Pyrano[2,
pyrazoles / Pyrano[2,3-b]pyridines 1 Pyrano[2,pyrimidine / l,8-Diazanaphthalenes Polyazanaphthalenes are biologically interesting compounds. For example 1 (quinolphs) and 2 (azinphos-methyl) are used as insecticides 'I. Our interest in azanaphthalenes stemmed from the possible utility as antischistosomal agents. Schistosomiasis is one of the most difficult diseases to treat and is a national problem in Egypt. In a previous work we reported several new approaches for synthesis of polyazanaphthalenes utilising readily obtainable starting materials 2,3). In conjunction with this work we report here the results of our investigation aiming to develop synthetic approaches ArCH=C , CH3COCHZC02Et E~o%' : ~ CN H3C
to polyazanaphthalenes utilizing ethyl 6-amino-4-aryl-5-cyano-2methyl-4H-pyran-3-carboxylates 4 as starting material. Efficient syntheses of derivatives of 4 have recently been reported. Now we have found that the cinnamonitriles 3a-c react with ethyl acetoacetate to yield the 4H-pyrans 4a-c. Structure 4 was elucidated by 'H NMR. Compounds 4a-c react with malononitrile to yield 1 : 1 adducts. Several isomeric structures seemed possible for these adducts. Thus, addition of the amino function in 4 to the cyano function could afford an amidine. This may then afford a pyrano[2,3-b]pyridine by addition of side chain methylene to the cyano function at C-3. Alternately, pyrano[2,3-dlpyrimidines may be formed by addition of the amidine amino function to the cyano group. However, 'H NMR revealed the absence of a pyran 4-H signal. Thus, we expected that the formed condensed pyran derivatives undergo further rearrangement yielding either the 1,6-diazanaphthalene 5 or 1,3,8-triazanaphthalene. The latter structure could be readily eliminated based on 'H NMR which revealed the absence of a CH2 signal. Thus, the 1,6-diazanaphthalene structure 5 was assigned for the reaction products. The formation of 5 from 4 and malononitrile is assumed to proceed via pyrano[2,3-d]pyridines. Several pyrano [2,3-b]pyridines could be prepared earlier by refluxing derivatives of 4 with malononitrile in ethanol in the presence of piperidine for a short period5).
Compound 4 a reacts with phenylhydrazine to yield the pyridine derivative 6. It is believed that 6 is produced by addition of phenylhydrazine to the double bond in 4 yielding an intermediate Michael adduct. This then undergoes ring opening and recyclization yielding 6. Attempted conversion of 4b, c into derivatives of 6 by treatment with phenylhydrazine resulted in formation of phenylhydrazones 7a, b.
The reaction of 4 a -c with hydrazine hydrate affords the pyrano[2,3-c]pyrazoles 8a-c. The formation of 8 a -c from 4 a -c and hydrazine hydrate can be rationalized by assuming that 4 a -c is in equilibrium with a chain tautomer which is in equilibrium with ethyl acetoacetate and 3a-c. Thus, hydrazine hydrate reacts with ethyl acetoacetate to form 3-methyl-2-pyrazolin-5-one (9) which then reacts with 3a-c to form 8a-c.
In contrast to the behaviour of 4 toward hydrazine hydrate, 4b reacts with hydroxylamine hydrochloride to yield the isoxazolo[3,4blpyridine derivative 10. Compound 10 is assumed to be formed by addition of hydroxylamine to the double bond at C-2 in 4b