Electrochemical Oxidative Regioselective C-H Cyanation of Imidazo[1,2-a]pyridines

Article abstract of DOI:10.1021/acs.joc.0c03026

Electrochemical oxidative regioselective C-H cyanation of imidazo[1,2-a]pyridines was developed using readily available TMSCN as the cyano source. The KH₂PO₄/K₂HPO₄buffer was essential for this transformation. This protocol was compatible with a broad range of substituted imidazo[1,2-a]pyridines and provided the C3 cyanated products in moderate to excellent yields.

Full text of DOI:10.1021/acs.joc.0c03026

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Article
Electrochemical Oxidative Regioselective C−H Cyanation of
Imidazo[1,2‑a]pyridines
Ting Cui, Yanling Zhan, Changhui Dai, Jun Lin, Ping Liu,* and Peipei Sun*
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ABSTRACT: Electrochemical oxidative regioselective C−H
cyanation of imidazo[1,2-a]pyridines was developed using readily
available TMSCN as the cyano source. The KH2PO4/K2HPO4
buffer was essential for this transformation. This protocol was
compatible with a broad range of substituted imidazo[1,2-
a]pyridines and provided the C3 cyanated products in moderate to excellent yields.
and practical cyanation methods of heterocycles is still a
challenging task.
INTRODUCTION
■
Cyano exists in many therapeutic drugs and plays a unique
role.1 Moreover, as a versatile functional group, cyano can be
expediently converted into a number of other useful functional
groups, such as carbamoyl, carboxyl, aminomethyl, carbonyl,
and nitrogen-containing heterocycles, and therefore has
extensive applications in organic synthesis.2 On the other
hand, heterocyclic compounds undoubtedly occupy an
extremely key position in organic chemistry, especially in
medicinal chemistry, so the synthesis of heterocyclic nitriles
has aroused great attention of chemists over the past few
decades. The direct cyanation of heterocycles is the main
approach to obtain heterocyclic nitriles. Palladium-catalyzed
cross-coupling of heteroaryl halides with several cyanides such
as NaCN, KCN, Zn(CN)2, and K4[Fe(CN)6] provided the
effective protocols for this purpose (Scheme 1a).3 However,
these methods still have some limitations, e.g., the narrow
heterocycle scope and the catalyst deactivation by cyanide.4
The C−H bond cyanation of arenes provided a new approach
for the preparation of aryl nitriles,5 and this strategy can be
used in the cyanation of some heteroarenes. For example, using
pyridyl as the directing group, Ackermann et al.6 and Chang et
al.7 independently demonstrated the cobalt-catalyzed C−H
cyanation of (hetero)arenes, in which N-cyano-N-phenyl-p-
toluenesulfonamide (NCTS) and N-cyanosuccinimide were
employed as the cyano sources, respectively (Scheme 1b). A
series of transition metals such as Pd-,8 Cu-,9 and Zn-
catalyzed10 cyanations of aromatic heterocycles were devel-
oped in recent years, in which DMF, isonitrile, K4[Fe(CN)6],
NaCN, and nitromethane were employed as the cyanating
reagents (Scheme 1c). An electrochemical C−H cyanation of
electron-rich (hetero)arenes was reported by Gooßen et al, in
which poisonous NaCN was needed (Scheme 1d).11 Dixon
and co-workers12 used TMSCN as the cyano source, achieving
the C−H cyanation of 6-ring N-containing heteroaromatics in
the presence of Tf2O and N-methylmorpholine (NMM)
(Scheme 1e). All the same, in view of the diversity and
complexity of heterocyclic compounds, developing the efficient
On the other hand, electrochemical synthesis is considered
as a clean, environmentally benign, and powerful synthetic
strategy in organic transformations and has attracted great
attention in recent years in spite of being around for many
decades.13 There are a few examples concerning the C(sp2)−H
or C(sp3)−H bond cyanation under the electrochemical
conditions.11,14 The electrocatalytic C−H activation is
expected to play an important role in the direct functionaliza-
tion of heterocyclic compounds. Imidazo[1,2-a]pyridine is
regarded as a kind of “drug bias” building block in medicinal
chemistry;15 thus, the functional modification of this hetero-
cycle is of great value in pharmaceutical synthesis, and a lot of
remarkable works were developed in this area.16 In
continuation of our long-standing interest in the selective
direct C−H bond functionalization of imidazo[1,2-a]-
pyridines,17 as well as on electrochemical synthesis,18 herein
we want to describe an electrochemical oxidative C−H
cyanation of imidazo[1,2-a]pyridines using TMSCN as the
cyano source to synthesize C3 cyanated products (Scheme 1f).
RESULTS AND DISCUSSION
■
We began our investigation by using 2-phenylimidazo[1,2-
a]pyridine (1a) and TMSCN (2) as the model substrates to
explore the reaction conditions (Table 1). The reaction was
performed in an undivided cell equipped with a graphite felt
electrode as the anode and a platinum plate electrode as the
cathode, and nBu4NPF6 was employed as the electrolyte. In 10
mL of CH3CN, under a 5 mA constant current, a trace amount
Special Issue: Electrochemistry in Synthetic Organic
Chemistry
Received: December 24, 2020
https://dx.doi.org/10.1021/acs.joc.0c03026
© XXXX American Chemical Society
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A

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Scheme 1. Cyanation of Heterocycles
of product 3a was found (entry 1). In CH2Cl2, the reaction
could not take place at all (entry 2). We were surprised to find
that the addition of KH2PO4/K2HPO4 buffer could effectively
promote the reaction. When the cosolvent of CH3CN and
buffer (pH 9) with the ratios (v/v) of 9:1, 1:1, and 1:4 was
used, the desired C3-cyanated product 3a was obtained in
30%, 52%, and 76% yields, respectively (entries 3−5).
However, a lower yield of 65% was obtained when a pH 8
buffer was used (entry 6). The supporting electrolyte was then
reaction did not occur in the absence of an electric current
(entry 19).
