An efficient synthesis of 11-aryl-10-oxo-7,8,10,11-tetrahydro-1H-[1,2,3]triazolo [4′,5′:3,4]benzo[1,2-b][1,6]naphthyridine derivatives under catalyst-free conditions

Introduction

Naphthyridines are an important class of heterocycles with significant pharmacological and biological activities, especially antibacterial activity [1–5]. Many triazoles are also bioactive [6]. To the best of our knowledge, only one example of a triazolobenzonaphthyridine has been described in the literature concerning the synthesis and potential application as an antimicrobial agent [7]. As a continuation of our research devoted to the development of new methods for preparing heterocycles via multi-component reactions [8–12], we now report the synthesis of a series of substituted triazolobenzonaphthyridines 4 by a three-component reaction of an aromatic aldehyde, 1H-benzo[d][1,2,3]triazol-5-amine and tert-butyl 2,4-dioxopiperidine-1-carboxylate (Scheme 1).

Scheme 1

Results and discussion

The required benzotriazolamine 1 was prepared in a two-step procedure starting with commercially available 4-nitrobenzene-1,2-diamine as described in the literature [13]. Subsequently, the amine 1 was allowed to react with equimolar amounts of aromatic aldehyde 2 and tert-butyl 2,4-dioxopiperidine-1-carboxylate (3) in ethanol under reflux conditions. This reaction produced the desired product 4 in high yield (Scheme 1).

Synthesis of product 4a from the amine 1, 4-chlorobenzaldehyde (2a) and tert-butoxycarbonyl (BOC) derivative 3 was used as a model reaction for optimization. Several reaction parameters including temperature, catalysts and solvents were varied. Only trace amount of 4a was detected by TLC for the reaction conducted at room temperature. The reaction could not be catalyzed by bases (5 mol%), such as DBU, Et₃N, piperidine and NaHCO₃ using a variety of solvents, including alcohols, N,N-dimethylformamide, acetonitrile, dioxane and tetrahydrofuran. The highest yield of 4a of 92% was obtained for the reaction conducted in ethanol without any additive under reflux conditions. After cooling, the resulting precipitate of 4a was filtered. By using this simple workup, compound 4a was obtained in an analytically pure form. Crystallization was not necessary. The remaining products 4b–l were synthesized in high yields under similar conditions. As can be seen from Scheme 1, benzaldehydes substituted with an electron-withdrawing or electron-donating group can successfully be used. The steric hindrance of an ortho-substitution does not hinder the product formation, as evidenced by synthesis of 4i and 4l in the respective yields of 94% and 91%. All products were characterized by IR, ¹H NMR and HRMS.

The mechanism of the formation of 4 is suggested in Scheme 2. As can be seen, the initial Knoevenagel condensation product 5 undergoes Michael addition with 1. The resultant adduct 6 undergoes an intramolecular cyclization to 7 which is a direct precursor to 4. The observed regioselectivity for the addition reaction of 1 is apparently a result of a higher reactivity of the position 4 in comparison to the position 6. More specifically, the electron density at position 4 is greater than that at position 6 because the position 4 is ortho to the amino group and α to the nitrogen atom of the adjacent triazole.

Scheme 2

Conclusion

A mild, facile, efficient and environmentally benign method was developed for the synthesis of 1H-[1,2,3]triazolo[4′,5′:3,4]benzo[1,2-b][1,6]naphthyridine-9(6H)-carboxylate derivatives 4 under catalyst-free conditions.

Experimental

Melting points were determined in open capillaries and are uncorrected. IR spectra were recorded on a Tensor 27 spectrometer in KBr pellets. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were taken in DMSO-d₆ with Me₄Si as internal standard using a Bruker-400 spectrometer. HR-MS analyses were carried out using a Bruker-micro-TOF-Q-MS analyzer. 1H-Benzo[d][1,2,3]triazol-5-amine (2) was prepared by a two-step procedure from the 4-nitrobenzene-1,2-diamine according to the literature [13].