Copper-Catalyzed Decarboxylative/Click Cascade Reaction: Regioselective Assembly of 5-Selenotriazole Anticancer Agents

Article abstract of DOI:10.1021/acs.orglett.7b03734

A simple and efficient Cu-catalyzed decarboxylative/click reaction for the preparation of 1,4-disubstituted 5-arylselanyl-1,2,3-triazoles from propiolic acids, diselenides, and azides has been developed. The mechanistic study revealed that the intermolecular AAC reaction of an alkynyl selenium intermediate occurred. The resulting multisubstituted 5-seleno-1,2,3-triazoles were tested for in vitro anticancer activity by MTT assay, and compounds 4f, 4h, and 4p showed potent cancer cell-growth inhibition activities.

Full text of DOI:10.1021/acs.orglett.7b03734

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Decarboxylative/Click Cascade Reaction:
Regioselective Assembly of 5‑Selenotriazole Anticancer Agents
Fei-hu Cui,†,‡ Jing Chen,‡ Zu-yu Mo,‡ Shi-xia Su,‡ Yan-yan Chen,† Xian-li Ma,† Hai-tao Tang,‡
Heng-shan Wang,‡ Ying-ming Pan,*,‡ and Yan-li Xu*,†,‡
†College of Pharmacy, Guilin Medical University, Guilin 541004 People’s Republic of China
‡State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and
Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, People’s Republic of China
S
* Supporting Information
ABSTRACT: A simple and efficient Cu-catalyzed decarbox-
ylative/click reaction for the preparation of 1,4-disubstituted 5-
arylselanyl-1,2,3-triazoles from propiolic acids, diselenides, and
azides has been developed. The mechanistic study revealed
that the intermolecular AAC reaction of an alkynyl selenium
intermediate occurred. The resulting multisubstituted 5-
seleno-1,2,3-triazoles were tested for in vitro anticancer activity
by MTT assay, and compounds 4f, 4h, and 4p showed potent
cancer cell-growth inhibition activities.
Scheme 1. Reported Synthesis Routes to 1,4-Disubstituted 5-
Selanyl-1,2,3-triazoles
rganoselenium compounds have been extensively studied
1
Odue to their well-recognized biological activities. The
introduction of selenium into organic molecules is widely
adopted in drug design and regulation of biological processes.2
1,2,3-Triazoles are important versatile N-heterocyclic com-
pounds with diverse pharmacological and biological functions.3
For example, the multisubstituted 5-heterofunctionalized 1,2,3-
triazoles, a kind of privileged triazoles, have been found in a
variety of pharmaceutical molecules and drug candidates.4 It
can be anticipated that the functionalization of multisubstituted
1,2,3-triazoles with organoselenium groups would result in
profound effects on their biological and pharmacological
activities.
In 2002, Sharpless5 and Meldal6 reported a copper(I)-
catalyzed azide−alkyne cycloaddition (CuAAC) reaction
producing 1,4-disubstituted 1,2,3-triazoles with high regiose-
lectivities, where 5-copper(I) triazolide acted as the key reactive
intermediate. It was then concluded that the interception of
copper intermediates by electrophilic reagents was an effective
method for the synthesis of fully substituted 1,2,3-triazoles.7
Recently, Xu’s group8 reported a Cu-catalyzed interrupted click
reaction using electrophilic sulfenylating reagents (PhSO2ER, E
= N, S, Se) to trap the 5-copper(I) triazolide intermediate for
the preparation of multisubstituted 5-heteroatom functionalized
triazoles (Scheme 1a). Although the reaction afforded the target
products in high yields, the use of excess strong base
significantly limited its application potential.
of fully substituted 1,2,3-triazoles is still a great challenge9 due
to the high activation barrier. Most of the intermolecular AACs
of internal alkynes require high temperatures10 and/or
heteroatom-functionalized internal alkynes, such as haloal-
In contrast to the well-developed Cu-catalyzed AACs of
terminal alkynes, the direct reaction of internal alkynes and
azides, especially the intermolecular reaction, for the synthesis
Received: December 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03734
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
kynes,11 ynamides,12 and thioalkyne.13 For example, Sun and
co-workers reported an efficient iridium-catalyzed intermolec-
ular AAC of internal thioalkynes for the synthesis of
multisubstituted 5-thio functionalized triazoles under mild
reaction conditions.14 However, the substitution of the S atom
with a Se atom led to an unsatisfactory yield of 5-seleno-
functionalized triazole (Scheme 1b). With the increasing
interest in organoselenium compounds, efficient and practical
synthetic methods for constructing multisubstituted 5-seleno-
functionalized triazoles are still in high demand. Based on our
previous work of click reactions and the formation of C−Se
bond,15 we developed a simple and efficient method for the
preparation of 1,4-disubstituted 5-arylselanyl-1,2,3-triazoles
from propiolic acids, diselenides and azides, in which alkynyl
selenium was formed first via decarboxylative reactions,
followed by the intermolecular AAC reaction of azides to
afford 5-seleno-triazoles (Scheme 1c).
