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CAS No. : | 1080-32-6 | MDL No. : | MFCD00009078 |
Formula : | C11H17O3P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AIPRAPZUGUTQKX-UHFFFAOYSA-N |
M.W : | 228.22 | Pubchem ID : | 14122 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.45 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 61.47 |
TPSA : | 45.34 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.49 cm/s |
Log Po/w (iLOGP) : | 2.41 |
Log Po/w (XLOGP3) : | 1.7 |
Log Po/w (WLOGP) : | 3.3 |
Log Po/w (MLOGP) : | 2.1 |
Log Po/w (SILICOS-IT) : | 1.95 |
Consensus Log Po/w : | 2.29 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.23 |
Solubility : | 1.36 mg/ml ; 0.00594 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.27 |
Solubility : | 1.23 mg/ml ; 0.0054 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.89 |
Solubility : | 0.0293 mg/ml ; 0.000128 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.38 |
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 |
---|---|---|
at 150 - 170℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With lithium aluminium tetrahydride In diethyl ether for 4h; Heating; | |
59% | With lithium aluminium tetrahydride In diethyl ether at 20℃; Inert atmosphere; | |
With lithium aluminium tetrahydride |
With lithium aluminium tetrahydride In tert-butyl methyl ether at 0 - 30℃; | 1 Example 1 Preparation of benzyl phosphine A mixture of lithium aluminium hydride (25 g) in methyl tertiary butyl ether (MTBE) (800 ml) was cooled to 0 to 5°C and added a solution of diethylbenzylphosphonate in methyl tertiary butyl ether (100 g in 200ml). The temperature of reaction mixture was raised to 25 to 30 °C and stirred for 14 to 16 hour. After completion of the reaction, the reaction mixture was cooled to 0 to 5°C and 6N hydrochloric acid was added slowly. Further raised the temperature of reaction mixture to 25 to 30 °C and stirred for 30-45 minutes. The layers were separated, the aqueous layer was extracted with MTBE (250ml) and the combined organic layer was washed with deoxygenated water. The organic layer was dried over sodium sulfate and concentrated to obtain the title compound as non-distillable liquid. | |
With lithium aluminium tetrahydride In toluene at 0℃; for 16h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | METHOD 1 (Ref. 180,217) The phosphonate (7.3) (5.0 g, 22 mmol) was then added dropwise with cooling to a stirring mixture of concentrated nitric and sulphuric acids [50 ml (1:1 v/v)] at 0°C. The mixture was allowed to warm to room temperature and stirred for a further 1 h. The reaction was poured onto ice and extracted into toluene (3 x 100 ml). The combined organic fractions were washed with water (3 x 50 ml) and saturated NaHCO3(3 x 50 ml) and dried over MgSO4. Removal of toluene under reduced pressure yielded a pale green oil (5.3 g, 88 %) which was found to be a mixture of the title compound and its ortho isomer in a molar ratio of ca. 85:15 respectively (determined by 31P NMR). Analysis by TLC in a range of solvent systems failed to separate the two isomers. Repeated attempts to purify the mixture by silica gel chromatography were of limited success, only increasing the isomeric ratio to 90:10 (overall yield, 71%). | |
With sulfuric acid; nitric acid | ||
With sulfuric acid; nitric acid at 0℃; for 0.666667h; | 3 4.1.3 4-Nitrobenzylphosphonic acid (3) Diethyl benzylphosphonate61,62(6, 500 mg, 0.0022 mmol) was treated with a 1:1 mixture of conc. H2SO4 and conc. HNO3 (5 mL) at 0 °C in a round bottom flask. The reaction mixture was stirred at 0 °C for 40 min and then treated with ice/cold water. The crude reaction mixture was extracted with ethyl acetate and then the organic layer washed with brine, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography in silica gel with AcOEt/hexanes (50:50) to yield diethyl 4-nitrobenzylphosphonate 7 as a yellowish oil. This intermediate was hydrolyzed with conc. HCl as described in section 4.1.2 furnishing 4-nitrobenzylphosphonic acid 3 as light yellow crystals in 60% overall yield (mp 224-227 °C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With hydrogenchloride for 6h; Heating; | |
87% | With hydrogenchloride In water at 100 - 110℃; for 28h; | 1 40 mL of concentrated hydrochloric acid was added to 15 grams of benzyl diethyl phosphonate in a 100 mL round bottom flask. The resulting mixture was refluxed at about 100-110° C. with for about 28 hours under a nitrogen atmosphere and stirred using a magnetic stir bar. The reaction mixture was cooled to room temperature and the solid crystals were separated from the non-solids via filtration on a Whatman 54 filter paper using a Buchner funnel. The resulting solids product was washed with 10 mL of cold water and then vacuum dried (20 mm Hg) at about 60-70° C. for 16 hours. The isolated product weighed 9.87 grams (87% yield), and exhibited a melting point of about 175-177° C. NMR studies were consistent with the known structure of benzyl phosphonic acid. |
77% | Stage #1: O,O-diethyl benzylphosphonate With boron tribromide In hexane; toluene at 70℃; for 6h; Stage #2: With methanol In hexane; toluene at 20℃; |
70% | With hydrogenchloride; water for 24h; Reflux; | 2 4.1.2 Benzylphosphonic acid (2) Diethyl benzylphosphonate 59 (6, 500 mg, 0.0022 mmol) was treated with conc. HCl (8 mL) and stirred under reflux for 24 h in a round bottom flask. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered, washed with cold water and dried in vacuum. Benzylphosphonic acid (2) was isolated in 70% yield (mp 160-163 °C). 60 1H NMR (DMSO-d6, 250 MHz): δH (ppm) 7.30-7.17 (m, 5H), 2.94 (d, br, 2J(1H-31P) = 21.4 Hz, 2H); 13C NMR (DMSO-d6, 62.5 MHz): δC (ppm) 35.4 (d, br, 1J(13C-31P) = 131.4 Hz), 126.0 (d, 5J(13C-31P) = 3.0 Hz), 128.0 (d, 4J(13C-31P) = 2.5 Hz), 129.8 (d, 3J(13C-31P) = 6.5 Hz), 134.2 (d, 2J(13C-31P) = 8.6 Hz); 31P NMR (DMSO-d6, 101.0 MHz): δ 20.9 (s); IR (ATR) νmax (cm-1) = 1491, 1458, 1260, 1074, 989, 942, 782, 701, 693; HRMS (ESI-TOF) m/z: calcd. for C7H9O3P [M-H]- = 171.0211; observed [M-H]- = 171.0201. |
With hydrogen bromide In 1,4-dioxane Irradiation; | ||
(acid hydrolysis); | ||
Multi-step reaction with 2 steps 1: 90 percent / LiBr / acetonitrile / 3 h / 70 - 75 °C 2: aniline / methanol | ||
Multi-step reaction with 2 steps 2: H2O | ||
Multi-step reaction with 2 steps 2: H2O | ||
With hydrogenchloride In methanol | R.115 REFERENCE EXAMPLE 115 REFERENCE EXAMPLE 115 A solution of diethyl benzylphosphonate (25 g) in methanol (10 ml) and concentrated hydrochloric acid (500 ml) solution was refluxed for 4 days. The mixture was cooled to room temperature, and precipitated crystal was collected by filtration to give benzylphosphonic acid (11.17 g) as colorless crystals. m.p. 171-173° C.; 1 H-NMR (200 MHz, DMSO-d6) δ 2.96 (2H, d, J=21.6 Hz), 7.13-7.34 (5H, m). IR (KBr) 2779, 2330, 1497, 1458, 1263, 1074, 993, 943, 781, 694, 527, 428 cm-1. Elemental Analysis for C7 H9 O3 P; Calcd. C, 48.85; H, 5.27; P, 18.00: Found. C, 48.75; H, 5.01; P, 17.78. | |
With trimethylsilyl bromide In N,N-dimethyl-formamide | ||
With hydrogenchloride; water Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium <i>tert</i>-butylate In toluene Reflux; Inert atmosphere; | Wittig-Horner general procedure for stilbene 10 synthesis General procedure: To a flame dried round flask was added aryl aldehyde (8.32 mmol) and toluene (83 mL), followed by diethylbenzylphosphonate (1.73 mL, 8.32 mmol). The reaction was stirred at room temperature for 20 min, and KOtBu (980 mg, 8.73 mmol) was added. The reaction was heated to reflux for 7 h monitoring for the disappearance of the aryl aldehyde. The reaction was quenched with water (50.0 mL) and ethyl acetate (75.0 mL) and washed with water (3*75 mL) and brine (3*50 mL). The organic layer was dried over Na2SO4 gravity filtered, and evaporated in vacuo. Purification using flash column chromatography (ethyl acetate/hexanes) afforded the product stilbene 10. |
With sodium hydride In 1,2-dimethoxyethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.9% | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | 2.4.3. (E)-9-styrylanthracene (3, t-APE) Diethyl benzylphosphonate (1.10 g, 4.8 mmol) and 9-anthraldehyde (1.00 g, 4.8 mmol) were added into a 100 mLround-bottom flask with the protection of N2. N,N-Dimethylformamide(30 mL) was added to above flask, then cooled to0 C. The N,N-Dimethylformamide solution of t-BuOK (0.54 g,4.8 mmol) was added dropwise to above flask, stirred for 30 min at0 C, followed with stirring at room temperature until the 9-anthraldehyde was consumed completely (monitored by thinlayerchromatography). The reaction was terminated with ice water,and the product was extracted with ethyl acetate 100 mL. Afterthe solvent was evaporated, the crude product was purified bychromatography on a silica gel column (petroleum ether: ethylacetate 4:1 as eluent) to give the title compound as a pure (E)-9-styrylanthracene (1.3 g, 86.9%): |
With sodium methylate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With trichlorophosphate at 60℃; for 4h; | |
20% | With trichlorophosphate at 60℃; for 4h; | |
With phosphorus pentachloride In benzene for 3h; Heating; |
With trichlorophosphate Reflux; | ||
Multi-step reaction with 2 steps 1: sodium hydroxide / ethanol / 8 h 2: thionyl chloride / Reflux | ||
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 0.33 h / Reflux; Microwave irradiation 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 - 22 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sodium hydroxide / ethanol 2: thionyl chloride / 1,2-dichloro-ethane / 4 h / Reflux | ||
