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CAS No. : | 73183-34-3 | MDL No. : | MFCD00799570 |
Formula : | C12H24B2O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IPWKHHSGDUIRAH-UHFFFAOYSA-N |
M.W : | 253.94 | Pubchem ID : | 2733548 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 73.68 |
TPSA : | 36.92 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.24 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.27 |
Log Po/w (WLOGP) : | 2.25 |
Log Po/w (MLOGP) : | 0.36 |
Log Po/w (SILICOS-IT) : | 0.21 |
Consensus Log Po/w : | 1.02 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.78 |
Solubility : | 0.423 mg/ml ; 0.00167 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.68 |
Solubility : | 0.528 mg/ml ; 0.00208 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.08 |
Solubility : | 0.21 mg/ml ; 0.000826 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.38 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
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* 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 |
---|---|---|
76% | With potassium acetate In dimethyl sulfoxide at 85℃; for 1.25 h; Inert atmosphere | Preparation 24terf-Butyl (4-bromopyhdin-2-yl)carbannate (0.494 g, 1 .81 mmol), bis(pinacolato)diboron (1 .4 g 5.51 mmol ) and potassium acetate (0.535 g , 5.45 mmol) were stirred in dimethylsulfoxide (8 ml_). The mixture was flushed with nitrogen for 10 minutes. [1 ,1 '- Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (0.150 g, 0.184 mmol) was added and the system flushed for a further 5 minutes with nitrogen before heating the reaction mixture to 85°C under nitrogen for 1 hour. The reaction mixture was diluted in ethyl acetate (15 ml_) and washed with aqueous hydrochloride solution (10 ml_, 0.2 M). Some of the product went into the aqueous layer and some stayed in the organic layer. The aqueous layer was treated with saturated aqueous sodium carbonate carefully until ~pH 6 was achieved then extracted with ethyl acetate (10 ml_). The organics were dried over sodium sulfate, filtered and concentrated in vacuo to give title compound as a white solid (0.44 g, 76percent).1HNMR (de -DMSO): δ 1 .29 (s, 12H), 1 .45 (s, 9H), 7.15-7.17 (d, 1 H), 8.07 (s, 1 H), 8.24- 8.25 (d, 1 H), 9.77 (s, 1 H)LCMS Rt = 0.68 min MS m/z 183.1 [MH]+ |
56% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 80℃; for 5 h; | A solution of intermediate 20b (352 mg), potassium acetate (380 mg), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (360 mg) and Pd(dppf)Cl2.CH2Cl2 (105 mg) in dry DMF (10 mL) was stirred at 80° C. for 5 h. The volatiles were removed under reduced pressure, the residue dissolved in EtOAc and the organic layer was washed with water, dried and the volatiles were removed under reduced pressure. The crude product was purified through washing with heptane to yield the desired compound (56percent yield). LC-MS (Method 1): m/z [M (boronic acid)+H]+=239.2 (MW (boronic acid) calc.=238.05); Rt=2.3 min. |
56% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 80℃; for 5 h; | Intermediate 20c) A solution of intermediate 20b (352 mg), potassium acetate (380 mg), 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'- bi(1 ,3,2-dioxaborolane) (360 mg) and Pd(dppf)CI2-CH2CI2 (105 mg) in dry DMF (10 mL) was stirred at 80 °C for 5 h. The volatiles were removed under reduced pressure, the residue dissolved in EtOAc and the organic layer was washed with water, dried and the volatiles were removed under reduced pressure. The crude product was purified through washing with heptane to yield the desired compound (56percent yield) LC- S (Method 1): m/z [M (boronic acid)+H]+ = 239.2 (MW (boronic acid) calc. = 238.05); R, = 2.3 min. |
53% | With potassium acetate In N,N-dimethyl-formamide at 80℃; for 2 h; Inert atmosphere | Step 6.1. tert-Butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-2-yl]carbamate To a solution of 6.76 (24.8 mmol) of tert-butyl (4-bromopyrid-2-yl)carbamate (Deady, Leslie W.; Korytsky, Olga L.; Rowe, Jeffrey E.; Aust. J. Chem.; 35; 10; 1982; 2025-2034) in 150 mL of dimethylformamide are added 8.0 g (81 mmol) of potassium acetate predried at 130° C. and 6.9 g (27 mmol) of bis(pinacolato)diboron. A stream of argon is then sparged through for a few moments, and 1.2 g (1.5 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) are added. The mixture is stirred at 80° C. under argon for 2 hours and then poured into saturated aqueous ammonium chloride solution. The product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is stripped off under reduced pressure. The residue is triturated in 300 mL of refluxing diisopropyl ether and the insoluble matter is separated out by filtration. The filtrate is cooled and partially concentrated under reduced pressure. After adding 70 mL of hexane, the precipitate formed is isolated by filtration to give 4.2 g of an orange-colored solid after drying. Yield: 53percent m.p.: 188-193° C. 1H NMR (CDCl3) δ: 8.15 (m, 2H), 7.65 (broad s, 1H), 7.15 (d, 1H), 1.40 (s, 9H), 1.20 (s, 12H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.19% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 95℃; for 5 h; Inert atmosphere | Intermediate 702: 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole Compound 701 (0.2 g, 1.24 mmol) was dissolved in 5 ml of 1,4-dioxane, added with 0.378 g (1.49 mmol) of bis(pinacolato)diboron, 0.365 g (3.72 mmol) of potassium acetate, and 0.11 g (0.124 mmol) of [1,1-bis(di-phenylphosphino)ferrocene]palladium chloride dichloromethane complex under the protection of nitrogen, heated to 95 °C and reacted for 5 h, and then cooled to room temperature. 15 mL of water was added, stirred for 1 h, and filtered to afford 0.114 g of solid. Yield: 44.19percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.9% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 85℃; for 24 h; Inert atmosphere | A mixture of potassium acetate (1.56 g, 15.91 mmol) , Pd (dppf) Cl2 (190 mg, 0.27 mmol) , 1- (cyclopropylmethyl) -4-iodo-1H-pyrazole (1.31 g, 5.30 mmol) and bis (pinacolato) diboron (1.62 g, 6.36 mmol) in DMF (25.00 mL) was stirred at 85 under N2 for 24 h and cooled to rt, and then filtered through a Celite pad. The filtrate was diluted with water (50 mL) , and then extracted with EtOAc (50 mL × 3) . The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 3/1 to give a yellow oily product (1.11 g, 84.9) .[1449]MS (ESI, pos. ion) m/z: 249.1 [M+1] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.15 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 12 h; Inert atmosphere; Sealed tube | b) 1 -(Cyclopropylmethyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 H- pyrazoleTo a degassed (N2 bubbling) solution of the compound of Intermediate Example 9(a) (0.15 g, 0.75 mmol) in 1,4-dioxane (10 ml) were added 4,4,4*,4',5,5,5',5'-octa- methyl-2,2'-bi(l,3,2-dioxaborolane) (0.23 g, 0.9 mmol, 1.2 eq.), Pd(dppf Cl2 (0.12 g, 0.15 mmol, 0.2 eq.) and potassium acetate (0.25 g, 2.55 mmol, 3.4 eq.). using the procedure of Intermediate Example 1(b). The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 30 percent ethyl acetate in hexane) to give the product in 81 percent yield (0.15 g). LC-MS (ESI):Calculated mass: 248.13; Observed mass: 249.2 [(M+H]+ (rt: 1.58 min). |
0.15 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 12 h; Sealed tube; Inert atmosphere | To a degassed (N2 bubbling) solution of the compound of Intermediate Example 9(a) (0.15 g, 0.75 mmol) in 1,4-dioxane (10 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.23 g, 0.9 mmol, 1.2 eq.), Pd(dppf)Cl2 (0.12 g, 0.15 mmol, 0.2 eq.) and potassium acetate (0.25 g, 2.55 mmol, 3.4 eq.). using the procedure of Intermediate Example 1(b). The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 30percent ethyl acetate in hexane) to give the product in 81percent yield (0.15 g). LC-MS (ESI): Calculated mass: 248.13; Observed mass: 249.2 [(M+H]+ (rt: 1.58 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium acetate In N,N-dimethyl-formamide at 100℃; for 2 h; Inert atmosphere | A vial was charged with 5-bromo-2-fluoroaniline (1 g, 5.26 mmol), bis(pinacolato)diboron (1.6 g , 6.31 mmol), potassium acetate (1.03 g, 10.52 mmol), Pd(dppf)Cl2 * CH2C12 (129 mg, 0.158 mmol), and DMF (10 mL) under nitrogenatmosphere. After stirring for 2 h at 100 °C the reaction mixture was concentrated in vacuo, the residue was triturated with EtOAc and filtered through a pad of celite. The filtrate was adsorbed on silica gel. Purification by flash silica gel chromatography using a gradient of 0- 30percent EtOAc/hexane afforded 1.25 g of pinacol 3-amino-4-fluoroboronate as a light yellow oil (quant.): 1H NMR (CDC13, ppm) δ 1.36 (s, 12H), 3.71 (broad s, 2H), 7.00 (dd, 1H), 7.19 (m, 1H), 7.26 (dd, 1H); [M+H]+ m/z 238. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With (2,2,2-trifluoroethoxy)trimethylsilane; cesium fluoride; dichlorobis(trimethylphosphine)nickel In tetrahydrofuran at 100℃; for 12 h; Inert atmosphere; Sealed tube | Under an argon atmosphere,4.2 mg (0.015 mmol) of dichlorobis (trimethylphosphine) nickel,72.8 mg (0.5 mmol) of 5-chloro-2-fluoroaniline,152 mg (1.0 mmol) of cesium fluoride,140 mg (0.55 mmol) of 4,4,5,5,4 ', 4', 5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolanyl)180 mg (1.05 mmol) of trimethyl (2,2,2-trifluoroethoxy) silane and 0.5 mL of tetrahydrofuran were added and sealed,And the mixture was stirred at 100 ° C. for 12 hours.After the reaction vessel was cooled to room temperature, 1 mL of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted three times with 8 mL of ethyl acetate, and the obtained organic phases were combined.The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: chloroform: ethyl acetate = 4: 1: 0 to 4: 1: 1)96 mg (pale yellow liquid, yield 81percent) of 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline was obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 2 h; Microwave irradiation | A solution of 5-bromo-1-methylpyridin-2-one (200.0 mg, 1.06 mmol), bis(pinacolato)diboron (410.0 mg, 1.61 mmol), potassium acetate (270 mg, 2.67 mmol), Pd (dppf)Cl2 (80 mg, 0.11 mmol) in dioxane (5 mL) was heated at 100° C. for 2 h under microwave. The mixture was filtered, washed with water and extracted with ethyl acetate (20 mL*3). The combined organics were dried over Na2SO4, filtered and concentrated to give the crude title compound (59.0 mg, 23.6percent). LCMS (M+H)+ 236. |
160 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In ethylene glycol at 80℃; for 3 h; | To a stirred suspension of 5-bromo-l-methylpyridin-2(lH)-one (470 mg, 2.49 mmol), potassium acetate (736 mg, 7.49 mmol) and bis(pinacolato)diboron (952 mg, 3.74 mmol) in degassed polyethylene glycol-400 (15 mL) was added [1, 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (204 mg, 0.24 mmol) at RT. The resultant suspension was stirred for 3 h at 80 °C. The reaction mixture was cooled to RT, diluted with ethyl acetate (100 mL) and washed with water (100 mL) followed by brine (100 mL). The organic layer was concentrated and the residue obtained purified by flash column chromatography to afford 160 mg of the titled product; 1H NMR (300 MHz, CDC13) δ 1.30 (s, 12H), 3.54 (s, 3H), 6.53 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.75 (s, 1H); APCI- MS (m/z) 236 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; tricyclohexylphosphine In 1,4-dioxane at 80℃; for 5 h; Inert atmosphere | To a mixture of 5-bromo-1-methylpyridin-2(1H)-one (1.0 g, 5.32 mmol), KOH (0.78 g, 7.98 mmol) and bis(pinacolato)diboron (0.162 g, 6.38 mmol) in 1 ,4-dioxane (20 mL), tricyclohexyiphosphine (149 mg, 0.532 mmol), Pd2dba3 (487 mg, 0.532 mmol) were added under N2 atmosphere. The mixture was stirred at about 80 °C for about 5 h. Then water was added, the aqueous layer was extracted with EtOAc (50 mL x 2), and the organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and the residue was purified by column chromatograph on silica gel to provide ]-methyl-5-(4, 4,5, 5-tetramethyl-], 3, 2-dioxaborolan-2-yl)pyridin-2(]H)-one (0.80 g, 64percent): ‘H NMR (CDC13) 7.70 (s, 1 H), 7.54 (d, J= 8.8 Hz, 1 H), 6.47 (d, J= 8.8 Hz, 1 H), 3.49 (s, 3 H), 1.24(s, 12 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