With the optimized conditions in hand, we turned to
examine the scope and limitation of the cyanation of
imidazopyridines. As shown in Scheme 2, our method was
successfully amenable to a wide range of imidazo[1,2-
a]pyridines. We first changed the substituents and positions
on the phenyl on the C2-position of the imidazo[1,2-
a]pyridine. The results showed that the reactions of substrates
1 with both electron-donating groups (R2 = Me, OMe, Ph)
and weak electron-withdrawing groups (R2 = F, Cl, Br, CF3)
on the different position of the benzene ring of 2-phenyl-
imidazo [1,2-a]pyridines afforded the C3-cyanated products in
moderate to good yields (3ab−3an, 3f). Then 2-phenyl-
imidazo [1,2-a]pyridines bearing various substituents on the
pyridine rings were tested. The position of substituents on the
pyridine rings showed no obvious effect on the reaction;
substrates with a methyl group at the C-5, C-6, C-7, or C-8
position of 2-phenylimidazo[1,2-a]pyridines reacted smoothly
with TMSCN and afforded the desired products in 79−85%
yields (3ba, 3ca, 3da, and 3e). When 8- and 7-methoxyl-
n
examined. The use of other electrolytes such as Bu4NBF4 or
LiClO4 did not bring better results (entries 7 and 8).
Gratifyingly, the best yield of 82% was obtained in the absence
of electrolyte (entry 9). The electrode material has a great
influence on the electrochemical reactions. A variety of
electrodes were tested (entries 9−13), and C(+)/Pt(−) was
proved to be the best one for this transformation (entry 9).
Using MeOH or TFE (2,2,2-trifluoroethanol) as the solvent,
the yields were reduced (entries 14−16). In other buffer
solutions such as Na2CO3/NaHCO3 or NH3/NH4Cl, the
lower yields were obtained (entries 17 and 18). Finally, the
B
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a
Table 1. Optimization of Reaction Conditions
c
b
entry
anode/cathode
J/mA cm−2
solvent
buffer
electrolyte
yield (%)
1
C(+)/Pt(−)
C(+)/Pt(−)
C(+)/Pt(−)
C(+)/Pt(−)
C(+)/Pt(−)
C(+)/Pt(−)
C(+)/Pt(−)
C(+)/Pt(−)
C(+)/Pt(−)
C(+)/C(−)
Pt(+)/Pt(−)
C(+)/Fe(−)
C(+)/Ni(−)
Pt(+)/Pt(−)
C(+)/Pt(−)
C(+)/Pt(−)
C(+)/Pt(−)
C(+)/Pt(−)
C(+)/Pt(−)
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
CH3CN (10 mL)
DCM (10 mL)
CH3CN (9 mL)
CH3CN (5 mL)
CH3CN (2 mL)
CH3CN (2 mL)
CH3CN (2 mL)
CH3CN (2 mL)
CH3CN (2 mL)
CH3CN (2 mL)
CH3CN (2 mL)
CH3CN (2 mL)
CH3CN (2 mL)
MeOH (2 mL)
MeOH (2 mL)
TFE (2 mL)
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NBF4
LiClO4
trace
0
2
3
pH 9 (1 mL)
pH 9 (5 mL)
pH 9 (8 mL)
pH 8 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
pH 9 (8 mL)
30
52
76
65
71
40
82
23
56
29
50
5
4
5
6
7
8
9
10
11
12
13
14
15
16
56
79
62
8
d
17
CH3CN (2 mL)
CH3CN (2 mL)
CH3CN (2 mL)
nBu4NBF4
nBu4NBF4
e
18
19
0
a
Reaction conditions: graphite felt anode, platinum plate cathode (10 mm × 10 mm), constant current (5.0 mA), 1a (0.2 mmol), 2 (0.6 mmol, 3.0
b
c
equiv), supporting electrolyte (0.05 M), solvent (10 mL), undivided cell, under air, rt, 6 h. Isolated yields based on 1a. Unless otherwise specified,
buffer prepared from KH2PO4 and K2HPO4 at 4 M with respect to phosphate ion. Buffer prepared from Na2CO3 and NaHCO3. Buffer prepared
d
e
from NH3 and NH4Cl.
substituted imidazopyridines were treated with TMSCN, the
corresponding products could be obtained in 84% and 81%
yields, respectively (3bb and 3cb). Besides, the electron-
withdrawing groups (R1 = F, Cl, and CF3) on pyridine rings
were well tolerated and gave the desired products in moderate
to good yields (3bc, 3cc−3ce, and 3db). The substrates with
2-naphthyl and 2-thienyl on the 2-position of imidazo[1,2-
a]pyridines were also investigated and furnished 3g, 3h, 3j, and
3k in 69−77% yields. Next, imidazopyridines with substituents
on both pyridine rings and 2-phenyl were studied. When
substrates with a methyl group at the C-6, C-7, or C-8 position
of 2-phenylimidazo[1,2-a]pyridines, it seemed that electronic
effect and the position of substituents on the 2-phenyl showed
no obvious impact; various functional groups, including
electron-donating (Me, OMe) and electron-withdrawing
groups (F, CN, SO2Me), were well-tolerated, and the reactions
gave the desired products 3i, 3l, and 3m in high yields (70−
84%). It should be noted that, for the unsubstituted
imidazo[1,2-a]pyridine and the imidazo[1,2-a]pyridines with
substituents such as Me, CF3, or COOEt on the 2-position,
almost no corresponding products were obtained, and most of
the substrates were recovered (3q−3t). The cyclic voltamme-
try (CV) experiments for these reactants 1q−1t were
performed, and no obvious oxidation peaks were observed in
the 0−2.0 V region (see Supporting Information). In addition,
some other imidazo-fused heterocycles such as benzo[d]-
imidazo[2,1-b]thiazole, imidazo[2,1-b]thiazole, and imidazo-
[1,2-a]quinoline were also tested, and the corresponding
cyanated products were obtained in 65−75% yields (3n−3p).
Furthermore, when the amount of 1a was increased to 1 mmol
in the same reaction conditions, a 72% yield of 3a was
obtained, indicating that the reaction efficiency did not
strikingly decrease.
In order to gain a good insight into the mechanism of this
reaction, we conducted several control experiments. When 1a
was employed as the reactant, in the absence of TMSCN,
product 3a was not obtained under the standard reaction
conditions (Scheme 3a), which indicated that the cyano in 3a
was derived from TMSCN but not CH3CN. A kinetic isotope
experiment was also done. When 1a and a 3-deuterated
compound 1a′ were used to react with TMSCN separately
under standard conditions for 30 min, product 3a was obtained
in 15.3% and 11.9% yields, respectively, and the ratio was
nearly 1.29; for 60 min, this ratio was nearly 1.07 (Scheme
3b,c), which suggested that the C−H bond cleavage of
imidazo[1,2-a]pyridine might not be the rate-determining step
of this reaction.
