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TCI Practical Example: Dehydration of a Carbamoyl Group Using Trifluoromethanesulfonic Anhydride

We are proud to present the synthesis of 4-bromobenzonitrile by the dehydration reaction of 4-bromobenzamide by using trifluoromethanesulfonic anhydride.

Used Chemicals

• Trifluoromethanesulfonic Anhydride (= Tf₂O) [T1100]
• Triethylamine (= Et₃N) [T0424]
• 4-Bromobenzamide [B4216]
• Dichloromethane

Procedure

Trifluoromethanesulfonic anhydride (0.32 mL, 2.0 mmol, 1.3 eq.) was slowly added to a solution of 4-bromobenzamide (300 mg, 1.5 mmol), and triethylamine (0.54 mL, 3.9 mmol, 2.6 eq.) in dichloromethane (3 mL) at 0 °C and the mixture was stirred at r.t. for 2 hours. Then additional triethylamine (1.1 mL, 7.8 mmol, 5.2 eq.) and trifluoromethanesulfonic anhydride (0.64 mL, 3.9 mmol, 2.6 eq.) were added at 0 °C and the mixture was stirred at room temperature for overnight. The reaction mixture was quenched with water (15 mL) and the aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with 2 mol/L HCl aq. (15 mL), sat. NaHCO₃ aq. (15 mL), and brine (15 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography (on silica gel, ethyl acetate:hexane = 1:8) to give 4-bromobenzonitrile a pale yellow solid (165 mg, 61% yield).

Experimenter’s Comments

The reaction mixture was monitored by UPLC.

Analytical Data

4-Bromobenzonitrile

¹H NMR (400 MHz, CDCl₃); δ 7.64 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H).

Lead Reference

• A Practical Method for the Preparation of Nitriles from Primary Amides Under Non-Acidic Conditions
  • D. S. Bose, B. Jayalakshmi, Synthesis 1999, 64.