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CAS No. : | 1504-58-1 | MDL No. : | MFCD00040914 |
Formula : | C9H8O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NITUNGCLDSFVDL-UHFFFAOYSA-N |
M.W : | 132.16 | Pubchem ID : | 123115 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 40.35 |
TPSA : | 20.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.09 cm/s |
Log Po/w (iLOGP) : | 1.99 |
Log Po/w (XLOGP3) : | 1.43 |
Log Po/w (WLOGP) : | 1.11 |
Log Po/w (MLOGP) : | 2.1 |
Log Po/w (SILICOS-IT) : | 2.02 |
Consensus Log Po/w : | 1.73 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.0 |
Solubility : | 1.31 mg/ml ; 0.0099 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.46 |
Solubility : | 4.58 mg/ml ; 0.0347 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.27 |
Solubility : | 0.703 mg/ml ; 0.00532 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.17 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethanolamine; Eosin In water monomer; acetonitrile at 20℃; for 0.333333h; Irradiation; Inert atmosphere; | |
98% | With hydrogen In methanol for 2h; | |
98% | With hydrogen In toluene at 20℃; |
97% | With hydrogen In toluene at 20℃; for 18h; | |
97% | With Lindlar's catalyst; hydrogen In ethyl acetate at 20℃; for 15h; | |
96% | With hydrogen In ethyl acetate at 20℃; for 15h; | |
96% | With dimethylamine borane In ethanol at 25℃; for 0.5h; stereoselective reaction; | |
95% | With 2,2'-ethane-1,2-diylbissulfanyl-bis-ethanol; hydrogen In toluene for 24h; Ambient temperature; | |
95% | With dmap; formic acid; Au9924Ag0.76 In N,N-dimethyl-formamide at 70℃; for 2h; Inert atmosphere; Green chemistry; stereoselective reaction; | |
95% | With pyridine; hydrogen In ethanol at 20℃; for 1.5h; | |
93% | With sodium tetrahydridoborate; hydrogen; nickel(II) acetate tetrahydrate; Ethane-1,2-diamine In methanol at 20℃; for 3.5h; | |
93% | With ammsnium formate In N,N-dimethyl-formamide at 80℃; Green chemistry; diastereoselective reaction; | |
93% | With manganese powder; water monomer; palladium diacetate In acetonitrile at 25℃; for 24h; Schlenk technique; Inert atmosphere; diastereoselective reaction; | |
92% | Stage #1: 3-Phenyl-2-propyn-1-ol With potassium-t-butoxide; Cu(OAc)2*H2O; 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride; <i>tert</i>-butyl alcohol In toluene at 25℃; for 16h; Inert atmosphere; Stage #2: With N,N,N-tributylbutan-1-aminium fluoride In tetrahydrofuran; toluene at 0℃; diastereoselective reaction; | General procedure for the copper-catalyzed semihydrogenation of alkynes: for liquid substrates (1a, b, c, e, k, o, p, q, t, u, v, x, y, aa, ab, ac) General procedure: In air, Cu(OAc)2·H2O (5.0mg, 5mol%) and IPr·HCl (10.6mg, 5mol%) were placed in a screw-capped reaction vial. The vial was moved in to a glove box and t-BuOK (5.6mg, 10mol%) and solvent (1.0ml) were added. The vial was moved out of the glove box and connected to an argon line through a needle. The mixture was raised to 50°C and stirred for 1h. PMHS (131mg, 4.0equiv) wasthen added dropwise with a microsyringe and the solution was stirred for an additional 30min. After the mixture was changed to the specified reaction temperature, liquid alkyne (0.5mmol) and t-BuOH (74mg, 2.0equiv) was added dropwise. The mixture was stirred for a specified period of time. The reaction mixture was subsequently hydrolyzed by adding 1M NaOH aqueous (2ml) (for substrates with no hydroxyl group) or 1M TBAF in THF (2ml) at 0°C (for substrates with a hydroxyl group) for several hours. The mixture was extracted with ether (2ml×3). Crude products wereobtained after evaporation and purified by silica gel chromatography. |
90% | With sodium hydroxide; sodium tetrahydridoborate; Ethane-1,2-diamine In sodium hydroxide; ethanol at 20℃; for 4h; | |
90% | With quinoline; hydrogen In methanol at 20℃; for 4h; | |
88% | With formic acid; gold nanoparticles on rutile titania; triethylamine In acetone for 1h; Reflux; stereoselective reaction; | |
88% | With borane-ammonia complex; copper(II) sulphate In ethanol at 40℃; for 3h; stereoselective reaction; | |
87% | With hydrogen In methanol | |
87% | With sodium tetrahydridoborate; anhydrous nickel acetate; Ethane-1,2-diamine In ethanol for 4.5h; | |
87.7% | With hydrogen In toluene for 0.666667h; | |
86% | With hydrogen In ethyl acetate at 20℃; for 12h; | |
85% | With Lindlar catalyst; hydrogen In methanol at 20℃; for 72h; | |
84% | With hydrogen In acetonitrile at 110℃; for 15h; chemoselective reaction; | |
82% | With Au0998Ag0002; hydrogen; diethylamine at 90℃; for 24h; chemoselective reaction; | |
80% | With hydrogen In methanol at 20℃; for 2.5h; | |
79% | With hydrogen In N,N-dimethyl-formamide at 40℃; for 3h; | |
78% | With palladium diacetate; 4,4,5,5-tetramethyl-1,3,2-dioxaborolane In dichloromethane at 25℃; for 12h; Schlenk technique; Inert atmosphere; | 58 Replace the gas environment in the Shrek tube with a nitrogen environment, add 3-phenyl-2-propyn-1-ol 0.25 mmol, palladium acetate 0.0025 mmol, methylene chloride 0.5 mL, and add pinacol borane 0.25 with stirring mmol, at room temperature for 12 h. After the completion of the reaction, the reaction solution was subjected to column chromatography. The target product obtained in 78% yield was a colorless liquid. |
78% | With palladium diacetate; 4,4,5,5-tetramethyl-1,3,2-dioxaborolane In dichloromethane at 25℃; for 12h; Sealed tube; Inert atmosphere; chemoselective reaction; | |
76% | With methanol; sodium tetrahydridoborate; hydrogen; nickel(II) acetate tetrahydrate; Ethane-1,2-diamine at 20℃; for 4.5h; Inert atmosphere; | |
70% | With hydrogen | |
69% | With manganese powder; water monomer In tetrahydrofuran at 20℃; for 24h; | |
69% | With quinoline; hydrogen In ethyl acetate at 22℃; for 1h; Schlenk technique; | |
69% | With water monomer; copper (II) acetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; lithium tert-butylate; 5,5,5',5'-tetramethyl-[2,2']bi[[1,3,2]dioxaborinanyl] In N,N-dimethyl-formamide at 100℃; for 36h; Schlenk technique; Inert atmosphere; Glovebox; | |
68% | With potassium hydroxide; hydrogen In methanol | |
68% | With sodium tetrahydridoborate; hydrogen; nickel(II) acetate tetrahydrate; Ethane-1,2-diamine In methanol at 0 - 22℃; for 6h; | |
60% | With palladium on carbon; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In ethanol for 12h; Inert atmosphere; Reflux; | |
30% | With hydrogen In glycerol at 100℃; for 24h; | |
With palladium(0) Hydrogenation; | ||
With acetic acid ester; colloid; palladium(0) Hydrogenation; | ||
With hydrogen In pyridine | ||
With quinoline; hydrogen In benzene for 0.5h; | ||
With hydrogen In toluene at 20℃; for 2h; | ||
With hydrogen | ||
Multi-step reaction with 2 steps 1: 82 percent / copper(I) cyanide / tetrahydrofuran / 2 h / 0 °C 2: 75 percent / tetra-n-butylammonium fluoride (TBAF) / tetrahydrofuran; dimethylsulfoxide / 0.5 h / 80 °C | ||
Multi-step reaction with 2 steps 1: 82 percent / copper(I) cyanide / tetrahydrofuran / 2 h / 0 °C 2: NaH / hexamethylphosphoric acid triamide / 0.75 h / Ambient temperature | ||
With sodium tetrahydridoborate; hydrogen; nickel(II) acetate tetrahydrate; Ethane-1,2-diamine In ethanol at 20℃; for 10h; Inert atmosphere; | ||
92 %Chromat. | With formic acid; (η3-allyl)(N,N'-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)chloropalladium(II); triethylamine; triphenylphosphine In acetonitrile at 70℃; for 2h; Inert atmosphere; | |
With 2,2'-ethane-1,2-diylbissulfanyl-bis-ethanol; hydrogen In ethyl acetate at 20℃; for 17h; | ||
With hydrogen In ethanol at 20℃; for 10h; | ||
With quinoline; 10% palladium on barium sulfate; hydrogen In methanol | ||
63 %Chromat. | With methanol; borane-ammonia complex; C20H45Cl2CoNP2 at 50℃; for 20h; chemoselective reaction; | |
With hydrogen In methanol for 48h; Inert atmosphere; | ||
96.296 % de | With sodium tetrahydridoborate; hydrogen; Co(OAc)2.4H2O; Ethane-1,2-diamine In tetrahydrofuran; ethanol; water monomer at 20℃; for 24h; Autoclave; Glovebox; diastereoselective reaction; | |
With hydrogen In toluene at 23℃; | ||
95 %Chromat. | With hydrogen In ethanol at 50℃; for 5.5h; Schlenk technique; Sealed tube; | |
52 %Chromat. | With borane-ammonia complex; cobalt(II)(2,6-bis(morpholinomethyl)pyridine)bromide In methanol at 80℃; for 14h; stereoselective reaction; | |
27 %Chromat. | With methanol; toluene-4-sulfonic acid at 25℃; for 2h; Inert atmosphere; Sealed tube; Irradiation; | |
548 mg | With quinoline; hydrogen In ethanol at 20℃; for 1h; | 7 Example 7 (2Z)-3-Phenyl-2-propen-1-ol To a solution of 3-phenyl-2-propyn-1-ol (800 mg) () and quinoline (780 mg) in ethanol (20 mL), Lindlar's catalyst (160 mg) was added and the mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name) and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→60:40) to give the title compound (548 mg) having the following physical properties. 1H-NMR(CDCl3):δ 7.39-7.19, 6.58, 5.89, 4.45, 1.47. |
89 %Chromat. | With formic acid; C25H23ClN2Pd; triethylamine; triphenylphosphine In water monomer; acetonitrile at 70℃; for 1h; Inert atmosphere; diastereoselective reaction; | |
With hydrogen; NiFe3; N-butylamine In ethanol; water monomer at 40℃; for 11h; diastereoselective reaction; | ||
With Pd-BaSO4; hydrogen | ||
With quinoline; hydrogen In ethyl acetate at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; phosphorus tribromide | |
98% | With bromine; triphenylphosphine In dichloromethane at 0℃; | |
98% | With bromine; triphenylphosphine In dichloromethane at 0℃; for 1h; |
96% | With bromine; triphenylphosphine In dichloromethane at 0 - 20℃; for 1.5h; Inert atmosphere; | |
95% | With bromine; triphenylphosphine In dichloromethane at 0℃; for 1h; | |
93.5% | With phosphorus tribromide; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1h; | |
92% | With bromine; triphenylphosphine In dichloromethane at 0℃; for 1h; | |
92% | With bromine; triphenylphosphine In dichloromethane at 0℃; for 1h; | |
92% | With pyridine; phosphorus tribromide In diethyl ether at -40 - 20℃; for 3.5h; | |
92% | With bromine; triphenylphosphine In dichloromethane at 0℃; for 1.5h; | |
92% | With phosphorus tribromide In diethyl ether at 0℃; for 2h; Inert atmosphere; | Preparation of 1g: In a 200 mL three necked flask equipped with a dropping funnel, a Et2O solution of PBr3 (3.42 g,12.6 mmol) was slowly added to a mixture of 3-phenyl-2-propyn-1-ol (5.0 g, 30.8 mmol) and Et2O,and the reaction was conducted for 2 h at 0 °C. Then, the reaction mixture was added to coldNaHCO3 aq., and the resultant solution was extracted with Et2O. The organic layer was washed withBrine, dried with Na2SO4, filtered, and concentrated in vacuo. The obtained crude mixture waspurified by distillation, which gave 1-bromo-3-phenylprop-2-yne as colorless oil in 92% yield (5.54g, 28.4 mmol). |
90% | With carbon tetrabromide; triphenylphosphine In tetrahydrofuran at 0℃; for 2h; | 14.1 Example14: Compound 36 (25,4S)-l-(2,2-diphenylacetyl)-4-((3-phenylprop-2-yn-l- yl)-oxy)pyrroIidine-2-carboxyic acid 1. Procedure for the preparation of Compound 36b 36a 36b To a stirred solution of 36a (200 mg, 1.5 mmol) and PPh3 (430 mg, 1.65 mmol) in THF (4 mL) was added CBr4 (600 mg, 1.8 mmol) at 0°C and the mixture was stirred at 0°C for 2 h, TLC (PE:EA=1 :1) showed the starting material was consumed. The reaction was repeated (4.8 g, 36 mmol) and the reaction mixtures were combined, then most of the THF was removed in vacuo and the residue was partitioned between EA (50 mL) and water (30 mL). The organic layer was separated, washed with brine (30 mL x 2), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by chromatography (PE) to give 36b (6.5 g, 90 %) as a colorless oil. |
90% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 2h; | |
90% | With pyridine; phosphorus tribromide In diethyl ether at -40 - 20℃; for 25h; | |
89% | With bromine; triphenylphosphine In dichloromethane at 0℃; | |
85% | With phosphorus tribromide at 0℃; for 0.5h; | |
83% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
83% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 16h; | D General procedure for the synthesis of derivatives of (3-bromoprop-1-ynyl) benzene To a solution of the corresponding propargylalcohol (3.83 mmol) in anhydrous DCM (15 ml) under Ar, CBr4 (5.75 mmol) was added and the reaction mixture was cooled at 0°C. PPh3 (5.94 mmol) was added slowly. The reaction mixture was allowed to reach room temperature and stirred for 16 hours. Ethanol (2 ml) was added and the reaction mixture stirred for 20 min. The solvent was removed under reduced pressure and the crude purified by flash chromatography, silica gel, hexane.; D: (3-bromoprop-1-ynyl)benzene; [Show Image] From 3-phenylprop-2-yn-1-ol (828 mg, 6.26 mmol), CBr4 (2.49 g, 7.51 mmol), Ph3P (2.05 g, 7.83 mmol) and DCM (15 ml), afforded the titled compound (1.01 g, 83%). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.47 (m, 2H), 7.34 (m, 3H), 4.18 (s, 2H). |
83% | With pyridine; phosphorus tribromide In diethyl ether at 0℃; Reflux; Inert atmosphere; | |
83% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; | |
83% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; | |
82% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 2.16667h; Inert atmosphere; | |
82% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; Inert atmosphere; | 4.4. General procedure for bromination of alcohol General procedure: To a solution of alcohol derivative (0.75 mmol) in dry DCM, CBr4 (1.2 equiv), PPh3 (1.5 equiv) were added under an inert atmosphere at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was then poured into DCM, and the organic layer was washed with brine. The organic layer was then dried over anhydrous Na2SO4 and evaporated, and the purified product was obtainedvia flash chromatography by using hexane ethyl acetate aseluent. 4.4.2. (3-bromoprop-1-yn-1-yl)benzene (32a) Following the general procedure, pure product 32a was isolatedby flash chromatography on silica gel (hexane: EtOAc 4:1). State:liquid; yield:, 113 mg, 82%; Experimental data were properly matched with previously reported one [27]. |
82% | Stage #1: 3-Phenyl-2-propyn-1-ol With carbon tetrabromide In dichloromethane at 0℃; for 0.166667h; Stage #2: With triphenylphosphine In dichloromethane at 0 - 20℃; for 2.16667h; | |
81% | With phosphorus tribromide at 0℃; for 0.5h; | |
81% | With bromine; triphenylphosphine In dichloromethane at 0℃; for 2h; | |
81% | Stage #1: 3-Phenyl-2-propyn-1-ol With carbon tetrabromide In dichloromethane at 0℃; for 0.166667h; Stage #2: With triphenylphosphine In dichloromethane at 0 - 20℃; for 1h; | |
78% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 0℃; for 1h; Inert atmosphere; | |
77% | With phosphorus tribromide In pyridine; diethyl ether at 50℃; for 2.5h; | |
77% | With pyridine; phosphorus tribromide In diethyl ether for 1h; Heating; | |
73.2% | With phosphorus tribromide In 1,2-dimethoxyethane at 20℃; for 2h; Inert atmosphere; | |
70% | With bromine; triphenylphosphine In dichloromethane at 0 - 20℃; | 4.5. Synthesis of (3-bromoprop-1-yn-1-yl)benzene (9a) [22] A stirred solution of triphenylphosphine (2.89 g, 10.00 mmol) in dichloromethane (34 mL) was cooled to 0 °C. Bromine (0.56 mL, 1.74 g, 10.90 mmol) was added dropwise at 0 °C until a yellow suspension was formed. A solution of 3-phenylprop-2-yn-1-ol in dichloromethane (17 mL) was added slowly to the suspension. The resulting yellow solution was stirred for 1 h at 0 °C. The solution was allowed to warm to room temperature and n-hexane (68 mL) was added. A white precipitate was formed and the reaction mixture was stirred for 30 min at room temperature. The white solid was filtered over silica and the filter cake was washed with n-hexane (3 x 100 mL). The organic phases were collected and the volatiles were removed under reduced pressure. The crude product was subjected to column chromatography (SiO2, n-hexane/ethyl acetate 29:1) to afford (3-bromoprop-1-yn-1-yl)benzene (9a) as a colorless oil in 70% yield (1.37 g, 7.00 mmol). 1H NMR (300 MHz, CDCl3) δ 4.16 (s, 2H, 1-H), 7.28-7.35 (m, 3H, arom. H), 7.42-7.48 (m, 2H, arom. H); 13C NMR (75 MHz, CDCl3) δ 15.27 (C-1), 84.19 (acetylenic C), 86.71 (acetylenic C), 122.12 (arom. C), 128.31 (arom. C), 128.85 (arom. C), 131.86 (arom. C); HRMS (APCI, 5 kV, [M+H]+) calculated for [C9H8Br]+ 194.9803 found 194.9805. |
68% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 25℃; for 10h; | |
61% | With phosphorus tribromide at 0 - 20℃; | |
61% | With phosphorus tribromide In diethyl ether at 0 - 20℃; | The propargyl alcohol (1.0 g, 7.57 mmol, 0.94 mL) was dissolved in 30 mL anhydrous ether and the solution was cooled to 0° C. PBr3 (1.5 equivalents, 3.07 g, 11.35 mmol, 1.07 mL) was then added dropwise, and the solution was allowed to warm to room temperature. Upon completion of the reaction (monitored by TLC) the reaction mixture was added to ice and extracted with EtOAc. The organic layer was then washed with a saturated solution of NaHCO3 and brine and dried over Na2SO4. The crude product was concentrated under reduced pressure and purified via column chromatography (15% EtOAc in hexane). Yellow oil, 61% yield, 900 mg. Analytical data is consistent with that previously reported (Vyas, D.; Hazra, C.; Oestreich, M. Org. Lett. 2011, 13 (16), 4462). |
58% | With pyridine; phosphorus tribromide In diethyl ether at 0℃; for 4h; | |
48% | With bromine; triphenylphosphine In Carbon tetrachloride | |
41% | With pyridine; phosphorus tribromide In diethyl ether at 0℃; for 4h; | 2S.A Pyridine was added (0.18 ml, 2.27 mmol) to a solution of the alcohol (1.50 g,11.35 mmol) in diethyl ether (19 ml) at 0 °C followed by the addition of PBr3 (0.44 ml,4.54 mmol). This solution was stirred at 0 °C for 4 h. and the reaction was quenchedwith NaHCO3 and extracted with EtOAc. The combined organic layers were washedwith brine, dried, filtered and concentrated followed by purification by flash columnchromatography (15% EtOAc/hex) to yield the desired product 2s1 as a yellow oil(913mg, 41%). |
With chloroform; phosphorus tribromide | ||
With pyridine; phosphorus tribromide | ||
With pyridine; phosphorus tribromide In diethyl ether | ||
With carbon tetrabromide; triphenylphosphine In dichloromethane at 0℃; | ||
With pyridine; phosphorus tribromide In diethyl ether for 2.5h; Ambient temperature; | ||
1.57 g | With phosphorus tribromide In pyridine; diethyl ether at 0℃; for 4h; | |
With phosphorus tribromide In diethyl ether at 0℃; | ||
With pyridine; phosphorus tribromide In diethyl ether | ||
With 1H-imidazole; bromine; triphenylphosphine In dichloromethane at 0℃; | ||
With bromine; triphenylphosphine | ||
With carbon tetrabromide; triphenylphosphine In benzene at 0℃; for 2h; | ||
Multi-step reaction with 2 steps 1: CH2Cl2; triethylamine / 0.5 h / 0 °C 2: LiBr / acetone / Ambient temperature | ||
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether 2: 81 percent / MgBr2 / diethyl ether / 1 h / 15 °C | ||
With pyridine; phosphorus tribromide In diethyl ether at -70℃; Inert atmosphere; | ||
With pyridine; phosphorus tribromide at 7 - 20℃; for 2.33333h; | 7.A Part A [2036] 3-Bromo-1-phenylpropyne 3-Phenyl-2-propyn-1-ol (5 g, 37.83 mmol), anyhdrous diethyl ether (10 mL), and anhydrous pyridine (0.76 mL) were combined with stirring under nitrogen. To the resulting reaction mixture cooled to about 7° C. with an ice bath was added dropwise over 20 minutes a solution of phosphorous tribromide (1.8 mL (18.92 mmol) in anhydrous diethyl ether (20 mL). The ice bath was then removed, and the solution was stirred at room temperature for 2 hours. The reaction was complete, and the resulting reaction mixture was diluted with ice water. The organic layer was separated, and the aqueous layer was washed with diethyl ether (3×). The combined organic layers were washed with water (2×), saturated aqueous sodium bicarbonate (2×), and brine (2×), dried with magnesium sulfate, diluted with 8/2 hexane/ethyl acetate (100 mL), filtered through silica, and concentrated under reduced pressure. The resulting oil was filtered through silica with a dichloromethane rinse. The filtrate was concentrated under reduced pressure to provide a slightly cloudy oil (7.22 g). 3-Bromo-1-phenylpropyne was confirmed by NMR analysis. | |
With pyridine; phosphorus tribromide In diethyl ether at 0℃; Reflux; Inert atmosphere; | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane 2: lithium bromide / tetrahydrofuran; dichloromethane | ||
With carbon tetrabromide; triphenylphosphine In dichloromethane Inert atmosphere; Cooling with ice; | ||
