Polyhalogenated heterocyclic compounds. Part 43. Reactions of 4-lithio-2,6-dibromo-3,5 difluoro pyridine

4-Lithio-2,6-dibromo-3,5-difluoropyridine (2), readily prepared from 2,4,6-tribromo-3,5 difluoropyridine 1, reacts with a range of electrophiles to give various functionalised pyridine derivatives. A subsequent X-ray crystallographic study of 2,6-dibromo-3,5-difluoro(4-pyridyl) methylphenyl ketone 3e shows an unusual solid state lattice packing arrangement.


Introduction
The use of a variety of per-halogenated heterocyclic system in the preparation of many commercially significant plant protection agents and fibre reactive dyes, continues to provide a stimulus for the synthesis of novel polyhalogenated heterocyclic derivatives and the subsequent development of their chemistry.Whilst an extensive chemistry of perfluoro-and per-chloro-fluoro heterocyclic systems has emerged, studies concerning the synthesis and chemistry of per-bromo-fluoro heterocycles are relatively scarce.However, in an earlier paper in this series, we demonstrated that 2,4,6tribromo-3,5-difluoro pyridine 1 was a synthetically useful "building block" that could be used for the preparation of a wide range of polyhalogenated heterocyclic derivatives upon reaction with a range of hard and soft nucleophiles.In an effort to exploit the organometallic chemistry of 1, we demonstrated, in a preliminary experiment, that debromo-lithiation occurs exclusively at the 4-position and that the organolithium species 2 that is generated may be trapped by allyl bromide.
In this paper, we report further reactions of the lithio-pyridine 2 with electrophiles and, subsequently, an unusual X-ray crystal structure of a pyridyl-arene derivative prepared by such a process.

Results and Discussion
Organolithium derivative 2 is readily generated by clean reaction of 1 with n-BuLi in diethylether at low temperature.De-bromometallation occurs exclusively at the 4 position, because the carbanionic carbon atom in 2 is stabilised by the presence of two ortho fluorine substituents, rather than only one ortho fluorine atom in the case of substitution of the 2 position.Trapping of the lithium derivative 2 by a range of electrophiles occurs readily upon warming the ethereal solution to room temperature, giving the desired products 3. ( In contrast, reaction of 2 with acetyl chloride gave the bi-pyridyl derivative 4, even when a deficiency of acetyl chloride was used as the electrophilic species.A mechanism for this process is given in Scheme and indicates that intermediate ketone 5 is more reactive than acetyl chloride due to the presence of the highly electron withdrawing pyridyl ring adjacent to the carbonyl group in this system.A similar process involving a perfluoroheterocyclic lithiated system was reported by Coe during the course of this work.In summary, 2 may be trapped by a range of electrophiles leading to various products depending on the electrophilic system, thus extending the synthetic utility of perbromo-fluoro heterocycles such as 1.

X-Ray crystallography
A single crystal of 3e was grown that was suitable for X-ray crystallography.We expected to observe significant face-to-face π-π interaction between the electron poor pyridine ring and the relatively electron rich aryl ring, as is observed in many systems involving a combination of highly fluorinated aromatic derivatives and hydrocarbon aromatic systems.However, as shown in Figs. 1 and 2, the molecules in the crystal form stacks along the a direction that are arranged in a herring bone configuration in which the pyridine subunits adopt an edge-to-face Page 205  ARKAT USA, Inc configuration with the aromatic ring of the adjacent molecule.Furthermore, at first sight, it appears that face-to-face π-π interactions between adjacent pyridine rings is occurring but the calculated interplanar distance (3.68A) is too large for any such interaction to be significant.Consequently, the crystal structure observed is probably due to the adoption of the most favourable stacking arrangement and the minimisation of unfavourable electron pair interactions.

Experimental Section General Procedures.
All solvents were dried before use by literature procedures.NMR spectra were recorded on a Varian VXR 400S NMR spectrometer with tetramethylsilane and trichlorofluoromethane as internal standards and deuteriochloroform as solvent, unless otherwise stated.In 19 F NMR spectra, upfield shifts are quoted as negative.Coupling constants are given in Hz.Mass spectra were recorded a Fisons VG Trio 1000 spectrometer coupled with a Hewlett Packard 5890 series II gas chromatograph.IR spectra were recorded on a Perkin-Elmer 1600 FT IR spectrometer using KBr plates while elemental analyses were obtained on either a Perkin-Elmer 240 or a Carlo Erba Elemental Analyser.Melting points were recorded at atmospheric pressure and are uncorrected.Column chromatography was performed on silica gel (Merck no. 1-09385)and TLC analysis was performed on silica gel TLC plates (Merck).2,4,6-Tribromo-3,5-difluoropyridine was synthesised according to the literature procedure.