Polyhalogenoheterocyclic compounds. Part 53. 1 Sonogashira reactions of 2,4,6-tribromo-3,5-difluoropyridine

Palladium catalysed Sonogashira reactions between 2,4,6-tribromo-3,5-difluoropyridine and a variety of phenylacetylene derivatives gave a series of 4-bromo-2,6-bis(2-phenylethynyl)-3,5-difluoropyridine derivatives arising from displacement of bromine atoms attached to positions ortho to ring nitrogen.


Introduction
It is now well established that the incorporation of fluorine atoms into heterocyclic molecules can have a significant effect upon the chemical and biological properties of these systems. 2,3This has been used to great effect in the development of various commercially important life-science products, such as 5-fluorouracil, 5-fluoroprimaquine and Ciprofloxacin, that owe their useful biological activity to the presence of a fluorine substituent located on the heterocyclic ring. 3owever, efficient synthesis of functional fluorinated heterocyclic derivatives is not trivial and presents a considerable challenge to the synthetic chemist. 4][7][8] Consequently, effective methodology for the synthesis of selectively fluorinated polyfunctional heterocyclic systems is an important research goal.† Dick Chambers was Chairman of the RSC Heterocyclic Group during the period 1987-1989.
In this series, we are developing the chemistry of perhalogenated heteroaromatic systems and we have demonstrated that perfluorinated heterocyclic derivatives, such as pentafluoropyridine, are very useful polyfunctional heterocyclic scaffolds 4,9 because, in principle, all of the fluorine atoms are activated towards nucleophilic attack and may be replaced by appropriate nucleophilic species. 10Related polybromofluoropyridine derivatives are, potentially, very valuable scaffolds for the synthesis of pyridine derivatives because not only are nucleophilic substitution reactions possible, involving either replacement of fluorine or bromine depending upon the nature of the nucleophile, 11 but also palladium catalysed processes involving activation of a carbon-bromine bond.We have developed efficient methodology for the synthesis of various polybromofluoroheteroaromatic systems 11 and are exploring the use of these novel scaffolds for a variety of synthetic applications.
In this paper we describe palladium catalysed Sonogashira reactions 12 of the readily prepared 2,4,6-tribromo-3,5-difluoropyridine 11 and demonstrate the use of this readily accessible system as an excellent building block for the synthesis of polyfunctional fluoropyridine derivatives.

Results and Discussion
Sonogashira reaction of 2,4,6-tribromo-3,5-difluoropyridine 1 with various phenylacetylene substrates 2a-f, in the presence of a palladium catalyst (PdCl 2 (PPh 3 ) 2 ), copper (I) iodide and either triethylamine or cesium carbonate, gave the corresponding diacetylenic pyridine systems 3a-f and these results are collated in Table 1.In all cases the isolated yields are fair and reflect the sometimes difficult purification steps required for palladium catalysed processes.We found that the reactions were not especially sensitive to the presence of either an electron releasing or withdrawing group on the aromatic ring because, in these cases, the substituents in the aryl group are relatively remote from the reaction centre.
A consideration of the generally accepted mechanism for Sonogashira reactions 12 (Scheme 1) allows us to assess the effect of using perhalogenated heterocyclic substrates as starting materials.
In the first stage, the palladium species acts as a nucleophile and reaction with an electron deficient halogenated heterocycle is, therefore, a favoured process.Insertion of the palladium nucleophile occurs at the weaker and softer carbon-bromine bond rather than at the stronger carbon-fluorine bond, at positions that are ortho to ring nitrogen.Although most other nucleophiles attack preferentially at the 4-rather than the 2-position in perhalogentated pyridines, 2,4 these insertion reactions present a further example where transition metal induced reactions give a different outcome for displacement of either fluorine or bromine in heteroaromatic systems, suggesting some involvement of charge on nitrogen in the transition state. 13,14SSN 1424-6376 Page 48

X-ray Crystallography
Single crystals of 3b, 3c and of two polymorphs of 3d (3dA and 3dB) were grown and their structures determined by X-ray analysis (Figs. 1-3).In the structures of 3b and 3c the molecules are packed in layers in which the bromine atoms are sandwiched between two heterocycles of adjacent molecules.In the case of polymorphs 3dA and 3dB, the molecules form stacks and are linked together by π−π interactions between both the terminal phenyl and heterocyclic rings.The heterocycles in the stacks are parallel to each other in the structure of 3dA and anti-parallel in the polymorph 3dB.In conclusion, palladium catalysed Sonogashira reactions involving 2,4,6-tribromo-3,5difluoropyridine give products arising from the displacement of bromine atioms located at the 2and 6-positions, ortho to ring nitrogen, further demonstrating the use of perhalogenated scaffolds for synthetic applications.