* 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 hydrogen In methanol; ethyl acetate for 14 h;
Method 4: General conditions for the reduction of tetrahydropyridines to piped dines in the presence of a boronate ester: The boronate ester is dissolved in ethyl acetate/methanol (1: 1 v/v) (0.4 M final ester concentration) after which Pd(OH)2 (0.35 equiv) is added and the reaction is allowed to stir under an atmosphere Of H2 for 14h. At this point the reaction is filtered through and concentrated in vacuo to provide the desired piperidine in quantitative yield.; Example 8: Piperidine 8 was prepared in 2 steps from compound 1 using Method 4 followed by pinacol ester deprotection using Method 2. [M-H]- = 228.2 m/z. Activity: B
With hydrogenchloride In tert-butyl methyl ether at 20℃;
Method 3: General conditions for the deprotection of a 7V-Boc carbamate in the presence of a boronate ester: The boronate ester is dissolved in te/t-butylmethylether (0.4 M final ester concentration) after which point HCl (g) is bubbled in over the course of 15 min. The reaction is allowed to stir at room temperature for an additional hour after which point the solvent is removed under a stream of nitrogen to provide the desired HCl amine salt as a white solid in quantitative yield.; Example 2: Tetrahydropyridine 2 was prepared in 3 steps starting with the deprotection of 1 using Method 3. The resulting HCl amine salt was dissolved in dichloromethane (0.2 M). Benzyl chloroformate (1.2 equiv) was added followed by triethylamine (3.0 equiv). The reaction was allowed to stir at room temperature for 2h after which point it was diluted with IN HCl and extracted with excess dichloromethane. The organic layer was dried over MgSψ4 and concentrated to provide the desired carbamate in quantitative yield, which was converted directly to boronic acid 2 using Method 2. [M-H]- = 260.1 m/z. Activity: B
96%
With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃;
To tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1 -carboxylate 51 (3 g, 9.7 mmol) in dichloromethane (5 mL) was added hydrochloric acid in 1,4-dioxane (4 N, 5 mL). The reaction was stirred at room temperature overnight, then concentrated twice from toluene. The residue was washed with ethyl acetate and dried under vacuum to produce compound 52 as an HC1 salt (2.3 g, 96percent). The data from the lH NMR spectrum were consistent with the structure of the compound.
90%
With hydrogenchloride In diethyl ether; tert-butyl methyl ether at 20℃;
tert-butyl 4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-5 ,6-dihydropyridine- 1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HC1 in Et20 (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et20 to give the title compound (1.434 g, 90 percent).UPLC-MS: 0.51 mm, 210.3 [M+H]+, method 9.
90%
With hydrogenchloride In diethyl ether; tert-butyl methyl ether at 20℃;
tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HCl in Et2O (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et2O to give the title compound (1.434 g, 90percent).UPLC-MS: 0.51 min, 210.3 [M+H]+, method 9.
8 g
With hydrogenchloride In dichloromethane; isopropyl alcohol for 12 h;
Step 1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinium chloride Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCl in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the solvent is again evaporated to give the title compound. Yield: 8 g; LC (method 11): tR=0.68 min; Mass spectrum (ESI+): m/z=210 [M+H]+.
8 g
With hydrogenchloride In dichloromethane; isopropyl alcohol for 12 h;
Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (1 0 g) is d issolved in d ichloromethane (1 00 m L) and 5 M HCI in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): tR = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]+.
8 g
With hydrogenchloride In dichloromethane; isopropyl alcohol for 12 h;
Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCI in isopropanol (120 mL) and stirred for 1 2 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): tR = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]+.
With sodium periodate; ammonium acetate; In water; acetone; at 20℃;
Intermediate 108 (1-[(1,1-Dimethylethyl) oxy] carbonyl}-1, 2,3, 6-tetrahydro-4-pyridinyl) boronic acid Sodium periodate (2.08 g, 9.75 mmol) was added in portions to a mixture of 1,1- dimethylethyl 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-3, 6-dihydro-1 (2H)-pyridine- carboxylate (1.0 g, 3.25 mmol, TDC Research Inc) and ammonium acetate (750 mg, 9.74 mmol) in acetone (40 mL) and water (40 mL) at room temperature, under nitrogen. The reaction was stirred overnight, filtered through a Celite pad, washed with acetone and the organic solvent removed. Brine (50 mL) was added and the solution was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated to give the title compound. MS calcd for (C10H18NO4 + H) + : 228 MS found (electrospray) : (M+H)'= 228
With sodium periodate; ammonium acetate; In water; acetone; at 23℃; for 12h;
Method 1: General conditions for the conversion of boronate esters to boronic acids: The boronate ester (1.0 eq), sodium periodate (5.0 eq) and ammonium acetate (5.0 eq) are dissolved in acetone/water 2: 1 (0.05 M boronate ester) and stirred for 12 hours at 23 0C until TLC or LCMS indicated conversion to the boronic acid is complete. One option for isolation is to precipitate the product by dilution of the mixture with IN aqueous HCl and collection of the solid boronic acid by filtration. Alternately, the mixture is partitioned between water and ethyl acetate, and the organic layer washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified either by recrystallization and trituration (heptane, acetonitrile, or other solvents) or by flash silica gel chromatography (0.5% to 10% methanol/dichloromethane) to afford pure boronic acid.; Example 1: Tetrahydropyridine 1 was prepared in 1 step from commercially available 4-(4 ,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine-l-carboxylate using Method 1 and was isolated after precipitation from the reaction mixture. [M-H]- = 226.1 m/z. Activity: C
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 80℃; for 18h;
A solution of <strong>[1532-71-4]1-<strong>[1532-71-4]bromoisoquinoline</strong></strong> (0.35 g, 1.68 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (US 2004/0186103) (0.5 g, 1.68 mmol), dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) (0.065 g, 0.05 mol equiv.) and potassium carbonate (0.66 g, 5.0 mmol) in 1,2-dimethoxyethane (10 mL) was heated at 80 °C for 18 hours. The reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was purified' by column chromatography on silica gel eluting with ethyl acetate: pentane 50 : 50 to afford the title compound as a pale yellow oil, 0.14 g. LRMS (APCI+): m/z [M+H]+ 311
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; ethanol; water; at 160℃; for 0.25h;Microwave irradiation;
A solution containing <strong>[50998-17-9]6-bromo-quinoxaline</strong> (417 mg, 2.0 mmol), 4-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert- butyl ester (600 mg, 1.94 mmol), tetrakis [triphenylphosphine] palladium (108 mg, 0.1 mmol) and sodium carbonate (2 M solution, 3 mL) in 5 ml_ of dioxane/ethanol/water <n="265"/>(7:3:1 ) was heated at 160 C using microwave reactor for 15 minutes. After the reaction, ethylacetate was added and the mixture was filtered, washed with water. After concentration under vacuum, the product was purified using column chromatography (5% methanol in dichloromethane)
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; ethanol; water; at 160℃; for 0.25h;Microwave irradiation;
A solution containing <strong>[50998-17-9]6-bromo-quinoxaline</strong> (417 mg, 2.0 mmol), 4-(4 ,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert- butyl ester (600 mg, 1.94 mmol), tetrakis [triphenylphosphine] palladium (108 mg, 0.1 mmol) and sodium carbonate (2 M solution, 3 ml_) in 5 ml_ of dioxane/ethanol/water (7:3:1 ) was heated at 160 C using microwave reactor for 15 minutes. After the reaction, ethylacetate was added and the mixture was filtered, washed with water. After concentration under vacuum, the product was purified using column chromatography (5% methanol in dichloromethane)
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃;
A mixture of <strong>[2516-40-7]2-bromo-benzothiazole</strong> (0.38 g, 1.1 mmol), 4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester (0.5 g, 1.62 mmol), potassium carbonate (0.67 g, 4.85 mmol), Pd(dppf)CI2 (0.132 g, 0.16 mmol) and 4/1 /dioxane/water (10 ml) was degassed for 15 minutes. Then it was heated at 90 °C for overnight. Cooled to room temperature and diluted with EtOAc (200 ml_). The organic layer was washed with water (100 ml), dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel to give the desired product 21 BB (0.4 g, 78percent).
