Synthesis of 3-( 1 H-1 , 2 , 3-Triazol-1-yl )-2-( arylselanyl ) pyridines by Copper-Catalyzed 1 , 3-Dipolar Cycloaddition of 2-( Arylselanyl )-3-azido-pyridines with Terminal Alkynes

*e-mail: ricardo.schumacher@ufpel.edu.br; diego.alves@ufpel.edu.br Synthesis of 3-(1H-1,2,3-Triazol-1-yl)-2-(arylselanyl)pyridines by Copper-Catalyzed 1,3-Dipolar Cycloaddition of 2-(Arylselanyl)-3-azido-pyridines with Terminal Alkynes Ricardo F. Schumacher,* Patrick B. Von Laer, Eduardo S. Betin, Roberta Cargnelutti, Gelson Perin and Diego Alves* LASOL, CCQFA, Universidade Federal de Pelotas (UFPel), P.O. Box 354, 96010-900 Pelotas-RS, Brazil


Introduction
Nitrogen heterocycles represent a large spectrum of compounds found in several natural and bioactive molecules. 1 In this context, the heterocycles of five members containing three nitrogen atoms, well known as triazoles, are important units of this class present in several medicines worldwide consumed, as example the antifungal agents (fluconazole, itraconazole and voriconazole). 2 A great number of triazole derivatives have been synthesized and their chemistry has attracted a good deal of interest and activity from a variety of standpoints such as structure, stereochemistry, reactivity and applications to organic synthesis. 3Still, their importance can be measured by the large number of publications elucidating the biological properties for new synthetic derivatives. 4 In this context, considerable effort has been applied to the development of an efficient, green, mild and relatively cheap method for the synthesis of triazoles and the copper-catalyzed azide-alkyne cycloaddition (CuAAC) definitively features a significant advance in this field, specially for 1,2,3-triazoles. 5 On the other hand, organoselenium compounds are a class of versatile and useful organic substrates that has emerged in recent years being subject of many reviews 6 and books. 7These compounds are well known as precursors to introduce an unsaturated carbon-carbon bond on organic molecules by an intramolecular syn elimination of selenoxide in oxidant media, 8 firstly described by Jones et al. in 1970. 9 However, in recent years, organic selenium compounds have been used in an increased spectrum of applications in organic synthesis such as ionic liquids 10 and asymmetric catalysis. 6,11 Moreover, organoselenium compounds are widely studied as agents with a diverse array of biological effects, these include antioxidant action, antitumoral, anticonvulsant, hepatoprotective and antinociceptive. 12 With this background, the synthesis of seleniumcontaining 1,2,3-triazoles 13 emerged as an opportunity for research, which combines the potentiality of triazoles with the organoselenium portion.Very recently, some CuAAC protocols were reported for the synthesis of organoselenium-functionalized triazoles in excellent yields under mild reaction conditions. 13However, a synthetic approach, which could incorporate to these molecules another synthetic and biological important unit, the pyridine, has not to be published so far.Realizing the importance of this research, we described here a synthetic methodology to the synthesis of 3-(1H-1,2,3-triazol-1yl)-2-(arylselanyl)pyridines combining organoselenides, pyridines and triazoles on the same molecule.
With these starting materials in hand, we envisioned to obtain the 3-(1H-1,2,3-triazol-1-yl)-2-(arylselanyl) pyridines 6 as the desired products.In view of our expertise in recent publications on this field, we decided to employ the azides 4 on copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC) using sodium ascorbate as reducer agent in a mixture of THF/H 2 O as solvent in air. 13 As a preliminary experiment we reacted the 3-azido-2-phenylselanyl-pyridine 4a with phenyl acetylene 5a in the presence of 5 mol% of Cu(OAc) 2 .H 2 O and 10 mol% of sodium ascorbate and the desired triazole 6a was obtained in 90% yield after 6 h at room temperature (Scheme 2).
Inspection of Table 2 shows that the reaction worked well for a variety of differently substituted alkynes 5 and different arylselenides directly attached to the pyridine ring 4. A closer inspection of the results revealed that the reaction is not sensitive to the electronic effects in alkynes 5.A wide range of groups attached to the alkynes such as electron rich, -neutral and -poor reacted efficiently with the 3-azido-2-(phenylselanyl)pyridine 4a under these conditions and produced the functionalized 1,2,3-triazoles 6a-d as products in moderate to good yields.For example, alkynes containing p-methyl, p-methoxy or p-chloro groups afforded the desired products in 90, 75 and 80% yield, respectively (Table 2, entries 2-4).We also observed that the reaction is tolerant to different functional groups directly attached to the alkyne, for example ester 5e and alcohol 5f, which gave the expected triazoles 6e and 6f, respectively, in good yields (Table 2, entries 5 and 6).
In an attempt to broaden the scope of our methodology, the possibility of performing the reaction with other 2-(arylselanyl)-3-azido-pyridines was also investigated.As illustrated in Table 2, the CuAAC reaction of 4b-f with phenyl acetylene 5a, under the same reaction conditions, led to the corresponding triazole products 6g-k in good to excellent yields (Table 2,. The use of different 2-(arylselanyl)-3-azido-pyridines 4b-f, containing electron-donating and withdrawing groups afforded the required products in satisfactory yields, demonstrating that the reaction is not sensitive to the electronic effect of the aromatic ring attached to the selenium atom (Table 2, entries 7-10).Comparing the entries 7 and 11 (Table 2), we realized that when the aryl selenide 4f bearing an ortho-methyl group was used, no steric influence in the formation of the desired product 6k is perceived in this cycloaddition reaction.
The use of an internal alkyne, the 1,2-diphenyl acetylene 5g, was also investigated under the optimal reaction condition, but after 24 h no product could be observed and the starting materials were quantitatively recovered (Table 2, entry 12).
Finally, in order to explore this CuAAC reaction between phenyl acetylene 5a and the 2-(phenylselanyl)-3-azido-pyridine 4a envisioning the possibility to obtain the product 6a in a shorter reaction time and using cleaner methods, we performed the reaction employing focused   microwave irradiation (using an irradiation power of 100 W) and ultrasound conditions (60% of amplitude) (Scheme 3).Results presented in Scheme 3 revealed that under both non-classical methods, the product 6a could be obtained in excellent yields after only 10 min, demonstrating the efficient use of alternative energy sources to this synthesis.