reaction revealed strong effects of reaction solvent on its
performance, and toluene was found to be the optimal medium
(Table 1, entries 6 vs 7−12). Besides, the reaction performed
without Cu catalyst failed to give the desired product of 4a
(Table 1, entry 13). The reaction were performed at room
temperature and 60 °C, giving the desired product of 1-benzyl-
4-phenyl-5-(phenylselanyl)-1H-1,2,3-triazole (4a) in 10% and
20% yields, respectively (Table 1, entries 14 and 15). In
addition, the reaction was scalable and practical since a
satisfactory yield (80%) could be obtained when the reaction
was performed on a 1 mmol scale. Therefore, the trans-
formation conditions were optimized as 10 mol % Cu(OAc)2·
H2O, 20 mol % 1,10-Phen, 1.2 equiv K2CO3 in toluene,
reaction temperature 120 °C, and reaction time 6 h.
Under the optimal reaction conditions, the substrate scopes
were explored. The results are summarized in Scheme 2. A
We initiated our study with the model reaction of 3-
phenylpropiolic acid (1a), diselenide (2a), and benzyl azide
(3a) under various reaction conditions, and the results are
summarized in Table 1. The reaction under the catalysis of 10
Scheme 2. Synthesis of 1,4-Disubstituted 5-Arylselanyl-1,2,3-
triazoles
a
a
Table 1. Optimization of the Reaction Conditions
yield (%)
entry
catalyst
CuCl2
ligand
solvent
toluene
4a
4a′
1
20
50
30
48
50
82
20
<5
<5
40
<5
0
30
30
40
40
38
10
60
80
70
50
75
<5
30
20
60
10
2
Cu(OAc)2·H2O
CuBr2
toluene
toluene
toluene
toluene
toluene
DMSO
DMF
3
4
CuSO4
5
CuSO4
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
6
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
7
8
9
1,4-dioxane
THF
10
11
12
MeCN
H2O
b
13
toluene
toluene
toluene
toluene
0
c
14
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
1,10-Phen
1,10-Phen
1,10-Phen
10
20
80
d
15
e
16
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), 3a (0.2 mmol),
catalyst (10 mol %), ligand (20 mol %), K2CO3 (0.24 mmol), solvent
b
(2.0 mL), 120 °C, 6 h. Isolated yield. Without Cu(OAc)2·H2O and
c
d
e
1,10-Phen. Room temperature. 60 °C. Reaction conditions: 1a (1
mmol), 2a (1 mmol), 3a (1 mmol), Cu(OAc)2.H2O (10 mol %), 1,10-
Phen (20 mol %), K2CO3 (1.2 mmol), toluene (5.0 mL), 120 °C for
12 h
a
Reaction conditions: 1 (0.3 mmol), 2 (0.3 mmol), 3 (0.3 mmol),
Cu(OAc)2·H2O (10 mol %), 1,10-Phen (20 mol %), K2CO3 (0.36
mmol), toluene (2.0 mL), 120 °C. Isolated yield.
