Radical Conjugated Addition: Addition of Dialkyl Phosphonodifluoromethyl Radical onto Unsaturated Ketones

Abstract

The free radical addition of phosphonodifluoromethyl radical is reported from iodophosphonate and sodium dithionite, triethylborane, or dilauroyl peroxide as initiator. Triethylborane promoted the radical conjugated addition onto enones.

Key words

radical reaction - fluorine - enone - phosphonate - alkene

References and Notes

• 1a Blackburn GM. England DA. Kolkmann F. J. Chem. Soc., Chem. Commun.  1981,  930 
• 1b Blackburn GM. Kent DE. Kolkmann F. J. Chem. Soc., Perkin Trans. 1  1984,  1119 
• 1c Thatcher GR. Campbell AS.
  J. Org. Chem.  1993,  58:  2272 
• 1d Chambers RD. O’Hagan D. Lamont RB. Jain SC. J. Chem. Soc., Chem. Commun.  1990,  1053 
• 1e Kim CU. Luh BY. Misco PF. Bronson JJ. Hitchcock MJM. Ghazoulli I. Matin JC. J. Med. Chem.  1990,  33:  1207 
• 1f Smyth MS. Ford H. Burke TR. Tetrahedron Lett.  1992,  33:  4137 
• 1g Jakeman DL. Ivory AJ. Williamson MP. Blackburn GM. J. Med. Chem.  1998,  41:  4439 
• 1h Berkowitz DB. Bose M. Pfannenstiel TJ. Doukov T. J. Org. Chem.  2000,  65:  4498 
• 1i Berkowitz DB. Bose M. J. Fluorine Chem.  2001,  112:  13 
• 1j O’Hagan D. Rzepa HS. Chem. Commun.  1997,  645 
• 2a Yang Z.-Y. Burton DJ. J. Org. Chem.  1991,  56:  5125 
• 2b Julià L. Bosch MP. Rodriguez S. Guerrero A.
  J. Org. Chem.  2000,  65:  5098 
• 2c Sato K. Nakazato S. Enko H. Tsujita H. Fujita K. Yamamoto T. Omote M. Ando A. Kumadaki I. J. Fluorine Chem.  2003,  121:  105 
• 2d Sato K. Omote M. Ando A. Kumadaki I. J. Fluorine Chem.  2004,  125:  509 
• 2e Xiao F. Wu F. Shen Y. Zhou L. J. Fluorine Chem.  2005,  126:  63 
• 2f Ghattas W. Hess CR. Iacazio G. Hardré R. Klinman JP. Réglier M.
  J. Org. Chem.  2006,  71:  8618 
• 2g Moreno B. Quehen C. Rose-Hélène M. Leclerc E. Quirion J.-C. Org. Lett.  2007,  9:  2477 
• 2h Yang X. Yuan W. Gu S. Yang X. Xiao F. Shen Q. Wu F. J. Fluorine Chem.  2007,  128:  540 
• 2i Godineau E. Schenk K. Landais Y. J. Org. Chem.  2008,  73:  6983 
• 2j Leung L. Linclau B. J. Fluorine Chem.  2008,  129:  986 
• 3a Yang Z. Burton DJ. Tetrahedron Lett.  1991,  32:  1019 
• 3b Yang Z. Burton DJ. J. Org. Chem.  1992,  57:  4676 
• 4 Hu C. Chen J. J. Chem. Soc., Perkin Trans. 1  1993,  327 
• 5a Lequeux T. Lebouc F. Lopin C. Yang H. Gouhier G. Piettre S. Org. Lett.  2001,  3:  185 
• 5b Pignard S. Lopin C. Gouhier G. Piettre SR. J. Org. Chem.  2006,  71:  31 
• 5c Murakami S. Kim S. Ishii H. Fuchigami T. Synlett  2004,  815 
• 6a Huang B. Wu F. Zhou C. J. Fluorine Chem.  1995,  75:  1 
• 6b Wu F. Huang B. Lu L. Huang W. J. Fluorine Chem.  1996,  80:  91 
• 6c Petrik V. Cahard D. Tetrahedron Lett.  2007,  48:  3327 
• 6d Li Y. Li H. Hu J. Tetrahedron  2009,  65:  478 
• 7 Li A. Chen Q. Synthesis  1996,  606 
• 8 Yang X. Zhu Y. Fang X. Yang X. Wu F. Shen Y.
  J. Fluorine Chem.  2007,  128:  174 
• 9 Nair KD. Guneratne RD. Modak AS. Burton DJ.
  J. Org. Chem.  1994,  59:  2393 
• 10 Henry-dit-Quesnel A. Toupet L. Pommelet J.-C. Lequeux T. Org. Biomol. Chem.  2003,  1:  2486 
• 12 Xu Y. Prestwich GD. Org. Lett.  2002,  4:  4021 
• 13 Li Y. Liu J. Zhang L. Zhu L. Hu J. J. Org. Chem.  2007,  72:  5824 
• 14 Chambers RD. Jaouhari R. O’Hagan D. Tetrahedron  1989,  45:  5101 
• 15a Quiclet-Sire B. Zard SZ. J. Am. Chem. Soc.  1996,  118:  9190 
• 15b Studer A. Amrein S. Synthesis  2002,  835 
• 15c Jean-Baptiste L. Yemets S. Legay R. Lequeux T.
  J. Org. Chem.  2006,  71:  2352 
• 16a Buttle LA. Motherwell WB. Tetrahedron Lett.  1994,  35:  3995 
• 16b Dolbier WR. Chem. Rev.  1996,  96:  1557 
• 17 Srikanth GSC. Castle SL. Tetrahedron  2005,  61:  10377 
• 18a Lequeux TP. Percy JM. J. Chem. Soc., Chem. Commun.  1995,  2111 
• 18b Kawamoto AM. Campbell MM. J. Chem. Soc., Perkin Trans. 1  1997,  1249 
• 18c Murano T. Muroyama S. Yokomatsu T. Shibuya S. Synlett  2002,  1657 
• 18d Hikishima S. Isobe M. Koyanagi S. Soeda S. Shimeno H. Sibuya S. Yokomatsu T. Bioorg. Med. Chem.  2006,  14:  1660 

