Ammonium Chloride → HCID 67188901, compound

HRID 2266241Notes

Reaction equation

HRID 2266241 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][Si](C(C)(C)C)(C)C.C([Li])(C)(C)C.[CH3:21][O:22]N(C)C([C@@H]1CCCN(C(OC(C)(C)C)=O)C1)=O.[Cl-].[NH4+].[O:42]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]([C@@H:58]1[CH2:63][CH2:62][CH2:61][N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59]1)=[O:57])[Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44].OC1C=[CH:76][CH:75]=[CH:74][C:73]=1[C:78]([C@@H:80]1[CH2:85][CH2:84][CH2:83][N:82]([C:86]([O:88][C:89]([CH3:92])([CH3:91])[CH3:90])=[O:87])[CH2:81]1)=[O:79].[CH3:93][O:94][CH2:95][CH2:96][CH2:97][CH2:98][Mg]Cl>CCOCC.O1CCCC1>[OH:57][C@:56]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])([C@@H:58]1[CH2:63][CH2:62][CH2:61][N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59]1)[CH2:98][CH2:97][CH2:96][CH2:95][O:94][CH3:93].[OH:79][C@:78]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([C@@H:80]1[CH2:85][CH2:84][CH2:83][N:82]([C:86]([O:88][C:89]([CH3:90])([CH3:91])[CH3:92])=[O:87])[CH2:81]1)[CH2:73][CH2:74][CH2:75][CH2:76][O:22][CH3:21]

Participants

11

Reactant 7

HCID 25517Ammonium ChlorideHCID 112199121-Bromo-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-benzeneHCID 30025965(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylateHCID 67191653HCID 67191653, compoundHCID 67191868HCID 67191868, compoundHCID 178418306HCID 178418306, compoundHCID 178495008HCID 178495008, compound

Product 2

HCID 67188901HCID 67188901, compoundYield 47%HCID 67189723HCID 67189723, compoundYield 45%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent2×HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of bromo-2-[(tert-butyl)dimethylsiloxy]benzene (2.1 g, 7.4 mmol) in Et2O (35 mL) was cooled to −78° C. and treated with 1.7 M tert-butyllithium in hexanes (8.6 mL, 15 mmol). The reaction was stirred for 30 min and a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) in Et2O was added slowly. The reaction was allowed to stir and warm to rt over a two-hour period. Saturated aq ammonium chloride was added to quench the reaction. The aq phase was extracted with Et2O three times. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed by evaporation and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give a mixture of (2-tert-butyldimethylsiloxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone and (2-hydroxyphenyl)((R)—N-Boc-piperidin-3-yl)methanone. A −20° C. solution of the crude mixture in tetrahydrofuran was treated with 1.3 M 4-methoxybutylmagnesium chloride in THF (14.9 mL, 19.4 mmol). The reaction was stirred and allowed to warm to rt over a two hour period. The reaction was quenched with ammonium chloride. The aq layer was extracted with Et2O. The combined organic layers were dried over MgSO4 and filtered. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes to afford 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)[tertbutyldimethylsiloxy]benzene (874 mg, 47%) and 2-((S)-1-hydroxy-5-methoxy-1-((R)—N-Boc-piperidin-3-yl)pentyl)phenol (650 mg, 45%).

Workup

  1. stirringto stir
  2. customto quench
  3. customthe reaction
  4. extractionThe aq phase was extracted with Et2O three times
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over MgSO4
  7. customThe solvent was removed by evaporation
  8. customthe crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes
  9. customto give
  10. stirringThe reaction was stirred
  11. temperatureto warm to rt over a two hour period
  12. customThe reaction was quenched with ammonium chloride
  13. extractionThe aq layer was extracted with Et2O
  14. dry with materialThe combined organic layers were dried over MgSO4
  15. filtrationfiltered
  16. customThe solvent was evaporated
  17. customthe crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes

Sources & evidence

ORD record
ord-5e488c1214da4de8bf8e55729b57b8ea
Source dataset
uspto-grants-2010_12
Patent number
US07858624B2

Reaction notes

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