6-Nitro-1H-indole → Methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester

HRID 2404638Notes

Reaction equation

HRID 2404638 reaction equation
[C:1]([O:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]([N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N+:43]([C:46]1[CH:54]=[C:53]2[C:49]([CH:50]=[CH:51][NH:52]2)=[CH:48][CH:47]=1)([O-:45])=[O:44]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:18])[CH2:9][C:10](=[O:11])[N:12]([CH3:13])[CH2:14][C:15]([N:52]1[C:53]2[C:49](=[CH:48][CH:47]=[C:46]([N+:43]([O-:45])=[O:44])[CH:54]=2)[CH:50]=[CH:51]1)=[O:17])([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 4

HCID 785026-Nitro-1H-indoleHCID 81531DiisopropylethylamineHCID 2774761Tetramethylfluoroformamidinium hexafluorophosphateHCID 513582342-(2-((tert-Butoxycarbonyl)(methyl)amino)-N-methylacetamido)acetic acid

Product 1

HCID 66675158Methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamic acid tert-butyl esterYield 30%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a mixture of {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid (13.8 g, 53 mmol) and TFFH (21.0 g, 79.5 mmol) in anhydrous THF (125 mL) was added DIEA (27.7 mL, 159 mmol) at room temperature under nitrogen. The solution was stirred at room temperature for 20 min. A solution of 6-nitroindole (8.6 g, 53 mmol) in THF (75 mL) was added and the reaction mixture was heated at 60° C. for 18 h. The solvent was evaporated and the crude mixture was re-partitioned between EtOAc and water. The organic layer was separated, washed with water (×3), dried over Na2SO4 and concentrated. Diethyl ether followed by EtOAc was added. The resulting solid was collected via filtration, washed with diethyl ether and air dried to yield methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester (6.42 g, 30%). 1H NMR (400 MHz, DMSO-d6) δ 1.37 (m, 9H), 2.78 (m, 3H), 2.95 (d, J=1.5 Hz, 1H), 3.12 (d, J=2.1 Hz, 2H), 4.01 (d, J=13.8 Hz, 0.6H), 4.18 (d, J=12.0 Hz, 1.4H), 4.92 (d, J=3.4 Hz, 1.4H), 5.08 (d, J=11.4 Hz, 0.6H), 7.03 (m, 1H), 7.90 (m, 1H), 8.21 (m, 1H), 8.35 (d, J=3.8 Hz, 1H), 9.18 (m, 1H); HPLC ret. time 3.12 min, 10-99% CH3CN, 5 min run; ESI-MS 405.5 m/z (MH+).

Workup

  1. temperaturethe reaction mixture was heated at 60° C. for 18 h
  2. customThe solvent was evaporated
  3. customthe crude mixture was re-partitioned between EtOAc and water
  4. customThe organic layer was separated
  5. washwashed with water (×3)
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. additionwas added
  9. filtrationThe resulting solid was collected via filtration
  10. washwashed with diethyl ether and air
  11. customdried

Sources & evidence

ORD record
ord-bd60b5ff5734472d8084e72534a15fbb
Source dataset
uspto-grants-2014_08
Patent number
US08802700B2

Reaction notes

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