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CAS No. : | 542-28-9 | MDL No. : | MFCD00006645 |
Formula : | C5H8O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OZJPLYNZGCXSJM-UHFFFAOYSA-N |
M.W : | 100.12 | Pubchem ID : | 10953 |
Synonyms : |
δ-Valerolactone;5-Valerolactone;oxan-2-one
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 25.32 |
TPSA : | 26.3 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) : | -7.16 cm/s |
Log Po/w (iLOGP) : | 1.35 |
Log Po/w (XLOGP3) : | -0.35 |
Log Po/w (WLOGP) : | 0.71 |
Log Po/w (MLOGP) : | 0.5 |
Log Po/w (SILICOS-IT) : | 1.64 |
Consensus Log Po/w : | 0.77 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.24 |
Solubility : | 57.6 mg/ml ; 0.575 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.26 |
Solubility : | 182.0 mg/ml ; 1.82 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.82 |
Solubility : | 15.2 mg/ml ; 0.152 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.07 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P210-P264-P270-P280-P301+P312+P330-P302+P352-P305+P351+P338+P310-P332+P313-P362+P364-P370+P378-P403+P235-P501 | UN#: | 3082 |
Hazard Statements: | H227-H302-H315-H318 | 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 |
---|---|---|
12% | With ammonium acetate; sodium cyanoborohydride In methanol | EXAMPLE 21 N-4-Tetrahydropyranyl-4-(1H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-N-{3-[6-(3-pyrrolidin-1-yl-1-{4-tolyl}-prop-1E-enyl)-pyridin-2-yl]-prop-2E-enyl}-benzamide STR32 (a) 4-Amino-tetrahydropyran A mixture of tetrahydropyranone (1.0 g, 10.0 mmol), ammonium acetate (7.69 g, 100.0 mmol), 3 Å molecular sieve powder (2.5 g) and sodium cyanoborohydride (1.25 g, 20.0 mmol) suspended in dry methanol (50 ml) under a blanket of argon was refluxed for 2 hours and allowed to cool to room temperature. The suspension was filtered and concentrated under reduced pressure. The residue was partitioned between DCM and water. The organic layer was extracted with 1M HCl (*2). The combined extracts were basified with 5M sodium hydroxide solution and extracted with DCM. The combined organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield 4-amino-tetrahydropyran as a colourless oil (120 mg, 12percent). 1 H-NMR; δ (CDCl3), 3.95-3.86 (2H, m), 3.38-3.27 (2H, m), 2.85-2.73 (1H, m), 1.79-1.67 (2H, m), 1.40-1.24 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: at 95 - 120℃; for 0.5 h; Stage #2: at 0 - 25℃; for 5 h; Heating / reflux |
518 g 6-VALEROLACTONE and 5 ml phosphorous tribromide were fed into a 11 three-necked flask. The mixture was heated up to a temperature of 95 °C to 105 °C under stirring and 550 g bromine were added, while the temperature was kept constant between 100 and 120 °C. Subsequently, 5 ml phosphorus tribromide and 236 g bromine were added at a temperature of 110 °C. After the reaction mixture had been allowed to stand for 30 minutes, it was cooled down to a temperature of 0 to 10 °C. Then, 11 methanol and lg p-toluenesulfonic acid were added, while the temperature was kept constant at 25 °C. After 5 hours of refluxing, the excess material was distilled off and the lower organic layer was separated. The organic layer was then washed with 500 ml of 10percent sodium hydroxide and 500 ml water. After separation of the organic layer, the product was isolated by fractional distillation (139 to 142 °C/28 hPa) and 612.7 g of the title compound were obtained (yield 45percent, purity > 96percent by GC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide In ethanol at 20 - 80℃; for 2.5 h; | Valerolactone (1.0 g, 10 mmol) was added to a solution of NaOH (0.44 g,11 mmol) dissolved in ethanol (90percent, 23 mL) and the mixture was stirred at 80° for 30 min then at ambient temperature for 2 h. Excess solvent was then removed under reduced pressure to yield the sodium salt quantitatively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With ammonia In ethanol at 80℃; for 6h; Sealed bomb; | A 5-HYDROXYPENTANAMIDE STEP A 5-HYDROXYPENTANAMIDE TETRAHYDRO-2H-PYRAN-2-ONE (20 g) was dissolved in EtOH (50 mL) and placed in a sealed bomb. An excess of ammonia (gas) was charged into the bomb. The bomb was heated to 80C for 6 hrs at 250 psi. Upon concentration in vacuo, the crude white solid was filtered and dried to obtain 15.76 g. Yield : 67% 1H NMR (DMSO-d6) 8 7.2 (br s, 1 H), 6.65 (br s, 1 H), 4.35 (t, 1 H), 3.38 (q, 2 H), 2.04 (t, 2 H), 1.5 (p, 2 H), 1.4 (p, 2 H) ; |
With ammonia; benzene | ||
With ammonia; water |
With ammonia In methanol | ||
With ammonia In methanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tetrabutylammomium bromide; hydrogen bromide In water for 0.166667h; Microwave irradiation; | |
With sulfuric acid; water; hydrogen bromide | ||
With hydrogen bromide |
With hydrogen bromide | ||
With hydrogen bromide Heating; | ||
With water; boron tribromide 1.) dichloromethane, room temp., 16 h, 2.) 0 deg C; Yield given. Multistep reaction; | ||
With hydrogen bromide; acetic acid at 20 - 70℃; for 4h; | ||
With sulfuric acid; hydrogen bromide; sodium bromide at 85 - 90℃; | 1.2; 2-9 The second step of the synthesis of intermediate II: In a 500 mL four-necked flask equipped with a mechanical stirrer, a thermometer, a condenser, and a dropping funnel, add intermediate 40 g (0.4 mol), 121.5 g (0.6 mol) of 40% hydrobromic acid, and 104 g (1 mol) of sodium bromide, and stir. The temperature was raised to 85-90C, and 100 g (1 mol) of concentrated sulfuric acid was added dropwise to the reaction kettle. After the dropwise addition was completed, the temperature was maintained for 1-2 hours to stop the reaction. The reaction solution was cooled to room temperature, extracted with 200 mL of dichloromethane, and washed with 200 mL of water. After drying over magnesium sulfate, 68.1 g of white solid was obtained after desolvation, with the content of 85%, and the reaction proceeded to the next step without purification. The intermediate formula II was: 5H9BrO2, English name: 5-bromovaleric acid, molecular weight: 181.03, and the Exact point: 38-40C. ,Boiling point: 142-145C / 13mmHg; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With hydrazine hydrate In methanol; water at 20℃; for 5h; Cooling with ice; | 3.2.3. General Procedure for the Synthesis of Acyl Hydrazides 3a-3k General procedure: To a stirred solution of esters 2a-2j (70 mmol) in MeOH (30 mL) cooled in an ice-water bath was added dropwise 80% aqueous hydrazine hydrate (6.26 g, 100 mmol). The resulting solution was stirred at room temperature (2a-2b or 2d-2j), or reflux (2c), until the completion of reaction as indicated by TLC analysis (typically within 5 h). The reaction mixture was evaporated on a rotary evaporator to give a residue, which was purified by column chromatography through a short silica gel column to yield 3a-3k after trituration with n-hexane if possible. |
With hydrazine hydrate | ||
With hydrazine hydrate In ethanol for 2h; Reflux; | 4-(4-(4-bromobenzyl)-5-mercapto-4H-1,2,4-triazol-3-yl)butan-1-ol (22) The solution of δ-valerolactone (3.79ml, 40mmol) and hydrazine hydrate (4ml) in ethanol (40ml) was heated under reflux for 2h and then evaporated to dryness to afford 21 as a white solid. The mixture of 1-bromo-4-isothiocyanoatomethylbenzene (4.56g, 20mol) and 21 (2.64g, 20mmol) in ethanol (30ml) was heated under reflux for 2h before it was evaporated to remove most of the solvent. Water (30ml) and potassium carbonate (2.76g, 20mmol) were added to the residue and the resulting mixture was heated under reflux for 1h. The solution was cooled in an ice bath and carefully neutralized with 6N HCl. The precipitate so obtained was filtered off, washed with water and dichloromethane, and then dried in vacuo to give 22 as a white solid (3.73g, 58% for two steps). 1H-NMR (d6-DMSO, 400 MHz) δ 1.35 (m, 2H), 1.49 (m, 2H), 2.48 (t, 2H, J=6.8), 3.28 (q, 2H), 4.37 (t, 1H, -OH), 5.19 (s, 2H), 7.20 (d, 2H, J=8.4), 7.54 (d, 2H, J=8.4), 13.70 (s, 1H, -SH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide; In ethanol; at 20 - 80℃; for 2.5h; | Valerolactone (1.0 g, 10 mmol) was added to a solution of NaOH (0.44 g,11 mmol) dissolved in ethanol (90%, 23 mL) and the mixture was stirred at 80 for 30 min then at ambient temperature for 2 h. Excess solvent was then removed under reduced pressure to yield the sodium salt quantitatively. |
In sodium hydroxide; toluene; | Sodium 5-Hydroxypentanoate (21) A suspension of 800 mg (8.0 mmol) of d-valerolactone in 8 mL (8.0 mmol, 1.0 equiv) of 1 N aqueous sodium hydroxide was heated at 65 C overnight. The clear solution was cooled and concentrated. Toluene was added and the resultant slurry was concentrated to give a white solid: IR (nujol mull) 1550 cmmin1. | |
With sodium hydroxide; In water; at 70℃; | A solution of delta-valerolactone (10 .0 g, 100 mmol) and NaOH (4.00 g, 100 mmol) in water (100 mL) was stirred overnight at 70 C. The reaction mixture was cooled to rt and concentrated in vacuo to give white solid NAG4. This solid was suspended in acetone (100 mL) and refluxed overnight with benzyl bromide (20.5 g, 120 mmol) and tetrabutylammonium bromide (1.61 g, 0.50 mmol). Acetone was removed in vacuo to afford an oily residue, which was dissolved in EtOAc and washed with sat NaHC03 (aq.) and brine. The organic layer was dried over Na2S04 and concentrated in vacuo give the oily product NAG5 (17.1 g, 82% yield). |
With sodium hydroxide; In water; at 70℃; | solution of delta-valerolactone (10.0 g, 100 mmol) and NaOH (4.00 g, 100 mmol) in water (100 mL) was stirred overnight at 70 C. The reaction mixture was cooled to rt and concentrated in vacuo to give white solid NAG4. This solid was suspended in acetone (100 m L) and refluxed overnight with benzyl bromide (20.5 g, 120 mmol) and tetrabutylammonium bromide (1 .61 g, 0.50 mmol). Acetone was removed in vacuo to afford an oily residue, which was dissolved in EtOAc and washed with sat. NaHC03 (aq.) and brine. The organic layer was dried over Na2S04 and concentrated in vacuo to give NAG5 as oily product (1 7.1 g, 82% yield). | |
With sodium hydroxide; In water; at 70℃; | A solution of delta-valerolactone (10 .0 g, 100 mmol) and NaOH (4.00 g, 100 mmol) in water (100 mL) was stirred overnight at 70 C. The reaction mixture was cooled to rt and concentrated in vacuo to give white solid NAG4. This solid was suspended in acetone (100 mL) and refluxed overnight with benzyl bromide (20.5 g, 120 mmol) and tetrabutylammonium bromide (1 .61 g, 0.50 mmol). Acetone was removed in vacuo to afford an oily residue, which was dissolved in EtOAc and washed with sat NaHC03 (aq.) and brine. The organic layer was dried over Na2S04 and concentrated in vacuo give the oily product NAG5 (1 7.1 g, 82% yield). 1 H NMR (CDCI3, 500 MHz): delta 7.35 (m, 5H), 3.64 (q, 2H, J 6 Hz, 1 1 .5 Hz), 2.41 (t, 2H, J 7.5 Hz), 1 .75 (m, 2H), 1 .60 (m, 2H), 1 .44 (t, 1 H, J 6 Hz). | |
With sodium hydroxide; In water; at 70℃;Inert atmosphere; | A solution of delta-valerolactone (10 .0 g,100 mmol) and NaOH (4.00 g, 100 mmol) in water (100 mL) was stirred overnight at 70 00 The reactionmixture was cooled to rt and concentrated in vacuo to give white solid NAG4. This solid was suspended in acetone (100 mL) and refluxed overnight with benzyl bromide (20.5 g, 120 mmol) and tetrabutylammonium bromide (1 .61 g, 0.50 mmol). Acetone was removed in vacuo to afford an oily residue, which was dissolved in EtOAc and washed with sat NaHCO3 (aq.) and brine. The organic layerwas dried over Na2SO4 and concentrated in vacuo give the oily product NAG5 (17.1 g, 82% yield). 1H NMR (ODd3, 500 MHz): O 7.35 (m, 5H), 3.64 (q, 2H, J6 Hz, 11.5 Hz), 2.41 (t, 2H, J7.5 Hz), 1.75 (m, 2H), 1.60 (m, 2H), 1.44 (t, 1 H, J 6 Hz). | |
With sodium hydroxide; | (1) Synthesis of benzyl ester of 5-hydroxypentanoic acid To 100 ml of 1N aqueous sodium hydroxide solution was added 10 g/0.1 mol of delta-valerolactone, and the mixture was stirred at 65 C. for 12 hours. The reaction mixture was allowed to cool to room temperature, and the water was distilled off under reduced pressure. The resulting white crystals were dried at 60 C. under reduced pressure for 24 hours to completely remove the water. 13.8 g of sodium salt of 5-hydroxypentanoic acid was obtained. | |
With sodium hydroxide; In water; at 20 - 70℃; | A solution of delta-valerolactone (1 0 .0 g,15 100 mmol) and NaOH (4.00 g, 100 mmol) in water (1 00 ml) was stirred overnight at 70 c. The reactionmixture was cooled to room temperature and concentrated in vacuo to give white solid NAG4. This solidwas suspended in acetone (1 00 ml) and refluxed overnight with benzyl bromide (20.5 g, 120 mmol) andtetrabutylammonium bromide (1.61 g, 0.50 mmol). Acetone was removed in vacuo to afford an oilyresidue, which was dissolved in EtOAc and washed with sat NaHCO3 (aq.) and brine. The organic layer20 was dried over Na2SO4 and concentrated in vacuo give NAG5 as an oily product (17.1 g, 82% yield). 1 HNMR (CDCI3, 500 MHz): delta7.35 (m, 5H), 3.64 (q, 2H, J 6Hz, 11.5 Hz), 2.41 (t, 2H, J 7.5 Hz), 1.75 (m,2H), 1.60 (m, 2H), 1.44 (t, 1 H, J 6Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In N,N,N,N,N,N-hexamethylphosphoric triamide; water for 17h; Irradiation; | |
44% | With palladium 10% on activated carbon; W(OTf)<SUB>6</SUB>; hydrogen at 135℃; for 12h; | 29 Preparation of n-valeric acid from δ-valerolactone General procedure: Specific methods are as follows: propiolactone was added (0.36g, 5mmol), palladium on carbon (10%, 26.5mg, 0.025mmol, 0.5mol%) in the reactor and W (OTf)6(107.8mg, 0.1mmol, 2mol%). A hydrogen balloon connected to the top of the reactor, and the reactor was purged with hydrogen gas atmosphere. Hydrogen atmosphere at normal pressure, the reaction was stirred at 135 deg.] C after 12h, detected by gas, γ- valerolactone complete conversion of starting material, and only n-valeric acid. The method carried out as follows completion of the hydrogenation reaction of the ring-opening reaction system separation, to obtain the desired product n-valeric acid: The reaction was completed reaction mixture was dissolved with methylene chloride, filtered to remove the palladium on carbon catalyst and W (OTf)699% yield measured propionic acid, purity of the product was 99%. NMR data for the product using the embodiment of the present invention is the NMR identified the product as follows:The specific reaction procedure and the operation method were the same as those of Example 27, The yield was 44% and the purity of the product was 99%. The product was subjected to nuclear magnetic identification using the manner described in the present invention, and the NMR data of the product were as follows: |
With water; iodine; nickel at 280℃; Hydrogenation; |
