Nitro-1,8-naphthyridines preparation

Tile same methodology as mentioned for the preparation of (9) was applied for the synthesis of 8-nitro-l,6-naphthyridines. Heating diethyl N- 3-nitropyridin-4-yl)aminomethylenemalonate (12) in diphenyl ether yields ethyl 8-nitro-l,6-naphthyridin-4(lH)-one 3-carboxylate (13) (63JCS4237, 30%) and acid treatment of 4-( y, y-diethoxypropylamino)-5-nitro-2-(/3,/3 -trifluoroethoxy)-pyridine (14) gives in a similar way 8-nitro-5-(/3, /3-triflu-oroethoxy)-l,2-dihydro-l,6-naphthyridine (15, 76%). Subsequent oxidation with chloranil, acid hydrolysis, and methylation with methyl iodide gives 8-nitro-6-methyl-l,6-naphthyridin-5(6H)-one (16,63%) (81JHC941). 

In this method the nitro group in the aliphatic nitro compound is usually present on a carbon atom, which is also activated by CO-functioiiality (aldehyde, ester, arylketoiie). A successful application of this method is the Borsche modification of the Friedlander synthesis, involving condensation of A-(3-amino-4-picolylidene)-p-toluidine (17) with [Pg.289]

Many reports deal with the preparation of numerous hydroxynitronaph-thyridones and nitronaphthyridinediones. By the nitration of 4-hydroxy-l,X-naphthyridin-2(lH)-ones (X = 5,6,7, and 8) (51a-51d) using nitric acid in acetic acid, the corresponding 3-nitro substituted compounds (52a-52d) were obtained in reasonable-to-good yield (75JMC726 77MI1 96MI1). 

Treatment of 4-hydroxy-l-phenyl-l,8-naphthyridin-2-(lH)-one (76) with sodium nitrite gave the 3-nitroso derivative (77), which could be oxidized to 4-hydroxy-3-nitro-l-phenyl-l,8-naphthyridin-2(lH)-one (30a) (94SC3289). According to the authors, this method of preparing (30a) is more convenient for large-scale preparation than the one using A-phenyl-3-azaisatoic anhydride as starting material (see Section II,A,4,a) [(29a) (30a)]. 

Tile easy availability of (di)nitronaphthyridones, in which the lactam part can easily be converted into an iminochloride, has successfully led to preparation of the parent (di)nitronaphthyridines by removal of the chloro atom. For that purpose the chloro atom in the 2- and 4-chloro derivative of the 3-nitro-l,5-, -1,6-, and -1,8-naphthyridines (78a-78e) was first substituted with tosylhydrazine to give the corresponding tosyl-hydrazide, which then was hydrolyzed in alkaline solution into the corresponding 3-nitro-l,5-, -1,6-, and -1,8-naphthyridines (79a, 79b, and 79c). 

Attempts to obtain 5-nitro-l,7-naphthyridine and 3,6-dinitro-l,8-naph-thyridine (83) from the corresponding 8-chloro-5-nitro-l,7-naphthyridine and 2-chloro-3,6-dinitro-l,8-naphthyridine using the similar reaction failed (85JHC761 98MI2). However, 3,6-dinitro-l,8-naphthyridine (83) could be prepared in 21% yield by hydrazino-dechlorination of 2-chloro-3,6-dinitro-1,8-naphthyridine (82) and subsequent cupric sulfate oxidation of the intermediate 2-hydrazino-3,6-dinitro-l,8-naphthyridine (93LA471). 

However, attempts to prepare 3-nitro-l,8-naphthyridine (11) by the Skraup reaction—heating of 2-amino-5-nitropyridine with glycerol in the presence of an oxidant—were not successful (74YZ1328). 

Deuterio-3-nitro-l,6-naphthyridine (168) was prepared from 4-chloro-3-nitro-l,6-naphthyridine (166) by a reaction with tosyl hydrazide and subsequent hydrolysis of the 4-tosylhydrazino derivative (167) with Na2C03/ D20 solution (83RTC359). 7-Deuterio-l,8-naphthyridin-2(lH)-one was prepared by heating l,8-naphthyridin-2(lH)-one with deuterium oxide at 230°C for 35 h (85JHC761). This deuterio compound could be converted into 2-chloro-(or 2-ethoxy-) 7-deuterio-3,6-dinitro-l,8-naphthyridine. 

Similar 2-hydroxy-3-nitro-l,8-naphthyridines (94) have been prepared by condensation of 2-aminonicotinaldehydes with nitroacetic ester in the presence of piperidine [Eq. (30)].87... 

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