Methyl iodide → HCID 66748117, compound

HRID 2402148Notes

Reaction equation

HRID 2402148 reaction equation
[C:1]([C:3]1[C:4]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[CH3:30]I>CN(C)C=O>[C:1]([C:3]1[C:4]([CH:19]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH3:30])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]

Participants

4

Reactant 2

HCID 6328Methyl iodideHCID 66747680HCID 66747680, compound

Product 1

HCID 66748117HCID 66748117, compoundYield 78.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
-25 °C

Procedure

A 1 L flask was charged with a big egg-shape stirring bar and ethyl 4-cyano-5-morpholin-4-yl-3-(2-naphthylmethyl)thiophene-2-carboxylate (14.5 g, 35.7 mmol). To the flask was added N,N-dimethylformamide (240 mL) and the mixture was evacuated and purged with nitrogen (×3). To the flask was added tetrahydrofuran (60 mL), and the mixture was stirred until it became a clear yellow solution. The solution was cooled to ˜−25° C. in a dry ice-acetone bath (the temperature was actively controlled by slow addition of dry ice between −30˜−40° C.). 1 M of Potassium tert-butoxide in tetrahydrofuran (42.8 mL) was added dropwise over 3 min. The mixture turned deep purple immediately. After the addition the mixture was stirred for 10 min at this temperature. Methyl iodide (11.1 mL, 178 mmol) was added over 1 min. By the end of addition the mixture turned light red. After stirring the resulting mixture at 0° C. for 10 min, the reaction was quenched by addition of 10 mL of water. All volatiles were removed under reduced pressure and the resulting mixture was distributed between brine and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with 10% LiCl (aq) soln (×3), then brine, dried, and concentrated to provide a yellow syrup. Purification on a silica gel column (gradient elution 5-20% EtOAc/hexanes) provided Ethyl 4-cyano-5-(morpholin-4-yl)-3-[1-(2-naphthyl)ethyl]thiophene-2-carboxylate as a white solid (11.8 g, 78.7% yield). LCMS: (AA) ES+ 421; 1H NMR (400 MHz, CDCl3) δ 7.90-7.82 (m, 2H), 7.82-7.70 (dd, J=15.4, 8.1 Hz, 2H), 7.50-7.37 (m, 3H), 5.82-5.67 (q, J=7.3 Hz, 1H), 4.40-4.25 (qd, J=6.1, 5.0, 3.1 Hz, 2H), 3.86-3.72 (t, J=4.8 Hz, 4H), 3.54-3.44 (t, J=4.8 Hz, 4H), 1.95-1.85 (d, J=7.3 Hz, 3H), 1.42-1.31 (t, J=7.1 Hz, 3H).

Workup

  1. additionA 1 L flask was charged with a big egg-shape
  2. customthe mixture was evacuated
  3. custompurged with nitrogen (×3)
  4. additionTo the flask was added tetrahydrofuran (60 mL)
  5. stirringthe mixture was stirred until it
  6. additionwas actively controlled by slow addition of dry ice between −30˜−40° C.)
  7. addition1 M of Potassium tert-butoxide in tetrahydrofuran (42.8 mL) was added dropwise over 3 min
  8. additionAfter the addition the mixture
  9. stirringwas stirred for 10 min at this temperature
  10. additionBy the end of addition the mixture
  11. stirringAfter stirring the resulting mixture at 0° C. for 10 min
  12. customthe reaction was quenched by addition of 10 mL of water
  13. customAll volatiles were removed under reduced pressure
  14. extractionThe aqueous layer was extracted with EtOAc (×2)
  15. washThe combined organic layers were washed with 10% LiCl (aq) soln (×3)
  16. dry with materialbrine, dried
  17. concentrationconcentrated
  18. customto provide a yellow syrup
  19. customPurification
  20. washon a silica gel column (gradient elution 5-20% EtOAc/hexanes)

Sources & evidence

ORD record
ord-fa0e9a6ed41d481791b53d1e758ce6f8
Source dataset
uspto-grants-2014_08
Patent number
US08796271B2

Reaction notes

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