280 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; for 12 h; Inert atmosphere | Step 2. Bis(pinacolato)diboron (247 g, 0.974 mol, 1.5 eq) was added to a solution of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (150 g, 0.65 mol, 1.0 eq) in 1,4-dioxane (1500 ml) at room temperature. Potassium acetate (127 g, 1.30 mol, 2 eq) was then added and the reaction flask was purged with argon for 20 min. PdCl2(dppf) DCM (26.0 g, 31.8 mmol, 0.05 eq) was added and the mixture was purged with argon for further 10 min followed by stirring at 80° C. for 12 h. After completion of the reaction (monitored by TLC, 10percent ethyl acetate-hexane Rf=0.3), the mixture was cooled to room temperature and filtered through a bed of diatomaceous earth. The bed of diatomaceous earth was washed with ethyl acetate and the combined organic layers were evaporated under reduced pressure to give 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (280 g crude) as a brown oil. LCMS purity: 57.8percent; (ES+): m/z 279.18 (M+H+); tr=1.95 min. The compound was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium acetate In 1,4-dioxane at 70 - 120℃; for 18 h; | To a solution of 6-bromo-2,3-dihydro-isoindol-l-one (1 equiv) in dry dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 20 minutes. PdCl2(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction mixture was heated to 70°C for 2 hours under nitrogen then heated to 1200C for 16 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic phases dried (MgSO4), filtered and concentrated in vacuo. The residue was sonicated in EtOAc, the suspension was filtered onto a sintered funnel and the collected grey solid was dried and used without further purification. 6-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-l-one: (82 percent yield, 29 percent purity, main impurity being the boronic acid 43 percent) m/z (LC-MS, ESP): 519.5 [2M+H]+ R/T = 3.38 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium acetate In 1,4-dioxane at 100℃; for 7 h; | A mixture of compound B2.2 (1 equiv., 17 mmol, 3.8 g), bis(pinacolato)diboron (1.1 equiv., 18 mmol, 4.7 g), potassium acetate (2 equiv., 33 mmol, 3.3 g) and trans- dichlorobis(triphenylphoshpine) palladium(II) (0.03 equiv., 0.5 mmol, 0.41 g) in dioxane (180 ml) was stirred at 1000C under Ar for 7 h. Water was added and the aqueous layer was extracted with dichloromethane. The organic layer was dried with MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluens: dichloromethane) to give a white powder B2.3(3.7 g, yield = 81percent, purity (LC) = 81percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With methanol; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; copper(l) chloride; sodium t-butanolate In tetrahydrofuran at 20℃; for 24 h; Inert atmosphere | General procedure: CuCl (1.5 mg, 0.015 mmol), NaOt-Bu (2.9 mg, 0.03 mmol), and Xantphos ligand (8.7 mg, 0.015 mmol) were placed in an oven-dried Schlenk tube under nitrogen and THF (0.45 mL) were added. The reaction mixture was stirred for 30 min at room temperature and then bis(pinacolato)diboron (127 mg, 0.5 mmol) in THF (0.3 mL) was added. The reaction mixture was stirred for 10 min and α,β-acetylenic ester 2 (0.5 mmol) was added, followed by MeOH (40 μL, 1 mmol). The reaction tube was washed with further THF (0.2 mL), sealed, and stirred until no starting material was detected by TLC. The reaction mixture was filtered through a pad of Celite and concentrated. The product was purified by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium acetate In dimethyl sulfoxide at 20 - 80℃; | To a solution of compound 4-bromo-l -phenyl- lH-pyrazo Ie (0.5 g, 2.3 mmol) in DMSO (50 mL) was added KOAc (0.66 g, 6.8 mmol), bis(pinacolato)diboron (0.63 g, 2.5 mmol) and .yen.dCb(dpp{) (0.076g, 0.11 mmol) at room temperature. The reaction mixture was stirred overnight at 8O0C. The result mixture was diluted with EA, washed with brine, dried over Na2SO4, concentrated, purified by chromatography (EA:PE=1: 12) to give l-phenyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH- pyrazole (0.3 g, 50percent) as light yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.15% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 8 h; Inert atmosphere | A mixture of 4-iodo-1-phenyl-1H-pyrazole (706 mg, 2.59 mmol) , potassium acetate (762 mg, 7.76 mmol) , bis (pinacolato) diboron (860 mg, 3.37 mmol) and Pd (dppf) Cl2(212 mg, 0.26 mmol) was suspended in DMSO (15 mL) . The system was exchanged with N2. The mixture was stirred at 80 for 8 h. The reaction mixture was diluted with water (60 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were washed with saturated aqueous NaCl (15 mL) , dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 20/1 to give a yellow solid product (340 mg, 48.15) .[1650]MS (ESI, pos. ion) m/z: 271.05 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium acetate; triethylamine In 1,4-dioxane at 110℃; | A mixture of 1 , 1 -dimethylethyl 5-bromo-lH-benzimidazole-l -carboxylate (10.2 mmol), bis(pinacolato)diboron (11.2 mmol), palladium(II) acetate (1.02 mmol), dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium(II) (1.02 mmol), and potassium acetate (30.4 mmol) in triethylamine (2 mL) and 1,4-dioxane (50 mL) was heated at 110 °C overnight. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (10percent ethyl acetate/petroleum ether) to afford the title product as a solid (42percent). |
1.47 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; palladium diacetate; triethylamine In 1,4-dioxane at 110℃; Inert atmosphere | 1 ,1 -Dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-benzimidazole-1 - carboxylateTo a solution of 1 , 1 -dimethylethyl 5-bromo-1 /-/-benzimidazole-1 -carboxylate (3.02 g) in 1 ,4- dioxane (50 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (2.837 g), potassium acetate (7.978 g) and TEA (2 mL). Pd(OAc)2 (227 mg) and Pd(dppf)CI2 (743 mg) were added under nitrogen and the reaction mixture was stirred under reflux (1 10 °C) overnight. The reaction mixture was washed with water three times and with saturated brine and dried over sodium sulfate. Solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum ether / EtOAc 8:1 ) to afford 1.47 g of the titled compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.5% | With potassium acetate In 1,4-dioxane at 50℃; for 16 h; Inert atmosphere | 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11-II)To a solution of compound 11-II-a (600 mg, 2.73 mmol) in dioxane (15 mL) was added KOAc (800 mg, 8.2 mmol), bis(pinacolato)diboran (1.39 g, 5.4 mmol) and Pd(dppf)Cl2 (0.06 g, 0.08 mmol) at RT. The reaction mixture was degassed by purging with argon for 30 minutes and stirred at 50° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction was quenched with H2O and extracted with EtOAc (3.x.100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography (15percent EtOAc/Hexane) to afford 11-II (500 mg, 68.5percent) as off white solid. TLC: 30percent EtOAc/Hexane (Rf: 0.4); 1H-NMR (CDCl3, 200 MHz): δ 7.90 (s, 1H), 7.79 (s, 1H), 5.56 (q, J=6.0 Hz, 1H), 3.55-3.25 (m, 2H), 1.63 (d, J=6.0 Hz, 3H), 1.35 (s, 12H), 1.15 (t, J=7.2 Hz, 3H); Mass: 267 [M++1]. |
68.5% | With potassium acetate In 1,4-dioxane | 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5-II) To a solution of compound 5-II-a (600 mg, 2.73 mmol) in dioxane (15 mL) was added KOAc (800 mg, 8.2 mmol), bis(pinacolato)diboran (1.39 g, 5.4 mmol) and Pd(dppf)Cl2 (0.06 g, 0.08 mmol) at RT. The reaction mixture was degassed by purging with argon for 30 minutes and stirred at 50° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction was quenched with H2O and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography (15percent EtOAc/Hexane) to afford 5-II (500 mg, 68.5percent) as off white solid. TLC: 30percent EtOAc/Hexane (Rf: 0.4); 1H-NMR (CDCl3, 200 MHz): δ 7.90 (s, 1H), 7.79 (s, 1H), 5.56 (q, J=6.0 Hz, 1H), 3.55-3.25 (m, 2H), 1.63 (d, J=6.0 Hz, 3H), 1.35 (s, 12H), 1.15 (t, J=7.2 Hz, 3H); Mass: 267 [M++1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.6% | Stage #1: With potassium acetate In N,N-dimethyl-formamide for 0.166667 h; Stage #2: at 80℃; |
To a solution of 21c (0.79g, 3.64mmol) and bis(pinacolato)diboron (1.1 Ig, 4.37mmol) in DMF (2OmL), was added KOAc (1.07g, 10.92mmol). The mixture was 25 degassed with N2 and stirred for lOmin, then was added Pd(dppf)Cl2 (89mg, 0.109mmol). The resulting mixture was degassed with N2 and stirred at 800C overnight. After the reaction was complete, DMF was evaporated and the residue was purified by column chromatography (EA:PE=1 : 10) to afford 21d (0.63g, 65.6percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In tetrahydrofuran for 5 h; Reflux | Step 5: tert-Butyl {1 -[4-(4,4,5,5-tetramethy-1 ,3,2-dioxaborolan-2-yl)phenyl]- cyclobutyl}carbamate [lnt-1 B] 27.75 g (55 mmol) [1-(4-Bromophenyl)cyclobutyl]carbamic acid fe/f-butyl ester, 23.76 mmol (93.6 mmol) bis-(pinacolato)diboron, 25 g (255 mmol) potassium acetate and 2.08 g (2.55 mmol) 1 , 1 '-bis(diphenylphosphino)ferrocenedichloro- palladium(ll) in 500 mL degassed THF were heated for three hours at reflux. The colour of the reaction mixture turned from dark red to black. Due to an incomplete reaction heating was continued for another two hours. The reaction mixture was poured on water (400 mL) and diluted with ethyl acetate (700 mL). After stirring for 30' the organic phase was separated and the aqueous phase was reextracted twice with ethyl acetate (400 and 200 mL). The combined organic extracts were washed with brine (200 mL) and dried (sodium sulfate). After evaporation of the solvent the residue was purified by chromatography (Biotage) yielding 28.99 g (91.3percent) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 7.51 -7.67 (m, 3H), 7.38 (d, 2H), 2.22-2 42 (m, 4H), 1.88-2.02 (m, 1 H), 1.63-1.80 (m, 1 H), 1.00-1.38 (m, 21 H) ppm. |
90.8% | With potassium acetate In tetrahydrofuranReflux | 10 g (30.7 mmol) [1 -(4-Bromophenyl)-cyclobutyl]-carbamic acid tert. -butyl ester, 8.56 g (33.7 mmol) bis-(pinacolato)diboron, 750.9 mg (0.92 mmol) 1 ,1 '- bis(diphenylphosphino)ferrocenedichloropalladium(ll) and 9.03 g (92 mmol) potassium acetate are given in 180 mL THF which has been degassed for 10'. The reaction mixture is heated at reflux until the starting material has disappeared (usually two hours). At 60 °C the reaction mixture turns dark. The reaction mixture is poured on water (200 ml_) and ethyl acetate (500 ml_) is added. The mixture is vigorously stirred for two hours. After separation of the organic phase the aqueous phase is extracted once more with ethyl acetate (300 ml_). The combined organic extracts are washed with brine and dried (sodium sulfate). After evaporation of the solvent the residue, a black oil, is purified by chromatography on silicagel (eluents: hexane/ ethyl acetate). 10.4 g (90.8percent) of the title compound are obtained.MS (ES+, M+1 ): 3741H-NMR (400 MHz, d6-DMSO): δ 7.61 (d, 2H), 7.55-7.65 (br. 1 H), 7.35 (d, 2H), 2.22-2.42 (m, 4H), 1 .88-2.02 (m, 1 H), 1 .65-1 .82 (m, 1 H), 1 .00-1 .38 (m, 21 H). |
87% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 80℃; for 10 h; Inert atmosphere | Potassium acetate (2.41 g) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.25 g) are sequentially added to a DMF (25 mL) solution of the product (3.21 g) of Reference Example 56(3), and the mixture was placed in a nitrogen atmosphere. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (360 mg) was added thereto, and the mixture was stirred at 80° C. for 10 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (3.20 g, yield: 87percent) as a colorless solid. 1H-NMR (CDCl3) δ: 7.79 (2H, d, J=8.0 Hz), 7.43 (2H, d, J=8.0 Hz), 5.07 (1H, br s), 2.59-2.31 (4H, m), 2.14-2.03 (1H, m), 1.90-1.78 (1H, m), 1.36 (9H, s), 1.34 (12H, s) ESI-MS m/z 374 (MH+) |
87% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In water; N,N-dimethyl-formamide at 80℃; for 10 h; Inert atmosphere | Reference Example 56(4) tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutylcarbamate Potassium acetate (2.41 g) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.25 g) are sequentially added to a DMF (25 mL) solution of the product (3.21 g) of Reference Example 56(3), and the mixture was placed in a nitrogen atmosphere. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (360 mg) was added thereto, and the mixture was stirred at 80°C for 10 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (3.20 g, yield: 87percent) as a colorless solid. 1H-NMR (CDCl3) δ: 7.79 (2H, d, J = 8.0 Hz), 7.43 (2H, d, J = 8.0 Hz), 5.07 (1H, br s), 2.59 - 2.31 (4H, m), 2.14 - 2.03 (1H, m), 1.90 - 1.78 (1H, m), 1.36 (9H, s), 1.34 (23H, s) ESI-MS m/z374 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium acetate In 1,4-dioxane at 80℃; for 2 h; Inert atmosphere | 1 ,1-Dimethylethyl 5-bromo-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (Preparation 53) (2.7g, 8.7 mmol), potassium acetate (2.55g, 26 mmol), [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.63g, 0.87 mmol) and 4.4.4'.4'.5.5.5'.5'-octamethyl-2.2'-bi-1 .3,2-dioxaborolane (4.39g, 17 mmol) were dissolved in 1 ,4-dioxane (40ml), stirred at 800C under nitrogen for 2h and allowed to cool. Water (30ml) was added and the mixture was extracted with ethyl acetate (3x 20ml).The combined organic phases were concentrated in vacuo. Purification of the residue by flash chromatography (ethyl acetate in cyclohexane 15percent) gave 1 ,1- dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1 H)- isoquinolinecarboxylate as a clear gel (3.25g, 105percent). LCMS (Method formate): Retention time 1.51 min, MH+ = 360 |
89% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 90℃; Inert atmosphere | A mixture of tert-butyl 5-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (0.500 g, 1.60 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.488 g, 1.92 mmol) in DMF (8 mL) was subjected to 3 evacuate-fill cycles with nitrogen. Potassium acetate (0.472 g, 4.80 mmol) and PdCi2(dppf) DCM complex (0.117 g, 0.160 mmol) were added, the mixture was subjected to 2 more evacuate-fill cycles with nitrogen, and heated 90 °C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with EtOAc, washed sequentially with water, 10percent aqueous LiCl and saturated brine, dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes, to provide tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(17i)- carboxylate as a white solid (0.514 g, 89percent yield). Mass spectrum m/z 360 (M+H)+. |
57% | With potassium acetate In 1,4-dioxane at 80℃; for 2 h; Inert atmosphere | 1 ,1-Dimethylethyl 5-bromo-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 27) (0.281 g, 0.899 mmol), potassium acetate (0.265 g, 2.70 mmol), [1,f- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.066 g, 0.090 mmol) and 4i4i4li4Ii5,5,5',5'-octamethyl-2,2'-bi-1I3,2-dioxaborolane (0.274 g, 1.079 mmol) were dissolved in 1 ,4-dioxane (5 ml) and the resulting mixture was stirred at 800C under nitrogen for 2 hours then cooled to room temperature and diluted with water (15 ml). The aqueous phase was extracted with AcOEt (3 x 10 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (c-Hexane/AcOEt: 15percent) gave 1,1- dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1 H)- isoquinolinecarboxylate 158 mg, 57percent) as a light yellow oil. LCMS: retention time 1.54 min; no mass ion detected. |
15.45 g | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos In 1,4-dioxane at 120℃; for 48 h; Inert atmosphere | Intermediate E: tert-Butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinoline-2(lH)-carboxylate A solution of tert-butyl 5-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (20.00 g, 64.1 mmol), bis(pinacolato)diboron (Boron Molecular, Research Triangle, NC, 24.40 g, 96 mmol), potassium phosphate (40.8 g, 192 mmol), Pd2(dba)3 (Sigma- Aldrich, St. Louis, MO, 0.750 g, 3.20 mmol) and X-Phos (Strem Chemicals Inc., Newburyport, MA, 7.63 g, 16.02 mmol) in 100 mL dioxane was placed under argon and was heated to 120 °C for 48 hours. LC/MS showed mostly product, so the reaction mixture was allowed to cool to room temperature, diluted with diethyl ether, and filtered through a plug of diatomaceous earth eluting with diethyl ether. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (0 to 15percent EA in heaxanes) to provide tert-butyl 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate (15.45 g, 43.0 mmol) as a light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.56 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane; dimethyl sulfoxide at 90℃; for 3 h; Inert atmosphere; Sealed tube | Step 1: 2-(Methylsulfonyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine In a pressure vessel equipped with a magnetic stirring bar was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(l,3,2-dioxaborolane) (1.291 g, 5.08 mmol) and 5- bromo-2-(methylsulfonyl)pyridine (1 g, 4.24 mmol). The solids were suspended in dioxane (15 mL) and DMSO (0.5 mL). Potassium acetate (0.831 g, 8.47 mmol) was added and the reaction mixture was degassed with argon with sonication for 5 min. PdCl2(dppf)-CH2Cl2 adduct (0.173 g, 0.212 mmol) was added. The vessel was capped and heated within an oil bath for 3 h at 90°C. After 3 h, the reaction was cooled to room temperature while stirring. The reaction mixture was filtered, and the filtrate was concentrated. The aqueous layer was diluted with water and was extracted with ethyl acetate. Brine was used to help break up layers. The organic layer was dried over MgS04, filtered and concentrated under vacuum to give 1.56 g of a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.3% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 3 h; Sealed tube; Inert atmosphere | To a solution of 10 (1.00 g, 4.17 mmol) in dry degassed l,4-dioxane (15 mL) was added bis(pinacolato)diboron (1.27 g, 5.00 mmol), potassium acetate (1.35 g, 13.75 mmol), and Pd(dppf)Cl2 (0.26 g, 0.35 mmol). The reaction mixture was heated at 80 °C for 3 h in a sealed tube under argon. The reaction mixture was filtered through silica gel flash column with CH2Cl2 and the organic layer was evaporated under reduced pressure, and the residue was washed with n-hexane to obtain the title compound (1.03 g, 86.3 percent). 1H-NMR (400 MHz, CDCl3) δ: 9.14 (s, 1H), 8.30 (m, 2H), 4.48 (s, 3H), 1.38 (s, 12H). |
66% | With potassium acetate In dimethyl sulfoxide at 80℃; for 2 h; | To the solution of 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (480 mg, 2 mmol) in DMSO (5 mL) was added pinacol diborane (1.02 g, 4 mmol), KOAc (588 mg, 6 mmol) and PdCl2(dppf)DCM (160 mg, 0.2 mmol), degassed with N2. The mixture was stirred at 80 0C for 2 h. The reaction mixture was diluted with DCM (100 mL) and washed with brine (2 x 100 mL), dried (Na2SO4) and evaporated under vacuum, then purified by prep-TLC (hexanes - EtOAc) to give 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine as white solid (380 mg, 66percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium acetate In dichloromethane; dimethyl sulfoxide at 80℃; | Example 46; 6-(2,3-Dihydro-1H-indol-5-yl)-4-morpholin-4-yl-1-(1-pyridin-3-ylmethyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (Scheme 36)1 mmol (198 mg) 5-bromoindoline, 1.5 mmol (381 mg) bispinacolatodiboron, 0.1 mmol (73 mg) Pd(dppf)Cl2.CH2Cl2 and 3 mmol (296 mg) KOAc are suspended in DMSO and heated at 80 C overnight. The mixture is diluted with EtOAc, filtered over Celite and concentrated. Flash chromatography (5-20percent EtOAc in hexanes) gave 69 mg (28percent) of the boronate. This was added to a solution of 50 mg 6-Chloro-4-morpholin-4-yl-1-(1-pyridin-3-ylmethyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine in 2 mL DME and 250 uL of a 2M Na2CO3 solution. 10 mol percent Pd(PP3)4 was added and the mixture was stirred at 95C overnight. The solvents were removed and the product was purified by HPLC (TFA buffers). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 150℃; for 4 h; Inert atmosphere | Compound I-23 (120 g, 388 mmol) in a nitrogen environment, dimethylforamide (DMF) was dissolved in 1.2 L, here bis (pinacolato) diboron (118 g, 466 mmol) and (1,1'-bis (diphenylphosphine) ferrocenedichloropalladium (II) (3.17 g, 3.88 mmol) and into a potassium acetate (114g, 1,164 mmol) was heated to reflux for 4 hours at 150 . After the reaction was completed, the reaction solution into water and then filter the mixture, and dried in a vacuum oven. Thus separated and purified the resulting residue was purified by flash columnchromatography to compound I-24 (124 g, 90percent) was obtained. |
82% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 150℃; for 12 h; Inert atmosphere | Synthesis Example 29: Synthesis of Intermediate I-29 4-bromo-p-terphenyl (50 g, 162 mmol, TCI) was dissolved in dimethylforamide (DMF, 1 L) under a nitrogen environment, bis(pinacolato)diboron (49 g, 194 mmol), (1,1′-bis(diphenylphosphine)ferrocene)dichloropalladium (II) (1.3 g, 1.62 mmol), and potassium acetate (40 g, 405 mmol) were added thereto, and the mixture was heated and refluxed at 150° C. for 12 hours. When the reaction was complete, water was added to the reaction solution, and the mixture was filtered and dried in a vacuum oven. This obtained residue was separated and purified through flash column chromatography to obtain Compound I-29 (47 g and 82percent). HRMS (70 eV, EI+): m/z calcd for C24H25BO2: 356.1948. found: 356. Elemental Analysis: C, 81percent; H, 7percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 90℃; Inert atmosphere | 3.1.1. Preparation of (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (934-2) At 90° C. under N2 atmosphere, to a stirred solution of 4-bromo-2-fluorophenylmethanol (500 mg, 2.44 mmol) in dioxane (5 mL) were added B2Pin2 (929 mg, 3.66 mmol), Pd(dppf)Cl2.DCM (198 mg, 0.24 mmol) and KOAc (717 mg, 7.32 mmol). After being stirred at 90° C. overnight, the reaction mixture was cooled down to room temperature and partitioned between EA and H2O. The layers were separated and the organic layer was washed with brine, dried over Na2SO4. Solvents were removed under vacuum and the residue was purified by flash chromatography (silica gel, 0˜20 ethyl acetate in petroleum ether) to provide (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (934-2) (300 mg, 48percent) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium acetate In 1,4-dioxane for 2 h; Reflux | The mixture of 5-bromo-2-methoxy-3-nitropyridine (5 g, 21 .5 mmol),4,4,4',4',5,5,5',5' -octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (6.6 g, 25.8 mmol) ,PdCl2(dppf)-CH2Cl2 (500 mg) and potassium acetate (6.3 g, 64.5 mmol) in anhydrous 1 ,4-dioxane (200 ml_) was refluxed for 2h. Then the solvents were removed. The crude product was purified by chromatography on silica gel using petroleumether:EtOAc =10:1 as eluent to afford 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine in 81 percent yield (5 g). m/z 281 (M+H)+. |
81% | With palladium dichloro <1,1'-bis(diphenylphosphino)ferrocene>; potassium acetate In 1,4-dioxane for 2 h; Reflux | The mixture of 5-bromo-2-methoxy-3-nitropyridine (5 g, 21.5 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.6 g, 25.8 mmol), PdCl2(dppf)-CH2Cl2 (500 mg) and potassium acetate (6.3 g, 64.5 mmol) in anhydrous 1,4-dioxane (200 mL) was refluxed for 2 h. Then the solvents were removed. The crude product was purified by chromatography on silica gel using petroleum ether:EtOAc=10:1 as eluent to afford 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in 81percent yield (5 g). m/z 281 (M+H)+. |
