Acetonitrile → 3-Chloro-7-cyclohexyl-2,6-naphthyridine

HRID 468779Notes

Reaction equation

HRID 468779 reaction equation
Br[C:2]1[C:3]([CH:9]=[N:10][C:11]([CH3:14])([CH3:13])C)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(#N)C.[CH:18]1(C#C)[CH2:23][CH2:22]C[CH2:20][CH2:19]1>ClCCl.[Zn]>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[C:3]([CH:4]=1)=[CH:9][N:10]=[C:11]([CH:13]1[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20]1)[CH:14]=2

Participants

6

Reactant 3

HCID 6342AcetonitrileHCID 70263EthynylcyclohexaneHCID 86674941N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropan-2-amine

Product 1

HCID 866749423-Chloro-7-cyclohexyl-2,6-naphthyridineYield 55%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

A round-bottom flask containing N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropan-2-amine (164.5 mg, 0.5969 mmol), DPPPNiCl2 (16.0 mg, 0.0295 mmol) and zinc (84.0 mg, 1.28 mmol) was evacuated and purged with nitrogen 5 times. Acetonitrile (6 mL, 100 mmol) and cyclohexylacetylene (86.0 uL, 0.658 mmol) were added to the flask and the reaction mixture was stirred at 80° C. under a nitrogen balloon for 30 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered through celite, rinsing with dichloromethane. The filtrate was evaporated in vacuo and the crude product purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-40% ethyl acetate in dichloromethane) to yield 80.4 mg (55%) of 3-chloro-7-cyclohexyl-2,6-naphthyridine. LCMS (ESI): M+H=247.2; 1H NMR (500 MHz, DMSO) δ 9.39 (s, 1H), 9.28 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 2.91-2.81 (m, 1H), 1.97 (d, J=11.3 Hz, 2H), 1.84 (d, J=13.0 Hz, 2H), 1.75 (d, J=12.9 Hz, 1H), 1.58 (ddd, J=24.8, 12.5, 2.9 Hz, 2H), 1.49-1.37 (m, 2H), 1.27 (ddd, J=16.3, 12.6, 9.2 Hz, 1H).

Workup

  1. customwas evacuated
  2. custompurged with nitrogen 5 times
  3. temperatureThe reaction mixture was cooled to room temperature
  4. filtrationfiltered through celite
  5. washrinsing with dichloromethane
  6. customThe filtrate was evaporated in vacuo
  7. customthe crude product purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-40% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-d9d88a1365aa47eca660d7e508c4ca4c
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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