Amino-2,7-naphthyridines preparation

The 2,7-naphthyridine system 53 (Scheme 8.4.18) was combined with 2,4-dinitrochlorobenzene and 2-amino glycerol for in situ reaction of the resulting Zincke salt. The resulting naphthyridinium 54 was trapped by Bradsher cycloaddition with (Z)-vinyl ether 55, providing tetracycle 56 (X-ray) upon internal addition of one of the diastereotopic hydroxymethyl groups to the resulting iminium. This approach was also extended to the use of chiral 2,7-naphthyridinium salts, prepared via the analogous Zincke process. ... 

In this method the nitro group in the aliphatic nitro compound is usually present on a carbon atom, which is also activated by CO-functioiiality (aldehyde, ester, arylketoiie). A successful application of this method is the Borsche modification of the Friedlander synthesis, involving condensation of A-(3-amino-4-picolylidene)-p-toluidine (17) with [Pg.289]

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). 

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... 

A range of enantiomerically pure (R)- and (S)-, (E)- or (Z)-oxime ethers of 2,3-dihydro[l,8]naphthyridine have been prepared from 2-amino-6-methylpyridine <2000EJM815>. The selective acetylation of the same compounds in the 1-, 4-, or 1,4-positions has also been reported <1996JHC1185>. 

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 amino carbinol pyridines 264, prepared from 263 by DoM reaction and aliphatic or aromatic carboxaldehyde quench, are useful intermediates for condensed naphthyridines 266-268. The thermolytic reaction proceeds via intramolecular Diels-Alder reactions of the aza-orf/io-quinodimethane species 265 (Scheme 79) (84CC1304). 

Czuba07 prepared 2-, 3-, and 4-bromo-1,5-naphthyridine and treated them with potassium amide in liquid ammonia. The results of this study were explained by the intermediacy of 1,5-naphthyridyne-3,4 (133)149 in the reaction of the 3- and 4-bromo derivatives. A competing addition-elimination mechanism was also suggested since the ratios of the amino products from the 3- and 4-bromo compounds were not the same.147... 

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. 

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... 

These heterocycles are prepared exclusively by the electrocyclization of in situ generated ortho-diazonium thiolates <78PJC2039>. This is illustrated by the syntheses of (i) antiinflammatory 7-amino[l,2,3]thiadiazolo[5,4-6]pyridine-6-carboxylic acids (202) <76USP3965108> from penta-substituted pyridines (201) and (ii) antibacterial thiadiazolo[5,4-h][l,8]naphthyridine carboxylic acids (203) (Equation (25)) <80CPB76l>. 

However, attempts to prepare 3-nitro-l,8-naphthyridine (11) by the Skraup reaction—heating of 2-amino-5-nitropyridine with glycerol in the presence of an oxidant—were not successful (74YZ1328). 

Ethyl-4-hydroxy-6-iodo-7-methyl[ 1,8]naphthyridine-3-carboxylate has been prepared by thermal rearrangement of diethyl- [(5-iodo-6-methyl-2-pyridinyl)amino]-methylenejmalonate in diphenyl ether as illustrated in Eq. 1 and is described (1). 

The preparation of l-amino-2,6-naphthyridine ° (60) and 1-amino-2,7-naphthyridine (61) in yields of 23% and 56%, respectively, has been... 

The reactions of N-substituted 2-chloro- or 4-chloronicotinamides with nitriles containing an active methylene group in the presence of bases were used for the preparation of amino derivatives of l, 6-naphthyridin-5(6//)-one or 2,7-naphthyri-din-1 (2//)-one, respectively (1996MI1, 1997JHC397). 

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