A one-pot, copper-catalyzed azidation/click reaction of aryl and heteroaryl bromides in an environmentally friendly deep eutectic solvent

Article abstract of DOI:10.1016/j.tet.2017.10.050

In an effort to avoid the hazards of isolating and handling azides in click chemistry, many groups have turned to in situ generation of azides from halide precursors. This option is readily accomplished for alkyl azides, but is more challenging for aryl a

Full text of DOI:10.1016/j.tet.2017.10.050

Accepted Manuscript
A one-pot, copper-catalyzed azidation/click reaction of aryl and heteroaryl bromides in
an environmentally friendly deep eutectic solvent
Arjun Kafle, Scott T. Handy
PII:
S0040-4020(17)31087-6
10.1016/j.tet.2017.10.050
TET 29053
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 August 2017
Revised Date: 16 October 2017
Accepted Date: 17 October 2017
Please cite this article as: Kafle A, Handy ST, A one-pot, copper-catalyzed azidation/click reaction of aryl
and heteroaryl bromides in an environmentally friendly deep eutectic solvent, Tetrahedron (2017), doi:
10.1016/j.tet.2017.10.050.
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ACCEPTED MANUSCRIPT
A One-Pot, Copper-Catalyzed Azidation/Click Reaction of Aryl and
Heteroaryl Bromides in an Environmentally Friendly Deep Eutectic Solvent
Arjun Kaflea and Scott T. Handya,b
a Molecular Biosciences Program, Middle Tennessee State University, Murfreesboro, TN 37132
United States
bDepartment of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132
United States
Scott.Handy@mtsu.edu
R
N N
NaN3
N
Ar-Br
Ar
R
CuI, DMEDA
choline chloride/glycerol
65-80 oC, 5-12 h
ABSTRACT
In an effort to avoid the hazards of isolating and handling azides in click chemistry, many groups
have turned to in situ generation of azides from halide precursors. This option is readily
accomplished for alkyl azides, but is more challenging for aryl azides. In this paper, we discuss
our success in transforming aryl bromides into 1,4-disubstituted triazoles employing DMEDA as
a ligand with a copper catalyst in a deep eutectic solvent. Further, we are able to recycle the
solvent, catalyst, and ligand several times, thereby increasing the attractiveness of this method
.
1. Introduction
Corresponding author. Tel.: +615-904-8114; fax: +615-898-5182; e-mail: Scott.Handy@mtsu.edu
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The copper-catalyzed Huisgen reaction of an azide and an alkyne (CuAAC) has very rapidly
become one of the preeminent reactions in organic chemistry.1 It generally affords very good
yields of the triazole product as a single regioisomer and tolerates a wide range of functionality,
enabling its utilization in areas ranging from biological to materials research.2 As broad as this
application has been, the azide component remains a limitation. Organic azides are well known
to be unstable and explosive compounds and thus their isolation is not desirable, particularly on
larger scale.3 As a result, it is not surprising that many groups have explored ways to generate
azides in situ.
For alkyl azides, this is usually simple as the azide anion is a good nucleophile. Thus, the
combination of an alkyl halide with sodium azide in the presence of an alkyne and a copper
catalyst accomplishes both the synthesis of the azide and the click reaction in one pot.4 The first
reported example of this approach was in 2004 from the Fokin group.4c They reported a
microwave-assisted, three-component, one-pot procedure in which the Cu(I) catalyst was
prepared in situ by comproportionation of a Cu(0)/Cu(II) couple for the synthesis of 1,4-
disubstituted 1,2,3-triazoles with 100% regioselectivity at 125 °C. The reaction times were quite
short, and the products were easy to isolate in very high yield, although the reaction temperature
was relatively high.
For aryl azides, the problem is more difficult, as direct nucleophilic displacement is not
generally an option. In substrates which can undergo facile SNAr reactions, Ramana has reported
successful one-pot azidation/click tandems, but this scope is quite narrow.5 Substitution of other
types of leaving groups have been reported, including iodoniums6 and diazonium salts,7 but in all
of these cases hazardous reagents and/or poorly accessible starting materials still limit their
general application.
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The most ideal situation would be the direct conversion of an aryl halide to an aryl azide.
