2.7- Naphthyridine preparation

Chloro-5,7-dimethyl-l,8-naphthyridine reacts readily with meth-anolic methoxide (65°, 30 min) and with other alkoxides, benzyl-amine, and hydrazine. 4-Chloro-7-acetamino-l,8-naphthyridine (prepared in moderate yield from the 4-oxo analog) has been alkyl-aminated (150°, 9 hr, 62% yield). The degree of reactivity in... 

The 2,7-naphthyridine system 53 (Scheme 8.4.18) was combined with 2,4-dinitrochlorobenzene and 2-amino glycerol for in situ reaction of the resulting Zincke salt. The resulting naphthyridinium 54 was trapped by Bradsher cycloaddition with (Z)-vinyl ether 55, providing tetracycle 56 (X-ray) upon internal addition of one of the diastereotopic hydroxymethyl groups to the resulting iminium. This approach was also extended to the use of chiral 2,7-naphthyridinium salts, prepared via the analogous Zincke process. ... 

The benzothiazine equivalent of a 1,7 naphthyridine (58) has also been prepared. The reaction did not work in alcoholic solvents, but when DMF was used 57 rearranged to provide the desired product in moderate yield. 

Tile same methodology as mentioned for the preparation of (9) was applied for the synthesis of 8-nitro-l,6-naphthyridines. Heating diethyl N- 3-nitropyridin-4-yl)aminomethylenemalonate (12) in diphenyl ether yields ethyl 8-nitro-l,6-naphthyridin-4(lH)-one 3-carboxylate (13) (63JCS4237, 30%) and acid treatment of 4-( y, y-diethoxypropylamino)-5-nitro-2-(/3,/3 -trifluoroethoxy)-pyridine (14) gives in a similar way 8-nitro-5-(/3, /3-triflu-oroethoxy)-l,2-dihydro-l,6-naphthyridine (15, 76%). Subsequent oxidation with chloranil, acid hydrolysis, and methylation with methyl iodide gives 8-nitro-6-methyl-l,6-naphthyridin-5(6H)-one (16,63%) (81JHC941). 

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]

Many reports deal with the preparation of numerous hydroxynitronaph-thyridones and nitronaphthyridinediones. By the nitration of 4-hydroxy-l,X-naphthyridin-2(lH)-ones (X = 5,6,7, and 8) (51a-51d) using nitric acid in acetic acid, the corresponding 3-nitro substituted compounds (52a-52d) were obtained in reasonable-to-good yield (75JMC726 77MI1 96MI1). 

Treatment of 4-hydroxy-l-phenyl-l,8-naphthyridin-2-(lH)-one (76) with sodium nitrite gave the 3-nitroso derivative (77), which could be oxidized to 4-hydroxy-3-nitro-l-phenyl-l,8-naphthyridin-2(lH)-one (30a) (94SC3289). According to the authors, this method of preparing (30a) is more convenient for large-scale preparation than the one using A-phenyl-3-azaisatoic anhydride as starting material (see Section II,A,4,a) [(29a) (30a)]. 

Tile easy availability of (di)nitronaphthyridones, in which the lactam part can easily be converted into an iminochloride, has successfully led to preparation of the parent (di)nitronaphthyridines by removal of the chloro atom. For that purpose the chloro atom in the 2- and 4-chloro derivative of the 3-nitro-l,5-, -1,6-, and -1,8-naphthyridines (78a-78e) was first substituted with tosylhydrazine to give the corresponding tosyl-hydrazide, which then was hydrolyzed in alkaline solution into the corresponding 3-nitro-l,5-, -1,6-, and -1,8-naphthyridines (79a, 79b, and 79c). 

Attempts to obtain 5-nitro-l,7-naphthyridine and 3,6-dinitro-l,8-naph-thyridine (83) from the corresponding 8-chloro-5-nitro-l,7-naphthyridine and 2-chloro-3,6-dinitro-l,8-naphthyridine using the similar reaction failed (85JHC761 98MI2). However, 3,6-dinitro-l,8-naphthyridine (83) could be prepared in 21% yield by hydrazino-dechlorination of 2-chloro-3,6-dinitro-1,8-naphthyridine (82) and subsequent cupric sulfate oxidation of the intermediate 2-hydrazino-3,6-dinitro-l,8-naphthyridine (93LA471). 

Deuterio-3-iiitro-l,6-iiaphthyridiiie (168) was prepared from 4-chloro-3-iiitro-l,6-iiaphthyridiiie (166) by a reaction with tosyl hydrazide and subsequent hydrolysis of the 4-tosylhydrazino derivative (167) with Na2C03/ D2O solution (83RTC359). 7-Deuterio-l,8-naphthyridin-2(lH)-one was prepared by heating l,8-naphthyridin-2(lH)-one with deuterium oxide at 230°C for 35 h (85JHC761). Tliis deuterio compound could be converted into 2-chloro-(or 2-ethoxy-) 7-deuterio-3,6-dinitro-l,8-naphthyridine. 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

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