2- Amino-1,8 -naphthyridine, nitration

Several approaches to the synthesis of nitronaphthyridines and their derivatives are reported. Very common ones are those in which the construction of the nitronaphthyridine system was achieved by using nitro synthons (see Section II,A) or by nitration of the naphthyridine ring, although a successful nitration requires the presence of electron-donating substituents (see Section II,B). Furthermore, the oxidation of the amino group in aminonaphthyridines... 

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. 

Tlie products of nitration of 2-amino-5-phenyl-l,8-naphthyridin-7(8H)-one (63) vary depending on whether the reaction is carried out with nitric acid in sulfuric acid or in acetic anhydride (74GCI499). In sulfuric acid the phenyl ring was found to be nitrated more easily than the naphthyridine ring, yielding a mixture of 3- and 4-nitrophenyl derivatives (64) in acetic... 

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). 

Nitration, suggested to involve nitrosation/oxidation, occurs during diazotization of some substituted 2-amino-1,8-naphthyridine derivatives (15).41 The selectivity of this process was contrasted with that of the nitronium ion reaction. 

Note Unsubstituted 1,8-naphthyridine resists nitration even under severe conditions, but the presence of an electron-releasing amino or oxo substituent enables more facile 3/6-nitration to occur. Even so, if a phenyl group is also present, extranuclear nitration occurs first. 

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. 

For 2,6-naphthyridine (184) and 2,7-naphthyridine (185), the C-1 o-adducts are both kinetically and thermodynamically stable (70JHC419 81JHC1349). At room temperature, 184 was aminated with potassium amide and potassium nitrate in liquid ammonia in 54% yield, but the yield was only 18% from low-temperature amination with potassium amide and potassium permanganate in liquid ammonia (Scheme 69). Similarly, permanganate oxidation afforded only 8% l-amino-2,7-naphthyridine (81JHC1349). 

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