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CAS No. : | 541-47-9 | MDL No. : | MFCD00004366 |
Formula : | C5H8O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YYPNJNDODFVZLE-UHFFFAOYSA-N |
M.W : | 100.12 | Pubchem ID : | 10931 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 27.45 |
TPSA : | 37.3 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) : | -6.03 cm/s |
Log Po/w (iLOGP) : | 1.22 |
Log Po/w (XLOGP3) : | 1.24 |
Log Po/w (WLOGP) : | 1.04 |
Log Po/w (MLOGP) : | 0.79 |
Log Po/w (SILICOS-IT) : | 0.19 |
Consensus Log Po/w : | 0.89 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.18 |
Solubility : | 6.68 mg/ml ; 0.0667 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.62 |
Solubility : | 2.39 mg/ml ; 0.0239 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.04 |
Solubility : | 91.5 mg/ml ; 0.914 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.49 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338+P310-P312-P332+P313-P403+P233-P405-P501 | UN#: | 3261 |
Hazard Statements: | H302+H312-H315-H318-H335 | Packing Group: | Ⅲ |
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 |
---|---|---|
durch Wasserabspaltung und Verseifung des Reaktionsprodukts; | ||
With formic acid | ||
With potassium pyrosulfate at 140 - 145℃; Bildung des Aethylesters; |
Verseifen des Esters nach Wasserabspaltung; | ||
With phosphorus trichloride Bildung des Aethylesters; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With methanethiosulfonic acid at 70℃; for 1.5h; | |
87% | With methanesulfonic acid at 70℃; for 4h; | 2.1 1.0g (6.58mmol) of hydroquinone and 0.85g (7.50mmol) 3- methyl-2-butenoic acid after mixing 10mL disposable methane sulfonic acid was added to the heated and stirred 4h at 70 , TLC detection reaction complete, stirring was stopped, was added 125mL of water, followed by extraction with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Chloroform - n-hexane to give the compound as a white solid, a CX-21, a yield of about 87%. |
85% | With methanesulfonic acid at 85℃; for 3h; |
84% | With methanesulfonic acid at 85℃; for 3h; | |
83% | With methanesulfonic acid at 85℃; for 3h; Inert atmosphere; | |
80% | With methanesulfonic acid at 70℃; for 1h; | |
80% | With methanesulfonic acid at 70℃; for 0.5h; | |
75% | With methanesulfonic acid at 80℃; for 3h; | 1.5 (5) Preparation of Compound 2: 1.52 g (10 mmol) of trimethylhydroquinone and 1 g (10 mmol) of 3,3-dimethacrylate were added to methanesulfonic acid.The reaction mixture was stirred at 80 ° C for 3 hours. After cooling, the reaction mixture was poured into 50 mL of ice water and the mixture was evaporated, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic phase was combined and washed with saturated sodium hydrogen carbonate solution and water. The organic phases were combined again and the solvent was evaporated.The obtained crude yellow product was obtained with ethyl acetate: n-hexane = 1:2Recrystallization, obtaining pure white crystals as compound 2,The yield was 75%. |
75% | With methanesulfonic acid at 80℃; for 3h; | 1.3 (3) Preparation of compound 2: 1.52 g (10 mmol) of trimethylhydroquinone and3,3-Dimethacrylic acid1g (10mmol) was added to methanesulfonic acid, and the reaction was stirred at 80°C for 3 hours. After cooling, the reaction solution was added to 50mL of ice water and stirred. The resulting mixture was extracted 3 times with 50mL of ethyl acetate and combined The organic phase is washed with saturated sodium bicarbonate solution and water, the organic phases are combined again, and the solvent is evaporated. The obtained yellow crude product was recrystallized with ethyl acetate:n-hexane=1:2 to obtain pure white crystals as compound 2 with a yield of 75%. |
72% | With methanesulfonic acid at 70℃; for 0.5h; | |
72% | With methanesulfonic acid at 70℃; for 2h; | 4.1.2. Synthesis of 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl) butanoic acid 5 To a mixture of 3-methylbut-2-enoic acid (7.5 g, 65.7 mmol) andmethyl sulfonic acid (50 mL), trimethylhydroquinone (10 g,65.7 mmol) was added. The mixture was stirred at 70 °C for 2 h. Aftercompletion of the reaction, the mixture was then cooled to room temperature,added 100 mL water and extracted with ethyl acetate(3 × 100 mL). The organic phase was washed with water, dried withanhydrous Na2SO4 and removed most of solvent. The precipitate wascollected by filtration to afford 11.1 g (72%) of the pure product as awhite power, m.p.116-117 °C; 1H NMR (400 MHz, DMSO-d6) δ: 8.01 (s,1H), 2.57 (s, 2H), 2.27 (s, 3H), 2.10-2.09 (m, 6H), 1.34 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ: 168.7, 149.8, 143.15, 128.25, 124.0,122.2, 121.3, 45.6, 35.4, 27.6 (2C), 15.4, 13.3, 12.8; HR-TOF-MS withESI as ionization technique (m/z): calcd for C14H18NaO3 [M + Na]+257.1148, found: 257.1148. |
65% | With methanesulfonic acid for 3h; Heating; | 4.1. Synthesis of 6-hydroxy-4,4,5,7,8-peptamethyl-chroman-2-one Compound 1′ was prepared according to the methodology describedby Rohde and co-workers with minor modifications13 from the reactionof the 2,3,5-trimethylhydroquinone with 3,3-dimethylacrylic acid andmethanesulfonic acid. A mixture of the 2,3,5-trimethylhydroquinone(2 g, 13.1 mmol) with 3,3-dimethylacrylic acid (1.45 g, 14.5 mmol) andmethanesulfonic acid (10 mL) was stirred at 85 °C for 3 h and thencooled to room temperature. The mixture was extracted with CH2Cl2(2×100 mL) and combined organic layer was washed with saturatedNaHCO3 (3×100 mL) and water (3×100 mL) and dried over MgSO4.After filtration and evaporation, a residue was obtained and recrystallizedfrom hexane and CH2Cl2 (5:1, v/v) to give the desiredproduct as a white solid (2.0 g, 8.5 mmol, 65% yield); m.p. 180-182 °C.1H NMR (400 MHz, CDCl3, 303 K) δ: 4.72 (s, 1H), 2.55 (s, 2H), 2.37 (s,3H), 2.23 (s, 3H), 2.19 (s, 3H), 1.46 (s, 6H). 13C NMR (100 MHz, CDCl3,303 K) δ: 169.1, 149.0, 143.8, 128.5, 123.7, 122.1, 119.1, 46.3, 35.7,27.9, 14.6, 12.5, 12.2. Data are consistent with those reported in the literature.13 See SI for synthetic route. |
21% | With methanesulfonic acid at 70℃; for 12h; Inert atmosphere; | |
With isopentyl ether; hydrogen fluoride at 110℃; | ||
In various solvent(s) at 70℃; | ||
With methanesulfonic acid at 70℃; | ||
With methanesulfonic acid at 60℃; | ||
With methanesulfonic acid Inert atmosphere; | ||
With methanesulfonic acid at 60℃; for 6h; | 11 Example 11; Synthesis of 6-hydroxy-4,4,5,7,8-pentamethylchroman-2-oneComparative Example from JP 2003321463. Trimethylhydroquinone (6.6 mmol) is dissolved in 3-methylcrotonic acid (6.7 mmol), methanesulfonic acid (8 ml) is subsequently added, and the brown solution is heated at 60° C. After about 6 hours, the brown solution is added to ice (about 50 g) and extracted a number of times with ethyl acetate. The solvent is removed by distillation, giving 930 mg of 6-hydroxy-4,4,5,7,8-pentamethylchroman-2-one.1H NMR (DMSO-d6) δ 2.56 (s, 2H), 2.26 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H), 1.32 (s, 6H)EI-MS: 234.1 (M+), 219.1 192.0 | |
With methanesulfonic acid at 70℃; for 1.5h; | ||
With methanesulfonic acid at 70℃; for 1.5h; | ||
With methanesulfonic acid at 85℃; for 3h; Inert atmosphere; | 6-Hydroxy-4,4,5,7,8-pentamethylchroman-2-one (8). Trimethylhydroquinone (5 g, 32 mmol) was mixed with 3,3-dimethylacrylic acid (4 g, 40 mmol) and methanesulfonic acid (50 mL). The mixture was stirred at 85 °C under nitrogen for 3 h and then cooled to room temperature. To the mixture was added 300 g of ice with stirring. The mixture was extracted with EA, and washed with NaHCO3 water, and dried with MgSO4. The product was obtained by recrystallization with Hex:EA=1:1 solution (v/v) as white solid. 1H NMR (500 MHz, CDCl3) δ 4.67 (s, 1H), 2.58 (s, 2H), 2.39 (s, 3H), 2.22 (d, J = 14.1 Hz, 6H), 1.19 (s, 6H) | |
With methanesulfonic acid at 70℃; | ||
With methanesulfonic acid at 85℃; for 3h; Inert atmosphere; | 2.1 1) Dissolve 4g of 2,3,5-trimethylhydroquinone and 2.9g of 3,3-dimethacrylic acid in 20mL of methanesulfonic acid, stir and react for 3h at 85°C under the protection of nitrogen; after the reaction solution is cooled to room temperature , Add 700g water and stir for 20 minutes, add 50mL ethyl acetate and extract 3 times, wash the organic phase with saturated sodium bicarbonate solution 3 times, 100mL each time, and then wash 3 times with water, 100mL each time, and finally dry with anhydrous magnesium sulfate , The organic phase was concentrated and recrystallized with n-hexane/ethyl acetate (1:1) to obtain a white solid product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With oxalyl dichloride In dichloromethane at 20℃; | |
96% | With thionyl chloride at 0℃; for 3h; | |
92% | With thionyl chloride 1.) reflux, 1.3 h, 2.) room temperature, 2.5 h, 3.) reflux, 1 h; |
90% | With thionyl chloride 1) 2 h, RT, 2) 1.5 h, 110 deg C; | |
89% | With thionyl chloride at 80℃; | |
85% | With thionyl chloride In hexane for 24h; Heating; | |
84% | With oxalyl dichloride In dichloromethane at 0℃; for 5h; | |
64% | With thionyl chloride | |
With phosphorus trichloride at 100℃; | ||
With N,N-dimethyl-formamide | ||
With thionyl chloride In pentane | ||
With N,N,N,N,N,N-hexamethylphosphoric triamide; thionyl chloride | ||
With thionyl chloride | ||
With oxalyl dichloride; sodium methylate 1) MeOH, 2) benzene, 0 deg C, 3 h; Multistep reaction; | ||
With thionyl chloride In N,N-dimethyl-formamide for 2h; Heating; | ||
With phosphorus trichloride Heating; | ||
With oxalyl dichloride In hexane | ||
With oxalyl dichloride In toluene at 50℃; for 5h; | ||
With thionyl chloride 1.) RT, 1.5 h, 2.) reflux, 5 min; | ||
With oxalyl dichloride In benzene at 70℃; for 1h; | ||
With oxalyl dichloride In dichloromethane for 1h; Heating; | ||
With oxalyl dichloride | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 1h; | ||
With thionyl chloride | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 1h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at -30 - 20℃; | ||
With thionyl chloride In toluene at 55 - 60℃; for 22h; | 1.1 Senecioic acid (5 kg, 42.17 mol), DMF (115.9 ml, 1.49 mol) and toluene (7.5 L) were placed in a four-neck flask (inner volume 20 L) equipped with a thermometer and a stirrer, the obtained mixture was heated to 55°C, and thionyl chloride (6.55 kg, 55.07 mol) was added dropwise over 14 hr. During the dropwise addition, the temperature of the mixture was maintained at 55 to 65°C. After completion of the dropwise addition, the reaction mixture was further stirred for 8 hr while maintaining the temperature of the mixture at 55 to 65°C. After completion of the reaction, toluene was evaporated under reduced pressure (30 - 35°C/3.3 kPa), and toluene (2000 ml) was added and evaporated (35 - 40°C/3.3 kPa). Toluene (2000 ml) was further added and evaporated again (50 - 60°C/3.3 kPa), whereby the impurity was removed as much as possible. As a result, a solution (17.87 kg) of senecioyl chloride in toluene [equivalent to senecioyl chloride (4.28 kg, 36.1 mol), yield 85.6%] was obtained. | |
With thionyl chloride In benzene | ||
With thionyl chloride In dichloromethane for 1h; Reflux; | ||
With thionyl chloride at 20℃; for 4h; | ||
With thionyl chloride; sodium hydroxide In N,N-dimethyl acetamide; water at -5℃; for 0.416667h; Inert atmosphere; | ||
With thionyl chloride Inert atmosphere; | ||
