Hexamethylphosphoramide → 2-(2'-Chloro-3-methylbiphenyl-4-yl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)-ethoxy]phenyl}propanenitrile

HRID 2194883Notes

Reaction equation

HRID 2194883 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[C:10]([CH3:17])[CH:9]=1.CN(C)P(N(C)C)(N(C)C)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([Cl:47])[C:41]=1[O:48][CH2:49][CH2:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58]I)=[CH:54][CH:53]=1>C1COCC1.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:58][C:55]2[CH:56]=[CH:57][C:52]([O:51][CH2:50][CH2:49][O:48][C:41]3[C:42]([Cl:47])=[CH:43][C:44]([CH3:46])=[CH:45][C:40]=3[Cl:39])=[CH:53][CH:54]=2)[C:15]#[N:16])=[C:10]([CH3:17])[CH:9]=1

Participants

7

Reactant 4

HCID 12679HexamethylphosphoramideHCID 2733832Lithium HexamethyldisilazideHCID 584884431,3-Dichloro-2-{2-[4-(iodomethyl)phenoxy]ethoxy}-5-methylbenzeneHCID 67448254(2'-Chloro-3-methylbiphenyl-4-yl)acetonitrile

Product 1

HCID 674478152-(2'-Chloro-3-methylbiphenyl-4-yl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)-ethoxy]phenyl}propanenitrile

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution (2′-chloro-3-methylbiphenyl-4-yl)acetonitrile (1 eq.) from step 1 in THF (0.10M) at −78° C. was added hexamethylphosphoramide (HMPA; 4 eq.) then lithium hexamethyldisilazide (LiHMDS; 1.2 eq.). The reaction mixture was stirred 30 min at −78° C. To the resulting solution was cannulated over 10 min a solution of 1,3-dichloro-2-{2-[4-(iodomethyl)phenoxy]ethoxy}-5-methylbenzene (II.1; 1.05 eq.). The final mixture was allowed to warm slowly to 0° C., stiffed an extra 2 h, poured in saturated aqueous NH4Cl and finally extracted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 20% in 30 min) afforded the desired compound as a colorless oil.

Workup

  1. waitTo the resulting solution was cannulated over 10 min
  2. temperatureto warm slowly to 0° C.
  3. waitstiffed an extra 2 h
  4. extractionfinally extracted with EtOAc
  5. extractionThe organic extract
  6. washwas washed with water, brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customPurification by column chromatography on silica gel (Combi-Flash by ISCO)
  11. washeluting with Hex/EtOAc (10 to 20% in 30 min)

Sources & evidence

ORD record
ord-49dbf3f1f1294f3aa0879418f75299a6
Source dataset
uspto-grants-2012_12
Patent number
US08334308B2

Reaction notes

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