With bromine; triphenylphosphine | ||
With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 1h; | ||
With carbon tetrabromide; triphenylphosphine In dichloromethane at 0℃; for 3h; Inert atmosphere; | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 °C 2: lithium bromide / tetrahydrofuran | ||
With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | ||
With phosphorus tribromide In diethyl ether at 0 - 20℃; Inert atmosphere; | ||
With phosphorus tribromide In diethyl ether at 0 - 20℃; Inert atmosphere; | ||
With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | ||
With bromine; triphenylphosphine In dichloromethane at 0℃; for 1h; | ||
With phosphorus tribromide In dichloromethane at 0℃; for 6h; Inert atmosphere; | ||
With bromine; triphenylphosphine In dichloromethane at 0 - 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; triethylamine In dichloromethane at 20℃; for 16.5h; | |
90.6% | With 5% MoO3 modified mesoporous silica In cyclohexane at 35℃; for 0.5h; | |
83% | With triethylamine for 16h; Inert atmosphere; |
With sodium acetate at 125℃; | ||
201 mg | With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: methylmagnesium bromide With copper(l) iodide In tetrahydrofuran; diethyl ether at -35 - 10℃; for 1.5h; Inert atmosphere; Stage #2: 3-Phenyl-2-propyn-1-ol In tetrahydrofuran; diethyl ether at 5 - 20℃; for 4h; | 43A 43A. (E)-2-methyl-3-phenylprop-2-en-1-ol . A stirred suspension of copper(I) iodide (7.21 g, 37.8 mmol) in THF (dry) (35 mL) was placed under nitrogen, cooled to -35 °C, and treated with methylmagnesium bromide (3M in diethylether) (25.2 mL, 76 mmol) dropwise over 30 min. The reaction was warmed to 10 °C with stirring over 1 h, re-cooled to 5 °C, and treated with 3- phenylprop-2-yn-1-ol (1 g, 7.57 mmol) drop wise over 5 min. The reaction mixture was then slowly warmed to 20 °C and stirred 4 h. The reaction was quenched with saturated aq. NH4Cl solution (25 mL) drop wise over 30 min., and the resulting mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by flash chromatography gave 43A (yellow liquid, 0.81 g, 5.47 mmol, 72 % yield).1 1H NMR (400 MHz, CHLOROFORM-i/) d 7.33- 7.39 (m, 2H), 7.28 - 7.31 (m, 2H) 7.22 - 7.26 (m, 1H), 6.54 (s, 1H), 4.21 (s, 2H), 1.92 (d, J= 1.5 Hz, 3H). |
With copper(l) iodide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 5h; Inert atmosphere; | |
100% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 12h; Inert atmosphere; | |
99% | Stage #1: iodobenzene With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 0.166667h; Inert atmosphere; Stage #2: Prop-2-ynyl alcohol Inert atmosphere; |
99% | Stage #1: iodobenzene With copper (I) iodide; palladium 10% on activated carbon; potassium carbonate; triphenylphosphine In 1,2-dimethoxyethane; water monomer at 20℃; for 0.333333h; Stage #2: Prop-2-ynyl alcohol In 1,2-dimethoxyethane; water monomer at 80℃; for 18h; | 3-phenylprop-2-yn-1-ol 6f (CAS Registry Number: 1504-58-1) To a stirred mixture of 1,2-dimethoxyethane (10 mL) / H2O (10 mL) were added iodobenzene (1 mL,8.9 mmol, 1 eq), K2CO3 (3.0 g, 21.7 mmol, 2.5 eq), CuI (68 mg, 0.36 mmol, 0.04 eq), PPh3 (188 mg, 0.72 mmol, 0.08 eq), 10% Pd/C (180 mg, 0.02 mmol Pd, 0.02 eq). The reaction mixture was stirred for 20 min at room temperature. The propargyl alcohol (1.29 mL, 22.25 mmol, 2.5 eq) was added and the reaction mixture was heated at 80 °C for 18 h with TLC monitoring. The reaction mixture was filtered on a pad of Celite and the filtrate evaporated under reduced pressure. The crude product was dissolved in 20 mL of EtOAc and 20 mL of H2O, the aqueous layer was extracted with EtOAc (3 x 20 mL). The organic layers were combined, dried (MgSO4), filtered and solvent removed under reduced pressure to give the crude product which was purified by column chromatography (SiO2, 10% cyclohexane/EtOAc) to afford the corresponding alcohol 6f as a colourless oil (1.18 g, 99%). |
99% | Stage #1: iodobenzene; Prop-2-ynyl alcohol With trans-bis(triphenylphosphine)palladium(II) dichloride; diethylamine at 20℃; for 0.25h; Inert atmosphere; Stage #2: With copper (I) iodide at 50℃; for 1h; Inert atmosphere; | |
99% | With copper (I) iodide; palladium 10% on activated carbon; potassium carbonate; triphenylphosphine In 1,2-dimethoxyethane; water monomer at 80℃; for 18h; Inert atmosphere; | 1 EXAMPLE 1 (E)-2-cyano-3-(3,4-dihydroxyphenyl) 3-phenylprop-2-ynyl Acrylate Under argon, iodobenzene (8.9 mmol) was solubilized in a mixture of 1,2-dimehoxythane (10 mL) and water (10 mL). Next, were successively added potassium carbonate (21.7 mmol), copper iodide (0.36 mmol), triphenylphosphine (0.72 mmol) and 10% palladium on carbon (0.02 mmol Pd) and then left with stirring for 20 mins at room temperature. Propargylic alcohol was then added and the reaction mixture was brought to 80° C. for 18 h. After cooling, the reaction mixture was filtered on Celite and the filter evaporated in vacuum. Next, the residue was dissolved in 20 mL of ethyl acetate and 20 mL of water and the aqueous phase was extracted with ethyl acetate (3*20 mL), dried with magnesium sulfate, filtered and evaporated in vacuum. The crude product is purified on silica (10% cyclohexane ethyl acetate) and the alcohol is isolated (99%) in the form of a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.59-7.24 (m, 5H), 4.52 (s, 2H), 2.12 (se, 1H). |
99.8% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 12h; Inert atmosphere; | |
99.8% | With copper (I) iodide; trans-bis(triphenylphosphine)palladium(II) dichloride; triethylamine at 20℃; for 12h; Inert atmosphere; | |
98% | With copper (I) iodide; potassium carbonate In N,N-dimethyl-formamide at 100℃; | |
98% | Stage #1: iodobenzene With copper (I) iodide; trans-bis(triphenylphosphine)palladium(II) dichloride; triethylamine at 20℃; for 0.0833333h; Stage #2: Prop-2-ynyl alcohol at 20℃; for 12h; | |
98% | Stage #1: iodobenzene With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide at 20℃; for 0.0833333h; Stage #2: Prop-2-ynyl alcohol at 20℃; for 12h; | |
98% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 12h; | |
97% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine | |
95% | With potassium carbonate In water monomer at 45℃; for 1.5h; | 2.3.1. Typical procedure for Sonogashira reaction General procedure: Halobenzene (1.0 mmol), acetylene (1.0 mmol), Pdg-C3N4-Fe-GO(1.5 mol%) and K2CO3 (2.0 mmol in 5.0 mL water) as a base were mixed in water (5.0 mL). The resulting mixture was then heated at 45 °C for appropriate reaction time. Upon completion of the reaction (traced byTLC, ratio of n-hexane/ethyl acetate: 8/2), Pdg-C3N4-Fe-GO was collected magnetically, washed with EtOH three times and dried in oven at 100 °C overnight. On the other hand, the filtrate, was cooled to room temperature and the organic layer was extracted with diethyl ether (10 mL). The resulting coupling product was purified by column chromatography over silica gel (Scheme 1a). |
95% | With piperidine; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide In toluene at 30℃; | |
95% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; 1,1,3,3-tetramethylguanidine at 30℃; for 0.5h; Schlenk technique; Inert atmosphere; Green chemistry; | |
94% | With potassium carbonate In methanol at 105℃; for 6h; | |
94% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 16h; | |
94% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); di-i-propyl amine at 0 - 20℃; for 12h; | |
94% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 23℃; for 24h; Inert atmosphere; | 4.4.1. (E)-(3-Iodoprop-1-en-1-yl)benzene (1a) A 100mL flask was charged with Pd(PPh3)Cl2 (70 mg, 0.1 mmol) and CuI (38 mg, 0.2 mmol). After the flask was evacuated and refilled with argon, NEt3 (20 mL) was added and the suspension was stirred at room temperature. A solution of iodobenzene (10a, 2.04 g, 10 mmol) and propargyl alcohol (616 mg, 11 mmol) in NEt3 (10 mL) was added to the suspension. After the reaction was complete (monitored by TLC), the mixture was filtered through a plug of Celite and washed with EtOAc (20 mL x 3). The combined solution was concentrated and purified by column chromatography on silica gel (Hexane/EtOAc 3:1, v/v) to afford 3-phenylprop-2-yn-1-ol (11a, 1.24 g, 94% yield) as a yellow oil. |
93% | With pyrrolidine at 25℃; | |
93% | Stage #1: iodobenzene With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 0.166667h; Inert atmosphere; Stage #2: Prop-2-ynyl alcohol at 20℃; Inert atmosphere; | |
93% | Stage #1: iodobenzene With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine for 0.166667h; Inert atmosphere; Stage #2: Prop-2-ynyl alcohol Inert atmosphere; | |
92% | With triethylamine In N,N-dimethyl-formamide at 90℃; for 4.5h; | General procedure for the Sonogashira coupling reaction General procedure: Aryl halide (1 mmol), terminal alkyne (1.2 mmol), triethylamine (2 mmol) and h-Fe3O4mTiO2-NH2-Pd (20 mg) were added to 3 ml DMF and the reaction mixture wasstirred at 90C for the appropriate time. After completion of the reaction, the reactionmixture was cooled to room temperature and diluted with hot ethanol (10 ml). After that,the catalyst was separated by an external magnet from the cooled mixture, washed withacetone, dried in an oven and re-used for a consecutive run under the same reaction conditions.The filtrate was concentrated and the resulting residue was purified by short columnchromatography on silica gel to afford the desired product. |
91% | With piperidine; copper (I) iodide; "Si"-SH-Pd(0) for 2h; Ambient temperature; | |
91% | With 2C2H3O2(1-)*Pd(2+)*3Na(1+)*C18H12O9PS3(3-); potassium-t-butoxide; glycerol at 100℃; for 2h; Schlenk technique; Inert atmosphere; chemoselective reaction; | |
91.3% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 8h; Inert atmosphere; | |
91% | With triethylamine In N,N-dimethyl-formamide for 4h; Heating; Green chemistry; | General procedure for the Sonogashira coupling reaction General procedure: Aryl halide (1 mmol), terminal alkyne (1.2 mmol), triethylamine (2 mmol) and Fe3O4(at)SiO2-T/Pd (20 mg) were added to 3 mL DMF as solvent and the reaction mixture was stirred at 90 °C for the appropriate time. After completion of the reaction, the reaction mixture was cooled and diluted with hot ethanol (10 mL). Then, the catalyst was separated by an external magnet from the cooled mixture, washed with acetone, dried in an oven and re-used for a consecutive run under the same reaction conditions. The filtrate was concentrated and the resulting residue was purified by short column chromatography on silica gel to afford the desired product in excellent yield [40]. |
91% | With potassium carbonate In ethanol; water monomer at 86℃; for 2.8h; Green chemistry; | 2.7. Typical procedure for Sonogashira reaction General procedure: PdGO/Fe3O4/PAA/DCA (10 mol%) and K2CO3 (3mmol) were added to a mixture ofhalobenzene (1mmol) and acetylene (1.2mmol) in water:EtOH (2:1) as the solvent(Scheme 2). The reaction mixture was then refluxed for appropriate reaction time.The progress of the reaction was monitored by TLC. At the end of the reaction,the catalyst was filtered by an external magnet. After that, the organic layer wasextracted with diethyl ether and purified by column chromatography over silica gelby using hexane/ethyl acetate (4:1) as eluent to furnish the corresponding product.Upon completion of the coupling reaction, to recycle the catalyst, the recoveredcatalyst was washed with EtOH two times and dried in the oven at90 °C overnight. |
90% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In tetrahydrofuran for 6h; | |
90% | With potassium carbonate In ethanol at 80℃; for 6h; | |
90% | With copper (I) iodide; C13H21I2N5OPd; triphenylphosphine; methyloxirane In N,N-dimethyl-formamide at -78 - 25℃; Inert atmosphere; | |
90% | With palladium; potassium carbonate In water monomer at 80℃; for 4h; | |
90% | With 1,4-diaza-bicyclo[2.2.2]octane In water monomer at 60℃; for 3h; | |
90% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In acetonitrile at 20℃; for 12h; Inert atmosphere; Schlenk technique; | |
90% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; di-i-propyl amine In tetrahydrofuran at 20℃; for 14h; | |
90% | With potassium carbonate In ethanol; water monomer at 60℃; for 2.15h; | |
90% | With potassium carbonate at 85℃; for 24h; Inert atmosphere; Green chemistry; | 4.6 General procedure for the Sonogashira reaction General procedure: To a mixture of the catalyst 3 (20mg containing 0.05mol% Pd for aryl iodides and 40mg containing 0.1mol% Pd for aryl bromides and chlorides), aryl halide (1mmol), alkyne (1.5mmol), and K2CO3 (1.5mmol, 207mg) was added PEG 200 (2mL) under argon atmosphere. The reaction mixture was stirred for the appropriate reaction time at 85 or 130°C (see, Table 2). The progress of the reaction was monitored by using gas chromatography. After completion of the reaction, pure products were obtained by using column chromatography with hexane and ethyl acetate as eluents. |
89% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; di-i-propyl amine In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; | |
88% | With piperidine In various solvent(s) for 2h; Heating; | |
88% | With copper (I) iodide; triethylamine; dichlorotriphenylphosphorane | |
88% | With palladium; potassium carbonate In water monomer at 60℃; for 3h; Green chemistry; | 2.3. General procedure for Sonogashira coupling reaction General procedure: The freshly prepared solution of palladium in water (2 mol%)was added to the aryl iodide (1 mmol), alkyne (1.2 mmol), and K2CO3(2 mmol) in a 25 mL flask and the mixture was vigorously stirred at 60°C for the appropriate times under aerobic conditions.After completion (as monitored by TLC), the reaction mixture was cooled and the organic layer was extracted with EtOAc, washed with water, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography. The purity of the compounds was checked by 1H NMR and yields are based on aryl iodide. All the products are known and the spectroscopic data (FT-IR and NMR) and melting points were consistent with those reported in the literature [6-9]. |
88% | With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl acetamide at 50℃; for 24h; Inert atmosphere; | |
88% | Stage #1: iodobenzene With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In tetrahydrofuran for 0.5h; Cooling with ice; Stage #2: Prop-2-ynyl alcohol In tetrahydrofuran at 20℃; for 0.5h; | 2 8.0 g (39.2 mmol) of iodobenzene was dissolved in 50 mL of tetrahydrofuran, and 7.93 g (78.4 mmol) of triethylamine, 566 mg (0.784 mmol) of bis(triphenylphosphine)palladium(II) dichloride and 519 mg (2.74 mmol) of copper(I) iodide were added thereto while cooling in an ice bath, followed by stirring for 30 minutes. To the resultant solution, 10 mL of a solution of 2.20 g (39.2 mmol) of propargyl alcohol in tetrahydrofuran was added using a dropping funnel, followed by heating to room temperature, and the resultant solution was stirred for 30 minutes and passed through a short column (silica gel 64-210 μm diameter, 1.5 cm inner diameter×25 cm height) thereby terminating the reaction. The obtained solution was washed three times with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated thereby obtaining 6.29 g of a brownish oily substance. The oily substance was subjected to silica gel column chromatography (289 g, 2.1 cm inner diameter×40 cm length) using hexane-ethyl acetate (0-20-100%, step gradient) as an eluent thereby obtaining 3-phenylprop-2-yn-1-ol (a brownish oily substance, 4.56 g) (yield 88%). 4.00 g (30.3 mmol) of 3-phenylprop-2-yn-1-ol was dissolved in 8 mL of tetrahydrofuran. To the resultant solution, 20 mL of a solution of 12.3 g (121 mmol) of triethylamine and 11.8 g (60.6 mmol) of p-toluenesulfonyl chloride in tetrahydrofuran was added under a condition of -10° C. The solution was heated to 0° C. and stirred for 90 minutes, and subsequently the reaction solution was added to a separatory funnel containing 400 mL of ethyl acetate. 20 mL of 1M hydrochloric acid was added thereto, and the separatory funnel was shaken thoroughly to remove triethylamine. The same operation was repeated again and the solution was washed four times with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated thereby obtaining 10.0 g of a brownish oily substance. |
87% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In acetonitrile at 20℃; Inert atmosphere; | |
87% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 10h; Sealed tube; Inert atmosphere; | |
87% | With potassium carbonate In ethanol at 90℃; for 3.3h; | 2.6. Sonogashira coupling reaction General procedure: The catalytic activity of the synthesized Pd(at)Hal-2N-TCT-EDA was investigated for promotingthe Sonogashira reaction. Pd(at)Hal-2N-TCT-EDA (10 mol%) and K2CO3 (3.0 mmol) were added to the mixture of halobenzene (1.0 mmol) and acetylene (1.2 mmol) in EtOH. The reaction mixture was then refluxed at 90 °C for appropriate reaction time(Scheme 1). The reaction was monitored by thin layer chromatography (TLC, n-hexane/ethyl acetate; 4:1). When the reaction was completed, Pd(at)Hal-2N-TCT-EDA was filtered.After that, the organic layer was extracted with diethyl ether and purified by column chromatography over silica gel by using hexane/ethyl acetate (4:1) as eluentto furnish the corresponding product. To recycle the catalyst, the recovered catalyst was washed with EtOH two times and dried in an oven at 90 °C overnight. The coupling products were characterized by comparing their melting points and 1H NMR and13C NMR spectra with authentic samples (see Supporting Information). |
87% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 10h; Inert atmosphere; Sealed tube; | |
87% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 12h; | |
86% | With Cs2CO3 In methanol at 65℃; for 24h; | |
85% | With copper (I) iodide; triethylamine; triphenylphosphine at 90℃; for 12h; Inert atmosphere; | |
85% | With tetrabutylammonium bromide; potassium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; for 5h; | |
85% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 40℃; for 12h; Schlenk technique; | |
85% | With piperidine; 1,3-bis(5-ferrocenylisoxazoline-3-yl)benzene; tetrabutylammonium bromide; palladium diacetate In water monomer; N,N-dimethyl-formamide at 60℃; for 4h; | |
85% | With potassium carbonate In ethanol; water monomer at 75℃; for 1.83333h; | 2.4. Catalytic test: typical procedure for Sonogashira reaction General procedure: A mixture of acetylene (1.2mmol), halobenzene (1. mmol), catalyst (1.5mol%) and K2CO3 (2.0mmol in 5.0mL water) in aqueous media (2:1 mixture of water: EtOH) was heated at 75°C for appropriate reaction time. The reaction was monitored by TLC and upon completion of the reaction, the catalyst was easily filtered, washed with EtOH several times and dried in oven at 90°C overnight. On the other hand, the organic layer in filtrate was extracted with diethyl ether (15mL). The desired product was purified by column chromatography over silica gel (Scheme 1). |
83% | Stage #1: iodobenzene With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine for 0.0833333h; Stage #2: Prop-2-ynyl alcohol for 18h; | |
80% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) at 55℃; for 3h; Ionic liquid; Green chemistry; | General procedure for Sonogashira couplingreactions General procedure: In a 4 mL screw-cap vial, 0.5 mmol of corresponding iodoarenecompound, 1.5 equiv of phenylacetylene or propargyl alcohol,0.005 equiv PdCl2(PPh3)2, and 0.8 mL of ionic liquid weremixed and stirred at 55 °C for 3 h. After cooling, the mixturewas partitioned between 5 mL of water and 5 mL of pentane.After separation, the aqueous phase was extracted subsequentlywith 2 × 5 mL of pentane. The combined organic phase waswashed with brine, dried over MgSO4, filtered, and the solventwas evaporated under reduced pressure (ca. 10 mmHg). Theoily residue was purified by chromatography on silica gel(Merck Silicagel 60 (0.063-0.200 mm) for column chromatography(70-230 mesh ASTM)) eluted with n-pentane/EtOAc.The purity of the isolated products was >98%. The detailed experimentalprocedure as well as the characterization of isolatedcompounds are provided in Supporting Information File 1. |
79% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; | |
76% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; Inert atmosphere; | Representative procedure: preparation of 1a General procedure: A round-bottomed flask containing a magentic stirbar and iodobenzene (911.5 mg, 4.468 mmol,1.0 equiv) was added with PdCl2(PPh3)2 (62.9 mg, 0.0896 mmol, 0.02 equiv), CuI (34.9 mg, 0.183mmol, 0.04 equiv) and 5.0 mL of Et3N. The resulted mixture was thoroughly degassed by a steadystream of argon for 15 min before propargyl alcohol (0.14 mL, 270.2 mg, 4.820 mmol, 1.1 equiv)was added via syringe. Ther resulted reaction mixture was allowed to stir at room temperatureunder argon overnight. The reaction mixture was diluted with saturated aqueous NH4Cl and theseparated aqueous layer was extracted with 3xEtOAc. Combined organic phases were washed withsaturated aqueous NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to givea crude material. The crude material was purified by SiO2 column chromatography eluting with10% EtOAc-hexane to give the desired product 1a as a brown oil (451.5 mg, 76%); IR (neat):νmax 3323, 2918, 1490, 1020, 754 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.46-7.39 (m, 2H), 7.34-7.25 (m, 3H), 4.49 (s, 2H), 2.11 (br s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 131.6, 128.3, 128.2,122.5, 87.3, 85.4, 51.3; HRMS (ESI-Orbitrap) m/z: [M+H]+ Calcd for C9H9O 133.0648; Found133.0649. |
73% | With triethylamine In water monomer; N,N-dimethyl-formamide at 80℃; for 6h; | |
72% | Stage #1: iodobenzene With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide In tetrahydrofuran for 0.0833333h; Inert atmosphere; Stage #2: Prop-2-ynyl alcohol With triethylamine In tetrahydrofuran at 20℃; for 4h; Inert atmosphere; | |
70% | With triethylamine In N,N-dimethyl-formamide at 80℃; for 20h; | |
61% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); diethylamine; copper chloride (I) at 0 - 20℃; for 17h; Inert atmosphere; | |
59% | With N,N,N-tributylbutan-1-aminium fluoride; triphenylphosphine In tetrahydrofuran; water monomer at 60℃; for 24h; | |
55% | With palladium diacetate; copper (I) iodide; triethylamine; triphenylphosphine In water monomer; acetonitrile Ambient temperature; | |
47% | With potassium hydroxide In ethanol for 24h; Reflux; Inert atmosphere; | |
In diethylamine | ||
With diethylamine for 5h; Ambient temperature; | ||
With piperidine; sodium iodide; anhydrous zinc chloride for 0.75h; Ambient temperature; Yield given; | ||
9.4 mmol | With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; N-butylamine In diethyl ether at 25℃; for 6h; | |
With copper (I) iodide; diethylamine at 20℃; for 21.5h; | ||
75 % Spectr. | With piperidine; 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate at 80℃; for 2h; | |
With copper (I) iodide; potassium carbonate; triphenylphosphine In 1,2-dimethoxyethane; water monomer at 70℃; for 7h; | ||
86 %Chromat. | With carbonate caesium monohydrate; palladium(II) N,N'--(triphenylphosphonium)methyl]salicylidene}-1,2-ethanediamine dichloride; sodium lauryl sulfate In water monomer at 60℃; for 10h; | |
87 %Chromat. | With piperidine at 20℃; for 6h; | |
Inert atmosphere; | ||
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In N,N-dimethyl-formamide | ||
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In dimethyl sulfoxide at 40 - 45℃; | ||
With copper (I) iodide; trans-bis(triphenylphosphine)palladium(II) dichloride; diethylamine at 20℃; for 16h; Inert atmosphere; | ||
75 %Chromat. | With triethylamine at 20℃; for 3h; neat (no solvent); | |
94 %Chromat. | With triethylamine at 20℃; for 5h; Neat (no solvent); | |
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; di-i-propyl amine; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; | ||
With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In tetrahydrofuran at 40℃; | ||
99 %Chromat. | With piperidine In water monomer at 20℃; for 3h; | 2.4. General procedure for the Sonogashira coupling reaction General procedure: An aryl halide (1.0 mmol) and a terminal alkyne (1.2 mmol) were added to a mixture of PS-dtz-Pd(II) (0.001 mmol), piperidine (2.0 mmol), and water (3 ml) in a glass flask under vigorous stirring. The mixture was stirred at room temperature for 3 h under aerobic conditions. After completion of the reaction, the mixture was filtered to recover the catalyst. The polymer was washed with water and acetonitrile, vacuum dried, and stored for a new run. After GC analysis, the solvent was removed under vacuum, and the crude product was subjected to silica gel column chromatography using CHCl3-CH3OH (97:3) as eluent to afford the pure product. |
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; di-i-propyl amine In toluene at 20℃; Inert atmosphere; | ||
96 %Chromat. | With potassium carbonate In neat (no solvent) at 25℃; for 1.33h; Sonication; Green chemistry; | |
95 %Chromat. | With triethylamine In neat (no solvent) at 20℃; for 3h; | 4.2 General procedure for the Sonogashira coupling reaction General procedure: An aryl halide (1.0mmol) and a terminal alkyne (1.0mmol) was added to a mixture of PS-triazine-Pd(II) (0.001mmol) and base (1mmol) in a glass flask under vigorous stirring. The mixture was stirred at room temperature for 3h under aerobic conditions. Upon completion of the reaction, the reaction mixture was dissolved in chloroform (2mL). The palladium catalyst was separated from the mixture by filtration, washed with acetonitrile (10mL), and reused in the next run. Then to the chloroform solution was added toluene (1.0mmol) as the internal standard for GC analysis. After the analysis, the solvent was removed under vacuum, and the crude product was subjected to silica gel column chromatography using CHCl3-CH3OH (95:5) as eluent to afford the pure product. |
91 %Chromat. | With triethylamine at 20℃; for 3h; | General Procedure for the Sonogashira Coupling Reaction General procedure: Aryl halide (1.0 mmol), PVC-triazole-Pd(II) (40 mg, 0.01mmol Pd), base (1.0 mmol), and terminal alkyne (1.0 mmol),were added to a flask, and the reaction mixture was stirred atroom temperature for 3 h under aerobic conditions. Uponcompletion of the reaction, the reaction mixture was dissolvedin chloroform (2 ml). The palladium catalyst wasseparated from the mixture by filtration, washed with acetonitrile(10 ml), and reused in the next run. Then to the chloroformsolution was added toluene (1.0 mmol) as the internalstandard for GC analysis. |
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; Inert atmosphere; Schlenk technique; | ||
94 %Chromat. | With triethylamine at 20℃; for 3h; | 2.3. General procedure for Sonogashira coupling reaction General procedure: An aryl halide (1.0 mmol) and a terminal alkyne (1.2 mmol) were added to a mixture of PVC-dtz-Pd(II) (0.01 mmol) and Et3N (1.0 mmol) in a glass flask under vigorous stirring. The mixture was stirred at room temperature for 3 h under aerobic conditions. After completion of the reaction, the mixture was filtered to recover the catalyst. The polymer was washed with water and acetonitrile, vacuum dried, and stored for subsequent runs. After GC analysis, the solvent was removed under vacuum, and the crude product was subjected to silica gel column chromatography, using CHCl3-CH3OH (97:3) as the eluent, affording the pure product. |
95 %Chromat. | With pyridine at 20℃; for 3h; Green chemistry; | |
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 30℃; for 3h; | ||
60 %Chromat. | With C18H18N2O8PdS2(2-)*2Na(1+)*3H2O; triethylamine In water monomer at 80℃; for 6h; | |
With copper (I) iodide; palladium diacetate; triethylamine; triphenylphosphine at 20℃; Inert atmosphere; | ||
With copper (I) iodide; palladium diacetate; triethylamine; triphenylphosphine at 20℃; Inert atmosphere; | ||
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; for 16h; Inert atmosphere; | ||
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; di-i-propyl amine; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; | ||
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine at 20℃; | ||
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In tetrahydrofuran at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; Schlenk technique; Stage #2: allyl bromide In tetrahydrofuran at 20℃; Inert atmosphere; Schlenk technique; | |
97% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran at 20℃; Stage #2: allyl bromide In tetrahydrofuran at 60℃; for 1.5h; Further stages.; | |
95% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran at 20℃; for 2h; Stage #2: allyl bromide In tetrahydrofuran at 20℃; for 2h; |
95% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: allyl bromide In tetrahydrofuran at 20℃; for 2h; | |
95% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: allyl bromide In tetrahydrofuran at 0 - 20℃; | |
95% | With sodium hydride In tetrahydrofuran at 20℃; for 2h; | |
95% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: allyl bromide In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | |
95% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: allyl bromide In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; | |
94% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: allyl bromide In tetrahydrofuran; mineral oil at 0 - 20℃; for 2h; Inert atmosphere; | |
94% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: allyl bromide In tetrahydrofuran; mineral oil at 0 - 20℃; for 2h; Inert atmosphere; | |
81% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Stage #2: allyl bromide In tetrahydrofuran; mineral oil at 0 - 20℃; | |
60% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 2h; Schlenk technique; Stage #2: allyl bromide In tetrahydrofuran; mineral oil at 0 - 20℃; for 2h; | |
With sodium hydride | ||
Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: allyl bromide In tetrahydrofuran at 20℃; for 1h; | ||
Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.75h; Inert atmosphere; Stage #2: allyl bromide In tetrahydrofuran at 20℃; Inert atmosphere; | ||
Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2h; Stage #2: allyl bromide In tetrahydrofuran at 0 - 20℃; for 2h; | ||
Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h; Stage #2: allyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; | ||
Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: allyl bromide at 20℃; Inert atmosphere; | 1,6-Enynes 1 by the Williamson Reaction; General Procedure 1 General procedure: The alcohol (1 equiv) was added dropwise to a suspension of NaH (1.1 equiv) in freshly distilled DMF or THF (0.67 M) at 0 °C. The reaction mixture was allowed to warm to r.t. and stirred for 30 min. The alkene bromide (1.5 equiv) was then added portionwise at r.t. The mixture was stirred until completion of the reaction, as monitored by TLC. The reaction mixture was quenched with 3.5% aq HCl (15 mL). The aqueous phase was extracted with Et2O (3 × 15 mL). The combined organic phase was dried over MgSO4, filtrated, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel) if necessary or distillation. The products thus obtained were characterized by NMR and MS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydride In tetrahydrofuran; toluene at 0 - 20℃; | |
82% | With sodium hydride In toluene; paraffin 1.) room temperature, 2 h, 2.) room temperature, 3 h; | |
82% | With sodium hydride In tetrahydrofuran for 12h; Schlenk technique; |
80% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: propargyl bromide In tetrahydrofuran at 20℃; for 0.0833333h; Inert atmosphere; | |
76% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: propargyl bromide In tetrahydrofuran; toluene; mineral oil at 0 - 20℃; for 2h; Inert atmosphere; | |
65% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: propargyl bromide In tetrahydrofuran for 0.0833333h; Inert atmosphere; | |
52% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: propargyl bromide In tetrahydrofuran at 0 - 20℃; for 12h; | |
With sodium hydride | ||
Stage #1: 3-Phenyl-2-propyn-1-ol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃; for 14h; Further stages.; | ||
With sodium hydride In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With copper(I) oxide; potassium phosphate In dimethyl sulfoxide at 100℃; for 24h; Molecular sieve; Sealed tube; Inert atmosphere; diastereoselective reaction; | 4.3.1 General procedures II for the synthesis of 3a-n General procedure: Method A: An oven-dried 10mL pressure glass vial, equipped with a magnetic stir bar, was charged with Cu2O (0.05mmol, 7mg), DCC (0.5mmol, 103mg), the 3-substituted-2-bromo-2-propen-1-ol 1 (0.5mmol) and K3PO4 (2mmol, 425mg). After addition of molecular sieve 4 (5 beads) the sealed tube was evacuated and backfilled with argon (two times). Then, freshly distilled DMSO (2mL) was added and the reaction mixture was stirred at 100°C for 24h. After cooling to room temperature, the reaction mixture was diluted with saturated oxalic acid (30mL) and extracted with EtOAc (3×20mL). The combined organic layers were washed with saturated NaHCO3 (50mL) and water (50mL), dried over anhydrous MgSO4, filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel to afford the 2-iminooxazolidine 3 in analytically pure form. |
(i) CuCl, (ii) (heating); Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With iodine; sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran | |
94% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: With iodine In tetrahydrofuran; ethyl acetate at -78℃; for 1h; Inert atmosphere; | |
92% | With iodine; sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran; diethyl ether; ethyl acetate |
91% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium bis(2-methoxyethoxy)aluminium dihydride In diethyl ether; toluene for 24h; Inert atmosphere; Stage #2: With iodine In diethyl ether; toluene at -78℃; for 1h; Inert atmosphere; | (Z)-3-Iodo-3-phenylprop-2-en-1-ol To a solution of 3-phenylprop-2-yn-1-ol(33.0 g, 0.25 mol) in anhydrous Et2O (125.0mL) Red-Al [sodium bis(2-methoxyethoxy) aluminum hydride] (125.0 mL, 70% intoluene, 0.51 mol) was added dropwise at -78 °C. The reaction mixture was stirredat RT for 24 hr. Then, it was cooled to 0 °C and EtOAc (30.0 mL) was addeddropwise and stirred at RT for 30 min. The reaction mixture was cooled to -78°C, a solution of iodine (77.50 g, 0.30 mol; Et2O (100.0 mL)) was addedand stirred for 1hr at -78°C. The reaction mixture was quenched with asaturated solution Na2S2O3 (150 mL) andextracted with Et2O/EtOAc (3x150.0 mL). The combined organic layerwas washed with a saturated solution of NaHCO3 (150.0 mL) and brine(150.0 mL), dried over MgSO4, filtered, and concentrated to providethe corresponding alcohol (59.10 g, 91%) after silica gel column chromatography(Hex: EtOAc, 3:1) |
87% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium bis(2-methoxyethoxy)aluminium dihydride Stage #2: With iodine | |
86% | Stage #1: 3-Phenyl-2-propyn-1-ol With sodium bis(2-methoxyethoxy)aluminium dihydride In diethyl ether at 0 - 20℃; for 4h; Inert atmosphere; Stage #2: With iodine In diethyl ether; ethyl acetate at -78 - 20℃; for 5h; Inert atmosphere; | |
67% | Stage #1: 3-Phenyl-2-propyn-1-ol In tetrahydrofuran; toluene at 0℃; Stage #2: With iodine In tetrahydrofuran; toluene at -78 - 0℃; | |
51% | Stage #1: 3-Phenyl-2-propyn-1-ol With lithium aluminium tetrahydride; sodium methylate In tetrahydrofuran at 0℃; for 1h; Stage #2: With carbonic acid dimethyl ester In tetrahydrofuran for 0.5h; Stage #3: With iodine In tetrahydrofuran at 0℃; Further stages.; | |
With iodine; sodium bis(2-methoxyethoxy)aluminium dihydride 1) Et2O, 0 deg C 2) -78 to 23 deg C, 1h; Yield given. Multistep reaction; | ||
With iodine; sodium bis(2-methoxyethoxy)aluminium dihydride | ||
With iodine; sodium bis(2-methoxyethoxy)aluminium dihydride | ||
With iodine; sodium bis(2-methoxyethoxy)aluminium dihydride In diethyl ether | ||
Stage #1: 3-Phenyl-2-propyn-1-ol With sodium bis(2-methoxyethoxy)aluminium dihydride In diethyl ether Stage #2: With iodine In diethyl ether | ||
Stage #1: 3-Phenyl-2-propyn-1-ol With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran at 0℃; Stage #2: With iodine In tetrahydrofuran at -78 - 20℃; Further stages.; | ||
Multi-step reaction with 2 steps 1: LiAlH4; NaOMe / tetrahydrofuran / 20 °C 2: I2 / tetrahydrofuran / 20 °C | ||
Stage #1: 3-Phenyl-2-propyn-1-ol With sodium bis(2-methoxyethoxy)aluminium dihydride In diethyl ether at 0 - 20℃; for 1h; Stage #2: In ethyl acetate at 0℃; Stage #3: With iodine In tetrahydrofuran at -78 - 20℃; for 1h; Further stages.; | ||
Multi-step reaction with 2 steps 1.1: Red-Al / diethyl ether / 1 h / 0 - 20 °C 1.2: 0 °C 2.1: iodine / tetrahydrofuran / 1 h / -78 - 20 °C | ||
Stage #1: 3-Phenyl-2-propyn-1-ol With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran at 0℃; Stage #2: With iodine at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyrrolidine; copper(l) iodide In water at 70℃; for 0.5h; | |
93% | With piperidine; (BeDABCO)<SUB>2</SUB>Pd<SUB>2</SUB>Cl<SUB>6</SUB> In water at 50℃; for 3h; | |
90% | With diisopropylammonium bromide; tri tert-butylphosphoniumtetrafluoroborate In various solvent(s) at 80℃; for 12h; |
88% | With pyrrolidine at 80℃; | |
85% | With triethylamine In N,N-dimethyl-formamide for 6.5h; Heating; Green chemistry; | General procedure for the Sonogashira coupling reaction General procedure: Aryl halide (1 mmol), terminal alkyne (1.2 mmol), triethylamine (2 mmol) and Fe3O4(at)SiO2-T/Pd (20 mg) were added to 3 mL DMF as solvent and the reaction mixture was stirred at 90 °C for the appropriate time. After completion of the reaction, the reaction mixture was cooled and diluted with hot ethanol (10 mL). Then, the catalyst was separated by an external magnet from the cooled mixture, washed with acetone, dried in an oven and re-used for a consecutive run under the same reaction conditions. The filtrate was concentrated and the resulting residue was purified by short column chromatography on silica gel to afford the desired product in excellent yield [40]. |
82% | With copper(l) iodide; C13H21I2N5OPd; triphenylphosphine; methyloxirane In N,N-dimethyl-formamide at -78 - 80℃; Inert atmosphere; | |
82% | With tetrabutylammomium bromide; potassium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; for 12h; | |
80% | With pyrrolidine; copper(l) iodide In water at 70℃; for 0.5h; | |
80% | With triethylamine In N,N-dimethyl-formamide at 90℃; for 7h; | General procedure for the Sonogashira coupling reaction General procedure: Aryl halide (1 mmol), terminal alkyne (1.2 mmol), triethylamine (2 mmol) and h-Fe3O4mTiO2-NH2-Pd (20 mg) were added to 3 ml DMF and the reaction mixture wasstirred at 90C for the appropriate time. After completion of the reaction, the reactionmixture was cooled to room temperature and diluted with hot ethanol (10 ml). After that,the catalyst was separated by an external magnet from the cooled mixture, washed withacetone, dried in an oven and re-used for a consecutive run under the same reaction conditions.The filtrate was concentrated and the resulting residue was purified by short columnchromatography on silica gel to afford the desired product. |
78% | With bis-triphenylphosphine-palladium(II) chloride; N-butylamine for 4h; Inert atmosphere; Reflux; | 4.2.1. Synthesis of compounds (37, 44, 31a, 31b, 13, 17) To a solution of bromo aryl derivative (1 mmol) in dry degassed n-butylamine (7 mL), PdCl2 (PPh3)2 (3 mol %), corresponding alkyne compound (1.2 equiv) in were added under an inert atmosphere, and the mixture was refluxed for 4 h. The mixture was then poured into ethyl acetate, and the organic layer was washed with brine. The organic layer was then dried over anhydrous Na2SO4 and evaporated, and the purified product was obtained via flash chromatography by using hexane ethyl acetate as eluent. 4.2.2. 3-phenylprop-2-yn-1-ol (31a) Following the general procedure, pure product 31a was isolatedby flash chromatography on silica gel (hexane: EtOAc 2:1). State: liquid; yield: 103 mg, 78%; Experimental data properly matched with previously reported one [24]. |
78% | With potassium carbonate In ethanol at 90℃; for 5h; | 2.6. Sonogashira coupling reaction General procedure: The catalytic activity of the synthesized Pd(at)Hal-2N-TCT-EDA was investigated for promotingthe Sonogashira reaction. Pd(at)Hal-2N-TCT-EDA (10 mol%) and K2CO3 (3.0 mmol) were added to the mixture of halobenzene (1.0 mmol) and acetylene (1.2 mmol) in EtOH. The reaction mixture was then refluxed at 90 °C for appropriate reaction time(Scheme 1). The reaction was monitored by thin layer chromatography (TLC, n-hexane/ethyl acetate; 4:1). When the reaction was completed, Pd(at)Hal-2N-TCT-EDA was filtered.After that, the organic layer was extracted with diethyl ether and purified by column chromatography over silica gel by using hexane/ethyl acetate (4:1) as eluentto furnish the corresponding product. To recycle the catalyst, the recovered catalyst was washed with EtOH two times and dried in an oven at 90 °C overnight. The coupling products were characterized by comparing their melting points and 1H NMR and13C NMR spectra with authentic samples (see Supporting Information). |
