* 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.
Stage #1: With water; sodium hydroxide In tetrahydrofuran at 23℃; for 0.333333 h; Stage #2: Aqueous phosphate buffer
The general method for synthesizing unprotected organoboronic acids was as follows. Under ambient atmosphere, to a 100 mL flask equipped with a stir bar and charged with MIDA boronate (2) (5 mmol) as a solution in THF (50 mL) was added aqueous NaOH (1.0 M, 15 mL). The mixture was vigorously stirred for 20 min. The mixture was then transferred to a separatory funnel and was diluted with EbO (50 mL) and 0.5 M pH 7 sodium phosphate buffer (50 mL). The mixture was shaken, and the phases were separated. The aqueous phase was extracted with THFiEt2O (1 :1 , 2 x 25 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. Residual solvent was co-evaporated with MeCN, and the resulting solid was placed under vacuum ( ~ 1 Torr) for 30 min. All boronic acids thus obtained were judged to be > 95percent pure by 1 H-NMR and were utilized in cross-coupling reactions immediately after preparation. An example of this method is depicted in the scheme below. To form unprotected organoboronic acid 1a, the general procedure was followed using MIDA boronate 2a (1.127 g, 5.002 mmol) to yield the 1a as an off white solid (0.531 g, 95percent). TLC (EtOAc) Rf = 0.46, stained with KMnO4. 1H-NMR (500 MHz, DMSO-d6:D2O 95:5 w/ TMS) δ 7.81 (dd, / = 1 .5, 0.5 Hz, 1 H), 7.07 (dd, / = 3.0, 0.5 Hz, 1 H), 6.48 (dd, / = 3.5, 2.0 Hz, 1 H). 13C-NMR (125 MHz, DMSO-d6:D2O 95:5 w/ TMS) δ 146.4, 121.5, 1 10.3. HRMS (El +) Calculated for C4HsO3B (M) + : 1 12.0332, Found: 1 12.0332.
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, p. 6961 - 6963
[2] Patent: WO2010/36921, 2010, A2, . Location in patent: Page/Page column 41
Reference：
[1] Journal of the American Chemical Society, 1938, vol. 60, p. 111 - 115
[2] , Gmelin Handbook: B: B-Verb.13, 4.7.2.2, page 189 - 196,
12
[ 166328-14-9 ]
[ 7732-18-5 ]
[ 13331-23-2 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 17, p. 7431 - 7441
13
[ 166328-14-9 ]
[ 13331-23-2 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 17, p. 7431 - 7441
14
[ 13331-23-2 ]
[ 540-37-4 ]
[ 59147-02-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
With C7H10N2*Pd(2+)*2Cl(1-); potassium carbonate In methanol; water for 0.166667 h; Reflux; Schlenk technique
General procedure: A 20mL Schlenk tube with a magnetic stir bar was charged with aryl halide (2mmol), arylboronic acid (2.4mmol), K2CO3 (5mmol), 10mL of solvent [H2O, H2O–MeOH (1:1), H2O–EtOH (1:1), H2O–EG (1:1)] and an aliquot of 0.01M solution of palladium complexes PdCl2(L)2 or Pd[(L)4]Cl2 in MeOH (0.001–0.2molpercent) under air atmosphere. The reaction mixture was placed in a preheated oil bath: at 100°C for MeOH–H2O, at 110°C for EtOH–H2O, at 140°C for H2O and at 160°C for EG–H2O; and stirred under reflux for the given time. After this time, the mixture was cooled, acidified by 5M HCl (in the case of acids) and diluted with 10mL of H2O and 10mL of Et2O (or EtOAc). The organic phase was separated, and the aqueous layer was extracted with Et2O EtOAc) (2×10mL). The combined organic layers were washed with H2O (10mL), brine (10mL), and dried over Na2SO4. The pure products were obtained by a simple filtration of ether solution through silica gel pad and evaporation of a solvent.
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In methanol; toluene at 100℃; for 16 h; Inert atmosphere
General procedure: According to a procedure by Oxford et al.,[3] furan-2-boronic acid (168 mg, 1.5 mmol, 1.5 eq), aryl halide (1.0 mmol, 1.0 eq), Pd(PPh3)4 (116 mg, 0.1 mmol, 10 molpercent) and cesium carbonate (350 mg, 1.1 mmol, 1.1 eq) were suspended in a toluene/MeOH mixture (4:1, 10 mL). The reaction mixture was stirred for 16 h at 100 °C. The reaction mixture was diluted with EtOAc (8 mL) and the organic layer was extracted was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography.
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; water; N,N-dimethyl-formamide; at 70℃; for 7h;
Example 347 2-(4-Furan-2-yl-thiazol-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5347) 4-Furan-2-yl-thiazol-2-ylamine <strong>[502145-18-8]4-Bromo-thiazol-2-ylamine</strong> (100 mg, 0.34 mmol) was combined with 57 mg (0.51 mmol) of 2-furan boronic acid. To this mixture was added 5 mL of MeOH, 1 mL of sat. NaHCO3 (aq), and 0.8 mL of DMF. Reaction mixture was degassed and Pd[P(Ph)3]4 (25 mg) was added. Reaction mixture was heated at 70 C. for 7 hours. The reaction mixture was brought to room temperature and filtered. The filtrate was evaporated and purified using reverse phase HPLC.
With potassium phosphate; In ethanol; water; at 80℃; for 1h;Inert atmosphere;
General procedure: Inside an argon atmosphere glove box, halide (0.5mmol), boronic acid (0.75mmol), K3PO4 (1.5mmol), PPPd (4mg, 1.4wt% Pd, 0.0005mmol), solvent (2ml, H2O/EtOH v/v=2:3) were mixed in a 5ml vessel and sealed. Then it was moved out of the glove box and heated in an oil bath to 80C for 2-6h. After cooled down to r.t. for about half an hour, the mixture was filtered. Take a small amount of the liquid for GC analysis. The solid part was washed three times with ethanol. The combined liquid was dried and purified by column to give pure coupling product. For recycle experiments, the solid part after washing was degassed and used into the next cycle. Combing the recycled catalyst from X reaction times was marked as Re-PPPd-X.
90%
With potassium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 2h;
General procedure: To a mixture of aryl halide (1 mmol), arylboronic acid (1.2 mmol), Pd-AcAc-Am-Fe3O4/SiO2 (30 mg ), and K2CO3 (3 mmol), DMF: water (8:2, 5 mL) was added and stirred at 80 C under aerobic conditions. After completion of reaction, monitored by TLC, the reaction mixture was cooled. The catalyst was separated by using external magnet. The product was extracted with ethylacetate (2×10 mL) The organic layer was dried with Na2SO4 and then concentrated on a rotary evaporator afforded corresponding biaryls in excellent yield. The crude products were then purified by column chromatography (2 % ethyl acetate). All synthesized products were confirmed from physical constant IR, 1H and 13C NMR.
