DOI:
10.1039/C5RA15919A
(Paper)
RSC Adv., 2015,
5, 78422-78426
Mild Cu(OAc)2·H2O-catalyzed synthesis of multi-substituted 1,2,4-triazoles from amidines with nitriles via a N–N/C–N coupling†
Received
8th August 2015
, Accepted 3rd September 2015
First published on 3rd September 2015
Abstract
A simple and efficient Cu(OAc)2·H2O-catalyzed aerobic oxidation of amidines with nitriles for the synthesis of multi-substituted 1,2,4-triazoles has been achieved. The procedure constructs multi-substituted 1,2,4-triazoles and has the advantages of operational simplicity, broad substrate scope, and no need for prefunctionalized reagents. A possible mechanism has been proposed via the cascade N–H functionalization and N–N/C–N bond formation.
Introduction
1,2,4-Triazoles are predominant structural motifs in numerous functional molecules, natural products, agrochemicals and pharmaceutical compounds with potential therapeutic properties such as antibacterial, antifungal and anticancer activities (Fig. 1).1 Therefore, a lot of effort has been focused on the synthesis of 1,2,4-triazoles.2–4 Among them, the most common method involves the intramolecular and intermolecular condensation reactions of nitrogen-containing compounds.5 For example, the microwave-assisted N-acylation of amide derivatives with hydrazine hydrochlorides6 and a multi-step reaction starting from aldehyde and hydrazine.7 In addition, a lot of attention has also been paid to develop the metal-catalyzed methods8 such as the palladium-catalyzed chemoselective monoarylation of hydrazides.9
![image file: c5ra15919a-f1.tif](/image/article/2015/RA/c5ra15919a/c5ra15919a-f1.gif) |
| Fig. 1 Several 1,2,4-triazole derivatives, which show biological activities and medicinal value. | |
Recently, copper-catalyzed C–N bond formations have evolved as major methods for the synthesis of novel heterocyclic compounds with obvious advantages of low cost and environmental friendliness.10,11 For example, Punniyamurthy reported a copper(II)-catalyzed aerobic oxidative synthesis of 1,3,5-triaryl-1,2,4-triazoles from bisarylhydrazones.12
![image file: c5ra15919a-s1.tif](/image/article/2015/RA/c5ra15919a/c5ra15919a-s1.gif) |
| Scheme 1 | |
Nagasawa and Ueda reported a copper-catalyzed tandem addition/oxidative cyclization reaction of aryl nitriles with benzamidine hydrochlorides or 2-aminopyridines to obtain 3,5-disubstituted-1,2,4-triazoles and 1,2,4-triazolopyridine.13 However, these established methods suffer from some limitations, including operation difficulties, expensive reagents, formation of undesirable products, restricted substrate scope and need for additive or strong base in the transformation.14 Therefore, developing a green method to synthesize multi-substituted 1,2,4-triazoles under mild conditions without the need of a strong base and additives is still meaningful. Inspired by our previous results on the copper-catalyzed formation of C–N, C–C and C–S bonds,15 especially the highly efficient synthesis of quinazolines from N-aryl amidines and alcohols,15e herein, we disclose a new copper-catalyzed synthesis of multi-substituted 1,2,4-triazoles from amidines and nitriles through a N–H functionalization/N–N bond-forming process that uses air as the oxidant in the absence of additives and a strong base (Scheme 1). From a conceptual standpoint, it should be one of the most straightforward and greener approaches towards the preparation of multi-substituted 1,2,4-triazoles.
Results and discussion
It has been reported that the versatility of the reaction depends greatly on the catalyst, ligand, base and solvent used. To optimize the reaction conditions, N-phenylbenzimidamide (1a) and benzonitrile (2a) were initially chosen as the model substrates in the reaction (Table 1). In the pursuit of our program directed towards the best catalyst, a series of copper sources were screened. The results showed that the yield of 1,3,5-triphenyl-1,2,4-triazole (3aa) was considerably higher when using Cu(OAc)2·H2O (10 mol%) as the catalyst as compared to other copper sources such as Cu(acac)2, Cu(OTf)2, CuO, CuCl2 and CuI (Table 1, entries 1–5). No desired product was observed in the absence of a copper salt (entry 6). It was observed that the yield decreased to 45% in the presence of 5 mol% of the catalyst, whereas no significant increase was observed using 20 mol% of the catalyst (entries 7 and 8). The experimental results for entries 9–11 in Table 1 also showed that DMF, DMSO, and xylene were not as effective as toluene in the reaction (Table 1, entries 9–11). Further investigation revealed that the ligand played an important role and phen (1,10-phenanthroline) proved to be the best ligand (entries 12 and 13). Decreasing the amount of ligand also resulted in a considerably lower yield (entry 14). The nature of the base had an important effect on the reaction and sodium carbonate was found to be the most effective base in the reaction (entries 15–19). It was also observed that a considerably lower yield was obtained if the reaction temperature was decreased (Table 1, entry 20). As a conclusion for the experiments, the optimum results were obtained when amidines (1.0 equivalent) and nitriles (1.2–2 equivalent) were allowed to react with Cu(OAc)2·H2O (10 mol%), phen (0.1 equivalent), and Na2CO3 (2.0 equivalent) in toluene at 110 °C for 24 h.
