing) <n="35"/>Purity (HPLC): 82.52%HPLC conditions column: COSMOSIL5C8-MS (4.6phi x 250 mm); detection wavelength: 275 nm; elution condition 1: methanol/0.1M ammonium acetate aqueous solution=50/50 (400C); elution condition 2: methanol/0. IM ammonium acetate aqueous solution =800/200; purity =100- (the sum total of impurities detected on elution conditions 1 and 2)1H-NMR (DMSO-d6 measurement temperature 700C); 2.05(2H,m), 2.23(2H,m), 2.28(3H,s), 3.48 (2H,m),3.59(2H,m), 4.71(lH,m), 6.87(2H,m), 7.09 (2HNo.m) ,7.13(2H,m), 7.28(2H,m), 7.38(2H,m), 7.50(2H,m)IR(KBr^m"1) ; 2714,1506,1288,1217,1033,813This compound could be further purified by recrystallizing from a mixed solution of ethyl acetate of ten-times volume and water of two-times volume, and drying at 600C.Form: colorless scaly crystalPurity (HPLC): 99.8% (HPLC conditions were the same as the above)Melting point of its pure product: 218.1 to 219.3C(decomposing) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In toluene; | 4,4'-dibromotriphenylamine: A mixture of 4,4'-dibromodiphenylamine (7.3 g. 22 mmol), cyclohexane-1,4-dione (2.5 g., 23.3 mole), para-toluenesulfonic acid (0.1 g.) and toluene (100 ml) was kept at reflux with a Dean-Stark phase separator containing 4A molecular sieves. After 18 hours at reflux, the reaction was diluted with toluene, and the toluene solution was washed with water, dried and concentrated. The residue was dissolved in hexanes, and the hexanes solution was passed through a column of silica gel to afford 4,4'-dibromotriphenylamine as a colorless glass, 5.04 g., 67% yield. Mass Spec (m/z): 401, 403, 405 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.8% | In a 1000 mL 4-neck glass reactor fitted with a stirrer, a N2 inlet tube, a Claisen adapter with a thermocouple plunging in the reaction medium, and a Barrett trap with a condenser were introduced successively : 500.00 g phenol (5.31 mol), 1.336 g 1-octanethiol (0.009 mol), 110.72 g aluminum chloride (0.830 mol) and 59.43 g methanol (1.855 mol). The reactor was sealed and under nitrogen and was heated up to 50C. Using a powder dispenser, 37.230 g of 1,4-cyclohexanedione (0.332 mol) were added to the mixture over a period of 2 hours. The mixture was held at 50C for 7 hours. (0172) Providing cooling with an ice batch, 132.80 g of sodium hydroxide, 370.00 g water and 1.700 g of palladium on carbon and 78.47 g (0173) a-methylstyrene (0.664 mol) were added slowly to the mixture. (0174) The mixture was then transferred to a Parr reactor, the air in the reactor was evacuated by 3 pressure / depressure cycles with nitrogen, and the temperature was increased to 260C under autogeneous pressure and held at temperature for 6 hours. When the mixture had cooled down, (0175) l, :4',l"-terphenyl-4,4"-diol was extracted from the reaction mixture upon addition of methylisobutylketone, acetic acid and water. (0176) The corresponding yield is shown in Table 1. | |
With hydrogenchloride; sodium hydroxide;palladium-carbon; palladium; In water; acetic acid; | Example 3 'One-pot' process synthesis of 4,4§-dihydroxy-p-terphenyl To a 1 l three-necked flask fitted with nitrogen inlet, stirrer, thermometer and long air condenser was charged 1,4- cyclohexadione (0.40 mole, 44.8g) and phenol (6.4 mole, 600g). The mixture was heated to 50C to form a solution and concentrated hydrochloric acid (sg = 1.18) (20 ml) was added. The mixture was then stirred at 50C for 7.0 hours. Sodium hydroxide (0.75 mole, 30g) and 5% palladium on carbon (2.0g) was added and with the condenser arranged for distillation, low boiling materials were removed (ca 50 ml) until the pot temperature reached 180C. The mixture was then left at reflux (180-185C) for 4.0 hours, cooled to 50C and glacial acetic acid (60 ml) and water (100 ml) added. The solid product was collected, washed with water (3 x 300 ml) at 50C until the odour of phenol was no longer apparent and dried under vacuum at 100C; yield 36.7g (35.0% yield based on l,4-cyclohexadione taking into account the catalyst (2.0g)). The product was recrystallized from N-methyl pyrrolidone (NMP) (175 ml), heated to 150C and filtered to remove the Pd/C catalyst. The product was collected, washed once with cold NMP (50 ml) and twice with methanol (50 ml) dried under vacuum at 120C for 3 hrs. The yield was 24.43g and the mp was 378 - 381C. The infra red spectrum was identical with that of the product of Example 2. | |
Manufacturing of 1 ,1 ':4',1 "-terphenyl-4,4"-diol Comparative Example 1 : prepared according to example 2 from EP 0 343 798 Al In a 1000 mL 4-neck glass reactor fitted with a stirrer, a N2 inlet tube, a Claisen adapter with a thermocouple plunging in the reaction medium, and a Barrett trap with a condenser were introduced 500.00 g of phenol (5.32 mol), 19.64 g of concentrated HC1 (0.199 mol). Using a powder dispenser, 37.261 g of 1,4-cyclohexanedione (0.332 mol) were added to the mixture over a period of 2 hours. The mixture was held at 50C for 7 hours. Providing cooling with an ice batch, 24.95 g of sodium hydroxide, and 1.663 g of palladium on carbon were added slowly to the mixture. Under nitrogen the reaction mixture was then heated to 180C and held at that temperature for 4 hours during which period, 15.53 g of distillate were collected. At the end of the reaction 50 g of glacial acetic acid and 85 g of water were added, causing a solid to precipitate. The solid (4.38 g) was isolated by filtration on Buchner funnel, dried at 120C at 50 mbar and analyzed by HPLC (l,r:4',l"-terphenyl-4,4"-diol, 49 % purity, 2.5 % yield). The two liquid phases (filtrate) were separated in a separation funnel and the organic phase (1309.99 g) was analyzed by HLPC to contain 0.13 % of l,l ei henyl-4,4"-diol (2.1 % yield). The total yield is thus 4.6 % yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 12h; | To a solution of bis-trioxane diol (50 mg, 0.08 mmol) in CH2Cl2 (3 mL) was added 1,4-cyclopentanedione (90 mg, 0.80 mmol) and/7-toluenesulfonic acid monohydrate (TsOH-H2O5 3 mg, 0.02 mmol). The reaction was stirred at room temperature for 12 h. The reaction was quenched with saturated aq NaHCO3 (5 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic solution was washed with brine, dried over MgSO4 and concentrated in vacuo. The purification of the crude product by column chromatography (elution with 25% EtOAc in Hexanes) gave LH-isobudiol-ketal-4-one (45 mg, 78%) as a white solid: [alpha]o21 = + 70 (c = 0.75, CHCl3); mp 104-106 C; IR (thin film) 2938,2880, 2359, 2320, 1712, 1635, 1587, 1558, 1442, 1374, 1316, 1249, 1220, 1181, 1114, 1046, 1008, 959, 921, 872, 834, 747; 1H NMR (400 MHz, CDCl3) delta 5.36 (s, IH), 5.35 (s, IH), 4.59-4.54 (m, IH), 4.60 (q, J= 6.0, 8.2, 16.4 Hz, IH), 4.25 (t, J= 6.4 Hz, 1 H) 4.08 (d, J= 8.8 Hz, IH), 3.96 (d, J= 8.8 Hz, IH), 2.75 (sextet, J= 7.2 Hz, 1 H) 2.68-2.55 (m, 3H), 2.48-2.40 (m, 2 H), 2.36-2.22 (m, 3H), 2.11-1.69 (m, 15 H), 1.70-1.16 (m, 22H including s at 1.41 and d at 1.35 withJ= 10.0 Hz), 0.92-0.80 (m, 14 H including d at 0.93 with J= 6.0 Hz); 13C NMR (400 MHz, CDCl3) delta 210.8, 107.2, 103.3, 102.8, 88.8, 88.21, 83.4, 81.1, 81.0, 73.3, 72.6, 70.8, 52.4, 52.2, 44.7, 44.2. 