80% | With potassium acetate In N,N-dimethyl-formamide at 80℃; | AL 2-Methoxy-3-nitro-5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridine; To a dry flask was added 5-bromo-2-methoxy-3-nitropyridine (1.3 g, 5.0 mmol),4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.6 g, 6.4 mmol), and Pd(dppf)Cl2 (0.2 g, 0.25 mmol). Potassium acetate (1.5 g, 15 mmol) was weighed directly into the flask. The flask was then evacuated and back filled with N2. Anhydrous N,N-dimethylformamide (30 mL) was added and the reaction was heated at 80 0C in an oil bath overnight. The reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting material was purified by silica gel chromatography (eluting with 0-50percent ethyl acetate in hexane) to yield the product (0.2 g, 15percent). ESI-MS m/z calc. 280.12, found 199.1 (MW[-C6Hio]+l)+. Retention time 0.7 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With potassium acetate In N,N-dimethyl-formamide at 80℃; | AH. Methyl 2-methoxy-5-(4 A5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2- <n="105"/>vDnicotinate; To a dry flask was added methyl 5-bromo-2-methoxynicotinate (0.5 g, 2.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.61 g, 2.4 mmol), and Pd(dppf)Cl2 (82 mg, 0.10 mmol). Potassium acetate (0.6 g, 6.0 mmol) was weighed directly into the flask. The flask was then evacuated and back filled with N2. Anhydrous N,N- dimethylformamide (10.0 mL) was added and the reaction was heated at 80 0C in an oil bath overnight. The reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (10 mL) and washed with water (1OmL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting material was purified by silica gel chromatography (eluting with 0-70percent ethyl acetate in hexanes) to yield the product (0.36 g, 72percent). ESI-MS m/z calc. 249.11, found 250.3 (MW+1)+. Retention time 1.84 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 80℃; for 10 h; Inert atmosphere | To a solution of 4-bromo-1-(oxan-4-yl)-1H-pyrazole (1.0 g, 4.33 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 38 (1.32 g, 5.19 mmol) in 10 ml of DMF was added potassium acetate (1.27 g, 12.98 mmol), followed by 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (177 mg, 0.22 mmol) under argon. The resulting mixture was stirred at 80 0C for 10 h and then diluted with 40 ml of water. The mixture was extracted with EA (30 ml × 3). The combined organic phase was washed with water (30 ml × 3), brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EA/PE, 1/4) to afford 39 as a white solid in 68percent yield. NMR (300 MHz, CDCl3) δ 7.80 (s, 1H), 7.75 (s, 1H), 4.42-4.31 (m, 1H), 4.12-4.07 (m, 2H), 3.57-3.49 (m, 2H), 2.13-1.99 (m, 4H), 1.32 (s, 12H). |
68% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 80℃; for 10 h; Inert atmosphere | To a solution of 4-bromo-1-(oxan-4-yl)-1H-pyrazole 26a (1.00 g, 4.33 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.32 g, 5.19 mmol) in 10 mL of DMF was added potassium acetate (1.27 g, 12.98 mmol), followed by 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (177 mg, 0.22 mmol) under argon. The resulting mixture was stirred at 80 °C for 10 h and then diluted with 40 mL of water. The mixture was extracted with EA (3 × 30 mL). The combined organic phase was washed with water (3 × 30 mL), brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EA/PE, 1:4) to afford 25c as white solid in 68percent yield. 1H NMR (300 MHz, CDCl3) δ 7.80 (s, 1H), 7.75 (s, 1H), 4.42-4.31 (m, 1H), 4.12-4.07 (m, 2H), 3.57-3.49 (m, 2H), 2.13-1.99 (m, 4H), 1.32 (s, 12H). |
19% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 90℃; | C. To a solution of 4-bromo-l-(tetrahydro-2H-pyran-4-yl)-lH- pyrazole (2.90 g, 12.6 mmol) in dimethyl sulfoxide (25 mL) was added potassium acetate (4.94 g, 50.4 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (6.40 g, 25.2 mmol). The mixture was degassed for 10 min, and then [l, -bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.922 g, 1.26 mmol) was added. The mixture was degassed for another 10 minutes and heated at 90 °C overnight, diluted with ethyl acetate (80 mL), washed with water (2 x 20 mL), brine (20 mL), dried and filtered. The solvent of the filtrate was removed and the residue was purified by flash column chromatography eluted with 20percent ethyl acetate in hexanes to afford l-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (0.66 g, 19percent) as a white solid. 1H NMR (400 Hz, CDCls) δ 7.81 (s, 1H), 7.76 (s, 1H), 4.42-4.32 (m, 1H), 4.14-4.06 (m, 2H), 3.58-3.50 (m, 2H), 2.16-1.98 (m, 4H), 1.32 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In dimethyl sulfoxide at 80℃; for 2 h; Inert atmosphere | General procedure: The compoundTert-Butyl 4- (4-iodo-1H-pyrazol-1- yl) nicardine- 1 -carboxylate (1.00 g, 2.650 mmol)Dissolved in DMSO (llmL)Then, bis (pinacolato) diboron (942.5 mg, 3.710 mmol)And CH3C00K (1.04 g, 10.60 mmol),After pumping gas (N2) three times,Pd (PPh3) 2Cl2 (93.0 mg, 0.130 mmol) was added.After the reaction was stirred at 80 ° C for 2 hours,The mixture was cooled to room temperature and filtered off with suction. The filtrate was washed with brine (100 mL × 3), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) The title compound was obtained as a white solid (878.6 mg, 87.9percent).The title compound was prepared according to the procedure described in Example 1, Step 3, 4-Iodo-1- (tetrahydro-211-pyran-4-yl) -1H-pyrazole was used (278 mg, 1.0 mmol), Bis (pinacolato) diboron (355 mg, 1.4 mmol), CH30Κ (392 mg, 4.0 mmol) and Pd (dppf) CI2 · CH2Cl2 (82 mg, 0.1 mmol) Prepared. The crude product was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) The title compound was purified as a brown solid (225 mg, 81percent). |
38.5% | With potassium acetate In dimethyl sulfoxide at 95℃; for 16 h; Inert atmosphere | As shown in step 2-iii of Scheme 2, a mixture of 1 -(tetrahydro-2H-pyran-4-yl)-4- iodo-lH-pyrazole (Compound 1011, 1.0 g, 3.60 mmol), potassium acetate (776 mg, 7.91 mmol), and bis(pinacol)diboron (1.37 g, 5.39 mmol) in DMSO was flushed with nitrogen for 30 minutes. Tetrakis(triphenylphosphine)palladium (0) (623.3 mg, 0.539 mmol) was added and the reaction heated at 95°C for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through a plug of Florisil.(R)., which was subsequently washed with EtOAc/hexanes. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography (0-50percent EtOAc/hexanes) to provide 1- (tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazole as a while solid (Compound 1012, 385 mg, 38.5percent yield): 1H NMR (300 MHz, CDCl3) δ 7.80 (s, IH), 7.75 (s, IH), 4.36 (m, IH), 4.08 (d, 2H), 3.57 (t, 2H), 2.08 (m, 4H), 1.32 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.5% | With potassium acetate In dimethyl sulfoxide at 80℃; for 4 h; | A mixture of tert-butyl 4-(4-bromo-3-methyl-pyrazol-l-yl)piperidine-l-carboxylate (2.7 g), 4,4,4',4>,5,5,5>,5>-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (4.98 g), 1,1 '- bis(diphenylphosphino)ferrocenedichloropalladium(II) - CH2Cl2 adduct (0.634 g) and potassium acetate (2.31 g) in DMSO (40 ml) was stirred at 80 0C for 4 hours. The reaction mixture was allowed to cool to room temperature under stirring over a period of 1 hour, quenched with water (25 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic phases were washed with water (3 x 30 ml), brine (1 x 20 ml), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 10 to 30percent ethyl acetate in petroleum ether to afford tert-butyl 4-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol- l-yl)piperidine-l-carboxylate (0.937 g, 30.5 percent) as a white solid. NMR Spectrum(DMSOd): 1.24 (s, 12H), 1.41 (s, 9H), 1.71 (dd, IH), 1.76 (dd, IH), 1.89-1.96 (m, 2H), 2.22 (s, 3H), 2.85 (bs, 2H), 3.95-4.07 (m, 2H), 4.20-4.29 (m, IH), 7.82 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; tricyclohexylphosphine In 1,4-dioxane at 110℃; Sealed tube | A solution of 5-bromopyridin-2-ol SM1 (0.1 g, 0.57 mmol), 4,4,4,4,5,5,5,5-octamethyl- 2,2-bi(1,3,2-dioxaborolane) SM2 (0.88 g, 3.45 mmol), Tricyclohexyl phosphine (0.032 g, 0.114mmol), Pd2(dba)3 (0.052 g, 0.057 mmol) and KOAc (0.17 g, 1.71 mmol) dissolved with dioxane (10 mL) in sealed tube was stirred at 110 °C overnight. After consumption of the starting material (by LC-MS), the solvent from reaction mixture was removed under reduced pressure, the residue was diluted with brine and extracted with EtOAc. Combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain cmde product, which waspurified by silica gel column chromatography to afford compound 3 (0.08 g, 64percent) as a black liquid.TLC: 50percent EA/PE. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium acetate In 1,4-dioxane at 120℃; for 0.666667 h; microwave irradiation | A mixture of 5-bromo-3-pyridinesulfonamide (6.33 mmol), bis(pinacolato)diboron (6.96 mmol), potassium acetate (18.99 mmol), and dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.32 mmol) in 1,4-dioxane (15 mL) was irradiated in the microwave at 120 0C for 40 min. The reaction was filtered through Celite, washed with dioxane, and the filtrate was concentrated in vacuo to provide the title compound as a brown solid (quantitative). MS(ES)+ m/e 203 [M+H]+ for acid. Alternatively, the residue can be purified by trituration in dichloromethane to give a light brown solid. IH NMR (400 MHz, DMSO-J6) δ ppm 8.76 (s, 2 H), 8.22 (s, 1 H), 7.45 (br s, 2 H), 1.13 (s, 12 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: With potassium acetate In 1,4-dioxane for 0.25 h; Stage #2: at 100℃; for 20 h; |
3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-pyridine A suspension of 3.50 g (15.50 mmol) of 3-bromo-5-trifluoromethyl-pyridine, 0.54 g (0.8 mmol) of bis(triphenylphosphine)palladium(II) chloride and 4.55 g (46.5 mmol) of potassium acetate in 75 ml of dioxane was stirred for 15 min; then, 6.42 g (24.8 mmol) of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl](bis-pinacolatodiboron) was added and the mixture was heated up to 100° C. After 20 hours, it was poured into crashed ice, the pH was adjusted to 9-10 with sodium carbonate solution and the mixture then extracted three times with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 3.48 g (82percent) of the title compound as a colorless solid. MS: 273.1 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 115℃; Inert atmosphere | To a mixture of 3- (4-bromo-1H-pyrazol-1-yl) propanenitrile (20.00 mmol, 4.00 g) , bis (pinacolato) diboron (6.00 g, 23.63 mmol) , Pd (dppf) Cl2(0.74 g, 1.00 mmol) and potassium acetate (4.00 g, 39.53 mmol) was added 1, 4-dioxane (40 mL) via syringe under N2. The mixture was stirred at 115 overnight. The mixture was cooled to rt and filtered through a Celite pad. The filter cake was washed with DCM. The combined filtrates were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 2/1 to give a light yellow oily product (1.80 g, 36.0, containing bis (pinacolato) diboron) .[0848]MS (ESI, pos. ion) m/z: 248.1 [M+1]+ and[0849]1H NMR (600 MHz, DMSO-d6) : δ (ppm) 8.03 (s, 1H) , 7.80 (d, J 2.2 Hz, 1H) , 7.66 (s, 1H) , 7.51 (d, J 1.6 Hz, 1H) , 6.28 (t, J 2.0 Hz, 1H) , 4.40 (dt, J1 9.5 Hz, J2 6.4 Hz, 4H) , 3.06 (dt, J1 13.0 Hz, J2 6.4 Hz, 4H) , 1.26 (s, 12H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With potassium acetate In 1,4-dioxane for 0.5 h; Inert atmosphere; Sealed tube Stage #2: at 100℃; |
A 100 mL sealed tube was charged with 4-(4-bromophenyl)pyridine (0.9 g, 3.8mmol), bis(pinacolato)diboron (1.17 g, 4.61 mmol), potassium acetate (0.745 g, 7.6mmol) and 1-4 dioxane (10 mL). The reaction mixture was purged with argon for 30mm. Then, Pd(dppf)C12 (0.75 g, 0.05 eq) was added and heated at 100 00 over night.After cooing, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuo to yield crude product, which was purified by combif lash to yield title compound (1.0 g, 100.0percent). LCMS: (M+H) = 282.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With potassium acetate In dimethyl sulfoxide at 85℃; for 3 h; Inert atmosphere | A mixture of 5-bromobenzo[c/|thiazole (428 mg, 2.00 mmol), bis(pinacolato)diboron (558 mg, 2.20 mmol) and potassium acetate (588 mg, 6.00 mmol) in dimethyl sulfoxide (7 mL) was sparged with nitrogen while stirring for 5 min. Dichloro 1 ,1-bis(diphenylphosphino)ferrocene palladium(ll) dichloromethane (293 mg, 0.40 mmol) was then added and the reaction stirred at 85 0C for 3 h. After this time, the mixture was filtered through a pad of Celite and the filter cake was washed with ethyl acetate (75 mL) then water (20 mL). The filtrate was diluted with ethyl acetate (100 mL) and washed with water (2 x 75 ml_), then brine (75 ml_). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica, gradient 0percent to 50percent ethyl acetate in methylene chloride) to afford 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzo[d]thiazole (3) (200 mg, 38percent) as a light brown solid: 1H NMR (300 MHz, DMSO-cfe) δ 9.41 (s, 1 H), 8.32 (s, 1 H), 8.18 (d, 1 H, J = 8.0 Hz), 7.72 (d, 1 H, J = 8.0 Hz), 1.33 (s, 12H); ESI MS m/z 262.