Materials and methods
Proton nuclear magnetic resonance spectra ( 1 H NMR) were obtained at 400 MHz on a DPX-400 NMR spectrometer.Carbon-13 nuclear magnetic resonance spectra ( 13 C NMR) were obtained at 100 MHz on a DPX-400 NMR spectrometer.Spectra were recorded in CDCl 3 or DMSO-d 6 solutions.Chemical shifts are reported in ppm, referenced to the solvent peak of CDCl 3 , DMSO-d 6 or tetramethylsilane (TMS) as the external reference.Data are reported as follows: chemical shift (d), multiplicity, coupling constant (J) in Hertz and integrated intensity.Low-resolution mass spectra were obtained with a Shimadzu GC-MS-QP2010 mass spectrometer.High resolution mass spectra (HRMS) were recorded on a Bruker Micro TOF-QII spectrometer 10416.A Cole Parmer-ultrasonic processor Model CPX 130, with a maxim power of 130 W, operating at amplitude of 60% and a frequency of 20 kHz was used in Scheme 3. A Microwave CEM Discover Legacy apparatus, with magnetic frequency of 2.45 MHz and power of 300 W, operating at 50 °C, was used in Scheme 3. Baker silica gel (particle size 0.040-0.063mm) was used for flash chromatography.Thin layer chromatography (TLC) was performed using Merck Silica Gel GF254, 0.25 mm thickness.For visualization, TLC plates were either placed under ultraviolet light, or stained with iodine vapor, or 5% vanillin in 10% H 2 SO 4 and heat as developing agents.Most reactions were monitored by TLC for disappearance of starting material.

General procedure for the preparation of 3-azido-2arylselanylpyridine 4
To a solution of 3-amino-2-arylselanylpyridine 3 (1.0 mmol) in THF (2.0 mL), iso-pentyl nitrite (1.15 mmol) followed by trimethylsilyl azide (1.15 mmol) was added drop by drop at 0 °C under air.Then the mixture was stirred at 0 °C for 10 min, the ice bath was removed, and the mixture was stirred at room temperature for 6 h.The solvent was removed under vacuum and the product was isolated by column chromatography using hexane or hexane/ethyl acetate as eluent.

Scheme 1 .
Scheme 1. Synthetic route to obtain the starting material 4a.
and available catalytic amount of copper(II) acetate and sodium ascorbate, using THF/H 2 O as solvent in air.The reaction does not show to suffer steric or electronic influence of the substituents of the aryl selenide 4 or at the alkyne 5 and all products were obtained in good to excellent yields.These molecules comprise a new class of organoselenium-substituted triazole compounds that associated to pyridine moieties are plausible candidates to present potent pharmacological properties.carried out using (2-arylselanyl)-3-azido-pyridine 4 (0.30 mmol), alkyne 5 (0.33 mmol), Cu(OAc) 2 .H 2 O (0.015 mmol), sodium ascorbate (0.03 mmol) in THF/H 2 O (1:1) (1.0 mL) as solvent at r.t. in air; b reactions were monitored by thin layer chromatography (TLC); c reaction was performed at 50 °C; d obtained as a 10:1 mixture of regioisomers; e obtained as a 10:0.4mixture of regioisomers.

Table 1 .
Synthesis of the starting materials 4a-f