Efficient Synthesis of 5-Trifluoromethylthio-1,2,3-Triazoles: One-Pot Multicomponent Reaction from Elemental Sulfur and TMSCF 3

Article abstract of DOI:10.1055/s-0039-1690716

A sequential multistep reaction toward 5-trifluoromethyl thio-1,2,3-triazoles has been established, starting from alkynes, organo azides, S ₈, and (trifluoromethyl)trimethylsilane (TMSCF ₃). This reaction features mild conditions, easy operation, and readily available substrates.

Full text of DOI:10.1055/s-0039-1690716

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
paper
A
en
L.-L. Zhang et al.
Paper
Synthesis
Efficient Synthesis of 5-Trifluoromethylthio-1,2,3-Triazoles: One-
Pot Multicomponent Reaction from Elemental Sulfur and TMSCF3
Lin-Lin Zhang
R1
R1
R2
N3
Meng-Tian Li
Liang-Liang Shen
Qin-Pei Wu*
S
1) CuI, KF, DMF, 0 °C
CF3
+
2)
S8, TMSCF3
N
N
R2
Ag2CO3, 1,10-phen
N
School of Chemistry and Chemical Engineering, Beijing
Institute of Technology, No 10 Liangxiang Donglu, Beijing
102488, P. R. of China
20 examples, up to 81% yield
qpwu@bit.edu.cn
Received: 15.08.2019
Accepted after revision: 29.09.2019
Published online: 21.10.2019
tuted 1,2,3-triazoles have been reported in recent years.
Xu’s group10 developed a three-component click reaction of
azides, alkynes, and aryl halides by using Cu/Pd transmeta-
lation relay catalysis. Song’s group reported an iridium-cat-
alyzed11 cycloaddition of azides to ynamides and a regiodi-
vergent rhodium(I)-catalyzed12 azide-thioalkyne cycloaddi-
tion (RhAAC) to form 5-amido-1,2,3-triazoles and either 4-
or 5-sulfonyl-1,2,3-triazoles, respectively. Recently, the
methods for synthesizing fully substituted 5-thio-1,2,3-tri-
azoles have been widely studied, such as the cycloaddition
of thioalkynes to azides under IrAAC13 or RuAAC14 reaction
reactions, and the electrophilic sulfenylation of Cu(I) tri-
azolides using benzene thiosulfonate under CuAAC10b,15 re-
actions.
DOI: 10.1055/s-0039-1690716; Art ID: ss-2019-h0451-op
Abstract A sequential multistep reaction toward 5-trifluoromethyl-
thio-1,2,3-triazoles has been established, starting from alkynes,
organoazides, S8, and (trifluoromethyl)trimethylsilane (TMSCF3). This
reaction features mild conditions, easy operation, and readily available
substrates.
Key words copper iodide, sulfur, triazole, (trifluoromethyl)trimethyl-
silane, multicomponent reaction
The trifluoromethylthio group (SCF3) has been used as a
structural motif in drug design due to its unique properties,
such as high lipophilicity (Hansch lipophilicity parameter 
= 1.44) and electron-withdrawing properties.1 This group
also enhances drugs’ cell-membrane permeability, meta-
bolic stability, bioavailability, and pharmacokinetics.2 In ad-
dition, the 1,2,3-triazole core shows high solubility, good
metabolic stability, strong hydrogen bonds, and dipole-
dipole interactions.3 The triazole moiety is also an ideal
spacer or linker used in conjugating with biomacromole-
cules4 or linking multitarget drugs.5 Furthermore, 1,2,3-tri-
azole derivatives exhibit extensive biological activities,
such as anticancer, anti-HIV, antituberculosis, antifungus,
antibacteria, antivirus, and anti-inflammation.6
The Huisgen 1,3-dipolar cycloaddition of azides and in-
ternal alkynes (AAC) is the most straightforward and atom-
economical approach for synthesizing 1,2,3-triazloes. Nev-
ertheless, this method has some disadvantages, such as low
regioselectivities, high reaction temperatures, and long re-
action times.7 In 2002, Sharpless8 and Meldal9 reported
copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) re-
actions to regioselectively synthesize 1,4-di-substituted
1,2,3-triazoles. Synthetic methods for various fully substi-
O
O
S
N
SCF3
N
R2
R1
N
(a)
R2
N
N
Bu3SnOMe
CuCl
N
N
O
+
R1
SCF3
ref 14
R1
SnBu3
AlCl3
R2 N3
N
R2
R1
SCF3
(b)
(c)
N
N
Cp*RuCl(cod)
+
R1
refs 15,16
R2
SCF3
or [Rh(CO)2Cl]2
R2 N3
R1
N
N
N
CuI, S8, TMSCF3
Ag2CO3, 1,10-phen
+
R1
SCF3
R2 N3
This work
Features:
• One-pot multistep reaction, mild conditions
• S8 and TMSCF3 as trifluoromethylthiolation reagents
• Readily available substrates
Scheme 1 Strategies for constructing 5-trifluoromethylthio-1,2,3-tri-
azoles
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
L.-L. Zhang et al.