78%
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃;
A mixture of <strong>[2516-40-7]2-bromo-benzothiazole</strong> (0.38 g, 1.1 mmol), 4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.5 g, 1.62 mmol), potassium carbonate (0.67 g, 4.85 mmol), Pd(dppf)CI2 (0.132 g, 0.16 mmol) and 4/1 /dioxane/water (10 ml) was degassed for 15 minutes. Then it was heated at 90 CC for overnight. Cooled to room temperature and diluted with EtOAc (200 ml_). The organic layer was washed with water (100 ml), dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel to give the desired product 21 BB (0.4 g, 78percent).
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; toluene; at 90℃;Inert atmosphere;
Compound 105a. To a solution of ethyl 3-bromoisonicotinate (0.2 g, 0.925 mmol, 1.0 equiv) in Toluene (8 mL) and water (2 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.429 g, 1.39 mmol, 1.5 equiv), K2CO3 (0.255 g, 1.85 mmol, 2.0 equiv) and resulting reaction mixture purged with N2 gas for 10 minute, followed by the addition of Pd(PPh2)Cl2 (0.033 g, 0.046 mmol. 0.05 equiv). The resulting reaction mixture was heated at 90 C. for overnight. Product formation was confirmed by LCMS. After the completion of reaction, the mixture was filtered through celite bed, washed with ethyl acetate (100 mL). Filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography (0-20% ethyl acetate in hexane as an eluent) to obtain 1?-(tert-butyl) 4-methyl 3?,6?-dihydro-[3,4?-bipyridine]-1?,4(2?H)-dicarboxylate (0.130 g, 44.4% Yield) as an yellow oil. (0848) LCMS 319.2 [M+H]+ (0849) 1H NMR (400 MHz, DMSO-d6) delta 8.65 (d, J=4.8 Hz, 1H), 8.59-8.52 (m, 1H), 7.63 (d, J=4.8 Hz, 1H), 5.68 (br. s., 1H), 3.96 (br. s., 2H), 3.87-3.69 (m, 3H), 3.52 (br. s., 2H), 2.27 (br. s., 2H), 1.53-1.25 (m, 9H), 1.07 (s, 3H).
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; for 14h;Inert atmosphere; Reflux;
PdCl2(PPh3)2 (0.7 g, 1.03 mmol, 0.05 eq.) was added to a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (6.3 g, 20.5 mmol, 1.0 eq.) in THF (120 mL) under nitrogen. To this was added <strong>[59786-31-1]3-bromoisonicotinic acid methyl ester</strong> (4.4 g, 20.5 mmol, 1.0 eq.). This was followed by the addition of a solution of Na2CO3 (8.7 g, 82.1 mmol, 4.0 eq.) in water (41 mL). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The resulting solution was diluted with EtOAc (100 mL), and washed with saturated aqueous NaCl (2*100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:10) to yield 3',6'-dihydro-2'H-[3,4']bipyridinyl-4,1'-dicarboxylic acid 1'-t-butyl ester 4-methyl ester (5.6 g) as a yellow oil. H-NMR: (300 MHz, CDCl3, ppm): 8.65 (1H, d, J=4.8 Hz), 8.54 (1H, s), 7.65 (1H, d, J=4.8 Hz), 5.65 (1H, m), 4.08 (2H, m), 3.90 (3H, s), 3.65 (2H, m), 2.34 (2H, m), 1.51 (9H, s).
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; for 1h;Reflux;
A degassed solution of <strong>[884495-37-8]2-chloro-5-fluoro-3-amino-pyridine</strong> (3.5 g), 4- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2/f-pyridine-l-carboxylic acid tert-butyl ester (8.89 g) (prepared as described in WO 2006/003494) and bis(triphenylphosphine)palladium(II) chloride (0.84 g) in dioxane (157 ml) was treated with a degassed solution of sodium carbonate (7.6 g) in water (72 ml). The reaction mixture was stirred at reflux for 1 hour, cooled to ambient temperature and the solvent evaporated in vacuo. The residue was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane / ethyl acetate 8:2) afforded 3-amino-5-fluoro-3',6'-dihydro-2'H-[2,4']bipyridinyl-r-carboxylic acid tert-hutyl ester (4.6 g) as a solid. MS (ES+) 294 (MEta+), 238 (M-isoprene); IH NMR (400 MHz, CDCl3) 1.48 (s, 9H), 2.53 (m, 2H), 3.64 (t, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 5.99 (m, IH), 6.70 (dd, IH), 7.85 (d, IH).
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; for 1h;Reflux;
Step A: A degassed solution of <strong>[884495-37-8]2-chloro-5-fluoro-3-amino-pyridine</strong> (3.5 g), 4- (4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2//-pyridine-l -carboxylic acid tert-butyl ester (8.89 g) (prepared as described in WO 2006/003494) and bis(triphenylphosphine)palladium(II) chloride (0.84 g) in dioxane (157 ml) was treated with a degassed solution of sodium carbonate (7.6 g) in water (72 ml). The reaction mixture was stirred at reflux for 1 hour, cooled to ambient temperature and the solvent evaporated in vacuo. The residue was diluted with ethyl acetate, washed with water then brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane / ethyl acetate 8:2) afforded 3-amino-5-fluoro-31,6'-dihydro-2'//-[2,4']bipyridinyl-lt- carboxylic acid tert-butyl ester (4.6 g) as a solid. MS (ES+) 294 (MH+), 238 (M-isoprene); IH NMR (400 MHz, CDCl3) 1.48 (s, 9H), 2.53 (m, 2H), 3.64 (t, 2H), 3.99 (m, 2H), 4.08 (m, 2H), 5.99 (m, IH), 6.70 (dd, IH), 7.85 (d, IH).