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium 2-ethylhexanoic acid In 1,4-dioxane at 110℃; for 4 h; Inert atmosphere | To a solution of 5-bromo-1-methyl-1H-benzo[dlimmdazole (1.0 g, 4.74 mmol) indioxane (10 mL) were added 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (1.5 g,5.68 mmol), sodium 2-ethylhexanoate (1.968 g, 11.86 mmol) and Pd(dppf)C12.DCM (247 mg,0.474 mmol) under N2. The mixture was stirred at 110 °C for 4 h, poured into H20 (60 mL) andextracted with EA (50 mL x 2). The organic layers were dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column chromatography (PE/EA = 1/1) to afford 1 -methyl-S -(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-benzo[d]imidazole (1.0 g, 82 percent) as a yellow solid. LC-MS m/z: 259.1 [M+Hf’. tR= 1.67 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.6% | With potassium acetate In dimethyl sulfoxide at 150℃; for 2.33333 h; Microwave irradiation | Step 5:A suspension of 5-bromo-3-methyl-1 H-pyrazolo[3,4-b]pyridine (1.04 g, 40.987mmol), bis(pinacolato)diboron (1.93 g, 7.45 mmol, 1.5 Eq), potassium acetate (1.66 g, 16.9mmol, 3.04 Eq) and [1 ,1 '-Bis(diphenylphophino)ferrocene]palladium(ll) dichloride dichlroromethane complex (1 :1 )(0.109 g, 0.149 mmol, 0.03 Eq) in 10 mL anhydrous DMSO was degassed by bubbling nitrogen via needle for 20 min. The reaction was then heated in a microwave reactor at 15O0C for 2 hours (high absorption). After this time, the reaction was cooled to room temperature and then poured in H2O (200 ML) and EtOAc (200 <n="56"/>mL). The bi-layered mixture was filtered through compacted celite and the filtrate was dried over Na2SO4 and concentrated in vacuo to a dark oil which was purified by biotage column (Si 40 + M); packed with hexanes; eluted with EtOAc/Hexanes (0-30percent: 900 mL, 30-30percent: 900 ml_, 30-50percent; 900 mL, 27 mL fractions) to afford the product as a white solid (1.19 g, 93.6percent). 1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.88 (d, J=1.51 Hz, 1 H) 8.51 (d, J=1.51 Hz, 1 H) 2.60 (s, 3 H) 1.30 (s, 6 H) 1.25 (s, 6 H); NH not seen in NMR. |
28.95% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 100℃; for 4 h; Inert atmosphere | Step 3: 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazolo[3,4-b]pyridine To a solution of 5-bromo-3-methyl-lH-pyrazolo[3,4-b]pyridine (25 g, 0.12 mol) in dimethylsulphoxide (500 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (46 g, 0.18 mmol) and potassium acetate (35.3 g, 0.36 mmol) and the mixture was degassed (3 times). To the reaction mixture was added l,l '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (9.8 g, 0.012 mol) and the mixture was degassed (3 times). The reaction mixture was stirred at 100 °C under nitrogen for 4 h. The reaction mixture was cooled to RT and then poured in water (lOOOmL) and ethyl acetate (500 mL). The bi-layered mixture was filtered through celite, the organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 5percent to 6percent ethyl acetate in petroleum ether) affording 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazolo[3,4-b]pyridine (9 g, 28.95 percent): H NMR (400 MHz, Chloroform-d): δ 8.90 (s, 1H), 8.49 (s, 1H), 2.59 (s, 3H), 1.38 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.9% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate In dichloromethane at 100℃; for 3 h; Inert atmosphere | P3Br 26.60G (86.03Mmol, 1.0Eq.), Bis pinacolate diboronic 103.23g (1.2eq.), Potassium acetate 25.33g (3eq.) And bis (diphenylphosphino)ferrocenepalladium (II) were weighed dichloride dichloromethane complex 2.11g of (0.03 eq) in 1L three neck round bottom flask, sufficiently reduced pressure after degassing and nitrogen substitution, cyclopentyl methyl ether 300mL under a nitrogen atmosphere It was added, followed by reflux and stirring at 100 .After 3 hours, stopped heating, the reaction mixture was returned to room temperature.After extraction three times with toluene, the combined organic solvent layer, anhydrous sodium sulfate was added and left for a while.Filtration of the sodium sulphate, the solution was concentrated under reduced pressure.The resulting oil using toluene as eluent leads to activated charcoal column chromatography, it was collected, concentrated under reduced pressure The fractions containing the desired product.The resulting yellow oil was dissolved in hot methanol and cooled with ice after standing at room temperature.The purpose of the precipitated needle-shaped crystals "P3Bpin" were collected (yield: 28.48g, yield: 92.9percent). |
92.9% | at 100℃; for 3 h; Inert atmosphere | P3Br (26.60 g, 86.03 mmol, 1.0 eq.), bispinacolato diboron (103.23 g, 1.2 eq.), potassium acetate (25.33 g, 3 eq.), and a bis(diphenylphosphino) ferrocene-palladium(II) dichloride dichloromethane complex (2.11 g, 0.03 eq.) were weighed and put into a 1 L three-necked round bottom flask. Degassing under reduced pressure and nitrogen purge were sufficiently performed. Thereafter, cyclopentyl methyl ether (300 mL) was added thereto in a nitrogen atmosphere, and the mixture was refluxed and stirred at 100° C. After three hours, heating was stopped, and the temperature of the reaction liquid was returned to room temperature. Extraction was performed with toluene three times, the organic solvent layers were then unified, anhydrous sodium sulfate was added thereto, and the mixture was allowed to stand for a while. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The resulting oil was caused to pass through an activated carbon column chromatography using toluene as an eluent, and a fraction containing a desired product was collected and concentrated under reduced pressure. The resulting yellow oil was dissolved in hot methanol, was allowed to stand at room temperature, and was then cooled with ice. A desired product “P3Bpin” of precipitated acicular crystals was collected (yield: 28.48 g, yield: 92.9percent). |
90% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 150℃; for 4 h; Inert atmosphere | Nitrogen environment at the intermediate I-1 (140 g, 453 mmol) dmf dimethylformamide (DMF) 3 L and then dissolved in, here the bis (pinacolato) diboron (138 g, 543 mmol) and (1,1 'bis (diphenylphosphine) ferrocene ) dichloropalladium (II) (3.70 g, 4.53 mmol) and into a potassium acetate (133g, 1,359 mmol) was heated to reflux for 4 hours at 150 . After the reaction was completed, the reaction solution into water and then filter the mixture, and dried in a vacuum oven. The thus obtained residue was purified by flash column chromatography purification Intermediate I-22 (145 g, 90percent) as to obtain a. |
82% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 150℃; for 12 h; Inert atmosphere | Inthe nitrogen ambient, after intermediate I-1s (50 g, 162 mmol) were melted inthe dimethylforamide (DMF) 1L here bis (pinacolato) diborons (49 g, 194 mmol),(1,1'-bis(diphenylphosphine)ferrocene) dichloropalladium (II)(Pd(dppf)Cl(sub)2(/sub)) (1.3 g, 1.62 mmol) and potassium acetate (KOAc) (40 g,405 mmol) were put and 150 heated for 12 hours and itrefluxed. After water wasput in into the reaction solution after the reaction completion and the mixturewas filtered it dried in the vacuum oven. The residue obtained in this way wasrefined to the flash column chromatography after dividing and intermediate I-2s(47 g, 82 percent) were obtained. |
79% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In toluene for 10 h; Inert atmosphere; Reflux | 50.0 g (161.71 mmol) of the intermediate 3-bromo-1,1 ': 3,1'-terphenyl, 53.38 g (210.22 mmol) of bis pinacolato diboron, 47.61 g (485.12 mmol) of potassium acetate,14.59 g (12.62 mmol) of Pd (dppf) Cl2 was added to 580 mL of tolueneAnd the mixture was heated under reflux in a nitrogen stream for 10 hours. The resulting mixture was added to 1500 mL of methanol, and the crystallized solid was filtered, and the filtrate was washed with dichloromethane silica gel / celite. An organic solvent was removed in an appropriate amount and then recrystallized with a nucleic acid to obtain a compound L-4 (45.6 g, 79 percent Yield). The result of the analysis of the produced compound L-4 is shown below. |
71% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 150℃; for 6 h; Inert atmosphere | 130 g (420 mmol) of the intermediate I-4 was dissolved in 1.3 L of dimethylforamide (DMF) under a nitrogen environment, 128 g (505 mmol) of bis(pinacolato)diboron, 3.43 g (4.2 mmol) of (1,1'-bis(diphenylphosphine)ferrocene)dichloropalladium (II) and 124 g (1,260 mmol) of potassium acetate were added thereto, and the mixture was heated and refluxed at 150° C for 6 hours. When the reaction was terminated, water was added to the reaction solution, and the mixture was filtered and dried in a vacuum oven. Then, the obtained residue was separated and purified through flash column chromatography, obtaining 106 g of an intermediate I-5 (a yield: 71 percent). (0106) HRMS (70 eV, EI+): m/z calcd for C24H25BO2: 356.1948, found: 356. (0107) Elemental Analysis: C, 81 percent; H, 7 percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 150℃; for 48 h; | Intermediate I-3 (130 g, 491 mmol) was dissolved in dimethylforamide (DMF)After dissolving in 1.4 L, bis (pinacolato) diboron (150 g, 589 mmol) and(1,1'-bis (diphenylphosphine) ferrocene) dichloropalladium (II) (4.01 g, 4.91 mmol) Potassium acetate (145 g, 1.473 mmol) was added and the mixture was stirred at 150 ° C for 48 hours And heated to reflux. After completion of the reaction, water was added to the reaction solution, the mixture was filtered,And dried in a vacuum oven. The residue thus obtained was purified by flash column chromatographyTo obtain Intermediate I-4 (119 g, 68percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With potassium acetate In 1,4-dioxane at 80℃; for 21 h; | A dioxane (16.5 mL) solution of 4-bromo-2,6-difluorobenzoic acid (0.4 g, 1.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.5 g, 2.0 mmol), PdCl2(dppf) (0.12 g, 0.17 mmol) and potassium acetate (0.49 g, 4.9 mmol) was placed in a sealed vial and degassed by vacuum-N2 refill cycle twice. The mixture was heated to 80° C. for 21 h, cooled to room temperature and filtered through a short bed of silica gel. The filtrate was concentrated and purified by flash column chromatography (ISCO 12 g silica gel cartridge, 20-100percent ethyl acetate-hexanes) to give the expected product as a brown oil (0.11 g, 19percent). MS (ES-) m/z: 283 (M-H); LC retention time: 1.48 min (Analytical HPLC Method D). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.9% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate In 1,4-dioxane at 80℃; for 6 h; Inert atmosphere | A solution of 4 (1.68 g, 8.8 mmol), bis(pinacolato)diboron (3.4 g, 13.2 mmol), PdCl2(dppf) (756 mg, 0.88 mmol), and KOAc (2.587 g, 26.4 mmol) in degassed 1,4-dioxane (60 ml) was stirred at 80 °C for 6 h under N2. The reaction was quenched by adding water, and extracted by dichloromethane. The organic phase was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum/dichloromethane=1/3) to give compound 5 (1.86 g, 88.9percent) as yellow solid. Mp: 73 °C. MS(EI): m/z=238 (M+). 1H NMR (CDCl3, 400 M Hz) δ/ppm: 9.92 (s, 1H), 7.73 (d, H), 7.43 (d, 1H), 1.34 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 110℃; for 16 h; Inert atmosphere | A mixture of 2 (303 mg, 1 mmol), bis(pinacolato)diboron (370 mg, 1.5 mmol), KOAc (400 mg, 4 mmol) and Pd(dppf)Ci2 (10 mg, 0.05 mmol) in dioxane (5 mL) under 2 was heated to 110 °C for 16 h. After cooled to rt, the mixture was partitioned between EtOAc (10 mL) and aHC03 (10 mL). The aqueous phase was extracted with EA (10 mL*2). The combined organic phases were washed with brine, dried over MgS04, filtered, concentrated and purified by flash chromatography (25percent EtOAc in petroleum) to provide the desired product (250 mg, 89percent). LRMS m/z (M+H), 281 found, 281 required. |
70% | With 1,1'-bis-(diphenylphosphino)ferrocene; potassium acetate In 1,4-dioxane at 90℃; for 18 h; Inert atmosphere | Intermediate of Formula (VI)(RS)-4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclohex-3-enecarboxylic acid ethyl ester A mixture of (RS)-4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid ethyl ester (3.0 g, 9.92 mmol), potassium acetate (2.92 g, 29.8 mmol) and bis(pinacolato)diboron (3.78 g, 14.9 mmol) in 1,4-dioxane (30 ml) was purged with argon. Addition of 1,1'-bis(diphenylphosphino)ferrocene (0.17 g, 0.30 mmol) and dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct (0.22 g, 0.30 mmol) was followed by stirring at 90° C. for 18 h. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (150 ml). The layers were separated. The organic layer was washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (1.95 g, 70percent) as light yellow oil. MS m/e: 281 ([M+H]+) |