Using the more reactive aryl iodides, the Fokin group in 2004 demonstrated in situ generation of
aryl azides.8 Thus, treatment of an aryl iodide with sodium azide and a copper catalyst formed
from copper sulfate, sodium ascorbate, and L-proline with sodium carbonate in DMSO/water at
60 °C formed the azide, which then underwent a CuAAC reaction with an alkyne. Again, yields
were good, although reaction times were longer (overnight). Further, reaction was limited to aryl
iodides, with aryl bromides failing to afford any triazole product.
The following year, Liang and co-workers employed very similar reaction conditions which a
change in ligand from proline to trans-N,N'-dimethyl-1,2-diaminocyclohexane to overcome this
limitation and reported the first successful one-pot azidation/click reactions of aryl bromides.9
Since this report, these basic conditions (copper catalyst, ligand, and sodium ascorbate) have
been used by several groups with little modification to perform these reactions, most frequently
on simple benzenoid aromatics.10
With one recent exception, to the best of our knowledge, there has been no attempt to develop a
system in which the catalyst could be recycled or used at a lower loading than 10 mol% for the
one-pot conversion of aryl bromides to aryl triazoles and in this one case, only one example was
reported with an unusual alkyne, making its generality uncertain.11 With this in mind and our
ongoing interest in the combination of unusual solvents and catalyst recycling, we elected to
study the application of a recyclable deep eutectic solvent (DES) based upon choline chloride
and glycerol for the one-pot azidation/click reaction of aryl bromides.12
DES are a rapidly growing variation on the idea of ionic liquids.13 In general, they are
comprised of a mixture of two or more components that exhibit a very dramatic depression in
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melting point compared to the pure components in the mixture, most typically via a combination
of a salt with a hydrogen-bond donor or a salt with another metal salt capable of forming
complex anions. Although many such solvents have been reported, choline chloride (CC – 2-
hydroxyethyltrimethylammonium chloride) is the most widespread salt component as it is
inexpensive, biodegradable, and available on large scale due to its use as a dietary additive in
13f
animal feed.13c,
While the CC/urea combination is the most frequently used,14 the
combination with glycerol in a 1:2 molar ratio is another very easily formed DES and was the
focus of this work.15 It is worth noting that the CuAAC reaction has been reported before by
Ilgen and Koenig using an unusual DES comprised of a 7 : 2 : 1 mixture of D- sorbitol, urea and
NH4Cl respectively, as a solvent and 5 mol% CuI as a catalyst yielding 91% of 1,4-disubstituted
1,2,3-triazole in 5 hrs.16 This reaction gave a 55% yield under the similar conditions with another
deep eutectic solvent – L-carnitine/urea which was attributed to the higher reactivity of the melt.
(Scheme 5) In both cases, no attempt was made at catalyst and solvent recycling and the reaction
was only studied for alkyl azides.
2. Results and discussions
In light of Köenig’s success, we elected to pursue a one-pot azidation/click reaction in the easily
available, inexpensive, and non-toxic DES choline chloride/glycerol (CC/G). We hoped to
achieve conditions that would enable the conversion of aryl bromides to aryl azides and also be
able to recycle the solvent and catalyst.
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Table 1. Survey of Click Reactions Using Deep Eutectic Mixtures
CuI (10 mol%)
NaN3 (1.2 equiv)
N
N
N
+
Br
L3 (20 mol%)
CC/G (2 mL)
75 oC, 8 h
3
1
2
(1.0 mmol)
(1.0 mmol)
O
H
N
N
OH
NH
H
N
N
N,N’ - Dimethyl-
ethylenediamine (L3)
L- Proline
L1
1, 10- Phenanthroline
L2
yielda (%)
entry
modified conditions
ligand L1 instead of L3
ligand L2 instead of L3
standard conditions
without ligand
0
0
1
2
3
4
88
trace
60
0
5
6
7
5 mol% CuI
without CuI
CC/Urea instead of CC/Glycerol
11
a Isolated yields
Initial screening was done using bromobenzene as the aryl halide and phenyl acetylene as the
alkyne. Several different ligands commonly used in copper-catalyzed chemistry were explored,
including proline, N,N'-dimethylethylenediamine (DMEDA), and phenanthroline. Of these, only
DMEDA afforded the desired triazole product, fortunately in good yield (88%). (Table 1)
While proline is a very common ligand for copper catalyzed chemistry, it has not been reported
by any group to be effective for the one-pot azidation/click reaction of aryl bromides – only aryl
iodides. It seems likely that DMEDA, a stronger electronic rich sigma donor, is likely better able
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to both stabilize and activate the copper catalyst, compared to proline.17 As such, it is likely that
other 1,2- N,N'-dimethylamines would also work under the present conditions.
