2- Amino-l,8-naphthyridines

A low-temperature nitration of 2-amino-l,8-naphthyridine (59a) and 2-amino-l,5-naphthyridine (59b) yielded the 2-nitramino-l,8-naphthyridine (60a, 65%) (98MI3) and 2-nitramino-l,5-naphthyridine (60b, 70%) (63RTC988) respectively. Attempts to rearrange (60a) and (60b) to 2-amino-3- (or 6-) nitro-l,8-(or -1,5-) naphthyridines failed. 

Nitration of 2-amino-l,8-naphthyridin-5(8H)-one (67a) in acetic acid or in acetic anhydride does not occur in HNO3/H2SO4 the products obtained were difficult to separate (72GCI253). Hydrolysis of the amino group under nitration conditions has also been observed with 6- and 7-carboxy-2-aminonaphthyridin-5(8H)-ones (67b/67c), yielding the corresponding (68b/ 68c) (72GCI253). 

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 Skraup reaction, in all of its modifications, has proved to be unsuccessful as a method of obtaining anthyridines. Thus when 2-amino-l,8-naphthyridine (112 R = H) and 3-amino-l,5-naphthyridine (127) are subjected to the modified Skraup reaction using sulfo-mix the products are either triazaphenanthrenes or naphthyridine by-products (75MI21103). Similarly 3,5-diaminopyridine (126) gives 1,5,9-triazaphenanthrene (129) as the only tricyclic product (see Section 2.11.5.3) (67MI21102). 

The water-soluble compound 2-amino[l,8]naphthyridine is a novel DNA-binding photosensitizer, which may be employed for the one-electron oxidation of DNA. It is also reported to be an excellent chromophore for the design of artificial electron-accepting nucleobases <1999TL6029>. 

Pyrido[2,3-d pyrimidine (71) with malononitrile gave 2-amino-1,8-naphthyr-idine-3-carbonitrile (72, R=CN) (reactants, MeOH, 20°C 75%) or with ethyl cyanoacetate gave ethyl 2-amino-l,8-naphthyridine-3-carboxylate (72, R=CC>2Et) (likewise 8%) other activated methylene synthons also gave products but in very poor yield, even at appreciably increased temperatures.1030... 

Amino-l,8-naphthyridine-3-carboxamide with benzaldehyde gave 2-phenyl-1,2-dihydropyrimido[4,5-h 1,8 naphthyridin-4(3//)-one (35) (AcOH, reflux ... 

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. 

The product obtained in the amination of 1,8-naphthyridine (11) with KNH2/NH3 is found to be independent of the temperature of the reaction. At room temperature only 2-amino-l,8-naphthyridine (58) is formed (29%) ... 

Under nonhydrolytic conditions, 2-amino-l,8-naphthyridines (82) do, however, undergo the normal cyclization reactions with a-bromo ketones. Thus, imidazo[l,2- ]naphthyridines (83) are readily obtained." ... 

Condensation of 2-amino-l,8-naphthyridine-3-carboxamide 400 with aromatic aldehydes in glacial acetic acid affords 2-aryl-l,2,3,4-tetrahydropyrimido[4,5-Z>][l,8]naphthyridin-4-ones 401, whose oxidation with nitrobenzene in glacial acetic acid gives 2-arylpyrimido[4,5-Z>][l,8]naphthyridin-4(3//)-ones 402. Compounds 402 were also synthesized without isolation of naphthyridones intermediate 401 formed by condensation of amide 400 with aromatic aldehydes on refluxing in a mixture of nitrobenzene and glacial acetic acid (1987IJC(B)1194). 

Anthyridines are prepared in moderate yields by thermal cyclization of enaminones derived from 2-amino-l,8-naphthyridines (Table VIII, entry 6), or from dienaminones derived from 2,6-diaminopyridine (Table VIII, entry 7). 

In contrast to the DDA units described above, there are comparatively few dimeric AAD modules. Zimmerman and co-workers have developed a convenient synthesis of 2,6-diaminopyridine-3-carboxaldehyde (DPC), which undergoes a Friedlander reaction with ketones to produce 2-amino-1,8-naphthyridines [37]. For example, the reaction of DPC with tetra-cyclo[6.3.0.0 0 ]undecane-2,7-dione followed by acylation with octanoic anhydride produced 55. A number of diketones reacted similarly with DPC to produce bis-2-amino-l,8-naphthyridines with varying chromophore orientations. 

Pyridine 366 with a variety of activated and nonactivated ketones yields 2-amino-l,8-naphthyridines (09H(79)411) and bis(2-amino-l, 8-naphthyridines) in moderate to good yields, providing a convenient synthesis for useful building blocks utilized as new host-guest and selfassembling systems (93JOC6625). 

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