Triphenylphosphine → Ethyl 3-amino-4,5,6,7-tetrahydrobenzofuran-2-carboxylate

A solution of resin bound PPh3 (Polymer Laboratories, 1.48 mmol/g, 150-300 μM; 3.8 g, 5.7 mmol) in THF (35 mL) at 0° C. was treated with diethyl azodicarboxylate (40% wt. in hexane; 2.60 mL, 5.7 mmol), ethyl glycolate (0.54 mL, 5.7 mmol) and a solution of 2-oxo-cyclohexanecarbonitrile (0.5 g, 4.1 mmol) in THF (10 mL). The reaction mixture warmed to rt over 12 h. Filtration and concentration afforded the uncyclized intermediate, which was dissolved in THF (25 mL) and added drop-wise to a slurry of sodium hydride (95%; 0.29 g, 11.4 mmol) in THF (10 mL) at 0° C. The reaction mixture was heated to 40° C. for 12 h. The reaction was quenched with satd. aq. NH4Cl (5 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were dried (by using, for example, Na2SO4) and concentrated. Purification by FCC (50% EtOAc/hexanes) afforded the desired product as a pale yellow solid (0.36 g). MS: 210.2. 1H NMR (400 MHz, CD3OD) δ ppm 4.26 (q, J=7.1, Hz, 2H), 2.55-2.47 (m, 2H), 2.35-2.28 (m, 2H), 1.90-1.79 (m, 2H), 1.79-1.71 (m, 2H), 1.33 (t, J=7.1, Hz, 3H).

1. customat 0° C.
2. filtrationFiltration and concentration
3. customafforded the uncyclized intermediate, which
4. temperatureThe reaction mixture was heated to 40° C. for 12 h
5. customThe reaction was quenched with satd
6. extractionaq. NH4Cl (5 mL) and the mixture was extracted with EtOAc (3×50 mL)
7. dry with materialThe combined organic layers were dried (by using, for example, Na2SO4)
8. concentrationconcentrated
9. customPurification by FCC (50% EtOAc/hexanes)

ORD record

ord-f13eec25d997469c93822e5fe9c03946

Source dataset

uspto-grants-2012_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08193178B2