Synthesis of glucose-tagged triazolium ionic liquids and their application as solvent and ligand for copper(I) catalyzed amination

Article abstract of DOI:10.1016/j.tetlet.2013.06.114

Glucose-linked 1,2,3-triazolium ionic liquids have been synthesized as a new class of chiral solvents by copper(I) catalyzed regioselective cycloaddition of a glucose azide with a glucose alkyne followed by quaternization with methyl iodide. The tagging of glucose to triazolium core makes these molecules act as reusable ligand and solvent in copper(I) catalyzed amination of aryl halides with aqueous ammonia. While the free hydroxyl groups of sugar help in stabilizing copper(I) species during the reaction thus acting as a ligand, the triazolium salt which makes it a liquid at room temperature serves as a reusable solvent. These chiral ionic liquids derived from low-cost natural sources can find utility in various transition-metal catalyzed reactions, and can be explored for asymmetric synthesis in future.

Full text of DOI:10.1016/j.tetlet.2013.06.114

Accepted Manuscript
Synthesis of glucose-tagged triazolium ionic liquids and their application as
solvent and ligand for copper(I) catalyzed amination
Abadh Kishor Jha, Nidhi Jain
PII:
S0040-4039(13)01090-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.114
TETL 43167
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
11 May 2013
18 June 2013
22 June 2013
Please cite this article as: Jha, A.K., Jain, N., Synthesis of glucose-tagged triazolium ionic liquids and their
application as solvent and ligand for copper(I) catalyzed amination, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.06.114
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Graphical Abstract
Leave this area blank for abstract info.
Synthesis of glucose-tagged triazolium ionic liquids
and their application as solvent and ligand for copper(I) catalyzed amination
Abadh Kishor Jha and Nidhi Jain*
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Synthesis of glucose-tagged triazolium ionic liquids and their
application as solvent and ligand for copper(I) catalyzed amination
Abadh Kishor Jha and Nidhi Jain*
Department of Chemistry, Indian Institute of Technology, New Delhi-110016
E-mail: njain@chemistry.iitd.ac.in
Abstract
Glucose-linked 1,2,3-triazolium ionic liquids have been synthesized as a new class of chiral
solvents by copper(I) catalyzed regioselective cycloaddition of a glucose azide with a glucose
alkyne followed by quaternization with methyl iodide. The tagging of glucose to triazolium core
makes these molecules act as reusable ligand and solvent in copper(I) catalyzed amination of aryl
halides with aqueous ammonia. While the free hydroxyl groups of sugar help in stabilizing
copper(I) species during the reaction thus acting as a ligand, the triazolium salt which makes it a
liquid at room temperature serves as a reusable solvent. These chiral ionic liquids derived from
low-cost natural sources can find utility in various transition- metal catalyzed reactions, and can
be explored for asymmetric synthesis in future.
Keywords: triazolium cation, glucose, ionic liquids, amination, copper(I) iodide
Ionic liquids (ILs) are low-melting molten salts composed entirely of ions, and many of them
are liquid at room temperature.1 They are versatile solvents suitable for a myriad of applications
owing to their unique properties such as wide liquid range, thermal stability, excellent solubility
for organic as well as inorganic compounds, attractive recyclability, and negligible vapour
pressure.2 Most of the research on ionic liquids has been dominated by imidazolium salts with
fluorine containing anions.3 Imidazolium salts functionalized with various moieties such as 4-
hydroxyproline, TEMPO, ruthenium complexes, carboxylic acid, amine, thiol, hydroxyl,
bipyridine etc. have been developed and used as supported reagents and catalysts in a variety of
reactions.4 Some amount of progress has also taken place over the past few years in the
development of chiral ILs derived from naturally occurring chiral precursors such as (-)-
ephedrine, (S)-nicotine, (-) menthol, and amino acids.5 Glycoside based ILs containing
ammonium, pyridinium, sulfonium, and imidazolium cations have also been reported.6 However,
there are no reports of carbohydrate based ILs tethered to a triazolium core. Compared to the
huge advancements made with imidazolium ILs, studies of triazolium ILs are fewer.7 So far, the

