Isoquinoline-5-boronic acid

To a solution of 5-bromoisoquinoline (1.46 g, 7.0 mmol), prepared according to a known procedure (Reference: Brown, W. D. et. al. Synthesis 2002, 83), in THF (20 mL) at-78 °C were added triisopropyl borate (2.4 mL, 10.5 mmol) and t- butyllithium (1.7 M, 9.5 mL). The solution was then slowly warmed to room temperature and kept stirring overnight. The solution was quenched with 1N HCl (10 mL) and the solid was obtained after decanting THF. The solid was identified as isoquinolinyl-5-boronic acid (1.0 g, 82percent). MS (ESI) (M+1) = 174.12.A 2.5 M solution of n-BuLi (1.2 equiv., 3 mmol, 1.2 ml) in 20 ml of freshly distilled THF, cooled to -78°C, was added with a solution of 5-bromoisoquinoline (2.5 mmol, 520 mg) in 5 ml of THF. The resulting mixture was allowed to react at this temperature over 45'. A solution of triisopropylborate (1.2 equiv., 3 mmol, 0.7 ml) was then added and the mixture was stirred at the same temperature for 5' and then allowed to warm to room temperature and stirred for an additional hour. The mixture was quenched by slow addition of a 5percent NaOH solution (30 ml). The aqueous layer was separated and acidified to pH 5/6 by addition of 10percent HCl at OSynthesis of isoquinolin-5-yl-5-boronic acid; A 2.5 M solution of n-BuLi (1.2 equiv., 3 mmol, 1.2 ml) in 20 ml of freshly distilled THF, cooled to -78°C was added with a solution of 5-bromoisoquinoline (2.5 mmol, 520 mg) in 5 ml of THF. The resulting mixture was allowed to react at this temperature over 45'. A solution of triisopropylborate (1.2 equiv., 3 mmol, 0.7 ml) was then added and the mixture was stirred at the same temperature for 5' and then allowed to warm to room temperature and stirred for an additional hour. The mixture was quenched by slow addition of a 5percent NaOH solution (30 ml). The aqueous layer was separated and acidified to pH 5/6 by addition of HCl 10percent at O°C. Extraction with ethyl acetate, evaporation of the organic phase and crystallisation from diethyl ether gave 250 mg of a white solid. Yield = 58percent. General procedure: To a solution under argonof brominated derivative in 1, 4-dioxane (0.1-0.6 mmol, 1 eq., 0.1M)were added the boronic acid or boronic ester (1.5 eq.) and a 2 MNa2CO3 aqueous solution (5 eq.). The mixture was degassed withargon for 10 min before the addition of PdCl2(PPh3)2 (0.05 eq.). Thesolution was refluxed overnight. Ethyl acetate was added and theresulting mixture was washed with water. The organic phase wasdried over MgSO4 and filtered. After evaporation under reducedpressure, the crude was purified by column chromatography.General procedure: Benzyl bromide 3 (1.0 eq), the appropriate boronic acid (1.5 eq), Pd(dppf)Cl2 (0.1 eq), and K2CO3(3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system was flushedwith argon. A degassed mixture of 3:1 acetone:water (3 mL) was added, and the reaction was heated ina microwave to 100 C for 30 min. The product was purified via silica gel chromatography in ethylacetate/hexanes.A solution of 5-bromoindazole (197 mg, 1.00 mmol, commercial product), To a solution of Isoquinoline-5-horonic acid (103.8 mg, 0.6 mmoi) and Cu(OAc)2 (15.6 mg, 0.08 mmoi) in toluene (10 mU) were added 2, 6-Lutidine (42.8 mg, 0.4 mmol), Laurie acid (8.0 mg, 0.04 nunol) and compound A3 (300 mg, 0.4 mmoi). The mixture wasstirred under air atmosphere for two days at room temperature. The mixture was concentratedand the residue was purified by column chromatography on silica gel (MeOH/DCM = 1/20)and prep-HPLC to afford compound 58 (40 mg, yield 11.5%) as white solid. Partial 'H NMR(CDC13 400 MHz) 59 2 ( I H) 8 56 (dd I = 6 0 Hz IH) 8 17 (d J = b 0 Hz I H) 7.61(d, J::: 8.0 Hz. 1H), 7.46 (t, J::: 7.6 Hz, IH), 7.16 (d, J 7.6 Hz, 1Ff), 6.79 (s, 11-1), 4.92(s, 1H), 481-472 (in, 1H), 4.47-4.43 (rn, IH), 4.42-4.34 (rn, IH), 367-3.79 (in, 1H), 3.70-3.44 (m, 16H), 3.35-3.23 (in. 2H), 3.19-3.10 (rn, 2H), 2.73-2.65 (in, 1H), 2.61-2.55 (s, 1H), 2.52-2.45 (rn, TH), 2.33-2.45 (rn, 1FI), 2.33-2.21 (rn, IOFI), 0, 98-0, 85 (m, 41:1). LCMS: , n/z874.4 [MF[IProduction of 5-(2-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyridin-3-yl)isoquinoline (I-33) Compound (IV-1) (307 mg, 0.961 mmol), Compound (IV-1) (307 mg, 0.961 mmol), 5-Isoquinoline boronic acid (V-33) (258 mg, 1.44 mmol), (A-taPhos) 2 PdCl 2 (34.1 mg, 0.0481 mmol) and cesium carbonate (626 mg, 1.92 mmol) were dissolved in 1, 4-dioxane (4.0 mL) and water (0.80 mL)Followed by stirring at 110 C. for 14 hours. The reaction solution was allowed to cool, Water was added and extracted with ethyl acetate.The organic layer was washed successively with water and saturated brine, After drying with anhydrous sodium sulfate, It was filtered.After distilling off the solvent under reduced pressure, The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate)Compound (I-33)(Yield 222 mg, Yield 63%)As a white solid.

Molecular Weight:172.98
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:173.0648087
Monoisotopic Mass:173.0648087
Topological Polar Surface Area:53.4
Heavy Atom Count:13
Complexity:177
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes