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CAS No. : | 21524-34-5 | MDL No. : | MFCD00051547 |
Formula : | C15H23Br | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FUMMYHVKFAHQST-UHFFFAOYSA-N |
M.W : | 283.25 | Pubchem ID : | 140846 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.6 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 77.88 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -3.77 cm/s |
Log Po/w (iLOGP) : | 3.81 |
Log Po/w (XLOGP3) : | 5.99 |
Log Po/w (WLOGP) : | 5.82 |
Log Po/w (MLOGP) : | 5.57 |
Log Po/w (SILICOS-IT) : | 5.63 |
Consensus Log Po/w : | 5.36 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.45 |
Solubility : | 0.00101 mg/ml ; 0.00000355 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.77 |
Solubility : | 0.000484 mg/ml ; 0.00000171 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -5.71 |
Solubility : | 0.000547 mg/ml ; 0.00000193 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.98 |
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 |
---|---|---|
94% | Stage #1: With magnesium In tetrahydrofuran for 2 h; Inert atmosphere; Reflux Stage #2: With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 20℃; for 5.5 h; Reflux; Inert atmosphere |
1L three bottles,To a solution of 32.5 g of 2,4,6-triisopropylbromobenzene,5.6 g of magnesium turnings and 300 mL of anhydrous THF,20 g of o-chlorobromobenzene was dropwise added,2,4,6-triisopropyl-2-bromobiphenyl Grignard reagent,Refluxed for 2 hours,Down to room temperature,2.4 g of tetrakis (triphenylphosphine) palladium was added,Stirred for 30 minutes,18.8 g of di-tert-butylphosphonium chloride was added dropwise at room temperature,The reaction was refluxed for 5 hours.And the mixture was added dropwise to the reaction solution under ice-water bath200 mL of saturated aqueous ammonium chloride was quenched,Liquid separation,The organic phase is dissolved,Add methanol crystallization,And filtered to obtain 41.7 g of white 2-di-tert-butylphosphine-2,4,6-triisopropylbiphenyl,Yield 94percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: With n-butyllithium In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere Stage #2: at 0℃; for 1 h; Inert atmosphere |
Under the protection of nitrogen, 200 ml of THF and 31g of 2, 4, 6-tri-isopropyl-bromobenzene was added to 1L three-mouth bottle. The temperature was cooled down to 0 °C, and 46 ml of 2.5M n-butyl lithiumwas added dropwise. The reaction was continued for 1 hour after the addition. At 0 °C, 24.6g O-dibromobenzene was added dropwise. The reaction was continued for 1 hour after the addition. At0 °C, 42 ml of 2.5M n-butyl lithiumwas added dropwise to the reaction liquid.After the addition, the reaction was continued for 1 hour. 26.7g of dicyclohexyl phosphine was added dropwise, and the temperature was naturally warmed to react at room temperature for 2 hours. 200 ml saturated ammonium chloride aqueous solution was added dropwsie to the reaction liquid under the ice bath to quench the reaction. After phase separation, the organic phase was precipitated, and methanol was added for crystallization. Byfiltering, 44.5g white product of 2’-dicyclohexyl phosphino-2, 4, 6-tri-isopropyl biphenyl was obtained, with a yield of 89percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Stage #1: With magnesium; ethylene dibromide In tetrahydrofuranInert atmosphere; Reflux Stage #2: With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere Stage #3: With copper(l) chloride In tetrahydrofuran; hexane at 20 - 75℃; for 48 h; |
EXAMPLE THREE: Synthesis of Ligand 6; An oven-dried three-neck 100 rnL round bottom flask, which was equipped with a magnetic stir bar and charged with Magnesium shavings (360 mg, 15.36 mmol), was fitted with a reflux condenser, glass stopper, and rubber septum. The flask was evacuated and backfilled with argon (this process was repeated a total of 3 times) and then THF (40 mL) and 2,4,6-triisopropylbromobenzene (3.62 g, 12.8 mmol) were added via syringe. The reaction was heated to reflux and 1 ,2-dibromethane (40 μL) was added dropwise. The reaction was allowed to stir at reflux for 1 h and then was cooled to room temperature. A separate oven-dried 500 mL round bottom schlenk flask, which was equipped with a magnetic stir bar and fitted with a septum, was evacuated and backfilled with argon (this process was repeated a total of 3 times) and then THF (160 mL) and 1 ,4-dimethoxy-2- fluorobenzene (2 g, 12.8 mmol) were added to the flask via syringe. The reaction was cooled to -78 0C and n-BuLi (2.5 M in Hexane, 5.12 mL, 12.8 mmol) was added dropwise over a 15 min period. The solution was stirred for 30 min and the Grignard reagent, which was prepared in the first reaction vessel, was added via cannula transfer over a 20 min period and allowed to stir at -78 0C for 1 h. The reaction was warmed to room temperature slowly where it was stirred for an additional 3 h. Under a constant flow of argon the septum was removed and anhydrous CuCl (1.267 g, 12.8 mmol) was added quickly. The ClP(t-Bu)2 (2.44 mL, 12.8 mmol) was then added via syringe and the schlenk tube was sealed with a Teflon screw cap. The reaction was heated to 75 0C for 48 h and then cooled to room temperature. The reaction was quenched with 30percent aqueous NH4OH (100 mL) and the resulting suspension was extracted with EtOAc (200 mL). The organic layer was washed with 30percent aqueous NH4OH (3 x 100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated on a rotary evaporator to yield a thick yellow oil. The crude material was taken up in minimum amount of hot MeOH and placed in a -25 0C freezer over night to yield 1.11 g (18percent) of white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: 2,4,6-triisopropyl-1-bromobenzene With 2-methyltetrahydrofuran; magnesium; lithium hydroxide for 1h; Inert atmosphere; Sealed tube; Milling; Stage #2: carbon dioxide for 0.75h; Sealed tube; Milling; | |