Multi-step reaction with 2 steps 1: sodium hydroxide / ethanol / 12 h / 85 °C 2: thionyl chloride / 12 h / 80 °C / Inert atmosphere | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; Reflux; | 4.1.1. General protocol for the synthesis of phosphonchloride14ae14h General procedure: The phosphonchlorides (14ae14h) were prepared fromsubstituted phosphonates [49]. The corresponding materials13ae13e were obtained from commercial source whereas 13f-13hwere prepared via Arbuzov reaction [33]. 13f and 13g were synthesizedaccording to the following procedure. A 10mL Schlenktube with a magnetic stir bar was charged with triisopropyl phosphiteor triethyl phosphite (20 mmol), methyl iodide (30 mmol, 1.5equiv) and N,N-dimethylformamide (10 mL). The reaction mixturewas sealed under N2 atmosphere and stirred at 80 °C for 4 h. Thereaction was monitored by TLC. Upon completion, the mixture wasdiluted with 2 N sodium hydroxide (15 mL) and extracted withdichloromethane (2 20 mL). The organic phases were combinedand washed with water, brine and dried over anhydrous Na2SO4.After being filtered and concentrated, the residue was purified bycolumn chromatography on silica gel to give the desired phosphonates(2.80 g, 78% for 13f and 2.64 g, 87% for 13g) as colorlessoil. 13h were prepared according to the method described by Maet al. [36] as a colorless oil (1.47 g, 53%). 14ae14h were preparedaccording to following procedure. Phosphonate (20 mmol) wasdissolved in dry dichloromethane. The mixture was cooled to 0 °C,and oxalyl chloride (30 mmol, 1.5 equiv) was added slowly. Themixture was stirred at ambient temperature for 30 min and thenallowed to warm to room temperature. Several drops of N,N-dimethylformamide were added as catalyst and the reactionmixture was then refluxed for 8 h. The solvent was evaporatedunder reduced pressure and additional dichloromethane (15 mL)was evaporated three more times to obtain the desired product as agarnet oil. The product was used for the next step without furtherpurification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 15-crown-5; sodium hydride In tetrahydrofuran at 0 - 25℃; for 2h; | |
71% | With potassium hydroxide | |
58% | With potassium <i>tert</i>-butylate In toluene Reflux; Inert atmosphere; | Wittig-Horner general procedure for stilbene 10 synthesis General procedure: To a flame dried round flask was added aryl aldehyde (8.32 mmol) and toluene (83 mL), followed by diethylbenzylphosphonate (1.73 mL, 8.32 mmol). The reaction was stirred at room temperature for 20 min, and KOtBu (980 mg, 8.73 mmol) was added. The reaction was heated to reflux for 7 h monitoring for the disappearance of the aryl aldehyde. The reaction was quenched with water (50.0 mL) and ethyl acetate (75.0 mL) and washed with water (3*75 mL) and brine (3*50 mL). The organic layer was dried over Na2SO4 gravity filtered, and evaporated in vacuo. Purification using flash column chromatography (ethyl acetate/hexanes) afforded the product stilbene 10. |
21% | Stage #1: O,O-diethyl benzylphosphonate With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: 4-methyl-benzaldehyde In tetrahydrofuran at 20℃; for 1h; | |
Stage #1: O,O-diethyl benzylphosphonate With 18-crown-6 ether; sodium methylate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 4-methyl-benzaldehyde In N,N-dimethyl-formamide at 20 - 120℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 130℃; for 16h; Sealed tube; | |
98% | at 150℃; for 6h; | |
97% | for 0.00833333h; Heating; microwave irradiation; |
95% | for 0.0833333h; Irradiation; | |
95% | for 0.0333333h; microwave irradiation; | |
95% | at 150℃; for 0.5h; Microwave irradiation; | 1 EXAMPLE 1 Compound (R) -1 Synthesis 25mL microwave reaction bottle,Add 5 mL (42 mmol) of benzyl bromide,9.5 mL (55 mmol) of triethyl phosphite,150 °C microwave heating conditions,Reaction for 30 minutes. The reaction system was cooled to room temperature and purified by distillation under reduced pressure.Diethyl benzylphosphonate 9.5 g was obtained in a yield of 95%. |
95% | at 140℃; for 0.0833333h; Microwave irradiation; | |
92% | at 120 - 150℃; for 3h; | |
92% | at 120℃; for 12h; Inert atmosphere; | |
92% | for 3h; Reflux; | |
89.9% | In toluene at 140℃; for 2h; | 2.4.1. Diethyl benzylphosphonate (1) Diethyl benzylphosphonate as the basis compound for thesynthesis of the t-APE isomers was prepared according to literature[18,19]. Benzyl bromide (1.50 g, 8.8 mmol) was suspended in 5 mLof toluene, containing triethylphosphite (6.00 g, 35 mmol). The mixture was refluxed at 140 °C for 2 h. Excess triethylphosphite and toluene were removed by distillation to give the required product as a yellow oil (1.80 g, 89.9%). 1H NMR (400 MHz, DMSO-d6) δ 7.53-7.25 (m, 5H),3.96-3.91 (m, 4H), 3.15 (d, J 21.6 Hz, 2H), 1.21(t, J 7.1 Hz, 6H). |
87% | at 150℃; for 4h; | |
82% | at 140℃; for 0.333333h; Inert atmosphere; Microwave irradiation; | |
80% | In xylene Heating; | |
73% | for 24h; Reflux; | |
72% | at 135℃; for 12h; Inert atmosphere; | 1 4.1.1 Diethyl benzylphosphonate (6) Triethylphosphite57,58 (0.5 mL, 0.0029 mmol) was added to benzyl bromide (500 mg, 0.0029 mmol) in a round bottom flask under inert atmosphere and stirred at 135 °C for 12 h. The crude reaction mixture was purified by column chromatography silica gel with AcOEt/hexanes (50:50, rf = 0.44) as eluent to yield (6) as a colorless oil (72%). |
Heating; | ||
at 100℃; for 2h; | ||
at 130℃; | ||
at 140℃; | ||
In N,N-dimethyl-formamide Heating; | ||
With 1-n-butyl-3-methylimidazolium bistrifluoromethylsulfonylamide at 110℃; for 0.333333h; | ||
at 185℃; for 3h; | ||
at 130 - 160℃; for 6h; | ||
at 180℃; | ||
In 1,4-dioxane for 20h; Inert atmosphere; Reflux; | ||
for 8h; Reflux; | ||
at 150℃; for 16h; Dean-Stark; Inert atmosphere; | ||
In tetrahydrofuran at 70℃; for 24h; Inert atmosphere; | 2.1 Synthesis General procedure: Diphenylbutadiene derivatives utilized in this investigation were prepared by using Horner-Wadsworth-Emmons reaction [23] (Scheme 1a) in about 35-60% yields. In a typical procedure, triethyl phosphite (5.74 mmol) was added to the THF solution of benzyl bromide (2.3 mmol) and refluxed for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature and further cooled to 0 °C using an ice bath. Sodium hydride (11.5mmol) was added to this mixture and stirred for 5 min. Aldehyde (2.3 mmol) was subsequently added drop wise to the pale/dark pink colored solution and stirring was continued for additional 30 min. In the case of methyl substituted aldehydes, corresponding (E) geometric isomer of α-methyl cinnamaldehyde (Aldrich) was used. Thin Layer Chromatography (TLC) was utilized to monitor the progress of the reaction and the reaction was quenched by adding water. The organic layer was extracted using dichloromethane and concentrated under reduced pressure. The crude reaction mixture so obtained was purified by column chromatography using silica gel, 5% ethyl acetate in petroleum ether. Starting materials, 4-methylcinnamaldehyde required for the synthesis of ( 2) and nitro cinnamaldehyde required for synthesis of (3) and (5), were obtained by DDQ oxidation of 4-allyl toluene [40] (Scheme 1b) and by simple nitration using a nitrating mixture generated by mixing KNO3 with H2SO4 of α-methyl-cinnamaldehyde (scheme 1c), respectively. Characterization data for all the synthesized dienes were given in the Supplementary information. | |
at 150℃; for 16h; Dean-Stark; Inert atmosphere; | ||
With tetrabutylammonium bromide at 125℃; for 4h; | ||
In acetonitrile at 140℃; for 16h; | ||
at 140℃; for 6h; | ||
In tetrahydrofuran at 75℃; for 30h; | ||
With N,N,N-tributyl-1-butanaminium iodide at 130℃; for 6h; | General Procedure for Arbuzov Reaction (8a,b and 14a-f) General procedure: Triethyl phosphite (1.6 equiv) was added to aryl bromide (1.0 equiv) containing acatalytic amount of tetrabutylammonium iodide (0.01 equiv) and the reaction mixture washeated at 130 °C for 6 h. Excess triethyl phosphite was removed by heating at 80 °C undervacuum. The aryl phosphonate was obtained as colorless oil, which was used for the next stepwithout further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: ortho-bromobenzaldehyde In tetrahydrofuran at 0 - 20℃; | |
90% | With 15-crown-5; sodium hydride In tetrahydrofuran at 0 - 25℃; for 2h; | |
50% | Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran; paraffin oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: ortho-bromobenzaldehyde In tetrahydrofuran; paraffin oil at 20℃; for 17h; Inert atmosphere; |
50% | Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran at 0℃; Stage #2: ortho-bromobenzaldehyde In tetrahydrofuran at 0 - 20℃; for 8h; | |
Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: ortho-bromobenzaldehyde In tetrahydrofuran at 0 - 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 14h; | |
75% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 14h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium hydride In tetrahydrofuran at 25℃; for 3.5h; Heating / reflux; | 12.1 N-Boc-4-piperidone (10 g, 50 mmol) and diethyl benzylphosponate (12.6g, 55 mmol) were taken up in dry THF (50 ml) under N2. NaH (2.4 g, 60 mmol, 60 wt % in oil dispersion) was added to the solution at 25 °C. The resulting mixture was heated at reflux for 3.5 h. The solution was partitioned between EtOAc and saturated NH4Cl, the aqueous layer was extracted with EtOAc and the combined EtOAc layers were washed with brine and dried over MgSO4. Filtration and concentration afforded a yellow oil. Purification via flash chromatography (10/1 hexanes/Et2O, SiO2) gave 9.85 g (72 %) of the desired compound as a solid, m.p. = 63-65 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 10h; | 5 To a suspension of NaH (26 mg, 1 mmol) and 15C5 (5 I1L, 3 mol %) in THF (5 mL) was added phosphonate 43 (25 mg, 0.12 mmol) and aldehyde 28 (15.8 mg, 0.05 mmol) at 0 °C and the reaction mixture was stirred for 10 h at rt. The reaction was quenched by addition of water and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgS04), and concentrated in vacuo. Final purification of the residue by flash column chromatography (35% EtOAc in hexanes) afforded compound 59 (17 mg, 90%) as a clear oil : lH NMR 8 7. 50-7. 47 (m, 2H), 7.37-7. 34 (m, 2H), 7.26-7. 20 (m, 1H), 6.98 (d, J= 8.5 Hz, 2H), 6.91-6. 87 (m, 2H), 3.90 (s, 3H), 3.46-3. 41 (m, 1H), 2.77-2. 75 (m, 1H), 2.72-2. 68 (m, 2H), 2.16-2. 11 (m, 1H), 1.90-1. 81 (m, 2H), 1.74-1. 55 (m, 3H), 1.26 (s, 3H), 1. 11 (s, 3H), 0.89 (s, 3H) ; 13 C NMR 8 149.2, 142.9, 137.9, 129.2, 128.9 (2C), 128.8, 127.4, 126.5, 126.4 (2C), 122.9, 120.8, 107.2, 78.2, 77.3, 56.3, 47.0, 38.6, 37.9, 28.5, 27.6, 23.4, 20.1, 14.5 ; HRMS (EI) calcd for C25H3003 [M+], 378. 2195; found 378. 2195. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In N-methyl-acetamide; | Step 1 (E)-3-Fluoro-4-(2-phenylethenyl)pyridine Diethyl benzylphosphonate (2.8 ml, 13.4 mmol) was added to a solution of sodium methoxide (0.75 g, 13.6 mmol) in anhydrous dimethylformamide (15 ml) and the resultant mixture stirred at room temperature, under nitrogen, for ten minutes. A solution of <strong>[40273-47-0]3-fluoropyridine-4-carboxaldehyde</strong> [prepared by the method of F. Marsais and G. Queguiner, Tetrahedron, 1983, 39, 2009] (1.55 g, 12.4 mmol) in anhydrous dimethylformamide (10 ml) was added and the reaction mixture stirred at room temperature under nitrogen for 21 hours. The reaction mixture was poured into ice-water (125 ml), the precipitated solid collected under suction and washed with water. The aqueous filtrate was extracted with ethyl acetate (100 ml), the extract dried (MgSO4) and concentrated in vacuo to an off. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Hg; phosphorus pentachloride; triethylamine; In dichloromethane; ethyl acetate; benzene; | (b) 1-[N-[Ethoxy(phenylmethyl)phosphinyl]-L-alanyl]-L-proline, phenylmethyl ester A mixture of phenylmethylphosphonic acid diethyl ester (0.92 g., 4.04 mmole) and phosphorus pentachloride (0.85 g., 4.08 mmole) in dry benzene (7 ml.) is refluxed under argon for one hour. The cooled solution is evaporated to dryness at room temperature (0.5 mm. of Hg.), taken up in dry benzene (about 5 ml.) and again evaporated to dryness. The colorless residue is then taken up in dry dichloromethane (10 ml.) and treated with <strong>[13485-59-1]L-alanyl-L-proline</strong>, phenylmethyl ester, hydrochloride salt (1.2 g., 3.84 mmole). The resulting suspension is cooled to 0 (ice bath) under argon and treated dropwise with a solution of triethylamine (1.7 ml., 12.3 mmole) in dry dichloromethane (5 ml.) over a period of 15 minutes. After the addition is complete, the ice bath is removed and the mixture is allowed to stir at room temperature for 30 minutes. The mixture is diluted with ethyl acetate, filtered and evaporated to dryness. The residue is taken up in ethyl acetate and washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, saturated sodium chloride, dried (Na2 SO4) and evaporated. The residue is purified by flash chromatography on silica gel (100 g.) eluding with acetone-hexane (2:3) to give 1.56 g. of 1-[N-[ethoxy(phenylmethyl)phosphinyl]-L-alanyl]-L-proline, phenylmethyl ester as a colorless oil. Tlc (ethyl acetate) shows a single spot at Rf 0.16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: O,O-diethyl benzylphosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: (1R,2Z,4S,5R,6R,7S,8S,9S)-2,4,5,7-tetraethyl-4-formyl-8-methoxymethoxy-5-(methoxymethoxy)methyl-9-methylbicyclo-[4.3.0]non-2-ene In tetrahydrofuran; hexane at -78 - 0℃; for 3h; Inert atmosphere; | |
88% | Stage #1: O,O-diethyl benzylphosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: (1R,2Z,4S,5R,6R,7S,8S,9S)-2,4,5,7-tetraethyl-4-formyl-8-methoxymethoxy-5-(methoxymethoxy)methyl-9-methylbicyclo-[4.3.0]non-2-ene In tetrahydrofuran; hexane at -78 - 0℃; for 3h; Inert atmosphere; | 4.2.18. (1R,2Z,4S,5R,6R,7S,8S,9S)-2,4,5,7-Tetraethyl-8-methoxymethoxy-5-(methoxymethoxy)methyl-9-methyl-4-(1E)-styrylbicyclo[4.3.0]non-2-ene (33) The following reaction was carried out under argon. To a cooled (-78 °C), stirred solution of diethyl benzylphosphonate (0.10 mL, 0.46 mmol) in THF (1.0 mL) was added n-BuLi (0.15 mL of 2.63 M solution in hexane, 0.39 mmol). The mixture was stirred at -78 °C for 30 min and a solution of 32 (31.7 mg, 77.2 μmol) in THF (1.0 mL) was added dropwise at -78 °C. The mixture was warmed to 0 °C over 3 h, quenched with saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (5 mL×3). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 1:100 to 1:60) to provide 32.9 mg (88%) of 33 as a colorless oil: TLC Rf 0.57 (EtOAc/hexane, 1:4); [α]D24 -2.6 (c 0.83, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.81 (t, J=7.5 Hz, 6H), 1.03 (t, J=7.5 Hz, 3H), 1.09 (t, J=7.5 Hz, 3H), 1.28 (d, J=6.6 Hz, 3H), 1.38-1.73 (m, 6H), 1.80-1.97 (m, 2H), 2.13-2.27 (m, 3H), 2.40 (t, J=11.1 Hz, 1H), 3.37 (s, 3H), 3.46 (s, 3H), 3.56 (d, J=10.5 Hz, 1H), 3.58 (d, J=4.2 Hz, 1H), 3.59 (d, J=10.5 Hz, 1H), 4.53 (d, J=7.2 Hz, 1H), 4.64 (d, J=7.2 Hz, 1H), 4.68 (d, J=7.2 Hz, 1H), 4.68 (d, J=7.2 Hz, 1H), 5.13 (br s, 1H), 6.21 (d, J=16.1 Hz, 1H), 6.27 (d, J=16.1 Hz, 1H), 7.19 (tt, J=1.5, 7.1 Hz, 1H), 7.27-7.32 (m, 2H), 7.35 (dd, J=1.5, 8.4 Hz, 2H); 13C NMR (68 MHz, CDCl3) δ 9.5, 9.6, 12.3, 13.6, 14.7, 21.7, 28.1, 28.3, 28.9, 41.0, 44.5, 44.7, 44.9, 51.1, 52.6, 55.4, 55.7, 70.6, 86.3, 93.8, 97.1, 124.3, 126.1 (2C), 126.6, 128.4 (2C), 131.8, 137.9, 138.3, 142.7; IR (neat) 2960, 2880, 1470 cm-1; HRMS calcd for C31H48O4 [M]+ 484.3553, found 484.3550. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: diethyl iodomethanephosphonate With chloro(1,5-cyclooctadiene)rhodium(I) dimer; 1,1'-bis(diphenylphosphino)ferrocene; phenylzinc iodide In tetrahydrofuran at 40℃; for 1h; Inert atmosphere; Stage #2: iodobenzene In tetrahydrofuran at 60℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: p-nitrobenzotrifluoride; O,O-diethyl benzylphosphonate With potassium <i>tert</i>-butylate In tetrahydrofuran at -78℃; for 0.583333h; Stage #2: With potassium permanganate; ammonia In tetrahydrofuran for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: O,O-diethyl benzylphosphonate With sodium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; for 1h; Stage #2: C16H15FN2O In tetrahydrofuran at -78℃; for 2h; | 168 Example 168; (R,E)-l-(4-fluorophenyl)-5,6-dimethyl-5-styryl-4,5-dihydro-lH-indazole; [00364] A 1 M THF solution of NaHMDS (5.59 mL, 3 eq) was added to diethyl benzylphosphonate (1.48 g, 3.5 eq) in THF (50 mL) at -78 0C . The mixture was stirred at 0 0C for 1 h, then cooled to -78 0C. The aldehyde from reaction 144i (503 mg, 1.86 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at -78 0C for 2 h, and quenched with saturated NH4Cl (100 mL). THF was evaporated in EPO vacuo. The residue was extracted with EtOAc (3x100 mL). The extracts were washed with brine (10 mL), dried (MgSO4) and concentrated. Silica gel chromatography (0- 15% EtOAc-hexanes) gave Example 168 (401.5 mg, 63%). MS found: (M+H)+=345. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetra-(n-butyl)ammonium iodide at 120℃; for 24h; Inert atmosphere; | 1 Example 1 Preparation of benzyl phosphonite by triethyl phosphite and benzyl alcohol To a 20 mL tubular reactor was added benzyl alcohol (54.0 mg, 0.50 mmol), triethyl phosphite (166.0 mg,1.0 mmol, 2.0 equiv.) And tetrabutylammonium iodide (3.7 mg, 0.01 mmol, 2 mol%) were protected from vacuum nitrogen and then heated to 120 ° C for 24 h under solvent-free conditions. TLC monitoring reaction is complete,The product was purified by column chromatography and the yield was 90% |
90% | With tetra-(n-butyl)ammonium iodide In neat (no solvent) at 125℃; for 24h; Inert atmosphere; Schlenk technique; Sealed tube; Green chemistry; | |
84% | With zinc(II) iodide In toluene for 12h; Inert atmosphere; Reflux; |
84% | With zinc(II) iodide In toluene at 80℃; for 12h; | General Procedure for Phosphonate Synthesis with Various Phosphites General procedure: To a stirred solution of ZnI2 (1.5 eq) in anhydrous toluene or DMF was added a trialkyl phosphite (3 eq) followed by benzyl alcohol. The reaction mixture was allowed to stir and heated overnight (approximately 12 hours). After it had cooled to room temperature, the reaction mixture was immediately placed on a vacuum line to remove volatiles. The residue then was washed with NaOH until the solids dissolved, extracted with ether, dried (MgSO4), and concentrated in vacuo. The resulting oil was purified via flash column chromatography on silica gel to afford the desired phosphonate. |
70% | With zinc(II) iodide In tetrahydrofuran at 75℃; for 16h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: O,O-diethyl benzylphosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: C27H46O5 In tetrahydrofuran; hexane at -78 - 0℃; for 3h; Inert atmosphere; | 4.4.6. (1R,2Z,4R,5R,6R,7S,8S,9S)-4,5,7-Triethyl-4-[(1E,3E)-2-ethyl-4-phenylbuta-1,3-dien-1-yl]-8-hydroxy-5-hydroxymethyl-2,9-dimethylbicyclo[4.3.0]non-2-ene (53) The following reaction was carried out under argon. To a cooled (-78 °C), stirred solution of diethyl benzylphosphonate (40 μL, 0.19 mmol) in THF (1.0 mL) was added n-BuLi (50 μL of 2.69 M solution in hexane, 0.13 mmol). The mixture was stirred at -78 °C for 30 min and then a solution of aldehyde obtained above (6.2 mg, 14 μmol) in THF (0.7 mL) was added dropwise at -78 °C. The mixture was warmed to 0 °C over 3 h, quenched with saturated aqueous NH4Cl (10 mL) at 0 °C, and extracted with EtOAc (5 mL×3). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 1:70 to 1:50) to provide 5.6 mg (78%) of styryl derivative as a colorless oil: TLC Rf 0.58 (EtOAc/hexane, 1:4); [α]D25.5 -21.0 (c 0.21, CHCl3); 1H NMR (300 MHz, CDCl3)δ0.82 (t, J=7.5 Hz, 3H), 0.85-0.92 (m, 3H), 1.01 (t, J=7.4 Hz, 3H), 1.02 (t, J=7.4 Hz, 3H), 1.26 (d, J=6.0 Hz, 3H), 1.30-1.43 (m, 4H), 1.53-1.59 (m, 2H), 1.62-1.72 (m,1H), 1.78-1.88 (m, 1H), 1.83 (s, 3H), 2.06 (dq, J=7.4, 13.4 Hz, 1H), 2.31-2.41 (m, 1H), 2.35 (t, J=10.8 Hz, 1H), 2.75 (dq, J=7.4, 13.7 Hz, 1H), 3.37 (s, 3H), 3.46 (s, 3H), 3.59 (d, J=9.6 Hz, 1H), 3.60 (d, J=3.6 Hz, 1H), 3.65 (d, J=9.6 Hz, 1H), 4.53 (d, J=6.8 Hz, 1H), 4.63 (d, J=6.6 Hz, 1H), 4.67 (d, J=6.6 Hz, 1H), 4.69 (d, J=6.8 Hz, 1H), 5.43 (br s, 1H), 5.46 (s, 1H), 6.45 (d, J=16.2 Hz, 1H), 6.68 (d, J=16.2 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.30 (t, J=7.6 Hz, 2H), 7.41 (d, J=7.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 9.5, 9.8, 12.4, 14.4, 14.7, 18.9, 21.5, 22.8, 29.0, 29.9, 40.7, 45.6 (2C), 46.2, 52.3, 54.4, 55.5, 55.8, 70.5, 86.2, 94.1, 97.2, 124.6, 126.2 (2C), 126.8, 127.5, 128.7 (2C), 135.0, 135.4 (2C), 139.8, 141.6; IR (neat) 2960, 2930, 2860, 1460 cm-1; HRMS calcd for C34H52O4 [M]+ 524.3864, found 524.3866. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: O,O-diethyl benzylphosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: (1S,2Z,4R,5R,6R,7S,8S,9R)-2,4,5,7-tetraethyl-4-formyl-8-methoxymethoxy-5-(methoxymethoxy)methyl-9-methylbicyclo[4.3.0]non-2-ene In tetrahydrofuran; hexane at -78 - 0℃; for 2h; Inert atmosphere; | 4.3.8. (1S,2Z,4R,5R,6R,7S,9R)-2,4,5,7-Tetraethyl-5-formyl-9-methyl-4-(1E)-styrylbicyclo[4.3.0]non-2-en-8-one (45) The following reaction was carried out under argon. To a cooled (-78 °C), stirred solution of diethyl benzylphosphonate (0.72 mL, 3.5 mmol) in THF (4.0 mL) was added n-BuLi (2.63 M solution in hexane, 1.0 mL, 2.6 mmol). The mixture was stirred at -78 °C for 30 min and a solution of 44 (35.0 mg, 85.2 μmol) in THF (2.2 mL) was added dropwise at -78 °C. The mixture was warmed to 0 °C over 2 h, quenched with saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (5 mL×3). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 1:100) to provide 39.6 mg (96%) of the styryl derivative as a colorless oil: TLC Rf 0.69 (EtOAc/hexane, 1:4); [α]D23 +15.8 (c 0.80, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.76 (t, J=7.5 Hz, 3H), 0.79 (t, J=7.8 Hz, 3H), 1.01 (t, J=7.2 Hz, 3H), 1.06 (t, J=7.5 Hz, 3H),1.03-1.07 (m, 3H), 1.26-1.42 (m, 1H), 1.52-1.87 (m, 5H), 2.16-2.30 (m, 5H), 2.46 (m, 1H), 3.23 (s, 3H), 3.38 (s, 3H), 3.30-3.44 (m, 2H), 3.57 (d, J=9.6 Hz, 1H),4.41 (br, 1H), 4.49 (d, J=6.6 Hz, 1H), 4.58 (d, J=6.9 Hz, 1H), 4.61 (d, J=6.9 Hz, 1H), 5.40 (br s, 1H), 6.22 (d, J=16.2 Hz, 1H), 6.34 (d, J=16.2 Hz, 1H), 7.16 (t, J=7.2 Hz, 1H), 7.24-7.34 (m, 4H); 13C NMR (68 MHz, CDCl3) δ 8.5, 10.0, 12.6, 12.9, 20.1, 24.7 (2C), 28.3, 28.4, 29.1, 43.5, 46.2, 46.3, 46.4 (2C), 55.0, 55.7, 72.5, 94.4, 97.3 (2C), 123.0, 126.0 (2C), 126.4, 128.3 (2C), 130.6, 136.0, 138.6, 140.0; IR (neat) 2960, 2930 cm-1; HRMS calcd for C31H48O4 [M]+ 484.3553, found 484.3552. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaH; In 1,2-dimethoxyethane; | This is based on Journal of Heterocyclic Chemistry, 18(5), 967-72, 1981. NaH (1.3 g, 28 mmol) was added to a mixture of 3-carbaldehydebenzo[b]thiophene (4.27 g, 25 mmol), diethyl benzylphosphonate (5.76 g, 25 mmol) in 50 mL of 1,2-dimethoxyethane at 0 C. under N2 and stirred for 15 minutes at 0 C. and 3 h at room temperature. The reaction mixture was then poured into ice water and filtrated. The solid from the filtration was recrystallized from ethanol to yield 4.5 g of desired product was obtained as a yellow solid. Synthesis of benzo[b]naphtha[2,1-d]thiophene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran at 85℃; for 1h; Inert atmosphere; Stage #2: N-ethyl-3-formylindole In tetrahydrofuran at 85℃; for 12h; Inert atmosphere; | 2.2. General experimental procedure for the synthesis of the A-E General procedure: To diethyl phenyl methyl phosphonate A1 (0.471 g, 2.06 mmol) in dry THF (10 mL) was added NaH (0.043 g, 1.72 mmol). After initial effervescence the suspension was stirred for 1 h at 85 °C under nitrogen. To this 1-ethyl indole-3,5-carboxyaldehyde 6 (0.100 g, 0.689 mmol) in dry THF (10 mL) was added drop wise and the mixture heated to reflex at 85 °C for 12 h. Then cooled to room temperature and poured in to water and extracted with ethylacetate (2× 20 mL). The organic layer was added brine solution (2× 10 mL) and layer was separated and dried with Na2SO4, filtered and concentrated. The crude product was purified by column chromatography using hexane:ethylacetate (60:40) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In the stream of argon, 15.7g of diethyl benzylphosphonate and 100 mL of THF were put in a 1000 mL-recovery flask, and the resulting solution was cooled to -65C. Then, 9.1 g of potassium tert-butoxide was added thereto, and the resulting mixture was allowed to react for 90 minutes. Subsequently, to this reaction liquid, 180 mL of a THF solution in which 17.2g of intermediate i-1 was dissolved was added dropwise, and the resulting mixture was allowed to react for two hours. The reaction liquid was heated with stirring to room temperature over 1 hour, and was allowed to react at room temperature for further 2 hours. The resulting reaction liquid was separated into an aqueous phase and an organic phase by adding clean water and toluene. After extracting the aqueous phase with toluene, the toluene and the organic phase were mixed and washed with clean water and saturated saline, dried with sodium sulfate and concentrated. The resulting solids were re-crystallized from toluene, and the solids thus obtained were dried under reduced pressure, whereby 19.7g of yellowish white solids were obtained. The solids were identified as intermediate i-2 by FD-MS (field desorption mass spectrometry) analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: O,O-diethyl benzylphosphonate With sodium methylate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 6-bromo-2-pyridinecarbaldehyde In N,N-dimethyl-formamide at 0 - 120℃; for 3h; | Intermediate 1 1(E)-2-Bromo-6-styrylpyridine. To a solution of diethyl benzylphosphonate (4.57 mL, 21.91 mmol) in dimethylformamide (50 mL) at room temperature was added sodium methoxide (2.367 g, 43.8 mmol) and 18-Crown-6 (2.316 g, 8.76 mmol). After stirring at room temperature for 5 min, the reaction was cooled to 0°C and treated with 6-bromopicolinaldehyde (4.89 g, 26.3 mmol) as a solid in one portion. The ice bath was removed and the reaction stirred at room temperature for 1 h. The reaction was gradually warmed to 120°C and held there for 2 h. The reaction was cooled to room temperature and poured into water (500 mL) with vigorous stirring. The resulting suspension was extracted with diethyl ether, washed with water (3X), then brine, dried over magnesium sulfate, and concentrated to an oil. The oil was dissolved in hexanes and reconcentrated to give something that appeared to be crashing out as a solid. The resulting residue (solid in oil) was suspended in ethanol, concentrated, and pumped under high vacuum to give a dark-colored, moist solid. The resulting residue was suspended in ethanol (total volume (solid+solution) = 20 ml). The resulting suspension was placed in the freezer and held there overnight. The resulting precipitate was collected by filtration to give 2.46 g (43%) as a faint tan powder. ¾-NMR (CDCI3, 500 MHz) δ 7.69 (d, J=16.2, 1H), 7.60 (d, J=8.9, 2H), 7.53 (dd, J=7.9, 7.6, 1H), 7.41 (dd, J=7.6, 7.3, 2H), 7.31-7.38 (m, 3H), 7.11 (d, J=16.2, 1H). C-NMR (CDCI3, 126 MHz) δ 157.2, 142.3, 138.8, 136.3, 134.5, 128.9, 128.8, 127.4, 126.4, 126.2, 120.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Intermediate 17(E)-2-Bromo-4-styrylpyridine. To a solution of diethyl benzylphosphonate (4.57 mL, 21.91 mmol) in dimethylformamide (50 mL) at room temperature was added sodium methoxide (2.367 g, 43.8 mmol) and 18-Crown-6 (2.316 g, 8.76 mmol). After stirring at room temperature for 5 min, the reaction was cooled to 0°C and treated with 2-bromoisonicotinaldehyde (4.89 g, 26.3 mmol) as a solid in one portion. The ice bath was removed and the reaction stirred at room temperature for 1 h. The reaction was gradually warmed to 120°C and held there for 2 h. The reaction was cooled to room temperature and poured into water (500 mL) with vigorous stirring. The resulting suspension was extracted with diethyl ether (3X), washed with water, then brine, dried over magnesium sulfate, and concentrated to an oil. The resulting residue was purified by column chromatography (6percent EtOAc/Hex- > 12percent EtO Ac/Hex) to give 2.12 g (37percent) as an oil. 3/4-NMR (CDCI3, 500 MHz) delta 8.35 (d, J=5.2, IH), 7.52-7.62 (m, 3H), 7.43 (m, 2H), 7.30-7.40 (m, 3H), 6.98 (d, J=16.2, IH) 13C-NMR (CDCI3, 126 MHz) delta 150.4, 147.7, 143.1, 135.8, 134.8, 129.3, 129.0, 127.3, 125.0, 124.6, 120.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With copper(l) iodide; caesium carbonate In 1,2-dimethoxyethane at 80℃; for 2h; Inert atmosphere; | |
80% | With copper(l) iodide; caesium carbonate In 1,2-dimethoxyethane at 85℃; for 3h; Inert atmosphere; | General procedure: Under an argon atmosphere, the carbonyl compounds (0.40 mmol), TsNHNH2 (0.42 mmol, 1.05 eq) and DME (1.0 mL) were successively added to a flame-dried Schlenk flask. The reaction was heated at 60 ºC with stirring for 30 minutes. After the solution cooled down to room temperature H-Phosphonate 1b (0.40 mmol, 1.0 eq), Cs2CO3 (0.60 mmol, 1.5 eq), and CuI (0.04 mmol, 10 mol %) were sequentially added to the system. The mixture was stirred to 85oC. When the reaction was considered complete, as determined by TLC analysis, the reaction mixture was cooled to room temperature and filtered through a short plug of silica gel [washed with EtOAc]. Solvent was then removed in vacuo to provide a crude mixture, which was purified by silica gel column chromatography to afford pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: O,O-diethyl benzylphosphonate With tetrabutylammomium bromide; sodium hydroxide In toluene Stage #2: 4-methoxy-benzaldehyde In toluene at 35℃; for 4h; | Synthesis of stilbenes in SL-PTC system General procedure: A mixture of DEBP (0.01 mol), TBAB (5 × 10-4 mol), solid NaOH (0.04 mol) and toluene (30 mL) was introduced into a 100 mL flask and stirred at 1400 rpm. Aldehyde (0.01 mol) in 15 mL of toluene was added dropwise at 35 °C. The reaction mixture was stirred for an appropriate time. After completion of the reaction as indicated by TLC, H2O (10 mL) was added and the layers were separated. The organic layerwaswashedwith three 10-mL portions of 5% HCl solution. The organic phase was dried over magnesiumsulphate and evaporated to dryness. The residuewas chromatographed and the product was identified by FT-IR and NMR (1H NMR and 13CNMR). |
84% | With sodium hydroxide at 40℃; for 2h; | 8 A batch of stilbene type compound was prepared by using the following reaction conditions in substantially the same manner as in Example 2, and the reaction conditions and the results are shown in Table 1. |
62% | With sodium hydride In tetrahydrofuran; mineral oil at 50℃; for 0.5h; Inert atmosphere; |
1.33 g | With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: O,O-diethyl benzylphosphonate With tetrabutylammomium bromide; sodium hydroxide In toluene Stage #2: 3-nitro-benzaldehyde In toluene at 35℃; for 0.666667h; | Synthesis of stilbenes in SL-PTC system General procedure: A mixture of DEBP (0.01 mol), TBAB (5 × 10-4 mol), solid NaOH (0.04 mol) and toluene (30 mL) was introduced into a 100 mL flask and stirred at 1400 rpm. Aldehyde (0.01 mol) in 15 mL of toluene was added dropwise at 35 °C. The reaction mixture was stirred for an appropriate time. After completion of the reaction as indicated by TLC, H2O (10 mL) was added and the layers were separated. The organic layerwaswashedwith three 10-mL portions of 5% HCl solution. The organic phase was dried over magnesiumsulphate and evaporated to dryness. The residuewas chromatographed and the product was identified by FT-IR and NMR (1H NMR and 13CNMR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydroxide at 40℃; for 1.5h; | 9 A batch of stilbene type compound was prepared by using the following reaction conditions in substantially the same manner as in Example 2, and the reaction conditions and the results are shown in Table 1. |
