Highly Efficient and Practical Thiocyanation of Imidazopyridines Using an N-Chlorosuccinimide/NaSCN Combination

Article abstract of DOI:10.1002/ejoc.201600485

A direct C–H thiocyanation of imidazo[1,2-a]pyridines, and a practical sequential one-pot condensation/C–H thiocyanation process, using a combination of N-chlorosuccinimide/NaSCN for the synthesis of 3-thiocyanatoimidazo[1,2-a]pyridines have been develope

Full text of DOI:10.1002/ejoc.201600485

DOI: 10.1002/ejoc.201600485
Full Paper
Thiocyanation
Highly Efficient and Practical Thiocyanation of Imidazopyridines
Using an N-Chlorosuccinimide/NaSCN Combination
Hailei Zhang, Qian Wei, Shiqiang Wei, Jingping Qu, and Baomin Wang*
[
a]
[a]
[a]
[a]
[a]
Abstract: A direct C–H thiocyanation of imidazo[1,2-a]pyr- mentally friendly, and easy to carry out. They use readily avail-
idines, and a practical sequential one-pot condensation/C–H able starting materials and mild reaction conditions, show a
thiocyanation process, using a combination of N-chlorosuccin- wide functional group tolerance, and give good to excellent
imide/NaSCN for the synthesis of 3-thiocyanatoimidazo[1,2- yields.
a]pyridines have been developed. The reactions are environ-
Introduction
sulfur-containing derivatives, such as thiazolidines or cyclic thio-
[
7]
ureas. The literature on thiocyanate-substituted arenes and
Imidazo[1,2-a]pyridines are significant members of the family
of fused polyheterocycles. The great importance of these com-
pounds can be seen by their occurrence and application in sev-
eral fields, including materials science, natural products chemis-
try, and medicinal chemistry. Several imidazopyridines have
recently been reported to have remarkable therapeutic value,
[
8]
heterocycles such as indoles and pyrroles is ever growing,
however, examples of imidazo[1,2-a]pyridines and imidazo[1,2-
a]pyrimidines incorporating a thiocyanate group remain com-
paratively infrequent. In 2015, Hajra et al. developed the first
example of a direct and environmentally benign system for the
thiocyanation of imidazopyridines using eosin Y as a photore-
[
1]
showing antifungal, antibacterial, antiviral, antiparasitic, antiin-
[
9]
flammatory, antiulcer, and antiprotozoal properties.[2] Conse-
dox catalyst under ambient conditions. Subsequently, Wang's
group independently disclosed a catalyst-free highly regiose-
lective C-3 thiocyanation of imidazopyridines in the presence
quently, some products with imidazo[1,2-a]pyridine skeletons
have progressed to the market, including alpidem (anxio-
[
10]
[
3a]
[3b]
[3a]
of K S O , proceeding by a radical pathway.
2 2 8
lytic),
imidine (antiulcer),
saripidem (anxiolytic),
zolpidem (insomnia),
zol-
[
2a]
olprinone (cardiotonic),[3c] minodronic
Due to the importance of step, atom, and redox economy in
industrial and green chemistry, and especially due to the low
threshold residual tolerance in the synthesis of pharmaceuti-
[
3d]
acid (antiosteoporosis), and many others. In addition, consid-
erable attention has recently been given to some unusual pro-
ton-transfer reagents and N-heterocyclic carbenes, which are
[
11]
cals,
the exploration of efficient, practical, and highly select-
[
4]
ive metal-free methods for the direct functionalization of C–H
synthesized based on imidazo[1,2-a]pyridines.
[
12]
bonds has been the subject of intense research for decades.
The biological profile of privileged imidazo[1,2-a]pyridines
has been shown to be mainly dependent on the nature of the
substituents at the C-2 and C-3 positions; the introduction of
sulfur-containing groups onto the N-heterocyclic rings may also
impart significant biological properties. As a result, extensive
effort has been put into the discovery of efficient and practical
approaches for the synthesis and functionalization of imidazo-
One-pot sequential transformations, which represent a valuable
way of introducing complexity and diversity into industrially
and medically important compounds while avoiding the need
for the isolation of intermediates and for purification steps,
[
11d,13]
have risen to prominence.
In connection with our interest
in accessing biologically active molecules containing C–X
[
14]
[
5]
through cheap, green, and sustainable methods,
in this pa-
pyridine cores from readily available starting materials. Or-
ganic thiocyanates are an important class of sulfur-containing
organic compounds. They occur in biologically important com-
pounds such as the anticancer natural products formed by de-
glycosylation of glucosinolates derived from cruciferous vegeta-
per we report a generally applicable method for the construc-
tion of diversely SCN-substituted imidazopyridines. The method
has a broad substrate scope, gives excellent yields, and pro-
ceeds under simple reaction conditions. Notably, the use of
EtOH as a green and efficient reaction solvent to synthesize and
functionalize the imidazopyridine moiety in a one-pot conden-
sation and direct C–H functionalization process allowed us to
dispense with the use of metal salts, the preformation of imid-
azo[1,2-a]pyridines, and the exclusion of air and moisture.
