Pinacol

3-Iodopyrazolopyrimidines or 3-Bromopyrazolopyrimidines (1 equiv.), Na₂CO₃ or K₃PO₄ (2–4 equiv.), Pd(PPh₃)₄ or Pd(II)Cl₂dppf.DCM, (0.05 equiv.) and boronic acids or boronate pinacol esters (1–2 equiv.) were dissolved in a mixture of dimethoxyethane (1.5 mL) and water (0.5 mL) and then heated in a microwave at 80 °C for one hour. The reaction was monitored by thin layer chromatography. After cooling, ethyl acetate and water were added and the organic phase was separated. The water phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na₂SO₄ and evaporated under reduced pressure. The crude product was then purified via flash chromatography over silica, eluting with either a hexanes/EtOAc or CH₂Cl₂/MeOH gradient. If necessary, further purification was performed with preparatory RP-HPLC.

Step 1. To 2-fluoroaniline (9.90 mmol) in a pressure vessel was added hexafluoroacetone sesquihydrate (10.9 mmol, 1.1 eq) neat and p-toluenelsuphonic acid (0.990 mmol, 0.1 eq). The vessel was then purged with argon, sealed and heated on an oil bath overnight (12 h) at 90° C. The reaction contents were then diluted with ethyl acetate and washed with NaHCO₃ (3 × 100 mL; sat.). The ethyl acetate phase was then washed with brine (100 mL), dried over Na₂SO₄, and concentrated to a solid residue. The desired product was then isolated by silica gel using hexanes/ethyl acetate and following recrystallization from 10:1 hexanes/ethyl acetate to afford 2-(4-Amino-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol as white prisms. ESI-MS (m/z): 278 [M+1]⁺. Step 2. To a solution of 2-(4-Amino-3-fluorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.48 mmol) in DMF (2.5 mL) was added sodium nitrite (2.98 mmol, 1.2 eq) in water (1.5 mL) and 6M hydrochloric acid (3 eq), while maintaining the temperature between 0~5 °C. Stirring was continued for 30 min, and then potassium iodide (3.72 mmol,1.5 eq) was added in small portions. The resulting mixture was then allowed to stir overnight at room temperature. The reaction mixture was then diluted with Et₂O (200 mL), washed with a saturated sodium thiosulphate (3 x 150 mL) and dried over Na₂SO₄. The solvent was removed in vacuo leaving a dark crude oil which was separated on silica gel (EtOAc/Hex) to obtain 1,1,1,3,3,3-Hexafluoro-2-(3-fluoro-4-iodophenyl)propan-2-ol. Step 3. To 4-bromomethylphenylboronic acid pinacol ester (1.68 mmol) was added MeCN (5 mL), followed by addition of K₂CO₃ (5.04 mmol, 3.0 eq), 1-(pyridinyl-4-methyl)-piperazine (2.02 mmol, 1.2 eq), and NaI (2 mole %). The mixture was allowed to stir overnight at rt (~23° C) under an argon balloon. The remaining reaction mixture was then diluted with H₂O (50 mL) and extracted with CHCl₃ (3 × 100 mL). The organic washes were combined, dried over Na₂SO₄, concentrated to a solid residue and again extracted with 12:1 hexanes / CH₂Cl₂ (3 × 100 mL) and concentrated in vacuo to a yellow crystalline. The product 1-(4-pyridinyl-methyl)-piperazine-4-benzyl-para-boronic pinacol ester was isolated by recrystallization from hexanes and used without further purification within the following synthetic step. Step 4. A mixture of 1,1,1,3,3,3-Hexafluoro-2-(3-fluoro-4-iodophenyl)propan-2-ol ( 0.183 mmol), 1-(4-pyridinyl-methyl)-piperazine-4-benzyl-para-boronic pinacol ester (2.20 mmol, 1.2 eq), Pd(PPh₃)₄ (5 mol%), K₂CO₃ (0.550 mmol, 3 eq) and 3 : 1 dioxane / H₂O (4 mL) in a 20 mL pressure vessel was degassed for 5 min, purged with argon, sealed and heated for 2h at 80°C oil bath. Upon completion, as determined by reverse-phase HPLC, the mixture was allowed to cool and was then extracted with EtOAc (3 × 25 mL). The combine organic layers were washed with saturated NaHCO₃ (2 × 25 mL) and dried over Na₂SO₄. The solvent was removed in vacuo leaving a brown solid crude which was then isolated by flash chromatography on silica gel (CH₂Cl₂ / MeOH) to obtain the title compound. ESI-MS (m/z): 528 [M+1]⁺; ¹H-NMR (400 MHz, CHCl₃ 7.26) δ 8.46 (d, J = 5.2 Hz, 2H), 7.62 (s, 1H), 7.59 (s, 1H), 7.53-7.49 (m, 3H), 7.40 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 5.2 Hz, 2H), 3.58 (s, 2H), 3.53 (s, 2H), 2.51 (b, 8H).