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CAS No. : | 3466-32-8 | MDL No. : | MFCD00025065 |
Formula : | C7H7BrO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FJLFSYRGFJDJMQ-UHFFFAOYSA-N |
M.W : | 235.10 | Pubchem ID : | 77014 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 47.24 |
TPSA : | 42.52 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.85 cm/s |
Log Po/w (iLOGP) : | 1.64 |
Log Po/w (XLOGP3) : | 1.25 |
Log Po/w (WLOGP) : | 2.93 |
Log Po/w (MLOGP) : | 2.28 |
Log Po/w (SILICOS-IT) : | 1.8 |
Consensus Log Po/w : | 1.98 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.42 |
Solubility : | 0.888 mg/ml ; 0.00378 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.74 |
Solubility : | 4.27 mg/ml ; 0.0181 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.57 |
Solubility : | 0.0634 mg/ml ; 0.00027 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.9 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
91% | With potassium phosphate In 1-methyl-pyrrolidin-2-one at 100℃; for 18 h; Inert atmosphere | Pd(acac)2 (6.1 mg, 0.02 mmol, 0.5 mol percent) and Xantphos (23.2 mg, 0.04 mmol, 1 mol o) are introduced into a flared flask provided with coolant. 4-bromophenylmethylsulfone of formula (III, XBr) (1.17 g, 5 mmol), acetylpicoline of formula (II) (541 mg, 4 mmol) and K3PO4 (2.55 g, 12.0 mmol, 3 eq) are added thereto. Once the argon atmosphere has been stabilized with vacuum-argon cycles, anhydrous and degassed NMP (15 ml) is added with a syringe. The mixture is then kept stirred under stirring in an argon atmosphere for 18 h at 100° C. The conversion is quantitative. The reaction mixture is diluted with a saturated solution of NaHCO3 (50 mL) and extracted with AcOEt (4.x.50 mL). The combined organic phases were washed with an aqueous solution saturated with NaHCO3 (30 mL), anhydrified on MgSO4 and concentrated in a vacuum. The residue was purified by silica gel chromatography using AcOEt/cyclohexane as eluent in a gradient from 5:5 to 10:0. 1.05 g product were obtained, for a molar yield of 91percent as a white crystalline solid. |
75% | With tris-(dibenzylideneacetone)dipalladium(0); [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; sodium t-butanolate In toluene for 5 h; Inert atmosphere; Reflux | Xantphos 0.00267 g (0.0046 mmol) and Pd2(dba)3 0.00177 g (0.0031 mmol) in 15 ml of anhydrous toluene were charged in a reactor under inert atmosphere. 4-bromophenyl methyl sulfone 0.724 g (3.078 mmol) and 3-acetyl-6-methyl pyridine 0.416 g (3.079 mmol) were then added. The mixture was heated to reflux and a suspension of t-BuONa 0.71 g in 15 ml of anhydrous toluene was added dropwise over about 4 h. After about 1 h from completion of the addition, the reaction mixture was cooled to 20 °C and a solution of diluted hydrochloric acid to acidic pH was added. The aqueous phase was separated and added dropwise over 1 h to a mixture of water 8.3 g, ethyl acetate 15.3 g and sodium bicarbonate 2.1 g at 60 °C. At addition completed and after maintaining the temperature at 60 °C for 1 h, it was checked that the pH was between 4 and 7, the mixture was cooled to 20 °C filtered and dried under vacuum at 50 °C. 0.67 g of the compound of formula 1 was obtained with a yield of 75 percent. |
75% | With tris-(dibenzylideneacetone)dipalladium(0); [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; sodium t-butanolate In toluene for 4 h; Inert atmosphere; Reflux | Xantphos 0.00267 g (0.0046 mmol) and Pd2(dba)3 0.00177 g (0.0031 mmol) in 15 ml of anhydrous toluene were charged in a reactor under inert atmosphere. 4-bromophenyl methyl sulfone 0.724 g (3.078 mmol) and 3-acetyl-6-methyl pyridine 0.416 g (3.079 mmol) were then added. The mixture was heated to reflux and a suspension of t-BuONa 0.71 g in 15 ml of anhydrous toluene was added dropwise over about 4 h. After about 1 h from completion of the addition, the reaction mixture was cooled to 20°C and a solution of diluted hydrochloric acid to acidic pH was added. The aqueous phase was separated and added dropwise over 1 h to a mixture of water 8.3 g, ethyl acetate 15.3 g and sodium bicarbonate 2.1 g at 60°C. At addition completed and after maintaining the temperature at 60°C for 1 h, it was checked that the pH was between 4 and 7, the mixture was cooled to 20°C filtered and dried under vacuum at 50 °C. 0.67 g of the compound of formula 1 was obtained with a yield of 75 percent. |
72% | With tris-(dibenzylideneacetone)dipalladium(0); [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; sodium t-butanolate In toluene for 5 h; Inert atmosphere; Reflux | EXAMPLE 1 [0068] Synthesis of 1-(6-methylpyridin-3-yl)-2-[(4-methylsulfonyl)-phenyl]-ethanone. [0069] Xantphos 0.027 g (0.0477 mmol) and Pd2(dba)3 0.0182 g (0.0198 mmol) in 100 ml of anhydrous toluene were charged in a reactor under inert atmosphere. 4-bromophenyl methyl sulfone 9.3 g (39.7 mmol) and 3-acetyl-6-methyl pyridine 5.4 g (39.7 mmol) were then added. The mixture was heated to reflux and a suspension of t-BuONa 8.4 g in 100 ml of anhydrous toluene was added dropwise over about 4 h. After about 1 h from completion of the addition, the reaction mixture was cooled to 20° C. and a solution of diluted hydrochloric acid to acidic pH was added. The aqueous phase was separated and added dropwise over 1 h to a mixture of water 83.3 g, ethyl acetate 153 g and sodium bicarbonate 20.1 g at 60° C. At addition completed and after maintaining the temperature at 60° C. for 1 h, it was checked that the pH was between 4 and 7, the mixture was cooled to 20° C., filtered, and dried under vacuum at 50° C. 8.3 g of the compound of formula 1 were obtained with a yield of 72percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 23℃; for 12h; | |
100% | With dihydrogen peroxide In propyl alcohol; lithium hydroxide monohydrate at 25℃; for 5h; | |
100% | With sodium (meta)periodate; ruthenium on carbon In lithium hydroxide monohydrate at 20℃; for 2h; | 6 Add 0.01 g of Ru / C catalyst and 235 mg (1.1 mmol) of sodium periodate to the reaction flask, add 3 mL of water, and then add 203 mg (1 mmol) of 4-bromoanisole I-6 to the reaction with stirring In the flask, react for 2h at room temperature. The reaction of 4-bromoanisole was detected by TLC, and the reaction was stopped. The reaction solution was filtered and washed with dichloromethane (10 mL × 2), and the filtrate and the washing solution were combined. It was washed twice with saturated sodium chloride solution, and water was removed with anhydrous sodium sulfate. The solvent was distilled off and dried to obtain high-quality compound II-6, yield 100%. |
99% | With dihydrogen peroxide In lithium hydroxide monohydrate; butan-1-ol at 50℃; for 3h; | |
99% | With (Bu4N)2[{MoO(O2)2}2(μ-O)]; dihydrogen peroxide In acetonitrile for 24h; | Encouraged by the proficiency of 1 in the oxygenation of MPS,the catalytic performance of 1 was examined with additional substrateslisted in Chart 1 under the same conditions as those for theMPS reaction, and the results are collected in Table 1. Using oneequiv of H2O2, the reaction of BPS produced 53% sulfoxide and23% sulfone at 3 h, which indicates both a 100% utility of H2O2and lack of selectivity for sulfoxide. With 2.0 equiv of H2O2, BPSwas converted to the corresponding sulfone at 24 h. Compared tothe reactions of MPS and BPS, the reaction with PPS is significantlyslower, yielding 50% sulfoxide and 30% sulfone at 4 h. The reactionwith 4BT was slightly faster than that of MPS and resulted in 81%sulfoxide and 5% sulfone in 0.5 h (TOF: 910 h1). Lastly, PTEproceeded to 66% sulfoxide and 9% sulfone in 0.5 h for a TOF of660 h1. At 24 h, the reaction with PTE still contained 10% sulfoxidealong with 86% sulfone. This is possibly due to the conversionof PTE to the corresponding aldehyde as a minor side product |
99% | With sodium (meta)periodate In dichloromethane; lithium hydroxide monohydrate; acetonitrile at 75℃; for 1h; | |
98% | With anhydrous potassium sulfate; sulfuric acid potassium salt; potassium peroxomonosulfate; wet-montmorillonite In dichloromethane for 3h; Ambient temperature; | |
98% | With potassium peroxomonosulfate; kaolin In dichloromethane for 5h; Ambient temperature; | |
98% | With dihydrogen peroxide In lithium hydroxide monohydrate at 80℃; for 5.08333h; Green chemistry; | 2.6. General procedure for catalytic oxidation of sulfides to sulfones General procedure: To a stirred solution of 5 mmol sulfide in 5 mL water, 0.01 mmol of Ti containing catalyst [PATi (2.81 mg) or PMATi (3.77 mg)] was added, followed by addition of 50% H2O2 (1.36 mL, 20 mmol) in a round bottom flask. The Ti: substrate molar ratio was maintained at 1 : 500 and the substrate: H2O2 molar ratio at 1 : 4. The reaction was conducted at 80 °C temperature. The reaction was monitored by thin-layer chromatography (TLC) and GC. After completion of the reaction, the system was allowed to cool to room temperature. The sulfone obtained was then isolated, purified and characterized by following similar procedure as mentioned under above section. |
98% | With oxygen at 100℃; for 20h; Schlenk technique; chemoselective reaction; | |
97% | With dihydrogen peroxide In lithium hydroxide monohydrate at 20℃; for 1.33333h; Green chemistry; chemoselective reaction; | 2.4. General procedure for oxidation of sulfides General procedure: The catalytic protocol for the oxidation of sulfides was as follows:catalyst (0.005 mmol of Nb) [Catalyst 1 (16.7 mg) or Catalyst 2 (13.9mg)] and 5 mmol of the substrate was placed in a 50 mL two-neckedround-bottomed flask. With constant magnetic stirring at room temperature,50% H2O2 (0.68 mL, 10 mmol) was added to the reactionmixture. The molar ratio of Nb:MPS:oxidant was fixed at 1:1000:2000.Thin-layer chromatography (TLC) and GC were used to monitor theprogress of the reaction. As the reaction was completed, the catalyst wasseparated from the mixture by filtering and repeatedly washed withacetone. The unreacted organic substrates, also the products of the reactionwere extracted using diethyl ether and dried with anhydrousNa2SO4 subsequently distilled under reduced pressure to remove theexcess of diethyl ether. Column chromatography was carried out topurify the products where ethyl acetate:hexane (1:9) was used as themobile phase. IR, NMR spectral analysis, and melting point determinationwere mainly applied for the characterization of the obtainedproducts. |
96% | With oxygen In phosphate buffer; <i>tert</i>-butyl alcohol at 55℃; for 10h; | |
96% | With potassium peroxomonosulfate In methanol; lithium hydroxide monohydrate at 0 - 20℃; for 16h; | |
96% | With dihydrogen peroxide In acetonitrile at 20℃; for 0.5h; | |
95% | With dihydrogen peroxide In lithium hydroxide monohydrate at 20℃; for 10h; | |
95% | With oxygen; epi-Cercosporin In methanol at 25℃; for 24h; Irradiation; | 5 Example 5 Catalytic Synthesis of 4-Bromo-Phenyl methyl Sulfone by Cercosporin Catalyst In a 10 mL reaction tube, cercosporin (0.005 mmol) and 4-bromo-phenyl methyl sulfide (0.5 mmol) were sequentially added.2mL of methanol, then oxygen protection, 15W white light irradiation, room temperature 25 ° C reaction for 24h.Rapid object separated by thin layer silica gel plates 300-500 The reaction solution was evaporated to dryness using a rotary evaporator the solvent used is acetic acid eluent ethyl acetate / petroleum ether (v: v = 1: 5),4-Bromo-phenyl methyl sulfone was obtained in a yield of 95%. |
95% | With sodium (meta)periodate; ammonium acetate; C24H28ClN4O2Ru(1+)*F6P(1-) In dichloromethane; lithium hydroxide monohydrate; acetonitrile at 25℃; for 8h; | |
94% | With 1-butyl-3-methylimidazolium perrhenate; dihydrogen peroxide; 1-n-butyl-3-methylimidazolium tetrafluoroborate In lithium hydroxide monohydrate at 60℃; for 2h; Schlenk technique; Inert atmosphere; Green chemistry; | 2.3 Catalytic oxidation of sulfides General procedure: To a stirred solution of sulfide (10mmol) and [C4mim][ReO4] (0.1955g, 5 mol%) in [C4mim][BF4] (2mL), an aqueous solution of hydrogen peroxide (35% in water) (3.5mL, 40mmol) is added in 2-3 portions at 60°C. The progress of the reaction is followed by TLC. The reaction mixture is extracted with diethyl ether (5×10mL) and the extract is dried over anhydrous MgSO4. The yield and selectivity of methyl phenyl sulfone are calculated from calibration curves (r2>0.999) recorded using 3-methylanisole and 1,4-diacetylbenzene as internal standard. The crude product is obtained by rolling evaporation and purified by column chromatography separation (silica gel using hexane/ethyl acetate 90:10 v/v). The RTIL phase is diluted with CH2Cl2 and then treated with MnO2 to destroy the excess peroxide. The obtained liquid is first dried over anhydrous MgSO4 and then for 4h in vacuo at 50°C to remove CH2Cl2. Fresh substrate and hydrogen peroxide are then added for a new reaction cycle. All products are characterized by melting point, 1H NMR, 13C NMR and IR spectroscopy (see Supporting information). |
94% | With lithium hydroxide monohydrate; N-(benzenesulfonyl)-N-fluorobenzenesulfonamide at 50℃; for 24h; chemoselective reaction; | |
93% | With tert.-butylhydroperoxide; lanthanum(III) oxide In lithium hydroxide monohydrate; ethyl acetate at 150℃; for 5.5h; | |
91% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; Cooling with ice; | |
89% | With potassium permanganate; Rexyn 101 H ion exchange resin In dichloromethane for 6h; Heating; | |
88% | With dihydrogen peroxide In lithium hydroxide monohydrate; acetonitrile at 60℃; for 0.5h; | |
88% | With dihydrogen peroxide at 20℃; for 0.333333h; Green chemistry; chemoselective reaction; | |
88% | With diethylene glycol dibutyl ether; oxygen; sodium trifluoro-methanesulfinate at 20℃; for 48h; Irradiation; | |
86% | With dihydrogen peroxide In 1,2-dichloro-ethane for 0.416667h; Reflux; | |
86% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; 4-methoxyisoquinoline; oxygen; copper(II) sulphate In methanol at 65℃; for 72h; Schlenk technique; Sealed tube; Green chemistry; | 17 Example 17: Preparation of 4-bromophenyl methyl sulfone from 4-bromophenyl methyl sulfide TEMPO (3.9 mg, 0.025 mmol) was added to a 100 mL Schlenk reaction tube in turn. Methanol (1 mL), CuSO4 (4.0 mg, 0.025 mmol), 4-methoxyisoquinoline (39.8 mg, 0.25 mmol), 4-bromophenyl methyl sulfide(101.6 mg, 0.5 mmol), Filled with 1 atm of oxygen, The sealed reaction tube was heated to 65 ° C for 72 h. After completion of the reaction, the mixture was cooled to room temperature, and an appropriate amount of ethyl acetate was added, and a blue solid was precipitated from the reaction mixture, which was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography. The product was obtained in a yield of 86%. |
85.8% | With sulfur(VI) fluoride; dihydrogen peroxide; potassium carbonate In methanol at 23 - 32℃; Sealed tube; | 12 Example 12: Synthesis of 4-bromophenylmethyl sulfone Add 4 mL of methanol to a 25 mL round bottom two-necked flask, then add 4-bromoanisole (0.5mmol, 62.1mg), then add 30% H2O2 (6.0eq., 0.3mL), potassium carbonate (4.0eq., 276.4 mg), using two straight piston straight-bending joints at the same time, while connecting the balloon with a hose, while injecting SO2F2 gas, stirring and reacting at room temperature of 2332 for 2040min under sealed conditions. After the reaction, the solid potassium carbonate was removed by filtration, dried with anhydrous sodium sulfate to remove water and filtered again. The solvent was concentrated to obtain a crude product, which was finally separated and purified by column chromatography to obtain 99.3 mg of 4-bromophenylmethyl sulfone with a yield of 85.8 %. |
