Synthesis pyrido-fused ring systems

Microwave-assisted solvent-free synthesis of pharmacologically important pyrido fused-ring systems has recently been accomplished and is an improved method for assembly of a variety of pyridopyridazine and quinoline derivatives. Benz-1,3-oxazine formation has also been investigated in dry media using AI2O3-KF as a solid base (Scheme 8.75) [187]. 

Scheme 8.75. MW-assisted synthesis of pyrido fused-ring systems.

The development of a cost-effective microwave-assisted procedure for synthesis of pyrido fused-ring systems, by applying the tert-amino effect, has been described by Van der Eycken and coworkers (Scheme 10.62) [126]. 

The synthesis of pyridodiazine ring systems can be classified according to the relative location of nitrogen atoms in the diazine nucleus of the fused ring system as shown in formulas 246-248 for pyrido[v,y-2]pyridazines, pyrido[ ,y- ]pyr-imidines, and pyrido[x,y- ]pyrazines, respectively (Figure 2). Such fused ring systems have been subdivided according to the site of fusion z, that is, whether it is b-d. 

Several papers have been published on the synthesis and properties of fused-ring systems incorporating the 1,4-thiazine structure, mainly pyrido-[2,3-6]-l,4-thiazines, pyrazino[2,3-6]-1,4-thiazines, and pyrimido-[4,5-Z)]-l,4-thiazines, including some sulphur isosteres of dihydropteridines [e.g. (112)]. A detailed account of ring-chain tautomerism in 6-hydroxy-... 

Synthesis of the ortho- and peri-fused pyrido[3,2,l- 1[l,3,2]benzodiazaphosphorine ring system was accomplished from the quinoline carboxamide derivative 197 by treatment with phosphoryl chloride <1978JHC1169, 1979JHC897>. The iV-chloropropyl derivative 198b could be transformed to the tetracycle 199 (Scheme 27) <1979JHC897>. 

Compounds 39 and 40, in which a pyrazole ring is fused to a pyrido[2,3-2,]pyrazinc, are produced as a 3 2 mixture by reaction of pyridine-2,3-diamine with 3-methyl-l-phenylpyrazoline-4,5-dione (Equation 9) <1999T8475>, and the synthesis of compound 41 (Scheme 11) exemplifies a different approach to the same ring system <1997JCM318, 1997JRM2026>. 

The proton affinities of the pyrido[2,3-/ ]pyrazine system for N-1 = 205.56, N-4 = 212.02, and N-5 = 216.32 kcal moP showed that the most basic site is at N-5, which is in agreement with the formation of the quaternary salt derivatives 16-19 as intermediates for the synthesis of imidazopyridopyrazine fused rings <1994H(38)283, 1991JCC675>. 

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