An efficient CuI/DBU-catalyzed one-pot protocol for synthesis of 1,4-disubstituted 1,2,3-triazoles

Abstract

A convenient CuI/DBU catalyzed one-pot method has been developed for the synthesis of 1,4-disubstituted 1,2,3-triazoles through the coupling of aryl iodides with sodium azide, followed by the intermolecular cyclization between the generated aryl azides and phenylacetaldehyde derivatives or alkynes in DMSO. The established protocol was compatible with a wide scope of substrates in good to excellent yields.

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Introduction

1,4-Disubstituted 1,2,3-triazoles, as an important class of organic compounds, display a vast spectrum of properties.¹ The classical copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction has been generally considered as the most striking method for regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles, which was independently discovered by the groups of Sharpless² and Meldal.³ An alternative method based upon enolate-mediated organocatalytic azide–aldehyde [3 + 2] cycloaddition reaction has been developed for the high-yielding and regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles.⁴

It is well-known that aryl azides are the indispensable intermediates for both the CuAAC reaction and the organocatalytic azide–aldehyde [3 + 2] cycloaddition. The preferred preparation method for aryl azides is the coupling of sodium azide with aryl halides, although the replacement of diazonium salts or some activated aryl halides with sodium azide usually works well.⁵ In 2004, D. W. Ma and coworkers reported that the coupling reaction of aryl halides with sodium azide catalyzed by CuI/L-proline underwent well at a relatively low temperature to provide aryl azides in good to excellent yields in DMSO or EtOH/H₂O.⁶ After that, cuprous catalyst systems together with the ligands or bases, such as CuI/diamine,⁷ CuBr/N,N′-dimethylethylenediamine,⁸ Cu₂O/tetraethylammonium prolinate⁹ and CuFeO₂/L-proline¹⁰ were reported. Except cuprous catalyst systems, heterogeneous metallic Cu(0) or cupric salts were also used as catalysts. In 2014, D. M. Cui and co-workers reported the synthesis of aryl azides via a coupling reaction of aryl iodides with sodium azide catalyzed by heterogeneous Cu(0) under mild conditions in the presence of L-proline and diisopropylamine.¹¹ At the same year, B. M. Bhanage and co-workers firstly reported a protocol for the coupling of aryl iodides with sodium azide to aryl azides using Cu(TMHD)₂ as the catalyst in DMF at 100 °C.¹² However, most of the methods mentioned above have the drawbacks such as high reaction temperature and long reaction time, which lead to the decomposition of the generated aryl azides.

Considering the dangerous properties of organic azides, one-pot methods for synthesis of 1,4-disubstituted 1,2,3-triazoles avoiding separating the generated organic azides from the reaction mixtures have gained great attentions in recent years. The developed protocols were suitable for the reaction among alkyl¹³ or aryl¹⁴ halides, sodium azide and alkynes. To the best of our knowledge, there is no report on the one-pot reaction among aryl halides, sodium azide and phenylacetaldehyde derivatives to give 1,4-disubstituted 1,2,3-triazoles. In continuous with our previous work on the one-pot reaction for synthesis of 1,4-disubstitued 1,2,3-triazoles,¹⁵ the main aim of this paper is to establish a one-pot reaction among aryl halides, sodium azide and phenylacetaldehyde derivatives. The two-step one-pot reactions among aryl iodides, sodium azide and phenylacetaldehyde derivatives (or alkynes) catalyzed by CuI/DBU in DMSO could provide 1,4-disubstitued 1,2,3-triazoles in good to excellent yields.

Results and discussion

The reaction among aryl iodides, sodium azide and phenylacetaldehyde derivatives proceeded by a two-step process for synthesis of 1,4-disubstituted 1,2,3-triazoles. The first process is to form aryl azide from aryl iodide and sodium azide, which is a key step and usually carried out at a relatively high reaction temperature in DMSO. The subsequent process is the reaction of phenylacetaldehyde derivatives with the formed aryl azide, which could be smoothly carried out in DMSO catalyzed by DBU at room temperature.⁴ For optimizing the conditions for synthesis of aryl azides, the reaction between iodobenzene and sodium azide was selected as the model reaction (Scheme 1).

Scheme 1 Model reaction for optimizing the reaction conditions.