70% | With potassium acetate In 1,4-dioxane at 90℃; for 18 h; Inert atmosphere | Intermediate of Formula (VI)(RS)-4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclohex-3-enecarboxylic acid ethyl esterA mixture of (RS)-4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid ethyl ester (3.0 g, 9.92 mmol), potassium acetate (2.92 g, 29.8 mmol) and bis(pinacolato)diboron (3.78 g, 14.9 mmol) in 1,4-dioxane (30 ml) was purged with argon. Addition of 1,1'-bis(diphenylphosphino)ferrocene (0.17 g, 0.30 mmol) and dichloro(1,1'-bis(diphenylphosphino) ferrocene)palladium(II) dichloromethane adduct (0.22 g, 0.30 mmol) was followed by stirring at 90° C. for 18 h. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (150 ml). The layers were separated. The organic layer was washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (1.95 g, 70percent) as light yellow oil. MS m/e: 281 ([M+H]+) |
70% | With potassium acetate In 1,4-dioxane at 90℃; for 18 h; Inert atmosphere | A mixture of (RS)-4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid ethyl ester (3.0 g, 9.92 mmol), potassium acetate (2.92 g, 29.8 mmol) and bis(pinacolato)diboron (3.78 g, 14.9 mmol) in 1,4-dioxane (30 ml) was purged with argon. Addition of 1,1'- bis(diphenylphosphino)ferrocene (0.17 g, 0.30 mmol) and dichloro(l,l'- bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct (0.22 g, 0.30 mmol) was followed by stirring at 90 °C for 18 h. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (150 ml). The layers were separated. The organic layer was washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (1.95 g, 70percent) as light yellow oil. MS m/e: 281 ([M+H]+) |
70% | With potassium acetate In 1,4-dioxane at 90℃; for 18 h; Inert atmosphere | Intermediate of Formula (VI)(RS)-4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclohex-3-enecarboxylic acid ethyl ester A mixture of (RS)-4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid ethyl ester (3.0 g, 9.92 mmol), potassium acetate (2.92 g, 29.8 mmol) and bis(pinacolato)diboron (3.78 g, 14.9 mmol) in 1,4-dioxane (30 ml) was purged with argon. Addition of 1,1'-bis(diphenylphosphino)ferrocene (0.17 g, 0.30 mmol) and dichloro(1,1'-bis(diphenylphosphino) ferrocene)palladium(II) dichloromethane adduct (0.22 g, 0.30 mmol) was followed by stirring at 90° C. for 18 h. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (150 ml). The layers were separated. The organic layer was washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (1.95 g, 70percent) as light yellow oil. MS m/e: 281 ([M+H]+) |
70% | With potassium acetate In 1,4-dioxane at 90℃; for 18 h; Inert atmosphere | A mixture of (RS)-4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid ethyl ester (3.0 g, 9.92 mmol), potassium acetate (2.92 g, 29.8 mmol) and bis(pinacolato)diboron (3.78 g, 14.9 mmol) in 1,4-dioxane (30 ml) was purged with argon. Addition of Ι,Γ- bis(diphenylphosphino)ferrocene (0.17 g, 0.30 mmol) and dichloro(l,l'- bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct (0.22 g, 0.30 mmol) was followed by stirring at 90 °C for 18 h. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (150 ml). The layers were separated. The organic layer was washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (1.95 g, 70percent) as light yellow oil. MS m/e: 281 ([M+H]+) |
70% | With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 90℃; for 18 h; Inert atmosphere | Intermediate of formula (VI)(RS)-4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-cyclohex-3-enecarboxylic acid ethyl ester A mixture of (RS)-4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid ethyl ester (3.0 g, 9.92 mmol), potassium acetate (2.92 g, 29.8 mmol) and bis(pinacolato)diboron (3.78 g, 14.9 mmo l ) in 1 , 4-di o x an e ( 3 0 ml ) w a s p ur g e d with ar go n . A d diti o n o f 1 , 1 '-bis(diphenylphosphino)ferrocene (0.17 g, 0.30 mmol) and dichloro(l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct (0.22 g, 0.30 mmol) was followed by stirring at 90 °C for 18 h. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (150 ml). The layers were separated. The organic layer was washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (1.95 g, 70percent) as light yellow oil. MS m/e: 281 ([M+H]+) |
70% | With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 90℃; for 18 h; Inert atmosphere | (RS)-4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclohex-3-enecarboxylic acid ethyl ester A mixture of (RS)-4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid ethyl ester (3.0 g, 9.92 mmol), potassium acetate (2.92 g, 29.8 mmol) and bis(pinacolato)diboron (3.78 g, 14.9 mmol) in 1,4-dioxane (30 ml) was purged with argon. Addition of 1,1'-bis(diphenylphosphino)ferrocene (0.17 g, 0.30 mmol) and dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct (0.22 g, 0.30 mmol) was followed by stirring at 90° C. for 18 h. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (150 ml). The layers were separated. The organic layer was washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (1.95 g, 70percent) as light yellow oil. MS m/e: 281 ([M+H]+) |
67% | With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 2 h; Inert atmosphere | Step 2 Preparation of ethyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (i-llc).To a solution of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -enecarboxylate (i-i ib)(20 g, 66.2 mmol) in 1,4-dioxane (500 mL) was added bis(pinacolato)diboron (34 g, 132.4mmol) and potassium acetate (19 g, 198 mmol). The mixture was purged with nitrogen for 20minutes, Pd(dppf)C12 (4.9 g, 6.6 mmol) was added and the reaction was stirred at 100 °C for 2h. The resulting mixture was filtered over Celite and the filtrate was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1) to give the titlecompound (12 g, 67percent) as a yellow oil. LCMS (ESI) calc’d for C15H25B04 [M+H]: 281,found:281. |
67% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 2 h; Inert atmosphere | Step 2 Preparation of ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (i-11c) [0291] To a solution of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (i-11b) (20 g, 66.2 mmol) in 1,4-dioxane (500 mL) was added bis(pinacolato)diboron (34 g, 132.4 mmol) and potassium acetate (19 g, 198 mmol). The mixture was purged with nitrogen for 20 minutes, Pd(dppf)Cl2 (4.9 g, 6.6 mmol) was added and the reaction was stirred at 100° C. for 2 h. The resulting mixture was filtered over Celite and the filtrate was diluted with water (500 mL) and extracted with ethyl acetate (500 mL×3). The combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EtOAc=20:1) to give the title compound (12 g, 67percent) as a yellow oil. LCMS (ESI) calc'd for C15H25BO4 [M+H]+: 281. found: 281. |
63.1% | With potassium acetate In 1,4-dioxane at 20 - 80℃; Inert atmosphere | Alternative prepartion of Intermediate 1-9; Ethyl 4-(trifluoromethylsulfonyloxy)cyclohex-3-enecarboxylate (325 g) was added as a solution in degassed dioxane (3250 mL) to bis(pinacolato)diboron (300 g), (1,1'- bis(diphenylphosphino)ferrocene)-dichloropalladium(II) acetone adduct (44.2 g) and 1,1'- bis(diphenylphosphino)ferrocene (30.1 g), Potassium acetate (317 g) in dioxane (2178 mL) at 20 0C under nitrogen. The red suspension was stirred at 80 0C for 1 hour. The solvent was evaporated. The crude product was taken up into ethyl acetate (4550 mL) and water (650 mL) washed with saturated aqueous brine (2x3250 mL) dried (MgSO^ and evaporated. The crude brown oil was purified by flash silica chromatography, elution gradient 0 to 10percent EtOAc in isohexane to afford ethyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3-enecarboxylate (190 g, 63.1 percent) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 1.16 - 1.22 (15H, m), 1.46 - 1.61 (IH, m), 1.88 - 1.99 (IH, m), 2.13 - 1.99 (IH, m), 2.15 - 2.31 (3H, m), 2.39 - 2.50 (IH, m), 4.02 - 4.11 (2H, m), 6.48 (IH, s). |
37.9% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxaneInert atmosphere; Reflux | The mixture of VI-2 (3 g, 10.4 mmol), VI-2A (3.17 g 12.5 mmol), KOAc (2.0 g, 20.8 mmol) and Pd(dppf)Cl2 (0.3 g) in dioxane (60 mL) was heated to reflux under nitrogen overnight. After concentrated under reduced pressure, the residue was partitioned between H2O (60 mL) and DCM (60 mL), the aqueous phase was extracted with DCM, and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (PE:EA=5:1) to afford VI-3 (1.1 g, yield: 37.9percent). |
4.42 g | With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere | General procedure: (2) Compound 3 (1000 mg), bis(pinacolato)diborane (933 mg) and potassium acetate (865 mg) were added to 1,4-dioxane (29 mL), and the mixture was subjected to nitrogen substitution. To this were added a palladium chloride (dppf)-methylene chloride complex (72 mg) and dppf (49 mg) and then nitrogen substitution was carried out, and the mixture was stirred at 80 °C overnight. To the reaction solution were added water and ethyl acetate, and the mixture was stirred, and filtered through Celite. The organic layer was separated, and anhydrous magnesium sulfate and activated charcoal were added, and the mixture was filtered through Celite. The solvent was distilled off under reduced pressure. To the obtained residue was added methanol, and the solid was collected by filtration to obtain Compound 4 (803 mg). (2) A treatment was carried out in a manner similar to the Example 9 (2) using Compound 2 (5.4 g) to obtainCompound 3 (4.42 g).MS (m/z): 281 [M+H]+ |
0.84 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In dimethyl sulfoxide at 50℃; for 4.5 h; Inert atmosphere | Under argon gas atmosphere, dimethyl sulfoxide (26 mL)suspension of 4-trifluoromethanesulfonyloxy cyclo hex-3-ene-carboxylic acidethyl (1.57 g), bis pinacolato diborane (1.39 g),[1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloridedichloromethane complex (1: 1) (0.13 g) and potassium acetate (1.53 g) was stirredfor 4.5 hours at 50 ° C. After cooling the reaction mixture to roomtemperature, water was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and then distilled off under reduced pressure. The crudeproduct obtained was purified by aminopropyl silyl silica gel columnchromatography (eluting solvent: n- hexane / ethyl acetate = 100 / 0~85 / 15)to give the title compound (0.84 g). |
60.6 mg | With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 60℃; for 18 h; Inert atmosphere | A suspension of the Compound 2 (2.0 g), the Compound 3 (1.85 g), dichloro[1 , 1 ‘-bis(diphenylphosphino)ferrocene] palladium(II) dichloromethane adduct (270 mg), 1,1’-bis (diphenylphosphino)ferrocene (183 mg), and potassium acetate (1.95 g) in 1 ,4-dioxane (33 mE) was stirred at 60° C. under a nitrogen atmosphere for 18 hours. The reaction mixture was allowed to cool to room temperature, and then ethyl acetate, water, and saturated brine were added thereto, and the resulting mixture was stirred, and extracted with ethyl acetate. The resulting organic layers were washed with saturated brine, dried, and concentrated under reduced pressure. The resulting residues were purified by silica gel colunm chromatography (hexane:ethyl acetate=99:10 to 90:10) to give the Compound 4 (1.44 g) as a colorless liquid. MS (APCI): m/z 296 [M+NH4)] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium acetate In N,N-dimethyl-formamide at 95℃; for 5.16667 h; | Step 3:A solution of the 6-iodochroman 11c (1.0 g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for an additional 5 min before being heated to 950C for 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted 3 times with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield). |
84% | With potassium acetate In N,N-dimethyl-formamide at 95℃; for 5.16 h; | A solution of the 6-iodochroman 11c (1.O g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for about 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for about an additional 5 min before being heated to 950C for about 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted 3 times with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield). |