Not surprisingly, both ligand and copper were important for reaction, but the catalyst loading
could be lowered to 5 mol% with a modest decrease in yield, (Table 1, entry 5) indicating that
some further optimization of this parameter may be possible. It is also worth noting that use of
the more common choline chloride/urea DES afforded a very low yield (Table 1, entry 7) of the
triazole product, presumably due to the urea interfering in the catalytic cycle of the reaction.18
Armed with this success, a wider range of aryl bromide were explored including electron rich
and deficient, ortho-substituted, heteroaromatic, and even dibromo arenes. (Figure 1) Yields
ranged from excellent to modest. Not surprisingly, iodobenzene afforded a better yield when
compared to the less reactive bromide (Figure 1, compound 3). Interestingly, electron-deficient
aryl bromides did not afford better yields when compared to the reaction with electron-rich para-
bromoanisole (Figure 1, compound 5) and ortho substitution did not appear to affect the reaction
negatively based upon the examples studied. In the case of 3,6-dibromocarbazole, only a 40 %
yield of the monotriazole product (12), was observed, which can likely be attributed to its poor
solubility in the DES.
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Figure 1. Reactions with Phenylacetylene
CuI (10 mol%)
NaN3 (1.2 equiv)
L3 Ligand (20 mol%)
N
N
N
+
Ph
R Br
Ph
R
CC/G (2.0 mL)
75 oC, 5-12 h
R = aryl
heteroaryl
32-88%a
N
NO2
N
N
N
N
N
N
N
N
OMe
4, 53% (64%)c
3, 88% (96%)b
5, 51%
Me
O
N
N
N
N
N
NC
N
N
N
N
8, 56%
7, 56%
6, 34%
CN
S
N
N
N
N
N
N
N
N
N
S
N
Br
S
9, 57% (69%)c
11, 43% (52%)c
10, 46% (45%)
Br
N
a, b, c = Isolated yields
N
N
a. 0.50 or 1.0 mmol scale reaction
b. Using iodobenzene instead of
bromobenzene
N
H
c. 2.0 mmol scale reaction
12, 40% (46%)c
The reaction between phenylacetylene and 2,4-dibromothiazole resulted in 4-bromo-2-(4-phenyl-
1H-1,2,3-triazol-1-yl)thiazole (11) as a major product. For unequivocal determination of the
regioselectivity of this reaction, compound 11 (the only isomer formed) was crystallized from an
o
ether solution layered with pentane at 4 C and the resulting crystal subjected to x-ray
crystallography (Figure 2).
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Figure 2. X-ray Structure of Compound 11
To further probe the utility of these reaction conditions, the reaction of various alkynes with
different aryl bromides were performed. (Figure 3) Various functionalized alkynes afforded
reasonable yields of the anticipated triazoles. 1-Ethynylcyclohexene and 1-hexyne were found to
react successfully with heteroaryl 3-bromothiophene (17 and 24) resulting in yields of the
predicted products comparable to those observed with the generally more reactive
phenylacetylene, thus supporting the generality of these reaction conditions.
