Indole → HCID 53783081, compound

HRID 1368956Notes

Reaction equation

HRID 1368956 reaction equation
[H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.C([Li])(C)(C)C.N1C2C(=CC=CC=2)C=C1.CON(C)[C:30]([CH:32]([NH:41][C:42]([CH:44]([NH:49][C:50](=[O:59])[O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31].P(=O)(O)(O)O>CCOCC>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=2)[CH:7]=[C:8]1[C:30]([CH:32]([NH:41][C:42]([CH:44]([NH:49][C:50](=[O:59])[O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31]

Participants

8

Reactant 6

HCID 798IndoleHCID 1004Phosphoric AcidHCID 249055-BromoindoleHCID 82127Potassium hydrideHCID 54260837HCID 54260837, compoundHCID 178418306HCID 178418306, compound

Product 1

HCID 53783081HCID 53783081, compoundYield 32.9%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent4×

Conditions

Temperature
0 °C

Procedure

A mixture comprised of potassium hydride (0.29 g, 2.56 mmol, 67% in mineral oil) in anhydrous ether (5 mL) was cooled to 0° C. and then a solution comprised of 5-bromo-1H-indole (0.5 g, 2.56 mmol) in anhydrous ether (5 ml) was added. The mixture was stirred for 15 minutes and then cooled to −78° C. under nitrogen. A solution comprised of tert-butyllithium (3 mL in pentane, 5.08 mmol) in anhydrous ether (5 mL) was cooled to −78° C. and added to the indole mixture over 2 minutes. The mixture was stirred for 10 minutes and then a solution comprised of benzyl 1-[1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate (0.3 g, 0.64 mM) in ether (10 mL) was added. The mixture was allowed to warm to room temperature and then poured into a cold solution at 0° C. of phosphoric acid (25 mL, 1 M in water). The aqueous layer was separated and extracted with ethyl acetate (25 mL). The organic layers were combined and washed with saturated sodium bicarbonate (25 mL), dried (MgSO4) and concentrated. The product was purified from the residue by flash chromatography on silica gel eluting with 1:2 ethyl acetate/hexanes to provide benzyl 1-[1-(1H-indol-2-ylcarbonyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate (112 mg, 0.21 mmol) as a white solid. MS (ESI) m/z=526(M+1); 1H NMR (CDCl3): δ 0.8-1.05 (d, J=4 Hz, 6H), 1.5 (s, 1H), δ 1.5-1.78 (m, 3H), δ 2.00 (m, 1H), δ 2.4 (m, 1H), δ 2.65 (m, 2H), δ 4.35 (m, 1H), δ 5.17 (s, 2H), δ 5.25 (d,J=6 Hz 1H), δ 5.75 (m, 1H), δ 6.55 (s, 1H) 7.05 (d, J=4 Hz, 1H), δ 7.1-7.45 (m, 10H) 7.7(d, J=4 Hz, 1H), δ 8.15 (d, J=4 Hz, 1H) 8.78 (m, 1H). (C32H35N3O4).

Workup

  1. additionwas added
  2. temperaturecooled to −78° C. under nitrogen
  3. temperaturewas cooled to −78° C.
  4. stirringThe mixture was stirred for 10 minutes
  5. additionwas added
  6. temperatureto warm to room temperature
  7. customThe aqueous layer was separated
  8. extractionextracted with ethyl acetate (25 mL)
  9. washwashed with saturated sodium bicarbonate (25 mL)
  10. dry with materialdried (MgSO4)
  11. concentrationconcentrated
  12. customThe product was purified from the residue by flash chromatography on silica gel eluting with 1:2 ethyl acetate/hexanes

Sources & evidence

ORD record
ord-e99496c257ce49f99e7519668a2bd56c
Source dataset
uspto-grants-2003_06
Patent number
US06576630B1

Reaction notes

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