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CAS No. : | 62938-08-3 | MDL No. : | MFCD03701623 |
Formula : | C15H23Br | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SNRYBGHMHAJTTM-UHFFFAOYSA-N |
M.W : | 283.25 | Pubchem ID : | 4447507 |
Synonyms : |
|
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3261 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
13 %Chromat. | With C33H30F3N2NiO2P; tert-butylmagnesium chloride In tetrahydrofuran; diethyl ether at 20℃; for 24 h; Schlenk technique; Inert atmosphere | General procedure: A Schlenk flask was charged with an appropriate amount of complex 6 (0.05mmol, 5.0molpercent) and the corresponding bromo, chloro, fluoro or iodo arene (1.0mmol). The flask was cycled with nitrogen and vacuum. Afterwards THF (2.0mL) and a diethylether solution of tert-butyl-magnesiumchloride (0.75mL, 1.5mmol, 2.0M in diethylether) were added. The flask was sealed and heated at 70°C for 24h or stirred at room temperature. After that time, the mixture was cooled and a NH4Cl solution was added. The mixture was extracted with dichloromethane and the organic layer was dried with Na2SO4. n-Dodecane was added and an aliquot was taken for GC–MS analysis. The coupling products were confirmed by GC–MS and NMR analysis using n-dodecane as internal standard. The analytical properties of the products are in agreement with literature data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetrakis(trimethylphosphine)cobalt(0); dimethyl zinc(II) In tetrahydrofuran; hexane at 20 - 66℃; for 0.166667h; | |
90% | With bis(triphenylphosphine)nickel(II) chloride; magnesium In tetrahydrofuran at 20℃; for 18h; Inert atmosphere; | 10 General procedure for the homocoupling reaction of halogenobenzyl halide 1 General procedure: In a flamed Schlenk tube under nitrogen atmosphere, [NiCl(1-naph)(PPh3)2] (0.05 mmol, 0.05 equiv) was introduced with metal dust (0.55 mmol, 0.55 equiv) and halogenobenzyl halide derivatives 1 (1 mmol, 1 equiv) in anhydrous and degassed THF (3 mL, c=0.66 mol L-1). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 h. Water (3 mL) was added and aqueous layer was extracted with ethyl acetate (3*5 mL). Combined organic layers were combined and washed with saturated aqueous solution of NaCl (5 mL) and dried over MgSO4. After filtration, solvent was removed under vacuum to give the crude product 2, which was purified by flash chromatography on silica gel with pentane as eluent. |
58% | With magnesium In diethyl ether for 3h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 18-crown-6 ether; potassium carbonate In acetone Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In N,N-dimethyl-formamide at 75℃; for 6h; Inert atmosphere; | |
82% | In N,N-dimethyl-formamide at 70 - 75℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 18-crown-6 ether; potassium carbonate In acetone for 24h; Heating; | |
83% | With 18-crown-6 ether; potassium carbonate In acetone for 48h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium <i>tert</i>-butylate In benzene at 80℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: 2-hydroxycylooctanone With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 3,5-di-tert-butylbenzyl bromide In N,N-dimethyl-formamide at -15℃; for 24h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: (5Z)-2-hydroxycycloocten-1-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 3,5-di-tert-butylbenzyl bromide In N,N-dimethyl-formamide at -15℃; for 24h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 18-crown-6 ether; potassium carbonate In tetrahydrofuran Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: (R,R)-4,5-bis-(2-methoxyphenyl)imidazolidin-2-one With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 4,4'-bipyridine; bis(p-xylyl)-[26]crown-6; 3,5-di-tert-butylbenzyl bromide In acetonitrile at 20℃; for 168h; Stage #2: With ammonium hexafluorophosphate In acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 76 percent / KO-tBu / benzene / 6 h / 80 °C 2: 66 percent / KO-tBu; Pd2(dba)3; BINAP / 18-c-6 / benzene / 8 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With hexamethylenetetramine In ethanol; chloroform for 7h; Reflux; | |
Multi-step reaction with 2 steps 1: 82 percent / dimethylformamide / 5 h / 70 - 75 °C 2: N2H4*H2O / ethanol / 0.25 h / Heating | ||
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 25 °C / Inert atmosphere 2: hydrazine / tetrahydrofuran / 3 h / 70 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: sodium azide / N,N-dimethyl-d<SUB>6</SUB>-formamide / 2 h / 70 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 7500.75 Torr / Autoclave | ||
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide / 6 h / 75 °C / Inert atmosphere 2.1: hydrazine hydrate / ethanol / 0.33 h / Reflux 2.2: 0.25 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In DMF (N,N-dimethyl-formamide) at 20℃; for 24h; | 8 Intermediate 8: 4- (3, 5-DI-TERT-BUTYL-BENZYL)-3, 4-dihydro-2H- benzo [1, 4] oxazine-6-carbaldehyde Intermediate 8: 4- (3, 5-DI-TERT-BUTYL-BENZYL)-3, 4-dihydro-2H- benzo [1, 4] oxazine-6-carbaldehyde. To a solution of DMF (14 ML) and Intermediate 5 (0.220 g, 1.35 mmol) was added sodium hydride (0.068 g, 2.84 mmol) and 3,5-di-tert-butyl-benzyl bromide (0.458 g, 1.62 MMOL). The reaction was stirred at room temperature for 24 hours. The DMF was removed in vacuo and the reaction mixture was diluted with ethyl acetate, washed with 1N HCI, NAHCO3, and then brine. The organic layer was dried with magnesium sulfate and concentrated. MS: M+-1=364. 2 Da. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate In N,N-dimethyl-formamide; acetone Heating / reflux; | 3.2 3,5-Bis(t-butyl)-1-(bromomethyl)benzene(170 mg, 0.60 mmol), t-butyl piperazine carboxylate(102 mg, 0.55 mmol) and potassium carbonate(151 mg, 1.10 mmol) were dissolved in a solvent mixture of acetone(2 mg) and DMF(0.2 ml), and the mixture was stirred overnight while heated under reflux. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, and then the filtrate was evaporated under reduced pressure. The concentrate was subjected to silica gel column chromatography(n-hexane:ethyl acetate=4:1) to give 120 mg(yield 56%) of the title compound as a white solid. 1H-NMR (300 MHz, CDCl3) δ: 1.31(s, 18H), 1.42(s, 9H), 2.46(t, 4H), 3.38(t, 4H), 3.49(s, 2H), 7.11(s, 2H), 7.27(s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydride In N,N-dimethyl-formamide for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hydride In N,N-dimethyl-formamide for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate In N,N-dimethyl-formamide at 45℃; for 18h; | 6 To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.40 g, 0.001 mol) in DMF (10 mL), was added 3,5-di-tert-butyl-benzyl bromide (0.30 g, 0.0011 mol) and powdered potassium carbonate (0.96 g, 0.007 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (9:1 Hexanes/EtOAc) to give the desired product as oil 0.56 g in 92% yield. 1H NMR (CDCl3) δ 7.19 (m, 10H), 7.12 (t, 2H), 7.01 (d, 2H), 6.82 (d, 1H), 6.63 (s, 1H), 6.59 (d, 1H), 4.17 (t, 1H), 3.67 (s, 3H), 3.62 (s, 2H), 3.57 (t, 2H), 3.55 (s, 2H), 3.10 (d, 2H), 2.58 (t, 2H), 1.77 (t, 2H), 1.26 (s, 18H). 13C NMR (CDCl3) δ 173.3, 160.6, 151.8, 145.1, 140.1, 136.5, 130.8, 129.8, 129.7, 129.6, 129.5, 127.6, 124.5, 122.6, 122.1, 117.0, 114.6, 67.3, 61.3, 53.4, 52.3, 51.2, 51.1, 42.7, 36.1, 32.9, 28.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium azide In N,N-dimethyl-d<SUB>6</SUB>-formamide at 70℃; for 2h; | |
95% | With sodium azide In N,N-dimethyl-formamide at 20℃; for 24h; | |
91% | With sodium azide In acetone for 22h; Reflux; | 3,5-Di-tert-butylbenzylazide (5c): The title compound was synthesized according to a procedure by Feringa.23,5-Di-tBu-benzylazide (1.50 g, 5.3 mmol) and NaN3 (2.58 g, 39.7 mmol, 7.5 eq) was added to acetone (45 mL) and refluxed for 22 hrs. The reaction mixture was cooled to room temperature, added H2O (25 mL) and extracted with DCM (3 x 20 mL). The combined organic phase was then dried over MgSO4, filtered and evaporated under reduced pressure, affording 5c as a lightly yellow oil (1.18 g, 4.8 mmol, 91% yield).1H NMR data was in accordance with previously reported spectra for this compound.4Synthesis is similar to the one reported for 5a2 except for the usage of anhydrous acetone.1H NMR (400 MHz, CDCl3):7.40 (s, 1H, HAr-4), 7.13 (d, J = 1.3 Hz, 2H, HAr-2 and HAr-6), 4.32 (s, 2H, CH2), 1.33 (s, 18H, 2x tBu) ppm. |
82% | With sodium azide In dimethyl sulfoxide at 25℃; | |
With sodium azide In dimethyl sulfoxide at 20℃; Inert atmosphere; | ||
With sodium azide In N,N-dimethyl-formamide at 50℃; for 19h; | 4 4.4. 1-(Azidomethyl)-3,5-di-tert-butylbenzene (1d) General procedure: The title compound 1a was prepared according to a publishedprocedure.39,40 A mixture of 1-bromoheptane (5.00 g, 27.9 mmol)and NaN3 (2.72 g, 41.9 mmol) in DMF (50 mL) was heated to50 C for 19 h. The suspension was then added DCM (80 mL) andwashed with water (3 100 mL), before it was dried over MgSO4and evaporated. Yielding 1a as a lightly yellow oil (3.06 g,21.7 mmol, 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 130℃; for 0.166667h; microwave irradiation; | 52.a To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (84 mg, 0.19 mmol) in CH3CN (5 ml) was added 1-Bromomethyl-3,5-di-tert-butyl-benzene (80.0 mg, 0.28 mmol), and diisopropylethylamine (66 μl, 0.38 mmol). The reaction was microwaved at 130° C. for 10 minutes. The reaction was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (109 mg, 85%). Calcd for C41H54F3NO2 (M+H) 649.87, Found 650.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With copper(l) iodide; tetra-(n-butyl)ammonium iodide; potassium carbonate In acetonitrile at 40℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 1,1‐bis[(4S)‐4‐isopropyl‐4,5‐dihydrooxazol‐2‐yl]ethane With tert.-butyl lithium In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran at -78 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In tetrahydrofuran for 15h; Inert atmosphere; Reflux; | |
80% | In tetrahydrofuran at 60℃; for 36h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 1h; | 4.1.2.3. 3,5-Di-tert-butylbenzyl bromide (5b) 3,5-Di-t-butylbenzoic acid (5.00 g, 0.021 mol) was dissolved in anhydrous THF (250 mL) under argon atmosphere and the solution cooled to 0 °C. Lithium aluminum hydride (1.62 g, 0.043 mol) was added in small portions and the solution stirred at room temperature overnight. The reaction was quenched with water, Et2O (100 mL) was added and the mixture acidified with concentrated HCl solution until the solid residue was dissolved. The medium was extracted with Et2O and the organic phase dried over MgSO4, filtered and concentrated to yield 4.31g of 5a. 1H NMR δ (CDCl3) 1.34 (s, 18H, di-t-butyl), 4.70 (s, 2H, PhCH2OH), 7.23 (d, 2H, J = 1.8 Hz, 2-CH and 6-CH), 7.38 (t, 1H, J = 1.8 Hz, 4-CH). Crude alcohol 5a (4.25 g) was dissolved in anhydrous CH2Cl2 (500 mL) and cooled at 0 °C. Triphenylphosphine (10.23 g, 0.039 mol) and carbon tetrabromide (12.93 g, 0.039 mol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography on silica gel with hexanes to yield 4.62 g (86%) of bromide 5b. 1H NMR δ (CDCl3) 1.33 (s, 18H, di-t-butyl), 4.52 (s, 2H, PhCH2Br), 7.23 (d, 2H, J = 1.8 Hz, 2-CH and 6-CH), 7.37 (t, 1H, J = 1.8 Hz, 4-CH); 13C NMR (75 MHz) δ (CDCl3) 31.4 (6×), 34.8 (2×), 34.9, 122.7, 123.3 (2×), 136.8, 151.3 (2×). |