The CV experiments on 1a and 2 were performed (Figure
1). The oxidation peak of 1a was observed at 1.30 V (vs SCE),
while no obvious oxidation peak of 2 was found in the 0−2.0 V
region. These results indicated that our electrochemical
oxidative C−H cyanation might begin with the oxidation of
1a at the anode.
Based on the above experimental results and previous
reports, a plausible mechanism for this electrochemical
oxidative C−H cyanation is proposed in Scheme 4. First, 1a
was oxidized at the anode to form the radical cation
intermediate A.19 Intermediate A was then captured by
nucleophile TMSCN to deliver adduct B. Further oxidation
of B on the anode gave the cation intermediate C. Final
C
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a
Scheme 2. Substrate Scope for Electrochemical Oxidative Cyanation of Imidazopyridines
a
Reaction conditions: graphite felt anode, platinum plate cathode (10 mm × 10 mm), constant current (5.0 mA), 1 (0.2 mmol), 2 (0.6 mmol 3.0
b
equiv), CH3CN/pH 9 buffer (1:4 (v/v), 10 mL), undivided cell, under air, rt, 6 h. All yields are isolated based on 1. Compounds 1a (1 mmol) and
2 (3 mmol 3.0 equiv), CH3CN/pH 9 buffer (1:4 (v/v), 50 mL), undivided cell, under air, rt, 12 h.
Scheme 3. Control Experiments
Figure 1. CV scans (scan rate 100 mv s−1) of substrate 1a (0.01 M)
or 2 (0.01 M) in CH3CN containing nBu4NPF6 (0.02 M) at a
platinum-wire electrode under air.
deprotonation of the cation intermediate B generated the
desired product 3a. At the same time, concomitant cathodic
reduction of a proton released hydrogen gas during the
reaction.
D
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13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 153.4, 146.9, 131.2,
Scheme 4. Proposed Mechanism
130.2, 129.1, 128.8, 127.3, 125.6, 118.2, 114.8, 112.8, 93.9.
2-(p-Tolyl)imidazo[1,2-a]pyridine-3-carbonitrile (3ab).20 This
compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 5:1, v/v): white solid (39.1 mg,
84% yield); mp 148−150 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.34 (d, J = 6.7 Hz, 1H), 8.09 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 9.0 Hz,
1H), 7.46−7.42 (m, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.06 (t, J = 6.8 Hz,
1H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
153.5, 146.8, 140.4, 129.7, 128.7, 128.4, 127.2, 125.6, 118.0, 114.6,
112.9, 93.5, 21.5.
2-(4-Methoxyphenyl)imidazo[1,2-a]pyridine-3-carbonitrile
(3ac).20 This compound was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 5:1, v/v): white
1
solid (40.3 mg, 81% yield); mp 204−206 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 8.36 (d, J = 6.7 Hz, 1H), 8.17 (d, J = 8.8 Hz, 2H),
7.76 (d, J = 9.0 Hz, 1H), 7.49−7.45 (m, 1H), 7.11−7.04 (m, 3H),
3.90 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 161.2,
153.3, 146.8, 128.8, 128.8, 125.6, 123.7, 117.9, 114.6, 114.4, 113.1,
93.0, 55.4.
2-(4-Fluorophenyl)imidazo[1,2-a]pyridine-3-carbonitrile (3ad).20
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 5:1, v/v): white solid (36.5 mg, 77%
yield); mp 193−195 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.35
(d, J = 6.7 Hz, 1H), 8.20−8.16 (m, 2H), 7.75 (d, J = 9.0 Hz, 1H),
7.50−7.46 (m, 1H), 7.20 (t, J = 8.7 Hz, 2H), 7.11 (t, J = 6.6 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 163.8 (d, J = 250.7 Hz),
152.3, 146.8, 129.3 (d, J = 8.6 Hz), 129.0, 127.4 (d, J = 3.2 Hz),
125.7, 118.1, 116.1 (d, J = 21.9 Hz), 114.9, 112.7, 93.6.
In summary, we have developed an efficient method for the
electrochemical oxidative C−H thiocyanation of imidazopyr-
idines and similar heterocycles under mild conditions.
Commercial readily available TMSCN was utilized as the
source of the cyano functional group. A variety of C3 cyanated
imidazopyridine products were obtained in satisfactory yields.
This electrochemical method may be applied to the field of
drug development of imidazopyridine derivatives.
2-(4-Bromophenyl)imidazo[1,2-a]pyridine-3-carbonitrile (3ae).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 5:1, v/v): white solid (43.4 mg, 73%
yield); mp 165−167 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.39
(d, J = 6.6 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.9 Hz, 1H),
7.67 (d, J = 8.3 Hz, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 6.7 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 152.1, 146.7, 132.3,
130.0, 129.2, 128.8, 125.7, 124.7, 118.2, 115.1, 112.5, 93.9; HRMS
+
(ESI) m/z [M + H]+ calcd for C14H9BrN3 297.9974, found
EXPERIMENTAL SECTION
■
297.9977.
General Information. All reagents were obtained from
commercial suppliers and used without further purification. Reactions
were monitored by thin-layer chromatography. Column chromatog-
raphy was performed using silica gel (300−400 mesh). The NMR
spectra were recorded on Bruker Avance 400 spectrometers at 400
MHz (1H) and 100 MHz (13C{1H}) in CDCl3 using TMS as an
internal standard. The following abbreviations were used to explain
the multiplicities: s = singlet, d = doublet, dd = doublet of doublet, t =
triplet, td = triplet of doublet, q = quartet, m = multiplet. High-
resolution mass spectra (HRMS) were obtained with an AB Triple
5600 mass spectrometer by ESI on a TOF mass analyzer. Melting
points are uncorrected.
