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

HRID 1502297Notes

Reaction equation

HRID 1502297 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-9283223825a04b98ad3274b6147bc6c1
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Reaction notes

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