84% | With diethylene glycol dibutyl ether; oxygen at 110℃; for 20h; | |
80% | With tetra-n-butylammonium tetrafluoroborate; oxygen In dichloromethane at 20℃; for 10h; Electrochemical reaction; Green chemistry; | |
79% | With lithium hydroxide monohydrate In acetonitrile at 20℃; Electrochemical reaction; Flow reactor; | |
75% | With potassium permanganate supported on montmorillonite K10 at 20℃; for 3h; | |
75% | With potassium peroxomonosulfate In methanol; lithium hydroxide monohydrate at 5 - 20℃; for 5h; | |
73% | With diethylene glycol dibutyl ether; oxygen at 150℃; Green chemistry; | |
59% | With tetra-n-butylammonium tetrafluoroborate; lithium hydroxide monohydrate In methanol at 25℃; for 10h; Electrochemical reaction; | |
55% | With Benzo<c>thioxanthon; oxygen In acetonitrile at 20℃; Sealed tube; Irradiation; | General procedure E to the synthesis of sulfones General procedure: A solution of sulfides 1 (0.2 mmol, 1.0 equiv) or sulfoxides 2 (0.2 mmol, 1.0 equiv), photocatalyst (c, 5 mol%), and ACN (1 mL, 0.2 M) was sealed in an oven-dried reaction tube equipped with an oxygen balloon (gas-switch three times with oxygen balloon). The reaction was agitated under 18 W 405 nm LEDs at room temperature for 12 to 24 h. The progress of the reaction was monitored by GC-MS or/and TLC. After completion of the reaction, the solvent was removed under reduced pressure, and the crude product 3 was purified by flash silica chromatography using n-hexane and ethyl acetate as eluent (v/v, 80:20). |
52% | With hydrogenchloride; tetra-n-butylammonium perchlorate; oxygen In lithium hydroxide monohydrate; acetonitrile for 0.166667h; Electrochemical reaction; Flow reactor; Green chemistry; | |
51% | With potassium peroxomonosulfate In lithium hydroxide monohydrate; propan-2-one at 20℃; for 16h; | 1013.2 Step-2: Synthesis of 1-bromo-4-(methylsulfonyl)benzene To a stirred solution of (4-bromophenyl)(methyl)sulfane (0.5 g, 2.47 mmol) in acetone (10 mL) was added Oxone(0.76 g, 2.47 mmol) in water (5mL) then, reaction mass was stirred at room temperature for 16h. Reaction was monitored by TLC. On completion reaction was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulphate, concentrated under reduced pressure obtained 1-bromo-4-(methylsulfonyl)benzene (0.3g, 51%) as light brown solid. MS: 235.17[M++1] |
45% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane | 65 To a solution of 4-bromothioanisole (22.3 g, 11 mmol) in DCM (250 ml) was added m-chloroperoxybenzoic acid (40 g, 23 mmol) in 10 g portions. The precipitate was removed by filtration and washed with DCM. The filtrate was evaporated in vacuo and the resultant solid recrystallized from EtOH (c.a 180 ml) to yield the title compound as colourless crystals 11.7 g (45%). Mp 103-106° C. |
With permanganate(VII) ion; glacial acetic acid | ||
With lithium hydroxide monohydrate; permanganate(VII) ion | ||
With dihydrogen peroxide; glacial acetic acid | ||
With potassium permanganate; glacial acetic acid | ||
With dihydrogen peroxide In glacial acetic acid | ||
With manganese sulphate; dihydrogen peroxide; Sodium hydrogenocarbonate In acetonitrile at 20℃; for 24h; | ||
With potassium peroxomonosulfate In methanol | ||
Multi-step reaction with 2 steps 1.1: aq. hydrogen peroxide; MnSO4*H2O / acetonitrile / 24 h / 20 °C 2.1: VO(acac)2; (R)-diiodo Shiff base ligand / CHCl3 / 1 h / 22 °C 2.2: aq. hydrogen peroxide / CHCl3 / 20 h / 0 °C | ||
With hydrated [2-percarboxyethyl]-functionalized silica In carbon dioxide at 40℃; for 3h; Supercritical conditions; Autoclave; liquid CO2; chemoselective reaction; | ||
With dihydrogen peroxide In chloroform-d1; lithium hydroxide monohydrate at 35℃; for 0.25h; | ||
With dihydrogen peroxide In lithium hydroxide monohydrate at 20℃; for 24h; Green chemistry; chemoselective reaction; | ||
With (dimethyl dioctadecylammonium)7[PW11O39]; dihydrogen peroxide In 1,4-dioxane; lithium hydroxide monohydrate at 59.84℃; for 0.5h; | 2.3. Catalytic reaction General procedure: Catalyst (8 μmol), 1,4-dioxane (2 ml), substrate (1 mmol), and H2O2( 2.5 mmol, 30% aq.) were charged in the reaction flask. The reaction was carried out at 333 K for 0.5 h. After reaction, with the dropping of temperature, the catalyst gradually precipitated from solution. It was separated by centrifugation and washed with Et2O, then dried under vacuum and used for the next oxidation cycle. The filtrate was analyzed by GC using bromobenzene as internal standard. The organic products were obtained by vacuum rotary evaporator, and identified by 1H NMR. | |
With Na10K22[Zr24O22(OH)10(H2O)2(W2O10H)2(GeW9O34)4(GeW8O31)2]*85H2O; dihydrogen peroxide In dodecane; acetonitrile at 60℃; for 1h; Sealed tube; | ||
With lithium hydroxide monohydrate; dihydrogen peroxide; molybdenum(VI) oxide at 20℃; for 18h; Ionic liquid; | ||
With dihydrogen peroxide In lithium hydroxide monohydrate at 20℃; for 3h; Green chemistry; | ||
With dihydrogen peroxide In acetonitrile at 35℃; for 2.3h; Green chemistry; | General procedure for oxidation of sulfides General procedure: The oxidation of sulfides was performed in a round-bottom flask containing a mixture of sulfide (1 mmol), H2O2 (2 mmol) and catalyst (1 mol%, 17 mg based on AAS) at room temperature (Scheme 2). Progress of the reaction was monitored by TLC. After completion of the reaction,the catalyst was separated by external magnet, washed with water/ethanol and reused for subsequent recycling runs. The products were extracted by CH2Cl2. Evaporation of CH2Cl2 under vacuum gave corresponding sulfoxides or sulfones. | |
With 5Na(1+)*10K(1+)*17H(1+)*54H2O*Sc6Sb2W6O19(22+)*6SbW9O33(9-); dihydrogen peroxide In acetonitrile at 80℃; for 3h; | ||
With 6C16H36N(1+)*(x)H2O*Mo7O26(6-); dihydrogen peroxide In acetonitrile at 22℃; for 4h; | ||
With 22C2H7N*22H(1+)*124H2O*18Na(1+)*2Ti7O6(SbW9O33)4(20-); dihydrogen peroxide In acetonitrile at 60℃; for 1h; | ||
With C4H12NO(1+)*4C2H8N(1+)*3H(1+)*4Na(1+)*2Ce(3+)*32H2O*C4H11NO*3SeW9O33(8-)*W4O9(6+); dihydrogen peroxide In acetonitrile at 40℃; for 1h; | ||
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 16h; | 438 Example 438 [002088] Synthesis of 4-(((trans)-4-(4-(methylsulfonyl)phenyl)cyclohexyl)oxy)-lH- l,2,3-triazole-5-carboxylic acid (438) To a solution of (4-bromophenyl)(methyl)sulfane (438A, 4.5 g, 22.17 mmol) in dichloromethane (100 mL) was added m-chlorobenzoperoxoic acid (11.44 g, 66.51 mmol) in several portions at 0 °C, stirred at room temperature for 16 hours, and filtered. The filtrate was washed with saturated aqueous NaHCCb solution (60 mL x 2) and brine (60 mL), dried over anhydrous sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 40% v/v) to furnish Compound 438B. LC-MS (ESI) m/z: 235 [M+H]+; 1H-NMR (CDCb, 400 MHz): d (ppm) 3.05 (s, 3H), 7.72 (d, J = 8.4 Hz, 2H), 7.81 (d, J= 8.8 Hz, 2H). | |
With dihydrogen peroxide; 2O33SbW9(9-)*53H2O*4C2H7N*8.5H(1+)*11.5Na(1+)*[Zr4W8Sb4P5O49(OH)5](2-) In acetonitrile at 45℃; for 1h; | ||
With dihydrogen peroxide In lithium hydroxide monohydrate; acetonitrile at 50℃; for 0.5h; | 3. Experimental method for catalytic oxidation of various thioethers by catalyst 2a General procedure: The catalytic oxidation reactions of the various thioethers was performed in a 25-mL glass round bottom flask connected to a refluxing condenser under magnetic stirring at room temperature which was heated (50°C). The desired amount of catalyst 2a was added into the flask, along with 1mL of acetonitrile solution containing thioether and oxidant. The reaction vessel was sealed and stirred into a thermostatted oil bath. Reaction progress was monitored by TLC and gas chromatography. After the reaction, the vessel was cooled to room temperature and extracted with ethyl acetate for GC analysis. The thioether oxidation products (sulfoxide and sulfone) were identified with GC-MS and quantified using gas chromatography with internal standard techniques. | |
With dihydrogen peroxide; 19K(1+)*7Na(1+)*68H2O*((Dy2SiW10O38)4(W3O8)(OH)4(H2O)2)(26-) In lithium hydroxide monohydrate; acetonitrile at 50℃; for 0.5h; Sealed tube; | ||
With 64H2O*21Na(1+)*10H(1+)*4CO3(2-)*[(AsO4){Ni8(OH)6(SiW9O34)2}2](23-) at 70℃; for 2h; | ||
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 16h; | 438 Synthesis of 4-(((trans)-4-(4-(methylsulfonyl)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (438) To a solution of (4-bromophenyl)(methyl)sulfane (438A, 4.5 g, 22.17 mmol) in dichloromethane (100 mL) was added m-chlorobenzoperoxoic acid (11.44 g, 66.51 mmol) in several portions at 0 oC, stirred at room temperature for 16 hours, and filtered. The filtrate was washed with saturated aqueous NaHCO3 solution (60 mL x 2) and brine (60 mL), dried over anhydrous sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 40% v/v) to furnish Compound 438B. LC-MS (ESI) m/z: 235 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.05 (s, 3H), 7.72 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H). | |
With dihydrogen peroxide; 3C2H7N*20H2O*4Na(1+)*12H(1+)*Ti6W4O18(OH)(H2O)3(11+)*3SbW9O33(9-) In acetonitrile at 60℃; for 1h; | ||
With dihydrogen peroxide; DyH8O80P2W20Zn4(11-)*23H2O*11K(1+) In lithium hydroxide monohydrate; acetonitrile at 40℃; for 1h; | ||
With dihydrogen peroxide; O117Si3Ti6W30(18-)*9C2H7N*18H(1+)*11H2O In acetonitrile at 60℃; for 0.666667h; | ||
With dihydrogen peroxide; C15H30N5O10Ta In methanol; lithium hydroxide monohydrate at 20℃; for 2h; Inert atmosphere; Sealed tube; | 2.2 Catalytic reactions General procedure: General procedure. 0.5mmol of sulfide and 1.0mL of solvent (methanol or acetonitrile, concentration 0.5M) were introduced into a 3mL vial, then dinitrogen was fluxed for ca. 3 minutes. Then, while keeping the vial under a cone under N2 flux, the catalyst (1.0mol %) and the appropriate amount (2.0 or 3.0 equiv.) of 30% aqueous solution of hydrogen peroxide were added to the mixture. The sealed vial was either thermostated at 45°C through an oil bath or left at room temperature, under stirring. After 1.5 or 2.0h (in relation to the substrate), additional equivalent of oxidant was added dropwise when necessary. At the end of the reaction, the mixture was treated with 5.0mg of MnO2 to quench the excess of oxidant and, after 10 minutes, filtered. The progress of the reaction was monitored through GC-FID analysis, by withdrawing an aliquot of 20 μL and adding 5 μL of n-hexadecane (internal standard). The oxidation products were identified by comparison of their GC retention times with those of authentic samples. | |
With dihydrogen peroxide In lithium hydroxide monohydrate; acetonitrile at 40℃; for 1h; Green chemistry; | ||
With thio-xanthene-9-one; oxygen In butanone at 35 - 40℃; for 24h; Schlenk technique; UV-irradiation; Green chemistry; | 4.1. A typical procedure for the visible-light-promoted aerobic oxidation of sulfides 3 or sulfoxides1 in a ketone solvent General procedure: To a dried Schlenk tube equipped with a stirrer bar which wasevacuated and backfilled with oxygen, were added thioxanthone(10.6 mg, 0.05 mmol, 5.0% mol) and sulfide3 or sulfoxide 1(1.0 mmol), then 5 mL of DEK or MEK was added into the reactiontube via a syringe. The mixture was irradiated by a purple LED lampat 35e40C under oxygen atmosphere (1 atm). After 24 h, thesolvent was removed and the residue was purified by flash column chromatography on silica gel to give the corresponding sulfone2. | |
With dihydrogen peroxide; 28Na(1+)*70H2O*(Pr4As2O6(OH)2WO(WO3)2(AsW9O33)4)(28-) In lithium hydroxide monohydrate; acetonitrile at 40℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With Caswell No. 744A; lithium hydroxide monohydrate; triethylamine In methanol at 60℃; for 24h; Inert atmosphere; Irradiation; | |
75% | With ammonium hydroxide at 200 - 210℃; for 20h; 1) autoclave; 2) standing 48 h,; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In diethylamine at 55℃; for 5h; | |
70% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diethylamine at 55℃; for 5h; Inert atmosphere; | |
With diisopropylamine In 1,4-dioxane at 20℃; for 12h; | 124.A Example 124; N-[(5-Isoquinolyl)sulfonyl]-N-[3-(4-methanesulfonyl)phenylpropyl]-1,3-propylenediamine hydrochloride (Exemplary Compound No. 3-50); (Step A) Synthesis of 3-(4-methanesulfonyl)phenyl-2-propyn-1-ol (Intermediate 98) A solution of dichlorobis(benzonitrile)palladium(II) (230 mg, Aldrich), copper(I) iodide (76 mg), tri(tert-butyl)phosphine (299 μl), N,N-diisopropylamine (3.4 ml, Tokyo Kasei Kogyo), 4-bromophenylmethylsulfone (4.7 g, Lancaster) and 2-propyn-1-ol (1.4 ml, Tokyo Kasei Kogyo) in 1,4-dioxane (25 ml) was stirred at room temperature for 12 hours. The reaction mixture was added with ethyl acetate (50 ml), and the deposited precipitates were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was added with ethyl acetate (40 ml) and washed successively with water (30 ml) and saturated brine (30 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (1.52 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 4-bromoohenyl methyl sulfone; trimethylsilylacetylene With trans-bis(triphenylphosphine)palladium dichloride; triethylamine at 20℃; for 0.25h; Inert atmosphere; Stage #2: With copper(l) iodide at 50℃; for 3h; Inert atmosphere; | |
76% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In dichloromethane at 20℃; | |
With copper-palladium |
With triethylamine In dichloromethane at 20℃; for 72h; Inert atmosphere of argon; | 2-1 Bromo-4-methanesulfonyl benzene (50.78 g, 213 mmol) was placed in a 3-necked round bottomed flask and purged with argon. Copper(l) iodide (2.05 g, 10.6 mmol) and bis(triphenylphosphine)palladium(ll) chloride (PdCI2(PPh3)2) (7.55 g, 10.6 mmol) were added while purging with argon, followed by the addition of triethylamine (200 ml_) and anhydrous dichloromethane (200 ml_). (Thmethylsilyl)acetylene (61 ml_, 425 mmol) was added and the reaction mixture was stirred at room temperature over 72 hours. The mixture was concentrated, then partitioned between ethyl acetate and water. The combined organic layers were washed with 1 N hydrochloric acid, water, and brine, dried over magnesium sulfate, filtered, and concentrated to afford crude (4-methanesulfonyl-phenylethynyl)-trimethyl-silane (54 g, 213 mmol), which was used in the next step without further purification. MS (ESI+) cald. for C-ι2H-i6θ2SSi [(M+H)+] 252, obsd. 253. | |
With copper(l) iodide; triethylamine In dichloromethane at 20℃; | ||
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; for 24h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 15h;Inert atmosphere; | Step 1: Synthesis of 1-(4-(methylsulfonyl)phenyl)piperazin [231] 1-Bromo-4-(methylsulfonyl)benzene (275 mg, 1.169 mmol), piperazine (302 mg, 3.507 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), BINAP (44 mg, 0.070 mmol), and sodium-tert-butoxide (169 mg, 1.754 mmol) were suspended in toluene (5 ml), and then the resulting liquid was stirred at 100oC under nitrogen stream for 15 hours. Distilled water (15 ml) was added to the resulting reaction liquid, followed by extraction with MC (20 ml x 3). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (15% MeOH/MC), to obtain 56 mg of pale yellow solid (20%). |