With thionyl chloride for 3h; Reflux; | 3 3-Methyl-but-2-enoic acid phenylamide A mixture of 3-methyl-but-2-enoic acid (100 g, 1 mol) and SOCl2 (119 g, 1 mol) was heated at reflux for 3 h. The excess SOCl2 was removed under reduced pressure. CH2Cl2 (200 mL) was added followed by the addition of aniline (93 g, 1.0 mol) in Et3N (101 g, 1 mol) at 0° C. The mixture was stirred at room temperature for 1 h and quenched with HCl (5%, 150 mL). The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with water (2*100 mL) and brine (100 mL), dried over Na2SO4 and concentrated to give 3-methyl-but-2-enoic acid phenylamide (120 g, 80%). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3.58333h; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h; | ||
With oxalyl dichloride In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane at 20℃; for 1h; | ||
With oxalyl dichloride In dichloromethane at 20℃; for 2.16667h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.166667h; | 4.21. General procedure for the preparation of compounds 8a-g, 9a-g, 10a-e and 11a-e General procedure: Oxalyl chloride (2.0 mmol) was added drop-wise to a stirred mixture of the corresponding acrylic acid derivatives (Acrylic acid, Methacrylic acid, 3,3-Dimethacrylic acid, Trans-2-butenoic acid, Trans-2-pentenoic acid, 4-methyl-2-pentenoic acid, Trans-2-hexenoic acid) (1.0 mmol) and DMF (0.02 mmol) in dichloromethane (16 mL) at room temperature for 10 min, and the mixture was distilled and dissolved in dichloromethane (16 mL) immediately. The solution was used for the next step without further purification. Then, the solution was added drop-wise to a solution of compounds 6a-d (0.4 mmol) and diisopropylethylamine (0.4 mmol) in dichloromethane (15 mL) in an ice bath. Upon completion of the addition, the reaction mixture was removed from the ice bath and placed at room temperature for 30 min and monitored by TLC. The mixture was washed with 10% K2CO3 (50 mL * 3) followed by saturated aqueous NaCl (50 mL * 1), and the organic phase was separated, dried, and evaporated to yield 8a-g, 9a-g, 10a-e and 11a-e which were purified by dichloromethane. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 23℃; for 2h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride In chloroform at 20℃; for 1.08333h; | 8 Production of peujaponicinol B Senecioic acid (500 mg, 5.0 mmol) was placed in a 30 mL eggplant flask,5 mL of chloroform was added as a solvent.Here, oxalyl chloride (0.4 mL, 0.55 mmol, 11 mol%) was slowly added over 5 minutesIt dropped down.The reaction was started at room temperature, and stirring was continued for a further 1 hour after foaming was completed.Thereafter, chloroform as a solvent was distilled off under reduced pressure.The residue was dissolved again in chloroform, and the excess oxalyl chloride was removed by repeating vacuum distillation of chloroform twice,Pale yellow oilTo obtain Senecio acid chloride. | |
With oxalyl dichloride In dichloromethane at 0℃; for 5h; | 41.1 As shown in the above-described reaction formulae, 3,3-dimethylacrylic acid (2a, lOOmg, 0.999mmole) was dissolved in 3ml of anhydrous dbhloromethane and stirred in cold ice under nitrogen atmosphere, oxalyl chloride(356.8μ£, 3.996mmol) was added thereto dropwisely and stirred at 0? for 5 hours. The reaction solution was cooled to room temperature and concentrated to obtain 3,3-dimethylacryloyl chloride (19a) to dissolve in anhydrous dichloromethane. | |
With trichlorophosphate at 80℃; | 4.1.1. General procedure for the synthesis of 16a-h General procedure: We used indole 7 as starting material to synthesize interediates15a-c by the method reported in the literature [32]. Different substituted acrylic acids were chlorinated by POCl3 to obtain the corresponding acyl chloride at 80 °C. Under an ice bath, differently substituted acryl chloride was dissolved in dichloromethane and stirred at 0 °C for 10-30 min. Another intermediates 15a-c were added to the above acryl chloride solution, and then added NaHCO3 solid powder, stirred at 0 °C for 0.5-3 h. After the reaction was completed, the reaction mixture was filtered and solvent was distilled off under reduced pressure. The crude product was purified using flash chromatography with dichloromethane/methanol(v/v, from 50:1 to 20:1) as eluents | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 0.5h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; | ||
With thionyl chloride at 80℃; for 3h; | ||
With thionyl chloride In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogenchloride In piperidine | 131.1 Step 1 Step 1 3-Benzylthio-3-methylbutanoic acid A solution of 3,3-dimethylacrylic acid (7 g, 70 mmol) and benzyl mercaptan (8.9 mL, 7.5 mmol) in piperidine (70 mL) was heated to reflux for 2 days. Piperidine was then evaporated and the product was partitioned between EtOAc and an aqueous solution of 1N HCl. The organic phase was washed with brine and dried over MgSO4. After evaporation of the solvent the product was distilled with a Kugelrohr apparatus under high vacuum (1 mmHg) to give 15.5 g of the title compound (99% yield). 1 H NMR (CDCl3) δ 1.50 (6H, s), 2.67 (2H, s), 3.82 (2H, s), 7.30 (5H, m). |
90% | With piperidine for 24h; Heating; | |
81% | With piperidine for 22h; Heating; |
67% | With piperidine for 18h; Reflux; Cooling with ice; | 6 Separately, a mixture of 3-methylbut-2-enoic acid (20.0 g, 0.2 mol) and benzyl mercaptan (25.0 g, 0.2 mol) in piperidine (40 mL) was stirred under reflux for 18 hours. The reaction mixture was cooled in an ice-bath, then acidified with 6M aqueous HC1 and thenextracted with EtOAc. The combined organic layers were washed with brine dried (Na2504) and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/EtOAc) to afford 30 g of 3-(benzylthio)-3-methylbutanoic acid (67% yield) as a yellow oil. This material (15.0 g, 66.9 mmol) was added in one portion to liquid ammonia (100 mL) at -60°C. Sodium (3.1 g, 134.7 mmol) was then added in small pieces overa 30 minute period. The resulting reaction mixture was stirred for 3 hours at -60°C and then slowly warmed to room temperature. A stream of nitrogen was passed through the mixture to remove an excess of ammonia. The residue was dissolved in dilute aqueous hydrochloric acid and then extracted with CH2C12. The combined organic layers were washed with brine, dried |
With piperidine; ethanol; sodium ethanolate at 100℃; | ||
With piperidine Heating; | ||
With piperidine for 14h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With phosphorus pentoxide In methanesulfonic acid at 70℃; for 0.333333h; Inert atmosphere; Microwave irradiation; | General procedures for the synthesis of 5- and 7-hydroxy-2,2-dimethyl-4-chromanones. A solution of the appropriate resorcinol 1 in methanesulfonic acid and 3,3-dimethylacrylic acid were added to a suspension of P2O5 in methanesulfonic acid under N2 atmosphere. The reaction mixture was heated following three different procedures: a) irradiation by microwave at 70 C ina sealed reactor for 10 minutes; b) irradiation by microwave at 70 C in a sealed reactor for 20minutes; c) irradiation by microwave at 70 C in a sealed reactor for 1 hour; d) conventionalheating at 70 C for about 12 hours. The reaction mixture was poured onto water/ice and thenextracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4. Solvent was removed under reduced pressure. The crude compounds were purified and isolated bychromatography on silica gel (hexane/EtOAc). |
96% | With methanesulfonic acid; phosphorus pentoxide at 70℃; | |
94% | With methanesulfonic acid; phosphorus pentoxide at 70℃; for 0.5h; |
92% | With methanesulfonic acid; phosphorus pentoxide at 70℃; for 0.5h; Inert atmosphere; | |
85% | With trifluoroacetic acid at 80℃; for 1h; | |
80% | With zinc(II) chloride; trichlorophosphate at 50℃; for 2h; | |
80% | With trifluorormethanesulfonic acid at 70℃; for 2h; | |
59% | With zinc(II) chloride; trichlorophosphate at 50℃; for 3h; | 4.1.1 7-Hydroxy-2,2-dimethylchroman-4-one (3) A mixture of resorcinol 1 (10.00g, 90.82mmol), 3-methyl-2-butenoic acid (2) (9.09g, 90.82mmol), zinc chloride (13.74g, 136.22mmol) and phosphorus oxychloride (139.24g, 0.91mol) was heated at 50°C for 3h. The reaction mixture was then poured into ice water (80mL), and the resulting precipitate was filtered off. The residue was purified by silica column chromatography to afford 3 (10.27g, 59%) as brown solid. mp 172-174°C, ESI-MS m/z calcd for C11H13O3 [M+ H]+ 193.1, found 193.4. |
With hydrogen fluoride | ||
With antimony(III) chloride at 140℃; | ||
With tin(ll) chloride at 140℃; | ||
With methanesulfonic acid; phosphorus pentoxide at 70℃; for 30h; | ||
With zinc(II) chloride In dichloromethane for 6h; Reflux; | ||
12.8 g | With zinc(II) chloride; trichlorophosphate at 50℃; for 2h; | |
With methanesulfonic acid for 1h; Inert atmosphere; Reflux; | 1 Resorcinol 6.87g(0.0625mol) and (6.25g 0.0625mol) of 3-methyl-2-butenoic acid, 100ml methanesulfonic acid; 1000mL roundbottom flask, N2 protection, controlling the reaction temperature in 70 to 80 DEG C, under magnetic stirring reflux reaction 1H, using TLC to monitor the reaction situation, after the reaction is completed, cooling to room temperature, Pour the reaction liquid into the 500g in the ice water mixture, static to room temperature,Gradually release a large number of solids filtration light pink solid, 11.61g, the yield was 96.8%. Recrystallization of white crystals, the recrystallization of white crystals. | |
1.2 g | With zinc(II) chloride; trichlorophosphate at 50℃; for 2h; | Synthesis of 7-hydroxy-2, 2-dimethylchroman-4-one (S3). To a stirred suspension of resorcinol (1.3 g, 12 mmol), 3, 3-dimethylacrylic acid (1.2 g, 12 mmol) and phosphorous oxychloride (9.6 mL, 104 mmol) was added unfused ZnCl2 (2.3 g, 17mmol). The mixture was heated at 50 °C for 2 h. The resulting deep-red, homogeneous solution was then poured onto 100 g of crushed ice and allowed to sit for 12 h. The precipitate was collected by vacuum filtration, washed with H2O (3 x 25 mL) and dried in air, which was purified by chromatography (hexanes-EtOAc = 70:30) on silica gel to afford S3 (1.2 g). |
4.88 g | Stage #1: 3-Methylbutenoic acid; recorcinol With methanesulfonic acid at 70 - 80℃; for 1h; Inert atmosphere; Reflux; Stage #2: With hydrogenchloride; zinc amalgam In ethanol; water for 96h; Reflux; | 1 Preparation of 7-{3-[4-(3-trifluoromethylphenyl)piperazinyl]propoxy}-2,2-dimethyl-4-chromanone 6.87 g (0.0625 mol) of resorcinol, 6.25 g (0.0625 mol) of 3-methyl-2-butenoic acid, 100 mL of methanesulfonic acid was added to a 1000 mL round bottom flask, passed to N2, Control reaction temperature between 70 ~ 80 , under the magnetic stirring reflux reaction 1h, The reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature. The reaction solution was poured into 500 g of ice-water mixture, allowed to stand to room temperature, and gradually precipitated a large amount of solid, The filtrate was filtered to give 11.61 g of a pale pink solid in a yield of 96.8%. Recrystallization give white crystals. 10 g (0.0521 mol) of chromanone was dissolved in 100 mL of ethanol, A freshly prepared zinc amalgam was added to a 500 mL round bottom flask, Heating reflux reaction, add hydrochloric acid 3mL per hour, keep the solution pH = 1 ~ 2. The reaction was stopped for 4 days, the reaction was quenched, ethanol was removed by steaming, extracted with dichloromethane (3 x 50 mL) The organic phases were combined, dried over anhydrous magnesium sulfate, and the white oil was isolated by column chromatography using cyclohexane to give 4.88 g of white crystals in 52.7% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With aluminum (III) chloride; at 5 - 20℃; for 0.333333h; | (0554) Step-I: To a cooled (0-5C) solution of 3,3-dimethylacrylic acid (10 g, 1.0 eq) in dry benzene (50 ml) was added anhydrous aluminum chloride (16 g, 1.2 eq) in small portions and the temperature was kept below 5C. The reaction mixture was stirred for 20 minutes and then allowed to attain to room temperature. After completion of reaction, diethyl ether (50 ml) was added to reaction mixture and it was then cooled to 0C. Hydrochloric acid (IN) was added to the reaction mixture until all of the solid dissolved and pH was less than 2. The aqueous layer was extracted with diethyl ether (3 x 50 ml). The organic layer was concentrated to reduce the volume to 50 ml and then extracted with saturated aq. sodium bicarbonate solution (6 x 30 ml). The combined aqueous layers were acidified with hydrochloric acid until the pH was less than 2. The aqueous layer was extracted with diethyl ether (3 x 50 ml). The combined organic layers were dried over anhydrous sodium sulfate and distilled to afford compound 17A (17.5 g, yield: 98%) as a low melting off white solid. |
