Base-catalyzed hydrogen–deuterium exchange and dehalogenation reactions of 1,2,3-triazole derivatives

Article abstract of DOI:10.1016/j.tet.2016.08.033

An efficient and convenient synthesis of deuterium-labeled 1,2,3-triazoles using base-catalysis with DMSO-d₆as the deuterium source was developed. A series of deuterated 1,2,3-triazoles bearing various substituents were produced by hydrogen–deuterium exchange reactions of pre-synthesized original 1,2,3-triazoles, giving high level of deuteration and high yields. The catalytic system was successfully extended to the dehalogenation and halogen–deuterium exchange procedures of iodo-functionalized 1,2,3-triazolyl derivatives. This study forms a promising basis for the future development of 1,2,3-triazolyl-containing organic derivatives, polymeric materials and biomedical molecules.

Full text of DOI:10.1016/j.tet.2016.08.033

Tetrahedron xxx (2016) 1e5
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Base-catalyzed hydrogenedeuterium exchange and dehalogenation
reactions of 1,2,3-triazole derivatives
,
,
a,
*
Dong Wang a b, Si Chen a, Jing Wang a, Didier Astruc b , Baohua Chen
*
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of
Gansu Province, Lanzhou 730000, PR China
b ISM, UMRS CNRS 5255, Univ. Bordeaux, 351 Cours de la Liberation, 33405 Talence Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and convenient synthesis of deuterium-labeled 1,2,3-triazoles using base-catalysis with
DMSO-d6 as the deuterium source was developed. A series of deuterated 1,2,3-triazoles bearing various
substituents were produced by hydrogenedeuterium exchange reactions of pre-synthesized original
1,2,3-triazoles, giving high level of deuteration and high yields. The catalytic system was successfully
extended to the dehalogenation and halogenedeuterium exchange procedures of iodo-functionalized
1,2,3-triazolyl derivatives. This study forms a promising basis for the future development of 1,2,3-
triazolyl-containing organic derivatives, polymeric materials and biomedical molecules.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 17 June 2016
Received in revised form 9 August 2016
Accepted 11 August 2016
Available online xxx
Keywords:
Hydrogenedeuterium exchange
Dehalogenation
1,2,3-Triazole
Base catalyst
Deuterium-labeled reagents
1. Introduction
or harsh conditions, however. Therefore the development of effi-
cient and convenient methodologies for the synthesis of specifically
́
With the development of analytical methods for the detection of
stable isotopes by NMR spectroscopy or mass spectrometry, iso-
topically labeled compounds have recently been recognized to be
remarkably useful in many respects, including the investigation of
reaction kinetics and mechanisms, structural elucidation of bi-
ological macromolecules, study of drug metabolisms, quantitative
analyses of environmental pollutants and residual pesticides, and
exploration of new non-linear optical materials.1,2 In particular, the
use of isotopically labeled compounds as internal standards is a key
step in the investigation of samples originating from environ-
mental, animal and human studies.3 The rising demand for iso-
topically labeled compounds has led to an increased interest in the
development of isotope-labeling methods. This is especially the
case for the hydrogenedeuterium exchange strategy that stands as
a conventional technique for the preparation of deuterium-labeled
reagents. Such reactions are promoted by acids, bases, transition
metals, enzymes, or microwave irradiation, and super- or sub-
critical conditions.1b,4 The applications of existing hydro-
genedeuterium exchange systems are largely restricted by their
high catalyst cost, low deuteration efficiency, low regioselectivity,
deuterium-labeled compounds still remains an important and
challenging task.
As a family of five-membered nitrogen-containing heterocyclic
compounds, 1,2,3-triazoles have a myriad of applications in bio-
medical science, synthetic organic/inorganic chemistry, environ-
mental science, and material science,5 because 1,2,3-triazole
derivatives possess many interesting features, such as antibacte-
rial properties, anti-allergic properties, anti-HIV, antineoplastic
activity, and unique coordinating behaviors to metal centers.6 Since
the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction
assembling 1,4-disubstituted 1,2,3-triazoles was discovered by the
groups of Sharpless7 and Meldal8 in 2002, the applications of 1,2,3-
triazoles form a fast-growing field. In a related context, the finding
of efficient and simple synthetic protocols for the synthesis of
deuterium-labeled 1,2,3-triazoles would greatly promote the uses
of this very large family of compounds.
