J. Chen, H. Yang, M. Zhang et al.
Tetrahedron Letters 65 (2021) 152755
The replacement of ammonium thiocyanate with potassium thio-
cyanate resulted in a slight decrease in yield due to its poor solu-
bility in organic solvent (Table 1, entry 6). Further increasing the
equivalent of ammonium thiocyanate did not observably improve
the yield (Table 1, entry 7). Furthermore, the results of some con-
trolled experiments showed that the reaction did not proceed
without current in air or nitrogen atmosphere (Table 1, entries 8,
1
0). Notably, the efficiency and yield of the reaction was not
affected in air under the constant current electrolysis conditions
(Table 1, entry 9).
With the optimized conditions in hand, we next turned to
explore the functional group tolerances for the thiocyanation of
imidazopyridines (Table 2). Significantly, good functional group
tolerance of imidazopyridines could be achieved. For instance,
electron effect did not affect the reactivity so much. Imidazopyridi-
nes containing electron-neutral or electron-rich substituents at
any aryl ring were transformed to the corresponding products in
good to excellent yields (Tables 2, 3a–e, p). Electron-poor func-
2
Scheme 1. Oxidative C(sp )-H thiocyanation.
2 3 3
tional groups, such as MeSO -, CN–, CF - and CH OOC–, could also
cell under controlled potential conditions, which was not
easy-operating, especially for industrial preparation (Scheme 1b).
Herein, with the aid of anodic oxidation and cathode hydrogen
evolution, the 3-thiocyanatoimidazopyridines can be furnished
under mild conditions without the usage of redox catalysts and
excess oxidants in a simple undivided cell (direct electrolysis)
be tolerated and showed moderate to good reactivity under the
present reaction conditions (Tables 2, 3f, g, h, i, q). Additionally,
the results of 3b and 3c showed that the steric effect of the thiocya-
nation reaction was not obvious. Substrates with halogen groups,
such as fluoro, chloro or bromo, furnished the desired products
in good yields, which could be further converted to other useful
functional groups (Tables 2, 3j, k, l, 3r, s, t). The naphthyl and thie-
nyl substituted substrates were abided smoothly with excellent
yields under this transformation (Tables 2, 3m and n). Interest-
ingly, the styryl substituted imidazopyridine also got an excellent
result (Tablse 2, 3o), while the di-substituted substrate was effec-
tive for thiocyanation as well (Tables 2, 3u). Moreover, 2-
phenylimidazo[1,2–a]pyrimidine was also tested and could be
transformed into the thiocyanated product with 93% yield
(Tables 2, 3v). Unfortunately, when using imidazo[1,2–a]pyridine
as the substrate, no desired product 3w was obtained under stan-
dard conditions. A reasonable explanation is that the imidazo[1,2-
a]pyridine is not easily oxidized because of its relatively high oxi-
dation potential. Notably, the selenocyanated products 3x and 3y
were obtained in moderate yield, which extended the scope of
the reaction to selenocyanation (Scheme 2). The structure of 3b
and 3r were confirmed by X-ray crystallographic analysis (see Sup-
porting Information for details).
(Scheme 1c). During the preparation of this manuscript, Wang
and coworkers have described selected examples of this transfor-
mation [15m].
To optimize the reaction conditions, 7-methyl-2-phenylimidazo
[
4
1,2–a]pyridine 1a and ammonium thiocyanate (NH SCN) 2 were
used as the model substrates in this study (Table 1). The desired
product 3a was obtained in 95% yield as the best reaction result
after investigating a series of the key reaction factors. At the same
time, H
2
can be detected by GC- TCD. The optimal condition was
À2
conducting the electrolysis at a constant current of 10 mAÁcm
at room temperature, using an undivided cell equipped with a plat-
inum plate cathode and a graphite rod anode (Table 1, entry 1).
Neither decreasing nor increasing the current would improve the
reaction yields in the condition of the same faraday efficiency
(Table 1, entries 2–3). The influence of the electrode materials
was investigated as well. From our experiment result, it seems that
the replacement of anode from graphite rod to platinum plate
leads to a tiny decrease of reaction yield (Table 1, entry 4). How-
ever, the absence of acetic acid in the reaction system lead to a sev-
ere decrease of the efficiency of thiocyanation (Table 1, entry 5).
To explore the synthetic potential of this electrochemical oxida-
2
tive C(sp )–H dehydrogenative thiocyanation, some imidazo[2,1-b]
thiazoles, such as 4a-4f, were synthesized and explored the reac-
tivity under standard conditions (Table 3). Satisfactorily, corre-
sponding thiocyanated products 5a-5f could be successfully
obtained in 60–95% yield.
Then, this thiocyanation reaction on a gram scale was also car-
ried out. When 5 mmol of 1a reacted with 10 mmol of 2, the
desired products of 3a were obtained in 85% isolated yields, with
Table 1
Optimization of conditions.[a]
2
the generation of H at the same time (Scheme 3). Thus, this result
exhibited a great potential of this electrochemical synthesis in the
construction of various biologically active imidazopyridines.
In order to gain more insight of the reaction mechanism, some
controlled experiments were designed and practiced in Scheme 4.
Interestingly, both TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxy
and triethyl phosphite P(OEt) [21b] could fully inhibit the reac-
3
tion, which suggested that the reaction probably proceeded
through a radical process.
Entry
Variation from the standard conditions
Yield (%)[b]
1
2
3
4
5
6
7
8
9
none
95
90
93
90
80
85
96
n.d.
95
n.d.
8 mA instead of 10 mA, 3 h
12 mA instead of 10 mA, 2.2
Pt(+) |Pt(-) instead of C(+) | Pt(-)
no HOAc
KSCN (2 equiv) instead of NH
NH SCN (4 equiv) instead of NH
4
4
SCN (2 equiv)
SCN (2 equiv)
4
without current
reaction in the air
without current in air
At last, to study the redox potential (Fig. 1), cyclic voltammetry
(CV) experiments of 1a and 2 were performed. Obviously, the oxi-
dation peaks of 1a and 2 were observed at 1.72 V Vs Ag/AgCl and
1
0
[a]
Standard conditions: C anode, Pt cathode, constant current = 10 mA, 1a
0.2 mmol), 2 (0.4 mmol), HOAc (0.4 mmol), CH CN (10.0 mL), room temperature,
.5 h; H was detected by gas chromatography. n.d. = not detected. Isolated yields
were showed.
1
.96 V Vs Ag/AgCl respectively. The onset potential of two sub-
(
2
3
[b]
strates are almost the same, which indicated that both 1a and 2
might be oxidized at anode under standard conditions.
2
2
Chen, Jifang