45% | Stage #1: O,O-diethyl benzylphosphonate With tetrabutylammomium bromide; sodium hydroxide In toluene Stage #2: 4-nitrobenzaldehdye In toluene at 35℃; for 0.5h; | Synthesis of stilbenes in SL-PTC system General procedure: A mixture of DEBP (0.01 mol), TBAB (5 × 10-4 mol), solid NaOH (0.04 mol) and toluene (30 mL) was introduced into a 100 mL flask and stirred at 1400 rpm. Aldehyde (0.01 mol) in 15 mL of toluene was added dropwise at 35 °C. The reaction mixture was stirred for an appropriate time. After completion of the reaction as indicated by TLC, H2O (10 mL) was added and the layers were separated. The organic layerwaswashedwith three 10-mL portions of 5% HCl solution. The organic phase was dried over magnesiumsulphate and evaporated to dryness. The residuewas chromatographed and the product was identified by FT-IR and NMR (1H NMR and 13CNMR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: O,O-diethyl benzylphosphonate With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: C23H35F3O6Si In tetrahydrofuran at 20℃; for 3h; Inert atmosphere; diastereoselective reaction; | 4.9 Synthesis of 13 To a solution of diethyl benzylphosphonate (2.70g, 11.71mmol) in THF (15mL) at -78°C under nitrogen atmosphere was added NaHMDS (5.80mL, 2.0M in THF, 11.71mmol). After stirring for 30min, a solution of 4 (1.44g, 2.93mmol) in THF (10mL) was added dropwise. The mixture was stirred for 3h at room temperature and then diluted with brine (20mL) and extracted with ethyl ether (30mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. Flash chromatography on silica gel (petroleum ether:ethyl acetate=20:1) of the residue yielded 13 (978mg, 59%) as colorless oil: [α]D21.1 +94.0 (c 0.51, CHCl3); 1H NMR (400MHz, CDCl3, 25°C) δ 7.40-7.30 (m, 5H, Ph), 7.22 (d, J=8.5Hz, 2H, aryl), 6.85 (d, J=8.6Hz, 2H, aryl), 6.60 (d, J=16.0Hz, 1H, PhCH=CH), 6.22 (dd, J=16.0, 7.6Hz, 1H, PhCH=CH), 6.02 (dt, J=12.6, 5.7Hz, 1H, CH=CHCH2), 5.64 (d, J=12.6Hz, 1H, CH=CHCH2), 4.89 (d, J=6.2Hz, 1H, CH3OCH2), 4.81 (d, J=6.2Hz, 1H, CH3OCH2), 4.72 (d, J=7.6Hz, 1H, PhCH=CHCH), 4.40 (s, 2H, O-CH2-aryl), 4.31 (d, J=5.6Hz, 2H, CH=CHCH2), 3.81 (s, 3H, OCH3), 3.37 (s, 3H, CH2OCH3), 0.91 (s, 9H, SiC(CH3)3), 0.11 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3); 13C NMR (101MHz, CDCl3) δ 159.2, 136.6, 135.9, 134.0, 130.4, 129.4, 128.7, 128.0, 127.1, 126.6, 125.2 (q, J=294Hz, CF3), 121.9, 113.8, 92.8, 83.0 (q, J=24.7Hz, CF3C), 74.7, 72.3, 67.2, 56.7, 55.3, 25.7, 18.1, -3.8, -5.1; 19F NMR (376MHz, CDCl3) δ -70.78 (s, 3F, CF3); IR (thin film) vmax 2942, 2896, 2853, 1642, 1513, 1457, 1252, 1181, 1086cm-1; Anal. Calcd for C30H41F3O5Si: C, 63.58; H, 7.29. Found: C, 63.58, H, 7.42%. |
Yield | Reaction Conditions | Operation in experiment |
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96% | Stage #1: O,O-diethyl benzylphosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: 2-(diphenylphosphino)formylferrocene In tetrahydrofuran; hexane at 25 - 60℃; for 13.5h; | 2.6.3. General procedure for the Horner-Wadsworth-Emmons reaction of ferrocenecarboxaldehydes and diethylbenzyl phosphonates General procedure: The respective diethyl benzylphosphonate (3.1 equiv.) dissolved in anhydrous tetrahydrofuran (8 mL/mmol) was treated dropwise within 10 min with n-BuLi (2.5 M in hexanes, 2.0 equiv.) at 78 °C. After stirring for 30 min at this temperature a solution of the ferrocenecarboxaldehyde (1.0 equiv.) in anhydrous tetrahydrofuran (5 mL/mmol) was added within 3 min. The reaction mixture was stirred for 90 min at 25 °C and for 12 h at 60 °C. After addition of brine the organic phase was separated, washed with three times with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product obtained was filtered through a pad of alumina (dichloromethane) and subsequently recrystallized from toluene. |
Yield | Reaction Conditions | Operation in experiment |
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78% | Stage #1: O,O-diethyl benzylphosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: 2-(bis(5-methylfuran-2-yl)phosphino)formylferrocene In tetrahydrofuran; hexane at 25 - 60℃; for 13.5h; | 2.6.3. General procedure for the Horner-Wadsworth-Emmons reaction of ferrocenecarboxaldehydes and diethylbenzyl phosphonates General procedure: The respective diethyl benzylphosphonate (3.1 equiv.) dissolved in anhydrous tetrahydrofuran (8 mL/mmol) was treated dropwise within 10 min with n-BuLi (2.5 M in hexanes, 2.0 equiv.) at 78 °C. After stirring for 30 min at this temperature a solution of the ferrocenecarboxaldehyde (1.0 equiv.) in anhydrous tetrahydrofuran (5 mL/mmol) was added within 3 min. The reaction mixture was stirred for 90 min at 25 °C and for 12 h at 60 °C. After addition of brine the organic phase was separated, washed with three times with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product obtained was filtered through a pad of alumina (dichloromethane) and subsequently recrystallized from toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: O,O-diethyl benzylphosphonate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: 2-(tri-n-butylstannyl)formylferrocene In tetrahydrofuran; hexane at 25 - 60℃; for 13.5h; | 2.6.3. General procedure for the Horner-Wadsworth-Emmons reaction of ferrocenecarboxaldehydes and diethylbenzyl phosphonates General procedure: The respective diethyl benzylphosphonate (3.1 equiv.) dissolved in anhydrous tetrahydrofuran (8 mL/mmol) was treated dropwise within 10 min with n-BuLi (2.5 M in hexanes, 2.0 equiv.) at 78 °C. After stirring for 30 min at this temperature a solution of the ferrocenecarboxaldehyde (1.0 equiv.) in anhydrous tetrahydrofuran (5 mL/mmol) was added within 3 min. The reaction mixture was stirred for 90 min at 25 °C and for 12 h at 60 °C. After addition of brine the organic phase was separated, washed with three times with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product obtained was filtered through a pad of alumina (dichloromethane) and subsequently recrystallized from toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: O,O-diethyl benzylphosphonate With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃; for 0.0666667h; Inert atmosphere; Stage #2: 3-formyl-1H-indazole-6-carbonitrile In N,N-dimethyl-formamide at 0℃; for 0.666667h; Inert atmosphere; | 4.2.3 (E)-3-(2-(Pyridin-4-yl)vinyl)-1H-indazole-6-carbonitrile (1) To a suspension of 4-(chloromethyl)pyridine hydrochloride (3.28g, 20mmol) in PhH (50mL) was added 40% aq NaOH (1.35mL). The resulting mixture was sonicated for 10min and filtered. The residue was treated with additional PhH (10mL), sonicated and filtered. The combined PhH layers were dried (Na2SO4) to give a solution of 4-(chloromethyl)pyridine in PhH. To a solution of diethyl phosphite (3.03g, 22mmol) in PhH (35mL) was added freshly cut Na (510mg, 22mmol). The resulting mixture was refluxed (oil temp. 90°C) for 30min then cooled to 0°C. The solution of 4-(chloromethyl)pyridine in PhH obtained above was added dropwise to this solution via dropping funnel over 10min. After addition, the resulting mixture was refluxed for 3h (oil temp. 100°C) and LC-MS indicated the completion of reaction. After cooling to rt, the insoluble white precipitate (NaCl) was filtered off and rinsed with PhH (20mL). The filtrate was concentrated and dried under high vacuum to give 3.50g colorless oil which was redissolved in DMF (25mL). It was cooled to 0°C and treated with t-BuOK (3.36g, 30mmol) portion wise over 2min; the reaction turned dark reddish brown. After stirring for 2min at 0°C, a solution of 3-formyl-1H-indazole-6-carbonitrile54 (1.71g, 10mmol) in DMF (15mL) was added dropwise by pipette over 5min. After addition, the resulting mixture was stirred for 40min at 0°C before quenching with ice, 2M aq HCl, H2O and adjusted pH to about 8 using NaHCO3. The resulting precipitate was collected by filtration and rinsed with H2O, then dried under high vacuum to give the title compound (2.016g, 82%) as a beige solid. 1H NMR (400MHz, DMSO-d6) δ 13.90 (s, 1H), 8.60-8.54 (m, 2H), 8.43 (d, J=8.0Hz, 1H), 8.20 (s, 1H), 7.88 (d, J=16.8Hz, 1H), 7.73-7.67 (m, 2H), 7.60-7.52 (m, 2H); MS ESI 247.0 [M+H]+, calcd for [C15H10N4+H]+ 247.1. HRMS (ESI) m/z calcd for [C15H10N4+H]+ 247.0984, found 247.0985; HPLC: >99A% at 214nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.0833333h; Stage #2: 3-(4-nitrophenyl)-propenal In tetrahydrofuran at 0℃; for 0.5h; | 2.1 Synthesis General procedure: Diphenylbutadiene derivatives utilized in this investigation were prepared by using Horner-Wadsworth-Emmons reaction [23] (Scheme 1a) in about 35-60% yields. In a typical procedure, triethyl phosphite (5.74 mmol) was added to the THF solution of benzyl bromide (2.3 mmol) and refluxed for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature and further cooled to 0 °C using an ice bath. Sodium hydride (11.5mmol) was added to this mixture and stirred for 5 min. Aldehyde (2.3 mmol) was subsequently added drop wise to the pale/dark pink colored solution and stirring was continued for additional 30 min. In the case of methyl substituted aldehydes, corresponding (E) geometric isomer of α-methyl cinnamaldehyde (Aldrich) was used. Thin Layer Chromatography (TLC) was utilized to monitor the progress of the reaction and the reaction was quenched by adding water. The organic layer was extracted using dichloromethane and concentrated under reduced pressure. The crude reaction mixture so obtained was purified by column chromatography using silica gel, 5% ethyl acetate in petroleum ether. Starting materials, 4-methylcinnamaldehyde required for the synthesis of ( 2) and nitro cinnamaldehyde required for synthesis of (3) and (5), were obtained by DDQ oxidation of 4-allyl toluene [40] (Scheme 1b) and by simple nitration using a nitrating mixture generated by mixing KNO3 with H2SO4 of α-methyl-cinnamaldehyde (scheme 1c), respectively. Characterization data for all the synthesized dienes were given in the Supplementary information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: O,O-diethyl benzylphosphonate With 15-crown-5; sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.666667h; Inert atmosphere; Stage #2: N-ethyl-4-piperidone In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; | 4-benzylidene-1-ethylpiperidine (7) In a flame-dried and argon-flushed roundbottomflask, to a solution of diethyl benzylphosphonate (1.2 mL, 1.27 g, 5.57 mmol, 1.5equiv) and 15-crown-5 (150 μL, 167 mg, 0.76 mmol, 0.2 equiv) in dry THF (17 mL) at 0°C was added sodium hydride 60% dispersion in mineral oil (223 mg, 5.57 mmol, 1.5equiv, portion-wise addition). After stirring 40 min at 0 °C, a solution of 1-ethyl-4-piperidone (500 L, 472 mg, 3.71 mmol, 1 equiv) in dry THF (30 mL) was addeddropwise at 0 °C. After stirring at 0 °C for 10 min, the reaction mixture was allowed towarm up and stir at room temperature until completion (TLC in CH2Cl2/MeOH 9/1),which occurred after 4 days. The mixture was cooled to 0 °C, diluted with deionizedwater, and then the product was extracted three times with EtOAc. The organic layer waswashed with saturated aqueous NaHCO3 and saturated brine, then dried over MgSO4. Thesolvent was removed under reduced pressure to yield a yellow oil that was purified on asilica gel column (CH2Cl2/MeOH 96/4) to afford the desired product as a pale yellowishoil (337 mg, 45 % yield) |