80%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In methanol; toluene;Inert atmosphere; Schlenk technique; Reflux;
According to the literature procedure,19 a two-neckround-bottom flask equipped with an N2 balloon and a rubbercap was charged with 2-furylboronic acid (1.00 g, 8.93mmol),iodobenzene (696 mg, 4.47mmol), Pd(PPh3)4 (514 mg, 10mol%), and Cs2CO3 (1551 mg, 4.76 mmol). Toluene (10 mL)and methanol (2.5 mL) were added via syringe, and the mixturewas refluxed overnight. The resulting suspension was dilutedwith H2O and was extracted with EtOAc three times. The combinedorganic layer was dried over Na2SO4 and concentratedin vacuo. The crude material was subjected to silica gel chromatography(eluent: hexane) to give 2-phenylfuran as paleyellow oil in 80% yield (514 mg, 3.57mmol). NMR data were identical with those reported in the literature.20 1HNMR (400MHz, CDCl3) delta 6.48 (dd, J = 1.8, 3.3 Hz, 1H), 6.646.67(m,1H), 7.237.29(m, 1H, overlapped with CDCl3), 7.357.42(m,2H), 7.457.50(m, 1H), 7.657.71(m, 2H).
With 1,1'-bis-(diphenylphosphino)ferrocene; triethylamine;palladium diacetate; In N,N-dimethyl-formamide; at 50 - 90℃;Inert atmosphere;
A mixture of Pd(OAc)2 (146 mg, 0.7 mmol) and 1,1-bis(diphenylphosphino)ferrocene (478 mg, 0.9 mmol) in DMF (65 ml) under an argon atmosphere was stirred at 50 for 15 min and cooled to rt. The reaction mixture was evacuated, then flushed with argon. 3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (5.0 g, 21.5 mmol), 2-furanboronic acid (2.65 g, 23.7 mmol) and triethylamine (4.3 ml) were added. The reaction mixture was again evacuated, then flushed with argon. The mixture was heated at 90 overnight. After cooling to rt, the black mixture was concentrated to dryness. The residue was dissolved in dichloromethane (800 ml), washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by silica gel chromatography using a n-heptane /EtOAc gradient for elution, providing the title compound as yellow solid (2.84 g, 60%).MS: M=220.3 (M+H)+
60%
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere;
A mixture of Pd(OAc)2 (146 mg, 0.7 mmol) and l,l-bis(diphenylphosphino)ferrocene (478 mg, 0.9 mmol) in DMF (65 ml) under an argon atmosphere was stirred at 50 for 15 min and cooled to rt. The reaction mixture was evacuated, then flushed with argon. 3-Amino-6-bromopyrazine- 2-carboxylic acid methyl ester (5.0 g, 21.5 mmol), 2-furanboronic acid (2.65 g, 23.7 mmol) and triethylamine (4.3 ml) were added. The reaction mixture was again evacuated, then flushed with argon. The mixture was heated at 90 overnight. After cooling to rt, the black mixture was concentrated to dryness. The residue was dissolved in dichloromethane (800 ml), washed with water, dried over MgS04, filtered and evaporated. The crude product was purified by silica gel chromatography using a n-heptane/EtOAc gradient for elution, providing the title compound as yellow solid (2.84 g, 60%).MS: M = 220.3 (M+H)+
0.15 eq. palladium (II) acetate and 0.2 eq. 1,1'-bis(diphenylphosphino)-ferrocene were combined in dimethylformamide under nitrogen and heated to 50 C. for 20 minutes. Het is as defined herein. The reaction was allowed to cool to room temperature and 1.0 eq. of the pyrazine, 1.5 eq. of the boronic acid and 1.15 eq. of triethylamine were added. The reaction was heated to 90 for 12 hours and allowed to cool to room temperature. The DMF was removed by rotary evaporation. The crude reaction mixture was dissolved in chloroform and washed twice with 1N aq. HCl and then twice with saturated aq. NaHCO3 solution. The organic layer was dried over sodium sulfate, filtered and concentrated. Material was purified by silica gel chromatography using 100% chloroform as eluent.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 13h;Heating / reflux;
Reference Example 61 6-(2-Furyl)-2-pyridinecarbonitrile 6-Chloro-2-pyridinecarbonitrile (0.90 g, 6.5 mmol) and 2-furanboric acid (1.1 g, 9.8 mmol) were dissolved in toluene (80 ml)-ethanol (205 ml), and potassium carbonate (2.2 g, 15.9 mmol) and water (20 ml) were added thereto.. The mixture was deairated under reduced pressure for 10 minutes. tetrakis(triphenylphosphine)palladium (0) (0.36 g, 0.31 mmol) was added to the reaction mixture under argon atmosphere, and the mixture was refluxed for 13 hrs.. The reaction mixture was combined with ethyl acetate and water.. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography.. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.97 g, 87 %). mp. 90.2-90.3 C1H-NMR (CDCl3) delta: 6.57 (1H, dd, J = 1.6, 3.5 Hz), 7.20 (1H, m), 7.51 (1H, dd, J = 1.6, 6.9 Hz), 7.56 (1H, dd, J = 0.6, 1.6 Hz), 7.80-7.89 (2H, m). IR(KBr): 3155, 3057, 2237, 1604, 1574, 1491, 1440, 1168, 1006, 922, 804 cm-1.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 5.66667h;Heating / reflux;
2-Bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (3.00 g, 11.2 mmol) and Pd(PPh3)4 (416 mg, 0.36 mmol) were dissolved in dimethoxyethane (3.6 ml) under an argon atmosphere and stirred for 10 minutes. The reaction solution was added with 2-furanboronic acid (1.45 g, 12.9 mmol), immediately added with 1 M aqueous sodium carbonate (28 ml) and refluxed. After 5.5 hours, the reaction solution was cooled to room temperature. The solvent was evaporated, and the residue was added with water and extracted with ether. The insoluble solids were removed by filtration, and the filtrate was washed with saturated brine, dehydrated over MgSO4 and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:50) to obtain Compound XI-1 (1.00 g, 35%). Compound XI-1: <1>H-NMR (400 MHz, CDCL3) 7.61 (d, J = 2.0 Hz, 1 H), 7.44 (d, J = 1.1 Hz, 1 H), 7.42 (dd, J = 8.1, 2.0 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 1 H), 6.58 (d, J = 3.4 Hz, 1 H), 6.44 (dd, J = 3.1, 1.1 Hz, 1 H), 1.70 (s, 4 H), 1.33 (s, 6 H), 1.29 (s, 6 H)
2-amino-6-furan-2-yl-5-nitro-3H-pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,4-dioxane; water; acetone;
b 2-Amino-6-furan-2-yl-5-nitro-3H-pyrimidin-4-one To a stirred solution of 15.7 g (75.3 mmol) 2-amino-6-chloro-5-nitro-3H-pyrimidin-4-one in 300 ml dioxane and 100 ml water at room temperature were added 8.40 g (75.0 mmol) 2-furylboronic acid, 8.70 g (7.53 mmol) tetrakis(triphenylphosphine)palladium(O) and 150 ml (300 mmol) 2M aqueous sodium carbonate solution. The reaction mixture was heated at reflux for 7 h, then concentrated in vacuo. The residue was resuspended in acetone and the insoluble material collected by filtration. This solid material was then dissolved in 1.2 1 water and acidified to pH 4-5 with 25% hydrochloric acid. The resulting crystals were collected by filtration and washed with water. After drying in vacuo they were additionally washed with dichloromethane to afford 7.33 g (44%) 2-amino-6-furan-2-yl-5-nitro-3H-pyrimidin-4-one as a yellow crystalline solid. ES-MS m/e (%): 221 ([M-H]-, 100).
