Electrochemical Oxidative C-H Thiocyanation or Selenocyanation of Imidazopyridines and Arenes

Article abstract of DOI:10.1055/a-1299-3009

Regioselective electrochemical oxidative C-H thiocyanation or selenocyanation of imidazopyridines was achieved by using an undivided electrolytic cell. Transition-metal-and oxidant-free conditions are striking features of this protocol. A library of thioc

Full text of DOI:10.1055/a-1299-3009

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–F
letter
A
en
T. Cui et al.
Letter
Synlett
Electrochemical Oxidative C–H Thiocyanation or Selenocyanation
of Imidazopyridines and Arenes
Ting Cuia
Xiaofeng Zhanga
Jun Lina,b
Zitong Zhua
Ping Liu*a,b
Peipei Sun*a
R2
N
R1
SCN
NH4SCN
N
R2
N
Pt(+)/Pt(–)
R1
R2
N
undivided cell
N
R1
KSeCN
N
SeCN
40 examples, yields 52–88%
R1 = aryl, alkyl; R2 = alkyl, halo, CN, CF3, etc.
a College of Chemistry and Materials Science, Nanjing Normal
University; Jiangsu Provincial Key Laboratory of Material Cycle
Processes and Pollution Control; Jiangsu Collaborative Innova-
tion Center of Biomedical Functional Materials, Nanjing
210023, P. R. of China
pingliu@njnu.edu.cn
b Changzhou Innovation and Development Institute, Nanjing
Normal University, Changzhou 213022, P. R. of China
sunpeipei@njnu.edu.cn
Corresponding Authors
Received: 12.09.2020
Accepted after revision: 28.10.2020
Published online: 28.10.2020
K2S2O8,17e,f (NH4)2S2O8,17g] or other reagents (I2,18a Select-
fluor,18b NCS18c), in the generation of which waste is un-
avoidable. Therefore, the preparation of organothiocyanates
by more environmentally friendly methods is still highly
desirable.
Imidazo[1,2-a]pyridine is recognized as an important
structural motif in medicinal chemistry,19 and the structur-
al modification of this heterocycle by C–H functionalization
DOI: 10.1055/a-1299-3009; Art ID: St-2020-l0500-l
Abstract Regioselective electrochemical oxidative C–H thiocyanation
or selenocyanation of imidazopyridines was achieved by using an undi-
vided electrolytic cell. Transition-metal- and oxidant-free conditions are
striking features of this protocol. A library of thiocyanated imidazopyri-
dines with a broad range of functional groups were synthesized in high
yields. This method was also applicable to the thiocyanation or seleno-
cyanation of some electron-rich arenes.
Previous work
Key words electrochemical oxidation, C–H functionalization, thiocya-
A. Hajra, 2015 21a
nation, selenocyanation, imidazopyridines, arenes
R2
R2
eosin Y
blue LED
N
N
R1
R1
+ NH4SCN
(a)
(b)
(c)
N
N
MeCN
ambient air, r.t.
SCN
Organothiocyanates (RSCN) have been used as versatile
synthetic precursors of sulfur-containing compounds, such
as thiols,1 thioethers,2 vinyl sulfides,3 disulfides,4 phospho-
nothioates,5 and sulfur-functionalized heterocycles.6 SCN
group-containing natural products, such as fasicularin and
9-thiocyanatopupukeanane have been isolated and their bi-
ological activities studied.7 In addition, organothiocyanates
are more stable than thiols and can serve as alternative pre-
cursors for gold thiolate assemblies in electrochemical anal-
ysis.8 Consequently, increasing efforts have been devoted to
developing new methods to introduce SCN groups onto or-
ganic molecules. A series of thiocyanating reagents,9 includ-
ing N-thiocyanatophthalimide,10 N-thiocyanatosuccinim-
ide,11 N-thiocyanatosaccharin,12 N-thiocyanatodibenzene-
sulfonimide,13 aroyl isothiocyanates,14 trimethylsilyl
isothiocyanate,15 and various thiocyanate salts (NH4SCN,
KSCN, NaSCN) have been used for this purpose. Among
these reagents, the cheap and readily available thiocyanate
salts have been favored in recent years.16 However, many
reactions of thiocyanate salts require the presence of stoi-
chiometric oxidants [CAN,17a oxone,17b DDQ,17c Mn(OAc)3,17d
H. Wang, 2015 21b
R2
R2
N
N
K2S2O8 (1.5 equiv)
DCE, r.t.