major field of application for 1,2,3-triazolium ILs has been in ionic liquid tagging of
organocatalysts which enables a better catalytic performance, better solubility, and easy
recycling of catalysts. Examples include chiral 1,2,3-triazolium ionic liquid tethered to (S)-
proline, and TADDOLs8 which have been used in asymmetric catalysis, and have been found to
give higher yields and stereoselectivities than the bare organocatalyst. As part of our ongoing
research on developing ligand-tagged ionic liquids9 as stable media for transition metal
nanoparticle catalyzed reactions,10 we initiated the design and synthesis of sugar-tethered
triazolium salts as a new class of ionic liquids for metal catalyzed reactions. Copper(I) catalyzed
cycloaddition continues to be the most popular method for synthesis of 1,4-disubstituted
triazoles.11 Taking the regioselectivity of click chemistry to our advantage, we decided to
synthesize 1,4-disubstituted triazolium ILs with sugars occupying the 1,4-position.The obvious
advantage of these novel ILs was that they were synthesized starting from low-cost natural
sources. Further, owing to the presence of many hydroxyl groups in the sugar, we believed that
these ILs might provide high coordination ability to the metal centre that could be tuned by
varying the electron density of their oxygens through a proper protecting group pattern. In this
paper we report the synthesis of novel glucose-linked triazolium based ionic liquids, and a
preliminary study on their application in copper(I) catalyzed amination of aryl halides with
aqueous ammonia. A lot of work on amination of aryl halides catalyzed by palladium and copper
using direct or indirect amine sources has been carried out in the last decade.12 While use of
palladium offers large substrate scope, its hyper catalytic activity reduces selectivity leading to
formation of appreciable amounts of secondary and tertiary amines as by-products.13 Copper, on
the other hand is much cheaper compared to palladium, and is stabilized with nitrogen and
oxygen based donor ligands. However its application in aniline synthesis using aqueous
ammonia often requires harsh reaction conditions of high temperature, large excess of ammonia
and ligand making the protocol a little less attractive.14 Hence, the development of a mild
catalytic system for selective mono amination still represents a major advance. Our preliminary
findings on application of glucose-tethered triazolium ionic liquids for copper catalyzed
amination of simple iodo, bromo, and chlorobenzene using aqueous ammonia as amine source
gave promising results. On completion of reaction, the ionic liquid could be recovered and
reused after extraction of products in organic solvent. The rationale of choosing glucose as the
sugar tag was its ready availability and low cost. The synthesis of many more ILs starting from

other monosaccharide or disaccharide molecules can be accomplished by this route. This work
can further be extended to a variety of other substrates with different electronic and steric
constraints to examine the scope and versatility of the catalytic system.
The synthesis of ionic liquids IL-1, IL-2, and IL-3 (Figure 1) with varied hydroxyl group
reactivity was carried out in several steps. The first step involved preparation of the IL
precursors: glucose alkyne 3 and glucose azide 6 from commercially available D-glucose
(Scheme 1) by reported methods.15 Compound 3 was synthesized by selectively protecting D-
glucose as a diacetonide in the furanose form 2 with a free 3-hydroxy group which on subsequent
treatment with propargyl bromide at RT yielded the isopropylidene protected glucose alkyne 3 in
44% overall yield. Compound 6 was prepared by protection of glucose as its pentaacetate
derivative 4 followed by selective bromination at anomeric position with HBr to yield 5 which
was further transformed to azide on exchange with sodium azide. Final ILs were obtained by
copper(I) catalyzed cycloaddition of respective azide with glucose alkyne to yield 1,4-
disubstituted 1,2,3-triazole16 followed by quaternization with methyl iodide (Scheme 2). The ILs
(IL-1, IL-2, and IL-3) were highly soluble in water and completely insoluble in diethyl ether and
methylene chloride. Therefore their purification was achieved by extraction of the impurities in
these two organic solvents from the aqueous phase. The methylation of 8 with methyl iodide
resulted in addition of two methyl units; one at triazole N-3 and a second methylation at C6-
primary hydroxy of furanose ring. The dimethylation was evident from an increase of 29 mass
units from 8 resulting from loss of a primary hydroxyl proton of OH and addition of two methyl
groups leading to the synthesis of IL-1. A similar dimethylation at N-3 and primary OH of 10
gave IL-2. The structure of ILs was confirmed by NMR and mass spectroscopic analysis. The
molecular ion peak at 660.26 in HRMS corresponded to the molecular mass of glucose linked
1
triazolium cation of IL-1. The four acetate groups appeared at (2.14-2.24) ppm in HNMR
13
corresponding to twelve protons, and at 20-21 and 171-174 ppm in the CNMR spectra for the
four methyl and four carbonyl groups respectively. The partial isopropylidene glucose protection
was evident from signals at 1.39 and 1.54 ppm revealing six methyl protons of isopropylidene
13
group. Signals at 25-26 ppm and 112.9 ppm in CNMR could be assigned to the two methyl
carbons and one quaternary carbon respectively of isopropylidene group. The quaternization of
1
nitrogen was confirmed by the methyl signal at 4.21 ppm in H NMR and at 38 ppm in 13C
NMR. An additional methyl signal at 40 ppm pointed out towards the methylation of primary