(i) tBuLi, THF, hexane, (ii) /BRN= 1900390/; Multistep reaction; | ||
With tert.-butyl lithium 1.) THF, pentane, -78 deg C, 30 min, 2.) 15 min; Yield given. Multistep reaction; |
With (2’,4’,6’-triisopropyl-[1,1’-biphenyl]-2-yl)-diphenylphosphine; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; palladium diacetate; caesium carbonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃; for 6h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dicyclohexyl({2’,6’-dimethoxy-[1,1‘-biphenyl]-2-yl})phosphane; tripotassium phosphate tribasic In tetrahydrofuran; toluene at 100℃; for 16h; | |
99% | With dicyclohexyl({2’,6’-dimethoxy-[1,1‘-biphenyl]-2-yl})phosphane; tripotassium phosphate tribasic; tris((1E,4E)-1,5- diphenylpenta-1,4-dien-3-one) dipalladium In tetrahydrofuran; toluene at 100℃; for 16h; Heating; | |
97% | Stage #1: 2,4,6-triisopropyl-1-bromobenzene; phenylboronic acid With potassium hydroxide In decane; toluene for 0.0833333h; Schlenk technique; Glovebox; Sealed tube; Inert atmosphere; Stage #2: With C29H43PTi; palladium diacetate In decane; toluene at 100℃; for 0.5h; Schlenk technique; Glovebox; Sealed tube; Inert atmosphere; |
95% | With tris-(dibenzylideneacetone)dipalladium(0); C26H50P2; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 60℃; for 24h; Inert atmosphere; Sealed tube; | |
93% | With potassium fluoride; 2-(diphenylphosphino)phenylferrocene In tetrahydrofuran at 30 - 32℃; for 72h; | |
92% | With potassium carbonate In xylene at 140℃; for 20h; | |
90% | With dicyclohexyl({2’,6’-dimethoxy-[1,1‘-biphenyl]-2-yl})phosphane; tripotassium phosphate tribasic; tris-(dibenzylideneacetone)dipalladium(0) In tetrahydrofuran; toluene at 100℃; for 16h; Inert atmosphere; | 2,4,6-triisopropyl-1,1′-biphenyl To a 50 mL oven-dried flask was added 2-bromo-1,3,5-triisopropylbenzene (10.14 g, 0.036 mol, 1.0 equiv.), phenyl boronic acid (7.32 g, 0.06 mol, 1.6 equiv.), K3PO4 (17.0 g, 0.80 mol, 2.2 equiv), Pd2(dba)3 (0.366 g, 0.4 mmol) and SPhos (0.328 g, 0.8 mmol). The flask was evacuated and back-filled with argon three times prior to 40 mL of dry THF and 40 mL of dry toluene was added via syringe. The mixture was then stirred and heated in a 100° C. oil bath for 16 hr. Upon reaction completion, as determined by GC-MS, the mixture was filtered through silica and washed with EtOAc. The filtrate was collected and the solvent was removed under vacuum. The crude residue was purified by flash chromatography on silica gel using an EtOAc/hexanes mixture (0 to 10% EtOAc) as the eluent to get a white solid (9 g, 90%). 1H NMR (600 MHz, Chloroform-d) δ 7.42 (dd, J=8.1, 6.8 Hz, 2H), 7.39-7.34 (m, 1H), 7.23-7.19 (m, 2H), 7.09 (s, 1H), 2.97 (p, J=7.0 Hz, 1H), 2.62 (ddd, J=12.7, 7.7, 6.4 Hz, 2H), 1.34 (dd, J=7.0, 0.9 Hz, 5H), 1.11 (dd, J=6.9, 0.9 Hz, 11H) ppm. 13C NMR (151 MHz, CDCl3) δ 147.82, 146.51, 140.84, 137.08, 129.80, 127.91, 126.40, 120.53, 77.26, 77.05, 76.84, 34.28, 30.28, 24.25, 24.13 ppm |
81% | With 2Na(1+)*C26H18N2O8PdS2(2-); potassium carbonate In lithium hydroxide monohydrate at 20℃; for 10h; | General procedure: The Suzuki reaction was performed in a 50 mL round-bottomed flask, aryl halide (0.5 mmol), arylboronic acid (0.65 mmol), K2CO3 (1 mmol), Complex 1 (0.2-1 mol%) and water (4 mL) were charged and stirred for the required time at room temperature for aryl bromides or at 100 °C for aryl chlorides. After completion, the mixture was cooled down to room temperature, diluted with water (10 mL) and extracted with diethyl ether (3 × 15 mL). The organic layer was washed with brine (3 × 15 mL), dried over anhydrous Na2SO4. The crude products were chromatographed on silica gel (ethyl acetate/hexane). |
52% | With tripotassium phosphate monohydrate In lithium hydroxide monohydrate; toluene at 100℃; for 1.5h; | |
15% | With tripotassium phosphate tribasic In N,N-dimethyl-formamide at 120℃; for 6h; Inert atmosphere; Schlenk technique; Green chemistry; | |
99 %Spectr. | With tripotassium phosphate tribasic; tris-(dibenzylideneacetone)dipalladium(0); rac-1-(4-tert-butylphenoxy)-2-[bis(2-tolyl)phosphanyl]ferrocene In toluene at 50℃; for 24h; Inert atmosphere; | |
With dicyclohexyl({2’,6’-dimethoxy-[1,1‘-biphenyl]-2-yl})phosphane; tripotassium phosphate tribasic; tris-(dibenzylideneacetone)dipalladium(0) In toluene at 100℃; for 16h; Inert atmosphere; | ||
With tripotassium phosphate tribasic; tris-(dibenzylideneacetone)dipalladium(0); 1-(4-iodophenyl)-2-(dicyclohexylphosphino)-4,5-dimethyl-1H-imidazole In toluene at 50℃; for 24h; Inert atmosphere; | ||
81 %Chromat. | With tripotassium phosphate monohydrate; 5-(dicyclohexylphosphino)-1-([2.2]paracyclophan-4-yl)-4-pentyl-1H-1,2,3-triazole; palladium diacetate In toluene at 70℃; for 24h; | |
25 %Chromat. | With trineopentylphosphine; palladium diacetate; anhydrous sodium carbonate In tetrahydrofuran; lithium hydroxide monohydrate at 50℃; for 24h; Inert atmosphere; Glovebox; | |
99 %Chromat. | With [(η7-C7H7)Ti(η5-C5H4P(cyclohexyl)2)]; palladium diacetate; potassium hydroxide In toluene at 100℃; for 1h; Inert atmosphere; Glovebox; Schlenk technique; | |
With potassium carbonate In ethanol; lithium hydroxide monohydrate at 120℃; for 0.166667h; Green chemistry; | ||