R1
R1
+ KSCN
N
N
SCN
B. Wang, 2016 21c
R2
R2
N
N
NCS (1.5 equiv)
EtOH, r.t.
R1
+
NaSCN
KSCN
R1
N
N
N
SCN
M.-P. Song, 2020 21d
R2
I2 (20 mol%)
PIDA (1.5 equiv)
R2
N
N
R1
R1
+
(d)
(e)
N
H2O, r.t.
SCN
R2
N
This work
R1
NH4SCN
N
R2
N
Pt(+)/Pt(–)
undivided cell
SCN
R1
R2
N
N
R1
KSeCN
N
SeCN
Scheme 1 C–H thiocyanation reactions of imidazopyridines
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
T. Cui et al.
Letter
Synlett
has received much attention in recent years.20 The direct C–
H thiocyanation of imidazo[1,2-a]pyridines has also been
studied by several groups. In 2015, Hajra and co-workers
developed a visible-light-induced C-3 thiocyanation of im-
idazo heterocycles with NH4SCN under transition-metal-
free conditions (Scheme 1a).21a Shortly after this work, an
efficient method for this reaction was realized by Wang and
co-workers using K2S2O8 and KSCN (Scheme 1b).21b In 2016,
the Wang group used a combination of NaSCN and NCS for
the C-3 thiocyanation of imidazo heterocycles (Scheme
1c).21c More recently, Song and co-workers accomplished C–
H thiocyanation and selenocyanation of imidazo heterocy-
cles with I2 and iodobenzene diacetate (PIDA) in aqueous
media (Scheme 1d).21d
of 4:1 mixtures of MeCN with MeOH, DMF, or CH2Cl2 (10
mL) as solvents showed that pure MeCN was optimal (en-
tries 1 and 9–11). Increasing the amount of NH4SCN to five
equivalents did not significantly raise the yield of 3a (entry
12). Replacing NH4SCN with KSCN slightly reduced the yield
of 3a (80%) (entry 13). In addition, when the reaction was
performed under an Ar atmosphere, 3a was obtained in a
similar yield (82%) (entry 14).
Table 1 Optimization of the Reaction Conditionsa
Pt(+)/Pt(–)
electrolyte, solvent
constant current
N
N
+
NH4SCN
N
N
r.t., 6 h
SCN
undivided cell
Electrochemical oxidation is a powerful and straightfor-
ward method in organic synthesis, because it provides ac-
cess to C–H-functionalized products without the use of oxi-
dants or other additives.22 In 2019, Lei and co-workers
demonstrated the feasibility of electrochemically induced
C–H amination,23a phosphonylation,23b sulfenylation,23c and
halogenation23d of imidazo heterocycles. In 2020, Yang,
Wang, and co-workers successfully achieved C-3 thiometh-
ylation of imidazopyridines by a three-component reaction
under electrochemical conditions.23e For electrochemical C–
H selenylation of imidazopyridines, two reports have been
published by the groups of Kim and Xu.23f,g Recently, elec-
trochemical oxidative C–H thiocyanations of ketones24a and
of ketene dithioacetals24b were also reported by the Zeng
and Wang groups, respectively. As part of our continuing ef-
forts to develop new methods for the functionalization of
imidazopyridines,25 we describe electrochemical oxidative
C–H thiocyanations or selenocyanations of imidazopyri-
dines or electron-rich arenes (Scheme 1e).
