2-Amino-7-methyl-1,8-naphthyridine

Kelly et al. (51,52) designed a two-binding-site host that accelerates an Sn2 reaction between a primary aliphatic amine and an alkyl bromide. Their host (Figure 14) acts as a template for the two reactants, amino-methyl- and bromomethyl-naphthyridine each aminopyridone group of the host forms three hydrogen bonds to each reactant. This binding is rather strong (K s > 10 M ). The authors observed a sixfold acceleration of the Sn2 reaction but could not prove or disprove that turnover was catalytic. 

Amide-induced pyridine-pyrimidine transformation is also reported with 2-bromo-l, 5-naphthyridine. 2-Methyl-4-amino-l, 3,5-triazanaphtha-lene is obtained, together with its 4-amino derivative The presence of the amino group at position 4 is certainly due to a SnH amino-dehydrogenation in preformed 2-methyl-l,3,5-triazanaphthalene (63RTC997, 73RC459, 94MI1). 

The ring closure of N-(l-methyl-2-oxo-l,4-dihydropyrid-3-yl)amino-methylenemalonate (985) in refluxing Dowtherm A for 25 min under nitrogen gave 1,7-naphthyridine-3-carboxylate (986) in 83% yield (81JHC941). 

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-... 

Pharmaceutically important 3-substituted-[l,8]naphthyridine-2,4-diones have been prepared by the reaction of 2-methyl-477-pyrido[2,3-r/][3,l]oxazin-4-one with active methylene compounds (Scheme 66) <1997J(P1)1487, 2003JOC4567> and by the same group via an intramolecular azadiene-ketene electrocyclization reaction of amino-nicotinic acid derivatives in a related process <2001JOC4413>. 

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. 

E. V. Brown105 has described the synthesis of 2-methyl-l,8-naphthyridine, and several new derivatives by the EMME synthesis, starting with 2-amino-6-methylpyridine. 

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. 

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... 

Quite similar to the conversion of 17 and 83 into 151 is the reaction of 2,6-dibromo- 1,5-naphthyridine (155) with KNH2/NH3, which gives ring transformation into 6-bromo-2-methyl-1,3,5-triazanaphthalene (156), as well as 2-amino-6-bromo- 1,5-naphthyridine and 2,6-diamino-1,5-naphthyridine.74... 

It has been reported that 2-bromo(chloro)-l,7-naphthyridine (22) with KNH2/NH3 gives 4-amino-2-methyl-l,3,7-triazanaphthalene (162),25 in addition to 2-amino-l,7-naphthyridine (53) and two tele amination products, 4-amino-(55) and 8-amino-1,7-naphthyridine (54). 

Lappin s publication, 1,8-naphthyridine (72 R = NH2) was obtained under similar conditions from the 6-amino derivative of 70 by Adams et al.127 The special behavior of the 6-substituted derivatives of 70 was ascribed by Lappin126 to the steric hindrance effect of the 6-substituent. Some later results,29 128 however, contradicted Lappin s concept. On vacuum distillation of the 2-(6-methyl-2-pyridylaminomethylene)acetoacetate and -cyano-acetate, Antaki did not obtain the 1,8-naphthyridines but instead the 3-substituted 6-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidines.29 By the thermal ring closure of 70 (R = 5-CONH2) Richardson and McCarty128 obtained a product described as a 1,8-naphthyridine of type 72. 

Flowers et al.164 reacted perfluoro-2-methyl-2-pentene with 2-aminopyri-dine or 2-amino-4-methylpyridine in tetrahydrofuran at room temperature to obtain the pyrido[1.2-u]pyrimidines (95). Reaction with 2-amino-6-methylpyridine yielded the 1,8-naphthyridine (96). 

The amino moiety of the 3-carbohydrazide group of unsaturated and 6,7,8,9-tetrahydro-4-oxo-47/-pyrido[l,2-n]pyrimidine-3-carbohydrazides was condensed with acetone and 5-nitro-2-furoaldehyde (830MR687 88EUP252809). The reaction of 6-methyl-6,7,8,9-tetrahydro-4-oxo-4//-pyrido[l,2-a]pyrimidine-3-carbohydrazide with diethyl 2-[2-dimethyl-amino)vinyl]-6-methylpyridine-3,5-dicarboxylate in boiling ethanol for 4 hours afforded N-( 1,6-naphthyridin-6-yl)-4-oxo-4//-pyrido[ 1,2-a]pyrimi-dine-3-carboxamide 426 (85MIP1). 

Hydroxy-2-methyl-3-phenylpropyl)amino]pyridine (24) underwent dehy-drative cyclization to give 3-methyl-4-phenyl-l,2,3,4-tetrahydro-l,5-naphthyridine (25) (70% H2S04, 0°C —>25°C, 15h 65%) that was easily dehydrogenated to give 3-methyl-4-phenyl-l,5-naphthyridine (26) (neat substrate, Pd/C, 200°C, 3 h 56%).879 Also other examples.48 485 865 967 1232 1245... 

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... 

Methyl 6-bromo-4-[A -(2-ethoxycarbonylethy] )-/V-ethyl amino -3-pyridinecar-boxylate (26) gave ethyl 7-bromo-l-ethyl-4-oxo-l,2,3,4-tetrahydro-l,6-naphthyridine-3-carboxylate (27) (substrate, Bu OH, NaH, 20°C, 30 min 85%) an analog likewise.1408... 

Ethyl 5-amino-7-benzylseleno-8-cyano-4-(fur-2-yl)-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (41) underwent deheterylation to give ethyl 5-amino-7-benzylseleno-8-cyano-2-methyl-1,6-naphthyridine-3-carboxylate (42) (AcOH, reflux, 1 h then 20°C, 24 h 72%).959... 

The structure of 7-amino-5-bromo-4-methyl-2-oxo-l,2,3,4-tetrahydro-l, 6-naphthy-ridine-3-carbonitrile (1), prepared by an ambiguous synthesis, has been confirmed by x-ray analysis.779 Mass spectral fragmentation patterns for bromo-1, 6-naphthyridines to have been investigated.546... 

---