Formaldehyde → (1S,4S)-2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]octan-5-one

HRID 1916159Notes

Reaction equation

[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1CCC[C@H:11]1C(O)=O.[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1.C=O>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:11][C@@H:23]3[CH2:22][CH2:21][C@H:20]2[CH2:19][C:18]3=[O:24])=[CH:5][CH:4]=1

Participants

Conditions

Temperature: 50 °C

Procedure

A solution of p-anisidine (E-2, 8.13 g, 66.0 mmol, 1.1 equiv), L-proline (2.07 g, 18.0 mmol, 0.3 equiv), 2-cyclohexen-1-one (E-1, 11.54 g, 120.0 mmol, 2.0 equiv), and 37% aqueous formaldehyde (4.47 mL, 60.0 mmol, 1.0 equiv) was made in DMSO (100 mL) and the reaction was heated to 50° C. for 24 h. The reaction was cooled and diluted with ethyl acetate (500 mL) and washed with water (5×100 mL). The organic phase was dried over MgSO4 and concentrated to an oil. The crude residue was purified by chromatography on silica gel (0 to 80% ethyl acetate in hexanes) to afford the E-3 as a beige solid. 1HNMR (500 MHz, CDCl3) δ 6.86 (d, J=9.0 Hz, 2H), 6.64 (d, J=9.0 Hz, 2H), 4.24-4.19 (m, 1H), 3.76 (s, 3H), 3.68-3.63 (m, 1H), 3.48 (d, J=9.5 Hz, 1H), 2.70-2.60 (m, 2H), 2.42 (d, J=18.5 Hz, 1H), 2.22-2.12 (m, 1H), 2.06-1.93 (m, 2H), 1.86-1.78 (m, 1H) ppm; ESI MS [M+H] for C14H17NO2=232.0.

Workup

temperatureThe reaction was cooled
washwashed with water (5×100 mL)
dry with materialThe organic phase was dried over MgSO4
concentrationconcentrated to an oil
customThe crude residue was purified by chromatography on silica gel (0 to 80% ethyl acetate in hexanes)
customto afford the E-3 as a beige solid

Sources & evidence

ORD record: ord-5b214c05d32a4b729eaa1bd626bf2872
Source dataset: uspto-grants-2013_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08618102B2

Reaction notes

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