2.7- Naphthyridine reduction

Catalytic hydrogenation (Pd/C) of 2-chloro-3-nitro-l,5-naphthyridine (125, R = Cl) in methanolic solution afforded 3-amino-l,5-naphthyridine (126, R = H, 74%) isolated in the form of its trihydrochloride (40MI1). Similar Pd/C hydrogenation of 2-ethoxy-3-nitro-l,5-naphthyridine (125, R = OEt) gave 3-amino-2-ethoxy-l,5-naphthyridine (126, R = OEt, 47%) (80RTC83). Reduction with tin(II) chloride in hydrochloric acid also leads to 126, (R = OEt, 73%) (63RTC997). 

Tin(II) chloride reduction of both 4-chloro-3-nitro-l,8-naphthyridine (129, R = Cl) (79PJC1665) and 3-nitro-l,8-naphthyridine (129, R = H) (76S691) gave in 30-35% yield 3-amino-l,8-naphthyridine (130, R = H) reduction of the 4-amino-3-nitro compound (129, R = NH2) yielded 3,4-diamino-l,8-naphthyridine (130, R = NH2,37%) (79PJC1665). 

Subjecting 8-chloro-5-iiitro-l,7-iiaphthyridiiie (97) to reduction with tin(II) chloride leads, besides loss of the chloro atom and reduction of the nitro group, i.e., formation of 5-amino-l,7-naphthyridine (131, 22%), to the formation of small amounts of 5-amino-6,8-dichloro- (132, 1.5%) and 5-amino-6-(or 8-)chloro-l,7-naphthyridine (133, 2.5%) (88PJC305). 

Catalytic reduction of 3-nitro-7-phenyl-l,8-naphthyridin-2(lH)-one (136) with palladium on carbon in 2-ethoxyethanol gave the l,2-di(l,8-... 

Reduction of 8-nitro-5-(/3,/3,/3-trifluoroethoxy)-l,6-naphthyridine (141) afforded the corresponding 8-amino compound (142, 45%) (81JHC941). 

The cathodic reduction of substituted nitrophenylpyridines, pyridiniums or dihydropyridines gives naphthyridine... 

The application of the Friedlander reaction to 3-aminopyridine-2-carbaldehyde (135) gives good yields of the 2,3-disubstituted 1,5-naphthyridines (136) (75CR(C)(280)38l). The intramolecular cyclization of /3- (3-aminopyridinyl)acrylic acid (137) results in the formation of l,5-naphthyridin-2-one (138) (66JHC357), whilst the condensation of 3-aminopyridine-2-carboxylic acid or its esters (139) with active methylene compounds yields 4-oxo (132) and 4-hydroxy-2-oxo compounds (134 R = H) after hydrolysis and decarboxylation of the intermediates (140) and (134 R = C02Et). Reductive cyclization of the 3-nitropyridine derivative (141) gives the 1,5-naphthyridine (142) (71JOC450). 

The reductive cyclization of ethyl (2-methoxy-5-nitro-4-pyridyl)pyruvates (187) with H2/Pd followed by treatment of the intermediates (188) with toluenesulfonyl chloride gave the 6-methoxy-l,7-naphthyridin-2-ones (189) (65JA3530, 73JOC1824). 

JAP624149) and a wide variety of l-lV-alkylperhydro-l,7-naphthyridines (207) have been obtained by reaction of the ether (208) with various alkylamines (66KGS427). A convenient synthesis of 5-hydroxy-2-oxo-l,2,3,4-tetrahydro-l,7-naphthyridine (211) starts from the 3-substituted amino isonicotinaldehyde (209) which undergoes a Wittig reaction followed by reduction to give (210), a compound that cyclizes readily in acid solution to (211) (82CPB1257). 

A novel synthesis75 of, presumably, a hexahydro-l,5-naphthyridine (27) resulted as a by-product of the preparation of a dipyrrolenyl derivative by reductive cyclization of the ketone 26. The stereochemistry about the bridgehead carbon atoms was not established. 

The piperidine derivative (42), on treatment with acrylonitrile in base, affords 43, which, on catalytic reduction, gives the perhydro-1,6-naphthyridine (44) of unspecified stereochemistry.90... 

Reduction of compound 115 with lithium aluminum hydride afforded the perhydro derivative in good yield. A variety of 1,3,6,8-tetrasubstituted derivatives of 2,7-naphthyridine have been prepared by displacement of the chlorine atoms of compound 116.131... 

The dehalogenation of naphthyridines with hydrogen over palladium on calcium carbonate in a weakly basic alcoholic solution gives excellent yields (90-95%) of reduced compounds.38,45,134,137,138 This method for removal of halogens has been extensively used and generally surpasses the classic hydrazine-copper sulfate reduction method. 

The use of other metal catalysts in attempted reductions of halo-naphthyridines has resulted in reduction of the ring or, at best, in the formation of mixtures. 

The reductive cyclization of appropriately substituted nitropyridines (e.g., 22) affords 1,7-naphthyridines (23).15 2-Cyano-3-pyridyl acetonitrile... 

The 1,5-, 1,6-, 1,7-, 1,8-, 2,6-, and 2,7-naphthyridines have been electro-chemically reduced to afford radicals that decay by a slow shift of hydrogen from nitrogen to carbon.143 The resulting radicals dimerize readily. In acid media the first reduction step produces a radical-cation that is relatively stable in the 1,7- and 2,6-naphthyridines, whereas in 2,7-naphthyridine, the species is stable for a few minutes only. All of these radical-cations undergo a hydrogen shift from nitrogen to carbon to form unstable radicals that react with original cation radicals to form dimers. The process is an acid- or base-catalyzed first-order reaction.144... 

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