Chinese Chemical Letters  2014, Vol.25 Issue (12):1643-1647   PDF    
A dicationic, podand-like, ionic liquid water system accelerated copper-catalyzed azide-alkyne click reaction
Mohammad Javaheriana , Foad Kazemib, Masoumeh Ghaemia    
aDepartment of Chemistry, College of Science, Shahid Chamran University, Ahvaz, Iran;
bDepartment of Chemistry, University for Advanced Studies in Basic Sciences, Iran
Abstract: In this work, an effective, task specific, dicationic, podand-like ionic liquid was synthesized and applied to improve the capability features of click reaction. Moreover, to broaden the scope and decreasing the serious limitations of preparation methods of organic azides, a simple green procedure for the preparation of alkyl azides, the fundamental starting materials in click reactions, from alcohols under solvent-free conditions and microwave irradiation has been reported, for the first time.
Key words: Dicationic ionic liquid     Click chemistry     1,2,3-Triazoles     Alkyl azides     Alkynes     Microwave irradiation    
1. Introduction

The 1,3-dipolar cycloaddition of azides with alkynes (CuAAC) was first reported more than 100 years ago and investigated in detail by Huisgen [1]. In 2001,Sharpless and co-workers discovered that copper(I) catalysts in solution can improve the rate and regioselectivity of the cycloaddition reaction [2, 3, 4]. Frequently,1,2,3-triazoles are potential targets due to numerous applications in biology,agrochemicals,drug discovery and also as dyes [5, 6]. The use of benign solvents,such as water and ionic liquids,is significant in the practice of green chemistry. While water is a preferable solvent because of its abundance,safety,nontoxicity,cheapness and environmentally-friendly aspects in click reaction,and furthermore,the limited solubility of the less polar reactants can cause difficulties in a reaction step. The possibility of using a variety of solvents is one of the remarkable features of CuAAC reactions,which often are mixture of water and watermiscible organic solvents,such as DMSO,THF,t-BuOH or even biphasic media,which have been traditionally used as solvent system [7]. The use of ionic liquids is an acceptable way to meet the principles of green chemistry [8]. Ionic liquids have received great attention in various fields of science due to their unique properties, such as extremely low vapour pressure,non-flammability, tunability,high thermal stability and also solubility of many substances [9, 10]. Moreover,it has been shown that ionic liquids, especially imidazolium based ones,have substantial effects on chemical reactions as catalysts or alternative to conventional solvents [9, 10, 11]. It has been noticed that multifunctional,cationic, ionic liquids may be more effective than conventional monocationic analogs [12]. 2. Experimental

The alkyl tosylates were synthesized according to the method in reference [13]. Melting points were recorded on Buchi Melting point apparatus D-545; IR Spectra (KBr disks) were recorded on Stjean Baptist Ave Bomem 450 instrument. NMR Spectra were recorded on Bruker Avance DPX (400 MHz) in DMSO and D2O with TMS as internal standard for protons and solvent signals as internal standard for carbon spectra. Chemical shift values are reported ind (ppm) and coupling constants are given in Hz. MW irradiation was done by Micro SYNTH Labstation med CHEM Kit P/N 70140. The progress of all reactions was monitored by TLC on 2 cm×5 cm precoated silica gel-60 F-254 plates of thickness of 0.25 mm (Merck).

The chromatograms were visualized under UV 254-336 nm and iodine tank. 2.1. The synthesis of ionic liquid b

An agate mortar was charged with dry K2CO3 (5 g),tetraethylene glycol (10 mmol,1.72 mL),TsCl (24 mmol,4.57 g) and grinded for 5 min. Upon reaction completion,monitored by TLC (CCl4/EtOAc,4:1,v/v),the excess of TsCl was removed by wetting the reaction mixture with drops of t-BuOH and irradiating in a domestic microwave oven for 2 min. The prepared tetraethylene glycol ditosylate,was isolated by extraction with ether (3×10 mL). Then,1-methylimidazole (25 mmol,2 mL) was added to the tetraethylene glycol ditosylate (10 mmol,4.74 g) and allowed to stir at r.t. for 30 min. The work-up was performed by washing the synthesized ionic liquid with ether (3×50 mL). 2.2. General procedure for the synthesis of triazoles

A mixture of an alkyl azide (1 mmol),phenylacetylene (1 mmol,0.109 mL),CuSO4·5H2O (0.1 mmol,0.02 g),sodium ascorbate (0.1 mmol,0.01 g),was dissolved in 5 mL of ionic liquid/H2O (1:1) and stirred vigorously at room temperature. After the completion of the reaction,monitored by TLC,the product was isolated by extraction with ether (3×10 mL) and the solvent was removed by a rotary evaporator. The prepared 1,2,3-triazole was purified by recrystalization technique in water and ethanol.

