TCI Practical Example: Introduction of Carbonyl Group by Using 2,4,6-Trichlorophenyl Formate

We are proud to present the synthesis of the amide via the introduction of carbonyl group by 2,4,6-trichlorophenyl formate. The arylcarboxylic acid ester after palladium-catalyzed carbonylation can be converted to carboxylic acid derivatives by treatment of various nucleophiles.

Used Chemicals

• 2,4,6-Trichlorophenyl Formate [T3121]
• 2-Iodofluorene [I0793]
• Palladium(II) Acetate (= Pd(OAc)₂) [A1424]
• 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (= Xantphos) [B2709]
• Triethylamine (= Et₃N) [T0424]
• Morpholine [M0465]
• 4-Dimethylaminopyridine (= DMAP) [D1450]
• Toluene
• THF

Procedure

A solution of 2-iodofluorene (500 mg, 1.71 mmol), 2,4,6-trichlorophenyl formate (579 mg, 2.57 mmol), palladium(II) acetate (38.4 mg, 0.171 mmol), Xantphos (198 mg, 0.342 mmol) and triethylamine (470 µL, 3.42 mmol) in toluene (10 mL) was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was washed with acetonitrile to give 1 as a pale yellow solid (462 mg, 69% yield).
A solution of 1 (460 mg, 1.18 mmol), triethylamine (330 µL, 2.36 mmol), DMAP (7.2 mg, 59 µmol) and morpholine (154 µL, 1.77 mmol) in THF (5 mL) was stirred at 45 °C for 20 hours. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 0:100 - 50:50) to give 2 as a white solid (305 mg, 93% yield).

Experimenter’s Comments

The reaction mixture at the first step was monitored by TLC (hexane:ethyl acetate = 1:19, Rf = 0.34).
The reaction mixture at the second step was monitored by TLC (hexane:ethyl acetate = 1:1, Rf = 0.26).

Analytical Data

2,4,6-Trichlorophenyl 9H-Fluorene-2-carboxylate (1)
¹H NMR (400 MHz, CDCl₃); δ 8.41 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.94-7.88 (m, 2H), 7.62 (d, J = 6.2 Hz, 1H), 7.48–7.38 (m, 4H), 4.02 (s, 2H).

(9H-Fluoren-2-yl)(morpholino)methanone (2)
¹H NMR (400 MHz, CDCl₃); δ 7.81 (d, J = 7.6 Hz, 2H), 7.62-7.56 (m, 2H), 7.43-7.32 (m, 3H), 3.94 (s, 2H), 3.72 (brs, 8H).

Lead Reference

• Trichlorophenyl Formate: Highly Reactive and Easily Accessible Crystalline CO Surrogate for Palladium-Catalyzed Carbonylation of Aryl/Alkenyl Halides and Triflates.
  • T. Ueda, H. Konishi, K. Manabe, Org. Lett. 2012, 14, 5370.

Other References

• Pd-Catalyzed External-CO-Free Carbonylation: Preparation of 2,4,6-Trichlorophenyl 3,4-Dihydronaphthalene-2-Carboxylate
  • H. Konishi, T. Ueda, K. Manabe, Org. Synth. 2014, 91, 39.
• Formic Acid Derivatives as Practical Carbon Monoxide Surrogates for Metal-Catalyzed Carbonylation Reactions
  • H. Konishi, K. Manabe, Synlett 2014, 25, 1971.