Synthesis of 1-Amino-3-oxo-2,7-naphthyridines via Smiles Rearrangement: A New Approach in the Field of Chemistry of Heterocyclic Compounds

In this paper we describe an efficient method for the synthesis of new heterocyclic systems: furo[2,3-c]-2,7-naphthyridines 6, as well as a new method for the preparation of 1,3-diamino-2,7-naphthyridines 11. For the first time, a Smiles rearrangement was carried out in the 2,7-naphthyridine series, thus gaining the opportunity to synthesize 1-amino-3-oxo-2,7-naphthyridines 4, which are the starting compounds for obtaining furo[2,3-c]-2,7-naphthyridines. The cyclization of alkoxyacetamides 9 proceeds via two different processes: the expected formation of furo[2,3-c]-2,7-naphthyridines 10 and the ‘unexpected’ formation of 1,3-diamino-2,7-naphthyridines 11 (via a Smiles type rearrangement).

Moreover, the literature has reported patents on the biological activity of 1-oxo-2,7naphthyridines, showing that some derivatives of the latter are physiologically active compounds and provide anti-inflammatory and analgesic action and can be used as therapeutic agents for treatment of inflammatory immune diseases and chronic inflammations [8,9].
Taking into account the abovementioned results, that are very interesting from both the chemical and the biological point of view, we think that it would be useful to combine these two heterocyclic systems into one molecule (Figure 1, compounds IV), as a 'nice' precondition for further interesting research. Until recently all our attempts to synthesize furo[2,3-c]-2,7-naphthyridines IV have failed and it is only in this study that we have been able to solve this problem by using the Smiles rearrangement. It should also be noted, that the furo[2,3-c]-2,7-naphthyridine IV system is currently not known in the literature.
Taking into account the abovementioned results, that are very interesting from both the chemical and the biological point of view, we think that it would be useful to combine these two heterocyclic systems into one molecule (Figure 1, compounds IV), as a 'nice' precondition for further interesting research. Until recently all our attempts to synthesize furo[2,3-c]-2,7-naphthyridines IV have failed and it is only in this study that we have been able to solve this problem by using the Smiles rearrangement. It should also be noted, that the furo[2,3-c]-2,7-naphthyridine IV system is currently not known in the literature.
In compounds 4 a lactam-lactim (NH/OH) tautomerism is possible, via the protonmigration of a hydrogen atom between the two basic centers. The IR spectroscopic data strongly show that 1-amino-3-oxo-2,7-naphthyridines 4a,b in the solid state exist only in the lactam 4 (NH) tautomeric form: showing carbonyl group absorptions at 1636-1638 cm −1 , nitrile groups at 2208-2210 cm −1 , and NH in the region 3222-3226 cm −1 . Interestingly, in solution the situation changes, as confirmed by NMR spectra, where the presence of the proton of NH group at 10.53-10.86 ppm was observed (see Supplementary Materials). Moreover, by further alkylation of 1-amino-3-oxo-2,7-naphthyridines 4a,b in basic conditions, the corresponding O-alkylated derivatives were obtained in high (Schemes 3 and 4).
In compounds 4 a lactam-lactim (NH/OH) tautomerism is possible, via the proton-migration of a hydrogen atom between the two basic centers. The IR spectroscopic data strongly show that 1-amino-3-oxo-2,7-naphthyridines 4a,b in the solid state exist only in the lactam 4 (NH) tautomeric form: showing carbonyl group absorptions at 1636-1638 cm −1 , nitrile groups at 2208-2210 cm −1 , and NH in the region 3222-3226 cm −1 . Interestingly, in solution the situation changes, as confirmed by NMR spectra, where the presence of the proton of NH group at 10.53-10.86 ppm was observed (see Supplementary Materials). Moreover, by further alkylation of 1-amino-3-oxo-2,7-naphthyridines 4a,b in basic conditions, the corresponding O-alkylated derivatives were obtained in high yields (Schemes 3 and 4).