38.22, 38.2, 37.3, 37.2, 37.1, 36.59, 36.55, 35.9, 34.7, 34.5, 34.4, 34.3, 30.9, 30.7, 30.3, 26.1, 26.0, 24.6, 24.59, 24.4, 20.2, 13.4, 13.2, 11.1; HRMS (FAB) calculated for C4oH6iOii [(M+H)+] 717.4214, found 717.4181. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 2Tetra[2,3-b:8,9-b'] dithiophene-5,13-dione and Tetra[2,3-b:9,8-b']dithiophene-5,13-dione. A 1:2 mixture of <strong>[932-41-2]2,3-thiophenedicarboxaldehyde</strong> (0.85 g, 6.07 mmol) and benzo[1,2-b]thiophene-4,5-dicarboxaldehyde (1.66 g, 8.70 mmol) was dissolved in THF (200 mL) in a 500-mL round-bottom flask with a stir bar, then 1,4-cyclohexanedione (0.83 g, 7.40 mmol) was added and the solution was stirred until uniform. After the addition of 15% KOH (2 mL), precipitate began to form immediately, and vigorous stirring was continued overnight. The solution was filtered to yield 3.87 g of a light brown powder made up of insoluble quinones which were used directly in the next step: MS (70 eV, EI) m/z 370 (100%, M+). | ||
Tetra[2,3-b:8,9-b']dithiophene-5,13-dione and Tetra[2,3 -b:9,8- b']dithiophene-5,13-dione.A 1 :2 mixture of <strong>[932-41-2]2,3-thiophenedicarboxaldehyde</strong> (0.85 g, 6.07 mmol) and benzo[1 ,2-b]thiophene-4,5-dicarboxaldehyde (1.66 g, 8.70 mmol) was dissolved in THF (200 ml) in a 500-ml round-bottom flask with a stir bar, then 1 ,4-cyclohexanedione (0.83 g, 7.40 mmol) was added and the solution was stirred until uniform. After the addition of 15 % KOH (2 ml), precipitate began to form immediately, and vigorous stirring was continued overnight. The solution was filtered to yield 3.87 g of a light brown powder made up of insoluble quinones which were used directly in the next step: MS (70 eV, El) m/z 370 (100 %, M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 1,3-cyclohexadiene (400 mg, 5 mmol) and tetraphenylporphyrine (5 mg) in dichloromethane (10 ml) is irradiated in the presence of molecular oxygen (1.15 bar) for 1 hour, at 5 C., with a white bulb (200 W). The peroxide is obtained with a quantitative yield. The unprocessed peroxide in solution in dichloromethane is placed in a bath at -70 C.; 4 molar equivalents of 1,4 cyclohexanedione (2.3 g, 20 mmol) and 0.4 equivalent of trimethylsilyl trifluoromethane sulphonate (500 mul, 2.8 mmol) are added and the reaction mixture is kept under stirring at -70 C. for 4 hours. The reaction is stopped by adding triethylamine (1000 mul). After returning to ambient temperature, the reaction medium is washed with distilled water, dried on magnesium sulphate and evaporated to dryness. Chromatography on silica column (hexane/ethyl acetate eluent, 70/30, v/v) is used to separate the two isomer trioxanes 26a and 26b (overall yield: 2%). [0257] Isomer 26a: [0258] NMR 1H (250 MHz, CDCl3) delta, ppm: 5.70 (m, 1H, H6), 5.57 (m, 1H, H7), 4.50 (m, 1H, H5), 4.25 (ddd, 1H, H10), 2.68 (m, 1H), 2.45 (m, 5H), 2.32 (m, 2H), 2.03 (m, 2H), 1.90 (m, 1H), 1.55 m, 1H). [0259] MS (DCI/NH3+) m/z (%): 241 (2), 242 (MNH4+, 100), 243 (16), 244 (5). [0260] Isomer 26b: [0261] NMR 1H (250 MHz, CDCl3) delta, ppm: 6.00 (m, 1H), 5.73 (m, 1H), 4.50 (m, 1H), 4.20 (m, 1H), 2.60-1.80 (m, 12H). [0262] MS (DCI/NH3+) m/z (%): 241 (2), 242 (MNH4+, 100), 243 (17), 244 (5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | A mixture of alpha-terpinene (420 mg, 3.0 mmol) and tetraphenylporphyrine (5 mg) in dichloromethane (5 ml) is irradiated in the presence of molecular oxygen (1.15 bar) for 7 hours, at 5 C., with a white bulb (200 W). The peroxide is obtained with a quantitative yield. The unprocessed peroxide in solution in dichloromethane is placed in a bath at -70 C.; 6 molar equivalents of <strong>[637-88-7]1,4-cyclohexadione</strong> (2.05 g, 18.3 mmol) and 0.4 equivalent of trimethylsilyl trifluoromethane sulphonate (200 mul, 1.1 mmol) are added and the reaction mixture is kept under stirring at -70 C. for 2 hours. The reaction is stopped by adding triethylamine (400 mul). After returning to ambient temperature, the reaction medium is washed with distilled water, dried on magnesium sulphate and evaporated to dryness. The functionalised trioxane 16 is purified by chromatography on silica column (hexane/ethyl acetate eluent, 85/15, v/v) (yield: 38%). [0179] NMR 1H (250 MHz, CDCl3) delta, ppm: 5.40 (m, 1H, H6), 4.00 (m, 1H, H5), 2.67 (m, 1H), 2.41 (m, 4H), 2.22 (m, 4H), 2.00 (m, 3H), 1.50 (m, 1H), 0.99 (m, 9H). [0180] MS (DCI/NH3+) m/z (%): 297 (26), 298 (MNH4+, 100), 299 (48), 300 (8), 301 (1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | A mixture of 1,4-diphenyl-1,3-cyclopentadiene (50 mg, 0.23 mmol) and tetraphenylporphyrine (5 mg) in dichloromethane (5 ml) is irradiated in the presence of molecular oxygen (1.15 bar) for 1 hour, at 5 C., with a white bulb (200 W). The peroxide is obtained with a quantitative yield. The unprocessed peroxide in solution in dichloromethane is placed in a bath at -70 C.; 10 molar equivalents of <strong>[637-88-7]1,4-cyclohexadione</strong> (260 mg, 2.3 mmol) and 0.5 equivalent of trimethylsilyl trifluoromethane sulphonate (20 mul, 0.11 mmol) are added and the reaction mixture is kept under stirring at -70 C. for 4 hours. The reaction is stopped by adding triethylamine (40 mul). After returning to ambient temperature, the reaction medium is washed with distilled water, dried on magnesium sulphate and evaporated to dryness. The functionalised trioxane 2 is purified by chromatography on silica column (hexane/ethyl acetate eluent, 80/20, v/v) (yield: 55%). [0085] NMR 1H (250 MHz, CDCl3) delta, ppm: 7.60-7.30 (m, 10H, H-phenyl), 6.35 (d, JHH=1.6 and 4.0 Hz, 1H, H6), 5.26 (s large, 1H, H5), 3.31 and 3.05 (2×d, 2JHH=17.0 Hz, 2×1H, H2C6), 2.56-2.43 (m, 5H), 2.26 (m, 1H), 2.05 (m, 2H). [0086] MS (DCI/NH3+) m/z (6): 363 (MH+, 24), 364 (7), 380 (MNH4+, 100), 381 (27), 382 (7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.7% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 40℃; for 3h; | A 100 mL round bottom flask, equipped with stir bar, was charged with 1,4-cyclohexanedione (2.0 g, 17.84 mmol) and 3-chloroperoxybenzoic acid (4.5 g, 26.08 mmol). Dichloromethane (22 mL) was added and the reaction mixture stirred and refluxed for 3 h at 40 C. The reaction mixture was cooled to room temperature and dried with anhydrous MgSO4. Solvent was removed via rotary evaporation. The crude product was washed three times with cold diethyl ether (100 mL for each wash) and dried in vacuo at room temperature. Yield: 1.4814 g (64.7%). 1H NMR (300 MHz, CDCl3/TMS, ppm) delta: 4.4 (t, 2H, -C(O)OCH2CH2C(O)-), 2.84 (dd, 2H, -CH2C(O)O-), 2.72 (m, 4H, -CH2C(O)CH2-); 13C NMR (400 MHz, CDCl3, ppm) delta: 204.9 (-C(O)-), 173.3 (-C(O)O-), 63.3 (-CH2O-), 44.7(-OCH2CH2C(O)-), 38.6 (-C(O)CH2CH2C(O)-), 27.9 (-CH2C(O)O-). |
Yield | Reaction Conditions | Operation in experiment |