1a
2a
3a
Entry Anode/Cathode Solvent
Electrolyte
Yieldb (%)
1
2
3
4
5
6c
7
8
9
Pt(+)/Pt(–)
C(+)/Pt(–)
Pt(+)/C(–)
Pt(+)/Ni(–)
Pt(+)/Fe(–)
Pt(+)/Pt(–)
Pt(+)/Pt(–)
Pt(+)/Pt(–)
Pt(+)/Pt(–)
Pt(+)/Pt(–)
Pt(+)/Pt(–)
Pt(+)/Pt(–)
Pt(+)/Pt(–)
Pt(+)/Pt(–)
MeCN
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NBF4
LiClO4
89
60
54
70
40
0
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
78
60
80
81
70
90
80
82
MeCN
MeCN–MeOH (4:1)
MeCN–DMF (4:1)
MeCN–DCM (4:1)
MeCN
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NPF6
10
11
12d
13e
14f
MeCN
MeCN
We began our investigation by using 2-phenylimid-
azo[1,2-a]pyridine (1a; 0.2 mmol) as a model substrate and
NH4SCN (0.4 mmol, 2 equiv) as a thiocyanating agent in
MeCN (Table 1). Initially, the electrolysis was conducted at a
constant current (5 mA) in an undivided cell equipped with
a platinum plate anode and cathode, and containing
Bu4NPF6 (0.05 M) as an electrolyte under air. Gratifyingly,
the desired product 2-phenylimidazo[1,2-a]pyridin-3-yl
thiocyanate (3a) was obtained in 89% yield after six hours
(Table 1, entry 1). Encouraged by this result, we conducted
extensive investigations of the reaction conditions. The
electrode materials were important for this transformation.
Reactions carried out with a carbon rod as the anode or
cathode were less efficient, affording the product 3a in low-
er yields (60 and 54%; respectively) (entries 2 and 3). Re-
placement of the platinum plate cathode with a Ni or Fe
electrode with a comparable surface area also gave inferior
results (entries 4 and 5). The reaction did not proceed in
the absence of an electric current (entry 6). The supporting
electrolyte had an obvious influence on the reaction out-
come. Replacement of Bu4NPF6 by Bu4NBF4 or LiClO4
brought lower yields (entries 7 and 8). Further evaluations
a Reaction conditions: Anode (10 × 10 mm), cathode (10 × 10 mm), con-
stant current (5.0 mA), 1a (0.2 mmol), 2a (0.4 mmol, 2.0 equiv), support-
ing electrolyte (0.05 M), MeCN (10 mL), under air, r.t., 6 h, undivided cell.
b Isolated yields based on 1a.
c No electric current.
d NH4SCN (1.0 mmol, 5 equiv).
e KSCN (0.4 mmol, 2.0 equiv).
f Under Ar.
With the optimized conditions in hand, we investigated
the substrate scope and limitations of the C–H thiocyana-
tion of imidazopyridines to study the generality of this
method. Gratifyingly, a wide range of imidazo[1,2-a]pyri-
dines were suitable for this transformation (Scheme 2). We
first explored the effects of substituents on the C-2 position
of the imidazo[1,2-a]pyridine. For 2-phenylimidazo[1,2-
a]pyridines, an electron-donating methyl or methoxy group
on the para-position of the benzene ring was well tolerated
in the reaction, and the C-3 thiocyanated products 3b and
3c were produced in good yields (80 and 79%, respectively).
The presence of electron-withdrawing substituents such as
F, Cl, or CF3 also had no obvious effect to the reaction, and
satisfactory yields of 70–80% were obtained (3d–i). The re-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
T. Cui et al.
Letter
Synlett
actions of imidazo[1,2-a]pyridines substituted with 2-
naphthyl, biphenyl-4-yl-, and 2-thienyl groups proceeded
well and gave the corresponding products 3j–m in yields of
66–80%. Furthermore, unsubstituted imidazo[1,2-a]pyri-
dine (1n) and 2-methylimidazo[1,2-a]pyridine (1o) were
found to be suitable substrates, delivering the C-3 thiocya-
nated products 3n and 3o, respectively, in yields of 82 and
84%. In addition, for the reactants 1a and 1b, a chemical ox-
idation method21d gave comparable yields of 83 and 75%, re-
spectively.