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Figure 3. Alkyne Studies
CuI (10 mol%)
NaN3 (1.2 equiv)
L3 Ligand (20 mol%)
N
N
N
R
R' Br
R
+
CC/G (2.0 mL)
R’
75 oC, 9-12 h
R' = aryl
48-76%a
hetero aryl
N
N
N
N
N
N
N
N
N
15, 53%
14, 50%
%
, 48
13
OMe
N
N
MeO
N
N
N
N
NO2
N
N
N
S
18, 56%
17, 62%
16, 53%
OH
HO
OH
N
N
N
N
N
NO2
N
N
N
N
19, 58%
20, 52%
N
N
O2N
N
N
N
N
HO
N
N
N
S
23, 65%
22, 76%
24, 59%
a = Isolated yield
Next, the scalability of the reaction protocol was evaluated by performing the gram-scale
synthesis of 1,4-diphenyl-1H-1,2,3-triazole (3) employing 10.0 mmol each of 1 and 2 in the
presence of DMEDA and CuI in a deep eutectic solvent. The desired product (3) was isolated in
89% yield (Scheme 1) demonstrating the utility of the protocol in large scale synthesis of 1,4-
disubstituted triazoles.
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CuI (10 mol%)
NaN3 (1.2 equiv)
N
N
N
+
Br
L3 (20 mol%)
CC/G (14 mL)
75 oC, 8 h
2
3
1
yield = 89 %
(10.0 mmol)
(10.0 mmol)
Scheme 1. Scale-up Experiment
More modest scale-up (2 mmol) was performed on four other combinations. (Figure 1)
Interestingly, an overall increase of 6-12% in yield was observed for these reactions, affording
improved yields of compounds 4, 9, 11, and 12 respectively. These observations strongly support
the scalability of this reaction protocol accompanied by a modest increase in the reaction yield in
comparison to small scale reactions.
One other key feature of the DES was also explored – its recyclability. This feature was
demonstrated using two reactions (Tables 2 and 3). All reactions were carried out using 1.0
mmol aryl halides, 1.0 mmol alkyne, 1.2 mmol sodium azide, 0.1 mmol CuI, 0.2 mmol DMEDA,
and 2 mL solvent kept in a reaction vessel and stirred at 75 °C for the specified time. Product
separation was accomplished by extraction with ethyl acetate. Each cycle represents a
subsequent use of the recycled reaction medium which includes catalyst and ligand
.
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Table 2. Recycling Study Using Bromobenzene
For Table 2, during the extraction process, the addition of ethyl acetate resulted in a
suspension which made layer separation more difficult and raised the possibility of catalyst
leaching. In the presence of copper catalyst, the addition of ligand gives a bluish green color to
the mixture. But, after the second cycle, the reaction mixture turned reddish. This may be
presumed to be the result of a significant decrease in the ligand concentration during the previous
extraction processes. In the fourth cycle, the addition of 0.2 mmol of DMEDA restored activity,
giving an 83% yield. This suggests that a small amount of catalyst is also sufficient to drive the
reaction if there is a certain minimum amount of ligand present in the reaction medium.
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Table 3. Recycling Study Using Iodobenzene and 1-Hexyne
In case of Table 3, a different reaction using iodobenzene was explored for recycling. Not
surprisingly, yields were good for the initial reaction and two subsequent recyclings, with less
reduction in yield than had been observed in the case of bromobenzene. While part of this
observation can be attributed to the higher reactivity of iodobenzene, it is also likely a feature of
the easy and complete extraction of the product because of its high solubility in EtOAc and the
fact that no suspension was formed. As a result, leaching of both the catalyst and ligand
presumably decreased allowing more efficient recycling of reaction medium and catalyst,
although the observed decrease in yield suggests some loss (most likely of ligand) even in this
case.
3. Conclusions
In conclusion, we have developed a convenient, versatile, and scalable one-pot method for the
synthesis of N-aryl 1,2,3-triazoles starting from aryl and heteroaryl bromides in which both the
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solvent (an environmentally friendly DES) and the catalyst are recyclable. Key features include
the use of simple and relatively inexpensive reaction conditions, the ability to use a wide range
of aryl and heteroaryl bromides as well as alkynes with moderate to good efficiency, and the
ability to recycle the catalyst and solvent (with ligand leaching being the current limiting
feature). This method serves to considerably expand the range of triazoles that are readily
available for further study and application.