In addition, it was interesting to compare the physico-chemical properties of these two classes of compounds. Thus, furo[2,3-c]-2,7-naphthyridines 7 have a very higher solubility and lower melting point compared with thieno[2,3-c]-2,7-naphthyridines 8. Moreover, compounds 7 and 8 showed different 1 H NMR data: the singlet signal of the In addition, it was interesting to compare the physico-chemical properties of these two classes of compounds. Thus, furo[2,3-c]-2,7-naphthyridines 7 have a very higher solubility and lower melting point compared with thieno[2,3-c]-2,7-naphthyridines 8. Moreover, compounds 7 and 8 showed different 1 H NMR data: the singlet signal of the NH 2 group in compounds 7a,b were observed at 5.58 and 5.62 ppm, while in 8a,b the same proton signal was shifted to a weaker field at 6.47 and 6.50 ppm. Signals of the remaining protons of these compounds differ slightly between themselves ( Figure 2). In order to increase the scope of furo[2,3-c]-2,7-naphthyridines, the obtained 3-oxo-2,7naphthyridines 4 were alkylated by various other alkyl halides under basic conditions. The corresponding O-alkylated derivatives of 2,7-naphthyridine 9a-p were obtained in high yields (75-89%, Scheme 4, Table 1). In the 1 H NMR spectra of compounds 9a-p the singlet signals of the OCH 2 CO and NH groups were present at 4.69-4.92 ppm and 8.04-10.13 ppm, respectively (see Supplementary Materials). The IR spectra also confirmed their structures, namely that they showed the absorption bands of nitrile group at 2201-2208 cm −1 , of carbonyl group at 1662-1698 cm −1 , and of NH group at 3166-3352 cm −1 .
conditions. The corresponding O-alkylated derivatives of 2,7-naphthyridine 9a-p were obtained in high yields (75-89%, Scheme 4, Table 1). In the 1 H NMR spectra of compounds 9a-p the singlet signals of the OCH2CO and NH groups were present at 4.69-4.92 ppm and 8.04-10.13 ppm, respectively (see Supplementary Materials). The IR spectra also confirmed their structures, namely that they showed the absorption bands of nitrile group at 2201-2208 cm −1 , of carbonyl group at 1662-1698 cm −1 , and of NH group at 3166-3352 cm −1 .
Thus, it was observed that amides deriving from cyclic (pyrrolidine and piperidine) 9a,b,h or from aromatic amines 9c-g,i-l gave only the expected aminoamides of furo[2,3-c]-2,7-naphthyridine 10a-l in very good yields (70-83%). Therefore, it seems that in these cases only the activated CH 2 group, which by the action of sodium ethoxide gave the relevant nucleophile CH − , was able to attack the nitrile group with formation of the condensed furan derivatives 10, via an intramolecular nucleophilic addition (AN i ).
In contrast, the amides deriving from non-aromatic primary amines 9m-o (benzylamine or 2-furylmethylamine) furnished only the 1,3-diamino-2,7-naphthyridines 11a-c again in good yields (71-74%). Thus, in these cases a Smiles type rearrangement occurred. Finally it must be remarked that in the instance of compound 9p with primary amine [(1-methyl-2-phenylethyl)amine] no reaction occurred. This can be explained by the fact that, as is known, Smiles type rearrangements take place through the formation of a spirointermediate oxazolidinone ring (that is, a 'Meisenheimer' complex), the formation of which in this case is impossible due to the presence of the methyl near the NH group.
Such O→N Smiles type rearrangement was deeply investigated by us in the case of cycloalka[c]pyridine and pyrano [3,4-c]pyridine systems [40].
Concerning the structure of furo[2,3-c]-2,7-naphthyridines 10a-l and of 1,3-diamino-2,7-naphthyridines 11a-c, the first and most important information about their structure was given by IR spectra. In fact, the IR of the furo[2,3-c]-2,7-naphthyridines 10 showed the bands of the carbonyl group of the amide (1616-1654 cm −1 ) as well as of the NH 2 group (3271-3488 cm −1 ), while the absorption bands of the nitrile group, characteristic of the initial compounds 9 and also confirmed by the 13 C NMR spectrum, disappeared. Further, in the 1 H NMR spectra of compounds 10a-l the protons of the NH 2 group at C-1 were observed at 5.61-5.83 ppm, whereas the signals of the OCH 2 CO group of starting 9a-l were absent (see Supplementary Materials).
The IR spectra of compounds 11 still showed the characteristic absorption bands of nitrile group at 2186-2199 cm −1 , thus indicating that the cyclization process did not occur, as confirmed also by the 13 C NMR spectrum. In the 1 H NMR spectra of compounds 11 the protons of the NH group at 6.40-6.60 ppm were observed, while the signals of the OCH 2 CO group were absent. The 13 C NMR spectra also confirmed their structure (see Supplementary Materials).
The structure of compounds 10 and 11 was confirmed also by the MS spectroscopy. Finally to gain a definitive confirmation of the structures of compounds 11, their synthesis from the 3-chloro-2,7-naphthyridines 2a,b was performed (Scheme 4).
It must be remembered, that the observed Smiles type rearrangement represents a new and effective method for the synthesis of 1,3-diamino-2,7-naphthyridines 11.

