Copper-catalyzed cascade click/nucleophilic substitution reaction to access fully substituted triazolyl-organosulfurs

Article abstract of DOI:10.1039/c9ob02081k

A novel cascade click/nucleophilic substitution reaction is developed to access 4-heterofunctionalized fully substituted triazolyl-organosulfurs using thiocyanates as both leaving groups and organosulfur precursors. This method features high regioselectivities and board substrate scope. 33 examples are shown to demonstrate the structural diversity through the synthesis of fully substituted triazolyl-organosulfurs including triazolyl-thiocyanates, triazolyl-sulfinylcyanides, triazolyl-thioethers, triazolyl-thiols and triazolyl-disulfides from internal thiocyanatoalkynes.

Full text of DOI:10.1039/c9ob02081k

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Copper-catalyzed cascade click/nucleophilic
substitution reaction to access fully substituted
triazolyl-organosulfurs†
Cite this: Org. Biomol. Chem., 2019,
7, 9933
1
Ming Li, Kun Dong, Yubin Zheng* and Wangze Song
*
A novel cascade click/nucleophilic substitution reaction is developed to access 4-heterofunctionalized
fully substituted triazolyl-organosulfurs using thiocyanates as both leaving groups and organosulfur pre-
cursors. This method features high regioselectivities and board substrate scope. 33 examples are shown
to demonstrate the structural diversity through the synthesis of fully substituted triazolyl-organosulfurs
including triazolyl-thiocyanates, triazolyl-sulfinylcyanides, triazolyl-thioethers, triazolyl-thiols and triazo-
lyl-disulfides from internal thiocyanatoalkynes.
Received 25th September 2019,
Accepted 7th November 2019
DOI: 10.1039/c9ob02081k
rsc.li/obc
Cai’s group reported an intramolecular electrophilic inter-
Introduction
rupted click/Ullman coupling tandem reaction using copper in
7
Triazoles, as important structures with diverse bioactivities, a catalytic amount and halides as electrophiles. Recently, Xu,
have been widely applied in medicinal chemistry, agrochem- Song and other groups developed various electrophilic inter-
1
icals, dyes, polymers, and materials science. The Huisgen 1,3- rupted click reactions by trapping the 5-cuprate-triazoles
dipolar cycloaddition reaction between azides and internal with other electrophiles such as benzenesulfonothioates,
alkynes is considered to be the most straightforward and atom p-toluenesulfono(dithioperoxoate), electrophilic amination
3
economical approach to prepare fully substituted 1,2,3-tri- reagents, Bu SnOMe, sulfoximines, boronic acids, and
8
,9
azoles, but suffering from low regioselectivities, high tempera- N-tosylhydrazones. Most recently, Lautens’ group disclosed
2
ture, and long reaction time. In 2002, the copper-catalyzed the intramolecular electrophilic interrupted click/acylation
azide–alkyne cycloaddition (CuAAC) reaction, independently domino reaction using acyl chlorides as electrophiles
1
0
developed by Sharpless, Fokin, and Meldal’s group, showed (Scheme 1a). The structural diversity of 5-heterofunctiona-
the excellent performance for regioselectively preparing 1,4-di- lized fully substituted 1,2,3-triazoles are broadly expanded by
substituted 1,2,3-triazoles. It was accomplished through the the above electrophilic interrupted click reactions. However,
protonation of the key 5-cuprate–triazole intermediates in high these transformations severely depend on the highly reactive
yields and efficiencies under mild conditions from terminal electrophiles in order to overcome the parasitic protonation.
alkynes, which has an enduring impact as the privileged Methods for the synthesis of 4-heterofunctionalized fully sub-
3
example of “click chemistry”. 1,4,5-Fully substituted triazoles stituted triazoles by the cascade click reaction are still
could be obtained from the post-transformations of 5-cuprate– undeveloped.
1
1
12
13
13
triazole intermediates by transition-metal-catalyzed direct ary-
Our group,
and the Fokin,
Mascareñas,
López,
4
5
12,14
14
lation, Cu-catalyzed C–H bond functionalization, and Cu- Jia,
and Sun groups addressed the diverse and regio-
6
–10
catalyzed electrophilic interrupted click reaction.
In 2005, selective issues for preparing functionalized fully substituted
Wu’s group disclosed an electrophilic interrupted click reac- triazoles by chelated metal-catalyzed AAC reactions
tion, where 5-cuprate-triazoles could be successfully trapped (Scheme 1b). However, the diversity of triazolyl-organosulfurs
6
by electrophiles such as halides and acyl chlorides. However, is limited only to the 5-heterofunctionalized-triazoles from the
a stoichiometric amount of copper was required in order to internal thioalkynes, and it is very hard to reverse the initial
avoid the protonation of Cu(I)–triazole intermediates. Later, regioselectivities by overturning the chelation manner between
the transition metal (such as Rh, Ru, and Ir) and internal
thioalkyne. Recently, diversity-oriented synthesis (DOS), as a
State Key Laboratory of Fine Chemicals, School of Chemical Engineering,
powerful strategy to access various substituted patterns of
Dalian University of Technology, Dalian, 116024, P. R. China.
E-mail: zybwl@163.com, wzsong@dlut.edu.cn
1
5
heterocyclic compounds, attracted our attention. However,
the strategy remains challenging and undisclosed for the DOS
of different fully substituted triazolyl-organosulfurs, including
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02081k
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 9933–9941 | 9933

View Article Online
Paper
Organic & Biomolecular Chemistry
cascade reaction for the DOS of triazolyl-organosulfurs in high
1,4-regioselectivity. Thiocyanate is an excellent candidate
because cyanate functionalized as an ideal leaving group, and
1
7
the sulfur served as a precursor. Diverse fully substituted
-heterofunctionalized-triazoles, including triazolyl-thiocya-
4
nates, triazolyl-sulfinylcyanides, triazolyl-thioethers, triazolyl-
thiols and triazolyl-disulfides, could be obtained via the
cascade click/nucleophilic substitution reactions, which
remarkably expanded the structural diversity as well as simpli-
fied the preparation procedures. 33 examples are shown to
demonstrate the structural diversity accomplished by this
methodology (Scheme 1c).
Results and discussion
For the preparation of fully substituted 4-thiocyanato-1,2,3-tri-
azole (3a), internal thiocyanatoalkyne (1a) and benzyl azide
(
2a) were initially chosen as the model substrates for optimiz-
ing the reaction conditions (Table 1). None of the desired AAC
products were observed with CuI or Cu(II) as catalysts (Table 1,
entries 1 and 2). To our delight, (CuOTf) PhMe and Cu
Scheme 1 Cascade click/nucleophilic substitution reaction for the syn-
2
thesis of 4-heterofunctionalized triazolyl-organosulfurs.
(MeCN) PF as catalysts could supply 4-thiocyanato-1,2,3-tri-
4
6
azole (3a) in moderate yields and good 1,4-regioselectivities
Table 1, entries 3 and 4). The yield could be further improved
triazolyl- at 80 °C due to the thermodynamic control (Table 1, entry 5).