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76% | Step 1: (1,4-Dioxa-spiro[4.5]dec-8-ylidene)-acetic acid ethyl ester Triethyl phosphonoacetate (1.14 ml, 7.04 mmol) was dissolved in 15 ml THF and cooled to 0-5 C. Sodium hydride (310 mg, 7.04 mmol, 55%) was added and the reaction mixture stirred for 1 hour at 0-5 C. <strong>[637-88-7]1,4-Cyclohexanedione</strong> (1.0 g, 6.40 mmol) dissolved in 10 ml THF was added drop wise and stirred for 16 hours at room temperature. The reaction mixture was quenched with saturated NaHCO3-solution and extracted two times with ethyl acetate. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10?0:100 gradient). The desired compound was obtained as a colourless liquid (1.10 g, 76%), MS: m/e=227.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
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63.75% | 100 mg of 4- (4- trifluoromethoxyphenoxy) piperidine, 64 mg of 1,4- cyclohexanedione and 0.02 ml of triethylamine were heated in 15 ml of ethanol and reacted at 50C to 60C for 6 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and ethyl acetate was added thereto to prepare an ethyl acetate solution, to which p-toluenesulfonic acid was added. After leaving at room temperature for 30 minutes, the precipitate was filtrated and washed with ethyl acetate. The obtained crystal was air-dried and 139 mg of 1- (4-hydroxyphenyl)-4- (4- trifluoromethoxyphenoxy) piperidine p-toluenesulfonate was obtained. m. p. : 218. 9-219. 6C 1H-NMR (300 MHz, DMSO-d6) 8ppm : 1.9-2. 2 (2H, br), 2.27 (3H, s), 2.2-2. 4 (2H, br), 3.62 (2H, br), 4.77 (1H, br), 6.90 (2H, d, J = 8.9 Hz), 7.11 (2H, d, J = 7.8 Hz), 7.1-7. 2 (2H, m), 7.32 (2H, d, J = 8.9 Hz), 7. 45-7. 55 (2H, m), 7. 49 (2H, d, J = 7.9 Hz).; 4.00 g of 4- (4- trifluoromethoxyphenoxy) piperidine, 2.575 g of 1,4- cyclohexanedione and 2.16 ml of triethylamine were heated in 60 ml of ethanol and reacted at 50C to 60C for 6 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and ethyl acetate was added thereto to prepare an ethyl acetate solution, to which 4.37 g of p- toluenesulfonic acid monohydrate was added. After leaving at room temperature for 30 minutes, the precipitate was filtrated, washed with ethyl acetate and air-dried, and 5.116 g of 1- (4-hydroxyphenyl)-4- (4- trifluoromethoxyphenoxy) piperidine p-toluenesulfonate was obtained (yield 63. 75%). m. p. : 218. 9-219. 6C 1H-NMR (300 MHz, DMSO-d6) 8ppm : 1.9-2. 2 (2H, br), 2.27 (3H, s), 2.2-2. 4 (2H, br), 3.62 (2H, br), 4.77 (1H, br), 6.90 (2H, d, J, 8.9 Hz), 7.11 (2H, d, J = 7.8 Hz), 7.1-7. 2 (2H, m), 7.32 (2H, d, J = 8.9 Hz), 7.45-7. 55 (2H, m), 7.49 (2H, d, J = 7.9 Hz). | |
61.2% | A suspension in 4 ml of 90% ethanol containing 100 mg of 4- (4- trifluoromethoxyphenoxy) piperidine, 86 mg of 1,4- cyclohexanedione and 100 mg of 5% palladium-carbon (containing 54% of water) was stirred under argon stream at 70 to 80C for 10 hours. After cooling the reaction mixture to room temperature, the catalyst was removed by filtration. To the mother liquor was added 201 mg of p-toluenesulfonic acid monohydrate and the mixture was concentrated under reduced pressure. 8 ml of ethyl acetate was added to the residue and the mixture was concentrated under reduced pressure. 8 ml of ethyl acetate was further added to the residue and washing by dispersing was conducted at 70C. After ice-cooling, the precipitated crystal was filtrated, vacuum-dried at room temperature and 123 mg of 1- (4- hydroxypheriyl)-4- (4-trifluoromethoxyphe noxy) piperidine p-toluenesulfonate was obtained (yield 61. 2%). m. p. : 218.9-219. 6C H-NMR (300 MHz, DMSO-d6) 8ppm : 1.9-2. 2 (2H, br), 2.27 (3H, s), 2.2-2. 4 (2H, br), 3.62 (2H, br), 4.77 (1H, br), 6.90 (2H, d, J = 8.9 Hz), 7.11 (2H, d, J = 7.8 Hz), 7.1-7. 2 (2H, m), 7.32 (2H, d, J = 8.9 Hz), 7.45-7. 55 (2H, m), 7.49 (2H, d, J = 7.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 20 - 60℃; | Example 2: Preparation of di-(p-dodccgamma]atiilino)-l,4- cyclohexanes|0055| In a l OOnil reaction vessel, equipped with a mechanical stirrer, nitrogen blanket, reflux condenser and thermocouple are charged 1 ,4- cyclohexanedione (2.4 grams. 0.02 IM), p-dupsilondccylaniline ( 13 grams, 0.050M), glacial acetic acid (1.0 grams. 0.016M) and 30ml of THF. To this stirring solution at room temperature is added 7.2 grams (0.031 M) of sodium triaceloxyborohydridc (STAB-H) all at once. The reaction may cxotherm up to 50C over 5 minutes. The temperature is this slowly raised to 600C and held for one hour with vigorous stirring. The temperature is then lowered Io 25C where a second 5.2 gram (0.24M) portion of STAB-H is added. I'hc temperature is then raised again to 6O0C with vigorous stirring and held at 600C for two hours. At this 2008P01616point STAB salt balls may fall out of solution, at which point more TIFF may have to added and the salt balls broken up.[0056] After the reaction is complete, the temperature is reduced to 30C and the reaction solution is diluted with 100ml of hexanes and transferred to a separator)' funnel. The product solution is then washed with three 50ml portions of 5% aqueous NaC)H, 'one 50ml portion of 5% aqueous sodium carbonate and two 50ml portions of water before drying the organic layer over anhydrous magnesium sulfate. The dried solution was filtered and the solvents removed under vacuum to yield 8.5 grams of a reddish viscous liquid. This liquid is then passed through a 2 by 8 inch column of silica gel using hexanes initially as the column solvent. The starting reactants and by-products pass through the column first. The column solvent is then changed to a 5% THF in hexanes to flush the desired products off the column. The product is a mixture of the cis and ttans p- cyclohcxane isomers. The product is a viscous dark burgundy colored liquid. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 20 - 60℃; | Example 3: Preparation of di-(p-liexylanilhio)-l,4- cvclohexanes|0057| In a 250ml reaction vessel, equipped with a mechanical stirrer, nitrogen blanket, reflux condenser and thermocouple are charged 1 A- cyclohexancdione (5.0 grams, 0.044M), p-nhexylaiiilinc ( 17.7 grams, 0.10M), glacial acetic acid ( 1.5 grams, 0.025M) and 75ml of THF. To this stirring solution at room temperature are added 13 grams (0.06M) of sodium t?acetoxyborohydride (STAB-H) all at once. The reaction may exotherm up to 500C over 5 minutes. The temperature is this slowly raised to 600C and held for one hour with vigorous stirring. The temperature is then lowered to 25C where a second 1.3 gram (0.06M) portion of STAB-H is added. The temperature is then raised again to 600C with vigorous stirring and held at 600C for one and half hours. At this point STAB salt balls may fall out of solution, at which point more THF may have to added and the salt balls broken up.