45% | Stage #1: O,O-diethyl benzylphosphonate With 15-crown-5; sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.666667h; Inert atmosphere; Stage #2: N-ethyl-4-piperidone In tetrahydrofuran; mineral oil at 0 - 20℃; | 49 Example 49 4-benzylidene-1-ethylpiperidine (7). In a flame-dried and argon-flushed roundbottom flask, to a solution of diethyl benzylphosphonate (1.2 mL, 1.27 g, 5.57 mmol, 1.5 equiv) and 15-crown-S (150 pL, 167 mg, 0.76 mmol, 0.2 equiv) in dry THF (17 mL) at 0 00 was added sodium hydride 60% dispersion in mineral oil (223 mg, 5.57 mmol, 1.5 equiv, portion-wise addition). After stirring 40 mm at 0 00 a solution of 1-ethyl-4-piperidone (500 pL, 472 mg, 3.71 mmol, 1 equiv) in dry THF (30 mL) was added dropwise at 0 00 After stirring at 0 00 for 10 mm, the reaction mixture was allowed to warm up and stir at room temperature untilcompletion (TLC in 0H2012/MeOH 9/1), which occurred after 4 days. The mixture was cooled to 0 00 diluted with deionized water, and then the product was extracted three times with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and saturated brine, then dried over MgSO4. The solvent was removed under reduced pressure to yield a yellow oil that was purified on a silica gel column (0H2012/MeOH 96/4) to afford the desiredproduct as a pale yellowish oil (337 mg, 45 % yield). R = 0.33 in 0H2012/MeOH 85/15; 1HNMR (CD3OD, 300 MHz): O 7.33-7.26 (m, 2H), 7.21-7.15 (m, 3H), 6.35 (5, 1H), 2.65 (dd, J=6.5, 5.1 Hz, 2H), 2.58-2.49 (m, 6H), 2.48-2.42 (m, 2H), 1.15 (t, J= 7.3 Hz, 3H); 130 NMR(CD3OD, 75MHz): O 139.2, 138.8, 129.9, 129.2, 127.4, 125.1, 55.7, 54.9, 53.2, 36.4, 29.3,11.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With sodium hydride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; mineral oil; for 6h;Reflux; | To a solution of diethyl benzylphosphonate (256 mg, 1.12 mmol) and 4-thiazolecalbaldehyde (122 mg, 1.08 mmol) in 3 ml of dry 1,2-dimethoxyethane, 60percentsodium hydride in oil (80 mg, 2.0 mmol) and 3 drops of DMF were added. The mixture was heated slowly to reflux with stirring for 6h. After cooled to rt, a large excess of water was added and the solution was extracted three times with CH2Cl2. The combined organic layerwas washed with brine and dried over anhydrous MgSO4. Evaporation of the solvent gave acrude solid, which was purified by silica gel column chromatography employing a 1:3mixture of AcOEt-hexane as an eluent to afford 81 mg (40 percent) of (E)-4-styrylthiazole (1b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; mineral oil; for 6h;Reflux; | General procedure: To a solution of diethyl benzylphosphonate (256 mg, 1.12 mmol) and 4-thiazolecalbaldehyde (122 mg, 1.08 mmol) in 3 ml of dry 1,2-dimethoxyethane, 60%sodium hydride in oil (80 mg, 2.0 mmol) and 3 drops of DMF were added. The mixture was heated slowly to reflux with stirring for 6h. After cooled to rt, a large excess of water was added and the solution was extracted three times with CH2Cl2. The combined organic layerwas washed with brine and dried over anhydrous MgSO4. Evaporation of the solvent gave acrude solid, which was purified by silica gel column chromatography employing a 1:3mixture of AcOEt-hexane as an eluent to afford 81 mg (40 %) of (E)-4-styrylthiazole (1b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | Stage #1: O,O-diethyl benzylphosphonate With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-[3-(dimethylamino)propoxy]benzaldehyde In tetrahydrofuran; hexane for 16h; Inert atmosphere; | 1 Example 1-Preparation of (E)-N,N-dimethyl-3-(4-styrylphenoxy)propan-1-amine 15a n-BuLi (2.5M in hexanes, 0.57 mL, 1 .42 mmol) was added to a stirred solution of diethyl benzylphosphonate (0.3 mL, 1 .42 mmol) in THF (2 mL) at 0 °C, and stirred for 30 min. A solution of the aldehyde 17a (0.24 mL, 1 .21 mmol) in THF was then added dropwise to the reaction, which was then stirred for 16 h. The reaction mixture was quenched with NH4CI (sat. aq. sol. 20 mL) and extracted with EtOAc (3 x 30 mL). The organic phase was dried (Na2S04), filtered and concentrated in vacuo to yield the crude product. Purification by recrystallisation in Pet Ether (40-60 °C) afforded the title compound as a white solid (22 mg, 7%). mp 75-77 °C; umax (cm 1) 2940 (w), 2774 (w), 1687 (w), 1602 (m), 1510 (s), 1246 (s), 1 178 (s), 1055 (s); δΗ (400 MHz, DMSO-d6) 7.56 (2H, m, arom.), 7.53 (2H, apparent ddd J 8.7, 2.9, 2.1 , H10, H1 1 ) 7.36 (2H, m, arom.), 7.23 (2H, m, arom.), 7.08 (1 H, d, J 16.3, H7), 6.94 (2H, apparent ddd J 8.7, 2.9, 2.1 , H12, H13), 4.01 (2H, t J 6.5, H15), 2.44 (2H, t, J 7.0, H17), 2.21 (6H, s, H18), 1 .87 (2H, m, H16); 5C (100 MHz, DMSO-06) 158.4 (C14), 137.4 (C6), 129.6 (C9), 128.7 (C2, C3), 128.1 (C8), 127.8 (C10, C1 1 ), 127.2 (C1 ), 126.2 (C4, C5), 126.1 (C7), 1 14.7 (C12, C13), 65.7 (C15), 55.5 (C17), 44.9 (C18), 26.6 (C16); m/z (ESI+) 282 ([M+H]+); HRMS (ESI+) C19H24NO ([M+H]+) requires 282.1852, found 282.1855. |
7% | Stage #1: O,O-diethyl benzylphosphonate With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.5h; Stage #2: 4-[3-(dimethylamino)propoxy]benzaldehyde In tetrahydrofuran; hexane for 16h; | (E)-N,N-Dimethyl-3-(4-styrylphenoxy)propan-1-amine OX03371 n-BuLi (2.5M in hexanes, 0.57 mL, 1.42 mmol) was added to a stirred solution of diethyl benzylphosphonate (0.3 mL, 1.42 mmol) in THF (2 mL) at 0 °C, and stirred for 30 min. A solution of the aldehyde 17a (0.24 mL, 1.21 mmol) in THF was then added dropwise to the reaction, which was then stirred for 16 h. The reaction mixture was quenched with NH4Cl (sat. aq. sol. 20 mL) and extracted with EtOAc (3 x 30 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to yield the crude product. Purification by recrystallisation in Pet Ether (40-60°C) afforded the title compound as a white solid (22 mg, 7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium hydride In tetrahydrofuran; mineral oil at -10 - 20℃; for 3.33333h; Inert atmosphere; | |
51% | With potassium <i>tert</i>-butylate In toluene at 120℃; for 0.666667h; Microwave irradiation; | 1 25mL microwave reaction bottle,Add 0.5 g (4.1 mmol) of salicylaldehyde,1.1 g (4.5 mmol) of diethyl benzyl phosphate and 15 mL of toluene,Then 1.38 g (12 mmol) of potassium tert-butylate are added,The reaction was carried out for 40 minutes under microwave heating at 120°C. Cool to room temperatureWater quench, ethyl acetate extraction, saturated sodium chloride wash,Anhydrous sodium sulfate drying, concentration, column layer Analysis, 0.41 g of (E)-o-styrylphenol was obtained as a white solid.Yield 51%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | General procedure: To a flame-dried 100 mL round-bottom flask NaHMDS (2 mmol, 1 eq) in THF (5 mL) were addedand the solution was cooled down to 0 C. A solution of the corresponding benzyl phosphonate(II) (2 mmol, 1 eq) in THF (12 mL) was added dropwise under stirring. The reaction was stirred fora further 10 min at 0 C, then a solution of the haloaldehyde (I) (2 mmol, 1 eq) in THF (4 mL) wasadded dropwise. The mixture was allowed to warm from 0 C to room temperature 12-14 h understirring. The reaction mixture was quenched with water (10 mL). The aq layer was extracted withEt2O (3 x 10 mL). The combined organic layers were washed with 10% aq NaHSO3 (2 x 5 mL)and then with brine (10 mL). The combined organic layers were dried over Na2SO4 andconcentrated by evaporation in vacuo to give 10a-c. (10a: E/Z: 10:1, 10b: E, 10c: E/Z: 20:1). TheE-isomers of compounds 10a?-c? was obtained using column chromatography (2.0% EtOAc inpetroleum ether) from mixtures of 10a-c. The E/Z ratio was determined by 1H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: O,O-diethyl benzylphosphonate With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: N,N,N′,N'-tetrakis(4-benzoylphenyl)ethylenediamine In tetrahydrofuran for 72h; Inert atmosphere; Reflux; | 2.2.2. General procedure for the preparation of 3(a-e) General procedure: To tert-BuOK (1290 mg, 11.5 mmol) in a two-necked round bottomflask under nitrogen was added THF (100.0 mL) and diethyl-4-methylbenzylphosphonate (1.18 g, 3.84 mmol). After stirring the resultingsolution for at rt for 1 h, 2 (500 mg, 0.64 mmol) was added, and thereaction mixture heated at reflux for 72 h. After this time, the mixturewas cooled to rt, diluted with chloroform (300.0 mL), washed with 1%aqueous HCl, water, and brine, and dried over MgSO4. Following filtration,the resulting solution was concentrated under reduced pressureto afford the crude product. Purification was by column chromatography. N,N,N′,N′-Tetrakis(4-(1,2-diphenylvinyl)phenyl) ethylenediamine(3a) was prepared by the reaction of tert-BuOK (1290 mg, 11.5 mmol), diethyl benzyl phosphonate (876 mg, 3.84 mmol), and 2 (500 mg,0.64 mmol). The crude product was purified by column chromatographyto afford 3a (552 mg, 80.0%) as pale yellow powders.Mp = 105-107 °C (uncorrected); TLC Rf 0.70 (CHCl3:n-hexane = 2:1);UV-Vis (chloroform): λmax (ε) = 292, 362 nm; IR (KBr): ν(cm-1) = 3023 (w), 2922 (s), 2853 (m), 1590 (m), 1505 (s), 1374 (m),1220 (m), 1181 (m), 812 (m), 695 (s); 1H NMR (600 MHz, CDCl3, δ) δ7.37-7.25 (m, 16H), 7.23-7.16 (m, 8H), 7.14-7.04 (m, 20H), 7.01-6.88(m, 16H), 4.11-4.02 (m, 4H); Anal. Calcd for C82H64N2: C, 91.41; H,5.99; N, 2.60. Found: C, 91.39; H, 6.06; N, 2.60. |