(
triazolyl-thiocyanates,
triazolyl-sulfinylcyanides,
thioethers, triazolyl-thiols and triazolyl-disulfides, because The mildly decreased yield and regioselectivity were observed
most transition metal catalysts may be easily poisoned or at 100 °C (Table 1, entry 6). Improving the catalyst loading may
strongly bound by sulfur. In addition, the 1 : 1 regioisomer accelerate the catalytic cycles. The yield could be increased to
mixture is usually obtained for the internal thioalkynes partici- 79% using 5% catalyst loading, and kept in 77% yield using
pating in the [3 + 2] cycloadditions due to their low reactivity 10% catalyst loading (Table 1, entries 7 and 8). High concen-
1
6
and the difficulty in their regiocontrol by the CuAAC process.
tration (0.5 M) of solvent promoted the intermolecular reaction
Herein, we first integrate the leaving groups into the internal and gave 85% yield with good regioselectivity (11 : 1) (Table 1,
alkynes and develop the novel click/nucleophilic substitution entry 9). The reaction could also occur in THF and DCE
a
Table 1 Optimization of the reaction conditions
b,c
b
Entry
Catalyst
CuI
Loading [%]
Solvent
Conc. [M]
Temperature [°C]
Yield [%]
3a/3a′
1
2
3
4
5
6
7
8
9
0
1
2
3
2.5
2.5
2.5
2.5
2.5
2.5
5
10
5
5
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
THF
3
3
3
3
3
3
3
3
3
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.5
0.5
0.5
0.5
0.5
60
60
60
60
80
100
80
80
80
80
80
80
80
0
0
—
—
4
CuSO ·5H
2
O
PhMe
(CuOTf)
2
60
62
71
65
79
77
85
82
82
Trace
0
8 : 1
8 : 1
8 : 1
6 : 1
8 : 1
8 : 1
11 : 1
9 : 1
11 : 1
—
Cu(MeCN)
Cu(MeCN)
Cu(MeCN)
Cu(MeCN)
Cu(MeCN)
Cu(MeCN)
Cu(MeCN)
Cu(MeCN)
Cu(MeCN)
Cu(MeCN)
4
PF
4
PF
4
PF
4
PF
4
PF
4
PF
4
PF
4
PF
4
PF
4
PF
6
6
6
6
6
6
6
6
6
6
1
1
1
1
5
5
5
DCE
Toluene
2
H O
—
a
b
1
Conditions: 1a (1.0 equiv.), 2a (1.5 equiv.), catalyst, solvent, for 24 h. Determined by H NMR of the crude mixture with toluene as an internal
c
standard. The combined yield of 3a and 3a′ was reported.
9934 | Org. Biomol. Chem., 2019, 17, 9933–9941
This journal is © The Royal Society of Chemistry 2019

View Article Online
Organic & Biomolecular Chemistry
Paper
(
Table 1, entries 10 and 11) but cannot proceed in toluene or Table 3 Cascade click/nucleophilic substitution reaction to access fully
water due to polarity and solubility issues (Table 1, entries 12
and 13).
a,b
substituted 4-thio-1,2,3-triazoles
With the optimized conditions in hand, we explored the
substrate scope of the azide-internal thiocyanatoalkyne cyclo-
addition reaction. Various internal thiocyanatoalkynes (1) and
azides (2) were used as substrates to afford fully substituted
4
-thiocyanato-1,2,3-triazoles (3) in good yields (up to 81%),
chemoselectivities, and regioselectivities. Using Cu(MeCN) PF
as a catalyst, the synthesis of fully substituted 4-thiocyanato-
,2,3-triazoles (3) in CHCl is shown in Table 2. The electronic
4
6
1
3
effect was not obvious for the electron-rich and electron-
deficient substrates as they showed similar yields (3a–3h)
despite a dramatically decreased yield (63%) for the o-methox-
ylphenyl substituted derivative (3i). In addition to benzyl
azide, the yields for electron-rich azides (3j and 3k) were
slightly lower than those of electron-poor azide (3l). To our
delight, the reaction could also occur for the secondary azide,
which would be used for the enantioselective CuAAC reactions
in the future (3m). Unfortunately, the utilization of aryl
azides gave lower yields than that of alkyl azides in this trans-
formation (3n and 3o). 3p was acquired from the phenylethyl
azide in 79% yield. We were pleased to find that the compli-
cated butyl azide could offer 3q in good yields (81%).
a
18
Reaction conditions: 1 (1.0 equiv.), 2 (1.5 equiv.), Cu(MeCN)
5 mol%), THF (0.5 M), 80 °C in a sealed tube for 12–24 h, then 4 (2
equiv.) was added to the mixture at 0 °C, then warmed to rt for 12 h.
4 6
PF
(
b
c
Yield of the isolated product. 1′ was used instead of 1.
After the fully substituted 4-thiocyanato-1,2,3-triazoles (3) in Table 3. The preparation of fully substituted 4-thio-1,2,3-tri-
were prepared well, the cascade click/nucleophilic substitution azoles (5) was evaluated using a variety of Grignard reagents
reaction to access fully substituted triazolyl-organosulfurs was (4) as nucleophiles. THF was used as the solvent instead of
developed in a “one-pot, three-component” manner as shown CHCl
nucleophilic attacking step. The reactivity of leaving groups,
CN and –Ts, was carefully examined by the preparation of 5a,
b, and 5h. In general, internal thiocyanatoalkynes (1) could
in Table 3 in order to be compatible with the following
3
–
5
Table 2 Reaction scope of the fully substituted 4-thiocyanato-1,2,3-
triazoles
a,b
give higher yields compared to S-(phenylethynyl) 4-methyl-
benzenesulfonothioate (1′). For the primary alkyl Grignard
reagents as nucleophiles, 5a–5c were acquired in good yields.
When the secondary alkyl Grignard reagents were used as
nucleophiles, the yields of 5d–5f decreased quickly because of
the steric hindrance effect. 5g was prepared in 70% yield using
the benzyl Grignard reagent. Aryl Grignard reagents were also
good nucleophiles to give 72–74% yields without obvious elec-
tronic effects (5h–5j).
The applicability of the synthesis of fully substituted 4-thio-
cyanato-1,2,3-triazoles was investigated in Scheme 2. It is very
significant for the late-stage modifications of natural com-
pounds by the AAC reaction to introduce the functionality.
Internal thiocyanatoalkyne (1a) and glycosyl azide (2r) were
used as substrates, which efficiently offered unique glycosyl
thiocyanates (3r). It could be potentially used as a novel glyco-
conjugation approach (Scheme 2a). Treating with trifluoroace-
tic anhydride (TFAA) and H O , the controlled oxidation could
2
2
produce triazolyl 4-sulfinylcyanide (6a) in moderate yields
(
Scheme 2b).
Next, we explored the applicability of the cascade click/
nucleophilic substitution reaction for DOS of various fully sub-
stituted triazolyl-organosulfurs in Scheme 3. The tandem reac-
tion could be performed on the gram scale. Treating with 1a
(6.5 mmol, 1.03 g) using methylmagnesium bromide (4a), 5a
a
Reaction conditions: 1 (1.0 equiv.), 2 (1.5 equiv.), Cu(MeCN)
4
PF
6
b
(
5 mol%), CHCl
the isolated product.
3
(0.5 M), 80 °C in a sealed tube for 12–24 h. Yield of
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 9933–9941 | 9935

View Article Online
Paper
Organic & Biomolecular Chemistry
share a common internal thiocyanatoalkyne precursor by the
tandem click/nucleophilic substitution reactions.
Conclusions
In summary, we first disclosed the synthesis of fully substi-
tuted 4-thiocyanato-1,2,3-triazoles in high regioselectivities,
chemoselectivities, yields, and broad substrate scope by the
CuAAC reaction. Beyond this research, we developed the
cascade click/nucleophilic substitution reaction in a “one-pot,
three-component” manner using the thiocyanates as both
Scheme 2 The application of the synthesis of 4-thiocyanato-1,2,3- leaving groups and organosulfur precursors to access 4-hetero-
triazoles.
functionalized fully substituted triazolyl-organosulfurs, such
as triazolyl-thiocyanates, triazolyl-sulfinylcyanides, triazolyl-
thioethers, triazolyl-thiols, and triazolyl-disulfides, from a
common internal thiocyanatoalkyne precursor. More than 30
examples are shown to validate the structural diversity of this
methodology for diversity-oriented synthesis (DOS) of various
fully substituted triazolyl-organosulfurs. Further mechanistic
studies and advanced theoretical calculations for the tran-
sition states and intermediates are underway in our laboratory.
