Acetic Acid → 1-(4-Fluorophenyl)-5-[(2-methyl-2H-tetrazol-5-yl)methyl]-1H-indole

HRID 394587Notes

Reaction equation

HRID 394587 reaction equation
[C:1](O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[NH:26][N:25]=[N:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[CH:8][CH:7]=1.CC(C)([O-])C.[K+].IC>CN1C(=O)CCC1.O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[N:23]=[N:24][N:25]([CH3:1])[N:26]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[CH:10][CH:11]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 6328Methyl iodideHCID 23665647Potassium tert-butoxideHCID 178505848HCID 178505848, compound

Product 1

HCID 181772331-(4-Fluorophenyl)-5-[(2-methyl-2H-tetrazol-5-yl)methyl]-1H-indole

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
0 °C

Procedure

A solution of the cyanomethyl compound, sodium azide, triethylamine hydrochloride in 1,2-dimethoxyethane was boiled at reflux for 2 days. After cooling to room temperature, the reaction mixture was filtered and the volatile solvents were evaporated in vacuo. Water (100 mL) and glacial acetic acid (15 mL) were added and the resulting mixture was extracted with ethyl acetate (2×150 mL). The combined organic phases were washed with water (200 mL) and brine (200 mL) and subsequently dried (Na2SO4). Evaporation of the solvents in vacuo gave 1-(4-fluorophenyl)-5-(tetrazol-5-ylmethyl)-1H-indole as an oil containing some residual acetic acid (14 g). A solution of the crude tetrazole in NMP (200 mL) was cooled with ice and potassium tert-butoxide (6.4 g) was added cautiously at 10-20° C. over 20 minutes. When the addition was complete the reaction mixture was cooled at 0° C. and iodomethane (7 mL) was added. After stirring at room temperature for 2 h, water (200 mL) was added and the resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with water (2×200 mL) and brine (2×250 mL), dried (Na2SO4) and the volatile solvents evaporated in vacuo. The resulting mixture of 1- and 2-methyl-substituted tetrazoles was separated by column chromatography on silica gel (ethyl acetate/heptane 1:2). Evaporation of the fastest eluting fractions in vacuo afforded pure 1-(4-fluorophenyl)-5-(2-methyltetrazol-5-ylmethyl)-1H-indole (11a) as an oil (3.7 g): 1H NMR (CDCl3) δ 4.25 (s, 3H), 4.30 (s, 2H), 6.60 (d, 1H), 7.10-7.20 (m, 3H), 7.20 (d, 1H), 7.30-7.45 (m, 3H), 7.60 (broad s,1H).

Workup

  1. additionwas added cautiously at 10-20° C. over 20 minutes
  2. additionWhen the addition
  3. extractionthe resulting mixture was extracted with ethyl acetate (2×200 mL)
  4. washThe combined organic phases were washed with water (2×200 mL) and brine (2×250 mL)
  5. dry with materialdried (Na2SO4)
  6. customthe volatile solvents evaporated in vacuo
  7. additionThe resulting mixture of 1- and 2-methyl-substituted tetrazoles
  8. customwas separated by column chromatography on silica gel (ethyl acetate/heptane 1:2)
  9. customEvaporation of the
  10. washfastest eluting fractions in vacuo

Sources & evidence

ORD record
ord-e6aaa0509fe6406999464ec0c0ab5131
Source dataset
uspto-grants-2003_08
Patent number
US06602889B1

Reaction notes

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