1-Hydroxybenzotriazole → Benzimidazole

HRID 603294Notes

Reaction equation

HRID 603294 reaction equation
[CH3:1][CH2:2][N:3]=[C:4]=[N:5][CH2:6][CH2:7][CH2:8]N(C)C.Cl.Br[C:14]1C=C(N)C(N)=CC=1.C(N1CCC[C@H]1C(O)=O)(OC(C)(C)C)=O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(O)(=O)C>[N:5]1[C:6]2[CH:7]=[CH:8][CH:14]=[CH:1][C:2]=2[NH:3][CH:4]=1

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 3235934-Bromobenzene-1,2-diamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride

Product 1

HCID 5798Benzimidazole

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
65 °C

Procedure

EDCI.HCl (2.348 g, 12.25 mmol) was added to a mixture of 4-bromobenzene-1,2-diamine (2.078 g, 11.11 mmol), N-Boc-L-proline (2.311 g, 10.74 mmol) and 1-hydroxybenzotriazole (1.742 g, 12.89 mmol) in CH2Cl2 (40 mL), and stirred at ambient conditions for 19 h. The mixture was then diluted with CH2Cl2, washed with water (2×), dried (brine; MgSO4), filtered, and concentrated in vacuo to provide a brown foam. Acetic acid (40 mL) was added to the foam, and the mixture was heated at 65° C. for 90 min. The volatile component was removed in vacuo, and the residue was dissolved in EtOAc and washed carefully with saturated NaHCO3 solution (2×), and the organic phase was dried (brine; MgSO4), filtered, and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; EtOAc) to provide benzimidazole M1a as a tan foam (2.5 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 12.49-12.33 (four br s, 1H), 7.71 (d, J=2, 0.54H), 7.60 (app br s, 0.46H), 7.50 (d, J=8.6, 0.45H), 7.40 (d, J=8.4, 0.55H), 7.26 (m, 1H), 4.96-4.87 (m, 1H), 3.64-3.51 (m, 1H), 3.44-3.38 (m, 1H), 2.38-2.21 (m, 1H), 1.99-1.85 (m, 3H), 1.39 (s, 3.7H), 1.06 (s, 5.3H). LC/MS: Anal. Calcd. for [M+H]+ C16H2181BrN3O2; 368.03. found: 368.18.

Workup

  1. washwashed with water (2×)
  2. dry with materialdried (brine; MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customto provide a brown foam
  6. customThe volatile component was removed in vacuo
  7. dissolutionthe residue was dissolved in EtOAc
  8. washwashed carefully with saturated NaHCO3 solution (2×)
  9. dry with materialthe organic phase was dried (brine; MgSO4)
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-8ba976cc0e0e444f900a7786b4e747a0
Source dataset
uspto-grants-2011_03
Patent number
US07906655B2

Reaction notes

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