Experimental
General methods
Unless otherwise noted, all commercially available reagents
and solvents were used without further additional purification.
Thin layer chromatography was performed using precoated
silica gel plates and visualized with UV light at 254 nm. Flash
column chromatography was performed with silica gel
1
13
(
40–60 μm). H and C nuclear magnetic resonance (NMR)
spectra were obtained using a Bruker Avance II 400 MHz or
Bruker Avance III 500 MHz spectrometer recorded in ppm (δ)
downfield of TMS (δ = 0) in CDCl3 unless noted otherwise.
Scheme 3 The application of the cascade click/nucleophilic substi- Signal splitting patterns were described as singlet (s), doublet
tution reaction.
(d), triplet (t), quartet (q), quintet (quint), or multiplet (m),
with coupling constants (J) in hertz (Hz). High resolution
mass spectra (HRMS) were recorded with Agilent apparatus
(
(
TOF mass analyzer type) using an Electron Spray Injection
ESI) mass spectrometer. Melting points were determined by
was afforded in 66% yield (4.29 mmol, 1.21 g) after column
purification (Scheme 3a). The cascade click reaction could be
extended to the solid-phase synthesis. (Azidomethyl) poly-
styrene resin (2s) could be employed for the preparation of
fully substituted 4-thio-1,2,3-triazole (5s) using the Grignard
reagent (4a) as a nucleophile. It provided a powerful method-
ology for surface modification and heterogeneous multicom-
ponent catalysis (Scheme 3b). Thiocyanates could be con-
sidered as the precursors for DOS of the thioethers, thiols, and
XP-4 melting point apparatus.
Preparation of substrates
All substrates were prepared according to the literature
methods and their spectral data matched with literature
studies.
9
b,17b,19,20
1
7
Representative procedure for the synthesis of fully substituted
-thiocyanato-1,2,3-triazoles
disulfides. Besides organometallic reagents, hydrides were
also good nucleophiles for transforming the thiocyanates into
4
thiols. Thiol (7a) was obtained by cascade click/reduction reac- To a vial containing (thiocyanatoethynyl)benzene 1a (32 mg,
tion. The disulfide (8a) could be afforded by the oxidation of 0.2 mmol, 1 equiv.) in CHCl3 (0.4 mL) and Cu(MeCN) PF
4
6
the related thiol (Scheme 3c). Therefore, fully substituted tria- (3.8 mg, 5 mol%) was added BnN 2a (40 mg, 0.3 mmol, 1.5
3
zolyl-thiocyanates (3), triazolyl-thioethers (5), triazolyl-sulfinyl- equiv.). The mixture was stirred at 80 °C for 24 h. The mixture
cyanides (6), triazolyl-thiols (7) and triazolyl-disulfides (8) was purified with flash column chromatography (20% EtOAc
9936 | Org. Biomol. Chem., 2019, 17, 9933–9941
This journal is © The Royal Society of Chemistry 2019

View Article Online
Organic & Biomolecular Chemistry
Paper
in petroleum ether) to give the pure product 3a (46 mg, 78%)
as a yellow oil.
1-Benzyl-4-thiocyanato-5-(m-tolyl)-1H-1,2,3-triazole (3h). 45 mg,
1
74% yield, yellow oil. H NMR (400 MHz, CDCl , TMS):
3
1
-Benzyl-4-thiocyanato-5-phenyl-1H-1,2,3-triazole (3a). 45 mg, δ 7.45–7.38 (m, 2H), 7.33–7.31 (m, 3H), 7.10–7.07 (m, 3H), 7.02
1
13
7
8% yield, yellow oil. H NMR (400 MHz, CDCl
3 3
, TMS): (s, 1H), 5.49 (s, 2H), 2.40 (s, 3H). C NMR (100 MHz, CDCl ):
δ 7.56–7.49 (m, 3H), 7.28–7.22 (m, 5H), 7.04–7.02 (m, 2H), 5.47 δ 142.4, 139.3, 134.3, 131.7, 130.2, 129.2, 129.0, 128.7, 127.7,
1
3
(
1
s, 2H). C NMR (100 MHz, CDCl
3
): δ 142.2, 134.1, 130.9, 126.6, 126.3, 124.1, 109.3, 53.2, 21.3. HRMS (ESI-TOF) m/z
+
29.6, 129.4, 129.0, 128.7, 127.6, 126.4, 124.2, 109.2, 53.2. calcd for C17
HRMS (ESI-TOF) m/z calcd for C H N S (M + Na) 315.0674,
found 315.0680.
H
14
N
4
S (M + Na) 329.0832, found 329.0836.
+
1-Benzyl-4-thiocyanato-5-(2-methoxyphenyl)-1H-1,2,3-triazole
1
6
12 4
1
3
(3i). 41 mg, 63% yield, yellow oil. H NMR (400 MHz, CDCl ,
1
-Benzyl-4-thiocyanato-5-(4-methoxyphenyl)-1H-1,2,3-triazole TMS): δ 7.57–7.53 (m, 1H), 7.28–7.25 (m, 3H), 7.08 (d, J =
1
13
(
3b). 48 mg, 75% yield, yellow oil. H NMR (400 MHz, CDCl , 4.0 Hz, 2H), 7.04–7.00 (m, 3H), 5.43 (s, 2H), 3.71 (s, 3H).
C
3
3
TMS): δ 7.33–7.31 (m, 3H), 7.20 (d, J = 8.0 Hz, 2H), 7.10–7.08 NMR (100 MHz, CDCl ): δ 157.1, 139.2, 134.1, 132.8, 131.2,
1
3
(
m, 2H), 7.04 (d, J = 8.0 Hz, 2H), 5.49 (s, 2H), 3.90 (s, 3H).
C
128.7, 128.4, 127.8, 127.3, 121.0, 113.0, 111.4, 109.1, 55.5, 53.5.
+
NMR (100 MHz, CDCl ): δ 161.5, 142.2, 134.3, 131.0, 129.0, HRMS (ESI-TOF) m/z calcd for C H N OS (M + Na) 345.0781,
3
17 14 4
1
28.7, 127.5, 126.2, 115.9, 114.9, 109.4, 55.5, 53.1. HRMS found 345.0783.
+
(ESI-TOF) m/z calcd for C17
H
14
N
4
OS (M + Na) 345.0781, found
1-(4-Methoxybenzyl)-4-thiocyanato-5-phenyl-1H-1,2,3-triazole
1
3
45.0784.