3-Ethyl-1-methylimidazolium tosylate: IR (neat,cm-1 ):y819, 1011,1456,1189,1570,1655,2924,2974,3152; 1H NMR (400 MHz,D2O):d1.28 (t,3H.J= 7.36 Hz),2.13 (s,3H),3.66 (s, 3H),3.93-3.98 (q,2H,J= 7.34 Hz),7.05-7.07 (d,2H,J= 8 Hz),7.17- 7.23 (d,2H),7.54-7.55 (d,2H,J= 4.1 Hz),8.43 (s,1H); 13C NMR (100 MHz,D2O):d 14.55,20.61,35.66,44.70,121.78,123.41, 123.45,125.41,129.22,135.18,140.96,141.45.

Tetraethylene glycol bis(1-methyl-3-imidazolium) ditosylate: IR (neat,cm-1 ):ε 819,1011,1217,1454,1575,1647,2873,2961, 3112; 1H NMR (400 MHz,D2O): δ 2.11 (s,3H),3.41-3.46 (t,4H, J= 7.2 Hz),3.48-3.50 (t,2H,J= 7 Hz),3.55 (s,6H),3.56-3.66 (t,4H, J= 6.4 Hz),4.14 (s,2H),6.82-6.88 (d,4H,J= 8 Hz),7.04-7.06 (d,4H, J= 8 Hz),7.20-7.22 (d,2H,J= 8 Hz),7.51-7.53 (d,2H,J= 8 Hz),8.51 (s,2H); 13C NMR (100 MHz,D2O): δ 21.73,36,51.47,65.80,70.37, 71.50,123.69,124.06,125.38,128.98,138.16,142.26,144.53.

1-Octyl-4-phenyl-1H-1,2,3-triazole: mp: 100-102°C,IR (KBr, cm-1 ): υ 962,759,1078,1494,2848,2919,2954,3121; 1H NMR (400 MHz,DMSO-d6):d0.83 (t,3H,J= 7 Hz),1.24-1.28 (m,10H, J= 4 Hz),1.84 (q,2H,J= 7.12 Hz),4.38 (t,2H,J= 7.04 Hz),7.31-7.35 (m,1H,J= 5.01 Hz),7.44-7.46 (t,2H,J= 6.39 Hz),7.83-7.85 (2H,q, J= 5.12 Hz),8.58 (1H,s); 13C NMR (100 MHz,DMSO-d6): δ 14.40, 22.51,26.30,28.81,28.96,30.06,31.62,49.97,121.69,125.55, 128.23,129.35,131.35.

Diethyleneglycol bis-1H-1,2,3-triazole: mp: 155-157°C,IR (KBr,cm-1 ): υ 759,805,916,1113,1464,2866,2886,3135; 1H NMR (400 MHz,DMSO-d6): δ 3.94 (t,2H,J= 5.10 Hz),4.59 (t,2H, J= 5.08 Hz),7.28 (m,3H,J= 5.26 Hz),7.74 (d,2H,J= 7.66 Hz),7.79 (s,1H); 13C NMR (100 MHz,DMSO-d6): δ 50.40,69.30,120.76, 25.80,128.32,128.88,147.71. Triethylene glycol bis-1H-1,2,3-triazole: mp: 159-161°C,IR (KBr,cm-1 ): υ 757,805,916,1115,1462,2868,2891,3130; 1H NMR (400 MHz,DMSO-d6): δ 3.58 (s,4H),3.86 (t,4H,J= 5.80 Hz), 4.52 (t,4H,J= 5.80 Hz),7.28-7.34 (m,3H,J= 9.14 Hz),7.44 (d,2H, J= 12.17 Hz),7.87 (s,1H); 13C NMR (100 MHz,DMSO-d6): δ 50.45, 69.46,70.47,125.61,128.19,128.91,130.68,146.60; Anal. Calcd. for C22H24N6O2.(H2O): C,62.58; H,6.15; N,19.89. Found: C,62.92; H,6.07; N,19.31.

