Potassium Phosphate, Tribasic → 3-chloro-5-{1-[(3-methyl phenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-4-pyridinecarbonitrile

HRID 1910073Notes

Reaction equation

HRID 1910073 reaction equation
Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]#[N:9].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([N:21]2[C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)=[O:20])[CH:15]=[CH:16][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.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]>[Cl:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([C:19](=[O:20])[CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[CH:13]=2)[CH2:22][CH2:23]3)[C:7]=1[C:8]#[N:9]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 111375993,5-Dichloropyridine-4-carbonitrileHCID 668241231-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole

Product 1

HCID 668238123-chloro-5-{1-[(3-methyl phenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-4-pyridinecarbonitrileYield 28.4%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 3,5-dichloro-4-pyridinecarbonitrile (400 mg, 2.312 mmol), 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (872 mg, 2.312 mmol), Pd2(dba)3 (42.3 mg, 0.046 mmol) and K3PO4 (982 mg, 4.62 mmol) in 9 mL of dioxane and 3 mL of water in a microwave tube was degassed and backflushed with nitrogen, followed by addition of tri-(t-butyl)phosphonium tetrafluoroborate salt (26.8 mg, 0.092 mmol). The mixture was degassed and backflushed with nitrogen. The mixture was heated in a microwave reactor at 120° C. for 40 minutes. LCMS showed there was no stating material. The mixture was cooled to room temperature, and the mixture was filtered. The filtered solid was purified by silica gel column chromatography on a silica gel cartridge using gradient elution of 100% CH2Cl2 to 90:10:1 CH2Cl2/CH3OH/NH3OH. The combined product fractions were evaporated to dryness to give 3-chloro-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-4-pyridinecarbonitrile as a pale yellow solid (255 mg, 26% yield). LCMS [M+1] 388. 1H NMR (400 MHz, DMSO-d6) δ 2.31 (s, 3H), 3.24 (t, J=8.34 Hz, 2H), 3.85 (s, 2H), 4.25 (t, J=8.46 Hz, 2H), 7.06-7.14 (m, 3H), 7.20-7.27 (m, 1H), 7.51 (d, J=8.34, 1H), 7.58 (s, 1H), 8.21 (d, J=8.34 Hz, 1H), 8.82 (s, 1H), 8.93 (s, 1H).

Workup

  1. customwas degassed
  2. customThe mixture was degassed
  3. temperatureThe mixture was cooled to room temperature
  4. filtrationthe mixture was filtered
  5. customThe filtered solid was purified by silica gel column chromatography on a silica gel cartridge
  6. washelution of 100% CH2Cl2 to 90:10:1 CH2Cl2/CH3OH/NH3OH
  7. customThe combined product fractions were evaporated to dryness

Sources & evidence

ORD record
ord-bea661c7fbfe4e5dbcf631543698a71c
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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