94% | 3-methyl-3-phenylbutanoic acid (2) 3-Methyl-2-butenoic acid (1, 5.10 g, 50.9 mmol) and AlCl3 (20.4 g, 153 mmol) were placed in a one-neck round-bottomed flask. Benzene (50 mL) was added, which produced vigorous bubbling. Upon completion of the bubbling, a capped condenser (i.e. closed system) was attached, the reaction mixture was stirred and placed in an oil bath at 65 C. The pressure in the system was occasionally released. The progress of the reaction was followed by following the loss of starting material by GC. If the reation was not complete within 1 h, a small quantity of AlCl3 was added and stirring was continued. To the solution was added diethyl ether and the mixture was cooled to 0 C. Slowly conc. HCl and some water were added until all the solid dissolved and the pH was less than 2. The aqueous layer was extracted with diethyl ether three times. The organic layer was concentrated to 150 mL and then was extracted with a saturated sodium hydrogen carbonate solution six times. The combined aqueous layer were acidified with conc. HCl until the pH was less than 2. The acidic aqueous layer was extracted with diethyl ether three times and the accumulated organic layer was dried with magnesium sulfate. The solution was filtered and the diethyl ether was removed in vacuo producing a white solid (8.51 g, 47.7 mmol) in 94% yield, which did not need further purification. mp 55-56 C. 1H-NMR (400 MHz, CDCl3) 10.45 (bs, 1H, CO2H), 7.38 (d, 2H, J=7.2 Hz, H-11 and H-7), 7.32 (t, 2H, J=7.2 Hz, H-10 and H-8), 7.21 (t, 2H, J=7.2 Hz, H-9), 2.65 (s, 2H, H-2), 1.47 (s, 6H, H-5 and H-4); Mass spectrum (EI) 178 (23, M+), 119 (100, [C9H11]+). For pioneering work to form 2 see: F. J. Eijkman (1908) Chem. Kentr. II, p. 110; or A. Hoffman (1929) J. Am. Chem. Soc. 51:2542. | |
77% | With aluminum (III) chloride; at 0 - 20℃; for 17.33h; | A solution of 3-methylbut-2-enoic acid (10.0 g; 0.10 mol) in dry benzene (25 mL) was stirred in an ice-bath while anhydrous aluminum chloride (16.0 g; 0.12 mol) was added in small portions over 1 h and the temperature was kept below 5C. The reaction mixture was cooled and stirred for twenty minutes, then the cooling bath was removed and the mixture was vigorously stirred and allowed to attain room temperature. After being stirred for 16 hours, the reaction was poured over a large quantity of ice and the excess of benzene was removed in vacuo. The water was <n="161"/>removed by filtration and the brown gum was triturated in ethanol- water (1:1 ratio). The resulting off-white solid was collected by suction filtration and dried at 50C under vacuum overnight (13.7 g; 77% yield).1H NMR (300 MHz, DMSO-d6) δ(ppm): 11.78 (br. s., 1 H), 7.33-7.43 (m, 2 H), 7.21- 7.33 (m, 2 H), 7.07-7.21 (m, 1 H), 2.56 (s, 2 H), 1.37 (s, 6 H). |
46% | Preparation of 3-Methyl-3-phenylbutanoic Acid (MD015) 3-methyl-2-butenoic acid (97%, 5.26 g, 51.0 mmol) and AlCl3 (20.4 g, 153 mmol) were placed in a one-neck round-bottomed flask (250 ml) under an argon atmosphere. Benzene (50 ml, 560 mmol) was added producing vigorous bubbling. Upon completion of the bubbling, a condenser capped by a balloon with argon was attached. The reaction mixture was stirred in an oil bath at 65 C. for 1 h and 35 min. Diethyl ether was added to the solution and the mixture was cooled to 0 C. Concentrated HCl and water were added slowly until the entire solid dissolved and the pH was less than 2. The aqueous layer was extracted with diethyl ether four times. The organic layer was concentrated to 150 ml and extracted with a saturated sodium hydrogen carbonate solution six times (6*150 ml). The combined aqueous layers were acidified with concentrated HCl until the pH was less than 2. The acidic aqueous layer was extracted with diethyl ether four times and the accumulated organic layer was dried with magnesium sulfate. The solution was filtered and the diethyl ether was removed in vacuo, producing a white solid (4.42 g, 24.8 mmol) in 46% yield, which did not need further purification, mp 55.5-57.0 C. 1H-NMR (400 MHz, CDCl3) 11.25 (bs, 1H, CO2H), 7.37 (d, 2H, J=7.6 Hz, H-11 and H-7), 7.31 (t, 2H, J=7.2 Hz, H-10 and H-8), 7.20 (t, 1H, J=7.2 Hz, H-9), 2.65 (s, 2H, H-2), 1.47 (s, 6H, H-4 and H-5). | |
26.3 g | With aluminum (III) chloride; at 10 - 40℃; for 1.5h; | Aluminum chloride (24.1 g) was added to a solution of 3-methyl-2-butene acid (15 g) in benzene (100 mL) at 10 C.After stirring for 30 minutes, the mixture was stirred at 40 C. for 1 hour. After cooling to 0 C., ice water was added, the mixture was extracted with tert-butyl methyl ether, concentrated to some extent, and the organic layer was extracted with a saturated aqueous sodium hydride solution. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid and extracted with tert-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound J1 (26.3 g). |
With aluminum (III) chloride; In benzene; at 0 - 20℃;Inert atmosphere; | To a solution of 3-methylbut-2-enoic acid (1.0 g, 10.0 mmol) in anh. benzene (2.5 mL), cooled at 0-5 C, AlCl3 (1.60 g, 12.0 mmol) was added portionwise over 1 h under an argon atmosphere. The reaction mixture was stirred for further 20 min at this temperature and afterwards at r.t. overnight. Then, the reaction mixture was poured into ice and it was allowed to stir for 15 min. Benzene was evaporated under vacuo and the resulting solid residue was slurried in a mixture of EtOH-water 1:1. The solids were filtered and dried under vacuum. The crude solid was slurried in water, the pH was adjusted to 3 with 1 N HCI and it was extracted 3 times with Et2O. The combined organic phases were extracted six times with Na2CO3 sat. sol. The basic aqueous phases were combined, the pH was readjusted to 3 with 3 N HCI and it was extracted again with Et2O. After checking that both ethereal phases contained desired product by HPLC/MS, they were combined, dried over Na2SO4, filtered and concentrated to dryness. The crude product obtained was used in the next step without further purification (0.835 g, 47% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.8% | In tetrachloromethane for 24h; Heating; | |
87% | With sulfuric acid for 16h; Reflux; | |
72% | With sulfuric acid for 10h; Heating; |
70% | With zeolite RE H-Y at 150℃; for 8h; | |
52% | With copper dichloride at 130℃; for 24h; | |
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With aluminum (III) chloride for 5h; Reflux; | |
89% | With aluminum (III) chloride for 5h; Reflux; | |
86% | With aluminum (III) chloride at 80℃; for 5h; | 2.14 3,3-Dimethyl-2,3-dihydro-lH-inden-l-one (RLE-14.1) A solution of 3-methylcrotonic acid (19.0 mmol, 1.90 g) in benzene (10.0 mL) was slowly added to AICU (57.0 mmol, 7.60 g) in a 100 mL round-bottom flask. The resulting mixture was heated to reflux for 5 h, cooled to 0 °C, quenched with 1M HCI (50.0 mL) and extected with EtOAc (3 x 50.0 mL). The combined organics were washed with a saturated aqueous solution of NaHCCh (3 x 100 mL) and saturated aqueous solution of NaCI (100 mL), dried (MgSC ) and concentrated under reduced pressure. Flash chromatography (9:1, hexanes/EtOAc) gave 2.62 g of 14.1 (86% yield) as an orange oil. 1H NMR (400 MHz, Chloroform-d) δ 7.72 - 7.67 (m, 1H), 7.65 - 7.57 (m, 1H), 7.53 - 7.47 (m, 1H), 7.39 - 7.32 (m, 1H), 2.60 - 2.58 (m, 2H), 1.47 - 1.36 (m, 6H); 13C NMR (101 MHz, Chloroform-d) d 205.7, 163.7, 135.1, 134.8, 127.2, 123.4, 123.2, 52.8, 38.4, 29.8. |
83% | With aluminum (III) chloride at 0 - 80℃; for 3.16667h; | 1 preparation of compound 1-1 3After all of the dissolved dimethyl3acrylicacid 30g (299.85mmol) in 150mL of benzene while maintaining the 0 C wasadded dropwise a AlCl3120g (899.6mmol) slowly. 0 C, stirring for 10 minutes at room temperature to 80 C andstirred for 3 hours. After completion of the reaction and then after cooling to room temperature the reaction was terminatedby cold hydrochloric acid and extracted with distilled water and EA. Purification of the rotary evaporator to remove the solventof dichloromethane and hexane and the organic layer was dried over anhydrous MgSO4 by column chromatography as adeveloping solvent to obtain the title compound 1140.0g(83%). |
80% | With aluminum (III) chloride for 5h; Reflux; | |
80% | With aluminum (III) chloride for 5h; Reflux; | |
78% | With aluminum (III) chloride for 5h; Reflux; Inert atmosphere; | 8.8-1 Synthesis of [Reaction Formula 8-1] [intermediate 8-a] Dried after the nitrogen into the reactor 3-methyl crotonic acid100.0 g (999 mmol), stirring for inserting and removing a 500 ml benzene. Aluminum chloride 399.5 g (2996 mmol) is slowly into the stirring the reflux time 5. After the reaction, 1500 ml hydrochloride 6N low temperature reaction mixture 30 ingredient blended slowly place as ethyl acetate and water extraction of organic layer after, concentrating it under reduced pressure which comprises purifying an vacuum distilling a derivative is represented by the following [intermediates 8-a] 125.0g (yield 78%)is obtained. |
73% | With aluminum (III) chloride at 0℃; Reflux; | 1.1 Step 1: Preparation of 3,3-dimethyl-indan-1-one Step 1: Preparation of 3,3-dimethyl-indan-1-one [0236] 3,3-dimethyl acrylic acid in 250 ml of benzene was cooled to 0° C. in an ice bath. To this solution, 99 g (0.75 moles) of anhydrous aluminum chloride was slowly added using a spatula over a period of 20 minutes with stirring, after which the ice bath was removed and the reaction mixture was gradually heated to reflux. The reaction mixture was refluxed for 7-8 h, then excess benzene was distilled off and the mixture was quenched with ice-cold dilute hydrochloric acid (HCl). The mixture was then diluted with ethylacetate (100 ml), the organic layer was separated and the aqueous layer was again washed with ethyl acetate (50 ml). The combined organic layer was washed with water (3×100 ml) until the pH was neutral, and then dried over anhydrous sodium sulfate and concentrated under vacuum. 43.0 g of reddish brown liquid was obtained, which was distilled under vacuum to give 29 g of the desired product, 3,3-dimethyl-indan-1-one (distilled at 82-84° C. at 10 mm). Yield=73%, purity=99%. 1H NMR (DMSO-d6, 300 MHz): δ 7.3-7.8 (m, 4H, Ar-H), δ 2.5 (s, 2H, O═C-CH2), δ 1.3 (s, 6H, -CH3). LC/MS: 161 (M+1). |
69% | With H-USY zeolite at 130℃; for 20h; | |
62% | With aluminium trichloride for 1h; Heating; | |
12.6 g | With aluminum (III) chloride for 5h; Reflux; | 3-Methylcrotonic acid (9.46 g, 95 mmol) was slowly added to aluminum chloride(38.0 g, 285 mmol) in benzene, and the mixture was stirred at reflux for 5 h. Thismixture was poured into ice-cold hydrochloric acid. The organic layer was washedwith sodium carbonate solution, separated, and concentrated to give a3,3-dimethyl-1-indanone (12.6 g). |
