Dichloromethane → 3-Chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine

HRID 1027276Notes

Reaction equation

HRID 1027276 reaction equation
FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:18])[CH2:14][C:13](=[CH2:15])[CH2:12][C:11]([CH3:17])([CH3:16])[NH:10]1.B1C2CCCC1CCC2.[Cl:28][C:29]1[N:30]=[N:31][CH:32]=[C:33](Cl)[CH:34]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:28][C:29]1[N:30]=[N:31][C:32]([CH2:15][CH:13]2[CH2:12][C:11]([CH3:17])([CH3:16])[NH:10][C:9]([CH3:18])([CH3:8])[CH2:14]2)=[CH:33][CH:34]=1

Participants

10

Reactant 5

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 789669-Borabicyclo(3.3.1)nonaneHCID 199596873,5-DichloropyridazineHCID 867106932,2,6,6-Tetramethyl-4-methylenepiperidine 2,2,2-trifluoroacetate

Product 1

HCID 867106923-Chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazineYield 99.7%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
65 °C

Procedure

To 50 mL flask was added 2,2,6,6-tetramethyl-4-methylenepiperidine 2,2,2-trifluoroacetate (1.1 g, 4.12 mmol) and 9-BBN (0.5 M in THF) (16.5 mL, 8.23 mmol) and the reaction mixture was heated at 65° C. for 1 h. The reaction was cooled to RT and 3,5-dichloropyridazine (0.61 g, 4.12 mmol), K2CO3 (1.7 g, 12.35 mmol), and PdCl2(dppf).CH2Cl2 (0.17 g, 0.21 mmol) in 1,4-dioxane (8.5 mL)/H2O (1.7 mL) were added and heated at 60° C. overnight. The reaction mixture was cooled to RT, diluted with EtOAc, filtered through celite and concentrated in vacuo. The crude material was adjusted to pH 3 using 12 M HCl aqueous solution and loaded onto an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford 3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine (1.1 g) MS [M+H+]=268.2.

Workup

  1. temperatureThe reaction was cooled to RT
  2. temperatureheated at 60° C. overnight
  3. temperatureThe reaction mixture was cooled to RT
  4. filtrationfiltered through celite and
  5. concentrationconcentrated in vacuo
  6. washThe crude material was washed with methanol
  7. washthen eluted with 2 N ammonia in methanol
  8. concentrationThe product-containing fractions were concentrated

Sources & evidence

ORD record
ord-34696a799e5d4677a757d393de0e6b5a
Source dataset
uspto-grants-2014_05
Patent number
US08729263B2

Reaction notes

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