44 %Chromat. | With palladium on activated carbon; W(OTf)<SUB>6</SUB>; hydrogen In neat (no solvent) at 135℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; sodium hydroxide; at 65℃; | Synthesis of Benzyl 5-Hydroxypentanoate A solution of delta-valerolactone (10 g, 100 mmol) in 1M aqueous sodium hydroxide (100 mL) was heated overnight with stirring at 65 C. The solution was concentrated in vacuo to dryness and any residual water removed under high vacuum at -190 C. The resulting white powder was broken up and suspended in acetone (40 mL). With stirring, benzyl bromide (17 g, 101.4 mmol) and tetrabutylammonium bromide (0.82 g, 2.539 mmol) were added. The mixture was heated at 45 C. with stirring for 72 hours, cooled, and concentrated. The resulting white oily powder was dissolved in ethyl acetate (300 mL) and washed twice each with saturated NaHCO3 and brine. The organic portion was dried over anhydrous MgSO4, filtered, and then concentrated. The result was a yellow oil, which was purified by column chromatography (column 10"L*2"W; eluted with a gradient of 100% hexanes?+30%?50% ethyl acetate in hexanes) to afford the product as a pale yellow oil (3.11 g, 15%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With molecualar sevies 4A;tetrachlorobis(tetrahydrofuran)hafnium(IV); In toluene; at 120℃; for 10.0h; | By combining diversely the carboxylic acid of various structure and alcohol, the scope of substrate application of the tetravalent hafnium compound was examined. A Soxhlet tube filled with dried molecular sieves 4A (about 1.5 g) was connected to the top of a 5 ml eggplant flask contained with a teflon coated magnetic stirrer, and a cooling tube was further attached over said Soxhlet tube. Unless there is a particular point of concern, toluene solvent (2 ml) and 0.1 mol %, 0.2 mol % or 1 mol % of hafnium chloride (IV)?(THF)2 were added to carboxylic acid (10 mmol) and alcohol (10 mmol), and heating reflux was conducted in the argon for several hours at 120C. After the reaction, the mixture solution was purified by direct silica gel column chromatography (eluant hexane:ethyl acetate=4:1 to 8:1), and the solution was dried under reduced pressure. The results are shown in Table 2. In Table 2, the following are shown: for the experiment of Entry 3, toluene solvent (5 ml) was used; for the experiment of Entry 4, 4-phenyl butanoic acid (36 mmol) and toluene solvent (4 ml) were used; for the experiment of Entry 5, the numerical value of yield showed in parenthesis is the value in the case the inventors wanted to use the catalyst; for the experiment of Entry 9, o-xylene solvent (2 ml) was used; for the experiment of Entry 14, enantiomer of carboxylic acid was used and at a yield of 84%, the enantiomer of ester was obtained; for the experiment of Entry of 17, 1,3,5-mesitylene solvent(2 ml) was used; for the experiments of Entry 18 and 19, the lactone value is shown for the yield. [TABLE-US-00002] TABLE 2 [CHEMMOL-00003] HfCl4.(THF)2 reaction entryRCO2H ROH (1 mol %) time (h) yield (%) 1 [CHEMMOL-00004] [CHEMMOL-00005] 0.2 6 97 2 [CHEMMOL-00006] [CHEMMOL-00007] 0.2 24 92 3 [CHEMMOL-00008] [CHEMMOL-00009] 0.1 18 >99 4 [CHEMMOL-00010] EtC(CH2OH)3 0.2 24 >99 5 [CHEMMOL-00011] [CHEMMOL-00012] 0.2 5 94 (36) 6 [CHEMMOL-00013] l-menthol 0.2 36 >99 7 [CHEMMOL-00014] [CHEMMOL-00015] 0.2 13 >99 8 [CHEMMOL-00016] Et3COH 1.0 24 0 9 [CHEMMOL-00017] PhOH 0.2 36 91 10 [CHEMMOL-00018] [CHEMMOL-00019] 0.2 10 92 11 [CHEMMOL-00020] [CHEMMOL-00021] 0.1 18 98 12 [CHEMMOL-00022] [CHEMMOL-00023] 0.2 7 96 13Et2CHCO2H [CHEMMOL-00024] 0.2 60 98 14 [CHEMMOL-00025] [CHEMMOL-00026] 0.2 13 98 15PhCO2H [CHEMMOL-00027] 0.2 15 92 16 [CHEMMOL-00028] [CHEMMOL-00029] 0.2 10 92 17PhCO2H3,5-Me2C5H3OH 1.0 24 95 18 [CHEMMOL-00030] 0.2 10 98 19 [CHEMMOL-00031] 0.2 10 94 [0022] As it is also shown in Table 2, every carboxylic acid reacted with primary and secondary alcohol, under the presence of the catalyst of 0.2 mol % and under, and produced ester quantitatively, but as it is shown from the experiment of Entry 8, it did not react with tertiary alcohol. Furthermore, as it is shown from the experiment of Entry 17, the aromatic substrates (benzoic acid and phenol) showed lower reactivity compared to aliphatic substrates, and when carboxylic acid and alcohol are both aromatics, the ester could be obtained at a high yield, by increasing the catalyst amount up to 1 mol %. Moreover, when the reactivity is low, it is also effective to use a benzene solvent of higher boiling point, for example, o-xylene of the experiment of Entry 9 or 1,3,5-mesitylene of the experiment of Entry 17 and to conduct heating reflux. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With Dowex 50W-X8 resin at 20℃; Inert atmosphere; Reflux; | |
99% | With sulfuric acid for 5h; Heating; | |
99% | With H+ Dowex resin Heating; |
98% | With sulfuric acid for 24h; Heating; | |
97% | With sulfuric acid for 48h; Reflux; | 4.4.1 Methyl 5-hydroxypentanoate17 Sulfuric acid (conc. 95-97%, 1 mL, 18.76 mmol) was added to a stirred solution of δ-valerolactone (15.00 g, 149.82 mmol) in methanol (269 mL). The reaction mixture was maintained at reflux while stirring for 48 h and then cooled to 0 °C and NaHCO3 (1.90 g) added. The mixture was stirred for 10 min at 0 °C, then it was filtered through Celite and the solvent removed under reduced pressure to give the crude methyl ester (19.12 g, 97%) as a milky white oil which was used without further purification; vmax/cm-1 (film) 3418, 2954, 1732, 1441; δH (300 MHz) 1.53-1.62 [2H, m, C(3)H2], 1.64-1.76 [2H, m, C(4)H2], 2.36 [2H, t, J 7.4, C(2)H2], 3.52 (1H, br s, OH), 3.61 [2H, t, J 6.3, C(5)H2], 3.67 (3H, s, OCH3). |
96% | With sulfuric acid for 17h; Reflux; | |
95% | With toluene-4-sulfonic acid Heating; | |
94% | With amberlyst-15 for 20h; | |
94% | With sulfuric acid for 4h; Heating; | |
90% | With hydrogenchloride In water for 16h; Reflux; Inert atmosphere; | 4.8 4.8 Methyl 5-hydroxypentanoate 10 To a solution of lactone 9 (3.850 g, 38.5 mmol) in MeOH (40 mL) was added concentrated HCl (four drops) at room temperature. The reaction mixture was then heated at reflux for 16 h. After being cooled to room temperature, the reaction was quenched with saturated NaHCO3 solution (10 mL), after which MeOH was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (300 mL). The solution was washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1) to afford hydroxyl ester 10 (4.579 g, 90% yield) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 3.68 (s, 3H), 3.65-3.63 (m, 2H), 2.36 (t, J = 7.2 Hz, 2H), 1.75-1.69 (m, 2H), 1.65-1.58 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 174.1, 62.2, 51.5, 33.6, 32.0, 21.1; HRMS (ESI) m/z 133.0864 [M+H]+ (calcd for C6H13O3, 133.0859). |
86% | With hydrogen cation | |
85% | With sulfuric acid for 21h; Reflux; | |
84% | With sodium methylate at 20℃; for 1.5h; | |
83% | With triethylamine | |
76% | With sulfuric acid for 16h; Heating; | |
73% | With sulfuric acid for 12h; Heating; | |
62% | With sulfuric acid for 10h; Heating; | |
55% | With sulfuric acid at 20℃; for 10h; Reflux; | |
39% | With sulfuric acid at 65℃; for 2h; | |
With magnesium methanolate | ||
With toluene-4-sulfonic acid for 18h; Heating; | ||
With sulfuric acid for 5h; Heating; | ||
With triethylamine at 20℃; for 16h; | ||
With sulfuric acid | ||
With sulfuric acid for 5h; Reflux; | 6 6.4 mL (69.3 mmol, 1.0 equiv.) δ-Valerolactone was added to 150 mL CH3OH (to 0.5M) together with 12 drops of H2SO4 and the mixture was heated at reflux for 5 hr. The reaction mixture was then cooled to 0° C. and 1.00 g NaHCO3 was added with stirring. The result suspension was placed in the -40° C. freezer for 2 hrs to precipitate the unconsumed base, which was then filtered off. The solvent was evaporated under water aspirator (bath temp. <35° C.) and dried on a mechanical pump. The crude alcohol, so prepared was dissolved in 250 mL CH2Cl2 (to 0.3M) and 15 mL (104 mmol, 1.5 equiv.) Et3N and cooled to 0° C. 6.5 mL (83.2 mmol, 1.2 equiv.) Methanesulfonyl chloride was added dropwise. The reaction was then allowed to warm to room temperature and stirred 2 hrs, when TLC showed complete consumption of the alcohol. The reaction was cooled back to 0° C. and 50 mL 1N HCl was added. The organic layer was separated, dried over Na2SO4, filtered, and concentrated to provide the crude mesylate, which was used without further purification. | |
With DOWEX EX50-WX8 resin for 3h; Reflux; Inert atmosphere; | ||
With triethylamine at 20℃; for 18h; | ||
With sulfuric acid at 20℃; Inert atmosphere; Reflux; | ||
With potassium carbonate at 20℃; for 14h; | ||
With potassium carbonate at 20℃; for 21h; | ||
With sodium | 11 Example 11: Synthesis of compound 1 (FSA) Compound 1 is synthesized in four steps from commercially available starting materials (see figure 11). Phenylhydrazine (11.4) (1 eq.) and piperonal (11.5) (1 eq.) is dissolved in anhydrous EtOH and AcOH (0.2 eq.) added . The reaction is stirred at r.t. until completion and the solvent evaporated off to afford crude 11.6. The crude product is redissolved in anhydrous THF followed by addition of HCI (0.5 eq.) and glutaric semialdehyde (1 eq.). The reaction is refluxed under argon atmosphere until completion and the solvent evaporated off to afford crude 11.7. Crude 11.7 is added Pd/C under argon followed by addition of acetic acid. The mixture is stirred at r.t. until completion, filtered through celite and the solvent evaporated off to afford crude 11.8. The crude product was purified by silica gel chromatography to afford pure 11.8. 11.8 is dissolved in anhydrous DMF and Et3ll (5 eq.). HATU (1.05 eq.) is added to the mixture followed by addition of 5- methyltryptamine hydrochloride. The reaction is stirred at r.t. until completion and worked up by addition of EtOAc and sat. aq . NaHCC>3. The phases are separated and the organic phase washed with sat. aq . NaHCC>3 (3x), sat. aq . NaCI (lx), dried over Na2S04and evaporated to dryness to afford crude 1. The crude product was purified by silica gel chromatography to afford 1. | |
With potassium carbonate Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5h; | |
90% | In tetrahydrofuran at -80℃; | |
89% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.533333h; Inert atmosphere; Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; Enzymatic reaction; |
83% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Stage #2: chloro-trimethyl-silane In tetrahydrofuran at -78 - 23℃; | |
81% | With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at 20℃; for 1.17h; | 6-(Trimethylsiloxy)-3,4-dihydro-2H-pyran (2c).10 1.6 M n-BuLi in hexane (14 mL, 22 mmol) was added dropwise for 40 min to a mixture of diisopropylamide (3.1 mL, 22 mmol) and THF (18 mL) cooled by dry ice-ethanol bath. A mixture of -valerolactone (2.0 g, 20 mmol) and THF (4 mL) was added dropwise for 10 min, followed by addition of chlorotrimethylsilane (4.3 mL, 34 mmol). Then the reaction mixture was allowed to warm to RT, kept at this temperature for 1 h. After evaporation of THF, the mixture was filtered on funnel with suction and washed with hexane. The filtrate solution was evaporated and dried in a vacuum. The crude product of was purified by distillation with microscale distillator under reduced pressure (15 Torr, b.p. 76-77 °C), affording cyclic ester enolate 2c (2.8 g, 81 % yield): |
79% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; Inert atmosphere; Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane for 1h; Inert atmosphere; | |
77% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran; hexane; cyclohexane at -78℃; for 0.25h; Inert atmosphere; Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane; cyclohexane at -78 - 20℃; Inert atmosphere; | |
60% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.166667h; Stage #2: chloro-trimethyl-silane In tetrahydrofuran at 20℃; for 1h; | |
With n-butyllithium; diisopropylamine 1.) THF, -78 deg C, 10 min, 2.) 3 h, warm. to RT; Yield given. Multistep reaction; | ||
With lithium diisopropyl amide In tetrahydrofuran at -70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1.5h; Inert atmosphere; Stage #2: benzyl bromide In tetrahydrofuran; hexane at -78℃; for 3h; Inert atmosphere; | |
82% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; Stage #2: benzyl bromide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; hexane at -78 - 20℃; | |
68% | With lithium diisopropyl amide In tetrahydrofuran at -78 - -30℃; for 3.5h; | 3-benzyltetrahydro-2H-pyran-2-one (S3) To a stirred solution of tetrahydropyran-2-one (2.0 g , 20 mmol) in THF (40 mL) at -78 °C was slowly added LDA(20 mL, 22 mmol, 1.09 M THF solution). After stirred at that temperature for 30 min, benzyl bromide (2.85 mL, 24S7mmol) was added to the reaction mixture. The resultant mixture was warmed to -30 °C over 3 h , quenched with sat.NH4Cl aqueous solution. The aqueous layer was extracted with EtOAc. The combined organic layer was washedwith brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel columnchromatography (40% EtOAc/n-heptane) to afford S3 (2.58 g, 68%) as a colorless oil. The spectral data is inagreement with the data previously reported.4 |
59% | With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - 20℃; for 5h; | |
With lithium diisopropyl amide 1.) THF, -78 deg C, 2.) HMPA, -78 deg C to -40 deg C; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tetrabutyl ammonium fluoride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | II Preparation Example II (Compound No. HD 1-Route II) [0036] Compound 19 (25 g, 0.25 mol) and (trifluoromethyl)trimethylsilane (39 g, 0.27 mol) were dissolved in 150 mLof dry THF. 2.7 mL of TBAF (1 M in THF) was added dropwise under nitrogen atmosphere at 0 °C, followed by spontaneouswarming and then the mixture was reacted at room temperature overnight. The solvent was rotatory evaporated, andthe residue was distilled under reduced pressure by the lubropump. Fractions of 72-74 °C were collected to give compound20. (46.3g, 77%, colorless liquid) 1HNMR (300 MHz, CDCl3) δ 3.79 (dd, J = 6.4, 2.6 Hz, 2H), 1.72 - 1.57(m, 6H), 0.21 (s, 9H), |
77% | With tetrabutyl ammonium fluoride In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; | 1 5.1.10.1 Trimethyl((2-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)oxy)silane (22b) δ-Valerolactone (25 g, 0.25 mol) and TMSCF3 (39 g, 0.27 mol) were dissolved in dry THF (150 mL), and 1 M TBAF in THF (2.7 mL, 2.7 mmol) was added dropwise with stirring at 0 °C and then stirred overnight at room temperature. The solvent was removed and the residue was distilled under reduced pressure. Compound 22b was collected at 72-74 °C (15 mmHg) as a clear colorless liquid (46.3 g, 77%). 1H NMR (300 MHz, CDCl3) δ 3.82-3.76 (m, 2H), 1.82-1.59 (m, 6H), 0.21 (s, 9H). |
75% | With tetrabutyl ammonium fluoride In tetrahydrofuran 0 deg C - rt; |
74% | With N,N-dimethyl-formamide; magnesium chloride at 20℃; for 18h; | 3.2. General procedure for trifluoromethylation of carbonyl substrates General procedure: The substrate (0.25 mmol) and TMSCF3 (0.5 mmol) in DMF(2 mL) were placed in a 25 mL round-bottom ask. To this solutionwas added MgCl2 (0.025 mmol), and the mixture was stirredvigorously at room temperature. Completion of the reaction wasmonitored by TLC. The reaction mixture was puried by chroma-tography (using 200:1 petroleum ether/ethyl acetate solvent sys-tem) to afford the pure trimethylsilyl ethers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With quinuclidine-N-oxide; tert.-butyl lithium In tetrahydrofuran; hexane at -78℃; for 0.333333h; Stage #2: allyl bromide In tetrahydrofuran; hexane at -30℃; for 2h; Further stages.; | |
88% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.333333h; Inert atmosphere; Stage #2: allyl bromide In tetrahydrofuran at -90℃; for 3.5h; Inert atmosphere; | |
85% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; Inert atmosphere; Green chemistry; Stage #2: allyl bromide With 1,3-dimethyl-2-imidazolidinone In tetrahydrofuran at -30℃; Inert atmosphere; Green chemistry; |
63% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Schlenk technique; Stage #2: allyl bromide In tetrahydrofuran at -78 - -20℃; Inert atmosphere; Schlenk technique; | |
58% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 2h; Stage #2: allyl bromide With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran; hexane at -78 - -40℃; Further stages.; | |
41% | With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - 25℃; for 5h; | |
41% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene for 2h; Stage #2: allyl bromide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; n-heptane; ethylbenzene for 0.5h; | |
41% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene for 2h; Inert atmosphere; Cooling with acetone-dry ice; Sealed tube; Stage #2: allyl bromide With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran; n-heptane; ethylbenzene at -40℃; for 3.5h; Cooling with acetone-dry ice; | P.3 3. Synthesis of A-allyl-Δ-valerolactone (avl) (b) A 500 mL round bottom flask, equipped with stir bar, was sealed with a septum, purged with nitrogen for 30 min and cooled in a dry ice/acetone bath. A solution of lithium diisopropylamine (2.0 M in THF/heptane/ethyl benzene, 33 mL, 66 mmol) was added to the round bottom flask. A nitrogen purged solution of δ-valerolactone (5.43 mL, 60 mmol) in THF (60 mL) was added dropwise via syringe over 1.5 h. After an additional 30 min of stirring, a solution of allyl bromide (6.21 mL, 72 mmol) in hexamethylphosphoramide (12.51 mL, 72 mmol) was added dropwise via syringe over 30 min. The reaction mixture was warmed up to -40° C. using a dry ice/acetone bath and stirred for 3 h. The reaction was quenched with excess NH4Cl solution and warmed to room temperature. The crude product was washed twice with brine, dried with anhydrous magnesium sulfate and concentrated via rotary evaporator. Column chromatography using CH2Cl2 gave a viscous yellow product. Yield: 3.4262 g (41%). 1H NMR (300 MHz, CDCl3/TMS, ppm) δ: 5.7 (m, 1H, H2C=CH-), 5.08 (m, 2H, H2C=CH-), 4.28 (m, 2H, -C(O)OCH2-), 2.53-2.58 (m, 2H, H2C=CHCH2-), 2.27 (m, 1H, H2C=CHCH2CH-), 2.06 (m, 1H, H2C=CHCH2CHCH2-), 1.89 (m, 2H, C(O)OCH2CH2-), 1.55 (m, 1H, H2C=CHCH2CHCH2-); 13C NMR (400 MHz, CDCl3, ppm) δ: 173.8 (-C(O)O-), 135.0 (H2C=CH-), 117.4 (H2C=CH-), 68.4 (-C(O)OCH2-), 39.2 (H2C=CHCH2CH-), 35.4 (H2C=CHCH2-), 24.0 (-CH2CH2CH2-), 21.9 (-CH2CH2CH2-). |
35% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; | |
With lithium diisopropyl amide 1) -78 deg C 2) HMPA; Yield given. Multistep reaction; | ||
With lithium diisopropyl amide 1.) -70 deg C; Multistep reaction; | ||
With N,N,N,N,N,N-hexamethylphosphoric triamide; lithium diisopropyl amide 1.) THF, -78 deg C, 30 min, 2.) THF, -30 deg C, 3 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With ethanol; sodium 1.) 0 deg C, 1 h, 2.) r.t., 20 h; | |
