[309-88-6]  · C7H11F6N  · Diethyl(1,1,2,3,3,3-hexafluoropropyl)amine  · (MW 223.16)

(conversion of the hydroxy group of alcohols to the fluoro group; preparation of 2,3,3,3-tetrafluoropropionate esters and other fluorine-containing carbonyl compounds)

Alternate Names: PPDA; Ishikawa reagent.

Physical Data: bp 56-57 °C/58 mmHg, 51 °C/40 mmHg.

Solubility: sol diethyl ether.

Analysis of Reagent Purity: 19F NMR (see Takaoka et al.).2

Preparative Methods: diethyl(1,1,2,3,3,3-hexafluoropropyl)amine, commonly called the perfluoropropene-diethylamine adduct (PPDA) or the Ishikawa reagent, is readily prepared in yields of 72-89% by reaction of hexafluoropropene (F-propene) with diethylamine in diethyl ether solution (eq 1).2,3 The reaction is conducted in a glass pressure vessel cooled to -70 °C and liquefied F-propene is added to the amine-ether solution. The mixture is brought to rt overnight and worked up. The resulting product is a 3:1 molar mixture of the fluoroalkylamine and the (E)-fluoroenamine (established by 19F NMR), bp 56-57 °C/58 mmHg. When prepared by bubbling F-propene into Et2NH-Et2O at 0-5 °C, the reagent with molar ratio 1:1, bp 51 °C/40 mmHg, is obtained.3 The reagent may be used directly, without distillation.

Handling, Storage, and Precautions: after distillation, the oil may be stored in a tightly stoppered vessel at or below rt. Only a slight discoloration is observed after six months. The reagent should be handled in a fume hood.

Conversion of Alcohols to Alkyl Fluorides.

The typical reaction of this reagent is the one-step conversion of alcohols to the corresponding fluoro compounds with concomitant formation of tetrafluorodiethylpropionamide (eq 2).2 Similarly, acyl fluorides are readily obtained from carboxylic acids (eq 3).2 The reaction is markedly enhanced when Sodium Fluoride is added as a scavenger for the liberated HF.3 The pure (E)-fluoroenamine, prepared by another route, shows no fluorinating ability.

Primary alcohols react with the reagent at rt with diethyl ether as solvent during 6-20 h to give the corresponding alkyl fluorides in yields of 50-89%.2,4,5 With benzyl alcohol, a 25% yield of dibenzyl ether is also obtained.2 Secondary and tertiary alcohols give generally good yields of fluoride (55-80%), but significant amounts of alkenes and dialkyl ethers (formed via carbocation intermediates) are also isolated. Thus 2-octanol affords 62% 2-fluorooctane and 25% of a mixture of trans-2-octene, cis-2-octene, and 1-octene (4:3:1). In MeCN as solvent the yield of alkene exceeds 50%. While cholesterol in CH2Cl2 at 0-5 °C gives 83% of fluoride, borneol forms a rearranged fluoride and camphene. Notably, t-butyl alcohol in CCl4 yields 78% of t-butyl fluoride and 9% of isobutene. 1-Adamantanol in THF gives 81% of 1-fluoroadamantane (eq 4).2 Several mechanisms, involving SN1 and SN2 processes, have been proposed to account for the observed products (eq 5).2

Aliphatic bromo- and chloro-substituted alcohols react with PPDA to give 40-70% yields of the corresponding fluorides.4 However, cyclic halogenated alcohols provide very little fluoride but, primarily, tetrafluoropropionate esters. Thus 3-bromoborneol affords the fluoro ester in 65% (eq 6). A suggested mechanism for this side reaction involves the formation of an aminoacetal which undergoes fragmentation with HF (eq 7).4

a,b-Unsaturated alcohols do not give the corresponding fluorides with PPDA because undesirable reactions, such as isomerization, cyclization, and dehydration, may occur in the presence of the HF produced by fluorination. In order to obviate these side reactions, Diisopropylethylamine is added to neutralize the HF. Under these conditions, geraniol is converted into geranyl 2,3,3,3-tetrafluoropropionate in 41% yield (eq 8). No fluoride is isolated.6