[0058] After the reaction is complete, the temperature is reduced to 3O0C] and the reaction solution is diluted with 120ml of ethyl acetate and transferred to a separatory funnel. The product solution is then washed with three 50ml portions of 5% aqueous NaOH, one 50ml portion of 5% aqueous sodium carbonate and 2008P01617two 50ml portions of water before drying the organic layer over anhydrous magnesium sulfate. The dried solution is filtered and the solvents removed under vacuum to yield 8.5 grams of a reddish viscous liquid. An approx. lOgrain portion of this liquid is then passed through a 2 by 6 inch column of silica gel using 1 %THF in hexanes initially as the column solvent. The starling reactants and by-products pass through the column first. The column solvent is then changed lo a 3% THF in hexanes to Hush the desired products off the column. The product is a 5 gram mixture of the cis and trans p-cyclohexane isomers. The product is a viscous dark burgundy colored liquid which may slowly solidify on standing. Some of the trans isomer can be separated from the isomer mixture by recryslalliz;ation from hot methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With bis(glycerol)boric acid; bis(glycerol)boric acid; at 60℃; for 0.833333h;Green chemistry; | General procedure: 2-Aminobenzamide (1 mmol) were added to the mixture of carbonyl compound (1 mmol) in H[Gly2B] (0.5 g) in a 25 mL pyrex flask connected to a condenser and the resulted mixture was stirred magnetically for the appropriate time (Table 1) at 60 C. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate (3:1) as a mobile phase. After completion of the reaction, water (20 mL) was added and stirred magnetically for 5 min. Insoluble crude products were filtered and recrystallized from EtOH. To recover the H[Gly2B], after the isolation of insoluble products, water was evaporated, and the remaining viscous liquid was washed with methyl tert-butyl ether (5 mL) and dried under reduced pressure. As H[Gly2B] is too hydrophilic, in order for the complete removal of water, an additional lyophilization step was run. For this, recovered H[Gly2B] was frozen in liquid nitrogen and lyophilized to near-dryness over 2 days [20]. (H[Gly2B] was recovered in 98% yield). White powder, mp: > 300 C, upsilonmax (KBr): 3450, 3390, 3020, 2975, 1700, 1650 cm- 1. 1H NMR (500 MHz, DMSO-d6): delta (ppm) 1.09 (m, 4H), 1.47 (m, 4H), 6.8 (t, J = 7.5 Hz, 2H), 7.08 (d, J = 7.5 Hz, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.76 (d, J = 7.5 Hz, 2H), 9.8 (s, 2H), 10.7 (s, 2H). 13C NMR (125 MHz, DMSO-d6): delta (ppm) 21.8, 81.7, 112.5, 115.7, 116.8, 127.5, 132.9, 147.1, 166.6. Anal. Calcd for C20H20N4O2: C, 68.95; H, 5.79; N, 16.08%; found: C, 69.01; H, 5.83; N, 16.01%. |
Yield | Reaction Conditions | Operation in experiment |
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83% | Synthesis Example 1: Production of Compound (10a) To a 1-L round-bottom flask were added lithium chloride (LiCl) (1.68 g, 33 mmol) and cerium(III)trichloride heptahydrate (14.4 g, 0.33 mol). The flask was immersed in an oil bath and heated at 90C for 2 hours under vacuum to dry. The obtained reactant mixture was crushed into a powder, and the powdered reactant mixture was returned to the flask. The flask was immersed again in an oil bath and heated at 90C for 1 hour under vacuum. A stirring bar was added to the flask, and the flask was immersed again in an oil bath and heated at 150C for 3 hours under vacuum while stirring. While the content in the flask was still hot, argon gas was introduced into the flask. Dry tetrahydrofuran (THF) (200 mL) was added thereto and the mixture was suspended. The resulting suspension was stirred at room temperature (i.e., about 23C, the same applies hereinafter) for about 8 hours. A solution of cyclohexane-1,4-dione (1.68 g, 15 mmol) in THF (15 mL) was added to the suspension via a cannula. The mixture was stirred at room temperature for 2 hours and cooled to -78C, thereby obtaining Suspension A. To another 1-L round-bottom flask were added 1,4-dibromobenzene (10.7 g, 45 mmol) and dry THF (90 mL). A hexane solution of n-butyllithium (29.5 mL, 1.57 M, 45 mmol) was gradually added thereto dropwise at -78C (addition rate: 4.5 cm3/min). After completion of dropwise addition, the mixture was stirred at -78C for 30 minutes, and the resulting solution was added to Suspension A via a cannula, thereby obtaining a mixture. The mixture was stirred at -78C for 1 hour, followed by stirring at room temperature for 2 hours. Thereafter, a saturated NH4Cl aqueous solution (50 mL) was added to the mixture to stop the reaction. The resulting product was passed through Celite, and the filtrate was concentrated with an evaporator. Then, ethyl acetate was added to the residue (concentrate), the crude product was extracted and dried over anhydrous Na2SO4, and an ethyl acetate solution was thereby obtained. The solution was concentrated with an evaporator, and the residue (concentrate) was recrystallized from chloroform to yield a white solid (5.32 g). This white solid was identified by nuclear magnetic resonance (1H-NMR, 13C-NMR) analysis and mass spectrometry as Compound (10a) represented by the following General Formula (10a): [Show Image] The yield of Compound (10a) was 83%. 1H NMR (270 MHz, CDCl3) delta1.71 (s, 2H), d 2.07 (s, 8H), 7.34 (d, J = 8.6 Hz, 4H), 7.47 (d, J = 8.6 Hz, 4H);13C NMR (67.5 MHz, CDCl3) delta 33.2 (CH2), 72.3 (4), 121.5 (4), 127.2 (CH), 131.6 (CH), 144.6 (4); HRMS (FAB, negative) m/z calcd for C18H17Br2O2[M-H]-: 422.9595, found 422.9576; mp: 177.7-178.7C. |
Yield | Reaction Conditions | Operation in experiment |
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56% | Under N2 2-(2-bromophenyl)acetaldehyde dimethyl acetal55 (5, 1.03 g, 4.20 mmol) was dissolved in THF abs (32 mL) and cooled down to -78 C. Subsequently, n-BuLi (1.48 M in n-hexane, 3.12 mL, 4.62 mmol) was added slowly. After 20 min a solution of cyclohexane-1,4-dione (0.946 g, 8.4 mmol in THF, 12 mL) was added rapidly and the mixture was stirred for 2 h at -78 C and 1 h at rt. Then H2O was added (30 mL), after addition of CH2Cl2 the layers were separated and the aqueous layer was extracted with CH2Cl2 (2x), the combined organic layers were dried (Na2SO4), concentrated in vacuo and the residue was purified by FC (5 cm, cyclohexane/ethyl acetate 2:1, 20 cm, 30 mL, Rf = 0.20). Colorless solid, mp 45 C, yield 652 mg (56%). C16H22O4 (278.4). MS (EI): m/z (%) = 278 [M, 1], 246 [M-MeOH, 2], 189 [M-MeOH, -CH3CH2CO, 50], 157 [M-2 MeOH, -CH3CH2CO, 100]. MS (ESI-): m/z (%) = 555 [(2M-H)-,15], 277[(M-H)-, 100]. IR: inlMMLBox (cm-1) = 3424 (m, broad, v, OH), 3057 (w, v, C-H, arom), 2938 (s,v, C-H, alkyl), 2833 (m, v, OCH3), 1710 (s, v, CO), 1443 (m, delta, C-H, alkyl), 760 (s, delta, C-H, o-disubst. arom). 1H NMR (DMSO-d6): delta (ppm) = 2.14-2.28 (m, 6H, (CH2CH2)2CO), 2.84 (?dt?, J = 14.4/9.5 Hz, 2H, (CH2CH2)2CO), 3.30 (s, 6H, Ar-CH2CH(OCH3)2), 3.33 (d, J = 5.3 Hz, 2H, Ar-CH2CH(OCH3)2), 4.67 (t, J = 5.4 Hz, 1H, Ar-CH2CH(OCH3)2), 5.33 (s, 1H, OH), 7.16-7.24 (m, 2H, Ar-H), 7.30-7.34 (m, 1H, Ar-H), 7.38-7.42 (m, 1H, Ar-H). |
