Trifluoroacetic acid → Ethyl 5-amino-4-cyano-3-iodothiophene-2-carboxylate

HRID 2401710Notes

Reaction equation

HRID 2401710 reaction equation
[C:1]([C:3]1[C:4]([I:25])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:6][C:7]=1[NH:8]CC1C=CC(OC)=CC=1OC)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:7]1[S:6][C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([I:25])[C:3]=1[C:1]#[N:2]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 59250031Ethyl 4-cyano-5-[(2,4-dimethoxybenzyl)amino]-3-iodothiophene-2-carboxylate

Product 1

HCID 66747549Ethyl 5-amino-4-cyano-3-iodothiophene-2-carboxylateYield 92.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of ethyl 4-cyano-5-[(2,4-dimethoxybenzyl)amino]-3-iodothiophene-2-carboxylate (4.50 g, 9.53 mmol) in dichloromethane (100 mL) at room temperature was added trifluoroacetic acid (22.5 mL, 292 mmol). The mixture was then stirred at room temperature for 10 minutes. The solvent was evaporated and the excess trifluoroacetic acid was removed by azeotroping with toluene. The crude material was diluted with ethyl acetate, then treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate five times and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield ethyl 5-amino-4-cyano-3-iodothiophene-2-carboxylate (2.85 g, 88%). LCMS: (FA) ES+, 323. 1H NMR (400 MHz, d6-DMSO) δ: 8.18 (s, 2H), 4.20-4.16 (m, 2H), 2.50-2.48 (m, 3H). To a suspension of 5-amino-4-cyano-3-iodothiophene-2-carboxylate (2.85 g, 8.85 mmol) in acetonitrile (46.2 mL) under argon was added diiodomethane (2.49 mL, 31.0 mmol). The mixture was heated to 38° C. for 30 minutes, then amyl nitrite (2.59 g, 22.1 mmol) was added dropwise over 5 minutes. The reaction was slowly allowed to cool to room temperature then the mixture was concentrated and column chromatography was performed to yield the title compound (3.20 g, 79%). LCMS: (FA) ES+, 434. 1H NMR (400 MHz, d6-DMSO) δ: 4.33-4.27 (m, 2H), 2.51-2.47 (m, 3H).

Workup

  1. customThe solvent was evaporated
  2. customthe excess trifluoroacetic acid was removed
  3. customby azeotroping with toluene
  4. additionThe crude material was diluted with ethyl acetate
  5. additiontreated with saturated sodium bicarbonate solution
  6. extractionThe mixture was extracted with ethyl acetate five times
  7. dry with materialthe combined organic extracts were dried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-8b00300860f54c8ea3a23de95c42c6ba
Source dataset
uspto-grants-2014_08
Patent number
US08796268B2

Reaction notes

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