Pd(II)-Catalyzed Asymmetric Fluorination of α-Aryl-α-cyanophosphonates with the Aid of 2,6-Lutidine

Abstract

We describe herein the catalytic asymmetric fluorination of α-cyanophosphonates using chiral Pd(II)-bisphosphine complexes. While metal complexes failed to promote the reaction alone, a reaction system involving Pd(II) and organic base such as 2,6-lutidine was developed. The Pd(II) complex activates the substrates through coordination of the nitrile group, and 2,6-lutidine abstracts an acidic proton, thereby affording the desired fluorinated products in good yields with up to 78% ee. The products may be useful as novel physiological phosphate mimics in medicinal chemistry.

Key words

asymmetric catalysis - fluorine - α-cyanophosphonate - palladium - medicinal chemistry

References and Notes

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11

For detailed discussion on the effect of additional organic bases, see ref. 6e.

13

Representative Procedure
To a mixture of α-cyanophosphonate 1a (25.3 mg, 0.1 mmol), NFSI (47.2 mg, 0.15 mmol), and the Pd complex 5a (4.5 mg, 2.5 mol%) was added EtOH (0.2 mL) at -20 °C. At this temperature, 2,6-lutidine (12 µL, 0.1 mmol) was added dropwise, and the reaction mixture was stirred until complete consumption of the starting material (TLC, hexane-EtOAc = 2:1). Then, sat. aq NH₄Cl was added for quenching, and the products were extracted with EtOAc. Usual workup, followed by flash column chromatography (hexane-EtOAc = 2:1), afforded the fluorinated product 3a as a colorless oil.
Compound 3a: ¹H NMR (400 MHz, CDCl₃): δ = 1.30 (t, J = 7.1 Hz, 3 H), 1.35 (t, J = 7.1 Hz, 3 H), 4.14-4.32 (m, 4 H), 7.46-7.51 (m, 3 H), 7.63-7.68 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.1 (d, J = 4.9 Hz), 16.2 (d, J = 5.8 Hz), 65.7 (d, J = 7.4 Hz), 65.9 (d, J = 7.4 Hz), 87.6 (dd, J = 173.5, 195.8 Hz), 114.4 (d, J = 28.0 Hz), 126.0 (t-like, J = 4.9 Hz), 128. 7 (d, J = 1.6 Hz), 130.1 (dd, J = 1.7, 20.7 Hz), 130.5. ¹⁹F NMR (376 MHz, CDCl₃, std: TFA): δ = -90.95 (d, J = 87.2 Hz). HPLC (DAICEL CHIRALPAK AD-H, n-hexane-IPA = 99:1, 1.0 mL/min, 254 nm): t _R (major) = 43.0 min., t _R (minor) = 47.0 min.