2-(4-(Trifluoromethyl)phenyl)imidazo[1,2-a]pyridine-3-carboni-
trile (3af). This compound was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 5:1, v/v): white
1
solid (40.2 mg, 70% yield); mp 157−159 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 8.40 (d, J = 6.7 Hz, 1H), 8.32 (d, J = 8.2 Hz, 2H),
7.79 (t, J = 8.3 Hz, 3H), 7.55−7.51 (m, 1H), 7.16 (t, J = 6.8 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 151.5, 146.9, 134.6,
131.7 (q, J = 32.7 Hz), 129.2, 128.0, 126.0 (q, J = 3.7 Hz), 125.7,
123.9 (q, J = 272.3 Hz), 118.4, 115.2, 112.3, 94.5; HRMS (ESI) m/z
+
[M + H]+ calcd for C15H9F3N3 288.0743, found 288.0743.
2-([1,1′-Biphenyl]-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile
(3ag). This compound was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 5:1, v/v): white
General Procedure for the Electrochemical Reaction. To an
undivided three-necked flask (25 mL) were added 2-phenylimidazo-
[1,2-a]pyridine (1a, 38.8 mg, 0.2 mmol), TMSCN (2, 75 μL, 0.6
mmol, 3 equiv), CH3CN, and KH2PO4/K2HPO4 pH 9 buffer (1:4,
(v/v), 10 mL). The flask was equipped with a graphite felt electrode
as the anode and platinum plate electrode (10 mm × 10 mm) as the
cathode. The reaction mixture was electrolyzed and stirred at a
constant current (5 mA) under air at room temperature for 6 h. After
the reaction was completed, the mixture was diluted with water (30
mL) and then extracted with DCM (10 mL × 3). The combined
organic phases were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo, and the crude product was obtained. The
residue was purified by silica gel chromatography using petroleum
ether/ethyl acetate (5:1) as an eluent to give the desired product 3a.
2-Phenylimidazo[1,2-a]pyridine-3-carbonitrile (3a).20 This com-
pound was purified by silica gel column chromatography (petroleum
ether/ethyl acetate = 5:1, v/v): white solid (35.9 mg, 82% yield; for 1
1
solid (42.5 mg, 72% yield); mp 235−237 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 8.40 (d, J = 6.7 Hz, 1H), 8.30 (d, J = 8.4 Hz, 2H),
7.79 (t, J = 8.8 Hz, 3H), 7.69 (d, J = 7.3 Hz, 2H), 7.50 (t, J = 7.7 Hz,
3H), 7.41 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 6.5 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ (ppm) 153.1, 146.9, 142.9, 140.2, 130.1, 128.9,
128.9, 127.8, 127.7, 127.7, 127.1, 125.7, 118.2, 114.8, 112.9, 93.8;
+
HRMS (ESI) m/z [M + H]+ calcd for C20H14N3 296.1182, found
296.1183.
2-(m-Tolyl)imidazo[1,2-a]pyridine-3-carbonitrile (3ah). This
compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 5:1, v/v): white solid (36.8 mg,
79% yield); mp 136−138 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.34 (d, J = 6.7 Hz, 1H), 8.10−7.98 (m, 2H), 7.75 (d, J = 9.0 Hz,
1H), 7.47−7.38 (m, 2H), 7.29 (s, 1H), 7.07 (t, J = 6.5 Hz, 1H), 2.45
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 153.4, 146.8,
138.8, 131.1, 131.0, 128.9, 128.7, 127.9, 125.6, 124.4, 118.1, 114.7,
1
mmol of 1a, 157.7 mg, 72% yield); mp 147−149 °C; H NMR (400
+
MHz, CDCl3) δ (ppm) 8.39−8.37 (m, 1H), 8.22−8.19 (m, 2H), 7.78
(d, J = 9.1 Hz, 1H), 7.56−7.46 (m, 4H), 7.11 (t, J = 6.8 Hz, 1H);
112.8, 93.8, 21.5; HRMS (ESI) m/z [M + H]+ calcd for C15H12N3
234.1026, found 234.1027.
E
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2-(3-Fluorophenyl)imidazo[1,2-a]pyridine-3-carbonitrile (3ai).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 5:1, v/v): white solid (36.0 mg, 76%
yield); mp 194−196 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.39
(dt, J = 6.8, 1.0 Hz, 1H), 8.01−7.99 (m, 1H), 7.94−7.90 (m, 1H),
7.79 (d, J = 9.1 Hz, 1H), 7.53−7.48 (m, 2H), 7.21−7.12 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 163.1 (d, J = 246.6 Hz),
151.9, 146.8, 133.3 (d, J = 8.2 Hz), 130.7 (d, J = 8.2 Hz), 129.1,
125.7, 122.9 (d, J = 3.0 Hz), 118.3, 117.1 (d, J = 21.2 Hz), 115.1,
114.3 (d, J = 23.4 Hz), 112.4, 94.2; HRMS (ESI) m/z [M + H]+ calcd
127.3, 123.3, 114.7, 113.1, 94.1, 16.9; HRMS (ESI) m/z [M + H]+
calcd for C15H12N3 234.1026, found 234.1027.
+
8-Methoxy-2-phenylimidazo[1,2-a]pyridine-3-carbonitrile (3bb).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (41.8 mg, 84%
yield); mp 143−145 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.25−8.23 (m, 2H), 7.99 (d, J = 6.6 Hz, 1H), 7.53−7.44 (m, 3H),
7.01−6.97 (m, 1H), 6.74 (d, J = 7.8 Hz, 1H), 4.08 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ (ppm) 152.4, 149.3, 141.0, 131.0, 130.0,
128.9, 127.4, 118.1, 114.9, 112.8, 104.9, 94.8, 56.4; HRMS (ESI) m/z
[M + H]+ calcd for C15H12N3O+ 250.0975, found 250.0976.
+
for C14H9FN3 238.0775, found 238.0776.