With N-Bromosuccinimide; triphenylphosphine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 3,6-bis(5'-bromo-4'-dodecyl-2,2'-bithiophen-5-yl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione With potassium carbonate In 1-methyl-pyrrolidin-2-one at 60℃; for 0.5h; Inert atmosphere; Stage #2: 3,5-di-tert-butylbenzyl bromide In 1-methyl-pyrrolidin-2-one at 60 - 80℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In a dried flask was zinc powder (2.493 g, 38.13 mmol) suspended in anhydrous tetrahydrofuran (23 mL) under nitrogen. The resulting suspension was warmed to 60° C., then 1,2-dibromoethane (0.137 mL, 1.59 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.161 mL, 1.27 mmol) was added and stirred at room temperature for 45 min. Then, 1-(bromomethyl)-3,5-di-tert-butylbenzene (9 g, 31.77 mmol) dissolved in anhydrous tetrahydrofuran (23.00 mL) was added over 10 min. Stirring continued at room temperature for 16 h, then stirring was switched off to let the solids settle. The supernatant was used in the next transformation. To a solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (4 g, 23.31 mmol) and Pd(PPh3)4 (0.539 g, 0.47 mmol) in tetrahydrofuran (120 mL) under nitrogen in a dried flask was added a freshly prepared solution of (3,5-di-tert-butylbenzyl)zinc(II) bromide (11.08 g, 31.78 mmol) in tetrahydrofuran (46 mL). The resulting bright yellow solution was heated to 60° C. for 35 min, then stirred at room temperature for 1 h. The reaction was quenched by addition of methanol (50 mL). The solution was diluted with EtOAc and washed with NH4Cl. The organic layer was dried over MgSO4, filtered and evaporated to yield a brown oil. The crude was redissolved in MTBE (180 mL) and solids were filtered off. Hydrogen chloride (4 M in dioxane, 6.42 mL, 25.66 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 10 min. The solid was collected by filtration and washed with MTBE. Redissolved in MTBE/satd NaHCO3. The phases were separated, the organic phase dried over Na2SO4, filtered and evaporated to yield methyl 2-(3,5-di-tert-butylbenzyl)isonicotinate (7.132 g, 90percent) as a brown oil. 1H NMR (600 MHz, cdcl3) delta 1.28 (s, 18H), 3.89 (s, 3H), 4.19 (s, 2H), 7.11 (d, 2H), 7.27 (t, 1H), 7.64 (dd, 1H), 7.71 (s, 1H), 8.68 (d, 1H). MS m/z 340 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 0.166667h; Microwave irradiation; | 49 Example 49: 1-fr2-αr3.5-bis(1.1- dimethylethyl)phenvnmethyl)oxy)phenvnmethyl)-Λ/-(2,6-difluorophenyl)-1H- pyrazole-3-carboxamide; To a solution of /V-(2,6-difluorophenyl)-1-[(2-hydroxyphenyl)methyl]-1H-pyrazole-3- carboxamide (33 mg, 0.1 mmol) and cesium carbonate (33 mg, 0.1 mmol) in DMF (0.4 ml) was added a solution of 3,5-di-f-butylbenzyl bromide (28 mg, 0.1 mmol, Aldrich) in DMF (0.1 ml). Reaction vessel was sealed and heated in microwave using initial 150 W to 100 0C for 10 min. The reaction mixture was dissolved in DMSO (0.5 ml) and purified by MDAP on Sunfire C18 column (Method D) using Acetonitrile-Water with a TFA modifier. The solvent was evaporated in vacuo using the Genevac to give the title compound (18 mg); LCMS: (System 3) MH+ = 532, tREτ = 1.54 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With copper In 1-methyl-pyrrolidin-2-one at 60℃; for 11h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 3,5-di-tert-butylbenzyl bromide With magnesium In diethyl ether at 20℃; for 2h; Inert atmosphere; Stage #2: 3-(O-tert-butyl(dimethyl)silyl)estrone In tetrahydrofuran; diethyl ether at 20℃; Inert atmosphere; Stage #3: With water; ammonium chloride In tetrahydrofuran; diethyl ether | 4.1.3. Procedure for the Grignard reaction (synthesis of compounds 9-15) General procedure: Powdered magnesium (705 mg, 28.99 mmol) was flame activated under argon in a dry tri-necked flask and left to cool down to room temperature. Dry Et2O (5.6 mL) was added to the activated Mg powder and a small portion (0.1 mL) of bromide solution (2.26 g of 3c in 4.0 mL of Et2O) was added and the reaction started with the heat from the hand or with a few drops of MeI (gas evolution and cloudy solution with heat). The rest of the bromide was then added slowly taking care not to boil off the solvent. The mixture was stirred at room temperature for 2 h. A small amount of the solution was used for a test with Michler’s reagent refPreviewPlaceHolder[43]. A blue-green coloration indicated that the Grignard’s reagent was formed. The Grignard reagent solution was added slowly at room temperature to a solution of 3-t-butyldimethylsilyl-O-estrone (TBS-E1) refPreviewPlaceHolder[44] (400 mg, 0.96 mmol) in anhydrous THF (24 mL) and the mixture was stirred overnight at room temperature under argon atmosphere. The mixture was poured in a saturated aqueous NH4Cl solution, extracted with EtOAc, dried over MgSO4, filtered and concentrated. Since the Rf of starting TBS-E1 and the final product were very similar, the remaining starting product was reduced to TBS-E2 by dissolving the crude product in anhydrous MeOH (5 mL) and adding excess (4-5 eq.) of NaBH4. After 1 h at room temperature, water was added, and the mixture was extracted with EtOAc, dried over MgSO4, filtered and concentrated. Purification by flash chromatography on silica gel with hexanes/EtOAc (9/1) yielded 364 mg (65%) of 3-TBS-9 and 3-TBS-E2, which was not recovered. Only the alkylated compound (3-TBS-9) was submitted to the deprotection procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere; | 4.2. Preparation of dialkylated malononitriles 17f-q General procedure: To a solution of malononitrile in DMF (30 mL per gram of malononitrile) were added DBU (2.2 equiv) and alkyl halide (2.2 equiv), and the reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature and water (150 mL per gram of malononitrile) and dichloromethane (150 mL per gram of malononitrile) was added to the reaction mixture. The aqueous layer was extracted with dichloromethane (150 mL per gram of malononitrile) and the combined organic layer was washed with brine, dried over MgSO4, and evaporated. The residue was purified by silica gel chromatography to afford the dialkylated malononitrile. |