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃;
To a slurry of anhydrous potassium carbonate (3.50 g, 25.3 mmol) in dry degassed NN- dimethylformamide (35 mL) is added <strong>[1735-53-1]4-bromo-3-trifluoromethyl benzonitrile</strong> (2.00 g,8.00 mmol) followed by bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.92 g,1.25 mmol) and the reaction mixture is heated at 80 C overnight. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, filtered through Celite, and the solvent is removed in vacuo. The crude material is purified via silica gel chromatography using 4% ethyl acetate/petroleum ether as eluent to afford the desired product (1.2O g, 56%).
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; at 80℃; for 1h;Inert atmosphere;
Preparation 4 4-(4-Fluoro-2-hydroxymethylphenyl)piperidine-1-carboxylic Acid t-Butyl Ester Methyl 2-bromo-5-fluorobenzoate (1.8 g, 7.5 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (2.3 g, 7.5 mmol), THF (69 mL, 850 mmol) and 2 M of sodium carbonate in water (15.0 mL, 30.0 mmol) were combined, and the mixture was degassed and flushed with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (158 mg, 225 mumol) was added, and the mixture was again degassed and flushed with nitrogen. The mixture was heated at 80 C. for 1 hour. The mixture was then cooled and the layers separated, diluted with EtOAc (50 mL), washed with saturated aqueous NaCl (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc in hexanes). A solution of the crude material and Pearlman's Catalyst (0.1:0.4, Palladium hydroxide:carbon black, 1.1 g, 1.5 mmol) in MeOH (60.8 mL, 150 mmol) was hydrogenated at 1 atm at room temperature overnight. The mixture was then evacuated, purged with nitrogen, filtered through Celite and concentrated to yield a colorless oil. This oil was dissolved in THF (30 mL, 400 mmol) and treated with borane-dimethyl sulfide complex (1.3 mL, 15.0 mmol) at room temperature. The mixture was heated to reflux for 5 hours. After cooling to room temperature, MeOH (20 mL) was slowly added and removed by rotary evaporation. Another 20 mL of MeOH was added and removed by rotary evaporation. The residue was then dissolved in EtOAc (100 mL) and washed with 1N HCl and sat. NaHCO3, dried over Na2SO4, filtered and concentrated. The material was then purified by silica gel chromatography (0-50% EtOAc in hexanes) to yield the title compound (924 mg) as a colorless sticky solid. 1H NMR (CDCl3) delta (ppm) 7.21 (br.s, 1H); 7.16 (m, 1H); 6.98 (m, 1H); 4.76 (br.s, 2H); 4.24 (m, 2H); 2.89 (m, 1H); 2.80 (m, 2H); 1.72 (m, 2H); 1.60 (m, 2H); 1.47 (s, 9H).
With hydrogen;palladium(II) hydroxide; In methanol; ethyl acetate; for 14h;
Method 4: General conditions for the reduction of tetrahydropyridines to piped dines in the presence of a boronate ester: The boronate ester is dissolved in ethyl acetate/methanol (1: 1 v/v) (0.4 M final ester concentration) after which Pd(OH)2 (0.35 equiv) is added and the reaction is allowed to stir under an atmosphere Of H2 for 14h. At this point the reaction is filtered through and concentrated in vacuo to provide the desired piperidine in quantitative yield.; Example 8: Piperidine 8 was prepared in 2 steps from compound 1 using Method 4 followed by pinacol ester deprotection using Method 2. [M-H]- = 228.2 m/z. Activity: B
92%
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; under 2585.81 Torr; for 10h;
5 g (16.2 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1(2H)-tert-butyl carboxylic acid is dissolved in methanol after (150 mL), Pd/C (1 g) was added at room temperature under H 2 (gas) 50 psi.The reaction was carried out at room temperature for 10 h, and the reaction was directly filtered after completion of the reaction.The filtrate is concentrated to obtain the product4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine-1-carboxylic acid tert-butyl ester 4.6 g, yield 92 %.
With hydrogenchloride; In tert-butyl methyl ether; at 20℃;
Method 3: General conditions for the deprotection of a 7V-Boc carbamate in the presence of a boronate ester: The boronate ester is dissolved in te/t-butylmethylether (0.4 M final ester concentration) after which point HCl (g) is bubbled in over the course of 15 min. The reaction is allowed to stir at room temperature for an additional hour after which point the solvent is removed under a stream of nitrogen to provide the desired HCl amine salt as a white solid in quantitative yield.; Example 2: Tetrahydropyridine 2 was prepared in 3 steps starting with the deprotection of 1 using Method 3. The resulting HCl amine salt was dissolved in dichloromethane (0.2 M). Benzyl chloroformate (1.2 equiv) was added followed by triethylamine (3.0 equiv). The reaction was allowed to stir at room temperature for 2h after which point it was diluted with IN HCl and extracted with excess dichloromethane. The organic layer was dried over MgSpsi4 and concentrated to provide the desired carbamate in quantitative yield, which was converted directly to boronic acid 2 using Method 2. [M-H]- = 260.1 m/z. Activity: B
100%
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 4h;
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-5,6-dihydropyridine-1(2H)-carboxylate (5g, 16 mmol) in dioxane (10 mL) was added 4N HCl dioxane solution (24.2 mL, 97 mmol) at RT, and the reaction was stirred at RT for 4 h. The mixture was concentrated under reduced pressure to afford the title compound (4 g, yield 100percent) as a white solid.MS (ES+) C11H21BCINO2 requires: 209, found 210 [M+H]+.
100%
With hydrogenchloride; In ethyl acetate; at 0 - 26℃; for 3h;
Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (ARK PHARMA, 25 g, 80.851 mmol) was dissolved in 250 mL of EtOAc and HCI 4N in EtOAc (SYMAX FINE CHEMICALS, 250 mL) was added at 0 °C. The mixture was allowed to 26 °C and stirred for 3 h. The reaction mixture was evaporated under reduced pressure. The crude was washed with diethyl ether and filtered to give title compound (20 g, quantitative). NMR (400 MHz, DMSO-d6) delta ppm: 9.30 (br s, 2H), 6.40-6.30 (m, 1 H), 3.64- 3.52 (m, 2H), 3.15-3.00 (m, 2H), 2.34-2.22 (m, 2H), 1.21 (s, 12H).
96%
With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃;
To tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1 -carboxylate 51 (3 g, 9.7 mmol) in dichloromethane (5 mL) was added hydrochloric acid in 1,4-dioxane (4 N, 5 mL). The reaction was stirred at room temperature overnight, then concentrated twice from toluene. The residue was washed with ethyl acetate and dried under vacuum to produce compound 52 as an HC1 salt (2.3 g, 96percent). The data from the lH NMR spectrum were consistent with the structure of the compound.
90%
With hydrogenchloride; In diethyl ether; tert-butyl methyl ether; at 20℃;
tert-butyl 4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-5 ,6-dihydropyridine- 1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HC1 in Et20 (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et20 to give the title compound (1.434 g, 90 percent).UPLC-MS: 0.51 mm, 210.3 [M+H]+, method 9.
