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BTC (Triphosgene) Coupling

Extreme Toxicity

BTC (bis(trichloromethyl) carbonate, also known as triphosgene) releases phosgene upon contact with water or nucleophilic solvents. Phosgene is fatal if inhaled even in small quantities. All work with BTC must be performed in a well-ventilated fume hood with the sash as low as possible. Keep all reagents and solvents rigorously dry. Have a phosgene detection badge visible in the hood.

Dry Technique Required

BTC reacts violently with water to release phosgene gas. All glassware, solvents, and reagents must be thoroughly dried. Use dry DCM or THF from the solvent purification system. Work under inert atmosphere (N2 or Ar).

Overview

BTC (triphosgene) is used to activate carboxylic acids as acid chlorides for coupling to sterically hindered amines. This is particularly useful for forming amide bonds between N-methylated amino acids or other difficult substrates where standard coupling reagents (HATU, COMU, etc.) fail.

Procedure

  1. Dry the resin thoroughly by washing 3x with dry DCM.
  2. In a separate dry flask under inert atmosphere, dissolve the Fmoc-amino acid (3-5 eq) in dry DCM.
  3. Cool the solution to 0 C.

  4. Add BTC (1 eq relative to amino acid, i.e., 0.33 eq of phosgene equivalents) and a non-nucleophilic base such as 2,4,6-collidine (6-10 eq) or 2,6-lutidine.

    Note

    Do not use nucleophilic bases such as triethylamine or DIPEA. These will react with the acid chloride intermediate.

  5. Stir at 0 C for 15-30 minutes to form the acid chloride.

  6. Add the activated acid chloride solution directly to the dried resin.
  7. Agitate at room temperature for 2-4 hours or overnight for difficult couplings.
  8. Wash resin 3x DMF, 3x DCM.
  9. Check by LCMS for completion. Repeat if necessary.

Safety Reminders

Phosgene Exposure

  • Always work in the fume hood.
  • Never open a container of BTC outside the fume hood.
  • Wear appropriate PPE: lab coat, safety glasses, and nitrile gloves.
  • Have a phosgene detection badge in the hood.
  • If you smell freshly cut hay or grass, leave the area immediately and alert others -- this is the characteristic odor of phosgene.
  • Dispose of all BTC waste in designated halogenated waste containers.