77% | With cobalt-2-(hydroxyimino)-1-phenylpropan-1-one; potassium carbonate; ethylene glycol In N,N-dimethyl-formamide for 15h; Irradiation; | |
70% | With pyrrolidine; triphenylphosphine In water at 120℃; for 2.33333h; | |
70% | With potassium carbonate In ethanol; water at 60℃; for 4.5h; | |
65% | With triethylamine In N,N-dimethyl-formamide at 80℃; for 24h; | |
58% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); diethylamine In tetrahydrofuran for 1h; Heating; | |
10% | With copper(l) iodide; triethylamine; triphenylphosphine at 90℃; for 96h; Inert atmosphere; | |
93 %Chromat. | With copper(l) iodide; sodium carbonate In N,N-dimethyl acetamide; water at 50℃; for 3h; | |
91 %Chromat. | With piperidine; [Pd(H3CCOCHC(NCH2C6H4OCH3)CH3)(CH3)(P(C6H5)3)] at 40℃; for 3h; | |
97 %Chromat. | With pyridine at 20℃; for 3h; neat (no solvent); | |
92 %Chromat. | With piperidine In water at 20℃; for 3h; | 2.4. General procedure for the Sonogashira coupling reaction General procedure: An aryl halide (1.0 mmol) and a terminal alkyne (1.2 mmol) were added to a mixture of PS-dtz-Pd(II) (0.001 mmol), piperidine (2.0 mmol), and water (3 ml) in a glass flask under vigorous stirring. The mixture was stirred at room temperature for 3 h under aerobic conditions. After completion of the reaction, the mixture was filtered to recover the catalyst. The polymer was washed with water and acetonitrile, vacuum dried, and stored for a new run. After GC analysis, the solvent was removed under vacuum, and the crude product was subjected to silica gel column chromatography using CHCl3-CH3OH (97:3) as eluent to afford the pure product. |
94 %Chromat. | With potassium carbonate In neat (no solvent) at 25℃; for 1.67h; Sonication; Green chemistry; | |
97 %Chromat. | With piperidine In neat (no solvent) at 20℃; for 3h; | 4.2 General procedure for the Sonogashira coupling reaction General procedure: An aryl halide (1.0mmol) and a terminal alkyne (1.0mmol) was added to a mixture of PS-triazine-Pd(II) (0.001mmol) and base (1mmol) in a glass flask under vigorous stirring. The mixture was stirred at room temperature for 3h under aerobic conditions. Upon completion of the reaction, the reaction mixture was dissolved in chloroform (2mL). The palladium catalyst was separated from the mixture by filtration, washed with acetonitrile (10mL), and reused in the next run. Then to the chloroform solution was added toluene (1.0mmol) as the internal standard for GC analysis. After the analysis, the solvent was removed under vacuum, and the crude product was subjected to silica gel column chromatography using CHCl3-CH3OH (95:5) as eluent to afford the pure product. |
92 %Chromat. | With 2-methoxyethylamine at 20℃; for 3h; | General Procedure for the Sonogashira Coupling Reaction General procedure: Aryl halide (1.0 mmol), PVC-triazole-Pd(II) (40 mg, 0.01mmol Pd), base (1.0 mmol), and terminal alkyne (1.0 mmol),were added to a flask, and the reaction mixture was stirred atroom temperature for 3 h under aerobic conditions. Uponcompletion of the reaction, the reaction mixture was dissolvedin chloroform (2 ml). The palladium catalyst wasseparated from the mixture by filtration, washed with acetonitrile(10 ml), and reused in the next run. Then to the chloroformsolution was added toluene (1.0 mmol) as the internalstandard for GC analysis. |
92 %Chromat. | With triethylamine at 20℃; for 3h; | 2.3. General procedure for Sonogashira coupling reaction General procedure: An aryl halide (1.0 mmol) and a terminal alkyne (1.2 mmol) were added to a mixture of PVC-dtz-Pd(II) (0.01 mmol) and Et3N (1.0 mmol) in a glass flask under vigorous stirring. The mixture was stirred at room temperature for 3 h under aerobic conditions. After completion of the reaction, the mixture was filtered to recover the catalyst. The polymer was washed with water and acetonitrile, vacuum dried, and stored for subsequent runs. After GC analysis, the solvent was removed under vacuum, and the crude product was subjected to silica gel column chromatography, using CHCl3-CH3OH (97:3) as the eluent, affording the pure product. |
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; | ||
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine at 80℃; Inert atmosphere; | ||
Stage #1: bromobenzene With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine for 0.166667h; Inert atmosphere; Stage #2: propargyl alcohol | ||
82 %Chromat. | With triethylamine In N,N-dimethyl-formamide at 70℃; for 10h; Inert atmosphere; | Sonogashira coupling reaction General procedure: The typical reaction was carried out with a terminal alkyne (1.0 mmol), an arylhalide (1.0 mmol), Et3N (2.0 mmol), and the catalyst (0.1 g, 0.05 mmol based onCu) in DMF (3.0 mL). The reaction mixture was stirred for 10 h at 70 °C under an Ar atmosphere. After completion of the reaction, the mixture was filtered to recover the catalyst. The catalyst was washed with dry toluene, vacuum dried, and stored fora new run. After GC analysis, the solvent was removed under vacuum, and the crudeproduct was subjected to silica gel column chromatography using CHCl3/CH3OH(97:3) as eluent to afford the pure product. |
With potassium carbonate In ethanol at 50℃; for 4.5h; | ||
With bis-triphenylphosphine-palladium(II) chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In tetrahydrofuran at 0℃; for 0.25h; | 23.1 Step 1: 1-phenyl-2-propyn-1-yl methanesulfonate Step 1: 1-phenyl-2-propyn-1-yl methanesulfonate.To an ice-cold solution of 1-phenyl-2-propyn-1-ol (0.50 g, 3.8 mmol) in THF (15 ML), under a N2 atmosphere, was added Et3N (0.78 ML, 5.7 mmol), followed by methanesulfonyl chloride (0.35 ML, 4.5 mmol).After 15 minutes, the reaction mixture was diluted with EtOAc (50 ML), washed with 2N HCl, H2O, saturated NaHCO3, and saturated NaCl. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give the mesylate 7 (0.79 mg, 100%), which was used without further purification. |
99% | With triethylamine In dichloromethane at -20℃; for 1.5h; | |
98% | With triethylamine In dichloromethane at 0℃; for 2h; |
98% | With triethylamine In dichloromethane at 0℃; for 2h; | 1.1 first step: Weigh first (1.68g, 30mmol) and triethylamine (4.55g, 45mmol),Into 40 ml of dichloromethane, MsCl (4.47 g, 39 mmol) was added slowly and stirred at 0 ° C for 2 h.After the reaction is completed, HCl (2M) is added, extraction is carried out, and then washed with sodium hydrogencarbonate.Further, it was washed with NaCl, dried with MgS04, and finally dried to give the desired product (Yield: 98%). |
90% | With triethylamine In dichloromethane at -20℃; for 0.5h; | |
80% | Stage #1: 3-Phenyl-2-propyn-1-ol With triethylamine In tetrahydrofuran at 0℃; Stage #2: methanesulfonyl chloride In tetrahydrofuran at 0 - 20℃; | General procedure for the preparation of benzyl mesylates General procedure: To a flask that was charged with the benzyl alcohol (10 mmol), triethylamine (20 mmol) in THF (25 mL) cooled at 0 °C, was added mesyl chloride (20 mmol) in THF (50 mL) over half an hour. Then the mixture was allowed to stir at room temperature for about 20-30 min. Cold water was added to the mixture, then the mixture was extracted with diethyl ether (125 mLx1). Triethylamine (5 mol) was added into the crude product solution to remove the unreacted mesyl chloride. Then the solution was washed with saturated aqueous NaHCO3 (10 mL), cold water (25 mL) and brine (25 mL). The solution was dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure gave the benzyl mesylate products, which are used in the coupling reaction without further purification. |
71% | With triethylamine In dichloromethane at 20℃; for 3.5h; | |
71% | With triethylamine In dichloromethane | Mesylatioon Procedure 3-Phenylprop-2-ynyl Methylsulfonate Mesylatioon Procedure To a solution of 3-phenyl-2-propyn-1-ol (100 g, 0.757 mole) and Et3N (158 mL, 1.13 mole) in 3 liters of dry CH2Cl2 chilled to 5° C. was added methanesulfonyl chloride (59 mL, 0.757 mole) via an addition funnel, maintaining the internal temperature about 5° C. (addition complete after approximately 45 minutes). After one hour at 5° C., TLC indicated most of starting material was consumed. One mL of methanesulfonyl chloride was added, and the reaction mixture stirred for an additional 30 minutes at 5° C. TLC indicated complete consumption of starting material. The mixture then was washed with 1N HCl (3*250 mL), dried (Na2SO4), and concentrated to yield 113 g of Intermediate 90 as a yellow liquid (71%). 1H NMR (400 MHz, CDCl3) δ: 7.48-7.45 (m, 2H), 7.39-7.34 (m, 3H), 5.09 (s, 2H), 3.16 (s, 3H). |
67% | With triethylamine In dichloromethane at 0 - 20℃; | |
With triethylamine In diethyl ether | ||
With triethylamine In dichloromethane for 0.25h; | ||
In dichloromethane; triethylamine at 0℃; for 0.5h; | ||
With triethylamine In dichloromethane for 0.5h; | ||
With triethylamine In tetrahydrofuran for 1.5h; Ambient temperature; | ||
With triethylamine In diethyl ether at 20℃; for 12h; | ||
With triethylamine In dichloromethane at 20℃; for 0.5h; | ||
With triethylamine In dichloromethane at -50 - 0℃; | ||
With triethylamine In diethyl ether at 0℃; for 1h; | ||
With triethylamine In diethyl ether | ||
With triethylamine In diethyl ether at 0 - 20℃; for 1.5h; | ||
With triethylamine In dichloromethane | ||
With triethylamine In dichloromethane at 0℃; | ||
With triethylamine In dichloromethane at 0℃; Inert atmosphere; | ||
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | Preparation of allenoic acids 9a - 9i and 11 General procedure: Step 2. To a solution of the individual propargylic alcohol 13a - 13i (1 equiv.) and triethylamine (2 - 2.5 equiv.) in CH2Cl2 (0.2 M) (or THF (0.1 M) for 3-(4-methoxyphenyl)prop-2-yn-1-ol and 3-(4-nitrophenyl)prop-2-yn-1-ol) was added methanesulfonyl chloride (1.5 - 1.75 equiv.) dropwise at 0 °C under Ar. The resulting reaction mixture was stirred at 0 °C to ambient temperature. After completion, sat. aq.NaHCO3 was added to the reaction mixture and the aqueous layer was extracted with EtOAc (3x50 mL). The combined organic extracts were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo to afford the mesylate. The crude products 14a -14i were either used in the next step without any further purification if sufficiently pure according to NMR, or purified by flash column chromatography on silica if needed. | |
With triethylamine In dichloromethane | ||
With triethylamine In dichloromethane at 0 - 20℃; | H.2.A Example H2:; (3-Chloro-4-{4-[2-(2,4-dichloro-phenoxy)-ethoxymethyl]-5- phenyl-isoxazol-3-yl} -phenyl)-acetic acid. [00148] Step A: 3-Phenyl-prop-2-yn-l-ol 37 (3.0 g, 22.7 mmol) is dissolved in DCM (50 mL). The solution is cooled to 0°C, then methanesulfonyl chloride (4.5 mL, 34.1 mmol) and triethyl amine (4.7mL, 34.1 mmol) is added. The mixture is allowed to warm to room temperature and stirred overnight at room temperature. The mixture is washed with H20 (2x30 mL). The organic layer is dried (MgS04), filtered, and concentrated to afford crude methanesulfonic acid 3-phenyl-prop-2-ynyl ester 38 as a clear oil: 'H-NMR (400 MHz, CDC13) 8 = 7.47-7.32 (m, 5H), 4.38 (s, 2H), 3.67 (s, 3H). | |
With triethylamine In tetrahydrofuran at -40℃; for 1h; Inert atmosphere; | ||
With triethylamine In tetrahydrofuran at 0℃; for 0.0833333h; | ||
With triethylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; Schlenk technique; | ||
With triethylamine In dichloromethane at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium hydroxide In diethyl ether at 0℃; for 1h; | |
84% | With trimethylamine hydrochloride; potassium carbonate In dichloromethane at 0 - 5℃; | |
84% | Stage #1: 3-Phenyl-2-propyn-1-ol With n-butyllithium In tetrahydrofuran; hexane at -78℃; Stage #2: p-toluenesulfonyl chloride In tetrahydrofuran; hexane at -80℃; for 48h; |
67% | With potassium hydroxide Inert atmosphere; | |
58% | With potassium hydroxide In diethyl ether at 20℃; for 1.5h; | |
42% | With triethylamine In tetrahydrofuran at -10 - 0℃; for 1.5h; | 2 Production Example 2 Synthesis of 4-methylbenzene sulfonic acid 3-phenylprop-2-yn-1-yl Production Example 2 Synthesis of 4-methylbenzene sulfonic acid 3-phenylprop-2-yn-1-yl (0055) (0056) 8.0 g (39.2 mmol) of iodobenzene was dissolved in 50 mL of tetrahydrofuran, and 7.93 g (78.4 mmol) of triethylamine, 566 mg (0.784 mmol) of bis(triphenylphosphine)palladium(II) dichloride and 519 mg (2.74 mmol) of copper(I) iodide were added thereto while cooling in an ice bath, followed by stirring for 30 minutes. To the resultant solution, 10 mL of a solution of 2.20 g (39.2 mmol) of propargyl alcohol in tetrahydrofuran was added using a dropping funnel, followed by heating to room temperature, and the resultant solution was stirred for 30 minutes and passed through a short column (silica gel 64-210 μm diameter, 1.5 cm inner diameter×25 cm height) thereby terminating the reaction. The obtained solution was washed three times with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated thereby obtaining 6.29 g of a brownish oily substance. The oily substance was subjected to silica gel column chromatography (289 g, 2.1 cm inner diameter×40 cm length) using hexane-ethyl acetate (0-20-100%, step gradient) as an eluent thereby obtaining 3-phenylprop-2-yn-1-ol (a brownish oily substance, 4.56 g) (yield 88%). 4.00 g (30.3 mmol) of 3-phenylprop-2-yn-1-ol was dissolved in 8 mL of tetrahydrofuran. To the resultant solution, 20 mL of a solution of 12.3 g (121 mmol) of triethylamine and 11.8 g (60.6 mmol) of p-toluenesulfonyl chloride in tetrahydrofuran was added under a condition of -10° C. The solution was heated to 0° C. and stirred for 90 minutes, and subsequently the reaction solution was added to a separatory funnel containing 400 mL of ethyl acetate. 20 mL of 1M hydrochloric acid was added thereto, and the separatory funnel was shaken thoroughly to remove triethylamine. The same operation was repeated again and the solution was washed four times with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated thereby obtaining 10.0 g of a brownish oily substance. (0057) The oily substance was subjected to silica gel column chromatography (995 g, 4.1 cm inner diameter×38 cm length) using hexane-ethyl acetate (0-10%, step gradient) as an eluent thereby obtaining 3.60 g (yield 42%) of the titled compound. (0058) 1H NMR (270 MHz, CDCl3):δ 2.39 (3H, s), 4.95 (2H, s), 7.24-7.37 (7H, m), 7.85 (2H, m) |
With potassium hydroxide In ice-water; diethyl ether | 5.1 Toluene-4-sulfonic acid (3-phenyl-2-propyn-1-yl) ester Example 5.001 Toluene-4-sulfonic acid (3-phenyl-2-propyn-1-yl) ester 25 g of 3-phenyl-2-propyn-1-ol and 40 g of toluene-4-sulfonic acid chloride are dissolved in 500 ml of diethyl ether and cooled to -20° C. 26.6 g of finely powdered potassium hydroxide are added in portions to that solution, over a period of 20 minutes, in such a manner that the internal temperature of the reaction mixture does not exceed -5° C. When the addition is complete, the reaction mixture is stirred for 2 hours at from 0 to 5° C. and then introduced into one litre of ice-water. Extraction is carried out twice using one litre of diethyl ether each time. The organic phases are washed once with 500 ml of saturated sodium chloride solution, combined, dried over sodium sulfate and concentrated, yielding toluene-4-sulfonic acid (3-phenyl-2-propyn-1-yl) ester in the form of a colourless resin. | |
With potassium hydroxide In diethyl ether at 0℃; for 0.5h; | ||
With potassium hydroxide In dichloromethane at 0℃; for 1h; | ||
With potassium hydroxide In diethyl ether at 0℃; for 0.5h; | ||
With potassium hydroxide In diethyl ether | 2 3-Phenyl-2-propynyl-tosylate EXAMPLE 2 STR15 3-Phenyl-2-propynyl-tosylate To a cooled solution of 3-phenyl-2-propyn-1-ol (5.0 g, 38 mmol) and 4-toluenesulfonyl chloride (8.62 g, 45 mmol) in Et2 O (200 mL) was added powdered KOH (10.66 g, 190 mmol), in portions, over 20 minutes. The reaction was stirred at 0° C. for 5 hours, and was then poured into ice water. The layers were separated, the aqueous layer extracted twice with Et2 O, and the combined organics dried (MgSO4). The solvent was removed under reduced pressure, and the solid residue was triturated with hot hexanes. A white solid was filtered, washed with hexanes, and dried to give 3-phenyl-2-propynyl-1-tosylate, 8.32 g, 76%, mp 76°-78° C. Anal. Calc. for C16 H14 SO3: C, 67.11; H, 4.93; S, 11.20. Found: C, 67.15; H, 4.93; S, 10.96. MS (m/e, relative intensity): 286 (M+, 2), 131 (M-SO2 Tol, 39), 115 (M--OSO2 Tol, 100); 1 H-NMR (CDCl3): δ2.39 (s, 3H), 4.95 (s, 2H), 7.23-7.35 (m, 7H), 7.85 (dd, J=1.7, 6.5 Hz, 2H). | |
With potassium hydroxide In ethanol at 0℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With water monomer; 1,3-dibromo-1,3,5-triazinane-2,4,6-trione In acetonitrile for 0.166667h; | |
73% | With hydrogenchloride; N-Bromosuccinimide In 1,4-dioxane; water monomer at 20℃; for 5h; | Representative procedure: 2,2-dichlorooxygenation of alkynol 1a General procedure: A solution of alkynol 1a (95.8 mg, 0.725 mmol, 1.0 equiv) in 3.6 mL of 1,4-dioxane was addedwith NCS (193.3 mg, 1.448 mmol, 2.0 equiv) and 1 M aqueous HCl (0.38 mL, 0.38 mmol, 0.5equiv). The resulted solution was allowed to stir at room temperature until the reaction was judgedcomplete by TLC (typically 5 h). Upon completion, the reaction mixture was diluted with water.The separated aqueous phase was extracted with 3xEtOAc. The combined organic phases werewashed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered and concentrated toa crude material. The crude material was purified by SiO2 column chromatography eluting 10%EtOAc-hexane to give the corresponding 2,2-dichloroketone 2a-Cl as a yellow oil (117.2 mg,74%); |
With N-Bromosuccinimide In acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With silica gel; 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium perchlorate In dichloromethane | |
99% | With copper diacetate; 2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate In toluene at 50℃; | |
98% | With 1-methyl-1H-imidazole; [2,2]bipyridinyl; tetrakis(actonitrile)copper(I) hexafluorophosphate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In acetonitrile at 20℃; for 2h; |
98% | With 1-methyl-1H-imidazole; [2,2]bipyridinyl; 2,2,6,6-tetramethyl-piperidine-N-oxyl; tetrakis(acetonitrile)copper(I) trifluoromethanesulfonate; oxygen In acetonitrile at 100℃; for 0.0166667h; | |
95% | With oxygen; 2,3-dicyano-5,6-dichloro-p-benzoquinone; sodium nitrite In dichloromethane; acetic acid at 20℃; for 20h; | |
94% | With C23H35N3O3(1+)*Br(1-); copper In chlorobenzene at 80℃; for 15h; | |
93% | With chromium (VI) oxide In toluene at 75℃; Fixed-bed flow reactor; Inductive heating; | |
