1,4-Dioxane → 4-Bromo-2-pyridazin-4-yl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile

HRID 2402072Notes

Reaction equation

HRID 2402072 reaction equation
Br[C:2]1[S:3][C:4]([C:10]2[N:14]=[CH:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:11]=2)=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][N:29]=[N:28][CH:27]=1)CCC.[Cl-].[Li+].O1CCOCC1>CO.C(Cl)Cl.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]([C:26]2[CH:31]=[CH:30][N:29]=[N:28][CH:27]=2)[S:3][C:4]=1[C:10]1[N:14]=[CH:13][N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:11]=1

Participants

8

Reactant 4

HCID 312751,4-DioxaneHCID 433294Lithium ChlorideHCID 64097334-(Tributylstannyl)pyridazineHCID 667492652,4-Dibromo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile

Product 1

HCID 667492984-Bromo-2-pyridazin-4-yl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrileYield 57.7%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of 2,4-dibromo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile (0.248 g, 0.594 mmol), 4-(tributylstannyl)pyridazine (2.30 mg, 0.624 mmol), copper(I) iodide (34.0 mg, 0.178 mmol), lithium chloride (75.6 mg, 1.78 mmol) and tetrakis(triphenylphosphine)palladium(0) (34.3 mg, 0.0297 mmol) in dry 1,4-dioxane (5.0 mL, 64 mmol) was sonicated under a nitrogen atmosphere for 2 min then heated in a capped vial to 130° C. in microwave machine for 20 mins. The suspension was cooled to rt, diluted with 20% MeOH/DCM (˜100 mL), treated with 12 g of silica gel then rotavaped and dried under high vacuum. The coated silica gel was chromatographed on a silica column eluting with MeOH/DCM (0/100 to 5/95) to afford a solid product (0.143 g, yield 57.7%). LCMS: (AA) ES+, 417, 419. 1H NMR (300 MHz, CDCl3) δ: 9.55 (s, 1H), 9.37-9.39 (m, 1H), 8.40 (s, 1H), 7.69-8.00 (m, 1H), 5.55-5.60 (m, 1H), 4.08-4.13 (m, 1H), 3.73-3.81 (m, 1H), 2.18-2.30 (m, 1H), 2.03-2.16 (m, 2H), 1.68-1.82 (m, 3H).

Workup

  1. customwas sonicated under a nitrogen atmosphere for 2 min
  2. temperatureThe suspension was cooled to rt
  3. additiontreated with 12 g of silica gel
  4. customdried under high vacuum
  5. customThe coated silica gel was chromatographed on a silica column
  6. washeluting with MeOH/DCM (0/100 to 5/95)

Sources & evidence

ORD record
ord-d7092d19ee6941dfbd3da95400d071b9
Source dataset
uspto-grants-2014_08
Patent number
US08796271B2

Reaction notes

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