1.6- Naphthyridines, 2-amino

This section includes the chemistry of all types of amino group attached to 1,7-naphthyridine aspects already covered are indicated by cross-references. 

Note These amino compounds have been made by primary synthesis (see Chapter 15), by aminolysis of halogeno-1,7-naphthyridines (see Section 17.2), by reduction of nitro-1,7-naphthyridines, (see Section 20.1), or by direct amination as illustrated in Section 16.1.3 and by further examples here. 

8-Dichloro-l,7-naphthyridine (3, X = C1) gave 5,8-dichloro-l,7-naphthyridin-2-amine (4, X = Cl) (substrate, KNH2/NH3, 5 min then KMn04 in slowly 15 min 52%) likewise the dibromo derivative (3, X = Br) gave 5,8-dibromo-l,7-naphthyridin-2-amine (4, X = Br) (33%).819 

7-Naphthyridine 7-methiodide (5) underwent addition of ammonia and subsequent oxidation to give a mixture from which were isolated the hydriodide of 7-methyl-1,7-naphthyridin-8(7//)-imine (6, X = NH), 7-methyl-l,7-naphthyridin-8(7//)-one, and two ring contraction products (substrate, liquid NH3, —33°C KMn04 in slowly 20 min each in 5% yield).372 cf 460 

Note The oxidative removal of hydrazino groups has been exemplified in Section 16.1.1 as well as here, hydrolysis to naphthyridinones in Section 18.1.1, and transamination in Section 17.1 under aminolysis. l,7-Naphthyridin-4-amine gave a charge transfer complex with tetracyanoqui-nodimethane.416 

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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. 

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... 

Czuba65 has reported the isolation of three products (17-19) from the Skraup reaction with 3,5-diaminopyridine and has suggested that the 3-amino-1,5-naphthyridine is the logical precursor to compounds 18 and 19. 

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. 

An odd tele substitution also occurring in one ring has been observed on amination of 2-bromo-l,5-naphthyridine, yielding 4-amino-1,5-naphthyridine.21... 

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... 

A logical extension of the syntheses of the l,X-naphthyridines is the application of the Skraup reaction to aminonaphthyridines. When 4-amino-1,5-naphthyridine (78) is reacted with glycerol under Skraup reaction conditions, the expected pyrido-l,5-naphthyridine (79) is obtained.44 When... 

Somewhat similarly, 3-aminopicolinic acid with ethyl acetoacetate gave 2-methyl-l,5-naphthyridin-4(l//)-one (neat reactants, reflux, 4 h 13%).1000 3-Amino-2-pyridinecarbonitrile (31) with diethyl malonate gave 4-amino-1,5-naphthyridin-2(l//)-one (32) (neat reactants, EtONa, reflux, 7.5 h 36%).725... 

Ethyl 6-p-chlorophenoxy-4-(3-diethylaminopropyl)amino-1,5-naphthyridine-3-carboxylate (9a, R = C02Et) gave 2-/ -chlorophenoxy-8-(3-diethylaminopro-pyl)amino-7-hydroxymethyl-l,5-naphthyridine (9a, R = CH2OH) 11AIH,-Et20, 10 min substrate/Et2OJ, dropwise then 20°C, 1 h 32%).967... 

Phenoxy-l,5-naphthyridine (26) underwent aminolysis to afford 4-(4-diethy-lamino-l-methylbutyl) amino-1,5-naphthyridine (27) [neat H2NCHMe(CH2)3 NEt2, reflux, 3 h 90%].101... 

The hydrolysis of amino-1,5-naphthyridines has been covered in Section 4.1.1. Other reported reactions are illustrated by the following examples. 

Ethyl 4-amino-1,5-naphthyridine-3-carboxylate Ethyl 4-amino-2-oxo-l,2-dihydro-l, 5-naphthyridine-3-carboxylate Ethyl 4-anilino-1,5-naphthyridine-3-carboxylate Ethyl 7-bromo-1 -ethyl-4-oxo- 1,4-dihydro-1,5-naphthyridine-3-carboxylate Ethyl 7-bromo-4-oxo-l,4-dihydro-l, 5-naphthyridine-3-carboxylate Ethyl 6-butoxy-4-oxo-l,4-dihydro-l, 5-naphthyridine-3-carboxylate Ethyl 4-butylamino-l,5-naphthyridine-3-carboxylate... 

Amination of 1,5-naphthyridine (1) with sodamide in liquid ammonia at room temperature was reported by Hart " to give 2-amino-1,5-naphthyridine... 

Reaction of 2-bromo-l,5-naphthyridine (17) with KNH2/NH3 gives, in addition to 2-amino-1,5-naphthyridine (48 77%) formed via 149, 4-amino-... 

To 15 mL liquid ammonia containing potassium amide, obtained by a reaction with 0.15 g potassium was added 0.20 g 1,5-naphthyridine. After the mixture was stirred for 10 min and 0.80 g KMn04 was added in small portions, the mixture was stirred for another 10 min. The potassium amide was then decomposed with (NH4)2S04. After evaporation of the ammonia, a concentrated aqueous solution of ammonia was added, and the mixture was continuously extracted with chloroform over 48 h. The residue obtained on evaporation of the chloroform was taken up in a minimum amount of methanol and developed by use of an Autoliner Desaga (model 121000) on a plate (20 x 40 cm) covered by a 2-mm layer of silica gel DFW and eluted with chloroform/ethanol (10 1) to give one band, which was extracted with methanol. Evaporation of methanol afforded 80 mg 2-amino-1,5-naphthyridine, in a yield of 36%, m.p., 203.5-205°C. 

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