[0105] Piperazine (0.98g, 11.5MMOL), Pd (II) acetate (0.017g), sodium t-butoxide (0.37g, 4. [2MMOL)] and BINAP (0.049g) were stirred at room temperature in 10 mL dry toluene for 15 min. [1-BROMO-4-METHANESULFONYL-BENZENE] (0.9 g, 3.8mmol) in 10 mL dry toluene was added into the reaction mixture. Then the reaction mixture was refluxed at [110C] for 20 hrs. The reaction mixture was filtered through a celite bed and washed with toluene. The toluene was concentrated and the reaction mixture was taken in ethyl acetate and extracted with 1.5 (N) [HCL] solution three times. The combined aqueous layers were washed with diethyl ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate, concentrated and chromatographed [(9/1-CHC13/MEOH)] to afford the product. | ||
With tetra-(n-butyl)ammonium iodide; at 120 - 140℃; for 5h; | Production Example 366 1-(4-Methylsulfonylphenyl)piperazine A mixture of 3.0 g 1-bromo-4-methylsulfonyl benzene, 3.3 g piperazine and 470 mg tetrabutyl ammonium iodide was stirred at 120C to 140C for 5 hours.. water was added to the mixture, then insolubles were filtered off, the filtrate was extracted with dichloromethane.. The organic layer was washed with brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated, and the residue was purified by NH silica gel column chromatography, to give 2.8 g of the title compound as a white solid.1H-NMR (CDCl3) delta: 3.00(s, 3H), 3.02(m, 4H), 3.31(m, 4H), 6.92(d, J=8.6Hz, 2H), 7.98(d, J=8.6Hz, 2H), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 4-bromoohenyl methyl sulfone; 6-methoxy-3,4-dihydro-1(2H)-naphthalenone In toluene Heating / reflux; Stage #2: With sodium t-butanolate In toluene at 20 - 80℃; for 1 - 2h; Stage #3: With water In toluene at 40℃; | 32 Add 6-methoxytetralone (1.0 eq. ), 4-bromophenyl-methyl-sulfone (1.02 eq. ), Pd (OAc) 2 (0.025 eq. ), DPEphos ligand [(Oxydi-2, 1-phenylene) bis (diphenylphosphine)] (0.026 eq. ) and toluene (12 vols) to a three-neck flask equipped with a reflux condenser and nitrogen vent purge. Then add sodium t-butoxide (2.5 eq. ) in one portion. The reaction mixture exotherms to approximately 40°C and forms a heterogeneous yellow mixture. Heat the heterogeneous yellow reaction mixture to 75°-80°C for 1-2 hours. Cool the yellow slurry to room temperature and slowly quench the reaction with water (12 vols), keeping the temperature below 40°C. Cool the aqueous slurry to room temperature and stir for 2 to 3 hours. Filter the slurry over polypropylene and wash the solids with water (3x2 vols). Dry the resulting filter cake in a vacuum overnight at 50° C to provide crude 2- (4-methanesulfonyl-phenyl)-6-methoxy-3, 4-diliydro-2H-naphthalen-1-one (91%). Add 2- (4-methanesulfonyl-phenyl)-6-methoxy-3, 4-dihydro-2H-naphthalen-1-one (1. 0 eq.), hyflo (20 wt%), and toluene (7.5 vols) to a three neck flask with a reflux condenser and nitrogen vent purge. While stirring at room temperature, add PBr3 (1. 75 eq. ) in one portion. Heat the reaction to reflux (-110° C) overnight allowing it to vent through a caustic scrubber. After refluxing for 15 hours, cool the yellow solution to 45°C and slowly add THF (20 vols). Stir this mixture for 30 minutes at 45'and filter it, while warm, over a pad of Hyflo. Wash the pad with 45°C THF (2X2 vols). Concentrate the filtrate at reduced pressure to remove all of the THF. Carefully add water (7.5 vols) to the remaining mixture keeping the temperature below 40°C. Cool the slurry to room temperature and stir it for 2 to 3 hours. Filter the slurry over a polypropylene pad and wash it with water (2x2 vols). Dry the resulting filter cake in a vacuum oven overnight at 50°C to provide the title compound (74%). |
Stage #1: 4-bromoohenyl methyl sulfone; 6-methoxy-3,4-dihydro-1(2H)-naphthalenone In toluene Heating / reflux; Stage #2: With sodium t-butanolate In toluene at 40 - 80℃; | 33 To a 3-neck flask equipped with a reflux condenser and nitrogen vent purge, add 6-methoxytetralone (1. 0 eq. ), 4-bromophenyl-methyl-sulfone (1. 02-1. 05 eq. ), Pd (OAc) 2 (0.025 eq. ), DPEphos ligand (0.026 eq. ) and toluene 10-12 volumes. Add sodium t- butoxide (2.5 eq. ) in one portion and allow mixture to exotherm to-40°C. Heat to 75° to 80° C. Upon the reaction completion, as judged by HPLC analysis, cool to room temperature. Add 12 volumes water slowly keeping the temperature <40°C. Stir 2 to 3 hours. Filter over polypropylene pad and wash with water (3 x 2 volumes). Dry the filter cake overnight at 50° C to give 2- (4-methanesulfonylphenyl)-6-methoxytetralone. Combine 2- (4-methanesulfonylphenyl)-6-methoxytetralone (1.0 eq. ), hyflo (20%/weight), and toluene (7.5 volumes). Add PBr3 (1. 5-1. 75 eq. ) in one portion while stirring at room temperature. Heat contents to reflux (-110° C) overnight. Upon reaction completion, as judged by HPLC analysis (usually 15 hours), cool solution to 45°C and slowly add 20 volumes THF. Stir for 30 minutes at 45° and filter warm over a pad of hyflo. The pad is washed with 2x2 volumes THF at 45° C. Concentrate filtrate to approximately 7 volumes. Add 7.5 volumes water to the remaining mixture keeping the temperature below 40° C. (NOTE: initial addition of water is very exothermic with large evolution of HBr). Cool slurry to room temperature and stir for 2 to 3 hours. Filter over a polypropylene pad and wash with 2 x 2 volumes water. Dry filter cake overnight at 60°C under vacuum to give l-bromo-2- (4-methanesulfonylphenyl)-3, 4-dihydro-6- methoxynaphthalene. Combine l-bromo-2-(4-methanesulfonylphenyl)-3, 4-dihydro-6- methoxynaphthalene and 2,3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ, 1.8 equiv.) in 10 volumes acetonitrile and 5 volumes of THF. Under nitrogen atmosphere, heat reaction contents to 73-75°C. Monitor reaction progress by GC analysis until reaction completion. Additional DDQ (0.2-0. 3 equiv.) may be required for reaction completion. Cool contents to ambient temperature and add 10 volumes 1 N sodium hydroxide. Stir for approximately 1 hour and filter. Rinse filter cake with 2 volumes water, 3x5 volumes 50% acetonitrile/water and finally 3 volumes methanol. Vacuum dry the filter cake at 65°C to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium phosphate In toluene at 130℃; for 6h; | 89 After adding 33.4 g (142 mmol) of 4-methanesulfonyl-bromobenzene, 2.67 g (11.9 mmol) of palladium acetate, 5.31 g (17.8 mmol) of 2-(di-tert-butylphosphino)biphenyl and 50.3 g (237 mmol) of potassium phosphate to a solution of 25.0 g (119 mmol) of 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester in toluene (375 ml), the reactor was sealed and the mixture was subsequently stirred at 130°C for 6 hours. Acetic acid ethyl ester was added to the reaction mixture, which was then filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester = 2:1) to obtain 31.0 g of 3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester (yield: 69%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With chloro-trimethyl-silane; triphenylphosphine; zinc In tetrahydrofuran; ethyl acetate | 107 3-Cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide A mixture of zinc dust (2.6 g, 40 mmol, Aldrich, -325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.38 g, 2 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (220 mg, 2 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (6.16 g, 20 mmol) in dry tetrahydrofuran (5 mL) over 10 min. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (10 mL), and the stirring was stopped to allow the excess zinc dust to settle down (~2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (270 mg, 0.5 mmol) and triphenylphosphine (520 mg, 2 mmol) in dry tetrahydrofuran (25 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (4.23 g, 18 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. for 24 h. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (150 mL), and the organic compound was extracted into ethyl acetate (3*150 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*300 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (6.01 g, 99%) as a viscous yellow oil: EI-HRMS m/e calcd for C18H24O4S (M+) 336.1395, found 336.1395. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With chloro-trimethyl-silane; triphenylphosphine; zinc In tetrahydrofuran | 108 3-Cyclohexyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide A mixture of zinc dust (2.6 g, 40 mmol, Aldrich, -325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.37 g, 2 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (217 mg, 2 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (5.88 g, 20 mmol) in dry tetrahydrofuran (5 mL) over 5 min. During the addition, the temperature rose to 50° C. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (10 mL), and the stirring was stopped to allow the excess zinc dust to settle down (~2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (270 mg, 0.5 mmol) and triphenylphosphine (520 mg, 2 mmol) in dry tetrahydrofuran (25 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (4.23 g, 18 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. for 24 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (150 mL), and the organic compound was extracted into ethyl acetate (3*100 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/2 hexanes/ethyl acetate) afforded (E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (5.79 g, 99%) as a low melting white solid: EI-HRMS m/e calcd for C17H22O4S (M+) 322.1238, found 322.1236. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); N,N,N′,N′-tetramethyl-N″-tert-butylguanidine; 4,4'-di-tert-butyl-2,2'-bipyridine; zinc In dimethyl sulfoxide at 80℃; for 8h; Inert atmosphere; | |
79% | With caesium carbonate; XPhos In toluene; <i>tert</i>-butyl alcohol at 150℃; for 0.0833333h; Microwave; | Aniline (273 μL, 3.0 mmol), 1-bromo-4-methanesulfonylbenzene (705 mg, 3.0 mmol), Pd(OAc)2 (2 mol%, 13.5 mg), X-Phos (4 mol%, 57 mg), Cs2CO3 (1.37g, 4.2 mmol), toluene (15 mL) and tert-BuOH (3 mL) was mixed in a sealed vial and stirred in the microwave reactor for 5 min at 150 0C. Precipitated Cs2CO3 was filtered off and to the remaining solution was added DCM and water. The organic phase was passed through a phase separation filter and concentrated to give the product as a solid (592 mg, 79%). LC/MS (an20p5): Rt 1.9 min, m/z 248 [M+H]. 1H NMR (DMSO-cfe): δ 7.02 (t, 1 H), 7.13 (d, 2H), 7.19 (d, 2H), 7.34 (t, 2H), 7.69 (d, 2H), 8.87 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With norborn-2-ene; caesium carbonate In acetonitrile at 130℃; for 2h; microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With norborn-2-ene; caesium carbonate In acetonitrile at 130℃; for 2h; microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: (E)-3-cyclooctyl-2-iodo-acrylic acid methyl ester With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 25 - 45℃; Stage #2: 4-bromoohenyl methyl sulfone With triphenylphosphine In tetrahydrofuran at 50℃; for 24h; | 6 Example 6 A mixture of zinc dust (1.3 g, 20 mmol, Aldrich, -325 mesh) and dry tetrahydrofuran (3 ML) under argon was treated with 1,2-dibromoethane (0.38 g, 2 mmol).. The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again.. This process was repeated three times to make sure the zinc dust was activated.. The activated zinc dust suspension was then treated with trimethylsilyl chloride (220 mg, 2 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclooctyl-2-iodo-acrylic acid methyl ester (3.22 g, 10 mmol) in dry tetrahydrofuran (4 ML) over 10 min.. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (8 ML), and the stirring was stopped to allow the excess zinc dust to settle down (~2 h).. In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (135 mg, 0.25 mmol) and triphenylphosphine (260 mg, 1 mmol) in dry tetrahydrofuran (10 ML) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (2.12 g, 9 mmol) and the freshly prepared zinc compound in tetrahydrofuran.. The resulting brick red solution was heated at 50° C. for 24 h The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (100 ML), and the organic compound was extracted into ethyl acetate (3*75 ML).. The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 ML), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.. Flash chromatography (Merck silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-3-cyclooctyl-2-(4-(methanesulfonyl)-phenyl)-acrylic acid methyl ester (2.85 g, 90%) as a light yellow semi-solid: EI-HRMS m/e calcd for C19H26O4S (M+) 350.1552, found 350.1554. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: (E)-2-iodo-pent-2-enoic acid methyl ester With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 25 - 45℃; Stage #2: 4-bromoohenyl methyl sulfone With triphenylphosphine In tetrahydrofuran at 50℃; for 24h; | 1 Example 1 A mixture of zinc dust (2.36 g, 36 mmol, Aldrich, -325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.28 g, 1.5 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (163 mg, 1.5 mmol), and the suspension was stirred for 15 min at 25 C. The reaction mixture was then treated dropwise with a solution of (E)-2-iodo-pentenoic acid methyl ester (2.9 g, 12 mmol) in dry tetrahydrofuran (3 mL) over 3 min. The reaction mixture was then stirred at 40-45 C. for 1 h and then stirred overnight at 25 C. The reaction mixture was then diluted with dry tetrahydrofuran (10 mL), and the stirring was stopped to allow the excess zinc dust to settle down (2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (135 mg, 0.25 mmol) and triphenylphosphine (260 mg, 1 mmol) in dry tetrahydrofuran (16 mL) was stirred at 25 C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (2.11 g, 9 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50 C. for 24 h. The reaction mixture was then cooled to 25 C. and then poured into a saturated aqueous ammonium chloride solution (100 ml.), and the organic compound was extracted into ethyl acetate (350 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/2 hexanes/ethyl acetate) afforded (E)-2-(4-(methanesulfonyl)-phenyl)-pentenoic acid methyl ester (1.88 g, 78%) as a viscous yellow oil: EI-HRMS m/e calcd for C13H16O4S (M+) 268.0769, found 268.0772. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: (E)-2-Iodo-4-methyl-2-pentenoic acid, methyl ester With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 25 - 45℃; Stage #2: 4-bromoohenyl methyl sulfone With triphenylphosphine In tetrahydrofuran at 50℃; for 24h; | 2 Example 2 A mixture of zinc dust (1.71 g, 26 mmol, Aldrich, -325 mesh) and dry tetrahydrofuran (2 mL) under argon was treated with 1,2-dibromoethane (0.28 g, 1.5 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (163 mg, 1.5 mmol), and the suspension was stirred for 15 min at 25 C. The reaction mixture was then treated dropwise with a solution of (E)-2-iodo-4-methyl-pentenoic acid methyl ester (2.22 g, 8.7 mmol) in dry tetrahydrofuran (3 mL) over 2 min. The reaction mixture was then stirred at 40-45 C. for 1 h and then stirred overnight at 25 C. The reaction mixture was then diluted with dry tetrahydrofuran (8 mL), and the stirring was stopped to allow the excess zinc dust to settle down (2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (81 mg, 0.15 mmol) and triphenylphosphine (156 mg, 0.6 mmol) in dry tetrahydrofuran (15 mL) was stirred at 25 C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (1.64 g, 7 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50 C. for 24 h. The reaction mixture was then cooled to 25 C. and then poured into a saturated aqueous ammonium chloride solution (100 mL), and the organic compound was extracted into ethyl acetate (350 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/2 hexanes/ethyl acetate) afforded (E)-2-(4-(methanesulfonyl)-phenyl)-4-methyl-pentenoic acid methyl ester (1.876 g, 95%) as a viscous yellow oil: EI-HRMS m/e calcd for C14H18O4S (M+) 282.0926, found 282.0933. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 25 - 45℃; Stage #2: 4-bromoohenyl methyl sulfone With triphenylphosphine at 50℃; for 24h; | 5 Example 5 A mixture of zinc dust (2.6 g, 40 mmol, Aldrich, -325 mesh) and dry tetrahydrofuran (3 ML) under argon was treated with 1,2-dibromoethane (0.38 g, 2 mmol).. The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again.. This process was repeated three times to make sure the zinc dust was activated.. The activated zinc dust suspension was then treated with trimethylsilyl chloride (220 mg, 2 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (6.16 g, 20 mmol) in dry tetrahydrofuran (5 ML) over 10 min.. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (10 ML), and the stirring was stopped to allow the excess zinc dust to settle down (~2 h).. In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (270 mg, 0.5 mmol) and triphenylphosphinc (520 mg, 2 mmol) in dry tetrahydrofuran (25 ML) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (4.23 g, 18 mmol) and the freshly prepared zinc compound in tetrahydrofuran.. The resulting brick red solution was heated at 50° C. for 24 h.. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (150 ML), and the organic compound was extracted into ethyl acetate (3*150 ML).. The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*300 ML), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.. Flash chromatography (Merck silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (6.01 g, 99%) as a viscous yellow oil: EI-HRMS m/e calcd for C18H24O4S (M+) 336.1395, found 336.1395. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: (E)-4-cyclopentyl-2-iodo-but-2-enoic acid methyl ester With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 25 - 45℃; Stage #2: 4-bromoohenyl methyl sulfone With triphenylphosphine In tetrahydrofuran at 50℃; for 24h; | 21 Example 21 A mixture of zinc dust (0.98 g, 15 mmol, Aldrich, -325 mesh) and dry tetrahydrofuran (3 ML) under argon was treated with 1,2-dibromoethane (0.14 g, 0.75 mmol).. The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again.. This process was repeated three times to make sure the zinc dust was activated.. The activated zinc dust suspension was then treated with trimethylsilyl chloride (82 mg, 0.75 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-4-cyclopentyl-2-iodo-but-2-enoic acid methyl ester (1.47 g, 5 mmol) in dry tetrahydrofuran (1.5 ML) over 3 min.. After the addition, the reaction mixture was stirred for 1 h at 40-45° C. and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (5 ML), and the stirring was stopped to allow the excess zinc dust to settle down (~2 h).. In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) and triphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (10 ML) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (0.94 g, 4 mmol) and the freshly prepared zinc compound in tetrahydrofuran.. The resulting brick red solution was heated at 50° C. for 24 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material.. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (75 ML), and the organic compound was extracted into diethyl ether (3*50 ML).. The combined ether extracts were washed with a saturated aqueous sodium chloride solution (1*100 ML), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.. Biotage chromatography (FLASH 40M, silica, 3/7 hexanes/diethyl ether) afforded (E)-4-cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoic acid methyl ester (1.10 g, 86%) as a colorless oil: EI-HRMS m/e calcd for C17H22O4S (M+) 322.1235, found 322.1239. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 25 - 50℃; Stage #2: 4-bromoohenyl methyl sulfone With triphenylphosphine In tetrahydrofuran at 50℃; for 24h; | 4 Example 4 A mixture of zinc dust (2.6 g, 40 mmol, Aldrich, -325 mesh) and dry tetrahydrofuran (3 ML) under argon was treated with 1,2-dibromoethane (0.37 g, 2 mmol).. The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again.. This process was repeated three times to make sure the zinc dust was activated.. The activated zinc dust suspension was then treated with trimethylsilyl chloride (217 mg, 2 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (5.88 g, 20 mmol) in dry tetrahydrofuran (5 ML) over 5 min.. During the addition, the temperature rose to 50° C. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (10 ML), and the stirring was stopped to allow the excess zinc dust to settle down (~2 h).. In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (270 mg, 0.5 mmol) and triphenylphosphine (520 mg, 2 mmol) in dry tetrahydrofuran (25 ML) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (4.23 g, 18 mmol) and the freshly prepared zinc compound in tetrahydrofuran.. The resulting brick red solution was heated at 50° C. for 24 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material.. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (150 ML), and the organic compound was extracted into ethyl acetate (3*100 ML).. The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 ML), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.. Flash chromatography (Merck silica gel 60, 230-400 mesh, 3/2 hexanes/ethyl acetate) afforded (E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (5.79 g, 99%) as a low melting white solid: EI-HRMS m/e calcd for C17H22O4S (M+) 322.1238, found 322.1236. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 145℃; for 6h; | A mixture of 4-benzyloxy-2(1H)pyridone (6.87 g, 34.1 mmol, Aldrich), 4-bromophenyl methyl sulphone (8.01 g, 34.1 mmol, Combi-Blocks Inc.), copper(I) iodide (1.30 g, 6.82 mmol, Aldrich), 8-hydroxyquinoline (0.99 g, 6.82 mmol, Alfa Aesar) and potassium carbonate (6.12 g, 44.3 mmol, EMD) in DMSO (100 mL) was heated at 145 C. for 6 h, cooled to room temperature and then diluted with 10% NH4OH aqueous solution (50 mL) and EtOAc (100 mL). The resulting mixture was filtered and the solid was washed with H2O and EtOAc to give 8.0 g crude product as a greenish solid. MS (ESI) 356 (M+H). | |
With potassium carbonate;copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 145℃; for 6h; | Step C. Preparation of 4-(benzyloxy)-l-(4-(methylsulfonyl)phenyl)pyridine-2(lH)- one[00123] A mixture of 4-benzyloxy-2(lH)-pyridone (6.87 g, 34.1 mmol, Aldrich), 4-bromophenyl methyl sulphone (8.01 g, 34.1 mmol, Combi-Blocks Inc.), copper(I) iodide (1.30 g, 6.82 mmol, Aldrich), 8-hydroxyquinoline (0.99 g, 6.82 mmol, Alfa Aesar) and potassium carbonate (6.12 g, 44.3 mmol, EMD) in DMSO (100 mL) was heated at 145 0C for 6 h, cooled to room temperature and then diluted with 10% NH4OH aqueous solution (50 mL) and EtOAc (100 mL). The resulting mixture was filtered and the solid was washed with H2O and EtOAc to give 8.O g crude product as a greenish solid. MS (ESI) 356 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium carbonate In dimethyl sulfoxide at 160℃; for 0.5h; Microwave irradiation; | 40.C A mixture of tert-butyl 4-(2-oxo-1,2-dihydropyrimidin-4-yloxy)piperidine-1-carboxylate (266.5 mg, 0.90 mmol,), 4-bromophenyl methyl sulfone (212.2 mg, 0.90 mmol, commercially available from Sigma-Aldrich Corporation), copper(I) iodide (60.4 mg, 0.32 mmol, commercially available from Sigma-Aldrich Corporation), 8-hydroxyquinoline (47 mg, 0.32 mmol, commercially available from Alfa Aesar) and potassium carbonate (188 m g, 1.35 mmol, EMD) in DMSO (7.5 mL) was heated under Microwave conditions (160° C., 30 min) and cooled to room temperature. The reaction mixture was diluted with EtOAc and then filtered. The filtrate was washed with H2O and the aqueous layer was back extracted with EtOAc (2×). The combined organic layers were washed with H2O/brine (1:1, 4×), dried (Na2SO4) and evaporated. The residual was purified by flash chromatography (0 to 100% EtOAc/Hexanes, twice) to yield 168.5 mg (55%) of Example 40 as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=8.25 Hz, 2 H), 7.63 (d, J=8.25 Hz, 2 H), 7.54 (d, J=7.15 Hz, 1 H), 6.05 (d, J=7.70 Hz, 1 H), 5.44-5.57 (m, 1 H), 3.80 (app brs, 2 H), 3.18-3.31 (m, 2 H), 3.10 (s, 3 H), 1.95-2.08 (m, 2 H), 1.65-1.85 (m, 2 H), 1.48 (s, 9 H). MS (ESI) 450 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium carbonate In dimethyl sulfoxide at 100℃; for 16h; | 158.E Benzyl 4-(5-methyl-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (34 mg, 0.099 mmol), 4-bromophenyl methylsulphone (23.35 mg, 0.099 mmol), potassium carbonate (20.59 mg, 0.149 mmol), and copper(I) iodide (3.78 mg, 0.020 mmol) were combined in 0.4 mL DMSO was degassed with bubbling nitrogen subsurface for 20 seconds and then heated in a 100° C. oil bath for 16 hours. To the reaction mixture was added 5 mL EtOAc which was then washed with 3 mL each of saturated aqueous NH4Cl, NaHCO3, NaCl, water, dried with MgSO4 and filtered. The EtOAc filtrate was then purified directly with flash chromatography (EtOAc as eluant) to yield product (24 mg, 0.048 mmol, 49%) as a yellow foam. 1H NMR (500 MHz, CDCl3) δ 1.81-1.93 (m, 2 H) 1.92-2.00 (m, 2 H) 2.02 (s, 3 H) 3.09 (s, 3 H) 3.48-3.63 (m, 2 H) 3.66-3.78 (m, 2 H) 4.58 (br. s., 1 H) 5.16 (s, 2 H) 5.96 (br. s., 1 H) 7.10 (br. s., 1 H) 7.30-7.45 (m, 5 H) 7.61 (d, J=8.25 Hz, 2 H) 8.06 (d, J=8.25 Hz, 2 H). MS (ESI) 497.6 (M+1). |
48% | With copper(l) iodide; potassium carbonate In dimethyl sulfoxide at 100℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.74% | Stage #1: 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitrile; 4-bromoohenyl methyl sulfone With potassium carbonate In dimethyl sulfoxide at 190℃; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide | 221.A A mixture of 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitrile (200 mg, 1.469 mmol, Medinoah), 1-bromo-4-(methylsulfonylbenzene (345 mg, 1.469 mmol), 4,7-dimethoxy-1,10-phenanthroline (70.6 mg, 0.294 mmol), copper(I) iodide (56.0 mg, 0.294 mmol) and potassium carbonate (609 mg, 4.41 mmol) in DMSO (3 mL) was heated at 190° C. To the reaction mixture was added H2O (10 mL) and the pH adjusted to 2 using with 1N HCl. The resulting aqueous mixture was extracted with EtOAc (40 mL, 2×). The combined extracts were dried over Na2SO4 and concentrated to give a brown oil. The crude oil was purified by flash chromatography (SiO2, 0-5% MeOH/CH2Cl2) to give a yellow solid (35 mg, 0.084 mmol, 5.74%). MS (ESI) 291 (M+H). |
5% | With copper(l) iodide; 4,7-dimethoxy-1,10-phenanthroline; potassium carbonate In dimethyl sulfoxide at 190℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; for 17h; | To a stirred solution of methyl (2S)-2-(teAt-butoxycarbonyl)-amino-2-[8-aza-bicyclo [3.2.1]-oct-3-yl]-exo-acetate (step 5 of intermediate 2, 1.0 g, 3.35 mmol) in dry toluene (30 ml) was added 1-bromo-4-methanesulphonyl benzene (0.787g, 3.35 mmol), BINAP (0.312g, 0.5 mmol), palladium acetate (0.074g, 0.33 m mol) and CS2CO3 (1.52 g, 4.67 mmol) under N2 atmosphere. The reaction mixture was then heated at 90°C for 17 hours. The reaction mixture was allowed to come at room temperature. The solvent was removed under reduced pressure and added dichloromethane (50 ml). The organic layer was washed with water (25 ml) and dried over anhydrous Na2SO4. The solvent was concentrated under reduced pressure to get a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 30% ethyl acetate in hexane as an eluent to yield the title compound (0.52g, 34%). mp: 102-1040C MS: m/z 451(M-1) 1HNMR (CDCI3, 200 MHz):δ 1.37 (s, 9H), 1.4-1.5 (m, 1 H), 1.55-1.9 (m, 5H), 2.05-2.2 (m, 2H), 2.3-2.55 (m, 1 H), 3.03 (s, 3H), 3.66 (s, 3H), 4.0-4.2 (m, 1 H), 4.3-4.4 (m, 2H), 4.86-5.0 (m, 1 H), 6.75 (d, J=8.9Hz, 2H), 7.73 (d, J=8.9Hz, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; (S,S)-1,2-diaminocyclohexane;copper(l) iodide; In 1,4-dioxane; at 20 - 110℃; | Step 1.5: 2-Chloro-7-(4-methanesulfonyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine In a seal tube, <strong>[335654-06-3]2-chloro-7H-pyrrolo[2,3-d]pyrimidine</strong> (600 mg, 3.56 mmol), 4-bromophenylmethylsulfone (700 mg, 4.10 mmol), CuI (239 mg, 1.23 mmol), and K3PO4 (2.67 g, 12.3 mmol) are suspended in 1,4-dioxane (30 mL). Then, trans-1,2-diaminocyclohexane (149 muL, 1.23 mmol) is added at rt. The reaction vial is flushed with Ar and the mixture is heated to 110 C. for 3 h. After cooling to rt, the reaction mixture is concentrated under reduce pressure. The residue is suspended in EtOAc and washed with saturated aqueous NaCl solution (3*). The organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The solid residue is triturated with small amounts of EtOAc to yield the title compound as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium phosphate; johnphos In toluene at 100℃; for 24h; | 181 An oven dried round bottom flask was charged with 181b (960 mg, 4.0 mmol), 1-bromo-4-(methylsulfonyl)benzene (1.13 g, 4.8 mmol), potassium phosphate (1.7 g, 8.0 mmol), palladium acetate (18 mg, 0.08 mmol) and 2-(di-tert-buytlphosphino)biphenyl (36 mg, 0.12 mmol). The flask was purged 3 times with nitrogen; toluene (10 mL) was added through the septum and the mixture was heated at 100° C. for 24 h. The reaction mixture was cooled to rt and diluted with ethyl acetate. The suspension was washed with brine solution (3*50 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (30%-50% EtOAc-hexane) to afford example 181c (982 mg, 62%) as a white solid. MS (ES) [M+H] calculated for C29H22O7S, 394.11; found 395.30. The title compound was synthesised using an analogous procedure described for Example 156 using example 181c. 1H NMR (400 MHz, chloroform-d) δ ppm 1.34 (d, J=6.18 Hz, 3H) 3.11 (s, 3H) 3.43 (s, 3H) 3.65-3.70 (m, 2H) 4.13-4.18 (m, 1H) 6.86 (s, 1H) 7.20 (d, J=6.21 Hz, 2H) 7.50 (t, J=6.01 Hz, 1H) 7.57 (s, 1H) 7.73 (s, 1H) 7.91 (d, J=6.11 Hz, 2H) 8.41-8.43 (m, 2H). MS (ES) [M+H] calculated for C23H24N3O5S, 454.14; found 454.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 4-bromoohenyl methyl sulfone With chlorosulfonic acid at 150℃; for 3h; Stage #2: With ammonium hydroxide In water at 0℃; for 3h; | 4.1.6. 