Yield | Reaction Conditions | Operation in experiment |
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80% | With acetic acid; In ethanol; at 50℃; for 1h; | Synthesis of Compound B; 34.9 g (0.31 mole) of 1,4-cyclohexanedione, 90 g (0.62 mol) of phenylhydrazin-HCl, and 1 mL of acetic acid were put into a 1L one-neck round flask, and 600 mL of ethanol was added thereto. The resulting mixture was heated at 50 C for 1 hour, and was cooled to room temperature. The resulting solid was filtered, was washed several times with ethanol, and was dried in a vacuum to collect 73 g of pink Compound A with a yield of 80%. 600 mL of acetic acid and 120 mL of sulfuric acid were put into a 5L one-neck round flask, and were cooled in an ice bath. 217.5 g (0.74mole) of Compound A was added to the resulting mixture, and was strongly stirred at 0 C for 10 minutes. The ice bath was removed, and the resulting mixture was stirred at room temperature for 10 minutes. The resulting mixture was heated by a heating mantle. The heating was stopped at a temperature of about 45 C, and the resulting mixture was stirred. When the resulting mixture was stable, the resulting mixture was slowly cooled to room temperature, and was stirred at room temperature. The resulting solid was filtered, was washed with acetic acid, water, and ethyl ether in this order, and was dried in a vacuum to collect 51 g of Compound B with a yield 26.7%. 1H NMR (300MHz, DMSO-d6) delta 11.01 (2H), 8.19 (2H), 8.10 (2H), 7.45 (2H), 7.36 (2H), 7.12 (2H) |
Yield | Reaction Conditions | Operation in experiment |
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66% | With sodium acetate; In ethanol; at 20 - 50℃; | <strong>[637-88-7]1,4-Cyclohexanedione</strong> (5.62 g, 50 mmol) dissolved in absolute ethanol (EtOH) (100 mL) was added with stirring to a mixture of powdered 4-bromophenylhydrazine hydrochloride (22.4 g, 100 mmol), sodium acetate (8.2 g, 100 mmol) and absolute ethanol (200 mL) at room temperature. The mixture was quickly heated to 50 C, and thereafter, the temperature was allowed to cool to 0 C. A precipitate was filtered off, washed carefully with water to give 1 (yield 66%). |
66% | With sodium acetate; In ethanol; at 20 - 60℃; for 2h;Inert atmosphere; Schlenk technique; | <strong>[637-88-7]1,4-Cyclohexanedione</strong> (5.62 g, 50 mmol) was dissolved in absolute ethanol (EtOH) (100 mL) and was added with stirring to a mixture of powdered 4-bromophenylhydrazine hydrochloride (22.4 g,100 mmol), sodium acetate (8.2 g, 100 mmol) and absolute ethanol(200 mL) at room temperature. The mixture was quickly heated to 50 C and kept stirring for 2 h, and then, the mixture was cooled to room temperature and poured into ice water with stirring. A precipitate was filtered off and washed carefully with water to give 1 yield 66%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.8% | With potassium hydroxide; In ethanol; for 1h; | To a 250 mL round bottom flask was added 17.3 g (0.124 mol) of thiophene-2,3-dicarboxyaldehyde,6.6 g (0.059 mol) of 1,4-cyclohexanedione and 70 mL of ethanol were added, and 70 mL of 15% potassium hydroxide was added dropwise, followed by stirring for 1 hour.After completion of the reaction, the solution was filtered and then dried to obtain 17.5 g (92.8%) of the compound represented by the formula 5-a. |
84% | With potassium hydroxide; In ethanol; at 20℃; | Thiophene-2,3-dicarboxaldehyde (5 g, 35.7 mmol) was dissolved in EtOH (450 mL) in a 1 L round-bottom flask with a stir bar, followed by the addition of 2 g 1,4-cyclohexane dione (17.8 mmol). Upon the addition of a 15% KOH solution (20 mL), a precipitate began to form immediately. The mixture was stirred for an additional hour then filtered to yield 4.8 g (15 mmol, 84%) of quinone as a yellow powder. Mp: 380-383 C, MS (EI): m/z 320 (M+). |
Yield | Reaction Conditions | Operation in experiment |
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68% | With potassium hydroxide; In ethanol; at 60℃; for 1h; | 4,5-dicarboxaldehyde benzo [c] [1,2,5] thiadiazole (0.20 g, 1.04 mmol) and 1,4-cyclohexanedione (58 mg, 0.52 mmol) was added to ethanol (50 mL) and an ethanolic solution of potassium hydroxide (32 mg) was added dropwise at 60 C, After stirring for 1 hour at 60 C, the reaction mixture was cooled to room temperature, the solid was filtered off and washed with ethanol, And dried, to give the compound pentacene [2,3-c: 9,10-c '] bis ([1,2,5] thiadiazole) -6,13_ dione (0. 15g, 68%) |
Yield | Reaction Conditions | Operation in experiment |
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83% | Synthesis Example 1 Compound (Ia-1) To a 1-L round-bottom flask were added lithium chloride (LiCl) (1.68 g, 33 mmol) and cerium(III)trichloride heptahydrate (14.4 g, 0.33 mol). This flask was immersed in an oil bath, and heated at 90 C. for 2 hours under vacuum to dry. The obtained reactant mixture was crushed into a powder, and the powdered reactant mixture was returned to the flask. The flask was immersed again in an oil bath, and heated at 90 C. for 1 hour under vacuum. A stirring bar was added to the flask, and the flask was immersed again in an oil bath and heated at 150 C. for 3 hours under vacuum while stirring. While the content in the flask was still hot, argon gas was introduced into the flask. Dry tetrahydrofuran (THF) (200 mL) was added thereto, and the mixture was suspended. The resulting suspension was stirred at room temperature (i.e., about 23 C.; the same applies hereinafter) for about 8 hours. A solution of cyclohexane-1,4-dione (1.68 g, 15 mmol) in THF (15 mL) was added to the suspension via a cannula. The mixture was stirred at room temperature for 2 hours and cooled to -78 C., thereby obtaining Suspension A. [0330] To another 1-L round-bottom flask were added 1,4-dibromobenzene (10.7 g, 45 mmol) and dry THF (90 mL). A solution of n-butyllithium in hexane (29.5 mL, 1.57 M, 45 mmol) was gradually added thereto dropwise at -78 C. (addition rate: 4.5 cm3/min). After completion of dropwise addition, the mixture was stirred at -78 C. for 30 minutes, and the resulting solution was added to Suspension A obtained above via a cannula, thereby obtaining a mixture. [0331] The mixture was stirred at -78 C. for 1 hour, followed by stirring at room temperature for 2 hours. A saturated NH4Cl aqueous solution (50 mL) was then added to the mixture to stop the reaction. The resulting product was passed through Celite, and the filtrate was concentrated with an evaporator. Then, ethyl acetate was added to the residue (concentrate) to extract a crude product, which was dried over anhydrous Na2SO4, thereby obtaining an ethyl acetate solution. The solution was concentrated with an evaporator, and the residue (concentrate) was recrystallized from chloroform to yield the target compound as a white solid (5.32 g) (yield: 83%). [0332] 1H NMR (270 MHz, CDCl3) delta 1.71 (s, 2H), d 2.07 (s, 8H), 7.34 (d, J=8.6 Hz, 4H), 7.47 (d, J=8.6 Hz, 4H); 13C NMR (67.5 MHz, CDCl3) delta 33.2 (CH2), 72.3 (4), 121.5 (4), 127.2 (CH), 131.6 (CH), 144.6 (4); HRMS (FAB, negative) m/z calcd for C18H17Br2O2 [M-H]-: 422.9595, found 422.9576; mp: 177.7-178.7 C. |
