Reactions of 1,6-Naphthyridines

Reported reactions of 1,6-naphthyridine or its hydro derivatives are illustrated in the following classified examples. 

Note Although simple C-alkylation of 1,6-naphthyridine is rare, concomitant C-alkylation and A-acylations are well represented (see Reissert reactions below). 

Decahydro-1,6-naphthyridine has been 1,6-dimethylated, as was its 1,5-naphthyridine isomer (see Section 2.1.3).1203 

6-Naphthyridine gave only its 6-methiodide (10) (Mel, AcMe, reflux, 12 h 85% 1214 kinetics961) or its l,6-bis(methofluorosulfonate) (11) (neat FSOaMe, exothermic 90%).1061 Other such quaternary salts have been prepared1002 and their physical chemistry examined.993 1002 

6-Naphthyridine with tetracyanoethylene oxide gave l,6-naphthyridin-6-ium-6-dicyanomethanide (12) (substrate, THF, 5°C synthon/THFJ, dropwise, 5°C, 24 h 63%) 857 also analogous reactions.101,857 

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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-... 

In contrast, the reaction of 1,6- and 1,8-naphthyridines with NH2 -NH3 leads to adducts 48 and 49, respectively, resulting from attachment to position 2, whether the temperature is kept at -40°C or raised to 10°C.108 109 As usual, the adducts are characterized by an increased shielding of H and C... 

A convenient procedure was developed (1996IZV437, 2000IZV121) for the synthesis of 1,6-naphthyridine derivatives 81 containing the alkylselanyl substituent at position 7. Thus, multicomponent condensation of cyanoselenoacetamide, 2-fur-furylideneacetoacetic ester 82 and alkyl halides was carried out under the action of a two-fold excess of A-methylmorpholine. The reaction involves the Thorpe dimerization of the cyanoselenoamide yielding compound 83, its reaction with a molecule of ester 82 to form adduct 84, regioselective cyclocondensation of the adduct 84... 

Shortly after Gabriel and Colman reported cinchomeronylacetic ester, Pels reported a similar quinolinimidoacetic ester (40) to provide a 1,6-naphthyridine (41).The structure of the isolated compound was not unambiguously determined for more than 30 years.More recently, the reaction has been shown to produce both 41 and 42 in a 3 1 ratio... 

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... 

Azolo[1,6]naphthyridines. Benzimidazonaphthyridines can be prepared from a one-pot reaction of o-phenylene-diamine, acrolein, and the cyclic keto ester 235 in the presence of molecular sieves and air (Equation 63) <2006SC1671>. 

The obvious method for the preparation of this naphthyridine is the Skraup reaction applied to 4-aminopyridine after early failures,0, 80 the authors of this chapter81 utilized the sulfo-mix described by Utermohlen,82 to obtain 1,6-naphthyridine (2) in 40% yield. 

Kato and co-workers83 have applied the Skraup reaction to 4-aminopyridine 1-oxide and some of its methyl derivatives and have obtained the parent 6-oxide, the 5,7-dimethyl-, 5-methyl-, 7-methyl-, and the 8-methyl-l,6-naphthyridine 6-oxides. 1,6-Naphthyridine 6-oxide has also been prepared from 4-aminopyridine JV-oxide and 1, l-diacetoxy-2-propene.84... 

The condensation and cyclization of EMME with 4-aminopyridine and 4-aminoquinoline affords, in each case, the 1,6-naphthyridine ring system.59 Albert11 used this reaction to prepare the hydroxy ester (34), which he converted into the parent 1,6-naphthyridine by the following sequence of reactions. 

Treatment of the pyranopyridine (50) with methanolic ammonia gave compound 51.93 This is the same reaction used earlier by Ikekawa to form the 1,6-naphthyridine ring system. 

Tan and Taurins18 recently reported a new synthesis of 1,7-naphthyridine (3) which involves a six-step sequence starting with ethyl 2-cyano-3-pyridyl acetate. Although the overall yield is low, the method is of value since it can be modified to yield 6- and 8-substituted derivatives. The later reactions in this sequence are outlined below. 

Two products (128 and 129) were obtained when 1,6-naphthyridin-4-one (127) reacted with phosphorus pentabromide.143 It is presumed that 128 is the precursor of 129. The 4-bromo derivative was obtained when compound 127 was treated with phosphorus oxybromide. The 3-bromo-l,6-naphthyridin-4-one (130) was prepared in good yield from compound 127, and on reaction with phosphorus oxybromide the 3,4-dibromo-l,6-naphthyridine (131) could be obtained. The reaction of l,7-naphthyridin-8-one with phosphorus oxybromide is unique,144 since it appears to be the only example in this series, in which further bromination occurs with this reagent, affording 8-monobromo and 3,8-dibromo-l,7-naphthyridine. 

Diamino-1,6-naphthyridine (94) was formed on reaction of 2,4-dibromo-l,6-naphthyridine (92) with KNH2/NH56. The intermediacy of... 

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... 

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... 

The Meisenheimer reaction of the l,X-naphthyridine 1-oxides has been examined in some detail.72 75 Table II lists the relative yields of the 2-, 3-, and 4-chloronaphthyridines formed. As the amount of 2-chloronaphthyridine decreases, the 3-chloro and 4-chloro isomers increase in the series 1,7-, 1,5-, 1,8-, and 1,6-naphthyridine. 

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