Alkyl-2,6-naphthyridines

Most known C-alkyl-1,5-naphthyridines have been made by primary syntheses (see Chapter 1) and most A-alkyl-1,5-naphthyridinium salts by quaternization. Other reported approaches are illustrated in Section 2.1.3 and by the following examples. 

Note 1,5-Naphthyridinecarboxylic acids have been made by primary synthesis (see Chapter 1) and by oxidation of alkyl-1,5-naphthyridines (see Section 2.2.2). The remaining routes involving oxidation of aldehydes or hydrolysis of esters are exemplified here. 

These aldehydes have been made by oxidation of alkyl-1,5-naphthyridines (see Section 2.2.2). 

Ch. 2 1,5-Naphthyridine, Alkyl-1,5-naphthyridines, and Aryl-1,5-naphthyridines Ch. 3 Halogeno-1,5-naphthyridines Ch. 4 Oxy-1,5-naphthyridines Ch. 5 Thio-1,5-naphthyridines... 

The antibacterial agent nalidixic acid [389-08-2] (37) is formed by reaction of 2-ainino-6-methylpyridine [1824-81 -3] with an alkoxymethylenemalonic ester to form the 1,8-naphthyridine carboxyUc ester followed by alkylation and ester hydrolysis (37). 

Similarly, a number of l-alkyl(aryl)-4-ehloro-3-nitro-l,8-naphthyridin-2 (IH)-ones (100) have been reported to reaet with ammonia or alkylamines to afford the eorresponding 4-amino eompounds [101, R = H, CH3, C2H5, CH(CH3)2, CH2 CfiHs] (91JHC2029, 91MI2 92JMC4866). 

Sodium hydrosulfite successfully reduced the iiitro group in a number of l-A -alkyl(aryl) 4-(substituted) amino-3-nitro-l,8-naphthyridin-2(lH)-ones (143) to give the corresponding 3-amino derivatives (144) (91JHC2029, 91MI2 92JMC4866). Tliese products could not be purified but were used in their crude form for further annelation into imidazonaphthyridin-4(5H)-ones (see Section III,G). 

One representative of the oxazolo[4,5-/][ 1,6]naphthyridine system, viz. the ester 62, is produced in four steps by annulation of 2-(dicthy lam ino)oxazolo[4,5- pyridine (Scheme 20). Whether the final product exists mainly as the hydroxy tautomer or as the 9//-6-one cannot be deduced from the spectral data presented alkylation occurs either at the oxygen or at N-9, and gives either 63 or 64 <1993SC2931>. 

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 Friedlander condensation of 2,6-diaminopyridine-3,5-dicarbaldehyde (393) with various ketones has been reported (77JOC3410). Reaction of the aldehyde with acetophenone, with deoxybenzoin and with a-tetralone generates the 5,10-dihydro-l,9,10-anthyridine derivatives (394 R = H), (394 R = Ph) and (395) respectively, whilst with acenaphthenone the nonacyclic anthyridine (396) is obtained. The condensation between 2-amino-3-ethoxy-carbonyI-l,8-naphthyridine (225) and alkyl carboxylates under basic conditions produces 4-hydroxy-1,9,10-anthyridin-2-ones (397) (79BAP571). 

The regioselective alkylation of [1,6]- and [l,7]-naphthyridines using benzylstannane and ethyl chloroformate has been described <2000TL8053> as an excellent route to give substituted dihydronaphthyridines (Scheme 4). 

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>. 

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. 

Very few synthetic compounds other than the sulfa drugs have shown useful activity against systemic bacterial infections, particularly those due to Gram-negative bacteria. Activity of this kind was discovered in a series of l-alkyl-4-quinolones (60BRP830832), but the most active of these, l,2-dimethyl-6-nitro-4-quinolone and l-methyl-6-nitro-4-quin-olone-3-carboxylic acid, produced eye damage (opacity of the lens) that precluded clinical trial. A closely related 1,8-naphthyridine derivative, nalidixic acid (255), was later found to be effective, and it is largely used for urinary tract infections. The quinolone oxolinic acid (256) is also used for this purpose. These compounds inhibit enzymes concerned in DNA synthesis. 

A wide variety of 1 -iV-alkylperhydro- 1,7-naphthyridines (68) were prepared100 by reacting the ether (67) with various alkyl amines. 

The naphthyridines undergo N-alkylation reactions as expected. Thus, N-6 and N-7 are methylated first in 1,6- and in 1,7-naphthyridine, respectively. The quaternary iV-methyl salts are oxidized by potassium ferricyanide to afford the JV-methyl-a-one derivatives (95-98).54-56 The kinetics of... 

The availability of 1,8-naphthyridine and its alkyl derivatives has spawned a veritable explosion of studies aimed at examining the behavior of this ring system as a ligand. Much of this work has been done by Hendricker and co-workers, initially caused by the availability of 1,8-naphthyridine synthesized by Kress and Paudler. 

Heterocyclic azides react with enamines31 1,8-naphthyridine azides give isolable triazolines.220 The bicyclic enamine 2-N-morpholinonorbornene with aryl and benzoyl azides furnishes stable, crystalline aminotri-azolines.39,213 Likewise, alkyl azidoformates yield stable triazolines.30,221... 

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. 

Decahydro-1,5-naphthyridine underwent A-alkylation by 2-14-W-acetylaniIino)-buta-1,3-dienyl]-l,3,3-trimethyl-3/7-indolium perchlorate to give 1,5-bis 4-( 1,3,3-trimethyl-3/7-indolio)buta-l,3-dienyl decahydro-1,5-naphthyridine bisperchlorate (10) with loss of acetanilide (substrate, EtOH, Me2NCHO, 40°C synthonj, dropwise 6 h 29%) 1203 also methylation to 1,5-dimethyl-decahydro-1,5-naphthyridine (no details).1089... 

Although alkyl and aryl groups attached to a heterocyclic nucleus can undergo a wide variety of reactions and do have significant steric and electronic effects on adjacent substituents, little such data on 1,5-naphthyridines can be found in the literature. 

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