90%
With hydrogenchloride; In diethyl ether; tert-butyl methyl ether; at 20℃;
tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HCl in Et2O (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et2O to give the title compound (1.434 g, 90percent).UPLC-MS: 0.51 min, 210.3 [M+H]+, method 9.
With hydrogenchloride; In methanol; at 20℃; for 1h;
The mixture of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (4.0 g, 12.9 mmol) in HCl/MeOH (20 mL) was stirred at room temperature for lhour. Then it was concentrated to give 4-(4,4,5,5-Tetramethyl- [l,3,2]dioxaborolan-2-yl)-l,2,3,6-tetrahydro-pyridine hydyochloride (2.9 g, 11.8mmol, yield:91.4percent)which was used in the next step without further purification. ESI-MS (M+1): 210 calc. for CnH2oBN02 209
8 g
With hydrogenchloride; In dichloromethane; isopropyl alcohol; for 12h;
Step 1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinium chloride Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCl in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the solvent is again evaporated to give the title compound. Yield: 8 g; LC (method 11): tR=0.68 min; Mass spectrum (ESI+): m/z=210 [M+H]+.
8 g
With hydrogenchloride; In dichloromethane; isopropyl alcohol; for 12h;
Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (1 0 g) is d issolved in d ichloromethane (1 00 m L) and 5 M HCI in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): tR = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]+.
8 g
With hydrogenchloride; In dichloromethane; isopropyl alcohol; for 12h;
Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCI in isopropanol (120 mL) and stirred for 1 2 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): tR = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]+.
4-(4-acetyl-3-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.3%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; barium hydroxide monohydrate; In water; N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere;
nder argon, N- (4-bromo-2-nitrophenyl) acetamide 8a (7.00 g, 27.02 mmol),4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6-Dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester8b (8.77 g, 28.37 mmol),1,1'-bis (diphenylphosphino) ferrocenepalladium dichloride dichloromethane complex (2.34 g, 2.70 mmol) and barium hydroxide monohydrate (5.12 g, 27.02 mmol)Was dissolved in a mixed solvent of 120 mL of N, N-dimethylformamide and water (V / V = 5/1)Heated to 100 ° C for 4 hours.The reaction mixture was cooled to room temperature, 150 mL of ethyl acetate and 150 mL of water were added,The aqueous phase was extracted with ethyl acetate (50 mL). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A)getTert-Butyl 4- (4-acetylamino-3-nitrophenyl) -5,6- dihydropyridine- 1 (2H) -carboxylate 8c (8.72 g,Orange solid), yield: 89.3percent.
83.9%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; tricyclohexylphosphine; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;
Under the protection of argon, the N - (4 - bromo -2 - nitrophenyl) acetamide 3 b (550 mg, 2 . 12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 9 a (853 mg, 2 . 76 mmol), three-ring [...] (59 mg, 0 . 212 mmol), tris(dibenzylideneacetone)dipalladium (97 mg, 0 . 106 mmol) and cesium carbonate (2.08 g, 6 . 37 mmol) dissolved in 40 ml water and 1, 4 - dioxane (V/V=1/4) mixed solvent in, 80 °C reaction 2 hours. The reaction cooling to room temperature, concentrated under reduced pressure, adding 50 ml ethyl acetate and 20 ml water, layered, organic phase using saturated sodium chloride solution (20 ml) washing, drying with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, the obtained residue by silica gel column chromatography (eluant: B system) purification, to obtain 4-(4-acetyl-3-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 9 b (644 mg, yellow solid), yield: 83.9percent.
3-amino-5-chloro-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; for 16h;Reflux;
This example illustrates the preparation of 2-chloro-Lambda/-{5,6-dichloro-l'-[4-(5-chloro- pyrimidin-2-yl)-benzyl]- 1 ',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-3-yl} -isonicotinamide (Compound B8 of Table B).The title compound was prepared from 3-amino-5,6-dichloro-3',4',5',6'-tetrahydro- 2'H-[2,4']bipyridinyl-r-carboxylic acid tert-butyl ester according to procedures analogous to those described in Example 5, Steps C-E. 3-Amino-5,6-dichloro-3',4',5',6'-tetrahydro-2'H- [2,4']bipyridinyl-r-carboxylic acid tert-butyl ester was prepared as follows:Step A: A degassed solution of <strong>[78607-32-6]2,5-dichloro-3-amino-pyridine</strong> (40.75 g), 4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (77.25 g) (prepared as described in WO 2006/003494) and bis(triphenylphosphine)- palladium(II) chloride (8.76 g) in dioxane (1500 ml) was treated with a degassed solution of sodium carbonate (79 g) in water (800 ml). The reaction mixture was heated to reflux for 16 hours, cooled to ambient temperature and the solvent evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the aqueous layer extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (eluent: cyclohexane / ethyl acetate 8:2) afforded 3- amino-5-fluoro-3',6'-dihydro-2'H-[2,4']bipyridinyl-r-carboxylic acid tert-butyl ester (60 g) as a yellow solid. MS (ES+) 310 / 311 (MEta+), 254 / 256 (MH+-isobutene).
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 80℃;Inert atmosphere;
2-Bromothiophene-3-carboxylic acid methyl ester (3.0 g, 14.0 mmol, 1.0 eq.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (4.2 g, 14.0 mmol, 1.0 eq.), THF (150 mL) and Na2CO3 (28 mL, 56 mmol, 4.0 eq.) were combined.The mixture was degassed and purged with nitrogen (3*). PdCl2(PPh3)2 (0.3 g, 0.4 mmol, 0.03 eq.) was added, and the mixture was again degassed and purged with nitrogen (3*), then heated at 80° C. overnight.The mixture was then cooled and the layers were separated.The THF layer was diluted with EtOAc (150 mL), washed with saturated aqueous NaCl (50 mL) and dried over Na2SO4.The material was filtered and applied onto a silica gel column and purified by chromatography with PE/EtOAc (20:1~10:1) to yield 4-(3-methoxycarbonylthiophen-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (4.2 g) as a yellow solid.
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; for 18h;Inert atmosphere; Reflux;
A solution of <strong>[78071-37-1]4-bromothiophene-3-carboxylic acid methyl ester</strong> (500 mg, 2.3 mmol, 1.0 eq.) in THF (40 mL) was combined with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.7 g, 2.3 mmol, 1 eq.) under nitrogen.A solution of Na2CO3 (960 mg) in water (4.5 mL) was added, followed by the addition of PdCl2(PPh3)2 (80 mg, 0.1 mmol, 0.4 eq.).The resulting solution was stirred for 18 hours while the temperature was maintained at reflux in an oil bath.The resulting solution was diluted with EtOAc (50 mL), then washed with saturated aqueous NaCl (2*100 mL).The organic layer was concentrated and the residue was applied onto a silica gel column and eluted with EtOAc/PE (1:30) to yield 4-(4-methoxycarbonylthiophen-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.4 g) as a light yellow oil.H-NMR: (300 MHz, CDCl3, ppm): 8.10 (1H, d, J=3.6 Hz), 7.05 (1H, d, J=3.6 Hz), 4.15 (2H, m), 3.85 (3H, s), 3.66 (2H, m), 2.38 (2H, s), 1.51 (9H, s).