Yield | Reaction Conditions | Operation in experiment |
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8.9 g | With sulfuric acid; acetic acid; at 30 - 110℃; for 2.5h;Inert atmosphere; | In a 3,000-ml three-necked flask equipped with a reflux condenser and a mechanical stirrer, to <strong>[2243-56-3]1-naphthylhydrazine hydrochloride</strong> (108.7 g, 558.4 mmol) and 1,4-cyclohexanedione (25.0 g, 223.4 mmol), 1,200 mL of acetic acid was added, and the mixture was stirred under a stream of argon. Sulfuric acid (165 mL, 3,095 mmol) was added dropwise at 30 C. or less. After that, the mixture was stirred at 110 C. After 2 hr, the reaction liquid was charged into 2.4 L of cold water, followed by stirring for 30 min. The resultant was filtered to provide a brown solid. The resultant solid was stirred under reflux with 500 mL of methanol for 30 min, and then a precipitate was taken by filtration. To the solid, 500 mL of THF was added, and the mixture was stirred under heating to reflux for 30 min, followed by separation by filtration. The resultant filtrate was brought to dryness to provide 8.9 g of Compound (101-A) as a reddish brown solid. |
Yield | Reaction Conditions | Operation in experiment |
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78% | With perchloric acid; In methanol; at 20℃; for 24h; | General procedure: To a solution of o-benzoquinone dioxime (5mmol) in methanol (10mL) were added relevant ketone (6 mmol) and 70% perchloric acid (20 mmol). The reaction mixture was stirred for 24 h at room temperature. The presence of parent o-benzoquinone dioxime was monitored by TLC (eluent: ethyl acetate). After disappearance of the starting o-benzoquinone dioxime, the mixture was poured into water (80mL). The product was extracted with chloroform (3×40 mL), the extract was washed with water (2×100 mL), dried over magnesium sulfate, and evaporated in vacuo to give the crude product, which was purified by column chromatography (chloroform/methanol, 9:1). Pure fractions were collected, solvents were evaporated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With methanesulfonic acid; In toluene; at 20℃; for 1h;Green chemistry; | The 1,4-cyclohexanedione (10.0 g) was dissolved in 100mL of toluene, stirring at room temperature was added methanesulfonic acid (0.21 g of) and 6-chloro-3,5-dihydroxy - hexanoic acid methyl ester (38.4 g of ), stirring was continued for 1 hour. The reaction mixture was poured into aqueous sodium bicarbonate, extracted twice with toluene, the combined organic phases were washed once with brine, dried over sodium sulfate, and concentrated to dryness by column chromatography to give 34.7 g of the desired product, yield 83% molar. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 1h;Green chemistry; | The 1,4-cyclohexanedione (15.0 g of) was dissolved in 150mL of dichloromethane, stirring at room temperature was added p-toluenesulfonic acid (0.53 g) and 6-acetyl-3,5-dihydroxy - hexanoate butyl ester (73.4g), the reaction was continued for 1 hour. The reaction solution was poured into aqueous sodium hydrogen carbon acid, extracted twice with toluene, the combined organic phases were washed once with brine, dried over sodium sulfate, concentrated to dry column chromatography to give the desired product 60.3 g, molar yield of 75% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid; In tetrahydrofuran; at 20℃; for 1h;Green chemistry; | The 1,4-cyclohexanedione (10.0 g) was dissolved in 100mL of tetrahydrofuran stirring at room temperature was added p-toluenesulfonic acid (0.37 g) and 6-cyano-3,5 - dihydroxy-hexanoic acid ethyl ester (37.7 g), stirring was continued for 1 hour. The reaction mixture was poured into aqueous sodium bicarbonate, extracted twice with toluene, the combined organic phases were washed once with brine, dried over sodium sulfate, and concentrated to dryness by column chromatography to give the desired product 36.3 g, molar yield of 85% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sulfur; triethylamine; for 1h;Reflux; | General procedure: To a solution of cyclohexan-1,4-dione in 1,4-dioxane (40 mL)containing triethylamine (0.50 mL) each of elemental sulfurand any of 2-cyano-N-phenylacetamide (1.60 g, 0.01 mol),N-(4-chlorophenyl)-2-cyanoacetamide (1.94 g, 0.01 mol) or2-cyano-N-(4-methoxyphenyl) acetamide (1.90 g, 0.01 mol) wasadded. The whole reaction mixture was heated under refluxfor 1 h then poured onto ice/water containing few drops ofhydrochloric acid and the formed solid product, in each case,was collected by filtrations.2-Amino-6-oxo-N-phenyl-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carboxamide (3a)HPLC purity=89% (C-18 NovaPak column; MeOH-H2O,80 : 20), RT=20 min; orange crystals (ethanol), yield 70%(2.00 g), mp 183-185C; (IR (KBr) numax 3493, 3329, 3055,2984, 1689, 1675, 1639, 1583; 1H-NMR (DMSO-d6, 200 MHz)delta: 1.65-1.92 (2t, 4H, 2CH2), 2.79 (s, 2H, CH2), 4.85 (s, 2H,D2O exchangeable, NH2), 7.26-7.38 (m, 5H, C6H5), 8.28 (s,1H, D2O exchangeable, NH); 13C-NMR (DMSO-d6, 75 MHz)delta: 18.6, 38.8, 40.0 (3CH2), 119.5, 120.5, 124.8, 127.2, 133.5,138.4, 140.2, 141.8 (C6H5, thiophene C), 164.8, 166.2 (2CO);EI-MS: m/z 286 [M]+ (26%); Anal. Calcd for C15H14N2O2S(286.35): C, 62.92; H, 4.93; N, 9.78; S, 11.17%. Found: C,63.19; H, 4.69; N, 9.84; S, 11.36%. |
70% | With sulfur; triethylamine; In 1,4-dioxane; for 2h;Reflux; | General procedure: To a solution of cyclohexan-1,4-dione (1.12 g, 0.01 mol) in1,4-dioxane (40 mL) containing triethylamine (0.50 mL) each of elemental sulfur (0.32 g, 0.01 mol) and any of 2-cyano-N-phenylacetamide (1.60 g, 0.01 mol), N-(4-chlorophenyl)-2-cyanoacetamide (1.94 g, 0.01 mol) or N-(4-nitrophenyl)-2-cyanoacetamide (2.05 g, 0.01 mol) wereadded. The reaction mixture was heated under reflux for 2 hthen poured onto ice/water containing few drops of hydrochloricacid. The formed solid product, in each case, wascollected by filtration.2-Amino-6-oxo-N-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (3a) Orange crystals (ethanol), yield70% (2.00 g), m.p. 183-185 C; (IR (KBr) numax 3493, 3329,3055, 2984, 1689, 1639, 1583; 1H NMR (DMSO-d6, 200MHz): delta = 8.28 (s, 1H, D2O exchangeable, NH), 7.48-7.24(m, 4H, C6 H4), 4.85 (s, 2H, D2O exchangeable, NH2), 2.79(s, 2H, CH2), 1.92-1.65 (2t, 4H, 2CH2), 13C NMR (DMSOd6,75MHz): delta = 166.2, 164.8 (2CO), 141.8, 140.2, 138.4,133.5, 127.2, 124.8, 122.5, 120.5 (C6H5, thiophene C),40.0, 38.8, 18.6 (3CH2); EIMS: m/z 286 [M]+ (26%);analysis calcd for C15H14N2O2S (286.35): C, 62.96; H,4.93; N, 9.78; S, 11.20%. Found: C, 63.19; H, 4.69; N,9.84; S, 11.36%. |
