1,8-Naphthyridines II: synthesis of novel polyfunctionally substituted 1,8-naphthyridinones and their degradation to 6-aminopyridones

Reaction of 6-chloro-3-cyano-5-formyl-1,4-dimethyl-(1 H )-pyridin-2-one ( 1 ) with [(ethoxy-carbonyl)methylene]triphenylphosphorane ( 2 ) afforded 5-ethoxycarbonylvinyl-2-pyridone derivative 3 . Azidation of 3 yielded 6-azido-2-pyridone derivative 4 , in excellent yield. Refluxing 4 with one equivalent of triphenylphosphine (aza-Wittig reaction) gave imino-phosphorane derivative 5 , and subsequent hydrolysis (Staudinger reaction) gave 6-amino-2-pyridone 6 . When aminopyridone 6 was refluxed in 1,2-dichlorobenzene it cyclised to the novel 1,8-naphthyridin-2-one 7 . Reaction of compound 1 with malononitrile in an ethanolic solution containing TEA afforded 6-chloropyridone derivative 18 , which reacted with sodium azide to furnish the corresponding azido compound 19. Reduction of 19 with Na 2 S 2 O 4 did not give the corresponding aminopyridone 20 but rather the interesting 1,8-naphthyridin-2(1 H )-ones 21 . Alternatively, compound 21 could also be obtained by refluxing aminopyridone 9 with malononitrile in an ethanolic solution containing TEA. On the other hand, reacting 9 with phenacylcyanide, under the same reaction conditions as used for the synthesis of 21 , did not afford the new 1,8-naphthyridine-2-one 22 , but rather 6-amino-3-cyano-1,4-dimethyl-(1 H )- pyridine-2-one ( 23 ), via the thermal degradation of the intermediate 22 .

Refluxing compound 4 with one equivalent of triphenylphosphine in dry toluene for 30 minutes yields 6-[(triphenylphosphoranylidene)amino]pyridone 5, and subsequent acid hydrolysis of 5 with a mixture of acetic acid/water (5:1) provided the corresponding 6-aminopyridone derivative 6, in excellent yield.Attempts to obtain 6-aminopyridone 6 by direct aminolysis of the chlorinated derivative 3 were unsuccessful, and only E-isomer was obtained for compounds 3, 4, 5 and 6.In all cases, the 1 H NMR spectra include a characteristic AB system (≈ 7.02 and 7.61 ppm, with typical trans-coupling constant J = 16 Hz) due to the trans-configuration of vinylic protons in these compounds.

Scheme 3
In order to construct new derivatives of the interesting 1,8-naphthyridines of type 17, that are alkylated at the heterocyclic nitrogens, we attempted reaction of the azidopyridone 4 with alkylamines.Refluxing compound 4 with an excess of alkylamines 13a,b in absolute EtOH for 3 hours, gave in each case two products, 6-aminopyridone 6 (minor product) and new 6alkylamino-3-cyano-5-ethoxycarbonylvinyl-1,4-dimethyl-(1H)-pyridine-2-one 15 (major product), which were readily separated by preparative silica gel TLC (PLC).The structures of the major components 15a,b, which formed via the nucleophilic substitution of the azido group at pyridinic C-6 in 4 with amino group, were substantiated on the basis of IR, 1 H NMR and mass spectroscopy.The IR spectra showed no azide absorption at 2140 cm -1 , but the absorption band at 3400 cm -1 was assigned as an NH function.The 1 H NMR spectra of 15a,b revealed the presence of signals for NH and alkyl protons at C-6 in addition to signals of other groups.Furthermore, their structures were supported by correct mass spectra, which were compatible with assigned structures (see Experimental).Analytical data are in accordance with the proposed structures for compounds 15a,b.The mechanism of the formation of 6 from the reaction of 4 with alkylamines 13a,b is assumed to proceed via the formation of nitrene intermediate 14, which then abstracts hydrogen under these reaction conditions to give compound 6 (Scheme 4).Attention was next turned to the cyclization of 6-alkylaminopyridone 15 to 1,8naphthyridine-2,7-dione 17, which failed when 15 was heated in different solvent of higher boiling points.Variation of solvent, temperature and reaction time gave no polyfunctionally substituted 1,8-naphthyridin-2,7-dione 17.When we examined the reaction of 15a,b with nonnucleophilic bases, such as NaH and t-BuOK, varying solvent and time, the starting materials were recovered and no cyclization was observed.However, refluxing 15a,b with sodium ethoxide for 3 h gave the corresponding acids 16a,b.
Our interest in developing synthetic approaches with a view to synthesize new derivatives of the interesting 1,8-naphthyridine-2-one of type 21, the azidopyridone 19, in which the 5-position is substituted with methylenemalononitrile group, was thus investigated as a good starting material for this purpose.Treatment of compound 1 with an equimolecular amount of malononitrile in ethanol, in the presence of triethylamine at room temperature for 2 hours afforded the 6-chloropyridone 18. Reaction of compound 18 with sodium azide in MeOH at room temperature for 2 hours gave the corresponding 6-azidopyridone 19.Reduction of the azide moiety in 19 with Na 2 S 2 O 4 gave aminopyridone 20, which cyclised spontaneously to afford the hitherto unknown 7-amino-3,6-dicyano-1,4-dimethyl-naphthy-ridine-2-one (21) (Scheme 5).The structure of 21 was substantiated by its elemental analysis and spectral data.The IR spectrum revealed the presence of the amino function (NH 2 ) at 3322 and 3231 cm -1 .Furthermore, the 1 H NMR gave strong evidence for the formation of compound 21.The data confirmed the absence of the methine proton (-CH=C) at C-5 in azidopyridone 19, the presence of two singlets at δ 8.53 ppm and 7.82 ppm attributable to the amino group at C-7 and the H-5 proton, respectively, in addition of signals due to two methyl groups in their expected positions.Moreover, structure 21 was supported by correct mass spectrum, which was compatible with assigned structure (see Experimental).To obtain unequivocal evidence for the structure, ARKAT USA, Inc.

