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Electrostatically Enhanced 3-and 4-Pyridyl Borate Salt Nucleophiles and Bases
Stephen H. Dempsey ; Alex Lovstedt ; Steven R. Kass ;
Abstract: A variety of electrostatically enhanced 3- and 4-pyridylborate salt catalysts are reported and show significant improvement over an activated noncharged neutral control compound. Their nucleophilicity in a stoichiometric SN2 reaction and catalytic performance in a urethane synthesis are evaluated along with three methods for rapidly evaluating the basicity of these species. That is, qualitative titrations in CH2Cl2 and CHCl3 were carried out, two separate solution-state IR studies in CCl4 and CDCl3 are reported, and the proton affinities of the anionic components of the salts were computed. Charge differences between the anion and its protonated zwitterionic conjugate acid are evaluated along with the highest occupied molecular orbitals of the anions in relationship to some of the surprising reactivity findings that were observed in the two kinetic studies.
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CAS No. : | 1692-15-5 |
Formula : | C5H6BNO2 |
M.W : | 122.92 |
SMILES Code : | C1=C(C=CN=C1)B(O)O |
MDL No. : | MFCD01074545 |
InChI Key : | QLULGIRFKAWHOJ-UHFFFAOYSA-N |
Pubchem ID : | 2734379 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302+H312+H332-H315-H319-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 14h; | Suzuki coupling reaction of tert-butyl 4-bromophenylcarbamate (800 mg, 2.95 mmol) with 4-pyridineboronic acid (300 mg, 2.46 mmol) in the presence of Pd(PPh3)4 (57 mg, 0.05 mmol) and K2C03 (678 mg, 4.9 mmol) in dioxane- H20 (4: 1, 10 mL) at 90 C for 14 hr. tert-Butyl 4-(pyridin-4- yl)phenylcarbamate (600 mg, 75%) was obtained after flash column chromatography (DCM:MeOH, 20: 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 12h;Inert atmosphere; | The compound 1-bromo-4-iodobenzene (20 g, 104.5 mmol) was dissolved in 0.5 L of tetrahydrofuran (THF) in a nitrogen atmospherePyridin-4-yl-boronic acid (15.4 g, 125.4 mmol) and tetrakis (triphenylphosphine) palladium (1.2G, 1 mmol) were added and stirred. Saturated water-saturated potassuim carbonate (17.3 g, 125.4 mmol) was added and heated to 80 CThe mixture was heated to reflux for a period of time. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with dichloromethane (DCM)The water was removed with MgSO4, filtered and concentrated under reduced pressure. The residue thus obtained was purified by flash column chromatographySeparation and purification were conducted to obtain the compound I-6 (15 g, 80%). |
58% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 20 - 110℃; for 24.166h;Inert atmosphere; | Specifically: under argon protection, p-bromoiodobenzene (3.4 g, 12 mmol), 4-pyridineboronic acid (1.3 g, 10 mmol), tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mol) and sodium carbonate (3.2 g, 30 mmol) was added to a 250 mL three-neck bottle. After adding toluene (100 mL), ethanol (30 mL) and water (10 mL), the mixture was evaporated, and then stirred at room temperature for 10 minutes, then heated to reflux to 110 C and stirred for 24 h. Then, it was filtered, concentrated, extracted with saturated brine, dried, and purified by column chromatography to give the product 4-pyridinebromobenzene (yield 58%). |
