trifluoropropanoyl chloride 4 followed by formation of
enamine 7. No further reaction is observed until 85 °C where
enamine 7 is converted to vinamidinium salt 818 with a t1/2
) 120 min (Scheme 3).
cafluorooctanoic acid25 12 with 1 equiv of POCl3 in DMF
at 60-85 °C, the vinamidinium 8 was obtained in 20% assay
yield26 and perfluorohexanoic acid 16 was observed by
LCMS and 19F NMR spectroscopy.27
Scheme 3. Conversion of Enamine 7 to Vinamidinium Salts 8
and 1
Scheme 4. Conversion of Perfluorooctanoic Acid 12 to
Perfluorohexanoic Acid 16
Examination of the DMF solution by 31P and 19F NMR
spectroscopy revealed the formation of a range of fluoro-
-
substituted phosphate anions, including PF6 , demonstrating
This intriguing mechanistic departure from the expected
reactivity suggests that two key parameters are the concen-
tration of Vilsmeier reagent and the reaction temperature.
At high concentrations of Vilsmeier reagent and low tem-
peratures, the enamine 7 is converted to 3c. The small amount
of 1 observed in the synthesis of 3c is likely the result of
the exotherm produced upon rapid addition of POCl3 to
DMF. After reaction at 85 °C, the bis-hexafluorophosphate
1d may be isolated in 67% yield, although the process clearly
remains to be optimized in order to maximize recovery.28
that phosphorus serves as a fluoride scavenger in the
reaction.19 Vinamidinium 8 can be converted to the dim-
ethylaminomethylene vinamidinium 1 by addition of a
second equivalent of POCl3 with a t1/2 < 10 min (60 °C).
Consistent with this observation, independent reaction of 8
with 1 equiv of POCl3 in DMF gave 1d in a quantitative
assay yield and in an unoptimized 87% isolated yield.
Remarkably, this is the first report of the direct formylation
of a Vinamidinium salt.20
The conversion of 7 to 8 is formally the result of CF3 loss
coupled with the addition of 1 equiv of Vilsmeier. We
propose the mechanism outlined in Scheme 3 to rationalize
these observations. Thermally induced elimination of fluo-
ride21 yields a gem-difluoride iminium 9, which undergoes
a [2 + 2] cycloaddition with DMF to give 10.22 Subsequent
bond reorganization via a retro [2 + 2] liberates difluoro-
carbonyl 11 to produce 8. We were unable to detect carbonyl
difluoride in the reaction mixture presumably due to its
volatility23 or reactivity.24 However, upon reaction of tride-
(22) A [2 + 2] cycloaddition of DMF and F2CdC(CF3)C(O)F liberating
carbonyldifluoride and Me2NC(H)dC(CF3)C(O)F has been reported: En-
gland, D. C.; Solomon, L.; Krespan, C. G. J. Fluor. Chem. 1973, 3, 63.
For additional [2 + 2] reactions of fluoro-olefins and DMF with the
extrusion of carbonyldifluoride, see: England, D. C. Angew. Chem., Intl.
Ed. Engl. 1973, 12, 1023.
(23) Bp -83 °C. Franz, R. J. Fluor. Chem. 1980, 15, 423.
(24) Carbonyldifluoride reacts with DMF to give difluoromethylamine
in 80% yield: Brauer, D. J.; Buerger, H.; Grunwald, M.; Pawelke, G.; Wilke,
J. Z. Anorg. Allg. Chem. 1986, 537, 63.
(25) Achilefu, S.; Mansuy, L.; Selve, C.; Thiebaut, S. J. Fluor. Chem.
1995, 70, 19.
(26) Dication 1 is also observed in ∼10% yield.
(27) The identity of the undecafluorohexanoic acid 16 was confirmed
by comparison with an authentic sample obtained from TCI.
(13) ReactIR 4000, ASI Mettler Toledo. Please note that etching of the
IR probe was observed during this study.
(14) Raman Holoprobe, Kaiser Optical Systems, Inc., Ann Arbor, MI.
(15) Xiao, L.; Kitazume, T. J. Fluor. Chem. 1997, 86, 99.
(16) Cullen, W. R.; Dawson, D. S.; Styan, G. E. Can. J. Chem. 1965,
43, 3392.
(28) To a solution of trifluoropropanoic acid (5.3 g, 0.041 mol) in DMF
(50 mL) at 60 °C was added POCl3 over 15 min while maintaining the
temperature below 65 °C. After the addition was complete, the mixture
was heated to 75 °C and POCl3 (6 mL, 0.05 mol) was added while
maintaining the temperature below 85 °C. The mixture was heated for 6 h
and cooled. The dark red DMF solution was added to a solution of sodium
hexafluorophosphate (9.2 g, 0.06 mol) in water (100 mL) while maintaining
the temperature below 15 °C. The slurry was aged for 30 min at 5-10 °C,
filtered washing with 5:1 water/DMF, and dried to give 1d as an off-white
solid (13.2 g, 67%): DSC, peak 212.3 °C 1H NMR (400 MHz CD3CN) δ
8.02 (1H, s), 3.53 (3H, s), 2.89 (3H, s); 13C NMR (100 MHz CD3CN) δ
165.7, 92.1, 50.5, 44.6; 19F NMR (376 MHz, CD3CN) δ -73.3 (d, J )
709 Hz). Anal. Calcd for C10H21F12N3P2: C, 25.38; H, 4.47; N, 8.88; P,
13.09. Combustion analysis found: C, 25.50; H, 4.33. ICP-AES analysis,
found: P, 12.86. Compound 1e was prepared analogously using sodium
tetrafluoroborate: colorless solid; DSC, peak 216.0 °C; 1H NMR (400 MHz
CD3CN) δ 8.05 (1H, s), 3.51 (3H, s), 2.89 (3H, s); 13C NMR (100 MHz
(17) Allen, A. D.; Andraos, J.; Kresge, A. J.; McAllister, M. A.; Tidwell,
T. T. J. Am. Chem. Soc. 1992, 114, 1878.
(18) Davies, I. W.; Taylor, M.; Marcoux, J. F.; Wu, J.; Dormer, P. G.;
Hughes, D.; Reider, P. J. J. Org. Chem. 2001, 66, 251.
(19) The exact identity of all the counteranions produced in the reaction
is unclear, although PF6- is clearly a major component by NMR (19F NMR
(376 MHz, CD3CN) δ -73.3 (d, J ) 709 Hz). Quench into excess NaBF4
leads to 1:1 salt 1e.
(20) Mannich reaction of 1,4-diazapenium has been noted: Mohrle, H.;
von der Lieck-Waldheim, U. Z. Naturforsch. Sect. B 1996, 51, 421.
(21) Use of fluoride abstracting agents at, e.g., AgOAc, AgOTf, TMSCl
and BF3, did not improve the yield of 8 substantially.
Org. Lett., Vol. 4, No. 17, 2002
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