1.5- Naphthyridine, amino-, formation

It was reported that the Niemeiitowski synthesis of 4-hydroxy-3-iiitro-7-pheiiyl-l,8-iiaphthyridiii-2(lH)-oiie (25) from ethyl 2-amiiio-6-pheiiyhii-cotiiiate (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). 

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). 

However, in view of the results mentioned earlier, direct attack of the amide ion on position 2 seems highly unlikely. An Sn(ANRORC) mechanism, starting with an attack of the amide ion at position 6 containing the amino group, seems to be involved. Adduct formation at a position already occupied by an amino group is not unprecedented. The conversion of 4-amino-2-bromoquinoline into 4-amino-2-methylquinazoline (72RTC841) and of 4-amino-2-bromo-l,5-naphthyridine into 4-amino-2-methyl-l,3,5-... 

The conversion of 3-amino-4-oxo-l,jc-naphthyridines (117) into the corresponding 3-diazo-4-oxo compounds (118) followed by photolysis results in the formation of azaindoles (119) via nitrogen evolution and ring contraction (56LA(599)233, 60JCS1794). 

At low temperature, 1,7-naphthyridine is converted to a mixture of adducts 50 and 52 the formation of the formerly proposed 51 was definitely ruled out. Positions 2 and 8 have the lowest electron densities. However, on warming the reaction mixture to 10°C, only 52 is detected as the apparently more stable adduct. When the solution of 50 and 52 in NH2"-NH3 was treated with potassium permanganate not only were the 2-amino- and 8-amino-1,7-naphthyridines formed but also the 4-amino isomer, indicating the possible intermediacy of the undetected 4-ff-adduct. 

The amination reaction carried out at -33°C gives a mixture consisting of 4-amino-, 8-amino-, and 2-amino-1,7-naphthyridine, 4-amino-2-methyl-1,3,7-triazanaphthalene, and some unsubstituted 1,7-naphthyridine. The composition of this mixture is not related to that of the adducts described above in any simple way. Adducts 54 and 56 are suggested to be involved in the formation of the 8-amino and 4-amino derivatives, respectively, by a tele-amination mechanism.111 Scheme 3 illustrates one of these proposed paths. 

Under these conditions the amination reaction yields a mixture of 2-amino- and 8-amino-1,7-naphthyridines in a nearly 1 1 ratio. Here again the observed a-adduct is responsible for the formation of only one of the products, the 2-amino compound, which arises by a tele amination mechanism. The other amine requires some other as yet undetected a-adduct.111... 

H- and 13C-NMR spectroscopy of a solution of 13 in KNH2/NH3 shows that H-l and C-l have undergone upheld shifts of 4.24 ppm and 83.7 ppm, respectively (Tables II and III).20 This is due to the formation of 1-amino-dihydro-2,6-naphthyridinide (14). Because 2,6-naphthyridine is reported to have the lowest electron density at position 11819 (Table I), the formation of cr-adduct 14 is in good agreement with these calculations. The spectrum of... 

However, 3-methyl-1,8-naphthyridine (37b) reacts with KNH2/NH3 in a completely different way than do 37a and 37c.15 H- and 13C-NMR spectroscopy unequivocally show the formation of the 1 1 cr-adduct 2-amino-3-methyldihydro-l,8-naphthyridinide (40) (Table V). No addition at C-7 is observed, although this position is also vulnerable to nucleophilic attack (see Section II,A,4). Similar behavior has been found in the Chichibabin animation of 3-methylpyridine the amide predominantly attacks C-2 and not C-6.33 This result has been explained by an ion dipole attraction between the incoming amide ion and the methyl substituent.34 This type of attractive interaction also possibly determines the attack on C-2 in 37b. 

Addition of potassium permanganate to a solution of 6 in KNH2/NH3 at -40CC did improve the yields of 53 and 54 considerably (26% and 19%, respectively)16 however, some 4-amino-l,7-naphthyridine (55 10%) was also found unexpectedly. The formation of 55 suggests the intermediacy of 4-aminodihydro-l,7-naphthyridinide (10), although no indication for its existence has been found by NMR spectroscopy. 

Convincing evidence has also been presented for the formation of the intermediate 3,4-didehydro-1-ethyl-l,5-naphthyridin-2[l//]-one (75),53 of the anion of 2-amino-3,4-didehydro-1,5-naphthyridine (76)52 and of 2-bromo-3,4-didehydro-l,5-naphthyridine (77).52... 