mol % of CuCl2 and 1.2 equiv of K2CO3 in toluene afforded the
desired product 4a in 20% yield (Table 1, entry 1). Other
copper(II) catalysts including Cu(OAc)2·H2O, CuBr2, and
CuSO4 were able to catalyze the reaction, producing 4a in
yields of 50%, 30%, and 48%, respectively (Table 1, entries 2−
4). The catalysis of CuSO4/1,10-Phen resulted in a similar yield
of 4a (Table 1, entry 5). Luckily, the yield was dramatically
increased to 82% under the catalysis of Cu(OAc)2·H2O/1,10-
Phen (Table 1, entry 6). Further investigations on the model
series of para-substituted aromatic propiolic acids bearing
electron-donating and electron-withdrawing groups on the aryl
ring were tested first. The results suggest that desired products,
1,4-disubstituted 5-arylselanyl-1,2,3-triazoles, were produced in
71−83% yields (Scheme 2, 4b−h). To our delight, single
crystals of 4h were obtained by gradual crystallization in a
B
DOI: 10.1021/acs.orglett.7b03734
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
mixture of petroleum ether and ethyl acetate and characterized
as 1-benzyl-5-(phenylselanyl)-4-(4-(trifluoromethyl)phenyl)-
1H-1,2,3-triazole. The reactions of diselenide (2a) and benzyl
azide (3a) with 3-o-tolylpropiolic acid or 3-(m-fluorophenyl)-
propiolic acid afforded the desired products 4i and 4j in 73%
and 77% yields, respectively, suggesting that this transformation
was tolerant toward the electronic and steric effects of aromatic
rings. It is worth noting that the reaction of heteroaryl-
substituted propiolic acid, 3-(thiophene-3-yl)propiolic acid, also
performed well under the optimal conditions and produced 1-
benzyl-5-(phenylselanyl)-4-(thiophene-3-yl)-1H-1,2,3-triazole
(4k) in 67% yield. In addition, 3-(naphthalen-2-yl)propiolic
acid was well tolerated in this reaction with the formation of 4l
in 82% yield. Non-2-ynoic acid, hept-2-ynoic acid, 4,4-
dimethylpent-2-ynoic acid, and 3-cyclopropylpropiolic acid
were also found to be suitable substrates for the transformation,
and their reaction afforded the corresponding 1,4,5-trisub-
stituted triazoles 4m−p in 62%−68% yields.
Scheme 3. Control Experiments
The scope of azidomethyl aromatic substrate was then
examined. The reaction was performed on the substituted
benzyl azides bearing electron-donating groups, such as Me,
OMe, and Ph, or electron-withdrawing groups including Cl, Br,
and CF3 on the aromatic ring, affording the expected 1,4,5-
trisubstituted triazoles in 65%−86% yields (Scheme 2, 5a−g).
The reactions of benzyl azides with electron-donating groups
on the benzene ring gave the corresponding products in higher
yields than those of the azides bearing electron-withdrawing
groups on the benzene ring. The heteroaryl-substituted azide
substrate, 3-(azidomethyl)thiophene, also reacted smoothly,
affording the desired product 5h in 61% yield. In addition, the
azide containing a naphthalene moiety was found to be a
suitable substrate, and its reaction gave product 5i in 72% yield.
Product 5j was obtained in the yield of 64% as (1-
azidoethyl)benzene treated with 3-phenylpropiolic acid (1a)
and diselenide (2a). The reactions of other substrates including
1-azidohexane and (azidomethyl)cyclohexane also proceeded,
giving the desired products 5k and 5l in yields of 69% and 68%,
respectively. The reaction was also found to be highly tolerant
toward the substitutions on diselenides, and the corresponding
products 6a−e were isolated in good yields. In addition, the
reaction of 1,2-diphenyldisulfane was able to afford the desired
product 6f in 53% yield.
reaction under an O2 atmosphere produced 4a and 4a′ in 83%
and 5% yields, respectively (Scheme 3, eq 5), the same as those
obtained under air atmosphere. However, the reaction
performed under N2 atmosphere afforded 4a and 4a′ in yields
of 5% and 82%, respectively (Scheme 3, eq 6). These results
demonstrated the important role of O2 in the reaction.
On the basis of these experimental results and previous
reports,16,17 a plausible mechanism is proposed and depicted in
Scheme 4. First, the coordination of 1,10-phenanthroline to
Scheme 4. Proposed Mechanism
To explore the possible reaction pathway, control experi-
ments were carried out. First, the reaction of 1a and 2a worked
well under the standard conditions and produced phenyl-
(phenylethynyl)selane (7) in 77% yield (Scheme 3, eq 1). The
reaction of phenyl(phenylethynyl)selane 7 and benzyl azide
(3a) under the optimal conditions afforded the desired product
4a in 82% yield (Scheme 3, eq 2). In addition, the mixture of 1a
and 2a under the standard conditions for 6 h and then addition
of 3a leaded the formation 4a in 75% yield (Scheme 3, eq 3).