Table 1 Optimization of reaction conditionsa
![image file: c5ra15919a-u1.tif](/image/article/2015/RA/c5ra15919a/c5ra15919a-u1.gif)
|
Entry |
Catalyst |
Ligand |
Solvent |
Base |
Yieldb (%) |
Reaction conditions: N-phenylbenzimidamide (0.5 mmol), benzonitrile (1 mmol), catalyst (0.1 mmol), ligand (0.1 mmol), base (2 mmol), solvent (2 mL) under reflux in air for 24 h. Isolated yield. Cu(OAc)2·H2O (5 mol%). Cu(OAc)2·H2O (20 mol%). N,N,N′,N′-Tetramethylethylenediamine. 1,10-Phenanthroline (5 mol%). 90 °C. |
1 |
CuO |
Phen |
Toluene |
Na2CO3 |
53 |
2 |
CuCl2 |
Phen |
Toluene |
Na2CO3 |
65 |
3 |
Cu(OTf)2 |
Phen |
Toluene |
Na2CO3 |
70 |
4 |
Cu(acac)2 |
Phen |
Toluene |
Na2CO3 |
73 |
5 |
CuI |
Phen |
Toluene |
Na2CO3 |
Trace |
6 |
— |
Phen |
Toluene |
Na2CO3 |
— |
7 |
Cu(OAc)2·H2O |
Phen |
Toluene |
Na2CO3 |
45c |
8 |
Cu(OAc)2·H2O |
Phen |
Toluene |
Na2CO3 |
75(76d) |
9 |
Cu(OAc)2·H2O |
Phen |
DMSO |
Na2CO3 |
22 |
10 |
Cu(OAc)2·H2O |
Phen |
DMF |
Na2CO3 |
37 |
11 |
Cu(OAc)2·H2O |
Phen |
Xylene |
Na2CO3 |
72 |
12 |
Cu(OAc)2·H2O |
Ph3P |
Toluene |
Na2CO3 |
55 |
13 |
Cu(OAc)2·H2O |
TMEDAe |
Toluene |
Na2CO3 |
Trace |
14 |
Cu(OAc)2·H2O |
Phen |
Toluene |
Na2CO3 |
51f |
15 |
Cu(OAc)2·H2O |
Phen |
Toluene |
NaOH |
60 |
16 |
Cu(OAc)2·H2O |
Phen |
Toluene |
K2CO3 |
36 |
17 |
Cu(OAc)2·H2O |
Phen |
Toluene |
t-BuOk |
21 |
18 |
Cu(OAc)2·H2O |
Phen |
Toluene |
Et3N |
45 |
19 |
Cu(OAc)2·H2O |
Phen |
Toluene |
— |
20 |
20 |
Cu(OAc)2·H2O |
Phen |
Toluene |
Na2CO3 |
42g |
With the optimized reaction conditions in hand, we examined the scope of this process and obtained more information to explore the mechanism of the reaction. Therefore, N-arylamidines with different substituents 1a–1d and various nitriles 2a–2h were employed as substrates and the results are presented in Scheme 2. In general, the presence of an electron-donating or -withdrawing group at the para-position of N-arylamidine was tolerated and a good yield was obtained. However, nitriles bearing electron-withdrawing groups (4-CF3 or 4-Cl) gave the desired products in higher yields than those with electron-donating groups (4-OMe) on the phenyl ring (Scheme 2, 3aa–3ad). It was worth mentioning that the influence of steric hindrance was observed in the reaction. For example, nitriles bearing a p-methyl or p-chloro group on the phenyl ring gave the corresponding products in higher yields than those of nitriles bearing an o-methyl or o-chloro group (Scheme 2, 3ab, 3ae, 3af, 3ag). Furthermore, the reaction using a heteroaromatic nitrile also provided triazoles 3ah in a considerable yield. Subsequently, the desired products, 3,5-disubstituted-1H-1,2,4-triazoles, could be obtained in good yields when benzamidine hydrochloride 4 was used in the reaction (Scheme 3). To the best of our knowledge, we found that even with the absence of ligand, excellent activity towards the desired product could be achieved with a concentration of Cu(OAc)2·H2O as low as 3 mol%, which made the process even more economically efficient. Similarly, no significant substituent effect was observed with excellent yields being obtained for benzamidine hydrochloride bearing both electron-donating and electron-withdrawing substituents, whereas nitriles with electron-withdrawing substituents gave higher yields than those with electron-donating substituents. Furthermore, aliphatic nitriles such as cyclohexyl nitrile were compatible with the cyclization conditions and produced 5ah in good yields. From the 1H NMR and 13C NMR spectra, we found that some of the products were mixtures when determined in DMSO-d6 (see ESI†); the results are in accordance with Xu's reports.16 It may be due to the NH-tautomerism. To the best of our knowledge, the Cu(OAc)2·H2O catalyzed tandem reaction can be applied to gram-scale synthesis and an 85% yield was obtained when 1.6 g (10 mmol) of benzamidine hydrochloride was used under the optimized conditions.
