* 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.
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.
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.
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] +
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).
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.
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
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)+.
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).
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.
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
Reference：
[1] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 117
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9542 - 9555
[3] Patent: WO2017/107089, 2017, A1, . Location in patent: Page/Page column 37; 38
[4] Patent: WO2017/68412, 2017, A1, . Location in patent: Page/Page column 208; 209
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 11, p. 4978 - 4992
19
[ 73183-34-3 ]
[ 1004294-80-7 ]
Reference：
[1] Patent: WO2015/189744, 2015, A1,
20
[ 67927-44-0 ]
[ 73183-34-3 ]
[ 1016641-53-4 ]
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).
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.
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8903 - 8925,23
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 26, p. 7136 - 7139
[3] New Journal of Chemistry, 2018, vol. 42, # 21, p. 17346 - 17350
[4] Chemical Communications, 2008, # 6, p. 733 - 734
[5] Tetrahedron, 2012, vol. 68, # 17, p. 3444 - 3449
[6] Organic Letters, 2010, vol. 12, # 5, p. 1024 - 1027
22
[ 15115-52-3 ]
[ 73183-34-3 ]
[ 1002334-12-4 ]
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
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]+.
Reference：
[1] Patent: US2009/143361, 2009, A1, . Location in patent: Page/Page column 52
[2] Patent: US2009/143367, 2009, A1, . Location in patent: Page/Page column 37
[3] Patent: US2010/120763, 2010, A1, . Location in patent: Page/Page column 47
[4] European Journal of Organic Chemistry, 2012, # 3, p. 595 - 603
25
[ 942590-05-8 ]
[ 73183-34-3 ]
[ 1021918-86-4 ]
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.
Reference：
[1] Patent: CN105254613, 2016, A, . Location in patent: Paragraph 0107; 0108; 0109
27
[ 1024120-52-2 ]
[ 73183-34-3 ]
[ 1029716-44-6 ]
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].
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).
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+)
Reference：
[1] Patent: WO2008/74997, 2008, A1, . Location in patent: Page/Page column 88
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 12, p. 2496 - 2500
35
[ 215184-78-4 ]
[ 73183-34-3 ]
[ 1035235-26-7 ]
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.
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.
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).
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 143 - 146
[2] Patent: WO2008/108988, 2008, A1, . Location in patent: Page/Page column 53
[3] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1305 - 1313
[4] Patent: WO2009/74812, 2009, A1, . Location in patent: Page/Page column 41
[5] Patent: US2010/69441, 2010, A1, . Location in patent: Page/Page column 21-22
[6] Patent: US2010/204477, 2010, A1, . Location in patent: Page/Page column 31
[7] Patent: CN105367547, 2016, A, . Location in patent: Paragraph 0034; 0035; 0036
[8] Patent: CN107382995, 2017, A, . Location in patent: Paragraph 0007; 0014; 0015; 0016; 0117; 0018; 0019-0022
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).
Reference：
[1] Chemistry Letters, 2008, vol. 37, # 6, p. 664 - 665
[2] Chemistry Letters, 2008, vol. 37, # 6, p. 664 - 665
[3] Bulletin of the Chemical Society of Japan, 2008, vol. 81, # 12, p. 1535 - 1553
42
[ 1762-84-1 ]
[ 73183-34-3 ]
[ 1080632-76-3 ]
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
Reference：
[1] Patent: KR2015/117173, 2015, A, . Location in patent: Paragraph 0284-0286
[2] Patent: US2017/331067, 2017, A1, . Location in patent: Paragraph 0248-0251
[3] Patent: US2017/40550, 2017, A1, . Location in patent: Paragraph 0083
43
[ 73183-34-3 ]
[ 188582-62-9 ]
[ 1082066-29-2 ]
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.
Reference：
[1] Patent: US2018/194762, 2018, A1, . Location in patent: Paragraph 0740-0741
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 18, p. 4984 - 4995
44
[ 152684-30-5 ]
[ 73183-34-3 ]
[ 1083168-94-8 ]
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.
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.
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 37, p. 7318 - 7327
47
[ 50-00-0 ]
[ 70882-08-5 ]
[ 73183-34-3 ]
[ 1048976-83-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2008, vol. 47, # 26, p. 4851 - 4854
[2] Angewandte Chemie - International Edition, 2008, vol. 47, # 26, p. 4851 - 4854
48
[ 1040377-02-3 ]
[ 73183-34-3 ]
[ 1040377-03-4 ]
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).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5169 - 5180
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6804 - 6820
[3] Patent: WO2015/81257, 2015, A2, . Location in patent: Page/Page column 84-85
[4] Patent: WO2011/79804, 2011, A1, . Location in patent: Page/Page column 41
[5] Patent: US2012/245178, 2012, A1, . Location in patent: Page/Page column 25
[6] Patent: WO2009/87212, 2009, A2, . Location in patent: Page/Page column 145-146
49
[ 1175274-93-7 ]
[ 73183-34-3 ]
[ 1040377-03-4 ]
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).
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)
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.
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).
Reference：
[1] Patent: WO2008/150827, 2008, A1, . Location in patent: Page/Page column 59
[2] Patent: WO2011/28741, 2011, A1, . Location in patent: Page/Page column 215
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4613 - 4618
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 3795 - 3803
54
[ 73183-34-3 ]
[ 436799-33-6 ]
[ 1084953-47-8 ]
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+).
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
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]+.
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.
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).
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
Reference：
[1] Patent: JP2016/88927, 2016, A, . Location in patent: Paragraph 0211; 0213
[2] Patent: US2018/94000, 2018, A1, . Location in patent: Paragraph 0506
[3] Patent: KR2016/11036, 2016, A, . Location in patent: Paragraph 0263 - 0267
[4] Patent: KR2015/135070, 2015, A, . Location in patent: Paragraph 0204-0207
[5] Patent: KR2016/19747, 2016, A, . Location in patent: Paragraph 0224-0227
[6] Patent: EP2947071, 2015, A1, . Location in patent: Paragraph 0104-0107
61
[ 73183-34-3 ]
[ 1115023-84-1 ]
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).
Reference：
[1] Patent: KR2017/124412, 2017, A, . Location in patent: Paragraph 0174-0176
[2] Patent: KR2015/84657, 2015, A, . Location in patent: Paragraph 1187
62
[ 183065-68-1 ]
[ 73183-34-3 ]
[ 1008119-07-0 ]
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).
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).
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)]
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)
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).
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)
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.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5849 - 5853
[2] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 290
[3] Patent: WO2017/197151, 2017, A1, . Location in patent: Page/Page column 40
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[1] Journal of the American Chemical Society, 2017, vol. 139, # 7, p. 2825 - 2832
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[ 1083326-75-3 ]
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]+.
Reference：
[1] Organic Process Research and Development, 2018, vol. 22, # 3, p. 368 - 376
[2] Patent: US2014/134133, 2014, A1, . Location in patent: Paragraph 0441
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 3, p. 637 - 646
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 14, p. 6087 - 6109
[5] European Journal of Medicinal Chemistry, 2018, vol. 146, p. 460 - 470
[6] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1675 - 1685
[7] Patent: WO2012/32067, 2012, A1, . Location in patent: Page/Page column 61
[8] Patent: WO2014/28968, 2014, A1, . Location in patent: Page/Page column 87; 88
[9] Patent: US9326987, 2016, B2, . Location in patent: Page/Page column 166; 167
[10] Patent: CN106674200, 2017, A, . Location in patent: Paragraph 0096; 0097
Reference：
[1] Patent: WO2014/60432, 2014, A1,
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7381 - 7399
81
[ 149108-74-7 ]
[ 73183-34-3 ]
[ 1121057-77-9 ]
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).
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]+
Reference：
[1] Patent: WO2015/89327, 2015, A1, . Location in patent: Paragraph 0297
[2] Patent: CN108570048, 2018, A, . Location in patent: Paragraph 0590; 0592-0593
[3] Patent: WO2018/169700, 2018, A1, . Location in patent: Page/Page column 00343
[4] Patent: US2013/123281, 2013, A1, . Location in patent: Paragraph 0127; 0128
83
[ 73183-34-3 ]
[ 150-78-7 ]
[ 1073339-07-7 ]
Reference：
[1] Chemical Communications, 2010, vol. 46, # 18, p. 3170 - 3172
[2] Chemical Communications, 2010, vol. 46, # 18, p. 3170 - 3172
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
Reference：
[1] Patent: CN108047258, 2018, A, . Location in patent: Paragraph 0005; 0014; 0015
90
[ 13535-01-8 ]
[ 73183-34-3 ]
[ 1073354-99-0 ]
Reference：
[1] Patent: WO2013/126608, 2013, A1, . Location in patent: Paragraph 00394
[2] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1031 - 1050
[3] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 270 - 285
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 37, p. 7318 - 7327
93
[ 368-48-9 ]
[ 73183-34-3 ]
[ 1036990-42-7 ]
[ 1218790-39-6 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 37, p. 7318 - 7327
94
[ 26163-07-5 ]
[ 73183-34-3 ]
[ 1036991-24-8 ]
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)+
Reference：
[1] Patent: WO2017/120429, 2017, A1, . Location in patent: Page/Page column 262
[2] Advanced Synthesis and Catalysis, 2010, vol. 352, # 11-12, p. 2002 - 2010
[3] European Journal of Organic Chemistry, 2012, # 3, p. 595 - 603
[4] Patent: WO2017/98440, 2017, A1, . Location in patent: Page/Page column 248
95
[ 5683-33-0 ]
[ 73183-34-3 ]
[ 1036991-24-8 ]
[ 1321518-05-1 ]
[ 1310385-02-4 ]
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 11, p. 4133 - 4136
[2] Patent: WO2015/89119, 2015, A1, . Location in patent: Page/Page column 34
96
[ 1183903-41-4 ]
[ 73183-34-3 ]
[ 1000801-76-2 ]
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]+
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.