11

The elimination of HI was also observed when crude 5b was treated with DBU in CH₂Cl₂ over 2 h at 20 ˚C.

19

Typical Procedure for the Synthesis of Phosphonate 12a
To a solution of the 2-cyclohexenone (0.073 mL, 0.76 mmol) and iodo-difluoromethylphosphonate 2 (200 mg, 0.58 mmol) in CH₂Cl₂ (5 mL) at 20 ˚C under N₂ was slowly added a solution of Et₃B (0.058 mL, 1 M in n-hexane). Addition of Et₃B (5 × 0.058 mL) was realized every 1 h until complete consumption of the iodophosphonate. After 6 h under stirring, the solvents were evaporated under reduced pressure, and the crude mixture was purified by flash column chromatography (n-C₅H₁₂-EtOAc, 3:2) to afford the phosphonoketone 12a (125 mg, 69%). ^¹H NMR (250 MHz, CDCl₃): δ = 1.30 (d, ^³ J _HH = 6.2 Hz, 12 H), 1.53-1.67 (m, 2 H), 2.05-2.61 (m, 7 H), 4.78 (dsept, ^³ J _HH = ^³ J _HP = 6.2 Hz, 2 H). ^¹9F NMR (235 MHz, CDCl₃): δ = -115.7 (ddd, ^² J _FF = 299 Hz, ^² J _FP = 108 Hz, ^³ J _FH = 13 Hz), -118.14 (ddd, ^² J _FF = 299 Hz, ^² J _FP = 108 Hz, ^³ J _FH = 13 Hz). ^³¹P NMR (101 MHz, CDCl₃): δ = 4.64 (t, ^² J _PF = 108 Hz). ^¹³C (63 MHz, CDCl₃):
δ = 23.7 (m, i-Pr and CH₂), 24.0 (d, ^³ J _CP = 2.5 Hz, i-Pr), 24.2 (s, CH₂), 39.8 (dt, ^³ J _CF = ^³ J _CP = 4.6 Hz, CH₂), 40.9 (s, CH₂), 42.8 (dt, ^² J _CF = 20.6 Hz, ^² J _CP = 15.3 Hz, CH), 73.8 (d, ^² J _CP = 3.0 Hz, i-Pr), 73.9 (d, ^² J _CP = 3.0 Hz, i-Pr), 121.9
(dt, ^¹ J _CF = 263.0 Hz, ^¹ J _CP = 214.0 Hz, CF₂), 208.9 (s, CO). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₂₄F₂O₄P: 313.1380; found: 313.1366.
Phosphonate 12b: ^¹H NMR (250 MHz, CDCl₃): δ = 1.31 (d, ^³ J _HH = 6.2 Hz,12 H), 1.97-2.38 (m, 6 H), 2.84-2.91 (m, 1 H), 4.80 (dsp, ^³ J _HH = ^³ J _HP = 6.2 Hz, 2 H). ^¹9F NMR (235 MHz, CDCl₃): δ = -119.04 (ddd,^² J _FF = 298 Hz, ^² J _FP = 101 Hz, ^³ J _FH = 15 Hz), -117.10 (ddd, ^² J _FF = 298 Hz, ^² J _FP = 101 Hz, ^³ J _FH = 17 Hz). ^³¹P NMR (101 MHz, CDCl₃): δ = 4.79 (t, ^² J _PF = 108 Hz). ^¹³C (63 MHz, CDCl₃): δ = 22.1 (dt, ^³ J _CF = ^³ J _CP = 5.1 Hz, CH₂), 23.7 (d, ^³ J _CP = 4.2 Hz, i-Pr), 24.0 (d, ^³ J _CP = 3.3 Hz, i-Pr), 37.5 (s, CH₂), 38.1 (dt, ^³ J _CF = ^³ J _CP = 3.0 Hz, CH₂), 40.5 (dt, ^² J _CF = 21.4 Hz, ^² J _CP = 15.2 Hz, CH), 73.8 (d, ^² J _CP = 7.2 Hz, i-Pr), 73.81 (d, ^² J _CP = 7.1 Hz, i-Pr), 119.9 (dt, ^¹ J _CF = 262.0 Hz, ^¹ J _CP = 217.0 Hz, CF₂), 215.8 (s, CO). ESI-HRMS: m/z [M + H]⁺ calcd for C₁₂H₂₂F₂O₄P: 299.1224; found: 299.1213.