1-(4-Chlorobenzyl)-4-phenyl-1H-1,2,3-triazole: mp: 165- 168°C,IR (KBr,cm-1 ): υ 63,1016,1221,1351,1411,1492, 2995,3113; 1H NMR (400 MHz,DMSO-d6): &fdelta; 5.66 (s,2H),7.33-7.47 (m,7H,J= 6.59 Hz),7.83 (d,2H,J= 7.44 Hz); 8.64 (s,1H); 13C NMR (100 MHz,DMSO-d6): δ 98.71,122.07,125.63,128.39,129.27, 129.36,130.33,130.56,135.45,147.16.

3-Phenyl-1-propyl-1H-1,2,3-triazole: IR (KBr,cm-1 ): υ 744, 1115,1370,1453,1495,1602,2857,2938,3026; 1H NMR (400 MHz,DMSO-d6): d 2.33 (q,2H,J= 7.20 Hz),2.72 (t,2H, J= 7.30 Hz),4.43 (t,2H,J= 7.08 Hz),7.21-7.33 (m,2H,J= 7.08 Hz), 7.34-7.37 (t,3H,J= 7.40 Hz),7.43-7.47 (t,2H,J= 7.28 Hz),7.84 (s, 1H),7.85 (d,2H,J= 7.90 Hz); 13C NMR (100 MHz,DMSO-d6): d 22.27,33.36,51.27,119.07,125.31,126.61,127.83,127.96,128, 130.27,142.16,142.72. 3. Results and discussion

Even though,many benign properties of ionic liquids make them attractive from a green chemistry standpoint,their preparation procedures continue to suffer from historical limitations,such as use of a large amount of toxic solvents,long reaction times,low yields. Herein,we report a facile synthesis of a podand task specific and water soluble imidazolium based ionic liquid; 3-alkyl-1-methylimidazolium tosylate under neat reaction condition and used for [3+2] cycloaddition of different organic azides with a terminal alkynei.e.,click reaction. In the presence of ionic liquids and water,the reactions of terminal alkyne with organic azides underwent easily to generate the corresponding regiospecific 1,4-disubstituted-1,2,3-triazoles in excellent yields and short reaction times at r.t.,Scheme 1 and Table 1.

Scheme 1. Synthesis of ionic liquid.

Table 1
Preparation of the ionic liquids a and b.

As shown in Table 1,a green approach for the scalable preparation of alkyl tosylates under solvent free conditions has been applied from alcohols as available starting materials,instead of traditional use of a large amount of a toxic solvent like pyridine and laborious procedure. Ethanol and tetraethylene glycol were reacted with tosyl chloride in the presence of potassium carbonate as a cheap and weak basic solid support [13]. Then the prepared alkyl tosylates reacted with 1-methylimidazole to generate the corresponding ionic liquids a and b in short reaction times and high yields,under neat conditions without use of any toxic solvents, such as toluene,acetonitrile,etc.[9, 10, 14]. Additionally,recovery of these two task specific ionic liquids was quantitatively done from the reaction mixture by simple extracting and reused for several times in similar reactions. In direct alkylation reactions, care should be taken during addition of the alkylating agent. The addition should be slow and under an inert atmosphere to a cool controlled temperature solution. Therefore,a small excess of nucleophile is advised to avoid traces of the alkylating agent in the product. According to our literature survey,ionic liquids comprising tosylate as counter ion may be prepared from alcohols in the presence of pyridine as base,and toluene as solvent with 1-methylimidazole under nitrogen atmosphere and refluxing for hours [14]. But the current work has apparent superiority to other works; due to its simplicity,high rate and,more importantly, avoiding use of any solvent.

Click chemistry reactions are,by definition,highly exothermic. Therefore,presence of water in click reactions is beneficial,not just for reactivity reasons,but also because water is the best heat-sink for handling the enormous heat output when click reactions are performed on larger scales [15]. Therefore,a combination of water and ionic liquid medium was chosen to accelerate the reaction. Initially,we focused on the catalytic activity of ionic liquidsaand b. So,these two task specific ionic liquids were investigated for a typical [3+2] cycloaddition reaction of diethylene glycol diazide and phenyl acetylene in the presence of different Cu catalysts,at r.t. in water,that the ionic liquidband CuSO4/NaAsc as a more useful catalyst were selected,Scheme 2 and Table 2.

Scheme 2. Preparation of 1,2,3- triazole in the presence of ILs (a or b).

Table 2
Using of the prepared ionic liquids in a typical click reaction.

One restriction of the click-like reactions involving azides is the limitations of selecting commercially available alkyl azides. In CuAAC reactions,this problem can be decreased by developing one-pot procedures for preparing organic azides [16]. In our continuing efforts in developing simple and practical scalable procedures in organic transformations,we explored the possibility of developing one-pot procedure of preparing alky azides from alcohols by grinding and microwave irradiation,sequentially, Scheme 3 and Table 3.

Scheme 3. One-pot preparation of alkyl azides from alcohols.

Table 3
The sequential one-pot preparation of azides from alcohols in overall 7 min.

After preparing the alkyl azides,to determine the best volume ratio of solvents,different volume ratios of IL(b) and water were examined,Table 4.

Table 4
Determination of the best volume ratio of water and IL.

To improve the scope of our method,a serial reactions between azides and phenyacetylene in the presence of CuSO4/NaAsc as the best examined catalyst in a mixture of ionic liquid b and water with the ratio of 1:1 was carried out,Scheme 4 and Table 5.

Scheme 4. Preparation of 1,2,3-triazoles in the presence of IL(b).

Table 5
A [3+2] cycloaddition of the prepared alkyl azides with phenylacetylene in the presence of CuSO4/NaAsc in mixture of IL (b)/water.

As shown in Table 5,to explore the scope of this modification, different kinds of alkyl azides,i.e.,benzylic containing EDG s and EWGs,aliphatic 1° and 2° with short and long chains and,more importantly,the oligomers of ethylene glycol diazides were submitted to the click reaction; which all of them afforded the expected transformation and leading to their corresponding 1,4-disubstituted-1,2,3-triazoles in short reaction times and high yields,exclusively. Noticeably,the bis-triazole synthesized compounds (Table 5,entries 9-11) are valuable nitrogen-electron donors in coordination chemistry,such as transition metal catalyzed,cross-coupling reaction types reported by Suzuki [17], Stille [18],etc.Although,electronic effects are known to influence click reactions [19],but with benzylic azides (entries 4-8) not any significant differences between substituents were observed,even though the less yield of 2-chlorobenzyl azide (entry 7) may be attributed to steric hindrance. The oligomers of ethylene glycol diazides (entries 9-11) showed nearly similar results,but longer aliphatic chains and alicylic azizdes (entries 1-3) exhibit longer reaction times; probably due to steric considerations of their chains. 4. Conclusion

Most of the published click methods involving combined systems of water and an organic co-solvent,but most of them have used of toxic solvents,such as DMF,DMSO,CHCl3,CH3CN etc.or often entirely toxic organic solvents like PhCH3,benzene or have shown long reaction times or use of especial additives and high temperature [7, 20, 21, 22, 23, 24, 25, 26]. Apparently,in this work an interesting kind of podand IL was applied,not only as a safe modification,but also to enhance the catalytic features and improve the reaction rate and yield as a task specific IL or co-solvent. In conclusion,we have developed a versatile,highly efficient and environmentally friendly system for the Huisgen [3+2] cycloaddition of organic azides and terminal alkynes by using tetraethylene glycol bis-(1-methyl-3-imidazolium) ditosylate as a co-solvent,or task specific podand IL,at r.t. Thus,it can be claimed that,these results not only have broaden the scope of this so-called click reaction,but also,we have extended a simple,practical method,based on the green chemistry principles,to supply the required azides as starting material from alcohols without any laborious works. Moreover,it should be emphasized that all of the reaction steps from starting alcohols to triazoles includes only single products which were separated by simple experimental methods,such as filtration for triazoles and liquid-liquid extraction for alkyl azides without any work-up difficulties.


Authors thank the Shahid Chamran University of Ahvaz for its financial support (No. 2013). Thanks are also due to JundiShapur University of Medical Sciences for use of its microwave reactor.

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