Hydrochloric Acid → 8-(3-Amino-phenyl)-3-benzyl-3-aza-bicyclo[3.2.1]octan-8-ol

HRID 1295507Notes

Reaction equation

HRID 1295507 reaction equation
[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=3)([OH:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=[NH:37])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl>C1(C)C=CC=CC=1.CC(O)=O.CC(O)=O.[Pd]>[NH2:37][C:19]1[CH:18]=[C:17]([C:15]2([OH:16])[CH:13]3[CH2:12][CH2:11][CH:10]2[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14]3)[CH:22]=[CH:21][CH:20]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 136809Benzophenone imineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 694278793-Benzyl-8-(3-bromo-phenyl)-3-aza-bicyclo[3.2.1]octan-8-ol

Product 1

HCID 694262238-(3-Amino-phenyl)-3-benzyl-3-aza-bicyclo[3.2.1]octan-8-ol

Reagents, catalysts & solvents 2

HCID 4144353Palladium (II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

3-Benzyl-8-(3-bromo-phenyl)-3-aza-bicyclo[3.2.1]octan-8-ol (4.69 g, 7.82 mmol) was dissolved in toluene (40 mL) in a flame dried RB flask. To this was added benzophenone imine (1.57 mL, 9.38 mmol), sodium t-butoxide (1.05 g, 11.0 mmol), then BINAP (racemic, 0.487 g, 0.782 mmol). The reaction was degassed (evac./N2 purged 3×) before adding palladium II acetate (0.175 g, 0.782 mmol), then heated to 100° C. in an oil bath under N2 overnight (or until judged complete by TLC). The imine was cooled to room temperature, treated with 6 N HCl (25 mL), and heated to 100° C. After 1 h, the reaction was cooled to room temperature, filtered through a Celite pad, rinsed with ether (50 mL) then water (50 mL). The filtrate was washed with ether (2×100 mL), then the aqueous layer was basified to pH 10 with 1 N NaOH, and saturated aqueous Na2CO3 solution. The product was extracted with EtOAc (3×100 mL), washed with saturated aqueous NaCl solution (1×100 mL), dried over Na2SO4, filtered through a Silica pad (2×3 in) eluted with 100% EtOAc and concentrated to an orange foam (2.34 g, 97%). (TLC 50% EtOAc/hexanes Rf 0.30); 1H NMR (400 MHz, CDCl3) δ 7.38–7.20 (m, 5H), 7.12 (t, J=7.9 Hz, 1H), 6.86 (d, J=7.9 Hz, 1H), 6.79 (s, 1H), 6.59 (m, 1H), 3.64–3.57 (m, 2H−NH2, 2H), 2.85 (d, J=9.9 Hz, 2H), 2.58 (m, 2H), 2.34 (br s, 2H), 1.77 (d, J=7.1 Hz, 2H), 1.43 (m, 2H); APCI MS m/z 309.2 (M+1)+.

Workup

  1. customdried RB flask
  2. customThe reaction was degassed
  3. custom(evac./N2 purged 3×)
  4. temperatureheated to 100° C
  5. temperaturethe reaction was cooled to room temperature
  6. filtrationfiltered through a Celite pad
  7. washrinsed with ether (50 mL)
  8. washThe filtrate was washed with ether (2×100 mL)
  9. extractionThe product was extracted with EtOAc (3×100 mL)
  10. washwashed with saturated aqueous NaCl solution (1×100 mL)
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered through a Silica pad (2×3 in)
  13. washeluted with 100% EtOAc
  14. concentrationconcentrated to an orange foam (2.34 g, 97%)

Sources & evidence

ORD record
ord-d7af92db03154ddebc3642742fbde929
Source dataset
uspto-grants-2007_07
Patent number
US07241887B2

Reaction notes

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