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; | EXAMPLE 3; Synthesis of (2S)-N-(cyanomethyl)-4-methyl-2-[(R)-phenyl(4'-pyridin-4-yl-1,1'-biphenyl-4-yl)methyl]oxy} pentanamide; Step 1 4-(4-bromophenyl)pyridine; Pyridin-4-ylboronic acid (500 mg, 4.07 mmol), 1-bromo-4-iodobenzene (1.27g, 4.47 mmol) and 2M Na2CO3 (6.1 ml, 12.2 mmol) were dissolved in 20 ml DMF and the solution was degassed 3 times. PdCl2(dppf) (149mg, 0.203 mmol) was added and the mixture was stirred overnight at 80C. The solution was cooled, poured into 100 ml NaHCO3 (sat.) and extracted 3 times with 20ml ethyl acetate. The combined organic layers were then washed with 4 x water, then dried with Na2SO4. 4-(4-bromophenyl)pyridine was obtained and used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); water; at 90℃; for 4.0h; | A solution of <strong>[22200-50-6]4-chloro-7-iodoquinoline</strong> 14-A (500 mg, 1.73 mmol), pyridin-3-ylboronic acid 14-B (212 mg, 1.73 mmol), 2M K2CO3 solution (2.6 ml, 5.19 mmol) and [ (C6H5) 3P] 4Pd (100 mg) in DMF (5 ml) were heated to 90 C for 4 hours. The solution was filtrated and extracted with EtOAC. The organic layer was concentrated and purified by column chromatography using hexane/EtOAC (1/1) to give 234 mg of the compound 14-C. |
46% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); water; at 90℃; for 4.0h; | A solution of <strong>[22200-50-6]4-chloro-7-iodoquinoline</strong> 11-A (500 mg, 1.73 mmol), pyridin-4-ylboronic acid 11-B (212 mg, 1.73 mmol), 2M K2CO3 solution (2.6 ml, 5.19 mmol) and [(C6H5) 3P] 4Pd (100 mg) in DMF (5 ml) were heated to 90 C for 4 hours. The solution was filtrated and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography using hexane/ EtOAc (1/1) to give 193 mg of compound 11-C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 150℃; for 0.25h;Microwave irradiation; Sealed tube; | Example A5; 4-(3,5-Difluoro-4-(l-(4-(trifluoromethyl)benzyl)azetidin-3-yloxy)phenyl)-l-(methylsulfonyl)piperidineineA5g Example A5[0022] Step A: In a microwave vial, a mixture of pyridin-4-ylboronic acid (160 mg, 1.3 mmol), 5-bromo-l,3-difluoro-2-methoxybenzene A5a (223 mg, 1 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) is dissolved/suspended in dimethylformamide (3 mL). To the mixture are added cesium carbonate (978 mg, 3 mmol) and water (3 mL). The vial is sealed and subjected to microwave irradiation (150 C, 15 min). The mixture is filtered through a syringe filter and washed with ethyl acetate. Water is added and the mixture extracted with ethyl acetate (4x). The organic phase is dried over sodium sulfate and concentrated. The crude material is purified by flash chromatography (ethylacetate/hexanes gradient) to afford 4-(3,5-difluoro-4-methoxyphenyl)pyridine A5b as a white solid: 1H-NMR (400 MHz, CDC13) delta 8.69 (d, J= 6 Hz, 2 H), 7.44 (d, J= 6 Hz, 2H), 7.22 (d, J = 9.6 Hz, 2H), 4.09 (s, 3H); MS calcd. for C12Hi0F2NO ([M+H]+): 222.1, found: 222.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90℃; for 13.0h; | Reference Production Example 50; To 13 ml of N,N-dimethylformamide was added 2 g of <strong>[7617-93-8]1-bromo-2,5-bis(trifluoromethyl)benzene</strong>, 5.34 g of cesium carbonate, 0.24 g of tetrakis (triphenylphosphinepalladium) and 1.12 g of 4-pyridineboronic acid, and the mixture was stirred at 90C for 13 hours. Thereafter, the resultant reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate three times. The organic layers obtained by extraction were combined and washed with saturated saline, dried over anhydrous magnesium sulfate, then, concentrated. The resultant residue was subjected to silica gel column chromatography to obtain 1.6 g of 4-(2,5-bistrifluoromethylphenyl)pyridine. [Show Image] 1H-NMR:7.28(d,2H),7.59(s,1H),7.82(d,1H),7.94(d,1H),8.70-8.72 (m,2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 120.0℃; for 10.0h; | Reference Production Example 31; To 9 ml of 1,4-dioxane was added 1.5 g of <strong>[203626-41-9]2-iodo-3-chlorobenzo trifluoride</strong>, 1. 