74% | Stage #1: O,O-diethyl benzylphosphonate With potassium <i>tert</i>-butylate In tetrahydrofuran for 1h; Inert atmosphere; Stage #2: N,N,N′,N'-tetrakis(4-benzoylphenyl)ethylenediamine In tetrahydrofuran for 72h; Reflux; | 2 0.56 g (4.99 mmol) of potassium tert-butoxide was added to a round bottom flask, Air was removed for 30 minutes using a vacuum pump, then argon gas was introduced. Then, 300 ml of THF was added using a syringe0.88 g (3.84 mmol) of diethylbenzyl phosphonate were mixed and stirred for 1 hour. Then, in Example 1Was added 0.5 g (0.64 mmol) of the compound prepared in Reference Example 1 and refluxed for 72 hours. After the reaction, a 1% aqueous solution of HCl was added,After cooling down, it was diluted with chloroform. The organic layer was then washed with water and saturated aqueous NaCl solution,After removing fine water using MgSO4, the solvent was distilled off under reduced pressure. Then,Chromatography yielded 74%The light yellow, 7 (N, N, N ', N'-tetrakis (4- (1-phenyl-2- (4- tertbutylphenyl)Vinyl) phenyl) ethylenediamine). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: methyl 4-formylbenzoate In tetrahydrofuran at 0 - 20℃; for 1h; | To a solution of NaH (72 mg, 3.0 mmol, 1.5 eq) in THF (4.0 mL) was added diethylbenzylphosphonate (0.69 g, 3.0 mmol, 1.5 eq) in THF (1.0 mL) at 0oC for 0.5 h, then,methyl 4-formylbenzoate (0.32 g, 2.0 mmol, 1.5 eq) in THF (1.0 mL) was addeddropwise. The resulting solution was stirred at room temperature for 1.0 h, extractedwith EtOAc (3 × 20 mL), the combined EtOAc layers were washed with brine (3 × 20mL) and dried over Na2SO4 and concentrated in vacuo. Purification by flash columnchromatography (PE : EtOAc = 20:1, v/v) afforded the desired product 6q. |
Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: methyl 4-formylbenzoate In tetrahydrofuran at 20℃; for 1h; | 4.1.6. General synthesis of the compound 25 General procedure: To a suspension of NaH (1.5 equiv.) in THF was added the correspondingphosphate reagent (1.5 equiv.) in THF at 0 °C withstirring. After stirring for 0.5 h, methyl 4-formylbenzoate (1.0equiv.) in THF was added dropwise to the reaction mixture. Theresulting mixture was stirred at room temperature for 1 h, quenched with H2O, extracted with EtOAc, and dried over Na2SO4.Compound 22 was obtained by silica gel chromatography. To aproduct 22 in EtOH was added hydrazine monohydrate (15.0equiv.) andwas then refluxed overnight. After cooling, the resultingprecipitate was filtered to give 23. A solution of the compound 23,bromoacetic acid (1.0 equiv.) and EDCI (1.0 equiv.) in DMF wasstirred at room temperature for 1 h. The crude was diluted withEtOAc,washed with H2O, and dried over Na2SO4. The resulting solidwas used for the next reaction without purification. DIEA (5.0equiv.) was added to a solution of the crude product 24 in DMF andthen the mixture was stirred overnight at 70 °C. After cooling, thereaction mixture was diluted with H2O, extracted with EtOAc, anddried over Na2SO4. Purification by preparative HPLC (H2O with 0.1%TFA/ACN with 0.1% TFA, 50/50 to 95/5 in 35 min, flow rate 1.0 mL/min) afforded the pure compound 25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.3% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 50 - 60℃; for 2h; Inert atmosphere; Large scale; | 5 Preparation of benvitimod 100L reactor was added anhydrous tetrahydrofuran 20L, 3,5-diethylamino-4-isopropylbenzaldehyde 10 kg (37.84 mol) and 8.64 kg of benzyl phosphonic acid diethyl ester (commercially available, 37.84 mol)open the stirring, the reactor vacuum and filled with nitrogen,Continuous replacement three times to make it complete,A suspension of potassium tert-butoxide and anhydrous tetrahydrofuran (4.25 kg: 20 L) was added dropwise,The reaction temperature is not higher than 50 °C, the addition is completed, the reaction is continued for 2 hours,After completion of the reaction, 5 kg of potassium t-butoxide and 30 L of distilled water were added and reacted at 60 ° C for 2 hours. To tetrahydrofuran, add 50L ethyl acetate, extract the separation, distilled water to wash the pH to 7, evaporated to acetic acid B Ester to give a pale yellow solid which was recrystallized twice from a mixed solvent of ethyl acetate-n-hexane,Dried in vacuo to give 8.88 kg of a white solid, the molar yield was 92.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: O,O-diethyl benzylphosphonate With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.333333h; Inert atmosphere; Stage #2: 10-(2-ethylhexyl)-3,7-diformylphenoxazine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; | 2.2. Materials 3,7-Di(2-phenylethenyl)-10-(2-ethylhexyl)phenoxazine (4) wasprepared by the reaction of the di-aldehyde 3 with an excess ofdiethyl benzylphosphonate in dry tetrahydrofuran (THF). Potassiumtert-butoxide (0.4 g, 4 mmol) and dry THF (10 mL) were placedin a flask at room temperature under nitrogen atmosphere. Diethylbenzylphosphonate (0.73 mL, 3.2 mmol) was added dropwise tothe solution at 0 °C under nitrogen. The reaction mixture wasstirred for 20 min. Then di-aldehyde 3 (0.24 g, 0.7 mmol)was addedto the reaction mixture. The resulting solution was stirred at roomtemperature under the basic conditions for 2 h, by which time thestarting compound 3 reacted completely. Then the mixture waspoured into ice water and extracted with chloroform. Organicfraction was dried by Na2SO4 and the solvent was removed byevaporation. The product was purified by column chromatographywith silica gel using ethyl acetate/hexane (vol. ratio 1:5) as aneluent. Yield: 0.27 g (79%) of yellow crystals. M.p.: 155 °C (DSC).MS (APCI+, 20 V): 500,29 ([M+H]+, 100%). 1H NMR (400 MHz,DMSO, δ, ppm): 7.54 (d, J 7.3 Hz, 4H, Ar), 7.35 (t, J 7.3 Hz, 4H, Ar),7.23 (t, J 7.3 Hz, 2H, Ar), 7.09-7.01 (m, 6H, Ar, CHCH), 6.98 (d,J 8.5 Hz, 2H, Ar), 6.73 (d, J 8.5 Hz, 2H, Ar), 3.56 (m, 2H, CH2),1.87-1.76 (m, 1H, CH), 1.48-1.19 (m, 8H, CH2), 0.89 (t, J 7.1 Hz, 3H,CH3), 0.83 (t, J 7.1 Hz, 3H, CH3). 13C NMR spectrum (CDCl3, δ,ppm): 11.65, 14.15, 23.15, 26.32, 29.46, 32.37, 37.21, 63.14, 114.78,118.78, 120.47, 124.42, 126.47, 127.41, 128.08, 128.78, 135.23, 137.61,142.77. Elemental analysis for C36H37NO % Calc.: C 86.53, H 7.46, N2.80; % Found: C 86.02, H 7.53, N 2.77. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.2% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 21h; Inert atmosphere; Reflux; | 4.3.2 Synthesis of 3-(1-(4-bromophenyl)-2-phenylvinyl)-9-ethyl-9H-carbazole (2) Compound 1(3.78g, 10mmol) and diethyl benzylphosphonate(3.42g, 15mmol) were dissolved in 150mL dry THF and stirred under N2. Then potassium tert-butoxide (2.24g, 20mmol) was added quickly at 0°C.The solution reacted at 0°Cfor 3h, at room temperature for12h and then refluxed for 6h. When the reaction mixture was cooled to room temperature, it was poured into ice water and extracted with dichloromethane. The combined organic layer was dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography with petroleum ether/CH2Cl2 (4:1) as an eluent to afford compound 2in yield of 78.2%(3.6g).1H NMR (600MHz, CDCl3) δ 8.11-7.89 (m, 2H), 7.52-7.08 (m, 14H), 7.07-7.01 (d, J=29.3Hz, 1H), 4.45-4.35 (q, 2H), 1.53-1.44 (t, 3H). |
72.9% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 21h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 21h; Inert atmosphere; Reflux; | |
80% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 25h; Inert atmosphere; Reflux; | 1.2 (2) Synthesis 9-ethyl-3-(1,2-diphenylvinyl)-6-bromocarbazole; In a 250 mL vessel with a stirrer3-benzoyl-6-bromo-9-ethyl-9H-carbazole (3.78 g, 10 mmol) and diethyl benzylphosphonate (3.42 g, 15 mmol) were added, and then Dry THF 150 mL was added under nitrogen atmosphere, followed by the slow addition of potassium tert-butoxide (2.24 g, 20 mmol) at 0° C., followed by maintaining the temperature for 1 h, then refluxing for 24 h; after the reaction was terminated and cooled to room temperature, the reaction mixture Extraction with CH2Cl2; the organic layer was washed with water and then dried over anhydrous MgSO4;The column was finally separated to give 9-ethyl-3-(1,2-diphenylvinyl)-6-bromocarbazole in a yield of 80% (3.643 g). |
80% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; Inert atmosphere; | 2.1.3. Synthesis of 3-bromo-9-ethyl-6-(1, 2-diphenylvinyl)-9H-carbazole (3) (3-bromo-9-ethyl-9H-carbazol-6-yl)(phenyl)methanone(1) (3.78 g,10 mmol) and diethyl phenylmethylphosphonate (3.42 g, 15 mmol)were added to anhydrous THF (150 mL) in a double neck round bottomflask under an argon atmosphere. After the mixture was cooled to 0 °Cin ice water bath, t-BuOK (2.24 g, 20 mmol) were added and thenkeeping 0 °C reacted 3 h. Subsequently, the mixture was allowed towarm to room temperature continued reaction 12 h and then heated toreflux for 6 h. Upon completion of the reaction, the mixture was concentratedin vacuo. The resulting residue was washed with water(40 mL) and extracted with dichloromethane (3×20 mL). The organiclayer was collected and evaporated the solvent. The crude product waspurified by silica-gel chromatography (dichloromethane: petroleumether 1:2 as eluent) to give 3 as a yellowish solid in 80% yield (3.643 g).1H NMR (600 MHz, CDCl3) δ 8.13 (d, J=37.1 Hz, 1H), 7.95 (d,J=53.5 Hz, 1H), 7.56-7.08 (m, 14H), 7.04 (d, J=8.7 Hz, 1H), 4.37(dd, J=10.9, 7.1 Hz, 2H), 1.50-1.44 (m, 3H). 13C NMR (151 MHz,CDCl3) d(ppm): 144.34, 144.14, 144.07, 141.76, 140.45, 139.33,139.13, 135.37, 131.90, 131.87, 130.72, 128.42, 128.09, 128.02,126.77, 126.63, 126.60, 125.09, 123.88, 123.48, 121.83, 111.87,108.13, 37.86, 13.84. MS: (m/z) 451.091. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: 6-(10-(3-formyl-9-hexyl-9H-carbazol-6-yl)anthracen-9-yl)-9-hexyl-9H-carbazole-3-carbaldehyde In tetrahydrofuran at 0 - 20℃; for 36.5h; Inert atmosphere; | 2.4.3. General procedure for synthesis of 9,10-bis(9-hexyl-6-((E)-styryl)-9H-carbazol-3-yl)anthracene (6a-c) General procedure: To mechanically stirred solution of aryl phosphonate (5a-c) (3eq) inTHF (for 5c in DMF) was added NaH (for 5c KOt-Bu) (8 eq.) portionwiseat 0 °C and the mixture stirred for 30 min under N2 atmosphere.Thereafter, solution of compound (4) (1 eq.) was added dropwise tocooled mixture within 10 min. The solution was allowed to stir for anadditional 30 min, then warmed to RT and stirred for 36 h. The reactionwas quenched with cold water and extracted with dichloromethane.The combined organic layers were washed with brine and dried(MgSO4). The solvent was evaporated to afford crude product (6a-c). 2.4.3.1. 9-Hexyl-3-(10-(9-hexyl-3-styryl-9H-carbazol-6-yl)anthracen-9-yl)-6-styryl-9H-carbazole (6a). 