Sodium Carbonate → 1H-indole-6-carboxylic acid

HRID 1672145Notes

Reaction equation

HRID 1672145 reaction equation
Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1C1CCCCC1)=[CH:8][CH:7]=[C:6]([C:17]([O:19]C)=[O:18])[C:5]=2Cl.C1(B(O)O)C=CC=CC=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1.CCO>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=2)[CH:10]=[CH:2]1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 66827Phenylboronic AcidHCID 433294Lithium ChlorideHCID 59802493Methyl-2-bromo-7-chloro-3-cyclohexyl-1H-indole-6-carboxylate

Product 1

HCID 5952301H-indole-6-carboxylic acid

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 21863594Toluene ethanolSolvent

Conditions

Temperature
60 °C

Procedure

To a mixture of methyl 2-bromo-7-chloro-3-cyclohexyl-1H-indole-6-carboxylate (841.8 mg, 2.27 mmol), phenylboronic acid (409 mg, 3.35 mmol), Pd(PPh3)4 (267 mg, 0.231 mmol), LiCl (188 mg, 4.44 mmol) and Na2CO3 (589 mg, 5.56 mmol) under N2 at r.t. in a re-usuable sealed tube was charged with a mixture of PhMe/EtOH (10 ml/10 ml) and then water (6.6 ml). The sealed tube was closed and the reaction mixture stirred at 60° C. for 3 hr, left standing at r.t. overnight, and then re-stirred at 60° C. for 2 hr 40 min. After cooling to r.t., the mixture was partitioned between CH2Cl2 and H2O (50 ml/50 ml). The organic layer was separated and evaporated to give a residue, which was purified by Biotage flash chromatography (gradient elution, 0 to 20% EtOAc/Hexane) to gave 1H-indole-6-carboxylic acid, 7-chloro-3-cyclohexyl-2-phenyl-, methyl ester (755 mg, 90%). 1H NMR (500 MHz): (CD3OD) δ 7.77 (d, J=8.3, 1H), 7.61 (d, J=8.3, 1H), 7.58-7.52 (overlapping m, 4H), 7.47 (m, 1H), 3.95 (s, 3H), 2.92 (m, 1H), 2.03 (m, 2H), 1.88-1.78 (overlapping m, 5H), 1.38 (m, 3H); Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=368.06, 370.03, HPLC Rt=2.085 min.

Workup

  1. customThe sealed tube was closed
  2. waitleft
  3. waitstanding at r.t. overnight
  4. stirringre-stirred at 60° C. for 2 hr 40 min
  5. temperatureAfter cooling to r.t.
  6. customthe mixture was partitioned between CH2Cl2 and H2O (50 ml/50 ml)
  7. customThe organic layer was separated
  8. customevaporated
  9. customto give a residue, which
  10. customwas purified by Biotage flash chromatography (gradient elution, 0 to 20% EtOAc/Hexane)

Sources & evidence

ORD record
ord-5dc62c4ca5a348bbb3c8089d8afd3965
Source dataset
uspto-grants-2011_08
Patent number
US07998951B2

Reaction notes

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