62 g of potassium carbonate, 0.17 g of tetrakis(triphenylphosphinepalladium) and 0.72 g of 4-pyridineboronic acid, and the mixture was stirred at 90C for 4 hours and at 120C for 10 hours. Thereafter, the resultant reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate three times. The organic layers obtained by extraction were combined and washed with saturated saline, dried over anhydrous magnesium sulfate, then, concentrated. The resultant residue was subjected to silica gel column chromatography to obtain 0.5 g of 4-(2-chloro-6-trifluoromethylphenyl)pyridine. [Show Image] 1H-NMR:7.18(d 2H),7.49(t,1H),7.69-7.73(m,2H),8.71(d,2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium carbonate; triphenylphosphine;palladium diacetate; In 1,4-dioxane; water; at 80℃; for 16h; | Palladium (II) acetate (0.47 g, 2.09 mmol) was added to a stirred solution of intermediate 4 (5.0 g, 29.83 mmol), 4-pyridineboronic acid (8.15 g, 59.67 mmol) and triphenylphosphine (0.78 g, 2.98 mmol) in a mixture of 1,4-dioxane (125 ml) and a 1.5 M solution of potassium carbonate (74.5 ml, 111.87 mmol). The mixture was stirred at 80 C for 16h. and then the solvents were evaporated in vacuo. The mixture was partitioned between water and DCM and the organic layer was separated, dried(Na2S04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 5/95). The desired fractions were collected and evaporated in vacuo to yield intermediate 11 (4.2 g, 53%) as a pale brown solid. |
53% | With potassium carbonate;palladium diacetate; triphenylphosphine; In 1,4-dioxane; at 80℃; for 16h; | Example A11 2-Methyl-8-pyridin-4-yl-imidazol[1,2-a]pyrazine Palladium (II) acetate (0.47 g, 2.09 mmol) was added to a stirred solution of intermediate 4 (5.0 g, 29.83 mmol), 4-pyridineboronic acid (8.15 g, 59.67 mmol) and triphenylphosphine (0.78 g, 2.98 mmol) in a mixture of 1,4-dioxane (125 ml) and a 1.5 M solution of potassium carbonate (74.5 ml, 111.87 mmol). The mixture was stirred at 80 C. for 16 h. and then the solvents were evaporated in vacuo. The mixture was partitioned between water and DCM and the organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 5/95). The desired fractions were collected and evaporated in vacuo to yield intermediate 11 (4.2 g, 53%) as a pale brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 100℃; for 24.0h; | 1.67 g of bis(triphenylphosphine)palladium(II)chloride (2.38 mmol) and 15.8 g of sodium carbonate (149 mmol) are added to a solution of 18 g of tert-butyl 4-bromo-2- nitrobenzoate (59.6 mmol) and 10.98 g of pyridine-4-ylboronic acid (89 mmol) in a mixture of 200 ml of dimethoxy ethane and 100 mL of water. The reaction medium is heated at 100C for 24 hours and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (CH2Cl2/AcOEt: 100:0 to 70:30, 30 min). The product is isolated in the form of an oil which crystallizes to yield 14.64 g (82%) of crystals.MS (m/z): (M+l) 301.0.1H NMR: deltaEta ppm (400 MHz, DMSO): 8.73 (2H, d, CHarom, J=6.0Hz), 8.44 (1H, s, CHarom), 8.24 (1H, dd, CHarom, J=8.0Hz), 7.97 (1H, d, CHarom, J=8.0Hz), 7.85 (2H, dd, CHarom, J=4.4Hz), 1.54 (9H, s). |
82% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 24.0h; | Example 20a Tert-butyl 2-nitro-4-(pyridin-4-yl)benzoate 1.67 g of bis(triphenylphosphine)palladium(II)chloride (2.38 mmol) and 15.8 g of sodium carbonate (149 mmol) are added to a solution of 18 g of <strong>[890315-72-7]tert-butyl 4-bromo-2-nitrobenzoate</strong> (59.6 mmol) and 10.98 g of pyridine-4-ylboronic acid (89 mmol) in a mixture of 200 ml of dimethoxyethane and 100 mL of water. The reaction medium is heated at 100 C. for 24 hours and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (CH2Cl2/AcOEt: 100:0 to 70:30, 30 min) The product is isolated in the form of an oil which crystallizes to yield 14.64 g (82%) of crystals. MS (m/z): (M+1) 301.0. 1H NMR: deltaH ppm (400 MHz, DMSO): 8.73 (2H, d, CHarom, J=6.0 Hz), 8.44 (1H, s, CHarom), 8.24 (1H, dd, CHarom, J=8.0 Hz), 7.97 (1H, d, CHarom, J=8.0 Hz), 7.85 (2H, dd, CHarom, J=4.4 Hz), 1.54 (9H, s). |
82% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 24.0h; | 1.67 g of bis(triphenylphosphine)palladium(II)chloride (2.38 mmol) and 15.8 g of sodium carbonate (149 mmol) are added to a solution of 18 g of <strong>[890315-72-7]tert-butyl 4-bromo-2-nitrobenzoate</strong> (59.6 mmol) and 10.98 g of pyridine-4-ylboronic acid (89 mmol) in a mixture of 200 ml of dimethoxyethane and 100 mL of water. The reaction medium is heated at 100C for 24 hours and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (CH2Cl2/AcOEt: 100:0 to 70:30, 30 min). The product is isolated in the form of an oil which crystallizes to yield 14.64 g (82%) of crystals. MS (m/z): (M+1) 301.0. 1H NMR: deltaH ppm (400 MHz, DMSO): 8.73 (2H, d, CHarom, J=6.0Hz), 8.44 (1H, s, CHarom), 8.24 (1H, dd, CHarom, J=8.0Hz), 7.97 (1H, d, CHarom, J=8.0Hz), 7.85 (2H, dd, CHarom, J=4.4Hz), 1.54 (9H, s) |
82% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 24.0h; | Example 20a: tert-butyl 2-nitro-4-(pyridin-4-yl)benzoate 1.67 g of bis(triphenylphosphine)palladium(II)chloride (2.38 mmol) and 15.8 g of sodium carbonate (149 mmol) are added to a solution of 18 g of tert-butyl 4-bromo-2- nitrobenzoate (59.6 mmol) and 10.98 g of pyridine-4-ylboronic acid (89 mmol) in a mixture of 200 ml of dimethoxyethane and 100 mL of water. The reaction medium is heated at 100C for 24 hours and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (CH2Cl2/AcOEt: 100:0 to 70:30, 30 min). The product is isolated in the form of an oil which crystallizes to yield 14.64 g (82%) of crystals. MS (m/z): (M+l) 301.0. 1H NMR: deltaEta ppm (400 MHz, DMSO): 8.73 (2H, d, CHarom, J=6.0Hz), 8.44 (1H, s, CHarom), 8.24 (1H, dd, CHarom, J=8.0Hz), 7.97 (1H, d, CHarom, J=8.0Hz), 7.85 (2H, dd, CHarom, J=4.4Hz), 1.54 (9H, s). |
82% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 24.0h; | Example 20a: tert-butyl 2-nitro-4-(pyridin-4-yl)benzoate 1.67 g of bis(triphenylphosphine)palladium(II)chloride (2.38 mmol) and 15.8 g of sodium carbonate (149 mmol) are added to a solution of 18 g of tert-butyl 4-bromo-2- nitrobenzoate (59.6 mmol) and 10.98 g of pyridine-4-ylboronic acid (89 mmol) in a mixture of 200 ml of dimethoxyethane and 100 mL of water. The reaction medium is heated at 100C for 24 hours and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (CH2Cl2/AcOEt: 100:0 to 70:30, 30 min). The product is isolated in the form of an oil which crystallizes to yield 14.64 g (82%) of crystals. MS (m/z): (M+l) 301.0. 1H NMR: deltaEta ppm (400 MHz, DMSO): 8.73 (2H, d, CHarom, J=6.0Hz), 8.44 (1H, s, CHarom), 8.24 (1H, dd, CHarom, J=8.0Hz), 7.97 (1H, d, CHarom, J=8.0Hz), 7.85 (2H, dd, CHarom, J=4.4Hz), 1.54 (9H, s). |
82% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 24.0h; | 1.67 g of bis(triphenylphosphine)palladium(II)chloride (2.38 mmol) and 15.8 g of sodium carbonate (149 mmol) are added to a solution of 18 g of <strong>[890315-72-7]tert-butyl 4-bromo-2-nitrobenzoate</strong> (59.6 mmol) and 10.98 g of pyridine-4-ylboronic acid (89 mmol) in a mixture of 200 ml of dimethoxyethane and 100 mL of water. The reaction medium is heated at 100C for 24 hours and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (CH2Cl2/AcOEt: 100:0 to 70:30, 30 min). The product is isolated in the form of an oil which crystallizes to yield 14.64 g (82%) of crystals. MS (m/z): (M+1) 301.0. 1H NMR: deltaH ppm (400 MHz, DMSO): 8.73 (2H, d, CHarom, J=6.0Hz), 8.44 (1H, s, CHarom), 8.24 (1H, dd, CHarom, J=8.0Hz), 7.97 (1H, d, CHarom, J=8.0Hz), 7.85 (2H, dd, CHarom, J=4.4Hz), 1.54 (9H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; triphenylphosphine; In 1,4-dioxane; water; at 90℃; for 12h;Inert atmosphere; | General procedure: The appropriate mono-, di- or tri-iodo TPA derivative (300 mg)and pyridin-4-ylboronic acid were dissolved in a mixture ofdioxane/H2O (25 mL, 4/1). Ar was bubbled through the mixture for10 min and [PdCl2(PPh3)2], Na2CO3 and PPh3 were added. The reaction mixture was stirred at 90 °C for 12 h. The cooled reactionmixture was diluted with H2O (50 mL) and extracted with CH2Cl2(2 50 mL). The combined organic extracts were thenwashed withbrine and dried (Na2SO4). Finally, the solvents were evaporatedunder vacuum and the crude product was purified by columnchromatography (SiO2, appropriate eluent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; at 110℃; for 48h;Inert atmosphere; | In the Ar gas protection,Using the intermediate H as a starting material (620 mg; 5 mmol)Were charged into a 50 ml two-necked flask,1,4-dibromobenzene(1.2 g; 5 mmol), 10 mg of Pd (pph3) 4, anhydrous potassium carbonate (1.38 g, 5 mmol)5ml distilled oxygen,40ml anhydrous oxygen-free toluene,110 ° C reflux reaction 48h.Saturated ammonium chloride solution was quenched and extracted with ethyl acetate.The solvent was removed by rotary evaporator,The crude product was then purified by column chromatography to give the substituent (11) as a white solid 700mg(61percent). |
26.26% | A 500 mL sealed tube was charged with pyridin-4-ylboronic acid (1.6 g, 13.0 mmol) 1,4-dibromobenzene (3.07 g, 13.0 mmol), sodium carbonate (5 mL, 2M solution) and mixture of toluene (10 mL) and water (10 mL). The reaction mixture was purged with argon for 30 mm. Then, Pd(PPh3)4 (0.75 g, 0.05 eq) was added to the reactionmixture and the said mixture was heated at 90 00 for about 12 h. 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 crude product, which was purified by column chromatography to yield title compound (0.8 g, 26.26percent) as a white solid. LCMS: (M+2) = 236.0; 1H NMR:(DMSO-d6, 300MHz) 68.64-8.66 (d, 2H), 7.71- 7.80 (m, 6H). | |
26.26% | A 500 mL sealed tube was charged with pyridin-4-ylboronic acid (1.6 g, 13.0 mmol)1 ,4-dibromobenzene (3.07 g, 13.0 mmol), sodium carbonate (5 mL, 2M solution) andmixture of toluene (10 mL) and water (10 mL). The reaction mixture was purged withargon for 30 mm. Then, Pd(PPh3)4 (0.75 g, 0.05 eq) was added to the reactionmixture and heated at 90 00 about 12 h. After cooling, the reaction mixture wasextracted 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 column chromatography to yield title compound (0.8 g, 26.26percent) as a white solid. LCMS: (M+2) = 236.0; 1H NMR: (DMSO-d6, 300MHz ) 68.64-8.66 (d, 2H), 7.71- 7.80 (m, 6H). |