(3j). 42 mg, 65% yield, yellow solid, mp = 90–92 °C. H NMR
1
-Benzyl-4-thiocyanato-5-(p-tolyl)-1H-1,2,3-triazole (3c). 43 mg, (400 MHz, CDCl
3
, TMS): δ 7.63–7.54 (m, 3H), 7.28 (d, J =
1
7
1% yield, yellow oil. H NMR (400 MHz, CDCl , TMS): 4.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 2H),
δ 7.36–7.32 (m, 5H), 7.17 (d, J = 8.0 Hz, 2H), 7.11–7.08 (m, 2H), 5.44 (s, 2H), 3.80 (s, 3H). C NMR (100 MHz, CDCl ): δ 159.9,
.49 (s, 2H), 2.48 (s, 3H). C NMR (100 MHz, CDCl ): δ 142.3, 142.0, 130.9, 129.6, 129.4, 129.2, 126.4, 126.1, 124.4, 114.3,
3
41.3, 134.3, 130.1, 129.4, 129.0, 128.7, 127.6, 126.3, 121.2, 109.2, 55.3, 52.8. HRMS (ESI-TOF) m/z calcd for C17
09.3, 53.1, 21.5. HRMS (ESI-TOF) m/z calcd for C H N S (M + Na) 345.0781, found 345.0783.
M + Na) 329.0831, found 329.0836.
3
13
3
1
3
5
1
1
H
14
N
4
OS
+
1
7
14 4
+
(
1-(4-Methylbenzyl)-4-thiocyanato-5-phenyl-1H-1,2,3-triazole
1
1-Benzyl-4-thiocyanato-5-(4-ethylphenyl)-1H-1,2,3-triazole (3d). (3k). 42 mg, 69% yield, yellow oil. H NMR (400 MHz, CDCl ,
3
1
4
7 mg, 74% yield, yellow oil. H NMR (400 MHz, CDCl , TMS): TMS): δ 7.60–7.53 (m, 3H), 7.27 (d, J = 4.0 Hz, 2H), 7.11 (d, d,
3
1
δ H NMR (400 MHz, CDCl
3
, TMS): δ 7.37 (d, J = 8.0 Hz, 2H), J = 8.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 5.46 (s, 2H), 2.34 (s,
1
3
7
5
.32–7.28 (m, 3H), 7.19 (d, J = 8.0 Hz, 2H), 7.11–7.08 (m, 2H), 3H). C NMR (100 MHz, CDCl
.50 (s, 2H), 2.75 (q, J = 8.0 Hz, 2H), 1.33 (t, J = 8.0 Hz, 3H).
NMR (100 MHz, CDCl
3
): δ 142.1, 138.7, 131.1, 130.9,
1
3
C
129.7, 129.6, 129.3, 127.6, 126.3, 124.3, 109.2, 53.0, 21.1.
+
3 14 4
): δ 147.4, 142.4, 134.3, 129.5, 129.0, HRMS (ESI-TOF) m/z calcd for C17H N S (M + Na) 329.0831,
1
28.9, 128.7, 127.6, 126.2, 121.3, 109.3, 53.1, 28.8, 15.2. HRMS found 329.0834.
+
(ESI-TOF) m/z calcd for C H N S (M + Na) 343.0988, found
1-(4-Chlorobenzyl)-4-thiocyanato-5-phenyl-1H-1,2,3-triazole
1
8
16 4
1
3
43.0990.
(3l). 48 mg, 74% yield, yellow solid, mp = 103–105 °C. H NMR
1
3
-Benzyl-4-thiocyanato-5-(4-(tert-butyl)phenyl)-1H-1,2,3-tri- (400 MHz, CDCl , TMS): δ 7.63–7.54 (m, 3H), 7.28 (d, J = 8.0
1
13
azole (3e). 53 mg, 76% yield, yellow oil. H NMR (400 MHz, Hz, 4H), 7.01 (d, J = 8.0 Hz, 2H), 5.47 (s, 2H). C NMR
CDCl , TMS): δ 7.92 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), (100 MHz, CDCl ): δ 142.1, 134.9, 132.5, 121.1, 129.5, 129.5,
.43–7.37 (m, 5H), 5.81 (s, 2H), 1.39 (s, 9H). C NMR 129.2, 129.1, 126.6, 124.1, 109.1, 52.5. HRMS (ESI-TOF) m/z
3
3
1
3
7
(
+
100 MHz, CDCl ): δ 153.0, 152.0, 133.5, 129.3, 129.1, 127.9, calcd for C H ClN S (M + Na) 349.0285, found 349.0285.
3
16 11
4
1
27.4, 126.0, 125.6, 112.0, 106.4, 53.5, 34.9, 31.2. HRMS (ESI-TOF)
4-Thiocyanato-5-phenyl-1-(2,3,4,5-tetrahydro-[1,1′-biphenyl]-
2-yl)-1H-1,2,3-triazole (3m). 49 mg, 68% yield, brown oil. H
+
1
m/z calcd for C20
20 4
H N S (M + H) 349.1481, found 349.1484.
1
-Benzyl-4-thiocyanato-5-(4-bromophenyl)-1H-1,2,3-triazole NMR (400 MHz, CDCl , TMS): δ 7.64–7.61 (m, 3H), 7.24–7.19
3
1
(
3f). 57 mg, 77% yield, yellow solid, mp = 102–104 °C. H NMR (m, 5H), 6.95–6.92 (m, 2H), 6.28 (t, J = 4.0 Hz, 1H), 5.38 (s, 1H),
(
400 MHz, CDCl
3
, TMS): δ 7.67 (d, J = 12.0 Hz, 2H), 7.33–7.31 2.52–2.45 (m, 1H), 2.27–2.22 (m, 3H), 2.16–2.10 (m, 1H),
1
3
(m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 7.08–7.06 (m, 2H), 5.50 (s, 1.82–1.78 (m, 1H). C NMR (100 MHz, CDCl ): δ 142.2, 139.2,
3
13
2
H). C NMR (100 MHz, CDCl
3
): δ 141.1, 134.0, 132.7, 131.1, 134.4, 132.3, 130.8, 129.7, 129.4, 128.4, 127.5, 126.3, 125.5,
1
29.1, 128.9, 127.5, 126.7, 125.7, 123.1, 109.0, 53.4. HRMS 124.8, 109.3, 56.5, 31.0, 25.3, 18.2. HRMS (ESI-TOF) m/z calcd
+
+
(ESI-TOF) m/z calcd for C H BrN S (M + Na) 392.9780, for C H N S (M + Na) 381.1144, found 381.1147.
16 11 4 21 18 4
found 392.9782.
1,5-Diphenyl-4-thiocyanato-1H-1,2,3-triazole (3n). 22 mg,
1
1
-Benzyl-4-thiocyanato-5-(4-chlorophenyl)-1H-1,2,3-triazole 40% yield, yellow solid, mp = 168–170 °C. H NMR (400 MHz,
1
(3g). 44 mg, 68% yield, yellow solid, mp = 161–163 °C. H NMR CDCl , TMS): δ 8.06 (d, J = 4.0 Hz, 2H), 7.70–7.65 (m, 5H),
3
1
3
(400 MHz, CDCl
3 3
, TMS): δ 7.52 (d, J = 8.0 Hz, 2H), 7.34–7.31 7.60–7.54 (m, 3H). C NMR (100 MHz, CDCl ): δ 151.9, 135.0,
(
2
m, 3H), 7.19 (d, J = 8.0 Hz, 2H), 7.08–7.06 (m, 2H), 5.50 (s, 131.9, 130.9, 129.9, 129.1, 128.4, 127.9, 125.9, 113.8, 107.1.
13
+
H). C NMR (100 MHz, CDCl ): δ 141.1, 137.5, 133.9, 130.9, HRMS (ESI-TOF) m/z calcd for C H N S (M + H) 279.0698,
3
15 10 4
1
29.8, 129.1, 128.9, 127.5, 126.8, 122.6, 109.0, 53.4. HRMS found 279.0703.