4. Experimental section
General Information. All the reactions were done under an air atmosphere. 1H and 13C NMR of
all the compounds were recorded on JEOL AS (500 and 125 MHz, respectively) NMR
instrument and chemical shifts were recorded in ppm. All the chemical shifts were recorded
taking CDCl3 or DMSO as a standard reference.19 The following conventions are used for
multiplicities: s, singlet; d, doublet; t, triplet; m, multiplet; dd, doublet of doublet; tt, triplet of
triplet; dt, double of triplet; ddd, doublet of double doublet; br, broad. Varian 8000 FT-IR was
used to collect IR spectra. All the extracts were concentrated under reduced pressure using a
Buchi Rotary Evaporator. During purification and identification of compounds, Thin Layer
Chromatography (TLC) was performed on silica coated TLC plates and it was monitored by
short wavelength (254 nm) UV light. The product was purified by silica gel column
chromatography. ACS grade reagents were employed during the experiments.
4.1. General Procedure (1.0 mmol scale reaction)
To a reaction vessel (3-dram scintillation glass vial), terminal alkyne (1.0 mmol), aryl bromide
(1.0 mmol), 0.079 g (1.20 mmol) sodium azide, 0.019 g (0.10 mmol) CuI, 0.018 mg (0.2 mmol)
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ligand (N,N'-dimethylethylenediamine, L3), and 2.0 mL solvent (1:2 molar mixture of choline
chloride and glycerol) was added and placed in a sand bath heated at 75 °C (unless otherwise
specified) over a magnetic hot plate. The reaction mixture was stirred for the specified time (5-12
hr). The resulting mixture was extracted by EtOAc and concentrated in vacuo. The residue
obtained was purified by flash column chromatography.
4.2. General Procedure (0.5 mmol scale reaction)
To a reaction vessel (3-dram scintillation glass vial), terminal alkyne (0.50 mmol), aryl
bromide (0.50 mmol), 0.040 g (0.60 mmol) sodium azide, 9.5 mg (0.05 mmol) CuI, 8.8 mg
(0.10 mmol) ligand (N,N'-dimethylethylenediamine, L3), and 1.5 mL solvent (1:2 molar mixture
of choline chloride and glycerol) was added and placed in a sand bath heated at 75 °C (unless
otherwise specified) over a magnetic hot plate. The reaction mixture was stirred for the specified
time (5-12 hr). The resulting mixture was extracted by EtOAc and concentrated in vacuo. The
residue obtained was purified by flash column chromatography.
4.3. Characterization Data for Isolated Compounds
Characterization data for the compounds 3, 4, 5, 8, 9, 10, 13, 15, 18, 21, 22, and 25 can be found
in the supplementary information.
3-(4-phenyl-1H-1,2,3-triazol-1-yl)benzonitrile (6)
Reaction (0.5 mmol scale) was stirred for 12 hours under standard condition. Yield: 41%; white
o
solid, mp 208 C. 1H NMR (DMSO-d6, 500 MHz) δ = 9.42 (s, 1H), 8.48 (m, 1H), 8.34 (dd, J =
7.5, 2.5 Hz,1H), 8.0 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 6.0 Hz, 2H), 7.85 (t, J = 8.0 Hz, 1H), 7.52
(t, J = 7.5, Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ = 147.6, 137.0,
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132.3, 131.4, 129.9, 129.2, 128.5, 125.4, 124.6, 123.4, 119.9, 177.9, 112.8. IR (neat) 3123, 3100,
2925, 2233, 1588, 1477, 1402, 1235, 1045, 1019, 907, 810, 773, 686 cm-1. HRMS (EI):
[M+H]+, calcd for C15H11N4, 247.0983, found 247.0985.
2-(4-phenyl-1H-1,2,3-triazol-1-yl)benzonitrile (7)
Reaction (1 mmol scale) was stirred for 12 hours under standard condition. Yield: 56%; white
solid, mp 148-150 °C. 1H NMR (CDCl3, 500 MHz) δ = 8.47 (s, 1H), 7.99 – 7.96 (m, 1H), 7.95 –
7.91 (m, 2H), 7.89 (dd, J = 7.5, 1.5 Hz, 1H), 7.86 – 7.81 (m, 1H), 7.62 (td, J = 7.5, 1.5 Hz, 1H),
7.48 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ = 148.7, 138.6,
134.6, 134.5, 129.7, 129.6, 129.1, 128.8, 126.2, 125.4, 119.9, 115.9, 105.4. IR (neat) 3131, 2922,
2232, 1601, 1579, 1509, 1484, 1449, 1414, 1230, 1162, 1026, 993, 763, 688 cm-1. HRMS: M+,
calcd for C15H10N4, 246.09054, found 246.09052.