79% | With sodium ethoxide In ethanol at 20℃; | OOO.1 General procedure: Similar to as described in General Procedure Y Step 1, diethyl oxalate was reacted withoxan-2-one to give the title compound (3.8 g, 79%) as a light yellow liquid. LC-MS (ES, m/z): 201[M+H] .; Step 1: A solution of cycloalkylketone (1.0 eq.) in EtOH (0.5 mL/mmol) was cooled to 0 °C, then sodium ethoxide (21% wt solution in EtOH, 1.1 eq.) was added. To this mixture was added diethyl oxylate (1.0 eq.) and the mixture was allowed to warm to room temperature overnight. In vacuo concentration provided the desired product of sufficient purity to be used directly (yield assumed to be quantitative). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dibutyltin diacetate In tetrahydrofuran at 65℃; for 4h; | General procedure for ring-opening processes General procedure: An oven-dried reaction flask (20 mL) was charged with amine(1, 4.38 mmol), lactone (2, 2.19 mmol, 1.0 equiv), dibutyltin acetate(20 mol%) and THF (5 mL). The resulting mixture was stirred at65 C for 4 h. The crude products were purified by flash columnchromatography on silica gel to give the desired product. |
With sodium hydride 1) THF, 0 deg C, 30 min, 2) 1 h; Yield given. Multistep reaction; | ||
In 1,4-dioxane at 20℃; for 14h; Inert atmosphere; Autoclave; | 4.2.29. 3-(2-Hydroxyethyl)-N-methyl-6-heptenamide (25) General procedure: A mixture of 24 (401.0 mg, 2.60 mmol) and 40% aqueous methylamine solution (1.0 mL, 12 mmol) in dioxane (5 mL) was heated in a stainless autoclave at 200 °C. After 14 h, the reaction mixture was allowed to cool to rt, and then concentrated. The residue was subjected to flash chromatography (EtOAc/MeOH 20:1 v/v) to provide 25 (302.9 mg, 63%) as a colorless oil |
With lithium hydroxide In neat (no solvent) at 200℃; for 0.5h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With lithium diisopropyl amide In tetrahydrofuran at -78℃; | |
77% | With n-butyllithium; diisopropylamine In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; hexane at -78 - -40℃; | |
76% | With lithium diisopropyl amide |
70% | With N,N,N,N,N,N-hexamethylphosphoric triamide; butyllithium; diisopropylamine In tetrahydrofuran at -70 - 0℃; for 6h; | |
70% | With lithium diisopropyl amide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide at -70℃; | |
70% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With N,N,N,N,N,N-hexamethylphosphoric triamide; lithium diisopropyl amide at -15℃; for 0.25h; Stage #2: methyl iodide at 0℃; for 6h; Further stages.; | |
63% | With lithium diisopropyl amide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; hexane at -78 - -40℃; | |
46% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With N,N,N,N,N,N-hexamethylphosphoric triamide; lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran; hexane at -78℃; for 2h; Inert atmosphere; | |
46% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; hexane at -78℃; for 1.05h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; hexane at -78℃; for 2.03333h; Inert atmosphere; | |
44% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran at -65 - -60℃; for 1h; Stage #2: methyl iodide With 1,3-dimethyl-2-imidazolidinone In tetrahydrofuran at -65℃; for 4h; | |
42% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran; hexane at -78 - -35℃; for 1h; Inert atmosphere; | |
25% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -40℃; for 0.166667h; Stage #2: methyl iodide In tetrahydrofuran; hexane at -78 - 0℃; for 4h; | 6.al 3-Methyltetrahydro-2H-pyran-2-one A solution of n-butyllithium (1.0 M in hexanes, 5.49 mL, 5.49 mmol) was added dropwise to diisopropylamine (910 μL , 6.49 mmol) in THF (4 mL) at 0 °C and the mixture stirred at 0 °C for 30 minutes to give a pale yellow solution of LDA, which was then cooled to -40 °C. A cold (-40 °C) solution of δ-valerolactone (500 mg, 4.99 mmol) in THF (4 mL) was added dropwise via cannula and the resultant mixture stirred at -40 °C for 10 minutes before being cooled to -78 °C. Iodomethane (466 μL, 7.49 mmol) was then added dropwise and the mixture slowly warmed to 0 °C over four hours. The reaction was quenched by the slow addition of acetic acid (320 μL ), diluted with ethyl acetate (10 mL) and water (15 mL) and the aqueous phase extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with sat. aq. NaHC03and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (15% to 17.5% ethyl acetate/hexanes with 1% Et3N) gave α -methyl- δ-valerolactone XXXIX (144 mg, 25%) as a colourless oil.1H NMR (400 MHz, CDC13) δ 4.37 - 4.26 (m, 2H), 2.58 (ddt, J = 11.1, 7.0, 7.0 Hz, 1H), 2.09 (tt, J = VIA, 6.2 Hz, 1H), 1.98 - 1.83 (m, 2H), 1.54 (ddt, 7 = 13.4, 11.1, 7.4 Hz, 1H), 1.26 (d, J = 6.9 Hz, 3H). |
With N,N,N,N,N,N-hexamethylphosphoric triamide; lithium diisopropyl amide 1) THF, -70 deg C; Yield given. Multistep reaction; | ||
With potassium naphthalenide 1) THF, 20 deg C, 10 min; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With diisobutylaluminium hydride In diethyl ether; hexane at -78℃; for 2h; | |
91% | With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 2h; | |
88% | With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 0.25h; |
With diisobutylaluminium hydride In toluene at -70℃; for 1h; | ||
With diisobutylaluminium hydride | ||
With diisobutylaluminium hydride In tetrahydrofuran; toluene at -78℃; for 0.75h; | ||
With diisobutylaluminium hydride | ||
With diisobutylaluminium hydride In tetrahydrofuran at -20℃; | ||
With diisobutylaluminium hydride In toluene at -60℃; for 16h; Inert atmosphere; | ||
With diisobutylaluminium hydride In dichloromethane at -78℃; | ||
With diisobutylaluminium hydride | ||
With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 1h; Inert atmosphere; | ||
With diisobutylaluminium hydride In dichloromethane at -78℃; for 1h; Inert atmosphere; | ||
With diisobutylaluminium hydride | ||
With diisobutylaluminium hydride In dichloromethane at -78℃; for 2h; | 212 Example 212: (S)-N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-(tetrahydro-2H -pyran-2-yl)acetamide and (R)-N-(4-((7-chloro-1-methyl -2-((l -methyl -2-oxo-5-(trifl uoromethyl)- 1,2-dihydropyridin-3 -yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-(tetrohydro-2H -pyran-2-yl)acetamide [1067] Synthesis of compound (±)-212.1. To a solution of d-valerolactone (10.0 g, 99.88 mmol, 1.0 equiv) in DCM (300 mL) was added diisobutylaluminium hydride (1M in DCM, 120 mL, 119.85 mmol, 1.2 equiv) at -78 °C and stirred for 2 h. The reaction was quenched by the addition of methanol (30 mL) followed by saturated potassium sodium tartrate solution (100 mL). The precipitated solids were removed by filtration and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (±)-212.1. It was used in the next step without further purification. 1H NMR (DMSO-d6, 400 MHz): δ 6.17-6.15 (m, 1H), 4.65 (bs, 1H), 3.84-3.81 (m, 1H), 3.38-3.34 (m, 1H), 1.73-1.57 (m, 2H), 1.45-1.32 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With trimethoxysilane; lithium methanolate In tetrahydrofuran for 0.5h; Ambient temperature; | |
87.7% | With hydrogen In 1,2-dimethoxyethane at 80℃; for 2h; | 2B; 4B Example 2B (Synthesis of 1,5-pentanediol) In the same apparatus as in Example 1, The residue (Ir-Pt -Re catalyst (1)) obtained in Example 1, and 0.342 g (3.0 mmol) of ε-caprolactone were added, It was made up with 1,2-dimethoxyethane to make ε-caprolactone 5%. Pressurized to 8.0 MPa with hydrogen gas, the mixture was reacted at 80 °C. for 2 hours with stirring. After completion of the reaction, the resulting reaction solution was cooled to room temperature, And then filtered through a syringe equipped with a membrane filter (0.45 μm). When the obtained filtrate was analyzed by gas chromatography, The conversion of ε-caprolactone is 100% The yield of 1,6-hexanediol was 92.3% The selectivity was 92.3% The yield of 1-hexanol was 8.0% The selectivity was 8.0%. In Example 1A, The catalyst was added to the Ir-Pt-Re catalyst (2) prepared in Example 2, Except that the 1,2-dimethoxyethane solution of 5% ε-caprolactone was changed to a 50% δ-valerolactone 1,2-dimethoxyethane solution (δ-valerolactone is 7.5 mmol) The reaction was carried out in the same manner as in Example 1A. When the obtained filtrate was analyzed by gas chromatography, the conversion of δ-valerolactone was 92.5% . The yield of 1,5-pentanediol was 87.7%. The selectivity was 94.8%, the yield of 1-pentanol was 4.9%, and the selectivity was 5.3%. |
79% | With sodium tetrahydroborate; C36H30F6N10Ni4O10(2+)*2C2F3O2(1-); zinc(II) chloride In tetrahydrofuran at 45℃; for 12h; |
75% | With hydrogen; C28H25BrMnN2O2P; lithium tert-butoxide In propan-1-ol at 100℃; for 24h; Autoclave; | |
73% | With dichloro(benzene)ruthenium(II) dimer; 2-((dicyclohexylphosphino)methyl)-1-methyl-1H-imidazolin; potassium <i>tert</i>-butylate; hydrogen In tetrahydrofuran at 100℃; for 4.5h; | |
72% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With phenylsilane; fac-[Mn-(xantphos)(CO)3Br] at 100℃; for 6h; Inert atmosphere; Stage #2: With water; sodium hydroxide In methanol at 20℃; Inert atmosphere; | |
52% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With polyethylsiloxane at 100℃; for 24h; Stage #2: With sodium hydroxide In tetrahydrofuran for 3h; Heating; | |
With lithium triethylborohydride In various solvent(s) for 0.416667h; ΔH; | ||
With samarium diiodide; water In tetrahydrofuran at 29.9 - 30.1℃; Inert atmosphere; Schlenk technique; chemoselective reaction; | ||
With hydrogen In 1,4-dioxane at 160℃; for 12h; | ||
96 %Spectr. | With (o-PPh2C6H4NH2)[EtNH(CH2)2NHEt]RuCl2; hydrogen; sodium methylate In tetrahydrofuran at 100℃; for 4h; Glovebox; Schlenk technique; Autoclave; | |
99 %Chromat. | With HN(CH2CH2C3H3N2Mes)2Cl2; potassium <i>tert</i>-butylate; hydrogen; cobalt(II) chloride In tetrahydrofuran at 100℃; for 16h; Autoclave; Glovebox; | |
93 %Chromat. | With hydrogen In water at 130℃; for 12h; Autoclave; | 6 Example 2 General procedure: 1 mmol of β-Butyrolactone serving as the substrate, 100 mg of catalyst (1) [Pt that is 2 mol % of the substrate, Mo that is 0.5 mol % of the substrate, in terms of metal], and 3 mL of water were charged in an autoclave having a Teflon (trade name) inner cylinder and reacted at 130° C. for 12 hours under the condition of hydrogen pressure of 5 MPa to form reaction products. The conversion ratio (cony. [%]) of the substrate was measured using HPLC, and the yield of each one of the reaction products was measured using a gas chromatograph mass spectrometer (GC-MS). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen In acetone for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; tin(ll) chloride; palladium dichloride; 1,3,5-trimethyl-benzene 1) acetonitrile, 90 deg C, 100 psi, 2 h; 2) 18.5 h; Yield given. Multistep reaction. Yields of byproduct given; | ||
54.6 mg | Stage #1: homoalylic alcohol for 0.5h; Inert atmosphere; Molecular sieve; Stage #2: carbon monoxide With (acetylacetonato)dicarbonylrhodium (l); diphenylphosphinous acid methyl ester; hydrogen; lithium chloride In toluene at 40℃; for 20h; Molecular sieve; Stage #3: With aluminum oxide; sodium acetate; pyridinium chlorochromate In dichloromethane at 20℃; for 12h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With Octanoic acid; dihydrogen peroxide In water monomer at 50℃; for 5h; Ionic liquid; Enzymatic reaction; | |
99% | With dihydrogen peroxide; lithium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate In water monomer; 1,2-dichloro-ethane at 70℃; for 2h; | 27 In Examples 24 to 30, as shown in Chem. 1, lactones were synthesized from various cyclic ketones by a Baeyer-Villiger oxidation reaction using hydrogen peroxide. In Example 24, when 2-methylcyclohexanone, which was an asymmetric cyclic ketone, was used, a corresponding ε-caprolactone was obtained at a high yield with normal regioselectivity. In Example 25, when 4-isopropenylcyclohexanone, which was a cyclic ketone having a substituent with an olefinic bond, was used, a corresponding ε-caprolactone was obtained at a yield of 56%, and no epoxidation of the olefin was observed. In Example 26, when 4-hydroxycyclohexanone was used, a five-membered lactone having a hydroxyethyl group was obtained. In this case, it is construed that after a corresponding ε-caprolactone was formed, this lactone was obtained by rearrangement therefrom into a five-membered ring having a smaller ring strain. In Examples 27 to 29, when a five-membered ring ketone and a four-membered ring ketone were used, corresponding six-membered ring lactone and five-membered ring lactone were obtained at a high yield. In Example 30, when a condensed ring ketone having an olefinic bond inside the ring was used, a corresponding condensed ring lactone was obtained at a high yield with normal regioselectivity, and no epoxidation of the olefin was observed.In addition, commercially available products were used for 2-methylcyclohexanone of Example 24 and cyclopentanone of Example 27, and starting raw materials of the other Examples were synthesized in accordance with the methods described in the literatures (*1 to 5 shown in Chem. 1). |
98% | With dihydrogen peroxide In dichloromethane for 72h; Ambient temperature; |
98% | With di-sodium tetraborate; dihydrogen peroxide In water monomer; benzene at 55℃; for 24h; | |
96% | With Potassium peroxomonosulfate; mesoporous silica In dichloromethane at 20℃; for 2h; | |
96% | With oxygen; 1-n-butyl-3-methylimidazolium trifluoromethanesulfonate at 20℃; for 0.25h; Electrochemical reaction; Green chemistry; | General procedure for oxidation reactions General procedure: A mixture of [bmim][OTf] (20 mL) and ketone (0.1 mol) in a three-electrode cell fitted with activated carbon fiber as the anode and Pt cathode was subjected to electro-catalytic oxidation at a constant current at room temperature for an appropriate time. O2 gas was charged into the cell through a O2 bomb to a desired amount at the flow rate of 15 mL min-1. A magnetic stirrer was employed during the electro-oxidation. The progress of the reaction was monitored by GC. After completion of the reaction, the organic phase was extracted with dichloromethane (3×20 mL). The solvent was removed and the residue was purified by preparative thin-layer chromatography on silica gel (ethyl acetate: hexane, 1:10) to afford the desired pure product. The rest of the ionic liquid was recovered. Fresh substrates were then recharged to the recovered electro-catalytic system and then recycled under identical reaction conditions. The target substrates were characterized by Elemental analysis, NMR spectra or compared with their authentic samples. Spectroscopic data for selected products is as follows. Tetrahydro-2H-pyran-2-one (Table 3, entry 13). Colourless oil, bp: 229-232 °C/760 mm (Ref. [54] 230-231 °C/760 mm). |
95% | With sec-decanepersulfonic acid In Carbon tetrachloride at 17℃; for 0.0833333h; | |
95% | With sec-decanepersulfonic acid In Carbon tetrachloride at 21.9℃; for 0.0833333h; | |
95% | With sec-decanepersulfonic acid In Carbon tetrachloride at 21.9℃; for 0.0833333h; other substrate, other solvent; | |
95% | With oxygen; benzaldehyde In 1,2-dichloro-ethane at 20℃; for 5h; | |
94% | With calcium tetrakis(pentafluorophenyl)borate undecahydrate; dihydrogen peroxide; oxalic acid In 1,2-dichloro-ethane at 50℃; for 3h; | |
94% | With 2,2'-diperoxyphenic acid In dichloromethane at 20℃; for 5h; Schlenk technique; | |
93% | With hydrogenchloride In chloroform at 20℃; for 12h; | |
92% | With magnesium monoperoxyphthalate hexahydrate In acetonitrile at 70℃; for 2h; | |
90% | With Mg10Al2(OH)24CO3; oxygen; benzaldehyde In 1,2-dichloro-ethane at 40℃; for 5h; | |
90% | With bismuth trifluoromethanesulphonate In dichloromethane at 20℃; for 0.333333h; | |
90% | With N-hydroxyphthalimide; oxygen; benzaldehyde In 1,2-dichloro-ethane at 40℃; for 18h; | |
90% | With dihydrogen peroxide In water monomer; ethyl acetate at 40℃; for 0.5h; Flow reactor; Enzymatic reaction; | |
89% | With bis-trimethylsilanyl peroxide; 1-n-butyl-3-methylimidazolium trifluoromethanesulfonate at 25℃; for 2h; Ionic liquid; Inert atmosphere; | |
89% | With dihydrogen peroxide In 1,2-dichloro-ethane for 24h; Reflux; | |
88% | With 1-n-butyl-3-methylimidazolium hydrogen sulfate; urea-hydrogen peroxide at 50℃; for 5h; | |
88% | With oxygen; benzaldehyde In 1,2-dichloro-ethane at 20℃; for 9h; | 2.3 Catalytic B-V Oxidation General procedure: The catalytic oxidation of ketone was carried out in a roundbottomflask of 25 mL volume equipped with magnetic stirrer.In the typical experiment, the flask was charged withsubstrate (2 mmol), CuPcTs-Zn2Al-LDH (8.0 mg), dichloroethane(10 mL), benzaldehyde (5 mmol), naphthalene(inert internal standard, 0.3 mmol) and then the mixture wasstirred at room temperature. Dioxygen was bubbled throughthe solution (10 mL min-1). We sampled during the reactionand the products were analyzed by GC-FID and GC-MSanalysis. |