+
(ESI-TOF) m/z calcd for C16
H
11ClN
4
S (M + Na) 349.0285,
Methyl 4-(4-thiocyanato-5-phenyl-1H-1,2,3-triazol-1-yl)benzo-
1
found 349.0286.
ate (3o). 30 mg, 44% yield, yellow oil. H NMR (400 MHz,
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 9933–9941 | 9937

View Article Online
Paper
Organic & Biomolecular Chemistry
CDCl
3
, TMS): δ 8.12 (d, J = 8.0 Hz, 2H), 7.55–7.48 (m, 3H), 7.43 THF (13 mL) was added BnN
3
2a (1.30 g, 9.8 mmol, 1.5 equiv.).
1
3
(d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 3.96 (s, 3H).
C
The mixture was stirred at 80 °C for 48 h. Then, MeMgBr 4a
NMR (100 MHz, CDCl
3
): δ 165.6, 141.6, 139.1, 131.4, 131.0, (4.33 mL, 3.0 M, 2 equiv.) was added to the mixture at 0 °C.
1
29.6, 129.5, 127.3, 124.6, 124.0, 108.9, 52.6. HRMS (ESI-TOF) The mixture was warmed to rt and stirred for 24 h. The
+
m/z calcd for C H N O S (M + Na) 359.0573, found mixture was quenched with a saturated aqueous NH Cl solu-
1
7
12
4
2
4
3
59.0575.
-Phenethyl-4-thiocyanato-5-phenyl-1H-1,2,3-triazole
tion (50 mL) and then extracted with DCM (3 × 50 mL). The
1
(3p). organic phase was washed with brine, dried over Na
8 mg, 79% yield, brown solid, mp = 89–91 °C. H NMR concentrated in vacuo. The mixture was purified with flash
, TMS): δ 7.55–7.46 (m, 3H), 7.25–7.23 (m, column chromatography (20% EtOAc in petroleum ether) to
H), 6.99 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 4.52 (t, J = give the pure product 5a (1.21 g, 66%) as a colorless oil.
2 4
SO and
1
4
(400 MHz, CDCl
3
3
8
1
3
.0 Hz, 2H), 3.20 (t, J = 8.0 Hz, 2H). C NMR (100 MHz,
): δ 142.7, 136.4, 130.7, 129.3, 129.3, 128.9, 128.7, 127.3,
25.8, 124.1, 109.4, 50.7, 36.3. HRMS (ESI-TOF) m/z calcd for
Representative procedure for the solid-phase synthesis of fully
substituted 4-thio-1,2,3-triazoles
CDCl
3
1
+
C H N S (M + H) 307.1012, found 307.1017.
To a vial containing (thiocyanatoethynyl)benzene 1a (96 mg,
1
7
14 4
2
4 6
-(4-(4-Thiocyanato-5-phenyl-1H-1,2,3-triazol-1-yl)butyl)iso- 0.6 mmol) in THF (2 mL) was added Cu(MeCN) PF (22.8 mg,
1
indoline-1,3-dione (3q). 65 mg, 81% yield, yellow oil. H NMR 10 mol%) and azidomethyl polystyrene 2s (500 mg, f =
1
(
(
4
2
1
1
400 MHz, CDCl , TMS): δ 7.84 (dd, J = 8.0, 4.0 Hz, 2H), 7.74 1.20 mmol g− , 0.6 mmol) and the mixture was shaken at
3
dd, J = 8.0, 4.0 Hz, 2H), 7.59–7.57 (m, 3H), 7.41–7.39 (m, 2H), 80 °C. The reaction was monitored by IR. When the azide
.37 (t, J = 8.0 Hz, 2H), 3.64 (t, J = 8.0 Hz, 2H), 1.92–1.85 (m, band (∼2100 cm− ) was disappeared (24 h), the mixture was
1
1
3
H), 1.70–1.63 (m, 2H). C NMR (100 MHz, CDCl ): δ 168.3, cooled to 0 °C. MeMgBr (0.4 mL, 3.0 M, 2 equiv.) was added to
41.9, 134.1, 131.9, 130.9, 129.6, 129.4, 126.1, 124.3, 123.3, the mixture at 0 °C. The mixture was warmed to rt and stirred
09.2, 48.8, 36.8, 26.9, 25.4. HRMS (ESI-TOF) m/z calcd for for 12 h. The solid was filtered off, washed with THF (20 mL),
3
+
C H N O S (M + Na) 426.0995, found 426.0996.
H O (20 mL), H O–MeOH (20 mL), MeOH (20 mL), MeOH–
2
1
17
5
2
2
2
(
2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(5-phenyl-4-thiocyanato- CHCl
3
3
(1 : 1) (20 mL) and CHCl (20 mL), and dried in vacuo at
1
H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 40 °C for 24 h to afford yellow resin 1-benzyl-4-phenyl-5-
1
(3r). 76 mg, 71% yield, yellow oil. H NMR (400 MHz, CDCl , (methylthio)-1H-1,2,3-triazole on polymer support 5s (598 mg).
3
TMS): δ 7.68–7.61 (m, 3H), 7.56 (d, J = 8.0 Hz, 2H), 5.86 (t, J = Elemental analysis (%) = C, 84.47; H, 7.02; N, 4.58 ( f =
.0 Hz, 1H), 5.59 (d, J = 8.0 Hz, 1H), 5.32–5.27 (m, 1H), 5.15 (t, 1.09 mmol g− ).
1
8
J = 8.0 Hz, 1H), 4.27–4.22 (m, 1H), 4.19–4.12 (m, 1H), 3.89–3.85 1-Benzyl-4-(methylthio)-5-phenyl-1H-1,2,3-triazole (5a). 39 mg,
1
3
1
(m, 1H), 2.14 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.89 (s, 3H).
C
70% yield, colorless oil. H NMR (400 MHz, CDCl
3
, TMS):
NMR (100 MHz, CDCl
3
): δ 170.4, 170.2, 169.2, 168.3, 143.4, δ 7.47–7.45 (m, 3H), 7.29–7.27 (m, 3H), 7.25–7.23(m, 2H),
1
3
1
6
C
31.5, 129.9, 129.4, 126.5, 123.3, 108.7, 84.5, 75.0, 73.0, 69.2, 7.08–7.06 (m, 2H), 5.49 (s, 2H), 2.51 (s, 3H). C NMR
7.4, 61.7, 20.7, 20.5, 20.3. HRMS (ESI-TOF) m/z calcd for (100 MHz, CDCl ): δ 140.0, 136.6, 135.2, 129.6, 129.5, 128.9,
3
+
23
H
24
N
4
O
9
S (M + Na) 555.1156, found 555.1160.
128.8, 128.2, 127.4, 126.4, 52.5, 17.2. HRMS (ESI-TOF) m/z
+
calcd for C H N S (M + H) 282.1059, found 282.1064.
1
6
15 3
Representative procedure for the cascade click/nucleophilic
substitution reaction to access fully substituted 4-thio-1,2,3-
triazoles
1
-Benzyl-4-(ethylthio)-5-phenyl-1H-1,2,3-triazole (5b). 40 mg,
1
6
7% yield, yellow oil. H NMR (400 MHz, CDCl
3
, TMS):
δ 7.47–7.45 (m, 3H), 7.29–7.27 (m, 3H), 7.24–7.22 (m, 2H),
To a vial containing (thiocyanatoethynyl)benzene 1a (32 mg, 7.07–7.05 (m, 2H), 5.48 (s, 2H), 2.94 (q, J = 8.0 Hz, 2H), 1.25 (t,
.2 mmol, 1 equiv.) in THF (0.4 mL) and Cu(MeCN) PF J = 8.0 Hz, 3H). Compound 5b is a known compound, and the
3.8 mg, 5 mol%) was added BnN3 2a (40 mg, 0.3 mmol, proton spectrum is fully consistent with the reported
0
4
6
(
1
1
6
.5 equiv.). The mixture was stirred at 80 °C for 24 h. Then, the literature.
