Hydrochloric Acid → 6-(2,2-Dimethyl-propyl)-isochroman-4-ylamine hydrochloride

Neo-pentylmagnesium bromide (10 mL, 9.1 mmol, 1.0 M in ether) was added dropwise to a solution of zinc chloride (18.2 mL, 0.5 M in tetrahydrofuran, 9.1 mmol) over 0.5 h and the reaction mixture stirred at RT for an additional 0.5 h. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (250 mg, 0.30 mmol) was added to the reaction mixture followed by (6-Bromo-isochroman-4-yl)-carbamic acid tert-butyl ester (1.00 g, 3.04 mmol) and the reaction mixture heated at reflux for 1 h. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was re-dissolved in ethyl acetate and washed with water, sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography over silica (83:17 hexanes/ethyl acetate) yielded the desired protected amine (303 mg, 31%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.30–7.23 (m, 1H), 7.00 (d, J=6.3 Hz, 1H), 6.74 (s, 1H), 5.09–5.06 (m, 1H), 4.79–4.65 (m, 3H), 4.13–3.85 (m, 2H), 2.45 (s, 2H), 1.46 (s, 9H), 0.89 (s, 9H); ESI MS m/z 320 [C19H29NO3+H]+. A solution of protected amine (303 mg, 0.95 mmol) in hydrogen chloride (20 mL, 4 N in 1,4-dioxane, 80 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 6-(2,2-Dimethyl-propyl)-isochroman-4-ylamine hydrochloride (210 mg, quantitative) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J=7.6 Hz, 1H), 7.01 (d, J=7.6, 1.2 Hz, 1H), 6.73 (d, J=1.2 Hz, 1H), 4.75 (ABq, J=15.0 Hz, 2H), 3.96–3.80 (m, 3H), 2.44 (s, 2H), 1.73 (m, 2H), 0.89 (s, 9H); ESI MS m/z 220 [C14H21NO+H]+.

1. additionwas added to the reaction mixture
2. temperaturethe reaction mixture heated
3. temperatureat reflux for 1 h
4. temperatureThe reaction mixture was cooled
5. concentrationconcentrated under reduced pressure
6. dissolutionThe residue was re-dissolved in ethyl acetate
7. washwashed with water, sodium chloride
8. dry with materialdried (sodium sulfate)
9. filtrationfiltered
10. concentrationconcentrated under reduced pressure
11. customPurification by flash column chromatography over silica (83:17 hexanes/ethyl acetate)
12. customyielded the
13. concentrationThe reaction mixture was concentrated under reduced pressure

ORD record

ord-1a5c3123b4d6499f9d1152026a680e9d

Source dataset

uspto-grants-2007_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07244725B2