88% | With potassium peroxomonosulfate In aq. phosphate buffer at 20℃; for 0.166667h; Green chemistry; | |
86% | With Ag/WO3 nanobars; dihydrogen peroxide In acetonitrile at 80℃; for 9h; Green chemistry; | 2.2. Reaction setup General procedure: Liquid phase oxidation reaction was carried out in a two-neck round bottom flask. The reaction temperature was ranged between RT and 100 °C. Small aliquots of the sample were withdrawn from the reaction mixture at regular intervals for analysis using a syringe. At the end of the reaction, the catalyst was separated by filtration and the products were analyzed by GC (FID) and GCMS |
86% | With oxygen; benzaldehyde In 1,2-dichloro-ethane at 45℃; for 5h; | |
85% | With bis-trimethylsilanyl peroxide; anhydrous tin tetrachloride In dichloromethane at 25℃; for 3h; | |
85% | With dihydrogen peroxide; iodine; acetic acid at 20℃; for 1h; | |
85% | With potassium peroxomonosulfate at 40℃; for 5h; Ionic liquid; | |
83% | With dihydrogen peroxide In water monomer at 50℃; for 3h; | 2.3. General Procedures of BV oxidation General procedure: Ionic hybrid (0.5 mmol) and ketone (10 mmol) was added toa 25mL flask equipped with a condenser and magnetic stirrer. The reaction was started after the addition of H2O2 aqueous (35 wt.%, 25mmol)in dropwise at 50 °C under vigorous stirring. The progress of the reaction was monitored by TLC (hexane/ethyl acetate=4/1). After the completion,the mixture was extracted with diethyl ether (3 × 15 mL).The combined organic layer was washed with aqueous of NaHCO3(3 × 15 mL) and water (3 × 15 mL), then dried over anhydrous MgSO4, filtered, and concentrated under vacuum to afford the crude product. The crude product was purified by column chromatography using hexane-ethyl acetate 4:1 (V/V) as eluent. The obtained product was identified by comparing TLC, 1H NMR and IR spectra data with authentic sample. The catalyst was recovered by washed with diethylether (3 × 10 mL), and then dried under vacuum at 80 °C over 8 h.Oxidant efficiency is determined by iodometric titration methods described in literature [25]. The results revealed that the amount of H2O2 present at the reaction endpoint was 2-3 mmol. |
82% | With 3-chloro-benzenecarboperoxoic acid; trifluoroacetic acid In dichloromethane for 0.5h; 0 deg C to room temperature; | |
81% | With 3-chloro-benzenecarboperoxoic acid In 1,2-dichloro-ethane at 40℃; for 2h; | |
81% | With 3-chloro-benzenecarboperoxoic acid In 1,2-dichloro-ethane at 40℃; for 2h; with/without catalyst; varying reaction time; | |
81% | With 1,1,2,2-tetrahydroperoxy-1,2-diphenylethane; Potassium bicarbonate In acetonitrile at 40℃; for 2.5h; | Bayer-Villiger reaction (Scheme 2, entry 7) General procedure General procedure: To a mixture of ketone (1 mmol) in CH3CN (4 mL), THPDPE (1 mmol) and KHCO3 (1 mmol) were added and the solution was stirred at room temperature. After the completion of the reaction, as monitored by TLC, Na2SO3 (3 M, 1mL) and saturated NaCl (5 mL) were added to the mixture and the corresponding products were extracted with CHCl3 (3 × 5 mL). All of the products were characterized on the basis of their melting points, IR, 1H NMR, and 13C NMR spectral analysis and compared with those reported |
80% | With aluminum(III) oxide; potassium peroxomonosulfate In dichloromethane for 24h; Heating; | |
77% | With oxygen; benzaldehyde; 1-n-butyl-3-methylimidazolium bistrifluoromethylsulfonylamide; 1,1'-azobis(1-cyanocyclohexanenitrile) at 90℃; for 2h; | |
77.97% | Stage #1: cyclopentanone With C5H10NO2(1+)*2H(1+)*O40PW12(3-) In phenyl cyanide at 50℃; for 0.0833333h; Stage #2: With dihydrogen peroxide In phenyl cyanide at 50℃; for 6h; | 1-15; 1-5 Example 1: In a 25 mL three-necked flask equipped with a spherical condenser and a thermometer, add 5 mmol of cyclopentanone, 0.175mmol of catalyst [ProH]H2PW12O40, 3.6mL of solvent benzonitrile and a certain amount of internal standard biphenyl. Heating in a water bath at 50°C and turning on magnetic stirring, after stirring for 5 minutes, slowly add 1.67mL H2O2 (30 wt%) dropwise, react at 50°C for 6h. After the reaction is over, the reaction automatically divides into two phases, add a small amount of ethyl acetate/ether to extract the aqueous phase, and combine the organic phases. The organic phase is dried by rotary steaming and then adding anhydrous magnesium sulfate, analyze the conversion rate of cyclopentanone and the yield of δ-cyclovalerolactone in the reaction by gas chromatography, the calculated conversion rate of cyclopentanone is 94.38%, the yield of δ-cyclovalerolactone is 77.97%, and the selectivity of the reaction can reach 82.62%. |
76% | Stage #1: cyclopentanone With N-hydroxyphthalimide; 1,1-Diphenylmethanol; 2,2'-azobis(isobutyronitrile); oxygen In acetonitrile at 75℃; Stage #2: With 1,1,1,3',3',3'-hexafluoro-propanol; toluene-4-sulfonic acid at 60℃; | |
70% | With diphenyl hydrogen phosphate; iodobenzene; 3-chloro-benzenecarboperoxoic acid In acetonitrile at 20℃; for 24h; | |
68% | With maleic anhydride; urea-hydrogen peroxide complex In dichloromethane at 0℃; for 8h; | |
35% | With urea hydrogen peroxide addition compound In decane; ethyl acetate at 20℃; for 6h; | General procedures for BVO with the biocatalysts and activity assays General procedure: A solution of ketone (0.5 mmol) in ethyl acetate (1.5 mL) and n-decane (0.5 mmol, internal standard) was introduced into the 25-mL round-bottom ask, whereupon the biocatalyst (0.005-0.03 g) and UHP (or 60% aqueous H2O2) 1 mmol were added. The flask was sealed with septum and mixed in a thermostat shaker (±0.5 °C) with orbital stirring of 180 rpm at 25-70 °C for 29-50 h, depending on the reaction rate. Periodically, during the reaction, 100 L of the samples diluted with ethyl acetate were collected to monitor progress of the reaction utilising GC. When the reaction was completed, the catalyst was filtered off and washed with ethyl acetate (3 × 5 mL). The filtrate was washed with 5 mL of a 10% NaHCO3 solution in water, dried over anhydrous MgSO4 and concentrated in vacuum. The yields of the lactones after purication by column chromatography (with hexane:ethyl acetate ratio of 4:1 as an eluent) were in the range of 85-99%. |
34% | With [ReO3(η2-hydrotris(pyrazol-1-yl)-methane)(1,3,5-triaza-7-phosphaadamantane)][ReO4]; dihydrogen peroxide In 1,2-dichloro-ethane at 70℃; for 6h; Inert atmosphere; | |
34% | With bis-trimethylsilanyl peroxide; 1-hexyl-3-methylimidazolium chloroaluminate(III) at 0 - 20℃; for 3h; Acidic conditions; Inert atmosphere; | General procedure for cyclic ketones oxidation General procedure: The ketone (1.5 mmol) and silyl peroxide (2.25 mmol for reactions with bis(silyl) peroxides and 3 mmol for reactions with t-butyl silyl peroxides) were added dropwise at 0 °C into the freshly synthesised [hmim][AlxCly] (2 mmol for reactions with bis(silyl) peroxides and 3 mmol for reactions with t-butyl silyl peroxides). Next, the solution was stirred under a nitrogen atmosphere at room temperature for 1-24 h (depending on the reaction rate). After this time, 5 ml of water was added to the post-reaction mixture, and the water phase was extracted with methylene chloride or diethyl ether (10× 5 ml). The organic layer was washed with 5 ml of water, dried over anhydrous MgSO4, filtered, concentrated in a vacuum (50 °C, 100 mbar) and purified by column chromatography (hexane:ethyl acetate (4:1)) when necessary. All products were characterised by comparison of their NMR spectra (see Supplementary data) with authentic samples [20]. |
31% | With air; 4-aminoperbenzoic acid In dichloromethane at 20℃; for 15h; | |
31% | With [ReOCl3(PPh3)2]; dihydrogen peroxide In water monomer; 1,2-dichloro-ethane at 70℃; for 6h; | General procedure: In typical conditions, Re catalysts were used as stock solutions (for this, 10.0 mg of the compound 1-10 were dissolved in 2.00 mL of 1,2-dichloroethane, 1,2 DCE). The required amount of this stock solution for the desired oxidant/catalyst molar ratio (1000:1) was transferred to a second flask containing 3.00 mL of 1,2-dichloroethane. 1.7 mmol of H2O2 as a 30% aqueous solution (102 μL) and 1.7 mmol of substrate were then added, and the reaction solution was stirred for 6 h at the desired temperature (typically 70 °C) and normal pressure (dinitrogen atmosphere). Then, 120 μL of cycloheptanone (internal standard) and 10.00 mL of diethyl ether (to extract the substrate and the organic products from the reaction mixture) were added. The obtained mixture was stirred during 10 min and then a sample (1 μL) was taken from the organic phase and analysed by GC using the internal standard method. Blank tests indicate that no oxidation takes place in the absence of the Re catalyst or the oxidant. |
30% | With urea hydrogen peroxide addition compound; Potassium bicarbonate; phenyl cyanide In 2,2,2-trifluoroethanol at 50℃; for 72h; Inert atmosphere; Sealed tube; | 12 General Baeyer-Villiger procedure General procedure: To a flame dried crimp top vial under argon, KHCO3 (80mg, 0.8mmol, 0.2equiv) was weighed, followed by urea hydrogen peroxide (564mg, 24mmol, 6.0equiv). The ketone (4.0mmol, 1.0equiv) was added at this stage if it was a solid. The vial was then sealed and evacuated, followed by backfilling with argon (repeated three times). Afterward, the solvent (8.0mL), benzonitrile (2.48mL, 24mmol, 6.0equiv) and, if it was a liquid, the ketone (4.0mmol, 1.0equiv), were added via syringe. The reaction was allowed to run for the specified time at 50°C, after which it was cooled down to room temperature. The pressure was released with a needle, then the vial was opened. The mixture was diluted with CH2Cl2 (40mL) and water (20mL). The layers were separated and the resulting aqueous solution was extracted with CH2Cl2 (2×40mL). The combined organic layers were dried (MgSO4), concentrated in vacuo, and the crude product was subjected to flash chromatography on silica gel (5:1 petroleum ether:EtOAc) to afford the corresponding product(s). |
26% | With dihydrogen peroxide In 1,2-dichloro-ethane at 40℃; for 5h; | |
84 % Chromat. | With oxygen; benzaldehyde In 1,2-dichloro-ethane Ambient temperature; | |
With 3-chloro-benzenecarboperoxoic acid In chloroform Heating; | ||
99 % Chromat. | With dihydrogen peroxide In dichloromethane 1) 4 h, room temperature; 2) reflux, 6 h; | |
98 % Chromat. | With oxygen; benzaldehyde In benzene for 17h; Ambient temperature; | |
17 % Chromat. | With dihydrogen peroxide; n-tetradecanoic acid In toluene for 24h; immobilised Candida antarctica lipase (comp. A and B); | |
With oxygen; benzaldehyde In 1,2-dichloro-ethane at 25℃; for 20h; Yield given; | ||
63 % Chromat. | With oxygen; benzaldehyde In Carbon tetrachloride at 40℃; for 5h; | |
With sec-decanepersulfonic acid In Carbon tetrachloride at 17℃; | ||
With oxygen; benzaldehyde at 49.85℃; for 6h; Yield given; | ||
76 % Chromat. | With hexagonal mesoporous silica supported peroxycarboxylic acid In hexane at 20℃; for 4h; | |
With dihydrogen peroxide; toluene-4-sulfonic acid In various solvent(s) at 60℃; | ||
With dihydrogen peroxide In various solvent(s) at 20℃; for 2h; | ||
With carbon dioxide; oxygen; 2,2-dimethypropanal at 20℃; for 18h; | ||
With perfluoro(methylcyclohexane); water monomer; dihydrogen peroxide In 1,4-dioxane at 50℃; for 5h; | ||
70 % Chromat. | With dihydrogen peroxide; 1-n-butyl-3-methylimidazolium tetrafluoroborate In water monomer at 60℃; for 24h; | |
With [(triphosPO)Pt(CH2Cl2)](BF4)2; dihydrogen peroxide In 1,2-dichloro-ethane at 70℃; | ||
With Sn-palygorskite; dihydrogen peroxide In 1,4-dioxane at 70℃; for 24h; | ||
With peroxymonosulfuric acid at 34.85℃; | ||
With Peroxyacetic acid In acetonitrile at 60℃; for 12h; | ||
With Potassium peroxomonosulfate; potassium peroxomonosulfate; mesoporous silica In carbon dioxide at 40℃; | ||
With dihydrogen peroxide In 1,4-dioxane at 70℃; for 24h; | ||
99 % Chromat. | With dihydrogen peroxide In nitromethane; water monomer at 59.85℃; for 0.75h; | |
With dihydrogen peroxide In various solvent(s) at 60℃; for 20h; | ||
With Sn-Beta-2 zeolite; dihydrogen peroxide In various solvent(s) at 56℃; for 7h; | ||
21 %Turnov. | With dihydrogen peroxide In tert-butyl methyl ether at 56℃; for 6h; | |
With [SiO2]-CH2CH2CO3H In supercritical carbon dioxide at 40℃; Flow conditions; | ||
With tert.-butylhydroperoxide In 1,4-dioxane at 70℃; for 12h; | ||
With dihydrogen peroxide In water monomer; acetonitrile at 75℃; for 12h; | ||
With dihydrogen peroxide In water monomer; 1,2-dichloro-ethane at 75℃; for 10h; | ||
With sodium peroxodisulphate In 1,4-dioxane at 20℃; for 24h; Green chemistry; | ||
With phosphite dehydrogenase; Physcomitrella patens Y160H Baeyer-Villiger monooxygenase; Phosphate; NADPH In 1,4-dioxane at 25℃; Enzymatic reaction; regioselective reaction; | 2.7 Conversions and GC/GC-MS analysis For GC and GC-MS analysis, samples of 500μl 50mM Tris-HCl (pH 7.5) containing 2mM substrate, 5% dioxane, 100μM NADPH, 3.0μM PTDH, 10mM phosphite and 1μM BVMO were incubated shaking at 25°C from 1 to 20h. The reactions were stopped by extraction with ethyl acetate (3×0.5ml, including 0.1% mesitylene as an internal standard), dried with magnesium sulfate and analyzed directly by GC or GC-MS [5] to determine the degree of conversion. | |
With D-glucose; recombinant steroid monooxygenase from Rhodococcus rhodochrous IFO 3338; β‐cyclodextrin In N,N-dimethyl-formamide at 25℃; Enzymatic reaction; | 4.6 Biocatalysis using resting cells General procedure: Biotransformations were carried out at 25 °C in Tris-HCl buffer (50 mM, pH 8.0) using resting cells of E. coli BL21 (DE3) expressing STMO at a final OD600 nm of 15 in 24-well deep well plates covered with a breathable AeraSeal sealing film (Excel Scientific, Victorville, USA). The reaction mixtures of a total volume of 2.5 ml contained 5 mM 3-phenylcyclobutanone, 10 mM β-cyclodextrine, 100 mM glucose, and 2% (v/v) of dimethylformamide. Samples were taken after 0, 3, and 20 h, extracted with ethyl acetate and analyzed by GC-MS. (0019) Further biotransformations were carried out in order to verify the conversion of substrates established through a spectrophotometric assay, using a series of substances against which the enzyme was shown active alongside with other typical BVMO substrates, which were not shown to be converted in spectrophotometric studies. The substances were assayed at a final concentration of 2 mM together with 50 mM glucose for cofactor regeneration and included progesterone, 11-ketoprogesterone, 4-androstene-3,17-dione, prasterone, corticosterone, cyclopentanone, cyclohexanone, 2-phenylcyclohexanone, bicyclo[3.2.0]-hept-2-en-6-one, 1-indanone, norcamphor, cyclohexyl methyl ketone, cyclopentyl methyl ketone, 3-acetylindole, acetophenone, and 2-decanone. | |
15 %Chromat. | With dihydrogen peroxide; molybdenum(VI) oxide In water monomer at 40℃; for 12h; | 2.2. Catalytic activity General procedure: The catalytic activity of the transition metal oxides is measured in a 25 mL round bottom flask equipped with condenser. In a typical procedurefor the oxidation of cyclic ketones is as follows. Tungsten oxide (50 mg) is mixed with 2-heptylcyclopentanone (2.5 mmol, 450 mg), the oxidizing agent of aqueous hydrogen peroxide (30 wt.%;6.2 mmol) is slowly added dropwise to this mixture with stirring at 40 °C. The resultant mixture is stirred for 12 h. The catalyst is separated by filtration. Conversion of 2-heptylcyclopentanone and selectivityof δ-dodecalactone are determined by quantitative GC analyses of the organic phase. The organic phase is evaporated under reduced pressure and further purified by column chromatography over silica gel using 1:5 ethyl acetate-hexane as eluent to furnish the pure δ-dodecalactone. |
With xenobiotic reductase A from Pseudomonas putida; cyclohexanone monooxygenase from Acinetobacter calcoaceticus; NADPH In aq. phosphate buffer; N,N-dimethyl-formamide at 30℃; for 1h; Enzymatic reaction; | ||
With recombinant cyclohexanone monooxygenase from Acinetobacter sp. NCIMB9871 In methanol at 20℃; for 2h; Enzymatic reaction; chemoselective reaction; | 2.3 Biotransformations General procedure: Whole-cell biotransformations were performed in 40mL amber glass vials using 1mL reaction volumes. The biotransformation reaction mixture (BRM) consisted of 0.1g wet weight/mL in 200mM Tris-HCl (pH 8), 100mM glucose and 100mM glycerol. The reactions were initiated by the addition of substrate (10mM) dissolved in methanol. Reactions were performed at 20°C for 2h, where after the reactions were stopped and extracted using an equal volume (2 times 0.5mL) of ethyl acetate containing 2mM 1-undecanol or 2mM 3-octanol as internal standard. GC-MS analysis was carried out on a Finnigan Trace GC ultra (ThermoScientific) equipped with a FactorFour VF-5ms column (60m×0.32mm×0.25μm, Varian). Chiral separation (Table S2) was performed using either a Chiraldex G-TA or B-TA column (30m×0.25mm×0.12μm, Astec). | |