With aluminum (III) chloride Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.35% | With triethylamine; In tetrahydrofuran; for 20h;Reflux; Inert atmosphere; | Add 0.04 mol of 2-mercaptothiophene, 0.04 mol to a 250 mL round bottom flask3-methyl-2-butenoic acid,80 mL of tetrahydrofuran, 11 mL of triethylamine was added dropwise with stirring, and the reaction was heated under reflux for 20 h under nitrogen.The reaction is completed.The tetrahydrofuran was evaporated, and after cooling, 40 mL of ethyl acetate and water were added.The pH of the solution was adjusted to 2 with 18% hydrochloric acid, and the organic layer was collected.The organic layers were combined and dried over anhydrous magnesium sulfate. After suction filtration, the filtrate was evaporated to remove the solvent, and after cooling, a brown solid precipitated.Recrystallization from petroleum ether gave a white powdery solid, yield 5.47 g, yield 63.35%. |
63.35% | With triethylamine; In tetrahydrofuran; for 20h;Reflux; Inert atmosphere; | Add 0.04 mol of 2-mercaptothiophene to a 250 mL round bottom flask.0.04 mol of 3-methyl-2-butenoic acid, 80 mL of tetrahydrofuran,11 mL of triethylamine was added dropwise with stirring, and the reaction was heated under reflux for 20 h under nitrogen.The reaction is completed. Evaporate the tetrahydrofuran and cool it.Add 40 mL of ethyl acetate and water, and adjust the pH of the solution to 2 with 18% hydrochloric acid.The organic layer was collected, and the aqueous layer was extracted with ethyl acetate.It was dried over anhydrous magnesium sulfate. Filter by suction and evaporate the solvent from the filtrate.After cooling, the brown solid precipitated and recrystallized from petroleum ether to give a white powdery solid.The yield was 5.47 g, and the yield was 63.35%. |
63.35% | With triethylamine; In tetrahydrofuran; for 20h;Inert atmosphere; Reflux; | 0.04 mol of 2-mercaptothiophene, 0.04 mol of 3-methyl-2-butenoic acid and 80mL tetrahydrofuran were added to a 250 mL round bottom flask. 11 mL of triethylamine was added dropwise with stirring under the protection of nitrogen, heated and refluxed for 20 h. After completion of the reaction, tetrahydrofuran was evaporated, cooled, 40 mL of ethyl acetate and water were added, and the pH of the solution was adjusted to 2 with 18% hydrochloric acid. The organic layer was collected, the aqueous layer was evaporated, suction filtered, the solvent was evaporated from the filtrate, cooled and a brown solid was precipitated. The resulting solids were recrystallized from petroleum ether to give a white powdery solid. The yield was 5.47 g, and the yield was 63.35%. |
63.4% | With triethylamine; In tetrahydrofuran; for 20h;Inert atmosphere; Reflux; | Add 0.04 mol of 2-mercaptothiophene to a 250 mL round bottom flask.0.04 mol of 3-methyl-2-butenoic acid, 80 mL of tetrahydrofuran,11 mL of triethylamine was added dropwise with stirring.Under a nitrogen atmosphere, the reaction was heated to reflux for 20 h, and the reaction was completed. After evaporating the tetrahydrofuran, after cooling, 40 mL of ethyl acetate and water were added, and the pH of the solution was adjusted to 2 with 18% hydrochloric acid, and the organic layer was collected.It was dried over anhydrous magnesium sulfate. Filter by suction and evaporate the solvent from the filtrate.After cooling, a brown solid precipitated, which was crystallized from petroleum ether to yield white powdery solid, yield 5.47 g, yield 63.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With aluminium trichloride; trichlorophosphate for 5h; Ambient temperature; | |
72% | With phosphorus pentoxide In methanesulfonic acid at 70℃; for 12h; Inert atmosphere; | General procedures for the synthesis of 5- and 7-hydroxy-2,2-dimethyl-4-chromanones. A solution of the appropriate resorcinol 1 in methanesulfonic acid and 3,3-dimethylacrylic acid were added to a suspension of P2O5 in methanesulfonic acid under N2 atmosphere. The reaction mixture was heated following three different procedures: a) irradiation by microwave at 70 C ina sealed reactor for 10 minutes; b) irradiation by microwave at 70 C in a sealed reactor for 20minutes; c) irradiation by microwave at 70 C in a sealed reactor for 1 hour; d) conventionalheating at 70 C for about 12 hours. The reaction mixture was poured onto water/ice and thenextracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4. Solvent was removed under reduced pressure. The crude compounds were purified and isolated bychromatography on silica gel (hexane/EtOAc). |
Stage #1: orcinol; 3-Methylbutenoic acid With aluminum (III) chloride; trichlorophosphate at 20℃; for 6h; Stage #2: With water Cooling with ice; | 44.1 Anhydrous 5-methylbenzen-1,3-diol (3.678 g), 3,3-dimethylacrylic acid (3.3 mL) and aluminum chloride (14.76 g) were added to phosphoryl chloride (45 mL) and the mixture was shaken at room temperature for 6 hours. The reaction solution was poured into ice, and the precipitates were filtered, washed with water and dried. The precipitates were purified by column chromatography on silica gel (Solvent; petroleum ether/ethyl acetate = 25/1) to give the titled compound (3.8 g) as a colorless powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With trifluoroacetic acid at 80℃; for 1h; | |
80% | With polyphosphoric acid at 100℃; Inert atmosphere; | Synthesis of 7-methoxy-2,2-dimethylchroman-4-one (14): Compounds 10 (5.0 g, 40.32 mmol) and 11 (4.03 g, 40.32 mmol) were taken in round bottom flask and polyphosphoric acid (PPA, 20.0 g) was added to it. The reaction mixture was heated at 100oC. The progress of reaction was monitored using TLC (10% Ethyl acetate-Hexane). After completion, the reaction mixture was poured on ice and extracted by ethyl acetate. The organic layer was washed with NaHCO3 solution. Organic layer was then separated and dried over anhydrous sodium sulphate (Na2SO4) and concentrated. The crude material was purified by column chromatography using silicagel (100-200 mesh size) using ethyl acetate:hexane (2:98) which yielded pure compound 12 as off white solid. Yield: 80%; mp: 79-80C; Rf: 0.85 (10% Ethyl acetate-Hexane); 1H NMR (CDCl3, 300 MHz, δ ppm): 1.44 (s, 6H, 2xCH3), 2.46 (s, 2H, CH2), 3.81 (s, 3H, OCH3), 6.34 (d, J = 7.6 |
80% | With Polyphosphoric acid at 100℃; |
56% | With PPA at 90℃; for 6h; | |
45% | With bismuth(lll) trifluoromethanesulfonate In toluene at 110℃; regioselective reaction; | General procedure for the preparation of 4-chromanones from the phenol and the carboxylic acids. General procedure: To a solution of the phenol (5, 1.0 mmol) and the acrylic acid (6 or 7, 1.0 mmol) in 8 mL of toluene was added bismuth(III) triflate (41 mg, 0.06 mmol, 20 mol%). The reaction was heated under reflux for 12-24 h and then cooled. Removal of the solvent under vacuum and purification by PTLC eluted with 5% ether in hexane (8-10% ether in hexanes for the methoxy-substituted products) showed several bands. The major band (bright fluorescent blue) was isolated and extracted with ether to give the 4-chromanone 4 or 8. The other bands consisted of varying amounts of the aryl ester of the carboxylic acid and unreacted phenol. The following compounds were prepared. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With aluminium chloride anhydrous; trichlorophosphate for 5h; Ambient temperature; | |
90% | Stage #1: 3-Methylbutenoic acid With boron trifluoride diethyl ether complex; trichlorophosphate at 0℃; for 0.25h; Stage #2: 3,5-dihydroxyphenol at 25℃; for 5h; | |
88% | With boron trifluoride diethyl ether complex at 70℃; for 2h; |
84% | With boron trifluoride diethyl ether complex at 25 - 80℃; | |
83% | With boron trifluoride diethyl ether complex at 70℃; for 2.5h; | |
82% | With anhydrous zinc chloride; trichlorophosphate at 50℃; for 5h; | |
70% | With PPA | |
70% | With boron trifluoride diethyl ether complex at 70℃; for 3h; | 1.1 [1] Take a 100ml reaction flask, dissolve phloroglucinol (6.48g, 40mmol) in BF3-Et20 (40mL), stir magnetically . Dissolve, add 3,3-dimethylacrylic acid (4.8g, 48mmol), 70 of stirring reactions, TLC monitoring reaction, the product is concentrated after 3h. The degree no longer changes, the reaction ends. The reaction solution was poured into 300 mL of ice water, extracted with ethyl acetate 2-3 times, and the organic phases were combined and saturated washed 2-3 times with brine, dried over anhydrous sodium sulfate, and rotary evaporated to obtain a yellow oily crude product, which was purified by column chromatography (petroleum ether: ethyl acetate) ester = 8:1) to yield Intermediate 1 as a pale yellow solid (70%). |
60% | With anhydrous zinc chloride; trichlorophosphate at 20℃; for 18h; | |
With anhydrous zinc chloride; trichlorophosphate at 50℃; for 3.5h; | ||
With diphosphorus pentoxide at 70℃; for 0.5h; | 42.1 40 ml of methanesulfonic acid was added to 1.99 g of diphosphorus pentoxide under nitrogen atmosphere. Thereafter, a mixture consisting of 3.15 g of 1,3,5-trihydroxybenzene and 3,3-dimethylacrylic acid was added to the reaction solution at 70° C. The reaction solution was stirred at 70° C. for 30 minutes and then cooled to a room temperature. The reaction solution was added to ice water, followed by extraction with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 2.81 g of the subject compound. 1H-NMR (CDCl3) δ (ppm): 1.43 (s, 6H), 2.68 (s, 2H), 5.53 (br.s, 1H), 5.87 (d,-J=2.4 Hz, 1H), 5.93 (d, J=2.4 Hz, 1H), 12.03 (s, 1H) | |
With trichlorophosphate | 2 Preparation of 5,7-dihydroxy-2,2-dimethylchroman-4-one (Id) Example 2 Preparation of 5,7-dihydroxy-2,2-dimethylchroman-4-one (Id) Phosphoryl chloride (14 ml, 152 mmol) is initially introduced, and 3-methylcrotonic acid (1.6 g, 16 mmol), then zinc chloride (3.1 g, 23 mmol) and then phloroglucine (2 g, 16 mmol) are slowly added with stirring. The mixture is stirred overnight at room temperature. The suspension is subsequently poured slowly onto about 50 g of ice with ice-bath cooling, during which a solid precipitates, which is filtered off and dried at 45° C. in a vacuum drying cabinet, giving 5,7-dihydroxy-2,2-dimethylchroman-4-one. | |
With boron trifluoride diethyl ether complex In water monomer at 70℃; for 3h; | ||
With potassium carbonate at 60℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | With piperidine at 105 - 110℃; for 32h; | 1 Synthesis of3-(4-methoxyphenylthio)-3-methyl-butyric acid 10430] A heavy-walled screw-cap tube was charged with3-methyl-2-butenoic acid (13.86 gm) 3,3-dimethylacrylic acid, (138.4 mmol), 4-methoxythiophenol (143.2 mmol), and piperidine (41.6 mmol) [Aldrich]. The mixture was heated to 105-110° C. for 32 hours, then cooled to room temperature. The reaction mixture was dissolved in ethyl acetate (EtOAc) (700 ml) with stirring, and the resulting solution was washed with IM aqueous HC1 (50 mlx2), water (50 ml), and saturated aqueous NaC1 (50 ml). The organic solution was thereafter dried over Na504. Concentration of this organic solution under reduced pressure afforded an oil and 2 days incubation at -20° C. yielded a crystalline solid. Forty ml of pentane were added to the solid, which was then crushed and filtered. The solid was washed on filter paper with pentane (20 ml, 2 times) to yield the product 3-(4-methoxyphenylthio)-3-me- thyl-butyric acid, as pale yellow crystals (31.4 grams, 94.4% yield, m.p. 62-64° C.), [‘H-NMR (CDC13): d7.5 (t, 2H, J=8 Hz), d6.9 (t, 2H, J=6.7 Hz), d3.9 (s, 3H, J=16.1 Hz), d2.6 (s, 2H), dl.3 (s, 6H)]. |