1-Benzyl-4-(propylthio)-5-phenyl-1H-1,2,3-triazole (5c). 42 mg,
mixture was cooled to 0 °C. MeMgBr 4a (0.13 mL, 3.0 M, 2
equiv.) was added to the mixture at 0 °C. The mixture was 68% yield, yellow oil. H NMR (400 MHz, CDCl , TMS):
1
3
warmed to rt and stirred for 12 h. The mixture was quenched δ 7.47–7.45 (m, 3H), 7.29–7.27 (m, 3H), 7.24–7.22 (m, 2H),
with a saturated aqueous NH
extracted with DCM (3 × 4 mL). The organic phase was washed 1.63–1.56 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H). C NMR (100 MHz,
with brine, dried over Na SO and concentrated in vacuo. The CDCl ): δ 138.9, 137.9, 135.2, 129.7, 129.6, 128.8, 128.8, 128.2,
4
Cl solution (2 mL) and then 7.07–7.04 (m, 2H), 5.48 (s, 2H), 2.90 (q, J = 8.0 Hz, 2H),
1
3
2
4
3
mixture was purified with flash column chromatography (20% 127.4, 126.5, 52.5, 36.7, 23.0, 13.1. HRMS (ESI-TOF) m/z calcd
+
EtOAc in petroleum ether) to give the pure product 5a (39 mg, for C H N S (M + Na) 332.1192, found 332.1193.
1
8
19 3
7
0%) as a colorless oil.
1-Benzyl-4-(isopropylthio)-5-phenyl-1H-1,2,3-triazole
(5d).
5 mg, 56% yield, yellow solid, mp = 53–55 °C. H NMR
400 MHz, CDCl , TMS): δ 7.47–7.44 (m, 3H), 7.29–7.27 (m,
1
3
(
Representative procedure for the gram-scale preparation of fully
substituted 4-thio-1,2,3-triazoles
3
3
H), 7.23–7.21 (m, 2H), 7.06–7.03 (m, 2H), 5.48 (s, 2H),
1
3
To a flask containing (thiocyanatoethynyl)benzene 1a (1.03 g, 3.43–2.38 (m, 1H), 1.21 (d, J = 8.0 Hz, 6H). C NMR (100 MHz,
.5 mmol, 1 equiv.) and Cu(MeCN) PF (121 mg, 5 mol%) in CDCl ): δ 139.4, 138.1, 135.2, 129.8, 129.6, 128.8, 128.8, 128.2,
6
4
6
3
9938 | Org. Biomol. Chem., 2019, 17, 9933–9941
This journal is © The Royal Society of Chemistry 2019

View Article Online
Organic & Biomolecular Chemistry
Paper
1
27.3, 126.6, 52.6, 39.2, 23.3. HRMS (ESI-TOF) m/z calcd for equiv.) in DCM at 0 °C. The mixture was stirred at 0 °C for 1 h.
+
C H N S (M + Na) 332.1192, found 332.1193.
Then, 3a (29 mg, 0.1 mmol, 1 equiv.) in DCM was added to the
1
8
19 3
1
-Benzyl-4-(cyclopropylthio)-5-phenyl-1H-1,2,3-triazole (5e). mixture. The mixture was stirred at 60 °C overnight. When the
1
3
4 mg, 55% yield, colorless oil. H NMR (400 MHz, CDCl
3
,
reaction was completed as determined by TLC, the mixture
TMS): δ 7.47–7.44 (m, 3H), 7.29–7.27 (m, 3H), 7.24–7.22 (m, was quenched with water in 0 °C and then extracted with DCM
2
0
H), 7.07–7.05 (m, 2H), 5.48 (s, 2H), 2.23–2.18 (m, 1H), (3 × 4 mL). The organic phase was washed with brine, dried
.82–0.79 (m, 2H), 0.62–0.58 (m, 2H). C NMR (100 MHz, over Na SO and concentrated in vacuo. The mixture was puri-
2 4
1
3
CDCl ): δ 139.6, 138.5, 135.2, 129.8, 129.7, 128.8, 128.8, 128.2, fied with flash column chromatography (50% EtOAc in pet-
3
1
C
27.5, 126.6, 52.6, 15.2, 8.5. HRMS (ESI-TOF) m/z calcd for roleum ether) to give the pure product 6a (16 mg, 51%) as a
+
18
H
17
N
3
S (M + Na) 330.1035, found 330.1038.
colorless oil.
1
-Benzyl-4-(cyclopentylthio)-5-phenyl-1H-1,2,3-triazole (5f).
1-Benzyl-5-phenyl-1H-1,2,3-triazole-4-sulfinyl cyanide (6a).
1
1
4
2 mg, 63% yield, colorless oil. H NMR (400 MHz, CDCl
3
,
16 mg, 51% yield, colorless oil. H NMR (400 MHz, CDCl
3
,
TMS): δ 7.47–7.43 (m, 3H), 7.28–7.26 (m, 3H), 7.24–7.22 (m, 2H), TMS): δ 7.69–7.67 (m, 1H), 7.62 (t, J = 8.0 Hz, 2H), 7.40–7.38
1
3
7
2
.06–7.04 (m, 2H), 5.48 (s, 2H), 3.61–3.58 (m, 1H), 1.95–1.90 (m, (m, 2H), 7.36–7.34 (m, 3H), 7.15–7.13 (m, 2H), 5.30 (s, 2H).
H), 1.70–1.65 (m, 2H), 1.57–1.50 (m, 4H). C NMR (100 MHz, NMR (125 MHz, CDCl
C
1
3
3
): δ 143.3, 133.1, 132.3, 132.0, 129.7,
CDCl
3
): δ 139.1, 138.7, 135.3, 129.8, 129.6, 128.8, 128.2, 127.4, 129.6, 129.2, 127.9, 123.1, 112.8, 106.6, 53.6. HRMS (ESI-TOF)
+
1
26.6, 52.6, 47.4, 33.5, 24.5. HRMS (ESI-TOF) m/z calcd for m/z calcd for C H N OS (M + Na) 331.0630, found 331.0640.
16 12 4
+
C H
20 21
N
3
S (M + Na) 358.1348, found 358.1352.
Representative procedure for the synthesis of fully substituted
4-thiol-1,2,3-triazoles
1
-Benzyl-4-(benzylthio)-5-phenyl-1H-1,2,3-triazole (5g). 50 mg,
1
7
0% yield, yellow solid, mp = 88–90 °C. H NMR (400 MHz,
CDCl
3
, TMS): δ 7.39 (t, J = 8.0 Hz, 1H), 7.32–7.28 (m, 5H), To a vial containing (thiocyanatoethynyl)benzene 1a (32 mg,
PF
d, J = 8.0 Hz, 2H), 5.41 (s, 2H), 4.09 (s, 2H). C NMR (3.8 mg, 5 mol%) was added BnN3 2a (40 mg, 0.3 mmol,
100 MHz, CDCl ): δ 139.7, 137.6, 137.5, 135.3, 129.6, 129.5, 1.5 equiv.). The mixture was stirred at 80 °C for 24 h. Then, the
29.0, 128.7, 128.5, 128.3, 128.2, 127.2, 127.0, 126.0, 52.4, 39.6. mixture was cooled to 0 °C. LiAlH (7.6 mg, 0.2 mmol, 1
HRMS (ESI-TOF) m/z calcd for C H N S (M + Na) 380.1192, equiv.) was added to the mixture at 0 °C. The mixture was
7
.17–7.12 (m, 3H), 7.05–7.03 (m, 2H), 6.98–6.95 (m, 2H), 6.77 0.2 mmol, 1 equiv.) in THF (0.4 mL) and Cu(MeCN)
4
6
1
3
(
(
1
3
4
+
2
2
19 3
found 380.1195.
warmed to rt and stirred for 12 h. The mixture was quenched
1
-Benzyl-5-phenyl-4-(phenylthio)-1H-1,2,3-triazole (5h). 49 mg, with water (2 mL) and then extracted with DCM (3 × 4 mL).