[
6]
bles, but they can also be used as masked mercapto com-
pounds, or as versatile precursors for the construction of new
[
a] State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science
and Technology, Dalian University of Technology,
Dalian 116024, P. R. China
E-mail: bmwang@dlut.edu.cn
http://gs1.dlut.edu.cn/Supervisor/Front/dsxx/new/
Default.aspx?WebPageName=wangbaomin
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600485.
Results and Discussion
We began our investigation using the reaction of 2-phenylimid-
azo[1,2-a]pyridine (3a) and NaSCN as a model system. We
Eur. J. Org. Chem. 0000, 0–0
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Table 1. Optimization of reaction conditions.[a]
tested various oxidants and solvents to optimize the reaction
conditions. As summarized in Table 1, in the preliminary investi-
gation we screened various oxidants, and N-chlorosuccinimide
(
NCS) showed the best performance, giving the corresponding
product (i.e., 4aa) in 89 % yield at room temperature under air
Table 1, entry 3). Encouraged by the initial results, we tested
other common solvents, including Et O, CH Cl , DMSO, DMF,
MeOH, EtOH, and EtOAc (Table 1, entries 4–10). The best results
93 %) were obtained using EtOH and EtOAc (Table 1, entries 9
(
Yield[b] [%]
2
2
2
Entry
Oxidant (equiv.)
(2.0)
Solvent
t [h]
1
2
3
4
5
6
7
8
9
I
2
MeCN
MeCN
MeCN
6
31
88
89
trace
61
83
84
90
93
93
(
NBS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.5)
NCS (1.2)
–
0.5
0.5
6
and 10). When NaSCN was replaced by other readily available
Et
2
O
thiocyanates, such as NH SCN or KSCN, a slight decrease in the
4
CH
2
Cl
2
6
product yield was observed (Table 1, entries 11 and 12). The
influence on the reaction outcome of the amount of oxidant
was then assessed. A decrease in yield was observed when the
amount of oxidant decreased, and notably, none of the target
product was formed in the absence of NCS (Table 1, entries 13
and 14).
DMSO
DMF
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2
MeOH
EtOH
EtOAc
EtOH
EtOH
EtOH
EtOH
10
11
12
13
14
[
[
c]
92
83
67
n.r.
d]
Having established optimal reaction conditions, the general-
ity of the transformation was investigated. As outlined in
Table 2, imidazo[1,2-a]pyridine derivatives bearing a variety of
functional groups on any of the aryl rings tolerated the thio-
cyanation reaction with NaSCN, and structurally diverse prod-
6
[
a] Reaction conditions: imidazopyridine 3a (0.50 mmol), NaSCN (1.0 mmol),
oxidant, solvent (2.0 mL), open to air. [b] Isolated yield; n.r.: no reaction.
c] NH SCN (1.0 mmol) was used. [d] KSCN (1.0 mmol) was used.
[
4
Table 2. Direct thiocyanation of imidazopyridines and indoles.[a]
[
a] Reaction conditions: imidazopyridine 3 (0.5 mmol), NaSCN (1.0 mmol), NCS (0.75 mmol), EtOH (2 mL) under air. Isolated yield. [b] KSeCN was used.
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2

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ucts were formed smoothly in high yields with extremely high evaporation. They generally have increased atom efficiency and
regioselectivity. Satisfyingly, imidazopyridines bearing func- potentially lower environmental impact.[11d,13] However, to the
tional groups such as –OH, –Cl, –Br, –NO , and –CF were well best of our knowledge, there is no literature precedent for the
2
3
tolerated under the established reaction conditions and gave preparation of 3-thiocyanatoimidazopyridines by one-pot se-
the desired products in good yields (Table 2, 4ea, 4ga, 4ia, quences using commercially available α-bromo ketones and 2-
4
ag, and 4ff). In addition, steric and electronic effects were also aminopyridines as starting materials. With this in mind, our op-
assessed, and turned out to be insignificant (Table 2, 4ea, 4ia, timized reaction conditions were further validated by using
and 4ag). It is worth noting that the thiocyanation reaction of them for a sequential one-pot condensation and C–H thiocyan-
2-furyl and naphthyl-substituted imidazopyridines successfully ation procedure. 2-Pphenyl-3-thiocyanato imidazopyridine
took place under these conditions (Table 2, 4ja and 4ka). We (4aa) was obtained by the one-pot reaction in 83 % yield
were delighted to find that gratifying yields were also obtained (Table 3). The first step involves the formation of the 2-phenyl-
from imidazoheterocycles like imidazopyrimidine, imidazo[2,1- imidazo[1,2-a]pyridine core by condensation of 2-aminopyri-
b]thiazole, and benzo[d] imidazo[2,1-b]thiazole (Table 2, 4ah, dine and α-bromoacetophenone in the presence of NaHCO3;
4
ai, and 4aj). Moreover, imidazopyridine (3aa) reacted effec- this is then followed by C–H thiocyanation at C-3. In an attempt
tively with KSeCN to give the corresponding selenocyanated to expand the scope of the method, the one-pot procedure was
product in 82 % yield (Table 2, 7aa). The extension of our proto- applied to different α-bromo ketones and 2-aminopyridines,
col to the thiocyanation of indoles was also explored. Gratify- and the results are shown in Table 3. Strikingly, the reaction
ingly, indoles with functional groups like a methyl group and tolerated a variety of functional groups such as methyl, alkoxy,
an ester group also gave the thiocyanated products in excellent hydroxy, halogen, trifluoromethyl, and nitryl, and the expected
yields of 89–96 % (Table 2, 4w–4y).
