Phenylacetic Acid → (1-hydroxycyclobutyl)(phenyl)acetic acid

To a dried 250 mL round bottom flask containing 2 M lithium diisopropyl amide in THF (2 eq.) in THF (60 mL) at 0° C., was added phenyl acetic acid (1.0 g, 7.35 mmol, 1 eq). The resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then cooled to −78° C. and a mixture of cyclobutanone (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (0.617 g, 8.82 mmol, 1.2 eq.) in THF (20 mL) was added dropwise. The resulting mixture was then stirred at −78° C. and then at ambient temperature for 3 hours. Reaction progress was monitored by TLC (TLC eluent: 30% EtOAc in hexane). The reaction mixture was poured into an EtOAc/water mixture and the aqueous layer was extracted with EtOAc. The aqueous layer was then acidified with dilute hydrochloric acid and extracted with DCM. The DCM solution was washed with brine and concentrated. The residue was purified by column chromatography using silica gel eluting with 15% EtOAc in hexane to yield 2-(1-hydroxycyclobutyl)-2-phenylacetic acid (1.1 g, 73%). 1H NMR (300 MHz, CDCl3) δ: 7.42-7.26 (m, 5H), 3.88 (s, 1H), 2.24-2.19 (m, 2H), 2.10-2.05 (m, 2H), 1.93-1.87 (m, 3H). m/z (ESI) 189 (M+H)+ (-Dehydroxy mass observed).

1. temperatureThe reaction mixture was then cooled to −78° C.
2. stirringThe resulting mixture was then stirred at −78° C.
3. waitat ambient temperature for 3 hours
4. customReaction progress
5. extractionthe aqueous layer was extracted with EtOAc
6. extractionextracted with DCM
7. washThe DCM solution was washed with brine
8. concentrationconcentrated
9. customThe residue was purified by column chromatography

ORD record

ord-4540b8cac6e845a9ab66dc749f1682e7

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09340549B2