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.
Reference：
[1] Patent: WO2013/57711, 2013, A1, . Location in patent: Page/Page column 50
[2] Patent: WO2013/88404, 2013, A1, . Location in patent: Page/Page column 97
[3] Patent: US2015/342951, 2015, A1, . Location in patent: Paragraph 0863-0867
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 19, p. 6477 - 6485
103
[ 13114-22-2 ]
[ 73183-34-3 ]
[ 25015-63-8 ]
[ 1112209-14-9 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 1, p. 84 - 87
104
[ 943-72-6 ]
[ 73183-34-3 ]
[ 25015-63-8 ]
[ 1112209-14-9 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 1, p. 84 - 87
105
[ 6358-77-6 ]
[ 73183-34-3 ]
[ 1000339-10-5 ]
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).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 8h;Heating;
4-Bromobenzo [c] [1,2,5] thiadiazole (100 g, 0.46 mol),4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi-1,3,2-dioxaborolane(141 g, 0.55 mol), Pd (dppf) Cl2 (32 g, 0.04 mol) and KOAc (90 g, 0.92 mol) were placed in a flask, To this was added 1,4-dioxane (2 L) and dissolved, followed by heating and stirring for 8 hours. After completion of the reaction, Distilled water was added and the organic layer was extracted with ethyl acetate.The obtained organic layer was dried over Na2SO4, distilled under reduced pressure,Purification by column chromatography afforded compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]thiadiazole(72 g, yield 60percent) was obtained as white crystals.
With isopropylmagnesium chloride; In tetrahydrofuran; at -10 - 30℃; for 9h;Inert atmosphere; Large scale;
1.3 kg of compound (CZT-8) was dissolved in 6.5 liters of dry tetrahydrofuran,Nitrogen protection,Down to -10 degrees,A solution of 3.2 liters of 2N isopropylmagnesium chloride in tetrahydrofuran was slowly added,After the completion of heating to 20 degrees,Add 1.0 publicjinEven boronic acid6.5 liters of tetrahydrofuran solution,Control the temperature between 20 degrees to 30 degrees,After the completion of the reaction at room temperature for 9 hours.Add 9 liters of ethyl acetate and 10 liters of water,Stir for 2 hours,Dispensing,Dried and concentrated.Recrystallization gave 1.2 kg of a white solid(CZT-9). Yield 81%
44%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 0.166667h;Inert atmosphere;
C. A mixture of tert-butyl 4-(4-bromo- lH-pyrazol- 1 -yl)piperidine- 1-carboxylate (20.0 g, 0.61 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (30.8 g, 0.12 mmol) and potassium acetate (17.8 g, 0.18 mol) in 50 mL of dimethyl sulfoxide was purged with nitrogen gas for 10 min. After the addition of [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.55 g, 4.85 mmol), the mixture was purged with nitrogen gas for another 10 minutes, heated at 80 C overnight under nitrogen atmosphere and filtered through celite and washed with ethyl acetate. The filtrate was extracted with ethyl acetate (2 x 200 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and removal of the solvent, the residue was purified by column chromatograph eluted with hexane to afford an oil which was recrystallized from hexane to afford tert-butyl 4-(4-(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazol- 1 -yl)piperidine- 1 -carboxylate as a white solid in 44% yield (10 g). 1H NMR (400 MHz, CDC13) delta 7.79 (s, 1H), 7.72 (s, 1H), 4.32-4.13 (m, 3H), 2.95-2.80 (m, 2H), 2.15-2.05 (m, 2H), 1.93-1.82 (m, 2H), 1.47 (s, 9H), 1.31 (s, 12H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere;
As shown in step 3-iii of Scheme 3, tert-butyl 4-(4-bromo-lH-pyrazol-l- yl)piperidine-l-carboxylate (Compound 1014, 10.52 g, 31.86 mmol), 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (9.71 g, 38.23 mmol), and potassium acetate (9.38 g, 95.58 mmol) were taken up in 105 mL of 1,4-dioxane. The mixture was flushed with nitrogen for 20 minutes and PdCl2(dppf) (1.3 g, 1.59 mmol) was added. The reaction was heated at 900C for 11 hours. The reaction was cooled to room temperature and filtered through a plug of Florisil, which was subsequently rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford a dark brown oil that was dissolved in hexanes and eluted through a second plug of Florisil with 1 :2 EtOAc/hexanes. The filtrate was concentrated under reduced pressure to give a tan oil, which was triturated with hexanes and stirred at 00C until a white precipitate formed. The precipitate was collected by vacuum filtration, washed with hexanes, and dried to afford 6.79 g of tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine- 1-carboxylate (Compound 1015).
5.4 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; Sealed tube;
d) tert-Butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine- 1 -carboxylateTo a (N2 bubbling) solution of the compound of Intermediate Example 5(c) (8 g, 24.2 mmol) in 1,4-dioxane (100 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- (1,3,2-dioxaborolane) (7.36 g, 29 mmol, 1.2 eq.), Pd(dppf)Cl2 (2 g, 2.42 mmol, 0.1 eq.) and potassium acetate (8 g, 82.4 mmol, 3.4 eq.) using the procedure of Intermediate Example 1(b). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 10 % ethyl acetate in hexane) to give the product in 59 % yield (5.4 g). LC-MS (ESI): Calculated mass: 377.29; Observed mass: 378.3[(M+H]+ (RT: 1.83 min).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 10h;Inert atmosphere;
General procedure: 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 68% yield.
5.4 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 12h;Inert atmosphere;
To a (N2 bubbling) solution of the compound of Intermediate Example 5(c) (8 g, 24.2 mmol) in 1,4-dioxane (100 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-(1,3,2-dioxaborolane) (7.36 g, 29 mmol, 1.2 eq.), Pd(dppf)Cl2 (2 g, 2.42 mmol, 0.1 eq.) and potassium acetate (8 g, 82.4 mmol, 3.4 eq.) using the procedure of Intermediate Example 1(b). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 10% ethyl acetate in hexane) to give the product in 59% yield (5.4 g). LC-MS (ESI): Calculated mass: 377.29; Observed mass: 378.3 [(M+H]' (RT: 1.83 min).
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 16.0h;Inert atmosphere;
STEP 2. 1-(4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-5,6-DIHYDROPYRIDIN-1(2H)-YL)ETHANONE 1-acetyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (6.77 g, 24.8 mmol), bis(pinacolato)diboron (6.92 g, 27.3 mmol), potassium acetate (2.93 g, 49.6 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium(ii)complex with dichloramethane (1.01 g, 1.24 mmol) were taken up in dioxane (83 mL). The mixture was purged with nitrogen and then was heated to 80 C. After 16 h, the reaction mixture was cooled to RT, diluted with 150 mL of EtOAc and washed with 50 mL of water and 50 mL of brine, then dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0% to 90% EtOAc/hexanes) afforded 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as an orange oil. MS (ESI, pos. ion) m/z: 252.1 (M+1).
methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 80℃; for 23h;Inert atmosphere;
A 250-mL round bottom flask, with stirrer bar, was charged with 2-(4- (bromomethyl)phenyl)acetate (3.45 g, 14.2 mmol, 1.0 eq.), pinacol diborane (4.32 g, 17.0 mmol, 1.2 eq.), tetrakis(triphenylphosphine)palladium(0) (1.64 g, 1.42 mmol, 0.10 eq.), and K2CO3 (5.88 g, 42.6 mmol, 3.0 eq.). Dioxane (80 mL) was added. The resulting mixture was stirred under Ar at 80 C for 23 hrs. After cooling to room temperature, the reaction was diluted with ethyl acetate (200 mL) and then filtered through celite. The filtrate was washed with sat. sodium chloride (3 x 25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (9.5 g) was purified by chromatography on silica gel using hexane/ethyl acetate (10:0 to 0: 10) as eluent to afford methyl 2-(4-((4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (2.88 g, 70% yield) as a colorless semisolid. ]H NMR (CDC13, 500 MHz) delta 7.14 (s, 4H), 3.67 (s, 3H), 3.57 (s, 2H), 2.27 (s, 2H), 1.23 (s, 12H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 80℃;Inert atmosphere;
Methyl 2-(4-(bromomethyl)phenyl)acetate (1.03 g, 4.24 mmol) was mixed with Pd(PPh3)4 (500 mg, 0.4 mmol, 4,4,41,4',5,5,51,5'-octamethyl-2,21-bi(l,3,2-dioxaborolane) (1.27 g, 5 mmol), K2CO3 (1.75 g, 12.7 mmol) and dioxane (20 mL) under inert Argon atmoshphere. The resulting mixture was heated at 80 C and stirred over night. After cooled to room temperature, the mixture was diluted with EtOAc (100 mL) and filtered through celite. After concentration, the crude was purified with column (silica gel, 10~30% EA/hexane) gave the product, methyl 2-(4-((4,4,5,5-tetramethyl- [,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (721 mg) as semi- solid. HPLC-MS tR = 2.17 min (UV254 ?m); mass calculated for formula Ci6H23BO4290.2, observed LCMS m/z 291.3 (M+H).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 20 - 85℃; for 4.66667h;
Synthesis of 2-(2,3-dichlorophenyl)-4,4,5,5-tetramethyl-1,3-2-dioxaborolane(Compound 16)[0167] A mixture of 1,2-dichloro-3-iodobenzene (7.9229 g, 28.50 mmol), bis(pinacolato)diboron (12.8674 g, 50.20 mmol), potassium acetate (8.0214 g, 82 mmol) and 1,1'-[bis(bisphenyl phosphino)ferrocene]dichloropalladium (II) (1.010 g, 1.38 mmol) in anhydrous DMSO (88 mL) was stirred at room temperature for ten minutes at 85 °C (oil bath temperature) for 4.5 hours. The mixture was cooled to room temperature and poured into ice. The mixture was extracted with EtOAc (3 x 150 mL). The combined organic solution was washed with sat. NaCl (3x100 mL), dried over Na2SO4, and concentrated. The resulting residue was purified with flash column chromatography on silica gel to afford 5.7869 g of the desired product as white solid in 74.5percent yield. 1H-NMR (CDCl3): delta 7.557 (dd, J= 7.0-8.0 Hz and 1.5 Hz, 1 H), 7.050 (dd, J= 7.5-8.0 Hz and 1.5 Hz, 1 H), 7.172 (d, J= 7.5-8.0 Hz, 1 H), 1.368 (s, 9 H).
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 18h;
2-Methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile: To a solution of <strong>[144649-99-0]2-methoxy-5-bromobenzonitrile</strong> (5.0 g, 23.6 mmol) in /?-dioxane (125 mL), bis(pinacolato)diborane (9.0 g, 35.4 mmol), KOAc ( 7.0 g, 71.3 mmol), and Pd(dppf)Cl2 ( 0.863 g, 1.17 mmol) were added. The resulting mixture was stirred for 18 h at 80 °C. The cooled reaction crude was diluted with 1200 mL EtOAc, washed with H20 and brine, dried (Na2S04), filtered, and concentrated in vacuo. The residue was purified by column chromatography on Si02 (Hexanes/EtOAc) to afford the title compound (5.6 g, 92percent).
92%
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 18h;
Preparation of Intermediate 1-2; 5-(2-Chloropyrimidin-4-yl)-2-methoxybenzonitrileReagents: (a) Pd(dppf)Cl2, KOAc, /?-dioxane: (b) 2,4-dichloropyrimidine, K2C03,Pd(PPh3)4, CH3CN, H20, reflux, 5 h;[0209] Step 1. 2-Methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile: To a solution of <strong>[144649-99-0]2-methoxy-5-bromobenzonitrile</strong> (5.0 g, 23.6 mmol) in /?-dioxane (125 mL), bis(pinacolato)diborane (9.0 g, 35.4 mmol), KOAc (7.0 g, 71.3 mmol), and Pd(dppf)Cl2 (0.863 g, 1.17 mmol) were added. The resulting mixture was stirred for 18 h at 80 °C. The cooled reaction crude was diluted with 120 mL EtOAc, washed with H20 and brine, dried (Na2S04), filtered, and concentrated in vacuo. The residue was purified by column chromatography on Si02 (Hexanes/EtOAc) to afford the title compound (5.6 g, 92percent). GC/MS (EI, M+) 245
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃;
Potassium acetate (477 mg, 4.76 mmol) was added to a solution of 5-bromo-2- methylindole (500 mg, 2.4 mmol), bis(pinacolato)diboron (725 mg, 2.86 mmol), and [1 ,1 '-bis-(diphenylphosphino)ferrocene]-dichloropalladium (II) dcm complex (178 mg, 0.24 mmol) in 1 ,4-dioxane (25 mL) in a 20 mL vial. The vial was capped and heated to 80°C, reaction was heated at this temperature with stirring overnight.The reaction mixture was concentrated, dissolved in EtOAc, and filtered through a 5g silica plug. This filtrate was concentrated and purified on an 80g silica column using 0- 10percent ethyl acetate in hexanes to furnish 202mg (33percent) of a clear colorless oil. LCMS m/z 258.3 (M+1 ) 1 H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.39 (s, 21 H) 2.40 (s, 3 H) 6.24 (s, 1 H) 7.25 (d, J=8.20 Hz, 1 H) 7.60 (d, J=8.20 Hz, 1 H) 7.94 (br. s., 1 H) 8.08 (s, 1 H)
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 87℃; for 4h;Inert atmosphere;
Add to the 500ml three-necked flask in turn2,7-dibromo-9- (heptadecane-9-yl) -9H- carbazole (5.61g, 0.01mol),Bis-boronic acid pinacolyl diborane (5.08 g, 0.02 mol), PdCl 2 (dppf) (0.05 g), CH 3 COOK (1.6 g, 0.016 mol),Under a nitrogen atmosphere, 1,4-dioxane (50 ml), which was deoxygenated with water, was added, and the mixture was refluxed at 87 C for 4 h.It was then cooled to room temperature, passed through a column (eluted with DCM) and evaporated to remove solvent.Add silica gel powder and sample through the column. A white solid was obtained.