products were formed exclusively in moderate to high yields
One-pot reaction sequences offer economic and environ- (Table 3, 4ba–4ia and 4ag). It is worth noting that 2-furyl and
mental benefits through eliminating the need for time-consum- naphthyl-substituted imidazopyridines as well as imidazohet-
ing intermediate work-ups, and decreasing the use of organic erocycles were compatible with our reaction conditions, and
solvents for extraction and purification, as well as energy for gave the relevant derivatives in good yields (Table 3, 4ja, 4ka,
Table 3. Thiocyanation of imidazopyridines in a sequential one-pot process.[a]
[
(
a] Reaction conditions: α-bromo ketones 1 (0.55 mmol), 2-aminopyridines 2 (0.5 mmol), NaHCO
4 mL) under air. Isolated yield.
3
(0.6 mmol), NaSCN (1.0 mmol), NCS (0.75 mmol), EtOH
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4
ah, and 4aj). By comparing with previously reported results, it
can clearly be seen that the new method significantly de-
creased the reaction time and eliminated work-up procedures
for intermediates. But above all, it also successfully eliminated
the use of detrimental solvents, and was environmentally
friendly, with a high atom economy.
Control experiments were carried out to get a better insight
into the probable mechanism, as shown in Figure 1. Firstly, 3-
chloro-2-phenylimidazo[1,2-a]pyridine (5aa), which was pre-
pared from NCS and 3aa, was treated with NaSCN (2 equiv.) in
EtOH at room temperature for a period of 8 h to determine
whether 5aa could be transformed into the final product (i.e.,
4
aa) by nucleophilic substitution (Figure 1, a). Notably, al-
though the thiocyanation reaction did occur in the presence of
NaSCN, 4aa was obtained in only 17 % yield, which indicates
that the reaction is less likely to proceed by nucleophilic substi-
tution. In a further experiment, preprepared N-thiocyanatosuc-
cinimide and 3aa were mixed in EtOH at room temperature,
and this immediately led to the formation of 4aa in 96 % yield.
This strongly suggests that direct C–H thiocyanation is com-
pletely predominant over nucleophilic substitution in the reac-
tion (Figure 1, b).
Figure 2. Proposed mechanism.
[
15]
Figure 3. Gram-scale reactions.
Conclusions
In summary, a simple, green, and versatile oxidative system for
the selective thiocyanation of imidazopyridines to give the cor-
responding thiocyanated product has been developed. The re-
action takes place in the presence of NCS using NaSCN as thio-
cyanato-transfer reagent in EtOH under mild conditions. Com-
Figure 1. Control experiments.
On the basis of the above experimental results, along with pared with reported procedures, this method is environmen-
[
15]
previously published examples,
a plausible reaction mecha- tally friendly and practical, and has the advantages of short
nism for the thiocyanation of imidazo[1,2-a]pyridines by the N- reaction times and high yields. Moreover, the use of EtOH as an
chlorosuccinimide/NaSCN combination is shown in Figure 2. In efficient solvent for the synthesis and functionalization of the
the predominant mechanism, N-thiocyanatosuccinimide is imidazo[1,2-a]pyridine moiety in a one-pot sequential conden-
formed by the reaction of NCS with NaSCN. This is followed by sation/C–H functionalization process has been shown to be reli-
regioselective electrophilic attack on the C-3 position of 3aa to able. Both transformations proceeded in good yields, and toler-
generate imidazolenium intermediate A. Loss of a proton from ated a wide range of functional groups. Last but not least, this
A gives the desired product (i.e., 4aa) and succinimide. Alterna- study paves the way for the synthesis of thiocyanated and se-
tively, but less likely, electrophilic substitution of 3aa with NCS lenocyanated imidazopyridines and other imidazo-heterocycles
results in the formation of 5aa, and then nucleophilic substitu- through the addition of NCS in EtOH. The reaction should gain
tion of 5aa with NaSCN would deliver product 4aa. Further much attention in multidisciplinary fields for the preparation of
investigations of the detailed mechanism are in progress in our potentially biologically active imidazopyridine derivatives.
laboratory.