93% | With chromium (VI) oxide In toluene at 75℃; | A.3 EXAMPLESThe following examples exemplify oxidation reactions on a laboratory scale that were carried out with the inventive process in a flow-through reactor. The present invention is of course not limited to these.Glass tubes with a length of 12 cm and an internal diameter of 8.5 mm were used as the tubular reactor. The tubes were provided with screw connections on both ends so as to be able to attach the HPLC and suitable tubing. After having filled the reactor, the free internal volume for the fluid was 4 ml. For experiments under pressure (example group B and example 4 of the example group C), a PEEK (polyether ether ketone) reactor having the same dimensions was used and was equipped with a reaction pressure regulator. In the following reaction schemes the reactor in the inductor is indicated with the designated graphic symbol “1”.The inductor had the following performance characteristics: inductivity: 134 μHenry, winding count for the spool:=16, cross sectional area=2.8 mm2 (the cross sectional area results from the number of the conductor wires in the inductor and their diameter.) The diameter of the gap for receiving the tubular reactor was 12 mm. For all experiments the inductor was operated with a frequency of 25 kHz.In the experiments the specified frequency of 25 kHz was left constant and the heating control was undertaken solely through the PWM (PWM=on/off switch for a square wave signal at a fixed fundamental frequency). In addition, the PWM is given in ‰ and/or the achieved reaction temperatures in ° C. The induced temperature was measured with a thermocouple and an infrared thermometer. The thermocouple was mounted directly behind the reactor in the fluid so as to permit an accurate as possible measurement. However, due to the metallic components of the thermocouple, a minimum distance of 4 cm had to be observed. A laser infrared thermometer with close focus optics was used for the second temperature measurement. The measurement point had a diameter of 1 mm. With this method the surface temperature of the reactor should be measured in order to obtain a second measurement point for the temperature determination. The emission factor of the material is an important constant for an infrared measurement. It is a measure of the heat emission. An emission factor of 0.85 was used and corresponds to that of an average glass.For the example groups A and B, particles of CrO2 were employed as the oxygen carrier; they can be obtained by heating Cr(III) oxide at 300° C. in an oxygen atmosphere for 2 hours. The length and diameter of the particles were approx. 0.3 μm and approx. 0.03 μm respectively. The surface area determined by BET (nitrogen) was approx. 30 m2/g. A commercial product is available under the name MagTrieve These particles are themselves not heatable by electromagnetic induction. They were therefore employed as the heating medium in a mixture with manganese ferrite powder (reaction example A1) and in a mixture with MagSilica (each in the volume ratio 1:1) for the other reaction examples.For the example group C, particles of NiO2 (nickel peroxide) mixed with MagSilica (each in the volume ratio 1:1) as the heating medium.For each reaction the reactor, charged with the oxidizing agent and the heating medium was inserted into the inductor and connected on the inlet side with a pump, on the outlet side with a collection vessel. Initially, toluene was pumped through the reactor until constant flow conditions were obtained. The reaction temperature was then adjusted by regulating the power of the inductor. Once a constant temperature was reached the reaction solution was fed through the reactor. The reaction temperatures and the flow rates as well as the isolated yields are given for the individual examples (yields after distilling off the solvent under vacuum and downstream processing of the residue by flash chromatography (SiO2, ethyl acetate/petroleum ether). The products were identified from their 1H nuclear magnetic resonance spectra and further analytical literature data. The listed yields were each obtained with a single pass of the reactants.Reaction Examples Group A:The starting products were introduced as a solution in toluene (0.15 molar). Comparative: For preparing the target products in the batch process, the following yields were obtained: Product 3: 46% after 7 hours, Product 5: 95% after 22 hours, Product 7: 62% after 7 hours, Product 9: 95% after 7 hours. Furthermore, the downstream processing (product separation from the heating medium and oxidizing agent) in the inventive process is considerably easier, as the filtration and washing steps are obviated. This applies to all reaction examples. |
92% | With [bis(acetoxy)iodo]benzene; magnesium sulfate In 1,2-dichloro-ethane at 45℃; for 4h; chemoselective reaction; | |
91% | With manganese(IV) oxide In dichloromethane at 20℃; | |
90% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione | |
89% | With Iron(III) nitrate nonahydrate; oxygen; 2,3-dicyano-5,6-dichloro-p-benzoquinone In 1,2-dichloro-ethane at 60℃; for 3h; Schlenk technique; Green chemistry; | |
89% | With Burgess Reagent; dimethyl sulfoxide at 20℃; for 0.0833333h; Schlenk technique; Inert atmosphere; | |
86% | With Iron(III) nitrate nonahydrate; 2,2,6,6-tetramethyl-piperidine-N-oxyl; oxygen; sodium chloride In 1,2-dichloro-ethane at 25℃; for 4h; | |
86% | With fluorosulfonyl fluoride; potassium carbonate; dimethyl sulfoxide at 20℃; for 12h; chemoselective reaction; | |
85% | With calcium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen In acetonitrile at 0 - 20℃; for 3h; | |
85% | With 1-methyl-1H-imidazole; tetrakis(acetonitrile)copper(I) trifluoromethanesulfonate; 4,4'-Dimethoxy-2,2'-bipyridin; 9-azabicyclo[3.3.1]nonane N-oxyl; oxygen In acetonitrile at 20℃; for 1h; | |
85% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate In dichloromethane; water at 20℃; for 3h; Green chemistry; chemoselective reaction; | The procedure for the oxidation of benzyl alcohol is as follows: General procedure: A mixture of H2O (5 mL) and CH2Cl2 (5 mL) wasadded to the chlorinated polymeric beads (2 g). (The unchlorinated beads were obtained from HaloSource, Inc. The unchlorinated beads were chlorinated by soaking the beads in bleach solution, with pH adjusted to 7 by additionof AcOH, for an hour. Then, the chlorinated beads were filtered and dried in air.) After addition of TEMPO (10 mg,0.064 mmol) and benzyl alcohol (0.2 g, 1.8 mmol), NaHCO3(0.5 g) was added to the mixture. The mixture was stirred at r.t. for 3 h and filtered. The residue on the filter paper was washed with H2O (20 mL) and CH2Cl2 (10 mL), and the organic phase of the filtrate was separated, dried over MgSO4, and filtered. The solvent was removed under vacuum to obtain benzaldehyde. |
85% | With potassium osmate(VI) dihydrate; potassium carbonate; potassium hexacyanoferrate(III) In water; acetonitrile at 60℃; for 3h; chemoselective reaction; | |
84.5% | With sodium hydrogencarbonate; Dess-Martin periodane In 1,2-dichloro-ethane at 20℃; for 5.5h; | |
83% | With 1,3,5,7-tetrakis-(4-(diacetoxyiodo)phenyl)adamantane; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In dichloromethane at 20℃; | |
83% | With silica gel; N-(2,2,6,6-tetramethyl-1-oxopiperidin-1-ium-4-yl)acetamide tetrafluoroborate In dichloromethane at 20℃; for 24h; Sealed tube; | |
83% | With 1-methyl-1H-imidazole; copper(l) iodide; C20H25N4O2 In acetonitrile at 25℃; for 4h; | |
81% | With dmap; copper(l) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen In acetonitrile at 20℃; for 6h; chemoselective reaction; | |
81% | With Iron(III) nitrate nonahydrate; tempol; sodium chloride In 1,2-dichloro-ethane at 25℃; for 7h; chemoselective reaction; | |
81% | With Iron(III) nitrate nonahydrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; sodium chloride | |
80% | With triethylamine at 60℃; for 24h; | Catalytic Oxidation of 3-phenyl-2-propyn-1-ol.Complex 8 (4.1 mg, 0.010 mmol), NEt3 (7 μL, 0.05 mmol), 3-phenyl-2-propyn-1-ol (69 mg, 0.52 mmol), and a 1,3,5-tri-tert-butylbenzene internal standard (13 mg, 0.051 mmol) were dissolved in 1,2-dichloroethane-d4 (1 mL). An initial 1H NMR spectrum was recorded, and then the reaction mixture heated at 60° C. for 24 h under air with stirring in a 100 mL roundbottom flask equipped with an air condenser. The reaction mixture was cooled to room temperature, and then the mixture transferred to an NMR tube. Examination of the 1H spectrum revealed the formation of 3-phenyl-2-propyn-1-al in 80% yield. 1H NMR (400 MHz, 1,2-dichloroethane-d4) δ 9.42 (s, 1H), 7.63 (d, 2H, J=7.6 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.43 (t, 2H, J=7.6 Hz). 13C{1H} NMR (100 MHz, 1,2-dichloroethane-d4): δ 176.8, 133.4, 131.5, 129.0, 119.6, 94.4, 88.6.6. |
79% | With 2-azaadamantane-N-oxyl; oxygen In aq. acetate buffer at 20℃; for 6h; Green chemistry; Enzymatic reaction; chemoselective reaction; | |
75% | With tert.-butylhydroperoxide; [2,2]bipyridinyl In dichloromethane; water at 20℃; | |
73% | With oxygen; acetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone; sodium nitrite In dichloromethane at 20℃; for 10h; Sealed tube; | |
73% | With oxygen; 2,3-dicyano-5,6-dichloro-p-benzoquinone; sodium nitrite In dichloromethane; acetic acid at 20℃; for 10h; Sealed tube; | |
73% | With oxygen; acetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone; sodium nitrite In dichloromethane at 20℃; for 12h; | |
72% | With pyridinium chlorochromate In dichloromethane at 0℃; for 1h; | |
71% | With acetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone; sodium nitrite In dichloromethane for 10h; | |
71% | With 2-Picolinic acid; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; manganese (II) nitrate tetrahydrate; oxygen; acetic acid at 15℃; for 3h; | |
71% | With 2-Picolinic acid; sodium nitrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; manganese (II) nitrate tetrahydrate; oxygen; acetic acid at 16℃; for 3h; | |
68% | With acetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone; sodium nitrite In dichloromethane at 21℃; for 22h; Inert atmosphere; | |
62% | With tert.-butylhydroperoxide; [copper(II)(salqu)] In decane; acetonitrile at 70℃; for 5h; | |
52% | With 2,3-dicyano-5,6-dichloro-p-benzoquinone In fluorobenzene for 2h; Heating; | |
51% | With copper(l) iodide; oxygen; N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)ethane-1,2-diamine In acetonitrile at 25℃; for 24h; Inert atmosphere; | 2.3. Typical procedure for oxidation of alcohols General procedure: The copper salt and the ligand (each 0.025 mmol) were added to CH3CN (1 mL) in an Ar atmosphere and stirred for 30min. Then 4-OH-TEMPO (0.025 mmol) and substrate (0.5mmol) were added successively, and the mixture was stirred at room temperature. The reaction progress was checked using thin-layer chromatography. The reaction conversion and yield were obtained from GC measurements using nitrobenzene or nonane as an internal standard, or by column chromatography. |
40% | With manganese(II) triflate; 1-Adamantanecarboxylic acid; C32H38N4O2; dihydrogen peroxide In water; acetonitrile at 0℃; for 2h; chemoselective reaction; | |
39% | With 1-methyl-1H-imidazole; [2,2]bipyridinyl; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; tetrakis(acetonitrile)copper(I) trifluoromethanesulfonate; sodium chloride In neat (no solvent) Milling; Green chemistry; | General procedure to prepare carbonyl compounds 2a-v. General procedure: 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO, 9.4 mg,0.06 mmol, 3 mol %), 2,2′-bipyridyl (9,4 mg, 0.06 mmol,3 mol %), [Cu(CN)4]OTf (22.6 mg, 0.06 mmol, 3 mol %) and1-methylimidazole (NMI, 11.5 mg, 11.2 μL, 0.14 mmol,7 mol %) were placed in a zirconia-milling beaker (45 mL)equipped with four balls (two balls × 5 mm , two balls ×12 mm ) of the same material. The jar was sealed and ballmilled for 1 min. Then, benzyl alcohol (216.3 mg, 207 μL,2.0 mmol), NaCl (1.0 g) together with other two zirconia balls(12 mm ) were added and the reaction mixture was subjectedto grinding for further 10 minutes overall (two cycles of5 minutes each). The first milling cycle was followed by a breakof 2 min leaving in the meantime the uncovered jar in open air.The progress of the reaction was monitored by TLC analysis(heptane/AcOEt 9:1 v/v) and GC-MS analysis on an aliquot ofthe crude. Upon completion of the ball milling process, the jarwas opened, the milling balls were removed and the resultingcrude product (adsorbed on NaCl) was then easily transferredinto a separating funnel filled with an aqueous 10% citric acidsolution (20 mL). The aqueous phase was extracted withcyclopentyl methyl ether (or alternatively with AcOEt)(3 × 15 mL). The combined organic fractions were washed withH2O (25 mL) and brine (25 mL), then dried over Na2SO4, andconcentrated in vacuo to give benzaldehyde in high yield (195 mg, 92%) and good purity (>93% by GC analysis). Alternatively, after completion of the reaction, the resulting crudeproduct (adsorbed on NaCl) can be also easily purified by ashort column chromatography on silica gel using heptane/ethylacetate (9:1 v/v) as the eluents to afford pure aldehyde 2b inhigh yield (202 mg, 95%) as a colourless liquid. |
35% | With tert.-butylhydroperoxide In dichloromethane at 20℃; for 6h; Inert atmosphere; Sealed tube; | Typical procedure for carbon nitride supported copper nanoparticles catalyzedoxidation of propargylic alcohols (Entry 3, Table 1) General procedure: 1-(Naphthalene-1-yl)-3-phenylprop-2-yn-1-ol (1j) (0.1 mmol), CuNPs-CN (10 mol%), TBHP(10 eq.) and DCM (1 mL) were added into a 10-mL sealed tube in air. The mixture wasstirred at 40 oC for 2 hours. Then, the reaction mixture was purified by flash columnchromatography on silica gel (hexanes/EtOAc 15:1). |
With pyridinium chlorochromate In dichloromethane for 1.5h; Ambient temperature; | ||
With manganese(IV) oxide In dichloromethane at 20℃; | ||
With poly[4-(diacetoxyiodo)styrene]; 2,2,6,6-tetramethyl-piperidine-N-oxyl In acetone at 20℃; for 4h; | ||
With pyridinium chlorochromate In dichloromethane at 0 - 20℃; for 3h; | ||
With manganese(IV) oxide In tetrahydrofuran at 20℃; for 24h; | ||
90 % Chromat. | With tert.-butylhydroperoxide; [(Me3tacn)Ru(CF3CO2)2(H2O)]CF3CO2-SiO2 In hexane at 45℃; for 16h; | |
With NBu4[O2V(O2CC2H2Ph)2]; oxygen In acetonitrile at 80℃; for 1h; Inert atmosphere; Molecular sieve; | ||
80 %Spectr. | With VO(O-i-Pr)(8-hydroxyquinolinate)2; triethylamine In 1,2-dichloroethane-d4 at 60℃; for 24h; | |
With N-(2,2,6,6-tetramethyl-1-oxopiperidin-1-ium-4-yl)acetamide tetrafluoroborate In dichloromethane at 20℃; | ||
With Dess-Martin periodane In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | ||
With manganese(IV) oxide In chloroform for 5h; Inert atmosphere; Reflux; | ||
> 99 %Chromat. | With 1-methyl-1H-imidazole; [2,2]bipyridinyl; 2,2,6,6-tetramethyl-piperidine-N-oxyl; tetrakis(acetonitrile)copper(I) trifluoromethanesulfonate; oxygen In acetonitrile at 100℃; for 0.0833333h; Inert atmosphere; Flow reactor; | |
With manganese(IV) oxide In dichloromethane at 20℃; | ||
With manganese(IV) oxide In dichloromethane at 20℃; Inert atmosphere; Schlenk technique; | ||
With manganese(IV) oxide In dichloromethane at 20℃; Inert atmosphere; | ||
With Arabidopsis thaliana berberine bridge enzyme-like protein 15 L182V; oxygen In dimethyl sulfoxide at 30℃; for 24h; Enzymatic reaction; | 2.4. Substrate screening General procedure: Reactions were carried out in 50 mM MES buffer pH 7.0 in the presence of 20% (v/v) DMSO. A total volume of 2 mL reaction mixture was incubated in 11 mL glass test tube with screw cap (Pyrex,Darmstadt, Germany) at 30 C in an orbital shaker at 110 rpm. The reaction was started by the addition of 10 L enzyme to achieve a final enzyme concentration of 1.2 M. After 24 h the reaction mixture was extracted with ethyl acetate (2 1 mL), the combined organic phase was dried with Na2SO4 and subjected to GC analysis to identify putative products. | |
With [1-methyl-3-butylimidazolium][AuCl4] encapsulated in zeolitic imidazolate framework - 8-6.25%-900 In toluene at 130℃; for 96h; Schlenk technique; | 2.3. Catalytic reactions General procedure: In a typical run, alcohol (0.05 mmol), toluene (1 mL), and [Bmim][AuCl4] (at) ZIF-8-x-T (10 mol Au% based on alcohols) were added to a 25 mL Schlenk tube. The reaction mixture was stirred at 130 °C under atmospheric air. After reaction, qualitative analyses of the reaction mixtures were performed on a GC-MS spectrometer (Agilent, 7890BGC/5977 A MS) equipped with a HP-5 MS capillary column (0.25mm×30 m). | |
With manganese(IV) oxide In dichloromethane | ||
With manganese(IV) oxide In dichloromethane at 20℃; for 18h; | ||
> 99 %Chromat. | With 1-methyl-1H-imidazole; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; C23H16CuF5N2O5S In acetonitrile at 20℃; for 24h; | 2.3. Oxidations General procedure: A series of catalytic oxidation reactions was performed in 5 ml/3 mlMeCN solutions at room temperature under open air. The reaction wasset up by adding 1 mmol of 1-octanol, 5 mol % of copper(I)catalyst,5 mol % of TEMPO and 10 mol % of NMI into a 20 ml test tube, whichwas equipped with a magnetic stirrer bar. The reaction was stirred1500 rpm for 24 h for 1-octanol, 3 h for cinnamyl alcohol and 3-phenyl-1-propanol and 1 h for benzyl alcohol. After the reaction, 0.7 ml of thereaction solution and an internal standard (acetophenon 40 μl or 1,2-dichlorobenzene 40 μl, more information see ESI) were diluted withEtOAc (100 ml). GC samples (1.5 ml) were prepared by filtrating thesolution through a layer of silica gel (1 cm thick). The yields were determinedusing GC-MS with calibration curves. |
With manganese(IV) oxide In dichloromethane at 20℃; for 16h; | ||
89 %Spectr. | With 1-methyl-1H-imidazole; [2,2]bipyridinyl; 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy; copper(I) bromide In acetonitrile at 20℃; for 2h; | General Procedure for Alcohol Oxidation: 1-Adamantanecarbaldehyde (2j) General procedure: To a solution of 1-adamantanemethanol (1j) (66.5 mg, 0.400 mmol), 1-Me-AZADO (1.99 mg, 12.0 μmol), bpy (1.87 mg, 12.0 μmol), and DMAP (2.93 mg, 24.0 μmol) in MeCN (2.0 mL) was added CuOTf·1/2benzene (6.04 mg, 24.0 μmol) at room temperature. The mixture was stirred at the same temperature under ambient air for 3 h. The reaction was quenched with sat. aq. NaHCO3 and the mixture extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, and evaporated. The crude product was purified by flash column chromatography (AcOEt/hexane = 0/100 to 1/100) to afford 1-adamantanecarbaldehyde (2j) (61.0 mg, 0.371 mmol, 92%) as a colorless solid. |
98 %Chromat. | With 1-methyl-1H-imidazole; copper(l) iodide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; C12H8F3NOS In acetonitrile at 20℃; for 24h; | 2.3. Oxidations General procedure: Oxidation reactions were performed in 3 ml or 5 ml MeCN solutionsat room temperature under open air conditions. The reaction was set upby adding 4 mol% of copper(I)iodine, 4 mol% of ligand, solvent, 5 mol%of TEMPO, 1 mmol of alcohol and 10 mol% of NMI into a 20 ml test tube,which was equipped with a magnetic stir bar. The reaction was stirred at 1500 rpm for 1 h, 3 h or 24 h depending on the substrate.After the reaction, the reaction solution and an internal standard(acetophenone 40 μL or 1,2-dichlorobenzene 40 μL, see ESI for moreinformation) were diluted with EtOAc (50 mL). GC samples (1.5 mL)were prepared by filtrating the solution through a layer of silica gel (1cm thick). The yields were determined using GC-FID with calibration curves and identified using GC-MS and/or 1H/13C/HMBC/HSQC NMR. |
With pyridinium chlorochromate In dichloromethane at 20℃; for 1h; Inert atmosphere; | ||
With Dess-Martin periodane In dichloromethane at 0℃; | ||
With manganese(IV) oxide In dichloromethane at 0 - 20℃; for 5h; | ||
98 %Chromat. | With copper(l) iodide; di(pyridin-2-yl)amine; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In acetonitrile at 20℃; for 24h; | Oxidations General procedure: Oxidation reactions were performed in 3 mL MeCN or in a mixture of2 mL MeCN and 1 mL H2O solutions at room temperature under open airconditions. The reaction was set up by adding 2.5 mol% of copper(I)iodine, 2.5 mol% of ligand, 3 mL solvent, 4 mol% of TEMPO and 1 mmol of alcohol into a 20 ml test tube, which was equipped with a magneticstir bar. The reaction was stirred at 1500 rpm for 1 h, 3 h or 24 h depending on the substrate. After the reaction, the reaction solution andan internal standard (acetophenone 40 μL or 1,2-dichlorobenzene 40 μL,see ESI for more information) were diluted with EtOAc (50 mL). GCsamples (1.5 mL) were prepared by filtrating the solution through alayer of silica gel (1 cm thick). The yields were determined using GC-FIDwith calibration curves and identified using GC-MS and/or 1H/13C/HMBC/HSQC NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triphenylphosphine; diethylazodicarboxylate In benzene at 20℃; for 1h; | |
78% | Stage #1: 3-Phenyl-2-propyn-1-ol With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: tiolacetic acid In tetrahydrofuran at 0 - 20℃; for 24h; Inert atmosphere; | (3-Methylbut-2-en-1-yl)(3-phenylprop-2-yn-1-yl)sulfane (3c) and (2-Methylallyl)(3-phenylprop-2-yn-1-yl)sulfane (3d) DIAD (1.1 equiv, 11 mmol, 2.3 mL) was added dropwise to a stirred solution of 3-phenylprop-2-yn-1-ol (10 mmol, 1.30 g, 1.25 mL) and PPh3 (1.1 equiv, 11 mmol, 2.9 g) in anhyd THF (0.2 M) at 0 °C under argon. After the mixture had stirred for 10 min at 0 °C, thioacetic acid (1 equiv, 11 mmol, 837 mg, 775 mL) was added dropwise and the resulting reaction mixture was stirred at r.t. for 24 h. The solvent and volatiles were removed in vacuo. The crude reaction mixture was triturated with hexanes (20 mL) and the precipitate filtered off. The crude product was purified by flash chromatography (silica gel; petroleum benzine/Et2O, 90:10) to afford S-(3-phenylprop-2-yn-1-yl) ethanethioate;18d yield: 1.50 g (78%); orange oil. |
