2-Chlorobenzimidazole → HCID 178472428, compound

HRID 1596524Notes

Reaction equation

HRID 1596524 reaction equation
Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])[CH3:12].C(N(C(C)C)CC)(C)C>CCO>[CH2:11]([O:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:18][CH2:17]1)=[O:15])[CH3:12]

Participants

5

Reactant 3

HCID 785722-ChlorobenzimidazoleHCID 81531DiisopropylethylamineHCID 409963Ethyl 4-aminocyclohexanecarboxylate

Product 1

HCID 178472428HCID 178472428, compoundYield 32.2%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
200 °C

Procedure

A mixture of 2-Chlorobenzimidazole (I) (0.9 g, 5.9 mmol) and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were placed in a glass high pressure a tube. Diisopropylethylamine (2.8 mL, 16.2 mmol) was added, the reaction vessel was sealed and heated to 200° C. for 4 h and allowed to cool to room temperature. Next was added 5 mL EtOH and heated to dissolve the reaction mixture. The reaction mixture was partitioned between aqueous NaHCO3 and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. Purification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc) gave the cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (J) (0.5 g) and the trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (0.5 g) Data for (J): 1H NMR (300 MHz, CDCl3) δ 7.28 (br s, 2H), 7.02 (m, 2H), 5.16 (br s, 1H), 4.15 (q, 2H), 3.97 (br s, 1H), 2.40 (br s, 1H), 1.80-1.54 (m, 8H), 1.22 (t, 3H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288]. Later fractions gave the trans isomer (K) (0.5 g): 1H NMR (300MH, CDCl3) δ 7.28 (br s, 2H), 7.02 (m, 2H), 4.82 (br s, 1H), 4.15 (q, 2H), 3.64 (m, 1H), 2.20 (br d, 3H), 1.96 (br d, 2H), 1.42 (m, 2H), 1.22 (t, 3 H), 1.20 (m, 2H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288].

Workup

  1. customthe reaction vessel was sealed
  2. temperatureto cool to room temperature
  3. temperatureheated
  4. dissolutionto dissolve the reaction mixture
  5. customThe reaction mixture was partitioned between aqueous NaHCO3 and EtOAc
  6. washthe organic layer was washed with water and brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customPurification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc)

Sources & evidence

ORD record
ord-d000c568587c4d139815f77ffb1010c6
Source dataset
uspto-grants-2001_09
Patent number
US06291499B1

Reaction notes

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