97 %Chromat. | With [bis(2-diphenylphosphinophenyl)amide]PdCl; tripotassium phosphate monohydrate In 1,4-dioxane at 110℃; for 12h; | Procedures of Suzuki reactions outlined in Table1. General procedure: A round-bottom flask was sequentially charged with 5a or 5b (1.0mg for each single experiment, corresponding to 0.1mol%), aryl halide (1.0equiv), arylboronic acid (1.5equiv), base (K3PO4·H2O or K3PO4, 2.0equiv), solvent (4mL 1,4-dioxane or 2mL toluene), and a magnetic stir bar. The flask was capped with a glass stopper and heated in an oil bath at prescribed temperatures (110, 100, or 80°C) with stirring for 12h. After being cooled to room temperature, the reaction mixture was diluted with diethyl ether (8mL), filtered through a pad of Celite, and treated with aqueous NaOH solution (3mL, 1M). The diethyl ether solution was separated from the aqueous layer, dried over MgSO4, and evaporated to dryness under reduced pressure to afford the desired product. Isolation and characterization of the biaryls prepared were made on 4-methyl-biphenyl [19], 4-acetyl-biphenyl [20], 4-phenylbenzaldehyde [21], 4-nitro-biphenyl [22], 2-fluoro-biphenyl [23], 2-phenylthiophene [24], biphenyl [25], 3,5-dimethyl-biphenyl [26], 2,4,6-trimethyl-biphenyl [27], 2,4,6-triisopropyl-biphenyl [28], 4-methoxy-biphenyl [29], 4-dimethylamino-biphenyl [20], whose 1H and 13C{1H} NMR spectra (in CDCl3) were all verified to be identical to those that we reported previously [8b]. The identity of 2-methyl-1-phenylnaphthalene was verified by GC/MS and 1H and 13C{1H} NMR spectra [30]. |
33 %Chromat. | With [(trineopentylphosphine)PdCl2]2; anhydrous sodium carbonate In lithium hydroxide monohydrate; toluene at 50℃; Sealed tube; Inert atmosphere; | |
34 %Chromat. | With [(nitron)Pd(Py)Br2]; potassium hydroxide In lithium hydroxide monohydrate; isopropanol at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | 1L three bottles,To a solution of 32.5 g of 2,4,6-triisopropylbromobenzene,5.6 g of magnesium turnings and 300 mL of anhydrous THF,20 g of o-chlorobromobenzene was dropwise added,2,4,6-triisopropyl-2-bromobiphenyl Grignard reagent,Refluxed for 2 hours,Down to room temperature,2.4 g of tetrakis (triphenylphosphine) palladium was added,Stirred for 30 minutes,18.8 g of di-tert-butylphosphonium chloride was added dropwise at room temperature,The reaction was refluxed for 5 hours.And the mixture was added dropwise to the reaction solution under ice-water bath200 mL of saturated aqueous ammonium chloride was quenched,Liquid separation,The organic phase is dissolved,Add methanol crystallization,And filtered to obtain 41.7 g of white 2-di-tert-butylphosphine-2,4,6-triisopropylbiphenyl,Yield 94%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With [2-(2-methyl-1,3-dioxolan-2-yl)phenyl]diphenylphosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 100℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With cis,cis,cis-tetrakis[(diphenylphosphanyl)methyl]cyclopentane; potassium carbonate In xylene at 130℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 1-(7-benzofuranyl)-2-di(3,5-di-tert-butyl-4-methoxyphenyl)phosphinenaphthalene In toluene at 80℃; for 0.5h; Glovebox; Inert atmosphere; | 6 In a glove box, 1.0 mmol of a halogenated aromatic or heterocyclic aromatic hydrocarbon compound, 2.0 mmol of 1-naphthylboronic acid, Pd2 (dba) 3, a phosphine ligand and 3.0 mmol of potassium phosphate were charged in 7 mL of anhydrous toluene under nitrogen,After heating to 80 ° C, the reaction was carried out for a period of time. The results are shown in Table 1. The amount of Pd2 (dba) 3 and the phosphine ligand is divided into three types: (1) 0.25 mol% Pd2 (dba) 3, 0.5 mol% phosphine ligand, or (2) 0.5 mol% Pd2 (dba) mol% phosphine ligand, or (3) 1.0 mol% Pd2 (dba) 3, 2.0 mol% phosphine ligand, depending on the amount of ligand used in Table 1. |
98% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate In tetrahydrofuran; toluene at 100℃; for 12h; | |
98% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris(dibenzylideneacetone)dipalladium (0) In toluene at 100℃; for 12h; |
84% | With tris-(dibenzylideneacetone)dipalladium(0); potassium phosphate monohydrate; C30H25FeP In toluene at 70℃; for 24h; Sealed tube; | |
83% | With potassium phosphate; C29H37O2P; palladium diacetate In toluene at 110℃; for 3h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Tedicyp; sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h; | ||
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 150℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With ethanol; cobalt(II) tetrabutylporphyrin; potassium hydroxide; at 150℃; for 6h;Inert atmosphere; | 1-Bromo-2,4,6-triisopropylbenzene (1i) (36 m L, 0.142 mmol), Co(tbp) (4.2 mg,0.007 mmol) and KOH (319.5 mg, 5.7 mmol) were added in EtOH(2.0 mL). The mixture was degassed for three freeze-pump-thawcycles, purged with N2, and heated to 150C for 10 h. 100% yieldof 1,3,5-triisopropylbenzene was detected by GC-MS analysis usingdecalin as internal standard. The reaction mixture was puriedwith silica gel column chromatography using hexane as eluent toget the rst fast moving fraction as 1,3,5-triisopropylbenzene(27.4 mg, 0.13 mmol) in 94% yield.1H NMR (CDCl3, 400 MHz)d 1.28 (d, 18H,2J 6.9 Hz), 2.85e2.95 (m, 3 H), 6.94 (s, 3 H). |
72%Spectr. | With dimethyl(phenyl)silyllithium; In tetrahydrofuran; at 30℃; for 1h;Inert atmosphere; | General procedure: vial with a screw cap and a silicon-coated rubber septum wasconnected to a vacuum/nitrogen manifold through a needle,and it was evacuated and refilled with nitrogen three times. Dimethylphenylsilyllithium (0.4 M in THF, 2.5 mL, 2.0 equiv)was added to the vial under nitrogen atmosphere. 1-Bromo-3,5-dimethylbenzene (93.5 mg, 0.51 mmol) was added to the vial,then stirred at 30 C. After 1 h, the reaction mixture was analyzedby GC to check completeness of the reaction. When thereaction was complete, H2O was added and the mixture wasextracted three times with Et2O. The organic layer was washedwith water and the combined organic layer was then dried overMgSO4 followed by filtration and evaporation. The crudeproduct was purified by silica-gel column chromatography with hexane eluent, then further purified by gel permeation chromatographyto give 3da in 63% isolated yield (76.5 mg, 0.318mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium t-butanolate In toluene at 80℃; for 4h; | |
98% | With C36H37NP2; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 110℃; for 120h; Inert atmosphere; Schlenk technique; Glovebox; | |
97% | With tris-(dibenzylideneacetone)dipalladium(0); trineopentyl phosphine; sodium t-butanolate In toluene at 80℃; for 3h; Inert atmosphere; Glovebox; |
