Pyrido[3,2-b][1,4]oxazine and pyrido[2,3-b][1,4]benzoxazine systems from tetrafluoropyridine derivatives

Pyrido[3,2-b][1,4]oxazine and pyrido[2,3-b][1,4]benzoxazine systems were synthesised by annelation reactions involving highly fluorinated pyridine derivatives and nitrogen and oxygen centred difunctional nucleophiles by sequential regioselective nucleophilic aromatic substitution processes


Introduction
In a series of publications, a strategy of utilising highly fluorinated heteroaromatic substrates [1a,b] for the synthesis of a range of functional polycyclic scaffolds with applications in parallel synthesis programmes within the drug discovery arena [1c-f] has developed.For example, penta-and tetrafluoropyridine derivatives have been used as substrates in annelation reactions involving reaction with appropriate difunctional nucleophiles to give various tetrahydro-pyridopyrazine [2], imidazopyridine [3], dipyridoimidazole [4], furopyridine [5] and thienopyridine systems [6] that are very difficult heterocyclic scaffolds to access by conventional reported methodologies.

Results and discussion
Initially, model reactions of 4-phenylsulfonyl tetrafluoropyridine 1 and 4-cyano tetrafluoropyridine 2 with representative aliphatic and aryl nitrogen centred nucleophiles were performed before annelation reactions were attempted in order to determine the regioselectivity of S N Ar processes of these systems.
Since the nitrogen centre in N,O-centred difunctional nucleophiles can be expected to be more nucleophilic than oxygen sites in appropriate conditions, this would determine the regioselectivity of subsequent annelation processes.Reactions of 1 and 2 with diethylamine have been reported previously [2c] but these results are included here again for clarity (Scheme 1).
The regioselectivity of reactions of 1 with nitrogen centred nucleophiles (Scheme 1) depends on the nature of the substrates involved.Diethylamine gave products 3a-c arising from predominant ortho-substitution whereas aniline, a softer nucleophile, gave products 4a-d arising from a modest preference for substitution at the softer meta-fluorine site, which is still sufficiently activated towards nucleophilic attack by the presence of the adjacent phenylsulfonyl group.From these two experiments, only product 3a could be separated from the product mixtures while all other products were identified by diagnostic 19 F NMR shift data.Resonances of fluorine atoms ortho to ring nitrogen typically appear in the -66 --96 ppm range while meta fluorine occur between -135 --155 ppm.Mono-and di-substituted products were further characterised by mass spectrometry.

Scheme 1. Reactions of 1 and 2 with monofunctional nitrogen nucleophiles
Corresponding reaction of 2 with diethylamine and aniline gave products arising from initial substitution ortho to ring nitrogen in both cases (Scheme 1).All products could be isolated due to the less complex product mixtures formed and the structure of 6 was confirmed by X-ray crystallography (Fig. 1).
Crystal 6 (Fig. 1) contains two virtually identical planar (within 0.13Å) crystallographically independent molecules.The planar configuration of the molecule is probably augmented by a weak intramolecular intermolecular contacts that link two adjacent molecules into centrosymmetrical dimers (Fig. 3).
Similarly to 6, structure 8c also contains two almost identical crystallographically independent molecules.
In this case the only difference between the molecules is the orientation of the methyl groups, reflecting a non-identical crystal environment of the two molecules.In the absence of strong hydrogen bonds, the packing of molecules 8c in the crystal is dominated by π…π interactions between the heteroaromatic ring systems (the shortest corresponding interatomic contacts are N1…C4(-x,1-y,1-z) 3.502(2) and N11…C12 (x,1.5-y,-0.5+z) 3.404(2)Å) and these interactions link the molecules in columns along the [001] direction (Fig. 3).

General
All starting materials were obtained commercially and all solvents were dried using literature procedures.

X-Ray crystallography
All X-ray single crystal data were collected on a Bruker SMART CCD 6000 diffractometer (graphite monochromator, λMoKα, λ =0.71073Å) equipped with Cryostream (Oxford Cryosystems) open-flow nitrogen cryostats at the temperature of 120.0(2)K.All structures were solved by direct methods and refined by full-matrix least squares on F 2 for all data using SHELXTL software [7].All non-disordered non-hydrogen atoms were refined anisotropically and hydrogen atoms were refined isotropically.Crystal data and parameters of refinement are listed in Table 1.Crystallographic data for the structure have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 990353-990356.

2 Reactions with Aniline 3.2.1 Reaction of 1 with aniline
gas chromatograph.Elemental analyses were obtained on an Exeter Analytical CE-440 elemental analyser.Melting points and boiling points were recorded at atmospheric pressure unless otherwise stated and are uncorrected.Column chromatography was carried out on silica gel (230-400 mesh) and t.l.c.analysis was performed on silica gel t.l.c.plates.Reactions of 1 and 2 with diethylamine were reported previously [2c].3.

Table 1 .
Crystal data and parameters of refinement of the structures 6 and 8a-c.C14 H 1 F 2 N 2 O 3 S C 17 H 10 F 2 N 2 O 3 S C 9 H 7 F 2 N 3 O