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TCI Practical Example: Condensation Using Diethyl Cyanophosphonate

We are proud to present the amidation of 4-biphenylacetic acid with benzylamine using diethyl cyanophosphonate as a condensing agent.

Used Chemicals

• 4-Biphenylacetic Acid [B1278]
• Benzylamine [B0406]
• Diethyl Cyanophosphonate [C1242]
• Triethylamine [T0424]
• DMF

Procedure

To a 4-necked round-bottom flask was equipped with a magnetic stir bar and charged with 4-biphenylacetic acid (1.91 g, 9.0 mmol, 1.0 equiv.), benzylamine (1.1 mL, 10.0 mmol, 1.1 equiv.), and DMF (46 mL) under nitrogen atmosphere. Triethylamine (1.7 mL, 12.0 mmol, 1.3 equiv.) was added at room temperature. The flask was cooled to 5 °C in an ice bath and then diethyl cyanophosphonate (2.06 g, 11.0 mmol, 1.2 equiv.) was added dropwise at 5 °C. The mixture was stirred at room temperature for 19 hours. The mixture was poured into water (200 mL). The precipitate was filtered, washed with water (50 mL) and dried under reduced pressure. The obtained crude product was purified by recrystallization (toluene:IPA = 1:1), giving 1 as a white needle-shaped crystal (2.36 g, 87%).

Experimenter’s Comments

All operations were done in the fume hood.
The reaction mixture was monitored by TLC (dichloromethane:methanol = 50:1, Rf = 0.61).
The wastewater was adjusted to pH 10 using 1 mol/L NaOH aq. This waste was treated with an aqueous solution of sodium hypochlorite, and confirmed to be completely decomposed using CN test paper and then discarded.

Analytical Data

2-([1,1'-biphenyl]-4-yl)-N-benzylacetamide (1)

¹H NMR (400 MHz, CDCl₃); δ 8.61 (t, 1H, J = 5.7 Hz), 7.65 (d, 2H, J = 8.2 Hz), 7.61 (d, 2H, J = 8.2 Hz), 7.51–7.43 (m, 2H), 7.42–7.29 (m, 5H), 7.28–7.21 (m, 3H), 4.30 (d, 2H, J = 6.0 Hz), 3.54 (s, 2H).

¹³C NMR (101 MHz, CDCl₃); δ 170.1 140.0, 139.5, 138.3, 135.7, 129.6, 128.9, 128.3, 127.3, 127.3, 126.8, 126.6, 42.3, 42.0.

Lead Reference

• Discovery of Antiglioma Activity of Biaryl 1,2,3,4-Tetrahydroisoquinoline Derivatives and Conformationally Flexible Analogues
• • M. L. Mohler, G-S. Kang, S-S. Hong, R. Patil, O. V. Kirichenko, W. Li, I. M. Rakov, E. E. Geisert, D. D. Miller, J. Med. Chem. 2006, 49, 5845.

Other References

• Diethylphosphoryl cyanide. A new reagent for the synthesis of amides.
• • S.-I. Yamada, Y. Kasai, T. Shioiri, Tetrahedron Lett. 1973, 18, 1595.