Iodine → N-(2'-Chloro-6'-methyl-phenyl)-4-ethylaniline

HRID 603347Notes

Reaction equation

HRID 603347 reaction equation
[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].CO[C:12]1[CH2:17][CH:16]=[C:15]([CH2:18][CH3:19])[CH2:14][CH:13]=1.II>O1CCCC1.ClC1C=CC=CC=1.C(O)(=O)C.CCCCCCC.C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1

Participants

9

Reactant 3

HCID 807Iodine3×HCID 68972-Chloro-6-methylanilineHCID 141110231-Methoxy-4-ethylcyclohexa-1,4-diene

Product 1

HCID 57952157N-(2'-Chloro-6'-methyl-phenyl)-4-ethylaniline

Reagents, catalysts & solvents 5

HCID 24193Titanium TetrachlorideCatalystHCID 176Acetic AcidSolventHCID 7964ChlorobenzeneSolventHCID 8028TetrahydrofuranSolvent2×HCID 22263336Toluene heptaneSolvent

Conditions

Temperature
-35 °C

Procedure

A solution of 3.0 g 2-Chloro-6-methyl-aniline in 3.5 ml of tetrahydrofuran and 31 ml of chlorobenzene is cooled down to −40 to −45° C. At this temperature, 4.01 g of titanium-tetrachloride is added to the solution, followed by the addition of 6.18 g of 1-Methoxy-4-ethylcyclohexa-1,4-diene. The reaction mixture is allowed to warm up to approx. −35° C. and stirred for 3 hours at this temperature. A solution of 8.06 g of iodine in 16.4 ml of tetrahydrofuran and 1.8 ml of acetic acid is added to the reaction mixture and the temperature is allowed to warm up to 0° C. The mixture is stirred for 30 minutes at 0° C. and 2 hours at 25° C. Then 2.68 g of iodine is added to the reaction mixture and stirring is continued for additional 24 hours at 25° C. Again, 2.68 g of iodine is added and stirring is continued for additional 72 hours at 25° C. The reaction is finally quenched by pouring the reaction mixture onto a mixture of 250 ml of aqueous sodium bisulfite (38-40%) and 450 ml of saturated aqueous sodium carbonate. The water phase is extracted with ethyl acetate (1×200 ml and 2×100 ml), the ethyl acetate phases are unified and washed with 100 ml of brine. The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to give a dark viscous liquid. The liquid was dissolved in heptane/toluene and the solution was filtered over silicagel to obtain, after evaporation of the solvent, 2.0 g of crude product. The product can be used directly in the next step. Alternatively, it can be purified e.g. by column chromatography on silica gel with heptane/toluene (7:3) as eluent to yield pure N-(2′-Chloro-6′-methyl-phenyl)-4-ethylaniline.

Workup

  1. temperatureto warm up to 0° C
  2. stirringThe mixture is stirred for 30 minutes at 0° C. and 2 hours at 25° C
  3. stirringstirring
  4. waitis continued for additional 24 hours at 25° C
  5. stirringstirring
  6. waitis continued for additional 72 hours at 25° C
  7. customThe reaction is finally quenched
  8. additionby pouring the reaction mixture
  9. additiononto a mixture of 250 ml of aqueous sodium bisulfite (38-40%) and 450 ml of saturated aqueous sodium carbonate
  10. extractionThe water phase is extracted with ethyl acetate (1×200 ml and 2×100 ml)
  11. washwashed with 100 ml of brine
  12. dry with materialThe organic phase was dried over anhydrous sodium sulfate
  13. customevaporated in vacuo
  14. customto give a dark viscous liquid
  15. filtrationthe solution was filtered over silicagel
  16. customto obtain
  17. customafter evaporation of the solvent, 2.0 g of crude product
  18. customAlternatively, it can be purified e.g. by column chromatography on silica gel with heptane/toluene (7:3) as eluent

Sources & evidence

ORD record
ord-2ae4ded5b6d041b0a6a285587680982d
Source dataset
uspto-grants-2011_03
Patent number
US07906677B2

Reaction notes

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