Amino-1,8-naphthyridines cyclizations

Representatives of the pyrrolo[3,2-/][l,7]naphthyridine ring system, viz. 61, have been obtained by palladium-catalyzed cyclization of the corresponding 5-alkenyl-6-amino[l,7]naphthyridines (Scheme 19) <2002H(56)443>, although this reaction appears not to be general and its scope is as yet undefined. 

Azolo[l,8]naphthyridines. The reactions of the chloronaphthyridine 229 with o-phenylenediamine at 200 °C and with sodium azide in acetic acid give the fused-ring products 230 and 231, respectively (Scheme 54) <2003IJB192>. Amino acid-substituted naphthyridines can be cyclized to the fused imidazolones 232 upon treatment with phosphorus oxychloride and under microwave irradiation (Equation 62) <2002SC857>. Acylation of 2-hydrazino-naphthyridines followed by heating gives W-acyl compounds which are cyclized intramolecularly to the [l,2,4]tri-azolo[4,3- ][l,8]naphthyridines 233 (Scheme 55) <1996IJB106>. The same compounds may also be obtained from... 

When Af-(6-amino-2-pyridyl)aminomethylenemalonate (1001, R = NH2, R1 = H) was heated in a 1 1 mixture of acetic anhydride and Dowtherm A, 7-acetamido-l,8-naphthyridine-3-carboxylate (1003, R = NHAc, R1 = H) was obtained (62BEP612258). This product (1003, R = NHAc, R1 = H) was also prepared in 58% yield, by the cyclization of Ar-(6-acetamido-2-pyridyl)aminomethylenemalonate (1001, R = AcNH, R1 = H) in boiling Dowtherm A for 15 min, and in 88% yield in the reaction of 2-amino-6-acetamidopyridine and EMME under similar conditions (71G129). 

The cyclization of diethyl iV-substituted N-(6-alkyl-2-pyridyl)amino-methylenemalonates (265, R2 = Et) in polyphosphoric acid at 200-230°C for 10 min gave 1-substituted 7-alkyl- 1,4-dihydro-1,8-naphthyridine-3-carboxylic acids (1022, R = Me, Et R1 = alkyl R2 = H) in 17-56% yields (71GEP2108046). From the mother liquor, 2-(substituted amino)-6-alkylpyridines could be recovered. 

Diethyl mercapto[(2-pyridyl)amino]methylenemalonate (1724) was treated with methylene iodide in DMF in the presence of potassium carbonate at 50-60°C for 6 hr to give 3-(2-pyridyl)-l,3-thiazetidin-2-ylidene malonate (1725) (89EUP312794). Thiazetidinylidenemalonate ( 1725) was cyclized in fuming sulfuric acid at 0°C for 12 hr to give 4-oxo-l,3-thiazeto[3,2-u]-l,8-naphthyridine-3-carboxylic acid (1726) in 61% yield. 

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... 

JAP624149) and a wide variety of l-lV-alkylperhydro-l,7-naphthyridines (207) have been obtained by reaction of the ether (208) with various alkylamines (66KGS427). A convenient synthesis of 5-hydroxy-2-oxo-l,2,3,4-tetrahydro-l,7-naphthyridine (211) starts from the 3-substituted amino isonicotinaldehyde (209) which undergoes a Wittig reaction followed by reduction to give (210), a compound that cyclizes readily in acid solution to (211) (82CPB1257). 

Amino-5,6,7,8-tetrahydro[l,6]naphthyridine-3-carbonitriles have been further cyclized with guanidine hydrochloride to give tetraazaanthracenes <2002JME5173>. 

Aryl-l,2-dihydro-3-nitro[l,8]naphthyridines have been obtained by the 6jt-thermal electrocyclization of l-(2-arylide-neamino-3-pyridyl)-2-nitroethylenes, obtained in situ from aromatic aldehydes and l-(2-amino-3-pyridyl)-2-nitroethylene in xylene <2002SC747>. 2-Chlorotetrahydro[l,8]naphthyridines have also been obtained from 2,6-dichloropyridines using a free radical xanthate-mediated cyclization <20040L3671>. 

Solid-phase syntheses have become increasingly popular during the period of this review, with examples including the synthesis of 5,6,7,8-tetrahydro[l,6]naphthyridines from Meldrum s acids derived from /3-amino alcohols via Hantzsch condensation and cyclization with cyclative cleavage from the resin (using 70% trifluoroacetic acid (TFA)/dichloromethane (DCM) followed by 5% triethylamine/DCM) <1999S1951> and also of isoquinolinones and 5-oxo-5,6-dihydro-[l,6]naphthyridines <1995JOC5748>. 