These results indicate that 7 is a possible intermediate for the
formation of 4a, and potassium 3-phenylpropiolate (1a′)
reacted with 2a and 3a in the presence of 10 mol % of
Cu(OAc)2·H2O, 20 mol % 1,10-Phen, affording the desired
product of 4a in 75% yield (Scheme 3, eq 4). This result
suggests that K2CO3 play an important role on removes acidic
H from propiolic acid, which in turn reacts with Cu and then
this new species generated acts on the cleavage of Ph(Se)2. The
reaction performed in the different molar ratio of 1a/2a/3a
such as 1:0.5:1, 1:0.2:1, 0.5:0.5:1, and 0.5:1:1 under the
standard conditions, and 2a always existed (detected by GC−
MS) even though the reaction time was prolonged to 24 h. The
Cu(OAc)2·H2O to form the active copper(II) intermediate A
that then reacts with phenylacetic acid (1a) to afford copper(II)
intermediate B. The decarboxylation of B produces copper(II)
intermediate C and releases one molecular CO2.16 The reaction
of C with diphenyl diselenide (2a) gives intermediate D. The
reductive elimination of D results in phenyl(phenylethynyl)-
selane (7), as well as copper(I) species E. The complexation of
E with phenyl(phenylethynyl)selane (7) and azide (3a)
generates intermediate F, which undergoes oxidative cyclization
C
DOI: 10.1021/acs.orglett.7b03734
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to form intermediate G.17 The reductive elimination of G
affords the desired product 4a and copper(I) species E. Finally,
E is converted into A under air atmosphere to fulfill the
reaction, and another possible pathway for this transformation
is a cycloadditions with carboxylic acid and azide, which then
undergoes decarboxylation followed by C−Se bond formation
with copper catalysis. For details, see the Supporting
Information.
Accession Codes
CCDC 1577235 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
The in vitro cytoxicity of all synthetic products 4a−p, 5a−l,
and 6a−f, were determined by the methylthiazoltetrazolium
(MTT) assay on the human bladder cancer cells (T-24),
human ovarian cancer cells (SK-OV-3), human cervical cancer
cells (HeLa226), human gastric cancer (MGC-803), and HL-
7702 (human liver normal cell line) cell lines with the
commercial anticancer drug, 5-fluorouracil (5-FU), as the
positive control. The results can be found in the Supporting
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: panym@mailbox.gxnu.edu.cn.
*E-mail: yanli.xu@163.com.
ORCID
Heng-shan Wang: 0000-0001-6474-8323
Ying-ming Pan: 0000-0002-3625-7647
Yan-li Xu: 0000-0003-1373-6431
Notes
Information. To our delight, 4f (IC50 = 7.12 μM), 4h (IC50
8.78 μM), and 4p (IC50 = 6.34 μM) exhibited potent inhibitory
activities against MGC-803 cell lines. Compounds 4f (IC50
=
=
The authors declare no competing financial interest.
7.88 μM) were found to be powerful cytotoxic agents against
T-24 cell lines (Figure 1). Compound 4f induced the highest
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21362002), Guangxi Natural Science Foundation of China
(2016GXNSFEA380001, 2016GXNSFGA380005,
2016GXNSFAA380323, and 2017GXNSFBA198205), State
Key Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources (Guangxi Normal University)
(CMEMR2017-B16), and Key R & D Project for Science
Research and Technology Development of Guilin
(GZWBXKF2016006, 20170108-10).
Figure 1. Anticancer activity of 5-selanyl-1,2,3-triazoles.
REFERENCES
■
apoptosis rate of T-24 cells, and it caused cell arrest in the G2/
M phase according to flow cytometric analysis. Further
experiments confirmed that 4f triggered T-24 cells apoptosis
by increasing the production of intracellular Ca2+ and up-
regulating the expression of reactive oxygen species (ROS) (see
the Supporting Information for details).
In summary, we report a novel and efficient Cu-catalyzed
decarboxylative/click reaction, involving the intermolecular
AAC reaction of an alkynyl selenium intermediate, for the
preparation of 1,4-disubstituted 5-arylselanyl-1,2,3-triazoles
from propiolic acids, diselenides and azides. The catalytic
reaction featured with high efficiency and regioselectivity, mild
reaction conditions, and easy operation, as well as excellent
compatibility with air. The synthesized multisubstituted 5-
seleno-1,2,3-triazoles 4f, 4h, and 4p exhibited potent anticancer
activities in vitro. In addition, the action mechanism of 4f on T-
24 cells was determined by fluorescence staining assay and flow
cytometric analysis to be the induction of G2/M phase arrest
and apoptosis by increasing the production of intracellular Ca2+
and up-regulating the expression of reactive oxygen species
(ROS).
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03734.
Experimental procedures, biological assays, character-
ization data, and NMR spectra for all products (PDF)
́
Grela, E.; Palus, J.; Rudzinska-Szostak, E.; Grabowiecka, A.; Biernat,
M.; Berlicki, L. J. Med. Chem. 2016, 59, 8125. (h) Iwasaki, M.; Miki,
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DOI: 10.1021/acs.orglett.7b03734
Org. Lett. XXXX, XXX, XXX−XXX