MeCN (10 mL)
1
N
8
5
nBu4NPF6 (0.05 M)
N
7
6
2
R
+
NH4SCN
R
N
Pt(+)/Pt(–)
5 mA, r.t., 6 h
undivided cell
N
4
3
SCN
4
1
2a
Cl
F
CF3
N
N
N
N
N
N
SCN
SCN
SCN
4a, 77%
4b, 84%
4c, 79%
F
Cl
N
N
N
N
N
N
MeCN (10 mL)
R2
1
N
R2
8
SCN
SCN
SCN
4f, 83%
nBu4NPF6 (0.05 M)
N
7
2
R1
R1
+
NH4SCN
4d, 73%
4e, 88%
N
N
4
Pt(+)/Pt(–)
5 mA, r.t., 6 h
undivided cell
6
F3C
3
NC
N
N
5
N
N
SCN
N
N
3
1
2a
SCN
SCN
N
SCN
4i, 86%
N
N
N
OMe
4g, 76%
4h, 74%
N
N
Br
SCN
3a, 85%, 83%a
SCN
SCN
3b, 80%, 75%a
Cl
N
N
N
3c, 79%
N
Cl
N
Cl
N
F
SCN
N
N
N
N
SCN
SCN
4l, 75%
F
N
4j, 81%
N
4k, 78%
SCN
3d, 73%
SCN
SCN
3e, 70%
Scheme 3 Substrate scope of imidazopyridines. Reagents and condi-
tions: platinum plate anode (10 × 10 mm), platinum plate cathode (10 ×
10 mm), constant current (5 mA), Bu4NPF6 (0.05 M), 1 (0.2 mmol), 2a
(0.4 mmol, 2 equiv), MeCN (10 mL), air, r.t., 6 h, undivided cell.
3f, 77%
Cl
N
N
N
Cl
CF3
CF3
N
N
N
SCN
3g, 80%
SCN
3h, 76%
SCN
3i, 80%
sired products 5a and 5b in yields of 79 and 70%, respec-
tively. The fused azaheterocycles imidazo[1,2-a]quinoline
and imidazo[1,2-a]pyrazine were also found to be suitable
substrates and gave the corresponding thiocyanated prod-
ucts 5c and 5d in yields of 63 and 68%, respectively. Al-
though the thiocyanation of electron-rich arenes by elec-
trochemical synthesis has been reported previously,26 we
wondered whether these substrates were suitable for our
conditions. The results showed that arenes substituted with
N
N
N
N
N
N
SCN
SCN
SCN
3l, 80%
3j, 66%
3k, 73%
N
N
N
N
N
S
N
SCN
3o, 84%
SCN
3n, 82%
SCN
3m, 71%
Scheme 2 Substrate scope of imidazopyridines. Reagents and condi-
tions: platinum plate anode (10 × 10 mm), platinum plate cathode (10 ×
10 mm), constant current (5 mA), Bu4NPF6 (0.05 M), 1 (0.2 mmol), 2a
(0.4 mmol, 2 equiv), MeCN (10 mL), air, r.t., 6 h, undivided cell. a 1 (0.2
mmol), KSCN (0.3 mmol, 1.5 equiv), I2 (20 mol%), PIDA (0.3 mmol, 1.5
equiv), H2O (1 mL), air, r.t., 12 h.
CH3CN (10 mL)
nBu4NPF6 (0.05 M)
H
Het
1
SCN
Het
+
NH4SCN
Pt(+)/Pt(–)
5 mA, r.t., 6 h
undivided cell
2a
5
N
S
N
N
S
N
N
N
Next, we turned our attention to imidazopyridines
bearing substituents on the pyridine ring. Electronic effects
of substituents on the pyridine ring had no obvious influ-
ence on the reaction outcome. As shown in Scheme 3, elec-
tron-donating (R = Me) or electron-withdrawing (R = F, Cl,
Br, CF3, CN) functional groups were well tolerated, pro-
viding the corresponding products 4a–l in good yields
(73–88%).