To demonstrate the practical applicability of the one-pot
process on a larger scale, a gram-scale synthesis of 4aa was Experimental Section
attempted using this protocol. To our delight, the reaction pro-
ceeded smoothly, and the expected product (i.e., 4aa) was iso-
lated in 85 % yield (Figure 3, a). Furthermore, we also investi-
gated the selenocyanation of imidazopyridines in one pot (Fig-
fraction boiling in the 60–90 °C range. Unless otherwise noted, all
ure 3, b). Selenocyanated product 7aa was prepared in good reactions were carried out under air in oven-dried glassware with
General Remarks: Unless otherwise noted, all reagents and chemi-
cals (AR grade) were purchased from commercial suppliers and
used without further purification. Petroleum ether (PE) refers to the
yield under our developed reaction conditions.
magnetic stirring. The progress of the reactions was monitored by
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TLC (silica gel, Polygram SILG/UV 254 plates). Column chromatogra- 3-Thiocyanato-1H-indole (4w):[10] White solid (94 %). H NMR
1
1
13
phy was carried out on silica gel (100–200 mesh). H and C NMR
(400 MHz, CDCl ): δ = 8.85 (br. s, 1 H), 7.74–7.72 (m, 1 H), 7.31–7.29
3
13
spectra were recorded with a Bruker Avance II 400 MHz instrument, (m, 2 H), 7.24–7.20 (m, 2 H) ppm. C NMR (101 MHz, CDCl ): δ =
3
and 19F NMR spectra were recorded with a Bruker Avance III
71 MHz instrument. CDCl and [D ]DMSO were used for NMR spec-
136.2, 131.5, 127.7, 123.8, 121.9, 118.5, 112.9, 112.5, 91.2 ppm.
4
-Methyl-3-thiocyanato-1H-indole (4x):[16] Brown solid (96 %). 1H
3
6
2
troscopy, and tetramethylsilane was used as an internal reference.
NMR (400 MHz, CDCl ): δ = 8.50 (br. s, 1 H), 7.67 (d, J = 6.8 Hz, 1
3
Data for 1H NMR spectra are recorded as follows: chemical shift
13
H), 7.31–7.29 (m, 1 H), 7.25–7.20 (m, 2 H), 2.51 (s, 3 H) ppm.
C
(
δ, ppm), multiplicity (s singlet, d doublet, t triplet, m multiplet or
unresolved, br. broad, dd doublet of doublets), coupling constants
in Hz, integration. Data for C and F NMR spectra are reported in
terms of chemical shift (δ, ppm). HRMS (ESI) measurements were
made with an HRMS/MS instrument (LTQ Orbitrap XL TM).
NMR (101 MHz, CDCl ): δ = 142.3, 135.2, 128.7, 123.0, 121.5, 118.0,
3
112.5, 111.4, 88.5, 12.0 ppm.
1
3
19
[
16]
Ethyl 3-Thiocyanato-1H-indole-2-carboxylate (4y):
White
solid. H NMR (400 MHz, CDCl ): δ = 9.89 (br. s, 1 H), 7.91 (d, J =
1
3
8
.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.42–7.39 (m, 1 H), 7.32–7.29
General Procedure for the Direct C–H Thiocyanation of Imidazo-
pyridines: A mixture of imidazopyridine 3 (0.5 mmol) and NaSCN
1.0 mmol) was dissolved in EtOH (2.0 mL) at room temperature in
13
(
(
m, 1 H), 4.53–4.48 (m, 2 H), 1.51–1.47 (m, 3 H) ppm. C NMR
101 MHz, CDCl ): δ = 160.6, 135.6, 128.6, 128.3, 126.8, 122.7, 120.5,
3
(
112.8, 110.8, 98.4, 62.4, 14.3 ppm.
an oven-dried flask, then NCS (0.75 mmol) was added immediately.
The reaction proceeded under an air atmosphere for 0.5–1.0 h until
TLC indicated the complete consumption of starting material. The
reaction mixture was concentrated under vacuum, and the crude
product was purified by column chromatography using petroleum
ether/ethyl acetate as eluent to give the product (i.e., 4).
2
-(3-Thiocyanatoimidazo[1,2-a]pyridin-2-yl)phenol (4ea):[ Pale
9]
1
yellow solid. H NMR (400 MHz, DMSO): δ = 11.56 (s, 1 H), 8.78 (d,
J = 6.0 Hz, 1 H), 8.07 (d, J = 7.6 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H),
.68–7.64 (m, 1 H), 7.37 (d, J = 7.2 Hz, 2 H), 7.08–7.03 (m, 2 H) ppm.
C NMR (101 MHz, [D ]DMSO): δ = 157.0, 149.3, 146.1, 131.4, 129.6,
7
13
6
129.2, 125.6, 119.6, 117.4, 115.4, 110.3, 98.0 ppm.