1-{3-[2-(4-Chlorophenyl)-5-(2-Furanyl)-1-Methyl-1H-Indol-3-yl]-1-Oxopropyl}-4-(Phenylmethyl)-4-Piperidinol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
In 1,2-dimethoxyethane;
EXAMPLE 52 1-{3- [2-(4-Chlorophenyl)-5-(2-Furanyl)-1-Methyl-1H-Indol-3-yl]-1-Oxopropyl}-4-(Phenylmethyl)-4-Piperidinol 2-Furanylboronic acid (40 mg, 0.36 mmol) and aqueous sodium carbonate (2M, 1 mL) were added to a solution of 1-{3-[5-bromo-2-(4-chlorophenyl)-1-methyl-1H-indol-3-yl]-1-oxopropyl}-4-(phenylmethyl)-4-piperidinol (Example 49, 100 mg, 0.18 mmol) in 1,2-dimethoxyethane (10 mL) and the mixture was degassed. Tris(dibenzylideneacetone) dipalladium(0) (66 mg) and tris(2-furanyl)phosphine (2 mg) were added and the mixture was degassed, then heated to 75 C. overnight. The mixture was cooled and poured into aqueous sodium hydrogen carbonate (saturated, 50 mL) and extracted with ethyl acetate (4*25 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by medium pressure liquid chromatography on silica gel, eluding with ethyl acetate: isohexane (1:1), to give the title compound (30 mg, 30%). 1H NMR (360 MHz, CDCl3) delta7.95 (1H, d, J 1.7 Hz), 7.61 (1H, dd, J 1.6, 8.3 Hz), 7.49-7.47 (3H, m), 7.34-7.26 (6H, m), 7.12 (2H, dd, J 1.6, 8.3 Hz), 6.63 (1H, d, J 3.2 Hz), 4.34 (1H, br d, J 12.6 Hz), 3.57 (3H, s), 3.37 (1H, br d, J 10.5 Hz), 3.18 (1H, dt, Jt 11.3, Jd 1.5 Hz), 3.10-3.04 (2H, m), 2.90-2.82 (1H, m), 2.63 (2H, s), 2.58-2.52 (2H, m), 1.47-1.42 (2H, m), 1.34 (1H, br d, J 13.8 Hz), and 1.22-1.16 (1H, m). m/z (ES+) 553, 555 (M+1).
A) 23.0 g of tert. butoxycarbonyl-piperazine (formula X) were dissolved in 600 ml ethanol under nitrogen at 30 C. 25 g of 2-furanboronic acid (formula VIII) and 22.0 g of 80% pure (D)-glyceraldehyde (formula IX) in 400 ml ethanol were heated to reflux for 7 hours. The mixture was cooled down to room temperature and concentrated to dryness. The residue was dissolved in 200 ml ethyl acetate and 50 ml methyl-tert.-butylether and successively washed with a solution of 20 g of KOH in 200 ml water. The residue was further washed with six portions of 150 ml water before drying over sodium sulfate. After evaporation of the solvent, 54.7 g of 4-((2S)-1-furan-2-yl-2-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester (formula XI) was obtained. [alpha]D20=+34.6 (c=1, methanol). Melting point: 92 to 93
3-cyano-naphthalene-1-carboxylic acid [2S-(3,4-dichloro-phenyl)-4-piperazin-1-yl-butyl]-amide[ No CAS ]
[ 453-17-8 ]
[ 939972-38-0 ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; for 5h;Heating / reflux;
3.O g of S-cyano-naphthalene-i-carboxylic acid [2S-(3,4-dichloro-phenyl)-4- piperazin-1-yl-butyl]-amide (formula VII, from reaction step E)), 806 mg of 2- furanboronic acid (formula VIII) and 945 mg of 80% pure (D)-glyceraldehyde (formula IX) in ethanol were heated to reflux for 5 hours. The mixture was kept at room temperature over night before distilling off the organic solvent. The product obtained was purified by column chromatography (ethyl acetate till ethanol) to deliver 1.3 g of pure crystalline 3-cyano-?/-[(2S)-2-(3,4- dichlorophenyl)-4-{4-[(1 fi,2S)-1-(2-furyl)-2,3-dihydroxypropyl]piperazin-1- yl}butyl]-?/-methyl-1-naphthamide (formula I). MD20 = -27,6 (c = 1 , methanol).MS-data (ES+): M+ bei m/z = 635 Melting point = 140-142 0C
In ethanol; at 20℃;Heating / reflux;Product distribution / selectivity;
F) 3.0 g of 3-cyano-naphthalene-1-carboxylic acid [2S-(3,4-dichloro-phenyl)-4-piperazin-1-yl-butyl]-amide (formula VII, from reaction step E)), 806 mg of 2-furanboronic acid (formula VIII) and 945 mg of 80% pure (D)-glyceraldehyde (formula IX) in ethanol were heated to reflux for 5 hours. The mixture was kept at room temperature over night before distilling off the organic solvent. The product obtained was purified by column chromatography (ethyl acetate till ethanol) to deliver 1.3 g of pure crystalline 3-cyano-N-[(2S)-2-(3,4-dichlorophenyl)-4-{4-[(1R,2S)-1-(2-furyl)-2,3-dihydroxypropyl]piperazin-1-yl}butyl]-N-methyl-1-naphthamide (formula I). [alpha]D20=-27.6 (c=1, methanol). MS-data (ES+): M+ bei m/z=635 Melting point=140-142 C.
Example 286; Preparation of N-{5-[3-(2-furanyl)-6-quinoxalinyl]-3-pyridinyl}benzenesulfonamide; A slurry of 7-bromo-2-chloroquioxaline (0.82 mmol), a boronic acid such as 2-furan boronic acid (0.82 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.06 mmol), in 1,4-dioxane (4 ml) and 2M solution potassium carbonate (2 ml) was stirred at 100 C. for 3 hour. Then N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.90 mmol) was added and the reaction mixture stirred at 100 C. for 18 hours. The reaction was cooled to ambient temperature, the organic layer separated and purified directly on silica by column chromatography (50% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give the title compound (50 mg, 14%) as a tan solid. MS (ES)+ m/e 429.0 [M+H]+.