With potassium carbonate; palladium; In toluene; at 80℃; for 16h;Inert atmosphere; | Under N2 gas purification system, Compound A, 0.9 equivalents of compound B, 0.05 equivalents of Pd (0) and 4.0 equivalents of potassium carbonate into toluene, the mixture at a temperature of 80 deg. C oil bath with stirring. After 16 hours, water was added to the mixture, was extracted, the product was eluted with methylene chloride and hexane (2: 1) through the column to obtain a white solid compound C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium fluoride; tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 1h;Inert atmosphere; Microwave irradiation; | A flask was charged with <strong>[158580-57-5]methyl 4-bromo-2-nitrobenzoate</strong> (520 mg, 2 mmol), pyridin-4-ylboronic acid (369 mg, 3 mmol), KF(349 mg, 3 mmol), Pd(PPh3)4(35 mg, 0.03 mmol), and a cosolvent mixture of H2O/EtOH/1,2-dimethoxyethane (3:2:7, 8 mL). The mixture was purged with argon for 10 min and then stirred at 110 C under microwave irradiation for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate, the organic phase was dried by sodium sulfate and concentrated, the residue was purified by chromatography on silica gel (dichloromethane/methanol=50:1) to giveRas an off-white solid (276 mg, 54%), mp 95-96 C.1H NMR (300 MHz, CDCl3)delta8.76 (d,J= 5.0 Hz, 2H), 8.14 (s, 1H), 7.96-7.80 (m, 2H), 7.53 (d,J= 5.3 Hz, 2H), 3.96 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4h; | General procedure: To a solution of and halide in the indicated solvent is added boronic acid or ester, carbonate base, and palladium catalyst at room temperature. After stirring at 100 °C overnight, the mixture is cooled and concentrated.Following Procedure B using 5 (150 mg, 1.04 mmol), 4-pyridinylboronic acid (191 mg, 1.56 mmol), sodium carbonate (220 mg, 2.1 mmol), dioxane (5 mL), water (0.5 mL), and Pd(dppf)Cl2 (50 rng, 0.07 mmol ), react at 90 °C for 4 hours and then purify with silica gel column chromatography (EA:PE = 1 :2) to give A3S as a solid (100 mg, 78percent yield). (MS: [M+H]+ 188.1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.5% | With tetrakis(triphenylphosphine) palladium(0); sodium hydroxide; In water; toluene; for 18.0h;Reflux; Inert atmosphere; | 21.3 g of compound 3, 12.9 g of 4-pyridineboronic acid, 50 ml of toluene, 50 ml of a 2M aqueous solution of sodium hydroxide, 2.3 g of tetrakis(triphenylphosphine)palladium, were added in the reaction vessel, and refluxed under a nitrogen atmosphere for 18 hours, Cooled to room temperature, 10ml 50% aqueous sodium hydroxide was added, stirred for 15min, the aqueous layer was separated, the aqueous layer was adjusted with acetic acid rhoEta = about 6, solid precipitated, yield obtained 15.3g white solid milrinone (yield 72.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In butan-1-ol; at 110℃; for 3h;Inert atmosphere; | 4-Pyridyl boronic acid (73 mg, 0.591 mmol, 1.2 equivalents), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (47 mg, 0.99 mmol, 0.2 equivalents), potassium phos-phate (315 mg, 1.478 mmol, 3 equivalents) and tris(dibenzylideneacetone) dipal-ladium(0) (23 mg, 0.025 mmol, 0.05 equivalents) were added to <strong>[910543-72-5]1-methyl-3-amino-5-bromopyridin-2-one</strong> (100 mg, 0.493 mmol, 1 equivalent) in butan-1-ol (5 mL) and the reaction mixture was heated to 110 C for 3 hours. The solution was then cooled and filtered through a pad of celite, which was washed with MeOH. The solution was concentrated and the residue taken up in MeOH and filtered through a SCX column and then purified by column chromatography (5% MeOH in CHCl3) to give a brown solid (45 mg, 46%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 90℃; for 8h;Inert atmosphere; | 4-pyridine boronic acid (197 mg, 1.6 mmol), K2CO3 (220 mg, 1.6 mmol) was added in a 50 mL two-necked flask under argon.Compound (d) (273 mg, 0.4 mmol) and Pd(PPh3) 4 (46 mg, 0.04 mmol),Add 30 mL of a mixed solvent of toluene and ethanol (1:1 by volume).The mixture was reacted at 90 C for 8 hours. After the reaction is over, cool to room temperature.The solvent was removed under reduced pressure. 