Cyclobutanone → 4-(Adamantan-1-ylmethoxy)-3-(1-hydroxycyclobutyl)benzonitrile

Temperature

0 °C

To a cooled (0° C.) stirred solution of 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile (3.20 g, 9.24 mmol) in tetrahydrofuran (40 mL) was added a solution of isopropylmagnesium chloride lithium chloride complex in tetrahydrofuran (1.3 M, 15.0 mL, 19.5 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 h and cyclobutanone (1.52 mL, 20.33 mmol) was added. Stirring was continued at 0° C. for 2 h and quenched with saturated ammonium chloride solution (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10% to 25% gradient of ethyl acetate in hexanes to afford 4-(adamantan-1-ylmethoxy)-3-(1-hydroxycyclobutyl)benzonitrile as colorless solid (2.34 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.62-7.53 (m, 2H), 7.00-6.93 (m, 1H), 3.64 (s, 2H), 3.43 (s, 1H), 2.59-2.36 (m, 4H), 2.17-2.00 (m, 4H), 1.84-1.61 (m, 13H).

1. stirringStirring
2. waitwas continued at 0° C. for 2 h
3. customquenched with saturated ammonium chloride solution (30 mL)
4. extractionThe mixture was extracted with ethyl acetate (3×50 mL)
5. washThe combined organic layers were washed with brine (50 mL)
6. dry with materialdried over anhydrous magnesium sulfate
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. customThe residue was purified by column chromatography
10. washeluting with a 10% to 25% gradient of ethyl acetate in hexanes

ORD record

ord-93e8b7f6d1874fc5b7855c1d3eb3b9d5

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08952169B2