1,4-Diazabicyclo(3.2.2)nonane → 2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-fluoren-9-one

Temperature

90 °C

A catalyst solution was prepared by mixing tris(dibenzylideneacetone)dipalladium (Pd2(dba)3; 20 mg, 0.022 mmol; Alfa) and racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 38 mg, 0.061 mmol; Strem) in toluene (1 mL) and heating the mixture to 90° C. for 15 min. The solution was cooled, and then added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (112 mg, 0.889 mmol; see J. Med. Chem. 1993, 36, 2311) and 2-bromofluoren-9-one (320 mg, 1.24 mmol; Aldrich) in toluene (3 mL). Sodium tert-butoxide (120 mg, 1.25 mmol; Aldrich) was then added, and the reaction mixture was flushed with nitrogen and heated to 80-85° C. overnight. After cooling to room temperature, the mixture was filtered through diatomaceous earth and purified by chromatography (35 g silica gel, 1-16% gradient of NH4OH-MeOH (1:10) in CH2Cl2) to afford the title compound (116 mg, 0.382 mmol; 43% yield): 1H NMR (300 MHz, CD3OD) δ ppm 7.48 (d, J=7 Hz, 1H), 7.39-7.44 (m, 3H), 7.14 (ddd, J=7, 6, 3 Hz, 1H), 7.09 (d, J=3 Hz, 1H), 6.93 (dd, J=8, 3 Hz, 1H), 4.10-4.17 (m, 1H), 3.66 (dd, J=6, 5 Hz, 2H), 2.95-3.17 (m, 6H), 2.09-2.23 (m, 2H), 1.84 (ddd, J=19, 10, 5 Hz, 2H); MS (DCl/NH3): m/z 305 (M+1)+.

1. customA catalyst solution was prepared
2. temperatureThe solution was cooled
3. customthe reaction mixture was flushed with nitrogen
4. temperatureheated to 80-85° C. overnight
5. temperatureAfter cooling to room temperature
6. filtrationthe mixture was filtered through diatomaceous earth
7. custompurified by chromatography (35 g silica gel, 1-16% gradient of NH4OH-MeOH (1:10) in CH2Cl2)

ORD record

ord-5d6cde51780e4d7390482f555045ccbd

Source dataset

uspto-grants-2008_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07365193B2