With triphenylphosphine; diethylazodicarboxylate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 23℃; for 6h; stereoselective reaction; | 4.4.1. (E)-(3-Iodoprop-1-en-1-yl)benzene (1a) A 50 mL oven-dried flask was charged with LiAlH4 (190 mg,5 mmol) and dry THF (15 mL). The mixture was cooled to 0 C, followed by a slow addition of 11a (660 mg, 5 mmol, in 5 mL THF). The mixture was stirred at room temperature until the reaction was complete (monitored by 1H NMR). The mixture was then cooled to 0 C and carefully quenched by H2O (1.2 mL), 15% NaOH (1.2 mL)and H2O (1.2 mL) to afford a suspension, which was filtered through Celite and washed with EtOAc (30 mL x 3). The combined solution was concentrated and purified by column chromatography on silica gel (Hexane/EtOAc 3:1, v/v) to afford (E)-3-phenylprop-2-en-1-ol (12a, 636 mg, 95% yield) as a colorless oil. |
78% | Stage #1: 3-Phenyl-2-propyn-1-ol With tetrahydropyrrolo[2,1-c][1,2,4]triazole carbene; diphenylsilane In N,N-dimethyl-formamide; mineral oil at 20℃; Inert atmosphere; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Inert atmosphere; chemoselective reaction; | |
71% | With chloro(pentamethylcyclopentadienyl)ruthenium(II) tetramer; hydrogen In dichloromethane at 20℃; for 2.03333h; Schlenk technique; |
58% | With formaldehyd; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; water; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 80℃; for 5h; stereoselective reaction; | |
33% | With methanol; borane-ammonia complex; C16H29Cl2CoN2P at 50℃; for 16h; Inert atmosphere; Schlenk technique; chemoselective reaction; | |
With lithium aluminium tetrahydride In tetrahydrofuran for 3h; Heating; Yield given; | ||
With lithium aluminium tetrahydride; sodium methylate In tetrahydrofuran at 20℃; | ||
With hydrogen In d(4)-methanol at 24.84℃; | ||
Multi-step reaction with 2 steps 1: 82 percent / copper(I) cyanide / tetrahydrofuran / 2 h / 0 °C 2: NaH / hexamethylphosphoric acid triamide / 0.75 h / Ambient temperature | ||
Stage #1: 3-Phenyl-2-propyn-1-ol With Red-Al In diethyl ether at 0 - 20℃; for 1h; Stage #2: In ethyl acetate at 0℃; | ||
98 % de | With Pd3Pb/SiO2; RhSb/SiO2; hydrogen In tetrahydrofuran at 25℃; for 12h; | |
With Dimethylphenylsilane; water In dimethyl sulfoxide at 70℃; for 0.333333h; Inert atmosphere; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: 3-Phenyl-2-propyn-1-ol With lithium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: With lithium aluminium tetrahydride; cerium(III) chloride In tetrahydrofuran at -78 - -20℃; for 24h; | |
With carbon monoxide; hydrogen In tetrahydrofuran at 70℃; for 6h; Autoclave; | 2.3. General experimental procedure for synthesis of alkenes viasemi-hydrogenation of alkynes General procedure: To a 100 mL high-pressure reactor, phenylacetylene (1 mmol),Pd (0.96 mol%) in a 10 mL THF were transferred under an inertatmosphere. The reactor was flushed three times with nitrogen then pressurized with desired 150 psi of syngas, then heated at70C with constant stirring (400 rpm) for 6 h. After the comple-tion of reaction, the reactor cooled down to room temperature andthe remaining syngas was carefully depressurized. The resultantreaction mixture filtered off by simple filtration. The filtrate was then collected in sample vial and the product was extracted for fur-ther analysis such as GC, GC-MS,1H &13C NMR and matched with those of authentic data. Selective experiments were performed in triplicate and it was observed that results showed variation of ±2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen In tetrahydrofuran at 20℃; for 0.0833333h; | 6 In Example 6, hydrogenation reaction was conducted under the same condition as Example 1 for THF diluted solution concentration of the substance to be reduced, its flow rate, and hydrogen 9 flow rate, using 3-phenyl-2-propin-1-ol as the substance to be reduced. The reaction time was within five minutes. The analytical result of the reaction product by 1H-NMR showed almost complete hydrogenation of 3-phenyl-2-propin-1-ol, and 3-phenyl-1-propanol was obtained at about 100 % yield (See Fig. 6.). |
97% | With N-tert-butylaminoborane In methanol at 20℃; for 9h; | |
93% | With hydrogen In tetrahydrofuran at 20℃; for 1h; |
91% | With carbon dioxide; hydrogen at 60℃; | |
88% | With methanol; palladium diacetate; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In dichloromethane at 25℃; for 12h; Schlenk technique; Inert atmosphere; | 59 Replace the gas environment in the Shrek tube with a nitrogen environment, add 3-phenyl-2-propyn-1-ol 0.25 mmol, palladium acetate 0.0025 mmol, methylene chloride 0.5 mL, and add pinacol borane 0.525 with stirring mmol, 0.275 mmol of methanol at room temperature for 12 h. The reaction solution obtained after the completion of the reaction was subjected to column chromatography, and the target product obtained in 88% yield was a colorless liquid. |
88% | With methanol; palladium diacetate; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In dichloromethane at 25℃; for 12h; Sealed tube; Inert atmosphere; chemoselective reaction; | |
57% | With (S)-(+)-5,5’-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4’-bi-1,3-benzodioxole; (dimethoxy)methylsilane; copper diacetate; isopropyl alcohol In tetrahydrofuran at 60℃; for 18h; Sealed tube; Inert atmosphere; | |
52% | With 4-methyl-morpholine; tetrahydroxydiboron; 5%-palladium/activated carbon In 1,2-dichloro-ethane at 50℃; for 24h; | |
96 % Spectr. | With hydrogen In hexane at 20℃; for 2h; | |
72 % Spectr. | With hydrogen In ethanol at 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In various solvent(s) at 150℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; ammonium acetate; In water; acetonitrile; at 20℃; for 0.5h; | General procedure: To a solution of alcohol (1 mmol) in MeCN-H2O (9:1, 3 mL) were successively added TEMPO (7.8 mg,5 mol%), NH4OAc (0.308 g, 4 equiv), and PhI(OAc)2 (0.708g, 2.2 equiv). The suspension was stirred at roomtemperature (progress of the reaction was monitored byTLC) for the reaction time indicated in Table 2. The resultantclear two-phase reaction mixture was concentrated, dilutedwith H2O and Et2O, and the organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure.The residue was purified by flash column chromatography(PE-Et2O or PE-CH2Cl2) to give 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 2-(((2,6-diisopropylphenyl)imino)methyl)pyridine; cobalt(II) chloride; zinc In tetrahydrofuran at 25℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; Inert atmosphere; | Synthesisof 3-[3-(naphthalene-1-yloxy)prop-1-yn-1-yl]pyridine General procedure: Mitsunobu reaction of α-naphthol 12 (500 mg, 3.468 mmol) with 3-(pyridin-3-yl)prop-2-yn-1-ol (462 mg, 3.468 mmol) in the presence of triphenylphosphane (1.09 mg, 4.155 mmol) and DEAD (725 mg, 4.163 mmol) as described above gave 818 mg (91%) of the product as a colorless oil; |
50% | With triphenylphosphine; diethylazodicarboxylate In benzene at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 97% 2: 3% | With hydrogen In dichloromethane at 25℃; for 3h; | |
80% | With hydrogen In tetrahydrofuran at 50℃; for 16h; Autoclave; Glovebox; stereoselective reaction; | |
1: 94.7 % de 2: 21% | With hydrogen In methanol at 20℃; for 0.0194444h; Inert atmosphere; Schlenk technique; Green chemistry; | 2.3 Catalytic reactions under continuous flow General procedure: In a typical experiment, a deaereated solution of alkyne in methanol (0.1M) was allowed to flow through the PdMonoBor column catalyst (29mg, reactor volume 176 μL) at 0.2mLmin-1 together with a H2 flow of 1.3mLmin-1 at r.t. This resulted in a H2 pressure at the reactor inlet of ca. 1.2bar (corresponding to a H2/alkyne molar ratio of ca. 2.8), while the hydrogen gas was released at atmospheric pressure at the outlet of the reactor. Therefore, the pressure drop generated by monolithic reactor was ca. 0.2bar. The attainment of the steady-state conditions (ca. 1h) was taken as the reaction start time. The reaction was typically monitored for 14h time-on-stream by periodically analyzing the product solution for conversion and selectivity by GC, while 5.0mL aliquots were sampled at 1h intervals for Pd leaching determination by ICP-OES. The amount of Pd in solution was below the detection limit in each sample (0.006ppm). |
1: 74 % Spectr. 2: 9 % Spectr. | With hydrogen In tetrahydrofuran at 20℃; for 0.333333h; Title compound not separated from byproducts; | |
With hydrogen In tetrahydrofuran at 50℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 20℃; for 0.25h; | |
78% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 0 - 20℃; | |
72% | Stage #1: 3-Phenyl-2-propyn-1-ol With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 10℃; for 0.166667h; Stage #2: trichloroacetonitrile at 0℃; for 0.166667h; Reflux; | 12.3 3. Procedure for the preparation of 40a 3. Procedure for the preparation of 40a To a solution of 3-phenylprop-2-yn-l-ol (1.00 g, 7.57 mmol) in DCM (20 mL) was added DBU (1 15 mg, 0.757 mmol) and the mixture was stirred at RT for 10 min then cooled to 0°C. Trichloroacetonitrile (2.20 g, 15.1 mmol) was added and the mixture was then heated at reflux for 10 min, TLC (PE:EA=10: 1) showed that the starting material was consumed. The mixture was concentrated in vacuo and the residue was purified by chromatography (PE:EA=1 :0 to 20:1) to give 40a (1.50 g, 72%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 92% 2: 8% | With hydrogen In dichloromethane at 25℃; for 3h; | |
With 1,1'-bis(diphenylphosphino)ferrocene; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; Butane-1,4-diol; potassium <i>tert</i>-butylate at 110℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With diphenyl phosphoryl azide; triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | |
85% | With triphenylphosphine; 2-Acetyl-1-azido-1,2-dihydro-1λ3-benzo[d][1,2]iodazol-3-one In tetrahydrofuran Schlenk technique; Inert atmosphere; | |
Multi-step reaction with 2 steps 1: Et3N / benzene / 1 h / 25 - 30 °C 2: NaN3 / dimethylsulfoxide; benzene / 6 h / 35 - 40 °C |
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane 2: Caswell No. 744A / N,N-dimethyl-formamide | ||
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 0.08 h / 0 °C 2: Caswell No. 744A / N,N-dimethyl-formamide / 1 h / 20 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 0.08 h / 0 °C 2: Caswell No. 744A / N,N-dimethyl-formamide / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 20 - 80℃; for 12h; | To a stirring mixture of 3-chloro-4-methoxyiodobenzene (0.3 g, 1.1 mmol),(PPh3)2PdCl2 (31 mg, 0.044 mmol), triethylamine (1.2 mL, 8.9 mmol) in dimethylformamide (3 mL) was added to phenylethynylcarbinol (O.29 g, 2.2 mmol) at temperature in the range of 20-400C under nitrogen atmosphere. The mixture was then stirred at 8O0C for 12 hours. After cooling the mixture to temperature in the range of20-400C it was diluted with water (15 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layers were collected, combined, washed with, water (2 x 5 mL), dried over anhydrous sodium sulphate, and concentrated to give the desired compound.1H NMR (200 MHz, DMSO-J15): δ 7.61-7.31 (m, 7H), 6.85 (d, J = 8.7 Hz, IH), 5.66 (d, J= 4.2 Hz, IH), 3.90 (s, 3H). IR (KBr, cm"1): 3377, 2226, 1598. MS: m/z (CI) 272 (M+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | SYNTHESIS EXAMPLE 24: Synthesis of 2-tert.-butyl-4-chloro-5-(3'-phenyl-2'-propynyloxy)-3(2H)-pyridazinone (Compound No. 494) To 1.3 g (0.01 mol) of 3-hydroxy-1-phenyl-1-propyne was added 50 ml of N,N-dimethylformamide, and then 0.45 g of 55% sodium hydride was added thereto at 0 C. The resulting mixture was stirred for one hour. Thereafter, 2.2 g (0.01 mol) of 2-tert.-butyl-4,5-dichloro-3(2H)-pyridazinone was added thereto at room temperature and the mixture was stirred overnight at room temperature. The resulting solution was poured into water and then extracted with benzene. The benzene layer was dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure. The crystals thus obtained were recrystallized from benzene-n-hexane to give 2.0 g of the captioned product. M.P.: 142.5~146.5 C. NMR (CDCl3, delta, TMS): 1.62 (9H, s), 5.08 (2H, s), 7.33 (5H, bs,), 7.93 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With piperidine; tetrabutylammomium bromide In water at 60℃; for 5h; | |
89% | With copper(l) iodide; sodium carbonate In water at 90℃; for 6h; | |
80% | With copper(l) iodide; sodium carbonate In N,N-dimethyl acetamide; water at 70℃; for 12h; |
72% | With potassium carbonate In ethanol at 90℃; for 7h; | 2.6. Sonogashira coupling reaction General procedure: The catalytic activity of the synthesized Pd(at)Hal-2N-TCT-EDA was investigated for promotingthe Sonogashira reaction. Pd(at)Hal-2N-TCT-EDA (10 mol%) and K2CO3 (3.0 mmol) were added to the mixture of halobenzene (1.0 mmol) and acetylene (1.2 mmol) in EtOH. The reaction mixture was then refluxed at 90 °C for appropriate reaction time(Scheme 1). The reaction was monitored by thin layer chromatography (TLC, n-hexane/ethyl acetate; 4:1). When the reaction was completed, Pd(at)Hal-2N-TCT-EDA was filtered.After that, the organic layer was extracted with diethyl ether and purified by column chromatography over silica gel by using hexane/ethyl acetate (4:1) as eluentto furnish the corresponding product. To recycle the catalyst, the recovered catalyst was washed with EtOH two times and dried in an oven at 90 °C overnight. The coupling products were characterized by comparing their melting points and 1H NMR and13C NMR spectra with authentic samples (see Supporting Information). |
45% | With potassium carbonate In ethanol; water at 60℃; for 5.45h; | |
With potassium carbonate In ethanol at 50℃; for 5.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; | |
90% | With pyridine; dmap In dichloromethane at 20℃; for 12h; | |
78% | With dmap; triethylamine In dichloromethane at 20℃; |
With dmap; triethylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | Preperation of Propargyl Esters General procedure: To the solution of 3-phenyl-2-propyn-1-ol (1.32 g, 10.0 mmol),NEt3 (7.0 mL, 50.0 mmol) and 4-(dimethylamino)pyridine (DMAP) (127.5 mg, 1.05 mmol) in methylene chloride(CH2Cl2) (50 mL) at 0°C was added pivaloyl chloride (1.35 mL,11.0 mmol) slowly under Ar and the mixure was warmed toroom temperature. After stirring for 2 h, the mixture wasquenched with water and extracted with chloroform (CHCl3).The combined extracts were washed with 1.0 M aqueoussolution of HCl and 3.0 M aqueous solution of NaOH, driedover Na2SO4 and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane/CH2Cl2=75/25) to give 11a (1.89 g, 88%) asa colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 3-Phenyl-2-propyn-1-ol With methylmagnesium chloride In tetrahydrofuran at 5 - 30℃; for 0.5h; Industry scale; Stage #2: (4-methylsulfanylphenyl)magnesium chloride In tetrahydrofuran at 18 - 70℃; for 3h; Industry scale; Stage #3: carbon dioxide; acetic anhydride With potassium hydroxide; potassium <i>tert</i>-butylate more than 3 stages; | 1.1 PREPARATIVE EXAMPLE 1 Synthesis of Common Intermediate A flask is charged with 66.6 kg of THF and the vessel inerted with nitrogen. This was followed by the addition of 19.0 kg of 3-phenyl-2-propyn-1ol and then by a 16.6 kg THF flush. The batch was then cooled to approx. 5° C. and 49.8 kg of methyl magnesium chloride (3.0 M) was added slowly over 30 min. and achieved a final batch temperature between 25 and 30° C. Then 92.2 kg of 4-thioanisole magnesium chloride was added (1.8 M) and the batch was heated to 65 to 70° C. under 2 to 10 psig back pressure. The batch was aged at this temperature for 3 h then cooled to 18° C. and vacuum pulled to 250 mmHg. Carbon dioxide (dry, 10.7 kg) was then charged slowly from a cylinder over 100 min to achieve a 5 psig pressure in the vessel. The batch was heated (30 to 35° C.) and aged further for 70 min. The vessel pressure was vented and a series of pressure purges completed to remove residual carbon dioxide in the headspace. Then 64.7 kg of potassium tert-butoxide in THF (1.0 M sol) was charged followed by a 5.0 kg THF flush. The batch was aged at 32° C. for 30 min. A sample was then taken to confirm by IR that there was no residual carbon dioxide in solution. The batch temperature was then adjusted to 23° C. and 28.6 kg of acetic anhydride was added, followed by a 10.0 kg THF flush. The batch was aged for 90 min before 303.9 kg of THF was added and the contents heated to 40° C. Then 16.1 kg of 45 wt % potassium hydroxide was added followed by a water flush (4.0 kg). The batch was aged at 40° C. for 7 h. Next 277.8 kg of an aqueous 1.4 M magnesium chloride solution was added and the batch was aged for 15 min at 40° C. Agitation was then ceased and the two layers were allowed to settle. The layers were separated and then the organic layer was concentrated to 340 L at 20° C. under a vacuum of 125 mm Hg. Then 18.1 kg of water was added and finally, 542.8 kg of isopropyl acetate was added slowly over 4 h and 30 min at 20° C. to complete the crystallization of the batch. The batch was cooled to 0° C. then filtered and washed with 175 kg of water and 195 kg of cold (0° C.) isopropyl acetate. Filtration and drying provided 53.2 kg of the desired crystalline hydrated magnesium salt product (84% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 3-Phenyl-2-propyn-1-ol With lithium aluminium tetrahydride; sodium methylate In tetrahydrofuran at 0℃; for 1h; Stage #2: carbonic acid dimethyl ester In tetrahydrofuran at 15℃; for 0.5h; Stage #3: With iodine In tetrahydrofuran at -78℃; | 7 Example 7; (Z) [4-(3,5-Diphenyl-pent-2-en-4-ynyloxy)-2-methyl-phenoxy]-acetic acid; Sodium methoxide (27 mg, 0.50 mmol) was added to a solution of 3-phenylprop-2- yn-1-ol (661 mg, 5.0 mmol; prepared according to J. Org. Chem. 1986, 51, 46) in dry tetra- hydrofuran (20 mL). The resulting solution was cooled down to 0 °C, the reaction flask was flushed with nitrogen and 1 M solution of lithium aluminum hydride in tetrahydrofuran (6 mL, 6.0 mmol) was added. The reaction mixture was stirred for 1 h under cooling in atmosphere of nitrogen; then warmed up to 15 °C and dimethyl carbonate (900 mg, 10 mmol) was added. The mixture was stirred for 30 min, cooled down to-78 °C, a solution of iodine (2.54 g, 10 mmol) in dry tetrahydrofuran (5 mL) was added and the mixture was stirred for 3 h under cooling and then was kept overnight in a refrigerator. The reaction mixture was poured into aqueous solution of sodium thiosulfate and extracted with ethyl acetate (3 x 20 mL). The combined organic solutions were filtered through a short path of silica gel, silica gel was washed ethyl acetate (20 mL) and the filtrates were dried with anhydrous sodium sulfate. Evaporation of the organic solution gave sufficiently pure crude (Z)-3-iodo-3-phenylprop-2- en-1-ol. Yield: 1.20 g (92 %). RF (Si02, hexane/ethyl acetate 75: 25) 0.55. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | |
85% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; | |
85% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; |
83% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 2℃; Inert atmosphere; | |
80% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 0.0833333h; Inert atmosphere; | Example 2-Iodophenol 1 (2.2 g, 10 mmol) and triphenylphosphine (2.62 g, 10 mmol) were added to a Shrek bottle, and 3-phenyl-2-propyn-1-ol 2 ( 1.452 g, 11 mmol), use tetrahydrofuran as solvent and stir at 0 °C for 5 minutes, add dropwise diisopropyl azodicarboxylate (2.02 g, 10 mmol), and extract with aqueous sodium bicarbonate solution and diethyl ether after reaction for 5 hours. The organic layer was suspended to dryness, and the product (3) was obtained by silica gel column chromatography with a yield of 80%. |
77% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; | |
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 2-iodobenzaldehyde With <i>tert</i>-butylamine In N,N-dimethyl-formamide Inert atmosphere; Stage #2: 3-Phenyl-2-propyn-1-ol With [Pd(η(5)-C5H5)Fe(η(5)-C5H3-C(CH3)=N-C6H4-4-CH3)Cl(P(C6H5)3)]; sodium carbonate; lithium chloride In N,N-dimethyl-formamide at 100℃; for 24h; Inert atmosphere; | 4.2. General procedure for synthesis of isoquinolines General procedure: To a solution of o-halobenzaldehyde (0.25 mmol) in DMF (1 mL), tert-butyl amine (0.75 mmol) was added. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 12 h (or 100 °C for 4 h). After the haloaldehyde was consumed completely (monitored by TLC), alkynes (0.50 mmol), Na2CO3 (0.50 mmol), LiCl (0.25 mmol), palladacycle (1 mol %), and DMF (1 mL) were added to the mixture. Then the vial was placed in a preheated oil bath and heated at 100 °C under stirring for 24 h. After the reaction was complete (monitored by TLC), the mixture was diluted with CH2Cl2 (10 mL), filtered through a pad of Celite, and extracted with CH2Cl2. The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl acetate/hexane) to afford the pure product. |