Paper
Synthesis
Trifluoromethylthio-1,2,3-triazoles combine the advan-
tages of the SCF3 group and the 1,2,3-triazole core, possess-
ing enhanced bioactivity and bioavailability.2,16 Few syn-
thetic methods for this type of compound have been de-
scribed. Recently, Xu’s group17 reported a two-step method
(Scheme 1a). Bench-stable 5-stannyltriazoles, obtained via
a copper-catalyzed click reaction, serve as powerful nucleo-
philic reagents to react with a specific electrophilic
trifluoromethylthiolation reagent, generating the 5-tri-
floromethylthiotriazoles. Ruthenium(II)-18 and rhodium(I)-
catalyzed19 azide-alkyne cycloaddition reactions between
azides and alkynyltrifluoromethyl sulfides afforded 5-tri-
fluoromethylthio-1,2,3-triazoles (Scheme 1b). These meth-
ods, however, involve an indirect two-step strategy
(Scheme 1a) or noble-metal catalysts and commercially un-
available starting materials (Scheme 1b). In continuation of
our studies on the synthesis of functionalized 1,2,3-tri-
azoles,20 we herein report a one-pot multicomponent reac-
tion to synthesize 5-trifluoromethylthio-1,2,3-triazoles
from elemental sulfur and TMSCF3 (Scheme 1c).
We have reported a multistep reaction for synthesis of
various thiotriazoles from sulfur powder.21 Under similar
reaction conditions, phenylacetylene and 4-methoxybenzyl
azide (PMBN3) were chosen as model substrates to conduct
the reaction and the desired trifluoromethylthiotriazole 1a
was formed in 41% yield, and the protonated triazole 4 was
Table 1 Optimization of the Reaction Conditionsa
N
N
PMB
F3C
PMB
N3
1) Cu(I), 0 °C
N
N
N
N
+
+
2) S8, 1,10-phen,
TMSCF3
PMB
S
H
Ph
Ph
1a
4, side product
Entry
Additive (mol equiv)
Cu(I)
Silver salt
Ligand
Solvent
Yield (%)b of 1a
c
1
2
K2CO3 (2.0)
Et3N (2.0)
NaOH (2.0)
KOH (2.0)
18-crown-6 (2.0)
KF (2.0)
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Ag2CO3
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
MeCN
THF
41
28
34
trace
0
c
Ag2CO3
c
3
Ag2CO3
c
4
Ag2CO3
c
5
Ag2CO3
c
6
Ag2CO3
48
62
36
75
23
38
25
27
19
18
26
32
0
c
7
KF (1.0)
Ag2CO3
d
8
KF (1.0)
Ag2CO3
9
KF (1.0)
KF (1.0)
Ag2CO3
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
KF (1.0)
AgNO3
AgOAc
AgOTf
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
KF (1.0)
KF (1.0)
KF (1.0)
KF (1.0)
PPh3
KF (1.0)
bpy
KF (1.0)
DMEDA
KF (1.0)
CuSCN
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
KF (1.0)
CuCN
CuOTf
CuIe
CuI
–
KF (1.0)
30
13
0
KF (1.0)
KF (1.0)
KF (1.0)
CuI
trace
–
KF (1.0)
CuI
a Reaction conditions: 1) phenylacetylene (35 L, 0.31 mmol), PMBN3 (49 mg, 0.30 mmol), Cu(I) (0.39 mmol), additive, solvent (2 mL), 0 °C, 3 h. 2) S8 (29 mg,
0.90 mmol), silver salt (332 mg, 1.20 mmol), 1,10-phen (13 mg, 0.07 mmol), TMSCF3 (0.18 mL, 1.20 mmol), rt, 12 h.
b Isolated yields.
c Ag2CO3 (166 mg, 0.60 mmol).
d Ag2CO3 (17 mg, 0.06 mmol).
e CuI (11 mg, 0.06 mmol).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

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L.-L. Zhang et al.
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Synthesis
also detected in 44% yield (Table 1, entry 1). To improve the
yield of 1a, the effect of additive bases was first examined.
Results indicated that Et3N, NaOH, KOH, and 18-crown-6
were all less efficient than K2CO3 (entries 2–5). KF led to a
good yield and the addition of Ag2CO3 improved the yield to
75% (entries 6–10). Other silver salts led to much lower
yields (entries 11–13). Various ligands were also examined
(entries 8, 14–17), and 1,10-phenanthroline (1,10-phen)
was found to be the most effective. Displacement of CuI
with CuSCN, CuCN, and CuOTf led to failures and a much
lower yield, respectively (entries 18–20). Catalytic amount
of CuI gave protonated triazole 4 in 73% yield, while the de-
sired product 1a in only 13% yield (entry 21). Dramatic ef-
fects of solvents on the performance were observed, as the
desired product was not generated in a solution of other
solvents like toluene, acetonitrile, and tetrahydrofuran (en-
tries 22–24). Thus, the conversion conditions were opti-
mized as 1 equivalent PMBN3, 1.05 equivalents phenylacet-
ylene, 1.3 equivalents CuI, 1.0 equivalents KF in DMF at 0 °C
for 3 h in step 1; and 3 equivalents S8, 4 equivalents Ag2CO3,
22 mol% 1,10-phen, and 4 equivalents TMSCF3 at room tem-
perature for 12 hours in step 2.
Under the optimized reaction conditions, the scope
with respect to terminal alkynes was examined (Scheme 2).
Electron-donating groups (methoxyl and alkyl groups) on
aryl alkynes favored this multicomponent reaction to form
products 1a–d in quite good yields. Electron-withdrawing
groups led to lower yields (1e–g). Alkylalkynes afforded the
desired products in moderate yields (1h–j). The next set of
tests examined the influence of azides (Scheme 3). Under
the standard one-pot reaction conditions, both benzyl
azide and 4-methylbenzyl azide were transformed into the
corresponding 5-trifluoromethylthio ethers 2a and 2b in
quite good yields. Electron-withdrawing groups decreased
the yields (2c–e). The heterocyclic azides were also suitable
substrates (2f, 2g). 2-Phenethyl azide produced the expect-
ed product 2h in 72% yield. Phenyl azide and azidoacetate
could not support this transformation under the reaction
conditions (2i, 2j).