With potassium phosphate tribasic heptahydrate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; XPhos; In ethanol; at 20℃; for 0.5h;
General procedure: Method (1): Synthesis from 4-tert-butylchlorobenzene as a raw material: K3P04 · 7H20 (3.0 g, 8.85 mmol) and bis-pinacol borate (749 mg, 2.95 mmol) were sequentially added to the reaction flask.The catalyst-chloro (2-dicyclohexyl phosphino-2 ', 4', 6'-tri - triisopropyl-1,1'-biphenyl) (1,1'-biphenyl -2-amino-2'_ -yl)palladium(II) (12 mg, 0.015 mmol) and ligand 2-dicyclohexylphosphine-2',4',6/-triisopropylbiphenyl (4 mg, 0.008 mmol), followed by EtOH (6 mL) The mixture was stirred, and p-tert-butylchlorobenzene (0.5 mL, 2.95 mmol) was added and the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (2 mL) After washing with ethyl acetate (6 mL) in three portions, the filtrate was combined, and the solvent was evaporated to dryness, and the solvent was separated by silica gel (200 to 300 mesh). The eluent was petroleum ether and ethyl acetate. 10~80:1), obtained as a white solid, identified by NMR spectrum as 4-tert-butylphenylboronic acid pinacol ester, yield 98%
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 85℃; for 18h;Inert atmosphere;
(IV) Synthesis of Compound (12); (4-[{4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl}(4H-1,2,4-triazol-4-yl)amino]benzonitrile); <Method A>; Compound (12) was synthesized according to the scheme below.; Here, Compound (16) was synthesized according to the scheme below.; (i) Synthesis of Compound (14) (4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl alcohol) (see Non-patent Literature 14 (Filippis, A.; Morin, C.; Thimon, C., Synth. Commun. 2002, 32, 2669-2676)); Under argon atmosphere, PdCl2(dppf)·CH2Cl2 (245 mg, 300 mumol), potassium acetate (2.94 g, 30.0 mmol) and bis(pinacolato)diboron (2.79 g, 11.0 mmol) were sequentially added to a DMSO (30 mL) solution of Compound (13) (2.34 g, 10.0 mmol) at room temperature, and the mixture was stirred at 85 C for 18 hours. The mixture was cooled to room temperature, and then water (250 mL) was added to the mixture and the mixture was extracted with ethyl acetate (100 mL × 3). All the organic phases were mixed, sequentially rinsed with water (100 mL × 3) and a saline solution (100 mL × 1), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (60 g of silica gel, n-hexane/EtOAc = 5/1) to obtain Compound (14) as a colorless solid. TLC Rf = 0.41 (n-hexane/EtOAc = 2/1) 1H NMR (300 MHz, CDCl3) delta 1.35 (s,12H,4CH3), 4.72 (s, 2H, benzylic CH2), 7.34-7.41 (AA'BB', 2H, aromatic), 7.78-7.84 (AA'BB', 2H, aromatic).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 85℃; for 18h;Inert atmosphere;
<strong>[28342-75-8]1,3-dibromo-4,6-difluorobenzene</strong> (300 mg, 1.1 mmol), bis(pinacolato)diboron (620 mg, 2.4 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropallad ium(II) [Pd(dppf)Cl2](54 mg, 0.07 mmol), and potassium acetate (545 mg, 5.6 mmol) were placed in a reaction flask. To ensure a nitrogen atmosphere in the reaction flask, the gas in the reaction flask was drawn out by vacuum pumping and the reaction flask was refilled with nitrogen gas three times. To the reaction flask, 5 ml of dimethyl sulfoxide (DMSO) was added to obtain a mixture. The mixture was heated to and kept at 85° C. for reaction for 18 hours. Thereafter, the temperature of the mixture was slowly reduced to 20° C., the solvents in the mixture were removed from the reaction flask by vacuum pumping, and the residue in the reaction flask was washed several times with ethyl acetate and with a saturated sodium chloride aqueous solution to collect an organic layer. The organic layer was dehydrated using sodium sulfate (Na2SO4) to obtain a crude product. The crude product was subjected to column chromatography (SiO2, ethyl acetate:n-hexane=1:4), and then was dissolved in n-hexane at a relatively high temperature, followed by cooling in a refrigerator for 12 hours, thereby obtaining white solids (496 mg, 45percent yield). (0085) The spectrum analysis for the white solids is: 1H NMR (400 MHz, CDCl3): delta 8.11 (t, J=7.5 Hz, 1H), 6.71 (t, J=9.2 Hz, 1H), 1.33 (s, 24H); 19F NMR (376 MHz, CDCl3, 298 K): delta ?94.18 (t, J=11.2 Hz). The white solids were confirmed to be Compound L4-4 having a chemical structure represented by
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In water; dimethyl sulfoxide; at 85℃; for 18h;Inert atmosphere;
The compound 1(1 eq, 0.53 mmol) was dissolved in DMSO (2 mL) followed by the addition of potassium acetate (3 eq, 1.59 mmol), bis(pinacolato)diboron (1.1 eq, 0.59 mmol) and Pd(dppf)Cl2 (0.2 eq, 0.11 mmol). The mixture was deoxygenated by three successive argon bubbling/vaccum cycles. The reaction was then heated at 85C under argon for 18h. Water (5 mL) was added and the resulting black solution was extracted 3 times with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried, filtered and evaporated under vaccum. The resulting paste was purified using column chromatography (silica gel, 70/30 Hex/EtOAc) to afford the desired compound (Rf = 0.3) as a colourless oil (113 mg, 91%). 1H-NMR (CDCI3, 600 MHz) delta 7.79 (d, J = 7.7 Hz, 2H), 7.36 (d, J = 7.7 Hz, 2H), 4.71 (s, 2H), 1.35 (s, 12H); 13C-NMR (CDC13, 150 MHz) delta 144.1, 135.2, 126.2, 83.9, 65.4, 25.0.
90%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;
p-Bromobenzyl alcohol (Compound 1, 1.0 g, 5.35 mmol) was dissolved in 10 mL of dry 1,4-dioxane solution, and boranoic acid pinacol ester (247 mg, 5.88 mmol), potassium acetate and pdCl 2 ( Dppf), under N2 protection, heat to 85 C to stir the reaction. After the reaction was completed by thin layer chromatography, the solvent was evaporated under reduced pressure, and ethyl acetate (200 ml) was added and thenThe organic phase was dried over anhydrous sodium sulfate and concentrated under reduced vacuo.The crude product was purified by column chromatography (mobile phase ethyl acetate: petroleum ether = 1:8-1:4)Obtained 181 mg of a pale yellow oily liquid with a yield of 90%.
With potassium acetate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;
Under an argon atmosphere, (4-bromophenyl)methanol (3.0 g) and bis(pinacolato)diboron (4.5 g) was dissolved in dioxane (35 ml), and dichlorobis(triphenylphosphine)palladium(II) (567 mg) and potassium acetate (4.7 g) were added thereto, followed by stirring at 80 C. for 1 day. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in DME (35 ml) and water (18 ml), and tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (3.5 g) was added thereto under an argon atmosphere. In addition, sodium carbonate (3.1 g) and tetrakis(triphenylphosphine)palladium (339 mg) were added thereto, followed by stirring at 70 C. for 1 day. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl {2-[[4'-(hydroxymethyl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (2.8 g).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 6h;Inert atmosphere;
(3) 1 g of 1- (4-bromobenzene) ethanol was dissolved30 ml 1,4-dioxane solution,Two equivalents of bis (pinacolato) diboron,3 equivalents of potassium acetate,5% equivalent of [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride Under argon atmosphere at 80 C,After 6 hours of reaction, the product was obtained by column chromatography.
1500 mg
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃; for 16h;
A mixture of (4-bromophenyl)methanol (1 g, 5.35 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.07 g, 16.04 mmol), KOAc (1.05 g, 10.69 mmol) and Pd(dppf)Cl2.CH2Cl2 (873.27 mg, 1.07 mmol) in 1,4-Dioxane (20 mL) was stirred at 90 C for 16 hours. After cooling to r.t., the mixture was concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0 to 50%) to give the product (1500 mg) as oil. H NMR (400MHz DMSO-d6) _ = 7.63 (d, 2H), 7.32 (d, 2H), 5.23 (t, 1H), 4.51 (d, 2H), 1.29 (s, 12H).
16 g
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In 1,4-dioxane; at 85℃; for 3h;Inert atmosphere;
4-Bromobenzyl alcohol (15 g, 80.2 mmol), bis(pinacolato)diboron (30.6 g, 120.3 mmol), potassium acetate (23.6 g, 240 mmol) and Pd (PPh3)2Cl2 (5.6 g, 8 mmol) were added to 150 mL of dioxane, and the mixture was stirred at 85 C. for 3 hours under a nitrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure, and then extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residues were purified by column chromatography (eluent: petroleum ether:ethyl acetate 60:1-10:1) to give 16 g of title product.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 95℃; for 16.0h;
Example 22,4-Dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine.To a solution of 3-bronio-2,4-diniethylpyridine (476 nig, 2.56 mmol) in DMSO (14 mL) was added bis(pinocolato) diboron (3.25 g, 12.8 mmol), potassium acetate (1.26 g, 12.8 mmol) andPdCl2(dppf)-CH2Cl2 adduct (209 mg, 0.256 mmol). Reaction was heated at 95°C for 16 h. Water was added and the aqueous phase was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduce pressure. The residue was purified via FCC (40-70percent EtOAc/heptane) to give the title compound. lH NMR (400 MHz, CDC13) delta ppm 8.35 (d, J=5.1 Hz, 1 H), 6.91 (d, J=5.1 Hz, 1 H), 2.64 (s, 3 H), 2.42 (s, 3 H); 1.43 (s, 12 H); MS (ESI+) m/z 234 A (M+H)+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 5.0h;Inert atmosphere;
A mixture of <strong>[27063-93-0]3-bromo-2,4-dimethyl-pyridine</strong> (500 mg, 2.69 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1023 mg, 4.03 mmol), Pd(dppf)Cl2 (219 mg, 0.27 mmol), and potassium acetate (526 mg, 5.37 mmol) in 1,4-dioxane (15 mL) was stirred at 110° C. under N2 for 5 hours. The mixture was used in the next step directly without any purification. LCMS (ESI): [M+H]+=234.1.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane;Inert atmosphere; Reflux;
2-bromo-1 H-benzo[d]imidazole (177 mg, 0.9 mmol), bispinacolato diboron (250 mg, 0.99 mmol) and KOAc (265 mg, 2.7 mmol) were dissolved in dioxane (9 ml). After purging with N2, Pd(dppf)CI2 (37 mg, 0.045 mmol) was added. After stirring overnight at reflux temperature the reaction was cooled to room temperature the reaction mixture was diluted with some ethyl acetate (20 ml). The mixture was filtrated through a pad of celite and the solvent was evaporated under reduced pressure to give 2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- benzofdlimidazole as a black oil. The crude product was used in the next step without further purification
2-(4-bromo-3,5-dichlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; 2-(((2,6-diisopropylphenyl)imino)methyl)pyridine; In n-heptane; for 18h;Reflux;
Step 1: Preparation of 2-(4-bromo-3,5-dichlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4,4,4',4',5,5,5',5'-Octamethyl[2,2'-bi-1,3,2-dioxaborolane] (4.88 g, 19.2 mmol), 2,6-bis(1-methylethyl)-N-(2-pyridinylmethylene)benzenamine (0.195 g, 0.73 mmol), and bis(1,5-cyclooctadiene)diiridium(I) dichloride (0.32 g, 0.48 mmol) were added to a solution of 1,3-dichloro-2-bromobenzene (6.6 g, 29.5 mmol) in heptane (10 mL). The reaction mixture color changed from yellow to forest green to brick red within the first minute. The reaction mixture was refluxed for 18 h. The mixture was then partitioned between EA and water, and the aqueous extract was washed twice with EA. The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The solid residue was purified by column chromatography over silica gel eluted with PE-EA (8:1) to give 2-(3,5-dichloro-4-(bromo)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7 g, yield 68percent) as a white solid. 1H NMR (400 MHz, CDCl3): delta 7.75 (s, 2H), 1.34 (s, 12H) ppm.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 3h;
[00321] To a solution of 6-bromo-l -methyl- lH-benzo[d] imidazole (5 g, 23.8 mmol) in dioxane (60 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (9.1 g, 35.7 mmol), Pd(dppf)Cl2 (0.5 g) and potassium acetate (4.67 g, 47.6 mmol). The reaction mixture was heated at 100 °C for 3 h, cooled and concentrated. The crude reaction mixture was purified by column chromatography. (6 g, yield 98percent) MS (ESI+) e/z: 259.1.