8-Fluoro-2-phenylimidazo[1,2-a]pyridine-3-carbonitrile (3bc).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (34.1 mg, 72%
yield); mp 135−137 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.25−8.22 (m, 3H), 7.57−7.50 (m, 3H), 7.23−7.18 (m, 1H), 7.06
(td, J = 7.7, 7.3, 4.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 153.4, 151.5 (d, J = 256.5 Hz), 139.5 (d, J = 28.6 Hz), 130.7,
130.5, 129.1, 127.5, 121.9 (d, J = 5.4 Hz), 114.1 (d, J = 6.5 Hz), 112.3
(d, J = 1.5 Hz), 111.6 (d, J = 16.3 Hz), 95.3; HRMS (ESI) m/z [M +
2-(3-Chlorophenyl)imidazo[1,2-a]pyridine-3-carbonitrile (3aj).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 5:1, v/v): white solid (37.0 mg, 73%
yield); mp 189−191 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.41−8.40 (m, 1H), 8.21 (q, J = 1.2 Hz, 1H), 8.11−8.09 (m, 1H),
7.80 (d, J = 9.1 Hz, 1H), 7.54−7.45 (m, 3H), 7.15 (td, J = 6.9, 1.0 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 151.8, 146.8, 135.2,
132.9, 130.3, 130.2, 129.1, 127.4, 125.7, 125.3, 118.3, 115.1, 112.4,
+
94.2; HRMS (ESI) m/z [M + H]+ calcd for C14H9ClN3 254.0480,
+
H]+ calcd for C14H9FN3 238.0775, found 238.0776.
found 254.0481.
7-Methyl-2-phenylimidazo[1,2-a]pyridine-3-carbonitrile (3ca).20
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (39.1 mg, 84%
yield); mp 147−149 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.17−8.14 (m, 3H), 7.52−7.42 (m, 4H), 6.86−6.84 (m, 1H), 2.43 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 153.3, 147.2, 140.4,
131.3, 130.0, 128.9, 127.2, 124.7, 117.3, 116.7, 113.1, 93.2, 21.6.
7-Methoxy-2-phenylimidazo[1,2-a]pyridine-3-carbonitrile (3cb).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (40.3 mg, 81%
yield); mp 173−175 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.15−8.09 (m, 3H), 7.51−7.42 (m, 3H), 6.98 (d, J = 2.3 Hz, 1H),
6.72 (dd, J = 7.4, 2.4 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 160.6, 153.6, 148.7, 131.3, 130.0, 128.9,
127.1, 125.8, 113.2, 109.4, 95.8, 92.6, 55.9; HRMS (ESI) m/z [M +
H]+ calcd for C15H12N3O+ 250.0975, found 250.0975.
2-(3-Bromophenyl)imidazo[1,2-a]pyridine-3-carbonitrile (3ak).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 5:1, v/v): white solid (41.6 mg, 70%
yield); mp 175−177 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.40−8.36 (m, 2H), 8.13 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 9.0 Hz,
1H), 7.61 (d, J = 7.9 Hz, 1H), 7.53−7.49 (m, 1H), 7.40 (t, J = 7.9 Hz,
1H), 7.14 (t, J = 6.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 151.5, 146.8, 133.1, 130.5, 130.3, 129.1, 125.7, 125.7, 123.3,
118.3, 115.1, 112.4, 94.1; HRMS (ESI) m/z [M + H]+ calcd for
+
C14H9BrN3 297.9974, found 297.9974.
2-(2-Methoxyphenyl)imidazo[1,2-a]pyridine-3-carbonitrile (3al).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 5:1, v/v): white solid (42.3 mg, 85%
yield); mp 129−131 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.37
(d, J = 6.8 Hz, 1H), 8.01 (dd, J = 7.7, 1.5 Hz, 1H), 7.73 (d, J = 9.0 Hz,
1H), 7.46−7.39 (m, 2H), 7.12−7.02 (m, 3H), 3.99 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ (ppm) 157.0, 149.4, 146.2, 131.3, 130.9,
128.2, 125.4, 120.9, 120.6, 117.9, 114.4, 112.6, 111.1, 97.3, 54.6;
HRMS (ESI) m/z [M + H]+ calcd for C15H12N3O+ 250.0975, found
250.0976.
7-Fluoro-2-phenylimidazo[1,2-a]pyridine-3-carbonitrile (3cm).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (33.7 mg, 71%
yield); mp 185−187 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.35−8.32 (m, 1H), 8.19−8.17 (m, 2H), 7.56−7.48 (m, 3H), 7.42
(dd, J = 8.6, 2.0 Hz, 1H), 6.98 (td, J = 7.1, 2.1 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ (ppm) 162.3 (d, J = 257.8 Hz), 154.6,
147.5 (d, J = 14.0 Hz), 130.8, 130.5, 129.1, 127.3, 127.1 (d, J = 11.0
Hz), 112.5, 107.1 (d, J = 29.1 Hz), 102.5 (d, J = 24.0 Hz), 93.7;
2-(2-Fluorophenyl)imidazo[1,2-a]pyridine-3-carbonitrile (3am).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 5:1, v/v): white solid (38.4 mg, 81%
yield); mp 195−197 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.43
(d, J = 6.7 Hz, 1H), 8.01 (t, J = 7.5 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H),
7.54−7.47 (m, 2H), 7.15 (t, J = 6.8 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 160.1 (d, J = 252.4 Hz), 148.2, 146.6, 131.8
(d, J = 8.4 Hz), 130.9 (d, J = 2.8 Hz), 128.8, 125.7, 124.7 (d, J = 3.6
Hz), 119.4 (d, J = 13.4 Hz), 118.3, 116.4 (d, J = 21.7 Hz), 115.0,
116.4 (d, J = 21.7 Hz), 96.8; HRMS (ESI) m/z [M + H]+ calcd for
+
HRMS (ESI) m/z [M + H]+ calcd for C14H9FN3 238.0775, found
238.0776.
7-Chloro-2-phenylimidazo[1,2-a]pyridine-3-carbonitrile (3cd).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (36.9 mg, 73%
yield); mp 193−195 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.30−8.28 (m, 1H), 8.19−8.16 (m, 2H), 7.77 (d, J = 1.4 Hz, 1H),
7.56−7.48 (m, 3H), 7.09 (dd, J = 7.2, 2.0 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ (ppm) 154.2, 146.6, 135.6, 130.7, 130.5, 129.1,
127.3, 125.8, 117.2, 116.4, 112.4, 94.1; HRMS (ESI) m/z [M + H]+
+
C14H9FN3 238.0775, found 238.0776.
2-(2-Chlorophenyl)imidazo[1,2-a]pyridine-3-carbonitrile (3an).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 5:1, v/v): white solid (39.5 mg, 78%
yield); mp 170−172 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.42
(d, J = 6.8 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.69−7.67 (m, 1H),
7.57−7.51 (m, 2H), 7.46−7.39 (m, 2H), 7.16 (t, J = 6.8 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 151.8, 146.4, 133.2,
132.0, 131.0, 130.6, 130.4, 128.8, 127.1, 125.7, 118.5, 115.1, 111.6,
+
calcd for C14H9ClN3 254.0480, found 254.0480.
