Ammonia → 5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole

HRID 1372844Notes

Reaction equation

HRID 1372844 reaction equation
I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+].[F-].[K+].N>C1COCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[NH:17][CH:18]=[CH:19]4)=[CH:3][CH:4]=1)[CH2:8]2

Participants

9

Reactant 5

HCID 222AmmoniaHCID 11430Potassium CarbonateHCID 522689Potassium FluorideHCID 27343615-Indolylboronic acidHCID 210726043-(4-Iodophenoxy)-1-azabicyclo[2.2.2]octane

Product 1

HCID 113246115-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Under N2, the product of Example 1A (329 mg, 1 mmol), 5-indolylboronic acid (Frontier, 193 mg, 1.2 mmol), Pd2(dba)3 (Aldrich, 24 mg, 0.025 mmol), (tBu3P)2Pd (26 mg, 0.05 mmol), K2CO3 (276 mg, 2 mmol) and KF (80 mg, 1.4 mmol) in THF (8 mL) was stirred at 60° C. overnight. The reaction was monitored with TLC. After the reaction was complete, it was diluted with EtOAc (30 mL) and washed with brine (2×5 mL). The organic solution was concentrated under reduced pressure and the title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (80 mg, yield, 25%). 1H NMR (300 MHz, CD3OD) δ 1.44–1.58 (m, 1H), 1.62–1.90 (m, 2H), 2.01–2.15 (m, 1H), 2.16–2.24 (m, 1H), 2.74–3.04 (m, 5H), 3.27–3.40 (m, 1H), 4.51–4.59 (m, 1H), 6.46 (dd, J=3.4, 1.1 Hz, 1H), 6.95 (dt, J=8.8, 2.6 Hz, 2H), 7.22 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.40 (dt, J=8.5, 1.0 Hz, 1H), 7.54 (dt, J=9.2, 2.6 Hz, 2H), 7.71 (dd, J=1.7, 0.7 Hz, 1H) ppm. MS (DCl/NH3): m/z 319 (M+H)+.

Workup

  1. washwashed with brine (2×5 mL)
  2. concentrationThe organic solution was concentrated under reduced pressure
  3. customthe title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm
  4. customEluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (80 mg, yield, 25%)

Sources & evidence

ORD record
ord-e0388185aac04761848817857317f999
Source dataset
uspto-grants-2007_01
Patent number
US07160876B2

Reaction notes

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