85% | With piperidine at 103 - 107℃; for 17h; | |
82% | With piperidine at 105℃; for 32h; |
82% | With piperidine at 10℃; for 32h; | 7.1 A heavy- walled screw cap tube was charged with 3-methyl-2-butenoic acid (13.86 g, 138.4 mmol), 4-methoxy thiophenol (20.0 g, 138.4 mmol), and piperidine (3.45 g, 41.6 mmol). This mixture was heated to 100C for 32 hours, cooled to room temperature and dissolved in EtOAc (700 mL). The resulting solution was washed with IM aqueous HCl, H2O, and saturated aqueous NaCl before being dried over Na2SO4. Concentration of the dry solution under reduced pressure afforded an oil which upon standing in the freezer provided a crystalline solid. 3-(4-methoxy-phenylsulfanyl)-3- methyl-butyric acid was isolated as pale-yellow crystals by washing the crystalline solid with pentane. (27.33 g, 82%). 1H NMR (300 MHz, CDCl3) δ: 7.48 (2H, d, J=9.0 Hz), 6.89 (2H, d, J=8.9 Hz), 3.83 (3H, s), 2.54 (2H, s), 1.40 (6H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With methanesulfonic acid at 70℃; for 12h; | Synthesis of 6-Hydroxy-7-methoxy-2,2-dimethyl-4-chromanon (12) A mixture of 2-methoxy-hydroquinone 10 (150 mg, 1mmol) and 3,3-dimethyleacrilic acid 11 (1.2 mmol) in methenesulfonicacid (15 ml, 1.5% H2O according to KarlFischer analysis) was vigorously stirred at 70 oC. When reactioncompleted (TLC monitoring), the crude reaction mixturewas allowed to cool, poured into ice-water (200 mL) andextract with ether (3x25 ml). The fractions were washed with1 N NaOH solution (3x20 ml) and the joined basic fractionswere acidified and extracted with ether (3x25 mL). Theacidic organic fractions were washed with water, saturatedbrine (1x20 mL) and dried over Na2SO4. The solvent wasremoved by vacuum to afford the crude product. This wasfurther purified by column chromatography using ethylacetate-hexane (2:8) to afford compound 12, which was identifiedby comparison with an authentic sample. Yield 210 mg,95%; 1H NMR (200 MHz, CDCl3): 1.43 (s, 6H), 2.60 (s,2H), 3.92 (s, 3H), 5.2 (s, 1H), 6.33 (s, 1H), 7.29 (s, 1H); MS(ESI): m/z 223 [M+1]+; Anal.Calcd for C12H14O4: C, 64.85;H, 6.35. Found: C, 64.80; H, 6.30. |
91% | With methanesulfonic acid; phosphorus pentoxide at 70℃; for 0.5h; | |
91% | With methanesulfonic acid; phosphorus pentoxide | 4 Example 4: Synthesis of Compound of Formula (4) (7-Methoxy-2,2-Dimethyl-6-Chromanol) (See FIG. 5) Compound of formula (4) (=Lipochroman-6, CAS 83923-51-7) is prepared according to literature procedures (see FIG. 5 for the reaction scheme).First Step a): MeSO3H (solvent), P2O5 (50 mol-%, based on 2-methoxy-1,4-hydroquinone), yield: 91%. (F. Camps, J. Coll, A. Messeguer, M. A. Perics, S. Ricart, W. S. Bowers, D. M. Soderlund, Synthesis 1980, 725-727: “An Improved Procedure for the Preparation of 2,2-Dimethyl-4-chromanones.”)Second Step b): LiAlH4, Et2O, yield: 87%.(P. Anastasis, P. E. Brown, J. Chem. Soc., Perkin Trans. 1 1982, 2013-2018: “Analogues of antijuvenile hormones”.) |
84% | With trifluoroacetic acid at 80℃; for 1h; | |
48% | With PPA 1.) 30 deg C, 4 h, 100 deg C, 1 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium azide In water; acetic acid at 20 - 95℃; for 49h; | 7.a According to the method of S. Nagarajan et al.(J Org. Chem., 1986, 57, 4856), to a stirred solution of 3,3-dimethylacrylic acid (20 g, 0.2 mol) in glacial acetic acid (50 niL) was added a solution of sodium azide (52 g, 0.8 mol) in water (100 mL) in one portion. The clear yellow solution was stirred for 1 h at RT and then heated in an oil bath at 95 0C for 2 days. Water (50 mL) was added to the cooled orange solution. This solution was poured into a separatory funnel and extracted with ether (5x 200 mL). The combined organic extracts were dried over anh. MgSO4 and concentrated to an orange oil (26.0 g, 91%). This oil was used without further purification. |
83% | With sodium azide; acetic acid Heating; | |
75% | With sodium azide; acetic acid In water at 95℃; for 48h; |
With sodium azide; acetic acid In water at 95℃; for 48h; | ||
With sodium azide; acetic acid In water at 95℃; for 48h; | ||
With sodium azide In water at 20 - 95℃; for 49h; | 9 Example 9; 3-(dichloroamino)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-N,N,3-trimethylbutan-1 - aminium 4-methylbenzenesulfonate(Compound 38-45) LAH- V CbzOSu Cbz. ,, -^ ^,- . y „ N NH2N, MeOH3-Azido-3-methylbutanoic acidX . OHTo a stirred solution of 3,3-dimethylacrylic acid (20 g, 0.2 mol) in glacial acetic acid (50 mL) was added a solution of sodium azide (52 g, 0.8 mol) in water (100 mL) in one portion. The clear yellow solution was stirred for 1 hour at room temperature and then heated in an oil bath at 95 QC for 2 days. Water (50 mL) was added to the cooled orange solution. This solution was poured into a separatory funnel and extracted with ether (5 x 200 mL). The combined organic extracts were dried over anhydrous MgS04 and concentrated to an orange oil. This oil was used without further purification. 1 H NMR (CDCIs, 400 MHz): δ 1 .44 (s, 6H), 2.55 (s, 2H), 1 1 .80 (bs, 1 H). | |
7.1 g | With sodium azide; acetic acid at 95℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With [bmim]PF6; triethylamine In water at 100℃; for 20h; | |
45% | With sodium hydroxide; cetyltrimethylammonim bromide In toluene at 95℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With bismuth(lll) trifluoromethanesulfonate In toluene at 110℃; | General procedure for the preparation of 4-chromanones from the phenol and the carboxylic acids. General procedure: To a solution of the phenol (5, 1.0 mmol) and the acrylic acid (6 or 7, 1.0 mmol) in 8 mL of toluene was added bismuth(III) triflate (41 mg, 0.06 mmol, 20 mol%). The reaction was heated under reflux for 12-24 h and then cooled. Removal of the solvent under vacuum and purification by PTLC eluted with 5% ether in hexane (8-10% ether in hexanes for the methoxy-substituted products) showed several bands. The major band (bright fluorescent blue) was isolated and extracted with ether to give the 4-chromanone 4 or 8. The other bands consisted of varying amounts of the aryl ester of the carboxylic acid and unreacted phenol. The following compounds were prepared. |
18% | With PPA |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium acetate In water at 100℃; for 10h; | |
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; titanium(IV) oxide In benzotrifluoride for 8h; Irradiation; | ||
With oxygen In water at 20℃; for 336h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With di-isopropyl azodicarboxylate; thiamine diphosphate In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 1,2,3-Benzotriazole With thionyl chloride In dichloromethane at 25℃; for 0.5h; Stage #2: 3-Methylbutenoic acid In dichloromethane at 25℃; for 3h; | |
90% | With thionyl chloride In dichloromethane at 20℃; for 2h; | 1.1 Step 1: 1-Benzotriazol-1-yl-3-methyl-but-2-en-1-one 1H-Benzotriazole (2.14 g, 18.0 mmol, 4 equiv.) was dissolved in dichloromethane (25 ml) and thionyl chloride (330 μl, 4.5 mmol, 1 equiv.) was added at room temperature. (450 mg, 4.5 mmol) 3-Methyl-but-2-enoic acid [CAS 541-47-9] was added and the mixture was stirred for 2 hours at room temperature. The suspension was filtered and the filtrate was extracted once with 2N NaOH solution and twice with dichloromethane. The organic extracts were combined, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:cyclohexane gradient 0:100 to 50:50. The desired 1-benzotriazol-1-yl-3-methyl-but-2-en-1-one (810 mg, 90% yield) was obtained as a light yellow solid, MS: m/e=202.1 (M+H+). |
90% | With thionyl chloride In dichloromethane at 20℃; for 2h; | 1.1 Ste 1: l-Benzotriazol-l-yl-3-methyl-but-2-en-l-onelH-Benzotriazole (2.14 g, 18.0 mmol, 4 equiv.) was dissolved in dichloromethane (25 ml) and thionyl chloride (330 μ, 4.5 mmol, 1 equiv.) was added at room temperature. (450 mg, 4.5 mmol) 3-Methyl-but-2-enoic acid [CAS 541-47-9] was added and the mixture was stirred for 2 hours at room temperature. The suspension was filtered and the filtrate was extracted once with 2N NaOH solution and twice with dichloromethane. The organic extracts were combined, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flashchromatography on a silica gel column eluting with an ethyl acetate:cyclohexane gradient 0: 100 to 50:50. The desired l-benzotriazol-l-yl-3-methyl-but-2-en-l-one (810 mg, 90 % yield) was obtained as a light yellow solid, MS: m/e = 202.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With diphosphorus tetraiodide; tetraethylammonium bromide In carbon disulfide at 20℃; for 12h; | |
84.2% | With bromine In dichloromethane at 10 - 30℃; | 1 A process for the preparation of 2, 2-dimethylvinylboronic acid The first step, to the magnetic stirring 1L four bottles,500 g of dichloromethane was added,100 · 12g (L OOmol) 3,3-Dimethacrylic acid,A solution of 239.72 g (L 50 mol) of bromine was added dropwise at 10 to 30 ° C,After completion of the dropwise addition, the reaction is allowed to proceed for about 2 to 4 hours,Reaction process TLC detection reaction,3, 3-Dimethacrylic acid reaction to 90% or more,Cooling to 20 ~ 30 ° C,With 20% sodium carbonate aqueous solution to adjust PH9 ~ 10, 50 ~ 60 ° C reaction for 2 to 3 hours,After the temperature was lowered to room temperature, the organic layer was separated,The aqueous layer was extracted with methylene chloride,After the water layer product was extracted to 95%The organic layer was combined, dried and distilled to obtain the product 2, 2-dimethylvinyl bromide 113. 60 g, content 99.6% (GC), yield 84.2%. |
82% | With tetraethylammonium bromide; Dess-Martin periodane In dichloromethane at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | |
91% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | 5 This example describes the synthesis of compound 6 via a regioselective esterification reaction: To a solution of 3-methyl-2-butenoic acid (7.4 mg, 7.4 μmol), EDCI (1.7 mg, 9.0 μmol) and DMAP (1.0 mg, 8.2 μmol) in dichloromethane (1 mL) was added 3 (2.1 mg, 6.7 μmol). The mixture was stirred at room temperature for 2 h, and then diluted with dichloromethane (8 mL) and washed with water, saturated sodium bicarbonate, water and then brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by RP-HPLC (gradient elution: 5-65% CH3CN in water in 55 min) to give 5 (2.4 mg) in 91 % yield. [α]D20 +34.0 (c, 1.7 MeOH); 1H NMR (600 MHz, CD3OD) δ 1.64 (m, -CH2, IH), 1.73 (m, -CH2, IH), 1.89 (m, -CH2, IH), 1.92 (s, -CH3, 3H), 2.00 (t, J= 13 Hz, -CH2, IH), 2.08 (dd, J= 4.3, 5.1 Hz, -CH2, IH); 2.12 (m, -CH2, 2H), 2.17 (s, -CH3, 3H), 2.20-2.27 (m, -CH2CH2- 4H), 3.51 (dd, J= 5.6, 9.1 Hz, - =CHCH2NHCO-, IH), 3.86 (dd, J= 6.7, 9.1 Hz, ^CHCH2NHCO-, IH), 3.93 (t, J = 3.2 Hz, CHOH, IH), 4.99 (dt, J= 5.3, 5.5 Hz, CHOH, IH), 5.39 (m, -CHOH, IH), 5.52 (m, -CH=CH-, 2H), 5.75 (m, -(CH3)2C=CH-, IH); 13C NMR (75 MHz,CD3OD) δ 22.9, 26.3, 28.8, 30.0, 33.6, 36.3, 37.8, 38.6, 41.5, 69.4, 73.2, 75.5, 76.9, 119.6, 131.3, 136.1, 161.1, 170.0, 177.2, 179.0; IR (cm"1) 3365, 2929, 1673, 1644, 1540, 1440, 1202; HRMS (ES+) m/z 396.2010 MH+ (396.2022 Calcd for C20H30NO7 MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium phosphate; carbon dioxide; CrH6Mo6O24(3-)*3H3N*3H(1+) In dimethyl sulfoxide at 80℃; for 24h; Green chemistry; | |