N-[5-bromo-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide[ No CAS ]
[ 374790-93-9 ]
[ 1438429-57-2 ]
Yield
Reaction Conditions
Operation in experiment
353 mg of 2-furylboronic acid, 624 mg of sodium carbonate in 25 cm3 of water, and 311 mg of tetrakis(triphenylphosphine)palladium are added to 1.25 g of N-[5-bromo-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared in Example 63, in 125 cm3 of dioxane, and the mixture is refluxed for 18 hours, 611 mg of 2-furan-2-yl-4,4,5,5-tetramethyl[1,3,2]dioxaborolane are then added and heating is continued for 4 hours at reflux. 75 cm3 of ethyl acetate and 75 cm3 of water are added and the reaction medium is filtered through a sinter funnel packed with Celite. The organic phase is separated out after settling of the phases has taken place, washed with 75 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50 C.) to give 2 g of an oil, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 mum; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (75/25 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50 C.) to give 1.20 g of N-[5-(2-furyl)-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a beige-coloured solid. [0886] 1H NMR spectrum (300 MHz, (CD3)2SO-d6, delta in ppm): -0.09 (s: 9H); 0.82 (t, J=8 Hz: 2H); 0.97 (t, J=7.5 Hz: 3H); 1.68 (mt: 2H); 2.43 (t, J=7 Hz: 2H); 3.55 (t, J=8 Hz: 2H); 5.17 (s: 2H); 5.61 (d, J=3.5 Hz: 1H); 5.68 (broad s: 2H); 6.38 (dd, J=3.5 and 1.5 Hz: 1H); 7.07 (d, J=8.5 Hz: 2H); 7.19 (d, J=8.5 Hz: 2H); 7.36 (broad t, J=7.5 Hz: 1H); 7.43 (broad t, J=7.5 Hz: 2H); 7.50 (broad d, J=7.5 Hz: 2H); 7.59 (s: 1H); 7.61 (d, J=1.5 Hz: 1H); 8.20 (s: 1H); 10.58 (unresolved peak: 1H). [TABLE-US-00057] EI m/z = 581M+. m/z = 464[M - OCH2CH2Si(CH3)3]+ m/z = 91[C6H5CH2]+
With caesium carbonate; lithium chloride;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; for 2h;Heating / reflux;
To a solution of 0.10 g of <strong>[23611-75-8]methyl <strong>[23611-75-8]6-chloropyrazine-2-carboxylate</strong></strong> in 2.9 mL of dioxane, 65 mg of 2-furanboronic acid, 74 mg of lithium chloride, 0.57 g of cesium carbonate, 21 mg of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and 24 mg of tris(dibenzylideneacetone)dipalladium(0) were added, and the mixture was heated under reflux for 2 hours. To the reaction mixture, water and ethyl acetate were added, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate = 87:13 to 83:17 to obtain 74 mg of methyl 6-(2-furyl)pyrazine-2-carboxylate as a white solid. 1H-NMR (CDCl3) delta: 4.05 (3H, s), 6.60 (1H, dd, J = 3.5, 1.8 Hz), 7.30-7.32 (1H, m), 7.62-7.65 (1H, m), 9.12 (1H, s), 9.12 (1H, s)
With C11H20N3(1+)*C2F6NO4S2(1-); palladium diacetate; at 60℃; for 3h;Ionic liquid; Inert atmosphere;
General procedure: An oven-dried reaction tube equipped with a magnetic stirrer bar was charged with the aryl-boronic acid (Table 1) or the substituted alkene (Table 2) (1.3 mmol), aryl (or benzyl) bromide (1.1 mmol), Pd(OAc)2 (5-6 mol%), [PAIM][NTf2] (4 mmol), and [BMIM][PF6] (7 mL).The reaction mixture was stirred under a nitrogen atmosphere at 60-70 C, and the progress of the reaction was monitored by TLC. After completion (2-3 h in the Suzuki reaction and 4-7 h for the Heck reaction) the reaction mixture was extracted 3 times with hexane/ethylacetate (80:20) and the products were purified by flash column chromatography using hexane/ethyl acetate (80:20) or DCM/MeOH (95:5).
79%
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere;
General procedure: A solution of aryl halide (1 equivalent), the corresponding furan-2-boronic acid (1.2 equivalents) and potassium carbonate (2.5 equivalents) in a mixture of dioxane (1 mL/mmol): water (0.3 mL/mmol) was added in a three-necked flask equipped with reflux condenser, and degassed for 20 minutes in an argon stream. Pd(dppf)2C12 (5mo1%) was added and the mixture was stirred for 16 h at 100 C. After cooling to room temperature, water and dichloromethane were added and the phases are separated. The organic phase was washed three times with water, then the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and the solvents were distilled off in vacuo. The crude product was purified by column chromatography (stationary phase: silica gel, eluent: petroleum ether).
62%
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; for 3h;Inert atmosphere;
Step 1. 2-PhenylfuranTo a solution of (furan-2-yl)boronic acid (3.0 g, 26.81 mmol) in dioxane (50.0 mL) and water (1.0 mL) was added bromobenzene (2.10 g, 13.38 mmol), K3PO4 (9.3 g, 43.81 mmol) and Pd(PPh3)4 (767 mg, 0.66 mmol) with stirring for 3h at 95C in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (1 % ethyl acetate in petroleum ether) to afford 2-phenylfuran as colorless oil (1.20g, 62%). 'H-NMR (300 MHz, CDCI3): delta 7.69 - 7.72 (m, 2H), 7.50 (d, / = 0.6 Hz, 1H), 7.38 - 7.49 (m,2H), 7.26 - 7.31 (m, 2H), 6.68 - 6.69 (m, 1H), 6.47 - 6.49 (m, 1H)
50%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In methanol; toluene; at 100℃; for 16h;Inert atmosphere;
General procedure: According to a procedure by Oxford et al.,[3] furan-2-boronic acid (168 mg, 1.5 mmol, 1.5 eq), aryl halide (1.0 mmol, 1.0 eq), Pd(PPh3)4 (116 mg, 0.1 mmol, 10 mol%) and cesium carbonate (350 mg, 1.1 mmol, 1.1 eq) were suspended in a toluene/MeOH mixture (4:1, 10 mL). The reaction mixture was stirred for 16 h at 100 C. The reaction mixture was diluted with EtOAc (8 mL) and the organic layer was extracted was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography.
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 140℃; under 10343.2 Torr; for 0.5h;Microwave irradiation;
Furan-2-boronic acid (22) (3.6 g, 32.14 mmol) was coupled to bromobenzene (21) (4.2 g, 26.79 mmol) using Method E, except that Cs2CO3 (17.47 g, 53.58 mmol), Pd(PPha)4 (6.20 g, 0.54 mmol), toluene (25 mL) and EtOH (25 mL) were used and the reaction heated in a CEM Discover microwave at 140 C. (200 W, 200 psi). The crude product was purified by dry-flash chromatography eluting with EtOAc in heptane to yield the title compound. Yield: 2.94 g, 62%; LC tr 1.50 min; HPLC Purity: 84%
With tetrakis(triphenylphosphine) palladium(0); triethylamine; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere;
General procedure: A mixture of bromoaldehyde (1.0 mmol), furan-2-boronic acid (1.2 mmol.), Et3N (7.0 mmol) in DMF was degasified with argon for 30 minutes. Now the catalyst Pd(PPh3)4 (2 mol%) was added to it. The mixture was then heated with stirring under argon atmosphere at 100 oC till the reaction was completed (monitored by TLC). When the reaction was completed, the reaction mixture was cooled to room temperature and poured into ice water (30 mL) and extracted with ether (3 × 20 mL). Organic layer was washed successively with NaHCO3 solution, 5% brine and dried over anhydrous Na2SO4. Then the solvent was evaporated and the crude product thus obtained was then purified by column chromatography [silica gel, pet ether (60-80 oC) - EtOAc].
With trisodium tris(3-sulfophenyl)phosphine; palladium diacetate; sodium carbonate; In water; acetonitrile; at 100℃; for 3h;Inert atmosphere;
General procedure: An argon purged mixture of compound 18 (150 mg, 0.38 mmol), phenylboronic acid (58 mg, 0.48 mmol), Na2CO3 (122 mg, 1.14 mmol), Pd(OAc)2 (4.3 mg, 19 mumol) and TPPTS (33 mg, 0.057 mmol) in water-MeCN (2:1, 2.5 ml) was stirred at 100 C for 3 h. After cooling, the mixture was neutralized by the addition of aq HCl (1 M), volatiles were removed in vacuo. The residue was purified twice by reverse phase HPFC on C-18 column (0?100% MeOH in water). Compound 19a (96 mg, 73%) was obtained as a white crystalline solid after recrystallization (MeOH-water 1:4).
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In ethanol; water; toluene; at 80℃;Schlenk technique; Inert atmosphere;
In a Schlenk flask, 2,5- dibromo-1,4-phenylenediamine (200 mg, 0.752 mmol) and 2-furanylboronic acid 16 (337 mg, 3.0 mmol) were charged under the protection of nitrogen. After adding 15 ml toluene, 10 ml ethanol and 5 ml Cs2CO3 aqueous solution (2.0 mol/l), the mixture was degassed for 30 mm. Pd(PPh3)4 (87 mg, 0.0752 mmol) was added. The mixture was then heated to 80 C, stirred overnight, poured into brine andextracted with dichloromethane for several times. The organic phase was dried over Mg2SO4 and the solvent was evaporated in vacuo. The product was purified by chromatography on silica gel to give product 17 as golden yellow flaky crystal. 1H NMR (400 MHz, CDCI3, ppm): 3.99 (br, 4H), 6.51 (dd, i 3.39, 1.85 Hz, 2H), 6.62 (dd, J = 3.39, 0.70 Hz, 2H), 6.98 (s, 2H), 7.50 (dd, J = 1.84, 0.69 Hz, 2H). ?3C NMR(100 MHz, CDCI3, ppm): 153.0, 141.7, 135.7, 117.8, 115.8, 111.7, 107.3. m/z[M-fHj calcd for C,4H,3N202 241.0978; HR-ESI observed 241.0972.
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In methanol; toluene; at 80℃; for 1h;
Example 14 Preparation of 4-(furan-2-yl)-1-phenyl-1H-pyrazole (Formula Ib-iii) <strong>[15115-52-3]4-bromo-1-phenyl-1H-pyrazole</strong> (140 mg, 0.627 mmol), furan-2-ylboronic acid (88.2 mg, 0.941 mmol), Pd(PPh3)4 (70 mg, 0.062 mmol), and Cs2CO3 (400 mg, 1.254 mmol) were combined in toluene-methanol (1:1) (2 ml). The reaction mixture was heated under microwave at 80 C. for 60 minutes. The reaction mixture was then filtered and washed with toluene-ethanol (5 ml), and the filtrate was concentrated. The crude product was column purified using 15-20% ethyl acetate/hexanes, and was then further purified by preparative HPLC to yield the desired 4-(furan-2-yl)-1-phenyl-1H-pyrazole (22 mg, 0.10 mmol 16.7%). The HPLC purity of the final product was 99.72%. LC-MS [M+H] 211 (C13H10N2O+H expected 211.08). The 1H-NMR spectra was in accordance with the chemical structure.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; N-benzyl-N,N,N-triethylammonium chloride; cesium fluoride; In water; toluene; at 110℃; for 2h;Microwave irradiation; Inert atmosphere;
General procedure: Method A: In a20 mL microwave Biotage tube, a mixture of <strong>[71759-89-2]4-iodo-1H-imidazole</strong>(1a) (0.194 g, 1.0 mmol), a boronic acid 2(2.0 mmol), CsF (0.456 g,3.0 mmol), PdCl2(dppf)(0.041 g, 0.05 mmol) and BnEt3NCl(0.011 g, 0.05 mmol) in toluene(7 mL) and water (7 mL)was purged with argon andheated under microwaveirradiation. When the reaction was complete, the mixture was cooled toroom temperature and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel to provide compounds 3a-3i and 3k-3o in yields ranging from 40 to 91%. Time and temperaturereactions were collected in Table 1.
With tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; tricyclohexylphosphine; In water; N,N-dimethyl-formamide; at 130℃; for 1h;Inert atmosphere; Microwave irradiation;
General procedure: <strong>[4532-25-6]7-chloroimidazo[1,2-a]pyridine</strong> (5) (300 mg, 1.97 mmol) was dissolved in 8:1 DMF:H2O (13.1 mL) in a microwave vial affixed with a magnetic stir bar. Thiophen-2-ylboronic acid was added followed by sodium carbonate (834 mg, 7.86 mmol). The reaction mixture was degassed with argon. Pd2(dba)3 (36 mg, 0.039 mmol) and P(Cy)3 (33 mg, 0.118 mmol) was added to the reaction mixture and the vial was sealed. The reaction was heated by microwave irradiation to 130 C for 1 h. After, the reaction mixture was diluted with ethyl acetate and washed three times with saturated sodium bicarbonate and three times with deionized water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The crude product was absorbed onto silica. The product was purified via flash chromatography utilizing a DCM/MeOH gradient and isolated as a brown solid (223 mg, 59%).
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; water; toluene; at 100℃; for 1h;Microwave irradiation;
General procedure: AG10 vial in a Microwave 300 vessel was charged with 6-bromopyridinecarboxaldehyde,or <strong>[122918-25-6]6-bromopyridinecarbonitrile</strong>(1 eq), boronic acid (2 eq),Na2CO3 (4 eq), and Pd(PPh3)2Cl2(10 mol%). Toluene/EtOH/water/ (2/1/1 mL) were next added. The resulting mixturewas irradiated using the closed vessel mode at 100C for 60 min. The mixture wasthen extracted with dichloromethane, washed with a saturated solution of NaHCO3,dried over MgSO4, and concentrated by rota-evaporation under vacuum.The crude product was purified by flash chromatography, with a pentane /AcOEt (9/1to 7/3) as the eluent.
General procedure: A pressure flask was charged with <strong>[64874-38-0]2-amino-6-bromonaphthyridine</strong> (0.56 mmol) and arylboronic acid(1.12 mmol), K2CO3 (1 g, 7.24 mmol), Bu4NBr (0.3 g, 0.93 mmol), H2O (1.5 mL, 83.3 mmol), and DME(30 mL). Nitrogen was bubbled into the mixture for 5 min before [(A-taPhos)2PdCl2 (5 mg, 7.06*10-3mmol) was introduced and the flask was screwed up. The mixture was heated at 120 C for 16 h. After cooling, the volatiles were removed under vaccum before the residues were subjected to column chromatography to afford the target molecules.