42 %Chromat. | With dihydrogen peroxide In 1,4-dioxane; water monomer at 15℃; for 24h; | |
97.2 %Chromat. | With oxygen; benzaldehyde In 1,2-dichloro-ethane for 4h; | |
84 %Chromat. | With oxygen; benzaldehyde In benzene at 25℃; for 6h; regioselective reaction; | 4.2 General procedure for Baeyer-Villiger oxidation General procedure: In a two-necked 25 mL round-bottom flask was charged with L-BIOX (0.01 mmol, 1.2 mg), a ketone (1 mmol), and benzene (2 mL) before addition of benzaldehyde (3 mmol, 306 μL) and benzene (1 mL). After purging with O2 gas, the mixture was allowed to stir at 25 °C in a water bath attached with a gas bag filled with O2 gas (1 atm). After appropriate reaction time, to the reaction mixture was added dodecane followed by filtration through a short plug of Celite and MgSO4 to remove a catalyst and the filtrate was analyzed by GC or 1H NMR. Spectral properties of products (2a, 2b, 2d, 2g, 2h) were identical with those of commercial (TCI, nacalai tesque, Kanto) authentic sample. Spectral properties of products (2c, 2e, 2f, 2i) were identical with those of authentic sample synthesized according to the reported procedure.42 Spectral property of 2c′ was identical with the reported data.43 |
With dihydrogen peroxide In 1,2-dichloro-ethane at 70℃; for 9h; | ||
68.9 %Spectr. | With oxygen In 1,2-dichloro-ethane at 49.99℃; for 6h; Calcination; | |
With dihydrogen peroxide In 1,2-dichloro-ethane at 90℃; for 6h; | 2.3 B-V Oxidation of Ketones with H2O2 General procedure: SnO2/GO nanocomposites (0.05 g) and ketones (1.0 mmol) were mixed in 1,2-dichloroethane (15 mL) under vigorously stirring. H2O2 (30 wt%, 2.0 mmol) was then added dropwise at 90 °C. The reaction progress was monitored by GC. After the reaction, catalyst was separated by centrifugation. The liquid reaction mixture was extracted by ethyl ether and then quantitatively analyzed by a 6890 N gas chromatograph (Agilent Co.) equipped with the capillary column (HP19091G-B213, 30 m x 0.32 mm x 0.25 μm). The recovered catalyst was washed with ethanol and distilled water repeatedly, and dried at 40 °C overnight for reused. | |
With dihydrogen peroxide In neat (no solvent) at 20℃; for 6h; Green chemistry; | ||
With glucose dehydrogenase; D-glucose; potassium chloride; NADPH In aq. buffer at 30℃; Enzymatic reaction; regioselective reaction; | ||
With benzaldehyde In toluene at 60℃; for 8h; | 7 In 10 mL of toluene solution containing 10 mg of hydroxylated multi-walled carbon nanotubes (MWCNT) added 2 mmol of Cyclopentanone and 4 mmol of benzaldehyde and the reaction was carried out at 60 ° C for 8 hours. The conversion of cyclohexanone was 93% and the selectivity of cyclopentene lactone was greater than 99% by detection analysis | |
With dihydrogen peroxide In 1,4-dioxane; water monomer at 80℃; for 8h; | ||
With dihydrogen peroxide In methanol at 70℃; for 6h; | ||
With benzaldehyde In 1,2-dichloro-ethane at 50℃; for 6h; | 4.4 Catalytic reaction General procedure: The catalytic activity of mesoporous silica materials including Cu containing Fe3O4mSiO2 was evaluated with different cyclic ketones. The activity tests were performed in a three-neck flask placed in temperature-controlled oil bath. In a typical synthesis, the reaction mixture consists of catalyst (50mg), cyclohexanone (2mmol, 206 μL), benzaldehyde (4mmol, 0.424g) and 1,2-dechloroethane (10mL) was stirred vigorously stirred with magnet and heated to 50°C for 6h, equipped with a reflux condenser. Air was introduced into the flask continuously at 20mL/min. The obtained products were centrifuged and analyzed using HP 9790II gas chromatograph equipped with poly-capillary column and hydrogen flame ionization detector. The dodecane was chosen as an internal standard to calculate the conversion of ketones, selectivity of caprolactone and the conversion of aldehydes. The used catalysts were collected with a magnet and filtered, washed with ethanol and dried at 100°C for 6h and then subjected to the next catalytic cycle. | |
With C13H9NO5S(2-)*Sn(4+)*2CH3(1-)*1.5CH4O; dihydrogen peroxide In water monomer at 60℃; for 1h; Sonication; | ||
With oxygen In aq. phosphate buffer; acetonitrile at 42℃; for 4h; Enzymatic reaction; | ||
With dihydrogen peroxide In neat (no solvent) at 20℃; for 4h; Green chemistry; | 2.3 Typical Procedure for Oxidation of Ketone General procedure: Ketone (2 mmol), H2O2(2.2 ml approx 20 mmol) and 25 mgAg-NPsmont were taken in 10 ml round bottom flask andthe reaction mixture was stirred at room temperature for 4 h.After completion of the reaction, the solid catalyst was recoveredby filtration. The product obtained contains water as abyproduct was removed by using anhydrous sodium sulphate.The conversion of the reaction was determined using GC. | |
With dihydrogen peroxide In 1,2-dichloro-ethane for 0.0833333h; Microwave irradiation; | 2.4. Baeyer-Villiger oxidation reaction of ketones General procedure: After 0.1 mmol ketone, 40 mL 30% H2O2, and 3 mL of solvent were mixed in a 10-mL glass flask equipped with a reflux condenser,a given amount of catalyst was added. Then the reaction was carried out under microwave irradiation at a desired power for different times without stirring. The reaction products were analyzed by GC and GC/MS to evaluate the structures of the products,the conversion, and the selectivity.For comparison, the catalytic reaction was also carried out at 80 °C using conventional oil-bath heating and magnetic stirring.It was found that conversion of cyclohexanone could reach 90% after 6 h with 30%PW12/CNTsSiO2 or 30%PW12/CNTs-SSiO2 as catalyst. | |
With 3-chloro-benzenecarboperoxoic acid In chloroform Reflux; | 1.1; 2-9 Step 1 Synthesis of intermediate I: In a 100 mL four-necked flask equipped with a magnetic stirrer, thermometer and condenser, add 8.6 g (85%, 0.0425 mol) of m-chloroperoxybenzoic acid and 19 mL of dry chloroform, and add dropwise at room temperature. A solution of 2.1 g (0.025 mol) of cyclopentanone in dry chloroform (13 mL). After the dropwise addition, the mixture was heated to reflux and monitored until the cyclopentanone content was less than 0.5% to stop the reaction, and then post-processed. The reaction mixture was cooled with an ice water bath, filtered to remove the m-chlorobenzoic acid precipitate, and the filtrate was washed with about 10% sodium sulfite aqueous solution until KI- Until the starch test paper does not change color, the solvent is removed by rotary evaporation. The residue is washed with 10% potassium carbonate aqueous solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain the intermediate I crude product and the intermediate I molecular formula. : C5H8O2, English name: δ-Valerolactone, molecular weight: 100.12, boiling point: 218-220 ° C; | |
With baeyer-villiger monooxygenases 2 In ethanol at 24℃; for 24h; Enzymatic reaction; | ||
With Octanoic acid; dihydrogen peroxide; Lipase B from Candida antarctica, immobilised on Immobead 150, recombinant from yeast In water monomer at 20℃; for 20h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 23℃; for 6h; Inert atmosphere; | 1 Ethyl 2-oxotetrahydro-2H-pyran-3-carboxylate (1a) Ethyl 2-oxotetrahydro-2H-pyran-3-carboxylate (1a) To a solution of LHMDS (3.43 g, 20.5 mmol, 2.05 equiv) in THF (20 mL) was added a mixture of delta-valerolactone (1.00 g, 10.0 mmol, 1.00 equiv) and diethyl carbonate (1.3 mL, 11.0 mmol, 1.10 equiv) at -78° C. After stirring at room temperature for 6 hours, the reaction was quenched with glacial acetic acid (5 mL), diluted with Et2O (20 mL), and stirred for 5 minutes. The insoluble white solid was filtered off and rinsed with more Et2O. The filtrate was concentrated and purified by column chromatography (50% to 65% Et2O in PET) to afford 1a as a colorless oil (1.20 g, 70% yield); 1H NMR (300 MHz, CDCl3) δ 4.46-4.31 (m, 2H), 4.25 (qd, J=7.1, 1.7 Hz, 2H), 3.56 (dd, J=8.3, 7.5 Hz, 1H), 2.38-2.08 (m, 2H), 2.08-1.80 (m, 2H), 1.30 (t, J=7.1 Hz, 3H). All characterization data match those reported. |
46% | With sodium ethanolate at 130℃; | |
With acetic acid In ethanol; water | D.A Step A Step A Precaration of ethyl tetrahydro-2-oxo-2H-pyran-3-carboxylate Sodium metal (3.0 g) is dissolved in absolute ethanol (60 mL) under nitrogen and the solution is concentrated under vacuum. Diethyl carbonate (50 mL) and δ-valerolactone (11.5 g) are added to the solid sodium ethoxide and the solution is heated on an oil bath at 130° C. Ethanol is distilled off through a 2-two inch vigreux column at 80°-95° C. during 30 minutes (15 mL collected). The oil bath temperature is then increased to 150° C. and distillate (11 mL) is collected up to 120° C. A solid forms during the distillation. The reaction mixture is cooled and diluted with diethyl ether (100 mL). The mixture is filtered and the solid residue is washed with ether. The solid residue is stirred with water (80 mL) and acetic acid (8 mL) and the mixture is extracted with diethyl ether (100 mL). The extract is dried over magnesium sulfate and concentrated to afford an oil (13.1 g). Short path vacuum distillation gives ethyl tetrahydro-2-oxo-2H-pyran-3-carboxylate (9.1 g), bp 115°-118° C. (0.5 mm/Hg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With methanol; sodium hydride In n-heptane at 20 - 65℃; for 13h; Inert atmosphere; | 1.B.1 Step 1: (£)-(2-Oxotetrahydropyran-3-ylidene)methanolate (sodium salt) A 5 L, 3 -neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with sodium hydride (59.91 g of 60% w/w, 1.498 mol) followed by heptane (1.5 L) which provided a grey suspension. Stirring was commenced and the pot temperature was recorded at 19 °C. The vessel was then charged with ethyl alcohol (3.451 g, 74.91 mmol) added via syringe which resulted in gas evolution. The addition funnel was charged with a clear pale yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 h which resulted in gas evolution and a gradual exotherm to 45 °C. The resulting thick white suspension was then heated to 65 °C for 2 h and then allowed to cool to room temperature. The mixture was continued to stir at room temperature overnight (about 10 h). The reaction mixture was vacuum filtered through a glass frit Buchner funnel (medium porosity) under a stream of nitrogen. The filter cake was displacement washed with heptane (2 X 250 mL) and pulled for a few min. The slightly heptane wet cake was transferred to a glass tray and dried in a vacuum oven at 45 °C for 15 h to provide a white solid (205 g, 1.36 mol, 91% yield) as the desired product, (£)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt). |
91% | With sodium hydride In ethanol; n-heptane at 20 - 65℃; for 13h; | 16.1a Step 1a: A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with sodium hydride (59.91 g of 60% w/w, 1.498 mol) followed by heptane (1.5 L) which provided a grey suspension. Stirring was commenced and the internal temperature was recorded at 19° C. The vessel was then charged with ethyl alcohol (3.451 g, 74.91 mmol) added via syringe, which resulted in gas evolution. The addition funnel was charged with a clear pale yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 h, which resulted in gas evolution and a gradual exotherm to 45° C. The resulting thick white suspension was then heated to 65° C. for 2 h and then allowed to cool to room temperature. The mixture continued to stir at room temperature overnight (about 10 h). The reaction mixture was vacuum filtered through a glass frit Buchner funnel (Medium porosity) under a stream of nitrogen. The filter cake was displaced and washed with heptane (2×250 ml) and pulled for a few minutes. The slightly heptane wet cake was transferred to a glass tray and dried in a vacuum oven at 45° C. for 15 h to provide a white solid (205 g, 1.36 mol, 91% yield) as the desired product (E)-(2-oxotetrahydropyran-3-ylidene)methanolate. 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 3.90-3.83 (m, 2H), 2.09 (t, J=6.3 Hz, 2H), 1.57 (qd, J=6.4, 4.7 Hz, 2H). |
91% | With sodium hydride In ethanol; n-heptane at 19 - 65℃; for 13h; Inert atmosphere; | 1.B.1 Step 1: (E)-(2-Oxotetrahydropyran-3-ylidene)methanolate (sodium salt) A 5 L, 3-neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with 50 sodium hydride (59.91 g of 60% w/w, 1.498 mol) followed by 51 heptane (1.5 L) which provided a grey suspension. Stirring was commenced and the pot temperature was recorded at 19° C. The vessel was then charged with 23 ethyl alcohol (3.451 g, 74.91 mmol) added via syringe which resulted in gas evolution. The addition funnel was charged with a clear pale yellow solution of 52 tetrahydropyran-2-one (150 g, 1.498 mol) and 53 ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 h which resulted in gas evolution and a gradual exotherm to 45° C. The resulting thick white suspension was then heated to 65° C. for 2 h and then allowed to cool to room temperature. The mixture was continued to stir at room temperature overnight (about 10 h). The reaction mixture was vacuum filtered through a glass frit Buchner funnel (medium porosity) under a stream of nitrogen. The filter cake was displacement washed with heptane (2×250 mL) and pulled for a few min. The slightly heptane wet cake was transferred to a glass tray and dried in a vacuum oven at 45° C. for 15 h to provide a white 54 solid (205 g, 1.36 mol, 91% yield) as the desired product, (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt). |
91% | With sodium hydride In ethanol; n-heptane at 19 - 65℃; for 13h; Inert atmosphere; | 3.1; 162.1 Step 1: (E)-(2-Oxotetrahydropyran-3-ylidene)methanolate (sodium salt) A 5 L, 3-neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with sodium hydride (59.91 g of 60% w/w, 1.498 mol) followed by heptane (1.5 L) which provided a grey suspension. Stirring was commenced and the pot temperature was recorded at 19 °C. The vessel was then charged with ethyl alcohol (3.451 g, 74.91 mmol) added via syringe which resulted in gas evolution. The addition funnel was charged with a clear pale yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 h which resulted in gas evolution and a gradual exotherm to 45 °C. The resulting thick white suspension was then heated to 65 °C for 2 h and then allowed to cool to room temperature. The mixture was continued to stir at room temperature overnight (about 10 h). The reaction mixture was vacuum filtered through a glass frit Buchner funnel (medium porosity) under a stream of nitrogen. The filter cake was displacement washed with heptane (2 x 250 mL) and pulled for a few min. The slightly heptane wet cake was transferred to a glass tray and dried in a vacuum oven at 45 °C for 15 h to provide a white solid (205 g, 1.36 mol, 91% yield) as the desired product, (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt). |
91% | With sodium hydride In ethanol; n-heptane at 19 - 65℃; for 13h; Inert atmosphere; | 1.B.1 Step 1: (E)-(2-Oxotetrahydropyran-3-ylidene)methanolate (sodium salt) A 5 L, 3 -neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with sodium hydride (59.91 g of 60% w/w, 1.498 mol) followed by heptane (1.5 L) which provided a grey suspension. Stirring was commenced and the pot temperature was recorded at 19 °C. The vessel was then charged with ethyl alcohol (3.451 g, 74.91 mmol) added via syringe which resulted in gas evolution. The addition funnel was charged with a clear pale yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 h which resulted in gas evolution and a gradual exotherm to 45 °C. The resulting thick white suspension was then heated to 65 °C for 2 h and then allowed to cool to room temperature. The mixture was continued to stir at room temperature overnight (about 10 h). The reaction mixture was vacuum filtered through a glass frit Buchner funnel (medium porosity) under a stream of nitrogen. The filter cake was displacement washed with heptane (2 X 250 mL) and pulled for a few min. The slightly heptane wet cake was transferred to a glass tray and dried in a vacuum oven at 45 °C for 15 h to provide a white solid (205 g, 1.36 mol, 91% yield) as the desired product, (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt). |
