2-Methyl-2-butene → 6-Chloro-5-[4-(hydroxymethyl)phenyl]-1H-indole-3-carboxylic acid

HRID 1054565Notes

Reaction equation

HRID 1054565 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:27].[Na+].O.OP([O-])(O)=O.[Na+]>CC#N.C(O)(C)(C)C.O.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:27])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1

Participants

9

Reactant 4

HCID 105532-Methyl-2-butene2×HCID 516949Sodium Phosphate, Monobasic, Monohydrate2×HCID 23668197Sodium Chlorite2×HCID 866985706-Chloro-5-(4-hydroxymethyl-phenyl)-1H-indole-3-carbaldehyde

Product 1

HCID 866985716-Chloro-5-[4-(hydroxymethyl)phenyl]-1H-indole-3-carboxylic acidYield 41%

Reagents, catalysts & solvents 4

HCID 962WaterSolvent3×HCID 6342AcetonitrileSolventHCID 6386tert-ButanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 6-chloro-5-(4-hydroxymethyl-phenyl)-1H-indole-3-carbaldehyde (422 mg, 1.48 mmol) in MeCN (18 mL), tert-butanol (18 mL) and 2-methyl-2-butene (12 mL, 110 mmol) at 0° C. was added a solution of sodium chlorite (1.25 g, 14.8 mmol) and sodium phosphate monobasic hydrate (2.04 g, 14.8 mmol) in water (9 mL) dropwise. The ice bath was removed and the solution was stirred at room temperature. After 5 hours, additional 2-methyl-2-butene (3 mL, 27.5 mmol) was added, followed by sodium chlorite (1.25 g, 14.8 mmol) and sodium phosphate monobasic hydrate (2.04 g, 14.8 mmol) in water (9 mL) dropwise. The resulting solution was stirred at room temperature. After 27 hours total reaction time, the solution was concentrated in vacuo to afford a pale yellow solid. Water (5 mL) was added to the solid and the mixture was extracted with EtOAc (2×50 mL). The combined organic layers were concentrated in vacuo and purified by flash chromatography (35-90% EtOAc/heptane, with 0.2% formic acid modifier) to afford a pale yellow solid. The solid was stirred in EtOAc (5 mL) at 55° C. for 6 hours, and the resulting slurry was cooled to room temperature. The precipitate was filtered and washed with EtOAc (1 mL) to afford the title compound (182 mg, 41% yield) as a cream-colored crystalline solid. MS (ES+) 300.0 (M−H)+. 1H NMR (400 MHz, CD3OD) δ 8.00 (s, 1 H) 7.98 (s, 1 H) 7.56 (s, 1 H) 7.40 (m, 4 H) 4.65 (s, 2 H).

Workup

  1. customThe ice bath was removed
  2. stirringThe resulting solution was stirred at room temperature
  3. waitAfter 27 hours total reaction time
  4. concentrationthe solution was concentrated in vacuo
  5. customto afford a pale yellow solid
  6. extractionthe mixture was extracted with EtOAc (2×50 mL)
  7. concentrationThe combined organic layers were concentrated in vacuo
  8. custompurified by flash chromatography (35-90% EtOAc/heptane, with 0.2% formic acid modifier)
  9. customto afford a pale yellow solid
  10. temperaturethe resulting slurry was cooled to room temperature
  11. filtrationThe precipitate was filtered
  12. washwashed with EtOAc (1 mL)

Sources & evidence

ORD record
ord-d17d88f23d6447d2917b3e3571ae2bff
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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