1,1'-Carbonyldiimidazole → 1H-Indole-3-carboxylic acid 1-azabicyclo[3.2.1]oct-5-ylmethyl ester

HRID 5383

Reaction equation

HRID 5383 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]12[CH2:32][C:29]([CH2:33]O)([CH2:30][CH2:31]1)[CH2:28][CH2:27][CH2:26]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:25]12[CH2:32][C:29]([CH2:33][O:11][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:12])([CH2:30][CH2:31]1)[CH2:28][CH2:27][CH2:26]2

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 69867Indole-3-Carboxylic AcidHCID 19795992{1-Azabicyclo[3.2.1]octan-5-yl}methanolHCID 178418244HCID 178418244, compound

Product 1

HCID 540484741H-Indole-3-carboxylic acid 1-azabicyclo[3.2.1]oct-5-ylmethyl esterYield 52.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of indole-3-carboxylic acid (1.45 g, 9 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.53 g, 9.4 mmol), stirred for one hour, and degassed with a stream of nitrogen over 10 minutes. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.2.1]octane-5-methanol (1.42 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (9.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The acid 1,1'-carbonyldiimidazole adduct (suspension) was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated in vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little 2-propanol and saturated aqueous sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo, and filtered through alumina (eluted with 5% methanol/methylene chloride). The concentrated filtrate was recrystallized from acetonitrile (2 crops) to afford 1.34 g (52%) of colorless solid; mp 183.5°-185.0° C.

Workup

  1. customdegassed with a stream of nitrogen over 10 minutes
  2. stirringstirred for 30 minutes
  3. concentrationconcentrated in vacuo
  4. stirringthe mixture was stirred overnight (18 hours)
  5. concentrationconcentrated in vacuo
  6. customThe residue was partitioned between methylene chloride (100 mL)
  7. additioncontaining a little 2-propanol and saturated aqueous sodium carbonate (50 mL)
  8. customthe organic layer was separated
  9. extractionThe aqueous solution was extracted with methylene chloride (2×50 mL)
  10. dry with materialthe combined organic solution was dried (Na2SO4)
  11. concentrationconcentrated in vacuo
  12. filtrationfiltered through alumina (eluted with 5% methanol/methylene chloride)
  13. customThe concentrated filtrate was recrystallized from acetonitrile (2 crops)

Sources & evidence

ORD record
ord-6541df2d7c0d4d2fa50faf847fad032f
Source dataset
uspto-grants-1993_09
Patent number
US05244907

Linked notes

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