Visible-light enabled C4-thiocyanation of pyrazoles by graphite-phase carbon nitride (g-C3N4)

Article abstract of DOI:10.1016/j.tetlet.2021.153253

Thiocyanation is an important and effective way to form C[sbnd]S bonds in organic synthetic methodology. Especially, thiocyanation of pyrazole attracts the attention of many researchers because sulfur-containing compounds are widely applied in many crucial fields such as organic materials, agrochemistry, nanotechnology, etc. Herein, we described A rapid metal- and additive-free method for C(sp²)-H thiocyanation of pyrazoles under visible light at room temperature by using a sustainable catalyst of graphite-phase carbon nitride (g-C₃N₄) and a thiocyanating agent of ammonium thiocyanate. The method presents many advantages, such as usage of eco-friendly photoredox catalyst, a wide range of substrates and a good yield of products, etc.

Full text of DOI:10.1016/j.tetlet.2021.153253

Tetrahedron Letters 77 (2021) 153253
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Visible-light enabled C4-thiocyanation of pyrazoles by graphite-phase
carbon nitride (g-C3N4)
⇑
⇑
Junyi Pan, Cheng Liu, Jianqiang Wang , Yunqiao Dai, Shengyu Wang, Cheng Guo
School of Chemistry and Molecular Engineering, Nanjing Tech University, 30 Puzhu South Road, Jiangsu, Nanjing 211816, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Thiocyanation is an important and effective way to form CAS bonds in organic synthetic methodology.
Especially, thiocyanation of pyrazole attracts the attention of many researchers because sulfur-containing
compounds are widely applied in many crucial fields such as organic materials, agrochemistry, nanotech-
nology, etc. Herein, we described A rapid metal- and additive-free method for C(sp2)-H thiocyanation of
pyrazoles under visible light at room temperature by using a sustainable catalyst of graphite-phase car-
bon nitride (g-C3N4) and a thiocyanating agent of ammonium thiocyanate. The method presents many
advantages, such as usage of eco-friendly photoredox catalyst, a wide range of substrates and a good yield
of products, etc.
Received 6 April 2021
Revised 26 May 2021
Accepted 18 June 2021
Available online 1 July 2021
Keywords:
Thiocyanation
Pyrazole
Rraphite-phase carbon nitride
Visible-light photocatalysis
Ó 2021 Elsevier Ltd. All rights reserved.
Sulfur-containing organic molecules are important structural
motifs in organic synthesis, organic materials, agrochemicals, nan-
otechnology, etc [1]. Therefore, many researchers make effort to
develop convenient methods for introducing sulfur element into
organic molecules and materials as well as pharmaceuticals. Thio-
cyanation is a popular and very useful conversion method to form
CAS bonds in organic synthesis methodology [2]. It is well known
that thiocyanate compounds can be easily converted to many
important thiol derivatives in different applications [3]. Because
of their enormous applications, numerous methods for the forma-
tion of the C-SCN bond have been developed to prepare aryl- and
heteroaryl thiocyanates, as shown in scheme 1, for example, cou-
pling of diazonium salts with metal thiocyanates under Sandmeyer
type conditions [4], cyanation of organosulfur and organometallic
compounds [5], metal-catalyzed coupling reaction with
trimethylsilylisothiocyanate (TMSNCS) or aryl halides with thio-
cyanate salts [6], thiocyanation of heteraromatics under normal
oxidative conditions (such as K2S2O8 [7], H2O2 [8], NBS [9]) and
the direct thiocyanation of CAH bonds with thiocyanates by
organic dyes under visible light [10]. However, these transforma-
tion methods usually require high temperature, strong base, result-
ing in a limited range of substrate applications. These homogenous
metals, organo-metal catalysts and organic dyes are difficult to
reuse and recycle, which is not suitable for continuous productive
process [11]. Heterogeneous carbon nitride materials as a class of
recyclable photocatalysts have been extensively applied to hydro-
gen generation, water oxidation, organic pollutants degradation,
organic synthesis, and carbon dioxide reduction [12]. To the best
of our knowledge, graphite-phase carbon nitride (g-C3N4) has not
been used in additive- and metal-free conditions for the thiocyana-
tion reactions under visible light. Moreover, it is worth mentioning
that graphite-phase carbon nitride (g-C3N4) has unique advantages
such as environmental protection, inexpensive preparation and
reusability [13].
Pyrazoles and their derivatives have attracted widespread
attentions in the fields of pharmacology and medicine because of
their interesting biological properties including antibacterial [14],
antitumor [14], cytotoxic [15], antiviral [16], antihypertensive
[17], antitubercular [18]. Although abundant methods are known
in the literature for thiocyanation of arenes, indoles, carbazoles,
pyrroles, and imidazopyridines [19], only limited methods are
known for the thiocyanation of the pyrazole moiety [20]. This
prompts us to study a direct C4-thiocyanation of pyrazoles with
commercially available and inexpensive ammonium thiocyanate
(NH4SCN) in the presence of graphite-phase carbon nitride
(g-C3N4) under visible light and with environmentally friendly
conditions.
On the basis of interest, our teams hope to directly achieve thio-
cyanation of CAH bonds without metals or any additives. Thus, we
began our study by using 1a and ammonium thiocyanate (NH4-
SCN) as model substrates (Table 1). Pleasantly, the expected thio-
cyanation product 2a was obtained with the yield of 33% by
using graphite-phase carbon nitride (g-C3N4, synthesized in SI) as
the photocatalyst under the blue LEDs at room temperature in
⇑
Corresponding authors.
E-mail addresses: jqwang@njtech.edu.cn (J. Wang), guocheng@njtech.edu.cn
(C. Guo).
https://doi.org/10.1016/j.tetlet.2021.153253
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

J. Pan, C. Liu, J. Wang et al.
Tetrahedron Letters 77 (2021) 153253
Table 2
Synthesis of 4-thiocyanato-1H-pyrazoles.
Scheme 1. Few previous works and our work of thiocyanation.
Table 1
Optimization of reaction conditions for forming product 2a.a
Entry
Catalyst
solvent
Yield (%)b
1
2
3
4
5
6
7
g-C3N4
g-C3N4
g-C3N4
g-C3N4
g-C3N4
g-C3N4
–
g-C3N4
g-C3N4
g-C3N4
DMF
DCE
1,4-Dioxane
THF
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
33
19
20
trace
15
91
trace
trace
0
8c
9d
10e
low (2k, 66%). In addition, 5-aminopyrazole compounds could also
be used in this reaction system. When both R1 and R2 were methyl,
the yield was low (2m, 63%). Then we tried to explored R1 and R2
were phenyl substituents under similar reaction conditions, the
corresponding target products 2o, 2q and 2r were obtained with
87%, 90% and 85%, respectively. To our surprise, when the substrate
was a pyrazolone compound, the reaction could still proceed
smoothly, and the corresponding compound 2s was produced in
a yield of 70%. It was worth noting that the 1-arylpyrazole skeleton
was present in drugs, antifungal compounds, and complexes with
phosphorescent properties [21]. Finally, the catalyst g-C3N4 could
be reused almost without losing activity (seen in SI).
Gram-scale applications for the present method were also per-
formed. As shown in Scheme 2, the reaction afforded the thio-
cyanated derivative in excellent yield (87%) under the standard
condition without any significant loss of reactive efficiency. Result
clearly demonstrated the potentially practical applicability of this
protocol for the thiocyanation of pyrazoles.
Probable mechanism of thiocyanation of pyrazole was deduced
by control experiments. When the reactions were performed in the
presence of radical scavengers (TEMPO), the reactions were inhib-
ited or less yield, suggesting the participation of radical species in
the transformations (Scheme 3). Then, the reactions were per-
formed in the presence of another radical scavenger 2,6-di-tert-
butyl-4-methylphenol (BHT). Expectedly, the formation of the
desired product 2a was also not observed and the SCN radical
was trapped by BHT (detected by LC-MS, seen in SI).
Finally, the reaction mechanism was proposed on the basis of
experimental results and the previously published reports [22],
as shown in Scheme 4. After the irradiation of visible light,
g-C3N4 was excited to an effective separation of the photo gener-
ated electron-hole pairs. Then, photo-generated electron reduced
oxygen to produce peroxy radical, and photo-generated hole oxi-
dized thiocyanate to generate thiocyano radical. Furthermore, the
pyrazole was attacked by the radical to generate intermediate A.
Whereafter, the intermediate compound undergoes oxidative
dehydrogenation to generate target product.
89
aReaction conditions: 1a (0.3 mmol), NH4SCN (0.9 mmol), g-C3N4 (30 mg), solvent
(4 ml), blue LED (450 nm, 0.1 W/cm2), under O2 for 48 h at room temperature.
bIsolated yield was based 1a. cUnder argon atmosphere. dIn the dark. eKSCN
(0.9 mmol) was used.
the presence of O2 atmosphere (Table 1, entry 1). With this encour-
aging result, next, we focused on the optimization of the reaction
conditions by screening this reaction in different solvents includ-
ing DEM, 1,4-dioxane, THF and toluene, but these yields were poor
(Table 1, entries 2–5). Probably, the solvents THF and 1,4-dioxane
could be reacted with superoxide to form peroxides. However,
Toluene could trap the radicals like BHT in scheme 3. Thus, these
solvents presented poor yields of product. Surprisingly, when
tested in DMSO, a good yield of 91% was obtained (Table 1, entry
6). Therefore, DMSO was used as the optimal solvent for condition
optimization. Besides, control experiments revealed that both of
the light and the photocatalyst were essential conditions for this
transformation (Table 1, entry 7 and 9). However, when O2 was
replaced with argon, almost trace product was observed, which
prove that O2 played an important role in the reaction. Finally,
using KSCN instead of NH4SCN to conduct experiments, and rela-
tively lower yield was observed (Table 1, entry 10).
With these optimized reaction conditions in hand, we then
turned our attention to check the generality and scope of this
method (Table 2). A wide variety of pyrazole derivatives with
R2 = R3 = Me and R1 = electron-withdrawing group or electron-
donating group were found suitable for thiocyanation by this
method, and the corresponding thiocyanated products were
obtained in good yields (2a-2j). Among them, when the methyl
group was connected to the meta position of the benzene ring,
the yield was the highest, and the compound 2g was produced
with a yield of 94%. When electron-withdrawing fluorine was
attached to the ortho position of the benzene ring, the yield was
2

J. Pan, C. Liu, J. Wang et al.
Tetrahedron Letters 77 (2021) 153253
Declaration of Competing Interest
Ph
N
Ph
N
g-C3N4, O2
NH4SCN
N
+
N
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
solvent
blue LED(450nm)
SCN
1.03 g
1.36 g
1.19 g
87%,
6 mmol,
18 mmol,
Scheme 2. Gram-Scale ReactionaaReaction conditions: 1a (6 mmol), NH4SCN
(18 mmol), g-C3N4 (100 mg), solvent (40 ml), blue LED (450 nm, 0.1 W/cm2),
under O2 for 72 h at room temperature.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153253.
Ph
N
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3

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