Reaction of 2-amino-3-bromo-1,5-naphthyridine (81) with potassium amide gives 2,3-diamino-1,5-naphthyridine (82), the formation of which can be explained by a site-specific addition of the amide ion to C-3 in the anionic intermediate (76).52 This addition pattern is very similar to the one observed... 

On dissolving 3-chloro-l,7-naphthyridine (98a) in liquid ammonia containing potassium amide unambiguous H-NMR evidence for the formation of the cr-adduct 2-amino-3-chloro-l,2-didehydro-l,7-naphthyridinide (103) has been obtained26 (Section II,B,1). Apparently tr-adduct formation at C-2 in 98a precedes the formation of the 3,4-didehydro compound (99). This... 

Chloro-l,7-naphthyridine (110 X = Cl) gives on animation with KNH2/ NH3 the tele product 2-amino-1,7-naphthyridine (53) in addition to the ipso product 8-amino-l,7-naphthyridine (54).10 25 The formation of 53 involves as intermediates anionic cr-adduct 111 (X = Cl) (its existence has been proved by NMR spectroscopy see Section I1,B,1) and probably 2-amino-2,8-dihydro-8-chloro-1,7-naphthyridine (112). The latter undergoes a base-catalyzed dehydrochlorination, yielding 53. Because there are four atoms between position 2 and 8. the reaction is called an even tele substitution. 

Amination of 5-bromo-l,6-naphthyridine (113) gives as tele product 2-amino-l,6-naphthyridine (51 ),24 but in addition to the intermediacy of anionic cr-adduct (114) (as proved by H-NMR spectroscopy), its formation involves anionic cr-adduct 115, which is formed by a proton shift from 114. The number of atoms between positions 2 and 5 is five, thus this reaction is referred to as an odd tele substitution. Both types of tele substitution involve Addition of the nucleophile as the initial step and Elimination of the leaving group as the last step. However, in the even tele substitution the elimination can be described to take place from a neutral dihydro species, while in the odd tele substitution the elimination must occur from an anionic intermediate. In the naphthyridines several examples of even and odd tele substitutions are found, and in the following sections the results of studies concerned with tele amination are presented. 

One example has been reported of the occurrence of an even tele substitution within one ring of the 1,7-naphthyridine system. Amination of 5-halogeno-l,7-naphthyridines (27) with potassium amide gave 8-amino-1,7-naphthyridine (54).28 This reaction bears a close analogy to the formation... 

Reaction of 2-bromo-l,5-naphthyridine (17) with KNH2/NH3 gives,22 in addition to 2-amino-l,5-naphthyridine (48 77%) formed via 149, 4-amino-1,5-naphthyridine (49 1%) and product C8H8N4, which was later proved to be 4-amino-2-methyl-1,3,5-triazanaphthalene (151 11%).23 The ring transformation of 17 into 151 is explained by the intermediary formation of C-4... 

Amino-2-bromo-1,5-naphthyridine (84) may be an intermediate (see Section III,B,l,a for its formation) that undergoes a covalent amination at C-4, yielding the gem 4,4-diamino-2-bromodihydro-l,5-naphthyridinide (153) and an amino debromination at C-2, yielding 85. Ring opening of 153... 

Sawyer and Wibberley5 demonstrated that the product obtained by Singh et al.i2 in the reaction of 2-amino-4-methylpyridine and acetylacetone in polyphosphoric acid was not the naphthyridine but was instead the enamine of type 5, which was formed by hydrolysis of the pyrido[l,2-a]pyrimidinium salt (6) when the reaction mixture was neutralized. Formation of both isomeric pyrido[l,2-c<]pyrimidinium salts with asymmetric 1,3-diketones (R1 R2) was occasionally observed.3... 

Thermolysis of 3-(2,2-dicyanovinyl)-4-(l-piperidyl)pyridine (15, X = CH2) in DMSO produces the naphthyridine (16, X = CH2) by means of the "tert-amino effect" proposed by Meth-Cohn and Suschitzky <95SL622>. Where, however, X is a N, O or S an alternative cyclisation takes place, when the pyridoazepines (17) are formed. This new variant of the "rert-amino effect" is postulated to arise by the intermediate formation of (18). 

Methyl 2-amino-l,6-naphthyridine-3-carboxylate (13, R = Me) underwent amino lysis to give 2-amino-l,6-naphthyridine-3-carbohydrazide (14, R = NH2) (neat H2NNH2 H20, reflux, 30 min 83%) or 2-amino-fV-amidino 1,6-naphthyridine-3-carboxamide [14, R = C( = NH)NH2] [HN=C(NH2)2, MeOH, reflux, 1 h 80%] 247 another example of such amide formation.108,946... 

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