Multi-step reaction with 2 steps 1: 1-hydroxy-1,2-benziodoxole-3(1H)-one-1-oxide / dimethylsulfoxide / 16 h / 20 °C 2: NaOH; H2O / dimethylsulfoxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With thionyl chloride; aniline In dichloromethane; triethylamine | 3 3-Methyl-but-2-enoic acid phenylamide Example 3 3-Methyl-but-2-enoic acid phenylamide A mixture of 3-methyl-but-2-enoic acid (100 g, 1 mol) and SOCl2 (119 g, 1 mol) was heated at reflux for 3 h. The excess SOCl2 was removed under reduced pressure. CH2Cl2 (200 mL) was added followed by the addition of aniline (93 g, 1.0 mol) in Et3N (101 g, 1 mol) at 0° C. The mixture was stirred at room temperature for 1 h and quenched with HCl (5%, 150 mL). The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with water (2*100 mL) and brine (100 mL), dried over Na2SO4 and concentrated to give 3-methyl-but-2-enoic acid phenylamide (120 g, 80%). |
Multi-step reaction with 2 steps 1: thionyl chloride | ||
Multi-step reaction with 2 steps 1: sodium hydroxide; thionyl chloride / N,N-dimethyl acetamide; water / 0.42 h / -5 °C / Inert atmosphere 2: N,N-dimethyl acetamide; water / 1 h / 0 - 20 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: thionyl chloride / 3 h / Reflux 2: triethylamine / 1 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 23 °C 2: triethylamine / dichloromethane / 2 h / 0 - 23 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogen bromide In water at 20 - 35℃; for 1h; | 1 Example 1 Compound 3A 250 g of 3,3-dimethylacrylic acid are added to 1 L 62% hydrobromic acid (HBr) at 20° C. with stirring. The mixture is stirred for 60 minutes at 20° C.-35° C., then extracted at 35° C. with 900 mL of toluene in several batches. The combined organic extracts are evaporated to dryness in vacuo. 417 g (92%) crude product are obtained. 408 g of the crude product are dissolved in 660 mL anisole and 70 mL solvent are distilled off in vacuo. The solution at a temperature of 35° C. is added to a mixture of 1 L anisole and 442.4 g aluminum chloride kept at a temperature of 20° C. The mixture is stirred for 4 hours at ambient temperature, then the solution is poured into 1.5 L of ice water and stirred for 80 minutes. The phases are separated and the organic phase is extracted with 250 mL of 62% hydrobromic acid. Then the organic phase is extracted with 1.5 L of sodium hydroxide solution at pH 10-11. After the phase separation the aqueous phase is washed twice more with 350 mL of toluene. The aqueous phase is adjusted to pH 1-2 with hydrobromic acid at 50-60° C. and extracted with 1.25 L toluene in 2 batches. These toluene phases are evaporated to dryness in vacuo and the residue is crystallized with 510 mL methylcyclohexane at 5° C. The solid obtained is separated off, washed with 100 mL methylcyclohexane and dried in vacuo at 50° C. Yield 149.8 g (32%) of compound 3A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: 3-Methylbutenoic acid With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78 - 0℃; for 0.5h; Stage #2: p-cyanophenyl methyl sulfide In tetrahydrofuran; n-heptane; ethylbenzene at -78 - 20℃; for 3h; | 1 Intermediate 1 [4-METHYL-6-F4- (METHYLTHIO) PHENYLL-2-PVRIDONE] Intermediate 1 [4-METHYL-6-F4- (METHYLTHIO) PHENYLL-2-PVRIDONE] To a stirred solution of [LITHIUM DIISOPROPYLAMIDE (50ML] of a 2M solution in heptane/THF/ethyl benzene, [0.] [1MOL)] in THF (50mL) at-78°C and under an atmosphere of nitrogen was added dropwise a solution of 3-methyl-2-butenoic acid (5g, 0. 05mol) in THF (50mL). The reaction was warmed to [0°C] for 30 minutes. After cooling to-78°C, a solution of 4- (methylthio) benzonitrile (7.45g, 0. [05MOL)] in THF (50mL) was added dropwise. Upon complete addition, the reaction was warmed to room temperature and stirred for 3 hours. Water [(150ML)] and ethyl acetate [(100ML)] were added to the reaction mixture and the resulting precipitate filtered, washed with ethyl acetate and dried to give the title compound (4.96g, 43%) LC retention time 2.75mins, MS m/z 232 (MH+). |
43% | Stage #1: 3-Methylbutenoic acid With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78 - 0℃; for 0.5h; Stage #2: p-cyanophenyl methyl sulfide In tetrahydrofuran; n-heptane; ethylbenzene at -78 - 20℃; for 3h; | 3.3.i Example 3.34-methyl-N-f (1-methvl-1 H-pvrazol-4-vl) methyll-6-f4- (methvlsulfonvl) phenvll-2-pvridinamine (i)4-Methyl-6-r4- (methylthio) phenvll-2-pyridone To a stirred solution of lithiumresulting precipitate filtered, washed with ethyl acetate and dried to give the title compound (4.96g, 43%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.5% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 20h; | 3 Synthesis and Spectral Data of Intermediates To a magnetically stirred solution of 3,3-dimethylacrylic acid (25.0 gram, 250 mmol) in dichloromethane (400 ml) were successively added N,O-dimethylhydroxylamine.hydrochloride (26.79 gram, 275 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.hydrochloride (52.66 gram, 275 mmol) and 1-hydroxybenzotriazole (16.87 gram, 124.8 mmol). The mixture was cooled with an ice-bath and N-methylmorpholine (82.36 ml, 749 mmol) was added and the resulting mixture was stirred at room temperature for 20 hours. Water (100 ml) was added and the organic layer was separated, and successively washed with citric acid (0.5 M aqueous solution), NaHCO3 (5% aqueous solution) and brine, dried over MgSO4, filtered and concentrated to give N-methoxy-N-methyl-acrylamide (29.53 gram, 78.5% yield). 1H-NMR (400 MHz, CDCl3) δ1.91 (d, J=2 Hz, 3H), 2.14 (d, J=2 Hz, 3H), 3.20 (s, 3H), 3.68 (s, 3H), 6.12 (br s, 1H). |
Stage #1: 3-Methylbutenoic acid With 4-methyl-morpholine; pivaloyl chloride In dichloromethane at 0 - 5℃; for 3 - 4h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane at 20℃; | 1 1. N-Methoxy-N.3-dimethyl-2-butenamide (I)To a solution of 3, 3 -dimethyl acrylic acid (100.12g, IM) in methylene dichloride (Hit) was added N-methyl morpholine (202g, 2M) and the solution was cooled to 0-5 0C. Pivaloyl chloride (120 g, IM) was added dropwise over a period of 20-30 mins, maintaining the temperature below 5 0C. After complete addition the reaction mixture was stirred till completion of reaction. After about 3-4 hrs, N,O-dimethyl hydroxyl amine ω hydrochloride was added and the reaction continued overnight below 20 0C. After completion of the reaction, the reaction mixture was quenched with water (1 lit) and stirred for 30 mins. The MDC layer separated and washed thoroughly with 10 % NaHCO3 solution. The organic phase separated and the solvent evaporated under reduced pressure to give the product as oil. S 1H NMR (CDCl3): 6.05 (s, IH), 3.62 (s, 3H)5 3.15 (s, 3H)3 2.03 (s, 3H), 1.85 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hydroxide In ethanol; water at 20℃; for 10h; Inert atmosphere; | ||
With sodium hydroxide at 100℃; | ||
With potassium hydroxide In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With methanesulfonic acid; phosphorus pentoxide; at 70℃; for 1.58333h;Heating; | reagent (225 mL) was heated to 70 0C and 3-methylbut-2-enoic acid (28.1 g, 281 mmol) and <strong>[827-99-6]3-(trifluoromethoxy)phenol</strong> (25.0 g, 140 mmol) were added. After 30 min, additional 3-methylbut-2-enoic acid (1 equiv, 14 g) was added and heating was continued. After 30 min, additional Eaton's reagent (150 mL) was added and heating was continued for 35 min. The dark solution was cooled and poured into ice. The aqueous suspension was extracted with Et2O (300 mL), and the organic portion was washed with water (75 mL) and brine (50 mL). The organic portion was dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (gradient elution, 0-20percent EtOAc/hexanes) to give the title compound (11.7 g, 45.0 mmol, 32percent) as a white solid. MS (ESI) m/z 261 (M+H)+. |
32% | With methanesulfonic acid; phosphorus pentoxide; at 70℃; for 1.58333h;Heating; | reagent (225 mL) was heated to 70 0C and 3-methylbut-2-enoic acid (28.1 g, 281 mmol) and <strong>[827-99-6]3-(trifluoromethoxy)phenol</strong> (25.0 g, 140 mmol) were added. After 30 min, additional 3-methylbut-2-enoic acid (1 equiv, 14 g) was added and heating was continued. After 30 min, additional Eaton's reagent (150 mL) was added and heating was continued for 35 min. The dark solution was cooled and poured into ice. The aqueous suspension was extracted with Et2O (300 mL), and the organic portion was washed with water (75 mL) and brine (50 mL). The organic portion was dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (gradient elution, 0-20percent EtOAc/hexanes) to give the title compound (11.7 g, 45.0 mmol, 32percent) as a white solid. MS (ESI) m/z 261 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With cesium fluoride In tetrahydrofuran at 125℃; | |
77% | With cesium fluoride In tetrahydrofuran at 125℃; for 24h; | 4.3 General procedure for the reaction of 2-alkenoic acids with arynes General procedure: The aryne precursor (1.5 equiv) was added to a mixture of 2-alkenoic acid (0.25 mmol) and CsF (4.0 equiv) in 15 mL of freshly distilled THF, and the reaction mixture was then stirred in a closed vial at 125 °C for 18 h. After allowing the reaction mixture to cool, additional aryne precursor (0.5 equiv) and CsF (1.0 equiv) were quickly added and heating was continued at 125 °C for 6 h. After the reaction mixture was allowed to cool to room temperature, it was eluted through a plug of silica gel with ethyl acetate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired 4-chromanones. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 45.2% 2: 27% | Stage #1: 3-Methylbutenoic acid; 2'-tert-butyldimethylsilyl-2-debenzoyl-10-triethylsilyl-7-propionyl-cephalomannine With 2-(1H-pyrrol-3-yl)pyridine; dicyclohexyl-carbodiimide In toluene at 65℃; for 10h; Stage #2: With pyridine; hydrogen fluoride In acetonitrile at 20℃; for 24h; | 10.6; 11.6 Step 6: 2-(3-methyl-2-butenoyl)-7-propionyl-10-deacetyl-cephalomannine; 2'-tert-butyldimethylsilyl-2-debenzoyl-10-triethylsilyl-7-propionyl-cephalomannin e (20 mg,0.0206 mmol) was dissolved in 1 ml of toluene, and 3-methyl-2-butenoic acid (20.6 mg, 0.206 mmol), PP (1.8 mg, 0.0124 mmol) and DCC (42.5 mg, 0.206 mmol) were added. After reacting at 65 °C for 10 h, 0.1 ml methanol was added, then filtered. The solid was washed with ethyl acetate. The filtrates were combined and evaporated to dryness, followed by a silica gel column chromatography (petroleum ether : ethyl acetate = 8: 1). The resulting product was contaminated with impurities such as DCU, and said product was deprotected, without a further purification, as follows. The product was dissolved in 1.4 ml of acetonitrile, then pyridine (0.683 ml) and HF (0.375 ml) were added sequentially. After reacting at room temperature for 24 h, 30 ml of ethyl acetate was added, then washed with saturated aqueous NaHCO3 (2 x 20 ml). The aqueous layer was extracted with ethyl acetate (3 x 50 ml). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The ethyl acetate layer was evaporated to dryness. And a silica gel column chromatography (n-hexane: ethyl acetate : acetone = 8: 3: 2) was carried out to yield the title product (7.5 mg, 45.2% of total yield over two steps). 1H (CDCl3, 300MHz): δ 7.29-7.42 (5H, m), 6.59 (1H, d, J = 8.7 Hz), 6.46 (1H, q, J = 6.9 Hz), 6.13 (1H, t, J = 8.9 Hz), 5.69 (1H, s), 5.58 (1H, dd, J = 1.8, 8.7 Hz), 5.39-5.45 (2H, overlapped), 5.25 (1H, s), 4.91 (1H, d, J = 7.8 Hz), 4.67 (1H, d, J = 1.8 Hz), 4.46 (1H, d, J = 8.1 Hz), 4.20 (1H, d, J = 8.1 Hz), 3.97 (1H, brs), 3.85 (1H, d, J = 6.3 Hz), 3.47 (1H, brs), 2.49 (1H, ddd, J = 7.3, 9.6, 14.5 Hz), 2.28 (1H, dd, J = 9.0, 15.3 Hz), 2.24 (2H, q, J = 7.2 Hz), 2.23 (3H, s), 2.20 (3H, s), 2.16 (1H, dd, J = 15.4, 9.0 Hz), 1.97 (3H, s), 1.91 (1H, m), 1.85 (3H, s), 1.79 (3H, s), 1.79 (3H, s), 1.76 (3H, d, J = 7.2 Hz), 1.20 (3H, s), 1.08 (3H, t, J = 8.1 Hz), 1.04 (3H, s). ESI-MS: m/z [M+Na]+ 846.3.3, [M+K]+862.3.; Example 11: Preparation of 2-(3-methyl-3-butenoyl)-7-propionyl-10-deacetyl -cephalomannine; [Show Image] Steps 1-6: Being the same as the procedures described in Steps 1-6 of Example 10. It was obtained as a side product in Step 6 of Example 10, 27% yield. 1H (CDCl3, 300MHz): δ 7.29-7.42 (5H, m), 6.59 (1H, d, J = 8.7 Hz), 6.46 (1H, q, J = 6.7 Hz), 6.11 (1H, t, J = 8.7 Hz), 5.58 (1H, d, J = 8.7 Hz), 5.41 and 5.40 (2H, overlapped), 5.24 (1H, s), 4.99 (1H, s), 4.92 (2H, brs), 4.67 (1H, d, J = 1.8 Hz), 4.51 (1H, d, J = 8.1 Hz), 4.23 (1H, d, J = 8.1 Hz), 3.95 (1H, brs), 3.84 (1H, d, J = 6.3 Hz), 3.48 (1H, brs), 3.11 (1H, d, J = 15.9 Hz), 3.03 (1H, d, J = 15.0 Hz), 2.49-2.53 (1H, m), 2.17-2.29 (3H, m), 2.22 (3H, s), 2.12 (1H, dd, J = 9.0, 15.4 Hz), 1.92 (1H, m), 1.87 (3H, s), 1.85 (3H, s), 1.79 (3H, s), 1.78 (3H, s), 1.76 (3H, d, J = 7.2 Hz), 1.19 (3H, s), 1.08 (3H, t, J =7.5 Hz), 1.01 (3H, s). ESI-MS: m/z, [M+Na]+ 846.3.3, [M+K]+ 862.3. |
