Nitro-1,8-naphthyridines reactions

A great number of N-substituted 4-hydroxy-3-nitro-l,8-naphthyridin-2 (IH)-ones are obtained by reaction of N-substituted azaisatoic anhydrides with ethyl nitroacetate carbanion (Section II,A,4,a). A very specific method, more recently developed, is that of the inverse Diels-Alder method, involving the reactions of enamines with 5-nitropyrimidine (Section II,A,4,b). 

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). 

The compounds 87a and 87b are aminated at position 4, yielding the 4-amino compound (88a, 40%) and the 2,4-diamino compound (88b, 11%) respectively the 2-ethoxy compound (87c), however, undergoes amination at position 4 as well at position 5, giving a mixture of the 4-amino compound (88c, 20%) and the 5-amino compound (89a, 14%).Tlie 2-chloro compound (87d) yields a highly complex reaction mixture from which the 5-amino compound (89b), the 2,4-diamino derivative (88b), and 2,5-diamino-l,8-naphthyridine (89c) could be isolated. l-Ethyl-3-nitro-l,8-naphthyridin-2(lH)-one (90a) and 3,6-dinitro-l-ethyl-l,8-naphthyridin-2(lH)-one (90b) were aminated exclusively in the 4-position to give compounds 91a (62%) and 91b (45%), respectively (93LA471). 

As discussed before, in liquid ammonia/potassium permanganate nucleo-phugal substituents at C-2, such as ones present in the naphthyridines (84c, 84e, 84h, 84i, 841, and 84m), could not be replaced by the amino group only SnH substitution takes place. However, it has been observed that in the reaction of the 2-chloro-3-nitro-l,8-naphthyridine (92c) with liquid methylamine/potassium permanganate S H substitution as well as methylamino-dechlorination takes place, yielding 2,4-bis-(methylamino)-3-nitro-l,8-naphthyridine (93c). 

Similar calculations were also carried out for the SnFI methylamination reactions of 2-R-3-nitro- and 2-R-3,6-dinitro-l,8-naphthyridines (R = FI, Cl, OCFI3, OFI, NFI2, NFICFI3, NFIPh). Tire calculations show that in these reactions the regioselectivity is also controlled by the interaction of the FIOMO of methylamine and LUMO of the nitro-1,8-naphthyridines and not by the formal charges (97LAR2601,97MI3). 

The amino moiety of the 3-carbohydrazide group of unsaturated and 6,7,8,9-tetrahydro-4-oxo-47/-pyrido[l,2-n]pyrimidine-3-carbohydrazides was condensed with acetone and 5-nitro-2-furoaldehyde (830MR687 88EUP252809). The reaction of 6-methyl-6,7,8,9-tetrahydro-4-oxo-4//-pyrido[l,2-a]pyrimidine-3-carbohydrazide with diethyl 2-[2-dimethyl-amino)vinyl]-6-methylpyridine-3,5-dicarboxylate in boiling ethanol for 4 hours afforded N-( 1,6-naphthyridin-6-yl)-4-oxo-4//-pyrido[ 1,2-a]pyrimi-dine-3-carboxamide 426 (85MIP1). 

The one-pot Stille cross-coupling reaction of compound 256 produced all four isomeric thieno[3,2-c]naphthyridines (1994JHC11). The stepwise formation of the C(7)-C(7a) and C(4)-N(5) bonds of the thieno[3,2-c]pyridine system can be considered as a modification of the above-described approaches. For example, aldehyde 256 reacts with arene 265 to give 266 reduction of its nitro group is accompanied by cyclization to form thieno[3,2-c]isoquinoline A-oxide (267) (1990JHC1127). 

The main use of nitro-1,5-naphthyridines has been as precursors for 1,5-naphthyridinamines. However, the presence of a powerfully electron-withdrawing nitro group is often of use to activate adjacent leaving groups such as halogeno toward nucleophilic replacement reactions. 

Nitropyrimidine (147) underwent a Diels-Alder-type addition by the enam-ine, l-acetyl-4-(pyrrolidin-l-yl)-l,2,3,6-tetrahydropyridine (146), and subsequent reactions to afford 6-methyl-3-nitro-5,6,7,8-tetrahydro-l,6-naphthyridine (148, R = Ac) (reactants, EtOH, reflux, 3 h 48%) and thence deacetylation to 3-nitro-5,6,7,8-tetrahydro-l,6-naphthyridine (148, R = H) (6M HC1, reflux, 90 min 89%) and oxidation to 3-nitro-l,6-naphthyridine (substrate, AcOH, EtOH, reflux, I2/EtOH I2EtOHJ, dropwise, reflux. 2 h 64%)656... 

Only two reactions of nitro-1,6-naphthyridines have been reported, as illustrated in the following examples. 

Note The only reported reaction of nitro-1,7-naphthyridines appears to be their reduction to the corresponding naphthyridinamines. 

Although nitro groups have a marked effect on the reactivity of other substituents on 1,8-naphthyridine,1273 the only reported reaction of the nitro group itself is reduction to an amino group, as illustrated by the following examples. 

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). 

It was reported that the Niementowski synthesis of 4-hydroxy-3-nitro-7-phenyl-l,8-naphthyridin-2(lH)-one (25) from ethyl 2-amino-6-phenylni-cotinate (23) and ethyl nitroacetate (24) in the presence of sodium was unsuccessful, producing only traces of (25), while condensation of ethyl 2-amino-6-phenylnicotinate (23) with the less reactive ethyl acetate resulted in the formation of 4-hydroxy-7-phenyl-l,8-naphthyridin-2(lH)-one in good yield [66JCS(C)315], It seems that the more reactive nitroacetate tends to precipitate rapidly from the reaction mixture as its sodio derivative, which explains the low yield of (25). 

Amino-l,8-naphthyridin-7(8H)-one (61a) and their 3-nitro and 6-nitro derivatives (61b) and (61c) respectively can be nitrated successfully. The nitro substituent enters preferentially at position 6, i.e., formation of 62a from 61a when position 6 is already occupied by a nitro group, the second nitro group is introduced at position 3, i.e., formation of 62b from 61c (69GCI823). It has been mentioned that diazotation of 61 (R=Ph) with sodium nitrite/sulfuric acid also gives the 3-nitro derivative [97JHC1501]. This reaction proceeds via nitrozation, in which the NO+ is the attacking electrophile. 

In conclusion, all results obtained thus far on this reaction show that it is especially the 4-position in the 3-nitro-l,8-naphthyridines which is strongly favored toward the attack of the carbanion of chloromethyl phenyl sulfone. When position 4 is occupied by a substituent no reaction occurs. This behavior is in accordance with the behavior observed in reactions with liquid ammonia and liquid methylamine. 

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