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.

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

References and Notes

1a Kirsch P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications   Wiley-VCH; Weinheim: 2004. 

1b Hiyama T. Kanie K. Kusumoto T. Morizawa Y. Shimizu M. Organofluorine Compounds: Chemistry and Applications   Springer; Berlin: 2000. 

1c Biomedical Frontiers of Fluorine Chemistry   Ojima I. McCarthy JR. Welch JT. ACS Symposium Series 639, American Chemical Society; Washington/DC: 1996. 

2a Asymmetric Fluoroorganic Chemistry: Synthesis, Application, and Future Directions   Ramachandran PV. ACS Symposium Series 746, American Chemical Society; Washington/DC: 2000. 

2b Mikami K. Itoh Y. Yamanaka M. Chem. Rev.  2004,  104:  1 

2c Iseki K. Tetrahedron  1998,  54:  13887 

3a Ibrahim H. Togni A. Chem. Commun.  2004,  1147 

3b Ma J.-A. Cahard D. Chem. Rev.  2004,  104:  6119 

3c Pihko PM. Angew. Chem. Int. Ed.  2006,  45:  544 

4a Hintermann L. Togni A. Angew. Chem. Int. Ed.  2000,  39:  4359 

4b Kim DY. Park EJ. Org. Lett.  2002,  4:  545 

4c Ma J.-A. Cahard D. Tetrahedron: Asymmetry  2004,  15:  1007 

4d Shibata N. Kohno J. Takai K. Ishimaru T. Nakamura S. Toru T. Kanemasa S. Angew. Chem. Int. Ed.  2005,  44:  4204 

4e Kim HR. Kim DY. Tetrahedron Lett.  2005,  46:  3115 

4f Bernardi L. Jørgensen KA. Chem. Commun.  2005,  1324 

4g Kim SM. Kim HR. Kim DY. Org. Lett.  2005,  7:  2309 

4h Suzuki S. Furuno H. Yokoyama Y. Inanaga J. Tetrahedron: Asymmetry  2006,  17:  504 

5a Enders D. Hüttl MRM. Synlett  2005,  991 

5b Marigo M. Fielenbach D. Braunton A. Kjærsgaard A. Jørgensen KA. Angew. Chem. Int. Ed.  2005,  44:  3703 

5c Steiner DD. Mase N. Barbas CF. Angew. Chem. Int. Ed.  2005,  44:  3706 

5d Beeson TD. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  8826 

5e Huang Y. Walji AM. Larsen CH. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  15051 

6a Hamashima Y. Yagi K. Takano H. Tamás L. Sodeoka M. J. Am. Chem. Soc.  2002,  124:  14530 

6b Hamashima Y. Suzuki T. Takano H. Shimura Y. Tsuchiya Y. Moriya K. Goto T. Sodeoka M. Tetrahedron  2006,  62:  7168 

6c Hamashima Y. Takano H. Hotta D. Sodeoka M. Org. Lett.  2003,  5:  3225 

6d Hamashima Y. Suzuki T. Shimura Y. Shimizu T. Umebayashi N. Tamura T. Sasamoto N. Sodeoka M. Tetrahedron Lett.  2005,  46:  1447 

6e Suzuki T. Goto T. Hamashima Y. Sodeoka M. J. Org. Chem.  2007,  72:  246 

6f Hamashima Y. Suzuki T. Takano H. Shimura Y. Sodeoka M. J. Am. Chem. Soc.  2005,  127:  10164 

6g For preparation of the Pd complexes, see: Fujii A. Hagiwara E. Sodeoka M. J. Am. Chem. Soc.  1999,  121:  5450 

7 Hamashima Y. Sodeoka M. Synlett  2006,  1467 

8 α-Fluorophosphonates have been used as mimics of a phosphate moiety. For a general review, see: Berkowitz DB. Bose M. J. Fluorine Chem.  2001,  112:  13 

Ru:

9a Murahashi S.-I. Naoto T. Taki H. Mizuno M. Takaya H. Komiya S. Mizuno Y. Oyasato N. Hiraoka M. Hirano M. Fukuoka A. J. Am. Chem. Soc.  1995,  117:  12436 

Rh:

9b Sawamura M. Hamashima H. Ito Y. J. Am. Chem. Soc.  1992,  114:  8295 

9c Kuwano R. Miyazaki H. Ito Y. J. Organomet. Chem.  2000,  603:  18 

Pd:

9d Takenaka K. Uozumi Y. Org. Lett.  2004,  6:  1833 ; and references therein

10 Iorga B. Ricard L. Savignac P. J. Chem. Soc., Perkin Trans. 1  2000,  3311 

11

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

Effective combination of Lewis acids and amines were previously reported. For examples, see:

12a Itoh K. Kanemasa S. J. Am. Chem. Soc.  2002,  124:  13394 

12b Barnes DM. Ji J. Fickes MG. Fitzgerald MA. King SA. Morton HE. Plagge FA. Preskill M. Wagaw SH. Wittenberger SJ. Zhang J. J. Am. Chem. Soc.  2002,  124:  13097 

12c Kumagai N. Matsunaga S. Shibasaki M. J. Am. Chem. Soc.  2004,  126:  13632 

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.

14 For preparation of racemic α-fluoro-α-cyanophosphonates by phosphorylation reaction, see: Yokoyama Y. Mochida K. Synthesis  1999,  1319