70% | With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride; triethylamine In acetonitrile at 20℃; for 12h; Inert atmosphere; Schlenk technique; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: ortho-bromobenzaldehyde With <i>tert</i>-butylamine In N,N-dimethyl-formamide Inert atmosphere; Stage #2: 3-Phenyl-2-propyn-1-ol With [Pd(η(5)-C5H5)Fe(η(5)-C5H3-C(CH3)=N-C6H4-4-CH3)Cl(P(C6H5)3)]; sodium carbonate; lithium chloride In N,N-dimethyl-formamide at 100℃; for 24h; Inert atmosphere; | 4.2. General procedure for synthesis of isoquinolines General procedure: To a solution of o-halobenzaldehyde (0.25 mmol) in DMF (1 mL), tert-butyl amine (0.75 mmol) was added. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 12 h (or 100 °C for 4 h). After the haloaldehyde was consumed completely (monitored by TLC), alkynes (0.50 mmol), Na2CO3 (0.50 mmol), LiCl (0.25 mmol), palladacycle (1 mol %), and DMF (1 mL) were added to the mixture. Then the vial was placed in a preheated oil bath and heated at 100 °C under stirring for 24 h. After the reaction was complete (monitored by TLC), the mixture was diluted with CH2Cl2 (10 mL), filtered through a pad of Celite, and extracted with CH2Cl2. The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl acetate/hexane) to afford the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 3-Phenyl-2-propyn-1-ol With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25h; Inert atmosphere; Stage #2: (2-nitroethenyl)benzene In tetrahydrofuran; hexane at -78 - 0℃; Inert atmosphere; | 5.2. β-(Allyloxy) nitroalkanes 3 (general procedure) General procedure: At -78 °C under N2, n-BuLi (0.937 mL, 1.5 mmol, 1.6 M solution in hexane) was added via syringe to a stirred solution of allylic alcohol 1 (1.5 mmol) in 10 mL dry DME or THF. After 15 min, a solution of nitroalkene 2 (1.0 mmol) in 1 mL dry DME or THF was added. The reaction mixture was warmed to 0 °C after 10 min and maintained at this temperature until complete by TLC. The reaction mixture was quenched with acetic acid (0.086 mL, 1.5 mmol), diluted with 30 mL diethyl ether, filtered through a pad of silica gel, and concentrated in vacuum. The crude oily products were purified by flash column chromatography (hexane/EtOAc 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With gold(I) chloride In nitromethane at 100℃; for 48h; regioselective reaction; | |
48% | With gold(I) chloride In 1,2-dichloro-ethane at 90℃; for 48h; Inert atmosphere; | |
48% | With sodium tetrachloroaurate(III) dihyrate In 1,2-dichloro-ethane at 90℃; for 48h; Inert atmosphere; Sealed tube; | 10 Example 10. Preparation of 2-(4-Fluorophenylthio)-3-phenylpropanal. 3-phenylprop-2-yn- l-ol (125 μ^, 1 mmol), 4-fluorobenzenethiol (160 μ^, 1.5 mmol) and the catalyst NaAuCl4-2H20 (8 mg, 2 mol%) in 1 ,2-dichloroethane solvent (2.5 mL) were treated as described for 4-Phenyl-3-(phenylthio)butane-2-one to obtain the product as a yellowish oil (125 mg, 0.48 mmol, 48% yield) at 90 °C for 48 h. IR (Neat): v = 3065, 1704, 1588, 1487, 1223, 826, 697 cm- H NMR (400 MHz, CDC13): δ = 2.98 (dd, J = 6.8 Hz, 14.4 Hz, 1 H, H-3), 3.20 (dd, J = 8.0 Hz, 14.8 Hz, 1 H, H-3), 3.74-3.78 (m, 1 H, H-2), 6.99-7.04 (m, 2 H, H-arom), 7.22-7.40 (m, 7 H, H-arom), 9.51 (d, J = 3.6 Hz, 1 H, H- l) ppm. NMR (100 MHz, CDC13): δ = 34.5, 58.8, 116.5, 116.7, 127.2, 128.9, 129.3, 136.4, 136.5, 137.4, 164.6, 193.9 ppm. HRMS: calcd. for Ci5Hi3FOSNa 283.0569; found 283.0582. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; | Synthesis of 2-[(3-phenylprop-2-yn-1-yl)oxy]naphthalene General procedure: To a stirred solution of β-naphthol 5 (500, mg,3.468 mmol), 3-phenylprop-2-yn-1-ol (458 mg, 3.468 mmol), and triphenylphosphane (1.09 g, 4.155 mmol) in tetrahydrofuran (20 ml) under nitrogen atmosphere was added diethyl azodicarboxylate (725 mg, 4.163 mmol) drop-wise and the mixture was further stirred at room temperature for 6 h. The solvent was evaporated under reduced pressure on a rotary evaporator to give a viscous residue. The residue was purified by flash silica gel column chromatography using 4% EtOAc in hexane to give 860 mg (96%) of 7a as an off-white solid; mp 95-96 °C; IR (KBr) 3045, 2230, 1625, 1596, 1466, 1379, 1256, 1214, 1181, 1118 cm-1; 1H NMR (300 MHz, CDCl3): δ 5.03 (s, 2H), 7.22-7.38 (m, 6H), 7.43-7.46 (m, 3H), 7.76-7.79 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 56.6, 83.7, 87.3, 107.4, 118.8, 122.2, 123.9, 126.4 (2C), 126.9, 127.6, 128.2, 128.6, 129.2, 129.4, 131.8 (2C), 134.3, 155.6; MS (APCI): m/z (%) 259 [MH+, 100]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap In dichloromethane at 20℃; for 27h; Schlenk technique; Inert atmosphere; | |
88% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | Preperation of Propargyl Esters To the solution of 3-phenyl-2-propyn-1-ol (1.32 g, 10.0 mmol),NEt3 (7.0 mL, 50.0 mmol) and 4-(dimethylamino)pyridine (DMAP) (127.5 mg, 1.05 mmol) in methylene chloride(CH2Cl2) (50 mL) at 0°C was added pivaloyl chloride (1.35 mL,11.0 mmol) slowly under Ar and the mixure was warmed toroom temperature. After stirring for 2 h, the mixture wasquenched with water and extracted with chloroform (CHCl3).The combined extracts were washed with 1.0 M aqueoussolution of HCl and 3.0 M aqueous solution of NaOH, driedover Na2SO4 and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane/CH2Cl2=75/25) to give 11a (1.89 g, 88%) asa colorless oil: 1H-NMR (500 MHz, CDCl3) δ: 7.47-7.44 (m,2H), 7.35-7.29 (m, 3H), 4.89 (s, 2H), 1.25 (s, 9H); 13C-NMR(126 MHz, CDCl3) δ: 177.9, 131.9, 128.7, 128.3, 122.3, 86.1,83.3, 52.8, 38.8, 27.1; IR (attenuated total reflectance (ATR))2974, 2236, 1279, 1136 cm-1; MS (FAB+) m/z=217 ([M+H]+);high resolution (HR)-MS (FAB+) Calcd for C14H17O2 [M+H]+:217.1229. Found: 217.1238. |
With dmap; triethylamine In dichloromethane at 20℃; for 2h; |
With dmap; triethylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 3h; | |
52% | With dmap; dicyclohexyl-carbodiimide In dichloromethane Inert atmosphere; | 1 Under argon, cyanoacetic acid (1.0 mmol) and the alcohol (0.8 mmol) were solubilized in 4 mL anhydrous dichloromethane and N,N′-dicyclohexylcarbodiimide (1.0 mmol) and N,N-dimethylaminopyridine (cat.) were successfully added at 0° C. After total consumption of the acid (CLC), the formed white precipitate was filtered and the filtrate evaporated in vacuum. The residue was purified on silica, (SiO2, 20% ethyl acetatecyclohexane) and the ester was obtained as a colorless oil (52%). 1H NMR (400 MHz, CDCl3): δ 7.64-7.28 (m, 5H), 5.06 (s, 2H), 3.57 (s, 2H). |
51% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; | 3-phenylprop-2-ynyl 2-cyanoacetate 8f Cyanoacetic acid 7a (85 mg, 1.0 mmol) and 3-phenylprop-2-yn-1-ol 6f (110 mg, 0.83 mmol) were dissolved in anhydrous DCM (4 mL) and cooled to 0 °C. DCC (206.3 mg, 1.0 mmol) and DMAP (cat.) were added to the solution. The reaction mixture was stirred for 2 h at 0 °C and left to react overnight at room temperature. The precipitate was filtered and the filtrate was evaporated under reduced pressure. Purification by column chromatography (SiO2, 20% EtOAc/cyclohexane) afforded the ester 8f as a colourless oil (90.6 mg, 51%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With [2,2]bipyridinyl; copper(l) iodide; potassium bromide; at 100℃; for 42h; | General procedure: 4.3 Typical procedure for copper-catalyzed synthesis of beta-haloalkenyl sulfone (Table 4): To a mixture of CuI (4.6 mg, 0.024 mmol), bpy (3.7 mg, 0.024 mmol), PhSO2Na (54.2 mg, 0.33 mmol), and KBr (107.1 mg, 0.9 mmol) in AcOH (0.3 mL) were added phenylacetylene (30.6 mg, 0.3 mmol), and the mixture was stirred at 80 C for 18 h in air. After the residue was dissolved in Et2O, the solution was washed with saturated sodium hydrogencarbonate, H2O, and saturated sodium chloride and dried over anhydrous magnesium sulfate. Chromatography on silica gel (40% diethyl ether/hexane) gave (E)-2-bromo-1-phenylsulfonyl-2-phenylethene (71.5 mg, 74%): |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With 1,3-dimethyl-2-imidazolidinone; 4,4?,5,5?-Tetrahydro-2,2?-bioxazole; copper(l) chloride; In water; acetic acid; at 60℃; for 18h; | General procedure: 4.2. Typical procedure hydrosulfonylation of alkynes (Table 2 ): To a mixture of CuCl (1.5 mg, 0.015 mmol), 2,2'-bis(2-oxazoline) (2.1 mg, 0.015 mmol), and PhSO2Na (54.2 mg, 0.33 mmol), in DMI (0.1 mL), H2O (0.1 mL), and AcOH (0.1 mL) were added phenylacetylene (30.6 mg, 0.3 mmol), and the mixture was stirred at 60 C for 18 h in air. After the residue was dissolved in Et2O, the solution was washed with H2O and saturated sodium chloride and dried over anhydrous magnesium sulfate. Chromatography on silica gel (40% diethyl ether/hexane) gave (E)-1-phenylsulfonyl-2-phenylethene (61.8 mg, 85%):1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With cis-[(H)(SePh)Fe(PMe3)4]; sodium t-butanolate In isopropyl alcohol at 60℃; for 24h; | |
77% | Stage #1: α-bromocinnamaldehyde With pyridine N-oxide; Triethoxysilane; C27H47FeP3Si In tetrahydrofuran at 30℃; for 6h; Schlenk technique; Stage #2: With sodium hydroxide In tetrahydrofuran; methanol at 60℃; for 24h; Schlenk technique; | |
75% | Stage #1: α-bromocinnamaldehyde With Triethoxysilane; [cis-Fe(H)(SPh)(PMe3)4] In tetrahydrofuran at 50℃; for 4h; Stage #2: With methanol; sodium hydroxide In tetrahydrofuran; water at 60℃; for 24h; | 2.2. General procedure for catalytic hydrosilylation of aldehydes General procedure: To a 25 mL Schlenk tube containing a solution of 1 in 2 mL of THF was added an aldehyde (1.0 mmol) and (EtO)3 SiH (0.20 g, 1.2 mmol). The reaction mixture was stirred at 50-55 °C until there was no aldehyde left (monitored by TLC and GC-MS). The reaction was then quenched byMeOH (2mL) and a 10% aqueous solution of NaOH (5 mL) with vigorous stirring at 60 °C for about 24 h.The organic product was extracted with diethyl ether (10 mL × 3), dried over anhydrous MgSO4, and concentrated under vacuum. The alcohol product was further purified using flash column chromatography (elute with 5-10% ethyl acetate in petroleum ether). The 1H NMR and 13C NMR spectra of the alcohol products are providedin Supporting information. |
75% | With ((2-iPr<SUB>2</SUB>PC<SUB>6</SUB>H<SUB>4</SUB>)<SUB>2</SUB>(MeO)Si)Fe(H)(PMe<SUB>3</SUB>); potassium <i>tert</i>-butylate; isopropyl alcohol at 60℃; for 24h; Schlenk technique; | |
Multi-step reaction with 2 steps 1: C24H41FFeNP3 / tetrahydrofuran / 7 h / 60 °C / Inert atmosphere; Schlenk technique 2: sodium hydroxide / methanol / 24 h / 60 °C / Inert atmosphere; Schlenk technique | ||
Multi-step reaction with 2 steps 1: C18H37F5FeP4 / tetrahydrofuran / 40 °C / Schlenk technique; Inert atmosphere 2: sodium hydroxide / methanol; water / 24 h / 60 °C / Schlenk technique; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: o-Ph<SUB>2</SUB>P(C<SUB>6</SUB>H<SUB>4</SUB>)Si(Me)<SUB>2</SUB>Fe(H)(PMe<SUB>3</SUB>)<SUB>3</SUB> / tetrahydrofuran / 4 h / 50 °C / Schlenk technique 2: sodium hydroxide / tetrahydrofuran; methanol / 50 °C / Schlenk technique |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With hydrogenchloride; N-chloro-succinimide In 1,4-dioxane; water monomer at 20℃; for 1h; | Representative procedure: 2,2-dichlorooxygenation of alkynol 1a General procedure: A solution of alkynol 1a (95.8 mg, 0.725 mmol, 1.0 equiv) in 3.6 mL of 1,4-dioxane was addedwith NCS (193.3 mg, 1.448 mmol, 2.0 equiv) and 1 M aqueous HCl (0.38 mL, 0.38 mmol, 0.5equiv). The resulted solution was allowed to stir at room temperature until the reaction was judgedcomplete by TLC (typically 5 h). Upon completion, the reaction mixture was diluted with water.The separated aqueous phase was extracted with 3xEtOAc. The combined organic phases werewashed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered and concentrated toa crude material. The crude material was purified by SiO2 column chromatography eluting 10%EtOAc-hexane to give the corresponding 2,2-dichloroketone 2a-Cl as a yellow oil (117.2 mg,74%); IR (neat): νmax 2926, 1691, 1260, 688 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.33-8.29 (m,2H), 7.61 (tt, J = 7.5, 1.2 Hz, 1H), 7.51-7.45 (m, 2H), 4.27 (s, 2H), 2.95 (br s, 1H); 13C{1H} NMR(75 MHz, CDCl3) δ 189.1, 134.1, 131.1, 131.0, 128.2, 83.6, 70.4; HRMS (ESI-TOF) m/z: [M]·/+Calcd for C9H935Cl2O2 218.9974; Found 218.9972. |
71% | With [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I); trichloroisocyanuric acid In water monomer; acetonitrile at 20℃; for 0.5h; | |
49% | With chloroform; water monomer; lithium perchlorate; N,N,N-tributyl-1-butanaminium iodide In acetonitrile at 20℃; for 6h; Electrochemical reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium tert-butylate; In 1,4-dioxane; at 98℃; for 18h; | To chloroquinoline 5 (775 mg,4.0 mmol) in 1,4-dioxane (12 mL) was added 3-phenyl-2-propyn-1-ol (1.0 mL, 8.0mmol). Potassium tert-butoxide (673mg, 6.0 mmol) was added, and the flask was rinsed with 1,4-dioxane (6 mL). The reaction was equipped with an air condenser and heated to 98 C open to air for 18 hours. After cooling to room temperature, ethyl acetate (15 mL) and H2O (15 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with 1:1 brine/H2O (15 mL) and brine (15 mL) and dried (MgSO4). After filtration, the reaction mixture was concentrated in vacuo. Purification by column chromatography (SiO2,19:1 hexanes/ethyl acetate) provided 995 mg (86% yield) of 6cas a white solid. mp: 58-60 C; 1H NMR (400 MHz, CDCl3):d7.72 (d, J = 8.4 Hz, 1H), 7.42-7.48 (m, 3H),7.23-7.32 (m, 4H), 6.81 (s,1H), 5.34 (s, 2H), 2.71 (s, 3H), 2.61 (s, 3H; 13C NMR (100MHz, CDCl3): d159.4, 147.4, 145.0, 135.9, 131.9, 129.6, 128.4, 128.2, 125.3, 123.5,122.7, 121.4, 112.2, 105.0,85.8, 84.9, 53.9, 19.0, 18.1; IR (neat): 3061, 2922, 2243, 1610, 1583, 1448,1323 cm-1; HRMS (ESI)m/z 310.1217 [310.1208 calcd for C20H17NONa (M+Na)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With methyl trifluoromethanesulfonate In 2,2,2-trifluoroethanol at 70℃; for 1h; | Methyl Triflate Catalyzed Meyer-Schuster Rearrangement; Cinnamaldehyde (2a); Typical Procedure General procedure: To a 25 mL round-bottomed flask were added 1-phenylprop-2-yn-1-ol (1a; 40 mg, 0.3 mmol), TFE (0.5 mL), and MeOTf (6 μL, 0.06 mmol, 0.2 equiv). Then the flask was immersed in a 70 °C preheated oil bathand the mixture was stirred for 1 h. After completion, the solution was removed and the residue was subject to flash chromatography (silica gel) with PE/EtOAc as eluent to afford the desired rearrangement product. |
With iron(III) trifluoromethanesulfonate In 1,4-dioxane Reflux; | Procedure for the synthesis of 6 To a mixture of propargyl alcohol 1a (0.2 mmol) in dioxane (1 mL), Fe(OTf)3 (0.2 mmol) was added, and the reaction was stirred at refluxing temperature until 1a disappeared completely monitored by TLC. Then the reaction was quenched by saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Finally the residue was purified through column chromatography on silica gel (200-300 mesh) with hexane/EtOAc as eluent to give 6. 2-Methylene-1,5-diphenyl-pentane-1,5-dione (6) 35 : yellow solid; m. p.56-57 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H), 7.50-7.45 (m, 2H), 7.41-7.34 (m, 4H), 5.89 (s, 1H), 5.61 (s, 1H), 3.17 (t, J = 7.2 Hz, 2H), 2.85 (t, J = 7.2 Hz, 2H); IR (KBr, cm-1) 3083, 3059, 3026, 2960, 2921, 2850, 1684, 1653, 1595, 1447, 1261, 1206, 1095, 1023, 1001, 799, 750, 708, 690. | |
With bismuth(lll) trifluoromethanesulfonate In 1,4-dioxane at 110℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With iron(III) trifluoromethanesulfonate In 1,4-dioxane at 110℃; for 16h; | 4.4 Preparation of 2a, 2d-2p, and 3a-3e General procedure: To a mixture of propargyl alcohol 1 (0.2mmol) in dioxane (1mL), Fe(OTf)3 (0.04mmol) and nucleophile (0.4 mmol) were added. The mixture was stirred at refluxing temperature until 1 disappeared completely monitored by TLC. Then the reaction was quenched by saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Finally the residue was purified through column chromatography on silica gel (200-300 mesh) with hexane/EtOAc as eluent to afford the products 2a, 2d-2p, and 3a-3e. |
94% | With iron(III) trifluoromethanesulfonate In 1,4-dioxane Reflux; Sealed tube; | 1 Propyl alcohol (2 mmol) was added in a 15 mL sealed tube, Solvent (10 to 20 mL), acid (0.3 to 0.5 mmol) and amine (3.9 to 4 l) The reaction was carried out under reflux conditions, the reaction was monitored by TLC, After the reaction of propynol was complete, 20 mL of water was added to the reaction solution, and 50 mL of ethyl acetate was added thereto, The resulting organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator, The resulting concentrate was purified by column chromatography to obtain [beta] -amino ketone |
With bismuth(lll) trifluoromethanesulfonate In 1,4-dioxane Sealed tube; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With iron(III) trifluoromethanesulfonate at 110℃; for 14h; | 4.4 Preparation of 2a, 2d-2p, and 3a-3e General procedure: To a mixture of propargyl alcohol 1 (0.2mmol) in dioxane (1mL), Fe(OTf)3 (0.04mmol) and nucleophile (0.4 mmol) were added. The mixture was stirred at refluxing temperature until 1 disappeared completely monitored by TLC. Then the reaction was quenched by saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Finally the residue was purified through column chromatography on silica gel (200-300 mesh) with hexane/EtOAc as eluent to afford the products 2a, 2d-2p, and 3a-3e. |
With bismuth(lll) trifluoromethanesulfonate In 1,4-dioxane Sealed tube; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.19 g | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 1h; | Diisopropyl azodicarboxylate (4.38 g, 20.57 mmol) was added to a solution of triphenylphosphine (5.40 g, 20.57 mmol) in dry THF (75 mL) at 0 C and the resulting mixture was stirred for 5 min at 0 C. A solution of <strong>[2042-14-0]4-methyl-3-nitrophenol</strong> (3.0 g, 19.59 mmol) and 3-phenylprop-2-yn-1-ol (2.72 g, 20.57 mmol) in THF (25 mL) was then added over 5 min and the resulting clear solution was allowed to warm to RT over 60 min. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to afford the title compound (5.19 g, 19.4 mmol) as yellow oil. 1H NMR (400 MHz, CDCI3): delta 7.71 (d, 1 H), 7.42-7.48 (m, 2H), 7.25-7.38 (m, 4H), 7.16-7.23 (m, 1 H), 4.97 (s, 2H), 2.56 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In acetonitrile at 60℃; for 5h; | 11 4.2. General procedure 2 for conversion of 3-bromo-1-sulfonylpyrrolidin-, piperidin-, azepan- or azocan-2-ones (2) to 1-sulfonylazetidin-, pyrrolidin-, piperidin-2-carboxylic esters (3, 5 or 6) (GP2) General procedure: To a stirred solution of the appropriate 3-bromo-1-sulfonylpyrrolidin-, piperidin-, azepan- or azocan-2-one 2 (1 mmol) in MeCN (4.5 mL) were added 10 equivalents of the appropriate alcohol, phenol or aniline (see information for each compound) followed by K2CO3 (414 mg, 3 mmol or 207 mg, 1.5 mmol as specified for each compound). The heterogeneous mixture was stirred at 60°C until completion of the reaction, as monitored by TLC. Filtration through a thin pad of silica gel (eluting with CH2Cl2 or MeCN when necessary) followed by concentration and drying under high vacuum (with warming at 50°C if necessary) afforded the pure compound type 3, 5 or 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 3-Phenyl-2-propyn-1-ol With hydrogen In methanol at 20℃; for 48h; Stage #2: pivaloyl chloride With dmap; triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | Syntheses of Starting Materials (Z)-3a To a solution of 3-Phenylprop-2-yn-1-ol (0.66 g, 5mmol) in 15 mL of anhydrous MeOH was added Lindlar catalyst(poisoned with lead) (255 mg).The reaction mixture was stirred for 48 h at room temperature under hydrogen atmosphere(4 atm). The reaction mixture was filtrated through a padof Celite, washed with MeOH (8 mL). The solution was concentrated in vacuo. Then product and 4-dimethylaminopyridine (DMAP)( 0.5 mol) in 10ml CH2Cl2 was added triethylamine (1.0g, 10mmol). The mixture was cooled to 0 °C. To this solution was added Pivaloyl chloride (900mg , 7.5mmol)in 5ml CH2Cl2 dropwise over 30 min. Next, the reaction mixture was stirred at room temperature. After 1 h, NaHCO3 (2M) was added, and theaqueous layer was extracted with CH2Cl2. The combined organic layers were washed with the saturated solution of NaHCO3 (aq), dried over Na2SO4,filtered, and concentrated under reduced pressure. The residue was purified with silica gel chromatography to provide pure product (10% EtOAc inhexanes).(Z)-3-phenylallyl pivalate, (Z)-3a the compound was isolated as a colorless oil (970 mg, 89% yield). This compound is known2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 3-Phenyl-2-propyn-1-ol; 2-Nitrobenzyl alcohol With triphenylphosphine; diethylazodicarboxylate In dichloromethane at 20℃; Stage #2: With iron; acetic acid In ethanol at 55 - 65℃; for 3h; | 3 o-Nitrobenzyl alcohol 3 (15.3 g, 0.1 mol),Phenyl propargyl alcohol 11 (13.5g, 0.102mol) andTriphenylphosphine (31.4g, 0.12mol)After adding to 200 mL of dichloromethane,After the mixture is completely dissolved,Diethyl azodicarboxylate (20.9 g, 1.2 eq) was added dropwise at room temperature.50mL dichloromethane mixed solution,Continue to stir at room temperature overnight.TLC detection of raw materials disappeared,The system is cooled to -40 ° C to stand still.Filter out the complex by-products of the complex,After the filtrate was concentrated, it was added directly to 250 mL of ethanol and 3.5 eq of reduced iron powder.Control the temperature 55-65 ° C dropwise addition of acetic acid solution (2.5 eq),After the dropwise addition, the temperature was raised to reflux reaction for 3 hours.The TLC test material disappeared basically, and the temperature was lowered to 50 ° C.Filter through diatomaceous earth and filter cake with ethanol.The filtrate was concentrated to dryness under reduced pressure and dichloromethane (150 mL).The aqueous layer is adjusted with a saturated aqueous solution of sodium carbonate pH=9-10,Wash with saturated sodium chloride, dry over anhydrous sodium sulfate,Column chromatography separation using n-heptane / ethyl acetate 10:1 to 6:1,19.2 g of a yellow oily liquid was obtained in a two-step yield of 81%. |