N
R
N
N
1) CuI, KF, DMF, 0 °C
+
N3
R
2) S8, Ag2CO3, 1,10-phen,
TMSCF3, r.t.
F3C
S
2
N
PMB
R
N
N
1) CuI, KF, DMF, 0 °C
Cl
N
R
+
PMBN3
S
2) S8, Ag2CO3, 1,10-phen,
TMSCF3, r.t.
F3C
N
N
S
R
N
N
S
N
N
N
1
N
N
Ph
Ph
Ph
2a, R = H, 70%
2b, R = Me, 81%
2c, R = Br, 63%
2d, R = F, 61%
2e, R = CN, 60%
S
S
F3C
N
N
F3C
F3C
N
PMB
PMB
F3C
PMB
N
N
N
N
N
N
2g, 55%
2f, 64%
F3C
S
F3C
S
S
O
N
N
N
N
Ph
N
EtO
N
N
N
N
n-pentyl
OMe
1a, 75%
1b, 74%
1c, 74%
Ph
Ph
Ph
S
F3C
S
F3C
S
N
F3C
N
PMB
N
PMB
N
N
PMB
F3C
N
N
N
N
2h, 72%
2i, trace
2j, trace
Cl
F3C
S
F3C
S
S
Scheme 3 Substrate effect of azides. Reagents and conditions: 1) phe-
nylacetylene (35 L, 0.31 mmol), azide (0.30 mmol), CuI (75 mg, 0.39
mmol), KF (18 mg, 0.30 mmol), DMF (2 mL), 0 °C, 3 h; 2): S8 (29 mg,
0.90 mmol), Ag2CO3 (332 mg, 1.20 mmol), 1,10-phen (13 mg, 0.07
mmol), TMSCF3 (0.18 mL, 1.20 mmol), rt, 12 h. Isolated yields are
shown. For 2f, step 2 of the reaction was carried out at 50 °C for 24 h.
NO2
OMe
O
1d, 75%
1e, 36%
1f, 48%
N
N
PMB
F3C
N
N
PMB
N
N
S
F3C
In addition, all reagents like phenylacetylene, PMBN3,
CuI, KF, 1,10-phen, TMSCF3, S8, and Ag2CO3 were mixed to-
gether to run this multicomponent reaction. The main
product was 1-phenyl-2-[(trifluoromethyl)thio]acetylene 3
in 64% yield and the expected trifluoromethyl thioether 1a
was formed in only 19% yield (Scheme 4, Eq 1). Cycloaddi-
tion of 3 with PMBN3 in the presence of CuI and 1,10-phen
was conducted, and only a trace amount of 1a was generat-
ed (Scheme 4, Eq 2). These results suggested that 3 was not
the key intermediate for the expected thiotriazole product
1a and the copper(I) triazolide should be essentially formed
in the first stage of the multistep reaction. Furthermore,
protonated triazole 4 was unreactive under the standard
S
O
1g, 30%
1h, 42%
N
N
PMB
PMB
F3C
N
N
N
N
F3C
S
S
OBz
OTs
1i, 36%
1j, 56%
Scheme 2 Substrate effect of alkynes. Reagents and conditions: 1)
alkyne (0.31 mmol), PMBN3 (49 mg, 0.30 mmol), CuI (75 mg, 0.39
mmol), KF (18 mg, 0.30 mmol), DMF (2 mL), 0 °C, 3 h; 2) S8 (29 mg,
0.90 mmol), Ag2CO3 (332 mg, 1.20 mmol), 1,10-phen (13 mg, 0.07
mmol), TMSCF3 (0.18 mL, 1.20 mmol), rt, 12 h. Isolated yields are
shown. For 1f, step 2 of the reaction was carried out at 50 °C for 24 h.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

D
L.-L. Zhang et al.
Paper
Synthesis
conditions (Scheme 2, Eq 3), suggesting that C–H trifluoro-
methylthiolation of 4 could not take place in the conditions
to afford the target compound 1a.
In conclusion, we have developed a new method for the
synthesis of 5-trifluoromethylthio-1,2,3-triazoles via a one-
pot multistep reaction from sulfur powder and TMSCF3. All
starting materials are readily available, including S8,
TMSCF3, alkynes, and azides.
CuI, KF, S8, Ag2CO3, TMSCF3
S
CF3
(1)
1a
+
+
PMBN3
1,10-phen, DMF,
0 °C, 3 h, rt, 12 h
19%
3, 64%
All reagents and starting materials were of analytical grade, and ob-
tained from commercial sources and used without further purifica-
tion. All solvents were dried by standard methods. All reactions were
conducted under argon in oven-dried glassware. Reactions were
monitored by TLC on silica gel plates. Column chromatography was
performed on silica gel (300–400 mesh) to purify the products. 1H
NMR, 13C NMR, and 19F NMR spectra were recorded on a NMR spec-
N
PMB
F3C
N
N
CuI, PMBN3
(2)
S
CF3
1,10-phen,
DMF, rt, 12 h
S
3
1a, trace
trometer at 400 MHz, 101 MHz and 376 MHz, respectively. 1H and 13
C
N
N
PMB
NMR spectra are referenced to SiMe4 or the residual solvent peak.
