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Cesium carbonate → 4-{2-[2-(2-(R)-Methyl-pyrrolidin-1-yl)-ethyl]-1H-indol-5-yl}-benzonitrile

HRID 424954
Notes
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Reaction equation

HRID 424954 reaction equation
C([O-])([O-])=O.[Cs+].[Cs+].[F-].[Cs+].[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH3:37])=[CH:24]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>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].C1(C)C=CC=CC=1.O>[CH3:37][C@@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[CH2:31][CH2:30][C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:14]1[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=1)=[CH:29][CH:28]=2
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 25953Cesium fluorideHCID 27342162-(Dicyclohexylphosphino)biphenylHCID 27343264-Cyanophenylboronic acidHCID 210414975-Bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-1H-indole

Product 1

HCID 11359413
4-{2-[2-(2-(R)-Methyl-pyrrolidin-1-yl)-ethyl]-1H-indol-5-yl}-benzonitrile
Yield 44.9%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
65 °C

Procedure

A reaction flask was charged with Cs2CO3 (1.14 g, 3.5 mmol), CsF (0.38 g, 2.5 mmol), 4-cyanophenylboronic acid (425 mg, 2.5 mmol), and H2O (10 mL) followed by a toluene solution (10 mL) of 5-bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-1H-indole (307 mg, 1.0 mmol). The resulting mixture was purged with nitrogen. To the reaction mixture was then added 2-dicyclohexylphosphino(biphenyl) (35 mg, 0.1 mmol) and Pd2(dba)3 (46 mg, 0.05 mmol). The resulting reaction mixture was then heated to 65° C. overnight under nitrogen after which HPLC indicated that all the 5-bromo-2-[2-(-(R)-methyl-pyrrolidin-1-yl-ethyl]-1H-indole was consumed. The reaction mixture was cooled to room temperature and IPAc (20 mL) was added. The organic layer was separated and concentrated. The residue was purified by column chromatography eluting with heptane/acetone/CH2Cl2/Et3N (600 mL/40 mL/5 mL/2 mL). The fractions containing product were combined and concentrated under reduced pressure to provide the title compound as a semi-solid (148 mg). 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.65-7.74 (m, 5H), 7.40 (d, J=8.5 Hz, 1H), 7.33 (dd, J=1.8, 8.5 Hz, 1H), 6.27 (s, 1H), 3.37-3.42 (m, 1H), 3.21-3.25 (m, 1H), 3.01-3.16 (m, 2H), 2.54-2.62 (m, 2H), 2.33 (q, J=8.78 Hz, 1H), 2.04-2.08 (m, 1H), 1.80-1.93 (m, 2H), 1.56-1.63 (m, 1H), 1.21 (d, J=6.2 Hz, 3H). 13C NMR (400 MHz, CDCl3) δ 146.99, 139.96, 135.61, 132.05, 130.30, 128.74, 127.32, 120.02, 119.13, 118.36, 111.13, 109.16, 99.49, 61.25, 53.68, 53.57, 32.92, 26.21, 22.14, 18.98. [M+H]+ at m/z 330.

Workup

  1. customThe resulting mixture was purged with nitrogen
  2. customThe resulting reaction mixture
  3. customwas consumed
  4. temperatureThe reaction mixture was cooled to room temperature
  5. additionIPAc (20 mL) was added
  6. customThe organic layer was separated
  7. concentrationconcentrated
  8. customThe residue was purified by column chromatography
  9. washeluting with heptane/acetone/CH2Cl2/Et3N (600 mL/40 mL/5 mL/2 mL)
  10. additionThe fractions containing product
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-a65d3bc921ec41f59dc2b50390e7abe8
Source dataset
uspto-grants-2012_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08106088B2

Reaction notes

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