Some procedures for C-5 or C-4 deuteration of 1,2,3-triazoles
have been reported, as shown in Scheme 1. They include the
preparations of deuterated 1,2,3-triazoles using aluminum (Scheme
1a),9 copper (Scheme 1b),10 magnesium (Scheme 1c)11 or lithium
(Scheme 1d)12 intermediates. These organometallics are somewhat
hazardous or sensitive to ambient atmosphere, however, which
causes inconveniences for practical applications. More recently,
Lakshman’s group13 reported the elegant preparation of deuterated
* Corresponding authors. E-mail addresses: d.astruc@ism.u-bordeaux1.fr
(D. Astruc), chbh@lzu.edu.cn (B. Chen).
http://dx.doi.org/10.1016/j.tet.2016.08.033
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2
D. Wang et al. / Tetrahedron xxx (2016) 1e5
1,2,3-triazoles by CuSO4/Na ascorbate-catalyzed CuAAC reaction in
a biphasic CH2Cl2/D2O medium (Scheme 1e).
DMSO-d6 organic bases Et3N and pyridine were employed (Table S1,
entries 5 and 6). The uses of CH2Cl2/D2O or CHCl3/D2O instead of
DMSO-d6 offered the desired deuterated product with very low
yields (Table S1, entries 7 and 8). Moreover, attempts involving
decreased catalytic amounts, reduction of the reaction time, or
lowering the reaction temperature provided deuteration with
lower deuterium contents (Table 1, entries 2, 4 and 5).
Following the efficiency of the reaction protocol described
above, the generality of this regioselective hydrogenedeuterium
exchange reaction was then evaluated. First, several original 1,4-
disubstituted 5-H 1,2,3-triazoles with various substituents at the
C-4 position were examined in the presence of 10e25 mol %
Cs2CO3. As shown in Fig. 1, phenyl moieties with electron-donating
(CH3, CH3O) groups at the ortho-position were tolerated, and the
corresponding deuterated products 1b-D and 1c-D were obtained
with 95% and 98% D contents, respectively. No direct correlation
could be drawn between the steric hindrance and the outcome. The
reaction of 1d-H smoothly proceeded, producing the desired
product 1d-D with 98% D content and 94% isolated yield. Moreover,
an electron-withdrawing substituent such as (3-F) on the phenyl
groups was also suitable (1e-H), but increased both reaction tem-
perature (95 ꢀC) and catalytic amount (25 mol %) were required in
order to obtain a satisfactory D content. This deuteration protocol
was successfully extended to the substrates bearing heteroatom-
containing (1f-H) and long-chain aliphatic (1g-H) fragments at C-
4 position, and excellent D contents and yields were obtained. More
importantly, this catalytic system provided a special deuteration
regioselectivity toward the C-5 position of the 1,2,3-triazoles in all
above-mentioned cases.
Scheme 1. Synthetic routes to deuterated 1,2,3-triazoles.
Hence, we report a general, straightforward and efficient route
to deuterated 1,2,3-triazoles by means of base-catalyzed hydro-
genedeuterium exchange reactions of pre-synthesized 1,4-
disubstituted 1,2,3-triazoles using DMSO-d6 as the deuterium
source (Scheme 1f). Additionally, the present catalytic system is
also useful in dehalogenation of 1,2,3-triazole derivatives. Contrary
to the use of D2O as a deuteration agent that is common,14 deu-
teration using DMSO-d6 is little known and has rarely been uti-
lized,15 although DMSO-d6 is a common NMR solvent.
2. Results/discussion
We initially optimized the conditions of the base-catalyzed
hydrogenedeuterium exchange reaction using 1,2,3-triazole 1a-H
as model substrates. In these preliminary experiments, hydro-
genedeuterium exchange reactions were conducted over several
bases in DMSO-d6. All tested inorganic bases, including Cs2CO3,
K2CO3, KOH, NaOH and K3PO4, work in this transformation (Table 1
Table 1
Optimization of the reaction conditionsa
Fig. 1. Substrate scope of 1,2,3-triazoles with groups at the C-4 position; D content (%Æ
2%). (a) Cs2CO3 (10 mol %). (b) Cs2CO3 (25 mol %).
The scope screening of substituents at the N-1 position was then
further investigated (Fig. 2). The results indicated that the presence
of electron-withdrawing substituents (4-Br, 2-Br, and 4-F) on the
phenyl groups caused lower hydrogenedeuterium exchange re-
activity. Decreased D contents (compared to compound 1d-D) were
detected even though reactions were carried out utilizing increased
catalyst loading (50 mol %) at higher temperature (95 ꢀC). With
original 1,2,3-triazoles (2d-H, 2e-H) containing electron-donating
substituents (C2H5, n-C4H9), Cs2CO3 efficiently catalyzed reactions
forming the corresponding deuterated triazolyl compounds 2d-D,
2e-D with excellent D contents and yields. On the other hand, with
n-C4H9 the D content was somewhat lower, which is probably at-
tributable to the relative bulk in the structure. It was found that the
reactions of 1,4-disubstituted 1,2,3-triazoles 2f-H, 2g-H, 2h-H
containing aliphatic groups proceeded smoothly, yielding the de-
sired deuterated compounds with 93e98% D contents. In the case
of 2h-D, a higher reaction temperature than for the other com-
pounds of this family is required in order to obtain a high level of
Entry Base (mol %) Temperature (oC) Time (h) D content (%)b Yield (%)c
1
2
3
4
5
None
Cs2CO3 (5)
Cs2CO3 (10) 70
Cs2CO3 (10) 70
Cs2CO3 (10) 60
70
70
4
4
4
2
8
0
0
91
96
89
86
92
91
91
93
a
The reaction was carried out with 1a-H (0.15 mmol) in the presence of Cs2CO3 in
DMSO-d6 (0.6 mL) under a nitrogen atmosphere.
