The synthesis of potential DNA intercalators. Part 3. Triazanaphthalenes, tetraaza-anthracenes and - phenanthrenes from isoxazolones

The reaction of bis-isoxazolinyl pyrimidines and pyridazines with bases leads to a novel synthesis of tri-and tetra azaheterocycles, capable of intercalation with DNA


Introduction
We have previously shown 1,2 that 2-isoxazolinyl azaheterocycles undergo rearrangement in the presence of bases, resulting in the annulation of a pyrimidine ring onto the azaheterocycle (Scheme 1).By contrast, the use of triethylamine, 3 photolysis 4 or pyrolysis 5 led to annelation of an imidazole ring onto the azaheterocycle (Scheme 1).

Scheme 1
This work was extended to the reaction of bis-isoxazolinyldiazaheterocyclic systems, 2 in which the rearrangements underwent more complex, but mechanistically consistent, pathways (Scheme 2).

Scheme 2
When the isoxazoline moiety contained an arylamino group at C-3, 6,7 base induced rearrangements led to competitive cyclisation through the arylamino group or the azaheterocycle, depending on the nucleophilicity of the latter (Scheme 3).Since imidazo [1,2-a]azaheterocycles such as those in Scheme 3 above may be converted to larger heterocycles that can be expected to intercalate with DNA because of their H-bonding donor and acceptor groups, [8][9][10] this work was extended to bis-isoxazolinyl diazaheterocycles. 2 Structures 1, 2, and 4 are clearly well set up as precursors for polycyclic structures which are of considerable interest as pharmacophores for therapeutic drugs.Such compounds have been used to reduce neurotoxin injury associated with anoxia or ischemia, 11 or as antiviral agents. 12ricyclic aza-heterocycles also display platelet-derived growth factor inhibitory activity. 13nfortunately, no definitive pattern emerged, that would allow prediction of the structure of the products from their reaction with bases.Thus, while the quinoxaline 3 gave the bisimidazoquinoxaline 4, the corresponding phthalazine 5 underwent partial annelation through the benzene ring to give 6 (Scheme 4).

Scheme 4
In this paper we intended to extend the range of bis-isoxazolones investigated, in the hope of more clearly defining the synthetic utility of this mode of heterocyclic synthesis.Herein we report the synthesis of the bis-isoxazolinylpyrimidines (7-14) and pyridazines (15-17), and the base catalysed reactions of 7-10, 13 and 15.

Scheme 5
Reaction of pyrimidine 7 with potassium carbonate in THF gave the bis-annelated tetraazaphenanthrene 21, rather than the anticipated 22: a suggested pathway for such a product is shown in Scheme 6.Some support for this pathway was found in the observation that reaction of 7 with potassium carbonate in ethanol gave the product 23 (Scheme 7).

Scheme 6 Scheme 7
The reaction of the aminoaryl derivatives 8 and 9 with potassium carbonate in THF followed the hoped pathway, with the annelation of two imidazole rings onto the pyrimidine to give 24 and 25 (Scheme 8).

Scheme 9
The reaction of 10 with sodium hydroxide at room temperature gave 26 while under reflux conditions afforded 27 (Scheme 10).A number of alternative tautomeric structures for 26 and 27 can be written.

Conclusions
][10] They could also serve as intermediates for new planar polycyclic heterocycles.

Experimental Section
General.Freshly distilled solvents were used throughout, and anhydrous solvents were dried according to Perrin and Armarego. 14Melting points were determined on a Philip Harris C4954718 apparatus and are uncorrected.Infrared spectra were recorded on a Thermonicolet (Nexus 670) FT-infrared spectrometer, using sodium chloride cells and measured as film or KBr disks. 1 H (300 MHz) and 13 C (75.5 MHz) NMR measurements were recorded on a Bruker 300 spectrometer in DMSO-d 6 , CD 2 Cl 2 or CDCl 3 using TMS as the internal reference.Mass spectra were recorded on a Varian Matt 311 spectrometer and relative abundances of fragments are quoted in parentheses after the m/z values.