CDCl3 was used as the NMR solvent. All products were further charac-
terized by HRMS (high-resolution mass spectra).
N
CuI, KF, S8, Ag2CO3, TMSCF3
1,10-phen, DMF, rt, 12 h
no reaction
(3)
H
1-(4-Methoxybenzyl)-4-phenyl-5-[(trifluoromethyl)thio]-1H-
1,2,3-triazole (1a); Typical Procedure
4
Scheme 4 Control experiments. Reagents and conditions: phenylacety-
lene (35 L, 0.31 mmol), PMBN3 (49 mg, 0.30 mmol), CuI (75 mg, 0.39
mmol), KF (18 mg, 0.30 mmol), S8 (29 mg, 0.90 mmol), Ag2CO3 (332
mg, 1.20 mmol), 1,10-phen (13 mg, 0.07 mmol), TMSCF3 (0.18 mL,
1.20 mmol), DMF (2 mL). Isolated yields are shown (see also Supporting
Information).
To a solution of PMBN3 (49 mg, 0.30 mmol) in DMF (2 mL) were added
CuI (75 mg, 0.39 mmol), KF (18 mg, 0.30 mmol), and phenylacetylene
(35 L, 0.31 mmol) at 0 °C. The reaction mixture was stirred at 0 °C
for 3 h until the triazole was completely formed. Then, to the solution
were added sulfur powder (29 mg, 0.90 mmol), Ag2CO3 (332 mg, 1.20
mmol), 1,10-phen (13 mg, 0.07 mol), and TMSCF3 (0.18 mL, 1.2
mmol). The reaction mixture was stirred at rt for 12 h. The solid was
filtered and washed with CH2Cl2 (30 mL). The organic filtrate was
washed with H2O (2 × 25 mL). The organic layer was dried (anhyd
MgSO4), filtered, and the solvent was removed under reduced pres-
sure. The residue was chromatographed on silica gel (EtOAc/PE 2:8) to
afford 1a as a pale yellow solid; yield: 80 mg (75%); mp 50–52 °C; Rf =
0.55 (EtOAc/PE 2:8).
On the basis of these preliminary results, we propose
the reaction mechanism described in Scheme 5. In the pres-
ence of KF, CuI, and 1,10-phen, CF3SiMe3 and S8 gets con-
verted into [(phen)Cu(SCF3)]2,22 which would react with
copper(I) triazolide A to form the key intermediate B. Re-
ductive elimination of B produces the 5-trifluoromethyl-
thiotriazole C.21
1H NMR (400 MHz, CDCl3):  = 8.04 (dd, J = 8.1, 1.6 Hz, 2 H), 7.50–7.38
(m, 3 H), 7.31 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.67 (s, 2 H),
3.79 (s, 3 H).
N
13C NMR (101 MHz, CDCl3):  = 159.89, 152.90, 129.59, 129.31,
129.25, 128.65, 127.66 (q, JF,C = 313.1 Hz), 127.45, 126.20, 114.50 (q,
JF,C = 2.5 Hz), 114.33, 55.33, 52.30.
R2
R1
N
N
+
Cu(I)Ln
R1
R2 N3
F3C
S
19F NMR (376 MHz, CDCl3):  = –41.54 (s, 3 F).
C
HRMS (ESI): m/z calcd for [C17H14F3N3OS + H]+: 366.0882; found:
366.0877.
N
R2
N
R2
N
N
R1
N
N
1-(4-Methoxybenzyl)-4-(4-methoxyphenyl)-5-[(trifluorometh-
yl)thio]-1H-1,2,3-triazole (1b)
LnCu
LnCu
R1
S
8 + Ag2CO3
A
Eluent: EtOAc/PE (1:9); yield: 88 mg (74%); pale yellow solid; mp 73–
SCF3
74 °C; Rf = 0.42 (EtOAc/PE 2:8).
B
1H NMR (400 MHz, CDCl3):  = 8.04–7.96 (m, 2 H), 7.34–7.27 (m, 2 H),
7.02–6.95 (m, 2 H), 6.90–6.84 (m, 2 H), 5.64 (s, 2 H), 3.84 (s, 3 H), 3.78
(s, 3 H).
13C NMR (101 MHz, CDCl3):  = 160.45, 159.87, 152.76, 129.54,
128.79, 127.71 (q, JF,C = 313.3 Hz), 126.30, 121.82, 114.31, 114.08,
113.59 (q, JF,C = 2.5 Hz), 55.30, 55.28, 52.22.
CuLn
S8
KF
–
CF3
TMSCF3
LnCuSCF3
DMF
CuLn
Scheme 5 Proposed mechanism
HRMS (ESI): m/z calcd for [C18H16F3N3O2S + H]+: 396.0988; found:
396.0982.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

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L.-L. Zhang et al.
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Synthesis
1-(4-Methoxybenzyl)-4-(4-pentyphenyl)-5-[(trifluorometh-
1H NMR (400 MHz, CDCl3):  = 7.32–7.24 (m, 2 H), 6.92–6.81 (m, 2 H),
yl)thio]-1H-1,2,3-triazole (1c)
5.66 (s, 2 H), 3.98 (s, 3 H), 3.79 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 160.10, 159.86, 144.15, 129.64, 127.28
(q, JF,C = 312.6 Hz), 125.42, 122.63 (q, JF,C = 2.9 Hz), 114.43, 55.32,
52.58, 52.54.
