2-HYDROXY-5-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)PYRIDINE

A solution of 5-bromopyridin-2-ol SM1 (0.1 g, 0.57 mmol), 4, 4, 4, 4, 5, 5, 5, 5-octamethyl- 2, 2-bi(1, 3, 2-dioxaborolane) SM2 (0.88 g, 3.45 mmol), Tricyclohexyl phosphine (0.032 g, 0.114mmol), Pd2(dba)3 (0.052 g, 0.057 mmol) and KOAc (0.17 g, 1.71 mmol) dissolved with dioxane (10 mL) in sealed tube was stirred at 110 °C overnight. After consumption of the starting material (by LC-MS), the solvent from reaction mixture was removed under reduced pressure, the residue was diluted with brine and extracted with EtOAc. Combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain cmde product, which waspurified by silica gel column chromatography to afford compound 3 (0.08 g, 64percent) as a black liquid.TLC: 50percent EA/PE.Under a nitrogen atmosphere, General procedure: A reaction solution of 3-bromo-5-((2, 4-dichlorobenzyl)oxy)pyridine (12a) (150.00mg, 0.45mmol) and 1-((5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)thiophen-2-yl)methyl)piperidine (13c) (138.27mg, 0.45mmol) in 1, 4-dioxane (15.00mL) was purged with nitrogen. Then PdCl2(PPh3)2 (15.44mg, 0.022mmol) and 1.0M of Na2CO3 (143.08mg, 1.35mmol) aqueous solution were added. The resulting mixture was purged with nitrogen and stirred at 90C for 2h. The reaction mixture was filtered through a Celite pad and washed well with MeOH. The residue was partitioned between DCM and saturated aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4 and concentrated in vacuo and the resulting crude mixture was purified by a silica gel column, eluting with EA:Hexane (1:1) to collect the title product (15) as a yellow solid (116.00mg, 59%)In a mixture of 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromen-7-yl pivalate (Ib4) (1 .2 g, 3.03 mmol) in 1 , 4-dioxane/water : 80/20 (v/v) (15 ml) were added 5-(4, 4, 5, 5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)pyridin-2-ol (736 mg, 3.33 mmol), Cs2C03 (2.10 g, 6.45 mmol) and [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with DCM (247 mg, 302.7 muetaetaomicronIota) and the mixture was stirred at 120C for 30 min. The reaction mixture was cooled to room temperature and silica Si60 (40-60 muetaeta) (4.4 g) was added. The mixture was concentrated under reduced pressure and the solid residue was purified by flash chromatography eluting with a gradient of n-heptane in EtOAc (10/90; v/v) to pure EtOAc, to give 401 mg (39%) of 4-(6-hydroxypyridin-3-yl)-2H-thiochromen-7-yl pivalate (Iu1 ). LC/MS (m/z, MH+): 342 (200 mg), Sodium hydride (36.2 mg), N, N-dimethylformamide (5 mL) was added and the mixture was stirred at room temperature for 15 minutes. Chloro(methoxy)methane (0.136 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Water was poured into the reaction solution, and the mixture was extracted three times with dichloromethane. The combined organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain crude title compound (240 mg) as an oil.General procedure: Under an N2 atmosphere, a solution of S3 (30 mg, 0.073 mmol) and 2-aminopyridine-5-boronic acid pinacol ester (11 mg, 0.081 mmol) in DMF (1.5 mL) and saturated aqueous NaHCO3 (0.5 mL) was treated with Pd(PPh3)4 (5mg, 3.7 mumol). The reaction mixture was heated under microwave irradiation at 120C for 20 minutes. The resulting mixture was diluted with water, and extracted with dichloromethane. The organics were combined, dried, filtered, and concentrated. Purification via preparative reverse phase HPLC afforded 11 as an off-white solid (11 mg, 26%).General procedure: Under an N2 atmosphere, a solution of S3 (30 mg, 0.073 mmol) and 2-aminopyridine-5-boronic acid pinacol ester (11 mg, 0.081 mmol) in DMF (1.5 mL) and saturated aqueous NaHCO3 (0.5 mL) was treated with Pd(PPh3)4 (5mg, 3.7 mumol). The reaction mixture was heated under microwave irradiation at 120C for 20 minutes. The resulting mixture was diluted with water, and extracted with dichloromethane. The organics were combined, dried, filtered, and concentrated. Purification via preparative reverse phase HPLC afforded 11 as an off-white solid (11 mg, 26%).In a 4 mL vial, a mixture of 2-(5-bromo-2, 5-dioxo- 13 -dihydro- 1 H-spiro [imidazolidine4, 2-inden] -1 -yl)-N- [(1S)-1 -cyclopropylethyl] -N-(4-fluorobenzyl)acetamide (0.06 g, 0.117 mmol), 5-(4, 4, 5, 5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)pyridin-2-ol (0.032 g, 0.146 mmol), potassiumcarbonate (0.049 g, 0.351 mmol), and PdC12(1 , 1 ?-bis(diphenylphosphino)ferrocene)dichloromethane adduct (7.62 mg, 9.33 jimol) in degassed dioxane (1 ml) and water (0.2 mL) was sealed under nitrogen and was heated at 95C for 7 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through a bed of diatomaceous earth. The filtrate was concentrated and the residue was purified by reverse-phase HPLC to give the titlecompound. 'H NMR (400 MHz, DMSO-d6, 90 C) 3 ppm 8.42 (brs, 1H), 7.74 (dd, J = 9.5, 2.8 Hz, 1H), 7.60 (d, J = 2.7 Hz, 1H), 7.42- 7.28 (m, 4H), 7.25 (d, J = 7.9 Hz, 1H), 7.16 -7.01 (m, 2H), 6.41 (d, J = 9.4 Hz, 1H), 4.63 (brs, 2H), 4.29-4.11 (m, 2H), 3.64-3.10 (m, 5H), 1.15 (d, J = 6.7Hz, 3H), 1.01 -0.89 (m, 1H), 0.55-0.43 (m, 1H), 0.31 -0.13 (m, 3H). MS (ESI) mlz 529(M+H).

6-Hydroxypyridine-3-boronic Acid Pinacol ester is used in the preparation of modified C3 Betulinic acid (B330250) derivatives as HIV maturation inhibitors.

Molecular Weight:221.06
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:221.1223235
Monoisotopic Mass:221.1223235
Topological Polar Surface Area:47.6
Heavy Atom Count:16
Complexity:369
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes