1,2-Dichloroethane → tert-butyl 5-(hydroxymethyl)-1H-indole-1-carboxylate

HRID 856995Notes

Reaction equation

HRID 856995 reaction equation
N[C@@H](C(N)=O)CC(C)C.[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C([O-])(O)=O.[Na+].CO.C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][OH:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]

Participants

8

Reactant 4

HCID 111,2-DichloroethaneHCID 5049666Sodium triacetoxyborohydrideHCID 7271815(R)-2-Amino-4-methylpentanamideHCID 11172622tert-Butyl 5-formyl-1H-indole-1-carboxylate

Product 1

HCID 21865484tert-butyl 5-(hydroxymethyl)-1H-indole-1-carboxylateYield 13.1%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

D-Leucinamide (1.0 g, 6.0 mmol), 1-(t-butyloxycarbonyl)-5-formylindole (Example 1, 1.23 g, 5.0 mmol) and DCE (15 mL) were mixed at room temperature. Sodium triacetoxyborohydride (1.48 g, 7.0 mmol) was added in one portion with vigorous stirring. After 2 h, another portion (0.15 g, 0.7 mmol) was added and stirring was continued for an additional 6 h. The reaction mixture was diluted with a saturated NaHCO3 solution (10 mL). Three extractions with EtOAc, washing the combined organic layers with brine, drying over Na2SO4 and filtration provided a solution. Removal of solvent in vacuo afforded an oil. Column chromatography (DCM:MeOH:95:5) provided three fractions, after removal of solvent in vacuo: (1) 1-(t-Butyloxycarbonyl)-5-hydroxymethylindole (162 mg, 11% yield, Rf=0.5): 1H NMR (CDCl3, 300 MHz): 8.11 (d, 1H, J=8), 7.61 (d, 1H, J=2), 7.54 (s, 1H), 7.31 (dd, 1H, J=8,2), 6.55 (d, 1H, J=3), 4.75 (s, 2H), 1.69 (s, 9H); (2) 2R-bis-(1-t-butyloxycarbonylindol-5-ylmethyl)amino-4-methylpentanamide BMS594447 (382 mg, 12% yield, Rf=0.4): 1H NMR (CDCl3, 300 MHz): 8.1 (d, 2H, J=8), 7.61 (d, 2H, J=2), 7.52 (s, 2H), 7.31 (dd, 2H, J=8,2), 6.62 (m, 1H), 6.56 (d, 2H, J=4), 6.05 (br s, 1H), 3.85 (d, 2H, J=16), 3.66 (d, 2H, J=16), 3.35 (m, 1H), 1.69 (s, 18H), 0.96 (d, 3H, J=7), 0.87 (d, 3H, J=7); MS (ES+): 589.4 (C35H45N3O5) and (3) the title product (986 mg, 55% yield, Rf=0.3): 1H NMR (CDCl3, 300 MHz): 8.10 (d, 1H, J=8), 7.61 (d, 1H, J=2), 7.49 (d, 1H, J=1), 7.28–7.20 (m, 3H), 6.55 (d, 1H, J=4), 3.93 (d, 1H, J=16), 3.77 (d, 1H, J=16), 3.28–3.20 (m, 1H), 1.69 (s, 9H), 0.94 (d, 3H, J=7), 0.85 (d, 3H, J=7); MS (ES+): 360 (C20H30N3O3, M++H).

Workup

  1. additionanother portion (0.15 g, 0.7 mmol) was added
  2. waitwas continued for an additional 6 h
  3. extractionThree extractions with EtOAc
  4. washwashing the combined organic layers with brine
  5. dry with materialdrying over Na2SO4 and filtration
  6. customprovided a solution
  7. customRemoval of solvent in vacuo
  8. customafforded an oil
  9. customafter removal of solvent in vacuo

Sources & evidence

ORD record
ord-97662cc7c6c44789ac4a6c856e3d54f2
Source dataset
uspto-grants-2006_12
Patent number
US07144894B2

Reaction notes

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