2-Phenyl-7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboni-
trile (3ce). This compound was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 8:1, v/v): white
1
solid (39.6 mg, 69% yield); mp 145−147 °C; H NMR (400 MHz,
+
97.3; HRMS (ESI) m/z [M + H]+ calcd for C14H9ClN3 254.0480,
CDCl3) δ (ppm) 8.50 (d, J = 7.1 Hz, 1H), 8.23−8.20 (m, 2H), 8.08
(s, 1H), 7.59−7.51 (m, 3H), 7.30−7.28 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ (ppm) 154.7, 145.1, 130.8 130.7 (q, J = 34.8
Hz), 130.5, 129.2, 127.4, 126.5, 122.6 (q, J = 272.8 Hz), 116.0 (q, J =
4.7 Hz), 111.9, 110.7 (q, J = 2.9 Hz), 95.1; HRMS (ESI) m/z [M +
found 254.0482.
8-Methyl-2-phenylimidazo[1,2-a]pyridine-3-carbonitrile (3ba).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (39.6 mg, 85%
yield); mp 132−134 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.21−8.17 (m, 3H), 7.53−7.44 (m, 3H), 7.20 (d, J = 7.0 Hz, 1H),
6.95 (t, J = 6.9 Hz, 1H), 2.68 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ (ppm) 152.7, 147.2, 131.5, 129.9, 128.9, 128.6, 127.5,
+
H]+ calcd for C15H9F3N3 288.0743, found 288.0744.
6-Methyl-2-phenylimidazo[1,2-a]pyridine-3-carbonitrile (3da).20
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (37.3 mg, 80%
F
https://dx.doi.org/10.1021/acs.joc.0c03026
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
yield); mp 147−149 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.16
(d, J = 7.9 Hz, 2H), 8.10 (s, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.52−7.43
(m, 3H), 7.26 (d, J = 9.2 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 152.9, 145.8, 131.8, 131.3, 130.0, 129.0,
127.1, 125.0, 123.4, 117.3, 113.0, 93.4, 18.2.
solid (43.7 mg, 83% yield); mp 162−164 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 8.18−8.14 (m, 3H), 7.20 (dt, J = 7.0, 1.0 Hz, 1H),
7.04−7.00 (m, 2H), 6.94 (t, J = 6.9 Hz, 1H), 3.88 (s, 3H), 2.67 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 161.0, 152.7, 147.1,
128.8, 128.3, 127.4, 124.1, 123.2, 114.4, 114.3, 113.4, 93.2, 55.4, 16.9;
HRMS (ESI) m/z [M + H]+ calcd for C16H14N3O+ 264.1131, found
264.1133.
6-Fluoro-2-phenylimidazo[1,2-a]pyridine-3-carbonitrile (3db).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (33.2 mg, 70%
yield); mp 194−196 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.34
(t, J = 2.5 Hz, 1H), 8.20−8.18 (m, 2H), 7.79 (dd, J = 9.8, 4.8 Hz,
1H), 7.57−7.50 (m, 3H), 7.45−7.40 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 154.3 (d, J = 242.8 Hz), 154.0 (d, J = 2.4 Hz),
144.3, 130.8, 130.4, 129.1, 127.2, 120.9 (d, J = 25.0 Hz), 118.7 (d, J =
8.7 Hz), 113.0 (d, J = 41.4 Hz), 112.2, 95.3; HRMS (ESI) m/z [M +
2-(4-Fluorophenyl)-8-methylimidazo[1,2-a]pyridine-3-carboni-
trile (3ic). This compound was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 8:1, v/v): white
1
solid (40.2 mg, 80% yield); mp 174−176 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 8.22−8.17 (m, 3H), 7.25−7.17 (m, 3H), 6.99 (t, J =
6.9 Hz, 1H), 2.68 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 163.7 (d, J = 250.3 Hz), 151.8, 147.2, 129.3 (d, J = 8.5 Hz),
128.6, 127.7 (d, J = 3.2 Hz), 127.6, 123.3, 116.0 (d, J = 21.8 Hz),
114.8, 113.0, 93.8, 16.9; HRMS (ESI) m/z [M + H]+ calcd for
+
H]+ calcd for C14H9FN3 238.0775, found 238.0776.
5-Methyl-2-phenylimidazo[1,2-a]pyridine-3-carbonitrile (3e).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (36.8 mg, 79%
yield); mp 148−150 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.20−8.17 (m, 2H), 7.66 (d, J = 8.9 Hz, 1H), 7.55−7.47 (m, 3H),
7.37 (dd, J = 8.9, 7.1 Hz, 1H), 6.77 (d, J = 7.0 Hz, 1H), 3.05 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 155.3, 147.8, 138.1,
131.4, 130.0, 129.1, 128.9, 127.7, 116.0, 115.5, 115.3, 93.0, 20.0;
+
C15H11FN3 252.0932, found 252.0932.
2-(4-Cyanophenyl)-8-methylimidazo[1,2-a]pyridine-3-carboni-
trile (3id). This compound was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 8:1, v/v): white
1
solid (36.1 mg, 70% yield); mp 255−257 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 8.36 (d, J = 8.5 Hz, 2H), 8.27 (d, J = 6.7 Hz, 1H),
7.81 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 7.0 Hz, 1H), 7.07 (t, J = 6.9 Hz,
1H), 2.72 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
150.2, 147.4, 135.8, 132.7, 129.1, 128.0, 127.8, 123.4, 118.6, 115.4,
113.2, 112.5, 95.1, 16.9; HRMS (ESI) m/z [M + H]+ calcd for
+
HRMS (ESI) m/z [M + H]+ calcd for C15H12N3 234.1026, found
234.1027.
2-(2,4-Dichlorophenyl)imidazo[1,2-a]pyridine-3-carbonitrile (3f).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 6:1, v/v): white solid (43.6 mg, 76%
yield); mp 210−212 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.44
(d, J = 6.5 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.66−7.53 (m, 3H),
7.43−7.41 (m, 1H), 7.19 (t, J = 6.6 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 150.7, 146.4, 136.5, 134.0, 132.8, 130.3,
129.2, 129.0, 127.5, 125.7, 118.6, 115.3, 111.3, 97.4; HRMS (ESI) m/
+
C16H11N4 259.0978, found 259.0979.