Reaction of 3-aminoisoquinolin-l (2//)-one and diethyl ethoxymethy-lenemalonate in boiling pyridine for 2.5 h yielded diethyl [(l-oxo-1,2-dihydro-3-isoquinolinyl)amino]methylene malonate (197), which was cyclized into abenzo[c][l,8]naphthyridine-2-carboxylate (198) and a pyrim-... 

It is of interest that, although the Skraup reaction62 on 3-amino-pyridine 1-oxide affords 1,5-naphthyridine, the EMME synthesis on this compound affords the l,7-naphthyridine-7-oxide.28 It has been suggested that the 3-aminopyridine 1-oxide is deoxygenated prior to the Skraup reaction so that, in fact, it is 3-aminopyridine that is directly converted to the 1,5-naphthyridine. The EMME cyclization, on the other hand, follows the expected direction of cyclization. 

A substituted 7-oxide (54) (see Section III, C) of 1,7-naphthyridine has been prepared by the condensation and cyclization of 3-amino-pyridine with EMME. 

Under nonhydrolytic conditions, 2-amino-1,8-naphthyridines (82) do, however, undergo the normal cyclization reactions with a-bromo ketones. Thus, imidazo[l,2- ]naphthyridines (83) are readily obtained.45... 

The cyclization of [(6-ethoxycarbonyl-2-pyridyl)amino]malonate 138 in Dowtherm A for 0.5 hour gave 48% 4-oxo-4//-pyrido[l,2-a]pyrimidine-3,6-dicarboxylate 139 and 6.8% 4-hydroxy-l,8-naphthyridine-3,7-dicarboxylate 140 (85JHC481). 

A suspension of the diazonium salt in toluene was gradually heated and kept at 120°C (bath temp.) for 30 minutes with stirring. After evaporation of the solvent under reduced pressure, the residue was made alkaline with 10% sodium carbonate and then extracted with chloroform. The chloroform extract was dried over anhydrous potassium carbonate. After evaporation of the solvent, the crystalline residue was recrystallized from ethyl acetate to give 6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoropyridine (mp 132°-133°C). The 3-fluoro derivative was hydrolyzed with a mixture of 15% hydrochloric acid and methanol (1 2 v/v) to give 6-amino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoropyridine. This compound was treated with diethyl ethoxymethylenemalonate at 130°-140°C to give N-[2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate (mp 144°-145°C) and then the product was cyclized by heating at 255°C to give ethyl 7-(4-ethoxycarbonyl-l-piperazinyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (mp 279°-281°C). 

Diethoxycarbonylvinyl)amino]-5,6-dimethylpyridine (17) underwent regioselective thermal cyclization to give ethyl 6,7-dimethyl-4-oxo-l,4-dihy-dro-l,5-naphthyridine-3-carboxylate (18) (Dowtherm A, reflux, 15 min 89% analogs likewise).1398... 

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... 

The ketone, 2-picolinoylmethyl-l,5-naphthyridine (23), underwent a-bromination and subsequent cyclization with thiourea to give 2-[2-amino-4-(pyridin-2-yl)thiazol-5-yl]-l,5-naphthyridine (24) [substrate, Br2, dioxane, 20°C, 1 h solid, EtOH, (H2X)2CS, reflux, 4 h 16%].268... 

A mixture if cis- and fraw.v-isomers of diethyl 2-amino-3-(2-aminoethyl) hexanedioate (1) underwent thermal cyclization to give a separable mixture of cis- and frani-3,4,4a,5,6,8a-hexahydro-l,7-naphthyridine-2,8(l//,7//)-dione (2) (by sublimation at 200°C/0.1 mmHg 69%).1087... 

Note Amino-1,8-naphthyridines and the like undergo a variety of cyclization reactions a few typical examples are given here. 

A mi no-6-oxo-l-phenyl-4-(iV-phenylcarbamoyl methyl)-1,6-dihydro-3-pyridi-necarbonitrile (15) underwent thermal cyclization to l-amino-6-hydroxy-8-imino-2,7-dipthenyl-2,3,7,8-tetrahydro-2,7-naphthyridin-3(2//)-one (16) (Et3N, Me2NCHO, reflux 60%) also somewhat similar cyclizations.802... 

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