6a was purified by a columnchromatograhpy on silica-gel using dichloromethane/hexane (1:1) asan eluent. Further purification of 6a was recrystallized with chloroformto yield compound as a yellow solid (0.155 g, 55%); m.p. 318.4 °C. FTIR(KBr, cm-1): 2945, 2851, 1626, 1593, 1487, 1387, 960, 805, 767, 755,692, 674.1H NMR (500 MHz, CDCl3): δH=8.28 (d, 2H, J=4.5), 8.22(dd, 2H, 2J=1 3J=11), 7.84 (dd, 4H, 2J=3 3J=7), 7.73 (d, 2H,J=9), 7.65-7.6 (m, 4H), 7.53 (dd, 4H, 2J=4.5 3J=7), 7.48 (d, 2H,J=9), 7.36-7.28 (m, 10H), 7.22 (t, 2H, J=14.5), 7.13 (dd, 2H,2J=6.5 3J=16.5), 4.44 (t, 4H, J=7), 2.06-2.0 (m, 4H), 1.56-1.5 (m,4H), 1.45-1.33 (m, 8H), 0.93 (t, 6H, J=7). 13C NMR (125 MHz,CDCl3): 143.4, 142.9, 140.6, 140.4, 133.3, 132.3132.2, 131.9, 131.4,131.3, 130.2, 130.0, 129.6, 128.8, 127.5, 127.4, 126.0, 125.8, 125.7,121.4, 111.7, 111.4, 46.1, 34.3, 31.8, 29.8, 25.3, 16.7.MS: C66H60N2;exp. m/z [M]+ 880,2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: 7,7′-bis(dimethylamino)-2,2′-bis(methoxymethoxy)-[1,1′-binaphthalene]-3,3′-dicarbaldehyde In tetrahydrofuran at 20℃; for 12h; | 2 Synthesis method: Benzyl phosphateDiethyl ester(501mg, 2.2mmol)Dissolved in 20mL anhydrous tetrahydrofuran and cooledTo 0 °C.To the above solution was added NaH (100 mg, 60%, 2.5 mmol).After stirring at 0 ° C for 1 hour,Add 7,7'-bis(dimethylamino)-2,2'-bis(methoxymethoxy)-[1,1'-binaphthalene]-3,3'-dialdehyde (516 mg, 1 mmol).Remove the ice bath,The reaction solution was stirred at room temperature for 12 hours.After the reaction,Add ice water,The organic phase was extracted twice with ethyl acetate. CombinedThe subsequent organic phase is washed with a saturated sodium chloride solution.It was then dried over anhydrous sodium sulfate.Rotate the organic solvent,The crude product obtained was subjected to silica gel column chromatography.Petroleum ether/ethyl acetate (V/V=12:1)Elution yielded 290 mg of the product as a yellow solid.The yield was 45%. |
45% | Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #2: 7,7′-bis(dimethylamino)-2,2′-bis(methoxymethoxy)-[1,1′-binaphthalene]-3,3′-dicarbaldehyde In tetrahydrofuran; hexane at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-bromo-benzaldehyde In tetrahydrofuran; mineral oil at 20℃; for 12h; Inert atmosphere; | General Procedure for HWE Olefination (9a) To a solution of arylphosphonate (1.2 equiv) in THF at 0 C under Ar atmosphere, NaH(60% dispersion in mineral oil, 2.0 equiv) was slowly added, and thereaction was stirred for 30 min. A solution of the correspondingbenzaldehyde (1.0 equiv) in THF was added dropwise and theresulting reaction mixture was stirred at rt for 12 h. The reactionwas monitored by TLC. After completion of the reaction, themixture was cooled to 0 C and excess NaH was quenched withwater. The reaction mixture was poured on ice, followed by theaddition of 2.0 N HCl till pH 6 was obtained and the product wasextracted with EtOAc. The combined organic layers were washedwith brine, dried over MgSO4, filtered, and concentrated in vacuo.Purification by Flash Column Chromatography (FCC) afforded thedesired (E)-stilbene. To a solution of arylphosphonate (1.2 equiv) in THF at 0 C under Ar atmosphere, NaH(60% dispersion in mineral oil, 2.0 equiv) was slowly added, and thereaction was stirred for 30 min. A solution of the correspondingbenzaldehyde (1.0 equiv) in THF was added dropwise and theresulting reaction mixture was stirred at rt for 12 h. The reactionwas monitored by TLC. After completion of the reaction, themixture was cooled to 0 C and excess NaH was quenched withwater. The reaction mixture was poured on ice, followed by theaddition of 2.0 N HCl till pH 6 was obtained and the product wasextracted with EtOAc. The combined organic layers were washedwith brine, dried over MgSO4, filtered, and concentrated in vacuo.Purification by Flash Column Chromatography (FCC) afforded thedesired (E)-stilbene.(E)-1-Bromo-4-styrylbenzene (9a). Purification by FCC (silica gel,0e5% EtOAc in hexanes) afforded 9a as a white solid (0.54 g, 30%yield). 1H NMR (CDCl3, 400 MHz) d 7.51e7.46 (m, 4H), 7.37 (d, J 8.8 Hz, 4H), 7.28 (d, J 8.0 Hz, 1H), 7.09 (d, J 16.0 Hz, 1H), 7.02(d, J 16.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 136.9, 136.2, 131.7,129.4,128.7,127.9,127.8,127.4,126.5,121.3; RP-HPLC purity 96.0% at254 nm, tR 25.32 min. |
30% | Stage #1: O,O-diethyl benzylphosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-bromo-benzaldehyde In tetrahydrofuran; mineral oil at 20℃; for 12h; Inert atmosphere; | 1.1.1 The general experimental procedure for HWE olefination is as follows (Compound 9a): To a solution of aryl phosphonate (1.2 equiv) in THF at 0° C. under argon gas was slowly added NaH (60% dispersion in mineral oil, 2.0 equiv) and the reaction stirred for 30 minutes. A solution of the corresponding benzaldehyde (1.0 eq) in THF was added dropwise and the resulting reaction mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to 0° C. and the excess NaH was quenched with water. The reaction mixture was poured into ice, then 2.0N HCl was added until pH 6, and the product was extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (FCC) gave the desired (E)-stilbene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium persulfate; silver(l) oxide In 1,2-dimethoxyethane; water at 40℃; | 16 Add phenylacetic acid (68 mg, 0.5 mmol), diethyl phosphite (69 mg, 0.5 mmol), sodium persulfate (238 mg, 1.0 mmol), and silver oxide (12.4 mg, 0.1 mmol) to the reaction flask.React with ethylene glycol dimethyl ether / water (2.5 mL: 2.5 mL) at 40 oC;TLC follows the reaction to completion;The crude product obtained after the reaction was separated by column chromatography (dichloromethane: methanol = 98: 2) to obtain the target product (yield 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; potassium carbonate In 1,4-dioxane at 100℃; for 4h; Schlenk technique; Inert atmosphere; | 4.2. Experimental procedure General procedure: In an oven dried 25 mL Schlenk tube was charged with benzyl ammonium triflates 1 (0.2 mmol), P(O)H compounds 2 (0.24 mmol, if it is liquid, add it after charging N2), Pd(OAc)2 (0.006 mmol, 3 mol %), DPPF (0.008 mmol, 4 mol %) and K2CO3 (0.4 mmol, 2.0 equiv), after charging N2 for three times, dioxane (2.0 mL) was added. The reaction mixture was reacted at 100 °C for 4 h. After completion of the reaction, the reaction mixture was concentrated under vacuum. The desired product was isolated by column chromatography over silica gel (300-400 mesh) using petroleum ether-ethyl acetate as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium methylate In N,N-dimethyl-formamide at 20℃; for 2h; | 2 Preparation Example 2: Meta-alkenyl aromatic compound: Add 98 mg (0.5 mmol) 2-methyl-5-(2-pyridyl)benzaldehyde, 114 mg (0.5 mmol) benzyl diethyl phosphate, 27 mg (0.5 mmol) sodium methoxide to a 20 mL pressure-resistant reaction tube 1mL DMF, stirred at room temperature for 2 hours, after the reaction, column chromatography. The target product 2-(4-methyl-3-styrenephenyl)pyridine was obtained in 126 mg with a yield of 86%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium methylate In N,N-dimethyl-formamide at 20℃; for 2h; | 3 Preparation Example 3: Meta-alkenyl aromatic compound: In a 20 mL pressure-resistant reaction tube, add 107 mg (0.5 mmol) 3-(2-pyridyl)-6-methoxybenzaldehyde, 114 mg (0.5 mmol) benzyl diethyl phosphate, 27 mg (0.5 mmol) sodium methoxide , 1mL DMF, stirred at room temperature for 2 hours, after the reaction,Column chromatography separated the target product 2-(3-styrene-4-methoxyphenyl)pyridine 112mg in 78% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium methylate In N,N-dimethyl-formamide at 20℃; for 2h; | 5 Preparation Example 5 of meta-alkenyl aromatic compound: Add 92 mg (0.5 mmol) 3-(2-pyrimidinyl)benzaldehyde, 114 mg (0.5 mmol) benzyl diethyl phosphate, 27 mg (0.5 mmol) sodium methoxide, 1 mL DMF to a 20 mL pressure-resistant reaction tube, and stir at room temperature 2 hours, after the reaction, column chromatography to obtain the target product 2-(3-styrenyl-phenyl)pyrimidine 119mg, yield 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium methylate In N,N-dimethyl-formamide at 20℃; for 2h; | 4 Preparation Example 4 of meta-alkenyl aromatic compound: Add 129 mg (0.5 mmol) 2-phenyl-5-(2-pyridyl)benzaldehyde, 114 mg (0.5 mmol) benzyl diethyl phosphate, 27 mg (0.5 mmol) sodium methoxide to a 20 mL pressure-resistant reaction tube 1mL DMF, stirred at room temperature for 2 hours, after the reaction, column chromatography to obtain the target product 2-(4-phenyl-3-styrylphenyl)pyridine 126mg, yield was 76%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium methylate In N,N-dimethyl-formamide at 20℃; for 2h; | 1 Preparation Example 2: Meta-alkenyl aromatic compound: Add 92 mg (0.5 mmol) 3-(2-pyridyl)benzaldehyde, 114 mg (0.5 mmol) benzyl diethyl phosphate, and 27 mg (0.5 mmol) sodium methoxide to a 20 mL pressure-resistant reaction tube.1mL DMF, stirred at room temperature for 2 hours, after the reaction, column chromatography to obtain the target product 2-(3-styrene phenyl)pyridine 121mg, yield 94%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.8% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 20 - 40℃; for 4h;Inert atmosphere; | Under nitrogen protection, to compound a (623mg, 1.64mmol) and diethyl benzylphosphonate (1122mg, 4.92mmol) was added N, N'- dimethylformamide (DMF, 6mL), stirring reaction for 30min To completely dissolve the solid. Control the reaction temperature at 25C, add potassium tert-butoxide (1838mg, 16.4mmol) to the reaction mixture, stir the reaction at room temperature for 2h, then warm up to 40C and stir the reaction for 2h; after stopping the reaction, add a large amount of water to the system to quench Reaction, acidify the system with acetic acid, filter under reduced pressure, extract, dry, and filter to remove the solvent; the residue is subjected to silica gel column chromatography (eluent: petroleum ether/dichloromethane = 7/1, v/v), vacuum After drying, intermediate compound b was obtained with a yield of 822 mg and a yield of 94.8%. |
Tags: 1080-32-6 synthesis path| 1080-32-6 SDS| 1080-32-6 COA| 1080-32-6 purity| 1080-32-6 application| 1080-32-6 NMR| 1080-32-6 COA| 1080-32-6 structure
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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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