97% | With C46H84Br2P2Pd2; sodium t-butanolate In toluene at 40℃; for 15h; Inert atmosphere; Sealed tube; | |
90% | With tris-(dibenzylideneacetone)dipalladium(0); rac-3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole; sodium t-butanolate In toluene at 110℃; for 20h; Inert atmosphere; | |
51% | With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | EXAMPLE TEN: Synthesis of Ligand 7; An oven-dried three-neck 250 mL round bottom flask, which was equipped with a magnetic stir bar and charged with magnesium shavings (559 mg, 24.3 mmol), was fitted with a reflux condenser, addition funnel, and glass stopper. The flask was purged with argon and then THF (15 mL) and 2,4,6-triisopropylbromobenzene (2.83 g, 10 mmol) were added via syringe. The reaction mixture was heated to reflux and 1 ,2-dibromethane (40 uL) was added via syringe. The reaction was allowed to stir at reflux for 1 h and then the addition funnel, which was charged with l,2-dibromo-3,4,5,6-tetramethylbenzene (2.92 g, 10 mmol) in 40 mL of THF, was opened and the solution was added over a 1 h period. The mixture was stirred for 5 h at reflux and then cooled to room temperature where CuCl (1.0 g, 10 mmol) was added quickly to the reaction mixture. Next, ClPCy2 (2.65 mL, 10 mmol) was then added in a dropwise fashion and the reaction mixture was heated to 75 0C for 60 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc, washed 3 times with 30% NH4OH, dried over MgSO4, and concentrated under reduced pressure. The crude material was recrystallized from benzene to yield the product as a white solid (1.507 g, 28% yield). 1H NMR (300 MHz, CDCl3) δ: 7.36 (s, 5H), 7.15 (s, 2H), 2.99 (septet, J= 7.0 Hz, IH), 2.44 (s, 3H), 2.35-2.14 (m, HH), 1.98 (s, 2H), 1.80-1.44 (m, 14H), 1.39-1.04 (m, 22H), 0.91 (d, J= 6.5 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3) δ: 150.9, 145.8, 145.4, 144.6, 140.0, 138.5, 135.8, 135.6, 135.5, 135.5, 128.6, 124.3, 40.2, 39.9, 35.4, <n="123"/>35.2, 34.5, 30.7, 29.5, 27.8, 27.7, 27.4, 27.2, 25.9, 25.0, 24.6, 21.2, 20.8, 17.7, 17.3 ppm (Observed complexity is due to P-C splitting). 31P NMR (121 MHz, CDCl3) δ: 16.33 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | EXAMPLE THREE: Synthesis of Ligand 6; An oven-dried three-neck 100 rnL round bottom flask, which was equipped with a magnetic stir bar and charged with Magnesium shavings (360 mg, 15.36 mmol), was fitted with a reflux condenser, glass stopper, and rubber septum. The flask was evacuated and backfilled with argon (this process was repeated a total of 3 times) and then THF (40 mL) and 2,4,6-triisopropylbromobenzene (3.62 g, 12.8 mmol) were added via syringe. The reaction was heated to reflux and 1 ,2-dibromethane (40 muL) was added dropwise. The reaction was allowed to stir at reflux for 1 h and then was cooled to room temperature. A separate oven-dried 500 mL round bottom schlenk flask, which was equipped with a magnetic stir bar and fitted with a septum, was evacuated and backfilled with argon (this process was repeated a total of 3 times) and then THF (160 mL) and 1 ,4-dimethoxy-2- fluorobenzene (2 g, 12.8 mmol) were added to the flask via syringe. The reaction was cooled to -78 0C and n-BuLi (2.5 M in Hexane, 5.12 mL, 12.8 mmol) was added dropwise over a 15 min period. The solution was stirred for 30 min and the Grignard reagent, which was prepared in the first reaction vessel, was added via cannula transfer over a 20 min period and allowed to stir at -78 0C for 1 h. The reaction was warmed to room temperature slowly where it was stirred for an additional 3 h. Under a constant flow of argon the septum was removed and anhydrous CuCl (1.267 g, 12.8 mmol) was added quickly. The ClP(t-Bu)2 (2.44 mL, 12.8 mmol) was then added via syringe and the schlenk tube was sealed with a Teflon screw cap. The reaction was heated to 75 0C for 48 h and then cooled to room temperature. The reaction was quenched with 30% aqueous NH4OH (100 mL) and the resulting suspension was extracted with EtOAc (200 mL). The organic layer was washed with 30% aqueous NH4OH (3 x 100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated on a rotary evaporator to yield a thick yellow oil. The crude material was taken up in minimum amount of hot MeOH and placed in a -25 0C freezer over night to yield 1.11 g (18%) of white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | EXAMPLE FORTY-SIX: Optimized Synthesis of 2-iodo-2',4',6'-triisopropyl-3,6- dimethoxybiphenyll-iodo-l'^'-triisopropyl-S^-dimethoxybiphenyl.; An oven-dried three-neck 500 mL round-bottom flask, which was equipped with a magnetic stir bar and charged with magnesium shavings (2.8 g, 116 mmol), was fitted with a reflux condenser, glass stopper, and rubber septum. The flask was purged with argon and then THF (100 mL) and 2,4,6- triisopropylbromobenzene (24.3 mL, 96 mmol) were added via syringe. The reaction <n="141"/>mixture was heated to reflux and 1 ,2-dibromethane (40 uL) was added via syringe. The reaction was allowed to stir at reflux for 1.5 h and was then cooled to room temperature. A separate oven-dried 2 L round bottom flask, which was equipped with a magnetic stir bar and fitted with a septum, was purged with argon and then THF (500 mL) and 1,4- dimethoxy-2-fluorobenzene (7.49 g, 48 mmol) were added to the flask via syringe. The reaction mixture was cooled to -78 0C and n-BuLi (2.5 M in Hexane, 19.4 mL, 48.5 mmol) was added in a dropwise fashion over a 40 min period. The solution was stirred for 1 h and the Grignard reagent, which was prepared in the first reaction vessel, was added via cannula over a 30 min period and allowed to stir at -78 0C for 1 h. The reaction mixture was warmed to room temperature slowly where it was stirred for an additional 12 h. The mixture was then cooled to 0 0C and a solution of Iodine in THF (1 M, 96 mL, 96 mmol) was added via syringe over a 15 min period and then the dark red solution was warmed to room temperature and stirred for 1 h. The solvent was removed via a rotary evaporator, and the remaining dark brown oil was taken up in Et2O, washed with a saturated solution of sodium sulfite, and washed with brine. The organic layer was then dried over MgStheta4, filtered, and the solvent was removed via rotary evaporator to give a yellow solid. The crude material was triturated with hexanes and filtered to give the desired product as an off- white solid (16.199 g, 72%, mp 189 - 191 0C). 