Citric Acid → HCID 178517395, compound

HRID 2210228Notes

Reaction equation

HRID 2210228 reaction equation
[CH:1]1(Br)[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([C:13]#[N:14])[CH:7]=1.[CH3:15][O:16]C(=O)OC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:9](=[CH:11][CH:12]=1)[NH:10][C:15](=[O:16])[N:14]=[C:13]2[CH:1]1[CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 311Citric AcidHCID 12021Dimethyl CarbonateHCID 78037BromocyclopropaneHCID 800192-Amino-5-chlorobenzonitrile

Product 1

HCID 178517395HCID 178517395, compoundYield 44%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
33 °C

Procedure

A 3-necked round bottom flask equipped with a thermometer, magnetic stirrer, addition funnel and septum inlet was oven dried and swept with Ar. The flask was charged with a suspension of 5.5 g (0.226 g-atom) of magnesium turnings (Aldrich) in 150 mL of dry THF. A 3.0 mL portion of cyclopropyl bromide (Aldrich, distilled) was added to the suspension in one portion, and the mixture heated to 33° C., at which time a gentle exotherm began. After this exotherm had stabilized at 48° C., the remaining 15.8 mL (0.235 mol total) of cyclopropyl bromide was added dropwise as a solution in 30 mL of dry THF to maintain an internal temperature of 48°-52° C. After the addition, the solution was kept at that temperature for 45 min using a heating mantle. (Note: 20 mL of this Grignard solution was removed via cannula for another reaction). A solution of 10.0 g (0.066 mol) of 4-chloro-2-cyanoaniline in 50 mL of dry THF was added dropwise at a rate which maintained an internal temperature of 47°-50° C. This temperature was maintained for 30 min after the addition was complete using a heating mantle. A 17.4 mL (0.206 mol) quantity of dimethylcarbonate (Aldrich) was added dropwise at a rate which maintained the temperature at 48°-55° C. After the addition, the reaction was kept at this temperature for 30 min using a heating mantle. The reaction solution was cooled to 25° C. and poured into a rapidly stirred mixture of ice and 500 mL of 1M citric acid. This mixture was extracted with two portions of CHCl3, the combined organic layers washed with 10% Na2CO3, dried over MgSO4, concentrated to a volume of approx. 450 mL and stored in the refrigerator under Ar overnight which caused the product to crystallize. The crystals were filtered and washed with cold CHCl3 to give 6.5 g (44%) of the title compound as a pale yellow solid. Chromatography of the mother liquors on 850 g of fine SiO2 using 35:1 CHCl3 --CH3OH provided an additional 5.2 g (35%).

Workup

  1. customA 3-necked round bottom flask equipped with a thermometer, magnetic stirrer, addition funnel and septum inlet
  2. customdried
  3. additionThe flask was charged with a suspension of 5.5 g (0.226 g-atom) of magnesium turnings (Aldrich) in 150 mL of dry THF
  4. additionA 3.0 mL portion of cyclopropyl bromide (Aldrich, distilled) was added to the suspension in one portion
  5. customhad stabilized at 48° C.
  6. temperatureto maintain an internal temperature of 48°-52° C
  7. additionAfter the addition
  8. custom(Note: 20 mL of this Grignard solution was removed via cannula for another reaction)
  9. temperaturemaintained an internal temperature of 47°-50° C
  10. temperatureThis temperature was maintained for 30 min
  11. additionafter the addition
  12. temperaturemaintained the temperature at 48°-55° C
  13. additionAfter the addition
  14. waitthe reaction was kept at this temperature for 30 min
  15. temperatureThe reaction solution was cooled to 25° C.
  16. extractionThis mixture was extracted with two portions of CHCl3
  17. washthe combined organic layers washed with 10% Na2CO3
  18. dry with materialdried over MgSO4
  19. concentrationconcentrated to a volume of approx. 450 mL
  20. customstored in the refrigerator under Ar overnight which
  21. customto crystallize
  22. filtrationThe crystals were filtered
  23. washwashed with cold CHCl3

Sources & evidence

ORD record
ord-9a4a4987aa3d442abbb51a2c527fdea5
Source dataset
uspto-grants-1995_10
Patent number
US05457201

Reaction notes

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