6 g
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium acetate; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere;
To a solution of <strong>[53484-16-5]6-bromo-1-methyl-1H-benzo[d]imidazole</strong> (5 g, 23.8 mmol) in dioxane (60 mL) was added 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (9.1 g, 35.7 mmol), Pd(dppf)C12 (0.5 g) and KOAc (4.67 g, 47.6 mmol). The reaction mixture was heated at 100 °C under nitrogen for 3 h until the reaction appeared complete by TLC analysis. The solvent was evaporated and the resulting residue was purified by flash chromatography on Si02 to afford the desired product (6 g, 93percent) as a pale solid. LCMS (m/z): 259.1 (M+1).
5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;
Example 210A 5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine A mixture of <strong>[1187449-01-9]4-bromo-5-chloropyridin-2-amine</strong> (7 g, 33.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (25.7 g, 101 mmol) and potassium acetate (4.97 g, 50.6 mmol) in N,N-dimethylformamide (200 mL) was stirred under nitrogen atmosphere. Pd(dppf)Cl2.dichloromethane adduct (0.741 g, 1.012 mmol) was added rapidly to the suspension. The resulting suspension was stirred at about 80° C. for 16 hours. After cooling to room temperature, the suspension was filtered and the filtrate was diluted with water. The aqueous layer was back extracted with methylene chloride (3*50 mL). The combined aqueous layers were concentrated. The crude product was washed with ethanol and filtered. The filtrate was combined with the organic layer from the previous extraction and concentrated in vacuo to afford the title compound (?60percent purity by 1HNMR analysis). MS (ESI+) m/z 255.1 (M+H)+.
4-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100.0%
A 100 mL sealed tube was charged with <strong>[39795-60-3]4-(4-bromophenyl)pyridine</strong> (0.9 g, 3.8mmol), bis(pinacolato)diboron (1.17 g, 4.61 mmol), potasium acetate (0.745 g, 7.6mmol) and 1-4 dioxane (10 mL). The reaction mixture was purged with argon for 30mm. Then, Pd(dppf)012 (0.75 g, 0.05 eq) was added to the reaction mixture and the mixture was heated at 100 00 over night. After cooling, 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 crudeproduct, which was purified by combiflash to yield title compound (1.0 g, 100.0percent). LOMS: (M+H) = 282.1
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; at 105℃;Inert atmosphere;
Under argon atmosphere, a mixture of <strong>[62162-97-4]2-bromophenanthrene</strong> (10.0 g, 38.9 mmol), bispinacolatodiboron (9.8 g, 38.9 mmol), dichloro[1,1?-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.953 g, 1.17 mmol), potassium carbonate (7.63 g, 78 mmol), and dioxane (200 mL) was stirred overnight at 105 C. After adding bispinacolatodiboron (2.02 g, 7.95 mmol) and dichloro[1,1?-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.953 g, 1.17 mmol), the mixture was stirred at 105 C. for 3 h. The reaction liquid was cooled to room temperature and purified by silica gel column chromatography to obtain the compound A6 (10.4 g, 88% yield).
78%
With 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride-chloroform adduct; potassium acetate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
Potassium acetate (11.03 g, 112 mmol),Bis (pinacol) diboron (17.12 g, 67.4 mmol),2-Bromophenanthrene (14.45 g, 56.2 mmol) and Pd(dppf)Cl2.CHCl3 complex (1.37 g, 1.686 mmol) were placed in an oven dried round bottom flask.Anhydrous dioxane (200 mL) was added and the mixture was bubbled with nitrogen for 15 min.The reaction was stirred at 100 C for 18 hours.Gas chromatography-mass spectrometry (GC-MS) analysis of the reaction mixture indicated complete conversion to the product.The reaction was cooled to room temperature and filtered to remove a base. The filtrate was concentrated in vacuo.The crude residue was partitioned between DCM and saturated NaHCO3 solution.The aqueous layer was re-extracted with DCM. The combined organics were washed sequentially with saturated aqueous NaHCO3 and brine then dried over sodium sulfate. The organics were then filtered and dried and loaded onto silica, and the mixture was purified by flash column chromatography (0-50% DCM / isohexane).4,4,5,5-tetramethyl-2-(phenanthr-2-yl)-1,3,2-dioxaborolane (13.32 g, 43.8 mmol, 78% yield) which foamed and solidified upon drying under high vacuum to give an off-white solid.
With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; tricyclohexylphosphine; In 1,4-dioxane; at 80℃; for 5h;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).
tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 95℃; for 16h;Inert atmosphere;
Step 2. tert-Butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate A 2 L round-bottomed flask was charged with <strong>[889858-12-2]tert-butyl 4-bromo-2-fluorobenzoate</strong> (30 g, 114 mmol), bis(pinocolato)diboron (41.5 g, 164 mmol), potassium acetate (32.1 g, 327 mmol), PdCl2(dppf)-CH2Cl2 (2.67 g, 3.27 mmol) and 1,4-dioxane (500 mL). The reaction mixture was degassed with argon for 15 min, then heated to 95° C. and maintained at this temperature for 16 h. After cooling down, the reaction mixture was evaporated to dryness, dissolved in DCM (300 mL), and filtered over celite washing with DCM (3*100 mL). The filtrate was washed with water (200 mL) and brine (2*200 mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified using flash chromatography on silica gel (0 to 10percent EtOAc in heptane over 30 min), giving tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (27 g, 90percent) as a solid. LCMS (m/z): 267 (MH+ (-tBu)), 1.23 min; 1H NMR (500 MHz, DMSO-d6) delta ppm 7.83 (t, 1H) 7.57 (d, 1H) 7.43 (d, 1H) 1.62-1.46 (m, 9H) 1.34-1.25 (m, 12H).
2-(dibenzo[b,d]furan-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 24h;Reflux;
31.3 g (126.7 mM) of <strong>[50548-45-3]1-bromodibenzo[b,d]furan</strong>, (<strong>[50548-45-3]1-bromodibenzo[b,d]furan</strong>),190.0 g (190.0 mM) bis (pinacolato) diboron, 4.6 g (6.3 mM) PdCl2(dppf) 37.3 g (380.1 mM) of KOAc was dissolved in 300 mL of 1,4-dioxane and refluxed for 24 hours. After the reaction was completed, distilled water and DCM (dichloromethane) were added at room temperature. The organic layer was dried with MgSO 4 and the solvent was removed by a rotary evaporator. The reaction product was purified by column chromatography (DCM: Hex = 1: 3) and recrystallized from methanol to obtain the desired compound 1-5-3 37 g (quant.).
98%
With palladium diacetate; calcium acetate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;
101g (410 mmol) of <strong>[50548-45-3]1-bromodibenzofuran</strong> was added to 500 ml flask under protectivegas, 273 g (1055 mmol) of bis (pinacolato) diborane (CAS 73183-34-3) wasdissolved in in 1500 ml dry DMF and degassed for 30 minutes. 121 g (1229 mmol) Calciumacetate and 8.4 g (37 mmol) palladium acetate are added subsequently, and thebatch was heated overnight at 80C . When the reaction was complete, themixture was diluted with 300 ml of toluene, and extracted with water. Thesolvent was removed in rotary evaporator, and the product was thenrecrystallized from heptane. Yield: 118 g (401mmol), 98% theory.