With sulfur; triethylamine; for 1h;Reflux; | General procedure: To a solution of cyclohexan-1,4-dione in 1,4-dioxane (40 mL) containing triethylamine (0.50 mL) each of elemental sulfur and any of 2-cyano-N-phenylacetamide (1.60 g, 0.01 mol), N-(4-chlorophenyl)-2-cyanoacetamide (1.94 g, 0.01 mol) or 2-cyano-N-(4-methoxyphenyl) acetamide (1.90 g, 0.01 mol) was added. The whole reaction mixture was heated under reflux for 1 h then poured onto ice/water containing few drops of hydrochloric acid and the formed solid product, in each case, was collected by filtrations. 2-Amino-6-oxo-N-phenyl-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carboxamide (3a) HPLC purity=89% (C-18 NovaPak column; MeOH-H2O, 80 : 20), RT=20 min; orange crystals (ethanol), yield 70% (2.00 g), mp 183-185C; (IR (KBr) numax 3493, 3329, 3055, 2984, 1689, 1675, 1639, 1583; 1H-NMR (DMSO-d6, 200 MHz) delta: 1.65-1.92 (2t, 4H, 2CH2), 2.79 (s, 2H, CH2), 4.85 (s, 2H, D2O exchangeable, NH2), 7.26-7.38 (m, 5H, C6H5), 8.28 (s, 1H, D2O exchangeable, NH); 13C-NMR (DMSO-d6, 75 MHz) delta: 18.6, 38.8, 40.0 (3CH2), 119.5, 120.5, 124.8, 127.2, 133.5, 138.4, 140.2, 141.8 (C6H5, thiophene C), 164.8, 166.2 (2CO); EI-MS: m/z 286 [M]+ (26%); Anal. Calcd for C15H14N2O2S (286.35): C, 62.92; H, 4.93; N, 9.78; S, 11.17%. Found: C, 63.19; H, 4.69; N, 9.84; S, 11.36%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With magnetite nanoparticles coated on sulfuric acid functionalized silica; In neat (no solvent); at 90℃; for 0.0333333h;Green chemistry; | General procedure: Fe3O4SiO2-SO3H (0.05 g) was added to the 1:1 mixtureof anthranilamide (1 mmol) and aldehydes or ketones(1 mmol). The mixture was stirred at room temperature (or inan oil bath at 70-100C) for the appropriate time as shown inTable 2. After completion of the reaction, as indicated byTLC (ethyl acetate:n-hexane 1:1), and cooling, hot ethanol(5 mL) was added to the mixture and stirred for 10 min. Inthe presence of an external magnet, the nanocatalyst wasremoved and then extracted solution was cooled to roomtemperature to recrystallize to afford the corresponding products in 82-96% yield. All of the 2,3-dihydroquinazolin-4(1H)-ones are known and were identified by comparison oftheir physical and spectroscopic data (IR, NMR) with thoseof authentic samples [21-37]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dichloro-ethane; for 8.0h;Reflux; | General procedure: The p-benzoquinone (0.096 mol) was dissolved in 100 mL of 1,2-dichloroethane, heated to 60 C., stirred until dissolution was complete, compound A-1 was added dropwise, and the reaction was completed by refluxing for 8 h.The reaction solution was allowed to naturally cool to room temperature and allowed to stand overnight to precipitate a solid, which was filtered by suction, washed with cold acetone, dried, and recrystallized from acetone to obtain compound A-2. Yield: 40-60%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.25% | With montmorillonite; In ethanol; toluene; at 20℃; for 0.333333h;Inert atmosphere; | Under the protection of nitrogen, using montmorillonite as a catalyst, a compound 1-1 (11.23, 100 mmol), 1-2 (5.52, 100 mmol), 200 ml of ethanol and 200 ml of toluene were stirred at room temperature for 20 min.Intermediate 1-3 15.21 g was obtained in a yield of 84.25%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Under nitrogen protection, 200 g of 1,4-cyclohexanedione was added to 1.2 L of methanol, stirred and dissolved, and then cooled to 5 C. 286 g of liquid bromine was added dropwise over 15 minutes, and the mixture was stirred for 15 minutes.163 g of thiourea was added, followed by stirring at 15 C to 25 C for 16 hours.Concentrated hydrochloric acid (12 mol/L) 200 mL and 1 L of water were added, and the mixture was stirred at 65 C to 70 C for 1 hour. After cooling, it is concentrated in vacuo to remove most of the methanol (temperature 35 C ~ 45 C, vacuum pressure -0.085 MPa ~ -0.1 MPa), after cooling, extract twice with 500 mL of toluene, the aqueous phase is 20% by weight aqueous solution of sodium hydroxide. (The mass percentage refers to the mass of sodium hydroxide as a percentage of the total mass of the sodium hydroxide aqueous solution). Adjust the pH to 12-14, extract three times with 1 L of dichloromethane, and combine the quality of the organic phase.The percentage is 10% aqueous solution of sodium hydrogencarbonate (the mass percentage refers to the mass of sodium bicarbonate as a percentage of the total mass of sodium bicarbonate aqueous solution) and the mass percentage is 15% of saline (the quality The percentage refers to the mass of sodium chloride as a percentage of the total mass of the aqueous salt solution) washed and dried over anhydrous sodium sulfate. Filtration, cooling and concentration in vacuo to remove most of the solvent (35 C ~ 45 C, -0.05 MPa ~ -0.1 MPa), add 100 mL of ethyl acetate, then add ethyl chloride solution (2.0 mol / L) 2L, at 15 C Stir at 25C for 1 hour, filter, wash with ethyl acetate, and dry in vacuo (45C to 55C, -0.01MPa~-0.1MPa) for 8 to 12 hours to obtain 274g of white solid as pramipexine intermediate III. 75.0%, HPLC purity 98.20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.6% | 1500 g of 1,2-dichloroethane and 112.0 g (1.0 mol) of 1,4-cyclohexanedione were added to a 5-liter four-necked flask.3.0 g of 30% aqueous hydrochloric acid, cooled,Keep the internal temperature between 10-15 C, slowly pass 156.0 g (2.2 mol) of chlorine gas, stir the reaction between 15-25 C for 3 h,Until the reaction is complete. Then nitrogen was bubbled for 2 hours.Blow up the generated hydrogen chloride and excess chlorine.Thereafter, 390 g (1.0 mol) of 1-[4-(3-dibutylamino-propoxy)-phenyl]-heptane-1,3-dione (VI), 152, was added to the obtained reaction liquid. Gram potassium carbonate,The reaction was stirred at 55-60 C for 5 hours, cooled to 20 C, filtered, and layered. To the obtained organic layer was added 30 g of 10% aqueous hydrochloric acid, stirred at 40-50 C for 4 hours, layered, water layer Extract twice with 1,2-dichloroethane,The organic phase was combined 100 grams each time. To the organic phase, 30 g of anhydrous sodium sulfate was added and dried for 4 hours. filter,The resulting filtrate was transferred to a 5 liter four-necked flask.Keep the internal temperature between 15-25 C, slowly pass 40 g of ammonia gas, then stir the reaction between 20-25 C for 3 hours; then,While maintaining the internal temperature between 20 and 30 C, 126 g (1.1 mol) of methanesulfonyl chloride was slowly added dropwise, and the reaction was stirred for 4 hours between 25 and 30 C. Filtration, the filtrate is recovered under reduced pressure,Then 2000 grams of water was added to the resulting residue.800 g of 10% aqueous hydrochloric acid, heated,Stir at 80-85 C for 3 hours, cool to 20 C,After filtration, the filter cake was washed with 100 g of a 5% aqueous hydrochloric acid solution, washed with 100 g of ethanol, and dried to obtain 513.5 g of white crystals of dronedarone hydrochloride. The yield is 86.6%.The liquid phase purity was 99.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With (S)-(-)-SEGphos; palladium diacetate; toluene-4-sulfonic acid; In 5,5-dimethyl-1,3-cyclohexadiene; at 85℃; for 14h;Inert atmosphere; | Compound II was prepared by the method of Bernhard Breit et al. (Org. Lett. 2018, 20, 3286-3290).To the reaction flask were added Pd(PPh3)4(3.56 g, 3.07 mmol, 2.0 mol%), (S)-(-)-SEGphos (4.69 g, 7.69 mmol,5.0 mol%) and p-toluenesulfonic acid (2.65). g, 15.39 mmol, 10 mol%), after 5 min of nitrogen, a compound of formula I(24.0 g, 153.85 mmol, 1.0 eq.), 1,4-cyclohexanedione (8.62 g, 0.5 eq.) and freshly distilled toluene ( 300 mL),warmed to 85 , stirred for 14 hours, cooled to room temperature, the solvent was removed under reduced pressure, by flash column chromatography (silica gel, n-hexane:EtOAC=. 3:. 1), to give a colorless oil II (30.32g , 93%, dr>99:1). |
