Alkyl-1,8-naphthyridines preparation

Chloro-5,7-dimethyl-l,8-naphthyridine reacts readily with meth-anolic methoxide (65°, 30 min) and with other alkoxides, benzyl-amine, and hydrazine. 4-Chloro-7-acetamino-l,8-naphthyridine (prepared in moderate yield from the 4-oxo analog) has been alkyl-aminated (150°, 9 hr, 62% yield). The degree of reactivity in... 

Attempts to prepare tricyclic homologues of the naphthyridines have been partially successful. 4-Amino-1,5-naphthyridine (109) reacts under Skraup conditions to give 4,5,9-triazaphenanthrene (110), and 1,8,9-triazaanthracene derivatives (111) can be isolated from the mixtures of products obtained by treatment of 2-amino-l,8-naphthyridin-7-one and its derivatives with ethyl ethoxymethylenemalonate, acetylacetone and alkyl /3-oxoglutarates (72JHC801) (see also earlier papers in that series). However, 2-amino-1,8-naphthyridine (112 R = H) reacts under Skraup conditions to give the 2-oxo derivative (113 R = H) instead of a 1,8,9-triazaanthracene, and 2-amino-1,6-naphthyridine behaves similarly (75MI21103). Under non-hydrolytic conditions, naphthyridines (112 R = Aik, Ar, H) cyclize... 

Alkylation of 4-hydroxy-l,7-naphthyridines gives 4-hydroxy-l,7-naph-thyridinium iodides (254) which on treatment with aqueous alkali yield l,7-naphthyridinium-4-olates (253). A number of derivatives (253 R = H, CN, CO2H) have been prepared in this manner. On the basis of IR spectroscopy, the acid derivatives (253 R = CO2H) have been formulated as mesomeric betaines rather than the inner salts 255. 

This chapter covers information on the preparation, physical properties, and reactions of 1,5-naphyhyridine and its C-alkyl, C-aryl, /V-alkyl, and /V-aryl derivatives as well as their respective ring-reduced analogs. In addition, it includes methods for introducing alkyl or aryl groups (substituted or otherwise) into 1,5-naphthyridines already bearing substituents and the reactions specific to the alkyl or aryl groups in such compounds. For simplicity, the term alkyl-l,5-naphthyridine in this chapter is intended to include alkyl-, alkenyl-, alkynyl-, aralkyl-, and cycloalkyl-1,5-naphthyridines likewise, aryl-l,5-naphthyridine includes both aryl-and heteroaryl-1,5-naphthyridines. 

Most such esters have been made by primary synthesis (see Chapter 22) and some by esterification of corresponding carboxylic acids (see Section 28.1.2) or from halogeno-1,8-naphthyridines (see Section 24.2). A few extranuclear esters have been prepared by passenger alkylations. For example, by S-ethoxycarbonyla-tion as in Chapter 26. 

Methyl (+ )-3-ethyl-2,3,3n,4-tetrahydro-1 i/-indolo[3,2,1 -de][ 1,5]naphthyridine-6-carboxylate 293 possessing psychostimulating activity was prepared by the alkylation of ester 294 with iodoethane in DMSO or by dehydration of hydroxyl derivative 295 (1988FRP2590990). 

Naphthyridines are generally prepared by thermal cyclization of enaminones derived from aminopyridines. As shown in Table VII, entry 1, thermal cyclization of the enaminone gives the 1,8-naphthridone (from which a series of A-alkyl derivatives has been prepared). An isomeric mixture of 1,6-naphthridones can be obtained if both 3 and 5 positions are available (Table VII, entry 2). 1,5-Naphthridines are synthesized from the appropriate enaminones (Table VII, entries 3 and 4). 

The related 6-6 bicyclic system, 2,10-diazabicyclo[4.4.0]dec-l-ene (3), was prepared from frani-decahydro-1,8-naphthyridine [9] and an alternative method via direct cyclization of bis(3-aminopropyl)malonic acid was developed for large scale operation [10]. Heinzer et fl/. [ 11 ] reported the preparation of a sterically strongly hindered bicyclic amidine, 3,3,6,9,9-pentamethyl-2,10-diazabicyclo[4.4.0]dec-l-ene (Eschenmoser amidine) (4) (Figure 3.2) and its N-alkylated analogues and their potential uses in the formations of salts of carboxylic acids and related proton complexes of bidentate hgands (Section 3.3.8) [11b]. 

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