General Procedure for the Thiocyanation of Imidazopyridines
in One-pot Process: 2-Aminopyridine (0.5 mmol), α-bromo ketone
2
-(4-Bromophenyl)-3-thiocyanatoimidazo[1,2-a]pyridine (4ga):
Pale yellow solid, m.p. 175.5–177.1 °C. H NMR (400 MHz, CDCl ):
δ = 8.42 (d, J = 6.4 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 2 H), 7.74 (d, J =
1
3
(0.55 mmol), and NaHCO3 (0.6 mmol) were dissolved in EtOH
(2.0 mL). The resulting mixture was stirred at 70 °C under air for 1–
8
(
1
.8 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 2 H), 7.49–7.45 (m, 1 H), 7.15–7.12
2
h until TLC indicated the complete consumption of starting mate-
m, 1 H) ppm. 13C NMR (101 MHz, CDCl ): δ = 151.7, 147.9, 132.0,
3
rial. When the reaction was complete, the mixture was cooled to
room temperature.
30.9, 130.2, 128.3, 124.4, 124.0, 118.3, 114.7, 107.9, 94.8 ppm.
HRMS (ESI): calcd. for C14H BrN S [M + H] 331.9680; found
+
9
3
NaSCN (1.0 mmol) and NCS (0.75 mmol) were added immediately,
and the reaction mixture was stirred under an air atmosphere for
331.9677.
2
-(3-Bromophenyl)-3-thiocyanatoimidazo[1,2-a]pyridine (4ha):
0
.5–1.0 h until TLC indicated the complete consumption of starting
1
White solid, m.p. 159.7–160.5 °C. H NMR (400 MHz, CDCl ): δ = 8.42
3
material. The resulting mixture was concentrated under vacuum,
and the crude product was purified by column chromatography
using petroleum ether/ethyl acetate as eluent to give the product
(
d, J = 6.8 Hz, 1 H), 8.22 (s, 1 H), 8.00 (d, J = 7.6 Hz, 1 H), 7.74 (d,
J = 8.8 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.49–7.45 (m, 1 H), 7.40–
.36 (m, 1 H), 7.14–7.11 (m, 1 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 151.2, 147.9, 134.0, 132.4, 131.6, 130.3, 128.3, 127.2, 124.4, 122.9,
7
(i.e., 4).
2
-Phenyl-3-thiocyanatoimidazo[1,2-a]pyridine (4aa):[9] White
118.3, 114.7, 107.8, 95.2 ppm. HRMS (ESI): calcd. for C14
H
9
BrN
3
S [M
1
+
solid. H NMR (400 MHz, CDCl ): δ = 8.41 (d, J = 4.4 Hz, 1 H), 8.06 + H] 329.9695; found 329.9700.
3
(
(
1
d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.54–7.44 (m, 4 H), 7.09
[9]
2
-(3-Nitrophenyl)-3-thiocyanatoimidazo[1,2-a]pyridine (4ia):
1
3
d, J = 5.2 Hz, 1 H) ppm. C NMR (101 MHz, CDCl ): δ = 153.0,
1
3
Yellow solid. H NMR (400 MHz, CDCl ): δ = 8.99 (s, 1 H), 8.50–8.45
m, 2 H), 8.33–8.32 (m, 1 H), 7.81 (d, J = 7.2 Hz, 1 H), 7.76–7.72 (m,
1 H), 7.57–7.53 (m, 1 H), 7.29–7.21 (m, 1 H) ppm. C NMR (101 MHz,
CDCl ): δ = 150.3, 148.6, 148.1, 134.3, 133.8, 129.8, 128.6, 124.5,
3
47.9, 132.0, 129.5, 128.8, 128.1, 124.4, 118.2, 114.4, 108.2, 94.7 ppm.
(
13
-Thiocyanato-2-(p-tolyl)imidazo[1,2-a]pyridine (4ba):[9] Pale
3
1
yellow solid. H NMR (400 MHz, CDCl ): δ = 8.40 (d, J = 4.8 Hz, 1 H),
3
3
124.0, 123.6, 118.6, 115.1, 107.3, 95.7 ppm.
7
(
(
.95 (d, J = 7.6 Hz, 2 H), 7.73 (d, J = 7.2 Hz, 1 H), 7.42 (s, 1 H), 7.32
d, J = 7.2 Hz, 2 H), 7.07 (s, 1 H), 2.42 (s, 3 H) ppm. 13C NMR
101 MHz, CDCl ): δ = 153.0, 147.8, 139.6, 129.5, 129.0, 128.7, 128.0,
[10]
2
-(Furan-2-yl)-3-thiocyanatoimidazo[1,2-a]pyridine (4ja):
1
3
White solid. H NMR (400 MHz, CDCl ): δ = 8.40 (d, J = 6.4 Hz, 1 H),
.76 (d, J = 8.8 Hz, 1 H), 7.66 (s, 1 H), 7.47–7.43 (t, 1 H), 7.23 (s, 1
H), 7.12–7.09 (t, 1 H), 6.60 (s, 1 H) ppm. C NMR (101 MHz, CDCl3):
δ = 148.1, 147.0, 144.2, 144.1, 128.3, 124.2, 118.1, 114.5, 111.9, 111.5,
3
1
24.4, 118.1, 114.3, 108.3, 94.4, 21.5 ppm.