b
The D content (%Æ2%) was determined by 1H NMR spectroscopy.
c
Isolated yield for the mixture of 1a-H and 1a-D.
and Table S1). Cs2CO3 exhibited a largely superior activity com-
pared with other bases. Indeed deuterium content of 96% and
isolated yield of 91% were reached with 10 mol % of Cs2CO3 within
4 h at 70 ꢀC (Table 1, entry 3). Moreover, 1H and 2H NMR spectra
indicated that the deuteration occurred at C-5 position with 100%
regioselectivity. The reaction did not proceed at all when the
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D. Wang et al. / Tetrahedron xxx (2016) 1e5
3
procedure using the Cs2CO3/DMSO system eliminates the problem.
Additionally, as expected, the replacement of DMSO-H6 by DMSO-
d6 allows the introduction of the deuterium atom at both the C-5
and methylene positions of the 1,2,3-triazoles (Scheme 3b). In the
cases of substrates bearing halogen atom on the benzene ring (such
as 1e-H, 2a-H, 2b-H, 2c-H and 2j-H), carbonehalogen bonds sur-
vived under the recorded conditions, i.e., no dehalogenated com-
pounds were generated.
Fig. 2. Substrate scope of 1,2,3-triazoles substituted at the at N-1 position; D content
(%Æ2%) (a) Cs2CO3 (50 mol %). (b) Cs2CO3 (10 mol %). (c) Cs2CO3 (25 mol %).
Scheme 3. Cs2CO3-promoted dehalogenation reactions of 1,4-disubstituted 5-iodo-
1,2,3-triazoles; halogen/deuterium exchange in 4a-I; D content (%Æ2%).
3. Conclusion
deuteration, perhaps due to its poor solubility in DMSO at lower
temperature. In addition, the present procedure was also effective
for the deuteration of the CH2 group between the triazole ring and
the benzene ring, and the dideuterated 1,2,3-triazole derivatives 2i-
D and 2j-D were isolated with extremely high D contents at both C-
5 and CH2 positions. In the cases of other substrates containing
juxta-cyclic CH2 groups, such as 1g-H, 2d-H, 2e-H, 2f-H, 2g-H and
2h-H, deuteration of these CH2 groups did not proceed at all.
The reactivity of 1,5-disubstituted 1,2,3-triazoles was then ex-
amined to figure out whether deuteration of 1,2,3-triazole at C-4
position could occur with this protocol. No deuterated 1,2,3-triazole
product was isolated, however, even with higher catalyst loading,
increased reaction temperature, and prolonged reaction time
(Scheme 2). The different catalytic results of 1,5-disubstituted 1,2,3-
triazole from its 1,4-disubstituted counterparts might be attributed
to the different electrostatic potential charges at C-4 and C-5 po-
sitions of 1,2,3-triazole12 resulting in different acidities.
In summary,
a Cs2CO3-catalyzed hydrogenedeuterium ex-
change reaction of 1,4-disubstituted 1,2,3-triazoles at C-5 position
using DMSO-d6 has been disclosed here. The high regioselectivity,
good catalytic efficiency, low costs of both catalyst and deuterium
source, broad substrate scope and easy-operation of this Cs2CO3-
catalyzed procedure enable an efficient, convenient, simply and
general access to deuterium-labeled 1,2,3-triazoles. In view of the
remarkable importance of 1,2,3-triazolyl derivatives in many fields,
this deuteration methodology could drive applications and ex-
tended studies of 1,2,3-triazoles. The present method is a very rare
one using DMSO-d6 that could be exploited and prove useful for
a large number of other hydrogenedeuterium exchange reactions.
It is all the more practical as DMSO-d6 is a biocompatible solvent
and reagent that is used in the same time as NMR solvent allowing
to easily determine the advancement of deuteration reactions and
deuterium content. In a more general context, both dehalogenation
and halogenedeuterium exchange reactions have been efficiently
conducted here by this means.