Scheme 5
In order to extend the scope of this reaction, 6-aminopyridone 9 was reacted with phenacylcyanide, with the hope of obtaining the interesting 1,8-naphthyridine derivative 22.However, surprisingly, 6-amino-3-cyano-1,4-dimethyl-(1H)-pyridine-2-one ( 23) was unexpectedly obtained as the only identifiable product, identical in all respects with the structure reported in the literature [32].The formation of 23 can be explained by the degradation of 1,8naphthyridine-2-ones intermediate 22.On the other hand, the formation of 21 from compound 9 and malononitrile under basic conditions implies that 1,8-naphthyridine-2-one 21 is more stable than 22 under these reaction conditions.
This observation prompted us to investigate the stability of 21 under various conditions.Compound 21 was unreactive in refluxing solvents such as bromobenzene, 1,2-dichlorobenzene or other high-boiling benzene derivatives for extended periods.However, refluxing 21 in piperidine for 30 minutes yielded 6-aminopyridone 23 as the sole product (Scheme 6).On the basis of these results, it may be concluded that the use of piperidine, as a basic reagent, facilitates the opening of the pyridine ring in 21.The proposed mechanism for the conversion of 1,8-naphthyridine-2-one 21 to 6-aminopyridone 23 may resemble the mechanism described previously [32].

Conclusions
This second-generation of our annulation strategy shows that the azidopyridone derivatives were converted to the corresponding aminopyridones in excellent yields.These amino compounds are useful precursors in the preparation of novel 1,8-naphthyridine-2-one and 1,8-naphthyridine-2,7-dione derivatives.The intramolecular cyclization of these ortho-substituted aminopyridone derivatives appears to be an unequivocal method for the synthesis of 1,8-naphthyridine derivatives, it is an efficient and convenient experimental procedure which requires only readily available starting materials.This synthetic approach, for the synthesis of polyfunctionally substituted 1,8-naphthyridine, may be useful in view of the pharmacological interest in this compound class.The novel cleavage of 1,8-naphthyridine ring systems to the corresponding aminopyridones has been described.

Experimental Section
General Procedures.Melting points were determined on a Gallenkamp apparatus and are uncorrected.Analytical thin-layer chromatography (TLC) was performed on Merck silica gel 60 plates, 0.25 mm thick with F-254 indicator.Visualization was accomplished by UV light.Solvents for extraction and chromatography were reagent grade and used as received. 1H NMR spectra were recorded with Bruker AM 400 spectrometer at 400 MHz with DMSO-d 6 and CDCl 3 as solvents and TMS as an internal standards; Chemical shifts (δ) are reported in ppm.Mass spectra were measured on a Gc/Ms-QP1000EX (EI, 70 eV) mass spectrometer.IR spectra were recorded with a Schimadzu 470 spectrophotometer in KBr disks.
Microanalyses were performed by the microanalytical Data Unit at Cairo University.