2-Bromo-5-methylsulfonylbenzenesulfonamide (16b) 4-Bromophenyl methyl sulfone (15b, 2.5 g) in chlorosulfonic acid (5 mL) was heated to 150 °C and stirred for 3 h. The resulting solution was cooled to 0 °C, which was then added to ice/water (10 g/4 mL) dropwise. The precipitate was washed with cold water (3 mL), and dried. Subsequent treatment of the solid with concd NH4OH (11 mL) at 0 °C for 3 h afforded the product, which was purified by flash column chromatography on a silica gel column with hexane/EtOAc (1:2) to provide a pale yellowish solid 16b in 82% yield. Mp 238-240 °C. 1H NMR (200 MHz, acetone-d6) δ 8.56-8.52 (m, 1H; ArH), 8.15-7.92 (m, 2H; ArH), 7.04 (br, 2H; SO2NH2), 3.25 (s, 3H; SO2CH3). 13C NMR (50 MHz, acetone-d6) δ 144.2, 141.5, 136.9, 132.1, 128.8, 125.7, 43.7. MS (EI) m/z = 313 [M]+. Anal. (C7H8BrNO4S2): C, 26.76; H, 2.57; N, 4.46. Found: C, 26.85; H, 2.58; N, 4.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine In acetonitrile at 25℃; for 48h; Inert atmosphere; | General procedure General procedure: Inside a N2 filled glovebox, benzenesulfonamide (250 mg, 1.590 mmol) and copper(I) iodide (15.14 mg, 0.080 mmol), 4-toluene bromide (326mg, 1.91 mmol), potassium carbonate (550 mg, 3.98 mmol), Acetonitrile (4 mL), and N1,N2dimethylethane-1,2-diamine (70.1 mg, 0.795 mmol) was charged into a vial. The vial was then heated to 70 oC for 8hr, LC indicated >97% conversion of benzenesulfonamide. The reaction mixture was then cooled to room temperature. 2N HCl (4mL) was added slowly, followed by EtOAc extraction (5mL x 3). The organic layers were combined, concentrated, and flash chromatographed (SiO2, 20:1--> 3:1 Heptane:EtOAc) to give N(p-tolyl) benzene sulfonamide as white solids (380 mg, 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate In N,N-dimethyl acetamide at 85℃; for 20h; Inert atmosphere; | Preparation of 1 -isopropoxy-3-(4-(methylsulfonyl)phenoxy)benzene3-isopropoxyphenol (1.43 g, 9.42 mmol) was charged into a round bottom flask. 4-bromophenylmethylsulfone (2.22 g, 9.42 mmol), cuprous iodide (359 mg, 1.88 mmol) and cesium carbonate (6.14 g, 18.8 mmol) were added along with DMAC (N,N-dimethylacetamide) (30 mL). The mixture was stirred under nitrogen at room temperature and 2,2,6,6-tetramethyl-3,5- heptanedione (0.78 mL, 3.77 mmol) was added. The mixture was heated under nitrogen at 85 °C for about 20 hours. Analysis by LCMS and TLC showed the reaction to be complete. The reaction mixture was poured into ammonium chloride solution (sat. aq.; 250 mL) and the aqueous was extracted with MTBE (2 x 100 mL). The aqueous layer was extracted a third time with 50 mL EtOAc. The combined extracts were washed with an equal volume of water, brine, dried over sodium sulfate, and concentrated to a dark colored oil. The residue was purified by flash column chromatography (Si02, 0%-40% ethyl acetate / heptane) to provide 1 -isopropoxy-3-(4- (methylsulfonyl)phenoxy) benzene as a pale colored oil (2.78 g, 96%). 1H NMR (400 MHz, CDCI3) δ ppm 1.33 (d, J=6.05 Hz, 6 H), 3.04 (s, 3 H), 4.46 - 4.56 (m, 1 H), 6.56 - 6.64 (m, 2 H), 6.74 (ddd, J=8.39, 2.34, 0.78 Hz, 1 H), 7.07 - 7.10 (m, 2 H), 7.27 (t, J=8.10 Hz, 1 H), 7.85 - 7.89 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium phosphate;palladium(II) acetylacetonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1-methyl-pyrrolidin-2-one; at 100℃; for 18h;Inert atmosphere;Product distribution / selectivity; | Pd(acac)2 (6.1 mg, 0.02 mmol, 0.5 mol %) and Xantphos (23.2 mg, 0.04 mmol, 1 mol o) are introduced into a flared flask provided with coolant. 4-bromophenylmethylsulfone of formula (III, XBr) (1.17 g, 5 mmol), acetylpicoline of formula (II) (541 mg, 4 mmol) and K3PO4 (2.55 g, 12.0 mmol, 3 eq) are added thereto. Once the argon atmosphere has been stabilized with vacuum-argon cycles, anhydrous and degassed NMP (15 ml) is added with a syringe. The mixture is then kept stirred under stirring in an argon atmosphere for 18 h at 100 C. The conversion is quantitative. The reaction mixture is diluted with a saturated solution of NaHCO3 (50 mL) and extracted with AcOEt (4×50 mL). The combined organic phases were washed with an aqueous solution saturated with NaHCO3 (30 mL), anhydrified on MgSO4 and concentrated in a vacuum. The residue was purified by silica gel chromatography using AcOEt/cyclohexane as eluent in a gradient from 5:5 to 10:0. 1.05 g product were obtained, for a molar yield of 91% as a white crystalline solid. |
75% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; for 5h;Inert atmosphere; Reflux; | Xantphos 0.00267 g (0.0046 mmol) and Pd2(dba)3 0.00177 g (0.0031 mmol) in 15 ml of anhydrous toluene were charged in a reactor under inert atmosphere. 4-bromophenyl methyl sulfone 0.724 g (3.078 mmol) and 3-acetyl-6-methyl pyridine 0.416 g (3.079 mmol) were then added. The mixture was heated to reflux and a suspension of t-BuONa 0.71 g in 15 ml of anhydrous toluene was added dropwise over about 4 h. After about 1 h from completion of the addition, the reaction mixture was cooled to 20 C and a solution of diluted hydrochloric acid to acidic pH was added. The aqueous phase was separated and added dropwise over 1 h to a mixture of water 8.3 g, ethyl acetate 15.3 g and sodium bicarbonate 2.1 g at 60 C. At addition completed and after maintaining the temperature at 60 C for 1 h, it was checked that the pH was between 4 and 7, the mixture was cooled to 20 C filtered and dried under vacuum at 50 C. 0.67 g of the compound of formula 1 was obtained with a yield of 75 %. |
75% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; for 4h;Inert atmosphere; Reflux; | Xantphos 0.00267 g (0.0046 mmol) and Pd2(dba)3 0.00177 g (0.0031 mmol) in 15 ml of anhydrous toluene were charged in a reactor under inert atmosphere. 4-bromophenyl methyl sulfone 0.724 g (3.078 mmol) and 3-acetyl-6-methyl pyridine 0.416 g (3.079 mmol) were then added. The mixture was heated to reflux and a suspension of t-BuONa 0.71 g in 15 ml of anhydrous toluene was added dropwise over about 4 h. After about 1 h from completion of the addition, the reaction mixture was cooled to 20C and a solution of diluted hydrochloric acid to acidic pH was added. The aqueous phase was separated and added dropwise over 1 h to a mixture of water 8.3 g, ethyl acetate 15.3 g and sodium bicarbonate 2.1 g at 60C. At addition completed and after maintaining the temperature at 60C for 1 h, it was checked that the pH was between 4 and 7, the mixture was cooled to 20C filtered and dried under vacuum at 50 C. 0.67 g of the compound of formula 1 was obtained with a yield of 75 %. |
72% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; for 5h;Inert atmosphere; Reflux; | EXAMPLE 1 [0068] Synthesis of 1-(6-methylpyridin-3-yl)-2-[(4-methylsulfonyl)-phenyl]-ethanone. [0069] Xantphos 0.027 g (0.0477 mmol) and Pd2(dba)3 0.0182 g (0.0198 mmol) in 100 ml of anhydrous toluene were charged in a reactor under inert atmosphere. 4-bromophenyl methyl sulfone 9.3 g (39.7 mmol) and 3-acetyl-6-methyl pyridine 5.4 g (39.7 mmol) were then added. The mixture was heated to reflux and a suspension of t-BuONa 8.4 g in 100 ml of anhydrous toluene was added dropwise over about 4 h. After about 1 h from completion of the addition, the reaction mixture was cooled to 20 C. and a solution of diluted hydrochloric acid to acidic pH was added. The aqueous phase was separated and added dropwise over 1 h to a mixture of water 83.3 g, ethyl acetate 153 g and sodium bicarbonate 20.1 g at 60 C. At addition completed and after maintaining the temperature at 60 C. for 1 h, it was checked that the pH was between 4 and 7, the mixture was cooled to 20 C., filtered, and dried under vacuum at 50 C. 8.3 g of the compound of formula 1 were obtained with a yield of 72%. |
With potassium phosphate tribasic trihydrate; triphenylphosphine-3,3',3"-trisulfonic acid, trisodium salt; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; at 80 - 90℃; for 20h;Inert atmosphere; | Example 1 - Synthesis of 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl) phenyl]ethanone of formula (I). Wherein BMS = 4-bromophenylmethylsulfone. [0051] Experimental Procedure [0052] To a four-neck round-bottom 100 ml flask equipped with mechanical stirring and condenser were added at 20-25 C and under nitrogen atmosphere Xantphos, TPPTS, palladium acetate, PVP, tripotassium phosphate trihydrate, BMS, 5-acetyl-2-methylpyridine and water according to the above amounts. A vacuum/nitrogen cycle was repeated for at least three times at 20-25 C. The resulting reaction mixture was heated up to 80-90 C and stirred for at least 20 h. The reaction mixture was then cooled down to 40-50C and diluted with water (200 ml). The resulting mixture was stirred at 40-45C for 15 min. and cooled down to -5-0C. The resulting reaction mixture was stirred at -5-0C for at least 2 h, then it was filtered and the cake was washed with water (3 x 50 ml) and dried at 60-65C under reduced pressure to afford crude product of formula (I) as a yellow solid (11.2g). Molar yield: 83.6%, Purity: 88.4% by HPLC A%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hypochlorite solution In water at 75℃; for 4h; | Sulfone chlorination with sodium hypochlorite-general procedure General procedure: To an aqueous solution of sodium hypochlorite (12-13 mL of a technical solution containing 0.10-0.12 g NaClO per 1 mL, 18 mmol, 3 equiv), was added the sulfone substrate (6 mmol, 1 equiv) in one portion and the mixture was stirred for the time given (Table 1) at 75 °C. The mixture was cooled to room temperature and the precipitate was filtered off, washed with H2O, dried in air, and crystallized from 2-PrOH (EtOH in the case of products 22 and 30). See Supplementary data for the characterization of the chlorination products obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | 4-bromophenyl methyl sulfone 80.04 g (0.34 mol) and 3-acetyl-6-methyl pyridine 46.03 g (0.34 mol) in 800 ml of toluene were charged in a reactor under inert atmosphere. The mixture was heated to reflux and Xantphos 0.236 g (0.41 mmol) and Pd2(dba)3 0.156 g (0.17 mmol) were added. A suspension of t-BuONa 72.08 g (0.75 mol) in 800 ml of toluene, kept at 60 C, was added dropwise over about 2 h. From the end of the addition, the reaction was kept for at least 1 h under stirring at that temperature before proceeding with the acid neutralisation. The mixture was cooled to 25 C and a solution containing 25% hydrochloric acid was added. The mixture was heated to reflux and was distilled to obtain the crystallisation of compound I as hydrochloride. The product was isolated at 5 C by filtration and was dried under vacuum at 50 C with a yield of 70%>. | |
70% | 4-bromophenyl methyl sulfone 80.04 g (0.34 mol) and 3-acetyl-6-methyl pyridine 46.03 g (0.34 mol) in 800 ml of toluene were charged in a reactor under inert atmosphere. The mixture was heated to reflux and Xantphos 0.236 g (0.41 mmol) and Pd2(dba)3 0.156 g (0.17 mmol) were added. A suspension of t-BuONa 72.08 g (0.75 mol) in 800 ml of toluene, kept at 60 C, was added dropwise over about 2 h. From the end of the addition, the reaction was kept for at least 1 h under stirring at that temperature before proceeding with the acid neutralisation. The mixture was cooled to 25 C and a solution containing 25% hydrochloric acid was added. The mixture was heated to reflux and was distilled to obtain the crystallisation of compound I as hydrochloride. The product was isolated at 5 C by filtration and was dried under vacuum at 50C with a yield of 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 100℃; for 16h; regiospecific reaction; | |
52% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 110℃; for 20h; | 7 4.5.2 General procedure 2 General procedure: A thick-glass screw-capped pressure tube (50mL) was charged with a suspension of starting imidazoline (3.0mmol), 1-bromo-4-(methylsulfonyl)benzene or 4-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide [21] (3.0mmol), Cs2CO3 (3.0mmol), and toluene (15mL). Pd(OAc)2 (0.12mmol) and BINAP (0.24mmol) were weighed as solids into a 10mL screw-capped vial and toluene (8mL) was added. The resulting suspension was heated at 110°C until a clear purple solution was obtained. The latter was rapidly transferred, while still hot, to the screw-capped pressure tube using a Pasteur pipette. The reaction vessel was filled with argon, sealed, and the reaction mixture was vigorously stirred at 110°C for 20h. The reaction mixture was cooled to ambient temperature and filtered through a Celite pad. The latter was washed with copious amounts of EtOAc, and the combined filtrate and washings were evaporated to dryness. The crude material was briefly fractionated on silica (CH2Cl2:MeOH, 95:5) and the fractions containing the N-aryl 2-imidazolines were collected and evaporated to dryness. The residue was either purified further by chromatography under the same conditions (methylsulfone compounds 8-21) or taken forward to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 100℃; | |
47% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 110℃; | 7 4.5.2 General procedure 2 General procedure: A thick-glass screw-capped pressure tube (50mL) was charged with a suspension of starting imidazoline (3.0mmol), 1-bromo-4-(methylsulfonyl)benzene or 4-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide [21] (3.0mmol), Cs2CO3 (3.0mmol), and toluene (15mL). Pd(OAc)2 (0.12mmol) and BINAP (0.24mmol) were weighed as solids into a 10mL screw-capped vial and toluene (8mL) was added. The resulting suspension was heated at 110°C until a clear purple solution was obtained. The latter was rapidly transferred, while still hot, to the screw-capped pressure tube using a Pasteur pipette. The reaction vessel was filled with argon, sealed, and the reaction mixture was vigorously stirred at 110°C for 20h. The reaction mixture was cooled to ambient temperature and filtered through a Celite pad. The latter was washed with copious amounts of EtOAc, and the combined filtrate and washings were evaporated to dryness. The crude material was briefly fractionated on silica (CH2Cl2:MeOH, 95:5) and the fractions containing the N-aryl 2-imidazolines were collected and evaporated to dryness. The residue was either purified further by chromatography under the same conditions (methylsulfone compounds 8-21) or taken forward to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 0.333333h; Sealed tube; Microwave irradiation; | General Procedure for the preparation of benzamides. General procedure: To a dry microwave vial, aryl halide (Br, I) (1 eqv.) and amine (2eqv.) were taken in dry 1,4-dioxane. 5 mol% of Pd(OAc)2, 5 mol% ofXantphos and DMAP (2 eqv.) were added followed by (0.25 or 0.3) equivalents ofCo2(CO)8 and the vial was sealed immediately andmicrowave irradiated for 20 min. The reactionmixture was concentrated under reduced pressure, diluted with ethyl acetate andwater, the ethyl acetate layer separated, dried over sodium sulphate, andconcentrated. Thecrude products obtained were subjected to purification by flash chromatographyon silica gel coloumn eluting with petroleum ether and ethyl acetate. |