With potassium phosphate; chloro(crotyl)(2-dicyclohexylphosphino-2?,4?,6?-triisopropybiphenyl)palladium(II); In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere;
4-(furan-2-yl)-2,6-dimethoxypyrimidine According to the general procedure, a mixture of <strong>[6320-15-6]6-chloro-2,4-dimethoxypyrimidine</strong> (175 mg, 1 .00 mmol), 2-furanboronic acid (168 mg, 1 .50 mmol), (7i-crotyl)Pd(XPhos)CI (14 mg, 0.02 mmol), 2 mL THF, and 4 mL of 0.5 M aqueous K3P04 are stirred at room temperature for 1 hour. The crude material is chromatographed on silica gel with a gradient of 0 - 10 % EtOAc/hexanes as the eluent to give 194 mg (0.94 mmol, 94 %) of 4-(furan-2-yl)-2,6-dimethoxypyrimidine as a colorless solid. H NMR (400 MHz, CDCI3, delta): 7.53 (dd, J = 0.9 Hz, 1 .9 Hz, 1 H), 7.19 (dd, J = 0.7 Hz, 3.5 Hz, 1 H), 6.69 (s, 1 H), 6.53 (dd, J = 1 .7 Hz, 3.4 Hz, 1 H) 4.02 (s, 3H), 3.99 (s, 3H). l3C NMR (100 MHz, CDCI3, delta): 172.6, 165.6, 157.4, 152.2, 144.6, 1 12.3, 1 1 1 .9, 95.0, 54.8, 54.0. Anal. Calcd. for C10H10N2O3: C, 58.25; H, 4.89; N, 13.59. Found: C, 58.19; H, 4.72; N, 13.42
With C7H10N2*Pd(2+)*2Cl(1-); potassium carbonate; In methanol; water; for 0.166667h;Reflux; Schlenk technique;
General procedure: A 20mL Schlenk tube with a magnetic stir bar was charged with aryl halide (2mmol), arylboronic acid (2.4mmol), K2CO3 (5mmol), 10mL of solvent [H2O, H2O-MeOH (1:1), H2O-EtOH (1:1), H2O-EG (1:1)] and an aliquot of 0.01M solution of palladium complexes PdCl2(L)2 or Pd[(L)4]Cl2 in MeOH (0.001-0.2mol%) under air atmosphere. The reaction mixture was placed in a preheated oil bath: at 100C for MeOH-H2O, at 110C for EtOH-H2O, at 140C for H2O and at 160C for EG-H2O; and stirred under reflux for the given time. After this time, the mixture was cooled, acidified by 5M HCl (in the case of acids) and diluted with 10mL of H2O and 10mL of Et2O (or EtOAc). The organic phase was separated, and the aqueous layer was extracted with Et2O EtOAc) (2×10mL). The combined organic layers were washed with H2O (10mL), brine (10mL), and dried over Na2SO4. The pure products were obtained by a simple filtration of ether solution through silica gel pad and evaporation of a solvent.
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In methanol; toluene; at 100℃; for 16.0h;Inert atmosphere;
General procedure: According to a procedure by Oxford et al.,[3] furan-2-boronic acid (168 mg, 1.5 mmol, 1.5 eq), aryl halide (1.0 mmol, 1.0 eq), Pd(PPh3)4 (116 mg, 0.1 mmol, 10 mol%) and cesium carbonate (350 mg, 1.1 mmol, 1.1 eq) were suspended in a toluene/MeOH mixture (4:1, 10 mL). The reaction mixture was stirred for 16 h at 100 C. The reaction mixture was diluted with EtOAc (8 mL) and the organic layer was extracted was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography.
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 0.5h;Inert atmosphere; Microwave irradiation;
To a degassed souton of 9:1 1 ,4-doxane:H2O (4 mL) was added 3-bromo-5-methythenzoc acid (0.300 g, 1.395 mmo), 2-furanboronc acid (0.187 g, 1.674 mmo), K2C03 (0.289 g, 2.093 mmo) and PdC2(PPh3)2 (0.049 g, 0.070 mmo), under an atmosphere of nitrogen. Thereaction was rradated n a CEM microwave reactor at 80 C for 30 mn, then cooed and passed through a pad of Cehte. The Cehte was washed with a portion of EtOAc (10 mL) and the entire mxture was concentrated to dryness. The residue was taken up n DCM (20 mL) and an aq. son. of 2 M HC (20 mL) was added. The two ayers were separated, and the aqueous ayer was further extracted with DCM (2 x 20 mL). The organcs were combined,washed wth brine, dried (Na2SO4) and concentrated n vacuo. The crude matera waspurfied by sWca g& chromatography (soera Botage, 24 g S Cartrdge, 0-40% EtOAc npetroeum benzne 40-60 C) with the fracUons contanng suspected product coflected andconcentrated n vacuo to yed 3-(furan-2-y)-5-methybenzoc acd (M4)(0.095 g, 34 % yed)as a white sohd. 1H NMR (400 MHz, CDC3): 6 8.24 8.20 (m, 1 H), 7.85 7.81 (m, 1 H), 7.777.71 (m, 1H), 7.50 (dd, J = 1.8, 0.8 Hz, 1H), 6.74 (dd, J = 3.4, 0.7 Hz, 1H), 6.50 (dd, J =3.3, 1.8 Hz, 1H), 2.46 (s, 3H).
2-fluoro-5-(furan-2-yl)-3-methylbenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 0.5h;Inert atmosphere; Microwave irradiation;
To a degassed souDon of 9:1 1 ,4-doxane:H2O (4 mL) was added 5-bromo-2-fiuoro-3-methybenzoc acid (M4) (0.200 g, 0.858 mmo), 2-furanboronc acid (0.106 g, 0.944 mmo),K2003 (0.178 g, 1.287 mmo) and PdC2(PPh3)2 (0.030 g, 0.043 mmo), under an atmosphere of ntrogen. The reaction was rradated n a CEM microwave reactor at 80 C for 30 mn, then cooed and passed through a pad of Cehte. The Cehte was washed with EtOAc (20 mL). The mixture was acdfied using 2 M HC (1 mL) and concentrated n vacuo.The crude matera was purfied by sWca g& chromatography (soera Botage, 24 g S Cartridge, 0-60% EtOAc n petroeum benzne 40-60 C). Fractions contanng the suspected product were concentrated n vacuo to give 2-fuoro-5-(furan-2-y)-3-methythenzoc acid (M 5) (0.050 g, 26 % yed) as a white sohd. LCMS B rt. 3.63 mn, m/z 221 .1 [M+H].
With potassium carbonate; In 1,4-dioxane; water; at 80℃; for 0.5h;Inert atmosphere; Microwave irradiation;
To a degassed souUon of 9:1 1 ,4-doxane:H2O (0.2 M), under an atmosphere of nitrogen, was added the benzoc acid (1 eq.), the boronc acd (3 eq.), K2C03 (1 .5 eq.) and the paHadum catayst (0.05 eq.).. The reaction was rradated n a CEM microwave at 80C for 30 minutes, then cooed and passed through a pad of Cehte. The Cehte was washed withEtOAc (20 mL). The mxture was acdfied usng 2 M HC (1 mL) and the organcs removed in vacuo. The sohd precptate was coflected va fHtraton to give the UDe compound. FoHowng the Suzuki couphng method A, 3-fuoro5-(furan-2-y)benzoc acid (55) was obtaned as a Ught brown sohd (39% yed). 1H NMR (400 MHz, CDC3): 68.18 (t, J= 1.4 Hz,1 H), 7.66 (ddd, J = 8.8, 2.5, 1.4 Hz, 1 H), 7.61 (ddd, J = 9.4, 2.5, 1.5 Hz, 1 H), 7.53 7.51 (m,1 H), 6.79 (dd, J = 3.4, 0.8 Hz, 1 H), 6.52 (dd, J = 3.4, 1.8 Hz, 1 H). LCMS B rt 3.65 mn, m/z205.1 [M-H].