HRMS (ESI): m/z calcd for [C13H12F3N3O3S + H]+: 348.0624; found:
348.0610.
Eluent: EtOAc/PE (1:9); yield: 97 mg (74%); colorless oil; Rf = 0.60
(EtOAc/PE 2:8).
1H NMR (400 MHz, CDCl3):  = 7.96 (d, J = 8.2 Hz, 2 H), 7.33–7.24 (m, 4
H), 6.87 (d, J = 8.7 Hz, 2 H), 5.66 (s, 2 H), 3.79 (s, 3 H), 2.64 (t, J = 7.7 Hz,
2 H), 1.72–1.59 (m, 2 H), 1.34 (dt, J = 7.5, 3.7 Hz, 4 H), 0.94–0.83 (m, 3
H).
13C NMR (101 MHz, CDCl3):  = 159.87, 153.00, 144.37, 129.53,
128.70, 127.30, 127.71 (q, JF,C = 313.2 Hz), 126.60, 126.30, 114.31,
114.05 (q, JF,C = 2.6 Hz), 55.30, 52.23, 35.77, 31.48, 30.91, 22.53, 14.01.
1-(4-Methoxybenzyl)-4-propyl-5-[(trifluoromethyl)thio]-1H-
1,2,3-triazole (1h)
Eluent: EtOAc/PE (1:9); yield: 43 mg (42%); white solid; mp 52–54 °C;
Rf = 0.57 (EtOAc/PE 2:8).
HRMS (ESI): m/z calcd for [C22H24F3N3OS + H]+: 436.1665; found:
1H NMR (400 MHz, CDCl3):  = 7.29–7.23 (m, 2 H), 6.86 (d, J = 8.7 Hz, 2
H), 5.57 (s, 2 H), 3.79 (s, 3 H), 2.78–2.67 (m, 2 H), 1.77 (dq, J = 14.9, 7.4
Hz, 2 H), 0.97 (t, J = 7.4 Hz, 3 H).
436.1656.
4-[2-(6-Methoxynaphthyl)]-1-(4-methoxybenzyl)-5-[(trifluoro-
methyl)thio]-1H-1,2,3-triazole (1d)
13C NMR (101 MHz, CDCl3):  = 159.78, 155.93, 129.47, 127.62 (q, JF,C
=
Eluent: EtOAc/PE (1:9); yield: 100 mg (75%); pale yellow solid; mp
312.2 Hz), 126.38, 115.48 (q, JF,C = 2.8 Hz), 114.24, 55.30, 52.17, 27.09,
88–90 °C; Rf = 0.48 (EtOAc/PE 2:8).
22.08, 13.88.
1H NMR (400 MHz, CDCl3):  = 8.49 (s, 1 H), 8.14 (dd, J = 8.6, 1.8 Hz, 1
H), 7.81 (d, J = 8.7 Hz, 2 H), 7.34 (d, J = 8.7 Hz, 2 H), 7.21–7.14 (m, 2 H),
6.93–6.86 (m, 2 H), 5.69 (s, 2 H), 3.94 (s, 3 H), 3.79 (s, 3 H).
HRMS (ESI): m/z calcd for [C14H16F3N3OS + H]+: 332.1039; found:
332.1023.
13C NMR (101 MHz, CDCl3):  = 159.90, 158.50, 153.04, 134.87,
130.15, 129.57, 128.65, 127.71 (q, JF,C = 313.4 Hz), 127.14, 126.92,
126.27, 125.22, 124.48, 119.36, 114.34, 114.24 (q, JF,C = 2.7 Hz),
105.69, 55.37, 55.32, 52.30.
HRMS (ESI): m/z calcd for [C22H18F3N3O2S + H]+: 446.1145; found:
446.1141.
1-(4-Methoxybenzyl)-2-{5-[trifluoromethyl)thio]-1H-1,2,3-tri-
azol-4-yl}ethyl 4-Methylbenzene-1-sulfonate (1i)
Eluent: EtOAc/PE (25:75); yield: 52 mg (36%); colorless oil; Rf = 0.45
(EtOAc/PE 25:75).
1H NMR (400 MHz, CDCl3):  = 7.71 (d, J = 8.3 Hz, 2 H), 7.31–7.22 (m, 4
H), 6.90–6.83 (m, 2 H), 5.55 (s, 2 H), 4.37 (t, J = 7.1 Hz, 2 H), 3.79 (s, 3
H), 3.13 (t, J = 7.1 Hz, 2 H), 2.43 (s, 3 H).
1-(4-Methoxybenzyl)-4-(4-nitrophenyl)-5-[(trifluorometh-
yl)thio]-1H-1,2,3-triazole (1e)
13C NMR (101 MHz, CDCl3):  = 159.94, 150.51, 144.88, 132.77,
129.84, 129.55, 127.91, 127.46 (q, JF,C = 312.3 Hz), 125.95, 117.08 (q,
JF,C = 2.5 Hz), 114.34, 67.69, 55.32, 52.37, 25.28, 21.62.
Eluent: EtOAc/PE (1:9); yield: 44 mg (36%); pale yellow solid; mp 65–
67 °C; Rf = 0.44 (EtOAc/PE 2:8).
1H NMR (400 MHz, CDCl3):  = 8.39–8.24 (m, 4 H), 7.41–7.29 (m, 2 H),
HRMS (ESI): m/z calcd for [C20H20F3N3O4S2 + H]+: 488.0920; found:
488.0914.