80% | With dmap; palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 0.333333h; Microwave irradiation; | General Procedure for the preparation ofbenzamides General procedure: To a dry microwave vial, aryl halide (Br, I) (1 eqv.) and amine (2 eqv.)were taken in dry 1,4-dioxane. 5 mol% of Pd(OAc)2, 5 mol% ofXantphos and DMAP (2 eqv.) were added followed by (0.25 or 0.3) equivalents ofCo2(CO)8 and the vial was sealed immediately andmicrowave irradiated for 20 min. The reaction mixture was concentrated under reducedpressure, diluted with ethyl acetate and water, the ethyl acetate layerseparated, dried over sodium sulphate, and concentrated. The crude products obtained were subjected topurification by flash chromatography on silica gel coloumn eluting withpetroleum ether and ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 110℃; | 7 4.5.2 General procedure 2 General procedure: A thick-glass screw-capped pressure tube (50mL) was charged with a suspension of starting imidazoline (3.0mmol), 1-bromo-4-(methylsulfonyl)benzene or 4-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide [21] (3.0mmol), Cs2CO3 (3.0mmol), and toluene (15mL). Pd(OAc)2 (0.12mmol) and BINAP (0.24mmol) were weighed as solids into a 10mL screw-capped vial and toluene (8mL) was added. The resulting suspension was heated at 110°C until a clear purple solution was obtained. The latter was rapidly transferred, while still hot, to the screw-capped pressure tube using a Pasteur pipette. The reaction vessel was filled with argon, sealed, and the reaction mixture was vigorously stirred at 110°C for 20h. The reaction mixture was cooled to ambient temperature and filtered through a Celite pad. The latter was washed with copious amounts of EtOAc, and the combined filtrate and washings were evaporated to dryness. The crude material was briefly fractionated on silica (CH2Cl2:MeOH, 95:5) and the fractions containing the N-aryl 2-imidazolines were collected and evaporated to dryness. The residue was either purified further by chromatography under the same conditions (methylsulfone compounds 8-21) or taken forward to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 110℃; | 7 4.5.2 General procedure 2 General procedure: A thick-glass screw-capped pressure tube (50mL) was charged with a suspension of starting imidazoline (3.0mmol), 1-bromo-4-(methylsulfonyl)benzene or 4-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide [21] (3.0mmol), Cs2CO3 (3.0mmol), and toluene (15mL). Pd(OAc)2 (0.12mmol) and BINAP (0.24mmol) were weighed as solids into a 10mL screw-capped vial and toluene (8mL) was added. The resulting suspension was heated at 110°C until a clear purple solution was obtained. The latter was rapidly transferred, while still hot, to the screw-capped pressure tube using a Pasteur pipette. The reaction vessel was filled with argon, sealed, and the reaction mixture was vigorously stirred at 110°C for 20h. The reaction mixture was cooled to ambient temperature and filtered through a Celite pad. The latter was washed with copious amounts of EtOAc, and the combined filtrate and washings were evaporated to dryness. The crude material was briefly fractionated on silica (CH2Cl2:MeOH, 95:5) and the fractions containing the N-aryl 2-imidazolines were collected and evaporated to dryness. The residue was either purified further by chromatography under the same conditions (methylsulfone compounds 8-21) or taken forward to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 110℃; | 7 4.5.2 General procedure 2 General procedure: A thick-glass screw-capped pressure tube (50mL) was charged with a suspension of starting imidazoline (3.0mmol), 1-bromo-4-(methylsulfonyl)benzene or 4-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide [21] (3.0mmol), Cs2CO3 (3.0mmol), and toluene (15mL). Pd(OAc)2 (0.12mmol) and BINAP (0.24mmol) were weighed as solids into a 10mL screw-capped vial and toluene (8mL) was added. The resulting suspension was heated at 110°C until a clear purple solution was obtained. The latter was rapidly transferred, while still hot, to the screw-capped pressure tube using a Pasteur pipette. The reaction vessel was filled with argon, sealed, and the reaction mixture was vigorously stirred at 110°C for 20h. The reaction mixture was cooled to ambient temperature and filtered through a Celite pad. The latter was washed with copious amounts of EtOAc, and the combined filtrate and washings were evaporated to dryness. The crude material was briefly fractionated on silica (CH2Cl2:MeOH, 95:5) and the fractions containing the N-aryl 2-imidazolines were collected and evaporated to dryness. The residue was either purified further by chromatography under the same conditions (methylsulfone compounds 8-21) or taken forward to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 110℃; | 7 4.5.2 General procedure 2 General procedure: A thick-glass screw-capped pressure tube (50mL) was charged with a suspension of starting imidazoline (3.0mmol), 1-bromo-4-(methylsulfonyl)benzene or 4-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide [21] (3.0mmol), Cs2CO3 (3.0mmol), and toluene (15mL). Pd(OAc)2 (0.12mmol) and BINAP (0.24mmol) were weighed as solids into a 10mL screw-capped vial and toluene (8mL) was added. The resulting suspension was heated at 110°C until a clear purple solution was obtained. The latter was rapidly transferred, while still hot, to the screw-capped pressure tube using a Pasteur pipette. The reaction vessel was filled with argon, sealed, and the reaction mixture was vigorously stirred at 110°C for 20h. The reaction mixture was cooled to ambient temperature and filtered through a Celite pad. The latter was washed with copious amounts of EtOAc, and the combined filtrate and washings were evaporated to dryness. The crude material was briefly fractionated on silica (CH2Cl2:MeOH, 95:5) and the fractions containing the N-aryl 2-imidazolines were collected and evaporated to dryness. The residue was either purified further by chromatography under the same conditions (methylsulfone compounds 8-21) or taken forward to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 110℃; | 7 4.5.2 General procedure 2 General procedure: A thick-glass screw-capped pressure tube (50mL) was charged with a suspension of starting imidazoline (3.0mmol), 1-bromo-4-(methylsulfonyl)benzene or 4-bromo-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide [21] (3.0mmol), Cs2CO3 (3.0mmol), and toluene (15mL). Pd(OAc)2 (0.12mmol) and BINAP (0.24mmol) were weighed as solids into a 10mL screw-capped vial and toluene (8mL) was added. The resulting suspension was heated at 110°C until a clear purple solution was obtained. The latter was rapidly transferred, while still hot, to the screw-capped pressure tube using a Pasteur pipette. The reaction vessel was filled with argon, sealed, and the reaction mixture was vigorously stirred at 110°C for 20h. The reaction mixture was cooled to ambient temperature and filtered through a Celite pad. The latter was washed with copious amounts of EtOAc, and the combined filtrate and washings were evaporated to dryness. The crude material was briefly fractionated on silica (CH2Cl2:MeOH, 95:5) and the fractions containing the N-aryl 2-imidazolines were collected and evaporated to dryness. The residue was either purified further by chromatography under the same conditions (methylsulfone compounds 8-21) or taken forward to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 4h; Inert atmosphere; | Preparation of 16 - A solution of 17 (1.00 g, 4.25 mmol), bis(pinacolato)diboron (3.20 g, 12.8 mmol) in 1,4-dioxane (10 mL) was treated with KOAc (535 mg, 5.46 mmol). The solution was degassed with argon for 10 mm. Pd(dppf)C12 (171 mg, 0.21 mmol) was added into this mixture and allowed to stir at 100°C for 4 h. The reaction mixture was cooled, poured into water (70 mL) and extracted with EtOAc (3 x 150 mL). The combinedorganic layers were washed with water (200 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2504 and concentrated in vacuo to afford crude product. The crude product was purified by Combiflash chromatography using 12 g redisep column (hexanes/EtOAc, 1: 1). The fractions were concentrated and dried under reduced pressure to afford 16 (850 mg, 77%) as a solid; MS (MM) m/z 327 [M-Hf. |
61.04% | Stage #1: 4-bromoohenyl methyl sulfone; bis(pinacol)diborane With potassium acetate In 1,4-dioxane for 0.333333h; Inert atmosphere; Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane at 90℃; | Intermediate 44a: 4,4,5,5-Tetramethyl-2-[4-(methylsulfonyl)phenyl]-1 ,3,2- d ioxaborolane This intermediate was synthesized form 1 -bromo-4-(methylsulfonyl)benzene (1 .35 g,1 .0 eq) by following the similar procedure described for the intermediate 5a to yieldthe desired compound(1.2 g, 61 .04%) as a white colour solid. 1H NMR: (ODd3, 300MHz) 6 7.87-7.91 (m, 4H), 2.98 (5, 3H), 1 .29 (5, 1 2H). |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 110℃; for 0.166667h; Microwave irradiation; | 4,4,5,5-Tetramethyl-2-phenyl-1,3,2-dioxaborolane General procedure: To 2 mL of 1,4-dioxane in microwave reaction vessel were added bromobenzene (0.20 g, 1.27 mmol), bis(pinacolato)diboron (0.36 g, 1.40 mmol), potassium acetate (0.38 g, 3.8 mmol), and PdCl2(dppf) (0.028 g, 0.038 mmol). The reaction mixture was heated to 110 °C by microwave irradiation at power 100 W for 10 min. After solvent was removed under reduced pressure, the residue was purified by dry column vacuum chromatography (DCVC) using dichloromethane (DCM) as eluent provided the 0.16 g in 62 % yield; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide; In 1,4-dioxane; at 130℃; for 16h;Inert atmosphere; Sealed tube; | Step A: tert-butyl 2- [4-(methylsulfonyl)phenyll- 1 -oxo-2,8-diazaspiro [4.51 decane-8-carboxylate:To a microwave vial was added <strong>[268550-48-7]tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (100 mg, 0.39 mmol), 1-bromo-4-(methylsulfonyl)benzene (140 mg, 0.59 mmol), potassiumphosphate tribasic (167 mg, 0.79 mmol), trans-N,N?-dimethylcyclohexane-1,2-diamine (2.5 jiL,0.02 mmol) and copper(I) iodide (15 mg, 0.08 mmol). Anhydrous dioxane (2 mL) was added, the vial was sealed and vacuum purged with nitrogen three times. The reaction mixture was then heated to 130 C for 16 h, cooled, filtered over a pad of CELITE and concentrated in vacuo. The crude residue was purified via MPLC (0-75% EtOAc/hexane gradient) to afford titlecompound. LCMS: m/z 409 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | EXAMPLE 2 [0070] Synthesis of 1-(6-methylpyridin-3-yl)-2-[(4-methylsulfonyl)-phenyl]-ethanone hydrochloride [0071] 4-bromophenyl methyl sulfone 80.04 g (0.34 mol) and 3-acetyl-6-methyl pyridine 46.03 g (0.34 mol) in 800 ml of toluene were charged in a reactor under inert atmosphere. The mixture was heated to reflux and Xantphos 0.236 g (0.41 mmol) and Pd2(dba)3 0.156 g (0.17 mmol) were added. A suspension of t-BuONa 72.08 g (0.75 mol) in 800 ml of toluene, kept at 60 C., was added dropwise over about 2 h. From the end of the addition, the reaction was kept for at least 1 h under stirring at that temperature before proceeding with the acid neutralisation. The mixture was cooled to 25 C. and a solution containing 25% hydrochloric acid was added. The mixture was heated to reflux and was distilled to obtain the crystallisation of compound I as hydrochloride. The product was isolated at 5 C. by filtration and was dried under vacuum at 50 C. with a yield of 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With palladium diacetate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 1h; Sealed tube; | General procedure: A mixture of arylhalide (I, Br) (1 mmol), Weinreb amine hydrochloride(1.5 mmol), Pd(OAc)2 (5 mol %), xantphos (6 mol %), triethylamine (3 mmol), and cobalt carbonyl (0.3 mmol) in 1,4-dioxane was heated at 90 °C for 1h in a septum-closed sealed tube. After cooling, the reaction mixture was concentrated in vacuum and the residue was extracted with ethylacetate and water. The ethylacetate layer was concentrated and the residue obtained was purified by flash column chromatography to get the desired product. Note: Carbon monoxide gas is highly toxic and should be handled by trained professionals in a well-ventilated fumehood with appropriate ventilation. In all the reactions, Co2(CO)8 was handled carefully in fumehoods using appropriate personal protective clothing and equipment. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With pyridine-4-carbonitrile; bis(pinacol)diborane In pentane at 80℃; for 36h; Inert atmosphere; Sealed tube; | |
60% | With triethylsilane; tris(pentafluorophenyl)borate In neat (no solvent) at 100℃; for 8h; Glovebox; Inert atmosphere; | Reduction of Sulfoxides and Sulfones; General Procedure General procedure: In a glovebox, an oven-dried 1-mL screw-capped sealed tube with a magnetic stir bar was charged with B(C6F5)3 (10 mol%), Et3SiH (10 equiv), and the indicated oxidized sulfur compound (0.20 mmol). The tube was sealed properly and transferred to an oil bath preheated at100 °C. After 8 h, the reaction was cooled to r.t. and passed through asmall plug of silica gel using Et2O. The crude material was collected ina glass vial and subjected to GLC analysis to determine the conversion with respect to starting material. The ethereal solution was dried (Na2SO4) and filtered, and the solvent was removed under reduced pressure. The mixture was then subjected to high vacuum at 70 °C until the unreacted hydrosilane was removed from the system. If needed, the residue was purified further by flash column chromatography (silica gel, cyclohexane/Et2O 9:1) to afford the desired sulfides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With [2,2]bipyridinyl; bis(1,5-cyclooctadiene)nickel (0) In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; | |