70%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 10h;Reflux;
500ml round bottom flask reactor, <strong>[50548-45-3]1-bromodibenzofuran</strong>(20.0g, 0.081mmol), bis(pinacolato)diboron (26.7g, 0.105mol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.3g, 0.002mol), potassium acetate (19.9g, 0.202mol), into a 1,4-dioxane 200ml were stirred for 10 hours under reflux after completion of the reaction was filtered a pad of celite. Filtrate was concentrated under a reduced pressure was separated and then the column was recrystallized from dichloromethane and heptane to give a intermediate 4-a> (17.0g, 70%).
70%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 10h;Reflux;
500ml round bottom flask reactor1-Bromo-dibenzofuran (20.0g, 0.081mmol), Bis (pinacolato) diboron (26.7g, 0.105mol),[1,1'-bis (diphenylphosphino) ferrocene] palladium in a Dijk (1.3g, 0.002mol),Potassium acetate (19.9g,0.202mol), into a 1,4-dioxane 200ml were stirred for 10 hours under reflux. After the completion of the reaction was filtered a pad of Celite. femaleAfter concentration under reduced pressure they were separated by liquid column and recrystallized with dichloromethane-heptane to give a (17.0g, 70%).
70%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 10h;Reflux;
<strong>[50548-45-3]1-bromodibenzofuran</strong> (20.0 g, 0.081 mmol) was charged in a 500 ml round bottom flask reactor,Bis (pinacol) diboron (26.7 g, 0.105 mol)[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (1.3 g, 0.002 mol)Potassium acetate (19.9 g, 0.202 mol), 200 ml of 1,4-dioxane and stirred under reflux for 10 hours.After the reaction was complete, the diatomaceous earth liner was filtered. The filtrate was concentrated under reduced pressure and then separated by column,And recrystallized from dichloromethane and heptane to obtain (17.0 g, 70%).
70%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 1h;Reflux;
In a 500-mL round-bottom flask reactor, <strong>[50548-45-3]1-bromodibenzofuran</strong> (20.0 g, 0.081 mmol), bis(pinacolato)diboron (26.7 g, 0.105 mol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium (1.3 g, 0.002 mol), potassium acetate (19.9 g, 0.202 mol), and 1,4-dioxane (200 ml) were stirred together for hrs under reflux. After completion of the reaction, filtration was performed through a celite pad. The filtrate was concentrated in a vacuum, purified by column chromatography, and recrystallized in dichloromethane and heptane to afford <Intermediate 4-a> (17.0 g, 70%).
70%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; for 10h;Reflux;
In a 500-mL round-bottom flask reactor, <strong>[50548-45-3]1-bromodibenzofuran</strong> (20.0 g, 81 mmol), bis(pinacolato)diboron (26.7 g, 105 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium (1.3 g, 0.002 mol), potassium acetate (19.9 g, 202 mmol), and 1,4-dioxane (200 ml) were stirred together for 10 hrs under reflux. Concentration in a vacuum was followed by column chromatographic purification. Recrystallization in dichloromethane and heptane afforded (17.0 g, 70%).
70%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 10h;Reflux;
Intermediate 8-a was synthesized according to Scheme 60 below:<strong>[50548-45-3]1-bromodibenzofuran</strong> (20.0g, 0.081mmol), bis (pinacolato) diboron (26.7g, 0.105mol) in 500ml round bottom flask reactor,200 ml of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (1.3 g, 0.002 mol), potassium acetate (19.9 g, 0.202 mol) and 1,4-dioxane were added and stirred under reflux for 10 hours. . After the reaction was completed, the celite pad was filtered. The filtrate was concentrated under reduced pressure and column separatedRecrystallization from dichloromethane and heptane gave <intermediate 8-a (17.0 g, 70%).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 90℃; for 8h;Inert atmosphere;
<strong>[144981-85-1]2-iodo-9,9'-dimethylfluorene</strong> (3.2 g, 10 mmol), bis(pinacolato)diboron (2.79 g, 11 mmol, potassium acetate (2.94 g, 30 mmol), DMF (80 mL) was added to a mixture of Pd(dppf)Cl2(360 mg, 0.5mmol). Under argon protection system, 90°C reactor 8 h. The reaction was stopped, the mixture was cooled to room temperature and poured into 200 mL of water, extracted with ethyl acetate (50 mL × 3), then with saturated brine several times, the combined organic phases were dried over anhydrous magnesium sulfate.Rotary evaporation under reduced pressure, the solvent was removed, the residue with petroleum ether: ethyl acetate = 20: 1 (v / v )as eluant separated by column chromatography on silica gel (200-300 mesh) to give a white solid 2.82 g, yield 88percent
80%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 100℃; for 6h;Inert atmosphere;
A three-necked flask was charged with <strong>[144981-85-1]2-iodo-9,9-dimethylfluorene</strong> (2g, 6.3mmol), bis (pinacolato) diboron (1.9g, 7.5mmol), potassium acetate (2.9g, 30mmol), Pd (dppf) Cl2 (150mg , 0.21 mmol) and 80mL DMF, under the protection of argon, the mixture was heated to 100oC reaction 6h, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine 3 times, the organic layer was dried over anhydrous sodium sulfate, and removed by rotary evaporation the solvent, the residue was purified by silica gel column chromatography, to V (petroleum ether): V (ethyl acetate) = 10: 1 as eluant to give a white solid was purified 1.6g, 80percent yield.
2-chloro-1-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
To (8 volumes) of tetrahydrofuran (THF), (0.2457 mol) of 2-bromo-9,9-difluoro-7- iodo-9H-fluorene was charged and the resultant reaction mixture was cooled to about -15°C.To this reaction mixture isopropyl magnesium chloride (1M in tetrahydrofuran (THF)) was added at about -15°C and stirred for about 30 mm. Then a solution of 2-chloro N,Nmethylmethoxyacetamide in toluene was added at about - 15°C and stirred for about 90 mm. Then the temperature of the resultant reaction mixture was raised to about 0°C and stirred for about 30 mm. Then iN HC1 was added to the reaction mixture and extracted with ethylacetate for thrice. The organic layer was separated and dried with anhydrous sodium sulphate, the organic layer was separated and distilled under vacuum below 45°C followed by isolation in isopropyl alcohol. To (20 volumes) of 1,4-dioxane the isolated solid was charged and stirred for about 15 mm. Then added bis pinacolato diboron, potassium acetate and palladium dppf chloride and the temperature of the resultant reaction mixture was raised to about 90°Cand maintained at about 90-95°C for about 16 hrs. Then cooled to about room temperature and diluted with water followed by extraction with ethyl acetate (3 times). The organic layer was separated and washed with brine solution, the organic layer was separated and dried with anhydrous sodium sulphate and then distilled the solvent completely at below 45°C under vacuum to yield the title compound. Yield: 58percent.
Under the protection of nitrogen atmosphere,2-bromobenzoxazole10mmol and bis(pinacol) diboron 10mmol were added to the three-necked bottle.Add 50 mL of dioxane to stir to dissolve, and pass nitrogen for 30 min. Add potassium acetate 10mmol,The temperature was raised to 100 ° C and the reaction was stirred for 12 h.The crude product was purified by silica gel column chromatography.The eluent is a 2:1 dichloromethane-n-hexane mixed solvent. A white crystalline product was obtained in a yield of 80percent.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;
A mixture of <strong>[902518-11-0]9-(2-bromophenyl)-9H-carbazole</strong> (10 g,31.04 mmol), 4,4,40,40,5,5,50,50-octamethyl-2,20-bi(1,3,2-dioxaborolane) (10.25 g, 40.35 mmol), 1,10-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethanecomplex (0.76 g, 0.93 mmol), potassium acetate (9.14 g,93.11 mmol), and anhydrous 1,4-dioxane (180 mL) was degassedwith nitrogen for 1 h while stirring. The reaction mixture was thenmaintained under a nitrogen atmosphere at 80 C for 24 h. Themixture was diluted with dichloromethane and washed thrice withdistilled water (100 mL). The organic layer was dried over anhydrousMgSO4 and evaporated in vacuo to yield the crude product,which was purified through column chromatography usingdichloromethane/n-hexane to obtain a white powder. Other intermediatecompounds, 3,6-dimethyl-9-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9H-carbazole and 3,6-di-tert-butyl-9-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9Hcarbazolewere prepared by similar procedures described above.1H NMR (500 MHz, CDCl3): d 0.79 (s, 12H), 7.18 (d, 2H, J 12 Hz),7.25 (t, 2H, J 18 Hz), 7.37 (t, 2H, J 18 Hz), 7.53 (t, 2H, J 18 Hz),7.69 (t, 1H, J 16 Hz), 7.96 (d, 1H, J 12 Hz), 8.14 (d, 2H, J 12 Hz).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;
A mixture of <strong>[902518-11-0]9-(2-bromophenyl)-9H-carbazole</strong> (10 g,31.04 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (10.25 g, 40.35 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex(0.76 g, 0.93 mmol), potassium acetate (9.14 g, 93.11 mmol),and anhydrous 1,4-dioxane (180 ml) was degassed with nitrogenfor 1 h while stirring. The reaction mixture was then maintained innitrogen at 80 °C for 24 h. The mixture was diluted withdichloromethane and washed with distilled water (100 mL) threetimes. The organic layer was dried over anhydrous MgSO4 andevaporated in vacuo to give the crude product, which was purifiedby column chromatography using dichloromethane/n-hexane andgave a white powder.1H NMR (500 MHz, CDCl3): delta 0.79 (s, 12H), 7.18 (d, 2H, J = 12 Hz),7.25 (t, 2H, J = 18 Hz), 7.37 (t, 2H, J = 18 Hz), 7.53 (t, 2H, J = 18 Hz),7.69 (t, 1H, J = 16 Hz), 7.96 (d, 1H, J = 12 Hz), 8.14 (d, 2H, J = 12 Hz).13C NMR (CDCl3): delta 24.4, 83.4, 109.7, 119.1, 119.9, 123.1, 125.5, 127.6,128.6, 132.1, 136.3, 142.1, 142.4.
5‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1,3‐benzothiazol‐2‐amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39.4%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 95℃;
4.0 g of <strong>[20358-03-6]2-amino-5-bromobenzothiazole</strong>, 5.7 g of bis(pinacolato)diboron, and 5.1 g of potassium acetate were dissolved in 40.0 mL of l,4-dioxane, and 426.0 mg of palladiumdi[l, l'-bis(diphenylphosphino)ferrocene]dichloride (PdCh(dppf)) was added thereto, and the resulting solution was stirred overnight at 95 C. The reaction mixture was concentrated, ethyl acetate was added thereto, and then the reaction mixture was washed with distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified with silica gel column chromatography (developing solvent: n-hexane/ethyl acetate = 2/1) to give 1.9 g of the title compound as a yellow solid (yield: 39.4 %). 1H-NMR (CDCl3, 400 MHz) d 7.97(s, 1H), 7.58(dd, 2H), 5.39(bs, 2H), l.36(s, 12H)
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃;Inert atmosphere;
The title compound is prepared according to General Procedure 8 described for Intermediate 14, using <strong>[20358-03-6]5-bromobenzothiazol-2-ylamine</strong> (1.70 g; 7.42 mmol; 1 eq.), bis(pinacolato)diboron (2.83 g; 11.13 mmol; 1.50 eq.), potassium acetate (1.60 g; 16.32 mmol; 2.20 eq.) and Pd(dppf)CI2 (618 mg; 0.817 mmol; 0.10 eq.), in dioxane (7 ml_). Conditions: 100 C overnight. Purification by FCC (0% to 30% EtOAc gradient in hexane) yields 5- (tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3-benzothiazol-2-amine (1.16 g; 3.27 mmol; 44%; white waxy solid; UPLC purity: 78%).
With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 70℃; for 18h;Inert atmosphere;
Compound A (2.00 g, 4.22 mmol), bis (pinacolato) diboron (2.36 g, 9.30 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) ([1,1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II), Pd (dppf) Cl2) (0.31g, 0.42mmol), 1,1'-bis (diphenylphosphino) ferrocene (1 Flask of 70 mL of 1'-bis (diphenylphosphino) ferrocene, dppf) (0.234 g, 0.42 mmol), potassium acetate (KOAc) (2.55 g, 26 mmol) and 1,4-dioxane (1,4-dioxaen) Was charged with nitrogen and reacted at 70 C. for 18 hours. After cooling to room temperature, the product was extracted with methylene chloride (MC) and washed well with water. The extracted organics were dried over anhydrous magnesium sulfate (anhydrous MgSO 4). Then, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 (eluent)) to obtain 1.58 g of compound A-1. (Yield 27.6%) GC-MS: 568.22 is a diagram showing an MS measurement result of Compound A-1.
4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)pyridine-2-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃; for 2h;Inert atmosphere;
A mixture of <strong>[131747-63-2]4-bromopyridine-2-carboxaldehyde</strong> (1.86 g; commercial), bis(pinacolato)diboron (2.82 g), potassium acetate (2.48 g) and [1,1?-bis(diphenylphosphino)ferrocene]- dichloropalladium(II) dichloromethane complex (408 mg) in dioxane (20 mL) was degassed for 5 mm with N2 and stirred at 90°C for 2 h. The mixture was cooled down to rt, diluted with EA, filtered through a pad of Celite, concentrated under reduced pressure and used directly in the next step.?H NMR (CDC13) oe: 10.13 (s, 1H); 8.82 (d, J = 4.6 Hz, 1H); 8.34 (s, 1H); 7.87 (d,J = 4.4 Hz, 1H); 1.33 (m, 12H).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃; for 2h;Inert atmosphere;
A mixture of <strong>[131747-63-2]4-bromopyridine-2-carboxaldehyde</strong> (1.86 g; commercial), bis(pinacolato)- diboron (2.82 g), potassium acetate (2.48 g) and Pd(dppf)Cl2.CH2Cl2 (408 mg) in dioxane (20 mL) was degassed for 5 min with N2 and stirred at 90°C for 2 h. The mixture was cooled down to rt, diluted with EA, filtered through a pad of Celite, concentrated under reduced pressure and used directly in the next step. :H NMR (CDCI3) delta: 10.13 (s, 1H); 8.82 (d, J = 4.6 Hz, 1H); 8.34 (s, 1H); 7.87 (d, J = 4.4 Hz, 1H); 1.33 (m, 12H).
2,2'-(5-methoxy-1,3-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 2.5h;Inert atmosphere;
The mixture of <strong>[74137-36-3]1,3-dibromo-5-methoxybenzene</strong> (0.5 g,1.88 mmol), bis(pinacolato)diboron (1.05 g, 4.1 mmol), PdCl2(dppf)(140 mg, 0.23 mmol), potassium acetate (1.1 g,11.3 mmol), and DMF(40 mL) were stirred for 2.5 h at 80 C. The solvent was removed invacuo and the residue was dissolved in CH2Cl2. The solution waswashed with water and dried over magnesium sulfate. The filtratewas concentrated to dryness, and the residue was purified by flashcolumn chromatography on silica gel (eluent: petroleum ether/CH2Cl2 = 10/1), gave compound 3 as a white solid. Yield: 383 mg(56%). 1H NMR (400 MHz, CDCl3) delta (ppm): 7.87 (s, 1H), 7.42 (d,J 0.9 Hz, 2H), 3.84 (s, 3H), 1.33 (s, 24H). 13C NMR (100 MHz, CDCl3) delta (ppm): 158.56, 133.60, 122.79, 83.78, 55.33, 24.87. MS (EI): m/z 359.9.
5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere;
To a suspension of <strong>[90858-86-9]4-bromo-5-methoxy-1H-indole</strong> (900 mg, 3.98 mmol), bispinacolatodiboron (5 g, 19.9 mmol, 5 eq), KOAc (1.95 g, 19.9 mmol, 5 eq) in dioxane (30 mL) was added PdCl2dppf (291 mg, 0.40 mmol, 0.1 eq) under Ar(g). The reaction mixture was heated up to 90°C overnight. It was then re-charged with bispinacolatodiboron (1 g, 4 mmol, 1 eq), KOAc (0.4 g, 4 mmol, 1 eq) and PdCl2dppf (145 mg, 0.20 mmol, 0.05 eq) and heated up to 9000 another night. It was then cooled down to rt, partitioned with water (40 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dried over MgSO4, filtered and the solvent was removed in vacuo. Purification by silica gel columnchromatography with hexane/EtOAc (1:0-1:1) yielded Intermediate 56 as a paleyellow solid (425 mg, 39percent).1H NMR (300MHz, DMSO-d5) oH. 10.86 (brs, 1H), 7.39 (dd, J=8.7, 0.8 Hz, 1H),7.29 (t, J=2.7 Hz, 1H), 6.81 (d, J=8.7 Hz, 1H), 6.55 (d, J=2.1 Hz, 1H), 3.72 (5,3H), 1.32 (5, 12H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 10h;Reflux;
In a 500 ml round bottom flask reactor 1-Bromodibenzofuran (1.3g, 0.002mol) of bis (pinacolato) diboron (26.7g, 0.105mol), [1,1'-bis (diphenylphosphino) ferrocene] dichloro palladium (20.0g, 0.081mmol) , Potassium acetate (19.9 g, 0.202 mol) and 1,4-dioxane (200 ml) were added and the mixture was stirred under reflux for 10 hours. After completion of the reaction, the celite pad was filtered. The filtrate was concentrated under reduced pressure, the column was separated, and recrystallized from dichloromethane and heptane to obtain (17.0 g, 70percent)
Step 2. Pd (PPh3) 2Cl2 (442mg, 0.60mmol) was added to the mixture of 301-01 (2.0g, 6.05mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (3.1g, 12.1mmol) and KOAc (1.78g, 18.2mmol) in 1, 4-dioxane (40mL) under N2. Then the mixture was heated to 80, stirred for 3h. Evaporation to remove the solvent, the residue was washed by EtOAc to give the mixture of 301-02 and 301-03 as brown powder in a yield of 98. The product was used without further purification. 301-2: Mass (m/z) : 379.17, [M+H] +, 301-03: Mass (m/z) : 296.01 [M+H] +.; Step 3. The compound 301-04 was prepared in a yield of 69.8as yellow solid (77.5mg) from the mixture (100mg) of 301-02 and 301-03 and 2, 4-dichlorothieno [2, 3-d] pyrimidine (100mg, 0.3mmol) according to the procedure for 99-01. Mass (m/z) : 419.99, [M+H] +.
methyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;
To a stirred solution of <strong>[206551-41-9]methyl 3-bromo-2-fluorobenzoate</strong> (5 g, 21.64 mmol) in 1,4-dioxane (50 mL) at room temperature were added (Bpin)2 (8.2 g, 32.46 mmol), KOAc (6.37 g, 64.93 mmol) and PdCl2(dppf) (1.7 g, 2.16 mmol) and degassed with argon for 5 min. The resulting mixture was then maintained at 100° C. for 16 h. The reaction mixture was filtered through celite pad and the filtrate was concentrated under reduced pressure to get methyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (8 g, crude compound) as a dark brown solid. The crude product was used for the next step without purification.
7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline A solution of <strong>[1126824-44-9]5-bromo-7-methoxyquinoline</strong> (0.407 g, 1.71 mmol, OxChem, Wood Dale, Ill., USA), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.912 g, 3.59 mmol), PdCl2(dppf) (0.051 g, 0.070 mmol), and potassium acetate (0.503 g, 5.13 mmol) in DMF (9 mL) was stirred at 90° C. for 1 h then at 100° C. for 45 min. The reaction mixture was diluted with EtOAc (100 mL), and washed with saturated, aqueous sodium bicarbonate (2*75 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was adsorbed onto silica and purified via column chromatography (silica gel, 0-80percent heptane/EtOAc) to give 7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline. MS (ESI, +ve) m/z: 286.1 (M+1)+.
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In N,N-dimethyl-formamide; at 90 - 100℃; for 1.75h;
A solution of <strong>[1126824-44-9]5-bromo-7-methoxyquinoline</strong> (0.407 g, 1.71 mmol, OxChem, Wood Dale, IL, USA), 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1 ,3,2-dioxaborolane) (0.912 g, 3.59 mmol), PdC12(dppf) (0.05 1 g, 0.070 mmol), and potassium acetate (0.503 g, 5.13 mmol) in DMF (9 mL) was stirred at 90 °C for 1 h then at 100 °C for 45 mm. The reaction mixture was diluted with EtOAc (100 mL), and washed with saturated, aqueous sodium bicarbonate (2 x 75 mL). The organic layer was separated, dried over anhydrous Na2504, and concentrated in vacuo. The crude product was adsorbed onto silica and purified via column chromatography (silica gel, 0?80percent heptane/EtOAc) to give 7-methoxy-5-(4,4,5,5 -tetramethyl- 1 ,3,2-dioxaborolan-2- yl)quinoline. MS (ESI, +ve) m/z: 286.1 (M + 1).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 90 - 100℃; for 1.75h;
7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline A solution of <strong>[1126824-44-9]5-bromo-7-methoxyquinoline</strong> (0.407 g, 1.71 mmol, OxChem, Wood Dale, Ill., USA), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.912 g, 3.59 mmol), PdCl2(dppf) (0.051 g, 0.070 mmol), and potassium acetate (0.503 g, 5.13 mmol) in DMF (9 mL) was stirred at 90° C. for 1 h then at 100° C. for 45 min. The reaction mixture was diluted with EtOAc (100 mL), and washed with saturated, aqueous sodium bicarbonate (2*75 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was adsorbed onto silica and purified via column chromatography (silica gel, 0-80percent heptane/EtOAc) to give 7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline. MS (ESI, +ve) m/z: 286.1 (M+1)+.
2-(2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 0.166667h;Microwave irradiation;
General procedure: To 2 mL of 1,4-dioxane in microwave reaction vessel were added bromobenzene (0.20 g, 1.27 mmol), bis(pinacolato)diboron (0.36 g, 1.40 mmol), potassium acetate (0.38 g, 3.8 mmol), and PdCl2(dppf) (0.028 g, 0.038 mmol). The reaction mixture was heated to 110 °C by microwave irradiation at power 100 W for 10 min. After solvent was removed under reduced pressure, the residue was purified by dry column vacuum chromatography (DCVC) using dichloromethane (DCM) as eluent provided the 0.16 g in 62 percent yield;
With lithium tert-butoxide; In methanol; water; at 50℃; for 48h;Glovebox;
In a glove box, t-BuOLi (1 mmol, 2 equivalents, 80.1 mg), B2pin2 (2 mmol, 4 equivalents, 507.9 mg), 0.85 mL of solvent methanol were added to a vial containing a stirrer.10 muL H 2 O, methyl iodide (0.5 mmol). The capped vial was removed from the glove box and the reaction mixture was stirred at 50 C for 48 hours. After cooling to room temperature, the reaction mixture was transferred to a test tube by methanol, and a certain amount of internal standard n-decane was added and diluted with ethyl acetate.The yield of the product methylboronic acid pinacol ester was determined by the GC-fid method to be 30%.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In tetrahydrofuran;
Secondary Precursor, <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> is mixed with Bis(pinacolato)diboron along with a catalytic amount of l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl2(dppf)) in THF also containing Potassium Carbonate resulting in Precursor VII.
N-benzyl-4-bromo-1,2,5,6-tetrahydropyridine[ No CAS ]
[ 73183-34-3 ]
[ 1048976-83-5 ]
Yield
Reaction Conditions
Operation in experiment
68%
With copper(I) oxide; 1,3-bis-(diphenylphosphino)propane; lithium tert-butoxide; In N,N-dimethyl-formamide; at 45 - 55℃;Inert atmosphere;
Under nitrogen protection, in the reaction bottle,N-Benzyl-1,2,5,6-tetrahydropyridine-4-bromo (25.2 g, 0.1 mol),Boronic acid pinacol ester (30.5g, 0.12mol),Cuprous oxide (1.43g, 0.01mol),1,3-bis(diphenylphosphino)propane (8.25 g, 0.02 mol),Lithium tert-butoxide (17.6 g, 0.22 mol) was dissolved in N,N-dimethylformamide (130 g), and the reaction was stirred at a temperature of 45 C to 55 C;The reaction mixture was filtered through celite, and the filter cake was rinsed with toluene (50 g).The filtrate was diluted with toluene (50 g) and the filtrate was washed with water (100 g).Layered, GC detected organic layer without N, N-dimethylformamide,The organic layer was washed with saturated brine (100 g) and evaporated to dryness.Add heptane / ethanol = 3:1 beating,After filtration, 20.3 g of an off-white solid N-benzyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester was obtained, HPLC: 99.6%, yield 68%.
tert-butyl N-[(3S)-1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl]carbamate[ No CAS ]
[ 62150-45-2 ]
[ 73183-34-3 ]
C22H25N5O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94.3%
to a 40 mL flask was placed <strong>[62150-45-2]4-bromopyridine-2-carbonitrile</strong> (1.0 equiv, 1.56 mmol, 286 mg), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-l,3,2-dioxaborolane (2.0 equiv, 3.12 mmol, 793 mg), Pd(dppf)Cl2(0.1 equiv, 0.16 mmol,114 mg), KOAc (3.0 equiv, 4.68 mmol, 460 mg) and dioxane (10 mL) under nitrogen. The reaction solution was stirred at 90 C for 1 h and cooled to rt. To this crude solution was added tert-butyl N-[(3S)-l-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl] carbamate (1.0 equiv, 1.56 mmol, 600 mg,?Step 28-1, Example 28?), Pd(DtBPF)Cl2(0.10 equiv, 0.16 mmol,102 mg), K2C03(3.0 equiv, 4.68 mmol, 647 mg) and H20 (1.0 mL) under nitrogen. The resulting solution was stirred at 80 C for 1 h and cooled to rt, quenched with water (20 mL) and extracted with ethyl acetate (3x30 mL). Organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue obtained was applied onto a silica gel column eluting with ethyl acetate/petroleum ether resulting in 600 mg (94.3%) of title compound as a yellow solid. MS (M+H)+= 408.2
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