“Flash” Solvent-free Synthesis of Triazoles Using a Supported Catalyst

A solvent-free synthesis of 1,4-disubstituted-1,2,3-triazoles using neat azides and alkynes and a copper(I) polymer supported catalyst (Amberlyst® A21•CuI) is presented herein. As it provides the products in high yields and purities within minutes, this method thus being characterized as a "flash" synthesis, and was exemplified through the synthesis of a 24-compound library on a small scale.


Introduction
Triazoles have gained in interest over the past few years following the introduction of the "clickchemistry" concept [1][2][3]. This approach concentrates on chemical reactions between highly reactive partners to provide ready access to structures that can be easily diversified, thanks to the generality of those reactions and their relative insensitivity to stereochemical and electronic considerations.

OPEN ACCESS
facilitated the reaction at lower temperature and furthermore only the 1,4-disubstituted regioisomer of the 1,2,3-triazole was formed. The conditions used to conduct such reactions can be addition of copper (I) salts in organic or aqueous systems often in conjunction with a base [11][12][13], copper (II) salts/ ascorbic acid system (to generate the copper (I) species in situ) [14][15][16], copper salts adsorbed on zeolites [17], charcoal [18] or clay [19], copper wire [20][21][22] and nanoparticles/clusters [23][24].  We recently proposed a new catalytic system based on copper (I) iodide chelated on Amberlyst ® A21 resin, for use in automated solution synthesis of 1,2,3-triazoles from organic azides and terminal alkynes [25,26]. The advantages of this catalyst are the ease of preparation, a good catalytic activity and the simple separation from the reaction product by filtration. This catalyst was successfully employed for the synthesis of triazole libraries in solvents, the reaction needing however a few hours to overnight to be completed.

Results and Discussion
In recent years there has been a growing pressure on organic chemists to not only find efficient reactions, that can achieve high yields and selectivities, but also to focus on the "greenness" of the processes [27]. One of the major environmental impacts of organic synthesis is the solvent use itself. During our work on this system, we found out that the A21•CuI polymer was able to catalyze triazole formation within only minutes using neat azides and alkynes derived from various organic structures, i.e. in a solvent-free manner (Scheme 1). Scheme 1. Solvent-free synthesis of triazoles using a polymer-supported copper (I) iodide.
We wish to report in this communication a new "flash" (quasi instantaneous) solvent-free method for the synthesis of triazoles using this polymer-supported catalyst [28][29][30][31]. When organic azides and terminal alkynes were mixed together and treated directly with A21•CuI catalyst, a rise in the mixture temperature was observed in most cases. As soon as the mixture cooled off, crystallization of the triazole usually occurred within five minutes and this was considered as the end of reaction (<0.5 h vs. more than 6 h in solution). Reaction products were then manually separated from the large beads of the catalyst. The results for the synthesis of 24 triazoles are presented in Table 1. In most cases, the yields were high (average 90%) and for the two-thirds of the formed triazoles were between 90% and quantitative. In all reactions, only the 1,4-isomer was observed and all products were pure with some minor exceptions. As previously observed with this system, the small excess of azide used was not detected in the reaction products, suggesting a possible sequestration by the polymer.
Yields for the reactions of benzyl azide (1a), ethyl azidoacetate (1c) and 3-azidotrifluoroacetamidopropane (1d) were good (averages between 89-98%). Products were usually isolated as highly crystalline solids and easily separated from the catalyst. Yields were lower, however, when using 3-azidopropanol (1b) and the corresponding triazoles were isolated in 80% average yield. This was mainly due to the sticky nature of the products which coated the polymer beads. In this case the reaction yields can be improved by washing the polymer beads with a solvent, but this step obviously diminishes the "greenness" of the approach.
The reaction yields of tripropargylamine (2d) were good when 3.3 eq. of the azide were used, and led exclusively to the corresponding tris(triazoles) 1a-d2d, with no mono-or bis(triazoles) being observed. In this case, traces of copper leaked out from the catalyst due to the presence of the amine centre in the products. This is obviously one of the limitations of this system. However, residual minute amounts of copper can be quickly and easily removed from solutions of the products using polymer-supported thiourea [32].
Finally, trimethylsilylacetylene (2f) was found not to react as well as the other alkynes and leading to a coloration of the polymer beads (light orange to red) suggesting side reactions. In order to obtain better conversions, it was the only alkyne used in excess based onto the azide. Yields were also good here in most cases (average 86%), but still lower for the cycloaddition with 1b.