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 0 - 80℃; for 8.5h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: (S,S)-1,2-diphenyl-1,2-diaminoethane With potassium carbonate In acetonitrile at 20℃; for 0.5h; Large scale; Stage #2: 3,5-di-tert-butylbenzyl bromide In acetonitrile at 20℃; for 12h; Large scale; | (1) Synthesis of chiral di-secondary amine 3 Add the reaction solvent to the 50L reactor:Acetonitrile (22.0L),Then add chiral ethylenediamine 1 (1.00kg, 4.71mol, 1.00equiv.) andAcid binding agent,The acid binding agent is preferably potassium carbonate (2.00kg, 14.47mol, 3.07equiv.),After stirring for 30 minutes at room temperature,Benzyl bromide 2 (2.81kg, 9.89mol, 2.10equiv.) was slowly added dropwise to the reaction kettle,Then it was stirred at room temperature for 12 hours.After TLC and HPLC are qualified, water (15L) is slowly added to the reaction kettle and stirred at room temperature for 1 hour. The lower aqueous phase was removed by liquid separation, and the upper organic phase was concentrated to obtain a pale yellow solid intermediate 3 (2.91 kg, yield 100%). |
83% | With potassium carbonate In acetonitrile at 20℃; for 24h; | |
80% | With tetrabutylammomium bromide; potassium carbonate In acetonitrile at 20℃; for 24h; |
With potassium carbonate In acetonitrile at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In toluene at 100℃; Inert atmosphere; Schlenk technique; | |
With sodium iodide In tetrahydrofuran at 20℃; Reflux; | 3.4. General Procedure of Synthesis of PTCs (Cinchona Alkaloids Derived) General procedure: The alkaloid (12.3 mmol, 1 eq.) and the appropriate substituted benzylic halide derivative(12.3 mmol, 1 eq.) were dissolved in THF (40 mL) with addition of a trace of NaI. The mixture washeated to reflux overnight and then cooled and stirred at ambient temperature for 1 h. In most cases theproduct precipitated as an off-white solid, but where this was not the case and the mixture containedonly a small amount of solid or no solid at all, then diethyl ether (20 mL) was added dropwise.The solid was removed via filtration and washed with THF (50 mL) or ether:THF, (1:1, v/v, 50 mL)and was dried under reduced pressure at 40 °C. Where the solid formed was not a fine powder it was then taken up in DCM and this solution was then added dropwise to rapidly stirring ether (100 mL).This usually gives a finely divided solid that could be filtered and dried. (Note: The cinchonine derivedPTCs are usually very insoluble. The quinidine derived PTCs are often completely soluble at the endof the reaction.) The di(t-butyl)benzyl PTC was prepared according to the standard procedure aboveand was filtered directly from the reaction mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13%Chromat. | With C33H30F3N2NiO2P; tert-butylmagnesium chloride; In tetrahydrofuran; diethyl ether; at 20℃; for 24h;Schlenk technique; Inert atmosphere; | General procedure: A Schlenk flask was charged with an appropriate amount of complex 6 (0.05mmol, 5.0molpercent) and the corresponding bromo, chloro, fluoro or iodo arene (1.0mmol). The flask was cycled with nitrogen and vacuum. Afterwards THF (2.0mL) and a diethylether solution of tert-butyl-magnesiumchloride (0.75mL, 1.5mmol, 2.0M in diethylether) were added. The flask was sealed and heated at 70°C for 24h or stirred at room temperature. After that time, the mixture was cooled and a NH4Cl solution was added. The mixture was extracted with dichloromethane and the organic layer was dried with Na2SO4. n-Dodecane was added and an aliquot was taken for GC?MS analysis. The coupling products were confirmed by GC?MS and NMR analysis using n-dodecane as internal standard. The analytical properties of the products are in agreement with literature data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 2h;Reflux; Inert atmosphere; | General procedure: N-Methyl-1-(naphthalen-1-yl)ethanamine (8) (0.37g, 2.00mmol), N,N-diisopropylethylamine (0.39g, 3.02mmol), 1-(bromomethyl)-4-tert-butylbenzene (0.50g, 2.20mmol) and acetonitrile (5mL) were mixed and stirred at reflux under an N2-atmosphere for 2h. The solvent was then removed at reduced pressure and CH2Cl2 (5mL) was added. The dichloromethane phase was washed with water (5mL) and the water phase was back extracted with CH2Cl2 (3×5mL). The combined organic fractions were dried over Na2SO4, and concentrated in vacuum. The crude product was purified by silica-gel column chromatography. Alternatively, the purification was done by filtration through a short silica-gel column (pentane:EtOAc, 9:1), followed by precipitation as it hydrochloride salt by addition of HCl saturated ether. The solid material was washed with cold pentane. Alternatively, using 8·HCl the reaction was run similarly, but employing a 3-fold excess of N,N-diisopropylethylamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: diethylene glycol With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran for 16h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethanol With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 2,2'-[1,2-ethanediylbis(oxy)]bisethanol With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran for 16h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: Tetraethylene glycol With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran for 16h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: C26H28BP With tert.-butyl lithium In tetrahydrofuran at -78 - -40℃; for 2h; Inert atmosphere; Schlenk technique; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran at -78 - 23℃; for 16h; Inert atmosphere; Schlenk technique; | General procedure for the preparation of borane-protected ligands (Ra,R,RP)-2d-j.BH3 General procedure: In a 10mL Schlenk tube (Ra)-4.BH3 (0.35mmol, 1.0equiv) was dissolved in 5mL of THF. After cooling to -78°C, tBuLi (0.87mmol, 2.5equiv) was added dropwise and the reaction was slowly warmed to -40°C over 2h. After cooling again to -78°C the appropriate electrophile (7-10equiv) was added in one portion and the mixture was stirred at room temperature for 16h. The reaction was quenched with 5mL of water and the aqueous phase was extracted with CH2Cl2 (3×3mL). The combined organic layers were dried over Na2SO4, the solvent was evaporated, and the resulting crude mixture was purified by flash chromatography (pentane/CH2Cl2) to afford the desired product as