91% | With sodium hydride In ethanol; n-heptane at 19 - 65℃; for 13h; Inert atmosphere; | 1.B.1 Step 1: (E)-(2-Oxotetrahydropyran-3-ylidene)methanolate (sodium salt) A 5 L, 3 -neck round bottom flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with sodium hydride (59.91 g of 60% w/w, 1.498 mol) followed by heptane (1.5 L) which provided a grey suspension. Stirring was commenced and the pot temperature was recorded at 19 °C. The vessel was then charged with ethyl alcohol (3.451 g, 74.91 mmol) added via syringe which resulted in gas evolution. The addition funnel was charged with a clear pale yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 h which resulted in gas evolution and a gradual exotherm to 45 °C. The resulting thick white suspension was then heated to 65 °C for 2 h and then allowed to cool to room temperature. The mixture was continued to stir at room temperature overnight (about 10 h). The reaction mixture was vacuum filtered through a glass frit Buchner funnel (medium porosity) under a stream of nitrogen. The filter cake was displacement washed with heptane (2 X 250 mL) and pulled for a few min. The slightly heptane wet cake was transferred to a glass tray and dried in a vacuum oven at 45 °C for 15 h to provide a white solid (205 g, 1.36 mol, 91% yield) as the desired product, (E)-(2-oxotetrahydropyran-3-ylidene)methanolate (sodium salt). |
77% | With sodium methylate In diethyl ether for 60h; | |
19% | With sodium hydride In ethanol; n-heptane at 19 - 65℃; Inert atmosphere; | 2.2 Stage 1 A 5 L 3 neck RB flask was fitted with a mechanical stirrer, a heating mantle, an addition funnel, a J-Kem temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with sodium hydride (59.91 g of 60% w/w, 1.498 mol) followed by heptane (1.5 L) which provided a grey suspension. Stirring was commenced and the pot temperature was recorded at 19° C. The vessel was then charged with ethyl alcohol (3.451 g, 74.91 mmol) added via syringe which resulted in gas evolution. The addition funnel was charged with a clear pale yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 hour which resulted in gas evolution and a gradual exotherm to 45° C. The resulting thick white suspension was then heated to 65° C. for 2 hours and then allowed to cool to RT. The mixture was continued to stir at RT overnight (about 10 hours). The reaction mixture was vacuum filtered through a glass frit Buchner funnel (Medium porosity) under a stream of nitrogen. The filter cake was displacement washed with heptane (2×250 mL) and pulled for a few minutes. The slightly heptane wet cake was transferred to a glass tray and dried in a vacuum oven at 45° C. for 15 hours to provide a white solid (205 g, 1.36 mol, 91% yield) as the desired product (E)-(2-oxotetrahydropyran-3-ylidene)methanolate. 1HNMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 3.90-3.83 (m, 2H), 2.09 (t, J=6.3 Hz, 2H), 1.57 (qd, J=6.4, 4.7 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: O,N-dimethyl-hydroxylamine hydrochloride With tris(methyl)aluminum In dichloromethane at 0℃; for 0.333333h; Inert atmosphere; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In dichloromethane at 0℃; for 0.333333h; Inert atmosphere; Stage #3: With hydrogenchloride In dichloromethane; chloroform; water monomer at 0℃; for 1h; Inert atmosphere; | |
92% | Stage #1: O,N-dimethyl-hydroxylamine hydrochloride With tris(methyl)aluminum In hexane; dichloromethane at 0℃; Inert atmosphere; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In hexane; dichloromethane at 0℃; Inert atmosphere; Stage #3: With hydrogenchloride In hexane; dichloromethane; chloroform; water monomer at 0℃; | |
92% | Stage #1: O,N-dimethyl-hydroxylamine hydrochloride With tris(methyl)aluminum In hexane; dichloromethane at 0℃; for 0.333333h; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In hexane; dichloromethane at 0℃; for 0.333333h; |
90% | Stage #1: O,N-dimethyl-hydroxylamine hydrochloride With tris(methyl)aluminum In dichloromethane; toluene at 0℃; for 0.333333h; Inert atmosphere; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In dichloromethane; toluene Inert atmosphere; Stage #3: With hydrogenchloride In dichloromethane; water monomer; toluene at 0℃; for 1h; Inert atmosphere; | |
78% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one; O,N-dimethyl-hydroxylamine hydrochloride With isopropylmagnesium chloride lithium chloride In tetrahydrofuran at -20℃; for 2.5h; Inert atmosphere; Stage #2: With water monomer; ammonia hydrochloride In tetrahydrofuran | |
76% | With isopropylmagnesium chloride lithium chloride In tetrahydrofuran at -20℃; for 2h; Schlenk technique; Inert atmosphere; | |
60% | Stage #1: O,N-dimethyl-hydroxylamine hydrochloride With tris(methyl)aluminum In dichloromethane; toluene at 20℃; for 0.5h; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In dichloromethane; toluene at 20℃; Stage #3: With hydrogenchloride In dichloromethane; water monomer; toluene at 0℃; | B.1 To a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (14.6 g, 150 mmol) in dry dichloromethane (150 mL) was added trimethylaluminum (2.0 M in toluene, 75 mL, 150 mmol) drop wise at room temperature. After stirring for 30 mins, tetrahydropyran-2-one (1O g, 100 mmol) in dichloromethane (50 mL) was added drop wise. The reaction mixture was stirred over night at room temperature. At 0 0C, 1 N HCl (80 mL) was added slowly (exothermic reaction) then the reaction mixture was extracted with dichloromethane (3 x 200 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (12O g column, dichloromethane to 20% methanol in dichloromethane) to give product (9.7 g, 60%). 1H NMR (CDCl3) δ 3.68 (s, 3H), 3.63 (t, J= 6.1 Hz, 2H), 3.17 (s, 3H), 2.46 (t, J = 7.0 Hz, 2H), 1.69-1.74 (m, 2H), 1.58-1.64 (m, 2H); MS EI m/z 162.21 (M + H)+. |
60% | Stage #1: O,N-dimethyl-hydroxylamine hydrochloride With tris(methyl)aluminum In dichloromethane; toluene at 20℃; for 0.5h; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In dichloromethane; toluene | H.1 To a stirred suspension of N,O-dimethylhydroxyamine hydrochloride (14.6 g, 150 mmol) in dry dichloromethane (150 mL) was added a solution of trimethylaluminum (2.0 M solution in toluene, 75 mL, 150 mmol) drop wise at room temperature. After stirring for 30 min, tetrahydropyran-2-one (10 g, 100 mmol) in dry dichloromethane (50 mL) was added drop wise. The reaction mixture was stirred over night. After cooling to 0 0C, IN HCl (80 mL, 80 mmol) was added slowly (exothermic reaction), diluted with dichloromethane (200 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (12O g column, 0 % methanol in dichloromethane to 20% methanol in dichloromethane) to give product (9.7 g, 60 %). 1H NMR (CDCl3) δ 3.68 (s, 3H), 3.63 (t, J= 6.1 Hz, 2H), 3.17 (s, 3H), 2.46 (t, J = 7.0 Hz, 2H), 1.69-1.74 (m, 2H), 1.58-1.64 (m, 2H). MS EI m/z 162 (M + H)+. |
37% | Stage #1: O,N-dimethyl-hydroxylamine hydrochloride With tris(methyl)aluminum In dichloromethane; toluene at 0℃; for 0.5h; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In dichloromethane; toluene at 0 - 20℃; for 16.5h; | 1 Synthesis Example 1 Synthesis of Diol Compounds 1 and 2(Synthesis of Intermediate Compound 1A) N, O-dimethylhydroxylamine hydrochloride (2.9 g, 30.0 mmol)In methylene chloride (10 mL)Trimethylaluminum toluene solution(2.0 M, 15.0 mL, 30.0 mmol) at 0 ° C.,And the mixture was stirred for 30 minutes.To the reaction solution,Valerolactone(2.0 g, 20.0 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 30 minutes, and further stirred at room temperature for 16 hours.The reaction solution was cooled to 0 ° C., hydrochloric acid (0.1 N, 5 mL) was added, and the mixture was stirred at room temperature for 1 hourI stirred. After addition of magnesium sulfate (4.0 g, 33.3 mmol), the mixture was stirred for 10 minutes, and the filtrate was recovered by filtration. Methylene chloride (50 mL) was added to the solid obtained by filtration and extracted, and the mixture was mixed with the above filtrate and concentrated to obtain an oily product 1A. Yield was 1.2 g and the yield was 37% |
31% | With isopropylmagnesium chloride lithium chloride In tetrahydrofuran; 2-methyltetrahydrofuran at -20℃; for 3.5h; | 1 To a suspension of lactone (4 g, 40 mmol, 1 eq) and N,O-dimethylhydroxyamine hydrochloride (6.04 g, 1 .55 eq) in THF (150 ml) at -20°C, 2.9 M solution of /-PrMgBr in 2- methyltetrahydrofuran (50 ml, 3.6 eq) was added dropwise over a period of 30 minutes. The mixture was stirred at -20°C for 3 hours and quenched with 50mL of saturated NH4CI solution. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (eluent 80/20 EtOAc/hexanes to100% EtOAc). Yield 2.0g (31 %). NMR (400MHz, CDCI3): 1.57-1.63 (m, 2H), 1.70-1.76 (m, 2H), 2.44-2.50 (m, 2H), 3.18 (s, 3H), 3.62 (t, 2H), 3.68 (s, 2H). LCMS (C18 column 20 x 2 mm, particle size 2.5 pm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3min, retention time 0.90 min), MS (ESI) m/z 162.4 [MH]+. |
31% | With isopropylmagnesium chloride lithium chloride In tetrahydrofuran; 2-methyltetrahydrofuran at -20℃; for 3.5h; | 1 To a suspension of lactone (4 g, 40 mmol, 1 eq) and N,O-dimethylhydroxyamine hydrochloride (6.04 g, 1 .55 eq) in THF (150 ml) at -20°C, 2.9 M solution of /-PrMgBr in 2- methyltetrahydrofuran (50 ml, 3.6 eq) was added dropwise over a period of 30 minutes. The mixture was stirred at -20°C for 3 hours and quenched with 50mL of saturated NH4CI solution. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (eluent 80/20 EtOAc/hexanes to100% EtOAc). Yield 2.0g (31 %). NMR (400MHz, CDCI3): 1.57-1.63 (m, 2H), 1.70-1.76 (m, 2H), 2.44-2.50 (m, 2H), 3.18 (s, 3H), 3.62 (t, 2H), 3.68 (s, 2H). LCMS (C18 column 20 x 2 mm, particle size 2.5 pm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3min, retention time 0.90 min), MS (ESI) m/z 162.4 [MH]+. |
With tris(methyl)aluminum 1) CH2Cl2, -78 deg C -> room temperature, overnight, 2) CH2Cl2, 0 deg C -> room temperature; Yield given. Multistep reaction; | ||
With tris(methyl)aluminum In dichloromethane | ||
With tris(methyl)aluminum In dichloromethane Inert atmosphere; | ||
With isopropylmagnesium chloride lithium chloride In tetrahydrofuran at -20 - 25℃; for 1h; Inert atmosphere; | ||
Stage #1: O,N-dimethyl-hydroxylamine hydrochloride With C2H6AlCl2 In hexane; dichloromethane at 0℃; for 1h; Inert atmosphere; Schlenk technique; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In hexane; dichloromethane at 20℃; for 24h; Inert atmosphere; Schlenk technique; | ||
Stage #1: O,N-dimethyl-hydroxylamine hydrochloride With tris(methyl)aluminum In tetrahydrofuran; n-heptane at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In tetrahydrofuran; n-heptane at 0 - 20℃; for 15h; Inert atmosphere; | ||
Stage #1: O,N-dimethyl-hydroxylamine hydrochloride With triethyl-aluminium In n-heptane; dichloromethane at -10 - 20℃; for 0.5h; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In n-heptane; dichloromethane at 0 - 20℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | 518 g 6-VALEROLACTONE and 5 ml phosphorous tribromide were fed into a 11 three-necked flask. The mixture was heated up to a temperature of 95 °C to 105 °C under stirring and 550 g bromine were added, while the temperature was kept constant between 100 and 120 °C. Subsequently, 5 ml phosphorus tribromide and 236 g bromine were added at a temperature of 110 °C. After the reaction mixture had been allowed to stand for 30 minutes, it was cooled down to a temperature of 0 to 10 °C. Then, 11 methanol and lg p-toluenesulfonic acid were added, while the temperature was kept constant at 25 °C. After 5 hours of refluxing, the excess material was distilled off and the lower organic layer was separated. The organic layer was then washed with 500 ml of 10percent sodium hydroxide and 500 ml water. After separation of the organic layer, the product was isolated by fractional distillation (139 to 142 °C/28 hPa) and 612.7 g of the title compound were obtained (yield 45percent, purity > 96percent by GC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diisobutylaluminium hydride; In dichloromethane; at -78℃; for 0.25h;Inert atmosphere; | General procedure: To a stirring solution of lactone (130 mg, 0.91 mmol) in methylene chloride (30 mL) at - 78C was slowly added DIBAL-H (1.1 M solution in cyclohexane, 1.0 mL, 1.1 mmol).* The reaction mixture was stirred for 15 minutes, then quenched with aqueous Rochelle?s salt. After the two layers were separated, the organic layer was washed twice with water and the aqueous layer was extracted with methylene chloride. The combined organic extracts were rinsed with brine, dried over MgSO4, and concentrated in vacuo to afford the crude product that was used for the next step without further purification. DIBAL reduction products from lactones 14-17 matched the literature data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With titanium(IV) isopropylate In tetrahydrofuran; diethyl ether at 0 - 20℃; for 4h; Inert atmosphere; | |
46% | With titanium(IV) isopropylate In tetrahydrofuran; diethyl ether at 0 - 20℃; for 4h; | |
46% | With titanium(IV) isopropylate In tetrahydrofuran; diethyl ether at 0 - 26℃; for 4h; | General procedure for synthesis of cyclopropanols (GP 1): To a stirred solution of δ-valerolactone (4.29 g, 42.68 mmol) and Ti(Oi-Pr)4 (12.18 g, 42.86 mmol) indry THF (120 mL) was added a 3 M solution of EtMgBr (30 mL, 90 mmol) in Et2O dropwise at 0o Cover 2 hr. The reaction mixture was allowed to warm to room temperature and stirred for anadditional 2 hr before the addition of a saturated aqueous solution of NH4Cl (50 mL). The aqueouslayer was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4,filtered and concentrated under reduced pressure. The resulting residue was purified by flashchromatography (50% ethyl acetate/hexane) to give S1 (2.55 g, 46%) as a clear, colorless oil. Physicaldata matched that reported by Taddei et al.1 |
With titanium(IV) isopropylate In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: tert-butyl propionate With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane at -78℃; Stage #3: tert-butyldimethylsilyl chloride With tert-butoxide In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5h; Stage #2: propargyl bromide With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran at -78 - -30℃; | |
59% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2h; Stage #2: propargyl bromide With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran at -78 - -30℃; for 2.33333h; | |
50.6% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -30℃; for 3h; Stage #2: propargyl bromide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; n-heptane; ethylbenzene for 0.333333h; |
50.6% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene for 2h; Inert atmosphere; Cooling with acetone-dry ice; Sealed tube; Stage #2: propargyl bromide In tetrahydrofuran; n-heptane; ethylbenzene at -30℃; for 3.33333h; Cooling with acetone-dry ice; | P.5 5. Synthesis of a-propargyl-Δ-valerolactone (pvl) (C) A 250 mL round bottom flask, equipped with stir bar, was sealed with a septum, purged with nitrogen for 30 min and cooled in a dry ice/acetone bath. A solution of lithium diisopropylamine (2.0 M in THF/heptane/ethyl benzene, 22 mL, 44 mmol) was added to the flask. A nitrogen purged solution of δ-valerolactone (3.62 mL, 40 mmol) in THF (40 mL) was added dropwise via syringe over 1.5 h. After an additional 30 min of stirring, a solution of propargyl bromide (4.34 mL, 48 mmol) in hexamethylphosphoramide (8.4 mL, 48 mmol) was added dropwise via syringe over 20 min. The reaction mixture was warmed up to -30° C. using a dry ice/acetone bath and stirred for 3 h. The reaction was quenched with excess NH4Cl solution and warmed to room temperature. The crude product was washed twice with brine, dried with anhydrous magnesium sulfate and concentrated via rotary evaporator. Column chromatography with CH2Cl2 gave a viscous yellow product. Yield: 2.8194 g (50.6%). 1H NMR (300 MHz, CDCl3/TMS, ppm) δ: 4.35 (m, 2H, -C(O)OCH2-), 2.69 (m, 2H, -C(O)CHCH2C≡CH), 2.53 (m, 1H-C(O)CHCH2C≡CH), 2.29 (m, 1H, -CHCH2CH2-), 2.05 (s, 1H, HC≡CCH2-), 1.96 (m, 2H, -CHCH2CH2-), 1.74 (m, 1H, -CHCH2CH2-); 13C NMR (400 MHz, CDCl3, ppm) δ: 172.8, 80.8, 70.1, 68.5, 38.5, 23.8, 21.7, 20.4. |
45% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 2h; Stage #2: propargyl bromide In tetrahydrofuran; hexane at -78 - -60℃; for 20h; | |
45% | With lithium diisopropyl amide at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With trifluoromethylsulfonic anhydride In dichloromethane at 0℃; for 96h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 86.3 percent / butyllithium / tetrahydrofuran; hexane / 0 °C 2: 14 percent / sodium borohydride / ethanol 3: 97.5 percent / sodium hydride / dimethylformamide / 2 h / 50 °C | ||