The present protocol was also applicable to some other
imidazopyridines (Scheme 4). As expected, a similar pro-
cess occurred with 4-phenylimidazo[2,1-b]thiazole and 2-
phenylimidazo[2,1-b][1,3]benzothiazole, providing the de-
NCS
SCN
NCS
5b, 70%
5a, 79%
5c,63%
OMe
SCN
MeO
MeO
SCN
OMe
N
N
N
SCN
OMe
N
NCS
5d, 68%
MeO
5g, 88%
5e, 87%
5f, 72%
Scheme 4 Substrate scope of other imidazopyridines and arenes. Re-
agents and conditions: platinum plate anode (10 × 10 mm), platinum
plate cathode (10 × 10 mm), constant current (5 mA), Bu4NPF6 (0.05
M), 1 (0.2 mmol), 2a (0.4 mmol, 2 equiv), MeCN (10 mL), air, r.t., 6 h,
undivided cell.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
T. Cui et al.
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strongly electron-donating groups, including 1,3,5-trime-
thoxybenzene, 1,3,4-trimethoxybenzene, and N,N,3-
trimethylaniline, underwent electrochemical oxidative
cross-coupling with NH4SCN to give the corresponding
products 5e–g in high yields of 87, 72, and 88%, respectively.
Encouraged by the feasibility of electrochemical oxida-
tive C–H thiocyanation, we further explored the C–H sele-
nocyanation of imidazopyridines (Scheme 5). To our de-
light, various 2-phenylimidazo[1,2-a]pyridines reacted
smoothly with KSeCN under the standard conditions to
give the 3-selenocyanated products 6a–f in acceptable
yields (52–65%). The presence of methyl, halo (F or Br), or
trifluoromethyl substituents on the benzene ring had no
significant effect on the reaction.
MeCN (30 mL)
nBu4NPF6 (0.05 M)
N
N
+
NH4SCN
(a)
(b)
N
Pt(+)/Pt(–)
10 mA, r.t., 12 h
undivided cell
N
SCN
3a
1a
2a
1.26 g, 83%
12 mmol
6 mmol
N
N
N
standard conditions
TEMPO (4 equiv)
+
NH4SCN
N
SCN
3a, < 5%
1a
2a
Scheme 6 Gram-scale reaction and control experiment
MeCN (10 mL)
nBu4NPF6 (0.05 M)
H
+
KSeCN
Het
SeCN
Het
Pt(+)/Pt(–)
5 mA, r.t., 6 h
undivided cell
6
1
2b
N
N
N
F
N
N
N
SeCN
6a, 65%
SeCN
SeCN
6c, 54%
6b, 63%
N
N
N
N
Br
CF3
N
N
SeCN
6f, 59%
SeCN
SeCN
6e, 55%
6d, 52%
Scheme 5 Substrate scope for electrochemical oxidative C–H seleno-
cyanation of imidazopyridines. Reagents and conditions: platinum plate
anode (10 × 10 mm), platinum plate cathode (10 × 10 mm), constant
current (5 mA), Bu4NPF6 (0.05 M), 1 (0.2 mmol), 2b (0.4 mmol, 2
equiv), MeCN (10 mL), air, r.t., 6 h, undivided cell.
Figure 1 CV scans (scan rate: 100 mV·s–1) of substrate 1a (0.01 M) or
2a (0.01 M) in MeCN containing Bu4NPF6 (0.02 M) at a platinum-wire
electrode under air
First, a thiocyanate radical intermediate B is formed by an-
odic oxidation of the thiocyanate anion.24b Radical B is
trapped by imidazopyridine 1a to produce the radical inter-
mediate C,21 which is oxidized at the anode by single-elec-
In addition, the reaction could be easily scaled up with-
out the loss of reactivity (Scheme 6a). When the reaction
was conducted with 6 mmol of 1a and 12 mmol of 2a by
increasing the current to 10 mA and prolonging the reac-
tion time to 12 hours, the thiocyanated product 3a was ob-
tained in 83% yield (5.0 mmol, 1.26 g). To investigate the
mechanism, a control experiment was conducted involving
the addition of the radical scavenger 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO; 4 equiv) to the model reaction. The
reaction was obviously suppressed, indicating that the reac-
tion possibly proceeds by a radical pathway (Scheme 6b).