98% | With (S)-((4,4?-bi-1,3-benzodioxole)-5,5?-diyl)bis(diphenylphosphine); palladium diacetate; toluene-4-sulfonic acid; In 5,5-dimethyl-1,3-cyclohexadiene; at 85℃; for 14h;Inert atmosphere; | General procedure: See Bernhard Breit et al. (Org. Lett. 2018, 20, 3286-3290)Method for the preparation of compound II.Add Pd(PPh3)4 to the reaction flask(3.56 g, 3.07 mmol, 2.0 mol%),(S)-(-)-SEGphos (4.69 g, 7.69 mmol, 5.0 mol%)And p-toluenesulfonic acid (2.65 g, 15.39 mmol, 10 mol%),After passing nitrogen for 5 minutes,Compound of formula I (24.0 g, 153.85 mmol, 1.0 eq.),1,4-cyclohexanedione (8.62 g, 0.5 equivalent)And freshly distilled toluene (300 mL), warmed to 85 C,Stir for 14 hours,After cooling to room temperature, the solvent was removed under reduced pressure.By flash column chromatography (silica gel column,N-hexane: EtOAc = 3:1),A colorless oil II (30.32 g, 93%, d.r. > 99:1) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With methanesulfonic acid; In toluene; at 95 - 112℃; for 10h;Dean-Stark; | General procedure: In a 300 mL round-bottom flask, placed were 10.0 g of 1,4-cyclohexanedione (from Tokyo Chemical Industry Co., Ltd., reagent), 25.1 g of trimethylolpropane (from Mitsubishi Gas Chemical Company, Inc.), 300 g of toluene (from Wako Pure Chemical Industries, Ltd., special grade reagent), and 0.26 g of methanesulfonic acid (from Tokyo Chemical Industry Co., Ltd., reagent), and the content was heated under normal pressure so as to control the temperature inside vessel within the range from 90 C. to 112 C., allowing a dehydration cyclization reaction to proceed. At this temperature, the reaction was allowed to continue while removing the water in the system resulted from the reaction, azeotropically with toluene through a Dean-Stark trap out from the system, for 10 hours until distillation of water came to the end. In the reaction system after removal of water, the product was found to form a slurry. The reaction slurry was cooled down to 25 C., filtered, washed with aqueous sodium hydroxide solution for neutralization, washed with water, and dried under reduced pressure, to obtain 30.3 g of Compound A (purity (determined by GC)=98.4%, isolation yield=97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With toluene-4-sulfonic acid; In toluene; at 90 - 112℃; for 4h;Dean-Stark; | In a 300 mL round-bottom flask, placed were 1.47 g of 1,4-cyclohexanedione (from Tokyo Chemical Industry Co., Ltd., reagent), 5.0 g of alpha,alpha,alpha-tris(hydroxymethyl) toluene (from Toronto Research Chemicals), 100 g of toluene (from Wako Pure Chemical Industries, Ltd., special grade reagent), and 0.08 g of para-toluenesulfonic acid monohydrate (from Wako Pure Chemical Industries, Ltd., special grade reagent), and the content was heated under normal pressure so as to control the temperature inside vessel within the range from 90 C. to 112 C., allowing a dehydration cyclization reaction to proceed. At this temperature, the reaction was allowed to continue while removing the water in the system resulted from the reaction, azeotropically with toluene through a Dean-Stark trap out from the system, for 4 hours until distillation of water came to the end. In the reaction system after removal of water, the product was found to form a slurry. The reaction slurry was cooled down to 25 C., filtered, washed with aqueous sodium hydroxide solution for neutralization, washed with water, and dried under reduced pressure, to obtain 5.0 g of Compound E (purity (determined by HPLC)=98.5%, isolation yield=86%). A reaction scheme of Example 7 is shown below. Structure of Compound E obtained in Example 7 was determined by 1HNMR, 13CNMR, DEPT, H-H COSY and HMQC spectra. 1H NMR (500 MHz, DMSO-d6) delta 0.74 (3H x 2, t, CH3CH2- x 2), 1.24 (2H x 2, q, CH3CH2- x 2), 1.62-1.70 & 1.81-1.91 (4H x 2, m, cyclohexane), 3.77 (2H x 2, s, CH2OH x 2), 3.96, 4.06 (4H x 2, 2d, -CH2-O-C- x 2), 7.19-7.24 (1H x 2, m, Ph), 7.27-7.34 (4H x 2, m, Ph); 13C NMR (125 MHz, DMSO-d6) delta 25.1, 31.3, 41.2, 63.3, 63.6, 96.9, 126.2, 126.5, 128.0, 142.0. Peaks at delta25.1 and 31.3 in 13CNMR were assigned to four methylene groups on the cyclohexane ring, observed by twos as being non-equivalent, referring to DEPT135 and HMQC spectra. Compound E obtained in Example 7 was identified by measuring HR-MS in DART-MS analysis. Since the mass number (molecular weight M plus one) of the protonated molecule [M+H]+ was observed to be 441.22717 (C26H33O6), the compositional formula of Compound E was determined as C26H32O6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With toluene-4-sulfonic acid; In toluene; at 90 - 112℃; for 10h;Dean-Stark; | General procedure: In a 300 mL round-bottom flask, placed were 10.0 g of 1,4-cyclohexanedione (from Tokyo Chemical Industry Co., Ltd., reagent), 25.1 g of trimethylolpropane (from Mitsubishi Gas Chemical Company, Inc.), 300 g of toluene (from Wako Pure Chemical Industries, Ltd., special grade reagent), and 0.26 g of methanesulfonic acid (from Tokyo Chemical Industry Co., Ltd., reagent), and the content was heated under normal pressure so as to control the temperature inside vessel within the range from 90 C. to 112 C., allowing a dehydration cyclization reaction to proceed. At this temperature, the reaction was allowed to continue while removing the water in the system resulted from the reaction, azeotropically with toluene through a Dean-Stark trap out from the system, for 10 hours until distillation of water came to the end. In the reaction system after removal of water, the product was found to form a slurry. The reaction slurry was cooled down to 25 C., filtered, washed with aqueous sodium hydroxide solution for neutralization, washed with water, and dried under reduced pressure, to obtain 30.3 g of Compound A (purity (determined by GC)=98.4%, isolation yield=97%). |
Tags: 637-88-7 synthesis path| 637-88-7 SDS| 637-88-7 COA| 637-88-7 purity| 637-88-7 application| 637-88-7 NMR| 637-88-7 COA| 637-88-7 structure
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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 |
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