Multi-step reaction with 3 steps 1: 1) BuLi 2: 14 percent / NaBH4 3: 98 percent / NaH / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In methanol at 20℃; for 1h; Inert atmosphere; Large scale; | 6 Synthesis of hydroxy acid 23 The reaction was performed in a 20 L rotary evaporation flask under slow flow of argon.A solution of valerolactone 22 (98% purity (TCI), 1.0 kg, 10 mol) and triethylamine (140 mL, 1mol) in dry methanol ( 4 L) was stirred at rt for 1 h, during which time slight exothermic effect(up to 28 °C) was observed. The mixture was concentrated in vacuum (25 °C heating bath),diluted with dry toluene ( 4 L), and evaporated under the reduced pressure, and the residue was dried on rotary evaporator at 4 mbar/25 °C followed by stirring under high vacuum (0.4-0.6 torr,rt) overnight to afford 23 as a colorless liquid, 1.39 kg (100% ), containing <1% of toluene. |
99% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With sulfuric acid In methanol for 12h; Reflux; Stage #2: With sodium hydrogencarbonate In methanol for 0.166667h; stereoselective reaction; | |
94% | With sulfuric acid In methanol for 12h; Reflux; | 80 [0417] To prepare 2, freshly distilled δ-valerolactone (1) (856 mg) in methanol (17 ml) was treated with concentrated H2SO4 (100 μΐ) and refluxed for 12 hours. The solution was cooled to -20°C, treated with NaHCC (80 mg), and stirred for 10 minutes. The reaction mixture was filtered and the solvent was removed in vacuum. The residue was taken up in DCM (10 ml), dried over Na2S04, filtered, and concentrated in vacuum to give methyl 5-hydroxypentanoate (2) (Huckstep et al, Synthesis 10:881-82 (1982), which is hereby incorporated by reference in its entirety) (1071 mg, 94%) as a colorless oil, 10248613-2 which was used directly without any further purification. 1H NMR (400 MHz, acetone- d6): δ 1.55 (2H, m), 1.68 (2H, m), 2.35 (2H, t, J = 7.4 Hz), 3.57 (2H, m), 3.64 (3H, s); 13C NMR (100 MHz, acetone-d6): δ 22.2, 32.9, 34.1, 51.5, 61.9, 174.2. See Figures 75A-B. |
85% | With sulfuric acid In methanol for 21h; Inert atmosphere; Reflux; | |
4.a 2-Phosphono-3-(3-hydroxypropyl)-succinic acid a) 5-Hydroxyvaleric acid methyl ester was prepared analogously to example 3a) from δ-valerolactone which was reacted further without additional purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; | EXAMPLE 7 A procedure similar to that described in Example 6 is used, and 200 parts of 5-valerolactone and 9 parts of <strong>[24307-26-4]dimethylpiperidinium chloride</strong> are heated to 175-180 C. and reacted at this temperature with 230 parts of phosgene and 70 parts of hydrogen chloride. The reaction time is 3.75 hours. Dissolved phosgene and hydrogen chloride are then blown out with nitrogen, and the crude product is distilled under reduced pressure. 241 parts of 98.1% pure 5-chloropentanoyl chloride are obtained. The 52 parts of distillation residue contain the catalyst and unconverted 5-valerolactone, which are reused in subsequent batches. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With aluminum (III) chloride; triethylamine; In 1,2-dichloro-ethane; at 20℃; for 1h; | STEP D: Preparation of iV-(indan-2-yl)-5-hydroxypentanamideA solution of 2.7 mL (18.75 mmol) Of Et3N in 5mL of 1,2-dichloroethane was added drop by drop under ice cooling to a suspension of 1.85 g (13.75 mmol) AlCl3 in 1OmL of dichloroethane. At room temperature a solution of 2.33g (13,75 mmol) 2-aminoindane HCl(and Et3N for the solvation of the hydrochloride) and 1.16 mL (12.5 mmol) delta- valerolactone in 7.5mL 1,2-dichloroethane was added to the mixture. After one hour of stirring at room temperature the mixture was quenched with ice water and stirred for another30 minutes. The suspension was filtered by Celite. After adding of dichloromethane, separating of the organic layer, washing it with water, drying it with Na2SO4 and evaporating of the solvent, followed.Yield: 100%; ESI-MS: 234 (M+H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: triethyl 2-ethylphosphonoacetate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one With diisobutylaluminium hydride In tetrahydrofuran; hexane at -78℃; Inert atmosphere; Warming; Stage #3: With water; ammonium chloride In tetrahydrofuran; hexane optical yield given as %de; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With sodium hydroxide In water at 70℃; Stage #2: benzyl bromide With tetrabutylammomium bromide at 60℃; | |
72% | With tri-n-butylammonium bromide; sodium hydroxide Inert atmosphere; | |
50% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With tetra(n-butyl)ammonium hydroxide In methanol for 2h; Reflux; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 2h; | 1 Step 1. A mixture of 174A (3.0 g, 30 mmol) and 1.0 M tetrabutylammonium hydroxide (7.77 g, 30 mmol) in methanol (30 mL) was heated to reflux for 2 h. The solvent was removed in vacuo to afford an oil. The oil was dissolved in 25 mL of DMF, and then benzyl bromide (5.1 g, 30 mmol) was added slowly. After having been stirred at room temperature for 2 h, water (150 mL) was added into the mixture. The mixture was extracted with EtOAc (150 mL x 2). The combined organic layers were dried over Na2S04 and concentrated. The crude was purified by SGC (PE : EtOAc = 20 : 1→15 : 1→10 : 1→5 : 1) to afford 174B (3.2 g, yield: 50%) as colorless oil. LC-MS (m/z) : 209.7 [M+l]+. |
40% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With sodium hydroxide In water at 70℃; for 16h; Stage #2: benzyl bromide With tetrabutylammomium bromide In acetone for 20h; Reflux; | 49.1 Step 1: benzyl 5-hydroxypentanoate To a suspension of valerolactone (5.0 g, 50 mmol, 1 eq.) in water (45 mL), was added a 32% NaOH solution in water (4.6 mL, 50 mmol, 1.0 eq.) and the mixture was stirred at 70°C for 16 h. The reaction mixture was then concentrated in vacuo. The residue was pulverized and suspended in acetone (50 mL) at room temperature and (re-Bu)4NBr (805 mg, 2.50 mmol, 0.05 eq.) and BnBr (7.1 mL, 60 mmol, 1.2 eq.) were added. The mixture was stirred at reflux for 20 h. After cooling down to room temperature, water and EtOAc were added and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed (water, brine), dried over Na2S04, filtered and concentrated under reduced pressure to afford the crude product (12 g). The residue was purified by column chromatography to afford the title compound (4.12 g, 40%) as a colorless oil. (1320) MS (ESN): [M+H]+ = 209.2 (1321) NMR (CDCb, 500 MHz) d (ppm): 7.40-7.30 (m, 5H); 5.13 (s, 2H); 3.65 (hr s, 2H); 2.42 (t, J = 7.5 Hz, 2H); 1.75 (m, 2H); 1.61 (m, 2H); 1.48 (hr s, 1H, OH) |
24% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With sodium hydroxide In tetrahydrofuran; water at 70℃; for 16h; Stage #2: benzyl bromide With tetrabutylammomium bromide In acetone at 60℃; for 4h; | 1 Step 1: Benzyl 5-hydroxypentanoate A mixture of tetrahydro-2H-pyran-2-one (1 g, 10 mmol) and sodium hydroxide (400 mg, 10 mmol) in water (15 ml) was stirred at 70° C. for 16 hours. The mixture was concentrated under reduced pressure to give a crude residue which was dissolved in acetone (20 ml), followed by sequential addition of tetrabutylammonium bromide (161 mg, 0.5 mmol) and benzyl bromide (2 g, 12 mmol) at room temperature. The mixture was stirred at 60° C. for 4 hours. TLC showed the reaction was complete. The mixture was concentrated and the residue was partitioned between ethyl acetate (30 ml) and water (50 ml). The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 33-50% ethyl acetate in hexane) to afford benzyl 5-hydroxypentanoate (500 mg, 24%) as light yellow solid. |
24% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With sodium hydroxide In water at 70℃; for 16h; Stage #2: benzyl bromide With tetrabutylammomium bromide In acetone at 60℃; for 4h; | 1 Step 1 : Benzyl 5-hydroxypentanoate A mixture of tetrahydro-2H-pyran-2-one (1 g, 10 mmol) and sodium hydroxide (400 mg, 10 mmol) in water (15 ml) was stirred at 70°C for 16 hours. The mixture was concentrated under reduced pressure to give a crude residue which was dissolved in acetone (20 ml), followed by sequential addition of tetrabutylammonium bromide (161 mg, 0.5 mmol) and benzyl bromide (2 g, 12 mmol) at room temperature. The mixture was stirred at 60°C for 4 hours. TLC showed the reaction was complete. The mixture was concentrated and the residue was partitioned between ethyl acetate (30 ml) and water (50 ml). The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 33-50% ethyl acetate in hexane) to afford benzyl 5-hydroxypentanoate (500 mg, 24%) as light yellow solid. |
15% | With tetrabutylammomium bromide; sodium hydroxide In water; acetone at -190 - 65℃; for 72h; | 11 Synthesis of Benzyl 5-hydroxypentanoate[0307] A solution of δ-valerolactone (10 g, 100 mmol) in 1M aqueous sodium hydroxide (100 mL) was heated overnight with stirring at 65°C. The solution was concentrated in vacuo to dryness and any residual water removed under high vacuum at -190°C. The resulting white powder was broken up and suspended in acetone (40 mL). With stirring, benzyl bromide (17 g, 101.4 mmol) and tetrabutylammonium bromide (0.82 g, 2.539 mmol) were added. The mixture was heated at 45°C with stirring for 72 hours, cooled, and concentrated. The resulting white oily powder was dissolved in ethyl acetate (300 mL) and washed twice each with saturated NaHCOj and brine. The organic portion was dried over anhydrous MgS04, filtered, and then concentrated. The result was a yellow oil, which was purified by column chromatography (column 10"L x 2"W; eluted with a gradient of 100% hexanes→ 30%→ 50% ethyl acetate in hexanes) to afford the product as a pale yellow oil (3.11 g, 15%). |
15% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With sodium hydroxide In water at 65℃; Stage #2: benzyl bromide With tetrabutylammomium bromide In water; acetone at 45℃; for 72h; | 19 Synthesis of Benzyl 5-hydroxypentanoate Synthesis of Benzyl 5-hydroxypentanoate A solution of δ-valerolactone (10 g, 100 mmol) in 1M aqueous sodium hydroxide (100 mL) was heated overnight with stirring at 65° C. The solution was concentrated in vacuo to dryness and any residual water removed under high vacuum at -190° C. The resulting white powder was broken up and suspended in acetone (40 mL). With stirring, benzyl bromide (17 g, 101.4 mmol) and tetrabutylammonium bromide (0.82 g, 2.539 mmol) were added. The mixture was heated at 45° C. with stirring for 72 hours, cooled, and concentrated. The resulting white oily powder was dissolved in ethyl acetate (300 mL) and washed twice each with saturated NaHCO3 and brine. The organic portion was dried over anhydrous MgSO4, filtered, and then concentrated. The result was a yellow oil, which was purified by column chromatography (column 10"L*2"W; eluted with a gradient of 100% hexanes→30%→50% ethyl acetate in hexanes) to afford the product as a pale yellow oil (3.11 g, 15%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With indium (III) iodide In toluene at 90℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; water; at 135℃; for 2h; | Step 1: Synthesis of 4-[6-chloro-5-(trifluoromethyl)-lH-l,3-benzodiazol-2- yl]butan-l-ol [0593] 4-chloro-5-(trifluoromethyl)benzene-l,2-diamine (5.00 g, 23.74 mmol) was dissolved in HC1 solution (4 M solution) (18.85 ml) at r.t. and delta-valerolactone (2.62g,26.12 mmol) was added slowly. The reaction was heated to 135 C for 2 hrs then slowly cooled to r.t. The reaction was quenched by the addition of sat. NaHC03 solution (200 ml) to pH 8. The mixture was extracted with EtOAc (3 x 150 ml) and the combined organic layers were dried over Na2S04, filtered and concentrated in vacuo to give the crude product as a brown solid which was triturated with ether (100 ml) to give the pure product (5.88 g,84%): MS (ESI+) for Ci2Hi2ClF3N20 m/z 293.4 [M+H]+; LC purity 90% (ret. time, 1.49 min); 1H NMR (250 MHz, CHLOROFORM-d) delta ppm 1.39 - 1.72 (2 H, m), 1.71 - 1.94 (2H, m), 2.87 (2 H, t, 7=7.61 Hz), 3.58 (2 H, t, 7=6.09 Hz), 7.42 - 7.96 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | [0553] Step 2: Synthesis of 4-(5-tert-Butyl-lH-benzoimidazol-2-yl)-butan-l-ol[0554] A mixture of 4-tert-butyl -benzene- 1,2-diamine (lg, 6.09mmol) and valerolactone (0.67g, 6.70mmol, l.leq.) in 4N HC1 aq (5ml) was sealed and heated for 2h at 100°C. LCMS analysis shows remaining diamine. Completion was achieved using excess of valerolactone (~1.3ml, 2eq.) heating at 100° for 4h. The reaction was cooled to RT and basified to pH 12 with a saturated solution of Na2C03. EtOAc (100ml) was added and organic separated, washed with saturated solution of Na2C03, water, brine, dried over Na2S04, filtered and concentrated. The residue was purified by flash columnchromatography over silica gel, eluted with DCM - MeOH from 2percent to 5percent gradually to yield 1.19g (79percent) of a beige solid; MS (ESI+) for C15H22N2O m/z 1 [M+H]+, 247.15; HPLC purity 100percent (ret. time, 1.42 min).1H NMR (500 MHz, CHLOROFORM-d) delta ppm 1.38 (9 H, s), 1.65 - 1.75 (2 H, m), 2.00 (2 H, quin, J=7.17 Hz), 2.98 (2 H, t, J=7.09 Hz), 3.72 (2 H, t, J=5.99 Hz), 7.31 (1 H, dd, J=8.51, 1.58 Hz), 7.48 (1 H, d, J=8.20 Hz), 7.56 (1 H, d, J=1.26 Hz). | |
67% | Compound 319(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-[[4-(5-tert-butyl-lH-benzimidazol-2-yl)butyl- isopropyl-amino]methyl]tetrahydrofuran-3,4-diolHStep 1. Preparation of 4-(5-tert-butyl-lH-benzimidazol-2-yl)butan-l-ol A mixture of 4-tert-butylbenzene-l,2-diamine (646 mg, 3.93 mmol) andtetrahydropyran-2-one (1.18 g, 11.80 mmol) in 50 mL of 4 M HC1 was refluxed for 8 h. Then the mixture was neutralized with K2C03 (aq) to pH = 8. The mixture was extracted with DCM (30 mL x4). The organic layers were concentrated and the residue was purified by SGC (DCM : MeOH = 20 : 1) to afford the product(650 mg, yield: 67 percent) as a pale solid. MS (ESI): m/z 247.7 [M+l]+. | |
49% | Compound 323(2R^R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5 ((4-(5-(tert-butyl) H-benzo[d]imidazol-2- yl)butyl)thio)methyI)tetrahydrofuran-3,4-diolStep 1. Preparation of 4-(5-tert-butyl-lH-benzimidazol-2-yl)butan-l-olA solution of 4-tert-butylbenzene-l,2-diamine (6 g, 36.59 mmol) andtetrahydropyran-2-one (6.09 g, 60.98 mmol) in 4 M HC1 (100 mL) was heated to 100° C overnight. The reaction was evaporated, added water (50 mL), adjusted to pH = 8 with aq. NaHC03, extracted with EA (3x100 mL), washed with water (20 mL) and brine (20 mL), dried and concentrated. The residue was purified by SGC to obtain the product (4.4 g, Yield 49percent). 1H NMR (500 MHz, MeOD): 57.50-7.28 (m, 3H), 3.60 (t, J = 6.5 Hz, 2H), 2.91 (t, J = 7.5 Hz, 2H), 1.90 (t, J = 7.0 Hz, 2H), 1.60 (t, J = 7.0 Hz, 2H), 1.37 (s, 9H) ppm; ESI-MS (m/z): 247.2[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With hydrogen; In methanol; at 375℃; for 5h; | Example 3 Preparation of delta-Valerolactone [0207] 10 ml of catalyst 1 reduced beforehand at 450 C. and 5 ml of glass powder used as static mixer vaporizer are placed in a vertical glass reactor 22 mm in diameter. [0208] The catalytic bed is heated under a stream of 10 l/h of hydrogen to 375 C. [0209] After stabilizing the catalytic bed under these conditions for 30 minutes, injection onto the catalytic bed, by means of a syringe pump, of a methanolic glutaric acid solution at 50% w/w at a flow rate of 10 ml/h is commenced. [0210] The reaction gas stream is then condensed in a receiver immersed in an ice-water bath. [0211] After injection for 5 hours under these conditions, the condensates are analyzed by GC. [0212] For a degree of conversion of 100%, a 65% yield of delta-valerolactone is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55%Chromat. | With Oxone; 2-iodo-3,4,5,6-tetramethylbenzoic acid; In water; acetonitrile; at 60℃; for 24.0h;Green chemistry; | General procedure: In a typical experiment, a round bottom flask containing 4-6mL of acetonitrile/water mixture (1:1) was charged with 0.5-1.0mmol of the diol, 5mol% of TetMe-IA, and oxone (2equiv). The resulting mixture was stirred at rt for benzylic diols and at 45C for aliphatic diols. At the end of the reaction, as judged from TLC analysis, little water was added to dissolve the inorganic salts, and the organic matter was extracted with EtOAc at least two times. The combined extract was dried over anhydrous Na2SO4, concentrated in vacuo to obtain the crude product, which was subjected to silica-gel column chromatography using ethyl acetate/pet ether to isolate the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | (Step 1) To a solution of <strong>[132-32-1]9-ethyl-9H-carbazol-3-amine</strong> (300 mg, 1.43 mmol) in toluene (4 mL) was added trimethylaluminium (1.8M in toluene solution, 1.189 mL, 2.14 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of 5-valerolactone (0.129 mL, 1.43 mmol) in toluene (4 mL) at room temperature, and the mixture was stirred at 80C for 4 hr. The reaction mixture was cooled to 0C, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxypentanamide (420 mg, 1.352 mmol, 95%) as a pale-yellow powder. MS (API) : 311 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - -40℃; | |
83% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; Inert atmosphere; | |
71% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: iodomethane With N,N’-dimethylpropyleneurea In tetrahydrofuran; hexane at 20℃; Inert atmosphere; | 3.2.1. Synthesis of 2,2-Dimethyl-δ-valerolactone (2h) To a magnetically stirred solution of diisopropylamine (23.27 g, 230 mmol) in dried THF (250 mL) cooled at -78 °C under N2 was added dropwise 1.6 M n-BuLi in n-hexane (131 mL, 210 mmol) via syringe. After addition, the resulting mixture was stirred at this temperature for 10 min, followed by dropwise addition of δ-valerolactone 2b (10.01 g, 100 mmol). The stirring was continued at this temperature for another 0.5 h, followed by successive additions of MeI (28.39 g, 200 mmol) and DMPU (14.10 g, 110 mmol) in a dropwise manner via syringe. After addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator to about 100 mL and then poured into ice-water (500 mL). The resulting aqueous mixture was extracted with CH2Cl2 (100 mL x 3), and the combined extracts were washed successively with 1Mhydrochloric acid (100 mL x 3) and 5% brine (100 mL), dried over anhydrous Na2SO4, and evaporated on a rotary evaporator to afford a residue, which was purified by column chromatography to yield a colorless oil. The colorless oil was subjected to the identical procedure described above once again to yield 2h after column chromatography. Colorless oil, 9.10 g (71%). 1H-NMR (DMSO-d6, 400 MHz) δ: 4.27 (t, J = 5.8 Hz, 2H), 1.78-1.84 (m, 2H), 1.68-1.71 (m, 2H), 1.17 (s, 6H). The 1H-NMR data were in good agreement with those reported [35]. |
56% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; | 23.1 Step 1: 3,3-Dimethyltetrahydropyran-2-one LiHMDS (1M in THF) (112 mL of 1 M, 112.00 mmol) was added to a solution of tetrahydropyran-2-one (5 g, 49.942 mmol) and MeI (29.640 g, 13 mL, 208.82 mmol) in THF (150 mL) at -78 °C. The reaction was then allowed to slowly warm to room temperature. After stirring overnight, the reaction mixture was quenched with saturated aq. NH4Cl (100 mL). After 15 min, the layers were separated, and the aqueous layer was extracted with EtOAc (3 × 100 mL). The organic layer and extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column using 0 then 20% ethyl acetate in heptane to provide 3,3-dimethyltetrahydropyran-2-one (3.77 g, 56%) as a clear pale-yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 4.40 - 4.28 (m, 2H), 1.97 - 1.86 (m, 2H), 1.78 - 1.72 (m, 2H), 1.35 - 1.27 (m, 6H). ESI-MS m/z calc. 128.08372, found 129.4 (M+1)+; Retention time: 1.35 minutes; LC method X. |
860 mg | With lithium hexamethyldisilazane In tetrahydrofuran; hexane at -60 - 20℃; | 3.1 Preparation of 3,3-dimethyltetrahydropyran-2-one (Step 1) To a solution of δ-valerolactone (0.9279 mL, 10 mmol) and iodomethane (2.49 mL, 40 mmol) in THF (20 mL) at -78°C, was slowly added a solution of LiHMDS (1.0 mol/L) in HEXANE (22 mL, 22 mmol). The addition was complete in 30 minutes keeping the temperature around -60°C all the time. The reaction was left to slowly warm up and was stirred at rt overnight. Acetic acid (~2 ml) was added to the reaction (causing the precipitation of white solid) and the whole mixture was concentrated. The residue was purified by column chromatography (gradient of EtOAc in hexane) (860 mg). H NMR (CDCI3) 4.35 (t, 2H); 1 .91 (quint, 2H); 1.76 (t, 2H); 1.30 (s, 6H). |
860 mg | With lithium hexamethyldisilazane In tetrahydrofuran; hexane at -78 - 20℃; | 2.1 Preparation of 3,3-dimethyltetrahydropyran-2-one To a solution of δ-valerolactone (0.9279 rnL, 10 rnrnol) and iodornethane (2.49 rnL, 40 rnrnol) in THE (20 rnL) at -78°C, was slowly added a solution of LiHMDS (1.0 rnol/L) in HEXANE (22 rnL, 22 rnrnol). The addition was cornplete in 30 rninutes keeping the ternperature around -60°C all the tirne. The reaction was left to slowly warrn up and was stirred at rt overnight. Acetic acid (-2rnl) was added to the reaction (causing the precipitation of white solid) and the whole rnixture was concentrated. The residue was purified by colurnn chrornatography (gradient of EtOAc in hexane)(860 rng). 1H NMR (CDCI3) 4.35 (t, 2H); 1.91 (quint, 2H); 1.76 (t, 2H); 1.30 (s, 6H). |
With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 16h; | 40 Example 40: N-(4-((2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide [0329] Synthesis of compound 40.2. To a solution of 40.1 (10 g, 99.88 mmol, 1.0 equiv) and methyl iodide (24.8 mL, 399.52 mmol, 4.0 equiv) in THF (200 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 219 mL, 219.7 mmol, 2.2 equiv) at -78 °C. The reaction mixture was stirred at room temperature for 16 h. It was poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash, 10% ethyl acetate in hexane as eluant) to afford 40.2. MS (ES): m/z 129.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one; 1-phenylimidazole With n-butyllithium In tetrahydrofuran at -78 - 25℃; for 1h; Stage #2: With Cumene hydroperoxide; C88H48F24N(1+)*I(1-) In tert-butyl methyl ether at 25℃; for 2h; enantioselective reaction; | Representative Procedure for Enantioselective Oxidative Cycloetherification of 2a: General procedure: To a stirring mixture of 2a (24.4 mg, 0.100 mmol), (R,R)-4 (17.0 mg, 0.0100 mmol, 10mol%) in methyl tert-butyl ether (0.500 mL) was added cumene hydroperoxide (contains ca.20% aromatic hydrocarbon, TCI, 0.0370 mL, 0.200 mmol, 2 equiv) at 25 °C. The reactionwas monitored by TLC analysis. After stirring for 2 h, the resulting mixture was poured intosaturated aqueous NaHSO3 (1.00 mL), and the aqueous layers were extracted with Et2O(twice). The combined organic layers were washed with brine and dried over anhydrousMgSO4. The solvents were removed in vacuo. The residue was purified by flash columnchromatography on silica gel (E. Merck Art. 9385, eluent: hexane-EtOAc = 4:1) to give(R)-3a (19.8 mg, 0.0810 mmol) in 81% yield. Enantiomeric excess of 3a was determined tobe 91% ee by HPLC analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,4,5,6-tetrahydro-2H-pyran-2-one; 1-phenylimidazole With n-butyllithium In tetrahydrofuran at -78 - 25℃; for 1h; Stage #2: With Cumene hydroperoxide; tetra-(n-butyl)ammonium iodide In ethyl acetate for 24h; | Synthesis of Authentic Samples: General procedure: To a stirring mixture of 2 (0.100 mmol) and Bu4NI (7.40 mg, 0.0200 mmol, 20 mol%) inEtOAc (1.00 mL) was added cumene hydroperoxide (contains ca. 20% aromatic hydrocarbon,TCI, 0.0370 mL, 0.200 mmol, 2 equiv) at 25 °C. The reaction was monitored by TLCanalysis. After stirring for 24 h, the resulting mixture was poured into saturated aqueousNaHSO3 (1.00 mL), and the aqueous layers were extracted with Et2O (twice). The combinedorganic layers were washed with brine and dried over anhydrous MgSO4. The solvents wereremoved in vacuo. The residue was purified by flash column chromatography on silica gel(E. Merck Art. 9385, eluent: hexane-EtOAc = 4:1) to give 3 in 30-60% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 23℃; for 6h; Inert atmosphere; | 1 Ethyl 2-oxotetrahydro-2H-pyran-3-carboxylate (1a) General procedure: Ethyl 2-oxotetrahydro-2H-pyran-3-carboxylate (1a) To a solution of LHMDS (3.43 g, 20.5 mmol, 2.05 equiv) in THF (20 mL) was added a mixture of delta-valerolactone (1.00 g, 10.0 mmol, 1.00 equiv) and diethyl carbonate (1.3 mL, 11.0 mmol, 1.10 equiv) at -78° C. After stirring at room temperature for 6 hours, the reaction was quenched with glacial acetic acid (5 mL), diluted with Et2O (20 mL), and stirred for 5 minutes. The insoluble white solid was filtered off and rinsed with more Et2O. The filtrate was concentrated and purified by column chromatography (50% to 65% Et2O in PET) to afford 1a as a colorless oil (1.20 g, 70% yield); 1H NMR (300 MHz, CDCl3) δ 4.46-4.31 (m, 2H), 4.25 (qd, J=7.1, 1.7 Hz, 2H), 3.56 (dd, J=8.3, 7.5 Hz, 1H), 2.38-2.08 (m, 2H), 2.08-1.80 (m, 2H), 1.30 (t, J=7.1 Hz, 3H). All characterization data match those reported. |
83% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 4h; | 2.1 synthesis and characterization of 8 A mixture of δ-valerolactone (10, 0.0100 mol, 1.00 g) and dimethyl carbonate (0.011 mol, 0.95 g, 0.88 mL) was added dropwise to a solution of LHMDS in THF (0.0205 mol, 20.5 mL of 1.0 M solution in THF) at -78 °C. The resulting mixture was warmed to rt and stirred at rt. After 4 h the reaction mixture was quenched by the dropwise addition of AcOH (glacial, 1.4mL) and diluted with Et2O (60 mL). The resulting suspension was vigorously stirred at rt for 5 min. The insoluble solid was filtered off, washed (Et2O, 2 × 20 mL) and the filtrate was concentrated in vacuo. The residue was purified by purified by column chromatography (PE:Et2O 2:1 → 1:1) affording 8 (1.32 g, 83%) as a pale-yellow liquid. IR (film) 2957 (C-H), 1721 (C=O), 1151 (C-O); 1H-NMR (400 MHz, CDCl3) δ 1.80 - 1.99(m, 2H), 2.09 - 2.26 (m, 2H), 3.53 (t, 1H, J = 8.0 Hz), 3.73 (s, 3H), 4.20 - 4.35 (m, 2H); 13CNMR(100 MHz, CDCl3) δ 20.7, 22.6, 47.0, 52.7, 69.3, 167.3, 169.4; HRMS (ES+) exactmass calculated for [M+Na]+ (C7H10NaO4) requires m/z 181.0471, found m/z 181.0474 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | 18-Bromo-octadeca-(6z,9z)-diene (0.50 g, 1.52 mmol) was dissolved in diethyl ether (1.5 mL), magnesium shavings (609 mg, 25.1 mmol) were added to the solution, and then one broken piece of iodine was added to the solution. The mixture was left standing for 10 minutes at room temperature, and then stirred with heating at 45 C. on an oil bath, and 18-bromo-octadeca-(6z,9z)-diene (5.0 g, 15.2 mmol) dissolved in diethyl ether (6 mL) was added dropwise to the mixture. The reaction was allowed at 45 C. for 1 hour, and then the reaction mixture was cooled to room temperature. Then, 6-valerolactone (300 muL, 3.23 mmol) was added to the reaction mixture, and the reaction was allowed at room temperature for 1 hour. Then, the reaction mixture was cooled to 4 C., and filtered, and the filtrate was washed with saturated aqueous sodium hydrogencarbonate. Then, anhydrous sodium sulfate was added to the organic layer for dehydration. The organic layer was filtered, and the solvent was evaporated by using a rotating evaporator to obtain a crude product. The crude product was purified by silica gel chromatography {elution solvent, hexane:ethyl acetate (continuous gradient)} to obtain 4-[(9z, 12z)-octadecadienyl]-(13z, 16z)-tricosadien-1,4-diol (1.64 g, 2.73 mmol) as colorless oil. Yield from 6-valerolactone was 85%. Proton nuclear magnetic resonance (1H NMR, 500 MHz) data of 4-[(9z,12z)-octadecadienyl]-(13z,16z)-tricosadien-1,4-diol delta=0.88 (t, 6H), 1.25-1.1.46 (m, 46H), 2.02-2.06 (m, 8H), 2.77 (t, 4H), 3.66 (t, 2H), 5.30-5.40 (m, 8H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 1-bromo-4-methoxy-benzene With iodine; magnesium In tetrahydrofuran at 50℃; for 2h; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In tetrahydrofuran at 20℃; for 3h; Reflux; | 1,1-bis(4-fluorophenyl)pentane-1,5-diol (3a) General procedure: A solution of 1-bromo-4-fluorobenzene (3.00 g, 17.14 mmol) in tetrahydrofuran (5 mL) was added to a suspension of magnesium (1.52 g, 62.5 mmol) and catalytic amount of iodine in tetrahydrofuran (25 mL) and reaction mixture was heated (50 C). After all iodine was consumed, the reaction mixture was stirred for 0.5 h and the remaining 1-bromo-4-methylbenzene (7.93 g, 45.35 mmol) in tetrahydrofuran (10 mL) was added slowly. The heating was maintained for additional 1.5 hours following the full consumption of magnesium and reaction media was cooled to a room temperature. delta-valerolactone (2.40 g, 24.8 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to the reaction solution, and the reaction mixture was refluxed for 3h. Upon completion, it was quenched with saturated aqueous solution of NH4Cl, and the tetrahydrofuran was evaporated in vacuo. The crude mixture was extracted with diethyl ether (3×25 mL), the organic layer was washed with NaCl (sat. aq.) and dried over anhydrous Na2SO4. The residue obtained upon evaporation of organic solvent in vacuo was purified by flash chromatography with ethyl acetate /hexane (1:9 to 1:1) to obtain compound 3a (3.96 g, 55%) as a white solid. |
Stage #1: 1-bromo-4-methoxy-benzene With iodine; magnesium In tetrahydrofuran at 50℃; for 3h; Inert atmosphere; Stage #2: 3,4,5,6-tetrahydro-2H-pyran-2-one In tetrahydrofuran for 3h; Reflux; Inert atmosphere; | General procedure D. General procedure: A solution of substituted bromobenzene (0.25 equiv., 15.62 mmol) in tetrahydrofuran (5 mL) was added to a suspension containing magnesium (1.00 equiv., 62.50 mmol) and a catalytic amount of iodine in tetrahydrofuran (25 mL). The reaction mixture was heated to 50 C. After iodine was fully consumed, the reaction mixture was stirred for 0.5 h, and the remaining substituted bromobenzene (0.75 equiv., 46.88 mmol) in tetrahydrofuran (10 mL) was added slowly. The heating was maintained for an additional 1.5 hours until magnesium was entirely consumed, then, the reaction mixture was cooled to room temperature. Next, selected lactone (0.40 equiv., 25.00 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction solution, and the reaction mixture was refluxed for 3h. Upon completion, the reaction was quenched with NH4Cl (sat. aq.), and tetrahydrofuran was evaporated in vacuo. The crude mixture was extracted with diethyl ether (3 × 25 mL), the combined organic layer was washed with NaCl (sat. aq.), dried over anhydrous Na2SO4, and the solvent was removed under vacuum. The obtained residue obtained was purified by flash chromatography with ethyl acetate/hexane (1:9 to 1:1) to afford the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Dissolve 1.2 g (4.06 mmol) of ((6-bromohexyl) oxy) (tert-butyl) dimethylsilane in 4 mL of diethyl ether,Add 2.43 g (100 mmol) of shavings magnesium,Subsequently, iodine 1 fragment was added. After standing at room temperature for 10 minutes,Stir while heating to 40 C in an oil bath,24.8 g (83.94 mmol) of ((6-bromohexyl) oxy) (tert-butyl) dimethylsilane dissolved in 21 mL of diethyl ether was added dropwise. The mixture was reacted at 40 C. for 2 hours and then cooled to 4 C.Subsequently, 3.67 mL (39.6 mmol) of δ-valerolactone was added,The reaction was allowed to proceed overnight at room temperature. Next, cool to 4 ,5% sulfuric acid was added dropwise to dissolve the remaining magnesium.After diluting this reaction solution with diethyl ether,Separated and washed with water and saturated brine. continue,The organic layer after washing was dehydrated by adding anhydrous sodium sulfate.After filtering this, the solvent was distilled off using a rotary evaporator to obtain a crude product. The crude product was purified by subjecting it to silica gel chromatography {elution solvent; hexane: ethyl acetate (continuous gradient)}.11-((tert-butyldimethylsilyl) oxy) -5- (6-((tert-butyldimethylsilyl) oxy) hexyl) undecane-1,5-diol14.0 g (26.3 mmol) was obtained as a colorless oil.The yield based on δ-valerolactone was 66%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 65% 2: 25% | With diisobutylaluminium hydride In dichloromethane; toluene at -70℃; for 3h; Inert atmosphere; Overall yield = 0.71 g; | Reduction of lactones and esters (general procedure) General procedure: A solution of 7.7 mmol {0.77 g of tetrahydropyran-2-one (19) [12] or 0.99 g of oxocan-2-one (20) [13] or 2.15 g of (9Z,12R)-12-hexyloctadec-9-en-12-olide (21) [14] or 1.12 g of methyl 6-hydroxyhexanoate (35) [15] or 2.29 g of methyl octadecanoate (28) [16] or 2.40 g of methyl (9Z,12R)-12-hydroxyoctadec-9-enoate (33) [17] in 12 mL of anhydrous CH2Cl2 was added dropwise to a solution of 4.0 mL (16.0 mmol) of a 73% solution of DIBAH in toluene and 15 mL of anhydrous CH2Cl2 (Ar, -70°C). After standing for 3 h at -70°C and addition of 20 mL of a 1 : 1 mixture of THF and water, the reaction mixture was allowed to warm up to room temperature, diluted with 50 mL of CH2Cl2, filtered through a bed of Al2O3 (5 cm), dried over Na2SO4, and evaporated. The reduction of tetrahydropyran-2-one (19) gave 0.71 g of a mixture of alcohol 22 and hydroxyaldehyde 24 in a 2.6 : 1.0 ratio (by 1H NMR). Tetrahydropyran-2-ol (22). Rf 0.28 (PE-TBME, 2 : 1). 1H NMR spectrum, δ, ppm: 1.30-1.90 m (6H, H4, H5, H3), 3.93 br.s (1H, OH), 3.30-3.95 m (2H, H6), 4.80 m (1H, H2). 13C NMR spectrum, δ, ppm: 19.51 (C4), 25.36 (C5), 30.97 (C3), 62.30 (C6), 98.84 (C2). Cf. [12]. 5-Hydroxyhexanal (24). Rf 0.43 (PE-TBME, 2 : 1). 1H NMR spectrum, δ, ppm: 1.35-1.85 m (4H, H4, H3), 2.40 m (2H, H2), 3.00 br.s (1H, OH), 3.40-3.75 m (2H, H5), 9.81 t (1H, H1, J 2.0 Hz). 13C NMR spectrum, δ, ppm: 29.26 (C3), 32.02 (C4), 43.64 (C2), 63.78 (C5), 202.50 (C1). Cf. [12]. |
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Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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