Amination of naphthyridines

The first paper on the addition of water to the C=N bond in naphthyridines (covalent hydration) appeared in 1963,9 but it was not until 1976 that the first report concerning covalent amination of naphthyridines using potassium amide in liquid ammonia was published.10... 

Amination of naphthyridines can be carried out under kinetic or thermodynamic conditions <83AHC(33)95>, for example treatment of 1,5-naphthyridine (1) with KNH2—NH3 gives addition at C-2 (kinetic adduct) at —40°C, and addition at C-4 (thermodynamic adduct) at 10°C. 

The amination of 2-bromo-l,5-naphthyridine also proceeds without rearrangement to yield 2-amino-1,5-naphthyridine (up to 80%) together with 1,5-naphthyridine (10%) and a substance (CgH8N4,10% yield) of unknown structure as by-products. Thus, here also it remains uncertain whether a 2,3-aryne is an intermediate. 

In all 3-nitronaphthyridines with an unsubstituted C-2 position (84a, 84f, and 84j) no traces of the corresponding 2-amino-3-nitro-l,X-naphthyridines (X = 5, 6, and 8) were obtained. As already mentioned, in the aminations of 2-R-3-nitronaphthyridines where R is a chloro or ethoxy group, no amino-dechlorination or amino-deethoxylation was observed. 

Substituted-3-aryl[l,6]naphthyridin-2-amines and 7-substituted-3-aryl[l,6]naphthyridin-2(l//)-ones have been prepared by diazotization of 3-aryl[l,6]naphthyridine-2,7-diamines, themselves obtained by the condensation cycli-zation of 4,6-diaminonicotinaldehyde and phenylacetonitrile <2000J(P1)1843>. Derivatives of cyanoacetic acid have rarely been used in the synthesis of naphthyridines, although a recent study has shown that they may be reacted with 4-piperidone derivatives to give [l,6]naphthyridines <2000CHE496>. 

Naphthyridine undergoes NH2" attachment at position 1 at -30°C. The NMR spectrum of the resulting adduct does not change at 20°C. Accordingly, the amination of the same substrate yields 1-amino-2,6-naphthyridine.110 A similar behavior is displayed by 2,7-naphthyridine, attachment of the reagent occurring at position l.110 Also in this case the Chichibabin amination occurs at room temperature at the same position. 

One route to the tetrahydro-1,8-naphthyridine (84) employs an intramolecular amination of compound 83 in the presence of sodium.47... 

Studies have been made of the covalent amination of 3-nitro-l,X-naph-thyridines (X = 5,6, and 8).27 35 In contrast to the parent systems and their halogen and methyl derivatives, 3-nitronaphthyridines undergo covalent amination with weak nucleophilic liquid ammonia at — 45 C. The electrophilic character of the naphthyridine system is enhanced by the presence of the nitro group. 3-Nitro-l,8-naphthyridine (41a) undergoes addition at... 

The mechanism of the Chichibabin amination of pyridine has been discussed in terms of an addition-elimination mechanism via a covalent a-adduct.38 39 The possible formation of 2,3-didehydropyridine (2,3-pyridyne) as intermediate in the Chichibabin amination has been advocated, but this is now definitely rejected.38 39 In this section we discuss the Chichibabin amination of the parent naphthyridines and their derivatives and the products that are obtained in these aminations. The formation of their precursors (the covalent n-adducts) has already been discussed in Section II,A and II,B. 

Amination of 1,5-naphthyridine (1) with sodamide in liquid ammonia at room temperature was reported by Hart40 togive2-amino-l,5-naphthyridine (48). Other work has shown that under the conditions described by Hart,... 

Other work has been carried out concerning the amination of 3-nitro-1,5-naphthyridine (46a) with liquid ammonia containing potassium permanganate.27 The 4-amino-3-nitro- 1,5-naphthyridine (50) is obtained in 50% yield. Its precursor, the covalent rr-adduct (47a), has been detected by NMR spectroscopy (see Section II,B,3). 

Chichibabin amination of 1,6-naphthyridine (4) with KNH2/NH3 at room temperature gives 2-amino-l,6-naphthyridine (51) in 33% yield.19 When the... 

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-1,8-naphthyridine (58) is formed (29%)19 at 50°C 58 is also the sole compound,5,50 in increased yield (78%). These... 

Extensive investigations have been carried out in order to establish the intermediary occurrence of didehydro-1,5-, -1,6-, -1,7-, and -1,8-naphthyri-dines in aminations of halogenonaphthyridines with potassium amide in liquid ammonia. These studies have definitively proved that 3,4-didehydro-1, X-naphthyridines (X = 5, 6, 7, 8) are intermediates in aminations of the 3-and 4-bromo (chloro) derivatives of the I. X-naphthyridines.22,24-48-50 No evidence has been found for the occurrence of 2,3-didehydro-1,X-naphthyridines in these reactions. Also, in the reaction of the 2-halogeno-l,X-naphthyridines no evidence for these 2,3-didehydro intermediates was obtained. 

These results combined with those obtained in the aminations of the 3-halogenoquinolines (Section III,B,1) show that 3,4-didehydro-1,5-naphthyri-dine (68) is an intermediate and that 2,3-didehydro-l,5-naphthyridine does not occur, because if it had, then 2-amino- 1,5-naphthyridine should have been formed. 4-Bromo-1,5-naphthyridine (70) also gives a mixture of 69 and 49. The ratio is 77 23, which indicates that the 4-bromo compound (70) undergoes SN(AE),pso aminodebromination to 4922 in addition to an SN(EA) process via 68, yielding 49 as well as 69. 

Amination of 4-bromo- and 4-chloro-l,8-naphthyridine (108a and 108b) also affords a mixture of 107 and 109 (ratio of about 30 70 determined by H-NMR spectroscopy of the crude reaction mixture).29 This ratio is somewhat different from that found in the amination of 105b (43 57) and indicates that 108 undergoes an aminodebromination at C-4 [SN(AE) pso], in addition to the SN(EA) reaction involving the intermediacy of 106 It was calculated that 4-bromo-1,8-naphthyridine reacts at about 40% according to this SN(AE) process and 60% according to the S EA) mechanism.29... 

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... 

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