1: 45.2% 2: 27% | Stage #1: 3-Methylbutenoic acid; 2'-tert-butyldimethylsilyl-2-debenzoyl-10-triethylsilyl-7-propionyl-cephalomannine With dicyclohexyl-carbodiimide In toluene at 65℃; for 10h; Stage #2: With pyridine; hydrogen fluoride In acetonitrile at 20℃; for 24h; | 10.6; 11 Step 6: 2-(3-chlorobenzoyl)-7-propionyl-10-deacetyl-cephalomannine2'-tert-butyldimethylsilyl-2-debenzoyl-10-triethylsilyl-7-propionyl-cephalomannine (23 mg, 0.0237 mmol) was dissolved in 1 ml of toluene, m-chlorobenzoic acid (37.1 mg, 0.237 mmol), PP (2.1 mg, 0.014 mmol) and DCC (48.9 mg, 0.237 mmol) were added. After reacting at 65° C. for 10 h, 0.1 ml methanol was added, then filtered. The solid was washed with ethyl acetate. The filtrates were combined and evaporated to dryness, followed by a silica gel column chromatography (petroleum ether:ethyl acetate=8:1). The resulting product was contaminated with impurities such as DCU, and said product was deprotected, without a further purification, as follows. The product was dissolved in 1.4 ml of acetonitrile, then pyridine (0.683 ml) and HF (0.375 ml) were added sequentially. After reacting at room temperature for 24 h, 30 ml of ethyl acetate was added, then washed with saturated aqueous NaHCO3 (2×20 ml), the aqueous layer was extracted with ethyl acetate (3×50 ml). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The ethyl acetate layer was evaporated to dryness. And a silica gel column chromatography (n-hexane:ethyl acetate:acetone=8:3:2) was carried out to yield the title product (17.5 mg, 78.3% of total yield over two steps).1H (CDCl3, 500 MHz): δ 8.10 (1H, s), 8.00 (1H, d, J=7.5 Hz), 7.59 (1H, dd, J=1.5, 8.0 Hz), 7.46 (1H, t, J=8.0 Hz), 7.30-7.414 (5H, m), 6.59 (1H, d, J=8.5 Hz), 6.44 (1H, q, J=7.0 Hz), 6.13 (1H, t, J=9.0 Hz), 5.62 (1H, d, J=7.5 Hz), 5.59 (1H, dd, J=2.5, 9.0 Hz), 5.44 (1H, dd, J=7.5, 10.5 Hz), 5.28 (1H, s), 4.92 (1H, d, J=8.5 Hz), 4.69 (1H, d, J=1.5 Hz), 4.30 (1H, d, J=8.5 Hz), 4.18 (1H, d, J=9.0 Hz), 3.97 (1H, d, J=6.5 Hz), 3.97 (1H, overlapped), 3.60 (1H, brs), 2.51 (1H, ddd, J=7.3, 9.5, 15.0 Hz), 2.34 (3H, s), 2.28 (2H, m, overlapped), 2.25 (2H, q, J=7.6 Hz) 1.92 (1H, m), 1.84 (3H, s), 1.82 (3H, s), 1.81 (3H, s), 1.73 (3H, d, J=6.9 Hz), 1.20 (3H, s), 1.09 (3H, t, J=7.5 Hz), 1.07 (3H, s). ESI-MS: m/z [M+Na]+ 902.3, [M+K]+ 918.3.Example 11Preparation of 2-(3-methyl-3-butenoyl)-7-propionyl-10-deacetyl-cephalomannine Steps 1-6: Being the same as the procedures described in Steps 1-6 of Example 10. It was obtained as a side product in Step 6 of Example 10, 27% yield.1H (CDCl3, 300 MHz): δ 7.29-7.42 (5H, m), 6.59 (1H, d, J=8.7 Hz), 6.46 (1H, q, J=6.7 Hz), 6.11 (1H, t, J=8.7 Hz), 5.58 (1H, d, J=8.7 Hz), 5.41 and 5.40 (2H, overlapped), 5.24 (1H, s), 4.99 (1H, s), 4.92 (2H, brs), 4.67 (1H, d, J=1.8 Hz), 4.51 (1H, d, J=8.1 Hz), 4.23 (1H, d, J=8.1 Hz), 3.95 (1H, brs), 3.84 (1H, d, J=6.3 Hz), 3.48 (1H, brs), 3.11 (1H, d, J=15.9 Hz), 3.03 (1H, d, J=15.0 Hz), 2.49-2.53 (1H, m), 2.17-2.29 (3H, m), 2.22 (3H, s), 2.12 (1H, dd, J=9.0, 15.4 Hz), 1.92 (1H, m), 1.87 (3H, s), 1.85 (3H, s), 1.79 (3H, s), 1.78 (3H, s), 1.76 (3H, d, J=7.2 Hz), 1.19 (3H, s), 1.08 (3H, t, J=7.5 Hz), 1.01 (3H, s). ESI-MS: m/z [M+Na]+ 846.3.3, [M+K]+ 862.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.6% | With iodine at 105℃; for 3h; Inert atmosphere; | 18 Example 18: Procedure for the synthesis of N,3-dimethyl-3-((3-(trifluoromethyl) phenyl)sulfonyl)butan-l-amine hydrochloride (71); Preparation of 3-methyl-3-((3-(trifluoromethyl)phenyl)thio)butanoic acid (62); 3 Trifluoromethylthiophenol (16) (25g, 140 mmol), 3,3-dimethylacrylic acid (61) (14.0 g, 140 mmol) and iodine (6.9 g, 27 mmol) were heated under Ar at 105 °C for 3 hours. The reaction was cooled, taken up in EtOAc (300 mL) and washed with Na2S2S03 (saturated solution) (3 x 100 mL). The organics were separated, dried (MgS04), concentrated in vacuo and the residue purified by automated column chromatography (3 % EtO Ac/Pet ether) to give 3-methyl-3-((3- (trifluoromethyl)phenyl)thio)butanoic acid (62) (30.61 g, 78.6 %); H NMR (300 MHz -CD3CI) δ 1.43 (s, 6 H), 2.55 (s, 2 H), 7.49 (t, 1 H, J = 7.68 Hz), 7.65 (d, 1 H, J = 7.8 Hz), 7.78 (d, 1 H, J = 7.71 Hz), 7.84 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With phosphorus pentoxide; In methanesulfonic acid; at 70℃; for 12h;Inert atmosphere; | A solution of the appropriate resorcinol 1 in methanesulfonic acid and 3,3-dimethylacrylic acid were added to a suspension of P2O5 in methanesulfonic acid under N2 atmosphere. The reaction mixture was heated following three different procedures: a) irradiation by microwave at 70 C ina sealed reactor for 10 minutes; b) irradiation by microwave at 70 C in a sealed reactor for 20minutes; c) irradiation by microwave at 70 C in a sealed reactor for 1 hour; d) conventionalheating at 70 C for about 12 hours. The reaction mixture was poured onto water/ice and thenextracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4. Solvent was removed under reduced pressure. The crude compounds were purified and isolated bychromatography on silica gel (hexane/EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 3-Methylbutenoic acid; N,0-dimethylhydroxylamine In toluene at 0℃; for 0.166667h; Stage #2: With phosphorus trichloride In toluene at 20 - 60℃; for 0.5h; | N-Methoxy-N-methylbenzamide (3a);38,39 Typical Procedure General procedure: A solution of NHMe(OMe) (0.360 g, 6.0 mmol) and benzoic acid (0.244 g, 2.0 mmol) was stirred in dry toluene (10 mL) at 0 °C for 10 min. A solution of PCl3 (0.137 g, 1.0 mmol) in dry toluene (2 mL) was then added dropwise to the mixture. The mixture was warmed to r.t. slowly and then stirred at 60 °C for 0.5 h. When the reaction was complete (TLC monitoring), the mixture was cooled to r.t. The mixture was then quenched with sat. NaHCO3 soln (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4). The solvent was removed in vacuo.The product was purified by column chromatography (silica gel, petroleum ether-EtOAc, 3:2) to give pure 3a as a colorless oil; yield: 320 mg (97%). |
With 1,1'-carbonyldiimidazole Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With phosphorus pentoxide In methanesulfonic acid at 70℃; for 1h; Inert atmosphere; Microwave irradiation; | General procedures for the synthesis of 5- and 7-hydroxy-2,2-dimethyl-4-chromanones. A solution of the appropriate resorcinol 1 in methanesulfonic acid and 3,3-dimethylacrylic acid were added to a suspension of P2O5 in methanesulfonic acid under N2 atmosphere. The reaction mixture was heated following three different procedures: a) irradiation by microwave at 70 C ina sealed reactor for 10 minutes; b) irradiation by microwave at 70 C in a sealed reactor for 20minutes; c) irradiation by microwave at 70 C in a sealed reactor for 1 hour; d) conventionalheating at 70 C for about 12 hours. The reaction mixture was poured onto water/ice and thenextracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4. Solvent was removed under reduced pressure. The crude compounds were purified and isolated bychromatography on silica gel (hexane/EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 19 %Chromat. 2: 20 %Chromat. 3: 14 %Chromat. 4: 25 %Chromat. | In methanol at 25℃; Inert atmosphere; Irradiation; | General procedure: General procedure for aryl 3-methyl-2-butenoate esters. Solutions of esters (1-9; 0.106mmol) were prepared in different organic media (100mL). Photoirradiations of the esters were performed as follow: i) analytical scale: a 2mL aliquot of solution was placed in a stoppered 3mL quartz cell and degassed with argon for 20min; ii) preparative scale: a 65mL aliquot was placed in a stoppered 100mL Erlenmeyer quartz flask and degassed with argon for 30min. The quartz cell as well as the Erlenmeyer quartz flask were placed in a home made optical bench provided with the possibility to use two or four lamps. The solutions of the esters were stirred during the irradiation process. Irradiations with λexc=313nm were carried out with four phosphorous-coated lamps (HelioQuartz, each of 18 Watts) that give a nearly parallel beam at 313nm. Irradiations with λexc=254nm were carried with four germicide lamps (Philips, each of 20 Watts). |
1: 14 %Chromat. 2: 11 %Chromat. 3: 21 %Chromat. 4: 22 %Chromat. | In cyclohexane at 25℃; Inert atmosphere; Irradiation; | General procedure: General procedure for aryl 3-methyl-2-butenoate esters. Solutions of esters (1-9; 0.106mmol) were prepared in different organic media (100mL). Photoirradiations of the esters were performed as follow: i) analytical scale: a 2mL aliquot of solution was placed in a stoppered 3mL quartz cell and degassed with argon for 20min; ii) preparative scale: a 65mL aliquot was placed in a stoppered 100mL Erlenmeyer quartz flask and degassed with argon for 30min. The quartz cell as well as the Erlenmeyer quartz flask were placed in a home made optical bench provided with the possibility to use two or four lamps. The solutions of the esters were stirred during the irradiation process. Irradiations with λexc=313nm were carried out with four phosphorous-coated lamps (HelioQuartz, each of 18 Watts) that give a nearly parallel beam at 313nm. Irradiations with λexc=254nm were carried with four germicide lamps (Philips, each of 20 Watts). |
1: 22 %Chromat. 2: 20 %Chromat. 3: 17 %Chromat. 4: 15 %Chromat. | In acetonitrile at 25℃; Inert atmosphere; Irradiation; | General procedure: General procedure for aryl 3-methyl-2-butenoate esters. Solutions of esters (1-9; 0.106mmol) were prepared in different organic media (100mL). Photoirradiations of the esters were performed as follow: i) analytical scale: a 2mL aliquot of solution was placed in a stoppered 3mL quartz cell and degassed with argon for 20min; ii) preparative scale: a 65mL aliquot was placed in a stoppered 100mL Erlenmeyer quartz flask and degassed with argon for 30min. The quartz cell as well as the Erlenmeyer quartz flask were placed in a home made optical bench provided with the possibility to use two or four lamps. The solutions of the esters were stirred during the irradiation process. Irradiations with λexc=313nm were carried out with four phosphorous-coated lamps (HelioQuartz, each of 18 Watts) that give a nearly parallel beam at 313nm. Irradiations with λexc=254nm were carried with four germicide lamps (Philips, each of 20 Watts). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 4H3N*4H(1+)*CuMo6O18(OH)6(4-); water; oxygen; sodium carbonate at 50℃; for 12h; | |
91% | With copper acetylacetonate; oxygen; sodium hydroxide; 1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene In water at 50℃; for 12h; Sealed tube; | |
