Reactions of 2,7-Naphthyridine

Reported reactions of 1,5-naphthyridine or the corresponding hydronaphthyr-idines are illustrated by the following classified examples. 

Decahydro-1,5-naphthyridine underwent A-alkylation by 2-14-W-acetylaniIino)-buta-1,3-dienyl]-l,3,3-trimethyl-3/7-indolium perchlorate to give 1,5-bis 4-( 1,3,3-trimethyl-3/7-indolio)buta-l,3-dienyl decahydro-1,5-naphthyridine bisperchlorate (10) with loss of acetanilide (substrate, EtOH, Me2NCHO, 40°C synthonj, dropwise 6 h 29%) 1203 also methylation to 1,5-dimethyl-decahydro-1,5-naphthyridine (no details).1089 

Note 1,5-Naphthyridine can undergo semidirect C- or iV-amination, but in the latter case the product must be a salt or a zwitterion. 

5- Naphthyridine (14) with potassium amide in liquid ammonia gave a solution of the adduct (15) that underwent oxidation to afford 1,5-naphthyridin-2-amine (16) [substrate, KNH2 (made in situ), liquid NH3, 10 min then KMn04, 10 min 36%].425 cf302,643,692,1047,1353,1371 

5-Naphthyridine (19) with chloromethyl phenyl sulfone gave 6,7-bisphenylsul-fonyl-6,6a,6b,7-tetrahydro-1 //-azirino [1,2-a] cyclopropa[c]-l,5-naphthyridine 

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The reaction of 1,5-naphthyridine (1) with bromine in chloroform does not yield any brominated products (54JCS1879). However, treatment of (1) with bromine in oleum was found to give a mixture of the 3-bromo- (13) and the 3,7-dibromo-l,5-naphthyridines (14) in 10% and 35% yield respectively (65JOC1607, 67LA(707)242). With bromine in pyridine the yields were 27% of (13) and 10% of (14) (68JOC1384), and application of this procedure to 1,6-naphthyridine (2) gave a mixture of 3-bromo- (15), 8-bromo- (16) and 3,8-dibromo-... 

The reaction of 1,5-naphthyridine with methyl iodide gave, as expected, the monomethiodide (134). Oxidation of the salt, under basic conditions, with potassium ferricyanide, afforded the A-methyl naphthyridinone (135).16 Repetition of this sequence yielded,... 

Nucleophilic chlorination of 1,5-naphthyridine mono- and di-N-oxides yields 2-chloro- and 2,6-dichloro-naphthyridines via electrophilic catalysis of the reaction of intermediates such as 430 with chloride ion. An interesting example of electrophilic catalysis is the... 

Kinetic control leads to ff-adducts other than the more stable ones in the reactions of 1,5- and 1,7-naphthyridines. 

As already described1 the electrophilic substitution reactions in the naphthyridines follow the pyridine pattern. Thus, 3-bromo derivatives are formed in all of the l,X-naphthyridines. In addition, dibromo derivatives are formed with the second bromine at the position / to the other ring nitrogen atom. This pattern prevails when either pyridine or nitrobenzene17 is used as a solvent rather than carbon tetrachloride. Bromination of 1,5-naphthyridine JV-oxide affords the 3,6-dibromo-l,5-naphthyridine as a minor product, apparently through prior de-N-oxygenation.18... 

This chapter covers information on the preparation, physical properties, and reactions of 1,5-naphyhyridine and its C-alkyl, C-aryl, /V-alkyl, and /V-aryl derivatives as well as their respective ring-reduced analogs. In addition, it includes methods for introducing alkyl or aryl groups (substituted or otherwise) into 1,5-naphthyridines already bearing substituents and the reactions specific to the alkyl or aryl groups in such compounds. For simplicity, the term alkyl-l,5-naphthyridine in this chapter is intended to include alkyl-, alkenyl-, alkynyl-, aralkyl-, and cycloalkyl-1,5-naphthyridines likewise, aryl-l,5-naphthyridine includes both aryl-and heteroaryl-1,5-naphthyridines. 

The conversions of 1,5-naphthyridine A-oxides into C-halogeno-l,5-naphthyr-idines by the Meissenheimer reaction (POCl3 or POBr3) or a related reaction (Br2 in Ac20) both suffer from the fact that two or more products are usually formed in each case. This introduces a sometimes difficult separation procedure, so that such... 

Note The conversion of 1,5-naphthyridine N-oxides to C-halogeno-1,5-naphthyridines (Meissenheimer reaction) has been discussed in Section 3.1.3. Other reported reactions are illustrated here. 

Note These esters have been made by primary synthesis (see Chapter 1), by the Reissert reaction (see Section 2.1.3), by esterification of 1,5-naphthyridine-carboxylic acids (see Section 7.1), and by various passenger introductions (see several chapters). Other possible routes have not been used. 

Azolo[1,5]naphthyridines. Imidazonaphthyridines can be prepared by the reaction of ammonium acetate with appropriately substituted naphthyridinium salts. For example, reaction of the ketone 236 in acetic acid with iron(m) chloride produces the tetracycle 237 <2001AJC105> (Equation 64). 

The reaction of 5-amino-2-hydroxypyridine and EMME refluxing diphenyl ether for 1 hr gave 4,6-dihydroxy-1,5-naphthyridine-3-carboxylate in 20% yield after vacuum sublimation of the crude product (71JOC1331). 

The application of the Friedlander reaction to 3-aminopyridine-2-carbaldehyde (135) gives good yields of the 2,3-disubstituted 1,5-naphthyridines (136) (75CR(C)(280)38l). The intramolecular cyclization of /3- (3-aminopyridinyl)acrylic acid (137) results in the formation of l,5-naphthyridin-2-one (138) (66JHC357), whilst the condensation of 3-aminopyridine-2-carboxylic acid or its esters (139) with active methylene compounds yields 4-oxo (132) and 4-hydroxy-2-oxo compounds (134 R = H) after hydrolysis and decarboxylation of the intermediates (140) and (134 R = C02Et). Reductive cyclization of the 3-nitropyridine derivative (141) gives the 1,5-naphthyridine (142) (71JOC450). 

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