1H NMR (300 MHz, CDCb) delta: 7.07 (s, 2H), 6.90 (d, J= 9.0 Hz, IH), 6.81 (d, J= 9.0 Hz, IH), 3.90 (s, 3H), 3.67 (s, 3H), 2.98 (septet, J = 7.0 Hz, IH), 2.39 (septet, J= 7.0 Hz, 2H), 1.33 (d, J= 7.0 Hz, 6H), 1.20 (d, 7.0 Hz, 6H), 1.02 (d, J= 7.0 Hz, 6H) ppm. 13C NMR (75 MHz, CDCb) delta: 152.7, 152.5, 148.4, 145.9, 136.4, 136.1, 121.0, 110.3, 109.4, 96.6, 57.0, 55.8, 34.3, 31.1, 24.8, 24.3, 23.9 ppm. IR (neat, cm"1): 2957, 2865, 1567, 1460, 1428, 1257, 1032, 755. Anal. Calcd. for C23H31IO2: C, 59.23; H, 6.70. Found: C, 59.23; H, 6.72. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | EXAMPLE FORTY-SEVEN: Synthesis of l-iodo-l'^'-triisopropyl-S^- dimethoxybiphenyl; l-iodo-l'^'-triisopropyl-S^-dimethoxybiphenyl. An oven-dried three-neck 500 mL round bottom flask, which was equipped with a magnetic stir bar and charged with magnesium shavings (2.8 g, 116 mmol), was fitted with a reflux condenser, glass stopper, <n="142"/>and rubber septum. The flask was purged with argon and then THF (45 rnL) and 2,4,6- triisopropylbromobenzene (11.4 mL, 45 mmol) were added via syringe. The reaction mixture was heated to reflux and 1 ,2-dibromethane (40 uL) was added via syringe. The reaction was allowed to stir at reflux for 1.5 h and was then cooled to room temperature. A separate oven-dried 2 L round bottom flask, which was equipped with a magnetic stir bar and fitted with a septum, was purged with argon and then THF (200 mL) and 3,5- dimethoxyfluorobenzene (3 mL, 22.5 mmol) were added to the flask via syringe. The reaction mixture was cooled to -78 0C and n-BuLi (2.5 M in Hexane, 9.2 mL, 23 mmol) was added in a dropwise fashion over a 40 min period. The solution was stirred for 1 h and the Grignard reagent, which was prepared in the first reaction vessel, was added via cannula over a 30 min period and allowed to stir at -78 0C for 1 h. The reaction mixture was warmed to room temperature slowly where it was stirred for an additional 12 h. The mixture was then cooled to 0 0C and a solution of Iodine in THF (1 M, 50 mL, 50 mmol) was added via syringe over a 15 min period and then the dark red solution was warmed to room temperature and stirred for 1 h. The solvent was removed via a rotary evaporator, and the remaining dark brown oil was taken up in Et2O, washed with a saturated solution of sodium sulfite, and washed with brine. The organic layer was then dried over MgSO4, filtered, and the solvent was removed via rotary evaporator to give a yellow solid. The crude material was triturated with hexanes and filtered to give the desired product as an off- white solid (5.059 g, 48%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE SIXTY-ONE: Synthesis of 2-iodo-2',4t,6'-triisopropyl-3-methoxybiphenyl; l-iodo-l'^'-triisopropyl-S-methoxybiphenyl. An oven-dried three-neck round bottom flask, which was equipped with a magnetic stir bar and charged with magnesium shavings (2.4 equiv), was fitted with a reflux condenser, glass stopper, and rubber septum. The flask was purged with argon and then THF (1 mL/mmol) and 2,4,6- triisopropylbromobenzene (2 equiv) were added via syringe. The reaction mixture was heated to reflux and 1 ,2-dibromethane (40 uL) was added via syringe. The reaction was allowed to stir at reflux for 1.5 h and was then cooled to room temperature. A separate oven-dried round bottom flask, which was equipped with a magnetic stir bar and fitted with a septum, was purged with argon and then THF (10 mL/mmol) and <strong>[456-49-5]<strong>[456-49-5]3-fluoroanisol</strong>e</strong> (1 equiv) were added to the flask via syringe. The reaction mixture was cooled to -78 0C and n-BuLi (1.05 equiv) was added in a dropwise fashion over a 40 min period. The solution was stirred for 1 h and the Grignard reagent, which was prepared in the first reaction vessel, was added via cannula over a 30 min period and allowed to stir at -78 0C for 1 h. The reaction mixture was warmed to room temperature slowly where it was stirred for an additional 12 h. The mixture was then cooled to 0 0C and a solution of Iodine in THF (I M, 2 equiv) was added via syringe over a 15 min period and then the dark red solution was warmed to room temperature and stirred for 1 h. The solvent was removed via a rotary evaporator, and the remaining dark brown oil was taken up in Et2O, washed with a saturated solution of sodium sulfite, and washed with brine. The organic layer was then dried over MgSO4, filtered, and the solvent was removed via rotary evaporator to give a yellow solid. The crude material was recrystallized to give the desired product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 2,4,6-triisopropyl-1-bromobenzene With magnesium Stage #2: 2-bromo-1-chlorobenzene Stage #3: With iodine In tetrahydrofuran | |
67% | Stage #1: 2,4,6-triisopropyl-1-bromobenzene With magnesium; ethylene dibromide In tetrahydrofuran for 1h; Inert atmosphere; Reflux; Stage #2: 2-bromo-1-chlorobenzene In tetrahydrofuran for 1.5h; Inert atmosphere; Reflux; Stage #3: With iodine In tetrahydrofuran at 20℃; Inert atmosphere; | |
48.1% | Stage #1: 2,4,6-triisopropyl-1-bromobenzene With diisobutylaluminium hydride; magnesium In tetrahydrofuran; hexane for 1.33333h; Inert atmosphere; Reflux; Stage #2: 2-bromo-1-chlorobenzene In tetrahydrofuran; hexane for 1.5h; Inert atmosphere; Reflux; Stage #3: With iodine In tetrahydrofuran; hexane at 20℃; Inert atmosphere; |
