Sodium Carbonate → Methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate

HRID 1518218Notes

Reaction equation

HRID 1518218 reaction equation
Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.C([O-])([O-])=O.[Na+].[Na+].[OH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O>COCCOC.C(O)C.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>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[OH:40])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 639844Methyl indole-6-carboxylateHCID 2773454(2-Hydroxyphenyl)boronic acidHCID 11175076Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate

Product 1

HCID 11995228Methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylateYield 60%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in WO2004/087714, from commercially available methyl indole-6-carboxylate) in a mixture of 1,2-dimethoxyethane and ethanol (5:2, v/v, 0.2 M) were added 2 eq of Na2CO3 (2 M aqueous solution), 1.3 eq of (2-hydroxyphenyl)boronic acid and 0.1 eq of tetrakis(triphenylphosphine)palladium(0). The mixture was degassed thoroughly with a stream of dry nitrogen and then heated to 100° C. overnight. The reaction mixture was allowed to cool, diluted with some EtOAc and filtered over a plug of CELITE. The filtrate was diluted with EtOAc and the organic phase washed with water, brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (1:7 EtOAc/petroleum ether, then 1:3) to afford the title compound as a light yellow solid (60%). 1H NMR (400 MHz, DMSO-d6, 300 K) 1.14-1.38 (m, 3H), 1.63-1.81 (m, 5H), 1.82-1.96 (m, 2H), 2.62-2.70 (m, 1H), 3.84 (s, 3H), 6.92 (t, J 7.4, 1H), 7.00 (d, J 8.0, 1H), 7.22 (dd, J 1.3, 7.5, 1H), 7.26 (dt, J 1.4, 8.0, 1H), 7.57 (dd, J 1.2, 8.5, 1H), 7.78 (d, J 8.5, 1H), 7.98 (d, J 1.2, 1H), 9.69 (s, 1H), 11.22 (s, 1H); MS (ES+) m/z 350 (M+H)+.

Workup

  1. customThe mixture was degassed thoroughly with a stream of dry nitrogen
  2. temperatureto cool
  3. additiondiluted with some EtOAc
  4. filtrationfiltered over a plug of CELITE
  5. additionThe filtrate was diluted with EtOAc
  6. washthe organic phase washed with water, brine
  7. dry with materialdried over Na2SO4
  8. filtrationbefore being filtered
  9. concentrationconcentrated in vacuo
  10. customThe crude material was purified by flash chromatography on silica gel (1:7 EtOAc/petroleum ether

Sources & evidence

ORD record
ord-3c1153be295c4280b0fa0304ea1acccf
Source dataset
uspto-grants-2012_07
Patent number
US08232390B2

Reaction notes

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