Ammonium Chloride → 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Temperature

0 °C

A flask equipped with a mechanical stirrer, a nitrogen inlet, an addition funnel and a thermowell was charged with 1-trimethylsilyl-4-iodopyrazole (225.1 g, 0.85 mol) and THF (2200 mL) at ambient temperature. This mixture was cooled to approximately −6° C. in an ice/salt/brine bath before a solution of isopropyl magnesium chloride in THF (2 M solution in THF, 510 mL, 1.02 mol, 1.2 equiv) was added at a rate such that the internal temperature did not exceed 0° C. The extent of metal/halogen exchange was monitored by GC and was found complete after about 10 min. To the orange brown solution was then added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (isopropylpinacolborate, 347 mL, 1.7 mol, 2.0 equiv) slowly at first keeping the temperature below 0° C. and then fairly rapidly after about half of the compound was added allowing the temperature to reach 5° C. (the reaction becomes quite thick and then thins out slowly). The reaction is then stirred at 0° C. for 10 min before being warmed to ambient temperature over 1 h and stirred at ambient temperature for an additional 1 h. The reaction mixture was cooled to approximately 6° C. and the saturated aqueous ammonium chloride solution (NH4Cl, 2.2 L) was added with a temperature increase to 25° C. The mixture was stirred for 5 minutes before being diluted with toluene (10 L). The layers were separated (a large amount of solid is present in the aqueous layer) and the organic layer was sequentially washed with water (6×2.2 L) and brine (2×2.2 L) before being dried over sodium sulfate (Na2SO4). The drying reagent, sodium sulfate (Na2SO4), was removed by filtration and the solution was concentrated under reduced pressure. Residual toluene was co-evaporated with n-heptane to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 90.3 g, 164.9 g theoretical, 54.8%) as a white solid. For 1: 1H NMR (400 MHz, DMSO-d6) δ 13.08 (bs, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 1.23 (s, 12H) ppm; C9H15BN2O2 (MW, 194.04), LCMS (EI) m/e 195 (M++H).

1. customA flask equipped with a mechanical stirrer, a nitrogen inlet, an addition funnel
2. additionwas added at a rate such that the internal temperature
3. customdid not exceed 0° C
4. customthe temperature below 0° C.
5. additionfairly rapidly after about half of the compound was added
6. customto reach 5° C.
7. temperaturebefore being warmed to ambient temperature over 1 h
8. stirringstirred at ambient temperature for an additional 1 h
9. temperatureThe reaction mixture was cooled to approximately 6° C.
10. temperatureincrease to 25° C
11. stirringThe mixture was stirred for 5 minutes
12. customThe layers were separated (a large amount of solid
13. washwas sequentially washed with water (6×2.2 L) and brine (2×2.2 L)
14. dry with materialbefore being dried over sodium sulfate (Na2SO4)
15. customThe drying reagent, sodium sulfate (Na2SO4), was removed by filtration
16. concentrationthe solution was concentrated under reduced pressure

ORD record

ord-4da9c48072294d2aa7c8a8b5b70de0ef

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09221845B2