![image file: c5ra15919a-s2.tif](/image/article/2015/RA/c5ra15919a/c5ra15919a-s2.gif) |
| Scheme 2 Copper-catalyzed synthesis of 1,3,5-trisubstituted-1H-1,2,4-triazoles.a Reaction conditions: 1 (1 mmol), 2 (2 mmol), Cu(OAc)2·H2O (10 mol%), 1,10-phenanthroline (10 mol%), toluene (2 mL) 110 °C, 24 h, air. | |
![image file: c5ra15919a-s3.tif](/image/article/2015/RA/c5ra15919a/c5ra15919a-s3.gif) |
| Scheme 3 Copper-catalyzed synthesis of 3,5-disubstituted-1H-1,2,4-triazoles.a The reactions were carried out using 1 mmol of amidines 4, 1.2 mmol nitriles 2 and 3 mol% of Cu(OAc)2·H2O with 3 mmol Na2CO3 in toluene at 110 °C in air for 24 h. | |
Furthermore, some controlled experiments were carried out to gain insight into the reaction mechanism. First, the reaction conditions were applied for the dimerization of benzamidine hydrochloride and symmetrical 1,2,4-triazoles were obtained in a moderate yield.17 Then, a radical inhibitor 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) (2 equiv.) was added to the reaction, no significant decrease in the yield was observed, suggesting that the reaction does not involve radical steps. The yield was dramatically decreased when the reaction was conducted under an argon atmosphere, which indicates that oxygen is critical for the achievement of the catalytic cycle. Thus, the reaction mechanism of the intermolecular C–N/N–N bond formations of amidines and nitriles to obtain the 1,2,4-triazoles derivatives was proposed based on the aforementioned results and literature,18 as shown in Scheme 4. First, the reaction of amidine 1 with Cu(OAc)2 leads to the formation of the Cu–N adduct A in the presence of base. Then, the Cu(II) complex B was formed by nitrile 2 coordinating to copper. Next, intermediate C was formed by an intermolecular nucleophilic attack of amidine on the nitrile and copper(III) complex D was formed via a Cu(OAc)2-promoted oxidation of C. Subsequent reductive elimination produced the coupling product along with a copper species with a lower oxidation state, which was oxidized to obtain Cu(II) by oxygen in the air to complete the catalytic cycle.
![image file: c5ra15919a-s4.tif](/image/article/2015/RA/c5ra15919a/c5ra15919a-s4.gif) |
| Scheme 4 Possible mechanism. | |
Conclusions
In summary, we developed an efficient Cu(OAc)2-catalyzed aerobic oxidation of amidines with nitriles for the synthesis of multi-substituted 1,2,4-triazoles, involving cascade N–H functionalization/N–N/C–N bond formation steps. We believe that the present conditions provided an attractive alternative to access this important type of heterocycle. Efforts aimed at related copper-catalyzed coupling reactions are currently under investigation.
Experimental
General information
All reactions were carried out in flame-dried reaction vessels. Reaction temperatures are reported as the temperature of the bath surrounding the reaction vessel. Commercially available chemicals were used without further purification. N-Arylamidines used were synthesized according to a literature procedure.19 All new compounds were fully characterized. Melting points were determined on a melting point apparatus in open capillaries and are uncorrected. 1H and 13C NMR spectra were obtained on a 300 MHz or 500 MHz NMR spectrometer using CDCl3 or DMSO-d6 as the NMR solvent and TMS as an internal standard. High resolution mass spectra (HRMS) data were obtained with an ionization mode of ESI† or APCI on an Agilent 6200 LC/MS TOF.
General procedures for 1,3,5-trisubstituted-1H-1,2,4-triazoles
N-Arylamidines (1 mmol), nitrile (1.5–2 mmol), Cu(OAc)2·H2O (0.1 mmol), Na2CO3 (2 mmol) and 1,10-phenanthroline (0.1 mmol) were stirred in toluene (2 mL) under reflux in air for 24 h in a pre-heated oil bath. After cooling to room temperature, the reaction was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (300–400 mesh) using petroleum ether/ethyl acetate as the eluent to obtain 3aa–3da.
General procedures for 3,5-disubstituted-1H-1,2,4-triazoles
Benzamidine hydrochloride (1 mmol), nitrile (1.5 mmol), Cu(OAc)2·H2O (0.03 mmol), Na2CO3 (3 mmol) were stirred in toluene (2 mL) under reflux in air for 24 h in a pre-heated oil bath. After cooling to room temperature, the reaction was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtrated, concentrated and purified by column chromatography on a silica gel (300–400 mesh) using petroleum ether/ethyl acetate as the eluent to obtain 5aa–5da.
Acknowledgements
We gratefully appreciate the National Natural Science Foundation of China (20972002 and 21272006) for financial support.
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Footnote |
† Electronic supplementary information (ESI) available: General experimental procedures, analytic data, images of 1H and 13C NMR of all products and other electronic format. See DOI: 10.1039/c5ra15919a |
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