The reaction between iodobenzene (1.0 mmol) and sodium azide (1.2 mmol) was carried out at 95 °C in DMSO (3.0 mL) at different amounts of CuI and DBU for 7 hours and monitored by HPLC per 30 minutes. Firstly, the amount of CuI used was fixed at 10 mol%. As shown in Fig. 1, it was found that the reaction obtained the best conversion (83%) in 3.5 hours in the presence of 15 mol% DBU among the tested amounts of DBU (10 mol%, 15 mol%, 20 mol%, 30 mol%). When increasing the loading of CuI to 20 mol% and keeping the ratio of CuI to DBU at 1.0 : 1.5, the conversion reached 97% in 2.5 hours, which was much higher than that obtained in the presence of 10 mol% CuI and 30 mol% DBU. While elevating the loading of CuI to 40 mol% in the presence of 30 mol% DBU, the conversion began to decrease after 2.0 hours, which indicated that a great amount of CuI might lead to the decomposition of the generated aryl azides. In addition, when the reaction was carried out catalyzed only by 20 mol% CuI in the absence of DBU, trace product was obtained, which indicated that the presence of DBU was crucial for the reaction. Finally, the 20 mol% CuI and 30 mol% DBU were selected for further investigation.

Fig. 1 The effects of the amount of CuI/DBU on the conversion of the model reaction.

Reaction temperature is an important factor for synthesis of aryl azides from aryl halides and sodium azide. To investigate the suitable reaction temperature, the reaction was carried out at different temperatures (105 °C, 95 °C, 80 °C, 60 °C and room temperature) catalyzed by 20 mol% CuI and 30 mol% DBU in DMSO for 2.5 hours. The results were summarized in Table 1. When the reaction was carried out at 95 °C, the highest isolated yield (95%) was obtained (Table 1, entry 2). When elevating the reaction temperature to 105 °C, 88% isolated yield was obtained (Table 1, entry 1). The slight decrease of the yield at 105 °C might be ascribed to the decomposition of phenyl azide at high reaction temperature.¹⁶ When the reactions were performed at 80 °C and 60 °C, the obtained yields were only 50% and 10% respectively (Table 1, entry 3 and 5). Prolonging the reaction time to 13.0 hours at 80 °C, the final yield was 80% (Table 1, entry 4). When the reaction was carried out at room temperature, no product was obtained (Table 1, entry 6). The results mentioned above indicated that a relatively high reaction temperature could facilitate the reaction. Therefore, 95 °C was selected as the optimized temperature for the reaction.

Table 1 The model reaction for synthesis of phenyl azide^a

Entry	Base (mol%)	CuI (mol%)	Temp. (°C)	Time (h)	Yield^b (%)
a The reactions were performed with iodobenzene (1.0 mmol), sodium azide (1.2 mmol), DBU (30 mol%) and CuI (20 mol%) in DMSO (3 mL) for 2.5–13.0 h.b Isolated yield.
1	DBU (30)	20	105	2.5	88
2	DBU (30)	20	95	2.5	95
3	DBU (30)	20	80	2.5	50
4	DBU (30)	20	80	13	80
5	DBU (30)	20	60	2.5	10
6	DBU (30)	20	r.t.	2.5	0

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Having established conditions for the coupling of iodobenzene with sodium azide, we next focused our attention to one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from iodobenzene, sodium azide and phenylacetaldehyde. Firstly, the one-pot reaction was carried out by adding all the reactants (iodobenzene, sodium azide and phenylacetaldehyde) in DMSO at 95 °C in the presence of 20 mol% CuI and 30 mol% DBU. Unfortunately, poor isolated products were obtained. Then, a two-step one-pot procedure was investigated. Initially, the reaction between the corresponding aryl iodides and sodium azide was carried out in DMSO at 95 °C in the presence of 20 mol% CuI and 30 mol% DBU. After the reaction was completed, the reaction mixture was cooled to room temperature and phenylacetaldehyde derivatives were added to react with the formed aryl azides, which were not separated from the reaction mixture. As shown in Table 2, various aryl iodides were then examined, and the corresponding 1,4-disubstituted 1,2,3-triazoles were obtained in good to excellent yields (Table 2, entries 1–12). The aryl iodides bearing the functional group such as Br or Cl were not been affected. Furthermore, the established one-pot protocol was also used for the reaction among aryl iodides, sodium azide and terminal alkynes, which have been reported previously.^13,14 Similarly, it was carried out firstly by adding all the reactants (aryl iodides, sodium azide and alkynes) in DMSO at 95 °C in the presence of 20 mol% CuI and 30 mol% DBU. It was very interesting that only homocoupling products 1,3-diynes were obtained instead of 1,4-disubstitued 1,2,3-triazoles. Even at room temperature, 1,3-diynes were the only products in 20 minutes. It indicated that the conditions were very suitable for the homocoupling reaction between alkynes.¹⁷ Therefore, the one-pot reaction among aryl iodides, sodium azide and alkynes was carried out according to the same procedure as that established for the reaction among aryl iodides, sodium azide and phenylacetaldehyde derivatives. As shown in Table 3, the established two-step one-pot reaction protocol was also suitable for the reaction among aryl iodides, sodium azide and alkynes, and the 1,4-disubstitued 1,2,3-triazoles could be obtained in good to excellent yields.

Table 2 Synthesis of 1,4-disubstituted 1,2,3-triazoles from aryl iodides, sodium azide and phenylacetaldehyde derivatives^a

Entry	Aryl iodide	Aldehyde	Temp. (°C)	Time (h)	Product	Yield^b (%)
a The reactions were performed with aryl iodides (1.0 mmol), sodium azide (1.2 mmol), DBU (30 mol%) and CuI (20 mol%) in DMSO (5 mL) for 0.5–5.0 h at 95 °C; and the subsequent reaction of the mixture was added aldehydes (1.0 mmol) and then was stirred for 0.5–2.0 h at room temperature.b Isolated yield.
1			95/r.t.	2.5/0.5		92
2			95/r.t.	2.5/1.0		91
3			95/r.t.	1.0/1.0		87
4			95/r.t.	1.0/0.5		82
5			95/r.t.	1.0/1.5		83
6			95/r.t.	5.0/1.0		80
7			95/r.t.	1.0/0.5		88
8			95/r.t.	5.0/1.5		85
9			95/r.t.	0.5/1.0		94
10			95/r.t.	1.5/2.0		82
11			95/r.t.	2.0/1.5		70
12			95/r.t.	3.5/2.0		75
13			95/r.t.	2.0/0.5		87
14			95/r.t.	2.0/1.0		80
15			95/r.t.	2.0/1.0		78

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Table 3 Synthesis of 1,4-disubstituted 1,2,3-triazoles from aryl iodides, sodium azide and alkynes^a

Entry	Aryl iodide	Alkyne	Temp. (°C)	Time (h)	Product	Yield^b (%)
a The reactions were performed with aryl iodides (1.0 mmol), sodium azide (1.2 mmol), DBU (30 mol%) and CuI (20 mol%) in DMSO (5 mL) for 0.5–5.0 h at 95 °C; and the subsequent reaction of the mixture was added alkynes (1.0 mmol) and then was stirred for 0.5–2.0 h at room temperature.b Isolated yield.
1			95/r.t.	2.5/0.5		93
2			95/r.t.	2.5/0.5		92
3			95/r.t.	1.0/1.0		90
4			95/r.t.	1.0/0.5		82
5			95/r.t.	1.0/1.0		80
6			95/r.t.	5.0/1.0		83
7			95/r.t.	1.0/0.5		80
8			95/r.t.	5.0/1.5		84
9			95/r.t.	0.5/1.0		94
10			95/r.t.	1.5/2.0		85
11			95/r.t.	2.0/1.5		82
12			95/r.t.	3.5/2.0		88
13			95/r.t.	2.0/0.5		90
14			95/r.t.	2.0/1.0		84
15			95/r.t.	2.0/1.0		80
16			95/r.t.	2.0/1.0		85
17			95/r.t.	2.0/0.5		92
18			95/r.t.	5.0/1.0		80
19			95/r.t.	1.0/1.0		89
20			95/r.t.	5.0/1.5		82

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Conclusions

In summary, we developed an efficient and simple two-step one-pot protocol for synthesis of 1,4-disubstituted 1,2,3-triazoles from aryl iodides, sodium azide and phenylacetaldehyde derivatives or from aryl iodides, sodium azide and alkynes in DMSO using CuI/DBU as the catalyst system. The established protocol has the advantages of short reaction time and high yields.

Acknowledgements

This work was supported financially by the Key Scientific and Technological Project of Henan province (no. 152102210285 and 152102310312), Innovative Talents Program of Henan Province (no. 164100510015 and 174100510025), Production-Learning-Research Cooperation Project of Henan province (no. 122107000014, 142107000081 and 122107000014), Foundation of Henan Educational Committee (14A350005 and 16A350015), Scientific Research Foundation for Doctors (no. 01036500508), Youth Foundation (no. 2012QK11) of Henan Normal University.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra23789d

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