Stage #1: 2,4,6-triisopropyl-1-bromobenzene With magnesium In tetrahydrofuran at 70℃; for 1h; Inert atmosphere; Stage #2: 2-bromo-1-chlorobenzene In tetrahydrofuran at 70℃; for 1.5h; Inert atmosphere; Stage #3: With iodine In tetrahydrofuran at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium phosphate; palladium diacetate; triphenylphosphine In 1,4-dioxane; water at 100℃; for 38h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: magnesium 1.2: 16 h / 70 °C / Inert atmosphere 2.1: hydrogenchloride / methanol; chloroform; water / 18 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 2,4,6-triisopropyl-1-bromobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25h; Stage #2: 2,2-dimethylmalononitrile In tetrahydrofuran; hexane at -78 - 23℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: magnesium; diisobutylaluminium hydride / tetrahydrofuran / 2 h / 70 °C / Schlenk technique 1.2: 70 °C / Schlenk technique 1.3: 2.67 h / 0 - 20 °C 2.1: n-butyllithium / toluene; pentane / 1.17 h / -78 °C / Schlenk technique 2.2: 24.25 h / -78 - 120 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium phosphate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) / tetrahydrofuran; toluene / 16 h / 100 °C / Inert atmosphere 2.1: Selectfluor; lithium bromide / acetonitrile / 20 °C / Inert atmosphere 3.1: magnesium; diisobutylaluminium hydride / tetrahydrofuran / 2 h / 70 °C 3.2: 3 h / 70 °C 3.3: 16 h / 25 °C 4.1: tetrahydrofuran / 20 °C | ||
Multi-step reaction with 4 steps 1.1: potassium phosphate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) / tetrahydrofuran; toluene / 16 h / 100 °C / Inert atmosphere 2.1: Selectfluor; lithium bromide / acetonitrile / 20 °C / Inert atmosphere 3.1: magnesium; diisobutylaluminium hydride / tetrahydrofuran / 2 h / 70 °C 3.2: 3 h / 70 °C 3.3: 16 h / 25 °C 4.1: acetonitrile / 0.5 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | A 10 mL oven-dried Schlenk tube was charged with magnesium (57.6 mg, 2.4 mmol) and anhydrous THF (1.5 mL), 5 drops of diisobutylaluminium hydride (DIBAL) was added and stirred for 5 min to activate magnesium. 2-bromo-1,3,5-triisopropylbenzene (566 mg, 2 mmol) was added potion-by-potion with vigorous stirring. The tube was capped with a rubber septum and was heated to 70 C. for 2 h (A). In another 10 mL oven-dried Schlenk tube was charged with <strong>[456-49-5]1-fluoro-3-methoxybenzene</strong> (126.2 mg, 1 mmol) and anhydrous THF (3.5 mL). The tube was cooled to -78 C. and 1.6 M n-BuLi solution in hexane (0.64 mL, 1 mmol) was added dropwise over 10 min under vigorous stirring. The mixture was stirred at -78 C. for 40 min (B). A was transferred into to B by syringe over 15 min at -78 C. An additional 1 mL of THF was used to rinse the reaction and was also transferred to B. The combined reaction mixture was stirred at -78 C. for another 1 h and then slowly warmed to room temperature and vigorously stirred for overnight. At this time, the mixture was cooled to 0 C. using ice bath, and iodine (762 mg, 3 mmol) in 4 mL anhydrous THF was added drop-wise over 5 min, then the reaction mixture was stirred for 30 min, and then warmed to stir at room temperature for 2 h. Then, the mixture was quenched with saturated Na2S2O3 (aq.) solution until the red color of bromine disappeared. The aqueous phase was extracted with Et2O (10 mL×3) and the combined organic phases were dried over anhydrous MgSO4. After concentration, the crude product was purified by silica gel chromatography (EtOAc/petroleum ether=1/20) followed by crystallization in methanol to get a white solid (205 mg, 40%), labeled as 2MeOTIP-I. 1H NMR (600 MHz, Chloroform-d) delta 7.45-7.37 (m, 4H), 7.36-7.32 (m, 3H), 7.00-6.96 (m, 1H), 6.85 (dd, J=8.2, 1.4 Hz, 1H), 4.02 (s, 3H), 2.76 (p, J=7.2 Hz, 1H), 2.58 (p, J=6.9 Hz, 1H), 2.44 (p, J=6.9 Hz, 1H), 1.33 (d, J=6.8 Hz, 3H), 1.19 (d, J=6.9 Hz, 3H), 1.14 (d, J=6.9 Hz, 3H), 1.10 (d, J=6.9 Hz, 3H), 0.88 (d, J=7.3 Hz, 3H), 0.81 (d, J=7.3 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3) delta 158.16, 148.92, 147.49, 145.41, 141.59, 140.23, 138.02, 130.75, 129.31, 128.40, 127.95, 127.09, 126.38, 119.70, 108.54, 77.24, 77.03, 76.82, 76.82, 56.41, 32.36, 30.59, 29.70, 25.09, 24.41, 24.33, 24.26, 23.55, 23.16, 22.81, 20.85 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | A 10 mL oven-dried Schlenk tube was charged with magnesium (57.6 mg, 2.4 mmol) and anhydrous THF (1.5 mL), 5 drops of diisobutylaluminium hydride (DIBAL) was added and stirred for 5 min to activate magnesium. 2-bromo-1,3,5-triisopropylbenzene (566 mg, 2 mmol) was added potion-by-potion with vigorous stirring. The tube was capped with a rubber septum and was heated to 70 C. for 2 h (A). In another 10 mL oven-dried Schlenk tube was charged with <strong>[405-06-1]2-fluoro-4-methoxy-1-methylbenzene</strong> (140 mg, 1 mmol) and anhydrous THF (3.5 mL). The tube was cooled to -78 C. and 1.6 M n-BuLi solution in hexane (0.64 mL, 1 mmol) was added dropwise over 10 min under vigorous stirring. The mixture was stirred at -78 C. for 40 min (B). A was transferred into to B by syringe over 15 min at -78 C. An additional 1 mL of THF was used to rinse the reaction and was also transferred to B. The combined reaction mixture was stirred at -78 C. for another 1 h and then slowly warmed to room temperature and vigorously stirred for overnight. At this time, the mixture was cooled to 0 C. using ice bath, and iodine (762 mg, 3 mmol) in 4 mL anhydrous THF was added drop-wise over 5 min, then the reaction mixture was stirred for 30 min, and then warmed to stir at room temperature for 2 h. Then, the mixture was quenched with saturated Na2S2O3 (aq.) solution until the red color of bromine disappeared. The aqueous phase was extracted with Et2O (10 mL×3) and the combined organic phases were dried over anhydrous MgSO4. After concentration, the crude product was purified by silica gel chromatography (EtOAc/petroleum ether=1/20) followed by crystallization in methanol to get a white solid (185 mg, 34%), labeled as 2MeO-SMeTIP-I. 1H NMR (600 MHz, Chloroform-d) delta 