6.93–6.86 (m, 2 H), 5.69 (s, 2 H), 3.80 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 160.08, 150.39, 148.12, 135.44,
129.70, 128.04, 127.46 (q, JF,C = 313.4 Hz), 125.70, 123.94, 116.08 (q,
JF,C = 2.5 Hz), 114.44, 55.33, 52.57.
1-(4-Methoxybenzyl)-2-{5-[trifluoromethyl)thio]-1H-1,2,3-tri-
azol-4-yl}ethyl Benzoate (1j)
Eluent: EtOAc/PE (2:8); yield: 73 mg (56%); white solid; mp 74–76 °C;
Rf = 0.39 (EtOAc/PE 2:8).
HRMS (ESI): m/z calcd for [C17H13F3N4O3S + Na]+: 433.0553; found:
1H NMR (400 MHz, CDCl3):  = 7.96–7.88 (m, 2 H), 7.58–7.50 (m, 1 H),
7.42–7.36 (m, 2 H), 7.25–7.20 (m, 2 H), 6.88–6.81 (m, 2 H), 5.59 (s, 2
H), 4.68 (t, J = 6.9 Hz, 2 H), 3.78 (s, 3 H), 3.27 (t, J = 6.9 Hz, 2 H).
433.0568.
4-(2-Chlorophenyl)-1-(4-methoxybenzyl)-5-[(trifluorometh-
yl)thio]-1H-1,2,3-triazole (1f)
13C NMR (101 MHz, CDCl3):  = 166.28, 159.85, 152.07, 132.93,
130.00, 129.57, 129.38, 128.30, 127.54 (q, JF,C = 312.2 Hz), 126.17,
116.77 (q, JF,C = 2.7 Hz), 114.31, 62.77, 55.29, 52.37, 25.05.
Step 2 was conducted at 50 °C for 24 h; eluent: EtOAc/PE (1:9); yield:
58 mg (48%); pale yellow oil; Rf = 0.54 (EtOAc/PE 2:8).
1H NMR (400 MHz, CDCl3):  = 7.52–7.47 (m, 1 H), 7.46–7.33 (m, 3 H),
HRMS (ESI): m/z calcd for [C20H18F3N3O3S + H]+: 438.1094; found:
7.33–7.27 (m, 2 H), 6.93–6.87 (m, 2 H), 5.68 (s, 2 H), 3.80 (s, 3 H).
438.1083.
13C NMR (101 MHz, CDCl3):  = 159.91, 152.64, 133.85, 132.06,
130.78, 129.80, 129.42, 128.52, 127.53 (q, JF,C = 312.6 Hz), 126.77,
126.13, 117.97 (q, JF,C = 2.7 Hz), 114.38, 55.31, 52.56.
1-Benzyl-4-phenyl-5-[(trifluoromethyl)thio]-1H-1,2,3-triazole
(2a)19
HRMS (ESI): m/z calcd for [C17H13ClF3N3OS + H]+: 400.0493; found:
Eluent: EtOAc/PE (1:9); yield: 70 mg (70%); colorless oil; Rf = 0.71
(EtOAc/PE 2:8).
400.0504.
1H NMR (400 MHz, CDCl3):  = 8.15–7.97 (m, 2 H), 7.51–7.42 (m, 3 H),
Methyl 1-(4-Methoxybenzyl)-5-[(trifluoromethyl)thio]-1H-1,2,3-
7.41–7.30 (m, 5 H), 5.74 (s, 2 H).
triazole-4-carboxylate (1g)
13C NMR (101 MHz, CDCl3):  = 152.92, 134.17, 129.35, 129.21,
129.00, 128.72, 128.66, 127.92, 127.65 (q, JF,C = 314.3 Hz), 127.45,
114.78 (q, JF,C = 2.7 Hz), 52.69.
Eluent: EtOAc/PE (2:8); yield: 31 mg (30%); pale yellow oil; Rf = 0.30
(EtOAc/PE 2:8).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

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L.-L. Zhang et al.
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Synthesis
HRMS (ESI): m/z calcd for [C16H12F3N3S + H]+: 336.0777; found:
336.0785.
1H NMR (400 MHz, CDCl3):  = 8.09–8.02 (m, 2 H), 7.51–7.40 (m, 3 H),
7.31 (dd, J = 5.1, 1.2 Hz, 1 H), 7.18 (dd, J = 3.6, 1.1 Hz, 1 H), 6.99 (dd, J =
5.2, 3.5 Hz, 1 H), 5.90 (d, J = 0.8 Hz, 2 H).
13C NMR (101 MHz, CDCl3):  = 152.84, 135.76, 129.42, 129.11,
128.69, 128.28, 127.64 (q, JF,C = 313.2 Hz), 127.47, 127.19, 127.06,
114.39 (q, JF,C = 2.3 Hz), 47.21.
1-(4-Methylbenzyl)-4-phenyl-5-[(trifluoromethyl)thio]-1H-1,2,3-
triazole (2b)19
Eluent: EtOAc/PE (1:9); yield: 85 mg (81%); pale yellow oil; Rf = 0.47
HRMS (ESI): m/z calcd for [C14H10F3N3S2 + H]+: 342.0341; found:
342.0349.
(EtOAc/PE 1:9).
1H NMR (400 MHz, CDCl3):  = 8.12–8.03 (m, 2 H), 7.50–7.42 (m, 3 H),
7.25–7.15 (m, 4 H), 5.70 (s, 2 H), 2.34 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 152.89, 138.65, 131.19, 129.64,
129.31, 129.26, 128.64, 127.96, 127.67 (q, JF,C = 313.2 Hz), 127.46,
114.65 (q, JF,C = 2.5 Hz), 52.52, 21.14.
