General Pathway for a Convenient One-Pot Synthesis of Trifluoromethyl-Containing 2-amino-7-alkyl(aryl/heteroaryl)-1,8-naphthyridines and Fused Cycloalkane Analogues

A convenient and general method for the synthesis in 26–73% yields of a new series of 7-alkyl(aryl/heteroaryl)-2-amino-5-trifluoromethyl-1,8-naphthyridines from direct cyclocondensation reactions of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones [CF3C(O)CH=C(R1)OR, where R1 = H, Me, Ph, 4-MePh, 4-OMePh, 4-FPh, 4-BrPh, 4-NO2Ph, 2-furyl, 2-thienyl and R = Me, Et] with 2,6-diaminopyridine (2,6-DAP), under mild conditions, is described. Another synthetic route also allowed the synthesis of 2-amino-5-trifluoromethyl-cycloalka[b][1,8]naphthyridines in 33–36% yields, from direct or indirect cyclo-condensation reactions of five-, six- and seven-membered 2-trifluoroacetyl-1-methoxy-cycloalkenes with 2,6-DAP.


Introduction
Among the nitrogenous heterocycles, naphthyridines and their derivatives represent an important class of organic molecules that attract the interest of both synthetic and medicinal chemists due to their exceptionally broad spectrum of biological activities as well as their use as important binding units in

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the molecular design of synthetic receptors [1]. Naphthyridine derivatives have attracted considerable attention primarily due to the presence of a 1,8-naphthyridine skeleton in many compounds which have been isolated from natural substances and exhibit various biological activities [2]. As a heterocyclic moiety, 1,8-naphthyridine also deserves special interest as in its molecule, the arrangement of the nitrogen atoms is optimal for chelation of various metal cations, including lanthanide ions [3].
In addition, has been recognized that attachment of a trifluoromethyl group into heterocycles can be used to modulate the physical, chemical and biological properties. It is well documented that the influence of the trifluoromethyl substituent on physiological activity is due mainly to the increased lipophilicity of the molecules, causing greater cell permeability and resistance to enzyme degradation [20]. Consequently, synthetic methodology to incorporate fluorine and fluorous synthons must be improved in order to prepare sophisticated fluoroorganic molecules on a practical scale. One of the most satisfactory methods for introducing a CF 3 group into heterocycles is via the trifluoromethylated building block approach. The trifluoroacetylation of enol ethers or acetals provided, in one step and in good yields, β-alkoxyvinyl trifluoromethyl ketones 1 which proved to be useful building blocks for the syntheses of many series of heterocyclic compounds [21].
Since the 50s various diamino-ketoester condensations involving reactions of cyclic and acyclic βketoesters or diketones with aminopyridines or diaminopyridines have been studied in an attempt to develop generalized predictions regarding the direction of ring closure to form diazepinones, naphthyridones, naphthyridines or pyrimidines [6,[12][13][14][15]19,22]. Whereas a literature review shows that the synthesis of trifluoromethylated naphthyridines and derivatives has been little explored and that 1,8-naphthyridines trifluoromethylated described are associated with satisfactory biological activities [14], the incorporation of trifluoromethyl group in a variety of 1,8-naphthyridines would be expected to provide highly desirable intermediates for the synthesis of new drug candidates. So, due to the great biological importance and employment of amino-naphthyridines as starting material for the synthesis of new tri and tetracyclic heterocycles, the development of new synthetic approaches remains an active research area [19,23].
The use of diethyl ethoxymethylenemalonate (EMME) [24], Conrad-Limpach [25], Knorr [26] and Skraup [27] methods have been particularly successful in the synthesis of certain quinolines. The adaptation of these reactions to the synthesis of the corresponding naphthyridines by employing aminopyridines instead of anilines should furnish convenient methods for the preparation of these types of compounds since aminopyridines are readily available [19]. However, these methods have not been as satisfactory for the preparation of 1,8-naphthyridines as they are the preparation of quinolines. In contrast to aniline derivatives, 2-aminopyridine derivatives may cyclize in two ways, one of which leads to the formation of 1,8-naphthyridines and the other leads to the formation of pyrimidines, and the latter course of reaction has is observed with more frequency [28]. In both types of cyclization, the pyridine ring functions as the electron donor and the carbonyl group in the side chain serves as the electron acceptor.
The formation of pyrimidines should not be surprising, since the resonance structures existing in the structure of the 2-aminopyridine derivatives strongly favor cyclization leading to the pyrimidine ring. Nevertheless, although the formation of a pyrimidine often occurs, an investigation of the synthesis of certain 1,8-naphthyridines from aminopyridines with diethylmalonate, ethoxymethylidenemalonate or ethyl acetoacetate has been made [14,19,29]. It is known that the synthesis of 1,8-naphthyridines has been performed successfully when 6-methyl-2-aminopyridine or 2,6-diaminopyridine are used as precursors, since 6-methyl or 6-amino groups activate the 3-position leading to those molecules [14,29]. Thus, the great difference in behavior of 2-aminopyridine and 2,6-diaminopyridine, for example, has usually been attributed to activation of the 3-position by the electron releasing amine group.
As an extension of this study we also developed the synthesis of compound 3b from the cyclocondensation reaction of enamino ketone intermediate 2b in methanol at reflux temperature for 24 hours (Scheme 1). The isolation of 2b was possible when the reaction of enone 1b with 2,6-DAP was carried out in methanol as solvent at 0 °C for 2 hours. Unfortunately, the enamino ketones 2a, 2c-j could be not isolated as pure compounds, under the same or similar reaction conditions. The structures of 3a-j were established on the basis of 1 H-and 13 C-NMR spectroscopy and literature data for similar compounds (chemical shifts and spin ± spin coupling constants) [5,9,12,14,22,41,46]. According to the literature, it is well known that the proton in the 4-position of the naphthyridine nucleus shows long-range coupling with fluorine atoms of the 5-trifluoromethyl substituent, but in some cases the outer signals of the quartets can appear as shoulders on the inner signals instead of as clearly resolved quartets [22]. This splitting of the H-4 signal is seen in all of the compounds having this structural feature and was clearly seen in 1 H-NMR spectral data of compounds 3a-j.
As an second extension of this study, we also developed the synthesis of trifluoromethyl substituted cycloalka[b] [1,8]naphthyridines 3 from the reactions of 2-trifluoroacetyl-1-methoxycycloalkenes 1 with 2,6-DAP (Scheme 4). Firstly, three examples of methoxycycloalkenes 1k-m were obtained by a direct acylation reaction of the cycloalkane dimethyl acetals with trifluoracetic anhydride in the presence of pyridine, as described in the literature [47,48]. Subsequently, the intramolecular cyclization reactions of trifluoroacetylated cycloalkenes 1k-m were carried out, applying the same conditions described for the preparation of 3a-j. This reaction condition allows to isolate, in one-pot, only the respective cycloalka[b] [1,8]naphthyridines 3l, 3m in 30-33% yields because the cyclization of 1k did not take place. This reaction condition allowed the isolation of enaminone 2k in 43% yield, derived from 2-trifluoroacetyl-1-methoxycyclopentene. The synthesis of 3k, in 78% yield, was only possible from intramolecular cyclization reaction of enaminone 2k in polyphosphoric acid medium (PPA), as shown in Scheme 4. The structures of compounds 2k, 3k-m were easily established on the basis of 1 H-and 13 C-NMR spectroscopy and literature data for similar compounds, such as trifluoromethyl-containing cycloalka[b]quinolines [37]. Any attempt to explain the low yield for the synthesis of compounds 3l and 3m and the absence of cyclization for 1k requires an examination of the structural effects on internal cycloalkenes 1k-m. Information from the literature for precursors of these compounds [47], obtained by calculation using AM1 semi-empirical method, indicate the possibility of non-planar conformations for these molecules, which would explain the difficulty in achieving [3+3] intramolecular cyclization in the case of 1k [37,48].

