Zohreh Mirjafary*a,
Leila Ahmadib,
Masomeh Moradib and
Hamid Saeidianb
aDepartment of Chemistry, Tehran Science and Research Branch, Islamic Azad University, Tehran, Iran
bDepartment of Science, Payame Noor University (PNU), PO Box: 19395-4697, Tehran, Iran. E-mail: zmirjafary@srbiau.ac.ir
First published on 8th September 2015
An efficient and practical synthesis of 1,4-disubstituted-1,2,3-triazoles under click conditions using a copper(II)–thioamide combination as an efficient heterogeneous catalyst is disclosed. Mild reaction conditions and high yields make this method an attractive option for the preparation of triazole derivatives. The key to this procedure was the generation of Cu(I) required for the azide-alkyne cycloaddition, which was achieved by in situ reduction of Cu(II) using thiobenzanilide as reduction agent and ligand.
Developing more efficient methods for the construction of compounds containing triazoles is a topic of immense importance. The synthesis of 1,2,3-triazoles strongly relies on copper(I)-catalyzed azide-alkyne [3 + 2] Huisgen cycloaddition reaction (CuAAC reaction) which is the best ‘click’ reaction to date, due to its wide range of applications in chemistry, biochemistry and polymer chemistry.12,13 A major advance in improving of this reaction was accomplished through the use of copper compounds as catalysts. 1,4-Disubstituted 1,2,3-triazoles were synthesized in the presence of copper(I) with high yields under very mild conditions. Various CuAAC reactions involving different sources of copper(I) and solvents have been developed, leading to 1,4-disubstituted-1,2,3-triazoles.14–20 Copper(I) salts are less used because of their general thermodynamic instability. One possible choice to protect the copper(I) center from oxidation or disproportionation and to enhance its catalytic activity in the CuAAC reactions is to use Cu(I) salts supported by nitrogen, sulfur and polydentate or auxiliary ligands.21–23 However, the preparation of such supported copper(I) catalysts are tedious, expensive and not always easy. On the other hand, recycling and reusability of them because of their generally homogeneous nature are difficult.
It should be noted that copper(II) salts did not work well in CuAAC reactions. Sharpless and co-workers established a very robust catalytic system for the CuAAC reactions, which made use of a less expensive copper(II) precatalyst, along with substoichiometric amounts of sodium ascorbate for an in situ reduction.14 Designing of new specific catalytic system for the CuAAC reactions has caused profound effects in optimizing the efficiency of a wide range of 1,4-disubstituted-1,2,3-triazoles. Development of such catalysts has resulted in more economical and environmentally friendly chemistry through replacing expensive, unstable, or toxic catalysts.
In the context of our general interest in the synthesis of heterocycles and following our research on thioamide chemistry,24–29 herein, we propose a facile synthesis of 1,4-disubstituted-1,2,3-triazoles via the CuAAC reaction in the presence of a copper(II)–thioamide combination as an efficient and inexpensive catalytic system (Scheme 1). Thioamides are a class of organosulfur compounds which recently become a very important functional group in coordination chemistry.30–32 The presence of nitrogen atom and the larger and less electronegative sulfur atom as soft donor enables the thioamides-NH to bind to a metal in different ways, giving a variety of complexes.32 Moreover organosulfur compounds generally can reduce copper(II) species.31 With these two promising properties of thioamides in hands, our attention were focused on using thiobenzanilide in the CuAAC reaction as an reduction agent and ligand.
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Scheme 1 One-pot synthesis of 1,4-disubstituted-1,2,3-triazoles 3 using copper(II)–thioamide combination. |
Entry | Catalyst | Solvent | T (°C) | Yield (%) |
---|---|---|---|---|
a Reaction conditions: solvent (5 mL, 1![]() ![]() |
||||
1 | No catalyst | H2O/EtOH | rt | 0 |
2 | CuCl2 | H2O/EtOH | rt | Trace |
3 | CuCl | H2O/EtOH | rt | 71 |
4 | CuCl/PhCSNHPh | H2O/EtOH | rt | 86 |
5 | CuCl2/PhCSNHPh | H2O/EtOH | rt | 95 |
6 | CuCl2/PhCSNHPh | H2O | rt | 58 |
7 | CuCl2/PhCSNHPh | EtOH | rt | 0 |
8 | CuCl2/PhCSNHPh | H2O/EtOH | 50 | 65 |
9 | CuCl2/PhCSNHPh | H2O/EtOH | 75 | 69 |
10 | CuCl2/PhCSNHPh | H2O/EtOH | rt | 70b |
11 | CuCl2/PhCSNHPh | H2O/EtOH | rt | 91c |
As mentioned above, organo-thiols and thiones generally can reduce copper(II) and disulfide compounds are formed according to eqn (1):31
2RSH + 2Cu2+ → RSSR + 2Cu+ + 2H+ | (1) |
It is conceivable that thiobenzanilide can exhibit thione–thiol tautomerism in the presence of Cu2+, so formation of the corresponding disulfide is possible. Acceleration of the CuAAC reaction by using CuCl2–thioamide combination supported that copper(II) is reduced to copper(I) (Table 1, entry 5 versus entry 2). During the redox reaction, thiobenzanilide acting as reduction agent is oxidized to the corresponding disulfide according to eqn (2).
![]() | (2) |
LC-Mass analysis of the alcoholic solution of catalyst system confirmed the formation of the corresponding disulfide of thiobenzanilide (Fig. 2). The disulfide formed relative low intensity [M + H]+ at m/z 425 under positive ion electrospray ionization (ESI) conditions. The most abundant ion in its ESI-MS is observed at m/z 180 as iminium fragment.
Reduction of Cu2+ to Cu+ by thiobenzanilide is also consistent with the result obtained by 1H NMR analysis of copper(I)–thioamide catalytic system in DMSO-d6 (Fig. 3). NMR spectrum of complex bearing Cu2+ due to paramagnetism properties could not be obtained. The 1H NMR appearance of copper–thioamide catalyst revealed that a redox reaction take place in the combination of CuCl2 with thiobenzanilide in ethanol. The univalence of the copper ions in catalytic system was also confirmed by the measured diamagnetism. It can be considered that probably the generated disulfide from thiobenzanilide acts as a ligand. Therefore the disulfide was synthesized through oxidation of thiobenzanilide by using DMSO–HCl system according to Scheme 4.33 The synthesized disulfide reacted with CuCl2 and CuCl to give the corresponding complexes. The latter complex gave 3a in moderate yield (76%), while the former afforded 3a in very low yield.
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Fig. 3 1H NMR spectra of copper(I)–thioamide catalyst (top) and the corresponding disulfide of thiobenzanilide (bottom). |
Comparison the 1H NMR spectrum of copper–thioamide catalyst with 1H NMR spectrum of the disulfide (Fig. 3) shows that the thioamide acts as ligand not disulfide. The 1H NMR spectrum of copper(I)–thioamide catalyst consisted of a broad line at δ = 11.82 ppm correlating with the NH and multiple lines for the aromatic protons at δ = 7.83–6.90 ppm.
Unfortunately, all attempts to get single crystals of copper(I)–thioamide catalytic system for X-ray crystallography were failed due to its high insolubility. Assignments of selected characteristic IR bands (4000–500 cm−1) for thiobenzanilide and copper(I)–thioamide catalyst are given in ESI (Fig. 1S and 2S†). The positions of bands provide significant hints regarding the bonding sites of the thiobenzanilide when complexed with copper(I). Thiobenzanilide can show thione–thiol tautomerism. The ν(S–H) band at 2550 cm−1 is absent in IR spectrum of thiobenzanilide but the ν(N–H) band is observed at 3418 cm−1, indicating that thiobenzanilide exists in the thione rather than the thiol form in the solid state.34 It shows that a adsorption band of the CS bond is a region 1570–1395 cm−1 (1526 cm−1 for thiobenzanilide),35 which is shifted to 1516 cm−1 after being reacted with copper(II), indicating that the sulfur of the C
S participates as a coordinating site. This coordination is confirmed by the absence of the strong band at 1361 cm−1 in IR spectrum of copper(I)–thioamide catalyst.36
Energy-dispersive X-ray spectroscopy (EDS) was used for the chemical characterization of copper(I)–thioamide catalyst. EDS analysis exhibited the existence of chlorine atoms in catalytic system (Fig. 4). CHN analysis exhibited 44.48% C, 3.05% H and 3.73% N. These results indicate that copper(I)–thioamide system has a polymeric or cluster structure which explain its stability and high insolubility.31 A possible structure of one unit in the polymeric complex of copper(I)–thioamide catalyst is shown in Fig. 5.
Next we turned our attention to apply copper(I)–thioamide catalyst for the reaction of phenylacetylene with a series of alkyl/aryl halide to obtain the corresponding 1,4-disubstituted-1,2,3-triazoles 3. All the substrates consistently furnished the desired triazoles in good to excellent yields (Table 2). Formation of azides proceeds via a SN2 mechanism (Scheme 5). It is worth noting that direct displacement reactions take place rapidly in benzylic systems. The π systems of the benzylic group provide extended conjugation, which stabilizes the TS in the SN2 mechanism,37 so benzyl halides afforded the corresponding triazoles in excellent yield, as shown in Table 2. Various alkyl halides were subjected to the same reaction conditions to obtain the corresponding 1,2,3-triazoles. The yields were good in general. The structure of the products was confirmed by 1H-NMR, 13C-NMR, GC-MS and comparison with authentic samples prepared by reported methods (see ESI†).20,38
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Scheme 5 Proposed mechanism for copper(I)–thioamide-catalyzed synthesis of 1,4-disubstituted 1,2,3-triazole derivatives 3. |
The reusability of the copper(I)–thioamide catalyst was also studied for the model reaction. The catalyst was recovered by simple filtration, washed with ethanol and reused with consistent activity even after eight catalytic cycles (Fig. 6).
A possible mechanism for this copper(I)–thioamide catalyst multicomponent reaction was proposed in Scheme 5. The reaction was initiated by the metalation of phenylacetylene in the presence of Cu+, resulting copper acetylide followed by coordination of alkyl/benzyl azides to the copper of the acetylide initiates an azide-alkyne 1,3-dipolar cycloaddition to form the desired products 3.
In summary, a very efficient protocol for the synthesis of 1,4-disubstituted 1,2,3-triazole derivatives was reported via a multicomponent reaction in the presence of a cheap and easily recyclable heterogeneous copper(I)–thioamide catalyst. The catalyst was easily prepared with the reaction of CuCl2 and thiobenzanilide. The catalyst was collected easily by filtration and the reusability of the catalyst was successfully tested for eight runs only a very slight loss of catalytic activity. Further studies of applicability of the heterogeneous copper(I)–thioamide catalyst for synthesis of useful organic compounds such as propargylamines are in progress.
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra16581d |
This journal is © The Royal Society of Chemistry 2015 |