1-{[5-(2-Chloropyridyl)]methyl}-4-phenyl-5-[(trifluoromethyl)-
thio]-1H-1,2,3-triazole (2g)
Eluent: EtOAc/PE (1:9); yield: 61 mg (55%); pale yellow oil; Rf = 0.56
(EtOAc/PE 2:8).
HRMS (ESI): m/z calcd for [C17H14F3N3S + H]+: 350.0933; found:
350.0943.
1H NMR (400 MHz, CDCl3):  = 8.48 (d, J = 2.5 Hz, 1 H), 8.08–7.99 (m, 2
H), 7.68 (dd, J = 8.3, 2.6 Hz, 1 H), 7.52–7.43 (m, 3 H), 7.35 (d, J = 8.2 Hz,
1 H), 5.72 (s, 2 H).
1-(4-Bromobenzyl)-4-phenyl-5-[(trifluoromethyl)thio]-1H-1,2,3-
13C NMR (101 MHz, CDCl3):  = 153.19, 152.27, 149.30, 138.68,
129.64, 128.77, 128.76, 128.71, 127.46 (q, JF,C = 313.3 Hz), 127.46,
124.78, 114.82 (q, JF,C = 2.6 Hz), 49.26.
triazole (2c)
Eluent: EtOAc/PE (1:9); yield: 78 mg (63%); pale yellow solid; mp 90–
92 °C; Rf = 0.68 (EtOAc/PE 2:8).
HRMS (ESI): m/z calcd for [C15H10ClF3N4S + H]+: 371.0340; found:
371.0352.
1H NMR (400 MHz, CDCl3):  = 8.05 (dt, J = 8.0, 1.4 Hz, 2 H), 7.54–7.40
(m, 5 H), 7.22 (d, J = 8.4 Hz, 2 H), 5.68 (s, 2 H).
13C NMR (101 MHz, CDCl3):  = 153.02, 133.08, 132.20, 129.67,
129.46, 129.04, 128.70, 127.57 (q, JF,C = 313.3 Hz), 127.45, 122.97,
114.76 (q, JF,C = 2.6 Hz), 51.99.
4-Phenyl-1-(2-phenethyl)-5-[(trifluoromethyl)thio]-1H-1,2,3-tri-
azole (2h)19
Eluent: EtOAc/PE (1:9); yield: 75 mg (72%); pale yellow oil; Rf = 0.70
(EtOAc/PE 2:8).
1H NMR (400 MHz, CDCl3):  = 8.09–7.94 (m, 2 H), 7.51–7.40 (m, 3 H),
7.29 (dddd, J = 12.4, 7.5, 4.6, 2.2 Hz, 3 H), 7.17–7.09 (m, 2 H), 4.80–
4.71 (m, 2 H), 3.35–3.27 (m, 2 H).
HRMS (ESI): m/z calcd for [C16H11BrF3N3S + H]+: 413.9882; found:
413.9888.
1-(4-Fluorobenzyl)-4-phenyl-5-[(trifluoromethyl)thio]-1H-1,2,3-
triazole (2d)
13C NMR (101 MHz, CDCl3):  = 152.30, 136.62, 129.33, 129.26,
128.84, 128.74, 128.66, 127.63 (q, JF,C = 313.0 Hz), 127.53, 127.27,
115.33 (q, JF,C = 2.4 Hz), 49.89, 36.60.
Eluent: EtOAc/PE (1:9); yield: 71 mg (61%); pale yellow solid; mp 81–
82 °C; Rf = 0.37 (EtOAc/PE 1:9).
1H NMR (400 MHz, CDCl3):  = 8.11–8.00 (m, 2 H), 7.51–7.39 (m, 3 H),
7.39–7.32 (m, 2 H), 7.10–7.02 (m, 2 H), 5.70 (s, 2 H).
HRMS (ESI): m/z calcd for [C17H14F3N3S + H]+: 350.0933; found:
350.0938.
13C NMR (101 MHz, CDCl3):  = 162.86 (d, JF,C = 248.2 Hz), 152.98,
129.99 (d, JF,C = 8.3 Hz), 129.90, 129.43, 129.08, 128.70, 127.59 (q, JF,C
=
313.3 Hz), 127.44, 116.02 (d, JF,C = 21.9 Hz), 114.65 (q, JF,C = 2.5 Hz),
51.95.
Supporting Information
HRMS (ESI): m/z calcd for [C16H11F4N3S + H]+: 354.0683; found:
354.0691.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690716.
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1-(4-Cyanobenzyl)-4-phenyl-5-[(trifluoromethyl)thio]-1H-1,2,3-
triazole (2e)
References
Eluent: EtOAc/PE (2:8); yield: 65 mg (60%); pale yellow oil; Rf = 0.33
(EtOAc/PE 2:8).
1H NMR (400 MHz, CDCl3):  = 8.09–8.02 (m, 2 H), 7.70–7.65 (m, 2 H),
7.51–7.40 (m, 5 H), 5.78 (s, 2 H).
13C NMR (101 MHz, CDCl3):  = 153.14, 139.07, 132.83, 129.63,
128.82, 128.76, 128.53, 127.47 (q, JF,C = 313.5 Hz), 127.44, 118.08,
115.01 (q, JF,C = 2.6 Hz), 112.92, 51.88.
HRMS (ESI): m/z calcd for [C17H11F3N4S + H]+: 361.0729; found:
361.0737.
