Lithium iodide → 1-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(4-methoxybenzyl)piperidin-4-ol

HRID 1721783Notes

Reaction equation

HRID 1721783 reaction equation
[Mg].[I-].[Li+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1.[CH:14]1[C:27]2[C:26]3([CH2:29][N:30]4[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]4)[CH2:28][CH:19]([C:20]4[C:25]3=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]=2[CH:17]=[CH:16][CH:15]=1>O1CCCC1.C(OCC)C>[CH:24]1[C:25]2[C:26]3([CH2:29][N:30]4[CH2:35][CH2:34][C:33]([CH2:10][C:9]5[CH:12]=[CH:13][C:6]([O:5][CH3:4])=[CH:7][CH:8]=5)([OH:36])[CH2:32][CH2:31]4)[CH2:28][CH:19]([C:18]4[C:27]3=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:20]=2[CH:21]=[CH:22][CH:23]=1

Participants

7

Reactant 4

HCID 66321Lithium iodideHCID 699934-Methyloxybenzyl chlorideHCID 5462224MagnesiumHCID 21480605(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone

Product 1

HCID 214806511-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(4-methoxybenzyl)piperidin-4-olYield 69%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

Magnesium turnings (0.32 g, 1.32 mmol, 1.3 eq) were stirred in the absence of solvent for 15 min under nitrogen. Diethyl ether (20 mL) and catalytic lithium iodide were added, and the suspension was stirred vigorously for an additional 15 min at which time 4-methoxybenzyl chloride (1.08 mL, 7.0 mmol, 8 eq) was syringed into the reaction flask in portions. The reaction was refluxed for 3 h to assure Grignard formation and recooled to room temperature. 1-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) (0.30 g, 1.00 mmol) was added dropwise as a tetrahydrofuran solution (25 mL). After stirring for 18 h, the reaction was quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×100 mL), dried with anhydrous sodium sulfate, filtered, and reduced to an oil. The reaction mixture was purified by flash chromatography over silica gel (25 mL, eluent: 20% ethyl acetate in hexane) to yield 0.29 g (69%) of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) 7.23 (m, 2H), 7.13 (m 4H), 6.88 (m, 6H), 4.25 (s, 1H), 3.78 (s, 3H), 3.41 (s, 2H), 2.76 (m, 2H), 2.66 (s, 2H), 2.57 (d, J=1.2 Hz, 2H), 2.52 (m, 2H), 1.67 (m, 2H), 1.47 (m, 2H), 1.57 (s, 1H) MS (CI, CH4) m/z 426 (M+1,100), 454 (M+29,13), 408 (20). The free base was dissolved in methanol and methylene chloride, acidified with ethereal HCl and the salt precipitated with ether dilution. The hydrochloride salt was filtered, rinsed with fresh ether, and dried in vacuo (50° C. 10 pascal 18 h) to yield a white solid, mp 267°-268° C. (dec).

Workup

  1. temperatureThe reaction was refluxed for 3 h
  2. customrecooled to room temperature
  3. customthe reaction was quenched with water (10 mL)
  4. extractionThe aqueous phase was extracted with ethyl acetate (200 mL)
  5. extractionThe organic extract
  6. washwas washed with water (2×100 mL)
  7. dry with materialdried with anhydrous sodium sulfate
  8. filtrationfiltered
  9. customThe reaction mixture was purified by flash chromatography over silica gel (25 mL, eluent: 20% ethyl acetate in hexane)

Sources & evidence

ORD record
ord-34b34aa6d9594e3cadc2309ad8a32cc9
Source dataset
uspto-grants-1996_04
Patent number
US05512575

Reaction notes

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