4-bromo-2-(4-phenyl-1H-1,2,3-triazol-1-yl)thiazole (11)
Reaction (1 mmol scale) was stirred for 12 hours under standard condition. Yield: 43%; off-
o
1
white solid, mp 118-120 C. H NMR (CDCl3, 500 MHz) δ = 8.62 (s, 1H), 7.91-7.89 (m, 2H),
7.47 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.18 (s, 1H). 13C NMR (CDCl3, 125 MHz) δ =
157.4, 148.9, 129.2, 129.1, 126.1, 123.2, 116.9, 115.5. IR(neat) 3166, 3108, 2920, 1521, 1451,
1417, 1227, 1022, 985, 877, 769, 695 cm-1. HRMS (EI): [M+H]+, calcd for C11H8BrN4S,
306.9653 and 308.9632, found 306.9650 and 308.9631.
3-bromo-6-(4-phenyl-1H-1,2,3-triazol-1-yl)-9H-carbazole (12)
Reaction (1 mmol scale) was stirred for 9 hours under standard condition. Yield: 40%; off-white
solid, mp > 250 oC). 1H NMR (500 MHz, DMSO-D6) δ = 11.82 (s, 1H), 9.31 (s, 1H), 8.82 (d, J =
2.0 Hz, 1H), 8.53 (d, J = 1.5 Hz, 1H), 7.05-7.98 (m, 3H), 7.76 (d, J = 9.0 Hz, 1H), 7.63 (dd, J =
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13
8.5, 2.0 Hz, 1H), 7.57 (dd, J = 15.0, 8.0 Hz, 3H), 7.43 (t, J = 7.5 Hz, 1H). C NMR (125 MHz,
DMSO-D6) δ = 148.0, 140.6, 140.2, 131.4, 130.2, 129.9, 129.8, 129.0, 126.2, 125.1, 124.3,
122.7, 121.0, 120.3, 114.4, 114.1, 113.1, 112.1. IR (neat) 3290, 2925, 2854, 1510, 1458, 1279,
1242, 950, 795, 762, 695 cm-1. HRMS (EI): [M+H]+, calcd for C20H14BrN4, 389.0401 and
391.0381, found 389.0404 and 391.0399.
4-(cyclohex-1-en-1-yl)-1-(naphthalen-2-yl)-1H-1,2,3-triazole (14)
Reaction (0.5 mmol scale) was stirred for 9 hours under standard condition. Yield: 50%; white
o
1
solid, mp 141-142 C. H NMR (CDCl3, 500 MHz) δ = 8.11 (s, 1H), 7.95-7.92 (m, 2H), 7.88-
7.85 (m, 3H), 7.55-7.50 (m, 2H), 6.66-6.65 (m, 1H), 2.47-2.44 (m, 2H), 2.26-2.22 (m, 2H), 1.82-
13
1.78 (m, 2H), 1.72-1.67 (m, 2H). C NMR (CDCl3, 125 MHz) δ = 150.2, 134.6, 133.3, 132.8,
129.9, 128.3, 127.9, 127.4, 127.0, 126.9, 125.9, 118.9, 118.1, 116.4, 26.5, 25.4, 22.5, 22.3. IR
(neat) 3134, 2929, 1607, 1514, 1484, 1424, 1366, 1235, 1216, 1037, 814, 754 cm-1. HRMS (EI):
[M+H]+, calcd for C18H18N3, 276.1500, found 276.1498.