(1) Shao, X.-X.; Xu, C.-F.; Lu, L.; Shen, Q.-L. Acc. Chem. Res. 2015, 48,
1227.
(2) (a) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105,
827. (b) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed.
2013, 52, 8214. (c) Xu, X.-H.; Matsuzaki, K.; Shibata, N. Chem.
Rev. 2015, 115, 731.
(3) (a) Ferreira, S. B.; Sodero, A. C.; Cardoso, M. F.; Lima, E. S.;
Kaiser, C. R.; Silva, F. P.; Ferreira, V. F. J. Med. Chem. 2010, 53,
2364. (b) Lauria, A.; Delisi, R.; Mingoia, F.; Terenzi, A.;
Martorana, A.; Barone, G.; Almerico, A. M. Eur. J. Org. Chem.
2014, 3289.
(4) Liebert, T.; Hänsch, C.; Heinze, T. Macromol. Rapid Commun.
2006, 27, 208.
(5) (a) Devender, N.; Gunjan, S.; Chhabra, S.; Singh, K.; Pasam, V. R.;
Shukla, S. K.; Sharma, A.; Jaiswal, S.; Singh, S. K.; Kumar, Y.; Lal,
J.; Trivedi, A. K.; Tripathi, R.; Tripathi, R. P. Eur. J. Med. Chem.
4-Phenyl-1-[(thiophen-2-yl)methyl]-5-[(trifluoromethyl)thio]-
1H-1,2,3-triazole (2f)
Step 2 was conducted at 50 °C for 24 h; eluent: EtOAc/PE (1:9); yield:
65 mg (64%); white solid; mp 65–67 °C; Rf = 0.42 (EtOAc/PE 1:9).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G

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L.-L. Zhang et al.
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Synthesis
2016, 109, 187. (b) Boechat, N.; Ferreira, M. L. G.; Pinheiro, L. C.
S.; Jesus, A. M. L.; Leite, M. M. M.; Junior, C. C. S.; Aguiar, A. C. C.;
Andrade, I. M.; Krettli, A. U. Chem. Biol. Drug Des. 2014, 84, 325.
(6) (a) Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem. Asian J. 2011, 6,
2696. (b) Dheer, D.; Singh, V.; Shankar, R. Bioorg. Chem. 2017,
71, 30.
(14) Destito, P.; Couceiro, J. R.; Faustino, H.; López, F.; Mascarenas, J.
L. Angew. Chem. Int. Ed. 2017, 56, 10766.
(15) (a) Wang, W.; Lin, Y.; Ma, Y.; Tung, C.-H.; Xu, Z. Org. Lett. 2018,
20, 2956. (b) Wang, W.; Peng, X.; Wei, F.; Tung, C.-H.; Xu, Z.
Angew. Chem. Int. Ed. 2016, 55, 649.
(16) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529.
(17) Wei, F.; Zhou, T.; Ma, Y.-D.; Tung, C.-H.; Xu, Z.-H. Org. Lett. 2017,
19, 2098.
(7) (a) Huisgen, R. Angew. Chem. Int. Ed. 1963, 2, 565. (b) Huisgen, R.
Angew. Chem. Int. Ed. 1963, 2, 633.
(8) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41, 2596.
(18) Shen, Q.; Han, E.-J.; Huang, Y.-G.; Chen, Q.-Y.; Guo, Y. Synthesis
2015, 47, 3936.
(9) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057.
(19) Song, W.-Z.; Zheng, N.; Li, M.; He, J.-N.; Li, J.-H.; Dong, K.; Ullah,
K.; Zheng, Y.-B. Adv. Synth. Catal. 2019, 361, 469.
(20) (a) Wu, G.-L.; Wu, Q.-P. ChemistrySelect 2018, 3, 5212. (b) Wu,
G.-L.; Wu, Q.-P. Adv. Synth. Catal. 2018, 360, 1949. (c) Wu, G.-L.;
Wu, Q.-P. Synthesis 2018, 50, 2768.
(21) Zhang, L.-L.; Li, Y.-T.; Gao, T.; Guo, S.-S.; Yang, B.; Meng, Z.-H.;
Dai, Q.-P.; Xu, Z.-B.; Wu, Q.-P. Synthesis 2019, in press; DOI:
10.1055/s-0039-1690618.
(10) (a) Wei, F.; Li, H.-Y.; Song, C.-L.; Ma, Y.-D.; Zhou, L.; Tung, C.-H.;
Xu, Z.-H. Org. Lett. 2015, 17, 2860. (b) Wei, F.; Wang, W.-G.; Ma,
Y.-D.; Tung, C.-H.; Xu, Z.-H. Chem. Commun. 2016, 52, 14188.
(11) Song, W.-Z.; Zheng, N. Org. Lett. 2017, 19, 6200.
(12) Song, W.-Z.; Zheng, N.; Li, M.; Dong, K.; Li, J.-H.; Ullah, K.; Zheng,
Y.-B. Org. Lett. 2018, 20, 6705.
(13) (a) Ding, S.; Jia, G.; Sun, J. Angew. Chem. Int. Ed. 2014, 53, 1877.
(b) Luo, Q.; Jia, G.; Sun, J.; Lin, Z. J. Org. Chem. 2014, 79, 11970.
(22) Weng, Z.; He, W.; Chen, C.; Lee, R.; Tan, D.; Lai, Z.; Kong, D.;
Yuan, Y.; Huang, K.-W. Angew. Chem. Int. Ed. 2013, 52, 1548.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–G