4-Iodoaniline → HCID 59426413, compound

HRID 502247Notes

Reaction equation

HRID 502247 reaction equation
[F:1][CH:2]([F:17])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:15]#[N:16])=[CH:9][N:10]2[CH2:13][CH3:14])=[CH:6][CH:5]=1.B(O[CH:28]([CH3:30])[CH3:29])(OC(C)C)OC(C)C.[Li+].CC([N-]C(C)C)C.CC(C)=[O:41].C(=O)=O.I[C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[NH2:51][C:50]1[CH:52]=[CH:53][C:47]([C:9]2[N:10]([CH2:13][CH:14]3[CH2:29][CH2:28][CH2:30][O:41]3)[C:11]3[C:7]([C:8]=2[C:15]#[N:16])=[CH:6][CH:5]=[C:4]([O:3][CH:2]([F:1])[F:17])[CH:12]=3)=[CH:48][CH:49]=1

Participants

9

Reactant 6

HCID 108934-IodoanilineHCID 11430Potassium CarbonateHCID 21531Triisopropyl borateHCID 2724682Lithium diisopropylamideHCID 11557722HCID 11557722, compoundHCID 18522661Acetone cardice

Product 1

HCID 59426413HCID 59426413, compoundYield 55%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of 6-difluoromethoxy-1-ethyl-1H-indole-3-carbonitrile (516.2 mg, 1.77 mmol) and tri-isopropyl borate (532.7 mg, 2.83 mmol) in THF (15 mL) is cooled to −78° C. and treated with LDA (1.5 M mono-THF in cyclohexane, 1.43 ml, 2.04 mmol). After the addition, the acetone/dry ice bath is exchanged for ice/water bath and the solution is stirred further for 30 min. The solution is cooled to −78° C. and a solution of 4-iodoaniline (390.2 mg, 1.78 mmol) in DMF (8 mL), K2CO3 (2M, 2.7 ml, 5.31 mmol) and PdCl2dppf (67.4 mg, 0.09 mmol) are added in sequence. The mixture is degassed by three successive cycles of vacuum pumping/N2 purging and is stirred overnight (ca. 16 h), after which it is poured into 4 volumes of water, and 4 volumes of ethyl acetate are added. The phases are separated, and the aqueous phase is extracted with more ethyl acetate. The organic phases are washed by water, saturated NaCl, dried over anhydrous MgSO4, filtered and evaporated. The remaining material is purified by column chromatography, eluting with 5-15% ethyl acetate/hexanes on silica gel to yield 367.5 mg (55.0% yield) of 2-(4-aminophenyl)-6-difluoromethoxy-1-(tetrahydrofuran-2-ylmethyl)-1H-indole-3-carbonitrile as a white solid.

Workup

  1. additionAfter the addition
  2. customThe mixture is degassed by three successive cycles of vacuum
  3. stirringis stirred overnight (ca. 16 h)
  4. additionafter which it is poured into 4 volumes of water, and 4 volumes of ethyl acetate
  5. additionare added
  6. customThe phases are separated
  7. extractionthe aqueous phase is extracted with more ethyl acetate
  8. washThe organic phases are washed by water, saturated NaCl
  9. dry with materialdried over anhydrous MgSO4
  10. filtrationfiltered
  11. customevaporated
  12. customThe remaining material is purified by column chromatography
  13. washeluting with 5-15% ethyl acetate/hexanes on silica gel

Sources & evidence

ORD record
ord-b6ea9cd2ca384295b9745248503c3e2d
Source dataset
uspto-grants-2010_08
Patent number
US07772271B2

Reaction notes

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