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In 1,2-dimethoxyethane; ethanol; water; at 80℃; for 18h;
<strong>[36178-05-9]3-Bromo-2-fluoropyridine</strong> (1.5 g, 8.5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (3.16 g, 10.2 mmol), trans- dichlorobis(triphenylphosphine)palladium (II) (0.48 g, 0.68 mmol), sodium carbonate (4.44 g, 41.9 mmol), and 6: 1 : 1 DME-H20-EtOH (20 mL) were combined in a sealed tube and stirred at 80 C for 18 h. The cooled reaction was diluted with CH2CI2 and washed with aqueous saturated NaHCC>3 solution; the aqueous layer was back-washed with CH2C12 (lx). The combined organic extracts were dried (MgSC>4), filtered, and concentrated in vacuo. Flash column chromatography (10% to 40% EtOAc/Hexanes) gave tert-butyl 4-(2-fluoropyridin-3-yl)- 5,6-dihydropyridine-l(2H)-carboxylate as a golden yellow oil. [M+l] = 279.2.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 110℃; for 20h;
A mixture of 160 <strong>[36178-05-9]3-bromo-2-fluoropyridine</strong> (1.8 g), 26 tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (3.4 g), 161 tetrakis(triphenylphosphine)palladium (0) (0.60 g), aqueous sodium carbonate (2M, 6.5 ml), and 46 1,4-dioxane (25 ml) was stirred at 110°C for 20 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated. The resulting residue was purified via silica gel column chromatography to obtain 162 tert-butyl 2-fluoro-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate as a pale yellow solid (Compound (27-1)).
With sodium acetate;bis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium (II) Dichloride; bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (II) dichloride; In 1,4-dioxane; water; at 120℃; for 1.5h;Sealed tube; microwave irradiation;
A 10 mL CEM microwave vessel was charged with <strong>[105752-11-2]3-amino-4-iodopyridine</strong> (139 mg, 0.63 mmol, Alfa Aesar), 3,6-dihydro-2H-pyridine-l-A^-boc-4-boronic acid pinacol ester (236 mg, 0.76 mmol, Frontier Scientific Inc.), NaOAc (155 mg, 1.90 mmol) and a stirbar. The vessel was sealed, and transferred into a glove box using a standard antichamber evacuate-refill cycle (3 times). The vessel was charged with A-Phos (45 mg, 0.063 mmol, Sigma-Aldrich), and sealed. The vessel was then transferred to a standard hood, and treated with dioxane (4 mL), and water (0.4 mL). The slurry was sonicated and was then heated in a microwave using a CEM explorer at 120 C for 30 min. The solution was treated with a second aliquat of 3,6-dihydro-2H-pyridine-l-A x>c-4-boronic acid pinacol ester (236 mg, 0.76 mmol, Frontier Scientific Inc.) and was then heated in a microwave using a CEM explorer at 120 C for 30 min The solution was treated with dichlorobis(di-?er?-butylphenylphosphine)palladium(II) (20 mg, 0.032 mmol, Alfa Aesar) and was then heated in a microwave using a CEM explorer at 120 C for 30 min. The solution was cooled to RT overnight under a stream of N2. The residue was treated with dry THF (5 mL) and SiliaMetS TAAcOH (1.29 g, 0.63 mmol, Silicycle). The vessel was crimped with a PTFE lined seal, and heated at 60 C for 3 h. The slurry was N2- pressure filtered through a glass frit (10 mL Bohdan) fitted with a 0.22 muiotaeta PTFE, 25 mm syringe filter unit (Millipore, SLFG025NK). The silica was washed with dry THF (5 x 5 mL), and concentrated in vacuo. The crude material was purified by silica gel chromatography (10% EtOH in DCE) to afford teri-butyl 3'-amino-5,6-dihydro-[4,4'- bipyridine]-l(2H)-carboxylate (77 mg, 0.28 mmol, 44 % yield). MS (ESI, pos. ion) m/z: 276.0 (M+l).
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 85℃;Inert atmosphere;
Step 1: To Methyl 3-(2-bromophenyl)propanoate (715 mg, 2.94 mmol) and 3,6- dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (1.0 g, 3.23 mmol) were added to a flask, followed by Pd(dppf)Cl2 (151 mg, 0.21 mmol) and K2C03 (1.22 g, 8.82 mmol). The reaction flask was purged with Ar (3x). Dry DMF (22 ml.) was added and the solution was degassed for 10 min. The reaction mixture was heated to 85 C overnight. The mixture was filtered through Celite and was concentrated. The crude residue was purified by silica gel chromatography (gradient, 10% to 30% EtOAc/hexanes) to give fert-butyl 4-(2-(3-methoxy-3- oxopropyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (23) as a pale yellow oil (970 mg, 96% yield). 1H NMR (400 MHz, CDCfe): delta 7.21-7.16 (m, 3H), 7.09-7.06 (m, 1H), 5.57-5.55 (m, 1H), 4.03 (q, 2H), 3.67 (s, 3H), 3.63 (t, 2H), 2.95-2.91 (m, 2H), 2.59-2.55 (m, 2H), 2.37-2.33 (m, 2H), 1.50 (s, 9H). LC/MS RT (5 min method) = 2.10 min. Mass observed: 246.19 (M-Boc+H).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; for 0.25h;Microwave irradiation;
6.01.04.02 4-(6-Methoxy-pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 0.5 g tetrakis (triphenylphosphine) palladium was added to 1.3 g <strong>[26452-81-3]4-chloro-6-methoxy-pyrimidine</strong> and 4-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester) and 9 mL 2 mol/L sodiumcarbonate in 40 mL dioxane. The reaction was stirred 15 min. under microwave conditions. Water was added and the reaction was extracted with DCM. The organic layer was dried and evaporated. The residue was purified by HPLC to give 1.44 g of the desired product. Rt: 1.38 min (method L)
tert-butyl 2'-amino-3'-nitro-5,6-dihydro-[4,4'-bipyridine]-1(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 80 - 90℃; for 20.0h;