84% | Stage #1: With potassium acetate In N,N-dimethyl-formamide for 0.0833333 h; Stage #2: at 95℃; for 5.08 h; |
A solution of the 6-ιodochroman 11c (1 0 g, 3 85 mmol), bιs[pιnocolato]dιborane (1 22 g, 4 81 mmol) and potassium acetate (1 10 g, 11 5 mmol) in DMF (36 mL) is degassed with Ar for 5 mm followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0 38 mmol) The reaction mixture is then degassed for an additional 5 mm before being heated to 950C for 5 h The reaction is then cooled to RT The crude reaction mixture is diluted with water and the product is extracted with EtOAc (3 x 100 mL) The combined organics are washed with water (100 mL) and brine (100 mL) The organic phase is then dried over MgSO4 and filtered and concentrated The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium acetate In N,N-dimethyl-formamide at 95℃; for 5 h; | A solution of the 6-iodochroman 11c (1.0 g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for an additional 5 min before being heated to 950C for 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash.(R). Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium acetate In N,N-dimethyl-formamide at 95℃; for 3 h; Inert atmosphere | Step 1. 2-(Chroman-6-yl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolaneTo a solution of 6-bromochroman (400 mg, 1.88 mmol) in N,N-dimethylformamide (50 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (620 mg, 2.44 mmol), KOAc (552.1 mg, 5.63 mmol) and Pd(dppf)Cl2 (155 mg, 0.19 mmol) with stirring for 3 h at 95°C maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was diluted with water, extracted with ethyl acetate (80 mL x 3) and the organic layers combined, dried over anhydrous magnesium sulfate, concentrated under vacuum to give the residue, which was applied onto a silica gel column with 1 percent ethyl acetate in petroleum ether to afford 2-(chroman-6-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane as colorless oil (320 mg, 59percent).*H-NMR (300 MHz, CDC13): δ 7.54 (d, J = 7.5 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 4.19 - 4.23 (t, J = 5.4 Hz, 2H), 2.78 - 2.83 (t, J = 6.3 Hz, 2H), 1.98 - 2.05 (m, 2H), 1.28 (s,12H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,2-dimethoxyethane; ethanol; water; toluene at 85℃; Inert atmosphere | To a solution of 24-3 (800 mg, 4.26 mmol) and potassium acetate (1.25 g, 12.77 mmol) in solvent (DME/H2.O/Tolunen/EtOH =10/1/6/3, 7 ml) was added Pd(dppf)Cl2.DCM (700 mg, 0.85 mmol) and Bis(pinacolato)diboron (2.44 g, 9.6 mmol). After having been degassed and recharged with nitrogen, the reaction mixture was stirred at 85 °C overnight. TLC showed the reaction was complete. After cooling to room temperature, water (10 ml) was added and extracted with ethyl acetate (30 ml x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA = 5:1) to afford 24-4 as a yellow solid (1.0 g, 98percent yield). |
98% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,2-dimethoxyethane; ethanol; water; toluene at 85℃; Inert atmosphere | Synthesis of Compound 11-4 (0401) To a solution of 11-3 (800 mg, 4.26 mmol) and potassium acetate (1.25 g, 12.77 mmol) in solvent (DME/H2O/Toluenen/EtOH=10/1/6/3, 7 mL) was added Pd(dppf)Cl2.DCM (700 mg, 0.85 mmol) and Bis(pinacolato)diboron (2.44 g, 9.6 mmol). After having been degassed and recharged with nitrogen, the reaction mixture was stirred at 85° C. overnight. TLC showed the reaction was complete. After cooling to room temperature, water (10 mL) was added and extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=5:1) to afford 11-4 as a yellow solid (1.0 g, 98percent). |
90% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane; 1,2-dimethoxyethane at 150℃; for 0.25 h; Inert atmosphere; Microwave irradiation | A mixture of 5-bromo-2-methoxypyrimidine (0.903 g, 4.78 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.46 g, 5.74 mmol), PdCl2dppf(DCM) (0.114 g, 0.14 mmol) and KOAc (1.407 g, 14.34 mmol) were placed under Ar in a 20 mL microwave flask. Anhydrous 1,2-dimethoxyethane (16 mL) was added and the flask was irradiated at 150 oC for 15 minutes. Note starting material and product are indistinguishable by TLC. The material was concentrated and slurried in EtOAc. The material was then filtered through celite and purified by column chromatography 0 to 60 percent EtOAC in Hexanes. The compound was isolated as a white solid (1.01 g, 90 percent yield).1H NMR (400 MHz, CDCl3) δ 8.97 (s, 2H), 4.20 (s, 3H), 1.50 (s, 12H).13C NMR (100 MHz, CDCl3) δ 165.7, 84.5, 77.4, 55.1, 25.2, 25.0. HRMS (EI+) m/z calculated for C11H17BN2O3 [M+H]+: 237.1405, found: 237.14008. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: With triphenylphosphine In toluene at 45℃; for 0.75 h; Inert atmosphere Stage #2: With potassium acetate In toluene for 3 h; Inert atmosphere; Reflux |
A suspension of N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (3.35 g, 11.9 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.24 g, 16.7 mmol, Beijing datianfengtuo) in toluene (100 mL) was degassed and charged with N2 for 3 times, then Pd(dba)3 (616 mg, 0.595 mmol, Matthey) and PPh3 (243 mg, 0.892 mmol) were added. The mixture was heated to 45° C. and stirred for 45 minutes, then KOAc (3.74 g, 23.8 mmol) was added. The resulted mixture was heated to reflux and stirred further for 3 hours, then cooled to rt, diluted with EtOAc (100 mL), and filtered through a CELITE®. The filtrate was washed with water (70 mL*3) and brine (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a white solid (2.90 g, 74percent). MS (ESI, pos. ion) m/z: 328.9 [M+H]+; 1H NMR (600 MHz, CDCl3): δ 8.32 (d, J=1.4 Hz, 1H), 8.06 (d, J=1.3 Hz, 1H), 6.66 (brs, 1H), 4.05 (s, 3H), 3.02 (s, 3H), 1.33 (s, 12H). |
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 4 h; Inert atmosphere | General procedure: A mixture of 16a (11.38 g, 30 mmol), bis(pinacolato)diboron (9.14 g, 36 mmol) and potassium acetate (5.89 g, 60 mmol) in 1,4-dioxane (200 mL) was degassed, and then PdCl2(dppf) (1.1 g, 1.5 mmol) was added. The reaction mixture was degassed and back-filled with argon (three cycles), stirred at 100 °C under argon atmosphere for 4 h, and then cooled to room temperature. The resulting mixture was filtered and the filtrate was concentrated and purified with column chromatography (silica gel, PE/EtOAc = 7:1) to afford 17a as a pale yellow solid (12.69 g, 99percent yield). |
60.4% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium acetate In N,N-dimethyl-formamide at 100℃; for 8 h; Inert atmosphere | A solution of the 2a (2.80 g, 10 mmol), bis(pinacolato)diborane(1.27 g, 5 mmol), Pd(dppf)2Cl2 (0.18 g, 0.25 mmol) and KOAc (1.47 g,15 mmol) in anhydrous DMF (30 ml) under N2 was stirred at 100 Cfor 8 h. DMF was removed under reduced pressure and add water(100 ml), extracted with ethyl acetate (3 100 ml), the organiclayer was washed with water (20 ml), dried with Na2SO4 andevaporated to give compound 3a as a white solid (1.98 g, 60.4percentyield). mp 90e92 C. 1H NMR (400 MHz, DMSO) d 9.25 (s, 1H, NH),8.21 (d, J 1.6 Hz, 1H, Ar-H), 7.78 (d, J 1.6 Hz, 1H, Ar-H), 3.94 (s, 3H,OCH3), 3.01 (s, 3H, CH3), 1.30 (s, 12H, CH3). ESI-MS: m/z 329.1[MH]. |
60.4% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate In N,N-dimethyl-formamide at 100℃; for 8 h; Inert atmosphere | A solution of the 2a(2.80 g, 10 mmol), bis(pinacolato)diborane (1.27 g, 5 mmol), Pd(dppf)2Cl2 (0.18 g, 0.25 mmol) and KOAc (1.47 g, 15 mmol) inanhydrous DMF (30 ml) under N2 was stirred at 100 C for 8 h.DMF was removed under reduced pressure and adding water(100 ml), extracted with ethyl acetate (3 100 ml), the organiclayer was washed with water (20 ml), dried with Na2SO4 and evaporatedto give compound 3a as a white solid (1.98 g, 60.4percent yield).Mp 90–92 C. 1H NMR (400 MHz, DMSO) d 9.25 (s, 1H, NH), 8.21(d, J = 1.6 Hz, 1H, Ar-H), 7.78 (d, J = 1.6 Hz, 1H, Ar-H), 3.94 (s, 3H,OCH3), 3.01 (s, 3H, CH3), 1.30 (s, 12H, CH3). ESI-MS: m/z 329.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere | Step 4. tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate A mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.223 g, 4.81 mmol), potassium acetate (1.289 g, 13.13 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.107 g, 0.131 mmol) in flask was flushed with N2, and then dioxane (12 mL) was added, followed by a solution of tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (1.45 g, 4.38 mmol) in dioxane (12 mL). The reaction mixture was purged with N2 for 5 min, and then heated in oil bath at 80° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography eluting with 0-30percent of EtOAc/heptane to yield the desired product as a highly viscous liquid (1.2 g, 89percent). LCMS (m/z): 254.1 (MH+-tBu), 1.21 min. |
80% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; for 3 h; | To a degassed solution of intermediate 1 (600 mg, 1.81 mmol)in dioxane (10.7 ml) was added bis—(pinacolato)diboron(603.8 mg, 2.35 mmol), potassium acetate (502.7 mg, 5.07 mmol) and dichloro[1, 1’—bis(diphenylphosphino)ferrocene] palladium dichloro methane complex (139.5 mg, 0.18 mmol) were added. The mixture was stirred at 80 °C for 3 h. Aftercooling down, the mixture was filtered and resulting filtrate concentrated to dryness at low pressure. Final normal phase purification (cHexane/DCM from 70/30 to 50/50) afforded pure title compound (448 mg, 80 percent yield) . Rt = 1.85 mm (analysis method 2) . MS (ESI) m/z 310.2 [M—H], [M—H] calculated:310.2. ‘H NMR (400 MHz, CDC13) 6 5.29 (s, 1H), 3.67 — 3.39 (m, 2H) , 2.15 — 1.96 (m, 2H) , 1.81 — 1.73 (m, 2H) , 1.49 (s, 9H) , 1.32 — 1.17 (m, 12H) |
70% | With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 18 h; Inert atmosphere | Step 2 To a degassed solution of 5-trifluoromethanesulfonyloxy-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (340 mg, 1.0 mmol, 1 eq) in dioxane (10 mL) was added bis-(pinacolato)-diboron (287 mg, 1.1 mmol, 1.1 eq), potassium acetate (302 mg, 3.0 mmol, 3 eq), 1,1'-bis(diphenylphosphino)ferrocene (17 mg, 0.03 mmol, 0.03 eq) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium) (23 mg, 0.03 mmol, 0.03 eq) were added. The mixture was stirred at 80° C. for 18 h. After cooling down, the mixture was filtered and the filtrate was concentrated and purified by flash chromatography using cyclohexane and ethyl acetate (100/0 to 96/4) to afford the corresponding boronic ester (225 mg, 70percent yield). |
70% | With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 18 h; | Step 2 To a degassed solution of 5-trifluoromethanesulfonyloxy-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (340 mg, 1.0 mmol, 1 eq) in dioxane (10 mL) was added bis-(pinacolato)-diboron (287 mg, 1.1 mmol, 1.1 eq), potassium acetate (302 mg, 3.0 mmol, 3 eq), 1,1'-bis(diphenylphosphino)ferrocene (17 mg, 0.03 mmol, 0.03 eq) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium) (23 mg, 0.03 mmol, 0.03 eq) were added. The mixture was stirred at 80° C. for 18 h. After cooling down, the mixture was filtered and the filtrate was concentrated and purified by flash chromatography using cyclohexane and ethyl acetate (100/0 to 96/4) to afford the corresponding boronic ester (225 mg, 70percent yield). |
54% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 85℃; Inert atmosphere | To a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) 4 (559 mg, 2.2 mmol), KOAc (588 mg, 6.0 mmol) and tert-butyl 5-(trifluoromethylsulfonyloxy)- 3,4-dihydropyridine-l(2H)-carboxylate 3 (662 mg, 2.0 mmol) in dry 1,4-dioxane (10 mL) was added Pd(dppf)Cl2'DCM (326 mg, 0.4 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then heated to 85°C and stirred overnight under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the crude product was purified by silica gel column chromatography, eluting with 100: 1 to 20: 1 PE/EA to afford the title compound as brown oil (336 mg, 54percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex; potassium acetate In 1,4-dioxane | 4-bromo-1,3-dimethyl-1H-pyrazole(5.00 g, 28.60 mmol) of anhydrous 1,4-dioxane (100.0 mL)4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) was added to the solution.(8.71 g, 34.32 mmol), potassium acetate (5.63 g, 57.41 mmol)And a dichloromethane complex of Pd(dppf)2Cl2 (2.38 g, 2.86 mmol).The reaction mixture is exhausted of air and filled with nitrogen several times, thenWarm to 100 ° C and stir overnight.The reaction mixture was concentrated under reduced pressure. After the resulting mixture was diluted with water (30 mL),It was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried with anhydrous sodiumThe residue obtained was purified by silica gel column chromatography (EtOAc /EtOAcThe title compound was obtained as a brown viscous liquid (3.80 g, yield 60percent). |
60% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 100℃; Inert atmosphere | To a suspension of 4-bromo-l,3-dimethyl-pyrazole (5.00 g, 28.60 mmol) in anhydrous 1,4-dioxane (100.0 mL) were added 4,4,4',4',5,5,5',5l-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (8.71 g, 34.32 mmol), acetoxy potassium (5.63 g, 57.41 mmol) and Pd(dppf)2Cl2 dichloromethane complex (2.38 g, 2.86 mmol). The mixture was degassed and refilled with nitrogen for several times and then heated to 100 °C and stirred overnight. The mixture was concentrated in vacuo. The residue was diluted with water (30 mL), and the resulting mixture was extracted with EtOAc (50 mLχ3). The combined organic layers was dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by silica chromatography (EtOAc/PE (v/v) = 1/20 to 1/8) to afford the title compound as brown sticky liquid (3.80 g, yield 60percent).MS (ESI, pos. ion) m/z: 223.3 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: With tetrakis(triphenylphosphine) palladium(0); potassium acetate In 1,4-dioxane at 80 - 90℃; Inert atmosphere Stage #2: With hydrogen In 1,4-dioxane at 20℃; |
Under nitrogen protection, 550 mL of dioxane and 3-nitro-5-bromopyridine (20.3 g, After 0.10 mol) of pinacol borate (25.4 g, 0.10 mol) and potassium acetate (14.7 g, 0.15 mol), after stirring uniformly, the catalyst PdCl2dppf (0.74 g, 0.001 mol) was finally added, and the temperature was slowly raised to 80- 90 ° C, Stir the reaction for 2-3 h. After the completion of the GC reaction, the reaction was stopped by cooling, and the reaction solution was filtered through celite to obtain a dark-black reaction solution. After charging at 1 atm of hydrogen, the mixture was reacted at room temperature overnight. After the reaction was completed, the activated carbon was decolorized, and the filtrate was distilled under reduced pressure until no liquid was poured. /Heptane mixed solvent is cooled and beaten for half an hour, filtered to obtain a light gray crude product, heated again with ethanol, and then cooled down, and the filter cake is rinsed with -20 ° C anhydrous ethanol, and dried to obtain a pale yellow solid 15.6 g, yield 71percent, HPLC purity 97.9percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 12 h; Inert atmosphere | To a solution of 5-bromo-2-(NN-dimethylamino)pyridine (8.5 g, 42.3 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (12.9 g, 50.7 mmol) in dioxane (10 mL) was added KOAc (8.3 g, 84.6 mmol) and Pd(dppf)Cl2 (1.55 g, 2.1 mmol) at 25 °C under N2. The mixture was heated to 100 °C and stirred at this temperature for 12 hours. LCMS showed that the reaction was complete. The mixture was filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50/1 to 3/1) to give 2-(2-(N,N-dimethylamino)pyrid-5-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8 g, 32.2 mmol, 76percent yield) as a yellow solid 1H NMR 400 MHz CDCl3 = 8.53 (s, 1H), 7.75-7.78 (d, 1H), 6.43-6.45 (d, 1H), 3.09 (s, 6H), 1.22-1.30 (m, 12H). ESI-MS (m/z): 249.2 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 100℃; for 13 h; Inert atmosphere | To a solution of 4-bromo-1- (3-methoxypropyl) -1H-pyrazole (2.1 g, 9.6 mmol) in DMSO (20 mL) were added bis (pinacolato) diboron (3.7 g, 15 mmol) , potassium acetate (2.4 g, 24 mmol) and Pd (dppf) Cl2(900 mg, 1.22 mmol) . The mixture was stirred at 100 under N2for 13 h, cooled to rt and quenched with saturated aqueous NaCl (30 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combinded orgainc layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 2/1 to give a light yellow oily product (1.3 g, 51) .[1271]MS (ESI, pos. ion) m/z: 267.0 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 4 h; Inert atmosphere | To a solution of 5-bromo-3-chloro-pyridin-2-ylamine (2.0 g, 9.64 mmol) in 1,4-dioxane (20 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.94 g, 11.57 mmol), potassium acetate (2.84 g, 28.92 mmol) and l, l'-bis(diphenylphosphino)ferrocene-palladium(n)dichloride (705 mg, 0.96 mmol). The reaction mixture was purged with nitrogen for 2 min and heated to 100 °C for 4 h and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 30percent ethyl acetate in hexane) affording 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.0 g, 84percent): NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 5.09 (s, 2H), 1.32 (s, 12H). |
84% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 4 h; Inert atmosphere | Preparative Example 10 Step 1: 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine To a solution of 5-bromo-3-chloro-pyridin-2-ylamine (2.0 g, 9.64 mmol) in 1,4-dioxane (20 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.94 g, 11.57 mmol), potassium acetate (2.84 g, 28.92 mmol) and 1 , l'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (705 mg, 0.96 mmol). The reaction mixture was purged with nitrogen for 2 min and heated to 100 °C for 4 h and subsequently concentrated to dryness in vacuo. The resulting viscous mass was diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 30percent ethyl acetate in hexane) affording 3-chloro-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.0 g, 84percent): H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 5.09 (s, 2H), 1.32 (s, 12H). |
78% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 85℃; for 2 h; Inert atmosphere | 9.2 Boronate 13: Compound 12 (4 g, 17.2 mmol),bis (pinacolato) diboron (4.79 g, 18.8 mmol), KOAc (3.37 g, 34.2 mmol) and Pd (dppf) Cl2 · CH2CI2 (0.210 g, 0.25 mmol) were charged into a flask. Dioxane (80 mL) was added. The mixture was stirred at 85°C for 2 hr under Ar. When LC-MS indicated that the reaction was completed, the mixture was cooled to room temperature. The mixture was filtered through diatomite and concentrated. The residue was diluted with ethyl acetate and hexane (3/1, 100 mL) , filtered through silica gel (300-400 mesh) , concentrated and crystallized by n-hexane to give boronate 13 (3.4 g, 78percent) as a white solid. |
78% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 85℃; for 2 h; Inert atmosphere | 9.2 Boronate 13: Compound 12 (4 g, 17.2 mmol), bis(pinacolato)diboron (4.79 g, 18.8 mmol), KOAc (3.37 g, 34.2 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.210 g, 0.25 mmol) were charged into a flask. Dioxane (80 mL) was added. The mixture was stirred at 85° C. for 2 hr under Ar. When LC-MS indicated that the reaction was completed, the mixture was cooled to room temperature. The mixture was filtered through diatomite and concentrated. The residue was diluted with ethyl acetate and hexane (3/1,100 mL), filtered through silica gel (300-400 mesh), concentrated and crystallized by n-hexane to give boronate 13 (3.4 g, 78percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; for 16 h; Inert atmosphere | Solution A: PdCI2(dppf)-CH2CI2 (0.958g, 1.174 mmol), KOAc (6.91 g, 70.4 mmol) and Bis- (pinacolato)-diboron (7.15g, 28.2 mmol) were placed into a 250ml_ flask and degassed.Solution B: In a separate vial, 5-bromo-2-methoxy nicotinitrile (5g, 23.47 mmol) was dissolved in 100ml_ of anhydrous dioxane. Solution B was added to solution A, and the reaction mixture heated to 80°C for 16h. The mixture was cooled down to rt, diluted with EtOAc and the remaining solid filtered off. The filtrate was evaporated under vacuum to yield a black oil. Purification by flash chromatography on silica gel (CH2CI2/MeOH, 95/5) gave the title compound (5.7 g, 89percent yield) as a beige powder. 1H-NMR (400 MHz, DMSO-d6, 298 K): ? ppm 1.31 (s, 12H) 4.03 (s, 3H) 8.31 (s, 1 H) 8.62 (s, 1 H). MS: 261 .5 [M+1 ]+, Rt (2)= 1.47min. |
89% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; for 16 h; | Solution A: PdCI2(dppf)-CH2CI2 (0.958g, 1.174 mmol), KOAc (6.91 g, 70.4 mmol) and Bis-(pinacolato)-diboron (7.15g, 28.2 mmol) were placed into a 250mL flask and degassed. Solution B: In a separate vial, 5-bromo-2-methoxy nicotinitrile (5g, 23.47 mmol) was dissolved in 100ml_ of anhydrous dioxane. Solution B was added to solution A, and the reaction mixture heated to 80°C for 16h. The mixture was cooled down to rt, diluted with EtOAc and the remaining solid filtered off. The filtrate was evaporated under vacuum to yield a black oil. Purification by flash chromatography on silica gel (CH2CI2/MeOH, 95/5) gave the title compound (5.7 g, 89percent yield) as a beige powder. 1 H-NMR (400 MHz, DMSO-d6, 298 K): δ ppm 1.31 (s, 12H) 4.03 (s, 3H) 8.31 (s, 1 H) 8.62 (s, 1 H). MS: 261 .5 [M+1]\ Rt (2)= 1.47min. |
89% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; for 16 h; | General procedure: 2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile Solution A: PdCl2(dppf)-CH2Cl2 (0.958 g, 1.174 mmol), KOAc (6.91 g, 70.4 mmol) and Bis-(pinacolato)-diboron (7.15 g, 28.2 mmol) were placed into a 250 mL flask and degassed. Solution B: In a separate vial, 5-bromo-2-methoxy nicotinitrile (5 g, 23.47 mmol) was dissolved in 100 mL of anhydrous dioxane. Solution B was added to solution A, and the reaction mixture heated to 80° C. for 16 h. The mixture was cooled down to rt, diluted with EtOAc and the remaining solid filtered off. The filtrate was evaporated under vacuum to yield a black oil. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5) gave the title compound (5.7 g, 89percent yield) as a beige powder. 1H-NMR (400 MHz, DMSO-d6, 298 K): δ ppm 1.31 (s, 12H) 4.03 (s, 3H) 8.31 (s, 1H) 8.62 (s, 1H). MS: 261.5 [M+1]+, Rt(2)=1.47 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 8 h; Inert atmosphere | Synthesis of 2-methoxy-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 28.12 To potassium acetate (8.9 g, 90.83 mmol), bis-(pinacolato)-diboron (8.1 g, 31.86 mmol) and bis(diphenylphosphine) ferrocene dichloropalladium (II) (0.34 g, 0.48 mmol) was added an anhydrous solution of 5-bromo-2-methoxyaniline (3.22 g, 15.93 mmol) in DMSO (40 mL) under anhydrous conditions in an atmosphere of nitrogen. The mixture was stirred at 80° C. for 8 h after which time the reaction was quenched with saturated NaCl aqueous solution (30 mL) and extracted with diethyl ether (3*20 mL). The combined ether extracts were dried over magnesium sulphate, filtered and concentrated. The crude product was purified by flash column chromatography (stationary phase; silica gel 230-400 mesh, mobile phase; 9:1 hexane/ethyl acetate). All homogenous fractions were collected and reduced in volume to afford the product 28.12 as a brown syrup (3.18 g, 80percent). νmax (DCM)/cm-1: 2926.38, 1599.02, 1431.11, 1356.01, 1221.39, 1142.48 1H NMR (CDCl3, 400 MHz) δH ppm: 1.35 (12H, s, 2*C(CH3)2), 3.89 (3H, s, OCH3), 6.15 (2H, br, NH2), 7.18 (1H, d, J 8.0 Hz, ArH), 7.25 (1H, d, J 2.5 Hz, ArH), 7.29 (1H, s, ArH). 13C NMR δc ppm: 24.5 (4*CH3), 55.1 (OCH3), 83.2 (2*C(CH3)2) 105.5 (ArCH), 113.7 (ArC), 120.6 (ArCH), 125.8 (ArCH), 135.0 (ArC), 149.7 (ArC). |
30% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 48 h; Inert atmosphere | 2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (60a) (0303) 5-Bromo-2-methoxyaniline (500 mg, 2.48 mmol, 1.0 equiv), bis(pinacolato)diboron (691 mg, 2.72 mmol, 1.1 equiv), potassium acetate (730 mg, 7.44 mmol, 3.0 equiv) and Pd(dppf)Cl2 (54.4 mg, 74.4 μmol, 0.03 equiv) were dissolved under Argon atmosphere in 7 ml DMSO and the mixture was stirred at 80° C. for 48 h. Water was added and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to dryness. The raw product was purified by flash chromatography; yield: 30percent (184 mg). 1H NMR (300 MHz, acetone-d6): δ 7.11-7.02 (m, 2H), 6.81 (d, J=7.9 Hz, 1H), 3.84 (s, 3H), 1.29 (s, 12H). |
[ 1231930-42-9 ]
6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole
[ 1231930-37-2 ]
4-Fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole
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