Materials and Methods
1 H and 13 C NMR spectra were recorded in DMSO-d 6 /CCl 4 (1/3) solution (300 MHz for 1 H and 75 MHz for 13 C, respectively) on a Mercury 300VX spectrometer (Varian Inc., Palo Alto, CA, USA). Chemical shifts were reported as δ (parts per million) relative to TMS as internal standard. The IR spectra were recorded on a Nicolet Avatar 330-FT-IR spectrophotometer (Thermo Nicolet, Madison, CA, USA) in Vaseline, ν max in cm -1 . MS spectra were recorded on Waters Q-Tof (Waters, Manchester, UK). Melting points were determined on an MP450 melting point apparatus. Elemental analyses were performed on an Elemental Analyzer Euro EA 3000. Compounds 1 [16] and 2a [16] have already been described.

Procedure for the Synthesis of Compound 2b
A mixture of compound 1 (2.70 g, 10 mmol), of hexamethyleneimine (1.24 mL, 11 mmol) and of triethylamine (1.53 mL, 11 mmol) in absolute ethanol (50 mL) was refluxed for 5 h. After cooling, water (50 mL) was added and the resulting crystals were filtered off, washed with water, dried, and recrystallized from ethanol.

General Procedure for the Synthesis of Compounds 4a,b
Aqueous solution of sodium hydroxide (50%, 8 g, 100 mmol) was added to a solution of compound 3 (10 mmol) in absolute ethanol (50 mL) and the mixture was refluxed for 15 h. After cooling, the water was added and the mixture was filtered off to remove white precipitate of the thiirane polymer. The filtrate was neutralized with HCl and the formed crystals of compound 4 were filtered off, washed with water and recrystallized from ethanol. 7-Isopropyl-3-oxo-1-pyrrolidin-1-yl-2,3,5,  5a,b and 6a,b To a suspension of compound 4/2 (10 mmol) and potassium carbonate (2.76 g, 20 mmol) in absolute DMF (50 mL) ethyl chloroacetate (1.28 mL, 12 mmol) or ethyl 2-mercaptoacetate (1.32 mL, 12 mmol) was added dropwise under stirring. The reaction mixture was maintained at 75-80 • C for 3 h, then cooled to room temperature, and poured onto ice water. The resulting crystals were filtered off, washed with water, dried, and recrystallized from ethanol.

General Procedure for the Synthesis of Compounds 9a-p
To a stirred suspension of compound 4 (1 mmol) and potassium carbonate (0.28 g, 2 mmol) in absolute DMF (25 mL) the corresponding alkyl chloride (1.2 mmol) was added. The reaction mixture was maintained at 75-80 • C for 3 h. Then the reaction mixture was cooled at room temperature, and water was added (50 mL). The resulting crystals were filtered off, washed with water, dried and recrystallized from ethanol. 7-Isopropyl-3-(2-oxo-2-pyrrolidin-1-ylethoxy)-