Next, cyclic voltammetry (CV) experiments were car-
ried out to study the redox potential of the substrates (Fig-
ure 1). NH4SCN (2a) had a lower oxidation potential (1.30 V
vs. SCE) than 2-phenylimidazo[1,2-a]pyridine (1a, 1.70 V
vs. SCE) in MeCN, indicating that the oxidation of NH4SCN
occurred prior to that of the imidazopyridine 1a under the
electrochemical reaction conditions.
cathode
anode
SCN
2a
1
−
H2
2
– e–
+ e–
H+
SCN
NCS
SCN
B
N
N
1a
N
N
SCN
C
– e–
N
N
N
N
– H+
Based on the above mechanistic studies and previous
reports in the literature,21,24b we proposed a radical mecha-
nism initiated by an electrochemical oxidation (Scheme 7).
SCN
SCN
D
3a
Scheme 7 Proposed mechanism
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
T. Cui et al.
Letter
Synlett
tron transfer to form the cation intermediate D. Finally,
deprotonation of cation D gives the desired product 3a.
In summary, we have developed a protocol for the elec-
trochemical oxidative C–H thiocyanation or selenocyana-
tion of imidazopyridines and electron-rich arenes.27 Cheap
and readily available NH4SCN and KSeCN are used as sourc-
es of SCN and SeCN, respectively. A broad scope of sub-
strates and a variety of functional groups are well tolerated
to give the thiocyanated or selenocyanated products in
moderate to excellent yields. This convenient method for
the synthesis of thiocyanated imidazopyridines might be
applicable in the field of pharmaceutical synthesis.
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Funding Information
This work was supported by the National Natural Science Foundation
of China (Project 21672104, 21502097) and the Priority Academic
Program Development of Jiangsu Higher Education Institutions.Natio
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1299-3009.
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

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T. Cui et al.
Letter
Synlett
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2.5 equiv), and MeCN (10 mL). The flask was equipped with two
platinum plate electrodes (10 × 10 mm) as the anode and cath-
ode, respectively. The reaction mixture was electrolyzed and
stirred at a constant current (5 mA) under air at r.t. for 6 h.
When the reaction was complete, the mixture was diluted with
H2O (30 mL) and extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic phases were dried (Na2SO4), filtered, and concen-
trated in vacuo. The resulting crude product was purified by
chromatography [silica gel, PE–EtOAc (5:1)] to give a white
solid; yield: 42.7 mg (85%); mp 115–117 °C.
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(27) 2-Phenylimidazo[1,2-a]pyridin-3-yl Thiocyanate (3a):21a
Typical Procedure
1H NMR (400 MHz, CDCl3):  = 8.48 (d, J = 6.6 Hz, 1 H), 8.08 (d,
J = 7.3 Hz, 2 H), 7.80 (d, J = 8.9 Hz, 1 H), 7.58–7.48 (m, 4 H), 7.16
(t, J = 6.7 Hz, 1 H). 13C NMR (100 MHz, CDCl3):  = 153.0, 147.9,
131.9, 129.5, 128.8, 128.8, 128.1, 124.4, 118.3, 114.5, 108.2,
94.7.
An undivided 25 mL three-necked flask was charged with 2-
phenylimidazo[1,2-a]pyridine (1a, 38.8 mg, 0.2 mmol), NH4SCN
(2a, 30.5 mg, 0.4 mmol, 2 equiv), Bu4NPF6 (194 mg, 0.5 mmol,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F