8-Methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine-3-
carbonitrile (3ie). This compound was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 8:1, v/v): white
1
solid (44.8 mg, 72% yield); mp 202−204 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 8.40 (d, J = 8.5 Hz, 2H), 8.25 (d, J = 6.7 Hz, 1H),
8.07 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 7.1 Hz, 1H), 7.06 (t, J = 6.9 Hz,
1H), 3.12 (s, 3H), 2.70 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 150.1, 147.3, 141.2, 136.7, 129.1, 128.1, 128.1, 128.0, 123.4,
115.5, 112.4, 95.1, 44.6, 16.9; HRMS (ESI) m/z [M + H]+ calcd for
C16H14N3O2S+ 312.0801, found 312.0804.
+
z [M + H]+ calcd for C14H8Cl2N3 288.0090, found 288.0090.
2-(Naphthalen-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (3g).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 6:1, v/v): white solid (39.8 mg, 74%
yield); mp 202−204 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.72
(s, 1H), 8.38 (d, J = 6.7 Hz, 1H), 8.31 (dd, J = 8.6, 1.7 Hz, 1H), 7.99
(dd, J = 8.9, 4.6 Hz, 2H), 7.91−7.88 (m, 1H), 7.80 (d, J = 9.0 Hz,
1H), 7.58−7.53 (m, 2H), 7.51−7.46 (m, 1H), 7.13−7.07 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 153.2, 146.9, 134.1,
133.3, 128.9, 128.9, 128.8, 128.5, 127.8, 127.2, 126.7, 125.6, 124.2,
118.1, 114.8, 113.0, 94.1; HRMS (ESI) m/z [M + H]+ calcd for
8-Methyl-2-(naphthalen-2-yl)imidazo[1,2-a]pyridine-3-carboni-
trile (3j). This compound was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 8:1, v/v): white
1
solid (43.6 mg, 77% yield); mp 162−164 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 8.69 (s, 1H), 8.31 (dd, J = 8.5, 1.5 Hz, 1H), 8.17 (d,
J = 6.6 Hz, 1H), 7.99−7.94 (m, 2H), 7.87 (dd, J = 6.0, 3.3 Hz, 1H),
7.54 (dt, J = 6.2, 3.4 Hz, 2H), 7.18 (d, J = 6.9 Hz, 1H), 6.92 (t, J = 6.8
Hz, 1H), 2.70 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
152.5, 147.2, 134.0, 133.2, 128.9, 128.8, 128.6, 128.5, 127.8, 127.5,
127.0, 127.0, 126.5, 124.4, 123.2, 114.7, 113.3, 94.3, 17.0; HRMS
(ESI) m/z [M + H]+ calcd for C19H14N3+ 284.1182, found 284.1183.
8-Methyl-2-(thiophen-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile
(3k). This compound was purified by silica gel column chromatog-
raphy (petroleum ether/ethyl acetate = 8:1, v/v): white solid (33.0
+
C18H12N3 270.1026, found 270.1027.
2-(Thiophen-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (3h).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (31.9 mg, 71%
yield); mp 145−147 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.34
(d, J = 6.7 Hz, 1H), 7.94 (dd, J = 3.7, 0.9 Hz, 1H), 7.76 (d, J = 9.1 Hz,
1H), 7.53−7.46 (m, 2H), 7.21 (dd, J = 5.0, 3.8 Hz, 1H), 7.13−7.10
(m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 148.5, 146.7,
134.4, 129.0, 128.4, 128.4, 127.3, 125.6, 117.9, 114.9, 112.3, 92.6;
HRMS (ESI) m/z [M + H]+ calcd for C12H8N3S+ 226.0433, found
226.0434.
1
mg, 69% yield); mp 140−142 °C; H NMR (400 MHz, CDCl3) δ
(ppm) 8.20 (d, J = 6.7 Hz, 1H), 7.93 (dd, J = 3.7, 0.9 Hz, 1H), 7.50
(dd, J = 5.0, 0.9 Hz, 1H), 7.25 (d, J = 7.0 Hz, 1H), 7.20 (dd, J = 5.0,
3.8 Hz, 1H), 7.00 (t, J = 6.9 Hz, 1H), 2.70 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ (ppm) 147.9, 147.1, 134.6, 128.4, 128.3, 128.1,
127.7, 127.2, 123.3, 114.8, 112.6, 93.0, 16.9; HRMS (ESI) m/z [M +
H]+ calcd for C13H10N3S+ 240.0590, found 240.0592.
2-(2-Fluorophenyl)-8-methylimidazo[1,2-a]pyridine-3-carboni-
trile (3ia). This compound was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 8:1, v/v): white
1
7-Methyl-2-(p-tolyl)imidazo[1,2-a]pyridine-3-carbonitrile (3la).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (41.0 mg, 83%
yield); mp 162−164 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.21
(d, J = 6.9 Hz, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.50 (s, 1H), 7.32 (d, J =
8.0 Hz, 2H), 6.90 (dd, J = 6.9, 1.3 Hz, 1H), 2.48 (s, 3H), 2.43 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 153.6, 147.2, 140.3,
140.3, 129.7, 128.5, 127.1, 124.7, 117.1, 116.6, 113.2, 92.9, 21.6, 21.5;
solid (39.2 mg, 78% yield); mp 144−146 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 8.26 (d, J = 6.7 Hz, 1H), 8.02 (td, J = 7.5, 1.7 Hz,
1H), 7.50−7.44 (m, 1H), 7.33−7.22 (m, 3H), 7.02 (t, J = 6.9 Hz,
1H), 2.70 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 160.0
(d, J = 252.0 Hz), 147.5 (d, J = 1.8 Hz), 147.0, 131.6 (d, J = 8.3 Hz),
131.1 (d, J = 2.9 Hz), 128.7, 127.5, 124.7 (d, J = 3.6 Hz), 123.3, 119.7
(d, J = 13.7 Hz), 116.3 (d, J = 21.7 Hz), 114.9, 111.8 (d, J = 2.2 Hz),
+
97.2, 16.9; HRMS (ESI) m/z [M + H]+ calcd for C15H11FN3
HRMS (ESI) m/z [M + H]+ calcd for C16H14N3 248.1182, found
+
252.0932, found 252.0933.
