Pyrrolidine → (NZ)-N-[5-methyl-3-(2,2,3,3-tetrafluoro-1,4-benzodioxin-6-yl)-1,3-thiazol-2-ylidene]pyrrolidine-1-carboxamide

HRID 2245366Notes

Reaction equation

HRID 2245366 reaction equation
[CH2:1]=[C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH2:3]1.[C:22](Cl)(Cl)=[O:23].C1(C)C=CC=CC=1.[CH:33]([N:36]([CH:39]([CH3:41])C)CC)([CH3:35])C.N1CCCC1>C(Cl)Cl.[NH4+].[OH-]>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[C:22]([N:36]2[CH2:33][CH2:35][CH2:41][CH2:39]2)=[O:23])/[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=3[CH:9]=2)[CH:3]=1

Participants

7

Reactant 4

HCID 31268Pyrrolidine2×HCID 81531DiisopropylethylamineHCID 19083224Phosgen tolueneHCID 866191675-Methylene-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazolidin-2-imine

Product 1

HCID 24852961(NZ)-N-[5-methyl-3-(2,2,3,3-tetrafluoro-1,4-benzodioxin-6-yl)-1,3-thiazol-2-ylidene]pyrrolidine-1-carboxamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 14923Ammonium HydroxideSolvent

Conditions

Temperature
-20 °C

Procedure

A solution of Example 22C (290 mg, 0.90 mmol) in CH2Cl2 (4.0 mL, 0.2 M) was added dropwise over 17 minutes to a −78° C. solution of 20% phosgene/toluene (630 μL, 1.2 mmol) in CH2Cl2 (5.0 mL, 0.2M). The mixture was stirred cold for 10 minutes after which diisopropylethylamine (140 μL, 0.80 mmol) was added dropwise over 3 minutes. The mixture was stirred cold for 45 minutes and allowed to warm to −20° C. over 1 hour; then allowed to warm to ambient temperature. After 1 hour at ambient temperature, pyrrolidine (135 μL, 1.6 mmol) was added and the mixture was stirred for 16 hours. To the solution was added more pyrrolidine (90 μL, 1.1 mmol), the mixture was stirred for 20 minutes, diluted with concentrated aqueous NH4OH (2 mL) and stirred for 5 minutes. The aqueous phase was separated and extracted with CH2Cl2 (3×). The combined organic phases were dried with Na2SO4, concentrated under reduced pressure, and chromatographed on Alltech silica eluting with 0-10% Et2O in 1:1 CH2Cl2/hexanes to provide the titled compound. 1H NMR (CD2Cl2) δ ppm 1.83 (m, 4H), 2.24 (d, 3H), 3.36 (m, 2H), 3.40 (m, 2H), 6.66 (d, 1H), 7.25 (d, 1H), 7.42 (dd, 1H), 7.54 (d, 1H); MS (ESI) 418 (M+H).

Workup

  1. additionwas added dropwise over 3 minutes
  2. temperatureto warm to ambient temperature
  3. waitAfter 1 hour at ambient temperature
  4. stirringthe mixture was stirred for 16 hours
  5. stirringthe mixture was stirred for 20 minutes
  6. stirringstirred for 5 minutes
  7. customThe aqueous phase was separated
  8. extractionextracted with CH2Cl2 (3×)
  9. dry with materialThe combined organic phases were dried with Na2SO4
  10. concentrationconcentrated under reduced pressure
  11. customchromatographed on Alltech silica eluting with 0-10% Et2O in 1:1 CH2Cl2/hexanes

Sources & evidence

ORD record
ord-7ef7c8f9522147638a13e1293e777386
Source dataset
uspto-grants-2010_03
Patent number
US07683084B2

Reaction notes

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