a foamy solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium iodide; In tetrahydrofuran; at 20℃;Reflux; | General procedure: The alkaloid (12.3 mmol, 1 eq.) and the appropriate substituted benzylic halide derivative(12.3 mmol, 1 eq.) were dissolved in THF (40 mL) with addition of a trace of NaI. The mixture washeated to reflux overnight and then cooled and stirred at ambient temperature for 1 h. In most cases theproduct precipitated as an off-white solid, but where this was not the case and the mixture containedonly a small amount of solid or no solid at all, then diethyl ether (20 mL) was added dropwise.The solid was removed via filtration and washed with THF (50 mL) or ether:THF, (1:1, v/v, 50 mL)and was dried under reduced pressure at 40 C. Where the solid formed was not a fine powder it was then taken up in DCM and this solution was then added dropwise to rapidly stirring ether (100 mL).This usually gives a finely divided solid that could be filtered and dried. (Note: The cinchonine derivedPTCs are usually very insoluble. The quinidine derived PTCs are often completely soluble at the endof the reaction.) The di(t-butyl)benzyl PTC was prepared according to the standard procedure aboveand was filtered directly from the reaction mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tetrabutyl ammonium fluoride In N,N-dimethyl-formamide at 40℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: diethylene glycol With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: 2,2'-[1,2-ethanediylbis(oxy)]bisethanol With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: Tetraethylene glycol With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In acetonitrile at 20℃; | 1,8-(3,5-di-tert-butylbenzyl)-4,11-diazoniatricyclo[9.3.1.14,8]hexadecane-1,8-diium dibromide (8) Compound 1 (2.35 g, 10.5 mmol) was dissolved in acetonitrile and two equiv. of 3,5-di-tert-butylbenzyl bromide (6.54 g, 23.1 mmol) were rapidly added. The solution was stirred at room temperature and the white precipitate formed was then separated by filtration, washed with a small quantity of CH3CN and dried under reduced pressure. The compound was obtained as a white powder in 58% yield (4.82 g, 6.09 mmol). Crystalline material was obtained from slow evaporation of a H2O/(CH3)2CO solution. Anal. calcd for C42H70Br2N4.(H2O): C, 62.37; H, 8.97; N, 6.93. Found: C, 62.81; H, 9.15; N, 7.03. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: C20H32N2O2 With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Inert atmosphere; Schlenk technique; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran; mineral oil at 20℃; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | In tetrahydrofuran at 75℃; Inert atmosphere; | |
In acetone at 50 - 65℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | In tetrahydrofuran; for 12h;Reflux; Inert atmosphere; | General procedure: 200 mg 1 was dissolved in anhydrous THF, 1.1 equiv of benzyl bromide was added, the mixture was refluxed under N2 for 12 h, the resulting mixture was concentrated and purified by flash column chromatography.(Et2O/MeOH or EA/MeOH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium hydride In N,N-dimethyl acetamide; mineral oil at 0 - 100℃; for 12h; | Compound 5 Sodium hydride (60% oil dispersion, 5.0 g) and 3,5-di-tert-butylbenzyl bromide (11.3 g,40.1 mmol) were added to a stirred solution of 41 (5.25 g, 19.7 mmol) in dry N,N-dimethylacetamide(100 mL) at 0 °C. The stirred mixture was heated at 100 °C for 12 h. After the mixture was cooled at0 °C, the reaction was quenched with water. The resulting precipitates were collected by filtration,washed with water, and triturated with EtOH to form the crude material. This material was thenrecrystallized from CHCl3/MeOH to afford 10.92 g of colorless crystals of 5 (16.3 mmol; 83%): mp132-135 °C; 1H NMR δ 7.41 (m, 2H), 7.26 (s, 4H), 6.32-6.39 (m, 4H), 4.86 (s, 4H), 4.24 (m, 4H),1.40-1.46 (m, 4H), 1.34 (s, 36H), 1.21-1.90 (m, 4H); 13C NMR δ 150.88, 143.62, 136.61, 135.47,134.41, 122.82, 122.19, 77.79, 34.85, 34.17, 31.51, 25.39; IR νmax 1461, 1300, 1226, 1071, 878 cm-1;MS (FAB+) m/z 672 [M+]. Anal. calcd for C48H62O2: C, 85.92; H, 9.31; N, 4.77. Found: C, 85.61 H,9.11, N, 4.38%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In N,N-dimethyl-formamide | 16 4.7 General method 1: N7-Alkylation of 5′-amino-5′-deoxy-N2-(4,4′-dimethoxytrityl)-2′,3′-O-(1-methylethylidene)guanosine derivatives 2, 5, and 8 General procedure: To a solution of compound 2, 5a, 5b, or 8 (1 eq) in DMF, the appropriate alkyl or aryl halide (10 eq) was added and the mixture was stirred for 24-48h, with monitoring by TLC (CHCl3-MeOH, 17:3) and LC-MS. After completion of reaction, the mixture was evaporated in vacuo and the residue was triturated with Et2O with the aid of sonication. The precipitate was filtered and chromatographed (SiO2; CHCl3-MeOH, 9:1) to afford the pure title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | Stage #1: 2,6-bis(benzimidazole-2'-yl)pyridine; 3,5-di-tert-butylbenzyl bromide With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: 3,5-di-tert-butylbenzyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 40℃; Inert atmosphere; | 2.4. Synthesis of ligands L2 through L6 General procedure: Monosubstituted ligands based upon the bzimpy skeleton have been synthesized by a general recipe as follows. The substituting agent (SA) was MeI, EtI, iPrI, 3,5-di-(tert-butyl)-benzyl bromide,and 4-bromobenzyl bromide for L2 through L6, respectively [20]. N,N-dimethylformamide was distilled with dehydrating agent CaH2 under inert argon atmosphere. A 250 cm3 three necked flask was charged with bzimpy (2.30 g, 7.38 mmol) and 100 cm3 of freshly distilled dimethylformamide and then degassed. NaH (dispersion 60%, 0.29 g, 7.38 mmol) was suspended in 10 cm3 of drydimethylformamide under an inert atmosphere and then addeddrop-by-drop to the basic solution cooled down at ca 0°C under argon. The mixture was allowed to stand at room temperaturefor 1 h. The mixture was cooled again to 0°C, SA (5.54 mmol)was added dropwise and the mixture was heated to 40°C for overnight. The purification by column chromatography was carried outon Al2O3 dichlomethane and methanol (150:1). The crude product was recrystallized from appropriate solvent (30 cm3). A single crystal of good quality was used for the X-ray diffraction studies. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In tetrahydrofuran at 75℃; for 12h; Inert atmosphere; | 4. Preparation and characterization of the chiral Catalysts with multiple Hydrogen-Bonding Donors. General procedure: General Procedure Under N2 protection, 9-amino(9-deoxy)epiquine-derived urea (150 mg, 1 equiv) was dissolved in THF (0.1 M), then various benzyl bromide (1.1 equiv) was added, the mixture was heated to reflux, after 12 h the mixture was concentrated and purified by flash chromatography. Catalyst 3d Obtained according to the general procedure, the crude product was purified by flash chromatography (Et2O/MeOH=10:1). Light yellow solid, 115mg, 48% yield, m.p. = 147-148, [a]D25 = -90.8 (c = 0.5, CHCl3). 1H NMR (500 MHz, CD3OD) δ 8.85 - 8.61 (m, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.77 - 6.58 (m, 10H), 6.33 (d, J = 10.0 Hz, 1H), 6.05 - 5.82 (m, 1H), 5.32 - 5.14 (m, 2H), 5.03 - 4.92 (m, 3H), 4.42 - 4.01 (m, 4H), 3.72 - 3.35 (m, 4H), 2.79 - 2.62 (m, 1H), 2.25 - 1.74 (m, 4H), 1.49 - 1.39 (m, 2H), 1.34 (s, 18H), 1.14 (d, J = 13.3 Hz, 1H). 13C NMR (126 MHz, CD3OD) δ 160.60, 158.73, 153.23, 148.55, 145.95, 145.52, 141.92, 137.95, 131.85, 129.27, 128.96, 128.66, 128.15, 128.07, 127.18, 125.78, 124.26, 120.76, 118.15, 102.43, 70.16, 67.98, 66.56, 61.22, 57.69, 56.59, 50.96, 50.20, 38.57, 35.83, 31.80, 29.07, 28.08, 25.60. HRMS (ESI): calculated for C44H57N4O3 [M-Br]+: 689.4425, found 689.4424. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In N,N-dimethyl-formamide at 80℃; for 24h; Inert atmosphere; Schlenk technique; | |
In N,N-dimethyl-formamide at 80℃; for 24h; Inert atmosphere; Schlenk technique; | 4.2. General procedure for the preparation of benzimidazolium salts(1a-h) General procedure: For the preparation of benzimidazolium salts (1a-h), N-(3,5-ditert-butylbenzyl)benzimidazole, (1.0 mmol) was dissolved in anhydrous dimethylformamide (DMF), (3 mL) and alkyl bromide(1.0 mmol) was added at room temperature. The reaction mixturewas stirred at 80 °C for 24 h under argon. After completion of thereaction, the DMF was removed by vacuum and diethyl ether(15 mL) was added to obtain a white crystalline solid, which wasfiltered off. The solid was washed with diethyl ether (3 x 10 mL)and dried under vacuum. The crude product was recrystallizedfrom ethanol/diethyl ether mixture (1:2, v/v) and completely driedunder vacuum. These known compounds were synthesized andcharacterized by 1H NMR, 13C NMR, IR and elemental analysistechniques. The results we found, are consistent with the literature[40]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: 3,5-di-tert-butylbenzyl bromide; methyl 1-(triphenylmethyl)-1H-imidazole-4-carboxylate In acetonitrile Reflux; Inert atmosphere; Stage #2: With diethylamine In methanol; acetonitrile for 1h; Reflux; Inert atmosphere; | 5 Example 5: Synthesis of CDP 1500 CDP 1500 (compound 20) was synthesized according to the scheme shown in FIG.Compound 15 (100 mg, 0.271 mmol) obtained in step 3 - 2 of Example 3 was dissolved in acetonitrile (3.0 mL) and 3,5-di-tert-butylbenzyl bromide (92.1 mg, 0 .325 mmol) was added. And heated under reflux overnight in an argon gas atmosphere. After completion of the reaction, the mixture was concentrated under reduced pressure, methanol (3.0 mL) and diethylamine (0.15 mL) were added to the resulting crude product, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give CDP 1200 (57.3 mg, 0.174 mmol, yield 64%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With sodium hydroxide In ethanol at 75℃; for 6h; | 1.4 Synthesis of Precursors for Squarylium Compound 14: 1-(bromomethyl)-3,5-di-tert-butylbenzene (4.94 g, 17.4 mmol) and phlorogucinol (1.10 g, 8.7 mmol) was added to a stirring quantity of 25 mL of ethanol at room temperature. The mixture was stirred until complete dissolution of ingredients. Subsequently, sodium hydroxide (0.697 g, 17.4 mmol) was added. The reaction was heated at 75°C for six hours. The reaction was checked by TLC (9Hex: 1 Eth Aoc), which indicated completion of reaction. The contents of the flask were filtered and extracted with 300 mL of water and 300 mL of dichloromethane. The organic layer was rotovaped. No further purification was carried out. 2 g of an orange powder was produced (43% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In N,N-dimethyl-formamide at 80℃; for 24h; | 6 4.2 General procedure for the preparation of benzimidazolium halides (1a-f) General procedure: A dimethylformamide (5mL) solution of N-(alkyl)-benzimidazole (5.0mmol) and alkyl halide (5.0mmol) was stirred at 80°C for 24 h. After completion of the reaction, the solvent was removed by vacuum and Et2O (15mL) was added to obtain a white crystalline solid, which was filtered off. The solid was washed with Et2O (3×10mL) and dried under vacuum. The crude product was recrystallized from EtOH/Et2O mixture (1:2, v/v) and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 2,2'-methylenebis[(4R,5S)-4,5-diphenyl-2-oxazoline] With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 3,5-di-tert-butylbenzyl bromide In tetrahydrofuran; mineral oil at 0 - 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37 % ee | With cesiumhydroxide monohydrate; N-[4-(trifluoromethyl)benzyl]cinchoninium bromide In toluene at 20℃; for 15h; Inert atmosphere; Glovebox; Overall yield = 79 percent; Overall yield = 33.1 mg; enantioselective reaction; | 3.3. Representative Procedure for the Enantioselective Catalytic Phase Transfer Benzylation General procedure: A flask was charged with α-OCF3-indanone 1 (0.10 mmol, 1.0 