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 0.5h;Inert atmosphere; Microwave irradiation;
To a degassed souUon of 9:1 1 ,4-doxane:H2O (0.2 M), under an atmosphere of nitrogen, was added the benzoc acid (1 eq.), the boronc acd (3 eq.), K2C03 (1 .5 eq.) and the paHadum catayst (0.05 eq.).. The reaction was rradated n a CEM microwave at 80C for 30 minutes, then cooed and passed through a pad of Cehte. The Cehte was washed withEtOAc (20 mL). The mxture was acdfied usng 2 M HC (1 mL) and the organcs removed in vacuo. The sohd precptate was coflected va fHtraton to give the UDe compound. FoHowng Suzuki couphng method A, using Pd(dppf)C2, 3-choro-5-(furan-2-y)benzoc acidwas obtained as a Ught brown sohd (39% yed). 1H NMR (400 MHz, DM80): 68.15 (t, J1.5, 1.5 Hz, 1 H), 8.02 (t, J = 1.9 Hz, 1 H), 7.83 (d, J = 2.0 Hz, 1 H), 7.78 (t, J = 1.9 Hz, 1 H),7.23 (d, J= 3.4 Hz, 1H), 6.65 (dd, J= 3.4, 1.8 Hz, 1H).
To a 100 mE round bottom flask equipped with a magnetic stirrer, reflux condenser and a nitrogen inlet were added 5,6-dichioropicolinic acid (5.00 g, 23.1 mmol), TEA (8.2 g, 81.0 mmol), ACN (39.5 g) and water (15.1 g). The solution was sparged for 30 mm with nitrogen (1 mE/mm) Afier sparging, triphenylphosphine (TPP; 0.18 g, 0.686 mmol) and palladium(II) acetate (0.078 g, 0.347 mmol) were added to the solution. Furan-2-boronic acid (3.3 g, 28.9 mmol) was added in one portion, and heating was initiated. The reaction mixture was heated to 55 C., and was sampled and analyzed by liquid chromatography. No boronic acid was remaining after two hours, and heating was stopped. The reaction mixture was allowed to cool overnight and then was heated to 45 C. Once at temperature, 50% sulfuric acid (7.1 g) was added. No precipitation was observed, so the mixture was cooled. After 30 mm at <5 C., no solids were observed and water (25.7 g) was added. A precipitate formed which was allowed to cool for 1 h and isolated by filtration. The flask was rinsed with cold mother liquor to isolate all of the product. The wetcake was then rinsed with cold ACN- water solution (8.75 g and 11.25 g, respectively). The palladium content was analyzed in the wetcake, wash and mother liquors, with 81% of the palladium in the mother liquor and wash, and 19% in the wet cake. 99% of the total palladium added was recovered.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene;Inert atmosphere; Reflux;
General procedure: 5-Bromo-2-methylisoindolin-1-one (520 mg, 2.30 mmol) and thiophene-2-boronic acid (442mg, 3.45 mmol) were dissolved in a mixure of toluene (12 mL) and EtOH (6 mL). A solutionof 2 M Na2CO3 (3 mL) and Pd(dppf)Cl2 (94 mg, 0.12 mmol) were added and the entiremixture heated at reflux under N2 for 2 h. Additional thiophene-2-boronic acid (294 mg, 2.30mmol) was added and reflux continued under N2 overnight. Upon cooling, the mixture wasdiluted with water (100 mL) and extracted with CH2Cl2 (6x50 mL). The combined organicfractions were dried (Na2SO4), filtered, and the solvent removed under reduced pressure togive a crude solid which was purified by flash column chromatography on silica gel (EtOAcas eluant). The title compound was isolated as a light-brown solid (510 mg, 97percent).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere;
Under the protection of nitrogen,Add 153 g (1 mol) of 5-chloropyrazolo[1,5]pyridine to 1500 mL of 1,4-dioxane.Add 300g of deionized water,2-furanboronic acid (1.2 mol) and potassium phosphate 424 g (2 mol),Replace the gas in the reaction system three times with nitrogen,Further adding catalyst Pd(dppf)Cl2 3g,Continue to replace the gas in the reaction system with nitrogen three times and then heat to 90 C to carry out the reaction.After 3 h of reaction, LCMS monitored the reaction of the starting material completely and cooled to room temperature.The reaction solution was extracted three times with ethyl acetate 2000 mL, and the organic phases were combined.Wash the organic phase once with 2000 mL of saturated sodium chloride solution.Dry with anhydrous magnesium sulfate,After concentration, it was separated and purified by column chromatography (VPE: VEA=5:1) to obtain 132 g of 5-furopyrazole[1,5]pyridine in a yield of 70%.
With palladium diacetate; potassium carbonate; triphenylphosphine; In water; N,N-dimethyl-formamide; at 100℃; for 3h;Microwave irradiation; Inert atmosphere; Sealed tube;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 100℃; for 18h;Inert atmosphere;
To a solution of 6-chloropyrazin-2-amine (1.00 g, 7.75 mmol, 1 eq.) in a solution of toluene and ethanol (20 mL, 1:1) was added furan-2-ylboronic acid (0.955 g, 8.52 mmol, 1.1 eq.), Na2CO3 (1.479 g, 13.95 mmol, 1.8 eq.) in H2O (10 mL), Pd(PPh3)4 (0.223 g, 0.193 mmol, 0.025 eq.). The reaction mixture was deoxygenated using N2 atmosphere and the reaction mixture was heated at 100° C. for 18 h. The reaction was monitored by NMR. The reaction mixture was filtered through Celite with wash of ethyl acetate (2*20 mL). The reaction mixture was diluted with water (50 mL) and extracted using ethyl acetate (2*50 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by CombiFlash on silica gel to afford 1.00 g (80percent) of 6-(furan-2-yl)pyrazin-2-amine.
6-(furan-2-yl)imidazo[1,2-a]pyrazin-8-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃;
General procedure: In a pressure tube were mixed 5-bromo-6-chloropyrazin-2-amine (4.32 g, 20.73 mmol), phenylboronic acid (2.78 g, 22.80 mmol, 1 .1 equiv.) and Na2003 (4.39 g, 41 .45 mmol, 2 equiv.) in a4:1 mixture of 1 ,4-dioxane : water (50 mL). The reaction mixture was sparged with argon andPd(PPh3)4 (1 .20 g, 1 .04 mmol, 5 mol%) was then added. The pressure tube was capped andthe reaction mixture was heated at 10000 overnight. After that time, the reaction mixture wascooled down to r.t., filtered and concentrated under reduced pressure. The obtained crude ma-terial was purified by flash chromatography on silica eluting with hexane: EtOAc = 1:0 - 1:1 to lead to the title product as a white solid (2.11 g, 50%). ESI-MS: 206.05 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) 6 7.93 (s, 1 H), 7.66 - 7.59 (m, 2H), 7.47 - 7.32 (m, 3H), 7.00 (br s, 2H).
4,6-di(furan-2-yl)pyrimidine-2,5-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; diisopropylamine; In ethanol; water; toluene; for 20h;Inert atmosphere; Reflux;
In the reaction vessel, <strong>[55583-59-0]4,6-dichloropyrimidine-2,5-diamine</strong>(500 mg, 2.79 mmol), 2-furanylboronic acid(0.718 g, 6.42 mmol), sodium carbonate(1.49 g, 14.0 mmol),And tetrakis (triphenylphosphine) palladium (0)(161 mg, 0.140 mmol) of toluene (28 mL)After adding ethanol (7 mL) and distilled water (7 mL) to the solution at room temperature and stirring for 20 hours under heating reflux condition under argon atmosphere, the reaction solution was cooled to room temperature. Distilled water (8 mL) was added and stirred, and the separated aqueous layer was extracted three times with ethyl acetate (12 mL).Thereafter, the total amount of the organic layer is combined, saturated aqueous sodium chloride solution (12 mL) is added thereto, the mixture is stirred and washed, anhydrous sodium sulfate is added to the separated organic layer for dehydration, and the filtrate after filtration is concentrated under reduced pressure. did.The concentrate thus obtained is purified by flash column chromatography (silica gel, n-hexane / ethyl acetate),4,6-Di (furan-2-yl) pyrimidine-2,5-diamine(0.433 g, 64% yield).
ethyl 4-amino-2-(2-furyl)pyrimidine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 25.5h;Inert atmosphere; Sealed tube; Microwave irradiation;
A vial was charged with commercially available ethyl 4-amino-2-chloro-pyrimidine- 5-carboxylate (1 g, 4.96 mmol), potassium carbonate (1.37 g, 9.92 mmol), 1 ,4- dioxane (12 ml_) and water (2 ml_). The resulting mixture was stirred vigorously until a cloudy solution was obtained and then placed under an atmosphere of nitrogen. Pd(amphos)2Cl2 (176 mg, 0.25 mmol) was added followed by 2- furylboronic acid (833 mg, 7.44 mmol), the vial sealed, the contents evacuated and backfilled with nitrogen (3 x cycles) and the mixture heated using microwave radiation at 100 C for 20.5 hours. More potassium carbonate (1028 mg, 7.44 mmol), Pd(amphos)2Cl2 (88 mg, 0.12 mmol) and 2-furylboronic acid (555 mg, 4.96 mmol) were added and stirring continued at 100 C for a further 5 h. The mixture was allowed to cool, diluted with DCM (100 ml_) and extracted with water (100 ml_). The aqueous layer was further extracted with DCM (100 ml_) and EtOAc (200 ml_). The combined organic extracts were dried over MgS04 and the solvent removed in vacuo. Purification by column chromatography on silica eluting with a gradient of 0.5 to 4% MeOH in DCM afforded the titled compound as a pale yellow solid. (1196) LC-MS (Method 3B): Rt 1.49 mins; MS m/z 234.1 = [M+H]+ (1197) 1 H NMR (500 MHz, Chloroform-d) d 8.92 (s, 1 H), 7.93 (s, 1 H), 7.63 (dd, J = 1.7, 0.9 Hz, 1 H), 7.35 (dd, J = 3.5, 0.8 Hz, 1 H), 6.57 (dd, J = 3.5, 1.7 Hz, 1 H), 5.81 (s, (1198) 1 H), 4.37 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H).
With copper(I) oxide; tert.-butylhydroperoxide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In toluene; at 60℃; for 20h;Schlenk technique;
Under an atmospheric oxygen atmosphere,To a 15 mL Schlenk reaction tube, 1- (2-thienyl) -1-acetone 1e (70.2 mg, 0.50 mmol),2-furan boronic acid 2e (44.7 mg, 0.40 mmol),Cuprous oxide (21.3mg, 0.17mmol),Tert-butyl hydroperoxide (182.2 mg, 2.0 mmol), 2,2,6,6-tetramethylpiperidine oxide (1.6 mg, 0.01 mmol) and toluene (toluene, 2.0 mL) were performed at 60 C. After 20h reaction, the reaction was cooled to room temperature, filtered through celite, and concentrated to obtain the crude product.The crude product was separated by chromatography using a prepared silica gel plate. The developing solvent or eluent was petroleum ether and ethyl acetate, and the volume ratio of petroleum ether and ethyl acetate was 20: 1. The product (E) -3- ( Furan-2-yl) -1- (thien-2-yl) prop-2-en-1-one (3e). The product was a pale yellow solid with a yield of 59% (60.2 mg).
methyl 6-(furan-2-yl)-5-(trifluoromethyl)pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;
A mixture of <strong>[1211518-35-2]methyl 6-chloro-5-(trifluoromethyl)pyridine-2-carboxylate</strong> (200 mg; 0.83 mmol), (furan-2-yl)boronic acid (158 mg; 1.42 mmol), potassium carbonate (2M aqueous solution) (793 muL; 1.58 mmol) in 4 mL of dioxane is stirred under argon. [1,1?-bis(di-tert- butylphosphino)-ferrocene]palladium (II) dichloride (163 mg; 0.250 mmol) is added and the reaction mixture is stirred at 100C for 1 hour. The reaction is quenched with methanol and purified by reverse phase chromatography-HPLC (modifier: trifluoroacetic acid). (0367) Yield: 165 mg (73 % of theory) (0368) Mass spectrometry (ESI+): m/z = 272 [M+H]+ (0369) HPLC (Method 1): Retention time = 1.038 min.
methyl 3,5-diamino-6-(furan-2-yl)pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In methanol; toluene;Inert atmosphere; Reflux;
General procedure: <strong>[1458-01-1]Methyl 3,5-diamino-6-chloropyrazine-2-carboxylate</strong> 2 (1 eq.) was combined with K2CO3 (10 eq.), the appropriate (het)aryl boronic acid (1.5 eq.) and Pd(PPh3)4 (5 mol%) in a two-neck round bottom flask. The flask was connected to a condenser and purged with nitrogen. A 4:1 mixture of anhydrous toluene: MeOH (60 mL) was added via syringe and the reaction mixture was heated at reflux for 0.5-18 h. The mixture was allowed to cool to room temperature and filtered through Celite (10 x 3 cm, eluting with 3 x 20 mL EtOAc). The filtrate was evaporated to dryness and the residue purified by silica gel flash column chromatography using EtOAc/pet spirit.
2-[4-(furan-2-yl)phenyl]-1,3-benzoxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With palladium diacetate; at 55 - 70℃; for 14h;Ionic liquid; Inert atmosphere;
General procedure: An oven-dried RB flask equipped with magnetic stirrer bar was charged with the IL solvent (5-7 mL), and the (p-bromophenyl)-benzoxazole or benzothiazoles (1.1 mmol). After stirring at r.t. under nitrogen atmosphere for 15-20 minutes, the boronic acid (1 mmol), Pd(OAc)2 or NiCl2(dppp) (10 mol%), and the piperidine-appended-IL [PAIM][NTf2] (2 mmol) were introduced and the reaction mixture was heated gently under stirring at 55-70 C, while monitoring the progress of the reaction by TLC. Upon completion, the reaction mixture was cooled to r.t. and the products were extracted 4 times with hexane/ethyl acetate (80:20). The solvent was removed under vacuum and the crude product was chromatographed with hexane/ethylacetate (70:30) mixture to afford pure compounds.
With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; at 60℃; for 4h;Sealed tube; Inert atmosphere;
To a degassed solution of <strong>[4175-78-4]2,5-dibromothiazole</strong>i (1.00 g, 4.12 mmol) and furan-2-ylboronic acid 2 (0.50 g, 4.47 mmol) in THF (20 mL) was added and K3P04 (1.70 g, 8.01 mmol) in a sealed tube and stirred for 5mm. Pd(0Ac)2 (0.09 mg, 0.41 mmol) was added at room temperature followed by addition of xantphos (0.24 g, 0.41 mmol) and the reaction mixture was heated at 60 C for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and solvent was removed under reduced pressure. Crude compound was purified by silica gel column chromatography eluting with 5% ethyl acetate in n-hexane to afford 0.30 g (32% yield) of 3 as an off-white solid. LCMS-Condition-i: [M+H]+ = 229.90; Rt = 2.24 min.
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