38% | With Iron(III) nitrate nonahydrate; oxygen; sodium 2,2,2-trifluoroacetate In ethyl acetate at 25℃; for 16h; | Typical procedure for the oxidation reaction (Table 1, entry 14). General procedure: In a test tube, trans-2-decenal (167 mg, 1.0 mmol) was added to a suspension of Fe(NO3)3·9H2O(4.1 mg, 0.010 mmol) and CF3COONa (28 mg, 0.20 mmol) in EtOAc (0.50 mL). O2 balloon (1atm) was attached at top of the test tube, and inner atmosphere was replaced by O2. After stirring16 h at 25 °C, EtOAc (3 mL) and 1M HCl aq. (1 mL) were added and resulting biphasic mixture wasstirred for 1 min. Organic phase was separated, and water phase was extracted by EtOAc (3 mL X2). To the collected organic phase was then added measured amount of biphenyl (as an internalstandard for NMR analysis). The conversion of substrate and the yield of products weredetermined by NMR analysis (400 MHz, CDCl3, 25 °C). Products were identified by comparison tothe NMR signals of authentic samples. The same reaction was performed twice for each reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With aluminum (III) chloride; In dichloromethane; at 65℃; for 1.5h;Inert atmosphere; | 3,3-Dimethylacrylic acid, (97%, 15.8 g, 157.9 mmol), AlCl3 (22 g, 164.9 mmol) and DCM (100 mL) were placed in a one-neck round-bottomed flask under an argon atmosphere. Bromobenzene (31 g, 197.4 mmol) was added producing vigorous bubbling. Upon completion of the bubbling, the reaction mixture was stirred in an oil bath at 65 C for 1 h and 30 min and overnight at rt under N2 atm. Reaction was poured in HCl:H2O (1:1) 200 mL slowly, EtOAc (300 mL) was added and the organic phase was separated, organics were washed with brine, dried over Na2SO4, and concentrated. The crude mixture 1H NMR data showed mixture of m,p-regioisomers. Crude material was crystallized from hexane to give pure 3-(3-bromophenyl)-3-methylbutanoicacid (meta isomer) (14 g, 54.7 mmol, 42%) as brown crystals.1H NMR (400 MHz, CDCl3) delta 7.52-7.50 (m, 1H), 7.37-7.35 (m, 1H), 7.35-7.30 (m, 1H), 7.23-7.20 (m, 1H), 2.66 (s, 2H), 1.47 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With bismuth(lll) trifluoromethanesulfonate; In toluene; at 110℃; | General procedure: To a solution of the phenol (5, 1.0 mmol) and the acrylic acid (6 or 7, 1.0 mmol) in 8 mL of toluene was added bismuth(III) triflate (41 mg, 0.06 mmol, 20 mol%). The reaction was heated under reflux for 12-24 h and then cooled. Removal of the solvent under vacuum and purification by PTLC eluted with 5% ether in hexane (8-10% ether in hexanes for the methoxy-substituted products) showed several bands. The major band (bright fluorescent blue) was isolated and extracted with ether to give the 4-chromanone 4 or 8. The other bands consisted of varying amounts of the aryl ester of the carboxylic acid and unreacted phenol. The following compounds were prepared. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With trifluorormethanesulfonic acid; trifluoroacetic anhydride In dichloromethane at 0℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.3 g | With Aluminum Chloride; In benzene; at 10 - 40℃; for 1h; | Aluminum chloride (24.1 g) was added to a solution of 3-methyl-2-butene acid (15 g) in benzene (100 mL) at 10 C., and the mixture was stirred at 40 C. for 1 hour. After cooling to 0 C., ice water was added, the mixture was extracted with tert-butyl methyl ether, and concentrated to some extent. The organic layer was extracted with saturated aqueous sodium hydride solution. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid and extracted with tert-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound J1 (26.3 g). |
With aluminium chloride anhydrous; | a) Production of 3-methyl-3-phenylbutanoic Acid To a solution of 3-methyl-2-butenoic acid (15 g) in benzene (100 mL), aluminum chloride (24.1 g) was added at 10 C., and the resultant mixture was stirred for 30 minutes and then stirred at 40 C. for 1 hour. After cooling the reaction solution to 0 C., ice water was added, and the resultant mixture was extracted with tert-butyl methyl ether, concentrated to some extent, and the organic layer was extracted with a saturated aqueous sodium bicarbonate solution. The pH of the aqueous layer was changed to 2 with concentrated hydrochloric acid, and the resultant mixture was extracted with tert-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 3-methyl-3-phenylbutanoic acid (26.3 g). 1H-NMR (400 MHz, CDCl3):1.46 (6H, s), 2.65 (2H, s), 7.20 (1H, t, J=7.2 Hz), 7.31 (11H, t, J=7.2 Hz), 7.37 (2H, d, J=7.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 9,10-dihydroanthracene; 3-Methylbutenoic acid With aluminum (III) chloride In dichloromethane at 20℃; for 48h; Inert atmosphere; Stage #2: With hydrogenchloride In water at 20℃; for 12h; Stage #3: With potassium hydroxide In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 9,10-dihydroanthracene; 3-Methylbutenoic acid With aluminum (III) chloride In dichloromethane at 20℃; for 48h; Inert atmosphere; Stage #2: With hydrogenchloride In water at 20℃; for 12h; Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 9,10-dihydroanthracene; 3-Methylbutenoic acid With aluminum (III) chloride In dichloromethane at 20℃; for 48h; Inert atmosphere; Stage #2: With hydrogenchloride In water at 20℃; for 12h; Overall yield = 95 percent; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tetrabutyl-ammonium chloride; potassium carbonate In water; toluene at 100℃; for 24h; Inert atmosphere; | 48 Preparation of (3-isopropylidene-2,2-dimethylcyclobutyl) methyl 3-methyl-2-butenoate The (3-isopropylidene-2,2-dimethylcyclobutyl) methyl methanesulfonate (1.29g, 5.56mmol) obtained in Example 47, toluene (40g), water (430mg),Isopentenic acid (3-methyl-2-butenoic acid)(690mg, 6.92mmol),Potassium carbonate (610mg, 4.39mmol)And tetrabutylammonium chloride (60mg, 0.23mmol) were placed in a nitrogen atmosphere reactor,And stirred at 100°C for 24 hours.Subsequently, water was added to the reaction mixture. The organic layer is separated and post-treated by conventional washing, drying and concentration. Then, the obtained concentrated solution was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to obtain the target compound (3-isopropylidene-2,2-dimethylcyclobutyl) methyl 3-methyl-2-butenoate (1.20 g, 5.06 mmol), the yield was 91%. |
91% | With tetrabutyl-ammonium chloride; potassium carbonate In water; toluene at 100℃; for 24h; Inert atmosphere; | 20 Preparation of (3-isopropylidene-2,2-dimethylcyclobutyl) methyl 3-methyl-2-butenoate (3-isopropylidene-2,2-dimethylcyclobutyl) methyl methanesulfonate (1.29g, 5.56mmol), toluene (40g), water (430mg), Reaction of isopentenic acid (3-methyl-2-butenoic acid) (690mg, 6.92mmol), potassium carbonate (610mg, 4.39mmol) and tetrabutylammonium chloride (60mg, 0.23mmol) in a nitrogen atmosphere And stir at 100°C for 24 hours. Subsequently, water was added to the reaction mixture, and the organic layer was separated, and post-treatment was performed by conventional washing, drying, and concentration. Then, the obtained concentrated liquid was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to obtain the target compound (3-isopropylidene-2,2-dimethylcyclobutyl) methyl 3-methyl-2-butenoate, (1.20 g, 5.06 mmol), the yield was 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With cobalt(II,III) oxide; hydrogen In hexane at 150℃; for 24h; Glovebox; Sealed tube; | 1-2 Co3O4 (0.5 g) reduced with a reducing agent in a glove box was put into a high-pressure reactor, and 3-methyl-2-butenoic acid (0.5 g, 5 mmol) and hexane (50 ml) were added thereto. After sealing the high-pressure reactor, the internal pressure was adjusted to 30 bar with hydrogen, and then heated to 150° C. for 24 hours and stirred for 24 hours. After the reaction, the reaction product was analyzed by gas chromatography to confirm that 3-methyl-butanol was prepared,The yield of 3-methyl-butanol was 93%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.6% | Stage #1: 3-Methylbutenoic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.5h; Stage #2: carvacrol In dichloromethane at 20℃; for 6h; | 1.1-1.3 Method 2: Take a 100ml single-necked flask, add 0.60g (6mmol) 3-methyl-2-butenoic acid and 25mL dichloromethane, then add 1.49g (7.2mmol) DCC and 0.07g (0.6mmol) DMAP, stir at room temperature Reaction 0.5h. Subsequently, 15 mL of dichloromethane solution containing 0.90 g (6 mmol) of 5-isopropyl-2-methylphenol was added dropwise to the above reaction solution, and the reaction was carried out at room temperature for 6 h. After suction filtration,The filtrate was washed with saturated aqueous sodium chloride solution,After drying, the solvent was removed under reduced pressure and separated by silica gel column chromatography (eluent was petroleum ether:Ethyl acetate V:V=50:1),Obtained 5-isopropyl-2-methylphenyl 3-methylbut-2-enoate (I-a-01), yield 55.6% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; | 4.2.3. (5S,6S,6aR,9S,11bR,14R)-5,6-dihydroxy-4,4-dimethyl-8-methylene-7-oxodo-decahydro-1H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-14-yl cyclohexanecarboxylate(16b) General procedure: Compound 14 (0.086 mmol) and cyclohexane carboxylic acid(0.129 mmol) were dissolved in anhydrous dichloromethane(10 mL), 0.16 mmol of 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI) and catalytic amount ofDMAP was added. The solution was stirred at room temperatureuntil compound 14 was disappear. Then, the solution was dilutedby saturated sodium bicarbonate water solution, and was extractedwith ethyl acetate for three times. The combined organic phaseswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The residue was subjected to columnchromatography (silica gel, ethyl acetate/petroleum ether, 1:8) toobtain compound 16b (86% yield). |
72% | With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; | 4.2.3. (5S,6S,6aR,9S,11bR,14R)-5,6-dihydroxy-4,4-dimethyl-8-methylene-7-oxodo-decahydro-1H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-14-yl cyclohexanecarboxylate(16b) General procedure: Compound 14 (0.086 mmol) and cyclohexane carboxylic acid(0.129 mmol) were dissolved in anhydrous dichloromethane(10 mL), 0.16 mmol of 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI) and catalytic amount ofDMAP was added. The solution was stirred at room temperatureuntil compound 14 was disappear. Then, the solution was dilutedby saturated sodium bicarbonate water solution, and was extractedwith ethyl acetate for three times. The combined organic phaseswere washed with brine, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The residue was subjected to columnchromatography (silica gel, ethyl acetate/petroleum ether, 1:8) toobtain compound 16b (86% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With hydrogenchloride; In chloroform; water; at 80℃; for 10h; | General procedure: Samples of triphenylphosphine (0.5 g, 0.0019 mol) and unsaturated carboxylic acids were dissolved in chloroform. Two drops of concentrated hydrochloric acid was added. The reactions were carried out at a temperature of 80 C in a water bath with a reverse refrigerator for 10 h. After the reaction was completed, the solvent was distilled, the precipitated crystals were filtered and dried in vacuo. |
Tags: 541-47-9 synthesis path| 541-47-9 SDS| 541-47-9 COA| 541-47-9 purity| 541-47-9 application| 541-47-9 NMR| 541-47-9 COA| 541-47-9 structure
[ 1119-72-8 ]
(2Z,4Z)-Hexa-2,4-dienedioic acid
Similarity: 0.77
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