2-(4-Methoxyphenyl)-8-methylimidazo[1,2-a]pyridine-3-carbon-
itrile (3ib). This compound was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 8:1, v/v): white
248.1183.
2-(4-Methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-carbon-
itrile (3lb). This compound was purified by silica gel column
G
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Article
chromatography (petroleum ether/ethyl acetate = 8:1, v/v): white
solid (43.1 mg, 82% yield); mp 159−161 °C; H NMR (400 MHz,
orcid.org/0000-0002-1716-2343; Email: sunpeipei@
njnu.edu.cn
1
CDCl3) δ (ppm) 8.18 (d, J = 6.9 Hz, 1H), 8.14−8.10 (m, 2H), 7.46
(s, 1H), 7.04−7.00 (m, 2H), 6.87 (dd, J = 6.9, 1.5 Hz, 1H), 3.88 (s,
3H), 2.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
161.0, 153.4, 147.2, 140.3, 128.7, 124.6, 123.9, 117.0, 116.4, 114.3,
113.4, 92.3, 55.4, 21.6; HRMS (ESI) m/z [M + H]+ calcd for
C16H14N3O+ 264.1131, found 264.1132.
Authors
Ting Cui − School of Chemistry and Materials Science, Jiangsu
Provincial Key Laboratory of Material Cycle Processes and
Pollution Control, Jiangsu Collaborative Innovation Center of
Biomedical Functional Materials, Nanjing Normal
University, Nanjing 210023, China
6-Methyl-2-(p-tolyl)imidazo[1,2-a]pyridine-3-carbonitrile (3m).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (41.5 mg, 84%
yield); mp 168−170 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.16
(s, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 9.1 Hz, 1H), 7.32 (t, J =
7.9 Hz, 3H), 2.44 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 153.2, 145.8, 140.3, 131.8, 129.7, 128.5, 127.1, 124.8, 123.5,
117.3, 113.2, 93.1, 21.5, 18.2; HRMS (ESI) m/z [M + H]+ calcd for
Yanling Zhan − School of Chemistry and Materials Science,
Jiangsu Provincial Key Laboratory of Material Cycle
Processes and Pollution Control, Jiangsu Collaborative
Innovation Center of Biomedical Functional Materials,
Nanjing Normal University, Nanjing 210023, China
Changhui Dai − School of Chemistry and Materials Science,
Jiangsu Provincial Key Laboratory of Material Cycle
Processes and Pollution Control, Jiangsu Collaborative
Innovation Center of Biomedical Functional Materials,
Nanjing Normal University, Nanjing 210023, China
Jun Lin − School of Chemistry and Materials Science, Jiangsu
Provincial Key Laboratory of Material Cycle Processes and
Pollution Control, Jiangsu Collaborative Innovation Center of
Biomedical Functional Materials and Changzhou Innovation
and Development Institute, Nanjing Normal University,
Nanjing 210023, China
+
C16H14N3 248.1182, found 248.1184.
2-Phenylbenzo[d]imidazo[2,1-b]thiazole-3-carbonitrile (3n).
This compound was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8:1, v/v): white solid (41.3 mg, 75%
yield); mp 176−178 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.15−8.10 (m, 3H), 7.75 (d, J = 8.0 Hz, 1H), 7.54−7.41 (m, 5H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 156.0, 151.4, 131.9,
131.2, 130.0, 129.9, 129.0, 127.1, 126.6, 126.1, 124.5, 113.4, 113.2,
94.5; HRMS (ESI) m/z [M + H]+ calcd for C16H10N3S+ 276.0590,
found 276.0590.
6-Phenylimidazo[2,1-b]thiazole-5-carbonitrile (3o). This com-
pound was purified by silica gel column chromatography (petroleum
ether/ethyl acetate = 8:1, v/v): white solid (30.6 mg, 68% yield); mp
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c03026
1
142−144 °C; H NMR (400 MHz, CDCl3) δ (ppm) 8.10−8.08 (m,
2H), 7.66 (d, J = 4.4 Hz, 1H), 7.53−7.44 (m, 3H), 7.10 (d, J = 4.5
Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 155.8, 153.0,
131.4, 129.8, 129.0, 126.7, 118.5, 115.2, 112.7, 94.5; HRMS (ESI) m/
z [M + H]+ calcd for C12H8N3S+ 226.0433, found 226.0434.
Notes
The authors declare no competing financial interest.
2-Phenyl-1,2-dihydroimidazo[1,2-a]quinoline-1-carbonitrile
(3p). This compound was purified by silica gel column chromatog-
raphy (petroleum ether/ethyl acetate = 8:1, v/v): white solid (35.0
mg, 65% yield); mp 156−158 °C; H NMR (400 MHz, CDCl3) δ
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21672104 and 21502097) and the
Priority Academic Program Development of Jiangsu Higher
Education Institutions.
1
(ppm) 8.93 (d, J = 8.6 Hz, 1H), 8.20 (d, J = 7.1 Hz, 2H), 7.81 (d, J =
7.9 Hz, 1H), 7.68 (t, J = 7.3 Hz, 2H), 7.60 (d, J = 9.4 Hz, 1H), 7.55−
7.46 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 154.6,
145.7, 133.5, 131.2, 130.7, 130.0, 129.9, 129.6, 129.0, 127.4, 126.1,
124.0, 116.6, 115.8, 115.4, 94.3; HRMS (ESI) m/z [M + H]+ calcd
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c03026.
1
Control experiments and copies of H NMR, 13C{1H}
NMR, and HRMS spectra for products 3 (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Ping Liu − School of Chemistry and Materials Science, Jiangsu
Provincial Key Laboratory of Material Cycle Processes and
Pollution Control, Jiangsu Collaborative Innovation Center of
Biomedical Functional Materials and Changzhou Innovation
and Development Institute, Nanjing Normal University,
Nanjing 210023, China; Email: pingliu@njnu.edu.cn
Peipei Sun − School of Chemistry and Materials Science,
Jiangsu Provincial Key Laboratory of Material Cycle
Processes and Pollution Control, Jiangsu Collaborative
Innovation Center of Biomedical Functional Materials,
Nanjing Normal University, Nanjing 210023, China;
H
https://dx.doi.org/10.1021/acs.joc.0c03026
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pubs.acs.org/joc
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