7
13
3
-Thiocyanato-2-(m-tolyl)imidazo[1,2-a]pyridine (4ca): White
1
solid, m.p. 170.5–171.8 °C. H NMR (400 MHz, CDCl ): δ = 8.42 (d,
J = 6.8 Hz, 1 H), 7.87–7.84 (m, 2 H), 7.74 (d, J = 9.2 Hz, 1 H), 7.46–
3
107.8, 93.5 ppm.
7
.39 (m, 2 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.11–7.08 (m, 1 H), 2.46 (s, 3
2-(Naphthalen-2-yl)-3-thiocyanatoimidazo[1,2-a]pyridine (4ka):
13
Yellow solid, m.p. 138.6–141.0 °C. 1H NMR (400 MHz, CDCl ): δ =
H) ppm. C NMR (101 MHz, CDCl ): δ = 153.2, 147.9, 138.6, 131.8,
3
3
1
2
2
30.3, 129.4, 128.6, 128.0, 125.9, 124.4, 118.2, 114.4, 108.2, 94.7,
1.6 ppm. HRMS (ESI): calcd. for C H N S [M + H] 266.0746; found
66.0750.
8.53 (s, 1 H), 8.36 (d, J = 6.4 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 7.95–
7.93 (m, 2 H), 7.84 (d, J = 4.8 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.52–
+
1
5 12 3
1
3
7.50 (m, 2 H), 7.41–7.38 (m, 1 H), 7.05–7.02 (m, 1 H) ppm. C NMR
101 MHz, CDCl ): δ = 152.8, 148.0, 133.6, 133.2, 129.3, 128.7, 128.6,
(
3
2
-(4-Methoxyphenyl)-3-thiocyanatoimidazo[1,2-a]pyridine
4da):[
10]
1
128.4, 128.1, 127.8, 127.0, 126.6, 125.8, 124.4, 118.2, 114.4, 108.2,
(
Brown solid. H NMR (400 MHz, CDCl ): δ = 8.42 (d, J =
3
+
9
4.9 ppm. HRMS (ESI): calcd. for C H BrN S [M + H] 302.0746;
14 9 3
6
.4 Hz, 1 H), 8.03 (d, J = 8.8 Hz, 2 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.47–
.43 (m, 1 H), 7.12–7.04 (m, 3 H), 3.88 (s, 3 H) ppm. 13C NMR
found 302.0753.
7
(
1
101 MHz, CDCl ): δ = 160.7, 152.9, 147.9, 130.2, 127.9, 124.5, 124.3,
18.0, 114.2, 108.2, 93.7, 55.4 ppm.
8-Methyl-2-phenyl-3-thiocyanatoimidazo[1,2-a]pyridine
3
(4ac): White solid. 1H NMR (400 MHz, CDCl ): δ = 8.25 (d, J =
[9]
3
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9]
4
.4 Hz, 1 H), 8.05 (d, J = 6.0 Hz, 2 H), 7.51–7.44 (m, 3 H), 7.19 (s, 1
2-Phenyl-3-selenocyanatoimidazo[1,2-a]pyridine (7aa):[ Yellow
1
3
1
H), 6.97 (m, 1 H), 2.66 (s, 3 H) ppm. C NMR (101 MHz, CDCl ): δ = solid. H NMR (400 MHz, CDCl ): δ = 8.41 (d, J = 6.8 Hz, 1 H), 7.97–
3
3
1
1
52.5, 148.2, 132.3, 129.3, 128.9, 128.7, 128.5, 126.8, 122.1, 114.4, 7.95 (m, 2 H), 7.71 (d, J = 8.8 Hz, 1 H), 7.52–7.48 (m, 2 H), 7.46–7.40
08.4, 94.8, 16.8 ppm.
(m, 2 H), 7.09–7.05 (m, 1 H) ppm. 13C NMR (101 MHz, CDCl ): δ =
3
1
53.5, 148.5, 132.5, 129.3, 129.1, 128.6, 127.8, 125.5, 118.1, 114.2,
7
(
-Methyl-2-phenyl-3-thiocyanatoimidazo[1,2-a]pyridine
4ad):[ White solid. H NMR (400 MHz, CDCl ): δ = 8.28 (d, J =
9]
1
99.0, 93.6 ppm.
3
7
.2 Hz, 1 H), 8.04 (d, J = 7.2 Hz, 2 H), 7.53–7.43 (m, 4 H), 7.19 (s, 1
1
3
H), 6.92 (d, J = 6.8 Hz, 1 H), 2.46 (s, 3 H) ppm. C NMR (101 MHz,
Acknowledgments
CDCl ): δ = 152.9, 148.3, 139.5, 132.1, 129.3, 128.7, 123.5, 116.9,
3
1
16.7, 108.5, 93.7, 21.5 ppm.