a) tert-Butyl 2'-amino-3'-nitro-5,6-dihydro-[4,4'-bipyridine]- 1(2H)-carbox (A27) An aqueous solution of 2 M Na2C03 (3.44 mL, 6.88 mmol) was added to a degassed mixture of fert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate A26 (1.42 g, 4.59 mmol), <strong>[84487-10-5]2-amino-4-bromo-3-nitropyridine</strong> A25 (0.500 g, 2.29 mmol) and PdCI2(PPh3)2 (0.080 g, 0.12 mmol) in 1 ,4-dioxane (30 mL). The reaction mixture was stirred at 80 - 90 C for 20 hours. The resulting mixture was concentrated in vacuo and partitioned between EtOAc (50 mL) and water (30 mL), then filtered through a pad of Celite. The layers were separated and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were washed with 1 : 1 water: saturated brine (30 mL), dried (MgS04), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica cartridge, 0-80% EtOAc in petroleum benzine 40-60 C) to give the title compound (0.583 g, 79%) as a bright yellow solid. H NMR (400 MHz, cfe-DMSO) delta 8.15 (d, J = 4.9 Hz, 1 H), 7.23 - 6.93 (s, 2H), 6.54 (d, J = 4.9 Hz, 1 H), 5.68 (s, 1 H), 3.97 - 3.75 (m, 2H), 3.58 - 3.40 (t, J = 5.5 Hz, 2H), 2.29 - 2.14 (td, J = 5.5, 2.5 Hz, 2H), 1.42 (s, 9H), LCMS- A rt 5.51 min, m/z (positive ion) 321 [M+H]+.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere; Sealed tube;
a) tert-Butyl 6-amino-5-nitro-5 6'-dihydro-[3 '-bipyridine]-1 ^ (A31) 5-Bromo-3-nitropyridin-2-amine A30 (2.50 g, 11.5 mmol), ferf-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (3.90 g, 12.6 mmol) and PdCI2(dppf) DCM solvate (474 mg, 5 mol%) were loaded into a flask, the flask was sealed and flushed with nitrogen. Dioxane (100 mL) was added, followed by a solution of K2C03 (4.76 g, 34.4 mmol) in water (50 mL). The mixture was degassed with three vacuum/nitrogen cycles, heated to 80 C for 16 hours, and allowed to cool. The mixture was concentrated, the aqueous residue diluted with water (400 mL) and chloroform (250 mL). The aqueous phase was extracted with chloroform (2 x 150 mL), the combined chloroform extracts washed with brine (200 mL), dried over Na2S04, filtered and evaporated. Column chromatography (0-80% EtOAc/hexanes) gave the title compound (3.058 g, 83%) as a yellow-orange solid. H NMR (400 MHz, CDCIs) delta 8.45 (d, J = 2.3 Hz, 1 H), 8.37 (d, J = 2.2 Hz, 1 H), 6.73 (br s, 2H), 6.06 (s, 1 H), 4.13 - 4.04 (m, 2H), 3.65 (t, J = 5.7 Hz, 2H), 2.48 (s, 2H), 1.49 (s, 9H). LCMS-A: rt 5.58 min; m/z (positive ion) 321.2 [M+H]+, 265.1 [M-tBu+2H]+.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 100℃;
Step 1. tert-butyl 4-(lH-imidazol-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate [0253] A mixture of 2-bromo-lH-imidazole (1.2 g, 8.16 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (3.0 g, 9.70 mmol), sodium carbonate (2.1 g, 19.8 mmol), and [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloro methane adduct (0.120 g, 0.16 mmol) in 1 ,4-dioxane (30 mL) and water (10 mL) stirred overnight at 100 C. The reaction mixture was cooled to room temperature, poured into ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 25% ethyl acetate-petroleum ether) to afford tert-butyl 4-(lH-imidazol-2-yl)- 5,6-dihydropyridine-l(2H)-carboxylate (0.300 g, 15%) as a light yellow solid. MS (ESI, pos. ion) m/z 250 [M+H]+.
5-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-benzimidazole-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.7 g
With dichloro[1,1?-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P?]palladium; sodium carbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere;
A mixture of <strong>[40197-20-4]5-bromo-1H-benzimidazol-2-carboxylic acid</strong> (3.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.7 g), dichloro[1,1?-bis(di-tert-butylphosphino)ferrocene]palladium (410 mg), 2 M aqueous sodium carbonate solution (50 ml), and dioxane (75 ml) was stirred at 95 C. overnight in an argon atmosphere, and then cooled to room temperature. After water (170 ml) and ethyl acetate (200 ml) were added to the reaction mixture, the reaction mixture was stirred for 20 minutes, and then subjected to liquid-liquid partition. The aqueous layer was washed with ethyl acetate (50 ml), and then citric acid was added thereto to adjust pH to be 6 to 7. The resulting solid was collected by filtration, and then dried under reduced pressure, thereby obtaining 5-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-benzimidazole-2-carboxylic acid (2.7 g) as a solid.
tert-butyl 4-(1-methyl-1H-imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate[ No CAS ]
tert-butyl 4-(1-methyl-1H-imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step 1. 4-Iodo-l-methyl-lH-imidazole and 5-iodo-l-methyl-lH-imidazole (1205) [00394] Under an atmosphere of nitrogen at 0 C, a solution of 4-iodo-lH-imidazole (5.82 g, 30.00 mmol) in THF (50 mL) was treated with portionwise addition of sodium hydride (60% dispersion in mineral oil, 1.44 g, 36.00 mmol). After stirring for 30 min at 0 C, iodomethane was added (2.8 mL, 45.00 mmol) and the mixture was stirred for 1 h at 0 C. The reaction mixture was poured into water (100 mL) and was extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 6.24 g (90%) of a -3 : 1 mixture of 4-iodo-l-methyl-lH-imidazole and 5- iodo-1 -methyl- lH-imidazole as a light yellow solid. MS (ESI) m/z 209 [M+H]+. Step 2. terf-Butyl 4-(l-methyl-lH-imidazol-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate and terf-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1207) [00395] A -3 : 1 mixture of 4-iodo-l -methyl- lH-imidazole and 5-iodo-l-methyl-lH-imidazole (6.24 g, 30.00 mmol), fert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (1 1.1 g, 36.00 mmol), Pd(dppf)Cl2 CH2Cl2 (2.45 g, 3.00 mmol) and sodium carbonate (6.36 g, 60.00 mmol) in water (60 mL) and 1,4-dioxane (300 mL) was stirred under an atmosphere of nitrogen for 3 h at 80 C. After cooling to ambient temperature, the reaction mixture was poured into EtOAc (100 mL) and was washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with a gradient of 1-5% DCM/MeOH) to afford 5 g (57%) of a -3 : 1 mixture of tert-butyl 4-(l-methyl-lH-imidazol-4-yl)- 3,6-dihydropyridine-l(2H)-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6- dihydropyridine-l(2H)-carboxylate as a yellow oil. MS (ESI) m/z 264 [M+H]+.
tert-butyl 4-(1-methyl-1H-imidazol-4-yl)piperidine-1-carboxylate[ No CAS ]
tert-butyl 4-(1-methyl-1H-imidazol-5-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step 1. 4-Iodo-l-methyl-lH-imidazole and 5-iodo-l-methyl-lH-imidazole (1205) [00394] Under an atmosphere of nitrogen at 0 C, a solution of 4-iodo-lH-imidazole (5.82 g, 30.00 mmol) in THF (50 mL) was treated with portionwise addition of sodium hydride (60% dispersion in mineral oil, 1.44 g, 36.00 mmol). After stirring for 30 min at 0 C, iodomethane was added (2.8 mL, 45.00 mmol) and the mixture was stirred for 1 h at 0 C. The reaction mixture was poured into water (100 mL) and was extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 6.24 g (90%) of a -3 : 1 mixture of 4-iodo-l-methyl-lH-imidazole and 5- iodo-1 -methyl- lH-imidazole as a light yellow solid. MS (ESI) m/z 209 [M+H]+. Step 2. terf-Butyl 4-(l-methyl-lH-imidazol-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate and terf-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1207) [00395] A -3 : 1 mixture of 4-iodo-l -methyl- lH-imidazole and 5-iodo-l-methyl-lH-imidazole (6.24 g, 30.00 mmol), fert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (1 1.1 g, 36.00 mmol), Pd(dppf)Cl2 CH2Cl2 (2.45 g, 3.00 mmol) and sodium carbonate (6.36 g, 60.00 mmol) in water (60 mL) and 1,4-dioxane (300 mL) was stirred under an atmosphere of nitrogen for 3 h at 80 C. After cooling to ambient temperature, the reaction mixture was poured into EtOAc (100 mL) and was washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with a gradient of 1-5% DCM/MeOH) to afford 5 g (57%) of a -3 : 1 mixture of tert-butyl 4-(l-methyl-lH-imidazol-4-yl)- 3,6-dihydropyridine-l(2H)-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6- dihydropyridine-l(2H)-carboxylate as a yellow oil. MS (ESI) m/z 264 [M+H]+. Step 3. tert-But l 4-(l-methyl-lH-imidazol-4-yl)piperidine-l-carboxylate and tert-butyl 4-(l- methyl-lH-imidazol-5-yl)piperidine-l-carboxylate (1209) [00396] A -3 : 1 mixture of tert-butyl 4-(l-methyl-lH-imidazol-4-yl)-3,6-dihydropyridine- l(2H)-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6-dihydropyridine-l(2H)- carboxylate (5 g, 19.01 mmol) and palladium on carbon (10 wt. %, 5 g) in MeOH (100 mL) was evacuated and backfilled with hydrogen several times and was then charged with hydrogen. The resulting mixture was stirred for 1 h at ambient temperature before being filtered and concentrated under vacuum, resulting in 1.7 g (34%) of a -3 : 1 mixture of tert-butyl 4-(l-methyl- lH-imidazol-4-yl)piperidine-l-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5- yl)piperidine-l-carboxylate as a yellow oil. MS (ESI) m/z 266 [M+H]+.
tert-butyl 4-(2-iodo-1-methyl-1H-imidazol-4-yl)piperidine-1-carboxylate[ No CAS ]
tert-butyl 4-(2-iodo-1-methyl-1H-imidazol-5-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step 1. 4-Iodo-l-methyl-lH-imidazole and 5-iodo-l-methyl-lH-imidazole (1205) [00394] Under an atmosphere of nitrogen at 0 C, a solution of 4-iodo-lH-imidazole (5.82 g, 30.00 mmol) in THF (50 mL) was treated with portionwise addition of sodium hydride (60% dispersion in mineral oil, 1.44 g, 36.00 mmol). After stirring for 30 min at 0 C, iodomethane was added (2.8 mL, 45.00 mmol) and the mixture was stirred for 1 h at 0 C. The reaction mixture was poured into water (100 mL) and was extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 6.24 g (90%) of a -3 : 1 mixture of 4-iodo-l-methyl-lH-imidazole and 5- iodo-1 -methyl- lH-imidazole as a light yellow solid. MS (ESI) m/z 209 [M+H]+. Step 2. terf-Butyl 4-(l-methyl-lH-imidazol-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate and terf-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1207) [00395] A -3 : 1 mixture of 4-iodo-l -methyl- lH-imidazole and 5-iodo-l-methyl-lH-imidazole (6.24 g, 30.00 mmol), fert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (1 1.1 g, 36.00 mmol), Pd(dppf)Cl2 CH2Cl2 (2.45 g, 3.00 mmol) and sodium carbonate (6.36 g, 60.00 mmol) in water (60 mL) and 1,4-dioxane (300 mL) was stirred under an atmosphere of nitrogen for 3 h at 80 C. After cooling to ambient temperature, the reaction mixture was poured into EtOAc (100 mL) and was washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with a gradient of 1-5% DCM/MeOH) to afford 5 g (57%) of a -3 : 1 mixture of tert-butyl 4-(l-methyl-lH-imidazol-4-yl)- 3,6-dihydropyridine-l(2H)-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6- dihydropyridine-l(2H)-carboxylate as a yellow oil. MS (ESI) m/z 264 [M+H]+. Step 3. tert-But l 4-(l-methyl-lH-imidazol-4-yl)piperidine-l-carboxylate and tert-butyl 4-(l- methyl-lH-imidazol-5-yl)piperidine-l-carboxylate (1209) [00396] A -3 : 1 mixture of tert-butyl 4-(l-methyl-lH-imidazol-4-yl)-3,6-dihydropyridine- l(2H)-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5-yl)-3,6-dihydropyridine-l(2H)- carboxylate (5 g, 19.01 mmol) and palladium on carbon (10 wt. %, 5 g) in MeOH (100 mL) was evacuated and backfilled with hydrogen several times and was then charged with hydrogen. The resulting mixture was stirred for 1 h at ambient temperature before being filtered and concentrated under vacuum, resulting in 1.7 g (34%) of a -3 : 1 mixture of tert-butyl 4-(l-methyl- lH-imidazol-4-yl)piperidine-l-carboxylate and tert-butyl 4-(l-methyl-lH-imidazol-5- yl)piperidine-l-carboxylate as a yellow oil. MS (ESI) m/z 266 [M+H]+.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 140℃; for 0.25h;Microwave irradiation;
III.1665-methoxy-2-(4-piperidyl)pyrimidine A mixture of 2.1 g (14.5 mmol) <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong>, 4.9 g (16.0 mmol) tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate, 339 mg (0.29 mmol) tetrakis(triphenylphosphine)palladium(0), 14.5 ml (29 mmol) 2M Na2CO3 solution and dioxane is heated to 140°C for 15 min using a microwave reactor. The reaction mixture is cooled to RT and DCM and water are added, the organic phase is separated and evaporated and purified by HPLC. Giving rise to tert-butyl 4-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate. Yield: 3.5 g (83percent), ESI-MS: m/z = 292 (M+H)+
83%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 140℃; for 0.25h;Microwave irradiation;
A mixture of 2.1 g (14.5 mmol) <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong>, 4.9 g (16.0 mmol) tert- butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 - carboxylate, 339 mg (0.29 mmol) tetrakis(triphenylphosphine)palladium(0), 14.5 ml (29 mmol) 2M Na2CO3 solution and dioxane is heated to 140°C for 15 min using a microwave reactor. The reaction mixture is cooled to RT and DCM and water are added, the organic phase is separated and evaporated and purified by HPLC. Giving rise to tert-butyl 4-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate.Yield: 3.5 g (83percent), ESI-MS: m/z = 292 (M+H)+
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 75℃; for 18h;Inert atmosphere;
To a mixture of <strong>[10075-48-6]5-bromo-3-methyl-1H-indole</strong> (0.4 17 g, 1.985 mmol), PdC12(dppf)-CH2C12 adduct (0.041 g, 0.050 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1 (2H)-carboxylate (0.675 g, 2.183 mmol) in a 40 ml reaction vial was added THF (10 mL) followed by a 3M aqueous solution of tripotassium phosphate (1.985 mL, 5.95 mmol). The vial was fitted with a Teflon-linedseptum cap. The system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and back-filled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 75 C for 18 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (125 mL). The mixture was poured into a separatory funnel and washed withwater (2X 50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give crude product. The crude product was dissolved in a small amount of DCM and charged to an ISCO silica gel (24 g) column, which was eluted over 20 minutes using a gradient of 0-50% ethyl acetate/heptane. The combined fractions were concentrated to give tert-butyl4-(3 -methyl- 1H-indol-5-yl)-5,6-dihydropyridine- 1 (2H)-carboxylate (0.510 g, 82 % yield) as a tan oil. LC retention time 1.10 mm [Method Al]. MS (E) m/z: 313 (M-H).