4-(cyclohex-1-en-1-yl)-1-(2-nitrophenyl)-1H-1,2,3-triazole (16)
Reaction (0.5 mmol scale) was stirred for 9 hours under standard condition. Yield: 53%; yellow
solid, mp 130-131 oC. 1H NMR (CDCl3, 500 MHz) δ = 8.04 (dd, J = 8.0, 1.0 Hz, 1H), 7.77 (td, J
= 8.0, 1.5 Hz, 1H), 7.68-7.65 (m, 2H), 7.62 (dd, J = 7.5, 1.0 Hz, 1H), 6.66-6.64 (m, 1H), 2.44-
13
2.41 (m, 2H), 2.26-2.22 (m, 2H), 1.82-1.77 (m, 2H), 1.72-1.67 (m, 2H). C NMR (CDCl3, 125
MHz) δ = 150.0, 144.4, 133.8, 130.5, 130.3, 127.7, 126.6, 126.4, 125.5, 119.5, 26.4, 25.4, 22.4,
22.2. IR (neat) 3152, 2929, 2862, 1607, 1525, 1503, 1354, 1045, 1026, 858, 788, 747, 706 cm-1.
HRMS (EI): [M+H]+, calcd for C14H15N4O2, 271.1195, found 271.1196.
4-(cyclohex-1-en-1-yl)-1-(thiophen-3-yl)-1H-1,2,3-triazole (17)
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Reaction (0.5 mmol scale) was stirred for 12 hours under standard condition. Yield: 62%; off-
o
white solid, mp 128-130 C. 1H NMR (CDCl3, 500 MHz) δ = 7.74(s, 1H), 7.52 (dd, J = 3.5, 1.0
Hz, 1H), 7.46-7.41 (m, 2H), 2.43-2.40 (m, 2H), 2.23-2.20 (m, 2H), 1.80-1.76 (m, 2H), 1.70-1.67
(m, 2H). 13C NMR (CDCl3, 125 MHz) δ = 149.7, 136.2, 127.2, 126.9, 125.9, 120.8, 116.8, 113.6,
26.5, 25.4, 22.5, 22.2. IR (neat) 3141, 3048, 2926, 2858, 1559, 1436, 1231, 1052, 791, 706 cm-1.
HRMS (EI): [M+H]+, calcd for C12H14N3S, 232.0910, found 232.0908.
4-(1-hydroxycyclopentyl)-1-phenyl-1H-1,2,3-triazole (19)
Reaction (1 mmol scale) was stirred for 12 hours under standard condition. Yield: 58%; white
1
solid, mp 120-123 °C. H NMR (CDCl3, 500 MHz) δ = 7.92 (s, 1H), 7.73 (dd, J = 8.5, 1.5 Hz,
2H), 7.52 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 1H), 2.33 (s, 1H, -OH), 2.25-2.19 (m, 2H),
2.09-1.97 (m, 4H), 1.91-1.84 (m, 2H). 13C NMR (CDCl3, 125 MHz) δ = 155.1, 137.2, 129.7,
128.7, 120.6, 118.3, 79.1, 41.4, 23.7. IR (neat) 3332, 3144, 2944, 1599, 1502, 1441, 1217, 1179,
1063, 937, 751 cm-1. HRMS: M+, calcd for C13H15N3O, 229.12151, found 229.12153.
1-(1-(2-nitrophenyl)-1H-1,2,3-triazol-4-yl)cyclopentan-1-ol (20)
Reaction (0.5 mmol scale) was stirred for 12 hours under standard condition. Yield: 52%; yellow
solid, mp 130-131 oC. 1H NMR (CDCl3, 500 MHz) δ = 8.06 (dd, J = 8.5, 1.5 Hz, 1H), 7.80-7.77
(m, 2H), 7.69 (td, J = 7.5, 1.0 Hz, 1H), 7.63 (dd, J = 7.5, 1.0 Hz, 1H), 2.39 (s, 1H, -OH), 2.25-
2.19 (m, 2H), 2.08-1.96 (m, 4H), 1.90-1.84 (m, 2H). 13C NMR (CDCl3, 125 MHz) δ = 155.0,
144.5, 133.9, 130.7, 130.4, 128.0, 125.6, 121.7, 79.0, 41.4, 23.7. IR (neat) 3353, 3141, 2955,
2873, 1532, 1510, 1365, 1231, 1067, 1015, 780, 747 cm-1. HRMS (EI): [M+H]+, calcd for
C13H15N4O3, 275.1144, found 275.1148.
