Naturally occurring naphthyridines

Whilst many alkaloids contain the pyridine ring system, the combination of two pyridine rings as exemplified in the naphthyridines is rather uncommon in nature. The alkaloid jasminine (436), a 2,7-naphthyridine derivative, has been isolated from Jasminium species (68AJC1321) whilst 4-methyl-2,6-naphthyridine (437) occurs in the aerial parts of Antirrhinum majus and aronticus (71P2849). 

This domino methodology not only allows to access naturally occurring quinolines such as 114a and 114b (chimanine B), but also a rapid access to the antima-larial active 1,8-naphthyridine 114c, which inhibits the growth plasmodium falciparum at a lower micromolar level [297]. 

Despite a general paucity of information on 2,6-naphthyridines, the system has been included in several reviews 50-52 57 58 61,265,436,1357 1430 1432 4-methyl-2,6-naphthyridine has been found to occur naturally in several Antirrhina species,226 241 267 and physical properties of the parent heterocycle (1) have been quite extensively studied, usually for comparison with those of the other unsubstituted naphthyridines (see Section 29.2.2). 

The pattern of deuterium distribution in isotope exchange products of 1,8-nap-hthyridine and its methyl-, hydroxyl-, amino- and nitro derivatives indicates that the rate and pathway of this process depend on the pH of the medium as well as the nature and position of substituent (1988ACH267). In neutral D20 and a D20-DC1 mixture, hydrogen atoms are replaced with deuterons exclusively at positions 2 and 7. In D20 solutions containing NaOD, hydrogen atoms are replaced with deuterons in all positions of the naphthyridine system. In neutral D20, the replacement of the protons in monomethyl-substituted 1,8-naphthyridines occurs predominantly in the ortho positions with respect to the nitrogen atoms (positions 7 and 2, 7). The high reactivity of these positions is determined by the inductive effect of the substituent. 

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