Aniline → Dimethyl indole-2,3-dicarboxylate

Temperature

115 °C

A 300 mL RBF was charged with N,N-Dimethylacetamide (DMA) (144 ml) and Acetic Acid (48.1 ml) was degassed with O2 for 5 min. To this was added aniline (2.94 ml, 32.2 mmol), dimethyl but-2-ynedioate (3.96 ml, 32.2 mmol), and Pd(OAc)2 (0.723 g, 3.22 mmol) and the reaction was heated to 115° C. under an atmosphere of O2. After 18 h, the reaction was cooled to ambient temperature, filtered through a pad of celite, diluted with EtOAc and washed with H2O. The organic was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes: 120 g SiO2) to afford dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol, 39.9% yield) as a yellow solid. The indole was dissolved in DMF (50 mL), treated with Cs2CO3 (6.30 g, 19.33 mmol), 4-Fluorobenzyl chloride (1.929 ml, 16.11 mmol) and KI (5.35 g, 32.2 mmol) and heated to 90° C. After 2 h, the reaction mixture was cooled to ambient temperature and partitioned between EtOAc and sat. aq. NH4Cl. The organic layer was washed with water (5×), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on ISCO (0-100% EtOAc-hexanes) to afford dimethyl 1-(4-fluorobenzyl)-1H-indole-2,3-dicarboxylate (3.79 g, 11.10 mmol, 34.5% yield) as a yellow solid. LCMS (m/z) ES+=342 (M+1).

1. customwas degassed with O2 for 5 min
2. temperaturethe reaction was cooled to ambient temperature
3. filtrationfiltered through a pad of celite
4. additiondiluted with EtOAc
5. washwashed with H2O
6. washThe organic was washed with brine
7. dry with materialdried (MgSO4)
8. filtrationfiltered
9. concentrationconcentrated
10. customThe residue was purified by ISCO (0-50% EtOAc-hexanes: 120 g SiO2)

ORD record

ord-fa916cf2b2c840ab925a79add2a01d12

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012642B2