4-butyl-1-(2-nitrophenyl)-1H-1,2,3-triazole (23)
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Reaction (0.5 mmol scale) was stirred for 12 hours under standard condition. Yield: 65%; yellow
oil. 1H NMR (CDCl3, 300 MHz) δ = 8.03 (dt, J = 7.8, 1.8 Hz, 1H), 7.78 (tt, J = 7.8, 1.8 Hz, 1H),
7.71-7.67 (m, 1H), 7.64-7.63 (m, 1H), 7.61 (s, 1H), 2.81 (t, J = 7.2 Hz, 2H), 1.77-1.67 (m, 2 H),
1.48-1.36 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz) δ = 149.1, 144.4, 133.8,
130.5, 127.8, 125.5, 122.2, 31.4, 25.2, 22.3, 13.8. IR (neat) 3145, 3074, 2959, 2933, 2866, 1611,
1536, 1510, 1357, 1235, 1041, 855, 784, 736 cm-1. HRMS (EI): [M+H]+, calcd for C12H15N4O2,
247.1195, found 247.1191.
4-butyl-1-(thiophen-3-yl)-1H-1,2,3-triazole (24)
Reaction (0.5 mmol scale) was stirred for 12 hours under standard condition. Yield: 59%;
colorless oil. 1H NMR (CDCl3, 500 MHz) δ = 7.66 (s, 1H), 7.52 (dd, J = 3.0, 1.5 Hz, 1H), 7.46-
7.42 (m, 2H), 2.78 (t, J = 7.5 Hz, 2H), 1.73-1.67 (m, 2 H), 1.45-1.38 (m, 2H), 0.95 (t, J = 7.5 Hz,
3H). 13C NMR (CDCl3, 125 MHz) δ = 148.6, 136.1, 127.0, 120.7, 113.5, 118.6, 31.4, 25.2, 24.6,
22.2, 13.7. IR (neat) 3109, 2960, 2929, 2862, 1566, 1547, 1469, 1425, 1227, 1045, 862, 780 cm-
1. HRMS (EI): [M+H]+, calcd for C10H14N3S, 208.0908, found 208.0907.
4.4.Recyclability of the Reaction Medium
To study the recyclability of the reaction medium, two reactions were employed (Table 3 and 4).
General method involved addition of phenylacetylene (1.00 mmol), bromobenzene (1.00 mmol),
sodium azide (1.20 mmol), CuI (0.10 mmol), ligand (0.20 mmol) (N,N'-
dimethylethylenediamine), and 2.0 mL of solvent (1:2 molar mixture of choline chloride and
glycerol) into a reaction vessel and placed in a sand bath heated at 65 °C. The reaction mixture
was stirred overnight. After the completion of reaction, the reaction mixture was extracted with
EtOAc. Once the extraction process was completed, additional reactant species i.e. aryl bromide,
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phenyl acetylene, and sodium azide were added to the same reaction vessel and reaction was
conducted under the same conditions. In this way, after the complete extraction of the desired
product in each cycle, a new cycle was carried out in the same vessel using the same reaction
medium. Unless specified, no additional ligand (N,N'-dimethylethylenediamine) and catalyst
were added.
4.5. Crystallographic data for compound 11
The structure was solved by SHELXT (Sheldrick 2015) program and refined by anisotropic
(isotropic for H atoms) full-matrix least-squares method against F2 of all reflections also by
SHEXL (Sheldrich, 2008). The positions of the hydrogen were geometrically calculated. Details
are available in CIF file, attached as a supplementary information. Alongside some useful
information is summarized in SI-7.
Supporting Information
The Supporting Information can be found at ………
Characterization data for isolated compounds
X-ray Crystallographic Data of compound 11 (CIF)
NMR Spectra of isolated products 3-25
5. Acknowledgements
The authors acknowledge support from Middle Tennessee State University and Dr. Anatoliy
Volkov and Dr. Irina Novozhilova for the crystal structure. Financial support for the acquisition
of the diffractometer by National Science Foundation is also acknowledged (MRI program, grant
ID 1626549).
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6. References and notes
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Beletskaya, I.P.; Cheprakov, A.V. Coord. Chem. Rev. 2004, 248, 2337-2364. Early
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18. It is worth noting that with more reactive aryl bromides, such as 1-bromo-2-nitrobenzene
(49%), 2-bromothiophene (40%), the one-pot azidation/click reaction did work in CC/U,
though always with a modest decrease in yield compared to CC/G.
19. Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512-7515.
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