95% | With [2,2]bipyridinyl; bis(1,5-cyclooctadiene)nickel (0) In tetrahydrofuran at 20℃; Inert atmosphere; | 7 Example 7 At room temperature, 100 mL of nitrogen-protected reaction flask,4-Bromobenzenesulfone (4.70 g, 20 mmol) was added,Selenium tetramethyl ammonium triflate (5.33g, 24mmol),2,2'-bipyridine (0.31g, 2mmol) andBis (1,5-cyclooctadiene) nickel (0.56 g, 2 mmol)Tetrahydrofuran (50 mL) was then added via syringe,At room temperature for 2 hours.The reaction solution was dried and the residue was treated with silicon(Eluting with petroleum ether: ethyl acetate = 2: 1 (v / v)) to give 4-trifluoromethylselylbenzenesulfone (5.88 g,97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 3h; Microwave irradiation; Inert atmosphere; | Step 1: Synthesis of Methyl 3-hydroxy-5-(4-(methylsulfonyl)phenoxy)benzoate (28) N,N-dimethylformamide (5 mL) was added to the mixture of methyl 3,5-dihydroxybenzoate 24 (5.0 mmol, 1.0 equiv.), 4-bromophenyl methyl sulfone (10.0 mmol, 2.0 equiv.), cesium carbonate (15.0 mmol, 3.0 equiv.), copper(I) iodide (1.0 mmol, 0.2 equiv.) and 2,2,6,6-tetramethyl-3,5-heptanedione (2.0 mmol, 0.4 equiv), and the mixture was stirred in a microwave reactor under argon for 3 h at 120 °C. After the reaction vials were cooled to room temperature and filtered over celite, the filtrate was washed with saturated aqueous ammonium chloride and brine successively, dried over anhydrous sodium sulfate, and concentrated in vacuum. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether, v/v, 10:90 to 50:50) to afford compound 28 as a beige solid (1.23 g, 76%), mp 131-132 °C. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.23 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.01 (s, 1H), 6.77 (s, 1H), 3.80 (s, 3H), 3.20 (s, 3H). Step 2: Synthesis of Esters 29a-b and 29d. To a stirred suspension of 28 (0.5 mmol, 1.0 equiv.) and triphenyl phosphine (1.0 mmol, 2.0 equiv.) in dry tetrahydrofuran (200 mL), under argon was added alkyl ethanol (0.64 mmol, 1.28 equiv.) at room temperature. The reaction was cooled to 0 °C and diisopropyl azodicarboxylate (1.0 mmol, 2.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 3h; Microwave irradiation; Inert atmosphere; | Step 2: Synthesis of Methyl Benzoates 26a-j General procedure: N,N-dimethylformamide (5 mL) was added to the mixture of 25 (5.0 mmol, 1.0 equiv.), 4-bromophenyl derivatives (6.0 mmol, 1.2 equiv.), cesium carbonate (10.0 mmol, 2.0 equiv.), copper(I) iodide (2 mmol, 0.4 equiv.) and 2,2,6,6-tetramethyl-3,5-heptanedione (4.0 mmol, 0.8 equiv), and the mixture was stirred in a microwave reactor under argon for 3 h at 120 °C. After the reaction vials were cooled to room temperature and filtered over celite the filtrate was washed with saturated aqueous ammonium chloride and brine successively, dried over anhydrous sodium sulfate, and concentrated in vacuum. The resulting residue was purified by silica gel chromatography (ethyl acetate/petroleum ether, v/v, 25:75 to 50:50) to afford methyl benzoate 26a-j. Methyl 3-((1-methoxypropan-2-yl)oxy)-5-(4-(methylsulfonyl)phenoxy)benzoate (26a). The title compound was obtained by condensation between benzoic acid 25 and 4-bromophenyl methyl sulfone according to general procedure G. Yellow oil (71%). 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J = 8.8 Hz, 2H), 7.33 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.14 (s, 1H), 7.08 (t, J = 2.2 Hz, 1H), 4.74-4.70 (m, 1H), 3.83 (s, 3H), 3.49-3.45 (m, 2H), 3.27 (s, 3H), 3.21 (s, 3H), 1.22 (d, J = 6.3 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With Quinuclidine; 4,4'-di-tert-butyl-2,2'-bipyridine nickel(II) bromide; [Ir(C6H2F2-C5H3NCF3)2(4,4′-di-tert-butyl-2,2′-dipyridyl)]; potassium carbonate In 1,4-dioxane at 20℃; for 20h; Inert atmosphere; Sealed tube; Irradiation; | |
69% | With 1,4-diaza-bicyclo[2.2.2]octane; Ir[dF(CF3)ppy]2(dtbbpy)PF6; sodium hydrogencarbonate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,4-dioxane at 20℃; for 20h; Inert atmosphere; Irradiation; Sealed tube; | 3) General procedure for aldehyde arylation General procedure: To a 5mL glass vial were added NiBr2.DME (3.7 mg, 0.012 mmol, 0.11 equiv), 4,4'-ditert-butyl-2,2'-bipyridine (dtbbpy, 3.2 mg, 0.012 mmol, 0.11 equiv) as ligand and 3 mLof dry 1,4-dioxane. This precatalyst vial was sealed and sonicated for around 15 minutes, until its content became homogeneous. A separated 5 mL vial equipped with a magnetic stir bar was charged with the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.2 mg, 0.0011 mmol, 1 mol %), 1,4-diazabicyclo[2.2.2]octane (DABCO, 6.2 mg, 0.055 mmol, 0.5 equiv), NaHCO3 (13.9 mg,0.16 mmol, 1.5 equiv), the aryl bromide (0.11 mmol, 1 equiv) and the aldehyde (0.22mmol, 2 equiv). The volatile aldehydes were added after the sparging. The precatalyst was syringed into the reaction vial before sparging with argon for 15 minutes. The vial was sealed with parafilm and the reaction was magnetically stirred and irradiated for 20 h with a blue LED lamp 6 cm away from the vial with a cooling fan to keep the reaction at room temperature. After that time, the reaction was quenched by exposure to air and filtered through a pad of silica with ethyl acetate and dichloromethane. After concentration, the residue was purified by flash chromatography on silica gel to afford the desired product.The isolated yields reported are the average yield of four simultaneous and identical reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 0.833333h;Inert atmosphere; | General procedure: This compound was made by amodification of the literature procedure. A mixture of commercially available <strong>[501435-91-2]5-bromo-2-fluoropyridine-3-boronic acid</strong> (4; 1.24 g, 5.63 mmol) in p-dioxane (15 mL)was degassed via nitrogen bubbling for 15 min. To the mixture was added1-iodobenzene (546 muL, 4.9 mmol) and Pd(PPh3)4 (283 mg, 0.25 mmol), followed byan additional minute of degassing, and then a solution of Na2CO3 (1.43 g, 13.48mmol) in 10 mL of water, which had been previously degassed for 5 min. Themixture was heated under nitrogen at 90 C for 50 min becoming a clear solution. Thecooled mixture was diluted with water and extracted with ethyl acetate (3x). Thecombined extracts were washed with brine, dried, and concentrated to leave a brownoil that was purified via silica gel flash chromatography (dry packing) using gradientelution with 0 - 2 % ethyl acetate in hexanes. Product fractions were combined andconcentrated to leave 5a (457 mg, 37 %) as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tert-butyl XPhos In 1,4-dioxane; <i>tert</i>-butyl alcohol at 80℃; for 16h; | 302 Example 302 (General Procedure X) A degas sed solution of 3-amino-i - [4-benzyloxy- 1 -[2- [methoxy(methyl)amino] -2- oxo-ethyl] cyclohexyl]pyrazole-4-carboxamide (1.0 g, 2.4 mmol), 1 -bromo-4- methylsulfonyl-benzene (622 mg, 2.65 mmol), potassium phosphate tribasic (1.05 g, 4.8 mmol), 2-di-tert-butylphosphino-2’ ,4’ ,6’ -triisopropylbiphenyl (53 mg, 0.12 mmol) and tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol) in 1,4-dioxane (20 mL)and tert-butyl alcohol (5 mL) was heated for 16 h at 80°C. The mixture was allowed to cool to room temperature and the solid removed by filtration through Celite and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 7% methanol in dichloromethane. The appropriate fractions were combined and concentrated underreduced pressure to afford 1.36 g (99%) of i-[4-benzyloxy-i-[2- [methoxy(methyl)amino] -2-oxo-ethyl] cyclohexyl] -3- (4-methylsulfonylanilino)pyrazole- 4-carboxamide as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With tris-(dibenzylideneacetone)dipalladium(0); sodium phosphate In 5,5-dimethyl-1,3-cyclohexadiene; water at 80℃; for 12h; Inert atmosphere; | 5 Example 5: Preparation of Trifluoroethyl ketone sulfonate intermediate I Under nitrogen protection, 28.7 g (0.096 mol) of 2,2,2-trifluoroacetophenone-4-boronic acid pinacol ester prepared in Example 2 was added to 144 mL of xylene and 60 mL of water, and added to 4 24.8 g (0.105 mol) of bromobenzyl sulfone, 23.6 g (0.144 mol) of sodium phosphate, and 0.22 g (0.00024 mol) of tris(dibenzylideneacetone)dipalladium. After vacuum degassing and nitrogen replacement, the mixture was heated to 80 ° C and reacted for 12 hours. After cooling, filtration, adding a 10% by mass aqueous solution of ammonium chloride (the mass concentration refers to the mass of ammonium chloride as a percentage of the total mass of the ammonium chloride aqueous solution) 60 mL and 120 mL of water, stirring and standing layering, The aqueous phase is combined with the organic phase using a 10% aqueous solution of sodium hydrogencarbonate (the mass concentration means the mass of sodium bicarbonate as a percentage of the total mass of the aqueous solution of sodium hydrogencarbonate)And the mass concentration is 15% saline (the mass concentration refers to the mass of sodium chloride as a percentage of the total mass of the saline solution), and dried over anhydrous sodium sulfate. 120g of diatomaceous earth was filtered and washed with toluene 250mL, concentrated in vacuo to remove most of the solvent (45 ° C ~ 55 ° C, -0.085MPa ~ -0.095MPa), add 120mL of cyclohexane, heated to 70 ~ 75 ° C for 1 hour, and cooled Stirring to 0 ° C ~ 5 ° C for 1 hour, filtration, washing and vacuum drying (35 ° C ~ 45 ° C, -0.01MPa ~ -0.1MPa) 12 to 16 hours to obtain trifluoroethyl ketone sulfone intermediate I, 23.9g The yield was 76.0% (total yield 73.7%, based on 4'-bromo-2,2,2-trifluoroacetophenone), HPLC purity 99.00%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.6% | With copper(I) oxide; 1,10-Phenanthroline; tetrabutyl ammonium fluoride In neat (no solvent) at 150℃; for 2h; Inert atmosphere; | Intermediate 77.1 : 6-methyl-1 -(4-(methylsulfonyl)phenyl)-1 H-indole-5-carbonitrile A suspension of 1 -bromo-4-(methylsulfonyl)benzene (542 mg, 2.305 mmol), 6-methyl-1 H-indole-5-carbonitrile (300 mg, 1 .921 mmol) 1 ,10-phenanthroline (69.2 mg, 0.384 mmol) and Cu20 (27.5 mg, 0.192 mmol) in a solution of TBAF in THF (1 M, 6 ml_, 6.00 mmol) was get rid off the organic solvent in high vacuum. The residue was heated at 150 °C for 2 hr under nitrogen protection. The mixture was re-dissolved in DCM, filtered and the filter was purified by CombiFlash, eluted with ethyl acetate in hexane (30- 70%, 30 min). The desired fraction was collected to afford the title compound (260 mg,43.6%) as white solid. 1 H NMR (400 MHz, DMSO-cfe) δ 8.23 - 8.10 (m, 3H), 7.98 - 7.85 (m, 3H), 7.79 - 7.61 (m, 1 H), 6.87 (dd, J= 3.4, 0.8 Hz, 1 H), 3.32 (s, 3H), 2.57 (s, 3H). LC-MS: [M+H]+ = 31 1 .2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1,10-Phenanthroline; copper(I) oxide; tetrabutyl ammonium fluoride / neat (no solvent) / 2 h / 150 °C / Inert atmosphere 2: N-Bromosuccinimide / N,N-dimethyl-formamide / 1 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.5% | With sulfuric acid; nitric acid at 0 - 10℃; for 0.5h; | 3 Add 120 ml of concentrated nitric acid (65%) to the reaction flask. Stir in an ice bath, add 50 ml of concentrated sulfuric acid (98%) at 0 °C, and add dropwise after 0.5 hours. 23.5 g of p-methanesulfonyl bromide (0.1 mol) was added to the reaction flask, and the reaction was carried out at 0 to 10 ° C for 0.5 hour. After the reaction, the reaction mixture was extracted with 500 ml of a saturated aqueous sodium hydrogen carbonate solution and 1000 ml of ethyl acetate. Collect the organic phase after the extraction, distillation under reduced pressure gave 25.3 g of o-nitro-methanesulfonyl bromide. The yield was 90.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine at 20℃; for 24h; Irradiation; Schlenk technique; | |
93% | Stage #1: methanol; 4-bromoohenyl methyl sulfone With nickel(II) chloride hexahydrate; cadmium(II) sulphide; triethylamine; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl acetamide for 0.00277778h; Schlenk technique; Sonication; Stage #2: In N,N-dimethyl acetamide at 20℃; Schlenk technique; Irradiation; | |
87% | With [nickel(II)dichloride(dimethoxyethane)]; 1,8-diazabicyclo[5.4.0]undec-7-ene; 4,4'-di-tert-butyl-2,2'-bipyridine; zinc In tetrahydrofuran at 40℃; for 24h; Inert atmosphere; Glovebox; Sealed tube; |
85% | With sodium hydroxide at 40℃; for 7h; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 4-bromoohenyl methyl sulfone With titanium(IV) isopropylate; 1,1'-bi-2-naphthol In tetrahydrofuran at -10 - 0℃; for 2h; Schlenk technique; Stage #2: C5H5Cl2NO2 In tetrahydrofuran at -50 - -30℃; for 2.5h; | 1.4-6.4 4) Asymmetric addition step: solvent I is tetrahydrofuran; take a dry Shrek bottle, add a stir bar and stir at 6-9r/s, add at least 20 times the weight of the solvent in the stirred Shrek bottle I dissolved BINOL,Adding tetraisopropyl titanate dropwise, adding at least 20 times by weight of solvent I to dissolve4-methylsulfonylbenzene bromide, stirred at -10 ° C to 0 ° C for 2 h;The system is cooled to between -50 ° C and -30 ° C, constant temperature, slowly add the intermediate oxazoline IV, keep the temperature stirring for at least 2.5 h, until the TLC test reaction is complete; after the TLC test reaction is complete, add appropriate amount The reaction was quenched with 5% dilute hydrochloric acid, and all the solvent I was distilled off under reduced pressure. The mixture was extracted repeatedly with 100 ml of deionized water and dichloromethane, and the organic phase was combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Removal of all dichloromethane, the intermediate oxazoline V;The mass ratio of the BINOL, tetraisopropyl titanate, 4-methylsulfonylbenzene bromide, and the intermediate oxazoline IV was 1:10:24:20. Yield 85%, 80% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dicyclohexyl(2′,4′,6′-tri-isopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphane; Orthoboric acid; palladium diacetate; Cs2CO3 In 1-methyl-pyrrolidin-2-one at 80℃; for 24h; Schlenk technique; Inert atmosphere; | |
95% | With oxygen; triethylamine; sodium iodide In acetonitrile at 32℃; for 24h; Schlenk technique; UV-irradiation; | |
82% | With nickel(II) bromide 2-methoxyethyl ether complex; 6-(pyrazol-1-yl)-2,2'-bipyridine; sodium iodide; Nitrous oxide; zinc powder In N,N-dimethyl acetamide at 25℃; |
70 %Spectr. | With 1-methylpyrrol-2-carboxaldoxime; potassium-t-butoxide In dimethyl sulfoxide at 30℃; for 16h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; bis(tricyclohexylphosphine)nickel(II) dichloride; 4,4'-diamino-2,2'-bipyridyl; magnesium chloride; zinc In dimethyl sulfoxide at 110℃; for 10h; Schlenk technique; | 7 Example 7, 1- (1,1-difluoroethyl) -4- (methylsulfonyl) benzene (Figure 8). To a 10 ml Schlenk reaction tube, add 4-Bromophenyl methyl sulfone(0.2 mmol),Bis (tricyclohexylphosphine) nickel dichloride (10 mol%), 4,4’-diamino-2,2’-bipyridine (10 mol%),4-dimethylaminopyridine (20 mol%), magnesium chloride (3 equivalents), zinc powder (2 equivalents),In other vacuum with nitrogen, and then the reaction solution was dissolved in DMSO 1(Before the reaction is ready, pass reactant 1 slowly into DMSO until the total volume does not increase, and the concentration is 0.7 mol / L after 19F NMR detection) Add 1mL,The reaction was carried out at 110 ° C for 10h. After the reaction was completed, the reaction was detected by TLC, and the target product was obtained by column chromatography (80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); N,N,N′,N′-tetramethyl-N″-tert-butylguanidine; 4-phenyl-N-methylpyridinium iodide; 4,4'-di-tert-butyl-2,2'-bipyridine; zinc In dimethyl sulfoxide at 80℃; for 8h; Inert atmosphere; | |
85.6% | With 1,4-diaza-bicyclo[2.2.2]octane; nickel(II) bromide dimethoxyethane; zinc In N,N-dimethyl acetamide at 20℃; for 18h; Inert atmosphere; Glovebox; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With trimethyl-(2-hydroxyethyl)ammonium chloride; potassium carbonate In glycerol at 90℃; for 2h; Sealed tube; | 2.7. Catalytic Sonogashira coupling reaction General procedure: The Sonogashira reaction was performed in a 10 mL screwcappedvial, phenylacetylene (1.1 mmol), aryl halide (1 mmol),K2CO3 (2 mmol), GO/Fe3O4G2/Co (1 mg, 0.4 mol%), and DES(ChCl:glycerol, 3 mL) was charged and stirred at 90 C for theproper time. The control of reaction, the separation of the catalyst,work-up process, and purification of the Sonogashira productswere analogous to that for the Suzuki reaction. |
88% | With sodium lauryl sulfate; potassium carbonate In water monomer for 12h; Reflux; Green chemistry; | 3.4. General procedure for the copper-free Sonogashira coupling General procedure: In a round bottom flask (5 mL) equipped with condenser andmechanical stirrer, aryl halide (1.0 mmol), terminal alkyne compound(1.1 mmol), K2CO3 (1 mmol), SDS (0.4 mmol, 0.1 gr), water(3 mL) and G3-Gu-Pd catalyst (12.5 mg, 1 mol% of palladium content)were added. Then the mixture was stirred with mechanicalstirrer at 95 °C. Reaction improvement was checked by TLC. Stirringwas continued to completion of reaction and time of the reactionwas mentioned (Table 5). After cooling the reaction mixture, G3-Gu-Pd catalyst was collected by the external magnet and theresulting product was extracted with ethyl acetate (3 x 5 mL). Thenextracted organic layer was dried over Na2SO4. After evaporatingthe solvent by vacuum distillation and purifying the residue withsilica gel column chromatography employing n-hexane/ethyl acetateeluent, pure corresponding product was obtained. |
