Cesium carbonate → 4-(3,4-Dichlorophenyl)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline

HRID 576134Notes

Reaction equation

HRID 576134 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]2[C:28]3[C:23](=[CH:24][C:25](B4OC(C)(C)C(C)(C)O4)=[CH:26][CH:27]=3)[C:22]([CH3:39])([CH3:38])[NH:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]2[C:28]3[C:23](=[CH:24][C:25]([C:2]4[CH:3]=[CH:4][C:5]5[N:6]([N:8]=[CH:9][N:10]=5)[CH:7]=4)=[CH:26][CH:27]=3)[C:22]([CH3:39])([CH3:38])[NH:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 115139346-Bromo-(1,2,4)triazolo(1,5-a)pyridineHCID 667885324-(3,4-Dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline

Product 1

HCID 498052794-(3,4-Dichlorophenyl)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinolineYield 60.6%

Reagents, catalysts & solvents 3

HCID 53485975CID 53485975CatalystHCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

6-Bromo-[1,2,4]triazolo[1,5-a]pyridine (600 mg, 3.03 mmol) was added to a mixture of the boronate ester from step E (873 mg, 1.68 mmol), cesium carbonate (1.97 g, 6.06 mmol) in DMF (60 mL) and water (12 mL). The reaction mixture was deoxygenated with argon. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (82 mg, 0.10 mmol) was added and the reaction mixture was stirred at 90° C. for 1 hour, cooled, diluted with water, and extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (0 to 100% 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide solution in dichloromethane) gave the desired 4-(3,4-dichlorophenyl)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (431 mg, 50% over 2 steps): 1H NMR (CDCl3, 500 MHz) 1H NMR (CDCl3, 500 MHz) δ 8.79 (s, 1H), 8.38 (s, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.77 (dd, J=8.0, 1.5 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.0, 1.5 Hz, 1H)), 7.21 (d, J=1.5 Hz, 1H), 6.99-6.92 (m, 2H), 4.08 (t, J=5.5 Hz, 1H), 3.45 (dd, J=13.5, 5.5 Hz, 1H), 3.10 (dd, J=13.5, 5.5 Hz, 1H), 1.68 (s, 3H), 1.60 (s, 1H), 1.57 (s, 3H); ESI MS m/z 423 [M+H]+.

Workup

  1. customThe reaction mixture was deoxygenated with argon
  2. temperaturecooled
  3. extractionextracted with dichloromethane (3×)
  4. washThe combined organic extracts were washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated
  7. customPurification by flash column chromatography (0 to 100% 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide solution in dichloromethane)

Sources & evidence

ORD record
ord-57543a81d39444c4bbdc604a6139b123
Source dataset
uspto-grants-2015_05
Patent number
US09034899B2

Reaction notes

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