7.46-7.29 (m, 4H), 7.25 (dd, J=8.3, 0.8 Hz, 2H), 7.12 (s, 1H), 6.78 (d, J=8.3 Hz, 1H), 3.97 (s, 3H), 2.73-2.59 (m, 1H), 2.54 (p, J=6.8 Hz, 1H), 2.37 (p, J=6.8 Hz, 1H), 2.13 (s, 3H), 1.37 (d, J=7.0 Hz, 3H), 1.28 (d, J=6.8 Hz, 3H), 1.18-1.07 (m, 6H), 0.88 (d, J=7.2 Hz, 3H), 0.82 (d, J=7.2 Hz, 3H) ppm. 13C NMR (151 MHz, Chloroform-d) delta 156.49, 147.77, 146.49, 144.69, 141.28 (d, J=23.7 Hz), 139.64, 138.22, 131.97, 131.47, 130.62, 130.17, 129.81, 127.88, 126.87 (d, J=11.2 Hz), 126.38, 120.38 (d, J=35.2 Hz), 109.03, 56.39, 34.27, 32.38, 30.78, 30.26, 29.50, 24.63 (d, J=5.6 Hz), 24.47, 24.29, 24.22, 24.11, 23.42 (d, J=11.7 Hz), 21.54 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | A 10 mL oven-dried Schlenk tube was charged with magnesium (57.6 mg, 2.4 mmol) and anhydrous THF (1.5 mL), 5 drops of diisobutylaluminium hydride (DIBAL) was added and stirred for 5 min to activate magnesium. 2-bromo-1,3,5-triisopropylbenzene (566 mg, 2 mmol) was added potion-by-potion with vigorous stirring. The tube was capped with a rubber septum and was heated to 70 C. for 2 h (A). In another 10 mL oven-dried Schlenk tube was charged with <strong>[82830-49-7]2-fluoro-1,4-dimethoxybenzene</strong> (156 mg, 1 mmol) and anhydrous THF (3.5 mL). The tube was cooled to -78 C. and 1.6 M n-BuLi solution in hexane (0.64 mL, 1 mmol) was added dropwise over 10 min under vigorous stirring. The mixture was stirred at -78 C. for 40 min (B). A was transferred into to B by syringe over 15 min at -78 C. An additional 1 mL of THF was used to rinse the reaction and was also transferred to B. The combined reaction mixture was stirred at -78 C. for another 1 h and then slowly warmed to room temperature and vigorously stirred for overnight. At this time, the mixture was cooled to 0 C. using ice bath, and iodine (762 mg, 3 mmol) in 4 mL anhydrous THF was added drop-wise over 5 min, then the reaction mixture was stirred for 30 min, and then warmed to stir at room temperature for 2 h. Then, the mixture was quenched with saturated Na2S2O3 (aq.) solution until the red color of bromine disappeared. The aqueous phase was extracted with Et2O (10 mL×3) and the combined organic phases were dried over anhydrous MgSO4. After concentration, the crude product was purified by silica gel chromatography (EtOAc/petroleum ether=1/20) followed by crystallization in methanol to get a white solid (162 mg, 30%), labeled as 25MeOTIP-I. 1H NMR (600 MHz, Chloroform-d) delta 7.39-7.29 (m, 4H), 7.28-7.24 (m, 1H), 7.21 (s, 1H), 6.90 (d, J=8.9 Hz, 1H), 6.82 (d, J=8.9 Hz, 1H), 3.91 (s, 3H), 3.71 (s, 3H), 2.66 (p, J=7.2 Hz, 1H), 2.55-2.45 (m, 1H), 2.34 (p, J=6.8 Hz, 1H), 1.23 (d, J=6.9 Hz, 3H), 1.11 (dd, J=12.6, 6.9 Hz, 6H), 1.04 (d, J=6.8 Hz, 3H), 0.81 (d, J=7.2 Hz, 3H), 0.72 (d, J=7.2 Hz, 3H) ppm. 13C NMR (151 MHz, Chloroform-d) delta 152.42 (d, J=24.3 Hz), 147.34, 145.33, 141.78, 137.81, 137.38, 137.03, 131.88, 131.03, 126.95, 126.24, 119.68, 109.92, 109.16, 56.81, 55.32, 32.61, 30.91, 29.66, 24.68 (d, J=2.3 Hz), 24.06, 23.75, 22.91 (d, J=21.4 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; In toluene; at 100℃; for 17h;Inert atmosphere; | Reactor thoroughly dried and purged with nitrogen was 300mL, 2-bromo-1,3,5-triisopropyl benzene 12.0g (42.4mmol), (2- methoxy-5-methylphenylboronic acid) 14.1g (85.0mmol), tripotassium phosphate (K3PO4) 27.0g (127mmol), Tris(dibenzylideneacetone)dipalladium(0) (chloroform adduct), 0.44g (0.42mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl 0.35g (0.85mmol), was charged with toluene 100mL, and the mixture was stirred for 17 hours at 100°C. The reaction solution was cooled to room temperature and filtered through celite. When the resultant residue by distilling off the filtrate purified by silica gel column chromatography, the desired product shown by the following formula (11) (hereinafter Compound (11) hereinafter) is 5.61 g (41percent yield) obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium phosphate; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris(dibenzylideneacetone)dipalladium(0) chloroform complex / toluene / 17 h / 100 °C / Inert atmosphere 2: boron tribromide / dichloromethane / 1.5 h / -78 - 20 °C / Inert atmosphere 3: bromine; acetic acid / dichloromethane / 0.67 h / 20 °C / Inert atmosphere; Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Under the protection of nitrogen, 200 ml of THF and 31g of 2, 4, 6-tri-isopropyl-bromobenzene was added to 1L three-mouth bottle. The temperature was cooled down to 0 C, and 46 ml of 2.5M n-butyl lithiumwas added dropwise. The reaction was continued for 1 hour after the addition. At 0 C, 24.6g O-dibromobenzene was added dropwise. The reaction was continued for 1 hour after the addition. At0 C, 42 ml of 2.5M n-butyl lithiumwas added dropwise to the reaction liquid.After the addition, the reaction was continued for 1 hour. 26.7g of dicyclohexyl phosphine was added dropwise, and the temperature was naturally warmed to react at room temperature for 2 hours. 200 ml saturated ammonium chloride aqueous solution was added dropwsie to the reaction liquid under the ice bath to quench the reaction. After phase separation, the organic phase was precipitated, and methanol was added for crystallization. Byfiltering, 44.5g white product of 2?-dicyclohexyl phosphino-2, 4, 6-tri-isopropyl biphenyl was obtained, with a yield of 89%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 1,3-bis(2,6-diisopropylphenyl)-4,5-dimethyl-3-imidazolium chloride; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate at 115℃; for 20h; Inert atmosphere; Glovebox; Sealed tube; | |
