2.7- Naphthyridin-l -one

Along the same lines, 3-cyanopyrano[4,3- ]pyridin-5-ones ring open and reclose when reacted with DMF followed by pyridine and a primary amine to give 5-cyano[2,7]naphthyridin-l-ones (Scheme 65) <1997RCB1041>. 

In 1958, Ikekawa10 synthesized 2,7-naphthyridine and various substituted derivatives. His approach involved the reaction of 4-methylnicotinic acid with formaldehyde to afford the lactone 99 (R = H). The reaction of 99 with ammonia in methanol yields the amide (100) which, on oxidation with chromium trioxide, afforded 2,7-naphthyridin-l-one (101). This substance was converted into 2,7-naphthyridine (102, R = H) by consecutive treatment with phosphorus oxychloride, hydrazine, and copper sulfate. The 3-methyl derivative was similarly prepared starting with acetaldehyde. 

Ethyl 2,6-dimethyl-4-phenylethynyl-3-pyridinecarboxylate (23) with ethanolic ammonia gave 6,8-dimethyl-3-phenyl-2,7-naphthyridin-l(2//)-one (24) (120°C, sealed 85%).1055... 

Compounds ( )-179 and 180, bearing the same 8//-isoquino[2,l-6]-[2,7]naphthyridin-8-one systems as those of the A. lamarckii alkaloids... 

Condensation of substituted pyrano[4,3-Z>]pyridine-5-one 166 with dimethylform-amide dimethyl acetal in xylene yielded enamine 167, which underwent recyclization to 2-alkyl-5-cyano-8-phenacyl-2,7-naphthyridin-l (27/)-ones 168 on treatment with primary amines (1997IZV1079). A change in the sequence of addition of the reagents to the pyranone 168 (first, treatment with benzylamine and then condensation with dimethylformamide dimethyl acetal) resulted in 8-benzoyl-3-cyano-4-(2-dimethyl-aminovinyl)-2-phenyl-1,6-naphthyridin-5(6//)-one 169. 

There are two derivatives, lophocladine A (4-phenyl-[2, 7]-naphthyridine-l(2 H)-one) and lophocladine B (4-phenyl-[2, 7]-naphtyridine-l-amine), which were isolated from a red alga Lophocladia sp. [54] (Fig. 2.7). 

N-Substituted amides derived from 2-chloro- or4-chloronicotinic acid react with CH-acidic nitriles in the presence of base to yield amino derivatives of [l,6]naphthytid-5(6//)-ones and [2,7]naphthyrid-l(2//)-ones <1997JHC397>. 3-(l-Alkylamino)pyridines react with electron-deficient alkynes (acetylene dicatboxylates) in the presence of acid to give l,2-dihydro[2,7]naphthyridine-3,4-dicarboxylates in up to 72% yield compounds unsubstituted at C-1 were readily oxidized with potassium permanganate to naphthyridine-l-ones <2005TL3953>. 

There are relatively few synthetic routes to 2,7-naphthyridines almost all are multistage and rely on annulation of a second pyridine ring to a suitably functionalised pyridine precursor. French workers have described an efficient, one-pot synthesis of l,3,6,8-tetramethyl-2,7-naphthyridine 1 which involves treatment of a mixture of acetyl chloride (1.6 mol) and aluminium chloride (0.3 mol) with t-butanol or t-butyl chloride (0.1 mol) at 35°C for half an hour, followed by careful addition of the reaction mixture to liquid ammonia. This gave 37% of 2,4,6-trimethylpyridine and 63% of the naphthyridine 1 in a total yield of 91%. 

Note It is quite remarkable that very few deliberate hydrolyses of these halogenonaphthyridines have been reported. 3-(3,5-Dimethyoxyphenyl)-2,7-difluoro-l,6-naphthyridine gave 3-(3,5-dimethox-yphenyl)-7-fluoro-l,6-naphthyridin-2(l//)-one (49) (NaOH, H20, THF, 53°C, 3 days >95%).564... 

A mi no-6-oxo-l-phenyl-4-(iV-phenylcarbamoyl methyl)-1,6-dihydro-3-pyridi-necarbonitrile (15) underwent thermal cyclization to l-amino-6-hydroxy-8-imino-2,7-dipthenyl-2,3,7,8-tetrahydro-2,7-naphthyridin-3(2//)-one (16) (Et3N, Me2NCHO, reflux 60%) also somewhat similar cyclizations.802... 

Phenyl-1 //-pyrano[3,4-c pyridin-l-one (41) gave 2-(2-hydroxyethyl)-3-phenyl-2,7-naphthyridin-1 (277)-one (42) (H2NCH2CH2OH, MeOH, reflux 82%).902... 

V-Benzyl-/V-(but-3-yny l)aminomethyl]-5-chloro-3-methoxy-1-phenylpyra-zin-2( I //)-one (45) underwent an intramolecular Diels-Alder reaction to afford 2-benzyl-8-chloro-6-methoxy-l,2,3,4-tetrahydro-2,7-naphthyridine (46) (PhBr, reflux 78 %).602... 

Chloro-5,7-dimethyl-l,8-naphthyridine 3-Chloro-2,7-dimethyl-l,8-naphthyridin-4(l//)-one... 

---