82%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 75℃; for 18h;Inert atmosphere;
To a mixture of <strong>[10075-48-6]5-bromo-3-methyl-1H-indole</strong> (0.417 g, 1.985 mmol),PdCl2(dppf)-CH2Cl2 adduct (0.041 g, 0.050 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.675 g, 2.183 mmol) in a 40 mL reaction vial were added THF (10 mL) followed by a 3 M aqueous solution of tripotassium phosphate (1.985 mL, 5.95 mmol). The vial was fitted with a Teflon-lined septum cap. The system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and back-filled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 75 C for 18 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (125 mL). The mixture was poured into a separatory funnel and washed with water (2 x 50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give crude product. The crude product was dissolved in a small amount of DCM and charged to an ISCO silica gel (24 g) column, which was eluted over 20 minutes using a gradient of 0-50% ethyl acetate/heptane. The combined fractions were concentrated to give tert-butyl 4-(3-methyl-1H-indol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.510 g, 1.632 mmol, 82% yield) as a tan oil. MS (M+1) m/z: 257.1 (MH+-tertbutyl). LC retention time 1.08 min [A1].
3,5-dimethyl-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8.93 g
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 5h;Inert atmosphere;
To <strong>[92992-85-3]2-bromo-3,5-dimethylpyridine</strong> (6.62 g) were added N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (10 g),sodium carbonate (7.54 g),1,4-dioxane (50 mL),water (50 mL) and tetrakis(triphenylphosphine)palladium(0)(1.87 g) and the mixture was stirred under a nitrogen stream at 100c for 5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine,dried over sodium sulfate,and treated with activated carbon. The solvent was evaporated and the obtained residue was purified by column chromatography (hexane:ethyl acetate)to give 3,5-dimethyl-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (8.93 g).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100.0℃; for 3.0h;Inert atmosphere;
Compound 1 (2.0 g, 7.8 mmol, 1 eq), PB03145 (2.89 g, 9.36 mmol, 1.2 eq)Pd(dppf)Cl2 (570 mg, 0.78 mmol, 0.1 eq),Potassium phosphate (4.97 g, 23.4 mmol, 3 eq) was added to a 100 ml single-mouth bottle.Add dioxane (10 ml), water (2 ml), and replace with nitrogen three times.The temperature was raised to 100 ° C, and the reaction was carried out for 3 hours, and the reaction was terminated by TLC.The reaction solution was cooled to room temperature and EA (100 mL) was added.Water (30 ml), the organic phase was separated and washed with saturated brine (50 ml).The organic phase was dried over magnesium sulfate and dried.Add n-heptane (100 ml) and filter to give a yellow solid (2.3 g crude).
ethyl 6-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 16h;Inert atmosphere;
To a stirred solution of ethyl 6-chloroimidazo[l,2-b]pyridazine-2-carboxylate (A50, 1.5 g, 6.64 mmol) in l,2-dimethoxy ethane(30 mL) and H20(6 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate(1, 3.08 g, 9.97 mmol) and Na2C03(2.11 g, 19.94 mmol). The reaction mixture was purged with N2 gas for 20 min. To the above reaction mixture was added[l, T-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane PdCl2(dppf).DCM(0.54 g, 0.664 mmol), and the resulting solution was further purged with N2 gas for 10 min then stirred for 16 h at 80C. The reaction mixture was filtered over celite bed and washed with ethylacetate/water mixture. The filtrate was washed with water, brine solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The obtained crude was purified by column chromatography using 0-10% MeOH in DCM as eluent to afford ethyl 6-(l-(tert-butoxycarbonyl)-l,2,3,6- tetrahydropyridin-4-yl)imidazo[l,2-b]pyridazine-2-carboxylate A51 as a brown solid. Yield: 2.0 g(8l%).LC-MS m/z: 370.98[M-H]
tert-butyl 4-(3-isopropylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.75h;Sealed tube; Inert atmosphere; Microwave irradiation;
General procedure: The boronic acid pinacol ester (1 equiv.), aryl halide (1 equiv.) and Pd(dppf)Cl2·CH2Cl2 adduct (0.1 equiv.) were dissolved in a mixture of DME and aqueous sodium carbonate (1M) in a microwave vial. The vial was sealed, evacuated and backfilled with N2. The reaction mixture was heated in the microwave at 120C for 45min and monitored by LCMS. The reaction mixture was concentrated in vacuo to give the crude material which was purified by Biotage column chromatography (see individual compounds for details of the eluent used).
tert-butyl 4-(3-(pyridin-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.75h;Sealed tube; Inert atmosphere; Microwave irradiation;
General procedure: The boronic acid pinacol ester (1 equiv.), aryl halide (1 equiv.) and Pd(dppf)Cl2·CH2Cl2 adduct (0.1 equiv.) were dissolved in a mixture of DME and aqueous sodium carbonate (1M) in a microwave vial. The vial was sealed, evacuated and backfilled with N2. The reaction mixture was heated in the microwave at 120°C for 45min and monitored by LCMS. The reaction mixture was concentrated in vacuo to give the crude material which was purified by Biotage column chromatography (see individual compounds for details of the eluent used).
tert-butyl 4-(4-(pyridin-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.75h;Sealed tube; Inert atmosphere; Microwave irradiation;
General procedure: The boronic acid pinacol ester (1 equiv.), aryl halide (1 equiv.) and Pd(dppf)Cl2·CH2Cl2 adduct (0.1 equiv.) were dissolved in a mixture of DME and aqueous sodium carbonate (1M) in a microwave vial. The vial was sealed, evacuated and backfilled with N2. The reaction mixture was heated in the microwave at 120°C for 45min and monitored by LCMS. The reaction mixture was concentrated in vacuo to give the crude material which was purified by Biotage column chromatography (see individual compounds for details of the eluent used).
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