40% | With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In N,N-dimethyl-formamide at 80℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium iodide In 1,2-dimethoxyethane; water at 65℃; | 1-Bromo-4-(methylsulfonyl)benzene General procedure: To a 10 mL round-bottom flask were added sulfonylhydrazine 1 (1.0 mmol), dimethyl phosphite 2 (0.6 mmol) and NaI (0.2 mmol) in mixed solvent DMF/H2O (10:1, v/v; 3 mL), and the solution was stirred for 5-10 h at 65 °C until sulfonylhydrazine 1 was completely consumed as indicated by TLC analysis. The crude products were then concentrated under reduced pressure, and purified by flash column chromatography (petroleum ether/EtOAc = 30:1 to 10:1), to obtain pure products 3, 6 and 7 with 54-95% yield. |
With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide at 60℃; for 2h; | 3 Example 3 A method for synthesizing organic sulfone molecules with a novel sulfone methylation reagent. Using sulfonyl hydrazide 1c (R = 4-Br-C6H4) (0.001 mol, 0.251 g) and dimethyl phosphite 2 (0.0011 mol, 0.121 g) as starting materials, dissolve it in 5 mL N,N-dimethylformamide (DMF) was added and the mixed solution was moved to 60 °C for 6 hours, and the reaction of raw material 1c was completed. Then, the solvent was drained and the crude product was separated by column chromatography with eluent gradient elution to obtain organic sulfone molecules 3c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With (1,2-dimethoxyethane)dichloronickel(II); tetrabutylammonium triphenyldifluorosilicate In N,N-dimethyl acetamide at 35℃; for 12h; Inert atmosphere; | General Procedure 2 General procedure: In a nitrogen-filled glove box, aromatic halide (0.2 mmol, 1.0equiv), TBAT (270 mg, 0.5 mmol, 2.5 equiv), NiCl2(glyme) (4.4mg, 0.02 mmol, 10 mol%), and DMA (1.0 mL) were charged to an8 mL vial equipped with a magnetic stirrer bar. The vinyltrimethoxysilane(59.1 mg, 0.4 mmol, 2.0 equiv) was added. The vialwas removed from the glove box, and the reaction mixture wasstirred at rt (35 °C) for 12 h. The reaction mixture was thendiluted with EtOAc and washed with water. The organic phasewas dried over Na2SO4, filtered, and concentrated, and theresidue was purified by column chromatography on silica gel togive the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium phosphate; copper(l) iodide; rac-diaminocyclohexane In 1,4-dioxane at 120℃; for 16h; | 3 Compound 151: To a solution of 1H-pyrrolo[2,3-b]pyridin-6-yl(2-thienyl)methanone (0.60 g, 2.63 mmol, 1.00 eq) in Dioxane (10 mL), 1-bromo-4-methylsulfonyl-benzene (1.24 g, 5.26 mmol, 2.00 eq), Potassium phosphate tribasic (1.67 g, 7.89 mmol, 3.00 eq), Copper(I) iodide (0.15 g, 0.789 mmol, 0.300 eq) and (±)-trans-1,2-Diaminocyclohexane (0.66 mL, 5.52 mmol, 2.10 eq) were added and reaction mixture was heated at 120°C for 16h. After completion, reaction mixture was diluted with water (100 mL) and solid was filter and wash with water and extracted with DCM (100 X 2). Organic was evaporated and dried with sodium sulfate, Crude product was purified by column chromatography using silicagel (100-200 mesh) and pure product was elute out at 0 to 50% ethyl acetate in hexane to obtain [1-(4- methylsulfonylphenyl)pyrrolo[2,3-b]pyridin-6-yl]-(2-thienyl)methanone (800 mg, 80% yield) as a white solid. MS(ESI): 382.9[M+H]+.1H NMR (400 MHz, DMSO-d6) d8.43 - 8.29 (m, 5H), 8.21 - 8.11 (m, 3H), 8.07 (d, J = 8.5 Hz, 1H), 7.32 (t, J = 4.4 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 4-bromoohenyl methyl sulfone With nickel(II) iodide; 1,4-bis(dicyclohexylphosphino)butane; sodium carbonate; cesium iodide In tetrahydrofuran for 0.25h; Schlenk technique; Glovebox; Stage #2: In tetrahydrofuran at 35℃; for 72h; Irradiation; | General Procedure A (solid aryl bromides). General procedure: An oven dried Schlenk tube containing a stir barwas charged with arylbromide (0.2 mmol), Na2CO3 (0.3 mmol, 31.8 mg, 1.5 equiv), and NiI2(0.02 mmol, 6.1 mg, 10 mol%). The Schlenk was transferred to a nitrogen filled gloveboxwhere dcyb (0.022 mmol, 9.9 mg, 11 mol%), CsI (0.04 mmol, 10.4 mg, 20 mol%), andanhydrous THF (0.2 M, 1 mL) was added. The Schlenk was sealed and the mixture was stirredfor 15 minutes. It was taken out of the glovebox and placed in a preheated reaction vessel at 35C (see pictures) and stirred for 72 hours under blue light irradiation. The mixture was quenchedwith 1M HCl (2 mL) and extracted with EtOAc, 0.5 cm3 of silica gel was added to the roundbottom flask and evaporated on a rotary evaporator set at 40 C and 100 mbar. The silica wasthen subjected to column chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate In tetrahydrofuran; water at 85℃; for 22h; Sealed tube; Inert atmosphere; | General procedure: Under nitrogen, to a stirred solution of methyl 4-bromo-2-methoxybenzoate (0.73 g,3.0 mmol, 1.0 eq) in THF/H2O (9:1 v/v, 6.0 mL) was added potassiumvinyltrifluoroborate (0.40 g, 3.0 mmol, 1.0 eq), Cs2CO3 (2.9 g, 9.0 mmol, 3.0 eq) andPdCl2(PPh3)2 (42 mg, 0.06 mmol, 0.02 eq) in a sealed tube, the resulting solution wasstirred at 85°C for 22 h. After being cooled to room temperature, the solution wasdiluted with EtOAc (20 mL), the aqueous layer was extracted with EtOAc (3 × 20mL). The combined EtOAc layers were washed with brine (3 × 10 mL), dried overNa2SO4, and concentrated in vacuo. Purification by flash column chromatography(PE : EtOAc = 30:1, v/v) afforded the desired product 6f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 1,4-diaza-bicyclo[2.2.2]octane; Ir[dF(CF3)ppy]2(dtbbpy)PF6; sodium hydrogencarbonate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,4-dioxane at 20℃; for 20h; Inert atmosphere; Irradiation; Sealed tube; | 3) General procedure for aldehyde arylation General procedure: To a 5mL glass vial were added NiBr2.DME (3.7 mg, 0.012 mmol, 0.11 equiv), 4,4'-ditert-butyl-2,2'-bipyridine (dtbbpy, 3.2 mg, 0.012 mmol, 0.11 equiv) as ligand and 3 mLof dry 1,4-dioxane. This precatalyst vial was sealed and sonicated for around 15 minutes, until its content became homogeneous. A separated 5 mL vial equipped with a magnetic stir bar was charged with the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.2 mg, 0.0011 mmol, 1 mol %), 1,4-diazabicyclo[2.2.2]octane (DABCO, 6.2 mg, 0.055 mmol, 0.5 equiv), NaHCO3 (13.9 mg,0.16 mmol, 1.5 equiv), the aryl bromide (0.11 mmol, 1 equiv) and the aldehyde (0.22mmol, 2 equiv). The volatile aldehydes were added after the sparging. The precatalyst was syringed into the reaction vial before sparging with argon for 15 minutes. The vial was sealed with parafilm and the reaction was magnetically stirred and irradiated for 20 h with a blue LED lamp 6 cm away from the vial with a cooling fan to keep the reaction at room temperature. After that time, the reaction was quenched by exposure to air and filtered through a pad of silica with ethyl acetate and dichloromethane. After concentration, the residue was purified by flash chromatography on silica gel to afford the desired product.The isolated yields reported are the average yield of four simultaneous and identical reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 1,4-diaza-bicyclo[2.2.2]octane; Ir[dF(CF3)ppy]2(dtbbpy)PF6; sodium hydrogencarbonate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,4-dioxane at 20℃; for 20h; Inert atmosphere; Irradiation; Sealed tube; | 3) General procedure for aldehyde arylation General procedure: To a 5mL glass vial were added NiBr2.DME (3.7 mg, 0.012 mmol, 0.11 equiv), 4,4'-ditert-butyl-2,2'-bipyridine (dtbbpy, 3.2 mg, 0.012 mmol, 0.11 equiv) as ligand and 3 mLof dry 1,4-dioxane. This precatalyst vial was sealed and sonicated for around 15 minutes, until its content became homogeneous. A separated 5 mL vial equipped with a magnetic stir bar was charged with the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.2 mg, 0.0011 mmol, 1 mol %), 1,4-diazabicyclo[2.2.2]octane (DABCO, 6.2 mg, 0.055 mmol, 0.5 equiv), NaHCO3 (13.9 mg,0.16 mmol, 1.5 equiv), the aryl bromide (0.11 mmol, 1 equiv) and the aldehyde (0.22mmol, 2 equiv). The volatile aldehydes were added after the sparging. The precatalyst was syringed into the reaction vial before sparging with argon for 15 minutes. The vial was sealed with parafilm and the reaction was magnetically stirred and irradiated for 20 h with a blue LED lamp 6 cm away from the vial with a cooling fan to keep the reaction at room temperature. After that time, the reaction was quenched by exposure to air and filtered through a pad of silica with ethyl acetate and dichloromethane. After concentration, the residue was purified by flash chromatography on silica gel to afford the desired product.The isolated yields reported are the average yield of four simultaneous and identical reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1,4-diaza-bicyclo[2.2.2]octane; Ir[dF(CF3)ppy]2(dtbbpy)PF6; sodium hydrogencarbonate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,4-dioxane at 20℃; for 20h; Inert atmosphere; Irradiation; Sealed tube; | 3) General procedure for aldehyde arylation General procedure: To a 5mL glass vial were added NiBr2.DME (3.7 mg, 0.012 mmol, 0.11 equiv), 4,4'-ditert-butyl-2,2'-bipyridine (dtbbpy, 3.2 mg, 0.012 mmol, 0.11 equiv) as ligand and 3 mLof dry 1,4-dioxane. This precatalyst vial was sealed and sonicated for around 15 minutes, until its content became homogeneous. A separated 5 mL vial equipped with a magnetic stir bar was charged with the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.2 mg, 0.0011 mmol, 1 mol %), 1,4-diazabicyclo[2.2.2]octane (DABCO, 6.2 mg, 0.055 mmol, 0.5 equiv), NaHCO3 (13.9 mg,0.16 mmol, 1.5 equiv), the aryl bromide (0.11 mmol, 1 equiv) and the aldehyde (0.22mmol, 2 equiv). The volatile aldehydes were added after the sparging. The precatalyst was syringed into the reaction vial before sparging with argon for 15 minutes. The vial was sealed with parafilm and the reaction was magnetically stirred and irradiated for 20 h with a blue LED lamp 6 cm away from the vial with a cooling fan to keep the reaction at room temperature. After that time, the reaction was quenched by exposure to air and filtered through a pad of silica with ethyl acetate and dichloromethane. After concentration, the residue was purified by flash chromatography on silica gel to afford the desired product.The isolated yields reported are the average yield of four simultaneous and identical reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 1,4-diaza-bicyclo[2.2.2]octane; Ir[dF(CF3)ppy]2(dtbbpy)PF6; sodium hydrogencarbonate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,4-dioxane at 20℃; for 20h; Inert atmosphere; Irradiation; Sealed tube; | 3) General procedure for aldehyde arylation General procedure: To a 5mL glass vial were added NiBr2.DME (3.7 mg, 0.012 mmol, 0.11 equiv), 4,4'-ditert-butyl-2,2'-bipyridine (dtbbpy, 3.2 mg, 0.012 mmol, 0.11 equiv) as ligand and 3 mLof dry 1,4-dioxane. This precatalyst vial was sealed and sonicated for around 15 minutes, until its content became homogeneous. A separated 5 mL vial equipped with a magnetic stir bar was charged with the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.2 mg, 0.0011 mmol, 1 mol %), 1,4-diazabicyclo[2.2.2]octane (DABCO, 6.2 mg, 0.055 mmol, 0.5 equiv), NaHCO3 (13.9 mg,0.16 mmol, 1.5 equiv), the aryl bromide (0.11 mmol, 1 equiv) and the aldehyde (0.22mmol, 2 equiv). The volatile aldehydes were added after the sparging. The precatalyst was syringed into the reaction vial before sparging with argon for 15 minutes. The vial was sealed with parafilm and the reaction was magnetically stirred and irradiated for 20 h with a blue LED lamp 6 cm away from the vial with a cooling fan to keep the reaction at room temperature. After that time, the reaction was quenched by exposure to air and filtered through a pad of silica with ethyl acetate and dichloromethane. After concentration, the residue was purified by flash chromatography on silica gel to afford the desired product.The isolated yields reported are the average yield of four simultaneous and identical reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With 1,4-diaza-bicyclo[2.2.2]octane; Ir[dF(CF3)ppy]2(dtbbpy)PF6; sodium hydrogencarbonate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,4-dioxane at 20℃; for 20h; Inert atmosphere; Irradiation; Sealed tube; | 3) General procedure for aldehyde arylation General procedure: To a 5mL glass vial were added NiBr2.DME (3.7 mg, 0.012 mmol, 0.11 equiv), 4,4'-ditert-butyl-2,2'-bipyridine (dtbbpy, 3.2 mg, 0.012 mmol, 0.11 equiv) as ligand and 3 mLof dry 1,4-dioxane. This precatalyst vial was sealed and sonicated for around 15 minutes, until its content became homogeneous. A separated 5 mL vial equipped with a magnetic stir bar was charged with the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.2 mg, 0.0011 mmol, 1 mol %), 1,4-diazabicyclo[2.2.2]octane (DABCO, 6.2 mg, 0.055 mmol, 0.5 equiv), NaHCO3 (13.9 mg,0.16 mmol, 1.5 equiv), the aryl bromide (0.11 mmol, 1 equiv) and the aldehyde (0.22mmol, 2 equiv). The volatile aldehydes were added after the sparging. The precatalyst was syringed into the reaction vial before sparging with argon for 15 minutes. The vial was sealed with parafilm and the reaction was magnetically stirred and irradiated for 20 h with a blue LED lamp 6 cm away from the vial with a cooling fan to keep the reaction at room temperature. After that time, the reaction was quenched by exposure to air and filtered through a pad of silica with ethyl acetate and dichloromethane. After concentration, the residue was purified by flash chromatography on silica gel to afford the desired product.The isolated yields reported are the average yield of four simultaneous and identical reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); lithium tert-butylate In N,N-dimethyl-formamide at 100℃; for 16h; Inert atmosphere; | 2 Step 2: tert-Butyl 4-[(4-methylsulfonylphenyl)-phenyl-methylene]piperidine-1-carboxylate A solution of tert-butyl 4-[(Z)-C-phenyl-N-(p-tolylsulfonylamino)carbonimidoyl]piperidine-1- carboxylate (2.0 g, 4.37 mmol, 1.0 equiv), 1-bromo-4-methylsulfonyl-benzene (1.23 g, 5.24 mmol, 1.2 equiv; CAS RN 3466-32-8), lithium tert-butoxide (0.70 g, 8.74 mmol, 2.0 equiv) and bis(triphenylphosphine)palladium(II) chloride (0.92 g, 1.31 mmol, 0.3 equiv) in DMF (30 mL) was stirred under an atmosphere of N2 at 100 °C for 16 h. The reaction mixture was filtered through a Celite pad, the filtrate concentrated and the residue purified by silica gel column chromatography (petroleum ether : ethyl acetate = 10 : 1 to 5 : 1) to give the desired product as light yellow oil (1.2 g, 64 %). MS (ESI): m/z = 372.3 [M+2H-tBu]+. |
Tags: 3466-32-8 synthesis path| 3466-32-8 SDS| 3466-32-8 COA| 3466-32-8 purity| 3466-32-8 application| 3466-32-8 NMR| 3466-32-8 COA| 3466-32-8 structure
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