Long-chain alcohols provide fluorides and esters on treatment with PPDA.7 For example, lauryl alcohol forms Me(CH2)10CH2F (45%) and Me(CH2)10CH2O2CCHFCF3 (22%). 1,2-Diols yield dioxolanes and 1,3-diols give dioxanes on reaction with PPDA.8 The use of THF, instead of Et2O or CH2Cl2, is essential to mitigate side reactions. Eq 9 illustrates the reaction with 1,3-propanediol. Monoesters of ethylene glycol and PPDA provide a mixture of fluoro ester and diester (eq 10).9 a-Hydroxy carboxylic acids, such as mandelic acid,10 and esters11,12 are readily fluorinated in 50-70% yields to the a-fluoro carboxylates. The reaction proceeds with inversion of configuration, as evidenced by the conversion of (R)-(-)-mandelic acid ethyl ester to (S)-(+)-2-fluoro-2-phenyl acetate with 74% ee.

Miscellaneous Applications.

The tetrafluoropropionamide obtained by hydrolysis of PPDA reacts with ArMgX to yield ArCOCHFCF3 and, subsequently, ArCOCHFCO2R.13 PPDA serves as a useful dehydrating agent for the synthesis of alkynic ketones from b-diketones in the presence of freeze-dried Potassium Fluoride in MeCN.14 Monofluorocarboxylic acids are prepared using PPDA, directly from hydroxy esters, or indirectly from monofluorinated alkylbenzenes, followed by oxidation of the phenyl ring to -CO2H.15 PPDA and ureas form an intermediate which undergoes cyclization in ROH to yield 6-alkoxy-1-alkylfluorocytosines.1 o-Bifunctional benzenes give heterocycles on reaction with PPDA.1

Related Reagents.


1. While there has been no comprehensive review of this reagent, a reasonably good summary is: Takaoka, A.; Iwakiri, H.; Fujiwara, N.; Ishikawa, N. Nippon Kagaku Kaishi 1985, 2161 (CA 1987, 107, 58 961h). An excellent introduction can be found in Ref. 2.
2. Takaoka, A.; Iwakiri, H.; Ishikawa, N. BCJ 1979, 52, 3377.
3. Cox, D. G.; Sprague, L. G.; Burton, D. J. JFC 1983, 23, 383.
4. Watanabe, S.; Fujita, T.; Usui, Y.; Kimura, Y.; Kitazume, T. JFC 1986, 31, 135.
5. Watanabe, S.; Fujita, T.; Sakamoto, M.; Endo, H.; Kitazume, T. JFC 1988, 38, 243.
6. Watanabe, S.; Fujita, T.; Sakamoto, M.; Kitazume, T. JFC 1988, 39, 17.
7. Watanabe, S.; Fujita, T.; Suga, K.; Nasuno, I. J. Am. Oil Chem. Soc. 1983, 60, 1678 (CA 1984, 100, 22 317u).
8. Watanabe, S.; Fujita, T.; Suga, K.; Nasuno, I. S 1984, 31.
9. Watanabe, S.; Fujita, T.; Sakamoto, M.; Kuramochi, T.; Kitazume, T. JFC 1987, 36, 361.
10. Cantrell, G. L.; Filler, R. JFC 1985, 27, 35.
11. Watanabe, S.; Fujita, T.; Usui, Y.; Kitazume, T. JFC 1986, 31, 247.
12. Watanabe, S.; Fujita, T.; Sakamoto, M.; Endo, H.; Kitazume, T. JFC 1990, 47, 187.
13. Ishikawa, N.; Takaoka, A.; Iwakiri, H.; Kubota, S.; Kagaruki, S. R. F. CL 1980, 1107.
14. Kitazume, T.; Ishikawa, N. CL 1980, 1327.
15. O'Hagan, D. JFC 1989, 43, 371.

Robert Filler

Illinois Institute of Technology, Chicago, IL, USA

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