1
7
2% yield, yellow solid, mp = 119–121 °C. H NMR (400 MHz, The organic phase was washed with brine, dried over Na SO
2 4
3
CDCl , TMS): δ 7.48–7.44 (m, 1H), 7.42–7.38 (t, J = 8.0 Hz, 2H), and concentrated in vacuo. The mixture was purified with flash
7
7
.31–7.28 (m, 3H), 7.24–7.19 (m, 4H), 7.15 (d, J = 8.0 Hz, 3H), column chromatography (10% MeOH in DCM) to give the pure
.09–7.05 (m, 2H), 5.52 (s, 2H). Compound 5h is a known com- product 7a (25 mg, 46%) as a colorless oil.
pound, and the proton spectrum is fully consistent with the
reported literature.
1-Benzyl-5-phenyl-1H-1,2,3-triazole-4-thiol (7a). 25 mg, 46%
1
6
1
yield, colorless oil.
3
H NMR (400 MHz, CDCl , TMS):
1
-Benzyl-4-((4-chlorophenyl)thio)-5-phenyl-1H-1,2,3-triazole δ 7.44–7.40 (m, 1H), 7.34 (t, J = 8.0 Hz, 2H), 7.29–7.26 (m, 3H),
1
13
(
(
2
7
5i). 56 mg, 74% yield, white solid, mp = 99–101 °C. H NMR 7.07–7.05 (m, 2H), 7.02–7.00 (m, 2H), 5.39 (s, 2H). C NMR
400 MHz, CDCl , TMS): δ 7.52–7.46 (m, 1H), 7.42 (t, J = 8.0 Hz, (100 MHz, CDCl ): δ 141.2, 138.8, 134.8, 129.9, 129.7, 128.8,
H), 7.31–7.28 (m, 3H), 7.21–7.18 (m, 2H), 7.15–7.10 (m, 4H), 128.6, 128.3, 127.5, 125.7, 52.6. HRMS (ESI-TOF) m/z calcd for
3
3
1
3
+
.09–7.06 (m, 2H), 5.51 (s, 2H). C NMR (100 MHz, CDCl
3
):
15 13 3
C H N S (M + Na) 290.0724, found 290.0728.
δ 141.1, 136.1, 134.9, 134.6, 132.4, 130.0, 129.8, 129.6, 129.1,
28.9, 128.9, 128.4, 127.4, 125.8, 52.9. HRMS (ESI-TOF) m/z
calcd for C21H16ClN S (M + Na) 400.0646, found 400.0647.
3
Representative procedure for the synthesis of fully substituted
4-disulfyl-1,2,3-triazoles
1
+
1
-Benzyl-5-phenyl-4-(p-tolylthio)-1H-1,2,3-triazole (5j). 51 mg, To a vial containing thiol 7a (25 mg, 0.09 mmol, 1 equiv.) in
1
7
2% yield, white solid, mp = 84–86 °C. H NMR (400 MHz, DMSO (0.4 mL) was added NaI (40.5 mg, 0.27 mmol, 3 equiv.)
CDCl , TMS): δ 7.46–7.42 (m, 1H), 7.41 (t, J = 8.0 Hz, 2H), and TBHP (0.05 mL, 5.5 M, 3 equiv.). The mixture was stirred
.30–7.28 (m, 3H), 7.15 (d, J = 8.0 Hz, 4H), 7.08–7.06 (m, 2H), at 100 °C for 12 h. Then, the mixture was cooled and quenched
3
7
7
(
1
3
.04 (d, J = 8.0 Hz, 2H), 5.50 (s, 2H), 2.29 (s, 3H). C NMR with water (2 mL) and then extracted with EtOAc (3 × 4 mL).
): δ 140.7, 137.2, 136.5, 135.1, 132.2, 129.8, The organic phase was washed with brine, dried over Na SO
29.7, 129.7, 129.1, 128.8, 128.8, 128.3, 127.4, 126.1, 52.8, 21.0. and concentrated in vacuo. The mixture was purified with flash
100 MHz, CDCl
3
2
4
1
+
HRMS (ESI-TOF) m/z calcd for C H N S (M + H) 358.1372, column chromatography (10% MeOH in DCM) to give the pure
2
2
19 3
found 358.1375.
product 8a (19 mg, 82%) as a colorless oil.
,2-Bis(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)disulfane (8a).
1
Representative procedure for the synthesis of triazolyl
sulfinylcyanides
1
19 mg, 82% yield, white solid, mp = 92–94 °C. H NMR
(
400 MHz, CDCl , TMS): δ 7.70 (d, J = 4.0 Hz, 4H), 7.37–7.31
3
1
3
Hydrogen peroxide (30 wt% solution in water, 10 equiv.) was (m, 12H), 7.25–7.23 (m, 4H), 5.36 (s, 4H). C NMR (100 MHz,
added dropwise to a solution of trifluoroacetic anhydride (10 CDCl ): δ 150.6, 134.3, 129.2, 129.0, 128.6, 128.5, 128.1, 126.9,
3
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 9933–9941 | 9939

View Article Online
Paper
Organic & Biomolecular Chemistry
1
24.0, 52.4. HRMS (ESI-TOF) m/z calcd for
C
30
H
24
N
6
S
2
2017, 19, 2098; (d) W. Wang, Y. Lin, Y. Ma, C.-H. Tung and
Z. Xu, Org. Lett., 2018, 20, 2956.
+
(M + H) 533.1578, found 533.1580.
9
(a) Z. Chen, Z. Liu, G. Cao, H. Li and H. Ren, Adv. Synth.
Catal., 2017, 359, 202; (b) J. Xu and Q. Song, Org. Chem.
Front., 2017, 4, 938; (c) X. Yu, J. Xu, Y. Zhou and Q. Song,
Org. Chem. Front., 2018, 5, 2463; (d) F. Wu, W. Zhou,
K. Chen, W. Chen, M. Liu and H. Wu, Adv. Synth. Catal.,
Conflicts of interest
There are no conflicts to declare.
2018, 360, 2435; (e) F.-H. Cui, J. Chen, Z.-Y. Mo, S.-X. Su,
Y.-Y. Chen, X.-L. Ma, H.-T. Tang, H.-S. Wang, Y.-M. Pan and
Y.-L. Xu, Org. Lett., 2018, 20, 925; (f) Z. Zhang, Q. Zhou,
F. Ye, Y. Xia, G. Wu, M. L. Hossain, Y. Zhang and J. Wang,
Adv. Synth. Catal., 2015, 357, 2277.
Acknowledgements
This work was supported by grants from the National Natural
Science Foundation of China (21978039 and 21702025), the
Science and Technology Innovation Foundation of Dalian City
1
0 E. M. Larin and M. Lautens, Angew. Chem., Int. Ed., 2019,
8, 13438.
1 (a) W. Song and N. Zheng, Org. Lett., 2017, 19, 6200;
b) W. Song, N. Zheng, M. Li, K. Dong, J. Li, K. Ullah and
5
(2019J12GX029), and the Fundamental Research Funds for the
1
Central Universities (DUT18LK25).