70% | With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium chloride In toluene at 110℃; for 24h; Inert atmosphere; | 2.1 (1) Synthesis of diamine compound 2b: Add 5mmol of (1S,2S)-(-)-1,2-diphenylethylenediamine, 18mmol of tBuONa, 15mmol of 2,4,6-triisopropyl bromobenzene, 1.5mmol of IPrMe·HCl, Mix 0.5 mmol of Pd(dba)2, add 20 mL of anhydrous toluene, and react at 110°C for 24 hours under a nitrogen atmosphere. After the reaction is completed, it is diluted with water, extracted with ethyl acetate 3 times, and dried with anhydrous Na2SO4. The solvent was spin-dried under reduced pressure, and the crude product was subjected to silica gel column chromatography to obtain a white solid (eluent: petroleum ether/dichloromethane = 10:1). Product yield: 2.15 g, yield: 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 1.2: 12 h / 20 °C 1.3: 12 h 2.1: trichlorosilane; triethylamine / toluene / 24 h / Reflux 2.2: 24 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With P(t-Bu)3 Palladacycle Gen. 3; potassium trimethylsilonate In tetrahydrofuran at 23℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: 2,4,6-triisopropyl-1-bromobenzene With magnesium; ethylene dibromide In tetrahydrofuran at 70℃; Schlenk technique; Inert atmosphere; Sealed tube; Stage #2: 1-fluoro-2-iodo-3-methoxybenzene In tetrahydrofuran at 70℃; Inert atmosphere; Sealed tube; Stage #3: With iodine In tetrahydrofuran at 20℃; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 1,3-Dichlorobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: 2,4,6-triisopropyl-1-bromobenzene With magnesium In tetrahydrofuran; hexane at 80℃; for 6h; Stage #3: methylmagnesium bromide; tert-butyldichlorophosphine Further stages; | 14 Example 14. [2,6-Bis(2,4,6-triisopropylphenyl)phenyl]-methyl-tert-butylphosphine (ZTPhos) Example 14. [2,6-Bis(2,4,6-triisopropylphenyl)phenyl]-methyl-tert-butylphosphine (ZTPhos) To an oven-dried 250 mL flask, equipped with a magnetic stir bar and a condenser, and charged with magnesium (0.56 g, 23.0 mmol), ca. 1 mL of a solution of 2,4,6-triisopropylbromobenzene (6.23 g, 22.0 mmol) in THE (10.0 mL) was added and heated. After the reaction was initiated, the rest solution was added dropwise and the reaction mixture was heated to reflux for 2 h to obtain a Grignard reagent. To another oven-dried two-neck 250 mL flask with THE (15 mL) and 1,3-dichlorobenzene (1.47 g, 10.0 mmol), n-butyllithium (4.8 mL of a 2.5 M solution in hexanes, 12.0 mmol) was added dropwise at -78° C. and stirred for 1 h. At that point the Grignard reagent was transferred via cannula to the solution, then warmed to room temperature, and the reaction solution was heated to 80° C. for 6 h. To a third oven-dried 250 mL flask, equipped with a magnetic stir bar and a condenser, and charged with CuBr (1.72 g, 12.0 mmol), the above reaction solution was transferred via cannula and the mixture was a stirred for 15 min. The mixture of tBuPCl2 (1.90 g, 12.0 mmol) and THF (5 mL) was added dropwise via cannula at -78° C. and the solution was heated to 70° C. for 6 h, 12.0 mL MeMgBr (1.0 M solution in THF, 12.0 mmol) was added dropwise at -78° C. and the reaction solution was warmed to room temperature for 12 h. 40 mL of ammonia (26.0%-28.0%) was added and stirred for 30 min, then the mixture was extracted with dichloromethane (3*50 mL), and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a light yellow oil. The residue was purified by column chromatography to give 3.09 g of [2,6-bis(2,4,6-triisopropylphenyl)phenyl]-methyl-tert-butylphosphine as a white crystalline material), 53% yield. m.p.: 145.3-146.7° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.6% | Stage #1: 2,4,6-triisopropyl-1-bromobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: 2,5-dimethoxy-4-chloro-benzene In tetrahydrofuran at -80 - -10℃; for 10h; Stage #3: With iodine In 2-methoxy-2-methylpropane at -10℃; for 6h; | 5.A; 5.C Step A A fully dried 1-L four-necked flask purged with nitrogen was charged with 2,4,6-triisopropylbromobenzene (a1) (93.5 g, 330 mmol) and tetrahydrofuran (450 ml). After cooling to -78° C. under a nitrogen atmosphere, a hexane solution of 15 mass % of n-butyllithium (197.3 g, 462 mmol) was added dropwise thereto over 1 hour. The mixture was then aged at -78° C. for 1 hour, so that a liquid a was prepared. In another fully dried 300-mL four-necked flask purged with nitrogen, 1-chloro-2,5-dimethoxybenzene (a2) (22.7 g, 132 mmol) was dissolved in tetrahydrofuran (120 ml), so that a liquid b was prepared. The liquid b was continuously added to the liquid a over 1 hour, such that the internal temperature was maintained at about -80° C. (reaction temperature A). The mixture was gradually heated to a temperature of -10° C. and aged for 8 hours, so that a yellow transparent liquid was obtained. Iodine (67.0 g, 264 mmol) was dissolved in tert-butyl methyl ether (200 ml) in advance, and the tert-butyl methyl ether solution of iodine was slowly added dropwise to the liquid obtained in the step A at -10° C. Then, the mixture was stirred as it was for 6 hours. The organic layer was washed twice with 250 ml of an aqueous solution of 10 mass % of sodium hydrogen sulfite, then washed with 250 ml of pure water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, recrystallization was performed from a mixed solvent of acetic acid and methanol (1:1). The resulting crystals were rinsed with cold methanol and dried under reduced pressure to obtain 2-iodo-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (iodine intermediate) (42.3 g, 90.5 mmol, 68.6%). In the measurement by gas chromatography, the purity was 99% or more. (Identification data of Biaryl-I) Melting point: 199 to 200° C. 1H NMR (500.15 MHz, CDCl3): δ 0.99 (d, J=6.9 Hz, 6H), 1.17 (d, J=6.9 Hz, 6H), 1.31 (d, J=6.9 Hz, 6H), 2.36 (septet, J=6.9 Hz, 2H), 2.95 (septet, J=6.9 Hz, 1H), 3.65 (s, 3H), 3.89 (s, 3H), 6.80 (d, J=8.9 Hz, 1H), 6.89 (d, J=8.9 Hz, 1H), 7.04 (s, 2H); 13C NMR (125.76 MHz, CDCl3): δ 23.6, 24.0, 24.5, 30.8, 34.1, 55.5, 56.8, 96.4, 109.2, 110.0, 120.7, 135.9, 136.2, 145.7, 148.2, 152.3, 152.5. |
Tags: 21524-34-5 synthesis path| 21524-34-5 SDS| 21524-34-5 COA| 21524-34-5 purity| 21524-34-5 application| 21524-34-5 NMR| 21524-34-5 COA| 21524-34-5 structure
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