2- Chloro-3- -1,8-naphthyridine formation

Subjecting 8-chloro-5-iiitro-l,7-iiaphthyridiiie (97) to reduction with tin(II) chloride leads, besides loss of the chloro atom and reduction of the nitro group, i.e., formation of 5-amino-l,7-naphthyridine (131, 22%), to the formation of small amounts of 5-amino-6,8-dichloro- (132, 1.5%) and 5-amino-6-(or 8-)chloro-l,7-naphthyridine (133, 2.5%) (88PJC305). 

The synthesis of the corresponding naphthyridone scaffold was carried out according to the methods reported by Chu et al. [12] and Sanchez et al. [13]. Namely, the hydrolysis of ethyl 2,6-dichloro-5-fluoronicotinate (3) [14] followed by reaction with thionyl chloride results in the formation of 2,6-dichloro-5-fluoronicotinyl chloride (4). Treatment of this compound with monoethyl malonate in THF under n-butyllithium followed by acidification and decarboxylation gives rise to ethyl 2,6-dichloro-5-fluoronicotinylacetate (5). Reaction of compound 5 with ethyl orthoformate in acetic acid followed by cyclopropylamine results in the formation of 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylate (6), the cyclization reaction of which under NaH/THF gives rise to the required ethyl l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (7), as shown in Scheme 3. 

Bromo- and 3-chloro-l,7-naphthyridine take up NH2 at position 2. Interestingly, the formation of (j-adducts precedes the appearance of... 

The reaction of 8-chloro-I,7-naphthyridine with KNH2 in liquid NH3 brings about the formation of adduct 57 by addition of the nucleophile to position 2.111,112 The pair of doublets due to H-2 centered at S 9.16 in the substrate are replaced by a new doublet at 5 5.16. The higher shielding of H-2 and the new multiplicity pattern substantiate the structure of the adduct. 

On dissolving 3-chloro-l,7-naphthyridine (98a) in liquid ammonia containing potassium amide unambiguous H-NMR evidence for the formation of the cr-adduct 2-amino-3-chloro-l,2-didehydro-l,7-naphthyridinide (103) has been obtained26 (Section II,B,1). Apparently tr-adduct formation at C-2 in 98a precedes the formation of the 3,4-didehydro compound (99). This... 

Chloro-l,7-naphthyridine (110 X = Cl) gives on animation with KNH2/ NH3 the tele product 2-amino-1,7-naphthyridine (53) in addition to the ipso product 8-amino-l,7-naphthyridine (54).10 25 The formation of 53 involves as intermediates anionic cr-adduct 111 (X = Cl) (its existence has been proved by NMR spectroscopy see Section I1,B,1) and probably 2-amino-2,8-dihydro-8-chloro-1,7-naphthyridine (112). The latter undergoes a base-catalyzed dehydrochlorination, yielding 53. Because there are four atoms between position 2 and 8. the reaction is called an even tele substitution. 

The 7-position in 1,8-naphthyridine is electrophilic coupling of the 7-chloro-l,8-naphthyridine (162) with 1 -terf-butyloxycarbonylamino-3-tributylstannyl-2-cyclohexene shows the expected readiness for product formation (163) (Scheme 34) (90TL1837). 

Spiro[3,l-benzoxazine-4,4 -piperidine]-2(l//)-ones (80) afford 5-chloro-1,2,3,4,4a, lOb-hexa-hydrobenzo[c][2,7]naphthyridines when treated with phosphorus oxychloride. The likely reaction pathway involves initial electrophilic attack at the carbonyl oxygen atom which promotes ring opening of the heterocycle and the formation of isocyanates (81). These undergo intramolecular [4 + 2]-cyclizations to yield quinolinones, and further reaction with excess reagent then gives the final products (82) (Scheme 17) <86CPB1901>. 

---