(
Y. Zheng, Org. Lett., 2018, 20, 6705; (c) W. Song, N. Zheng,
M. Li, K. Ullah and Y. Zheng, Adv. Synth. Catal., 2018, 360,
Notes and references
2
429; (d) W. Song, N. Zheng, M. Li, J. He, J. Li, K. Dong,
K. Ullah and Y. Zheng, Adv. Synth. Catal., 2019, 361, 469.
Asian J., 2011, 6, 2696; 12 (a) L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams,
1
For reviews, see: (a) S. G. Agalave, S. R. Maujan and
V. S. Pore, Chem.
b) P. Thirumurugan, D. Matosiuk and K. Jozwiak, Chem.
–
(
K. B. Sharpless, V. V. Fokin and G. Jia, J. Am. Chem. Soc.,
2005, 127, 15998; (b) B. C. Boren, S. Narayan,
L. K. Rasmussen, L. Zhang, H. Zhao, Z. Lin, G. Jia and
V. V. Fokin, J. Am. Chem. Soc., 2008, 130, 8923;
(c) J. R. Johansson, T. Beke-Somfai, A. S. Stalsmeden and
N. Kann, Chem. Rev., 2016, 116, 14726.
Rev., 2013, 113, 4905; (c) A. Lauria, R. Delisi, F. Mingoia,
A. Terenzi, A. Martorana, G. Barone and A. M. Almerico,
Eur. J. Org. Chem., 2014, 3289; (d) P. L. Golas and
K. Matyjaszewski, Chem. Soc. Rev., 2010, 39, 1338.
2
3
(a) R. Huisgen, Angew. Chem., Int. Ed. Engl., 1963, 2, 565;
(
b) R. Huisgen, Angew. Chem., Int. Ed. Engl., 1963, 2, 633.
13 (a) P. Destito, J. R. Couceiro, H. Faustino, F. López and
J. L. Mascareñas, Angew. Chem., Int. Ed., 2017, 56, 10766;
(b) J. Miguel-Ávila, M. Tomás-Gamasa, A. Olmos, P. J. Pérez
and J. L. Mascareñas, Chem. Sci., 2018, 9, 1947.
(a) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew.
Chem., Int. Ed., 2001, 40, 2004; (b) C. W. Tornøe,
C. Christensen and M. Meldal, J. Org. Chem., 2002, 67,
3
057; (c) V. V. Rostovtssev, L. G. Green, V. V. Fokin and 14 (a) S. Ding, G. Jia and J. Sun, Angew. Chem., Int. Ed., 2014,
K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596;
d) B. T. Worrell, J. A. Malik and V. V. Fokin, Science, 2013,
40, 457.
(a) K. Yamamoto, T. Bruun, J. Y. Kim, L. Zhang and
M. Lautens, Org. Lett., 2016, 18, 2644; (b) X. Tian, F. Yang,
D. Rasina, M. Bauer, S. Warratz, F. Ferlin, L. Vaccaro and
L. Ackermann, Chem. Commun., 2016, 52, 9777;
53, 1877; (b) Q. Luo, G. Jia, J. Sun and Z. Lin, J. Org. Chem.,
2014, 79, 11970.
(
3
15 (a) S. L. Schreiber, Science, 2000, 287, 1964;
(b) D. R. Spring, Org. Biomol. Chem., 2003, 1, 3867;
(c) M. D. Burke and S. L. Schreiber, Angew. Chem., Int. Ed.,
2004, 43, 46; (d) D. S. Tan, Nat. Chem. Biol., 2005, 1, 74;
(e) T. E. Nielsen and S. L. Schreiber, Angew. Chem., Int. Ed.,
2008, 47, 48; (f) C. J. O’Connor, H. S. G. Beckmann and
D. R. Spring, Chem. Soc. Rev., 2012, 41, 4444;
(g) T. Cañeque and R. Rodriguez, Nat. Chem., 2019, 11, 499;
(h) E. Llabani, R. W. Hicklin, H. Y. Lee, S. E. Motika,
L. A. Crawford, E. Weerapana and P. J. Hergenrother, Nat.
Chem., 2019, 11, 521.
4
(
c) S. Chuprakov, N. Chernyak, A. S. Dudnik and
V. Gevorgyan, Org. Lett., 2007, 9, 2333; (d) K. D. Yamajala,
M. Patil and S. Banerjee, J. Org. Chem., 2015, 80, 3003;
(
(
e) L. Ackermann and R. Vicente, Org. Lett., 2009, 11, 4922;
f) J. E. Hein, J. C. Tripp, L. B. Krasnova, K. B. Sharpless
and V. V. Fokin, Angew. Chem., Int. Ed., 2009, 48, 8018;
(
g) J. Deng, Y.-M. Wu and Q.-Y. Chen, Synthesis, 2005, 2730. 16 P. Huang, Q. Su, W. Dong, Y. Zhang and D. An,
5
6
L. Ackermann, H. K. Potukuchi, D. Landsberg and
R. Vicente, Org. Lett., 2008, 10, 3081.
(a) Y.-M. Wu, J. Deng, Y. Li and Q.-Y. Chen, Synthesis, 2005,
Tetrahedron, 2017, 73, 4275.
17 (a) X. Zeng, B. Chen, Z. Lu, G. B. Hammond and B. Xu,
Org. Lett., 2019, 21, 2772; (b) J. Y. See and Y. Zhao, Org.
Lett., 2018, 20, 7433; (c) T. Castanheiro, J. Suffert,
M. Donnard and M. Gulea, Chem. Soc. Rev., 2016, 45, 494;
(d) B. Bayarmagnai, C. Matheis, K. Jouvin and
L. J. Goossen, Angew. Chem., Int. Ed., 2015, 54, 5753.
1
314; (b) B. Wang, N. Liu, C. Shao, Q. Zhang, X. Wang and
Y. Hu, Adv. Synth. Catal., 2013, 355, 2564.
Q. Cai, J. Yan and K. A. Ding, Org. Lett., 2012, 14, 3332.
(a) W. Wang, X. Peng, F. Wei, C.-H. Tung and Z. Xu, Angew.
7
8
Chem., Int. Ed., 2016, 55, 649; (b) F. Wei, W. Wang, Y. Ma, 18 (a) E.-C. Liu and J. J. Topczewski, J. Am. Chem. Soc., 2019,
C.-H. Tung and Z. Xu, Chem. Commun., 2016, 52, 14188;
c) F. Wei, T. Zhou, Y. Ma, C.-H. Tung and Z. Xu, Org. Lett.,
141, 5135; (b) J. R. Alexander, A. A. Ott, E.-C. Liu and
J. J. Topczewski, Org. Lett., 2019, 21, 4355.
(
9940 | Org. Biomol. Chem., 2019, 17, 9933–9941
This journal is © The Royal Society of Chemistry 2019

View Article Online
Organic & Biomolecular Chemistry
Paper
1
9 B. L. Williamson, P. Murch, D. R. Fischer and P. J. Stang,
Synlett, 1993, 858.
0 (a) R. M. Neyyappadath, R. Chisholm, M. D. Greenhalgh,
C. Rodríguez-Escrich, M. A. Pericàs, G. Hähner and
A. D. Smith, ACS Catal., 2018, 8, 1067; (b) J. Izquierdo
and M. A. Pericàs, ACS Catal., 2016, 6, 348;
(c) A. Bastero, D. Font and M. A. Pericàs, J. Org. Chem.,
2007, 72, 2460.
2
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 9933–9941 | 9941