Cuprous oxide on charcoal-catalyzed ligand-free synthesis of 1,4-disubstituted 1,2,3-triazoles via click chemistry

Cuprous oxide on charcoal (Cu 2 O/C), the preparation of which is described for the first time, catalyzes the formation of 1,4-disubstituted 1,2,3-triazoles from organic azides and terminal alkynes in good to excellent yields (69-94%). These disubstituted triazoles can be equally efficiently generated in a one-pot process from alkyl bromides, sodium azide, and terminal acetylenes in 50% aqueous isopropanol containing a suspension of the catalyst. This obviates the necessity to isolate potentially explosive organic azides.


Introduction
Recent advances in the Huisgen 1,3-dipolar cycloaddition reaction have led to a renewed interest in its applications to the synthesis of 1,2,3-triazoles. 1 Small molecules containing the triazole functionality have been shown to exhibit a range of biological functions, including antitumor, antibacterial, antiparasitic and antiviral activity (Figure 1).Historically, 1,2,3-triazoles have been prepared via the Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes.1a,3 This reaction sometimes requires relatively high temperatures and long reaction times.The main disadvantage of this methodology is that regioisomeric mixtures of the 1,4-and 1,5-disubstituted 1,2,3-triazoles are often formed.Recently, Fokin and coworkers developed new methodology for the preparation of 1,5-dialkyl 1,2,3-triazoles in high yields from aryl azides and terminal alkynes in the presence of catalytic tetramethylammonium hydroxide or Cp*RuCl(PPh3)2. 4In addition, Sharpless 1c and Meldal 1e have found that catalytic copper(I) dramatically accelerates the reaction resulting in the highly regioselective formation of 1,4-disubstituted triazoles.This powerful, highly reliable, and selective reaction meets the set of stringent criteria required in click chemistry as defined by Sharpless et al. 1b Thus, the copper(I)catalysed process is the preferred methodology for effecting this reaction (See Scheme 1).The sources of copper(I) include: a) copper(I) salts, normally in the presence of a base and/or a ligand, b) in-situ reduction of copper(II) salts (e.g., copper sulfate with sodium ascorbate) and c) disproportionation of copper (0) and copper(II), generally limited to special applications. 5For instance, reactions performed in some of the commonly used solvents (e.g.water-alcohol solvent mixtures) can be problematic, especially for insoluble reagents or very soluble products, thus reducing the application scope.Another aspect to consider is the reaction time, which, in general, is relatively long, requiring 12-24 h for completion.The addition of some copper complexes 6 or ligands 5,7 was found to enhance the reaction rate.New and interesting advances in the title reaction involve heterogeneous catalysis.Thus copper(I) on charcoal, in the presence of triethylamine, was shown to be an efficient heterogeneous catalyst for the title reaction, the reaction times being reduced to 10-120 min. 8Copper(I) on zeolite was also recently found to catalyze the cycloaddition reaction from halides or tosylates, sodium azide, and alkynes. 9 5b is due to crystallite size under 100 nm, 12 in agreement with the nanoparticles shown in Figure 5a.The most noticeable peak broadening was produced in the direction perpendicular to (002) planes, as could be expected for weak bonding between basal planes in graphite.Figure 5c shows that the Cu2O (JCPDS 1-1142) was formed after ultrasonication of an aqueous CuSO4 solution containing suspended graphite (after drying at 120 o C overnight).Assuming catalysis by Cu(I), reduction by charcoal could account for the observed activity as described by Lipshutz.8a   (b) Application of the Cu2O/C catalyst for the preparation of 1,5-disubstituted 1,2,3-triazoles The selected area electron-diffraction pattern of the copper is in agreement with the presence of Cu2O. 13It is worthy of note that Cu2O very recently has been found to catalyze the 1,3-dipolar cycloaddition of azides and terminal alkynes. 14The reaction of benzyl azide (1a) with phenyl acetylene (2a) was chosen as a model system (Table 1).Initially, we attempted to adopt a previously reported reaction protocol [PS-EPG-terpyridine copper(I) complex/H2O/40 o C] 15 to synthesize the targeted product 3a, but to our surprise, 3a was not formed.Modification of the procedure reported by Chowdhury 16 with increased catalyst loading and manipulation of various parameters (Table 1) including different solvent systems did, however, provide 3a.It was found that the solvent system plays a very important role in terms of reaction rate, isolated yields, and regioselectivity with the 50% aqueous isopropanol mixture being especially efficacious (Table 1, entry 6).In addition, examination of the effect of various bases showed that triethylamine was the preferred one (Table 1).The TON and the turnover frequency (TOF) of the catalyst reached 1957.32 and 13.5 h -1 , respectively; these are, as far as we know, one of the higher TON and TOF obtained for heterogeneous catalysts.8a,17  With the optimized conditions (Table 1, entry 6) in hand, the scope of the reaction was explored by reacting various azido compounds (1a-f) with terminal alkynes (2a-e).The results are summarized in Table 2.All products were characterized by spectral and analytical data (see Experimental Section).The molecular structures of triazoles 3c, 3l, 3p and 3v were confirmed unambiguously by single-crystal X-ray analyses (see Figure 6). 18It is obvious that a wide variety of aryl, benzyl, and alkyl azides possessing different functional groups reacted successfully.a Chromatographically isolated yield of pure product.b The catalyst was not recovered.c No product formation was observed despite increasing the amount of 2,6-lutidine and catalyst.a Reaction was performed using 1 mL of H2O and 1 mL of Isopropanol at room temperature with 5 mol% Cu2O/C and 1.1 mL of Et3N.b Product was further purified by silica gel chromatography.

(c) Catalyst durability
Numerous control experiments indicated not only that the Cu2O/C on charcoal is essential for catalysis, but that it is also quite robust.For example, the recyclability of Cu2O/C was examined for the click reaction of benzyl azide (1a) with phenylacetylene (2a).Thus after the first reaction, which give 82% of 1-benzyl-4-phenyl-1H-1,2,3-triazole (3a), the catalyst was recovered by simple filtration, washed with water, dried under vacuum, and reused three times under similar reaction conditions to give 3a in 78% and 61% yields (Scheme 2).

Scheme 2 (d) One pot procedure
In an attempt to circumvent the risk of working with potentially explosive organic azides, we investigated the possibility of carrying out the click reaction without having to isolate the azides.
It is known that 1,4-disubstituted 1,2,3-triazoles can be prepared efficiently in a two step one-pot procedure, in a CuI-zeolite-catalyzed synthesis of triazoles from halides or tosylates, sodium azide, and alkynes at 90 o C. 9a Benzyl bromide and phenylacetylene were selected as model compounds to find the appropriate conditions for the desired one-pot process.Various reaction conditions were examined including the amount of Cu2O/C, the reaction temperature, and different solvent systems.Once again 50% aqueous isopropanol clearly stood out as the solvent system of choice providing a fast reaction rate at 80 o C (reflux), high yield, and selectivity (see Table 3).The scope of the reaction was explored by reacting sodium azide, benzyl bromide or alkyl bromides (4a-d) with terminal alkynes (2a-d).The results are summarized in Table 3.

(e) Application to other systems
The synthesis of 7a-e was carried out following recently described methodology. 19This procedure involves the condensation of salicylaldehyde derivatives with 2-aminophenols in the presence of phenylboronic and catalytic potassium cyanide to give the 2-(2hydroxyphenyl)benzoxazole derivatives (7a-e).(Scheme 3) The 2-(2-hydroxyphenyl)benzoxazole derivatives (7a-e) were subsequently alkylated with propargyl bromide in the presence of potassium carbonate to afford the corresponding benzoxazole derivatives 8a-e.These compounds, without purification, were reacted with benzyl azide, under the conditions described above to give the 1,2,3-triazole derivatives 9a-e.(Scheme 4).The structure of the 1,2,3-triazole derivatives 9a-e was unequivocally established by the usual spectroscopic means, as well as by X-ray crystal structure for compound 9d (Figure 7, vide infra). 20

Scheme 4
The mechanism of these reactions proceeds similarly to previous reports.8a -b,21,22

Conclusions
We describe in this paper a facile preparation of a new supported catalyst (Cu2O/C) for Copper-Catalyzed Alkyne-Azide Cycloaddition.This material was found to efficiently catalyze the formation of several 1,4-disubstituted 1,2,3-triazoles from organic azides and various terminal alkynes.In addition, a multicomponent, one-pot protocol for the synthesis of 1,4-disubstituted 1,2,3-triazoles from alkyl azides was devised.Considering the good triazole yields, the operational ease with which these reactions can be carried out, and the inexpensive chemicals involved, we believe this protocol will be of great benefit to medicinal and synthetic organic chemistry.

Experimental Section
General.TLC was performed on Merck-DC-F254 plates, detection was made by shining UV light.Flash column chromatography was performed using Merck silica gel (230-240 mesh).
Melting points were measured in open capillary tubes on a Büchi Melting Point B-540 apparatus and have not been corrected. 1H and 13 C NMR spectra were recorded on a JEOL Eclipse+400 (400 MHz, 100 MHz)) and a Varian VNMRS 400 (400 and 100 MHz) spectrometers.Chemical shifts (δ) are indicated in ppm downfield from internal TMS used as reference; the coupling constants (J) are given in Hz.IR spectra were measured on a Perkin Elmer GX FT-IR.Elemental analyses were performed on a Perkin-Elmer Series II CHNS/O Analyzer 2400.
General procedure for the preparation of 1,2,3-triazoles In a 10 mL round-bottomed flask fitted with a magnetic stirring bar was placed 1.0 equiv. of azide 1 and 1.0 equiv. of terminal alkyne 2 in 2 mL of [H2O: i PrOH (1:1)], further was added Cu2O/C (5% w/w) and 1.1 mL of Et3N (for 100 mg of alkyl azide).The reaction mixture was warmed to 80 °C and monitored by TLC until total conversion of the starting material.The crude reaction mixture was filtered through a filter paper, washed and extracted with EtOAc or CH2Cl2 (3 × 20 mL).The combined organic extracts were washed with 15 mL of saturated aq.NH4Cl, dried over anhydrous sodium sulfate, and evaporated under reduced pressure in vacuum.The crude reaction mixture was purified by column chromatography or crystallization to afford 3a-w.

Figure 2 .
Figure 2. Secondary electron SEM images of graphite milled for 40 minutes.

Figure 3 .
Figure 3. (a) Dark field TEM image of milled graphite, and (b) the corresponding selected area electron diffraction pattern.

Figure 4 .
Figure 4. Backscattered electrons SEM image of milled graphite, after treatment with a CuSO4 solution in an ultrasonic bath.Bright particles correspond to Cu2O.

Figure 5 .
Figure 5. X-ray diffraction patterns of a) unmilled graphite, b) graphite milled for 40 minutes, and c) milled graphite, after treatment with a CuSO4 solution in an ultrasonic bath.The formation of Cu2O can be observed.

Figure 5
Figure 5 shows the X-ray diffraction patterns of a) unmilled graphite, b) milled graphite and c) milled graphite after treatment with a CuSO4 solution followed by ultrasonication.The patterns shown in a) and b) correspond with the card JCPDS 23-64, for graphite.The peak broadening in Figure5bis due to crystallite size under 100 nm,12 in agreement with the nanoparticles shown in Figure5a.The most noticeable peak broadening was produced in the direction perpendicular to (002) planes, as could be expected for weak bonding between basal planes in graphite.Figure5cshows that the Cu2O (JCPDS 1-1142) was formed after

Table 2 .
Click reactions catalyzed by Cu2O/C a

Table 3 .
One-pot Cu2O/C synthesis of 1,4-disubstituted triazoles from halides and related compounds a a Run at 2 equiv of sodium azide, 1 mL of H2O and 1 mL of isopropanol at 80 o C with 5 mol % Cu2O/C and 4 equiv. of Et3N for 2 h.b Product was further purified by silica gel chromatography.