Alkyl-1,8-naphthyridines cyclizations

The cyclization of diethyl iV-substituted N-(6-alkyl-2-pyridyl)amino-methylenemalonates (265, R2 = Et) in polyphosphoric acid at 200-230°C for 10 min gave 1-substituted 7-alkyl- 1,4-dihydro-1,8-naphthyridine-3-carboxylic acids (1022, R = Me, Et R1 = alkyl R2 = H) in 17-56% yields (71GEP2108046). From the mother liquor, 2-(substituted amino)-6-alkylpyridines could be recovered. 

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... 

The N-acylation product of the reaction of enaminones with either 2-chloronicotinoyl chloride or 2,6-dichloro-5-fluoronicotinoyl chloride readily undergoes cyclization (either directly or on treatment with sodium hydride) to give high yields of 8-acyl-7-alkyl[l,6]naphthyridin-5(6//)-ones, which themselves are attractive precursors for elaboration to naphtho[2,3-, ][l,6]naphthyridin-5-ones and pyrido[2,3-f][l,6]naphthyridin-6-ones <2002T58>. 

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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