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

HRID 338310Notes

Reaction equation

HRID 338310 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]([O:19][CH3:20])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:27].[Na+].O.OP([O-])(O)=O.[Na+].[NH4+].[Cl-]>CC#N.C(O)(C)(C)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]([O:19][CH3:20])=[CH:15][CH:14]=1

Participants

9

Reactant 5

HCID 105532-Methyl-2-butene2×HCID 25517Ammonium ChlorideHCID 516949Sodium Phosphate, Monobasic, Monohydrate2×HCID 23668197Sodium Chlorite2×HCID 866986566-Chloro-5-(4-methoxy-phenyl)-1H-indole-3-carbaldehyde

Product 1

HCID 717658016-Chloro-5-(4-methoxy-phenyl)-1H-indole-3-carboxylic acidYield 211.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolventHCID 6386tert-ButanolSolvent

Procedure

To a solution of 6-chloro-5-(4-methoxy-phenyl)-1H-indole-3-carbaldehyde (27.7 g, 97 mmol) in MeCN (400 mL), tert-butanol (400 mL) and 2-methyl-2-butene (400 mL, 3.76 mol) at 0° C. was added a solution of sodium chlorite (82.0 g, 970 mmol) and sodium phosphate monobasic hydrate (134.0 g, 970 mmol) in water (400 mL) dropwise over 20 minutes. The ice bath was removed and the mixture was stirred at room temperature. At the 16-hour and 20-hour time points, additional 2-methyl-2-butene (200 mL, 1.88 mol) was added, followed by solid sodium chlorite (82.0 g, 970 mmol) and solid sodium phosphate monobasic hydrate (134.0 g, 970 mmol). After a total of 22 hours, the reaction mixture was poured into a solution of saturated NH4Cl (800 mL) and water (200 mL), then extracted with EtOAc (4×500 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo to afford 62 g of a mustard-colored semi-solid. This solid was triturated in CHCl3 (70 mL), filtered and dried under high vacuum to afford 18.5 g pale yellow solid. The solid was stirred in EtOAc (50 mL) overnight at 55° C., then filtered hot and washed with room temperature EtOAc to afford the title compound (19.5 g, 63% for 2 steps) as a pale yellow solid. MS (ES+) 302.5 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 12.10 (br. s., 1H), 11.93 (br. s., 1H), 8.07 (d, J=2.68 Hz, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.35 (d, J=8.54 Hz, 2H), 7.01 (d, J=8.78 Hz, 2H), 3.81 (s, 3H).

Workup

  1. customThe ice bath was removed
  2. extractionextracted with EtOAc (4×500 mL)
  3. dry with materialThe combined organic layers were dried over MgSO4
  4. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-bcf5702a0ad443648160c22feb93bacc
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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