Tetrahydrofuran → HCID 58299799, compound

HRID 875964Notes

Reaction equation

HRID 875964 reaction equation
Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:27]2[N:28]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C:29]3[N:30]=[C:31]([NH2:35])[N:32]=[CH:33][C:34]=3[C:26]=2[CH:25]=[CH:24][N:23]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C(Cl)Cl.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:22]1[C:27]2[N:28]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C:29]3[N:30]=[C:31]([NH:35][C:2]4[N:7]=[CH:6][C:5]([N:8]5[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]5)=[CH:4][CH:3]=4)[N:32]=[CH:33][C:34]=3[C:26]=2[CH:25]=[CH:24][N:23]=1

Participants

11

Reactant 6

HCID 8028TetrahydrofuranHCID 25517Ammonium ChlorideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 2733832Lithium HexamethyldisilazideHCID 11530243Tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylateHCID 58299587HCID 58299587, compound

Product 1

HCID 58299799HCID 58299799, compoundYield 72.6%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

Compound 196 (0.178 g, 0.521 mmol), compound 194 (0.125 g, 0.434 mmol), and LiHMDS 1M in THF (1.30 mL, 1.30 mmol) were combined in 5 mL of anhydrous toluene. N2 was bubbled through the solution briefly before adding Pd2(dba)3 (0.0298 g, 0.0326 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0377 g, 0.0652 mmol). The solution was then heated to 80° C. for 2 hours with microwave irradiation. The solution was diluted with DCM before it was poured into sat's NH4Cl. Partitioned the layers and washed the aqueous layer with 10% i-PrOH/DCM. The combined organics were dried over MgSO4 and then concentrated under vacuum. The residue obtained was purified on CombiFlash column (dry loaded), eluting with a gradient of 60% ethyl acetate/hexane to 100% ethyl acetate. The fractions containing the product were combined and concentrated under vacuum. The residue obtained was repurified on CombiFlash column (dry loaded), eluting with a gradient of 2% methanol/0.1% NH4OH (˜28% in water)/DCM to 4% methanol/0.2% NH4OH (˜28% in water)/DCM. The fractions containing the product were combined and concentrated under vacuum. The residue obtained was sonicated in methanol. Filtration provided an off-white solid as compound 197 (0.173 g, 72%). LCMS-ESI (POS), M/Z, M+1: Found 549.1.

Workup

  1. customN2 was bubbled through the solution briefly
  2. customPartitioned the layers
  3. washwashed the aqueous layer with 10% i-PrOH/DCM
  4. dry with materialThe combined organics were dried over MgSO4
  5. concentrationconcentrated under vacuum
  6. customThe residue obtained
  7. customwas purified on CombiFlash column (dry loaded)
  8. washeluting with a gradient of 60% ethyl acetate/hexane to 100% ethyl acetate
  9. additionThe fractions containing the product
  10. concentrationconcentrated under vacuum
  11. customThe residue obtained
  12. customwas repurified on CombiFlash column (dry loaded)
  13. washeluting with a gradient of 2% methanol/0.1% NH4OH (˜28% in water)/DCM to 4% methanol/0.2% NH4OH (˜28% in water)/DCM
  14. additionThe fractions containing the product
  15. concentrationconcentrated under vacuum
  16. customThe residue obtained
  17. filtrationFiltration

Sources & evidence

ORD record
ord-c4f85a8a47c442f4b40b8c95139fe082
Source dataset
uspto-grants-2015_03
Patent number
US08980903B2

Reaction notes

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