Polyhalogenated heterocyclic compounds. Part 44. 1 Reactions of perfluoro-(4-isopropylpyridine) with oxygen nucleophiles

Reactions between perfluoro-(4-isopropyl pyridine) 1 and a variety of oxygen nucleophiles gave mono, di-and tri-alkoxylated systems depending on reaction conditions. The barrier to rotation for the perfluoro-isopropyl group in several pyridine systems was measured by 19 F n.m.r. saturation transfer experiments.


Introduction
In earlier parts of this series, 1 we have described chemistry of a range of highly fluorinated heterocyclic systems including perfluoroalkylation reactions of fluoroheterocycles, which involve the trapping of perfluorinated carbanions.These carbanions are generated by addition of fluoride ion to fluoro-alkenes, and, therefore, in principle, a range of perfluoroalkylated heterocyclic derivatives may be obtained. 2,3However, the development of the chemistry of perfluoro-(alkylheterocycles), which were first synthesised some time ago, 2 has been severely hampered by the lack of efficient isolation techniques for realistic large scale synthesis.Consequently, only a few examples of reactions involving perfluoro-(alkylheterocycles) have been reported 2,4,5 which include various novel photochemical rearrangements 6 and the formation of remarkably stable valence isomers. 7ecently, we reported new methodology 8 for the synthesis and isolation of perfluoro-(isopropylheterocycles), which allows efficient scale up.Consequently, a wider exploration of the chemistry of these systems is now feasible.
In general, there is continued interest in the introduction of perfluoroalkyl groups into organic molecules due to, for example, the modification of surface properties and the increased lipophilicity that such groups can impart upon a wide range of substrates.These effects are exemplified by the range of surfactants and textile treatment agents bearing perfluoroalkyl groups that are currently commercially available. 9In particular, heterocyclic systems possessing perfluoroalkyl substituents (principally trifluoromethyl derivatives) are useful intermediates, for example, in the pharmaceutical and plant protection industries. 9Such factors, therefore, provide a stimulus to explore the chemistry of perfluoroalkylated heterocyclic systems and consequently, in this paper, we report our studies concerning reactions of a model perfluoroalkylated heterocyclic system, perfluoro-4-isopropyl pyridine 1, with a range of oxygen nucleophiles.

Results and Discussion
Following the procedures that we described previously, 8 1 was synthesised in good yield, on a large scale, by reaction of pentafluoropyridine with hexafluoropropene using a tertiary amine, tetrakis-(dimethylamino)ethene (TDAE), as a catalyst to generate active fluoride ion (Scheme 1).The reaction was carried out in the absence of solvent making product isolation easy.

Scheme 1
The site of nucleophilic substitution was regioselective at the 4-position of the pyridine ring, consistent with earlier observations.

Scheme 2
Reaction of 1 with a series of alkoxide ions in an appropriate solvent (MeOH or THF) gave mono, di and tri alkoxylated products 2, 3 and 4 in ratios that depend on the reaction stoichiometry (Table 1).Nucleophilic substitution of fluorine by alkoxide occurs initially at the 2-position, as established by n.m.r.studies and consistent with literature data. 2 Disubstituted products 3 gave 19 F n.m.r.spectra which exhibited only one resonance corresponding to ring-fluorine, in the range -145 --150 ppm, consistent with the presence of fluorine at the 3 and 5 positions and confirming the symmetrical nature of the 2,6-disubstituted pyridine system.Of course, if the second alkoxide nucleophilic substitution had occurred at the 5-position, two separate resonances corresponding to 3-and 6-ring fluorine atoms would have been observed, and this is clearly not the case here.Alkoxy groups present in the 3 position in 4a and 4b further hinder rotation of the sterically demanding perfluoroisopropyl group and both rotamers, A and B, are observed in the 19 F n.m.r.spectrum of 4a and 4b even at room temperature.
Coupling between the ring fluorine at the 5-position with the tertiary fluorine atom (CF-CF3) is very large (approx.94 Hz) in conformer B (Scheme 3) because, in this case, the two fluorine atoms can adopt a conformation which maximises 'through-space' interactions, whereas corresponding coupling is absent in conformer A.
Rates of exchange at various temperatures and the activation energies required for the rotation of the perfluoroisopropyl group between rotamers A and B were measured by 19 F n.m.r.saturation transfer experiments, involving irradiation of the resonance arising from the ring fluorine atom in 1, 4a and 4b.Activation energies for rotation of the perfluoroisopropyl group were calculated to be 100.3kJ mol -1 for 4a, 81.0 kJ mol -1 for 4b and 35.7 kJmol -1 for 1, reflecting the increased steric hindrance to rotation imparted by the methoxy and phenoxy groups compared to fluorine in this situation.The studies outlined above demonstrate that 1 is a di-or tri-functional electrophile and, in principle, could be used as a 'building block' for the synthesis of a variety of supramolecular and polymer systems upon reaction with an appropriate di-nucleophile (e.g. a diol).
Reaction of 1 with the disodium salt of resorcinol gave largely intractable material.However, fluoride ion promoted desilylation methodology, 11 which allows the formation of alkoxide ions according to Scheme 4, was successful because, for example, reaction of 1,3bis(trimethylsiloxy)benzene with 1 gave high yields of the dipyridyl system 5a (Scheme 5). ROH In summary, perfluoroisopropyl pyridine 1 reacts very efficiently with a range of mono-and di-functional oxygen nucleophiles.Extension of similar chemistry to the synthesis of a range of macrocyclic and polymeric systems will be described in future publications.

Experimental Section
General Procedures.All starting materials were obtained commercially (Aldrich, Lancaster or Fluorochem) and all solvents were dried using literature procedures.NMR spectra were recorded in deuteriochloroform, unless otherwise stated, on a Varian VXR 400S NMR spectrometer with tetramethylsilane and trichlorofluoromethane as an internal standards.Mass spectra were recorded on a Fisons VG-Trio 1000 Spectrometer coupled with a Hewlett Packard 5890 series II gas chromatograph using a 25m HP1 (methyl -silicone) column.Elemental analyses were obtained on a Exeter Analytical CE-440 elemental analyser.Melting points and boiling points were recorded at atmospheric pressure unless otherwise stated and are uncorrected.The progress of reactions were determined by either 19 F-NMR or gaschromatography on an Shimadzu GC8A system using an SE30 column.Distillation was performed using a Fischer Spaltrühr MS220 microdistillation apparatus.Column chromatography was carried out on silica gel (Merck no.109385, particle size 0.040-0.063nm)and TLC analysis was performed on silica gel TLC plates.