sugar hydroxyl under the employed reaction conditions. The assignments were further confirmed
1
by 2D NMR (1H-13C HMQC) spectroscopy (Supplementary). H NMR of IL-2 was similar to
that of IL-1 except that it showed the disappearance of all acetate proton signals in the range 2.0-
2.2 ppm, and the carbon signals from carbonyl and methyl in 13CNMR spectrum. Unlike IL-1
and IL-2, the methylation of 12 occurred with addition of two methyl groups at N-1 and N-3
nitrogen of triazole ring and not at C-6 hydroxyl of sugar giving IL-3. This was evident from the
lack of N-H stretching frequency peak in the IR spectra (Supplementary). The quaternary C-atom
in position 4 of the 1,2,3-triazole ring shifted upfield from (144-145) ppm to 139.5 ppm when
triazole was transformed to the corresponding 1,2,3-triazolium salt in all the three ILs. Likewise,
as expected a downfield shift of 6-10 ppm was observed in tertiary C-atom in position 5 on
transforming triazole to triazolium IL.
In an attempt to find new applications of these novel ILs in synthesis, preliminary study
involving amination of iodo-, bromo-, and chlorobenzene with aqueous ammonia catalyzed by
copper(I) iodide in ionic liquids IL-1, IL-2, and IL-3 using different co-solvents was explored.
It was observed that in the absence of ionic liquid, amination did not occur at all in THF alone
indicating that IL was indispensible for the reaction (Table 1, entry 4). Further of the three ILs,
IL-2 showed maximum efficiency in promoting amination compared to IL-1 and IL-3 (Table 1,
entries 1, 10, 11). The higher efficiency of IL-2 may be attributed to the free hydroxyl groups of
pyranose sugar that help in stabilizing copper(I) intermediate by forming a stable chelate. Ability
of sugars and amino sugars to act as ligands for copper catalyzed aniline synthesis has recently
been reported.6a,17 Further, it was found that amination of iodobenzene in THF at 60 °C, THF at
90 °C and THF-H2O at 90 °C with CuI (20 mol%) and glucose added externally (20 mol%) as a
ligand gave aniline in only 5%, 10%, and 15% yields respectively (Table 1, entry 5, 6 , 7). This
clearly demonstrates that tethering of glucose to triazolium core facilitates a homogeneous
catalytic reaction by bringing the substrate, reagent and catalyst in the same phase. Initially, the
intention of adding a co-solvent to IL was simply to reduce the viscosity of the reaction media,
and allow a more efficient stirring of the reactants. However, the nature of co-solvent played a
considerable role in controlling the reaction yield. The yield of aminated product based on co-
solvent followed the order THF≈DMSO > EtOH-H2O (1:1) > CH3CN > H2O (Table 1, entries 1,
14, 15, 16, 17). Of all the solvents tested, THF was the co-solvent of choice since it could be

easily removed during work-up leaving behind the amine in IL which could be easily extracted
using IL immiscible organic solvent such as hexane-ethyl acetate mixture. In contrast, DMSO
which also gave the aminated product in similar yield as THF was avoided since water miscible
ILs could not be recovered and reused after aqueous work-up with DMSO. As expected,
reactivity of halides for amination followed the order iodo- > bromo- > chloro- (Table 2, entry 1,
12, 13). Further studies exploring the scope and versatility of this system for amination with
different substrates are underway.
After completion of reaction, the products were extracted with diethyl ether leaving behind
catalyst in IL. The immobilized copper in IL, however, was found to be inactive when used as
such for the next batch of amination. The obvious logic therefore was to recover and reuse IL. To
accomplish the same, recovered CuI-IL system was diluted with methanol, and inactive copper
catalyst was removed by centrifugation. Removal of methanol under reduced pressure yielded
back the IL whose reusability for amination was tested by addition of a fresh lot of CuI to the
reaction mixture. The yield of amine after first and second recycle was found to be 70 and 64%
respectively (Table 1, entry 1).
1,2,3-triazolium ionic liquids with sugar at 1,4-position have been synthesized using click
chemistry. These compounds are the first example of low cost carbohydrate based ILs containing
a triazolium cation. Screening of these ILs for Cu(I) catalyzed amination reveals that they act as
reusable coordinating solvents and ligands that help in promoting amination of simple iodo,
bromo, and chloro benzene under mild conditions in the order IL-2 > IL-1 > IL-3. The higher
activity of IL-2 towards amination may be due to the free hydroxyl groups on pyranose sugar
responsible for imparting high stability to Cu(I) species during the reaction. Since these ILs
contain chiral sugar unit, their application in asymmetric reactions is in progress.
Acknowledgments
This work has been financially supported by the Department of Science and Technology, India
under the project RP02555. A. S. thanks the Council of Scientific and Industrial Research, India
for graduate fellowship.
Supporting Information
Supplementary
data
related
to
this
article
can
be
found
at
http://dx.doi.org/10.1016/j.tetlet.2013.02.022

