2.7- Naphthyridine amination

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. 

Chloro-6-methyl-l,5-naphthyridine reacts readily with methano-lic methoxide (65°, 7 hr, 75% yield), but more vigorous conditions (180°, 2-7 hrs, 30-85% yield) were used for various aminations. The 4-chlorodiazanaphthalene reacted with a sec-alkylamine under less vigorous conditions (95%, 36 hr, 85% yield) and with ammonia-phenol (180°, 3 hr, 50% yield) gave the phenoxy derivative which was also alkylaminated (200°, 3 hr, 90% yield).The 3-bromo and 3-bromo-2-ethoxy derivatives of428 were aminated with copper sulfate and concentrated ammonia (170°, 40 hr, 75% yield). 

The familiar pattern of 2-amination with sodamide ( — 33°, 90% yield) occurs also with 1,5-naphthyridine. Greater reactivity at the 2-position is attributed, as before, to a cyclic transition state with electrophilic attack at a ring-nitrogen concomitant with nucleophilic attack adjacent to the cationic center thus formed. 

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. 

The compounds 87a and 87b are aminated at position 4, yielding the 4-amino compound (88a, 40%) and the 2,4-diamino compound (88b, 11%) respectively the 2-ethoxy compound (87c), however, undergoes amination at position 4 as well at position 5, giving a mixture of the 4-amino compound (88c, 20%) and the 5-amino compound (89a, 14%).Tlie 2-chloro compound (87d) yields a highly complex reaction mixture from which the 5-amino compound (89b), the 2,4-diamino derivative (88b), and 2,5-diamino-l,8-naphthyridine (89c) could be isolated. l-Ethyl-3-nitro-l,8-naphthyridin-2(lH)-one (90a) and 3,6-dinitro-l-ethyl-l,8-naphthyridin-2(lH)-one (90b) were aminated exclusively in the 4-position to give compounds 91a (62%) and 91b (45%), respectively (93LA471). 

Treatment of ethyl 4-chloro-7-diethylamino-6-nitro-l,8-naphthyridine 3-carboxylate (104) with the amines RH [R = N(CH2)s NH(CH2)N(C2Hs)2] gives the corresponding 4-amino derivatives [105, R = N(CH2)s, 74% and 105, R = NH(CH2)N(C2Hs)2, 50%]. With diethylamine the 7-chloro-6-nitro derivative of nalidixic acid (i.e., 106) yields the 7-diethylamino compound 107 (62%) (79YZ155). 

It is interesting that somewhat similarly 4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l, 2- ]pyrimidine (A) was transformed into 5,6,7,8-tetrahydro-l,8-naphthyridin-4(lH)-one (B) by action of sec-amines (79H1407). Also in this transformation bond-breaking occurs between the ring nitrogen and the carbon of the carboxyl group. 

Also, the observed highly regioselective course in the SnFI substitutions in 2-R-3-nitro-l, 8-naphthyridines (R = FI, OFI, Cl, NFI2, OEt) with the anion of chloromethyl phenyl sulfone was explained by MNDO quantum-chemical calculations showing that, like in the aminations, the interaction of FIOMO of the nucleophile with LUMO of the nitronaphthyridines controls the regioselectivity (91JFIC1075). 

Die selekdve Redukdon einer Nitro-Gruppe zum Amin gelingt beim 2-Chlor-3-nitro-1,8-naphthyridin mit Zinn(II)-chlorid in salzsaurer Losung1 ... 

Nitro functions attached to 5,6,7,8-tetrahydro[l,6]naphthyridines may easily be reduced to the corresponding amine employing hydrogen with palladium-on-carbon as the catalyst <2001SC787>. 

The three-component coupling of arylacetaldehydes, secondary amines, and (hetero)aryl azides in refluxing benzene gave triazolines which underwent thermal reanangement to quinolines and [l,7]naphthyridines <1996J(P1)1359>. 

Bismuth(lll) chloride catalyzes the intramolecular hetero-Diels-Alder reaction of aldimines, generated in situ from aromatic amines and the A -allyl derivative of o-aminobenzaldehyde, in acetonitrile at reflux to generate [l,6]naphthyridine derivatives <2002TL1573>. The hetero-Diels-Alder reaction of 3-aryl-2-benzoyl-2-propeneni-triles and enol ethers yields 2-alkoxy, 6-diaryl-3,4-dihydro-2//-pyran-5-carbonitriles (Scheme 29) <1997M1157>. 

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>. 

The one-pot reaction of a piperidin-4-one, carbon disulfide, and 1,1-dicyanomethane generates condensed thio-pyranthiones (Scheme 46). These products are reactive to ring opening and react with amines to give condensed pyridines and ultimately [2,7]naphthyridines <1999CHE799>. 

Various heterocycles, but particularly thiopyrans, ring-open and reclose when reacted with amines to give a variety of condensed heterocycles, including [2,7]naphthyridines (Scheme 64) <1999CHE799>. 

Along the same lines, 3-cyanopyrano[4,3- ]pyridin-5-ones ring open and reclose when reacted with DMF followed by pyridine and a primary amine to give 5-cyano[2,7]naphthyridin-l-ones (Scheme 65) <1997RCB1041>. 

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