10 mL of water was added to the reaction mixture.The organic layer was combined and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure and separated by column chromatography.Dichloromethane (DCM) / methanol (MeOH) = (40:1),Obtained as a purple-black solid (190 mg, 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 20 - 100℃;Inert atmosphere; | 31 (0.172 g, 0.5 mmol, 1 eq.), 4-pyridinylboronic acid (0.092 g, 0.75 mmol, 1.5 eq.), Pd2(dba)3(0.023 g, 0.025 mmol, 0.05 eq.) and P(c-hexyl)3 (0.017 g, 0.06 mmol,0.12 eq.) were added to a 10mL round-bottom flask, containing astir bar. Next, the flask was evacuated and refilled with argon three times. Then, 1,4-dioxane was added (1.33 mL, 2.67 mL/mmol SM)together with 1.27M aq. K3PO4 solution (0.67 mL, 1.33 mL/mmolSM). The flask was stirred at ambient temperature for ~5 min andthen transferred to a pre-heated oil bath at 100 C. Heating wascontinued for 20 h, after which the mixture was cooled to ambient temperature. The mixture was neutralized (pH ~ 7) with 0.5M aq.HCl. The mixture was evaporated till dryness and re-suspended in MeOH and evaporated (three times). Next, the mixture wasadsorbed onto Celite (from MeOH) and eluted over a short silicapad (~5 cm) with 20% MeOH/DCM. The liquid was evaporated invacuo and purified by column chromatography 5/20% MeOH/EA.15 was isolated as a yellow solid (0.06 g, 0.175 mmol). Yield 35%.Melting point: 260-261 C. 1H NMR (300 MHz, DMSO-d6) delta:3.51-3.58 (m, 1H, H-5??), 3.61-3.68 (m, 1H, H-5'), 3.91 (q, J 3.6 Hz,1H, H-4'), 4.12 (br. s, 1H, H-3'), 4.45 (br. s, 1H, H-2'), 5.13-5.20 (m,2H, OH-3', OH-5'), 5.36 (br. s, 1H, OH-2'), 6.13 (d, J 6.3 Hz, 1H, H-1'), 6.38 (br. s, 2H, NH2), 7.47 (dd, J 4.5, 1.8 Hz, 2H, H-3Pyr, H-5Pyr),7.79 (s, 1H, H-6), 8.18 (s, 1H, H-2), 8.61 (dd, J 4.5, 1.8 Hz, 2H, H-2Pyr,H-6Pyr). 13C NMR (75 MHz, DMSO-d6) delta: 61.6 (C-50), 70.5 (C-30), 73.8(C-20), 85.2 (C-40), 87.1 (C-1?), 99.9 (C-4a), 114.0 (C-5), 122.8 (2C, C-3Pyr, C-5Pyr), 123.0 (C-6), 141.9 (C-4Pyr), 149.9 (2C, C-2Pyr, C-6Pyr),151.5 (C-7a), 152.0 (C-2), 157.4 (C-4). HRMS (ESI): calculated forC16H18N5O4: 344.1353 ([MH]), found: 344.1350. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 16h;Reflux; | General procedure: 10.0 g (81.4 mmol) of pyridine-3-boronic acid (CAS No.: 1692-25-7), 29.2 g (81.4 mmol) of 2-bromo-3'-iodobiphenyl (CAS No.: 1776936-09-4) and 93 ml of an aqueous 2 M Na2CO3 solution (186 mmol) are suspended in 75 ml of ethanol and 120 ml of toluene. To this suspension is added 0.94 g (0.82 mmol) of tetrakis(triphenyl)phosphinepalladium(0). The reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is removed, filtered through silica gel, washed three times with 150 ml of water and then concentrated to dryness. After the crude product has been filtered through silica gel with heptane/ethyl acetate, 19 g (79%) of 3-(2'-bromobiphenyl-3-yl)pyridine are obtained. |
Tags: Pyridine-4-boronic acid | Pyridines | Organoboron | Boronic Acids | Heterocyclic Building Blocks | Boronic Acids/Esters | Organometallic Reagents | 1692-15-5
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