Conclusions
We have presented in this communication our findings concerning a new method for the synthesis of 1,4-disubstituted 1,2,3-triazoles. This method provides an "instantaneous" access to the products when using only neat alkynes, azides and an easily prepared polymer-supported copper (I) catalyst, thus being characterized as a "flash" reaction. This method is one of the fastest and easiest compared to traditional thermal and microwave-assisted procedures [33], or to the copper (I) catalyzed versions of Huisgen's cycloaddition themselves. The triazoles were obtained regioselectively in very good yields and purities in only a few minutes, thus improving the access to these heterocycles. We are convinced this method will find many applications for the synthesis of simple and more complex triazole containing molecules.

General
Chemicals: Copper (I) iodide and propiolic acid methyl ester were purchased from Lancaster. Propargyl alcohol, tripropargylamine and trimethylsilylacetylene were purchased from Aldrich and phenylacetylene from Fluka. These chemicals were used without purification. Propargyl phenyl ether was prepared from propargyl bromide and phenol [34]. Azides were prepared from sodium azide and benzyl bromide, 3-chloropropanol, ethyl bromoacetate and 3-bromopropylamine hydrobromide (after treatment with ethyl trifluoroacetate) following published procedures [35][36][37][38]. Solvents: Acetonitrile (spectrometric grade, low water) was purchased from SDS France and used as such. Dichloromethane (SDS France) was treated with phosphorus pentaoxide at reflux (1 h) before being distilled. Melting points (mp) were determined using a Kofler apparatus after a first evaluation, calibration with a reference sample of a mp near the observed fusion and final measure of the melting point. Infrared spectra were recorded neat on a Jasco FT/IR-4100 in ATR mode (PIKE-MIRacle) between 4,000 and 400 cm -1 and are given in ν (cm -1 ). NMR spectra were recorded on a Bruker Avance DRX instrument in deuteriochloroform (unless otherwise noted) at 300 MHz for the 1 H and 75.5 MHz for the 13 C spectra. Chemical shifts (δ) are reported in part per million (ppm) relative to the tetramethylsilane signal as an internal reference. Couplings constants (J) are in hertz and signal multiplicities indicated as s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), dd (doublet of doublets). LC-MS analyses were done on a Shimadzu LCSM-2010 A instrument equipped with a SPD-M10 A PDA diode array detector (D 2 , lamp from 190 to 400 nm) and an ELSD-LT light scattering detector on an Alltima HP C8 3μ (Alltech) reversed phase (L= 53 mm; ID = 7 mm) HPLC column. The LC were ran using a 1 mL/min flow using a gradient between acetonitrile and water containing formic acid (0,1%): 0 to 1 min: 30% CH 3 CN, 1 to 5 min: from 30% to 100% CH 3 CN, 5 to 12 min : 100% CH 3 CN, 12 to 14,99 min: from 100% to 30% CH 3 CN, 14,99 to 20 min: 30% CH 3 CN. MS was recorded between m/z = 100 to 500 at the exit of the column using an ESI ionization and positive ion mode (detector= 1.5 kV, quadripole = 5 V).

Procedures
Dry Amberlyst ® A-21: Commercial wet Amberlyst ® A21 resin (Aldrich, 20-50 mesh, 100 g) was suspended in MeOH (500 mL) for 0.5 h and filtered (3 times) and then soaked in methylene chloride (500 mL) for 0.5 h and again filtered (3 times). The resulting resin was placed in a round-bottom flask on a rotoevaporator and dried at 50 °C under 10 mm Hg until it was free-flowing. The dried resin was then kept overnight under vacuum in a desiccator over P 2 O 5 . Specifications from the manufacturer indicate that the polymer contains 4.8 meq. of amine/g of dry resin. The azide (0,55 mmol) and alkyne (0,50 mmol) were placed together in an open small test tube. Amberlyst ® A21•CuI (1.35 mmol/g, 30 mg, 0.040 mmol, 8% mol) was added at once. A quick temperature rise was observed in most cases and the triazole crystallized out generally within 5 minutes. After half an hour, which was selected arbitrarily, the product was separated from the catalyst either manually or by dissolution in CH 2 Cl 2 or CH 3 CN (3 x 1 mL) and recovered after evaporation of the solvent.            [1,2,3]triazole-4-carboxylic acid methyl ester (1d2c): Prepared from 42 mg (0.50 mmol) propiolic acid methyl ester and 108 mg (0.55 mmol) N-(trifluoracetyl)-1-azido-3-aminopropane. The product was obtained as a beige solid (138 mg, 98 %).