2,6-Lutidine → 1-benzyl-5-[(3-methylphenyl)amino]-3-phenyl-1H-indole-2-carboxylic acid

HRID 2055741Notes

Reaction equation

HRID 2055741 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)CCCCCCCCCCCCC.N1C(C)=CC=CC=1C.[NH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]([C:52]([O:54]CC)=[O:53])=[C:39]2[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.O.[OH-].[Li+]>C(OCC)(=O)C.C1COCC1.CO.O.CC([O-])=O.CC([O-])=O.[Cu+2].C1(C)C=CC=CC=1>[CH2:45]([N:41]1[C:42]2[C:38](=[CH:37][C:36]([NH:35][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:44][CH:43]=2)[C:39]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)=[C:40]1[C:52]([OH:54])=[O:53])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1

Participants

10

Reactant 5

HCID 79372,6-LutidineHCID 11005Myristic AcidHCID 168937Lithium hydroxide, monohydrateHCID 27339503-Tolylboronic acidHCID 69229300ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate

Product 1

HCID 114873011-benzyl-5-[(3-methylphenyl)amino]-3-phenyl-1H-indole-2-carboxylic acidYield 50.9%

Reagents, catalysts & solvents 4

HCID 8895Cupric acetateCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolventHCID 21892291Methanol tetrahydrofuran waterSolvent

Procedure

3-Methylphenylboronic acid (0.20 g, 1.5 mmol), Cu(OAc)2 (0.036 g, 0.2 mmol), and myristic acid (0.046 g, 0.2 mmol) were combined in a 100-mL round-bottom flask with a large stir bar. A rubber septum was attached, and dry toluene (2 mL), 2,6-lutidine (0.116 mL, 1.0 mmol), and ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate (0.19 g, 0.5 mmol) were successively added. The resulting mixture was stirred at a high rate for 24 h, diluted with ethyl acetate (10 mL), filtered through a plug of silica gel, and then purified by column chromatography (5 to 25% EtOAc/hexanes) to give a gummy solid. To a stirred solution of the gummy solid in 15 mL of 2:1:1 THF/MeOH/water was added lithium hydroxide monohydrate (0.2 g, 4.8 mmol). The reaction was stirred at 40° C. for 5 h. Most of the organic solvents was removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid, and the solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min) The product was collected based on UV absorption and concentrated to give the title compound as a brown solid (0.11 g, 50%): 1H NMR (DMSO-d6) δ 2.18 (s, 3 H), 5.81 (s, 2 H), 6.51-6.53 (m, 1 H), 6.70-6.72 (m, 1 H), 6.75-6.80 (m, 1 H), 7.00-7.60 (m, 13 H), 7.88 (s,1 H), 12.86 (s, 1 H); MS (ESI) m/z 433 (MH+); MS (ESI) m/z 431 ([M-H]=); Anal. calcd. for C29H24N2O2.0.1H2O: C, 80.20; H, 5.62; N, 6.45. Found: C, 80.03; H, 5.61; N, 6.61.

Workup

  1. filtrationfiltered through a plug of silica gel
  2. custompurified by column chromatography (5 to 25% EtOAc/hexanes)
  3. customto give a gummy solid
  4. stirringThe reaction was stirred at 40° C. for 5 h
  5. customMost of the organic solvents was removed
  6. customthe solid was collected
  7. custompurified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min) The product
  8. customwas collected
  9. custombased on UV absorption
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-11485b95aba446a88d952a94b77a9b07
Source dataset
uspto-grants-2008_02
Patent number
US07332521B2

Reaction notes

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