19.2 g | Stage #1: 3-Phenyl-2-propyn-1-ol; 2-Nitrobenzyl alcohol With triethylamine; diethylazodicarboxylate In dichloromethane at 20℃; for 3h; Stage #2: With iron; acetic acid In ethanol; dichloromethane for 3h; Reflux; | 3.3 o-Nitrobenzyl alcohol 3 (15.3 g, 0.1 mol), benzynpropanol 11 (13.5 g, 0.102 mol) and triphenylphosphine (31.4 g, 0.12 mol) were added to 200 mL of dichloromethane, and then completely dissolved by stirring. After clearing, a mixed solution containing diethyl azodicarboxylate (20.9 g, 1.2 eq) and 50 mL of dichloromethane was added dropwise at room temperature. After the dropwise addition, the mixture was stirred at room temperature overnight, and the raw material disappeared by TLC. The system was cooled to -40 °C to stand still, and the solid by-product of the complex was filtered off. After the filtrate was concentrated, the solution was directly added to 250 mL of ethanol and 3.5 eq of reduced iron powder to control the temperature. Add acetic acid solution (2.5 eq) at 55-65 ° C,After the dropwise addition, the temperature was raised to reflux reaction for 3 hours. The raw material disappeared by TLC, and the temperature was reduced to 50 ° C. The mixture was filtered through Celite, and the filter cake was rinsed with ethanol. The filtrate was concentrated to dryness under reduced pressure.The aqueous layer was adjusted to pH = 9-10 with a saturated aqueous solution of sodium carbonate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated. After separation, 19.2 g of a yellow oily liquid was obtained. The yield in two steps was 81% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With bismuth(lll) trifluoromethanesulfonate; In 1,4-dioxane; at 110℃; for 5h; | General procedure: To a mixture of propargyl alcohol 1 (0.2 mmol) in dioxane (1 mL), Bi(OTf)3 (0.03 mmol) and nucleophile 2 (0.22 mmol) were added. The mixture was stirred at refluxing temperature until 1 disappeared monitored by TLC. Then the reaction was quenched by saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Finally the residue was purified through column chromatography on silica gel (200-300 mesh) with hexane/EtOAc as eluent to afford the products 3a-3i, 4b-4d, and 4g-4q. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With bismuth(lll) trifluoromethanesulfonate In 1,4-dioxane at 110℃; for 5h; | 4. Preparation of 3a-3i, 4b-4d, and 4g-4q General procedure: To a mixture of propargyl alcohol 1 (0.2 mmol) in dioxane (1 mL), Bi(OTf)3 (0.03 mmol) and nucleophile 2 (0.22 mmol) were added. The mixture was stirred at refluxing temperature until 1 disappeared monitored by TLC. Then the reaction was quenched by saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Finally the residue was purified through column chromatography on silica gel (200-300 mesh) with hexane/EtOAc as eluent to afford the products 3a-3i, 4b-4d, and 4g-4q. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With bismuth(lll) trifluoromethanesulfonate In 1,4-dioxane at 110℃; for 5h; | 4. Preparation of 3a-3i, 4b-4d, and 4g-4q General procedure: To a mixture of propargyl alcohol 1 (0.2 mmol) in dioxane (1 mL), Bi(OTf)3 (0.03 mmol) and nucleophile 2 (0.22 mmol) were added. The mixture was stirred at refluxing temperature until 1 disappeared monitored by TLC. Then the reaction was quenched by saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. Finally the residue was purified through column chromatography on silica gel (200-300 mesh) with hexane/EtOAc as eluent to afford the products 3a-3i, 4b-4d, and 4g-4q. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine In tetrahydrofuran at 70℃; for 12h; Inert atmosphere; | General procedures for the preparation of carbamates. General procedure: a. Phenyl or cyclohexyl isocyanate (1.1 mmol) was added to a solution of alcohol 1a-1j, 2a, or 2b (1 mmol) in anhydrous THF under a nitrogen atmosphere, and one or two drops of triethylamine were introduced via a syringe. The resulting homogeneous mixture was refluxed for 12 h. The mixture was cooled and extracted with methylene chloride (3 x 15 mL), the combined extracts were dried over Na2SO4 and evaporated under reduced pressure, and the residue was purified by flash column chromatography using ethyl acetate-hexane (2 : 8) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With bismuth(lll) trifluoromethanesulfonate; N-Bromosuccinimide In 1,4-dioxane at 101℃; Sealed tube; | 1 Preparation process Add 1,3-substituted propargyl alcohol, halogen source and acid into a sealed tube, and carry out the reaction under heating and reflux at 101 ° C;After the disappearance of 1,3-substituted propargyl alcohol was monitored by TLC, it was quenched by the addition of saturated saline water.The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated.The obtained concentrated solution was purified by column chromatography to obtain α-halo unsaturated aldehyde ketone, and the calculated yield was 91.0%.Among them, propargyl alcohol, halogen source, solvent and acid were sampled as 3-phenylprop-2-yn-1-ol (2mmol), NBS (2mmol),Dioxane (10mL)And bismuth triflate (0.1 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45%; 43% | With bismuth(lll) trifluoromethanesulfonate; N-Bromosuccinimide; hydroxylamine hydrochloride; In 1,4-dioxane; at 101℃; for 5h;Sealed tube; | The preparation process is: adding propargyl alcohol derivative, halogen source and acid in a sealed tube,The reaction was carried out at 101 C under heating and reflux, and hydroxylamine was added after the disappearance of the propargyl alcohol derivative was monitored by TLC.After 5 hours of reaction, saturated brine was added to quench the reaction, and the organic phase was extracted with ethyl acetate.The product is dried by anhydrous sodium sulfate and concentrated to obtain the isoxazole derivative. The purity of the product can be improved by column chromatography.Calculating the yield: the yield of isoxazole derivative I is 45%, the yield of isoxazole derivative II is 43%,The yield of the total isoxazole derivative was 88%.Among them, propargyl alcohol, halogen source, hydroxylamine,The solvent and acid loading were 3-phenylprop-2-yn-1-ol (2mmol), NBS (2mmol),Hydroxylamine hydrochloride (2.1 mmol), dioxane (10 mL) and bismuth triflate (0.1 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With bismuth(lll) trifluoromethanesulfonate; N-Bromosuccinimide; hydrazine hydrate In 1,4-dioxane at 101℃; for 5h; Sealed tube; | 1 The preparation process is: Add a propargyl alcohol derivative, a halogen source and an acid to a sealed tube, and carry out the reaction under heating at 101 °C. After the propargyl alcohol derivative is completely disappeared by TLC, hydrazine is added. After 5 hours of reaction, it is quenched with saturated saline, the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a pyrazole derivative. The purity of the product was improved by column chromatography, and the calculated yield was 91.0%. Of which propargyl alcohol, halogen source, hydrazine, solvent and acid were added as 3-phenylprop-2-yn-1-ol (2mmol), NBS (2mmol), hydrazine hydrate (2.1mmol), dioxane (10 mL) and bismuth triflate (0.1 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With di-2-methoxyethyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 16h; Inert atmosphere; | Compound SI-9: 3-Phenyl-2-propyn-1-ol (49 μL, 0.390 mmol), DMEAD (95.0 mg, 0.390 mmol), and triphenylphosphine (102 mg, 0.390 mmol) were added to a stirred solution of 5 (88.0 mg,0.355 mmol) in THF (3.5 mL), and the reaction mixture was stirred at room temperature under argon atmosphere. After 16 h, brine was added, and the mixture was extracted with AcOEt. The combined organic layers were dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (SiO2, hexane/ AcOEt = 5/1) to give the desired product SI-9 (126 mg, 0.348 mmol, 98%) as colorless oil; IR(ATR) n 688, 729, 754,779, 890, 1013, 1040, 1235, 1263, 1561, 1687 cm-1; 1H NMR (CDCl3): d 5.07 (s, 2H), 7.29-7.35(m, 4H), 7.40-7.43 (m, 3H) 7.55 (d, J = 7.8 Hz, 1H), 10.20 (s, 1H); 13C NMR (CDCl3): d 58.26,82.67, 88.22, 94.62, 118.35, 121.78, 123.08, 128.32 (2C), 128.92, 129.30, 131.76 (2C), 136.79,156.65, 196.34; (+)-ESI-HRMS. Calcd for C16H11I1Na1O2 (M+Na+): 384.9701. Found: 384.9694. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With pyridine; hydrogenchloride; N-iodo-succinimide In dichloromethane; water at 35℃; for 12h; | 3. General procedure for the preparation of 3a-3m General procedure: To a CH2Cl2 solution (3 mL) of Alkyne 1 ( 0.2 mmol, 1eq), N-iodosuccinimide (54 mg, 0.24 mmol, 1.2 eq) and pyridine (1.6 mg, 0.02 mmol, 0.1 eq) in a glass tube, was added dropwise 37 % HCl aqueous solution (25 μL, 0.3 mmol, 1.5 eq). The reaction was then stirred at 35 °C for 12 h with TLC monitoring. After the completion of the reaction, concentration of the reaction mixture, followed by purification via flash chromatography over SiO2 (petroleum to petroleum/ethyl acetate = 100/1 as the eluted solvent) afforded 3a-3m. |
75% | With N-iodo-succinimide; acetic acid; lithium chloride In dichloromethane at 20℃; for 24h; regiospecific reaction; | 2. General procedure for iodochlorination of alkynes General procedure: A 10 mL glass vial with a screw cap was charged with alkynes (0.2 mmol), NIS (0.3 mmol, 1.5equiv.), LiCl (0.4 mmol, 2 equiv.) and a solvent mixture of DCM (0.5 mL) and HOAc (0.5 mL).The reaction mixture was stirred at rt for 24 h. Upon completion, the reaction mixture was quenched with saturated NaCl solution and was extracted with EtOAc, the combined organic layers were dried with anhydrous Na2SO4, and the solvent was removed in vacuum. The residue was purified by flash silica gel column chromatography (eluted with hexanes and ethyl acetate) to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium 2-(difluoro(trifluoromethoxy)methoxy)-2,2-difluoroacetate; tetramethylammonium fluoride at 150℃; for 5h; Schlenk technique; Glovebox; Inert atmosphere; | 49 General procedure: Weigh 4-phenylbutanol (0.2mmol, 1.0equiv) and CF3OCF2OCF2CO2K (0.1mmol, 0.5equiv) in a 10mL dried Shrek tube, weigh CsF (0.1mmol, 0.5equiv) in a glove box, and Add 1 mL of solvent DMPU (N,N-dimethyl allyl urea), and react at 150°C for 5 hours under a nitrogen atmosphere. After the reaction, it was cooled to room temperature and filtered. The filtrate was added with 15 mL of water and 15 mL of ethyl acetate (or dichloromethane) for extraction three times. The layers were separated, the organic phases were collected, the organic phases were combined, washed once with saturated brine, dried with anhydrous Na2SO4, and concentrated , Purify by silica gel column chromatography to obtain the final product. Examples 37-63 are used to illustrate the deoxyfluorination method disclosed in the present invention, including most of the operation steps of Example 2. The differences are:Examples 37-63 respectively use the alcohol substrates corresponding to the fluorinated products (3-3a-3aa) in Table 6, for example, the alcohol substrates corresponding to the fluorinated product 3-3a areThe molar ratio of alcohol substrate, fluorinating reagent and fluorine salt is 1:1.5:0.5.The reaction time is 5h.TMAF is used as the fluoride salt.The amount of solvent added is 2 mL.The fluorinated products were separated by flash column chromatography and fluorine spectrum analysis to determine the yields of Examples 37-63, and the test results were filled in Table 6. |
70% | With potassium 2-(difluoro(trifluoromethoxy)methoxy)-2,2-difluoroacetate; tetramethylammonium fluoride at 150℃; for 5h; Glovebox; Inert atmosphere; Schlenk technique; Sealed tube; | |
50% | Stage #1: 3-Phenyl-2-propyn-1-ol With copper(l) chloride; diisopropyl-carbodiimide at 60℃; for 1h; Sealed tube; Microwave irradiation; Stage #2: With copper (II)-fluoride In water at 100℃; for 24h; Microwave irradiation; |
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 0 °C 2: potassium fluoride; 2C16H36N(1+)*C2H4O6S2(2-) / <i>tert</i>-butyl alcohol; water / 4 h / 90 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; | Sulfonamides 16 and 13a-k; General Procedure General procedure: A solution of PPh3 (472 mg, 1.8 mmol, 1.8 equiv) in dry THF (10 mL) was cooled to 0 °C under Ar and DEAD (282 L, 1.8 mmol, 1.8 equiv) in THF (3 mL) was quickly added under vigorous stirring. The resulting mixture was left to stir at 0 °C for 20 min, while the complex of DEAD with PPh3 precipitated as a white solid. Next, a solution of the corresponding alcohol (1.5 mmol, 1.5 equiv) in THF (2 mL) was added, and after 10 min at 0 °C a solution of sulfonamide 15 (1 mmol, 1.0 equiv) and DIPEA (210 L, 1.2 mmol, 1.2 equiv) in THF (5 mL) was added. The reaction mixture was stirred for 20 min at 0 °C and then at room temperature until the starting sulfonamide had been completely consumed (about 1-2 hours; TLC: SiO2, eluent: n-hexane/EtOAc, 70:30). All volatiles were removed under vacuum and the residue was dissolved in PhMe (5 mL). The solution became progressively more heterogeneous as the diethyl hydrazine-1,2-dicarboxylate precipitated as a white solid. The solid was filtered off and discarded, the filtrate was evaporated in vacuo and the resulting crude product was purified by column chromatography on silica gel with a linear gradient of MeOH in PhMe (2-5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With pyridine; N-iodo-succinimide; hydrogen bromide In dichloromethane; water at 35℃; for 12h; | 4. General procedure for the preparation of 4a-4m General procedure: To a CH2Cl2 solution (3 mL) of alkyne 1 ( 0.2 mmol, 1eq), N-iodosuccinimide (54 mg, 0.24 mmol, 1.2 eq) and pyridine (1.6 mg, 0.02 mmol, 0.1 eq) in a glass tube, was added dropwise 48 % HBr aqueous solution (51 μL, 0.3 mmol, 1.5 eq). The reaction was then stirred at 35 °C for 12 h with TLC monitoring. After the completion of the reaction, concentration of the reaction mixture, followed by purification via flash chromatography over SiO2 (petroleum to petroleum/ethyl acetate = 100/1 as the eluted solvent) afforded 4a-4m. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 1h; | General procedure for the preparation of3-substituted-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-ones General procedure: Propargyl alcohol 1a-l (1.0 mmol) was dissolved in dryDMF (10 mL) and then cooled to 0 °C. Anhydrous Et3N(0.3 g, 3 equiv.) and chloroacetyl chloride (0.14 g; 1.2mmol) were added, and the reaction mixture was allowedto stir at room temperature. After the disappearance of thestarting materials (monitored by TLC), sodium azide(0.13 g, 2.0 mmol) was added to the reaction mixture. Thereaction was heated to 100 °C, stirred for 5 h and thencooled to room temperature. The reaction mixture wastreated with water (10 mL) and extracted with ethyl acetate(3 × 10 mL). The combined organic extract waswashed with brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was subjectedto flash column chromatography with petroleumether/ethyl acetate (5/1) as eluent to afford the desiredproduct 3a-l.3-Phenyl-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one(3a): Yellow liquid; 1H NMR (400 MHz, CDCl3): δ 7.46-7.44 (m, 2 H), 7.34-7.27 (m, 3 H), 4.99 (s, 2 H), 3.90 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 167.8, 131.9, 129.0,128.4, 121.9, 87.3, 82.1, 53.9, 50.1; IR (film): 3025, 2965,1727, 1607, 1466, 1368, 1269, 1136, 1065, 742 cm-1. Anal.calcd for C11H9N3O2: C, 61.39; H, 4.22; N, 19.53; found: C,61.50; H, 4.35; N, 19.42%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 3-Phenyl-2-propyn-1-ol With 4-methylbenzenesulfonyl chloride; potassium hydroxide In diethyl ether at 0℃; for 1h; Inert atmosphere; Stage #2: toluene-4-sulfonic acid hydrazide With sodium hydride at 0 - 20℃; for 16h; | N-(3-Phenyl-2-propyn-1-yl)-N′-tosylhydrazine (1A); Typical Procedure To a solution of 3-phenyl-2-propyn-1-ol (1322.0 mg, 10.0 mmol) inEt2O (20.0 mL) were added KOH (2801.0 mg, 50.0 mmol) and p-TsCl(2097.0 mg, 11.0 mmol). The obtained mixture was stirred for 1 h at 0°C under argon atmosphere. Sat. aq NH4Cl (30.0 mL) was added to themixture and extracted with EtOAc (3 × 15.0 mL). The combined organiclayers were dried (Na2SO4). After filtration and removal of thesolvent under reduced pressure, the residue was added to a solutionof p-toluenesulfonyl hydrazide (9312.0 mg, 50.0 mmol) and NaH(480.0 mg, 20.0 mmol) at 0 °C. The obtained mixture was stirred for16 h at r.t. H2O (30.0 mL) was added to the mixture, and the productwas extracted with CHCl3 (3 × 15.0 mL). The combined organic layerswere dried (Na2SO4). After filtration and removal of the solvent underreduced pressure, the residue was purified by silica gel column chromatography(eluent: n-hexane/EtOAc 2:1); yield: 2163.0 mg (72%);white solid; mp 94-95 °C.Other N-(3-aryl-2-propyn-1-yl)-N′-tosylhydrazines and N-(3-alkyl-2-propyn-1-yl)-N′-tosylhydrazines 1 were obtained in the range of 65-71% yields by the same procedure.IR (neat): 3363, 2237, 1594, 1344, 1159 cm-1.1H NMR (400 MHz, CDCl3): = 2.34 (s, 3 H), 3.03 (br s, 2 H), 4.46 (s, 2H), 7.07 (d, J = 8.2 Hz, 2 H), 7.21-7.26 (m, 2 H), 7.27-7.32 (m, 3 H),7.85 (d, J = 8.3 Hz, 2 H).13C NMR (100 MHz, CDCl3): = 21.4, 43.2, 80.3, 86.6, 121.8, 128.1 (2C), 128.5, 129.0 (2 C), 129.5 (2 C), 131.5 (2 C), 131.8, 144.5.HRMS (ESI): m/z calcd for C16H17N2O2S [M + H]+: 301.1005; found:301.1005. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With tetracarbonylbis(μ-chloro)dirhodium(I); lithium hydroxide monohydrate In toluene at 80℃; for 3h; | General procedure for the synthesis of products 3 General procedure: A mixture of compounds 1 (0.1 mmol, 1.0 equiv), compounds 2 (0.12 mmol, 1.2 equiv), [RhCl(CO)2]2 (1 mol %) and H2O (9 μL, 5.0 equiv) in Tol (1.0 mL) were charged into a tube which was stirred at 80 °C for 3 h. After cooled to rt, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (PE/EA = 10/1) to afford products 3. |
Tags: 1504-58-1 synthesis path| 1504-58-1 SDS| 1504-58-1 COA| 1504-58-1 purity| 1504-58-1 application| 1504-58-1 NMR| 1504-58-1 COA| 1504-58-1 structure
[ 1719-19-3 ]
2-Methyl-4-phenylbut-3-yn-2-ol
Similarity: 0.85
[ 1719-19-3 ]
2-Methyl-4-phenylbut-3-yn-2-ol
Similarity: 0.85
[ 1719-19-3 ]
2-Methyl-4-phenylbut-3-yn-2-ol
Similarity: 0.85
[ 61266-36-2 ]
Methyl 4-(3-hydroxyprop-1-yn-1-yl)benzoate
Similarity: 0.60
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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