The authors thank the National Natural Science Foundation of
China (grant numbers 21542007, 21076035), the Program for
New Century Excellent Talents in University (NCET-11-0053), and
the Fundamental Research Funds of the Central Universities
6
-Chloro-2-phenyl-3-thiocyanatoimidazo[1,2-a]pyridine
3af):[
10]
1
(
White solid. H NMR (400 MHz, CDCl ): δ = 8.43 (s, 1 H),
3
8
.02 (d, J = 6.8 Hz, 2 H), 7.65 (d, J = 8.8 Hz, 1 H), 7.51–7.38 (m, 4 H)
13
ppm. C NMR (101 MHz, CDCl ): δ = 153.5, 146.3, 131.5, 129.7, (DUT15TD25) for their support of this work.
3
1
29.5, 128.8, 128.7, 122.9, 122.5, 118.6, 107.8, 95.7 ppm.
2
-Phenyl-3-thiocyanato-6-(trifluoromethyl)imidazo[1,2-a]pyr- Keywords: Synthetic methods · Aromatic substitution ·
1
idine (4ag): White solid, m.p. 172.3–174.8 °C. H NMR (400 MHz,
CDCl ): δ = 8.74 (s, 1 H), 8.04 (d, J = 6.8 Hz, 2 H), 7.82 (d, J = 8.8 Hz,
1
Nitrogen heterocycles · Thiocyanates · Sulfur
3
19
H), 7.59 (d, J = 8.8 Hz, 1 H), 7.50 (d, J = 7.2 Hz, 3 H) ppm. F NMR
1
3
(470 MHz, CDCl ): δ = –62.0 (s, 3 F) ppm. C NMR (101 MHz, CDCl3):
[1] a) K. S. Gudmundsson, B. A. Johns, Org. Lett. 2003, 5, 1369–1372; b) C.
Enguehard-Gueiffier, A. Gueiffier, Mini-Rev. Med. Chem. 2007, 7, 888–899;
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O. Lagerlund, D. Muthas, J. Gising, S. Yahiaoui, L. R. Odell, B. R. Srinivasa,
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Deperasinska, A. Makarewicz, D. Firmansyah, D. T. Gryko, B. Kozankiewicz,
Phys. Chem. Chem. Phys. 2015, 17, 8945–8950.
3
δ = 154.5, 147.8, 131.2, 130.0, 128.9, 128.8, 120.4 (q, J = 273.0 Hz),
1
24.0, 123.3 (q, J = 5.9 Hz), 119.0, 118.9 (q, J = 34.9 Hz), 118.7, 107.4,
+
9
7.1 ppm. HRMS (ESI): calcd. for C H F N S [M + H] 320.0464;
1
5 8 3 3
found 320.0469.
[
9]
6
-Phenyl-5-thiocyanatoimidazo[2,1-b]thiazole (4ah): White
1
solid. H NMR (400 MHz, CDCl ): δ = 7.97 (s, 2 H), 7.64–7.06 (m, 5
3
H) ppm. 13C NMR (101 MHz, CDCl ): δ = 154.4, 153.3, 132.1, 129.2,
3
1
28.8, 128.1, 117.8, 114.8, 108.4, 95.8 ppm.
[
10]
2
-Phenyl-3-thiocyanatobenzo[d]imidazo[2,1-b]thiazole (4ai):
1
White solid. H NMR (400 MHz, CDCl ): δ = 8.45 (d, J = 8.0 Hz, 1 H),
3
7
7
.93 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.55–7.42 (m, 2 H),
.02 (d, J = 8.0 Hz, 2 H), 3.91 (s, 3 H) ppm. C NMR (101 MHz,
[2] a) L. Almirante, L. Polo, A. Mugnaini, E. Provinciali, P. Rugarli, A. Biancotti,
A. Gamba, W. Murmann, J. Med. Chem. 1965, 8, 305–312; b) M. H. Fisher,
A. Lusi, J. Med. Chem. 1972, 15, 982–985; c) J. J. Kaminski, A. M. Doweyko,
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A. Elhakmaoui, R. Snoeck, G. Andrei, O. Chavignon, J.-C. Teulade, M. Wit-
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1
3
CDCl ): δ = 160.5, 155.5, 152.6, 144.1, 132.9, 130.1, 129.7, 126.9,
1
3
25.6, 124.5, 114.2, 113.7, 109.0, 96.9, 55.4 ppm.
2
-Phenyl-3-thiocyanatoimidazo[1,2-a]pyrimidine (4aj): Pale yel-
1
low solid, m.p. 198.2–201.3 °C. H NMR (400 MHz, DMSO): δ = 9.23–
9
.21 (m, 1 H), 8.84–8.82 (m, 1 H), 8.16 (d, J = 7.2 Hz, 2 H), 7.64–7.60
m, 2 H), 7.56–7.53 (m, 1 H), 7.43–7.40 (m, 1 H) ppm. 1 C NMR
3
(
(
101 MHz, DMSO): δ = 153.9, 151.8, 150.1, 134.7, 132.3, 130.0, 129.3,
1
28.9, 111.3, 110.6, 97.5 ppm. HRMS (ESI): calcd. for C H N S [M +
13 8 4
+
H] 253.0542; found 253.0546.
[
[
[
3] a) S. Z. Langer, S. Arbilla, J. Benavides, B. Scatton, Adv. Biochem. Psycho-
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2
-(4-Methoxyphenyl)-7-methyl-3-thiocyanatoimidazo[1,2-a]-
[10]
1
pyridine (4dd):
White solid. H NMR (400 MHz, CDCl ): δ = 8.27
3
(d, J = 6.8 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 2 H), 7.47 (s, 1 H), 7.03 (d,
J = 8.4 Hz, 2 H), 6.90 (d, J = 6.8 Hz, 1 H), 3.87 (s, 3 H), 2.46 (s, 3 H)
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ppm. 13C NMR (101 MHz, CDCl ): δ = 160.5, 152.8, 148.2, 139.5,
3
8
0; b) T. Mutai, H. Tomoda, T. Ohkawa, Y. Yabe, K. Araki, Angew. Chem.
1
30.1, 124.5, 123.5, 116.7, 116.5, 114.1, 108.5, 92.8, 55.4, 21.5 ppm.
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Song, Y. Zhang, X. Li, Organometallics 2008, 27, 1936–1943; d) A. John,
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6
-Chloro-2-(4-chlorophenyl)-3-thiocyanatoimidazo[1,2-a]-
[10]
1
pyridine (4ff):
White solid. H NMR (400 MHz, CDCl ): δ = 8.45
3
5] a) S. M. Roopan, S. M. Patil, J. Palaniraja, Res. Chem. Intermed. 2015, 1–
(
s, 1 H), 7.99 (d, J = 8.4 Hz, 2 H), 7.68 (d, J = 9.6 Hz, 1 H), 7.49 (d,
4
8
2; b) K. Pericherla, P. Kaswan, K. Pandey, A. Kumar, Synthesis 2015, 47,
87–912; c) A. K. Bagdi, S. Santra, K. Monir, A. Hajra, Chem. Commun.
1
3
J = 8.4 Hz, 2 H), 7.45–7.43 (m, 1 H) ppm. C NMR (101 MHz, CDCl3):
δ = 152.4, 146.3, 135.9, 130.0, 129.9, 129.7, 129.1, 123.2, 122.4, 118.7,
1
2015, 51, 1555–1575; d) S. Manna, R. Narayan, C. Golz, C. Strohmann,
07.4, 95.7 ppm.
A. P. Antonchick, Chem. Commun. 2015, 51, 6119–6122; e) R. Goel, V.
Luxami, K. Paul, RSC Adv. 2015, 5, 81608–81637.
2
-(3-Bromophenyl)-7-methyl-3-thiocyanatoimidazo[1,2-a]-
[10]
1
[6] a) C. J. Mussinan, M. E. Keelan, Sulphur Compounds in Foods, American
Chemical Society, Washington, DC, 1984, p. 1067–1286; b) A. T. Pham, T.
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A. J. Freyer, R. Reichwein, B. Carte, L. B. Killmer, L. Faucette, R. K. Johnson,
pyridine (4hd): Pale yellow solid. H NMR (400 MHz, CDCl ): δ =
8
3
.27 (d, J = 7.2 Hz, 1 H), 8.19 (s, 1 H), 7.98 (d, J = 7.6 Hz, 1 H), 7.55
(d, J = 8.0 Hz, 1 H), 7.47 (s, 1 H), 7.38–7.34 (m, 1 H), 6.94 (d, J =
1
3
6
1
1
.8 Hz, 1 H), 2.47 (s, 3 H) ppm. C NMR (101 MHz, CDCl ): δ = 151.1,
3
48.2, 139.8, 134.1, 132.2, 131.5, 130.2, 127.1, 123.5, 122.9, 117.3,
16.8, 108.0, 94.2, 21.5 ppm.
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Received: April 19, 2016
Published Online: ■
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Thiocyanation
H. Zhang, Q. Wei, S. Wei, J. Qu,
B. Wang* ............................................... 1–8
Highly Efficient and Practical Thio-
cyanation of Imidazopyridines Us-
ing an N-Chlorosuccinimide/NaSCN
Combination
A direct C–H thiocyanation of imidazo- and easy to carry out. They use readily
pyridines, and a practical sequential available starting materials and mild
one-pot condensation/C–H thiocyan- reaction conditions, show a wide func-
ation process, using a combination of tional-group tolerance, and give good
NCS/NaSCN have been developed. The to excellent yields.
reactions are environmentally friendly,
DOI: 10.1002/ejoc.201600485
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim