A dicationic, podand-like, ionic liquid water system accelerated copper-catalyzed azide-alkyne click reaction
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.
Table 1
Table 1 Preparation of the ionic liquids a and b.
|
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.
Table 2
Table 2 Using of the prepared ionic liquids in a typical click reaction.
|
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.
Table 3
Table 3 The sequential one-pot preparation of azides from alcohols in overall 7 min.
|
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
Table 4 Determination of the best volume ratio of water and IL.
|
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.
Table 5
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.
|
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.
Acknowledgments
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.