General
Unless otherwise indicated all common reagents and solvents were used as obtained from commercial suppliers without further purification. The melting points were determined using a Kofler Reichert-Thermovar and Electrothermal Mel-Temp 3.0 apparatus. 1 3a, 3m, 4i, 4j and CDCl 3 + TFA for 4g, using TMS as internal reference. Mass spectra were registered in a HP 6890 GC connected to a HP 5973 MSD and interfaced by a Pentium PC. The GC was equipped with a split-splitless injector, autosampler, cross-linked HP-5 capillary column (30 m, 0.32 mm of internal diameter), and helium was used as the carrier gas. The CHN elemental analyses were performed on a Perkin-Elmer 2400 CHN elemental analyzer (São Paulo University, USP/Brazil).

General procedure for the synthesis of 7-alkyl(aryl/heteroaryl)-2-amino-5-trifluoromethyl-1,8naphthyridines 3a-j
To a magnetically stirred solution of 2,6-diaminopyridine (1.08 g, 10 mmol) in methanol (40 mL), a solution of 1a-j (10 mmol) in methanol (40 mL) was added dropwise at 0 °C over a period of 2 h. The mixture was refluxed for an additional 24 h. After the end of the reaction, the solvent was evaporated under reduced pressure. The crude product was dissolved in ethanol and cooled (4-8 °C, 24 h). The solids 3b-j were isolated from the cooled solution by filtration under reduced pressure. The compound 3a was purified by flash chromatography eluting with ethyl acetate/n-hexane (1:2); yields: 26-73%.

Conclusions
In summary, we have developed a new, simple and convenient route for the preparation of a new series of 7-alkyl(aryl/heteroaryl)-2-amino-5-trifluoromethyl-1,8-naphthyridines 3a-j in moderate to good yields, derived from direct cyclocondensation reactions employing acyclic β-alkoxyvinyl trifluoromethyl ketones 1a-j and 2,6-DAP, under mild conditions by a conventional one-pot procedure.