Naphthyridines syntheses involving

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]

The benzo-fused dihydrotetrazolo[2,7]naphthyridine 308 is a minor end-product of a mixed Hantzsch pyridine synthesis involving 2-azido-3-nitrobenzaldehyde, /3-aminocrotononi trile, and methyl /3-aminocrotonate in ethanol (Scheme 76) <2001TL4507>. 

Less profound reduction of 1,6-naphthyridine afforded 1,2,3,4-tetrahydro-1,6-naphthyridine (7) (Pd/C, EtOH, H2, 20°C, 1 atm, 6 h 75%) 47 a somewhat similar procedure gave the same product (7) and a minor isomeric product, possibly 5,6,7,8-tetrahydro-l,6-naphthyridine.1243 Ostensibly, the hydro derivative (7) has also been made by a primary synthesis involving reductive cyclization of 4-(2-carboxyethyl)-3-nitropyriidne 1-oxide,134 but the melting points differ markedly. 

Yet another reaction used in the synthesis of 2,7-naphthyridine derivatives involves intramolecular cyclization of enamino nitriles under the action of acid catalysts. Thus compound 153 underwent cyclization to form 1-hydroxy-2,7-naphthyridine 154, used in the synthesis of sedative agent 155 (1988USP4859671). 

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. 

The Borsche modification of the Friedlander quinoline synthesis has been shown to be of general use97 in the preparation of 1,7-naphthyridines (60). The preparative sequence involves the synthesis of compound 58 and its condensation with a carbonyl compound (59). 

There are relatively few synthetic routes to 2,7-naphthyridines almost all are multistage and rely on annulation of a second pyridine ring to a suitably functionalised pyridine precursor. French workers have described an efficient, one-pot synthesis of l,3,6,8-tetramethyl-2,7-naphthyridine 1 which involves treatment of a mixture of acetyl chloride (1.6 mol) and aluminium chloride (0.3 mol) with t-butanol or t-butyl chloride (0.1 mol) at 35°C for half an hour, followed by careful addition of the reaction mixture to liquid ammonia. This gave 37% of 2,4,6-trimethylpyridine and 63% of the naphthyridine 1 in a total yield of 91%. 

Note 1,5-Naphthyridinecarboxylic acids have been made by primary synthesis (see Chapter 1) and by oxidation of alkyl-1,5-naphthyridines (see Section 2.2.2). The remaining routes involving oxidation of aldehydes or hydrolysis of esters are exemplified here. 

Many alkyl or aryl-1,8-naphthyridines have been made by primary synthesis (see Chapter 22). Other procedures involve the introduction of substituted or unsubstituted alkyl or aryl groups into existing 1,8-naphthyridines or the interconversion of such groups already in place. The following examples illustrate the methods used. 

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... 

A novel synthesis of amphimedine 105 has been reported by Prager et al. (89H847 91AJC277). It involves an azido ring expansion of a pyridyla-zafluorenol 185, by the Schmidt reaction, to 5-(4-pyridyl)benzo[a]-[2,7]naphthyridin-4-one 186, and then refunctionalization to the a-cyano precursor 187, followed by cyclization in polyphosphoric acid (Scheme 30). Guillier et al. (95JOC292) have described a new synthesis of the intermediate 186. 

A synthesis of 4-substituted and 3,4-disubstituted l,7-naphthyridine-2(lH)-thiones has been reported involving electrocyclic cyclization of 4-(l-arylalk-l-enyl)-3-isothiocyanatopyridines, generated in situ by the treatment of the respective isocyanides with in the presence of selenium (Scheme 33)45... 

---