equiv), CsOHH2O (0.20 mmol,2.0 equiv) and cat. 4 (0.010 mmol, 10.0 mol%) in a nitrogen-filled glovebox. Then anhydrous toluene(5.0 mL, 0.02 M) and 2 (0.15 mmol, 1.5 equiv) was added under an Ar atmosphere. The resulting mixture was stirred overnight or 48 h at room temperature. After that, the solvent was removed under reduced pressure and the residue was purified by flash silica-gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | In methanol; chloroform at 50℃; for 16h; Inert atmosphere; | 5 Preparation of Ia-5 (In Ia, R1 is 4-trifluoromethylphenyl, R2-R3 is tert-butyl, R4-R6 is H) In a 50mL three-necked flask, add Cn '0.43g, chloroform 8mL, methanol 4mL,3,5-di-tert-butylbenzyl bromide 0.50g. The reaction was heated to 50 ° C under argon atmosphere and reacted for 16 hours.After the reaction, it was cooled to room temperature, poured into 50 mL of ether, and filtered.The crude product was directly recrystallized from methanol / ether to obtain Ia-5 with a yield of 45% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Stage #1: Palmatrubine hydrochloride With potassium carbonate In N,N-dimethyl-formamide for 0.166667h; Stage #2: 3,5-di-tert-butylbenzyl bromide In N,N-dimethyl-formamide at 71℃; | 3.2.2. General Procedure for the Synthesis of 6a-j. General procedure: To a stirred solution of compound 3 (100 mg, 0.40 mmol) in anhydrous DMF (6 mL) wereadded K2CO3 (1.60 mmol) or K2CO3 (1.60 mmol) and NaI (1.60 mmol), 10 min. later, benzyl halide(1.6 mmol) or halogenated hydrocarbon (1.6 mmol) were added in the reaction system. The reactionmixture was heated at 71 °C for 2-24 h. The reaction system was cooled, filtered and the resulting residue was purified by flash chromatography over silica gel using CH2Cl2/CH3OH as the gradienteluent, to acquired desired compounds. |
With potassium carbonate In acetonitrile at 71℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 6h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 6h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 6h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: Tetraisopropyl methylenediphosphonate With n-butyllithium In tetrahydrofuran at -78℃; for 0.166667h; Inert atmosphere; Stage #2: 3,5-di-tert-butylbenzyl bromide With tetra-(n-butyl)ammonium iodide In tetrahydrofuran at -78 - 20℃; for 16h; Inert atmosphere; | 2.3.8. Tetraisopropyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethan-1,1-bisphosphonate (12) To a solution of tetraisopropyl methylenediphosphonate (347 mg,1.01 mmol) in dry THF (5 mL) was added nBuLi (0.61 mL, 0.958 mmol)at -78 °C under argon atmosphere. After 10 min, to the solution wasadded dropwise a solution of 3, 5-di-tert-butylbenzyl bromide 11(90.8 mg, 0.321 mmol) and tetrabutylammonium iodide (TBAI)(22.7 mg, 0.0615 mmol), and the reaction was stirred at room temperaturefor 16 h. The reaction mixture was diluted with water andextracted with EtOAc, and the organic layer was washed with water andbrine, dried over MgSO4, and concentrated under reduced pressure. Thecrude product was purified by flash column chromatography (EtOAc/CH2Cl2/MeOH = 100:100:0 to 100:100:1 to 100:100:5) to afford thetitle compound (126.5 mg, 0.231 mmol, 72%) as a colorless oil. 1HNMR (CDCl3, 500 MHz, δ): 7.25 (s, 1H), 7.10 (s, 2H), 4.79-4.70 (m,4H), 3.21 (td, J = 16.5, 6.0 Hz, 2H), 2.59 (tt, J = 24.0, 6.0 Hz, 1H),1.31-1.29 (m, 30H), 1.23 (d, J = 6.3, 6H), 1.20 (d, J = 6.3, 6H). 13CNMR(CDCl3, 125 MHz, δ): 150.36, 138.97 (t, J = 7.2 Hz, 2C), 123.17(2C), 120.28, 71.11 (t, J=3.6 Hz, 2C), 70.83 (t, J=3.0 Hz, 2C), 40.89(t, J = 133.8 Hz), 34.75 (2C), 32.00 (t, J = 4.8 Hz), 31.49 (6C), 24.17(4C), 23.88 (m, 2C), 23.70 (m, 2C). 31P-NMR (CDCl3, 202 MHz, δ):21.05 (s, 2P). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With trifuran-2-yl-phosphane; norbornene; caesium carbonate; palladium dichloride In 1,4-dioxane at 90℃; for 12h; Sealed tube; regioselective reaction; | General Procedure General procedure: Unless otherwise noted, in a glovebox, a 5.0 mL vial equipped with a Teflon coated stir bar was charged with PdCl2 (1.7 mg, 0.03mmol), P(2-furyl)3 (16.4 mg, 0.06 mmol), Cs2CO3 (391.0 mg,1.20 mmol), 1 (0.30 mmol), 2 (0.45 mmol), 3 (0.45 mmol), 4 (0.36 mmol) and NBE (56.5 mg, 0.6mmol) followed by sequential addition of 1,4-dioxane (3.0 mL). Next, the vial was sealed with a Teflon screw cap and removed from glovebox, and then, the mixture was allowed warm to 90 °C refluxed for an additional 12 h. After completion of the reaction, the mixture was filtered through a thin pad of celite. The filter cake was washed with ethyl acetate (3 × 2.0 mL), then the combined filtrate was concentrated in vacuo to provide a crude reaction mixture that was purified by silica gel column chromatography to affored the desired product 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In toluene at 60℃; for 5h; Inert atmosphere; | 2 Example 2: Alkylation of Cyclen-Glyoxal A General procedure: Cyclen-glyoxal A (1.2 eq, 5.6 mmol) is dissolved in 4 mL of toluene, and the alkylating agent B where X is a halogen or a mesyl (1 eq, 2.16 mmol) is added. The reaction mixture is then stirred under argon at 60° C. for 5 hours to 5 days (depending on the nature of the alkylating agent B). At the end of the reaction, the solid that has precipitated is filtered and washed abundantly with toluene. After drying in a desiccator, the product C obtained is used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1,2-dimethyl-1H-imidazole; 3,5-di-tert-butylbenzyl bromide In toluene at 96℃; for 24h; Stage #2: With hydroxide exchange resin In water | 1 Synthesis of 3-[(3,5-di-tert-butylphenyl)methyl]-1,2-dimethyl-1H-imidazolium Hydroxide A 100 mL round bottom flask equipped with a magnetic stir bar was charged with 8 g of 3,5-di-tert-butylbenzyl bromide, 2.99 g of 1,2-dimethylimidazole and 60 mL of toluene. A reflux condenser was then attached, and the mixture heated at 96° C. for 24 hours. After cooling, the mixture was filtered, and the solid residue was washed with ethyl acetate. The solids were then dried under vacuum. (0050) The resulting bromide salt was exchanged to the corresponding hydroxide salt by stirring it with hydroxide exchange resin in deionized water overnight. The solution was filtered, and the filtrate was analyzed for hydroxide concentration by titration of a small sample with a standard solution of 0.1 N HCl. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In N,N-dimethyl-formamide at 80℃; for 24h; | 2.2.1. Synthesis of L12HBr (2a) General procedure: The mixture of 1 (1 mmol) and 3,5-dimethylbenzyl bromide (2 mmol) was stirred in DMF (3 mL) at 80 °C for 24 h. After cooling to the room temperature and addition of Et2O (15 mL), the suspension was filtered. The solid was washed by EtOH (25 mL) and Et2O (2x5 mL) and dried in air. Yield: 91%. IR (NCN): 1558 cm-1. 1H NMR (CD3OD): = 9.78 (s, 2H, NCHN), 7.93-7.85 (m, 4H, Ar-H), 7.71-7.63 (m, 4H, Ar-H), 7.13 (s, 4H, Ar-H), 7.05 (s, 2H, Ar-H), 5.65 (s, 4H, NCH2), 5.45 (s, 4H, NCH2), 5.31 (s, 2H, =CH2), 2.29 (s, 12H, Me) ppm. 13C NMR (CD3OD): = 139.07, 135.75, 132.61, 131.62, 131.47, 130.49, 127.22, 127.16, 125.90, 118.65, 113.81, 113.35, 50.83, 49.00, 19.83 ppm. LC-MSMS: [M-Br]+ at m/z 607.20. Anal. Calc. for C36H38N4Br2: C, 62.97; H, 5.59; N, 8.16. Found: C, 63.07; H, 5.42; N, 7.77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In acetonitrile at 70℃; | 4.2 Step 2: Synthesis of tert-butyl N-[[2-[l-[(3,5-ditert-butylphenyl)methyl]pyridin- l-ium-3-yl]acetyl]amino]carbamate bromide: Tert-butyl N-[[2-(3-pyridyl)acetyl]amino]carbamate (0.40 mmol) and 3,5-ditert- butylbenzyl bromide (0.48 mmol) were dissolved in dry CH3CN. Then the solution was stirred at 70 °C overnight. The solvent was removed under vacuum and the crude purified by flash chromatography (gradient CH2CI2 → CH2Cl2/MeOH 80:20). 190 mg of the pure compound was obtained as a white solid (89% yield). (0414) 1HNMR (400 MHz, METHANOL-d4) d ppm 1.33 (m, 18 H) 1.45 (s, 9 H) 3.87 (s, 2 H) 5.80 (s, 2 H) 7.38 (d, J=1.70 Hz, 2 H) 7.53 (t, J=1.69 Hz, 1 H) 8.06 (dd, J=7.80, 6.40 Hz, 1 H) 8.53 (d, J=8.00 Hz, 1 H) 8.95 (d, J=6.15 Hz, 1 H) 9.15 (s, 1 H). (0415) 13C NMR (101 MHz, METHANOL-d4) δ ppm 27.10 (3 C) 30.31 (6 C) 34.48 (2 C) 65.02 (1 C) 80.69 (1 C) 122.97 (2 C) 123.72 (1 C) 127.59 (1 C) 132.39 (1 C) 136.89 (1 C) 142.47 (1 C) 144.92 (1 C) 146.69 (1 C) 152.37 (2 C) 156.45 (1C) 173.59 (1 C). HPLC-MS (m/z) [M]+ calcd 454.31, found 454.40. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 2-(N-tert-butoxycarbonylamino)ethanol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 3,5-di-tert-butylbenzyl bromide With tetra-(n-butyl)ammonium iodide In tetrahydrofuran; mineral oil at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 % ee | With sodium bis-(trimethyl-silyl)amide; C63H58NO(1+)*Br(1-) In toluene at -80℃; for 72h; Schlenk technique; Inert atmosphere; Overall yield = 65 percent; | Representative Procedure for Asymmetric Alkylation Reaction General procedure: A Schlenk tube was charged with 1 (0.2 mmol), 3k (0.02 mmol, 18.4 mg) undera nitrogen atmosphere, then NaHMDS (0.2 mmol, 0.4 mL, 0.5 M in Tol) and 2 (0.4mmol) in toluene (1.0 mL) were added separately. The reaction mixture was stirred at-80 oC and monitored by TLC. When completed, the reaction mixture was dilutedwith water (5.0 mL), and extracted with ethyl acetate (10 mL×3). The combinedorganic layer was washed with brine, dried with anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by chromatographycolumn on silica gel to afford product (S)-4.( |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15 % ee | With sodium bis-(trimethyl-silyl)amide; C63H58NO(1+)*Br(1-) In toluene at -80℃; for 24h; Schlenk technique; Inert atmosphere; Overall yield = 35 percent; | Representative Procedure for Asymmetric Alkylation Reaction General procedure: A Schlenk tube was charged with 1 (0.2 mmol), 3k (0.02 mmol, 18.4 mg) undera nitrogen atmosphere, then NaHMDS (0.2 mmol, 0.4 mL, 0.5 M in Tol) and 2 (0.4mmol) in toluene (1.0 mL) were added separately. The reaction mixture was stirred at-80 oC and monitored by TLC. When completed, the reaction mixture was dilutedwith water (5.0 mL), and extracted with ethyl acetate (10 mL×3). The combinedorganic layer was washed with brine, dried with anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by chromatographycolumn on silica gel to afford product (S)-4.( |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium hydroxide In water monomer at 100℃; | 7 Example 7, 3-(3,5-di-tert-butylbenzylthio)-5,5-dimethyl-4,5-dihydroisoxazole In a 25 mL reaction flask equipped with a reflux tube, add 5,5-dimethyl-3-thiocyano-4,5-dihydroisoxazole (0.4 mmol, 63 mg), 1 ml of water, and sodium hydroxide (4 mmol). , 160mg), 3,5-di-tert-butylbenzyl bromide (0.4mmol, 113mg) was added, stirring was started, the temperature was raised to 100° C. to react, and the reaction progress was tracked by TLC. After the reaction was completed, the reaction mixture was added with water and ethyl acetate. Ester extraction and stratification, the organic phase was removed by rotary evaporation, and the crude product was subjected to column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) to obtain a colorless oily pure product 3-(3,5-di-tertiary). butylbenzylthio)-5,5-dimethyl-4,5-dihydroisoxazole in 83% yield. |
Tags: 62938-08-3 synthesis path| 62938-08-3 SDS| 62938-08-3 COA| 62938-08-3 purity| 62938-08-3 application| 62938-08-3 NMR| 62938-08-3 COA| 62938-08-3 structure
[ 81093-21-2 ]
1-(Bromomethyl)-2,3-dimethylbenzene
Similarity: 0.82
[ 116175-22-5 ]
3-(Bromomethyl)-2-methyl-1,1'-biphenyl
Similarity: 0.80
[ 81093-21-2 ]
1-(Bromomethyl)-2,3-dimethylbenzene
Similarity: 0.82
[ 116175-22-5 ]
3-(Bromomethyl)-2-methyl-1,1'-biphenyl
Similarity: 0.80
[ 81093-21-2 ]
1-(Bromomethyl)-2,3-dimethylbenzene
Similarity: 0.82
[ 116175-22-5 ]
3-(Bromomethyl)-2-methyl-1,1'-biphenyl
Similarity: 0.80
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