Alkylthio-1,8-naphthyridines

This chapter summarizes the sparse data on 1,5-naphthyridines with substituents that are joined directly or indirectly to the nucleus through a sulfur atom. Included are any tautomeric or nontautomeric 1,5-naphthyridinethiones, extranuclear mercapto-1, 5-naphthyridines, alkylthio-1,5-naphthyridines, bis(l,5-naphthyridinyl) sulfides or disulfides, 1,5-naphthyridine sulfoxides or sulfones, and 1,5-naphthyridinesulfonic acids or their derivatives. However, several categories have no known representatives. 

Note One such sulfone has been prepared by primary synthesis (see Section 1.3.3) another by oxidation of an alkylthio-1,5-naphthyridine (see a preceding subsection). 

The thermal cyclization of N-(6-alkylthio-2-pyridyl)aminomethylene-malonate (1020) afforded 1,8-naphthyridines (1021) in good yields (78KGS1671 82FRP2500833 84JHC673). 

Cyclocondensations involving thioxo or alkylthio substituents are represented by the conversion of 6-methyl-4-(thien-2-yl)-2-thioxo-l,2,5,6,7,8-hexahydro-l,6-naphthyridine-3-catbonitrile into 4-hydroxy-9-methyl-4-(thien-2-yl)-7,8,9,10-tetrahydropyrido 2, 3 4,5 thieno 2.3-ft [ l,6Jnaphthyridin-2(17/)-one (3) (ClCH2C0CH2C02Et, EtOH, EtONa, reflux, 10 min 88%) 1429 also of 2-acetonylithio-8-benzylidene-6-isopropyl-4-phenyl-5,6,7,8-tetrahydro-l,6-naphthyridine-3-carbonitrile into 2-acetyl-8-benzylidene-6-isopropyl-4-phe-nyl-5,6,7,8-tetrahydrothieno 12,37 1,6]naphthyridin-3-amine (4) (EtONa, EtOH, 20°C 15 min 75%).946... 

Little use has been made of 1,8-naphthyridinethiones, alkylthio-1,8-naphthyridines, or their respective oxidation products. Available information is summarized in the following brief sections. 

Modifications of the C(2)-position are limited due to synthetic difficulties associated with direct introduction substituents at C-2. However, the synthesis of 2-phenylsubstituted fluoroquinolones has been developed [55], and6-fluoro-quinolon-2-carboxylic acids have been obtained by cychzation of the corresponding 2-amino-substituted 3-pentafluorobenzoyl acrylic acids [56], 2-Thio substituted quinolones are widely used for the synthesis [a]- or [b]-annelated fluoroquinolones, such as thiazolo-and azethydinoquinolones [57-59]. Synthesis of l-cyclopropyl-2-alkylthio-8-methoxyfluoroquinolones was described however elucidation of their antibacterial activity revealed no regularities associated with incorporation of 2-alkylthio substituents [60], AU known 2-aza analogues of quinolones and naphthyridines, derivatives of cinnohne, have not exhibited any remarkable antibacterial activity. 

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