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Table 1
Influence of reaction conditions on amination.a
NH2
X
3, 90 oC
aq. NH
Solvent,
K2CO3, IL1-IL3, 20 h
X=Cl, Br, I
Entry
1
X
Solvent
THF
I L
Yield(%)b
I
I
IL-2
IL-2
IL-2
-
82 (70)i (64)j
2
THF
30k(80)l(50)m
3
I
THF
70n (80)o
4c
I
THF
0
5d
I
THF
-
5
6e
I
THF
-
10
15
5
7f
I
THF-H2O (1:1)
EtOH:H2O (1:1)
-
-
8g
I
-
9h
I
IL-2
IL-1
IL-3
IL-2
IL-2
IL-2
IL-2
IL-2
IL-2
50
45
5
10
11
12
13
14
15
16
17
I
THF
I
THF
Br
Cl
I
THF
70
20
80
20
10
25
THF
DMSO
CH3CN
H2O
I
I
I
EtOH:H2O (1:1)
aReaction Conditions: Aryl halide (0.5 mmol), Commercial 20% aq. NH3 (0.75 mmol), CuI (0.1 mmol, 20 mol%), K2CO3 (1.5 mmol), IL (0.1
o
b
c
d
e
mmol, 20 mol%), 90 C, 20 h, Isolated yield, No IL, No Glucose, No IL, Glucose (20 mol%), Temperature (60 °C), No IL, Glucose (20
mol%), Temperature (90 °C), No IL, Glucose (20 mol%), 90 °C, No IL, Glucose (20 mol%), 90 °C, No Co-Solvent, Yield after Ist recycle,
jYield after 2nd recycle, kAt RT, lAt 120 oC, mIL (0.05 mmol, 10 mol%), nK2CO3 (1.0 mmol), oK2CO3 (2.0 mmol)
f
g
h
i
Legends:
Figure 1. Glucose-linked triazolium ionic liquids.
Scheme 1. Synthesis of (a) sugar alkyne and (b) sugar azide.
Scheme 2. Synthesis of glucose-linked triazolium ionic liquids.

O
HO
O
HO
N
O
O
OAc
O
HO
N
O
N
N
O
AcO
AcO
N
O
O
N
O
I
OAc
I
IL- 3
IL -1
O
O
HO
N
O
O
OH
N
O
HO
N
O
HO
I
OH
IL-2
Figure 1.
O
O
O
OH
O
O
O
O
O
DCM, NaOH
O
Acetone,
FeCl3
HO
HO
OH
a)
O
RT,
24 h
O
Br
RT
O
HO
OH
TBAB,12 h
3
1
1
2
OAc
O
OAc
O
OAc
O
NaOAc, Ac2O
90 oC, 2 h
b)
DCM, HBr
RT, 4 h
DMSO, NaN3
RT, 20 min
AcO
AcO
OAc
AcO
AcO
AcO
N3
AcO
OAc
OAc
OAc
Br
4
6
5
Scheme 1.
7
6
NaN3
3
3
CH3CN, CuI
DIPEA,100 o
MeOH, KOH
RT, 3 h
CH3CN, CuI
DIPEA, RT
C
O
O
O
O
O
O
O
O
O
N
O
O
OH
O
N
N
N
OAc
N
N
O
O
O
HO
HO
N
O
HN
O
O
O
AcO
N
O
9
11
AcO
OH
7
OAc
CH3CN, H2O
CH3CN, H2O
CH3CN, H2O
Ce(NH4)2(NO3)6
RT, 3 h
Ce(NH4)2(NO3)6
RT, 3 h
Ce(NH4)2(NO3)6
RT, 3 h
HO
HO
HO
O
O
HO
N
O
HO
N
O
O
OH
N
HO
N
O
N
OAc
O
O
O
O
HN
O
N
HO
HO
N
O
O
10
AcO
AcO
N
O
12
OH
8
OAc
CH3CN, CH3I
Reflux
CH3CN, CH3I
Reflux
CH3CN, CH3I
Reflux
IL- 3
IL-2
IL -1
Scheme 2.

1
Graphical Abstract
Leave this area blank for abstract info.
Synthesis of glucose-tagged triazolium ionic liquids
and their application as solvent and ligand for copper(I) catalyzed amination
Abadh Kishor Jha and Nidhi Jain*
X
,
a
q
.
N
H
O
3
,
C
u
I
O
HO
N
O
OH
NH2
N
Glucose
Glucose
O
O
HO
HO
N
O
k
c
i
l
C
.
I
OH
O
1
OH
O
O
I
Cu
N
n
o
i
t
a
z
N
i
n
r
e
t
N3
a
OH
u
Q
.
2