The presented deuteration methodology of 1,4-disubstituted
1,2,3-triazoles and the biphasic method reported earlier by Laksh-
man’s group13 that are both efficient are thus complementary. The
former is more general than the latter, since the former is effective
to pre-obtained 1,2,3-triazole compounds, regardless of synthetic
routes to original 1,2,3-triazole compounds.
Scheme 2. Investigation of the hydrogenedeuterium exchange reaction of 1,5-
disubstituted 1,2,3-triazoles.
The dehalogenation of halogeno derivatives, specifically that of
aryl halides, represents an important chemical transformation in
organic synthesis.16 Dehalogenation is generally achieved using
transition-metal catalysts, it would not only prevent environmental
or biologic contaminate from toxic halides, but also avoid undesired
further reactions caused by active halides. Moreover, dehalogena-
tion is an efficient deuteration strategy with the assistance of
deuterium sources.17 Interestingly, it was demonstrated that the
Cs2CO3/DMSO system also provides dehalogenation of 1,4-
disubstituted 5-iodo-1,2,3-triazoles producing 1,4-disubstituted 5-
H-1,2,3-triazoles. As shown in Scheme 3a, dehalogenation of iodo-
1,2,3-triazoles (4a-I, 4b-I, 4c-I) was efficient using DMSO-H6 as
solvent in the presence of 1 equiv of Cs2CO3, and up to 94% con-
versions and 88% yields. We know that 5-iodo-1,2,3-triazoles in
variable amounts are usually formed as by-products when CuI is
used as catalyst in azide-terminal alkyne cycloaddition,18 probably
resulting from some side reactions. This simple dehalogenation
4. Experimental section
4.1. General remarks
All reactions were performed under nitrogen using standard
Schlenk techniques, unless otherwise noted. All commercially
available reagents were used as received, unless indicated other-
wise. DMSO-d6 (99.9 atom % D) was purchased from Sigma-
eAldrich. Cs2CO3 was dried under vacuum before use. Flash column
chromatography was performed using silica gel (300e400 mesh).
1H NMR spectra were recorded using a 400 MHz spectrometer, 13
C
NMR spectra were recorded at 100 MHz using a 400 MHz spec-
trometer, and 2H NMR spectra were recorded at 62 MHz using
a 400 MHz spectrometer. Almost all the original 1,4-substituted
1,2,3-triazoles were characterized by 1H NMR using both CDCl3
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4
D. Wang et al. / Tetrahedron xxx (2016) 1e5
and DMSO-d6 as solvents, respectively. Deuterated 1,2,3-triazole
Appendix A. Supplementary data
products were characterized by 2H NMR using CH2Cl2 as solvent.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.08.033.
4.2. General procedure for the synthesis of original 1,4-
disubstituted 1,2,3-triazoles19,20
References and notes
A dried Schlenk tube equipped with a magnetic stir bar was
charged with the alkyne (1 mmol), organic azide (1 mmol), and
Cu(PPh3)2NO3 (0.005 mmol, 3.28 mg). The mixture was stirred at rt
(rt was w25 ꢀC) without exclusion of air under solvent-free con-
ditions. After the reaction was completed, the mixture was diluted
with ethyl acetate and filtered. The filtrate was removed under
reduced pressure to obtain the crude product that was further
purified by silica gel chromatography (petroleum ether/ethyl ace-
tate (20: 1) as eluent) to yield the corresponding deuterated
triazoles.
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4.3. Procedure for the synthesis of original 1,5-disubstituted
1,2,3-triazole (3-H)21
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(1 equiv) in H2O (5 mL) was added KOH powder (0.20 equiv), then
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4.4. General procedure for the synthesis of 1,4-disubstituted
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air under solvent-free conditions. The reaction mixture was diluted
with ethyl acetate and filtered. The filtrate was removed under
reduced pressure to provide the crude product that was further
purified by silica gel chromatography (petroleum ether/ethyl ace-
tate (20: 1) as eluent) to yield the corresponding 1,4-disubstituted
5-iodo-1,2,3-triazoles.
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A dried Schlenk tube equipped with a magnetic stirring bar was
charged under a nitrogen atmosphere, with pre-synthesized orig-
inal 1,2,3-triazoles (0.15 mmol), Cs2CO3 (0.02 mmol, 6.5 mg), and
DMSO-d6 (0.5 mL). The mixture was stirred at 70 or 95 ꢀC for 4 h.
After the reaction mixture was cooled down to rt, it was diluted
with CH2Cl2 (20 mL) and washed with H2O and brine. The com-
bined organic phase was dried over Na2SO4 and filtered. The filtrate
was removed under reduced pressure to obtain the crude product
that was further purified by silica gel chromatography (hexanes/
ethyl acetate (20: 1) as eluent) to yield corresponding deuterated
1,2,3-triazoles.
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Financial support from the project sponsored by the National
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