Cesium carbonate → 1-(4-{4-[2-(4-Chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine

HRID 410343Notes

Reaction equation

HRID 410343 reaction equation
Br[C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:8]2=[NH:27])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH2:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][C:38]=2[CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH2:42][CH2:41][C:40]([CH3:43])([CH3:44])[CH2:39][C:38]=2[CH2:45][N:46]2[CH2:47][CH2:48][N:49]([C:2]3[CH:29]=[CH:28][C:5]([CH2:6][N:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[N:9]([CH2:16][CH2:17][CH2:18][O:19][C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=5)[C:8]4=[NH:27])=[CH:4][CH:3]=3)[CH2:50][CH2:51]2)=[CH:33][CH:32]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 462409921-(4-Bromo-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamineHCID 585649441-((4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine

Product 1

HCID 462418171-(4-{4-[2-(4-Chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamineYield 11.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent2×

Conditions

Temperature
95 °C

Procedure

To a degassed solution of 1-(4-bromo-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (60 mg, 0.13 mmol) in anhydrous toluene (2 ml) was added Pd(OAc)2 (0.3 mg, 0.7 □mol). Nitrogen was bubbled through the suspension for 10 min before BINAP (8 mg, 11 □mol) was added. After a further 2 min 1-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazine (48 mg, 0.14 mmol) in degassed toluene (2 ml) was introduced and then after a additional 2 min Cs2CO3 (0.86 g, 2.6 mmol) was added and the reaction was stirred for 2 min. Throughout all of the additions nitrogen was continuously bubbled through the reaction mixture. The reaction was then sealed and heated to 95° C. where it was maintained for 2 h. After this time, the reaction was cooled to rt and additional Pd(OAc)2 and BINAP were introduced. The reaction was then sealed and heated to 95° C. where it was maintained for a further 22 h. The mixture was cooled to rt and filtered through Celite®. The collected solids were washed with additional toluene and dichloromethane and then the combined filtrate and washings were concentrated under reduced pressure to give the crude product. After purification by preparative HPLC, the product was redissolved in dichloromethane and washed with saturated NaHCO3 and H2O. The organic phase was separated, dried (Na2SO4) and filtered to provide 1-(4-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (10 mg, 11%). HPLC-MS 692 [M+1]+, 347 (100%).

Workup

  1. customNitrogen was bubbled through the suspension for 10 min before BINAP (8 mg, 11 □mol)
  2. additionwas added
  3. customThroughout all of the additions nitrogen was continuously bubbled through the reaction mixture
  4. customThe reaction was then sealed
  5. temperaturewas maintained for 2 h
  6. temperatureAfter this time, the reaction was cooled to rt
  7. additionadditional Pd(OAc)2 and BINAP were introduced
  8. customThe reaction was then sealed
  9. temperatureheated to 95° C. where it
  10. temperaturewas maintained for a further 22 h
  11. temperatureThe mixture was cooled to rt
  12. filtrationfiltered through Celite®
  13. washThe collected solids were washed with additional toluene and dichloromethane
  14. concentrationthe combined filtrate and washings were concentrated under reduced pressure
  15. customto give the crude product
  16. customAfter purification by preparative HPLC
  17. dissolutionthe product was redissolved in dichloromethane
  18. washwashed with saturated NaHCO3 and H2O
  19. customThe organic phase was separated
  20. dry with materialdried (Na2SO4)
  21. filtrationfiltered

Sources & evidence

ORD record
ord-67b48b16cb074b99b72971d836e62816
Source dataset
uspto-grants-2014_06
Patent number
US08759520B2

Reaction notes

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