Water → (R)-5-Bromo-3-(1-methyl-2-pyrrolidinyl methyl)-1H-indole

HRID 745008Notes

Reaction equation

HRID 745008 reaction equation
C(O[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[NH:20][CH:19]=1)=O)=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH3:9]

Participants

7

Reactant 4

HCID 962Water2×HCID 14798Sodium HydroxideHCID 11224090Phenylmethyl (2R)-2-((5-bromo-1H-indol-3-yl)carbonyl)-1-pyrrolidinecarboxylateHCID 21226445Aluminium lithium hydride3×

Product 1

HCID 11185464(R)-5-Bromo-3-(1-methyl-2-pyrrolidinyl methyl)-1H-indoleYield 71.5%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of (R)-3-(N-benzyloxycarbonyl-pyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole (1.04 g) in dry tetrahydrofuran (20 mL) was added dropwise to a stirred suspension of lithium aluminium hydride (0.27 g) in dry tetrahydrofuran (15 mL) at room temperature under an atmosphere of dry nitrogen. The mixture was heated under reflux with stirring for 18 hours and then cooled. Additional lithium aluminium hydride (50 mg) was added and refluxing was continued for an additional 3 hours. The mixture was again cooled, lithium aluminium hydride (40 mg) was added, and refluxing was continued for a further 18 hours. The mixture was cooled and water (0.44 mL) was carefully added with stirring, followed by 20% aqueous sodium hydroxide (0.44 mL), followed by more water (1.33 mL). The mixture was diluted with ethyl acetate and filtered through Celite (trademark) filter aid. The filtrate was washed with water, brine and then dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5) gave the title compound as a solid (0.51 g), m.p. 137°-140° C. (from dichloromethane/hexane); IR (KBr) 1620, 1595, 1570, 1480, 1450, 1435 cm-1 ; 1H NMR (DMSO-d6) δ 11.05 (br s, 1H), 7.65 (br d, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.21 (br d, 1H), 7.16 (dd, J=1.8 and 8.6 Hz, 1H), 3.03-2.94 (m, 2H), 2.47 (dd, J=9.2 and 14.0 Hz, 1H), 2.36-2.26 (m, 1H), 2.33 (s, 3H), 2.09 (dd, J=8.7 and 17.3 Hz, 1H), 1.73-1.38 (m,4H); 13C NMR (DMSO-d6) δ 134.8, 129.5, 124.7, 123.2, 120.7, 113.4, 112.1, 110.9, 66.1, 57.0, 40.5, 30.9, 29.1, 21.6; LRMS, m/z (relative intensity) 294 (M+ with 81Br, 1), 293 (2), 292 (M+ with 79Br, 1), 210 (14), 208 (15), 154 (8), 129 (42), 128 (19), 101 (26) 85 (57), 84 (100) 83 (30); [α]25D =+62° (methanol, c=0.10). Anal Calcd for C14H17N2Br. 0.25 H2O: C, 56.48; H, 5.93; N, 9.41. Found: C, 56.65; H, 5.69; N,9.23.

Workup

  1. temperatureThe mixture was heated
  2. temperatureunder reflux
  3. temperaturecooled
  4. temperaturerefluxing
  5. waitwas continued for an additional 3 hours
  6. temperatureThe mixture was again cooled
  7. temperaturerefluxing
  8. waitwas continued for a further 18 hours
  9. temperatureThe mixture was cooled
  10. stirringwith stirring
  11. filtrationfiltered through Celite (trademark)
  12. filtrationfilter aid
  13. washThe filtrate was washed with water, brine
  14. dry with materialdried (Na2SO4)
  15. customEvaporation of the solvent
  16. customgave an oil which
  17. customwas chromatographed on silica gel
  18. washElution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5)

Sources & evidence

ORD record
ord-1ce4dcfdb1614d04bc345d338902d660
Source dataset
uspto-grants-1996_09
Patent number
US05559246

Reaction notes

Loading…